Use of pyrazolopyrimidine derivatives for treatment of PI3kδ-related disorders

Abstract

To provide methods of treating inflammatory diseases, autoimmune diseases and cancers using new PI3K inhibitors.SOLUTION: Treatment methods include administering a compound of a formula (I) to a patient. (R2 is C1-6 alkyl, or C1-6 haloalkyl; R4 and R5 are halo, OH, CN, C1-6 alkyl, C1-6 haloalkyl, or the like; Cy is substituted / unsubstituted C3-7 cycloalkyl, 4-7 membered heteroalkyl, or the like.)SELECTED DRAWING: None

Description

[Technical Field]

[0001] This application claims the benefit of priority to U.S. Provisional Patent Application No. 61 / 771,480, filed March 1, 2013, the entire contents of which are incorporated herein by reference.

[0002] The present application provides methods for treating PI3Kδ-associated disorders using pyrazolopyrimidine derivatives. [Background technology]

[0003] Phosphoinositide 3-kinase (PI3K) belongs to a large family of lipid signaling kinases that phosphorylate phosphoinositides at the D3 position of the inositol ring (Non-Patent Document 1). PI3Ks are divided into three classes (classes I, II, and III) according to their structure, regulation, and substrate specificity. Class I PI3Ks, including PI3Kα, PI3Kβ, PI3Kγ, and PI3Kδ, are a family of dual-specificity lipid and protein kinases that catalyze the phosphorylation of phosphatidylinositol-4,5-diphosphate (PIP2) to generate phosphatidylinositol-3,4,5-triphosphate (PIP3). PIP3 functions as a second messenger that controls multiple cellular processes, including growth, survival, adhesion, and migration. All four class I PI3K isoforms exist as heterodimers consisting of a catalytic subunit (p110) and tightly coupled regulatory subunits that control its expression, activation, and subcellular localization. PI3Kα, PI3Kβ, and PI3Kδ bind to a regulatory subunit known as p85 and are activated by growth factors and cytokines through a tyrosine kinase-dependent mechanism (Non-Patent Document 2), whereas PI3Kγ binds to two regulatory subunits (p101 and p84) and its activation is triggered by activation of a G protein-coupled receptor (Non-Patent Document 3). PI3Kα and PI3Kβ are widely expressed. In contrast, PI3Kγ and PI3Kδ are primarily expressed in leukocytes (Non-Patent Document 4).

[0004] The specific tissue distribution of PI3K isoforms contributes to their distinct biological functions. Genetic ablation of either PI3Kα or PI3Kβ results in embryonic lethality, indicating that PI3Kα and PI3Kβ have essential, non-redundant functions, at least during development (Non-Patent Document 4). In contrast, mice lacking PI3Kγ and PI3Kδ are viable, fertile, and exhibit altered immune systems but have a normal lifespan. Deficiency of PI3Kγ results in impaired T cell activation as well as impaired recruitment of macrophages and neutrophils to inflammatory sites (Non-Patent Document 5). PI3Kδ mutant mice have specific defects in B cell signaling, resulting in impaired B cell development and reduced antibody responses after antigen stimulation (Non-Patent Document 6; Non-Patent Document 7; Non-Patent Document 8).

[0005] The phenotypes of PI3Kγ and PI3Kδ mutant mice suggest that these enzymes may play a role in inflammation and other immune system diseases, and this is supported by preclinical models. PI3Kγ mutant mice are largely protected from disease in mouse models of rheumatoid arthritis (RA) and asthma (Non-Patent Document 9; Non-Patent Document 10). In addition, treatment of wild-type mice with a selective inhibitor of PI3Kγ reduced glomerulonephritis and extended survival in the MRL-lpr model of systemic lupus nephritis (SLE), and suppressed arthritis and damage in RA models (Non-Patent Document 11; Non-Patent Document 9). Similarly, treatment of both PI3Kδ mutant and wild-type mice with a selective inhibitor of PI3Kδ has been shown to attenuate allergic airway inflammation and hyperresponsiveness in a mouse model of asthma (Non-Patent Document 12; Non-Patent Document 13) and attenuate disease in an RA model (Non-Patent Document 14).

[0006] B cell proliferation has been shown to play a major role in the progression of inflammatory autoimmune diseases (Non-Patent Document 15; Non-Patent Document 16). For example, B cells support T cell autoreactivity, a key component of inflammatory autoimmune diseases. Once activated and mature, B cells can access the inflammatory site and recruit inflammatory cells or differentiate into plasmablasts. Therefore, B cell activity can be influenced by B cell stimulatory cytokines, targeting B cell surface receptors, or B cell depletion. Rituximab (an IgG1κ mouse / human chimeric monoclonal antibody against the B cell surface receptor CD20) has been shown to deplete CD20+ B cells. The use of rituximab has been shown to be effective in treating idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, and vasculitis. For example, treatment with rituximab resulted in disease remission in patients with antineutrophil cytoplasmic antibody-associated (ANCA) systemic vasculitis (AASV) with documented peripheral B cell depletion (NPL 16; NPL 17). Similarly, complete remission was reported in one-third to two-thirds of patients with mixed cryoglobulinemia vasculitis after treatment with rituximab, including patients with severe forms of vasculitis that were resistant to or intolerant of other treatments (NPL 18). Similarly, rituximab has been shown to be effective in treating patients with idiopathic thrombocytopenic purpura (or immune thrombocytopenic purpura) (NPL 19; NPL 20; NPL 21) and autoimmune hemolytic anemia (NPL 22).

[0007] PI3Kδ signaling has been shown to be involved in B cell survival, migration, and activation (Non-Patent Document 23; and Non-Patent Document 24). For example, PI3Kδ is required for antigen-dependent B cell activation triggered by the B cell receptor. By blocking B cell adhesion, survival, activation, and proliferation, PI3Kδ inhibition can impair the ability of B cells to activate T cells, preventing their activation and reducing the secretion of autoantibodies and proinflammatory cytokines. Therefore, due to their ability to inhibit B cell activation, PI3Kδ inhibitors are expected to treat B cell-mediated diseases that can be treated by similar methods, such as B cell depletion with rituximab. Indeed, PI3Kδ inhibitors have been shown to be useful mouse models of various autoimmune diseases that can also be treated with rituximab, such as arthritis (Non-Patent Document 23). Furthermore, MZ and B-1 cells are almost absent in p110δ gene-deficient mice, suggesting that innate-like B cells associated with autoimmunity are sensitive to PI3Kδ activity (Non-Patent Document 23). PI3Kδ inhibitors can reduce the trafficking and activation of MZ and B-1 cells, which are involved in autoimmune diseases.

[0008] In addition to their potential role in inflammatory diseases, all four PI3K isoforms may play a role in cancer. The gene encoding p110α is frequently mutated in common cancers, including breast, prostate, colon, and endometrial cancers (Non-Patent Document 25; Non-Patent Document 26). 80% of these mutations are represented by one of three amino acid substitutions within the helix or kinase domain of the enzyme, resulting in significant upregulation of kinase activity, leading to oncogenic transformation in cell culture and animal models (Non-Patent Document 27; Non-Patent Document 28). There is evidence that such mutations may contribute to the development and progression of malignant tumors, but they have not been identified in other PI3K isoforms. Consistent overexpression of PI3Kδ has been observed in acute myeloblastic leukemia (Non-Patent Document 29), and inhibitors of PI3Kδ can block the growth of leukemic cells (Non-Patent Document 30). Increased expression of PI3Kγ is seen in chronic myeloid leukemia (Non-Patent Document 31). Altered expression of PI3Kβ, PI3Kγ, and PI3Kδ has also been observed in brain, colon, and bladder cancers (Non-Patent Document 32; Non-Patent Document 33; Non-Patent Document 34). Furthermore, all of these isoforms have been shown to be oncogenic in cell culture (Non-Patent Document 35). [Prior art documents] [Non-patent literature]

[0009] [Non-Patent Document 1] Cantley,Science,2002,296(5573):1655~7 [Non-patent document 2] Jimenez,et al.,J Biol Chem.,2002,277(44):41556~62 [Non-patent document 3] Brock, et al., J Cell Biol., 2003, 160(1):89~99 [Non-patent document 4] Vanhaesebroeck, et al.,Trends Biochem Sci.,2005,30(4):194~204 [Non-Patent Document 5] Sasaki,et al.,Science,2000,287(5455):1040~6

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[0010] Thus, there is a need for the development of novel PI3K inhibitors that can be used for inflammatory diseases, autoimmune diseases, and cancer. The present invention addresses this need and others. [Means for solving the problem]

[0011] overview The present invention relates to a compound of formula I: [ka] (In the formula, R 2 , R 3 , R 4 , R 5 , and Cy are defined below) or a pharmaceutically acceptable salt thereof, for the treatment of idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, vasculitis, systemic lupus erythematosus, lupus nephritis, pemphigus, membranous nephropathy, chronic lymphocytic leukemia (CLL), non-Hodgkin's lymphoma, hairy cell leukemia, mantle cell lymphoma, small lymphocytic lymphoma, follicular lymphoma, lymphoplasmacytic lymphoma, extranodal marginal zone lymphoma, Hodgkin's lymphoma, Waldenstrom's macroglobulinemia, prolymphocytic leukemia, acute lymphoblastic leukemia, or acute lymphoblastic leukemia, comprising administering to said patient a therapeutically effective amount of a compound of the formula (I) or a pharmaceutically acceptable salt thereof. The present invention provides methods for treating lymphoblastic leukemia, myelofibrosis, mucosa-associated lymphoid tissue (MALT) lymphoma, mediastinal (thymic) large B-cell lymphoma, lymphomatoid granulomatosis, splenic marginal zone lymphoma, primary effusion lymphoma, intravascular large B-cell lymphoma, plasma cell leukemia, extramedullary plasmacytoma, smoldering myeloma (also known as asymptomatic myeloma), monoclonal gammopathy of undetermined significance (MGUS), activated B-cell-like (ABC) diffuse large B-cell lymphoma, or germinal center B-cell (GCB) diffuse large B-cell lymphoma.

[0012] The present invention also provides a compound described herein, or a pharmaceutically acceptable salt thereof, for use in any of the methods described herein.

[0013] The invention further provides the use of a compound described herein, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for use in any of the methods described herein. [Brief explanation of the drawings]

[0014] [Figure 1] The crystal structure of the compound of Example 269 is shown. [Figure 2] Figure 1 shows the tumor inhibitory effect of twice-daily doses of Example 347 at 0.3, 1, 3, or 10 mg / kg for 14 days in the Pfeiffer human tumor xenograft model of diffuse large B-cell lymphoma (y-axis is tumor volume (mm3 ± SEM); x-axis is days post-implantation). DETAILED DESCRIPTION OF THE INVENTION

[0015] The present invention relates to a compound of formula I: [ka] (In the formula, R 2 is C 1~6 Alkyl or C 1~6 is haloalkyl; R 4 Halo, OH, CN, C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy, or C 1~4 haloalkoxy; R 5 Halo, OH, CN, C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy, or C 1~4 haloalkoxy; Cy may each be one, two, three, or four independently selected R 3 optionally substituted by a C group; 3~7 selected from cycloalkyl, 4- to 7-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl; Each R 3 is independently, Cy 1 , -(C 1~3 (Alkylene)-Cy 1 , Halo, CN, NO2, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Haloalkyl, OR a1 , S.R. a1 , C(=O)R b1 , C(=O)NR c1 R d1 , C(=O)OR a1 , OC(=O)R b1 , OC(=O)NR c1 R d1 , N.R. c1 R d1 , N.R. c1 C(=O)R b1 , N.R.c1 C(=O)OR b1 , N.R. c1 C(=O)NR c1 R d1 , C(=NR e )R b1 , C(=NR e )NR c1 R d1 , N.R. c1 C(=NR e )NR c1 R d1 , N.R. c1 S(=O)R b1 , N.R. c1 S(=O)NR c1 R d1 , S(=O)R b1 , S(=O)2R b1 , and S(=O)NR c1 R d1 Selected from the above; 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl is selected from 1, 2, 3, or 4 independently selected R 11 optionally substituted with a group; Each Cy 1 each of which is selected from 1, 2, 3, or 4 independently selected R 11 optionally substituted by a C group; 3~7 independently selected from cycloalkyl, 4- to 7-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl; Each R a1 , R c1 , and R d1 are independently H, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~7 cycloalkyl, 4- to 7-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl; 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~7Cycloalkyl, 4- to 7-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl each have one, two, or three independently selected R 11 optionally substituted with a group; Each R b1 independently, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~7 cycloalkyl, 4- to 7-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl; 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~7 Cycloalkyl, 4- to 7-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl each have one, two, or three independently selected R 11 optionally substituted with a group; or R c1 and R d1 together with the N atom to which they are attached, form -OH or C 1~3 forming a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted by alkyl; Each R e are independently H, CN, OH, and C 1~4 Alkyl, and C 1~4 alkoxy; and Each R 11 are independently OH, NO2, CN, halo, C 1~3 Alkyl, C 2~3 Alkenyl, C 2~3 Alkynyl, C 1~3 Haloalkyl, Cyano-C 1~3 Alkyl, HO-C 1~3 Alkyl, C 1~3 Alkoxy-C 1~3 Alkyl, C 3~7 Cycloalkyl, C 1~3 Alkoxy, C 1~3 Haloalkoxy, Amino, C 1~3 Alkylamino, di(C 1~3 Alkyl)amino, thio, C1~3 Alkylthio, C 1~3 Alkylsulfinyl, C 1~3 Alkyl sulfonyl, carbamyl, C 1~3 Alkylcarbamyl, di(C 1~3 Alkyl) carbamyl, carboxy, C 1~3 Alkyl carbonyl, C 1~4 Alkoxycarbonyl, C 1~3 Alkylcarbonylamino, C 1~3 Alkyl sulfonyl amino, amino sulfonyl, C 1~3 Alkylaminosulfonyl, di(C 1~3 Alkyl)aminosulfonyl, aminosulfonylamino, C 1~3 Alkylaminosulfonylamino, di(C 1~3 Alkyl)aminosulfonylamino, aminocarbonylamino, C 1~3 Alkylaminocarbonylamino, and di(C 1~3 alkyl)aminocarbonylamino) or a pharmaceutically acceptable salt thereof, for the treatment of idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, vasculitis, systemic lupus erythematosus, lupus nephritis, pemphigus, membranous nephropathy, chronic lymphocytic leukemia (CLL), non-Hodgkin's lymphoma, hairy cell leukemia, mantle cell lymphoma, small lymphocytic lymphoma, follicular lymphoma, lymphoplasmacytic lymphoma, extranodal marginal zone lymphoma, Hodgkin's lymphoma, Waldenstrom's macroglobulinemia, prolymphocytic leukemia, acute lymphoblastic leukemia, bone marrow leukemia, myeloma, ... Methods for treating fibrosis, mucosa-associated lymphoid tissue (MALT) lymphoma, mediastinal (thymic) large B-cell lymphoma, lymphomatoid granulomatosis, splenic marginal zone lymphoma, primary effusion lymphoma, intravascular large B-cell lymphoma, plasma cell leukemia, extramedullary plasmacytoma, smoldering myeloma (also known as asymptomatic myeloma), monoclonal gammopathy of undetermined significance (MGUS), activated B-cell-like (ABC) diffuse large B-cell lymphoma (ABC-DLBCL), or germinal center B-cell (GCB) diffuse large B-cell lymphoma (GCB-DLBCL) are provided.

[0016] In some embodiments, R 2 is C 1~3 Alkyl or C 1~3 In some embodiments, R 2 is methyl, ethyl, or 2,2-difluoromethyl. In some embodiments, R 2 is methyl. In some embodiments, R 2 is ethyl.

[0017] In some embodiments, R 4 is halo, CN, or C 1~3 In some embodiments, R 4 is F, Cl, CN, or methyl. In some embodiments, R 4 is F. In some embodiments, R 4 is Cl. In some embodiments, R 4 is CN. In some embodiments, R 4 is methyl.

[0018] In some embodiments, R 5 is halo, CN, or C 1~3 In some embodiments, R 5 is Cl, CN, or methyl. In some embodiments, R 5 is Cl. In some embodiments, R 5 is CN. In some embodiments, R 5 is methyl.

[0019] In some embodiments, Cy is C 3~6 cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl, each of which is selected from 1, 2, 3, or 4 independently selected R 3 In some embodiments, Cy is a 4-6 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, or 4 independently selected R 3In some embodiments, Cy is selected from a cyclopropyl ring, a phenyl ring, an azetidine ring, a pyrrolidine ring, a piperidine ring, a 3-oxo-morpholin-6-yl, a 2-oxo-pyrrolidin-4-yl, a 2-oxo-oxazolidin-4-yl, a 2-oxo-oxazolidin-5-yl, a pyrazole ring, a pyridine ring, and a pyrimidine ring, each of which is optionally substituted with one, two, three, or four independently selected R 3 It may be substituted by a group.

[0020] In some embodiments: Each R 3 is independently, Cy 1 , -(C 1~3 (Alkylene)-Cy 1 ,Haro,CN,C 1~6 Alkyl, OR a1 , N.R. c1 R d1 , C(=O)R b1 , C(=O)OR a1 , C(=O)NR c1 R d1 , and S(=O)R b1 C is selected from 1-6 Alkyl is one, two, three, or four independently selected R 11 optionally substituted with a group; Each Cy 1 independently, 1, 2, 3, or 4 independently selected R 11 optionally substituted by a C group; 3~7 is cycloalkyl; Each R a1 , R c1 , and R d1 are independently H and C 1~6 alkyl; 1~6 Alkyl is one, two, or three independently selected R 11 optionally substituted with a group; Each R b1 independently, one, two, or three independently selected R 11 C optionally substituted with a group 1~6 is alkyl; and Each R 11 are independently OH, CN, halo, cyano-C 1~3 Alkyl, C 1~3 Haloalkoxy, Amino, C 1~3 Alkylamino, di(C 1~3 Alkyl)amino, C 1~3 Alkyl carbonyl, C 1~3 Alkoxycarbonyl, carbamyl, C 1~3 Alkylcarbamyl, or di(C 1~3 alkyl)carbamyl.

[0021] In some embodiments: R 2 is C 1~3 Alkyl or C 1~3 is a fluoroalkyl; R 4 is halo, CN, or C 1~3 is alkyl; R 5 is halo, CN, or C 1~3 is alkyl; Cy may each be one, two, three, or four independently selected R 3 optionally substituted by a C group; 3~6 selected from cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl; Each R 3 is independently, Cy 1 , -(C 1~3 (Alkylene)-Cy 1 ,Haro,CN,C 1~6 Alkyl, OR a1 , N.R. c1 R d1 , C(=O)R b1 , C(=O)OR a1 , C(=O)NR c1 R d1 , and S(=O)R b1 C is selected from 1-6 Alkyl is one, two, three, or four independently selected R 11 optionally substituted with a group; Each Cy 1independently, 1, 2, 3, or 4 independently selected R 11 C optionally substituted by a group 3~7 is cycloalkyl; Each R a1 , R c1 , and R d1 are independently H and C 1~6 alkyl, 1~6 Alkyl is one, two, or three independently selected R 11 may be substituted with a group; Each R b1 independently, one, two, or three independently selected R 11 C optionally substituted with a group 1~6 is alkyl; and Each R 11 are independently OH, CN, halo, cyano-C 1~3 Alkyl, C 1~3 Haloalkoxy, Amino, C 1~3 Alkylamino, di(C 1~3 Alkyl)amino, C 1~3 Alkyl carbonyl, C 1~3 Alkoxycarbonyl, carbamyl, C 1~3 Alkylcarbamyl, or di(C 1~3 alkyl)carbamyl.

[0022] In some embodiments: R 2 is methyl, ethyl, or 2,2-difluoromethyl; R 4 is F, Cl, CN, or methyl; R 5 is Cl, CN, or methyl; Cy may each be one, two, three, or four independently selected R 3 optionally substituted by a C group; 3~6 selected from cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl; Each R 3 is independently, Cy 1 , -(C1~3 (Alkylene)-Cy 1 ,Haro,CN,C 1~6 Alkyl, OR a1 , N.R. c1 R d1 , C(=O)R b1 , C(=O)OR a1 , C(=O)NR c1 R d1 , and S(=O)R b1 C is selected from 1~6 Alkyl is one, two, three, or four independently selected R 11 optionally substituted with a group; Each Cy 1 independently, 1, 2, 3, or 4 independently selected R 11 C optionally substituted by a group 3~7 is cycloalkyl; Each R a1 , R c1 , and R d1 are independently H and C 1~6 alkyl, 1~6 Alkyl is one, two, or three independently selected R 11 optionally substituted with a group; Each R b1 independently, one, two, or three independently selected R 11 C optionally substituted with a group 1~6 is alkyl; and Each R 11 are independently OH, CN, halo, cyano-C 1~3 Alkyl, C 1~3 Haloalkoxy, Amino, C 1~3 Alkylamino, di(C 1~3 Alkyl)amino, C 1~3 Alkyl carbonyl, C 1~3 Alkoxycarbonyl, carbamyl, C 1~3 Alkylcarbamyl, or di(C 1~3 alkyl)carbamyl.

[0023] In some embodiments, R 2is methyl, ethyl, or 2,2-difluoromethyl; R 4 is F, Cl, CN, or methyl; R 5 is Cl, CN, or methyl; Cy is selected from a cyclopropyl ring, a phenyl ring, an azetidine ring, a pyrrolidine ring, a piperidine ring, a 3-oxo-morpholin-6-yl, a 2-oxo-pyrrolidin-4-yl, a 2-oxo-oxazolidin-4-yl, a 2-oxo-oxazolidin-5-yl, a pyrazole ring, a pyridine ring, and a pyrimidine ring, each of which is selected from one, two, three, or four independently selected R 3 optionally substituted with a group; Each R 3 is independently, Cy 1 , -(C 1~3 (Alkylene)-Cy 1 , Haro, C 1~6 Alkyl, OR a1 , N.R. c1 R d1 , C(=O)R b1 , C(=O)OR a1 , C(=O)NR c1 R d1 , and S(=O)R b1 C is selected from 1~6 Alkyl is one, two, three, or four independently selected R 11 optionally substituted with a group; Each Cy 1 are independently selected from cyclopropyl and cyclobutyl, each of which is selected from 1, 2, 3, or 4 independently selected R 11 optionally substituted with a group; Each R a1 , R c1 , and R d1 are independently H and C 1~4 alkyl; 1~4 Alkyl is one, two, or three independently selected R 11 optionally substituted with a group; Each R b1independently, one, two, or three independently selected R 11 C optionally substituted with a group 1~4 is alkyl; Each R 11 are independently OH, CN, halo, cyano-C 1~3 Alkyl, C 1~3 Alkoxy-C 1~3 Alkyl, C 1~3 Alkoxy, C 1~3 Haloalkoxy, Amino, C 1~3 Alkylamino, di(C 1~3 Alkyl)amino, C 1~3 Alkyl carbonyl, C 1~4 Alkoxycarbonyl, carbamyl, C 1~3 Alkylcarbamyl, or di(C 1~3 alkyl)carbamyl.

[0024] In some embodiments, the compound has Formula II: [ka] or a pharmaceutically acceptable salt thereof.

[0025] In some embodiments, the compound has Formula III: [ka] or a pharmaceutically acceptable salt thereof.

[0026] In some embodiments, the compound has Formula IV: [ka] (In the formula: G is NH, n is 1, and V is O; or G is NH, n is 0, and V is O or CH; or G is O, n is 0, and V is NH or a pharmaceutically acceptable salt thereof.

[0027] In some embodiments, the compound has Formula IVa: [ka] or a pharmaceutically acceptable salt thereof.

[0028] In some embodiments, the compound has Formula IVb: [ka] or a pharmaceutically acceptable salt thereof.

[0029] In some embodiments, the compound has Formula IVc: [ka] or a pharmaceutically acceptable salt thereof.

[0030] In some embodiments, the compound has formula IVd: [ka] or a pharmaceutically acceptable salt thereof.

[0031] In some embodiments, Formula I: [ka] The carbon marked with an asterisk in the formula is an asymmetric carbon, and the compound or salt is an (S)-enantiomer.

[0032] In some embodiments, the compound is described in U.S. Patent Application No. 13 / 601,349, filed August 31, 2012 (U.S. Patent Application Publication No. 2013 / 0059835), which is incorporated herein by reference in its entirety.

[0033] In some embodiments, the method is a method for treating idiopathic thrombocytopenic purpura (or idiopathic autoimmune thrombocytopenic purpura) (ITP). In some embodiments, the ITP is recurrent ITP. In some embodiments, the ITP is refractory ITP.

[0034] In some embodiments, the method is a method for treating autoimmune hemolytic anemia (AIHA).

[0035] In some embodiments, the method is a method for treating vasculitis. In some embodiments, the vasculitis is Behçet's disease, Cogan's syndrome, giant cell arteritis, polymyalgia rheumatica (PMR), Takayasu's arteritis, Buerger's disease (thromboangiitis obliterans), central nervous system vasculitis, Kawasaki disease, polyarteritis nodosa, Churg-Strauss syndrome, mixed cryoglobulinemic vasculitis (essential or hepatitis C virus (HCV)-induced), Henoch-Schönlein purpura (HSP), hypersensitivity vasculitis, microscopic polyangiitis, Wegener's granulomatosis, or antineutrophil cytoplasmic antibody-associated (ANCA) systemic vasculitis (AASV). In some embodiments, the method is a method for treating nephritis.

[0036] In some embodiments, the method of treating non-Hodgkin's lymphoma (NHL) is relapsed or refractory NHL or recurrent follicular NHL.

[0037] In some embodiments, the present application provides a method for treating aggressive lymphoma (e.g., germinal center B-cell-like (GCB) or activated B-cell-like (ABC)) in a patient, comprising administering to the patient a therapeutic amount of any of the compounds described herein or a pharmaceutically acceptable salt thereof.

[0038] In some embodiments, the present application provides a method for treating acute myeloid leukemia in a patient, comprising administering to the patient a therapeutic amount of any of the compounds described herein or pharmaceutically acceptable salts thereof.

[0039] In some embodiments, the present application provides a method for treating Burkitt's lymphoma in a patient, comprising administering to the patient a therapeutic amount of any of the compounds described herein, or a pharmaceutically acceptable salt thereof. It will be recognized that certain features of the invention that are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention that are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination.

[0040] At various times throughout this specification, divalently linked substituents are described. Each divalently linked substituent is specifically intended to include both the forward and backward forms of the linked substituent. For example, -NR(CR'R'') n -NR(CR'R'') n -and-(CR'R'') n It is understood that when the structure clearly requires a linking group, the Markush variable recited for that group is the linking group.

[0041] The term "n-membered," where n is an integer, generally refers to the number of ring atoms in the moiety where n is the number of ring atoms. For example, piperidinyl is an example of a 6-membered heterocycloalkyl ring, pyrazolyl is an example of a 5-membered heteroaryl ring, pyridyl is an example of a 6-membered heteroaryl ring, and 1,2,3,4-tetrahydro-naphthalene is an example of a 10-membered cycloalkyl group.

[0042] As used herein, the phrase "optionally substituted" means unsubstituted or substituted. As used herein, the term "substituted" means that a hydrogen atom has been removed and replaced with a substituent. It should be understood that substitution at a given atom is limited by the valence of the atom.

[0043] Throughout the definition, "C n~m " denotes a range inclusive of endpoints indicating the number of carbon atoms, where n and m are integers. Examples include C 1~4 , C 1~6 Examples include:

[0044] As used herein, "C" when used alone or in combination with other words n~m The term "alkyl" refers to a saturated hydrocarbon group that may be straight or branched, having n to m carbon atoms. In some embodiments, the alkyl group contains 1 to 6 carbon atoms, 1 to 4 carbon atoms, 1 to 3 carbon atoms, or 1 to 2 carbon atoms. Examples of alkyl moieties include, but are not limited to, chemical groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl; and higher homologs such as 2-methyl-1-butyl, n-pentyl, 3-pentyl, n-hexyl, 1,2,2-trimethylpropyl, and the like.

[0045] As used herein, "C n~m The term "alkenyl" refers to an alkyl group having one or more carbon-carbon double bonds and having n to m carbons. In some embodiments, the alkenyl moiety contains 2 to 6, 2 to 4, or 2 to 3 carbon atoms. Exemplary alkenyl groups include, but are not limited to, ethenyl, n-propenyl, isopropenyl, n-butenyl, sec-butenyl, and the like.

[0046] As used herein, "C n~mThe term "alkynyl" refers to an alkyl group having one or more carbon-carbon triple bonds and having n to m carbons. Exemplary alkynyl groups include, but are not limited to, ethynyl, propyn-1-yl, propyn-2-yl, and the like. In some embodiments, the alkynyl moiety contains 2 to 6, 2 to 4, or 2 to 3 carbon atoms.

[0047] As used herein, the term "alkylene," employed alone or in combination with other terms, refers to a divalent alkyl linking group. Examples of alkylene groups include, but are not limited to, ethane-1,2-diyl, propane-1,3-diyl, propane-1,2-diyl, butane-1,4-diyl, butane-1,3-diyl, butane-1,2-diyl, 2-methyl-propane-1,3-diyl, and the like.

[0048] As used herein, "C" when used alone or in combination with other words n~m The term "alkoxy" refers to a group of the formula -O-alkyl, where the alkyl group has n to m carbons. Exemplary alkoxy groups include methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), t-butoxy, and the like. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0049] As used herein, "C n~m The term "alkylamino" refers to a group of formula -NH(alkyl), where the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0050] As used herein, "C n~m The term "alkoxycarbonyl" refers to a group of formula -C(O)O-alkyl, where the alkyl group has n to m carbons. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0051] As used herein, "C n~m The term "alkylcarbonyl" refers to a group of formula -C(O)-alkyl, where the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0052] As used herein, "C n~m The term "alkylcarbonylamino" refers to a group of formula -NHC(O)-alkyl, where the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0053] As used herein, "C n~m The term "alkylsulfonylamino" refers to a group of formula -NHS(O)2-alkyl, where the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0054] As used herein, the term "aminosulfonyl" refers to a group of formula -S(O)2NH2.

[0055] As used herein, "C n~m The term "alkylaminosulfonyl" refers to a group of formula -S(O)NH(alkyl), where the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0056] As used herein, "di(C n~m The term "(alkyl)aminosulfonyl" refers to a group of formula -S(O)N(alkyl), where each alkyl group independently has n to m carbon atoms. In some embodiments, each alkyl group independently has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0057] As used herein, the term "aminosulfonylamino" refers to a group of formula -NHS(O)2NH2.

[0058] As used herein, "C n~m The term "alkylaminosulfonylamino" refers to a group of formula -NHS(O)NH(alkyl), where the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0059] As used herein, "di(C n~m The term "NHS(O)N(alkyl)aminosulfonylamino" refers to a group of formula -NHS(O)N(alkyl), where each alkyl group independently has n to m carbon atoms. In some embodiments, each alkyl group independently has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0060] As used herein, the term "aminocarbonylamino," employed alone or in combination with other terms, refers to a group of formula -NHC(O)NH2.

[0061] As used herein, "C n~m The term "alkylaminocarbonylamino" refers to a group of formula -NHC(O)NH(alkyl), where the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0062] As used herein, "di(C n~m The term "NHC(O)N(alkyl)aminocarbonylamino" refers to a group of formula -NHC(O)N(alkyl)2, where each alkyl group independently has n to m carbon atoms. In some embodiments, each alkyl group independently has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0063] As used herein, "C n~mThe term "alkylcarbamyl" refers to a group of formula -C(O)NH(alkyl), where the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0064] As used herein, the term "thio" refers to a group of formula -SH.

[0065] As used herein, "C n~m The term "alkylthio" refers to a group of formula -S-alkyl, where the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0066] As used herein, "C n~m The term "alkylsulfinyl" refers to a group of formula -S(O)-alkyl, where the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0067] As used herein, "C n~m The term "alkylsulfonyl" refers to a group of formula -S(O)-alkyl, where the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0068] As used herein, the term "amino" refers to a group of formula -NH2.

[0069] As used herein, the term "carbamyl" refers to a group of formula -C(O)NH2.

[0070] As used herein, the term "carbonyl," employed alone or in combination with other terms, refers to a group of formula --C(O)--.

[0071] As used herein, "cyano-C 1~3The term "alkyl" refers to a group of the formula -(C 1~3 represents the group (alkylene)-CN.

[0072] As used herein, "HO-C 1~3 The term "alkyl" refers to a group of the formula -(C 1~3 represents the group alkylene)-OH.

[0073] As used herein, "C 1~3 Alkoxy-C 1~3 The term "alkyl" refers to a group of the formula -(C 1~3 alkylene)-O(C 1~3 represents a group of (alkyl).

[0074] As used herein, the term "carboxy" refers to a group of formula -C(O)OH.

[0075] As used herein, "di(C n~m The term "N(alkyl)amino" refers to a group of formula -N(alkyl)2, where the two alkyl groups each independently have n to m carbon atoms. In some embodiments, each alkyl group independently has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0076] As used herein, "di(C n~m The term "(alkyl)carbamyl" refers to a group of formula -C(O)N(alkyl)2, where two alkyl groups each independently have n to m carbon atoms. In some embodiments, each alkyl group independently has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0077] As used herein, the term "halo" refers to F, Cl, Br, or I. In some embodiments, the halo group is F or Cl.

[0078] As used herein, "C n~mThe term "haloalkoxy" refers to a group of the formula -O-haloalkyl having n to m carbon atoms. An exemplary haloalkoxy group is OCF. In some embodiments, the haloalkoxy group is exclusively fluorinated. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0079] As used herein, "C" when used alone or in combination with other words n~m The term "haloalkyl" refers to an alkyl group having from one halogen atom to 2s+1 halogen atoms, which may be the same or different, where "s" is the number of carbon atoms in the alkyl group, which has n to m carbon atoms. In some embodiments, the haloalkyl group is exclusively fluorinated (e.g., a "fluoroalkyl" group). In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0080] As used herein, "cycloalkyl" refers to a non-aromatic cyclic hydrocarbon containing cyclized alkyl and / or alkenyl groups. Cycloalkyl groups can have 3, 4, 5, 6, or 7 ring-forming carbons (C 3~7 ) The ring-forming carbon atoms of a cycloalkyl group may be substituted with oxo or sulfido. Cycloalkyl groups also include cycloalkylidenes. Exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, and the like. In some embodiments, cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. The definition of cycloalkyl also includes moieties in which one or more aromatic rings are fused (i.e., share a common bond) to the cycloalkyl ring, e.g., benzo or thienyl derivatives such as cyclopentane, cyclohexane, and the like.

[0081] As used herein, "heteroaryl" refers to a monocyclic aromatic heterocycle having at least one heteroatom ring member selected from sulfur, oxygen, and nitrogen. In some embodiments, the heteroaryl ring has 1, 2, 3, or 4 heteroatom ring members independently selected from nitrogen, sulfur, and oxygen. In some embodiments, any of the ring-forming N atoms of the heteroaryl moiety can be an N-oxide. In some embodiments, the heteroaryl has 5 to 6 ring atoms and 1 or 2 heteroatom ring members independently selected from nitrogen, sulfur, and oxygen. In some embodiments, the heteroaryl is a 5- or 6-membered heteroaryl ring.

[0082] A 5-membered heteroaryl ring is a heteroaryl comprising a ring having 5 ring atoms, wherein one or more (e.g., 1, 2, or 3) ring atoms are independently selected from N, O, and S. Exemplary 5-membered heteroaryl rings are thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl, 1,2,3-triazolyl, tetrazolyl, 1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-triazolyl, 1,2,4-thiadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-triazolyl, 1,3,4-thiadiazolyl, and 1,3,4-oxadiazolyl.

[0083] A 6-membered heteroaryl ring is a heteroaryl containing a ring having 6 ring atoms, wherein one or more (e.g., 1, 2, or 3) ring atoms are independently selected from N, O, and S. Exemplary 6-membered heteroaryl rings are pyridyl, pyrazinyl, pyrimidinyl, triazinyl, and pyridazinyl.

[0084] As used herein, "heterocycloalkyl" refers to a non-aromatic monocyclic heterocycle having one or more ring-forming heteroatoms selected from O, N, or S. Monocyclic 4-, 5-, 6-, and 7-membered heterocycloalkyl groups are included in heterocycloalkyl. Exemplary heterocycloalkyl groups include pyrrolidin-2-one, 1,3-isoxazolidin-2-one, pyranyl, tetrahydropuran, oxetanyl, azetidinyl, morpholino, thiomorpholino, piperazinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, pyrrolidinyl, isoxazolidinyl, isothiazolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, imidazolidinyl, azepanyl, 3-oxo-morpholin-6-yl, 2-oxo-pyrrolidin-4-yl, 2-oxo-oxazolidin-4-yl, 2-oxo-oxazolidin-5-yl, etc. Ring-forming carbon atoms and heteroatoms of a heterocycloalkyl group may be optionally substituted by oxo or sulfido (e.g., C(O), S(O), C(S), or S(O), etc.). The heterocycloalkyl group can be attached to a ring-forming carbon atom or a ring-forming heteroatom. In some embodiments, the heterocycloalkyl group contains 0 to 3 double bonds. In some embodiments, the heterocycloalkyl group contains 0 to 2 double bonds. In some embodiments, the heterocycloalkyl group contains 1 or 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and has 4 to 7 or 4 to 6 ring atoms with one or more oxidized ring members.

[0085] In certain places, definitions or embodiments refer to specific rings (e.g., azetidine ring, pyridine ring, etc.). Unless otherwise specified, these rings can be bonded to any ring member, provided that the valence is not exceeded. For example, an azetidin-3-yl ring is bonded at the 3-position, but the azetidine ring can be bonded at any position on the ring.

[0086] The compounds described herein can be asymmetric (e.g., having one or more stereocenters). Unless otherwise specified, all stereoisomers, including enantiomers and diastereomers, are intended. Compounds of the present invention containing asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Methods for preparing optically active forms from optically inactive starting materials are known in the art, such as by resolution of racemic mixtures or stereoselective synthesis. Many geometric isomers of olefins, C=N double bonds, and the like, can also be contained in the compounds described herein, and all such stable isomers are contemplated within the present invention. Cis and trans geometric isomers of the compounds of the present invention are described and can be isolated as a mixture of isomers or as separate isomers.

[0087] In some embodiments, the compound has the (R) configuration. In some embodiments, the compound has the (S) configuration.

[0088] Resolution of racemic mixtures of compounds can be carried out by any of a number of methods known in the art. An exemplary method includes fractional recrystallization using a chiral resolving acid, which is an optically active, salt-forming organic acid. Suitable resolving agents for fractional recrystallization include, for example, the D- and L-forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, or various optically active camphorsulfonic acids, such as β-camphorsulfonic acid. Other resolving agents suitable for fractional recrystallization include α-methylbenzylamine (e.g., S- and R-forms, or diastereomerically pure forms), 2-phenylglycinol, norephedrine, ephedrine, N-methylephedrine, cyclohexylethylamine, 1,2-diaminocyclohexane, and the like.

[0089] Resolution of racemic mixtures can also be carried out by elution on a column packed with an optically active resolving agent (e.g., dinitrobenzoylphenylglycine). Appropriate elution solvent compositions can be determined by one skilled in the art.

[0090] The compounds described herein also include tautomers. Tautomers result from the interchange of a single bond with an adjacent double bond accompanied by the simultaneous migration of a proton. Tautomers include prototropic tautomers, which are isomeric protonation states with the same empirical formula and total charge. Exemplary prototropic tautomers include ketone-enol pairs, amide-imidic acid pairs, lactam-lactim pairs, enamine-imine pairs, and rings in which protons can occupy more than one position in the 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. Tautomers can be sterically locked into one form by equilibrium or appropriate substitution.

[0091] The compounds described herein also include all isotopes of atoms occurring as intermediates or final compounds.Isotopes include atoms with the same atomic number but different mass numbers.For example, isotopes of hydrogen include tritium and deuterium.

[0092] As used herein, the term "compound" is intended to include all stereoisomers, geometric isomers, tautomers, and isotopes of the depicted structure. Compounds identified herein by name or structure as one particular tautomeric form are intended to include other tautomeric forms unless otherwise specified.

[0093] All compounds, and pharmaceutically acceptable salts thereof, may be found together with other substances, such as water and solvents (eg, hydrates and solvates), or may be isolated.

[0094] In some embodiments, the compounds described herein, or salts thereof, are substantially isolated. "Substantially isolated" means that the compounds are at least partially or substantially separated from the environment in which they were produced or detected. Partial separation can include, for example, a composition enriched in the compounds described herein. Substantial separation can include a composition containing at least about 50% by weight, at least about 60% by weight, at least about 70% by weight, at least about 80% by weight, at least about 90% by weight, at least about 95% by weight, at least about 97% by weight, or at least about 99% by weight of the compounds described herein, or salts thereof. Methods for isolating compounds and their salts are routine in the art.

[0095] The phrase "pharmaceutically acceptable" is used herein to describe compounds, substances, compositions, and / or dosage forms that, according to sound medical judgment, are suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable risk-benefit ratio.

[0096] As used herein, the expressions "ambient temperature" and "room temperature" or "rt" are understood in the art and generally refer to a temperature, e.g., about the temperature of the room in which a reaction is carried out, e.g., a temperature of about 20°C to about 30°C.

[0097] The present invention also includes pharmaceutically acceptable salts of the compounds described herein. As used herein, "pharmaceutically acceptable salts" refers to derivatives of the disclosed compounds, in which the parent compound is modified by converting an existing acidic or basic moiety into its salt form. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. Pharmaceutically acceptable salts of the present invention include conventional non-toxic salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound containing a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent, or a mixture of the two; generally, non-aqueous media such as ether, ethyl acetate, alcohols (e.g., methanol, ethanol, isopropanol, or butanol), or acetonitrile (ACN) are preferred. Lists of suitable salts can be found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418 and Journal of Pharmaceutical Science, 66, 2 (1977), each of which is incorporated herein by reference in its entirety.

[0098] method The compounds described herein can modulate the activity of one or more various kinases, including, for example, phosphoinositide 3-kinase (PI3K). The term "modulation" is intended to refer to the ability to increase or decrease the activity of one or more members of the PI3K family. Accordingly, the compounds described herein can be used in methods of modulating PI3K by contacting the PI3K with any one or more compounds or compositions described herein. In some embodiments, the compounds of the present invention can act as inhibitors of one or more PI3Ks. In further embodiments, the compounds described herein can be used to modulate the activity of PI3K in an individual in need of receptor modulation by administering a modulating amount of a compound described herein, or a pharmaceutically acceptable salt thereof. In some embodiments, the modulation is inhibition.

[0099] If cancer cell growth and survival are affected by multiple signaling pathways, the present invention is useful for treating conditions characterized by drug-resistant kinase mutants. In addition, different kinase inhibitors with different selectivities among the kinases that regulate their activity can be used in combination. This approach should prove highly effective in treating conditions by targeting multiple signaling pathways, reducing the likelihood of intracellular drug resistance and the toxicity of disease treatment.

[0100] The kinases that the compounds bind to and / or modulate (e.g., inhibit) include any member of the PI3K family. In some embodiments, the PI3K is PI3Kα, PI3Kβ, PI3Kγ, or PI3Kδ. In some embodiments, the PI3K is PI3Kγ or PI3Kδ. In some embodiments, the PI3K is PI3Kγ. In some embodiments, the PI3K is PI3Kδ. In some embodiments, the PI3K comprises a mutant. A mutant can be a substitution of one amino acid for another, or a deletion of one or more amino acids. In such embodiments, the mutation can be within the kinase domain of the PI3K.

[0101] In some embodiments, more than one compound described herein is used to inhibit the activity of a single kinase (eg, PI3Kγ or PI3Kδ).

[0102] In some embodiments, more than one compound described herein is used to inhibit more than one kinase, such as at least two kinases (eg, PI3Kγ and PI3Kδ).

[0103] In some embodiments, one or more of the compounds are used in combination with another kinase inhibitor to inhibit the activity of one kinase (eg, PI3Kγ or PI3Kδ).

[0104] In some embodiments, one or more of the compounds are used in combination with another kinase inhibitor to inhibit the activity of more than one kinase (eg, PI3Kγ or PI3Kδ), such as at least two kinases.

[0105] The compounds described herein can be selective. "Selective" means that the compound binds to or inhibits a kinase with greater affinity or potency, respectively, compared to at least one other kinase. In some embodiments, the compounds described herein are selective inhibitors of PI3Kγ or PI3Kδ over PI3Kα and / or PI3Kβ. In some embodiments, the compounds described herein are selective inhibitors of PI3Kδ (e.g., over PI3Kα, PI3Kβ, and PI3Kγ). In some embodiments, the compounds described herein are selective inhibitors of PI3Kγ (e.g., over PI3Kα, PI3Kβ, and PI3Kδ). In some embodiments, the selectivity can be at least about 2-fold, 5-fold, 10-fold, at least about 20-fold, at least about 50-fold, at least about 100-fold, at least about 200-fold, at least about 500-fold, or at least about 1000-fold. Selectivity can be measured by methods routine in the art. In some embodiments, selectivity is measured by the K mATP concentrations can be tested. In some embodiments, the selectivity of the compounds described herein can be determined by cellular assays associated with specific PI3K kinase activity.

[0106] As used herein, the term "contacting" refers to attaching a specified moiety in an in vitro or in vivo system. For example, "contacting" a PI3K with a compound described herein includes administering a compound of the invention, e.g., a compound described herein, to an individual or patient, such as a human, that has PI3K, as well as introducing the compound into a sample containing a cellular or purified preparation that contains the PI3K.

[0107] As used herein, the terms "individual" or "patient," used interchangeably, refer to any animal, including a mammal, preferably a mouse, rat, other rodent, rabbit, dog, cat, pig, cow, sheep, horse, or primate, most preferably a human.

[0108] As used herein, the phrase "therapeutically effective amount" refers to an amount of an active compound or pharmaceutical agent that elicits the biological or medicinal response desired by a researcher, veterinarian, physician, or other clinician in a tissue, system, animal, individual, or human. In some embodiments, the dosage of the compound, or a pharmaceutically acceptable salt thereof, administered to a patient or individual is about 1 mg to about 2 g, about 1 mg to about 1000 mg, about 1 mg to about 500 mg, about 1 mg to about 100 mg, about 1 mg to about 50 mg, or 50 mg to about 500 mg.

[0109] As used herein, the term "treating" or "treatment" refers to one or more of: (1) preventing the disease; e.g., preventing the disease, condition, or disorder in an individual who is susceptible to the disease, condition, or disorder but who has not yet experienced or exhibited the symptoms or symptomology of the disease; (2) inhibiting the disease; e.g., inhibiting the disease, condition, or disorder (i.e., halting further progression of the symptoms and / or symptomology) in an individual who is experiencing or exhibiting the symptoms or symptomology of the disease, condition, or disorder; and (3) ameliorating the disease; e.g., ameliorating the disease, condition, or disorder (i.e., causing the symptoms and / or symptomology to improve), including reducing the severity of the disease, in an individual who is experiencing or exhibiting the symptoms or symptomology of the disease, condition, or disorder.

[0110] Combination therapy One or more additional pharmaceutical agents, such as chemotherapeutic agents, anti-inflammatory agents, steroids, immunosuppressants, as well as other agents, such as Bcr-Abl, Flt-3, EGFR, HER2, JAK (e.g., JAK1 or JAK2), c-MET, VEGFR, PDGFR, cKit, IGF-1R, RAF, FAK, Akt mTOR, PIM, and AKT (e.g., AKT1, AKT2, or AKT3) kinase inhibitors, or therapeutic antibodies, such as those described in WO 2006 / 056399, can be used in combination with the compounds of the invention to treat a PI3K-associated disease, disorder, or condition. The one or more additional pharmaceutical agents can be administered to the patient simultaneously or sequentially.

[0111] Exemplary antibodies for combination therapy use include, but are not limited to, trastuzumab (e.g., anti-HER2), ranibizumab (e.g., anti-VEGF-A), bevacizumab (trade name Avastin, e.g., anti-VEGF), panitumumab (e.g., anti-EGFR), cetuximab (e.g., anti-EGFR), Rituxan (anti-CD20), and antibodies directed against c-MET.

[0112] One or more of the following agents may be used in combination with the compounds of the invention, including, by way of a non-limiting list: cytostatics, cisplatin, doxorubicin, taxotere, taxol, etoposide, irinotecan, camptostar, topotecan, paclitaxel, docetaxel, epothilone, tamoxifen, 5-fluorouracil, methoxtrexate, temozolomide, cyclophosphamide, SCH66336, R115777, L778,123, BMS214662, Iressa, Tarceva, antibodies against EGFR, Gleevec™, Intron, ara-C, adriamycin, cytoxan, gemcitabine, uracil mustard, Chlormethine, ifosfamide, melphalan, chlorambucil, pipobroman, triethylenemelamine, triethylenethiophosphoramine, busulfan, carmustine, lomustine, streptozocin, dacarbazine, floxuridine, cytarabine, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, oxaliplatin, leucovirin, Eloxatin™, pentostatin, vinblastine, vincristine, vindesine, bleomycin, dactinomycin, daunorubicin, doxorubicin, epirubicin, idarubicin, mithramycin, deoxycoformycin, mitomycin C, L-asparaginase, teniposide 17α.Ethinyl estradiol, diethylstilbestrol, testosterone, prednisone, fluoxymesterone, dromostanolone propionate, testolactone, megestrol acetate, methylprednisolone, methyltestosterone, prednisolone, triamcinolone, chlorotrianisene, hydroxyprogesterone, aminoglutethimide, estramustine, medroxyprogesterone acetate, leuprolide, flutamide, toremifene, goserelin, cisplatin, carboplatin, hydroxyurea, amsacrine, procarbazine, mitotane, mitoxantrone, levamisole, navelbene, anastrazole, letrazole, capecitabine, reloxafine, droloxafine oloxafine), hexamethylmelamine, Avastin, Herceptin, Vexar, Velcade, Zevalin, Trisenox, Xeloda, vinorelbine, porfimer, Erbitux, liposomal, thiotepa, altretamine, melphalan, trastuzumab, Lerozole, fulvestrant, exemestane, fulvestrant, ifosfomide, rituximab Mab, C225, Cambus, clofarabine, cladribine, aphidicolon, Rituxan, sunitinib, dasatinib, tezacitabine, Sml1, fludarabine, pentostatin, triapine, didox, trimidox, amidox, 3-AP, MDL-101,731, bendamustine (Treanda), ofatumumab, or GS-1101 (also known as CAL-101).

[0113] Exemplary chemotherapeutic agents include proteosome inhibitors (eg, bortezomib), thalidomide, revlimid, and DNA damaging agents such as melphalan, doxorubicin, cyclophosphamide, vincristine, etoposide, carmustine, and the like.

[0114] Exemplary steroids include corticosteroids such as dexamethasone or prednisone.

[0115] Exemplary Bcr-Abl inhibitors include those compounds of the genera and species described in US Pat. No. 5,521,184, WO 04 / 005281, and US Provisional Patent Application No. 60 / 578,491, and pharmaceutically acceptable salts thereof.

[0116] Exemplary suitable Flt-3 inhibitors include compounds described in WO03 / 037347, WO03 / 099771, and WO04 / 046120, and pharmaceutically acceptable salts thereof.

[0117] Exemplary suitable RAF inhibitors include the compounds described in WO00 / 09495 and WO05 / 028444, and pharmaceutically acceptable salts thereof.

[0118] Exemplary suitable FAK inhibitors include compounds disclosed in WO04 / 080980, WO04 / 056786, WO03 / 024967, WO01 / 064655, WO00 / 053595, and WO01 / 014402, and pharmaceutically acceptable salts thereof.

[0119] Exemplary suitable mTOR inhibitors include the compounds disclosed in WO2011 / 025889, and pharmaceutically acceptable salts thereof.

[0120] In some embodiments, the compounds of the present invention may be used in combination with one or more other kinase inhibitors, including imatinib, particularly to treat patients who are resistant to imatinib or other kinase inhibitors.

[0121] In some embodiments, the compounds of the present invention can be used in combination with chemotherapeutic agents for the treatment of cancer, such as multiple myeloma, to improve the therapeutic response compared to the response to the chemotherapeutic agent alone, without increasing its toxic effects. Examples of additional pharmaceutical agents used in the treatment of multiple myeloma include, but are not limited to, melphalan, melphalan plus prednisone [MP], doxorubicin, dexamethasone, and Velcade (bortezomib). Further additional drugs used in the treatment of multiple myeloma include Bcr-Ab1, Flt-3, RAF, and FAK kinase inhibitors. Additive or synergistic effects are desirable results from combining the PI3K inhibitors of the present invention with additional drugs. Furthermore, resistance of multiple myeloma cells to drugs such as dexamethasone can be reversible with treatment with the PI3K inhibitors of the present invention. The drugs can be used in combination with the compounds in a single or sequential dosage form, or the drugs can be administered simultaneously or sequentially as separate dosage forms.

[0122] In some embodiments, a corticosteroid, such as dexamethasone, is administered to a patient in combination with a compound of the invention where the dexamethasone is administered intermittently as opposed to continuously.

[0123] In some further embodiments, the combination of the compounds of the present invention and other therapeutic agents may be administered to a patient before, during, and / or after bone marrow or stem cell transplantation.

[0124] Pharmaceutical Formulations and Dosage Forms When used as pharmaceuticals, the compounds described herein can be administered in the form of pharmaceutical compositions. These compositions can be formulated using methods well known in the pharmaceutical arts and can be administered by various routes, depending on whether local or systemic treatment is desired and the area to be treated. Administration can be topical (including transdermal, epithelial, ocular, and mucosal, including intranasal, intravaginal, and rectal delivery), pulmonary (e.g., inhalation or insufflation of aerosols, including powders or nebulizers; intratracheal or intranasal), oral, or parenteral. Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular, or injection or infusion; or intracranial, e.g., intrathecal or intraventricular, administration. Parenteral administration can be in the form of a single bolus dose or, for example, via a continuous infusion pump. Pharmaceutical compositions and formulations for topical administration can include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids, and powders. Conventional pharmaceutical carriers, aqueous, powder or oily bases, thickeners and the like may be necessary or desirable.

[0125] The present invention also includes pharmaceutical compositions comprising the compounds described herein or pharmaceutically acceptable salts thereof as an active ingredient in combination with one or more pharmaceutically acceptable carriers (excipients). In some embodiments, the compositions are suitable for topical administration. When preparing compositions according to the present invention, the active ingredient is usually mixed with an excipient, diluted by an excipient, or enclosed within such a carrier, for example, in the form of a capsule, sachet, paper, or other container. When the excipient serves as a diluent, it can be a solid, semi-solid, or liquid substance that acts as a solvent, carrier, or vehicle for the active ingredient. Thus, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (in solid or liquid media), for example, ointments containing up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile water for injection, and powders in sterile containers.

[0126] When preparing a formulation, the active compound may be milled to obtain the appropriate particle size before blending with other ingredients. If the active compound is substantially water-insoluble, it may be milled to a particle size of less than 200 mesh. If the active compound is substantially water-soluble, the particle size may be adjusted by milling to provide a substantially uniform distribution in the formulation, for example, about 40 mesh.

[0127] The compounds described herein can be milled using known milling methods, such as wet milling, to obtain particle sizes suitable for tablet formulations and other formulation types. Micronized (nanoparticulate) preparations of the compounds described herein can be prepared by methods known in the art, see, for example, International Application No. WO2002 / 000196.

[0128] Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia gum, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methylcellulose.The formulation can additionally contain: lubricants such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preservatives such as methylbenzoate and propylhydroxybenzoate; sweeteners; and flavoring agents.The composition of the present invention can be formulated to provide rapid, sustained, or delayed release of the active ingredient after administration to patients using methods known in the art.

[0129] The compositions can be formulated in unit dosage form, each dosage containing from about 5 to about 1000 mg (1 g), more usually about 100 to about 500 mg, of the active ingredient. The term "unit dosage form" refers to physically discrete units suitable for use in human subjects and other mammals as unit dosages, each unit containing a predetermined quantity of active material calculated to produce a desired therapeutic effect, in association with suitable pharmaceutical excipients.

[0130] In some embodiments, the compositions of the present invention contain about 5 to about 50 mg of the active ingredient. One of skill in the art will recognize that this specifically refers to compositions containing about 5 to about 10, about 10 to about 15, about 15 to about 20, about 20 to about 25, about 25 to about 30, about 30 to about 35, about 35 to about 40, about 40 to about 45, or about 45 to about 50 mg of the active ingredient.

[0131] In some embodiments, the compositions of the present invention contain about 50 to about 500 mg of the active ingredient. One of skill in the art will recognize that this specifically refers to compositions containing about 50 to about 100, about 100 to about 150, about 150 to about 200, about 200 to about 250, about 250 to about 300, about 350 to about 400, or about 450 to about 500 mg of the active ingredient.

[0132] In some embodiments, the compositions of the present invention contain about 500 to about 1000 mg of the active ingredient. One of skill in the art will recognize that this specifically refers to compositions containing about 500 to about 550, about 550 to about 600, about 600 to about 650, about 650 to about 700, about 700 to about 750, about 750 to about 800, about 800 to about 850, about 850 to about 900, about 900 to about 950, or about 950 to about 1000 mg of the active ingredient.

[0133] Similar dosages may be used for the compounds described herein in the methods and uses of the present invention.

[0134] The active compound may be effective over a wide dosage range and is generally administered in a pharmaceutically effective amount. However, it will be understood that the amount of the compound actually administered will usually be determined by a physician according to the relevant circumstances, including the condition being treated, the selected route of administration, the actual compound being administered, the age, weight and response of the individual patient, the severity of the patient's symptoms, etc.

[0135] To prepare solid compositions such as tablets, the primary active ingredient is mixed with pharmaceutical excipients to produce a solid preformulation composition containing a homogeneous mixture of the compound of the present invention. When these preformulation compositions are referred to as homogeneous, the active ingredient is usually evenly dispersed throughout the composition so that the composition can be easily subdivided into unit dosage forms of equal effectiveness, such as tablets, pills, and capsules. This solid preformulation is then subdivided into unit dosage forms of the type described above, containing, for example, about 0.1 to about 1000 mg of the active ingredient of the present invention.

[0136] The tablets or pills of the present invention can be coated or otherwise compounded to provide a dosage form with the advantage of prolonged action. For example, the tablets or pills can contain an inner medicinal and an outer medicinal component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer that serves to resist disintegration in the stomach and allow the inner component to pass intact into the duodenum or be delayed in release. A variety of materials can be used for such enteric layers or coatings, including a number of polymeric acids and mixtures of polymeric acids with materials such as shellac, cetyl alcohol, and cellulose acetate.

[0137] Liquid dosage forms into which the compounds and compositions of the present invention may be incorporated for oral or injectable administration include aqueous solutions, suitably flavored syrups, aqueous or oily suspensions, and elixirs and similar pharmaceutical vehicles, as well as flavored emulsions containing edible oils such as cottonseed oil, sesame oil, coconut oil, or peanut oil.

[0138] Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents, or mixtures thereof, and powders. The liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described above. In some embodiments, the compositions are administered by oral or intranasal respiratory route for local or systemic effect. The compositions may be nebulized by the use of an inert gas. Nebulized solutions may be inhaled directly from the nebulizing device, or the nebulizing device may be connected to a mask, tent, or intermittent positive pressure respirator. Solution, suspension, or powder compositions may be administered orally or intracavitarily from a device that delivers the formulation in an appropriate manner.

[0139] Topical formulations may contain one or more conventional carriers. In some embodiments, ointments may contain water and one or more hydrophobic carriers selected from, for example, liquid paraffin, polyoxyethylene alkyl ether, propylene glycol, white petrolatum, etc. The carrier composition of creams may be water-based in combination with glycerol and one or more other ingredients, such as glycerol monostearate, PEG-glycerol monostearate, and cetylstearyl alcohol. Gels may be formulated using isopropyl alcohol and water, appropriately combined with other ingredients, such as glycerol and hydroxyethylcellulose. In some embodiments, topical formulations contain at least about 0.1, at least about 0.25, at least about 0.5, at least about 1, at least about 2, or at least about 5 wt% of a compound described herein. The topical formulations may be suitably packaged, for example, in 100g tubes, which may be accompanied by instructions for treating a selected indication, such as psoriasis or other skin conditions.

[0140] The amount of compound or composition administered to a patient will vary depending on the purpose of the administration, such as prophylaxis or therapy, the condition of the patient, the method of administration, etc. In therapeutic applications, compositions may be administered to a patient already suffering from a disease in an amount sufficient to cure or at least partially arrest the symptoms of the disease and its complications. The effective dose will depend on factors such as the severity of the disease, the age, weight, and general condition of the patient, as well as on the disease state being treated, and will depend on the judgment of the attending clinician.

[0141] The compositions administered to patients may be in the form of pharmaceutical compositions described above. These compositions may be sterilized by conventional sterilization techniques or sterile filtered. Aqueous solutions may be packaged for use as is or lyophilized, with the lyophilized preparations being combined with a sterile aqueous carrier prior to administration. The pH of the compound formulation will generally be between 3 and 11, more preferably 5-9, and most preferably 7-8. It will be understood that the use of certain of the aforementioned excipients, carriers, or stabilizers may result in the formation of pharmaceutical salts.

[0142] Therapeutic dosages of the compounds of the invention may vary depending, for example, on the particular use for which the treatment is being administered, the method of administration of the compound, the health and condition of the patient, and the judgment of the prescribing physician. The proportion or concentration of a compound described herein in a pharmaceutical composition may vary depending on numerous factors, including dosage, chemical characteristics (e.g., hydrophobicity), and route of administration. For example, for parenteral administration, the compounds described herein may be provided in an aqueous physiological buffer solution containing about 0.1 to about 10% (w / v) compound. Some typical dosage ranges are about 1 μg / kg to about 1 g / kg of body weight per day. In some embodiments, the dosage range is about 0.01 mg / kg to about 100 mg / kg of body weight per day. The dosage will likely depend on variables such as the type and extent of the disease or disorder progression, the overall health of the particular patient, the relative biological efficacy of the selected compound, the excipient formulation, and its route of administration. Effective doses may be extrapolated from dose-response curves derived from in vitro or animal model test systems.

[0143] The compositions of the present invention may further comprise one or more additional pharmaceutical agents, such as a chemotherapeutic agent, a steroid, an anti-inflammatory compound, or an immunosuppressant, examples of which are listed herein.

[0144] kit The present invention also includes pharmaceutical kits useful for treating or preventing a PI3K-related disease or disorder, e.g., cancer, comprising one or more containers containing a pharmaceutical composition comprising a therapeutically effective amount of a compound described herein. As will be readily apparent to one of skill in the art, such kits may optionally further include one or more of a variety of conventional pharmaceutical kit components, e.g., a container containing one or more pharmaceutically acceptable carriers, additional containers, etc. Instructions, either an insert or label, indicating the amounts of components to be administered, directions for administration, and / or directions for mixing the components, may also be included in the kit.

[0145] synthesis The compounds described herein, including salts thereof, can be prepared using known organic synthesis techniques and can be synthesized according to any of a number of possible synthetic routes. In some embodiments, the compounds can be synthesized as described in U.S. Patent Application No. 13 / 601,349, filed August 31, 2012, the entire contents of which are incorporated herein by reference.

[0146] The reactions to synthesize the compounds described herein can be carried out in a suitable solvent, which can be readily selected by one skilled in the art of organic synthesis. A suitable solvent can be substantially non-reactive with the starting materials (reactants), intermediates, or products at the temperature at which the reaction is carried out, which can range, for example, from the freezing point of the solvent to the boiling point of the solvent. A given reaction can be carried out in one solvent or a mixture of two or more solvents. Depending on the particular reaction step, a suitable solvent for a particular reaction step can be selected by the skilled artisan.

[0147] Preparation of the compounds described herein can involve the protection and deprotection of various chemical groups. The need for protection and deprotection, and the selection of appropriate protecting groups, can be readily determined by one skilled in the art. Protecting group chemistry is described, for example, in T.W. Greene and P.G.M.Wuts, Protective Groups in Organic Synthesis, 3 rd Ed., Wiley & Sons, Inc., New York (1999), which is incorporated herein by reference in its entirety.

[0148] The reaction can be monitored according to any suitable method known in the art. For example, product formation can be monitored by nuclear magnetic resonance spectroscopy (e.g., 1 H or 13 The purity of the compound may be monitored by spectroscopic means such as spectroscopic methods, such as infrared spectroscopy, spectrophotometry (e.g., UV-visible), mass spectrometry, or chromatographic methods such as high performance liquid chromatography (HPLC), liquid chromatography mass spectrometry (LCMS), or thin-layer chromatography (TLC). Compounds can be purified by those skilled in the art by a variety of methods, including high performance liquid chromatography (HPLC) ("Preparative LC-MS Purification: Improved Compound Specific Method Optimization," Karl F. Blom, Brian Glass, Richard Sparks, Andrew P. Combs J. Combi. Chem. 2004, 6(6), 874-883, the entire contents of which are incorporated herein by reference) and normal-phase silica chromatography.

[0149] For example, compounds of formula I can be produced as shown in Scheme I. Compound (i) is halogenated with N-chlorosuccinimide, N-bromosuccinimide, or N-iodosuccinimide to form a compound of formula X 1= Cl, Br, or I. The halo group of (ii) can be coupled with Cy-M, where M is a boronic acid, boronic ester, or appropriately substituted metal (e.g., Cy-M is Cy-B(OH)2, Cy-Sn(Bu)4, or Zn-Cy), under standard Suzuki or Stille conditions (e.g., in the presence of a palladium(0) catalyst such as tetrakis(triphenylphosphine)palladium(0) and a base (e.g., a bicarbonate or carbonate base)), or under standard Negishi conditions (e.g., in the presence of a palladium(0) catalyst such as tetrakis(triphenylphosphine)palladium(0)), to give derivatives of formula (iii). Alternatively, Cy-M can be a cyclic amine (M is H attached to the amine nitrogen), and coupling to compound (ii) can be accomplished by heating in a base or under Buchwald conditions (e.g., in the presence of a palladium(0) catalyst such as tetrakis(triphenylphosphine)palladium(0) and a base (e.g., an alkoxide base)) to give ketone (iii). Reduction of ketone (iii) with an appropriate reagent, such as sodium tetrahydroborate, can provide alcohol (iv), which can be converted to a derivative bearing a leaving group (v) (e.g., Lg is a chloride by reaction with cyanuric chloride or a mesylate by reaction with methanesulfonic anhydride). Finally, reaction of compound (v) with 3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (vi) under basic conditions (e.g., NaH, CsCO or KCO) gives compound of formula I(vii).

[0150] [ka]

[0151] Alternatively, compounds of formula I can be prepared as shown in Scheme II: ketone compound (i) is halogenated with N-chlorosuccinimide, N-bromosuccinimide, or N-iodosuccinimide to form a ketone compound (i) of formula X 1= Cl, Br, or I to give compound (ii). Ketone (ii) is reduced with a suitable reagent, such as sodium tetrahydroborate, to give alcohol (iii), which is converted to a derivative having a leaving group (e.g., Lg is chloride by reaction with cyanuric chloride or mesylate by reaction with methanesulfonic anhydride), which is then reacted with a heterocycle to give heterocyclic derivative (iv). The enantiomers of compound (iv) can be separated by chiral chromatography to give single enantiomers of heterocyclic compound (v). Finally, the halo group of (v) is coupled with Cy-M, where M is a boronic acid, a boronic ester, or an appropriately substituted metal (e.g., Cy-M is Cy-B(OH)2, Cy-Sn(Bu)4, or Zn-Cy), under standard Suzuki or Stille conditions (e.g., in the presence of a palladium(0) catalyst such as tetrakis(triphenylphosphine)palladium(0) and a base (e.g., a bicarbonate or carbonate base)) or under standard Negishi conditions (e.g., in the presence of a palladium(0) catalyst such as tetrakis(triphenylphosphine)palladium(0)), to give derivatives (vi) of formula I.

[0152] [ka]

[0153] Compounds of formula I can also be produced as shown in Scheme III. Phenol (i) can be alkylated using Mitsunobu conditions (e.g., R'OH, DEAD, PhP) or standard alkylation conditions (R'-Lg, Lg = leaving group), respectively, to give ether derivatives (ii). The halo group of (ii) can be coupled with Cy-M, where M is a boronic acid, boronic ester, or appropriately substituted metal (e.g., Cy-M is Cy-B(OH)2, Cy-Sn(Bu)4, or Zn-Cy), under standard Suzuki or Stille conditions (e.g., in the presence of a palladium(0) catalyst such as tetrakis(triphenylphosphine)palladium(0) and a base (e.g., bicarbonate or carbonate base)) or standard Negishi conditions (e.g., in the presence of a palladium(0) catalyst such as tetrakis(triphenylphosphine)palladium(0)), to give derivatives of formula (iii). Alternatively, Cy-M can be a cyclic amine (M is H attached to the amine nitrogen), and coupling to compound (ii) is accomplished by heating in a base or under Buchwald conditions (e.g., in the presence of a palladium(0) catalyst, such as tetrakis(triphenylphosphine)palladium(0), and a base (e.g., an alkoxide base)) to provide a compound of formula (iii). Ketone (iii) can be rearranged using methods similar to those shown in Schemes I and II to provide compound (iv) of formula I. Alternatively, halo-ketone (ii) can be rearranged using methods similar to those shown in Schemes I and II to provide halo intermediate (v). Cy-M can also be coupled with halo intermediate (v) by Suzuki, Stille, Negishi, or Buchwald coupling using methods similar to those described in Schemes I and II to provide compound (vi) of formula I.

[0154] [ka]

[0155] Ketones that can be used in the methods of Schemes I, II, and III can be produced as shown in Scheme IV below. Carboxylic acid (i) is activated with a coupling agent (e.g., HBTU or HATU) and then reacted with N,O-dimethylhydroxylamine to give N-methoxy-N-methylcarboxamide. Phenols can be reacted with phenols under Mitsunobu conditions (e.g., R 2 OH, DEAD, Ph3P) or standard alkylation conditions (R 2 -Lg, where Lg is a leaving group), to give the ether derivative (ii), respectively. 1 is halo), is coupled with Cy-M, where M is a boronic acid, boronic ester, or appropriately substituted metal (e.g., Cy-M is Cy-B(OH), Cy-Sn(Bu), or Zn-Cy) under standard Suzuki or Stille conditions (e.g., in the presence of a palladium(0) catalyst such as tetrakis(triphenylphosphine)palladium(0) and a base (e.g., a bicarbonate or carbonate base)) or standard Negishi conditions (e.g., in the presence of a palladium(0) catalyst such as tetrakis(triphenylphosphine)palladium(0)), to give derivatives of formula (iii). Alternatively, Cy-M can be a cyclic amine (M is H and is attached to the amine nitrogen), and coupling to compound (ii) is carried out by heating in a base or under Buchwald conditions (e.g., in the presence of a palladium(0) catalyst such as tetrakis(triphenylphosphine)palladium(0) and a base (e.g., an alkoxide base)) to give amide (iii). Compound (iii) and the formula Me-MgX 2 (X 2 = halo) with a Grignard reagent to provide ketone (iv), which can be rearranged to provide compounds of Formula I using methods similar to those shown in Schemes I, II, and III.

[0156] [ka]

[0157] Ketones that can be used in the methods of Schemes I, II, and III can also be prepared as shown in Scheme V below. (i) A halo group (e.g., X 1 =I) can be coupled with a zinc reagent Cy-Zn (such as tert-butyl 3-iodoazetidine-1-carboxylate along with zinc dust) under standard Knochel / Negishi conditions (e.g., in the presence of a palladium(0) catalyst such as tri-(2-furyl)phosphine and tris(dibenzylideneacetone)dipalladium(0) and 1,2-dibromoethane and chlorotrimethylsilane) to give derivatives of formula (ii). Azetidine (ii) can be deprotected (e.g., with Pg=Boc, TFA) and then subjected to alkylation, acylation, or reductive amination (e.g., R 3 -Br, R 3 COCl, R 3 -SO2Cl, R 3 N=C=O or R 3 CHO etc.R 3 X and a reducing agent) to give ketone derivative (iii), which can be converted to compound (v) of formula I by methods similar to those shown in Schemes I, II, and III. Alternatively, the ketone (ii) can be reduced with a suitable reagent (NaBH or Corey chiral CBS catalyst to give predominantly one isomer of the alcohol), the resulting alcohol converted to a leaving group (e.g., Lg is a chloride by reaction with cyanuric chloride or a mesylate by reaction with methanesulfonic anhydride), and then the chloride or mesylate is reacted with a suitable heterocycle (e.g., similar to those shown in Schemes I, II, and III) to give derivatives of formula (iv). The amine protecting group is removed under standard conditions, and then alkylation, acylation, or reductive amination conditions (e.g., R 3 -Br, R 3 COCl, R 3 -SO2Cl, R 3 N=C=O or R 3 CHO etc.R 3 X and a reducing agent), to give compound (v) of formula I.

[0158] [ka]

[0159] Compounds of Formula I can be synthesized from acid chloride compound (i) as illustrated in Scheme VI. Condensation of acid chloride (i) with malononitrile in the presence of a base such as sodium hydride provides a dicyanoenol intermediate, which is O-methylated with a suitable reagent, such as dimethyl sulfate, in the presence of a suitable base, such as sodium bicarbonate, to provide enol ether (ii). Reaction of enol ether (ii) with hydrazine dihydrochloride in the presence of a suitable base, such as triethylamine, provides pyrazole compound (iii). Pyrazole compound (iii) is then reacted with formamide to provide pyrazolopyrimidine (iv). Finally, compound (iv) is reacted with a suitable compound bearing a leaving group (v) under basic conditions to provide compounds of Formula (vi).

[0160] [ka]

[0161] Compounds of Formula I can also be prepared as shown in Scheme VII. (i) The halo group, X 1 can be coupled with an alkene (e.g., an acrylate or acrylamide) under standard Heck conditions (e.g., in the presence of a palladium(II) catalyst, such as palladium acetate) to give an alkene of formula (ii). Reaction of alkene (ii) with nitromethane in the presence of DBU gives the nitro derivative (iii), which can be reduced and cyclized under standard conditions (e.g., NiCl / NaBH) to give the free amine to produce lactam (iv). The lactam can be converted to a nitro derivative (iii) under standard conditions (e.g., R 3 -X 2 , where X 2= halo, in the presence of a base such as TEA or NaH) to give the N-alkyl-lactam (v). Compounds of formula (v) and the pyrrolidines derived from the lactam (v) by reduction with a suitable reducing agent such as LiAlH4 can be converted to compounds of formula I using the conditions described in Schemes I, II and III.

[0162] [ka]

[0163] Compounds of Formula I can also be prepared as shown in Scheme VIII. (i) The halo group, X 1 can be coupled with an alkene boronic acid or ester under standard Suzuki conditions (e.g., in the presence of a palladium(0) catalyst such as tetrakis(triphenylphosphine)palladium(0)) to give an alkene of formula (ii). Epoxidation of alkene (ii) with mCPBA gives epoxide (iii), which can be converted to a secondary or primary amine (amine = NHR 3 ) to give amino compounds of formula (iv). Secondary or tertiary amines (iv) can be further reacted with carbonyldiamidazole or phosgene to give oxazolidinones (v), or with acetyl halides (e.g., chloroacetyl chloride in the presence of a base such as TEA) to give N-acyl derivatives that can be converted to morpholinone derivatives (vi) upon treatment with a base (e.g., NaH). Compounds of formula (iv, v, and vi) can be deprotected using standard conditions (e.g., compounds protected with a THP group can be treated with an acid such as TFA or HCl) to give compounds of formula I.

[0164] [ka]

[0165] Compounds of Formula I can also be prepared as shown in Scheme IX. Under appropriate conditions (A or B as described in JACS, 2001, 123(9), 1862-1871 and J. Org. Chem, 2011, 76, 358-372), Sharpless aminohydroxylation of alkenes of Formula (i) can yield either amino-hydroxy isomers (ii) or (iii). Compounds (ii) and (iii) can be reacted with carbonyldiamidazole or phosgene to produce oxazolidinones (iv), or with acetyl halides (e.g., chloroacetyl chloride in the presence of a base such as TEA) to give N-acyl derivatives that can be converted to morpholinone derivatives (v) upon treatment with a base (e.g., NaH). The alternative aminohydroxy isomers (iii) can be converted to oxazolidinone and morpholinone derivatives as shown in Scheme XV.

[0166] [ka]

[0167] Compounds of Formula I can also be prepared as shown in Scheme X. (i) A halo group (e.g., X 1 = Cl, Br, I) can be converted to boronate ester (ii) under standard conditions (e.g., pinnacle boronate ester in the presence of a palladium(0) catalyst such as tetrakis(triphenylphosphine)palladium(0). Boronate ester (ii) can be converted to an aryl or heteroaryl halide (e.g., R 3 -X 2 ) to give formula (iii). Formula (iii) can be converted to formula I using the reaction conditions described in Schemes I, II or III.

[0168] [ka]

[0169] In the formula, R 4 Compounds of Formula I, where X is ═F or CN, can be produced as shown in Scheme XI. Compound (i) is acylated with a suitable acylating reagent (e.g., Me—COCl) to give an ester, which can be rearranged under Lewis acid conditions (e.g., BF3 / HOAc complex) to give ketone (ii). Ketone (ii) can be halogenated with N-chlorosuccinimide, N-bromosuccinimide, or N-iodosuccinimide to give the ketone (ii), where X is a methyl group. 1 = Cl, Br, or I to give phenol (iii). Compound (iii) can be subjected to alkylation (e.g., R 2-X and a base such as NaH or Na2CO3; or under Mitsunobu conditions) to give ether (iv). The fluoro group of (iv) can be displaced (e.g., with NaCN or KCN) to give cyano derivative (v). The halo group of (v) can be coupled with Cy-M, where M is a boronic acid, a boronic ester, or an appropriately substituted metal (e.g., Cy-M is Cy-B(OH)2, Cy-Sn(Bu)4, or Zn-Cy), under standard Suzuki or Stille conditions (e.g., in the presence of a palladium(0) catalyst such as tetrakis(triphenylphosphine)palladium(0) and a base (e.g., a bicarbonate or carbonate base)), or under standard Negishi conditions (e.g., in the presence of a palladium(0) catalyst such as tetrakis(triphenylphosphine)palladium(0)), to give derivatives of formula (vi). Alternatively, Cy-M can be a cyclic amine (M is H and is attached to the amine nitrogen) and can be coupled with compound (v) by heating in a base or under Buchwald conditions (e.g., in the presence of a palladium(0) catalyst such as tetrakis(triphenylphosphine)palladium(0) and a base (e.g., an alkoxide base)) to give ketone (vi). Reduction of ketone (vi) with a suitable reagent such as sodium tetrahydroborate or Corey CBS can provide an alcohol, which can be converted to a derivative bearing a leaving group (e.g., Lg is a chloride by reaction with cyanuric chloride or a mesylate by reaction with methanesulfonic anhydride), which can then be reacted with 3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine under basic conditions (e.g., NaH or CsCO or KCO) to give compounds of formula I(viii). Alternatively, the last two steps can be reversed so that the ketone (v) can be reduced to give an alcohol, which can be converted to a leaving group and first substituted with a heterocycle, followed by a Suzuki, Stille, Negishi, or Buchwald coupling to give compounds (viii) of Formula I. Fluoro derivatives (iv) can also be converted to compounds of Formula I, omitting the cyanation step in Scheme XI.

[0170] [ka]

[0171] Compounds of Formula I can also be prepared as shown in Scheme XII. Compound (i) can be acylated with a suitable acylating reagent (e.g., Me-COCl) to form an ester, which can be rearranged under Lewis acid conditions (e.g., AlCl or BF / HOAc complex) to give ketone (ii). 1 S (e.g., NX 1 Halogenation of ketone (ii) with S=N-chlorosuccinimide, N-bromosuccinimide or N-iodosuccinimide to give 1 = Cl, Br, or I to give compound (iii). This phenol can be converted to the ether (iv) using standard conditions (e.g., an inorganic base such as K2CO3 and an alkyl halide such as Et-I). The halo group in (iv) can be converted to the ether (iii) using standard Suzuki or Stille conditions (e.g., in the presence of a palladium(0) catalyst such as tetrakis(triphenylphosphine)palladium(0) and a base (e.g., bicarbonate or carbonate base) where M is a boronic acid, boronic ester, or appropriately substituted metal (e.g., R 3 -M,R 3 -B(OH)2, R 3 -Sn(Bu)4, or Zn-R 3 , and R 3 is a substituted or unsubstituted olefin such as vinyl, 3-M to give the derivative of formula (v). This alkene is then dihydroxylated using Sharpless conditions to give the diol (vi). Enrichment of one enantiomer of the secondary alcohol can be achieved using standard Sharpless asymmetric dihydroxylation methods. The secondary alcohol is converted to an N-Boc-protected amine via a six-step process (e.g., silyl protection of the primary alcohol (e.g., TBS-Cl and DIEA), mesylation of the secondary alcohol, displacement of the mesylate with NaN3, reduction of the azide with Ph3P, Boc-protection of the resulting primary amine, and then deprotection of the silyl protecting group of the primary alcohol with TBAF) to give the amino-alcohol (vii). The amino-alcohol (vii) can be converted to an oxazolidinone by treatment with phosgene, followed by reduction of the ketone with a suitable reagent such as sodium tetrahydroborate or sodium borohydride to provide the alcohol (viii), which can be converted to a derivative bearing a leaving group (ix) (e.g., Lg is chloride by reaction with cyanuric chloride or mesylate by reaction with methanesulfonic anhydride). Finally, compound (ix) can be reacted with an appropriate heterocycle (x) (e.g., 3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine or 4-aminopyrido[2,3-d]pyrimidin-5(8H)-one) under basic conditions (e.g., NaH or CsCO or KCO) to provide compound (xi) of formula I.

[0172] [ka]

[0173] The present invention will be described in more detail by specific examples. The following examples are provided for illustrative purposes and are not intended to limit the present invention in any way. Those skilled in the art will readily recognize various non-critical parameters that can be changed or modified to achieve essentially the same results. The compounds of the examples have been found to be PI3K inhibitors according to at least one assay described herein. [Example]

[0174] The following exemplary compounds containing one or more chiral centers were obtained as racemates or mixtures of isomers unless otherwise specified. The stoichiometry of a specified salt of any of the products below indicates only the likely stoichiometry and should not be construed as excluding the possible formation of salts of other stoichiometries. The abbreviations "h" and "min" represent hours and minutes, respectively.

[0175] Example 1. 1-{1-[5-chloro-3-(1-isopropylazetidin-3-yl)-2-methoxy-4-methylphenyl]ethyl}-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine bis(trifluoroacetate) [ka]

[0176] Step 1. 1-(5-chloro-2-hydroxy-3-iodo-4-methylphenyl)ethanone To a stirred solution of 1-(5-chloro-2-hydroxy-4-methylphenyl)ethanone (from Oakwood, 50.0 g, 271 mmol) in acetic acid (300 mL) was added N-iodosuccinimide (73.1 g, 325 mmol), and the resulting mixture was stirred with mantle heating between 60 and 80 °C for 3.5 hours, then cooled to room temperature and stirred overnight. Water (500 mL) was added in small portions to the mixture to produce a dark solid. After stirring for 10 minutes, the solid was filtered, washing with additional water. The light-to-dark brown solid was dried under vacuum for 4 hours and then air-dried over the weekend to give 81.3 g (97%) of the desired product. LCMS calculated (M+H) for C9H9ClIO2 + : m / z = 310.9; Measured value: 311.0. 1 HNMR (300MHz, CDCl3): δ13.21(s,1H),7.71(s,1H),2.65(s,3H),2.63(s,3H)ppm.

[0177] Step 2. 1-(5-chloro-3-iodo-2-methoxy-4-methylphenyl)ethanone Potassium carbonate (72.4 g, 524 mmol) was added to a mixture of 1-(5-chloro-2-hydroxy-3-iodo-4-methylphenyl)ethanone (81.3 g, 262 mmol) and methyl iodide (19.6 mL, 314 mmol) in N,N-dimethylformamide (250 mL). The mixture was stirred at room temperature for 4 hours. Water (500 mL) was added and stirred for 15 minutes. The dark solid was filtered and dried under vacuum to give 42.3 g of the desired product. The filtrate was extracted with EtOAc (4 times). The combined filtrate was washed with water (2 times) and brine, dried (MgSO), filtered, and concentrated. The solid was dried under vacuum to give an additional 37.2 g of the desired product. The product was used without further purification. 10 H 11 LCMS calculated value for ClIO2 (M+H) + : m / z = 324.9; Measured value: 325.0. 1 HNMR (300MHz, CDCl3): δ7.62(s,1H), 3.78(s,3H), 2.65(s,3H), 2.62(s,3H)ppm.

[0178] Step 3. tert-Butyl 3-(3-acetyl-5-chloro-2-methoxy-6-methylphenyl)azetidine-1-carboxylate Zinc (1.71 g, 26.2 mmol) was suspended in N,N-dimethylformamide (45.0 mL) and 1,2-dibromoethane (210 μL, 2.5 mmol) was added. The mixture was heated at 60° C. for 10 minutes and cooled to room temperature. Chlorotrimethylsilane (330 μL, 2.6 mmol) was added, stirred at 60° C. for 10 minutes and cooled to room temperature. A solution of tert-butyl 3-iodoazetidine-1-carboxylate (from Oakwood, 6.25 g, 22.1 mmol) in N,N-dimethylformamide (5.0 mL) was then added and the mixture was stirred at room temperature for 1 hour. 1-(5-Chloro-3-iodo-2-methoxy-4-methylphenyl)ethanone (5.00 g, 15.4 mmol), tri-(2-furyl)phosphine (358 mg, 1.54 mmol), and tris(dibenzylideneacetone)dipalladium(0) (0.70 g, 0.77 mmol) were added sequentially, and the reaction mixture was warmed to 70 °C and stirred overnight. The mixture was cooled to room temperature and partitioned between ethyl acetate (EtOAc) and saturated NH4Cl solution. The layers were separated, and the aqueous layer was further extracted with EtOAc (twice). The combined organic layers were washed with water and brine, dried over MgSO4, and concentrated. The residue was purified on silica gel, eluting with 0-30% EtOAc in hexanes, to give 3.0 g (55%) of the desired product as an orange solid. 18 H 24 LCMS calculated value for ClNO4Na (M+Na) + : m / z = 376.1; Measured value: 376.0. 1 HNMR (400MHz, CDCl3): δ7.52(s,1H),4.32,(m,2H),4.16(m,3H),3.66(s,3H),2.59(s,3H),2.31(s,3H),1.45(s,9H)ppm.

[0179] Step 4. tert-Butyl 3-[3-chloro-5-(1-hydroxyethyl)-6-methoxy-2-methylphenyl]azetidine-1-carboxylate To a solution of tert-butyl 3-(3-acetyl-5-chloro-2-methoxy-6-methylphenyl)azetidine-1-carboxylate (1.3 g, 3.7 mmol) in methanol (20 mL) was added sodium tetrahydroborate (0.167 g, 4.41 mmol) while stirring at 0° C. The mixture was stirred at 0-5° C. for 1 hour. The reaction was quenched with water and extracted with EtOAc (3 times). The combined extracts were dried over MgSO4, filtered, and concentrated to give 1.3 g (100%) of the desired product. 18 H 26 LCMS calculated value for ClNO4Na (M+Na) + : m / z = 378.2; Measured value: 378.1. 1 HNMR (400MHz, CDCl3): δ7.37(s,1H),5.10(q,1H),4.30(m,2H),4.14(m,3H),3.63(s,3H),2.25(s,3H),1.48(d,3H),1.44(s,9H)ppm.

[0180] Step 5. tert-Butyl 3-[3-chloro-5-(1-chloroethyl)-6-methoxy-2-methylphenyl]azetidine-1-carboxylate Cyanuric acid chloride (from Aldrich, 1.22 g, 6.62 mmol) was weighed into a flask, and N,N-dimethylformamide (0.512 mL, 6.62 mmol) was added. After stirring for several minutes, a solution of tert-butyl 3-[3-chloro-5-(1-hydroxyethyl)-6-methoxy-2-methylphenyl]azetidine-1-carboxylate (1.5 g, 4.2 mmol) in methylene chloride (30 mL) was added. The resulting mixture was stirred at room temperature overnight. Water was added and then diluted with dichloromethane. The layers were separated, and the organic layer was washed with saturated NaHCO3 solution, water, brine, dried over MgSO4, and concentrated. The resulting residue was purified on silica gel, eluting with 0-35% EtOAc in hexanes, to give the desired product (1.36 g, 86%). 13 H 17 LCMS calculated for ClNO (M-Cl-Boc+H) + : m / z = 238.1; Found: 238.1. 1HNMR (400MHz, CDCl3): δ7.46(s,1H),5.44,(q,1H),4.32(m,2H),4.18-4.10(m,3H),3.67(s,3H),2.27(s,3H),1.79(d,3H),1.44(s,9H)ppm.

[0181] Step 6. tert-Butyl 3-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}azetidine-1-carboxylate At room temperature, sodium hydride (0.32 g, 8.0 mmol) was added to a suspension of 3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (from ChemBridge, 0.59 g, 4.0 mmol) in N,N-dimethylformamide (20 mL). The resulting mixture was stirred at room temperature for 25 minutes, during which time the suspension became a nearly clear solution. To the resulting mixture was added a solution of tert-butyl 3-[3-chloro-5-(1-chloroethyl)-6-methoxy-2-methylphenyl]azetidine-1-carboxylate (1.35 g, 3.61 mmol, from Example 1, Step 5) in N,N-dimethylformamide (10 mL). The mixture was stirred at 50° C. overnight. After cooling, the mixture was diluted with water and extracted with EtOAc (twice). The combined extracts were washed with water and brine, dried over MgSO4, and concentrated. The resulting residue was purified on silica gel, eluting with 0-10% MeOH in dichloromethane, to give 1.03 g (59%) of the desired product as a yellow gum. The racemic product was applied to a Phenomenex Lux-Cellulose 2 column (21.1 x 250 mm, 5 micron particle size) eluting with 10% ethanol in hexanes at a flow rate of 18 mL / min, 4 mg / injection, to give the two enantiomers. The retention time of the first peak was 8.34 min and the retention time of the second peak was 10.92 min. Peak 1 (463 mg), C 24 H 32 LCMS calculated for ClN6O3 (M+H) + : m / z = 487.2; Measured value: 487.1. 1HNMR (400MHz, CDCl3): δ7.37(s,1H),6.30,(q,1H),5.40(s,2H),4.23(m,2H),4.17 ~4.00(m,3H),3.57(s,3H),2.58(s,3H),2.16(s,3H),1.76(d,3H),1.37(s,9H)ppm.

[0182] Step 7. 1-[1-(3-azetidin-3-yl-5-chloro-2-methoxy-4-methylphenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine dihydrochloride To a solution of tert-butyl 3-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}azetidine-1-carboxylate (318 mg, 0.653 mmol) (peak 1 from above) in methylene chloride (3.2 mL) was added 4.0 M hydrochloric acid in 1,4-dioxane (1.6 mL, 6.5 mmol). The resulting mixture was stirred at room temperature for 75 minutes. The solvent was evaporated and the residue was dried under vacuum to give 0.30 g of the desired product as the bis-HCl salt. 19 H 24 LCMS calculated for ClNO (M+H) + : m / z = 387.2; Measured value: 387.1.

[0183] Step 8. 1-{1-[5-chloro-3-(1-isopropylazetidin-3-yl)-2-methoxy-4-methylphenyl]ethyl}-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine bis(trifluoroacetate) To a mixture of 1-[1-(3-azetidin-3-yl-5-chloro-2-methoxy-4-methylphenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine dihydrochloride (58 mg, 0.13 mmol), acetone (18.5 μL, 0.252 mmol), and triethylamine (54.5 μL, 0.391 mmol) in methylene chloride (1.0 mL) was added sodium triacetoxyborohydride resin (108 mg, 0.249 mmol). The resulting mixture was stirred at room temperature for 3 hours. The mixture was filtered and concentrated. The crude product was purified using RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile / water containing 0.05% TFA at a flow rate of 30 mL / min) to give 50 mg (60%) of the desired product as the TFA salt. 22 H 30 LCMS calculated for ClNO (M+H) + : m / z = 429.2; Found: 429.1. The product was isolated as a single enantiomer. 1 HNMR(500MHz,DMSO-d6):δ8.47(s,1H),7.46(s,1H),6.29(q,J=6.9Hz,1H),4.52(m,2H),4.21(m,1H),4.15(t,J=9.8Hz,1H),4.06( ppm.

[0184] Example 2. 1-{1-[3-(1-acetylazetidin-3-yl)-5-chloro-2-methoxy-4-methylphenyl]ethyl}-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine trifluoroacetate [ka]

[0185] Step 1. 1-[1-(3-azetidin-3-yl-5-chloro-2-methoxy-4-methylphenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine dihydrochloride To a solution of racemic tert-butyl 3-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}azetidine-1-carboxylate (146 mg, 0.300 mmol) (racemic intermediate from Example 1, Step 6) in methylene chloride (1.5 mL) was added 4.0 M hydrochloric acid in 1,4-dioxane (0.75 mL, 3.0 mmol). After stirring at room temperature for 2 hours, the solvent was evaporated and the resulting residue was dried in vacuo to give 138 mg of the desired product as the HCl salt. 19 H 24 LCMS calculated for ClNO (M+H) + : m / z = 387.2; Measured value: 387.1.

[0186] Step 2. 1-{1-[3-(1-acetylazetidin-3-yl)-5-chloro-2-methoxy-4-methylphenyl]ethyl}-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine trifluoroacetate To a mixture of 1-[1-(3-azetidin-3-yl-5-chloro-2-methoxy-4-methylphenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine dihydrochloride (20.0 mg, 0.0435 mmol, from Example 2, Step 1) and triethylamine (30.3 μL, 0.217 mmol) in methylene chloride (0.20 mL) was added acetyl chloride (6.18 μL, 0.0870 mmol). The resulting mixture was stirred at room temperature overnight. The solvent was evaporated, and the crude product was purified using RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile / water containing 0.05% TFA at a flow rate of 30 mL / min) to obtain the desired product as a TFA salt. The product was isolated as a racemic mixture. 21 H 26 LCMS calculated for ClN6O2 (M+H) +: m / z = 429.2; Measured value: 429.1. 1 HNMR(400MHz,DMSO-d6):δ8.35(s,1H),7.34(s,1H),6.26(q,1H),4.50(m,1H),4.28~4.20(m, 2H),4.01(m,1H),3.88(m,1H),3.52(s,3H),2.58(s,3H),2.18(s,3H),1.75~1.71(m,6H)ppm.

[0187] Example 3. 1-{1-[5-chloro-2-methoxy-4-methyl-3-(1-propionylazetidin-3-yl)phenyl]ethyl}-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine trifluoroacetate [ka]

[0188] This compound was synthesized using a method similar to Example 2, using propanoyl chloride instead of acetyl chloride. The product was isolated as a racemic mixture. 22 H 28 LCMS calculated for ClN6O2 (M+H) + : m / z = 443.2; Measured value: 443.2. 1 HNMR(400MHz,DMSO-d6)δ8.30(s,1H),7.33(s,1H),6.25(q,1H),4.49(m,1H),4.27~4.18(m,2H),4.02( m,1H),3.90(m,1H),3.54(s,3H),2.57(s,3H),2.18(s,3H),2.05(q,2H),1.72(d,3H),0.93(t,3H)ppm.

[0189] Example 4. 1-(1-{5-chloro-3-[1-(cyclopropylmethyl)azetidin-3-yl]-2-methoxy-4-methylphenyl}ethyl)-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine bis(trifluoroacetate) [ka]

[0190] This compound was synthesized using a method similar to that described in Example 1, using racemic 1-[1-(3-azetidin-3-yl-5-chloro-2-methoxy-4-methylphenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine dihydrochloride obtained in Example 2, Step 1, and cyclopropanecarboxaldehyde (from Aldrich) instead of acetone. The product was isolated as a racemic mixture. 23 H 30 LCMS calculated for ClNO (M+H) + : m / z = 441.2; Measured value: 441.1. 1 HNMR(400MHz,DMSO-d6):δ8.06(s,1H),7.13(s,1H),5.96(q,1H),4.22(m,2H),4.07(m,1H),3.90(m,1H),3.80(m, 1H),3.24(s,3H),2.68(t,2H),2.21(s,3H),1.80(s,3H),1.45(d,3H),0.64(m,1H),0.24(m,2H),0.01(m,2H)ppm.

[0191] Example 5. 1-{1-[5-chloro-2-methoxy-4-methyl-3-(1-methylazetidin-3-yl)phenyl]ethyl}-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine [ka]

[0192] This compound was synthesized using a method similar to that described in Example 1, using racemic 1-[1-(3-azetidin-3-yl-5-chloro-2-methoxy-4-methylphenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine dihydrochloride obtained in Example 2, Step 1, and formaldehyde instead of acetone. The crude product was purified using RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile / water containing 0.1% ammonium hydroxide at a flow rate of 30 mL / min) to give the desired product. The product was isolated as a racemic mixture. 20 H 26 LCMS calculated for ClNO (M+H) + : m / z = 401.2; Measured value: 401.2.

[0193] Example 6. 1-{1-[5-chloro-3-(1-ethylazetidin-3-yl)-2-methoxy-4-methylphenyl]ethyl}-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine [ka]

[0194] This compound was synthesized using a method similar to that described in Example 1, using racemic 1-[1-(3-azetidin-3-yl-5-chloro-2-methoxy-4-methylphenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine dihydrochloride obtained in Example 2, Step 1, and acetaldehyde instead of acetone. The crude product was purified using RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile / water containing 0.1% ammonium hydroxide at a flow rate of 30 mL / min) to give the desired product. The product was isolated as a racemic mixture. 21 H 28 LCMS calculated for ClNO (M+H) + : m / z = 415.2; Found: 415.1.

[0195] Example 7. 1-{1-[5-chloro-3-(1-isobutylazetidin-3-yl)-2-methoxy-4-methylphenyl]ethyl}-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine [ka]

[0196] This compound was synthesized using a method similar to that described in Example 1, using racemic 1-[1-(3-azetidin-3-yl-5-chloro-2-methoxy-4-methylphenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine dihydrochloride obtained in Example 2, Step 1, and isobutyraldehyde instead of acetone. The crude product was purified using RP-HPLC (XBridge C18 column, eluted with a gradient of acetonitrile / water containing 0.1% ammonium hydroxide at a flow rate of 30 mL / min) to give the desired product. The product was isolated as a racemic mixture. 23 H 32 LCMS calculated for ClNO (M+H) + : m / z = 443.2; Found: 443.1. 1 HNMR (400MHz, CDCl3): δ8.29(s,1H),7.38(s,1H),6.37(q,1H),5.37(s,2H),4.01(m,2H),3.87(m,1H),3.57(s,3 H),3.05(t,1H),2.86(t,1H),2.64(s,3H),2.18(d,2H),2.11(s,3H),1.82(d,3H),1.62(m,1H),0.89(d,6H)ppm.

[0197] Example 8. 1-{1-[3-(1-sec-butylazetidin-3-yl)-5-chloro-2-methoxy-4-methylphenyl]ethyl}-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine [ka]

[0198] This compound was synthesized using a method similar to that described in Example 1, using racemic 1-[1-(3-azetidin-3-yl-5-chloro-2-methoxy-4-methylphenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine dihydrochloride obtained in Example 2, Step 1, and 2-butanone instead of acetone. The crude product was purified using RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile / water containing 0.1% ammonium hydroxide at a flow rate of 30 mL / min) to give the desired product. The product was isolated as a mixture of diastereomers. 23 H 32 LCMS calculated for ClNO (M+H) + : m / z = 443.2; Found: 443.1.

[0199] Example 9. 1-(1-{5-chloro-2-methoxy-3-[1-(2-methoxyethyl)azetidin-3-yl]-4-methylphenyl}ethyl)-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine [ka]

[0200] This compound was synthesized using a method similar to that described in Example 1, using racemic 1-[1-(3-azetidin-3-yl-5-chloro-2-methoxy-4-methylphenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine dihydrochloride obtained in Example 2, Step 1, and methoxyacetaldehyde instead of acetone. The crude product was purified using RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile / water containing 0.1% ammonium hydroxide at a flow rate of 30 mL / min) to give the desired product. The product was isolated as a racemic mixture. 22 H 30 LCMS calculated for ClN6O2 (M+H) + : m / z = 445.2; Measured value: 445.2.

[0201] Example 10. 3-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}-N-methylazetidine-1-carboxamide [ka]

[0202] This compound was synthesized using a method similar to that described in Example 2, using methyl isocyanate instead of acetyl chloride. The crude product was purified using RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile / water containing 0.1% ammonium hydroxide at a flow rate of 30 mL / min) to give the desired product. The product was isolated as a racemic mixture. 21 H 27 LCMS calculated for ClN7O2 (M+H) + : m / z = 444.2; Found: 444.2.

[0203] Example 11. 5-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}-N,N-dimethylpyridine-2-carboxamide bis(trifluoroacetate) [ka]

[0204] Step 1. 1-(3-bromo-5-chloro-2-methoxy-4-methylphenyl)ethanone To a stirred solution of 1-(5-chloro-2-methoxy-4-methylphenyl)ethanone (5.00 g, 25.2 mmol, from Oakwood) in acetic acid (100 mL) was added N-bromosuccinimide (4.93 g, 27.7 mmol), and the resulting mixture was heated at 100° C. for 18 hours. After cooling to ambient temperature, the reaction mixture was concentrated in vacuo, then neutralized with saturated sodium bicarbonate, and the insoluble succinimide was filtered off. The filtrate was extracted with EtOAc. The combined organic layers were washed with brine, dried over sodium sulfate, and then concentrated to dryness under reduced pressure. The residue was purified on silica gel, eluting with 0 to 50% EtOAc in hexanes, to give the desired product (2.66 g, 38%). 10 H 11 LCMS calculated for BrClO2 (M+H) + : m / z = 277.0; Measured value: 277.0. 1 HNMR (DMSO-d6,300MHz):d7.70(1H,s),3.77(3H,s),2.57(3H,s),2.50(3H,s)ppm.

[0205] Step 2. 5-(3-acetyl-5-chloro-2-methoxy-6-methylphenyl)-N,N-dimethylpyridine-2-carboxamide To a mixture of 1-(3-bromo-5-chloro-2-methoxy-4-methylphenyl)ethanone (0.38 g, 1.4 mmol) and N,N-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-carboxamide (from PepTech, 0.46 g, 1.6 mmol) in 1,4-dioxane (6 mL) was added a solution of potassium carbonate (0.38 g, 2.7 mmol) in water (2 mL). N2 was bubbled through the reaction mixture. Tetrakis(triphenylphosphine)palladium(0) (0.095 g, 0.082 mmol) was added and the reaction was stirred at 100 °C overnight. The reaction was diluted with water and extracted with EtOAc. The combined organic layers were dried over MgSO4, concentrated, and purified on silica gel (eluting with 0-100% EtOAc in hexanes) to give the desired product. 18 H 20LCMS calculated for ClN2O3 (M+H) + : m / z = 347.1; Found: 347.1.

[0206] Step 3. 5-[3-chloro-5-(1-hydroxyethyl)-6-methoxy-2-methylphenyl]-N,N-dimethylpyridine-2-carboxamide To a solution of 5-(3-acetyl-5-chloro-2-methoxy-6-methylphenyl)-N,N-dimethylpyridine-2-carboxamide (106 mg, 0.306 mmol) in methanol (2 mL) was added sodium tetrahydroborate (14 mg, 0.37 mmol) while cooling to 0 °C. The mixture was stirred at room temperature for 1 h, then quenched with water and extracted with EtOAc. The organic layer was dried over MgSO and concentrated to give the crude alcohol. 18 H 22 LCMS calculated for ClN2O3 (M+H) + : m / z = 349.1; Found: 349.1.

[0207] Step 4. 5-[3-chloro-5-(1-chloroethyl)-6-methoxy-2-methylphenyl]-N,N-dimethylpyridine-2-carboxamide Cyanuric acid chloride (85 mg, 0.46 mmol) was added to N,N-dimethylformamide (0.036 mL, 0.46 mmol) at room temperature. After a white solid formed (10 min), methylene chloride (2 mL) was added, followed by 5-[3-chloro-5-(1-hydroxyethyl)-6-methoxy-2-methylphenyl]-N,N-dimethylpyridine-2-carboxamide (115 mg, 0.330 mmol, from Example 11, Step 3). After the addition, the mixture was stirred at room temperature overnight. Water was added and diluted with dichloromethane. The organic phase was washed with saturated NaHCO3 solution, water, and brine, then dried over MgSO4 and concentrated. The residue was purified on silica gel (eluted with 0-80% EtOAc in hexanes) to give the desired product (76 mg, 63%). 18 H 21 LCMS calculated for Cl2N2O2 (M+H) +: m / z = 367.1; Measured value: 367.0.

[0208] Step 5. 5-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}-N,N-dimethylpyridine-2-carboxamide bis(trifluoroacetate) To a solution of 3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (6.1 mg, 0.041 mmol) in N,N-dimethylformamide (0.4 mL) was added sodium hydride (60%, 2.0 mg, 0.082 mmol) at 0° C., and the mixture was stirred at room temperature for 10 minutes. To the resulting mixture was added a solution of 5-[3-chloro-5-(1-chloroethyl)-6-methoxy-2-methylphenyl]-N,N-dimethylpyridine-2-carboxamide (15.0 mg, 0.0408 mmol) in N,N-dimethylformamide (0.2 mL). The mixture was stirred at room temperature overnight. The crude mixture was purified by RP-HPLC (XBridge C18 column, eluted with a gradient of acetonitrile / water containing 0.05% TFA at a flow rate of 30 mL / min) to give the desired product as the bis-TFA salt. The product was isolated as a racemic mixture. 24 H 27 LCMS calculated for ClN7O2 (M+H) + : m / z = 480.2; Measured value: 480.1.

[0209] Example 13. 1-{1-[5-chloro-4-fluoro-3-(1-isopropylazetidin-3-yl)-2-methoxyphenyl]ethyl}-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine bis(trifluoroacetate) [ka]

[0210] Step 1. 1-(5-chloro-4-fluoro-2-hydroxyphenyl)ethanone To 4-chloro-3-fluorophenol (from Aldrich, 20 g, 100 mmol) was added acetyl chloride (14.1 mL, 199 mmol) with stirring under N2. The resulting mixture quickly became a clear solution at room temperature and was heated at 60 °C for 2 h. Aluminum trichloride (25.0 g, 187 mmol) was added in small portions, and the reaction mixture was heated at 180 °C for 30 min. The solid slowly dissolved at elevated temperature. The reaction mixture was then cooled to room temperature, carefully swirling the flask to form a thin layer of solid on the inside of the flask. It was then stirred overnight while cooling in an ice bath and slowly quenched with 1.0 N HCl (300 mL). The yellow precipitate was washed with water and dried under vacuum to give the desired product (23.8 g) as a yellow solid, which was used directly in the next step without further purification.

[0211] Step 2. 1-(5-chloro-4-fluoro-2-hydroxy-3-iodophenyl)ethanone A solution of 1-(5-chloro-4-fluoro-2-hydroxyphenyl)ethanone (23.8 g, 126 mmol) in acetic acid (100 mL) was treated with N-iodosuccinimide (34.1 g, 151 mmol) and stirred at 70 °C for 2 h. The reaction mixture was concentrated, diluted with EtOAc, and quenched with saturated NaHCO solution until bubbling ceased. The organic layer was separated, washed with water, dried over MgSO, and stripped to give the desired product, which was used directly in the next step without further purification.

[0212] Step 3. 1-(5-chloro-4-fluoro-3-iodo-2-methoxyphenyl)ethanone 1-(5-Chloro-4-fluoro-2-hydroxy-3-iodophenyl)ethanone (13 g, 41 mmol) was dissolved in N,N-dimethylformamide (41.3 mL). Methyl iodide (3.9 mL, 62 mmol) was added, followed by potassium carbonate (11 g, 83 mmol). The reaction was heated at 60° C. for 1 hour. The mixture was cooled to room temperature and diluted with ether. The organic layers were separated, combined, washed with water, dried over MgSO4, concentrated, and purified on silica gel (eluting with 0-10% EtOAc in hexanes) to give the desired product (10 g, 70%). LCMS calculated for C9H8ClFIO2 (M+H) + : m / z = 328.9; Measured value: 328.9.

[0213] Step 4. tert-Butyl 3-(3-acetyl-5-chloro-6-fluoro-2-methoxyphenyl)azetidine-1-carboxylate Zinc (0.682 g, 10.4 mmol) was suspended in N,N-dimethylformamide (12 mL) with 1,2-dibromoethane (0.0598 mL, 0.694 mmol). The mixture was heated at 70° C. for 10 minutes and then cooled to room temperature. Chlorotrimethylsilane (0.088 mL, 0.69 mmol) was added dropwise, and stirring was continued for 1 hour. A solution of tert-butyl 3-iodoazetidine-1-carboxylate (2.5 g, 8.7 mmol) in N,N-dimethylformamide (10 mL) was then added, and the mixture was heated at 40° C. for 1 hour. A mixture of 1-(5-chloro-4-fluoro-3-iodo-2-methoxyphenyl)ethanone (3.0 g, 9.1 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.16 g, 0.17 mmol), and tri-(2-furyl)phosphine (0.081 g, 0.35 mmol) in N,N-dimethylformamide (20 mL) was then added. The reaction mixture was warmed to 70° C. and stirred overnight. The mixture was then cooled to room temperature and partitioned with ether and saturated NH4Cl solution. The organic layer was washed with water, dried over MgSO4, concentrated, and purified on silica gel (eluting with 0-25% EtOAc in hexanes) to give the desired product (0.8 g). 17H 21 LCMS calculated value for ClFNO4Na (M+Na) + : m / z = 380.1; Measured value: 380.1.

[0214] Step 5. tert-Butyl 3-[3-chloro-2-fluoro-5-(1-hydroxyethyl)-6-methoxyphenyl]azetidine-1-carboxylate To a solution of tert-butyl 3-(3-acetyl-5-chloro-6-fluoro-2-methoxyphenyl)azetidine-1-carboxylate (0.17 g, 0.48 mmol) in methanol (3 mL) was added sodium tetrahydroborate (0.022 g, 0.57 mmol) while cooling to 0 °C. The mixture was stirred at room temperature for 1 hour, then quenched with water and extracted with EtOAc. The combined organic layers were dried over MgSO and concentrated to give the crude alcohol (0.19 g). 17 H 23 LCMS calculated value for ClFNO4Na (M+Na) + : m / z = 382.1; Measured value: 382.0.

[0215] Step 6. tert-Butyl 3-[3-chloro-5-(1-chloroethyl)-2-fluoro-6-methoxyphenyl]azetidine-1-carboxylate Cyanuric acid chloride (140 mg, 0.78 mmol) was added to N,N-dimethylformamide (0.059 mL, 0.77 mmol) at room temperature. After a white solid formed (approximately 10 min), methylene chloride (4 mL) was added, followed by tert-butyl 3-[3-chloro-2-fluoro-5-(1-hydroxyethyl)-6-methoxyphenyl]azetidine-1-carboxylate (197 mg, 0.547 mmol). After the addition, the mixture was stirred at room temperature overnight. Water was added and then diluted with dichloromethane. The organic phase was washed with saturated NaHCO3 solution, water, and brine, dried over MgSO4, and concentrated. The resulting residue was purified on silica gel (eluted with 0–30% EtOAc in hexanes) to give the desired product (110 mg, 53%).

[0216] Step 7. tert-Butyl 3-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-6-fluoro-2-methoxyphenyl}azetidine-1-carboxylate To a solution of 3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (7.9 mg, 0.053 mmol) in N,N-dimethylformamide (0.6 mL) was added sodium hydride (60%, 2.5 mg, 0.11 mmol) at 0° C., and the mixture was stirred at room temperature for 10 minutes. To the mixture was added a solution of tert-butyl 3-[3-chloro-5-(1-chloroethyl)-2-fluoro-6-methoxyphenyl]azetidine-1-carboxylate (20 mg, 0.053 mmol) in N,N-dimethylformamide (0.3 mL). The reaction mixture was stirred at 35° C. overnight, then quenched with water and extracted with ether. The combined organic layers were dried over MgSO4 and concentrated to give the desired product, which was used directly in the next step. 23 H 29 LCMS calculated value for ClFN6O3 (M+H) + : m / z = 491.2; Measured value: 491.1.

[0217] Step 8. 1-{1-[5-chloro-4-fluoro-3-(1-isopropylazetidin-3-yl)-2-methoxyphenyl]ethyl}-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine bis(trifluoroacetate) A mixture of tert-butyl 3-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-6-fluoro-2-methoxyphenyl}azetidine-1-carboxylate (14 mg, 0.028 mmol) in methylene chloride (0.2 mL) was treated with 4.0 M hydrochloric acid in dioxane (0.2 mL, 0.8 mmol) at room temperature for 1 hour, and then the solvent was removed to give 1-[1-(3-azetidin-3-yl-5-chloro-4-fluoro-2-methoxyphenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine HCl salt. To a mixture of the crude HCl salt in acetonitrile (0.1 mL) / methanol (0.1 mL) / tetrahydrofuran (0.1 mL) was added N,N-diisopropylethylamine (0.1 mL, 0.6 mmol), followed by acetone (0.050 mL, 0.68 mmol). The mixture was stirred for 30 minutes, and sodium triacetoxyborohydride (0.030 g, 0.14 mmol) was added. The reaction was stirred overnight at room temperature, then quenched and purified by RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile / water containing 0.05% TFA at a flow rate of 30 mL / min) to give the desired product as the TFA salt. The product was isolated as a racemic mixture. 21 H 27 LCMS calculated for ClFNO (M+H) + : m / z = 433.2; Found: 433.1.

[0218] Example 14. 5-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-6-methylphenyl}-N,N-dimethylpyridine-2-carboxamide bis(trifluoroacetate) [ka]

[0219] Step 1. 1-(5-chloro-2-ethoxy-3-iodo-4-methylphenyl)ethanone 1-(5-Chloro-2-hydroxy-3-iodo-4-methylphenyl)ethanone (18.9 g, 60.9 mmol) (from Example 1, Step 1) was dissolved in N,N-dimethylformamide (60.8 mL). Iodoethane (7.3 mL, 91 mmol) was added, followed by potassium carbonate (17 g, 120 mmol). The reaction was heated at 60° C. for 1 hour. The mixture was cooled to room temperature and diluted with ether. The combined organic layers were washed with water, dried over MgSO4, concentrated, and purified on silica gel (eluting with 0-10% EtOAc in hexanes) to give the desired product (18.9 g, 91.7%). 11 H 13 LCMS calculated value for ClIO2 (M+H) + : m / z = 339.0; Measured value: 339.0.

[0220] Step 2. 5-(3-acetyl-5-chloro-2-ethoxy-6-methylphenyl)-N,N-dimethylpyridine-2-carboxamide To a mixture of 1-(5-chloro-2-ethoxy-3-iodo-4-methylphenyl)ethanone (0.69 g, 2.0 mmol) and N,N-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-carboxamide (0.68 g, 2.4 mmol) in 1,4-dioxane (10 mL) was added a solution of potassium carbonate (0.56 g, 4.1 mmol) in water (3 mL, 200 mmol). N was bubbled through the reaction. Tetrakis(triphenylphosphine)palladium(0) (0.24 g, 0.20 mmol) was added and N was bubbled through. The reaction was stirred at 95 °C overnight. The reaction was diluted with water and extracted with EtOAc. The combined organic layers were dried over MgSO4, concentrated, and purified on silica gel (eluting with 0-90% EtOAc in hexanes) to give the desired product (0.6 g, 82%). 19 H 22 LCMS calculated for ClN2O3 (M+H) + : m / z = 361.1; Measured value: 361.0.

[0221] Step 3. 5-[3-chloro-6-ethoxy-5-(1-hydroxyethyl)-2-methylphenyl]-N,N-dimethylpyridine-2-carboxamide To a solution of 5-(3-acetyl-5-chloro-2-ethoxy-6-methylphenyl)-N,N-dimethylpyridine-2-carboxamide (0.60 g, 1.7 mmol) in methanol (10 mL) was added sodium tetrahydroborate (0.075 g, 2.0 mmol) while cooling to 0 °C. The mixture was stirred at room temperature for 1 h, then quenched with water and extracted with EtOAc. The extract was dried over MgSO and concentrated to give the crude alcohol (0.6 g). 19 H 24 LCMS calculated for ClN2O3 (M+H) + : m / z = 363.1; Measured value: 363.0.

[0222] Step 4. 5-[3-chloro-5-(1-chloroethyl)-6-ethoxy-2-methylphenyl]-N,N-dimethylpyridine-2-carboxamide Cyanuric acid chloride (0.43 g, 2.3 mmol) was added to N,N-dimethylformamide (0.18 mL, 2.3 mmol) at room temperature. After a white solid formed (10 min), methylene chloride (10 mL) was added, followed by 5-[3-chloro-6-ethoxy-5-(1-hydroxyethyl)-2-methylphenyl]-N,N-dimethylpyridine-2-carboxamide (0.6 g, 2 mmol). After the addition, the mixture was stirred at room temperature overnight, then diluted with dichloromethane and washed with saturated NaHCO3 solution. The organic layer was dried over MgSO4 and concentrated. The residue was purified on silica gel (eluting with 0-50% EtOAc in hexanes) to give the desired product (0.58, 90%). 19 H 23 LCMS calculated for Cl2NO2 (M+H) + : m / z = 381.1; Measured value: 381.0.

[0223] Step 5. 5-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-6-methylphenyl}-N,N-dimethylpyridine-2-carboxamide bis(trifluoroacetate) To a solution of 3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (47 mg, 0.31 mmol) in N,N-dimethylformamide (3 mL) was added sodium hydride (60%, 12.6 mg, 0.524 mmol) at 0° C., and the reaction mixture was stirred at room temperature for 10 minutes. To the mixture was added a solution of 5-[3-chloro-5-(1-chloroethyl)-6-ethoxy-2-methylphenyl]-N,N-dimethylpyridine-2-carboxamide (100 mg, 0.3 mmol, from Example 14, Step 4) in N,N-dimethylformamide (1 mL). The reaction was stirred at 35° C. overnight. The reaction was stopped and applied to RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile / water containing 0.05% TFA at a flow rate of 30 mL / min) to give the desired product as a bis-TFA salt. The product was isolated as a racemic mixture. 25 H 29 LCMS calculated for ClN7O2 (M+H) + : m / z = 494.2; Measured value: 494.1.

[0224] Example 16. 4-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}-N,N-dimethylpyridine-2-carboxamide [ka]

[0225] Step 1. 1-(3-bromo-5-chloro-2-methoxy-4-methylphenyl)ethanol Sodium tetrahydroborate (0.31 g, 8.1 mmol) was added to a mixture of 1-(3-bromo-5-chloro-2-methoxy-4-methylphenyl)ethanone (from Example 11, Step 1) (1.5 g, 5.4 mmol) in methanol (25 mL) at 0° C., and the resulting reaction mixture was stirred at room temperature for 1 h. The solvent was removed, and the resulting residue was diluted with ethyl acetate, washed with saturated NaHCO, water, brine, then dried over NaSO, filtered, and concentrated. The crude product was purified by silica gel chromatography (0.30 g, 90%), eluting with 0-40% EtOAc in hexanes.

[0226] Step 2. 4-[3-chloro-5-(1-hydroxyethyl)-6-methoxy-2-methylphenyl]pyridine-2-carbonitrile A mixture of 1-(3-bromo-5-chloro-2-methoxy-4-methylphenyl)ethanol (0.30 g, 1.1 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-carbonitrile (from Combi-Blocks, 0.27 g, 1.2 mmol), sodium carbonate (230 mg, 2.1 mmol), and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (1:1) (100 mg, 0.13 mmol) in acetonitrile (8 mL) / water (2 mL) was degassed and then refilled with N. The reaction was stirred at 95 °C for 2 h, then cooled, diluted with ethyl acetate, washed with saturated NaHCO, water, brine, dried over NaSO, filtered, and concentrated. The crude product was purified by silica gel chromatography, eluting with 0-40% EtOAc in hexanes (0.249 g, 75%). 16 H 16 LCMS calculated for ClN2O2 (M+H) + : m / z = 303.1; Measured value: 303.0.

[0227] Step 3. 4-[3-chloro-5-(1-chloroethyl)-6-methoxy-2-methylphenyl]pyridine-2-carbonitrile A mixture of cyanuric chloride (170 mg, 0.94 mmol) and N,N-dimethylformamide (73 μL, 0.94 mmol) was stirred at room temperature for 10 minutes, then a solution of 4-[3-chloro-5-(1-hydroxyethyl)-6-methoxy-2-methylphenyl]pyridine-2-carbonitrile (190 mg, 0.628 mmol) in methylene chloride (4 mL) was added, and the reaction was stirred at room temperature overnight. The mixture was diluted with methylene chloride, washed with saturated NaHCO3, water, brine, dried over Na2SO4, filtered, and concentrated. The crude product was used directly in the next step without purification (121 mg, 60%). 16 H 15 LCMS calculated for Cl2N2O (M+H) + : m / z = 321.0; Measured value: 321.0.

[0228] Step 4. 4-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}pyridine-2-carbonitrile Sodium hydride (20 mg, 0.50 mmol) was added to a mixture of 4-[3-chloro-5-(1-chloroethyl)-6-methoxy-2-methylphenyl]pyridine-2-carbonitrile (90 mg, 0.28 mmol), 3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (63 mg, 0.42 mmol) in N,N-dimethylformamide (4 mL), and the reaction was stirred at 30° C. overnight. The mixture was cooled, treated with water, and then filtered to give the desired product. 22 H 21 LCMS calculated for ClNO (M+H) + : m / z = 434.1; Found: 434.2.

[0229] Step 5. 4-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}pyridine-2-carboxylic acid A solution of sodium hydroxide (1.0 M) in water (0.70 mL, 0.70 mmol) was added to a mixture of 4-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}pyridine-2-carbonitrile (0.060 g, 0.14 mmol) in ethanol (1.0 mL), and the resulting mixture was heated at 95° C. for 6 hours. At this time, concentrated HCl was added to adjust the pH to approximately 3. The solvent was removed, and the residue was used in the next step without further purification. 22 H 22 LCMS calculated for ClN6O3 (M+H) + : m / z = 453.1; Measured value: 453.2.

[0230] Step 6. 4-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}-N,N-dimethylpyridine-2-carboxamide A 2.0 M solution of dimethylamine in THF (0.14 mL, 0.28 mmol) was added to a solution of 4-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}pyridine-2-carboxylic acid (9.6 mg, 0.021 mmol) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (10 mg, 0.03 mmol) in N,N-dimethylformamide (0.7 mL) at room temperature, followed by the addition of triethylamine (8.8 μL, 0.064 mmol). The reaction was stirred for 1 h. The crude mixture was purified using RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile / water containing 0.1% ammonium hydroxide at a flow rate of 30 mL / min) to give the desired product. The product was isolated as a racemic mixture. 24 H 27 LCMS calculated for ClN7O2 (M+H) + : m / z = 480.2; Measured value: 480.2.

[0231] Example 17. 4-(3-(1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-chloro-2-methoxy-6-methylphenyl)-N-methylpicolinamide [ka]

[0232] This compound was synthesized using a method similar to Example 16, Step 6, replacing 2.0 M dimethylamine in THF with 2.0 M methylamine in THF. The product was isolated as a racemic mixture. 23 H 25 LCMS calculated for ClN7O2 (M+H) + : m / z = 466.2; Measured value: 466.2.

[0233] Example 18. 4-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}-N-(2-hydroxyethyl)pyridine-2-carboxamide [ka]

[0234] This compound was synthesized using a method similar to Example 16, Step 6, substituting ethanolamine for 2.0 M dimethylamine in THF. The product was isolated as a racemic mixture. 24 H 27 LCMS calculated for ClN7O3 (M+H) + : m / z = 496.2; Found: 496.2.

[0235] Example 19. 4-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}-N-(2-hydroxyethyl)-N-methylpyridine-2-carboxamide [ka]

[0236] This compound was synthesized using a method similar to Example 16, Step 6, substituting 2-(methylamino)ethanol for 2.0 M dimethylamine in THF. The product was isolated as a racemic mixture. 25 H 29 LCMS calculated for ClN7O3 (M+H) + : m / z = 510.2; Found: 510.2.

[0237] Example 20 2-(4-(3-(1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-chloro-2-methoxy-6-methylphenyl)-1H-pyrazol-1-yl)ethanol [ka]

[0238] Step 1. 3-Bromo-1-chloro-5-(1-chloroethyl)-4-methoxy-2-methylbenzene A mixture of cyanuric chloride (1.7 g, 9.2 mmol) and N,N-dimethylformamide (710 μL, 9.2 mmol) was stirred at room temperature for 10 minutes, then a solution of 1-(3-bromo-5-chloro-2-methoxy-4-methylphenyl)ethanol (from Example 16, Step 1) (1.72 g, 6.15 mmol) in methylene chloride (34 mL) was added, and the reaction was stirred at room temperature overnight. The mixture was diluted with methylene chloride, washed with saturated NaHCO, water, brine, dried over NaSO, filtered, and concentrated. The crude product was purified by silica gel chromatography (1.01 g, 60%), eluting with 0-10% EtOAc in hexanes.

[0239] Step 2. 1-[1-(3-bromo-5-chloro-2-methoxy-4-methylphenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine Sodium hydride (36 mg, 0.91 mmol) was added to a mixture of 3-bromo-1-chloro-5-(1-chloroethyl)-4-methoxy-2-methylbenzene (150 mg, 0.503 mmol), 3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (110 mg, 0.76 mmol) in N,N-dimethylformamide (8 mL), and the reaction was stirred at 30 °C overnight. The mixture was diluted with methylene chloride, washed with saturated NaHCO, water, brine, dried over NaSO, filtered, and concentrated. The crude product was purified by silica gel chromatography (103 mg, 50%), eluting with 0-70% EtOAc in CHCl. 16 H 18 LCMS calculated for BrClNO (M+H) + : m / z = 410.0; Found: 410. The racemic product was applied to a Phenomenex Lux-Cellulose 1 column (21.1 x 250 mm, 5 micron particle size) eluting with 5% ethanol in hexanes at a flow rate of 18 mL / min, approximately 13 mg / injection, to give the two enantiomers.

[0240] Step 3. 1-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole A solution of potassium tert-butoxide (1.0 M) in THF (0.60 mL, 0.60 mmol) was added to a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.1 g, 0.5 mmol) in N,N-dimethylformamide (1.5 mL) at 0 °C. The reaction mixture was stirred at room temperature for 5 minutes, then cooled to 0 °C and treated with (2-bromoethoxy)(tert-butyl)dimethylsilane (0.2 mL, 0.8 mmol). The reaction was stirred overnight at room temperature, then diluted with ethyl acetate, washed with saturated NaHCO3, water, brine, dried over Na2SO4, filtered, and concentrated to give the crude product, which was purified by silica gel chromatography, eluting with 0-30% EtOAc in hexanes. 17 H34 Calculated value of BN2O3Si (M+H) + : m / z = 353.2; Found: 353.1.

[0241] Step 4. 2-(4-(3-(1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-chloro-2-methoxy-6-methylphenyl)-1H-pyrazol-1-yl)ethanol 1-[1-(3-bromo-5-chloro-2-methoxy-4-methylphenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.026 g, 0.062 mmol) (chiral pure, second peak from step 2), 1-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-4-(4,4,5, A mixture of 5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.024 g, 0.069 mmol), sodium carbonate (13 mg, 0.12 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (1:1) (6.1 mg, 0.0075 mmol) was degassed and then backfilled with N. The reaction mixture was stirred at 95 °C for 2 h, then treated with concentrated HCl (0.1 mL), and then stirred at room temperature for 1 h. The crude mixture was purified using RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile / water containing 0.1% ammonium hydroxide at a flow rate of 30 mL / min) to give the desired product. The product was isolated as a single enantiomer. 21 H 25 LCMS calculated for ClN7O2 (M+H) + : m / z = 442.2; Found: 442.2.

[0242] Example 21. 3'-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5'-chloro-3-fluoro-2'-methoxy-N,N,6'-trimethylbiphenyl-4-carboxamide trifluoroacetate [ka]

[0243] Step 1. Methyl 3'-(1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5'-chloro-3-fluoro-2'-methoxy-6'-methylbiphenyl-4-carboxylate A mixture of 1-[1-(3-bromo-5-chloro-2-methoxy-4-methylphenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (60 mg, 0.15 mmol, chiral pure, peak 1 from Example 20, Step 2), [3-fluoro-4-(methoxycarbonyl)phenyl]boronic acid (from Combi-Blocks, 0.041 g, 0.20 mmol), sodium carbonate (36 mg, 0.34 mmol), and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (1:1) (6 mg, 0.007 mmol) in acetonitrile (1.2 mL) / water (0.3 mL) was evacuated and then refilled with N. The reaction was stirred at 95° C. for 2 h. The solvent was then removed and the crude mixture was purified by silica gel chromatography, eluting with 0-70% EtOAc in CH2Cl2, to give the desired product (54 mg, 75%). 24 H 24 LCMS calculated value for ClFN5O3 (M+H) + : m / z = 484.2; Measured value: 484.1.

[0244] Step 2. 3'-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5'-chloro-3-fluoro-2'-methoxy-6'-methylbiphenyl-4-carboxylic acid Lithium hydroxide monohydrate (13 mg, 0.31 mmol) was added to a solution of the above-synthesized methyl 3'-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5'-chloro-3-fluoro-2'-methoxy-6'-methylbiphenyl-4-carboxylate (0.030 g, 0.062 mmol) in methanol (0.2 mL) / tetrahydrofuran (0.2 mL) / water (0.09 mL). The reaction was stirred at room temperature for 1.5 hours and then treated with concentrated HCl (60 μL) to adjust the pH to 2. The solvent was removed to give the crude product, which was used in the next step without further purification. 23 H 22 LCMS calculated value for ClFN5O3 (M+H) + : m / z = 470.1; Measured value: 470.2.

[0245] Step 3. 3'-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5'-chloro-3-fluoro-2'-methoxy-N,N,6'-trimethylbiphenyl-4-carboxamide trifluoroacetate A 2.0 M solution of dimethylamine in THF (0.1 mL, 0.2 mmol) was added to a solution of the above-synthesized 3'-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5'-chloro-3-fluoro-2'-methoxy-6'-methylbiphenyl-4-carboxylic acid (12 mg, 0.026 mmol) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (20 mg, 0.04 mmol) in N,N-dimethylformamide (0.7 mL) at room temperature, followed by the addition of triethylamine (11 μL, 0.077 mmol). The reaction was stirred for 1 hour and quenched with water. The crude mixture was subjected to RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile / water containing 0.05% TFA at a flow rate of 30 mL / min) to give the desired product as a TFA salt. The product was isolated as a single enantiomer. 25 H 27 LCMS calculated value for ClFN6O2 (M+H) +: m / z = 497.2; Found: 497.2.

[0246] Example 22 3'-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5'-chloro-3-fluoro-2'-methoxy-N,6'-dimethylbiphenyl-4-carboxamide trifluoroacetate [ka]

[0247] This compound was synthesized using a method similar to Example 21, Step 3, using 2.0 M methylamine in THF instead of 2.0 M dimethylamine in THF. The product was isolated as a single enantiomer. 24 H 25 LCMS calculated value for ClFN6O2 (M+H) + : m / z = 483.2; Measured value: 483.2.

[0248] Example 23 5-(3-(1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-chloro-2-methoxy-6-methylphenyl)-N-(2-hydroxyethyl)picolinamide trifluoroacetate [ka]

[0249] Step 1. 5-[3-chloro-5-(1-hydroxyethyl)-6-methoxy-2-methylphenyl]pyridine-2-carbonitrile A mixture of 1-(3-bromo-5-chloro-2-methoxy-4-methylphenyl)ethanol (0.15 g, 0.54 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-carbonitrile (from Frontier, 0.14 g, 0.59 mmol), sodium carbonate (110 mg, 1.1 mmol), and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (1:1) (52 mg, 0.064 mmol) in acetonitrile (4 mL) / water (1 mL) was degassed and then backfilled with N. The reaction was stirred at 95 °C for 2 h, cooled, diluted with ethyl acetate, washed with saturated NaHCO, water, brine, and then dried over NaSO, filtered, and concentrated. The crude product was purified by silica gel chromatography, eluting with 0-40% EtOAc in hexanes, to give the desired product (114 mg, 70%). 16 H 16 LCMS calculated for ClN2O2 (M+H) + : m / z = 303.1; Measured value: 303.0.

[0250] Step 2. 5-[3-chloro-5-(1-chloroethyl)-6-methoxy-2-methylphenyl]pyridine-2-carbonitrile A mixture of cyanuric chloride (170 mg, 0.94 mmol) and N,N-dimethylformamide (73 μL, 0.94 mmol) was stirred at room temperature for 10 minutes, then a solution of 5-[3-chloro-5-(1-hydroxyethyl)-6-methoxy-2-methylphenyl]pyridine-2-carbonitrile (190 mg, 0.628 mmol) in methylene chloride (4 mL) was added, and the reaction was stirred at room temperature overnight. The mixture was diluted with methylene chloride, washed with saturated NaHCO3, water, brine, dried over Na2SO4, then filtered and concentrated. The resulting crude product was used directly in the next step without further purification (110 mg, 55%). 16 H 15 LCMS calculated for Cl2N2O (M+H) + : m / z = 321.0; Measured value: 321.0.

[0251] Step 3. 5-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}pyridine-2-carbonitrile Sodium hydride (20 mg, 0.50 mmol) was added to a mixture of 5-[3-chloro-5-(1-chloroethyl)-6-methoxy-2-methylphenyl]pyridine-2-carbonitrile (90 mg, 0.28 mmol), 3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (63 mg, 0.42 mmol) in N,N-dimethylformamide (4 mL), and the reaction was stirred at 30° C. overnight. The mixture was treated with water and then filtered to give the desired product. 22 H 21 LCMS calculated for ClNO (M+H) + : m / z = 434.1; Found: 434.2.

[0252] Step 4. 5-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}pyridine-2-carboxylic acid A solution of sodium hydroxide (1.0 M) in water (0.70 mL, 0.70 mmol) was added to a mixture of 5-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}pyridine-2-carbonitrile (0.060 g, 0.14 mmol) in ethanol (1.0 mL). The reaction was heated at 95° C. for 6 hours, and then concentrated HCl was added to adjust the pH to approximately 3. The solvent was removed, and the resulting residue was used in the next step without further purification. 22 H 22 LCMS calculated for ClN6O3 (M+H) + : m / z = 453.1; Measured value: 453.2.

[0253] Step 5. 5-(3-(1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-chloro-2-methoxy-6-methylphenyl)-N-(2-hydroxyethyl)picolinamide trifluoroacetate Ethanolamine (15 μL, 0.25 mmol) was added to a solution of 5-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}pyridine-2-carboxylic acid (9.6 mg, 0.021 mmol) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (10 mg, 0.03 mmol) in N,N-dimethylformamide (0.7 mL) at room temperature, followed by triethylamine (8.8 μL, 0.064 mmol). The reaction was stirred for 1 h and then quenched with water. The crude mixture was applied to RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile / water containing 0.05% TFA at a flow rate of 30 mL / min) to give the desired product as the TFA salt. The product was isolated as a racemic mixture. 24 H 27 LCMS calculated for ClN7O3 (M+H) + : m / z = 496.2; Found: 496.2.

[0254] Example 24 4-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}-N-(2-hydroxyethyl)-N-methylpyridine-2-carboxamide trifluoroacetate [ka]

[0255] This compound was synthesized using a method similar to Example 23, using 2-(methylamino)ethanol instead of ethanolamine. The product was isolated as a racemic mixture. 25 H 29LCMS calculated for ClN7O3 (M+H) + : m / z = 510.2; Found: 510.2.

[0256] Example 40. 4-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-cyano-2-methoxy-6-methylphenyl}-N-(2-hydroxyethyl)-N-methylpyridine-2-carboxamide [ka]

[0257] Catalyst pregeneration: Dimethylacetamide anhydride (DMA) was purged with a gentle stream of N for 30 min before use. A 50 mM solution of H2SO4 was prepared in 10 mL of dimethylacetamide and 26.8 μL of concentrated H2SO4 and then purged with N2 for 10 min. An 8 mL vial equipped with a magnetic stir bar and a septum cap was charged with Pd(OAc)2 (22.5 mg, 100 μmol) and 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (95.3 mg, 200 μmol). The vial was evacuated and filled with N2 three times and purged with a gentle stream of N2 for 10 min. H2SO4 (2.0 mL, 50 mM DMA solution) was added, and the catalyst mixture was stirred for 30 min in an oil bath at 80 °C to give a homogeneous coffee-brown solution.

[0258] The above catalyst (0.05 mL) was added to a mixture of 4-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}-N-(2-hydroxyethyl)-N-methylpyridine-2-carboxamide (from Example 19) (4.0 mg, 0.0078 mmol), zinc (0.22 mg, 0.0034 mmol), and zinc cyanide (0.92 mg, 0.0078 mmol) in N,N-dimethylacetamide (0.1 mL). The mixture was degassed, and then the reaction was heated at 120° C. for 1.5 h. The crude mixture was applied to RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile / water containing 0.1% ammonium hydroxide at a flow rate of 30 mL / min) to give the desired product. The product was isolated as a racemic mixture. 26 H 29 LCMS calculated value for N8O3 (M+H) + : m / z = 501.2; Measured value: 501.2.

[0259] Example 41. 5-{3-[1-(4-amino-3-methyl-1H-pyrazolo[4,3-c]pyridin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}-N,N-dimethylpyridine-2-carboxamide bis(trifluoroacetate) [ka]

[0260] Step 1. N-(2,4-dimethoxybenzyl)-3-methyl-1H-pyrazolo[4,3-c]pyridin-4-amine A solution of 4-chloro-3-methyl-1H-pyrazolo[4,3-c]pyridine (330 mg, 1.9 mmol) and 1-(2,4-dimethoxyphenyl)methanamine (0.58 mL, 3.9 mmol) in 1-butanol was heated in a microwave oven for 40 minutes at 150° C. Purification by preparative LCMS (XBridge C18 column, eluting with a gradient of acetonitrile / water containing 0.1% ammonium hydroxide at a flow rate of 60 mL / min) gave the desired product (240 mg, 42%).16 H 19 LCMS calculated value for N4O2 (M+H) + : m / z = 299.1; Measured value: 299.2.

[0261] Step 2. 5-[3-chloro-5-(1-{4-[(2,4-dimethoxybenzyl)amino]-3-methyl-1H-pyrazolo[4,3-c]pyridin-1-yl}ethyl)-6-methoxy-2-methylphenyl]-N,N-dimethylpyridine-2-carboxamide A solution of N-(2,4-dimethoxybenzyl)-3-methyl-1H-pyrazolo[4,3-c]pyridin-4-amine (110 mg, 0.37 mmol) in N,N-dimethylformamide (2 mL) was treated with sodium hydride (30 mg, 0.75 mmol) and stirred at 20° C. for 30 minutes. The reaction mixture was treated with a solution of 5-[3-chloro-5-(1-chloroethyl)-6-methoxy-2-methylphenyl]-N,N-dimethylpyridine-2-carboxamide (130 mg, 0.34 mmol) in N,N-dimethylformamide (1 mL) and heated at 50° C. overnight. The reaction mixture was diluted with water and extracted with ethyl acetate (twice). The combined organic extracts were washed with water and brine, dried over magnesium sulfate, filtered, and concentrated to give a crude residue. Purification by preparative LCMS (XBridge C18 column, eluting with a gradient of acetonitrile / water containing 0.1% ammonium hydroxide at a flow rate of 60 mL / min) gave the desired product (110 mg, 49%). 34 H 38 LCMS (M+H) of ClN6O4 + : m / z = 629.3; Measured value: 629.1.

[0262] Step 3. 5-{3-[1-(4-amino-3-methyl-1H-pyrazolo[4,3-c]pyridin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}-N,N-dimethylpyridine-2-carboxamide bis(trifluoroacetate) A solution of 5-[3-chloro-5-(1-{4-[(2,4-dimethoxybenzyl)amino]-3-methyl-1H-pyrazolo[4,3-c]pyridin-1-yl}ethyl)-6-methoxy-2-methylphenyl]-N,N-dimethylpyridine-2-carboxamide (85 mg, 0.14 mmol) in methylene chloride (2 mL) was treated with trifluoroacetic acid (2 mL) and stirred at 20° C. for 3 hours and at 40° C. for 20 minutes. Purification by preparative LCMS (XBridge C18 column, eluting with a gradient of acetonitrile / water containing 0.1% trifluoroacetic acid at a flow rate of 60 mL / min) gave the desired product (44 mg, 46%). The product was isolated as a racemic mixture. 25 H 28 LCMS (M+H) of ClN6O2 + : m / z = 479.2; Measured value: 479.0. 1 HNMR(300MHz,DMSO-d6):δ12.8(brs,0.5H),8.50(brs,0.5H),8.37(brs,2H),7.91~7.86(m,0.5H),7.80~7.75(m,0.5H),7.68~7.58(m,3 H),7.17(d,J=7.3Hz,1H),6.19(q,J=6.9Hz,1H),3.04(s,3H),3.01(s,3H),2.94(s,3H),2.61(s,3H),2.05(s,3H),1.83(d,J=6.9Hz,3H).

[0263] Example 43 4-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-6-chloro-3-ethoxy-2-[5-(methylsulfonyl)pyridin-3-yl]benzonitrile [ka]

[0264] Step 1. 1-(3-bromo-5-chloro-4-fluoro-2-hydroxyphenyl)ethanone 1-(5-chloro-4-fluoro-2-hydroxyphenyl)ethanone (e.g., from Example 13, Step 1) (20.0 g, 101 mmol, 1.00 equiv.) and 50% aqueous sulfuric acid (120 mL) were placed in a flask. The resulting mixture was heated to 60°C in a water bath with stirring. N-bromosuccinimide (21.52 g, 120.9 mmol, 1.20 equiv.) was added in three portions [7.0 g + 7.0 g + 7.52 g] at 8-minute intervals. The reaction mixture was heated at 60°C for 3 hours, after which the reaction was complete. The reaction mixture was diluted with water (160 ml) and dichloromethane (DCM) (300 ml), and the mixture was stirred for 0.5 hours. The organic layer was separated, and the aqueous layer was extracted with dichloromethane (100 ml). The combined organic layers were washed with 1N HCl (100 ml x 2), water (100 ml), brine (60 ml), and concentrated under reduced pressure to give the crude product (29.1 g) as a yellow solid. The crude product was dissolved in HOAc (100 ml) and then diluted with water (200 ml) with stirring. The resulting mixture was stirred at room temperature for 20 minutes, and the product was collected by filtration and dried to give 1-(3-bromo-5-chloro-4-fluoro-2-hydroxyphenyl)ethanone (21.8 g, 80.9%) as a yellowish solid. 1 H-NMR (300MHz, CDCl3) δ13.18(s,1H,-OH),7.78(d,J=7.78Hz,1H),2.63(s,3H).

[0265] Step 2. 4-Acetyl-2-bromo-6-chloro-3-ethoxybenzonitrile 1-(3-Bromo-5-chloro-4-fluoro-2-hydroxyphenyl)ethanone (2.0 g, 7.5 mmol) was combined with potassium cyanide (0.58 g, 9.0 mmol) in N,N-dimethylformamide (16 mL, 210 mmol) and heated to 85° C. in an oil bath. After heating for 18 hours, the reaction was allowed to cool to room temperature, and iodoethane (0.90 mL, 11 mmol) and sodium carbonate (2.1 g, 15 mmol) were added. The reaction was heated to 65° C. and monitored by LC / MS. After heating for 3 hours, the reaction was complete and allowed to cool to room temperature, then dissolved in ethyl acetate, washed with water, brine, and dried over magnesium sulfate. The resulting solution was concentrated to give the crude product as a dark oil. The product was purified by flash column chromatography on silica gel eluting with a hexane:ethyl acetate gradient to give 4-acetyl-2-bromo-6-chloro-3-ethoxybenzonitrile (1.15 gm, 50%) as a solid residue. 11 LCMS calculated for H9BrClNO2 (M+H) + : m / z = 301.9, 303.9; Measured value: (not ionized).

[0266] Step 3. 2-Bromo-6-chloro-3-ethoxy-4-(1-hydroxyethyl)benzonitrile Sodium tetrahydroborate (38 mg, 0.99 mmol) was added to a mixture of 4-acetyl-2-bromo-6-chloro-3-ethoxybenzonitrile (200 mg, 0.7 mmol) in methanol (5 mL, 100 mmol) at 0° C. The reaction was stirred at room temperature for 1 hour, concentrated, and partitioned with water and EtOAc. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated to give crude 2-bromo-6-chloro-3-ethoxy-4-(1-hydroxyethyl)benzonitrile as a clear oil (0.15 gm, 100%). 11 H 11 LCMS calculated for BrClNO2 (M+H) + : m / z = 303.9, 305.9; Found: 304.0, 305.9.

[0267] Step 4. 2-Bromo-6-chloro-4-(1-chloroethyl)-3-ethoxybenzonitrile Cyanuric acid chloride (0.11 g, 0.59 mmol) was dissolved in N,N-dimethylformamide (3 mL, 40 mmol). After stirring for several minutes, a solution of 2-bromo-6-chloro-3-ethoxy-4-(1-hydroxyethyl)benzonitrile (150 mg, 0.49 mmol) in methylene chloride (3 mL, 50 mmol) was added. The resulting mixture was stirred at room temperature overnight. The reaction was partitioned between water and dichloromethane. The organic layer was washed with saturated NaHCO3 solution, water, brine, dried over MgSO4, and concentrated. The crude product was purified by flash column chromatography, eluting with a gradient of 0-30% EtOAc / hexanes, to give 2-bromo-6-chloro-4-(1-chloroethyl)-3-ethoxybenzonitrile (0.12 gm, 75%) as a semi-solid. 11 H 10 LCMS calculated for BrCl2NO (M+H) + : m / z = 323.9, 320.9; Measured value: (insufficient ionization).

[0268] Step 5. 4-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-2-bromo-6-chloro-3-ethoxybenzonitrile Sodium hydride (16 mg, 0.41 mmol) was added to a mixture of 3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (33 mg, 0.22 mmol) in N,N-dimethylformamide (3 mL, 40 mmol) and stirred for 10 minutes. 2-Bromo-6-chloro-4-(1-chloroethyl)-3-ethoxybenzonitrile (60 mg, 0.2 mmol) in N,N-dimethylformamide (2 mL) was added and the reaction was stirred at 50° C. overnight. The mixture was diluted with methylene chloride, washed with saturated NaHCO3, water, brine, dried over Na2SO4, filtered, and concentrated. The product was purified by flash column chromatography eluting with CHCl / MeOH 0-10% to give 4-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-2-bromo-6-chloro-3-ethoxybenzonitrile (0.05 gm, 60%) as a solid. 17 H 16 LCMS calculated for BrClNO (M+H) + : m / z = 437.0, 435.0; Found: 436.9, 434.7.

[0269] Step 6. 4-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-6-chloro-3-ethoxy-2-[5-(methylsulfonyl)pyridin-3-yl]benzonitrile To a mixture of 4-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-2-bromo-6-chloro-3-ethoxybenzonitrile (20 mg, 0.04 mmol) and 3-(methylsulfonyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (19 mg, 0.069 mmol) in acetonitrile (2 mL, 40 mmol) was added a solution of sodium carbonate (10 mg, 0.09 mmol) in water (0.5 mL, 30 mmol). The reaction was degassed by bubbling nitrogen through it. [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (1:1) (2 mg, 0.002 mmol) was added and further degassed with N. The reaction was heated at 100° C. for 2 hours. The crude product was purified by preparative LC-MS (acetonitrile, water, TFA) to give the desired product (0.004 g, 20%) as a white amorphous solid. The product was isolated as a racemic mixture. 23 H 22 LCMS calculated for ClN7O3S (M+H) + : m / z = 512.1; Measured value: 512.2. 1 HNMR(500MHz,DMSO)δ9.20(d,J=2.1Hz,1H),9.12(d,J=1.9Hz,1H),8.61(t,J=2.0Hz,1H),8.12(s,1H),7.80(s,1H),6.36(q,J=7. 0Hz,1H), 3.54(dt,J=14.0,7.0Hz,1H),3.37(s,3H),3.36~3.30(m,1H),2.58(s,3H),1.81(d,J=7.0Hz,3H),0.92(t,J=6.9Hz,3H).

[0270] Example 44 5-(3-(1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-chloro-6-cyano-2-ethoxyphenyl)-N,N-dimethylpicolinamide [ka]

[0271] The title compound was synthesized similarly to Example 43, Step 6, but using N,N-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinamide (Peptech, catalog number BE1622) to give a crude product that was purified by preparative LC-MS (acetonitrile, water, TFA) to give the desired product as a white amorphous solid (0.005 g, 22%). The product was isolated as a racemic mixture. 25 H 25 LCMS calculated for ClN8O2 (M+H) + : m / z = 505.1; Found: 505.1. 1 HNMR(500MHz,DMSO)δ8.72(dd,J=2.1,0.7Hz,1H),8.14~8.12(m,1H),8.11(s,1H),7.75(s,1H),7.71(dd,J=8.0,0.7Hz,1H),6.35(q,J= 7.0Hz,1H), 3.61~3.48(m,1H),3.42~3.31(m,1H),3.03(s,3H),2.95(s,3H),2.57(s,3H),1.80(d,J=7.1Hz,3H),0.92(t,J=7.0Hz,3H).

[0272] Example 65. 5-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}-N,N-dimethylnicotinamide [ka]

[0273] A mixture of 1-[1-(3-bromo-5-chloro-2-methoxy-4-methylphenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (25 mg, 0.061 mmol) (chiral pure, first peak from Example 20, Step 2), N,N-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinamide (from PepTech) (25 mg, 0.091 mmol), sodium carbonate (13 mg, 0.12 mmol), and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (1:1) (9.9 mg, 0.012 mmol) in acetonitrile (0.8 mL) / water (0.3 mL) was degassed with N and then stirred at 95° C. for 2 h. The mixture was filtered, and the filtrate was purified by RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile / water containing 0.1% ammonium hydroxide at a flow rate of 30 mL / min) to give the desired product. The product was isolated as a single enantiomer. 24 H 27 LCMS calculated for ClN7O2 (M+H) + : m / z = 480.2; Measured value: 480.2. 1 HNMR(500MHz,DMSO-d6)δ8.64(1H,s),8.54(1H,brs),8.13(1H,s),7.82(1H,m),7.53(1H,s),7.42(2H,br s),6.28(1H,q,J=6.5Hz),3.22(3H,s),2.95(6H,m),2.58(3H,s),2.04(3H,s),1.77(3H,d,J=6.5Hz)ppm.

[0274] Example 66. 5-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}-N,N-dimethylpyridine-2-carboxamide bis(trifluoroacetate) [ka]

[0275] 1-[1-(3-bromo-5-chloro-2-methoxy-4-methylphenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (25 mg, 0.061 mmol) (chiral pure, Example 20, first peak from step 2), N,N-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-diphenylmethyl)-2-methyl-4-methylphenyl)ethyl) ... A mixture of oxaborolan-2-yl)pyridine-2-carboxamide (25 mg, 0.091 mmol), sodium carbonate (13 mg, 0.12 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) dichloromethane complex (1:1) (9.9 mg, 0.012 mmol) was degassed with N2 and then stirred at 95 °C for 2 h. After cooling to room temperature, the mixture was filtered, and the filtrate was purified by RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile / water containing 0.05% trifluoroacetic acid at a flow rate of 30 mL / min) to give the desired product as the bis-TFA salt. The product was isolated as a single enantiomer. 24 H 27 LCMS calculated for ClN7O2 (M+H) + : m / z = 480.2; Measured value: 480.2. 1 HNMR(500MHz,DMSO-d6)δ:8.78(2H,brs),8.48(1H,m),8.36(1H,s),7.86(1H,brs),7.65(1H,brs),7.58(1H,s),6 .33(1H,q,J=7.0Hz),3.19(3H,s),3.03(3H,s),2.97(3H,s),2.62(3H,s),2.06(3H,s),1.81(3H,d,J=7.0Hz)ppm.

[0276] Example 67. 1-{1-[5-chloro-4-fluoro-3-(1-isopropylazetidin-3-yl)-2-methoxyphenyl]ethyl}-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine [ka]

[0277] Step 1. 1-[1-(3-azetidin-3-yl-5-chloro-4-fluoro-2-methoxyphenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine dihydrochloride Tert-butyl 3-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-6-fluoro-2-methoxyphenyl}azetidine-1-carboxylate (1.6 g, 3.2 mmol, from Example 13, Step 7) was treated with 4.0 M hydrochloric acid in dioxane (8.15 mL, 32.6 mmol) in methylene chloride (17 mL) at room temperature for 2 hours. The mixture was concentrated to dryness to give the desired product. 18 H 21 LCMS calculated for ClFNO (M+H) + : m / z = 391.1; Measured value: 391.1.

[0278] Step 2. 1-{1-[5-chloro-4-fluoro-3-(1-isopropylazetidin-3-yl)-2-methoxyphenyl]ethyl}-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine To a mixture of 1-[1-(3-azetidin-3-yl-5-chloro-4-fluoro-2-methoxyphenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine dihydrochloride (0.90 g, 1.9 mmol, Example 67, Step 1), acetone (1.0 mL, 14 mmol), and triethylamine (2.5 mL, 18 mmol) in methylene chloride (20 mL) was added sodium triacetoxyborohydride resin (2.5 g, 5.8 mmol). The mixture was stirred at room temperature for 2 hours, then filtered, washed with water, dried over MgSO4, filtered, and concentrated to give the crude product (870 mg, 100%). 21 H 27 LCMS calculated for ClFNO (M+H) + : m / z = 433.2; Found: 433.1.

[0279] Step 3. Single enantiomer of 1-{1-[5-chloro-4-fluoro-3-(1-isopropylazetidin-3-yl)-2-methoxyphenyl]ethyl}-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine The enantiomers of 1-{1-[5-chloro-4-fluoro-3-(1-isopropylazetidin-3-yl)-2-methoxyphenyl]ethyl}-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (870 mg, 2.0 mmol) were separated into two enantiomers on a Phenomenex Lux Cellulose-2 column eluted with 10% ethanol in hexanes at a flow rate of 18 mL / min and a column load of approximately 8 mg / injection. The first peak had a retention time of 10.9 min; the second peak had a retention time of 13.6 min. The first peak fraction (110 mg, 13%) was concentrated and purified using RP-HPLC (XBridge C18 column, eluted with a gradient of acetonitrile / water containing 0.1% ammonium hydroxide at a flow rate of 30 mL / min) to give the desired product. The product was isolated as a single enantiomer. 21 H 27 LCMS calculated for ClFNO (M+H) + : m / z = 433.2; Found: 433.1.

[0280] Example 68 (2S)-1-(3-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-6-fluoro-2-methoxyphenyl}azetidin-1-yl)propan-2-ol [ka]

[0281] To a mixture of 1-[1-(3-azetidin-3-yl-5-chloro-4-fluoro-2-methoxyphenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine dihydrochloride (15 mg, 0.032 mmol, from Example 67, Step 1) and triethylamine (18 μL, 0.13 mmol) in ethanol (0.53 mL) was added (S)-(−)-methyloxirane (6.8 μL, 0.097 mmol). The resulting mixture was heated at 90° C. for 3 hours and then purified by RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile / water containing 0.1% ammonium hydroxide at a flow rate of 30 mL / min) to give the desired product. The enantiomers were separated on a Phenomenex Lux Cellulose C-4 column (5 μM, 21.2×250 mm) eluting with 20% ethanol in hexanes at a flow rate of 18 mL / min to give two enantiomers. The first peak (2.7 mg, 18%) had a retention time of 8.9 min; 21 H 27 LCMS calculated value for ClFN6O2 (M+H) + : m / z = 449.2; Measured value: 449.1. 1 HNMR(DMSO-d6,500MHz)δ8.11(1H,s),7.42(1H,d,J=8.5Hz),7.25(2H,brs),6.21(1H,q,J=7.5Hz),4.28(1H,d,J=4.0Hz),3.82(3H, m),3.62(3H,s),3.55(1H,m),3.05(1H,m),2.97(1H,m),2.55(3H,s),2.28(2H,m),1.70(2H,d,J=7.5Hz),1.00(3H,d,J=6.0Hz)ppm. Second peak retention time 10.0 minutes.

[0282] Example 71 2-(3-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-6-fluoro-2-methoxyphenyl}azetidin-1-yl)ethanol [ka]

[0283] To a mixture of 1-[1-(3-azetidin-3-yl-5-chloro-4-fluoro-2-methoxyphenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine dihydrochloride (19 mg, 0.041 mmol, racemic intermediate from Example 67, Step 1) and triethylamine (28 μL, 0.20 mmol) in methanol (0.1 mL) / acetonitrile (0.1 mL) / tetrahydrofuran (0.1 mL), {[tert-butyl(dimethyl)silyl]oxy}acetaldehyde (39 μL, 0.20 mmol) was added, followed by sodium triacetoxyborohydride (22 mg, 0.10 mmol). The resulting mixture was stirred at room temperature overnight. The mixture was treated with 6.0 M aqueous hydrochloric acid (0.07 mL, 0.4 mmol) at room temperature for 10 min, then purified by RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile / water containing 0.1% ammonium hydroxide at a flow rate of 30 mL / min) to give the desired product (2.5 mg, 13%). The product was isolated as a racemic mixture. 20 H 25 LCMS calculated value for ClFN6O2 (M+H) + : m / z = 435.2; Found: 435.1.

[0284] Example 72. 1-{1-[5-chloro-4-fluoro-2-methoxy-3-(1-oxetan-3-ylazetidin-3-yl)phenyl]ethyl}-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine [ka]

[0285] To a mixture of 1-[1-(3-azetidin-3-yl-5-chloro-4-fluoro-2-methoxyphenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine dihydrochloride (19 mg, 0.041 mmol, racemic intermediate from Example 67, Step 1) and triethylamine (28 μL, 0.20 mmol) in methanol (0.1 mL) / acetonitrile (0.1 mL) / tetrahydrofuran (0.1 mL) was added 37% formaldehyde (15 μL, 0.20 mmol), followed by sodium triacetoxyborohydride (22 mg, 0.10 mmol). The resulting mixture was stirred at room temperature overnight. The mixture was purified by RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile / water containing 0.1% ammonium hydroxide at a flow rate of 30 mL / min) to give the desired product (1.2 mg, 6.3%). The product was isolated as a racemic mixture. 19 H 23 LCMS calculated for ClFNO (M+H) + : m / z = 405.2; Found: 405.1.

[0286] Example 94. 1-{1-[5-chloro-2-ethoxy-3-(1-isopropylazetidin-3-yl)-4-methylphenyl]ethyl}-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine bis(trifluoroacetate) [ka]

[0287] Step 1. Benzyl 3-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-6-methylphenyl}azetidine-1-carboxylate Cyanuric acid chloride (200 mg, 1.1 mmol) was added to N,N-dimethylformamide (0.083 mL, 1.1 mmol) at room temperature. After a white solid formed (approximately 10 min), methylene chloride (5 mL) was added, followed by benzyl 3-[3-chloro-6-ethoxy-5-(1-hydroxyethyl)-2-methylphenyl]azetidine-1-carboxylate (310 mg, 0.77 mmol). After the addition, the resulting mixture was stirred at room temperature overnight. Water was added and then diluted with dichloromethane. The organic phase was washed with saturated NaHCO3 solution, water, and brine, dried over MgSO4, concentrated, and purified on silica gel (eluted with 0-40% EtOAc / hexanes) to give the desired product (140 mg, 43%). 22 H 26 LCMS calculated for Cl2NO3 (M+H) + : m / z = 422.1; Measured value: 422.0.

[0288] A mixture of benzyl 3-[3-chloro-5-(1-chloroethyl)-6-ethoxy-2-methylphenyl]azetidine-1-carboxylate (0.375 g, 0.888 mmol), 3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.16 g, 1.1 mmol), cesium carbonate (0.43 g, 1.3 mmol), and potassium iodide (15 mg, 0.089 mmol) in N,N-dimethylformamide (2.8 mL) was heated at 140° C. for 1 hour. The mixture was diluted with ether and washed with water. The organic layer was concentrated and purified on silica gel (eluting with 0-100% EtOAc in hexanes) to give the desired product (0.24 g, 50%). 28 H 32 LCMS calculated for ClN6O3 (M+H) + : m / z = 535.2; Found: 535.0. The enantiomers were separated on a Phenomenex Lux Cellulose C-2 column (5 μM, 21.2 x 250 mm) eluting with 20% ethanol in hexanes at a flow rate of 18 mL / min and a column load of approximately 4.5 mg / injection, resulting in separation of the two enantiomers. 1st peak retention time: 21.2 min; 2nd peak retention time: 24.6 min.

[0289] Step 2. 1-[1-(3-azetidin-3-yl-5-chloro-2-ethoxy-4-methylphenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine To a mixture of benzyl 3-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-6-methylphenyl}azetidine-1-carboxylate (170 mg, 0.32 mmol, racemic intermediate) and 5% palladium (80 mg) in methanol (12 mL) was added 0.25 M aqueous hydrochloric acid (3.2 mL, 0.79 mmol). The suspension was hydrogenated under balloon pressure of H at room temperature for 2 hours. The suspension was filtered. The filtrate was neutralized with saturated NaHCO solution and extracted with dichloromethane. The combined organic layers were dried over MgSO, filtered, and concentrated to give the desired product (117 mg, 92%). 20 H 26 LCMS calculated for ClNO (M+H) + : m / z = 401.2; Measured value: 401.1.

[0290] Step 3. 1-{1-[5-chloro-2-ethoxy-3-(1-isopropylazetidin-3-yl)-4-methylphenyl]ethyl}-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine bis(trifluoroacetate) Acetone (9.3 μL, 0.13 mmol) was added to 1-[1-(3-azetidin-3-yl-5-chloro-2-ethoxy-4-methylphenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (10.2 mg, 0.0254 mmol) in methanol (0.1 mL) / tetrahydrofuran (0.1 mL) / acetonitrile (0.1 mL), the mixture was stirred at room temperature for 10 minutes, and sodium triacetoxyborohydride (16 mg, 0.076 mmol) was added. The reaction mixture was stirred at room temperature for 4 hours and then purified by RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile / water containing 0.05% TFA at a flow rate of 30 mL / min) to give the desired product (2.3 mg, 22%) as the TFA salt. The product was isolated as a single enantiomer. C 23 H 32 Calculated value for ClNO (M+H) + : m / z = 443.2; Found: 443.1.

[0291] Example 95 2-(3-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-6-methylphenyl}azetidin-1-yl)ethanol bis(trifluoroacetate) [ka]

[0292] To a mixture of 1-[1-(3-azetidin-3-yl-5-chloro-2-ethoxy-4-methylphenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (7.9 mg, 0.020 mmol, racemic intermediate from Example 94, Step 2) in tetrahydrofuran (0.09 mL) / acetonitrile (0.09 mL) / methanol (0.09 mL) was added {[tert-butyl(dimethyl)silyl]oxy}acetaldehyde (19 μL, 0.098 mmol), the mixture was stirred for 10 minutes, and sodium triacetoxyborohydride (12 mg, 0.059 mmol) was added. The resulting mixture was stirred at room temperature for 4 hours and then treated with 6.0 M aqueous hydrochloric acid (30 μL, 0.2 mmol) for 10 minutes. The mixture was purified by RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile / water containing 0.05% TFA at a flow rate of 30 mL / min) to give the desired product as a TFA salt (3.2 mg, 40%). The product was isolated as a racemic mixture. 22 H 30 LCMS calculated for ClN6O2 (M+H) + : m / z = 445.2; Measured value: 445.1.

[0293] Example 96 (2S)-1-(3-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-6-methylphenyl}azetidin-1-yl)propan-2-ol bis(trifluoroacetate) [ka]

[0294] Step 1. Benzyl 3-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-6-methylphenyl}azetidine-1-carboxylate The enantiomers of Example 94, Step 1 were separated on a Phenomenex Lux Cellulose C-2 column (5 μM, 21.2×250 mm) eluting with 20% ethanol in hexanes at a flow rate of 18 mL / min and a column load of approximately 4.5 mg / injection to separate the two enantiomers. 1st peak retention time: 21.2 min; 2nd peak retention time: 24.6 min.

[0295] Step 2. 1-[1-(3-azetidin-3-yl-5-chloro-2-ethoxy-4-methylphenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine Benzyl 3-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-6-methylphenyl}azetidine-1-carboxylate (the chiral intermediate from the first peak in the previous step) was hydrogenated in the presence of 5% palladium as described in Example 94, Step 2, to give the desired chiral product. 20 H 26 LCMS calculated for ClNO (M+H) + : m / z = 401.2; Measured value: 401.1.

[0296] Step 3. (2S)-1-(3-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-6-methylphenyl}azetidin-1-yl)propan-2-ol bis(trifluoroacetate) To a mixture of 1-[1-(3-azetidin-3-yl-5-chloro-2-ethoxy-4-methylphenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (10 mg, 0.02 mmol, chiral intermediate from Step 2) and triethylamine (9 μL, 0.07 mmol) in isopropyl alcohol (0.05 mL) was added (S)-(-)-methyloxirane (4.5 μL, 0.064 mmol). The resulting mixture was stirred at 90 °C overnight, cooled, and purified by RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile / water containing 0.05% TFA at a flow rate of 30 mL / min) to give the desired product (3.4 mg, 34%) as the TFA salt. The product was isolated as a single diastereomer. 23 H 32 LCMS calculated for ClN6O2 (M+H) + : m / z = 459.2; Measured value: 459.1.

[0297] Example 99 (2S)-1-(3-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-6-methylphenyl}azetidin-1-yl)-1-oxopropan-2-ol trifluoroacetate [ka]

[0298] To a mixture of 1-[1-(3-azetidin-3-yl-5-chloro-2-ethoxy-4-methylphenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (9.8 mg, 0.024 mmol, racemic intermediate from Example 94, Step 2), N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (14 mg, 0.037 mmol), and triethylamine (10 μL, 0.073 mmol) in N,N-dimethylformamide (0.15 mL) was added 85% aqueous (2S)-2-hydroxypropanoic acid (3.2 μL, 0.037 mmol). The resulting mixture was stirred at room temperature for 2 hours. The mixture was purified by RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile / water containing 0.05% TFA at a flow rate of 30 mL / min) to give the desired product as trifluoroacetic acid (TFA) salt (2.9 mg, 29%). The product was isolated as a racemic mixture. 23 H 30 LCMS calculated for ClN6O3 (M+H) + : m / z = 473.2; Measured value: 473.1.

[0299] Example 102 (2S)-1-(3-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}azetidin-1-yl)propan-2-ol [ka]

[0300] To a mixture of 1-[1-(3-azetidin-3-yl-5-chloro-2-methoxy-4-methylphenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine dihydrochloride (21 mg, 0.046 mmol) (the chiral intermediate of Example 1, Step 7, Peak 1) and triethylamine (20 μL, 0.1 mmol) in isopropyl alcohol (0.10 mL) was added (S)-(−)-methyloxirane (3.2 μL, 0.046 mmol). The resulting mixture was stirred at 90° C. After 90 minutes, additional (S)-(−)-methyloxirane (6.4 μL) was added and stirred at 90° C. overnight. After cooling, the mixture was diluted with methanol and purified using RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile / water containing 0.1% ammonium hydroxide at a flow rate of 30 mL / min) to give 6 mg (30%) of the product. The product was isolated as a single diastereomer. 22 H 30 LCMS calculated for ClN6O2 (M+H) + : m / z = 445.2; Measured value: 445.2.

[0301] Example 104 2-(3-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}azetidin-1-yl)ethanol [ka]

[0302] To a mixture of 1-[1-(3-azetidin-3-yl-5-chloro-2-methoxy-4-methylphenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine dihydrochloride (20 mg, 0.04 mmol) (chiral intermediate of Example 1, Step 7, Peak 1), {[tert-butyl(dimethyl)silyl]oxy}acetaldehyde (8.3 mg, 0.048 mmol), and triethylamine (19 μL, 0.14 mmol) in methylene chloride (0.3 mL) was added sodium triacetoxyborohydride resin (38 mg, 0.087 mmol). The resulting mixture was stirred at room temperature overnight. The mixture was filtered and concentrated. The crude product was dissolved in tetrahydrofuran (1 mL) and cooled to 0 °C. A 1.0 M solution of tetra-n-butylammonium fluoride in THF (0.44 mL, 0.44 mmol) was added and allowed to warm to room temperature. After 3 hours, the solvent was evaporated. The crude product was purified using RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile / water containing 0.1% ammonium hydroxide at a flow rate of 30 mL / min) to give 8.1 mg (40%) of the desired product. The product was isolated as a single enantiomer. 21 H 28 LCMS calculated for ClN6O2 (M+H) + : m / z = 431.2; Found: 431.3.

[0303] Example 105 (3-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}azetidin-1-yl)acetonitrile [ka]

[0304] To a mixture of 1-[1-(3-azetidin-3-yl-5-chloro-2-methoxy-4-methylphenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine dihydrochloride (16 mg, 0.035 mmol, chiral intermediate of peak 1 in Step 7 of Example 1) and triethylamine (14 μL, 0.10 mmol) in acetonitrile (0.7 mL) was added bromoacetonitrile (2.7 μL, 0.038 mmol). The resulting mixture was stirred at room temperature for 2.5 hours. The mixture was diluted with acetonitrile and purified using RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile / water containing 0.05% TFA at a flow rate of 30 mL / min) to obtain the desired product as a TFA salt. Pure fractions were partially evaporated and then basified by the addition of 1N NaOH. The aqueous mixture was extracted with dichloromethane (2 times). The extracts were dried (MgSO4), filtered, and concentrated. The solid was dried under vacuum to give 6.9 mg (46%) of the desired product. The product was isolated as a single enantiomer. 21 H 25 LCMS calculated for ClNO (M+H) + : m / z = 426.2; Measured value: 426.0.

[0305] Example 108. 1-(1-{5-chloro-2-methoxy-4-methyl-3-[1-(2,2,2-trifluoroethyl)azetidin-3-yl]phenyl}ethyl)-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine [ka]

[0306] A mixture of 1-[1-(3-azetidin-3-yl-5-chloro-2-methoxy-4-methylphenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine dihydrochloride (15 mg, 0.024 mmol, the chiral intermediate of the first peak of Example 1, Step 7), 2,2,2-trifluoroethyl trifluoromethanesulfonate (6.8 mg, 0.029 mmol), and triethylamine (12 μL, 0.085 mmol) in methylene chloride (0.3 mL) was stirred at room temperature over the weekend. The solvent was evaporated, and the crude product was purified using RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile / water containing 0.1% ammonium hydroxide at a flow rate of 30 mL / min) to give 4.5 mg (39%) of the desired product. The product was isolated as a single enantiomer. 21 H 25 LCMS calculated for ClF3N6O (M+H) + : m / z = 469.2; Measured value: 469.1.

[0307] Example 110 (2R)-2-(3-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}azetidin-1-yl)-N-methylpropanamide trifluoroacetate [ka]

[0308] A mixture of 1-[1-(3-azetidin-3-yl-5-chloro-2-methoxy-4-methylphenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine dihydrochloride (26 mg, 0.067 mmol, chiral intermediate of Peak 1 in Example 1, Step 7), (2R)-2-bromopropanoic acid (7.3 μL, 0.081 mmol), and triethylamine (19 μL, 0.13 mmol) in acetonitrile (0.8 mL) was stirred at room temperature overnight. Since the reaction was not complete, it was heated to 50° C. After 4 h, the solvent was evaporated. To the crude residue was added methylammonium chloride (4.5 mg, 0.067 mmol), N,N-dimethylformamide (0.2 mL), triethylamine (19 μL, 0.13 mmol), and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (45 mg, 0.10 mmol). The resulting mixture was stirred at room temperature overnight. The reaction mixture was added to a vial containing saturated NaHCO3 and extracted with EtOAc (twice). The organic layer was dried (MgSO4), filtered, and concentrated. The crude product was purified using RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile / water containing 0.05% TFA at a flow rate of 30 mL / min) to afford 1.4 mg (3.6%) of the desired product as the TFA salt. The product was isolated as a single diastereomer. 23 H 31 LCMS calculated for ClN7O2 (M+H) + : m / z = 472.2; Measured value: 472.2.

[0309] Example 113 2-(3-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}azetidin-1-yl)-3,3,3-trifluoropropan-1-ol [ka]

[0310] To a mixture of 1-[1-(3-azetidin-3-yl-5-chloro-2-methoxy-4-methylphenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine dihydrochloride (20 mg, 0.04 mmol, chiral intermediate from Peak 1 in Example 1, Step 7) and triethylamine (19 μL, 0.13 mmol) in acetonitrile (0.6 mL) was added 2-bromo-3,3,3-trifluoropropan-1-ol (from Synquest Labs, 9.2 mg, 0.048 mmol). N,N-Dimethylformamide (0.3 mL) was added, resulting in a clear solution, which was stirred at 70 °C overnight. The mixture was diluted with water and purified using RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile / water containing 0.1% ammonium hydroxide at a flow rate of 30 mL / min) to give 6.6 mg (30%) of the desired product. The product was isolated as a mixture of diastereomers. 22 H 27 LCMS calculated for ClF3N6O2 (M+H) + : m / z = 499.2; Measured value: 499.1.

[0311] Example 115 (2R)-3-(3-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}azetidin-1-yl)-1,1,1-trifluoropropan-2-ol [ka]

[0312] A mixture of 1-[1-(3-azetidin-3-yl-5-chloro-2-methoxy-4-methylphenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine dihydrochloride (20 mg, 0.044 mmol, chiral intermediate of peak 1 in Step 7 of Example 1), (2R)-2-(trifluoromethyl)oxirane (9.4 μL, 0.11 mmol), and triethylamine (18 μL, 0.13 mmol) in ethanol (0.3 mL) was heated in a microwave at 120° C. for 25 minutes. The mixture was diluted with MeOH and purified by RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile / water containing 0.1% ammonium hydroxide at a flow rate of 30 mL / min) to give 6.2 mg (28%) of the desired product. The product was isolated as a single enantiomer. 22 H 27 LCMS calculated for ClF3N6O2 (M+H) + : m / z = 499.2; Measured value: 499.1.

[0313] Example 118 (2S)-1-(3-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}azetidin-1-yl)-1-oxopropan-2-ol [ka]

[0314] To a mixture of 1-[1-(3-azetidin-3-yl-5-chloro-2-methoxy-4-methylphenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine dihydrochloride (15 mg, 0.033 mmol, chiral intermediate of Peak 1 in Step 7 of Example 1), (2S)-2-hydroxypropanoic acid (4.3 μL, 0.049 mmol) (L-lactic acid, 85% aqueous solution), and triethylamine (14 μL, 0.098 mmol) in N,N-dimethylformamide (0.2 mL) was added N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (19 mg, 0.049 mmol). The resulting mixture was stirred at room temperature overnight. The mixture was diluted with MeOH and purified using RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile / water containing 0.1% ammonium hydroxide at a flow rate of 30 mL / min) to give 3.0 mg (20%) of the desired product. The product was isolated as a single enantiomer. 22 H 28 LCMS calculated for ClN6O3 (M+H) + : m / z = 459.2; Found: 459.2.

[0315] Example 121 (2R)-1-(3-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}azetidin-1-yl)-1-oxopropan-2-ol trifluoroacetate [ka]

[0316] This compound was synthesized using a method similar to that described in Example 118 (starting from the chiral material in Example 1, Step 7, peak 1), using (R)-2-hydroxypropanoic acid instead of (2S)-2-hydroxypropanoic acid (4.3 μL, 0.049 mmol) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate instead of N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate. The crude product was purified using RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile / water containing 0.05% TFA at a flow rate of 30 mL / min) to give the desired product as the TFA salt. The product was isolated as a single enantiomer. 22 H 28 LCMS calculated for ClN6O3 (M+H) + : m / z = 459.2; Found: 459.2.

[0317] Example 139. Enantiomers of 1-{1-[5-chloro-2-ethoxy-4-fluoro-3-(1-isopropylazetidin-3-yl)phenyl]ethyl}-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine [ka]

[0318] Step 1. 1-(5-chloro-2-ethoxy-4-fluoro-3-iodophenyl)ethanone This compound was synthesized according to the method of Example 13, Step 3, using 1-(5-chloro-4-fluoro-2-hydroxy-3-iodophenyl)ethanone and iodoethane as starting materials. 10 H 10 LCMS calculated for ClFIO2 (M+H) + : m / z = 342.9; Measured value: 342.9.

[0319] Step 2. tert-Butyl 3-(3-acetyl-5-chloro-2-ethoxy-6-fluorophenyl)azetidine-1-carboxylate A round-bottom flask equipped with a magnetic stir bar and a rubber septum was charged with lithium chloride (3.9 g, 91 mmol). The flask was heated under high vacuum at 140° C. for 10 minutes, cooled to room temperature, and then filled with nitrogen. Zinc (6.0 g, 91 mmol) was added, and the flask was heated under high vacuum at 140° C. for 10 minutes, cooled to room temperature, and then filled with nitrogen. Tetrahydrofuran (THF) (38 mL) and 1,2-dibromoethane (233 μL, 2.70 mmol) were added via syringe. The mixture was heated at 60° C. for 10 minutes and then cooled to room temperature. A solution of chlorotrimethylsilane (68 μL, 0.54 mmol) and iodine (69 mg, 0.27 mmol) in THF (1 mL) was added, and the resulting mixture was stirred at 60° C. for 10 minutes and then cooled to room temperature. A solution of tert-butyl 3-iodoazetidine-1-carboxylate (12.17 g, 42.99 mmol) in THF (10 mL) was then added, and the mixture was stirred at 40° C. for 1 hour and at room temperature for 1 hour. A separate flask was charged with 1-(5-chloro-2-ethoxy-4-fluoro-3-iodophenyl)ethanone (13.0 g, 38.0 mmol), palladium acetate (170 mg, 0.76 mmol), 2'-(dicyclohexylphosphino)-N,N,N',N'-tetramethylbiphenyl-2,6-diamine (660 mg, 1.5 mmol), and toluene (35 mL), evacuated under high vacuum, and backfilled with nitrogen. The mixture was cooled to 0 °C, and the zinc reagent prepared above was added slowly via syringe. After the addition, the reaction was heated at 50 °C overnight. The reaction solution was partitioned between EtOAc and saturated NH4Cl solution. The layers were separated, and the aqueous layer was further extracted with EtOAc (twice). The combined organic layers were washed with water, brine, dried over MgSO4, and concentrated. The crude mixture was purified on a silica gel column to give the desired product as an orange oil (6.3 g, 45%). 18 H 23 LCMS calculated value for ClFNO4Na (M+Na) + : m / z = 394.1; Found: 394.1.

[0320] Step 3. tert-Butyl 3-[3-chloro-6-ethoxy-2-fluoro-5-(1-hydroxyethyl)phenyl]azetidine-1-carboxylate This compound was synthesized according to the method of Example 13, Step 5, using tert-butyl 3-(3-acetyl-5-chloro-2-ethoxy-6-fluorophenyl)azetidine-1-carboxylate and sodium tetrahydroborate as starting materials. 18 H 25 LCMS calculated value for ClFNO4Na (M+Na) + : m / z = 396.1; Found: 396.1.

[0321] Step 4. tert-Butyl 3-[3-chloro-5-(1-chloroethyl)-6-ethoxy-2-fluorophenyl]azetidine-1-carboxylate This compound was synthesized according to the method of Example 13, Step 6, using tert-butyl 3-[3-chloro-6-ethoxy-2-fluoro-5-(1-hydroxyethyl)phenyl]azetidine-1-carboxylate (racemic) and cyanuric acid chloride as starting materials.

[0322] Step 5. tert-Butyl 3-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-6-fluorophenyl}azetidine-1-carboxylate To a mixture of 3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (1.10 g, 7.37 mmol), cesium carbonate (3.2 g, 10 mmol), and potassium iodide (111 mg, 0.670 mmol) in DMF (20 mL) was added tert-butyl 3-[3-chloro-5-(1-chloroethyl)-6-ethoxy-2-fluorophenyl]azetidine-1-carboxylate (2.63 g, 6.70 mmol), and the mixture was stirred at 90 °C for 3 hours. The solvent was removed in vacuo. The residue was diluted with ethyl acetate and water. The aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with water, brine, dried over NaSO, filtered, and concentrated. The residue was purified on a silica gel column (eluted with 100% ethyl acetate) to give the desired product (2.15 g, 63%) as a foam. C 24 H 31 LCMS calculated value for ClFN6O3 (M+H) + : m / z = 505.2; Found: 505.2.

[0323] Step 6. 1-[1-(3-azetidin-3-yl-5-chloro-2-ethoxy-4-fluorophenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine dihydrochloride To a solution of tert-butyl 3-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-6-fluorophenyl}azetidine-1-carboxylate (275 mg, 0.544 mmol) in dichloromethane (2.4 mL) was added 4.0 M hydrochloric acid in dioxane (1.1 mL, 4.4 mmol). The reaction solution was stirred at room temperature for 6 hours. The solvent was removed under reduced pressure to give the desired product (250 mg, 96%) as a white solid. 19 H 23 LCMS calculated for ClFNO (M+H) + : m / z = 405.2; Found: 405.1.

[0324] Step 7. 1-{1-[5-chloro-2-ethoxy-4-fluoro-3-(1-isopropylazetidin-3-yl)phenyl]ethyl}-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine To a mixture of 1-[1-(3-azetidin-3-yl-5-chloro-2-ethoxy-4-fluorophenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine dihydrochloride (49 mg, 0.10 mmol), acetone (8.28 μL, 0.113 mmol), and triethylamine (44.3 μL, 0.318 mmol) in dichloromethane (0.67 mL) was added sodium triacetoxyborohydride resin (89 mg, 0.20 mmol). The resulting mixture was stirred at room temperature overnight. The mixture was filtered, concentrated, and then purified by preparative LCMS (XBridge C18 column, eluting with a gradient of acetonitrile / water containing 0.05% TFA at a flow rate of 60 mL / min) to give the racemic product. LCMS: Found m / z = 447.2 (M+H) + The racemic mixture was separated by chiral HPLC (Column IA, eluting with 5% ethanol / 95% hexanes at a flow rate of 18 mL / min) to give two peaks (Isomer 1: 9.5 mg, 21%; Isomer 2: 9.2 mg, 20%). Isomer 1 (eluting first, retention time: 4.4 min): 1 HNMR (400MHz, DMSO-d6): δ8.10(s,1H),7.45(d,1H),6.21(m,1H),3.70(m,5H),2. 91(m,2H),2.53(s,3H),2.17(m,1H),1.66(d,3H),1.31(t,3H),0.81(m,6H)ppm;C 22 H 29 LCMS calculated for ClFNO (M+H) + : m / z = 447.2; Found: 447.2. Isomer 2 (second elution, retention time: 19.5 min): C 22 H 29 LCMS calculated for ClFNO (M+H) + : m / z = 447.2; Found: 447.2.

[0325] Example 140. 1-(3-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-6-fluorophenyl}azetidin-1-yl)-2-methylpropan-2-ol [ka]

[0326] To a mixture of 1-[1-(3-azetidin-3-yl-5-chloro-2-ethoxy-4-fluorophenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine dihydrochloride (20 mg, 0.042 mmol, racemic intermediate of Example 139, Step 6) and triethylamine (18 μL, 0.12 mmol) in ethanol (1 mL) was added 2,2-dimethyl-oxirane (6.98 μL, 0.0837 mmol). The resulting mixture was heated at 120 °C in a microwave reactor for 45 minutes. The reaction was diluted with methanol and purified by RP-HPLC (XBridge C18 column, eluted with a gradient of acetonitrile / water containing 0.1% ammonium hydroxide at a flow rate of 30 mL / min) to give the desired product (3.4 mg, 17%) as a white solid. The product was isolated as a racemic mixture. C 23 H 31 LCMS calculated value for ClFN6O2 (M+H) + : m / z = 477.2; Measured value: 477.3.

[0327] Example 141. 1-(1-{5-chloro-2-ethoxy-4-fluoro-3-[1-(2,2,2-trifluoroethyl)azetidin-3-yl]phenyl}ethyl)-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine [ka]

[0328] To a mixture of 1-[1-(3-azetidin-3-yl-5-chloro-2-ethoxy-4-fluorophenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine dihydrochloride (19 mg, 0.040 mmol, racemic intermediate of Example 139, Step 6) and triethylamine (20 μL, 0.14 mmol) in dichloromethane (0.5 mL) was added 2,2,2-trifluoroethyl trifluoromethanesulfonic acid (ester) (11 mg, 0.048 mmol). The resulting mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure, and the crude mixture was purified by RP-HPLC (XBridge C18 column, eluted with a gradient of acetonitrile / water containing 0.1% ammonium hydroxide at a flow rate of 30 mL / min) to give the desired product (3.8 mg, 19%). The product was isolated as a racemic mixture. 21 H 24 LCMS calculated for ClF4N6O (M+H) + : m / z = 487.2; Measured value: 487.1.

[0329] Example 149 (2S)-1-(3-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-6-fluorophenyl}azetidin-1-yl)propan-2-ol [ka]

[0330] Step 1. Enantiomers of tert-butyl 3-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-6-fluorophenyl}azetidine-1-carboxylate The racemic mixture was separated by chiral HPLC (Column IA, eluting with 5% ethanol / 95% hexanes at a flow rate of 18 mL / min) to give two peaks: Isomer 1 (eluting first): retention time: 16.8 min; 24 H 31 ClFN6O3(M+H) +m / z = 505.2; Found: 505.2; Isomer 2 (second eluting): Retention time: 19.5 min; C 24 H 31 LCMS calculated value for ClFN6O3 (M+H) + : m / z = 505.2; Found: 505.2.

[0331] Step 2. 1-[1-(3-azetidin-3-yl-5-chloro-2-ethoxy-4-fluorophenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine dihydrochloride This compound was synthesized using a method similar to Step 6 of Example 139, starting with tert-butyl 3-{3-[(1S)-1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-6-fluorophenyl}azetidine-1-carboxylate (first peak in chiral separation). 19 H 23 ClFNO(M+H) + : m / z = 405.2; Found: 405.1.

[0332] Step 3. (2S)-1-(3-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-6-fluorophenyl}azetidin-1-yl)propan-2-ol To a mixture of 1-[1-(3-azetidin-3-yl-5-chloro-2-ethoxy-4-fluorophenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine dihydrochloride (46 mg, 0.11 mmol) (from isomer 1) and triethylamine (50 μL, 0.4 mmol) in isopropyl alcohol (0.3 mL) was added (S)-(−)-methyloxirane (16 μL, 0.23 mmol). The resulting mixture was stirred at 90° C. for 3 hours. After cooling, the mixture was diluted with acetonitrile and purified by RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile / water containing 0.1% ammonium hydroxide at a flow rate of 30 mL / min) to give the desired product (12 mg, 23%). The product was isolated as a single diastereomer. 1 HNMR(400MHz,DMSO-d6):δ8.05(s,1H),7.38(d,1H),6.15(m,1H),4.26(d,1H),3.76-3.60( m,6H),2.99(m,2H),2.48(s,3H),2.22(m,2H),1.62(d,3H),1.25(t,3H),0.93(d,3H)ppm; 22 H 29 LCMS calculated value for ClFN6O2 (M+H) + : m / z = 463.2; Measured value: 463.2.

[0333] Example 156 (2R)-2-(3-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}azetidin-1-yl)propan-1-ol [ka]

[0334] Step 1. (2S)-2-bromopropanoic acid methyl ester DMF (28 μL, 0.36 mmol) was added to a mixture of (2S)-2-bromopropanoic acid (0.552 g, 3.61 mmol) and oxalyl chloride (0.61 mL, 7.2 mmol) in dichloromethane (4.6 mL) at 0° C. The reaction mixture was stirred at room temperature overnight. The solvent was removed in vacuo. The residue was dissolved in dichloromethane and treated with methanol (1.5 mL, 36 mmol) and pyridine (0.44 mL, 5.4 mmol). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with saturated sodium bicarbonate solution, washed with brine, dried over NaSO, filtered, and concentrated to give the desired product (0.51 g, 85%).

[0335] Step 2. (2R)-2-(3-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}azetidin-1-yl)propanoate methyl To a solution of 1-[1-(3-azetidin-3-yl-5-chloro-2-methoxy-4-methylphenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine hydrochloride (20.1 mg, 0.0475 mmol, chiral intermediate of Example 1, Step 7) in acetonitrile (1 mL) was added triethylamine (23 μL, 0.17 mmol) and (2S)-2-bromomethylpropanoate (9.5 mg, 0.057 mmol). The reaction solution was stirred at room temperature for 4 hours. The solvent was removed to give the desired product (6.2 mg, 28%). 23 H 30 LCMS calculated for ClN6O3 (M+H) + : m / z = 473.2; Measured value: 473.3.

[0336] Step 3. (2R)-2-(3-{3-[(1S)-1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}azetidin-1-yl)propan-1-ol A solution of methyl (2R)-2-(3-{3-[(1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}azetidin-1-yl)propanoate (6.2 mg, 0.013 mmol) in dichloromethane (0.5 mL) was treated with 1.0 M diisobutylaluminum hydride in toluene (0.1 mL, 0.1 mmol) at 0° C. for 3 hours. The reaction was quenched with methanol and purified by preparative RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile / water containing 0.1% ammonium hydroxide at a flow rate of 30 mL / min) to give the desired product (0.8 mg, 14%). The product was isolated as a single diastereomer. 22 H 30 LCMS calculated for ClN6O2 (M+H) + : m / z = 445.2; Measured value: 445.1.

[0337] Example 158. 1-(3-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}azetidin-1-yl)-2-methylpropan-2-ol [ka]

[0338] This compound was prepared using a method similar to Example 140, starting with 1-[1-(3-azetidin-3-yl-5-chloro-2-methoxy-4-methylphenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine hydrochloride (chiral intermediate from Example 1, Step 7) and oxirane, 2,2-dimethyl-. The product was isolated as a single enantiomer. 23 H 32 LCMS calculated for ClN6O2 (M+H) + : m / z = 459.2; Measured value: 459.1 1HNMR(300MHz,DMSO-d6):δ 8.04(s,1H),7.23(bs,2H),7.16(s,1H),6.14(m,1H),3.96(s,1H),3.85(m,3H),3.45(s,3H),2 .94(m,1H),2.80(m,1H),2.49(s,3H),2.14(s,2H),2.00(s,3H),1.63(d,3H),0.98(s,6H)ppm.

[0339] Example 159. (2R)-2-(3-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}azetidin-1-yl)-N,N-dimethylpropanamide [ka]

[0340] Step 1. (2R)-2-(3-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}azetidin-1-yl)propanoic acid To a solution of methyl (2R)-2-(3-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}azetidin-1-yl)propanoate (chiral intermediate of Example 156, Step 2) (13 mg, 0.027 mmol) in acetonitrile (0.6 mL) and water (0.2 mL) was added lithium hydroxide (2.4 mg, 0.10 mmol). The reaction mixture was stirred at room temperature overnight. The reaction solution was diluted with ethyl acetate and 1 M HCl solution. The organic layer was separated, dried over Na2SO4, filtered, and concentrated to give the desired product (10.2 mg, 83%). C 22 H 28 LCMS calculated for ClN6O3 (M+H) + : m / z = 459.2; Measured value: 459.1.

[0341] Step 2. (2R)-2-(3-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}azetidin-1-yl)-N,N-dimethylpropanamide To a solution of (2R)-2-(3-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}azetidin-1-yl)propanoic acid (4 mg, 0.009 mmol) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (4 mg, 0.009 mmol) in DMF (0.3 mL) was added triethylamine (4 μL, 0.03 mmol) and dimethylamine hydrochloride (0.9 mg, 0.01 mmol) at room temperature. The reaction mixture was stirred for 1 h, then diluted with methanol and purified by preparative RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile / water containing 0.1% ammonium hydroxide at a flow rate of 30 mL / min) to give the desired product (2.7 mg, 63%). The product was isolated as a single diastereomer. 24 H 33 LCMS calculated for ClN7O2 (M+H) + : m / z = 486.2; Measured value: 486.1. 1 H NMR (300 MHz, DMSO-d): δ 8.09(s,1H),7.23(s,1H),6.18(m,1H),3.78(m,3H),3.50(s,3H),3.01(s,3H),3.0 -2.9(m,3H),2.77(s,3H),2.54(s,3H),2.06(s,3H),1.67(d,3H),0.98(d,3H)ppm.

[0342] Example 161. [1-(3-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}azetidin-1-yl)cyclobutyl]acetonitrile [ka]

[0343] To a solution of 1-[(1-(3-azetidin-3-yl-5-chloro-2-methoxy-4-methylphenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine dihydrochloride (10 mg, 0.022 mmol, chiral intermediate from Example 1, Step 7) in acetonitrile (0.1 mL) was added cyclobutylideneacetonitrile (4.1 mg, 0.044 mmol) followed by 1,8-diazabicyclo[5.4.0]undec-7-ene (13 μL, 0.087 mmol). The resulting mixture was stirred at room temperature overnight. The reaction mixture was diluted with acetonitrile and purified by preparative RP-HPLC (XBridge Purification on a C18 column (eluting with a gradient of acetonitrile / water containing 0.1% ammonium hydroxide at a flow rate of 30 mL / min) gave the desired product (4.3 mg, 41%). The product was isolated as a single enantiomer. 25 H 31 LCMS calculated for ClNO (M+H) + : m / z = 480.2; Measured value: 480.0.

[0344] Example 163. 1-{1-[5-chloro-2-methoxy-4-methyl-3-(1-methylpiperidin-4-yl)phenyl]ethyl}-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine [ka]

[0345] Step 1. tert-Butyl 4-(3-acetyl-5-chloro-2-methoxy-6-methylphenyl)piperidine-1-carboxylate This compound was synthesized using a method similar to Example 139, Step 2, using 1-(5-chloro-3-iodo-2-methoxy-4-methylphenyl)ethanone and tert-butyl 4-iodopiperidine-1-carboxylate as starting materials. 20 H 28 LCMS calculated value for ClNO4Na (M+Na) +: m / z = 404.1; Found: 404.1.

[0346] Step 2. tert-Butyl 4-[3-chloro-5-(1-hydroxyethyl)-6-methoxy-2-methylphenyl]piperidine-1-carboxylate This compound was synthesized using the method of Example 13, Step 5, using tert-butyl 4-(3-acetyl-5-chloro-2-methoxy-6-methylphenyl)piperidine-1-carboxylate and sodium tetrahydroborate as starting materials. 20 H 30 LCMS calculated value for ClNO4Na (M+Na) + : m / z = 406.1; Found: 406.1.

[0347] Step 3. tert-Butyl 4-[3-chloro-5-(1-chloroethyl)-6-methoxy-2-methylphenyl]piperidine-1-carboxylate This compound was synthesized using the method of Example 13, Step 6, using tert-butyl 4-[3-chloro-5-(1-hydroxyethyl)-6-methoxy-2-methylphenyl]piperidine-1-carboxylate (racemic) and cyanuric acid chloride as starting materials. 1 HNMR(400MHz,CDCl3):δ 7.44(s,1H),5.46(m,1H),4.23(bs,2H),3.73(s,3H),3.29(bs,1H),2.78(bs,2) H),2.40(s,3H),2.27-2.09(m,2H),1.78(d,3H),1.63(m,2H),1.43(s,9H)ppm.

[0348] Step 4. tert-Butyl 4-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}piperidine-1-carboxylate This compound was synthesized using the method of Example 139, Step 5, using tert-butyl 4-[3-chloro-5-(1-chloroethyl)-6-methoxy-2-methylphenyl]piperidine-1-carboxylate and 3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine as starting materials. 26 H 36 LCMS calculated for ClN6O3 (M+H) + : m / z = 515.3; Measured value: 515.2.

[0349] Step 5. 1-[1-(5-chloro-2-methoxy-4-methyl-3-piperidin-4-ylphenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine dihydrochloride This compound was synthesized using the method of Example 139, Step 6, using tert-butyl 4-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}piperidine-1-carboxylate as the starting material. 21 H 28 LCMS calculated for ClNO (M+H) + : m / z = 415.2; Found: 415.2.

[0350] Step 6. 1-{1-[5-chloro-2-methoxy-4-methyl-3-(1-methylpiperidin-4-yl)phenyl]ethyl}-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine This compound was synthesized using the method of Example 139, Step 7, starting with 1-[1-(5-chloro-2-methoxy-4-methyl-3-piperidin-4-ylphenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine dihydrochloride and formaldehyde. The product was isolated as a racemic mixture. 22 H 30 LCMS calculated for ClNO (M+H) + : m / z = 429.2; Measured value: 429.1.

[0351] Example 164. 1-(4-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}piperidin-1-yl)-2-methylpropan-2-ol [ka]

[0352] This compound was synthesized using a method similar to that described in Example 140, starting with 1-[1-(5-chloro-2-methoxy-4-methyl-3-piperidin-4-ylphenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine dihydrochloride (racemic intermediate of Example 163, Step 5) and oxirane, 2,2-dimethyl-. The product was isolated as a racemic mixture. 25 H 36 LCMS calculated for ClN6O2 (M+H) + : m / z = 487.3; Measured value: 487.3. 1 HNMR(300MHz,DMSO-d6):δ8.05(s,1H),,7.24(bs,2H),7.22(s,1H),6.16(m,1H),4.01(bs,1H),3.67(s,3 H),2.97(m,3H),2.49(s,3H),2.32(s,3H),2.15-2.04(m,6H),1.63(d,3H),1.40(m,2H),1.03(s,6H)ppm.

[0353] Example 166. 3-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}cyclobutanol trifluoroacetate [ka]

[0354] Step 1. 1-(5-chloro-2-methoxy-4-methyl-3-vinylphenyl)ethanone A mixture of 1-(5-chloro-3-iodo-2-methoxy-4-methylphenyl)ethanone (1.0 g, 3.2 mmol, from Example 1, Step 2), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (0.66 mL, 3.9 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (1:1) (0.26 g, 0.32 mmol), and potassium carbonate (1.3 g, 9.4 mmol) in 1,4-dioxane (10 mL) and water (5 mL) was degassed with N and heated at 80° C. overnight. After cooling to room temperature, the reaction mixture was diluted with water and ethyl acetate. The organic layer was washed with brine, dried over MgSO4, concentrated, and purified on a silica gel column (eluted with 0-10% EtOAc in hexanes) to give the desired product (0.60 g, 82%). 12 H 14 LCMS calculated for ClO2 (M+H) + : m / z = 225.1; Measured value: 225.1.

[0355] Step 2. 3-(3-acetyl-5-chloro-2-methoxy-6-methylphenyl)cyclobutanone To a solution of 1-(5-chloro-2-methoxy-4-methyl-3-vinylphenyl)ethanone (530 mg, 2.4 mmol) in ether (10 mL) was added copper zinc (1.8 g, 14 mmol). The reaction mixture was heated to 40 °C, and a solution of trichloroacetyl chloride (1.4 mL, 13 mmol) and phosphoryl chloride (1.2 mL, 13 mmol) in 1,2-dimethoxyethane (3 mL) was slowly added over 2 h. After the addition, the reaction mixture was stirred under reflux overnight. The reaction was quenched with saturated NaHCO3 solution and diluted with ether. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated. The residue and zinc (0.31 g, 4.7 mmol) in acetic acid (10 mL) were stirred at room temperature for 2 h and then refluxed overnight. Another portion of zinc was added and refluxed for an additional 4 h. The mixture was diluted with water and extracted with ether. The organic phase was washed successively with saturated NaHCO3 solution, water, and brine, then dried over MgSO4 and concentrated. The crude material was purified by flash chromatography (eluting with 0-30% ethyl acetate in hexanes) to give the desired product (0.17 g, 27%). 14 H 16 LCMS calculated for ClO3 (M+H) + : m / z = 267.1; Measured value: 267.0.

[0356] Step 3. 3-[3-chloro-5-(1-hydroxyethyl)-6-methoxy-2-methylphenyl]cyclobutanol This compound was synthesized according to the method of Example 13, Step 5, using 3-(3-acetyl-5-chloro-2-methoxy-6-methylphenyl)cyclobutanone and sodium tetrahydroborate as starting materials. 14 H 19 LCMS calculated value for ClO3Na (M+Na) + : m / z = 293.1; Measured value: 293.1.

[0357] Step 4. 3-[3-chloro-5-(1-chloroethyl)-6-methoxy-2-methylphenyl]cyclobutanol To a solution of 3-[3-chloro-5-(1-hydroxyethyl)-6-methoxy-2-methylphenyl]cyclobutanol (170 mg, 0.628 mmol) in dimethyl sulfoxide (1 mL) was added cyanuric acid chloride (64 mg, 0.34 mmol). After stirring overnight, the reaction mixture was diluted with ether and water. The aqueous layer was extracted once with ethyl acetate. The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated. The crude product was purified on a silica gel column to give the desired product (39.6 mg, 22%). C 14 H 18 LCMS calculated value of ClO2 (M-Cl) + : m / z = 253.1; Measured value: 253.2.

[0358] Step 5. 3-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}cyclobutanol trifluoroacetate This compound was synthesized according to the method of Example 139, Step 5, using 3-[3-chloro-5-(1-chloroethyl)-6-methoxy-2-methylphenyl]cyclobutanol and 3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine as starting materials. The product was isolated as a racemic mixture. 20 H 25 LCMS calculated for ClNO2 (M+H) + : m / z = 402.2; Found: 402.2.

[0359] Example 167 5-(3-(1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-chloro-2-methoxy-6-methylphenyl)-N,N-dimethylpicolinamide bis(2,2,2-trifluoroacetate) [ka]

[0360] Step 1. 1-(3-bromo-5-chloro-2-methoxy-4-methylphenyl)ethanone To a stirred solution of 1-(5-chloro-2-methoxy-4-methylphenyl)ethanone (5.00 g, 25.2 mmol, from Oakwood) in acetic acid (100 mL) was added N-bromosuccinimide (4.93 g, 27.7 mmol), and the resulting mixture was heated at 100° C. for 18 hours. After cooling to ambient temperature, the reaction mixture was concentrated in vacuo, then neutralized with saturated sodium bicarbonate, and the insoluble succinimide was removed by filtration. The filtrate was extracted with EtOAc. The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated to dryness under reduced pressure. The residue was purified on silica gel, eluting with 0-50% EtOAc in hexanes, to give the desired product (2.66 g, 38%). 10 H 11 LCMS calculated for BrClO2 (M+H) + : m / z = 277.0; Measured value: 277.0. 1 HNMR (DMSO-d6,300MHz):d7.70(1H,s),3.77(3H,s),2.57(3H,s),2.50(3H,s)ppm.

[0361] Step 2. 1-(3-bromo-5-chloro-2-methoxy-4-methylphenyl)ethanol Sodium tetrahydroborate (0.31 g, 8.1 mmol) was added to a mixture of 1-(3-bromo-5-chloro-2-methoxy-4-methylphenyl)ethanone (1.5 g, 5.4 mmol) in methanol (25 mL) at 0° C., and the resulting reaction mixture was stirred at room temperature for 1 h. The solvent was removed, and the resulting residue was diluted with ethyl acetate, washed with saturated NaHCO, water, and brine, then dried over NaSO, filtered, and concentrated. The crude product was purified by silica gel chromatography, eluting with 0 to 40% EtOAc in hexanes, to give the desired product (0.30 g, 90%).

[0362] Step 3. 3-Bromo-1-chloro-5-(1-chloroethyl)-4-methoxy-2-methylbenzene A mixture of cyanuric chloride (1.7 g, 9.2 mmol) and N,N-dimethylformamide (710 μL, 9.2 mmol) was stirred at room temperature for 10 minutes, then a solution of 1-(3-bromo-5-chloro-2-methoxy-4-methylphenyl)ethanol (from Example 16, Step 1) (1.72 g, 6.15 mmol) in methylene chloride (34 mL) was added, and the reaction was stirred at room temperature overnight. The mixture was diluted with methylene chloride, washed with saturated NaHCO, water, brine, dried over NaSO, filtered, and concentrated. The crude product was purified by silica gel chromatography, eluting with 0 to 10% EtOAc in hexanes, to give the desired product (1.01 g, 60%).

[0363] Step 4. 1-[1-(3-bromo-5-chloro-2-methoxy-4-methylphenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine A mixture of 3-bromo-1-chloro-5-(1-chloroethyl)-4-methoxy-2-methylbenzene (150 mg, 0.503 mmol), 3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (110 mg, 0.76 mmol, ACES Pharma Product List, Item No. 47024), potassium iodide (9.0 mg, 0.05 mmol), and cesium carbonate (330 mg, 1.0 mmol) in N,N-dimethylformamide (4 mL) was stirred at 140 °C for 1 h. The mixture was diluted with methylene chloride, washed with saturated NaHCO, water, brine, dried over NaSO, filtered, and concentrated. The crude product was purified by silica gel chromatography, eluting with 0-70% EtOAc in CHCl to give the desired product (103 mg, 50%). 16 H 18 LCMS calculated for BrClNO (M+H) +: m / z = 410.0; Found: 410.2. The racemic product was applied to a Phenomenex Lux-Cellulose 1 column (21.1 x 250 mm, 5 micron particle size) eluting with 5% ethanol in hexanes at a flow rate of 18 mL / min, approximately 13 mg / injection, to give two enantiomers. Peak 1, retention time: 12.35 min; Peak 2, retention time: 14.98 min.

[0364] Step 5. 5-(3-(1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-chloro-2-methoxy-6-methylphenyl)-N,N-dimethylpicolinamide bis(2,2,2-trifluoroacetate) 1-[1-(3-bromo-5-chloro-2-methoxy-4-methylphenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (25 mg, 0.061 mmol) (first peak from the previous chiral separation step), N,N-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-carboxamide (25 mg, 0.091 mmol, from PepTech Corp., Encyclopedia of Amino Acid Analogs and Boronic Acids) in acetonitrile (0.8 mL) / water (0.3 mL). A mixture of 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (1:1) (9.9 mg, 0.012 mmol) was degassed with N2 and then stirred at 95 °C for 2 h. After cooling to room temperature, the mixture was filtered and the filtrate was purified by RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile / water containing 0.05% trifluoroacetic acid at a flow rate of 30 mL / min) to give the desired product as the bis-TFA salt (2.9 mg, 6.7%). The product was isolated as a single enantiomer. 24 H 27 LCMS calculated for ClN7O2 (M+H) + : m / z = 480.2; Measured value: 480.2. 1HNMR(500MHz,DMSO-d6)δ:8.78(2H,brs),8.48(1H,m),8.36(1H,s),7.86(1H,brs),7.65(1H,brs),7.58(1H,s),6 .33(1H,q,J=7.0Hz),3.19(3H,s),3.03(3H,s),2.97(3H,s),2.62(3H,s),2.06(3H,s),1.81(3H,d,J=7.0Hz)ppm.

[0365] Example 183. 1-[1-(5-chloro-3-{1-[2-(dimethylamino)ethyl]-1H-pyrazol-4-yl}-2-methoxy-4-methylphenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine [ka]

[0366] Step 1. 1-(2-chloroethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole A mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.39 g, 2.0 mmol), 1-bromo-2-chloroethane (0.3 mL, 3 mmol), and cesium carbonate (1.3 g, 4.0 mmol) in acetonitrile (6 mL) was stirred at 75° C. for 5 hours. The mixture was diluted with ethyl acetate, washed with saturated NaHCO, water, brine, dried over NaSO, filtered, concentrated, and the product (0.45 g, 88%) was purified by chromatography eluting with hexanes / EtOAc (up to 30% EtOAc). 11 H 19 LCMS calculated for BClN2O2 (M+H) + : m / z = 257.1; Measured value: 257.0.

[0367] Step 2. N,N-dimethyl-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]ethanamine A mixture of 1-(2-chloroethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.10 g, 0.39 mmol), sodium iodide (58 mg, 0.39 mmol), and 2.0 M dimethylamine in THF (1.0 mL, 2.0 mmol) in N,N-dimethylformamide (0.5 mL) was stirred at 80° C. overnight. The solvent was removed to give the desired product, which was used in the next step. 13 H 25 LCMS calculated value for BN3O2 (M+H) + : m / z = 266.2; Measured value: 266.3.

[0368] Step 3. 1-[1-(5-chloro-3-{1-[2-(dimethylamino)ethyl]-1H-pyrazol-4-yl}-2-methoxy-4-methylphenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine 1-[1-(3-bromo-5-chloro-2-methoxy-4-methylphenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (Example 167, Peak 1 from Step 4, 10 mg, 0.024 mmol), N,N-dimethyl-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl]methyl]-4-methylphenyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine] ... A mixture of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (1:1) (4.0 mg, 0.0049 mmol) was evacuated, backfilled with N2, and stirred at 95 °C for 2 h. The crude product was purified using RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile / water containing 0.1% ammonium hydroxide at a flow rate of 30 mL / min) to give the desired product (3.1 mg, 28%). The product was isolated as a single enantiomer. 23 H 30 LCMS calculated for ClNO (M+H) + : m / z = 469.2; Measured value: 469.2.

[0369] Example 184 2-[(5-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}pyridin-2-yl)amino]ethanol [ka]

[0370] Step 1. 1-{1-[5-chloro-3-(6-fluoropyridin-3-yl)-2-methoxy-4-methylphenyl]ethyl}-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine A mixture of 1-[1-(3-bromo-5-chloro-2-methoxy-4-methylphenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (Example 167, Peak 1 from Step 4, 25.0 mg, 0.06 mmol), 2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (20 mg, 0.088 mmol), sodium carbonate (12 mg, 0.12 mmol), and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (1:1) (9.5 mg, 0.012 mmol) in acetonitrile (1 mL) / water (0.3 mL) was degassed with N and stirred at 95° C. for 2 h. The mixture was diluted with methylene chloride, washed with saturated NaHCO, water, brine, dried over NaSO, filtered, and concentrated. The product was purified by chromatography, eluting with CHCl / MeOH (up to 5% MeOH). 21 H 21 LCMS calculated for ClFNO (M+H) + : m / z = 427; Measured value: 427.2.

[0371] Step 2. 2-[(5-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}pyridin-2-yl)amino]ethanol A mixture of 1-{1-[5-chloro-3-(6-fluoropyridin-3-yl)-2-methoxy-4-methylphenyl]ethyl}-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (10 mg, 0.023 mmol) and ethanolamine (0.10 mL) in 1-butanol (1 mL) was stirred at 130° C. for 5 hours. The crude product was purified using RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile / water containing 0.1% ammonium hydroxide at a flow rate of 30 mL / min) to give the desired product (1.6 mg, 15%). The product was isolated as a single enantiomer. 23 H 27 LCMS calculated for ClN7O2 (M+H) + : m / z = 468.2; Found: 468.2.

[0372] Example 188 2-(5-(3-(1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-chloro-2-methoxy-6-methylphenyl)pyridin-2-yloxy)ethanol [ka]

[0373] Sodium hydride (20 mg, 0.5 mmol) was added to 1,2-ethanediol (0.5 mL, 9 mmol), and the mixture was stirred at room temperature for 10 minutes. At this time, 1-{1-[5-chloro-3-(6-fluoropyridin-3-yl)-2-methoxy-4-methylphenyl]ethyl}-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (10 mg, 0.023 mmol) was added, and the reaction was then stirred at 110° C. overnight. The crude product was purified using RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile / water containing 0.1% ammonium hydroxide at a flow rate of 30 mL / min) to give the desired product (1.8 mg, 17%). The product was isolated as a single enantiomer. 23 H 26 LCMS calculated for ClN6O3 (M+H)+ : m / z = 469.2; Measured value: 469.1.

[0374] Example 189 5-(3-(1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-chloro-2-(2,2-difluoroethoxy)-6-methylphenyl)-N,N-dimethylpicolinamide bis(2,2,2-trifluoroacetate) [ka]

[0375] Step 1. 5-(3-(1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-chloro-2-hydroxy-6-methylphenyl)-N,N-dimethylpicolinamide A 1.0 M solution of boron tribromide in CHCl (250 μL, 0.25 mmol) was added to a mixture of 5-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}-N,N-dimethylpyridine-2-carboxamide (Example 167, Step 5 (peak 1) 60 mg, 0.13 mmol) in methylene chloride (1.2 mL) at −78 °C, and the reaction was then allowed to warm to room temperature. At this time, concentrated HCl (0.1 mL) was added, and the mixture was stirred for 4 h. The reaction was quenched by the addition of saturated NaHCO. The mixture was then extracted with methylene chloride. The combined extracts were washed with brine, dried and concentrated to give the crude desired product (40 mg, 68%), which was used in the next step without further purification. 23 H 25 LCMS calculated for ClN7O2 (M+H) + : m / z = 466.2; Measured value: 466.2.

[0376] Step 2. 5-[3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-(2,2-difluoroethoxy)-6-methylphenyl]-N,N-dimethylpyridine-2-carboxamide Diisopropyl azodicarboxylate (13 μL, 0.064 mmol) was added to a mixture of 5-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-hydroxy-6-methylphenyl}-N,N-dimethylpyridine-2-carboxamide (15.0 mg, 0.0322 mmol), 2,2-difluoroethanol (7.9 mg, 0.096 mmol, from Alfa Aesar, item number B22201) and triphenylphosphine (17 mg, 0.064 mmol) in tetrahydrofuran (0.5 mL) at 0° C., and the reaction was then stirred at room temperature for 24 hours. The crude product was purified by RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile / water containing 0.05% trifluoroacetic acid at a flow rate of 30 mL / min) to give the desired product as the bis-TFA salt (1.6 mg, 6.6%). The product was isolated as a single enantiomer. 25 H 27 LCMS calculated for ClF2N7O2 (M+H) + : m / z = 530.2; Found: 530.2.

[0377] Example 192. 1-[1-(5-chloro-3-cyclopropyl-2-methoxy-4-methylphenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine [ka]

[0378] To a microwave vial was added 1-[1-(3-bromo-5-chloro-2-methoxy-4-methylphenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (15 mg, 0.037 mmol, from Peak 1 in Example 167, Step 4), potassium cyclopropyltrifluoroborate (8 mg, 0.06 mmol, from Frontier Scientific, Item No. C10298), potassium phosphate (23 mg, 0.11 mmol), and tetrakis(triphenylphosphine)palladium (4.2 mg, 0.0036 mmol), followed by toluene (0.3 mL) in water (0.1 mL). The vial was sealed and degassed with N three times. The reaction was heated at 110 °C for 20 h. The crude product was purified using RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile / water containing 0.1% ammonium hydroxide at a flow rate of 30 mL / min) to give the desired product (1.1 mg, 8%). The product was isolated as a single enantiomer. 19 H 23 LCMS calculated for ClNO (M+H) + : m / z = 372.2; Found: 372.2.

[0379] Example 195. 5-(3-(1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-chloro-2-ethoxy-6-methylphenyl)-N,N-dimethylpicolinamide bis(2,2,2-trifluoroacetate) [ka]

[0380] Step 1. 1-(3-bromo-5-chloro-2-ethoxy-4-methylphenyl)ethanone A round-bottom flask was charged with 1-(3-bromo-5-chloro-2-hydroxy-4-methylphenyl)ethanone (6.0 g, 23 mmol) in anhydrous DMF (22.8 mL). Potassium carbonate (6.3 g, 46 mmol) was then added, followed by iodoethane (2.73 mL, 34.2 mmol). The resulting suspension was stirred at 60° C. for 2 hours. The mixture was poured into 100 mL of water and extracted with 200 mL of ethyl ether. The organic layers were separated, combined, washed with water and saturated NaCl solution, dried over anhydrous sodium sulfate, filtered, and concentrated to give 6.0 g of a tan oil. 11 H 13 LCMS calculated for BrClO2 (M+H) + : m / z = 293.0; Measured value: 293.0.

[0381] Step 2. 1-(3-bromo-5-chloro-2-ethoxy-4-methylphenyl)ethanol Sodium tetrahydroborate (0.31 g, 8.1 mmol) was added to a mixture of 1-(3-bromo-5-chloro-2-ethoxy-4-methylphenyl)ethanone (1.5 g, 5.4 mmol) in methanol (25 mL) at 0° C., and the resulting reaction mixture was stirred at room temperature for 1 h. The solvent was removed, and the resulting residue was diluted with ethyl acetate, washed with saturated NaHCO, water, and brine, then dried over NaSO, filtered, and concentrated. The crude product was purified by silica gel chromatography (0.30 g, 90%), eluting with 0-30% EtOAc in hexanes.

[0382] Step 3. 3-Bromo-1-chloro-5-(1-chloroethyl)-4-ethoxy-2-methylbenzene A mixture of cyanuric chloride (1.7 g, 9.2 mmol) and N,N-dimethylformamide (710 μL, 9.2 mmol) was stirred at room temperature for 10 minutes, then a solution of 1-(3-bromo-5-chloro-2-ethoxy-4-methylphenyl)ethanol (1.72 g, 6.15 mmol) in methylene chloride (34 mL) was added, and the reaction was stirred at room temperature overnight. The mixture was diluted with methylene chloride, washed with saturated NaHCO, water, brine, dried over NaSO, filtered, and concentrated. The crude product was purified by silica gel chromatography (1.01 g, 60%), eluting with 0–10% EtOAc in hexanes.

[0383] Step 4. 1-(1-(3-bromo-5-chloro-2-ethoxy-4-methylphenyl)ethyl)-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine A mixture of 3-bromo-1-chloro-5-(1-chloroethyl)-4-ethoxy-2-methylbenzene (150 mg, 0.50 mmol), 3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (110 mg, 0.76 mmol), potassium iodide (9 mg, 0.05 mmol), and cesium carbonate (330 mg, 1.0 mmol) in N,N-dimethylformamide (4 mL) was stirred at 140 °C for 1 h. The mixture was diluted with methylene chloride, washed with saturated NaHCO, water, brine, dried over NaSO, filtered, and concentrated. The crude product was purified by silica gel chromatography (103 mg, 50%), eluting with 0-70% EtOAc in CHCl. 17 H 20 LCMS calculated for BrClNO (M+H) + : m / z = 423.1; Found: 423.0. The racemic product was applied to a Phenomenex Lux-Cellulose 1 column (21.1 x 250 mm, 5 micron particle size) eluting with 4% ethanol in hexanes at a flow rate of 18 mL / min, approximately 13 mg / injection, to give two enantiomers. Peak 1, retention time: 8.64 min; Peak 2, retention time: 10.64 min.

[0384] Step 5. 5-(3-(1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-chloro-2-ethoxy-6-methylphenyl)-N,N-dimethylpicolinamide bis(2,2,2-trifluoroacetate) A mixture of 1-[1-(3-bromo-5-chloro-2-ethoxy-4-methylphenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (25 mg, 0.061 mmol) (the first peak from the previous chiral separation step), N,N-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-carboxamide (25 mg, 0.09 mmol), sodium carbonate (13 mg, 0.12 mmol), and [1,1′-bis(diphenylphosphino)-ferrocene]dichloropalladium(II) dichloromethane complex (1:1) (9.9 mg, 0.012 mmol) in acetonitrile (0.8 mL) / water (0.3 mL) was degassed with N and then stirred at 95 °C for 2 h. After cooling to room temperature, the mixture was filtered and the filtrate was purified by RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile / water containing 0.05% trifluoroacetic acid at a flow rate of 30 mL / min) to give the desired product as the bis-TFA salt (2.3 mg, 5%). The product was isolated as a single enantiomer. 25 H 29 LCMS calculated for ClN7O2 (M+H) + : m / z = 494.2; Measured value: 494.2.

[0385] Example 200. 4-(3-(1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-chloro-2-methoxy-6-methylphenyl)-N,N-dimethylpicolinamide bis(2,2,2-trifluoroacetate) [ka]

[0386] Step 1. 4-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}pyridine-2-carbonitrile 1-[1-(3-bromo-5-chloro-2-methoxy-4-methylphenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (Example 167, Peak 1 from Step 4, 322 mg, 0.76 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-carbonitrile (210 mg, 0.91 mmol, Combi-Blocks) in acetonitrile (5 mL) / water (2 mL). A mixture of (from Catalog, Item No. PN-0143), sodium carbonate (130 mg, 1.2 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) dichloromethane complex (1:1) (99 mg, 0.12 mmol) was degassed with N2, and the reaction was stirred at 95 °C for 2 h. The mixture was diluted with methylene chloride, washed with saturated NaHCO3, water, brine, dried over Na2SO4, filtered, and concentrated. The product (0.28 g, 85%) was purified by chromatography, eluting with CHCl2 / MeOH (maximum 6% MeOH). 22 H 21 LCMS calculated for ClNO (M+H) + : m / z = 434.1; Found: 434.1.

[0387] Step 2. 4-(3-(1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-chloro-2-methoxy-6-methylphenyl)picolinic acid dihydrochloride 1.0 M sodium hydroxide (2.9 mL, 2.9 mmol) was added to a mixture of 4-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}pyridine-2-carbonitrile (0.250 g, 0.576 mmol) in ethanol (4.0 mL), and the resulting mixture was heated at 95° C. for 6 hours. At this time, concentrated HCl was added to adjust the pH to approximately 3. The solvent was removed, and the residue was used in the next step without further purification. 22 H 22 LCMS calculated for ClN6O3 (M+H) + : m / z = 453.1; Measured value: 453.2.

[0388] Step 3. 4-(3-(1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-chloro-2-methoxy-6-methylphenyl)-N,N-dimethylpicolinamide bis(2,2,2-trifluoroacetate) A 2.0 M solution of dimethylamine in THF (2.0 mL, 4.0 mmol) was added to a solution of 4-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}pyridine-2-carboxylic acid (250 mg, 0.552 mmol) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (370 mg, 0.83 mmol) in N,N-dimethylformamide (4 mL) at 0° C., followed by the addition of triethylamine (0.23 mL, 1.6 mmol). The reaction was stirred for 1 hour. The crude mixture was purified by RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile / water containing 0.05% trifluoroacetic acid at a flow rate of 30 mL / min) to give the desired product as the bis-TFA salt. The product was isolated as a single enantiomer. 24 H 27 LCMS calculated for ClN7O2 (M+H) + : m / z = 480.2; Measured value: 480.2. 1HNMR(DMSO-d6,500MHz)δ 8.67(brs,1H),8.36(s,1H),7.58(s,1H),7.41(m,2H),6.32(q,2H),3.20(s ,3H),3.00(s,3H),2.94(s,3H),2.62(s,3H),2.03(s,3H),1.80(d,3H)ppm.

[0389] Example 203 2-(4-(3-(1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-chloro-2-ethoxy-6-methylphenyl)-1H-pyrazol-1-yl)acetamide [ka]

[0390] Step 1. tert-Butyl [4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]acetate A 1.0 M solution of potassium tert-butoxide in THF (2.4 mL, 2.4 mmol) was added to a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.39 g, 2.0 mmol) in N,N-dimethylformamide (6.0 mL) at 0 °C. The reaction mixture was stirred at room temperature for 5 hours. After cooling to 0 °C, tert-butyl bromoacetate (0.5 mL, 3 mmol) was added to the mixture. The reaction mixture was stirred at room temperature for 2 hours, then diluted with ethyl acetate, washed with saturated NaHCO3, water, brine, dried over Na2SO4, filtered, and concentrated. The product (0.5 g, 81%) was purified by chromatography, eluting with hexanes / EtOAc (up to 30% EtOAc). 15 H 26 LCMS calculated value for BN2O4 (M+H) + : m / z = 309.2; Found: 309.1.

[0391] Step 2. (4-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-6-methylphenyl}-1H-pyrazol-1-yl)acetate tert-butyl A mixture of 1-[1-(3-bromo-5-chloro-2-ethoxy-4-methylphenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (70 mg, 0.16 mmol) (Example 195, Step 4, 1st peak), tert-butyl [4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]acetate (65 mg, 0.21 mmol), sodium carbonate (30 mg, 0.28 mmol), and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (1:1) (23 mg, 0.028 mmol) in acetonitrile (3 mL) / water (0.7 mL) was degassed with N and then stirred at 95° C. for 2 h. The mixture was diluted with methylene chloride, washed with saturated NaHCO, water, brine, dried over NaSO, filtered, and concentrated. The product (65 mg, 78%) was purified by chromatography, eluting with CHCl / MeOH (up to 5% MeOH). 26 H 33 LCMS calculated for ClN7O3 (M+H) + : m / z = 526.2; Found: 526.3.

[0392] Step 3. (4-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-6-methylphenyl}-1H-pyrazol-1-yl)acetic acid bistrifluoroacetate Trifluoroacetic acid (0.5 mL) was added to a solution of tert-butyl (4-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-6-methylphenyl}-1H-pyrazol-1-yl)acetate (0.065 g, 0.12 mmol) in methylene chloride (0.5 mL). The reaction was stirred at room temperature for 4 hours. The solvent was removed to give the crude product, which was used in the next step. 22 H 25 LCMS calculated for ClN7O3 (M+H) + : m / z = 470.2; Measured value: 470.1.

[0393] Step 4. 2-(4-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-6-methylphenyl}-1H-pyrazol-1-yl)acetamide Ammonium carbonate (20 mg, 0.21 mmol) was added to a solution of (4-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-6-methylphenyl}-1H-pyrazol-1-yl)acetic acid bistrifluoroacetate (10 mg, 0.021 mmol) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (10 mg, 0.03 mmol) in N,N-dimethylformamide (0.7 mL) at room temperature, followed by the addition of triethylamine (8.8 μL, 0.064 mmol). The reaction was stirred for 1 hour. The crude product was purified using RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile / water containing 0.1% ammonium hydroxide at a flow rate of 30 ml / min) to give the desired product (2.5 mg, 25%). The product was isolated as a single enantiomer. 22 H 26 LCMS calculated for ClN8O2 (M+H) + : m / z = 469.2; Measured value: 469.2.

[0394] Example 208. 6-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-6-methylphenyl}-N,N-dimethylnicotinamide bis(trifluoroacetate) [ka]

[0395] Step 1. 1-{1-[5-chloro-2-ethoxy-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethyl}-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine 1-[1-(3-Bromo-5-chloro-2-ethoxy-4-methylphenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.050 g, 0.12 mmol, Example 195, Peak 1 from Step 4) was mixed with potassium acetate (0.035 g, 0.35 mmol) and a solution of 4,4,5,5,4',4',5',5'-octamethyl-[2,2']bi[[1,3,2]dioxaborolanyl] (0.060 g, 0.24 mmol) in dimethyl sulfoxide (0.44 mL) in a microwave vial at room temperature. This was degassed with nitrogen, and then [1,1'-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) dichloromethane complex (1:1) (0.01 g, 0.01 mmol) was added. The reaction was heated in an oil bath at 105 °C overnight. It was allowed to cool, then dissolved in ethyl acetate, washed with water, brine, dried over magnesium sulfate, and concentrated. The product (15 mg, 20%) was purified by chromatography, eluting with CHCl / MeOH (up to 10% MeOH). 23 H 32 LCMS calculated for BClNO3 (M+H) + : m / z = 472.2; Measured value: 472.3.

[0396] Step 2. 6-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-6-methylphenyl}-N,N-dimethylnicotinamide bis(trifluoroacetate) A mixture of 1-{1-[5-chloro-2-ethoxy-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethyl}-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (15 mg, 0.032 mmol), 6-chloro-N,N-dimethylnicotinamide (12 mg, 0.064 mmol), sodium carbonate (9.0 mg, 0.085 mmol), and [1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) dichloromethane complex (1:1) (6.9 mg, 0.0085 mmol) in acetonitrile (0.9 mL) / water (0.2 mL) was degassed with N and then stirred at 95° C. overnight. The crude product was purified using RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile / water containing 0.05% trifluoroacetic acid at a flow rate of 30 ml / min) to give the desired product as a TFA salt (2 mg, 9%). The product was isolated as a single enantiomer. 25 H 29 LCMS calculated for ClN7O2 (M+H) + : m / z = 494.2; Measured value: 494.2.

[0397] Example 209. 5-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-4-methoxy-2-methyl-3-(1-methyl-1H-pyrazol-4-yl)benzonitrile [ka]

[0398] Preformed catalyst (0.05 mL, from Example 40) was added to a mixture of 1-{1-[5-chloro-2-methoxy-4-methyl-3-(1-methyl-1H-pyrazol-4-yl)phenyl]ethyl}-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (7.7 mg, 0.019 mmol), zinc (0.54 mg, 0.0082 mmol), and zinc cyanide (2.2 mg, 0.019 mmol) in N,N-dimethylacetamide (0.3 mL). The mixture was degassed with nitrogen three times. The reaction was heated at 120 °C for 1.5 h. The crude product was purified using RP-HPLC (XBridge C18 column, eluted with a gradient of acetonitrile / water containing 0.1% ammonium hydroxide at a flow rate of 30 mL / min) to give the desired product (2.1 mg, 27%). The product was isolated as a single enantiomer. 21 H 23 LCMS calculated value for NO (M+H) + : m / z = 403.2; Found: 403.2.

[0399] The experimental methods and LCMS mass spectral data for the following compounds are summarized in Table 1. [Table 1] 1 Synthesize listed compounds according to experimental methods; 2 Compounds isolated as single enantiomers.

[0400] Example 212. 4-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-2-azetidin-3-yl-6-chloro-3-ethoxybenzonitrile [ka]

[0401] Step 1. 1-(5-chloro-2-ethoxy-4-fluoro-3-iodophenyl)ethanone The desired compound was synthesized in 90% yield following the method of Example 13, Step 3, using iodoethane instead of iodomethane as the starting material to produce the racemic intermediate. 1 HNMR(300MHz, CDCl3)δ 7.68(d,J=8.3Hz,1H),3.94(q,J=7.0Hz,2H),2.61(s,3H),1.48(t,J=7.0Hz,3H). C 10 H 10 LCMS (M+H) of ClFIO2 + : m / z = 342.9, 344.9; Measured: 342.9, 344.8.

[0402] Step 2. 4-Acetyl-6-chloro-3-ethoxy-2-iodobenzonitrile A solution of 1-(5-chloro-2-ethoxy-4-fluoro-3-iodophenyl)ethanone (7.3 g, 21 mmol) in N,N-dimethylformamide (80 mL) was treated with potassium cyanide (2.1 g, 32 mmol) and stirred at 40° C. for 5 hours. The reaction mixture was diluted with ethyl acetate and poured into saturated sodium bicarbonate solution / water (1:1). The organic layer was separated, washed with saturated sodium bicarbonate solution, dried over magnesium sulfate, filtered, and concentrated to give a crude brown oil. The crude material was purified by flash column chromatography using ethyl acetate in hexanes (0% to 30%) to give the desired product (6.1 g, 81%) as a yellow solid. 1 HNMR (400MHz, CDCl3) δ 7.57 (s, 1H), 3.93 (q, J = 7.0Hz, 2H), 2.61 (s, 3H), 1.47 (t, J = 7.0Hz, 3H). C 11 H 10 LCMS (M+H) of ClINO2 + : m / z = 349.9; Measured value: 349.9.

[0403] Step 3. tert-Butyl 3-(3-acetyl-5-chloro-6-cyano-2-ethoxyphenyl)azetidine-1-carboxylate Zinc (4.60 g, 70.3 mmol) and oven-dried Celite (870 mg) were placed in a flask, which was heated with a heat gun while under high vacuum for 5 minutes and then filled with nitrogen. N,N-Dimethylacetamide (57 mL) and then 1,2-dibromoethane (430 μL, 5.0 mmol) were added, and the mixture was heated at 70° C. for 10 minutes and then cooled to room temperature. The reaction mixture was treated dropwise with chlorotrimethylsilane (630 μL, 5.0 mmol) and stirred at room temperature for 1 hour. The reaction mixture was treated dropwise with a solution of tert-butyl 3-iodoazetidine-1-carboxylate (18 g, 62 mmol) in N,N-dimethylacetamide (28 mL) (internal temperature kept below 40° C. using a water bath) and heated at 40° C. for 2 hours. The zinc-iodine reagent (transferred via cannula) was filtered through a plastic filter (properly sealed to avoid exposure to air) directly into a clean, dry flask flushed with nitrogen. The reaction mixture was treated with tris(dibenzylideneacetone)dipalladium(0) (720 mg, 0.79 mmol) and tri-(2-furyl)phosphine (370 mg, 1.6 mmol) and degassed with nitrogen for several minutes. The reaction mixture was quickly treated with a solution of 4-acetyl-6-chloro-3-ethoxy-2-iodobenzonitrile (14 g, 41 mmol) in N,N-dimethylacetamide (130 mL) (degassed with nitrogen) and heated at 70 °C for 2 hours. The reaction mixture was poured into saturated ammonium chloride solution and extracted with ethyl acetate (3 × 300 mL). The combined organic extracts were washed with water (4 x 500 mL) and brine (1 x 500 mL), dried over magnesium sulfate, filtered, and concentrated to give a crude dark oil. The crude material was purified by flash column chromatography using ethyl acetate in hexanes (5% to 45%) to give the desired product (14 g, 88%). 1 HNMR(300MHz, CDCl3)δ 7.46(s,1H),4.42~4.20(m,5H),3.80(q,J=7.0Hz,2H),2.59(s,3H),1.44(s,9H),1.37(t,J=7.0Hz,3H). C 15 H 16LCMS of ClN2O4 ([M-(t-Bu)+H]+H) + : m / z = 323.1; Measured value: 323.0.

[0404] Step 4. tert-Butyl 3-[3-chloro-2-cyano-6-ethoxy-5-(1-hydroxyethyl)phenyl]azetidine-1-carboxylate A solution of (3aS)-1-methyl-3,3-diphenyltetrahydro-3H-pyrrolo[1,2-c][1,3,2]oxazaborole (9.7 g, 35 mmol) in tetrahydrofuran (100 mL) was treated with a 1.0 M solution of borane-THF complex in tetrahydrofuran (42 mL, 42 mmol) and stirred at 20 °C for 15 minutes. The reaction mixture was cooled to -30 °C and slowly treated with a solution of tert-butyl 3-(3-acetyl-5-chloro-6-cyano-2-ethoxyphenyl)azetidine-1-carboxylate (13 g, 35 mmol) in tetrahydrofuran (110 mL). The flask containing the starting ketone was rinsed with additional tetrahydrofuran (20 mL) and added to the reaction mixture. The reaction mixture was warmed to 0 °C over a 30 minute period and stirred at 0 °C for 15 minutes. The reaction mixture was quenched with water at 0°C, poured into saturated sodium bicarbonate solution, and extracted with ethyl acetate. The aqueous layer was separated and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over magnesium sulfate, filtered, and concentrated to give a crude dark oil. The crude material was purified by flash column chromatography using ethyl acetate in hexanes (0% to 70%) to give the desired product (10.4 g, 78%) as a 98:2 mixture of enantiomers (retention time = 7.73 min and 9.41 min; ChiralPak AD-H column, 4.6 x 150 mm, 5 micron particle size, eluted with 5% ethanol in hexanes at 1 ml / min) as a yellow foam. 1 HNMR (300MHz, CDCl3) δ7.56(s,1H),5.15~5.07(m,1H),4.41~4.17(m,5H),3.74(q,J=7.0Hz,2H),2.12(d,J=3.7Hz,1H),1.49-1.37(m,15H). C 15 H 18LCMS of ClN2O4 ([M-(t-Bu)+H]+H) + : m / z = 325.1; Found: 325.1.

[0405] Step 5. tert-Butyl 3-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-6-cyano-2-ethoxyphenyl}azetidine-1-carboxylate A solution of tert-butyl 3-[3-chloro-2-cyano-6-ethoxy-5-(1-hydroxyethyl)phenyl]azetidine-1-carboxylate (98:2 enantiomeric mixture from Step 4) (10 g, 27 mmol) in methylene chloride (260 mL) at 0° C. was treated with triethylamine (11 mL, 82 mmol) and then methanesulfonic anhydride (7.1 g, 41 mmol) and stirred for 15 minutes at 0° C. The reaction mixture was diluted with dichloromethane, washed with water and brine, dried over magnesium sulfate, filtered, and concentrated to give the crude mesylate, which was used without further purification. A solution of the crude mesylate intermediate in N,N-dimethylformamide (140 mL) was treated with cesium carbonate (13 g, 41 mmol) and 3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (4.7 g, 31 mmol) and heated at 60° C. for 1 h. The reaction mixture was diluted with water and extracted with ethyl acetate (3×250 mL). The combined organic layers were washed with water and brine, dried over magnesium sulfate, filtered, and concentrated to give a crude oil. The crude material was purified by flash column chromatography (100% dichloromethane to 70% acetonitrile (with 3% methanol) / 30% dichloromethane) to give the desired product (8.7 g, 62% over two steps) as a yellow foam as a 95:5 mixture of enantiomers (retention times = 4.29 min and 6.00 min; Phenomenex Lux Cellulose C-1 column, 4.6 x 150 mm, 5 micron particle size, eluting with 15% ethanol in hexanes at 1 ml / min). This material was separated by chiral HPLC (Phenomenex Lux Cellulose C-1 column, 21.2 x 250 mm, 5 micron particle size, eluting with 15% ethanol in hexanes at 10 ml / min) to give 7.0 g of the desired Peak 1 material (retention time of 8.20 min). 1HNMR(300MHz,CDCl3)δ8.24(s,1H),7.51(s,1H),6.32(q,J=7.1Hz,1H),5.48(brs,2H),4.40~4.18(m,5H),4 .05~3.93(m,1H),3.81~3.65(m,1H),2.64(s,3H),1.81(d,J=7.1Hz,3H),1.48(t,J=7.0Hz,3H),1.43(s,9H). C 25 H 31 LCMS (M+H) of ClN7O3 + : m / z = 512.2; Measured value: 512.3.

[0406] Step 6. 4-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-2-azetidin-3-yl-6-chloro-3-ethoxybenzonitrile A solution of tert-butyl 3-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-6-cyano-2-ethoxyphenyl}azetidine-1-carboxylate (Peak 1 enantiomer from Step 5) (2.2 g, 4.2 mmol) in methylene chloride (11 mL) was treated dropwise with trifluoroacetic acid (11 mL) and stirred at room temperature for 30 minutes. The reaction mixture was concentrated to give an oil, which was reconcentrated from ethanol (2x) to give a residue. This material was dissolved in a minimum amount of methanol, added dropwise to ice-cold saturated sodium bicarbonate solution (100 mL), and extracted several times with 2:1 dichloromethane / isopropanol to give the desired product (1.8 g, quantitative), which was used without further purification. A small amount of the desired product was purified by preparative LCMS (XBridge C18 column, eluting with a gradient of acetonitrile / water containing 0.1% ammonium hydroxide at a flow rate of 60 ml / min) to give the desired product, which was isolated as a single enantiomer. 1HNMR(400MHz,DMSO-d6)δ 8.11(s,1H),7.47(s,1H),6.23(q,J=7.0Hz,1H),4.37~4.26(m,1H),3.91 ~3.61(m,6H),2.54(s,3H),1.71(d,J=7.1Hz,3H),1.32(t,J=7.0Hz,3H). C 20 H 23 LCMS (M+H) of ClNO + : m / z = 412.2; Found: 412.1.

[0407] Example 213 4-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-6-chloro-3-ethoxy-2-(1-methylazetidin-3-yl)benzonitrile [ka]

[0408] A solution of 4-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-2-azetidin-3-yl-6-chloro-3-ethoxybenzonitrile (the chiral intermediate of Example 212, Step 6) (0.30 g, 0.73 mmol) in methanol (7.3 mL) was treated with formaldehyde (37% aqueous solution) (0.54 mL, 7.3 mmol) and stirred at room temperature for 5 minutes. The reaction mixture was treated with sodium cyanoborohydride (0.092 g, 1.5 mmol) and stirred at room temperature for 2 hours. The reaction mixture was diluted with methanol and purified by preparative LCMS (XBridge C18 column, eluting with a gradient of acetonitrile / water containing 0.1% ammonium hydroxide at a flow rate of 60 ml / min) to give the desired product (0.16 g, 50%). The product was isolated as a single enantiomer. 1HNMR(400MHz,DMSO-d6)δ 8.11(s,1H),7.48(s,1H),6.27~6.18(m,1H),4.10~3.98(m,1H),3.96~3.86(m,2H),3.83~3.74(m,1H),3.7 2~3.64(m,1H),3.10~2.98(m,2H),2.54(s,3H),2.20(s,3H),1.71(d,J=6.9Hz,3H),1.32(t,J=6.7Hz,3H). C 21 H 25 LCMS (M+H) of ClNO + : m / z = 426.2; Measured value: 426.2.

[0409] Example 219. 4-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-6-chloro-3-ethoxy-2-[1-(2-hydroxyethyl)azetidin-3-yl]benzonitrile [ka]

[0410] A solution of 4-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-2-azetidin-3-yl-6-chloro-3-ethoxybenzonitrile (300 mg, 0.74 mmol, chiral intermediate of Example 212) in tetrahydrofuran (14 mL) was treated dropwise with triethylamine (260 μL, 1.8 mmol), followed by 2-bromoethanol (63 μL, 0.89 mmol) and stirred at 60° C. for 6 hours. The reaction mixture was treated with additional 2-bromoethanol (26 μL, 0.37 mmol) and stirred at 60° C. for an additional 6 hours. The reaction mixture was poured into saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was concentrated and purified by preparative LCMS (XBridge C18 column, eluting with a gradient of acetonitrile / water containing 0.1% ammonium hydroxide at a flow rate of 60 ml / min) to give the desired product (0.15 g, 44%). The product was isolated as a single enantiomer. 1HNMR(400MHz,DMSO-d6)δ 8.19(s,1H),7.56(s,1H),6.36~6.25(m,1H),4.48(brs,1H),4.19~4.07(m,1H),4.04~3.94(m,2H),3.91~3.82(m, 1H),3.81~3.72(m,1H),3.20~3.08(m,2H),2.62(s,2H),2.57(s,3H),1.79(d,J=6.8Hz,3H),1.40(t,J=6.6Hz,3H). C 22 H 27 LCMS (M+H) of ClN7O2 + : m / z = 456.2; Found: 456.1.

[0411] Example 220. 4-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-6-chloro-3-ethoxy-2-{1-[(2S)-2-hydroxypropyl]azetidin-3-yl}benzonitrile [ka]

[0412] A solution of 4-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-2-azetidin-3-yl-6-chloro-3-ethoxybenzonitrile (50 mg, 0.12 mmol, chiral intermediate of Example 212) in ethanol (1.7 mL) was treated with (S)-(-)-methyloxirane (21 μL, 0.30 mmol) and microwaved at 125° C. for 15 minutes. The reaction mixture was diluted with methanol and purified by preparative LCMS (XBridge C18 column, eluting with a gradient of acetonitrile / water containing 0.1% ammonium hydroxide at a flow rate of 60 mL / min) to give the desired product (27 mg, 47%). The product was isolated as a single diastereomer. 1HNMR(300MHz,DMSO-d6)δ 8.11(s,1H),7.48(s,1H),6.23(q,J=6.9Hz,1H),4.35(d,J=4.5Hz,1H),4.13~3.99(m,1H),3.97~3.88(m,2H),3.85~3.63(m,2H),3.61~ 3.51(m,1H),3.15~2.99(m,2H),2.55(s,3H),2.28(d,J=5.9Hz,2H),1.71(d,J=7.0Hz,3H),1.32(t,J=6.9Hz,3H),1.00(d,J=6.2Hz,3H). C 23 H 29 LCMS (M+H) of ClN7O2 + : m / z = 470.2; Found: 470.2.

[0413] Example 236. tert-Butyl 2-(3-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-6-cyano-2-ethoxyphenyl}azetidin-1-yl)-2-methylpropanoate [ka]

[0414] A solution of 4-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-2-azetidin-3-yl-6-chloro-3-ethoxybenzonitrile (0.38 g, 0.92 mmol, chiral intermediate of Example 212) in N,N-dimethylformamide (4.6 mL) was treated with potassium carbonate (0.51 g, 3.7 mmol) followed by tert-butyl 2-bromo-2-methylpropanoate (0.86 mL, 4.6 mmol) and heated at 60° C. for 3 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was separated, dried over magnesium sulfate, filtered, and concentrated to give a crude oil. The crude material was purified by flash column chromatography using methanol (0% to 10%) in dichloromethane to give the desired product (0.43 g, 83%). The product was isolated as a single enantiomer. 1HNMR(300MHz,DMSO-d6)δ 8.10(s,1H),7.44(s,1H),6.22(q,J=6.8Hz,1H),4.12~3.97(m,1H),3.88~3.70(m,4H),3.62~3. 48(m,2H),2.54(s,3H),1.70(d,J=7.0Hz,3H),1.33(t,J=6.9Hz,3H),1.17(s,9H),1.05(s,6H). C 28 H 37 LCMS (M+H) of ClN7O3 + : m / z = 554.3; Found: 554.3.

[0415] Example 237. 4-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-6-chloro-3-ethoxy-2-[1-(2-hydroxy-1,1-dimethylethyl)azetidin-3-yl]benzonitrile [ka]

[0416] Step 1. 2-(3-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-6-cyano-2-ethoxyphenyl}azetidin-1-yl)-2-methylpropanoic acid bis(trifluoroacetate) Tert-butyl 2-(3-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-6-cyano-2-ethoxyphenyl}azetidin-1-yl)-2-methylpropanoate (0.36 g, 0.65 mmol, chiral intermediate of Example 236) was dissolved in a premixed solution of trifluoroacetic acid (3.2 mL) / water (0.065 mL) and stirred at room temperature for 3 hours and at 50° C. for 30 minutes. The reaction mixture was concentrated and reconcentrated from acetonitrile (2×) to give the desired product as a gum. This gum was treated with a small amount of stirred methyl tert-butyl ether until a solid formed. The methyl tert-butyl ether was decanted, and the residue was concentrated to give the desired product (0.51 g, 109%), which was used without further purification. 24 H 29 LCMS (M+H) of ClN7O3 + : m / z = 498.2; Found: 498.3.

[0417] Step 2. 4-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-6-chloro-3-ethoxy-2-[1-(2-hydroxy-1,1-dimethylethyl)azetidin-3-yl]benzonitrile A solution of 2-(3-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-6-cyano-2-ethoxyphenyl}azetidin-1-yl)-2-methylpropanoic acid bis(trifluoroacetate) (0.10 g, 0.16 mmol) in tetrahydrofuran (0.9 mL) was cooled to −25° C., treated with 4-methylmorpholine (0.072 mL, 0.65 mmol) and isobutyl chloroformate (0.085 mL, 0.65 mmol), and stirred at −15° C. for 15 minutes. The reaction mixture was filtered through a disposable filter cartridge into a separate round-bottom flask. The solution was then cooled to −20° C., and a solution of sodium tetrahydroborate (0.031 g, 0.82 mmol) in a minimum amount of water was added dropwise. The reaction mixture was stirred at -15°C for 30 minutes, poured into water, and extracted with ethyl acetate. The organic layer was separated, concentrated, diluted with methanol, and purified by preparative LCMS (XBridge C18 column, eluting with a gradient of acetonitrile / water containing 0.1% ammonium hydroxide at a flow rate of 30 ml / min) to give the desired product (3.5 mg, 4%). The product was isolated as a single enantiomer. 1 HNMR(300MHz,DMSO-d6)δ 8.11(s,1H),7.50(s,1H),7.35(brs,2H),6.23(q,J=6.7Hz,1H),4.44~4.35(m,1H),4.04~3.88(m,1H),3.86~3.73(m, 1H),3.72~3.57(m,3H),3.12(d,J=4.7Hz,2H),2.54(s,3H),1.71(d,J=6.9Hz,3H),1.31(t,J=6.9Hz,3H),0.80(s,6H). C 24 H 31 LCMS (M+H) of ClN7O2 + : m / z = 484.2; Measured value: 484.2.

[0418] Example 239. 2-(3-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-6-cyano-2-ethoxyphenyl}azetidin-1-yl)-2-methylpropanamide [ka]

[0419] A solution of 2-(3-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-6-cyano-2-ethoxyphenyl}azetidin-1-yl)-2-methylpropanoic acid bis(trifluoroacetate) (0.05 g, 0.069 mmol, chiral intermediate from Example 237, Step 1) and 2.0 M ammonia in ethanol (0.17 mL, 0.34 mmol) in N,N-dimethylformamide (1 mL) was treated with triethylamine (0.048 mL, 0.35 mmol) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (0.046 g, 0.10 mmol) and stirred at room temperature for 1 hour. The reaction mixture was quenched with a few drops of water, diluted with methanol, and purified by preparative LCMS (XBridge C18 column, eluting with a gradient of acetonitrile / water containing 0.1% ammonium hydroxide at a flow rate of 60 ml / min) to give the desired product (25 mg, 73%). The product was isolated as a single enantiomer. 1 HNMR(400MHz,DMSO-d6)δ 8.11(s,1H),7.51(s,1H),7.23(s,1H),6.98(s,1H),6.23(q,J=7.0Hz,1H),4.09~3.96(m,1H),3.84~3.61(m,4H) ),3.39~3.34(m,1H),3.32~3.28(m,1H),2.54(s,3H),1.71(d,J=7.0Hz,3H),1.31(t,J=6.9Hz,3H),1.02(s,6H). C 24 H 30 LCMS (M+H) of ClN8O2 + : m / z = 497.2; Measured value: 497.3.

[0420] Example 247. 4-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-6-chloro-3-ethoxy-2-[1-(2-hydroxy-2-methylpropanoyl)azetidin-3-yl]benzonitrile [ka]

[0421] A solution of 4-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-2-azetidin-3-yl-6-chloro-3-ethoxybenzonitrile (0.04 g, 0.097 mmol, chiral intermediate of Example 212) and 2-hydroxy-2-methyl-propanoate (0.012 g, 0.12 mmol) in N,N-dimethylformamide (0.54 mL) was treated with triethylamine (0.034 mL, 0.24 mmol) followed by O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (0.048 g, 0.13 mmol) and stirred at room temperature for 30 minutes. The reaction mixture was diluted with methanol and acetonitrile and purified by preparative LCMS (XBridge C18 column, eluting with a gradient of methanol / water containing 0.1% ammonium hydroxide at a flow rate of 60 ml / min) to give the desired product (7 mg, 14%). The product was isolated as a single enantiomer. 1 HNMR(300MHz,DMSO-d6)δ 8.11(s,1H),7.54(d,J=4.5Hz,1H),6.25(q,J=7.2Hz,1H),5.08(s,1H),4.88~4.77(m,1H),4.73~4.60(m,1H),4.50~4.35(m,1 H),4.29~4.09(m,2H),3.85~3.73(m,2H),2.55(s,3H),1.73(d,J=7.0Hz,3H),1.37(t,J=6.3Hz,3H),1.26(s,3H),1.22(s,3H). C 24 H 29 LCMS (M+H) of ClN7O3 + : m / z = 498.2; Found: 498.2.

[0422] Example 261. 4-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-2-azetidin-3-yl-6-chloro-3-methoxybenzonitrile [ka]

[0423] Step 1. 4-Acetyl-6-chloro-2-iodo-3-methoxybenzonitrile A solution of 1-(5-chloro-4-fluoro-3-iodo-2-methoxyphenyl)ethanone (Example 13, Step 3 intermediate) (18 g, 54 mmol) in N,N-dimethylformamide (200 mL) was treated with potassium cyanide (5.2 g, 81 mmol) and stirred at 40° C. for 6 hours. The reaction mixture was diluted with ethyl acetate and poured into saturated sodium bicarbonate solution / water (1:1). The organic layer was separated, washed with saturated sodium bicarbonate solution, dried over magnesium sulfate, filtered, and concentrated to give a crude brown oil. The crude material was purified by flash column chromatography using ethyl acetate in hexanes (0% to 30%) to give the desired product (11 g, 61%) as a yellow solid. 1 HNMR (300MHz, CDCl3) δ 7.60 (s, 1H), 3.81 (s, 3H), 2.62 (s, 3H). C 10 LCMS (M+H) of H8ClINO2 + : m / z = 335.9; Measured value: 335.9.

[0424] Step 2. tert-Butyl 3-(3-acetyl-5-chloro-6-cyano-2-methoxyphenyl)azetidine-1-carboxylate Zinc (5.0 g, 77 mmol) and oven-dried Celite (520 mg) were placed in a flask, which was heated with a heat gun while under high vacuum for 5 minutes and then filled with nitrogen. N,N-Dimethylacetamide (53 mL) and then 1,2-dibromoethane (400 μL, 4.6 mmol) were added, and the mixture was heated at 70° C. for 15 minutes and then cooled to room temperature. The reaction mixture was treated dropwise with chlorotrimethylsilane (580 μL, 4.6 mmol) and stirred at room temperature for 1 hour. The reaction mixture was treated dropwise with a solution of tert-butyl 3-iodoazetidine-1-carboxylate (16 g, 58 mmol) in N,N-dimethylacetamide (26 mL) (internal temperature kept below 40° C. using a water bath) and heated at 40° C. for 2 hours. The zinc-iodine reagent (transferred via cannula) was filtered through a plastic filter (properly sealed to avoid exposure to air) directly into a clean, dry flask flushed with nitrogen. The reaction mixture was treated with tris(dibenzylideneacetone)dipalladium(0) (670 mg, 0.73 mmol) and tri-(2-furyl)phosphine (340 mg, 1.5 mmol) and degassed with nitrogen for several minutes. The reaction mixture was quickly treated with a solution of 4-acetyl-6-chloro-2-iodo-3-methoxybenzonitrile (13 g, 39 mmol) in N,N-dimethylacetamide (120 mL) (degassed with nitrogen) and heated at 70 °C for 2 hours. The reaction mixture was poured into saturated ammonium chloride solution and extracted with ethyl acetate (3 × 300 mL). The combined organic extracts were washed with water (4 x 500 mL) and brine (1 x 500 mL), dried over magnesium sulfate, filtered, and concentrated to give a crude dark oil. The crude material was purified by flash column chromatography using ethyl acetate in hexanes (5% to 40%) to give the desired product (12 g, 85%). 1 HNMR (400MHz, DMSO-d6) δ 7.79 (s, 1H), 4.39~4.29 (m, 1H), 4.28~4.11 (m, 4H), 3.68 (s, 3H), 2.58 (s, 3H), 1.38 (s, 9H).

[0425] Step 3. tert-Butyl 3-[3-chloro-2-cyano-5-(1-hydroxyethyl)-6-methoxyphenyl]azetidine-1-carboxylate A solution of (3aS)-1-methyl-3,3-diphenyltetrahydro-3H-pyrrolo[1,2-c][1,3,2]oxazaborole (4.3 g, 16 mmol) in tetrahydrofuran (46 mL) was treated with a 1.0 M solution of borane-THF complex in tetrahydrofuran (19 mL, 19 mmol) and stirred at 20 °C for 15 minutes. The reaction mixture was cooled to -30 °C and slowly treated with a solution of tert-butyl 3-(3-acetyl-5-chloro-6-cyano-2-methoxyphenyl)azetidine-1-carboxylate (5.7 g, 16 mmol) in tetrahydrofuran (49 mL). The flask containing the starting ketone was rinsed with additional tetrahydrofuran (9 mL) and added to the reaction mixture. After the addition was complete, the reaction temperature was -20 °C. The reaction mixture was allowed to warm to -5 °C over a 30 minute period. The reaction mixture was quenched with water at 0°C, poured into saturated sodium bicarbonate solution, and extracted with ethyl acetate. The aqueous layer was separated and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over magnesium sulfate, filtered, and concentrated to give a crude dark oil. The crude material was purified by flash column chromatography using ethyl acetate in hexanes (0% to 100%) to give the desired product (5.5 g, 97%) as a 97:3 enantiomeric mixture (retention time = 12.19 min and 13.18 min; Phenomenex Lux Cellulose C-2 column, 4.6 x 150 mm, 5 micron particle size, eluted with 8% ethanol in hexanes at 1 ml / min) as a beige foam. 1 HNMR(400MHz,DMSO-d6)δ 7.62(s,1H),5.48(d,J=4.6Hz,1H),5.00~4.90(m,1H),4.43~4.31(m,1H),4.30~4.10(m,4H),3.66(s,3H),1.38(s,9H),1.29(d,J=6.4Hz,3H). C 14 H 16 LCMS of ClN2O4 ([M-(t-Bu)+H]+H) + : m / z = 311.1; Found: 311.1.

[0426] Step 4. tert-Butyl 3-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-6-cyano-2-methoxyphenyl}azetidine-1-carboxylate A solution of tert-butyl 3-[3-chloro-2-cyano-5-(1-hydroxyethyl)-6-methoxyphenyl]azetidine-1-carboxylate (8.6 g, 23 mmol) (97:3 enantiomeric mixture from Step 3) in methylene chloride (220 mL) was treated with triethylamine (8.2 mL, 59 mmol) and then methanesulfonic anhydride (6.1 g, 35 mmol) at 0° C. and stirred at 0° C. for 15 minutes. The reaction mixture was diluted with dichloromethane, washed with water and brine, dried over magnesium sulfate, filtered, and concentrated to give the crude mesylate, which was used without further purification. A solution of the crude mesylate intermediate in N,N-dimethylformamide (82 mL) was cooled to 0° C. and treated with sodium hydride (1.2 g, 30 mmol) (60% solution in mineral oil) and stirred at 0° C. for 30 minutes. The reaction mixture was treated dropwise over a period of 10 minutes with a solution of tert-butyl 3-(3-chloro-2-cyano-6-methoxy-5-{1-[(methylsulfonyl)oxy]ethyl}phenyl)azetidine-1-carboxylate (11 g, 24 mmol) in N,N-dimethylformamide (170 mL), stirred at 0° C. for 30 minutes, and heated at 50° C. for 1 hour. The reaction mixture was diluted with water and saturated sodium bicarbonate solution and extracted with ethyl acetate (3×200 mL). The combined organic extracts were washed with water (4×150 mL) and brine, dried over magnesium sulfate, filtered, and concentrated to give a crude oil. The crude material was purified by flash column chromatography (2% methanol / 98% dichloromethane to 7% methanol / 93% dichloromethane [0.5% triethylamine in dichloromethane]) to give the desired product as a 9:1 enantiomeric mixture (9.1 g, 77% over two steps). This material was separated by chiral HPLC (retention times = 5.81 min and 8.94 min; Chiracel AD-H column, 20 x 250 mm, 5 micron particle size, eluting with 10% ethanol in hexanes at 18 ml / min, 10 mg / injection) to give 6.9 g of the desired peak 1 material. 1HNMR(400MHz,DMSO-d6)δ 8.11(s,1H),7.52(s,1H),6.25(q,J=7.0Hz,1H),4.45~4.33(m,1H),4.27~ 4.13(m,4H),3.70(s,3H),2.55(s,3H),1.73(d,J=7.1Hz,3H),1.37(s,9H). C 20 H 21 LCMS of ClN7O3 ([M-(t-Bu)+H]+H) + : m / z = 442.1; Found: 442.1.

[0427] Step 5. 4-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-2-azetidin-3-yl-6-chloro-3-methoxybenzonitrile A solution of tert-butyl 3-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-6-cyano-2-methoxyphenyl}azetidine-1-carboxylate (1.7 g, 3.3 mmol) in methylene chloride (30 mL) was treated with trifluoroacetic acid (20 mL) and stirred at room temperature for 20 minutes. The reaction mixture was concentrated to give a residue which was diluted with methanol (50 mL) and saturated sodium bicarbonate solution (50 mL). The aqueous solution was diluted with brine (50 mL) and extracted with a 5:1 mixture of dichloromethane / isopropanol (5 x 100 mL). The combined organic extracts were dried over sodium sulfate and concentrated to give the desired product (1.4 g, 97%). The product was isolated as a single enantiomer. 1 HNMR(300MHz,DMSO-d6)δ 8.11(s,1H),7.46(s,1H),7.34(brs,2H),6.24(q,J=6.9Hz,1H),4.40~4.26 (m,1H),3.90~3.68(m,4H),3.63(s,3H),2.55(s,3H),1.72(d,J=7.1Hz,3H). C 19 H 21 LCMS (M+H) of ClNO + : m / z = 398.1; Found: 398.1.

[0428] Example 262. 4-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-6-chloro-3-methoxy-2-(1-methylazetidin-3-yl)benzonitrile [ka]

[0429] A solution of 4-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-2-azetidin-3-yl-6-chloro-3-methoxybenzonitrile (the chiral intermediate of Example 261) (50 mg, 0.13 mmol) in methanol (3 mL) was treated with sodium cyanoborohydride (20 mg, 0.31 mmol) and then formaldehyde (37% aqueous solution) (37 μL, 0.50 mmol) and stirred at room temperature for 20 minutes. The reaction mixture was quenched with acetic acid (170 μL, 2.9 mmol), diluted with methanol, and purified by preparative LCMS (XBridge C18 column, eluting with a gradient of acetonitrile / water containing 0.1% ammonium hydroxide at a flow rate of 60 mL / min) to give the desired product (30 mg, 58%). The product was isolated as a single enantiomer. 1 HNMR(300MHz,DMSO-d6)δ 8.11(s,1H),7.46(s,1H),7.37(brs,2H),6.23(q,J=7.0Hz,1H),4.10~3.96(m,1H),3.95~3. 85(m,2H),3.63(s,3H),3.05~2.94(m,2H),2.55(s,3H),2.18(s,3H),1.72(d,J=7.1Hz,3H). C 20 H 23 LCMS (M+H) of ClNO + : m / z = 412.2; Found: 412.1.

[0430] Example 268. 4-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-6-chloro-2-[1-(2-hydroxyethyl)azetidin-3-yl]-3-methoxybenzonitrile [ka]

[0431] A solution of 4-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-2-azetidin-3-yl-6-chloro-3-methoxybenzonitrile (the chiral intermediate of Example 261) (400 mg, 1.0 mmol) in tetrahydrofuran (14 mL) was treated with triethylamine (350 μL, 2.5 mmol) and 2-bromoethanol (85 μL, 1.2 mmol) and stirred at 60° C. overnight. The reaction mixture was concentrated, diluted with methanol, and purified by preparative LCMS (XBridge C18 column, eluting with a gradient of acetonitrile / water containing 0.1% ammonium hydroxide at a flow rate of 60 mL / min) to give the desired product (0.14 g, 31%). The product was isolated as a single enantiomer. 1 HNMR(400MHz,DMSO-d6)δ 8.11(s,1H),7.46(s,1H),6.24(q,J=6.9Hz,1H),4.41(t,J=5.4Hz,1H),4.12~4.03(m,1H),3.97~3.88(m,2H), 3.64(s,3H),3.38~3.34(m,2H),3.09~3.01(m,2H),2.55(s,3H),2.41(t,J=5.9Hz,2H),1.72(d,J=7.0Hz,3H). C 21 H 25 LCMS (M+H) of ClN7O2 + : m / z = 442.2; Found: 442.2.

[0432] The compounds of Examples 268 and 269 were synthesized from the same chiral intermediate of Example 261. According to the crystal structure determination of Example 269, the stereochemistry of the 1-position carbon of the ethane-1,1-diyl group is S. Since the compound of Example 268 was synthesized from the same chiral intermediate as Example 269, a person skilled in the art would expect that the 1-position carbon of the ethane-1,1-diyl group of Example 268 also has the S configuration. Therefore, the compound of Example 268 is believed to be (S)-4-(1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-6-chloro-2-(1-(2-hydroxyethyl)azetidin-3-yl)-3-methoxybenzonitrile.

[0433] Example 269. 4-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-6-chloro-2-{1-[(2S)-2-hydroxypropyl]azetidin-3-yl}-3-methoxybenzonitrile [ka]

[0434] A solution of 4-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-2-azetidin-3-yl-6-chloro-3-methoxybenzonitrile (the chiral intermediate of Example 261) (2.5 g, 6.3 mmol) in ethanol (130 mL) was treated with (S)-(-)-methyloxirane (1.1 mL, 16 mmol) and microwaved at 120 °C for 25 minutes. The reaction mixture was concentrated to give a residue, which was purified by flash column chromatography and preparative LCMS (XBridge C18 column, eluting with a gradient of acetonitrile / water containing 0.1% ammonium hydroxide at a flow rate of 60 mL / min) using methanol in dichloromethane (0% to 10%; 0.5% triethylamine in methanol) to give the desired product (0.76 g, 26%). The product was isolated as a single diastereomer. 1HNMR(300MHz,DMSO-d6)δ 8.11(s,1H),7.46(s,1H),7.34(brs,2H),6.23(q,J=7.0Hz,1H),4.35(brs,1H),4.14~3.99(m,1H),3.98~3.87(m,2H),3.64 (s,3H),3.60~3.52(m,1H),3.13~2.99(m,2H),2.55(s,3H),2.28(d,J=5.9Hz,2H),1.75~1.69(m,3H),1.00(d,J=6.2Hz,3H). C 22 H 27 LCMS (M+H) of ClN7O2 + : m / z = 456.2; Found: 456.2.

[0435] Crystal structure determination of the compound of Example 269 C22, H26, N7, O2, Cl1+H2O Crystal data: C22H28ClF0N7O3, from ACN / water, colorless, needle-like, approximately 0.500x0.070x0.050mm, monoclinic, C2, a=25.941(7)Å, b=4.9767(13)Å, c=17.787(5)Å, β=101.967(4)°, Vol=2246.3(10)Å 3 , Z=4, T=-100℃, formula weight=473.96, density=1.401g / cm 3 , μ(Mo)=0.21mm -1

[0436] Data collection: Bruker SMART APEX-II CCD system, MoKalpha synchrotron, standard focus tube, anode power = 50 kV x 42 mA, crystal-plate distance = 5.0 cm, 512 x 512 pixels / frame, beam center = (256.13, 253.14), total frames = 704, oscillation / frame = 0.50°, exposure / frame = 120.1 sec / frame, SAINT integral, hkl min / max = (-27, 34, -6, 6, -23, 11), data input to shelx = 7578, unique data = 5186, 2θ range = 3.20–56.74°, 2θ completeness = 99.70%, R(int-xl) = 0.0331, SADABS correction applied.

[0437] Analysis and refinement: The structure was analyzed using XS (Shelxtl) and refined using the shelxtl software package. 2 Full matrix least squares refinement of, Int.Tab.Vol C Table 4.2.6.8 and 6.1.1.4 from scattering factors, number of data = 5186, number of constraints = 2, number of parameters = 313, data / parameter ratio = 16.57, F 2 Goodness of fit = 1.02, R-index [I>4σ(I)] R1 = 0.0524, wR2 = 0.1033, R-index (all data) R1 = 0.0826, wR2 = 0.1162, maximum difference peak and hole = 0.294 and -0.221 e / Å 3 , refined Flack parameter = 0.05 (8), all hydrogen atoms except for NH2 and water hydrogens were idealized using the riding model.

[0438] Results: The asymmetric unit contains one molecule and one water molecule, as shown in Figure 1 with the thermal ellipsoid plotted for the 50% probability level. The proposed structure is confirmed. The absolute configuration is determined based on the known S configuration at C21. The configuration at C7 is determined to be S. Flack parameters also confirm the correct configuration. Based on the crystal structure, the compound of Example 269 is believed to be 4-((S)-1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-6-chloro-2-(1-((S)-2-hydroxypropyl)azetidin-3-yl)-3-methoxybenzonitrile. The crystal structure is shown in Figure 1.

[0439] Examples 272 and 273. Diastereoisomers of 4-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-6-chloro-2-[1-(2-hydroxy-1-methylethyl)azetidin-3-yl]-3-methoxybenzonitrile [ka]

[0440] A solution of 4-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-2-azetidin-3-yl-6-chloro-3-methoxybenzonitrile (40 mg, 0.10 mmol) in methanol (2 mL) was treated with sodium cyanoborohydride (16 mg, 0.25 mmol) and then acetol (28 μL, 0.40 mmol) and stirred at room temperature for 1 hour. The reaction mixture was quenched with acetic acid (100 μL, 1.8 mmol), diluted with methanol, and purified by preparative LCMS (XBridge C18 column, eluting with a gradient of acetonitrile / water containing 0.1% ammonium hydroxide at a flow rate of 60 mL / min) to give the desired product as a mixture of diastereoisomers. This diastereomeric mixture was separated by chiral HPLC (retention times = 3.70 min and 6.58 min; Phenomenex Lux Cellulose C-4 column, 21.2 x 250 mm, 5 micron particle size, eluting with 20% ethanol in hexanes at 18 ml / min, 5 mg / injection) to give the desired peak 1 isomer (compound 272) (19 mg, 41%) and peak 2 isomer (compound 273) (23 mg, 50%). Peak 1: 1 HNMR(300MHz,DMSO-d6)δ 8.11(s,1H),7.47(s,1H),7.34(brs,2H),6.24(q,J=6.9Hz,1H),4.43(t,J=5.2Hz,1H),4.07~3.82(m,3H),3.64(s,3H),3.31~3 .24(m,1H),3.17~3.06(m,2H),3.06~2.97(m,1H),2.55(s,3H),2.21~2.11(m,1H),1.72(d,J=7.1Hz,3H),0.81(d,J=6.3Hz,3H). C 22 H 27 LCMS (M+H)+ for ClN7O2: m / z = 456.2; Found: 456.2. Peak 2: 1HNMR(300MHz,DMSO-d6)δ 8.11(s,1H),7.47(s,1H),7.35(brs,2H),6.24(q,J=7.0Hz,1H),4.43(t,J=5.5Hz,1H),4.06~3.91(m,2H),3.89~3.79(m,1H),3 .64(s,3H),3.30~3.24(m,1H),3.15~3.00(m,3H),2.55(s,3H),2.21~2.10(m,1H),1.72(d,J=7.1Hz,3H),0.82(d,J=6.2Hz,3H). C 22 H 27 LCMS (M+H) of ClN7O2 + : m / z = 456.2; Found: 456.2.

[0441] Example 281. 2-(1-acetylazetidin-3-yl)-4-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-6-chloro-3-methoxybenzonitrile [ka]

[0442] A solution of 4-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-2-azetidin-3-yl-6-chloro-3-methoxybenzonitrile (the chiral intermediate of Example 261) (60 mg, 0.15 mmol) in tetrahydrofuran (2 mL) was treated with triethylamine (53 μL, 0.38 mmol) and then acetyl chloride (13 μL, 0.18 mmol) at 0° C. and stirred overnight at 20° C. The reaction mixture was diluted with methanol and purified by preparative LCMS (XBridge C18 column, eluting with a gradient of acetonitrile / water containing 0.1% ammonium hydroxide at a flow rate of 60 mL / min) to give the desired product (39 mg, 59%). The product was isolated as a single enantiomer. 1HNMR(300MHz,DMSO-d6)δ 8.11(s,1H),7.52(d,J=2.5Hz,1H),7.36(brs,2H),6.26(q,J=7.0Hz,1H),4.57~4.36(m,3H), 4.30~4.21(m,1H),4.18~4.08(m,1H),3.71(d,J=3.1Hz,3H),2.55(s,3H),1.78~1.71(m,6H). C 21 H 23 LCMS (M+H) of ClN7O2 + : m / z = 440.2; Measured value: 440.1.

[0443] Example 285. 4-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-6-chloro-3-methoxy-2-[1-(methylsulfonyl)azetidin-3-yl]benzonitrile [ka]

[0444] A solution of 4-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-2-azetidin-3-yl-6-chloro-3-methoxybenzonitrile (the chiral intermediate of Example 261) (40 mg, 0.10 mmol) in dichloromethane (1 mL) was treated with triethylamine (35 μL, 0.25 mmol), cooled to 0 ° C, treated with methanesulfonyl chloride (9.3 μL, 0.12 mmol), and stirred at 0 ° C for 1 hour. The reaction mixture was diluted with methanol and purified by preparative LCMS (XBridge C18 column, eluting with a gradient of acetonitrile / water containing 0.1% ammonium hydroxide at a flow rate of 60 mL / min) to give the desired product (20 mg, 42%). The product was isolated as a single enantiomer. 1HNMR(300MHz,DMSO-d6)δ 8.12(s,1H),7.55(s,1H),7.35(brs,2H),6.25(q,J=7.0Hz,1H),4.54~4.40(m,1H) ,4.27~4.12(m,4H),3.68(s,3H),3.01(s,3H),2.55(s,3H),1.74(d,J=7.1Hz,3H). C 20 H 23 LCMS (M+H) of ClN7O3S + : m / z = 476.1; Found: 476.1.

[0445] Example 289. Methyl 3-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-6-cyano-2-methoxyphenyl}azetidine-1-carboxylate [ka]

[0446] A solution of 4-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-2-azetidin-3-yl-6-chloro-3-methoxybenzonitrile (the chiral intermediate of Example 261) (20 mg, 0.05 mmol) in dichloromethane (1 mL) was treated with triethylamine (20 μL, 0.14 mmol) and then methyl chloroformate (4.7 μL, 0.06 mmol) and stirred at room temperature for 1 hour. The reaction mixture was diluted with methanol and purified by preparative LCMS (XBridge C18 column, eluting with a gradient of acetonitrile / water containing 0.1% ammonium hydroxide at a flow rate of 60 mL / min) to give the desired product (12 mg, 52%). The product was isolated as a single enantiomer. 1 HNMR(300MHz,DMSO-d6)δ 8.11(s,1H),7.51(s,1H),7.34(brs,2H),6.25(q,J=7.0Hz,1H),4.53~4.38(m,1H) ,4.36~4.17(m,4H),3.71(s,3H),3.55(s,3H),2.55(s,3H),1.73(d,J=7.1Hz,3H). C 21 H23 LCMS (M+H) of ClN7O3 + : m / z = 456.2; Found: 456.1.

[0447] Example 292. 3-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-6-cyano-2-methoxyphenyl}-N-(tert-butyl)azetidine-1-carboxamide [ka]

[0448] A solution of 4-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-2-azetidin-3-yl-6-chloro-3-methoxybenzonitrile (the chiral intermediate of Example 261) (20 mg, 0.05 mmol) in N,N-dimethylformamide (1 mL) was treated with triethylamine (20 μL, 0.14 mmol) and then 2-isocyanato-2-methyl-propane (7.2 μL, 0.063 mmol) and stirred overnight at room temperature. The reaction mixture was diluted with methanol and purified by preparative LCMS (XBridge C18 column, eluting with a gradient of acetonitrile / water containing 0.1% ammonium hydroxide at a flow rate of 60 mL / min) to give the desired product (16 mg, 64%). The product was isolated as a single enantiomer. 24 H 30 LCMS (M+H) of ClN8O2 + : m / z = 497.2; Found: 497.2.

[0449] Example 293. 3-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-6-cyano-2-methoxyphenyl}azetidine-1-carboxamide [ka]

[0450] A solution of 3-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-6-cyano-2-methoxyphenyl}-N-(tert-butyl)azetidine-1-carboxamide (chiral intermediate of Example 292) (16 mg, 0.032 mmol) in trifluoroacetic acid (2 mL) was heated in a microwave at 120° C. for 10 minutes. The reaction mixture was diluted with methanol and purified by preparative LCMS (XBridge C18 column, eluting with a gradient of acetonitrile / water containing 0.1% ammonium hydroxide at a flow rate of 60 ml / min) to give the desired product (7 mg, 50%). The product was isolated as a single enantiomer. 1 HNMR(300MHz,DMSO-d6)δ 8.12(s,1H),7.62(s,1H),7.35(brs,2H),6.28(q,J=6.9Hz,1H),5.70(brs,1H),4.62~4.49(m ,1H),4.34~4.20(m,1H),3.83(s,3H),3.78~3.49(m,2H),2.55(s,3H),1.73(d,J=7.0Hz,3H). C 20 H 22 LCMS (M+H) of ClN8O2 + : m / z = 441.2; Measured value: 441.1.

[0451] Example 296. 3-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-6-cyano-2-methoxyphenyl}-N,N-dimethylazetidine-1-carboxamide [ka]

[0452] A solution of 4-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-2-azetidin-3-yl-6-chloro-3-methoxybenzonitrile (the chiral intermediate of Example 261) (40 mg, 0.10 mmol) in N,N-dimethylformamide (2 mL) was treated with triethylamine (40 μL, 0.29 mmol) and then p-nitrophenyl chloroformate (23 μL, 0.13 mmol) and stirred at room temperature for 1 hour. The reaction mixture was diluted with methanol and purified by preparative LCMS (XBridge C18 column, eluting with a gradient of acetonitrile / water containing 0.1% ammonium hydroxide at a flow rate of 60 mL / min) to give the desired product, which was used immediately. A solution of the p-nitrophenyl carbamate intermediate in tetrahydrofuran (1 mL) was treated with triethylamine (15 μL, 0.11 mmol) followed by a 1.0 M solution of dimethylamine in tetrahydrofuran (150 μL, 0.15 mmol) and heated in a sealed tube at 60° C. for 2 hours. The reaction mixture was concentrated, diluted with methanol, and purified by preparative LCMS (XBridge C18 column, eluting with a gradient of acetonitrile / water containing 0.1% ammonium hydroxide at a flow rate of 60 mL / min) to give the desired product (13 mg, 28%). The product was isolated as a single enantiomer. 1 HNMR(300MHz,DMSO-d6)δ 8.11(s,1H),7.49(s,1H),7.36(brs,2H),6.25(q,J=7.0Hz,1H),4.44~4.23(m,3H) ,4.22~4.10(m,2H),3.69(s,3H),2.76(s,6H),2.55(s,3H),1.73(d,J=7.1Hz,3H). C 22 H 26 LCMS (M+H) of ClN8O2 + : m / z = 469.2; Measured value: 469.1.

[0453] Example 298. 1-{1-[4,5-dichloro-3-(1-ethylazetidin-3-yl)-2-methoxyphenyl]ethyl}-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine [ka]

[0454] Step 1. 1-(4,5-dichloro-2-hydroxyphenyl)ethanone A solution of 3,4-dichlorophenol [AK Scientific] (30 g, 18 mmol) in acetyl chloride (19 mL, 270 mmol) was stirred at 60° C. for 2 hours. The reaction mixture was cooled to 20° C., treated with aluminum trichloride (37 g, 280 mmol) in small portions, and heated at 180° C. for 30 minutes. The reaction mixture was cooled to 20° C., and the solution hardened into a solid mass that did not easily crumble. This material was cooled to 0° C. and slowly quenched with small portions of 1 M HCl. The solid mass of material was slowly broken up with enough HCl to homogenize the heterogeneous mixture by stirring overnight at 20° C. The solid was filtered, washed with copious amounts of water, and dried under vacuum to give the desired product as a brown solid (38 g, quantitative).

[0455] Step 2. 1-(4,5-dichloro-2-hydroxy-3-iodophenyl)ethanone A solution of 1-(4,5-dichloro-2-hydroxyphenyl)ethanone (12 g, 59 mmol) in acetic acid (70 mL) was treated with N-iodosuccinimide (16 g, 71 mmol) and stirred at 90° C. for 18 hours. The reaction mixture was treated with additional N-iodosuccinimide (8 g, 36 mmol) and stirred at 90° C. for 4 hours. The reaction mixture was concentrated, diluted with ethyl acetate, and quenched with saturated sodium bicarbonate until effervescence ceased. The organic layer was separated, and the aqueous layer was re-extracted with ethyl acetate. The combined organic layers were dried and concentrated to give a brown solid. This material was recrystallized from methanol to give the desired product (9.0 g, 46%) as a brown solid. 1 HNMR (300MHz, CDCl3) δ 13.36 (s, 1H), 7.85 (s, 1H), 2.65 (s, 3H). LCMS of C8H6Cl2IO2(M+H) + : m / z = 330.9, 332.9; Measured: 330.8, 332.9.

[0456] Step 3. 1-(4,5-dichloro-3-iodo-2-methoxyphenyl)ethanone A solution of 1-(4,5-dichloro-2-hydroxy-3-iodophenyl)ethanone (16 g, 47 mmol) and potassium carbonate (17 g, 120 mmol) in N,N-dimethylformamide (40 mL) was treated with methyl iodide (6.4 mL, 100 mmol) and stirred at 60° C. for 1 hour. The reaction mixture was diluted with water and extracted with ethyl acetate (twice). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated to give a crude solid. The crude material was purified by flash column chromatography using ethyl acetate in hexanes (5% to 30%) to give the desired product (14 g, 84%) as an orange solid. 1 HNMR (300MHz, CDCl3) δ 7.69 (s, 1H), 3.79 (s, 3H), 2.60 (s, 3H). LCMS of C9H8Cl2IO2 (M+H) + : m / z = 344.9, 346.9; Measured: 344.8, 346.9.

[0457] Step 4. tert-Butyl 3-(3-acetyl-5,6-dichloro-2-methoxyphenyl)azetidine-1-carboxylate Zinc (4.5 g, 69 mmol) was suspended in N,N-dimethylformamide (54 mL) with 1,2-dibromoethane (420 μL, 4.9 mmol). The mixture was heated at 70° C. for 10 minutes and then cooled to room temperature. Chlorotrimethylsilane (620 μL, 4.9 mmol) was added dropwise, and stirring was continued for 1 hour. A solution of tert-butyl 3-iodoazetidine-1-carboxylate (17 g, 61 mmol) in N,N-dimethylformamide (30 mL) was then added, and the mixture was heated at 40° C. for 1 hour. A mixture of 1-(4,5-dichloro-3-iodo-2-methoxyphenyl)ethanone (14 g, 41 mmol), tris(dibenzylideneacetone)dipalladium(0) (710 mg, 0.77 mmol), and tri-(2-furyl)phosphine (360 mg, 1.6 mmol) in N,N-dimethylformamide (120 mL) was then added quickly. The reaction mixture was stirred at room temperature overnight. The reaction mixture was then partitioned between ethyl acetate and saturated ammonium chloride solution. The organic layer was washed with water, dried over magnesium sulfate, filtered, and concentrated to give a crude residue, which was purified by flash column chromatography using acetic acid in hexanes (0% to 25%) to give the desired product (12 g, 77%). 17 H 21 LCMS of Cl2NO4Na (M+Na) + : m / z = 396.1; Measured value: 396.0.

[0458] Step 5. tert-Butyl 3-[2,3-dichloro-5-(1-hydroxyethyl)-6-methoxyphenyl]azetidine-1-carboxylate A solution of tert-butyl 3-(3-acetyl-5,6-dichloro-2-methoxyphenyl)azetidine-1-carboxylate (9.6 g, 26 mmol) in methanol (240 mL) was treated with sodium tetrahydroborate (1.9 g, 51 mmol) in small portions over 5 minutes at 0° C. and stirred at 0° C. for 30 minutes. The reaction mixture was quenched with acetic acid (7.3 mL, 130 mmol) at 0° C. and treated with saturated sodium bicarbonate solution (approximately 50 mL). The reaction mixture was concentrated to remove most of the methanol (to approximately 60 mL), poured into saturated sodium bicarbonate solution (150 mL), and extracted with ethyl acetate (2×200 mL). The combined organic extracts were washed with water and brine, dried over sodium sulfate, filtered, and concentrated to give the desired product (9.6 g, quantitative), which was used without further purification. 13 H 16 LCMS of Cl2NO4 ([M-(t-Bu)+H]+H) + : m / z = 320.0; Measured value: 320.0.

[0459] Step 6. tert-Butyl 3-[2,3-dichloro-5-(1-chloroethyl)-6-methoxyphenyl]azetidine-1-carboxylate N,N-Dimethylformamide (0.92 mL, 12 mmol) was added to solid cyanuric acid chloride (2.2 g, 12 mmol) at room temperature (DMF was absorbed by the solid). The mixture was allowed to stand for 10 minutes, then treated with methylene chloride (60 mL) and stirred for several minutes to break up the solid. The reaction mixture was treated with a solution of tert-butyl 3-[2,3-dichloro-5-(1-hydroxyethyl)-6-methoxyphenyl]azetidine-1-carboxylate (3.0 g, 8.0 mmol) in methylene chloride (30 mL) and stirred at 35-40°C for 2 hours. The reaction mixture was treated with additional N,N-dimethylformamide (1 mL) and stirred at 35-40°C for 4 hours. The reaction required an additional 1 mL of N,N-dimethylformamide to reach completion and was stirred at 35-40°C overnight. The reaction mixture was diluted with water and dichloromethane. The organic phase was separated, washed with saturated sodium bicarbonate solution, water, and brine, dried over magnesium sulfate, filtered, and concentrated to give a crude residue. The crude material was purified by flash column chromatography using ethyl acetate in hexanes (5% to 40%) to give the desired product (2.8 g, 90%). 13 H 15 LCMS of Cl3NO3 ([M-(t-Bu)+H]+H) + : m / z = 338.0, 340.0; Measured values: 337.9, 339.9.

[0460] Step 7. tert-Butyl 3-{3-[1-(4-amino-3-methyl-1H-pyrazolo[4,3-c]pyridin-1-yl)ethyl]-5,6-dichloro-2-methoxyphenyl}azetidine-1-carboxylate A solution of tert-butyl 3-[2,3-dichloro-5-(1-chloroethyl)-6-methoxyphenyl]azetidine-1-carboxylate (1.0 g, 2.5 mmol) and 3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.43 g, 2.9 mmol) in N,N-dimethylformamide (23 mL) was treated with cesium carbonate (1.2 g, 3.8 mmol) and potassium iodide (42 mg, 0.25 mmol) and heated at 100° C. for 10 hours. The reaction mixture was diluted with ethyl acetate (75 mL) and water (75 mL). The aqueous layer was separated and re-extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with water, saturated sodium bicarbonate solution, and brine, dried over magnesium sulfate, filtered, and concentrated to give a crude residue. The crude material was purified by flash column chromatography using methanol in dichloromethane (0% to 10%) to give the desired product (0.97 g, 75%). 23 H 29 LCMS (M+H) of Cl2N6O3 + : m / z = 507.2, 509.2; Measured values: 507.0, 509.0.

[0461] Step 8. 1-[1-(3-azetidin-3-yl-4,5-dichloro-2-methoxyphenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine A solution of tert-butyl 3-{3-[1-(4-amino-3-methyl-1H-pyrazolo[4,3-c]pyridin-1-yl)ethyl]-5,6-dichloro-2-methoxyphenyl}azetidine-1-carboxylate (0.97 g, 1.9 mmol) in methylene chloride (20 mL) was treated with trifluoroacetic acid (10 mL) and stirred at 20° C. for 30 minutes. The reaction mixture was concentrated, and the residue was diluted with methanol (approximately 20 mL) and treated with saturated sodium bicarbonate solution (to pH approximately 8). The reaction mixture was concentrated to remove the methanol. The oil suspended in the aqueous layer was extracted into a 5:1 mixture of dichloromethane / isopropanol, dried over magnesium sulfate, filtered, and concentrated to give the desired product (0.77 g, 99%), which was used in the next step without further purification. 18H 21 LCMS (M+H) of Cl2NO + : m / z = 407.1, 409.1; Measured values: 407.0, 409.0.

[0462] Step 9. 1-{1-[4,5-dichloro-3-(1-ethylazetidin-3-yl)-2-methoxyphenyl]ethyl}-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine A solution of 1-[1-(3-azetidin-3-yl-4,5-dichloro-2-methoxyphenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (40 mg, 0.098 mmol) in methanol (2.6 mL) was treated with sodium cyanoborohydride (15 mg, 0.25 mmol) followed by acetaldehyde (22 μL, 0.39 mmol) and stirred for 20 minutes at 20° C. The reaction mixture was quenched with acetic acid (130 μL, 2.3 mmol), diluted with methanol, and purified by preparative LCMS (XBridge C18 column, eluting with a gradient of acetonitrile / water containing 0.1% ammonium hydroxide at a flow rate of 60 mL / min) to give the desired product as a mixture of enantiomers. This racemic mixture was separated by chiral HPLC (retention times = 18.6 min and 22.0 min; Phenomenex Lux Cellulose C-4 column, 21.2 x 250 mm, 5 micron particle size, eluting with 5% ethanol in hexanes at 18 ml / min, 2.5 mg / injection) to give the desired peak 1 isomer (11 mg, 265). 1 HNMR(300MHz,DMSO-d6)δ 8.11(s,1H),7.45(s,1H),7.33(brs,2H),6.21(q,J=6.9Hz,1H),3.98-3.77(m,3H),3.57(s,3H),2.92-2.8 3(m,1H),2.79-2.72(m,1H),2.55(s,3H),2.35-2.22(m,2H),1.70(d,J=7.1Hz,3H),0.86(t,J=7.1Hz,3H). C 20 H 25 LCMS (M+H) of Cl2NO + : m / z = 435.1; Measured value: 435.0.

[0463] Example 307. 4-[1-(4-amino-5-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)ethyl]-6-chloro-3-ethoxy-2-(1-isopropylazetidin-3-yl)benzonitrile [ka]

[0464] Step 1. tert-Butyl 3-{3-[1-(4-amino-5-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)ethyl]-5-chloro-6-cyano-2-ethoxyphenyl}azetidine-1-carboxylate The desired compound was synthesized according to the method of Example 212, Step 5 (chiral intermediate) using 5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (ACES Pharma) instead of 3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine as the starting material in 18% yield. 1 HNMR(500MHz,CDCl3)δ 8.13(s,1H),6.93(brs,1H),6.79(s,1H),6.17(q,J=7.1Hz,1H),5.24(s,2H),4.40~4.27(m,4H),4.27~4.18(m,1 H),4.03~3.92(m,1H),3.80~3.70(m,1H),2.43(s,3H),1.74(d,J=7.1Hz,3H),1.43(s,9H),1.40(t,J=7.0Hz,3H). C 26 H 32 LCMS (M+H) of ClN6O3 + : m / z = 511.2; Found: 511.2.

[0465] Step 2. 4-[1-(4-amino-5-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)ethyl]-2-azetidin-3-yl-6-chloro-3-ethoxybenzonitrile The desired compound was synthesized in 99% yield according to the method of Example 212, Step 6, using tert-butyl 3-{3-[1-(4-amino-5-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)ethyl]-5-chloro-6-cyano-2-ethoxyphenyl}azetidine-1-carboxylate instead of tert-butyl 3-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-6-cyano-2-ethoxyphenyl}azetidine-1-carboxylate as the starting material. 21 H 24 LCMS (M+H) of ClNO + : m / z = 411.2; Found: 411.1.

[0466] Step 3. 4-[1-(4-amino-5-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)ethyl]-6-chloro-3-ethoxy-2-(1-isopropylazetidin-3-yl)benzonitrile The desired compound was synthesized in 65% yield according to the method of Example 213, using 4-[1-(4-amino-5-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)ethyl]-2-azetidin-3-yl-6-chloro-3-ethoxybenzonitrile instead of 4-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-2-azetidin-3-yl-6-chloro-3-ethoxybenzonitrile as the starting material. The product was isolated as a single enantiomer. 1 HNMR(300MHz,dmso)δ 7.95(s,1H),7.19(s,1H),7.16-7.13(m,1H),6.58(s,2H),6.11(q,J=7.1Hz,1H),4.04~3.67(m,5H),3.04~2.92( m,2H),2.36(s,3H),2.27~2.12(m,1H),1.69(d,J=7.1Hz,3H),1.30(t,J=6.9Hz,3H),0.85(dd,J=6.1,1.8Hz,6H). C 24 H 30 LCMS calculated for ClNO (M+H) + : m / z = 453.2; Found: 453.3.

[0467] Example 315. 4-[-1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-2-{1-[(2S)-2-hydroxypropyl]azetidin-3-yl}-3-methoxy-6-methylbenzonitrile [ka]

[0468] Step 1. 4-Acetyl-5-hydroxy-2-methylbenzonitrile 1-(4-Bromo-2-hydroxy-5-methylphenyl)ethanone (8.5 g, 37 mmol, Alfa Aesar catalog number H29125) was combined with zinc cyanide (8.7 g, 74 mmol) in nitrogen-degassed N,N-dimethylformamide (75 mL), and tris(dibenzylideneacetone)dipalladium(0) (1.0 g, 1.1 mmol) and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (1.5 g, 2.6 mmol) were added. The reaction was again degassed with nitrogen, heated to 120° C., and monitored by LC / MS. After 18 hours of heating, the reaction was complete and allowed to cool to room temperature, dissolved in ethyl acetate, washed with water (twice), brine, dried over magnesium sulfate, and concentrated to give the crude product as a dark amber oil. The product was purified by FCC on silica gel eluting with a hexane:ethyl acetate gradient to give 4-acetyl-5-hydroxy-2-methylbenzonitrile (6.3 g, 98%) as a solid. 10 H 10 LCMS calculated value for NO2 (M+H) + : m / z = 176.1; Measured value: 176.2.

[0469] Step 2. 4-Acetyl-3-hydroxy-2-iodo-6-methylbenzonitrile 4-Acetyl-5-hydroxy-2-methylbenzonitrile (6.7 g, 38 mmol) was dissolved in acetic acid (80 mL) and N-iodosuccinimide (10 g, 46 mmol) was added. The reaction was heated to 80° C. in an oil bath and monitored by LC / MS. After 4 hours of heating, the reaction was complete. It was allowed to cool and concentrated in vacuo to give a dark oil. The oil was dissolved in ethyl acetate, washed with water, sodium bicarbonate (three times, remained slightly basic), brine, dried over magnesium sulfate, and concentrated to give the crude product as a dark oil. The product was purified by FCC on silica gel eluting with a hexane:ethyl acetate gradient to give 4-acetyl-3-hydroxy-2-iodo-6-methylbenzonitrile (7.2 g, 62%) as a pale yellow solid. 10 LCMS calculated value for H9INO2 (M+H) + : m / z = 301.9; Measured value: 301.9.

[0470] Step 3. 4-Acetyl-2-iodo-3-methoxy-6-methylbenzonitrile 4-Acetyl-3-hydroxy-2-iodo-6-methylbenzonitrile (5.0 g, 17 mmol) was dissolved in N,N-dimethylformamide (50 mL) and potassium carbonate (4.6 g, 33 mmol) and methyl iodide (2.1 mL, 33 mmol) were added. The reaction was heated to 60° C. and monitored by LC / MS. After 2 hours of heating, the reaction was complete. It was allowed to cool, diluted with ethyl acetate (300 mL), and filtered to remove any remaining solids. The organic layer was washed with water (3 times), brine, dried over magnesium sulfate, and concentrated to give the crude product as a dark solid. The product was purified by FCC on silica gel, eluting with a hexane:ethyl acetate gradient, to give 4-acetyl-3-methoxy-2-iodo-6-methylbenzonitrile (5.0 g, 96%) as a pale yellow crystalline solid. 11 H 11 LCMS calculated value of INO2 (M+H) + : m / z = 315.9; Measured value: 316.0.

[0471] Step 4. tert-Butyl 3-(3-acetyl-6-cyano-2-methoxy-5-methylphenyl)azetidine-1-carboxylate Zinc (1.70 g, 26.0 mmol) and Celite (oven-dried, 500 mg) were crushed and combined in a flask until a uniform solid appeared. The flask was heated with a heat gun under high vacuum for 5 minutes and then backfilled with nitrogen. The solid was suspended in N,N-dimethylacetamide (4.2 mL) and 1,2-dibromoethane (0.13 mL, 1.5 mmol) was added. The reaction mixture was heated at 70°C for 30 minutes and then cooled to room temperature. Chlorotrimethylsilane (0.16 mL, 1.3 mmol) was added dropwise and stirring was continued at room temperature for 2 hours. A solution of tert-butyl 3-iodoazetidine-1-carboxylate (2.70 g, 9.52 mmol) in N,N-dimethylacetamide (4.35 mL) was then slowly added, and the resulting mixture was heated at 50°C for 2 hours. The zinc-iodo reagent was allowed to cool to room temperature, taken up in a syringe, filtered through a PTFE filter (fitted with a needle), and added directly to a suspension of tris(dibenzylideneacetone)dipalladium(0) (0.111 g, 0.121 mmol), tri-(2-furyl)phosphine (0.056 g, 0.24 mmol), and 4-acetyl-2-iodo-3-methoxy-6-methylbenzonitrile (2.0 g, 6.3 mmol) in N,N-dimethylacetamide (19.6 mL), which had previously been degassed with N. The reaction mixture was again degassed with nitrogen and heated to 70 °C. After 30 minutes of heating, the reaction was complete as monitored by LC / MS. It was allowed to cool, dissolved in ethyl acetate, washed with water, brine, dried over magnesium sulfate, and concentrated to give the crude product as an oil. The product was purified by FCC on silica gel eluting with a hexane:ethyl acetate gradient to give tert-butyl 3-(3-acetyl-6-cyano-2-methoxy-5-methylphenyl)azetidine-1-carboxylate (1.8 g, 82%) as a clear oil. 15 H 17 LCMS calculated for N2O4 (M+H) + : m / z = 289.1; Measured value: 289.1.

[0472] Step 5. tert-Butyl 3-[2-cyano-5-(1-hydroxyethyl)-6-methoxy-3-methylphenyl]azetidine-1-carboxylate tert-Butyl 3-(3-acetyl-6-cyano-2-methoxy-5-methylphenyl)azetidine-1-carboxylate (2.2 g, 6.4 mmol) was dissolved in methanol (20 mL) and cooled in an ice bath. Sodium tetrahydroborate (0.26 g, 7.0 mmol) was added in small portions, and the reaction was monitored by LC / MS. After stirring for 1 hour, the reaction was complete. It was diluted with ethyl acetate and water. The combined organic layers were washed with water, saturated sodium bicarbonate, brine, dried over magnesium sulfate, and concentrated to give crude tert-butyl 3-[2-cyano-5-(1-hydroxyethyl)-6-methoxy-3-methylphenyl]azetidine-1-carboxylate (2.1 g, 99%) as a yellow foam. 15 H 19 LCMS calculated for N2O4 (M+H) + : m / z = 291.1; Measured value: 291.1.

[0473] Step 6. tert-Butyl 3-[3-(1-chloroethyl)-6-cyano-2-methoxy-5-methylphenyl]azetidine-1-carboxylate tert-Butyl 3-[2-cyano-5-(1-hydroxyethyl)-6-methoxy-3-methylphenyl]azetidine-1-carboxylate (2.1 g, 6.4 mmol) was dissolved in methylene chloride (50.0 mL) and N,N-dimethylformamide (0.59 mL), cooled in an ice bath, and thionyl chloride (0.56 mL, 7.7 mmol) was slowly added. After stirring for 2 hours, the reaction was determined to be complete by LC / MS and partitioned between ethyl acetate and water. The combined organic layers were washed with water, saturated sodium bicarbonate, brine, dried over magnesium sulfate, and concentrated to give crude tert-butyl 3-[3-(1-chloroethyl)-6-cyano-2-methoxy-5-methylphenyl]azetidine-1-carboxylate (2.2 g, 100%) as an oil. 15 H 18LCMS calculated for ClN2O3 (M+H) + : m / z = 309.1; Found: 309.1.

[0474] Step 7. tert-Butyl 3-{3-[-1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-6-cyano-2-methoxy-5-methylphenyl}azetidine-1-carboxylate tert-Butyl 3-[3-(1-chloroethyl)-6-cyano-2-methoxy-5-methylphenyl]azetidine-1-carboxylate (2.3 g, 6.3 mmol) was dissolved in N,N-dimethylformamide (68 mL) along with cesium carbonate (4.1 g, 13 mmol) and 3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (1.4 g, 9.4 mmol) and heated to 80° C. in an oil bath. The reaction was stirred for 18 hours and allowed to cool to room temperature. The reaction mixture was dissolved in ethyl acetate, filtered, washed with water, brine, dried over magnesium sulfate, and concentrated to give the crude product. The product was purified by FCC on silica gel using a (hexane:10% ethanol ethyl acetate) gradient to give tert-butyl 3-{3-[-1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-6-cyano-2-methoxy-5-methylphenyl}azetidine-1-carboxylate (1.5 g, 50%) as a semi-solid. 25 H 32 LCMS calculated value for N7O3 (M+H) +Found: 478.2. The enantiomers were separated by chiral column HPLC using a Phenomenex LUX Cellulose column, 21.1×250 mm, 5 micron, 15% ethanol in hexane, 18 ml / min, approximately 5 mg / injection to give: 1st peak retention time: 2.1 min, tert-butyl 3-{3-[-1-(4-amino-3-methyl-1H-pyrazolo[3,4-d...

Claims

1. Formula I: 【Chemistry 1】 (In the formula: R ２ is C １～６ Alkyl or C １～６ haloalkyl; R ４ is halo, OH, CN, C １～４ Alkyl, C １～４ Haloalkyl, C １～４ Alkoxy, or C １～４ haloalkoxy; R ５ is halo, OH, CN, C １～４ Alkyl, C １～４ Haloalkyl, C １～４ Alkoxy, or C １～４ haloalkoxy; Cy each independently represents 1, 2, 3, or 4 independently selected R ３ C may be substituted by a group; ３～７ selected from cycloalkyl, 4- to 7-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl; Each R ３ are independently １ , -(C １～３ (alkylene)-Cy １ , Haro, CN, NO ２ , C １～６ Alkyl, C ２～６ Alkenyl, C ２～６ Alkynyl, C １～６ Haloalkyl, OR ａ１ , S.R. ａ１ , C(=O)R ｂ１ , C(=O)NR ｃ１ R ｄ１ , C(=O)OR ａ１ , OC(=O)R ｂ１ , OC(=O)NR ｃ１ R ｄ１ , N.R. ｃ１ R ｄ１ , N.R. ｃ１ C(=O)R ｂ１ , N.R. ｃ１ C(=O)OR ｂ１ , N.R. ｃ１ C(=O)NR ｃ１ R ｄ１ , C(=NR ｅ ) R ｂ１ , C(=NR ｅ ) N.R. ｃ１ R ｄ１ , N.R. ｃ１ C (=NR ｅ ) N.R. ｃ１ R ｄ１ , N.R. ｃ１ S(=O)R ｂ１ , N.R. ｃ１ S (=O) ２ N.R. ｃ１ R ｄ１ , S(=O)R ｂ１ , S(=O) ２ R ｂ１ and S(=O) ２ N.R. ｃ１ R ｄ１ C is selected from １～６ Alkyl, C ２～６ Alkenyl, C ２～６ Each alkynyl is selected from 1, 2, 3, or 4 independently selected R １１ may be substituted with a group; Each Cy １ each of which is selected from 1, 2, 3, or 4 independently selected R １１ C may be substituted by a group; ３～７ independently selected from cycloalkyl, 4- to 7-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl; Each R ａ１ , R ｃ１ , and R ｄ１ are independently H, C １～６ Alkyl, C １～６ Haloalkyl, C ２～６ Alkenyl, C ２～６ Alkynyl, C ３～７ cycloalkyl, 4- to 7-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl; １～６ Alkyl, C ２～６ Alkenyl, C ２～６ Alkynyl, C ３～７ Cycloalkyl, 4- to 7-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl each have one, two, or three independently selected R １１ may be substituted with a group; Each R ｂ１ is independently １～６ Alkyl, C １～６ Haloalkyl, C ２～６ Alkenyl, C ２～６ Alkynyl, C ３～７ cycloalkyl, 4- to 7-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl; １～６ Alkyl, C ２～６ Alkenyl, C ２～６ Alkynyl, C ３～７ Cycloalkyl, 4- to 7-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl each have one, two, or three independently selected R １１ may be substituted with a group; Or R ｃ１ and R ｄ１ together with the N atom to which they are attached, are -OH or C １～３ forming a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted by alkyl; Each R ｅ are independently H, CN, OH, C １～４ Alkyl, and C １～４ alkoxy; and Each R １１ are independently OH, NO ２ , C.N., Halo, C. １～３ Alkyl, C ２～３ Alkenyl, C ２～３ Alkynyl, C １～３ Haloalkyl, Cyano-C １～３ Alkyl, HO-C １～３ Alkyl, C １～３ Alkoxy-C １～３ Alkyl, C ３～７ Cycloalkyl, C １～３ Alkoxy, C １～３ Haloalkoxy, Amino, C １～３ Alkylamino, di(C １～３ Alkyl)amino, thio, C １～３ Alkylthio, C １～３ Alkylsulfinyl, C １～３ Alkyl sulfonyl, carbamyl, C １～３ Alkylcarbamyl, di(C １～３ Alkyl) carbamyl, carboxy, C １～３ Alkylcarbonyl, C １～４ Alkoxycarbonyl, C １～３ Alkylcarbonylamino, C １～３ Alkyl sulfonylamino, aminosulfonyl, C １～３ Alkylaminosulfonyl, di(C １～３ alkyl)aminosulfonyl, aminosulfonylamino, C １～３ Alkylaminosulfonylamino, di(C １～３ alkyl)aminosulfonylamino, aminocarbonylamino, C １～３ Alkylaminocarbonylamino, and di(C １～３ alkyl)aminocarbonylamino) or a pharmacologic acceptable salt thereof, in a patient, for the treatment of idiopathic thrombocytopenic purpura (ITP), autoimmune hemolytic anemia, vasculitis, systemic lupus erythematosus, lupus nephritis, pemphigus, membranous nephropathy, chronic lymphocytic leukemia (CLL), non-Hodgkin's lymphoma, hairy cell leukemia, mantle cell lymphoma, small lymphocytic lymphoma, follicular lymphoma, lymphoplasmacytic lymphoma, extranodal marginal zone lymphoma, Hodgkin's lymphoma, Waldenstrom's macroglobulinemia, or prolymphocytic leukemia in said patient. , acute lymphoblastic leukemia, myelofibrosis, mucosa-associated lymphoid tissue (MALT) lymphoma, mediastinal (thymic) large B-cell lymphoma, lymphomatoid granulomatosis, splenic marginal zone lymphoma, primary effusion lymphoma, intravascular large B-cell lymphoma, plasma cell leukemia, extramedullary plasmacytoma, smoldering myeloma (also known as asymptomatic myeloma), monoclonal gammopathy of undetermined significance (MGUS), activated B-cell-like (ABC) diffuse large B-cell lymphoma, or germinal center B-cell (GCB) diffuse large B-cell lymphoma.

2. R ２ But, C １～３ Alkyl or C １～３ The method of claim 1 , wherein the alkyl group is a fluoroalkyl group.

3. R ２ The method of claim 1, wherein is methyl, ethyl, or 2,2-difluoromethyl.

4. R ２ The method of claim 1 , wherein is methyl.

5. R ２ The method of claim 1 , wherein is ethyl.

6. R ４ Halo, CN, or C １～３ The method according to any one of claims 1 to 5, wherein the alkyl group is an alkyl group.

7. R ４ The method of any one of claims 1 to 5, wherein is F, Cl, CN, or methyl.

8. R ４ The method according to any one of claims 1 to 5, wherein is F.

9. R ４ The method according to any one of claims 1 to 5, wherein is Cl.

10. R ４ The method according to any one of claims 1 to 5, wherein is CN.

11. R ４ The method according to any one of claims 1 to 5, wherein is methyl.

12. R ５ Halo, CN, or C １～３ The method according to any one of claims 1 to 11, wherein the alkyl group is an alkyl group.

13. R ５ The method of any one of claims 1 to 11, wherein is Cl, CN, or methyl.

14. R ５ The method according to any one of claims 1 to 11, wherein is Cl.

15. R ５ The method according to any one of claims 1 to 11, wherein is CN.

16. R ５ The method according to any one of claims 1 to 11, wherein is methyl.

17. Cy each independently represents 1, 2, 3, or 4 independently selected R ３ C may be substituted by a group; ３～６ The method of any one of claims 1 to 16, wherein the aryl group is selected from cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl.

18. Cy each independently represents 1, 2, 3, or 4 independently selected R ３ The method according to any one of claims 1 to 16, wherein the heterocycloalkyl is a 4- to 6-membered heterocycloalkyl optionally substituted by a group.

19. Cy each independently represents 1, 2, 3, or 4 independently selected R ３ The method according to any one of claims 1 to 16, wherein the ring is selected from a cyclopropyl ring, a phenyl ring, an azetidine ring, a pyrrolidine ring, a piperidine ring, a 3-oxo-morpholin-6-yl, a 2-oxo-pyrrolidin-4-yl, a 2-oxo-oxazolidin-4-yl, a 2-oxo-oxazolidin-5-yl, a pyrazole ring, a pyridine ring and a pyrimidine ring, each of which is optionally substituted by a group.

20. Each R ３ are independently １ , -(C １～３ (alkylene)-Cy １ , Haro, C.N., C １～６ Alkyl, OR ａ１ , N.R. ｃ１ R ｄ１ , C(=O)R ｂ１ , C(=O)OR ａ１ , C(=O)NR ｃ１ R ｄ１ and S(=O) ２ R ｂ１ and C is selected from １－６ Alkyl is one, two, three, or four independently selected R １１ may be substituted with a group; Each Cy １ is independently one, two, three, or four independently selected R １１ C may be substituted by a group; ３～７ is cycloalkyl; Each R ａ１ , R ｃ１ , and R ｄ１ are independently H and C １～６ alkyl, １～６ Alkyl is one, two, or three independently selected R １１ may be substituted with a group; Each R ｂ１ is independently one, two, or three independently selected R １１ C optionally substituted with a group １～６ is alkyl; and Each R １１ are independently OH, CN, halo, cyano-C １～３ Alkyl, C １～３ Haloalkoxy, Amino, C １～３ Alkylamino, di(C １～３ alkyl)amino, C １～３ Alkylcarbonyl, C １～３ Alkoxycarbonyl, carbamyl, C １～３ Alkylcarbamyl, or di(C １～３ alkyl)carbamyl; 20. The method according to any one of claims 1 to 19.

21. R ２ is C １～３ Alkyl or C １～３ is fluoroalkyl; R ４ is halo, CN, or C １～３ is alkyl; R ５ is halo, CN, or C １～３ is alkyl; Cy each independently represents 1, 2, 3, or 4 independently selected R ３ C may be substituted by a group; ３～６ selected from cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl; Each R ３ are independently １ , -(C １～３ (alkylene)-Cy １ , Haro, C.N., C １～６ Alkyl, OR ａ１ , N.R. ｃ１ R ｄ１ , C(=O)R ｂ１ , C(=O)OR ａ１ , C(=O)NR ｃ１ R ｄ１ and S(=O) ２ R ｂ１ and C is selected from １－６ Alkyl is one, two, three, or four independently selected R １１ may be substituted with a group; Each Cy １ is independently one, two, three, or four independently selected R １１ C optionally substituted by a group ３～７ is cycloalkyl; Each R ａ１ , R ｃ１ , and R ｄ１ are independently H and C １～６ alkyl, １～６ Alkyl is one, two, or three independently selected R １１ may be substituted with a group; Each R ｂ１ is independently one, two, or three independently selected R １１ C optionally substituted with a group １～６ is alkyl; and Each R １１ are independently OH, CN, halo, cyano-C １～３ Alkyl, C １～３ Haloalkoxy, Amino, C １～３ Alkylamino, di(C １～３ alkyl)amino, C １～３ Alkylcarbonyl, C １～３ Alkoxycarbonyl, carbamyl, C １～３ Alkylcarbamyl, or di(C １～３ alkyl)carbamyl; The method of claim 1.

22. R ２ is methyl, ethyl, or 2,2-difluoromethyl; R ４ is F, Cl, CN, or methyl; R ５ is Cl, CN, or methyl; Cy each independently represents 1, 2, 3, or 4 independently selected R ３ C may be substituted by a group; ３～６ selected from cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl; Each R ３ are independently １ , -(C １～３ (alkylene)-Cy １ , Haro, C.N., C １～６ Alkyl, OR ａ１ , N.R. ｃ１ R ｄ１ , C(=O)R ｂ１ , C(=O)OR ａ１ , C(=O)NR ｃ１ R ｄ１ and S(=O) ２ R ｂ１ and C is selected from １～６ Alkyl is one, two, three, or four independently selected R １１ may be substituted with a group; Each Cy １ is independently one, two, three, or four independently selected R １１ C optionally substituted by a group ３～７ is cycloalkyl; Each R ａ１ , R ｃ１ , and R ｄ１ are independently H and C １～６ alkyl, １～６ Alkyl is one, two, or three independently selected R １１ may be substituted with a group; Each R ｂ１ is independently one, two, or three independently selected R １１ C optionally substituted with a group １～６ is alkyl; and Each R １１ are independently OH, CN, halo, cyano-C １～３ Alkyl, C １～３ Haloalkoxy, Amino, C １～３ Alkylamino, di(C １～３ alkyl)amino, C １～３ Alkylcarbonyl, C １～３ Alkoxycarbonyl, carbamyl, C １～３ Alkylcarbamyl, or di(C １～３ alkyl)carbamyl; The method of claim 1.

23. R ２ is methyl, ethyl, or 2,2-difluoromethyl; R ４ is F, Cl, CN, or methyl; R ５ is Cl, CN, or methyl; Cy is selected from a cyclopropyl ring, a phenyl ring, an azetidine ring, a pyrrolidine ring, a piperidine ring, a 3-oxo-morpholin-6-yl, a 2-oxo-pyrrolidin-4-yl, a 2-oxo-oxazolidin-4-yl, a 2-oxo-oxazolidin-5-yl, a pyrazole ring, a pyridine ring, and a pyrimidine ring, each of which is joined by one, two, three, or four independently selected R ３ may be substituted with a group; Each R ３ are independently １ , -(C １～３ (alkylene)-Cy １ , Haro, C １～６ Alkyl, OR ａ１ , N.R. ｃ１ R ｄ１ , C(=O)R ｂ１ , C(=O)OR ａ１ , C(=O)NR ｃ１ R ｄ１ and S(=O) ２ R ｂ１ and C is selected from １～６ Alkyl is one, two, three, or four independently selected R １１ may be substituted with a group; Each Cy １ is independently selected from cyclopropyl and cyclobutyl, each of which is selected from 1, 2, 3, or 4 independently selected R １１ may be substituted with a group; Each R ａ１ , R ｃ１ , and R ｄ１ are independently H and C １～４ alkyl; １～４ Alkyl is one, two, or three independently selected R １１ may be substituted with a group; Each R ｂ１ is independently one, two, or three independently selected R １１ C optionally substituted with a group １～４ is alkyl; Each R １１ are independently OH, CN, halo, cyano-C １～３ Alkyl, C １～３ Alkoxy-C １～３ Alkyl, C １～３ Alkoxy, C １～３ Haloalkoxy, Amino, C １～３ Alkylamino, di(C １～３ alkyl)amino, C １～３ Alkylcarbonyl, C １～４ Alkoxycarbonyl, carbamyl, C １～３ Alkylcarbamyl, or di(C １～３ alkyl)carbamyl; The method of claim 1.

24. The compound has formula II: 【Chemistry 2】 or a pharma- ceutically acceptable salt thereof.

25. The compound has formula III: 【Chemistry 3】 or a pharma- ceutically acceptable salt thereof.

26. The compound has formula IV: 【Chemistry 4】 (In the formula: G is NH, n is 1 and V is O; or G is NH, n is 0, and V is O or CH ２ or G is O, n is 0, and V is NH. or a pharma- ceutically acceptable salt thereof.

27. The compound has formula IVa: 【Chemistry 5】 or a pharma- ceutically acceptable salt thereof.

28. The compound has formula IVb: 【Chemistry 6】 or a pharma- ceutically acceptable salt thereof.

29. The compound has formula IVc: 【Chemistry 7】 or a pharma- ceutically acceptable salt thereof.

30. The compound has the formula IVd: 【Chemistry 8】 or a pharma- ceutically acceptable salt thereof.

31. Formula I: 【Chemistry 9】 31. The method of any one of claims 1 to 30, wherein the asterisked carbon is an asymmetric carbon and the compound or salt is the (S)-enantiomer, or a pharma- ceutically acceptable salt thereof.

32. The compound comprising: 1-{1-[5-chloro-3-(1-isopropylazetidin-3-yl)-2-methoxy-4-methylphenyl]ethyl}-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine; 1-{1-[3-(1-acetylazetidin-3-yl)-5-chloro-2-methoxy-4-methylphenyl]ethyl}-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine; 1-{1-[5-chloro-2-methoxy-4-methyl-3-(1-propionylazetidin-3-yl)phenyl]ethyl}-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine; 1-(1-{5-chloro-3-[1-(cyclopropylmethyl)azetidin-3-yl]-2-methoxy-4-methylphenyl}ethyl)-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine; 1-{1-[5-chloro-2-methoxy-4-methyl-3-(1-methylazetidin-3-yl)phenyl]ethyl}-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine; 1-{1-[5-chloro-3-(1-ethylazetidin-3-yl)-2-methoxy-4-methylphenyl]ethyl}-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine; 1-{1-[5-chloro-3-(1-isobutylazetidin-3-yl)-2-methoxy-4-methylphenyl]ethyl}-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine; 1-{1-[3-(1-sec-butylazetidin-3-yl)-5-chloro-2-methoxy-4-methylphenyl]ethyl}-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine; 1-(1-{5-chloro-2-methoxy-3-[1-(2-methoxyethyl)azetidin-3-yl]-4-methylphenyl}ethyl)-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine; 3-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}-N-methylazetidine-1-carboxamide; 5-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}-N,N-dimethylpyridine 2-carboxamide; 1-{1-[5-chloro-4-fluoro-3-(1-isopropylazetidin-3-yl)-2-methoxyphenyl]ethyl}-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine; 5-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-6-methylphenyl}-N,N-dimethylpyridine-2-carboxamide; 4-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}-N,N-dimethylpyridine-2-carboxamide; 4-(3-(1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-chloro-2-methoxy-6-methylphenyl)-N-methylpicolinamide; 4-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}-N-(2-hydroxyethyl)pyridine-2-carboxamide; 4-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}-N-(2-hydroxyethyl)-N-methylpyridine-2-carboxamide; 2-(4-(3-(1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-chloro-2-methoxy-6-methylphenyl)-1H-pyrazol-1-yl)ethanol; 3'-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5'-chloro-3-fluoro-2'-methoxy-N,N,6'-trimethylbiphenyl-4-carboxamide; 3'-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5'-chloro-3-fluoro-2'-methoxy-N,6'-dimethylbiphenyl-4-carboxamide; 5-(3-(1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-chloro-2-methoxy-6-methylphenyl)-N-(2-hydroxyethyl)picolinamide; 4-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}-N-(2-hydroxyethyl)-N-methylpyridine-2-carboxamide; 4-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-cyano-2-methoxy-6-methylphenyl}-N-(2-hydroxyethyl)-N-methylpyridine-2-carboxamide; 5-{3-[1-(4-amino-3-methyl-1H-pyrazolo[4,3-c]pyridin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}-N,N-dimethylpyridine 2-carboxamide; 4-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-6-chloro-3-ethoxy-2-[5-(methylsulfonyl)pyridin-3-yl]benzonitrile; 5-(3-(1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-chloro-6-cyano-2-ethoxyphenyl)-N,N-dimethylpicolinamide 5-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}-N,N-dimethylnicotinamide 5-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}-N,N-dimethylpyridine-2-carboxamide; 1-{1-[5-chloro-4-fluoro-3-(1-isopropylazetidin-3-yl)-2-methoxyphenyl]ethyl}-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine; (2S)-1-(3-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-6-fluoro-2-methoxyphenyl}azetidin-1-yl)propan-2-ol; 2-(3-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-6-fluoro-2-methoxyphenyl}azetidin-1-yl)ethanol; 1-{1-[5-chloro-4-fluoro-2-methoxy-3-(1-oxetan-3-ylazetidin-3-yl)phenyl]ethyl}-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine; 1-{1-[5-chloro-2-ethoxy-3-(1-isopropylazetidin-3-yl)-4-methylphenyl]ethyl}-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine; 2-(3-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-6-methylphenyl}azetidin-1-yl)ethanol; (2S)-1-(3-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-6-methylphenyl}azetidin-1-yl)propan-2-ol; (2S)-1-(3-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-6-methylphenyl}azetidin-1-yl)-1-oxopropan-2-ol; (2S)-1-(3-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}azetidin-1-yl)propan-2-ol; 2-(3-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}azetidin-1-yl)ethanol; (3-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}azetidin-1-yl)acetonitrile; 1-(1-{5-chloro-2-methoxy-4-methyl-3-[1-(2,2,2-trifluoroethyl)azetidin-3-yl]phenyl}ethyl)-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine; (2R)-2-(3-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}azetidin-1-yl)-N-methylpropanamide; 2-(3-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}azetidin-1-yl)-3,3,3-trifluoropropan-1-ol; (2R)-3-(3-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}azetidin-1-yl)-1,1,1-trifluoropropan-2-ol; (2S)-1-(3-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}azetidin-1-yl)-1-oxopropan-2-ol; (2R)-1-(3-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}azetidin-1-yl)-1-oxopropan-2-ol; 1-{1-[5-chloro-2-ethoxy-4-fluoro-3-(1-isopropylazetidin-3-yl)phenyl]ethyl}-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine; 1-(3-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-6-fluorophenyl}azetidin-1-yl)-2-methylpropan-2-ol; 1-(1-{5-chloro-2-ethoxy-4-fluoro-3-[1-(2,2,2-trifluoroethyl)azetidin-3-yl]phenyl}ethyl)-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine; (2S)-1-(3-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-6-fluorophenyl}azetidin-1-yl)propan-2-ol; (2R)-2-(3-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}azetidin-1-yl)propan-1-ol; 1-(3-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}azetidin-1-yl)-2-methylpropan-2-ol; (2R)-2-(3-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}azetidin-1-yl)-N,N-dimethylpropanamide; [1-(3-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}azetidin-1-yl)cyclobutyl]acetonitrile; 1-{1-[5-chloro-2-methoxy-4-methyl-3-(1-methylpiperidin-4-yl)phenyl]ethyl}-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine; 1-(4-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}piperidin-1-yl)-2-methylpropan-2-ol; 3-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}cyclobutanol; 5-(3-(1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-chloro-2-methoxy-6-methylphenyl)-N,N-dimethylpicolinamide; 1-[1-(5-chloro-3-{1-[2-(dimethylamino)ethyl]-1H-pyrazol-4-yl}-2-methoxy-4-methylphenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine; 2-[(5-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}pyridin-2-yl)amino]ethanol; 2-(5-(3-(1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-chloro-2-methoxy-6-methylphenyl)pyridin-2-yloxy)ethanol; 5-(3-(1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-chloro-2-(2,2-difluoroethoxy)-6-methylphenyl)-N,N-dimethylpicolinamide; 5-(3-(1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-chloro-2-ethoxy-6-methylphenyl)-N,N-dimethylpicolinamide; 4-(3-(1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-chloro-2-methoxy-6-methylphenyl)-N,N-dimethylpicolinamide; 2-(4-(3-(1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-chloro-2-ethoxy-6-methylphenyl)-1H-pyrazol-1-yl)acetamide; 6-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-6-methylphenyl}-N,N-dimethylnicotinamide; 5-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-4-methoxy-2-methyl-3-(1-methyl-1H-pyrazol-4-yl)benzonitrile; 1-(1-(5-chloro-2-methoxy-4-methyl-3-(pyrimidin-5-yl)phenyl)ethyl)-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine; 1-(1-(3-(2-aminopyrimidin-5-yl)-5-chloro-2-methoxy-4-methylphenyl)ethyl)-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine; 4-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-2-azetidin-3-yl-6-chloro-3-ethoxybenzonitrile; 4-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-6-chloro-3-ethoxy-2-(1-methylazetidin-3-yl)benzonitrile; 4-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-6-chloro-3-ethoxy-2-[1-(2-hydroxyethyl)azetidin-3-yl]benzonitrile; 4-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-6-chloro-3-ethoxy-2-{1-[(2S)-2-hydroxypropyl]azetidin-3-yl}benzonitrile; tert-Butyl 2-(3-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-6-cyano-2-ethoxyphenyl}azetidin-1-yl)-2-methylpropanoate; 4-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-6-chloro-3-ethoxy-2-[1-(2-hydroxy-1,1-dimethylethyl)azetidin-3-yl]benzonitrile; 2-(3-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-6-cyano-2-ethoxyphenyl}azetidin-1-yl)-2-methylpropanamide; 4-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-6-chloro-3-ethoxy-2-[1-(2-hydroxy-2-methylpropanoyl)azetidin-3-yl]benzonitrile; 4-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-2-azetidin-3-yl-6-chloro-3-methoxybenzonitrile; 4-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-6-chloro-3-methoxy-2-(1-methylazetidin-3-yl)benzonitrile; 4-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-6-chloro-2-[1-(2-hydroxyethyl)azetidin-3-yl]-3-methoxybenzonitrile; 4-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-6-chloro-2-{1-[(2S)-2-hydroxypropyl]azetidin-3-yl}-3-methoxybenzonitrile; 4-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-6-chloro-2-[1-(2-hydroxy-1-methylethyl)azetidin-3-yl]-3-methoxybenzonitrile; 2-(1-acetylazetidin-3-yl)-4-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-6-chloro-3-methoxybenzonitrile; 4-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-6-chloro-3-methoxy-2-[1-(methylsulfonyl)azetidin-3-yl]benzonitrile; 3-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-6-cyano-2-methoxyphenyl}azetidine-1-carboxylate methyl; 3-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-6-cyano-2-methoxyphenyl}-N-(tert-butyl)azetidine-1-carboxamide; 3-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-6-cyano-2-methoxyphenyl}azetidine-1-carboxamide; 3-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-6-cyano-2-methoxyphenyl}-N,N-dimethylazetidine-1-carboxamide; 1-{1-[4,5-dichloro-3-(1-ethylazetidin-3-yl)-2-methoxyphenyl]ethyl}-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine; 4-[1-(4-amino-5-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)ethyl]-6-chloro-3-ethoxy-2-(1-isopropylazetidin-3-yl)benzonitrile; 4-[-1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-2-{1-[(2S)-2-hydroxypropyl]azetidin-3-yl}-3-methoxy-6-methylbenzonitrile; 4-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-6-chloro-3-ethoxy-2-[6-(1-hydroxy-1-methylethyl)pyridin-3-yl]benzonitrile; 4-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-6-chloro-3-ethoxy-2-pyrrolidin-1-ylbenzonitrile; 4-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-6-chloro-3-ethoxy-2-(3-methoxyazetidin-1-yl)benzonitrile; 4-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-3-ethoxy-2-(1-isopropylazetidin-3-yl)-6-methylbenzonitrile; 4-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-3-ethoxy-2-[1-(2-hydroxy-2-methylpropyl)azetidin-3-yl]-6-methylbenzonitrile; 4-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-3-ethoxy-2-[1-(2-hydroxy-2-methylpropanoyl)azetidin-3-yl]-6-methylbenzonitrile; 4-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-6-methylphenyl}pyrrolidin-2-one; 4-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-6-chloro-3-ethoxy-2-(2-oxo-1,3-oxazolidin-5-yl)benzonitrile; 6-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}morpholin-3-one; 5-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}-1,3-oxazolidin-2-one; 4-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-6-fluorophenyl}pyrrolidin-2-one; 4-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-6-chloro-3-ethoxy-2-(5-oxopyrrolidin-3-yl)benzonitrile; 4-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-6-fluorophenyl}-1,3-oxazolidin-2-one; 5-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-6-fluorophenyl}-1,3-oxazolidin-2-one; 4-(1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-6-chloro-2-(1-(2-hydroxypropyl)azetidin-3-yl)-3-methoxybenzonitrile; or a pharma- ceutically acceptable salt of any of the foregoing.

33. 2. The method of claim 1, wherein the method is a method for treating idiopathic thrombocytopenic purpura (ITP), autoimmune hemolytic anemia, vasculitis, systemic lupus erythematosus, lupus nephritis, pemphigus, membranous nephropathy, chronic lymphocytic leukemia (CLL), non-Hodgkin's lymphoma, hairy cell leukemia, mantle cell lymphoma, small lymphocytic lymphoma, follicular lymphoma, lymphoplasmacytic lymphoma, extranodal marginal zone lymphoma, activated B-cell-like (ABC) diffuse large B-cell lymphoma, or germinal center B-cell (GCB) diffuse large B-cell lymphoma.

34. 2. The method of claim 1, wherein the method is a method for treating idiopathic thrombocytopenic purpura (ITP) selected from recurrent ITP and refractory ITP.

35. 2. The method of claim 1, wherein the method is for treating a vasculitis selected from Behcet's disease, Cogan's syndrome, giant cell arteritis, polymyalgia rheumatica (PMR), Takayasu's arteritis, Buerger's disease (thromboangiitis obliterans), central nervous system vasculitis, Kawasaki disease, polyarteritis nodosa, Churg-Strauss syndrome, mixed cryoglobulinaemic vasculitis (essential or hepatitis C virus (HCV)-induced), Henoch-Schonlein purpura (HSP), hypersensitivity vasculitis, microscopic polyangiitis, Wegener's granulomatosis, or antineutrophil cytoplasmic antibody-associated (ANCA) systemic vasculitis (AASV).

36. 2. The method of claim 1, wherein the method is a method for treating a non-Hodgkin's lymphoma (NHL) selected from relapsed NHL, refractory NHL, and recurrent follicular NHL.

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