Heterocyclic amine as a PI3K inhibitor

Abstract

To provide new or improved agents which inhibit kinases such as PI3Ks.SOLUTION: The present invention provides heterocyclylamine derivatives of formula (I), where the variables are defined herein, that modulate the activity of phosphoinositide 3-kinases (PI3Ks) and are useful in the treatment of diseases related to the activity of PI3Ks including, for example, inflammatory disorders, immune-based disorders, cancer, and other diseases.SELECTED DRAWING: None

Description

Technical Field

[0001] This application claims the benefit of U.S. Provisional Patent Application No. 61 / 530,866, filed Sep. 2, 2011; U.S. Provisional Patent Application No. 61 / 594,882, filed Feb. 3, 2012; and U.S. Provisional Patent Application No. 61 / 677,445, filed Jul. 30, 2012, each of which is incorporated herein by reference in its entirety.

[0002] Field of the Invention The present invention provides heterocyclic amine derivatives, such as pyrazolopyrimidines, which modulate the activity of phosphoinositide 3-kinase (PI3K) and are useful in the treatment of diseases associated with PI3K activity, including, for example, inflammatory disorders, immune-based disorders, cancer, and other diseases.

Background Art

[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 (Cantley, Science, 2002, 296(5573):1655-7). PI3Ks are classified into three classes (class 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-bisphosphate (PIP2) to generate phosphatidylinositol-3,4,5-trisphosphate (PIP3). PIP3 functions as a second messenger that regulates several cellular processes, including growth, survival, adhesion, and migration. All four class I PI3K isoforms exist as heterodimers consisting of a catalytic subunit (p110) and a tightly associated regulatory subunit that regulates their expression, activation, and intracellular localization. PI3Kα, PI3Kβ, and PI3Kδ bind to a regulatory subunit known as p85 and are activated by growth factors and cytokines via a tyrosine kinase-dependent mechanism (Jimenez, et al., J Biol Chem., 2002, 277(44):41556-62), while PI3Kγ binds to two regulatory subunits (p101 and p84) and its activation is driven by the activation of G protein-coupled receptors (Brock, et al., J Cell Biol., 2003, 160(1):89-99). PI3Kα and PI3Kβ are ubiquitously expressed. In contrast, PI3Kγ and PI3Kδ are mainly expressed in leukocytes (Vanhaesebroeck, et al., Trends Biochem Sci., 2005, 30(4):194-204).

[0004] The differential 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 and non-redundant functions, at least during development (Vanhaesebroeck, et al., 2005). In contrast, mice lacking PI3Kγ and PI3Kδ are viable, fertile, and have a normal lifespan, although they exhibit immune system alterations. Deficiency in PI3Kγ causes defects in the chemotaxis of macrophages and neutrophils to sites of inflammation and in T cell activation (Sasaki, et al., Science, 2000, 287(5455):1040-6). PI3Kδ mutant mice have specific defects in B cell signaling that result in impaired B cell development and a reduced antibody response after antigen stimulation (Clayton, et al., J Exp Med. 2002, 196(6):753-63; Jou, et al., Mol Cell Biol. 2002, 22(24):8580-91; Okkenhaug, et al., Science, 2002, 297(5583):1031-4).

[0005] The phenotypes of PI3Kγ and PI3Kδ mutant mice suggest that these enzymes may play roles in inflammation and other immune-based diseases, which has been demonstrated in preclinical models. PI3Kγ mutant mice are generally protected from disease in mouse models of rheumatoid arthritis (RA) and asthma (Camps, et al., Nat Med. 2005, 11(9):936-43; Thomas, et al., Eur J Immunol. 2005, 35(4):1283-91). Furthermore, treatment of wild-type mice with a selective inhibitor of PI3Kγ has been shown to reduce glomerulonephritis and extend survival in the MRL-lpr model of systemic lupus erythematosus (SLE), as well as suppress joint inflammation and damage in the RA model (Barber, et al., Nat Med. 2005, 11(9):933-5; Camps, et al., 2005)). Similarly, treatment with a selective inhibitor of PI3Kδ in both PI3Kδ mutant and wild-type mice attenuates allergic bronchitis and hyperresponsiveness in a mouse model of asthma (Ali, et al., Nature. 2004, 431(7011):1007-11; Lee, et al., FASEB J. 2006, 20(3):455-65), and has been shown to attenuate disease in the RA model (Randis, et al., Eur. J. Immunol., 2008, 38(5):1215-24).

[0006] In addition to their potential roles in inflammatory disorders, all four class I PI3K isoforms may also play roles in cancer. The gene encoding p110α is frequently mutated in common cancers, including breast, prostate, colon, and endometrial cancers (Samuels, et al., Science, 2004, 304(5670):554; Samuels, et al., Curr Opin Oncol. 2006, 18(1):77-82). Eighty percent of these mutations show one of three amino acid substitutions in the helical or kinase domains of the enzyme, causing significant upregulation of kinase activity and resulting in oncogenic transformation in cell culture and animal models (Kang, et al., Proc Natl Acad Sci U S A. 2005, 102(3):802-7; Bader, et al., Proc Natl Acad Sci U S A. 2006, 103(5):1475-9). Such mutations have not been identified in other PI3K isoforms, but there is evidence that they may contribute to the development and progression of malignant lesions. In acute myeloblastic leukemia, consistent overexpression of PI3Kδ has been observed (Sujobert, et al., Blood, 2005, 106(3):1063-6), and PI3Kδ inhibitors can prevent the proliferation of leukemia cells (Billottet, et al., Oncogene. 2006, 25(50):6648-59). In chronic myeloid leukemia, increased expression of PI3Kγ is seen (Hickey, et al., J Biol Chem. 2006, 281(5):2441-50). Changes in the expression of PI3Kβ, PI3Kγ, and PI3Kδ have also been observed in brain, colon, and bladder cancers (Benistant, et al., Oncogene, 2000, 19(44):5083-90; Mizoguchi, et al., Brain Pathol. 2004, 14(4):372-7; Knobbe, et al., Neuropathol Appl Neurobiol. 2005, 31(5):486-90).Furthermore, all of these isoforms have been shown to be oncogenic in cell culture (Kang, et al., 2006).

[0007] Thus, new or improved agents that inhibit kinases such as PI3K are needed for the development of new and more effective pharmaceuticals (e.g., immunosuppressive agents for organ transplantation, etc.) aimed at enhancing or suppressing immune and inflammatory pathways; and for the prevention and treatment of autoimmune diseases (e.g., multiple sclerosis, rheumatoid arthritis, asthma, type I diabetes, inflammatory bowel disease, Crohn's disease, autoimmune thyroid disorders, Alzheimer's disease, nephritis), diseases involving hyperactive inflammatory responses (e.g., eczema), allergies, lung diseases, cancers (e.g., prostate cancer, breast cancer, leukemia, multiple myeloma), and some immune responses caused by other treatments (e.g., skin rashes or contact dermatitis or diarrhea). The compounds, compositions, and methods described herein relate to such needs. SUMMARY OF THE INVENTION

[0008] The present invention particularly provides a compound of formula I:

CHEMICAL

[0009] The present invention further provides a composition comprising a compound of the present invention, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

[0010] The present invention also provides a method of modulating the activity of a PI3K kinase, the method comprising contacting the kinase with a compound of the present invention or a pharmaceutically acceptable salt thereof.

[0011] The present invention further provides a method for treating a disease in a patient, wherein the disease is associated with abnormal expression or activity of PI3K kinase, and the method comprises administering to the patient a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof. The present invention further provides a method for treating an immune-based disease in a patient, the method comprising administering to the patient a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof.

[0012] The present invention also provides a method for treating cancer in a patient, the method comprising administering to the patient a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof. The present invention further provides a method for treating a lung disease in a patient, the method comprising administering to the patient a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof.

[0013] The present invention also provides a compound of the present invention or a pharmaceutically acceptable salt thereof for use in any of the methods described herein. The present invention further provides the use of a compound or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for use in any of the methods described herein. BRIEF DESCRIPTION OF THE DRAWINGS

[0014]

Figure 1

[0015] Detailed Description The present invention particularly provides a compound of formula I: CHEMICAL or a pharmaceutically acceptable salt thereof, wherein: X is CR 9 or N; W is CR 7 or N; Y is CR 8 , CR 8a or N; Z is a bond or C(=O); provided that -W=Y-Z- is -CR 7 =CR 8 , -N=CR 8 , -CR 7 =CR 8a -C(=O)-, -N=CR 8a -C(=O)-, or -CR 7 =N-C(=O)-; R 1 is C 1-3 alkyl; R 2 is halo, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, phenyl, or 5- to 6-membered heteroaryl; where the phenyl and 5- to 6-membered heteroaryl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from halo, OH, CN, C 1-4 alkyl, C 1-4 alkoxy, and C 1-4 haloalkoxy; R 3 is Cy, -(C 1-3 alkylene)-Cy, halo, CN, NO2, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, OR a , SR a , C(=O)R b , C(=O)NR c R d , C(=O)OR a , OC(=O)R b , OC(=O)NR c R d , NR c R d , NR c , C(=O)Rb , NR c C(=O)OR b , NR c C(=O)NR c R d , C(=NR e )R b , C(=NR e )NR c R d , NR c , C(=NR e )NR c R d , NR c S(=O)2R b , NR c S(=O)2NR c R d , S(=O)2R b , or S(=O)2NR c R d ; wherein said C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl are each optionally substituted by 1, 2, 3, or 4 independently selected R 3a groups; R 4 is H, 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, C 1-4 haloalkoxy, or cyclopropyl; R 6 is H, halo, OH, CN, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, or C 1-4 haloalkoxy; R 7 is H or C 1-4 alkyl; R 8 is H, halo, -OH, -CN, C1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, Cy 2 , -(C 1-3 (Alkylene)-Cy 2 , OR a2 , S.R. a2 , C(=O)R b2 , C(=O)NR c2 R d2 , C(=O)OR a2 , OC(=O)R b2 , OC(=O)NR c2 R d2 , N.R. c2 R d2 , N.R. c2 C(=O)R b2 , N.R. c2 C(=O)OR b2 , N.R. c2 C(=O)NR c2 R d2 , C(=NR e )R b2 , C(=NR e )NR c2 R d2 , N.R. c2 C(=NR e )NR c2 R d2 , N.R. c2 S(=O)R b2 , N.R. c2 S(=O)NR c2 R d2 , S(=O)R b2 , or S(=O)2NR c2 R d2 where C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl is one, two, three, or four independently selected R 11 groups, each optionally substituted; R 8a H, halo, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, Cy 2 , -(C1-3 (Alkylene)-Cy 2 、C(=O)R b2 、C(=O)NR c2 R d2 、C(=O)OR a2 、NR c2 R d2 、NR c2 C(=O)R b2 、NR c2 C(=O)OR b2 、NR c2 C(=O)NR c2 R d2 、NR c2 S(=O)R b2 、NR c2 S(=O)2NR c2 R d2 、S(=O)R b2 、or S(=O)2NR c2 R d2 ; where said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl is optionally substituted by 1, 2, 3, or 4 independently selected R 11 groups; R 9 is H, halo, OH, CN, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, or C 1-4 haloalkoxy; R 10 is H or C 1-4 alkyl;

[0016] each R a 、R b 、R c 、and R d is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, and Cy; where said C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl is optionally substituted by 1, 2, or 3 independently selected R3b is based and optionally substituted as desired; or R c and R d together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl group optionally substituted with -OH or C 1-3 alkyl; each R e is independently selected from H, CN, OH, C 1-4 alkyl, and C 1-4 alkoxy; each Cy is independently selected from C 3b cycloalkyl, 4- to 10-membered heterocycloalkyl, phenyl, naphthyl, and 5- to 10-membered heteroaryl, each optionally substituted with 1, 2, 3, or 4 independently selected R 3-7 groups; each R 3a is halo, CN, NO2, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, OR a1 , SR 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 , NR c1 R d1 , NR c1 , C(=O)R b1 , NR c1 , C(=O)OR b1 , NR c1 , C(=O)NR c1 R d1 , C(=NR e )R b1 , C(=NR e )NR c1 R d1 , NR c1 , C(=NR e )NR c1 R d1 , NR c1S(=O)R b1 , NR c1 S(=O)2NR c1 R d1 , S(=O)2R b1 , and S(=O)2NR c1 R d1 is independently selected from; wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl is optionally substituted with one, two, or three independently selected R 11 groups; Each R 3b is 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 , SR 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 , NR c1 R d1 , NR c1 C(=O)R b1 , NR c1 C(=O)OR b1 , NR c1 C(=O)NR c1 R d1 , C(=NR e )R b1 , C(=NR e )NR c1 R d1 , NR c1 C(=NR e )NR c1 R d1 , NR c1 S(=O)R b1 , NR c1 S(=O)2NR c1 R d1 , S(=O)R b1and S(=O)2NR c1 R d1 is independently selected from; wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl is optionally substituted with 1, 2, or 3 independently selected R 11 groups; Each Cy 1 is independently selected from C 11 cycloalkyl, 4- to 7-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl, each optionally substituted with 1, 2, 3, or 4 independently selected R 3-7 groups; Each R a1 , R b1 , R c1 , and R d1 is independently selected from 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; wherein said C 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 are optionally substituted with 1, 2, or 3 independently selected R 11 groups; or or R c1 and R d1 together with the N atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with -OH or C 1-3 alkyl; Each Cy 2 is independently selected from C 11 cycloalkyl, 4- to 7-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl, each optionally substituted with 1, 2, 3, or 4 independently selected R 3-7independently selected from cycloalkyl, 4- to 7-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl; each R a2 , R b2 , R c2 , and R d2 is independently selected from 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; provided that said C 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 are each optionally substituted with one, two, or three independently selected R 11 groups; or R c and R d2 together with the N atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with -OH or C 1-3 alkyl; and each R 11 is 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, C 1-3 alkylthio, C 1-3 alkylsulfinyl, C 1-3Alkylsulfonyl, carbamyl, C 1-3 Alkylcarbamyl, di(C 1-3 alkyl)carbamyl, carboxy, C 1-3 Alkylcarbonyl, C 1-3 Alkoxycarbonyl, C 1-3 Alkylcarbonylamino, C 1-3 Alkylsulfonylamino, 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, is independently selected from.

[0017] The present invention also provides a compound of formula I:

Chemical formula

[0018] R 8 is H, halo, -OH, -CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, Cy 2 ,-(C 1-3 alkylene)-Cy 2 , OR a2 , SR a2 , C(=O)R b2 , C(=O)NR c2 R d2 , C(=O)OR a2 , OC(=O)R b2 , OC(=O)NR c2 R d2 , NR c2 R d2 , NR c2 , C(=O)R b2 , NR c2C(=O)OR b2 , N.R. c2 C(=O)NR c2 R d2 , C(=NR e )R b2 , C(=NR e )NR c2 R d2 , N.R. c2 C(=NR e )NR c2 R d2 , N.R. c2 S(=O)R b2 , N.R. c2 S(=O)NR c2 R d2 , S(=O)R b2 , S(=O)2R b2 , or S(=O)2NR c2 R d2 where C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl is one, two, three, or four independently selected R 11 groups, each optionally substituted; R 8a H, halo, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, Cy 2 , -(C 1-3 (Alkylene)-Cy 2 , C(=O)R b2 , C(=O)NR c2 R d2 , C(=O)OR a2 , N.R. c2 R d2 , N.R. c2 C(=O)R b2 , N.R. c2 C(=O)OR b2 , N.R. c2 C(=O)NR c2 R d2 , N.R. c2 S(=O)R b2 , N.R. c2 S(=O)NR c2 R d2 , S(=O)Rb2 、 S(=O)2R b2 、 or S(=O)2NR c2 R d2 wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl is optionally substituted by 1, 2, 3, or 4 independently selected R 11 groups; R 9 is H, halo, OH, CN, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, or C 1-4 haloalkoxy; R 10 is H or C 1-4 alkyl; each R a 、 R b 、 R c 、 and R d are independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, and Cy; wherein said C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl is optionally substituted by 1, 2, or 3 independently selected R 3b groups; or R c and R d together with the N atom to which they are attached form a 4, 5, 6, or 7-membered heterocycloalkyl group optionally substituted by -OH or C 1-3 alkyl; each R e is independently selected from H, CN, OH, C 1-4 alkyl, and C 1-4 alkoxy; each Cy is optionally substituted by 1, 2, 3, or 4 independently selected R 3b groups, C 3-7independently selected from cycloalkyl, 4- to 10-membered heterocycloalkyl, phenyl, naphthyl, and 5- to 10-membered heteroaryl;

[0019] Each R 3a is halo, CN, NO2, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, OR a1 , SR 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 , NR c1 R d1 , NR c1 C(=O)R b1 , NR c1 C(=O)OR b1 , NR c1 C(=O)NR c1 R d1 , C(=NR e )R b1 , C(=NR e )NR c1 R d1 , NR c1 C(=NR e )NR c1 R d1 , NR c1 S(=O)R b1 , NR c1 S(=O)2NR c1 R d1 , S(=O)2R b1 , and S(=O)2NR c1 R d1 independently selected from; where said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl is optionally substituted with 1, 2, or 3 independently selected R 11 groups; Each R 3b is 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 、 SR 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 、 NR c1 R d1 、 NR c1 C(=O)R b1 、 NR c1 C(=O)OR b1 、 NR c1 C(=O)NR c1 R d1 、 C(=NR e )R b1 、 C(=NR e )NR c1 R d1 、 NR c1 C(=NR e )NR c1 R d1 、 NR c1 S(=O)R b1 、 NR c1 S(=O)2NR c1 R d1 、 S(=O)R b1 、 S(=O)2R b1 、 and S(=O)2NR c1 R d1 is independently selected from; wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl is optionally substituted with 1, 2, or 3 independently selected R 11 groups; each Cy 1 is optionally substituted with 1, 2, 3, or 4 independently selected R 11 groups, C 3-7independently selected from cycloalkyl, 4- to 7-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl; each R a1 , R b1 , R c1 , and R d1 is independently selected from 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; wherein said C 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 are each optionally substituted with one, two, or three independently selected R 11 groups; or R c1 and R d1 together with the N atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with -OH or C 1-3 alkyl; each Cy 2 is independently selected from C 11 cycloalkyl, 4- to 7-membered heterocycloalkyl, phenyl, 5- to 6-membered heteroaryl, or 9- to 10-membered bicyclic heteroaryl, each optionally substituted with one, two, three, or four independently selected R 3-7 groups; each R a2 , R b2 , R c2 , and R d2 is independently selected from 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; wherein said C1-6 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 are each optionally substituted with 1, 2, or 3 independently selected R 11 groups; or R c and R d2 together with the N atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with -OH or C 1-3 alkyl; and each R 11 is 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, C 1-3 alkylthio, C 1-3 alkylsulfinyl, C 1-3 alkylsulfonyl, 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 alkylsulfonylamino, 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, independently selected from:

[0020] In one embodiment of any of the foregoing embodiments, Cy is:

Chemical formula

[0021] In one embodiment of the foregoing embodiments, R 3 is:

Chemical formula

[0022] In one embodiment of the foregoing embodiments, R 3 is Cy, where each Cy is independently selected from an azetidine ring, a pyrazole ring, a pyridine ring, a pyrimidine ring, and a phenyl ring, each optionally substituted with 1, 2, 3, or 4 independently selected R3b groups.

[0023] In some embodiments:

Chemical formula

Chemical formula

[0024] In some embodiments:

Chemical formula

[0025] In some embodiments: [Chem.] the part is [Chem.] .

[0026] In some embodiments: [Chem.] the part is [Chem.] .

[0027] In some embodiments: [Chem.] the part is [Chem.] .

[0028] In some embodiments, R 1 is methyl. In some embodiments, R 2 is C 1-6 alkyl, C 1-3 alkoxy, or phenyl; where said phenyl is optionally substituted by 1, 2, 3, or 4 substituents independently selected from halo.

[0029] In some embodiments, each R a , R b , R c and R dis H, C 1-6 alkyl, and C 1-6 is independently selected from haloalkyl.

[0030] In some embodiments, R 3 is Cy or C(=O)NR c R d ; where each R c and R d is independently selected from C 1-6 alkyl. In some embodiments, R 3 is Cy. In some embodiments, R 3 is C(=O)NR c R d ; where each R c and R d is independently selected from C 1-6 alkyl.

[0031] In some embodiments, each Cy is independently selected from C 3b cycloalkyl, 4- to 7-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl, each optionally substituted with 1, 2, 3, or 4 independently selected R 3-7 groups.

[0032] In some embodiments, each Cy is independently selected from azetidine ring, pyrazole ring, pyridine ring, pyrimidine ring, and phenyl ring, each optionally substituted with 1, 2, 3, or 4 independently selected R 3b groups.

[0033] In some embodiments: each Cy is independently Cy 1 , -(C 1-3 alkylene)-Cy 1 , halo, CN, OH, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C(=O)R b1 , C(=O)NRc1 R d1 、 S(=O)R b1 、 and S(=O)2NR c1 R d1 1 or 2 Rs independently selected from 3b optionally substituted with 3-7 C cycloalkyl, 4- to 7-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl; wherein said C 1-6 alkyl is optionally substituted with 1, 2, or 3 independently selected R 11 groups; Cy 1 is C 3-6 cycloalkyl or 4- to 7-membered heterocycloalkyl; each R a1 、 R b1 、 R c1 、 and R d1 is selected from H, C 1-6 alkyl and C 1-6 haloalkyl; wherein said C 1-6 alkyl is optionally substituted with 1, 2, or 3 independently selected R 11 groups; and each R 11 is independently OH or C 1-3 alkoxy.

[0034] In some embodiments: each Cy is independently selected from Cy 1 、 -(C 1-3 alkylene)-Cy 1 、 halo, CN, OH, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C(=O)R b1 、 C(=O)NR c1 R d1 、 S(=O)R b1 、 and S(=O)2NR c1 R d1 selected from 1 R 3bindependently selected from an azetidine ring, a pyrazole ring, a pyridine ring, a pyrimidine ring, and a phenyl ring, optionally substituted as desired; wherein said C 1-6 alkyl is optionally substituted with 1, 2, or 3 independently selected R 11 groups; Cy 1 is C 3-6 cycloalkyl or 4- to 7-membered heterocycloalkyl; each R a1 , R b1 , R c1 , and R d1 is independently selected from H, C 1-6 alkyl, and C 1-6 haloalkyl; wherein said C 1-6 alkyl is optionally substituted with 1, 2, or 3 independently selected R 11 groups; and each R 11 is independently OH or C 1-3 alkoxy.

[0035] In some embodiments: each Cy is optionally substituted with 1 or 2 R 1 s independently selected from Cy 1-3 , -(C 1 alkylene)-Cy 1-6 , halo, CN, OH, C 1-6 alkyl, C 1-6 alkoxy, C b1 haloalkyl, C(=O)R c1 R d1 , C(=O)NR b1 R c1 R d1 , S(=O)R 3b , and S(=O)2NR 3-7 R 1-6 alkyl is optionally substituted with 1, 2, or 3 independently selected R 11 groups; Cy 1 is C3-6 is cycloalkyl or 4- to 7-membered heterocycloalkyl; Each R a1 、R b1 、R c1 、and R d1 is independently selected from H, C 1-6 alkyl and C 1-6 haloalkyl; wherein said C 1-6 alkyl is optionally substituted with 1, 2, or 3 independently selected R 11 groups; and Each R 11 is independently OH, CN, halo, C 1-3 alkyl, C 1-3 haloalkyl, HO-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, carbamyl, C 1-3 alkylcarbamyl, or di(C 1-3 alkyl)carbamyl.

[0036] In some embodiments: Each Cy is independently selected from azetidine ring, pyrazole ring, pyridine ring, pyrimidine ring, phenyl ring, each optionally substituted with one R 1 、-(C 1-3 alkylene)-Cy 1 、halo, CN, OH, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C(=O)R b1 、C(=O)NR c1 R d1 、S(=O)R b1 、and S(=O)2NR c1 R d1 selected from; wherein said C 3b alkyl is optionally substituted with 1, 2, or 3 independently selected R 1-6 groups; 11optionally substituted by a group; Cy 1 is C 3-6 cycloalkyl or 4- to 7-membered heterocycloalkyl; each R a1 、R b1 、R c1 、and R d1 is independently selected from H, C 1-6 alkyl and C 1-6 haloalkyl; where said C 1-6 alkyl is optionally substituted by 1, 2, or 3 independently selected R 11 groups; and each R 11 is independently OH, CN, halo, C 1-3 alkyl, C 1-3 haloalkyl, HO-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, carbamyl, C 1-3 alkylcarbamyl, or di(C 1-3 alkyl)carbamyl.

[0037] In some embodiments, R 4 is halo, CN, or C 1-4 alkyl. 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. In some embodiments, R 5 is halo or CN. In some embodiments, R 5 is Cl. In some embodiments, R 6 is H. In some embodiments, R 7 is H.

[0038] In some embodiments, R 8 is H, halo, CN, C 1-6 alkyl, or Cy 2 ; where Cy 2 is selected from C 11 cycloalkyl, phenyl, 5- to 6-membered heteroaryl, and 4- to 7-membered heterocycloalkyl, each optionally substituted with one or two independently selected R 3-6 groups.

[0039] In some embodiments, R 8 is H, halo, CN, C 1-6 alkyl, or Cy 2 ; where Cy 2 is selected from C 1-3 cycloalkyl, phenyl, 5- to 6-membered heteroaryl, or 4- to 7-membered heterocycloalkyl, each optionally substituted with one R 1-3 selected from OH, CN, halo, C 1-3 alkyl, C 1-3 haloalkyl, HO-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, carbamyl, C 11 alkylcarbamyl, and di(C 3-6 alkyl)carbamyl. In some embodiments, R 8 is H, halo, CN, methyl, or Cy 2 ; where Cy 2is each selected from OH, CN, fluoro, methyl, 2-hydroxyethyl, dimethylcarbamyl, amino, methylcarbamyl, and dimethylcarbamyl, and is optionally substituted with one R 11 selected from cyclopropyl, phenyl, pyrazole ring, pyridine ring, or pyrimidine ring.

[0040] In some embodiments, R 8 is H, methyl, F, Cl, or I. In some embodiments, R 8 is methyl. In some embodiments, R 8 is H. In some embodiments, R 8 is F. In some embodiments, R 8 is Cl. In some embodiments, R 8 is I.

[0041] In some embodiments, each R 11 is independently OH, CN, halo, C 1-3 alkyl, C 1-3 haloalkyl, HO-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, carbamyl, C 1-3 alkylcarbamyl, or di(C 1-3 alkyl)carbamyl.

[0042] In some embodiments, R 8a is H, halo, -CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, or Cy 2 as defined herein.

[0043] In some embodiments, R 8a is H or halo. In some embodiments, R 8a is H. In some embodiments, R 9 is H. In some embodiments, R 10 is H.

[0044] In some embodiments:

Chemical formula

Chemical formula

[0045] In some embodiments:

Chemical formula

Chemical formula

[0046] In some embodiments:

Chemical formula

Chemical formula

[0047] In some embodiments: [ka] The parts are: [ka] and; R 1 is methyl; R 2is phenyl; wherein said phenyl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from halo; R 3 is C(=O)NR c R d where each R c and R d is C 1-6 independently selected from alkyl; Cy may each be 1, 2, 3, or 4 independently selected R 3b optionally substituted with a C group; 3-7 selected from cycloalkyl, 4- to 7-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl; R 4 is halo, CN, or C 1-4 is alkyl; R 5 is halo or CN; R 6 , R 7 , R 9 , and R 10 are H, respectively; R 8 H, halo, CN, C 1-6 Alkyl, or Cy 2 where Cy 2 are each one or two independently selected R 11 optionally substituted with a group, C 3-6 selected from cycloalkyl, phenyl, 5- to 6-membered heteroaryl, and 4- to 7-membered heterocycloalkyl; R 8a is H or halo; and Each R 11 are independently OH, CN, halo, and C 1-3 Alkyl, C 1-3 Haloalkyl, HO-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, carbamyl, C 1-3 alkylcarbamyl, or di(C 1-3 alkyl)carbamyl.

[0048] In some embodiments:

Chemical formula

Chemical formula

[0049] In some embodiments:

Chemical formula

Chemical formula

[0050] In some embodiments, the compound is a compound of formula II:

Chemical formula

[0051] In some embodiments, the compound is a compound of formula III:

Chemical formula

[0052] In some embodiments, the compound is of formula IV: [Chemical formula] is a compound of formula (IV), or a pharmaceutically acceptable salt thereof.

[0053] In some embodiments, the compound is of formula V: [Chemical formula] is a compound of formula (V), or a pharmaceutically acceptable salt thereof.

[0054] In some embodiments, the compound is of formula VIa: [Chemical formula] is a compound of formula (VIa), or a pharmaceutically acceptable salt thereof.

[0055] In some embodiments, the compound is of formula VIb: [Chemical formula] is a compound of formula (VIb), or a pharmaceutically acceptable salt thereof.

[0056] In some embodiments, the compound is of formula VIa: [Chemical formula] is a compound of formula (VIa), or a pharmaceutically acceptable salt thereof, wherein: R 2 is methoxy or ethoxy; R 3b is C 1-3 alkyl optionally substituted with one or two groups independently selected from F, OH, and C 1-6 alkoxy groups; R 4is F, CN, methyl or ethyl; and R 5 is F, Cl, methyl or ethyl.

[0057] In some embodiments, the compound has Formula VIb: [ka] or a pharmaceutically acceptable salt thereof, wherein: R 2 is methoxy or ethoxy; R 3b is C(=O)NR c1 R d1 and; R 4 is F, CN, methyl or ethyl; and R 5 is F, Cl, methyl or ethyl.

[0058] In some embodiments, the compound has Formula IIa: [ka] or a pharmaceutically acceptable salt thereof, wherein: R 2 is C 1-6 Alkyl, C 1-3 alkoxy, or phenyl; wherein said phenyl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from halo; R 3 is Cy or C(=O)NR c R d where each R c and R d is C 1-6 independently selected from alkyl; Cy is Cy 1 , -(C 1-3 (Alkylene)-Cy 1 , Halo, CN, OH, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6Haloalkyl, C(=O)R b1 , C(=O)NR c1 R d1 , S(=O)R b1 , and S(=O)2NR c1 R d1 One or two Rs independently selected from 3b optionally substituted with C 3-7 selected from cycloalkyl, 4- to 7-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl; wherein said C 1-6 alkyl is optionally substituted with 1, 2, or 3 independently selected R 11 groups; Cy 1 is C 3-6 cycloalkyl or 4- to 7-membered heterocycloalkyl; Each R a1 , R b1 , R c1 , and R d1 is independently selected from H, C 1-6 alkyl and C 1-6 haloalkyl; wherein said C 1-6 alkyl is optionally substituted with 1, 2, or 3 independently selected R 11 groups; R 4 is halo, CN, or C 1-4 alkyl; R 5 is halo or CN; R 8 is H, halo, CN, C 1-6 alkyl, or Cy 2 ; where Cy 2 is each optionally substituted with one R 11 group and is selected from C 3-6 cycloalkyl, phenyl, 5- to 6-membered heteroaryl, and 4- to 7-membered heterocycloalkyl; and each R 11 is independently OH, CN, halo, C 1-3 alkyl, C 1-3 haloalkyl, HO-C 1-3 alkyl, C 1-3 alkoxy-C1-3 alkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, amino, C 1-3 alkylamino, di(C 1-3 alkyl)amino, carbamyl, C 1-3 alkylcarbamyl, or di(C 1-3 alkyl)carbamyl.

[0059] In some embodiments, the compound is of IIIa: [Chemical formula] a compound of, or a pharmaceutically acceptable salt thereof, wherein: R 2 is C 1-6 alkyl, C 1-3 alkoxy, or phenyl; wherein said phenyl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from halo; R 3 is Cy or C(=O)NR c R d ; wherein each R c and R d is independently selected from C 1-6 alkyl; Cy is optionally substituted with 1 or 2 R 1 each independently selected from Cy 1-3 -(C 1 alkylene)-Cy 1-6 halo, CN, OH, C 1-6 alkyl, C 1-6 alkoxy, C b1 haloalkyl, C(=O)R c1 R d1 S(=O)R b1 and S(=O)2NR c1 R d1 ; and is selected from C 3b cycloalkyl, 4- to 7-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl; wherein said C 3-7 cycloalkyl, 4- to 7-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl are optionally substituted with 1 or 2 R 1-6Alkyl is 1, 2, or 3 independently selected R 11 groups, optionally substituted; Cy 1 is C 3-6 cycloalkyl or 4- to 7-membered heterocycloalkyl; each R a1 、R b1 、R c1 、and R d1 is independently selected from H, C 1-6 alkyl and C 1-6 haloalkyl; wherein said C 1-6 alkyl is optionally substituted with 1, 2, or 3 independently selected R 11 groups; R 4 is halo, CN, or C 1-4 alkyl; R 5 is halo or CN; and each R 11 is independently OH, CN, halo, C 1-3 alkyl, C 1-3 haloalkyl, HO-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, carbamyl, C 1-3 alkylcarbamyl, or di(C 1-3 alkyl)carbamyl.

[0060] In some embodiments, the compound is of formula IVa:

Chemical formula

[0061] In some embodiments, the compound is of formula Va:

Chemical formula

[0062] In the above-described embodiments for formula IIa, IIIa, IVa or Va, R 2 is C 1-3 alkoxy; and R 3 is Cy.

[0063] In the above-described embodiments for formula IIa, IIIa, IVa or Va, R 2 is phenyl optionally substituted with 1, 2, 3 or 4 substituents independently selected from halo; and R 3 is C(=O)NR c R d wherein each R c and R d is independently selected from C 1-6 alkyl.

[0064] In any of the foregoing embodiments, R 2 or R 3 comprises at least one cyclic moiety.

[0065] In some embodiments, the compound is selected from: 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; 5-{3-[1-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-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; 5-{3-[1-(4-amino-3-iodo-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;

[0066] 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; 5-{3-[1-(4-amino-5-oxopyrido[2,3-d]pyrimidin-8(5H)-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}-N,N-dimethylpyridine-2-carboxamide; 4-amino-8-(1-{5-chloro-2-methoxy-4-methyl-3-[5-(methylsulfonyl)pyridin-3-yl]phenyl}ethyl)pyrido[2,3-d]pyrimidin-5(8H)-one; 5-{3-[1-(4-amino-5-oxopyrido[2,3-d]pyrimidin-8(5H)-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}nicotinonitrile; 4-amino-8-[1-(5-chloro-2-methoxy-4-methyl-3-pyridin-3-ylphenyl)ethyl]pyrido[2,3-d]pyrimidin-5(8H)-one; 4-amino-8-[1-(5-chloro-2-methoxy-4-methyl-3-pyrimidin-5-ylphenyl)ethyl]pyrido[2,3-d]pyrimidin-5(8H)-one; 3’-[1-(4-Amino-5-oxopyrido[2,3-d]pyrimidin-8(5H)-yl)ethyl]-5’-chloro-2’-methoxy-N,N,6’-trimethylbiphenyl-3-carboxamide; 4-Amino-8-{1-[5-chloro-3-(5-fluoropyridin-3-yl)-2-methoxy-4-methylphenyl]ethyl}pyrido[2,3-d]pyrimidin-5(8H)-one; 3’-[1-(4-Amino-5-oxopyrido[2,3-d]pyrimidin-8(5H)-yl)ethyl]-5’-chloro-2’-methoxy-N,N,6’-trimethylbiphenyl-3-sulfonamide; 5-{3-[1-(4-Amino-5-oxopyrido[2,3-d]pyrimidin-8(5H)-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}-N-methylpyridine-2-carboxamide; 4-Amino-8-{1-[5-chloro-3-(1-isopropylazetidin-3-yl)-2-methoxy-4-methylphenyl]ethyl}pyrido[2,3-d]pyrimidin-5(8H)-one; 4-Amino-8-{1-[5-chloro-2-ethoxy-3-(1-isopropylazetidin-3-yl)-4-methylphenyl]ethyl}pyrido[2,3-d]pyrimidin-5(8H)-one; 5-{3-[1-(4-Amino-5-oxopyrido[2,3-d]pyrimidin-8(5H)-yl)ethyl]-5-chloro-2-ethoxy-6-methylphenyl}-N,N-dimethylpyridine-2-carboxamide; 6-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-4-chloro-N-ethyl-3’,5’-difluoro-3-methylbiphenyl-2-carboxamide; 4-{3-[1-(4-Amino-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-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-cyano-2-methoxy-6-methylphenyl}-N-(2-hydroxyethyl)-N-methylpyridine-2-carboxamide;

[0067] 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; 5-{3-[1-(4-Amino-5-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-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-5-oxopyrido[2,3-d]pyrimidin-8(5H)-yl)ethyl]-5-chloro-6-cyano-2-ethoxyphenyl}-N,N-dimethylpyridine-2-carboxamide; 4-(1-(4-Amino-5-oxopyrido[2,3-d]pyrimidin-8(5H)-yl)ethyl)-6-chloro-3-ethoxy-2-(5-(methylsulfonyl)pyridin-3-yl)benzonitrile; 5-(3-{1-[4-Amino-3-(3-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]ethyl}-5-chloro-2-ethoxy-6-methylphenyl)-N,N-dimethylpyridine-2-carboxamide; 5-(3-{1-[4-Amino-3-(1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]ethyl}-5-chloro-2-ethoxy-6-methylphenyl)-N,N-dimethylpyridine-2-carboxamide; 5-(3-{1-[4-Amino-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]ethyl}-5-chloro-2-ethoxy-6-methylphenyl)-N,N-dimethylpyridine-2-carboxamide; 5-(3-{1-[4-Amino-3-(1-methyl-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]ethyl}-5-chloro-2-ethoxy-6-methylphenyl)-N,N-dimethylpyridine-2-carboxamide; 5-(3-{1-[4-Amino-3-(1H-pyrazol-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]ethyl}-5-chloro-2-ethoxy-6-methylphenyl)-N,N-dimethylpyridine-2-carboxamide; 5-[3-(1-{4-Amino-3-[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl}ethyl)-5-chloro-2-ethoxy-6-methylphenyl]-N,N-dimethylpyridine-2-carboxamide; 5-{3-[1-(4-Amino-3-cyclopropyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-6-methylphenyl}-N,N-dimethylpyridine-2-carboxamide; 5-{3-[1-(4-Amino-3-cyano-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-6-methylphenyl}-N,N-dimethylpyridine-2-carboxamide; 5-(3-{1-[4-Amino-3-(4-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]ethyl}-5-chloro-2-ethoxy-6-methylphenyl)-N,N-dimethylpyridine-2-carboxamide; 5-{4-Amino-1-[1-(5-chloro-3-{6-[(dimethylamino)carbonyl]pyridin-3-yl}-2-ethoxy-4-methylphenyl)ethyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-N,N-dimethylpyridine-2-carboxamide; 5-(3-{1-[4-Amino-3-(5-cyanopyridin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]ethyl}-5-chloro-2-ethoxy-6-methylphenyl)-N,N-dimethylpyridine-2-carboxamide; 5-(3-{1-[4-Amino-3-(2-aminopyrimidin-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]ethyl}-5-chloro-2-ethoxy-6-methylphenyl)-N,N-dimethylpyridine-2-carboxamide; 5-{3-[1-(4-Amino-3-{6-[(methylamino)carbonyl]pyridin-3-yl}-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-6-methylphenyl}-N,N-dimethylpyridine-2-carboxamide; 5-{3-[1-(4-Amino-3-pyridin-4-yl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-6-methylphenyl}-N,N-dimethylpyridine-2-carboxamide; 5-{3-[1-(4-Amino-3-pyridin-3-yl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-6-methylphenyl}-N,N-dimethylpyridine-2-carboxamide; 5-{3-[1-(4-Amino-3-{5-[(dimethylamino)carbonyl]pyridin-3-yl}-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-6-methylphenyl}-N,N-dimethylpyridine-2-carboxamide; 1-{1-[5-chloro-2-methoxy-4-methyl-3-(1-oxetan-3-ylazetidin-3-yl)phenyl]ethyl}-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine; 1-(1-{5-chloro-2-methoxy-4-methyl-3-[1-(tetrahydro-2H-pyran-4-yl)azetidin-3-yl]phenyl}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-methoxy-6-methylphenyl}-N,N-dimethylnicotinamide; and 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; or a pharmaceutically acceptable salt of any of the foregoing.

[0068] In some embodiments, the compound is selected from: 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; 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; 4-((R)-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; 4-((S)-1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-6-chloro-2-(1-((R)-2-hydroxypropyl)azetidin-3-yl)-3-methoxybenzonitrile; 4-((R)-1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-6-chloro-2-(1-((R)-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-hydroxyethyl)azetidin-3-yl)-3-methoxybenzonitrile; (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; and (R)-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; or a pharmaceutically acceptable salt of any of the foregoing.

[0069] In some embodiments, formula I: [Chemical formula] The starred carbon is a chiral carbon and the compound or the salt is the (S)-enantiomer.

[0070] In some embodiments, the compound is of formula IIa: [Chemical formula] a compound of or a pharmaceutically acceptable salt thereof, wherein: R 2 is methoxy, ethoxy, -OCHF2, methyl, -F, or -CHF2; R 4 is methyl, Cl, F, or CN; and R 5 is methyl, Cl, F, or CN.

[0071] In some embodiments, the compound is of formula IIa:

Chemical formula

[0072] In some embodiments, the compound is of formula IIb:

Chemical formula

[0073] In some embodiments, the compound is of formula IIIa:

Chem.

[0074] In some embodiments, the compound is of formula IVa:

Chem.

[0075] In some embodiments, the compound is of formula Va:

Chem.

[0076] In some embodiments, the compound is of formula VIII:

Chem.

[0077] In some embodiments, the compound is of formula IX:

Chemical formula

[0078] It is further understood that certain features of the invention described in the context of separate embodiments may also be provided in combination in a single embodiment.

[0079] The present application further provides a compound of formula VII:

Chemical formula

[0080] R 8 is H, halo, -OH, -CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, Cy 2 ,-(C 1-3 alkylene)-Cy 2 , OR a2 , SR a2 , C(=O)R b2 , C(=O)NR c2 R d2 , C(=O)ORa2 、 OC(=O)R b2 、 OC(=O)NR c2 R d2 、 NR c2 R d2 、 NR c2 、 NR b2 、 NR c2 C(=O)OR b2 、 NR c2 C(=O)NR c2 R d2 、 C(=NR e )R b2 、 C(=NR e )NR c2 R d2 、 NR c2 C(=NR e )NR c2 R d2 、 NR c2 S(=O)R b2 、 NR c2 S(=O)2NR c2 R d2 、 S(=O)R b2 、 S(=O)2R b2 、 or S(=O)2NR c2 R d2 ; wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl is optionally substituted with 1, 2, 3, or 4 independently selected R 11 groups; R 8a is H, halo, -CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, Cy 2 、 -(C 1-3 alkylene)-Cy 2 、 C(=O)R b2 、 C(=O)NR c2 R d2 、 C(=O)OR a2 、 NR c2 R d2 、 NR c2 C(=O)R b2 、 NR c2 C(=O)OR b2, NR c2 C(=O)NR c2 R d2 , NR c2 S(=O)R b2 , NR c2 S(=O)2NR c2 R d2 , S(=O)R b2 , S(=O)2R b2 , or S(=O)2NR c2 R d2 wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl is optionally substituted by 1, 2, 3, or 4 independently selected R 11 groups; R 9 is H, halo, OH, CN, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, or C 1-4 haloalkoxy; R 10 is H or C 1-4 alkyl; each R e is independently selected from H, CN, OH, C 1-4 alkyl, and C 1-4 alkoxy; each Cy 2 is independently selected from C 11 cycloalkyl, 4- to 7-membered heterocycloalkyl, phenyl, 5- to 6-membered heteroaryl, or 9- to 10-membered bicyclic heteroaryl, each optionally substituted by 1, 2, 3, or 4 independently selected R 3-7 groups; each R a2 , R b2 , R c2 , and R d2 [[ID=7,6]]is H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7Independently selected from cycloalkyl, 4- to 7-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl; wherein said C 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 are each optionally substituted with 1, 2, or 3 independently selected R 11 groups; or R c2 and R d2 together with the N atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with -OH or C 1-3 alkyl; and each R 11 is 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, C 1-3 alkylthio, C 1-3 alkylsulfinyl, C 1-3 alkylsulfonyl, 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 alkylsulfonylamino, 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, and is independently selected from

[0081] In one embodiment, the compound of formula VII is not the compound of Examples 310-311 and 323-325. In another embodiment, the compound of formula VII is selected from the compounds of Examples 310-311 and 323-325.

[0082] In some embodiments, R 1 is methyl. In some embodiments, R 2 is C 1-3 alkoxy. In some embodiments, R 4 is halo, CN, or C 1-4 alkyl. In some embodiments, R 4 is methyl. In some embodiments, R 5 is halo. In some embodiments, R 5 is chloro or fluoro. In some embodiments, R 6 is H.

[0083] In some embodiments, R 8 is C 1-6 alkyl. In some embodiments, R 8 is methyl. In some embodiments, R 10 is H. In some embodiments, G is NH, n is 0 and V is O. In some embodiments, G is NH, n is 0 and V is CH2. In some embodiments, G is NH, n is 1 and V is O. In some embodiments, G is O, n is 0 and V is NH.

[0084] In some embodiments, the compound is of formula VIIa:

Chem.

[0085] In some embodiments, the compound is of formula VIIb:

Chem.

[0086] In some embodiments: G is NH; n is 0; V is O; R 2 is C 1-3 alkoxy; R 4 is halo, CN, or C 1-4 alkyl; R 5 is halo; and R 6 is H.

[0087] In some embodiments: G is NH; n is 0; V is CH2; R 2 is C 1-3 alkoxy; R 4 is halo, CN, or C 1-4 alkyl; R 5is halo; and R 6 is H.

[0088] In some embodiments: G is NH; n is 1; V is O; R 2 is C 1-3 alkoxy; R 4 is halo, CN, or C 1-4 alkyl; R 5 is halo; and R 6 is H.

[0089] In some embodiments: G is O; n is 0; V is NH; R 2 is C 1-3 alkoxy; R 4 is halo; R 5 is halo; and R 6 is H.

[0090] In some embodiments, the compound is selected from: 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; and 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; or a pharmaceutically acceptable salt of any of the foregoing.

[0091] In some embodiments, the compound is selected from: 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; (S)-4-(3-((S)-1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-chloro-2-ethoxy-6-fluorophenyl)pyrrolidin-2-one; (R)-4-(3-((S)-1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-chloro-2-ethoxy-6-fluorophenyl)pyrrolidin-2-one; (S)-4-(3-((R)-1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-chloro-2-ethoxy-6-fluorophenyl)pyrrolidin-2-one; and (R)-4-(3-((R)-1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-chloro-2-ethoxy-6-fluorophenyl)pyrrolidin-2-one; or a pharmaceutically acceptable salt of any of the foregoing.

[0092] In some embodiments, Formula VII: [Chemical formula] The starred carbon is a chiral carbon, and the compound or salt is the (S)-enantiomer.

[0093] Conversely, for the sake of brevity, the various features of the invention described in the context of a single embodiment may be provided separately or in any suitable sub-combination.

[0094] Divalent linking substituents are described at various places in this specification. It is specifically intended that each divalent linking substituent include both the forward and reverse forms of the linking substituent. For example, -NR(CR’R’’) n - is -NR(CR’R’’) n - and -(CR’R’’) n NR- both. Where the structure clearly requires a linking group, the Markush variables described with respect to that group are understood to be the linking group.

[0095] The term "n-membered" (where n is an integer) generally refers to the number of ring-forming atoms in a moiety where the number of ring-forming atoms is n. 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.

[0096] As used herein, the expression "optionally substituted" means unsubstituted or substituted. As used herein, the term "substituted" means that a hydrogen atom has been removed and replaced by a substituent. It is understood that substitution at a given atom is limited by valence.

[0097] Throughout the definitions, the term "C n-m " indicates a range including the endpoints, where n and m are integers and indicate the number of carbons. Examples include C 1-4 、C 1-6 and the like.

[0098] As used herein, the term "C n-m alkyl", used alone or in combination with other terms, refers to a saturated hydrocarbon group that can be straight-chain or branched-chain and has n to m carbons. 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; higher homologs such as 2-methyl-1-butyl, n-pentyl, 3-pentyl, n-hexyl, 1,2,2-trimethylpropyl, and the like.

[0099] As used herein, "C n-m"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. Examples of alkenyl groups include, but are not limited to, ethenyl, n-propenyl, isopropenyl, n-butenyl, sec-butenyl, and the like.

[0100] As used herein, "C" n-m "Alkynyl" refers to an alkyl group having one or more carbon-carbon triple bonds and having n to m carbons. Examples of 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.

[0101] As used herein, the term "alkylene," used 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.

[0102] As used herein, "C" n-m The term "alkoxy," used alone or in combination with other terms, refers to a group represented by the formula -O-alkyl, where the alkyl group has n to m carbons. Examples of 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.

[0103] As used herein, "C" n-mThe term "alkylamino" refers to a group represented by the 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.

[0104] As used herein, "C" n-m The term "alkoxycarbonyl" refers to a group represented by the formula -C(O)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.

[0105] As used herein, "C" n-m The term "alkylcarbonyl" refers to a group represented by the 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.

[0106] As used herein, "C" n-m The term "alkylcarbonylamino" refers to a group represented by the 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.

[0107] As used herein, "C" n-m The term "alkylsulfonylamino" refers to a group represented by the 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.

[0108] As used herein, the term "aminosulfonyl" refers to a group represented by the formula -S(O)2NH2.

[0109] As used herein, "C" n-mThe term "alkylaminosulfonyl" refers to a group represented by the formula -S(O)2NH(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.

[0110] As used herein, the term "di(C n-m alkyl)aminosulfonyl" refers to a group represented by the formula -S(O)2N(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.

[0111] As used herein, the term "aminosulfonylamino" refers to a group represented by the formula -NHS(O)2NH2.

[0112] As used herein, n-m the term "Calkylaminosulfonylamino" refers to a group represented by the formula -NHS(O)2NH(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.

[0113] As used herein, n-m the term "di(Calkyl)aminosulfonylamino" refers to a group represented by the formula -NHS(O)2N(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.

[0114] As used herein, the term "aminocarbonylamino", used alone or in combination with other terms, refers to a group represented by the formula -NHC(O)NH2.

[0115] As used herein, n-mThe term "alkylaminocarbonylamino" refers to a group represented by the 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.

[0116] As used herein, the term "di(C n-m alkyl)aminocarbonylamino" refers to a group represented by the 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.

[0117] As used herein, the term "C n-m alkylcarbamyl" refers to a group represented by the 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.

[0118] As used herein, the term "thio" refers to a group represented by the formula -SH.

[0119] As used herein, the term "C n-m alkylthio" refers to a group represented by the 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.

[0120] As used herein, the term "C n-m alkylsulfinyl" refers to a group represented by the 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.

[0121] As used herein, the term "C n-mThe term "alkylsulfonyl" refers to a group represented by the formula -S(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.

[0122] As used herein, the term "amino" refers to a group represented by the formula -NH2.

[0123] As used herein, the term "carbamyl" refers to a group represented by the formula -C(O)NH2.

[0124] As used herein, the term "carbonyl", used alone or in combination with other terms, refers to the -C(O)- group.

[0125] As used herein, "cyano-C 1-3 alkyl" refers to a group represented by the formula -(C 1-3 alkylene)-CN.

[0126] As used herein, "HO-C 1-3 alkyl" refers to a group represented by the formula -(C 1-3 alkylene)-OH.

[0127] As used herein, "C 1-3 alkoxy-C 1-3 alkyl" refers to a group represented by the formula -(C 1-3 alkylene)-O(C 1-3 alkyl).

[0128] As used herein, the term "carboxy" refers to a group represented by the formula -C(O)OH.

[0129] As used herein, "di(C n-mThe term “(C1-Cm-alkyl)amino” refers to a group represented by the formula -N(alkyl)2, where the two alkyl groups each independently have from n to m carbon atoms. In some embodiments, each alkyl group independently has from 1 to 6, from 1 to 4, or from 1 to 3 carbon atoms.

[0130] As used herein, “di(C n-m -alkyl)carbamyl” refers to a group represented by the formula -C(O)N(alkyl)2, where the two alkyl groups each independently have from n to m carbon atoms. In some embodiments, each alkyl group independently has from 1 to 6, from 1 to 4, or from 1 to 3 carbon atoms.

[0131] As used herein, “halo” refers to F, Cl, Br, or I. In some embodiments, the halo group is F or Cl.

[0132] As used herein, “C n-m haloalkoxy” refers to a group represented by the formula -O-haloalkyl having from n to m carbon atoms. An example of a haloalkoxy group is OCF3. In some embodiments the haloalkoxy group is fluorinated only. In some embodiments, the alkyl group has from 1 to 6, from 1 to 4, or from 1 to 3 carbon atoms.

[0133] As used herein, the term “C n-m haloalkyl,” used alone or in combination with other terms, refers to an alkyl group having from 1 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, and where the alkyl group has from n to m carbon atoms. In some embodiments, the haloalkyl group is fluorinated only. In some embodiments, the alkyl group has from 1 to 6, from 1 to 4, or from 1 to 3 carbon atoms.

[0134] As used herein, "cycloalkyl" refers to a non-aromatic cyclic hydrocarbon containing a cyclic alkyl and / or alkenyl group. A cycloalkyl group may include monocyclic or polycyclic (e.g., having 2, 3, or 4 fused rings) groups and spiro rings. A cycloalkyl group may have 3, 4, 5, 6, or 7 ring-forming carbons (C 3-7 ). The ring-forming carbon atoms of a cycloalkyl group may optionally be substituted by oxo or sulfide. A cycloalkyl group also includes cycloalkylidene. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl, norcarnyl, and the like. In some embodiments, cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. A moiety having one or more aromatic rings fused to a cycloalkyl ring (i.e., sharing a bond), such as benzo or thienyl derivatives of cyclopentane, cyclohexane, etc., is also included in the definition of cycloalkyl. A cycloalkyl group containing a fused aromatic ring can be bonded through any ring-forming atom including the ring-forming atoms of the fused aromatic ring.

[0135] As used herein, "heteroaryl" refers to a monocyclic or polycyclic 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 ring-forming N of the heteroaryl moiety can be an N-oxide. In some embodiments, heteroaryl has 5 to 10 ring atoms and 1, 2, 3, or 4 heteroatom ring members independently selected from nitrogen, sulfur, and oxygen. In some embodiments, heteroaryl has 5 to 6 ring atoms and 1 or 2 heteroatom ring members independently selected from nitrogen, sulfur, and oxygen. In some embodiments, heteroaryl is a 5- or 6-membered heteroaryl ring.

[0136] A 5-membered heteroaryl ring is a heteroaryl containing a ring having 5 ring atoms, wherein one or more (e.g., 1, 2, or 3) of the ring atoms are independently selected from N, O, and S. Exemplary 5-membered ring heteroaryls 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.

[0137] 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) of the ring atoms are independently selected from N, O, and S. Exemplary 6-membered ring heteroaryls are pyridyl, pyrazinyl, pyrimidinyl, triazinyl, and pyridazinyl.

[0138] "Bicyclic C 9-10"Heteroaryl" is a bicyclic fused heteroaryl having 9 to 10 ring members.

[0139] As used herein, "heterocycloalkyl" refers to a non-aromatic monocyclic or polycyclic 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. The heterocycloalkyl group may also include spiro rings. Examples of heterocycloalkyl groups include pyrrolidin-2-one, 1,3-isoxazolidin-2-one, pyranyl, tetrahydrofuran, oxetanyl, azetidinyl, morpholino, thiomorpholino, piperazinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, pyrrolidinyl, isoxazolidinyl, isothiazolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, imidazolidinyl, azepanyl, benzoazepane, etc. The ring-forming carbon atoms and heteroatoms of the heterocycloalkyl group may optionally be substituted by oxo or sulfide (e.g., C(O), S(O), C(S), or S(O)2, etc.). The heterocycloalkyl group can be bonded via 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. A moiety having one or more aromatic rings (i.e., sharing a bond) fused to a cycloalkyl ring, such as benzo or thienyl derivatives of piperidine, morpholine, azepine, etc., is also included in the definition of heterocycloalkyl. A heterocycloalkyl group containing a fused aromatic ring can be bonded via any ring-forming atom including the ring-forming atoms of the fused aromatic ring. In some embodiments, heterocycloalkyl has 4 to 10, 4 to 7, or 4 to 6 ring atoms and one or more oxidized ring members, containing 1 or 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0140] At a particular place, the definition or embodiment refers to a particular ring (e.g., azetidine ring, pyridine ring, etc.). Unless otherwise indicated, these rings can be bonded through any ring member, provided that they do not exceed the valence of the atoms. For example, the azetidine ring can be bonded at any position of the ring, while the azetidin-3-yl ring is bonded at the 3-position.

[0141] The compounds described herein can be asymmetric (e.g., having one or more stereocenters). Unless otherwise indicated, all stereoisomers, such as enantiomers and diastereomers, are intended. The compounds of the present invention containing an asymmetrically substituted carbon atom can be isolated in optically active form or racemic form. Methods for preparing optically active forms from optically inactive starting materials, such as by resolution of a racemic mixture or stereoselective synthesis, are known in the art. Many geometric isomers of olefins, C=N double bonds, etc. can also be present in the compounds described herein, and all such stable isomers are intended in the present invention. The cis and trans geometric isomers of the compounds of the present invention are described and can be isolated as mixtures of isomers or as separated isomeric forms.

[0142] In some embodiments, the compound has an (R)-configuration. In some embodiments, the compound has an (S)-configuration.

[0143] The resolution of a racemic mixture of a compound can be carried out by any of a number of methods known in the art. Examples of methods include the fractional recrystallization method using a chiral resolution acid which is an optically active organic acid that forms salts. Resolution agents suitable for the fractional recrystallization method are, for example, optically active acids such as D- and L-tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid or various optically active camphorsulfonic acids such as β-camphorsulfonic acid. Other resolution agents suitable for the fractional recrystallization method include α-methyl-benzylamine in stereoisomerically pure form (e.g., S- and R-forms, or diastereomerically pure form), 2-phenylglycinol, norephedrine, ephedrine, N-methylephedrine, cyclohexylethylamine, 1,2-diaminocyclohexane and the like.

[0144] The resolution of a racemic mixture can also be carried out by elution on a column packed with an optically active resolution agent (e.g., dinitrobenzoylphenylglycine). Suitable elution solvent compositions can be determined by those skilled in the art.

[0145] The compounds of the present invention also include tautomeric forms. Tautomeric forms are generated by the exchange of a single bond and an adjacent double bond together with the simultaneous transfer of a proton. Tautomeric forms include prototropic tautomers which are isomeric protonated states having the same empirical formula and total charge. Examples of prototropic tautomers include keto-enol pairs, amide-imido acid pairs, lactam-lactim pairs, enamine-imine pairs, and cyclic forms where a proton can occupy two or more positions in a heterocyclic system, for example, 1H- and 3H-imidazole, 1H-, 2H- and 4H-1,2,4-triazole, 1H- and 2H-isoindole, and 1H- and 2H-pyrazole. Tautomeric forms can be in equilibrium or can be stereochemically fixed in one form by appropriate substitution.

[0146] The compounds of the present invention may also include all isotopes of atoms that occur in the intermediates or final compounds. Isotopes include atoms having the same atomic number but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium.

[0147] As used herein, the term "compound" is intended to include all stereoisomers, geometric isomers, tautomers, and isotopes of the indicated structure. A compound herein identified as a particular tautomeric form by name or structure is intended to include other tautomeric forms unless otherwise indicated.

[0148] All compounds, and their pharmaceutically acceptable salts, may exist with other substances such as water and solvents (e.g., hydrates and solvates), or may be isolated.

[0149] In some embodiments, the compounds of the present invention, or salts thereof, are substantially isolated. "Substantially isolated" means that the compound is at least partially or substantially separated from the environment in which it was formed or detected. Partially separated may include, for example, a composition rich in the compounds of the present invention. Substantially separated may include compositions containing at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 97%, or at least about 99% by weight of the compounds of the present invention or salts thereof. Methods for isolating compounds and their salts are conventional in the art.

[0150] The expression "pharmaceutically acceptable" as used herein refers to compounds, materials, compositions, and / or dosage forms that are suitable for use in contact with human and animal tissues within the scope of sound medical judgment, without excessive toxicity, irritation, allergic response, or other problems or complications, and commensurate with a reasonable benefit / risk ratio.

[0151] As used herein, the expressions "ambient temperature" and "room temperature" or "room temperature (rt)" are understood in the art and generally refer to the reaction temperature, which is approximately the temperature of the room in which the reaction is carried out, for example, a temperature of about 20°C to about 30°C.

[0152] The present invention also includes pharmaceutically acceptable salts of the compounds described herein. As used herein, "pharmaceutically acceptable salts" refer to derivatives of the disclosed compounds, where the parent compound is modified by converting an existing acid or base moiety into its salt form. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids, etc. Pharmaceutically acceptable salts of the present invention include, for example, conventional non-toxic salts of the parent compounds formed from non-toxic inorganic or organic acids. Pharmaceutically acceptable salts of the present invention can be synthesized from parent compounds containing basic or acidic moieties 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. A list 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.

[0153] Synthesis The compounds of the present invention, including their salts, can be prepared using known organic synthesis techniques and can be synthesized according to any of a number of possible synthetic routes.

[0154] The reactions for preparing the compounds of the present invention can be carried out in a suitable solvent that can be readily selected by those skilled in the art of organic synthesis. Suitable solvents can be substantially non-reactive with starting materials (reactants), intermediates, or products at the temperature at which the reaction is carried out, for example, in the range of the freezing temperature of the solvent to the boiling temperature 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 the particular reaction step can be selected by those skilled in the art.

[0155] The preparation of the compounds of the present invention 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 those skilled in the art. The chemical reactions of protecting groups can be found, 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 hereby incorporated by reference in its entirety.

[0156] The reaction can be monitored according to any suitable method known in the art. For example, nuclear magnetic resonance methods (e.g., 1 H or 13C), spectroscopic means such as infrared spectroscopy, spectrophotometry (e.g., ultraviolet-visible), mass spectrometry, or chromatographic methods such as high performance liquid chromatography (HPLC), liquid chromatography-mass spectrometry (LCMS), or thin layer chromatography (TLC) can be used to monitor the formation of the product. The compounds can be purified by various methods by those skilled in the art, 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, which is hereby incorporated by reference in its entirety) and normal phase silica chromatography.

[0157] For example, the compounds of formula I can be formed as shown in Scheme I. Compound (i) is halogenated with N-chlorosuccinimide, N-bromosuccinimide or N-iodosuccinimide to obtain compound (ii) where X 1 = Cl, Br, or I. The halo group of (ii) is coupled with R 3 -M where M is boronic acid, boronic ester or a suitably substituted metal (e.g., R 3 -B(OH)2, R 3 -Sn(Bu)4, or Zn-R 3 under standard Suzuki conditions or standard Stille conditions (e.g., in the presence of a palladium(0) catalyst such as tetrakis(triphenylphosphine)palladium(0) and a base (e.g., a hydrogen carbonate or carbonate base)) or standard Negishi conditions (e.g., in the presence of a palladium(0) catalyst such as tetrakis(triphenylphosphine)palladium(0)) to obtain a derivative of formula (iii). Alternatively, R 3 3 ​-M can be a cyclic amine (where M is H and is bonded to the amine nitrogen), and the coupling with compound (ii) can be carried out by heating in a base or under Buchwald conditions (for example, in the presence of a palladium(0) catalyst such as tetrakis(triphenylphosphine)palladium(0) and a base (such as an alkoxide base)) to obtain ketone (iii). Reduction of ketone (iii) with a suitable reagent such as sodium tetrahydroborate gives alcohol (iv), which can be converted to a derivative (v) having a leaving group (for example, the leaving group is a chloride by reaction with cyanuric chloride or a mesylate by reaction with methanesulfonic anhydride). Finally, compound (v) can be reacted with a suitable heterocycle (vi) (for example, 3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine or 4-aminopyrido[2,3-d]pyrimidin-5(8H)-one) under basic conditions (for example, NaH or CsCO3 or K2CO3) to obtain compound (vii) of formula I.

[0158] Scheme I

Chemical formula

[0159] Alternatively, the compound of formula I can also be formed as shown in Scheme II. The ketone compound (i) is halogenated with N-chlorosuccinimide, N-bromosuccinimide or N-iodosuccinimide to give X 1Compound (ii) can be obtained where = Cl, Br, or I. The ketone (ii) is reduced with a suitable reagent such as sodium tetrahydroborate to obtain alcohol (iii), which is converted to a derivative having a leaving group (e.g., the leaving group is chloride by reaction with cyanuric chloride or mesylate by reaction with methanesulfonic anhydride), and then reacted with a heterocycle to obtain a heterocyclic derivative (iv). The enantiomer (iv) of the compound can be separated by chiral chromatography to obtain a single enantiomer (v) of the heterocyclic compound. Finally, the halo group of (v) is reacted with R 3 -M where M is boronic acid, boronic ester or a suitably substituted metal (e.g., R 3 -B(OH)2, R 3 -Sn(Bu)4, or Zn-R 3 and is) R 3 -M under standard Suzuki conditions or standard Stille conditions (e.g., in the presence of a palladium(0) catalyst such as tetrakis(triphenylphosphine)palladium(0) and a base (e.g., a hydrogen carbonate 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 obtain a derivative (vi) of formula I.

[0160] Scheme II

Chemical formula

[0161] A compound of formula I where L is O, N, or S can be formed as shown in Scheme III. Thiol, phenol or amine (i) is alkylated using Mitsunobu conditions (e.g., R’OH, DEAD, Ph3P) or standard alkylation conditions (R’-Lg, Lg = leaving group) to obtain a thio-ether, ether, or alkylamine derivative (ii) respectively. The halo group of (ii) is reacted with R 3-M is R 3 -B(OH)2, R 3 -Sn(Bu)4, or Zn-R 3 wherein) R 3 -M and, under standard Suzuki conditions or standard Stille conditions (e.g., in the presence of a palladium(0) catalyst such as tetrakis(triphenylphosphine)palladium(0), and a base (e.g., a hydrogen carbonate or carbonate base)) or standard Negishi conditions (e.g., in the presence of a palladium(0) catalyst such as tetrakis(triphenylphosphine)palladium(0)) can be coupled to obtain a derivative of formula (iii). Alternatively, R 3 -M can be a cyclic amine (where M is H and is bonded to the amine nitrogen), and the coupling with compound (ii) can be 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 obtain a compound of formula (iii). Using methods similar to those shown in Schemes I and II, the ketone (iii) can be converted to obtain a compound (iv) of formula I. Alternatively, using methods similar to those shown in Schemes I and II, the halo-ketone (ii) can be converted to obtain a halo intermediate (v). By Suzuki, Stille, Negishi or Buchwald coupling of R 3 -M and the halo intermediate (v), a compound (vi) of formula I can also be obtained.

[0162] Scheme III

Chemical formula

[0163] The compound of formula I can be formed as shown in Scheme IV. Using a suitable acylation reagent (e.g., R 1 -COCl), compound (i) can be acylated to form an ester, which can be rearranged under Lewis acid conditions (e.g., BF3 / HOAc complex) to obtain a ketone (ii). NX1 S (e.g., NX 1 Using S = N-chlorosuccinamide, N-bromosuccinamide, or N-iodosuccinamide, halogenation of ketone (ii) gives compound (iii) where X 1 = Cl, Br, or I. Using standard conditions (e.g., Tf2O), phenol can be converted to triflate (iv). The triflate group of (iv) can be coupled with R 3 -M where M is boronic acid, boronic ester, or appropriately substituted metal (e.g., R 3 -B(OH)2, R 3 -Sn(Bu)4, or Zn-R 3 under standard Suzuki conditions or standard 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 under standard Negishi conditions (e.g., in the presence of a palladium(0) catalyst such as tetrakis(triphenylphosphine)palladium(0)) to give a derivative of formula (v). Alternatively, R 3 -M can be a cyclic amine (where M is H and is attached to the amine nitrogen), and the coupling with compound (iv) can be 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 (e.g., an alkoxide base)) to give ketone (v). The halo group of (v) can be coupled with R 2 -M where M is boronic acid, boronic ester, or appropriately substituted metal (e.g., R 3 -M is R 3 -B(OH)2, R 3 -Sn(Bu)4, or Zn-R 3 under standard Suzuki conditions or standard 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)) to give a derivative of formula (vi). Alternatively, R 3 ​3 -M can be a cyclic amine (where M is H and is bonded to the amine nitrogen), and the coupling with compound (iv) can be carried out by heating in a base or under Buchwald conditions (for example, in the presence of a palladium(0) catalyst such as tetrakis(triphenylphosphine)palladium(0) and a base (for example, an alkoxide base)) to obtain ketone (vi). Using methods similar to those shown in Schemes I and II, ketone (vi) can be converted to obtain compound (viii) of formula I.

[0164] Alternatively, using methods similar to those shown in Schemes I and II, halo-ketone (v) can be converted to obtain halo-intermediate (vii). By a method similar to that described in Schemes I and II, M-R 3 and compound (vii) can also obtain compound (viii) of formula I by Suzuki, Stille, Negishi or Buchwald coupling.

[0165] Scheme IV

Chemical formula

[0166] The ketones that can be used in the processes of Schemes I, II and III can be formed as shown in the following Scheme V. Carboxylic acid (i) is activated by a coupling agent (for example, HBTU, HATU or EDC), and then reacted with N,O-dimethylhydroxylamine to obtain N-methoxy-N-methylcarboxamide derivative (ii). Then, amide (ii) is reacted with a Grignard reagent of formula R 1 -MgX 1 (X 1 = halo) to obtain ketone (iii). Using methods similar to those shown in Schemes I, II and III, ketone (iii) can be converted to obtain a compound of formula I.

[0167] Scheme V [Chemical formula]

[0168] The ketones that can be used in the processes of Schemes I, II, and III can also be formed as shown in Scheme VI below. Carboxylic acid (i) can be activated with a coupling agent (e.g., HBTU or HATU) and then reacted with N,O-dimethylhydroxylamine to obtain N-methoxy-N-methylcarboxamide. Thiol, phenol, or amine can be alkylated using Mitsunobu conditions (e.g., R’OH, DEAD, Ph3P) or standard alkylation conditions (R’-Lg, Lg = leaving group) to obtain thio-ether, ether, or alkylamine derivative (ii), respectively. The halo group (X 1 is halo) of (ii) is coupled with R 3 -M where M is boronic acid, boronic ester, or a suitably substituted metal (e.g., R 3 -B(OH)2, R 3 -Sn(Bu)4, or Zn-R 3 and is) R 3 -M under standard Suzuki conditions or standard 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 under standard Negishi conditions (e.g., in the presence of a palladium(0) catalyst such as tetrakis(triphenylphosphine)palladium(0)) to obtain a derivative of formula (iii). Alternatively, R 3 -M can be a cyclic amine (M is H and is bonded to the amine nitrogen), and the coupling with compound (ii) can be 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., alkoxide base)) to obtain amide (iii). Compound (iii) and the formula R 1 -MgX 2 (X 2=(Hello) By reacting with a Grignard reagent, ketone (iv) can be obtained. Using methods similar to those shown in Schemes I, II, and III, ketone (iv) can be converted to obtain a compound of formula I.

[0169] Scheme VI

Chemical formula

[0170] The compounds that can be used in the processes of Schemes I - III can also be formed as shown in Scheme VII. Using standard cyanation conditions (e.g., Pd(0) and Zn(CN)2), halo - ketone (i) (where X 1 is halo) can be converted to cyano - ketone (ii). By hydrolysis of the cyano group of (ii) under acidic or basic conditions, a carboxylic acid is obtained, which is then coupled with an amine (HNR c R d ) using a coupling agent (e.g., HATU, HBTU, EDC) to obtain amide (iii). In some embodiments, R c and R d , together with the nitrogen atom to which they are attached, can cyclize as desired to form a 4 - to 7 - membered heterocycloalkyl group (thereby providing a compound where R 3 is C(O)R b and R b is a 4 - to 7 - membered heterocycloalkyl). Using methods similar to those shown in Schemes I, II, and III, the ketone of amide (iii) can be converted to obtain a compound of formula I.

[0171] Scheme VII

Chemical formula

[0172] Additional compounds that can be used in the processes of Schemes I - III can be formed as shown in Scheme VIII. Using standard nitration conditions (e.g., HNO3), ketone (i) can be converted to nitro - ketone (ii). Reduction of the nitro group of (ii) under standard conditions (e.g., Fe, Zn, H2 on Pd / C) gives an amino compound, which can be acylated with an appropriate acylating agent (e.g., RC=OCl, ROC=OCl, SO2Cl, RRNC=O) to give ketone (iii). Using a method similar to those shown in Schemes I, II, and III, ketone (iii) can be converted to obtain a compound of Formula I. In some embodiments, R c and R d together with the nitrogen atom to which they are attached can cyclize, optionally, to form a 4 - to 7 - membered heterocycloalkyl group (thereby providing a compound wherein R 3 is C(O)R b and R b is a 4 - to 7 - membered heterocycloalkyl).

[0173] Scheme VIII

Chemical Structure

[0174] Ketones that can be used in the processes of Schemes I, II, and III can also be formed as shown in Scheme IX below. The halo group of (i) (e.g., X 1 =I) is reacted with a zinc reagent R 3-Zn (e.g., tert-butyl 3-iodoazetidine-1-carboxylate and Zn powder, etc.) and coupling 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 obtain a derivative of formula (ii). Deprotect the azetidine (ii) (e.g., using TFA when Pg = Boc), and then react it under alkylation, acylation, or reductive amination conditions (e.g., RX such as R-Br, RCOCl, R-SO2Cl, RN=C=O or RCHO and a reducing agent) to obtain a ketone derivative (iii), which can be converted to a compound (v) of formula I by a method similar to those shown in Schemes I, II, and III. Alternatively, reduce the ketone (ii) with a suitable reagent (such as NaBH4 or Corey's chiral CBS catalyst to mainly obtain one isomer of the alcohol), convert the resulting alcohol to a leaving group (e.g., the leaving group is chloride by reaction with cyanuric chloride or mesylate by reaction with methanesulfonic anhydride), and then react the chloride or mesylate with a suitable heterocycle (e.g., in the same manner as shown in Schemes I, II, and III) to obtain a derivative of formula (iv). Remove the protecting group on the amine under standard conditions, and then react it under alkylation, acylation, or reductive amination conditions (e.g., RX such as R-Br, RCOCl, R-SO2Cl, RN=C=O or RCHO and a reducing agent) to obtain a compound (v) of formula I.

[0175] Scheme IX

Chemical Structure

[0176] The compound of formula I can also be formed as shown in Scheme X. Compound (i) is reacted with a heterocyclic ring (ii) substituted with a halo (e.g., 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine or 4-amino-6-iodopyrido[2,3-d]pyrimidin-5(8H)-one) under basic conditions (e.g., NaH or CsCO3 or K2CO3) to obtain compound (iii) where V = Cl, Br, or I. The halo group of (iii) is coupled with R 8 -M being R 8 -B(OH)2, R 8 -Sn(Bu)4, or Zn-R 8 being) R 3 -M under standard Suzuki conditions or standard Stille conditions (e.g., in the presence of a palladium(0) catalyst such as tetrakis(triphenylphosphine)palladium(0) and a base (e.g., a hydrogen carbonate 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 obtain a derivative of formula (iii). Alternatively, R 8 -M can be a cyclic amine (M being H and bonded to the amine nitrogen), and the coupling with compound (iii) 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 (e.g., an alkoxide base)) to obtain the compound (iv) of formula I.

[0177] Scheme X [Chemical formula]

[0178] The compound of formula I can also be formed as shown in Scheme XI. The cyano derivative (i) is hydrolyzed with an acid (e.g., in the presence of an acid or a base) to obtain the corresponding acid (ii). The carboxylic acid (ii) is reacted with an amine (e.g., HNR c2R d2 is dimethylamine)(iii) and an appropriate coupling agent (e.g., HATU, HBTU, EDC) are used in the presence of a base such as TEA or DIEA for coupling to obtain amide (iii). The carboxylic acid (ii) can be reduced to an alcohol (iv) where R t = H by an appropriate reducing agent (e.g., LAH or NaBH4), or converted to an ester and reacted with a Grignard reagent (e.g., R t MgBr) or an alkyllithium (e.g., R t Li) to obtain a secondary or tertiary alcohol (iv). By reacting with a suitable reagent such as cyanuric chloride and converting to a leaving group such as a halide, the alcohol (iv) is activated and then reacted with an appropriate amine (e.g., HNR c2 R d2 ) to obtain a compound (v) of formula I. Alternatively, the alcohol (iv) can be reacted under Mitsunobu conditions (e.g., in the presence of DEAD, triphenylphosphine and compound A (e.g., a phenol or heteroaryl having NH, e.g., imidazole)) to obtain a compound (vi) of formula I. Other modifications starting from the compounds shown in Scheme XI (e.g., esterification of an alcohol, etc.) will be apparent to those skilled in the art.

[0179] Scheme XI

Chemical Structure

[0180] The compound of formula I can be synthesized from the acid chloride compound (i) as shown in Scheme XII. A dicyanoenol intermediate is obtained by condensation of the acid chloride (i) with malononitrile in the presence of a base such as sodium hydride, and it can be O-methylated with a suitable reagent such as dimethyl sulfate in the presence of a suitable base such as sodium hydrogen carbonate to obtain the enol ether (ii). The pyrazole compound (iii) can be obtained by reaction of the enol ether (ii) with hydrazine dihydrochloride in the presence of a suitable base such as triethylamine. The pyrazolopyrimidine (iv) can then be obtained by reacting the pyrazole compound (iii) with formamide. Finally, the compound (iv) can be reacted with a suitable compound (v) having a leaving group under basic conditions to obtain the compound (vi) of formula I.

[0181] Scheme XII

Chemical Structure

[0182] The compound of formula I can be synthesized from commercially available 4-aminopyrido[2,3-d]pyrimidin-5(8H)-one (i). Halogenation of the compound (i) with a suitable reagent such as N-halosuccinimide (X 1 = Cl, Br or I, NX 1 S) gives the corresponding halo compound (ii). The compound (iv) can be obtained by reaction of the halo derivative (ii) with a compound (iii) having a leaving group in the presence of a suitable base (e.g., diisopropylethylamine). The halo compound (iv) is such that M is boric acid, a boronic acid ester or a suitably substituted metal (e.g., R 8a -M is R 8a -B(OH)2, R 8a -Sn(Bu)4, or Zn-R 8a ), and R 8a-M can be coupled with under standard Suzuki conditions or standard Stille conditions (e.g., in the presence of a palladium(0) catalyst such as tetrakis(triphenylphosphine)palladium(0) and a base (e.g., a hydrogen carbonate 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 obtain a derivative of formula (iii). Alternatively, R 8a -M can be a cyclic amine (where M is H and is bonded to the amine nitrogen), and the coupling with compound (iii) can be 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 obtain the compound (v) of formula I.

[0183] Scheme XIII [Chemical formula]

[0184] The compound of formula I can also be formed as shown in Scheme XIV. The halo group, X of (i) 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 obtain an alkene of formula (ii). A nitro derivative (iii) can be obtained by the reaction of alkene (ii) with nitromethane in the presence of DBU, and it can be reduced under standard conditions (e.g., NiCl2 / NaBH4) to obtain a free amine, which can be cyclized to form a lactam (iv). The lactam can be reacted under standard conditions (e.g., in the presence of a base such as TEA or NaH, where X 2 = halo for R 3a -X 2) can be alkylated to obtain N-alkyl-lactam (v). The compound of formula (v) and the pyrrolidine obtained by reducing lactam (v) with a suitable reducing agent such as LiAlH4 can be converted to the compound of formula I using the conditions described in Schemes I, II and III.

[0185] Scheme XIV

Chemical formula

[0186] The compound of formula I can also be formed as shown in Scheme XV. The halo group X of (i) 1 is coupled with R 3 -M where M is a metal appropriately substituted (for example, R 3 -M is R 3 B(OH)2; suitable starting materials for generating R 3 -M are shown in Scheme XII but are not limited thereto) under standard Suzuki conditions (for example, in the presence of a palladium(0) catalyst such as tetrakis(triphenylphosphine)palladium(0)) to obtain the alkene of formula (ii). Epoxidation of the alkene (ii) with mCPBA gives the epoxide (iii), which is reacted with a secondary or primary amine (amine = NHR c R d ; for primary amines, R c = H) to obtain the amino compound of formula (iv). The secondary or tertiary amine derivative (iv) is further reacted with carbonyldimidazole or phosgene to form oxazolidinone (v), or reacted with acetyl halide (for example, chloroacetyl chloride in the presence of a base such as TEA) to obtain an N-acyl derivative, which can be treated with a base (for example, NaH) to convert it to a morpholinone derivative (vi). The compounds of formula (iv, v, and vi) are deprotected using standard conditions (for example, a compound protected with a THP group can be treated with an acid such as TFA or HCl) to obtain the compound of formula I.

[0187] Scheme XV

Chem.

[0188] The compound of formula I can also be formed as shown in Scheme XVI. Under suitable conditions (A or B, described in JACS, 2001, 123(9), 1862 - 1871 and J. Org. Chem, 2011, 76, 358 - 372), either the amino - hydroxy isomer (ii) or (iii) of the alkene of formula (i) can be obtained by Sharpless amino - hydroxylation. Compounds (ii) and (iii) can be reacted with carbonyldimidazole or phosgene to form oxazolidinone (iv), or reacted with acetyl halide (e.g., chloroacetyl chloride in the presence of a base such as TEA) to obtain an N - acyl derivative, which can be treated with a base (e.g., NaH) to convert it to a morpholinone derivative (v). As shown in Scheme XV, the alternating amino - hydroxy isomer (iii) can be converted to oxazolidinone and morpholinone derivatives.

[0189] Scheme XVI

Chem.

[0190] The compound of formula I can be synthesized as shown in Scheme XVII. The halo group of (i) (e.g., X 1= Cl, Br, or I) can be converted to a boronate ester (ii) under standard conditions (e.g., in the presence of a palladium(0) catalyst such as tetrakis(triphenylphosphine)palladium(0), pinnacle boronate ester). Boronate (ii) can be reacted with an aryl halide or heteroaryl halide (e.g., R 3 -X 2 ) under Suzuki conditions (e.g., in the presence of a palladium(0) catalyst such as tetrakis(triphenylphosphine)palladium(0) and a base such as Na2CO3) to obtain formula (iii). Using the reaction conditions described in Scheme I, II, or III, formula (iii) can be converted to formula I.

[0191] Scheme XVII

Chemical Structure

[0192] R 4 = F or CN, the compound of formula I can be formed as shown in Scheme XVIII. Compound (i) is acylated with a suitable acylating reagent (e.g., R 1 -COCl) to form an ester, which is rearranged under Lewis acid conditions (e.g., BF3 / HOAc complex) to obtain ketone (ii). Ketone (ii) is halogenated with N-chlorosuccinimide, N-bromosuccinimide, or N-iodosuccinimide to obtain a phenol (iii) where X 1 = Cl, Br, or I. Compound (iii) is alkylated (e.g., with R 2 -X and a base such as NaH or Na2CO3; or under Mitsunobu conditions) to obtain an ether (iv). The fluoro group in (iv) is substituted (e.g., with NaCN or KCN) to obtain a cyano derivative (v). The halo group in (v) is reacted with M being a boronic acid, boronate ester, or appropriately substituted metal (e.g., R 3 -M being R 3-B(OH)2, R 3 -Sn(Bu)4, or Zn-R 3 wherein) R 3 -M and under standard Suzuki conditions or standard Stille conditions (e.g., in the presence of a palladium(0) catalyst such as tetrakis(triphenylphosphine)palladium(0) and a base (e.g., a hydrogen carbonate 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 effect a coupling to obtain a derivative of formula (vi). Alternatively, R 3 -M can be a cyclic amine (where M is H and is bonded to the amine nitrogen), and upon 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 effect a coupling with compound (v) to obtain a ketone (vi). Reduction of the ketone (vi) with a suitable reagent such as sodium tetrahydroborate or Corey's CBS reagent gives an alcohol, which is converted to a derivative having a leaving group (e.g., the leaving group is a chloride by reaction with cyanuric chloride or a mesylate by reaction with methanesulfonic anhydride), and then under basic conditions (e.g., NaH or CsCO3 or K2CO3) is reacted with a suitable heterocycle (e.g., 3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine or 4-aminopyrido[2,3-d]pyrimidin-5(8H)-one) to obtain a compound of formula I (viii). Alternatively, the ketone (v) can be reduced to an alcohol, which is converted to a leaving group, which is first substituted with a heterocycle and then a Suzuki, Stille, Negishi or Buchwald coupling is carried out such that the last two steps can be reversed to obtain a compound of formula I (viii). By excluding the cyanation step of Scheme XVIII, the fluoro derivative (iv) can also be converted to a compound of formula I.

[0193] Scheme XVIII [Chemical formula]

[0194] The compound of formula I can also be formed as shown in Scheme XIX. Compound (i) is acylated with a suitable acylating reagent (e.g., R 1 -COCl) to form an ester, which can be rearranged under Lewis acid conditions (e.g., AlCl3 or BF3 / HOAc complex) to give ketone (ii). NX 1 S (e.g., NX 1 S=N-chlorosuccinamide, N-bromosuccinamide or N-iodosuccinamide) is used for halogenation of ketone (ii) to give a compound (iii) where X 1 =Cl, Br, or I. Phenol can be converted to ether (iv) using standard conditions (e.g., an inorganic base such as K2CO3 and an alkyl halide such as Et-I). The halo group of (iv) is replaced by M which is a boronic acid, boronic ester or a suitably substituted metal (e.g., R 3 -M is 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) R 3-M is coupled under standard Suzuki conditions or standard Stille conditions (e.g., in the presence of a palladium(0) catalyst such as tetrakis(triphenylphosphine)palladium(0) and a base (e.g., a hydrogen carbonate or carbonate base)) to obtain a derivative of formula (v). Then, using Sharpless conditions, the alkene can be dihydroxylated to obtain a diol (vi). Enrichment of one enantiomer of the secondary alcohol can be achieved using the standard Sharpless asymmetric dihydroxylation method. The secondary alcohol is converted to an N-Boc protected amine, amino-alcohol (vii), via a 6-step process (e.g., silyl protection of the primary alcohol (e.g., TBS-Cl and DIEA), mesylation of the secondary alcohol, substitution 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). The amino-alcohol (vii) is converted to an oxazolidinone by treatment with phosgene and then the alcohol (viii) is obtained by reduction of the ketone with a suitable reagent such as sodium tetrahydroborate or sodium borohydride, which can be converted to a derivative (ix) having a leaving group (e.g., the leaving group is a chloride by reaction with cyanuric chloride or a mesylate by reaction with methanesulfonic anhydride). Finally, the compound (ix) is reacted with a suitable 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 Cs2CO3 or K2CO3) to obtain a compound (xi) of formula I.

[0195] Scheme XIX

Chemical Structure

[0196] Method The compounds of the present invention can modulate the activity of one or more of various kinases, including, for example, phosphoinositide 3-kinase (PI3K). The term "modulate" is intended to refer to the ability to increase or decrease the activity of one or more members of the PI3K family. Thus, the compounds of the present invention can be used in a method of modulating PI3K by contacting PI3K with any one or more of the 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 of the present invention can be used to modulate the activity of PI3K in an individual in need of receptor modulation by administering a modulating amount of the compound of the present invention or a pharmaceutically acceptable salt thereof. In some embodiments, modulating is inhibiting.

[0197] Considering that the growth and survival of cancer cells are affected by multiple signaling pathways, the present invention is useful in the treatment of disease states characterized by drug-resistant kinase variants. Further, different kinase inhibitors that exhibit different preferences for kinases whose activity is modulated can be used in combination. This approach can be highly effective in the treatment of disease states by targeting multiple signaling pathways, can reduce the likelihood of drug resistance occurring in cells, and can reduce the toxicity of treatment to the disease.

[0198] The kinases that the compounds of the present invention 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 contains a mutation. The mutation can be a substitution of one amino acid by another, or a deletion of one or more amino acids. In such embodiments, the mutation can be present in the kinase domain of the PI3K.

[0199] In some embodiments, two or more compounds of the present invention are used to inhibit the activity of one kinase (e.g., PI3Kγ or PI3Kδ).

[0200] In some embodiments, two or more compounds of the present invention are used to inhibit two or more kinases, e.g., at least two kinases (e.g., PI3Kγ or PI3Kδ).

[0201] In some embodiments, one or more of the compounds are used in combination with another kinase inhibitor to inhibit the activity of one kinase (e.g., PI3Kγ or PI3Kδ).

[0202] In some embodiments, one or more of the compounds are used in combination with another kinase inhibitor to inhibit the activity of two or more kinases (e.g., PI3Kγ or PI3Kδ), e.g., at least two kinases.

[0203] The compounds of the present invention can be selective. "Selective" means that the compound binds to or inhibits the kinase with a greater affinity or potency, respectively, compared to at least one other kinase. In some embodiments, the compounds of the present invention are selective inhibitors of PI3Kγ or PI3Kδ over PI3Kα and / or PI3Kβ. In some embodiments, the compounds of the present invention are selective inhibitors of PI3Kδ (e.g., over PI3Kα, PI3Kβ, and PI3Kγ). In some embodiments, the compounds of the present invention 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 conventional in the art. In some embodiments, selectivity can be tested at the K m ATP concentration. In some embodiments, the selectivity of the compounds of the present invention can be determined by a cell assay related to a specific PI3K kinase activity.

[0204] Another aspect of the present invention relates to a method of treating a kinase (e.g., PI3K)-related disease or disorder in an individual in need thereof (e.g., a patient) by administering a therapeutically effective amount or dose of one or more compounds of the present invention or a pharmaceutical composition thereof. PI3K-related diseases can include any disease, disorder or condition directly or indirectly related to the expression or activity of PI3K, including overexpression and / or abnormal activity levels. In some embodiments, the disease may be related to Akt (protein kinase B), mammalian target of rapamycin (mTOR), or phosphoinositide-dependent kinase 1 (PDK1). In some embodiments, mTOR-related diseases can be inflammation, atherosclerosis, psoriasis, restenosis, benign prostatic hyperplasia, bone disorders, pancreatitis, angiogenesis, diabetic retinopathy, atherosclerosis, arthritis, immunological disorders, kidney diseases, or cancer. PI3K-related diseases can also include any disease, disorder or condition that can be prevented, remitted, or cured by modulating the activity of PI3K. In some embodiments, the disease is characterized by abnormal activity of PI3K. In some embodiments, the disease is characterized by a mutant PI3K. In such embodiments, the mutation can be present in the kinase domain of PI3K.

[0205] Examples of PI3K-related diseases include, for example, immune-based diseases involving a system including rheumatoid arthritis, allergies, asthma, glomerulonephritis, lupus, or inflammation associated with any of the above.

[0206] Further examples of PI3K-related diseases include cancers such as breast cancer, prostate cancer, colon cancer, endometrial cancer, brain cancer, bladder cancer, skin cancer, uterine cancer, ovarian cancer, lung cancer, pancreatic cancer, kidney cancer, stomach cancer, or blood cancer.

[0207] In some embodiments, the blood cancer is acute myeloblastic leukemia (AML) or chronic myelogenous leukemia (CML), or B cell lymphoma.

[0208] Additional examples of PI3K-related diseases include lung diseases such as acute lung injury (ALI) and adult respiratory distress syndrome (ARDS).

[0209] Additional examples of PI3K-related diseases include osteoarthritis, restenosis, atherosclerosis, bone disorders, arthritis, diabetic retinopathy, psoriasis, benign prostatic hyperplasia, inflammation, angiogenesis, pancreatitis, kidney diseases, inflammatory bowel diseases, myasthenia gravis, multiple sclerosis, or Sjogren's syndrome, and the like.

[0210] As used herein, the term "contacting" refers to bringing together the indicated moieties in an in vitro or in vivo system. For example, "contacting" PI3K with a compound of the invention includes administering the compound of the invention to an individual or patient, such as a human, having PI3K; and introducing the compound of the invention into a sample, such as a cell preparation or purified preparation containing PI3K.

[0211] As used herein, the terms "individual" or "patient" used interchangeably refer to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses, or primates, and most preferably humans.

[0212] As used herein, the expression "therapeutically effective amount" refers to the amount of an active compound or pharmaceutical that induces a biological or pharmaceutical response sought 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 from about 1 mg to about 2 g, from about 1 mg to about 1000 mg, from about 1 mg to about 500 mg, from about 1 mg to about 100 mg, from about 1 mg to 50 mg, or from about 50 mg to about 500 mg.

[0213] As used herein, the terms "treating" or "treatment" refer to: (1) preventing a disease; e.g., preventing a disease, condition or disorder in an individual who may have a predisposition to the disease, condition or disorder but has not yet experienced or manifested the pathology or general symptoms of the disease; (2) inhibiting a disease; e.g., inhibiting a disease, condition or disorder in an individual who is experiencing or manifesting the pathology or general symptoms of the disease, condition or disorder (i.e., arresting further progression of the pathology and / or general symptoms); and (3) alleviating a disease; e.g., alleviating a disease, condition or disorder in an individual who is experiencing or manifesting the pathology or general symptoms of the disease, condition or disorder (i.e., reversing the pathology and / or general symptoms), e.g., reducing the severity of the disease; and refer to one or more of the foregoing.

[0214] Combination Therapy For the treatment of PI3K-related diseases, disorders or conditions, one or more additional pharmaceuticals, such as chemotherapeutic agents, anti-inflammatory agents, steroids, immunosuppressants, and inhibitors of Bcr-Abl, Flt-3, EGFR, HER2, JAK (e.g., JAK1 or JAK2), c-MET, VEGFR, PDGFR, cKit, IGF-1R, RAF, FAK, AktmTOR, PIM, and AKT (e.g., AKT1, AKT2, or AKT3) kinases, such as those described in WO 2006 / 056399, or other agents such as therapeutic antibodies, can be used in combination with the compounds of the present invention. The one or more additional pharmaceuticals can be administered to a patient simultaneously or sequentially.

[0215] Examples of antibodies for use in combination therapy 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 against c-MET.

[0216] One or more of the following agents can be used in combination with the compounds of the present invention and are presented as a non-limiting list: cell division inhibitors, cisplatin, doxorubicin, taxotere, taxol, etoposide, irinotecan, camptostar, topotecan, paclitaxel, docetaxel, epothilone, tamoxifen, 5-fluorouracil, methotrexate, temozolomide, cyclophosphamide, SCH66336, R115777, L778,123, BMS214662, Iressa, Tarceva, antibodies against EGFR, Gleevec™, Intron, ara-C, Adriamycin, Cytoxan, gemcitabine, uracil mustard, chloromethine, ifosfamide, melphalan, chlorambucil, pipobroman, triethylenemelamine, triethylenethiophosphoramide, 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, mitomycin, deoxycoformycin, mitomycin-C, L-asparaginase, teniposide 17.alpha.- Ethinyl estradiol, diethylstilbestrol, testosterone, prednisone, fluoxymesterone, drostanolone propionate, testolactone, megestrol acetate, methylprednisolone, methyltestosterone, prednisolone, triamcinolone, chlorotrianisene, hydroxyprogesterone, aminoglutethimide, estramustine, medroxyprogesterone acetate, leuprolide, flutamide, tamoxifen, goserelin, cisplatin, carboplatin, hydroxyurea, amsacrine, procarbazine, mitotane, mitoxantrone, levamisole, Navelbene, Anastrazole, Letrazole, capecitabine, Reloxafine, Droloxafine, hexamethylmelamine, avastin, herceptin, bexarotene, belotecan, zevalin, trisenox, xeloda, vinorelbine, porfimer, arcitumomab, liposomal, thiotepa, altretamine, melphalan, trastuzumab, Lerozole, fulvestrant, exemestane, fulvestrant, Ifosfomide, rituximab, C225, Campath, clofarabine, cladribine, aphidicolon, Ritian, sunitinib, dasatinib, tezacitabine, Sml1, fludarabine, pentostatin, triapine, didox, trimidox, amidox, 3-AP, MDL-101,731, and bendamustine (Treanda).

[0217] Examples of chemotherapeutic agents include proteasome inhibitors (e.g., bortezomib), thalidomide, lenalidomide, and DNA damaging agents such as melphalan, doxorubicin, cyclophosphamide, vincristine, etoposide, carmustine, etc.

[0218] Examples of steroid agents include corticosteroids such as dexamethasone or prednisone.

[0219] Examples of Bcr-Abl inhibitors include compounds and their pharmaceutically acceptable salts of the genera and species disclosed in U.S. Patent No. 5,521,184, International Publication No. 04 / 005281, and U.S. Patent Application No. 60 / 578,491.

[0220] Examples of suitable Flt-3 inhibitors include compounds and their pharmaceutically acceptable salts disclosed in International Publication Nos. 03 / 037347, 03 / 099771, and 04 / 046120.

[0221] Examples of suitable RAF inhibitors include compounds and their pharmaceutically acceptable salts disclosed in International Publication Nos. 00 / 09495 and 05 / 028444.

[0222] Examples of suitable FAK inhibitors include compounds and their pharmaceutically acceptable salts disclosed in International Publication Nos. 04 / 080980, 04 / 056786, 03 / 024967, 01 / 064655, 00 / 053595, and 01 / 014402.

[0223] Examples of suitable mTOR inhibitors include compounds and their pharmaceutically acceptable salts disclosed in International Publication No. 2011 / 025889.

[0224] In some embodiments, the compounds of the present invention can be used in combination with one or more other kinase inhibitors, including imatinib, particularly for treating patients who are resistant to imatinib or other kinase inhibitors.

[0225] In some embodiments, the compounds of the present invention can be used in combination with chemotherapeutic agents in the treatment of cancers such as multiple myeloma, and can improve the therapeutic response without worsening their toxic effects as compared to the response to chemotherapeutic agents alone. Examples of additional pharmaceuticals used in the treatment of multiple myeloma include, but are not limited to, for example, melphalan, melphalan + prednisone [MP], doxorubicin, dexamethasone, and Velcade (bortezomib). Further additional agents used in the treatment of multiple myeloma include Bcr-Abl, Flt-3, RAF and FAK kinase inhibitors. An additive or synergistic effect is a desirable result of combining the PI3K inhibitor of the present invention with the additional agent. Furthermore, resistance of multiple myeloma cells to agents such as dexamethasone can be reversible in the treatment with the PI3K inhibitor of the present invention. The agent can be combined with the compound of the present invention in a single or continuous dosage form, or the agent can be administered as a separate dosage form, simultaneously or sequentially.

[0226] In some embodiments, a corticosteroid such as dexamethasone is administered to a patient in combination with the compound of the present invention, where dexamethasone is administered intermittently rather than continuously.

[0227] In some further embodiments, a combination of the compound of the present invention and other therapeutic agents can be administered to a patient before, during, and / or after bone marrow transplantation or stem cell transplantation.

[0228] Pharmaceutical Preparations and Dosage Forms When used as a medicament, the compounds of the present invention can be administered in the form of pharmaceutical compositions. These compositions can be prepared by methods well known in the pharmaceutical art and can be administered by various routes depending on whether local or systemic treatment is desired and depending on the site to be treated. Administration can be local (including transdermal, epidermal, ocular, and delivery to mucous membranes including intranasal, vaginal, and rectal), transmucosal (including inhalation or insufflation of powders or aerosols, e.g., by nebulizer; intratracheal or intranasal), oral, or parenteral. Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal, or intramuscular 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, in the form of a continuous perfusion pump. Pharmaceutical compositions and formulations for local administration can include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, solutions, and powders. Conventional pharmaceutical carriers, aqueous, powder, or oily bases, thickeners, etc. may be required or desirable. The present invention also includes pharmaceutical compositions comprising the compounds of the present invention or pharmaceutically acceptable salts thereof as an active ingredient in combination with one or more pharmaceutically acceptable carriers (excipients). In some embodiments, the composition is suitable for local administration. In the preparation of the compositions of the present invention, the active ingredient is generally admixed with excipients and diluted with excipients or enclosed within such carriers in the form of, for example, capsules, sachets, papers, or other containers. When the excipient serves as a diluent, it can be a solid, semi-solid, or liquid material that functions as a vehicle, carrier, or medium for the active ingredient. Accordingly, the compositions can be in the form of tablets, pills, powders, troches, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments (e.g., containing up to 10% by weight of the active compound), soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.

[0229] In the preparation of the formulation, before combining the active compound with other ingredients, it can be milled to an appropriate particle size. If the active compound is substantially insoluble, it can be milled to a particle size of less than 200 mesh. If the active compound is substantially water-soluble, the particle size can be adjusted, for example, to about 40 mesh by milling to be substantially uniformly distributed in the formulation.

[0230] The compounds of the present invention can be milled using known milling procedures such as wet milling to obtain a particle size suitable for tablet formation and other formulation types. The micronized (nano-particle) formulations of the compounds of the present invention can be prepared by processes known in the art. See, for example, International Application No. WO2002 / 000196.

[0231] Some examples of suitable excipients include lactose, glucose, sucrose, sorbitol, mannitol, starch, acacia gum, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methylcellulose. The formulation may further include lubricants such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preservatives such as methyl benzoate and propyl hydroxybenzoate; sweetening agents; and flavoring agents. The compositions of the present invention can be formulated to provide rapid, sustained, or delayed release of the active ingredient after administration to a patient using procedures known in the art.

[0232] The composition can be formulated into unit dosage forms, and each dosage contains from about 5 to about 1000 mg (1 g), more generally from about 100 to about 500 mg of the active ingredient. The term "unit dosage form" refers to physically discrete units suitable as unit doses for human subjects and other mammals, each unit containing a predetermined quantity of the active material calculated to produce the desired therapeutic effect, together with suitable pharmaceutical excipients.

[0233] In some embodiments, the composition of the present invention contains from about 5 to about 50 mg of the active ingredient. Those skilled in the art will understand that this embodies a composition containing from 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.

[0234] In some embodiments, the composition of the present invention contains from about 50 to about 500 mg of the active ingredient. Those skilled in the art will understand that this embodies a composition containing from 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.

[0235] In some embodiments, the composition of the present invention contains from about 500 to about 1000 mg of the active ingredient. Those skilled in the art will understand that this embodies a composition containing from 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.

[0236] Dosages similar to those of the compounds described herein can be used in the methods and uses of the present invention.

[0237] The active compound can be effective over a wide range of dosages and is generally administered in a pharmaceutically effective amount. However, it will be understood that the amount of the compound actually administered is usually determined by the physician according to relevant circumstances including the condition being treated, the selected route of administration, the compound actually administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, etc.

[0238] To prepare solid compositions such as tablets, the main active ingredient is mixed with pharmaceutical excipients to form a solid preliminary formulation composition containing a homogeneous mixture of the compounds of the present invention. When these preliminary formulation compositions are said to be homogeneous, the active ingredient is generally uniformly dispersed throughout the composition so that the composition can be easily redispersed into equally effective unit dosage forms such as tablets, pills and capsules. Then, for example, the solid preliminary formulation is redispersed into unit dosage forms of the above type containing about 0.1 to about 1000 mg of the active ingredient of the present invention.

[0239] The tablets or pills of the present invention can be coated or otherwise formulated to provide a dosage form that provides the advantage of sustained action. For example, a tablet or pill can include an inner formulation component and an outer formulation component, in which the outer formulation component encloses the inner formulation component. The two components can be separated by an enteric layer, which serves to withstand disintegration in the stomach and allow the inner component to pass intact or delay its release into the duodenum. Various materials can be used for such enteric layers or coatings, such materials including several polymeric acids, as well as mixtures of polymeric acids with materials such as shellac, cetyl alcohol, and cellulose acetate.

[0240] Liquid forms in which the compounds and compositions of the present invention can be incorporated for oral or injectable administration include aqueous solutions, preferably flavored syrups, aqueous or oily suspensions, and flavored emulsions containing edible oils such as cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical vehicles.

[0241] Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents, or mixtures thereof, and powders. Liquid or solid compositions may, as described above, contain suitable pharmaceutically acceptable excipients. In some embodiments, the composition is administered by the oral or nasal respiratory route for local or systemic action. By use of an inert gas, the composition can be nebulized. The nebulized solution can be inhaled directly from the nebulizing device or the nebulizing device can be attached to a face mask, tent, or intermittent positive pressure breathing apparatus. Solutions, suspensions, or powder compositions can be administered orally or nasally from a device that delivers the formulation in a suitable manner.

[0242] Topical formulations can include one or more conventional carriers. In some embodiments, an ointment can include water and one or more hydrophobic carriers selected, for example, from liquid paraffin, polyoxyethylene alkyl ethers, propylene glycol, white petrolatum, and the like. The carrier composition of a cream can be based on a combination of water and glycerol and one or more other components, such as glycerol monostearate, PEG-glycerol monostearate, and cetylstearyl alcohol. A gel can be formulated using isopropyl alcohol and water, preferably in combination with other components such as glycerol, hydroxyethyl cellulose, and the like. In some embodiments, the topical formulation includes 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 weight % of a compound of the invention. The topical formulation can be suitably packaged, for example, in a 100 g tube, with instructions for treatment of a selected indication, such as psoriasis or other skin conditions, attached as desired.

[0243] The amount of the compound or composition to be administered to a patient varies depending on the substance to be administered, the purpose of administration such as prevention or treatment, the condition of the patient, the method of administration, etc. In therapeutic use, the composition is administered in an amount sufficient to cure or at least partially suppress the symptoms of the disease and its complications in a patient already suffering from the disease. The effective dosage depends on the judgment of the attending physician according to the disease state to be treated, as well as factors such as the severity of the disease, the age, weight, and general condition of the patient.

[0244] The composition to be administered to a patient can be in the form of the pharmaceutical compositions described above. These compositions can be sterilized by conventional sterilization techniques or by sterile filtration. The aqueous solution can be packaged for use as is or lyophilized, and the lyophilized preparation is mixed with a sterile aqueous carrier before administration. The pH of the compound preparation is generally between 3 and 11, more preferably between 5 and 9, and most preferably between 7 and 8. It will be understood that the use of certain of the excipients, carriers, or stabilizers described above results in the formation of pharmaceutical salts.

[0245] The therapeutic dosage of the compounds of the present invention can vary, for example, depending on the particular use for which the treatment is being carried out, 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 the compounds of the present invention in the pharmaceutical composition can vary depending on several factors, including the dosage, chemical characteristics (e.g., hydrophobicity), and route of administration. For example, for parenteral administration, the compounds of the present invention can be provided in an aqueous physiological buffer solution containing from about 0.1 to about 10 weight / volume % of the compound. Some general dosage ranges are from about 1 μg / kg body weight / day to about 1 g / kg body weight / day. In some embodiments, the dosage range is from about 0.01 mg / kg body weight / day to about 100 mg / kg body weight / day. The dosage is likely to depend on variable factors such as the type and progression of the disease or disorder, the overall health of the particular patient, the relative biological effectiveness of the selected compound, the formulation of the excipient, and the route of its administration. The effective dosage can be estimated from the dose-response curve obtained from in vitro or animal model test systems.

[0246] The composition of the present invention may further comprise one or more additional pharmaceuticals, such as chemotherapeutic agents, steroids, anti-inflammatory compounds, or immunosuppressive agents, examples of which are described herein.

[0247] Labeled Compounds and Assay Methods Another aspect of the present invention relates to the labeled compounds of the present invention (radioactive labels, fluorescent labels, etc.) that will be useful not only in imaging techniques but also in both in vitro and in vivo assays for localizing and quantifying PI3K in tissue samples including humans and for identifying PI3K ligands by inhibitory binding of labeled compounds. Accordingly, the present invention includes PI3K assays containing such labeled compounds.

[0248] The present invention further includes isotopically labeled compounds of the present invention. An "isotopically" or "radioactively labeled" compound is a compound of the present invention in which one or more atoms have been replaced or substituted by atoms having an atomic mass or mass number different from the atomic mass or mass number that generally occurs in nature (i.e., that occurs naturally). Suitable radionuclides that can be incorporated into the compounds of the present invention include, but are not limited to, 3 H (also denoted as T representing tritium), 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 18 F, 35 S, 36 Cl, 82 Br, 75 Br, 76 Br, 77 Br, 123 I, 124 I, 125 I and 131 I. The radionuclide incorporated into the radiolabeled compound of the present invention depends on the particular use of the radiolabeled compound. For example, in in vitro labeling and competitive assays of PI3K,3 H, 14 C, 82 Br, 125 I, 131 I, or 35 compounds incorporating S will generally be the most useful. In radiological imaging applications, 11 C, 18 F, 125 I, 123 I, 124 I, 131 I, 75 Br, 76 Br or 77 Br will generally be the most useful.

[0249] It is understood that a "radiolabeled" or "labeled compound" is a compound incorporating at least one radionuclide. In some embodiments, the radionuclide is selected from the group consisting of 3 H, 14 C, 125 I, 35 S and 82 Br. In some embodiments, one or more H atoms in any of the compounds described herein are each replaced by a deuterium atom.

[0250] The invention may further include a synthetic method for incorporating a radioisotope into the compounds of the invention. Synthetic methods for incorporating radioisotopes into organic compounds are known in the art, and those skilled in the art will readily understand methods applicable to the compounds of the invention.

[0251] The labeled compounds of the present invention can be used in screening assays to identify / evaluate compounds. For example, by monitoring the change in its concentration upon contact with PI3K via tracking the label, the ability of the labeled, newly synthesized or identified compound (i.e., the test compound) to bind to PI3K can be evaluated. For example, the ability of a (labeled) test compound to reduce the binding of another compound known to bind to PI3K (i.e., the standard compound) can be evaluated. Thus, the ability of a test compound to compete with the standard compound for binding to PI3K is directly correlated with its binding affinity. Conversely, in some other screening assays, the standard compound is labeled and the test compound is not. Thus, to evaluate the competition between the standard compound and the test compound, the concentration of the labeled standard compound is monitored and the relative binding affinity of the test compound is thus confirmed.

[0252] Kit The present invention also includes a pharmaceutical kit useful in the treatment or prevention of PI3K-related diseases or disorders such as cancer, for example. The kit includes one or more containers containing a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present invention. Such a kit may further include, if desired, one or more of the various conventional components of a pharmaceutical kit, such as containers containing one or more pharmaceutically acceptable carriers, additional containers, etc., as will be readily apparent to those skilled in the art. Instructions, either as an accompanying document or label, indicating the amount of the component to be administered, guidelines for administration, and / or guidelines for mixing the components may also be included in the kit.

[0253] 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 understand various non-critical parameters that can be changed or modified to yield essentially the same results. The compounds of the examples have been found to be PI3K inhibitors by at least one assay described herein.

Example

[0254] Unless otherwise indicated, the compounds of the following examples containing one or more chiral centers were obtained in the form of racemic compounds or mixtures of isomers. The stoichiometry of the salts shown in any of the following products is also only intended to indicate the most likely stoichiometry and should not be construed as excluding the formation of salts with other possible stoichiometries. The abbreviations "hour (h)" and "minute (min)" indicate hours and minutes, respectively.

[0255] 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)

Chem.

[0256] Step 1: 1-(5-Chloro-2-hydroxy-3-iodo-4-methylphenyl)ethanone

Chem.

[0257] Step 2: 1-(5-Chloro-3-iodo-2-methoxy-4-methylphenyl)ethanone

Chem.

[0258] Step 3: tert-Butyl 3-(3-acetyl-5-chloro-2-methoxy-6-methylphenyl)azetidine-1-carboxylate

Chem.

[0259] Step 4: tert-Butyl 3-[3-chloro-5-(1-hydroxyethyl)-6-methoxy-2-methylphenyl]azetidine-1-carboxylate [ka] 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) under stirring at 0 °C was added sodium tetrahydroborate (0.167 g, 4.41 mmol). The mixture was stirred at 0 - 5 °C for 1 h. The reaction was quenched with water and extracted with EtOAc (3x). The combined extracts were dried over MgSO4, filtered, and concentrated to afford 1.3 g (100%) of the desired product. C 18 H 26 LCMS (M+Na) for ClNO4Na + Calculated: m / z = 378.2; Found: 378.1. 1 1H NMR (400 MHz, CDCl3): δ 7.37 (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.

[0260] Step 5: tert-butyl 3-[3-chloro-5-(1-chloroethyl)-6-methoxy-2-methylphenyl]azetidine-1-carboxylate

Chemical Structure

[0261] 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 [Chemical formula] 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 (0.59 g, 4.0 mmol, manufactured by ChemBridge) 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 (2x). The combined extracts were washed with water and brine, dried over MgSO4, and concentrated. The resulting residue was purified by elution with 0-10% MeOH in dichloromethane on silica gel to give 1.03 g (59%) of the desired product as a yellow rubbery solid. 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 hexane at a flow rate of 18 mL / min and 4 mg / injection to give two enantiomers. The retention time of the first peak was 8.34 minutes and that of the second peak was 10.92 minutes. Peak 1 (463 mg), C 24 H 32 LCMS (M+H) for C + Calculated: m / z = 487.2; Found: 487.1. 1 H NMR (400 MHz, CDCl3): δ 8.21 (s, 1H), 7.37 (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.

[0262] 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 [Chem.] 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 above) in methylene chloride (3.2 mL) was added hydrogen chloride (1.6 mL, 6.5 mmol) in 1,4-dioxane. The resulting mixture was stirred at room temperature for 75 minutes. The solvent was evaporated and the residue was dried in vacuo to give 0.30 g of the desired product as the bis-hydrochloride. C 19 H 24 LCMS (M+H) for C + Calculated: m / z = 387.2; Found: 387.1.

[0263] 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) [Chem.] 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 concentration 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. C 22 H 30LCMS (M+H) for ClN6O + Calculated value: m / z = 429.2; Measured value: 429.1. The product was isolated as a single enantiomer. 1 1H NMR (500 MHz, DMSO-d6): δ 8.47 (s, 1H), 7.46 (s, 1H), 6.29 (q, J = 6.9 Hz, 1H), 4.52 (m, 2H), 4.21 (m, 1H), 4.15 (t, J = 9.8 Hz, 1H), 4.06 (t, J = 9.7 Hz, 1H), 3.53 (s, 3H), 3.39 - 3.27 (m, 1H), 2.61 (s, 3H), 2.11 (s, 3H), 1.75 (d, J = 6.8 Hz, 3H), 1.11 (dd, J = 6.0, 3.8 Hz, 6H) ppm.

[0264] 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

Chem.

[0265] 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

Chem.

[0266] 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

Chem.

[0267] 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

Chem.

[0268] 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)

Chem.

[0269] 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

Chem.

[0270] 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

Chem.

[0271] 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

Chem.

[0272] 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

Chemical Structure

[0273] 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

Chem.

[0274] 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

Chem.

[0275] 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)

Chem.

[0276] Step 1: 1-(3-Bromo-5-chloro-2-methoxy-4-methylphenyl)ethanone

Chem.

[0277] Step 2: 5-(3-Acetyl-5-chloro-2-methoxy-6-methylphenyl)-N,N-dimethylpyridine-2-carboxamide

Chem.

[0278] Step 3: 5-[3-chloro-5-(1-hydroxyethyl)-6-methoxy-2-methylphenyl]-N,N-dimethylpyridine-2-carboxamide

Chemical formula

[0279] Step 4:5-[3-Chloro-5-(1-chloroethyl)-6-methoxy-2-methylphenyl]-N,N-dimethylpyridine-2-carboxamide

Chem.

[0280] 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)

Chem.

[0281] Example 12: 5-{3-[1-(4-Amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}-N,N-dimethylpyridine-2-carboxamide trifluoroacetate

Chemical Structure

[0282] 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)

Chem.

[0283] Step 1: 1-(5-Chloro-4-fluoro-2-hydroxyphenyl)ethanone

Chem.

[0284] Step 2: 1-(5-Chloro-4-fluoro-2-hydroxy-3-iodophenyl)ethanone

Chem.

[0285] Step 3: 1-(5-Chloro-4-fluoro-3-iodo-2-methoxyphenyl)ethanone

Chemical formula

[0286] Step 4: tert-Butyl 3-(3-acetyl-5-chloro-6-fluoro-2-methoxyphenyl)azetidine-1-carboxylate

Chemical formula

[0287] Step 5: tert-butyl 3-[3-chloro-2-fluoro-5-(1-hydroxyethyl)-6-methoxyphenyl]azetidine-1-carboxylate

Chemical Structure

[0288] Step 6: tert-butyl 3-[3-chloro-5-(1-chloroethyl)-2-fluoro-6-methoxyphenyl]azetidine-1-carboxylate

Chemical formula

[0289] 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

Chemical formula

[0290] 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)

Chemical Structure

[0291] 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)

Chem.

[0292] Step 1: 1-(5-chloro-2-ethoxy-3-iodo-4-methylphenyl)ethanone

Chem.

[0293] Step 2: 5-(3-acetyl-5-chloro-2-ethoxy-6-methylphenyl)-N,N-dimethylpyridine-2-carboxamide

Chemical Structure

[0294] Step 3: 5-[3-Chloro-6-ethoxy-5-(1-hydroxyethyl)-2-methylphenyl]-N,N-dimethylpyridine-2-carboxamide

Chem.

[0295] Step 4: 5-[3-Chloro-5-(1-chloroethyl)-6-ethoxy-2-methylphenyl]-N,N-dimethylpyridine-2-carboxamide

Chem.

[0296] 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)

Chem.

[0297] Example 15: 5-{3-[1-(4-Amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-6-methylphenyl}-N,N-dimethylpyridine-2-carboxamide

Chem.

[0298] 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

Chemical formula

[0299] Step 1: 1-(3-Bromo-5-chloro-2-methoxy-4-methylphenyl)ethanol

Chemical formula

[0300] Step 2: 4-[3-Chloro-5-(1-hydroxyethyl)-6-methoxy-2-methylphenyl]pyridine-2-carbonitrile

Chem.

[0301] Step 3: 4-[3-Chloro-5-(1-chloroethyl)-6-methoxy-2-methylphenyl]pyridine-2-carbonitrile

Chem.

[0302] 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

Chemical Structure

[0303] 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

Chem.

[0304] 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

Chem.

[0305] 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

Chemical Structure

[0306] 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

Chemical Structure

[0307] 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

Chem.

[0308] 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

Chem.

[0309] Step 1: 3-Bromo-1-chloro-5-(1-chloroethyl)-4-methoxy-2-methylbenzene

Chem.

[0310] Step 2: 1-[1-(3-Bromo-5-chloro-2-methoxy-4-methylphenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine

Chemical formula

[0311] Step 3: 1-(2-{[tert-Butyl(dimethyl)silyl]oxy}ethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

Chemical formula

[0312] 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 [Chemical Structure] 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, first peak from step 2), 1-(2-{[tert-Butyl(dimethyl)silyl]oxy}ethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.024 g, 0.069 mmol), sodium carbonate (13 mg, 0.12 mmol) and a complex of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) with dichloromethane (1:1) (6.1 mg, 0.0075 mmol) in acetonitrile (0.5 mL) / water (0.1 mL) were degassed and then refilled with N2. The reaction mixture was stirred at 95 °C for 2 h, then treated with concentrated hydrochloric acid (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 concentration 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. C 21 H 25 LCMS (M+H) for ClN7O2 + Calculated: m / z = 442.2; Found: 442.2.

[0313] 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-carboxamidetri fluoroacetate

Chemical formula

[0314] 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

Chemical formula

[0315] 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

Chemical Structure

[0316] 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-carboxamidotrifluoroacetate [Chemical formula] 2.0 M dimethylamine in THF (0.1 mL, 0.2 mmol) was added to a solution of 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, and then triethylamine (11 μL, 0.077 mmol) was added. The reaction mixture was stirred for 1 hour and quenched with water. The crude mixture was subjected to RP-HPLC (XBridge C18 column, eluting with a concentration gradient of acetonitrile / water containing 0.05% TFA at a flow rate of 30 mL / min) to obtain the desired product as the TFA salt. The product was isolated as a single enantiomer. C 25 H 27 LCMS (M+H) for ClFN6O2 + Calculated: m / z = 497.2; Found: 497.2.

[0317] 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-carboxamidetri fluoroacetate

Chemical Structure

[0318] 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)picolinamidetri fluoroacetate

Chemical Structure

[0319] Step 1:5-[3-Chloro-5-(1-hydroxyethyl)-6-methoxy-2-methylphenyl]pyridine-2-carbonitrile

Chem.

[0320] Step 2: 5-[3-Chloro-5-(1-chloroethyl)-6-methoxy-2-methylphenyl]pyridine-2-carbonitrile

Chem.

[0321] 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

Chemical Structure

[0322] 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

Chem.

[0323] 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)picolylamide trifluoroacetate

Chem.

[0324] Example 24: 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)-N-methylpicolinamide trifluoroacetate

Chemical Structure

[0325] Example 25: 5-{3-[1-(4-Amino-5-oxopyrido[2,3-d]pyrimidin-8(5H)-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}-N,N-dimethylpyridine-2-carboxamide

Chemical Structure

[0326] Step 1:5-[3-Chloro-5-(1-chloroethyl)-6-methoxy-2-methylphenyl]-N,N-dimethylpyridine-2-carboxamide

Chem.

[0327] Step 2: 5-{3-[1-(4-Amino-5-oxopyrido[2,3-d]pyrimidin-8(5H)-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}-N,N-dimethylpyridine-2-carboxamide

Chem.

[0328] Example 26: 4-Amino-8-(1-{5-chloro-2-methoxy-4-methyl-3-[5-(methylsulfonyl)pyridin-3-yl]phenyl}ethyl)pyrido[2,3-d]pyrimidin-5(8H)-one bis(trifluoroacetate)

Chemical formula

[0329] Step 1: 3-Bromo-1-chloro-5-(1-chloroethyl)-4-methoxy-2-methylbenzene

Chemical formula

[0330] Step 2: 4-Amino-8-[1-(3-bromo-5-chloro-2-methoxy-4-methylphenyl)ethyl]pyrido[2,3-d]pyrimidin-5(8H)-one

Chem.

[0331] Step 3: 4-Amino-8-(1-{5-chloro-2-methoxy-4-methyl-3-[5-(methylsulfonyl)pyridin-3-yl]phenyl}ethyl)pyrido[2,3-d]pyrimidin-5(8H)-one bis(trifluoroacetate)

Chem.

[0332] Example 27: 5-{3-[1-(4-Amino-5-oxopyrido[2,3-d]pyrimidin-8(5H)-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}nicotinonitrile bis(trifluoroacetate)

Chemical Structure

[0333] Example 28: 4-Amino-8-[1-(5-chloro-2-methoxy-4-methyl-3-pyridin-3-ylphenyl)ethyl]pyrido[2,3-d]pyrimidin-5(8H)-one bis(trifluoroacetate)

Chemical Structure

[0334] Example 29: 4-Amino-8-[1-(5-chloro-2-methoxy-4-methyl-3-pyrimidin-5-ylphenyl)ethyl]pyrido[2,3-d]pyrimidin-5(8H)-one bis(trifluoroacetate)

Chemical formula

[0335] Example 30: 3’-[1-(4-Amino-5-oxopyrido[2,3-d]pyrimidin-8(5H)-yl)ethyl]-5’-chloro-2’-methoxy-N,N,6’-trimethylbiphenyl-3-carboxamide bis(trifluoroacetate)

Chemical formula

[0336] Example 31: 4-Amino-8-{1-[5-chloro-3-(5-fluoropyridin-3-yl)-2-methoxy-4-methylphenyl]ethyl}pyrido[2,3-d]pyrimidin-5(8H)-one bis(trifluoroacetate)

Chem.

[0337] Example 32: 3’-[1-(4-Amino-5-oxopyrido[2,3-d]pyrimidin-8(5H)-yl)ethyl]-5’-chloro-2’-methoxy-N,N,6’-trimethylbiphenyl-3-sulfonamide bis(trifluoroacetate)

Chem.

[0338] Example 33: 5-{3-[1-(4-Amino-5-oxopyrido[2,3-d]pyrimidin-8(5H)-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}-N-methylpyridine-2-carboxamide bis(trifluoroacetate)

Chem.

[0339] Example 34: 4-Amino-8-{1-[5-chloro-3-(1-isopropylazetidin-3-yl)-2-methoxy-4-methylphenyl]ethyl}pyrido[2,3-d]pyrimidin-5(8H)-one

Chem.

[0340] Step 1: tert-Butyl 3-{3-[1-(4-Amino-5-oxopyrido[2,3-d]pyrimidin-8(5H)-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}azetidine-1-carboxylate

Chem.

[0341] Step 2: 4-Amino-8-{1-[5-chloro-3-(1-isopropylazetidin-3-yl)-2-methoxy-4-methylphenyl]ethyl}pyrido[2,3-d]pyrimidin-5(8H)-one

Chem.

[0342] Example 35: 4-Amino-8-{1-[5-chloro-2-ethoxy-3-(1-isopropylazetidin-3-yl)-4-methylphenyl]ethyl}pyrido[2,3-d]pyrimidin-5(8H)-one bis(trifluoroacetate)

Chemical Structure

[0343] Step 1: Benzyl 3-(3-acetyl-5-chloro-2-ethoxy-6-methylphenyl)azetidine-1-carboxylate

Chemical Structure

[0344] Step 2: Benzyl 3-[3-chloro-6-ethoxy-5-(1-hydroxyethyl)-2-methylphenyl]azetidine-1-carboxylate

Chemical formula

[0345] Step 3: Benzyl 3-[3-chloro-5-(1-chloroethyl)-6-ethoxy-2-methylphenyl]azetidine-1-carboxylate

Chemical Structure

[0346] Step 4:Benzyl 3-{3-[1-(4-amino-5-oxopyrido[2,3-d]pyrimidin-8(5H)-yl)ethyl]-5-chloro-2-ethoxy-6-methylphenyl}azetidine-1-carboxylate

Chem.

[0347] Step 5: 4-Amino-8-{1-[5-chloro-2-ethoxy-3-(1-isopropylazetidin-3-yl)-4-methylphenyl]ethyl}pyrido[2,3-d]pyrimidin-5(8H)-one bis(trifluoroacetate)

Chem.

[0348] Example 36: 5-{3-[1-(4-Amino-5-oxopyrido[2,3-d]pyrimidin-8(5H)-yl)ethyl]-5-chloro-2-ethoxy-6-methylphenyl}-N,N-dimethylpyridine-2-carboxamide bis(trifluoroacetate) [ka] To a mixture of 4-aminopyrido[2,3-d]pyrimidin-5(8H)-one (47 mg, 0.29 mmol), cesium carbonate (130 mg, 0.39 mmol) and potassium iodide (4.4 mg, 0.026 mmol) in N,N-dimethylformamide (0.8 mL) was added 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, racemic intermediate), and the mixture was stirred at 140 °C for 1 h. The resulting mixture was diluted with MeOH, filtered, and the filtrate was purified by RP-HPLC (XBridge C-18 column, eluting with a concentration 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. C 26 H 28 LCMS (M+H) for ClN6O3 + Calculated: m / z = 507.2; Found: 507.1.

[0349] Example 37: 6-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-4-chloro-N-ethyl-3’,5’-difluoro-3-methylbiphenyl-2-carboxamide

Chemical formula

[0350] Step 1: 3-Acetyl-5-chloro-2-hydroxy-6-methylbenzonitrile

Chemical formula

[0351] Step 2: 6-Acetyl-4-chloro-2-cyano-3-methylphenyl trifluoromethanesulfonate

Chem.

[0352] Step 3: 6-Acetyl-4-chloro-3’,5’-difluoro-3-methylbiphenyl-2-carbonitrile

Chem.

[0353] Step 4: 4-Chloro-3’,5’-difluoro-6-(1-hydroxyethyl)-3-methylbiphenyl-2-carbaldehyde

Chemical formula

[0354] Step 5: 4-chloro-3',5'-difluoro-6-(1-hydroxyethyl)-3-methylbiphenyl-2-carboxylic acid [ka] To a solution of 4-chloro-3',5'-difluoro-6-(1-hydroxyethyl)-3-methylbiphenyl-2-carbaldehyde (1.00 g, 3.22 mmol) in methanol (40 mL) was added 1.0 M sodium hydroxide in water (16 mL, 16 mmol), followed by 1.0 M sodium hydroxide in water. After stirring overnight at room temperature, the mixture was slowly acidified with 1 N HCl to pH 5 and then extracted with EtOAc. The combined organic layers were washed with brine, dried over magnesium sulfate, and concentrated to dryness under reduced pressure. The crude residue was used directly in the next step (1.05 g, 100%).

[0355] Step 6: 4-chloro-N-ethyl-3',5'-difluoro-6-(1-hydroxyethyl)-3-methylbiphenyl-2-carboxamide [ka] A mixture of 4-chloro-3’,5’-difluoro-6-(1-hydroxyethyl)-3-methylbiphenyl-2-carboxylic acid (250 mg, 0.76 mmol), ethylamine hydrochloride (94 mg, 1.1 mmol) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (0.51 g, 1.1 mmol) in N,N-dimethylformamide (4 mL) was stirred at room temperature for 10 minutes. To the resulting mixture, N,N-diisopropylethylamine (0.40 mL, 2.3 mmol) was added. After stirring overnight at room temperature, the reaction was quenched with water and extracted with EtOAc. The combined organic layers were washed with water, brine, dried over magnesium sulfate and then concentrated to dryness. The residue was purified by elution on silica gel with 0 - 80% EtOAc in hexane to give the desired product (185 mg, 68%). C 18 H 19 LCMS (M + H) for ClF2NO2 + Calculated: m / z = 354.1; Found: 354.0.

[0356] Step 7: 1-{4-chloro-6-[(ethylamino)carbonyl]-3’,5’-difluoro-5-methylbiphenyl-2-yl}ethyl methanesulfonate

Chemical formula

[0357] Step 8: 6-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-4-chloro-N-ethyl-3',5'-difluoro-3-methylbiphenyl-2-carboxamide [ka] To a mixture of 3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (ChemBridge) (26 mg, 0.17 mmol) in N,N-dimethylformamide (0.5 mL) was added sodium hydride (14 mg, 0.35 mmol). After stirring at room temperature for 30 minutes, a mixture of 1-{4-chloro-6-[(ethylamino)carbonyl]-3',5'-difluoro-5-methylbiphenyl-2-yl}ethyl methanesulfonate (50 mg, 0.1 mmol) in N,N-dimethylformamide (0.5 mL) was added. The reaction was stirred overnight at room temperature and then quenched with water. The resulting mixture was purified by RP-HPLC (XBridge C18 column, eluting with an acetonitrile / water gradient 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 24 LCMS (M+H) for ClF2N6O + Calculated: m / z = 485.2; Found: 485.1.

[0358] Example 38: 4-{3-[1-(4-Amino-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}-N,N-dimethylpyridine-2-carboxamide [ka]

[0359] Step 1: 4-{3-[1-(4-amino-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}pyridine-2-carbonitrile [Chemistry] 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 (Example 16, Step 3) (90 mg, 0.28 mmol) and 4-aminopyrazolo[3,4-d]pyrimidine (manufactured by Acros Organics) (57 mg, 0.42 mmol) in N,N-dimethylformamide (4 mL), and the reaction mixture was stirred at 30 °C overnight. The mixture was treated with water and then filtered to obtain the desired product. C 21 H 19 LCMS (M+H) for ClN7O + Calculated: m / z = 420.1; Found: 420.1

[0360] Step 2: 4-{3-[1-(4-Amino-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}pyridine-2-carboxylic acid [Chemistry] 1.0 M Sodium hydroxide in water (0.3 mL, 0.3 mmol) was added to a mixture of 4-{3-[1-(4-amino-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}pyridine-2-carbonitrile (60 mg, 0.14 mmol) in ethanol (0.3 mL). The reaction mixture was heated at 95 °C for 6 hours and then treated with concentrated hydrochloric acid to adjust the pH to approximately 3. The solvent was removed under reduced pressure, and the resulting residue was used in the next step without further purification. C 21 H 20 LCMS (M+H) for ClN6O3 + Calculated: m / z = 439.1; Found: 439.2

[0361] [[ID=Z2]] Step 3:4-{3-[1-(4-Amino-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}-N,N-dimethylpyridine-2-carboxamide

Chem.

[0362] Example 39: 4-{3-[1-(4-Amino-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}-N-(2-hydroxyethyl)pyridine-2-carboxamide

Chem.

[0363] 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] Catalyst Preformation: Anhydrous dimethylacetamide (DMA) was purged with a gentle stream of N for 30 minutes before use. A 50 mM solution of H2SO4 was prepared in 10 mL of dimethylacetamide and 26.8 μL of concentrated sulfuric acid and then purged with N2 for 10 minutes. Pd(OAc)2 (22.5 mg, 100 μmol) and 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (95.3 mg, 200 μmol) were added to an 8 mL vial equipped with a magnetic stir bar and septum cap. The vial was evacuated and filled with N2 three times and purged with a gentle stream of N2 for 10 minutes. H2SO4 (2.0 mL, 50 mM in DMA) was added, and the catalyst mixture was stirred in an oil bath at 80 °C for 30 minutes to give a homogeneous coffee-brown solution.

[0364] 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 subjected to RP-HPLC (XBridge C18 column, eluting with a concentration gradient of acetonitrile / water containing 0.1% ammonium hydroxide at a flow rate of 30 mL / min) to afford the desired product. The product was isolated as a racemic mixture. C 26 H 29 LCMS (M+H) for N8O3 + Calculated: m / z = 501.2; Found: 501.2

[0365] 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)

Chemical formula

[0366] Step 1: N-(2,4-Dimethoxybenzyl)-3-methyl-1H-pyrazolo[4,3-c]pyridin-4-amine

Chemical formula

[0367] 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

Chemical Structure

[0368] 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 an acetonitrile / water gradient containing 0.1% trifluoroacetic acid at a flow rate of 60 mL / min) afforded the desired product (44 mg, 46%). The product was isolated as a racemic mixture. 25 H 28 LCMS (M+H) for ClN6O2 + Calculated value: m / z=479.2; Actual value: 479.0. 1H NMR (300MHz, DMSO-d6): δ 12.8(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, 3H), 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).

[0369] Example 42: 5-{3-[1-(4-Amino-5-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}-N,N-dimethylpyridine-2-carboxamide [ka] The desired compound was prepared in 18% yield following the procedure of Example 41, Step 2, using 5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (ACES Pharma, 57974) as the starting material. The product was isolated as a racemic mixture. 25 H 28 LCMS (M+H) for ClN6O2 +Calculated value: m / z = 479.2; Measured value: 479.3. 1H NMR (300 MHz, DMSO-d6): δ 8.46 (brs, 1H), 8.31 (brs, 1H), 8.28 (s, 1H), 7.87 - 7.83 (m, 1H), 7.65 - 7.61 (m, 1H), 7.51 (s, 1H), 7.48 (s, 1H), 6.24 (q, J = 7.0 Hz, 1H), 3.08 (s, 3H), 3.01 (s, 3H), 2.95 (s, 3H), 2.40 (s, 3H), 2.05 (s, 3H), 1.78 (d, J = 7.2 Hz, 3H).

[0370] 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

Chem.

[0371] Step 1: 1-(3-Bromo-5-chloro-4-fluoro-2-hydroxyphenyl)ethanone

Chem.

[0372] Step 2: 4-Acetyl-2-bromo-6-chloro-3-ethoxybenzonitrile

Chemical Structure

[0373] Step 3: 2-Bromo-6-chloro-3-ethoxy-4-(1-hydroxyethyl)benzonitrile [ka] 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 between 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 (0.15 gm, 100%) as a clear oil. 11 H 11 LCMS (M+H) for BrClNO2 +Calculated value: m / z = 303.9, 305.9; Measured value: 304.0, 305.9.

[0374] Step 4: 2-Bromo-6-chloro-4-(1-chloroethyl)-3-ethoxybenzonitrile

Chem.

[0375] Step 5: 4-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-2-bromo-6-chloro-3-ethoxybenzonitrile

Chem.

[0376] 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 [ka] 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) were added to sodium carbonate (10 mg, 0.09 mmol) in water (0.5 mL, 30 mmol). The reaction mixture was degassed by purging with nitrogen. A complex of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) and dichloromethane (1:1) (2 mg, 0.002 mmol) was added and the mixture was further degassed with N2. The reaction mixture was heated at 100 °C for 2 h. The crude product was purified by preparative LC-MS (acetonitrile, water, TFA) to afford the desired product as a white amorphous solid (0.004 g, 20%). The product was isolated as a racemic mixture. C 23 H 22 LCMS (M+H) for ClN7O3S + Calculated: m / z = 512.1; Found: 512.2. 1 H NMR (500 MHz, DMSO) δ 9.20 (d, J = 2.1 Hz, 1H), 9.12 (d, J = 1.9 Hz, 1H), 8.61 (t, J = 2.0 Hz, 1H), 8.12 (s, 1H), 7.80 (s, 1H), 6.36 (q, J = 7.0 Hz, 1H), 3.54 (dt, J = 14.0, 7.0 Hz, 1H), 3.37 (s, 3H), 3.36 - 3.30 (m, 1H), 2.58 (s, 3H), 1.81 (d, J = 7.0 Hz, 3H), 0.92 (t, J = 6.9 Hz, 3H).

[0377] 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

Chemical formula

[0378] Example 45: 5-{3-[1-(4-Amino-5-oxopyrido[2,3-d]pyrimidin-8(5H)-yl)ethyl]-5-chloro-6-cyano-2-ethoxyphenyl}-N,N-dimethylpyridine-2-carboxamide

Chemical formula

[0379] Step 1: 4-[1-(4-Amino-5-oxopyrido[2,3-d]pyrimidin-8(5H)-yl)ethyl]-2-bromo-6-chloro-3-ethoxybenzonitrile

Chemical formula

[0380] Step 2: 5-{3-[1-(4-Amino-5-oxopyrido[2,3-d]pyrimidin-8(5H)-yl)ethyl]-5-chloro-6-cyano-2-ethoxyphenyl}-N,N-dimethylpyridine-2-carboxamide

Chem.

[0381] Example 46: 4-(1-(4-Amino-5-oxopyrido[2,3-d]pyrimidin-8(5H)-yl)ethyl)-6-chloro-3-ethoxy-2-(5-(methylsulfonyl)pyridin-3-yl)benzonitrile [ka] The title compound was prepared in a manner similar to Example 45, Step 2, but using 3-(methylsulfonyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (Anisyn Inc., catalog number: CT601515-3) to give a crude product which was purified by preparative LCMS (acetonitrile, water, TFA) to give the desired product (0.005 g, 22%) as a white amorphous solid. The product was isolated as a racemic mixture. 24 H 21 LCMS (M+H) for ClN6O2S + Calculated: m / z = 525.1; Found: 525.2.

[0382] Example 47: 5-(3-{1-[4-Amino-3-(3-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]ethyl}-5-chloro-2-ethoxy-6-methylphenyl)-N,N-dimethylpyridine-2-carboxamide bis(trifluoroacetate) [Chemistry] 5-{3-[1-(4-Amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-6-methylphenyl}-N,N-dimethylpyridine-2-carboxamide (from Example 15) (15 mg, 0.025 mmol), (3-fluorophenyl)boronic acid (manufactured by Aldrich) (6.9 mg, 0.050 mmol), and sodium carbonate (16 mg, 0.15 mmol) in N,N-dimethylformamide (0.1 mL) / water (74 μL) were added with tetrakis(triphenylphosphine)palladium(0) (2.9 mg, 0.0025 mmol) under N2. The mixture was heated at 100 °C overnight. After cooling to room temperature, the mixture was filtered, and the filtrate was purified by RP-HPLC (XBridge C18 column, eluting with a concentration gradient of acetonitrile / water containing 0.05% trifluoroacetic acid at a flow rate of 30 mL / min) to obtain the desired product as the bis-TFA salt. The product was isolated as a racemic mixture. C 30 H 30 LCMS (M+H) for ClFN7O2 + Calculated: m / z = 574.2; Found: 574.2.

[0383] Example 48: 5-(3-{1-[4-Amino-3-(1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]ethyl}-5-chloro-2-ethoxy-6-methylphenyl)-N,N-dimethylpyridine-2-carboxamide bis(trifluoroacetate) [Chemistry] This compound was prepared according to the procedure described in Example 47 using 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (manufactured by Aldrich) instead of (3-fluorophenyl)boronic acid. The product was isolated as a racemic mixture. C 27 H 29 LCMS (M+H) for ClN9O2 + Calculated: m / z = 546.2; Found: 546.2.

[0384] Example 49: 5-(3-{1-[4-Amino-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]ethyl}-5-chloro-2-ethoxy-6-methylphenyl)-N,N-dimethylpyridine-2-carboxamide bis(trifluoroacetate) [Chemistry] This compound was prepared according to the procedure described in Example 47 using 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (manufactured by Aldrich) instead of (3-fluorophenyl)boronic acid. The product was isolated as a racemic mixture. C 28 H 31 LCMS (M+H) for C + Calculated: m / z = 560.2; Found: 560.2.

[0385] Example 50: 5-(3-{1-[4-Amino-3-(1-methyl-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]ethyl}-5-chloro-2-ethoxy-6-methylphenyl)-N,N-dimethylpyridine-2-carboxamide bis(trifluoroacetate)

Chemical formula

[0386] Example 51: 5-(3-{1-[4-Amino-3-(1H-pyrazol-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]ethyl}-5-chloro-2-ethoxy-6-methylphenyl)-N,N-dimethylpyridine-2-carboxamide bis(trifluoroacetate)

Chemical formula

[0387] Example 52: 5-[3-(1-{4-Amino-3-[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl}ethyl)-5-chloro-2-ethoxy-6-methylphenyl]-N,N-dimethylpyridine-2-carboxamide bis(trifluoroacetate)

Chem.

[0388] Example 53: 5-{3-[1-(4-Amino-3-cyclopropyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-6-methylphenyl}-N,N-dimethylpyridine-2-carboxamide bis(trifluoroacetate)

Chem.

[0389] Example 54: 5-{3-[1-(4-Amino-3-cyano-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-6-methylphenyl}-N,N-dimethylpyridine-2-carboxamide [ka] A mixture of 5-{3-[1-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-6-methylphenyl}-N,N-dimethylpyridine-2-carboxamide (13 mg, 0.021 mmol, racemic intermediate from Example 15) and copper cyanide (12 mg, 0.13 mmol) in N,N-dimethylformamide (0.2 mL) was heated at 120° C. overnight. The mixture was filtered and purified by RP-HPLC (XBridge C18 column, eluted with an acetonitrile / water gradient 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. 25 H 26 LCMS (M+H) for ClN8O2 + Calculated: m / z = 505.2; Found: 505.2.

[0390] Example 55: 5-(3-{1-[4-Amino-3-(4-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]ethyl}-5-chloro-2-ethoxy-6-methylphenyl)-N,N-dimethylpyridine-2-carboxamide bis(trifluoroacetate) [ka] This compound was prepared according to the procedure described in Example 47, using 4-fluorophenylboronic acid (Aldrich) instead of (3-fluorophenyl)boronic acid. The product was isolated as a racemic mixture. 30 H 30 LCMS (M+H) for ClFN7O2 + Calculated: m / z = 574.2; Found: 574.2.

[0391] Example 56: 5-{4-Amino-1-[1-(5-chloro-3-{6-[(dimethylamino)carbonyl]pyridin-3-yl}-2-ethoxy-4-methylphenyl)ethyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-N,N-dimethylpyridine-2-carboxamide tris(trifluoroacetate) [ka] This compound was prepared according to the procedure described in Example 47 using N,N-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-carboxamide (manufactured by PepTech) instead of (3-fluorophenyl)boronic acid. The product was isolated as a racemic mixture. C 32 H 35 LCMS (M+H) for C + Calculated value: m / z = 628.3; Measured value: 628.3.

[0392] Example 57: 5-(3-{1-[4-Amino-3-(5-cyanopyridin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]ethyl}-5-chloro-2-ethoxy-6-methylphenyl)-N,N-dimethylpyridine-2-carboxamide tris(trifluoroacetate)

Chemical formula

[0393] Example 58: 5-(3-{1-[4-Amino-3-(2-aminopyrimidin-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]ethyl}-5-chloro-2-ethoxy-6-methylphenyl)-N,N-dimethylpyridine-2-carboxamide tris(trifluoroacetate)

Chemical formula

[0394] Example 59: 5-{3-[1-(4-Amino-3-{6-[(methylamino)carbonyl]pyridin-3-yl}-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-6-methylphenyl}-N,N-dimethylpyridine-2-carboxamide tris(trifluoroacetate) [ka] This compound was prepared according to the procedure described in Example 47, using N-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-carboxamide (Frontier) instead of (3-fluorophenyl)boronic acid. The product was isolated as a racemic mixture. 31 H 33 LCMS (M+H) for ClN9O3 + Calculated: m / z = 614.2; Found: 614.2.

[0395] Example 60: 5-{3-[1-(4-Amino-3-pyridin-4-yl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-6-methylphenyl}-N,N-dimethylpyridine-2-carboxamide tris(trifluoroacetate) [ka] This compound was prepared according to the procedure described in Example 47, using 4-pyridinylboronic acid (Aldrich) instead of (3-fluorophenyl)boronic acid. The product was isolated as a racemic mixture. 29 H 30 LCMS (M+H) for ClN8O2 + Calculated: m / z = 557.2; Found: 557.2.

[0396] Example 61: 5-{3-[1-(4-Amino-3-pyridin-3-yl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-6-methylphenyl}-N,N-dimethylpyridine-2-carboxamide tris(trifluoroacetate) [ka] This compound was prepared according to the procedure described in Example 47, using 3-pyridinylboronic acid (Aldrich) instead of (3-fluorophenyl)boronic acid. The product was isolated as a racemic mixture. 29 H 30 LCMS (M+H) for ClN8O2 + Calculated: m / z = 557.2; Found: 557.2.

[0397] Example 62: 5-{3-[1-(4-Amino-3-{5-[(dimethylamino)carbonyl]pyridin-3-yl}-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-6-methylphenyl}-N,N-dimethylpyridine-2-carboxamide tris(trifluoroacetate) [ka] This compound was prepared according to the procedure described in Example 47 using N,N-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinamide (manufactured by PepTech) instead of (3-fluorophenyl)boronic acid. The product was isolated as a racemic mixture. C 32 H 35 LCMS (M+H) for C + Calculated: m / z = 628.3; Found: 628.3.

[0398] Example 63: 1-{1-[5-Chloro-2-methoxy-4-methyl-3-(1-oxetan-3-ylazetidin-3-yl)phenyl]ethyl}-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine

Chemical formula

[0399] Example 64: 1-(1-{5-Chloro-2-methoxy-4-methyl-3-[1-(tetrahydro-2H-pyran-4-yl)azetidin-3-yl]phenyl}ethyl)-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine

Chemical formula

[0400] 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

Chemical Structure

[0401] 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) [Chemical Formula] 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-dioxaborolan-2-yl)pyridine-2-carboxamide (25 mg, 0.091 mmol), sodium carbonate (13 mg, 0.12 mmol) and a complex of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) with dichloromethane (1:1) (9.9 mg, 0.012 mmol) in a mixture of acetonitrile (0.8 mL) / water (0.3 mL) were 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 concentration 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. C 24 H 27 LCMS (M+H) for ClN7O2 + Calculated: m / z = 480.2; Found: 480.2. 1 H NMR (500 MHz, 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 = 7.0 Hz), 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 = 7.0 Hz) ppm.

[0402] 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

Chem.

[0403] 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 hydrogen chloride 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 afford the desired product. C 18 H 21 LCMS (M+H) for ClFN6O + Calculated: m / z = 391.1; Found: 391.1.

[0404] 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 afford the crude product (870 mg, 100%). C 21 H 27 LCMS (M+H) for ClFN6O + Calculated: m / z = 433.2; Found: 433.1

[0405] Step 3:The 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 on a Phenomenex Lux cellulose-2 column eluting with 10% ethanol in hexane at a flow rate of 18 mL / min and column packing at approximately 8 mg / injection to give two separated enantiomers. First peak retention time 10.9 minutes; second peak retention time 13.6 minutes. The fraction of the first peak (110 mg, 13%) was concentrated and purified using RP-HPLC (XBridge C18 column, eluting with a concentration 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. C 21 H 27 LCMS (M+H) for ClFN6O + Calculated: m / z = 433.2; Found: 433.1

[0406] 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 [Chemical formula] 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 h and then purified by RP-HPLC (XBridge C18 column, eluting with an acetonitrile / water gradient 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) eluted with 20% ethanol in hexane 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 (M+H) for ClFN6O2 + Calculated: m / z = 449.2; Found: 449.1. 1 H NMR (DMSO-d6, 500MHz) δ 8.11(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.

[0407] 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] 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, Example 67, racemic intermediate from Step 1) and triethylamine (28 μL, 0.20 mmol) in methanol (0.1 mL) / acetonitrile (0.1 mL) / tetrahydrofuran (0.1 mL) were added {[tert-butyl(dimethyl)silyl]oxy}acetaldehyde (39 μL, 0.20 mmol), followed by sodium triacetoxyborohydride (22 mg, 0.10 mmol). The resulting mixture was stirred overnight at room temperature. The mixture was treated with 6.0 M hydrogen chloride in water (0.07 mL, 0.4 mmol) for 10 minutes at room temperature and then purified by RP-HPLC (XBridge C18 column, eluting with a concentration 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. C 20 H 25 LCMS (M+H) for ClFN6O2 + Calculated: m / z = 435.2; Found: 435.1.

[0408] 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

Chemical formula

[0409] Example 73: 1-{1-[5-Chloro-4-fluoro-3-(1-isopropylazetidin-3-yl)-2-methoxyphenyl]ethyl}-3-(difluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine [ka]

[0410] Step 1: tert-Butyl 3-{3-[1-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-6-fluoro-2-methoxyphenyl}azetidine-1-carboxylate tert-Butyl 3-[3-chloro-5-(1-chloroethyl)-2-fluoro-6-methoxyphenyl]azetidine-1-carboxylate (0.77 g, 2.0 mmol, Example 13, racemic intermediate from Step 6) in N,N-dimethylformamide (6.9 mL), 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.58 g, 2.2 mmol) were added potassium iodide (34 mg, 0.20 mmol) and cesium carbonate (0.99 g, 3.0 mmol). The resulting mixture was heated at 140 °C and stirred for 3 h. After cooling, the clear solution was taken up in water and ethyl acetate (EtOAc). The solid was diluted with water and EtOAc and stirred until dissolved. The organic layers were combined, concentrated and purified on silica gel (eluting with 0 - 100% EtOAc in hexane) to give the desired product (0.55 g, 45%). C 22 H 26 LCMS (M + H) for ClFIN6O3 + Calculated: m / z = 603.1; Found: 602.9.

[0411] Step 2: tert-Butyl 3-{3-[1-(4-amino-3-vinyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-6-fluoro-2-methoxyphenyl}azetidine-1-carboxylate tert-Butyl 3-{3-[1-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-6-fluoro-2-methoxyphenyl}azetidine-1-carboxylate (0.55 g, 0.91 mmol) in N,N-dimethylformamide (5 mL) / water (2.73 mL), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (0.281 g, 1.82 mmol), sodium carbonate (0.580 g, 5.47 mmol) solution was added tetrakis(triphenylphosphine)palladium(0) (0.105 g, 0.0910 mmol) under N2. The mixture was heated at 100 °C overnight. After cooling to room temperature, the mixture was diluted with water and extracted with EtOAc. The combined organic layers were concentrated and purified on silica gel (eluting with 0 - 100% EtOAc in hexanes, then 0 - 10% MeOH in dichloromethane) to give the desired product (0.34 g, 74%). C 24 H 29 LCMS (M + H) for ClFN6O3 + Calculated: m / z = 503.2; Found: 503.1.

[0412] Step 3: tert-Butyl 3-(3-{1-[4-amino-3-(1,2-dihydroxyethyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]ethyl}-5-chloro-6-fluoro-2-methoxyphenyl)azetidine-1-carboxylate A solution of tert-butyl 3-{3-[1-(4-amino-3-vinyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-6-fluoro-2-methoxyphenyl}azetidine-1-carboxylate (340 mg, 0.680 mmol) in tert-butyl alcohol (5 mL) was added with N-methylmorpholine N-oxide (87 mg, 0.74 mmol) and water (2.1 mL). To this solution was then added 4% osmium tetroxide (0.21 mL, 0.034 mmol). After stirring for 3 hours, an additional 1 equivalent of N-methylmorpholine N-oxide was added. The reaction mixture was stirred at room temperature overnight. The solution was diluted with water and extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated to give the crude product (0.4 g, 100%), which was used directly in the next step. C 24 H 31 LCMS (M+H) for ClFN6O5 + Calculated: m / z = 537.2; Found: 537.2.

[0413] Step 4: tert-butyl 3-{3-[1-(4-amino-3-formyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-6-fluoro-2-methoxyphenyl}azetidine-1-carboxylate To a solution of tert-butyl 3-(3-{1-[4-amino-3-(1,2-dihydroxyethyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]ethyl}-5-chloro-6-fluoro-2-methoxyphenyl)azetidine-1-carboxylate (0.40 g, 0.74 mmol) in tetrahydrofuran (5.6 mL) / water (3.4 mL) was added acetic acid (0.011 mL, 0.19 mmol) and sodium periodate (0.478 g, 2.23 mmol) at 0 °C. After stirring for 2 hours, the reaction mixture was diluted with water and extracted with EtOAc. The organic layers were combined, washed with brine, dried over MgSO4, filtered, and concentrated to give the desired product (0.35 g, 92%), which was used directly in the next step. C 23 H 27 LCMS (M+H) for ClFN6O4+ Calculated: m / z = 505.2; Found: 505.1.

[0414] Step 5: tert-Butyl 3-(3-{1-[4-amino-3-(difluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]ethyl}-5-chloro-6-fluoro-2-methoxyphenyl)azetidine-1-carboxylate To a solution of tert-butyl 3-{3-[1-(4-amino-3-formyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-6-fluoro-2-methoxyphenyl}azetidine-1-carboxylate (0.35 g, 0.69 mmol) in methylene chloride (4 mL) cooled to 0 °C, diethylaminosulfur trifluoride (0.23 mL, 1.7 mmol) was added dropwise. The mixture was stirred at room temperature for 2 hours, then diluted with dichloromethane, washed with water, dried over MgSO4, filtered, concentrated, and purified on silica gel (eluted with 0-100% EtOAc in hexanes) to give the desired product (0.21 g, 57%). 23 H 27 LCMS (M+H) for ClF3N6O3 + Calculated: m / z = 527.2; Found: 527.2.

[0415] Step 6: 1-[1-(3-azetidin-3-yl-5-chloro-4-fluoro-2-methoxyphenyl)ethyl]-3-(difluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine dihydrochloride tert-Butyl 3-(3-{1-[4-amino-3-(difluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]ethyl}-5-chloro-6-fluoro-2-methoxyphenyl)azetidine-1-carboxylate (0.21 g, 0.40 mmol) was treated with 4.0 M hydrogen chloride in dioxane (1 mL, 4 mmol) in methylene chloride (4 mL) at room temperature for 2 hours. The mixture was concentrated to give the desired product (0.177 g, 89%). 18 H 19 LCMS (M+H) for ClF3N6O +Calculated value: m / z = 427.1; Measured value: 427.1.

[0416] Step 7: 1-{1-[5-Chloro-4-fluoro-3-(1-isopropylazetidin-3-yl)-2-methoxyphenyl]ethyl}-3-(difluoromethyl)-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-(difluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine dihydrochloride (45 mg, 0.090 mmol), acetone (37 mg, 0.63 mmol) and triethylamine (63 μL, 0.45 mmol) in methylene chloride (0.9 mL), sodium triacetoxyborohydride resin (0.12 g, 0.27 mmol) was added. The mixture was stirred at room temperature for 2 hours, then filtered, concentrated and purified by RP-HPLC (XBridge C18 column, eluting with a concentration 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, 6.8%). The product was isolated as a racemic mixture. C 21 H 25 LCMS (M + H) for ClF3N6O + Calculated value: m / z = 469.2; Measured value: 469.2.

[0417] Example 74: 2-[3-(3-{1-[4-Amino-3-(difluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]ethyl}-5-chloro-6-fluoro-2-methoxyphenyl)azetidin-1-yl]ethanol

Chemical Structure

[0418] Example 76: (2S)-1-[3-(3-{1-[4-Amino-3-(difluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]ethyl}-5-chloro-6-fluoro-2-methoxyphenyl)azetidin-1-yl]propan-2-ol [ka] 1-[1-(3-Azetidin-3-yl-5-chloro-4-fluoro-2-methoxyphenyl)ethyl]-3-(difluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine dihydrochloride (51 mg, 0.10 mmol, Example 73, racemic intermediate from Step 6) and triethylamine (57 μL, 0.41 mmol) in ethanol (1.7 mL), (S)-(-)-methyloxirane (18 μL, 0.26 mmol) was added. The resulting mixture was heated at 90 °C for 3 h and purified by RP-HPLC (XBridge C18 column, eluting with a concentration 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, 5.3%). The product was isolated as a racemic mixture. C 21 H 25 LCMS (M+H) for ClF3N6O2 + Calculated: m / z = 485.2; Found: 485.1.

[0419] Example 77: 5-(1-(4-Amino-3-(difluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-2-fluoro-3-(1-((S)-2-hydroxypropyl)azetidin-3-yl)-4-methoxybenzonitrile

Chemical Structure

[0420] Example 79: 5-[3-(1-{4-Amino-3-[(3R)-3-hydroxybut-1-yn-1-yl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl}ethyl)-5-chloro-2-ethoxy-6-methylphenyl]-N,N-dimethylpyridine-2-carboxamide bis(trifluoroacetate) [ka] A mixture of 5-{3-[1-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-6-methylphenyl}-N,N-dimethylpyridine-2-carboxamide (9.8 mg, 0.016 mmol, racemic intermediate from Example 15) and copper(I) iodide (0.6 mg, 0.003 mmol) in N,N-dimethylformamide (0.32 mL) was treated with (2R)-but-3-yn-2-ol (11.3 mg, 0.162 mmol), triethylamine (4.5 μL, 0.032 mmol), and tetrakis-(triphenylphosphine)-palladium(0) (1.9 mg, 0.0016 mmol) under N. The mixture was stirred at room temperature under N for 1 hour. The mixture was then purified by RP-HPLC (XBridge C18 column, eluting with an acetonitrile / water gradient containing 0.05% TFA at a flow rate of 30 mL / min) to give the desired product (4.3 mg, 44%) as the bis-TFA salt. The product was isolated as a racemic mixture. 28 H 31 LCMS (M+H) for ClN7O3 + Calculated: m / z = 548.2; Found: 548.1.

[0421] Example 80: 5-[3-(1-{4-Amino-3-[(3S)-3-hydroxybut-1-yn-1-yl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl}ethyl)-5-chloro-2-ethoxy-6-methylphenyl]-N,N-dimethylpyridine-2-carboxamide bis(trifluoroacetate) [ka] This compound was prepared using a procedure similar to Example 79, substituting (2S)-but-3-yn-2-ol for (2R)-but-3-yn-2-ol. The product was isolated as a mixture of diastereomers. 28 H 31 LCMS (M+H) for ClN7O3+ Calculated value: m / z = 548.2; Measured value: 548.1.

[0422] Example 81: 5-{3-[1-(4-Amino-3-ethyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-6-methylphenyl}-N,N-dimethylpyridine-2-carboxamide

Chem.

[0423] Step 1: 5-{3-[1-(4-Amino-3-vinyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-6-methylphenyl}-N,N-dimethylpyridine-2-carboxamide To a solution of 5-{3-[1-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-6-methylphenyl}-N,N-dimethylpyridine-2-carboxamide (130 mg, 0.21 mmol, racemic intermediate from Example 15), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (66 mg, 0.43 mmol), and sodium carbonate (136 mg, 1.29 mmol) in N,N-dimethylformamide (1 mL) / water (0.64 mL) was added tetrakis(triphenylphosphine)palladium(0) (25 mg, 0.021 mmol) under N2. The mixture was heated at 100 °C overnight. After cooling to room temperature, the mixture was diluted with water and extracted with dichloromethane. The organic layer was concentrated and purified on silica gel (eluting with 0 - 100% EtOAc in hexane and then 0 - 10% MeOH in dichloromethane) to give the desired product (94 mg, 86%). C 26 H 29 LCMS (M + H) for C + Calculated value: m / z = 506.2; Measured value: 506.2.

[0424] Step 2: 5-{3-[1-(4-Amino-3-ethyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-6-methylphenyl}-N,N-dimethylpyridine-2-carboxamide 5-{3-[1-(4-amino-3-vinyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-6-methylphenyl}-N,N-dimethylpyridine-2-carboxamide (14 mg, 0.028 mmol) and 5% platinum on carbon (14 mg) were combined in methanol (1 mL) and 0.25 M hydrogen chloride in water (0.28 mL, 0.069 mmol) was added. The suspension was hydrogenated under balloon pressure of H2 at room temperature for 3 hours. The suspension was filtered, and the filtrate was purified by RP-HPLC (XBridge C18 column, eluted with an acetonitrile / water gradient containing 0.1% ammonium hydroxide at a flow rate of 30 mL / min) to give the desired product (3.9 mg, 28%). The product was isolated as a racemic mixture. 26 H 31 LCMS (M+H) for ClN7O2 + Calculated: m / z = 508.2; Found: 508.3.

[0425] Example 82: 5-(3-{1-[4-Amino-3-(difluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]ethyl}-5-chloro-2-ethoxy-6-methylphenyl)-N,N-dimethylpyridine-2-carboxamide bis(trifluoroacetate) [ka]

[0426] Step 1: 5-(3-{1-[4-amino-3-(1,2-dihydroxyethyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]ethyl}-5-chloro-2-ethoxy-6-methylphenyl)-N,N-dimethylpyridine-2-carboxamide To a solution of 5-{3-[1-(4-amino-3-vinyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-6-methylphenyl}-N,N-dimethylpyridine-2-carboxamide (80 mg, 0.16 mmol, from Example 81, Step 1) in tert-butyl alcohol (1 mL) was added N-methylmorpholine N-oxide (20 mg, 0.17 mmol) and water (0.50 mL). To this solution was then added 4% osmium tetraoxide (5.0 μL, 0.00079 mmol). After stirring for 3 hours, an additional equivalent of N-methylmorpholine N-oxide was added. The reaction was stirred overnight at room temperature. The solution was diluted with water and extracted with EtOAc. The combined organic layers were dried over MgSO, filtered, and concentrated to give the desired product (0.64 g, 95%). C 26 H 31 LCMS (M+H) for ClN7O4 + Calculated: m / z = 540.2; Found: 540.2.

[0427] Step 2: 5-{3-[1-(4-amino-3-formyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-6-methylphenyl}-N,N-dimethylpyridine-2-carboxamide To a solution of 5-(3-{1-[4-amino-3-(1,2-dihydroxyethyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]ethyl}-5-chloro-2-ethoxy-6-methylphenyl)-N,N-dimethylpyridine-2-carboxamide (70 mg, 0.13 mmol) in tetrahydrofuran (0.98 mL) and water (0.59 mL) was added acetic acid (1.9 μL, 0.034 mmol) and sodium periodate (83 mg, 0.39 mmol) at 0° C. After stirring for 2 hours, the reaction mixture was diluted with water and extracted with dichloromethane. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated to give the desired product (0.059 g, 90%). 25 H 27 LCMS (M+H) for ClN7O3 +Calculated: m / z = 508.2; Found: 508.1.

[0428] Step 3: 5-(3-{1-[4-amino-3-(difluoromethyl)-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 5-{3-[1-(4-amino-3-formyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-6-methylphenyl}-N,N-dimethylpyridine-2-carboxamide (8.8 mg, 0.017 mmol) in methylene chloride (0.1 mL) cooled to 0 °C, diethylaminosulfur trifluoride (5.7 μL, 0.043 mmol) was added dropwise. The mixture was stirred at room temperature for 3 hours, diluted with MeOH, and purified by RP-HPLC (XBridge C18 column, eluted with an acetonitrile / water gradient containing 0.05% TFA at a flow rate of 30 mL / min) to give the desired product (0.7 mg, 8%) as the bis-TFA salt. The product was isolated as a racemic mixture. 25 H 27 LCMS (M+H) for ClF2N7O2 + Calculated: m / z = 530.2; Found: 530.0.

[0429] Example 83: 5-(3-{1-[4-Amino-3-(hydroxymethyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]ethyl}-5-chloro-2-ethoxy-6-methylphenyl)-N,N-dimethylpyridine-2-carboxamide bis(trifluoroacetate) [ka] 5-{3-[1-(4-Amino-3-formyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-6-methylphenyl}-N,N-dimethylpyridine-2-carboxamide (5.6 mg, 0.011 mmol, from Example 82, Step 2) was treated with sodium tetrahydroborate (0.5 mg, 0.01 mmol) in methanol (0.09 mL) at room temperature for 1 hour. The mixture was purified by RP-HPLC (XBridge C18 column, eluting with a concentration gradient of acetonitrile / water containing 0.05% TFA at a flow rate of 30 mL / min) to give the desired product (2.5 mg, 45%) as the bis-TFA salt. The product was isolated as a racemic mixture. C 25 H 29 LCMS (M+H) for ClN7O3 + Calculated: m / z = 510.2; Found: 510.0.

[0430] Example 84: 5-[3-(1-{4-Amino-3-[(methylamino)methyl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl}ethyl)-5-chloro-2-ethoxy-6-methylphenyl]-N,N-dimethylpyridine-2-carboxamide tris(trifluoroacetate)

Chemical formula

[0431] Example 85: 5-[3-(1-{4-Amino-3-[(dimethylamino)methyl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl}ethyl)-5-chloro-2-ethoxy-6-methylphenyl]-N,N-dimethylpyridine-2-carboxamide tris(trifluoroacetate)

Chem.

[0432] Example 86: 5-(3-{1-[4-Amino-3-(fluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]ethyl}-5-chloro-2-ethoxy-6-methylphenyl)-N,N-dimethylpyridine-2-carboxamide bis(trifluoroacetate)

Chem.

[0433] Example 87: 3-{1-[4-Amino-3-(1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]ethyl}-5-chloro-2-ethoxy-N-ethyl-6-methylbenzamide

Chem.

[0434] Step 1: 1-(5-chloro-2-ethoxy-4-methyl-3-vinylphenyl)ethanone A mixture of 1-(5-chloro-2-ethoxy-3-iodo-4-methylphenyl)ethanone (1.1 g, 3.2 mmol, from Example 14, Step 1), 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) / water (5 mL) was degassed with N and heated at 80 °C overnight. After cooling to room temperature, the reaction mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO4, filtered, concentrated, and purified on silica gel (eluted with 0-10% EtOAc in hexanes) to give the desired product (0.64 g, 82%). 13 H 16 LCMS (M+H) for ClO2 + Calculated: m / z = 239.1; Found: 239.1.

[0435] Step 2: 1-[5-chloro-3-(1,2-dihydroxyethyl)-2-ethoxy-4-methylphenyl]ethanone To a solution of 1-(5-chloro-2-ethoxy-4-methyl-3-vinylphenyl)ethanone (0.59 g, 2.5 mmol) in tert-butyl alcohol (20 mL) was added N-methylmorpholine N-oxide (0.318 g, 2.72 mmol) and water (7.8 mL). 4% osmium tetraoxide (0.078 mL, 0.012 mmol) was then added to the solution. After 3 hours, an additional equivalent of N-methylmorpholine N-oxide was added. The reaction was stirred for an additional 3 hours. The solution was diluted with water and extracted with EtOAc. The combined organic layers were dried over MgSO4 and concentrated to give the desired product (0.64 g, 95%). C 13 H 17 LCMS for ClO4Na (M+Na) +Calculated value: m / z = 295.1; Measured value: 295.1.

[0436] Step 3: 3-Acetyl-5-chloro-2-ethoxy-6-methylbenzaldehyde To a solution of 1-[5-chloro-3-(1,2-dihydroxyethyl)-2-ethoxy-4-methylphenyl]ethanone (0.64 g, 2.3 mmol) in tetrahydrofuran (18 mL) and water (11 mL) were added acetic acid (35 μL, 0.61 mmol) and sodium periodate (1.50 g, 7.04 mmol) at 0 °C. After stirring for 30 minutes, the reaction mixture was diluted with water and extracted with EtOAc. The combined extracts were washed with brine, dried over MgSO4, filtered, and concentrated to give the desired product (0.58 g, 100%). C 12 H 14 LCMS (M+H) for ClO3 + Calculated value: m / z = 241.1; Measured value: 241.1.

[0437] Step 4: 3-Acetyl-5-chloro-2-ethoxy-6-methylbenzoic acid A solution of 3-acetyl-5-chloro-2-ethoxy-6-methylbenzaldehyde (0.58 g, 2.4 mmol) and sodium phosphate monobasic monohydrate (116 mg, 0.844 mmol) in acetonitrile (11.8 mL) and water (2.5 mL) was cooled in an ice bath. 30% hydrogen peroxide (0.98 mL, 9.6 mmol) was added, followed by solid sodium chlorite (0.545 g, 4.82 mmol). The mixture was stirred for 1 hour. The mixture was diluted with 1 M HCl solution and extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated to give the desired product (0.67 g, 100%). C 12 H 13 LCMS (M+Na) for ClO4Na + Calculated value: m / z = 279.1; Measured value: 279.0.

[0438] Step 5: 3-Acetyl-5-chloro-2-ethoxy-N-ethyl-6-methylbenzamide To a solution of 3-acetyl-5-chloro-2-ethoxy-6-methylbenzoic acid (0.26 g, 1.0 mmol) in N,N-dimethylformamide (5 mL) was added benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (0.67 g, 1.5 mmol). After stirring for 10 minutes, N,N-diisopropylethylamine (0.35 mL, 2.0 mmol) and 2.0 M ethylamine in THF (2.5 mL, 5.1 mmol) were added. The resulting mixture was stirred at room temperature for 2 hours. The reaction solution was diluted with water and extracted with dichloromethane. The combined organic layers were concentrated and purified by silica gel column (eluting with 0% - 50% EtOAc in hexane) to give the desired product (0.2 g, 70%). C 14 H 19 LCMS (M + H) for ClNO3 + Calculated: m / z = 284.1; Found: 284.1.

[0439] Step 6: 3-chloro-6-ethoxy-N-ethyl-5-(1-hydroxyethyl)-2-methylbenzamide 3-Acetyl-5-chloro-2-ethoxy-N-ethyl-6-methylbenzamide (0.2 g, 0.7 mmol) was treated with sodium tetrahydroborate (0.032 g, 0.84 mmol) in methanol (6 mL) at room temperature for 1 hour. The mixture was diluted with water and extracted with dichloromethane. The combined organic layers were dried over MgSO4, filtered, and concentrated to give the desired product. C 14 H 21 LCMS (M + H) for ClNO3 + Calculated: m / z = 286.1; Found: 286.1.

[0440] Step 7: 3-chloro-5-(1-chloroethyl)-6-ethoxy-N-ethyl-2-methylbenzamide A mixture of cyanuric chloride (0.15 g, 0.84 mmol) and N,N-dimethylformamide (0.065 mL, 0.84 mmol) was stirred at room temperature for 10 minutes, then a solution of 3-chloro-6-ethoxy-N-ethyl-5-(1-hydroxyethyl)-2-methylbenzamide (0.16 g, 0.56 mmol) in methylene chloride (3.1 mL) was added, and the reaction was stirred at room temperature overnight. The mixture was diluted with methylene chloride, washed with water, concentrated, and purified on silica gel (eluted with 0-40% EtOAc in hexanes) to give the desired product (0.13 g, 76%). 14 H 20 LCMS (M+H) for Cl2NO2 + Calculated: m / z = 304.1; Found: 304.1.

[0441] Step 8: 3-[1-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-N-ethyl-6-methylbenzamide A mixture of 3-chloro-...

Claims

1. Formula VIII: 【Chemical 1】 【wherein, X is CR ９ or N; W is CR ７ or N; Y is CR ８ , CR ８ａ , or N; Z is a bond or C(=O); However, provided that -W = Y - Z - is -CR ７ = CR ８ -, -N = CR ８ -, -CR ７ = CR ８ａ -C(=O)-, -N = CR ８ａ -C(=O)-, or -CR ７ = N - C(=O)-; R １ is C １－３ alkyl; R ２ is halo, C １－６ alkyl, C １－６ alkoxy, C １－６ haloalkyl, C １－６ haloalkoxy, phenyl, or 5- to 6-membered heteroaryl; wherein said phenyl and 5- to 6-membered heteroaryl are each independently selected from 1, 2, 3, or 4 substituents selected from halo, OH, CN, C １－４ alkyl, C １－４ alkoxy, and C １－４ haloalkoxy and may be substituted by; R ４ is H, 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, C １－４ haloalkoxy, or cyclopropyl; R ６ is H, halo, OH, CN, C １－４ alkyl, C １－４ haloalkyl, C １－４ alkoxy, or C １－４ haloalkoxy; R ７ is H or C １－４ and is alkyl; R ８ is H, halo, -OH, -CN, C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, C １－６ haloalkyl, Cy ２ , -(C １－３ alkylene)-Cy ２ , OR ａ２ , SR ａ２ , C(=O)R ｂ２ , C(=O)NR ｃ２ R ｄ２ , C(=O)OR ａ２ , OC(=O)R ｂ２ , OC(=O)NR ｃ２ R ｄ２ , NR ｃ２ R ｄ２ , NR ｃ２ , C(=O)R ｂ２ , NR ｃ２ , C(=O)OR ｂ２ , NR ｃ２ , C(=O)NR ｃ２ R ｄ２ , C(=NR ｅ ), R ｂ２ , C(=NR ｅ ), NR ｃ２ R ｄ２ , NR ｃ２ , C(=NR ｅ ), NR ｃ２ R ｄ２ , NR ｃ２ , S(=O)R ｂ２ , NR ｃ２ , S(=O) ２ , NR ｃ２ R ｄ２ , S(=O)R ｂ２ , S(=O) ２ R ｂ２ , or S(=O) ２ , NR ｃ２ R ｄ２ ; wherein said C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl may each be substituted by one, two, three or four independently selected R １１ groups; R ８ａ is H, halo, -CN, C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, C １－６ haloalkyl, Cy ２ , -(C １－３ alkylene)-Cy ２ , C(=O)R ｂ２ , C(=O)NR ｃ２ R ｄ２ , C(=O)OR ａ２ , NR ｃ２ R ｄ２ , NR ｃ２ C(=O)R ｂ２ , NR ｃ２ C(=O)OR ｂ２ , NR ｃ２ C(=O)NR ｃ２ R ｄ２ , NR ｃ２ S(=O)R ｂ２ , NR ｃ２ S(=O) ２ NR ｃ２ R ｄ２ , S(=O)R ｂ２ , S(=O) ２ R ｂ２ , or S(=O) ２ NR ｃ２ R ｄ２ and; wherein said C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl may each be substituted by one, two, three or four independently selected R １１ groups; R ９ is H, halo, OH, CN, C １－４ alkyl, C １－４ haloalkyl, C １－４ alkoxy, or C １－４ haloalkoxy; R １０ is H or C １－４ and is alkyl; Each R ｅ is independently selected from H, CN, OH, C １－４ alkyl, and C １－４ alkoxy; Each R ３ｂ is Cy １ ,-(C １－３ alkylene)-Cy １ halo, CN, NO ２ C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, C １－６ haloalkyl, OR ａ１ SR 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 NR ｃ１ R ｄ１ NR ｃ１ C(=O)R ｂ１ NR ｃ１ C(=O)OR ｂ１ NR ｃ１ C(=O)NR ｃ１ R ｄ１ C(=NR ｅ )R ｂ１ C(=NR ｅ )NR ｃ１ R ｄ１ NR ｃ１ C(=NR ｅ )NR ｃ１ R ｄ１ NR ｃ１ S(=O)R ｂ１ NR ｃ１ S(=O) ２ NR ｃ１ R ｄ１ S(=O)R ｂ１ S(=O) ２ R ｂ１ and S(=O) ２ NR ｃ１ R ｄ１ is independently selected from; wherein said C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl may each be substituted with one, two or three independently selected R １１ groups; Each Cy １ is each independently selected from one, two, three or four R １１ groups which may be substituted, and is independently selected from C ３－７ cycloalkyl, 4- to 7-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl; Each R ａ１ 、R ｂ１ 、R ｃ１ 、and R ｄ１ is independently selected from 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; wherein said C 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 may each be substituted with one, two or three independently selected R １１ groups; or R ｃ１ and R ｄ１ together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl group which may be substituted by -OH or C １－３ alkyl; Each Cy ２ is each independently selected from 1, 2, 3 or 4 R １１ groups which may be substituted, C ３－７ cycloalkyl, 4- to 7-membered heterocycloalkyl, phenyl, 5- to 6-membered heteroaryl, or 9- to 10-membered bicyclic heteroaryl; Each R ａ２ , R ｂ２ , R ｃ２ , and R ｄ２ is independently selected from 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; wherein said C 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 may each be substituted with one, two or three independently selected R １１ groups; or R ｃ2 and R ｄ２ together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl group which may be substituted by -OH or C １－３ alkyl; Each R １１ is OH, NO ２ , 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, C １－３ alkylthio, C １－３ alkylsulfinyl, C １－３ alkylsulfonyl, 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 alkylsulfonylamino, 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, independently selected from] a compound represented by, or a pharmaceutically acceptable salt thereof.

2. 【Fig. 2】 The moiety represented by 【Chemical Formula 3】 is, the compound according to claim 1, or a pharmaceutically acceptable salt thereof.

3. R １ The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R is methyl.

4. R ２ is C １－３ The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein is an alkoxy group.

5. R ４ is CN, or C １－４ The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein is alkyl.

6. R ５ The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein R is halo.

7. R ５ The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein R is Cl.

8. R ６ The compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein R is H.

9. R ７ The compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein R is H.

10. R ８ is H, halo, CN, C １－６ alkyl, or Cy ２ wherein Cy ２ is each independently selected from one or two R １１ groups which may be substituted, C ３－６ cycloalkyl, phenyl, 5- to 6-membered heteroaryl, and 4- to 7-membered heterocycloalkyl, the compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof.

11. R ８ H, halo, CN, C １－６ Alkyl, or Cy ２ where Cy ２ However, each is OH, CN, halo, C １－３ Alkyl, C １－３ Haloalkyl, HO-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, carbamyl, C １－３ Alkylcarbamyl, and di(C １－３ one R selected from alkyl)carbamyl １１ optionally substituted with C ３－６ 11. The compound of any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from cycloalkyl, phenyl, 5- to 6-membered heteroaryl, or 4- to 7-membered heterocycloalkyl.

12. R ８ is H, halo, CN, methyl, or Cy ２ wherein Cy ２ is cyclopropyl, phenyl, pyrazole ring, pyridine ring, or pyrimidine ring, each optionally substituted with one R １１ selected from OH, CN, fluoro, methyl, 2-hydroxyethyl, dimethylcarbamyl, amino, methylcarbamyl, and dimethylcarbamyl, the compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof.

13. R ８ａ is H, halo, -CN, C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, C １－６ haloalkyl, or Cy ２ and is the compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof.

14. R ８ａ The compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein R is H or halo.

15. R ９ The compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, wherein R is H.

16. R １０ The compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, wherein R is H.

17. Each R １１ is independently OH, CN, halo, C １－３ alkyl, C １－３ haloalkyl, HO-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, carbamyl, C １－３ alkylcarbamyl, or di(C １－３ alkyl)carbamyl, a compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof.

18. R ３ｂ is Cy １ , -(C １－３ alkylene)-Cy １ , halo, CN, OH, C １－６ alkyl, C １－６ alkoxy, C １－６ haloalkyl, C(=O)R ｂ１ , C(=O)NR ｃ１ R ｄ１ , S(=O)R ｂ１ , and S(=O) ２ NR ｃ１ R ｄ１ selected from the group consisting of; wherein said C １－６ alkyl may be substituted with one, two or three independently selected R １１ groups, the compound according to any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof.

19. A pharmaceutical composition comprising the compound according to any one of claims 1 to 18 or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

20. A pharmaceutical composition for inhibiting the activity of PI3K kinase, comprising the compound according to any one of claims 1 to 18 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

21. The pharmaceutical composition according to claim 20, wherein the PI3K is selected from the group consisting of PI3Kα, PI3Kβ, PI3Kδ and PI3Kγ.

22. The pharmaceutical composition according to claim 20, wherein the PI3K contains a mutation.

23. The pharmaceutical composition according to any one of claims 20 to 22, wherein the compound is a selective inhibitor for PI3Kδ over one or more of PI3Kα, PI3Kβ, and PI3Kγ.

24. A pharmaceutical composition for treating a disease of a patient, comprising the compound according to any one of claims 1 to 18 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

25. The pharmaceutical composition according to claim 24, wherein the disease is osteoarthritis, restenosis, atherosclerosis, bone disorder, arthritis, diabetic retinopathy, psoriasis, benign prostatic hyperplasia, inflammation, angiogenesis, pancreatitis, kidney disease, inflammatory bowel disease, myasthenia gravis, multiple sclerosis, or Sjögren's syndrome.

26. The pharmaceutical composition according to claim 24 or 25, which is used to administer two or more of the compounds.

27. The pharmaceutical composition according to claim 26, wherein the compound is used to be administered in combination with a kinase inhibitor that inhibits kinases other than PI3K kinase.

28. A pharmaceutical composition for treating immune-based diseases in a patient, comprising the compound according to any one of claims 1 to 18 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

29. The pharmaceutical composition according to claim 28, wherein the immune-based disease is rheumatoid arthritis, allergy, asthma, glomerulonephritis, lupus, or an inflammation associated with any of the foregoing.

30. A pharmaceutical composition for treating cancer in a patient, comprising the compound according to any one of claims 1 to 18 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

31. The pharmaceutical composition according to claim 30, wherein the cancer is breast cancer, prostate cancer, colon cancer, endometrial cancer, brain cancer, bladder cancer, skin cancer, uterine cancer, ovarian cancer, lung cancer, pancreatic cancer, kidney cancer, stomach cancer, or blood cancer.

32. The pharmaceutical composition according to claim 31, wherein the blood cancer is acute myeloblastic leukemia, chronic myelogenous leukemia, or B-cell lymphoma.

33. The pharmaceutical composition according to claim 30, wherein the cancer is diffuse large B-cell lymphoma.

34. A pharmaceutical composition for treating lung diseases in a patient, comprising the compound according to any one of claims 1 to 18 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

35. The pharmaceutical composition according to claim 34, wherein the lung disease is acute lung injury (ALI) or adult respiratory distress syndrome (ARDS).

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