This application claims the benefit of priority of U.S. Provisional Appl. No. 61/425,107, filed December 20, 2010, which is incorporated herein by reference in its entirety.

FIELD OF THE INVENTION

The present invention provides N-(l-(substituted-phenyl)ethyl)-9H-purin-6-amine derivatives that modulate the activity of phosphoinositide 3-kinases (PBKs) and are useful in the treatment of diseases related to the activity of PBKs including, for example, inflammatory disorders, immune-based disorders, cancer, and other diseases.

BACKGROUND OF THE INVENTION

The phosphoinositide 3-kinases (PBKs) belong 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). PBKs are divided into three classes (class I, II, and III) according to their structure, regulation and substrate specificity. Class I PBKs, which include ΡΒΚα, ΡΒΚβ, ΡΒΚγ, and ΡΒΚδ, are a family of dual specificity lipid and protein kinases that catalyze the phosphorylation of phosphatidylinosito-4,5-bisphosphate (PIP ₂ ) giving rise to phosphatidylinosito-3,4,5-trisphosphate (PIP3). PIP3 functions as a second messenger that controls a number of cellular processes, including growth, survival, adhesion and migration. All four class I PBK iso forms exist as heterodimers composed of a catalytic subunit (pi 10) and a tightly associated regulatory subunit that controls their expression, activation, and subcellular localization. ΡΒΚα, ΡΒΚβ, and ΡΒΚδ associate with a regulatory subunit known as p85 and are activated by growth factors and cytokines through a tyrosine kinase-dependent mechanism (Jimenez, et al, J Biol Chem., 2002, 277(44):41556-62) whereas ΡΒΚγ associates with two regulatory subunits (plOl and p84) and its activation is driven by the activation of G-protein- coupled receptors (Brock, et al, J Cell Biol, 2003, 160(l):89-99). PBKa and ΡΒΚβ are ubiquitously expressed. In contrast, ΡΒΚγ and ΡΒΚδ are predominantly expressed in leukocytes (Vanhaesebroeck, et al, Trends Biochem Sci., 2005, 30(4):194-204).

The differential tissue distribution of the PBK isoforms factors in their distinct biological functions. Genetic ablation of either PBKa or ΡΒΚβ results in embryonic lethality, indicating that ΡΒΚα and ΡΒΚβ have essential and non-redundant functions, at least during development (Vanhaesebroeck, et al., 2005). In contrast, mice which lack ΡΒΚγ and ΡΒΚδ are viable, fertile and have a normal life span although they show an altered immune system. ΡΒΚγ deficiency leads to impaired recruitment of macrophages and neutrophils to sites of inflammation as well as impaired T cell activation (Sasaki, et al., Science, 2000, 287(5455): 1040-6). ΡΒΚδ-mutant mice have specific defects in B cell signaling that lead to impaired B cell development and reduced antibody responses 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).

The phenotypes of the ΡΒΚγ and ΡΒΚδ-mutant mice suggest that these enzymes may play a role in inflammation and other immune-based diseases and this is borne out in preclinical models. ΡΒΚγ-mutant mice are largely 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). In addition, treatment of wild-type mice with a selective inhibitor of ΡΒΚγ was shown to reduce glomerulonephritis and prolong survival in the MRL-lpr model of systemic lupus nephritis (SLE) and to suppress joint inflammation and damage in models of RA (Barber, et al, Nat Med. 2005, 11(9):933-5; Camps, et al, 2005). Similarly, both ΡΒΚδ-mutant mice and wild-type mice treated with a selective inhibitor of ΡΒΚδ have been shown to have attenuated allergic airway inflammation and hyper-responsiveness 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 to have attenuated disease in a model of RA (Randis, et al, Eur. J. Immunol., 2008, 38(5): 1215-24).

In addition to their potential role in inflammatory diseases, all four class I PBK isoforms may play a role in cancer. The gene encoding pi 10a is mutated frequently in common cancers, including breast, prostate, colon and endometrial (Samuels, et al, Science, 2004, 304(5670):554; Samuels, et al, Curr Opin Oncol. 2006, 18(l):77-82). Eighty percent of these mutations are represented by one of three amino acid substitutions in the helical or kinase domains of the enzyme and lead to a significant upregulation of kinase activity resulting in oncogenic transformation in cell culture and in 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). No such mutations have been identified in the other PBK isoforms although there is evidence that they can contribute to the development and progression of malignancies. Consistent overexpression of ΡΒΚδ is observed in acute myeloblastic leukemia (Sujobert, et al, Blood, 2005, 106(3): 1063- 6) and inhibitors of PI3K5 can prevent the growth of leukemic cells (Billottet, et al., Oncogene. 2006, 25(50):6648-59). Elevated expression of ΡΙ3Κγ is seen in chronic myeloid leukemia (Hickey, et al, J Biol Chem. 2006, 281(5):2441-50). Alterations in expression of ΡΒΚβ, ΡΒΚγ and ΡΒΚδ have also been observed in cancers of the brain, colon and bladder (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). Further, these isoforms have all been shown to be oncogenic in cell culture (Kang, et al, 2006).

Thus, new or improved agents which inhibit kinases such as PBK are continually needed for developing new and more effective pharmaceuticals that are aimed at augmentation or suppression of the immune and inflammatory pathways (such as immunosuppressive agents for organ transplants), as well as agents 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 a hyperactive inflammatory response (e.g., eczema), allergies, lung diseases, cancer (e.g. , prostate, breast, leukemia, multiple myeloma), and some immune reactions (e.g. , skin rash or contact dermatitis or diarrhea) caused by other therapeutics. The compounds, compositions, and methods described herein are directed toward these needs and others.

I

and pharmaceutically acceptable salts thereof; wherein the variables are defined infra.

The present invention further provides compositions comprising a compound of the invention, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier. The present invention also provides methods of modulating an activity of a PI3K kinase, comprising contacting the kinase with a compound of the invention, or a pharmaceutically acceptable salt thereof.

The present invention further provides methods of treating a disease in a patient, wherein said disease is associated with abnormal expression or activity of a PI3K kinase, comprising administering to said patient a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof.

The present invention further provides methods of treating an immune -based disease in a patient, comprising administering to said patient a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof.

The present invention also provides methods of treating a cancer in a patient, comprising administering to said patient a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof.

The present invention further provides methods of treating a lung disease in a patient, comprising administering to said patient a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof.

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

The present invention further provides 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.

DETAILED DESCRIPTION

The present invention provides, inter alia, a compound of Formula I:

I

or a pharmaceutically acceptable salt thereof; wherein:

X is CH or N;

Y is CH or N;

R ¹ is selected from Ci_ ₆ alkyl, C ₂ _ ₆ alkenyl, C ₂ _ ₆ alkynyl, and Ci_ ₆ haloalkyl; wherein said Ci_6 alkyl, C ₂ _ ₆ alkenyl, and C ₂ _ ₆ alkynyl are each optionally substituted by 1 , 2, 3, or 4 groups independently selected from halo, OH, CN, NR ^la R ^2b , Ci_ ₆ alkoxy, and Ci_ ₆ haloalkoxy;

each R ^la and R ^2b is independently selected from H and Ci_ ₆ alkyl;

or any R ^la and R ^2b together with the N atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group, which is optionally substituted with 1 , 2, 3, or 4 substituents independently selected from Ci_ ₆ alkyl;

R ² is selected from halo, CN, Ci_ ₆ alkyl, Ci_ ₆ haloalkyl, -L-(Ci_6 alkyl), -L-(Ci_6 haloalkyl), and -L-(Ci_4 alkylene) _n -Cy ² and -(Ci_ ₄ alkylene) _n -Cy ² ; wherein said Ci_ ₆ alkyl in said Ci_ ₆ alkyl and -L-(Ci_6 alkyl) is optionally substituted by 1 , 2, 3, or 4 independently selected R ^2a groups;

L is O, NR ^B , S, S(O), S(0) ₂ , C(O), C(0)NR ^B , S(0)NR ^B , S(0) ₂ NR ^B , NR ^B C(0), NR ^B S(0), and NR ^B S(0) ₂ ;

R ^A and R ^B are each independently selected from H and Ci_ ₆ alkyl;

Cy ² is selected from C ₃ _ ₇ cycloalkyl, 4-7 membered heterocycloalkyl, phenyl, and 5-6 membered heteroaryl; each of which is substituted with p independently selected R ^2a groups; wherein p is 0, 1 , 2, 3, or 4;

each R ^2a is independently selected from OH, N0 ₂ , CN, halo, Ci_ ₆ alkyl, C ₂ _ ₆ alkenyl, C ₂ _ ₆ alkynyl, C ₃ _ ₇ cycloalkyl, Ci_ ₆ haloalkyl, Ci_ ₆ alkoxy, Ci_ ₆ haloalkoxy, amino, Ci_ ₆ alkylamino, di(Ci_ ₆ alkyl)amino, thio, Ci_ ₆ alkylthio, Ci_ ₆ alkylsulfmyl, Ci_ ₆ alkylsulfonyl, carbamyl, Ci_ ₆ alkylcarbamyl, di(Ci_ ₆ alkyl)carbamyl, carboxy, Ci_ ₆ alkylcarbonyl, Ci_ ₆ alkoxycarbonyl, Ci_ ₆ alkylcarbonylamino, Ci_ ₆ alkylsulfonylamino, aminosulfonyl, Ci_ ₆ alkylaminosulfonyl, di(Ci_ ₆ alkyl)aminosulfonyl, aminosulfonylamino, Ci_ ₆ alkylaminosulfonylamino, di(Ci_ ₆

alkyl)aminosulfonylamino, aminocarbonylamino, Ci_ ₆ alkylaminocarbonylamino, and di(Ci_ ₆ alkyl)aminocarbonylamino;

R ³ is halo, CN, N0 ₂ , Ci_ ₆ alkyl, C ₂ _ ₆ alkenyl, C ₂ _ ₆ alkynyl, Ci_ ₆ haloalkyl, -(Ci_ ₄ alkylene) _r - Cy ³ , OR ^a , SR ^a , C(0)R ^b , C(0)NR ^c R ^d , C(0)OR ^a , OC(0)R ^b , OC(0)NR ^c R ^d , NR ^c R ^d , NR ^c C(0)R ^b , NR ^c C(0)OR ^b , NR ^f C(0)R ^b , NR ^f C(0)OR ^b , NR ^c C(0)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(0)R ^b , NR ^c S(0) ₂ R ^b , NR ^f S(0) ₂ R ^b , NR ^c S(0) ₂ NR ^c R ^d , S(0)R ^b ,

S(0)NR ^c R ^d , S(0) ₂ R ^b , or S(0) ₂ NR ^c R ^d ; wherein said Ci_ 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;

Cy ³ is selected from C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, phenyl, and 5-6 membered heteroaryl; each of which is optionally substituted with 1, 2, 3, or 4 independently selected R ^3a groups;

provided that one of the following is true:

(1) R ³ is -(Ci_4 alkylene) _r -Cy ³ ; or

(2) R ² is selected from -L-(Ci_ ₄ alkylene) _n -Cy ² and -(Ci_ ₄ alkylene) _n -Cy ² ; or

(3) R ³ is -(Ci_4 alkylene) _r -Cy ³ ; and R ² is selected from -L-(Ci_ ₄ alkylene) _n -Cy ² and -(Ci_ ₄ alkylene) _n -Cy ² ;

each R ^3a is independently selected from halo, CN, N0 ₂ , Ci_ ₆ alkyl, C ₂ _ ₆ alkenyl, C ₂ _ ₆ alkynyl, Ci_ ₆ haloalkyl, C ₃ _ ₇ cycloalkyl, 4-7 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, (4-7 membered heterocycloalkyl)-Ci_ ₄ alkyl, phenyl-Ci_ ₄ alkyl, (5-6 membered heteroaryl)-Ci_ ₄ alkyl, OR ^a , SR ^a , C(0)R ^b , C(0)NR ^c R ^d , C(0)OR ^a , OC(0)R ^b , OC(0)NR ^c R ^d , NR ^c R ^d , NR ^c C(0)R ^b , NR ^c C(0)OR ^b , NR ^c C(0)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(0)R ^b , NR ^c S(0) ₂ R ^b , NR ^c S(0) ₂ NR ^c R ^d , S(0)R ^b , S(0)NR ^c R ^d , S(0) ₂ R ^b , and S(0) ₂ NR ^c R ^d ; wherein said Ci_ ₆ alkyl, C ₂ _ ₆ alkenyl, C ₂ _ ₆ alkynyl, C ₃ _ ₇ cycloalkyl, 4-7 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, (4-7 membered

heterocycloalkyl)-Ci_4 alkyl, phenyl-Ci_ ₄ alkyl, and (5-6 membered heteroaryl)-Ci_ ₄ alkyl are each optionally substituted by 1, 2, 3, or 4 groups independently selected from OH, N0 ₂ , CN, halo, Ci_6 alkyl, cyano-Ci_ ₆ alkyl, HO-Ci_ ₆ alkyl, Ci_ ₄ alkoxy-Ci_ ₆ alkyl, Ci_ ₆ haloalkyl, C ₂ _ ₆ alkenyl, C ₂ _ 6 alkynyl, C ₃ _ ₇ cycloalkyl, Ci_ ₆ haloalkyl, Ci_ ₆ alkoxy, Ci_ ₆ haloalkoxy, amino, Ci_ ₆ alkylamino, di(Ci_6 alkyl)amino, thio, Ci_ ₆ alkylthio, Ci_ ₆ alkylsulfmyl, Ci_ ₆ alkylsulfonyl, carbamyl, Ci_ ₆ alkylcarbamyl, di(Ci_ ₆ alkyl)carbamyl, carboxy, Ci_ ₆ alkylcarbonyl, Ci_ ₆ alkoxycarbonyl, Ci_ ₆ alkylcarbonylamino, Ci_ ₆ alkylsulfonylamino, aminosulfonyl, Ci_ ₆ alkylaminosulfonyl, di(Ci_ ₆ alkyl)aminosulfonyl, aminosulfonylamino, Ci_ ₆ alkylaminosulfonylamino, di(Ci_ ₆

alkyl)aminosulfonylamino, aminocarbonylamino, Ci_ ₆ alkylaminocarbonylamino, and di(Ci_ ₆ alkyl)aminocarbonylamino; R ⁴ is selected from H, OH, N0 ₂ , CN, halo, Ci_ ₆ alkyl, C ₂ _ ₆ alkenyl, C ₂ _ ₆ alkynyl, Ci_ ₆ haloalkyl, cyano-Ci_ ₆ alkyl, HO-Ci_ ₆ alkyl, Ci_ ₄ alkoxy-Ci_ ₆ alkyl, C ₃ _ ₇ cycloalkyl, Ci_ ₆ alkoxy, Ci_ ₆ haloalkoxy, amino, Ci_ ₆ alkylamino, di(Ci_ ₆ alkyl)amino, thio, Ci_ ₆ alkylthio, Ci_ ₆ alkylsulfinyl, Ci_6 alkylsulfonyl, carbamyl, Ci_ ₆ alkylcarbamyl, di(Ci_ ₆ alkyl)carbamyl, carboxy, Ci_ ₆ alkylcarbonyl, Ci_ ₆ alkoxycarbonyl, Ci_ ₆ alkylcarbonylamino, Ci_ ₆ alkylsulfonylamino, aminosulfonyl, Ci_ ₆ alkylaminosulfonyl, di(Ci_ ₆ alkyl)aminosulfonyl, aminosulfonylamino, Ci_ ₆ alkylaminosulfonylamino, di(Ci_ ₆ alkyl)aminosulfonylamino, aminocarbonylamino, Ci_ ₆ alkylaminocarbonylamino, and di(Ci_ ₆ alkyl)aminocarbonylamino;

R ⁵ is selected from halo, OH, CN, Ci_ ₄ alkyl, Ci_ ₄ alkoxy, and Ci_ ₄ haloalkoxy;

each R ^a , R ^c , and R ^d is independently selected from H, Ci_ ₆ alkyl, Ci_ ₆ haloalkyl, C ₂ _ ₆ alkenyl, C ₂ _ ₆ alkynyl, C ₃ _ ₇ cycloalkyl, 4-7 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, (4-7 membered heterocycloalkyl)-Ci_ ₄ alkyl, phenyl-Ci_ ₄ alkyl, and (5-6 membered heteroaryl)-Ci_ ₄ alkyl; wherein said Ci_ ₆ alkyl, C ₂ _ ₆ alkenyl, C ₂ _ ₆ alkynyl, C ₃ _ ₇ cycloalkyl, 4-7 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, (4-7 membered

heterocycloalkyl)-Ci_ ₄ alkyl, phenyl-Ci_ ₄ alkyl, and (5-6 membered heteroaryl)-Ci_ ₄ alkyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from OH, N0 ₂ , CN, halo, Ci_6 alkyl, C ₂ _ ₆ alkenyl, C ₂ _ ₆ alkynyl, Ci_ ₆ haloalkyl, cyano-Ci_ ₆ alkyl, HO-Ci_ ₆ alkyl, Ci_ ₄ alkoxy-Ci_ ₆ alkyl, C ₃ _ ₇ cycloalkyl, Ci_ ₆ haloalkyl, Ci_ ₆ alkoxy, Ci_ ₆ haloalkoxy, amino, Ci_ ₆ alkylamino, di(Ci_ ₆ alkyl)amino, thio, Ci_ ₆ alkylthio, Ci_ ₆ alkylsulfinyl, Ci_ ₆ alkylsulfonyl, carbamyl, Ci_ ₆ alkylcarbamyl, di(Ci_ ₆ alkyl)carbamyl, carboxy, Ci_ ₆ alkylcarbonyl, Ci_ ₆ alkoxycarbonyl, Ci_ ₆ alkylcarbonylamino, Ci_ ₆ alkylsulfonylamino, aminosulfonyl, Ci_ ₆ alkylaminosulfonyl, di(Ci_ ₆ alkyl)aminosulfonyl, aminosulfonylamino, Ci_ ₆

alkylaminosulfonylamino, di(Ci_ ₆ alkyl)aminosulfonylamino, aminocarbonylamino, Ci_ ₆ alkylaminocarbonylamino, and di(Ci_ ₆ alkyl)aminocarbonylamino;

each R ^b is independently selected from Ci_ ₆ alkyl, Ci_ ₆ haloalkyl, C ₂ _ ₆ alkenyl, C ₂ _ ₆ alkynyl, C ₃ _ ₇ cycloalkyl, 4-7 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, (4-7 membered heterocycloalkyl)-Ci_ ₄ alkyl, phenyl-Ci_ ₄ alkyl, and (5-6 membered heteroaryl)-Ci_ ₄ alkyl; each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from OH, N0 ₂ , CN, halo, Ci_ ₆ alkyl, C ₂ _ ₆ alkenyl, C ₂ _ ₆ alkynyl, Ci_ ₆ haloalkyl, cyano-Ci_ ₆ alkyl, HO- Ci_6 alkyl, Ci_ ₄ alkoxy-Ci_6 alkyl, C ₃ _ ₇ cycloalkyl, Ci_ ₆ haloalkyl, Ci_ ₆ alkoxy, Ci_ ₆ haloalkoxy, amino, Ci_ ₆ alkylamino, di(Ci_ ₆ alkyl)amino, thio, Ci_ ₆ alkylthio, Ci_ ₆ alkylsulfinyl, Ci_ ₆ alkylsulfonyl, carbamyl, Ci_ ₆ alkylcarbamyl, di(Ci_6 alkyl)carbamyl, carboxy, Ci_ ₆ alkylcarbonyl, Ci_6 alkoxycarbonyl, Ci_ ₆ alkylcarbonylamino, Ci_ ₆ alkylsulfonylamino, aminosulfonyl, Ci_ ₆ alkylaminosulfonyl, di(Ci_ ₆ alkyl)aminosulfonyl, aminosulfonylamino, Ci_ ₆

alkylaminosulfonylamino, di(Ci_ ₆ alkyl)aminosulfonylamino, aminocarbonylamino, Ci_ ₆ alkylaminocarbonylamino, and di(Ci_ ₆ alkyl)aminocarbonylamino;

each R ^e is independently selected from H, Ci_ ₄ alkyl, CN, OH, Ci_ ₄ alkoxy, Ci_ ₄

alkylsulfonyl, carbamyl, Ci_ ₄ alkylcarbamyl, di(Ci_ ₄ alkyl)carbamyl, and Ci_ ₄ alkylcarbonyl; each R is independently selected from Ci_ ₄ alkylsulfonyl, Ci_ ₄ alkylcarbonyl and Ci_ ₄ alkoxycarbonyl;

n is 0 or 1 ; and

r is 0 or 1.

In some embodiments, Ar is

In some embodiments, Ar is

In some embodiments, Ar is

In some embodiments, Ar is

In some embodiments, Ar is

In some embodiments, X is N and Y is CH; or X is CH and Y is N.

In some embodiments, R ⁴ is selected from OH, N0 ₂ , CN, halo, Ci_ ₆ alkyl, C ₂ - ₆ alkenyl, C ₂ _6 alkynyl, Ci_ ₆ haloalkyl, cyano-Ci_ ₆ alkyl, HO-Ci_ ₆ alkyl, Ci_ ₄ alkoxy-Ci_ ₆ alkyl, C ₃ _ ₇ cycloalkyl, Ci_ ₆ alkoxy, Ci_ ₆ haloalkoxy, amino, Ci_ ₆ alkylamino, di(Ci_ ₆ alkyl)amino, thio, Ci_ ₆ alkylthio, Ci_ ₆ alkylsulfmyl, Ci_ ₆ alkylsulfonyl, carbamyl, Ci_ ₆ alkylcarbamyl, di(Ci_ ₆ alkyl)carbamyl, carboxy, Ci_ ₆ alkylcarbonyl, Ci_ ₆ alkoxycarbonyl, Ci_ ₆ alkylcarbonylamino, Ci_ ₆ alkylsulfonylamino, aminosulfonyl, Ci_ ₆ alkylaminosulfonyl, di(Ci_ ₆ alkyl)aminosulfonyl, aminosulfonylamino, Ci_ ₆ alkylaminosulfonylamino, di(Ci_ ₆ alkyl)aminosulfonylamino, aminocarbonylamino, Ci_ ₆ alkylaminocarbonylamino, and di(Ci_ ₆ alkyl)aminocarbonylamino

In some embodiments, R ⁴ is selected from H, halo, CN, Ci_ ₆ alkyl, cyano-Ci_ ₆ alkyl, and Ci_6 halo alkyl.

In some embodiments, R ⁴ is selected from Ci_ ₆ alkyl, cyano-Ci_ ₆ alkyl, and Ci_ ₆ haloalkyl.

In some embodiments, R ⁴ is Ci_ ₆ alkyl.

In some embodiments, R ⁴ is H.

In some embodiments, R ⁴ is methyl.

In some embodiments, R ⁴ is F.

In some embodiments, R ⁴ is CI.

In some embodiments, R ⁴ is CN.

In some embodiments, R ¹ is Ci_ ₃ alkyl.

In some embodiments, R ¹ is methyl.

In some embodiments, R ¹ is ethyl.

In some embodiments, R ¹ is methyl or ethyl

In some embodiments, R ² is -(C _1-6 alkyl), -0-(Ci_ ₆ alkyl), -0-(Ci_ ₄ alkylene) _n -Cy ² , or -Cy ² ; wherein Ci_ ₆ alkyl is optionally substituted by 1 , 2, 3, or 4 independently selected R ^2a groups.

In some embodiments, R ² is Ci_ ₆ alkyl, -0-(Ci_ ₆ alkyl), -0-(Ci_ ₄ alkylene) _n -(4-7 membered heterocycloalkyl), or phenyl; wherein said phenyl is optionally substituted by 1 , 2, 3, or 4 independently selected R ^2a groups.

In some embodiments, R ² is methyl.

In some embodiments, R ² is methoxy.

In some embodiments, R ² is ethoxy.

In some embodiments, R ² is methoxy or ethoxy.

In some embodiments, R ² is Cy ² .

In some embodiments, R ² is phenyl; wherein phenyl is optionally substituted by 1 , 2, 3, or 4 groups independently selected from halo. In some embodiments, each R ^a is independently selected from OH, N0 ₂ , CN, halo, Ci_ ₆ alkyl, Ci_ ₆ haloalkyl, Ci_ ₆ alkoxy, Ci_ ₆ haloalkoxy, amino, Ci_ ₆ alkylamino, and di(Ci_ ₆

alkyl)amino.

In some embodiments, each R ^2a is independently halo.

In some embodiments, R ^A is H.

In some embodiments, R ⁵ is halo.

In some embodiments, R ⁵ is CI.

In some embodiments, R ⁵ is CI, F, methyl or CN.

In some embodiments, R ³ is CN, N0 ₂ , Cy ³ , C(0)NR ^c R ^d , NR ^f C(0)OR ^b , NR ^f S(0) ₂ R ^b , and NR ^c C(0)R ^b .

In some embodiments, R ³ is Cy ³ .

In some embodiments, Cy ³ is selected from 4-7 membered heterocycloalkyl, phenyl, and 5-6 membered heteroaryl; each of which is optionally substituted with 1 , 2, 3, or 4 independently selected R ^3a groups.

In some embodiments, Cy ³ is selected from phenyl, a piperidine ring, a l ,3-oxazolidin-2- one ring, an isoxazole ring, a pyrazole ring, a tetrazole ring, a triazole ring, a pyridine ring, and a pyrimidine ring; each of which is optionally substituted with 1 , 2, 3, or 4 independently selected R ^3a groups.

In some embodiments, Cy ³ is selected from phenyl, a piperidine ring, a pyrrolidon-2-one ring, a l ,3-oxazolidin-2-one ring, an isoxazole ring, a pyrazole ring, a tetrazole ring, a triazole ring, a pyridine ring, a pyrimidine ring, an azetidine ring, a pyrrole ring, a tetrahydrofuran ring, and a morpholin-2-one ring; each of which is optionally substituted with 1 , 2, 3, or 4

independently selected R ^3a groups;

In some embodiments, each R ^3a is independently selected from halo, CN, N0 ₂ , Ci_ ₆ alkyl, Ci_6 haloalkyl, C ₃ -7 cycloalkyl, 4-7 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, (4-7 membered heterocycloalkyl)-Ci_4 alkyl, phenyl-Ci_4 alkyl, (5-6 membered heteroaryl)-Ci_ ₄ alkyl, OR ^a , C(0)R ^b , C(0)NR ^c R ^d , C(0)OR ^a , NR ^c R ^d , NR ^c C(0)R ^b , S(0) ₂ R ^b , and S(0) ₂ NR ^c R ^d ; wherein said Ci_ ₆ alkyl, C ₃ -7 cycloalkyl, 4-7 membered heterocycloalkyl, phenyl, 5- 6 membered heteroaryl, (4-7 membered heterocycloalkyl)-Ci_4 alkyl, phenyl-Ci_4 alkyl, and (5-6 membered heteroaryl)-Ci_4 alkyl are each optionally substituted by 1 , 2, 3, or 4 groups independently selected from OH, CN, halo, Ci_ ₆ alkyl, Ci_ ₆ haloalkyl, cyano-Ci_ ₆ alkyl, HO-Ci_ ₆ alkyl, Ci_ ₄ alkoxy-Ci_ ₆ alkyl, Ci_ ₆ alkoxy, Ci_ ₆ aloalkoxy, amino, Ci_ ₆ alkylamino, and di(Ci_ ₆ alkyl)amino.

In some embodiments, each R ^3a is independently selected from halo, CN, N0 ₂ , Ci_ ₆ alkyl, Ci_6 haloalkyl, C ₃ -7 cycloalkyl, 4-7 membered heterocycloalkyl, OR ^a , C(0)R ^b , C(0)NR ^c R ^d , NR ^c R ^d , NR ^c C(0)R ^b , and S(0) ₂ R ^b ; wherein said Ci_ ₆ alkyl, C ₃ -7 cycloalkyl, and 4-7 membered heterocycloalkyl are each optionally substituted by 1, 2, 3, or 4 groups independently selected from OH, CN, halo, Ci_ ₆ alkyl, Ci_ ₆ haloalkyl, cyano-Ci_ ₆ alkyl, HO-Ci_ ₆ alkyl, Ci_ ₄ alkoxy-Ci_ ₆ alkyl, Ci_ ₆ alkoxy, Ci_ ₆ haloalkoxy, amino, Ci_ ₆ alkylamino, and di(Ci_ ₆ alkyl)amino.

In some embodiments:

each R ^a , R ^c , and R ^d is independently selected from H, Ci_ ₆ alkyl, C ₃ _ ₇ cycloalkyl, 4-7 membered heterocycloalkyl; wherein said Ci_ ₆ alkyl, C ₃ _ ₇ cycloalkyl, and 4-7 membered heterocycloalkyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from OH, CN, halo, Ci_ ₆ alkyl, Ci_ ₆ haloalkyl, Ci_ ₆ alkoxy, and Ci_ ₆ haloalkoxy; and

each R ^b is independently selected from Ci_ ₆ alkyl, C ₃ _ ₇ cycloalkyl, and 4-7 membered heterocycloalkyl; each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from OH, CN, halo, Ci_ ₆ alkyl, Ci_ ₆ haloalkyl, Ci_ ₆ alkoxy, and Ci_ ₆ haloalkoxy.

In some embodiments:

each R ^3a is independently selected from halo, CN, N0 ₂ , Ci_ ₆ alkyl, Ci_ ₆ haloalkyl, C ₃ _ ₇ cycloalkyl, 4-7 membered heterocycloalkyl, (4-7 membered heterocycloalkyl)-Ci_ ₃ alkyl, (5-6 membered heteroaryl)-Ci_ ₃ alkyl, OR ^a , C(0)R ^b , C(0)OR ^a , C(0)NR ^c R ^d , NR ^c R ^d , NR ^c C(0)R ^b , and S(0) ₂ R ^b ; wherein said Ci_ ₆ alkyl, C ₃ _ ₇ cycloalkyl, and 4-7 membered heterocycloalkyl are each optionally substituted by 1, 2, 3, or 4 groups independently selected from OH, CN, halo, Ci_ ₆ alkyl, Ci_ ₆ haloalkyl, cyano-Ci_ ₆ alkyl, HO-Ci_ ₆ alkyl, Ci_ ₄ alkoxy-Ci_ ₆ alkyl, Ci_ ₆ alkoxy, Ci_ ₆ haloalkoxy, amino, Ci_ ₆ alkylamino, di(Ci_ ₆ alkyl)amino, and C ₃ _ ₇ cycloalkyl;

each R ^a , R ^c , and R ^d is independently selected from H, Ci_ ₆ alkyl, Ci_ ₆ haloalkyl, C ₃ _ ₇ cycloalkyl, 4-7 membered heterocycloalkyl; wherein said Ci_ ₆ alkyl, C ₃ _ ₇ cycloalkyl, and C ₂ _ ₇ heterocycloalkyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from OH, CN, halo, Ci_ ₆ alkyl, Ci_ ₆ haloalkyl, Ci_ ₆ alkoxy, Ci_ ₆ haloalkoxy, and amino; and each R ^b is independently selected from Ci_ ₆ alkyl, Ci_ ₆ haloalkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl; each of which is optionally substituted with 1 , 2, 3, 4, or 5 substituents independently selected from OH, CN, halo, Ci_ ₆ alkyl, Ci_ ₆ haloalkyl, Ci_ ₆ alkoxy, Ci_ ₆ haloalkoxy, and amino.

In some embodiments:

Cy ³ is selected from phenyl, a piperidine ring, a pyrrolidon-2-one ring, a 1 ,3-oxazolidin- 2-one ring, an isoxazole ring, a pyrazole ring, a tetrazole ring, a triazole ring, a pyridine ring, a pyrimidine ring, an azetidine ring, a pyrrole ring, a tetrahydrofuran ring, and a morpholin-2-one ring; each of which is optionally substituted with 1 , 2, 3, or 4 independently selected R ^3a groups; each R ^a , R ^c , and R ^d is independently selected from H, Ci_ ₆ alkyl, Ci_ ₆ haloalkyl, C ₃ _ ₇ cycloalkyl, 4-7 membered heterocycloalkyl; wherein said Ci_ ₆ alkyl, C ₃ _ ₇ cycloalkyl, and C ₂ _ ₇ heterocycloalkyl are each optionally substituted with 1 , 2, 3, 4, or 5 substituents independently selected from OH, CN, halo, Ci_ ₆ alkyl, Ci_ ₆ haloalkyl, Ci_ ₆ alkoxy, Ci_ ₆ haloalkoxy, and amino; and

each R ^b is independently selected from Ci_ ₆ alkyl, Ci_ ₆ haloalkyl, C ₃ _ ₇ cycloalkyl, 4-7 membered heterocycloalkyl; each of which is optionally substituted with 1 , 2, 3, 4, or 5 substituents independently selected from OH, CN, halo, Ci_ ₆ alkyl, Ci_ ₆ haloalkyl, Ci_ ₆ alkoxy, Ci_ ₆ haloalkoxy, and amino.

In some embodiments:

Ar is

R ¹ is C 1-6 alkyl;

R ^A is H;

R ² is -(Ci_6 alkyl), -0-(Ci_ ₆ alkyl), -0-(Ci_4 alkylene) _n -Cy ² , or -Cy ² ; wherein Ci_ ₆ alkyl is optionally substituted by 1 , 2, 3, or 4 independently selected R ^2a groups;

Cy ² is selected from C ₃ _ ₇ cycloalkyl, 4-7 membered heterocycloalkyl, phenyl, and 5-6 membered heteroaryl; each of which is optionally substituted with 1 , 2, 3, or 4 independently selected R ^2a groups;

R ³ is CN, N0 ₂ , Cy ³ , C(0)NR ^c R ^d , NR ^f C(0)OR ^b , NR ^f S(0) ₂ R ^b , and NR ^c C(0)R ^b ; Cy ³ is selected from C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, phenyl, and 5-6 membered heteroaryl; each of which is optionally substituted with 1, 2, 3, or 4 independently selected R ^3a groups;

R ⁴ is selected from H, halo, Ci_ ₆ alkyl, cyano- Ci_ ₆ alkyl, and Ci_ ₆ haloalkyl; and

R ⁵ is halo.

In some embodiments:

Ar is

R ¹ is C 1-6 alkyl;

R ^A is H;

R ² is -(Ci_6 alkyl), -0-(Ci_ ₆ alkyl), -0-(Ci_4 alkylene) _n -Cy ² , or -Cy ² ; wherein Ci_ ₆ alkyl is optionally substituted by 1, 2, 3, or 4 independently selected R ^2a groups;

Cy ² is selected from C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, phenyl, and 5-6 membered heteroaryl; each of which is optionally substituted with 1, 2, 3, or 4 independently selected R ^2a groups;

R ³ is CN, N0 ₂ , Cy ³ , C(0)NR ^c R ^d , NR ^f C(0)OR ^b , NR ^f S(0) ₂ R ^b , and NR ^c C(0)R ^b ;

Cy ³ is selected from C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, phenyl, and 5-6 membered heteroaryl; each of which is optionally substituted with 1, 2, 3, or 4 independently selected R ^3a groups;

R ⁴ is selected from H, Ci_ ₆ alkyl, cyano- Ci_ ₆ alkyl, and Ci_ ₆ haloalkyl; and

R ⁵ is halo;

each R ^2a is independently selected from OH, N0 ₂ , CN, halo, Ci_ ₆ alkyl, Ci_ ₆ haloalkyl, Ci_6 alkoxy, Ci_ ₆ haloalkoxy, amino, Ci_ ₆ alkylamino, and di(Ci_ ₆ alkyl)amino;

each R ^3a is independently selected from halo, CN, N0 ₂ , Ci_ ₆ alkyl, Ci_ ₆ haloalkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, OR ^a , C(0)R ^b , C(0)NR ^c R ^d , NR ^c R ^d , NR ^c C(0)R ^b , and S(0) ₂ R ^b ; wherein said Ci_ ₆ alkyl, C3-7 cycloalkyl, and 4-7 membered heterocycloalkyl are each optionally substituted by 1, 2, 3, or 4 groups independently selected from OH, CN, halo, Ci_ ₆ alkyl, Ci_ ₆ haloalkyl, cyano-Ci_ ₆ alkyl, HO-Ci_ ₆ alkyl, Ci_ ₄ alkoxy-Ci_6 alkyl, Ci_ ₆ alkoxy, Ci_ ₆ haloalkoxy, amino, Ci_ ₆ alkylamino, and di(Ci_ ₆ alkyl)amino; each R ^a , R ^c , and R ^d is independently selected from H, Ci_ ₆ alkyl, Ci_ ₆ haloalkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl; wherein said Ci_ ₆ alkyl, C ₃ _ ₇ cycloalkyl, and C ₂ _ ₇ heterocycloalkyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from OH, CN, halo, Ci_ ₆ alkyl, Ci_ ₆ haloalkyl, Ci_ ₆ alkoxy, and Ci_ ₆ haloalkoxy; and each R ^b is independently selected from Ci_ ₆ alkyl, Ci_ ₆ haloalkyl, C ₃ _ ₇ cycloalkyl, 4-7 membered heterocycloalkyl; each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from OH, CN, halo, Ci_ ₆ alkyl, Ci_ ₆ haloalkyl, Ci_ ₆ alkoxy, and Ci_6 haloalkoxy.

In some embodiments:

R ¹ is C 1-6 alkyl;

R ^A is H;

R ² is Ci_6 alkyl, -0-(Ci_ ₆ alkyl), -0-(Ci_ ₄ alkylene) _n -(4-7 membered heterocycloalkyl), or phenyl; wherein said phenyl is optionally substituted by 1, 2, 3, or 4 independently selected R ^2a groups;

Cy ² is selected from C ₃ _ ₇ cycloalkyl, 4-7 membered heterocycloalkyl, phenyl, and 5-6 membered heteroaryl; each of which is optionally substituted with 1, 2, 3, or 4 independently selected R ^2a groups;

R ³ is CN, N0 ₂ , Cy ³ , C(0)NR ^c R ^d , NR ^f C(0)OR ^b , NR ^f S(0) ₂ R ^b , and NR ^c C(0)R ^b ;

Cy ³ is selected from C ₃ _ ₇ cycloalkyl, 4-7 membered heterocycloalkyl, phenyl, and 5-6 membered heteroaryl; each of which is optionally substituted with 1, 2, 3, or 4 independently selected R ^3a groups;

R ⁴ is selected from Ci_ ₆ alkyl, cyano- Ci_ ₆ alkyl, and Ci_ ₆ haloalkyl; and

R ⁵ is halo;

each R ^2a is independently selected from OH, N0 ₂ , CN, halo, Ci_ ₆ alkyl, Ci_ ₆ haloalkyl,

Ci_6 alkoxy, Ci_ ₆ haloalkoxy, amino, Ci_ ₆ alkylamino, and di(Ci_ ₆ alkyl)amino;

each R ^3a is independently selected from halo, CN, N0 ₂ , Ci_ ₆ alkyl, Ci_ ₆ haloalkyl, C ₃ _ ₇ cycloalkyl, 4-7 membered heterocycloalkyl, OR ^a , C(0)R ^b , C(0)NR ^c R ^d , NR ^c R ^d , NR ^c C(0)R ^b , and S(0) ₂ R ^b ; wherein said Ci_ ₆ alkyl, C ₃ _ ₇ cycloalkyl, and 4-7 membered heterocycloalkyl are each optionally substituted by 1, 2, 3, or 4 groups independently selected from OH, CN, halo, Ci_ ₆ alkyl, Ci_ ₆ haloalkyl, cyano-Ci_ ₆ alkyl, HO-Ci_ ₆ alkyl, Ci_ ₄ alkoxy-Ci_ ₆ alkyl, Ci_ ₆ alkoxy, Ci_ ₆ haloalkoxy, amino, Ci_ ₆ alkylamino, and di(Ci_ ₆ alkyl)amino;

each R ^a , R ^c , and R ^d is independently selected from H, Ci_ ₆ alkyl, Ci_ ₆ haloalkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl; wherein said Ci_ ₆ alkyl, C3-7 cycloalkyl, and C2-7 heterocycloalkyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from OH, CN, halo, Ci_ ₆ alkyl, Ci_ ₆ haloalkyl, Ci_ ₆ alkoxy, and Ci_ ₆ haloalkoxy; and each R ^b is independently selected from Ci_ ₆ alkyl, Ci_ ₆ haloalkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl; each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from OH, CN, halo, Ci_ ₆ alkyl, Ci_ ₆ haloalkyl, Ci_ ₆ alkoxy, and Ci_6 haloalkoxy.

In some embodiments:

R ¹ is methyl or ethyl;

R ^A is H;

R ² is selected from Ci_ ₆ alkyl, -0-(Ci_ ₆ alkyl), -0-(Ci_ ₄ alkylene) _n -(4-7 membered heterocycloalkyl), and phenyl; wherein said phenyl is optionally substituted by 1, 2, 3, or 4 independently selected halo groups;

R ³ is selected from CN, N0 ₂ , Cy ³ , C(0)NR ^c R ^d , NR ^f C(0)OR ^b , NR ^f S(0) ₂ R ^b , and

NR ^c C(0)R ^b ;

Cy ³ is selected from phenyl, a piperidine ring, a pyrrolidon-2-one ring, a 1,3-oxazolidin- 2-one ring, an isoxazole ring, a pyrazole ring, a tetrazole ring, a triazole ring, a pyridine ring, a pyrimidine ring, an azetidine ring, a pyrrole ring, a tetrahydrofuran ring, and a morpholin-2-one ring; each of which is optionally substituted with 1, 2, 3, or 4 independently selected R ^3a groups;

R ⁴ is selected from H, halo, Ci_ ₃ alkyl, CN, cyano-Ci_ ₆ alkyl, and Ci_ ₆ haloalkyl;

R ⁵ is selected from Ci_ ₃ alkyl, halo, and CN;

each R ^3a is independently selected from halo, CN, N0 ₂ , Ci_ ₆ alkyl, Ci_ ₆ haloalkyl, C ₃ _7 cycloalkyl, 4-7 membered heterocycloalkyl, (4-7 membered heterocycloalkyl)-Ci_ ₃ alkyl, (5-6 membered heteroaryl)-Ci_ ₃ alkyl, OR ^a , C(0)R ^b , C(0)OR ^a , C(0)NR ^c R ^d , NR ^c R ^d , NR ^c C(0)R ^b , and S(0) ₂ R ^b ; wherein said Ci_ ₆ alkyl, C3-7 cycloalkyl, and 4-7 membered heterocycloalkyl are each optionally substituted by 1, 2, 3, or 4 groups independently selected from OH, CN, halo, Ci_ ₆ alkyl, Ci_ ₆ haloalkyl, cyano-Ci_ ₆ alkyl, HO-Ci_ ₆ alkyl, Ci_ ₄ alkoxy-Ci_6 alkyl, Ci_ ₆ alkoxy, Ci_ ₆ haloalkoxy, amino, Ci_ ₆ alkylamino, di(Ci_ ₆ alkyl)amino, and C3_ ₇ cycloalkyl;

each R ^a , R ^c , and R ^d is independently selected from H, Ci_ ₆ alkyl, Ci_ ₆ haloalkyl, C ₃ _ ₇ cycloalkyl, 4-7 membered heterocycloalkyl; wherein said Ci_ ₆ alkyl, C ₃ _ ₇ cycloalkyl, and C ₂ _ ₇ heterocycloalkyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from OH, CN, halo, Ci_ ₆ alkyl, Ci_ ₆ haloalkyl, Ci_ ₆ alkoxy, Ci_ ₆ haloalkoxy, and amino each R ^b is independently selected from Ci_ ₆ alkyl, Ci_ ₆ haloalkyl, C ₃ _ ₇ cycloalkyl, 4-7 membered heterocycloalkyl; each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from OH, CN, halo, Ci_ ₆ alkyl, Ci_ ₆ haloalkyl, Ci_ ₆ alkoxy, Ci_6 haloalkoxy, and amino; and

each R is independently selected from Ci_ ₄ alkylcarbonyl and Ci_ ₄ alkoxy carbonyl.

In some embodiments, the compound is a compound of Formula II:

II

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is a compound of Formula Ila:

Ila

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is a compound of Formula III or IV:

III IV

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is a compound of Formula V or VI:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is a compound of Formula VII or VIII:

VII VIII

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is a compound of Formula III or IV:

Ilia IVa

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is a compound of Formula IXa, Formula IXb, Formula IXc, Formula IXd, Formula IXe, or Formula IXf:

IXd IXe IXf or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is selected from:

4-Chloro-3'-fluoro-3-methyl-6-[l-(9H-purin-6-ylamino)ethyl]b iphenyl-2-carbonitrile; 4-Chloro-3'-fluoro-3-methyl-6-[l-(9H-purin-6-ylamino)ethyl]b iphenyl-2-carboxamide; N- [ 1 -(4-chloro-3 '-fluoro-5 -methyl-6-nitrobiphenyl-2-yl)ethyl]-9H-purin-6-amine;

4-Chloro-3-(cyanomethyl)-3'-fluoro-6-[l-(9H-purin-6-ylamino) ethyl]biphenyl-2- carbonitrile;

1 - {4-Chloro-3'-fluoro-3-methyl-6-[ 1 -(9H-purin-6-ylamino)ethyl]biphenyl-2- yl}pyrrolidin-2-one;

l-{4-Chloro-3',5'-difluoro-3-methyl-6-[l-(9H-purin-6-ylamino )ethyl]biphenyl-2- yl}pyrrolidin-2-one;

3- {4-Chloro-3'-fluoro-3-methyl-6-[ 1 -(9H-purin-6-ylamino)ethyl]biphenyl-2-yl} - 1 ,3- oxazolidin-2-one;

N- { 1 - [4-chloro-3 '-fluoro-5 -methyl-6-( lH-tetrazol-5 -yl)biphenyl-2-yl] ethyl} -9H-purin-6- amine;

N- {4-chloro-3'-fluoro-3-methyl-6-[ 1 -(9H-purin-6-ylamino)ethyl]biphenyl-2- yl}acetamide;

Dimethyl {4-chloro-3'-fluoro-3-methyl-6-[ 1 -(9H-purin-6-ylamino)ethyl]biphenyl-2- yl} imidodicarbonate;

N- { 1 -[4-chloro-3 '-fluoro-5 -methyl-6-(4H-l ,2,4-triazol-4-yl)biphenyl-2-yl]ethyl} -9H- purin-6-amine; N- {4-chloro-3'-fluoro-3-methyl-6-[ 1 -(9H-purin-6-ylamino)ethyl]biphenyl-2-yl} -N- (methylsulfonyl)methanesulfonamide;

N- { 1 -[4-chloro-6-(2,6-difluoropyridin-4-yl)-5-methylbiphenyl-2-y l]ethyl} -9H-purin-6- amine;

l-{3-Chloro-6-methoxy-2-methyl-5-[l-(9H-purin-6-ylamino)ethy l]phenyl}pyrrolidm^ one;

4-Chloro-3\5'-difluoro-3-methyl-6-[l-(9H-purin-6-ylamino)eth yl]biphenyl-2- carboxamide;

N-(l-{5-chloro-3-[2-(dimethylamino)pyrimidin-5-yl]-2-methoxy -4-methylphe

9H-purin-6-amine;

l-{3-Chloro-6-methoxy-2-methyl-5-[l-(9H-purin-6-ylamino)ethy l]phenyl}piperidin-4- ol;

3'-Chloro-4-fluoro-6'-methoxy-2'-methyl-5'-[l-(9H-purin-6-yl amino)ethyl]biphenyl-3- carboxamide;

3'-Chloro-3-fluoro-6'-methoxy-2'-methyl-5'-[l-(9H-purin-6-yl amino)ethyl]biphenyl-4- carboxamide;

l-({3'-Chloro-3-fluoro-6'-methoxy-2'-methyl-5'-[l-( H-purin-6-ylamino)ethyl]biphenyl- 4-yl}carbonyl)azetidine-3-carbonitrile;

N-{l-[4-chloro-6-(3,5-dimethylisoxazol-4-yl)-3'-fluoro-5-met hylbiphenyl-2-yl]ethyl}- 9H-purin-6-amine;

N-{l-[4-Chloro-3'-fluoro-5-methyl-6-(lH-pyrazol-4-yl)bipheny l-2-yl]ethyl}-9H-purin-6- amine;

N-[l-(4-Chloro-3^5'-difluoro-5-methyl-6-pyridin-4-ylbiphenyl -2-yl)ethyl]-9H-purin-6- amine;

N-{l-[4-Chloro-3',5'-difluoro-5-methyl-6-(lH-pyrazol-4-yl)bi phenyl-2-yl]ethyl}-9H- purin-6-amine;

N- { 1 -[5-Chloro-3-(5-fluoropyridin-3-yl)-2-methoxy-4-methylphenyl ]ethyl} -9H-purin-6- amine;

N- { 1 -[5-Chloro-2-methoxy-3-(5-methoxypyridin-3-yl)-4-methylpheny l]ethyl} -9H-purin- 6-amine;

(4- {3-Chloro-6-methoxy-2-methyl-5-[l -(9H-purin-6-ylamino)ethyl]phenyl} - lH-pyrazol- l-yl)acetonitrile;

N- { 1 -[5 -chloro-2-methoxy-4-methyl-3-(l -methyl- 1 H-pyrazol-5 -yl)phenyl]ethyl} -9H- purin-6-amine;

N-{l-[5-chloro-3-(3,5-dimethylisoxazol-4-yl)-2-methoxy-4-met hylphenyl]ethyl}-9H- purin-6-amine;

N- { 1 -[5-chloro-2-methoxy-3-(2-methoxypyrimidin-5-yl)-4-methylphe nyl]ethyl} -9H- purin-6-amine;

N- {3'-chloro-6'-methoxy-2'-methyl-5'-[ 1 -(9H-purin-6-ylamino)ethyl]biphenyl-4- yl}acetamide;

N-[l-(5-chloro-3'-fluoro-2-methoxy-6-methylbiphenyl-3-yl)eth yl]-9H-purin-6-amine; N-[l-(5-chloro-3',5'-difluoro-2-methoxy-6-methylbiphenyl-3-y l)ethyl]-9H-purin-6- amine;

3'-chloro-6'-methoxy-2'-methyl-5'-[l-(9H-purin-6-ylamino)eth yl]biphenyl-4-carbonitrile;

3'-chloro-N-cyclopropyl-6'-methoxy-2'-methyl-5'-[l-(9H-pu rin-6- ylamino)ethyl]biphenyl-4-carboxamide;

N- { 1 -[5-chloro-2-methoxy-6-methyl-4'-(methylsulfonyl)biphenyl-3- yl]ethyl} -9H-purin- 6-amine;

N- { 1 -[3-(2-aminopyrimidin-5-yl)-5-chloro-2-methoxy-4-methylpheny l]ethyl} -9H-purin- 6-amine;

N- { 1 -[5-chloro-2-methoxy-3-(5-methoxypyridin-3-yl)-4-methylpheny l]ethyl} -9H-purin- 6-amine;

N-[l-(3',5-dichloro-2-methoxy-6-methylbiphenyl-3-yl)ethyl]-9 H-purin-6-amine;

N- { 1 -[5-chloro-3-(5-chloropyridin-3-yl)-2-methoxy-4-methylphenyl ]ethyl} -9H-purin-6- amine;

3,3'-dichloro-6'-methoxy-N,2'-dimethyl-5'-[l-(9H-purin-6-yla mino)ethyl]biphenyl-4- carboxamide;

N- { 1 -[5-chloro-2-methoxy-6-methyl-4'-(trifluoromethyl)biphenyl-3 -yl]ethyl} -9H-purin- 6-amine;

N-[l-(5-chloro-4'-ethoxy-3'-fluoro-2-methoxy-6-methylbipheny l-3-yl)ethyl]-9H-purin-6- amine;

3'-chloro-6'-methoxy-2'-methyl-5'-[l-(9H-purin-6-ylamino)eth yl]biphenyl-3-carbonitrile; {3'-chloro-6'-methoxy-2'-methyl-5'-[l-(9H-purin-6-ylamino)et hyl]biphenyl-4- yl}acetonitrile;

N- { 1 -[5-chloro-2-methoxy-4'-(methoxymethyl)-6-methylbiphenyl-3-y l]ethyl} -9H-purin- 6-amine;

N-{l-[5-chloro-2-methoxy-6-methyl-4'-(lH-pyrazol-l-yl)biphen yl-3-yl]ethyl}-9H-purin^ 6-amine;

N- { 1 -[5-chloro-2-methoxy-3'-(methoxymethyl)-6-methylbiphenyl-3-y l]ethyl} -9H-purin- 6-amine;

N-( 1 - {5 -chloro-2-methoxy-4-methyl-3 - [6-(tetrahydro-2H-pyran-4-yloxy)pyridin-3 - yl]phenyl}ethyl)-9H-purin-6-amine;

{3'-chloro-6'-methoxy-2'-methyl-5'-[l-(9H-purin-6-ylamino)et hyl]biphenyl-3- yl}acetonitrile;

N-[l-(3\5,5'-trichloro-2-methoxy-6-meth^^

N- { 1 -[5-chloro-2-methoxy-4-methyl-3-(6-morpholin-4-ylpyridin-3-y l)phenyl]ethyl} -9H- purin-6-amine;

N- { 1 -[5-chloro-3-(3-fluoro-2-morpholin-4-ylpyridin-4-yl)-2-metho xy-4- methylphenyl]ethyl}-9H-purin-6-amine;

N-[l-(5-chloro-2',5'-difluoro-2-methoxy-6-methylbiphenyl-3-y l)ethyl]-9H-purin-6^ amine;

N- { 1 -[5-chloro-3-(6-fluoropyridin-3-yl)-2-methoxy-4-methylphenyl ]ethyl} -9H-purin-6- amine;

N- { 1 -[5-chloro-2-methoxy-3-(6-methoxypyridin-3-yl)-4-methylpheny l]ethyl} -9H-purin- 6-amine;

5 - {3 -chloro-6-methoxy-2-methy 1-5 - [ 1 -(9H-purin-6-ylamino)ethyl]phenyl} nicotinonitrile; 3-(4- {3-chloro-6-methoxy-2-methyl-5-[ 1 -(9H-purin-6-ylamino)ethyl]phenyl} - 1H- pyrazol- 1 -yl)-3-(cyanomethyl)cyclobutanecarbonitrile;

N- { 1 -[5-chloro-2-methoxy-4-methyl-3-(5-methylpyridin-3-yl)phenyl ]ethyl} -9H-purin-6- amine;

N-(l - {5-chloro-2-methoxy-4-methyl-3-[5-(methylsulfonyl)pyridin-3- yl]phenyl} ethyl)- 9H-purin-6-amine; N- { 1 -[3-(6-aminopyridin-3-yl)-5-chloro-2-methoxy-4-methylphenyl] ethyl} -9H-purin-6- amine;

5 - {3 -chloro-6-methoxy-2-methy 1-5 -[ 1 -(9H-purin-6-ylamino)ethyl]phenyl} pyridine-2- carbonitrile;

N- { 1 -[5-chloro-3-(6-isopropoxypyridin-3-yl)-2-methoxy-4-methylph enyl]ethyl} -9H- purin-6-amine;

3'-chloro-N-ethyl-3-fluoro-6'-methoxy-2'-methyl-5'-[l-(9H-pu rin-6- ylamino)ethyl]biphenyl-4-carboxamide;

3'-chloro-3-fluoro-6'-methoxy-N,N,2'-trimethyl-5'-[l-(9H-pur in-6- ylamino)ethyl]biphenyl-4-carboxamide;

N- { 1 -[5-chloro-3'-fluoro-2-methoxy-6-methyl-4'-(pyrrolidin- 1 -ylcarbonyl)biphenyl-3- yl]ethyl} -9H-purin-6-amine;

N- { 1 -[5-chloro-3'-fluoro-2-methoxy-6-methyl-4'-(morpholin-4-ylca rbonyl)biphenyl-3- yl]ethyl} -9H-purin-6-amine;

3'-chloro-3-fluoro-6'-methoxy-N,2'-dimethyl-5'-[l-(9H-purin- 6-ylamino)ethyl]bi^ 4-carboxamide;

l-({3'-chloro-3-fluoro-6'-methoxy-2'-methyl-5'-[l-(9H-purin- 6-ylamino)ethyl]biph^ 4-yl} carbonyl)piperidin-4-ol;

3'-chloro-N-cyclobutyl-3-fluoro-6'-methoxy-2'-methyl-5'-[l-( 9H-purin-6- ylamino)ethyl]biphenyl-4-carboxamide;

N- { 1 -[5-chloro-3-(2-fluoropyridin-4-yl)-2-methoxy-4-methylphenyl ]ethyl} -9H-purin-6- amine;

N-[l-(3^5-dichloro-5'-fluoro-2-methoxy-6-methylbiphenyl-3-yl )ethyl]-9H-purin-6- amine;

N- { 1 -[5-chloro-2'-fluoro-2-methoxy-6-methyl-5'-(trifluoromethyl) biphenyl-3-yl]eth -

9H-purin-6-amine;

N- { 1 -[5-chloro-3-(6-fluoro-5-methylpyridin-3-yl)-2-methoxy-4-met hylphenyl]ethyl} - 9H-purin-6-amine;

N-[l-(5-chloro-2-methoxy-6-methyl-4'-morpholin-4-ylbiphenyl- 3-yl)ethyl]-9H-purm amine; N-[l-(3^5-dichloro-4'-fluoro-2-methoxy-6-m

amine;

N- { 1 -[5-chloro-2-methoxy-6-methyl-4'-(trifluoromethoxy)biphenyl- 3-yl]ethyl} -9H- purin-6-amine;

N-[l-(5-chloro-3'-ethoxy-2-methoxy-6-methylbiphenyl-3-yl)eth yl]-9H-purin-6-amine; N-[l-(4',5-dichloro-3'-fluoro-2-methoxy-6-methylbiphenyl-3-y l)ethyl]-9H-purin-6- amine;

N- { 1 -[5-chloro-4'-fluoro-2-methoxy-6-methyl-3'-(trifluoromethyl) biphenyl-3-yl]ethyl} - 9H-purin-6-amine;

3'-chloro-4-fluoro-6'-methoxy-N,N,2'-trimethyl-5'-[l-(9H-pur in-6- ylamino)ethyl]biphenyl-3-carboxamide;

N-[l-(5-chloro-4'-fluoro-2,3'-dimethoxy-6-methylbiphenyl-3-y l)ethyl]-9H-purin-6- amine;

N-[l-(5-chloro-2,3\4'-trimethoxy-6-methylbiphenyl-3-yl)ethyl ]-9H-purin-6-amine; N-[l-(3^5-dichloro-2,4'-dimethoxy-6-methylbiphenyl-3-yl)ethy l]-9H-purin-6-amine; N- { 1 -[5-chloro-3-(2-chloropyridin-4-yl)-2-methoxy-4-methylphenyl ]ethyl} -9H-purin-6- amine;

N-[l-(4',5-dichloro-2-methoxy-6-methylbiphenyl-3-yl)ethyl]-9 H-purin-6-amine;

N- { 1 - [5 -chloro-3 '-(dimethylamino)-2-methoxy-6-methylbiphenyl-3 -yl] ethyl} -9H-purin- 6-amine;

N-[l-(5-chloro-2,4'-dimethoxy-6-methylbiphenyl-3-yl)ethyl]-9 H-purin-6-amine;

N-[l-(5-chloro-2,4'-dimethoxy-3^6-dimethylbiphenyl-3-yl)ethy l]-9H-purin-6-amine; N-[l-(5-chloro-2,3'-dimethoxy-6-methylbiphenyl-3-yl)ethyl]-9 H-purin-6-amine;

N-{3'-chloro-6'-methoxy-2'-methyl-5'-[l-(9H-purin-6-ylamino) ethyl]biphenyl-3- yl}acetamide;

N-[l-(5-chloro-3^4'-difluoro-2-methoxy-6-methylbiphenyl-3-yl )ethyl]-9H-purin-6- amine;

N- { 1 -[5-chloro-3-(5-fluoro-6-methoxypyridin-3-yl)-2-methoxy-4-me thylphenyl]ethyl} - 9H-purin-6-amine;

3'-chloro-5-fluoro-6'-methoxy-2'-methyl-5'-[l-(9H-purin-6-yl amino)ethyl]biphenyl-3- carboxamide; N-(l-{5-chloro-2-methoxy-4-methyl-3-[5-(morpholin-4-ylcarbon yl)pyridin-3- yl]phenyl}ethyl)-9H-purin-6-amine;

N-(5-{3-chloro-6-methoxy-2-methyl-^

yl)acetamide;

5 - {3 -chloro-6-methoxy-2-methy 1-5 - [ 1 -(9H-purin-6-ylamino)ethyl]phenyl} nicotinonitrile; N- { 1 -[3-(2-aminopyrimidin-5-yl)-5-chloro-2-methoxy-4-methylpheny l]ethyl} -9H-purin- 6-amine;

N- { 1 -[5-chloro-2-methoxy-6-methyl-4'-(methylsulfonyl)biphenyl-3- yl]ethyl} -9H-purin- 6-amine;

N- { 1 -[5'-chloro-6'-methyl-4-(methylsulfonyl)-l , Γ:2', 1 ^M -terphenyl-3'-yl]ethyl} -9H-purin- 6-amine;

N-(l-{4-chloro-6-[2-(dimethylamino)pyrimidin-5-yl]-5-methylb iphenyl-2-yl^

purin-6-amine;

5'-chloro-N-cyclopropyl-6'-methyl-3'-[ 1 -(9H-purin-6-ylamino)ethyl]- 1 , Γ:2', 1 "-terphenyl- 4-carboxamide;

N- { 1 -[6-(2-aminopyrimidin-5-yl)-4-chloro-5-methylbiphenyl-2-yl]e thyl} -9H-purin-6- amine;

5'-chloro-6'-methyl-3'-[ 1 -(9H-purin-6-ylamino)ethyl]-l , Γ:2', 1 "-terphenyl-4-carbonitrile; N- { 1 -[4-chloro-6-(2-methoxypyrimidin-5-yl)-5-methylbiphenyl-2-yl ]ethyl} -9H-purin-6- amine;

N- {5'-chloro-6'-methyl-3'-[ 1 -(9H-purin-6-ylamino)ethyl]- 1 , Γ:2', 1 "-terphenyl-4- yl}acetamide;

N-{l-[4-chloro-3'-fluoro-5-methyl-6-(l-methyl-lH-pyrazol-4-y l)biphenyl-2-yl]ethyl}- 9H-purin-6-amine;

N-{l-[4-chloro-3'-fluoro-5-methyl-6-(l-methyl-lH-pyrazol-5-y l)biphenyl-2-yl]ethyl}- 9H-purin-6-amine;

N-{l-[4-chloro-3'-fluoro-5-methyl-6-(l,3,5-trimethyl-lH-pyra zol-4-yl)biphenyl-2- yl]ethyl} -9H-purin-6-amine;

N-{l-[4-chloro-6-(3,5-dimethylisoxazol-4-yl)-3',5'-difluoro- 5-methylbiphenyl-2- yl]ethyl} -9H-purin-6-amine; N-[l-(4-chloro-3 5'-difluoro-5-methyl-6-pyridin-3-ylbiphenyl-2-yl)ethyl]-9H-p urin-6- amine;

5'-chloro-3",5"-difluoro-6'-methyl-3'-[ 1 -(9H-purin-6-ylamino)ethyl]- 1 , Γ:2', 1 "-terphenyl- 4-carbonitrile;

N- { 1 -[4-chloro-6-(2,6-difluoropyridin-4-yl)-3^5'-difluoro-5-meth ylbiphenyl-2-yl]ethy - 9H-purin-6-amine;

N-[l-(4-chloro-3^5'-difluoro-5-methyl-6-pyrimidin-5-ylbiphen yl-2-yl)ethyl]-9H amine;

N- { 1 -[4-chloro-3^5'-difluoro-6-(2-methoxypyrimidin-5-yl)-5-methy lbiphenyl-2- yl]ethyl} -9H-purin-6-amine;

N-{5'-chloro-3'^5"-difluoro-6'-methyl-3'-[l-(9H-purin-6-ylam ino)ethyl]-l, :2', '- terphenyl-4-yl} acetamide;

N-{l-[4-chloro-6-(3,5-dimethyl-lH-pyrazol-4-yl)-3',5'-difluo ro-5-methylbiphenyl-2- yl]ethyl} -9H-purin-6-amine;

N- { 1 - [5 -fluoro-2-methoxy-6-methyl-4 ' -(methylsulfonyl)biphenyl-3 -yl] ethyl} -9H-purin- 6-amine;

N- [ 1 -(3 ' -ethoxy-5 -fluoro-2-methoxy-6-methylbiphenyl-3 -yl)ethyl] -9H-purin-6-amine;

N-cyclopropyl-3 ' -fluoro-6 ' -methoxy-2 ' -methyl-5 ' - [ 1 -(9H-purin-6- ylamino)ethyl]biphenyl-4-carboxamide;

N- { 1 -[5 -fluoro-2-methoxy-4-methyl-3-(l -methyl- lH-pyrazol-4-yl)phenyl] ethyl} -9H- purin-6-amine;

N- { 1 - [5 -fluoro-2-methoxy-4-methyl-3 -( 1 -methyl- 1 H-pyrazol-5 -yl)phenyl] ethyl} -9H- purin-6-amine;

N- { 1 -[3-(2-aminopyrimidin-5- yl)-5-fluoro-2-methoxy-4-methylphenyl]ethyl} -9H-purin- 6-amine;

N-{l-[4-Chloro-3 ^* ,5 ^* -difluoro-6-(lH-pyrazol-4-yl)biphenyl-2-yl]ethyl}-9H-p urin-6- amine;

N- { 1 -[5-Chloro-3-(5-chloropyridin-3-yl)-2-methoxyphenyl]ethyl} -9H-purin-6-amine; N- { 1 -[5-Chloro-4-methyl-2-(2-morpholin-4-ylethoxy)-3-pyridin-4-y lphenyl]ethyl} -9H- purin-6-amine;

N-[l-(5-Chloro-2,4-dimethyl-3-pyridin-4-ylphenyl)ethyl]-9H-p urin-6-amine; N- { 1 -[5-Chloro-6-methyl-4'-(methylsulfonyl)-2-(2-morpholin-4-yle thoxy)biphenyl-3- yl]ethyl} -9H-purin-6-amine;

N- { 1 -[4-chloro-3^5'-difluoro-6-(2-methoxypyrimidin-5-yl)biphenyl -2-yl]ethyl} -9H- purin-6-amine;

N- {5'-chloro-3",5"-difluoro-3'-[ 1 -(9H-purin-6-ylamino)ethyl]-l , 1 ^* :2 ^* , l"-terphenyl-4- yl}acetamide;

N-[l-(4-chloro-3^5'-difluoro-6-pyridin-4-ylbiphenyl-2-yl)eth yl]-9H-purin-6-amine; N-[l-(4-chloro-3^5'-difluoro-6-pyrimidin-5-ylbiphenyl-2-yl)e thyl]-9H-purin-6-am N- { 1 -[4-chloro-6-(2,6-difluoropyridin-4-yl)-3',5'-difluorobiphen yl-2-yl]ethyl} -9H-purin- 6-amine;

N- { 1 -[5 ^* -chloro-3",5"-difluoro-4-(methylsulfonyl)- 1 , Γ:2', 1 ^M -terphenyl-3 ^* -yl]ethyl} -9H- purin-6-amine;

N- { 1 -[6-(2-aminopyrimidin-5-yl)-4-chloro-3',5'-difluorobiphenyl- 2-yl]ethyl} -9H-purin- 6-amine;

N- { 1 -[5-chloro-2-methoxy-3-(2-methoxypyrimidin-5-yl)phenyl]ethyl } -9H-purin-6- amine;

N-{5'-chloro-2'-methoxy-3'-[l-(9H-purin-6-ylamino)ethyl]biph enyl-4-yl}acetamide; N- { 1 -[5 -chloro-2-methoxy-3-(l -methyl- lH-pyrazol-5-yl)phenyl] ethyl} -9H-purin-6- amine;

N- [ 1 -(5 -chloro-2-methoxy-3 -pyridin-4-ylphenyl)ethyl] -9H-purin-6-amine;

N- [ 1 -(5 -chloro-2-methoxy-3 -pyrimidin-5 -ylphenyl)ethyl] -9H-purin-6-amine;

N- { 1 -[5-chloro-3-(2,6-difluoropyridin-4-yl)-2-methoxyphenyl]ethy l} -9H-purin-6-amine; N- { 1 -[5-chloro-2-methoxy-4'-(methylsulfonyl)biphenyl-3-yl]ethyl} -9H-purin-6-amine; N- { 1 -[3-(2-aminopyrimidin-5-yl)-5-chloro-2-methoxyphenyl]ethyl} -9H-purin-6-amine; 3,5'-dichloro-2'-methoxy-N-methyl-3'-[l-(9H-purin-6-ylamino) ethyl]biphenyl-4- carboxamide;

N- { 1 -[5-chloro-3-(2-fluoropyridin-4-yl)-2-methoxyphenyl]ethyl} -9H-purin-6-amine; N- { 1 -[5-chloro-2-methoxy-3-(5-methoxypyridin-3-yl)phenyl]ethyl} -9H-purin-6-amine; N- { 1 -[5-chloro-3-(6-fluoropyridin-3-yl)-2-methoxyphenyl]ethyl} -9H-purin-6-amine; N- { 1 -[5-chloro-2-methoxy-3-(6-methoxypyridin-3-yl)phenyl]ethyl} -9H-purin-6-amine; N- { 1 -[3-(2-aminopyrimidin-5-yl)-5-chloro-4-methyl-2-(2-morpholin -4- ylethoxy)phenyl]ethyl}-9H-purin-6-amine;

N- { 1 -[5-chloro-3'-methoxy-6-methyl-2-(2-morpholin-4-ylethoxy)bip henyl-3-yl]ethyl} - 9H-purin-6-amine;

N- { 1 -[5-chloro-3-(5-chloropyridin-3-yl)-4-methyl-2-(2-morpholin- 4- ylethoxy)phenyl]ethyl}-9H-purin-6-amine;

N-{l-[5-chloro-4-methyl-3-(l -methyl- 1 H-pyrazol-5-yl)-2-(2 -morpholin-4- ylethoxy)phenyl]ethyl}-9H-purin-6-amine;

N- { 1 -[5-chloro-3^4'-dimethoxy-6-methyl-2-(2-morpholin-4-ylethoxy )biphenyl-3- yl]ethyl}-9H-purin-6-amine;

3,3'-dichloro-N,2'-dimethyl-6'-(2-morpholin-4-ylethoxy)-5'-[ l-(9H-purin-6- ylamino)ethyl]biphenyl-4-carboxamide;

N- { 1 -[5-chloro-4-methyl-3-[5-(morpholin-4-ylcarbonyl)pyridin-3-y l]-2-(2-morpho ylethoxy)phenyl]ethyl}-9H-purin-6-amine;

N- { 1 -[5-chloro-4-methyl-3-[5-(methylsulfonyl)pyridin-3-yl]-2-(2- morpholin-4- ylethoxy)phenyl]ethyl}-9H-purin-6-amine;

N- { 1 -[5-chloro-3-(5-methoxypyridin-3-yl)-4-methyl-2-(2-morpholin -4- ylethoxy)phenyl]ethyl}-9H-purin-6-amine;

N-(5- {3-chloro-2-methyl-6-(2-morpholin-4-ylethoxy)-5-[ 1 -(9H-purin-6- ylamino)ethyl]phenyl}pyridin-2-yl)acetamide;

3'-chloro-5-fluoro-2'-methyl-6'-(2-morpholin-4-ylethoxy)-5'- [l-(9H-purin-6- ylamino)ethyl]biphenyl-3-carboxamide;

N- { 1 -[5-chloro-3-(5-fluoro-6-methoxypyridin-3-yl)-4-methyl-2-(2- morpholin-4- ylethoxy)phenyl]ethyl}-9H-purin-6-amine;

N-{l-[5-chloro-3-(2-methoxypyrimidin-5-yl)-4-methyl-2-(2-mor pholin-4- ylethoxy)phenyl] ethyl} -9H-purin-6-amine; and

N- { 1 -[5-chloro-3-(5-fluoropyridin-3-yl)-4-methyl-2-(2-morpholin- 4- ylethoxy)phenyl]ethyl}-9H-purin-6-amine;

1. or a pharmaceutically acceptable salt of any of the aforementioned.

In some embodiment, the compound is selected from:

N- [ 1 -(5 -chloro-2-methoxy-4-methyl-3 -pyridazin-4-ylphenyl)ethyl] -9H-purin-6-amine; N- { 1 -[5-chloro-2-methoxy-4-methyl-3-(l ,3-thiazol-4-yl)phenyl]ethyl} -9H-purin-6- amine;

N- [ 1 -(3 -azetidin-3 -yl-5 -chloro-2-methoxy-4-methylphenyl)ethyl] -9H-purin-6-amine; N- { 1 -[3-(l -acetylazetidin-3-yl)-5-chloro-2-methoxy-4-methylphenyl]ethy l} -9H-purin-6- amine;

methyl 3- {3-chloro-6-methoxy-2-methyl-5-[ 1 -(9H-purin-6- ylamino)ethyl]phenyl} azetidine- 1 -carboxylate;

3- {3-chloro-6-methoxy-2-methyl-5-[ 1 -(9H-purin-6-ylamino)ethyl]phenyl} -N- methylazetidine- 1 -carboxamide;

N-( 1 - {5 -chloro-2-methoxy-4-methyl-3 - [ 1 -(methylsulfonyl)azetidin-3 -yl]phenyl} ethyl)-

9H-purin-6-amine;

N- { 1 -[5-chloro-3-(l -isopropylazetidin-3-yl)-2-methoxy-4-methylphenyl] ethyl} -9H- purin-6-amine;

N- { 1 - [5 -chloro-2-methoxy-4-methyl-3 -( 1 -methylazetidin-3 -yl)phenyl] ethyl} -9H-purin-6- amine;

N- { 1 -[5-chloro-4-fluoro-3-(l -isopropylazetidin-3-yl)-2-methoxyphenyl]ethyl} -9H-purin- 6-amine;

N- { 1 -[5-chloro-2-ethoxy-4-methyl-3-(l -methylazetidin-3-yl)phenyl]ethyl} -9H-purin-6- amine;

N- { 1 -[5-chloro-2-methoxy-4-methyl-3-(l -piperidin-4-yl- lH-pyrazol-4-yl)phenyl]ethyl} -

9H-purin-6-amine;

4- {3-chloro-6-methoxy-2-methyl-5-[ 1 -(9H-purin-6-ylamino)ethyl]phenyl} -N, 1 -dimethyl- lH-pyrrole-2-carboxamide;

N- { 1 -[5-chloro-2-methoxy-4-methyl-3-(l -methylpiperidin-4-yl)phenyl]ethyl} -9H-purin- 6-amine;

6- {3-chloro-6-methoxy-2-methyl-5-[ 1 -(9H-purin-6-ylamino)ethyl]phenyl} -N,N- dimethylpyridine-2-carboxamide;

6- {3-chloro-6-methoxy-2-methyl-5-[ 1 -(9H-purin-6-ylamino)ethyl]phenyl} -N,N- dimethylpyridazine-4-carboxamide;

5-{3-chloro-2-cyano-6-ethoxy-5-[l-(9H-purin-6-ylamino)ethyl] phenyl}-N,N- dimethylpyridine-2-carboxamide; 6-chloro-3-ethoxy-2-[6-(l-hydroxyethyl)pyridin-3-yl]-4-[l-(9 H-purin-6- ylamino)ethyl]benzonitrile;

N- { 1 -[5-chloro-3-(5-fluoropyridin-3-yl)-2-methoxy-4-methylphenyl ]propyl} -9H-purin-6- amine;

N-( 1 - {5 -chloro-2-methoxy-4-methyl-3 - [5 -(methylsulfonyl)pyridin-3 -yl]phenyl} propyl)-

9H-purin-6-amine;

(5-{3-chloro-6-methoxy-2-methyl-5-[l-(9H-purin-6-ylamino)eth yl]phenyl}pyridm^ yl)methanol;

2- (5- {3-chloro-6-methoxy-2-methyl-5-[ 1 -(9H-purin-6-ylamino)ethyl]phenyl}pyridin-2- yl)propan-2-ol;

N-(l - {5-chloro-2-methoxy-3-[6-(l -methoxy- 1 -methylethyl)pyridin-3-yl]-4- methylphenyl}ethyl)-9H-purin-6-amine;

3- ethoxy-6-methyl-2-[5-(methylsulfonyl)pyridin-3-yl]-4-[l-(9H- purin-6- ylamino)ethyl]benzonitrile;

N-{ 1 -[5-chloro-4-fluoro-2-methoxy-3-(l ,2,3,6-tetrahydropyridin-4-yl)phenyl]ethyl} -9H- purin-6-amine hydrochloride;

N- { 1 -[5-chloro-4-fluoro-2-methoxy-3-(morpholin-4-ylmethyl)phenyl ]ethyl} -9H-purin-6- amine;

5- {3-chloro-6-methoxy-2-methyl-5-[ 1 -(9H-purin-6-ylamino)ethyl]phenyl} -3-isopropyl- l,3-oxazolidin-2-one;

1 - {3-chloro-6-methoxy-2-methyl-5-[ 1 -(9H-purin-6-ylamino)ethyl]phenyl} -2-morpholin- 4-ylethanol ;

6- {3-chloro-6-methoxy-2-methyl-5-[ 1 -(9H-purin-6-ylamino)ethyl]phenyl} -4- isopropylmorpholin-3-one ;

4- {3-chloro-6-methoxy-2-methyl-5-[ 1 -(9H-purin-6-ylamino)ethyl]phenyl}pyrrolidin-2- one;

4- {3-chloro-6-methoxy-2-methyl-5-[ 1 -(9H-purin-6-ylamino)ethyl]phenyl} -1 - methylpyrrolidin-2-one;

N- { 1 -[4,5-dichloro-3-(l -isopropylazetidin-3-yl)-2-methoxyphenyl]ethyl} -9H-purin-6- amine ;

N- { 1 -[3-(l -acetylazetidin-3-yl)-4,5-dichloro-2-methoxyphenyl]ethyl} -9H-purin-6-amine; 2-(3- {2,3-dichloro-6-methoxy-5-[ 1 -(9H-purin-6-ylamino)ethyl]phenyl} azetidin- 1 - yl)ethanol ;

N-( 1 - {4,5 -dichloro-2-methoxy-3 - [ 1 -(tetrahydrofuran-3 -yl)azetidin-3 -yl]phenyl} ethyl)- 9H-purin-6-amine;

N-(l - {4,5-dichloro-2-methoxy-3-[l -(2,2,2-trifiuoro- 1 -methylethyl)azetidin-3- yl]phenyl}ethyl)-9H-purin-6-amine;

N- { 1 -[4,5-dichloro-2-methoxy-3-(l -methylazetidin-3-yl)phenyl]ethyl} -9H-purin-6- amine;

N-(l-{4,5-dichloro-2-methoxy-3-[l-(2-methoxyethyl)azetidin-3 -yl]phenyl}ethyl)-9H- purin-6-amine;

N-(l - {4,5-dichloro-3-[ 1 -(cyclopropylmethyl)azetidin-3-yl]-2-methoxyphenyl} ethyl)-9H- purin-6-amine;

N-(l - {4,5-dichloro-2-methoxy-3-[ 1 -(tetrahydrofuran-3 -ylmethyl)azetidin-3 - yl]phenyl}ethyl)-9H-purin-6-amine;

N-(l-{4,5-dichloro-2-methoxy-3-[l-(4,4,4-trifluorobutyl)azet idin-3-yl]phenyl}ethyl)-9H- purin-6-amine;

N-(l - {4,5-dichloro-2-methoxy-3-[ 1 -(1 ,3-thiazol-4-ylmethyl)azetidin-3-yl]phenyl} ethyl)- 9H-purin-6-amine;

N-(l-{4,5-dichloro-2-methoxy-3-[l-(3,3,3-trifluoropropyl)aze tidin-3-yl]phenyl}ethyl)- 9H-purin-6-amine;

(3- {2,3-dichloro-6-methoxy-5-[ 1 -(9H-purin-6-ylamino)ethyl]phenyl} azetidin-1 - yl)acetonitrile;

N-(l-{4,5-dichloro-2-methoxy-3-[l-(2,2,2-trifluoroethyl)azet idin-3-yl]phenyl}ethyl)-9H- purin-6-amine;

2-(3- {2,3-dichloro-6-methoxy-5-[ 1 -(9H-purin-6-ylamino)ethyl]phenyl} azetidin- 1 - yl)propan-l-ol;

N- { 1 -[4,5-dichloro-3-(l -cyclobutylazetidin-3-yl)-2-methoxyphenyl]ethyl} -9H-purin-6- amine;

N-(l - {4,5-dichloro-3-[ 1 -(2,2-difluoroethyl)azetidin-3-yl]-2-methoxyphenyl} ethyl)-9H- purin-6-amine; 5 - {3 -cyano-6-ethoxy-2-fluoro-5 - [ 1 -(9H-purin-6-ylamino)ethyl]phenyl} -N,N- dimethylpyridine-2-carboxamide;

4-ethoxy-2-fluoro-3 - [5 -(methylsulfonyl)pyridin-3 -yl]-5 - [ 1 -(9H-purin-6- ylamino)ethyl]benzonitrile;

6-chloro-3-ethoxy-2-(l-ethylazetidin-3-yl)-4-[l-(9H-purin-6- ylamino)ethyl]benzonitrile; and

6-chloro-3-ethoxy-2-(l -isopropylazetidin-3-yl)-4-[ 1 -(9H-purin-6- ylamino)ethyl]benzonitrile;

or a pharmaceutically acceptable salt of any of the aforementioned.

In some embodiments for each of the aforementioned species, the compound has the (Reconfiguration at the carbon atom in Formula I to which R ¹ is attached.

In some embodiments for each of the aforementioned species, the compound has the (S)- configuration at the carbon atom in Formula I to which R ¹ is attached.

It is appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, can also be provided in combination in a single

embodiment. Conversely, various features of the invention which are, for brevity, described in the context of a single embodiment, can also be provided separately or in any suitable subcombination.

At various places in the present specification, divalent linking substituents are described. It is specifically intended that each divalent linking substituent include both the forward and backward forms of the linking substituent. For example, -NR(CR'R") _n - includes both - NR(CR'R") _n - and -(CR'R") _n NR-. Where the structure clearly requires a linking group, the Markush variables listed for that group are understood to be linking groups.

The term "n-membered" where n is an integer typically describes 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.

Throughout the definitions, the term "C _n _ _m " is refered to indicate C _1-4 , C _1-6 , and the like, wherein n and m are integers and indicate the number of carbons, wherein n-m indicates a range which includes the endpoints. As used herein, the term "C _n _ _m alkyl", employed alone or in combination with other terms, refers to a saturated hydrocarbon group that may be straight-chain or branched, having n to m carbons. In some embodiments, the alkyl group contains from 1 to 6 carbon atoms, from 1 to 4 carbon atoms, from 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-l -butyl, n-pentyl, 3- pentyl, n-hexyl, 1,2,2-trimethylpropyl, and the like.

As used herein, the term "alkylene" refers to a divalent alkyl linking group. Examples of alkylene groups include, but are not limited to, ethan-l,2-diyl, propan-l,3-diyl, propan-l,2-diyl, butan-l,4-diyl, butan-l,3-diyl, butan-l,2-diyl, 2-methyl-propan-l,3-diyl, and the like.

As used herein, "C _n _ _m alkenyl" refers to an alkyl group having one or more double carbon-carbon bonds and having n to m carbons. In some embodiments, the alkenyl moiety contains 2 to 6 or to 2 to 4 carbon atoms. Example alkenyl groups include, but are not limited to, ethenyl, n-propenyl, isopropenyl, n-butenyl, sec-butenyl, and the like.

As used herein, "C _n _ _m alkynyf'refers to an alkyl group having one or more triple carbon- carbon bonds and having n to m carbons. Example alkynyl groups include, but are not limited to, ethynyl, propyn-l-yl, propyn-2-yl, and the like. In some embodiments, the alkynyl moiety contains 2 to 6 or 2 to 4 carbon atoms.

As used herein, the term "C _n _ _m alkoxy", employed alone or in combination with other terms, refers to a group of formula -O-alkyl, wherein the alkyl group has n to m carbons.

Example 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 or 1 to 4 carbon atoms.

As used herein, the term "C _n _ _m alkylamino" refers to a group of formula -NH(alkyl), wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6 or 1 to 4 carbon atoms.

As used herein, the term "C _n _ _m alkoxycarbonyl" refers to a group of formula -C(0)0- alkyl, wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6 or 1 to 4 carbon atoms.

As used herein, the term "C _n _ _m alkylcarbonyl" refers to a group of formula -C(0)-alkyl, wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6 or 1 to 4 carbon atoms. As used herein, the term "C _n _ _m alkylcarbonylamino" refers to a group of formula

-NHC(0)-alkyl, wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6 or 1 to 4 carbon atoms.

As used herein, the term "C _n _ _m alkylsulfonylamino" refers to a group of formula

-NHS(0) ₂ -alkyl, wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6 or 1 to 4 carbon atoms.

As used herein, the term "aminosulfonyl" refers to a group of formula -S(0) ₂ NH ₂ , wherein the alkyl group has n to m carbon atoms.

As used herein, the term "C _n _ _m alkylaminosulfonyl" refers to a group of formula

-S(0) ₂ NH(alkyl), wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6 or 1 to 4 carbon atoms.

As used herein, the term "di(C _n _ _m alkyl)aminosulfonyl" refers to a group of formula -S(0) ₂ N(alkyl) ₂ , wherein each alkyl group independently has n to m carbon atoms. In some embodiments, each alkyl group has, independently, 1 to 6 or 1 to 4 carbon atoms.

As used herein, the term "aminosulfonylamino" refers to a group of formula -

NHS(0) ₂ NH ₂ .

As used herein, the term "C _n _ _m alkylaminosulfonylamino" refers to a group of formula - NHS(0) ₂ NH(alkyl), wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6 or 1 to 4 carbon atoms.

As used herein, the term "di(C _n _ _m alkyl)aminosulfonylamino" refers to a group of formula

-NHS(0) ₂ N(alkyl) ₂ , wherein each alkyl group independently has n to m carbon atoms. In some embodiments, each alkyl group has, independently, 1 to 6 or 1 to 4 carbon atoms.

As used herein, the term "aminocarbonylamino", employed alone or in combination with other terms, refers to a group of formula -NHC(0)NH ₂ .

As used herein, the term "C _n _ _m alkylaminocarbonylamino" refers to a group of formula -

NHC(0)NH(alkyl), wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6 or 1 to 4 carbon atoms.

As used herein, the term "di(C _n _ _m alkyl)aminocarbonylamino" refers to a group of formula -NHC(0)N(alkyl) ₂ , wherein each alkyl group independently has n to m carbon atoms. In some embodiments, each alkyl group has, independently, 1 to 6 or 1 to 4 carbon atoms. As used herein, the term "C _n _ _m alkylcarbamyl" refers to a group of formula -C(O)- NH(alkyl), wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6 or 1 to 4 carbon atoms.

As used herein, the term "thio" refers to a group of formula -S-H.

As used herein, the term "C _n _ _m alkylthio" refers to a group of formula -S-alkyl, wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6 or 1 to 4 carbon atoms.

As used herein, the term "C _n _ _m alkylsulfmyl" refers to a group of formula -S(0)-alkyl, wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6 or 1 to 4 carbon atoms.

As used herein, the term "C _n _ _m alkylsulfonyl" refers to a group of formula -S(0) ₂ -alkyl, wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6 or 1 to 4 carbon atoms.

As used herein, the term "amino" refers to a group of formula -NH ₂ .

As used herein, the term "carbamyl" to a group of formula -C(0)NH ₂ .

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

As used herein, the term "carboxy" refers to a group of formula -C(0)OH.

As used herein, the term "di(C _n _ _m -alkyl)amino" refers to a group of formula -N(alkyl) ₂ , wherein the two alkyl groups each has, independently, n to m carbon atoms. In some

embodiments, each alkyl group independently has 1 to 6 or 1 to 4 carbon atoms.

As used herein, the term "di(C _n _ _m -alkyl)carbamyl" refers to a group of formula - C(0)N(alkyl) ₂ , wherein the two alkyl groups each has, independently, n to m carbon atoms. In some embodiments, each alkyl group independently has 1 to 6 or 1 to 4 carbon atoms.

As used herein, "C _n _ _m haloalkoxy" refers to a group of formula -O-haloalkyl having n to m carbon atoms. An example haloalkoxy group is OCF ₃ . In some embodiments, the haloalkoxy group is fluorinated only. In some embodiments, the alkyl group has 1 to 6 or 1 to 4 carbon atoms.

As used herein, the term "C _n _ _m haloalkyl", employed alone or in combination with other terms, refers to an alkyl group having from one halogen atom to 2s+l halogen atoms which may be the same or different, where "s" is the number of carbon atoms in the alkyl group, wherein the alkyl group has n to m carbon atoms. In some embodiments, the haloalkyl group is fluorinated only. In some embodiments, the alkyl group has 1 to 6 or 1 to 4 carbon atoms.

As used herein, the term "phenyl-Ci_4 alkyl" refers to a group of formula -C _1-4 alkylene- phenyl.

As used herein, "cycloalkyl" refers to non-aromatic cyclic hydrocarbons including cyclized alkyl and/or alkenyl groups. Cycloalkyl groups can include mono- or polycyclic (e.g., having 2, 3 or 4 fused rings) groups and spirocycles. Ring-forming carbon atoms of a cycloalkyl group can be optionally substituted by oxo or sulfido. Cycloalkyl groups also include

cycloalkylidenes. Example cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl, norcarnyl, adamantyl, and the like. In some embodiments, cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. Also included in the definition of cycloalkyl are moieties that have one or more aromatic rings fused (i.e., having a bond in common with) to the cycloalkyl ring, for example, benzo or thienyl derivatives of cyclopentane, cyclopentene, cyclohexane, and the like. A cycloalkyl group containing a fused aromatic ring can be attached through any ring-forming atom including a ring-forming atom of the fused aromatic ring.

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

A five-membered ring heteroaryl is a heteroaryl with a ring having five ring atoms wherein one or more (e.g., 1 , 2, or 3) ring atoms are independently selected from N, O, and S. Exemplary five-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. A six-membered ring heteroaryl is a heteroaryl with a ring having six ring atoms wherein one or more (e.g., 1 , 2, or 3) ring atoms are independently selected from N, O, and S. Exemplary six-membered ring heteroaryls are pyridyl, pyrazinyl, pyrimidinyl, triazinyl and pyridazinyl.

As used herein, the term "heteroarylalkyl" refers to a group of formula -alkylene- heteroaryl. In some embodiments, heteroarylalkyl is 5-6 membered heteroaryl ring, wherein the heteroaryl ring is monocyclic and has 1 , 2, or 3 heteroatom ring members independently selected from nitrogen, sulfur and oxygen.

As used herein, "4-7 membered heterocycloalkyl" refers to non-aromatic heterocycles having one or more ring-forming heteroatoms selected from O, N, or S and having 4-7 ring members. Heterocycloalkyl groups include spirocycles. Example "4-7 membered

heterocycloalkyl" groups include pyrrolidin2-one, l ,3-isoxazolidin-2-one, pyranyl, azetidinyl, morpholino, thiomorpholino, piperazinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, pyrrolidinyl, isoxazolidinyl, isothiazolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, imidazolidinyl, azepanyl, and the like. Ring-forming carbon atoms and heteroatoms of a heterocycloalkyl group can be optionally substituted by oxo or sulfido (e.g., C(O), S(O), C(S), or S(0) ₂ , etc.). The heterocycloalkyl group can be attached through a ring-forming carbon atom or a ring-forming heteroatom. In some embodiments, the heterocycloalkyl group contains 0 to 3 double or triple bonds. In some embodiments, the heterocycloalkyl group contains 0 to 2 double bonds.

As used herein, the term "heterocycloalkylalkyl" refers to a group of formula alkylene- heterocycloalkyl. In some embodiments, heterocycloalkylalkyl is 4-7 membered

heterocycloalkyl ring, wherein the heterocycloalkyl portion is monocyclic and has 1 , 2, or 3 heteroatom ring members independently selected from nitrogen, sulfur and oxygen.

As used herein, the term "cyano-Ci_ ₆ alkyl" refers to a group of formula -C _1-6 alkylene-

CN.

As used herein, the term "HO-Ci_ ₆ alkyl" refers to a group of formula -C _1-6 alkylene-OH.

As used herein, the term "Ci_ ₄ alkoxy-Ci_ ₆ alkyl" refers to a group of formula -C _1-6 alkylene-(Ci_ ₄ alkoxy).

The compounds described herein can be asymmetric (e.g., having one or more stereocenters). All stereoisomers, such as enantiomers and diastereomers, are intended unless otherwise indicated. Compounds of the present invention that contain asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Methods on how to prepare optically active forms from optically inactive starting materials are known in the art, such as by resolution of racemic mixtures or by stereoselective synthesis. Many geometric isomers of olefins, C=N double bonds, and the like can also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. Cis and trans geometric isomers of the compounds of the present invention are described and may be isolated as a mixture of isomers or as separated isomeric forms.

In some embodiments, the compound has the (^-configuration at the carbon attached to R ¹ . In some embodiments, the compound has the (^-configuration at the carbon attached to R .

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

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

Compounds of the invention also include tautomeric forms. Tautomeric forms result from the swapping of a single bond with an adjacent double bond together with the concomitant migration of a proton. Tautomeric forms include prototropic tautomers which are isomeric protonation states having the same empirical formula and total charge. Example prototropic tautomers include ketone - enol pairs, amide - imidic acid pairs, lactam - lactim pairs, enamine - imine pairs, and annular forms where a proton can occupy two or more positions of 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 sterically locked into one form by appropriate substitution. For example, purine includes the 9H and a 7H tautomeric forms:

Compounds of the invention can include both the 9H and 7H tautomeric forms.

Compounds of the invention can also include all isotopes of atoms occurring in the intermediates or final compounds. Isotopes include those atoms having the same atomic number but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium.

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

All compounds, and pharmaceutically acceptable salts thereof, can be found together with other substances such as water and solvents (e.g. hydrates and solvates) or can be isolated.

In some embodiments, the compounds of the invention, or salts thereof, are substantially isolated. By "substantially isolated" is meant that the compound is at least partially or substantially separated from the environment in which it was formed or detected. Partial separation can include, for example, a composition enriched in the compounds of the invention. Substantial separation can 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 invention, or salt thereof. Methods for isolating compounds and their salts are routine in the art.

The phrase "pharmaceutically acceptable" is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

The expressions, "ambient temperature" and "room temperature," as used herein, are understood in the art, and refer generally to a temperature, e.g. a reaction temperature, that is about the temperature of the room in which the reaction is carried out, for example, a temperature from about 20 °C to about 30 °C.

The present invention also includes pharmaceutically acceptable salts of the compounds described herein. As used herein, "pharmaceutically acceptable salts" refers to derivatives of the disclosed compounds wherein the parent compound is modified by converting an existing acid or base moiety to 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; and the like. The pharmaceutically acceptable salts of the present invention include the conventional non-toxic salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, non-aqueous media like ether, ethyl acetate, alcohols (e.g., methanol, ethanol, iso-propanol, or butanol) or acetonitrile (ACN) are preferred. Lists of suitable salts are 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.

Synthesis

Compounds of the invention, including salts thereof, can be prepared using known organic synthesis techniques and can be synthesized according to any of numerous possible synthetic routes.

The reactions for preparing compounds of the invention can be carried out in suitable solvents which can be readily selected by one of skill in the art of organic synthesis. Suitable solvents can be substantially non-reactive with the starting materials (reactants), the

intermediates, or products at the temperatures at which the reactions are carried out, e.g., temperatures which can range from the solvent's freezing temperature to the solvent's boiling temperature. A given reaction can be carried out in one solvent or a mixture of more than one solvent. Depending on the particular reaction step, suitable solvents for a particular reaction step can be selected by the skilled artisan.

Preparation of compounds of the 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 one skilled in the art. The chemistry 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 incorporated herein by reference in its entirety.

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

Compounds of Formula I can be formed as shown in Scheme I. The compound (i) can be halogenated with N-chlorosuccinamide, N-bromosuccinamide or N-iodosuccinamide to give compound (ii) where X = CI, Br, or I. The halo group of (ii) can be coupled to R ³ -M, where M is a boronic acid, boronic ester or an appropriately substituted metal (e.g., R ³ -M is R ³ -B(OH) ₂ or R ³ -Sn(Bu) ₄ ), under standard Suzuki conditions or standard Stille conditions (e.g., in the presence of a palladium(O) catalyst, such as tetrakis(triphenylphosphine)palladium(0) and a base (e.g., a bicarbonate or carbonate base) to give a derivative of formula (iii). Alternatively, R ³ -M can be a cyclic amine (where M is H and attached to the amine nitrogen) with coupling to compound (ii) being performed by heating in base or under Buchwald conditions (e.g., in the presence of a palladium(O) catalyst, such as tetrakis(triphenylphosphine)palladium(0) and a base (e.g., an alkoxide base)) to afford ketone (iii). Reductive amination of the ketone (iii) can furnish the amine intermediate (v). Alternatively, ketone (iii) can be reduced to give an alcohol which can be converted to the mesylate and reacted with sodium azide to give an azide derivative (iv). The azide of compound (iv) can be converted to an amine (v) under appropriate reducing conditions, such as trimethylphosphine or TMSI. The amine (v) can be reacted with an appropriate alkylating agent R ^A X (e.g., Mel) or reacted under reductive amination conditions to give compound (vi). Finally compound (vi) can be reacted with a heteroaryl halide compound (e.g., Ar-X) to give a compound of Formula I. The reaction of amine (v) with R ^A -X can be eliminated to give compounds of Formula I, wherein R ^A is H.

Scheme I

1 . R ^A -X (optional)

2. Ar-X

Alternatively, compounds of Formula I can also be formed as shown in Scheme II. The ketone compound (i) can be halogenated with N-chlorosuccinamide, N-bromosuccinamide or N- iodosuccinamide to give compound (ii) where X = CI, Br, or I. Ketone (ii) can be reduced to give an alcohol (iii) which can be converted to the mesylate and reacted with sodium azide to give an azide derivative (iv). The azide of compound (iv) can be converted to an amine (v) under appropriate reducing conditions, such as trimethylphosphine or TMSI. The amine (v) can be protected with a suitable protecting group (e.g., by reacting with Boc ₂ 0) and purified by chiral chromatography to afford a single enantiomer of amine compound (v). The amino group can be deprotected (e.g., TFA when P = Boc) and reacted with an appropriate alkylating agent R ^A X (e.g., Mel) and the resulting secondary amine can be reacted with a heteroaryl halide compound (e.g., Ar-X) to give a compound (vi). The reaction of amine (v) with R ^A -X can be eliminated to give compounds (vi), wherein R ^A is H. Finally, the halo group of (vi) can be coupled to R ³ -M, where M is a boronic acid, boronic ester or an appropriately substituted metal (e.g., R ³ -M is R ³ -B(OH) ₂ or R ³ -Sn(Bu) ₄ ), under standard Suzuki conditions or standard Stille conditions (e.g., in the presence of a palladium(O) catalyst, such as

tetrakis(triphenylphosphine)palladium(0) and a base (e.g., a bicarbonate or carbonate base)) to give a derivative of formula (vii). Alternatively, R ³ -M can be a cyclic amine (where M is H and attached to the amine nitrogen) with coupling to compound (vi) being performed by heating in base or under Buchwald conditions (e.g., in the presence of a palladium(O) catalyst, such as tetrakis(triphenylphosphine)palladium(0) and a base (e.g., an alkoxide base)) to afford compounds of Formula I (vii).

Scheme II

n l) Separation

Compounds of Formula I, wherein L is O, N, or S, can be formed as shown in Scheme III. The thiols, phenols or amines (i) can be alkylated using Mitsunobu conditions (e.g., R OH, DEAD, Ph ₃ P) or standard alkylating conditions (R -Lg, Lg = leaving group) to afford thioether, ether, or alkylamine derivatives (ii), respectively. The halo group (e.g., X = Br, I) of (ii) can be coupled to R ³ -M, where M is a boronic acid, boronic ester or an appropriately substituted metal (e.g., R ³ -M is R ³ -B(OH) ₂ or R ³ -Sn(Bu) ₄ ), under standard Suzuki conditions or standard Stille conditions (e.g., in the presence of a palladium(O) catalyst, such as tetrakis(triphenylphosphine)- palladium(O) and a base (e.g., a bicarbonate or carbonate base)) to give a derivative of formula (iii). Alternatively, R ³ -M can be a cyclic amine (where M is H and attached to the amine nitrogen) with coupling to compound (ii) being performed by heating in base or under Buchwald conditions (e.g., in the presence of a palladium(O) catalyst, such as tetrakis(triphenylphosphine)- palladium(O) and a base (e.g., an alkoxide base)) to afford compounds of formula (iii). The ketone (iii) can be transformed using similar methods as shown in Scheme I and II to afford compounds of Formula I (iv). Alternatively, the halo-ketone (ii) can be transformed using similar methods as shown in Scheme I and II to afford halo intermediate (v). Suzuki, Stille, Negishi or Buchwald coupling of R ³ -M with halo intermediate (v) by similar methods described in Schemes I and II can also afford compounds of Formula I (iv).

Scheme III

Compounds of Formula I can be formed as shown in Scheme IV. Compound (i) can be acylated with a suitable acylating reagent (e.g., R^-COCl) to form an ester which can be rearranged under Lewis acid conditions e.g., BF ₃ /HOAc complex) to afford ketone (ii).

Halogenation of ketone (ii) using NXS (e.g., NXS = N-chlorosuccinamide, N-bromosuccinamide or N-iodosuccinamide) can give compound (iii) where X = CI, Br, or I. The phenol can be converted to the triflate (iv) using standard conditions (e.g.,Tf ₂ 0). The triflate group of (iv) can be coupled to R ² -M, where M is a boronic acid, boronic ester or an appropriately substituted metal (e.g., R ² -M is R ² -B(OH) ₂ or R ² -Sn(Bu) ₄ ), under standard Suzuki conditions or standard Stille conditions (e.g., in the presence of a palladium(O) catalyst, such as

tetrakis(triphenylphosphine)palladium(0) and a base (e.g., a bicarbonate or carbonate base)) to give a derivative of formula (v). Alternatively, R ² -M can be a cyclic amine (where M is H and attached to the amine nitrogen) with coupling to compound (iv) being performed by heating in base or under Buchwald conditions (e.g., in the presence of a palladium(O) catalyst, such as tetrakis(triphenylphosphine)palladium(0) and a base (e.g., an alkoxide base)) to afford ketone (v). The halo group of (v) can be coupled to R ³ -M, where M is a boronic acid, boronic ester or an appropriately substituted metal (e.g., R ³ -M is R ³ -B(OH) ₂ or R ³ -Sn(Bu) ₄ ), under standard Suzuki conditions or standard Stille conditions (e.g., in the presence of a palladium(O) catalyst, such as tetrakis(triphenylphosphine)palladium(0) and a base (e.g., a bicarbonate or carbonate base)) to give a derivative of formula (vi). Alternatively, R ³ -M can be a cyclic amine (where M is H and attached to the amine nitrogen) with coupling to compound (iv) being performed by heating in base or under Buchwald conditions (e.g., in the presence of a palladium(O) catalyst, such as tetrakis(triphenylphosphine)palladium(0) and a base (e.g., an alkoxide base)) to afford ketone (vi). The ketone (vi) can be transformed using similar methods as shown in Scheme I and II to afford compounds of Formula I (viii).

Alternatively, the halo-ketone (v) can be transformed using similar methods as shown in

Scheme I and II to afford halo intermediate (viii). Suzuki, Stille, Negishi or Buchwald coupling of M-R ³ with compound (viii) by similar methods described in Schemes I and II can also afford compounds of Formula I (vii).

Ketones which can be used in the processes of Scheme I, II and III can be formed as shown in Scheme V below. The carboxylic acid (i) can be activated with a coupling agent (e.g., HBTU, HATU or EDC) and then reacted with N,O-dimethylhydroxylamine to give a N- methoxy-N-methylcarboxamide derivative (ii). Amide (ii) may then be reacted with a Grignard reagent of formula R^-MgX (X = halo) to give a ketone (iii). The ketone (iii) can be

transformed using similar methods as shown in Scheme I, II and III to afford compounds of Formula I.

Scheme IV

Ketones which can be used in the processes of Scheme I, II and III, can also be formed as shown in Scheme VI below. The carboxylic acid (i) can be activated with a coupling agent (e.g. HBTU or HATU) and then reacted with N,O-dimethylhydroxylamine to give a N-methoxy-N- methylcarboxamide. The thiols, phenols or amines can be alkylated using Mitsunobu conditions (e.g., R OH, DEAD, Ph ₃ P) or standard alkylating conditions (R -Lg, Lg = leaving group) to afford thioether, ether or alkylamine derivatives (ii), respectively. The halo group (e.g., X = Br, or I) of (ii) can be coupled to R ³ -M, where M is a boronic acid, boronic ester or an appropriately substituted metal (e.g., R ³ -M is R ³ -B(OH) ₂ or R ³ -Sn(Bu) ₄ ), under standard Suzuki conditions or standard Stille conditions (e.g., in the presence of a palladium(O) catalyst, such as

tetrakis(triphenylphosphine)palladium(0) and a base (e.g., a bicarbonate or carbonate base)) to give a derivative of formula (iii). Alternatively, R ³ -M can be a cyclic amine (where M is H and attached to the amine nitrogen) with coupling to compound (ii) being performed by heating in base or under Buchwald conditions (e.g., in the presence of a palladium(O) catalyst, such as tetrakis(triphenylphosphine)palladium(0) and a base (e.g., an alkoxide base)) to afford amides (iii) of Formula I. Reaction of compound (iii) with a Grignard reagent of formula R^MgX (X = halo) can give ketone (iv). The ketone (iv) can be transformed using similar methods as shown in Scheme I, II and III to afford compounds of Formula I.

Scheme VI

Compounds which can be used in the processes of Schemes I-III can also be formed as shown in Scheme VII. The halo-ketone (i) can be converted to the cyano-ketone (ii) using standard cyanation conditions (e.g., Pd(0) and Zn(CN) ₂ ). Hydrolysis of the cyano group of (ii) under acid or base conditions can give the carboxylic acid which can be coupled to amines using a coupling agent (e.g., HATU, HBTU, EDC) and appropriate amines (HNR ^c R ^d ) to give amide (iii). In some embodiments, R ^c and R ^d , along with the nitrogen atom to which they are attached can optionally cyclize to form a 4-7 membered heterocycloalkyl group (thereby providing compounds wherein R ³ is C(0)R ^b , wherein R ^b is 4-7 membered heterocycloalkyl). The ketone of amide (iii) can be transformed using similar methods as shown in Scheme I, II and III to afford compounds of Formula I.

Scheme VII

Additional compounds which can be used in the processes of Schemes I-III can be formed as shown in Scheme VIII. The ketone (i) can be converted to the nitro-ketone (ii) using standard nitration conditions (e.g., FiN0 ₃ ). Reduction of the nitro group of (ii) under standard conditions (e.g., Fe, Zn, H ₂ over Pd/C) can give the amino compound which can be acylated with appropriate acylating agents (e.g., RC=OCl, ROC=OCl, S0 ₂ C1, RRNC=0) to give ketone (iii). The ketone (iii) can be transformed using similar methods as shown in Scheme I, II and III to afford compounds of Formula I. In some embodiments, R ^c and R ^d , along with the nitrogen atom to which they are attached can optionally cyclize to form a 4-7 membered heterocycloalkyl group (thereby providing compounds wherein R ³ is C(0)R ^b , wherein R ^b is 4-7 membered

heterocycloalkyl). Scheme VIII

Further compounds which can be used in the processes of Schemes I-III can be formed as shown in Scheme IX. The ether (i) can be converted to a phenol (ii) using standard nitration conditions (e.g., BBr ₃ ). The halo-phenol (ii) can be converted to the cyano-phenol (iii) using standard cyanation conditions (e.g., CuCN or Pd(0) and Zn(CN) ₂ ). The phenol (iii) can be converted to the triflate (iv) using Tf ₂ 0. The triflate group of (iv) can be coupled to R ² -M, where M is a boronic acid, boronic ester or an appropriately substituted metal (e.g., R ² -M is R ² -B(OH) ₂ or R ² -Sn(Bu) ₄ ), under standard Suzuki conditions or standard Stille conditions (e.g., in the presence of a palladium(O) catalyst, such as tetrakis(triphenylphosphine)palladium(0) and a base (e.g., a bicarbonate or carbonate base)) to give a derivative of formula (v). Alternatively, R ² -M can be a cyclic amine (where M is H and attached to the amine nitrogen) with coupling to compound (iv) being performed by heating in base or under Buchwald conditions (e.g., in the presence of a palladium(O) catalyst, such as tetrakis(triphenylphosphine)palladium(0) and a base (e.g., an alkoxide base)) to afford ketone (v). Hydrolysis of the cyano group of (v) under acid or base conditions can give the carboxylic acid which can be coupled to amines using a coupling agent (e.g., HATU, HBTU, EDC) and an appropriate amine (HNRiR ₂ ) to give amide (vi). The ketone of amide (vi) can be transformed using similar methods as shown in Scheme I, II and III to afford compounds of Formula I. heme IX

Compounds of Formula I can be formed as shown in Scheme X. The halo (X ¹ ) group of (i) can be coupled to R ³ -M, where M is an appropriately substituted metal (e.g., R ³ -M is Zn(R ³ ) ₂ ); appropriate non-limiting starting materials for generating R ³ -M are shown in Scheme X) under standard Negishi conditions (e.g., in the presence of a palladium(O) catalyst, such as Pd ₂ (dba)3 or tetrakis(triphenylphosphine)palladium(0)) to give a protected amino derivative of formula (ii). The nitrogen protecting group Pg in formula (ii) (e.g., Boc or Cbz) can be removed under a variety of standard conditions (e.g., TFA or HCl for Boc and H ₂ over Pd/C for Cbz) to afford the free amine which can be further reacted with a variety of alkylating, arylating, acylating, or sulfonylating conditions (e.g., R ^3a -X ² ; where X ² = halo or other leaving group and R ^3a = alkyl, aryl, acyl, sulfonyl and a base, such as TEA) to give compounds of formula (iii). Compounds of formula (iii) can be converted to compounds of Formula I using conditions described in Scheme I. Scheme X

Alternatively, compounds of Formula I can be formed as shown in Scheme Xa wherein the protected amino derivative (ii) can be reduced to the alcohol which can be converted to a leaving group (e.g., Lg = mesylate or halo, such as CI or bromo) to give compounds of formula (iv). The leaving group of compound (iv) can be displaced with sodium azide to afford the azide derivative which can be reduced (e.g., trimethylphosphine or H ₂ over Pd/C) to give the corresponding amino derivative (v). Purination of the amino derivative under standard conditions and subsequent removal of the nitrogen protecting group (e.g., Boc or Cbz) under a variety of standard conditions (e.g., TFA or HCl for Boc and H ₂ over Pd/C for Cbz) can afford the free amine which can be further reacted under a variety of alkylating, arylating, acylating, sulfonylating conditions (e.g., R ^3a -X ¹ ; where X ¹ = halo and R ^3a = alkyl, aryl, acyl, sulfonyl and a base, such as TEA) to give compounds of formula (vii). Removal of the purine protecting group, when present, can give compounds of Formula I.

Scheme Xa

Compounds of Formula I can be formed as shown in Scheme XI. The halo group, of (i) can be coupled to an alkene (e.g., acrylate or acrylamide) under standard Heck conditions (e.g., in the presence of a palladium(II) catalyst, such as palladium acetate)) to give an alkene of formula (ii). Reaction of alkene (ii) with nitromethane in the presence of DBU can afford the nitro derivative (iii) which can be reduced under standard conditions (e.g., NiCl ₂ / NaBH ₄ ) to give the free amine that closes to form the lactam (iv). The lactam can be alkylated under standard conditions (R ^3a -X ² ; X ² = halo in the presence of a base, such as TEA or NaH) to give an N-alkyl-lactam (v). Compounds of formula (v) and pyrrolidines derived from the reduction of the lactam (v) with suitable reducing agents, such as LiAlH ₄ , can be converted to compounds of Formula I using conditions described in Scheme I.

Scheme XI

Compounds of Formula I can be formed as shown in Scheme XII. The halo group X ¹ of (i) can be coupled to R ³ -M, where M is an appropriately substituted metal (e.g., R ³ -M is R ³ B(OH) ₂ ; appropriate non-limiting starting materials for generating R ³ -M are shown in Scheme XII) under standard Suzuki conditions (e.g., in the presence of a palladium(O) catalyst, such as tetrakis(triphenylphosphine)palladium(0)) to give an alkene of formula (ii). Epoxidation of alkene (ii) with mCPBA can afford the epoxide (iii) which can be reacted with a secondary or primary amine (amine = NHR ^c R ^d ; R ^c = H for primary amine) to give amino compounds of formula (iv). Secondary or tertiary amine derivatives (iv) can be further reacted with carbonyldiamidazole or phosgene to form an oxazolidinone (v) or an acetyl-halide (e.g., chloro- acetylchloride in the presence of base, such as TEA) to give the N-acyl derivative which can be converted to the morpholinone derivative (vi) upon treatment with a base (e.g., NaH).

Compounds of formula (iv, v, and vi) can be deprotected using standard conditions (e.g., Pg = THP then treat with an acid, such as TFA or HC1) to give compounds of Formula I. Scheme XII

Compounds of Formula I can be synthesized as shown in Scheme XIII. The halo group (e.g., X ¹ = CI, Br, I) of (i) can be converted to the boronic ester (ii) under standard conditions (e.g., pinnacle boronate ester in the presence of a palladium(O) catalyst, such as

tetrakis(triphenylphosphine)palladium(0)) The boronate (ii) can be reacted with an arylhalide or heteroarylhalide (e.g., R ³ -X ² ) under Suzuki conditions (e.g., in the presence of a palladium(O) catalyst, such as tetrakis(triphenylphosphine)palladium(0) and a base, such as Na ₂ C03) to give compounds of formula (iii). Compounds of formula (iii) can be converted to compounds of Formula I using conditions described in Scheme I.

Scheme XIII

Methods

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

Given that cancer cell growth and survival is impacted by multiple signaling pathways, the present invention is useful for treating disease states characterized by drug resistant kinase mutants. In addition, different kinase inhibitors, exhibiting different preferences in the kinases which they modulate the activities of, may be used in combination. This approach could prove highly efficient in treating disease states by targeting multiple signaling pathways, reduce the likelihood of drug-resistance arising in a cell, and reduce the toxicity of treatments for disease.

Kinases to which the present compounds bind and/or modulate (e.g., inhibit) include any member of the PBK family. In some embodiments, the PBK is ΡΒΚα, ΡΒΚβ, ΡΒΚγ, or ΡΒΚδ. In some embodiments, the PI3K is ΡΒΚγ or ΡΒΚδ. In some embodiments, the PBK is ΡΒΚγ. In some embodiments, the PBK is ΡΒΚδ. In some embodiments, the PBK includes a mutation. A mutation can be a replacement of one amino acid for another, or a deletion of one or more amino acids. In such embodiments, the mutation can be present in the kinase domain of the PBK.

In some embodiments, more than one compound of the invention is used to inhibit the activity of one kinase (e.g., ΡΒΚγ or ΡΒΚδ).

In some embodiments, more than one compound of the invention is used to inhibit more than one kinase, such as at least two kinases (e.g., ΡΒΚγ and ΡΒΚδ).

In some embodiments, one or more of the compounds is used in combination with another kinase inhibitor to inhibit the activity of one kinase (e.g., ΡΒΚγ or ΡΒΚδ).

In some embodiments, one or more of the compounds is used in combination with another kinase inhibitor to inhibit the activities of more than one kinase (e.g., ΡΒΚγ or ΡΒΚδ), such as at least two kinases.

The compounds of the invention can be selective. By "selective" is meant that the compound binds to or inhibits a kinase with greater affinity or potency, respectively, compared to at least one other kinase. In some embodiments, the compounds of the invention are selective inhibitors of ΡΒΚγ or ΡΒΚδ over PBKa and/or ΡΒΚβ. In some embodiments, the compounds of the invention are selective inhibitors of ΡΒΚδ (e.g., over ΡΒΚα, ΡΒΚβ and ΡΒΚγ). In some embodiments, the compounds of the invention are selective inhibitors of ΡΒΚγ (e.g., over ΡΒΚα, ΡΒΚβ and ΡΒΚδ). In some embodiments, selectivity can be at least about 2-fold, 5- fold, 10-fold, at least about 20-fold, at least about 50-fold, at least about 100-fold, at least about 200-fold, at least about 500-fold or at least about 1000-fold. Selectivity can be measured by methods routine in the art. In some embodiments, selectivity can be tested at the K _m ATP concentration of each enzyme. In some embodiments, the selectivity of compounds of the invention can be determined by cellular assays associated with particular PBK kinase activity.

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

Examples of PI3K-associated diseases include immune-based diseases involving the system including, for example, rheumatoid arthritis, allergy, asthma, glomerulonephritis, lupus, or inflammation related to any of the above.

Further examples of PI3K-associated diseases include cancers such as breast, prostate, colon, endometrial, brain, bladder, skin, uterus, ovary, lung, pancreatic, renal, gastric, or hematological cancer.

In some embodiments, the hematological cancer is acute myeloblastic leukemia (AML) or chronic myeloid leukemia (CML), or B cell lymphoma.

Further examples of PI3K-associated diseases include lung diseases such as acute lung injury (ALI) and adult respiratory distress syndrome (ARDS).

Further examples of PI3K-associated diseases include osteoarthritis, restenosis, atherosclerosis, bone disorders, arthritis, diabetic retinopathy, psoriasis, benign prostatic hypertrophy, inflammation, angiogenesis, pancreatitis, kidney disease, inflammatory bowel disease, myasthenia gravis, multiple sclerosis, or Sjogren's syndrome, and the like.

As used herein, the term "contacting" refers to the bringing together of indicated moieties in an in vitro system or an in vivo system. For example, "contacting" a PI3K with a compound of the invention includes the administration of a compound of the present invention to an individual or patient, such as a human, having a PI3K, as well as, for example, introducing a compound of the invention into a sample containing a cellular or purified preparation containing the PI3K. As used herein, the term "individual" or "patient," used interchangeably, refers to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and most preferably humans.

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

As used herein, the term "treating" or "treatment" refers to one or more of (1) preventing the disease; for example, preventing a disease, condition or disorder in an individual who may be predisposed to the disease, condition or disorder but does not yet experience or display the pathology or symptomatology of the disease; (2) inhibiting the disease; for example, inhibiting a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., arresting further development of the pathology and/or symptomatology); and (3) ameliorating the disease; for example, ameliorating a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., reversing the pathology and/or symptomatology) such as decreasing the severity of disease.

Combination Therapies

One or more additional pharmaceutical agents such as, for example, chemotherapeutics, anti-inflammatory agents, steroids, immunosuppressants, as well as Bcr-Abl, Flt-3, EGFR, HER2, JAK, c-MET, VEGFR, PDGFR, cKit, IGF-1R, RAF and FAK kinase inhibitors such as, for example, 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 for treatment of PI3K- associated diseases, disorders or conditions. The one or more additional pharmaceutical agents can be administered to a patient simultaneously or sequentially.

Example 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 directed to c-MET.

One or more of the following agents may be used in combination with the compounds of the present invention and are presented as a non limiting list: a cytostatic agent, cisplatin, doxorubicin, taxotere, taxol, etoposide, irinotecan, camptostar, topotecan, paclitaxel, docetaxel, epothilones, tamoxifen, 5-fluorouracil, methoxtrexate, temozolomide, cyclophosphamide, SCH 66336, Rl 15777, L778,123, BMS 214662, Iressa, Tarceva, antibodies to EGFR, Gleevec™, intron, ara-C, adriamycin, Cytoxan, gemcitabine, Uracil mustard, Chlormethine, Ifosfamide, Melphalan, Chlorambucil, Pipobroman, Triethylenemelamine, Triethylenethiophosphoramine, Busulfan, Carmustine, Lomustine, Streptozocin, Dacarbazine, Floxuridine, Cytarabine, 6-

Mercaptopurine, 6-Thioguanine, Fludarabine phosphate, oxaliplatin, leucovirin, ELOXATIN™, Pentostatine, Vinblastine, Vincristine, Vindesine, Bleomycin, Dactinomycin, Daunorubicin, Doxorubicin, Epirubicin, Idarubicin, Mithramycin, Deoxycoformycin, Mitomycin-C, L- Asparaginase, Teniposide 17. alpha. -Ethinylestradiol, Diethylstilbestrol, Testosterone,

Prednisone, Fluoxymesterone, Dromostanolone propionate, Testolactone, Megestrolacetate, Methylprednisolone, Methyltestosterone, Prednisolone, Triamcinolone, Chlorotrianisene, Hydroxyprogesterone, Aminoglutethimide, Estramustine, Medroxyprogesteroneacetate, Leuprolide, Flutamide, Toremifene, goserelin, Cisplatin, Carboplatin, Hydroxyurea, Amsacrine, Procarbazine, Mitotane, Mitoxantrone, Levamisole, Navelbene, Anastrazole, Letrazole, Capecitabine, Reloxafine, Droloxafme, Hexamethylmelamine, Avastin, herceptin, Bexxar, Velcade, Zevalin, Trisenox, Xeloda, Vinorelbine, Porfimer, Erbitux, Liposomal, Thiotepa, Altretamine, Melphalan, Trastuzumab, Lerozole, Fulvestrant, Exemestane, Fulvestrant, Ifosfomide, Rituximab, C225, Campath, Clofarabine, cladribine, aphidicolon, rituxan, sunitinib, dasatinib, tezacitabine, Smll , fludarabine, pentostatin, triapine, didox, trimidox, amidox, 3-AP, MDL- 101 ,731 , and bendamustine (Treanda).

Example chemotherapeutics include proteosome inhibitors (e.g., bortezomib), thalidomide, revlimid, and DNA-damaging agents such as melphalan, doxorubicin,

cyclophosphamide, vincristine, etoposide, carmustine, and the like.

Example steroids include coriticosteroids such as dexamethasone or prednisone. Example Bcr-Abl inhibitors include the compounds, and pharmaceutically acceptable salts thereof, of the genera and species disclosed in U.S. Pat. No. 5,521,184, WO 04/005281, and U.S. Ser. No. 60/578,491.

Example suitable Flt-3 inhibitors include compounds, and their pharmaceutically acceptable salts, as disclosed in WO 03/037347, WO 03/099771, and WO 04/046120.

Example suitable RAF inhibitors include compounds, and their pharmaceutically acceptable salts, as disclosed in WO 00/09495 and WO 05/028444.

Example suitable FAK inhibitors include compounds, and their pharmaceutically acceptable salts, as disclosed in WO 04/080980, WO 04/056786, WO 03/024967, WO

01/064655, WO 00/053595, and WO 01/014402.

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

In some embodiments, the compounds of the invention can be used in combination with a chemotherapeutic in the treatment of cancer, such as multiple myeloma, and may improve the treatment response as compared to the response to the chemotherapeutic agent alone, without exacerbation of its toxic effects. Examples of additional pharmaceutical agents used in the treatment of multiple myeloma, for example, can include, without limitation, melphalan, melphalan plus 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. Additive or synergistic effects are desirable outcomes of combining a PI3K inhibitor of the present invention with an additional agent. Furthermore, resistance of multiple myeloma cells to agents such as dexamethasone may be reversible upon treatment with the PI3K inhibitor of the present invention. The agents can be combined with the present compound in a single or continuous dosage form, or the agents can be administered

simultaneously or sequentially as separate dosage forms.

In some embodiments, a corticosteroid such as dexamethasone is administered to a patient in combination with the compounds of the invention where the dexamethasone is administered intermittently as opposed to continuously. In some further embodiments, combinations of the compounds of the invention with other therapeutic agents can be administered to a patient prior to, during, and/or after a bone marrow transplant or stem cell transplant. Pharmaceutical Formulations and Dosage Forms

When employed as pharmaceuticals, the compounds of the invention can be administered in the form of pharmaceutical compositions. These compositions can be prepared in a manner well known in the pharmaceutical art, and can be administered by a variety of routes, depending upon whether local or systemic treatment is desired and upon the area to be treated.

Administration may be topical (including transdermal, epidermal, ophthalmic and to mucous membranes including intranasal, vaginal and rectal delivery), pulmonary {e.g., by inhalation or insufflation of powders or aerosols, including by nebulizer; intratracheal or intranasal), oral or parenteral. Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal intramuscular or injection or infusion; or intracranial, e.g., intrathecal or intraventricular, administration. Parenteral administration can be in the form of a single bolus dose, or may be, for example, by a continuous perfusion pump. Pharmaceutical compositions and formulations for topical administration may include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids and powders. Conventional pharmaceutical carriers, aqueous, powder or oily bases, thickeners and the like may be necessary or desirable.

This invention also includes pharmaceutical compositions which contain, as the active ingredient, the compound of the invention or a pharmaceutically acceptable salt thereof, in combination with one or more pharmaceutically acceptable carriers (excipients). In some embodiments, the composition is suitable for topical administration. In making the compositions of the invention, the active ingredient is typically mixed with an excipient, diluted by an excipient or enclosed within such a carrier in the form of, for example, a capsule, sachet, paper, or other container. When the excipient serves as a diluent, it can be a solid, semi-solid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient. Thus, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders. In preparing a formulation, the active compound can be milled to provide the appropriate particle size prior to combining with the other ingredients. 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 by milling to provide a substantially uniform distribution in the formulation, e.g. about 40 mesh.

The compounds of the invention may be milled using known milling procedures such as wet milling to obtain a particle size appropriate for tablet formation and for other formulation types. Finely divided (nanoparticulate) preparations of the compounds of the invention can be prepared by processes known in the art, e.g., see International App. No. WO 2002/000196.

Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose. The formulations can additionally include: lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl- and propylhydroxy-benzoates; sweetening agents; and flavoring agents. The compositions of the invention can be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient by employing procedures known in the art.

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

In some embodiments, the compositions of the invention contain from about 5 to about

50 mg of the active ingredient. One having ordinary skill in the art will appreciate that this embodies compositions containing about 5 to about 10, about 10 to about 15, about 15 to about 20, about 20 to about 25, about 25 to about 30, about 30 to about 35, about 35 to about 40, about 40 to about 45, or about 45 to about 50 mg of the active ingredient.

In some embodiments, the compositions of the invention contain from about 50 to about

500 mg of the active ingredient. One having ordinary skill in the art will appreciate that this embodies compositions containing about 50 to about 100, about 100 to about 150, about 150 to about 200, about 200 to about 250, about 250 to about 300, about 350 to about 400, or about 450 to about 500 mg of the active ingredient.

In some embodiments, the compositions of the invention contain from about 500 to about 1000 mg of the active ingredient. One having ordinary skill in the art will appreciate that this embodies compositions containing about 500 to about 550, about 550 to about 600, about 600 to about 650, about 650 to about 700, about 700 to about 750, about 750 to about 800, about 800 to about 850, about 850 to about 900, about 900 to about 950, or about 950 to about 1000 mg of the active ingredient.

Similar dosages may be used of the compounds described herein in the methods and uses of the invention.

The active compound can be effective over a wide dosage range and is generally administered in a pharmaceutically effective amount. It will be understood, however, that the amount of the compound actually administered will usually be determined by a physician, according to the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like.

For preparing solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention. When referring to these preformulation compositions as homogeneous, the active ingredient is typically dispersed evenly throughout the composition so that the composition can be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules. This solid preformulation is then subdivided into unit dosage forms of the type described above containing from, for example, about 0.1 to about 1000 mg of the active ingredient of the present invention.

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

The liquid forms in which the compounds and compositions of the present invention can be incorporated for administration orally or by injection include aqueous solutions, suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar

pharmaceutical vehicles.

Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders. The liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described supra. In some embodiments, the compositions are administered by the oral or nasal respiratory route for local or systemic effect. Compositions can be nebulized by use of inert gases. Nebulized solutions may be breathed directly from the nebulizing device or the nebulizing device can be attached to a face mask, tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions can be administered orally or nasally from devices which deliver the formulation in an appropriate manner.

Topical formulations can contain one or more conventional carriers. In some

embodiments, ointments can contain water and one or more hydrophobic carriers selected from, for example, liquid paraffin, polyoxyethylene alkyl ether, propylene glycol, white Vaseline, and the like. Carrier compositions of creams can be based on water in combination with glycerol and one or more other components, e.g. glycerinemonostearate, PEG-glycerinemonostearate and cetylstearyl alcohol. Gels can be formulated using isopropyl alcohol and water, suitably in combination with other components such as, for example, glycerol, hydroxyethyl cellulose, and the like. In some embodiments, topical formulations contain at least about 0.1, at least about 0.25, at least about 0.5, at least about 1, at least about 2, or at least about 5 wt % of the compound of the invention. The topical formulations can be suitably packaged in tubes of, for example, 100 g which are optionally associated with instructions for the treatment of the select indication, e.g., psoriasis or other skin condition.

The amount of compound or composition administered to a patient will vary depending upon what is being administered, the purpose of the administration, such as prophylaxis or therapy, the state of the patient, the manner of administration, and the like. In therapeutic applications, compositions can be administered to a patient already suffering from a disease in an amount sufficient to cure or at least partially arrest the symptoms of the disease and its complications. Effective doses will depend on the disease condition being treated as well as by the judgment of the attending clinician depending upon factors such as the severity of the disease, the age, weight and general condition of the patient, and the like.

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

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

The compositions of the invention can further include one or more additional

pharmaceutical agents such as a chemotherapeutic, steroid, anti-inflammatory compound, or immunosuppressant, examples of which are listed herein. Labeled Compounds and Assay Methods

Another aspect of the present invention relates to labeled compounds of the invention (radio-labeled, fluorescent-labeled, etc.) that would be useful not only in imaging techniques but also in assays, both in vitro and in vivo, for localizing and quantitating PI3K in tissue samples, including human, and for identifying PI3K ligands by inhibition binding of a labeled compound. Accordingly, the present invention includes PI3K assays that contain such labeled compounds.

The present invention further includes isotopically-labeled compounds of the invention. An "isotopically" or "radio-labeled" compound is a compound of the invention where one or more atoms are replaced or substituted by an atom having an atomic mass or mass number different from the atomic mass or mass number typically found in nature (i.e., naturally occurring). Suitable radionuclides that may be incorporated in compounds of the present invention include but are not limited to ³ H (also written as T for tritium), ⁿ C, ¹³ C, ¹⁴ C, ¹³ N, ¹⁵ N, ¹⁵ 0, ¹⁷ 0, ¹⁸ 0, ¹⁸ F, ³⁵ S, ³⁶ C1, ⁸² Br, ⁷⁵ Br, ⁷⁶ Br, ⁷⁷ Br, ¹²³ I, ¹²⁴ I, ¹²⁵ I and ¹³¹ I. The radionuclide that is incorporated in the instant radio-labeled compounds will depend on the specific application of that radio-labeled compound. For example, for in vitro PI3K labeling and competition assays,

3 14 82 125 131 35

compounds that incorporate H, C, Br, I , I, S or will generally be most useful. For radio-imaging applications ^U C, ¹⁸ F, ¹²⁵ I, ¹²³ I, ¹²⁴ I, ¹³¹ I, ⁷⁵ Br, ⁷⁶ Br or ⁷⁷ Br will generally be most useful.

It is understood that a "radio-labeled " or "labeled compound" is a compound that has incorporated at least one radionuclide. In some embodiments the radionuclide is selected from

3 14 125 35 82

the group consisting of Ή, ¹⁴ C, ^LLJ , ^JJ S and °"Br. In some embodiments, one or more H atoms for any compound described herein is each replaced by a deuterium atom.

The present invention can further include synthetic methods for incorporating radioisotopes into compounds of the invention. Synthetic methods for incorporating radio-isotopes into organic compounds are well known in the art, and an ordinary skill in the art will readily recognize the methods applicable for the compounds of invention.

A labeled compound of the invention can be used in a screening assay to

identify/evaluate compounds. For example, a newly synthesized or identified compound (i.e., test compound) which is labeled can be evaluated for its ability to bind a PI3K by monitoring its concentration variation when contacting with the PI3K, through tracking of the labeling. For example, a test compound (labeled) can be evaluated for its ability to reduce binding of another compound which is known to bind to a PI3K (i.e., standard compound). Accordingly, the ability of a test compound to compete with the standard compound for binding to the PI3K directly correlates to its binding affinity. Conversely, in some other screening assays, the standard compound is labeled and test compounds are unlabeled. Accordingly, the concentration of the labeled standard compound is monitored in order to evaluate the competition between the standard compound and the test compound, and the relative binding affinity of the test compound is thus ascertained.

Kits

The present invention also includes pharmaceutical kits useful, for example, in the treatment or prevention of PI3K-associated diseases or disorders, such as cancer, which include one or more containers containing a pharmaceutical composition comprising a therapeutically effective amount of a compound of the invention. Such kits can further include, if desired, one or more of various conventional pharmaceutical kit components, such as, for example, containers with one or more pharmaceutically acceptable carriers, additional containers, etc., as will be readily apparent to those skilled in the art. Instructions, either as inserts or as labels, indicating quantities of the components to be administered, guidelines for administration, and/or guidelines for mixing the components, can also be included in the kit.

The invention will be described in greater detail by way of specific examples. The following examples are offered for illustrative purposes, and are not intended to limit the invention in any manner. Those of skill in the art will readily recognize a variety of non-critical parameters which can be changed or modified to yield essentially the same results. The compounds of the Examples have been found to be PI3K inhibitors according to at least one assay described herein.

EXAMPLES

The example compounds below containing one or more chiral centers were obtained in racemate form or as isomeric mixtures, unless otherwise specified. At points throughout the Examples, the stereochemistry at the carbon attached to R ¹ has been indicated, as currently understood. Example 1. 4-Chloro-3'-fluoro-3-methyl-6-[l-(9H-purin-6-ylamino)ethyl]b iphi carbonitrile

Step 1. l-(3-Bromo-5-chloro-2-hydroxy-4-methylphenyl)ethanone

To a mixture of l-(3-bromo-5-chloro-2-methoxy-4-methylphenyl)ethanone (1.0 g, 3.6 mmol) in methylene chloride (20 mL) was added 1.0 M boron tribromide in methylene chloride (3.8 mL, 3.8 mmol) at -78 °C. After stirring at -78 °C for 10 minutes, the reaction was allowed to warm to 0 °C and was then quenched with water at 0 °C and extracted with dichloromethane. The combined organic layers were washed with brine and dried over sodium sulfate. The volatiles were removed under reduced pressure to afford l-(3-Bromo-5-chloro-2-hydroxy-4- methylphenyl)ethanone (0.91 g, 96%). 1H NMR (CDC1 ₃ , 300 MHz) δ 12.96 (IH, s), 7.72 (IH, s), 2.64 (3H, s), 2.59 (3H, s) ppm. Step 2. 3-Acetyl-5-chloro-2-hydroxy-6-meth lbenzonitrile

A mixture of l-(3-bromo-5-chloro-2-hydroxy-4-methylphenyl)ethanone (4.9 g, 18 mmol) and copper cyanide (2.5 g, 28 mmol) in N-methylpyrrolidinone (15 mL) was heated at 200 °C for 1 hour. The resulting mixtre was allowed to cool to room temperature and was then diluted with ethyl acetate and 1 N HC1. The organic and aqueous layers were separated and the aqeous layer was extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over magnesium sulfate and concentrated to dryness under reduced pressure to give 3-Acetyl-5-chloro-2-hydroxy-6-methylbenzonitrile (3.7 g, 96%). LCMS calculated for Ci ₀ H ₉ ClNO ₂ (M+H) ⁺ : m/z = 210.0; found: 210.1.

Step 3. 6-Acetyl-4-chloro-2-cyano-3-meth lphenyl trifluoromethanesulfonate

To a mixture of 3-acetyl-5-chloro-2-hydroxy-6-methylbenzonitrile (3.7 g, 18 mmol) in methylene chloride (70 mL) was added triethylamine (7.4 mL, 53 mmol) and

trifluoromethanesulfonic anhydride (4.4 mL, 26 mmol) at -78 °C. The reaction mixture was allowed to warm to room temperature gradually and then stirred at room temperature for 30 minutes. The mixture was quenched with water and extracted with dichloromethane. The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated to dryness. The resulting residue was purified on silica gel, eluting with 0 to 40%> ethyl acetate in hexane, to give the desired product (2.54 g, 42%> isolated yield for 3 steps). LCMS calculated for C ₁₁ H ₈ CIF ₃ NO ₄ S (M+H) ⁺ : m/z = 342.0; found: 342.1.

Step 4. 6-Acetyl-4-chloro-3 '-fluoro-3-methylbiphenyl-2-carbonitrile

A biphasic solution of 6-acetyl-4-chloro-2-cyano-3-methylphenyl

trifluoromethanesulfonate (2.54 g, 7.4 mmol) and (3-fluorophenyl)boronic acid (1.6 g, 1 1 mmol) in toluene (70 mL) and saturated sodium bicarbonate (70 mL) was bubbled with N ₂ to degas.

After tetrakis(triphenylphosphine)palladium(0) (0.43 g, 0.37 mmol) was added, the mixture was bubbled with N ₂ for 5 min. more and then heated at 80 °C for 2 hours. After cool to room temperature, the mixture was diluted with ethyl acetate. The layers were separated and the aq. layer was extracted with more ethyl acetate. The combined extracts were washed with brine, dried over Na ₂ S0 ₄ , filtered, and concentrated. The residue was purified on silica gel column, eluting with 0 to 40%> ethyl acetate in hexane, to give the desired product (2.1 g, 99%>). LCMS calculated for Ci ₆ Hi ₂ ClFNO (M+H) : m/z = 288.1; found: 288.1.

Step 5. 6-( 1 -Aminoethyl)-4-chloro-3 '-fluoro-3-meth lbiphenyl-2-carbonitrile

A mixture of 6-acetyl-4-chloro-3'-fluoro-3-methylbiphenyl-2-carbonitrile (50 mg, 0.2 mmol) and ammonium acetate (130 mg, 1.7 mmol) in methanol (0.98 mL) and acetonitrile (0.99 mL) was heated at 65 °C in a sealed tube for 30 min. After the mixture was cooled, sodium cyanoborohydride (22 mg, 0.35 mmol) was added. The reaction was heated at 65 °C for another 4 hours, then cooled to room temperature and quenched with saturated sodium bicarbonate and extracted with dichloromethane. The combined extracts were dried over magnesium sulfate and evaporated to dryness. The residue was used directly in next step. LCMS calculated for

Ci ₆ Hi ₅ ClFN ₂ (M+H) ⁺ : m/z = 289.1 ; found: 289.1.

Step 6. 4-Chloro-3 '-fluoro-3-methyl-6-f l-(9H-purin-6-ylamino)ethyl]biphenyl-2-carbonitrile

A mixture of 6-bromo-9H-purine (41 mg, 0.21 mmol), 6-(l-aminoethyl)-4-chloro-3'- fluoro-3-methylbiphenyl-2-carbonitrile (50 mg, 0.2 mmol), and N,N-diisopropylethylamine (0.060 mL, 0.35 mmol) in isopropyl alcohol (0.7 mL) was heated at 90 °C under nitrogen overnight. The mixture was evaporated and the resulting mixture was purified on RP-HPLC (XBridge C18 Column, eluting with a gradient of acetonitrile in water with 0.2% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product. LCMS calculated for C ₂ iHivClFN ₆ (M+H) ⁺ : m z = 407.1 ; found: 407.1.

Example 2. 4-Chloro-3'-fluoro-3-methyl-6-[l-(9H-purin-6-ylamino)ethyl]b iphenyl-2- carboxamide

Step 1. 6-Acetyl-4-chloro-3 '-fluoro-3-methylbiphenyl-2-carboxamide

A mixture of 6-acetyl-4-chloro-3'-fluoro-3-methylbiphenyl-2-carbonitrile (0.87 g, 3.0 mmol) and potassium hydroxide (0.34 g, 6.1 mmol) in ethanol (4 mL) was refluxed for 2 hours. The mixture was cooled, acidified with 1 N HCl, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, and evaporated to dryness under reduced pressure to yield the crude product. LCMS calculated for C ₁₆ H ₁₄ CIFNO ₂ (M+H) ⁺ : m/z = 306.1; found: 306.0.

Step 2. 6-( 1 -Aminoethyl)-4-chloro-3 '-fluoro-3-meth lbiphenyl-2-carboxamide

A mixture of 6-acetyl-4-chloro-3'-fluoro-3-methylbiphenyl-2-carboxamide (110 mg, 0.34 mmol)and ammonium acetate (270 mg, 3.4 mmol) in methanol (1.9 mL) and acetonitrile (2.0 mL) was heated at 65 °C in a sealed tube for 30 min. The mixture was cooled and sodium cyanoborohydride (43 mg, 0.69 mmol) was added. The reaction was heated at 65 °C for another 4 hours. The mixture was cooled, quenched with saturated sodium bicarbonate, and extracted with dichloromethane. The combined extracts were dried over magnesium sulfate and evaporated to dryness. The residue was used directly in next step (98 mg, 93%). LCMS calculated for C ₁₆ H ₁₇ CIFN ₂ O (M+H) ⁺ : m/z = 307.1; found: 306.9. Step 3. 4-Chloro-3 '-fluoro-3-methyl-6-[ l- 9H-purin-6-ylamino)ethyl]biphenyl-2-carboxamide

A mixture of 6-bromo-9H-purine (1 10 mg, 0.56 mmol), 6-(l-aminoethyl)-4-chloro-3'- fluoro-3-methylbiphenyl-2-carboxamide (0.086 g, 0.28 mmol), and N,N-diisopropylethylamine (0.16 mL, 0.94 mmol) in isopropyl alcohol (2 mL) was heated at 90 °C under nitrogen overnight. The mixture was evaporated and the resulting mixture was purified on RP-HPLC (XBridge CI 8 Column, eluting with a gradient of acetonitrile in water with 0.2% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product (49 mg, 41 %). LCMS calculated for

C _2I H _I9 C1FN ₆ 0 (M+H) ⁺ : m/z = 425.1 ; found: 425.0.

Example 3. V-[l-(4-chloro-3'-fluoro-5-methyl-6-nitrobiphenyl-2-yl)ethyl ]-9H-purin-6- amine

Step 1. l-(5-Chloro-2-hydroxy-4-methyl-3-nitrophenyl)ethanone

To a mixture of l-(5-chloro-2-methoxy-4-methyl-3-nitrophenyl)ethanone (8.9 g, 37 mmol, from Oakwood) in methylene chloride (200 mL) was added 1.0 M boron tribromide in methylene chloride (38.4 mL, 38.4 mmol) at -78 °C. After stirring at -78 °C for 10 minutes, the reaction was allowed to warm up to 0 °C, quenched with water at 0 °C, and extracted with dichloromethane. The combined organic layers were washed with brine, dried over sodium sulfate and filtered. After evaporating to dryness under reduced pressure, the residue was used directly in next step (8.2 g, 98%). LCMS calculated for C ₉ H ₉ C1N0 ₄ (M+H) : m/z = 230.0;

found: 230.1.

Step 2. 6-Acetyl-4-chloro-3-methyl-2-nitro henyl trifluoromethanesulfonate

To a mixture of l-(5-chloro-2-hydroxy-4-methyl-3-nitrophenyl)ethanone (8.6 g, 37 mmol) in methylene chloride (200 mL) was added triethylamine (16 mL, 110 mmol) followed by trifluoromethanesulfonic anhydride (9.4 mL, 56 mmol) at -78 °C. The reaction was allowed to warm up to room temperature gradually and stirred at room temperature for 30 min. The mixture was quenched with water and extracted with dichloromethane. The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated to dryness. The residue was purified on silica gel, eluting with 0 to 30% ethyl acetate in hexane, to give the desired product (11 g, 78% isolated yield for 2 steps). LCMS calculated for CioHsClFsNOeS (M+H) ⁺ : m/z = 362.0; found: 362.1.

Step 3. l-(4-Chloro-3 '-fluoro-5-methyl- -nitrobiphenyl-2-yl)ethanone

A biphasic solution of 6-acetyl-4-chloro-3-methyl-2-nitrophenyl

trifluoromethanesulfonate (3.0 g, 8.3 mmol), (3-fluorophenyl)boronic acid (1.7 g, 12 mmol) in toluene (80 mL) and saturated sodium bicarbonate in water (80 mL) was bubbled with N ₂ to degas. After tetrakis(triphenylphosphine)palladium(0) (0.48 g, 0.42 mmol) was added, the mixture was bubbled with N ₂ for 5 min. more and heated at 80 °C for 2 hours. After cooling to r. , the mixture was diluted with ethyl acetate. The layers were separated and the aq. layer was extracted with more ethyl acetate. The combined extracts were washed with brine, dried over Na ₂ S0 ₄ , filtered, and concentrated. The residue was purified on silica gel column, eluting with 0 to 30%) ethyl acetate in hexane, to give the desired product (2.35 g, 92%>). LCMS calculated for C1FN0 ₃ (M+H) ⁺ : m/z = 308.0; found: 308.1

Step 4. l-(4-Chloro-3 '-fluoro-5-methyl-6-nitrobi henyl-2-yl)ethanamine

A mixture of l-(4-chloro-3'-fluoro-5-methyl-6-nitrobiphenyl-2-yl)ethanone (50 mg, 0.2 mmol)and ammonium acetate (130 mg, 1.7 mmol) in methanol (1 mL) and acetonitrile (1 mL) was heated at 65 °C, in a sealed tube, for 30 min. The mixture was cooled to room temperature and sodium cyanoborohydride (22 mg, 0.35 mmol) was added. The reaction was heated at 65 °C for another 4 hours, cooled to room temperature, quenched with saturated sodium bicarbonate, and extracted with dichloromethane. The combined extracts were dried over magnesium sulfate and evaporated to dryness. The residue was used directly in next step. LCMS calculated for Ci ₅ Hi ₅ ClFN ₂ 0 ₂ (M+H) ⁺ : m/z = 309.1 ; found: 309.1.

Step 5. N-fl-(4-chloro-3 '-fluoro-5-meth -6-nitrobiphenyl-2-yl)ethylJ-9H^urin-6-amine

A mixture of 6-bromo-9H-purine (41 mg, 0.21 mmol), l-(4-chloro-3'-fluoro-5-methyl-6- nitrobiphenyl-2-yl)ethanamine (54 mg, 0.17 mmol), and N,N-diisopropylethylamine (0.06 mL, 0.35 mmol) in isopropyl alcohol (0.7 mL) was heated at 90 °C under nitrogen overnight. The mixture was evaporated and the resulting mixture was purified on RP-HPLC (XBridge CI 8 Column, eluting with a gradient of acetonitrile in water with 0.2% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product. LCMS calculated for C ₂ oHi ₇ ClFN ₆ 0 ₂ (M+H) ⁺ : m/z = 427.1 ; found: 427.1.

Example 4. 4-Chloro-3-(cyanomethyl)-3'-fluoro-6-[l-(9H-purin-6-ylamino) ethyl]biphenyl- 2-carbonitrile

Step 1. l-[ 3-Bromo-4-(bromomethyl)-5-chloro-2-methoxyphenyl]ethanone

A mixture of l-(3-bromo-5-chloro-2-methoxy-4-methylphenyl)ethanone (3.3 g, 12 mmol), N-bromosuccinimide (2.2 g, 13 mmol), and benzoyl peroxide (0.15 g, 0.60 mmol) in carbon tetrachloride (50 mL) was heated at reflux overnight. The mixture was cooled to room temperature and concentrated. The resulting residue was diluted with ethyl acetate and washed with water. The organic layers were dried over magnesium sulfate and evaporated to dryness. The crude product was used directly in next step. LCMS calculated for CioHi ₀ Br ₂ C10 ₂ (M+H) ⁺ : m/z = 355.1; found: 355.1.

Step 2. 6-Acetyl-4-chloro-3-(cyanomethyl)-3 '-fluorobiphenyl-2-carbonitrile

To a mixture of sodium cyanide (100 mg, 2.0 mmol) in water (0.5 mL) was added sulfuric acid (0.95 g, 0.97 mmol) at 0 °C (the reaction generates hydrogen cyanide and must be run in a fume hood with good ventilation), followed by a solution of 6-acetyl-3-(bromomethyl)- 4-chloro-3'-fluorobiphenyl-2-carbonitrile (70 mg, 0.2 mmol) in acetonitrile (2 mL). The reaction was heated at 80 °C for 1 hour with pH adjustment to 9 by addition of solid sodium cyanide. The reaction mixture was cooled and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated to dryness under reduced pressure. The residue was purified on silica gel, eluting with 0 to 40% ethyl acetate in hexane. LCMS calculated for Ci ₇ HnClFN ₂ 0 (M+H) : m/z = 313.1 ; found: 313.1.

Step 3. 6-( l-Aminoethyl)-4-chloro-3-(c anomethyl)-3 '-fluorobiphenyl-2-carbonitrile

A mixture of 6-acetyl-4-chloro-3-(cyanomethyl)-3'-fluorobiphenyl-2-carbon itrile (0.020 g, 0.064 mmol) and ammonium acetate (49 mg, 0.64 mmol) in methanol (0.4 mL) and acetonitrile (0.4 mL) was heated at 65 °C in a sealed tube for 30 min. The mixture was cooled to room temperature and sodium cyanoborohydride (8 mg, 0.13 mmol) was added. The reaction was heated at 65 °C for another 4 hours, cooled to room temperature, quenched with saturated sodium bicarbonate and extracted with dichloromethane. The combined extracts were dried over magnesium sulfate and evaporated to dryness. The residue was used directly in next step (20 mg, 100%). LCMS calculated for Ci ₇ Hi ₄ ClFN ₃ (M+H) ⁺ : m/z = 314.1 ; found: 313.9.

Step 4. 4-Chloro-3-(cyanomethyl)-3 '-fluoro-6-f l-(9H-purin-6-ylamino) ethyl] biphenyl-2- carbonitrile

A mixture of 6-bromo-9H-purine (22 mg, 0.1 1 mmol), 6-(l-aminoethyl)-4-chloro-3- (cyanomethyl)-3'-fluorobiphenyl-2-carbonitrile (17 mg, 0.054 mmol), and N,N- diisopropylethylamine (0.032 mL, 0.18 mmol) in isopropyl alcohol (0.4 mL) was heated at 90 °C under nitrogen overnight. The mixture was evaporated and the resulting mixture was purified on RP-HPLC (XBridge CI 8 Column, eluting with a gradient of acetonitrile in water with 0.2% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product (8 mg, 30%>). LCMS calculated for C ₂₂ Hi ₆ ClFN ₇ (M+H) ⁺ : m/z = 432.1 ; found: 432.1. Example 5. l-{4-Chloro-3'-fluoro-3-methyl-6-[l-(9H-purin-6-ylamino)ethy l]biphenyl-2- yl}pyrrolidin-2-one

Step 1. l-( 6-Amino-4-chloro-3 '-fluoro-5-methylbiphenyl-2-yl)ethanone

A mixture of l-(4-chloro-3'-fluoro-5-methyl-6-nitrobiphenyl-2-yl)ethanone (4.4 g, 14 mmol) in methanol (80 mL) was hydrogenated in the presence of 5% Pt/C (443 mg) under balloon pressure of hydrogen overnight. The catalyst was filtered and the filtrate was

concentrated under reduced pressure to give the desired product (4.0 g, 100%). LCMS calculated for Ci ₅ Hi ₄ ClFNO (M+H) ⁺ : m/z = 278.1 ; found: 278.1.

Step 2. l-( 6-Acetyl-4-chloro-3 '-fluoro-3-methylbiphenyl-2-yl)pyrrolidin-2-one

To a mixture of l-(6-amino-4-chloro-3'-fluoro-5-methylbiphenyl-2-yl)ethanone (100 mg, 0.4 mmol) and 4-dimethylaminopyridine (52.8 mg, 0.432 mmol) in tetrahydrofuran (1 mL) was added 4-chlorobutanoyl chloride (0.044 mL, 0.40 mmol). The reaction was stirred at room temperature for 1 hour. Potassium tert-butoxide (1 .0 M) in tetrahydrofuran (0.79 mL, 0.79 mmol) was added and the resulting mixture was stirred at room temperature for 2 hours, then quenched with aq. ammonium chloride and extracted with ethyl acetate. The combined organic layers were washed with water, brine, dried and evaporated. The resulting residue was purified on silica gel, eluting with 0 to 50%> ethyl acetate in hexane, to give the product (40 mg, 30%>). LCMS calculated for CI ₉ HI ₈ C1FN0 ₂ (M+H) ⁺ : m/z = 346. 1 ; found: 346.1 . Step 3. l-[6-( l-Aminoethyl)-4-chloro-3 '-fluoro-3-methylbiphenyl-2-yl]pyrrolidin-2-one

A mixture of l-(6-acetyl-4-chloro-3'-fluoro-3-methylbiphenyl-2-yl)pyrroli din-2-one (40 mg, 0.1 mmol) and ammonium acetate (89 mg, 1.2 mmol) and sodium cyanoborohydride (15 mg, 0.23 mmol) in methanol (0.4 mL) and acetonitrile (0.4 mL) was heated at 65 °C overnight in a sealed tube. The mixture was cooled to room temperature and quenched with saturated sodium bicarbonate and extracted with dichloromethane. The combined extracts were dried over magnesium sulfate and evaporated to dryness. The crude product was used directly in next step (34 mg, 80%). LCMS calculated for Ci ₉ Hi ₈ ClFNO (M-NH ₂ ) ⁺ : m/z = 330.1; found: 330.0.

Step 4. l-{4-Chloro-3 '-fluoro-3-methyl-6-f l-(9H-purin-6-ylamino)ethyl]biphenyl-2- yljpyrrolidin-2-one

A mixture of 6-bromo-9H-purine (21 mg, 0.11 mmol), l-[6-(l-aminoethyl)-4-chloro-3'- fluoro-3-methylbiphenyl-2-yl]pyrrolidin-2-one (34 mg, 0.098 mmol), and N,N- diisopropylethylamine (0.034 mL, 0.20 mmol) in isopropyl alcohol (0.4 mL) was heated at 90 °C under nitrogen overnight. The mixture was evaporated and the resulting mixture was purified on RP-HPLC (XBridge CI 8 Column, eluting with a gradient of acetonitrile in water with 0.2% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product. LCMS calculated for C ₂₄ H ₂₃ CIFN ₆ O (M+H) ⁺ : m/z = 465.2; found: 465.1.

Example 6. l-{4-Chloro-3',5 ^, -difluoro-3-methyl-6-[l-(9H-purin-6-ylamino)ethyl]biph enyl- 2-yl}pyrrolidin-2-one trifluoroacetate

Step 1. l-(4-Chloro-3',5'-difluoro-5-methyl-6-nitrobiphenyl-2-yl)eth anone

A biphasic solution of 6-acetyl-4-chloro-3-methyl-2-nitrophenyl

trifluoromethanesulfonate (9.6 g, 26 mmol) and (3,5-difluorophenyl)boronic acid (5.0 g, 32 mmol) in toluene (100 mL) and saturated sodium bicarbonate in water (100 mL) was bubbled with N ₂ to degas. After tetrakis(triphenylphosphine)palladium(0) (1.22 g, 1.06 mmol) was added, the mixture was bubbled with N ₂ for 5 min. more and heated at 80 °C for 2 hours. The mixture was cooled to room temperature and diluted with ethyl acetate. The layers were separated and the aq. layer was extracted with more ethyl acetate. The combined extracts were washed with brine, dried over Na ₂ S0 ₄ , filtered and concentrated. The residue was purified on silica gel column, eluting with 0-30% ethyl acetate in hexane, to give the desired product. LCMS calculated for CI ₅ HI IC1F ₂ N03 (M+H) ⁺ : m/z = 326.0; found: 326.0.

Step 2. l-( 6-Amino-4-chloro-3 ', 5 '-difluoro-5-methylbiphenyl-2-yl)ethanone

Into a flask was placed a suspension of iron (1.50 g, 26.9 mmol) (< ΙΟμιη) in ethanol (22 mL). 6.0 M hydrogen chloride in water (0.374 mL, 2.24 mmol) was added and the suspension was stirred for 2 h at 60 °C. A solution of 5.0 M ammonium chloride in water (3.86 mL, 19.3 mmol) was added followed by a solution of l-[4-chloro-3',5'-difluoro-6-(hydroxyamino)-5- methylbiphenyl-2-yl]ethanone (1.4 g, 4.5 mmol) in ethanol (5.2 mL). The resulting suspension was stirred at 60 °C for 1 hour. The mixture was cooled, filtered and evaporated in vacuo.

The residue was dissolved in a mixture of ethyl acetate and saturated sodium bicarbonate solution and stirred for a few minutes. The layers were separated and the ethyl acetate layer was washed with brine, dried over MgSC^ and evaporated in vacuo to give the desired product (0.95 g, 72%). LCMS calculated for Ci ₅ Hi ₃ ClF ₂ NO (M+H) ⁺ : m/z = 296.1 ; found: 296.0.

Step 3. l-( 6-Acetyl-4-chloro-3 ', 5 '-dtfluoro-3-meth lbiphenyl-2-yl)pyrrolidin-2-one

To a mixture of l-(6-amino-4-chloro-3',5'-difluoro-5-methylbiphenyl-2-yl)eth anone

(0.10 g, 0.34 mmol) and pyridine (0.041 mL, 0.51 mmol) in methylene chloride (2 mL) was added 4-chlorobutanoyl chloride (0.042 mL, 0.37 mmol). The reaction was stirred at room temperature for 1 hour, quenched with saturated sodium bicarbonate solution and extracted with ethyl acetate. The combined extracts were dried over MgSC^ and concentrated to dryness under reduced pressure. The resulting residue was treated with 1.0 M potassium tert-butoxide in tetrahydrofuran (0.84 mL, 0.84 mmol) in tetrahydrofuran (2 mL) at room temperature for 2 hours. The reaction was quenched with aq. NH ₄ C1, extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over MgSC^ and evaporated. The residue was purified on silica gel (eluting with 0-40% of ethyl acetate in hexanes) to give the desired product (15 mg, 12%). LCMS calculated for C ₁₉ H ₁₇ CIF ₂ NO ₂ (M+H) ⁺ : m/z = 364.1 ; found: 364.1.

Step 4. l-[6-( l-Aminoethyl)-4-chloro-3 ', 5 '-d luoro-3-methylbiphenyl-2-yl]pyrrolidin-2-one

A mixture of l-(6-acetyl-4-chloro-3',5'-difluoro-3-methylbiphenyl-2-yl)py rrolidin-2- (0.015 g, 0.041 mmol), ammonium acetate (0.032 g, 0.41 mmol), 1.0 M sodium

cyanoborohydride in tetrahydrofuran (0.10 mL, 0.10 mmol) in methanol (0.1 mL) and acetonitrile (0.1 mL) was heated at 65 °C overnight. The mixture was cooled to room

temperature, quenched with saturated sodium bicarbonate solution and extracted with dichloromethane. The combined organic layers were dried over MgS0 ₄ and concentrated to give the desired product. LCMS calculated for Ci ₉ Hi ₇ ClF ₂ NO (M-NH ₂ ) ⁺ : m z = 348.1; found: 348.0.

Step 5. l-{4-Chloro-3 5'-difluoro-3-methyl-6-[l-(9H^urin-6-ylamino)ethyl]biphenyl- 2- yljpyrrolidin-2-one trifluoroacetate

A mixture of l-[6-(l-aminoethyl)-4-chloro-3',5'-difluoro-3-methylbiphenyl -2- yl]pyrrolidin-2-one (0.014 g, 0.038 mmol), 6-bromo-9H-purine (0.011 g, 0.058 mmol) and N,N- diisopropylethylamine (0.013 mL, 0.077 mmol) in ethanol (0.2 mL) was heated at 100 °C overnight. The mixture was purified on prep LCMS (XBridge CI 8 Column, eluting with a gradient of acetonitrile in water with 0.05% trifluoroacetic acid, at flow rate of 30 mL/min, to afford the desired product as TFA salt. LCMS calculated for C ₂₄ H ₂₂ C1F ₂ N ₆ 0 (M+H) ⁺ : m/z = 483.1; found: 483.1.

Example 7. 3-{4-Chloro-3'-fluoro-3-methyl-6-[l-(9H-purin-6-ylamino)ethy l]biphenyl-2-yl}- l,3-oxazolidin-2-one

Step 1. 3-(6-Acetyl-4-chloro-3'-fluoro-3-methylbiphenyl-2-yl)-l,3-ox azolidin-2-one

To a mixture of l-(6-amino-4-chloro-3'-fluoro-5-methylbiphenyl-2-yl)ethanone (100 mg, 0.4 mmol) and 4-dimethylaminopyridine (53 mg, 0.43 mmol) in tetrahydrofuran (1 mL) was added 2-chloroethyl chloridocarbonate (0.041 mL, 0.40 mmol). The mixture was stirred at room temperature overnight. To the mixture was added 1.0 M potassium tert-butoxide in

tetrahydrofuran (0.79 mL) at 0 °C, and the resulting mixture stirred at room temperature for 2 hours, then quenched with aq. ammonium chloride, extracted with ethyl acetate. The combined organic layers were washed with brine, dried, and evaporated. The filtrate was applied on silica gel, eluting with 0 to 60% ethyl acetate in hexane, to give the desired product (14 mg, 10%). LCMS calculated for C _I8 H _I6 C1FN0 ₃ (M+H) ⁺ : m/z = 348.1 ; found: 348.0.

Step 2. 3-f 6-( 1 -Aminoethyl)-4-chloro-3 '-fluoro-3-methylbiphenyl-2-ylJ-l, 3-oxazolidin-2-one

A mixture of 3-(6-acetyl-4-chloro-3'-fluoro-3-methylbiphenyl-2-yl)-l,3-ox azolidin-2- one (14 mg, 0.040 mmol) and ammonium acetate (31 mg, 0.40 mmol) and sodium

cyanoborohydride (5 mg, 0.08 mmol) in methanol (0.1 mL) and acetonitrile (0.1 mL) was heated at 65 °C overnight in a sealed tube. The mixture was cooled to room temperature, quenched with saturated sodium bicarbonate and extracted with dichloromethane. The combined extracts were dried over magnesium sulfate and evaporated to dryness. The crude product was used directly in next step (10 mg, 70%). LCMS calculated for C _I8 H _I6 C1FN0 ₂ (M-NH ₂ ) ⁺ : m/z = 332.1 ; found: 332.1.

Step 3. 3-{4-Chloro-3'-fluoro-3-methyl-6-[l-(9H^urin-6-ylamino)ethyl ]biphenyl-2-yl}-l,3- oxazolidin-2-one

A mixture of 6-bromo-9H-purine (6.3 mg, 0.032 mmol), 3-[6-(l-aminoethyl)-4-chloro- 3'-fluoro-3-methylbiphenyl-2-yl]-l ,3-oxazolidin-2-one (10 mg, 0.03 mmol), and N,N- diisopropylethylamine (0.010 mL, 0.057 mmol) in isopropyl alcohol (0.1 mL) was heated at 90 °C under nitrogen overnight. The mixture was evaporated and the resulting mixture was purified on RP-HPLC (XBridge CI 8 Column, eluting with a gradient of acetonitrile in water with 0.2% ammonium hydroxide, at flow rate of 30 mL/min, to give the desired. LCMS calculated for C ₂₃ H ₂₁ CIFN ₆ O ₂ (M+H) ⁺ : m/z = 467. 1 ; found: 467.1 .

Example 8. V-{l-[4-chloro-3'-fluoro-5-methyl-6-(lH-tetrazol-5-yl)biphen yl-2-yl]ethyl}-9H- purin-6-amine

N=N

1-f 4-Chloro-3 '-fluoro-5-methyl-6-( lH-tetrazol-5-yl)biphenyl-2-ylJethanone

N=N

A mixture of 6-acetyl-4-chloro-3'-fluoro-3-methylbiphenyl-2-carbonitrile (100 mg, 0.3 mmol), azidotrimethylsilane (0.092 mL, 0.69 mmol), and dibutyloxostannane (13 mg, 0.052 mmol) in toluene (2.9 mL) was heated at reflux overnight. The mixture was evaporated to dryness and purified on silica gel, eluting with 0 to 50%> ethyl acetate in hexane, to give the desired product (85 mg, 70%). LCMS calculated for CI ₆ HI ₃ C1FN ₄ 0 (M+H) ⁺ : m/z = 33 1 . 1 ; found: 331.0.

Step 2. l-[ 4-Chloro-3 '-fluoro-5-methyl-6-( lH-tetrazol-5-yl)biphenyl-2-yl]ethanamine

N=N

A mixture of l-[4-chloro-3'-fluoro-5-methyl-6-(lH-tetrazol-5-yl)biphenyl- 2-yl]ethanone (85 mg, 0.26 mmol), ammonium acetate (198 mg, 2.57 mmol) and sodium cyanoborohydride (32 mg, 0.51 mmol) in methanol (0.9 mL) and acetonitrile (0.9 mL) was heated at 65 °C overnight in a sealed tube. The mixture was cooled to room temperature and quenched with saturated sodium bicarbonate and extracted with ethyl acetate. The combined extracts were dried over magnesium sulfate and evaporated to dryness. The crude product was used directly in next step (45 mg, 53%). LCMS calculated for Ci ₆ Hi ₃ ClFN ₄ (M-NH ₂ ) ⁺ : m/z = 315.1 ; found: 315.1.

Step 3. N-{l-f4-chloro-3 '-fluoro-5-methyl-6-(lH-tetrazol-5-yl)biphenyl-2-ylJethyl}-9 H^urin-6- amine

N=N

A mixture of 6-bromo-9H-purine (30 mg, 0.15 mmol), l-[4-chloro-3'-fluoro-5-methyl-6- (lH-tetrazol-5-yl)biphenyl-2-yl]ethanamine (45 mg, 0.14 mmol), and N,N-diisopropylethylamine (0.047 mL, 0.27 mmol) in isopropyl alcohol (0.5 mL) was heated at 90 °C under nitrogen overnight. The mixture was evaporated and the resulting mixture was purified on RP-HPLC (XBridge C 18 Column, eluting with a gradient of acetonitrile in water with 0.2% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product. LCMS calculated for

C ₂ iHi ₈ ClFN ₉ (M+H) ⁺ : m/z = 450.1 ; found: 450.1. Example 9. V-{4-chloro-3 ^, -fluoro-3-methyl-6-[l-(9H-purin-6-ylamino)ethyl]biphen yl-2- yl}acetamide

Step 1. N-acetyl-N-(6-acetyl-4-chloro-3 '-fluoro-3-methylbiphenyl-2-yl)acetamide

To a mixture of l-(6-amino-4-chloro-3'-fluoro-5-methylbiphenyl-2-yl)ethanone (100 mg, 0.4 mmol) in methylene chloride (2 mL) was added N,N-diisopropylethylamine (0.094 mL, 0.54 mmol) followed by acetyl chloride (0.038 mL, 0.53 mmol). The mixture was stirred at room temperature for 30 minutes, quenched with water and extracted with ethyl acetate. The combined organic layers were washed with brine and dried over sodium sulfate and concentrated. The residue was purified on silica gel, eluting with 0 to 60% ethyl acetate in hexane, to give the desired products (57 mg, 40%). LCMS calculated for C _I9 H _I8 C1FN0 ₃ (M+H) ⁺ : m/z = 362.1 ; found: 362.0. Step 2. N-[6-(l-aminoethyl)-4-chloro-3'-fluoro-3-methylbiphenyl-2-yl ]acetamide

A mixture of N-acetyl-N-(6-acetyl-4-chloro-3'-fluoro-3-methylbiphenyl-2-y l)acetamide (57 mg, 0.16 mmol), ammonium acetate (120 mg, 1.6 mmol) and sodium cyanoborohydride (20 mg, 0.32 mmol) in methanol (0.6 mL) and acetonitrile (0.6 mL) was heated at 65 °C overnight in a sealed tube. The mixture was then cooled to room temperature and quenched with saturated sodium bicarbonate and extracted with ethyl acetate. The combined extracts were dried over magnesium sulfate and evaporated to dryness. The crude product was used directly in next step. LCMS calculated for C _I7 H _I9 C1FN ₂ 0 (M+H) ⁺ : m/z = 321.1 ; found: 321.0. Step 3. N-{4-chloro-3 '-fluoro-3-methyl- -f l-(9H-purin-6-ylamino)ethyl]biphenyl-2-yl}acetamide

A mixture of 6-bromo-9H-purine (22 mg, 0.11 mmol), N-[6-(l-aminoethyl)-4-chloro-3'- fluoro-3-methylbiphenyl-2-yl]acetamide (32 mg, 0.10 mmol), and N,N-diisopropylethylamine (0.035 mL, 0.20 mmol) in isopropyl alcohol (0.4 mL) was heated at 90 °C under nitrogen overnight. The mixture was evaporated and the resulting mixture was purified on RP-HPLC (XBridge C18 Column, eluting with a gradient of acetonitrile in water with 0.2% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product. LCMS calculated for

C ₂₂ H ₂ iClFN ₆ 0 (M+H) ⁺ : m/z = 439.1; found: 439.3. Example 10. Dimethyl {4-chloro-3'-fluoro-3-methyl-6-[l-(9H-purin-6- ylamino)ethyl]biphenyl-2-yl}imidodicarbonate

Step 1. Dimethyl (6-acetyl-4-chloro-3'-fluoro-3-methylbiphenyl-2-yl)imidodica rbonate

To a mixture of l-(6-amino-4-chloro-3'-fluoro-5-methylbiphenyl-2-yl)ethanone (100 mg, 0.4 mmol) in methylene chloride (2 mL) was added N,N-diisopropylethylamine (0.094 mL, 0.54 mmol) followed by methyl chloroformate (0.033 mL, 0.43 mmol) . The mixture was stirred at room temperature for 30 min. To the reaction mixture was added a catalytic amount of DMAP and another equivalent of methyl chloroformate. The reaction was stirred at room temperature over a weekend, quenched with water and extracted with ethyl acetate. The combined organic layers were washed with brine and dried over sodium sulfate, then concentrated. The residue was purified on silica gel, eluting with 0 to 50% ethyl acetate in hexane, to give the bis-acylated product (67 mg, 50%). LCMS calculated for C _I9 H _I8 C1FN0 ₅ (M+H) ⁺ : m/z = 394.1 ; found: 394.1.

Step 2. Dimethyl [ 6-(l-aminoethyl)-4-chloro-3 '-fluoro-3-methylbiphenyl-2-yl]imidodicarbonate

A mixture of dimethyl (6-acetyl-4-chloro-3'-fluoro-3-methylbiphenyl-2- yl)imidodicarbonate (67 mg, 0.17 mmol), ammonium acetate (131 mg, 1.70 mmol) and sodium cyanoborohydride (21 mg, 0.34 mmol) in methanol (0.6 mL) and acetonitrile (0.6 mL) was heated at 65 °C overnight in a sealed tube. The mixture was then cooled to room temperature and quenched with saturated sodium bicarbonate and extracted with dichloromethane. The combined extracts were dried over magnesium sulfate and evaporated to dryness. The crude product was used directly in next step (67 mg, 100%). LCMS calculated for Ci ₉ H ₂ iClFN ₂ 0 ₄ (M+H) ⁺ : m/z = 395.1 ; found: 395.1.

Step 3. Dimethyl {4-chloro-3'-fluoro-3-methyl-6-[l-(9H-purin-6-ylamino)ethyl] biphenyl-2- ylj imidodicarbonate

A mixture of 6-bromo-9H-purine (36 mg, 0.18 mmol), dimethyl [6-(l-aminoethyl)-4- chloro-3'-fluoro-3-methylbiphenyl-2-yl]imidodicarbonate (66 mg, 0.17 mmol), and N,N- diisopropylethylamine (0.058 mL, 0.33 mmol) in isopropyl alcohol (0.6 mL) was heated at 90 °C under nitrogen overnight. The mixture was evaporated and the resulting mixture was purified on RP-HPLC (XBridge CI 8 Column, eluting with a gradient of acetonitrile in water with 0.2% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired. LCMS calculated for C ₂₄ H ₂₃ C1FN ₆ 0 ₄ (M+H) ⁺ : m/z = 513.1; found: 513.2.

Example 11. N-{ 1- [4-chloro-3 '-fluor o-5-methyl-6-(4H- 1 ,2,4-triazol-4-yl)biphenyl-2- yl] ethyl}-9H-purin-6-amine

Step 1. l-[4-Chloro-3'-fluoro-5-methyl-6- 4H-l,2,4-triazol-4-yl)biphenyl-2-ylJethanone

1 ,2-Hydrazinedicarboxaldehyde (0.095 g, 1.1 mmol) and then, drop by

drop, chlorotrimethylsilane (0.69 mL, 5.4 mmol) and triethylamine (0.35 mL, 2.5 mmol) were added to a suspension of l-(6-amino-4-chloro-3'-fluoro-5-methylbiphenyl-2-yl)ethanone (0.10 g, 0.36 mmol) in pyridine (2 mL). The mixture was heated at 100 °C overnight. Evaporation at reduced pressure of the solvent yielded a solid that was treated with water and extracted with dichloromethane. The extracts were dried over sodium sulfate and concentrated. The reside was purified on silica gel, eluting with 0 to 50% ethyl acetate in hexane, then 0 to 10% methanol in dichloromethane, to give the desired product (44 mg, 37%). LCMS calculated for C ₁₇ H ₁₄ CIFN ₃ O (M+H) ⁺ : m/z = 330.1; found: 330.0.

Step 2. l-[4-Chloro-3'-fluoro-5-methyl-6- 4H-l,2,4-triazol-4-yl)biphenyl-2-ylJethanamine

A mixture of l-[4-chloro-3'-fluoro-5-methyl-6-(4H-l,2,4-triazol-4-yl)biph enyl-2- yljethanone (44 mg, 0.13 mmol), ammonium acetate (103 mg, 1.33 mmol) and sodium cyanoborohydride (17 mg, 0.27 mmol) in methanol (0.5 mL) and acetonitrile (0.5 mL) was heated at 65 °C overnight in a sealed tube. The mixture was then cooled to room temperature and quenched with saturated sodium bicarbonate and extracted with dichloromethane. The combined extracts were dried over magnesium sulfate and evaporated to dryness. The crude product was used directly in next step (15 mg, 34%). LCMS calculated for C ₁₇ H ₁₇ CIFN ₄ (M+H) ⁺ : m/z = 331.1; found: 331.1.

Step 3. N-{l-[ 4-chloro-3 '-fluoro-5-methyl-6-(4H-l, 2, 4-triazol-4-yl)biphenyl-2-yl]ethyl}-9H- purin-6-amine

A mixture of 6-bromo-9H-purine (10 mg, 0.050 mmol), l-[4-chloro-3'-fluoro-5-methyl- 6-(4H-l,2,4-triazol-4-yl)biphenyl-2-yl]ethanamine (15 mg, 0.045 mmol), and N,N- diisopropylethylamine (0.016 mL, 0.091 mmol) in isopropyl alcohol (0.2 mL) was heated at 90 °C under nitrogen overnight. The mixture was evaporated and the resulting mixture was purified on RP-HPLC (XBridge CI 8 Column, eluting with a gradient of acetonitrile in water with 0.2% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product. LCMS calculated for C ₂ 2Hi ₉ ClFN ₈ (M+H) ⁺ : m/z = 449.1; found: 449.1. Example 12. V-{4-chloro-3 ^, -fluoro-3-methyl-6-[l-(9H-purin-6-ylamino)ethyl]biphen yl-2- yl}- V-(methylsulfonyl)methanesulfonamide

Step 1. N-(6-acetyl-4-chloro-3'-fluoro-3-methylbiphenyl-2-yl)-N- (methylsulfonyl)methanesulfonamide

To a mixture of l-(6-amino-4-chloro-3'-fluoro-5-methylbiphenyl-2-yl)ethanone (50 mg, 0.2 mmol) in methylene chloride (1 mL) was added 4-dimethylaminopyridine (33 mg, 0.27 mmol) followed by methanesulfonyl chloride (0.017 mL, 0.22 mmol). The mixture was stirred for 2 hours, quenched with water and extracted with ethyl acetate. The combined organic layers were washed with brine and dried over sodium sulfate and concentrated. The residue was purified on silica gel, eluting with 0 to 40%> ethyl acetate in hexane, to give the desired product (25 mg, 30%). LCMS calculated for Ci ₇ Hi ₈ ClFN0 ₅ S ₂ (M+H) ⁺ : m/z = 434.0; found: 434.1.

Step 2. N-f 6-(l-aminoethyl)-4-chloro-3 '-fluoro-3-methylbiphenyl-2-ylJ-N- (methylsulfonyl)methanesulfonamide

A mixture of N-(6-acetyl-4-chloro-3'-fluoro-3-methylbiphenyl-2-yl)-N- (methylsulfonyl)methanesulfonamide (25 mg, 0.058 mmol), ammonium acetate (44 mg, 0.58 mmol) and sodium cyanoborohydride (7 mg, 0.12 mmol) in methanol (0.2 mL) and acetonitrile (0.2 mL) was heated at 65 °C overnight in a sealed tube. The mixture was then cooled to room temperature and quenched with saturated sodium bicarbonate and extracted with

dichloromethane. The combined extracts were dried over magnesium sulfate and evaporated to dryness. The crude product was used directly in next step (21 mg, 84%). LCMS calculated for Ci ₇ Hi ₈ ClFN0 ₄ S ₂ (M-NH ₂ ) ⁺ : m/z = 418.0; found: 418.0.

Step 3. N-{4-chloro-3 '-fluoro-3-methyl-6-f l-(9H-purin-6-ylamino)ethyl]biphenyl-2-yl}-N- (methylsulfonyl)methanesulfonamide

A mixture of 6-bromo-9H-purine (10 mg, 0.053 mmol), N-[6-(l-aminoethyl)-4-chloro- 3'-fluoro-3-methylbiphenyl-2-yl]-N-(methylsulfonyl)methanesu lfonamide (21 mg, 0.048 mmol), and N,N-diisopropylethylamine (0.017 mL, 0.096 mmol) in isopropyl alcohol (0.2 mL) was heated at 90 °C under nitrogen overnight. The mixture was evaporated and the resulting mixture was purified on RP-HPLC (XBridge CI 8 Column, eluting with a gradient of acetonitrile in water with 0.2% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product. LCMS calculated for C ₂₂ H ₂ 3C1FN ₆ 0 ₄ S ₂ (M+H) ⁺ : m/z = 553.1; found: 553.1.

Example 13. V-{l-[4-chloro-6-(2,6-difluoropyridin-4-yl)-5-methylbiphenyl -2-yl]ethyl}-9H- purin-6-amine

Step 1. l-(3-Bromo-5-chloro-2-hydroxy-4-methylphenyl)ethanone

To a stirred solution of l-(5-chloro-2-hydroxy-4-methylphenyl)ethanone (10 g, 54 mmol, from Aldrich) in acetic acid (100 mL) was added N-bromosuccinimide (12 g, 65 mmol) and the resulting mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated in vacuo, neutralized with saturated sodium bicarbonate and filtered to remove insoluble succinimide. The filtrate was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, and then concentrated to dryness under reduced pressure. The crude product was recrystalized from a mixture of ethyl acetate and hexane (11.4 g, 80%).

Step 2. 6-Acetyl-2-bromo-4-chloro-3-meth lphenyl trifluoromethanesulfonate

To a mixture of l-(3-bromo-5-chloro-2-hydroxy-4-methylphenyl)ethanone (11 g, 40 mmol) in methylene chloride (200 mL) was added triethylamine (17 mL, 120 mmol) followed by trifluoromethanesulfonic anhydride (10 mL, 60 mmol) at -78 °C. The reaction was allowed to warm up to room temperature gradually and stirred at room temperature for 30 min. After the mixture was evaporated under reduced pressure at room temperature, the residue was diluted with ethyl acetate and washed with water. The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated to dryness. The residue was purified on silica gel, eluting with 0 to 30% ethyl acetate in hexane, to give the desired product (13.6 g, 86%>). LCMS calculated for CioH ₈ BrClF ₃ 0 ₄ S (M+H) ⁺ : m/z = 394.9; found: 394.9.

Step 3. l-(6-Bromo-4-chloro-5-methylbiphenyl-2-yl)ethanone

A biphasic solution of 6-acetyl-2-bromo-4-chloro-3-methylphenyl

trifluoromethanesulfonate (3.3 g, 8.3 mmol) and phenylboronic acid (1.2 g, 10 mmol) in toluene (30 mL) and saturated sodium bicarbonate in water (30 mL) was bubbled with N ₂ to degas. After tetrakis(triphenylphosphine)palladium(0) (0.385 g, 0.333 mmol) was added, the mixture was bubbled with N ₂ for 5 min. more and heated at 80 °C for 2 hours. After cooling to r. , the mixture was diluted with ethyl acetate. The layers were separated and the aq. layer was extracted with more ethyl acetate. The combined extracts were washed with brine, dried over Na ₂ S0 ₄ , filtered, and concentrated. The residue was purified on silica gel column, eluting with 0-20%> of ethyl acetate in hexane, to give the desired product (2.5 g, 93%>). LCMS calculated for

Ci ₅ Hi ₃ BrC10 (M+H) ⁺ : m/z = 323.0; found: 323.0.

Step 4. 1-f 4-Chloro-6-(2, 6-difluoropyridin-4- l)-5-methylbiphenyl-2-yl]ethanone

A biphasic solution of l-(6-bromo-4-chloro-5-methylbiphenyl-2-yl)ethanone (0.20 g, 0.62 mmol) and (2,6-difluoropyridin-4-yl)boronic acid (0.12 g, 0.74 mmol) in 1 ,4-dioxane (2.0 mL) and 10% Na ₂ C0 ₃ in water (0.98 mL, 0.93 mmol) ) was bubbled with N ₂ to degas. After tetrakis(triphenylphosphine)palladium(0) (29 mg, 0.025 mmol) was added the mixture was bubbled with N ₂ for 5 min. and heated at 100 °C overnight. The mixture was cooled to room temperature and diluted with ethyl acetate. The layers were separated and the aq. layer was extracted with more ethyl acetate. The combined extracts were washed with brine, dried over

Na ₂ S0 ₄ , filtered and concentrated. The residue was purified on silica gel column, eluting with 0- 30% of ethyl acetate in hexane, to give the desired product (60 mg, 30%). LCMS calculated for C ₂ oHi ₅ ClF ₂ NO (M+H) ⁺ : m z = 358.1 ; found: 358.0.

Step 5. l-[ 4-Chloro-6-(2, 6-difluoropyridin-4- l)-5-methylbiphenyl-2-yl]ethanamine

A mixture of l-[4-chloro-6-(2,6-difluoropyridin-4-yl)-5-methylbiphenyl-2- yl]ethanone (60 mg, 0.2 mmol), ammonium acetate (130 mg, 1.7 mmol) and sodium cyanoboro hydride (21 mg, 0.34 mmol) in methanol (0.6 mL) and acetonitrile (0.6 mL) was heated at 65 °C overnight in a sealed tube. The mixture was then cooled to room temperature and quenched with saturated sodium bicarbonate and extracted with dichloromethane. The combined extracts were dried over magnesium sulfate and evaporated to dryness. The crude product was used directly in next step (60 mg, 100%). LCMS calculated for C ₂₀ Hi ₅ ClF ₂ N (M-NH ₂ ) ⁺ : m/z = 342.1 ; found: 342.1.

Step 5. N-{l-[4-chloro-6-(2,6-difluoropyridin-4-yl)-5-methylbiphenyl -2-yl]eth^

A mixture of 6-bromo-9H-purine (36 mg, 0.18 mmol), l-[4-chloro-6-(2,6- difluoropyridin-4-yl)-5-methylbiphenyl-2-yl]ethanamine (60 mg, 0.17 mmol), and /V,N- diisopropylethylamine (0.058 mL, 0.33 mmol) in isopropyl alcohol (0.6 mL) was heated at 90 °C under nitrogen overnight. The mixture was evaporated and the resulting mixture was purified on RP-HPLC (XBridge CI 8 Column, eluting with a gradient of acetonitrile in water with 0.2% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product. LCMS calculated for C ₂₅ H ₂ oClF ₂ N ₆ (M+H) ⁺ : m/z = 477.1 ; found: 477.1. Example 18. l-{3-Chloro-6-methoxy-2-methyl-5-[l-(9H-purin-6- ylamino)ethyl]phenyl}pyrrolidin-2-o

Step 1. l-(3-Amino-5-chloro-2-methoxy- -methylphenyl)ethanone

l-(5-Chloro-2-methoxy-4-methyl-3-nitrophenyl)ethanone (5.0 g, 20 mmol) was hydrogenated in 100 mL of methanol in the presence of 0.5 g of 10% Pt/C, under a balloon pressure of hydrogen overnight. The catalyst was filtered off and the filtrate was concentrated. The residue was dissolved in dichloromethane and dried over sodium sulfate and then evaporated to dryness. The crude product was used directly in next step (4.4 g, 100%). LCMS calculated for C ₁₀ H ₁₃ CINO ₂ (M+H) ⁺ : m/z = 214.1; found: 214.1.

Step 2. l-(3-Acetyl-5-chloro-2-methoxy-6-methylphenyl)pyrrolidin-2-o ne

To a mixture of l-(3-amino-5-chloro-2-methoxy-4-methylphenyl)ethanone (100 mg, 0.5 mmol) and 4-dimethylaminopyridine (69 mg, 0.56 mmol) in tetrahydrofuran (1 mL) was added 4-chlorobutanoyl chloride (0.058 mL, 0.52 mmol). The reaction was stirred at room temperature for 1 hour. To the reaction mixture was added 1.0 M potassium tert-butoxide in tetrahydrofuran (1.03 mL, 1.03 mmol). The resulting mixture was stirred at room temperature for 2 hours, quenched with aq. ammonium chloride and extracted with ethyl acetate. The combined organic layers were washed with water, brine, dried and evaporated. The residue was purified on silica gel, eluting with 0 to 50% ethyl acetate in hexane, to give the product (20 mg, 20%). LCMS calculated for C ₁₄ H ₁₇ CINO ₃ (M+H) ⁺ : m z = 282.1; found: 282.1. Step 3. l-[3-(l-Aminoethyl)-5-chloro-2-methoxy-6-methylphenylJpyrrol idin-2-one

A mixture of l-(3-acetyl-5-chloro-2-methoxy-6-methylphenyl)pyrrolidin-2-o ne (20 mg, 0.07 mmol), ammonium acetate (55 mg, 0.71 mmol) and sodium cyanoborohydride (9.0 mg, 0.14 mmol) in methanol (0.2 mL) and acetonitrile (0.2 mL) was heated at 65 °C overnight in a sealed tube. The mixture was cooled to room temperature, quenched with saturated sodium bicarbonate and extracted with dichloromethane. The combined extracts were dried over magnesium sulfate and evaporated to dryness. The crude product was used directly in next step (11 mg, 50%). LCMS calculated for Ci ₄ H ₂ oClN ₂ 0 ₂ (M+H) ⁺ : m/z = 283.1; found: 283.1. Step 4. l-{3-Chloro-6-methoxy-2-methyl-5-f l-(9H-purin-6-ylamino)ethyl]phenyl}pyrrolidin-2- one

A mixture of 6-bromo-9H-purine (8.5 mg, 0.043 mmol), l-[3-(l-aminoethyl)-5-chloro-2- methoxy-6-methylphenyl]pyrrolidin-2-one (11 mg, 0.039 mmol), and N,N-diisopropylethylamine (0.014 mL, 0.078 mmol) in isopropyl alcohol (0.1 mL) was heated at 90 °C under nitrogen overnight. The mixture was evaporated and the resulting mixture was purified on RP-HPLC (XBridge C18 Column, eluting with a gradient of acetonitrile in water with 0.2% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product. LCMS calculated for C19H22CIN6O2 (M+H) ⁺ : m z = 401.1; found: 401.1.

Example 19. 4-Chloro-3',5'-difluoro-3-methyl-6-[l-(9H-purin-6-ylamino)et hyl]biphenyl-2- carboxamide

Step 1. 6-Acetyl-4-chloro-3',5'-difluoro-3-meth lbiphenyl-2-carbonitrile

A biphasic solution of 6-acetyl-4-chloro-2-cyano-3-methylphenyl

trifluoromethanesulfonate (4.5 g, 13 mmol) and (3,5-difluorophenyl)boronic acid (2.5 g, 16 mmol) in toluene (50 mL) and saturated sodium bicarbonate in water (50 mL) was bubbled with N ₂ to degas. After tetrakis(triphenylphosphine)palladium(0) (0.61 g, 0.53 mmol) was added, the mixture was bubbled with N ₂ for 5 min. and then heated at 80 °C for 2 hours. The mixture was cooled to room temperature and diluted with ethyl acetate. The layers were separated and the aq. layer was extracted with more ethyl acetate. The combined extracts were washed with brine, dried over Na ₂ S0 ₄ , filtered and concentrated. The residue was purified on silica gel column, eluting with 0-30% of ethyl acetate in hexane, to give the desired product (1.94 g, 48%). LCMS calculated for Ci ₆ HnClF ₂ NO (M+H) ⁺ : m/z = 306.0; found: 306.0.

Step 2. 6-Acetyl-4-chloro-3 ', 5 '-difluoro-3-methylbiphenyl-2-carboxamide

A mixture of 6-acetyl-4-chloro-3',5'-difluoro-3-methylbiphenyl-2-carbonit rile (0.20 g, 0.65 mmol) and potassium hydroxide (0.074 g, 1.3 mmol) in ethanol (0.9 mL) was refluxed for 2 hours. After cooled, the mixture was acidified with 1 N HCl and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, and evaporated to dryness under reduced pressure. The crude mixture was purified on silica gel, eluting with 0 to 80% ethyl acetate in hexane, to yield the desired product (61 mg, 29%). LCMS calculated for Ci ₆ Hi ₃ ClF ₂ N0 ₂ (M+H) ⁺ : m/z = 324.1; found: 324.0.

Step 3. 6-( l-Aminoethyl)-4-chloro-3 ', 5 '-difluoro-3-methylbiphenyl-2-carboxamide

A mixture of 6-acetyl-4-chloro-3',5'-difluoro-3-methylbiphenyl-2-carboxam ide (61 mg,

0.19 mmol), ammonium acetate (150 mg, 1.9 mmol) and sodium cyanoborohydride (24 mg, 0.38 mmol) in methanol (0.7 mL) and acetonitrile (0.7 mL) was heated at 65 °C overnight in a sealed tube. The mixture was then cooled to room temperature, quenched with saturated sodium bicarbonate and extracted with ethyl acetate. The combined extracts were dried over magnesium sulfate and evaporated to dryness. The crude product was used directly in next step (61 mg, 99%). LCMS calculated for Ci ₆ Hi ₃ ClF ₂ NO (M-NH ₂ ) ⁺ : m/z = 308.1; found: 308.0.

Step 4. 4-Chloro-3 ', 5 '-dtfluoro-3-methyl-6-[ l-(9H-purin-6-ylamino) ethyl] biphenyl-2- carboxamide

A mixture of 6-bromo-9H-purine (41 mg, 0.21 mmol), 6-(l-aminoethyl)-4-chloro-3',5'- difluoro-3-methylbiphenyl-2-carboxamide (61 mg, 0.19 mmol), and N,N-diisopropylethylamine (0.065 mL, 0.38 mmol) in isopropyl alcohol (0.7 mL) was heated at 90 °C under nitrogen overnight. The mixture was evaporated and the resulting mixture was purified on RP-HPLC (XBridge C 18 Column, eluting with a gradient of acetonitrile in water with 0.2% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product. LCMS calculated for C ₂₁ H ₁₈ CIF ₂ N ₆ O (M+H) ⁺ : m/z = 443.1 ; found: 443.1.

Example 20. V-(l-{5-chloro-3-[2-(dimethylamino)pyrimidin-5-yl]-2-methoxy -4- methylphenyl}ethyl)-9H-purin-6-ami

Step 1. l-(3-Bromo-5-chloro-2-methoxy-4-methylphenyl)ethanone

A mixture of l-(3-bromo-5-chloro-2-hydroxy-4-methylphenyl)ethanone (10 g, 38 mmol), dimethyl sulfate (4.3 mL, 46 mmol) and potassium carbonate (1 1 g, 76 mmol) in acetone (200 mL) was heated at reflux overnight. After evaporation to dryness, the mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, and evaporated to dryness. The residue was purified on silica gel, eluting with 0 to 20% ethyl acetate in hexane, to yield the desired product (8.8 g, 84%). LCMS calculated for Ci ₀ HnBrClO ₂ (M+H) ⁺ : m/z = 277.0; found: 277.0.

Step 2. l-{5-Chloro-3-[2-(dimethylamino)pyrimidin-5-ylJ-2-methoxy-4- methylpheny

A biphasic solution of l-(3-bromo-5-chloro-2-methoxy-4-methylphenyl)ethanone (0.10 g, 0.36 mmol) and N,N-dimethyl-5-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)pyrimidin-2- amine (0.1 1 g, 0.43 mmol) in 1 ,4-dioxane (1.2 mL) and 10% sodium carbonate in water (0.57 mL, 0.54 mmol) was bubbled with N ₂ to degas. After tetrakis(triphenylphosphine)palladium(0) (17 mg, 0.014 mmol) was added, the mixture was bubbled with N ₂ for 5 min. and heated at 100°C overnight. The mixture was cooled to r.t. and diluted with ethyl acetate. The layers were separated and the aq. layer was extracted with more ethyl acetate. The combined extracts were washed with brine, dried over Na ₂ S0 ₄ , filtered and concentrated. The residue was purified on silica gel column, eluting with 0-30%> of ethyl acetate in hexane, to give the desired product (60 mg, 50%). LCMS calculated for C16H19CIN3O2 (M+H) ⁺ : m/z = 320.1 ; found: 320.1.

Step 3. 5-f 3-( l-Aminoethyl)-5-chloro-2-methoxy-6-methylphenyl]-N,N-dimethy lpyrM amine

A mixture of l- {5-chloro-3-[2-(dimethylamino)pyrimidin-5-yl]-2-methoxy-4- methylphenyl}ethanone (60 mg, 0.2 mmol), ammonium acetate (150 mg, 1.9 mmol) and sodium cyanoborohydride (24 mg, 0.38 mmol) in methanol (0.7 mL) and acetonitrile (0.7 mL) was heated at 65 °C overnight in a sealed tube. The mixture was cooled to room temperature, quenched with saturated sodium bicarbonate and extracted with ethyl acetate. The combined extracts were dried over magnesium sulfate and evaporated to dryness. The crude product was used directly in next step (60 mg, 100%). LCMS calculated for Ci ₆ H ₂₂ ClN ₄ 0 (M+H) ⁺ : m/z = 321.1 ; found: 321.1. Step 4. N-(l-{5-chloro-3-[2-(dimethylamino)pyrimidin-5-yl]-2-metho

9H-purin- 6-am in e

A mixture of 6-bromo-9H-purine (41 mg, 0.20 mmol), 5-[3-(l-aminoethyl)-5-chloro-2- methoxy-6-methylphenyl]-N,N-dimethylpyrimidin-2-amine (60 mg, 0.2 mmol), and N,N- diisopropylethylamine (0.065 mL, 0.37 mmol) in isopropyl alcohol (0.7 mL) was heated at 90 °C under nitrogen overnight. The mixture was evaporated and the resulting mixture was purified on RP-HPLC (XBridge CI 8 Column, eluting with a gradient of acetonitrile in water with 0.2% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product. LCMS calculated for C ₂₁ H ₂₄ CIN ₈ O (M+H) ⁺ : m/z = 439.2; found: 439.1. 1H NMR (DMSO-d ₆ , 400 MHz) δ 12.91 (1H, br s), 8.29 (2H, s), 8.20 (1H, m), 8.13 (1H, s), 8.10 (1H, s), 7.61 (1H, s), 5.73 (1H, m), 3.46 (3H, s), 3.16 (6H, s), 2.06 (3H, s), 1.47 (3H, d, J= 6.8 Hz) ppm.

Example 60. l-{3-Chloro-6-methoxy-2-methyl-5-[l-(9H-purin-6- ylamino)ethyl]phenyl}piperidin-4-ol

Step 1. l-(5-Chloro-2-hydroxy-3-iodo-4-methylphenyl)ethanone

To a stirred solution of l-(5-chloro-2-hydroxy-4-methylphenyl)ethanone (20 g, 110 mmol) in acetic acid (200 mL) was added N-iodosuccinimide (29 g, 130 mmol) and the resulting mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated in vacuo, neutralized with saturated sodium bicarbonate, filtered off insoluble succinimide and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated to dryness under reduced pressure. The crude product was recrystalized from a mixture of ethyl acetate and hexane (25.8 mg, 77%). LCMS calculated for C ₉ H ₉ C1I0 ₂ (M+H) ⁺ : m/z = 311.0; found: 311.0.

Step 2. l-(5-Chloro-3-iodo-2-methoxy-4-methylphenyl)ethanone

A mixture of l-(5-chloro-2-hydroxy-3-iodo-4-methylphenyl)ethanone (10 g, 32 mmol), dimethyl sulfate (3.7 mL, 39 mmol) and potassium carbonate (8.9 g, 64 mmol) in acetone (200 mL) was heated at reflux overnight. After evaporation to dryness, the mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and evaporated to dryness. The residue was purified on silica gel, eluting with 0 to 20% ethyl acetate in hexane, to yield the desired product (8.99 g, 86%>). LCMS calculated for CioHnCU0 ₂ (M+H) ⁺ : m/z = 324.9; found: 324.9.

Step 3. 1-f 5-Chloro-3-(4-hydroxypiperidi -l-yl)-2-methoxy-4-methylphenyl]ethanone

To a mixture of l-(5-chloro-3-iodo-2-methoxy-4-methylphenyl)ethanone (150 mg, 0.46 mmol) and 4-hydroxypiperidine (56 mg, 0.56 mmol) in isopropyl alcohol (1 mL) was added 1,2- ethanediol (0.052 mL, 0.92 mmol), potassium phosphate (200 mg, 0.93 mmol), and copper(I) iodide (5 mg, 0.02 mmol). The reaction was heated at 80 °C overnight and then cooled to room temperature. Water was added, and the mixture was extracted with ethyl acetate. The combined organic phases were washed with brine and dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified on silica gel, eluting with 0 to 50% ethyl acetate in hexanes, to give the desired product (15 mg, 11%). LCMS calculated for Ci ₅ H ₂ iClN0 ₃ (M+H) ⁺ : m/z = 298.1; found: 298.0. Step 4. l-[3-(l-Aminoethyl)-5-chloro-2-methoxy-6-methylphenyl]piperi din-4-ol

A mixture of l-[5-chloro-3-(4-hydroxypiperidin-l-yl)-2-methoxy-4- methylphenyljethanone (15 mg, 0.050 mmol), ammonium acetate (39 mg, 0.50 mmol) and sodium cyanoborohydride (6 mg, 0.1 mmol) in methanol (0.2 mL) and acetonitrile (0.2 mL) was heated at 65 °C overnight in a sealed tube. The mixture was then cooled to room temperature, quenched with saturated sodium bicarbonate and extracted with dichloromethane. The combined extracts were dried over magnesium sulfate, filtered and concentrated to dryness. The resulting crude product was used directly in next step (7 mg, 50%>). LCMS calculated for Ci ₅ H ₂₄ ClN ₂ 0 ₂ (M+H) ⁺ : m/z = 299.1; found: 299.1.

Step 5. l-{3-Chloro-6-methoxy-2-methyl-5-[l-(9H-purin-6-ylamino)eth^

A mixture of 6-bromo-9H-purine (5 mg, 0.03 mmol), l-[3-(l-aminoethyl)-5-chloro-2- methoxy-6-methylphenyl]piperidin-4-ol (7 mg, 0.02 mmol), and N,N-diisopropylethylamine (0.0082 mL, 0.047 mmol) in isopropyl alcohol (0.1 mL) was heated at 90 °C under nitrogen overnight. The mixture was evaporated and the resulting mixture was purified on RP-HPLC (XBridge C18 Column, eluting with a gradient of acetonitrile in water with 0.2% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product. LCMS calculated for C ₂ oH ₂₆ ClN ₆ 0 ₂ (M+H) ⁺ : m/z = 417.2; found: 417.1. Example 61. 3'-Chloro-4-fluoro-6'-methoxy-2 ^, -methyl-5 ^, -[l-(9H-purin-6- ylamino)ethyl]biphenyl-3-carboxamide

Step 1. Methyl 3'-acetyl-5'-chloro-4-fluoro-2'-methoxy-6'-methylbiphenyl-3- carboxylate

A biphasic solution of l-(3-bromo-5-chloro-2-methoxy-4-methylphenyl)ethanone (0.800 mmol) and [4-fluoro-3-(methoxycarbonyl)phenyl]boronic acid (0.684 g, 3.45 mmol) in 1,4-dioxane (9.3 mL) and 10% sodium carbonate in water (4.58 mL, 4.32 mmol) was bubbled with N ₂ to degas. After tetrakis(triphenylphosphine)palladium(0) (133 mg, 0.115 mmol) was added, the mixture was bubbled with N ₂ for 5 min. and heated at 100 °C overnight. The mixture was cooled to room temperature and diluted with ethyl acetate. The layers were separated and the aq. layer was extracted with more ethyl acetate. The combined extracts were washed with brine, dried over Na ₂ S0 ₄ , filtered, and concentrated to crude product. LCMS calculated for Ci ₈ Hi ₇ ClF0 ₄ (M+H) ⁺ : m/z = 351.1; found: 351.1.

Step 2. 3 '-Acetyl-5 '-chloro-4-fluoro-2 '-methox -6'-methylbiphenyl-3-carboxamide

A mixture of methyl 3'-acetyl-5'-chloro-4-fluoro-2'-methoxy-6'-methylbiphenyl-3- carboxylate (50 mg, 0.1 mmol) and 7.0 M ammonia in methanol (2.0 mL, 14 mmol) was heated at 90 °C in a sealed tube overnight. After evaporating the mixture to dryness, the residue was used directly in next step. LCMS calculated for C _I7 H _I6 C1FN0 ₃ (M+H) ⁺ : m/z = 336.1; found: 336.0.

Step 3. 3 '-(l-Aminoethyl)-5 '-chloro-4-fluoro-2 '-methoxy-6'-methylbiphenyl-3-carboxamide

A mixture of 3 '-acetyl-5 '-chloro-4-fluoro-2'-methoxy-6'-methylbiphenyl-3-carboxamide (50 mg, 0.1 mmol), ammonium acetate (115 mg, 1.49 mmol) and sodium cyanoborohydride (19 mg, 0.30 mmol) in methanol (0.5 mL) and acetonitrile (0.5 mL) was heated at 65 °C overnight in a sealed tube. The mixture was then cooled to room temperature, quenched with saturated sodium bicarbonate and extracted with dichloromethane. The combined extracts were dried over magnesium sulfate, filtered and concentrated to dryness. The resulting crude product was used directly in next step (36 mg, 70%). LCMS calculated for C _I7 H _I6 C1FN0 ₂ (M-NH ₂ ) ⁺ : m/z = 320.1 ; found: 320.1. Step 4. 3'-Chloro-4-fluoro-6'-methoxy-2'-methyl-5'-[l-(9H^urin-6-yla mino)ethyl]biphenyl-3- carboxamide

A mixture of 6-bromo-9H-purine (23 mg, 0.12 mmol), 3'-(l-aminoethyl)-5'-chloro-4- fluoro-2'-methoxy-6'-methylbiphenyl-3-carboxamide (36 mg, 0.11 mmol), and N,N- diisopropylethylamine (0.037 mL, 0.21 mmol) in isopropyl alcohol (0.4 mL) was heated at 90 °C under nitrogen overnight. The mixture was evaporated and the resulting mixture was purified on RP-HPLC (XBridge CI 8 Column, eluting with a gradient of acetonitrile in water with 0.2% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product. LCMS calculated for C ₂₂ H ₂ iClFN ₆ 0 ₂ (M+H) ⁺ : m/z = 455.1; found: 455.1.

Example 62. 3'-Chloro-3-fluoro-6'-methoxy-2 ^, -methyl-5 ^, -[l-(9H-purin-6- ylamino)ethyl]biphenyl-4-carboxamide

Step 1. Methyl 3'-acetyl-5'-chloro-3-fluoro-2'-methoxy-6'-methylbiphenyl-4- carboxylat

A mixture of l-(3-bromo-5-chloro-2-methoxy-4-methylphenyl)ethanone (1.0 g, 3.6 mmol) and [3-fluoro-4-(methoxycarbonyl)phenyl]boronic acid (0.85 g, 4.3 mmol) in 1,4-dioxane (12 mL) and 10% sodium carbonate in water (5.73 mL, 5.40 mmol) was bubbled with N ₂ to degas. After tetrakis(triphenylphosphine)palladium(0) (166 mg, 0.144 mmol) was added, the mixture was bubbled with N ₂ for 5 min. more and heated at 100 °C overnight. The mixture was cooled to room temperature and diluted with ethyl acetate. The layers were separated and the aq. layer was extracted with more ethyl acetate. The combined extracts were washed with brine, dried over Na ₂ S0 ₄ , filtered, and concentrated to give crude product.

Step 2. 3 '-Acetyl-5 '-chloro-3-fluoro-2 '-methox -6'-methylbiphenyl-4-carboxamide

A mixture of methyl 3'-acetyl-5'-chloro-3-fluoro-2'-methoxy-6'-methylbiphenyl-4- carboxylate (25 mg, 0.071 mmol) and 7.0 M ammonia in methanol (2.0 mL, 14 mmol) was heated at 90 °C in a sealed tube overnight. After evaporating the mixture to dryness, the residue was used directly in next step.

Step 3. 3 '-(l-Aminoethyl)-5 '-chloro-3-fluoro-2 '-methoxy-6'-methylbiphenyl-4-carboxamide

A mixture of 3'-acetyl-5'-chloro-3-fluoro-2'-methoxy-6'-methylbiphenyl-4- carboxamide (25 mg, 0.074 mmol), ammonium acetate (57 mg, 0.74 mmol) and sodium cyanoborohydride (9 mg, 0.15 mmol) in methanol (0.3 mL) and acetonitrile (0.3 mL) was heated at 65 °C overnight in a sealed tube. The mixture was cooled to room temperature, quenched with saturated sodium bicarbonate and extracted with dichloromethane. The combined extracts were dried over magnesium sulfate, filtered and concentrated to dryness. The resulting crude product was used directly in next step (20 mg, 80%). LCMS calculated for C _I7 H _I6 C1FN0 ₂ (M-NH ₂ ) ⁺ : m/z = 320.1 ; found: 320.1. Step 4. 3 '-Chloro-3-fluoro-6'-methoxy-2 '-methyl-5 '-[ l-(9H-purin-6-ylamino)ethyl]biphenyl-4- carboxamide

A mixture of 6-bromo-9H-purine (13 mg, 0.065 mmol), 3'-(l-aminoethyl)-5'-chloro-3- fluoro-2'-methoxy-6'-methylbiphenyl-4-carboxamide (20 mg, 0.06 mmol), and N,N- diisopropylethylamine (0.021 mL, 0.12 mmol) in isopropyl alcohol (0.2 mL) was heated at 90 °C under nitrogen overnight. The mixture was evaporated and the resulting mixture was purified on RP-HPLC (XBridge CI 8 Column, eluting with a gradient of acetonitrile in water with 0.2% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product. LCMS calculated for C ₂₂ H ₂ iClFN ₆ 0 ₂ (M+H) ⁺ : m/z = 455.1 ; found: 455.0.

Example 63. l-({3'-Chloro-3-fluoro-6'-methoxy-2 ^, -methyl-5 ^, -[l-(9H-purin-6- ylamino)ethyl] biphenyl-4-yl} carbonyl)azetidine-3-carbonitrile

Step 1. 3'-Acetyl-5'-chloro-3-fluoro-2'-methoxy-6'-methylbiphenyl-4- carboxylic acid

A mixture of methyl 3'-acetyl-5'-chloro-3-fluoro-2'-methoxy-6'-methylbiphenyl-4- carboxylate (1.2 g, 3.4 mmol) and 3.75 M sodium hydroxide in water (10 mL, 38 mmol) in methanol (10 mL) was stirred at room temperature overnight. The mixture was neutralized with HCl and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure. The residue was used directly in next step (704 mg, 61%). LCMS calculated for C ₁₇ H ₁₅ CIFO ₄ (M+H) ⁺ : m/z = 337.1; found: 337.1.

Step 2. 1-f (3'-Acetyl-5 '-chloro-3-fluoro-2 '-methoxy-6'-methylbiphenyl-4-yl)carbonyl]azetidine-3- carbonitrile

To a solution of 3'-acetyl-5'-chloro-3-fluoro-2'-methoxy-6'-methylbiphenyl-4- carboxylic acid (70 mg, 0.2 mmol), azetidine-3-carbonitrile hydrochloride (30 mg, 0.25 mmol) and benzotriazol-l-yloxytris(dimethylamino)phosphonium hexafluorophosphate (0.11 g, 0.25 mmol) in N,N-dimethylformamide (0.42 mL) was added N,N-diisopropylethylamine (0.08 mL, 0.46 mmol). After being stirred at room temperature for 2h, the mixture was diluted with ethyl acetate, washed with water, brine, dried and concentrated to dryness. The residue was purified on silica gel, eluting with 0 to 60% ethyl acetate in hexane, to give the desired product (25 mg, 30%> in 3 steps). LCMS calculated for C ₂₁ H ₁₉ CIFN ₂ O ₃ (M+H) ⁺ : m/z = 401.1; found: 401.1.

Step 3. l-{[ 3 '-(l-Aminoethyl)-5 '-chloro-3-fluoro-2 '-methoxy-6'-methylbiphenyl-4- yl]carbonyl}azetidine-3-carbonitrile

A mixture of l-[(3'-acetyl-5'-chloro-3-fluoro-2'-methoxy-6'-methylbipheny l-4- yl)carbonyl]azetidine-3-carbonitrile (25 mg, 0.062 mmol), ammonium acetate (48 mg, 0.62 mmol) and sodium cyanoborohydride (8 mg, 0.1 mmol) in methanol (0.2 mL) and acetonitrile (0.2 mL) was heated at 65 °C overnight in a sealed tube. The mixture was cooled to room temperature, quenched with saturated sodium bicarbonate and extracted with dichloromethane. The combined extracts were dried over magnesium sulfate, filtered and concentrated to dryness. The resulting crude product was used directly in next step (21 mg, 84%). LCMS calculated for C21H19CIFN2O2 (M-NH ₂ ) ⁺ : m/z = 385.1; found: 385.1.

Step 4. l-({3'-Chloro-3-fluoro-6'-methoxy-2 '-methyl-5 '-[ l-(9H-purin-6-ylamino) ethyl] biphenyl- 4-yl}carbonyl)azetidine-3-carbonitrile

A mixture of 6-bromo-9H-purine (11 mg, 0.057 mmol), l-{[3'-(l-aminoethyl)-5'-chloro- 3-fluoro-2'-methoxy-6'-methylbiphenyl-4-yl]carbonyl}azetidin e-3-carbonitrile (21 mg, 0.052 mmol), and N,N-diisopropylethylamine (0.018 mL, 0.10 mmol) in isopropyl alcohol (0.2 mL) was heated at 90 °C under nitrogen overnight. The mixture was evaporated and the resulting mixture was purified on RP-HPLC (XBridge CI 8 Column, eluting with a gradient of acetonitrile in water with 0.2% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product. LCMS calculated for C26H24CIFN7O2 (M+H) ⁺ : m/z = 520.2; found: 520.1. Example 71. V-{l-[4-chloro-6-(3,5-dimethylisoxazol-4-yl)-3'-fluoro-5-met hylbiphenyl-2- yl] ethyl}-9H-purin-6-amine trifluoroacetate

Step 1. l-( 6-Bromo-4-chloro-3 '-fluoro- -methylbiphenyl-2-yl)ethanone

To a solution of sodium hydrogenecarbonate (0.21 g, 2.5 mmol) in water (5 mL) was added a solution of 6-acetyl-2-bromo-4-chloro-3-methylphenyl trifluoromethanesulfonate (0.50 g, 1.3 mmol) in toluene (5 mL) followed by(3-fluorophenyl)boronic acid (0.21 g, 1.5 mmol) and tetrakis(triphenylphosphine)palladium(0) (75 mg, 0.065 mmol). The mixture was bubbled with N ₂ for 5 min and then heated at 80 °C overnight. The reaction was diluted with water and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, concentrated and purified on silica gel (eluting with 0-20% of ethyl acetate in hexanes) to give the desired product (0.40 g, 93%). LCMS calculated for Ci ₅ Hi ₂ BrClFO (M+H) ⁺ : m/z = 341.0; found: 341.0.

Step 2. 1-f 4-chloro-6-(3, 5-dimethylisoxazol-4-yl)-3 '-fluoro-5-methylbiphenyl-2-ylJethanone

To a solution of sodium hydrogenecarbonate (49 mg, 0.58 mmol) in water (1 mL) was added a solution of l-(6-bromo-4-chloro-3'-fiuoro-5-methylbiphenyl-2-yl)ethanone (0.10 g, 0.29 mmol) in toluene (1 mL) followed by 3,5-dimethyl-4-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2- yl)isoxazole (78 mg, 0.35 mmol) and tetrakis(triphenylphosphine)palladium(0) (17 mg, 0.015 mmol). The reaction mixture was bubbled with N ₂ for 5 min and then heated at 80 °C overnight. The organic layer was concentrated and flashed on silica gel (eluting with 0-35% of ethyl acetate in hexanes) to afford the desired product (40 mg, 38%>). LCMS calculated for C ₂ oHi ₈ ClFN0 ₂ (M+H) ⁺ : m/z = 358.1 ; found: 358.1.

Step 3. 1-f 4-Chloro-6-(3, 5-dimethylisoxazol-4-yl)-3 '-fluoro-5-methylbiphenyl-2-ylJethanamine

A mixture of l-[4-chloro-6-(3,5-dimethylisoxazol-4-yl)-3'-fiuoro-5-methyl biphenyl-2- yljethanone (40 mg, 0.1 1 mmol), ammonium acetate (86 mg, 1.1 mmol) and 1.0 M sodium cyanoborohydride in tetrahydrofuran (0.28 mL, 0.28 mmol) in methanol (0.6 mL) and acetonitrile (0.6 mL) was heated at 65 °C overnight. The mixture was cooled to room

temperature, quenched with saturated sodium bicarbonate solution and extracted with dichloromethane. The combined organic layers were dried over MgSC^, filtered and concentrated to give the desired product (35 mg, 87%). LCMS calculated for C ₂ oH ₂ iClFN ₂ 0 (M+H) ⁺ : m/z = 359.1; found: 359.1.

Step 4. N-{l-[ 4-chloro-6-(3,5-dimethylisoxazol-4-yl)-3 '-fluoro-5-methylbiphenyl-2-ylJethyl}-9H- purin-6-amine trifluoroacetate

A mixture of l-[4-chloro-6-(3,5-dimethylisoxazol-4-yl)-3'-fluoro-5-methyl biphenyl-2- yljethanamine ( 35 mg, 0.098 mmol), 6-bromo-9H-purine (29 mg, 0.15 mmol) and N,N- diisopropylethylamine (0.034 mL, 0.20 mmol) in ethanol (0.7 mL) was heated at 100 °C for 2 hours. The residue was concentrated and purified on prep LCMS (XBridge CI 8 Column, eluting with a gradient of acetonitrile in water with 0.05% trifluoroacetic acid, at flow rate of 30 mL/min) to afford the desired product as TFA salt. LCMS calculated for C ₂₅ H ₂₃ C1FN ₆ 0 (M+H) ⁺ m/z = 477.2; found: 477.1.

Example 72. V-{l-[4-Chloro-3'-fluoro-5-methyl-6-(lH-pyrazol-4-yl)bipheny l-2-yl]ethyl}- 9H-purin-6-amine trifluoroacetate

Step 1. l-{4-Chloro-6-[ l-(l-ethoxyethyl)-lH-pyrazol-4-yl]-3 '-fluoro-5-methylbiphenyl-2- yljethanone

To a solution of sodium hydrogenecarbonate (0.049 g, 0.58 mmol) in water (1 mL) was added a solution of l-(6-bromo-4-chloro-3'-fluoro-5-methylbiphenyl-2-yl)ethanone (0.10 g, 0.29 mmol) in toluene (1 mL) followed byl-(l-ethoxyethyl)-4-(4,4,5,5-tetramethyl-l, 3,2- dioxaborolan-2-yl)-lH-pyrazole (0.093 g, 0.35

mmol) and tetrakis(triphenylphosphine)palladium(0) (0.017 g, 0.015 mmol). The resulting mixture was bubbled with N ₂ for 5 min and then heated at 80 °C over a weekend. The organic layer was concentrated and purified on silica gel (eluting with 0-30% of ethyl acetate in hexanes) to give the desired product (37 mg, 32%). LCMS calculated for C ₂₂ H ₂₃ CIFN ₂ O ₂ (M+H) ⁺ : m/z = 401.1; found: 401.1.

Step 2. l-{4-Chloro-6-[ l-(l-ethoxyethyl)-lH-pyrazol-4-yl]-3 '-fluoro-5-methylbiphenyl-2- yl ethanamine

A mixture of l-{4-chloro-6-[l-(l-ethoxyethyl)-lH-pyrazol-4-yl]-3'-fluoro- 5- methylbiphenyl-2-yl}ethanone (37 mg, 0.092 mmol), ammonium acetate (71 mg, 0.92 mmol) and 1.0 M sodium cyanoborohydride in tetrahydrofuran (0.23 mL, 0.23 mmol) in methanol (0.5 mL) and acetonitrile (0.5 mL) was heated at 65 °C overnight. The mixture was cooled to room temperature, quenched with saturated sodium bicarbonate solution, extracted with dichloromethane. The combined organic layers were dried over MgSC^, filtered and concentrated to give the desired product (35 mg). LCMS calculated for C ₂₂ H ₂₆ CIFN ₃ O (M+H) ⁺ : m/z = 402.2; found: 402.2. Step 3. N-{l-[4-Chloro-3'-fluoro-5-methyl-6-(lH^yrazol-4-yl)biphenyl -2-ylJethyl}-9H^urin-6- amine trifluoroacetate

A mixture of l-{4-chloro-6-[l-(l-ethoxyethyl)-lH-pyrazol-4-yl]-3'-fluoro- 5- methylbiphenyl-2-yl}ethanamine (35 mg, 0.087 mmol), 6-bromo-9H-purine (26 mg, 0.13 mmol) and N,N-diisopropylethylamine (0.030 mL, 0.17 mmol) in ethanol (0.6 mL) was heated at 100 °C overnight. The residue was concentrated and treated with 1.0 M hydrogen chloride in water (0.50 mL, 0.50 mmol) in tetrahydrofuran (0.5 mL) overnight. The mixture was diluted with MeOH and purified on prep LCMS (XBridge C18 Column, eluting with a gradient of acetonitrile in water with 0.05% trifluoroacetic acid, at flow rate of 30 mL/min) to afford the desired product as TFA salt. LCMS calculated for C ₂₃ H ₂₀ CIFN ₇ (M+H) ⁺ : m/z = 448.1; found: 448.1. Example 76. V-[l-(4-Chloro-3',5'-difluoro-5-methyl-6-pyridin-4-ylbipheny l-2-yl)ethyl]-9H- purin-6-amine bis(trifluoroacetate

Step 1. l-(6-Bromo-4-chloro-3',5'-difluoro-5-methylbiphenyl-2-yl)eth anone

To a solution of sodium hydrogenecarbonate (2.8 g, 34 mmol) in water (70 mL) was added a solution of 6-acetyl-2-bromo-4-chloro-3-methylphenyl trifluoromethanesulfonate (6.7 g, 17 mmol) in toluene (70 mL) followed by (3,5-difluorophenyl)boronic acid (2.9 g, 19 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.98 g, 0.85 mmol). The mixture was bubbled with N ₂ for 5 min and then heated at 80 °C overnight. The reaction was diluted with water and extracted with ethyl acetate. The combined organic layers were dried, filtered, concentrated and purified on silica gel (eluting with 0-15% of ethyl acetate in hexanes) to give the desired product (5.6 g). LCMS calculated for Ci ₅ HnBrClF ₂ 0 (M+H) ⁺ : m/z = 359.0; found: 359.0.

Step 2. l-(4-Chloro-3 ', 5 '-difluoro-5-meth l-6-pyridin-4-ylbiphenyl-2-yl)ethanone

To a solution of sodium hydrogenecarbonate (0.093 g, 1.1 mmol) in water (2 mL) was added a solution of l-(6-bromo-4-chloro-3',5'-difluoro-5-methylbiphenyl-2-yl)eth anone (0.20 g, 0.56 mmol) in toluene (2 mL) followed by 4-pyridinylboronic Acid (0.082 g, 0.67

mmol) and tetrakis(triphenylphosphine)palladium(0) (0.033 g, 0.029 mmol). The mixture was bubbled with N ₂ for 5 min and then heated at 80 °C overnight. The organic layer

was concentrated and flashed on silica gel (eluting with 0-35% of ethyl acetate in hexanes) to afford the desired product (13 mg, 6.5%). LCMS calculated for C ₂₀ Hi ₅ ClF ₂ NO (M+H) ⁺ : m/z = 358.1; found: 358.1.

Step 3. l-(4-Chloro-3 ', 5 '-difluoro-5-methyl-6-pyridin-4-ylbiphenyl-2-yl)ethanamine

A mixture of l-(4-chloro-3',5'-difluoro-5-methyl-6-pyridin-4-ylbiphenyl-2 -yl)ethanone (0.013 g, 0.036 mmol), ammonium acetate (0.028 g, 0.36 mmol) and 1.0 M sodium

cyanoborohydride in tetrahydrofuran (0.091 mL, 0.091 mmol) in methanol (0.1 mL) and acetonitrile (0.1 mL) was heated at 65 °C overnight. The mixture was cooled to room temperature, quenched with saturated sodium bicarbonate solution and extracted with dichloromethane. The combined organic layers were dried over MgSC^, filtered and concentrated to give the desired product. LCMS calculated for C2oHi ₈ ClF ₂ N ₂ (M+H) ⁺ : m/z = 359.1; found: 359.1.

Step 4. N-[l-(4-Chloro-3 5'-difluoro-5-methyl-6-pyridin-4-ylbiph^

amine bis(trifluoroacetate)

A mixture of l-(4-chloro-3',5'-difluoro-5-methyl-6-pyridin-4-ylbiphenyl-2 - yl)ethanamine (0.013 g, 0.036 mmol), 6-bromo-9H-purine (0.011 g, 0.054 mmol) and N,N- diisopropylethylamine (0.013 mL, 0.072 mmol) in ethanol (0.3 mL) was heated at 100 °C overnight. The mixture was purified on prep LCMS (XBridge CI 8 Column, eluting with a gradient of acetonitrile in water with 0.05% trifluoroacetic acid, at flow rate of 30 mL/min) to afford the desired product as TFA salt. LCMS calculated for C ₂₅ H ₂₀ C1F ₂ N ₆ (M+H) ⁺ : m/z = 477.1; found: 477.1.

Example 106. V-{l-[4-Chloro-3',5'-difluoro-5-methyl-6-(lH-pyrazol-4-yl)bi ph yl] ethyl}-9H-purin-6-amine

Step 1. l-{4-Chloro-6-[ l-(l-ethoxyethyl)-lH-pyrazol-4-yl]-3 ', 5 '-dtfluoro-5-methylbiphenyl-2- yljethanone

To a solution of sodium hydrogenecarbonate (0.093 g, 1.1 mmol) in water (2 mL) was added a solution of l-(6-bromo-4-chloro-3',5'-difluoro-5-methylbiphenyl-2-yl)eth anone (0.20 g, 0.56 mmol) in toluene (2 mL) followed byl-(l-ethoxyethyl)-4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-lH-pyrazole (0.18 g, 0.67

mmol) and tetrakis(triphenylphosphine)palladium(0) (0.064 g, 0.056 mmol). The mixture was bubbled with N ₂ for 5 min and then heated at 90 °C overnight. The organic layer

was concentrated and flashed on silica gel (eluting with 0-20% of ethyl acetate in hexanes) to afford the desired product (94 mg, 40%). LCMS calculated for C ₂₂ H ₂₂ CIF ₂ N ₂ O ₂ (M+H) ⁺ : m/z = 419.1; found: 419.1.

Step 2. l-{4-Chloro-6-[ l-(l-ethoxyethyl)-lH-pyrazol-4-yl]-3 ', 5 '-dtfluoro-5-methylbiphenyl-2- yljethanamine

111 A mixture of l-{4-chloro-6-[l-(l-ethoxyethyl)-lH-pyrazol-4-yl]-3',5'-difl uoro-5- methylbiphenyl-2-yl}ethanone (0.094 g, 0.22 mmol), ammonium acetate (0.17 g, 2.2 mmol) and 1.0 M sodium cyanoborohydride in tetrahydrofuran (0.56 mL, 0.56 mmol) in methanol (0.6 mL) and acetonitrile (0.6 mL) was heated at 65 °C overnight. The mixture was cooled to room temperature, quenched with saturated sodium bicarbonate solution and extracted with dichloromethane. The combined organic layers were dried over MgSC^, filtered and

concentrated to give the desired product. LCMS calculated for C22H25CIF2N3O (M+H) ⁺ : m/z = 420.2; found: 420.1. Step 3. N-{l-[ 4-chloro-3 ', 5 '-difluoro-5-methyl-6-( lH-pyrazol-4-yl)biphenyl-2-ylJethyl}-9H- purin-6-amine

A mixture of l-{4-chloro-6-[l-(l-ethoxyethyl)-lH-pyrazol-4-yl]-3',5'-difl uoro-5- methylbiphenyl-2-yl}ethanamine (0.074 g, 0.18 mmol), 6-bromo-9H-purine (0.053 g, 0.26 mmol) and N,N-diisopropylethylamine (0.061 mL, 0.35 mmol) in ethanol (0.6 mL) was heated at 100 °C overnight. The residue was concentrated and treated with 1.0 M hydrogen chloride in water (1.0 mL, 1.0 mmol) in tetrahydrofuran (1 mL) overnight. The mixture was diluted with MeOH and purified on prep LCMS (XBridge C18 Column, eluting with a gradient of acetonitrile in water with 0.2% ammonium hydroxide, at flow rate of 30 mL/min) to afford the desired product. LCMS calculated for C23H19CIF2N7 (M+H) ⁺ : m/z = 466.1 ; found: 466.1.

Example 108. V-{l-[5-Chloro-3-(5-fluoropyridin-3-yl)-2-methoxy-4-methylph enyl]ethyl}- 9H-purin-6-amine

Step 1. 6-Bromo-9-(tetrahydro-2H-pyran-2- l)-9H-purine

A solution of 6-bromo-9H-purine (5.0 g, 25 mmol) and /?-toluenesulfonic acid monohydrate (0.48 g, 2.5 mmol) in chloroform (100 mL) was cooled to 0 °C, treated with dihydropyran (3.4 mL, 38 mmol) and stirred at room temperature for 1 hour. The reaction mixture was washed with saturated sodium bicarbonate, water and brine, dried with MgS0 ₄ , filtered, concentrated and purified on silica gel (e luting with 0-50% of ethyl acetate in hexanes) to give the desired product (7.0 g, 98%).

Step 2. l-(3-Bromo-5-chloro-2-methoxy-4-methylphenyl)ethanol

To a solution of l-(3-bromo-5-chloro-2-methoxy-4-methylphenyl)ethanone (23 g, 83 mmol) in methanol (200 mL) was added sodium tetrahydroborate (5.0 g, 130 mmol) at 0 °C. The mixture was stirred at 0 °C for 1 hour and quenched with water (10 mL). The resulting mixture was concentrated under reduced pressure to about 30 mL. The residue was diluted with ethyl acetate, washed with water and brine, dried over MgS0 ₄ , filtered and evaporated to yield the desired product. LCMS calculated for CioHnBrClO (M-OH) ⁺ : m/z = 261.0, 263.0 ; found: 261.0, 263.0.

Step 3. l-( l-Azidoethyl)-3-bromo-5-chloro-2-methoxy-4-methylbenzene

To a solution of l-(3-bromo-5-chloro-2-methoxy-4-methylphenyl)ethanol (13.4 g, 47.9 mmol) in methylene chloride (150 mL), cooled at 0 °C was added N,N-diisopropylethylamine (14 mL, 80 mmol) followed by methanesulfonyl chloride (5.5 mL, 71 mmol). The mixture was stirred for 1 hour at 0 °C. Water (100 mL) was added while cold. The organic layer was separated, washed with brine, dried over MgS0 ₄ , filtered and concentrated to dryness under reduced pressure. The resulting crude mesylate was dissolved in N,N-dimethylformamide (140 mL) and sodium azide (6.2 g, 96 mmol) was added. The reaction was stirred at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate and washed with saturated sodium bicarbonate solution, water and brine, dried over MgS0 ₄ , filtered and concentrated. The residue was purified on silica gel (eluting with 0-30% of ethyl acetate in hexanes) to afford the desired product (12.2 g, 82%). LCMS calculated for CioHnBrClO (M-N ₃ ) ⁺ : m/z = 261.0, 263.0; found: 261.0, 263.0. Step 4. l-(3-Bromo-5-chloro-2-methoxy-4-meth lphenyl)ethanamine

To a stirred solution of l-(l-azidoethyl)-3-bromo-5-chloro-2-methoxy-4- methylbenzene6-(l-azidoethyl)-2-bromo-4-chloro-3-methylpheny l methyl ether (5.6 g, 18 mmo in tetrahydrofuran (80 mL) and water (20 mL) was added 1.0 M trimethylphosphine in tetrahydrofuran (22 mL, 22 mmol) at room temperature and the mixture was stirred at room temperature for 1 hour. The mixture was diluted with ethyl acetate, washed with saturated sodium bicarbonate solution, water and brine, dried over MgS0 ₄ , filtered and concentrated to give the desired product (5.0 g, 98%). LCMS calculated for CioHnBrClO (M-NH ₂ ) ⁺ : m/z = 261.0, 263.0; found: 260.0, 262.9.

Step 5. N-[ l-(3-bromo-5-chloro-2-methoxy-4-methylphenyl)ethyl]-9-(tetra hydro-2H-pyran-. 9H-purin- 6-am in e

A mixture of l-(3-bromo-5-chloro-2-methoxy-4-methylphenyl)ethanamine (5.0 g, 18 mmol), 6-bromo-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (7.0 g, 25 mmol) and N,N- diisopropylethylamine (9.4 mL, 54 mmol) in ethanol (100 mL) was heated at 100 °C (flushed with nitrogen) overnight. The reaction mixture was cooled, poured into saturated sodium bicarbonate solution and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over MgSC^, filtered and concentrated. The residue was purified on silica gel (e luting with 0-65% ethyl acetate in hexane) to afford the desired product. LCMS calculated for C ₂ oH ₂₄ BrClN ₅ 0 ₂ (M+H) ⁺ : m/z = 480.1, 482.1; found: 480.0, 482.1.

Step 6. N-{l-[ 5-Chloro-3-(5-fluoropyridin-3-yl)-2-methoxy-4-methylphenyl]e thyl}-9H-purin-6- amine

Into a microwave vial was added N-[ 1 -(3-bromo-5-chloro-2-methoxy-4- methylphenyl)ethyl]-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6- amine (0.046 g, 0.096 mmol), (5- fluoropyridin-3-yl)boronic acid (0.020 g, 0.14 mmol), 10%> sodium carbonate solution (0.23 mL, 0.23 mmol), 1,4-dioxane (0.9 mL) and tetrakis(triphenylphosphine)palladium(0) (0.011 g, 0.0096 mmol). The mixture was bubbled with N ₂ for 5 min and then heated at 100 °C for 2 hours. The cooled reaction was treated directly with 6.0 M hydrogen chloride in water (0.2 mL, 1 mmol) at room temperature for ~30 min. The mixture was diluted with MeOH, filtered and purified on Prep LCMS (XBridge CI 8 Column, eluting with a gradient of acetonitrile in water with 0.2% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product. LCMS calculated for C ₂₀ Hi ₉ ClFN ₆ O (M+H) ⁺ : m/z = 413.1; found: 413.1.

Example 113. V-{l-[5-Chloro-2-methoxy-3-(5-methoxypyridin-3-yl)-4-methylp henyl]ethyl}- 9H-purin-6-amine

Step 1. tert-Butyl [l-(3-bromo-5-chloro-2-methoxy-4-methylphenyl)ethyl]carbamat e

Di-tert-butyldicarbonate (10 g, 47 mmol) was added to a mixture of l-(3-bromo-5- chloro-2-methoxy-4-methylphenyl)ethanamine (6.6 g, 24 mmol) and triethylamine (9.9 mL, 71 mmol) in tetrahydrofuran (120 mL). After 2 hours, the mixture was quenched with saturated sodium bicarbonate solution, extracted with ethyl acetate, washed with water and brine, dried over MgS0 ₄ , filtered and concentrated under reduced pressure. The residue was purified on silica gel (e luting with 0-5 % MeOH in dichloromethane) to give the desired product (6.0 g, 67%). LCMS calculated for CioHnBrClO (M-NHBoc) ⁺ : m/z = 261.0, 263.0; found: 261.0, 263.0. The material was separated on chiral HPLC (ChiralPak AD-H column, 20 x 250 mm, 5 micron particle size, eluting with 2% EtOH in hexanes at 15 ml/min, column loading ~ 60 mg/injection) to separate the two enantiomers. Step 2. N-[l-(3-Bromo-5-chloro-2-methoxy-4-methylphenyl)ethyl]-9-(te trahydro-2H-pyran-2- yl)-9H-purin-6-amine

A mixture of tert-butyl [l-(3-bromo-5-chloro-2-methoxy-4- methylphenyl)ethyl] carbamate (0.84 g, 2.2 mmol) (second peak from chiral separation) was treated with 4.0 M hydrogen chloride in dioxane (3.0 mL, 12 mmol) at room temperature for 2 hours. The mixture was diluted with saturated sodium bicarbonate solution and extracted with dichloromethane. The combined organic layers were dried over MgSC^, filtered and

concentrated to give l-(3-bromo-5-chloro-2-methoxy-4-methylphenyl)ethanamine, which was combined with 6-bromo-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (0.82 g, 2.9 mmol, from Example 108, Step 1) and N,N-diisopropylethylamine (1.2 mL, 6.6 mmol) in ethanol (6 mL) and heated at 100 °C overnight. The reaction mixture was concentrated and purified on silica gel

(eluting with 0-65% ethyl acetate in hexanes) to afford the desired product. LCMS calculated for C ₂ oH ₂₄ BrClN ₅ 0 ₂ (M+H) ⁺ : m/z = 480.1, 482.1; found: 480.0, 482.0.

Step 3. N-{l-[5-Chloro-2-methoxy-3-(5-methoxypyridin-3-yl)-4-methylp henyl]ethyl}-9^ amine

Into a microwave vial was added N-[l-(3-bromo-5-chloro-2-methoxy-4- methylphenyl)ethyl]-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6- amine (0.12 g, 0.25 mmol) isolated in step 2, (5-methoxypyridin-3-yl)boronic acid (0.046 g, 0.30 mmol), 10%> sodium carbonate (0.60 mL, 0.62 mmol), 1,4-dioxane (1.5 mL) and

tetrakis(triphenylphosphine)palladium(0) (0.017 g, 0.015 mmol), the mixture was bubbled with N ₂ for 5 min and then heated at 100 °C for 2 hours. The resulting mixture was cooled to room temperature and then treated directly with 6.0 M hydrogen chloride in water (0.4 mL, 2 mmol) for ~30 minutes. The mixture was diluted with MeOH, filtered and purified on Prep LCMS (XBridge C18 Column, eluting with a gradient of acetonitrile in water with 0.2% ammonium hydroxide, at flow rate of 60 mL/min) to give the desired single enantiomer product. LCMS calculated for C ₂ iH ₂₂ ClN ₆ 0 ₂ (M+H) ⁺ : m/z = 425.1; found: 425.1. 1H NMR (DMSO-d ₆ , 300 MHz) δ 8.27-7.99 (6H, m), 7.63 (1H, s), 5.71 (1H, m), 3.79 (3H, s), 3.40 (3H, s), 1.94 (3H, s), 1.44 (3H, d, J= 6.9 Hz) ppm. Example 117. (4-{3-Chloro-6-methoxy-2-methyl-5-[l-(9H-purin-6-ylamino)eth yl]phenyl}- lH-pyrazol-l-yl)acetonitrile trifl roacetate

Step 1. l-{5-Chloro-3-[ l-(l-ethoxyethyl)- -pyrazol-4-yl]-2-methoxy-4-methylphenyl}ethanone

A biphasic solution of l-(3-bromo-5-chloro-2-methoxy-4-methylphenyl)ethanone (0.40 g, 1.4 mmol) and l-(l-ethoxyethyl)-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan- 2-yl)-lH-pyrazole (0.46 g, 1.7 mmol) in toluene (4 mL) and 10% sodium carbonate in water (3.0 mL, 2.9 mmol) was degassed under N ₂ . Tetrakis(triphenylphosphine)palladium(0) (83 mg, 0.072 mmol) was added and the mixture was bubbled with N ₂ for 5 min and heated at 100 °C overnight. The resulting solution was cooled to room temperature and the organic layer was purified on silica gel (eluting with 0-40%> of ethyl acetate in hexanes) to give the desired product (0.22 g, 45%>). LCMS calculated for C17H22CIN2O3 (M+H) : m/z = 337.1 ; found: 337.1 Step 2. 1-f 5-Chloro-2-methoxy-4-methyl-3-(lH-pyrazol-4-yl)phenylJethano ne

1 - {5-Chloro-3-[ 1 -(1 -ethoxyethyl)- lH-pyrazol-4-yl]-2-methoxy-4- methylphenyl}ethanone (0.22 g, 0.65 mmol) was treated with 1.0 M hydrogen chloride in water (3.9 mL, 3.9 mmol) in tetrahydrofuran (4 mL) overnight. The mixture was quenched

with saturated sodium bicarbonate and extracted with ethyl acetate. The organic layers were dried over MgS0 ₄ , filtered, concentrated and purified on silica gel (eluting with 0-60% of ethyl acetate in hexane) to afford the desired product (0.13 g, 75%). LCMS calculated for

Ci ₃ Hi ₄ ClN ₂ 0 ₂ (M+H) ⁺ : m/z = 265.1 ; found: 265.0.

Step 3. [ 4-(3-Acetyl-5-chloro-2-methoxy-6-methylphenyl)-lH-pyrazol-l- yl]acetonitrile

To a solution of l-[5-chloro-2-methoxy-4-methyl-3-(lH-pyrazol-4-yl)phenyl]eth anone

(0.13 g, 0.49 mmol) in N,N-dimethylformamide (2 mL) was added sodium hydride (60%> in oil, 0.014 g, 0.59 mmol) at 0 °C. The mixture was stirred for 1 hour at room temperature, followed by the addition of chloroacetonitrile (0.037 mL, 0.59 mmol) at 0 °C. The reaction was stirred at room temperature for 1 hour, quenched with water and extracted with ethyl acetate. The organic layers were dried over MgS0 ₄ , filtered and concentrated under reduced pressure. The resulting residue was purified on silica gel (eluting with 0-40% of ethyl acetate in hexanes) to afford the desired product (0.1 g, 67%). LCMS calculated for Ci ₅ Hi ₅ ClN ₃ 0 ₂ (M+H) ⁺ : m/z = 304.1 ; found: 304.1. Step 4. {4-[ 3-( I -Aminoethyl)-5-chloro-2-methoxy-6-methylphenyl] -1 H-pyrazol-l -yljacetonitrile

A mixture of [4-(3-acetyl-5-chloro-2-methoxy-6-methylphenyl)-lH-pyrazol-l - yl] acetonitrile (0.10 g, 0.33 mmol), ammonium acetate (0.254 g, 3.29 mmol) and 1.0 M sodium cyanoborohydride in tetrahydrofuran (0.82 mL, 0.82 mmol) in methanol (0.9 mL) and acetonitrile (0.9 mL) was heated at 65 °C overnight. The mixture was cooled to room

temperature, quenched with saturated sodium bicarbonate solution and extracted with

dichloromethane. The combined organic layers were dried over MgSC^ and concentrated to give the desired product. LCMS calculated for Ci ₅ Hi ₅ ClN ₃ 0 (M-NH ₂ ) ⁺ : m/z = 288.1 ; found: 288.0.

Step 5. (4-{3-Chloro-6-methoxy-2-methyl-5-[ l-(9H-purin-6-ylamino)ethyl] phenyl}- lH-pyrazol- l-yl) acetonitrile trifluoroacetate

A mixture of {4-[3-(l-aminoethyl)-5-chloro-2-methoxy-6-methylphenyl]-lH-p yrazol-l- yl} acetonitrile (0.12 g, 0.39 mmol), 6-bromo-9H-purine (0.12 g, 0.59 mmol) and N,N- diisopropylethylamine (0.14 mL, 0.79 mmol) in ethanol (1 mL) was heated at 100 °C

overnight. The mixture was purified on prep LCMS (XBridge CI 8 Column, eluting with a gradient of acetonitrile in water with 0.05% trifluoroacetic acid, at flow rate of 30 mL/min) to afford the desired product as TFA salt. LCMS calculated for C ₂ oH ₂ oClN ₈ 0 (M+H) ⁺ : m/z = 423.1 ; found: 423.1. 1H NMR (DMSO-d ₆ , 300 MHz) δ 9.06 (1H, br s), 8.44 (2H, m), 8.00 (1H, s), 7.70

(1H, s), 7.51 (1H, s), 5.73 (lH, m), 5.55 (2H, s), 3.42 (3H, s), 2.16 (3H, s), 1.53 (3H, d, J

Hz) ppm. Compounds Synthesized

Experimental procedures for compounds below are summarized in Table 1 below.

Table 1

purin-6-amine 1

nitrile

4-carboxamid 1

4-carboxamide

purin-6-amine 6-amine 1 Ex. Name

R ⁵ R ⁴ R ³ Salt Proc. ¹ No.

N- { 1 -[5-chloro-2-methoxy-6- S0 ₂ Me

methyl-4'-

1 16 ⁴ CI Me 108

(methylsulfonyl)biphenyl-3 - yl]ethyl} -9H-purin-6-amine 1

Synthesized according to the experimental procedure of compound listed;

2Two atropic isomers isolated;

3cis- and trans-isomers isolated;

4Single enantiomer.

Experimental procedures for compounds below are summarized in Table 2.

Table 2

yl]ethyl} -9H-purin-6-amine

Synthesized according to the experimental procedure of compound listed;

2Two atropic isomers isolated.

Analytical Data

1H NMR data (Varian Inova 500 spectrometer, a Mercury 400 spectrometer, or a Varian

(or Mercury) 300 spectrometer) and LCMS mass spectral data (MS) for the compounds of the Examples above is provided below in Table 3.

Table 3

Ex. MS

Solvent MHz ^J H NMR Spectra No. [M+H] ⁺

24 465.1 - - -

12.85 (IH, br s), 8.32 (IH, d, J= 3.2 Hz), 8.17 (IH, m), 8.15 (IH, s), 8.1 1 (IH, s), 8.08 (IH, d, J= 2.8 Hz), 7.83

25 472.2 DMSO-i/ ₆ 400 (IH, s), 7.44 (IH, d, J= 6.0 Hz), 7.29 (IH, t, J= 6.8 Hz),

7.19 (2H, m), 7.01 (IH, d, J= 7.2 Hz), 5.05 (IH, m), 3.79 (3H, s), 2.03 (3H, s), 1.29 (3H, d, J= 6.8 Hz) ppm.

26 497.1 - - -

27 451.2 - - -

28 412.1 - - -

29 430.1 - - -

30 419.1 - - -

31 477.1 - - -

32 472.1 - - -

33 41 1.1 - - -

34 425.1 - - -

35 428.1 - - -

12.83 (IH, br s), 8.67 (IH, s), 8.52 (0.5H, s), 8.42 (IH,

36 429.0 DMSO-i/ ₆ 400 s), 8.10 (4H, m), 7.69 (IH, s), 5.75 (IH, m), 3.44 (3H, s),

2.00 (3H, s), 1.48 (IH, d, J= 7.2 Hz) ppm.

37 485.1 - - -

38 462.1 - - -

39 456.2 - - -

12.93 (IH, s), 8.23 (IH, m), 8.1 1 (IH, m), 7.87 (IH, m),

40 419.1 DMSO-i/ ₆ 400 7.69-7.60 (4H, m), 5.74 (IH, m), 3.39 (3H, s), 1.97 (3H, s), 1.48 (3H, d, J= 4.4 Hz) ppm.

41 433.1 - - -

42 438.1 - - -

43 460.1 - - -

44 438.1 - - -

45 495.2 - - -

46 433.1 - - - Ex. MS

Solvent MHz ^J H NMR Spectra No. [M+H] ⁺

47 462.0 - - -

48 480.1 - - -

12.94 (IH, br s), 8.22-8.09 (4H, m), 7.71 (IH, m), 6.93 (0.5H, dd, J= 4.8 and 4.4 Hz), 6.82 (0.5H, dd, J= 4.8

49 498.1 DMSO-i/ ₆ 400 and 4.4 Hz), 5.37 (IH, m), 3.72 (4H, m), 3.54 (1.5H, s),

3.51 (1.5H, s), 3.36 (4H, m), 1.99 (1.5H, s), 1.97 (1.5H, s), 1.47 (3H, m) ppm.

50 430.1 - - -

12.91 (IH, br s), 8.22 (IH, s), 8.14-7.92 (3H, m), 8.03 (0.5H, m), 7.92 (0.5H, m), 7.68 (IH, s), 7.29 (IH, m),

51 413.1 DMSO-i/ ₆ 400

5.73 (IH, m), 3.42 (3H, s), 2.00 (3H, s), 1.48 (3H, d, J = 6.8 Hz) ppm.

12.88 (IH, br s), 8.17-8.00 (4H, m), 7.64-7.60 (2H, m),

52 425.1 DMSO-i/ ₆ 400 6.86 (IH, d, J= 8.4 Hz), 5.69 (IH, m), 3.84 (3H, s), 3.36

(3H, s), 1.96 (3H, s), 1.43 (3H, d, J= 6.8 Hz) ppm.

53 420.1 - - -

54 502.1 - - -

55 409.0 - - -

56 473.0 - - -

57 410.1 - - -

58 420.1 - - -

8.19 (IH, m), 8.14 (IH, s), 8.12 (IH, s), 8.04 (IH, m), 7.62 (2H, m), 6.82 (IH, d, J= 8.4 Hz), 5.73 (IH, m), 5.28

59 453.1 DMSO-i/ ₆ 300

(IH, m), 3.41 (3H, s), 2.02 (3H, s), 1.48 (3H, d, J= 6.6 Hz), 1.31 (6H, d, J= 6.0 Hz) ppm.

64 483.1 - - -

65 483.1 - - -

67 509.2 - - -

68 525.2 - - -

69 469.1 - - -

70 539.2 - - - Ex. MS

Solvent MHz ^J H NMR Spectra No. [M+H] ⁺

71 509.1 - - -

73 462.0 - - -

74 462.2 - - -

75 490.0 - - -

77 495.1 - - -

78 477.1 - - -

79 501.1 - - -

80 513.1 - - -

81 478.0 - - -

82 508.1 - - -

83 533.2 - - -

9.19 (1H, br s), 8.47 (2H, m), 8.34 (1H, d, J= 5.1 Hz),

84 413.1 DMSO-i/ ₆ 300 7.65 (1H, s), 7.33 (1H, m), 7.22 (1H, m), 5.75 (1H, m),

3.42 (3H, s), 2.01 (3H, s), 1.55 (3H, d, J= 6.9 Hz) ppm.

85 446.1 - - -

86 480.1 - - -

87 427.1 - - -

88 479.2 - - -

89 446.1 - - -

90 478.1 - - -

91 438.1 - - -

92 446.0 - - -

93 480.1 - - -

9.24 (1H, br s), 8.49 (2H, m), 7.57 (1H, s), 7.39 (2H, m), 7.28 (1H, m), 5.75 (1H, m), 3.34 (3H, s), 2.99 (1.5H, s),

94 483.2 DMSO-i/ ₆ 300

2.98 (1.5 H, s), 2.87 (1.5 H, s), 2.86 (1.5 H, s), 2.02 (3H, s), 1.55 (3H, d, J= 6.9 Hz) ppm.

95 442.1 - - -

96 454.1 - - -

97 458.1 - - - Ex. MS

Solvent MHz ^J H NMR Spectra No. [M+H] ⁺

9.1 1 (1H, br s), 8.51 (1H, d, J= 4.8 Hz), 8.45 (2H, m),

98 429.1 DMSO-i/ ₆ 300 7.65 (1H, s), 7.54 (1H, m), 7.41 (1H, m), 5.74 (1H, m),

3.42 (3H, s), 2.01 (3H, s), 1.54 (3H, d, J= 7.2 Hz) ppm.

99 428.0 - - -

100 437.2 - - -

101 424.1 - - -

102 438.1 - - -

103 424.1 - - -

104 451.1 - - -

105 430.0 - - -

107 494.1 - - -

8.17 (1H, m), 8.10 (1H, m), 8.08 (1H, s), 7.86 (1H, m),

109 443.1 DMSO-i/ ₆ 300 7.78 (1H, m), 7.61 (1H, s), 5.70 (1H, m), 3.94 (3H, s),

3.40 (3H, s), 1.98 (3H, s), 1.43 (3H, d, J= 6.6 Hz) ppm.

8.80 (1H, br s), 8.35 (2H, m), 8.08 (1H, m), 7.72 (1H, m), 7.65-7.59 (3H, m) 7.43 (0.5H, m), 7.35 (0.5 H, m), 5.75

1 10 455.1 DMSO-i/ ₆ 300

(1H, m), 3.40 (1.5H, s), 3.38 (1.5H, s), 2.00 (3H, s), 1.53 (3H, d, J= 6.6 Hz) ppm.

8.60 (1H, s), 8.57 (0.5H, m), 8.49 (0.5H, m), 8.16-8.07 (3H, m), 7.84 (0.5H, m), 7.73 (0.5H, m), 7.64 (1H, m),

1 1 1 508.1 DMSO-i/ ₆ 300 5.67 (1H, m), 3.58 (4H, m), 3.35 (3H, s), 3.29 (4H, m),

1.99 (1.5H, s), 1.96 (1.5H, s), 1.44 (3H, d, J= 6.9 Hz) ppm.

10.55 (1H, s), 8.15 (2H, m), 8.12 (1H, s), 8.09 (1H, s), 8.06 (1H, s), 7.70 (1H, m), 7.59 (1H, m), 5.69 (1H, m),

1 12 452.1 DMSO-i/ ₆ 300

3.37 (3H, s), 2.06 (3H, s), 1.97 (3H, s), 1.43 (3H, d, J = 6.6 Hz) ppm.

12.68 (1H, br s), 9.07 (1H, d, J= 0.9 Hz), 8.21-7.99 (5H,

1 14 420.0 DMSO-i/ ₆ 300 m), 7.72 (1H, s), 5.73 (1H, m), 3.42 (3H, s), 2.00 (3H, s),

1.49 (3H, d, J= 7.2 Hz) ppm. Ex. MS

Solvent MHz ^J H NMR Spectra

No. [M+H] ⁺

12.71 (1H, br s), 8.12-8.06 (4H, m), 7.55 (1H, s), 6.73

1 15 41 1.1 DMSO-i/ ₆ 300 (2H, s), 5.68 (1H, m), 3.43 (3H, s), 2.03 (3H, s), 1.43

(3H, d, J= 7.2 Hz) ppm.

8.22 (1H, m), 8.15 (1H, s), 8.12 (1H, s), 8.01 (2H, d, J =

9.0 Hz), 7.67 (1H, s), 7.62 (1H, m), 7.55 ((1H, m), 5.73

1 16 472.0 DMSO-i/ ₆ 300

(1H, m), 3.40 (3H, s), 3.29 (3H, s), 1.97 (3H, s), 1.49

(3H, d, J= 6.9 Hz) ppm.

Example 118. V-{l-[5-Fluoro-2-methoxy-6-methyl-4 ^, -(methylsulfonyl)biphenyl-3-yl]ethyl}- 9H-purin-6-amine

Step 1. 4-Fluoro-3-methylphenyl acetate

A solution of 4-fluoro-3-methylphenol (3.0 g, 23 mmol) and methylene chloride (96 mL) was cooled to 0 °C in an ice bath. Triethylamine (4.9 mL, 35 mmol) was introduced to the solution followed by dropwise addition of acetyl chloride (2.3 mL, 33 mmol). The ice bath was removed and the mixture was stirred for 1 hour. The mixture was then extracted with methylene chloride and washed with 0.5 N HCl, saturated sodium bicarbonate and brine. The extracts were dried over sodium sulfate, filtered and evaporated to give 4-fluoro-3-methylphenyl acetate (3.9 g, quantitative). ^λ Η NMR (400 MHz, CDC1 ₃ ): δ 7.00 (m, 1 H), 6.87 (m, 2 H), 2.29 (m, 6 H). Step 2. l-(5-Fluoro-2-hydroxy-4-methyl henyl)ethanone

A suspension of 4-fluoro-3-methylphenyl acetate (3.9 g, 23 mmol) in boron trifluoride acetic acid complex (47 mL, 340 mmol) was heated at 155 °C for 14 hours. The mixture was then cooled to 0 °C in an ice bath and ice was added directly to the mixture. The ice bath was subsequently removed and the mixture stirred until the ice added to the mixture was dissolved. The mixture was then diluted with cold water and filtered. The isolated rust-colored solid was washed with cold water and allowed to dry in air to give l-(5-Fluoro-2-hydroxy-4- methylphenyl)ethanone (3.2 g, 81%). 1H NMR (400 MHz, CDCI3): δ 11.98 (s, 1 H), 7.34(m, 1 H), 6.80 (m, 1 H), 2.60 (s, 3 H), 2.28 (s, 3 H).

Step 3. l-(3-Bromo-5-fluoro-2-hydroxy-4-meth lphenyl)ethanone

To a solution of l-(5-fluoro-2-hydroxy-4-methylphenyl)ethanone (2.2 g, 13 mmol) and acetic acid (20 mL, 400 mmol) was added N-bromosuccinimide (2.8 g, 16 mmol). The resulting mixture was stirred at room temperature for 18 hours. The reaction mixture was then

concentrated in vacuo, neutralized with saturated sodium bicarbonate and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated to dryness under reduced pressure. Purification on silica gel with ethyl acetate/hexanes (0-50%) gave l-(3-Bromo-5-fluoro-2-hydroxy-4-methylphenyl)ethanone (2.3 g,

71%). !H NMR (400 MHz, CDC1 ₃ ): δ 12.80 (s, 1 H), 7.40 (m, 1 H), 2.60 (s, 3 H), 2.40 (s, 3 H).

Step 4. l-(3-Bromo-5-fluoro-2-methoxy-4-methylphenyl)ethanone

To a mixture of l-(3-bromo-5-fluoro-2-hydroxy-4-methylphenyl)ethanone (0.3 g, 1 mmol) and potassium carbonate (0.43 g, 3.1 mmol) was added N,N-dimethylformamide (1 mL) and methyl iodide (0.17 mL, 2.7 mmol) with stirring. The resulting mixture was then heated at 60 °C for 1 hour. The mixture was diluted with water and extracted with ethyl acetate. The combined extracts were washed with brine, dried over sodium sulfate, and evaporated to dryness. The isolated residue was purified on silica gel, eluting with ethyl acetate/hexanes (0 to 20%) to yield l-(3-Bromo-5-fluoro-2-methoxy-4-methylphenyl)ethanone (0.24 g, 80%). LCMS calculated for Ci ₀ HnBrFO ₂ (M+H) ⁺ : m/z = 261.0, 263.0; Found: 260.9, 262.9. 1H NMR (400 MHz, CDC1 ₃ ): δ 7.35 (m, 1 H), 3.82 (s, 3 H), 2.61 (s, 3 H), 2.39 (s, 3 H).

Step 5. l-(3-Bromo-5-fluoro-2-methoxy-4-methylphenyl)ethanamine trifluoroacetate

A mixture of l-(3-bromo-5-fluoro-2-methoxy-4-methylphenyl)ethanone (140 mg, 0.55 mmol) and ammonium acetate (640 mg, 8.3 mmol) in acetonitrile (1.3 mL) and methanol (1.3 mL) was heated at 65 °C for 1 hour. Sodium cyanoborohydride (87 mg, 1.4 mmol) was added and the resulting mixture was heated at 65 °C for 3 hours. Purification by preparative LCMS (pH 2) RP-HPLC (XBridge CI 8 Column, eluting with a gradient of acetonitrile in water with 0.1% trifluoroacetic acid, at flow rate of 60 mL/min) gave l-(3-Bromo-5-fluoro-2-methoxy-4- methylphenyl)ethanamine trifluoroacetate (150 mg, 70%). LCMS calculated for CioHnBrFO (M-NH ₂ ) ⁺ : m/z = 245.0, 247.0; Found: 244.9, 246.9.

Step 6. N-f l-(3-Bromo-5-fluoro-2-methoxy-4-methylphenyl)ethyl]-9-(tetra hydro-2H-pyran-2- yl)-9H-purin-6-amine

A mixture of l-(3-bromo-5-fluoro-2-methoxy-4-methylphenyl)ethanamine

trifluoroacetate (130 mg, 0.35 mmol), 6-bromo-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (150 mg, 0.53 mmol, from Example 108, Step 1), N,N-diisopropylethylamine (0.31 mL, 1.8 mmol) and ethanol (2.0 mL) was heated at 95 °C for 1 hour. The resulting mixture was diluted with methanol and purified by preparative LCMS (pH 10) RP-HPLC (XBridge C18 Column, eluting with a gradient of acetonitrile in water with 0.2% ammonium hydroxide, at flow rate of 60 mL/min) to afford N-[l-(3-Bromo-5-fluoro-2-methoxy-4-methylphenyl)ethyl]-9-(te trahydro-2H- pyran-2-yl)-9H-purin-6-amine (40 mg, 47%). LCMS calculated for C ₂ oH ₂₄ BrFN ₅ 0 ₂ (M+H) ⁺ : m/z = 464.0, 466.0; Found: 464.1, 466.1.

Step 7. N-{l-[5-Fluoro-2-methoxy-6-methyl-4'-(methylsulfonyl)bipheny l-3-yl] ethyl} -9H-purin-6- amine

N-[ 1 -(3 -bromo-5 -fluoro-2-methoxy-4-methylphenyl)ethyl] -9-(tetrahydro-2H-pyran-2- yl)-9H-purin-6-amine (21 mg, 0.044 mmol), [4-(methylsulfonyl)phenyl]boronic acid (13 mg, 0.066 mmol), potassium carbonate (15 mg, 0.11 mmol), water (0.2 mL) , and 1 ,4-dioxane (0.40 mL) were added to a microwave vial. The mixture was degassed under nitrogen for 5 minutes. Tetrakis(triphenylphosphine)palladium(0) (5.1 mg, 4.4 μιηοΐ) was added to the mixture and the the vial was then sealed and bubbled under nitrogen for 5 minutes. The mixture was heated at 80 °C overnight. The cooled reaction mixture was then treated with 4.0 M hydrogen chloride in water (0.5 mL, 2 mmol) and was stirred at room temperature for 30 minutes. Purification by preparative LCMS (pH 10) RP-HPLC (XBridge CI 8 Column, eluting with a gradient of acetonitrile in water with 0.2% ammonium hydroxide, at flow rate of 60 mL/min) afforded N-{1- [5-Fluoro-2-methoxy-6-methyl-4'-(methylsulfonyl)biphenyl-3-y l]ethyl}-9H-purin-6-amine (13 mg, 66%). LCMS calculated for C ₂₂ H ₂₃ FN ₅ 0 ₃ S (M+H) ⁺ : m z = 456.1; Found: 456.0. Experimental procedures for compounds of Examples 118-123 are summarized in Table

4 below.

Table 4

Synthesized according to the experimental procedure of compound listed.

Analytical Data

1H NMR data (Varian Inova 500 spectrometer, a Mercury 400 spectrometer, or a Varian (or Mercury) 300 spectrometer) and LCMS mass spectral data (MS) for the compounds of Examples 118-123 is provided below in Table 5.

Table 5

Example 124. V-{l-[4-Chloro-3',5'-difluoro-6-(lH-pyrazol-4-yl)biphenyl-2- yl]ethyl}-9H- purin-6-amine

Step A: 2-Acetyl-6-bromo-4-chlorophenyl trifluoromethanesulfonate

The desired compound was prepared according to the procedure of Example 1, step 3, using l-(3-bromo-5-chloro-2-hydroxyphenyl)ethanone as the starting material in 97% yield.

LCMS for C ₉ H ₆ BrClF ₃ 0 ₄ S (M+H)+: m/z = 380.9, 382.9; Found: 380.8, 382.9.

Step B: l-( 6-Bromo-4-chloro-3 ', 5 '-dtfluorobiphenyl-2-yl)ethanone

A solution of sodium hydrogenecarbonate (2.0 g, 23 mmol) in water (50 mL) was treated with a solution of 2-acetyl-6-bromo-4-chlorophenyl trifluoromethanesulfonate (4.5 g, 12 mmol) in toluene (50 mL) followed by (3,5-difluorophenyl)boronic acid (2.0 g, 13

mmol) and tetrakis(triphenylphosphine)palladium(0) (0.67 g, 0.58 mmol). The reaction mixture was degassed with nitrogen for 5 min and heated at 80 °C overnight. The reaction mixture was diluted wih water and extracted with ethyl acetate (2 x lOOmL). The combined organic layers were washed with sodium bicarbonate, water, and brine, dried with sodium sulfate, filtered, and concentrated to a crude residue. Purification by flash column chromatography using ethyl acetate in hexanes (0% - 10%) gave the desired product (3.7 g, 82%>). LCMS for

Ci4H ₉ BrClF ₂ 0 (M+H)+: m/z = 344.9, 346.9; Found: 344.9, 346.8. Step C: l-{4-Chloro-6-[l-( l-ethoxyethyl)-lH-pyrazol-4-yl]-3 ', 5 '-dtfluorobiphenyl-2-yl}ethanone

A solution of l-(6-bromo-4-chloro-3',5'-difluorobiphenyl-2-yl)ethanone (300 mg, 0.87 mmol), l-(l-ethoxyethyl)-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan- 2-yl)-lH-pyrazole (250 mg, 0.96 mmol), and sodium carbonate (280 mg, 2.6 mmol) in 1,4-dioxane (3.0 mL, 38 mmol) was degassed with nitrogen 5 minutes, treated with tetrakis(triphenylphosphine)palladium(0) (100 mg, 0.087 mmol) degassed with additional nitrogen for 5 mins, and heated at 80 °C overnight. The reaction mixture was diluted with water and extracted with ethyl acetate (2 x 60mL). The combined organic layers were washed with water and brine, dried with sodium sulfate, filtered, and concentrated to a crude residue. Purification via preparative LCMS (XBridge CI 8 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) gave the desired product (190 mg, 54%). Step D: l-{4-Chloro-6-[l-(l-ethoxyethyl)-lH-pyrazol-4-yl]-3',5'-difl uorobiphenyl-2- yljethanamine

A solution of l-{4-chloro-6-[l-(l-ethoxyethyl)-lH-pyrazol-4-yl]-3',5'-difl uorobiphenyl- 2-yl}ethanone (190 mg, 0.47 mmol), ammonium acetate (360 mg, 4.7 mmol) in methanol (2 mL) and acetonitrile (2 mL) was heated at 65 °C for 3 hours. The reaction mixture was quenched with acetic acid (-100 uL) and poured into sodium bicarbonate (50 mL). This mixture was extracted with dichloromethane (3 x 60mL) and the combined organic layers were washed with brine, dried with sodium sulfate, filtered, and concentrated to a crude residue. Purification via preparative LCMS (XBridge CI 8 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) gave the desired product (60 mg, 32%). LCMS for C21H23CIF2N3O (M+H)+: m/z = 406.1; Found: 406.1.

Step E: N-{l-[ 4-Chloro-3 ', 5 '-difluoro-6-(lH-pyrazol-4-yl)biphenyl-2-yl]ethyl}-9H-purin- 6- amine

A solution of l-{4-chloro-6-[l-(l-ethoxyethyl)-lH-pyrazol-4-yl]-3',5'-difl uorobiphenyl- 2-yl}ethanamine (60 mg, 0.15 mmol), 6-bromo-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (63 mg, 0.22 mmol, from Example 108, Step 1), and N,N-diisopropylethylamine (77 0.44 mmol) in ethanol (2.8 mL) was heated in the microwave at 130 °C for 30 minutes. Alternatively, this reaction can be heated at 90 °C overnight on the benchtop. The reaction mixture was cooled to room temperature, treated with 6 M Hydrogen chloride in water (0.49 mL, 3.0 mmol), and stirred for 30 minutes. The reaction mixture was diluted slightly with methanol, filtered, and directly purified via preparative LCMS (XBridge CI 8 column, eluting with a gradient of

acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) to give the desired product (29 mg, 43%). LCMS for C22H17CIF2N7 (M+H)+: m/z = 452.1; Found:

452.0; !H NMR (300 MHz, DMSO-^): δ 12.8 (br s, 1 H), 8.32 - 8.23 (m, 1 H), 8.11 (s, 1 H),

8.06 (s, 1 H), 7.65 (s, 1 H), 7.46 (s, 1 H), 7.36 - 7.23 (m, 3 H), 7.09 - 7.01 (m, 1 H), 6.96 (d, J = 8.5 Hz, 1 H), 5.09 - 4.96 (m, 1 H), 1.34 (d, J= 6.7 Hz, 3 H).

Example 125. V-{l-[5-Chloro-3-(5-chloropyridin-3-yl)-2-methoxyphenyl]ethy l}-9H-purin- 6-amine

Step A: l-(3-Bromo-5-chloro-2-methoxyphenyl)ethanone

A solution of l-(3-bromo-5-chloro-2-hydroxyphenyl)ethanone (5.0 g, 20 mmol) in N,N- dimethylformamide (40 mL) was treated with potassium carbonate (5.5 g, 40 mmol) followed by methyl iodide (1.9 mL, 30 mmol) and heated at 60 °C overnight. The reaction mixture was diluted with water (300 mL) and extracted with ethyl acetate (2 x 150 mL). The organic layers were washed with water (3 x lOOmL) and brine, dried with sodium sulfate, filtered, and concentrated to give the crude product. Purification by flash column chromatography using ethyl acetate in hexanes (0% - 5% - 25%) gave the desired product (5.1 g, 96%). LCMS for

C ₉ H ₉ BrC10 ₂ (M+H)+: m/z = 262.9, 264.9; Found: 262.9, 264.9.

Step B: l-(3-Bromo-5-chloro-2-methoxyphenyl)ethanamine

The desired compound was prepared according to the procedure of Example 124, step D, using l-(3-bromo-5-chloro-2-methoxyphenyl)ethanone as the starting material in 56% yield.

LCMS for C ₉ H ₁₂ BrClNO (M+H)+: m/z = 264.0, 266.0; Found: 263.9, 265.9.

Step C: N-[ l-( 3-Bromo-5-chloro-2-methoxyphenyl) ethyl] -9- ( tetrahydro-2H-pyran-2

purin-6-amine

A solution of l-(3-bromo-5-chloro-2-methoxyphenyl)ethanamine (2.2 g, 8.5

mmol) in ethanol (69 mL), was treated with 6-bromo-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (3.6 g, 13 mmol, from Example 108, Step 1) and N,N-diisopropylethylamine (4.4 mL, 25 mmol) and heated at reflux overnight. The reaction mixture was cooled, poured into sodium

bicarbonate (150 mL) and extracted with ethyl acetate (2 x 150 mL). The combined organic layers were washed with water and brine, dried with sodium sulfate, filtered, and concentrated to a crude residue. Purification by flash column chromatography using acetonitrile in

dichloromethane (5% - 10%) and then ethyl acetate in hexanes (60% - 100%) gave the desired product (3.9 g, 98%). LCMS for C ₁₉ H ₂ 2BrClN ₅ 02 (M+H)+: m/z = 466.1, 468.1; Found:

466.0, 468.0. Step D: N-{l-[ 5-Chloro-3-(5-chloropyridin-3-yl)-2-methoxyphenyl]ethyl}-9H^ urin-6-amine A solution of N-[l-(3-bromo-5-chloro-2-methoxyphenyl)ethyl]-9-(tetrahydro- 2H-pyran- 2-yl)-9H-purin-6-amine (45 mg, 0.096 mmol) and (5-chloropyridin-3-yl)boronic acid (23 mg, 0.15 mmol) in water (0.5 mL) and 1,4-dioxane (1 mL) was treated with potassium carbonate (33 mg, 0.24 mmol) and tetrakis(triphenylphosphine)palladium(0) (11 mg, 9.6 μιηοΐ). The reaction mixture was degassed with nitrogen for 5 min and heated at 80 °C overnight. The reaction mixture was cooled treated directly with 6 M hydrogen chloride in water (170 1.0 mmol) and stirred at room temperature for ~30 minutes. The reaction mixture was diluted slightly with methanol, filtered, and directly purified via preparative LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) to give the desired product (6 mg, 15%). LCMS for C19H17CI2N6O (M+H)+: m/z = 415.1; Found: 415.0; NMR (300 MHz, DMSO-<¾): δ 8.72 (d, J = 1.8 Hz, 1 H), 8.66 (d, J =

2.3 Hz, 1 H), 8.20 - 8.09 (m, 4 H), 7.65 (d, J= 2.1 Hz, 1 H), 7.40 (d, J= 2.6 Hz, 1 H), 5.91 - 5.71 (m, 1 H), 3.52 (s, 3 H), 1.51 (d, J= 7.0 Hz, 3 H). Example 126. V-{l-[5-Chloro-4-methyl-2-(2-morpholin-4-ylethoxy)-3-pyridin -4- ylphenyl]ethyl}-9H-purin-6-amine

Step A: l-[3-Bromo-5-chloro-4-meth l-2-(2-morpholin-4-ylethoxy)phenyl]ethanone

A solution of l-(3-bromo-5-chloro-2-hydroxy-4-methylphenyl)ethanone (34 mg, 0.13 mmol), triphenylphosphine (47 mg, 0.18 mmol), and 4-morpholineethanol (23 μί, 0.19 mmol) in tetrahydrofuran (0.38 mL, 4.6 mmol) at -10 °C was treated with diisopropyl azodicarboxylate (35 μί, 0.18 mmol) dropwise and stirred at -10 °C for 15 min and warmed to 20 °C for 30 minutes. The reaction mixture was concentrated, diluted with ethyl acetate (5 mL), and washed with water and brine, dried with magnesium sulfate, filtered, and concentrated to a crude oil. Purification by flash column chromatography using ethyl acetate in hexanes (0% - 60%) gave the desired product (15 mg, 31%). LCMS for C ₁₅ H ₂ oBrClN0 ₃ (M+H)+: m/z = 376.0, 378.0; Found: 375.9, 378.0.

Step B: l-[ 5-Chloro-4-methyl-2-(2-mor holin-4-ylethoxy)-3-pyridin-4-ylphenyl]ethanone

The desired compound was prepared according to the procedure of Example 124, step C, g l-[3-bromo-5-chloro-4-methyl-2-(2-morpholin-4-ylethoxy)pheny l]ethanone and cesium carbonate (instead of sodium carbonate) as the starting materials in 62% yield. LCMS for C20H24CIN2O3 (M+H)+: m/z = 375.1; Found: 375.1.

Step C: 1-f 5-Chloro-4-methyl-2-(2-morpholin-4-ylethoxy)-3^yridin-4-ylph enylJethanamine

The desired compound was prepared according to the procedure of Example 124, step D, using l-[5-chloro-4-methyl-2-(2-morpholin-4-ylethoxy)-3-pyridin-4- ylphenyl]ethanone as the starting material in 98% yield. LCMS for C20H27CIN3O2 (M+H)+: m/z = 376.2; Found:

376.1.

Step D: N-{l-f5-Chloro-4-methyl-2-(2-morpholin-4-ylethoxy)-3^yridin- 4-ylphenylJethyl}-9H- purin-6-amine

The desired compound was prepared according to the procedure of Example 124, step E, using l-[5-chloro-4-methyl-2-(2-morpholin-4-ylethoxy)-3-pyridin-4- ylphenyl]ethanamine as the starting material in 12% yield. LCMS for C25H29CIN7O2 (M+H)+: m/z = 494.2; Found:

494.2; !H NMR (300 MHz, DMSO-^): δ 12.9 (s, 1 H), 8.65 (d, J= 5.0 Hz, 2 H), 8.26 - 8.15

(m, 1 H), 8.12 (s, 1 H), 8.06 (s, 1 H), 7.68 (s, 1 H), 7.47 - 7.29 (m, 2 H), 5.86 - 5.72 (m, 1 H), 4.08 - 4.00 (m, 1 H), 3.41 - 3.37 (m, 4 H), 2.31 - 2.28 (m, 2 H), 2.21 - 2.14 (m, 2 H) 2.10 - 2.04 (m, 2 H), 1.96 (s, 3 H), 1.48 (d, J= 7.0 Hz, 3 H).

Example 127. V-[l-(5-Chloro-2,4-dimethyl-3-pyridin-4-ylphenyl)ethyl]-9H-p urin-6-amine

Step A: l-(5-Chloro-2-hydroxy-4-methyl-3- ridin-4-ylphenyl)ethanone

A solution of l-(3-bromo-5-chloro-2-hydroxy-4-methylphenyl)ethanone (2.6 g, 9.9 mmol), 4-pyridinylboronic acid (1.6 g, 13 mmol), and potassium carbonate (5.5 g, 40 mmol) in 1 ,2-dimethoxyethane (48 mL) and water (24 mL) was degassed with nitrogen and treated with triphenylphosphine (260 mg, 0.99 mmol) and palladium acetate (0.22 g, 0.99 mmol). The reaction mixture was degassed with nitrogen for 5 min and heated at 90 °C for 20 hours. The reaction mixture was cooled to room temperature, concentrated to remove most of the DME, diluted with ethyl acetate (200 ml) and water (100 ml), and filtered over celite. The aqueous layer was separated and extracted with ethyl acetate (100 mL). The combined organic layers were washed with brine (100 ml), dried over sodium sulfate, filtered, and concentrated to a crude brown foam. Purification by flash column chromatography using ethyl acetate in hexanes

(0% - 60%) gave the desired product (1.2 g, 45%). LCMS for Ci4H ₁₃ ClNC>2 (M+H)+: m/z = 262.1; Found: 262.0.

Step B: 6-Acetyl-4-chloro-3-methyl-2-pyridin-4-ylphenyl trifluoromethanesulfonate

The desired compound was prepared according to the procedure of Example 1, step 3, using l-(5-chloro-2-hydroxy-4-methyl-3-pyridin-4-ylphenyl)ethanone as the starting material in

81% yield. LCMS for Ci ₅ H ₁₂ ClF ₃ N04S (M+H)+: m/z = 394.0; Found: 393.9.

Step C: l-(5-Chloro-2, 4-dimethyl-3-pyridin-4- lphenyl)ethanone

A solution of 6-acetyl-4-chloro-3-methyl-2-pyridin-4-ylphenyl trifluoromethanesulfonate (0.40 g, 1.0 mmol) in 1,4-dioxane (10 mL, 130 mmol) was degassed with nitrogen and treated with [1,1 '-bis(diphenylphosphino)ferrocene]dichloropalladium(II),comp lex with

dichloromethane (1 : 1) (41 mg, 0.051 mmol). The reaction mixture was degassed with nitrogen for 5 minutes, treated with 2.0 M dimethylzinc in toluene (0.76 mL, 1.5 mmol), and heated at 70 °C for 1.5 hours. The reaction mixture was cooled to room temperature diluted with ethyl acetate and water and filtered over celite to remove solids. The ethyl acetate layer was separated, washed with brine, dried over sodium sulfate, filtered, and concentrated to a crude brown gum. Purification by flash column chromatography using ethyl acetate in hexanes (0% -

20%) gave the desired product (0.18 g, 69%). LCMS for C ₁₅ H ₁₅ C1N0 (M+H)+: m/z = 260.1;

Found: 260.1.

Step D: l-(5-Chloro-2,4-dimethyl-3-pyridin-4-ylphenyl)ethanamine

The desired compound was prepared according to the procedure of Example 124, step D, using l-(5-chloro-2,4-dimethyl-3-pyridin-4-ylphenyl)ethanone as the starting material in 40% yield. LCMS for C ₁₅ H ₁₈ C1N ₂ (M+H)+: m/z = 261.1; Found: 261.0.

Step E: N-[l-(5-Chloro-2,4-dimethyl-3^yridin-4-ylphenyl)ethylJ-9H^ur in-6-amine

The desired compound was prepared according to the procedure of Example 124, step E, using l-(5-chloro-2,4-dimethyl-3-pyridin-4-ylphenyl)ethanamine as the starting material in 32% yield. LCMS for C20¾oClN6 (M+H)+: m/z = 379.1; Found: 379.1; !H NMR (400 MHz, DMSO-^): δ 12.9 (br s, 1 H), 8.67 - 8.64 (m, 2 H), 8.32 - 8.24 (m, 1 H), 8.12 (s, 2 H), 7.68 (s, 1

H), 7.22 (d, J = 5.1 Hz, 1 H), 7.21 (s, 1 H), 5.69 - 5.60 (m, 1 H), 2.04 (s, 3 H), 1.89 (s, 3 H), 1.47 (d, J= 6.6 Hz, 3 H).

Example 128. V-{l-[5-Chloro-6-methyl-4'-(methylsulfonyl)-2-(2-morpholin-4 - ylethoxy)biphenyl-3-yl]ethyl}-9H-purin-6-amine

Step A: l-[3-Bromo-5-chloro-4-methyl-2-(2-morpholin-4-ylethoxy)pheny l]ethanamine

The desired compound was prepared according to the procedure of Example 124, step D, using l-[3-bromo-5-chloro-4-methyl-2-(2-morpholin-4-ylethoxy)pheny l]ethanone as the starting material in 95% yield. LCMS for C ₁₅ H ₂ 3BrClN ₂ 02 (M+H)+: m/z = 377.1, 379.1; Found: 377.1, 379.1.

Step B: N-{l-[3-Bromo-5-chloro-4-methyl-2-(2-morpholin-4-ylethoxy)ph enyl]ethyl}-9- (tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine

The desired compound was prepared according to the procedure of Example 125, step C, using l-[3-bromo-5-chloro-4-methyl-2-(2-morpholin-4-ylethoxy)pheny l]ethanamine as the starting material in 50% yield. LCMS for C25H ₃₃ BrClN ₆ 03 (M+H)+: m/z = 579.1, 581.1;

Found: 579.2, 581.2.

Step C: N-{l-[5-Chloro-6-methyl-4'-(methylsulfonyl)-2-(2-morpholin-4 -ylethoxy)biphenyl-3- yl] ethyl} -9H-purin-6- amine

The desired compound was prepared according to the procedure of Example 125, step D, using N- { 1 -[3-bromo-5-chloro-4-methyl-2-(2-morpholin-4-ylethoxy)phenyl ]ethyl} -9- (tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine, [4-(methylsulfonyl)phenyl]boronic acid, and sodium carbonate (instead of potassium carbonate) as the starting materials in 27% yield. LCMS for C27H ₃ 2C1N ₆ 0 ₄ S (M+H)+: m/z = 571.2; Found: 571.3; !H NMR (400 MHz, DMSO-^): δ 12.9 (s, 1 H), 8.17 - 8.07 (m, 3 H), 8.00 (d, J= 7.9 Hz, 2 H), 7.67 (s, 1 H), 7.64 (d, J= 7.2 Hz, 1 H), 7.55 (d, J= 7.4 Hz, 1 H), 5.80 (s, 1 H), 4.15 - 3.84 (m, 1 H), 3.42 - 3.37 (m, 4 H), 3.28 (s, 3 H), 2.32 - 2.25 (m, 2 H), 2.17 - 2.12 (m, 2 H), 2.08 - 2.00 (m, 2 H), 1.98 (s, 3 H), 1.50 (d, J = 6.9 Hz, 3 H).

Experimental procedures for further com ounds are summarized in Table 6 below.

Experimental procedures for further compounds are summarized in Table 7 below.

Table 7

Experimental procedures for compounds below are summarized in Table 8.

Table 8

yntl lesized according to the experimental procedure of compound listed.

1H NMR data (Varian Inova 500 spectrometer, a Mercury 400 spectrometer, or a Varian (or Mercury) 300 spectrometer) and LCMS mass spectral data (MS) for the compounds above is provided below in Table 9.

Table 9

Example 163. V-[l-(5-Chloro-2-methoxy-4-methyl-3-pyridazin-4-ylphenyl)eth yl]-9H- purin-6-amine bis(trifluoroacetate

A mixture of N-[ 1 -(3-bromo-5-chloro-2-methoxy-4-methylphenyl)ethyl]-9-(tetrah ydro-

2H-pyran-2-yl)-9H-purin-6-amine (0.030 g, 0.062 mmol, from Example 113, step 2 chiral intermediate), 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridazine (0.015 g, 0.075 mmol, from Milestone Pharmtech), 1 M sodium carbonate solution (0.15 mL, 0.16 mmol) and tetrakis(triphenylphosphine)palladium(0) (4.3 mg, 0.0037 mmol) in 1,4-dioxane (0.5 mL) was bubbled with N ₂ for 5 minutes, then heated at 90 °C overnight. The cooled reaction was treated directly with 6.0 M hydrogen chloride in water (0.1 mL, 0.6 mmol) at room temperature (rt) for -30 minutes. The mixture was diluted with MeOH, filtered and purified on prep-LCMS

(XBridge C 18 Column, eluting with a gradient of acetonitrile in water with 0.05% trifluoroacetic acid, at flow rate of 30 mL/min) to afford the desired product as TFA salt. LCMS calculated for C ₁₉ H ₁₉ CIN ₇ O (M+H) ⁺ : m/z = 396.1 ; found: 396.1.

Example 164. V-{l-[5-Chloro-2-methoxy-4-methyl-3-(l,3-thiazol-4-yl)phenyl ]ethyl}-9H- purin-6-amine trifluoroacetate

Step 1. l-[5-Chloro-2-methoxy-4-methyl-3-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2- yl)phenylj ethanone

4,4,5,5-Tetramethyl-l ,3,2-dioxaborolane (2.2 mL, 15 mmol) was added to a mixture of l-(5-chloro-3-iodo-2-methoxy-4-methylphenyl)ethanone (2.0 g, 6.2 mmol, from Example 60, Step 2), bis(acetonitrile)palladium(II) chloride (32 mg, 0.12 mmol), 2-(dicyclohexylphosphino)- 2',6'-dimethoxy-l ,l'-biphenyl (0.20 g, 0.49 mmol) and triethylamine (2.6 mL, 18 mmol) in 1 ,4- dioxane (3.7 mL) under N ₂ and then the mixture was degassed with N ₂ . The reaction was then heated at 100 °C for 3 hours. The mixture was cooled to room temperature, filtered and purified on silica gel column (eluting with 0 to 20% EtOAc in hexanes) to give the desired product (1.3 g, 65%). LCMS calculated for Ci ₆ H ₂₃ BC10 ₄ (M+H) ⁺ : m/z = 325.1 ; found: 325.1.

Step 2. l-[5-Chloro-2-methoxy-4-methyl-3-(l,3-thiazol-4-yl)phenyl]et hanone

Into a microwave vial was added l-[5-chloro-2-methoxy-4-methyl-3-(4,4,5,5- tetramethyl-l ,3,2-dioxaborolan-2-yl)phenyl]ethanone (0.040 g, 0.12 mmol), 4-bromo-l ,3- thiazole (0.024 g, 0.15 mmol), 1 M sodium carbonate solution (0.30 mL, 0.31 mmol), 1 ,4- dioxane (1 mL) and tetrakis(triphenylphosphine)palladium(0) (8.5 mg, 0.0074 mmol). The mixture was bubbled with N ₂ for 5 minutes, and then heated at 95 °C overnight. The cooled reaction was purified on silica gel column (eluting with 0 to 30% EtOAc in hexanes) to give the desired product. LCMS calculated for C _I3 H _I3 C1N0 ₂ S (M+H) ⁺ : m/z = 282.0; found: 282.0.

Step 3. l-[5-Chloro-2-methoxy-4-methyl-3-(l,3-thiazol-4-yl)phenylJet hanamine

A mixture of l-[5-chloro-2-methoxy-4-methyl-3-(l,3-thiazol-4-yl)phenyl]et hanone

(6.0 mg, 0.021 mmol), ammonium acetate (20 mg, 0.2 mmol) and 1.0 M sodium

cyanoborohydride in THF (0.053 mL, 0.053 mmol) in methanol (0.05 mL)/acetonitrile (0.05 mL) was heated at 65 °C overnight. The mixture was cooled to room temperature, quenched with sat. NaHC0 ₃ solution, extracted with dichloromethane. The combined organic layers were dried over MgS0 ₄ and concentrated to give the crude product, which was used in the next step directly. LCMS calculated for Ci ₃ Hi ₃ ClNOS (M-NH ₂ ) ⁺ : m/z = 266.1 ; found: 266.0.

Step 4. N-{l-[ 5-Chloro-2-methoxy-4-methyl-3-( 1, 3-thiazol-4-yl)phenyl]ethyl}-9H-purin-6-amine trifluoroacetate

A mixture of l-[5-chloro-2-methoxy-4-methyl-3-(l,3-thiazol-4-yl)phenyl]et hanamine

(5.5 mg, 0.019 mmol), 6-bromo-9H-purine (5.8 mg, 0.029 mmol) and N,N- diisopropylethylamine (DIPEA) (0.010 mL, 0.058 mmol) in ethanol (0.1 mL) was heated at 100 °C overnight. The mixture was diluted with MeOH and purified on prep-LCMS (XBridge CI 8 Column, eluting with a gradient of acetonitrile in water with 0.05% trifluoroacetic acid, at flow rate of 30 mL/min) to afford the desired product as TFA salt. LCMS calculated for

CisHisClNeOS (M+H) ⁺ : m z = 401.1 ; found: 401.0.

Example 165. V-[l-(3-azetidin-3-yl-5-chloro-2-methoxy-4-methylphenyl)ethy l]-9H-purin-6- amine bis(trifluoroacetate)

Step 1. tert-Butyl 3-(3-acetyl-5-chloro-2-methoxy-6-methylphenyl)azetidine-l-ca rboxylate

Zinc (0.227 g, 3.48 mmol) was suspended with 1 ,2-dibromoethane (0.0434 g, 0.231 mmol) in N,N-dimethylformamide (DMF) (4.1 mL). The mixture was heated at 70 °C for 10 min and then cooled to room temperature. Chlorotrimethylsilane (0.029 mL, 0.23 mmol) was added dropwise and stirring was continued for 1 hour. A solution of tert-bvXy\ 3-iodoazetidine-l- carboxylate (0.82 g, 2.9 mmol, from Oakwood) in DMF (3 mL) was then added and the mixture was heated at 40 °C for 1 h before a mixture of l-(5-chloro-3-iodo-2-methoxy-4- methylphenyl)ethanone (0.987 g, 3.04 mmol, from Example 60, Step 2),

tris(dibenzylideneacetone)dipalladium(0) (0.052 g, 0.057 mmol) and tri-(2-furyl)phosphine

(0.027 g, 0.12 mmol) in DMF (8 mL) was added. The reaction mixture was warmed to 70 °C and stirred overnight. The mixture was then cooled to room temperature and partitioned between EtOAc and sat. NH ₄ C1 solution. The organic layer was washed with water, dried over MgS0 ₄ , concentrated and purified on silica gel (eluting with 0 to 30% EtOAc in hexanes) to give the desired product (0.57 g, 56%). LCMS calculated for Ci ₈ H ₂₄ ClN0 ₄ Na (M+Na) ⁺ : m/z = 376.1; found: 376.1.

Step 2. tert-Butyl 3-[3-(l-aminoethyl)-5-chloro-2-methoxy-6-methylphenyl]azetid ine-l- carboxylate

A mixture of tert-butyl 3 -(3 -acetyl-5 -chloro-2-methoxy-6-methylphenyl)azetidine- 1 - carboxylate (0.56 g, 1.6 mmol), ammonium acetate (1.0 g, 20 mmol) and 1.0 M sodium cyanoborohydride in THF (4.0 mL, 4.0 mmol) in methanol (4 mL)/acetonitrile (4 mL) was heated at 65 °C overnight. The mixture was cooled to room temperature, quenched with sat. NaHC0 ₃ solution, extracted with dichloromethane. The organic extracts were dried over MgS0 ₄ and concentrated to give the crude product, which was used in the next step without further purifications. LCMS calculated for Ci ₈ H ₂₇ ClN ₂ 0 ₃ Na (M+Na) ⁺ : m/z = 377.2; found: 377.1.

Step 3. N-f l-(3-Azetidin-3-yl-5-chloro-2-methoxy-4-methylphenyl)ethylJ- 9H^urin-6-amine bis(trifluoroacetate)

A mixture of tert-butyl 3-[3-(l-aminoethyl)-5-chloro-2-methoxy-6- methylphenyl]azetidine-l-carboxylate (0.36 g, 1.0 mmol), 6-bromo-9-(tetrahydro-2H-pyran-2- yl)-9H-purine (0.43 g, 1.5 mmol, from Example 108, Step 1) and DIPEA(0.53 mL, 3.0 mmol) in ethanol (6 mL) was heated at 100 °C overnight. The mixture was concentrated and purified on silica gel column (eluting with 0 to 100% EtOAc in hexanes) to give tert-butyl 3-[3- chloro-6-methoxy-2-methyl-5 -( 1 - { [9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6- yl]amino}ethyl)phenyl]azetidine-l-carboxylate. LCMS calculated for C ₂₈ H ₃₈ CIN ₆ O ₄ (M+H) ⁺ : m/z = 557.3; found: 557.3. The Boc intermediate isolated was treated with trifluoroacetic acid (0.8 mL, 10 mmol) in methylene chloride (5 mL) at room temperature for 1 hour. The mixture was stripped to dryness to give the desired product as TFA salt. 4 mg of the salt was purified on prep-LCMS (XBridge CI 8 Column, eluting with a gradient of acetonitrile in water with 0.05% trifluoroacetic acid, at flow rate of 30 mL/min) to afford the desired product as TFA salt. LCMS calculated for Ci ₈ H ₂₂ ClN ₆ 0 (M+H) ⁺ : m z = 373.2; found: 373.1 Example 166. V-{l-[3-(l-Acetylazetidin-3-yl)-5-chloro-2-methoxy-4-methylp henyl]ethyl}- 9H-purin-6-amine trifluoroaceta

Acetic anhydride (2.0 μί, 0.021 mmol) was added to a solution of N-[l-(3-azetidin-3-yl- 5-chloro-2-methoxy-4-methylphenyl)ethyl]-9H-purin-6-amine bis(trifluoroacetate) (8.5 mg, 0.014 mmol, from Example 165) and DIPEA(0.015 mL, 0.085 mmol) in methylene chloride (0.5 mL) at 0 °C and then the reaction was stirred at room temperature for 30 minutes. The crude mixture was purified on prep-LCMS (XBridge C 18 Column, eluting with a gradient of acetonitrile in water with 0.05% trifluoroacetic acid, at flow rate of 30 mL/min) to afford the desired product as TFA salt. LCMS calculated for C20H24CIN6O2 (M+H) ⁺ : m/z = 415.2; found: 415.1

Example 167. Methyl 3-{3-chloro-6-methoxy-2-methyl-5-[l-(9H-purin-6- ylamino)ethyl]phenyl}azetidine-l-carboxylate trifluoroacetate

Methyl chloroformate (1.6 μί, 0.021 mmol) was added to a solution of N-[l-(3-azetidin- 3-yl-5-chloro-2-methoxy-4-methylphenyl)ethyl]-9H-purin-6-ami ne bis(trifluoroacetate) (8.5 mg, 0.014 mmol, from Example 165) and DIPEA(0.015 mL, 0.085 mmol) in methylene chloride (0.5 mL) at 0 °C and then the reaction was stirred at room temperature for 30 minutes. The crude mixture was purified on prep-LCMS (XBridge C 18 Column, eluting with a gradient of acetonitrile in water with 0.05% trifluoroacetic acid, at flow rate of 30 mL/min) to afford the desired product as TFA salt. LCMS calculated for C ₂₀ H ₂₄ CIN ₆ O ₃ (M+H) ⁺ : m/z = 431.2; found: 431.1. 1H NMR (300 MHz, DMSC ¾) δ 8.30 (1H, br s), 8.18 (2H, m), 7.46 (1H, s), 5.68 (1H, m), 4.31 (3H, m), 4.14 (1H, m), 4.02 (1H, m), 3.75 (3H, s), 3.55 (3H, s), 2.16 (3H, s), 1.44 (3H, d, J= 6.9 Hz) ppm.

Example 168. 3-{3-Chloro-6-methoxy-2-methyl-5-[l-(9H-purin-6-ylamino)ethy l]phenyl}- N-methylazetidine-l-carboxamide trifluoroacetate

Methyl isocyanate (1.3 μί, 0.021 mmol) was added to a solution of N-[l-(3-azetidin-3-yl- 5-chloro-2-methoxy-4-methylphenyl)ethyl]-9H-purin-6-amine bis(trifluoroacetate) (8.5 mg, 0.014 mmol, from Example 165) and DIPEA(0.015 mL, 0.085 mmol) in methylene chloride (0.5 mL) at 0 °C and then the reaction was stirred at room temperature for 30 minutes. The crude mixture was purified on prep-LCMS (XBridge C 18 Column, eluting with a gradient of acetonitrile in water with 0.05% trifluoroacetic acid, at flow rate of 30 mL/min) to afford the desired product as TFA salt. LCMS calculated for C ₂₀ H ₂₅ CIN ₇ O ₂ (M+H) ⁺ : m/z = 430.2; found: 430.2. 1H NMR (300 MHz, DMSC ¾) δ 8.32 (1H, br s), 8.18 (2H, m), 7.44 (1H, s), 6.31 (1H, m), 5.68 (1H, m), 4.20 (3H, m), 3.96 (1H, m), 3.82 (1H, m), 3.75 (3H, s), 2.52 (3H, s), 2.15 (3H, s), 1.44 (3H, d, J = 6.9 Hz) ppm.

Example 169. V-(l-{5-Chloro-2-methoxy-4-methyl-3-[l-(methylsulfonyl)azeti din-3- yl] phenyl} ethyl)- 9H-purin-6-amine trifluoroacetate

Methanesulfonyl chloride (1.6 μί, 0.021 mmol) was added to a solution of N-[l-(3- azetidin-3-yl-5-chloro-2-methoxy-4-methylphenyl)ethyl]-9H-pu rin-6-amine bis(trifluoroacetate) (8.5 mg, 0.014 mmol, from Example 165) and DIPEA(0.015 mL, 0.085 mmol) in methylene chloride (0.5 mL) at 0 °C and then the reaction was stirred at room temperature for 30 minutes. The crude mixture was purified on prep-LCMS (XBridge C 18 Column, eluting with a gradient of acetonitrile in water with 0.05% trifluoroacetic acid, at flow rate of 30 mL/min) to afford the desired product as TFA salt. LCMS calculated for C ₁₉ H ₂₄ CIN ₆ O ₃ S (M+H) ⁺ : m/z = 451.1 ; found: 451.0. 1H NMR (300 MHz, DMSC ¾) δ 8.22 (1H, brs ), 8.15 (2H, m), 7.48 (1H, s), 5.67 (1H, m), 4.21 (3H, m), 4.05 (1H, m), 3.96 (1H, m), 3.76 (3H, s), 2.96 (3H, s), 2.10 (3H, s), 1.45 (3H, d, J= 6.9 Hz) ppm.

Example 170. N-{l-[5-Chloro-3-(l-isopropylazetidin-3-yl)-2-methoxy-4- methylphenyl]ethyl}-9H-purin- -amine bis(trifluoroacetate)

Step 1. Benzyl 3-(3-acetyl-5-chloro-2-methoxy-6-methylphenyl)azetidine-l-ca rboxylate

Zinc (1.15 g, 17.6 mmol) was suspended with 1 ,2-dibromoethane (0.101 mL, 1.17 mmol) in DMF (21 mL). The mixture was heated at 70 °C for 10 min and then cooled to room temperature. Chlorotrimethylsilane (0.149 mL, 1.17 mmol) was added dropwise and stirring was continued for 1 hour. A solution of benzyl 3-iodoazetidine-l-carboxylate (4.6 g, 15 mmol, from Pharmablock) in DMF (20 mL) was then added and the mixture was heated at 40 °C for 1 h before a mixture of l-(5-chloro-3-iodo-2-methoxy-4-methylphenyl)ethanone (5.0 g, 15 mmol, from Example 60, Step 2), tris(dibenzylideneacetone)dipalladium(0) (0.27 g, 0.29 mmol) and tri- (2-furyl)phosphine (0.14 g, 0.59 mmol) in DMF (40 mL) was added. The reaction mixture was warmed to 70 °C and stirred overnight. The mixture was then cooled to room temperature and partitioned between ether and sat. NH ₄ C1 solution. The organic layer was washed with water, dried over MgS0 ₄ , concentrated and purified on silica gel (eluting with 0 to 20% EtOAc in hexane) to give the desired product (2.5 g, 44%). LCMS calculated for C ₂₁ H ₂₃ CINO ₄ (M+H) ⁺ : m/z = 338.1; found: 388.1 Step 2. Benzyl 3-[ 3-( l-aminoethyl)-5-chloro-2-methoxy-6-methylphenylJazetidine-l- carboxylate

Titanium tetraethanolate (2.70 mL, 12.9 mmol) was added to a mixture of benzyl 3-(3- acetyl-5-chloro-2-methoxy-6-methylphenyl)azetidine-l-carboxy late (2.5 g, 6.4 mmol) in 2.0 M ammonia in ethanol (16.1 mL, 32.2 mmol) at 0 °C. The solution was stirred at 60 °C under N ₂ overnight. Sodium tetrahydroborate (0.366 g, 9.67 mmol) was added to the above mixture at 0 °C and the solution was stirred at room temperature for another 1 hour. The reaction mixture was quenched with 2 M ammonia in water and filtered. The solid was washed with acetonitrile. The solvent was removed and the residue was diluted with dichloromethane, washed with water and brine, dried over MgS0 ₄ and concentrated to give the desired product (2.47 g, 98%). LCMS calculated for C21H26CIN2O3 (M+H) ⁺ : m/z = 389.2; found: 389.1.

Step 3. Benzyl 3-(3-{l-[(tert-butoxycarbonyl)amino]ethyl}-5-chloro-2-methox y-6- methylphenyl)azetidine-l-carboxylate

Di-tert-butyldicarbonate (2.8 g, 13 mmol) was added to a mixture of benzyl 3-[3-(l- aminoethyl)-5-chloro-2-methoxy-6-methylphenyl]azetidine-l-ca rboxylate (2.47 g, 6.35 mmol) and DIPEA(3.3 mL, 19 mmol) in THF (32 mL). After stirring for 2 h at room temperature, the mixture was quenched with sat. NaHC0 ₃ solution, extracted with EtOAc. The combined organic layers were washed with water and brine, dried over MgS0 ₄ , concentrated and purified on silica gel (eluting with 0 to 30% EtOAc in hexanes) to give the desired product (1.8 g, 58%). LCMS calculated for C ₂ 6H ₃₃ ClN ₂ 0 ₅ Na (M+Na) ⁺ : m/z = 511.2; found: 511.0. The material was applied on chiral HPLC (ChiralPak AD-H column, 20 x 250 mm, 5 micron particle size, eluting with 20% EtOH in hexanes at 15 mL/min, column loading ~ 20 mg/injection) to separate the two enantiomers (Retention times: 7.08 min and 8.46 min).

Step 4. tert-Butyl [l-(3-azetidin-3-yl-5-chloro-2-methoxy-4-methylphenyl)ethyl] carbamate

Benzyl 3-(3- { 1 -[(tert-butoxycarbonyl)amino]ethyl} -5-chloro-2-methoxy-6- methylphenyl)azetidine-l-carboxylate (720 mg, 1.5 mmol) (second peak from chiral separation of previous step) and 5% palladium on carbon (100 mg) were combined in methanol (40 mL), to which was added 0.25 M HC1 in water (11 mL, 2.8 mmol). The suspension was hydrogenated under balloon pressure of H ₂ at room temperature for 1 hour. The suspension was then filtered, neutralized with sat. NaHC0 ₃ solution, concentrated, and extracted with dichloromethane. The combined organic layers were dried over MgS0 ₄ and concentrated to give the desired product (0.4 g). LCMS calculated for Ci ₈ H ₂₈ ClN ₂ 0 ₃ (M+H) ⁺ : m/z = 355.2; found: 355.1. Step 5. tert-Butyl {l-[5-chloro-3-(l-isopropylazetidin-3-yl)-2-methoxy-4- methylphenyl] ethyl} carbamate

To a mixture of tert-butyl [l-(3-azetidin-3-yl-5-chloro-2-methoxy-4- methylphenyl)ethyl] carbamate (20 mg, 0.06 mmol) in acetonitrile (0.2 mL)/methanol (0.2 mL)/THF (0.2 mL) was added acetone (48 μί, 0.65 mmol). The mixture was stirred at room temperature for 30 min before the addition of sodium triacetoxyborohydride (36 mg, 0.17 mmol). The mixture was stirred at room temperature for 4 hours. The mixture was then diluted with water and extracted with dichloromethane. The organic layers were dried over MgS0 ₄ and concentrated to give the crude product. LCMS calculated for C ₂ iH ₃₄ ClN ₂ 0 ₃ (M+H) ⁺ : m/z = 397.2; found: 397.2.

Step 6. N-{l-[ 5-Chloro-3-( l-isopropylazetidin-3-yl)-2-methoxy-4-methylphenyl]ethyl}-9H -purin- 6-amine bis(trifluoroacetate)

tert-Butyl { l-[5-chloro-3-(l-isopropylazetidin-3-yl)-2-methoxy-4- methylphenyl] ethyl} carbamate (19 mg, 0.048 mmol) was treated with 4.0 M HC1 in dioxane (60 0.24 mmol) in methylene chloride (50 at room temperature for 2 hours. The resultant mixture was concentrated to dryness to give l-[5-chloro-3-(l-isopropylazetidin-3-yl)-2-methoxy- 4-methylphenyl]ethanamine dihydrochloride. A mixture of the HC1 salt, 6-bromo-9-(tetrahydro- 2H-pyran-2-yl)-9H-purine (20 mg, 0.072 mmol, from Example 108, Step 1) and DIPEA(42 μΐ,, 0.24 mmol) in ethanol (0.3 mL) was heated at 100 °C overnight. The mixture was treated with 6.0 M HC1 in water (80 μί, 0.5 mmol) at room temperature for 10 min and then purified on prep- LCMS (XBridge C 18 Column, eluting with a gradient of acetonitrile in water with 0.05% trifluoroacetic acid, at flow rate of 30 mL/min) to afford the desired product as TFA salt. LCMS calculated for C ₂ iH ₂₈ ClN ₆ 0 (M+H) ⁺ : m/z = 415.2; found: 415.1. Example 171. /V-{l-[5-Chloro-2-methoxy-4-methyl-3-(l-methylazetidin-3-yl) phenyl]ethyl}- 9H-purin-6-amine bis(trifluoroacetate)

Step 1. Benzyl 3-{3-chloro-6-methoxy-2-methyl-5-[l-(9H-purin-6- ylamino) ethyl] phenyl} azetidine- 1 -carboxylate

Benzyl 3-(3- { 1 -[(tert-butoxycarbonyl)amino]ethyl} -5-chloro-2-methoxy-6- methylphenyl)azetidine-l -carboxylate (0.45 g, 0.92 mmol, from Example 170, Step 3, chiral intermediate) and was treated with 4.0 M HCl in dioxane (2 mL, 8 mmol) in methylene chloride (6 mL) at room temperature for 2 hours. The reaction mixture was then stripped to dryness to give benzyl 3- {3-[l -aminoethyl]-5-chloro-2-methoxy-6-methylphenyl} azetidine- 1 -carboxylate as a HCl salt. LCMS calculated for C21H26CIN2O3 (M+H) ⁺ : m/z = 389.2; found: 389.1. A mixture of the above HCl salt, 6-bromo-9H-purine (0.20 g, 1.0 mmol) and DIPEA(0.80 mL, 4.6 mmol) in ethanol (9 mL) was heated at 100 °C overnight. The mixture was concentrated and purified on silica gel (eluting with 0 to 5% MeOH in dichloromethane) to give the desired product (0.25 g, 55% in 2 steps). LCMS calculated for C ₂₆ H ₂₈ C1N ₆ 0 ₃ (M+H) ⁺ : m/z = 507.2; found: 507.1.

Step 2. N-{l-[ 5-Chloro-2-methoxy-4-methyl-3-( l-methylazetidin-3-yl)phenyl]ethyl}-9H-purin-6- amine bis(trifluoroacetate)

Benzyl 3- {3-chloro-6-methoxy-2-methyl-5-[ 1 -(9H-purin-6- ylamino)ethyl]phenyl} azetidine- 1 -carboxylate (255 mg, 0.503 mmol) and 5% palladium (125 mg) was combined in methanol (15 mL), to which was added 0.25 M HCl in water (5.0 mL, 1.2 mmol). The suspension was hydrogenated under balloon pressure of H ₂ at room temperature overnight. The suspension was filtered and concentrated to give N-[l-(3-azetidin-3-yl-5-chloro- 2-methoxy-4-methylphenyl)ethyl]-9H-purin-6-amine. LCMS calculated for C18H22CIN6O (M+H) ⁺ : m/z = 373.2; found: 373.1. The azetidine intermediate made above was combined with DIPEA(0.26 mL, 1.5 mmol) in methanol (0.5 mL)/acetonitrile (0.5 mL)/THF (0.5 mL), followed by the addition of 37% formaldehyde (0.19 mL, 2.5 mmol). The mixture was stirred at room temperature for 10 min before the addition of sodium triacetoxyborohydride (0.32 g, 1.5 mmol). The mixture was stirred at room temperature overnight, then diluted with MeOH and purified on prep-LCMS (XBridge CI 8 Column, eluting with a gradient of acetonitrile in water with 0.05% trifluoroacetic acid, at flow rate of 30 mL/min) to afford the desired product as TFA salt. LCMS calculated for Ci ₉ H ₂₄ ClN ₆ 0 (M+H) ⁺ : m/z = 387.2; found: 387.1.

Example 172. V-{l-[5-Chloro-4-fluoro-3-(l-isopropylazetidin-3-yl)-2- methoxyphenyl] ethyl}-9H-puri -6-amine bis(trifluoroacetate)

Step 1. l-(5-Chloro-4-fluoro-2-hydroxyphenyl)ethanone

To 4-chloro-3-fluorophenol (20 g, 100 mmol, from Aldrich) was added acetyl chloride (14.1 mL, 199 mmol) under N ₂ with stirring. The resulting mixture turned into a clear solution at room temperature and was heated at 60° C for 2 hours. To the resultant mixture was added aluminum trichloride (25.0 g, 187 mmol) in portions and the mixture was heated at 180 °C for 30 minutes. The solids slowly dissolved at high temp. The reaction mixture was then cooled to room temperature while the flask was swirled carefully in order for the solid to form a thin layer inside the flask and then slowly quenched with 1.0 N HCl (300 mL) while cooling in an ice-bath and stirred overnight. The yellow precipitate was washed well with water and dried under vacuum to give the desired product as a yellow solid (23.8 g), which was directly used in the next step without further purification.

Step 2. l-(5-Chloro-4-fluoro-2-hydroxy-3-iodophenyl)ethanone

A solution of l-(5-chloro-4-fluoro-2-hydroxyphenyl)ethanone (23.8 g, 126 mmol) in acetic acid (100 mL) was treated with N-iodosuccinimide (34.1 g, 151 mmol) and stirred at 70 °C for 2 hours. The reaction mixture was concentrated, diluted with EtOAc and quenched with sat. NaHC0 ₃ solution. The organic layer was separated, washed with water, dried over MgS04 and concentrated under reduced pressure to give the desired product to be used in the next step without further purification.

Step 3. l-(5-Chloro-4-fluoro-3-iodo-2-methoxyphenyl)ethanone

l-(5-Chloro-4-fluoro-2-hydroxy-3-iodophenyl)ethanone (13 g, 41 mmol) was dissolved in DMF (41.3 mL). Methyl iodide (3.9 mL, 62 mmol) was added followed by potassium carbonate (11 g, 83 mmol). The reaction was heated at 60 °C for 1 hour. The mixture was cooled to room temperature, diluted with ether, washed with water, dried over MgS0 ₄ , concentrated. The residue was purified on silica gel (eluting with 0 to 10% EtOAc in hexanes) to give the desired product (10 g, 70%). LCMS calculated for C ₉ H ₈ C1FI0 ₂ (M+H) ⁺ : m/z = 328.9; found: 328.9. Step 4. tert-Butyl 3-(3-acetyl-5-chloro-6-fluoro-2-methoxyphenyl)azetidine-l-ca rboxylate

Zinc (0.682 g, 10.4 mmol) was suspended with 1 ,2-dibromoethane (0.060 mL, 0.69 mmol) in DMF (12 mL). The mixture was heated at 70 °C for 10 min and then cooled to room temperature. Chlorotrimethylsilane (0.088 mL, 0.69 mmol) was added dropwise and stirring was continued for 1 hour. A solution of tert-butyl 3-iodoazetidine-l-carboxylate (2.5 g, 8.7 mmol, from Oakwood) in DMF (10 mL) was then added and the mixture was heated at 40 °C for 1 h before a mixture of l-(5-chloro-4-fluoro-3-iodo-2-methoxyphenyl)ethanone (3.0 g, 9.1 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.16 g, 0.17 mmol) and tri-(2-furyl)phosphine (0.081 g, 0.35 mmol) in DMF (20 mL) was added. The reaction mixture was warmed to 70 °C and stirred overnight. The mixture was then cooled to room temperature and partitioned between ether and sat. NH ₄ C1 solution. The organic layer was washed with water, dried over MgS0 ₄ , concentrated and purified on silica gel (eluting with 0 to 25% EtOAc in hexanes) to give the desired product (0.8 g). LCMS calculated for Ci ₇ H ₂ iClFN0 ₄ Na (M+Na) ⁺ : m/z = 380.1; found: 380.1. Step 5. tert-Butyl 3-[3-chloro-2-fluoro-5-(l-hydroxyethyl)-6-methoxyphenyl]azet idine-l- carboxylate To a solution of tert-butyl 3-(3-acetyl-5-chloro-6-fluoro-2-methoxyphenyl)azetidine-l- carboxylate (0.17 g, 0.48 mmol) in methanol (3 mL) cooled at 0 °C was added sodium tetrahydroborate (0.022 g, 0.57 mmol). The mixture was stirred at room temperature for 1 hour, then diluted with water and extracted with EtOAc. The combined organic layers were dried over MgS0 ₄ and concentrated to give the desired product (0.19 g). LCMS calculated for

Ci ₇ H ₂₃ ClFN0 ₄ Na (M+Na) ⁺ : m/z = 382.1 ; found: 382.0.

Step 6. tert-Butyl 3-[3-chloro-5-(l-chloroethyl)-2-fluoro-6-methoxyphenyl]azeti dine-l- carboxylate

Cyanuric chloride (140 mg, 0.78 mmol) was added to DMF (0.059 mL, 0.77 mmol) at room temperature. After the formation of a white solid (10 min), methylene chloride (4 mL) was added, followed by tert-butyl 3-[3-chloro-2-fluoro-5-(l-hydroxyethyl)-6- methoxyphenyl]azetidine-l-carboxylate (197 mg, 0.547 mmol). After the addition, the mixture was stirred at room temperature overnight. Water was added, and the resulting mixture was then diluted with dichloromethane. The organic phase was separated, washed with sat. NaHC0 ₃ solution, water and brine, dried over MgS0 ₄ , concentrated and purified on silica gel (eluting with 0 to 30% EtOAc in hexanes) to give the desired product (1 10 mg, 53%).

Step 7. tert-Butyl 3-[3-(l-azidoethyl)-5-chloro-6-fluoro-2-methoxyphenyl]azetid ine-l- carboxylate

A mixture of tert-butyl 3-[3-chloro-5-(l-chloroethyl)-2-fluoro-6- methoxyphenyl]azetidine-l -carboxylate (0.070 g, 0.18 mmol) and sodium azide (0.036 g, 0.56 mmol) in DMF (0.66 mL) was stirred at room temperature overnight. After diluting with ether, the mixture was washed with water, dried over MgS0 ₄ and concentrated to give the crude azide which was used in the next step without further purification. LCMS calculated for

Ci ₇ H ₂₂ ClFN ₄ 0 ₃ Na (M+Na) ⁺ : m/z = 407.1 ; found: 407.0.

Step 8. tert-Butyl 3-[3-(l-aminoethyl)-5-chloro-6-fluoro-2-methoxyphenyl]azetid ine-l- carboxylate

To a stirred solution of tert-butyl 3-[3-(l-azidoethyl)-5-chloro-6-fluoro-2- methoxyphenyl]azetidine-l -carboxylate (0.084 g, 0.22 mmol) in THF (1 mL)/water (0.2 mL) was added 1.0 M trimethylphosphine in THF (0.33 mL, 0.33 mmol) at room temperature and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were dried over MgSC^ and

concentrated to give the desired product to be used in the next step without further purification.

Step 9. N-{l-[5-Chloro-4-fluoro-3-(l-isopropylazetidin-3-yl)-2-metho xyphenyl]ethyl}-9H^urin- 6-amine bis(trifluoroacetate)

A mixture of tert-butyl 3-[3-(l-aminoethyl)-5-chloro-6-fluoro-2- methoxyphenyl]azetidine-l-carboxylate (22.5 mg, 0.0627 mmol), 6-bromo-9-(tetrahydro-2H- pyran-2-yl)-9H-purine (24 mg, 0.085 mmol, from Example 108, Step 1) and DIPEA(33 L, 0.19 mmol) in ethanol (1.0 mL) was heated at 100 °C overnight. The mixture was diluted with sat. NaHCC"3 solution, extracted with dichloromethane. The combined organic layers were dried over MgS04 and concentrated to give tert- vXy\ 3-[3-chloro-2-fluoro-6-methoxy-5-(l-{[9-(tetrahydro- 2H-pyran-2-yl)-9H-purin-6-yl]amino}ethyl)phenyl]azetidine-l- carboxylate (34 mg). LCMS calculated for C ₂₇ H ₃₅ CIFN ₆ O ₄ (M+H) ⁺ : m/z = 561.2; found: 561.2. The coupling product made above was treated with 4.0 M HC1 in dioxane (0.5 mL, 2 mmol) in methylene chloride (0.2 mL) at room temperature for 1 hour. The reaction mixture was then evaporated to dryness to give N- [ 1 -(3 -azetidin-3 -yl-5 -chloro-4-fluoro-2-methoxyphenyl)ethyl]-9H-purin-6-amine

dihydrochloride. The resultant HC1 salt was dissolved in methanol (0.2 mL)/acetonitrile (0.2 mL)/THF (0.2 mL) and treated with DIPEA(0.1 mL, 0.6 mmol) until the solid dissolved.

Acetone (0.05 mL, 0.6 mmol) was added and the resulting mixture was stirred at room temperature for 30 min before the addition of sodium triacetoxyborohydride (0.066 g, 0.31 mmol). The reaction mixture was stirred at room temperature for 4 h and then purified on prep- LCMS (XBridge C18 Column, eluting with a gradient of acetonitrile in water with 0.05% trifluoroacetic acid, at flow rate of 30 mL/min) to afford the desired product as TFA salt. LCMS calculated for C ₂₀ H ₂₅ CIFN ₆ O (M+H) ⁺ : m/z = 419.2; found: 419.1. 1H NMR (300 MHz, DMSO- d ₆ ) δ 9.96 (1H, m), 8.41 (1H, m), 8.23 (1H, s), 8.20 (1H, s), 7.53 (1H, s), 5.69 (1H, m), 4.52 (2H, m), 4.26 (1H, m), 4.12 (2H, m), 3.77 (3H, s), 2.08 (3H, m), 1.46 (3H, d, J= 6.9 Hz), 1.11 (6H, m) ppm. Example 173. V-{l-[5-chloro-2-ethoxy-4-methyl-3-(l-methylazetidin-3-yl)ph enyl]ethyl}- 9H-purin-6-amine

Step 1. l-(5-Chloro-2-ethoxy-3-iodo-4-methylphenyl)ethanone

l-(5-Chloro-2-hydroxy-3-iodo-4-methylphenyl)ethanone (18.9 g, 60.9 mmol, from

Example 60, Step 1) was dissolved in DMF (61 mL). Iodoethane (7.3 mL, 91 mmol) was added followed by potassium carbonate (17.0 g, 120 mmol). The reaction was heated at 60 °C for 1 hour. The mixture was cooled to room temperature, diluted with ether, washed with water, dried over MgS04, concentrated. The resulting residue was purified on silica gel (eluting with 0 to 10% EtOAc in hexanes) to give the desired product (18.9 g, 91.7%). LCMS calculated for

C11H13CUO2 (M+H) ⁺ : m z = 339.0; found: 339.0.

Step 2. Benzyl 3-(3-acetyl-5-chloro-2-ethoxy-6-methylphenyl)azetidine-l-car boxylate

Zinc (0.967 g, 14.8 mmol) was suspended with 1 ,2-dibromoethane (0.085 mL, 0.98 mmol) in DMF (17 mL). The mixture was heated at 70 °C for 10 min and then cooled to room temperature. Chlorotrimethylsilane (0.13 mL, 0.98 mmol) was added dropwise and stirring was continued for 1 hour. A solution of benzyl 3-iodoazetidine-l-carboxylate (3.9 g, 12 mmol, from Pharmablock) in DMF (10 mL) was then added and the mixture was heated at 40 °C for 1 h before a mixture of l-(5-chloro-2-ethoxy-3-iodo-4-methylphenyl)ethanone (4.4 g, 13 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.22 g, 0.24 mmol) and tri-(2-furyl)phosphine (0.12 g, 0.50 mmol) in DMF (30 mL) was added. The reaction mixture was warmed to 70 °C and stirred overnight. The mixture was then cooled to room temperature and partitioned between ether and sat. NH ₄ CI solution. The organic layer was washed with water, dried over MgS04, concentrated and purified on silica gel (eluting with 0 to 20%> EtOAc in hexanes) to give the desired product

(3.87 g, 78%). LCMS calculated for C22H ₂₅ C1N0 ₄ (M+H) : m/z = 402.1; found: 402.1 Step 3. Benzyl 3-[3-(l-aminoethyl)-5-chloro-2-ethoxy-6-methylphenylJazetidi ne-l-carboxylate

Titanium tetraethanolate (3.3 mL, 16 mmol) was added to a mixture of benzyl 3-(3- acetyl-5-chloro-2-ethoxy-6-methylphenyl)azetidine-l-carboxyl ate (3.2 g, 8.0 mmol) in 2.0 M ammonia in ethanol (19.9 mL, 39.8 mmol) at 0 °C. The solution was stirred at 60 °C under N ₂ overnight. Sodium tetrahydroborate (0.452 g, 11.9 mmol) was added to the resultant mixture at 0 °C and the reaction mixture was stirred at room temperature for another 1 hour. The mixture was then quenched with 2 M ammonia in water and filtered. The solid was washed with acetonitrile. The solvent was removed and the residue was diluted with dichloromethane, washed with water and brine, dried over MgS0 ₄ and concentrated to give the desired product (2.99 g, 93%). LCMS calculated for C ₂₂ H ₂ 8C1N ₂ 03 (M+H) ⁺ : m/z = 403.2; found: 403.2.

Step 4. Benzyl 3-(3-{l-[(tert-butoxycarbonyl)amino]ethyl}-5-chloro-2-ethoxy -6- methylphenyl)azetidine-l-carboxylate

Di-tert-butyldicarbonate (3.2 g, 15 mmol) was added to a mixture of benzyl 3-[3-(l- aminoethyl)-5-chloro-2-ethoxy-6-methylphenyl]azetidine-l-car boxylate (2.99 g, 7.42 mmol) and DIPEA(3.9 mL, 22 mmol) in THF (37 mL). After stirring overnight at room temperature, the mixture was quenched with sat. NaHC0 ₃ solution, extracted with EtOAc. The combined organic layers were washed with water and brine, dried over MgS0 ₄ , concentrated and purified on silica gel (eluting with 0 to 25% EtOAc in hexane) to give the desired product (2.1 g, 56%). LCMS calculated for C ₂ yH ₃₅ ClN ₂ 0 ₅ Na (M+Na) ⁺ : m/z = 525.2; found: 525.2. The material was applied on chiral HPLC (ChiralPak AD-H column, 20 x 250 mm, 5 micron particle size, eluting with 20% EtOH in hexanes at 15 ml/min, column loading ~ 20 mg/injection) to separate the two enantiomers (Retention times: 7.08 min and 8.46 min).

Step 5. Benzyl 3-{3-chloro-6-ethoxy-2-methyl-5-[ l-(9H-purin-6-ylamino)ethyl]phenyl}azetidine- 1-carboxylate

Benzyl 3-(3- { 1 -[(tert-butoxycarbonyl)amino]ethyl} -5-chloro-2-ethoxy-6- methylphenyl)azetidine-l-carboxylate (65 mg, 0.13 mmol, second peak from chiral separation in previous step) was treated with 4.0 M HC1 in dioxane (0.4 mL, 2 mmol) in methylene chloride (0.4 mL, 6 mmol) at room temperature for 2 hours. The reaction mixture was evaporated to dryness to give benzyl 3- {3-[l-aminoethyl]-5-chloro-2-ethoxy-6-methylphenyl}azetidine -l- carboxylate hydrochloride. LCMS calculated for C22H28CIN2O3 (M+H) ⁺ : m/z = 403.2; found: 403.1. A mixture of the above HC1 salt, 6-bromo-9H-purine (31 mg, 0.16 mmol) and

DIPEA(0.1 1 mL, 0.65 mmol) in ethanol (1 mL) was heated at 100 °C overnight. The

mixture was diluted with sat. NaHC0 ₃ solution, extracted with dichloromethane. The combined organic layers were dried over MgS0 ₄ and concentrated to give the desired product (83 mg). LCMS calculated for C ₂ 7H ₃₀ ClN ₆ O ₃ (M+H) ⁺ : m/z = 521.2; found: 521.1.

Step 6. N-{1 -[5-chloro-2-ethoxy-4-methyl-3-(l -methylazetidin-3-yl)phenyl] ethyl}-9H^ amine

Benzyl 3- {3-chloro-6-ethoxy-2-methyl-5-[ 1 -(9H-purin-6- ylamino)ethyl]phenyl}azetidine-l-carboxylate (83 mg, 0.16 mmol) and 5% palladium (74 mg) was combined in methanol (5 mL), to which was added 0.25 M HC1 in water (1.6 mL, 0.40 mmol). The suspension was hydrogenated under balloon pressure of H ₂ at room temperature overnight. The suspension was filtered and concentrated to give N-[l-(3-azetidin-3-yl-5-chloro- 2-ethoxy-4-methylphenyl)ethyl]-9H-purin-6-amine. LCMS calculated for Ci ₉ H ₂₄ ClN ₆ 0 (M+H) ⁺ : m/z = 387.2; found: 387.1. The azetidine made above was combined with DIPEA(0.1 mL, 0.6 mmol) in methanol (0.5 mL)/acetonitrile (0.5 mL)/THF (0.5 mL), followed by the addition of 37% formaldehyde (0.1 mL, 2 mmol). The mixture was stirred at room temperature for 10 min before the addition of sodium triacetoxyborohydride (0.17 g, 0.80 mmol). The reaction mixture was stirred at room temperature overnight, then diluted with MeOH and purified on RP-HPLC (XBridge C 18 Column, eluting with a gradient of acetonitrile in water with 0.2% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product. LCMS calculated for

C ₂ oH ₂₆ ClN ₆ 0 (M+H) ⁺ : m/z = 401.2; found: 401.1.

Example 174. 7V-{l-[5-chloro-2-methoxy-4-methyl-3-(l-piperidin-4-yl-lH-py razol-4- yl)phenyl] ethyl}-9H-purin-6-amine tris(trifluoroacetate)

Step 1. tert-Butyl 4-{4-[3-chloro-6-methoxy-2-methyl-5-(l-{[9-(tetrahydro-2H-py ran-2-yl)-9H- purin-6-yl]amino}ethyl)phenyl]-lH- razol-l-yl}piperidine-l-carboxylate

Into a microwave vial was added N-[l-(3-bromo-5-chloro-2-methoxy-4- methylphenyl)ethyl]-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6- amine (0.032 g, 0.066 mmol, from Example 113, Step 2, chiral intermediate), tert- vXy\ 4-[4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-lH-pyrazol-l-yl]piperidine-l-carboxylate (0.030 g, 0.080 mmol, from Combi-Blocks), sodium carbonate (0.014 g, 0.13 mmol), 1,4-dioxane (0.6 mL)/water (0.2 mL) and tetrakis(triphenylphosphine)palladium(0) (4.6 mg, 0.0040 mmol). The mixture was degassed with N ₂ for 5 minutes, and then heated at 120 °C overnight. The mixture was diluted with EtOAc, washed with sat. NaHC0 ₃ , water, brine, dried over Na ₂ S0 ₄ , filtered and concentrated to give the crude product (0.040 g) which was used in the next step directly. LCMS calculated for C ₃₃ H ₄₄ C1N ₈ 0 ₄ (M+H) ⁺ : m/z = 651.3; found: 651.2. Step 2. ]^-{l-[5-chloro-2-methoxy-4-methyl-3-(l-piperidin-4-yl-lH-py

9H-purin-6-amine tris(trifluoroacetate)

tert-Butyl 4-{4-[3-chloro-6-methoxy-2-methyl-5-(l-{[9-(tetrahydro-2H-py ran-2-yl)-9H- purin-6-yl]amino}ethyl)phenyl]-lH-pyrazol-l-yl}piperidine-l- carboxylate (0.040 g) was dissolved in CH ₂ CI ₂ (0.4 mL) and then TFA (0. 4 mL) was added. The mixture was stirred at room temperature for 1 hour. After evaporated to dryness, the residue was purified on RP-HPLC (XBridge C18 Column, eluting with a gradient of acetonitrile in water with 0.05% trifluoroacetic acid, at flow rate of 30 mL/min) to give the desired product. LCMS calculated for C ₂₃ H ₂₈ CIN ₈ O (M+H) ⁺ : m/z = 467.2; found: 467.2.

Example 175. 4-{3-Chloro-6-methoxy-2-methyl-5-[l-(9H-purin-6-ylamino)ethy l]phenyl}- N, 1-dimethyl- lH-pyrr ole-2-carboxamide

Step 1. 2-Benzyl 1-tert-butyl 4-iodo- lH-pyrrole- 1 ,2-dicarboxylate

A mixture of 2,2,2-trichloro-l -(4-iodo- lH-pyrrol-2-yl)ethanone (15.0 g, 44.3 mmol, from Ryan Scientific), benzyl alcohol (9.2 mL, 89 mmol), and triethylamine (8.0 mL, 58 mmol) was heated at 60 °C with stirring overnight. After cooling to room temperature, άι-tert- butyldicarbonate (10.6 g, 48.8 mmol), 4-dimethylaminopyridine (542 mg, 4.43 mmol) and methylene chloride (75.0 mL) was added. The mixture was stirred at room temperature for 3 hours. The reaction was then diluted with EtOAc and washed with water, aqueous citric acid, brine, dried and concentrated. The product was isolated by chromatography eluting with 0 to 10% EtOAc in hexanes. LCMS calculated for Ci ₇ Hi ₈ IN0 ₄ Na (M+Na) ⁺ : m/z = 450.0; found: 450.0. Step 2. 2-Benzyl 1-tert-butyl 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrrole-l ,2- dicarboxylate

At -78 °C to a solution of 2-benzyl 1-tert-butyl 4-iodo-lH-pyrrole-l,2-dicarboxylate (10.0 g, 23.4 mmol), and 2-isopropoxy-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (9.6 mL, 47 mmol) in THF (120 mL) was added dropwise a solution of 2.5 M n-butyllithium in hexane (11.2 mL, 28.1 mmol) with stirring. After completion of addition the mixture was stirred at this temperature for 35 min and then 2.5 M n-butyllithium in hexane (1.87 mL, 4.68 mmol) was added and stirred for another 30 minutes. The reaction was quenched with sat. NH ₄ C1 solution and then diluted with EtOAc. The organic layer was separated, washed with water twice, washed with brine, dried over Na ₂ S0 ₄ , and concentrated under reduced pressure. The product was isolated by chromatography eluting with 0 to 10% EtOAc in hexanes. LCMS calculated for C ₁₉ H ₂₃ BNO ₆ (M-r/Bu+l]+l) ⁺ : m/z = 372.2; found: 372.2.

Step 3. Benzyl l-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH- pyrrole-2- carboxylate

2-Benzyl 1 -tert-butyl 4-(4,4,5 ,5-tetramethyl- 1 ,3 ,2-dioxaborolan-2-yl)- lH-pyrrole- 1 ,2- dicarboxylate (0.5 g) was dissolved in CH ₂ C1 ₂ (1 mL) and then 4 N HC1 in dioxane (1 mL) was added. The reaction was stirred at room temperature for 1 hour. The solvent was removed under vacuum. The residue was redissolved in DMF (4 mL). To the resulting solution was added NaH (60% dispersion in mineral oil, 0.08 g, 2.0 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 10 minutes. Methyl iodide (0.11 mL, 2.0 mmol) was added and the reaction was stirred at room temperature for 3 hours. The reaction was quenched with sat. NH ₄ C1 solution and then diluted with EtOAc. After separation of layers, the organic phase was washed with water (twice) and brine; dried over Na ₂ S0 ₄ . The solvent was removed to provide the desired crude product which was used in the next step without further purification. LCMS calculated for ^Η ₂₅ ΒΝ0 ₄ (M+H) ⁺ : m/z = 342.2; found: 342.2.

Step 4. Benzyl 4-[3-chloro-6-methoxy-2-methyl-5-(l-{[9-(tetrahydro-2H-pyran -2-yl)-9H-purin- 6-yl]amino}ethyl)phenyl]-l-methyl-lH-pyrrole-2-carboxylate

A mixture of N-[ 1 -(3-bromo-5-chloro-2-methoxy-4-methylphenyl)ethyl]-9-(tetrah ydro-

2H-pyran-2-yl)-9H-purin-6-amine (0.032 g, 0.066 mmol, from Example 113, Step2, Chiral intermediate), benzyl 1 -methyl-4-(4,4,5 ,5-tetramethyl- 1 ,3 ,2-dioxaborolan-2-yl)- lH-pyrrole-2- carboxylate (0.027 g, 0.080 mmol), sodium carbonate (0.16 mL, 0.17 mmol), 1,4-dioxane (0.6 mL)/water (0.2mL) and tetrakis(triphenylphosphine)palladium(0) (4.6 mg, 0.0040 mmol) was degassed with N ₂ for 5 minutes, then heated at 95°C overnight. The mixture was diluted with EtOAc, washed with sat. NaHC0 ₃ , water, brine, and dried over Na ₂ S0 ₄ and concentrated. The crude product (20 mg, 50%) was purified by chromatography eluting with 0 to 40%> EtOAc in CH ₂ C1 ₂ . LCMS calculated for C ₃₃ H ₃₆ C1N ₆ 0 ₄ (M+H) ⁺ : m/z = 615.2; found: 615.2.

Step 5. 4-{3-Chloro-6-methoxy-2-methyl-5-f l-(9H-purin-6-ylamino) ethyl] phenyl} -1 -methyl- 1H- pyrrole-2-carboxylic acid

Pd/C (5%), 20 mg) was added to a solution of benzyl 4-[3-chloro-6-methoxy-2-methyl-5- ( 1 - { [9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl]amino } ethyl)phenyl] - 1 -methyl- 1 H-pyrrole-2- carboxylate (20 mg) in methanol (2.0 mL) and the reaction was stirred at room temperature under balloon pressure of H ₂ for 4 hours. The reaction mixture was filtered and to the filtrate was added cone. HC1 (30 μί). The mixture was stirred for 0.5 h to remove the THP group. The solvent was removed to yield the crude product which was used in the next step without further purification. LCMS calculated for C ₂ iH ₂₂ ClN ₆ 0 ₃ (M+H) ⁺ : m/z = 441.1; found: 441.2.

Step 6. 4-{3-Chloro-6-methoxy-2-methyl-5-[ l-(9H-purin-6-ylamino)ethyl]phenyl}-N, l-dimethyl- lH-pyrrole-2-carboxamide

2.0 M Methylamine in THF (0.2 mL, 0.4 mmol) was added to a solution of 4-{3-chloro- 6-methoxy-2-methyl-5 -[ 1 -(9H-purin-6-ylamino)ethyl]phenyl} - 1 -methyl- lH-pyrrole-2- carboxylic acid (10.0 mg, 0.02 mmol) and benzotriazol-l-yloxytris(dimethylamino)phosphonium hexafluorophosphate (24 mg, 0.054 mmol) in DMF (0.8 mL) at room temperature followed by addition of triethylamine (33 0.24 mmol). The reaction was stirred for 2 hours. The mixture was purified on RP-HPLC (XBridge CI 8 Column, eluting with a gradient of acetonitrile in water with 0.2% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product. LCMS calculated for C ₂₂ H ₂₅ C1N ₇ 0 ₂ (M+H) ⁺ : m z = 454.2; found: 454.2. Example 176. V-{l-[5-Chloro-2-methoxy-4-methyl-3-(l-methylpiperidin-4- yl)phenyl]ethyl}-9H-purin-6-amine

Step 1. Benzyl [ l-(3-bromo-5-chloro-2-methoxy-4-methylphenyl)ethyl] -carbamate

Benzyl chloroformate (0.41 mL, 2.8 mmol) was added to a mixture of l-(3-bromo-5- chloro-2-methoxy-4-methylphenyl)ethanamine hydrochloride (0.50 g, 1.6 mmol, made from Example 1 13, step 1 , chiral intermediate), and sodium carbonate (670 mg, 6.3 mmol) in methylene chloride (5 mL)/water (1 mL) at 0 °C. The reaction was stirred at room

temperature for 4 hours. The mixture was diluted with EtOAc, washed with water, brine, dried over Na ₂ S0 ₄ , filtered and concentrated. The resultant residue was purified by chromatography eluting with 0 to 20% EtOAc in hexanes to provide the desired product (0.5 g, 76%). LCMS calculated for Ci ₈ Hi ₉ BrClN0 ₃ Na (M+Na) ⁺ : m/z = 434.0; found: 434.1.

Step 2. tert-Butyl 4-[3-(l-{[(benzyloxy)carbonyl]amino}ethyl)-5-chloro-2-methox y-6- methylphenylJ-3, 6-dihydropyridine-l(2H)-carboxylate

A mixture of benzyl [1 -(3 -bromo-5-chloro-2-methoxy-4-methylphenyl)ethyl] carbamate (0.48 g, 1.2 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)-3,6- dihydropyridine-l(2H)-carboxylate (0.40 g, 1.3 mmol, from Aldrich), sodium carbonate (250 mg, 2.3 mmol) and [l, -bis(diphenylphosphino)ferrocene]dichloropalladium(II),compl ex with dichloromethane (1 : 1) (1 10 mg, 0.14 mmol) in acetonitrile (4.0 mL)/water (1 mL) was placed under vacuum and then refilled with N ₂ . The reaction was stirred at 95 °C for 3 hours. The mixture was diluted with EtOAc, washed with sat. NaHC0 ₃ , water, brine, dried over Na ₂ S0 ₄ , filtered and concentrated. The resultant residue was purified by chromatography eluting with 0 to 20%) EtOAc in hexanes to provide the desired product (0.55 g, 90%>). LCMS calculated for C ₂ 8H ₃₅ ClN ₂ 0 ₅ Na (M+Na) ⁺ : m/z = 537.2; found: 537.3. Step 3. tert-Butyl 4-{3-[l-aminoethyl]-5-chloro-2-methoxy-6-methylphenyl}-piper idine-l- carboxylate

Platinum on carbon (10 wt. % loading (dry basis), matrix activated carbon, 200 mg) was added to a solution of tert-butyl 4-[3-(l-{[(benzyloxy)carbonyl]amino}ethyl)-5-chloro-2- methoxy-6-methylphenyl]-3,6-dihydropyridine-l(2H)-carboxylat e (200 mg, 0.388 mmol) in ethanol (30 mL)/0.25 M HC1 in water (3.9 mL, 0.97 mmol) and then the reaction was stirred at room temperature under 30 psi of hydrogen atmosphere for 3 d. The mixture was adjusted to basic pH with ammonia and then the solvent was removed. The residue was diluted with methylene chloride, washed with sat. NaHC0 ₃ , water, brine, dried over Na ₂ S0 ₄ , filtered and concentrated to give the crude desired product (0.15 g) which was used in the next step without further purification. LCMS calculated for C2oH ₃₂ ClN ₂ 0 ₃ (M+H) ⁺ : m/z = 383.2; found: 383.3.

Step 4. 6-Chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purine

To a solution of 6-chloropurine (2.70 g, 17.5 mmol) and p-toluenesulfonic acid monohydrate (0.14 g, 0.71 mmol) in methylene chloride (30 mL) was added dihydropyran (2.39 mL, 26.2 mmol). The suspension was stirred for 3 h. The reaction mixture was washed with 2.5% Na ₂ C0 ₃ solution (100 mL x2), and brine (50 mL). The organic layer was dried over sodium sulfate and concentrated. The oil was treated with hexanes (100 mL) and stirred. The hexanes layer was decanted. The oil solidified upon standing to give the desired product (4.17 g, 98%).

Step 5. tert-Butyl 4-[3-chloro-6-methoxy-2-methyl-5-(l-{[9-(tetrahydro-2H-pyran -2-yl)-9H- purin-6-yl] amino} ethyl)phenyl]piperidine-l-carboxylate

A mixture of tert-butyl 4-{3-[l-aminoethyl]-5-chloro-2-methoxy-6- methylphenyl}piperidine-l-carboxylate (150 mg, 0.392 mmol), 6-chloro-9-(tetrahydro-2H- pyran-2-yl)-9H-purine (122 mg, 0.509 mmol), and sodium bicarbonate (35 mg, 0.41 mmol) in 1- butanol (4.7 mL) was degassed with N ₂ for ~ 5 minutes. The mixture was heated at 110 °C for 3 h under nitrogen. The solvent was removed under reduced pressure and the resulting residue was diluted with EtOAc, washed with sat. NaHC0 ₃ , water, brine, dried over Na ₂ S0 ₄ , filtered and concentrated. The residue was purified by chromatography eluting with 0 to 80% EtOAc in CH ₂ C1 ₂ to provide the desired product (0.25 g). LCMS calculated for C ₃₀ H ₄₂ CIN ₆ O ₄ (M+H) : m/z = 585.3; found: = 585.3 .

Step 6. N-f l-(5-Chloro-2-methoxy-4-methyl-3-piperidin-4-ylphenyl)ethy

4.0 M HC1 in dioxane (2.0 mL, 8 mmol) was added to a solution of tert-butyl 4-[3- chloro-6-methoxy-2-methyl-5 -( 1 - { [9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6- yl] amino }ethyl)phenyl]piperidine-l-carboxylate (250 mg, 0.43 mmol) in methylene chloride (1.0 mL, 16 mmol) and the reaction was stirred at room temperature for 1 hour. The solvent was removed to provide the desired product as HC1 salt which was used in the next step without further purification. LCMS calculated for C ₂ oH ₂₆ ClN ₆ 0 (M+H) ⁺ : m/z = 401.2; found: = 401.2.

Step 7. N-{l-[ 5-chloro-2-methoxy-4-methyl-3-( l-methylpiperidin-4-yl)phenyl]ethyl}-9H-purin- 6-amine

12.0 M Formaldehyde in water (0.4 mL, 5 mmol) was added to a mixture of N-[l-(5- chloro-2-methoxy-4-methyl-3-piperidin-4-ylphenyl)ethyl]-9H-p urin-6-amine (200 mg, 0.5 mmol) and DIPEA(0.35 mL, 2.0 mmol) in methylene chloride (5 mL) at 0 °C. The reaction was stirred for 10 minutes, and after this time sodium triacetoxyborohydride (160 mg, 0.75 mmol) was added. The reaction was stirred at 0 °C for 1 hour. The mixture was purified on RP- HPLC (XBridge CI 8 Column, eluting with a gradient of acetonitrile in water with 0.2% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product. LCMS calculated for C ₂ iH ₂₈ ClN ₆ 0 (M+H) ⁺ : m/z = 415.2; found: 415.3. 1H NMR (DMSO-< ₅ , 500 MHz) δ 9.67 (1H, br s), 8.72 (1H, br s), 8.35 (2H, s), 7.51 (1H, s), 5.75 (1H, m), 3.88 (3H, s), 3.49 (2H, m), 3.34 (1H, m), 3.12 (2H, m), 2.81 (1.5H, s), 2.80 (1.5H, s), 2.44-2.31 (2H, m), 2.36 (3H, s), 1.79 (2H, m), 1.49 (3H, d, J= 6.5 Hz) ppm.

Example 177. 6-{3-chloro-6-methoxy-2-methyl-5-[l-(9H-purin-6-ylamino)ethy l]phenyl}-V, V-dimethylpyridine-2-carboxamide bis(2,2,2-trifluoroacetate)

Stepl. tert-butyl {l-[5-chloro-2-methoxy-4-methyl-3-(4,4,5,5-tetramethyl-l,3,2 -dioxaborolan-2- yl)phenylj 'ethyl} carbamate

The tert-butyl [1 -(3 -bromo-5-chloro-2-methoxy-4-methylphenyl)ethyl] carbamate (1.5 g, 4.0 mmol, from Example 113, Step 1 Peak 2), was combined with potassium acetate (1.2 g, 12 mmol) and 4,4,5,5,4',4',5',5'-octamethyl-[2,2']bi[[l,3,2]dioxaborolany l] (2.0 g, 7.9 mmol) in dimethyl sulfoxide (15 mL, 210 mmol) at room temperature. The reaction was degassed with nitrogen and the [l, -bis(diphenylphosphino)ferrocene]dichloropalladium(II),compl ex with dichloromethane (1 : 1) (0.3 g, 0.4 mmol) was added. The reaction vessel was sealed and heated in an oil bath to 95 °C. After heating for 20 h the starting material was consumed. The reaction was allowed to cool and then diluted with EtOAc and washed with water, brine, dried over magnesium sulfate and concentrated to give the crude product as a dark colored oil. The oil was purified by chromatography on silica gel eluting with a hexane:EtOAc gradient to give tert-butyl {l-[5-chloro-2-methoxy-4-methyl-3-(4,4,5,5-tetramethyl-l,3,2 -dioxaborolan-2- yl)phenyl]ethyl} carbamate as a semisolid (1.1 g, 65%). LCMS calculated for C ₁₆ H ₂₄ BCIO ₃ (M+H) ⁺ : m/z = 310.6; found: 310.0.

Step 2. methyl 6-(3-{l-[(tert-butoxycarbonyl)amino]ethyl}-5-chloro-2-methox y-6- methylphenyl)pyridine-2-carboxylate

The tert-butyl {l-[5-chloro-2-methoxy-4-methyl-3-(4,4,5,5-tetramethyl-l,3,2 - dioxaborolan-2-yl)phenyl]ethyl} carbamate (0.3 g, 0.7 mmol), methyl 6-bromopyridine-2- carboxylate (0.38 g, 1.8 mmol), [l, -bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (1 : 1) (0.0575 g, 0.0705 mmol), palladium acetate (0.008 g, 0.04 mmol), cuprous monochloride (0.070 g, 0.70 mmol), and cesium carbonate (0.46 g, 1.4 mmol) were combined in DMF (18 mL). The mixture was degassed with nitrogen gas for 5 min and heated to 100 °C overnight in a sealed tube. The reaction was allowed to cool, diluted with EtOAc and washed with water, brine, dried over magnesium sulfate and concentrated to give crude product as a dark oil. The product was purified by chromatography on silica gel eluting with hexane:EtOAc gradient to give methyl 6-(3-{l-[(tert-butoxycarbonyl)amino]ethyl}-5- chloro-2-methoxy-6-methylphenyl)pyridine-2-carboxylate as a viscous oil (0.15 g, 50%). LCMS calculated for C22H ₂₈ C1N20 ₅ (M+H) ⁺ : m/z = 435.1; found: 435.1.

Step 3. 6-(3-{l-[ (tert-butoxycarbonyl)amino]ethyl}-5-chloro-2-methoxy-6- methylphenyl)pyridine-2-carboxylic acid

The methyl 6-(3- { 1 -[(fert-butoxycarbonyl)amino]ethyl} -5-chloro-2-methoxy-6- methylphenyl)pyridine-2-carboxylate (0.075 g, 0.17 mmol) was dissolved in methanol (5.0 mL) and the lithium hydroxide -monohydrate (0.022 g, 0.52 mmol) dissolved in water (0.5 mL) was added. The reaction was stirred at room temperature and monitored by LC/MS. After stirring for 18 h the reaction was complete. Acetic acid was added to adjust the pH 5 and the reaction was concentrated to give a semisolid residue. The crude was diluted with acetonitrile and concentrated 3 ^X to remove residual water and finally give 6-(3-{l-[(tert- butoxycarbonyl)amino]ethyl}-5-chloro-2-methoxy-6-methylpheny l)pyridine-2-carboxylic acid as a crude solid residue. LCMS calculated for C17H18CIN2O5 (M+H) ⁺ : m/z = 365.1; found: 365.0. Step 4. tert-butyl [l-(5-chloro-3-{6-[(dimethylamino)carbonyl]pyridin-2-yl}-2-m ethoxy-4- methylphenyl) ethyl] carbamate

The 6-(3- { 1 -[(tert-butoxycarbonyl)amino]ethyl} -5-chloro-2-methoxy-6- methylphenyl)pyridine-2-carboxylic acid (0.07 g, 0.2 mmol) was combined with DMF (3.0 mL) and DIPEA(0.14 mL, 0.83 mmol) at room temperature and the NNN',N'-tetramethyl-0-(7- azabenzotriazol-l-yl)uronium hexafluorophosphate (0.13 g, 0.33 mmol) was added. The reaction stirred for 10 min and dimethylamine hydrochloride (0.041 g, 0.50 mmol) was added. The reaction was stirred at room temperature for 3 h and was complete by LC/MS. The reaction mixture was diluted with EtOAc and washed with water, saturated ammonium chloride, brine, dried over magnesium sulfate and concentrated to give the desired product as an oil (0.06 g, 83%). LCMS calculated for C23H31CIN3O4 (M+H) ⁺ : m/z = 448.2; found: 448.1. Step 5. 6-{3-[ l-aminoethyl]-5-chloro-2-methoxy-6-methylphenyl}-N,N-dimethy lpy carboxamide dihydrochloride

The tert-butyl [l-(5-chloro-3-{6-[(dimethylamino)carbonyl]pyridin-2-yl}-2-m ethoxy-4- methylphenyl)ethyl]carbamate (0.06 gm, 0.13 mmol) was dissolved in 4 M HCl in dioxane (3 mL) and was stirred for 1 hour. The reaction was complete and the mixture was concentrated in vacuo to give the crude product as an oil. LCMS calculated for C18H23CIN3O2 (M+H) : m/z = 348.1; found: 348.1.

Step 6. 6-[3-chloro-6-methoxy-2-methyl-5-(l-{[9-(tetrahydro-2H-pyran -2-yl)-9H-purin-6- yl] amino} ethyl)phenyl] -N,N-dimethylpyridine-2-carboxamide

The 6-{3-[l-aminoethyl]-5-chloro-2-methoxy-6-methylphenyl}-N,N-d imethylpyridine-2- carboxamide (0.025 g, 0.072 mmol) was combined with 6-chloro-9-(tetrahydro-2H-pyran-2-yl)- 9H-purine (0.022 g, 0.14 mmol, from Example 176, Step 4) in 2-methoxyethanol (1.0 mL, 13 mmol) and DIPEA(0.037 g, 0.29 mmol) in a sealed tube. The reaction was heated to 105 °C in an oil bath for 18 hours. Without workup, the reaction was carried into the next step.

Step 7. 6-{3-chloro-6-methoxy-2-methyl-5-[ l-(9H-purin-6-ylamino)ethylJphenyl}-N,N- dimethylpyridine-2 -carboxamide bis(2 ,2 ,2-trifluoroacetate)

6-[3-Chloro-6-methoxy-2-methyl-5-(l-{[9-(tetrahydro-2H-pyran -2-yl)-9H-purin-6- yl] amino }ethyl)phenyl]-N,N-dimethylpyridine-2-carboxamide (0.04 gm, 0.072 mmol, from

Example 177, Step 6) was dissolved in a solution of 4 M HCl in dioxane (2 mL) and was stirred for 1 hour. The reaction mixture was purified without workup by prep HPLC on a C- 18 column eluting a water: acetonitrile gradient buffered with TFA (pH 2) to give the desired compound as a white amorphous solid (0.015 g, 45%). LCMS calculated for C23H25CIN7O2 (M+H) ⁺ : m/z = 466.1; found: 466.0. 1H NMR (300 MHz, DMSO- d ₆ ) δ 8.59 (s, 1H), 8.29 (m, 2H), 8.03 (t, J = 7.8 Hz, 1H), 7.64 (s, 1H), 7.57 (d, J= 7.7 Hz, 1H), 7.49 (d, J= 7.7 Hz, 1H), 5.72 (m, 1H), 3.41 (s, 3H), 2.99 (s, 3H), 2.91 (s, 3H), 1.96 (s, 3H), 1.52 (d, J= 6.9 Hz, 3H).

Example 178. 6-{3-chloro-6-methoxy-2-methyl-5-[l-(9H-purin-6-ylamino)ethy l]phenyl}- V, V-dimethylpyridazine-4-carboxamide bis(2,2,2-trifluoroacetate)

Step 1. 6-chloropyridazine-4-carbonyl chloride

6-oxo-l,6-dihydropyridazine-4-carboxylic acid (0.20 g, 1.4 mmol, Ark Pharm, Inc, catalog# AK-26372) was dissolved in phosphoryl chloride (8.0 mL, 86 mmol) and DMF (0.080 mL) under nitrogen. The reaction was heated to 80 °C in an oil bath and monitored by

LC/MS. After heating for 3 h the starting material was consumed (monitored for the methyl ester by adding aliquot to methanol). This reaction mixture was allowed to cool to room temperature and was concentrated in vacuo to remove the residual phosphoryl chloride. The crude product was used in the next step without purification.

Step 2. 6-chloro-N,N-dimethylpyridazine-4-carboxamide

The 6-chloropyridazine-4-carbonyl chloride (0.18 g, 1.04 mmol was dissolved in methylene chloride (12.0 mL) and a 2.0 M dimethylamine in THF (1.4 mL) was added at room temperature. The reaction was stirred for 1 h and was complete. The reaction was partitioned between EtOAc and water. The organic layer was washed with 1 N HC1, brine, dried over magnesium sulfate and concentrated to give the crude product as an amber oil. The product was purified by chromatography on silica gel eluting with hexane:EtOAc gradient to give 6-chloro- A ,N-dimethylpyridazine-4-carboxamide as a colorless viscous oil, (0.16 gm, 60%). LCMS calculated for C ₇ H ₉ CIN ₃ O (M+H) ⁺ : m/z = 186.0; found: 185.9.

Step3. 6-{3-chloro-6-methoxy-2-methyl-5-[l-(9H^urin-6-ylamino)ethyl ]phenyl}-N,N- dimethylpyridazine-4-carboxamide bis(2 ,2 ,2-trifluoroacetate)

Using procedures analogous to Example 177, but using 6-chloro-N,N- dimethylpyridazine-4-carboxamide from Example 178, Step 2, the title compound was prepared and purified by prep HPLC on a C- 18 column eluting with water: acetontrile gradient buffered to pH 2 with TFA to give 6-{3-chloro-6-methoxy-2-methyl-5-[l-(9H-purin-6- ylamino)ethyl]phenyl}-N,N-dimethylpyridazine-4-carboxamide as a white amorphous solid (0.015 g, 20%). LCMS calculated for C22H24CIN8O2 (M+H) ⁺ : m z = 467.2; found: 467.2. 1H NMR (300 MHz, DMSO- d ₆ ) δ 9.34 (d, J= 2.0 Hz, 1H), 8.70 (s, 1H), 8.32 (m, 2H), 7.86 (d, J = 2.0 Hz, 1H), 7.73 (s, 1H), 5.74 (m, 1H), 3.43 (s, 3H), 3.02 (s, 3H), 2.93 (s, 3H), 2.01 (s, 3H), 1.54 (d, J= 6.9 Hz, 3H).

Example 179. 5- {3-chloro-2-cyano-6-ethoxy-5- [ l-(9H-purin-6-ylamino)ethyl] phenyl}- V, V- dimethylpyridine-2-carboxamide bis(2,2,2-trifluoroacetate)

Step 1. 4-acetyl-2-bromo-6-chloro-3-ethoxybenzonitrile

The l-(3-bromo-5-chloro-4-fluoro-2-hydroxyphenyl)ethanone (3.0 g, 11 mmol, from Example 187, Step 2) was dissolved in DMF (24 mL) and potassium cyanide (0.88 g, 13 mmol) was added. The reaction was heated to 85 °C and monitored by LC/MS. After heating for 18 h the reaction was complete. The reaction was allowed to cool to room temperature and then potassium carbonate (3.1 g, 22 mmol) and iodoethane (1.3 mL, 17 mmol) were added. The reaction was heated to 60 °C overnight. After stirring for 18 h the reaction was complete. The crude was diluted with EtOAc and washed with water, brine, dried over magnesium sulfate and concentrated to give the crude product as a dark oil. The product was purified by

chromatography on silica gel eluting with hexane:EtOAc gradient to give 4-acetyl-2-bromo-6- chloro-3-ethoxybenzonitrile as an oil which solidified (2.1 g, 62%). LCMS calculated for CnHioBrClN0 ₂ (M+H) ⁺ : m/z = 301.9, 303.9; found: 301.6, 303.6.

Step 2. 4-( l-aminoethyl)-2-bromo-6-chloro-3-ethoxybenzonitrile

Titanium tetraisopropoxide (0.82 mL, 2.8 mmol) was added to a mixture of 4-acetyl-2- bromo-6-chloro-3-ethoxybenzonitrile (0.70 g, 2.3 mmol) and 2.0 M ammonia in ethanol (5.78 mL) at 0 °C. The reaction was heated and stirred at 60 °C under nitrogen for 3 hours. The reaction was allowed to cool to room temperature, cooled in an ice bath and sodium tetrahydroborate (0.131 g, 3.47 mmol) was added, the solution was stirred at room temperature for another 2 hours. The reaction mixture was quenched with 2 M ammonia in water, and was stirred to allow a precipitate to form. The slurry was filtered and the solid was washed with EtOAc. The organic solvent was removed under vacuum and the residue was dissolved in methylene chloride. The organic layer was then washed with sat'd NaHC0 ₃ , water, brine, dried over MgS04, filtered and concentrated to give 4-(l-aminoethyl)-2-bromo-6-chloro-3- ethoxybenzonitrile as an oil (0.7 g, 100%). The crude was used in the next step without purification. LCMS calculated for CnHi ₃ BrClN ₂ 0 (M+H) ⁺ : m/z = 302.9, 304.9; found: 302.9, 304.9.

Step 3. tert-butyl [l-(3-bromo-5-chloro-4-cyano-2-ethoxyphenyl)ethyl] carbamate

The 4-(l-aminoethyl)-2-bromo-6-chloro-3-ethoxybenzonitrile (0.7 g, 2.3 mmol) was dissolved in 1,4-dioxane (13 mL) and DIPEA(1.3 mL, 7.7 mmol) and the άι-tert- butyldicarbonate (0.757 g, 3.47 mmol) was added. The reaction was allowed to stir at room temperature overnight. The reaction was complete by LC/MS, and the reaction mixture was diluted with EtOAc and washed with 1 N HC1, brine, dried over magnesium sulfate and concentrated to give the crude product as an oil. The product was purified by chromatography on silica gel eluting with hexane: EtOAc gradient to give tert-butyl [l-(3-bromo-5-chloro-4-cyano- 2-ethoxyphenyl)ethyl]carbamate as a semi-solid (0.85 g, 90%). LCMS calculated for

CiiHioBrCINO (M+H) ⁺ : m/z = 285.9, 287.9; found: 285.9, 287.9. This racemic material was separated by chiral column HPLC: ChiralPak OJ-H 20 ^χ 250 mm, 15% ethanokhexane, 15 mL/min, loading 25 mg/ mL to give the separated enantiomers (Peak 1 retention time: 5.25 min, Peak 2 retention time: 6.45 min). The peak 2 enantiomer was used further in synthesis.

Step 4. 5-Bromo-N,N-dimethylpyridin -2-carboxamide

5-Bromopyridine-2-carboxylic acid (20 g, 100 mmol, Frontier Scientific catalog# B1704) was stirred in methylene chloride (30 mL) and cooled to 0 °C. 2.0 M Oxalyl chloride in methylene chloride (100 mL) was added slowly followed by DMF (0.8 mL). Vigorous degassing occurred. The mixture was stirred at 0 °C for 30 min and at rt overnight. The mixture was evaporated and redissolved in methylene chloride (130 mL). Dimethylamine hydrochloride (9.8 g, 120 mmol) was added and the mixture was cooled to 0 °C. Triethylamine (56.1 mL, 400 mmol) was added slowly (over 5 minutes) which caused significant exotherm and precipitation of a brown/orange solid. The mixture was stirred at rt for 2 h. The mixture was diluted with methylene chloride and washed with saturated sodium bicarbonate, brine, dried over sodium sulfate, filtered and evaporated. Purification on silica gel using ethyl acetate in hexanes (0-60%) gave the desired compound, (22.0 g, 100%). LCMS calculated for C ₈ Hi ₀ BrN ₂ O (M+H) ⁺ : m/z = 229.0, 231.0; found: 228.9, 230.9.

Step 5. {6-[(Dimethylamino)carbonyl]pyridin-3-yl}boronic acid

A mixture of 5-bromo-N,N-dimethylpyridine-2-carboxamide (23 g, 98 mmol),

4,4,5,5,4 ^, ,4 ^, ,5 ^* ,5 ^* -octamethyl-[2,2 ^, ]bi[[l,3,2]dioxaborolanyl] (27 g, 110 mmol), [1,1 ^* - bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (1 : 1) (4.8 g, 5.9 mmol), l,l'-bis(diphenylphosphino)ferrocene (3.3 g, 5.9 mmol), and potassium acetate (30 g, 300 mmol) in 1,4-dioxane (600 mL) was heated at 120 °C for 16 h. The mixture was cooled to rt and diluted with EtOAc. The organic solution was washed with saturated ammonium chloride solution which was discarded and then with water (1 L). The water wash was evaporated to give the desired compound (10 g, 50%>). LCMS calculated for CgHi ₂ BN ₂ 0 ₃ (M+H) ⁺ : m/z = 195.1; found: 195.1.

Step 6. tert-butyl [ l-(5-chloro-4-cyano-3-{6-[ (dimethylamino)carbonyl]pyridin-3-yl}-2- ethoxyphenyl) ethyl] carbamate

The tert-butyl [l-(3-bromo-5-chloro-4-cyano-2-ethoxyphenyl)ethyl]carbamate (0.05 g, 0.1 mmol, Example 179, peak 2) was combined with {6-[(dimethylamino)carbonyl]pyridin-3- yl}boronic acid (0.034 g, 0.17 mmol, Example 179, Step 5) in 1,4-dioxane (3.0 mL) and potassium carbonate (0.034 g, 0.25 mmol) dissolved in water (1.0 mL) in a tube. The reaction was degassed with nitrogen and the tetrakis(triphenylphosphine)palladium(0) (0.03 g, 0.02 mmol) was added and degassed again. The tube was sealed and heated in an oil bath to 90 °C. After heating for 18 h the reaction was complete. This was allowed to cool to room temperature and partitioned between EtOAc and water. The organic layer was washed with brine, dried over magnesium sulfate and concentrated to give the crude as a dark oil. The product was purified by chromatography on silica gel eluting with hexane:EtOAc gradient to give tert-butyl [l-(5-chloro- 4-cyano-3- {6-[(dimethylamino)carbonyl]pyridin-3-yl} -2-ethoxyphenyl)ethyl] carbamate as a viscous oil (0.04 g, 66%). LCMS calculated for C24H30CIN4O4 (M+H) ⁺ : m/z = 473.2; found: 473.1.

Step 7. 5-{3-[ l-aminoethylJ-5-chloro-6-cyano-2-ethoxyphenyl}-N,N-dimethylp yridine-2- carboxamide dihydrochloride

The tert-butyl [ 1 -(5 -chloro-4-cyano-3 - {6- [(dimethylamino)carbonyl]pyridin-3 -yl} -2- ethoxyphenyl)ethyl] carbamate from the above step (0.04 g, 0.085 mmol) was treated with 4 M HC1 in dioxane (4 mL) and stirred at room temperature for 1 hour. The reaction was

concentrated in vacuo to give 5-{3-[l-aminoethyl]-5-chloro-6-cyano-2-ethoxyphenyl}-N,N- dimethylpyridine-2-carboxamide as a semi-solid residue (0.05 g, 100%) . LCMS calculated for C19H22CIN4O2 (M+H) ⁺ : m/z = 373.1; found: 373.1.

Step 8. 5-{3-chloro-2-cyano-6-ethoxy-5-[ l-(9H-purin-6-ylamino)ethyl]phenyl}-N,N- dimethylpyridine-2-carboxamide bis(2 ,2 ,2-trifluoroacetate)

The 5-{3-[l-aminoethyl]-5-chloro-6-cyano-2-ethoxyphenyl}-N,N-dim ethylpyridine-2- carboxamide (0.05 g, 0.1 mmol) was combined with 6-chloro-9-(tetrahydro-2H-pyran-2-yl)-9H- purine (0.047 g, 0.20 mmol, from Example 176, Step 4) in 2-methoxyethanol (3.0 mL) and

DIPEA(0.069 mL, 0.39 mmol) in a sealed tube and heated to 105 °C. After heating for 18 h the reaction was complete. This was allowed to cool to room temperature and 4 M HC1 in dioxane (3 mL) was added. The reaction was stirred for 2 h and was complete. This was concentrated in vacuo and purified by prep HPLC on a C- 18 column eluting with water :acetonitrile gradient (buffered to pH 2 with TFA) to give 5-{3-chloro-2-cyano-6-ethoxy-5-[l-(9H-purin-6- ylamino)ethyl]phenyl}-N,N-dimethylpyridine-2-carboxamide as a white amorphous solid (0.020 g, 33%). LCMS calculated for C24H24CIN8O2 (M+H) ⁺ : m z = 491.1; found: 491.1. 1H NMR (300 MHz, DMSO- d ₆ ) δ 8.75 (s, 1H), 8.53 (m, 1H), 8.33 - 8.05 (m, 3H), 7.92 (s, 1H), 7.73 (d, J = 8.1 Hz, 1H), 5.81 (m, 1H), 4.07 - 3.89 (m, 1H), 3.42 (m, 1H), 3.04 (s, 3H), 2.96 (s, 3H), 1.56 (d, J = 6.9 Hz, 3H), 1.00 (t, J = 7.0 Hz, 3H).

Example 180. 6-chloro-3-ethoxy-2-[6-(l-hydroxyethyl)pyridin-3-yl]-4-[l-(9 H-purin-6- ylamino)ethyl] benzonitrile bis(2,2 2-trifluoroacetate)

Step 1. [6-(l-hydroxyethyl)pyridin-3-yl]boronic acid

1.0 M Methylmagnesium chloride in THF (0.4 mL, 0.4 mmol) was added dropwise to a mixture of 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine-2-ca rbaldehyde (50 mg, 0.2 mmol, Frontier Scientific, catalog #F2110) in THF (2 mL) at 0 °C. After stirring for 1 h at room temperature, the reaction was quenched with 1 N NH4CI and was extracted with EtOAc. The organic layer was washed with brine, dried over MgS0 ₄ , and concentrated to give the crude [6- (l-hydroxyethyl)pyridin-3-yl]boronic acid. This was used in the next step without purification.

Step 2. 6-chloro-3-ethoxy-2-[6-(l-hydroxyethyl)pyridin-3-yl]-4-[-l-( 9H-purin-6- ylamino) ethyl] benzonitrile bis(2 ,2 ,2-trifluoroacetate)

Using procedures analogous to Example 179, but using [6-(l -hydroxy ethyl)pyridin-3- yl]boronic acid from Step 1 above, in Example 179 Step 4, the title compound was prepared and purified by prep HPLC on a C- 18 column eluting with a water : acetonitrile gradient buffered to pH 2 with TFA, to give 6-chloro-3-ethoxy-2-[6-(l-hydroxyethyl)pyridin-3-yl]-4-[l-(9 H-purin-6- ylamino)ethyl]benzonitrile as a white amorphous solid (0.011 g, 35%). LCMS calculated for C23H23CIN7O2 (M+H) ⁺ : m/z = 464.1; found: 464.0. 1H NMR (300 MHz, CD ₃ OD) δ 8.74 (d, J = 1.8 Hz, 1H), 8.38 (m 2H), 8.29 - 8.18 (m, 2H), 7.89 (d, J= 8.2 Hz, 1H), 7.76 (s, 1H), 5.86 (m, 1H), 5.05 (m, J= 6.5 Hz, 1H), 4.08 - 3.87 (m, 1H), 3.58 - 3.43 (m, 1H), 1.70 (d, J= 6.9 Hz, 3H), 1.57 (d, J= 6.6 Hz, 3H), 1.08 (t, J= 7.0 Hz, 3H).

Example 181. V-{l-[5-chloro-3-(5-fluoropyridin-3-yl)-2-methoxy-4-methylph enyl]propyl}- 9H-purin-6-amine bis(2,2,2-trifluoroacetate

Step 1. l-(5-chloro-2-hydroxy-4-methylphenyl)propan-l-one

The 4-chloro-3 -methyl-phenol (2 g, 10 mmol) and the propionyl chloride (1.8 mL, 20. mmol) were combined and the mixture was heated at 60 °C for 2 hours. The reaction was concentrated in vacuo to remove excess propionyl chloride to give an oil. To this was added aluminum trichloride (2.7 g, 20. mmol) and the mixture was heated at 180 °C for 30 minutes. The reaction mixture was then cooled to room temperature and slowly quenched with 1 N HC1 while cooling in an ice bath. The reaction was partitioned between EtOAc and water. The organic layer was washed with 1 N HC1, water, brine, dried over magnesium sulfate and concentrated to give the crude product as a dark oil. The product was purified by

chromatography on silica gel eluting with hexane:EtOAc gradient to give l-(5-chloro-2-hydroxy- 4-methylphenyl)propan-l-one as a solid (1.5 g, 60%). LCMS calculated for CioHi ₂ C10 ₂ (M+H) ⁺ : m/z = 199.0; found: 198.9. Step 2. l-(3-bromo-5-chloro-2-methoxy-4-methylphenyl)propan-l-one

The l-(5-chloro-2-hydroxy-4-methylphenyl)propan-l-one (1.6 g, 8.0 mmol) was dissolved in acetic acid (20.0 mL) and N-bromosuccinimide (1.7 g, 9.7 mmol) was added. The reaction was warmed in an oil bath to 65 °C and monitored by LC/MS. After heating for 3 h the reaction was complete. This was allowed to cool to room temperature and was concentrated in vacuo. The residue was diluted with EtOAc and washed with water (twice), brine, dried over magnesium sulfate and concentrated to give l-(3-bromo-5-chloro-2-hydroxy-4- methylphenyl)propan-l-one as an amber oil. This oil was dissolved in DMF (10.0 mL) and potassium carbonate (3.3 g, 24 mmol) and methyl iodide (0.75 mL, 12 mmol) were added. The reaction was stirred at 65 °C for 18 hours. The reaction was complete, and the reaction mixture was diluted with EtOAc, washed with water, brine, dried over magnesium sulfate and concentrated to give the crude product as a dark oil. The product was purified by

chromatography on silica gel eluting with a hexane: EtOAc gradient to give l-(3-bromo-5- chloro-2-methoxy-4-methylphenyl)propan-l-one as an oil (1.8 g, 81%). LCMS calculated for CnHi ₃ BrC10 ₂ (M+H) ⁺ : m/z = 290.9, 292.9; found: 290.8, 292.9. Step 3. tert-butyl [l-(3-bromo-5-chloro-2-methoxy-4-methylphenyl)propyl] carbamate

Titanium tetraisopropoxide (3.0 mL, 10 mmol) was added to a mixture of l-(3-bromo-5- chloro-2-methoxy-4-methylphenyl)propan-l-one (2.5 g, 8.6 mmol) and 2.0 M ammonia in ethanol (21.4 mL) at 0 °C. The reaction was heated and stirred at 60 °C under nitrogen for 3 hours. The reaction was allowed to cool to room temperature, cooled in an ice bath and the sodium tetrahydroborate (0.486 g, 12.9 mmol) was added, the solution was stirred at room temperature for another 2 hours. The reaction mixture was quenched with 2 M ammonia in water, and was stirred to form the precipitate. The slurry was filtered, the solids were washed with EtOAc and the organic layer was concentrated in vacuo. The residue was diluted with methylene chloride, washed with sat'd NaHC0 ₃ , water, brine, dried over MgS0 ₄ , filtered and concentrated to give l-(3-bromo-5-chloro-2-methoxy-4-methylphenyl)propan-l-amine as an oil. This was diluted with 1,4-dioxane (48 mL) and DIPEA(5.0 mL) and the di-tert-butyldicarbonate (2.81 g, 12.9 mmol) was added. The reaction was allowed to stir at room temperature overnight. The reaction was complete by LC/MS, and the reaction mixture was diluted with EtOAc and washed with 1 N HC1, brine, dried over magnesium sulfate and concentrated to give the crude product as an oil. The product was purified by chromatography on silica gel eluting with a hexane: EtOAc gradient to give tert-butyl [l-(3-bromo-5-chloro-2-methoxy-4- methylphenyl)propyl] carbamate as a semisolid (2.0 g, 80%). LCMS calculated for CnHi ₃ BrC10 (M+H) : m/z = 274.9, 276.9; found: 274.9, 276.8. This racemic material was separated by chiral column HPLC: ChiralPak AD-H 20 ^χ 250 mm, 3% ethanokhexane, 18 mL/min, loading 10 mg/mL, to give the separated enantiomers. Peak 2 tert-butyl [l-(3-bromo-5-chloro-2-methoxy- 4-methylphenyl)propyl] carbamate was used further in synthesis. Step 4. tert-butyl {l-[5-chloro-3-(5-fluoropyridin-3-yl)-2-methoxy-4- methylphenyljpropy lcarbamate

The tert-butyl [ 1 -(3 -bromo-5 -chloro-2-methoxy-4-methylphenyl)propyl] carbamate peak 2 (0.075 g, 0.19 mmol) was combined with 3-fluoro-5-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)pyridine (0.081 g, 0.29 mmol, Frontier Scientific, catalog # F2018) in 1,4- dioxane (4.6 mL) and potassium carbonate (0.053 g, 0.38 mmol) in water (1.5 mL) in a tube. This was degassed with nitrogen and the tetrakis(triphenylphosphine)palladium(0) (0.02 g, 0.02 mmol) was added. The reaction was degassed with nitrogen, sealed and heated to 90 °C in an oil bath. The reaction was complete after 18 h, and the reaction mixture was allowed to cool and partitioned between EtOAc and water. The organic layer was washed with brine, dried over magnesium sulfate and concentrated to give the crude product as an oil. The product was purified by chromatography on silica gel eluting with a hexane:EtOAc gradient to give tert-butyl {l-[5- chloro-3-(5-fluoropyridin-3-yl)-2-methoxy-4-methylphenyl]pro pyl} carbamate as a viscous oil (0.05 g, 77%). LCMS calculated for C ₂₁ H ₂₇ CIFN ₂ O ₃ (M+H) ⁺ : m/z = 409.1; found: 409.1.

Step 5. 1-f 5-chloro-3-(5-fluoropyridin-3-yl)-2-methoxy-4-methylphenyl]p ropan-l -amine dihydrochloride

The tert-butyl { 1 -[5-chloro-3-(5-fluoropyridin-3-yl)-2-methoxy-4- methylphenyljpropyl} carbamate (0.05 g, 0.12 mmol) was diluted with 4 M HC1 in dioxane (4 mL) and was stirred at room temperature for 1 hour. The reaction was complete and the reaction mixture was concentrated to give l-[5-chloro-3-(5-fluoropyridin-3-yl)-2-methoxy-4- methylphenyl]propan-l -amine as a semi-solid (100%). LCMS calculated for Ci ₆ Hi ₆ ClFNO (M+H) ⁺ : m/z = 292.0; found: 292.0.

Step 6. N-{l-[ 5-chloro-3-(5-fluoropyridin-3-yl)-2-methoxy-4-methylphenyl]p ropyl}-9H-purin-6- amine bis (2, 2, 2-trifluoroacetate)

The l-[5-chloro-3-(5-fluoropyridin-3-yl)-2-methoxy-4-methylpheny l]propan-l-amine (0.030 g, 0.097 mmol) was combined with 6-chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (0.035 g, 0.14 mmol, from Example 176, Step 4) in 2-methoxyethanol (2.0 mL) and

DIPEA(0.051 mL, 0.29 mmol) in a sealed tube. The reaction was heated to 105 °C. After heating overnight, the reaction was allowed to cool to room temperature and was treated with 4 M HC1 in dioxane (3.0 mL) at room temperature. After stirring for 2 h the reaction was concentrated in vacuo to give a residue that was purified by prep HPLC on C-18 column eluting with a water: acetonitrile gradient buffered to pH 2 with TFA to give N-{l-[5-chloro-3-(5- fluoropyridin-3-yl)-2-methoxy-4-methylphenyl]propyl}-9H-puri n-6-amine as a white amorphous solid (0.012 g, 50%). LCMS calculated for C ₂ IH ₂ IC1FN ₆ 0 (M+H) ⁺ : m/z = 427.1; found: 427.1. 1H NMR (300 MHz, DMSO- d ₆ ) δ 8.90 (m, 1H), 8.65 (d, J= 2.1 Hz, 1H), 8.38 (m, 3H), 7.82 (d, J= 26.1 Hz, 1H), 7.67 (s, 1H), 5.57 (m, 1H), 3.39 (s, 3H), 2.03 (s, 3H), 1.99 - 1.76 (m, 2H), 0.95 (t, J= 7.3 Hz, 3H).

Example 182. V-(l-{5-chloro-2-methoxy-4-methyl-3-[5-(methylsulfonyl)pyrid in-3- yl] henyl}propyl)-9H-purin-6-amine bis 2,2,2-trifluoroacetate)

The title compound was prepared by methods analogous to Example 181, but using 3- (methylsulfonyl)-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2 -yl)pyridine (Peptech, catalog#

BE358) in Step 4. The product was purified by prep HPLC on a C-18 column eluting with water: acetonitrile gradient buffered to pH 2 with TFA to give N-(l-{5-chloro-2-methoxy-4-methyl-3- [5-(methylsulfonyl)pyridin-3-yl]phenyl}propyl)-9H-purin-6-am ine as white amorphous solid (0.012 g, 30%). LCMS calculated for C ₂₂ H ₂ 4C1N ₆ 0 ₃ S (M+H) ⁺ : m/z = 487.1; found: 487.0. 1H NMR (300 MHz, DMSO- d ₆ ) δ 9.12 (s, 1H), 8.87 (m, 2H), 8.32 (m, 3H), 7.71 (s, 1H), 5.57 (m, 1H), 3.39 (s, 6H), 2.05 (s, 3H), 1.91 (m, 2H), 0.96 (t, J= 7.3 Hz, 3H).

Example 183. (5-{3-chloro-6-methoxy-2-methyl-5-[l-(9H-purin-6- ylamino)ethyl]phenyl}pyridin-2-yl)methanol bis(2,2,2-trifluoroacetate)

Step 1. tert-butyl {l-[5-chloro-3-(6-formylpyridin-3-yl)-2-methoxy-4- methylphenyl] ethyl} carbamate

To a mixture of tert-butyl [l-(3-bromo-5-chloro-2-methoxy-4- methylphenyl)ethyl]carbamate (200 mg, 0.5 mmol, from Example 113, Step 1 peak 2) and 5- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine-2-carb aldehyde (150 mg, 0.63 mmol, Frontier Scientific, catalog# F2110) in 1,4-dioxane (4 mL) was added potassium carbonate (200 mg, 2 mmol) in water (2 mL). The reaction was degassed with N ₂ and

tetrakis(triphenylphosphine)palladium(0) (40 mg, 0.04 mmol) was added and degassed again with N ₂ . The reaction was heated at 100 °C overnight. The reaction was allowed to cool to room temperature and was partitioned between water and EtOAc. The organic layer was washed with brine, dried over MgSC^, filtered and concentrated to give the crude product. The product was purified by chromatography on silica gel eluting with a hexane:EtOAc gradient to give tert-butyl {l-[5-chloro-3-(6-formylpyridin-3-yl)-2-methoxy-4-methylphen yl]ethyl} carbamate as a yellow oil (0.15 g, 70%). LCMS calculated for C ₂ iH ₂₆ ClN ₂ 0 ₄ (M+H) ⁺ : m/z = 405.2; found: 405.1.

Step 2. tert-butyl (l-{5-chloro-3-[6-(hydroxymethyl)pyridin-3-yl]-2-methoxy-4- methylphenyl}ethyl)carbamate

Sodium tetrahydroborate (2.8 mg, 0.074 mmol) was added to a mixture of tert-butyl {1- [5-chloro-3-(6-formylpyridin-3-yl)-2-methoxy-4-methylphenyl] ethyl} carbamate (20 mg, 0.05 mmol) in methanol (2 mL) at 0 °C. The reaction was stirred for 1 h at 0 °C. The reaction mixture was partitioned between water and EtOAc. The combined organic layers was washed with brine, dried over MgSC^, filtered and concentrated to give crude product. This crude was used for next step. Step 3. (5-{3-chloro-6-methoxy-2-methyl-5-[ l-(9H-purin-6-ylamino)ethyl]phenyl}pyridin-2- yl)methanol bis(2 2 ,2-trifluoroacetate)

The title compound was prepared by methods analogous to Example 177 starting with Step 5, but using tert-bvXy\ (l-{5-chloro-3-[6-(hydroxymethyl)pyridin-3-yl]-2-methoxy-4- methylphenyl}ethyl)carbamate from Step 2 above to give the crude product. The reaction product was purified on prep HPLC on a C- 18 column eluting with a water: acetonitrile gradient buffered with TFA to give (5-{3-chloro-6-methoxy-2-methyl-5-[l-(9H-purin-6- ylamino)ethyl]phenyl}pyridin-2-yl)methanol as a white amorphous solid (0.005 g, 20%).

LCMS calculated for C ₂₁ H ₂₂ CIN ₆ O ₂ (M+H) ⁺ : m/z = 425.2; found: 425.1. 1H NMR (500 MHz, CD ₃ OD) δ 8.54 (s, 1H), 8.37 (s, 1H), 8.27 (s, 1H), 8.09 (bs, 1H), 7.85 (d, J= 8.1 Hz, 1H), 7.62 (s, 1H), 5.86 (m, 1H), 4.91 (s, 2H), 3.48 (s, 3H), 2.18 (s, 3H), 1.70 (d, J= 6.9 Hz, 3H).

Example 184. 2-(5- {3-chloro-6-methoxy-2-methyl-5- [ l-(9H-purin-6- ylamino)ethyl]phenyl}pyridin-2-yl)propan-2-ol bis(2,2,2-trifluoroacetate)

Step 1. 5-bromo-N-methoxy-N-methylpyridine-2-carboxamide

N, O-dimethylhydroxylamine hydrochloride (500 mg, 5 mmol) was added to a mixture of N,N,N',N'-tetramethyl-0-(7-azabenzotriazol-l-yl)uronium hexafluorophosphate (1400 mg, 3.7 mmol), DIPEA(1000 7 mmol) and 5-bromopyridine-2-carboxylic acid (500 mg, 2 mmol, Frontier Scientific catalog# B1704) in DMF (10 mL) at room temperature. The reaction was stirred overnight and was partitioned between water and EtOAc. The combined organic layer was washed with brine, dried over MgSC^, filtered and concentrated to give the crude product. The product was purified by chromatography on silica gel eluting with a hexane:EtOAc gradient to give 5-bromo-N-methoxy-N-methylpyridine-2-carboxamide as a clear oil (0.5 g, 60%).

LCMS calculated for C ₈ HioBrN ₂ 02 (M+H) ⁺ : m/z = 244.9, 246.9; found: 244.9, 246.9. Step 2. l-(5-bromopyridin-2-yl)ethanone

3.0 M Methylmagnesium chloride in THF (0.5 mL) was added dropwise to a mixture of 5-bromo-N-methoxy-N-methylpyridine-2-carboxamide (200 mg, 0.8 mmol) in THF (10 mL) at 0 °C. After stirring for 1 h at room temperature, the reaction was quenched with 1 N NH ₄ C1 and was extracted with EtOAc. The combined organic layer was washed with brine and dried over MgS0 ₄ , concentrated to give the crude product (0.15 g, 90%). This was used in the next step without purification. LCMS calculated for C ₇ H ₇ BrNO (M+H) ⁺ : m/z = 199.9, 201.9; found: 199.9, 201.9. Step 3. 2-(5-bromopyridin-2-yl)propan-2-ol

3.0 M Methylmagnesium chloride in THF (0.3 mL) was added dropwise to a mixture of l-(5-bromopyridin-2-yl)ethanone (100 mg, 0.5 mmol) in THF (10 mL) at 0 °C. After stirring for 1 h at room temperature, the reaction was quenched with 1 N NH ₄ C1 and was extracted with EtOAc. The combined organic layer was washed with brine and dried over MgS0 ₄ ,

concentrated to give crude product (0.1 g, 100%). Crude was used in next step without purification. LCMS calculated for C ₈ HnBrNO (M+H) ⁺ : m/z = 215.9, 217.9; found: 215.8, 217.8.

Step 4. 2-(5-{3-chloro-6-methoxy-2-methyl-5-[l-(9H-purin-6-ylamino)e thyl^

yl)propan-2-ol bis (2 2 ' ,2-trifluoroacetate)

The title compound was prepared by methods analogous to Example 177, but using 2-(5- bromopyridin-2-yl)propan-2-ol from Step 3 above to give the crude product. The reaction product was purified by prep HPLC on a C- 18 column eluting with a water: acetonitrile gradient buffered with TFA to give 2-(5-{3-chloro-6-methoxy-2-methyl-5-[l-(9H-purin-6- ylamino)ethyl]phenyl}pyridin-2-yl)propan-2-ol as a white amorphous solid (0.005 g, 20%>).

LCMS calculated for C23H26CIN6O2 (M+H) ⁺ : m z = 453.1; found: 453.0. 1H NMR (300 MHz, DMSO- d ₆ ) δ 8.85 (m, 1H), 8.42 (m, 3H), 7.86 (m, 2H), 7.64 (s, 1H), 5.75 (m, 1H), 3.36 (s, 3H), 2.03 (s, 3H), 1.55 (d, J= 6.9 Hz, 3H), 1.51 (s, 6H). Example 185. V-(l-{5-chloro-2-methoxy-3-[6-(l-methoxy-l-methylethyl)pyrid in-3-yl]-4- methylphenyl}ethyl)-9H-purin-6-amine bis(2,2,2-trifluoroacetate)

Step 1. 5-bromo-2-(l-methoxy-l-methylethyl)pyridine

2-(5-bromopyridin-2-yl)propan-2-ol (50 mg, 0.2 mmol, from Example 184, Step 3) was added to a mixture of NaH in mineral oil (10 mg, 0.5 mmol) in DMF (5 mL) . The reaction was stirred for 30 min and the methyl iodide (30 μΐ,, 0.5 mmol) was added and stirred for 2 hours. The reaction was partitioned between EtOAc and water. The combined organic layer was washed with brine, dried over MgSC^, filtered and concentrated to give crude product 5-bromo- 2-(l-methoxy-l -methylethyl)pyridine as an oil (0.05 g, 90%). LCMS calculated for C ₉ Hi ₃ BrNO (M+H) ⁺ : m/z = 230.0, 232.0; found: 230.0, 231.8.

Step 2. N-(l-{5-chloro-2-methoxy-3-[ 6-(l-methoxy-l-methylethyl)pyridin-3-yl]-4- methylphenylj ethyl) -9H-purin-6- amine bis(2 ,2 ,2-trifluoroacetate)

The title compound was prepared by methods analogous to Example 177, but using 5- bromo-2-(l-methoxy-l-methylethyl)pyridine from Step 1 above to give the crude product. The reaction product was purified by prep HPLC on a C- 18 column eluting with a water :acetonitrile gradient buffered with TFA to give N-(l- {5-chloro-2-methoxy-3-[6-(l-methoxy-l- methylethyl)pyridin-3-yl]-4-methylphenyl}ethyl)-9H-purin-6-a mine as a white amorphous solid (0.005 g, 30%). LCMS calculated for C24H28CIN6O2 (M+H) ⁺ : m/z = 467.2; found: 467.1. 1H NMR (300 MHz, DMSO- d ₆ ) δ 9.30 (m, 1H), 8.50 (m, 3H), 7.84 (m, 1H), 7.68 (d, J= 8.1 Hz, 1H), 7.62 (s, 1H), 5.76 (m, 1H), 3.31 (s, 3H), 3.10 (s, 3H), 2.04 (s, 3H), 1.57 (d, J = 6.8 Hz, 3H), 1.52 (s, 6H).

Example 186. 3-ethoxy-6-methyl-2- [5-(methylsulfonyl)pyridin-3-yl] -4- [ l-(9H-purin-6- ylamino)ethyl] benzonitrile bis(2,2,2-trifluoroacetate)

Step 1. tert-butyl (l-{5-chloro-4-cyano-2-ethoxy-3-[5-(methylsulfonyl)pyridin-3 - yl] phenyl} ethyl) carbamate

To tert-butyl [-1 -(3 -bromo-5-chloro-4-cyano-2-ethoxyphenyl)ethyl] carbamate (50 mg, 0.1 mmol, from Example 179, Step 3) and 3-(methylsulfonyl)-5-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)pyridine (30. mg, 0.11 mmol, Peptech, catalog # BE358) in 1,4-dioxane (4 mL) was added potassium carbonate (30 mg, 0.2 mmol) in water (2 mL). The reaction was degassed with N ₂ . Tetrakis(triphenylphosphine)palladium(0) (40 mg, 0.04 mmol) was added and degassed again with N ₂ . The reaction was heated at 100 °C overnight. The reaction was allowed to cool to room temperature and was partitioned between EtOAc and water. The

combined organic layer was washed with brine, dried over MgS0 ₄ , filtered and concentrated to give crude product. The product was purified by chromatography on silica gel eluting with a hexane:EtOAc gradient to give tert-butyl (l-{5-chloro-4-cyano-2-ethoxy-3-[5- (methylsulfonyl)pyridin-3-yl]phenyl}ethyl)carbamate as a yellow oil (0.030 g, 60%). LCMS calculated for C ₂₂ H ₂₇ C1N ₃ 0 ₅ S (M+H) ⁺ : m/z = 480.1; found: 480.1.

Step 2. tert-butyl (l-{4-cyano-2-ethoxy-5-methyl-3-[5-(methylsulfonyl)pyridin-3 - yl] phenyl} ethyl) carbamate

To tert-butyl ( 1 - {5 -chloro-4-cyano-2-ethoxy-3 - [5 -(methylsulfonyl)pyridin-3 - yl]phenyl}ethyl)carbamate (60 mg, 0.1 mmol) and methylboronic acid (6.4 mg, 0.11 mmol) in 1,4-dioxane (4 mL) was added sodium carbonate (20 mg, 0.2 mmol) in water (2 mL). The reaction was degassed with N ₂ . Dichloro(bis{di-tert-butyl[4-(dimethylamino)phenyl] phosphoranyl})palladium (4 mg, 0.005 mmol) was added and degassed again with N ₂ . The reaction was heated at 90 °C overnight. The reaction was allowed to cool to room temperature and was partitioned between EtOAc and water. The combined organic layer was washed with brine, dried over MgS0 ₄ , filtered and concentrated to give crude product. The product was purified by chromatography on silica gel eluting with a hexane: EtOAc gradient to give tert-butyl (1 - {4-cyano-2-ethoxy-5-methyl-3-[5-(methylsulfonyl)pyridin-3-yl ]phenyl} ethyl)carbamate as a yellow oil (0.030 g, 50%). LCMS calculated for C ₂ 3H3oN ₃ 0 ₅ S (M+H) ⁺ : m/z = 460.1; found: 460.2.

Step 3. 4-(-l-aminoethyl)-3-ethoxy-6-methyl-2-f 5-(methylsulfonyl)pyridin-3-yl]benzonitrile dihydrochloride

The tert-butyl ( 1 - {4-cyano-2-ethoxy-5 -methyl-3 - [5 -(methylsulfonyl)pyridin-3 - yl]phenyl}ethyl)carbamate (0.030 gm, 0.065 mmol) was dissolved in 4.0 M HC1 in dioxane (2 mL) and was stirred for 1 hour. The reaction was concentrated in vacuo to give 4-(l- aminoethyl)-3-ethoxy-6-methyl-2-[5-(methylsulfonyl)pyridin-3 -yl]benzonitrile as a semi-solid (0.035 g, 100%). LCMS calculated for Ci ₈ H ₂₂ N ₃ 0 ₃ S (M+H) ⁺ : m/z = 360.1; found: 360.2.

Step 4. 3-ethoxy-6-methyl-2- [5-(methylsulfonyl)pyridin-3-yl] -4- [ (lS)-l-(9H-purin-6- ylamino) ethyl] benzonitrile bis(2 ,2 ,2-trifluoroacetate)

6-Chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (35 mg, 0.15 mmol, from Example 176, Step 4) and DIPEA(0.04 mL, 0.2 mmol) were added to 4-(l-aminoethyl)-3-ethoxy-6- methyl-2-[5-(methylsulfonyl)pyridin-3-yl]benzonitrile in ethanol (2 mL). The reaction was heated to 120 °C overnight. The reaction was allowed to cool to room temperature and was concentrated in vacuo to give 3-ethoxy-6-methyl-2-[5-(methylsulfonyl)pyridin-3-yl]-4-(l-{[ 9- (tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl]amino}ethyl)benzoni trile as a solid residue. This intermediate was dissolved in 4.0 M HC1 in dioxane (1 mL) and was stirred for 10 minutes. The reaction was concentrated and was purified on prep HPLC on a C- 18 column eluting with water: acetonitrile gradient buffered with TFA to give 3-ethoxy-6-methyl-2-[5-(methylsulfonyl)pyridin- 3-yl]-4-[l-(9H-purin-6-ylamino)ethyl]benzonitrile as a white solid (0.010 g, 16 %). LCMS calculated for C ₂₃ H ₂ 4N ₇ 0 ₃ S (M+H) ⁺ : m/z = 478.1; found: 478.1. 1H NMR (300 MHz, DMSO- d ₆ ) δ 9.18 (d, J= 2.2 Hz, 1H), 9.09 (d, J= 2.0 Hz, 1H), 8.75 (m, 1H), 8.54 (t, J= 2.1 Hz, 1H), 8.33 (m, 2H), 7.68 (s, 1H), 5.80 (m, 1H), 3.99 - 3.79 (m, 1H), 3.40 (s, 3H), 3.34 (m, 1H), 2.47 (s, 3H), 1.58 (d, J= 6.9 Hz, 3H), 0.98 (t, J= 6.9 Hz, 3H). Example 187. V-{l-[5-Chloro-4-fluoro-2-methoxy-3-(l,2,3,6-tetrahydropyrid in-4- yl)phenyl] ethyl}-9H-purin-6-amine hydrochloride

Step 1. l-(5-Chloro-4-fluoro-2-hydroxyphenyl)ethanone

Acetyl chloride (3.6 mL, 51 mmol) was added to 4-chloro-3-fluorophenol (5.1 g, 35 mmol) and the resulting mixture was heated at 60 °C for 2 hours. Aluminum trichloride (7.0 g, 52 mmol) was added and the mixture was heated at 180 °C for 30 minutes. The mixture was cooled to room temperature. The mixture was cooled to 0 °C and 1 N HCI solution (100 mL) was added dropwise over 30 minutes. The precipitate was washed well with water and dried under vacuum to give the desired compound (6.6 g, 100%).

Step 2. l-(3-Bromo-5-chloro-4-fluoro-2-hydroxyphenyl)ethanone

To a stirred solution of l-(5-chloro-4-fluoro-2-hydroxyphenyl)ethanone (8.0 g, 42 mmol) in acetic acid (80 mL) was added N-bromosuccinimide (9.0 g, 50 mmol) and the resulting mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated, neutralized with saturated sodium bicarbonate solution and extracted with EtOAc. The combined organic layers were washed with brine, dried over sodium sulfate, and then concentrated to dryness under reduced pressure. The residue was purified on silica gel, eluting with 0 to 20% EtOAc in hexane, to yield the desired product (10.5 g, 93%>). LCMS calculated for

C ₈ H ₆ BrClF0 ₂ (M+H) ⁺ : m/z = 266.9, 268.9; found: 267.1, 269.1.

Step 3. l-(3-Bromo-5-chloro-4-fluoro-2-methoxyphenyl)ethanone

A mixture of l-(3-bromo-5-chloro-4-fluoro-2-hydroxyphenyl)ethanone (4.8 g, 18 mmol), potassium carbonate (6.5 g, 47 mmol) and methyl iodide (2.5 mL, 40 mmol) in DMF (10 mL) was heated at 60 °C for 1 hour. The mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over sodium sulfate, and evaporated. The residue was purified on silica gel, eluting with 0 to 20% EtOAc in hexane, to yield the desired compound (2.2 g, 44%). LCMS calculated for C ₉ H ₈ BrClF0 ₂ (M+H) ⁺ : m/z = 280.9, 282.9; found: 281.0, 283.0.

Step 4. l-(3-Bromo-5-chloro-4-fluoro-2-methoxyphenyl)ethanol

To a solution of l-(3-bromo-5-chloro-4-fluoro-2-methoxyphenyl)ethanone (3.8 g, 14 mmol) in methanol (30 mL, 800 mmol) was added sodium tetrahydroborate (0.83 g, 22 mmol) at 0 °C. The mix was stirred at 0 °C for 1 hour. Water (10 mL) was added to the mixture. The mixture was concentrated to about 30 mL. The residue was diluted with EtOAc, washed with water and brine, dried over magnesium sulfate and evaporated to yield the desired compound (3.9 g, 100%). LCMS calculated for C ₉ H ₈ BrClFO (M-OH) ⁺ : m/z = 264.9, 266.9; found: 265.0, 267.0. Step 5. l-(l-azidoethyl)-3-bromo-5-chloro-4-fluoro-2-methoxybenzene

To a solution of l-(3-bromo-5-chloro-4-fluoro-2-methoxyphenyl)ethanol (3.9 g, 14 mmol) in methylene chloride (42 mL), cooled at 0 °C was added DIPEA(4.0 mL, 23 mmol) followed by methanesulfonyl chloride (1.6 mL, 20 mmol). The mixture was stirred for 1 h at 0 °C. Water (100 mL) was added while cold. The organic layer was separated, washed with brine, dried over magnesium sulfate and concentrated to give l-(3-bromo-5-chloro-4-fluoro-2- methoxyphenyl)ethyl methanesulfonate. The mesylate was dissolved in DMF (41 mL) and sodium azide (1.8 g, 27 mmol) was added. The reaction was stirred for 2 hours. The reaction mixture was diluted with EtOAc and washed with saturated sodium bicarbonate solution, water and brine, dried over magnesium sulfate and concentrated. Purification on silica gel using 0- 30%) EtOAc in hexane gave the desired compound (3.3 g, 78%>). LCMS calculated for

C ₉ H ₈ BrClFO (M-N ₃ ) ⁺ : m z = 264.9, 266.9; found: 265.0, 267.0.

Step 6. l-(3-Bromo-5-chloro-4-fluoro-2-methoxyphenyl)ethanamine

To the stirred solution of l-(l-azidoethyl)-3-bromo-5-chloro-4-fluoro-2-methoxybenzene (3.3 g, 11 mmol) in THF (50 mL) and water (10 mL) was added 1.0 M trimethylphosphine in THF (13 mL) at room temperature and the mixture was stirred for 1 hour. The mixture was diluted with EtOAc, washed with saturated sodium bicarbonate solution, water, brine, dried over magnesium sulfate and concentrated to give the desired compound (2.9 g, 95%). LCMS calculated for C ₉ H ₈ BrClFO (M-NH ₂ ) ⁺ : m/z = 264.9, 266.9; found: 265.0, 267.0. Step 7. N-[l-(3-Bromo-5-chloro-4-fluoro-2-methoxyphenyl)ethyl]-9-(te trahydro-2H-pyran-2- yl)-9H-purin-6-amine

A mix of l-(3-bromo-5-chloro-4-fluoro-2-methoxyphenyl)ethanamine (1.6 g, 5.7 mmol) 6-chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (2.0 g, 8.5 mmol, from Example 176, Step 4) and DIPEA(3.0 mL, 17 mmol) in ethanol (30 mL) was heated at 100 °C overnight. The reaction mixture was cooled and poured into saturated sodium bicarbonate solution, extracted into

EtOAc, washed with water, brine, dried over magnesium sulfate and concentrated. Purification on silica gel using 0-65% EtOAc gave the desired compound (2.8 g, 100%). LCMS calculated for Ci ₉ H ₂ iBrClFN ₅ 0 ₂ (M+H) ⁺ : m/z = 484.1, 486.1; found: 484.0, 486.0. Step 8. tert-butyl 4-{3-chloro-2-fluoro-6-methoxy-5-[l-(9H-purin-6-ylamino)ethy l]phenyl}-3,6- dihydropyridine-l(2H)-carboxylate

Into a microwave vial was added N-[l-(3-bromo-5-chloro-4-fluoro-2- methoxyphenyl)ethyl]-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6 -amine (85 mg, 0.17 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6-dihydrop yridine-l(2H)- carboxylate (65 mg, 0.21 mmol, Aldrich #706531), sodium carbonate (420 μί, 0.44 mmol), 1,4- dioxane (1 mL) and tetrakis(triphenylphosphine)palladium(0) (12 mg, 0.010 mmol). The mixture was bubbled with nitrogen for 5 min and heated at 90 °C overnight. The mixture was diluted with water, extracted with EtOAc, dried over magnesium sulfate and concentrated.

Purification on silica gel using 0-100%) EtOAc in hexane gave the desired compound (47 mg, 46%). LCMS calculated for (M+H) ⁺ : m/z = 586.3; found: 587.2.

Step 9. N-{l-[ 5-Chloro-4-fluoro-2-methoxy-3-(l,2, 3, 6-tetrahydropyridin-4-yl)phenyl] ethyl} -9H- purin-6-amine hydrochloride

Into a microwave vial was added tert-butyl 4-{3-chloro-2-fluoro-6-methoxy-5-[l-(9H- purin-6-ylamino)ethyl]phenyl}-3,6-dihydropyridine-l(2H)-carb oxylate (10.5 mg, 0.021 mmol) and 4.0 M HC1 in 1,4-dioxane (1.0 mL). The mixture was stirred for 30 min and evaporated. Methylene chloride (1.0 mL) and DIPEA(15.6 μί, 0.090 mmol) were added followed by methanesulfonyl chloride (4.8 μί, 0.063 mmol). The mixture was stirred for 15 minutes. The solvents were evaporated. 1 N sodium hydroxide solution (1.0 mL) and methanol (1.0 mL) were added and the mixture was stirred for 1 hour. The solvents were evaporated and purification by preparative LC/MS (pH 10) gave the desired compound (4.0 mg, 40%). LCMS calculated for C ₂ oH ₂₃ ClFN ₆ 0 ₃ S (M+H) ⁺ : m/z = 481.1; found: 481.0. 1H NMR (DMSO-d ₆ , 500 MHz) δ 12.88 (1H, br s), 8.18 (2H, m), 7.63 (1H, m), 5.91 (1H, m), 5.78 (1H, br s), 3.94 (5H, m), 3.40 (2H, m), 2.98 (3H, s), 2.55 (2H, m), 2.39 (2H, m), 1.42 (3H, m). Example 188. V-{l-[5-Chloro-4-fluoro-2-methoxy-3-(morpholin-4-ylmethyl)ph enyl]ethyl}- 9H-purin-6-amine

Step 1. N-f l-(5-Chloro-4-fluoro-2-methoxy-3-vinylphenyl)ethyl]-9-(tetra hydro-2H-pyran-2-yl)- 9H-purin- 6-am in e

To a solution of N-[l-(3-bromo-5-chloro-4-fluoro-2-methoxyphenyl)ethyl]-9-

(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (50 mg, 0.10 mmol, from Example 187, Step 7) in water (0.21 mL) was added 1 ,2-dimethoxyethane (0.7 mL), potassium carbonate (14 mg, 0.10 mmol), pyridine :trivinylboroxin (1 : 1) (26 mg, 0.10 mmol) and tetrakis(triphenylphosphine)Pd(0) (5.2 mg, 0.0045 mmol). The mixture was bubbled with nitrogen for five min and heated at 80 °C overnight. The reaction was diluted with water and EtOAc. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated. Purification on silica gel using 0- 100 % EtOAc in hexane gave the desired compound (29 mg, 60%). LCMS calculated for C ₂ iH ₂₄ ClFN ₅ 0 ₂ (M+H) ⁺ : m/z = 432.2; found: 432.1. Step 2. 3-Chloro-2-fluoro-6-methoxy-5-(l-{[9-(tetrahydro-2H-pyran-2- yl)-9H-purin-6- yl] amino } ethyl)benzaldehyde N-[l-(5-Chloro-4-fluoro-2-methoxy-3-vinylphenyl)ethyl]-9-(te trahydro-2H-pyran-2-yl)- 9H-purin-6-amine (240 mg, 0.56 mmol) was dissolved in THF (10 mL) and 0.16 M osmium tetraoxide in water (700 μί) was added. Sodium metaperiodate (360 mg, 1.7 mmol) and water (1 mL, 60 mmol) were added. The reaction was stirred at 60 °C for 2 hours. Reagents were doubled. 0.16 M osmium tetraoxide in water (700 μί) was added. Sodium metaperiodate (360 mg, 1.7 mmol) and water (1 mL) were added and the mixture was warmed to 60 °C for another 2 hours. The mixture was evaporated and the solids were extracted with dichloromethane. The extracts were purified on silica gel using 0-60% EtOAc in hexanes to give the desired compound (50 mg, 20%). LCMS calculated for C ₂ oH ₂₂ ClFN ₅ 0 ₃ (M+H) ⁺ : m/z = 434.1; found: 434.1.

Step 3. N-{l-[ 5-Chloro-4-fluoro-2-methoxy-3-(morpholin-4-ylmethyl)phenylJe thyl}-9H^urin-6- amine

A mixture of 3-chloro-2-fluoro-6-methoxy-5-(l-{[9-(tetrahydro-2H-pyran-2- yl)-9H- purin-6-yl] amino }ethyl)benzaldehyde (10 mg, 0.023 mmol), in THF (0.95 mL) was stirred at 40 °C for 1 hour. Sodium triacetoxyborohydride (15 mg, 0.069 mmol) and acetic acid (50 μί, 0.88 mmol) were added and the mixture was stirred at 40 °C overnight. Morpholine (20 0.23 mmol) and sodium cyanoborohydride (14 mg, 0.23 mmol) were added and the mixture was heated at 40 °C for 1 hour. The solvents were stripped down and few drops of trifluoroacetic acid/THF solution (1 : 1) were added and the mixture stirred for 30 minutes. The mixture was treated with 6.0 M HC1 in water (0.5 mL, 3 mmol) for 30 minutes. Purification by preparative LCMS (pH 10) gave the desired compound (3.4 mg, 35%). LCMS calculated for

Ci ₉ H ₂₃ ClFN ₆ 0 ₂ (M+H) ⁺ : m/z = 421.2; found: 421.1. 1H NMR (DMSO-d ₆ , 500 MHz) δ 12.91 (1H, br s), 8.17 (2H, m), 7.72 (1H, m), 5.89 (1H, br s), 4.05 (3H, s), 3.50 (7H, m), 2.41 (4H, m), 1.42 (3H, m).

Example 189. 5-{3-Chloro-6-methoxy-2-methyl-5-[l-(9H-purin-6-ylamino)ethy l]phenyl}-3- isopropyl- 1 ,3-oxazolidin-2-one trifluoroacetate

Step 1. tert-Butyl [ l-(5-chloro-2-methoxy-4-methyl-3-vinylphenyl)ethyl] carbamate

To a solution of tert-butyl [l-(3-bromo-5-chloro-2-methoxy-4- methylphenyl)ethyl]carbamate (80 mg, 0.20 mmol) (Example 113, Step 1; peak 2 from chiral separation) in water (0.44 mL) was added 1 ,2-dimethoxyethane (1.0 mL), potassium carbonate (29 mg, 0.21 mmol), pyridine :trivinylboroxin (1 : 1) (80 mg, 0.32 mmol) and

tetrakis(triphenylphosphine)palladium(0) (11 mg, 0.0092 mmol). The resulting suspension was heated at 80 °C overnight. The reaction was diluted with water and EtOAc. The aqueous phase was extracted with EtOAc once. The combined organic solutions were washed with brine, dried over sodium sulfate and concentrated. The residue was purified on silica gel using 0-100% EtOAc in hexane to give the desired compound (68 mg, 100%). LCMS calculated for

C12H14CIO (M-NHBoc) ⁺ : m/z = 209.1; found: 209.0.

Step 2. N-f l-(5-Chloro-2-methoxy-4-methyl-3-vinylphenyl)ethylJ-9-(tetra hydro-2H-pyran-2-yl)- 9H-purin- 6-am in e

tert-Butyl [l-(5-chloro-2-methoxy-4-methyl-3-vinylphenyl)ethyl]carbamat e was stirred in 4 N HC1 (1.0 mL) for 30 min and evaporated to give l-(5-chloro-2-methoxy-4-methyl-3- vinylphenyl)ethanamine hydrochloride (480 mg, 1.8 mmol) which was stirred in 1-butanol (86 mL), with DIPEA(1.6 mL, 9.1 mmol) and 6-chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (650 mg, 2.7 mmol, from Example 176, Step 4). The reaction mixture was heated at 120 °C for 2 hours. The reaction mixture was cooled to room temperature and extracted with EtOAc. The extracts were washed with brine and evaporated. Purification on silica gel using 0-50% EtOAc in hexane gave the desired compound (780 mg, 100%). LCMS calculated for C22H27CIN5O2 (M+H) ⁺ : m/z = 428.2; found: 428.1. Step 3. N-f l-(5-Chloro-2-methoxy-4-methyl-3-oxiran-2-ylphenyl)ethyl]-9- (tetrahydro-2H- pyran-2-yl)-9H-purin-6-amine

N-[ 1 -(5 -chloro-2-methoxy-4-methyl-3 -vinylphenyl)ethyl] -9-(tetrahydro-2H-pyran-2-yl)- 9H-purin-6-amine (740 mg, 1.7 mmol) was stirred in methylene chloride (5.7 mL) and m- chloroperbenzoic acid (2.1 g, 8.7 mmol) was added. The mixture was stirred overnight. The suspension was filtered and and the solids were washed with dichloromethane. Evaporation of the filtrates gave the desired compound.

Step 4. l-[3-Chloro-6-methoxy-2-methyl-5-(l-{[9-(tetrahydro-2H^yran- 2-yl)-9H-purin-6- ylj ' amino} ethyl)phenylj ' -2-(isopropylamino)ethanol

N-[l-(5-chloro-2-methoxy-4-methyl-3-oxiran-2-ylphenyl)ethyl] -9-(tetrahydro-2H-pyran- 2-yl)-9H-purin-6-amine (140.0 mg, 0.32 mmol) was stirred in methylene chloride (1.1 mL). Isopropylamine (124 μΕ, 1.6 mmol) and DIPEA(282 μΕ, 1.62 mmol) were added. The mixture was stirred at 80 °C overnight. Methanol was added and purification by preparative LC/MS (pH 10) gave the desired compound (12.9 mg, 8%). LCMS calculated for CzsHseClNeOs (M+H) ⁺ : m/z = 503.3; found: 503.1.

Step 5. 5-{3-Chloro-6-methoxy-2-methyl-5-f l-(9H-purin-6-ylamino)ethyl]phenyl}-3-isopropyl- 1, 3-oxazolidin-2-one trifluoroacetate

To a solution of l-[3-chloro-6-methoxy-2-methyl-5-((15)-l-{[9-(tetrahydro-2H- pyran-2- yl)-9H-purin-6-yl] amino }ethyl)phenyl]-2-(ispropylamino)ethanol (7.0 mg, 0.014 mmol) in THF (0.2 mL, 2 mmol), N,N-carbonyldiimidazole (3.1 mg, 0.019 mmol) was added and the mixture was heated at 70 °C for 1 hour. The solvents were evaporated. 4.0 M HC1 in 1,4-dioxane (1.0 mL) was added and the mixture was stirred for 30 minutes. Evaporation and purification by preparative LC/MS (pH 2) gave the desired compound (2.0 mg, 37%). LCMS calculated for C21H26CIN6O3 (M+H) ⁺ : m/z = 445.2; found: 445.1.

Examplel90. l-{3-Chloro-6-methoxy-2-methyl-5-[l-(9H-purin-6-ylamino)ethy l]phenyl}-2- morpholin-4-ylethanol bis(trifluoroacetate)

Step 1. tert-Butyl [l-(5-chloro-2-methoxy-4-methyl-3-oxiran-2-ylphenyl)ethyl] carbamate

tert-Butyl [l-(5-chloro-2-methoxy-4-methyl-3-vinylphenyl)ethyl]carbamat e (460 mg, 1.4 mmol, from Example 189, Step 1) was stirred in methylene chloride (4.6 mL) and m- chloroperbenzoic acid (2.1 g, 8.5 mmol) was added. The mixture was stirred overnight at room temperature. The suspension was filtered and the collected solids were washed with methylene chloride. The filtrates were evaporated to give the desired compound.

Step 2. l-[3-(l-aminoethyl)-5-chloro-2-methoxy-6-methylphenylJ-2-mor pholin-4-ylethanol hydrochloride

tert-Butyl [l-(5-chloro-2-methoxy-4-methyl-3-oxiran-2-ylphenyl)ethyl]ca rbamate (100.0 mg, 0.29 mmol) was stirred in ethanol (2.00 mL, 34 mmol), with morpholine (130 mg, 1.5 mmol) and DIPEA(260 1.5 mmol). The mixture was stirred at 80 °C over the weekend. Purification by preparative LC/MS (pH 10) gave the Boc intermediate. LCMS calculated for C ₂ iH ₃₄ ClN ₂ 0 ₅ (M-NH ₂ ) ⁺ : m/z = 429.2; found: 429.2. 4 N HC1 (3.0 mL) was added and the mixture stirred for 30 minutes. Evaporation gave the desired compound as the hydrochloride salt (8.8 mg, 8 %).

Step 3. l-{3-chloro-6-methoxy-2-methyl-5-[ l-(9H-purin-6-ylamino)ethyl]phenyl}-2-morpholin- 4-ylethanol bis(trifluoroacetate)

To a solution of l-{3-[l-aminoethyl]-5-chloro-2-methoxy-6-methylphenyl}-2- morpholin-4ylethanol hydrochloride (4.6 mg, 0.014 mmol) in 1-butanol (0.67 mL), DIPEA(12 μί, 0.071 mmol) was added followed by 6-chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (5.1 mg, 0.021 mmol, from Example 176, Step 4)and the reaction mixture was heated at 120 °C for 1 hour. The reaction mixture was cooled to room temperature and 4.0 M HC1 in 1,4-dioxane (0.34 mL) was added. The mixture was stirred for 30 minutes. Purification by preparative LC/MS (pH 2) gave the desired compound (3.6 mg, 45%). LCMS calculated for C ₂ iH ₂₈ ClN ₆ 0 ₃ (M+H) ⁺ : m/z = 447.2; found: 447.1 Examplel91. 6-{3-Chloro-6-methoxy-2-methyl-5-[l-(9H-purin-6-ylamino)ethy l]phenyl}-4- isopropylmorpholin-3-one trifluoroacetate

Step 1. tert-Butyl (l-{5-chloro-3-[l-hydroxy-2-(isopropylamino)ethyl]-2-methoxy -4- methylphenyl}ethyl)carbamate

tert-Butyl [l-(5-chloro-2-methoxy-4-methyl-3-oxiran-2-ylphenyl)ethyl]ca rbamate (100 mg, 0.29 mmol, from Example 190, Step 1) was stirred in ethanol (2.0 mL, 34 mmol), 2- propanamine (120 μί, 1.5 mmol) and DIPEA(260 μί, 1.5 mmol) was added. The mixture was stirred at 80 °C over the weekend. Purification by preparative LC/MS (pH 10) gave the desired compound (5.7 mg, 5 %). LCMS calculated for C ₂ oH ₃₄ ClN ₂ 0 ₄ (M+H) ⁺ : m/z = 401.2; found: 401.1.

Step 2. tert-Butyl [l-(5-chloro-3-{2-[ (chloroacetyl) (isopropyl) amino] -1 -hydroxy ethyl} -2- methoxy-4-methylphenyl) ethyl] carbamate

To a solution of tert-butyl l-{5-chloro-3-[l-hydroxy-2-(isopropylamino)ethyl]-2- methoxy-4-methylphenyl}ethyl)carbamate (17 mg, 0.041 mmol) in methylene chloride (0.5 mL), triethyl 0.12 mmol) was added followed by the addition of chloroacetyl chloride (3.9 ol). The reaction mixture was stirred at room temperature for 30 minutes. Purification by preparative LC/MS (pH 10) gave the desired compound (17 mg, 100%). LCMS calculated for C ₂₂ H ₃₄ C1 ₂ N ₂ 0 ₅ Na (M+Na) ⁺ : m/z = 499.2; found: 499.2. Step 3. tert-Butyl {l-[5-chloro-3-(4-isopropyl-5-oxomorpholin-2-yl)-2-methoxy-4 - methylphenyl] ethyl} carbamate

To a solution of tert- vXy\ [l-(5-chloro-3-{2-[(chloroacetyl)(isopropyl)amino]-l- hydroxyethyl}-2-methoxy-4-methylphenyl)ethyl]carbamate (22 mg, 0.047 mmol) in THF (1.0 mL) cooled at 0 °C, sodium hydride (3.6 mg, 0.094 mmol; 60% dispersion in mineral oil) was added and the mixture was stirred for 1 hour. The mixture was quenched with water and extracted with EtOAc. The combined extracts were washed with brine, dried over sodium sulfate, and concentrated to give the desired compound (20 mg, 97%). LCMS calculated for C ₂₂ H ₃₃ ClN ₂ 0 ₅ Na (M+Na) ⁺ : m/z = 463.2; found: 463.1.

Step 4. 6-{3-Chloro-6-methoxy-2-methyl-5-f l-(9H-purin-6-ylamino) ethyl] phenyl} -4- isopropylmorpholin-3-one trifluoroacetate

To tert-butyl { 1 -[5-chloro-3-(4-isopropyl-5-oxomorpholin-2-yl)-2-methoxy-4- methylphenyl] ethyl} carbamate (20 mg, 0.045 mmol), 4.0 M HC1 in 1,4-dioxane (0.80 mL) was added and the mixture was stirred for 15 minutes. The solvents were evaporated to give the intermediate. To the residue was added 1-butanol (1.2 mL, 13 mmol), DIPEA(40 μί, 0.23 mmol) and 6-chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (16 mg, 0.068 mmol, from

Example 176, Step 4) and the reaction mixture was heated at 120 °C for 1 hour. The reaction mixture was cooled to room temperature and 4.0 M HC1 in 1,4-dioxane (0.80 mL) was added. The mixture was stirred for 30 minutes. Purification by preparative LC/MS (pH 2) gave the desired compound (8.2 mg, 32%). LCMS calculated for C^H^ClNeOs (M+H) ⁺ : m/z = 459.2; found: 459.2. 1H NMR (DMSO-d ₆ , 500 MHz) δ 8.92 (1H, br s), 8.17 (2H, m), 7.60 (1H, s), 5.89 (1H, br s), 5.23 (1H, m), 4.63 (1H, m), 4.12 (2H, m), 3.95 (3H, m), 3.62 (1H, m), 3.20 (1H, m), 2.45 (3H, s), 1.43 (3H, m), 1.04 (6H, m).

Example 192. Diastereoisomers of 4-{3-chloro-6-methoxy-2-methyl-5-[l-(9H-purin-6- ylamino)ethyl]phenyl}pyrrolidin-2-one

Step 1. Methyl (2E)-3-(3-{l-[(tert-butoxycarbonyl)amino]ethyl}-5-chloro-2-m ethoxy-6- methylphenyl)acrylate

Into a sealed tube was placed a suspension of tert-butyl [l-(3-bromo-5-chloro-2- methoxy-4-methylphenyl)ethyl]carbamate [from Example 1 13, step 1 , peak 2] (1.0 g, 2.6 mmol) in DMF (15 mL) that was degassed with nitrogen and treated with methyl acrylate (0.83 mL, 9.2 mmol), triphenylphosphine (97 mg, 0.37 mmol), and palladium acetate (59 mg, 0.26 mmol). Lastly, triethylamine (1.1 mL, 7.9 mmol) was added and the reaction mixture was heated at 130 °C for 16 hours. After cooling to room temperature, the mixture was filtered over Celite and the Celite was washed with EtOAc (100 mL). The EtOAc was washed with water, brine, dried over anhydrous sodium sulfate, filtered, and concentrated to a crude foam. The crude material was dissolved in 2: 1 hexane/dichloromethane and purified by flash column chromatography using EtOAc in hexanes (0% - 30% over 30 min) to give the desired product (0.68 g, 68%) as a white foam. LCMS for Ci ₄ Hi ₆ C10 ₃ (M-NHBoc) ⁺ : m/z = 267.1 ; Found: 266.9.

Step 2. Methyl 3-(3-{l-[(tert-butoxycarbonyl)amino]ethyl}-5-chloro-2-methox y-6- methylphenyl)-4-nitrobutanoate

A solution of methyl (2E)-3-(3-{ l-[(tert-butoxycarbonyl)amino]ethyl}-5-chloro-2- methoxy-6-methylphenyl)acrylate (1.5 g, 3.9 mmol) in nitromethane (1 1 mL) at 0 °C was treated with l ,8-diazabicyclo[5.4.0]undec-7-ene (0.59 mL, 3.9 mmol) and allowed to warm to room temperature. The reaction mixture was heated at 60 °C for 21 h, cooled to room temperature, poured into water (100 ml) and extracted with EtOAc (2 x 75 mL). The organic layer was separated, washed with brine solution, dried over anhydrous sodium sulfate, filtered, and concentrated to give a orange foam. The crude material was dissolved in dichloromethane and purified by flash column chromatography using EtOAc in hexanes (0% - 30% over 30 min) to give the desired product (0.93 g, 53%) as a white foam. LCMS for C ₂ oH ₂₉ ClN ₂ 0 ₇ Na

(M+Na) ⁺ : m/z = 467.2; Found: 467.1.

Step 3. Diastereoisomers of tert-butyl {l-[5-chloro-2-methoxy-4-methyl-3-(5-oxopyrrolidin-3- yl)phenyl] ethyl} carbamate

A solution of methyl 3-(3- { l-[(tert-butoxycarbonyl)amino]ethyl}-5-chloro-2-methoxy-6- methylphenyl)-4-nitrobutanoate (0.92 g, 2.1 mmol) in methanol (15 mL) was treated with nickel chloride hexahydrate (0.99 g, 4.1 mmol) and stirred for 5 minutes. The reaction mixture was cooled to 0 °C and treated with sodium tetrahydroborate (0.84 g, 22 mmol) in four portions. The ice bath was removed and the reaction mixture was stirred for 30 min and heated at 60 °C for 4.5 hours. The reaction mixture was diluted with saturated sodium bicarbonate (20 mL) and EtOAc (50 mL) and filtered over Celite. The Celite was washed with EtOAc and the filtrate

was concentrated to give the desired product as a mixture of diastereoisomers at the lactam carbon. The mixture of diastereoisomers was separated by chiral HPLC (ChiralPak AD-H column, 20 x 250 mm, 5 micron particle size, eluting with 60% ethanol in hexanes at 9 mL/min, column loading ~ 3 mg/injection) to give peak 1 (0.39 g, 49%, retention time: 6.25 min) and peak 2 (0.32 g, 40%>, retention time: 9.34 min) as white solids.

Step 4. Diastereoisomers of 4-[3-(l-aminoethyl)-5-chloro-2-methoxy-6- methylphenylJpyrrolidin-2-one

Solutions of the individual diastereoisomers of tert-butyl { l-[5-chloro-2-methoxy-4- methyl-3-(5-oxopyrrolidin-3-yl)phenyl]ethyl} carbamate (75 mg, 0.20 mmol [peak 1 from step 3]; 75 mg, 0.20 mmol [peak 2 from step 3]) in separate reaction flasks in methylene chloride (1 mL) were each treated individually with trifluoroacetic acid (1 mL) dropwise and stirred for 30 minutes. The reaction mixtures were individually concentrated to residues, diluted with saturated sodium bicarbonate, and extracted several times with dichloromethane to give diastereoisomer from peak 1 (60 mg, quantitative) and diastereoisomer from peak 2 (55 mg, quantitative) as colorless residues that were used without further purification. Peak 1 : LCMS for Ci ₄ Hi ₇ ClN0 ₂ (M-NH ₂ )+: m/z = 266.1 ; Found: 266.1. Peak 2: LCMS for Ci ₄ H ₂₀ ClN ₂ O ₂ (M+H) ⁺ : m/z = 283.1 ; Found: 283.1. Step 5. Diastereoisomers of 4-{3-chloro-6-methoxy-2-methyl-5-[l-(9H-purin-6- ylamino)ethyl]phenyl}pyrrolidin-2-one

Solutions of 4-[3-(l-aminoethyl)-5-chloro-2-methoxy-6-methylphenyl]pyrrol idin-2-one (43 mg, 0.15 mmol [peak 1 from step 4]; 43 mg, 0.15 mmol [peak 2 from step 4]) in separate reaction flasks in 1-butanol (2.4 mL) were each treated individually with 6-chloro-9-(tetrahydro- 2H-pyran-2-yl)-9H-purine (54 mg, 0.23 mmol, from Example 176, Step 4), and DIPEA(80 mL, 0.46 mmol) and heated at 105 °C for 20 hours. The reaction mixtures were individually concentrated on the rotary evaporater at 40 °C to remove 1-butanol to give the THP-containing intermediates. These intermediates were diluted with methanol (2 mL) and 6.0 M HC1 in water (0.25 mL, 1.5 mmol) and stirred for 30 min to remove the THP protecting groups. The reaction mixtures were individually diluted with methanol and purified by preparative LCMS (XBridge CI 8 Column, eluting with a gradient of acetonitrile in water with 0.1% trifluoroacetic acid, at flow rate of 60 mL/min). The LCMS fractions were concentrated to remove acetonitrile, treated with solid sodium bicarbonate, and extracted into EtOAc. The EtOAc was concentrated and the residues were reconcentrated from EtO Ac/heptane to give diastereoisomer from peak 1 (43 mg, 70%) and diastereoisomer from peak 2 (42 mg, 69%) as white solids. Peak 1 : 1H NMR (400 MHz, OMSO-de) δ 12.94 (br s, 1H), 8.25 - 8.16 (m, 1H), 8.15 - 8.08 (m, 1H), 7.88 (s, 1H), 7.52 (br s, 1H), 5.86 - 5.50 (m, 1H), 4.37 - 4.22 (m, 1H), 3.88 (s, 3H), 3.61 (dd, J= 10.1, 10.1 Hz, 1H), 3.26 - 3.17 (m, 1H), 2.59 (dd, J= 17.3, 11.5 Hz, 1H), 2.36 (dd, J= 17.2, 8.5 Hz, 1H), 2.22 (s, 3H), 1.43 (d, J= 6.9 Hz, 3H). LCMS for C ₁₉ H ₂₂ CIN ₆ O ₂ (M+H) ⁺ : m/z = 401.1; Found:

401.2. Peak 2: 1H NMR (400 MHz, DMSO-<¾) δ 12.94 (br s, 1H), 8.26 - 8.16 (m, 1H), 8.13 - 8.04 (m, 1H), 7.88 (s, 1H), 7.53 (br s, 1H), 5.81 - 5.59 (m, 1H), 4.38 - 4.23 (m, 1H), 3.88 (s, 3H), 3.66 (dd, J= 10.1 , 10.1 Hz, 1H), 3.31 - 3.24 (m, 1H), 2.59 - 2.52 (m, 1H), 2.29 (dd, J = 17.4, 8.4 Hz, 1H), 2.21 (s, 3H), 1.44 (d, J= 6.9 Hz, 3H). LCMS for C ₁₉ H ₂₂ CIN ₆ O ₂ (M+H) ⁺ : m/z = 401.1; Found: 401.1.

Example 193. Diastereoisomers of 4-{3-chloro-6-methoxy-2-methyl-5-[l-(9H-purin-6- ylamino)ethyl]phenyl}-l-methylpyrrolidin-2-one

Step 1. Diastereoisomers of tert-butyl {l-[5-chloro-2-methoxy-4-methyl-3-(l-methyl-5- oxopyrrolidin- 3 -yl)phenyl] ethyl} carbamate

Solutions of the individual diastereoisomers of tert-butyl {l-[5-chloro-2-methoxy-4- methyl-3-(5-oxopyrrolidin-3-yl)phenyl]ethyl} carbamate (0.31 g, 0.80 mmol [peak 1 from Examples 192, step 3]; 0.31 g, 0.80 mmol [peak 2 from Examples 192, step 3]) in DMF (4 mL) at 0 °C were each treated individually with sodium hydride dispersed in mineral oil (80 mg, 2.0 mmol). The ice bath was removed and the reaction mixtures were stirred for 30 min and heated at 60 °C for 30 minutes. The reaction mixtures were cooled down to 0 °C, treated with methyl iodide (0.060 mL, 0.96 mmol) in DMF (2 mL, 26 mmol), and stirred at room temperature for 16 hours. The reaction mixtures were cooled to 0 °C, quenched with saturated ammonium chloride, and extracted with EtOAc. The organic extract was concentrated to give a crude oil which was purified by preparative LCMS (XBridge CI 8 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) to give diastereoisomer from peak 1 (28 mg, 9%, retention time: 2.52 min) and diastereoisomer from peak 2 (56 mg, 18%, retention time: 2.51 min). Peak 1 : LCMS for C2oH ₂₉ ClN ₂ 0 ₄ Na (M+Na) ⁺ : m/z = 419.2; Found: 419.1. Peak 2: LCMS for C ₂ oH ₂₉ ClN ₂ 0 ₄ Na (M+Na) ⁺ : m/z = 419.2;

Found: 419.1. Step 2. Diastereoisomers of 4-[3-(l-aminoethyl)-5-chloro-2-methoxy-6-methylphenyl]-l- methylpyrrolidin-2-one trifluoroacetate

Solutions of the individual diastereoisomers of tert-butyl {l-[5-chloro-2-methoxy-4- methyl-3-(l-methyl-5-oxopyrrolidin-3-yl)phenyl]ethyl}carbama te (28 mg, 0.070 mmol [peak 1 from step 1]; 56 mg, 0.14 mmol [peak 2 from step 1]) in separate reaction flasks in methylene chloride (1 mL) were each treated individually with trifluoroacetic acid (1 mL) dropwise and stirred for 30 minutes. The reaction mixtures were individually concentrated to give diastereoisomer from peak 1 (38 mg, quantitative) and diastereoisomer from peak 2 (65 mg, quantitative) as residues that were used without further purification. Peak 1 : LCMS for

Ci ₅ Hi ₉ ClN0 ₂ (M-NH ₂ ) ⁺ : m/z = 280.1 ; Found: 280.1. Peak 2: LCMS for Ci ₅ H ₂₂ ClN ₂ 0 ₂ (M+H) ⁺ : m/z = 297.1 ; Found: 297.1.

Step 3. Diastereoisomers of 4-{3-chloro-6-methoxy-2-methyl-5-[l-(9H-purin-6- ylamino) ethyl] phenyl}- 1 -methylpyrrolidin-2 -one

The desired diastereoisomers were prepared according to the procedure of Examples 192, step 5, using the diastereoisomers of 4-[3-(l-aminoethyl)-5-chloro-2-methoxy-6-methylphenyl]- l-methylpyrrolidin-2-one trifluoroacetate as the starting materials in 48% yield (peak 1) and 67% yield (peak 2). Peak 1 : 1H NMR (400 MHz, DMSO-<¾) δ 12.94 (br s, 1H), 8.31 - 7.96 (m, 3H), 7.51 (br s, 1H), 5.89 - 5.52 (m, 1H), 4.31 - 4.10 (m, 1H), 3.86 (s, 3H), 3.71 (dd, J = 10.1 , 10.1 Hz, 1H), 2.79 (s, 3H), 2.75 - 2.65 (m, 1H), 2.46 - 2.38 (m, lH), 2.16 (s, 3H), 1.43 (d, J = 6.4 Hz, 3H). LCMS for C ₂₀ H ₂₄ ClN ₆ O ₂ (M+H) ⁺ : m z = 415.2; Found: 415.2. Peak 2: 1H NMR (400 MHz, DMSO-<¾) δ 12.94 (br s, 1H), 8.29 - 8.17 (m, 1H), 8.16 - 8.07 (m, 2H), 7.54 (br s, 1H), 5.91 - 5.47 (m, 1H), 4.32 - 4.10 (m, 1H), 3.87 (s, 3H), 3.76 (dd, J = 10.1 , 10.1 Hz, 1H), 3.44 - 3.36 (m, 1H), 2.79 (s, 3H), 2.68 (dd, J = 17.4, 1 1.7 Hz, 1H), 2.36 (dd, J= 17.4, 7.6 Hz, 1H), 2.16 (s, 3H), 1.44 (d, J= 6.9 Hz, 3H). LCMS for C ₂ oH ₂₄ ClN ₆ 0 ₂ (M+H) ⁺ : m/z = 415.2; Found:

415.2.

Example 194. V-{l-[4,5-Dichloro-3-(l-isopropylazetidin-3-yl)-2-methoxyphe nyl]ethyl}-9H- purin-6-amine bis(trifluoroacetate)

Step I. l-(4,5-Dichloro-2-hydroxyphenyl)ethanone A solution of 3,4-dichlorophenol [AK Scientific] (30 g, 18 mmol) in acetyl chloride (19 mL, 270 mmol) was stirred at 60°C for 2 hours. The reaction mixture was cooled to 20 °C, treated with aluminum trichloride (37 g, 280 mmol) portionwise, and heated at 180 °C for 30 minutes. The reaction mixture was cooled to 20 °C and the solution hardened into a solid block that was not easy to break apart. This material was cooled to 0 °C and quenched slowly with 1 M HC1 in portions. The solid block of material slowly broke apart with enough HC1 and this heterogenous mixture was stirred at 20 °C overnight to ensure uniformity. The solid was filtered, washed with copious amounts of water, and dried under vacuum to give the desired product (38 g, quantitative) as a tan solid.

Step 2. l-(4,5-Dichloro-2-hydroxy-3-iodophenyl)ethanone

A solution of l-(4,5-dichloro-2-hydroxyphenyl)ethanone (12 g, 59 mmol) in acetic acid (70 mL) was treated with N-iodosuccinimide (16 g, 71 mmol) and stirred at 90 °C for 18 hours. The reaction mixture was treated with additional N-iodosuccinimide (8 g, 36 mmol) and stirred at 90 °C for 4 hours. The reaction mixture was concentrated, diluted with EtOAc, and quenched with saturated sodium bicarbonate until the bubbling stopped. The organic layer was separated and the aqueous phase was re-extracted with EtOAc. The combined organic layers were dried and concentrated to give a brown solid. This material was recrystallized from methanol to give desired product (9.0 g, 46%) as a tan solid. LCMS for C ₈ H ₆ C1 ₂ I0 ₂ (M+H) ⁺ : m/z = 330.9, 332.9; Found: 330.8, 332.9.

Step 3. l-(4,5-Dichloro-3-iodo-2-methoxyphenyl)ethanone

A solution of l-(4,5-dichloro-2-hydroxy-3-iodophenyl)ethanone (16 g, 47 mmol) and potassium carbonate (17 g, 120 mmol) in DMF (40 mL) was treated with methyl iodide (6.4 mL, 100 mmol) and stirred at 60 °C for 1 hour. The reaction mixture was diluted with water and extracted with EtOAc (twice). The combined organic layers were dried with magnesium sulfate, filtered, and concentrated to give a crude solid. The crude material was purified by flash column chromatography using EtOAc in hexanes (5% - 30%) to give the desired product (14 g, 84%>) as an orange solid. LCMS for CgHsCLTOz (M+H) ⁺ : m/z = 344.9, 346.9; Found: 344.8, 346.9.

Step 4. tert-Butyl 3-(3-acetyl-5,6-dichloro-2-methoxyphenyl)azetidine-l-carboxy late Zinc (4.5 g, 69 mmol) was suspended with 1 ,2-dibromoethane (420 μΐ,, 4.9 mmol) in DMF (54 mL). The mixture was heated at 70 °C for 10 min and then cooled to room

temperature. Chlorotrimethylsilane (620 μί, 4.9 mmol) was added dropwise and stirring was continued for 1 hour. A solution of tert-butyl 3-iodoazetidine-l-carboxylate (17 g, 61 mmol) in DMF (30 mL) was then added and the mixture was heated at 40 °C for 1 h before a mixture of 1- (4,5-dichloro-3-iodo-2-methoxyphenyl)ethanone (14 g, 41 mmol),

tris(dibenzylideneacetone)dipalladium(0) (710 mg, 0.77 mmol) and tri-(2-furyl)phosphine (360 mg, 1.6 mmol) in DMF (120 mL) was added quickly. The reaction mixture was stirred overnight at room temperature. The reaction mixture was then partitioned between EtOAc and saturated ammonium chloride solution. The organic layer was washed with water, dried with magnesium sulfate, filtered, and concentrated to a crude residue that was purified by flash column

chromatography using EtOAc in hexanes (0% - 25%) to give the desired product (12 g, 77%). LCMS for Ci ₇ H ₂ iCl ₂ N0 ₄ Na (M+Na) ⁺ : m/z = 396.1; Found: 396.0. Step 5. tert-Butyl 3-[3-(l-aminoethyl)-5,6-dichloro-2-methoxyphenyl]azetidine-l -carboxylate A solution of tert-butyl 3-(3-acetyl-5,6-dichloro-2-methoxyphenyl)azetidine-l- carboxylate (1.0 g, 2.7 mmol) in 2.0 M ammonia in ethanol (13 mL, 27 mmol) at 0 °C was treated with titanium tetraisopropoxide (1.6 mL, 5.3 mmol) and stirred at 60 °C overnight. The reaction mixture was treated with sodium tetrahydroborate (0.15 g, 4.0 mmol) at 0 °C and the solution was stirred at room temperature for another 1 hour. The reaction mixture was quenched with 2 M ammonia in water and filtered. The solid was washed with acetonitrile. The filtrate was concentrated and the residue was diluted with dichloromethane, washed with water, dried with magnesium sulfate, filtered, and concentrated to give the desired product (1.0 g, 97%) that was used without further purification. LCMS for Ci ₃ Hi ₄ Cl ₂ N0 ₃ (M-[NH ₂ ]-[t-Bu]+H) ⁺ : m/z = 302.0, 304.0; Found: 301.9, 304.0.

Step 6. tert-Butyl 3-[3-(l-{[ (benzyloxy)carbonyl] amino} ethyl)- 5, 6-dichloro-2- methoxyphenylj azetidine-1 -carboxylate

A solution of tert-butyl 3-[3-(l-aminoethyl)-5,6-dichloro-2-methoxyphenyl]azetidine-l - carboxylate (4.1 g, 9.7 mmol) and DIPEA(3.4 mL, 20 mmol) in methylene chloride (49 mL) at 0 °C was treated with benzyl chloroformate (1.8 mL, 13 mmol) and stirred at 20 °C for 1 hour. The reaction mixture was diluted with dichloromethane (300 mL), washed with saturated sodium bicarbonate solution, water,and brine, dried with sodium sulfate, filtered and concentrated to a crude residue that was purified by flash column chromatography using EtOAc in hexanes (5% - 40%) to give the desired racemic product (4 g, 81%). This racemic material was separated by chiral HPLC (ChiralPak AD-H column, 20 x 250 mm, 5 micron particle size, eluting with 30% ethanol in hexanes at 12 mL/min, column loading ~ 135 mg/injection) to give the desired peak 2 isomer (1.9 g, 38%). Peak 2 isomer: LCMS for CzsHsoCbNzOjNa (M+Na) ⁺ : m/z = 531.2; Found: 531.2. Step 7. Single enantiomer of tert-butyl 3-[3-(l-aminoethyl)-5,6-dichloro-2- methoxypheny I] azetidine-l -carboxylate

A solution of tert-butyl 3-[3-(l-{[(benzyloxy)carbonyl]amino}ethyl)-5,6-dichloro-2- methoxyphenyl] azetidine-l -carboxylate [peak 2 isomer from step 6] (0.29 g, 0.57 mmol) in methanol (17 mL) and 0.25 M HC1 in water (5.7 mL, 1.4 mmol) was degassed with nitrogen, treated with 5% Pt/C (Degussa type) (73 mg, 25wt%), and stirred under a balloon of hydrogen for 1 hour. The reaction mixture was treated with additional 5% Pt/C (Degussa type) (100 mg) and stirred under a balloon of hydrogen for an additional 1 hour. The reaction mixture was filtered over Celite and neutralized with saturated sodium bicarbonate solution. The reaction mixture was concentrated to remove the methanol, extracted with dichloromethane, and concentrated to give the desired product (0.21 g, 99%) as a colorless foam that was used without further purification. LCMS for C13H14CI2NO3 (M-[NH ₂ ]-[t-Bu]+H) ⁺ : m/z = 302.0, 304.0; Found: 301.9, 304.0.

Step 8. N-[l-(3-Azetidin-3-yl-4,5-dichloro-2-methoxyphenyl)ethyl]-9H -purin-6-amine

A solution of tert-butyl 3-[3-(l-aminoethyl)-5,6-dichloro-2-methoxyphenyl]azetidine-l - carboxylate (0.11 g, 0.28 mmol), 6-chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (0.10 g, 0.42 mmol, from Example 176, Step 4), and DIPEA(0.15 mL, 0.85 mmol) in 1-butanol (2.8 mL) was heated at 105 °C for 20 hours. The reaction mixture was concentrated under high vacuum at 40 °C to remove the butanol to give the THP-containing intermediate. This intermediate was diluted with methanol (1.5 mL) and 6.0 M HC1 in water (0.94 mL, 5.7 mmol) and stirred at room temperature for 30 minutes. The reaction mixture was concentrated to give the Boc-containing intermediate which was dissolved in methylene chloride (1 mL) and trifluoroacetic acid (1 mL) and stirred at room temperature for 30 minutes. The reaction mixture was concentrated to a residue, diluted with methanol, and purified by preparative LCMS (XBridge CI 8 Column, eluting with a gradient of acetonitrile in water with 0.1% trifluoroacetic acid, at flow rate of 60 mL/min). The LCMS fractions were concentrated to remove acetonitrile, treated with solid sodium bicarbonate, and extracted into EtOAc. The organic phase was concentrated and the residues were reconcentrated from EtO Ac/heptane to give the desired product (38 mg, 34%) as a white solid. LCMS for dyHigCbNeO (M+H) ⁺ : m/z = 393.1; Found: 393.0. Step 9. N-{l-[ 4, 5-Dichloro-3-( I -isopropylazetidin-3-yl)-2-methoxyphenyl] ethyl} -9H-purin-6- amine bis(trifluoroacetate)

A solution of N-[l-(3-azetidin-3-yl-4,5-dichloro-2-methoxyphenyl)ethyl]-9H -purin-6- amine (18 mg, 0.045 mmol) in methanol (1 mL) was treated with acetone (0.026 mL, 0.36 mmol), stirred for 30 mins, treated with sodium triacetoxyborohydride (0.028 g, 0.13 mmol), and stirred at room temperature for 16 hours. The reaction mixture was purified by preparative LCMS (XBridge C18 Column, eluting with a gradient of acetonitrile in water with 0.1% trifluoroacetic acid, at flow rate of 60 mL/min) to give the desired product (16 mg, 54%). ¹ H NMR (400 MHz, DMSO-<¾) δ 10.16 (br s, 1H), 8.65 (br s, 1H), 8.36 - 8.15 (m, 2H), 7.76 (s, 1H), 5.87 - 5.54 (m, 1H), 4.58 - 4.41 (m, 2H), 4.40 - 4.30 (m, 1H), 4.28 - 4.15 (m, 2H), 3.84 (d, J= 6.7 Hz, 3H), 3.49 - 3.28 (m, 1H), 1.49 (d, J= 6.9 Hz, 3H), 1.25 (d, J= 6.5 Hz, 0.5H), 1.12 (dd, J= 6.4, 3.2 Hz, 5.5H). LCMS for Czo^CbNeO (M+H) ⁺ : m/z = 435.1; Found: 435.1.

Example 195. V-{l-[3-(l-Acetylazetidin-3-yl)-4,5-dichloro-2-methoxyphenyl ]ethyl}-9H- purin-6-amine

A solution of N-[l-(3-azetidin-3-yl-4,5-dichloro-2-methoxyphenyl)ethyl]-9H -purin-6- amine (25 mg, 0.064 mmol, from Example 194, Step 8) in acetonitrile (0.3 mL) was treated with DIPEA(28 μί, 0.16 mmol) followed by acetyl chloride (5.4 μΐ _^ , 0.076 mmol) and stirred at room temperature for 1 hour. The reaction mixture was treated with IN sodium hydroxide (200 μί) and heated briefly with a heat gun. The reaction mixture was diluted with methanol and purified by preparative LCMS (XBridge CI 8 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) to give the desired product (6.3 mg, 23%). 1H NMR (300 MHz, DMSO-<¾) δ 8.15 - 8.06 (m, 2H), 7.72 (s, 1H), 5.82 - 5.61 (m, 1H), 4.56 - 4.45 (m, 1H), 4.43 - 4.30 (m, 1H), 4.29 - 4.17 (m, 1H), 4.14 - 4.03 (m, 0.5H), 3.86 (s, 3H), 1.84 - 1.71 (m, 5H), 1.45 (d, J= 6.8 Hz, 3H). LCMS for Ci ₉ H ₂ iCl ₂ N ₆ 0 ₂ (M+H) ⁺ : m/z = 435.1; Found: 435.0.

Example 196. 2-(3-{2,3-Dichloro-6-methoxy-5-[l-(9H-purin-6- ylamino)ethyl]phenyl}azetidin-l-yl)ethanol bis(trifluoroacetate)

A solution of N-[l-(3-azetidin-3-yl-4,5-dichloro-2-methoxyphenyl)ethyl]-9H -purin-6- amine (25 mg, 0.064 mmol, from Example 194, Step 8) in methanol (1 mL) was treated with sodium cyanoborohydride (10 mg, 0.16 mmol) followed by {[tert- butyl(dimethyl)silyl]oxy}acetaldehyde (36 μΐ _^ , 0.19 mmol) and stirred at room temperature for 2 hours. The reaction mixture was diluted with EtOAc and washed with saturated sodium bicarbonate, water, and brine, dried with sodium sulfate, filtered and concentrated to give the intermediate silyl ether. This intermediate was dissolved in THF (1 mL), cooled at 0 °C, treated with 1.0 M tetra-N-butylammonium fluoride in THF (0.64 mL, 0.64 mmol), and stirred at room temperature for 3 hours. The reaction mixture was diluted with methanol and purified by preparative LCMS (XBridge CI 8 column, eluting with a gradient of acetonitrile in water with 0.1% trifluoroacetic acid, at flow rate of 60 mL/min) to give the desired product (19 mg, 54%). 1H NMR (300 MHz, OMSO-d ₆ ) δ 9.96 (br s, 1H), 8.50 (br s, 1H), 8.31 - 8.15 (m, 2H), 7.76 (s, 1H), 5.85 - 5.59 (m, 1H), 4.64 - 4.17 (m, 7H), 3.88 - 3.77 (m, 3H), 3.76 - 3.65 (m, 0.5H), 3.63 - 3.54 (m, 1H), 3.52 - 3.43 (m, 0.5H), 3.32 - 3.09 (m, 1H), 1.48 (d, J = 6.9 Hz, 3H). LCMS for C ₁₉ H ₂₃ CI ₂ N ₆ O ₂ (M+H) ⁺ : m/z = 437.1 , 439.1 ; Found: 437.1 , 439.1.

Example 206. (3-{2,3-Dichloro-6-methoxy-5-[l-(9H-purin-6- ylamino)ethyl]phenyl}azetidin-l-yl)acetonitrile bis(trifluoroacetate)

A solution of N-[l-(3-azetidin-3-yl-4,5-dichloro-2-methoxyphenyl)ethyl]-9H -purin-6- amine (20 mg, 0.051 mmol, from Example 194, Step 8) in acetonitrile (1 mL) was treated with DIPEA(22 μΕ, 0.13 mmol), cooled to 0 °C, treated with bromoacetonitrile (4.3 μί, 0.061 mmol), and stirred at 0 °C for 30 minutes. The reaction mixture was purified by preparative LCMS (XBridge C 18 Column, eluting with a gradient of acetonitrile in water with 0.1% trifluoroacetic acid, at flow rate of 60 mL/min) to give the desired product (13 mg, 47%>). 1H NMR (300 MHz, DMSO-<¾) δ 8.95 (br s, 1H), 8.48 - 8.22 (m, 2H), 7.71 (s, 1H), 5.88 - 5.55 (m, lH), 4.30 (br s, 2H), 4.13 (s, 1H), 4.01 - 3.84 (m, 2H), 3.80 (s, 3H), 1.50 (d, J = 6.9 Hz, 3H). LCMS for Ci ₉ H ₂ oCl ₂ N ₇ 0 (M+H) ⁺ : m/z = 432.1 , 434.1 ; Found: 432.1 , 434.1.

Example 207. V-(l-{4,5-Dichloro-2-methoxy-3-[l-(2,2,2-trifluoroethyl)azet idin-3- yl] phenyl} ethyl)- 9H-purin-6-amine bis(trifluoroacetate)

Step 1. Benzyl [l-(3-azetidin-3-yl-4,5-dichloro-2-methoxyphenyl)ethyl]carba mate

A solution of tert-bvXy\ 3-[3-(l-{[(benzyloxy)carbonyl]amino}ethyl)-5,6-dichloro-2- methoxyphenyl]azetidine-l-carboxylate (200 mg, 0.39 mmol, from Example 194, Step 6) in methylene chloride (10 mL) was treated with trifluoroacetic acid (5 mL) and stirred at room temperature for 30 minutes. The reaction mixture was concentrated to give a residue that was dissolved in methanol (~20 mL) and treated with saturated sodium bicarbonate solution (pH~8). The methanol was then removed in vacuo to give an aqueous suspension that was diluted with EtOAc. The organic layer was separated and washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give the desired product (180 mg, 98%) that was used without further purification. LCMS for C20H23CI2N2O3 (M+H) ⁺ : m/z = 409.1 , 411.1 ; Found: 409.1, 411.1.

Step 2. Benzyl (l-{4,5-dichloro-2-methoxy-3-[l-(2,2,2-trifluoroethyl)azetid in-3- yl] phenyl} ethyl) carbamate

A solution of benzyl [l-(3-azetidin-3-yl-4,5-dichloro-2-methoxyphenyl)ethyl]carba mate (170 mg, 0.43 mmol) in THF (5.8 mL) was treated with triethylamine (110 0.82 mmol), cooled to 0 °C, treated with 2,2,2-trifluoroethyl trifluoromethanesulfonate (150 mg, 0.64 mmol) and stirred at room temperature for 30 minutes. The reaction mixture was diluted with EtOAc and washed with saturated sodium bicarbonate, water, and brine, dried with sodium sulfate, filtered and concentrated to give the desired product (190 mg, 92%) that was used without further purification. LCMS for C22H24CI2F3N2O3 (M+H) ⁺ : m/z = 491.1 , 493.1 ; Found: 491.1, 493.1. Step 3. l-{4,5-Dichloro-2-methoxy-3-[l-(2,2,2-trifluoroethyl)azetidi n-3-yl]phenyl}ethanam dihydrochloride

A solution of benzyl (l-{4,5-dichloro-2-methoxy-3-[l-(2,2,2-trifluoroethyl)azetid in-3- yl]phenyl}ethyl)carbamate (190 mg, 0.39 mmol) in methanol (11 mL) was treated with 0.25 M HC1 in water (3.9 mL, 0.98 mmol), degassed with nitrogen for 5 minutes, treated with 5% Pt/C (Degussa type) (96 mg, 50wt%), and stirred under a balloon of hydrogen for 1 hour. The reaction mixture was filtered over a PTFE disposable filter. The filtrate was concentrated to give the desired product (180 mg, 99%) that was used without further purification. LCMS for C ₁₄ H ₁₈ CI ₂ F ₃ N ₂ O (M+H) ⁺ : m/z = 357.1, 359.1; Found: 357.0, 359.0.

Step 4. N-(l-{4,5-Dichloro-2-methoxy-3-fl-(2,2,2-trifluoroethyl)azet idin-3-ylJphenyl}ethyl)-9H- purin-6-amine bis (rifluoroacetate)

The desired compound was prepared according to the procedure of Example 194, step 8, using 1 - {4,5-dichloro-2-methoxy-3-[ 1 -(2,2,2-trifluoroethyl)azetidin-3-yl]phenyl} ethanamine dihydrochloride as the starting material in 42% yield. 1H NMR (300 MHz, DMSO-<¾) δ 8.91 - 8.72 (m, 1H), 8.55 - 8.16 (m, 2H), 7.69 (s, 1H), 6.00 - 5.50 (m, 1H), 4.51 - 4.18 (m, 3H), 4.13 - 3.50 (m, 7H), 1.50 (d, J= 6.9 Hz, 3H). LCMS for C ₁₉ H ₂₀ CI ₂ F ₃ N ₆ O (M+H) ⁺ : m/z = 475.1, 477.1; Found: 475.0, 477.0.

Example 210. V-(l-{4,5-Dichloro-3-[l-(2,2-difluoroethyl)azetidin-3-yl]-2

methoxyphenyl}ethyl)-9H-purin-6-amine bis(trifluoroacetate)

A solution of N-[l-(3-azetidin-3-yl-4,5-dichloro-2-methoxyphenyl)ethyl]-9H -purin-6 (15 mg, 0.038 mmol, from Example 194, Step 8) in DMF (1 mL) was treated with triethylamine (13 μί, 0.095 mmol), cooled to 0 °C, treated with 2,2-difluoroethyl

trifluoromethanesulfonate (12 mg, 0.058 mmol) and stirred at 0 °C for 20 minutes. The reaction mixture was purified by preparative LCMS (XBridge C 18 Column, eluting with a gradient of acetonitrile in water with 0.1% trifluoroacetic acid, at flow rate of 60 mL/min) to give the desired product (12 mg, 46%). 1H NMR (300 MHz, DMSO-<¾) δ 8.61 (br s, 1H), 8.40 - 8.1 1 (m, 2H), 7.76 (s, 1H), 5.89 - 5.55 (m, 1H), 4.66 - 4.33 (m, 7H), 3.90 - 3.65 (m, 4H), 1.49 (d, J = 6.1 Hz, 3H). LCMS for C ₁₉ H ₂₁ CI ₂ F ₂ N ₆ O (M+H) ⁺ : m/z = 457.1 , 459.1 ; Found: 457.1 , 459.1.

Example 211. 5- {3-Cyano-6-ethoxy-2-fluoro-5- [ l-(9H-purin-6-ylamino)ethyl] phenyl}-7\yV- dimethylpyridine-2-carboxamide bis(trifluoroacetate)

Step 1. l-(5-Chloro-2-ethoxy-4-fluoro-3-iodophenyl)ethanone

The desired compound was prepared according to the procedure of Example 172, Step 3, using ethyl iodide as the starting material in 90% yield. LCMS for C ₁₀ H ₁₀ CIFIO ₂ (M+H) ⁺ : m/z = 342.9, 344.9; Found: 342.9, 344.8.

Step 2. l-(5-Chloro-2-ethoxy-4-fluoro-3-iodophenyl)ethanamine

The desired compound was prepared according to the procedure of Example 179, step 2, using l-(5-chloro-2-ethoxy-4-fluoro-3-iodophenyl)ethanone as the starting material in 22% yield. LCMS for Ci ₀ Hi ₀ ClFIO (M-[NH ₂ ]) ⁺ : m/z = 326.9; Found: 327.0.

Step 3. Enantiomer of tert-butyl [l-(5-chloro-2-ethoxy-4-fluoro-3-iodophenyl)ethyl] carbamate

The desired racemic compound was prepared according to the procedure of Example 179, step 3, using l-(5-chloro-2-ethoxy-4-fluoro-3-iodophenyl)ethanamine as the starting material in 80% yield. This racemic material was separated by chiral HPLC (Chiralcel AD-H column, 20 x 250 mm, 5 micron particle size, eluting with 30% ethanol in hexanes at 12 mL/min, column loading ~ 30 mg/injection) to give the desired peak 2 isomer. LCMS for Ci ₀ Hi ₀ ClFIO (M- [NHBoc]) ⁺ : m/z = 326.9; Found: 326.9. Step 4. N-[l-(5-Chloro-2-ethoxy-4-fluoro-3-iodophenyl)ethyl]-9-(tetr ahydro-2H-pyran-2-yl)- 9H-purin- 6-am in e

A solution of tert-butyl [1 -(5 -chloro-2-ethoxy-4-fluoro-3-iodophenyl)ethyl] carbamate (1.0 g, 2.3 mmol) in methylene chloride (48 mL) was treated with trifluoroacetic acid (24 mL) and stirred at room temperature for 0.5 hour. The reaction mixture was concentrated and the residue was re-evaporated from methanol/toluene (2 x 50 mL) in order to remove all residual TFA to give the desired amine intermediate. A solution of the amine intermediate in ethanol (20 mL) was treated with DIPEA(1.2 mL, 6.8 mmol) followed by 6-chloro-9-(tetrahydro-2H-pyran- 2-yl)-9H-purine (0.81 g, 3.4 mmol, from Example 176, Step 4) and heated at 80 °C overnight. The reaction mixture was diluted with saturated sodium bicarbonate and diluted with EtOAc. The organic layer was separated and washed with water and brine, dried with sodium sulfate, filtered and concentrated to a crude residue which was purified by flash column chromatography using EtOAc in hexanes (0% - 65%) to give the desired product (1.2 g, 94%). LCMS for C ₂ oH ₂₃ ClFIN ₅ 0 ₂ (M+H) ⁺ : m/z = 546.1 ; Found: 546.0. Step 5. 5-[3-Chloro-6-ethoxy-2-fluoro-5-(l-{[9-(tetrahydro-2H-pyran- 2-yl)-9H-purin-6- yl] amino } ethyl)phenyl]pyridine-2-carbonitrile

A solution of N-[l-(5-chloro-2-ethoxy-4-fluoro-3-iodophenyl)ethyl]-9-(tetr ahydro-2H- pyran-2-yl)-9H-purin-6-amine (170 mg, 0.31 mmol), 5-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan- 2-yl)pyridine-2-carbonitrile (86 mg, 0.37 mmol, Frontier Scientific, Cat. No. C I 628), sodium carbonate (66 mg, 0.62 mmol) and [l, -bis(diphenylphosphino)ferrocene]dichloropalladium-

(II),complex with dichloromethane (1 : 1) (31 mg, 0.037 mmol) in acetonitrile (1.5 mL) and water (0.4 mL) was degassed with nitrogen for 10 min and stirred at 95 °C for 2 hours. The reaction mixture was diluted with EtOAc, washed with saturated sodium bicarbonate, water, and brine, dried over sodium sulfate, filtered and concentrated to a crude residue which was purified by flash column chromatography using EtOAc in hexanes (25% - 100%) to give the desired product (81 mg, 50%). LCMS for C ₂₆ H ₂₆ C1FN ₇ 0 ₂ (M+H) ⁺ : m/z = 522.2; Found: 522.2. Step 6. 5-{3-Chloro-6-ethoxy-2-fluoro-5-[ l-(9H-purin-6-ylamino)ethyl]phenyl}pyridine-2- carboxylic acid

A solution of 5-[3-chloro-6-ethoxy-2-fluoro-5-(l-{[9-(tetrahydro-2H-pyran- 2-yl)-9H- purin-6-yl]amino}ethyl)phenyl]pyridine-2-carbonitrile (0.070 g, 0.13 mmol) in ethanol (1.2 mL) was treated with 3 M sodium hydroxide in water (0.6 mL, 2 mmol) and stirred at 90 °C for 4 h in a sealed tube. The reaction mixture was cooled to 0 °C, quenched with 12 M HCl in water (0.1 mL, 2 mmol), and stirred at 20 °C for 30 minutes. The reaction mixture was treated with additional 12 M HCl in water (0.2 mL, 2 mmol) and stirred at 20 °C for 15 minutes. The reaction mixture was concentrated to give the desired product (61 mg, quantitative) which was used without further purification. LCMS for C ₂₁ H ₁₉ CIFN ₆ O ₃ (M+H) ₊ : m/z = 457.1; Found: 457.1.

Step 7. 5-{3-Chloro-6-ethoxy-2-fluoro-5-f l-(9H-purin-6-ylamino)ethyl]phenyl}-N,N- dimethylpyridine-2-carboxamide

A solution of 5-{3-chloro-6-ethoxy-2-fluoro-5-[l-(9H-purin-6- ylamino)ethyl]phenyl}pyridine-2-carboxylic acid (61 mg, 0.13 mmol) and benzotriazol-1- yloxytris(dimethylamino)phosphonium hexafluorophosphate (0.11 g, 0.26 mmol) in DMF (1.4 mL) was treated with 2.0 M dimethylamine in THF (0.26 mL, 0.52 mmol) followed

by triethylamine (0.072 mL, 0.52 mmol) and stirred at 20 °C for 3 hours. The reaction mixture was diluted with EtOAc and washed with water and brine. The organic layer was separated, dried with magnesium sulfate, filtered, and concentrated to give a crude oil. The crude material was purified by flash column chromatography using EtOAc in hexanes (0% - 70%) to give the desired product (4.7 mg, 7%). LCMS for C ₂₃ H ₂₄ CIFN ₇ O ₂ (M+H) ⁺ : m/z = 484.2; Found: 484.1.

Step 8. 5-{3-Cyano-6-ethoxy-2-fluoro-5-[ l-(9H-purin-6-ylamino) ethyl] phenyl} -N,N- dimethylpyridine-2-carboxamide bis(trifluoroacetate)

N,N-Dimethylacetamide (10 mL) was degassed with nitrogen for 10 minutes, then 27 uL of concentrated sulfuric acid was added (to generate a 50 mM solution), and then bubbled again with nitrogen for 10 minutes. Transfered 2.0 mL of this 50 mM sulfuric acid/DMA solution to a microwave vial and degassed again with nitrogen. Palladium acetate (23 mg, 0.10 mmol) was added, followed by dicyclohexyl(2',4',6'-triisopropylbiphenyl-2-yl)phosphine (96 mg, 0.20 mmol). The vial was crimp-capped and the mixture was again degassed with nitrogen bubbling for 10 minutes, and then heated at 80 °C for 30 min to give a homogeneous brown solution. This catalyst solution was used immediately.

A solution of 5-{3-Chloro-6-ethoxy-2-fluoro-5-[l-(9H-purin-6-ylamino)ethyl ]phenyl}-

N,N-dimethylpyridine-2-carboxamide (20 mg, 0.041 mmol), zinc (1.2 mg, 0.0179 mmol), and zinc cyanide (5.3 mg, 0.045 mmol) in N,N-dimethylacetamide (0.5 mL, 5.4 mmol) in a microwave tube was degassed by bubbling nitrogen through the solution for 10 min. The above palladium catalyst solution (150 uL) was added and the resulting mixture degassed again briefly with nitrogen and heated at 110 °C for 1 hour. The reaction mixture was purified by preparative LCMS (XBridge C18 Column, eluting with a gradient of acetonitrile in water with 0.1% trifluoroacetic acid, at flow rate of 60 mL/min) to give the desired product (20 mg, 83%). 1H NMR (300 MHz, DMSO-<¾) δ 8.85 - 8.79 (m, 1H), 8.77 (dd, J= 2.2, 0.8 Hz, 1H), 8.37 (s, 2H), 8.10 (d, J= 7.4 Hz, 1H), 8.02 (dd, J= 8.0, 2.2 Hz, 1H), 7.70 (d, J= 8.0 Hz, 1H), 5.94 - 5.59 (m, 1H), 3.91 - 3.73 (m, 1H), 3.66 - 3.44 (m, 1H), 3.03 (s, 3H), 2.96 (s, 3H), 1.56 (d, J= 6.9 Hz, 3H), 1.23 (s, 1H), 1.02 (t, J= 6.9 Hz, 3H). LCMS for C24H24FN8O2 (M+H) ⁺ : m/z = 475.2; Found: 475.2.

Example 212. 4-Ethoxy-2-fluoro-3-[5-(methylsulfonyl)pyridin-3-yl]-5-[l-(9 H-purin-6- ylamino)ethyl]benzonitrile bis(trifluoroacetate)

Step 1. l-{5-Chloro-4-fluoro-2-hydroxy-3-[ 5-(methylsulfonyl)pyridin-3-yl]phenyl}ethanone

The desired compound was prepared according to the procedure of Example 127, step A, using l-(5-chloro-4-fluoro-2-hydroxy-3-iodophenyl)ethanone (See, Example 172, Step 2) and 3- (methylsulfonyl)-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2 -yl)pyridine (PepTech Corp., Cat. No. BE358) as the starting materials in 87% yield. LCMS for CI ₄ HI ₂ C1FN0 ₄ S (M+H) : m/z = 344.0; Found: 343.9.

Step 2. l-{5-Chloro-2-ethoxy-4-fluoro-3-[ 5 <-(methylsulfonyl)pyridin-3-ylj ¹ phenyl} ethanone

A solution of l- {5-chloro-4-fluoro-2-hydroxy-3-[5-(methylsulfonyl)pyridin-3- yl]phenyl} ethanone (1.3 g, 3.6 mmol) in THF (32 mL) was treated with ethanol (0.28 mL, 4.73 mmol) and triphenylphosphine (1.3 g, 5.1 mmol). The reaction mixture was cooled to 0 °C, treated with diisopropyl azodicarboxylate (1.1 mL, 5.5 mmol) dropwise, and stirred at 20 °C for 1 hour. The reaction mixture was concentrated to remove most of the THF, diluted with EtOAc, washed with saturated sodium bicarbonate, water, brine, dried over sodium sulfate, filtered and concentrated to a crude residue which was purified by flash column chromatography using EtOAc in hexanes (15% - 65%) to give the desired product (1.2 g, 87%). LCMS for CI ₆ HI ₆ C1FN0 ₄ S (M+H) ⁺ : m/z = 372.0; Found: 372.1. Step 3. l-{5-Chloro-2-ethoxy-4-fluoro-3-[5-(methylsulfonyl)pyridin-3 -ylJphenyl}ethanam

The desired compound was prepared according to the procedure of Example 194, step 5, using l- {5-chloro-2-ethoxy-4-fluoro-3-[5-(methylsulfonyl)pyridin-3-y l]phenyl} ethanone as the starting material in 92% yield. LCMS for CI ₆ HI ₆ C1FN0 ₃ S (M-[NH ₂ ]) ⁺ : m/z = 356.1 ; Found: 356.0.

Step 4. Enantiomer of tert-butyl (l-{5-chloro-2-ethoxy-4-fluoro-3-[5-(methylsulfonyl)pyridin- 3- yl] phenyl} ethyl) carbamate

The desired racemic compound was prepared according to the procedure of Example 179, step 3, using l-{5-chloro-2-ethoxy-4-fluoro-3-[5-(methylsulfonyl)pyridin-3 - yl]phenyl}ethanamine as the starting material. This racemic material was separated by chiral

HPLC (ChiralPak AD-H column, 20 x 250 mm, 5 micron particle size, eluting with 10% ethanol in hexanes at 12 mL/min) to give the desired peak 1 isomer. LCMS for C ₂ iH ₂₇ ClFN ₂ 05S (M+H) ⁺ : m/z = 473.1 ; Found: 473.2. Step 5. l-{5-Chloro-2-ethoxy-4-fluoro-3-[5-(methylsulfonyl)pyridin-3 -yl]phenyl}ethanamine dihydrochloride The desired compound was prepared according to the procedure of Example 179, step 5, using tert-butyl ( 1 - {5 -chloro-2-ethoxy-4-fluoro-3 - [5 -(methylsulfonyl)pyridin-3 - yl]phenyl}ethyl)carbamate as the starting material in quantitative yield. LCMS for

C ₁₆ H ₁₉ CIFN ₂ O ₃ S (M+H) ⁺ : m/z = 373.1; Found: 373.1.

Step 6. N-(l-{5-chloro-2-ethoxy-4-fluoro-3-[ 5-(methylsulfonyl)pyridin-3-yl]phenyl}ethyl)-9H- purin-6-amine

The desired compound was prepared according to the procedure of Example 194, step 8, using 1 - {5-chloro-2-ethoxy-4-fluoro-3-[5-(methylsulfonyl)pyridin-3-y l]phenyl} ethanamine dihydrochloride as the starting material in 60% yield. LCMS for C ₂₁ H ₂₁ CIFN ₆ O ₃ S (M+H) ⁺ : m/z = 491.1; Found: 491.1.

Step 7. 4-Ethoxy-2-fluoro-3-[ 5-(methylsulfonyl)pyridin-3-yl]-5-[ l-(9H-purin-6- ylamino) ethyl) 'benzonitrile bis(trifluoroacetate)

The desired racemic compound was prepared according to the procedure of Example 211, step 8, using N-(l-{5-chloro-2-ethoxy-4-fluoro-3-[5-(methylsulfonyl)pyridi n-3-yl]phenyl}ethyl)- 9H-purin-6-amine as the starting material in 82% yield. 1H NMR (300 MHz, DMSO-d ₆ ) δ 9.17 (d, J= 2.2 Hz, 1H), 9.09 - 9.05 (m, 1H), 8.82 - 8.67 (m, 1H), 8.57 - 8.52 (m, 1H), 8.38 - 8.31 (m, 2H), 8.17 (d, J= 7.5 Hz, 1H), 5.92 - 5.70 (m, 1H), 3.97 - 3.84 (m, 1H), 3.54 - 3.44 (m, 1H), 3.40 (s, 3H), 1.58 (d, J= 6.9 Hz, 3H), 1.04 (t, J= 6.9 Hz, 3H). LCMS for C ₂₂ H ₂₁ FN ₇ O ₃ S (M+H) ⁺ : m/z = 482.1 ; Found: 482.2.

Example 213. 6-Chloro-3-ethoxy-2-(l-ethylazetidin-3-yl)-4-[l-(9H-purin-6- ylamino)ethyl]benzonitrile bis(trifluoroacetate)

Step 1. 4-Acetyl-6-chloro-3-ethoxy-2-iodobenzonitrile

A solution of l-(5-chloro-2-ethoxy-4-fluoro-3-iodophenyl)ethanone (1.0 g, 2.9 mmol, from Example 211, Step 1) and potassium cyanide (0.29 g, 4.4 mmol) in DMF (11 mL) was stirred at 40 °C for 3 hours. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (2 x 75 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated to a crude orange oil. The crude material was dissolved in 1 : 1 hexane/dichloromethane and purified by flash column chromatography using EtOAc in hexanes (0% - 30% over 30 min) to give the desired product (0.79 g, 77%). LCMS for C ₁₁ H ₁₀ CIINO ₂ (M+H) ⁺ : m/z = 349.9; Found: 349.9.

Step 2. tert-Butyl 3-(3-acetyl-5-chloro-6-cyano-2-ethoxyphenyl)azetidine-l-carb oxylate

The desired compound was prepared according to the procedure of Example 165, step 1, using 4-acetyl-6-chloro-3-ethoxy-2-iodobenzonitrile as the starting material in 82% yield.

LCMS for Ci ₉ H ₂ 3ClN ₂ 0 ₄ Na (M+Na) ⁺ : m/z = 401.1; Found: 401.0.

Step 3. tert-Butyl 3-[ 3-( l-aminoethyl)-5-chloro-6-cyano-2-ethoxyphenylJazetidine-l-ca rboxylate

The desired compound was prepared according to the procedure of Example 179, step 2, using tert-butyl 3-(3-acetyl-5-chloro-6-cyano-2-ethoxyphenyl)azetidine-l-carb oxylate as the starting material in quantitative yield. LCMS for CigFLeClNsOsNa (M+Na) ⁺ : m/z = 402.2; Found: 402.1.

Step 4. 2-Azetidin-3-yl-6-chloro-3-ethoxy-4-[ 1 -(9H-purin-6-ylamino)ethyl] benzonitrile

The desired compound was prepared according to the procedure of Example 194, step 8, using tert-butyl 3 - [3 -( 1 -aminoethy l)-5 -chloro-6-cyano-2-ethoxyphenyl] azetidine- 1 -carboxylate as the starting material in 90% yield. LCMS for Ci ₉ H ₂ iClN ₇ 0 (M+H) : m/z = 398.1; Found: 398.1.

Step 5. 6-Chloro-3-ethoxy-2-( 1 -ethylazetidin-3-yl)-4-[ l-(9H-purin-6-ylamino)ethyl]benzonitrile bis(trifluoroacetate)

A solution of 2-azetidin-3-yl-6-chloro-3-ethoxy-4-[l-(9H-purin-6- ylamino)ethyl]benzonitrile (45 mg, 0.11 mmol) in methanol (1.5 mL) was treated with sodium cyanoborohydride (0.022 g, 0.35 mmol) followed by acetaldehyde (0.079 mL, 1.4 mmol) and stirred at room temperature for 16 hours. The reaction mixture was diluted with methanol and purified by preparative LCMS (XBridge CI 8 Column, eluting with a gradient of acetonitrile in water with 0.1% trifluoroacetic acid, at flow rate of 60 mL/min) to give the desired product (27 mg, 40%). 1H NMR (400 MHz, DMSO-<¾) δ 10.02 (br s, 1H), 8.50 (br s, 1H), 8.26 (s, 1H), 8.19 (s, 1H), 7.79 (s, 1H), 5.80 - 5.61 (m, 1H), 4.69 - 4.47 (m, 3H), 4.42 - 4.31 (m, 1H), 4.30 - 4.15 (m, 2H), 3.95 - 3.84 (m, 1H), 3.21 - 3.07 (m, 1H), 1.49 (d, J= 6.9 Hz, 3H), 1.43 (t, J= 6.9 Hz, 3H), 1.23 (s, 1H), 1.08 (t, J= 7.2 Hz, 3H). LCMS for C ₂ iH ₂₅ ClN ₇ 0 (M+H) ⁺ : m/z = 426.2; Found: 426.2.

Example 214. 6-Chloro-3-ethoxy-2-(l-isopropylazetidin-3-yl)-4-[l-(9H-puri n-6- ylamino)ethyl] benzonitrile bis(trifluoroacetate)

The desired racemic compound was prepared according to the procedure of Example 213, step 5, using acetone as the starting material in 37% yield. This racemic material was separated by chiral HPLC (ChiralPak AD-H column, 20 x 250 mm, 5 micron particle size, eluting with 30% ethanol in hexanes at 12 mL/min) to give the desired peak 1 isomer (retention time: 13.6 min). 1H NMR (400 MHz, DMSO-<¾) δ 10.16 (br s, 1H), 8.50 (br s, 1H), 8.26 (s, 1H), 8.20 (s, 1H), 7.80 (s, 1H), 5.86 - 5.58 (m, 1H), 4.60 - 4.46 (m, 3H), 4.45 - 4.37 (m, 1H), 4.35 - 4.17 (m, 2H), 3.95 - 3.87 (m, 1H), 3.50 - 3.31 (m, 1H), 1.49 (d, J= 6.9 Hz, 3H), 1.44 (t, J= 6.9 Hz, 3H), 1.24 (d, J= 6.4 Hz, 2H), 1.13 (dd, J= 6.4, 3.0 Hz, 3H). LCMS for C ₂₂ H ₂₇ CIN ₇ O (M+H) ⁺ : m/z = 440.2; Found: 440.2.

Experimental procedures for further compounds are summarized in Table 10 below.

Table 10

Ex. Name

R Salt Proc.° No.

N-( 1 - {4,5 -dichloro-2-methoxy-3 - [ 1 -(tetrahydrofuran-3 -

202 ylmethyl)azetidin-3-yl]phenyl}ethyl)-9H-purin-6-amine - 194

N-(l-{4,5-Dichloro-2-methoxy-3-[l-(4,4,4-

203 trifluorobutyl)azetidin-3-yl]phenyl}ethyl)-9H-purin-6- - 194 amine

N-(l-{4,5-Dichloro-2-methoxy-3-[l-(l,3-thiazol-4-

204 ylmethyl)azetidin-3-yl]phenyl}ethyl)-9H-purin-6-amine - 194

N-(l-{4,5-Dichloro-2-methoxy-3-[l-(3,3,3-

205 trifluoropropyl)azetidin-3-yl]phenyl}ethyl)-9H-purin-6- ^CF ₃ - 194 amine

2-(3-{2,3-Dichloro-6-methoxy-5-[l-(9H-purin-6-

208 ylamino)ethyl]phenyl} azetidin- 1 -yl)propan- 1 -ol 2TFA 194 bistrifluoroacetate

N- { 1 -[4,5-Dichloro-3-(l -cyclobutylazetidin-3-yl)-2-

209 methoxyphenyl]ethyl}-9H-purin-6-amine 2TFA 194 bistrifluoroacetate

a ¹ H NMR data (Varian Inova 500 spectrometer, a Mercury 400 spectrometer, or a Varian (or Mercury) 300 spectrometer) and LCMS mass spectral data (MS) for the compounds above is provided below in Table 11. Table 11. 1H NMR data for compounds inTable 10 Ex. MS

Solvent MHz 1H NMR Spectra

No. [M+H] ⁺

δ 10.44 (br s, 1H), 9.93 (br s, 0.5H), 8.78 - 8.65 (m, 1H), 8.37 - 8.25 (m, 2H), 7.75 (s, 1H), 5.97 - 5.53 (m, 1H),

DMSO- 4.70 - 4.57 (m, 2H), 4.43 - 4.20 (m, 3H), 4.12 - 4.01 (m,

197 463.0,465.0 300

d ₆ 0.5H), 3.94 - 3.86 (m, 1.5H), 3.83 (s, 3H), 3.69 - 3.53 (m,

2H), 2.24 - 2.05 (m, 1H), 1.98 - 1.81 (m, 1H), 1.49 (d, J = 6.7 Hz, 3H).

δ 8.64 (br s, 1H), 8.34 - 8.20 (m, 2H), 7.68 (s, 1H), 5.83 -

489.0, DMSO- 5.57 (m, 1H), 4.29 - 4.04 (m, 4H), 3.81 (s, 3H), 3.74 -

198 300

491.0 d ₆ 3.38 (m, 3H), 1.48 (d, J= 6.9 Hz, 3H), 1.14 (d, J= 6.2

Hz, 3H).

δ 8.30 - 7.94 (m, 3H), 7.62 (s, 1H), 5.97 - 5.53 (m, 1H),

407.0, DMSO- 3.99 - 3.81 (m, 3H), 3.79 (s, 3H), 2.95 (dd, J= 8.9, 6.5

199 300

409.0 d ₆ Hz, 1H), 2.81 (dd, J= 8.8, 6.4 Hz, 1H), 2.15 (s, 3H), 1.44

(d, J= 6.9 Hz, 3H).

δ 8.16 - 7.97 (m, 3H), 7.63 (s, 1H), 5.87 - 5.54 (m, 1H),

451.0, DMSO- 4.00 - 3.83 (m, 3H), 3.79 (s, 3H), 3.31 - 3.26 (m, 4H),

200 300

453.0 d ₆ 3.21 (s, 3H), 3.07 - 2.94 (m, 1H), 2.94 - 2.82 (m, 1H),

1.44 (d, J= 6.9 Hz, 3H).

δ 8.30 - 7.97 (m, 3H), 7.62 (s, 1H), 5.88 - 5.53 (m, 1H), 4.01 - 3.84 (m, 3H), 3.80 (s, 3H), 3.00 - 2.91 (m, 1H),

DMSO-

201 447.0 300 2.87 - 2.77 (m, 1H), 2.16 (d, J= 6.6 Hz, 2H), 1.44 (d, J = d ₆

6.9 Hz, 3H), 0.81 - 0.63 (m, 1H), 0.49 - 0.25 (m, 2H), 0.09 - -0.02 (m, 2H).

δ 8.19 - 8.07 (m, 3H), 7.62 (s, 1H), 5.86 - 5.48 (m, 1H), 4.04 - 3.83 (m, 3H), 3.80 (s, 3H), 3.77 - 3.53 (m, 3H),

DMSO-

202 477.1 300 3.04 - 2.92 (m, 1H), 2.90 - 2.77 (m, 1H), 2.35 - 2.26 (m, d ₆

2H), 2.24 - 2.10 (m, 1H), 2.00 - 1.80 (m, 1H), 1.44 (d, J = 6.9 Hz, 3H). Ex. MS

Solvent MHz 1H NMR Spectra

No. [M+H] ⁺

δ 8.22 - 8.03 (m, 3H), 7.63 (s, 1H), 5.91 - 5.50 (m, 1H),

DMSO- 4.03 - 3.85 (m, 3H), 3.80 (s, 3H), 3.04 - 2.90 (m, 1H),

203 503.1 300

d ₆ 2.90 - 2.77 (m, 1H), 2.40 - 2.15 (m, 4H), 1.56 - 1.36 (m,

4H).

δ 9.03 (d, J= 2.0 Hz, 1H), 8.25 - 8.03 (m, 3H), 7.63 (s,

DMSO- 1H), 7.47 (d, J= 1.9 Hz, 1H), 5.97 - 5.50 (m, 1H), 4.08 -

204 490.0 300

d ₆ 3.85 (m, 3H), 3.80 (s, 3H), 3.66 (s, 2H), 3.20 - 3.11 (m,

1H), 3.09 - 2.97 (m, 1H), 1.44 (d, J= 6.9 Hz, 3H).

δ 8.25 - 7.97 (m, 3H), 7.63 (s, 1H), 5.97 - 5.45 (m, 1H),

DMSO- 4.02 - 3.84 (m, 3H), 3.80 (s, 3H), 3.01 (dd, J= 8.5, 6.3

205 489.0 300

d ₆ Hz, 1H), 2.93 - 2.86 (m, 1H), 2.41 - 2.18 (m, 2H), 1.44

(d, J= 6.9 Hz, 3H).

δ 10.01 (br s, 1H), 8.63 - 8.44 (m, 1H), 8.36 - 8.14 (m, 2H), 7.76 (s, 1H), 5.86 - 5.60 (m, 1H), 4.59 - 4.45 (m,

451.0, DMSO-

208 300 2H), 4.43 - 4.22 (m, 3H), 3.84 (d, J= 3.0 Hz, 3H), 3.70 - 453.0 d ₆

3.55 (m, 1H), 3.50 - 3.31 (m, 2H), 1.49 (d, J= 6.8 Hz, 3H), 1.28 - 1.17 (m, 0.5H), 1.16 - 1.02 (m, 2.5H).

δ 10.54 (br s, 1H), 9.83 (br s, 0.5H), 8.57 (br s, 1H), 8.39 - 8.16 (m, 2H), 7.75 (s, 1H), 5.71 (m, 1H), 4.60 - 4.47

447.1, DMSO-

209 300 (m, 2H), 4.45 - 4.21 (m, 2H), 4.19 - 4.06 (m, 2H), 3.89 - 449.1 d ₆

3.80 (m, 3H), 2.19 - 1.97 (m, 4H), 1.87 - 1.63 (m, 1H), 1.48 (d, J= 6.9 Hz, 3H), 1.23 (s, 1H).

Example A: PI3K6 scintillation proximity assay

Materials: [γ- ³³ Ρ]ΑΤΡ (lOmCi/mL) was purchased from Perkin-Elmer (Waltham, MA). Lipid kinase substrate, D-myo-Phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2)D (+)-sn- 1 ,2-di-O-octanoylglyceryl, 3-O-phospho linked (PIP2), CAS 204858-53-7, was purchased from Echelon Biosciences (Salt Lake City, UT). ΡΙ3Κδ (pi 10δ /ρ85α) was purchased from Millipore (Bedford, MA). ATP, MgCl ₂ , DTT, EDTA, MOPS and CHAPS were purchased from Sigma- Aldrich (St. Louis, MO). Wheat Germ Agglutinin (WGA) YSi SPA Scintillation Beads was purchased from GE healthcare life sciences (Piscataway, NJ ).

Assay: The kinase reaction was conducted in polystyrene 384-well matrix white plate from Thermo Fisher Scientific in a final volume of 25 μί. Inhibitors were first diluted serially in DMSO and added to the plate wells before the addition of other reaction components. The final concentration of DMSO in the assay was 0.5%. The PI3K assays were carried out at room temperature in 20 mM MOPS, pH 6.7, 10 mM MgCl ₂ , 5 mM DTT and CHAPS 0.03%.

Reactions were initiated by the addition of ATP, the final reaction mixture consisted of 20 μΜ PIP2, 20 μΜ ATP, 0.2 μθ [γ- ³³ Ρ] ATP, 4 nM PI3K5. Reactions were incubated for 210 minutes and terminated by the addition of 40 μΐ, SPA beads suspended in quench buffer: 150 mM potassium phosphate pH 8.0, 20% glycerol. 25 mM EDTA, 400 μΜ ATP. The final

concentration of SPA beads is 1.0 mg/mL. After the plate sealing, plates were shaken overnight at room temperature and centrifuged at 1800 rpm for 10 minutes, the radioactivity of the product was determined by scintillation counting on Topcount (Perkin-Elmer). IC ₅₀ determination was performed by fitting the curve of percent control activity versus the log of the inhibitor concentration using the GraphPad Prism 3.0 software. Table 12 shows PI3K5 scintillation proximity assay data for certain compounds described herein.

Table 12. IC50 data for PI3K6 scintillation proximity assay

A 79 C

B 80 A

A 81 A

A 82 A

C 83 A

C 84 A

A 85 D

A 86 ^a B/C

A 87 A

A 88 A

A 89 B

A 90 D

A 91 B

C 92 C

A 93 B

A 94 A ^a A/B 95 A

A 96 A

A 97 B

A 98 A ^a A/A 99 D

A 100 A

A 101 C

A 102 C

B 103 A

C 104 A

A 105 A

A 106 A

A 107 A

A 108 A

A 109 A

A 110 A

A 111 A

A 112 A

A 113 A

A 114 A

A 115 A

A 116 A

A 117 A

A 118 B ^a A/A 119 C ^a A/A 120 B

A 121 A

A 122 D

A 123 B 124 A 169 A

125 B 170 A

126 A 171 A

127 A 172 A

128 A 173 A

129 A 174 A

130 A 175 A

131 A 176 A

132 A 177 A

133 B 178 A

134 A 179 A

135 A 180 A

136 C 181 A

137 B 182 A

138 B 183 A

139 B 184 A

140 B 185 A

141 D 186 A

142 B 187 A

143 C 188 A

144 A 189 A

145 A 190 A

146 B 191 A

147 A 192 ^a A/A

148 B 193 ^a A/A

149 A 194 A

150 A 195 A

151 A 196 A

152 A 197 A

153 A 198 A

154 A 199 A

155 A 200 A

156 A 201 A

157 A 202 A

158 A 203 A

159 A 204 A

160 A 205 A

161 A 206 A

162 A 207 A

163 A 208 A

164 A 209 A

165 A 210 A

166 A 211 A

167 A 212 A

168 A 213 A 214 A

* "A" = <50 nM; "B" = 50 nM-100 nM; "C" = >100 nM to 250 nM; "D" = >250 nM to 500 nM; "E" = >500 nM to 1 μΜ; and "F" = >1 μΜ; nt = not tested

atwo isomers were isolated in the corresponding experiments and they were tested respectively

Example B: B cell proliferation assay

To acquire B cells, human PBMC are isolated from the peripheral blood of normal, drug free donors by standard density gradient centrifugation on Ficoll-Hypague (GE Healthcare, Piscataway, NJ) and incubated with anti-CD 19 microbeads (Miltenyi Biotech, Auburn, CA). The B cells are then purified by positive immunosorting using an autoMacs (Miltenyi Biotech) according to the manufacture's instruction.

The purified B cells (2xl0 ⁵ /well/200 μΕ) are cultured in 96-well ultra-low binding plates (Corning, Corning, NY) in RPMI1640, 10% FBS and goat F(ab')2 anti-human IgM (10 μg/ml) (Invitrogen, Carlsbad, CA) in the presence of different amount of test compounds for three days.

[ ³ H] -thymidine (1 μα/well) (PerkinElmer, Boston, MA) in PBS is then added to the B cell cultures for an additional 12 hours before the incorporated radioactivity is separated by filtration with water through GF/B filters (Packard Bioscience, Meriden, CT) and measured by liquid scintillation counting with a TopCount (Packard Bioscience). Example C: Pfeiffer cell proliferation assay

Pfeiffer cell line (diffuse large B cell lymphoma) was purchased from ATCC (Manassas, VA) and maintained in the culture medium recommended (RPMI and 10% FBS). To measure the anti-proliferation activity of the compounds, the Pfeiffer cells were plated with the culture medium (2xl0 ³ cells / well/ per 200 μΐ) into 96-well ultra- low binding plates (Corning, Corning, NY), in the presence or absence of a concentration range of test compounds. After 3-4 days, [ ³ H] -thymidine (1 μΟΛνεΙΙ) (PerkinElmer, Boston, MA) in PBS wass then added to the cell culture for an additional 12 hours before the incorporated radioactivity was separated by filtration with water through GF/B filters (Packard Bioscience, Meridenj, CT) and measured by liquid scintillation counting with a TopCount (Packard Bioscience). Table 13 shows Pfeiffer cell proliferation data for certain compounds described herein.

Table 13: IC50 data for Pfeiffer cell proliferation assay* Example ICso (nM) 46 A

1 C 47 D

2 A 48 A

3 D 49 A

5 A 50 ^a D/ C

6 A 51 A

7 A 52 A

8 D 53 A

9 B 60 D

10 B 71 A

11 A 72 A

12 A 73 A

13 A 74 ^a A/A

14 A 75 ^a A/B

15 A 76 A

16 A 77 A

17 A 78 A

18 B 79 B

19 A 80 A

20 B 81 A

21 A 82 A

22 A 83 A

23 A 84 A

24 B 86 ^a D/D

25 A 87 A

26 A 88 A

27 B 89 C

28 B 91 D

29 B 92 B

30 B 93 D

31 A 94 A

32 A 95 C

33 A 96 A

34 A 97 B

35 D 98 A

36 A 100 D

37 A 106 A

38 D 107 B

39 D 109 A

40 A 110 B

41 D 111 A

42 B 112 A

43 B 124 A

44 B 166 A

45 B 170 A 174 A 199 A

176 A 200 A

177 A 201 A

178 A 202 A

179 A 203 A

180 A 204 A

187 A 205 A

194 A 208 A

195 A 212 B

196 A 213 A

197 A

* "A" = <100 nM; "B" = 100 nM-500 nM; "C" = >500 nM to 1 μΜ; "D" = >1 μΜ

atwo isomers were isolated in the corresponding experiments and they were tested respectively

Example D: Akt phosphorylation assay

Ramos cells (B lymphocyte from Burkitts lymphoma) are obtained from ATCC

(Manassas, VA) and maintained in RPMI1640 and 10% FBS. The cells (3xl0 ⁷ cells /tube/3 mL in RPMI) are incubated with different amounts of test compounds for 2 h at 37 °C and then stimulated with goat F(ab')2 anti-human IgM (5 μg/mL) (Invitrogen) for 17 minutes in a 37 °C water bath. The stimulated cells are spun down at 4 °C with centrifugation and whole cell extracts are prepared using 300 μΙ_, lysis buffer (Cell Signaling Technology, Danvers, MA). The resulting lysates are sonicated and supematants are collected. The phosphorylation level of Akt in the supematants are analyzed by using PathScan phospho-Aktl (Ser473) sandwich ELISA kits (Cell Signaling Technology) according to the manufacturer's instruction.

Various modifications of the invention, in addition to those described herein, will be apparent to those skilled in the art from the foregoing description. Such modifications are also intended to fall within the scope of the appended claims. Each reference, including all patent, patent applications, and publications, cited in the present application is incorporated herein by reference in its entirety.