CA2761445A1 - Bicyclic pyrimidine pi3k inhibitor compounds selective for p110 delta, and methods of use - Google Patents

Abstract

Formula (I) ((Ia) and (Ib)) compounds wherein (i) X1 is N and X2 is S, (ii) X1 is CR7 and X2 is S, (iii) X1 is N and X2 is NR2, or (iv) X1 is CR7 and X2 is O, including stereoisomers, tautomers, metabolites and pharmaceutically acceptable salts thereof, are useful for inhibiting the delta isoform of PI3K, and for treating disorders mediated by lipid kinases such as inflamma-tion, immunological, and cancer. Methods of using compounds of Formula (I) for in vitro, in situ, and in vivo diagnosis, preven-tion or treatment of such disorders in mammalian cells, or associated pathological conditions, are disclosed.

Description

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P110 DELTA, AND METHODS OF USE

[0001] CROSS REFERENCE TO RELATED APPLICATIONS

[0002] This non-provisional application filed under 37 CFR 1.53(b), claims the benefit under 35 USC 119(e) of U.S. Provisional Application Serial Nos.
61/181452 filed on 27 May 2009 and 61/287607 filed on 17 December 2009, which are incorporated by reference in their entirety.

[0003] FIELD OF THE INVENTION

[0004] The invention relates generally to compounds for treating disorders mediated by lipid kinases such as inflammation, immunological, and cancer, and more specifically to compounds which inhibit P13 kinase activity. The invention also relates to methods of using the compounds for in vitro, in situ, and in vivo diagnosis or treatment of mammalian cells, or associated pathological conditions.

[0005] BACKGROUND OF THE INVENTION

[0006] Phosphatidylinositol (PI), a phospholipid found in cell membranes, plays an important role in intracellular signal transduction. Cell signaling via 3'-phosphorylated phosphoinositides has been implicated in a variety of cellular processes, e.g., malignant transformation, growth factor signaling, inflammation, and immunity (Rameh et al (1999) J.
Biol Chem, 274:8347-8350). The enzyme responsible for generating these phosphorylated signaling products, phosphatidylinositol 3-kinase (also referred to as PI 3-kinase or P13K), was originally identified as an activity associated with viral oncoproteins and growth factor receptor tyrosine kinases that phosphorylate phosphatidylinositol (PI) and its phosphorylated derivatives at the 3'-hydroxyl of the inositol ring (Panayotou et al (1992) Trends Cell Biol 2:358-60).

[0007] Phosphoinositide 3-kinases (P13K) are lipid kinases that phosphorylate lipids at the 3-hydroxyl residue of the inositol ring of phosphoinositols (Whitman et al (1988) Nature, 332:664). The 3'-phosphorylated phospholipids (PIP3s) generated by P13-kinases act as second messengers recruiting kinases with lipid binding domains (including plekstrin homology (PH) regions), such as Akt and phosphoinositide-dependent kinase-1 (PDK1).

Binding of Akt to membrane PIP3s causes the translocation of Akt to the plasma membrane, bringing Akt into contact with PDK1, which is responsible for activating Akt.
The tumor-suppressor phosphatase, PTEN, dephosphorylates PIP3 and therefore acts as a negative regulator of Akt activation. The P13-kinases Akt and PDK1 are important in the regulation of many cellular processes including cell cycle regulation, proliferation, survival, apoptosis and motility and are significant components of the molecular mechanisms of diseases such as cancer, diabetes and immune inflammation (Vivanco et al (2002) Nature Rev.
Cancer 2:489;
Phillips et al (1998) Cancer 83:41).

[0008] P13 kinase is a heterodimer consisting of p85 and pl 10 subunits (Otsu et al (1991) Cell 65:91-104; Hiles et al (1992) Cell 70:419-29). Four distinct Class I PI3Ks have been identified, designated P13K a (alpha), (3 (beta), 8 (delta), and y (gamma), each consisting of a distinct 110 kDa catalytic subunit and a regulatory subunit.
More specifically, three of the catalytic subunits, i.e., p 110 alpha, p 110 beta and p 110 delta, each interact with the same regulatory subunit, p85; whereas pl 10 gamma interacts with a distinct regulatory subunit, pl0l . The patterns of expression of each of these PI3Ks inhuman cells and tissues are also distinct.

[0009] The pl 10 delta isoform has been implicated in biological functions related to immune-inflammatory diseases, including signaling from the B-cell receptor, T
cell receptor, FcR signaling of mast cells and monocyte/macrophage, and osteoclast function/RANKL
signaling (Deane J and Fruman D A (2004) Annu. Rev. Immunol. 2004. 22:563-98;
Janas et al., The Journal of Immunology, 2008, 180: 739 -746; Marone R et al., Biochim.
Biophy.
Acta 2007, 1784:159-185. Deletion of the P13K delta gene or selective introduction of a catalytically inactive mutant of P13K delta causes a nearly complete ablation of B cell proliferation and signaling, and impairment of signaling through T cells as well.

[0010] SUMMARY OF THE INVENTION

[0011] The invention relates generally to Formula I compounds with P13 kinase inhibitory activity and selective binding to the pl 10 delta isoform relative to binding to the p 110 alpha isoform. Formula I compounds at least 10 fold selective in binding to the p 110 delta isoform relative to binding to the p 110 alpha isoform.

[0012] Formula I compounds have the structures:

mor mor X1 N X2 ~N
R1 `XZ 3 R1~X1 I ~ 3 N R N R
la Ib [0013] and stereoisomers, tautomers, or pharmaceutically acceptable salts thereof.
The various substituents, including Xi, X2, mor, R', R2, R2" and R3, are as defined herein.

[0014] Another aspect of the invention provides a pharmaceutical composition comprising a Formula I compound and a pharmaceutically acceptable carrier, glidant, diluent, or excipient.

[0015] Another aspect of the invention provides the use of a Formula I
compound in the manufacture of a medicament for treating a disease or disorder selected from cancer, immune disorders, cardiovascular disease, viral infection, inflammation, metabolism/endocrine function disorders and neurological disorders, and mediated by the p 110 delta isoform of P13 kinase.

[0016] The invention also relates to methods of using the Formula I compounds for in vitro, in situ, and in vivo diagnosis or treatment of mammalian cells, organisms, or associated pathological conditions, such as cancer, systemic and local inflammation, immune-inflammatory diseases such as rheumatoid arthritis, immune suppression, organ transplant rejection, allergies, ulcerative colitis, Crohn's disease, dermatitis, asthma, systemic lupus erythematosus, Sjogren's Syndrome, multiple sclerosis, scleroderma/systemic sclerosis, idiopathic thrombocytopenic purpura (ITP), anti-neutrophil cytoplasmic antibodies (ANCA) vasculitis, chronic obstructive pulmonary disease (COPD), psoriasis, and for general joint protective effects.

[0017] Another aspect of the invention provides a method of treating a disease or disorder which method comprises administering a Formula I compound to a patient with a disease or disorder selected from cancer, immune disorders, cardiovascular disease, viral infection, inflammation, metabolism/endocrine function disorders and neurological disorders, and mediated by the p 110 delta isoform of P13 kinase. The method may further comprise administering an additional therapeutic agent selected from a chemotherapeutic agent, an anti-inflammatory agent, an immunomodulatory agent, a neurotropic factor, an agent for treating cardiovascular disease, an agent for treating liver disease, an anti-viral agent, an agent for treating blood disorders, an agent for treating diabetes, and an agent for treating immunodeficiency disorders.

[0018] Another aspect of the invention provides a kit for treating a condition mediated by the p 110 delta isoform of P13 kinase, comprising a first pharmaceutical composition comprising a Formula I compound; and instructions for use.

[0019] DETAILED DESCRIPTION OF EXEMPLARY EMBODIMENTS

[0020] Reference will now be made in detail to certain embodiments of the invention, examples of which are illustrated in the accompanying structures and formulas.
While the invention will be described in conjunction with the enumerated embodiments, it will be understood that they are not intended to limit the invention to those embodiments. On the contrary, the invention is intended to cover all alternatives, modifications, and equivalents which may be included within the scope of the present invention as defined by the claims.
One skilled in the art will recognize many methods and materials similar or equivalent to those described herein, which could be used in the practice of the present invention. The present invention is in no way limited to the methods and materials described.
In the event that one or more of the incorporated literature, patents, and similar materials differs from or contradicts this application, including but not limited to defined terms, term usage, described techniques, or the like, this application controls.

[0021] DEFINITIONS

[0022] The term "alkyl" as used herein refers to a saturated linear or branched-chain monovalent hydrocarbon radical of one to twelve carbon atoms (C1-C12), wherein the alkyl radical may be optionally substituted independently with one or more substituents described below. In another embodiment, an alkyl radical is one to eight carbon atoms (C1-C8), or one to six carbon atoms (C1-C6). Examples of alkyl groups include, but are not limited to, methyl (Me, -CH3), ethyl (Et, -CH2CH3), 1-propyl (n-Pr, n-propyl, -CH2CH2CH3), 2-propyl (i-Pr, i-propyl, -CH(CH3)2), 1-butyl (n-Bu, n-butyl, -CH2CH2CH2CH3), 2-methyl-l-propyl (i-Bu, i-butyl, -CH2CH(CH3)2), 2-butyl (s-Bu, s-butyl, -CH(CH3)CH2CH3), 2-methyl-2-propyl (t-Bu, t-butyl, -C(CH3)3), 1-pentyl (n-pentyl, -CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2-methyl-2-butyl (-C(CH3)2CH2CH3), methyl-2-butyl (-CH(CH3)CH(CH3)2), 3-methyl-l-butyl (-CH2CH2CH(CH3)2), 2-methyl-l-butyl (-CH2CH(CH3)CH2CH3), 1-hexyl (-CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH3), 3-hexyl (-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl (-CH(CH3)CH(CH3)CH2CH3), 4-methyl-2-pentyl (-CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl (-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (-CH(CH2CH3)CH(CH3)2), 2,3 -dimethyl-2-butyl (-C(CH3)2CH(CH3)2), 3,3 -dimethyl-2-butyl (-CH(CH3)C(CH3)3, 1-heptyl, 1-octyl, and the like.

[0023] The term "alkylene" as used herein refers to a saturated linear or branched-chain divalent hydrocarbon radical of one to twelve carbon atoms (C1-C12), wherein the alkylene radical may be optionally substituted independently with one or more substituents described below. In another embodiment, an alkylene radical is one to eight carbon atoms (C1-C8), or one to six carbon atoms (C1-C6). Examples of alkylene groups include, but are not limited to, methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), and the like.

[0024] The term "alkenyl" refers to linear or branched-chain monovalent hydrocarbon radical of two to eight carbon atoms (C2-Cs) with at least one site of unsaturation, i.e., a carbon-carbon, sp2 double bond, wherein the alkenyl radical may be optionally substituted independently with one or more substituents described herein, and includes radicals having "cis" and "trans" orientations, or alternatively, "E" and "Z" orientations.
Examples include, but are not limited to, ethylenyl or vinyl (-CH=CHz), allyl (-CHzCH=CHz), and the like.

[0025] The term "alkenylene" refers to linear or branched-chain divalent hydrocarbon radical of two to eight carbon atoms (C2-Cs) with at least one site of unsaturation, i.e., a carbon-carbon, sp2 double bond, wherein the alkenyl radical may be optionally substituted, and includes radicals having "cis" and "trans" orientations, or alternatively, "E" and "Z"
orientations. Examples include, but are not limited to, ethylenylene or vinylene (-CH=CH-), allyl (-CHzCH=CH-), and the like.

[0026] The term "alkynyl" refers to a linear or branched monovalent hydrocarbon radical of two to eight carbon atoms (C2-Cs) with at least one site of unsaturation, i.e., a carbon-carbon, sp triple bond, wherein the alkynyl radical may be optionally substituted independently with one or more substituents described herein. Examples include, but are not limited to, ethynyl (-C CH), propynyl (propargyl, -CHzC CH), and the like.

[0027] The term "alkynylene" refers to a linear or branched divalent hydrocarbon radical of two to eight carbon atoms (C2-Cs) with at least one site of unsaturation, i.e., a carbon-carbon, sp triple bond, wherein the alkynyl radical may be optionally.
Examples include, but are not limited to, ethynylene (-C C-), propynylene (propargylene, -CHzC C-), and the like.

[0028] The terms "carbocycle", "carbocyclyl", "carbocyclic ring" and "cycloalkyl"
refer to a monovalent non-aromatic, saturated or partially unsaturated ring having 3 to 12 carbon atoms (C3-C12) as a monocyclic ring or 7 to 12 carbon atoms as a bicyclic ring.
Bicyclic carbocycles having 7 to 12 atoms can be arranged, for example, as a bicyclo [4,5], [5,5], [5,6] or [6,6] system, and bicyclic carbocycles having 9 or 10 ring atoms can be arranged as a bicyclo [5,6] or [6,6] system, or as bridged systems such as bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane and bicyclo[3.2.2]nonane. Examples of monocyclic carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-l-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-l-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, adamantanyl, and the like.

[0029] "Aryl" means a monovalent aromatic hydrocarbon radical of 6-20 carbon atoms (C6-C20) derived by the removal of one hydrogen atom from a single carbon atom of a parent aromatic ring system. Some aryl groups are represented in the exemplary structures as "Ar". Aryl includes bicyclic radicals comprising an aromatic ring fused to a saturated, partially unsaturated ring, or aromatic carbocyclic ring. Typical aryl groups include, but are not limited to, radicals derived from benzene (phenyl), substituted benzenes, naphthalene, anthracene, biphenyl, indenyl, indanyl, 1,2-dihydronaphthalene, 1,2,3,4-tetrahydronaphthyl, and the like. Aryl groups are optionally substituted independently with one or more substituents described herein.

[0030] "Arylene" means a divalent aromatic hydrocarbon radical of 6-20 carbon atoms (C6-C20) derived by the removal of two hydrogen atom from a two carbon atoms of a parent aromatic ring system. Some arylene groups are represented in the exemplary structures as "Ar". Arylene includes bicyclic radicals comprising an aromatic ring fused to a saturated, partially unsaturated ring, or aromatic carbocyclic ring. Typical arylene groups include, but are not limited to, radicals derived from benzene (phenylene), substituted benzenes, naphthalene, anthracene, biphenylene, indenylene, indanylene, 1,2-dihydronaphthalene, 1,2,3,4-tetrahydronaphthyl, and the like. Arylene groups are optionally substituted.

[0031] The terms "heterocycle," "heterocyclyl" and "heterocyclic ring" are used interchangeably herein and refer to a saturated or a partially unsaturated (i.e., having one or more double and/or triple bonds within the ring) carbocyclic radical of 3 to about 20 ring atoms in which at least one ring atom is a heteroatom selected from nitrogen, oxygen, phosphorus and sulfur, the remaining ring atoms being C, where one or more ring atoms is optionally substituted independently with one or more substituents described below. A

heterocycle may be a monocycle having 3 to 7 ring members (2 to 6 carbon atoms and 1 to 4 heteroatoms selected from N, 0, P, and S) or a bicycle having 7 to 10 ring members (4 to 9 carbon atoms and 1 to 6 heteroatoms selected from N, 0, P, and S), for example: a bicyclo [4,5], [5,5], [5,6], or [6,6] system. Heterocycles are described in Paquette, Leo A.;
"Principles of Modem Heterocyclic Chemistry" (W.A. Benjamin, New York, 1968), particularly Chapters 1, 3, 4, 6, 7, and 9; "The Chemistry of Heterocyclic Compounds, A
series of Monographs" (John Wiley & Sons, New York, 1950 to present), in particular Volumes 13, 14, 16, 19, and 28; and J. Am. Chem. Soc. (1960) 82:5566.
"Heterocyclyl" also includes radicals where heterocycle radicals are fused with a saturated, partially unsaturated ring, or aromatic carbocyclic or heterocyclic ring. Examples of heterocyclic rings include, but are not limited to, pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidino, morpholino, thiomorpholino, thioxanyl, piperazinyl, homopiperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, dihydroisoquinolinyl, tetrahydroisoquinolinyl, pyrazolidinylimidazolinyl, imidazolidinyl, 2-oxa-5-azabicyclo[2.2.2] octane, 3-oxa-8-azabicyclo[3.2.1]octane, 8-oxa-3-azabicyclo[3.2.1]octane, 6-oxa-3-azabicyclo[3.1.1]heptane, 2-oxa-5-azabicyclo[2.2.1]heptane, 3-azabicyco[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl, azabicyclo[2.2.2]hexanyl, 3H-indolyl quinolizinyl and N-pyridyl ureas. Spiro moieties are also included within the scope of this definition. Examples of a heterocyclic group wherein 2 ring carbon atoms are substituted with oxo (=O) moieties are pyrimidinonyl and 1, 1 -dioxo-thiomorpholinyl. The heterocycle groups herein are optionally substituted independently with one or more substituents described herein.

[0032] The term "heteroaryl" refers to a monovalent aromatic radical of 5-, 6-, or 7-membered rings, and includes fused ring systems (at least one of which is aromatic) of 5-20 atoms, containing one or more heteroatoms independently selected from nitrogen, oxygen, and sulfur. Examples of heteroaryl groups are pyridinyl (including, for example, 2-hydroxypyridinyl), imidazolyl, imidazopyridinyl, pyrimidinyl (including, for example, 4-hydroxypyrimidinyl), pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxadiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, triazolyl, thiadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and furopyridinyl.
Heteroaryl groups are optionally substituted independently with one or more substituents described herein.

[0033] Examples of bicyclic heteroaryl groups include:
IN IN / N /

5IN \ I ? N \ I &N \ N \ N ON
N
/
N
N N=N 0I'-NH N-NH O
N

&9i N \ NH N-O N-S
~

N~/ $~ IN / I k N 1,1 N \ ' N
~// ' HN NH

N N
N N
N
/NH \ NH IN NJ, U1, NN J I N
N IN IN
IN INS I / S~ I
S~ IN
N

\ 0 / NHO S\ 1 / HN
1 I \ N S~
N IN I / LNH I

s~ 1 / s~ \ I I / NH

H
O

i N ~N N~
~k N \ N N N \ I $~~ N \ I
N N N N
N N~N NN
NN ~ N \ IN) IN") \N N N N

[0034] The heterocycle or heteroaryl groups may be carbon (carbon-linked), or nitrogen (nitrogen-linked) bonded where such is possible. By way of example and not limitation, carbon bonded heterocycles or heteroaryls are bonded at position 2, 3, 4, 5, or 6 of a pyridine, position 3, 4, 5, or 6 of a pyridazine, position 2, 4, 5, or 6 of a pyrimidine, position 2, 3, 5, or 6 of a pyrazine, position 2, 3, 4, or 5 of a furan, tetrahydrofuran, thiofuran, thiophene, pyrrole or tetrahydropyrrole, position 2, 4, or 5 of an oxazole, imidazole or thiazole, position 3, 4, or 5 of an isoxazole, pyrazole, or isothiazole, position 2 or 3 of an aziridine, position 2, 3, or 4 of an azetidine, position 2, 3, 4, 5, 6, 7, or 8 of a quinoline or position 1, 3, 4, 5, 6, 7, or 8 of an isoquinoline. Ring nitrogen atoms of the heterocycle or heteroaryl groups may be bonded with oxygen to form N-oxides.

[0035] By way of example and not limitation, nitrogen bonded heterocycles or heteroaryls are bonded at position 1 of an aziridine, azetidine, pyrrole, pyrrolidine, 2-pyrroline, 3-pyrroline, imidazole, imidazolidine, 2-imidazoline, 3-imidazoline, pyrazole, pyrazoline, 2-pyrazoline, 3-pyrazoline, piperidine, piperazine, indole, indoline, 1H-indazole, benzimidazole, position 2 of a isoindole, or isoindoline, position 4 of a morpholine, and position 9 of a carbazole, or (3-carboline.

[0036] The terms "treat" and "treatment" refer to both therapeutic treatment and prophylactic or preventative measures, wherein the object is to prevent or slow down (lessen) an undesired physiological change or disorder, such as the development or spread of cancer.
For purposes of this invention, beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, diminishment of extent of disease, stabilized (i.e., not worsening) state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or total), whether detectable or undetectable. "Treatment" can also mean prolonging survival as compared to expected survival if not receiving treatment. Those in need of treatment include those already with the condition or disorder as well as those prone to have the condition or disorder or those in which the condition or disorder is to be prevented.

[0037] The phrase "therapeutically effective amount" means an amount of a compound of the present invention that (i) treats or prevents the particular disease, condition, or disorder, (ii) attenuates, ameliorates, or eliminates one or more symptoms of the particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of the particular disease, condition, or disorder described herein. In the case of cancer, the therapeutically effective amount of the drug may reduce the number of cancer cells; reduce the tumor size; inhibit (i.e., slow to some extent and preferably stop) cancer cell infiltration into peripheral organs; inhibit (i.e., slow to some extent and preferably stop) tumor metastasis; inhibit, to some extent, tumor growth; and/or relieve to some extent one or more of the symptoms associated with the cancer. To the extent the drug may prevent growth and/or kill existing cancer cells, it may be cytostatic and/or cytotoxic. For cancer therapy, efficacy can be measured, for example, by assessing the time to disease progression (TTP) and/or determining the response rate (RR).

[0038] "Inflammatory disorder" as used herein can refer to any disease, disorder, or syndrome in which an excessive or unregulated inflammatory response leads to excessive inflammatory symptoms, host tissue damage, or loss of tissue function.
"Inflammatory disorder" also refers to a pathological state mediated by influx of leukocytes and/or neutrophil chemotaxis.

[0039] "Inflammation" as used herein refers to a localized, protective response elicited by injury or destruction of tissues, which serves to destroy, dilute, or wall off (sequester) both the injurious agent and the injured tissue. Inflammation is notably associated with influx of leukocytes and/or neutrophil chemotaxis. Inflammation can result from infection with pathogenic organisms and viruses and from noninfectious means such as trauma or reperfusion following myocardial infarction or stroke, immune response to foreign antigen, and autoimmune responses. Accordingly, inflammatory disorders amenable to treatment with Formula I compounds encompass disorders associated with reactions of the specific defense system as well as with reactions of the nonspecific defense system.

[0040] "Specific defense system" refers to the component of the immune system that reacts to the presence of specific antigens. Examples of inflammation resulting from a response of the specific defense system include the classical response to foreign antigens, autoimmune diseases, and delayed type hypersensitivity response mediated by T-cells.
Chronic inflammatory diseases, the rejection of solid transplanted tissue and organs, e.g., kidney and bone marrow transplants, and graft versus host disease (GVHD), are further examples of inflammatory reactions of the specific defense system.

[0041] The term "nonspecific defense system" as used herein refers to inflammatory disorders that are mediated by leukocytes that are incapable of immunological memory (e.g., granulocytes, and macrophages). Examples of inflammation that result, at least in part, from a reaction of the nonspecific defense system include inflammation associated with conditions such as adult (acute) respiratory distress syndrome (ARDS) or multiple organ injury syndromes; reperfusion injury; acute glomerulonephritis; reactive arthritis;
dermatoses with acute inflammatory components; acute purulent meningitis or other central nervous system inflammatory disorders such as stroke; thermal injury; inflammatory bowel disease;
granulocyte transfusion associated syndromes; and cytokine-induced toxicity.

[0042] "Autoimmune disease" as used herein refers to any group of disorders in which tissue injury is associated with Immoral or cell-mediated responses to the body's own constituents.

[0043] "Allergic disease" as used herein refers to any symptoms, tissue damage, or loss of tissue function resulting from allergy. "Arthritic disease" as used herein refers to any disease that is characterized by inflammatory lesions of the joints attributable to a variety of etiologies. "Dermatitis" as used herein refers to any of a large family of diseases of the skin that are characterized by inflammation of the skin attributable to a variety of etiologies.
"Transplant rejection" as used herein refers to any immune reaction directed against grafted tissue, such as organs or cells (e.g., bone marrow), characterized by a loss of function of the grafted and surrounding tissues, pain, swelling, leukocytosis, and thrombocytopenia. The therapeutic methods of the present invention include methods for the treatment of disorders associated with inflammatory cell activation.

[0044] "Inflammatory cell activation" refers to the induction by a stimulus (including, but not limited to, cytokines, antigens or auto-antibodies) of a proliferative cellular response, the production of soluble mediators (including but not limited to cytokines, oxygen radicals, enzymes, prostanoids, or vasoactive amines), or cell surface expression of new or increased numbers of mediators (including, but not limited to, major histocompatability antigens or cell adhesion molecules) in inflammatory cells (including but not limited to monocytes, macrophages, T lymphocytes, B lymphocytes, granulocytes (i.e., polymorphonuclear leukocytes such as neutrophils, basophils, and eosinophils), mast cells, dendritic cells, Langerhans cells, and endothelial cells). It will be appreciated by persons skilled in the art that the activation of one or a combination of these phenotypes in these cells can contribute to the initiation, perpetuation, or exacerbation of an inflammatory disorder.

[0045] The term "NSAID" is an acronym for "non-steroidal anti-inflammatory drug"

and is a therapeutic agent with analgesic, antipyretic (lowering an elevated body temperature and relieving pain without impairing consciousness) and, in higher doses, with anti-inflammatory effects (reducing inflammation). The term "non-steroidal" is used to distinguish these drugs from steroids, which (among a broad range of other effects) have a similar eicosanoid-depressing, anti-inflammatory action. As analgesics, NSAIDs are unusual in that they are non-narcotic. NSAIDs include aspirin, ibuprofen, and naproxen. NSAIDs are usually indicated for the treatment of acute or chronic conditions where pain and inflammation are present. NSAIDs are generally indicated for the symptomatic relief of the following conditions: rheumatoid arthritis, osteoarthritis, inflammatory arthropathies (e.g.
ankylosing spondylitis, psoriatic arthritis, Reiter's syndrome, acute gout, dysmenorrhoea, metastatic bone pain, headache and migraine, postoperative pain, mild-to-moderate pain due to inflammation and tissue injury, pyrexia, ileus, and renal colic. Most NSAIDs act as non-selective inhibitors of the enzyme cyclooxygenase, inhibiting both the cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) isoenzymes. Cyclooxygenase catalyzes the formation of prostaglandins and thromboxane from arachidonic acid (itself derived from the cellular phospholipid bilayer by phospholipase A2). Prostaglandins act (among other things) as messenger molecules in the process of inflammation. COX-2 inhibitors include celecoxib, etoricoxib, lumiracoxib, parecoxib, rofecoxib, rofecoxib, and valdecoxib.
[0001] The terms "cancer" refers to or describe the physiological condition in mammals that is typically characterized by unregulated cell growth. A "tumor"
comprises one or more cancerous cells. Examples of cancer include, but are not limited to, carcinoma, lymphoma, blastoma, sarcoma, and leukemia or lymphoid malignancies. More particular examples of such cancers include squamous cell cancer (e.g., epithelial squamous cell cancer), lung cancer including small- cell lung cancer, non-small cell lung cancer ("NSCLC"), adenocarcinoma of the lung and squamous carcinoma of the lung, cancer of the peritoneum, hepatocellular cancer, gastric or stomach cancer including gastrointestinal cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatoma, breast cancer, colon cancer, rectal cancer, colorectal cancer, endometrial or uterine carcinoma, salivary gland carcinoma, kidney or renal cancer, prostate cancer, vulval cancer, thyroid cancer, hepatic carcinoma, anal carcinoma, penile carcinoma, as well as head and neck cancer.
[0002] A "chemotherapeutic agent" is a chemical compound useful in the treatment of cancer, regardless of mechanism of action. Classes of chemotherapeutic agents include, but are not limited to: alkylating agents, antimetabolites, spindle poison plant alkaloids, cytotoxic/antitumor antibiotics, topoisomerase inhibitors, antibodies, photosensitizers, and kinase inhibitors. Chemotherapeutic agents include compounds used in "targeted therapy"
and conventional chemotherapy. Examples of chemotherapeutic agents include:
erlotinib (TARCEVA , Genentech/OSI Pharm.), docetaxel (TAXOTERE , Sanofi-Aventis), 5-FU
(fluorouracil, 5-fluorouracil, CAS No. 51-21-8), gemcitabine (GEMZAR , Lilly), PD-0325901 (CAS No. 391210-10-9, Pfizer), cisplatin (cis-diamine, dichloroplatinum(II), CAS
No. 15663-27-1), carboplatin (CAS No. 41575-94-4), paclitaxel (TAXOL , Bristol-Myers Squibb Oncology, Princeton, N.J.), trastuzumab (HERCEPTIN , Genentech), temozolomide (4-methyl-5-oxo- 2,3,4,6,8-pentazabicyclo [4.3.0] nona-2,7,9-triene- 9-carboxamide, CAS
No. 85622-93-1, TEMODAR , TEMODAL , Schering Plough), tamoxifen ((Z)-2-[4-(l,2-diphenylbut-l-enyl)phenoxy]-N,N-dimethylethanamine, NOLVADEX , ISTUBAL , VALODEX ), and doxorubicin (ADRIAMYCIN ), Akti-1/2, HPPD, and rapamycin.
[0003] More examples of chemotherapeutic agents include: oxaliplatin (ELOXATIN
, Sanofi), bortezomib (VELCADE , Millennium Pharm.), sutent (SUNITINIB , SU11248, Pfizer), letrozole (FEMARA , Novartis), imatinib mesylate (GLEEVEC , Novartis), XL-518 (Mek inhibitor, Exelixis, WO 2007/044515), ARRY-886 (Mek inhibitor, AZD6244, Array BioPharma, Astra Zeneca), SF-1126 (P13K inhibitor, Semafore Pharmaceuticals), BEZ-235 (P13K inhibitor, Novartis), XL-147 (P13K inhibitor, Exelixis), (Novartis), fulvestrant (FASLODEX , AstraZeneca), leucovorin (folinic acid), rapamycin (sirolimus, RAPAMUNE , Wyeth), lapatinib (TYKERB , GSK572016, Glaxo Smith Kline), lonafamib (SARASARTM, SCH 66336, Schering Plough), sorafenib (NEXAVAR
, BAY43-9006, Bayer Labs), gefitinib (IRESSA , AstraZeneca), irinotecan (CAMPTOSAR , CPT-11, Pfizer), tipifarnib (ZARNESTRATM, Johnson & Johnson), ABRAXANETM (Cremophor-free), albumin-engineered nanoparticle formulations of paclitaxel (American Pharmaceutical Partners, Schaumberg, I1), vandetanib (rINN, ZD6474, ZACTIMA , AstraZeneca), chloranmbucil, AG1478, AG1571 (SU 5271; Sugen), temsirolimus (TORISEL , Wyeth), pazopanib (G1axoSmithKline), canfosfamide (TELCYTA , Telik), thiotepa and cyclosphosphamide (CYTOXAN , NEOSAR ); alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelamines including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide and trimethylomelamine; acetogenins (especially bullatacin and bullatacinone);
a camptothecin (including the synthetic analog topotecan); bryostatin;
callystatin; CC-1065 (including its adozelesin, carzelesin and bizelesin synthetic analogs);
cryptophycins (particularly cryptophycin 1 and cryptophycin 8); dolastatin; duocarmycin (including the synthetic analogs, KW-2189 and CB1-TM1); eleutherobin; pancratistatin; a sarcodictyin;
spongistatin; nitrogen mustards such as chlorambucil, chlornaphazine, chlorophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard;
nitrosoureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimnustine; antibiotics such as the enediyne antibiotics (e.g., calicheamicin, calicheamicin gamma 11, calicheamicin omegall (Angew Chem. Intl. Ed. Engl. (1994) 33:183-186);
dynemicin, dynemicin A; bisphosphonates, such as clodronate; an esperamicin;
as well as neocarzinostatin chromophore and related chromoprotein enediyne antibiotic chromophores), aclacinomysins, actinomycin, authramycin, azaserine, bleomycins, cactinomycin, carabicin, carminomycin, carzinophilin, chromomycinis, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, morpholino-doxorubicin, cyanomorpholino-doxorubicin, pyrrolino-doxorubicin and deoxydoxorubicin), epirubicin, esorubicin, idarubicin, nemorubicin, marcellomycin, mitomycins such as mitomycin C, mycophenolic acid, nogalamycin, olivomycins, peplomycin, porfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; anti-metabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs such as denopterin, methotrexate, pteropterin, trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine;
androgens such as calusterone, dromostanolone propionate, epitiostanol, mepitiostane, testolactone; anti-adrenals such as aminoglutethimide, mitotane, trilostane;
folic acid replenisher such as frolinic acid; aceglatone; aldophosphamide glycoside;
aminolevulinic acid; eniluracil; amsacrine; bestrabucil; bisantrene; edatraxate; defofamine;
demecolcine;
diaziquone; elfornithine; elliptinium acetate; an epothilone; etoglucid;
gallium nitrate;
hydroxyurea; lentinan; lonidainine; maytansinoids such as maytansine and ansamitocins;
mitoguazone; mitoxantrone; mopidanmol; nitraerine; pentostatin; phenamet;
pirarubicin;
losoxantrone; podophyllinic acid; 2-ethylhydrazide; procarbazine; PSK
polysaccharide complex (JHS Natural Products, Eugene, OR); razoxane; rhizoxin; sizofiran;
spirogermanium; tenuazonic acid; triaziquone; 2,2',2"-trichlorotriethylamine;
trichothecenes (especially T-2 toxin, verracurin A, roridin A and anguidine); urethan;
vindesine;
dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine;
arabinoside ("Ara-C"); cyclophosphamide; thiotepa; 6-thioguanine; mercaptopurine;
methotrexate;

platinum analogs such as cisplatin and carboplatin; vinblastine; etoposide (VP-16);
ifosfamide; mitoxantrone; vincristine; vinorelbine (NAVELBINE ); novantrone;
teniposide;
edatrexate; daunomycin; aminopterin; capecitabine (XELODA , Roche);
ibandronate; CPT-11; topoisomerase inhibitor RFS 2000; difluoromethylomithine (DMFO); retinoids such as retinoic acid; and pharmaceutically acceptable salts, acids and derivatives of any of the above.
[0004] Also included in the definition of "chemotherapeutic agent" are: (i) anti-hormonal agents that act to regulate or inhibit hormone action on tumors such as anti-estrogens and selective estrogen receptor modulators (SERMs), including, for example, tamoxifen (including NOLVADEX ; tamoxifen citrate), raloxifene, droloxifene, 4-hydroxytamoxifen, trioxifene, keoxifene, LY 117018, onapristone, and FARESTON
(toremifine citrate); (ii) aromatase inhibitors that inhibit the enzyme aromatase, which regulates estrogen production in the adrenal glands, such as, for example, 4(5)-imidazoles, aminoglutethimide, MEGASE (megestrol acetate), AROMASIN (exemestane;
Pfizer), formestanie, fadrozole, RIVISOR (vorozole), FEMARA (letrozole; Novartis), and ARIMIDEX (anastrozole; AstraZeneca); (iii) anti-androgens such as flutamide, nilutamide, bicalutamide, leuprolide, and goserelin; as well as troxacitabine (a 1,3-dioxolane nucleoside cytosine analog); (iv) protein kinase inhibitors such as MEK inhibitors (WO
2007/044515);
(v) lipid kinase inhibitors; (vi) antisense oligonucleotides, particularly those which inhibit expression of genes in signaling pathways implicated in aberrant cell proliferation, for example, PKC-alpha, Raf and H-Ras, such as oblimersen (GENASENSE , Genta Inc.); (vii) ribozymes such as VEGF expression inhibitors (e.g., ANGIOZYME ) and HER2 expression inhibitors; (viii) vaccines such as gene therapy vaccines, for example, ALLOVECTIN , LEUVECTIN , and VAXID ; PROLEUKIN rIL-2; topoisomerase 1 inhibitors such as LURTOTECAN ; ABARELIX rmRH; (ix) anti-angiogenic agents such as bevacizumab (AVASTIN , Genentech); and pharmaceutically acceptable salts, acids and derivatives of any of the above.
[0005] Also included in the definition of "chemotherapeutic agent" are therapeutic antibodies such as alemtuzumab (Campath), bevacizumab (AVASTIN , Genentech);
cetuximab (ERBITUX , Imclone); panitumumab (VECTIBIX , Amgen), rituximab (RITUXAN , Genentech/Biogen Idec), pertuzumab (OMNITARGTM, 2C4, Genentech), trastuzumab (HERCEPTIN , Genentech), tositumomab (Bexxar, Corixia), and the antibody drug conjugate, gemtuzumab ozogamicin (MYLOTARG , Wyeth).
[0006] Humanized monoclonal antibodies with therapeutic potential as chemotherapeutic agents in combination with the P13K inhibitors of the invention include:
alemtuzumab, apolizumab, aselizumab, atlizumab, bapineuzumab, bevacizumab, bivatuzumab mertansine, cantuzumab mertansine, cedelizumab, certolizumab pegol, cidfusituzumab, cidtuzumab, daclizumab, eculizumab, efalizumab, epratuzumab, erlizumab, felvizumab, fontolizumab, gemtuzumab ozogamicin, inotuzumab ozogamicin, ipilimumab, labetuzumab, lintuzumab, matuzumab, mepolizumab, motavizumab, motovizumab, natalizumab, nimotuzumab, nolovizumab, numavizumab, ocrelizumab, omalizumab, palivizumab, pascolizumab, pecfusituzumab, pectuzumab, pertuzumab, pexelizumab, ralivizumab, ranibizumab, reslivizumab, reslizumab, resyvizumab, rovelizumab, ruplizumab, sibrotuzumab, siplizumab, sontuzumab, tacatuzumab tetraxetan, tadocizumab, talizumab, tefibazumab, tocilizumab, toralizumab, trastuzumab, tucotuzumab celmoleukin, tucusituzumab, umavizumab, urtoxazumab, and visilizumab.
[0007] A "metabolite" is a product produced through metabolism in the body of a specified compound or salt thereof. Metabolites of a compound may be identified using routine techniques known in the art and their activities determined using tests such as those described herein. Such products may result for example from the oxidation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, enzymatic cleavage, and the like, of the administered compound. Accordingly, the invention includes metabolites of compounds of the invention, including compounds produced by a process comprising contacting a compound of this invention with a mammal for a period of time sufficient to yield a metabolic product thereof.
[0008] The term "package insert" is used to refer to instructions customarily included in commercial packages of therapeutic products, that contain information about the indications, usage, dosage, administration, contraindications and/or warnings concerning the use of such therapeutic products.
[0009] The term "chiral" refers to molecules which have the property of non-superimposability of the mirror image partner, while the term "achiral" refers to molecules which are superimposable on their mirror image partner.
[0010] The term "stereoisomers" refers to compounds which have identical chemical constitution, but differ with regard to the arrangement of the atoms or groups in space.
Stereoisomers include enantiomers and diastereomers.
[0011] "Diastereomer" refers to a stereoisomer with two or more centers of chirality and whose molecules are not mirror images of one another. Diastereomers have different physical properties, e.g. melting points, boiling points, spectral properties, and reactivities.

Mixtures of diastereomers may separate under high resolution analytical procedures such as electrophoresis and chromatography. Diastereomers include geometric isomers, cis/trans and E/Z isomers, and atropisomers.
[0012] "Enantiomers" refer to two stereoisomers of a compound which are non-superimposable mirror images of one another.
[0013] Stereochemical definitions and conventions used herein generally follow S. P.
Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994. The compounds of the invention may contain asymmetric or chiral centers, and therefore exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the compounds of the invention, including but not limited to, diastereomers, enantiomers and atropisomers, as well as mixtures thereof such as racemic mixtures, form part of the present invention. Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane-polarized light.
In describing an optically active compound, the prefixes D and L, or R and S, are used to denote the absolute configuration of the molecule about its chiral center(s).
The prefixes d and 1 or (+) and (-) are employed to designate the sign of rotation of plane-polarized light by the compound, with (-) or 1 meaning that the compound is levorotatory. A
compound prefixed with (+) or d is dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of one another. A specific stereoisomer may also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture. A 50:50 mixture of enantiomers is referred to as a racemic mixture or a racemate, which may occur where there has been no stereoselection or stereospecificity in a chemical reaction or process. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two enantiomeric species, devoid of optical activity.
[0014] The term "tautomer" or "tautomeric form" refers to structural isomers of different energies which are interconvertible via a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) include interconversions via migration of a proton, such as keto-enol and imine-enamine isomerizations. Valence tautomers include interconversions by reorganization of some of the bonding electrons.
[0015] The phrase "pharmaceutically acceptable salt" as used herein, refers to pharmaceutically acceptable organic or inorganic salts of a compound of the invention.
Exemplary salts include, but are not limited, to sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate "mesylate", ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate (i.e., 1,1'-methylene-bis(2-hydroxy-3-naphthoate)) salts. A
pharmaceutically acceptable salt may involve the inclusion of another molecule such as an acetate ion, a succinate ion or other counter ion. The counter ion may be any organic or inorganic moiety that stabilizes the charge on the parent compound. Furthermore, a pharmaceutically acceptable salt may have more than one charged atom in its structure.
Instances where multiple charged atoms are part of the pharmaceutically acceptable salt can have multiple counter ions. Hence, a pharmaceutically acceptable salt can have one or more charged atoms and/or one or more counter ion.
[0016] If the compound of the invention is a base, the desired pharmaceutically acceptable salt may be prepared by any suitable method available in the art, for example, treatment of the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, methanesulfonic acid, phosphoric acid and the like, or with an organic acid, such as acetic acid, trifluoroacetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, a pyranosidyl acid, such as glucuronic acid or galacturonic acid, an alpha hydroxy acid, such as citric acid or tartaric acid, an amino acid, such as aspartic acid or glutamic acid, an aromatic acid, such as benzoic acid or cinnamic acid, a sulfonic acid, such as p-toluenesulfonic acid or ethanesulfonic acid, or the like.
[0017] If the compound of the invention is an acid, the desired pharmaceutically acceptable salt may be prepared by any suitable method, for example, treatment of the free acid with an inorganic or organic base, such as an amine (primary, secondary or tertiary), an alkali metal hydroxide or alkaline earth metal hydroxide, or the like.
Illustrative examples of suitable salts include, but are not limited to, organic salts derived from amino acids, such as glycine and arginine, ammonia, primary, secondary, and tertiary amines, and cyclic amines, such as piperidine, morpholine and piperazine, and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium.
[0018] The phrase "pharmaceutically acceptable" indicates that the substance or composition must be compatible chemically and/or toxicologically, with the other ingredients comprising a formulation, and/or the mammal being treated therewith.
[0019] A "solvate" refers to an association or complex of one or more solvent molecules and a compound of the invention. Examples of solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, DMSO, ethylacetate, acetic acid, and ethanolamine.
[0020] The terms "compound of this invention," and "compounds of the present invention" and "compounds of Formula I" include compounds of Formulas I and stereoisomers, tautomers, solvates, metabolites, and pharmaceutically acceptable salts and prodrugs thereof.
[0021] Any formula or structure given herein, including Formula I compounds, is also intended to represent hydrates, solvates, and polymorphs of such compounds, and mixtures thereof.
[0022] Any formula or structure given herein, including Formula I compounds, is also intended to represent isotopically labeled forms of the compounds as well as unlabeled forms.
Isotopically labeled compounds have structures depicted by the formulas given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, and chlorine, such as, but not limited to 2H (deuterium, D), 3H (tritium), 11 C, 13C, 14C, 15N, 18F, 31P, 32P, 35S, 36C1, and 1251. Various isotopically labeled compounds of the present invention, for example those into which radioactive isotopes such as 3H, 13C, and 14C are incorporated.
Such isotopically labelled compounds may be useful in metabolic studies, reaction kinetic studies, detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays, or in radioactive treatment of patients. Deuterium labelled or substituted therapeutic compounds of the invention may have improved DMPK (drug metabolism and pharmacokinetics) properties, relating to distribution, metabolism, and excretion (ADME).
Substitution with heavier isotopes such as deuterium may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements. An 18F labeled compound may be useful for PET
or SPECT
studies. Isotopically labeled compounds of this invention and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and preparations described below by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent. Further, substitution with heavier isotopes, particularly deuterium (i.e., 2H or D) may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements or an improvement in therapeutic index. It is understood that deuterium in this context is regarded as a substituent in the compound of the formula (I). The concentration of such a heavier isotope, specifically deuterium, may be defined by an isotopic enrichment factor. In the compounds of this invention any atom not specifically designated as a particular isotope is meant to represent any stable isotope of that atom. Unless otherwise stated, when a position is designated specifically as "H" or "hydrogen", the position is understood to have hydrogen at its natural abundance isotopic composition. Accordingly, in the compounds of this invention any atom specifically designated as a deuterium (D) is meant to represent deuterium.

[0023] FORMULA I COMPOUNDS OF THE INVENTION
[0024] Formula I compounds include compounds selected from Formulas la and Ib:
mor mor X1 --- N X2 I~N
R1 `X2 I R1~X1 I 1,o,~ N R 3 N R 3 la lb [0025] and stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, [0026] wherein (i) X1 is N and X2 is S, (ii) X1 is CR7 and X2 is S, (iii) X1 is N and X2 is NR2, or (iv) X1 is CR7 and X2 is 0;

[0027] R1 is selected from [0028] C1-C12 alkyl, [0029] C2-Cg alkenyl, [0030] C2-Cg alkynyl, [0031] C6-C20 aryl, [0032] C2-C20 heterocyclyl, [0033] C3-C12 carbocyclyl, [0034] C1-C20 heteroaryl, [0035] -(C1-C12 alkylene)-(C3-C12 carbocyclyl), [0036] -(C1-C12 alkylene)-(C2-C20 heterocyclyl), [0037] -(C1-C12 alkylene)-(C2-C20 heterocyclyl)-(C2-C20 heterocyclyl), [0038] -(C1-C12 alkylene)-(C2-C20 heterocyclyl)-(C3-C12 carbocyclyl), [0039] -(C1-C12 alkylene)-(C2-C20 heterocyclyl)-C(=O)-(C2-C20 heterocyclyl), [0040] -(C1-C12 alkylene)-(C1-C20 heteroaryl), [0041] -(CI-C12 alkylene)-(C2-C20 heterocyclyl)-(Ci-Ci2 alkyl), [0042] -(CI-C12 alkylene)-(C6-C20 aryl)-(Ci-Ci2 alkyl), [0043] -(Ci-Cu2 alkylene)-(Ci-C20 heteroaryl)-(Ci-Ci2 alkyl), [0044] -(CI-Ci2 alkylene)-C(=O)-(C2-C20 heterocyclyl), [0045] -(CI-Ci2 alkylene)-NHR2', [0046] -(CI-Ci2 alkylene)-NR 2'-(Ci-Ci2 alkyl), [0047] -(CI-Ci2 alkylene)-NR 2'-(C3-Ci2 carbocyclyl), [0048] -(CI-Ci2 alkylene)-NR2'-(C2-C20 heterocyclyl), [0049] -(CI-C12 alkylene)-NR 2'-(Ci-C20 heteroaryl), [0050] -(CI-C12 alkylene)-NR2'-(C6-C20 aryl), [0051] -(CI-Ci2 alkylene)-NR 2'-(Ci-Ci2 alkylene)-(C3-Ci2 carbocyclyl), [0052] -(CI-Ci2 alkylene)-NR 2'-(Ci-Ci2 alkylene)-(Ci-C20 heteroaryl), [0053] -(CI-Ci2 alkylene)-NR 2'-(Ci-Ci2 alkylene)-(Ci-C20 heterocyclyl), [0054] -(CI-Ci2 alkylene)-NR 2'-(Ci-Ci2 alkylene)-(C6-C20 aryl), [0055] -(CI-Ci2 alkylene)-NR 2'-(Ci-Ci2 alkylene)-NHC(=O)-(Ci-C20 heteroaryl), [0056] -(CI-Ci2 alkylene)-(C2-C20 heterocyclyl)-N(Ci-Ci2 alkyl)R2', [0057] -(CI-C12 alkylene)-(C2-C20 heterocyclyl)-(Ci-Ci2 alkyl)-N(Ci-Ci2 alkyl)R2', [0058] -(C2-C12 alkenylene)-(C2-C20 heterocyclyl), [0059] -(Ci-C20 heteroaryl)-(C2-C20 heterocyclyl), [0060] -(CI-C20 heteroaryl)-(C3-Ci2 carbocyclyl), [0061] -C(=O)-(C2-C20 heterocyclyl), [0062] -C(=O)-(CI-C20 heteroaryl), [0063] -C(=O)-(C2-C20 heterocyclyl)-(C2-C20 heterocyclyl), [0064] -C(=O)-(C2-C20 heterocyclyl)-(Ci-C20 heteroaryl), [0065] -C(=O)-(Ci-Ci2 alkyl), [0066] -C(=O)-NR2'-(CI-C12 alkyl), and [0067] -CR4=CR5R6 where R4 is selected from H, F, Cl, Br, I, and CI-C12 alkyl, and R5 and R6 form C2-C20 heterocyclyl, CI-C20 heteroaryl, or C3-Ci2 carbocyclyl, [0068] where alkyl, alkenyl, alkynyl, alkylene, carbocyclyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more groups independently selected from F, Cl, Br, I, -CH3, -CH2CH3, -CH2CH(CH3)2, -CH2NH2, -CH2N(CH3)2, -CH2CH2NH2, -CH2CH2N(CH3)2, -CH2OH, -CH2OCH3, -CH2CH2OH, -C(CH3)2OH, -CH2C(CH3)2OH, -CH(OH)CH(CH3)2, -C(CH3)2CH2OH, -CH2CH2SO2CH3, -CN, -CF3, -CO2H, -CHO, -COCH3, -CO2CH3, -CO2C(CH3)3, -COCH2OH, -COC(OH)(CH3)2, -COCH(OH)CH3, -CONH2, -CONHCH3, -CON(CH3)2, -CH2CONH2, -CH2CON(CH3)2, -C(CH3)2CONH2, -NO2, -NH2, -NHCH3, -N(CH3)2, -NHCOCH3, -N(CH3)COCH3, -NHS(O)2CH3, -N(CH3)C(CH3)2CONH2, -N(CH3)CH2CH2S(O)2CH3, =O, -OH, -OCH3, -S(O)2N(CH3)2, -SCH3, -CH2OCH3, -S(O)2CH3, -C(O)-cyclopropyl, cyclopropyl, cyclobutyl, oxetanyl, and morpholino;

[0069] R2 and R2' are independently selected from H, Ci-C12 alkyl, C2-Cg alkenyl, C2-Cg alkynyl, -(CI-C12 alkylene)-(C3-CI2 carbocyclyl), -(CI-CIZ alkylene)-(C2-heterocyclyl), -(CI-C12 alkylene)-C(=O)-(C2-C20 heterocyclyl), -(CI-CI2 alkylene)-(C6-C20 aryl), and -(C1-C12 alkylene)-(C1-C20 heteroaryl), where alkyl, alkenyl, alkynyl, alkylene, carbocyclyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more groups independently selected from F, Cl, Br, I, -CH3, -CH2OH, -CN, -CF3, -CO2H, -COCH3, -CO2CH3, -CONH2, -CONHCH3, -CON(CH3)2, -NO2, -NH2, -NHCH3, -NHCOCH3, -NHS(O)2CH3, -OH, -OCH3, -S(O)2N(CH3)2, -SCH3, -CH2OCH3, and -S(O)2CH3;

[0070] R3 is a bicyclic heteroaryl group selected from:

N~ N / N / c 5N \ I ? N \ I AN \ N \ N ON N

N N=N O/_NH N-NH O
N

N N
N~/ $~ N / Ik N 1\ N \ ' // - ' HN NH
N N O

N N
NH/NH / NnN/N& N N

N N N

i INS I / S~ I
N

I / 5S' / NHO ~\ I / HN
1 I \ N
N N I / ly NH
O

s~ 1 SSS \ 1 I / NH
NH N O NON N
H

~N
N N~
N IN'~!1 N SkN c I
N N N N
N N~N /N N"N
11 5N N 5ON IN IN"
N N ~N N

[0071] where the wavy line indicates the site of attachment;

[0072] optionally substituted with one or more groups independently selected from C1-C12 alkyl, C2-Cg alkenyl, C2-Cg alkynyl, C3-C12 carbocyclyl, C2-C20 heterocyclyl, C6-C20 aryl, C1-C20 heteroaryl, -(C1-C12 alkylene)-(C2-C20 heterocyclyl), -NH-(CI-alkylene)-(C2-C20 heterocyclyl), -N(C1-C12 alkyl)-(C1-C12 alkylene)-(C2-C20 heterocyclyl), -NH-(C2-C20 heterocyclyl), -O-(C2-C20 heterocyclyl), -NH-(C3-carbocyclyl), -O-(C3-C12 carbocyclyl), F, Cl, Br, I, -CN, -CO2H, -CONH2, -CONH(C1-C12 alkyl), -CON(C1-C12 alkyl)2, -CO(C1-C12 alkyl), -NO2, -NH2, -NH(C1-C12 alkyl), -N(C1-C12 alkyl)2, -NHCO(C1-C12 alkyl), -NHS(O)2(C1-C12 alkyl), -N(C1-C12 alkyl)S(O)2(C1-C12 alkyl), -OH, -O(C1-C12 alkyl), -NHC(=O)NH(C1-C12 alkyl), -SH, -S(C1-C12 alkyl), -S(O)(C1-C12 alkyl), -S(O)2(C1-C12 alkyl), -S(O)2NH2, -S(O)2NH(C1-C12 alkyl), and -S(O)2N(C1-C12 alkyl)2, where alkyl, alkenyl, alkynyl, alkylene, carbocyclyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more groups independently selected from F, Cl, Br, I, --CN, -CF3, -CO2H, -COCH3, -CO2CH3, -CONH2, -CONHCH3, -CON(CH3)2, -NO2, -NH2, -NHCH3, -NHCOCH3, -NHS(O)2CH3, =0, -OH, -OCH3, -S(O)2N(CH3)2, -SH, -SCH3, -CH2OCH3, and -S(O)2CH3;

[0073] R7 is selected from H, C1-C12 alkyl, C2-Cg alkenyl, C2-Cg alkynyl, -(C1-alkylene)-(C3-C12 carbocyclyl), -(C1-C12 alkylene)-(C2-C20 heterocyclyl), -(C1-alkylene)-C(=O)-(C2-C20 heterocyclyl), -(C1-C12 alkylene)-(C6-C20 aryl), and -(C1-C12 alkylene)-(C1-C20 heteroaryl), where alkyl, alkenyl, alkynyl, alkylene, carbocyclyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more groups independently selected from F, Cl, Br, I, -CH3, -CH2OH, -CN, -CF3, -CO2H, -COCH3, -CO2CH3, -CONH2, -CONHCH3, -CON(CH3)2, -NO2, -NH2, -NHCH3, -NHCOCH3, -NHS(O)2CH3, =0, -OH, -OCH3, -S(O)2N(CH3)2, -SCH3, -CH2OCH3, and -S(O)2CH3;

[0074] mor is a morpholine group or a bicyclic structure selected from:

.nnnr nnn P dVW ,n W

[0075] optionally substituted with one or more groups selected from F, Cl, Br, I, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -C(CH3)3, -CH2OCH3, -CHF2, -CN, -CF3, -CH2OH, -CH2OCH3, -CH2CH2OH, -CH2C(CH3)20H, -CH(CH3)OH, -CH(CH2CH3)OH, -CH2CH(OH)CH3, -C(CH3)20H, -C(CH3)20CH3, -CH(CH3)F, -C(CH3)F2, -CH(CH2CH3)F, -C(CH2CH3)2F, -CO2H, -CONH2, -CON(CH2CH3)2, -COCH3, -CON(CH3)2, -NO2, -NH2, -NHCH3, -N(CH3)2, -NHCH2CH3, -NHCH(CH3)2, -NHCH2CH2OH, -NHCH2CH2OCH3, -NHCOCH3, -NHCOCH2CH3, -NHCOCH2OH, -NHS(O)2CH3, -N(CH3)S(O)2CH3, =0, -OH, -OCH3, -OCH2CH3, -OCH(CH3)2, -SH, -NHC(=O)NHCH3, -NHC(=O)NHCH2CH3, -S(O)CH3, -S(O)CH2CH3, -S(O)2CH3, -S(O)2NH25 -S(O)2NHCH3, -S(O)2N(CH3)25 -CH2S(O)2CH3;

[0076] and wherein the IC50 binding activity to pl 10 delta is ten or more times lower than the binding activity to p 110 alpha;

[0077] with the proviso that a Formula Ib compound wherein (ii) X1 is CR7 and X2 is S, RI is -(C1-C12 alkylene)-(C2-C20 heterocyclyl), R3 is optionally substituted benzo[d]imidazol-1-yl, and R' is H, excludes the C2-C20 heterocyclyl of R1 substituted with -S(O)2CH3.

[0078] Exemplary Formula I compounds include where mor is an unsubstituted morpholine group, having the structures Ic and Id:

(0) (0) N N

/ N / N
\ N R ` N R
R~ 'X2 I ~ 3 R~ 'X1 3 Ic Id [0079] Exemplary Formula I compounds include thiazolopyrimidines where (i) X1 is N and X2 is S :

(0) (0) N N
N D R1~ /~N R1S \ N i S Ni \R3 N N~ \R3 [0080] Exemplary Formula I compounds include thienopyrimidines where (ii) X1 is CR7 and X2 is S:

C:) RN

N N R1 R1 I ii [0081] Exemplary Formula I compounds include purines where (iii) X1 is N and X2 is NR2:

(0) (0) 2 EN) N R2 \
N
R1 _< I N R1 N

N R3 N N olk R3 [0082] Exemplary Formula I compounds include furanopyrimidines where (iv) X1 is CR7 and X2 is 0:

C0) C0) R7 N N iv \ N
N O

O N R3 N l \ R3 [0083] In additional exemplary embodiments, mor is selected from the structures:
O O ,~~\ 'C )'A C c r N

H C INrc02cH3 C ! ~ ~nnnr O CCN N
VV
`nnn W% w ~nnnr [0084] where the wavy line indicates the attachment to the 4-position of the pyrimidine ring.

[0085] Exemplary embodiments of R1 include the groups:

N N N /--- c N

O O/'O
N N N
o N--N\ F 0 ~V\ HO
O OHO

N N N
>
N ^Y/ .N

-N

N/-- N N N N
C

N ~N Q NH HO
_/) O N

N N

N
OH
O O

N N

-N N /-N
S'O OJ O'sj O \ O

v N N v H2N v v N vN O=D
S O HNJ
OD

N N N N
HO
v v N_ N N N
\
O v HO '10 v HO

PN pN N v N 2HO(j HO

WO 2010/138589 PCT/US2010/036199 f-\ N

\~N~ O NN -N

O~
O N~ N N
HO \-J

O~
HOHO/, /~N HN

HO-O( N-\_ HO N~ I/
0, F
\N FCN

/~ HO ~\
O l N~ N O N\-,NH
p 0, OS-N
HN N
HO

- H2N"-- O

O N
HN HZN"--i OH
NJ1 (IN' OH ~ii CO OH OH
O

O-"N
N O N

O
OH
N~ \
p /O H2N N 0 NJ~-t /, O~

D N *0~-N\>-O
O

HN

O~ 5- O~- O
N N N N
NJ
O=~ O~--~
0 T O N O~ O

NO ON N N
N~ O, N N NJ
O HO
O
N
N
H 0~-N
N~ N
N N~
~N
N
O O >,,OH

H

-() NJ CN
O N N H2N p,' o OH

/ N O H
N- N
~
N~

O HO O O
N N
ON

-p HO
HO
~
b OH
HO/ O N ~

O

F O
F F
N
F CN
HO N>r-- ~ F N ~-- O O
O p O

O O
N
N N ON
N

F FF I
NN C/
N

O_ O O
N HO N

N ~N O
() 0 /
O'O N
0 N- O~S~
"-N -N p O
o o 0 N O
/ HO--_ / N -j /
N N 0--/ \ N
p p p o [0086] where the wavy line indicates the site of attachment to the Formula I
structure.

[0087] Exemplary embodiments of R1 also include the groups:

NH NH
NH NH NH --~N
O \
O
O~ O
N

N N~
N
NH
H H H
N` ` H
N N N-N
off a OJ \ / ~~

N N N
% NH H H % H
cNH
cN N N
SN O~ S J o N N N
N H IIH O %H
N H \ N N ~ N
/N N N-% -N N N
O NH HO HO OH OH

HO N N

qOH
HU HO HO OH

N
N N N
N
O HN HN

N N
N N
N~
~
N
O N
N' N
O

CN N
N

N ~~ ~N O F N
F -/~= 7~ 7~
OH -N\ HO
HO

N
N N N NJ C-) N N

~-o NH2 O
O
O

N N
N N

C

HO OH O N-N/-- /-~
~N N N F N
N HO F
O
/N HO \ OH

N/*-- F N
(1 N
HO N F
HO N p HO N
,r--~ V
HO

N N /I- N
vv NJ
N ~ N) N /
v HO" `CF3 HO

N N N N N
O O O
O NH / O

N ~\ N N
Y v v p O -N N N
N
N >(j / O v HO

N N N N N
v -N HO HO HO

O
SO2Me N N N N
HO F F
N- N- N- N-v v >~ 0 p O O O H2N

v N N N HO v v pp N- rN N N ~N\
O v HO-~ J
HO y N N
pP
N N
HO

[0088] Exemplary embodiments include the R3 bicyclic heteroaryl substituted with one or more groups independently selected from F, Cl, Br, I, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -C(CH3)3, -CH2OCH3, -CHF2, -CH2CN, -CN, -CF3, -CH2OH, -CH2OCH3, -CH2CH2OH, -CH2CH2CH2OH, -CH2C(CH3)20H, -CH(CH3)OH, -CH(CH2CH3)OH, -CH2CH(OH)CH3, -CH2CH(OCH3)CH3, -C(CH3)20H, -CH(CH3)OCH3, -C(CH3)20CH3, -CH(CH3)F, -C(CH3)F2, -CH(CH2CH3)F, -C(CH2CH3)2F, -C(CH2CH3)F2, -CO2H, -CONH2, -CON(CH2CH3)2, -COCH3, -CON(CH3)2, -NO2, -NH2, -NHCH3, -N(CH3)2, -NHCH2CH3, -NHCH(CH3)2, -NHCH2CH2OH, -NHCH2CH2OCH3, -NHCOCH3, -NHCOCH2CH3, -NHCOCH2OH, -NHS(O)2CH3, -N(CH3)S(O)2CH3, -OH, -OCH3, -OCH2CH3, -OCH(CH3)2, -SH, -NHC(=O)NHCH3, -NHC(=O)NHCH2CH3, -S(O)CH3, -S(O)CH2CH3, -S(O)2CH3, -S(O)2NH2, -S(O)2NHCH3, -S(O)2N(CH3)2, -CH2S(O)2CH3, and a group selected from F F F
Fa F Fd_ -_q-F 'NH ~O $r F
~ ~IO
b O
NH
N
IJ

N I S N
OH Ny O
N --NO, N (D

N
N

[0089] Exemplary embodiments include where the R3 bicyclic heteroaryl is a purine having the structure:

/(R9),, N
}=N

[0090] where R8 is selected from H, F, Cl, Br, I, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -C(CH3)3, -CH2OCH3, -CHF2, -CH2CN, -CN, -CF3, -CH2OH, -CH2OCH3, -CH2CH2OH, -CH2C(CH3)2OH, -CH(CH3)OH, -CH(CH2CH3)OH, -CH2CH(OH)CH3, -CH2CH(OCH3)CH3, -C(CH3)20H, -C(CH3)20CH3, -CH(CH3)F, -C(CH3)F2, -CH(CH2CH3)F, -C(CH2CH3)2F, -CO2H, -CONH2, -CON(CH2CH3)2, -COCH3, -CON(CH3)2, -NO2, -NH2, -NHCH3, -N(CH3)2, -NHCH2CH3, -NHCH(CH3)2, -NHCH2CH2OH, -NHCH2CH2OCH3, -NHCOCH3, -NHCOCH2CH3, -NHCOCH2OH, -NHS(O)2CH3, -N(CH3)S(O)2CH3, -OH, -OCH3, -OCH2CH3, -OCH(CH3)2, -SH, -NHC(=O)NHCH3, -NHC(=O)NHCH2CH3, -S(O)CH3, -S(O)CH2CH3, -S(O)2CH3, -S(O)2NH2, -S(O)2NHCH3, -S(O)2N(CH3)2, -CH2S(O)2CH3, and a group selected from s F F F
Fa F F
F
-_-F 'NH 0 $~
b I~N
IJ
O

Ny ~
O
/NO

N
/ N V

[0091] R9 is independently selected from F, Cl, Br, I, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH(CH3)2, -CH2OH, -CH2CH2OH, -CN, -CF3, -CO2H, -COCH3, -CO2CH3, -CONH2, -CONHCH3, -CON(CH3)2, -NO2, -NH2, -NHCH3, -NHCOCH3, -NHS(O)2CH3, -OH, -OCH3, -S(O)2N(CH3)2, -SCH3, -CH2OCH3, and -S(O)2CH3; and [0092] n is 0, 1, 2, 3, or 4.

[0093] Exemplary Formula I compounds include the structures:

O O

N\ N
R1-/N I / R1 N I ~X _ N NXN S N N

O O
N N
R1 \ I N R1 \
N "J' N N

[0094]

[0095] Exemplary Formula I compounds include compounds selected from Formulas le and If:

O (0) N N
X1 N X2 i~N
f~~~X2 3 f~~X1 I %\

le if [0096] and stereoisomers, geometric isomers, tautomers, or pharmaceutically acceptable salts thereof, [0097] wherein (i) X1 is N and X2 is S, (ii) Xi is CR7 and X2 is S, (iii) X1 is N and X2 is NR2, or (iv) X1 is CR7 and X2 is 0;

[0098] R1 is selected from [0099] Ci-C12 alkyl, [00100] C2-Cg alkenyl, [00101] C2-Cg alkynyl, [00102] C6-C20 aryl, [00103] -(C1-C12 alkylene)-(C3-C12 carbocyclyl), [00104] -(C1-C12 alkylene)-(C2-C20 heterocyclyl), [00105] -(C1-C12 alkylene)-(C2-C20 heterocyclyl)-(C2-C20 heterocyclyl), [00106] -(C1-C12 alkylene)-(C2-C20 heterocyclyl)-(C3-C12 carbocyclyl), [00107] -(C1-C12 alkylene)-(C2-C20 heterocyclyl)-C(=O)-(C2-C20 heterocyclyl), [00108] -(C1-C12 alkylene)-(C1-C20 heteroaryl), [00109] -(C1-C12 alkylene)-(C2-C20 heterocyclyl)-(C1-C12 alkyl), [00110] -(C1-C12 alkylene)-(C6-C20 aryl)-(C1-C12 alkyl), [00111] -(C1-C12 alkylene)-(C1-C20 heteroaryl)-(C1-C12 alkyl), [00112] -(C1-C12 alkylene)-C(=O)-(C2-C20 heterocyclyl), [00113] -(C1-C12 alkylene)-NHR2, [00114] -(C1-C12 alkylene)-NR 2-(C1-C12 alkyl), [00115] -(C1-C12 alkylene)-N(C1-C12 alkyl)(C2-C20 heterocyclyl), [00116] -(C1-C12 alkylene)-NR 2-(C1-C12 alkylene)-(C1-C20 heteroaryl), [00117] -(C1-C12 alkylene)-NR 2-(C1-C12 alkylene)-(C1-C20 heterocyclyl), [00118] -(C1-C12 alkylene)-NR 2-(C1-C12 alkylene)-NHC(=O)-(C1-C20 heteroaryl), [00119] -(C1-C12 alkylene)-(C2-C20 heterocyclyl)-N(C1-C12 alkyl)R2, [00120] -(C1-C12 alkylene)-(C2-C20 heterocyclyl)-(C1-C12 alkyl)-N(C1-C12 alkyl)R2, [00121] -(C1-C12 alkylene)-NR2-(C2-C20 heterocyclyl), [00122] -(C2-C12 alkenylene)-(C2-C20 heterocyclyl), [00123] -NR2-(C2-C20 heterocyclyl), [00124] -C(=O)-(C2-C20 heterocyclyl), and [00125] -C(=O)-(C1-C12 alkyl), [00126] where alkyl, alkenyl, alkynyl, alkylene, carbocyclyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more groups independently selected from F, Cl, Br, I, -CH3, -CH2CH3, -CH2CH(CH3)2, -CH2OH, -CH2CH2OH, -C(CH3)20H, -CH(OH)CH(CH3)2, -C(CH3)2CH2OH, -CH2CH2SO2CH3, -CN, -CF3, -CO2H, -COCH3, -CO2CH3, -CO2C(CH3)3, -COCH(OH)CH3, -CONH2, -CONHCH3, -CON(CH3)2, -C(CH3)2CONH2, -NO2, -NH2, -NHCH3, -N(CH3)2, -NHCOCH3, -N(CH3)COCH3, -NHS(O)2CH3, -N(CH3)C(CH3)2CONH2, -N(CH3)CH2CH2S(O)2CH3, =0, -OH, -OCH3, -S(O)2N(CH3)2, -SCH3, -CH2OCH3, -S(O)2CH3, cyclopropyl, oxetanyl, and morpholino;

[00127] R2 is selected from H, C1-C12 alkyl, C2-Cg alkenyl, C2-Cg alkynyl, -(C1-C12 alkylene)-(C3-C12 carbocyclyl), -(C1-C12 alkylene)-(C2-C20 heterocyclyl), -(CI-alkylene)-C(=O)-(C2-C20 heterocyclyl), -(C1-C12 alkylene)-(C6-C20 aryl), and -(C1-C12 alkylene)-(C1-C20 heteroaryl), where alkyl, alkenyl, alkynyl, alkylene, carbocyclyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more groups independently selected from F, Cl, Br, I, -CH3, -CH2OH, -CN, -CF3, -CO2H, -COCH3, -CO2CH3, -CONH2, -CONHCH3, -CON(CH3)2, -NO2, -NH2, -NHCH3, -NHCOCH3, -NHS(O)2CH3, -OH, -OCH3, -S(O)2N(CH3)2, -SCH3, -CH2OCH3, and -S(O)2CH3;

[00128] R3 is selected from:

~N
\ I 5& \ I N IN' N
N
N
N N=N O/-NH N'NH O
N
S N \ NH N-O N-S

/~N i ' N O

N N
NH/NH / NnN/N& N N

N N N

i INS I / S~ I
N

I / 5S' / NHO ~\ I / HN
1 I \ N
N N I / ly NH
O

s~ 1 SSS \ 1 I / NH
I s~ \
NH N O NON N
H

[00129] where the wavy line indicates the site of attachment;

[00130] each of which are optionally substituted with one or more groups independently selected from F, Cl, Br, I, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -C(CH3)3, -CH2OCH3, -CHF2, -CN, -CF3, -CH2OH, -CH2OCH3, -CH2CH2OH, -CH2C(CH3)2OH, -CH(CH3)OH, -CH(CH2CH3)OH, -CH2CH(OH)CH3, -CH2CH(OCH3)CH3, -C(CH3)2OH, -C(CH3)2OCH3, -CH(CH3)F, -C(CH3)F2, -CH(CH2CH3)F, -C(CH2CH3)2F, -CO2H, -CONH2, -CON(CH2CH3)2, -COCH3, -CON(CH3)2, -NO2, -NH2, -NHCH3, -N(CH3)2, -NHCH2CH3, -NHCH(CH3)2, -NHCH2CH2OH, -NHCH2CH2OCH3, -NHCOCH3, -NHCOCH2CH3, -NHCOCH2OH, -NHS(O)2CH3, -N(CH3)S(O)2CH3, =0, -OH, -OCH3, -OCH2CH3, -OCH(CH3)2, -SH, -NHC(=O)NHCH3, -NHC(=O)NHCH2CH3, -S(O)CH3, -S(O)CH2CH3, -S(O)2CH3, -S(O)2NH2, -S(O)2NHCH3, -S(O)2N(CH3)2, -CH2S(O)2CH3, and groups selected from F s F F F
'NH O $r F F~~

b N NHNH $~ p IJ
O
N I _S OH
Ny O
N
' / i' N nN

N
N

[00131] R7 is selected from H, CI-C12 alkyl, C2-Cg alkenyl, C2-Cg alkynyl, -(C1-C12 alkylene)-(C3-C12 carbocyclyl), -(C1-C12 alkylene)-(C2-C20 heterocyclyl), -(C1-alkylene)-C(=O)-(C2-C20 heterocyclyl), -(C1-C12 alkylene)-(C6-C20 aryl), and -(C1-C12 alkylene)-(C1-C20 heteroaryl), where alkyl, alkenyl, alkynyl, alkylene, carbocyclyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more groups independently selected from F, Cl, Br, I, -CH3, -CH2OH, -CN, -CF3, -CO2H, -COCH3, -CO2CH3, -CONH2, -CONHCH3, -CON(CH3)2, -NO2, -NH2, -NHCH3, -NHCOCH3, -NHS(O)2CH3, -OH, -OCH3, -S(O)2N(CH3)2, -SCH3, -CH2OCH3, and -S(O)2CH3;

[00132] and wherein the IC50 binding activity to pl 10 delta is ten or more times lower than the binding activity to p 110 alpha;

[00133] with the proviso that a Formula If compound wherein (ii) X1 is CR7 and X2 is S, RI is -(C1-C12 alkylene)-(C2-C20 heterocyclyl), R3 is optionally substituted benzo[d]imidazol-1-yl, and R7 is H, excludes the C2-C20 heterocyclyl of R1 substituted with -S(O)2CH3.

[00134] The Formula I compounds of the invention may contain asymmetric or chiral centers, and therefore exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the compounds of the invention, including but not limited to, diastereomers, enantiomers and atropisomers, as well as mixtures thereof such as racemic mixtures, form part of the present invention.

[00135] In addition, the present invention embraces all geometric and positional isomers. For example, if a Formula I compound incorporates a double bond or a fused ring, the cis- and trans-forms, as well as mixtures thereof, are embraced within the scope of the invention. Both the single positional isomers and mixture of positional isomers are also within the scope of the present invention.

[00136] In the structures shown herein, where the stereochemistry of any particular chiral atom is not specified, then all stereoisomers are contemplated and included as the compounds of the invention. Where stereochemistry is specified by a solid wedge or dashed line representing a particular configuration, then that stereoisomer is so specified and defined.

[00137] The compounds of the present invention may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and it is intended that the invention embrace both solvated and unsolvated forms.

[00138] The compounds of the present invention may also exist in different tautomeric forms, and all such forms are embraced within the scope of the invention. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies which are interconvertible via a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) include interconversions via migration of a proton, such as keto-enol and imine-enamine isomerizations. Valence tautomers include interconversions by reorganization of some of the bonding electrons.

[00139] The present invention also embraces isotopically-labeled compounds of the present invention which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. All isotopes of any particular atom or element as specified are contemplated within the scope of the compounds of the invention, and their uses. Exemplary isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine and iodine, such as 2H 3 H, 11c> 13c> 14c> 13N> 15N> 15O> 170> 180> 32P> 33P>
35S> 18F > 36C1> 1231 >
and 125I. Certain isotopically-labeled compounds of the present invention (e.g., those labeled with 3H and 14C) are useful in compound and/or substrate tissue distribution assays. Tritiated (3H) and carbon-14 (14C) isotopes are useful for their ease of preparation and detestability.
Further, substitution with heavier isotopes such as deuterium (i.e., 2H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances.
Positron emitting isotopes such as 150, 13N, 11C and 18F are useful for positron emission tomography (PET) studies to examine substrate receptor occupancy. Isotopically labeled compounds of the present invention can generally be prepared by following procedures analogous to those disclosed in the Schemes and/or in the Examples herein below, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

[00140] BIOLOGICAL EVALUATION

[00141] The relative efficacies of Formula I compounds as inhibitors of an enzyme activity (or other biological activity) can be established by determining the concentrations at which each compound inhibits the activity to a predefined extent and then comparing the results. Typically, the preferred determination is the concentration that inhibits 50% of the activity in a biochemical assay, i.e., the 50% inhibitory concentration or "IC50"=
Determination of IC50 values can be accomplished using conventional techniques known in the art. In general, an IC50 can be determined by measuring the activity of a given enzyme in the presence of a range of concentrations of the inhibitor under study. The experimentally obtained values of enzyme activity then are plotted against the inhibitor concentrations used.
The concentration of the inhibitor that shows 50% enzyme activity (as compared to the activity in the absence of any inhibitor) is taken as the IC50 value.
Analogously, other inhibitory concentrations can be defined through appropriate determinations of activity. For example, in some settings it can be desirable to establish a 90% inhibitory concentration, i.e., IC90, etc.

[00142] Accordingly, a "selective P13K delta inhibitor" can be understood to refer to a compound that exhibits a 50% inhibitory concentration (IC50) with respect to P13K delta that is at least at least 10-fold lower than the IC50 value with respect to any or all of the other Class I P13K family members.

[00143] Determination of the activity of P13 kinase activity of Formula I
compounds is possible by a number of direct and indirect detection methods. Certain exemplary compounds described herein were assayed for their ability to inhibit P13K
alpha, beta, gamma, and delta isoforms (Example 901). The range of IC50 values for inhibition of P13K

delta was less than 1 nM (nanomolar) to about 10 gM (micromolar). Certain exemplary compounds of the invention had P13K delta inhibitory IC50 values less than 10 nM. The compounds are selective for the pl 108 (delta) isoform, which is a class la P13 kinase, over other class la P13 kinases, and are thus selective for the pl 108 isoform over both the pl l0a (alpha) isoform and the pl 10(3 (beta) isoform. In particular, they are selective for pl 108 (delta) over pl l0a (alpha). The compounds are also selective for the pl 108 isoform over pl 10y (gamma), which is a class Ib kinase. The selectivity exhibited by Formula I
compounds of the invention for p l 108 (delta) over the p l l Oa (alpha) isoform of P13 kinase is at least 10 fold, as exemplified by the ratios of biochemical IC50 values (Example 901).

[00144] Certain Formula I compounds may have antiproliferative activity to treat hyperproliferative disorders such as cancer. The Formula I compounds may inhibit tumor growth in mammals and may be useful for treating human cancer patients.
Formula I
compounds may be tested for in vitro cell proliferation activity and in vivo tumor growth inhibition according to the methods in WO 2006/04603 1; US 2008/0039459; US
2008/0076768; US 2008/0076758; WO 2008/070740; WO 2008/073785, which are incorporated by reference herein.

[00145] Evaluation of drug-induced immunosuppression by the compounds of the invention may be performed using in vivo functional tests, such as rodent models of induced arthritis and therapeutic or prophylactic treatment to assess disease score, T
cell-dependent antibody response (TDAR), and delayed-type hypersensitivity (DTH). Other in vivo systems including murine models of host defense against infections or tumor resistance (Burleson GR, Dean JH, and Munson AE. Methods in Immunotoxicology, Vol. 1. Wiley-Liss, New York, 1995) may be considered to elucidate the nature or mechanisms of observed immunosuppression. The in vivo test systems can be complemented by well-established in vitro or ex vivo functional assays for the assessment of immune competence.
These assays may comprise B or T cell proliferation in response to mitogens or specific antigens, measurement of signaling through the P13K pathway in B or T cells or immortalized B or T
cell lines, measurement of cell surface markers in response to B or T cell signaling, natural killer (NK) cell activity, mast cell activity, mast cell degranulation, macrophage phagocytosis or kill activity, and neutrophil oxidative burst and/or chemotaxis. In each of these tests determination of cytokine production by particular effector cells (e.g., lymphocytes, NK, monocytes/macrophages, neutrophils) may be included. The in vitro and ex vivo assays can be applied in both preclinical and clinical testing using lymphoid tissues and/or peripheral blood (House RV. "Theory and practice of cytokine assessment in immunotoxicology"
(1999) Methods 19:17-27; Hubbard AK. "Effects of xenobiotics on macrophage function:
evaluation in vitro" (1999) Methods;19:8-16; Lebrec H, et al (2001) Toxicology 158:25-29).

[00146] Collagen-Induced Arthritis (CIA) 6-week detailed study using an autoimmune mechanism to mimic human arthritis; rat and mouse models (Example 902).
Collagen-induced arthritis (CIA) is one of the most commonly used animal models of human rheumatoid arthritis (RA). Joint inflammation, which develops in animals with CIA, strongly resembles inflammation observed in patients with RA. Blocking tumor necrosis factor (TNF) is an efficacious treatment of CIA, lust as it is a highly efficacious therapy in treatment of RA
patients. CIA is mediated by botÃh'T-cells and antibodies (B--cells).
Macrophages are believed to play an i ~portant role in mediating tissue damage during disease development, CIA is induced by immunizing animals with collagen emulsified in Complete Freund's Adjuvant (CFA). It is most commonly induced in the DBA/1 mouse strain, but the disease can also be induced in Lewis rats.

[00147] There is good evidence that B-cells play a key role in the pathogenesis of autoimmune and/or inflammatory disease. Protein-based therapeutics that deplete B cells such as Rituxan are effective against autoantibody-driven inflammatory diseases such as rheumatoid arthritis (Rastetter et al. (2004) Annu Rev Med 55:477). CD69 is the early activation marker in leukocytes including T cells, thymocytes, B cells, NK
cells, neutrophils, and eosinophils. The CD69 human whole blood assay (Example 903) determines the ability of compounds to inhibit the production of CD69 by B lymphocytes in human whole blood activated by crosslinking surface IgM with goat F(ab')2 anti-human IgM.

[00148] The 'I'-cell Dependent Antibody Response ("TAI;.) is a predictive assay for immune function testing when potential immunotoxic effects of compounds need to he studied. The IgNI-IDIaque Forming Cell (PFC) assay, using Sheep Red Blood Cells (SIl"BC) as the antigen, is currently a widely accepted and validated standard test. TDAR
has proven to be a highly predictable assay for adult exposure immunotoxicity detection in mice based on the US National Toxicology Program (NTP) database (M.I. Luster et al (1992) Fundam.
Appl. Toxicol. 18:200-210). The utility of this assay stems from the fact that it is a holistic measurement involving several important components of an immune response. A
TDAR is dependent on functions of the following cellular compartments: (1) antigen-presenting cells, such as macrophages or dendritic cells; (2) T-helper cells, which are critical players in the genesis of the response, as well as in isotype switching; and (3) B-cells, which are the ultimate effector cells and are responsible for antibody production.
Chemically-induced changes in any one compartment can cause significant changes in the overall TDAR (M.P.
Holsapple In: G.R. Burleson, J.H. Dean and A.E. Munson, Editors, Modern Methods in Immunotoxicology, Volume 1, Wiley-Liss Publishers, New York, NY (1995), pp. 71-108).
Usually, this assay is performed either as an ELISA for measurement of soluble antibody (R.J. Smialowizc et al (2001) Toxicol. Sci. 61:164-175) or as a plaque (or antibody) forming cell assay (L. Guo et al (2002) Toxicol. Appl. Pharmacol. 181:219-227) to detect plasma cells secreting antigen specific antibodies. The antigen of choice is either whole cells (e.g.
sheep erythrocytes) or soluble protein antigens (T. Miller et al (1998) Toxicol. Sci. 42:129-135).

[00149] Exemplary Formula I compounds in Tables 1-3 were made, characterized, and tested for inhibition of P13K delta and selectivity according to the methods of this invention, and have the following structures and corresponding names (ChemDraw Ultra, Version 9Ø1, CambridgeSoft Corp., Cambridge MA).

[00150] Table 1.

No. Structure Name 101 (O) 4-(1-((2-(isoquinolin-5-yl)-4-morpholinothieno [3,2-d]pyrimidin-6-N yl)methyl)piperidin-4-yl)morpholine S N N

Q N N
-N

O~
102 C~~ 4-(6-((4-(cyclopropylmethyl)piperazin-1-yl)methyl)-2-(1 H-pyrrolo [2,3-N c]pyridin-4-yl)thieno[3,2-d]pYrimidin-S N 4-yl)morpholine N
~N 5"N H
N o N

103 ~~~ 4-((4-morpholino-2-(1 H-pyrrolo [2,3-c]pyridin-4-yl)thieno [3,2-d]pyrimidin-N 6-yl)methyl)morpholine s I ~N _ N NH
N

104 C~~ 1-((2-(7-chloroquinolin-4-yl)-4-morpholinothieno [3,2-d]pyrimidin-6-N yl)methyl)-N,N-dimethylpiperidin-4-s I IN I Cl amine 5N \
N
~N
-N
N
105 C~~ 2-methyl-2-(4-((4-morpholino-2-(1 H-pyrrolo[2,3-c]pyridin-4-yl)thieno[3,2-N d]pyrimidin-6-yl)methyl)piperazin- l -s N yl)propanamide N NH
CN
N
J

O

106 C~~ 2-methyl-2-(4-((4-morpholino-2-(1H-pyrrolo[3,2-c]pyridin-4-yl)thieno[3,2-N d]pyrimidin-6-yl)methyl)piperazin- l -s N yl)propanamide N NH
N \ N

ci O

107 (0) 1-((2-(isoquinolin-8-yl)-4-morpholinothieno [3,2-d]pyrimidin-6-N yl)methyl)-N,N-dimethylpiperidin-4-s N N amine N \ I /
N I \
-N

108 2-(4-((2-(l -aminoisoquinolin-4-yl)-4-ON) morpholinothieno [3,2-d]pyrimidin-6-yl)methyl)piperazin-l -yl)-2-s N methylpropanamide N N i H2Nt 109 ~0~ 1-((2-(isoquinolin-5-yl)-4-morpholinothieno [3,2-d]pyrimidin-6-N yl)methyl)-N,N-dimethylpiperidin-4-S . N / N amine d-< N

-N
110 (0) 1-((2-(1H-benzo[d]imidazol-l-yl)-4-morpholinothieno [3,2-d]pyrimidin-6-N yl)methyl)-N,N-dimethylpiperidin-4-g N amine N" N q N
-N

111 0 2-(4-((2-(7-methoxy-1 H-pyrrolo [2,3-c]pyridin-4-yl)-4-N morpholinothieno [3,2-d]pyrimidin-6-N yl)methyl)piperazin-l-yl)-2-N N NH methylpropanamide 112 C0~ 2-methyl-2-(4-((7-methyl-4-morpholino-2-(1 H-pyrrolo [2,3-N c]pyridin-4-yl)thieno [3,2-d]pyrimidin-S N 6-yl)methyl)piperazin-l-N NH yl)propanamide N N

o 113 2-(4-((2-(7-chloro-1 H-pyrrolo [2,3-( ) c]pyridin-4-yl)-4-N morpholinothieno [3,2-d]pyrimidin-6-N yl)methyl)piperazin-l-yl)-2-N N NH methylpropanamide O NJ N CI

114 (0) 4-(8-((4-tert-butylpiperidin- l -yl)methyl)-9-methyl-6-morpholino-9H-N purin-2-yl)isoquinolin-l-amine N N
N

115 HO p 2-(1-((2-(1-aminoisoquinolin-4-yl)-9-methyl-6-morpholino-9H-purin-8-N yl)methyl)piperidin-4-yl)propan-2-ol ON N

N~ NH2 116 _N O 1-((2-(lH-indazol-l-yl)-4-morpholinothieno [3,2-d]pyrimidin-6-C N Y1)methY1)-N,N-dimethYlpiperidin-4-N S amine NN
Ni 117 ~~~ N,N-dimethyl-l -((2-(2-methyl-1 H-benzo [d]imidazol- l -yl)-4-N morpholinothieno [3,2-d]pyrimidin-6-g N yl)methyl)piperidin-4-amine NN
N
-N

118 HO O 2-(1-((9-methyl-6-morpholino-2-(1H-pyrrolo[2,3-c]pyridin-4-yl)-9H-purin-8-C N yl)methyl)piperidin-4-yl)propan-2-ol N\/,N N 51N ~ H
N N

N
119 HO O 2-(1-((9-methyl-6-morpholino-2-(1H-pyrrolo[3,2-c]pyridin-4-yl)-9H-purin-8-C N yl)methyl)piperidin-4-yl)propan-2-ol NN I ~ N
\ NH
N
N
N /

120 C~~ 4-(6-((4-methylpiperazin-l-yl)methyl)-2-(quinolin-5-yl)thieno[3,2-N d]pyrimidin-4-yl)morpholine s N (NkXc5N

N
121 O 2-(4-((2-(7-fluoro-1 H-pyrrolo [3,2-c]pyridin-4-yl)-4-N morpholinothieno [3,2-d]pyrimidin-6-N yl)methyl)piperazin-l-yl)-2-N N NH methylpropanamide O N> J N F

122 C~~ 4-(6-((4-cyclopropylpiperazin-l-yl)methyl)-2-(1 H-pyrrolo [2,3-N c]pyridin-4-yl)thieno[2,3-d]pyrimidin-N 4-yl)morpholine N S N NH
N

123 4-((4-morpholino-2-(1 H-pyrrolo [3,2-0 (0) c]pyridin-4-yl)thieno[3,2-d]pyrimidin-~D N 6-yl)methyl)morpholine N S ~N
NH
\ I N 51,!0, N 124 C~~ 4-(1-((9-methyl-6-morpholino-2-(1H-pyrrolo[2,3-c]pyridin-4-yl)-9H-purin-8-N yl)methyl)piperidin-4-yl)morpholine N I N
N N NH
N
OJ

125 -N O N,N-dimethyl-l-((4-morpholino-2-(1H-pyrrolo[3,2-c]pyridin-3-yl)thieno[3,2-N d]pyrimidin-6-yl)methyl)piperidin-4-N s N N amine N
NH

126 C~~ 2-methyl-2-(4-((7-methyl-4-morpholino-2-(1 H-pyrrolo [3,2-N c]pyridin-4-yl)thieno [3,2-d]pyrimidin-S N _ 6-yl)methyl)piperazin- l -N NH yl)propanamide N \ N
No /
N

O

127 CO~ 4-(6-((4-(1-amino-2-methyl-l-oxopropan-2-yl)piperazin- l -N yl)methyl)-4-morpholinothieno [3,2-S N _ d]pyrimidin-2-yl)-1H-pyrrolo[2,3-N \ NH c]pyridine 6-oxide N

No N+
O

128 2-(4-((2-(benzofuran-3-yl)-4-ON) morpholinothieno [3,2-d]pyrimidin-6-yl)methyl)piperazin-l -yl)-2-N methylpropanamide N N I \ p O NJ O
H2N"

129 OH O 2-(1-((2-(3-amino-lH-indazol-l-yl)-9-N methyl-6-morpholino-9H-purin-8-yl)methyl)piperidin-4-yl)propan-2-ol N N ., N N N
N-130 2-(1-((2-(l -aminoisoquinolin-4-yl)-4-) morpholinothieno[3,2-d]pyrimidin-6-(0 N yl)methyl)piper'din-4-yl)propan-2-ol S ~N
~
N N

HO

131 C~~ 2-methyl-2-(4-((7-morpholino-5-(1H-pyrrolo[2,3-c]pyridin-4-yl)thiazolo[5,4-N d]pyrimidin-2-yl)methyl)piperazin- l -N N yl)propanamide N S N NH
N
O

132 CO~ 2-methyl-2-(4-((2-(7-methyl-1 H-pyrrolo[2,3-c]pyridin-4-yl)-4-N morpholinothieno [3,2-d]pyrimidin-6-S . N _ yl)methyl)piperazin-l-yl)propanamide N N \ NH

N- -O

133 C~~ 4-(1-((9-methyl-6-morpholino-2-(1H-pyrrolo[3,2-c]pyridin-4-yl)-9H-purin-8-N yl)methyl)piperidin-4-yl)morpholine ~N I N
N I NH
N /

N
OJ
134 O 1-((2-(1 H-indazol-3-yl)-4-C morpholinothieno[3,2-d]pyrimidin-6-N yl)methyl)-N,N-dimethylpiperidin-4-S N amine N \ N
N NH
-N

135 0 0 2-(4-((2-(isoquinolin-8-yl)-4-H2N N morpholinothieno[3,2-d]pyrimidin-6-N yl)methyl)piperazin-l -yl)-2-`N S
C y,-136 N methylpropanamide -N -N 0 N,N-dimethyl-l-((4-morpholino-2-(1H-pyrrolo[2,3-b]pyridin-3-yl)thieno[3,2-N d]pyrimidin-6-yl)methyl)piperidin-4-N S amine N N
NH
137 C0 2-(1-((2-(l -(ethylamino)isoquinolin-4-yl)-4-morpholinothieno [3,2-N d]pyrimidin-6-yl)methyl)piperidin-4-s N / yl)propan-2-ol N N I \

N NH
HO

138 (0) 2-(1-((2-(benzofuran-3-yl)-9-methyl-6-morpholino-9H-purin-8-N yl)methyl)piperidin-4-yl)propan-2-ol ~N \N
N N N I \
O
HO

139 C0 4-(9-methyl-6-morpholino-8-((4-morpholinopiperidin-l -yl)methyl)-9H-N purin-2-yl)isoquinolin- l -amine N N
N N N I \

N>
OJ

140 ~~~ 2-methyl-2-(4-((2-(2-methylbenzofuran-3-yl)-4-N morpholinothieno [3,2-d]pyrimidin-6-s N yl)methyl)piperazin-l-yl)propanamide ~N> N

O NJ O

141 CO~ 2-(2-(l -aminoisoquinolin-4-yl)-4-morpholinothieno [3,2-d]pyrimidin-6-N yl)propan-2-ol N
HO N

142 2-methyl-2-(4-((2-(2-methyl-1 H-( ) pyrrolo[2,3-c]pyridin-4-yl)-4-N
N 1 meth l i erazin-l- 1 ro anamide NH y) Y)pp y)p p N

O

143 2-methyl-2-(4-((2-(2-methyl-1 H-) pyrrolo[3,2-c]pyridin-4-yl)-4-(0 N

N NH y 1)methYl)piperazin-l-Y1)propanamide N
N
N

O

144 2-(4-((2-(l -acetamidoisoquinolin-4-yl)-ON) 4-morpholinothieno [3,2-d]pyrimidin-6-yl)methyl)piperazin-l -yl)-2-s N
N methylpropanamide N
O NJ N NH

145 C~~ 2-(1-((9-methyl-2-(2-methylbenzofuran-3-yl)-6-morpholino-N 9H-purin-8-yl)methyl)piperidin-4-r-lN . N _ yl)propan-2-ol N N N \

HO
146 (0) 1-((2-(benzo[b]thiophen-3-yl)-4-morpholinothieno [3,2-d]pyrimidin-6-N yl)methyl)-N,N-dimethylpiperidin-4-s N amine N \ N I \
S
-N

147 C~~ 2-(1-((2-(1-aminoisoquinolin-5-yl)-9-methyl-6-morpholino-9H-purin-8-N 1)methYl)piperidin-4-Y1)propan-2-ol N N / N y N N N I \ NH2 HO
148 C~~ N-(4-(6-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)-4-N morpholinothieno [3,2-d]pyrimidin-2-N N yl)isoquinolin-l-yl)acetamide N N

N NH
HO-~, O--k 149 -N 0 N,N-dimethyl-l-((4-morpholino-2-(1H-pyrrolo [3,2-c]pyridin-1-yl)thieno [3,2-N d]pyrimidin-6-yl)methyl)piperidin-4-N
N S I N amine \ NAN

150 C~~ 1-((2-(isoquinolin-4-yl)-4-morpholinothieno [3,2-d]pyrimidin-6-N yl)methyl)-N,N-dimethylpiperidin-4-amine S ~N
\ I ~
N I /
N
-N

151 CO~ 2-(4-((2-(2-ethyl-lH-pyrrolo[2,3-c]pyridin-4-yl)-4-N morpholinothieno [3,2-d]pyrimidin-6-S N yl)methyl)piperazin-l-yl)-2-N NH methylpropanamide N~ N

O

152 C~~ 4-(1-((7-morpholino-5-(1H-pyrrolo[3,2-c]pyridin-4-yl)thiazolo[5,4-N d]pyrimidin-2-yl)methyl)azetidin-3-~N N xL.~'NH yl)morpholine r pN S N N
(I) N

153 C~~ 2-methyl-2-(4-((2-(5-methyl-1 H-pyrrolo[2,3-c]pyridin-4-yl)-4-N morpholinothieno [3,2-d]pyrimidin-6-yl)methyl)piperazin-l-yl)propanamide NH
S - N 6N' N N O

154 C~~ 4-(1-((9-methyl-2-(2-methyl-1 H-benzo [d]imidazol-l-yl)-6-morpholino-N 9H-purin-8-yl)methyl)piperidin-4-yl) morpholine N N
-N

O~

155 0 4-(8-((4-(2-methoxypropan-2-(0) yl)piperidin- l -yl)methyl)-9-methyl-6-morpholino-9H-purin-2-yl)isoquinolin-N 1-amine N N N /
N
N NHZ

156 (0) 1-(8-((4-(2-hydroxypropan-2-yl)piperidin- l -yl)methyl)-9-methyl-6-N morpholino-9H-purin-2-yl)-1 H-N benzo[d]imidazol-2(3H)-one N N N N
OA NH
HO

157 (O) 2-(1-((9-methyl-2-(2-methyl-1 H-benzo [d]imidazol-l-yl)-6-morpholino-N 9H-purin-8-yl)methyl)piperidin-4-N N yl)propan-2-ol N r NIN

~N
HO

158 (O) 2-(1-((2-(2-ethyl-lH-benzo[d]imidazol-1-yl)-9-methyl-6-morpholino-9H-N purin-8-yl)methyl)piperidin-4-N N yl)propan-2-ol r N :: I NIN
N
HO

159 (O) 2-(1-((2-(2-cyclopropyl-lH-benzo [d]imidazol-l-yl)-9-methyl-6-N morpholino-9H-purin-8-N yl)methyl)piperidin-4-yl)propan-2-ol r N N IN O
N
HO

160 2-(4-((2-(isoquinolin-4-yl)-4-ON) morpholinothieno [3,2-d]pyrimidin-6-yl)methyl)piperazin-l-yl)-2-s N methylpropanamide N) N
O NJ N

161 (O) 2-(1-((2-(2-(methoxymethyl)-1H-benzo [d]imidazol-1-yl)-9-methyl-6-N morpholino-9H-purin-8-N N yl)methyl)piperidin-4-yl)propan-2-ol i N :: I NIN
N
/O
HO

162 OH O 2-(1-((2-(1H-indazol-3-yl)-9-methyl-6-CN~ morpholino-9H-purin-8-yl)methyl)piperidin-4-yl)propan-2-ol IN
N N Z
N I N

N-NH

163 2-(4-((2-(2-fluorobenzofuran-3-yl)-4-ON) morpholinothieno [3,2-d]pyrimidin-6-yl)methyl)piperazin-l -yl)-2-s ~ N methylpropanamide N N
O NJ F O

164 (0) 4-(6-((4-(dimethylamino)piperidin- l -yl)methyl)-4-morpholinothieno [3,2-N d]pyrimidin-2-yl)isoquinoline 2-oxide s I N

N

N
-N O

165 C0~ 2-(l-((9-methyl-2-(2-methyl- I H-pyrrolo[2,3-c]pyridin-4-yl)-6-N morpholino-9H-purin-8-N N yl)methyl)piperidin-4-yl)propan-2-ol N N NH

N
HO

166 (0) 2-(1-((2-(2-methoxy-lH-benzo [d]imidazol-l-yl)-9-methyl-6-N morpholino-9H-purin-8-N N yl)methyl)piperidin-4-yl)propan-2-ol N
N
N~
D
HO

167 (O) 2-(1-((2-(2-amino-lH-benzo [d]imidazol-l-yl)-9-methyl-6-N morpholino-9H-purin-8-N yl)methyl)piperidin-4-yl)propan-2-ol r N NN
N

HO

168 C~~ 4-(1-((7-morpholino-5-(1H-pyrrolo[2,3-c]pyridin-4-yl)thiazolo[5,4-N d]pyrimidin-2-yl)methyl)azetidin-3-N ~6N yl)mor pholine N S H
N
C N>

169 C~~ 2-methyl-2-(4-((7-morpholino-5-(1H-pyrrolo[3,2-c]pyridin-4-yl)thiazolo[5,4-N d]pyrimidin-2-yl)methyl)piperazin- l -~N N yl)propanamide r N S NH
N
c_i>
N

O

170 C~~ 2-methyl-2-(4-((2-(6-methyl-1 H-pyrrolo[3,2-c]pyridin-4-yl)-4-N morpholinothieno [3,2-d]pyrimidin-6-S NZ! N yl)methyl)piperazin-l-yl)propanamide N N NH

N
N

O

171 (0) 2-methyl-2-(4-((4-morpholino-2-N(quinolin-4-yl)thieno [3,2-d]pyrimidin-6-yl)methyl)piperazin- l -S N yl)propanamide N N
~otN
O NJ

172 (0) 4-(1-((2-(2-methyl-lH-benzo [d]imidazol- l -yl)-4-N morpholinothieno [3,2-d]pyrimidin-6-S N yl)methyl)azetidin-3 -yl)morpho line N NN
p /~-- N
C N

OJ

173 (O) 1-(4-morpholino-6-((3-morpholinoazetidin- l -N yl)methyl)thieno [3,2-d]pyrimidin-2-S yl)-1H-benzo[d]imidazol-2(3H)-one N N Nl O/T
N P N H
~

174 CO~ 4-(1-((4-morpholino-2-(1H-pyrrolo[3,2-c]pyridin-4-yl)thieno[3,2-N d]pyrimidin-6-yl)methyl)azetidin-3-S N _ yl)morpholine N N \ NH
N /

N>

175 C~~ 2-methyl-2-(4-((2-(6-methylimidazo [ 1,2-a]pyridin-5-yl)-4-N morpholinothieno [3,2-d]pyrimidin-6-S N yl)methyl)piperazin-l-yl)propanamide N \ N UN, N

CND

>N
O

176 ~~~ 2-methyl-2-(4-((2-(2-methyl-2H-indazol-3-yl)-4-morpholinothieno[3,2-N d]pyrimidin-6-yl)methyl)piperazin- l -s N yl)propanamide N
~N-N
O N

177 -N 0 1-(6-((4-(dimethylamino)piperidin-l-yl)methyl)-4-morpholinothieno [3,2-C N d]pyrimidin-2-yl)indolin-2-one N S N
NN
O

178 (O) 2-(1-((2-(2-(hydroxymethyl)-1H-benzo [d]imidazol-l-yl)-9-methyl-6-N morpholino-9H-purin-8-N IN yl)methyl)piperidin-4-yl)propan-2-ol /-< N I NIN

HON
HO

179 0 4-(8-((4-(2-methoxypropan-2-0 yl)piperidin- l -yl)methyl)-9-methyl-2-() (2-methyl-lH-benzo[d]imidazol-l-yl)-N 9H-purin-6-yl)morpholine N N ., N N N

180 ~~~ 2-(4-((2-(l -amino-6-fluoroisoquinolin-N F 4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin- l -s N yl)-2-methylpropanamide N
N

181 C~~ (3S,4R)-3-fluoro-N,N-dimethyl-l-((9-methyl-2-(2-methyl-1 H-N benzo [d]imidazol-l-yl)-6-morpholino-N N 9H-purin-8-yl)methyl)piperidin-4-amine N N
N~ \
N
1: "1 -N F

182 (O) 4-(5-(1H-indazol-3-yl)-2-((3-morpholinoazetidin- l -N yl)methyl)thiazolo [5,4-d]pyrimidin-7-N N yl)morpholine N S N
N,N
ci) N H

183 (0) 1-(7-morpholino-2-((3-morpholinoazetidin- l -N yl)methyl)thiazolo[5,4-d]pyrimidin-5-N yl)- l H-benzo [d]imidazol-2(3H)-one N S N N
O/_NH
OJ

184 (O) 4-(5-(2-(difluoromethyl)-1 H-benzo [d]imidazol-l -yl)-2-((3 -N morpholinoazetidin- l -N N yl)methyl)thiazolo[5,4-d]pyrimidin-7-Nf -</S N N yl)morpholine v -N
F~
N
F
O

185 ~ 2-(4-((2-(l -amino-7-fluoroisoquinolin-N 4-yl)-4-morpholinothieno[3,2-F d]pyrimidin-6-yl)methyl)piperazin-l-s N yl)-2-methylpropanamide N N

186 (O) 2-(1-((9-methyl-6-morpholino-2-(2-(trifluoromethyl)-1 H-N benzo [d]imidazol- l -yl)-9H-purin- 8 -yl)methyl)piperidin-4-yl)propan-2-ol N !-N \~ N I NN

F N
F F
HO

187 2-isobutyl-4-((9-methyl-2-(2-methyl-() 1H-benzo[d]imidazol-l-yl)-6-N morpholino-9H-purin-8-~N yl)methyl)morpholine N NIN_ \
O ~N

188 CO~ 2-(1-((2-(2-(dimethylamino)-1H-benzo [d]imidazol-l-yl)-9-methyl-6-N morpholino-9H-purin-8-N N _ yl)methyl)piperidin-4-yl)propan-2-ol i N N:: I N~N'_ \
NrN
H
O

189 (O) 2-(1-((2-(2-ethyl-2H-indazol-3-yl)-9-methyl-6-morpholino-9H-purin-8-N yl)methyl)piperidin-4-yl)propan-2-ol /~N XrQ
N N -N
HO

190 2-(4-((2-(2-ethyl-2H-indazol-3-yl)-4-ON) morpholinothieno [3,2-d]pyrimidin-6-yl)methyl)piperazin-l -yl)-2-s L N methylpropanamide N x N
N-N

H2N"~-191 C~~ 2,2-diethyl-4-((9-methyl-2-(2-methyl-1 H-benzo [d]imidazol- l -yl)-6-N morpholino-9H-purin-8-N yl)methyl)morpholine N NN

OJ N

192 H2N 2-methyl-2-(4-((2-(2-methyl-lH-O O benzo[d]imidazol-l-yl)-4-morpholinothieno [3,2-d]pyrimidin-6-4 () N yl)methyl)piperazin-l-yl)propanamide ON
g N
N N \
N

193 0 O 4-(5-(2-methyl-lH-benzo[d]imidazol-N~ 1-yl)-2-((3-morpholinoazetidin-l-N yl)methyl)thiazolo[5,4-d]pYrimidin-7-yl)morpholine N N N

S N~N 194 C~~ 2,6-dimethyl-4-((9-methyl-2-(2-methyl-1 H-benzo [d]imidazol-l-yl)-6-N morpholino-9H-purin-8-N yl)methyl)morpholine / :: I N
NAN \ I
N
195 (O) 2-( 1-((2-(2-isopropyl-lH-benzo [d]imidazol-1-yl)-9-methyl-6-N morpholino-9H-purin-8-N NI N /----<I :: I N NIN

N
HO

196 C~~ 2,2-dimethyl-4-((9-methyl-2-(2-methyl-1 H-benzo [d]imidazol-l-yl)-6-N morpholino-9H-purin-8-N yl)methyl)morpholine / I ~N
N N N" N
O~ N

197 (O) 2-(1-((2-(2-(1,1-difluoroethyl)-1 H-benzo [d]imidazol-l-yl)-9-methyl-6-N morpholino-9H-purin-8-N N yl)methyl)piperidin-4-yl)propan-2-ol r N :: I
N NIN
N
F
O
HO

198 C~~ (R)-2-(1-((2-(2-(l-hydroxyethyl)-1H-benzo [d]imidazol-l-yl)-9-methyl-6-N morpholino-9H-purin-8-N yl)methyl)piperidin-4-yl)propan-2-ol N N:]l N N
N
HO OH

199 C~~ (S)-2-(1-((2-(2-(1-hydroxyethyl)-1H-benzo [d]imidazol-l-yl)-9-methyl-6-N morpholino-9H-purin-8-N yl)methyl)piperidin-4-yl)propan-2-ol N N:: I NN
N
HO OH

200 (O) 4-(8-((4-(2-methoxypropan-2-yl)piperidin- l -yl)methyl)-9-methyl-2-N (2-methylbenzofuran-3-yl)-9H-purin-6-N N yl)morpholine N N N
O
-O

201 (O) 2-methyl-2-(4-((2-(8-methylimidazo [ 1,2-a]pyridin-5-yl)-4-N morpholinothieno [3,2-d]pyrimidin-6-s N yl)methyl)piperazin-l-yl)propanamide N UN' N
~N>
_ N

> -NH2 O

202 2-(4-((2-(imidazo [ 1,5-a]pyridin-8-yl)-(0) 4-morpholinothieno[3,2-d]pyrimidin-6-N yl)methyl)piperazin-l -yl)-2-methylpropanamide ()\ N N

N

O

methyl-N-((2-(2-methyl-1H-(0) benzo[d]imidazol-1-yl)-4-N
morpholinothieno [3,2-d]pyrimidin-6-s yl)methyl)-2-morpholinopropan-l-N H N N amine N~ ~N

204 _ C 0) 4-(6-((3,4-dihydroisoquinolin-2(1H)-yl)methyl)-2-(2-methyl-lH-N benzo [d]imidazol- l -yl)thieno [3,2-N S d]pyrimidin-4-yl)morpholine N N \
/~-- N

205 (0) 2-(1-((2-(2-(benzyl(methyl)amino)-1 H-benzo [d]imidazol-l-yl)-9-methyl-6-N morpholino-9H-purin-8-N yl)methyl)piperidin-4-yl)propan-2-ol i N :: I ' N N11__ \
l~N
N

HO C
C
206 (0) 2-(1-((9-methyl-2-(2-(methylamino)-1 H-benzo [d]imidazol- l -yl)-6-N morpholino-9H-purin-8-N yl)methyl)piperidin-4-yl)propan-2-ol N N~N \

HN
HO

207 (0) 2-(1-((9-methyl-6-morpholino-2-(2-phenyl-1 H-benzo [d]imidazol- l -yl)-9H-N purin-8-yl)methyl)piperidin-4-N yl)propan-2-ol N N N \
eN
O
HO
208 (0) 1-(3-(6-((4-(dimethylamino)piperidin-1-yl)methyl)-4-morpholinothieno [3,2-N d]pyrimidin-2-yl)benzo [b]thiophen-2-S N yl)ethanone N
S

209 (0) 2-(1-((5-(1H-indazol-3-yl)-7-morpholinothiazolo [5,4-d]pyrimidin-2-N yl)methyl)piperidin-4-yl)propan-2-ol r -<N I -N S
N-NH
O
H
210 (0) 2-(1-((5-(2-methylbenzofuran-3-yl)-7-morpholinothiazolo [5,4-d]pyrimidin-2-N yl)methyl)piperidin-4-yl)propan-2-ol i,N I N
\
N S N -:-HO
HO

211 (O) 2-methyl-2-(4-((5-(2-methylbenzofuran-3-yl)-7-N morpholinothiazolo [5,4-d]pyrimidin-2-N N yl)methyl)piperazin-l-yl)propanamide i N S N \
NJ O

O
212 (O) 4-(5-(2-methylbenzofuran-3-yl)-2-((3-morpholinoazetidin- l -N yl)methyl)thiazolo [5,4-d]pyrimidin-7-N - N yl)morpholine N S N \
O
-N

O~
213 (O) 4-(1-((2-(2-methylbenzofuran-3-yl)-4-morpholinothieno [3,2-d]pyrimidin-6-N yl)methyl)azetidin-3 -yl)morpho line s ~N

N Fk:: N \
O
C-) 214 (O) 2-(4-((2-(6-fluoroimidazo [ 1,2-a]pyridin-5-yl)-4-N morpholinothieno [3,2-d]pyrimidin-6-S NZ N yl)methyl)piperazin-l-yl)-2-N N methylpropanamide ~N N
N F
> -NH2 O

215 (O) 2-(4-((2-(1H-indazol-3-yl)-4-morpholinothieno [3,2-d]pyrimidin-6-N yl)methyl)piperazin-l -yl)-2-s methylpropanamide N

N N 1 \
No N-NH
N

O

216 C0~ N,N-dimethyl-l -((4-morpholino-2-(1 H-pyrrolo[2,3-c]pyridin-3-yl)thieno[3,2-N d]pyrimidin-6-yl)methyl)piperidin-4-S N amine N
NH
-N

217 (0) 4-(6-((4-(dimethylamino)piperidin- l -yl)methyl)-4-morpholinothieno [3,2-N d]pyrimidin-2-yl)isoquinolin-1(2H)-one iN
N

N O
N H

218 C~~ 2-(1-((2-(2-(2-hydroxyethyl)-1H-benzo [d]imidazol-l-yl)-9-methyl-6-N morpholino-9H-purin-8-N N yl)methyl)piperidin-4-yl)propan-2-ol N N N~N
N

219 (0) 2-(1-((9-methyl-6-morpholino-2-(2-(pyridin-3-yl)-1 H-benzo[d]imidazol-l-N yl)-9H-purin-8-yl)methyl)piperidin-4-N yl)propan-2-ol i N N IN
\
N
N~
HO

220 ( 0) 1-(8-((4-(2-hydroxypropan-2-yl)piperidin- l -yl)methyl)-9-methyl-6-N morpholino-9H-purin-2-yl)-2-methyl-N 1H-indazol-3(2H)-one N N NZN
N
O
HO

221 F (0) 4-(6-((6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)methyl)-2-(2-methyl-lH-N benzo [d]imidazol- l -yl)thieno [3,2-N s N d]pyrimidin-4-yl)morpholine NN \
~N
222 (0) 2-(1-((2-(imidazo[1,5-a]pyridin-8-yl)-9-methyl-6-morpholino-9H-purin-8-N yl)methyl)piperidin-4-yl)propan-2-ol N I iN
N N N N
HO

223 C~~ 2-(1-((5-(2-methyl-lH-benzo [d]imidazol- l -yl)-7-N morpholinothiazolo [5,4-d]pyrimidin-2-N N yl)methyl)piperidin-4-yl)propan-2-ol N f -</ :]I S NIN

N
HO

224 (O) 2-(1-((9-methyl-6-morpholino-2-(2-(tetrahydrofuran-2-yl)-1 H-N benzo [d]imidazol- l -yl)-9H-purin-8-N yl)methyl)piperidin-4-yl)propan-2-ol /--<I :: I "

N
N N IN
e0- N
HO

225 (O) 2-(1-((2-(3-fluoroquinolin-4-yl)-9-methyl-6-morpholino-9H-purin-8-N yl)methyl)piperidin-4-yl)propan-2-ol N IN N N N
F N
HO

226 C~~ (3R,4S)-1-((2-(2-ethyl-lH-benzo [d]imidazol-l-yl)-9-methyl-6-N morpholino-9H-purin-8-yl)methyl)-3-~N :][I I fluoro-N,N-dimethylpiperidin-4-amine i N N N N
N
-N F

227 C~~ (3S,4R)-1-((2-(2-ethyl-lH-benzo [d]imidazol-1-yl)-9-methyl-6-N morpholino-9H-purin-8-yl)methyl)-3-N N fluoro-N,N-dimethylpiperidin-4-amine i N
N~N
N
0 \
J-N
i -N F

228 C~~ N,N-dimethyl-l-((2-(3-methylisoquinolin-4-yl)-4-N morpholinothieno [3,2-d]pyrimidin-6-S yl)methyl)piperidin-4-amine N

N
-N

229 C~~ N,N-dimethyl-1-((2-(2-methylbenzo[b]thiophen-3-yl)-4-N morpholinothieno [3,2-d]pyrimidin-6-s N yl)methyl)piperidin-4-amine N \ I N I \
S
N

230 2-methyl-2-(4-((7-methyl-2-(2-methyl-() 1H-benzo[d]imidazol-1-yl)-4-N morpholinothieno [3,2-d]pyrimidin-6-s NZ N - yl)methyl)piperazin-l-yl)propanamide N \ NN \

O NJ N
H2Nt 231 C~~ 2-(1-((7-methyl-2-(2-methyl-1 H-benzo [d]imidazol- l -yl)-4-N morpholinothieno [3,2-d]pyrimidin-6-s - N yl)methyl)piperidin-4-yl)propan-2-ol NlN-111 N \
N
P
HO-232 C0~ 4-(1-((7-methyl-2-(2-methyl-1 H-benzo [d]imidazol- l -yl)-4-N morpholinothieno [3,2-d]pyrimidin-6-S N yl)methyl)piperidin-4-yl)morpholine N N-N \

-N
O~
233 (0) 2-(1-((9-methyl-6-morpholino-2-(2-propyl-1 H-benzo [d]imidazol- l -yl)-9H-N purin-8-yl)methyl)piperidin-4-N yl)propan-2-ol N N N1~ \
N
H O

234 H2N 2-(4-((2-(3-methoxy-IH-indazol-l-yl)-\~0 4 -morpholinothieno[3,2-d]pyrimidin-6-N yl)methyl)piperazin-l -yl)-2-(0) N methylpropanamide N

N N
1.
N-O
235 OH 2-(1-((2-(3-methoxy-1H-indazol-l-yl)-C N~ 9-methyl-6-morpholino-9H-purin-8-yl)methyl)piperidin-4-yl)propan-2-ol N N N

N::1 N" _N
N-O

236 OH 2-(1-((9-ethyl-2-(2-methyl-lH-N~ benzo [d]imidazol-1-yl)-6-morpholino-9H-purin-8-yl)methyl)piperidin-4-yl)propan-2-ol N N XXNQ
N
237 (O) 2-(1-((2-(2-cyclobutyl-lH-benzo [d]imidazol-l -yl)-9-methyl-6-N morpholino-9H-purin-8-N yl)methyl)piperidin-4-yl)propan-2-ol N f -<I :: I
N N N
N
HO

238 (O) 2-(1-((9-methyl-6-morpholino-2-(2-morpholino-1 H-benzo [d]imidazol- l -N yl)-9H-purin-8-yl)methyl)piperidin-4-N yl)propan-2-ol N N N N' ~ /

~ N N
J
HO O

240 (O) 2-methyl-2-(4-((2-(2-methyl-1 H-benzo [d]imidazol- l -yl)-4-N morpholinofuro [3,2-d]pyrimidin-6-0 N yl)methyl)piperazin-l-yl)propanamide N ~,p N N
N
ci O

241 (O) 2-(1-((2-(2-methyl-lH-benzo [d]imidazol- l -yl)-4-N morpholinofuro [3,2-d]pyrimidin-6-O N yl)methyl)piperidin-4-yl)propan-2-ol N N
~,-N
OH

242 (O) 2-(2-methyl-1 H-benzo [d]imidazol-l-yl)-4-morpholino-6-((3-N morpholinoazetidin- l -O N yl)methyl)furo[3,2-d]pyrimidine N N N
v ,-N
OJ

243 (O) 2-(4-((2-(benzo[d]isothiazol-3-yl)-4-morpholinothieno [3,2-d]pyrimidin-6-N yl)methyl)piperazin-l -yl)-2-S N methylpropanamide N \ N
N-S
N

O

244 (O) 2-(1-((5-(8-methylimidazo[1,2-a]pyridin-5-yl)-7-N morpholinothiazolo [5,4-d]pyrimidin-2-N N yl)methyl)piperidin-4-yl)propan-2-ol i UN
N \S I N Nn -~Sl\ ) I
OH

245 (O) 2-(1-((2-(3-ethoxy-IH-indazol-l-yl)-9-methyl-6-morpholino-9H-purin-8-N yl)methyl)piperidin-4-yl)propan-2-ol N
N N:: NIN
N
O
HO

246 (O) 2-(3-(6-((4-(dimethylamino)piperidin-1-yl)methyl)-4-morpholinothieno [3,2-N d]pyrimidin-2-yl)benzo [b]thiophen-2-s N yl)propan-2-ol N
S
-N HO

247 HO CO 2-(1-((9-isopropyl-2-(2-methyl-lH-benzo [d]imidazol-l-yl)-6-morpholino-N 9H-purin-8-yl)methyl)piperidin-4-NU/N N yl)propan-2-ol ~N
N~N \
~
248 (O) 2-(4-((5-(imidazo[1,2-a]pyridin-5-yl)-7-morpholinothiazolo[4,5-d]pyrimidin-N 2-yl)methyl)piperazin- l -yl)-2-~s N methylpropanamide N `N DI N N N
K:) >NH2 O

249 (O) 2-(1-((2-(imidazo[1,2-a]pyridin-5-yl)-4-morpholinofuro [3,2-d]pyrimidin-6-N yl)methyl)piperidin-4-yl)propan-2-ol O I N
N N N N
OH

250 (O) 2-(imidazo[1,2-a]pyridin-5-yl)-4-morpholino-6-((3-morpholinoazetidin-N 1-yl)methyl)furo [3,2-d]pyrimidine N
N VNI/ N
N

N
OJ
251 (O) 2-(1-((2-(cinnolin-4-yl)-9-methyl-6-morpholino-9H-purin-8-N yl)methyl)piperidin-4-yl)propan-2-ol N N
N'N
HO

252 (O) 2-ethyl-l-(8-((4-(2-hydroxypropan-2-yl)piperidin- l -yl)methyl)-9-methyl-6-N morpholino-9H-purin-2-yl)-1 H-N indazol-3(2H)-one N f -</ :: I N N
N
O
HO

253 C~~ (S)-2-(1-((9-methyl-6-morpholino-2-(2-(tetrahydrofuran-2-yl)-1 H-N benzo [d]imidazol- l -yl)-9H-purin-8-N yl)methyl)piperidin-4-yl)propan-2-ol r N N N
N ::Il N
"/H
O
HO

254 C~~ (R)-2-(1-((9-methyl-6-morpholino-2-(2-(tetrahydrofuran-2-yl)-1 H-N benzo [d]imidazol- l -yl)-9H-purin-8-N N yl)methyl)piperidin-4-yl)propan-2-ol r N :: I NIN
C)~ - N
H
O
HO

255 (O) 2-(1-((2-(2-(ethylamino)-1H-benzo [d]imidazol-l-yl)-9-methyl-6-N morpholino-9H-purin-8-N N yl)methyl)piperidin-4-yl)propan-2-ol r N
N!N \
N :: I

HN

256 (O) 4-(5 -(2-methyl-1 H-benzo [d]imidazol-1-yl)-2-((3-morpholinoazetidin-l-N yl)methyl)thiazolo[4,5-d]pyrimidin-7-4g yl)morpholine pN N N N
N
C N>
OJ

257 (O) 3-(1-((9-methyl-2-(2-methyl-1 H -benzo [d]imidazol-l-yl)-6-morpholino-N 9H-purin-8-yl)methyl)piperidin-4-N N _ yl)oxetan-3-ol N'"-'N:: N~N \

~N
OH
O
[00151] Table 2.

No. Structure Name 258 CO~ 2,2-dimethyl-N-((9-methyl-2-(2-methyl-1 H-benzo [d]imidazol-1-yl)-N 6-morpholino-9H-purin-8-r-lN L N yl)methyl)propan- l -amine NH N N N
N
259 C~~ 1-(9-methyl-2-(2-methyl-lH-benzo [d]imidazol- l -yl)-6-N morpholino-9H-purin-8-yl)-N-((3-N . methyloxetan-3---</ yl)methyl)methanamine NH / N N
N
O

260 C~~ 1-(l-((9-methyl-2-(2-methyl-lH-benzo [d]imidazol- l -yl)-6-N morpholino-9H-purin-8-N ZN yl)methyl)piperidin-4-~N Nyl)cyclobutanol OH

261 C~~ 2-(1-((9-methyl-6-morpholino-2-(2-(pyrrolidin- l -yl)-1 H-N benzo [d]imidazol- l -yl)-9H-purin-N JLN 8-yl)methyl)piperidin-4-yl)propan-</ 2-01 N
HO G

262 C~~ 2-(1-((2-(2-(3-fluorooxetan-3-yl)-1 H-benzo [d]imidazol- l -yl)-9-N methyl-6-morpholino-9H-purin-8-N yl)methyl)piperidin-4-yl)propan-2-/</ :: I - of N
N N IN \ 9 eF--N
O O
H

263 C~~ 3-(1-((2-(2-ethyl-lH-benzo [d]imidazol- l -yl)-9-methyl-N 6-morpholino-9H-purin-8-N L N c yl)methyl)piperidin-4-yl)oxetan-3-of N N NN \
OH
O

264 C~~ 2-methyl-2-(4-((9-methyl-2-(2-methyl-1 H-benzo[d]imidazol- l -yl)-N 6-morpholino-9H-purin-8-~N . N yl)methyl)piperazin- l -yl)propan- l -of N N NLN \
N- N
~OH

265 CO~ 2-(1-((9-methyl-2-(2-methyl-lH-benzo [d]imidazol- l -yl)-6-N morpholino-9H-purin-8-yl)methyl)piperidin-3-yl)propan-2-N ::(I , ~--~~ of C N N N

HO
266 CO~ 2-methyl-l-(1-((9-methyl-2-(2-methyl-1 H-benzo [d]imidazol- l -yl)-N 6-morpholino-9H-purin-8-N yl)methyl)piperidin-4-yl)propan-2-N :[I , f --/ of N N LN \ I

OH
267 CO~ 4-(9-methyl-2-(2-methyl-1 H-benzo [d]imidazol- l -yl)-8-((4-N (2,2,2-trifluoroethyl)piperazin- l -N yl)methyl)-9H-purin-6-~--~~ N yl)morpholine ~N N N.ZN
`N~

~-F
F F

268 (4-methyl-l-((9-methyl-2-(2-(O) methyl- lH-benzo[d]imidazol-l-yl)-N 6-morpholino-9H-purin-8-NI yl)methyl)piperidin-4-yl)methanol N N NN N

N
OH

269 C~~ (R)-2-hydroxy-l-(4-((9-methyl-2-(2-methyl-1 H-benzo [d]imidazol- l -N yl)-6-morpholino-9H-purin-8-N yl)methyl)piperazin- l -yl)propan- l --N l NIN one N N
O~

HO
270 ~~~ adamantan-l-yl-[9-methyl-2-(2-methyl-benzoimidazol- l -yl)-6-N morpholin-4-yl-9H-purin-8-~NH N yl methyl]-amine XLNQ 271 C0 N-((9-methyl-2-(2-methyl-1 H-benzo [d]imidazol- l -yl)-6-N N morpholino-9H-purin-8-yl)methyl)-NH N N 2,3-dihydro-lH-inden-l-amine r N I N~\N \
N
272 ~ (4R)-N-((9-methyl-2-(2-methyl-(0) [d]imidazol-1-yl)-6-N morpholino-9H-purin-8-NH N yl)methyl)bicyclo[2.2.1]heptan-2-~r I
N N" 'N \ / amine N

273 CO~ 1-(((9-methyl-2-(2-methyl-lH-benzo [d]imidazol- l -yl)-6-HO N morpholino-9H-purin-8-NH N N yl)methylamino)methyl)cyclohexan r of N NIN
N

274 ~~~ (1-((9-methyl-2-(2-methyl-1 H-benzo [d]imidazol- l -yl)-6-HO N morpholino-9H-purin-8-NH N N yl)methylamino)cyclopentyl)metha nol N Ni `N

N

275 C~~ N,1-dimethyl-N-((9-methyl-2-(2-methyl- 1 H-benzo [d]imidazol- l -yl)-N 6-morpholino-9H-purin-8-N NN N yl)methyl)piperidin-4-amine N N'I'lkN

N

276 4-(8-(isoindolin-2-ylmethyl)-9-(0) methyl-2-(2-methyl-lH-N benzo [d]imidazol- l 9~, N 6-yl)morpholine N N~N

277 4-(8-((4-0 (cyclopropylmethyl)piperazin-l-N yl)methyl)-9-methyl-2-(2-methyl-N 1 H-benzo [d]imidazol-l-yl)-9H-~N N purin-6-yl)morpholine N N~NII

278 O 4-(8-((4,4-difluoropiperidin- l --F F 1)methy1)-9-methy1-2-(2-methy1 N 1 H-benzo [d]imidazol- l -yl)-9H-N N purin-6-yl)morpholine N
N N _N
N

279 N-((9-methyl-2-(2-methyl-1 H-/ (O) benzo[d]imidazol-l-yl)-6-N morpholino-9H-purin-8-yl)methyl)-N H N 1-phenylethanamine /
N NIN \ I

N

280 4-(8-((4-(methoxymethyl)piperidin-0 1-yl)methyl)-9-methyl-2-(2-() methyl- l H-benzo [d]imidazol- l -yl)-N 9H-purin-6-yl)morpholine N N ~, N N N

N
281 4-((9-methyl-2-(2-methyl-1 H-(0) morpholino-9H-purin-8-Ho N~N 1 yl)methylamino)cyclohexanol /---N

282 C0 1-(9-methyl-2-(2-methyl- l H-benzo [d]imidazol- l -yl)-6-N N morpholino-9H-purin-8-yl)-N-((l -NH N N methY1PiPeridin-2-\~
N :: I " N N \ yl)methyl)methanamine N
283 4-(8-((dihydro-1 H-pyrido [ 1,2-N (0) a]pyrazin-2(6H,7H,8H,9H,9aH)-N yl)methyl)-9-methyl-2-(2-methyl-~-N N N 1H-benzo[d]imidazol-l-yl)-9H-~i l purin-6-yl)morphohne N Ni `N

284 ~ 1-methyl-N-((9-methyl-2-(2-methyl-1 H-benzo [d]imidazol- l -yl)-N 6-morpholino-9H-purin-8-N NH N N yl)methyl)piperidin-4-amine N N~N
N

285 C ) N,2-dimethyl-N-((9-methyl-2-(2-methyl-1 H-benzo [d]imidazol- l -yl)-N 6-morpholino-9H-purin-8-N N yl)methyl)propan-l-amine ~ NN

N N N

286 1-(4-((9-methyl-2-(2-methyl-1 H-benzo[d]imidazol-l-yl)-6-N
/~ morpholino-9H-purin-8-~j-N_ rNH N yl)methylamino)piperidin-l-~/
N N N yl)ethanone 287 O 4-(1-((9-methyl-2-(2-methyl-lH-C benzo[d]imidazol-l-yl)-6-N morphohno-9H-purin-8-yl)methyl)pyrrolidin-3-yl)morpholine N N ~N

N Ni`N

N
288 ~~~ N-((9-methyl-2-(2-methyl-1 H-benzo [d]imidazol- l -yl)-6-N morpholino-9H-purin-8-oaNHN XL yl)methyl)tetrahydro-2H-pyran-4-N amine N

289 F F F p 4-(9-methyl-2-(2-methyl-lH-(J benzo[d]imidazol-l-yl)-8-((3-N (trifluoromethyl)pyrrolidin- l -yl)methyl)-9H-purin-6-NN i - yl)morpholine N N X N \ I

~N
290 C~~ N-methyl-l-(9-methyl-2-(2-methyl-1 H-benzo [d]imidazol-l-yl)-6-N morpholino-9H-purin-8-yl)-N-ON N ((tetrahydrofuran-2-r N
-< yl)methyl)methanamine N N~N \
~N
291 N 1-((9-methyl-2-(2-methyl-1 H-(0) benzo[d]imidazol-l-yl)-6-N morpholino-9H-purin-8-\-X/ :: I N N yl)methyl)piperidine-4-carbonitrile N
l N Ni `N \

292 C~~ 2-methyl-l-((9-methyl-2-(2-methyl-1 H-benzo [d]imidazol- l -yl)-HO,/\- N 6-morpholino-9H-purin-8-NH N L N q yl)methylamino)propan-2-ol N N!N \
N
293 (0) 3,3,3-trifluoro-N-((9-methyl-2-(2-F methyl-1 H-benzo [d]imidazol- l -yl)-F3--~ N 6-morpholino-9H-purin-8-F ~-N H N N yl)methyl)propan- l -amine N I NAN \

294 C0~ 4,4-difluoro-N-((9-methyl-2-(2-methyl-1 H-benzo[d]imidazol- l -yl)-F N 6-morpholino-9H-purin-8-FNN I N yl)methyl)cyclohexanamine N NLNII~~

295 ~ 1-isopropyl-N-methyl-N-((9-methyl-2-(2-methyl-1 H-i N benzo[d]imidazol-l-yl)-6---N NN morpholino-9H-purin-8-N N N yl)methyl)piperidin-4-amine )--N

296 0 N,N-diethyl-l-((9-methyl-2-(2-N methyl- lH-benzo[d]imidazol-l-yl)-N 6-morpholino-9H-purin-8-yl)methyl)pyrrolidin-3 -amine N` /N I N
N NIN
N
297 C0~ 1-(9-methyl-2-(2-methyl-lH-benzo [d]imidazol- l -yl)-6-N morpholino-9H-purin-8-yl)-N-0 NH N N ((tetrahydrofuran-3-I N yl)methyl)methanamine N N
i 1 N
298 0 N-methyl-N-(l-((9-methyl-2-(2-N -Jkl methyl-1 H-benzo [d]imidazol- l -yl)-6-morpholino-9H-purin-8-N yl)methyl)pyrrolidin-3-6N N N yl)acetamide \-</ :: I /l N NIN
~N

299 HO (R)-(l-((9-methyl-2-(2-methyl-lH-(o) benzo[d]imidazol-l-yl)-6-N morpholino-9H-purin-8-N N 'NI yl)methyl)pyrrolidin-3-yl)methanol ~N N^N \
N
300 C~~ 4-(8-((3,3-dimethylpyrrolidin-l-yl)methyl)-9-methyl-2-(2-methyl-N 1 H-benzo [d]imidazol-1-yl)-9H-N N purin-6-yl)morpholine / N
~N NN

301 CO~ 4-(8-((3,3-diethylpyrrolidin-l-yl)methyl)-9-methyl-2-(2-methyl-N 1 H-benzo [d]imidazol-1-yl)-9H-N N purin-6-yl)morpholine ~ N
~N ~N'N
N
302 4-(8-((3-isobutylpyrrolidin- l -( yl)methyl)-9-methyl-2-(2-methyl-N 1 H-benzo [d]imidazol-l-yl)-9H-purin-6-yl)morpholine N N ~N

N Ni N \
N
303 ~~~ N-((9-methyl-2-(2-methyl-lH-benzo [d]imidazol- l -yl)-6-N morpholino-9H-purin-8-yl)methyl)-NH N N 2-phenylpropan-2-amine i N N'IN
'IN
N

304 0 4-(9-methyl-2-(2-methyl-lH-Q 0 benzo [d]imidazol- l -yl)-8-((l, l -dioxo-4-(tetrahydro-2H-thiopyran-N CN 4-yl)piperazin-l-yl)methyl)-9H--N N purin-6-yl)morpholine ` ~
N I NI
N
N

305 HOB (S)-(l-((9-methyl-2-(2-methyl-lH-() benzo[d]imidazol-l-yl)-6-N morpholino-9H-purin-8-N N yl)methyl)pyrrolidin-3-yl)methanol N
306 -N/ C~~ 1-((2-(2-ethyl-lH-benzo [d]imidazol-1-yl)-9-methyl-N 6-morpholino-9H-purin-8-N N N yl)methyl)-N,N-dimethylpiperidin-- \N N N 4-amine rN

307 C~~ 2-(1-((2-(2-(l-fluorocyclopropyl)-1 H-benzo [d]imidazol-l -yl)-9-N methyl-6-morpholino-9H-purin-8-N yl)methyl)piperidin-4-yl)propan-2-/</ :: I " of N
N N IN N
F
HO

308 C~~ 2-(1-((2-(2-(cyclopropylmethyl)-1 H-benzo [d]imidazol-l -yl)-9-N methyl-6-morpholino-9H-purin-8-N yl)methyl)piperidin-4-yl)propan-2-/</ :: I of N N
N
HO

309 C~~ 4-(1-((2-(2-ethyl-lH-benzo [d]imidazol- l -yl)-9-methyl-N 6-morpholino-9H-purin-8-N yl)methyl)azetidin-3-yl)morpholine N N. N

N

310 4-(8-((3,3-dimethyl-4-(2-(0) l -N yl)methyl)-2-(2-ethyl-1 H-~N benzo[d]imidazol-l-yl)-9-methyl-~N N NN_ 9H-purin-6-yl)morpholine N
N~

O=S

311 2-((1-((2-(2-ethyl-1 H-(0) 6-morpholino-9H-purin-8-~N N yl)methyl)azetidin-3-0 N N yl)(methyl)amino)-2-H2N c N methylpropanamide ~N

312 4-(2-(2-ethyl-1 H-benzo[d]imidazol-l-yl)-9-methyl-N 8-((4-(2-1 (methylsulfonyl)ethyl)piperazin- l -N~N N yl)methyl)-9H-purin-6-N yl)morpholine o~S

313 C~~ 1-(1-((2-(2-ethyl-lH-benzo [d]imidazol- l -yl)-9-methyl-N 6-morpholino-9H-purin-8-~N N yl)methyl)azetidin-3-yl)-2-N N N N methylpropan-l-ol / N
HO

314 C0~ 4-(2-(2-ethyl-lH-benzo [d]imidazol- l -yl)-9-methyl-N 8-((4-(oxetan-3-yl)piperidin- l -N I yl)methyl)-9H-purin-6-N
/--~ yl)morpholine N N N~N

N
O

315 C0 2-(1-((9-methyl-2-(2-methyl-l H-benzo [d]imidazol- l -yl)-6-N morpholino-9H-purin-8-N yl)methyl)azetidin-3-yl)propan-2-ol N
N N ~N
N
H
O
316 C0 3-(1-((9-methyl-2-(2-methyl-1 H-benzo [d]imidazol- l -yl)-6-N morpholino-9H-purin-8-~N N yl)methyl)piperidin-4-yl)pentan-3-i 'l N N^N ol N
/N
HO

317 C0 4-(1-((9-methyl-2-(2-methyl-1 H-benzo [d]imidazol- l -yl)-6-N morpholino-9H-purin-8-N yl)methyl)piperidin-4-fN N N \ yl)tetrahydro-2H-pyran-4-ol O

318 (S)-4-(8-((3-(1,1-dioxo-(0) isothiazolidin-2-yl)pyrrolidin-l-N yl)methyl)-9-methyl-2-(2-methyl-1 H-benzo [d]imidazol-l-yl)-9H-/ I purin-6-yl)morpholine N N N N
/ ~t -- N
N O

319 C~~ 2-(1-((9-methyl-2-(2-(1-methyl-1 H-pyrazol-5-yl)-1 H-N benzo [d]imidazol- l -yl)-6-N N morpholino-9H-purin-8-N~N N~N yl)methyl)piperidin-4-yl)propan-2-of N
N~
HO

320 CO~ (R)-4-(8-((3-(1,1-dioxo-isothiazolidin-2-yl)pyrrolidin-l-N yl)methyl)-9-methyl-2-(2-methyl-N 1H-benzo [d]imidazol-l-yl)-9H-purin-6-yl)morpholine N N:: NIN

cr N321 O N-((9-methyl-2-(2-methyl-1 H-() benzo[d]imidazol-1-yl)-6-N morpholino-9H-purin-8-yl)methyl)-N 2-(4-methylthiazol-2-yl)ethanamine HN /N N"N

N
N
S\L

((9-methyl-2-(2-methyl-1H-(0) benzo[d]imidazol-l-yl)-6-N morpholino-9H-purin-8-yl)methyl)-N 2-(pyridin-2-yl)ethanamine HN /N N" N

/'N
N

323 C0~ 1-(l-((9-methyl-2-(2-methyl-lH-benzo [d]imidazol- l -yl)-6-N morpholino-9H-purin-8-N xN~ yl)methyl)piperidin-4-N yl)cyclopentanol N
OP' 324 C~~ 7-((2-(2-ethyl-lH-benzo [d]imidazol-1-yl)-9-methyl-N 6-morpholino-9H-purin-8-N yl)methyl)-2-oxa-7-/- < azaspiro[3.5]nonane N N NZN
N
O

325 C0~ 4-(2-(2-ethyl-lH-benzo [d]imidazol-1-yl)-9-methyl-N 8-((3-(tetrahydro-2H-pyran-4-N N yl)azetidin-l-yl)methyl)-9H-purin-N /-</N N N 6-yl)morpholine oop 326 C~~ N,N-dimethyl-l -((9-methyl-2-(2-methyl-1 H-benzo[d]imidazol- l -yl)-N 6-morpholino-9H-purin-8-N yl)methyl)piperidine-4--(r :: I '- carboxamide N N IN O

N-327 ~0 8-((9-methyl-2-(2-methyl-1 H-benzo [d]imidazol- l -yl)-6-N morpholino-9H-purin-8-yl)methyl)-~N 1-oxa-3,8-diazaspiro[4.5]decan-2-N \N I N N \ one O
O"N
H
328 CO~ 4-(1-((9-methyl-2-(2-methyl-lH-benzo [d]imidazol- l -yl)-6-N morpholino-9H-purin-8-N l yl)methyl)azetidin-3-yl)morpholine N N N N \
v /~ - N
~N

329 O 4-(9-methyl-2-(2-methyl-1 H-benzo[d]imidazol-l-yl)-8-((4-(2-N (methylsulfonyl)ethyl)piperazin- l -r-<l yl)methyl)-9H-purin-6-CN, N N N \ yl)morpholine N
0, 330 4-(8-((3,3-dimethyl-4-(2-(0) (methylsulfonyl)ethyl)piperazin- l -N 1 meth 1 9 meth 12 2 meth 1 ~N I -N 1H-benzo[d]imidazol-l-yl)-9H-CN % N N / purin-6-yl)morpholine ~ N
O~~ N
0=S
331 C0 4-(1-((2-(2-ethyl-lH-benzo [d]imidazol- l -yl)-9-methyl-N 6-morpholino-9H-purin-8-N _ yl)methyl)azetidin-3-yl)-2,2-~ N N N V dimethylmorpholine N
332 C0~ 2-(1-((5-(2-ethyl-lH-benzo [d]imidazol-1-yl)-7-N morpholinothiazolo [5,4-N N d]pyrimidin-2-yl)methyl)piperidin-~5 N~N 4-yl)propan-2-ol N
O
HO
333 0 -((9-methyl-2-N'Jkl (2-methyl-1 H-benzo [d]imidazol- l -xH C J yl)-6-morpholino-9H-purin-8-N yl)methyl)pyrrolidin-3-::I N yl)acetamide N\-</N
N NIN
N

334 CO (R)-4-(I-((9-methyl-2-(2-methyl-I H-benzo [d]imidazol- l -yl)-6-N CO morpholino-9H-purin-8-H yl)methyl)pyrrolidin-3-N yl)morpholine N N N
**-</ :: I N N N \

N
335 0 (S)-N-methyl-N-(l -((9-methyl-2-N" (0) (2-methyl-lH-benzo[d]imidazol-l-H yl)-6-morpholino-9H-purin-8-N yl)methyl)pyrrolidin-3-N N yl)acetamide ~ N
~N NN

336 CO (S)-4-(1-((9-methyl-2-(2-methyl-1 H-benzo [d]imidazol-1-yl)-6-N H CO) morpholino-9H-purin-8-N yl)methyl)pyrrolidin-3-yl)morpholine N~N I ~N

N N N \
N
337 C~~ 2-(1-((2-(2-ethoxy-lH-benzo [d]imidazol-1-yl)-9-methyl-N 6-morpholino-9H-purin-8-/-/N yl)methyl)piperidin-4-yl)propan-2-:: I of N
N NIN
O1 \
l--_ N

OH /

338 C~~ 2-(1-((2-(2-isopropoxy-lH-benzo [d]imidazol- l -yl)-9-methyl-N 6-morpholino-9H-purin-8-N N yl)methyl)piperidin-4-yl)propan-2-of NN11-- \
N
OH

339 C~~ 2-methyl-2-(1-((9-methyl-2-(2-methyl-1 H-benzo [d]imidazol-1-yl)-N 6-morpholino-9H-purin-8-r--N JLN yl)methyl)piperidin-4-yl)propan-l-of N N
N
OH

340 C~~ 4-(8-((4-tert-butylpiperazin-l-yl)methyl)-9-methyl-2-(2-methyl-N 1 H-benzo [d]imidazol- l -yl)-9H-N purin-6-yl)morpholine i N N N N
NJ N

341 C~~ 2-(1-((2-(2-ethyl-lH-benzo [d]imidazol- l -yl)-9-methyl-N 6-morpholino-9H-purin-8-N yl)methyl)piperidin-4-yl)-2-~--~~ methylpropan-l-ol N N N
N
OH

342 C0~ N-((9-methyl-2-(2-methyl-1 H-benzo [d]imidazol- l -yl)-6-N morpholino-9H-purin-8-yl)methyl)-2-(pyrazin-2-yl)ethanamine FN NH N N N

N

343 C~~ 7-((9-methyl-2-(2-methyl-lH-benzo [d]imidazol- l -yl)-6-N morpholino-9H-purin-8-yl)methyl)-N I N 7-azaspiro [3.5 ]nonan-2-ol N N NN
HO

344 (0) 2-(1-(2-(9-methyl-2-(2-methyl-lH-N benzo [d]imidazol- l -yl)-6-morpholino-9H-purin-8-"IN yl)ethyl)piperidin-4-yl)propan-2-ol Ho N N~
N

345 C~~ 4-(2-(2-ethyl-lH-benzo [d]imidazol- l -yl)-8-((3-N fluoro-1,3'-biazetidin-1'-yl)methyl)-N N 9-methyl-9H-purin-6-N N N N \ yl)morpholine p -N
p F

346 C~~ 2-methyl-l-(1-((9-methyl-2-(2-methyl-1 H-benzo [d]imidazol- l -yl)-N 6-morpholino-9H-purin-8-N N yl)methyl)piperidin-4-yl)propan-l-r N N N~N \ of / N
HO

347 C~~ azetidin-l-yl(l-((9-methyl-2-(2-methyl- 1 H-benzo [d]imidazol- l -yl)-N 6-morpholino-9H-purin-8-N yl)methyl)azetidin-3-yl)methanone N N NZ N

N
O

348 C~~ (1-((9-methyl-2-(2-methyl-lH-benzo [d]imidazol- l -yl)-6-N morpholino-9H-purin-8-yl)methyl)azetidin-3-yl)(pyrrolidin-N ::(I , ~--~r 1-yl)methanone O N N N
N

349 C~~ (R)-azetidin-l-yl(l-((9-methyl-2-(2-methyl-1 H-benzo [d]imidazol- l -N yl)-6-morpholino-9H-purin-8-N yl)methyl)pyrrolidin-3-~--~/ 'lN yl)methanone N N
v ~N
GNO

350 C0~ (R)-(l-((2-(2-ethyl-lH-benzo [d]imidazol- l -yl)-9-methyl-N 6-morpholino-9H-purin-8-N N yl)methyl)pyrrolidin-3-~--~~ yl)(pyrrolidin-l-yl)methanone N N C~O

351 C~~ (R)-N,N-dimethyl-l-((9-methyl-2-(2-methyl-1 H-benzo [d]imidazol- l -N yl)-6-morpholino-9H-purin-8-N I yl)methyl)pyrrolidine-3-~--~i N carboxamide N N~N
\/ ,N
--NCO

352 C0 (R)-1-((2-(2-ethyl- l H-benzo [d]imidazol-1-yl)-9-methyl-N 6-morpholino-9H-purin-8-N yl)methyl)-N,N-~--~i N dimethylpyrrolidine-3-carboxamide N~N

_N
--NCO
/
353 C0 2,2-dimethyl-4-(1-((9-methyl-2-(2-methyl-1 H-benzo [d]imidazol-1-yl)-N 6-morpholino-9H-purin-8-N yl)methyl)azetidin-3-yl)morpholine i N N N N
N

354 C~~ 4-(2-(2-ethyl-lH-benzo [d]imidazol- l -yl)-9-methyl-N 8-((3-(1,1-dioxo-N l N thiomorpholino)azetidin-l-N N N~N V / yl)methyl)-9H-purin-6-/ yl)morpholine N
N
O=S
O

355 C~~ 4-(2-(2-methyl-lH-benzo [d]imidazol- l -yl)-9-methyl-N 8-((3-(1,1-dioxo-~N thiomorpholino)azetidin-l-yl)methyl)-9H-purin-6-N %N N N \
N yl)morpholine v , 0 =(--) O
356 C~~ 2-methyl-2-(4-((9-methyl-2-(2-methyl-1 H-benzo[d]imidazol- l -yl)-N 6-morpholino-9H-purin-8-/'N N yl)methyl)piperazin-l-yl)propane-N N N!N~ 1,3-diol HO NJ
'l-tOH

357 C~~ (R)-3-methyl-2-(4-((9-methyl-2-(2-methyl-1 H-benzo [d]imidazol- l -yl)-N 6-morpholino-9H-purin-8-N N yl)methyl)piperazin- l -yl)butan- l -ol z :: I ~N NIN
`N~ N
-COH

358 C0~ 2-(1-((2-(2-(2-methoxyethylamino)-1 H-N benzo[d]imidazol- l -yl)-9-methyl-N N 6-morpholino-9H-purin-8-~N N~N yl)methyl)piperidin-4-yl)propan-2-ol N
HN
HO

359 (R)-1-(1-((9-methyl-2-(2-methyl-HOh- C~~ 1H-benzo [d]imidazol-l-yl)-6-morpholino-9H-purin-8-N Y1)methYl)piperidin-4-Y1)propan-1-N\-</ N I N of NXN i N
360 O (S)-1-(1-((9-methyl-2-(2-methyl-HO N) 1 H-benzo [d]imidazol-l -yl)-6-morpholino-9H-purin-8-yl)methyl)piperidin-4-yl)propan- l -N\--</ N I N of N NX
N I
N
361 C0 (S)-3-methyl-2-(4-((9-methyl-2-(2-methyl-1 H-benzo [d]imidazol- l -yl)-N 6-morpholino-9H-purin-8-r--N yl)methyl)piperazin- l -yl)butan- l -ol N> N N XXNQ
NJ N
III.
OH

362 C~~ 2-(1-((5-(2-methyl-lH-benzo [d]imidazol- l -yl)-7-N morpholinothiazolo [5,4-N N d]pyrimidin-2-yl)methyl)piperidin-N~S I 3-yl)propan-2-ol N N
N
OH

363 C~~ N,N-dimethyl-l -((9-methyl-2-(2-methyl-1 H-benzo[d]imidazol- l -yl)-N 6-morpholino-9H-purin-8-rN . yl)methyl)azetidine-3-carboxamide N N NI
N
N
O
N-364 C~~ (R)-(l-((9-methyl-2-(2-methyl-lH-benzo [d]imidazol- l -yl)-6-N morpholino-9H-purin-8-N yl)methyl)pyrrolidin-3-~ N
'l yl)(pyrrolidin-l-yl)methanone N N N^N
~N
G N' O

365 C~~ (1-((2-(2-ethyl-lH-benzo [d]imidazol- l -yl)-9-methyl-N 6-morpholino-9H-purin-8-yl)methyl)azetidin-3-yl)(pyrrolidin-N ::[I , 1-yl)methanone O N N N N
N
G

366 CO~ 1-((2-(2-ethyl-lH-benzo [d]imidazol- l -yl)-9-methyl-N 6-morpholino-9H-purin-8-N N _ yl)methyl)-N,N-dimethylazetidine-~N N L N V? 3-carboxamide N
O
N-367 ~ 2-(1-(2-(2-(2-ethyl-lH-N benzo [d]imidazol- l -yl)-9-methyl-6-morpholino-9H-purin-8-Ho ,N ~ yl)ethyl)piperidin-4-yl)propan-2-ol 'N

8 ~ 2-methyl-2-(4-(2-(9-methyl-2-(2-N methyl-1 H-benzo [d]imidazol- l -yl)-N~N N L N 6-morpholino-9H-purin-8-0 u ~~ yl)ethyl)piperazin-l-N"2 / " N yl)propanamide ~N

369 CO~ 8-((9-methyl-2-(2-methyl-1 H-benzo [d]imidazol- l -yl)-6-N morpholino-9H-purin-8-yl)methyl)-N 1,4-dioxa-8-azaspiro [4.5 ]decane i N N N N
N
O

370 C0 8-((9-methyl-2-(2-methyl-1 H-benzo [d]imidazol- l -yl)-6-N morpholino-9H-purin-8-yl)methyl)-N = N 1-oxa-8-azaspiro[4.5]decane NN I NLN

O N

371 CO~ N-(2-(1-((9-methyl-2-(2-methyl-1 H-benzo [d]imidazol- l -yl)-6-N morpholino-9H-purin-8-~/N _ yl)methyl)piperidin-4-yl)propan-2-N <N N N V yl)acetamide - N

O
372 (S)-2-(1-((9-methyl-2-(2-methyl-HOW ~~~ 1 H-benzo [d]imidazol-l -yl)-6-morpholino-9H-purin-8-N yl)methyl)piperidin-4-yl)butan-2-ol N N NI N
N" N
N
373 HO C o (S)-1-(1-((9-methyl-2-(2-methyl-1 H-benzo [d]imidazol- l -yl)-6-N morpholino-9H-purin-8-yl)methyl)piperidin-4-yl)ethanol N XXNQ

N
374 HOi (R)-1-(1-((9-methyl-2-(2-methyl-Co 1 H-benzo [d]imidazol- l -yl)-6-N morpholino-9H-purin-8-yl)methyl)piperidin-4-yl)ethanol NN XXN#Q

/ N

375 (0) 4-(8-((dihydro-1 H-pyrido [ 1,2-N a]pyrazin-2(6H,7H,8H,9H,9aH)-N yl)methyl)-9-methyl-2-(2-methyl-~N N 1H-benzo[d]imidazol-l-yl)-9H-i I purin-6-yl)morpholine N NIN

376 L I O N,N-diethyl-l-((9-methyl-2-(2-N C methyl- lH-benzo[d]imidazol-l-yl)-N 6-morpholino-9H-purin-8-yl)methyl)pyrrolidin-3 -amine N~N I N

N NIN \
N
377 (0) 4-(8-((dihydro-lH-pyrido[1,2-N a]pyrazin-2(6H,7H,8H,9H,9aH)-N yl)methyl)-9-methyl-2-(2-methyl-~_N N N 1H-benzo[d]imidazol-l-yl)-9H-",-/ I N purin-6-yl)morpholine N N

N
378 I O N,N-diethyl-l-((9-methyl-2-(2-N C methyl- lH-benzo[d]imidazol-l-yl)-N 6-morpholino-9H-purin-8-N N N

N NNN \ 1 N
379 C~~ 8-((9-methyl-2-(2-methyl-lH-benzo [d]imidazol- l -yl)-6-N morpholino-9H-purin-8-yl)methyl)-N 2,8-diazaspiro[4.5]decan-l-one RC ~i I N
ANQ
N
H
380 C~~ 8-((9-methyl-2-(2-methyl-lH-benzo [d]imidazol- l -yl)-6-N morpholino-9H-purin-8-yl)methyl)-~N I . 3-oxa-8-azabicyclo[3.2.1]octane ~ N

N N NN \ I
O

381 C~~ (R)-2-(4-((9-methyl-2-(2-methyl-1 H-benzo [d]imidazol- l -yl)-6-N morpholino-9H-purin-8-~N = N yl)methyl)piperazin-l-yl)butan-l-ol N N N~N
N
N
HO

382 (S)-2-(4-((9-methyl-2-(2-methyl-(0) (S)-2-(4-((9-methyl-2-(2-methyl-1 H-benzo [d]imidazol- l -yl)-6-N morpholino-9H-purin-8-~N . N yl)methyl)piperazin-l-yl)butan-l-ol N N N~N
N
N

HO
383 .O~ 2-(1-((9-methyl-2-(2-methyl-l H-benzo [d]imidazol-1-yl)-6-N morpholino-9H-purin-8-~N N yl)methyl)piperidin-4-yl)propan-2-N N N~N amine \
N

384 CO~ 5-((9-methyl-2-(2-methyl-1 H-benzo [d]imidazol-1-yl)-6-N morpholino-9H-purin-8-yl)methyl)-~N l 2-oxa-5-azabicyclo[2.2.1]heptane ~ N
rN N NN

385 CO~ (1-((2-(2-ethyl-lH-benzo [d]imidazol- l -yl)-9-methyl-N 6-morpholino-9H-purin-8-N . yl)methyl)-4-methylpiperidin-4-N N N N \ yl)methanol N
OH

386 C~~ 4-(9-methyl-2-(2-methyl-lH-benzo [d]imidazol- l -yl)-8-((3-N (piperidin-l-yl)azetidin-l-N yl)methyl)-9H-purin-6-N N NN yl)morpholine N

387 CO~ 4-(8-((4-tert-butylpiperazin-l-yl)methyl)-2-(2-ethyl-1 H-N benzo [d]imidazol- l -yl)-9-methyl-I 9H-purin-6-yl)morpholine It, N
N
N N
No N
388 CO~ (S)-1-(1-((2-(2-ethyl-lH-benzo [d]imidazol- l -yl)-9-methyl-N 6-morpholino-9H-purin-8-f N yl)methyl)azetidin-3-yl)-2-N N N N \ methylpropan-1-ol / N
HOI

389 CO~ N-methyl-l-((9-methyl-2-(2-methyl- 1 H-benzo [d]imidazol- l -yl)-N 6-morpholino-9H-purin-8-yl)methyl)-N-(tetrahydrofuran-3-N :11 , ~--~r yl)piperidin-4-amine N \ I
N
-N

b O
390 (0) 1-((2-(2-ethyl-lH-benzo [d]imidazol- l -yl)-9-methyl-N 6-morpholino-9H-purin-8-N N yl)methyl)-N-methyl-N-~N I N~N (tetrahydrofuran-3-yl)piperidin-4-~ amine -N

ZD
O
391 CO~ 7-((2-(2-ethyl-lH-benzo [d]imidazol- l -yl)-9-methyl-N 6-morpholino-9H-purin-8-/N yl)methyl)-2-methyl-7-N N~N azaspiro[3.5]nonan-2-ol N N

HO
392 CO~ 4-(2-(2-(2-ethyl-lH-benzo [d]imidazol- l -yl)-9-methyl-~--~ N 6-morpholino-9H-purin-8-0 N N N yl)ethyl)-2,2-dimethylmorpholine r N N, N
N

393 C~~ (S)-azetidin-l-yl(l-((2-(2-ethyl-lH-benzo [d]imidazol- l -yl)-9-methyl-N 6-morpholino-9H-purin-8-N N yl)methyl)pyrrolidin-3-~N \ yl)methanone N L
N
N co 394 C~~ 9-((2-(2-ethyl-lH-benzo [d]imidazol-1-yl)-9-methyl-N 6-morpholino-9H-purin-8-N N yl)methyl)-1-oxa-4,9-~N N~N diazaspiro [5.5 ]undecan-3 -one O N

~NH
O

395 O~ 4-(8-((1 S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-N ylmethyl)-2-(2-ethyl-1 H-benzo [d]imidazol- l -yl)-9-methyl-NN ~ L 9H-purin-6-yl)morpholine N N N N \
HNJ ~N

396 CO~ (3-methyl-l-((9-methyl-2-(2-methyl-1 H-benzo [d]imidazol- l -yl)-N 6-morpholino-9H-purin-8-N yl)methyl)pyrrolidin-3-N--1 N I yl)(pyrrolidin-l-yl)methanone N N N \
O / N
v 397 C~~ 2,2-dimethyl-4-(2-(9-methyl-2-(2-methyl-1 H-benzo[d]imidazol- l -yl)-N 6-morpholino-9H-purin-8-0 N N N yl)ethyl)morpholine N N~N

398 CO~ (S)-1-((2-(2-ethyl-lH-benzo [d]imidazol- l -yl)-9-methyl-N 6-morpholino-9H-purin-8-yl)methyl)-N,N-N ::(I , r ~--~ dimethylpyrrolidine-3-carboxamide N N N
N
N O

399 CO~ (S)-(l-((2-(2-ethyl-lH-benzo [d]imidazol- l -yl)-9-methyl-N 6-morpholino-9H-purin-8-N yl)methyl)pyrrolidin-3-N N NI N yl)(pyrrolidin-l-yl)methanone / N

GN O

400 C0 9-((9-methyl-2-(2-methyl-1 H-benzo [d]imidazol- l -yl)-6-N morpholino-9H-purin-8-yl)methyl)-N 1,5 -dioxa-9-azaspiro [5.5 ]undecane ~r I N
N NN
O N
UO

401 0 4-(8-((4-tert-butylpiperazin-l-yl)methyl)-2-(2-ethyl-lH-N CNI
benzo [d]imidazol- l -yl)-9H-purin-~N N N 6-yl)morpholine N :: I N~N

H N

402 C0 2-(4-((2-(2-ethyl-lH-benzo [d]imidazol- l -yl)-9-methyl-N 6-morpholino-9H-purin-8-N yl)methyl)piperazin- l -yl)-2-/-- ., methylpropan- l -ol N N N
~N :: I
eztN
N

-;/\-OH
403 C0~ 4-(8-((4-tert-butylpiperazin-l-yl)methyl)-2-(2-cyclopropyl-1 H-N benzo [d]imidazol- l -yl)-9-methyl-N I t 9H-purin-6-yl)morpholine ~N N N N
eN
N

404 C0~ 2-((1R,5S,6r)-3-((9-methyl-2-(2-methyl-1 H-benzo [d]imidazol- l -yl)-N 6-morpholino-9H-purin-8-N yl)methyl)-3-~N N N azabicyclo[3.1.0]hexan-6-yl)propan-2-ol Hli- -N
"H
HO`

405 C0~ (R)-1-(1-((2-(2-ethyl-lH-benzo [d]imidazol- l -yl)-9-methyl-N 6-morpholino-9H-purin-8-N yl)methyl)azetidin-3-yl)-2-N rN N N \ methylpropan-1-ol N
HO

406 2-methyl-2-(4-((9-methyl-2-(2-(0) 2-methyl-2-(4-((9-methyl-2-(2-methyl-1 H-benzo[d]imidazol- l -yl)-N 6-morpholino-9H-purin-8-N yl)methyl)piperazin-l-i ~N N NIN yl)propanamide `N~ N

O =Y\

407 CO~ (R)-1-(1-(8-((4-(2-hydroxypropan-2-yl)piperidin- l -yl)methyl)-9-N methyl-6-morpholino-9H-purin-2-,N N yl)-1H-benzo[d]imidazol-2-N N N N yl)propan-2-ol N
HO HO

408 CO~ (S)-1-(1-(8-((4-(2-hydroxypropan-2-yl)piperidin- l -yl)methyl)-9-N methyl-6-morpholino-9H-purin-2-N N yl)-1H-benzo[d]imidazol-2-NN N~N yl)propan-2-ol N
HO HO' 409 CO~ (R)-8-((2-(2-ethyl-lH-benzo [d]imidazol- l -yl)-9-methyl-N 6-morpholino-9H-purin-8-N yl)methyl)octahydropyrazino[2,1-c][1,4]oxazine N~ N

410 C0 4-methyl-5-((9-methyl-2-(2-methyl-1 H-benzo[d]imidazol- l -yl)-N 6-morpholino-9H-purin-8-N L yl)methylamino)pentane- 1,4-diol r NH N I NIN
HO
OH
411 0 2-(1-(8-((4-tert-butylpiperazin-l-N yl)methyl)-6-morpholino-9H-purin-N 2-yl)-1 H-benzo [d]imidazol-2-ON N yl)ethanol r N
N NZN
H

HO
412 (O) (1 S,2R)-2-(4-((9-methyl-2-(2-methyl-1 H-benzo[d]imidazol- l -yl)-N 6-morpholino-9H-purin-8-yl)methyl)piperazin- l -N NN
N :]I N~ yl)cyclopentanol (J/ ~- N
N

OH
413 CO~ 2-(4-((2-(2-cyclopropyl-lH-benzo [d]imidazol- l -yl)-9-methyl-N 6-morpholino-9H-purin-8-N N yl)methyl)piperazin-l-yl)-2-N r-<"N N N methylpropan- l -ol (-i /
N eN
~OH

414 C0~ 4-(2-(2-ethyl-lH-benzo [d]imidazol- l -yl)-9-methyl-N 8-((4-(3-methyloxetan-3-N N yl)piperazin-l-yl)methyl)-9H-N N N~N purin-6-yl)morpholine `N~ N

415 C0~ (S)-4-(8-((hexahydropyrrolo[1,2-a]pyrazin-2(1 H)-yl)methyl)-9-N methyl-2-(2-methyl-1 H-N N benzo[d]imidazol-l-yl)-9H-purin-~--~~ I - 6-yl)morpholine N N N N
N) N

416 C0~ (R)-4-(8-((hexahydropyrrolo[1,2-a]pyrazin-2(1 H)-yl)methyl)-9-N methyl-2-(2-methyl-1 H-N benzo[d]imidazol-l-yl)-9H-purin-NN I NIN 6-yl)morpholine o / N

417 ethyl 2-(( 1 S,4S)-5-((2-(2-ethyl-lH-C0 benzo [d]imidazol-1-yl)-9-methyl-N 6-morpholino-9H-purin-8-N yl)methyl)-2,5-~--~~ N diazabicyclo [2.2. 1 ]heptan-2-yl)-2-N N N~N methylpropanoate N
O
O

418 CO)benzo[d]imidazol- 1-((2-(2-ethyl-lH-l 6-morpholino-9H-purin-8-N NN V _ yl)methyl)-N-methyl-N-(oxetan-3-~N I N yl)piperidin-4-amine N
-N

b-419 CO~ N-((1-((2-(2-ethyl-lH-benzo [d]imidazol- l -yl)-9-methyl-N 6-morpholino-9H-purin-8-N N yl)methyl)azetidin-3-yl)methyl)-N-~ methyltetrahydrofuran-3-amine N N NIN
~N

420 C0 2-(1-((5-(2-ethyl-lH-benzo [d]imidazol-1-yl)-7-N morpholinothiazolo[4,5-g d]pyrimidin-2-yl)methyl)piperidin-N I N N V 4-yl)propan-2-ol DJN

OH
421 CO~ N-((1-((2-(2-ethyl-lH-benzo [d]imidazol-1-yl)-9-methyl-N 6-morpholino-9H-purin-8-~N yl)methyl)azetidin-3-yl)methyl)-N-/ methyloxetan-3-amine N 1~
N
::(NIN
N
I.,)--N--CO

422 CO~ 4-(2-(2-ethyl-lH-benzo [d]imidazol- l -yl)-8-((3-N (tetrahydro-2H-pyran-4-yl)azetidin-N . N 1-yl)methyl)-9H-purin-6-<' N N yl)morpholine N
H

e~:N
O

423 0 2-methyl-2-(4-((2-(2-methyl-lH-benzo [d]imidazol- l -yl)-6-N~ N morpholino-9H-purin-8-yl)methyl)piperazin- l -NN ~~ - yl)propanamide N N N \
H ~N

424 OH O 2-ethyl-l-(8-((4-(2-hydroxypropan-2-yl)piperidin- l -yl)methyl)-6-N morpholino-9H-purin-2-yl)-1 H-N~N indazol-3(2H)-one N NIN
,-/ N
O
425 H N O 2-(4-((2-(2-ethyl-lH-z O benzo[d]imidazol-l-yl)-6-N (N) morpholino-9H-purin-8-yl)methyl)piperazin- l -yl)-2-N methylpropanamide N I N~N \
H
N
426 OH O 2-(1-((2-(2-(2-hydroxyethyl)-1H-( N~ benzo [d]imidazol- l -yl)-6-morpholino-9H-purin-8-yl)methyl)piperidin-4-yl)propan-2-N~N I N ~ of H N N \
HO

427 CO~ 2-(4-((2-(2-(2-hydroxyethyl)-1H-benzo [d]imidazol- l -yl)-9-methyl-N 6-morpholino-9H-purin-8-~N N yl)methyl)piperazin- l -yl)-2-N N N N methylpropan-l-ol N N
-A-OH HO

428 CO~ 1-(8-((4-tert-butylpiperazin-l-yl)methyl)-9-methyl-6-morpholino-N 9H-purin-2-yl)-N-methyl-1 H-~N benzo[d]imidazol-2-amine N N N~N \

No HNrN

429 C~~ 4-methyl-l-((9-methyl-2-(2-methyl-1 H-benzo [d]imidazol- l -yl)-N 6-morpholino-9H-purin-8-r N NI N
N N:: I NIN \
~N
HO

430 C~~ 2-(1-((2-(2-ethylbenzofuran-3-yl)-9-methyl-6-morpholino-9H-purin-N 8-yl)methyl)piperidin-4-yl)propan-N N N
O
OH

431 CO~ N-((9-methyl-2-(2-methyl-1 H-benzo [d]imidazol- l -yl)-6-N morpholino-9H-purin-8-yl)methyl)-2-(l H-pyrazol- l -yl)ethanamine N:]~
It, NH N N,N

~N
N~
J

432 ~ (1-aminocyclopropyl)(4-((2-(2-ethyl- 1 H-benzo [d]imidazol- l -yl)-9-N methyl-6-morpholino-9H-purin-8-N yl)methyl)piperazin- l -~N
N N N \ yl)methanone N
N
J

433 C ) 2-(1-(2-(5-(2-ethyl-lH-N benzo [d]imidazol- l -yl)-7-morpholinothiazolo [5,4-NN d]pyrimidin-2-yl)ethyl)piperidin-4-HO N~s N::~
11 yl)propan-2-ol N

434 (0) 2-(1-(8-((4-tert-butylpiperazin-l-yl)methyl)-9-methyl-6-morpholino-N 9H-purin-2-yl)-1 H-N ~ benzo[d]imidazol-2-yl)ethanol (I) N N N \ j N
HO

435 N-methyl- l -(9-methyl-6-(0) pyran-4-yl)azetidin-l-yl)methyl)-N 9H-purin-2-yl)-1 H---(N benzo[d]imidazol-2-amine N N N N'~
NN
H
O
436 ~ 4-(5-(2-ethyl-1 H-benzo [d]imidazol-l-yl)-2-((3-(1,1-N dioxo-thiomorpholino)azetidin- l -3~ N yl)methyl)thiazolo[5,4-N s N N V/ d]pyrimidin-7-yl)morpholine v J-N
~N
o 437 O 0 2-(4-((2-(2-ethyl-lH-H2N N benzo[d]imidazol-l-yl)-9-methyl-(N 6-morpholino-9H-purin-8-N yl)methyl)piperazin- l -yl)-2-N methylpropanamide N N \ 4) N

438 0~ 0 2-(4-((2-(2-cyclopropyl-lH-H2N N benzo[d]imidazol-l-yl)-9-methyl-C N 6-morpholino-9H-purin-8-C yl)methyl)piperazin- l -yl)-2-`N N ~N
methylpropanamide N NLN \
N
439 0 0 2-(4-((2-(2-isopropyl-lH-H2N N benzo[d]imidazol-l-yl)-9-methyl-(N 6-morpholino-9H-purin-8-N yl)methyl)piperazin- l -yl)-2-N methylpropanamide N N-.4N \
N
440 0 2-(4-((2-(2-ethyl-1 H-benzo[d]imidazol-1-yl)-9-methyl-N 6-morpholino-9H-purin-8-~N yl)methyl)piperazin- l -yl)-2-~N N N~N~ methylpropane-l,3-diol NJ/

HOFt HO
441 C0 4-(8-((4-isopropylpiperazin-l-yl)methyl)-9-methyl-2-(2-methyl-N 1 H-benzo [d]imidazol- l -yl)-9H-N L N purin-6-yl)morpholine N N N1 N \

N
N~

442 C~~ 4-(2-(2-ethyl-lH-benzo [d]imidazol- l -yl)-8-((4-N isopropylpiperazin- l -yl)methyl)-9-N N methyl-9H-purin-6-yl)morpholine N N N~N
N - N

443 C~~ 1-(8-((4-(2-hydroxypropan-2-yl)piperidin-l-yl)methyl)-9-methyl-N 6-morpholino-9H-purin-2-yl)-2-N isopropyl- lH-indazol-3(2H)-one N N NN
N
O
HO

444 CO~ 4-(8-((4-cyclobutylpiperazin-l-yl)methyl)-2-(2-ethyl-1 H-N benzo [d]imidazol- l -yl)-9-methyl-N 9H-purin-6-yl)morpholine NJ N
d 445 C~~ 4-(8-((4-tert-butylpiperazin-l-yl)methyl)-2-(isoquinolin-4-yl)-9-N methyl-9H-purin-6-yl)morpholine NJ N

446 C0 4-(9-methyl-2-(2-methyl-1 H-benzo [d]imidazol- l -yl)-8-((4-N (oxetan-3-yl)piperidin- l -yl)methyl)-9H-purin-6-N :[I , ~--~~ yl)morpholine N N
N
O

447 C0 N-methyl- l -(9-methyl-6-morpholino-8-((4-(oxetan-3 -N yl)piperidin- l -yl)methyl)-9H--iN purin-2-yl)-1H-benzo[d]imidazol-\N 2-amine N N11__ -9 NN
H
O
448 C0~ 4-(5-(2-methyl-lH-benzo [d]imidazol-l-yl)-2-((3-(1,1-N dioxo-thiomorpholino)azetidin- l -3~ N yl)methyl)thiazolo[5,4-SiNN / d]pyrimidin-7-yl)morpholine ~N
~N

449 C0~ 4-(2-(2-isopropyl-lH-benzo [d]imidazol- l -yl)-9-methyl-N 8-((3-(i,1-dioxo-N N thiomorpholino)azetidin-l-r NlN \ yl)methyl)-9H-purin-6-N N
:]~ -p _ yl)morpholine N

O=(J

450 C0 4-(2-(2-cyclopropyl-lH-benzo [d]imidazol- l -yl)-9-methyl-N 8-((4-(oxetan-3-yl)piperidin- l -N N _ yl)methyl)-9H-purin-6-NN N L N V J yl)morpholine N
O

451 2-(1-(2-(2-(2-ethyl-lH-(0) benzo[d]imidazol-l-yl)-9-methyl-N 6-morpholino-9H-purin-8-:]~
HON
N yl)ethyl)azetidin-3-yl)propan-2-ol N NX N
N

452 1-(2-(2-(2-ethyl-1 H-(O) benzo[d]imidazol-l-yl)-9-methyl-HOCN 6-morpholino-9H-purin-8-N~N l - yl)ethyl)-4-methylpiperidin-4-ol N N NEN \

53 2-methyl-2-(4-((9-methyl-2-(2-(0) 2-methyl-2-(4-((9-methyl-2-(2-(methylamino)-1 H-N benzo [d]imidazol- l -yl)-6-N N morpholino-9H-purin-8-~N N N yl)methyl)piperazin- l -yl)propan-l-~ of N HNrN
OH

454 O 4-(2-(2-(azetidin- l -yl)- l H-N benzo [d]imidazol-l-yl)-8-((4-tert-N butylpiperazin- l -yl)methyl)-9-~N N methyl-9H-purin-6-yl)morpholine N
N ::,, NLN \
/ N1_N
G

455 OH O 2-(1-((2-(2-(azetidin-l-yl)-lH-( N) benzo [d]imidazol- l -yl)-9-methyl-6-morpholino-9H-purin-8-yl)methyl)piperidin-4-yl)propan-2-N N of rN
ON

456 ethyl 2-methyl-2-(4-((9-methyl-2-(0) (2-methyl-lH-benzo[d]imidazol-l-N yl)-6-morpholino-9H-purin-8-N I yl)methyl)pip eridin- l -N N N yl)propanoate O N N
`0 457 (0) 4-(8-((4-tert-butylpiperazin-l-N yl)methyl)-2-(2-(1,1-difluoroethyl)-N 1 H-benzo [d]imidazol- l -yl)-9H-~N N NI N
H NIN
N
F F

458 O 1-(2-(2-(2-ethyl-1 H-benzo[d]imidazol-1-yl)-9-methyl-Ho N 6-morpholino-9H-purin-8-N N yl)ethyl)-3-methylazetidin-3-ol N"ZN

EN
459 CO~ 4-(2-(2-(1,1-difluoroethyl)-1 H-benzo [d]imidazol- l -yl)-9-methyl-N 8-((4-(oxetan-3-yl)piperidin- l -N :]l N yl)methyl)-9H-purin-6-N N N ~ N yl)morpholine F N
F
O

460 CO~ (S)-(l-((2-(2-ethyl-lH-benzo [d]imidazol-1-yl)-9-methyl-N 6-morpholino-9H-purin-8-N , yl)methyl)azetidin-3-yl)(3-/- <I I 'IN hydroxypyrrolidin-l-yl)methanone O N N N'^N \
N
HO

461 CO~ (R)-(1-((2-(2-ethyl-lH-benzo [d]imidazol- l -yl)-9-methyl-N 6-morpholino-9H-purin-8-yl)methyl)azetidin-3-yl)(3-N ::(I , N
N \ hydroxypyrrolidin-l-yl)methanone N
N
HO

462 HO (0) 2-(1-((2-(2-tert-butyl-lH-benzo [d]imidazol- l -yl)-9-methyl-N 6-morpholino-9H-purin-8-yl)methyl)piperidin-4-yl)propan-2-N~N I j of N N \ Q
N

463 C~~ 4-(8-((4-tert-butylpiperazin-l-yl)methyl)-2-(2-(1,1-difluoroethyl)-N 1 H-benzo [d]imidazol- l -yl)-9-N ::,I I methyl-9H-purin-6-yl)morpholine N N N
eN
N
~( F

464 C0~ 4-(8-((4-tert-butylpiperazin-l-yl)methyl)-9-methyl-2-(2-N (trifluoromethyl)-1 H-N benzo[d]imidazol-l-yl)-9H-purin-/--~I ~ N N 6-yl)morpholine ~N
N
F-///~/ N
F F

465 7-(2-(2-(2-ethyl-1 H-~/~ N) benzo [d]imidazol-1-yl)-9-methyl-HO_ O( N N 6-morpholino-9H-purin-8-~/ `~'N yl)ethyl)-7-azaspiro[3.5]nonan-2-ol N N'Q/j EN

466 C ) 1-(2-(2-(2-ethyl-1 H-benzo[d]imidazol-1-yl)-9-methyl-Ho N 6-morpholino-9H-purin-8-yl)ethyl)-3-isopropylazetidin-3-ol N WIN
11__ N

467 ~ 4-(9-methyl-2-(2-methyl-1 H-benzo [d]imidazol- l -yl)-8-((3-N (tetrahydro-2H-pyran-4-yl)azetidin-N N 1-yl)methyl)-9H-purin-6-NN N N \ yl)morpholine N
co 468 C0~ 4-(2-(2-(1,1-difluoroethyl)-1H-benzo [d]imidazol- l -yl)-9-methyl-N 8-((3-(tetrahydro-2H-pyran-4-N N yl)azetidin-l-yl)methyl)-9H-purin-N~N 6-yl)morpholine N N
F -N
F
O
O

469 C~~ 4-((2-(2-ethyl-lH-benzo [d]imidazol- l -yl)-9-methyl-N 6-morpholino-9H-purin-8-N yl)methyl)-1-isopropylpiperazin-2-r one N NN
N ~N
0 e4 470 C~~ 4-(5-(2-isopropyl-lH-benzo [d]imidazol- l -yl)-2-((3-N (tetrahydro-2H-pyran-4-yl)azetidin-N N 1-yl)methyl)thiazolo[5,4-1 d]pyrimidin-7-y1)morpholine N S N N
N
O

471 C 0 4-(8-((4-tert-butylpiperazin-l-N yl)methyl)-2-(2-isopropyl-1 H-N benzo [d]imidazol- l -yl)-9-methyl-ON N 9H-purin-6-yl)morpholine r N NN
N
472 C~~ 1-(8-((4-tert-butylpiperazin-l-yl)methyl)-9-methyl-6-morpholino-N 9H-purin-2-yl)-2-ethyl-1 H-indazol-N p 3(2H)-one r cN N N N
N
N
O

473 CO~ 2-(4-((2-(2-(1,1-difluoroethyl)-1 H-benzo [d]imidazol-1-yl)-9-methyl-N 6-morpholino-9H-purin-8-N yl)methyl)piperazin- l -yl)-2-~--~r methylpropan- l -ol F N
-~~-OH

474 C~~ 2-methyl-2-(4-((9-methyl-6-morpholino-2-(2-(trifluoromethyl)-N 1 H-benzo [d]imidazol- l -yl)-9H-N N purin-8-yl)methyl)piperazin-l-~--<r yl)propan-l-ol ~N N :: I N N \
F
-2?-- N
F F
OH
475 CO~ 4-(8-((4-tert-butylpiperazin-l-yl)methyl)-9-methyl-2-(quinolin-4-N yl)-9H-purin-6-yl)morpholine I ~N

476 HO 2-(4-((2-(2-isopropyl-lH-V~ O benzo [d]imidazol- l -yl)-9-methyl-N 6-morpholino-9H-purin-8-N- N yl)methyl)piperazin-l-yl)-2-N N N methylpropan- l -ol N NN \
N

477 OH o 2-(1-((2-(2-((1R,2S)-2-fluorocyclopropyl)-1 H-N benzo [d]imidazol- l -yl)-9-methyl-6-morpholino-9H-purin-8-N\ _<N yl)methyl)piperidin-4-yl)propan-2-N N -N\ p of F

478 HO O (R)-2-(1-((2-(2-(2,2-difluorocyclopropyl)-1 H-C N benzo [d]imidazol- l -yl)-9-methyl-N N 6-morpholino-9H-purin-8-i ::1 yl)methyl)piperidin-4-yl)propan-2-N N-N \ p of / L N
F F

479 OH O 2-(1-((2-(2-((1s,2R)-2-fluorocyclopropyl)-1 H-(0) [d]imidazol- l -yl)-9-methyl-6-morpholino-9H-purin-8-NN - yl)methyl)piperidin-4-yl)propan-2-N N N of N

F

480 HO 0 2-(1-((2-(2-((1R,2R)-2-fluorocyclopropyl)-1 H-( N benzo [d]imidazol- l -yl)-9-methyl-6-morpholino-9H-purin-8-N ~'lN yl)methyl)piperidin-4-yl)propan-2-N Ni `N \ p of / L
a_ F

481 HO O (S)-2-(1-((2-(2-(2,2-difluorocyclopropyl)-1 H-N benzo [d]imidazol- l -yl)-9-methyl-N N 6-morpholino-9H-purin-8-i N yl)methyl)piperidin-4-yl)propan-2-N N~N of N
F F

482 CO~ 4-(5-(2-methyl-lH-benzo [d]imidazol-l -yl)-2-((3-N (tetrahydro-2H-pyran-4-yl)azetidin-N 1-yl)methyl)thiazolo[5,4-NS d]pyrimidin-7-yl)morpholine N S N
N
O

483 CO~ 4-(5-(2-ethyl-lH-benzo [d]imidazol- l -yl)-2-((3-N (tetrahydro-2H-pyran-4-yl)azetidin-N 1-yl)methyl)thiazolo[5,4-d]pyrimidin-7-yl)morpholine N S N N\ 9 I',/,- N
co 484 CO~ 4-(5-(2-cyclopropyl-lH-benzo [d]imidazol- l -yl)-2-((3-N (tetrahydro-2H-pyran-4-yl)azetidin-N 1-yl)methyl)thiazolo[5,4-// d]pyrimidin-7-yl)morpholine N S N

co 485 CO~ 2-(1-((2-(2-ethyl-4-fluoro-lH-benzo [d]imidazol- l -yl)-9-methyl-N 6-morpholino-9H-purin-8-N N yl)methyl)piperidin-4-yl)propan-2-N~N I NIN of tNF
HO

486 CO~ 1-(1-((2-(2-ethyl-lH-benzo [d]imidazol- l -yl)-9-methyl-N 6-morpholino-9H-purin-8-N yl)methyl)azetidin-3-yl)piperidin-N N N~N \ 4-of p -N
N

HO
487 CO~ 2-(1-((2-(2-(azetidin-l-ylmethyl)-1 H-benzo [d]imidazol-l -yl)-9-N methyl-6-morpholino-9H-purin-8-N .I yl)methyl)piperidin-4-yl)propan-2-of N N
N
N
OH
488 OH 2-(4-((2-(2-cyclopropyl-lH-0 benzo [d]imidazol- l -yl)-6-N morpholino-9H-purin-8-N yl)methyl)piperazin- l -yl)-2-~N N methylpropan-l-ol H NN
N

489 OH 2-(4-((2-(2-ethyl-lH-0 benzo[d]imidazol- l -yl)-6-N morpholino-9H-purin-8-N yl)methyl)piperazin- l -yl)-2-N N methylpropan-l-ol H NN
N
490 OH 2-(4-((2-(2-isopropyl-lH-0 benzo [d]imidazol- l -yl)-6-N CN~ morpholino-9H-purin-8-yl)methyl)piperazin- l -yl)-2-~N N N methylpropan-l-ol N N N \ I
~N
491 CO~ 4-(2-(2-ethyl-lH-benzo [d]imidazol-l -yl)-8-((3-(4-N fluoropiperidin- l -yl)azetidin- l -N -~~
yl)methyl)-9-methyl-9H-purin-6-N N N N yl)morpholine N
N

F
492 C~~ 4-(8-((3-(4,4-difluoropiperidin-l-yl)azetidin- l -yl)methyl)-2-(2-ethyl-N 1 H-benzo [d]imidazol- l -yl)-9-N methyl-9H-purin-6-yl)morpholine N~--~~N N ! N

p -N
N

F
F

493 4-(2-(2-(2-ethyl-1 H-O ( N) benzo [d]imidazol- l -yl)-9-methyl-6-morpholino-9H-purin-8-~NN-\ N -isopropylpiperazin-2-N N \ one N

494 C0~ 1'-((2-(2-ethyl-lH-benzo [d]imidazol- l -yl)-9-methyl-N 6-morpholino-9H-purin-8-N yl)methyl)-1,3'-biazetidin-3-ol N N N LN \
~N
N
e4 p HO
495 C0 4-(2-(2-ethyl-lH-benzo [d]imidazol-1-yl)-9-methyl-N 8-((4-(tetrahydro-2H-pyran-4-r-<.,N _ yl)piperazin-l-yl)methyl)-9H-NIN \ purin-6-yl)morpholine N
CN-) - N
O

496 (0) 4-(5-(2-ethyl-lH-benzo [d]imidazol- l -yl)-2-((4-N (oxetan-3-yl)piperidin- l -N yl)methyl)thiazolo[5,4-d]pyrimidin-7-yl)morpholine N S N

-~--N
O

497 ~0 4-(5-(2-cyclopropyl-1 H-benzo [d]imidazol- l -yl)-2-((4-N (oxetan-3-yl)piperidin- l -N I yl)methyl)thiazolo[5,4-N d]pyrimidin-7-yl)morpholine N S N~N

N
O

498 N-methyl- l -(7-morpholino-2-((3-) (tetrahydro-2H-pyran-4-yl)azetidin-N 1-yl)methyl)thiazolo [5,4-N N d]pyrimidin-5-yl)-1H-benzo[d]imidazol-2-amine N S N N
NN
H
ci 499 CO~ 4-(2-(2-cyclopropyl-lH-benzo [d]imidazol- l -yl)-9-methyl-N 8-((3-(tetrahydro-2H-pyran-4-yl)azetidin-l-yl)methyl)-9H-purin-N NN
~N I N 6-yl)morpholine N

O
500 ethyl 2-(4-((2-(2-cyclopropyl-1 H-( ) benzo[d]imidazol-l-yl)-9-methyl-N 6-morpholino-9H-purin-8-N yl)methyl)piperazin-l-yl)-2-N
~N
N N methylpropanoate Y-~

501 C~~ 4-(2-(2-ethyl-lH-benzo [d]imidazol- l -yl)-9-methyl-N 8-((1-(tetrahydro-2H-(1,1-dioxo)-N N _ thiopyran-4-yl)azetidin-3-N N~N yl)methyl)-9H-purin-6-N / N yl)morpholine s0,11 502 ethyl 2-methyl-2-(4-((9-methyl-2-(2-methyl-lH-benzo[d]imidazol-l-(0) N yl)-6-morpholino-9H-purin-8-- yl)methyl)piperazin- l -~N N N /) yl)propanoate O N

503 C~~ 4-(2-(2-ethyl-lH-benzo [d]imidazol- l -yl)-9-methyl-N 8-((1-(tetrahydro-2H-pyran-4-N N yl)azetidin-3-yl)methyl)-9H-purin-N 6-yl)morpholine N N N
/ N
O

504 F 4-(2-(2-ethyl-lH-/ O benzo[d]imidazol-l-yl)-8-((4-(l-- ( ) fluoro-2-methylpropan-2-N~ N yl)piperazin-l-yl)methyl)-9-~N N N methyl-9H-purin-6-yl)morpholine ~N NLN I

tN

505 ~ tert-butyl 4-((9-methyl-2-(2-N methyl-1 H-benzo [d]imidazol- l -yl)-6-morpholino-9H-purin-8-~~ yl)methyl)piperidine-l-carboxylate / N l 91) O_~N
O
506 C~~ 2-methyl-2-(4-((9-methyl-2-(2-methyl-1 H-benzo [d]imidazol- l -yl)-N 6-morpholino-9H-purin-8-rN yl)methyl)piperazin-l-yl)propanoic ~N N N!N~ acid O NJ

HO
507 methyl 2-methyl-2-(4-((9-methyl-() 2-(2-methyl-lH-benzo[d]imidazol-N 1-yl)-6-morpholino-9H-purin-8-N N yl)methyl)pip eridin- l -N " N yl)propanoate j-l-<N O N ~

-O

508 ~~~ 2-methyl-2-(4-((9-methyl-2-(2-methyl-1 H-benzo[d]imidazol- l -yl)-N 6-morpholino-9H-purin-8-N yl)methyl)pip eridin- l -N "N yl)propanamide O N
HZN

509 ~~~ 2-methyl-2-(4-((9-methyl-2-(2-methyl-1 H-benzo[d]imidazol- l -yl)-N 6-morpholino-9H-purin-8-yl)methyl)piperidin- l -yl)propan- l -N N of N
HOr-~

510 C~~ 4-(8-((4-tert-butylpiperazin-l-yl)methyl)-9-methyl-6-morpholino-N 9H-purin-2-yl)isoquinolin-l-amine N \N

N> N

511 C~~ 8-(2-(2-(2-ethyl-lH-benzo [d]imidazol- l -yl)-9-methyl-N 6-morpholino-9H-purin-8-o~N N N yl)ethyl)-3-oxa-8-N 1 NNN azabicyclo [3.2. 1 ]octane N

512 CO~ 2-(1-(9-methyl-6-morpholino-8-((4-(oxetan-3-yl)piperidin-l-N yl)methyl)-9H-purin-2-yl)-1 H-N benzo[d]imidazol-2-yl)ethanol r N N NN
N
HO

O

513 C~~ 4-(2-(2-ethyl-lH-benzo [d]imidazol-1-yl)-9-methyl-N 8-((4-(oxetan-3-yl)piperazin-l-N ~ yl)methyl)-9H-purin-6-~--~~ yl)morpholine NO N N N \
N

514 4-(1-((2-(2-ethyl-1 H-(0) 6-morpholino-9H-purin-8-N N yl)methyl)azetidin-3-yl)piperazin-Nr-<lN
N N \ 2-one D~ -p / N
~N
O
HN

515 CO~ (S)-3-(2-(2-ethyl-lH-benzo [d]imidazol-1-yl)-9-methyl-N 6-morpholino-9H-purin-8-yl)-1-N N isopropylpiperidin-3-ol N v N J~
OH ~ N N

516 OH (S)-2-(1-((2-(2-(l-methoxyethyl)-01 H-benzo [d]imidazol-l -yl)-9-N methyl-6-morpholino-9H-purin-8-yl)methyl)piperidin-4-yl)propan-2-\--(/N I N of N NLN \ Q

517 CO~ N-(l-(8-((4-(2-hydroxypropan-2-yl)piperidin-l-yl)methyl)-9-methyl-N 6-morpholino-9H-purin-2-yl)-1 H-N J(LN _ benzo[d]imidazol-2-yl)acetamide r N N N~N \
N
HN
HO /O

518 CO~ (R)-3-(2-(2-ethyl-lH-benzo [d]imidazol- l -yl)-9-methyl-N 6-morpholino-9H-purin-8-yl)-1-N isopropylpiperidin-3-ol N OH NIN
N

519 OH (R)-2-(1-((2-(2-(l-methoxyethyl)-C01 H-benzo [d]imidazol-l -yl)-9-N methyl-6-morpholino-9H-purin-8-yl)methyl)piperidin-4-yl)propan-2-N I of N N N
/II.? N
/O

520 C0 4-(9-methyl-2-(2-methyl- l H-benzo [d]imidazol- l -yl)-8-N (piperidin-4-ylmethyl)-9H-purin-6-N yl)morpholine f-<N:: N IN HN N

521 C0 2-((1 S,4S)-5-((2-(2-ethyl-lH-benzo [d]imidazol- l -yl)-9-methyl-N 6-morpholino-9H-purin-8-N . N yl)methyl)-2,5-N N L N diazabicyclo[2.2.1]heptan-2-yl)-2-C / methylpropan-l-ol N
HO

522 4-(2-(2-(2-ethyl-1 H-0 (0N) benzo [d]imidazol- l -yl)-9-methyl-6-morpholino-9H-purin-8-HN N~N N yl)ethyl)-6-isopropylpiperazin-2-N NlN / one / EN

523 HO Cod 1-(4-((2-(2-ethyl-lH-benzo [d]imidazol- l -yl)-9-methyl-N 6-morpholino-9H-purin-8-~-N N N yl)methyl)piperazin-l-yl)-2-N N N methylpropan-2-ol / ~N

524 1-((2-(2-ethyl-1 H-HO (O) benzo[d]imidazol-l-yl)-9-methyl-N 6-morpholino-9H-purin-8-N N yl)methyl)azetidin-3-ol N :]l NIN
N
525 C~~ 2-methyl-2-(4-((9-methyl-2-(2-methyl-1 H-benzo[d]imidazol- l -yl)-N 6-morpholino-9H-purin-8-N yl)methyl)piperidin-l-yl)propanoic N N acid O dN
HO

526 (R)-methyl 2-(4-((2-(2-ethyl-1 H-(O) benzo[d]imidazol-l-yl)-9-methyl-N 6-morpholino-9H-purin-8-Ho N IN yl)(hydroxy)methyl)piperidin-l-N Nyl)-2-methylpropanoate / L
O N N

-0 527 (S)-methyl 2-(4-((2-(2-ethyl-1 H-(O) benzo[d]imidazol-l-yl)-9-methyl-N 6-morpholino-9H-purin-8-Ho N N yl)(hydroxy)methyl)piperidin-l-N N L N yl)-2-methylpropanoate O N

-0 528 O methyl 2-(4-(2-(2-ethyl-1 H-benzo[d]imidazol-l-yl)-9-methyl-N 6-morpholino-9H-purine-8-O lN carbonyl)piperidin-l-yl)-2-N Nmethylpropanoate O N
-o 529 C~~ 4-(2-(2-ethyl-lH-benzo [d]imidazol- l -yl)-9-methyl-N 8-((1-(oxetan-3-yl)azetidin-3-N N yl)methyl)-9H-purin-6-f'N yl)morpholine N Z
N N

530 C~~ 4-(8-(azetidin-3-ylmethyl)-2-(2-ethyl-1 H-benzo [d]imidazol-l -yl)-9-N methyl-9H-purin-6-yl)morpholine N I - N

N N~N
HN N

531 C~~ 2-(3-((2-(2-ethyl-lH-benzo [d]imidazol- l -yl)-9-methyl-N 6-morpholino-9H-purin-8-yl)methyl)azetidin-l-yl)-2-N :]:I , N methylpropanamide ~ N~N
N N
>NH2 532 CO~ methyl 2-(3-((2-(2-ethyl-lH-benzo [d]imidazol-1-yl)-9-methyl-N 6-morpholino-9H-purin-8-N yl)methyl)azetidin-l-yl)-2-f'N methylpropanoate N Z \
N

]

533 C0 2-(3-((2-(2-ethyl-lH-benzo [d]imidazol- l -yl)-9-methyl-N 6-morpholino-9H-purin-8-N yl)methyl)azetidin-l-yl)-2-i methylpropan- l -ol r fN N, N
N

HO
534 1-(3-((2-(2-ethyl-1 H-(0) benzo[d]imidazol-l-yl)-9-methyl-N 6-morpholino-9H-purin-8-N yl)methyl)azetidin-l-yl)-2-N N!N methylpropan-2-ol HO
535 C0~ 4-(2-(2-(2-ethyl-lH-benzo benzo[d]imidazol- l -yl)-9-methyl-N 6-morpholino-9H-purin-8-0 N N N yl)ethyl)-3,3-dimethylmorpholine N N~N

/ EN

536 (S)-1-(1-((2-(2-ethyl-1 H-( ) benzo[d]imidazol-l-yl)-9-methyl-N 6-morpholino-9H-purin-8-N NN yl)methyl)azetidin-3-yl)pyrrolidin-N N N" N 'P /j 3-ol N
N

H O\\' 537 ~ 4-(2-(2-ethyl-1 H-N benzo [d]imidazol-1-yl)-9-methyl-s 8-(2-(3-(1,1-dioXo-u N thiomorpholino)azetidin-l-N yl)ethyl)-9H-purin-6-yl)morpholine 538 (R)-1-(1-((2-(2-ethyl-1 H-(O) benzo[d]imidazol-l-yl)-9-methyl-N 6-morpholino-9H-purin-8-N N yl)methyl)azetidin-3-yl)pyrrolidin-N N N~N \ 3-01 N
N

HO

539 4-(2-(2-ethyl-1 H-() benzo[d]imidazol-1-yl)-9-methyl-o, N 8-(2-(1,1-dioxo-o' UN~N thiomorpholino)ethyl)-9H-purin-6-N :NN yl)morpholine N

540 C ) 4-(8-(2-(4,4-difluoropiperidin-l-yl)ethyl)-2-(2-ethyl-1 H-F~ N benzo [d]imidazol- l -yl)-9-methyl-F~~(~/N-` N N 9H-purin-6-yl)morpholine --~N N N1 N

541 O~ 2-(3-((2-(2-ethyl-1 H-benzo [d]imidazol- l -yl)-9-methyl-N 6-morpholino-9H-purin-8-N yl)methyl)azetidin-l-yl)acetamide f'N NN
N

542 2-methyl- l -(4-((9-methyl-2-(2-) methyl-1 H-benzo [d]imidazol- l -yl)-N 6-morpholino-9H-purin-8-ND~ yl)methyl)piperidin-l-yl)propan-2-N WIN of N
HO \

543 C0 4-(9-methyl-2-(2-methyl- l H-benzo [d]imidazol-l -yl)-8-((1-(2-N (methylsulfonyl)ethyl)azetidin-3-N yl)methyl)-9H-purin-6-N~N \ yl)morpholine N )N

S"O
544 4-(9-methyl-2-(2-methyl-1 H-(0) benzo [d]imidazol-l -yl)-8-((1-(2-(methylsulfonyl)ethyl)piperidin-4-N yl)methyl)-9H-purin-6-yl)morpholine /N eNiI N /

dN N
\ S'~O
O
545 CO~ (R)-2-(3-((2-(2-ethyl-lH-benzo [d]imidazol-1-yl)-9-methyl-N 6-morpholino-9H-purin-8-yl)methyl)azetidin-l-N :][I , N yl)propanamide f'N N~N
N N
O~-NH2 O
546 CO~ (S)-2-(3-((2-(2-ethyl-lH-benzo [d]imidazol- l -yl)-9-methyl-N 6-morpholino-9H-purin-8-N I yl)methyl)azetidin-l-N yl)propanamide f'N N~N
N ~N
~-NH2 547 CO~ 4-(1-((2-(2-isopropyl-lH-benzo [d]imidazol- l -yl)-9-methyl-N 6-morpholino-9H-purin-8-N yl)methyl)azetidin-3-yl)morpholine :][I , r /N
N NXN \ /
p -N N

548 CO~ 4-(1-((2-(2-cyclopropyl-lH-benzo [d]imidazol- l -yl)-9-methyl-N 6-morpholino-9H-purin-8-N l yl)methyl)azetidin-3-yl)morpholine N N N
p -N
CN

549 0 2-(5-(2-ethyl-1 H-N benzo [d]imidazol- l -yl)-7-Ho N o morpholinothiazolo[5,4-N ~N
d]pyrimidin-2-yl)-1-(4-(2-s N N hydroxypropan-2-yl)piperidin-l-~N yl)ethanone 550 O 1-(l -((2-(2-isopropyl-1 H-benzo[d]imidazol-l-yl)-9-methyl-N 6-morpholino-9H-purin-8-/-/N yl)methyl)azetidin-3-yl)piperidin-N N N.,N \ / 4-ol PN
N

HO

551 C0~ 1-(1-((2-(2-ethyl-lH-benzo [d]imidazol-1-yl)-9-methyl-N 6-morpholino-9H-purin-8-N N yl)methyl)azetidin-3-yl)-4-N N N%~N methylpiperidin-4-ol 2 ' -N
N
OH
552 4-(8-((3 ,3-dimethylpiperazin- l -(O) yl)methyl)-2-(2-ethyl-lH-N benzo [d]imidazol- l -yl)-9-methyl-9H-purin-6-yl)morpholine N N N N
N
HN

553 C0 4-(2-(2-ethyl- l H-benzo [d]imidazol-1-yl)-9-methyl-N 8-(((l S,4S)-5-(methylsulfonyl)-2,5-N N diazabicyclo[2.2.1]heptan-2-~N N N yl)methyl)-9H-purin-6-0 yl)morpholine N
O S

554 (0) 1-(1-((2-(2-ethyl-lH-benzo [d]imidazol- l -yl)-9-methyl-N 6-morpholino-9H-purin-8-N N yl)methyl)piperidin-4-yl)azetidin-N N N~N 3-01 N
N

H p 555 C0~ 1-isopropyl-4-((2-(2-isopropyl-lH-benzo [d]imidazol- l -yl)-9-methyl-N 6-morpholino-9H-purin-8-N yl)methyl)piperazin-2-one /~
N N XNIN \
O=>
N
556 4-(1-((2-(2-ethyl-1 H-( ) benzo[d]imidazol-l-yl)-9-methyl-N 6-morpholino-9H-purin-8-N N yl)methyl)azetidin-3-yl)-1-N N NN methylpiperazin-2-one N
N
~
O
N

557 ~ 4-(2-(2-ethyl-1 H-N benzo [d]imidazol-1-yl)-9-methyl-o N/-\ N N N 8-(2-(4-(tetrahydro-2H-pyran-4-' N yl)piperazin-l-yl)ethyl)-9H-purin-/ NN

N 6-yl)morpholine 558 ~0~ 2-(4-((9-methyl-2-(2-methyl-1 H-benzo [d]imidazol- l -yl)-6-N morpholino-9H-purin-8-N yl)methyl)piperidin-l-yl)acetamide N NN
N N
~-NH2 559 (R)-2-(4-((9-methyl-2-(2-methyl-(0) (R)-2-(4-((9-methyl-2-(2-methyl-1 H-benzo [d]imidazol- l -yl)-6-N morpholino-9H-purin-8-N N yl)methyl)pip eridin- l -yl)propanamide N~N
N -N

O
560 C0 (S)-2-(4-((9-methyl-2-(2-methyl-1 H-benzo [d]imidazol- l -yl)-6-N morpholino-9H-purin-8-N I yl)methyl)pip eridin- l -N
yl)propanamide N~N
N -N
~-NH2 561 CO~ (R)-4-(2-(2-ethyl-lH-benzo [d]imidazol-l-yl)-8-((4-(3-N fluoropyrrolidin-l -yl)piperidin- l -N N yl)methyl)-9-methyl-9H-purin-6-N yl)morpholine ~N N

N

F
562 CO~ 4-(8-((3,3-difluoro-1,3'-biazetidin-1'-yl)methyl)-2-(2-ethyl-1 H-N benzo [d]imidazol-1-yl)-9-methyl-9H-purin-6-yl)morpholine i ~N XXNQ
N N y -N

F -~3 F

563 C~~ 4-(2-(2-isopropyl-lH-benzo [d]imidazol- l -yl)-9-methyl-N 8-(((l S,4S)-5-(methylsulfonyl)-2,5-N N diazabicyclo[2.2.1]heptan-2-~N N~N V yl)methyl)-9H-purin-6-yl)morpholine N
O 'SN

564 CO~ 4-(2-(2-isopropyl-lH-benzo [d]imidazol- l -yl)-9-methyl-N 8-((4-(tetrahydro-2H-pyran-4-N yl)piperazin-l-yl)methyl)-9H-~ N
N N N purin-6-yl)morpholine CND cc 565 C~~ (S)-4-(2-(2-ethyl-lH-benzo [d]imidazol-l-yl)-8-((4-(3-N fluoropyrrolidin-l -yl)piperidin- l -N yl)methyl)-9-methyl-9H-purin-6-N
I tN
N yl)morpholine N N
N
F

566 O 2-(4-(2-(2-ethyl-1 H-benzo[d]imidazol-1-yl)-9-methyl-N 6-morpholino-9H-purine-8-N carbonyl)piperazin-l-yl)-2-N"'N_ methylpropanamide N
N

567 C~~ (4-tert-butylpiperazin-l-yl)(2-(2-ethyl- 1 H-benzo [d]imidazol- l -yl)-9-N methyl-6-morpholino-9H-purin-8-0 N yl)methanone N N::l NIN
N N

568 C~~ 3-(4-((9-methyl-2-(2-methyl-lH-benzo [d]imidazol- l -yl)-6-N morpholino-9H-purin-8-N N yl)methyl)pip eridin- l -N
N yl)propanenitrile ::~-N
N

569 C~~ (2-(2-ethyl-lH-benzo[d]imidazol-1-yl)-9-methyl-6-morpholino-9H-N purin-8-yl)(4-(2-hydroxypropan-2-0 ~ zN , yl)piperidin-l-yl)methanone N N N
N
HO

570 ~~~ 4-(8-((l-(isoxazol-5-ylmethyl)piperidin-4-yl)methyl)-9-N methyl-2-(2-methyl-1 H-N ~~ benzo[d]imidazol-l-yl)-9H-purin-N N N 6-yl)morpholine /
NN N

571 ~~~ 4-(8-((l-(isoxazol-5-ylmethyl)azetidin-3-yl)methyl)-9-N methyl-2-(2-methyl-1 H-N N benzo[d]imidazol-l-yl)-9H-purin-N N h 6-yl)morpholine ,o N N

572 CO~ (S)-4-(9-methyl-2-(2-methyl-lH-benzo [d]imidazol- l -yl)-8-((l -N (tetrahydrofuran-3-yl)azetidin-3-N :(l I yl)methyl)-9H-purin-6-N
yl)morpholine f'N N~N
N N
O

573 CO~ (R)-4-(9-methyl-2-(2-methyl-1 H-benzo [d]imidazol- l -yl)-8-((l -N (tetrahydrofuran-3-yl)azetidin-3-N N yl)methyl)-9H-purin-6-f'N yl)morpholine N't N )N
co 574 CO~ 2-(1-((2-(2-ethyl-lH-benzo [d]imidazol- l -yl)-4-N morpholinothieno [3,2-d]pyrimidin-S N 6-yl)methyl)piperidin-4-yl)propan-2-ol N N N \

N
O
H
575 4-(8-(2-(3,3-dimethyl-4-0 C N) (methylsulfonyl)piperazin- l -/-\ yl)ethyl)-2-(2-ethyl-lH-s-N N--\N -N benzo[d]imidazol-l-yl)-9-methyl-N N N 9H-purin-6-yl)morpholine N

576 (0) 4-(8-((4-(3,3-difluoroazetidin-l-yl)piperidin-l -yl)methyl)-2-(2-N ethyl-1 H-benzo [d]imidazol- l -yl)-9-N methyl-9H-purin-6-yl)morpholine N N N~N
N
N
FV
F
577 C~~ 1-tert-butyl-4-((2-(2-ethyl-lH-benzo [d]imidazol- l -yl)-9-methyl-N 6-morpholino-9H-purin-8-N :: I ~ yl)methyl)piperazin-2-one r N N N N
~ N
O
N
578 CO~ (S)-2-amino-l-(4-((9-methyl-2-(2-methyl-1 H-benzo [d]imidazol- l -yl)-N 6-morpholino-9H-purin-8-N yl)methyl)piperidin- l -yl)propan- l -one N N

dN N
OIH
H2N ~~~

579 3-methyl-2-(3-((9-methyl-2-(2-(0) 3-methyl-2-(3-((9-methyl-2-(2-methyl-1 H-benzo [d] imidazol- l -yl)-N 6-morpholino-9H-purin-8-yl)methyl)azetidin-l-yl)butanamide N dXXNQ

580 C~~ N,2-dimethyl-2-(3-((9-methyl-2-(2-methyl-1 H-benzo[d]imidazol- l -yl)-N 6-morpholino-9H-purin-8-N yl)methyl)azetidin-l-N N ! N yl )propanamide O N -N

581 C~~ (S)-3-(2-(2-isopropyl-lH-benzo [d] imidazol- l -yl)-9-methyl-N 6-morpholino-9H-purin-8-yl)-1-N N methylpiperidin-3-ol NJ' N N N 9 OHS
S
-N

582 CO~ (R)-3-(2-(2-isopropyl-lH-benzo [d]imidazol- l -yl)-9-methyl-N 6-morpholino-9H-purin-8-yl)-1-N methylpiperidin-3-ol Ki<N
~ OHS N N

583 C~~ 4-(2-(2-isopropyl-lH-benzo [d]imidazol- l -yl)-8-(1-'N O N isopropyl-3-methoxypiperidin-3-~N N yl)-9-methyl-9H-purin-6-N N N N yl)morpholine N
584 CO~ 4-(2-(2-isopropyl-lH-benzo [d]imidazol- l -yl)-8-(1-N isopropyl-3 -methoxypiperidin-3-N yl)-9-methyl-9H-purin-6-N i N yl)morpholine O N :]I N" N

N

585 ~ N,2-dimethyl-2-(4-((9-methyl-2-(2-methyl-1 H-benzo[d]imidazol- l -yl)-N 6-morpholino-9H-purin-8-N N yl)methyl)pip eridin- l -N N yl)propanamide ( J-1 IN:~
O N _ -NH

586 CO~ (S)-4-(2-(2-ethyl-lH-benzo [d]imidazol-l-yl)-8-((3-(3-N fluoropyrrolidin-l -yl)azetidin-l-N yl)methyl)-9-methyl-9H-purin-6-yl)morpholine ~N N N

/ N
F

587 O 1'-((2-(2-ethyl-1 H-benzo[d]imidazol-l-yl)-9-methyl-N 6-morpholino-9H-purin-8-r-lN N yl)methyl)-3-methyl-1,3'-N N N!N biazetidin-3-ol p -N
N
HO-~
588 CO~ 1-(1-((2-(2-ethyl-lH-benzo [d]imidazol- l -yl)-9-methyl-N 6-morpholino-9H-purin-8-N yl)methyl)azetidin-3-yl)pyrrolidin-N N N 2-one N
p EN

589 ~~~ 4-(8-((3-(3,3-difluoropyrrolidin- l -yl)azetidin- l -yl)methyl)-2-(2-ethyl-N 1 H-benzo [d]imidazol- l -yl)-9-,N methyl-9H-purin-6-yl)morpholine N
::(I
r N N N \
N

F
590 ~~~ (R)-4-(2-(2-ethyl-1 H-benzo [d]imidazol-l -yl)-8-((3-(3-N fluoropyrrolidin-l -yl)azetidin-l-N N yl)methyl)-9-methyl-9H-purin-6-yl)morpholine N N~N
p -N
F

591 C0~ (R)- l -isopropyl-3-(2-(2-isopropyl-1 H-benzo [d]imidazol- l -yl)-9-OH N methyl-6-morpholino-9H-purin-8-rN yl)piperidin-3-ol I N
N N::: N"N
N
592 C0~ (S)-1-isopropyl-3-(2-(2-isopropyl-1 H-benzo [d]imidazol- l -yl)-9-OH N methyl-6-morpholino-9H-purin-8-a rN yl)piperidin-3-ol N N N"N
N

593 C0 (2-(2-ethyl- l H-benzo [d]imidazol-1-yl)-9-methyl-6-morpholino-9H-N purin-8-yl)(4-(tetrahydro-2H-(1,1-0 N = dioxo)-thiopyran-4-yl)piperazin-l-N N N N yl)methanone `NJ / -N
O-os 594 C0~ N-tert-butyl- l -((2-(2-ethyl-1 H-benzo [d]imidazol- l -yl)-9-methyl-N 6-morpholino-9H-purin-8-N yl)methyl)azetidin-3-amine N r NN

p N
NH

595 0 N-(2-(2-(2-ethyl-lH-p=5 (0N) benzo [d]imidazol- l -yl)-9-methyl-6-morpholino-9H-purin-8-HN--X_(N . N yl)ethyl)tetrahydro(1,1-N
N l N dioxo)thiophen-3-amine D

EN
596 C0~ 4-(8-((2,2-dimethyl-4-(methylsulfonyl)piperazin- l -N yl)methyl)-2-(2-ethyl-1 H-N benzo[d]imidazol-1-yl)-9-methyl-9H-purin-6-yl)morpholine N-/N N

NJ
0=

597 CO~ 2-((1 S,4S)-5-((2-(2-ethyl-lH-benzo [d]imidazol- l -yl)-9-methyl-N 6-morpholino-9H-purin-8-N yl)methyl)-2,5-/--~~ diazabicyclo [2.2. 1 ]heptan-2-N N N yl)acetamide N

N -~ J N
~NH2 598 C~~ 4-(2-(2-ethyl-lH-benzo [d]imidazol-1-yl)-9-methyl-N 8-(((l S,4S)-5-(oxetan-3-yl)-2,5-N diazabicyclo[2.2.1]heptan-2-/--/ I N yl)methyl)-9H-purin-6-N N N N yl)morpholine N.__/ N

599 CO~ 2-methyl-2-(4-(methyl(9-methyl-2-(2-methyl-1 H-benzo [d]imidazol- l -N yl)-6-morpholino-9H-purin-8-N N yl)amino)piperidin-l-N~ I ~ yl)propanamide (Is' N N /
N N
>NH2 O
600 (0) 2-(2-ethyl-lH-benzo[d]imidazol-l-yl)-N,N-bis(2-methoxyethyl)-9-N methyl-6-morpholino-9H-purine-8-0 N N carboxamide OSN N~N \
N

601 C~~ (4-(dimethylamino)piperidin-l-yl)(2-(2-ethyl-1 H-N benzo [d]imidazol- l -yl)-9-methyl-0 N 6-morpholino-9H-purin-8-r yl)methanone N
N N N
N
-N

602 2-methyl-2-(3-((9-methyl-2-(2-(0) 2-methyl-2-(3-((9-methyl-2-(2-methyl-1 H-benzo[d]imidazol- l -yl)-N 6-morpholino-9H-purin-8-yl)methyl)pyrrolidin- l -N :]:
ItN
r yl)propanamide CN N
O
-Y~-603 C~~ 2-methyl-2-(3-((9-methyl-2-(2-methyl-1 H-benzo [d]imidazol-1-yl)-N 6-morpholino-9H-purin-8-N N yl)methyl)pyrrolidin- l -N N N yl)propanamide /
CN~ N
O
-Y~-604 CO~ 1-(3-hydroxy-3-(2-(2-isopropyl-1 H-benzo [d]imidazol- l -yl)-9-N methyl-6-morpholino-9H-purin-8-N L yl)piperidin-l-yl)ethanone OH % N N
O -N

605 CO~ (S)-8-((2-(2-ethyl-lH-benzo [d]imidazol- l -yl)-9-methyl-N 6-morpholino-9H-purin-8-N N yl)methyl)-4,4-/" dimethylhexahydropyrazino [2,1-~N N N N c][1,4]oxazin-3(1H)-one N EN
O
O
606 CO~ (R)-8-((2-(2-ethyl-lH-benzo [d]imidazol-1-yl)-9-methyl-N 6-morpholino-9H-purin-8-N yl)methyl)-4,4-~N N N dimethylhexahydropyrazino [2,1-c][1,4]oxazin-3(1H)-one N

O
O

607 O N-(2-(2-(2-ethyl-lH-0=5 ( 0 N ) benzo [d]imidazol-1-yl)-9-methyl-P 6-morpholino-9H-purin-8-~N N .N yl)ethyl)-N-methyl-1,1-dioxo-N N / tetrahydrothiophen-3-amine / EN___________ 608 C0 4-(2-(2-ethyl-lH-benzo [d]imidazol-l -yl)-8-((4-(3-N fluoroazetidin- l -yl)piperidin- l -N N _ yl)methyl)-9-methyl-9H-purin-6-~N N~N \ yl)morpholine N
p F

609 ~~~ 2-methyl-2-(4-((9-methyl-2-(2-methyl-1 H-benzo[d]imidazol- l -yl)-N 6-morpholino-9H-purin-8-N N yl)methylene)peridin-l/~ :~ -h yl)prop anamide O N N

610 ~~~ 2-methyl-2-(4-((9-methyl-2-(2-methyl-1 H-benzo [d]imidazol- l -yl)-N 6-morpholino-9H-purin-8-N yl)methylene)piperidin-l-N N N yl)prop anamide O N N
H2N"

611 C~~ (2-(2-ethyl-1 H-benzo [d]imidazol-1-yl)-9-methyl-6-morpholino-9H-N purin-8-yl)(hexahydropyrrolo [ 1,2-N N a]pyrazin-2(1H)-yl)methanone N N NN

N) N

612 O~ (2-(2-ethyl-1 H-benzo [d]imidazol-1-yl)-9-methyl-6-morpholino-9H-N purin-8-yl)(hexahydropyrrolo [ 1,2-N N a]pyrazin-2(1H)-yl)methanone N N NN

N) N

613 C~~ 4-(9-methyl-2-(2-methyl-lH-benzo [d]imidazol- l -yl)-8-N (piperidin-4-ylidenemethyl)-9H-N purin-6-yl)morpholine r I N

N N~N \
N
HN

614 C~~ 4-(8-(((3S,5R)-3,5-dimethylpiperazin- l -yl)methyl)-2-N (2-ethyl-1 H-benzo [d]imidazol- l -N ::[I , yl)-9-methyl-9H-purin-6-~--~r yl)morpholine ~N N N

HN N

615 CO~ 4-(9-methyl-2-(2-methyl-1 H-benzo [d]imidazol- l -yl)-8-N (piperidin-4-ylidenemethyl)-9H-N N purin-6-yl)morpholine :rN

HN N

616 ~~~ 2-(3-((2-(2-ethyl-1 H-benzo [d]imidazol- l -yl)-9-methyl-N 6-morpholino-9H-purin-8-N yl)methylene)azetidin-l-yl)-2-/ N N N \ methylpropanamide O N / }N

617 2-(3-((2-(2-ethyl-1 H-(O) benzo[d]imidazol-l-yl)-9-methyl-N 6-morpholino-9H-purin-8-N N yl)methylene)azetidin-l-yl)-2-N N V / methylpropanamide O N / J= N

618 0 1-(4-(2-(2-ethyl-1 H-(O) benzo[d]imidazol-l-yl)-9-methyl-N 6-morpholino-9H-purine-8-~-N N carbonyl)-1,4-diazepan-l-yl)ethanone O N NIN

619 CO~ (2-(2-ethyl-1 H-benzo [d]imidazol-HO 1-yl)-9-methyl-6-morpholino-9H-N purin-8-yl)(4-hydroxypiperidin- l -N NI yl)methanone O N NN
N
620 C0 (2-(2-ethyl- l H-benzo [d]imidazol-1-yl)-9-methyl-6-morpholino-9H-N purin-8-yl)(pyrrolidin- l -N N yl)methanone ~/j I N 9 0 N N! N \
~N
621 CO~ azetidin- l -yl(2-(2-ethyl-1 H-benzo [d]imidazol- l -yl)-9-methyl-N 6-morpholino-9H-purin-8-L N N yl)methanone N
O N :]l NIN \

622 CO~ (2-(2-ethyl-1 H-benzo [d]imidazol-1-yl)-9-methyl-6-morpholino-9H-N purin-8-yl)(2-N N N (hydroxymethyl)piperidin-l-H O ON N.1 N \ yl)methanone i 1 N
623 HO (2-(2-ethyl-lH-benzo[d]imidazol-1-yl)-9-methyl-6-morpholino-9H-N purin-8-yl)(4-N N (hydroxymethyl)piperidin-l-~. -~/ ::]l yl)methanone O N N IN N

624 C O~ 4-(2-(2-ethyl-lH-0=\ benzo [d]imidazol- l -yl)-9-methyl-N N 6-morpholino-9H-purine-8-~-N N _ carbonyl)piperazine-l-O N \ carbaldehyde NIN
~N
625 CN O~ (2-(2-ethyl-1 H-benzo [d]imidazol-1-yl)-9-methyl-6-morpholino-9H-purin-8-yl)(3-HO N N (hydroxymethyl)piperidin-l-N yl)methanone O N NN
~N
626 N (2-(2-ethyl-lH-benzo[d]imidazol-O 1-yl)-9-methyl-6-morpholino-9H-N purin-8-yl)(4-(pyridin-3-C N yl)piperazin- l -yl)methanone `-N N N

O N N"N \
~N
627 CN ON-(2-(dimethylamino)-2-oxoethyl)-2-(2-ethyl-1 H-benzo [d]imidazol- l -~NO yl)-N,9-dimethyl-6-morpholino-N N 9H-purine-8-carboxamide j I N Q
0 N N!N \
~N

628 0 (2-(2-ethyl-lH-benzo[d]imidazol-1-yl)-9-methyl-6-morpholino-9H-(0) purin-8-yl)(4-(2-N methoxyethyl)piperazin-l-N yl)methanone N

N
629 O~ (2-(2-ethyl- 1 H-benzo [d]imidazol-F 1-yl)-9-methyl-6-morpholino-9H-N purin-8-yl)(4-fluoropiperidin-l-N N N yl)methanone O N NN
N
630 C ~ 2-(2-ethyl-lH-benzo[d]imidazol-l-yl)-N-(2-methoxyethyl)-N,9-N dimethyl-6-morpholino-9H-purine-O
-N N , N 8-carboxamide O N N~N \
N
631 vN- 4-(2-(2-ethyl-lH-O benzo [d]imidazol-1-yl)-9-methyl-6-morpholino-9H-purine-8-N
() N carbonyl)-N,N-dimethylpiperazine-N N N 1-carboxamide O N N_ _N
N
632 (S)-(3-(dimethylamino)pyrrolidin-(ON) 1-yl)(2-(2-ethyl-1 H-benzo [d]imidazol-1-yl)-9-methyl-N , N 6-morpholino-9H-purin-8-0 N N N yl)methanone N

633 OH CO~ (R)-(2-(2-ethyl-lH-benzo [d]imidazol- l -yl)-9-methyl-N 6-morpholino-9H-purin-8-yl)(3-N N N hydroxypiperidin-l-yl)methanone >/-X/ 31 '-O N N N c N
634 CO~ (2-(2-ethyl-lH-benzo[d]imidazol-O~ 1-yl)-9-methyl-6-morpholino-9H-N purin-8-yl)(1,4-oxazepan-4-N N yl)methanone O N NIN
N
635 CO~ 2-(2-ethyl-lH-benzo[d]imidazol-l-yl)-N,9-dimethyl-N-(l -N methylpyrrolidin-3-yl)-6-i N N morpholino-9H-purine-8-N N V carboxamide N ON
:: I -1 N
636 _O~ N-(2-cyanoethyl)-2-(2-ethyl-lH-benzo [d]imidazol- l -yl)-N,9-N_ N dimethyl-6-morpholino-9H-purine-N N N 8-carboxamide O N N~N
N
637 O~ N-(cyanomethyl)-2-(2-ethyl-1 H-N C benzo [d]imidazol- l -yl)-N,9-N dimethyl-6-morpholino-9H-purine-N N 8-carboxamide O N NIN
N

638 C ) 2-(2-ethyl-lH-benzo[d]imidazol-l-yl)-N-(2-hydroxyethyl)-N,9-HO N dimethyl-6-morpholino-9H-purine-8-carboxamide DN
N N N
N
639 (2-(2-ethyl-lH-benzo[d]imidazol-F (0) 1-yl)-9-methyl-6-morpholino-9H-N purin-8-yl)(3-F
F N N N (trifluoromethyl)piperidin-l-O N yl)methanone N~N
N
640 C 0~ (4,4-difluoropiperidin- l -yl)(2-(2-F ethyl-1 H-benzo [d]imidazol- l -yl)-9-F~ N methyl-6-morpholino-9H-purin-8-N N yl)methanone 0 N NIN \
~N
641 0 (2-(2-ethyl- 1 H-benzo [d]imidazol-0~ 1-yl)-9-methyl-6-morpholino-9H-purin-8-yl)(4-( N (methoxymethyl)piperidin- l -N N yl)methanone N
642 F F F 0 (2-(2-ethyl-lH-benzo[d]imidazol-() 1-yl)-9-methyl-6-morpholino-9H-N purin-8-yl)(3-(trifluoromethyl)pyrrolidin- l -N N yl)methanone \
N

643 C~~ 2-(2-ethyl-lH-benzo[d]imidazol-l-yl)-N,9-dimethyl-6-morpholino-N-N (1,1-dioxo-tetrahydrothiophen-3-O~g~ N yl)-9H-purine-8-carboxamide O O N N.1N
N
644 (R)-(2-(2-ethyl-1 H-(O) benzo[d]imidazol-l-yl)-9-methyl-N 6-morpholino-9H-purin-8-yl)(2-(hydroxymethyl)pyrrolidin- l -N N
HO ON Q yl)methanone O N N N /
N
645 O NH2 C O~ 1-(2-(2-ethyl-lH-benzo [d]imidazol- l -yl)-9-methyl-N 6-morpholino-9H-purine-8-NN carbonyl)piperidine-4-carboxamide i O N NN \
i 1 N

646 CO~ tert-butyl 3-(2-(2-ethyl-1 H-benzo [d]imidazol-1-yl)-9-methyl-0 N 6-morpholino-9H-purin-8-4OlN N yl)pyrrolidine-l-carboxylate i I
N NIN

~647 C~~ tert-butyl 4-(2-(2-ethyl-1 H-benzo [d]imidazol-1-yl)-9-methyl-N 6-morpholino-9H-purin-8-N yl)piperidine-l-carboxylate ON<N I NlN
N

648 CO~ 4-((2-(2-ethyl-lH-benzo [d]imidazol- l -yl)-9-methyl-N 6-morpholino-9H-purin-8-N yl)methyl)-3-isopropylpiperazin-2-/ one N N N
O N
HNJ

649 CO~ 4-((2-(2-ethyl-lH-benzo [d]imidazol-1-yl)-9-methyl-N 6-morpholino-9H-purin-8-N yl)methyl)-3,3-dimethylpiperazin-2-one N N N
O HN~ N

650 C0 (2-(2-ethyl- l H-benzo [d]imidazol-1-yl)-9-methyl-6-morpholino-9H-N purin-8-yl)(4-methylpiperazin- l -O<N yl)methanone r N N N_ N ~
N
N

651 CO~ (2-(2-ethyl-1 H-benzo [d]imidazol-1-yl)-9-methyl-6-morpholino-9H-N purin-8-yl)(4-isopropylpiperazin- l -O N yl)methanone ~N N::l NINL
NO N

652 CO~ 1-(4-(2-(2-ethyl-lH-benzo [d]imidazol- l -yl)-9-methyl-N 6-morpholino-9H-purine-8-0 N _ carbonyl)piperazin-l-yl)ethanone Imo' ~
~N N NIN \ 9 NO N
O' 653 C~~ (4-(cyclopropylmethyl)piperazin-l-yl)(2-(2-ethyl-1 H-N benzo [d]imidazol- l -yl)-9-methyl-0 N ::(I , 6-morpholino-9H-purin-8-N yl)methanone N N N N
NJ N

654 CO~ 1-(4-(2-(2-ethyl-lH-benzo [d]imidazol- l -yl)-9-methyl-N 6-morpholino-9H-purine-8-0 N N carbonyl)piperazin-l-yl)-2-N N N N methylpropan- l -one NO N
O

655 C~~ (4-cyclobutylpiperazin-l -yl)(2-(2-ethyl-1 H-benzo [d]imidazol- l -yl)-9-N methyl-6-morpholino-9H-purin-8-0 N yl)methanone N N :: I N N
N N
656 (4-O (0) (cyclopropanecarbonyl)piperazin-N 1-yl)(2-(2-ethyl-1 H-N benzo[d]imidazol-1-yl)-9-methyl-N N 6-morpholino-9H-purin-8-yl)methanone O N NI N
~N

657 CO~ (2-(2-ethyl-1 H-benzo [d]imidazol-1-yl)-9-methyl-6-morpholino-9H-N purin-8-yl)(4-0 N N (methylsulfonyl)piperazin- l -N N N V yl)methanone N
,SN
O%.
N, 658 CO~ 2-(3-hydroxy-3-(2-(2-isopropyl-1 H-benzo [d]imidazol- l -yl)-9-N methyl-6-morpholino-9H-purin-8-OH N yl)piperidin-l-yl)-2-i methylpropanamide O N

659 CO~ (2-(2-ethyl-1 H-benzo [d]imidazol-1-yl)-9-methyl-6-morpholino-9H-N purin-8-yl)(4-(2-hydroxy-2-O N L N _ methylpropyl)piperazin- l-N N N V yl)methanone N N N
HOY

660 Q N (2-(2-ethyl-lH-benzo[d]imidazol-CNJ ~1-yl)-9-methyl-6-morpholino-9H-N~ purin-8-yl)(4-(pyridin-2-c yl)piperazin- l -yl)methanone `N N O N ~IN-l N ~N

661 CO~ 2-(3-hydroxy-3-(2-(2-isopropyl-1 H-benzo [d]imidazol- l -yl)-9-OH N methyl-6-morpholino-9H-purin-8-N ~Q , yl)piperidin-1-yl)-2-N methylpropanamide 662 CO~ (R)-2-(3-(2-(2-isopropyl-lH-benzo [d]imidazol-1-yl)-9-methyl-N 6-morpholino-9H-purin-8-yl)-3-N methoxypiperidin-l-yl)-2-DO
methylpropanamide O N O N - 1 N ::I \

H2N~ / N

663 C~~ (S)-2-(3-(2-(2-isopropyl-lH-benzo [d]imidazol- l -yl)-9-methyl-N 6-morpholino-9H-purin-8-yl)-3-N ::!a'2 ~
e O
N N N N
~-t /

664 CO~ (R)-1-(3-(2-(2-isopropyl-lH-benzo [d]imidazol- l -yl)-9-methyl-N 6-morpholino-9H-purin-8-yl)-3-NN N methoxypiperidin-l-yl)ethanone O ~ NIN

665 C~~ (S)-1-(3-(2-(2-isopropyl-lH-benzo [d]imidazol-1-yl)-9-methyl-N 6-morpholino-9H-purin-8-yl)-3-I N methoxypiperidin-l-yl)ethanone ( N O / N N
/ N
O

666 C~~ (2-(2-ethyl-lH-benzo[d]imidazol-1-yl)-9-methyl-6-morpholino-9H-N purin-8-yl)(4-(oxetan-3-0 N yl)piperazin- l -yl)methanone I
N N:: NIN \
N

667 CO~ 2-(4-(2-(2-isopropyl-1 H-benzo [d]imidazol- l -yl)-4-N morpholinofuro [3,2-d]pyrimidine-O O N 6-carbonyl)piperazin-l-yl)-2-N \ N N methylpropanamide 668 CO~ 2-(4-(2-(2-ethyl-lH-benzo [d]imidazol- l -yl)-4-N morpholinofuro [3,2-d]pyrimidine-O O IIQ N 6-carbonyl)piperazin-l-yl)-2-1 I methylpropanamide N NN \

O N~ N

669 CO~ (2-(2-ethyl-1 H-benzo [d]imidazol-1-yl)-4-morpholinofuro [3,2-N d]pyrimidin-6-yl)(4-(2-~- \ I O hydroxypropan-2-yl)piperidin-l-yl)methanone N N N
N
HO

670 C0 (4-(2-hydroxypropan-2-yl)piperidin- l -yl)(2-(2-isopropyl-N 1 H-benzo [d]imidazol-l -yl)-4-0 0 morpholinofuro[3,2-d]pyrimidin-6-~- \ N yl)methanone N NN
N
O
HO

671 C~~ (2-(2-(1,1-difluoroethyl)-1 H-benzo [d]imidazol-1-yl)-9-methyl-N 6-morpholino-9H-purin-8-yl)(4-(2-0 N N hydroxypropan-2-yl)piperidin-l-NN N N yl)methanone N
F F
HO
672 CO~ (2-(2-ethyl-1 H-benzo [d]imidazol-1-yl)-9-methyl-6-morpholino-9H-N purin-8-yl)(4-(l -hydroxy-2-ON N methylpropan-2-yl)piperazin-l-N N N L N V/ yl)methanone N~ N
x,OH

673 (R)-(2-(2-ethyl-1 H-(O) benzo[d]imidazol-1-yl)-9-methyl-N 6-morpholino-9H-purin-8-yl)(2-o N N methylpiperidin-l-yl)methanone N::
i '1 N N~\N

N
674 (S)-(2-(2-ethyl-1 H-(O) benzo[d]imidazol-1-yl)-9-methyl-N 6-morpholino-9H-purin-8-yl)(2-o N N methylpiperidin-l-yl)methanone i N N N" _N
N
' 675 O~ (2-(2-ethyl-1 H-benzo [d]imidazol-1-yl)-9-methyl-6-morpholino-9H-N purin-8-yl)(3-(1,1-0 dioxo)thiomorpholinoazetidin- l -N yl)methanone N N N IN p N

N
OHO

676 CO~ 4-(2-(2-isopropyl-lH-benzo [d]imidazol- l -yl)-9-methyl-N 8-(pyridin-3-yl)-9H-purin-6-orpholine N N :eN'~ yl)m r ~ -<N N \
N
677 (O) 2-(4-(2-(2-ethyl-lH-benzo [d] imidazol- l -yl)-9-methyl-N 6-morpholino-9H-purin-8-N ~ N yl)piperidin-l-yl)acetamide N X
H2N,C C~-N N N

678 CO~ tert-butyl 3-(2-(2-ethyl-1 H-benzo [d]imidazol- l -yl)-9-methyl-N 6-morpholino-9H-purin-8-0 N yl)azetidine-l-carboxylate N
/ - ~>~N:: I O N N \ I

EN__________ 679 C~~ (R)-1-(3-((2-(2-ethyl-lH-benzo [d]imidazol- l -yl)-9-methyl-N 6-morpholino-9H-purin-8-N yl)methyl)azetidin-l-yl)-2-i hydroxypropan-l-one N N 9/, ~N N
HOB O

680 C~~ 4-(8-(azetidin-3-yl)-2-(2-ethyl-lH-benzo [d]imidazol- l -yl)-9-methyl-N 9H-purin-6-yl)morpholine HN~N X
N N" N N

681 C~~ 1-((2-(2-ethyl-lH-benzo [d]imidazol-1-yl)-9-methyl-N 6-morpholino-9H-purin-8-N yl)methyl)-3-isopropylpiperazin-2-0 / one N N N N
HNJ N

682 CO~ (2-(2-ethyl-2H-indazol-3-yl)-9-methyl-6-morpholino-9H-purin-8-N yl)(4-(2-hydroxypropan-2-0 N N yl)piperidin-l-yl)methanone i N ND N
N_N

HO

683 C O~ 4-(2-(2-isopropyl-lH-benzo [d]imidazol- l -yl)-8-(3-0 N methoxyphenyl)-9-methyl-9H-N purin-6-yl)morpholine Nb<NX1&NQ

/ N

684 CO~ 4-(8-(3-ethoxy-l-isopropylpiperidin-3-yl)-2-(2-N isopropyl-1 H-benzo [d]imidazol- l -D~-(N yl)-9-methyl-9H-purin-6-'~ yl)morpholine N O N N N
N
685 CO~ (2-(2-ethyl-lH-benzo[d]imidazol-1-yl)-9-methyl-6-morpholino-9H-N purin-8-yl)(3-morpholinoazetidin-0 N N 1-yl)methanone i N NX,L N \ 9 686 CO~ (2-(2-ethyl-1 H-benzo [d]imidazol-1-yl)-9-methyl-6-morpholino-9H-N purin-8-yl)(4-(oxazol-2-0 N l N ylmethyl)piperazin-l-yl)methanone N N~N \ I
(-) N N

687 C~~ 4-(1-((2-(imidazo[1,2-a]pyridin-5-yl)-4-morpholinothieno [3,2-N d]pyrimidin-6-yl)methyl)piperidin-S N 4-yl)morpholine N \ N N U N
~N

O~
688 C~~ 1-((2-(imidazo[1,2-a]pyridin-5-yl)-4-morpholinothieno [3,2-N d]pyri midin-6-yl)methyl)-N,N-S I N dimethylpiperidin-4-amine N N N
I U
-N

689 C~~ 5-(6-((4-(dimethylamino)piperidin-1-yl)methyl)-4-N morpholinothieno [3,2-d]pyrimidin-S N 2-yl)imidazo[1,2-a]pyridin-8-ol N N
I

/ OH
-N

690 C~~ 2-(4-((2-([ 1,2,4]triazolo[4,3-a]pyridin-5-yl)-4-N morpholinothieno [3,2-d]pyrimidin-S N N 6-yl)methyl)piperazin-l-yl)-2-I N N methylpropanamide ~N
N

>NH2 O

691 CO~ 2-(4-((2-(imidazo[1,2-a]pyridin-5-yl)-7-methyl-4-N morpholinothieno [3,2-d]pyrimidin-S 1 N 6-yl)methyl)piperazin-l-yl)-2-\ - N N methylpropanamide N i N

O

692 CO~ 2-(1-((9-methyl-2-(2-methylimidazo [ 1,2-a]pyridin-5-yl)-N 6-morpholino-9H-purin-8-~N JLN/.' yl)methyl)piperidin-4-yl)propan-2-N N of N N
HO

693 CO~ 2-methyl-2-(4-((2-(2-methylimidazo [ 1,2-a]pyridin-5-yl)-N 4-morpholinothieno [3,2-g N d]pyrimidin-6-yl)methyl)piperazin-\ N N 1-yl)propanamide N N i N

>NH2 O

694 C~~ 2-methyl-2-(4-((2-(7-methylimidazo [ 1,2-a]pyridin-5-yl)-N 4-morpholinothieno [3,2-g N d]pyrimidin-6-yl)methyl)piperazin-e \ N N N 1-yl)propanamide 695 C~~ 2-methyl-2-(4-((4-morpholino-2-(1 H-pyrrolo [2,3-b]pyridin-4-N yl)thieno [3,2-d]pyrimidin-6-S N y1)methyl)piperazin-l-N NH yl)propanamide N
~~ 6 696 C~~ 2-methyl-2-(4-((7-methyl-4-morpholino-2-(1 H-pyrrolo [2,3-N b]pyridin-4-yl)thieno[3,2-S / N _ d]pyrimidin-6-yl)methyl)piperazin-N \ -N I NH 1-yl)propanamide H J I ~N

697 C~~ 2-(4-((2-(imidazo[1,2-a]pyridin-5-yl)-4-morpholinothieno [3,2-N d]pyrimidin-6-yl)methyl)piperazin-S N 1-yl)-2-methylpropanamide N
N !%j' N

O

698 O~ 2-(1-((2-(imidazo[1,2-a]pyridin-5-yl)-9-methyl-6-morpholino-9H-N purin-8-yl)methyl)piperidin-4-~N N ~ yl)propan-2-ol N N N I N ~N
I /
HO

699 CO~ 2-(1-((5-(imidazo[1,2-a]pyridin-5-yl)-7-morpholinothiazolo[5,4-N d]pyrimidin-2-yl)methyl)piperidin-N N 4-yl)propan-2-ol N \S N iN
HO

700 CO~ 4-(5-(imidazo[1,2-a]pyridin-5-yl)-2-((3-morpholinoazetidin-l-N yl)methyl)thiazolo[5,4-N N d]pyrimidin-7-yl)morpholine pN S N N UN

N
O

701 OH O 2-(1-((2-(2-ethyl-lH-( benzo[d]imidazol-l-yl)-6-N morpholino-9H-purin-8-N

of H N I N

N
702 OH O 2-(1-((2-(2-methyl-lH-( benzo[d]imidazol-1-yl)-6-N morpholino-9H-purin-8-yl)methyl)piperidin-4-yl)propan-2-N\ N I of H NIN \
N

[0001] Table 3.

No. Structure Name 703 (0) 2-(4-(2-(2-ethyl-lH-benzo [d]imidazol- l -yl)-9-N methyl-6-morpholino-9H-purin-~--(N N 8-yl)piperidin-l-yl)-2-H N N~--/ ~N methylpropanamide O .N
704 C0 (2-(2-ethyl-lH-benzo [d]imidazol- l -yl)-4-N morpholinothieno [3,2-O S N d]pyrimidin-6-yl)(4-(2-hydroxypropan-2-yl)piperidin-l-N
N N yl)methanone N

HO
705 C0 (R)-(2-(2-ethyl-lH-benzo [d]imidazol- l -yl)-9-N methyl-6-morpholino-9H-purin-O N 8-yl)(3-fluoropyrrolidin-l-yl)methanone N N::l NIN \

F
706 C0 (2-(2-ethyl-lH-benzo [d]imidazol- l -yl)-9-N methyl-6-morpholino-9H-purin-0 N ::(I I 8-yl)(3-(tetrahydro-2H-pyran-4-yl)azetidin-l-yl)methanone N N N
~N
O

707 CO~ N-ethyl-4-(2-(2-ethyl-lH-benzo [d]imidazol- l -yl)-9-N methyl-6-morpholino-9H-0 N purine-8-carbonyl)piperazine-l-~--~~ carboxamide ~N> N N IN NO N

HN-O
708 (2-(2-ethyl-1 H-(O) benzo[d]imidazol-l-yl)-9-N methyl-6-morpholino-9H-purin-0 N N 8-yl)(pyridin-3-yl)methanone N N" _N
N
N

709 0 0 (S)-N-(2-(2-(2-ethyl-lH-0=5: benzo[d]imidazol-l-yl)-9-N methyl-6-morpholino-9H-purin-8-yl)ethyl)-N-methyl-(1,1-/N~N N \ dioxo)-tetrahydrothiophen-3-N ~N N amine EN__________ 710 D (R)-N-(2-(2-(2-ethyl-1 H-0=5 ) benzo[d]imidazol-l-yl)-9-N methyl-6-morpholino-9H-purin-8-yl)ethyl)-N-methyl-(1,1-N~N dioxo)-tetrahydrothiophen-3-N N N amine EN__________ 711 O 1-((2-(2-ethyl-1 H-() benzo[d]imidazol-l-yl)-9-N methyl-6-morpholino-9H-purin-8-yl)methyl)-4-0 ~I isopropylpiperazin-2-one N \ N N N Q

NJ
712 ~~~ 2-(5-(2-ethyl-1 H-benzo benzo[d]imidazol- l -yl)-7-~--~ N morpholinothiazolo[5,4-HD NON N N d]pyrimidin-2-yl)- 1 -(4-(l -N~N hydroxy-2-methylpropan-2-s yl)piperazin- l -yl)ethanone N

713 4-(2-(2-isopropyl-1 H-(O) benzo[d]imidazol-l-yl)-8-(3-N methoxy- l -(2-(methylsulfonyl)ethyl)piperidin-O N
3-yl)-9-methyl-9H-purin-6-(N N N \ yl)morpholine \ --N
O/S\O

714 CO~ tert-butyl 3-(2-(2-ethyl-1 H-benzo [d]imidazol- l -yl)-9-N methyl-6-morpholino-9H-purin-N
~0 O N 8-yl)-3-methoxyazetidine-l-~N carboxylate N N

EN__________ 715 O (2,2-dimethyl-4-(methylsulfonyl)piperazin-l-N yl)(2-(2-ethyl-1 H-O N benzo[d]imidazol-l-yl)-9-methyl-6-morpholino-9H-purin-N N N 8-yl)methanone NJ N
O =S.-O
716 O 2-(3-(2-(2-isopropyl-1 H-benzo[d]imidazol-l-yl)-9-N methyl-6-morpholino-9H-purin-0 N 8-yl)-3-methoxypiperidin-l-yl) acetamide i XtLNQ
N O
N

717 CO~ 2-(4-((2-(2-ethyl-lH-benzo [d]imidazol- l -yl)-9-N methyl-6-morpholino-9H-purin-N 8-yl)methyl)-3,3-/--/ dimethylpiperazin-l-N N N yl)acetamide N

C~_j 718 CO~ (S)-1-(3-((2-(2-ethyl-lH-benzo [d]imidazol- l -yl)-9-N methyl-6-morpholino-9H-purin-N 8-yl)methyl)azetidin-l-yl)-2-hydroxypropan-l-one NIN

~N N
HO O

719 CO~ (2-(2-ethyl-lH-benzo [d]imidazol- l -yl)-7-N methyl-4-morpholinothieno [3,2-O S N d]pyrimidin-6-yl)(4-(2-hydroxypropan-2-yl)piperidin-l-N N N yl)methanone N

HO
720 (O) 3-(2-(2-ethyl-lH-benzo [d]imidazol- l -yl)-9-N methyl-6-morpholino-9H-purin-/~ OH N 8-yl)-1-(tetrahydro-2H-pyran-4-O, -N~~ yl)azetidin-3-ol ~/ N N
EN________ 721 CO~ 1-(3-((2-(2-ethyl-lH-benzo [d]imidazol- l -yl)-9-N methyl-6-morpholino-9H-purin-N 8-yl)methyl)azetidin-l-yl)-2-v hydroxy-2-methylpropan-l-one N N
N N

722 C~~ (R)-1-(4-((2-(2-ethyl-lH-benzo [d]imidazol- l -yl)-9-N methyl-6-morpholino-9H-purin-N , 8-yl)methyl)-3,3-f--i N dimethylpiperazin- l -yl)-2-N N N N hydroxypropan- l -one NJ

723 CO~ (S)-1-(4-((2-(2-ethyl-lH-benzo [d]imidazol- l -yl)-9-N methyl-6-morpholino-9H-purin-N N 8-yl)methyl)-3,3-~N N dimethylpiperazin- l -yl)-2-N~ ~ N hydroxypropan-l-one HO' 'p 724 CO~ 1-(4-(2-(2-ethyl-lH-benzo [d]imidazol- l -yl)-9-N methyl-6-morpholino-9H-0 N purine-8-carbonyl)piperazin-l-~--(~ yl)propan- l -one N N
N N
ci' O 725 (O) methyl 4-(2-(2-ethyl-1 H-benzo [d]imidazol-1-yl)-9-N methyl-6-morpholino-9H-O N L N purine-8-carbonyl)piperazine-l-N
carboxylate N N N
N
N
O-~
O
726 CO~ (2-(2-ethyl-lH-benzo [d]imidazol- l N : : ] , 8-yl)(4-(2,2,2-N NI N V trifluoroethyl)piperazin- l-F IJ N / yl)methanone N
N
FL~--/
F

727 C0~ (R)-1-(4-(2-(2-ethyl-lH-benzo [d]imidazol- l -yl)-9-N methyl-6-morpholino-9H-0 N purine-8-carbonyl)piperazin-l-N N yl)-2-hydroxypropan-l-one N N NN
HO H cJ N
O

728 0~ (S)-1-(4-(2-(2-ethyl-1 H-benzo [d]imidazol- l -yl)-9-N methyl-6-morpholino-9H-0 N purine-8-carbonyl)piperazin-l-/ yl)-2-hydroxypropan-l-one ~N N N N- \ I
H OH NO N
"0 729 C0~ (2-(2-ethyl-lH-benzo [d] imidazol- l -yl)-9-N methyl-6-morpholino-9H-purin-0 N N 8-yl)(4-(1,1-~:::,:
It, dioxotetrahydrothiophen-3-z N N N yl)piperazin- l -yl)methanone N N

00 730 C0~ 4-(9-methyl-2-(2-methyl-1 H-benzo [d]imidazol-l -yl)-8-((1-N (1,1-dioxo-tetrahydrothiophen-3-N I yl)piperidin-4-yl)methyl)-9H-purin-6-yl)morpholine N N \
N -N

731 CO~ 2-(4-(2-(2-ethyl-lH-benzo [d]imidazol- l -yl)-7-N methyl-4-morpholinothieno [3,2-O S N d]pyrimidine-6-(N& I N carbonyl)piperazin- l-yl)-2-O N~N methylpropanamide H2Nf 732 (2-(2-ethyl-1 H-(O) benzo[d]imidazol-l-yl)-9-N methyl-6-morpholino-9H-purin-O N 8-yl)(3-methylpyrrolidin-l-yl)methanone N N N N

N
733 OH O 2-(1-((2-(2-isopropyl-lH-( benzo[d]imidazol-l-yl)-6-N morpholino-9H-purin-8-yl)methyl)piperidin-4-yl)propan-N N 2-ol JI`
H N \ I
N

734 CO~ 2-(1-(1-(2-(2-ethyl-lH-benzo [d]imidazol- l -yl)-9-N methyl-6-morpholino-9H-purin-N 8-yl)ethyl)piperidin-4-yl)propan-/-</N ::[I , 2-ol N ~N
~N
OH

735 C~~ 2-(1-(1-(2-(2-ethyl-lH-benzo [d]imidazol- l -yl)-9-N methyl-6-morpholino-9H-purin-N 8-yl)ethyl)piperidin-4-yl)propan-N
:::]:l , i 2-ol N N N~N
N
OH

736 CO~ (4-(2-hydroxypropan-2-yl)piperidin-l-yl)(2-(2-N isopropyl-1 H-benzo [d]imidazol-O N N 1-yl)-9-methyl-6-morpholino-,, N N~N 9H-purin-8-yl)methanone N :] I N

OH
737 CO~ 4-(8-(((2R,6S)-2,6-dimethyl-4-(methylsulfonyl)piperazin-l-N yl)methyl)-2-(2-ethyl-1 H-N benzo[d]imidazol-l-yl)-9-~N N N methyl-9H-purin-6-yl)morpholine N
O =S6 "O
738 C~~ 3-(2-(2-ethyl-lH-benzo [d]imidazol- l -yl)-9-N methyl-6-morpholino-9H-purin-~/ N 8-yl)-l-isopropylazetidin-3-ol N
NZN
N

739 O 4-(2-(2-ethyl-1 H-() benzo[d]imidazol-l-yl)-8-(l-N isopropyl-3-methoxyazetidin-3-0 N yl)-9-methyl-9H-purin-6->-NL yl)morpholine N:: I NLN
N
740 4-(8-((2,2-dimethyl-4-(oxetan-3-(0) yl)piperazin-l-yl)methyl)-2-(2-N ethyl-1 H-benzo [d]imidazol- l -yl)-9-methyl-9H-purin-6-/ N ~~ yl)morpholine N N N N
NJ N

741 1-(4-((2-(2-ethyl-1 H-(O) benzo[d]imidazol-l-yl)-9-N methyl-6-morpholino-9H-purin-N 8-yl)methyl)-3,3-/--/ dimethylpiperazin-l-yl)-2-N N N N hydroxy-2-methylpropan-l-one NJ N
O
OH
742 CO~ 2-(3-(2-(2-isopropyl-lH-benzo [d]imidazol- l -yl)-9-N methyl-6-morpholino-9H-purin-0 N 8-yl)-3-methoxypiperidin-l-yl)acetamide N N N
N
O

743 CO~ 2-(3-(2-(2-isopropyl-lH-benzo [d]imidazol- l -yl)-9-N methyl-6-morpholino-9H-purin-0N 8-yl)-3-methoxypiperidin-l-N yl)acetamide NDL N N
~=O

744 CO~ 4-(2-(2-ethyl-lH-benzo [d]imidazol- l -yl)-9-N methyl-8-((7-(oxetan-3-yl)-4,7-N N diazaspiro[2.5]octan-4-r--<i yl)methyl)-9H-purin-6-N N N N yl)morpholine NJ

745 CO~ 2-(3-(2-(2-ethyl-lH-benzo [d]imidazol- l -yl)-9-N methyl-6-morpholino-9H-purin-OH N 8-yl)-3-hydroxypiperidin-l-yl)-N,N-dimethylacetamide N N N I

O
-N

746 CO~ 3-(2-(2-ethyl-lH-benzo [d]imidazol- l -yl)-9-N methyl-6-morpholino-9H-pur n-OH N N 8-yl)-1-(2-hydroxy-2-~N methylpropyl)piperidin-3-ol N
N
HO

747 CO~ 4-(2-(2-ethyl-lH-benzo [d]imidazol- l -yl)-9-N methyl-8-(l -(tetrahydro-2H-/~ N pyran-4-yl)azetidin-3-yl)-9H-O rN~N I purin-6-yl)morpholine ~--/ ~ N N

EN__________ 748 CO~ N-(2-(2-(2-ethyl-lH-benzo [d]imidazol- l -yl)-9-N methyl-6-morpholino-9H-purin-N N 8-yl)ethyl)-N, 3-dimethyl-1,1-Or N dioxotetrahydrothiophen-3-NN N amine ~)N

749 0 2-(4-(9-ethyl-2-(2-methyl-1 H-benzo[d]imidazol-l-yl)-6-N morpholino-9H-purine-8-0 N carbonyl)piperazin-l-yl)-2-methylpropanamide N N NZN

O ( N

750 \,O O 4-(8-((2,2-dimethyl-4-O=S (methylsulfonyl)piperazin-l-N~
C N yl)methyl)-2-(2-isopropyl-1 H -benzo [d]imidazol- l -yl)-9H-,N - purin-6-yl)morpholine N N N \ I
H
N

751 HO 2-(1-((2-(2-(1,1-difluoroethyl)-( 1H-benzo[d]imidazol-l-yl)-6-N morpholino-9H-purin-8-yl)methyl)piperidin-4-yl)propan-N 2-ol N rN :]I
N NJ`N \
N
F F

752 HO O 2-(1-((2-(2-cyclopropyl-lH-( benzo[d]imidazol-l-yl)-6-N morpholino-9H-purin-8-yl)methyl)piperidin-4-yl)propan-N rN :]I
N 2-ol N H NLN
N

O 1 H-benzo [d]imidazol- l -yl)-6-N CN morpholino-9H-purin-8-yl)methyl)azetidin-3-N N yl)morpholine \ I
H N IN
N
F F

754 OH O (4-(2-hydroxypropan-2-( N) yl)piperidin-l -yl)(2-(2-isopropyl-1 H-benzo [d]imidazol-1-yl)-6-morpholino-9H-purin-8-N // ~N yl)methanone O H N N \
N

755 0 4-(2-(2-(1,1 -difluoroethyl)-1H-(0~ benzo[d]imidazol-l-yl)-8-((3-(tetrahydro-2H-pyran-4-N yl)azetidin- l -yl)methyl)-9H-N N purin-6-yl)morpholine H N IN N
F F

756 0 4-(2-(2-isopropyl-lH-( benzo[d]imidazol-l-yl)-8-((3-(tetrahydro-2H-pyran-4-N yl)azetidin- l -yl)methyl)-9H-N N purin-6-yl)morpholine N N IN ~N

757 OH 0 (2-(2-ethyl-lH-( benzo[d]imidazol-l-yl)-6-N morpholino-9H-purin-8-yl)(4-(2-hydroxypropan-2-yl)piperidin-l-N~ rN yl)methanone r 0 benzo [d]imidazol- l -yl)-6-N (N) morpholino-9H-purin-8-yl)methyl)azetidin-3-N N yl)morpholine H N IN N

759 (9-ethyl-2-(2-methyl-1 H-(O) benzo[d]imidazol-l-yl)-6-N morpholino-9H-purin-8-yl)(4-(2-O N hydroxypropan-2-yl)piperidin-l-i yl)methanone N N N N
N
HO

760 C0 (4-(2-hydroxypropan-2-yl)piperidin-l-yl)(9-methyl-2-(2-N methyl-1 H-benzo [d]imidazol-l-O N yl)-6-morpholino-9H-purin-8-N N yl)methanone N N N~N \
HO

761 CO~ 2-(4-((2-(2-ethyl-lH-benzo [d]imidazol- l -yl)-6-N morpholino-9H-purin-8-N N yl)methyl)piperidin-l-yl)-2-methylpropanamide H NIN
N N
>NH2 O
762 0 4-(1-((2-(2-isopropyl-lH-N O benzo [d]imidazol- l -yl)-6-(N) morpholino-9H-purin-8-yl)methyl)azetidin-3-N N yl)morpholine \ Q
H N IN
N

763 H2N 2-(4-((2-(2-ethyl-lH-O benzo[d]imidazol-l-yl)-9-methyl-6-morpholino-9H-purin-N N 8-yl)fluoromethylene)piperidin-1-yl)-2-methylpropanamide F N N N \
~N
764 CO~ (2-(2-ethyl-lH-benzo [d]imidazol- l -yl)-9-N methyl-6-morpholino-9H-purin-0 N 8-yl)(piperazin-l-yl)methanone N N:: I NN

HNJ ~N

765 C~~ 3-(2-(2-ethyl-lH-benzo [d]imidazol- l -yl)-9-N methyl-6-morpholino-9H-purin-OH N N 8-yl)-1-~N \ (methylsulfonyl)piperidin-3-ol N N
O' \ / N

766 CO~ 4-(2-(2-ethyl-lH-benzo [d]imidazol-l -yl)-8-(3-N methoxy- l -O (N N (methylsulfonyl)piperidin-3-yl)-~/r 9-methyl-9H-purin-6-O. =N N N N yl)morpholine O' \

767 CO~ 1-(2-(2-ethyl-1 H-benzo [d]imidazol- l -yl)-9-N methyl-6-morpholino-9H-O N purine-8-carbonyl)piperidine-4-r N carbonitrile N N N N~ \
N
N

768 CO~ (2-(2-ethyl-lH-benzo [d]imidazol- l -yl)-9-N methyl-6-morpholino-9H-purin-8-yl)(4-(2-0 N ::[, , hydroxyethyl)piperazin- l -N N N N yl)methanone NJ N
HO

769 OH O (9-(2-hydroxyethyl)-2-(2-( ) isopropyl- 1 H-benzo [d]imidazol-1-yl)-6-morpholino-9H-purin-8-yl)(4-(2-hydroxypropan-2-// N N - yl)piperidin- l -yl)methanone O N N N
N
HO

770 HO D o D 2-(1-((2-(2-ethyl-lH-D D benzo[d]imidazol-l-yl)-6-D D (octadeuterio)morpholino-9H-D N D purin-8-yl)methyl)piperidin-4-N\ N yl)propan-2-ol N N N
\
H
N
771 O (5-(2-ethyl-1 H-() benzo[d]imidazol-l-yl)-7-N morpholinothiazolo [5,4-O d]pyrimidin-2-yl)(4-(2-j hydroxypropan-2-yl)piperidin-l-N S N N yl)methanone N

OH

772 CO~ 3-(2-(2-ethyl-lH-benzo [d]imidazol- l -yl)-9-N methyl-6-morpholino-9H-purin-OH N 8-yl)-1-(tetrahydro-2H-pyran-4-N N yl)piperidin-3-ol N N \
O

773 CO~ 2-amino-l-(4-(2-(2-ethyl-lH-benzo [d]imidazol- l -yl)-9-N methyl-6-morpholino-9H-O N L N _ purine-8-carbonyl)piperazin-l-N N N \ yl)ethanone N ::l N
ezz N
O=~

774 CO~ (2-(2-ethyl-lH-benzo [d]imidazol- l -yl)-9-N methyl-6-morpholino-9H-purin-O N I 8-yl)(4-(1-~--~~ hydroxyethyl)piperidin- l -N N N \ yl)methanone - N
OH

775 (S)-2-(1-((2-(2-ethyl-1 H-(O),' benzo[d]imidazol-l-yl)-9-N methyl-6-(3-methylmorphohno)-N 9H-purin-8-yl)methyl)piperidin-~--~i N 4-yl)propan-2-ol N N N~N
OH

776 CO~ (4-(1,3-dihydroxypropan-2-yl)piperazin-l -yl)(2-(2-ethyl-1 H-N benzo[d]imidazol- l -yl)-9-O N N methyl-6-morpholino-9H-purin-,, _N 8-yl)methanone :]l NN
N /
N
N) 'N
HOO
HO

777 (0) (4-(cyclopropanecarbonyl)piperazin N -1-yl)(2-(2-(dimethylamino)-1 H-O N benzo[d]imidazol-l-yl)-9-methyl-6-morpholino-9H-purin-N N N N 8-yl)methanone N NN
O

778 C~~ (R)-1-(4-(2-(2-(dimethylamino)-1 H-benzo [d]imidazol- l -yl)-9-N methyl-6-morpholino-9H-O N purine-8-carbonyl)piperazin-l-O, yl)-2-hydroxypropan-l-one N N
N N
(-ilL
O) HO
779 CO~ N-(1-(2-(2-ethyl-lH-benzo [d]imidazol- l -yl)-9-N methyl-6-morpholino-9H-0 N purine-8-carbonyl)piperidin-4-N yl)acetamide N
Q / N L
N
O
)-NH

780 C0 (1-aminocyclopropyl)(4-((2-(2-ethyl- 1 H-benzo [d]imidazol- l -N yl)-9-methyl-6-morpholino-9H-N e N purin-8-yl)methyl)-3,3-N N N N V dimethylpiperazin-l-) 1 methanone NJ J-N Y ) O

781 (R)-2-(1-((2-(2-ethyl-1 H-benzo[d]imidazol-l-yl)-9-N methyl-6-(3-methylmorpholino)-~N N 9H-purin-8-yl)methyl)piperidin-N N NON \ 4-yl)propan-2-ol HO
782 CO~ N-(1-(2-(2-ethyl-lH-benzo [d]imidazol- l -yl)-9-N methyl-6-morpholino-9H-0 N . N purine-8-carbonyl)piperidin-4-N N I N yl)propionamide N
O N
NH

783 CO~ N-(1-(2-(2-ethyl-lH-benzo [d]imidazol- l -yl)-9-N methyl-6-morpholino-9H-0 N = N purine-8-carbonyl)piperidin-4-N N N N / yl)-2-hydroxy-2-Q / methylpropanamide O N
NH
7~ HO

784 O 4-(2-(2-isopropyl-1 H-benzo[d]imidazol-l-yl)-7-N methyl-6-((l -(tetrahydro-2H-S ` N pyran-4-yl)azetidin-3-NN yl)methyl)thieno[3,2-N d]pyrimidin-4-yl)morpholine O

785 CO~ 4-(2-(2-ethyl-lH-benzo [d]imidazol-l -yl)-8-(1-N isopropyl-1H-1,2,4-triazol-5-yl)-N,N N :: 1 N 9-methyl-9H-purin-6-N / N N \ yl)morpholine N / N

786 CO~ (2-(2-ethyl-lH-benzo [d]imidazol- l -yl)-9-N methyl-6-morpholino-9H-purin-O N L N 8-yl)(3-(oxetan-3-ylamino)azetidin-l-N p "..) / yl)methanone - N
HN

787 CO~ N-(1-(2-(2-ethyl-lH-benzo [d]imidazol- l -yl)-9-N methyl-6-morpholino-9H-O N L N purine-8-carbonyl)azetidin-3-NN N N yl)propionamide 2 ' J-N
HN
O

788 HO O (2-(2-(dimethylamino)-1H-benzo [d]imidazol- l -yl)-6-C N morpholino-9H-purin-8-yl)(4-(2-N N N hydroxypropan-2-yl)piperidin-l-O N I yl)methanone ) NZN
H N

789 CO~ (S)-(4-(2-hydroxypropan-2-yl)piperidin-l-yl)(2-(2-(l-N methoxyethyl)-1 H-O<N r = N benzo[d]imidazol-l-yl)-9-N N N L N methyl-6-morpholino-9H-purin-8-yl)methanone N
0.
OH

790 C0 1-(4-(2-(2-ethyl-lH-benzo [d]imidazol- l -yl)-9-N methyl-6-morpholino-9H-purin-OH N = 8-yl)-4-hydroxypiperidin-l-yl)-/ I N
HO N N NN 2-hydroxy-2-methylpropan-l-~ one 791 CO~ 1-(3-(2-(2-ethyl-lH-benzo [d]imidazol- l -yl)-9-N methyl-6-morpholino-9H-purin-0 N N 8-yl)-3-methoxypiperidin-1-yl)-~N 2-methylpropan-2-ol N
HO

792 CO~ 4-(6-((2,2-dimethyl-4-(oxetan-3-yl)piperazin- l -yl)methyl)-2-(2-N ethyl-1 H-benzo [d]imidazol- l -S = N yl)thieno[3,2-d]pyrimidin-4-N N~N yl)morpholine N v N
O

793 CO~ (2,2-dimethyl-4-(oxetan-3-yl)piperazin-l -yl)(5-(2-ethyl-1 H-N benzo[d]imidazol- l -yl)-7-0 N . _ morpholinothiazolo[5,4-S NN
N d]pyrimidin-2-yl)methanone N

NJ N

794 OH O (R)-(4-(2-hydroxypropan-2-C yl)piperidin-l-yl)(2-(2-(l-N methoxyethyl)-1 H-N N benzo[d]imidazol-l-yl)-9-methyl-6-morpholino-9H-purin-0 N N N 8-yl)methanone N
,O

795 CO~ 1-(4-(2-(2-ethyl-1 H-benzo [d]imidazol- l -yl)-9-N methyl-6-morpholino-9H-O,<N = N _ purine-8-carbonyl)piperazin-l-N N N N / yl)-2-hydroxy-2-methylpropan-NO N 1-one O

OH
796 CO~ 4-(1-((5-(2-ethyl-lH-benzo [d]imidazol- l -yl)-7-N morpholinothiazolo [5,4-N N d]pyrimidin-2-N~S NAN yl)methyl)azetidin-3-~N yl)piperazin-2-one N

HN-~

797 CO~ (2-(2-ethyl-lH-benzo [d]imidazol- l -yl)-9-N methyl-6-morpholino-9H-purin-O N L N 8-yl)(3-(4-hydroxypiperidin-l-N N -N V yl)azetidin-l-yl)methanone EN
N
HO

798 CO~ (2-(2-cyclopropyl-lH-benzo [d]imidazol- l -yl)-9-N methyl-6-morpholino-9H-purin-O<N N 8-yl)(4-(2-hydroxypropan-2-N N 1 N yl)piperidin- l-yl)methanone N
OH

799 CO~ (2-(2-cyclopropyl-lH-benzo [d]imidazol- l -yl)-9-N methyl-6-morpholino-9H-purin-O N N 8-yl)(3-morpholinoazetidin-l-ON N ' N \ yl)methanone p _N
(I) 800 C0 1-(4-(2-(2-ethyl-lH-benzo [d]imidazol- l -yl)-9-N methyl-6-morpholino-9H-purin-O N N 8-yl)-4-methoxypiperidin-l-yl)-HO NC N N N 2-hydroxy-2-methylpropan-l-~ ~ one 801 CO~ (4-(2-hydroxypropan-2-yl)piperidin-l-yl)(2-(2-N (methoxymethyl)-1 H-O N . N benzo[d]imidazol-l-yl)-9-NN methyl-6-morpholino-9H-purin-N NN 8-yl)methanone ,O
HO

802 CO~ (2-(2-(2-hydroxypropan-2-yl)-1 H-benzo [d]imidazol- l -yl)-9-N methyl-6-morpholino-9H-purin-O N L N 8-yl)(4-(2-hydroxypropan-2-~--( L V yl)piperidin- l-yl)methanone N N N N

N
HO
OH
803 O (R)-(2-(2-(l-methoxyethyl)-1H-N O benzo [d]imidazol- l -yl)-9-(N) methyl-6-morpholino-9H-purin-8-yl)(3 -morpholinoazetidin-l-N, N ~ yl)methanone O / N IN
N
/O

804 CO~ N,N-diethyl-4-(2-(2-ethyl-1 H-benzo [d]imidazol- l -yl)-9-N methyl-6-morpholino-9H-O N . N purine-8-carbonyl)piperazine-l-~N N carboxamide NO / J=
N
O=<
N-\

805 0 (S)-(4-tert-butylpiperazin-l-N yl)(2-(2-(l-methoxyethyl)-1H-N ( ~
benzo [d]imidazol- l -yl)-9-NN A N methyl-6-morpholino-9H-purin-O N N N \ 8-yl)methanone N
/O

806 CO~ N-(1-(2-(2-ethyl-lH-benzo [d]imidazol- l -yl)-9-N methyl-6-morpholino-9H-0 N N purine-8-carbonyl)piperidin-4-NN I N N V yl)-N-methylacetamide O N
~_N

807 (4-O (O) (cyclopropanecarbonyl)piperazin N -1-y1)(2-(2-ethyl-1 H-N benzo [d]imidazol- l -yl)-6-N N N morpholino-9H-purin-8-~--~~ yl)methanone O H N N
~N
808 1 -(4-(2-(2-ethyl-1 H-O CN 0 benzo[d]imidazol-l-yl)-6-Nmorpholino-9H-purine-8-carbonyl)piperazin- l -yl)propan-N N 1-one O N N,L N
H
809 CO~ 4-(2-(2-ethyl-lH-benzo [d]imidazol- l -yl)-9-N methyl-8-(l -(1-methylpiperidin-N N 4-yl)-1H-1,2,4-triazol-5-yl)-9H-r N> < purin-6-yl)morpholine N-N N :]I N N
JN
N

810 0 (2-(2-(1, 1 -difluoroethyl)- 1H-N O benzo [d]imidazol- l -yl)-9-(N) methyl-6-morpholino-9H-purin-8-yl)(3 -morpholinoazetidin-l-N N yl)methanone O N:]l N IN
F N
F

811 CO~ 1-(3-(2-(2-ethyl-lH-benzo [d]imidazol- l -yl)-9-N methyl-6-morpholino-9H-purin-N 8-yl)-3-methoxyazetidin-l-yl)-2-O N :f, HO N~N hydroxy-2-methylpropan-l-one N N
~N
812 O 4-(1-((2-(2-ethyl-1 H-benzo[d]imidazol-l-yl)-6-N morpholino-9H-purin-8-N yl)methyl)azetidin-3-rr N N N N yl)piperazin-2-one CN N
HN

813 CO~ 4-(2-((2,2-dimethyl-4-(oxetan-3-yl)piperazin-1-yl)methyl)-5-(2-N ethyl-1 H-benzo [d]imidazol- l -N yl)thiazolo[5,4-d]pyrimidin-7-N S N N / yl)morpholine NJ ~N
O

814 CO~ 1-(3-((5-(2-ethyl-lH-benzo [d]imidazol- l -yl)-7-N morpholinothiazolo [5,4-N j d]pyrimidin-2-yl)methyl)azetidin-l-yl)-2-S N N hydroxy-2-methylpropan-l-one N N
O
OH
815 CO~ 4-(2-(2-ethyl-lH-benzo [d]imidazol- l -yl)-9-N methyl-6-morpholino-9H-0 N purine-8-carbonyl)-N-N N NI N isopropylpiperazine-l-NO / N carboxamide O=<
NH
816 CO~ 4-(8-(l-cyclopentyl-lH-1,2,4-triazol-5-yl)-2-(2-ethyl-1 H-N benzo [d]imidazol- l -yl)-9-N N L N methyl-9H-purin-6-N v> < yl)morpholine N
N N N
_,~_N
817 CO~ 4-(2-(2-ethyl-lH-benzo [d]imidazol-l -yl)-8-(l -N isopropyl-1 H-imidazol-2-yl)-9-N N N methyl-9H-purin-6-// I yl)morpholine N N N N \
,,) - N

818 0 1-(4-(2-(2-ethyl-1 H-N benzo [d]imidazol- l -yl)-6-(0) N morpholino-9H-purine-8-c carbonyl)piperazin-l-yl)-2-`N
NI methylpropan- l -one 819 1-(4-(2-(2-ethyl-1 H-O (O) benzo[d]imidazol-l-yl)-6-~ morpholino-9H-purine-8-N

N carbonyl)piperazin- l -yl)-2,2-ON N dimethylpropan- l -one ~i I N
0 H N~N
~N

820 O 0 (2-(2-ethyl-lH-__ benzo[d]imidazol-l-yl)-6-N morpholino-9H-purin-8-yl)(3-CO ND (1,1-dioxo)-thiomorpholinoazetidin- l -0N I I yl)methanone O H N N
N
821 CO~ (2-(2-(hydroxymethyl)-1 H-benzo [d]imidazol- l -yl)-9-N methyl-6-morpholino-9H-purin-0 N 8-yl)(4-(2-hydroxypropan-2-N NI N yl)piperidin- l-yl)methanone N
HOJN
H
O
822 CO~ 4-(2-(2-ethyl-lH-benzo [d]imidazol-l -yl)-8-(l -N isobutyl-1 H- 1,2,4-triazol-5 -yl)-N N . N 9-methyl-9H-purin-6-N N><N N N yl)morpholine N

823 CO~ 1-(4-(2-(2-ethyl-1 H-benzo [d]imidazol- l -yl)-9-N methyl-6-morpholino-9H-purin-0 O N N 8-yl)-4-methoxypiperidin-l-yl)-HO ~N~N 2-hydroxyethanone N L
~/- N

824 CO~ 1-(3-((2-(2-ethyl-lH-benzo [d]imidazol- l -yl)-9-N methyl-6-morpholino-9H-purin-N N 8-yl)methyl)azetidin-l-yl)-2-methylpropan- l -one N N N
Y
N J N

825 C~~ cyclopropyl(3-((2-(2-ethyl-lH-benzo [d]imidazol- l -yl)-9-N methyl-6-morpholino-9H-purin-N N 8-yl)methyl)azetidin-l-N N I yl)methanone N
z ::(I
b N N

826 0 4-(2-(2-ethyl-lH-benzo [d]imidazol-l -yl)-8-(3-methoxy-l-(2-O N = N (methylsulfonyl)ethyl)azetidin-0 --N3-yl)-9-methyl-9H-purin-6-S N N yl)morpholine O N
827 CO~ 4-(2-(2-ethyl-lH-benzo [d]imidazol-1-yl)-8-(3-N methoxy-l-(tetrahydro-2H-O N pyran-4-yl)azetidin-3-yl)-9-O N~N N N \ methyl-9H-purin-6-O yl)morpholine 828 O tert-butyl 3 -(2-(2-ethyl- l H-benzo [d]imidazol- l -yl)-9-N methyl-6-morpholino-9H-purin-0 F N ::I 8-yl)-3-fluoroazetidine-l-YN~ carboxylate 0 / N N \
N

829 CO~ (S)-1-(4-((5-(2-ethyl-lH-benzo [d]imidazol- l -yl)-7-N morpholinothiazolo [5,4-N . N _ d]pyrimidin-2-yl)methyl)-3,3-~S N N dimethylpiperazin- l -yl)-2-NJ N hydroxypropan-l-one ~4 HO
830 C0 (S)-(2-(2-(l-methoxyethyl)-1H-benzo [d]imidazol- l -yl)-9-N methyl-6-morpholino-9H-purin-0 N 8-yl)(3-morpholinoazetidin-l-N N N V yl)methanone /O/, N
N P
~

831 N CN O2-(5-(2-(2-ethyl-lH-benzo [d]imidazol- l -yl)-9-methyl-6-morpholino-9H-purin-N-N N N 8-yl)-lH-1,2,4-triazol-l-yl)-N,N-L N~N dimethylethanamine N N
N
832 CO~ 1-(8-(l-isopropyl-lH-1,2,4-triazol-5-yl)-9-methyl-6-N morpholino-9H-purin-2-yl)-N,N-N-N N :]I N dimethyl-lH-benzo[d]imidazol-2-amine N N N N
N,LN
833 C0 1-(3-(2-(2-ethyl-lH-benzo [d]imidazol- l -yl)-9-N methyl-6-morpholino-9H-purin-0 N 8-yl)-3-methoxyazetidin-l-yl)-2-HO N N methylpropan-2-ol -fC
~N

834 CO~ 4-(2-(2-ethyl-lH-benzo [d]imidazol-l -yl)-8-(3-N fluoroazetidin-3-yl)-9-methyl-HNN _ 9H-purin-6-yl)morpholine i NN
~N
835 0- O (2-(2-ethyl-lH-( N benzo [d]imidazol- l -yl)-6-N morpholino-9H-purin-8-yl)(3-morpholinoazetidin- l -N N :j - yl)methanone O N NIN
H
N
836 CO~ 4-(2-(2-ethyl-lH-benzo [d]imidazol-l -yl)-8-(l -N isopropyl-4-methyl-lH-pyrazol-N-N N L N 5-yl)-9-methyl-9H-purin-6-yl)morpholine ~N
837 C O~ 1-(5-(2-(2-ethyl-lH-benzo [d]imidazol- l -yl)-9-HO N methyl-6-morpholino-9H-purin-8-yl)-4-methyl-1 H-pyrazol- l-N- N N N N
yl)-2-methylpropan-2-ol N

N
838 (0) 1-(5-(2-(2-ethyl-lH-benzo [d]imidazol- l -yl)-9-HO N methyl-6-morpholino-9H-purin-N,N N N 8-yl)-lH-1,2,4-triazol-l-yl)-2-N~N L N L N V 9 methylpropan-2-ol ~N

839 CO~ 1-(3-(2-(2-ethyl-lH-benzo [d]imidazol- l -yl)-9-N methyl-6-morpholino-9H-purin-F N 8-yl)-3-fluoroazetidin-1-yl)-2-HO NN methylpropan-2-ol NI N
~N
840 C0 (S)-1-(3-(2-(2-ethyl-lH-benzo [d]imidazol- l -yl)-9-N methyl-6-morpholino-9H-purin-O O N N 8-yl)-3-methoxyazetidin-l-yl)-2-HO_N~N hydroxypropan-l-one ~ N N
N
841 CO~ (4-(2-hydroxypropan-2-yl)piperidin-l-yl)(9-methyl-2-(2-N (methylamino)-1 H-O N benzo[d]imidazol-l-yl)-6-morpholino-9H-purin-8-N N N IN yl)methanone HNrN
HO

842 CO~ 1-(4-(2-(2-(dimethylamino)-1H-benzo [d]imidazol- l -yl)-9-N methyl-6-morpholino-9H-0 N N purine-8-carbonyl)piperazin-l-N L N V yl)prop an- l -one NN :: I -00 ' N
N N
/_71O

843 CO~ (2-(2-(dimethylamino)-1 H-benzo [d]imidazol- l -yl)-9-N methyl-6-morpholino-9H-purin-O N = N _ 8-yl)(3-morpholinoazetidin-l-N N N N \ yl)methanone NN

844 CO~ (2-(2-(dimethylamino)-1H-benzo [d]imidazol- l -yl)-9-N methyl-6-morpholino-9H-purin-0 N . 8-yl)(4-(2-hydroxypropan-2-N NI N yl)piperidin- l-yl)methanone N
/ NN
HO

845 CO~ 1-(4-((2-(2-ethyl-lH-benzo [d]imidazol- l -yl)-9-N methyl-6-morpholino-9H-purin-N I 8-yl)methyl)piperidin-l-yl)-2-hydroxy-2-methylpropan-l-one N
N N
HO)-O
846 CO~ (5-(2-ethyl-lH-benzo [d]imidazol- l -yl)-7-N morpholinothiazolo [5,4-ON N d]pyrimidin-2-yl)(3-morpholinoazetidin-l-pN S N N yl)methanone N N

847 CO~ (S)-1-(4-(2-(2-(l-methoxyethyl)-1 H-benzo [d]imidazol- l -yl)-9-N methyl-6-morpholino-9H-O N L N _ purine-8-carbonyl)piperazin-l-N I N L N V yl)prop an- l -one N
N
O~ iO

848 CO~ 1-(4-(9-methyl-2-(2-(methylamino)-1 H-N benzo[d]imidazol- l -yl)-6-O N L N _ morpholino-9H-purine-8-N N N N carbonyl)piperazin- l -yl)propan-D 1-one N HN N
O~ 1 849 CO~ 2-(3-(2-(2-ethyl-lH-benzo [d]imidazol- l -yl)-9-N methyl-6-morpholino-9H-purin-HO O N :: I I 8-yl)-3-methoxyazetidin-l-~N~N yl)ethanol N L
N
850 C0 2-(3-(2-(2-ethyl-lH-benzo [d]imidazol- l -yl)-9-N methyl-6-morpholino-9H-purin-HO F N N 8-yl)-3-fluoroazetidin-l-yl)-2-~N. methylpropan-l-ol N L
N
851 \ ,,O 1-(4-((2-(2-ethyl-1 H-benzo [d]imidazol- l -yl)-9-(0) N methyl-6-morpholino-9H-purin-N 8-yl)methyl)piperidin-l -yl)-2-Nmethylpropan- - l -one tN

N

852 ~O 0 cyclopropyl(4-((2-(2-ethyl-lH->-/< C benzo [d]imidazol-l-yl)-9-N methyl-6-morpholino-9H-purin-8-yl)methyl)piperidin- l -N I yl)methanone N

853 O 4-(2-(2-ethyl-1 H-() benzo[d]imidazol-l-yl)-9-N methyl-8-(pyridin-2-yl)-9H-purin-6-yl)morpholine N N

854 CO~ 2-hydroxy-l-(3-((2-(2-isopropyl-1 H-benzo [d]imidazol- l -yl)-9-N methyl-6-morpholino-9H-purin-N l 8-yl)methyl)azetidin-l-yl)-2-N N N methylpropan- l -one N N
HO) O
855 CO~ 2-hydroxy-2-methyl-1-(3-((9-methyl-2-(2-methyl-1 H-N benzo [d]imidazol- l -yl)-6-1 .1 N morpholino-9H-purin-8-N
yl)methyl)azetidin-l-yl)propan-N N 1-one N N
HO
O
856 CO~ 2-(1-(8-(4-(2-hydroxypropan-2-yl)piperidine- l -carbonyl)-9-N methyl-6-morpholino-9H-purin-O N 2-yl)-1H-benzo[d]imidazol-2-ON NN yl)acetonitrile N
HO N

857 CO~ (4-(2-hydroxypropan-2-yl)piperidin-l -yl)(9-methyl-6-N morpholino-2-(2-0 N (trifluoromethyl)-1 H-benzo[d]imidazol-l-yl)-9H-N N N purin-8-yl)methanone F~ N
F F
HO

858 CO~ (2-(2-(difluoromethyl)-1 H-benzo [d]imidazol- l -yl)-9-N methyl-6-morpholino-9H-purin-0 N :][I I 8-yl)(4-(2-hydroxypropan-2-yl)piperidin- l -yl)methanone N N N
F N
F
O
HO
859 CO~ (S)-1-(3-((2-(2-(1-hydroxyethyl)-1 H-N benzo [d]imidazol- l -yl)-9-I ~, N
NI N N~N 8-yl)methyl)azetidin-l-yl)-2--9 methylpropan- l -one N N

860 C0 (R)-1-(3-((2-(2-(1-hydroxyethyl)-1 H-N benzo [d]imidazol- l -yl)-9-N N methyl-6-morpholino-9H-purin-N I N .N 8-yl)methyl)azetidin-l-yl)-2-methylpropan- l -one N

861 (0) (R)-2-hydroxy-1-(3-((2-(2-(1-hydroxyethyl)-1 H-N benzo [d]imidazol- l -yl)-9-N methyl-6-morpholino-9H-purin-N NN 8-yl)methyl)azetidin-l-yl)-2-/ N methylpropan- l -one N N
HO O OH

862 (S)-1-(4-((2-(2-ethyl-1 H-(0) benzo[d]imidazol-l-yl)-9-N methyl-6-morpholino-9H-purin-N N 8-yl)methyl)piperidin-l-yl)-2-N N N hydroxypropan-l-one N ~N
O~4 OH

863 C0~ 1-(4-(2-(2-ethyl-lH-benzo [d]imidazol- l -yl)-9-N methyl-6-morpholino-9H-O N purine-8-carbonyl)piperidin-l-N N N yl)-2-methylpropan- l -one N EN
O

864 (O) (1-(cyclopropanecarbonyl)piperidin N -4-yl)(2-(2-ethyl-1 H-O N benzo[d]imidazol-l-yl)-9-N N N methyl-6-morpholino-9H-purin-8-yl)methanone N EN
O
865 C0~ cyclopropyl(4-(1-(2-(2-ethyl-1 H-benzo [d]imidazol- l -yl)-9-N methyl-6-morpholino-9H-purin-HO N N 8-yl)-1-hydroxyethyl)piperidin-N N 1 N 1-yl)methanone N EN
O

866 C0~ (9-methyl-2-(2-(methylamino)-1 H-benzo [d]imidazol- l -yl)-6-N morpholino-9H-purin-8-yl)(3-O N N morpholinoazetidin-l-NN k yl)methanone N N N

OH
867 C0~ (R)-(2-(2-(l-hydroxyethyl)-1H-benzo [d]imidazol- l -yl)-9-N methyl-6-morpholino-9H-purin-O N / N 8-yl)(3-morpholinoazetidin-l-N ~ N yl)methanone N
o HOAN

868 (S)-(2-(2-(1-hydroxyethyl)-1 H-(0) benzo[d]imidazol-l-yl)-9-N methyl-6-morpholino-9H-purin-O N / N 8-yl)(3-morpholinoazetidin-l-r IN N ~N " N yl)methanone N HO/,e::rN
of 869 (2-(2-isopropyl-1 H-(0) benzo[d]imidazol-l-yl)-9-N methyl-6-morpholino-9H-purin-O N N 8-yl)(3-morpholinoazetidin-l-r IN N N N yl)methanone \ N
0j 870 0- (2-(2-(2-hydroxyethyl)-1H-(0) Nbenzo[d]imidazol-l-yl)-9-methyl-6-morpholino-9H-purin-8-yl)(3 -morpholino azetidin-l-N~ N NI N

P N
HO

871 C~~ (4-(2-hydroxypropan-2-yl)piperidin-l-yl)(9-methyl-2-(2-N methyl-3H-imidazo[4,5-0 N N N c]pyridin-3-yl)-6-morpholino-9H-purin-8-yl)methanone N N:]l N N

H
O
872 (9-methyl-2-(2-methyl-3H-(0) (9-methyl-2-(2-methyl-3H-imidazo[4,5-c]pyridin-3-yl)-6-N morpholino-9H-purin-8-yl)(3-ON XLN~) ;li1n:etidin l-P ' ~_ N N
~

O~
873CO~ (4-(2-hydroxypropan-2-yl)piperidin-l -yl)(9-methyl-2-(2-N methyl-1 H-imidazo [4,5-O N - NI N c]pyridin-l-yl)-6-morpholino-N N,N \ /N 9H-purin-8-yl)methanone N

HO
874 C~~ (9-methyl-2-(2-methyl-lH-imidazo[4,5-c]pyridin-l-yl)-6-N morpholino-9H-purin-8-yl)(3-0 N X~XN~N linoazetidinl-yl)methanone N :]~ C
N
N

875 CO~ (4-(2-hydroxypropan-2-yl)piperidin-l-yl)(2-N (imidazo [ 1,2-a]pyridin-5-yl)-9-O N . N methyl-6-morpholino-9H-purin-i N N N N N 8-yl)methanone HO

876 CO~ 1-(4-((5-(2-ethyl-lH-benzo [d]imidazol- l -yl)-7-N morpholinothiazolo [5,4-N d]pyrimidin-2-S yl)methyl)piperidin-l-yl)-2-N N hydroxy-2-methylpropan- l -one N N
O
OH
877 0 O (2-(2-methoxy-lH-N CND benzo[d]imidazol-l-yl)-9-methyl-6-morpholino-9H-purin-8-yl)(3 -morpholinoazetidin-l-O N yl)methanone O N N~N

O N

878 CO~ (2-(2-(difluoromethyl)-1 H-benzo [d]imidazol- l -yl)-9-N methyl-6-morpholino-9H-purin-O N L N 8-yl)(3-morpholinoazetidin-l-N N N \ yl)methanone F~ N
p -N
N F

879 CO~ (2-(2-(2-hydroxyethyl)-1H-benzo [d]imidazol- l -yl)-9-N methyl-6-morpholino-9H-purin-O N L 8-yl)(4-(2-hydroxypropan-2-N Nj N yl)piperidin- l-yl)methanone N
N
HO
H
O
880 C0 1-(4-(2-(2-(2-hydroxyethyl)-1 H-benzo [d]imidazol- l -yl)-9-N methyl-6-morpholino-9H-O N L N purine-8-carbonyl)piperazin-l-N N A N yl)prop an- l -one N
NJ N
HO
O

881 CO~ 1-(4-(9-methyl-2-(2-methyl-3H-imidazo[4,5-c]pyridin-3-yl)-6-N morpholino-9H-purine-8-O N N N carbonyl)piperazin-l-yl)propan-1-one N N N N._ ~
N~ N
/_t 882 CO~ 1-(4-(9-methyl-2-(2-methyl-1 H-imidazo[4,5-c]pyridin-l-yl)-6-N morpholino-9H-purine-8-O N L N carbonyl)piperazin-l-yl)propan-N 1-one N N N ~i N
N rj /_iO

883 CO~ 1-(8-(4-(2-hydroxypropan-2-yl)piperidine- l -carbonyl)-9-N methyl-6-morpholino-9H-purin-ON . N _ 2-yl)-1H-benzo[d]imidazol-N N NN V 2(3H)-one O~_ NH

HO
884 CO~ (4-(2-hydroxypropan-2-yl)piperidin-l-yl)(2-(2-methoxy-N 1 H-benzo [d]imidazol- l -yl)-9-ON = _ methyl-6-morpholino-9H-purin-N N Nj N11 V/ 8-yl)methanone H
O
885 CO~ 1-(4-(2-(2-methoxy-lH-benzo [d]imidazol- l -yl)-9-N methyl-6-morpholino-9H-O N - N purine-8-carbonyl)piperazin-l-N N yl)prop an- l -one N
N~ / -_ o/'--- N
/_\1O

[0002] ADMINISTRATION OF FORMULA I COMPOUNDS

[0003] The Formula I compounds of the invention may be administered by a route appropriate to the condition to be treated. Suitable routes include oral, parenteral (including subcutaneous, intramuscular, intravenous, intraarterial, intradermal, intrathecal and epidural), transdermal, rectal, nasal, topical (including buccal and sublingual), vaginal, intraperitoneal, intrapulmonary and intranasal. For local immunosuppressive treatment, the compounds may be administered by intralesional administration, including perfusing or otherwise contacting the graft with the inhibitor before transplantation. It will be appreciated that the preferred route may vary with for example the condition of the recipient. Where the compound is administered orally, it may be formulated as a pill, capsule, tablet, etc.
with a pharmaceutically acceptable carrier or excipient. Where the compound is administered parenterally, it may be formulated with a pharmaceutically acceptable parenteral vehicle and in a unit dosage injectable form, as detailed below.
[0004] A dose to treat human patients may range from about 10 mg to about 1000 mg of Formula I compound. A typical dose may be about 100 mg to about 300 mg of the compound. A dose may be administered once a day (QID), twice per day (BID), or more frequently, depending on the pharmacokinetic and pharmacodynamic properties, including absorption, distribution, metabolism, and excretion of the particular compound. In addition, toxicity factors may influence the dosage and administration regimen. When administered orally, the pill, capsule, or tablet may be ingested daily or less frequently for a specified period of time. The regimen may be repeated for a number of cycles of therapy.

[0005] METHODS OF TREATMENT WITH FORMULA I COMPOUNDS
[0006] Formula I compounds of the present invention are useful for treating a human or animal patient suffering from a disease or disorder arising from abnormal cell growth, function or behavior associated with P13 kinase, in particular with the pl 108 (delta) isoform of P13 kinase such as an immune disorder, cardiovascular disease, viral infection, inflammation, a metabolism/endocrine disorder or a neurological disorder, may thus be treated by a method comprising the administration thereto of a compound of the present invention as defined above. A human or animal patient suffering from cancer may also be treated by a method comprising the administration thereto of a compound of the present invention as defined above. The condition of the patient may thereby be improved or ameliorated.
[0007] Formula I compounds may be useful for in vitro, in situ, and in vivo diagnosis or treatment of mammalian cells, organisms, or associated pathological conditions, such as systemic and local inflammation, immune-inflammatory diseases such as rheumatoid arthritis, immune suppression, organ transplant rejection, allergies, ulcerative colitis, Crohn's disease, dermatitis, asthma, systemic lupus erythematosus, Sjogren's Syndrome, multiple sclerosis, scleroderma/systemic sclerosis, idiopathic thrombocytopenic purpura (ITP), anti-neutrophil cytoplasmic antibodies (ANCA) vasculitis, chronic obstructive pulmonary disease (COPD), psoriasis, and for general joint protective effects.
[0008] Methods of the invention also include treating such diseases as arthritic diseases, such as rheumatoid arthritis, monoarticular arthritis, osteoarthritis, gouty arthritis, spondylitis; Behcet disease; sepsis, septic shock, endotoxic shock, gram negative sepsis, gram positive sepsis, and toxic shock syndrome; multiple organ injury syndrome secondary to septicemia, trauma, or hemorrhage; ophthalmic disorders such as allergic conjunctivitis, vernal conjunctivitis, uveitis, and thyroid-associated ophthalmopathy;
eosinophilic granuloma; pulmonary or respiratory disorders such as asthma, chronic bronchitis, allergic rhinitis, ARDS, chronic pulmonary inflammatory disease (e.g., chronic obstructive pulmonary disease), silicosis, pulmonary sarcoidosis, pleurisy, alveolitis, vasculitis, emphysema, pneumonia, bronchiectasis, and pulmonary oxygen toxicity;
reperfusion injury of the myocardium, brain, or extremities; fibrosis such as cystic fibrosis;
keloid formation or scar tissue formation; atherosclerosis; autoimmune diseases, such as systemic lupus erythematosus (SLE), autoimmune thyroiditis, multiple sclerosis, some forms of diabetes, and Reynaud's syndrome; and transplant rejection disorders such as GVHD and allograft rejection; chronic glomerulonephritis; inflammatory bowel diseases such as chronic inflammatory bowel disease (CIBD), Crohn's disease, ulcerative colitis, and necrotizing enterocolitis; inflammatory dermatoses such as contact dermatitis, atopic dermatitis, psoriasis, or urticaria; fever and myalgias due to infection; central or peripheral nervous system inflammatory disorders such as meningitis, encephalitis, and brain or spinal cord injury due to minor trauma; Sjogren's syndrome; diseases involving leukocyte diapedesis;
alcoholic hepatitis; bacterial pneumonia; antigen-antibody complex mediated diseases;
hypovolemic shock; Type I diabetes mellitus; acute and delayed hypersensitivity; disease states due to leukocyte dyscrasia and metastasis; thermal injury; granulocyte transfusion-associated syndromes; and cytokine-induced toxicity.
[0009] The methods of the invention can have utility in treating subjects who are or can be subject to reperfusion injury, i.e., injury resulting from situations in which a tissue or organ experiences a period of ischemia followed by reperfusion. The term "ischemia" refers to localized tissue anemia due to obstruction of the inflow of arterial blood.
Transient ischemia followed by reperfusion characteristically results in neutrophil activation and transmigration through the endothelium of the blood vessels in the affected area.
Accumulation of activated neutrophils in turn results in generation of reactive oxygen metabolites, which damage components of the involved tissue or organ. This phenomenon of "reperfusion injury" is commonly associated with conditions such as vascular stroke (including global and focal ischemia), hemorrhagic shock, myocardial ischemia or infarction, organ transplantation, and cerebral vasospasm. To illustrate, reperfusion injury occurs at the termination of cardiac bypass procedures or during cardiac arrest when the heart, once prevented from receiving blood, begins to reperfuse. It is expected that inhibition of P13K
delta activity may result in reduced amounts of reperfusion injury in such situations.

[0010] PHARMACEUTICAL FORMULATIONS
[0011] In order to use a Formula I compound for the therapeutic treatment (including prophylactic treatment) of mammals including humans, it is normally formulated in accordance with standard pharmaceutical practice as a pharmaceutical composition.
According to this aspect of the invention there is provided a pharmaceutical composition comprising a compound of this invention in association with a pharmaceutically acceptable diluent or carrier.
[0012] A typical formulation is prepared by mixing a compound of the present invention and a carrier, diluent or excipient. Suitable carriers, diluents and excipients are well known to those skilled in the art and include materials such as carbohydrates, waxes, water soluble and/or swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water and the like. The particular carrier, diluent or excipient used will depend upon the means and purpose for which the compound of the present invention is being applied. Solvents are generally selected based on solvents recognized by persons skilled in the art as safe (GRAS) to be administered to a mammal. In general, safe solvents are non-toxic aqueous solvents such as water and other non-toxic solvents that are soluble or miscible in water. Suitable aqueous solvents include water, ethanol, propylene glycol, polyethylene glycols (e.g., PEG 400, PEG 300), etc. and mixtures thereof. The formulations may also include one or more buffers, stabilizing agents, surfactants, wetting agents, lubricating agents, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, perfuming agents, flavoring agents and other known additives to provide an elegant presentation of the drug (i.e., a compound of the present invention or pharmaceutical composition thereof) or aid in the manufacturing of the pharmaceutical product (i.e., medicament).
[0013] The formulations may be prepared using conventional dissolution and mixing procedures. For example, the bulk drug substance (i.e., compound of the present invention or stabilized form of the compound (e.g., complex with a cyclodextrin derivative or other known complexation agent) is dissolved in a suitable solvent in the presence of one or more of the excipients described above. The compound of the present invention is typically formulated into pharmaceutical dosage forms to provide an easily controllable dosage of the drug and to enable patient compliance with the prescribed regimen.
[0014] The pharmaceutical composition (or formulation) for application may be packaged in a variety of ways depending upon the method used for administering the drug.
Generally, an article for distribution includes a container having deposited therein the pharmaceutical formulation in an appropriate form. Suitable containers are well known to those skilled in the art and include materials such as bottles (plastic and glass), sachets, ampoules, plastic bags, metal cylinders, and the like. The container may also include a tamper-proof assemblage to prevent indiscreet access to the contents of the package. In addition, the container has deposited thereon a label that describes the contents of the container. The label may also include appropriate warnings.
[0015] Pharmaceutical formulations of the compounds of the present invention may be prepared for various routes and types of administration. For example, a compound of Formula I having the desired degree of purity may optionally be mixed with pharmaceutically acceptable diluents, carriers, excipients or stabilizers (Remington's Pharmaceutical Sciences (1980) 16th edition, Osol, A. Ed.), in the form of a lyophilized formulation, milled powder, or an aqueous solution. Formulation may be conducted by mixing at ambient temperature at the appropriate pH, and at the desired degree of purity, with physiologically acceptable carriers, i.e., carriers that are non-toxic to recipients at the dosages and concentrations employed. The pH of the formulation depends mainly on the particular use and the concentration of compound, but may range from about 3 to about 8. Formulation in an acetate buffer at pH 5 is a suitable embodiment.
[0016] The compound ordinarily can be stored as a solid composition, a lyophilized formulation or as an aqueous solution.
[0017] The pharmaceutical compositions of the invention will be formulated, dosed and administered in a fashion, i.e., amounts, concentrations, schedules, course, vehicles and route of administration, consistent with good medical practice. Factors for consideration in this context include the particular disorder being treated, the particular mammal being treated, the clinical condition of the individual patient, the cause of the disorder, the site of delivery of the agent, the method of administration, the scheduling of administration, and other factors known to medical practitioners. The "therapeutically effective amount" of the compound to be administered will be governed by such considerations, and is the minimum amount necessary to prevent, ameliorate, or treat the hyperproliferative disorder.
[0018] As a general proposition, the initial pharmaceutically effective amount of the inhibitor administered parenterally per dose will be in the range of about 0.01-100 mg/kg, namely about 0.1 to 20 mg/kg of patient body weight per day, with the typical initial range of compound used being 0.3 to 15 mg/kg/day.
[0019] Acceptable diluents, carriers, excipients and stabilizers are nontoxic to recipients at the dosages and concentrations employed, and include buffers such as phosphate, citrate and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzyl ammonium chloride;
hexamethonium chloride; benzalkonium chloride, benzethonium chloride; phenol, butyl or benzyl alcohol; alkyl parabens such as methyl or propyl paraben; catechol;
resorcinol;
cyclohexanol; 3-pentanol; and m-cresol); low molecular weight (less than about 10 residues) polypeptides; proteins, such as serum albumin, gelatin, or immunoglobulins;
hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine, or lysine; monosaccharides, disaccharides and other carbohydrates including glucose, mannose, or dextrins; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose or sorbitol; salt-forming counter-ions such as sodium; metal complexes (e.g., Zn-protein complexes); and/or non-ionic surfactants such as TWEENTM, PLURONICSTM or polyethylene glycol (PEG). The active pharmaceutical ingredients may also be entrapped in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization, for example, hydroxymethylcellulose or gelatin-microcapsules and poly-(methylmethacylate) microcapsules, respectively, in colloidal drug delivery systems (for example, liposomes, albumin microspheres, microemulsions, nano-particles and nanocapsules) or in macroemulsions. Such techniques are disclosed in Remington's Pharmaceutical Sciences 16th edition, Osol, A. Ed. (1980).
[0020] Sustained-release preparations of compounds of Formula I may be prepared.
Suitable examples of sustained-release preparations include semipermeable matrices of solid hydrophobic polymers containing a compound of Formula I, which matrices are in the form of shaped articles, e.g., films, or microcapsules. Examples of sustained-release matrices include polyesters, hydrogels (for example, poly(2-hydroxyethyl-methacrylate), or poly(vinyl alcohol)), polylactides (US 3773919), copolymers of L-glutamic acid and gamma-ethyl-L-glutamate, non-degradable ethylene-vinyl acetate, degradable lactic acid-glycolic acid copolymers such as the LUPRON DEPOT TM (injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate) and poly-D-(-)-3-hydroxybutyric acid.
[0021] The formulations include those suitable for the administration routes detailed herein. The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Techniques and formulations generally are found in Remington's Pharmaceutical Sciences (Mack Publishing Co., Easton, PA). Such methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more accessory ingredients. In general the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product.
[0022] Formulations of a compound of Formula I suitable for oral administration may be prepared as discrete units such as pills, capsules, cachets or tablets each containing a predetermined amount of a compound of Formula I. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surface active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered active ingredient moistened with an inert liquid diluent.
The tablets may optionally be coated or scored and optionally are formulated so as to provide slow or controlled release of the active ingredient therefrom. Tablets, troches, lozenges, aqueous or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, e.g., gelatin capsules, syrups or elixirs may be prepared for oral use.
Formulations of compounds of Formula I intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents including sweetening agents, flavoring agents, coloring agents and preserving agents, in order to provide a palatable preparation.
Tablets containing the active ingredient in admixture with non-toxic pharmaceutically acceptable excipient which are suitable for manufacture of tablets are acceptable. These excipients may be, for example, inert diluents, such as calcium or sodium carbonate, lactose, calcium or sodium phosphate; granulating and disintegrating agents, such as maize starch, or alginic acid;
binding agents, such as starch, gelatin or acacia; and lubricating agents, such as magnesium stearate, stearic acid or talc. Tablets may be uncoated or may be coated by known techniques including microencapsulation to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate alone or with a wax may be employed.
[0023] For treatment of the eye or other external tissues, e.g., mouth and skin, the formulations may be applied as a topical ointment or cream containing the active ingredient(s) in an amount of, for example, 0.075 to 20% w/w. When formulated in an ointment, the active ingredients may be employed with either a paraffinic or a water-miscible ointment base. Alternatively, the active ingredients may be formulated in a cream with an oil-in-water cream base. If desired, the aqueous phase of the cream base may include a polyhydric alcohol, i.e., an alcohol having two or more hydroxyl groups such as propylene glycol, butane 1,3-diol, mannitol, sorbitol, glycerol and polyethylene glycol (including PEG
400) and mixtures thereof. The topical formulations may desirably include a compound which enhances absorption or penetration of the active ingredient through the skin or other affected areas. Examples of such dermal penetration enhancers include dimethyl sulfoxide and related analogs. The oily phase of the emulsions of this invention may be constituted from known ingredients in a known manner, including a mixture of at least one emulsifier with a fat or an oil, or with both a fat and an oil. A hydrophilic emulsifier included together with a lipophilic emulsifier acts as a stabilizer. Together, the emulsifier(s) with or without stabilizer(s) make up the so-called emulsifying wax, and the wax together with the oil and fat make up the so-called emulsifying ointment base which forms the oily dispersed phase of the cream formulations. Emulsifiers and emulsion stabilizers suitable for use in the formulation of the invention include Tween 60, Span 80, cetostearyl alcohol, benzyl alcohol, myristyl alcohol, glyceryl mono-stearate and sodium lauryl sulfate.
[0024] Aqueous suspensions of Formula I compounds contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions.
Such excipients include a suspending agent, such as sodium carboxymethylcellulose, croscarmellose, povidone, methylcellulose, hydroxypropyl methylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia, and dispersing or wetting agents such as a naturally occurring phosphatide (e.g., lecithin), a condensation product of an alkylene oxide with a fatty acid (e.g., polyoxyethylene stearate), a condensation product of ethylene oxide with a long chain aliphatic alcohol (e.g., heptadecaethyleneoxycetanol), a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol anhydride (e.g., polyoxyethylene sorbitan monooleate). The aqueous suspension may also contain one or more preservatives such as ethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents and one or more sweetening agents, such as sucrose or saccharin.
[0025] The pharmaceutical compositions of compounds of Formula I may be in the form of a sterile injectable preparation, such as a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,3-butanediol or prepared as a lyophilized powder. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile fixed oils may conventionally be employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid may likewise be used in the preparation of injectables.
[0026] The amount of active ingredient that may be combined with the carrier material to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. For example, a time-release formulation intended for oral administration to humans may contain approximately 1 to 1000 mg of active material compounded with an appropriate and convenient amount of carrier material which may vary from about 5 to about 95% of the total compositions (weight:weight). The pharmaceutical composition can be prepared to provide easily measurable amounts for administration. For example, an aqueous solution intended for intravenous infusion may contain from about 3 to 500 g of the active ingredient per milliliter of solution in order that infusion of a suitable volume at a rate of about 30 mL/hr can occur.
[0027] Formulations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
[0028] Formulations suitable for topical administration to the eye also include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent for the active ingredient. The active ingredient is preferably present in such formulations in a concentration of about 0.5 to 20% w/w, for example about 0.5 to 10%
w/w, for example about 1.5% w/w.
[0029] Formulations suitable for topical administration in the mouth include lozenges comprising the active ingredient in a flavored basis, usually sucrose and acacia or tragacanth;
pastilles comprising the active ingredient in an inert basis such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.
[0030] Formulations for rectal administration may be presented as a suppository with a suitable base comprising for example cocoa butter or a salicylate.
[0031] Formulations suitable for intrapulmonary or nasal administration have a particle size for example in the range of 0.1 to 500 microns (including particle sizes in a range between 0.1 and 500 microns in increments microns such as 0.5, 1, 30 microns, 35 microns, etc.), which is administered by rapid inhalation through the nasal passage or by inhalation through the mouth so as to reach the alveolar sacs. Suitable formulations include aqueous or oily solutions of the active ingredient. Formulations suitable for aerosol or dry powder administration may be prepared according to conventional methods and may be delivered with other therapeutic agents such as compounds heretofore used in the treatment or prophylaxis disorders as described below.
[0032] Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the active ingredient such carriers as are known in the art to be appropriate.
[0033] The formulations may be packaged in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water, for injection immediately prior to use. Extemporaneous injection solutions and suspensions are prepared from sterile powders, granules and tablets of the kind previously described.
Preferred unit dosage formulations are those containing a daily dose or unit daily sub-dose, as herein above recited, or an appropriate fraction thereof, of the active ingredient.
[0034] The invention further provides veterinary compositions comprising at least one active ingredient as above defined together with a veterinary carrier therefore.
Veterinary carriers are materials useful for the purpose of administering the composition and may be solid, liquid or gaseous materials which are otherwise inert or acceptable in the veterinary art and are compatible with the active ingredient. These veterinary compositions may be administered parenterally, orally or by any other desired route.

[0035] COMBINATION THERAPY
[0036] The compounds of Formula I may be employed alone or in combination with other therapeutic agents for the treatment of a disease or disorder described herein, such as inflammation or a hyperproliferative disorder (e.g., cancer). In certain embodiments, a compound of Formula I is combined in a pharmaceutical combination formulation, or dosing regimen as combination therapy, with a second therapeutic compound that has anti-inflammatory or anti-hyperproliferative properties or that is useful for treating an inflammation, immune-response disorder, or hyperproliferative disorder (e.g., cancer). The second therapeutic agent may be an NSAID anti-inflammatory agent. The second therapeutic agent may be a chemotherapeutic agent. The second compound of the pharmaceutical combination formulation or dosing regimen preferably has complementary activities to the compound of Formula I such that they do not adversely affect each other. Such compounds are suitably present in combination in amounts that are effective for the purpose intended. In one embodiment, a composition of this invention comprises a compound of Formula I, or a stereoisomer, tautomer, or pharmaceutically acceptable salt or prodrug thereof, in combination with a therapeutic agent such as an NSAID.
[0037] The combination therapy may be administered as a simultaneous or sequential regimen. When administered sequentially, the combination may be administered in two or more administrations. The combined administration includes coadministration, using separate formulations or a single pharmaceutical formulation, and consecutive administration in either order, wherein preferably there is a time period while both (or all) active agents simultaneously exert their biological activities.
[0038] Suitable dosages for any of the above coadministered agents are those presently used and may be lowered due to the combined action (synergy) of the newly identified agent and other therapeutic agents or treatments.

[0039] The combination therapy may provide "synergy" and prove "synergistic", i.e., the effect achieved when the active ingredients used together is greater than the sum of the effects that results from using the compounds separately. A synergistic effect may be attained when the active ingredients are: (1) co-formulated and administered or delivered simultaneously in a combined, unit dosage formulation; (2) delivered by alternation or in parallel as separate formulations; or (3) by some other regimen. When delivered in alternation therapy, a synergistic effect may be attained when the compounds are administered or delivered sequentially, e.g., by different injections in separate syringes, separate pills or capsules, or separate infusions. In general, during alternation therapy, an effective dosage of each active ingredient is administered sequentially, i.e., serially, whereas in combination therapy, effective dosages of two or more active ingredients are administered together.
[0040] In a particular embodiment of therapy, a compound of Formula I, or a stereoisomer, tautomer, or pharmaceutically acceptable salt or prodrug thereof, may be combined with other therapeutic, hormonal or antibody agents such as those described herein, as well as combined with surgical therapy and radiotherapy. Combination therapies according to the present invention thus comprise the administration of at least one compound of Formula I, or a stereoisomer, tautomer, or pharmaceutically acceptable salt or prodrug thereof, and the use of at least one other cancer treatment method. The amounts of the compound(s) of Formula I and the other pharmaceutically active chemotherapeutic agent(s) and the relative timings of administration will be selected in order to achieve the desired combined therapeutic effect.

[0041] METABOLITES OF COMPOUNDS OF FORMULA I
[0042] Also falling within the scope of this invention are the in vivo metabolic products of Formula I described herein. Such products may result for example from the oxidation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, enzymatic cleavage, and the like, of the administered compound. Accordingly, the invention includes metabolites of compounds of Formula I, including compounds produced by a process comprising contacting a compound of this invention with a mammal for a period of time sufficient to yield a metabolic product thereof.
[0043] Metabolite products typically are identified by preparing a radiolabelled (e.g., 14C or 3H) isotope of a compound of the invention, administering it parenterally in a detectable dose (e.g., greater than about 0.5 mg/kg) to an animal such as rat, mouse, guinea pig, monkey, or to man, allowing sufficient time for metabolism to occur (typically about 30 seconds to 30 hours) and isolating its conversion products from the urine, blood or other biological samples. These products are easily isolated since they are labeled (others are isolated by the use of antibodies capable of binding epitopes surviving in the metabolite).
The metabolite structures are determined in conventional fashion, e.g., by MS, LC/MS or NMR analysis. In general, analysis of metabolites is done in the same way as conventional drug metabolism studies well known to those skilled in the art. The metabolite products, so long as they are not otherwise found in vivo, are useful in diagnostic assays for therapeutic dosing of the compounds of the invention.

[0044] ARTICLES OF MANUFACTURE
[0045] In another embodiment of the invention, an article of manufacture, or "kit", containing materials useful for the treatment of the diseases and disorders described above is provided. In one embodiment, the kit comprises a container comprising a compound of Formula I. The kit may further comprise a label or package insert, on or associated with the container. The term "package insert" is used to refer to instructions customarily included in commercial packages of therapeutic products, that contain information about the indications, usage, dosage, administration, contraindications and/or warnings concerning the use of such therapeutic products. Suitable containers include, for example, bottles, vials, syringes, blister pack, etc. The container may be formed from a variety of materials such as glass or plastic.

The container may hold a compound of Formula I or a formulation thereof which is effective for treating the condition and may have a sterile access port (for example, the container may be an intravenous solution bag or a vial having a stopper pierceable by a hypodermic injection needle). At least one active agent in the composition is a compound of Formula I.
The label or package insert indicates that the composition is used for treating the condition of choice, such as cancer. In addition, the label or package insert may indicate that the patient to be treated is one having a disorder such as a hyperproliferative disorder, neurodegeneration, cardiac hypertrophy, pain, migraine or a neurotraumatic disease or event. In one embodiment, the label or package inserts indicates that the composition comprising a compound of Formula I can be used to treat a disorder resulting from abnormal cell growth.
The label or package insert may also indicate that the composition can be used to treat other disorders. Alternatively, or additionally, the article of manufacture may further comprise a second container comprising a pharmaceutically acceptable buffer, such as bacteriostatic water for injection (BWFI), phosphate-buffered saline, Ringer's solution and dextrose solution. It may further include other materials desirable from a commercial and user standpoint, including other buffers, diluents, filters, needles, and syringes.
[0046] The kit may further comprise directions for the administration of the compound of Formula I and, if present, the second pharmaceutical formulation.
For example, if the kit comprises a first composition comprising a compound of Formula I
and a second pharmaceutical formulation, the kit may further comprise directions for the simultaneous, sequential or separate administration of the first and second pharmaceutical compositions to a patient in need thereof.
[0047] In another embodiment, the kits are suitable for the delivery of solid oral forms of a compound of Formula I, such as tablets or capsules. Such a kit preferably includes a number of unit dosages. Such kits can include a card having the dosages oriented in the order of their intended use. An example of such a kit is a "blister pack".
Blister packs are well known in the packaging industry and are widely used for packaging pharmaceutical unit dosage forms. If desired, a memory aid can be provided, for example in the form of numbers, letters, or other markings or with a calendar insert, designating the days in the treatment schedule in which the dosages can be administered.
[0048] According to one embodiment, a kit may comprise (a) a first container with a compound of Formula I contained therein; and optionally (b) a second container with a second pharmaceutical formulation contained therein, wherein the second pharmaceutical formulation comprises a second compound with anti-hyperproliferative activity.

Alternatively, or additionally, the kit may further comprise a third container comprising a pharmaceutically-acceptable buffer, such as bacteriostatic water for injection (BWFI), phosphate-buffered saline, Ringer's solution and dextrose solution. It may further include other materials desirable from a commercial and user standpoint, including other buffers, diluents, filters, needles, and syringes.
[0049] In certain other embodiments wherein the kit comprises a composition of Formula I and a second therapeutic agent, the kit may comprise a container for containing the separate compositions such as a divided bottle or a divided foil packet, however, the separate compositions may also be contained within a single, undivided container.
Typically, the kit comprises directions for the administration of the separate components. The kit form is particularly advantageous when the separate components are preferably administered in different dosage forms (e.g., oral and parenteral), are administered at different dosage intervals, or when titration of the individual components of the combination is desired by the prescribing physician.

[0050] PREPARATION OF FORMULA I COMPOUNDS
[0051] Compounds of Formula I may be synthesized by synthetic routes that include processes analogous to those well-known in the chemical arts, particularly in light of the description contained herein, and those for other heterocycles described in:
Comprehensive Heterocyclic Chemistry II, Editors Katritzky and Rees, Elsevier, 1997, e.g.
Volume 3;
Liebigs Annalen der Chemie, (9):1910-16, (1985); Helvetica Chimica Acta, 41:1052-60, (1958); Arzneimittel-Forschung, 40(12):1328-31, (1990), each of which are expressly incorporated by reference. Starting materials are generally available from commercial sources such as Aldrich Chemicals (Milwaukee, WI) or are readily prepared using methods well known to those skilled in the art (e.g., prepared by methods generally described in Louis F. Fieser and Mary Fieser, Reagents for Organic Synthesis, v. 1-23, Wiley, N.Y. (1967-2006 ed.), or Beilsteins Handbuch der organischen Chemie, 4, Aufl. ed. Springer-Verlag, Berlin, including supplements (also available via the Beilstein online database).
[0052] In certain embodiments, thiazolopyrimidine compounds of Formula I (Xi is N
and X2 is S) may be readily prepared using procedures well-known to prepare thiazoles, pyrimidines, and thiazolopyrimidines (US 6608053; US 6492383; US 6232320; US
6187777;
US 3763156; US 3661908; US 3475429; US 5075305; US 2003/220365; GB 1390658; GB
1393161; WO 93/13664).
[0053] In certain embodiments, purine compounds of Formula I (Xi is N and X2 is NR2) may be readily prepared using well-known procedures to prepare purines (Hammarstrom et al (2007) Tetrahedron Lett. 48(16):2823-2827; Cerna et al (2006) Organic Letters 8(23):5389-5392; Chang et al (2006) J. Med. Chem. 49(10):2861-2867;
Yang et al (2005) J. Comb. Chem. 7:474-482; Liu et al (2005) J. Comb. Chem. 7:627-636;
Hocek et al (2004) Synthesis 17:2869-2876; Hammarstrom et al (2003) Tetrahedron Lett.
44:8361-8363;
Hammarstrom et al (2002) Tetrahedron Lett. 43:8071-8073; Booth et al (1987) J.
Chem. Soc, Perkin Trans. 1: Organic and Bio-Organic Chem. 7:1521-1526; Booth et al (1981) J. Chem.
Soc., Chemical Communications 15:788-789; Yoneda et al (1976) J. Chem. Soc., Perkin Trans. 1: Organic and Bio-Organic Chem. 14:1547-1550; Taylor et al (1971) J.
Org. Chem.
36(21):3211-3217; Lister, J. H.; Fenn, M. D. The Purines, Supplementary 1, John Wiley &
Sons, 1996, Volume 54; The Chemistry of Heterocyclic Compounds, Editors Weissberger, A.; Taylor E. C., Wiley Interscience, 1971, Volume 24; Legraverend, M.;
Grierson, D. S.
(2006) Bioorg. Med. Chem. 14:3987-4006; Hocek, M. (2003) Eur. J. Org. Chem.

254;US 7122665; US 6743919; US 5332744; US 4728644; US 3016378; US
2008/0058297;
US 2003/0139427; WO 2008/043031).
[0054] Synthetic chemistry transformations and protecting group methodologies (protection and deprotection) useful in synthesizing Formula I compounds and necessary reagents and intermediates are known in the art and include, for example, those described in R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); T. W.
Greene and P. G.M. Wuts, Protective Groups in Organic Synthesis, 3rd Ed., John Wiley and Sons (1999); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995) and subsequent editions thereof.
[0055] Compounds of Formula I may be prepared singly or as compound libraries comprising at least 2, for example 5 to 1,000 compounds, or 10 to 100 compounds. Libraries of compounds of Formula I may be prepared by a combinatorial `split and mix' approach or by multiple parallel syntheses using either solution phase or solid phase chemistry, by procedures known to those skilled in the art. Thus according to a further aspect of the invention there is provided a compound library comprising at least 2 compounds, or pharmaceutically acceptable salts thereof.
[0056] A purine compound may be prepared by using 2,4,8-trichloropurine as a starting material. The three chloro groups can be displaced by various substituents. More specifically, the most reactive chloro group (i.e., chloro at position 4) is substituted with a morpholino group to form morpholinopurine.

[0057] For illustrative purposes, Scheme 1 shows a general method for preparing Formula I purine compounds, as well as key intermediates. For a more detailed description of the individual reaction steps, see the General Procedures and Examples sections. Those skilled in the art will appreciate that other synthetic routes may be used to synthesize the inventive compounds. Although specific starting materials and reagents are depicted and discussed in the General Procedures, Examples, Scheme 1, other starting materials and reagents can be easily substituted to provide a variety of derivatives and/or reaction conditions. In addition, many of the exemplary compounds prepared by the described methods can be further modified in light of this disclosure using conventional chemistry well known to those skilled in the art.
[0058] Scheme 1 N'\ ,N 0 ' N N N N 1a)BuLi / / H /
\N <N I i\ MeOH \N \ 1b Electro hile H N CI PISA N CI N CI ) p EtOAc COD (0) (0) n N

R,~N MeOH A R1~N I Cs2CO3 Rj-N
N CI H N CI DMF A N N CI
n(Ci Ijo R2 COD
aryl boronic acid or aryl boronate R1~N - N
PdCI2(PPh3)2 N NR3 1M Na2CO3/ACN n(() [0059] In preparing compounds of Formulas I, protection of remote functionality (e.g., primary or secondary amine) of intermediates may be necessary. The need for such protection will vary depending on the nature of the remote functionality and the conditions of the preparation methods. Suitable amino-protecting groups include acetyl, trifluoroacetyl, t-butoxycarbonyl (BOC), benzyloxycarbonyl (CBz) and 9-fluorenylmethyleneoxycarbonyl (Fmoc). The need for such protection is readily determined by one skilled in the art. For a general description of protecting groups and their use, see T. W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991.

[0060] METHODS OF SEPARATION
[0061] In the methods of preparing Formula I compounds, it may be advantageous to separate reaction products from one another and/or from starting materials.
The desired products of each step or series of steps is separated and/or purified to the desired degree of homogeneity by the techniques common in the art. Typically such separations involve multiphase extraction, crystallization from a solvent or solvent mixture, distillation, sublimation, or chromatography. Chromatography can involve any number of methods including, for example: reverse-phase and normal phase; size exclusion; ion exchange; high, medium and low pressure liquid chromatography methods and apparatus; small scale analytical; simulated moving bed (SMB) and preparative thin or thick layer chromatography, as well as techniques of small scale thin layer and flash chromatography.
[0062] Another class of separation methods involves treatment of a mixture with a reagent selected to bind to or render otherwise separable a desired product, unreacted starting material, reaction by product, or the like. Such reagents include adsorbents or absorbents such as activated carbon, molecular sieves, ion exchange media, or the like.
Alternatively, the reagents can be acids in the case of a basic material, bases in the case of an acidic material, binding reagents such as antibodies, binding proteins, selective chelators such as crown ethers, liquid/liquid ion extraction reagents (LIX), or the like.
Selection of appropriate methods of separation depends on the nature of the materials involved, such as, boiling point and molecular weight in distillation and sublimation, presence or absence of polar functional groups in chromatography, stability of materials in acidic and basic media in multiphase extraction, and the like.
[0063] Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods well known to those skilled in the art, such as by chromatography and/or fractional crystallization.
Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereoisomers to the corresponding pure enantiomers. Also, some of the compounds of the present invention may be atropisomers (e.g., substituted biaryls) and are considered as part of this invention. Enantiomers can also be separated by use of a chiral HPLC column.

[0064] A single stereoisomer, e.g., an enantiomer, substantially free of its stereoisomer may be obtained by resolution of the racemic mixture using a method such as formation of diastereomers using optically active resolving agents (Eliel, E.
and Wilen, S.
"Stereochemistry of Organic Compounds," John Wiley & Sons, Inc., New York, 1994;
Lochmuller, C. H., (1975) J. Chromatogr., 113(3):283-302). Racemic mixtures of chiral compounds of the invention can be separated and isolated by any suitable method, including:
(1) formation of ionic, diastereomeric salts with chiral compounds and separation by fractional crystallization or other methods, (2) formation of diastereomeric compounds with chiral derivatizing reagents, separation of the diastereomers, and conversion to the pure stereoisomers, and (3) separation of the substantially pure or enriched stereoisomers directly under chiral conditions. See: "Drug Stereochemistry, Analytical Methods and Pharmacology," Irving W. Wainer, Ed., Marcel Dekker, Inc., New York (1993).
[0065] Under method (1), diastereomeric salts can be formed by reaction of enantiomerically pure chiral bases such as brucine, quinine, ephedrine, strychnine, a-methyl-(3-phenylethylamine (amphetamine), and the like with asymmetric compounds bearing acidic functionality, such as carboxylic acid and sulfonic acid. The diastereomeric salts may be induced to separate by fractional crystallization or ionic chromatography. For separation of the optical isomers of amino compounds, addition of chiral carboxylic or sulfonic acids, such as camphorsulfonic acid, tartaric acid, mandelic acid, or lactic acid can result in formation of the diastereomeric salts.
[0066] Alternatively, by method (2), the substrate to be resolved is reacted with one enantiomer of a chiral compound to form a diastereomeric pair (E. and Wilen, S.
"Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., 1994, p.
322).
Diastereomeric compounds can be formed by reacting asymmetric compounds with enantiomerically pure chiral derivatizing reagents, such as menthyl derivatives, followed by separation of the diastereomers and hydrolysis to yield the pure or enriched enantiomer. A
method of determining optical purity involves making chiral esters, such as a menthyl ester, e.g., (-) menthyl chloroformate in the presence of base, or Mosher ester, a-methoxy-a-(trifluoromethyl)phenyl acetate (Jacob III. J. Org. Chem. (1982) 47:4165), of the racemic mixture, and analyzing the 1H NMR spectrum for the presence of the two atropisomeric enantiomers or diastereomers. Stable diastereomers of atropisomeric compounds can be separated and isolated by normal- and reverse-phase chromatography following methods for separation of atropisomeric naphthyl-isoquinolines (WO 96/15111). By method (3), a racemic mixture of two enantiomers can be separated by chromatography using a chiral stationary phase ("Chiral Liquid Chromatography" (1989) W. J. Lough, Ed., Chapman and Hall, New York; Okamoto, J. Chromatogr., (1990) 513:375-378). Enriched or purified enantiomers can be distinguished by methods used to distinguish other chiral molecules with asymmetric carbon atoms, such as optical rotation and circular dichroism.

[0067] GENERAL PREPARATIVE PROCEDURES
[0068] General Procedure A C-2 Suzuki coupling NH
R4. O= B I \ R4.

N N N _ R~--</ I N 24 R1 N , NH
N:: "k N Cl Pd catalyst N I \
R2, R2/

[0069] The Suzuki-type coupling reaction is useful to attach a fused bicyclic heterocycle or a fused bicyclic heteroaryl at the 2-position of the pyrimidine ring of a 2-chloro-purine 21. The Suzuki-type coupling reaction is useful to attach a fused bicyclic heterocycle or a fused bicyclic heteroaryl at the 2-position of the pyrimidine ring of thiazolopyrimidines (i), thienopyrimidines (ii), furanopyrimidines (iv), and pyrrolopyrimidines (v). For example, 21 may be combined with about 1.5 equivalents of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-c]pyridine 24, and dissolved in 3 equivalents of sodium carbonate as a 1 molar solution in water and an equal volume of acetonitrile. A catalytic amount, or more, of a low valent palladium reagent, such as bis(triphenylphosphine)palladium(II) dichloride, is added. A variety of boronic acids or boronic esters can be used in place of the indazole boronic ester indicated.
Also alternatively, a nitrogen of the fused bicyclic heterocycle or a fused bicyclic heteroaryl may be protected, for example as N-THP. In some cases potassium acetate was used in place of sodium carbonate to adjust the pH of the aqueous layer. The reaction is then heated to about 140-150 C under pressure in a microwave reactor such as the Biotage Optimizer (Biotage, Inc.) for 10 to 30 minutes. The contents are extracted with ethyl acetate, or another organic solvent.
After evaporation of the organic layer the Suzuki coupling products 22 may be purified on silica or by reverse phase HPLC. Substituents R", R2', R4, may be R', R2, R4 as defined, or protected forms or precursors thereof.
[0070] A variety of palladium catalysts can be used during the Suzuki coupling step to form compounds, including exemplary embodiments 22. Suzuki coupling is a palladium mediated cross coupling reaction of a heteroarylhalide, such as 21, with a boronic acid such as 24. Low valent, Pd(II) and Pd(0) catalysts may be used in the Suzuki coupling reaction, including PdC12(PPh3)2, Pd(t-Bu)3, PdC12 dppf CH2C12, Pd(PPh3)4, Pd(Oac)/PPh3, C12Pd[(Pet3)]2, Pd(DIPHOS)2, C12Pd(Bipy), [PdCI(Ph2PCH2PPh2)]2, C12Pd[P(o-tol)3]2, Pd2(dba)3/P(o-tol)3, Pd2(dba)/P(furyl)3, C12Pd[P(furyl)3]2, C12Pd(PmePh2)2, C12Pd[P(4-F-Ph)3]2, C12Pd[P(C6F6)3]2, C12Pd[P(2-COOH-Ph)(Ph)2]2, C12Pd[P(4-COOH-Ph)(Ph)2]2, and encapsulated catalysts Pd EnCatTM 30, Pd EnCatTM TPP30, and Pd(II)EnCatTM
BINAP30 (US
2004/0254066).
[0071] General Procedure B C-6 Nitrogen Substitution CI mor N

N CI N CI
R2, R2, [0072] To a 2,6-dichloro purine intermediate 27 in a solvent such as ethanol is added a morpholine or a morpholine analog, and a non-nucleophilic base such as triethylamine (Net3, 1.5 eq, 63 l). Alternatively, acetonitrile may be used as the solvent and potassium carbonate may be used as the base. The reaction mixture is stirred at room temperature for about 1 hour or overnight, volatiles removed in vacuo and residue partitioned between DCM
and brine. If the mixture is insoluble it may be sonicated and the solid product was collected by filtration. Drying with magnesium sulfate and evaporation of the solvent gives N'-(2-chloro purin-6-yl)-amine substituted intermediate 28, often as a crystalline solid, or by trituration. Substituents R" and R2' may be R1 and R2 as defined, or protected forms or precursors thereof.

[0073] General Procedure C N-9 Nitrogen Alkylation R4' R4 R~~--<~ N R1 ~
N N R3' CSC03 N N R3 H DMF I
R2.

[0074] 9-H Purine intermediate 29 is brought up into DMF and 2 equiv of cesium carbonate is added to the reaction mixture. The reaction is heated to 50 C
whereupon 1 to 3 equivalents of an alkyl halide R2'-X are added to the reaction mixture. The reaction is monitored by TLC or LC/MS and stirred until completion, typically several hours. The reaction mixture is extracted with EtOAc and water, and the organic layer is dried, filtered and concentrated to get crude 9-alkylated purine 30 which is used directly in the next reaction or purified by reverse phase HPLC. Substituents R", R3' and R4' may be R', R3 and R4 as defined, or protected forms or precursors thereof.
CO) N CO) N
N N electrophile N ::l J`
iN
% N N K2CO3 N RN CH3CN
H

of R=Me or Et R' [0075] In an embodiment of N-alkylation of a piperidine group, to a suspension of 4-((9-methyl-2-(2-methyl-1 H-benzo [d]imidazol-1-yl)-6-morpholino-9H-purin-8 -yl)methyl)piperidinium chloride or 4-((2-(2-ethyl-lH-benzo[d]imidazol-1-yl)-9-methyl-6-morpholino-9H-purin-8-yl)methyl)piperidinium chloride (0.4 mmol), potassium carbonate (0.25 g, 1.8 mmol) in acetonitrile (2.0 mL) is added an electrophile (1.4 mmol). The resulting mixture is stirred in a pressure tube at about 95 C for 5-18 hours. The reaction mixture is filtered, concentrated, and may be purified by RP-HPLC.
[0076] General Procedure D THP Deprotection p O
CNJ N

R~N IN~R3' McOHD ~N IN~R3' H
p 31 32 [0077] Generally, N-9-tetrahydropyranyl substituted 31 may be treated with catalytic amounts of para-toluenesulfonic acid (PTSA) in a solution of methanol and heated to about 50 C until the tetrahydropyran (THP) group is removed to afford compound 32.
The reaction may be monitored by LC-MS or TLC. Substituents R" and R3' may be R1 and R3 as defined, or protected forms or precursors thereof.
[0078] General Procedure E Displacement of alkyl bromide with amines:
O) CO
( ) N R N
i Br~N N NHR2 R-N'N I- N

N N" 'CI DIPEA N NCI
/ DCM /

[0079] Generally, substituted 33 is suspended in dichloromethane whereupon 3 equivalents of Hunig's base (DIPEA) and 1.5 equivalents of an amine (NHR2) are added to the reaction mixture. Other solvents such as tetrahydrofuran and methanol, or mixtures of solvents can be employed. The reaction is monitored by TLC or LC-MS until complete, usually within 30 minutes. The reaction mixture is extracted with water and the organic layer is dried, filtered and concentrated to dryness. The intermediate 34 can be taken as crude into subsequent reactions or in some cases is purified by column chromatography.
[0080] General Procedure F Amide Coupling co) EN) R10 N' R" N
R1~N I I H R" N
N N R3' Cs2CO3 N N R3 DMF
O n( O

HO R10'N\ 35 R11 36 [0081] A 2,6,8 substituted, 9-alkylcarboxyl purine 35, where n is 1 to 12, is treated with 1.5 eq HATU (2-(7-aza--11-1-berizotriazoie-1 hexafluorophosphate), an excess (such as 3 eq) of an alkylamine (HNR10Rii) and an excess (such as 3 eq) of cesium carbonate in dimethylformamide (DMF). Alternatively, other coupling reagents may be used. The reaction is stirred until complete and extracted in ethylacetate with saturated bicarbonate solution. The organic layer is dried, filtered and concentrated to yield the acylated, crude intermediate, which is purified via reverse phase HPLC to yield product 36. Substituents R" and R3' may be R1 and R3 as defined, or protected forms or precursors thereof.
[0082] General Procedure G Stille Coupling 2 (0) 3 R2 (0) R N Br_R N
R2 N N Pd tetrakis R2 -N N
~~N ~N
N N " 'SnBu Cu-TC or Cul N N" R3 3 1,4-dioxane R2, R2, [0083] To intermediate 37 in a microwave vial is added 1.2 equivalents of an aryl bromide, 1 equivalent of copper (I) iodide or copper thiophene-carboxylate, and 1,4-dioxane as solvent. The reaction mixture is degassed under nitrogen for 5 minutes prior to addition of 0.12 equivalents of tetrakis(triphenylphosphine)palladium(0). The reaction is heated in a CEM or Biotage microwave for 20-30 minutes at 140 C. The crude reaction mixture is filtered and periodically passed through a Biotage Isolute scx-2 basic spe cartridge before being purified via normal or reverse phase chromatography to afford pure product 38.
Substituents R2' and R3' may be R2 and R3 as defined, or protected forms or precursors thereof.
[0084] General Procedure H N-9 alkylation of purines [0085] Scheme 1 shows a general method for preparation of polyfunctionalized purines begins with protection of the N-9 nitrogen of 2,6-dichloro-9H-purine as the tetrahydropyranyl group (THP). Displacement of the more reactive chloro group with morpholine gives 4-(2-chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)morpholine. The C-8 proton is removed with strong base and reacted with various electrophiles (R'). After deprotection with mild acid, N-9 is alkylated of N-9 with various electrophiles (R). Suzuki coupling at C-2 chloro by General Procedure A with various boronate reagents and palladium catalysts gives carbon-linked C2-C20 heterocyclyl and carbon-linked CI-C20 heteroaryl as R3.

[0086] General Procedure I C-2 halo Buchwald coupling of amine-heteroaryls \

C ) /O) Pd2(dba)3 L.
N XPhos N
Cs2CO3 Rl~N N DMF or 1,4-dioxane R1N I

[0087] A microwave tube is charged with Xphos (2-Dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, CAS Reg. No. 564483-18-7, 0.1 equiv.), tris(dibenzylideneacetone)dipalladium(0) (0.05 equiv.), cesium carbonate (2 equiv.), the corresponding 2-chloropurine 39 (1 equiv.) and an amine (1.2 equiv.), such as a benzimidazole. The vessel is evacuated and refilled with nitrogen prior to the addition of DMF or 1,4-dioxane. The mixture is heated in a microwave device, such as Biotage at about 140 C for about 25-35 minutes. The reaction mixture is cooled to room temperature, filtered and concentrated. Typically, the crude product 40 is purified by flash chromatography or RP-HPLC.
[0088] Alternatively, the reaction can be performed by a modified procedure: A
microwave tube is charged with palladium acetate (0.10 equiv.), bis(tri-t-butylphosphine)palladium (0.10 equiv.), sodium t-butoxide (2 equiv.), the corresponding 2-chloropurine 39 (1 equiv.) and the amine (2 equiv.). The vessel is evacuated and refilled with nitrogen prior to the addition of toluene. The mixture is heated in a Biotage microwave at about 140 C for about 25-35 minutes. The reaction mixture is cooled to room temperature, filtered and concentrated. Typically, the crude product 40 is purified by flash chromatography or RP-HPLC.
[0089] The Buchwald (and Suzuki) couplings may be conducted with a variety of palladium catalysts and ligands, including: Chloro{[t-butylXPhos][2-(2-aminoethylphenyl)palladium(II))/[t-butylXPhos] admixture (molar PdP/P = 1:1), Chloro(2-di-t-butylphosphino-2',4',6'-tri-i-propyl-1, l'-biphenyl)[2-(2-aminoethyl)phenyl]
palladium(II), Chloro(2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl)[2-(2-aminoethylphenyl)]palladium(II) methyl-t-butylether adduct, Chloro[2-(dicyclohexylphosphino)-3,6-dimethoxy-2'-4,-6'-tri-i-propyl-l, 1'-biphenyl][2-(2-aminoethyl)phenyl]palladium(II), Chloro(2-dicyclohexylphosphino-2',6'-di-i-propoxy-1,1'-biphenyl)[2-(2-aminoethylphenyl)]palladium(II), methyl-t-butylether adduct, Chloro(2-dicyclohexylphosphino-2',4',6'-tri-i-propyl-1, l' -biphenyl)[2-(2-aminoethyl)phenyl]
palladium(II) methyl-t-butylether adduct.
[0090] A variety of phosphorus ligands may also be employed in the Buchwald (and Suzuki) couplings, including: 2-Dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, Xphos (CAS Reg. No. 564483-18-7), racemic-2-Di-t-butylphosphino-1,1'-binaphthyl (CAS
Reg.
No. 255836-67-0), 2-(Di-t-butylphosphino)biphenyl, JohnPhos (CAS Reg. No.
224311-51-7), 2-Di-t-butylphosphino-2'-(N,N-dimethylamino)biphenyl (CAS Reg. No. 224311-49-3), 2-Di-t-butylphosphino-2'-methylbiphenyl (CAS Reg. No. 255837-19-5), 2-Di-t-butylphosphino-3,4,5,6-tetramethyl-2',4',6'-tri-i-propylbiphenyl (CAS Reg. No. 857356-94-6), 2-Di-t-butylphosphino-2',4',6'-tri-i-propyl-1,1'-biphenyl, t-butylXPhos (CAS Reg. No.

8), 2-(Dicyclohexylphosphino)biphenyl (CAS Reg. No. 247940-06-3), 2-Dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl, S-Phos (CAS Reg. No.

6), 2'-Dicyclohexylphosphino-2,6-dimethoxy-3-sulfonato-1,1'-biphenyl hydrate sodium salt, 2-(Dicyclohexylphosphino)-3,6-dimethoxy-2'-4'-6'-tri-i-propyl-1,1'-biphenyl (BrettPhos), 2-(Dicyclohexylphosphino)-2'-(N,N-dimethylamino)biphenyl, DavePhos (CAS Reg. No.
213697-53-1), 2-Dicyclohexylphosphino-2',6'-di-i-propoxy-1,1'-biphenyl, RuPhos (CAS
Reg. No. 787618-22-8), 2'-Dicyclohexylphosphino-2,6-di-i-propyl-4-sulfonato-1,1'-biphenyl hydrate sodium salt (CAS Reg. No. 870245-84-4), 2-Dicyclohexylphosphino-2'-methylbiphenyl, MePhos (CAS Reg. No. 251320-86-2), 2-(Dicyclohexylphosphino)-2',4',6'-tri-i-propyl-1,1'-biphenyl, X-Phos (CAS Reg. No. 564483-18-7) 2-Diphenylphosphino-2'-(N,N-dimethylamino)biphenyl (CAS Reg. No. 240417-00-9).
See:
Mauger, C. C. and Mignani, G. A. Aldrichimica Acta (2006) 39:17; Schlummer, B.
and Scholz, U. Adv. Synth. Catal. (2004) 346:1599 for reviews. Buchwald and Suzuki coupling reagents are available from commercial sources including Strem Chemicals, Inc., 7 Mulliken Way, Newburyport, MA 01950-4098 USA.
[0091] General Procedure J Multi-Step Benzimidazole Formation by Buchwald coupling of amino-heteroaryls ) N N

R1-/ X NH2 R1~N D I
N N CI N NXN

C0) 1. 0 HATU

R1~ , NXN
2. AcOH N
N \\--R2 !-N

O
HOlj~ R8 R,O)R8 O O
R81~1 O1~1 R8 [0092] 2-Chloropurine 39 is reacted with 1,2-diaminobenzene via General Procedure I for Buchwald Coupling to give 2-amino heteroaryl intermediate 41 which is subsequently transformed to 42 via one of two possible routes. In the top route;
Intermediate 41 and acid with R8 functional group (1.5 eq) and HATU (1.5 eq) are dissolved in DMF (100 eq) whereupon N,N-diisopropylethylamine (3-5 eq) is added. The reaction is stirred overnight at room temperature and then concentrated to dryness. The crude is dissolved in acetic acid (100 eq) and heated at 90 C for 18 hours to cyclize to product 42. In the middle route, 41 is dissolved directly in either the acid (or ester) with R8 functional group and refluxed overnight to cyclize to product 42. In the lower route, 41 is acylated with anhydride (1 to 1.5 equiv.) in the presence of a tertiary amine base such as iPr2Net. Final products are purified via reverse phase HPLC and may be subsequently purified by chiral SFC (supercritical fluid chromatography) when enantiomers are present and require separation (Liu et al (2003) Chromatographia 58(11/12):775-779).

[0093] General Procedure K C2-carboxyl amide formation O
co) HR2NH BTU fl N N
TEA
O ,N I N DMF O ,N I %N
HO IN N!N R2N--~N
NIN \

[0094] To a mixture of 2-(2-ethyl-lH-benzo[d]imidazol-1-yl)-9-methyl-6-morpholino-9H-purine-8-carboxylic acid 42 (1 equiv), HBTU (1.5 equiv.) in N,N-dimethylformamide is added triethylamine (TEA). The resulting mixture is stirred at room temperature for about 5 minutes before the addition of the amine (R2NH, 1 equiv.). The reaction mixture is then stirred at room temperature for 2-18 hours. The reaction mixture is concentrated and purified by RP-HPLC to give the amide product 43. Other coupling agents, such as HATU, HCTU, TBTU, and PyBOP, can be used.

[0095] General Procedure L Reductive amination co) N co) N
N
r I ketone N
N I :]l N N NaHB(OAc)3 N NN11__ HN / N DCE N /~N
R'~ R
R=Me or Et R"
[0096] In an exemplary embodiment of the general procedure for reductive amination of amine groups, a suspension of 4-(8-(azetidin-3-ylmethyl)-2-(2-ethyl-lH-benzo[d]imidazol-1-yl)-9-methyl-9H-purin-6-yl)morpholine or 4-(8-(azetidin-3-ylmethyl)-2-(2-methyl-lH-benzo[d]imidazol-1-yl)-9-methyl-9H-purin-6-yl)morpholine (1 equiv.) in 1,2-dichloroethane is added a ketone (about 1.5-2.0 equiv.). The resulting mixture is stirred at room temperature for 15 minutes before the addition of sodium triacetoxyborohydride (about 1.5-2.0 equiv.).
The reaction is then stirred at room temperature for about 18 hours. The reaction was then quenched by the addition of methanol. The mixture may be purified by chromatography, including RP-HPLC. Also, the mixture may be loaded onto an ISOLUTE SCX-2 column, washed with MeOH, and eluted with 2M NH3 in MeOH to give the desired product.

o J Co) N N NaBH(OAc)3 N I N
H

H N N R3 R2N N N Rs [0097] In an exemplary embodiment of reductive amination of a 2-carboxaldehyde purine interemediate, a mixture of 9-methyl-2-(2-methyl-benzoimidazol-l-yl)-6-morpholin-4-yl-9H-purine-8-carbaldehyde where R2 is methyl and R3 is 2-methyl-benzoimidazol-1-yl (0.1g, 0.264 mmol), AcOH (0.03 mL, 0.53 mmol) and amine in CH2C12 (4 mL) was stirred at room temperature fro 2 h. Sodium triacetoxyborohydride (78 mg, 0.37 mmol) was added and stirring continued for 18 h. Potassium carbonate (K2CO3) saturated solution was added and product extracted with CH2C12 (4x). Organics combined were dried (MgS04) and concentrated. Flash chromatography with CH2C12:Methanol:Ammonium hydroxide (100:5:0.5) afforded the 2-aminomethyl product.
[0098] Alternatively, to a mixture of an aldehyde (1 mmol) and amine (1-1.2 mmol) in 1,2-dichloroethane (8-20 mL) was added acetic acid (2 mmol) and trimethoxymethane (10 mmol), or micronized 4A (angstrom) molecular sieves. The mixture was stirred at room temperature for 0.5-4 hr. Sodium triacetoxyborohydride (1.1-1.5 mmol) was added. The resulting mixture was stirred at room temperature for 4-20 hr. The contents were partitioned between DCM and diluted NaOH. The organic layer was separated. The aqueous layer was extracted with DCM. The combined organic solutions were dried (Na2SO4). The crude was purified by chromatography or reverse phase HPLC, or used directly if pure enough for subsequent transformations.

[0099] EXAMPLES
[00100] The chemical reactions described in the Examples may be readily adapted to prepare a number of other P13K inhibitors of the invention, and alternative methods for preparing the compounds of this invention are deemed to be within the scope of this invention. For example, the synthesis of non-exemplified compounds according to the invention may be successfully performed by modifications apparent to those skilled in the art, e.g., by appropriately protecting reactive functional groups, by utilizing other suitable reagents known in the art other than those described, and/or by making routine modifications of reaction conditions. Alternatively, other reactions disclosed herein or known in the art will be recognized as having applicability for preparing other compounds of the invention.

[00101] Chiral SFC (supercritical fluid chromatography) may be used to separate enantiomers (Liu et al (2003) Chromatographia 58(11/12):775-779) [00102] 1H NMR spectra were recorded at ambient temperature using an NMR
spectrometer, including a Varian Unity Inova (400MHz) spectrometer with a triple resonance 5mm probe. Chemical shifts are expressed in ppm relative to tetramethylsilane.
The following abbreviations have been used: br = broad signal, s = singlet, d =
doublet, dd =
double doublet, t = triplet, q = quartet, m = multiplet.
[00103] High Pressure Liquid Chromatography - Mass Spectrometry (LCMS) experiments to determine retention times (RT) and associated mass ions may be performed, for example by one of the following methods. The spectrometers have an electrospray source operating in positive and negative ion mode. Additional detection was achieved using a Sedex 85 evaporative light scattering detector.
[00104] Method A: Experiments performed on a Waters Platform LC quadrupole mass spectrometer linked to a Hewlett Packard HP 1100 LC system, with diode array detector and a 100 position autosampler, using a Phenomenex Luna 3 m C,8(2) 30 x 4.6mm and a mL/minute flow rate. The mobile phase consisted of formic acid 0.1 % in water (solvent A) and formic acid 0.1% in methanol (solvent B). The initial solvent system was 95% solvent A
and 5% solvent B for the first 0.5 minute followed by a gradient up to 5%
solvent A and 95%
solvent B over the next 4 minutes. The final solvent system was held constant for a further 1 minute.
[00105] Method B: Experiments performed on a Waters Platform LC quadrupole mass spectrometer linked to a Hewlett Packard HP 1100 LC system, with diode array detector and a 100 position autosampler, using a using a Phenomenex Luna 3 m C,8(2) 30 x 4.6mm and a 2 mL/minute flow rate The mobile phase consisted of formic acid 0.1 % in water (solvent A) and formic acid 0.1% in acetonitrile (solvent B). The initial solvent system was 95% solvent A and 5% solvent B for the first 0.50 minute followed by a gradient up to 5%
solvent A and 95% solvent B over the next 4 minutes. The final solvent system was held constant for a further 1 minute.
[00106] Method C: Experiments performed on a Waters ZMD quadrupole mass spectrometer linked to a Waters 1525 LC system, with a Waters 996 diode array detector and a Waters 2700 autosampler, using a Phenomenex Luna 3 m C,8(2) 30 x 4.6mm and a 2 mL/minute flow rate. The mobile phase consisted of formic acid 0.1 % in water (solvent A) and formic acid 0.1% in methanol (solvent B). The initial solvent system was 95% solvent A

and 5% solvent B for the first 0.5 minute followed by a gradient up to 5%
solvent A and 95%
solvent B over the next 4 minutes. The final solvent system was held constant for a further 1 minute.
[00107] Method D: Experiments performed on a Waters ZMD quadrupole mass spectrometer linked to a Waters 1525 LC system, with a Waters 996 diode array detector and a Waters 2700 autosampler, using a Phenomenex Luna 3 m C18(2) 30 x 4.6mm and a 2 mL/minute flow rate. The mobile phase consisted of formic acid 0.1 % in water (solvent A) and formic acid 0.1% in acetonitrile (solvent B). The initial solvent system was 95% solvent A and 5% solvent B for the first 0.5 minute followed by a gradient up to 5%
solvent A and 95% solvent B over the next 4 minutes. The final solvent system was held constant for a further 1 minute.
[00108] Method E: Experiments performed on a Waters Micromass ZQ2000 quadrupole mass spectrometer linked to a Hewlett Packard HP 1100 LC system, with a DAD
UV detector and a CTC HTS PAL autosampler, using a Higgins Clipeus 5 m Cl8 100x3.0 mm column (at 40 C) and a 1 mL/minute flow rate. The mobile phase consisted of formic acid 0.1% in water (solvent A) and formic acid 0.1% in methanol (solvent B).
The initial solvent system was 85% solvent A and 15% solvent B for the first 1 minute followed by a gradient up to 5% solvent A and 95% solvent B over the next 12 minutes. The final solvent system was held constant for a further 7 minutes.
[00109] Method F: Experiments performed on a Waters Micromass ZQ2000 quadrupole mass spectrometer linked to a Hewlett Packard HP 1100 LC system, with a DAD
UV detector and a CTC HTS PAL autosampler, using a Higgins Clipeus 5micron CIS
100x3.Omm column and a 1 mL/minute flow rate. The mobile phase consisted of formic acid 0.1 % in water (solvent A) and formic acid 0.1 % in acetonitrile (solvent B).
The initial solvent system was 85% solvent A and 15% solvent B for the first 1 minute followed by a gradient up to 5% solvent A and 95% solvent B over the next 14 minutes. The final solvent system was held constant for a further 5 minutes.
[00110] Microwave experiments were carried out using a CEM Explorer, Smith Synthesizer or a Biotage InitiatorTM, which uses a single-mode resonator and dynamic field tuning, both of which give reproducibility and control. Temperatures from 40-250 C can be achieved and pressures up to 20 bar can be reached.
[00111] Unless otherwise stated, all reactions were performed under an inert, i.e. argon or nitrogen, atmosphere.

[00112] RI Reagents:
[00113] Example 1 3-(Tetrahydropyran-4-yl)azetidine-l-carboxylic acid tent-butyl ester O
OD-<C N4 O~
[00114] Step 1: Trifluoromethanesulfonic acid 3,6-dihydro-2H-pyran-4-yl ester ~\ O F
O ~rO-s- -F
'/ O F

[00115] To a solution of diisopropylamine (35.2 mL, 0.25 mol) in anhydrous THE
(200 mL) at -20 C was added a 2.5M solution on n-buyllithium in hexanes (100 mL, 0.25 mol) over a 10 min period under an argon atmosphere. The reaction mixture was stirred at -20 C for 15 min. A solution of tetrahydropyran-4-one (21.0 mL, 0.23 mol) in anhydrous THE (160 mL) was added dropwise over a 20 min period (internal temperature < -65 C). The reaction mixture was stirred for 3 hours at -78 C then a solution of N,N-bis(trifluoromethanesulfonyl)aniline (86.4 g, 0.24 mmol) in anhydrous THE (240 mL) was added dropwise over a 45 min period. The resulting mixture was stirred at -78 C for 1.5 hours then allowed to reach room temperature and stirred for 18 hours. The solvents were removed in vacuo to give a residue which was partitioned between EtOAc (500 mL) and water (250 mL). The organic layer was separated and washed with water (250 mL), 2M
NaOH in water (3 x 300 mL) and brine (2 x 200 mL), dried over Na2SO4, filtered and concentrated to give Trifluoromethanesulfonic acid 3,6-dihydro-2H-pyran-4-yl ester as a brown oil (43.7 g, 83%). 'H NMR (400 MHz, CHC13 -d): 6 5.83-5.80 (m, 1 H);
4.26 (dd, J
= 2.9, 0.4 Hz, 2 H); 3.89 (t, J = 5.5 Hz, 2 H); 2.46 (ttd, J = 5.5, 2.9, 1.4 Hz, 2 H).
[00116] Step 2: 3-(3,6-Dihydro-2H-pyran-4-yl)azetidine-l-carboxylic acid tent-butyl ester O
O~
[00117] Zinc activation: To a suspension of zinc powder (20.3 g, 0.31 mol) and Celpure P65 in anhydrous DMA (48 mL) was added a 7:5 (v:v) mixture of TMS-C1:1,2-dibromoethane (6.2 mL) was added dropwise. The reaction mixture was stirred at room temperature for 45min.

[00118] Zinc insertion: A solution of 3-iodoazetidine-l-carboxylic acid tent-butyl ester (72.9 g, 0.26 mol) in anhydrous DMA (120 mL) was added dropwise to the mixture described above over a 30 min period. The reaction mixture was stirred for 1 hour at room temperature.
[00119] Coupling reaction: A mixture of trifluoromethanesulfonic acid 3,6-dihydro-2H-pyran-4-yl ester (42.7 g, 0.18 mol), Pd(dppf)C12.DCM (4.5 g, 5.5 mmol) and Cul (2.1 g, 11.0 mmol) was sonicated for 5 min. The vessel was then evacuated and back-filled with argon. The zincate mixture was quickly filtered through a grade-3 sintered funnel and added onto the palladium-containing mixture. The resulting reaction mixture was stirred at 85 C for 18 hours then cooled to room temperature. EtOAc (1L) and a 1M aqueous solution of ammonium chloride (0.5 L) were added and the mixture was stirred for 30 min.
Water (0.5L) was added to the reaction mixture and the organic layer was separated, was washed with water and brine, dried over Na2SO4, filtered and concentrated.
[00120] Purification: The residue was taken up in cyclohexane (ca 200 mL) and loaded onto a 600g column of silica gel 60 pre-conditionned with cyclohexane.
The product was eluted with a gradient of EtOAc in cyclohexane (0%-50%). The appropriate fractions were combined and concentrated to give the title compound as a dark-coloured oil (22.85 g, 52%). The mixed fractions were combined and concentrated to give a residue which was subjected to automated flash chromatography (Si-PPC, EtOAc:cyclohexane, gradient 5:95 to 50:50). The appropriate fractions were combined to give 3-(3,6-Dihydro-2H-pyran-4-yl)azetidine-1-carboxylic acid tent-butyl ester as a dark-coloured oil (7.8 g, 18 %). 'H NMR
(400 MHz, CHC13 -d): 6 5.56-5.53 (m, 1 H); 4.17-4.13 (m, 2 H); 4.02 (t, J =
8.6 Hz, 2 H);
3.85-3.78 (m, 4 H); 3.20-3.09 (m, 1 H); 2.11-2.06 (m, 2 H); 1.44 (s, 9 H).
[00121] Step 3: A mixture of 3-(3,6-dihydro-2H-pyran-4-yl)azetidine-l-carboxylic acid tent-butyl ester (28.6 g, 0.12 mol) and 10% palladium on charcoal (5.0 g) in IMS (500 mL) was stirred under hydrogen (4 bar) at room temperature for 36 hours. The reaction mixture was filtered through a bed of Celite which was washed with IMS. The filtrates were combined and concentrated to give a residue which was reacted as above for 18 hours. The reaction mixture was worked up as above to give a residue which was dried under reduced pressure to give 3-(Tetrahydropyran-4-yl)azetidine-1-carboxylic acid tent-butyl ester as a beige solid (26.7 g, 92%). IH NMR (300 MHz, CHC13 -d): 6 4.03-3.90 (m, 4 H);
3.63 (dd, J
= 8.6, 5.7 Hz, 2 H); 3.37 (td, J = 11.8, 2.0 Hz, 2 H); 2.32-2.19 (m, 1 H);
1.63-1.48 (m, 3 H);
1.44 (s, 9 H); 1.29-1.12 (m, 2 H).
[00122] Example 2 (4-Methylpiperidin-4-yl)pyrrolidin-l-ylmethanone H
N
O

G
[00123] Step 1: 4-Methyl-4-(pyrrolidine-l-carbonyl)piperidine-l-carboxylic acid tert-butyl ester Oyo<
N

O

G
[00124] To a solution of 4-methylpiperidine-1,4-dicarboxylic acid mono-tent-butyl ester (229 mg, 0.94 mmol) in DMF (10 mL) were added DIPEA (0.493 mL, 2.83 mmol), pyrrolidine (0.118 mL, 1.41 mmol) and HATU (537 mg, 1.41 mmol). The reaction mixture was stirred at room temperature for 18 hours and then partitioned between water and EtOAc.
The organic layer was separated and washed with a 0.1N aqueous HC1 solution and brine, dried over Na2SO4, filtered and concentrated to give 4-Methyl-4-(pyrrolidine-l-carbonyl)piperidine-l-carboxylic acid tent-butyl ester as a white solid (279 mg, 100 %).
LCMS (Method H): RT 4.00 min; [M+Na]+ 319 [00125] Step 2: A solution of 4-methyl-4-(pyrrolidine-l-carbonyl)piperidine-l-carboxylic acid tent-butyl ester (296 mg, 1.0 mmol) in TFA (5 mL), DCM (5 mL) and water (0.1 mL) was stirred at room temperature for 2 hours and then concentrated under reduced pressure. The residue was taken up in MeOH and and loaded onto an Isolute SCX-cartridge (10 g). The cartridge was washed with MeOH and the desired product was eluted with 2M NH3 in MeOH. The solvents were removed to give the desired product as a white solid (196 mg, 66%). LCMS (Method A): RT 0.31 min; [M+H]+ 197 [00126] Example 3 (3-Methylpyrrolidin-3-yl)pyrrolidin-1-ylmethanone H

O NJ

[00127] Step 1: 3-Methylpyrrolidine-1,3-dicarboxylic acid 1-tent-butyl ester OyOtBu N

OH
C
O
[00128] To a solution of 3 -methylpyrrolidine- 1,3 -dicarboxylic acid 1-tent-butyl ester 3-methyl ester (370 mg, 1.52 mmol) in IMS (5 mL) was added a 1M aqueous solution of sodium hydroxide (2.0 mL, 2.0 mmol). The reaction mixture was stirred at room temperature for 2 hours, and then concentrated under reduced pressure. The residue was partitioned between EtOAc and a 0.1M aqueous solution of HC1. The organic layer was separated and washed with brine, dried over Na2SO4, filtered and concentrated to give the desired product as a white solid (348 mg, 100%). 1H NMR (400 MHz, CHC13-d): 6 3.85-3.75 (m, 1 H); 3.52-3.41 (m, 2 H); 3.27-3.15 (m, 1 H); 2.39-2.30 (m, 1 H); 1.83-1.74 (m, 1 H);
1.51-1.40 (m, 9 H); 1.38 (s, 3 H).
[00129] Step 2: 3-Methyl-3-(pyrrolidine-l-carbonyl)pyrrolidine-l-carboxylic acid tent-butyl ester OYOtBu O NJ

[00130] To a solution of 3 -methylpyrrolidine- 1,3 -dicarboxylic acid 1-tent-butyl ester (348 mg, 1.52 mmol) in DMF (10 mL) were added DIPEA (0.53 mL, 3.04 mmol), pyrrolidine (0.25 mL, 3.04 mmol) and HATU (693 mg, 1.82 mmol). The reaction mixture was stirred at room temperature for 18 hours and then partitioned between water and EtOAc.
The organic layer was separated and washed with a 0.1N aqueous HC1 solution and brine, dried over Na2SO4, filtered and concentrated to give the desired product as a white solid (334 mg, 78 %). 1H NMR (400 MHz, CHC13-d): 6 3.61-3.38 (m, 8 H); 2.00-1.79 (m, 6 H); 1.47-1.44 (m, 9 H); 1.33 (s, 3 H).
[00131] Step 3: A solution of 3-methyl-3-(pyrrolidine-l-carbonyl)pyrrolidine-l-carboxylic acid tent-butyl ester (330 mg, 1.17 mmol) in TFA (5 mL), DCM (5 mL) and water (0.1 mL) was stirred at room temperature for 2 hours and then concentrated under reduced pressure. The residue was taken up in MeOH and and loaded onto an Isolute SCX-cartridge (10 g). The cartridge was washed with MeOH and the desired product was eluted with 2M NH3 in MeOH. The solvents were removed to give (3-Methylpyrrolidin-3-yl)pyrrolidin-1-ylmethanone as a white solid (169 mg, 79%). 'H NMR (400 MHz, CHC13-d):
6 3.55-3.40 (m, 5 H); 3.06-2.92 (m, 2 H); 2.32-2.20 (m, 2 H); 2.01-1.82 (m, 5 H); 1.71 (m, 1 H); 1.33 (s, 3 H).
[00132] Example 4 1-(2-(Methanesulfonyl)ethyl)-2,2-dimethylpiperazine o (NH
N
SO

[00133] Step 1: 4-(2-(Methanesulfonyl)ethyl)-3,3-dimethylpiperazine-l-carboxylic acid tent-butyl ester O
O rN'O
N*
SO

[00134] Step 2: A mixture of 3,3-dimethylpiperazine-l-carboxylic acid tent-butyl ester (500 mg, 2.33 mmol) and methyl vinyl sulfone (510 L, 619 mg, 5.83 mmol) in MeOH (15 mL) was heated to 65 C for 5.5 h then stirred at room temperature for 96 h.
The reaction mixture was concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, McOH:DCM, 0-3%) affording 1-(2-(Methanesulfonyl)ethyl)-2,2-dimethylpiperazine as a white waxy solid (550 mg, 74%). 'H NMR (CDC13, 300 MHz): 6 3.47-3.40 (m, 2 H); 3.15 (s, 2 H); 3.09 (t, J = 6.4 Hz, 2 H); 3.03 (s, 3 H);
2.89 (t, J = 6.4 Hz, 2 H); 2.58-2.50 (m, 2 H); 1.45 (s, 9 H); 1.04 (s, 6 H).
[00135] Step 3: A mixture of 4-(2-methanesulfonylethyl)-3,3-dimethylpiperazine-l-carboxylic acid tent-butyl ester (510 mg, 1.59 mmol) and TFA (5 mL) in DCM (10 mL) was stirred at room temperature for 2 h. The reaction mixture was loaded onto an Isolute SCX-2 cartridge which was washed with MeOH/DCM and the product eluted with 2M
NH3/MeOH
affording 1-(2-(Methanesulfonyl)ethyl)-2,2-dimethylpiperazine as a white solid (320 mg, 91%). 1H NMR (CDC13, 300 MHz): 6 3.49 (s, 1 H); 3.12-3.03 (m, 5 H); 2.92-2.84 (m, 4 H);
2.60 (s, 2 H); 2.53-2.47 (m, 2 H); 1.06 (s, 6 H).
[00136] Example 5 4-Azetidin-3-yl-2,2-dimethylmorpholine H
N
r N /~

O

[00137] Step 1: 3-(2,2-Dimethylmorpholin-4-yl)azetidine-l-carboxylic acid tent-butyl ester O
NO-~
~
N
0*
[00138] A mixture of 2,2-dimethylmorpholine (260 mg, 2.26 mmol) and 3-oxoazetidine-l-carboxylic acid tent-butyl ester (464 mg, 2.71 mmol) in DCE (15 mL) was stirred at room temperature for 2 h before the addition of sodium triacetoxyborohydride (957 mg, 4.52 mmol). The resulting mixture was stirred for 16 h, then diluted with DCM and washed with H20. The organic phase was dried (phase separator) and concentrated in vacuo.
The resulting residue was purified by column chromatography (Si-PCC, EtOAc:cyclohexane, 0-40%) affording the title compound as an oil (492 mg, 81%). 'H NMR (CDC13, 300 MHz): 6 3.95-3.85 (m, 2 H); 3.80-3.71 (m, 4 H); 3.07-2.88 (m, 1 H); 2.32-2.22 (m, 2 H); 2.14-2.06 (m, 2 H); 1.44 (s, 9 H); 1.25 (s, 6 H).
[00139] Step 2: A mixture of 3-(2,2-dimethylmorpholin-4-yl)azetidine-l-carboxylic acid tent-butyl ester (492 mg, 1.82 mmol) and TFA (5 mL) in DCM (10 mL) was stirred at room temperature for 2 h. The reaction mixture was loaded onto an Isolute SCX-cartridge, washed with MeOH/DCM and eluted with 2M NH3/MeOH affording 4-Azetidin-3-yl-2,2-dimethylmorpholine as a white solid (302 mg, 97%). 1H NMR (CDC13, 300 MHz): 6 3.73 (t, J = 4.8 Hz, 2 H); 3.64-3.51 (m, 4 H); 3.18-3.11 (m, 1 H); 2.23 (t, J
= 4.8 Hz, 2 H);
2.23-2.07 (m, 1 H); 2.06 (s, 2 H); 1.25 (s, 6 H).
[00140] Example 6 4-Azetidin-3-yl-thiomorpholine 1,1-dioxide H
/~N
Nom/
O; S 1/
O
[00141] Step 1: 3-(1,l-Dioxo-l-thiomorpholin-4-yl)azetidine-l-carboxylic acid tert-butyl ester O
~N
OZ ZS

O

[00142] To a refluxing solution of 3-aminoazetidine-1-carboxylic acid tent-butyl ester (10.0 g, 58.1 mmol) in EtOH (50 mL) was added drop wise a solution of divinyl sulfone (5.9mL, 6.86 g, 58.1 mmol) in EtOH (50 mL). The resulting mixture was stirred at reflux for 15.5 h, cooled to room temperature and concentrated in vacuo. The resulting beige solid was triturated with Et20, affording the title compound as a white solid (10.8 g, 64%). 'H NMR
(CDC13, 300 MHz): 6 3.97 (dd, J = 8.8, 7.1 Hz, 2 H); 3.76 (dd, J = 8.8, 7.1 Hz, 2 H); 3.36-3.26 (m, 1 H); 3.13-3.05 (m, 4 H); 2.90-2.83 (m, 4 H); 1.44 (s, 9 H).
[00143] Step 2: A mixture of 3-(1,1-dioxo-l-thiomorpholin-4-yl)-azetidine-l-carboxylic acid tent-butyl ester (3.35 g, 11.5 mmol) and TFA (15 mL) in DCM
(30 mL) was stirred at room temperature for 2 h. The reaction mixture was loaded onto an Isolute SCX-2 cartridge which was washed with MeOH/DCM and the product eluted with 2M
NH3/MeOH
affording 4-Azetidin-3-yl-thiomorpholine 1,1-dioxide as a white solid (2.0 g, 91%). 1H NMR
(CDC13, 300 MHz): 6 3.64-3.53 (m, 4 H); 3.49-3.39 (m, 1 H); 3.08 (m, 4 H);
2.86-2.79 (m, 4 H); 1.83 (s, 1 H).
[00144] Example 7 Methyl(piperidin-4-yl)(tetrahydro-furan-3-yl)amine NH

N

[00145] Step 1: 4-[Methyl(tetrahydrofuran-3-yl)amino]piperidine-l-carboxylic acid tent-butyl ester [00146] A mixture of 4-(methylamino)piperidine-l-carboxylic acid tent-butyl ester (200 mg, 0.93 mmol), dihydrofuran-3-one (145 l, 161 mg, 1.87 mmol), 4A
powdered molecular sieves (550 mg) and DIPEA (323 l, 241 mg, 1.87 mmol) in DCM (10 mL) was stirred at room temperature for 30 min before the addition of sodium triacetoxyborohydride (396 mg, 1.87 mmol). The reaction mixture was stirred at room temperature for 16 h then diluted with DCM and washed with H20. The organic phase was dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, MeOH:DCM, 0-10%) affording the title compound as an oil (132 mg, 50%). 1H
NMR
(CDC13, 300 MHz): 6 4.33-4.05 (m, 2 H); 4.01-3.91 (m, 1 H); 3.90-3.73 (m, 2 H); 3.68-3.48 (m, 1 H); 3.47-3.23 (m, 1 H); 2.72-2.56 (m, 2 H); 2.21 (s, 3 H); 2.11-1.94 (m, 1 H); 1.93-1.78 (m, 1 H); 1.76-1.63 (m, 2 H); 1.76-1.63 (m, 1 H); 1.54-1.46 (m, 2 H);
1.46 (s, 9 H).
[00147] Step 2: A mixture of 4-[methyl(tetrahydrofuran-3-yl)amino]piperidine-l-carboxylic acid tent-butyl ester (132 mg, 0.46 mmol) and TFA (2 mL) in DCM (5 mL) was stirred at room temperature for 2 h. The reaction mixture was loaded onto an Isolute SCX-2 cartridge which was washed with MeOH/DCM and the product eluted with 2M
NH3/MeOH
affording Methyl(piperidin-4-yl)(tetrahydro-furan-3-yl)amine as a white solid (84 mg, quant.). 1H NMR (CDC13, 300 MHz): 6 3.98-3.91 (m, 1 H); 3.88-3.83 (m, 1 H);
3.80-3.73 (m, 1 H); 3.61-3.53 (m, 1 H); 3.42-3.35 (m, 1 H); 3.26-3.14 (m, 2 H); 2.71-2.53 (m, 2 H);
2.57-2.46 (m, 1 H); 2.23 (s, 3 H); 2.05-1.97 (m, 1 H); 1.93-1.77 (m, 1 H);
1.78-1.72 (m, 2 H); 1.64-1.49 (m, 2 H).
[00148] Example 8 Methylpiperidin-4-yl(tetrahydropyran-4-yl)amine NH

N
O
[00149] Step 1: 4-[Methyl(tetrahydropyran-4-yl)amino]piperidine-l-carboxylic acid tent-butyl ester O
NbO~
O

[00150] A mixture of 4-methylaminopiperidine-l-carboxylic acid tent-butyl ester (200 mg, 0.93 mmol), tetrahydropyran-3-one (187 mg, 1.87 mmol), 4A powdered molecular sieves (550 mg) and DIPEA (323 l, 241 mg, 1.87 mmol) in DCM (10 mL) was stirred at room temperature for 30 min before the addition of sodium triacetoxyborohydride (396 mg, 1.87 mmol). The reaction mixture was stirred at room temperature for 16 h then diluted with DCM
and washed with H20. The organic phase was dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, MeOH:DCM, 0-10%) affording 4-[Methyl(tetrahydropyran-4-yl)amino]piperidine-l-carboxylic acid tent-butyl ester as an oil (101 mg, 36%). 1H NMR (CDC13, 300 MHz): 6 4.24-4.07 (m, 2 H); 4.06-3.96 (m, 2 H); 3.43-3.32 (m, 2 H); 2.78-2.63 (m, 4 H); 2.25 (s, 3 H); 1.77-1.60 (m, 8 H);
1.46 (s, 9 H).

[00151] Step 2: A mixture of 4-[methyl(tetrahydropyran-4-yl)-amino]-piperidine-l-carboxylic acid tent-butyl ester (101 mg, 0.34 mmol) and TFA (2 mL) in DCM (5 mL) was stirred at room temperature for 2 h. The reaction mixture was loaded onto an Isolute SCX-2 cartridge which was washed with MeOH/DCM and the product eluted with 2M
NH3/MeOH
affording Methylpiperidin-4-yl(tetrahydropyran-4-yl)amine as a white solid (66 mg, 97%).
1H NMR (CDC13, 300 MHz): 6 4.05-3.97 (m, 2 H); 3.38 (td, J = 10.9, 3.8 Hz, 2 H); 3.19 (d, J = 12.1 Hz, 2 H); 2.84-2.57 (m, 5 H); 2.27 (s, 3 H); 1.80-1.49 (m, 8 H).
[00152] Example 9 Methyl(oxetan-3-yl)piperidin-4-ylamine NH

N
O
[00153] Step 1: 4-(Methyl(oxetan-3-yl)amino)piperidine-l-carboxylic acid tent-butyl ester O

N

O
[00154] A mixture of 4-(methylamino)piperidine-l-carboxylic acid tent-butyl ester (200 mg, 0.93 mmol) and oxetan-3-one (56 mg, 0.78 mmol) in DCE (6 mL) was stirred at room temperature for 2 h before the addition of sodium triacetoxyborohydride (264 mg, 1.24 mmol). The resulting mixture was stirred for 16 h, then loaded onto an Isolute cartridge which was washed with MeOH/DCM and the product eluted with 2M
NH3/MeOH.
The resulting oil was purified by column chromatography (Si-PCC, MeOH/DCM, 0-20%) affording 4-(Methyl(oxetan-3-yl)amino)piperidine-l-carboxylic acid tent-butyl ester as an oil (40 mg, 16%). 1H NMR (CDC13, 300 MHz): 6 4.66 (t, J = 6.6 Hz, 2 H); 4.61 (t, J
= 6.6 Hz, 2 H); 4.16 (s, 2 H); 3.95 (p, J = 6.6 Hz, 1 H); 2.63 (t, J = 12.5 Hz, 2 H); 2.39 (tt, J = 11.7, 3.7 Hz, 1 H); 2.20 (s, 3 H); 1.60 (d, J = 12.5 Hz, 2 H); 1.46 (s, 9 H); 1.44-1.28 (m, 2 H).
[00155] Step 2: A mixture of 4-(methyl(oxetan-3-yl)amino)piperidine-l-carboxylic acid tent-butyl ester (150 mg, 0.55 mmol) and TFA (4 mL) in DCM (10 mL) was stirred at room temperature for 2 h. The reaction mixture was loaded onto an Isolute SCX-2 cartridge which was washed with MeOH/DCM and the product eluted with 2M NH3/MeOH
affording Methyl(oxetan-3-yl)piperidin-4-ylamine as a white solid (94 mg, quant.). 1H
NMR (CDC13, 300 MHz): 6 4.67 (t, J = 6.7 Hz, 2 H); 4.61 (t, J = 6.7 Hz, 2 H); 3.97 (p, J =
6.7 Hz, 1 H);
3.14 (d, J = 12.3 Hz, 2 H); 2.56 (td, J = 12.2, 4.0 Hz, 2 H); 2.48-2.26 (m, 2 H); 2.22 (s, 3 H); 1.63 (d, J = 12.3 Hz, 2 H); 1.40 (qd, J = 12.2, 4.0 Hz, 2 H).
[00156] Example 10 4-Azetidin-3-ylpiperazin-2-one H

c O~N
HNJ
[00157] Step 1: 3-(3-Oxopiperazin-1-yl)azetidine-l-carboxylic acid tent-butyl ester IOII
~
O~N~N x O

HNJ
[00158] A mixture of piperazin-2-one (1.52 g, 15.1 mmol), 3-oxoazetidine-l-carboxylic acid tent-butyl ester (2.0 g, 11.6 mmol) and trimethyl orthoformate (12.8 mL, 12.4 g, 117 mmol) in AcOH (0.7 mL) and DCE (50 mL) was stirred for 5h before the addition of triacetoxyborohydride (4.9 g, 23.2 mmol). The resulting mixture was stirred for 16 h then partitioned between DCM and H20. The organic layer was dried (Na2SO4) and concentrated in vacuo. The resulting oil was purified by column chromatography (Si-PCC, MeOH:DCM, 0-10%) affording the title compound as a foam (827 mg, 28%). 1H NMR (CDC13, 300 MHz):
6 6.24 (s, 1 H); 3.97 (dd, J = 8.9, 7.1 Hz, 2 H); 3.82 (dd, J = 5.2, 2.2 Hz, 2 H); 3.40 (td, J =
5.2, 2.2 Hz, 2 H); 3.24-3.15 (m, 1 H); 3.07 (s, 2 H); 2.60 (t, J = 5.4 Hz, 2 H); 1.44 (s, 9 H).
[00159] Step 2: A mixture of 3-(3-oxopiperazin-1-yl)azetidine-l-carboxylic acid tert-butyl ester (400 mg, 1.57 mmol) and TFA (3 mL) in DCM (6 mL) was stirred at room temperature for 2 h. The reaction mixture was loaded onto an Isolute SCX-2 cartridge which was washed with MeOH/DCM and the product eluted with 2M NH3/MeOH
affording 4-Azetidin-3-ylpiperazin-2-one as a white solid (227 mg, 93%). 1H NMR (CDC13, 300 MHz):
6 6.08 (s, 1 H); 3.63-3.56 (m, 3 H); 3.42-3.35 (m, 3 H); 3.31 (t, J = 6.74 Hz, 1 H); 3.03 (s, 2 H); 2.59-2.51 (m, 2 H).
[00160] Example 11 (S)-l-Azetidin-3-ylpyrrolidin-3-ol H
N
HOõ~N

[00161] Step 1: 3-((S)-3-Hydroxypyrrolidin-1-yl)azetidine-l-carboxylic acid tent-butyl ester O

NAO
[00162] A mixture of (S)-pyrrolidin-3-ol (261 mg, 3.0 mmol), 3-oxoazetidine-l-carboxylic acid tent-butyl ester (513 mg, 3.0 mmol) and 4A powdered molecular sieves (1.0 g) in DCE (10 mL) was stirred at room temperature for 6 h before the addition of sodium triacetoxyborohydride (1.27 g, 6.0 mmol). The reaction mixture was filtered through celite, washing with DCM. The filtrate was concentrated in vacuo and the resulting residue was purified by column chromatography (Si-PCC, Acetone:DCM, 0-40%) affording 3-((S)-3-Hydroxypyrrolidin-l-yl)azetidine-l-carboxylic acid tent-butyl ester as a brown oil (390 mg, 54%). LCMS (Method A): RT 0.28 min [M+H]+ 243.0 [00163] Step 2: A mixture of 3-((S)-3-hydroxypyrrolidin-1-yl)azetidine-l-carboxylic acid tent-butyl ester (390 mg, 1.61 mmol) and TFA (2 mL) in DCM (4 mL) was stirred at room temperature for 2 h. The reaction mixture was loaded onto an Isolute SCX-2 cartridge which was washed with MeOH/DCM and the product eluted with 2M NH3/MeOH
affording the title compound as a white solid (244 mg, quant.). 1H NMR (CDC13, 300 MHz):
6 4.40-4.33 (m, 1 H); 3.70-3.60 (m, 4 H); 3.44-3.34 (m, 1 H); 2.88-2.77 (m, 1 H);
2.73-2.52 (m, 3 H); 2.47 (dd, J = 10.1, 5.2 Hz, 1 H); 2.30-2.12 (m, 2 H); 1.84-1.69 (m, 1 H).
[00164] Example 12 (R)-l-Azetidin-3-ylpyrrolidin-3-ol H
/~N
HO-~ INS/

[00165] Step 1: 3-((R)-3-Hydroxypyrrolidin-1-yl)azetidine-l-carboxylic acid tert-butyl ester iO
-~
N~
HOQ
[00166] A mixture of I-pyrrolidin-3-ol (261 mg, 3.0 mmol), 3-oxoazetidine-l-carboxylic acid tent-butyl ester (513 mg, 3.0 mmol) and 4A powdered molecular sieves (1.0 g) in DCE (10 mL) was stirred at room temperature for 6 h before the addition of sodium triacetoxyborohydride (1.27 g, 6.0 mmol). The reaction mixture was filtered through celite, washing with DCM. The filtrate was concentrated in vacuo and the resulting residue was purified by column chromatography (Si-PCC, Acetone:DCM, 0-40%) affording 3-((R)-3-Hydroxypyrrolidin-l-yl)azetidine-l-carboxylic acid tent-butyl ester as a brown oil (479 mg, 66%). LCMS (Method A): RT 0.28 min [M+H]+ 243.0 [00167] Step 2: A mixture of 3-(I-3-Hydroxypyrrolidin-1-yl)azetidine-l-carboxylic acid tent-butyl ester (479 mg, 1.98 mmol) and TFA (3 mL) in DCM (6 mL) was stirred at room temperature for 2 h. The reaction mixture was loaded onto an Isolute SCX-cartridge, washed with MeOH/DCM and eluted with 2M NH3/MeOH affording the title compound as a white solid (260 mg, 92%). 1H NMR (CDC13, 300 MHz): 6 4.41-4.33 (m, 1 H); 3.69-3.58 (m, 4 H); 3.45-3.32 (m, 1 H); 2.88-2.79 (m, 1 H); 2.65 (d, J =
10.1 Hz, 1 H);
2.55-2.41 (m, 3 H); 2.30-2.12 (m, 2 H); 1.83-1.70 (m, 1 H).
[00168] Example 13 1 -Methylpiperazin-2-one O-)-~NH
,NJ
[00169] Step 1: 4-Methyl-3-oxopiperazine-l-carboxylic acid tent-butyl ester IOIII
0 N 0_~

[00170] To a solution of 3-oxopiperazine-l-carboxylic acid tent-butyl ester (500 mg, 2.50 mmol) in DMF (20 mL) cooled on an ice-bath was added sodium hydride (120 mg, 3.00 mmol, 60% dispersion in mineral oil) and the resulting mixture stirred for 10 min. Methyl iodide (233 L, 532 mg, 3.75 mmol) was added and the resulting mixture stirred at room temperature for 18 h. The reaction mixture was quenched with H2O and extracted with EtOAc. The combined organics were dried (Na2SO4) and concentrated in vacuo affording 4-Methyl-3-oxopiperazine-l-carboxylic acid tent-butyl ester as a yellow oil (300 mg, 56%). 1H
NMR (CDC13, 300 MHz): 6 4.08 (s, 2 H); 3.65 (t, J = 5.4 Hz, 2 H); 3.35 (t, J =
5.4 Hz, 2 H);
3.00 (s, 3 H); 1.47 (s, 9 H).
[00171] Step 2: A mixture of 4-methyl-3-oxopiperazine-l-carboxylic acid tent-butyl ester (300 mg, 1.40 mmol) and TFA (1 mL) in DCM (2 mL) was stirred at room temperature for 2 h. The reaction mixture was loaded onto an Isolute SCX-2 cartridge, washed with MeOH/DCM and eluted with 2M NH3/MeOH affording 1-Methylpiperazin-2-one as a white solid (128 mg, 80%). 1H NMR (CDC13, 300 MHz): 6 3.52 (s, 2 H); 3.32 (t, J =
5.5 Hz, 2 H);
3.09 (t, J = 5.5 Hz, 2 H); 2.97 (s, 3 H); 1.83 (s, 1 H).
[00172] Example 14 4-Azetidin-3-yl-l-methylpiperazin-2-one H
U
O4~N
"IN
[00173] Step 1: 3-(4-Methyl-3-oxopiperazin-1-yl)azetidine-l-carboxylic acid tert-butyl ester O~
~N
o N /~' ~NJ
[00174] A mixture of 1-methylpiperazin-2-one (128 mg, 1.12 mmol), 3-oxoazetidine-1-carboxylic acid tent-butyl ester (231 mg, 1.35 mmol) and 4A powdered molecular sieves (150 mg) in DCE (4 mL) was stirred at room temperature for 1.5 h before the addition of sodium triacetoxyborohydride (475 mg, 2.24 mmol). The reaction mixture was filtered through celite, washing with DCM. The filtrate was concentrated in vacuo and the resulting residue was purified by column chromatography (Si-PCC, MeOH:EtOAc, 0-10%) affording 3-(4-Methyl-3-oxopiperazin-1-yl)azetidine-l-carboxylic acid tent-butyl ester as an oil (211 mg, 70%). 1H NMR (CDC13, 300 MHz): 6 3.99-3.92 (m, 2 H); 3.81 (dd, J = 8.8, 5.1 Hz, 2 H); 3.36 (t, J = 5.5 Hz, 2 H); 3.20-3.14 (m, 1 H); 3.08 (t, J = 5.5 Hz, 2 H);
2.97 (s, 3 H);
2.70-2.56 (m, 2 H); 1.44 (s, 9 H).
[00175] Step 2: A mixture of 3-(4-methyl-3-oxopiperazin-1-yl)azetidine-l-carboxylic acid tent-butyl ester (211 mg, 0.78 mmol) and TFA (2 mL) in DCM (4 mL) was stirred at room temperature for 2 h. The reaction mixture was loaded onto an Isolute SCX-2 cartridge which was washed with MeOH/DCM and the product eluted with 2M NH3/MeOH
affording 4-Azetidin-3-yl-l-methylpiperazin-2-one as a white solid (125 mg, 95%). 1H NMR
(CDC13, 300 MHz): 6 3.63 (m, 4 H); 3.37-3.27 (m, 3 H); 3.03 (s, 2 H); 2.96 (s, 3 H);
2.58 (t, J = 5.6 Hz, 2 H); 2.13-1.97 (m, 1 H).
[00176] Example 15 2-Azetidin-3-ylpropan-2-ol H
N
HO

[00177] Step 1: 3-(1-Hydroxy-l-methylethyl)azetidine-l-carboxylic acid tent-butyl ester YO
N

HO

[00178] A 50mL round-bottomed flask was charged with a solution of azetidine-1,3-dicarboxylic acid 1-tent-butyl ester 3-methyl ester (1 g, 4.65 mmol) in anhydrous THE (10 mL) at 4 C, under argon. A 3.0 M solution of methylmagnesium bromide in Et20 (3.72 mL, 11.15 mmol) was added dropwise over 5 min and the reaction mixture was stirred for 5 h at room temperature. The reaction was quenched with a saturated aqueous solution of NH4C1(5 mL) and water (10 mL). The aqueous phase was extracted with EtOAc (20 mL). The organic layer was dried over sodium sulphate and concentrated in vacuo to give 3-(1-Hydroxy-l-methylethyl)azetidine-l-carboxylic acid tent-butyl ester as a colourless oil (0.8 g, 80%). 'H
NMR (CDC13, 400MHz) 6 3.95-3.75 (m, 4H); 2.60-2.50 (m, 1 H); 1.43 (s, 9 H);
1.17 (s, 6 H).
[00179] Step 2: A 25 mL round-bottomed flask was charged with a solution of 3-(1-hydroxy-l-methylethyl)azetidine-l-carboxylic acid tent-butyl ester (0.8 g, 3.72 mmol) in DCM/TFA (3 mL / 3 mL). The reaction mixture was stirred for 1 h at room temperature. The reaction mixture was loaded onto an Isolute SCX-2 cartridge. The cartridge was washed with MeOH and the desired product was eluted using 2 M NH3 in MeOH to give 2-Azetidin-3-ylpropan-2-ol as a white solid (0.36 g, 84%). 1H NMR (CDC13, 400MHz) 6 3.55-3.62 (m, 4H); 2.75-2.65 (m, 1 H); 1.15 (s, 6 H).
[00180] Example 16 3-Fluoro-[1,3']biazetidinyl H

P
P
F
[00181] Step 1: 3-Fluoro-[1,3']biazetidinyl-l'-carboxylic acid tent-butyl ester P

P
F

[00182] A I OmL round-bottomed flask was charged with a solution of 3-oxoazetidine-1-carboxylic acid tent-butyl ester (0.14 g, 0.82 mmol), 3-fluoroazetidine hydrochloride (0.1 g, 0.9 mmol) in DCE (3 mL), trimethoxymethane (0.88 mL, 8.5 mmol) and acetic acid (0.046 mL, 0.81 mmol). The reaction mixture was stirred for 3 h at room temperature.
Sodium triacetoxyborohydride (0.26 g, 1.22 mmol) was added and the reaction mixture was stirred for 18 h at room temperature. The reaction mixture was partitioned between DCM and water; the organic phase was washed with brine, dried over sodium sulphate and concentrated. The residue was purified by flash chromatography (Si-PPC, EtOAc : cyclohexane, gradient 40:60 to 100:0) to give 3-Fluoro-[1,3']biazetidinyl-l'-carboxylic acid tent-butyl ester as a colourless oil (0.109 g, 59%). 'H NMR (CDC13, 400MHz) 6 5.15 (dt, J = 57.1, 5.3 Hz, 1 H);
3.93 (dd, J
= 9.1, 7.0 Hz, 2 H); 3.74-3.59 (m, 4 H); 3.45-3.38 (m, 1 H); 3.31-3.25 (m, 1 H); 3.23-3.17 (m, 1 H); 1.43 (s, 9 H).
[00183] Step 2: A 25mL round-bottomed flask was charged with a solution of 3-fluoro- [1,3' ]biazetidinyl- 1' -carboxylic acid tent-butyl ester (0.109 g, 0.47 mmol) in DCM/TFA (2 mL / 2 mL). The reaction mixture was stirred for 90 min at room temperature.
The reaction mixture was loaded onto an Isolute SCX-2 cartridge. The cartridge was washed with MeOH and the desired product was eluted using 2 M NH3 in MeOH to give 3-Fluoro-[1,3']biazetidinyl as a colourless oil (0.058 g, 94%). 1H NMR (CDC13, 400MHz) 6 5.14 (dp, J = 57.2, 5.3 Hz, 1 H); 3.75-3.46 (m, 8 H); 3.34-3.24 (m, 1 H); 3.27-3.10 (m, 1 H).
[00184] Example 17 1-Azetidin-3-ylpiperidin-4-ol H
P
N

HO

[00185] Step 1: 3-(4-Hydroxypiperidin-1-yl)azetidine-l-carboxylic acid tent-butyl ester YO
P
N
HO

[00186] A I OmL round-bottomed flask was charged with a solution of 3-oxoazetidine-1-carboxylic acid tent-butyl ester (1 g, 5.84 mmol), 4-hydroxypiperidine (0.65 g, 6.42 mmol) and 4 A molecular sieves (10 g) in DCE (50 mL). The reaction mixture was stirred for 4 h at room temperature. Sodium triacetoxyborohydride (2.48 g, 11.68 mmol) was added and the reaction mixture was stirred for 18 h at room temperature. The suspension was filtered through Celite and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography (Si-PPC, EtOAc : cyclohexane, gradient 0:100 to 100:0) to give 3-(4-Hydroxypiperidin-1-yl)azetidine-l-carboxylic acid tent-butyl ester as a colourless oil (0.34 g, 23%). 'H NMR (CDC13, 400MHz) 6 3.92 (t, J = 7.8 Hz, 2 H); 3.87-3.72 (m, 3 H);
3.07 (m, 1 H); 2.68-2.63 (m, 2 H); 2.09-2.03 (m, 2 H); 1.96-1.91 (m, 2 H); 1.69-1.55 (m, 2 H); 1.43 (s, 9 H).
[00187] Step 2: A 25 mL round-bottomed flask was charged with a solution of 3-(4-hydroxypiperidin-1-yl)azetidine-l-carboxylic acid tent-butyl ester (0.34 g, 1.33 mmol) in DCM/TFA (4 mL / 4 mL). The reaction mixture was stirred for 7 h at room temperature. The reaction mixture was loaded onto an Isolute SCX-2 cartridge. The cartridge was washed with MeOH and the desired product was eluted using 2 M NH3 in MeOH to give 1-Azetidin-3-ylpiperidin-4-ol as a colourless oil (0.194 g, 94%). 1H NMR (CDC13, 400MHz) 6 3.75-3.68 (m, 1 H); 3.67-3.51 (m, 4 H); 3.25-3.17 (m, 1 H); 2.66-2.56 (m, 3 H);
2.03-1.84 (m, 5 H); 1.65-1.53 (m, 2 H).
[00188] Example 18 1-Azetidin-3-yl-4-fluoropiperidine UH

N
F

[00189] Step 1: 3-(4-Fluoropiperidin-1-yl)azetidine-l-carboxylic acid tent-butyl ester P
N
F

[00190] A 10 mL round-bottomed flask was charged with a solution of 3-oxoazetidine-l-carboxylic acid tent-butyl ester (1 g, 5.84 mmol), 4-fluoropiperidine hydrochloride (0.97 g, 6.42 mmol) and 4 A molecular sieves (10 g) in DCE (50 mL). The reaction mixture was stirred for 4 h at room temperature. Sodium triacetoxyborohydride (2.48 g, 11.68 mmol) was added and the reaction mixture was stirred for 18 h at room temperature.
The suspension was filtered through Celite and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography (Si-PPC, EtOAc : cyclohexane, gradient 0:100 to 100:0) then (Si-PPC, MeOH: DCM, 0:100 to 5:95) to give 3-(4-Fluoropiperidin-l-yl)azetidine-l-carboxylic acid tent-butyl ester as a colourless oil (0.59 g, 39%). 1H NMR
(CDC13, 400MHz) 6 4.80-4.58 (m, 1 H); 3.97-3.89 (m, 2 H); 3.85-3.76 (m, 2 H);
3.08 (t, J
= 6.4 Hz, 1 H); 2.50-2.28 (m, 4 H); 1.99-1.82 (m, 4 H); 1.48-1.38 (m, 9 H).

[00191] Step 2: A 25 mL round-bottomed flask was charged with a solution of 3-(4-fluoro-piperidin-1-yl)-azetidine-l-carboxylic acid tent-butyl ester (0.59 g, 2.26 mmol) in DCM/TFA (4 mL / 4 mL). The reaction mixture was stirred for 6 h at room temperature. The reaction mixture was loaded onto an Isolute SCX-2 cartridge. The cartridge was washed with MeOH and the desired product was eluted using 2 M NH3 in MeOH to give 1-Azetidin-3-yl-4-fluoropiperidine as a pale yellow oil (0.263 g, 74%). 1H NMR (CDC13, 400MHz) 6 4.60 (m, 1 H); 3.64-3.52 (m, 4 H); 3.26-3.18 (m, 1 H); 2.45-2.38 (m, 2 H);
2.28-2.17 (m, 2 H); 1.96-1.81 (m, 4 H) [00192] Example 19 1-Azetidin-3-yl-4,4-difluoropiperidine H
N
N

F
F
[00193] Step 1: 3-(4,4-Difluoropiperidin-1-yl)azetidine-l-carboxylic acid tent-butyl ester P

F
F

[00194] A 10 mL round-bottomed flask was charged with a solution of 3-oxoazetidine-l-carboxylic acid tent-butyl ester (0.51 g, 3 mmol), 4,4-difluoropiperidine hydrochloride (0.71 g, 4.5 mmol) and 4 A molecular sieves (0.8 g) in DCE (8 mL). The reaction mixture was stirred for 7 h at room temperature. Sodium triacetoxyborohydride (1.27 g, 6 mmol) was added and the reaction mixture was stirred for 18 h at room temperature. The suspension was filtered through Celite and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography (Si-PPC, EtOAc: cyclohexane, gradient 0:100 to 75:25) to give 3-(4,4-Difluoropiperidin-1-yl)azetidine-l-carboxylic acid tent-butyl ester as a yellow oil (0.69 g, 83%). 1H NMR (CDC13, 400MHz) 6 3.94 (dd, J = 8.7, 7.1 Hz, 2 H); 3.78 (dd, J = 8.7, 5.3 Hz, 2 H); 3.17-3.10 (m, 1 H); 2.45-2.41 (m, 4 H); 2.10-1.94 (m, 4 H); 1.43 (s, 9 H).
[00195] Step 2: A 25 mL round-bottomed flask was charged with a solution of 3-(4,4-difluoropiperidin-l-yl)azetidine-l-carboxylic acid tent-butyl ester (0.684 g, 2.47 mmol) in DCM/TFA (4 mL / 4 mL). The reaction mixture was stirred for 3 h at room temperature. The reaction mixture was loaded onto an Isolute SCX-2 cartridge. The cartridge was washed with MeOH and the desired product was eluted using 2 M NH3 in MeOH to give 1-Azetidin-3-yl-4,4-difluoropiperidine as a pale yellow oil (0.279 g, 64%). 1H NMR
(CDC13, 400MHz) 6 3.64-3.54 (m, 4 H); 3.30-3.25 (m, 1 H); 2.43-2.37 (m, 4 H); 2.06-1.93 (m, 5 H).
[00196] Example 20 [1,3']Biazetidinyl-3-ol H

PN
N
P
HO

[00197] Step 1: 3-Hydroxy-[1,3']biazetidinyl-l'-carboxylic acid tent-butyl ester O
~_O
N
v N

HO
[00198] A 10 mL round-bottomed flask was charged with a solution of 3-oxoazetidine-1-carboxylic acid tent-butyl ester (0.52 g, 3.1 mmol), azetidin-3-ol hydrochloride (0.5 g, 4.6 mmol) and 4 A molecular sieves (0.7 g) in DCE (8 mL). The reaction mixture was stirred for 7 h at room temperature. Sodium triacetoxyborohydride (1.3 g, 6.13 mmol) was added and the reaction mixture was stirred for 18 h at room temperature. The suspension was filtered through Celite and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography (Si-PPC, MEOH:DCM, gradient 0:100 to 40:60) to give 3-Hydroxy-[1,3']biazetidinyl-l'-carboxylic acid tent-butyl ester as yellow oil (0.69 g, 99%). 1H NMR
(CDC13, 400MHz) 6 4.45-4.35 (m, 1 H); 3.96 (dd, J = 9.3, 6.7 Hz, 2 H); 3.74 (dd, J = 9.3, 4.5 Hz, 2 H); 3.66 (td, J = 8.8, 6.7 Hz, 2 H); 3.40-3.37 (m, 1 H); 3.20 (td, J =
8.8, 4.5 Hz, 2 H);
1.43 (s, 9 H).
[00199] Step 2: A 25 mL round-bottomed flask was charged with a solution of 3-hydroxy-[1,3']biazetidinyl-l'-carboxylic acid tent-butyl ester (0.69 g, 3.05 mmol) in DCM/TFA (4 mL / 4 mL). The reaction mixture was stirred for 30 min at room temperature.
The reaction mixture was loaded onto an Isolute SCX-2 cartridge. The cartridge was washed with MeOH and the desired product was eluted using 2 M NH3 in MeOH to give [1,3']Biazetidinyl-3-ol as a colourless oil (0.225 g, 58%). LCMS (Method A):
RT = 0.29min, [M+H]+ 288.9 [00200] Example 21 1-Azetidin-3-yl-4-methylpiperidin-4-ol H
N
N

OH
[00201] Step 1: 3-(4-Hydroxy-4-methylpiperidin-1-yl)azetidine-l-carboxylic acid tert-butyl ester -O
NP /V
OH

[00202] A 50 mL round-bottomed flask was charged with a solution of 3-oxoazetidine-1-carboxylic acid tent-butyl ester (0.57 g, 3.33 mmol), 4-methylpiperidin-4-ol (0.46 g, 3.99 mmol) and 4 A molecular sieves (3.34 g) in DCE (20 mL). The reaction mixture was stirred for 6 h at room temperature. Sodium triacetoxyborohydride (1.41 g, 6.66 mmol) was added and the reaction mixture was stirred for 18 h at room temperature. The suspension was filtered through Celite and the solution was concentrated in vacuo. The residue was purified by flash chromatography (Si-PPC, EtOAc:cyclohexane, 0:100 to 100:0) to give 3-(4-Hydroxy-4-methylpiperidin-l-yl)azetidine-l-carboxylic acid tent-butyl ester as a colourless oil (0.49 g, 55%). 'H NMR (CDC13, 400MHz) 6 3.93 (dd, J = 8.7, 7.17 Hz, 2 H);
3.82 (dd, J
= 8.7, 5.5 Hz, 2 H); 3.15-3.07 (m, 1 H); 2.58-2.44 (m, 2 H); 2.27 (td, J =
11.0, 3.5 Hz, 2 H);
1.77-1.54 (m, 4 H); 1.42 (s, 9 H); 1.26 (t, J = 6.7 Hz, 3 H).
[00203] Step 2: A 25 mL round-bottomed flask was charged with a solution of 3-(4-hydroxy-4-methylpiperidin- 1-yl)azetidine-l-carboxylic acid tent-butyl ester (0.2 g, 0.74 mmol) in DCM/TFA (3 mL / 3 mL). The reaction mixture was stirred for 4 h at room temperature. The reaction mixture was loaded onto an Isolute SCX-2 cartridge.
The cartridge was washed with MeOH and the desired product was eluted using 2 M
NH3 in MeOH to give 1-Azetidin-3-yl-4-methylpiperidin-4-ol as a colourless oil (0.107 g, 85%). 1H
NMR (CDC13, 400MHz) 6 3.61 (t, J = 7.3 Hz, 2 H); 3.54 (t, J = 7.3 Hz, 2 H);
3.29-3.15 (m, 1 H); 3.04 (s, 2 H); 2.40 (d, J = 10.8 Hz, 2 H); 2.30-2.18 (m, 2 H); 1.67-1.56 (m, 4 H);
1.23 (s, 3 H).
[00204] Example 22 4-Oxetan-3-ylpiperazine-l-carboxylic acid tent-butyl ester I
CN) N
O
[00205] A solution of piperazine-l-carboxylic acid tent-butyl ester (1.56 g, 8.38 mmol) and oxetan-3-one (500 mg, 6.94 mmol) DCE (60 mL) was stirred at ambient temperature for 90 min. Sodium triacetoxyborohydride (2.34 g, 11.04 mmol) was added and the mixture stirred for 17 h, then loaded onto an Isolute SCX-2 cartridge (25 g). The cartridge was then washed with methanol and the desired product was subsequently eluted using 2 M
NH3 in MeOH. The product was collected and concentrated in vacuo. The resultant residue was purified by flash chromatography (Si-PPC, DCM: MeOH; 100:0 to 99:1 to 98:2) to afford 4-Oxetan-3-ylpiperazine-l-carboxylic acid tent-butyl ester as a white solid (1.0 g, 59 %). 1H
NMR (CDC13, 400MHz) 6 4.69-4.58 (m, 4 H); 3.51-3.44 (m, 5 H); 2.27 (m, 4 H) and 1.46 (s, 9 H).
[00206] Example 23 2-Hydroxy-2-methyl-7-azaspiro[3.5]nonane-7-carboxylic acid benzyl ester HO

N
O1~1 O

[00207] To a stirred solution of 2-oxo-7-azaspiro[3.5]nonane-7-carboxylic acid benzyl ester (164 mg, 0.60 mmol) in dry THE (2 mL) was added dropwise a 1.4 M
solution of methylmagnesium bromide in toluene/THF (0.56 mL, 0.78 mmol) under an atmosphere of nitrogen, at -78 C. After 1 h the solution was quenched with saturated NH4C1("q) and the resulting mixture partitioned between EtOAc and water. The organic layer was dried (Na2SO4) and evaporated to give a residue, which was purified by column chromatography (Si-PCC, 0-70 % EtOAc in cyclohexane) to give 2-Hydroxy-2-methyl-7-azaspiro[3.5]nonane-7-carboxylic acid benzyl ester (96 mg, 55 %) as a colourless oil. LCMS
(Method H): RT 4.13 min, [M+H]+ 290.4 [00208] Example 24 Azetidin-1-yl-I-pyrrolidin-3-ylmethanone FN [00209] Azetidine hydrochloride (96 mg, 1.03 mmol) was added to a solution of I-pyrrolidine-1,3-dicarboxylic acid 1-tent-butyl ester (200 mg, 0.93 mmol), HATU
(391 mg, 1.03 mmol) and DIPEA (410 L, 2.35 mmol) in DMF (17 mL) and the resulting mixture stirred at ambient temperature for 1 h, then concentrated in vacuo. The resulting oil was partitioned between EtOAc and water. The organic layer was separated, washed with water and brine, then dried (MgSO4) and concentrated in vacuo to give I-3-(azetidine-l-carbonyl)-pyrrolidine-l-carboxylic acid tent-butyl ester as a colourless oil. TFA (3 mL) was added to a solution of I-3-(azetidine-l-carbonyl)pyrrolidine-l-carboxylic acid tent-butyl ester in DCM
(10 mL) and the mixture stirred at ambient temperature for 1 h, then loaded onto an Isolute SCX-2 cartridge (10 g). The cartridge was then washed with methanol and the desired product was subsequently eluted using 2 M NH3 in MeOH. The product was collected and concentrated in vacuo to afford Azetidin-1-yl-I-pyrrolidin-3-ylmethanone as a brown oil (77 mg, 54 %). 1H NMR (CDC13, 400MHz) 6 4.18 (t, J = 7.7 Hz, 2 H); 4.01 (t, J =
7.7 Hz, 2 H);
3.18-3.04 (m, 3 H); 2.96 (m, 1 H); 2.88-2.71 (m, 2 H); 2.35-2.23 (m, 2 H) and 2.04-1.84 (m, 2 H).
[00210] Example 25 Azetidin-1-yl-(S)-pyrrolidin-3-ylmethanone FN CIN H

[00211] Azetidine hydrochloride (96 mg, 1.03 mmol) was added to a solution of I-pyrrolidine-1,3-dicarboxylic acid 1-tent-butyl ester (200 mg, 0.93 mmol), HATU
(391 mg, 1.03 mmol) and DIPEA (410 L, 2.35 mmol) in DMF (17 mL) and the resulting mixture stirred at ambient temperature for 1 h, then concentrated in vacuo. The resulting oil was partitioned between EtOAc and water. The organic layer was separated, washed with water and brine, then dried (MgSO4) and concentrated in vacuo to give I-3-(azetidine-carbonyl)pyrrolidine-1-carboxylic acid tent-butyl ester as a colourless oil.
TFA (3 mL) was added to a solution of I-3-(azetidine-l-carbonyl)pyrrolidine-l-carboxylic acid tent-butyl ester in DCM (10 mL) and the mixture stirred at ambient temperature for 1 h, then loaded onto an Isolute SCX-2 cartridge (10 g). The cartridge was then washed with methanol and the desired product was subsequently eluted using 2 M NH3 in MeOH. The product was collected and concentrated in vacuo to afford Azetidin-1-yl-(S)-pyrrolidin-3-ylmethanone as a brown oil (130 mg, 91 %). 'H NMR (CDC13, 400MHz) 6 4.21-4.11 (m, 2 H); 4.02 (t, J =
7.7 Hz, 2 H); 3.18-3.07 (m, 2 H); 2.95 (dd, J = 11.5, 7.7 Hz, 1 H); 2.88-2.71 (m, 1 H);
2.33-2.22 (m, 2 H); 2.15 (m, 2 H) and 2.05-1.82 (m, 2 H).
[00212] Example 26 Pyrrolidin-1-yl-(R)-pyrrolidin-3-ylmethanone O
CN
-k'CN
[00213] Pyrrolidine (51 L, 1.03 mmol) was added to a solution of I-pyrrolidine-1,3-dicarboxylic acid 1-tent-butyl ester (200 mg, 0.93 mmol), HATU (391 mg, 1.03 mmol) and DIPEA (410 L, 2.35 mmol) in DMF and the resulting mixture stirred at ambient temperature for 1 h, then concentrated in vacuo. The resulting oil was partitioned between EtOAc and water. The organic layer was separated, washed with water and brine, then dried (MgSO4) and concentrated in vacuo to give I-3-(pyrrolidine-l-carbonyl)pyrrolidine-l-carboxylic acid tent-butyl ester as a colourless oil. TFA (3 mL) was added to a solution of I-3-(pyrrolidine-l-carbonyl)pyrrolidine-l-carboxylic acid tent-butyl ester in DCM
(10 mL) and the mixture stirred at ambient temperature for 1 h, then loaded onto an Isolute SCX-2 cartridge (10 g). The cartridge was then washed with methanol and the desired product was subsequently eluted using 2 M NH3 in MeOH. The product was collected and concentrated in vacuo to afford Pyrrolidin-l-yl-(R)-pyrrolidin-3-ylmethanone as a yellow oil (121 mg, 77 %).
iH NMR (CDC13, 400MHz) 6 3.50-3.42 (m, 3 H); 3.19 (s, 1 H); 3.14 (s, 1 H);
3.00 (s, 2 H);
2.96-2.59 (m, 3 H); 2.04-1.92 (m, 3 H) and 1.89-1.81 (m, 2 H).
[00214] Example 27 Pyrrolidin-1-yl-(S)-pyrrolidin-3-ylmethanone CN -Jj CNH
[00215] Pyrrolidine (51 L, 1.03 mmol) was added to a solution of (S)-pyrrolidine-1,3-dicarboxylic acid 1-tent-butyl ester (200 mg, 0.93 mmol), HATU (391 mg, 1.03 mmol) and DIPEA (410 L, 2.35 mmol) in DMF and the resulting mixture stirred at ambient temperature for 1 h, then concentrated in vacuo. The resulting oil was partitioned between EtOAc and water. The organic layer was separated, washed with water and brine, then dried (MgSO4) and concentrated in vacuo to give (S)-3-(pyrrolidine-l-carbonyl)pyrrolidine-l-carboxylic acid tent-butyl ester as a colourless oil. TFA (3 mL) was added to a solution of (S)-3-(pyrrolidine-1-carbonyl)pyrrolidine-l-carboxylic acid tent-butyl ester in DCM (10 mL) and the mixture stirred at ambient temperature for 1 h, then loaded onto an Isolute SCX-2 cartridge (10 g). The cartridge was then washed with methanol and the desired product was subsequently eluted using 2 M NH3 in MeOH. The product was collected and concentrated in vacuo to afford the title compound as a pale brown oil (110 mg, 70 %). 1H NMR
(CDC13, 400MHz) 6 4.01 (m, 3 H); 3.52-3.41 (m, 3 H); 3.25-3.11 (m, 2 H); 3.10-2.97 (m, 2 H);
2.89 (dt, J = 11.4, 7.5 Hz, 1 H); 2.11-1.99 (m, 1 H); 2.01-1.91 (m, 2 H) and 1.93-1.82 (m, 2 H).
[00216] Example 28 Azetidin-3-yl-azetidin-1-ylmethanone Nj-~NH

[00217] Azetidine hydrochloride salt (515 mg, 5.50 mmol) was added to a solution of azetidine-1,3-dicarboxylic acid mono-tent-butyl ester (1.0 g, 4.97 mmol), HATU
(2.09 g, 5.50 mmol) and DIPEA (2.18 mL, 12.52 mmol) in DMF (100 mL) and the resulting mixture stirred at ambient temperature for 1 h, then concentrated in vacuo. The resulting oil was partitioned between EtOAc and water. The organic layer was separated, washed with water and brine, then dried (MgSO4) and concentrated in vacuo to give 3-(azetidine-l-carbonyl)azetidine-l-carboxylic acid tent-butyl ester as a colourless oil. TFA
(3 mL) was added to a solution of 3-(azetidine-l-carbonyl)-azetidine-l-carboxylic acid tent-butyl ester in DCM (15 mL) and the mixture stirred at ambient temperature for 1 h, then loaded onto an Isolute SCX-2 cartridge (25 g). The cartridge was then washed with methanol and the desired product was subsequently eluted using 2 M NH3 in MeOH. The product was collected and concentrated in vacuo to afford the title compound as a colourless oil (260 mg, 37 %). 1H
NMR (CD3OD, 400MHz) 6 4.19-4.08 (m, 2 H); 4.07-3.92 (m, 2 H); 3.91-3.78 (m, 2 H);
3.72-3.52 (m, 3 H) and 2.36-2.21 (m, 2 H).
[00218] Example 29 Azetidin-3-yl-pyrrolidin-1-ylmethanone O
CN
NH
[00219] Pyrrolidine (271 L, 5.50 mmol) was added to a solution of azetidine-1,3-dicarboxylic acid mono-tent-butyl ester (1.0 g, 4.97 mmol), HATU (2.09 g, 5.50 mmol) and DIPEA (2.18 mL, 12.52 mmol) in DMF (100 mL) and the resulting mixture stirred at ambient temperature for 1 h, then concentrated in vacuo. The resulting oil was partitioned between EtOAc and water. The organic layer was separated, washed with water and brine, then dried (MgSO4) and concentrated in vacuo to give 3-(pyrrolidine-l-carbonyl)azetidine-l-carboxylic acid tent-butyl ester as a colourless oil. TFA (3 mL) was added to a solution of 3-(pyrrolidine-1-carbonyl)-azetidine-l-carboxylic acid tent-butyl ester in DCM (15 mL) and the mixture stirred at ambient temperature for 1 h, then loaded onto an Isolute SCX-2 cartridge (25 g).
The cartridge was then washed with methanol and the desired product was subsequently eluted using 2 M NH3 in MeOH. The product was collected and concentrated in vacuo to afford the title compound as a colourless oil (550 mg, 72 %). 1H NMR (CD3OD, 400MHz) 6 3.93-3.65 (m, 5 H); 3.43-3.28 (m, 4 H) and 2.00-1.81 (m, 4 H).
[00220] Example 30 4-Oxetan-3-ylpiperidine H
N
O
[00221] Step 1: 2-(1-(tent-Butoxycarbonyl)piperidin-4-ylidene)malonic acid diethyl ester OyO-~
N

O I O

[00222] To anhydrous THE (50 mL) at 0 C a solution of TiC14 (13.75 mL, 0.126 mol) in CC14 (10 mL) was added dropwise. To the resulting yellow suspension were a solution of 4-oxopiperidine-l-carboxylic acid tent-butyl ester (10 g, 0.05 mol) and diethylmalonate (6.85 mL, 0.05 mol) in anhydrous THE (50 mL) added, followed by addition of pyridine (26 mL).
The dark yellow suspension was allowed to warm to ambient temperature and stirred at ambient temperature for 17 h, then partitioned between EtOAc and citric acid (10 %, aq.).
The organic layer was separated and washed with water and brine, then dried (MgS04) and concentrated in vacuo to afford 2-(1-(tent-Butoxycarbonyl)piperidin-4-ylidene)malonic acid diethyl ester as a brown oil (17 g, 100 %). 1H NMR (CDC13, 400MHz) 6 4.27-4.18 (m, 4 H);
3.55-3.44 (m, 4 H); 2.65 (m, 4 H); 1.49 (s, 9 H) and 1.32-1.26 (m, 6 H).
[00223] Step 2: 2-(1-(tent-Butoxycarbonyl)piperidin-4-yl)malonic acid diethyl ester OyO-~
N
O O
~'__O 0-[00224] To IMS (200 mL) at 0 C, NaBH4 (1.87 g, 0.047 mol) and a solution of 2-(1-(tert-butoxycarbonyl)piperidin-4-ylidene)malonic acid diethyl ester (17 g, 0.050 mol) in IMS
(200 mL) were added. The resulting mixture was allowed to warm to ambient temperature and stirred for 1 h, then quenched with water and concentrated in vacuo. The resulting oil was then partitioned between EtOAc and water. The organic layer was separated and washed with brine, then dried (MgSO4) and concentrated in vacuo to afford the title compound as a yellow oil (14.6 g, 85 %). LCMS (Method H): RT= 3.90 min, [M+Na]+ 366.
[00225] Step 3: 4-(2-Hydroxy-l-(hydroxymethyl)ethyl)piperidine-l-carboxylic acid tent-butyl ester OyO-~
N

HO OH

[00226] To a solution of 2-(1-(tent-butoxycarbonyl)piperidin-4-yl)malonic acid diethyl ester (14.6 g, 0.043 mol) in anhydrous THE (100 mL) and anhydrous toluene (100 mL), LiBH4 (2.1 g. 0.96 mol) was added portion wise. The resulting mixture was heated at 60 C
for 17 h, then stirred at ambient temperature for 24 h. The reaction mixture was slowly added to aqueous HC1(0.1 M, 350 mL) and then extracted with EtOAc. The organic layer was separated and washed with brine, then dried (MgS04) and concentrated in vacuo.
The resultant residue was purified by flash chromatography (Si-PPC, EtOAc: MeOH
100:0 to 98:2 to 95:5 to 90:10 to 80:20) to afford the title compound as a colourless oil (6.91 g, 63 %).
iH NMR (CDC13, 400MHz) 6 3.90-3.75 (m, 4 H); 2.75-2.58 (m, 4 H); 1.77-1.61 (m, 4 H);
1.52 (m, 1 H); 1.45 (s, 9 H) and 1.26-1.13 (m, 1 H).
[00227] Step 4: To a solution of 4-(2-hydroxy-l-(hydroxymethyl)ethyl)piperidine-l-carboxylic acid tent-butyl ester (7.62 g, 0.029 mol) in anhydrous THE (100 mL) at 0 C, a solution of n-BuLi (1.6 M in hexanes, 18.4 mL, 0.029 mol) was added dropwise.
The resulting mixture was stirred at 0 C for 30 min, then a solution of toluenesulfonyl chloride (5.26 g, 0.028 mol) in anhydrous THE (50 mL) was added by canula. The thick reaction mixture was allowed to warm to ambient temperature and stirred for 2 h. A
solution of n-BuLi (1.6 M in hexanes, 18.4 mL, 0.029 mol) was added dropwise and the reaction mixture heated at 60 C for 2 h, then concentrated in vacuo. The resulting oil was partitioned between EtOAc and water. The organic layer was separated and washed with brine, then dried (MgSO4) and concentrated in vacuo. The resultant residue was purified by flash chromatography (Si-PPC, pentane:EtOAc; gradient from 100:0 to 20:80) to afford 4-oxetan-3-ylpiperidine-1-carboxylic acid tent-butyl ester as a white solid (5.33 g, 75 %). TFA (10 mL) was added to a solution of 4-oxetan-3-yl-piperidine-l-carboxylic acid tent-butyl ester (7.1 g, 0.029 mol) in DCM (100 mL) and the mixture stirred at ambient temperature for 2 h. The reaction mixture was loaded onto an Isolute SCX-2 cartridge (50 g), the cartridge was washed with MeOH before the desired product was eluted using 2 M NH3 in MeOH.
The product was collected and concentrated in vacuo. The resultant residue was purified by flash chromatography (Si-PPC, DCM: 2 M NH3 in MeOH 100:0 to 98:2 to 95:5 to 90:10 to 85:15 to 80:20) to afford 4-Oxetan-3-ylpiperidine as a colourless oil which solidified on standing (2.05 g, 49 %). 1H NMR (CDC13, 300MHz) 6 4.75 (dd, J = 7.9, 6.0 Hz, 2 H); 4.52-4.42 (m, 2 H); 3.14-3.04 (m, 2 H); 2.81-2.67 (m, 1 H); 2.61 (td, J = 12.2, 2.6 Hz, 2 H);
1.85-1.68 (m, 1 H); 1.60 (m, 2 H) and 1.02 (qd, J = 12.2, 4.0 Hz, 2 H).
[00228] Example 31 3-(Tetrahydropyran-4-yl)azetidine [00229] To a solution of 3-(tetrahydropyran-4-yl)azetidine-l-carboxylic acid tent-butyl ester (730 mg, 3.0 mmol) in DCM (10 mL) were added water (0.15 mL) and TFA (10 mL).
The reaction mixture was stirred at room temperature for 4 hours and the concentrated under reduced pressure to give a residue that was taken up in MeOH. The resulting solution was loaded onto a SCX-2 cartridge (10 g) which was washed with MeOH. The desired product was eluted with a 2M solution of ammonia in MeOH. The appropriate fractions were combined and concentrated to give 3-(Tetrahydropyran-4-yl)azetidine as a yellow oil (393 mg, 92%). IH NMR (300 MHz, CDC13): 6 3.96 (dd, J = 11.0, 4.0, 2 H); 3.65 (dd, J = 8.0, 8.0 Hz, 2 H); 3.44 (dd, J = 7.6, 7.6 Hz, 2 H); 3.37 (ddd, J = 11.9, 11.9, 2.1, 2 H); 2.50 (m, 1 H);
1.75 (m, 1 H); 1.53 (m, 2 H); 1.18 (ddd, J = 25.0, 11.9, 4.3, 2 H).
[00230] Example 32 1-Azetidin-3-ylpyrrolidin-2-one H
O
JIN
N

[00231] Step 1: 3-(4-Chlorobutyrylamino)azetidine-l-carboxylic acid tert-butyl ester 0\\
N~-O
O
N
CI H

[00232] A mixture of 3-aminoazetidine-l-carboxylic acid tert-butyl ester (730 mg, 4.24 mmol) and triethylamine (1.74 mL, 1.29 g, 12.72 mmol) in DCM (10 mL) was cooled to 0 C before the addition of 4-chlorobutyrylchloride (523 L, 657 mg, 4.66 mmol). The resulting mixture was stirred for 16 h then quenched with H2O and extracted with DCM. The combined organic extracts were washed with brine then dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, EtOAc:cyclohexane, 30-70%) affording 3-(4-Chlorobutyrylamino)azetidine-l-carboxylic acid tert-butyl ester as a brown oil (1.04 g, 89%).
[00233] Step 2: 3-(2-Oxopyrrolidin-1-yl)azetidine-l-carboxylic acid tert-butyl ester 0\\
N~`O
O N ~I Y

[00234] A solution of 3-(4-chlorobutyrylamino)azetidine-1-carboxylic acid tert-butyl ester (1.04 g, 3.76 mmol) in DMF (15 mL) was cooled to 0 C before the addition of NaH
(180 mg, 4.51 mmol). The resulting mixture was allowed to stir for 2 h then quenched with H2O and extracted with EtOAc. The organic phase was washed with H2O and brine, then dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, EtOAc:cyclohexane, 20-100%) affording 3-(2-Oxopyrrolidin-l-yl)azetidine-1-carboxylic acid tert-butyl ester as a brown oil (320 mg, 35%).

(CDC13, 300 MHz): 6 4.99 (m, 1 H), 4.15 (m, 2 H), 3.97 (m, 2 H), 3.57 (t, J =
7.0 Hz, 2 H), 2.42 (t, J = 8.1 Hz, 2 H), 2.15-2.02 (m, 2 H) and 1.45 (s, 9 H) [00235] A mixture of 3-(2-oxopyrrolidin-l-yl)azetidine-l-carboxylic acid tert-butyl ester (320 mg, 1.33 mmol) and TFA (1.5 mL) in DCM (3 mL) was stirred at room temperature for 4 h. The reaction mixture was loaded onto an Isolute SCX-2 cartridge, washed with MeOH/DCM and eluted with 2M NH3/MeOH affording 1-Azetidin-3-ylpyrrolidin-2-one as a white solid (174 mg, 93%). 1H NMR (CDC13, 300 MHz): 6 5.05 (m, 1 H), 3.85-3.76 (m, 4 H), 3.61 (m, 2 H), 2.41 (m, 2 H) and 2.07 (m, 2 H) [00236] Example 33 1-Azetidin-3-yl-3,3-difluoropyrrolidine H
"ON
N

F F

[00237] Step 1: 3-(3,3-Difluoropyrrolidin-l-yl)azetidine-l-carboxylic acid tert-butyl ester 'ON

F F

[00238] A mixture of 3,3-difluoropyrrolidine hydrochloride (200 mg, 1.17 mmol), 3-oxoazetidine-l-carboxylic acid tert-butyl ester (284 mg, 1.99 mmol) and triethylamine (295 L, 221 mg, 2.18 mmol) in DCE (10 mL) was stirred at room temperature for 1 h before the addition of sodium triacetoxyborohydride (745 mg, 3.52 mmol). The resulting mixture was stirred for 72 h then diluted with DCM and washed with H20. The organic phase was dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, EtOAc:cyclohexane, 0-50%) affording 3-(3,3-Difluoropyrrolidin-1-yl)azetidine-l-carboxylic acid tert-butyl ester as a colourless oil (193 mg, 63%). 1H NMR
(CDC13, 300 MHz): 6 3.95 (m, 2 H), 3.82 (dd, J = 8.9, 4.9 Hz, 2 H), 3.32 (m, 1 H), 2.91 (m, 2 H), 2.82-2.63 (m, 2 H), 2.33-2.32 (m, 2 H) and 1.43 (s, 9 H).
[00239] A mixture of 3-(3,3-difluoropyrrolidin-1-yl)azetidine-1-carboxylic acid tert-butyl ester (193 mg, 0.74 mmol) and TFA (1 mL) in DCM (2 mL) was stirred at room temperature for 2 h. The reaction mixture was loaded onto an Isolute SCX-2 cartridge, washed with MeOH/DCM and eluted with 2M NH3/MeOH affording 1-Azetidin-3-yl-3,3-difluoropyrrolidine as a white solid (122 mg, quant.). 1H NMR (CDC13, 300 MHz): 6 3.63 (m, 4H),3.48(m,1H),2.87(t,J=13.1Hz,2H),2.70(t, J = 7.0 Hz, 2 H) and 2.29 (m, 2 H) [00240] Example 34 3,3-Difluoro-[1,3']biazetidinyl H
P
F -~3 F

[00241] Step 1: 3,3-Difluoro-[1,3']biazetidinyl-l'-carboxylic acid tert-butyl ester YO
N
v F -~3 F
[00242] A 25mL round-bottomed flask was charged with a solution of 3-oxoazetidine-1-carboxylic acid tert-butyl ester (0.4 g, 2.34 mmol), 3,3-difluoroazetidine hydrochloride (0.364 g, 2.80 mmol) and 4 A molecular sieves (2.43 g) in DCE (10 mL). The reaction mixture was stirred for 3 h at room temperature. Sodium triacetoxyborohydride (0.99 g, 4.67 mmol) was added and the reaction mixture was stirred for 18 h at room temperature. The suspension was filtered through Celite and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography (Si-PPC, MeOH : DCM, gradient 0:100 to 10:90) to give the title compound as a colourless oil (0.33 g, 57%). IH NMR (300 MHz, CDC13): 6 4.02-3.69 (m, 4 H), 3.65 (t, J = 12.15 Hz, 4 H), 3.55-3.48 (m, 1 H), 1.43 (s, 9 H).
[00243] Step 2: 3,3-Difluoro-[1,3']biazetidinyl [00244] A I OmL round-bottomed flask was charged with a solution of 3,3-difluoro-[1,3']biazetidinyl-l'-carboxylic acid tert-butyl ester (0.15 g, 0.61 mmol) in DCM/TFA (3 mL/3 mL). The reaction mixture was stirred for 3 h at room temperature. The reaction mixture was loaded onto an Isolute SCX-2 cartridge. The cartridge was washed with MeOH
and the desired product was eluted using 2 M NH3 in MeOH to give 3,3-Difluoro-[1,3']biazetidinyl as a colourless oil (0.033 g, 37%). IH NMR (300 MHz, CDC13): 6 3.73-3.55 (m, 8 H), 3.57-3.43 (m, 1 H), 2.77 (s, 1 H) [00245] Example 35 4-(3,3-Difluoroazetidin-1-yl)piperidine H
N
F
F
[00246] Step 1: 4-(3,3-Difluoroazetidin-l-yl)piperidine-l-carboxylic acid tert-butyl ester O
-O
N

F -~3 F
[00247] A I OmL round-bottomed flask was charged with a solution of 4-oxopiperidine-l-carboxylic acid tert-butyl ester (0.4 g, 0.20 mmol), 3,3-difluoroazetidine hydrochloride (0.31 g, 0.24 mmol) and 4 A molecular sieves (2.4 g) in DCE (10 mL). The reaction mixture was stirred for 3 h at room temperature. Sodium triacetoxyborohydride (0.85 g, 4.01 mmol) was added and the reaction mixture was stirred for 18 h at room temperature.
The suspension was filtered through Celite and the filtrate was concentrated in vacuo to give 4-(3,3-Difluoroazetidin-l-yl)piperidine-l-carboxylic acid tert-butyl ester as a colourless oil (0.53 g, 96%). IH NMR (300 MHz, CDC13): 6 3.94-3.90 (m, 2 H), 3.57 (t, J =
11.9 Hz, 4 H), 2.96-2.81 (m, 2 H), 2.34-2.23 (m, 1 H), 1.71-1.58 (m, 2 H), 1.45 (s, 9 H), 1.35-1.21 (m, 2 H).
[00248] Step 2: 4-(3,3-Difluoroazetidin-1-yl)piperidine [00249] A 25 mL round-bottomed flask was charged with a solution of 4-(3,3-difluoroazetidin-l-yl)piperidine-l-carboxylic acid tert-butyl ester (0.265 g, 0.96 mmol) in DCM/TFA (3 mL / 3 mL). The reaction mixture was stirred for 3 h at room temperature. The reaction mixture was loaded onto an Isolute SCX-2 cartridge. The cartridge was washed with MeOH and the desired product was eluted using 2 M NH3 in MeOH to give 4-(3,3-Difluoroazetidin-1-yl)piperidine as a white solid (0.154 g, 91%). IH NMR (300 MHz, CDC13): 6 3.54 (t, J = 11.9 Hz, 4 H), 3. 10 (dt, J = 12.7, 3.9 Hz, 2 H), 2.59 (td, J = 11.9, 2.6 Hz, 2 H), 2.24-2.13 (m, 1 H), 1.76-1.65 (m, 2 H), 1.30-1.15 (m, 2 H).
[00250] Example 36 3-Methyl-[1,3']biazetidinyl-3-ol H
N
N

OH
[00251] Step 1: 3-Hydroxy-3-methylazetidine-l-carboxylic acid benzyl ester -O -N

_~3 OH
[00252] To a 3.0 M solution of methylmagnesium bromide in Et20 (0.98 mL, 2.92 mmol), at 0 C, was added a solution of 3-oxoazetidine-l-carboxylic acid benzyl ester (0.5 g, 2.44 mmol) in anhydrous THE (5 mL) dropwise over 5 min under argon. The reaction mixture was stirred for 18 h at room temperature, and then quenched by addition of a saturated aqueous solution of NH4C1(2.5 mL) and water (5 mL). The aqueous phase was extracted with EtOAc (10 mL). The organic layer was separated, dried over sodium sulphate and concentrated in vacuo to give 3-Hydroxy-3-methylazetidine-l-carboxylic acid benzyl ester as a colourless oil (0.54 g, 99%). LCMS (Method A): RT = 3.60min, [M+H]+
221.9 [00253] Step 2: 3-Methylazetidin-3-ol H
N
_~3 OH
[00254] A 25 mL round-bottomed flask was charged with a solution of 3-hydroxy-methylazetidine-l-carboxylic acid benzyl ester (0.57 g, 2.58 mmol) in EtOH (5 mL) and acetic acid (0.25 mL). The reaction mixture was flushed with nitrogen and 10%
Pd/C (67 mg, 0.29 mmol) was added. The reaction mixture was stirred under a hydrogen atmosphere for 36 h at room temperature. The reaction mixture was loaded onto an Isolute SCX-2 cartridge.
The cartridge was washed with MeOH and the desired product was eluted using 2 M NH3 in MeOH to give the 3-Methylazetidin-3-ol as an orange oil (0.125 g, 56%). IH NMR
(300 MHz, CDC13): 6 3.19-3.03 (m, 4 H), 1.45 (s, 3 H).
[00255] Step 3: 3 -Hydroxy-3 -methyl- [ 1,3']biazetidinyl-1'-carboxylic acid tert-butyl ester O

N
P /V
_~3 OH
[00256] A 10 mL round-bottomed flask was charged with a solution of 3-oxoazetidine-1-carboxylic acid tert-butyl ester (0.21 g, 1.23 mmol), 3-methylazetidin-3-ol (0.13 g, 1.48 mmol) and 4 A molecular sieves (1.2 g) in DCE (5 mL). The reaction mixture was stirred for 3 h at room temperature. Sodium triacetoxyborohydride (0.52 g, 2.47 mmol) was added and the reaction mixture was stirred for 18 h at room temperature. The suspension was filtered through Celite and the solution was concentrated in vacuo. The residue was purified by flash chromatography (Si-PPC, EtOAc : cyclohexane, 0:100 to 100:0) to give 3-Hydroxy-methyl-[1,3']biazetidinyl-l'-carboxylic acid tert-butyl ester as a colourless oil (0.09 g, 30%).
'H NMR (300 MHz, CDC13): 6 3.93 (dd, J = 9.2, 7.2 Hz, 2 H), 3.82-3.70 (m, 2 H), 3.50-3.40 (m, 1 H), 3.32 (d, J = 8.1 Hz, 2 H), 3.21 (d, J = 8.1 Hz, 2 H), 1.51 (s, 3 H), 1.43 (s, 9 H).
[00257] Step 4: 3-Methyl-[1,3']biazetidinyl-3-ol [00258] A 10 mL round-bottomed flask was charged with a solution of 3-hydroxy-methyl-[1,3']biazetidinyl-l'-carboxylic acid tert-butyl ester (0.09 g, 0.37 mmol) in DCM/TFA (2 mL / 2 mL). The reaction mixture was stirred for 90 min at room temperature.
The reaction mixture was loaded onto an Isolute SCX-2 cartridge. The cartridge was washed with MeOH and the desired product was eluted using 2 M NH3 in MeOH to give 3-Methyl-[1,3']biazetidinyl-3-ol as a colourless oil (0.04 g, 76%). IH NMR (300 MHz, CDC13):
6 3.68-3.51 (m, 6 H), 3.25 (d, J = 7.6 Hz, 2 H), 3.15 (d, J = 7.6 Hz, 2 H), 1.49 (s, 3 H).
[00259] Example 37 (R)-l-Azetidin-3-yl-3-fluoropyrrolidine H
P

F
[00260] Step 1: 3-(I-3-Fluoropyrrolidin-l-yl)azetidine-l-carboxylic acid tert-butyl ester ~_O
N
v F
[00261] A 25 mL round-bottomed flask was charged with a solution of 3-oxoazetidine-1-carboxylic acid tert-butyl ester (0.4 g, 2.34 mmol), 1-3-fluoropyrrolidine hydrochloride (0.35 g, 2.8 mmol) and 4 A molecular sieves (2.43 g) in DCE (10 mL). The reaction mixture was stirred for 2.5 h at room temperature. Sodium triacetoxyborohydride (0.99 g, 4.68 mmol) was added and the reaction mixture was stirred for 18 h at room temperature.
The suspension was filtered through Celite and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography (Si-PPC, EtOAc: cyclohexane, gradient 30:70 to 100:0) to give 3-(I-3-Fluoropyrrolidin-l-yl)azetidine-l-carboxylic acid tert-butyl ester as a colourless oil (0.348 g, 61%). IH NMR (300 MHz, CDC13): 6 5.30-5.20 (m, 3 H), 4.01-3.92 (m, 2 H), 3.91-3.82 (m, 2 H), 2.87-2.78 (m, 2 H), 2.17-2.11 (m, 3 H), 1.43 (s, 9 H).
[00262] Step 2: (R)-l-Azetidin-3-yl-3-fluoropyrrolidine [00263] A 25 mL round-bottomed flask was charged with a solution of 3-(I-3-fluoropyrrolidin-l-yl)azetidine-l-carboxylic acid tert-butyl ester (0.175 g, 0.72 mmol) in DCM/TFA (5 mL / 5 mL). The reaction mixture was stirred for 3 h at room temperature. The reaction mixture was loaded onto an Isolute SCX-2 cartridge. The cartridge was washed with MeOH and (R)-1-Azetidin-3-yl-3-fluoropyrrolidine was eluted using 2 M NH3 in MeOH
to give the title compound as a colourless oil (0.088 g, 85%). 'H NMR (300 MHz, CDC13): 6 5.31-5.07 (m, 1 H), 3.73-3.56 (m, 4 H), 3.55-3.21 (m, 1 H), 2.95-2.87 (m, 2 H), 2.83-2.74 (m, 2 H), 2.66 (m, 1 H), 2.28-1.95 (m, 2 H) [00264] Example 38 (S)-l-Azetidin-3-yl-3-fluoropyrrolidine H
N
F

[00265] Step 1: 3-((S)-3-Fluoropyrrolidin-l-yl)azetidine-l-carboxylic acid tert-butyl ester O
YO
N

F
[00266] A 25 mL round-bottomed flask was charged with a solution of 3-oxoazetidine-1-carboxylic acid tert-butyl ester (0.4 g, 2.34 mmol), (S)-3-fluoropyrrolidine hydrochloride (0.35 g, 2.8 mmol) and 4 A molecular sieves (2.43 g) in DCE (10 mL). The reaction mixture was stirred for 2.5 h at room temperature. Sodium triacetoxyborohydride (0.99 g, 4.68 mmol) was added and the reaction mixture was stirred for 18 h at room temperature.
The suspension was filtered through Celite and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography (Si-PPC, EtOAc: cyclohexane, gradient 30:70 to 100:0) to give 3-((S)-3-Fluoropyrrolidin-l-yl)azetidine-l-carboxylic acid tert-butyl ester as a colourless oil (0.342 g, 60%). IH NMR (300 MHz, CDC13): 6 5.34-5.10 (m,1 H), 4.01-3.93 (m, 2 H), 3.91-3.81 (m, 2 H), 3.41-3.31 (m, 1 H), 2.94-2.67 (m, 3 H), 2.56-2.46 (m, 1 H), 2.24-2.06 (m, 2 H), 1.43 (s, 9 H).
[00267] Step 2: (S)-l-Azetidin-3-yl-3-fluoropyrrolidine [00268] A 25 mL round-bottomed flask was charged with a solution of 3-(I-3-fluoropyrrolidin-l-yl)azetidine-l-carboxylic acid tert-butyl ester (0.228 g, 0.93 mmol) in DCM/TFA (6 mL/6 mL). The reaction mixture was stirred for 4 h at room temperature. The reaction mixture was loaded onto an Isolute SCX-2 cartridge. The cartridge was washed with MeOH and : (S)-1-Azetidin-3-yl-3-fluoropyrrolidine was eluted using 2 M
NH3 in MeOH to give the title compound as a colourless oil (0.108 g, 75%). IH NMR
(300 MHz, CDC13): 6 5.46-4.86 (m, 1 H), 4.05-3.79 (m, 4 H), 3.78-3.20 (m, 1 H), 2.95-2.80 (m, 2 H), 2.70-2.62 (m, 2 H), 2.46-2.37 (m, 1 H), 2.29-1.97 (m, 2 H) [00269] Example 39 1 -tert-Butylpiperazin-2-one H
~N O=
N
[00270] Step 1: 4-tert-Butyl-3-oxopiperazine-l-carboxylic acid benzyl ester O K D
~O
~N O=
N
[00271] To a solution of (2-tert-butylaminoethyl)carbamic acid benzyl ester (1.44 g, 5.75 mmol) and triethylamine (2.4 mL, 17.26 mmol) in DCM (50 mL), at room temperature, was added dropwise chloroacetyl chloride (0.55 mL, 6.9 mmol) and the reaction mixture was stirred for 6 h at room temperature. The aqueous phase was extracted with EtOAc (10 mL).
The reaction mixture was partitioned between DCM and a staturated aqueous solution of NaHCO3. The organic layer was separated, dried over sodium sulphate and concentrated in vacuo. The brown residue was dissolved in dry THE (50 mL) and sodium hydride 60% in mineral oil (0.345 g, 8.63 mmol) was added and the reaction mixture was stirred at room temperature for 18 h. The reaction mixture wass quenched with water and partitioned between EtOAc and water. The organic layer was washed with brine, separated, dried over sodium sulphate and concentrated in vacuo. The residue was dissolved in MeOH, loaded onto an Isolute SCX-2 cartridge, and eluted using MeOH to give 4-tert-Butyl-3-oxopiperazine-l-carboxylic acid benzyl ester as yellow oil (1.57 g, 94%). LCMS (Method A): RT
= 3.96min, [M+H]+ 291.2 [00272] Step 2: 1-tert-Butylpiperazin-2-one [00273] A 10 mL round-bottomed flask was charged with a solution of 4-tert-butyl-3-oxopiperazine-l-carboxylic acid benzyl ester (0.75 g, 2.58 mmol) in EtOH (5 mL). The reaction mixture was flushed with nitrogen and 10% Pd/C (67 mg, 0.13 mmol) was added.
The reaction mixture was stirred under a hydrogen atmosphere for 18 h. The reaction mixture was loaded onto an Isolute SCX-2 cartridge. The cartridge was washed with MeOH and the desired product was eluted using 2 M NH3 in MeOH to give 1-tert-Butylpiperazin-2-one as grey oil (0.276 g, 69%). IH NMR (300 MHz, CDC13): 6 3.50 (s, 2 H), 3.37 (t, J
= 5.5 Hz, 2 H), 3.06 (t, J = 5.5 Hz, 2 H), 1.48-1.41 (m, 9 H) [00274] Example 40 (2-(1 S,4S)-2,5-Diazabicyclo[2.2.1]hept-2-yl-2-methylpropan-l-ol HO <
N
H

[00275] 2-Bromo-2-methylpropionic acid ethyl ester (155 L, 1.06 mmol) was added to a solution of potassium carbonate (145 mg, 1.05 mmol) and (1S,4S)-2,5-diazabicyclo[2.2. 1]heptane-2-carboxylic acid tent-butyl ester (200 mg, 1.01 mmol) in anhydrous acetonitrile (1 mL). The resulting mixture was heated at 80 C for 48 h, then cooled to ambient temperature and partitioned between EtOAc and water. The organic layer was separated, washed with brine, then dried (MgS04) and concentrated in vacuo. The resultant residue was purified by flash chromatography (Si-PPC, DCM: MeOH;
100:0 to 98:2) to give (1S,4S)-5-(1-ethoxycarbonyl-l-methylethyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tent-butyl ester as a pale brown oil. To a solution of (lS,4S)-5-(l-ethoxycarbonyl-l-methylethyl)-2,5-diazabicyclo[2.2.1]-heptane-2-carboxylic acid tent-butyl ester (1 mmol) in anhydrous THE (5 mL) at 0 C, a solution of LiAlH4 (1 M in THF, 3.2 mL, 3.2 mmol) was added dropwise. The reaction mixture was allowed to warm to ambient temperature and stirred for 1 h. The reaction mixture was loaded onto an Isolute SCX-2 cartridge (10 g), washed with MeOH before the desired product was eluted using 2 M NH3 in MeOH. The product was collected and concentrated in vacuo to afford the title compound as a brown oil (168 mg, 99 %). 'H NMR (CDC13, 400MHz) 6 3.37 (bs, 1 H); 3.31 (d, J = 10.2 Hz, 1 H); 3.21 (d, J = 10.2 Hz, 1 H); 3.15-3.00 (m, 2 H); 2.81-2.61 (m, 2 H);
2.45 (s, 2 H);
1.76 (d, J = 10.0 Hz, 1 H); 1.56 (d, J = 10.0 Hz, 1 H); 1.46 (t, J = 5.02 Hz, 1 H); 1.03 (s, 3 H) and 1.00 (s, 2 H).
[00276] Example 41 (1S,4S)-2-Methanesulfonyl-2,5-diazabicyclo[2.2.1]heptane IN, `O
SO
N

N
H
[00277] Methanesulfonyl chloride (120 L, 1.55 mmol) and DIPEA (187 L, 1.07 mmol) were added to a solution of (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tent-butyl ester (200 mg, 1.01 mmol) in DCM (20 mL) and the reaction mixture stirred at ambient temperature for 17 h, then partitioned between EtOAc and water. The organic layer was separated and washed with brine, then dried (MgSO4) and concentrated in vacuo to give (1S,4S)-5-methanesulfonyl-2,5-diazabicyclo[2.2.1]-heptane-2-carboxylic acid tent-butyl ester.
TFA (3 mL) was added to a solution of (1S,4S)-5-methanesulfonyl-2,5-diazabicyclo[2.2.1 ]heptane-2-carboxylic acid tent-butyl ester in DCM (10 mL) and the mixture stirred at ambient temperature for 30 min. The reaction mixture was loaded onto an Isolute SCX-2 cartridge (10 g); the cartridge was washed with MeOH before the desired product was eluted using 2 M NH3 in MeOH. The product was collected and concentrated in vacuo to afford the title compound as a white solid (170 mg, 96 %). 1H NMR
(CDC13, 400MHz) 6 4.37 (d, J = 2.0 Hz, 1 H); 3.83 (d, J = 2.0 Hz, 1 H); 3.41 (dd, J =
9.2, 2.19 Hz, 1 H); 3.25 (d, J = 9.2 Hz, 1 H); 3.20 (d, J = 10.3 Hz, 1 H); 3.01 (dd, J = 10.3, 2.14 Hz, 1 H);
2.89 (s, 3 H); and 1.79 (bs, 2 H) [00278] Example 41a 3,3-dimethyl-l-(methylsulfonyl)piperazine 11 x--~
-S-N NH
u \~~
O
[00279] A mixture of 2,2-dimethylpiperazine-1-carboxylic acid tert-butyl ester (1.0 g, 4.60 mmol) and NEt3 (1.3 mL, 9.34 mmol) in DCM (11 mL) was cooled to 0 C
before the drop wise addition of a solution of methanesulfonyl chloride (580 mg, 5.00 mmol) in DCM
(2 mL). The resulting mixture was warmed to r.t. and allowed to stir for 30 min before H2O
was added. The organic phase was dried (phase separator) and concentrated in vacuo. The resulting residue was dissolved in DCM (10 mL) and TFA (2 mL) was added. The resulting mixture was allowed to stir at r.t. for 30 min then concentrated in vacuo. The resulting residue was partitioned between DCM and sat. aq. NaHCO3 and the aqueous phase was loaded onto an Isolute SCX-2 cartridge which was washed with H2O and MeOH.
The product was eluted with 2M NH3/MeOH affording the title compound (800 mg, 90%). LCMS
(method A): RT 0.29 min [M+H]+ 193.3 [00280] Example 41b 4-(2-Hydroxy-1,1-dimethylethyl)piperazine-l-carboxylic acid tert-butyl ester O
Y- NI/N
H 0 ~
O
[00281] To a solution of 4-(l-ethoxycarbonyl-l-methylethyl)piperazine-l-carboxylic acid tert-butyl ester (500 mg, 1.67 mmol) in THE (5 mL) at 0 C was added LiAlH4 (3 mL, 1M in THF) drop wise. The resulting mixture was allowed to stir for 2.5 h then quenched with H2O (0.1 mL), 20% aq. NaOH (0.1 mL) and H2O (0.3 mL). The mixture was diluted with EtOAc and H20, filtered through Celite then the organic layer separated, dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, MeOH:DCM, 0-10%) affording the title compound as a colourless oil (217 mg, 50%). 1H NMR (CDC13, 400 MHz): 6 5.30 (1 H, brd s), 3.42 (6 H, m), 3.35 (4 H, brd s), 2.51 (6 H, brd s), 1.03 (9 H, s) [00282] Example 41c 2-Methyl-2-piperazin-l-ylpropan-l-ol NN H
[00283] HO ~--i [00284] To a solution of 4-(2-hydroxy-1,1-dimethylethyl)piperazine-l-carboxylic acid tert-butyl ester (110 mg, 0.43 mmol) in DCM (3 mL) was added TFA (1 mL) and the resulting mixture stirred for 3 h. The reaction mixture was loaded onto an Isolute SCX-2 cartridge which was washed with MeOH/DCM and the product eluted with 2M
NH3/MeOH
affording the title compound as an off-white solid (62 mg, 91 %). 1H NMR
(CDC13, 400 MHz): 6 3.32 (2 H, s), 2.90 (5 H, t, J = 4.78 Hz), 2.38-2.13 (4 H, m), 1.03 (6 H, s) [00285] Example 41d 7-Oxetan-3-yl-4,7-diazaspiro[2.5]octane O>-N\-/N H

[00286] Step 1: 7-Oxetan-3-yl-4,7-diazaspiro[2.5]octane-4-carboxylic acid benzyl ester r~'NAO
N

[00287] A mixture of 4,7-diazaspiro[2.5]octane-4-carboxylic acid benzyl ester oxalate (200 mg, 0.59 mmol), oxetan-3-one (50 mg, 0.69 mmol), NEt3 (82 L, 0.59 mmol) and 4A
powdered molecular sieves (1.0 g) in DCE (10 mL) was stirred at r.t. for 2 h before the addition of sodium triacetoxyborohydride (164 mg, 0.78 mmol). The resulting mixture was stirred for 68 h then loaded onto an Isolute SCX-2 cartridge which was washed with MeOH
and the product eluted with 2M NH3/MeOH affording the title compound. LCMS
(method H): RT 2.01 min, [M+H]+ 303.3 [00288] Step 2: 7-Oxetan-3-yl-4,7-diazaspiro[2.5]octane O\NNH

[00289] To a solution of 7-oxetan-3-yl-4,7-diazaspiro[2.5]octane-4-carboxylic acid benzyl ester in IMS (3 mL) was added 10% Pd/C (60 mg) and the resulting mixture stirred under an atmosphere of H2 at r.t. for 20 h. The reaction mixture was filtered through Celite and the filtrate loaded onto an Isolute SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH affording the title compound (90 mg, 90%).

(CDC13, 400 MHz): 6 4.63-4.63 (2 H, m), 3.50-3.42 (2 H, m), 3.00-2.98 (2 H, m), 2.35-2.25 (2 H, m), 2.15 (2 H, s), 2.05-2.03 (2 H, m), 0.68-0.63 (2 H, m), 0.52-0.51 (2 H, m) [00290] Example 4le 1-Azetidin-3-yl-2-methylpropan-l-ol N

O

[00291] i) 3-(Methoxymethylcarbamoyl)azetidine-1-carboxylic acid tert-butyl ester O
~-O
N

O
N-O

[00292] A mixture of N,O-dimethylhydroxylamine hydrochloride (773 mg, 7.93 mmol) and diisopropylethylamine (1.38 mL, 7.93 mmol) in dichloromethane (5 mL) was added to a mixture of azetidine-1,3-dicarboxylic acid mono-tert-butyl ester (1.0 g, 5.30 mmol) and N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (1.27 g, 6.63 mmol) in dichloromethane (10 mL). The resulting reaction mixture was stirred at RT under nitrogen atmosphere for 16 h. The organic phase was washed with water (1 x 25 mL), 10%
aqueous citric acid solution (2 x 25 mL), brine (1 x 30 mL), and dried over sodium sulphate.
The solvents were reduced in vacuo to afford the title compound as pale yellow oil (1.06 g, 82%). IH NMR (400 MHz, CDC13): 6 4.14 (2 H, m), 4.05 (2 H, t, J = 8.72 Hz), 3.66 (4 H, s), 3.20 (3 H, s), 1.43 (9 H, s).
[00293] ii) 3-(Isobutyryl)azetidine-1-carboxylic acid tert-butyl ester O
~-O
N

O

[00294] A solution of 3-(methoxymethylcarbamoyl)azetidine-l-carboxylic acid tert-butyl ester (1.06 g, 4.34 mmol) in anhydrous tetrahydrofuran (15 mL) was cooled to 4 C
under argon gas. 2M solution of isopropyl magnesium chloride (4.35 mL, 8.68 mmol) was added dropwise and the resulting reaction mixture was stirred at 4 C for 5 min. The temperature was allowed to rise to RT and stirred for lh then the mixture was stirred at 40 C
for 1 h. The reaction mixture was quenched by addition of a saturated solution of ammonium chloride (5 mL) and water (10 mL). The aqueous phase was extracted with ethyl acetate (3 x 20 mL). The organic layer was dried over sodium sulfate, filtered and the solvents reduced in vacuo to afford the title compound as a pale yellow oil (950 mg, 96%) IH NMR
(400 MHz, CDC13): 6 4.03-4.01 (4 H, m), 3.59-3.59 (1 H, m), 2.61-2.61 (1 H, m), 1.43 (9 H, s), 1.11 (6 H, d, J = 6.94 Hz).
[00295] iii) 3-(1-Hydroxy-2-methylpropyl)azetidine-l-carboxylic acid tert-butyl ester O
~-O
N

O

[00296] Sodium borohydride (237 mg, 6.26 mmol) was added to a solution of 3-(isobutyryl)azetidine-l-carboxylic acid tert-butyl ester (0.95 g, 4.18 mmol) in ethanol (7.5 mL). The resulting reaction mixture was stirred at RT for 2 h. Saturated hydrogen carbonate (25 mL) was added and the resulting mixture was stirred for further 15 min.
The aqueous phase was extracted with dichloromethane (3 x 25 mL). The organic layer was dried over sodium sulfate and the solvents reduced in vacuo to give the crude product as yellow oil. The residue was purified by column chromatography (Si-PCC, ethyl acetate:
cyclohexane:
gradient 0:100 to 40:60). The solvents were reduced in vacuo to afford the title compound as colourless oil (840 mg, 88%). IH NMR (400 MHz, CDC13): 6 3.91-3.90 (3 H, m), 3.71 (1 H, dd, J = 8.54, 6.04 Hz), 3.51 (1 H, dd, J = 7.21, 4.97 Hz), 2.70-2.63 (1 H, m), 1.65-1.63 (1 H, m), 1.44 (9 H, s), 0.90 (6 H, t, J = 6.59 Hz).

[00297] iv) Trifluoroacetic acid (3 mL) was added to a solution of 3 -(1 -hydroxy-2-methylpropyl)azetidine-1-carboxylic acid tert-butyl ester (0.84 g, 3.66 mmol) in dichloromethane (12 mL). The resulting reaction mixture was stirred at RT for 40 min. The solvents were reduced in vacuo. The resulting residue was loaded onto an Isolute SCX-2 cartridge (5g). The cartridge was washed with DCM /MeOH, the desired product was subsequently eluted using a mixture of 2M NH3 in MeOH and DCM. The solvents were reduced in vacuo to afford 1-Azetidin-3-yl-2-methylpropan-l-ol as a white solid (0.42 g, 88%). IH NMR (400 MHz, CDC13): 6 3.63-3.62 (3 H, m), 3.53-3.51 (2 H, m), 2.88-2.87 (1 H, m), 1.62-1.62 (1 H, m), 0.89 (6 H, dd, J = 6.84, 4.72 Hz) [00298] Example 41f (Azetidin-3-ylmethyl)methyl(tetrahydrofuran-3-yl)amine N

F

O

[00299] i) 3-{[Methyl(tetrahydrofuran-3-yl)-amino]methyl}azetidine-l-carboxylic acid tert-butyl ester O
YO
N

F

O

[00300] A mixture of 3-ethylaminomethyl-azetidine-l-carboxylic acid tert-butyl ester (200 mg, 1.0 mmol), dihydrofuran-3-one (0.155 mL, 2.0 mmol), diisopropylethylamine (0.347 mL, 2.0 mmol) and 4 A molecular sieves (600 mg) in DCM (10 mL) was stirred at RT
for 30 min. Sodium triacetoxyborohydride (424 mg, 2 mmol) was added and the resulting reaction mixture was stirred at RT under nitrogen atmosphere for 60 h. The suspension was filtered through Celite and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (Si-PPC, MeOH:DCM, gradient 0:100 to 5:95) to afford the title compound as a colourless oil (257 mg, 95%). 'H NMR (400 MHz, CDC13): 6 4.04-3.92 (3 H, m), 3.83 (1 H, dd, J = 8.89, 6.90 Hz), 3.75 (1 H, q, J = 8.07 Hz), 3.64 (1 H, dd, J = 8.87, 6.21 Hz), 3.56-3.55 (2 H, m), 3.14 (1 H, m), 2.67-2.66 (2 H, m), 2.51 (1 H, dd, J =
12.33, 7.20 Hz), 2.17 (3 H, s), 2.05 (1 H, s), 1.89-1.79 (1 H, m), 1.44 (9 H, s).

[00301] ii) Trifluoroacetic acid (3 mL) was added to a solution of 3-{[methyl(tetrahydrofuran-3-yl)amino]methyl}azetidine-l-carboxylic acid tert-butyl ester (257 mg, 0.95 mmol) in dichloromethane (12 mL). The resulting reaction mixture was stirred at RT for 1.5 h. The solvents were reduced in vacuo. The resulting residue was loaded onto an Isolute SCX-2 cartridge (5 g). The cartridge was washed with DCM /MeOH, the desired product was subsequently eluted using a mixture of 2M NH3 in MeOH and DCM to afford (Azetidin-3-ylmethyl)methyl(tetrahydrofuran-3-yl)amine as colourless oil (140 mg, 86%). IH
NMR (400 MHz, CDC13): 6 3.94 (1 H, td, J = 8.62, 4.35 Hz), 3.84 (1 H, dd, J =
8.76, 6.50 Hz), 3.76-3.65 (3 H, m), 3.62 (1 H, dd, J = 8.76, 6.50 Hz), 3.38 (2 H, t, J =
7.31 Hz), 3.09-3.07 (1 H, m), 2.99-2.88 (1 H, m), 2.64 (1 H, dd, J = 12.50, 7.22 Hz), 2.53 (1 H, dd, J =
12.50, 7.22 Hz), 2.15 (3 H, s), 2.01 (1 H, dtd, J = 12.34, 7.72, 3.21 Hz), 1.83 (1 H, dtd, J =
12.35, 8.40, 6.96 Hz) [00302] Example 41g (Azetidin-3-ylmethyl)methyloxetan-3-ylamine N

F
/ -CO

[00303] i) 3-[(Methyl(oxetan-3-yl)amino)methyl]azetidine-l-carboxylic acid tert-butyl ester O
~-o N

F
/N-<O

[00304] A mixture of 3-(methylamino)methylazetidine-1-carboxylic acid tert-butyl ester (450 mg, 2.25 mmol), oxetan-3-one (135 mg, 1.88 mmol), in dichloromethane (10 mL) was stirred at RT for 1.5 h. Sodium triacetoxyborohydride (797 mg, 3.76 mmol) was added and the resulting reaction mixture was stirred at RT under nitrogen atmospherefor 18 h. The mixture was diluted with water, the phases were separated and the aqueous phase was extracted with EtOAc (2 x 25 mL). The combined organic layers were dried over sodium sulfate, filtered and the solvents reduced in vacuo The residue was purified by column chromatography (Si-PPC, MeOH:DCM, gradient 0:100 to 5:95) to afford the title compound as a colourless oil (330 mg, 69%). IH NMR (400 MHz, CDC13): 6 4.64 (2 H, t, J
= 6.58 Hz), 4.57 (2 H, t, J = 6.26 Hz), 4.01 (2 H, t, J = 8.40 Hz), 3.57-3.55 (3 H, m), 2.71-2.61 (1 H, m), 2.41 (2 H, d, J = 7.57 Hz), 2.08 (3 H, s), 1.44 (9 H, s).

[00305] ii) Trifluoroacetic acid (3 mL) was added to a solution of 3-[(methyl(oxetan-3-yl)amino)methyl]azetidine-l-carboxylic acid tert-butyl ester (330 mg, 1.29 mmol) in dichloromethane (12 mL) The resulting reaction mixture was stirred at RT for 1.5 h. The solvents were reduced in vacuo. The resulting residue was loaded onto an Isolute SCX-2 cartridge (5 g). The cartridge was washed with DCM /MeOH, the desired product was subsequently eluted using a mixture of 2M NH3 in MeOH and DCM to afford (Azetidin-3-ylmethyl)methyl(oxetan-3-yl)amine as colourless oil (180 mg, 90%). IH NMR (400 MHz, CDC13): 6 4.64 (2 H, t, J = 6.59 Hz), 4.57 (2 H, t, J = 6.31 Hz), 3.72 (2 H, t, J = 7.87 Hz), 3.58-3.49 (1 H, m), 3.37 (2 H, t, J = 7.22 Hz), 2.92-2.82 (1 H, m), 2.44 (3 H, m), 2.06 (3 H, s) [00306] Example 41h Azetidin-3-yl-((S)-3-hydroxypyrrolidin-1-yl)methanone N
O

O

[00307] i) 3-((S)-3-Hydroxypyrrolidine-l-carbonyl)azetidine-l-carboxylic acid tert-butyl ester oY0 N

O C P
O

[00308] (S)-Pyrrolidin-3-ol (0.276 g, 3.17 mmol) was added to a mixture of azetidine-1,3-dicarboxylic acid mono-tert-butyl ester (0.4 g, 2.11 mmol) and N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (0.61 g, 3.17 mmol) in dichloromethane (7 mL). The resulting reaction mixture was stirred at RT under nitrogen atmosphere for 48 h. The mixture was diluted with DCM (10 mL) and washed with water (1 x 15 mL), 10% aqueous citric acid solution (2 x 15 mL) and brine (2 x 15 mL), and dried over sodium sulphate. The solvents were reduced in vacuo to afford the title compound as colourless oil (0.46 g, 81%). IH NMR (400 MHz, CDC13): 6 4.55-4.48 (1 H, m), 4.17 (2 H, s), 4.05-4.04 (2 H, m), 3.50-3.47 (5 H, m), 2.01-2.00 (2 H, m), 1.43 (9 H, d, J =
0.96 Hz).

[00309] ii) Trifluoroacetic acid (3 mL) was added to a solution of 3-((S)-3-hydroxypyrrolidine-l-carbonyl)azetidine-l-carboxylic acid tert-butyl ester (460 mg, 1.7 mmol) in dichloromethane (12 mL). The resulting reaction mixture was stirred at RT for 2 h.
The solvents were reduced in vacuo. The resulting residue was loaded onto an Isolute SCX-2 cartridge (10 g). The cartridge was washed with DCM /MeOH, the desired product was subsequently eluted using a mixture of 2M NH3 in MeOH and DCM to afford Azetidin-3-yl-((S)-3-hydroxypyrrolidin-1-yl)methanone as colourless oil (243 mg, 84%). IH
NMR (400 MHz, DMSO, d6): 6 4.28-4.18 (1 H, m), 3.72-3.17 (10 H, m), 2.11-2.10 (1 H, m), 1.81-1.80 (2 H, m) [00310] Example 41i Azetidin-3-yl-((R)-3-hydroxypyrrolidin-1-yl)methanone N

O

O

[00311] i) 3-((R)-3-Hydroxypyrrolidine-l-carbonyl)azetidine-l-carboxylic acid tert-butyl ester N

O

O

[00312] (R)-Pyrrolidin-3-ol (0.276 g, 3.17 mmol) was added to a mixture of azetidine-1,3-dicarboxylic acid mono-tert-butyl ester (0.4 g, 2.11 mmol) and N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (0.61 g, 3.17 mmol) in dichloromethane (7 mL). The resulting reaction mixture was stirred at RT under nitrogen atmosphere for 18 h. The mixture was diluted with DCM (10 mL) and washed with water (1 x 15 mL), 10% aqueous citric acid solution (2 x 15 mL) and brine (2 x 15 mL), and dried over sodium sulfate. The solvents were reduced in vacuo to afford the title compound as colourless oil (0.42 g, 74%). IH NMR (400 MHz, CDC13): 6 4.54-4.52 (1 H, m), 4.11-4.09 (4 H, m), 3.50-3.48 (5 H, m), 2.01-2.00 (2 H, m), 1.43 (9 H, d, J = 0.78 Hz) [00313] ii) Trifluoroacetic acid (3 mL) was added to a solution of 3-((R)-3-hydroxypyrrolidine-l-carbonyl)azetidine-l-carboxylic acid tert-butyl ester (420 mg, 1.55 mmol) in dichloromethane (12 mL) The resulting reaction mixture was stirred at RT for 2 h.
The solvents were reduced in vacuo. The resulting residue was loaded onto an Isolute SCX-2 cartridge (10 g). The cartridge was washed with DCM /MeOH, the desired product was subsequently eluted using a mixture of 2M NH3 in MeOH and DCM to afford Azetidin-3-yl-((R)-3-hydroxypyrrolidin-1-yl)methanone as colourless oil (225 mg, 85%). IH
NMR (400 MHz, DMSO, d6): 6 4.26-4.22 (1 H, m), 3.47-3.44 (10 H, m), 2.13-2.09 (1 H, m), 1.81 (2 H, m) [00314] R3 Reagents:

[00315] Example 42 4-Bromo-lH-pyrrolo[2,3-c]pyridine-l-carboxylic acid tert-butyl ester O
Br N
O
N

[00316] A mixture of 4-bromo-lH-pyrrolo[2,3-c]pyridine (248 mg, 1.26 mmol), di-tert-butyl dicarbonate (302 mg, 1.38 mmol), DMAP (31 mg, 0.25 mmol), triethylamine (140 mg, 1.38 mmol) and acetonitrile (8 mL) were stirred at room temperature for 2.5 h. The reaction mixture was evaporated and the residue was purified by column chromatography (Si-PPC, cyclohexane:EtOAc, gradient 0:100 to 50:50) to give the title compound (316 mg, 84%) as a colorless oil. LCMS (Method C): RT= 4.07 min, [M+H-`Bu]+ 241 (79Br), 243 ("Br) [00317] Example 43 4-Bromo-6-oxypyrrolo[2,3-c]pyridine-l-carboxylic acid tert-butyl ester O~
Br It , , N~
O
N

[00318] To a solution of 4-bromo-lH-pyrrolo[2,3-c]pyridine-l-carboxylic acid tert-butyl ester (316 mg, 1.06 mmol) in DCM (10 mL) was added a saturated aqueous solution of NaHCO3 (10 mL) and the resulting mixture cooled to 0 C. 3-Chloroperbenzoic acid (70-75 % in H20) (524 mg, 2.13 mmol) was added to the reaction mixture which was allowed to warm to room temperature and stirred for a further 20 h. The mixture was partitioned between water and DCM and the aqueous layer was extracted with DCM (2 x 10 mL). The combined organic extracts were dried (phase separator) and evaporated to give the title compound as an orange solid (317mg, 95%). LCMS (Method C): RT 3.48 min, [M+H]+

(79Br), 315 ("Br) [00319] Example 44 1-Benzenesulfonyl-4-bromo-2-methyl-lH-pyrrolo[3,2-c]pyridine Br N
I
OS;O , 6 [00320] Step 1: 1-Benzenesulfonyl-lH-pyrrolo[3,2-c]pyridine N I ~ ~
i NN ;O
O

[00321] A 100mL round-bottomed flask was charged with a solution of 1H-pyrrolo[3,2-c]pyridine (1.0 g, 8.4 mmol) in anhydrous THE (50 mL). NaH (60% in mineral oil, 0.41 g, 10.2 mmol) was added and the reaction mixture was stirred for 5 min at room temperature. To this solution was added dropwise, at 0 C, benzenesulfonyl chloride (1.35 mL, 10.2 mmol) and the resulting mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with water (30 mL) and extracted with EtOAc (3x100 mL).
The organic layers were combined, dried (Na2SO4) and concentrated in vacuo to give the title compound as a white solid (1.29 g, 55 %). IH NMR (DMSO, 300 MHz): 6 8.95 (s, 1 H);
8.49 (d, J = 5.8 Hz, 1 H); 8.13-8.05 (m, 2 H); 8.02-7.94 (m, 2 H); 7.79-7.71 (m, 1 H); 7.69-7.59 (m, 2 H); 7.01 (dd, J = 3.7, 0.9 Hz, 1 H).

[00322] Step 2: 1-Benzenesulfonyl-lH-pyrrolo[3,2-c]pyridine 5-oxide O. +
N

i OS;O
, 6 [00323] A 100 mL round-bottomed flask was charged with a solution of 1-benzenesulfonyl-lH-pyrrolo[3,2-c]pyridine (0.6 g, 2.3 mmol) in dioxane (20 mL). To the resultant solution was added mCPBA (0.6 g, 3.45 mmol) and the mixture was stirred at room temperature for 30 min. The reaction mixture was concentrated in vacuo then the residue was dissolved in DCM (50 mL), and washed successively with aqueous sodium sulfite solution, aqueous sodium bicarbonate solution and brine. The organic layer was isolated then dried (Na2SO4) and concentrated in vacuo to give the title compound as a white solid (0.6 g, 95%).
IH NMR (DMSO, 300 MHz): 6 8.61 (dd, J = 1.8, 0.7 Hz, 1 H); 8.13 (dd, J = 7.2, 1.8 Hz, 1 H); 8.09-8.04 (m, 2 H); 8.01 (d, J = 3.7 Hz, 1 H); 7.92 (d, J = 7.2 Hz, 1 H);
7.80-7.73 (m, 1 H); 7.69-7.61 (m, 2 H); 6.83 (dd, J = 3.7, 0.8 Hz, 1 H).

[00324] Step 3: 1-Benzenesulfonyl-4-bromo-lH-pyrrolo[3,2-c]pyridine Br N
I
/O S, 6 [00325] A 250mL round-bottomed flask, under nitrogen, fitted with a thermometer probe and a condenser/inert gas bubbler (via a Claisen head), was charged with a solution of 1-benzenesulfonyl-lH-pyrrolo[3,2-c]pyridine 5-oxide (3.5 g, 12.8 mmol) in acetonitrile (50 mL) and dioxane (50 mL). To this solution was added dropwise phosphorus oxybromide (12 g, 40.9 mmol) and the resulting mixture was stirred at 70 C for 18 h. The precipitate formed was removed by filtration and washed several times with dioxane. The solution was concentrated in vacuo and partitioned between DCM, water and brine. The organic layer was isolated then dried (Na2SO4) and concentrated in vacuo. The resultant residue was purified by flash chromatography (Si-PCC, 0-20% EtOAc in cyclohexane) to give the desired product (3.1 g, 72%). IH NMR (CDC13, 300 MHz): 6 8.23 (d, J = 5.7 Hz, 1 H); 7.94-7.85 (m, 3 H);
7.67-7.59 (m, 2 H); 7.55-7.48 (m, 2 H); 6.75 (dd, J = 3.7, 0.8 Hz, 1 H).

[00326] Step 4: 1-Benzenesulfonyl-4-bromo-2-methyl-lH-pyrrolo[3,2-c]pyridine O
N- .
Br SO
N

[00327] A 50mL round-bottomed flask, under nitrogen, fitted with a thermometer probe and a condenser/inert gas bubbler (via a Claisen head) was charged with a solution of 1-benzenesulfonyl-4-bromo-lH-pyrrolo[3,2-c]pyridine (0.43 g, 1.27 mmol) in anhydrous THE (8 mL). To the resultant solution, at -35 C, was added dropwise a solution of lithium diisopropylamide (2.OM in heptane/THF/ethyl benzene, 1.27 mL, 2.54 mmol) and the mixture was stirred at -35 C for 30 min. Methyl iodide (0.48 mL, 7.63 mmol) was added dropwise and solution was allowed to reach room temperature and stirred for 3 h. The reaction was quenched by addition of IN HC1(3 mL). The solution was diluted with water (7 mL), extracted with EtOAc (2x50 mL). The organic extracts were pooled, was dried (Na2SO4) and concentrated in vacuo. The resultant residue was purified by flash chromatography (Si-PPC, 0-100% EtOAc:cyclohexane) to give the desired product (0.43 g, 96 %) as a white powder. LCMS (Method A) RT = 4.67min, [M+H]+ 351 (79Br), 353 ("Br) [00328] Example 45 1-Benzenesulfonyl-4-bromo-2-methyl-lH-pyrrolo[2,3-c]pyridine Br N
NS
O' [00329] Step 1: 1-Benzenesulfonyl-4-bromo-lH-pyrrolo[2,3-c]pyridine -Br N-S\
N

[00330] A 50mL round-bottomed flask was charged with a solution of 4-bromo-lH-pyrrolo[2,3-c]pyridine (0.7 g, 3.55 mmol) in anhydrous DCM (20 mL). NaOH (0.43 g, 10.7 mmol) and benzenetriethylammonium chloride (0.016 g, 0.07 mmol) were added and the reaction mixture was stirred for 3 h at room temperature. The reaction mixture was filtered through Celite , the Celite bed was washed with DCM and the resulting filtrate was concentrated in vacuo. The resultant solid residue was triturated with diethyl ether and the precipitate collected by filtration to give the title compound as an off-white solid (0.96 g, 80%). LCMS (Method A): RT = 4.29min, [M+H]+ 337 (79Br), 339 ("Br) [00331] Step 2: 1-Benzenesulfonyl-4-bromo-2-methyl-lH-pyrrolo[2,3-c]pyridine Br N
N
O"S' [00332] A 50mL round-bottomed flask, under nitrogen fitted with a thermometer probe, and a condenser/inert gas bubbler (via a Claisen head), was charged with a solution of 1-benzenesulfonyl-4-bromo-lH-pyrrolo[2,3-c]pyridine (0.96 g, 2.84 mmol) in anhydrous THE (10 mL). To the resultant solution, at -35 C, was added dropwise a solution of lithium diisopropylamide (2.OM in heptane/THF/ethyl benzene, 2.84 mL, 5.68 mmol) and the mixture then stirred at -35 C for 45 min. Methyl iodide (1.06 mL, 17.04 mmol) was added to the reaction mixture dropwise. The resulting solution was allowed to reach room temperature and was stirred for 3h. The reaction was quenched by addition of a solution of IN HC1(5 mL); the solution was diluted with water (15 mL) and extracted with EtOAc (2x75 mL). The organic layer was dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash chromatography (Si-PPC, 0-100% DCM : cyclohexane). The residue was triturated with EtOAc (2 mL) and the precipitate was collected by filtration to give the title compound as a white solid (0.39 g, 39 %). LCMS (Method A): RT = 4.47min, [M+H]+ 351 (79Br), (8'Br) [00333] Example 46 1-Benzenesulfonyl-4-tributylstannanyl-lH-pyrrolo[2,3-c]pyridine n I ___ 3 N N
S
O~

[00334] 1-Benzenesulfonyl-4-bromo-lH-pyrrolo[2,3-c]pyridine (0.34 g, 1.0 mmol) was dissolved in THE (5 mL) and diethyl ether (5 mL) and the solution cooled to -78 C.
n-Butyllithium (0.756 M in hexanes, 1.2 mL, 5.0 mmol) was added over 5 min then the mixture was stirred for 15 min before addition of tributyltin chloride (0.39 g, 1.2 mmol) over min. The reaction mixture was stirred at -78 C for 1 hour then allowed to warm to room temperature and diluted with cyclohexane (50 mL). The reaction mixture was washed with water (3x30 mL) followed by brine, before the organic phase was dried (MgSO4) and evaporated. The crude residue was purified by chromatography on alumina using 30% EtOAc in cyclohexane. The material was further purified by flash chromatography (Si-PPC), eluting with 5-10% EtOAc in cyclohexane to yield the title product. 'H NMR (CDC13, 300 MHz): 6 9.23 (s, 1H), 8.36 (s, 1H), 7.91-8.00 (m, 2H), 7.71, d, J=1.lHz, 1H), 7.55-7.63 (m, 1H), 7.42-7.53 (m, 2H), 6.59 (d, J=1.lHz, 1H), 1.45-1.65 (m, 6H), 1.21-1.38 (m, 6H), 1.09-1.20 (m, 6H), 0.85 (t, J=7.5Hz, 9H).

[00335] Example 47 4-Bromo-7-methyl-lH-pyrrolo[2,3-c]pyridine Br N

H

[00336] 5-Bromo-2-methyl-3-nitropyridine (217 mg, 1 mmol) was dissolved in THE
(10 mL) and the solution was cooled to -50 C under argon. Vinylmagnesium bromide (3 mL, 1 M in THF) was added immediately in one portion, resulting in a bright orange solution. The orange solution was stirred at -40 C for 30 min and the reaction was quenched by the addition of NH4C1(10 mL of saturated. aqueous solution). The mixture was diluted with water and extracted with EtOAc (2x10 mL). The combined organic extracts were dried (MgSO4) and concentrated. The crude material was purified by chromatography on silica (Si-PPC) using EtOAc in cyclohexane (20-80%) as eluent to give the product as a pale yellow crystalline solid (63 mg, 30%). 'H NMR (CDC13) 8.23 (s, 1H), 7.41-7,45 (m, 1H), 6.62-6.65 (m, 1H), 2.73 (s, 3H) [00337] Example 48 4-Bromo-6-methyl-lH-pyrrolo[3,2-c]pyridine Br ~ \
N
H

[00338] A mixture of 6-methyl-lH-pyrrolo[3,2-c]pyridin-4-ol (J.Het.Chem., 1996, 303) (161 mg, 1.09 mmol) and phosphorus oxybromide (1.87 g, excess) was heated in a sealed tube at 120 C for 50 minutes. The reaction mixture was poured onto water (10 mL), basified with aqueous NaHCO3 to pH 8 and the organic product extracted into DCM. The organic layer was dried (phase separator), evaporated and the residue purified by column chromatography (Si-PCC, cyclohexane:ethyl acetate, gradient 100:0 to 70:30) to give 4-bromo-6-methyl-lH-pyrrolo[3,2-c]pyridine (20 mg, 12 %) as a white solid.. LCMS
RT = 2.00 min, [M+H]+ 211 [00339] Example 49 4-Bromo-5-methyl-lH-pyrrolo[2,3-c]pyridine Br Y Y
N~ N
H

[00340] To a stirred suspension of vinylmagnesium bromide (1 M in THF, 37.5 mL, 37.50 mmol) was added dropwise a solution of 3-bromo-2-methyl-5-nitropyridine (2.50 g, 11.52 mmol) in THF, under an atmosphere of nitrogen, at 0 C. The resulting solution was allowed to warm to RT and stirred for 1 day then quenched with saturated NH4C1(. The resulting mixture was partitioned between EtOAc and water, the organic layer separated, dried (MgSO4) and evaporated to give a red crude oil, which was purified by column chromatography (Si-PCC, 5 0-100 % EtOAc in cyclohexane) followed by reverse phase HPLC (Phenomenex Gemini 5u C18, 0.1 % formic acid in water on a gradient of methanol 5-75 %). The relevant HPLC fractions were loaded onto an Isolute SCX-2 cartridge, the cartridge was washed with MeOH and the desired product eluted with 2 M NH3 in MeOH to give the title compound as a pale yellow solid (22 mg, 1 %). LCMS (Method H):
RT 2.23 min, [M+H]+ 211.1 (79Br), 213.1 ("Br) [00341] Example 50 1-Benzenesulfonyl-4-bromo-2-methyl-lH-pyrrolo[2,3-c]pyridine Br I
N
N
O

[00342] Step 1: 1-Benzenesulfonyl-4-bromo-lH-pyrrolo[2,3-c]pyridine - o Br 7 N-S`
N

[00343] A 50mL round-bottomed flask was charged with a solution of 4-bromo-lH-pyrrolo[2,3-c]pyridine (0.7 g, 3.55 mmol) in anhydrous DCM (20 mL). NaOH (0.43 g, 10.7 mmol) and benzenetriethylammonium chloride (0.016 g, 0.07 mmol) were added and the reaction mixture was stirred for 3 h at room temperature. The reaction mixture was filtered through Celite, the Celite bed was washed with DCM and the resulting filtrate was concentrated in vacuo. The resultant solid residue was triturated with diethyl ether and the precipitate collected by filtration to give the title compound as an off-white solid (0.96 g, 80%). LCMS (Method A): RT = 4.29min, [M+H]+ 337 (79Br), 339 ("Br) [00344] Step 2: 1-Benzenesulfonyl-4-bromo-2-methyl-lH-pyrrolo[2,3-c]pyridine Br N
S"O

[00345] To a solution of 1-benzenesulfonyl-4-bromo-lH-pyrrolo[2,3-c]pyridine (0.96 g, 2.84 mmol) in anhydrous THF (10 mL), at -35 C, was added a solution of lithium diisopropylamide (2.OM in heptane/THF/ethyl benzene, 2.84 mL, 5.68 mmol) dropwise. The mixture was stirred at -35 C for 45 min and then methyl iodide (1.06 mL, 17.04 mmol) was added dropwise. The resulting solution was allowed to reach room temperature and was stirred for 3h. The reaction mixture was quenched by addition of an aqueous solution of IN
HC1(5 mL); the solution was diluted with water (15 mL) and extracted with EtOAc (2x75 mL). The organic extracts were combined, dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash chromatography (Si-PPC, DCM:cyclohexane, gradient 0:100 to 100:0). The residue was triturated in EtOAc (2 mL) and collected by filtration to give the title compound as a white solid (0.39 g, 39 %). LCMS (Method A): RT = 4.47min, [M+H]+ 351 (79Br), 353 ("Br) [00346] Example 51 1-Benzenesulfonyl-4-bromo-2-ethyl-lH-pyrrolo[2,3-c]pyridine Br N-S`
N

[00347] To a solution of 1-benzenesulfonyl-4-bromo-lH-pyrrolo[2,3-c]pyridine (0.63 g, 1.86 mmol) in anhydrous THF (10 mL), at -35 C, was added a solution of lithium diisopropylamide (2.OM in heptane/THF/ethyl benzene, 1.86 mL, 3.77 mmol) dropwise. The reaction mixture was stirred at -35 C for 30 min and then ethyl iodide (0.90 mL, 11.18 mmol) was added dropwise. The resulting solution was allowed to reach room temperature and was stirred for 4h. The reaction mixture was quenched by addition of a solution of IN HC1(5 mL); the solution was diluted with water (15 mL) and extracted with EtOAc (2x75 mL). The organic extracts were combined, washed with brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash chromatography (Si-PPC, EtOAc:
cyclohexane 0:100 to 70:30). The residue was triturated in EtOAc (2 mL) and collected by filtration to give the title compound as a white solid (0.27 g, 40 %). LCMS (Method H): RT =
4.65min, [M+H]+ 367 (79Br), 369 ("Br) [00348] Example 52 5-Bromo-8-methylimidazo[1,2-a]pyridine Br N-N

[00349] Step 1: 2-Bromo-5-methylpyridine 1-oxide N Br [003501 A mixture of 2-bromo-5-methylpyridine (2.0 g, 11.6 mmol) and 3-chloroperbenzoic acid (3.0 g, 14.8 mmol) in chloroform (7 mL) was stirred at 50 C for 3 hours, cooled down to room temperature and filtered. The filtrate was concentrated under reduced pressure to give a residue that was purified by flash chromatography (Si-PPC, MeOH:EtOAc, gradient 0:100 to 10:90) to give 2-Bromo-5-methylpyridine 1-oxide as a white solid (2.0 g, 91 %). 1H NMR (400 MHz, CHC13-d): 6 8.24 (s, 1 H); 7.52 (d, J = 8.3 Hz, 1 H); 6.93 (d, J = 8.33 Hz, 1 H); 2.29 (s, 3 H).
[00351] Step 2: (6-Bromo-3-methylpyridin-2-yl)-tert-butylamine N N Br H
[00352] To a solution of 2-bromo-5-methylpyridine 1-oxide (2.0 g, 10.6 mmol) in DCM (40 mL) and trifluorobenzene (17 mL) at 0 C were added tert-butylamine (8.0 mL, 76.7 mmol) andp-toluenesulfonic anhydride (11.4 g, 35.0 mmol) portion-wise.
The reaction mixture was stirred at 0 C for 1.5 hours and then filtered. The filtrate was concentrated to give a residue that was purified by flash chromatography (Si-PPC, Et20:pentane, gradient 0:100 to 100:0) to give (6-Bromo-3-methylpyridin-2-yl)-tert-butylamine as a colourless oil (500 mg, 19 %). 1H NMR (400 MHz, CHC13-d): 6 6.98 (d, J = 7.5 Hz, 1 H); 6.59 (d, J = 7.5 Hz, 1 H); 4.05 (s, 1 H); 1.96 (s, 3 H); 1.47 (s, 9 H).

[00353] Step 3: 6-Bromo-3-methylpyridin-2-ylamine H2N N Br [00354] A solution of (6-bromo-3-methylpyridin-2-yl)-tert-butylamine (500 mg, 2.06 mmol) in DCE (2 mL) and TFA (2 mL) was heated at 120 C for 10 min in a microwave reactor, and then concentrated under reduced pressure. The residue was taken up in MeOH
and loaded onto an Isolute SCX-2 cartridge (10 g). The cartridge was washed with MeOH
then the desired product eluted with 2 M NH3 in MeOH to give 6-Bromo-3-methylpyridin-2-ylamine as a white solid (359 mg, 93%). 1H NMR (400 MHz, CHC13-d): 6 7.11 (d, J = 7.5 Hz, 1 H); 6.77 (d, J = 7.5 Hz, 1 H); 4.50 (s, 2 H); 2.07 (s, 3 H).
[00355] Step 4: A mixture of 6-bromo-3-methylpyridin-2-ylamine (359 mg, 1.92 mmol) and chloroacetaldehyde (1 mL, 50 wt. % in water) in IMS (4 mL) was stirred at 100 C
in a sealed tube for 1.5 hours, then cooled to room temperature and loaded onto an Isolute SCX-2 cartridge (10 g). The cartridge was washed with MeOH then eluted with 2 M NH3 in MeOH to give 5-Bromo-8-methylimidazo[1,2-a]pyridine as a beige solid (387 mg, 95%). 1H
NMR (400 MHz, CHC13-d): 6 7.79 (d, J = 1.3 Hz, 1 H); 7.69 (d, J = 1.3 Hz, 1 H); 6.96 (d, J
= 7.3 Hz, 1 H); 6.91 (dq, J = 7.3, 1.1 Hz, 1 H); 2.61 (d, J = 1.1 Hz, 3 H).
[00356] Example 53 5-Bromo-6-fluoroimidazo[1,2-a]pyridine Br F / N >

[00357] Step 1: 2-Bromo-3-fluoropyridine 1-oxide \ F

N Br [00358] A mixture of 2-bromo-3-fluoropyridine (1.0 g, 5.7 mmol) and 3-chloroperbenzoic acid (1.5 g, 7.4 mmol) in chloroform (3.5 mL) was stirred at 50 C for 18 hours, cooled down to room temperature and filtered. The filtrate was concentrated under reduced pressure to give a residue that was purified by flash chromatography (Si-PPC, MeOH:EtOAc, gradient 0:100 to 5:95) to give 2-Bromo-3-fluoropyridine 1-oxide as a white solid (878 mg, 80 %). 'H NMR (400 MHz, CHC13-d): 6 8.25 (dt, J = 6.6, 1.3 Hz, 1 H); 7.25-7.17 (m, 1 H); 7.06 (ddd, J = 8.7, 6.6, 1.3 Hz, 1 H).
[00359] Step 2: (6-Bromo-5-fluoropyridin-2-yl)-tert-butylamine F

N Br H

[00360] To a solution of 2-bromo-3-fluoropyridine 1-oxide (511 mg, 2.7 mmol) in DCM (10 mL) and trifluorobenzene (4 mL) at 50 C were added tert-butylamine (2.5 mL, 23.9 mmol) and p-toluenesulfonic anhydride (3.7 g, 11.4 mmol) portion-wise.
The reaction mixture was stirred at 50 C for 2 hours and then filtered. The filtrate was concentrated to give a residue that was purified by flash chromatography (Si-PPC, Et20:pentane, gradient 0:100 to 5:95) to give (6-Bromo-5-fluoropyridin-2-yl)-tert-butylamine as a colourless oil (30 mg, 5 %). 'H NMR (400 MHz, CHC13-d): 6 7.13 (dd, J = 8.8, 7.3 Hz, 1 H); 6.29 (dd, J
= 8.8, 2.5 Hz, 1 H); 4.49 (s, 1 H); 1.40 (s, 9 H).
[00361] Step 3: 6-Bromo-5-fluoropyridin-2-ylamine H2N N Br [00362] A solution of (6-bromo-5-fluoropyridin-2-yl)-tert-butylamine (46 mg, 0.19 mmol) in DCE (2 mL) and TFA (2 mL) was heated at 120 C for 10 min in a microwave reactor, and then concentrated under reduced pressure. The residue was taken up in MeOH
and loaded onto an Isolute SCX-2 cartridge (5 g). The cartridge was washed with MeOH
then the desired product eluted with 2 M NH3 in MeOH to give 6-Bromo-5-fluoropyridin-2-ylamine as an off-white solid (25 mg, 71%). 'H NMR (400 MHz, CHC13-d): 6 7.21 (dd, J =
8.7, 7.2 Hz, 1 H); 6.39 (dd, J = 8.7, 2.7 Hz, 1 H); 4.89-3.75 (s, 2 H).
[00363] Step 4: A mixture of 6-bromo-5-fluoropyridin-2-ylamine (25 mg, 0.13 mmol) and chloroacetaldehyde (0.1 mL, 50 wt. % in water) in IMS (2 mL) was stirred at 100 C in a sealed tube for 18 hours, then cooled to room temperature and loaded onto an Isolute SCX-2 cartridge (5 g). The desired product was washed with MeOH then eluted with 2 M NH3 in MeOH to give 5-Bromo-6-fluoroimidazo[1,2-a]pyridine as a yellow oil (25 mg, 89%). 1H
NMR (400 MHz, CHC13-d): 6 7.84 (s, 1 H); 7.76 (m, 1 H); 7.61 (ddd, J = 9.73, 4.67, 0.71 Hz, 1 H); 7.21-7.16 (m, 1 H).
[00364] Example 54 5-Bromo-7-methyl-imidazo[1,2-a]pyridine Br N

[00365] A mixture of 6-bromo-4-methyl-pyridin-2-ylamine (374 mg, 2.0 mmol) and chloroacetaldehyde (1 mL, 50 wt. % in water) in IMS (4 mL) was stirred at 100 C in a sealed tube for 18 hours, then cooled to room temperature and loaded onto an Isolute cartridge (10 g). The cartridge was washed with MeOH then the product was eluted with 2 M
NH3 in MeOH. After the solvents were removed, the residue was purified by flash chromatography (Si-PPC, MeOH:DCM, gradient 0:100 to 5:95) to give 5-Bromo-7-methyl-imidazo[1,2-a]pyridine as an orange solid (340 mg, 82%). IH NMR (400 MHz, CHC13-d): 6 7.72-7.70 (m, 1 H); 7.63-7.62 (m, 1 H); 7.38-7.37 (m, 1 H); 6.92-6.90 (m, 1 H); 2.40 (m, 3 H).
[00366] Example 55 5-Bromo-2-methylimidazo[1,2-a]pyridine Br [00367] A mixture of 6-bromopyridin-2-ylamine (1.0 g, 5.6 mmol) and 1-chloropropan-2-one (0.5 mL, 6.3 mmol) in IMS (4 mL) was stirred at reflux for 36 hours, then cooled to room temperature and loaded onto an Isolute SCX-2 cartridge (20 g). The cartridge was washed with MeOH then the desired product eluted with 2 M NH3 in MeOH.
After the solvents were removed, the residue was purified by flash chromatography (Si-PPC, McOH:Et2O, gradient 0:100 to 10:100) to give 5-Bromo-2-methylimidazo[1,2-a]pyridine as a yellow oil (547 mg, 45%). LCMS (Method H): RT = 0.31 min and 2.04 min, [M+H]+
211(79Br) and 213 (81 Br) [00368] Example 56 5-bromo-[1,2,4]triazolo[4,3-a]pyridine Br N
[00369] Step 1: (6-Bromopyridin-2-yl)hydrazine H2N,N N Br H
[00370] A mixture of 2,6-dibromopyridine (1.44 g, 6.1 mmol) and hydrazine (1.65 mL, 32.2 mmol) in butanol (100 mL) was stirred at reflux for 18 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was partitioned between an aqueous saturated solution of sodium bicarbonate and EtOAc. The organic layer was separated and washed with brine, dried over Na2SO4, filtered and concentrated to give (6-Bromopyridin-2-yl)hydrazine as a white solid (1.0 g, 92%). IH NMR
(400 MHz, CHC13-d): 6 7.36-7.28 (m, 1 H); 6.82 (d, J = 7.70 Hz, 1 H); 6.67 (d, J = 7.7 Hz, 1 H); 5.97 (s, 1 H); 3.80 (s, 2 H).
[00371] Step 2: A solution of (6-bromopyridin-2-yl)hydrazine (500 mg, 2.66 mmol) in diethoxymethyl acetate (2.5 mL) was stirred at room temperature for 18 hours.
The reaction mixture was diluted with pentane and filtered. The precipitate was washed with pentane and dried at 50 C under vacuum for 1 hour to give 5-bromo-[ 1,2,4]triazolo[4,3-a]pyridine as a beige solid (410 mg, 78%). IH NMR (400 MHz, CHC13-d): 6 8.98 (s, 1 H); 7.83 (dt, J = 9.2, 0.9 Hz, 1 H); 7.22 (dd, J = 9.2, 7.0 Hz, 1 H); 7.09 (dd, J = 7.0, 0.9 Hz, 1 H).
[00372] Example 57 8-Benzyloxy-5-bromo-imidazo[1,2-a]pyridine Br N'\
N
OBn [00373] Step 1: 6-Bromo-2-nitropyridin-3-ol HO n O2N N Br [00374] To a suspension of 6-bromopyridin-3-ol (2.5 g, 14.4 mmol) in acetic acid (20 mL) at 0 C was added fuming nitric acid (0.9 mL, 22.4 mmol). The reaction mixture was stirred at room temperature for 1hour and then at 60 C for 1 hour. The reaction mixture was colled to 0 C and l OM aqueous hydroxide was added dropwise until pH 4-5 (ca 25 mL). The resulting mixture was diluted with water and partially concentrated under reduced pressure.
The residue was extracted twice with EtOAc. The organic fractions were combined and washed with water and brine, dried over Na2SO4, filtered and concentrated. The residue was azeotroped with toluene to give 6-Bromo-2-nitropyridin-3-ol as an orange solid (2.2 g, 71 %).
'H NMR (400 MHz, DMSO-d6 ): 6 11.92 (s, 1 H); 7.86-7.83 (d, J = 8.6 Hz, 1 H);
7.61 (d, J = 8.6 Hz, 1 H).
[00375] Step 2: 3-Benzyloxy-6-bromo-2-nitropyridine BnO

O2N N Br [00376] To a solution of 6-bromo-2-nitropyridin-3-ol (1.0 g, 4.6 mmol), in anhydrous DMF (15 mL) at 0 C was added 60% sodium hydride in mineral oil (200 mg, 5.0 mmol). The reaction mixture was stirred at 0 C for 5 min and at room temperature for 15 min. Benzyl bromide (0.6 mL, 5.0 mmol) was added dropwise and the resulting mixture was stirred at 60 C for 1 hour, cooled to room temperature, diluted with water and extracted with EtOAc.
The organic layer was separated and washed with water and brine, dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (Si-PPC, Et20:pentane, gradient 0:100 to 100:0) to give 3-Benzyloxy-6-bromo-2-nitropyridine as a yellow solid (956 mg, 67%). IH NMR (400 MHz, CHC13-d): 6 7.60 (d, J = 8.6 Hz, 1 H);
7.41-7.35 (m, 6 H); 5.25 (s, 2 H).
[00377] Step 3: 3-Benzyloxy-6-bromopyridin-2-ylamine Bn0 nE
H2N N Br [00378] A mixture of 3-benzyloxy-6-bromo-2-nitropyridine (1.6 g, 5.2 mmol) and iron powder (2.9 g, 51.8 mmol) in acetic acid (25 mL) and IMS (25 mL) was stirred at reflux for 1 hour, then cooled to room temperature and filtered though a pad of celite. The filtrate was concentrated under reduced pressure to give a residue that was partitioned between an aqueous saturated solution of sodium bicarbonate and EtOAc. The organic layer was separated and washed with water and brine, dried over Na2SO4, filtered and concentrated.
The residue was purified by flash chromatography (Si-PPC, EtOAc:cyclohexane, gradient 0:100 to 40:60) to give 3-Benzyloxy-6-bromopyridin-2-ylamine as a pale yellow solid (1.0 g, 71%). IH NMR (400 MHz, CHC13-d): 6 7.41-7.34 (m, 5 H); 6.82 (d, J = 8.1 Hz, 1 H); 6.71 (d, J = 8.1 Hz, 1 H); 5.04 (s, 2 H); 4.80 (s, 2 H).
[00379] Step 4: A mixture of 3-benzyloxy-6-bromopyridin-2-ylamine (1.0 g, 3.6 mmol) and chloroacetaldehyde (1.2 mL, 50 wt. % in water) in IMS (12 mL) was stirred at reflux for 1 hour, then concentrated under reduced pressure. The residue was partitioned between an aqueous saturated solution of sodium bicarbonate and EtOAc. The organic layer was separated and washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (Si-PPC, McOH:Et2O, gradient 0:100 to 1:99) to give 8-Benzyloxy-5-bromo-imidazo[1,2-a]pyridine as an beige solid (960 mg, 88%).
LCMS (Method H) RT 3.08 min; [M+H]+ 303 (79Br) and 305 ("Br) [00380] Example 58 3-Fluoro-2-nitrophenylamine F
[00381] Step 1: 3-Fluoro-2-nitro-N-(triphenylphosphoranylidene)benzenamine PhPh NPPh F
[00382] To a solution of 1-azido-3-fluoro-2-nitrobenzene (500 mg, 2.75 mmol) in THE
(4 mL) and water (1 mL) was added triphenylphosphine (720 mg, 2.75 mmol). The reaction mixture was stirred at room temperature for 45 min then partitioned between water and EtOAc. The organic layer was separated and washed with brine, dried over Na2SO4, filtered and concentrated. The residue was subjected to flash chromatography (Si-PCC, Et20) to give the desired product as a yellow solid (844 mg, 73%). LCMS (Method A): RT 4.36 min;
[M+H]+ 417 [00383] Step 2: A 2-5 mL microwave vial equipped with a magnetic follower was charged with 3-fluoro-2-nitro-N-(triphenylphosphoranylidene)benzenamine (585 mg, 1.4 mmol), water (3 mL) and TFA (0.1 mL). The reaction mixture was irradiated at 160 C for 15 min and then partitioned between water and EtOAc. The organic layer was separated and washed with an saturated aqueous solution of sodium bicarbonate and brine, dried over Na2SO4, filtered and concentrated. The residue was subjected to flash chromatography (Si-PCC, 0-100% Et20 in pentane) to give 3-Fluoro-2-nitrophenylamine as an orange solid (218 mg, 100%). IH NMR (CDC13, 400 MHz): 6 7.22 (ddd, J = 8.2, 8.2, 5.5 Hz, 1 H);
6.57 (ddd, J
= 8.5, 1.4, 1.4 Hz, 1 H); 6.48 (ddd, J = 11.3, 8.2, 1.4 Hz, 1 H.
[00384] Example 59 2-Methylaminobenzoimidazole-l-carboxylic acid tert-butyl ester O
OAN /
N N
H

[00385] Di-tert-butyl dicarbonate (951 mg, 4.36 mmol) was added to a suspension of (1H-benzoimidazol-2-yl)methylamine (583 mg, 3.96 mmol) in water (5 mL) and the resulting reaction mixture was stirred at 35 C for 2 h. The mixture was diluted with water and extracted with DCM (2 x 15 mL) and EtOAc (2 x 15 mL). The combined organic layers were dried over sodium sulfate, filtered and the solvents reduced in vacuo. The crude residue was purified by column chromatography (Si-PCC, EtOAc:cyclohexane, gradient 0:100 to 30:70) to afford the title compound as a pale-brown solid (720 mg, 74%). 'H NMR (400 MHz, CDC13): 6 7.55 (1 H, d, J = 8.04 Hz), 7.38 (1 H, d, J = 7.85 Hz), 7.16 (2 H, td, J = 7.65, 1.27 Hz), 6.99 (1 H, td, J = 7.75, 1.20 Hz), 3.14 (3 H, d, J = 4.99 Hz), 1.67 (9 H, s) [00386] Formula I(i) thiazole intermediates wherein (i) X1 is N and X2 is S
[00387] Example 65a 4-(5-chloro-2-((3-morpholinoazetidin-1-yl)methyl)thiazolo[5,4-d]pyrimidin-7-yl)morpholine (0) N
N I N" CI
S N"CI
P
N>
OJ
[00388] A solution of 5-chloro-7-morpholin-4-yl-thiazolo[5,4-d]pyrimidine-2-carbaldehyde (3.0 g, 10.54 mmol) and 4-azetidin-3-ylmorpholine (1.8 g, 12.66 mmol) in DCE
(200 mL) was stirred at ambient temperature for 2 h. Sodium triacetoxyborohydride (3.5 g, 16.5 mmol) was added and the mixture stirred for 18 h, then loaded onto an Isolute SCX-2 cartridge (50 g). The cartridge was then washed with MeOH and the desired product was subsequently eluted using 2 M NH3 in MeOH. The eluent was collected and concentrated in vacuo. The resultant residue was purified by flash chromatography (Si-PPC, DCM: MeOH
100:0 to 99:1 to 98:2 to 95:5) to afford 4-(5-chloro-2-((3-morpholinoazetidin-l-yl)methyl)thiazolo[5,4-d]pyrimidin-7-yl)morpholine as a cream solid (2.66 g, 61 %). LCMS
(Method C): RT = 2.68 min, [M+H]+ 411.3 [00389] Example 65b 2-methyl-2-(4-((7-morpholino-5-(tributylstannyl)thiazolo[5,4-d]pyrimidin-2-yl)methyl)piperazin- l -yl)propanamide CO) N
--/N I N Y
N S N~Sn N

O

[00390] A mixture of 2-[4-(5-chloro-7-morpholin-4-yl-thiazolo[5,4-d]pyrimidin-ylmethyl)-piperazin-1-yl]-isobutyramide (1.0 g, 2.2 mmol), hexabutylditin (1.4 mL, 2.7 mmol), and PdC12 {PtBuz(Ph p-Nme2)}2 (161 mg, 0.2 mmol) in dioxane (10 mL) was degassed and then subjected to microwave irradiation at 150 C for 30 min. The reaction mixture was diluted with MeOH and loaded onto an Isolute SCX-2 cartridge (25 g). The cartridge was then washed with MeOH and the desired product was subsequently eluted using 2 M NH3 in MeOH. Appropriate fractions were combined and concentrated to give a residue which was subjected to flash chromatography (Si-PPC, MeOH:DCM, gradient 0:100 to 10:90). Appropriate fractions were combined and concentrated to give 2-methyl-2-(4-((7-morpholino-5 -(tributylstannyl)thiazolo [5,4-d]pyrimidin-2-yl)methyl)piperazin-l -yl)propanamide as a yellow oil (1.1 g, 67 %)._LCMS (Method C) RT= 4.83 min; [M
+ H]+
694.1 (116Sn) 696.1 (118Sn) [00391] Example 65c 5-Chloro-7-morpholin-4-yl-thiazolo[5,4-d]pyrimidine-2-carbaldehyde CO) N
N N
<I
H S \NCI

[00392] 5-Chloro-7-morpholin-4-yl-thiazolo[5,4-d]pyrimidine (5.1g, 0.02mol) was suspended in THE (200mL) and the resulting solution was cooled to -78 C
whereupon the starting material precipitated from solution. LiHMDS (1M in THF, 25mL, 1.25equiv) was added dropwise to the stirred suspension. After addition was complete, the mixture was stirred for 30min, then DMF (9mL, 6 equiv) was added and the resulting solution was stirred for 15min at -78 C and then warmed to 0 C and stirred for 15 min. The solution was re-cooled to -78 C and then cannulated (via a wide-bore double-ended needle) into a stirred solution of -0.5M HC1(600mL). The product precipitated from solution as a pale yellow powder. This was isolated by filtration through a sintered glass funnel, washed with water and dried in vacuo overnight to give 5g of 5-Chloro-7-morpholin-4-yl-thiazolo[5,4-d]pyrimidine-2-carbaldehyde (87.7%). 1H NMR (400 MHz, CDC13): 6 3.83-3.88 (m, 4 H), 4.06-4.15 (m, 2 H), 4.72 (m, 2 H) and 9.95 (s, 1 H).
[00393] Example 65d 5-Chloro-2-[3-(1,1-Dioxo-l-thiomorpholin-4-yl)azetidin-l-ylmethyl]-7-morpholin-4-ylthiazolo [5,4-d]pyrimidine N
CO) N
, I N
N S NCI
P
N>
0=SJ
i O

[00394] A mixture of 5-chloro-7-morpholin-4-yl-thiazolo[5,4-d]pyrimidine-2-carbaldehyde (400 mg, 1.40 mmol), 4-azetidin-3-ylthiomorpholine- 1, 1 -dioxide (321 mg, 1.69 mmol) and 4A powdered molecular sieves (600 mg) in DCE (20 mL) was stirred at room temperature for 4 h before the addition of sodium triacetoxyborohydride (595 mg, 2.80 mmol). The reaction mixture was stirred for 65 h then filtered through celite, washing with DCM. The organic phase was washed with brine (x 1) and concentrated in vacuo affording 5-Chloro-2-[3-(1,1-Dioxo-l -thiomorpholin-4-yl)azetidin-1-ylmethyl]-7-morpholin-ylthiazolo[5,4-d]pyrimidine as an orange powder (572 mg, 89%). LCMS (Method H): RT
2.43 min [M+H]+ 459.2 [00395] Example 65e 5-Chloro-7-morpholin-4-yl-2-[3-(tetrahydropyran-4-yl)azetidin-1-ylmethyl] thiazolo[5,4-d]pyrimidine Co) iN I - N
N S N CI

[00396] A mixture of 5-chloro-7-morpholin-4-yl-thiazolo[5,4-d]pyrimidine-2-carbaldehyde (650 mg, 2.28 mmol), 3-(tetrahydropyran-4-yl)azetidine (313 mg, 2.22 mmol) and 4A powdered molecular sieves (1.2 g) in DCE (40 mL) was stirred at room temperature for 4 h before the addition of sodium triacetoxyborohydride (941 mg, 4.44 mmol). The reaction mixture was stirred for 24 h then filtered through celite, washing with DCM. The organic phase was washed with brine (x 1) and concentrated in vacuo. The residue was purified by column chromatography (Si-PCC, MeOH:EtOAc, 0-20%) affording 5-Chloro-7-morpholin-4-yl-2-[3-(tetrahydropyran-4-yl)azetidin-1-ylmethyl] thiazolo[5,4-d]pyrimidine as an orange powder (630 mg, 67%). LCMS (Method A): RT 2.54 min [M+H]+ 410.2 [00397] Example 65f 2-[1-(5-Chloro-7-morpholin-4-ylthiazolo[5,4-d]pyrimidin-2-ylmethyl)piperidin-4-yl]propan-2-ol (0) N
N ~N
N,S I NCI
HO

[00398] A mixture of 5-chloro-7-morpholin-4-yl-thiazolo[5,4-d]pyrimidine-2-carbaldehyde (5.11 g, 17.9 mmol), 2-piperidin-4-ylpropan-2-ol (3.08 g, 21.5 mmol) and 4A
powdered molecular sieves (9 g) in DCE (85 mL) was stirred at room temperature for 1.5 h before the addition of sodium triacetoxyborohydride (7.61 g, 35.9 mmol). The reaction mixture was stirred for 90 h then filtered through celite, washing the celite bed with DCM.
The organic phase was washed with brine and concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, EtOAc:DCM, 0-100%) affording 2-[1-(5-Chloro-7-morpholin-4-ylthiazolo[5,4-d]pyrimidin-2-ylmethyl)piperidin-4-yl]propan-2-ol as an orange solid (4.96 g, 67%). LCMS (Method A): RT 2.77 min [M+H]+ 412.2 [00399] Example 65g 5-Chloro-2-((E)-2-methoxyvinyl)-7-morpholin-4-yl-thiazolo[5,4-d]pyrimidine (0) N
O~N I N
S NICI

[00400] To a stirred suspension of (methoxymethyl)triphenylphosphonium chloride (3.37 g, 9.83 mmol) in dry THE (40 mL) was added dropwise a 1 M solution of LiHMDS in THE (9.8 mL, 9.8 mmol) under an atmosphere of nitrogen, at 0 C. After 15 min the solution was cooled to -78 C and a suspension of 5-chloro-7-morpholin-4-yl-thiazolo[5,4-d]pyrimidine-2-carbaldehyde (2.0 g, 7.02 mmol) in dry THE (40 mL) was added.
The mixture was allowed to warm to RT after 5 min, stirred for a further 1.5 h then quenched with H20. The resulting precipitate was filtered, washed with EtOAc and dried under vacuum to give 5-chloro-2-((E)-2-methoxyvinyl)-7-morpholin-4-yl-thiazolo[5,4-d]pyrimidine (730 mg, 33 %) as a pale yellow solid. IH NMR (CDC13, 300 MHz): 6 7.48 (d, J = 12.8 Hz, 1 H), 6.01 (d, J = 12.8 Hz, 1 H), 4.44-4.24 (br s, 4 H), 3.83 (m, 4 H), 3.79 (s, 3 H).
[00401] Example 65h 2-{1-[2-(5-Chloro-7-morpholin-4-yl-thiazolo[5,4-d]pyrimidin-2-yl)ethyl]piperidin-4-yl}propan-2-ol (0) N

HO N
S NCI
[00402] 5-Chloro-2-((E)-2-methoxyvinyl)-7-morpholin-4-yl-thiazolo[5,4-d]pyrimidine (730 mg, 2.33 mmol) was stirred in 37 wt. % HC1(aq) / THE (4:8 mL) at 50 C
for 2 h. The solution was allowed to cool, partitioned between EtOAc and saturated NaHCO3 (, the organic layer separated and washed with brine. The organic layer was dried (Na2SO4) and concentrated in vacuo to give a residue (1.4 g), which was taken up in DCE (30 mL). 2-Piperidin-4-ylpropan-2-ol (300 mg, 2.10 mmol) and powdered 4A molecular sieves were then added. The reaction mixture was stirred at room temperature for 5 h, sodium triacetoxyborohydride (900 mg, 4.25 mmol) was added and the resulting mixture stirred for a further 18 h. The reaction mixture was loaded onto an Isolute SCX-2 cartridge, washed with MeOH then the desired product eluted with 2 M NH3 in MeOH. The resulting residue was purified by column chromatography (Si-PCC, 0-10 % MeOH in DCM) to give the title compound as an orange solid (120 mg, 12 % over 2 steps). LCMS (Method H): RT =
2.55 min, [M+H]+ 426.5 [00403] Example 65i 2-(5-Chloro-7-morpholin-4-yl-thiazolo[5,4-d]pyrimidin-2-yl)l-[4-(l -hydroxy- l -methylethyl)piperidin-l-yl]ethanone (0) HO O N
N
/
S
N CI

[00404] To a stirred solution of 5-chloro-2-methyl-7-morpholin-4-yl-thiazolo[5,4-d]pyrimidine (500 mg, 1.85 mmol) in THE (30 mL) was added dropwise a 1 M
solution of LiHMDS in THE (2.80 mL, 2.80 mmol) under an atmosphere of nitrogen, at -78 C.
After 2 h, the solution was poured onto a bed of CO2(s) and the resulting mixture allowed to warm to RT. The mixture was partitioned between DCM and 0.1 M HC1(, the organic layer separated, dried (phase separator) and concentrated in vacuo. The resultant crude was purified by flash chromatography (Si-PCC, 0-5 % MeOH in DCM) to give a residue (200 mg), a portion of which (58 mg) was taken up in DMF (2 mL) and 2-piperidin-4-ylpropan-2-ol (32 mg, 0.22 mmol), HATU (84 mg, 0.22 mmol) and DIPEA (0.10 mL, 0.55 mmol) were added.
The reaction mixture was stirred at RT for 18 h, the mixture was partitioned between EtOAc and water, the organic layer dried (MgSO4) and evaporated to give a dark orange oil.

Purification by column chromatography (Si-PCC, 0-10 % MeOH in DCM) gave the title compound (40 mg, 49 %) as a dark orange solid. LCMS (Method H): RT 3.96 min, [M+H]+
440.4 [00405] Example 65i Nl-(7-morpholino-2-((3-morpholinoazetidin-l-yl)methyl)thiazolo[5,4-d]pyrimidin-5-yl)benzene-1,2-diamine CO) N
P H S N N

C N>
OJ

[00406] A mixture of 5-chloro-7-morpholin-4-yl-2-(3-morpholin-4-ylazetidin-l-ylmethyl)-thiazolo[5,4-d]pyrimidine (500 mg, 1.22 mmol), 1,2-diaminobenzene (300 mg, 2.77 mmol), palladium acetate (80 mg, 0.36 mmol), BINAP (110 mg, 0.18 mmol) and cesium carbonate (600 mg, 1.84 mmol) in 1,4-dioxane (5 mL) ) was purged with argon gas then subjected to microwave irradiation at 150 C for 30 min. The reaction mixture was loaded onto an Isolute SCX-2 cartridge (25 g), washed with MeOH before the desired product was eluted using 2 M NH3 in MeOH. The product was collected and concentrated in vacuo. The resultant residue was purified by flash chromatography (Si-PPC, DCM: 2 M NH3 in MeOH
100:0 to 99:1 to 98:2 to 97:3) to afford Nl-(7-morpholino-2-((3-morpholinoazetidin-l-yl)methyl)thiazolo[5,4-d]pyrimidin-5-yl)benzene-1,2-diamine as a white solid (283 mg, 48 %). LCMS (Method H): RT = 2.40 min, [M+H]+ 483.
[00407] Example 65k 2-[1-(7-Morpholin-4-yl-5-(tributylstannanyl)thiazolo[5,4-d]pyrimidin-2-ylmethyl)piperidin-4-yl]propan-2-ol (0) <N ::I -N

S NSnv~
OH

[00408] A mixture of 2-[1-(5-chloro-7-morpholin-4-ylthiazolo[5,4-d]pyrimidin-2-ylmethyl)piperidin-4-yl]propan-2-ol (500 mg, 1.21 mmol), hexabutylditin (910 L, 1.81 mmol), and PdC12 {PtBu2(Ph p-Nmez)}2 (85 mg, 0.116 mmol) in 1,4-dioxane (5 mL) was purged with argon gas and then subjected to microwave irradiation at 150 C
for 30 min. The reaction mixture was diluted with MeOH and loaded onto an Isolute SCX -2 cartridge (10 g). The cartridge was then washed with MeOH and the desired product was subsequently eluted using 2 M NH3 in MeOH. The product was collected and concentrated in vacuo. The resultant residue was purified by flash chromatography (Si-PPC, DCM: MeOH;
100:0 to 98:2 to 95:5) to afford to afford the title compound as a yellow solid (681 mg, 84 %). 1H NMR
(CDC13, 400MHz) 6 4.31 (m, 4 H); 3.82 (m, 6 H); 3.05 (m, 2 H); 2.16 (m, 2 H);
1.74 (m, 2 H); 1.65-1.54 (m, 7 H); 1.43-1.24 (m, 9 H); 1.19 (s, 6 H); 1.13 (m, 6 H); 0.88 (t, J = 7.3 Hz, 9 H) [00409] Example 651 4-(5-chloro-2-((4-(oxetan-3-yl)piperidin-l-yl)methyl)thiazolo [5,4-d]pyrimidin-7-yl)morpholine (0) N DI N
N/ S NiCI
O

[00410] A solution of 5-chloro-7-morpholin-4-ylthiazolo[5,4-d]pyrimidine-2-carbaldehyde (1.0 g, 3.52 mmol), 4-oxetan-3-ylpiperidine (536 mg, 4.23 mmol) and molecular sieves (4 A, powdered, 6.56 g) in DCE (30 mL) was stirred at ambient temperature for 4 h. Sodium triacetoxyborohydride (1.49 g, 7.05 mmol) was added and the mixture stirred for 6 h, then filtered through a pad of Celite and the filtrate was concentrated in vacuo. The resultant residue was purified by flash chromatography (Si-PPC, DCM: MeOH;
gradient from 100:0 to 97:3) to afford the title compound as a cream solid (334 mg, 41 %). LCMS
(Method A): RT = 2.48 min, M+H+ = 410 [00411] Example 65m 2-(5-Chloro-7-morpholin-4-ylthiazolo[5,4-d]pyrimidin-2-yl)-l-[4-(2-hydroxy-1,1-dimethylethyl)piperazin-l-yl]ethanone (0) ~N~/N~( ~~N
HO ~/ II I
S N CI

[00412] A mixture of (5-chloro-7-morpholin-4-ylthiazolo[5,4-d]pyrimidin-2-yl)acetic acid (80 mg, 0.25 mmol), 2-methyl-2-piperazin-l-ylpropan-l-ol (48 mg, 0.31 mmol), HATU
(116 mg, 0.31 mmol) and DIPEA (133 L, 0.76 mmol) in DMF (3 mL) was stirred at r.t. for 65 h then loaded onto an Isolute SCX-2 cartridge which was washed with MeOH
and the product eluted with 2M NH3/MeOH/DCM. The resulting residue was purified by column chromatography (Si-PCC, MeOH:DCM, 0-10%) affording the title compound as an orange solid (65 mg, 56%). LCMS (method H): RT 2.02 min [M+H]+ 455.3 [00413] Example 65n 5-(2-Ethylbenzoimidazol-1-yl)-7-morpholin-4-ylthiazolo[5,4-d]pyrimidine (0) /N I N
\i l S N'\N \
e_N

[00414] A mixture of 5-chloro-7-morpholin-4-ylthiazolo[5,4-d]pyrimidine (3.0 g, 11.7 mmol), 2-ethylbenzimidazole (1.88 g, 12.9 mmol), tris(dibenzylideneacetone)dipalladium (534 mg, 0.60 mmol), XPhos (1.11 g, 2.34 mmol) and Cs2CO3 (7.62 g, 23.4 mmol) in dioxane (60 mL) was purged with argon then heated at 120 C for 16 h in a sealed tube. The reaction mixture was filtered through Celite , and the filtrated partitioned between EtOAc and H20. The organic phase was washed with brine, then dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, EtOAc:DCM, 0-90%) followed by recrystallisation from 1PrOAc affording the title compound (3.17 g, 74%). LCMS (method A): RT 2.74 min [M+H]+ 367.1 [00415] Example 65o 5-(2-Ethylbenzoimidazol-1-yl)-2-iodo-7-morpholin-4-ylthiazolo [5,4-d]pyrimidine CO) I ~N 1 N
/l S Ni\N \

e~N

[00416] A solution of 5-(2-ethylbenzoimidazol-1-yl)-7-morpholin-4-ylthiazolo[5,4-d]pyrimidine (1.92 g, 5.23 mmol) in THE (60 mL) was cooled to -40 C before the drop wise addition of LiHMDS (6.3 mL, 6.28 mmol, 1 M solution in THF). The resulting mixture was warmed to -5 C over 30 min then mixture was cooled back to -30 C before the addition of a solution of 1-chloro-2-iodoethane (2.0 g, 10.47 mmol) in THE (6 mL). The resulting mixture was allowed to warm to 0 C then quenched with NH4C1 and extracted with EtOAc.
The combined organics were washed with brine then dried (Na2SO4) and concentrated in vacuo.

The resulting residue was purified by column chromatography (Si-PCC, EtOAc:DCM, 50-80%) followed by recrystallisation from 1PrOAc affording the title compound as a yellow solid (1.58 g, 62%). LCMS (method A): RT 3.50 min [M+H]+ 493.0 [00417] Example 65p (5-Chloro-7-morpholin-4-ylthiazolo[5,4-d]pyrimidin-2-yl)-[4-(1-hydroxy- l -methylethyl)piperidin- l -yl]methanone C~~

O <N N
S N CI
OH

[00418] A mixture of 5-chloro-7-morpholin-4-ylthiazolo[5,4-d]pyrimidine-2-carboxylic acid (200 mg, 0.67 mmol), 2-piperidin-4-ylpropan-2-ol (105 mg, 0.73 mmol), HATU (278 mg, 0.73 mmol) and DIPEA (130 L, 0.75 mmol) in DCM (7 mL) was allowed to stir at r.t. for 18 h. The reaction mixture was concentrated in vacuo and the resulting residue purified by column chromatography (Si-PCC, MeOH:DCM, 0-2%) affording the title compound as a white solid. 1H NMR (CDC13, 400 MHz): 6 5.15 (1 H, d, J = 13.36 Hz), 4.79 (1 H, d, J = 13.25 Hz), 4.35 (4 H, brd s), 3.85 (4 H, t, J = 4.75 Hz), 3.16-3.13 (1 H, m), 1.92 (2 H, t, J = 15.39 Hz), 1.75-1.60 (1 H, m), 1.49-1.38 (4 H, m), 1.22 (6 H, d, J = 6.97 Hz).
[00419] Example 65q (5-Chloro-7-morpholin-4-ylthiazolo[5,4-d]pyrimidin-2-yl)-(2,2-dimethyl-4-oxetan-3-ylpiperazin-1-yl)methanone Co) 0 (N N
r rN S NCI
N> J

[00420] A mixture of 5-chloro-7-morpholin-4-ylthiazolo[5,4-d]pyrimidine-2-carboxylic acid (100 mg, 0.33 mmol), 3,3-dimethyl-l-oxetan-3-ylpiperazine (62 mg, 0.36 mmol), HATU (278 mg, 0.37 mmol) and DIPEA (65 L, 0.37 mmol) in DCM (3 mL) was allowed to stir at r.t. for 18 h. The reaction mixture was concentrated in vacuo and the resulting residue purified by column chromatography (Si-PCC, MeOH:DCM, 0-2%) affording the title compound as a yellow solid._LCMS (method H): RT 2.67 min, [M+H]+
453.3 [00421] Example 65r 5-(2-Ethylbenzoimidazol-1-yl)-7-morpholin-4-ylthiazolo[5,4-d]pyrimidine-2-carbaldehyde Co) O N ~

IN N_\ /
eN

[00422] A mixture of 5-chloro-7-morpholin-4-ylthiazolo[5,4-d]pyrimidine-2-carbaldehyde (1.0 g, 3.51 mmol), 2-ethylbenzimidazole (512 mg, 3.71 mmol), tris(dibenzylideneacetone)dipalladium (90 mg, 2.5 mol%), XPhos (158 mg, 10 mol%) and Cs2CO3 (1.6 g, 4.91 mmol) in dioxane (30 mL) was purged with argon then heated at 115 C
for 17 h. The reaction mixture was filtered through Celite which was washed with hot dioxane, and the filtrated concentrated in vacuo. The resulting residue was triturated with Et20 and the resulting brown solid collected by filtration and dried in vacuo affording the title compound (1.23 g, 88%). 'H NMR (CDC13, 400 MHz): 6 10.01 (1 H, s), 8.09-8.09 (1 H, m), 7.75-7.74 (1 H, m), 7.33-7.26 (2 H, m), 5.00-4.00 (4 H, brd s), 3.93 (4 H, t, J = 4.72 Hz), 3.37 (2 H, q, J = 7.45 Hz), 1.46 (3 H, t, J = 7.45 Hz).
[00423] Example 65s [5-(2-Ethylbenzoimidazol-1-yl)-7-morpholin-4-ylthiazolo[5,4-d]pyrimidin-2-yl]methanol (0) / \N 1 HO S N! N_ (N
[00424] To a solution of 5-(2-ethylbenzoimidazol-1-yl)-7-morpholin-4-ylthiazolo[5,4-d]pyrimidine-2-carbaldehyde (1.2 g, 3.04 mmol) in DCE (30 mL) was added MeOH
(3 mL) and NaBH4 (119 mg, 3.15 mmol) and the resulting mixture stirred at r.t. for 4 h. The reaction mixture was concentrated in vacuo and the resulting residue triturated with H20. The resulting solid was collected by filtration and dried in vacuo affording the title compound (1.18 g, 98%). LCMS (method H): RT 2.42 min, [M+H]+ 397.4 [00425] Example 65t 2-Bromomethyl-5-(2-ethylbenzoimidazol-1-yl)-7-morpholin-4-ylthiazolo [5,4-d]pyrimidine / \N 1 ~
Br S N N` \
(N

[00426] To a suspension of [5-(2-ethylbenzoimidazol-1-yl)-7-morpholin-4-ylthiazolo[5,4-d]pyrimidin-2-yl]methanol (1.18 g, 2.97 mmol) in DCM (60 mL) was added PBr3 (3.36 mL, 3.36 mmol, 1M solution in DCM) and the resulting mixture allowed to stir at r.t. for 1 h. The reaction mixture was diluted with DCM and the organic phase washed with H2O and brine, then dried (MgSO4) and concentrated in vacuo affording the title compound as a yellow solid (673 mg, 49%). LCMS (method H): RT 3.24 min, [M+H]+ 459.1 and 461.1 (1:1) [00427] Example 65u [5-(2-Ethylbenzoimidazol-1-yl)-7-morpholin-4-ylthiazolo[5,4-d]pyrimidin-2-ylmethyl]phosphonic acid dimethyl ester (0) i N I N
P, S
O; N~N 94' -O _N

[00428] A mixture of 2-bromomethyl-5-(2-ethylbenzoimidazol-1-yl)-7-morpholin-4-ylthiazolo[5,4-d]pyrimidine (670 mg, 1.46 mmol) in trimethylphosphite (10 mL) was heated to reflux (120 C) for 1 h then concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, MeOH:DCM, 0-2%) then (Si-PCC, MeOH:EtOAc, 0-5%) affording the title compound as a yellow solid (620 mg, 87%). LCMS (method H):
RT 2.46 min, [M+H]+ 489.3 [00429] Example 65v 3-[5-(2-Ethylbenzoimidazol-1-yl)-7-morpholin-4-ylthiazolo[5,4-d]pyrimidin-2-ylmethylene]azetidine-l-carboxylic acid tert-butyl ester (0) N
S NN \
~ eN
O
O

[00430] To a solution of diisopropylamine (200 L, 1.42 mmol) in THE (0.5 mL) at -78 C was added n-BuLi (556 L, 1.42 mmol, 2.5 M in hexanes) and the resulting mixture stirred for 20 min. The resulting solution was added to a suspension of [5-(2-ethylbenzoimidazol-1-yl)-7-morpholin-4-ylthiazolo [5,4-d]pyrimidin-2-ylmethyl]phosphonic acid dimethyl ester (620 mg, 1.27 mmol) in THE (11 mL) at -78 C. The resulting mixture was warmed to r.t. before a solution of 3-oxo-azetidine-l-carboxylic acid tert-butyl ester (250 mg, 1.46 mmol) in THE (1.5 mL) was added. The resulting mixture was stirred at r.t. for 5 h then quenched with H20. The mixture was concentrated in vacuo and the residue was partitioned between DCM and brine. The organic phase was dried (MgSO4) and concentrated in vacuo. The resulting residue was filtered through a pad of silica affording the title compound (493 mg, 73%). LCMS (method H): RT 3.72 min, [M+H]+ 534.3 [00431] Example 65w 2-Azetidin-3-ylmethyl-5-(2-ethylbenzoimidazol-l-yl)-7-morpholin-4-ylthiazolo [5,4-d]pyrimidine (0) N ~

S N N \
H ~N

[00432] Step 1: 3-[5-(2-Ethylbenzoimidazol-1-yl)-7-morpholin-4-ylthiazolo[5,4-d]pyrimidin-2-ylmethyl]azetidine-1-carboxylic acid tert-butyl ester (0) NN 11 _<, S N, N \

eN
O
O

[00433] To a solution of 3-[5-(2-ethylbenzoimidazol-1-yl)-7-morpholin-4-ylthiazolo [5,4-d]pyrimidin-2-ylmethylene]azetidine-l-carboxylic acid tert-butyl ester (493 g, 0.92 mmol) in AcOH (20 mL) was added 10% Pd(OH)2/C (200 mg) and the resulting mixture stirred under an atmosphere of H2 for 2 h. The reaction mixture was filtered through Celite , washing with EtOAc. The filtrate was loaded onto an Isolute SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH affording the title compound.
[00434] Step 2: To a solution of 3-[5-(2-ethylbenzoimidazol-1-yl)-7-morpholin-4-ylthiazolo[5,4-d]pyrimidin-2-ylmethyl]azetidine-l-carboxylic acid tert-butyl ester in DCM

(10 mL) was added TFA (3 mL) and the resulting mixture allowed to stir at r.t.
for 1 h. The reaction mixture was loaded onto an Isolute SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH affording 2-Azetidin-3-ylmethyl-5-(2-ethylbenzoimidazol- 1-yl)-7-morpholin-4-ylthiazolo[5,4-d]pyrimidine as a yellow oil (209 mg, 52% over two steps).-'H NMR (CDC13, 400 MHz): 6 7.99-7.98 (1 H, m), 7.75-7.74 (1 H, m), 7.28-7.25 (2 H, m), 4.41 (4 H, brd s), 3.89-3.84 (5 H, m), 3.59 (2 H, t, J
= 7.25 Hz), 3.48 (2 H, s), 3.36-3.34 (5 H, m), 1.43 (3 H, t, J = 7.47 Hz) [00435] Example 65x 4-[l-(5-Chloro-7-morpholin-4-ylthiazolo[5,4-d]pyrimidin-2-ylmethyl)azetidin-3-yl]piperazin-2-one (o) i,N I N
N S NCI
N
O
~ H

[00436] A mixture of 5-chloro-7-morpholin-4-ylthiazolo[5,4-d]pyrimidine-2-carbaldehyde (285 mg, 1.00 mmol), 4-azetidin-3-ylpiperazin-2-one (190 mg, 1.22 mmol) and 4A powdered molecular sieves (1.0 g) in DCE (10 mL) was allowed to stir at r.t. for 5 h before the addition of sodium triacetoxyborohydride (420 mg, 1.98 mmol). The resulting mixture was allowed to stir for 16 h then filtered through Celite which was washed with DCM. The filtrate was concentrated in vacuo and the resulting residue purified by column chromatography (Si-PCC, MeOH:DCM, 2-10%) affording the title compound (321 mg, 75%). LCMS (method A): RT 1.96 and 0.33 min [M+H]+ 424.3 [00437] Example 65X (5-Chloro-7-morpholin-4-ylthiazolo[5,4-d]pyrimidin-2-yl)-(3-morpholin-4-ylazetidin- l -yl)methanone CO) 0 iiN N
N S NiCI
v [00438] To a suspension of 5-chloro-7-morpholin-4-ylthiazolo[5,4-d]pyrimidine-carboxylic acid (301 mg, 1.0 mmol) in DCM (6 mL) was added oxalyl chloride (847 L, 10.00 mmol) and the resulting mixture allowed to stir at r.t. for 1 h then concentrated in vacuo and azeotroped with toluene. The resulting yellow solid was suspended in a mixture of DCM (6 mL) and NEt3 (418 L, 3.00 mmol) at 0 C before the addition of 4-azetidin-3-ylmorpholine (142 mg, 1.00 mmol). The resulting mixture was warmed to r.t.
after 1 h then stirred for a further 30 min. The reaction mixture was partitioned between DCM
and H20, the organic phase dried (Na2SO4) and concentrated in vacuo. The resulting residue was triturated with EtOAc and dried in vacuo affording the title compound as an off-white solid (269 mg, 63%). LCMS (method H): RT 2.19 min [M+H]+ 425.3 [00439] Example 65z 5-Chloro-7-morpholin-4-yl-thiazolo[4,5-d]pyrimidine-2-carbaldehyde (0) O S / N
' Il H N N CI

[00440] To a suspension of 5-chloro-7-morpholin-4-yl-thiazolo[4,5-d]pyrimidine (2 g, 7.79 mmol) in anhydrous tetrahydrofuran, cooled to -78 C under nitrogen atmosphere, lithium bis(trimethylsilyl)amide (11.7 mL, 11.68 mmol) was added dropwise at -78 C and the resulting reaction mixture stirred at -78 C for 1 h. Subsequently DMF was slowly added and the mixture stirred for further 30 min. The temperature was allowed to rise to -5 C over min and then cooled again to -78 C. The resulting reaction mixture was transferred via cannula into ice-cold aqueous 1M HC1(400 mL) and stirred vigorously. The aqueous phase was extracted with ethyl acetate (2 x 150 mL). The organic layer was washed with water (1 x 125 mL), brine (2 x 125 mL), dried over Na2SO4 and filtered. The solvent was reduced in vacuo to afford the title compound as an orange-brown solid (1.82 g, 82%). IH
NMR (400 MHz, CDC13): 6 10.19 (1 H, s), 4.03 (4 H, t, J = 4.90 Hz), 3.87 (4 H, t, J =
4.90 Hz).
[00441] Example 66a 5-Chloro-7-morpholin-4-yl-2-(3-morpholin-4-yl-azetidin-l-ylmethyl)-thiazolo[4,5-d]pyrimidine N
(0) S
IN N NCI

~

[00442] A mixture of 5-chloro-7-morpholin-4-yl-thiazolo[4,5-d]pyrimidine-2-carbaldehyde (250 mg, 0.88 mmol), 4-azetidin-3-yl-morpholine (150 mg, 1.05 mmol) and 4 A molecular sieves (1.0 g) in 1,2-dichloroethane (15 mL) was stirred at RT
under nitrogen atmosphere for 1.5 h. Sodium triacetoxyborohydride (280 mg, 1.32 mmol) was added and the reulting reaction mixture was stirred at RT for 16 h. The solvent was reduced in vacuo and the residue was loaded on an Isolute SCX-2 cartridge (l0g). The cartridge was washed with DCM/MeOH, the desired product was subsequently eluted using a mixture of 2M
NH3 in MeOH and DCM. The resulting residue was further purified by column chromatography (Si-PCC, MeOH: DCM: 0:100 to 6:94 by volume). The solvents were reduced in vacuo to afford the title compound as a yellow solid (165 mg, 46%). LCMS (Method A): RT 2.31 min, [M+H]+ 411. IH NMR (400 MHz, CDC13): 6 4.11 (2 H, s), 3.95 (4 H, t, J = 4.85 Hz), 3.83 (4 H, t, J = 4.84 Hz), 3.74-3.67 (6 H, m), 3.22 (2 H, t, J = 6.84 Hz), 3.12-3.11 (1 H, m), 2.34 (4 H, s) [00443] Example 66b 2-[1-(5-Chloro-7-morpholin-4-yl-thiazolo[4,5-d]pyrimidin-2-ylmethyl)piperidin-4-yl]propan-2-ol (0) S ~ NN CI
N
N
O
[00444] A mixture of 5-chloro-7-morpholin-4-yl-thiazolo[4,5-d]pyrimidine-2-carbaldehyde (400 mg, 1.4 mmol), 2-piperidin-4-yl-propan-2-ol (242 mg, 1.7 mmol), and 4 A
molecular sieves (1.5 g) in 1,2-dichloroethane (20 mL) was stirred at RT for 6 h. Sodium triacetoxyborohydride (593 mg, 2.8 mmol) was added and the resulting reaction mixture was stirred at RT under nitrogen atmospherefor 18 h. The suspension was filtered through Celite and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (Si-PPC, (10% MeOH in EtOAc): EtOAc, gradient 0:100 to 20:80) to afford the title compound as an orange solid (344 mg, 60%). IH NMR (400 MHz, CDC13):
6 3.98-3.93 (6 H, m), 3.85 (5 H, m), 3.08 (2 H, m), 2.28 (2 H, m), 1.79 (2 H, m), 1.48 (3 H, m), 1.23-1.21 (6 H, m).
[00445] Example 66c 2-[4-(5-Chloro-7-morpholin-4-yl-thiazolo[4,5-d]pyrimidin-2-ylmethyl)piperazin- l -yl]isobutyramide (0) N
S

N N N CI
N

>~ N
O
[00446] A mixture of 5-chloro-7-morpholin-4-yl-thiazolo[4,5-d]pyrimidine-2-carbaldehyde (250 mg, 0.88 mmol), 2-piperazin-1-yl-isobutyramide (173 mg, 1.01 mmol) and 4 A molecular sieves (1.0 g) in 1,2-dichloroethane (15 mL) was stirred at RT under nitrogen atmosphere for 4 h. Sodium triacetoxyborohydride (280 mg, 1.32 mmol) was added and the reulting reaction mixture was stirred at RT for 16 h. The solvent was reduced in vacuo and the residue was loaded on an Isolute SCX-2 cartridge (25g). The cartridge was washed with DCM/MeOH and the desired product was subsequently eluted using a mixture of 2 M NH3 in MeOH and DCM. The resulting residue was further purified by column chromatography (Si-PCC, MeOH: DCM: gradient 0:100 to 6:94). The solvents were reduced in vacuo to afford the title compound as a yellow solid (275 mg, 60%). LCMS
(Method H):
RT 2.41 min, [M+H]+ 440. 'H NMR (400 MHz, CDC13): 6 7.04 (1 H, br s), 5.22 (1 H, br s), 3.97-3.95 (6 H, m), 3.85 (4 H, t, J = 4.80 Hz), 2.67 (8 H, m), 1.25 (6 H, s) [00447] Example 66d 2-[4-(7-Morpholin-4-yl-5-(tributylstannanyl)thiazolo[4,5-d]pyrimidin-2-ylmethyl)piperazin- l -yl]isobutyramide N
(0) S

N :~
N N N SnBu3 N

N
O
[00448] A mixture of 2-[4-(5-chloro-7-morpholin-4-yl-thiazolo[4,5-d]pyrimidin-ylmethyl)piperazin-l-yl]isobutyramide (120 mg, 0.27 mmol), PdC12{PtBu2(Php-NMe2)}2 (19.5 mg, 0.027 mmol) and hexabutylditin (0.203 mL, 0.405 mmol) in 1,4-dioxane (1.2 mL) was purged with argon gas and then subjected to microwave irradiation at 150 C for 30 min.
The crude residue was loaded onto an Isolute SCX-2 cartridge (20g) and washed with DCM/MeOH, the desired product was subsequently eluted using a mixture of 2 M
NH3 in MeOH and DCM. The resulting residue was further purified by column chromatography (Si-PCC, cyclohexane:acetone, gradient 100:0 to 60:40). The solvents were reduced in vacuo to afford the title compound as a yellow gum (210 mg, 62%) LCMS (Method A): RT
4.26 min, [M+H]+ 694 (116Sn) 696 (118Sn). IH NMR (400 MHz, CDC13): 6 7.06 (1 H, s), 5.20 (1 H, s), 3.97 (2 H, s), 3.92 (4 H, t, J = 4.60 Hz), 3.84 (4 H, t, J = 4.60 Hz), 2.65 (8 H, m), 1.60-1.58 (6 H, m), 1.35-1.33 (6 H, m), 1.25 (6 H, s), 1.16-1.14 (6 H, m), 0.87 (9 H, t, J
= 7.32 Hz) [00449] Example 66e 4-[5-(2-Ethylbenzoimidazol-1-yl)-7-morpholin-4-ylthiazolo[5,4-d]pyrimidin-2-ylmethylene]piperidine-l-carboxylic acid benzyl ester CO) N ~N
S NN \ I
N ~N
O~
O

[00450] To a solution of diisopropylamine (121 L, 0.86 mmol) in THE (0.5 mL) at -78 C was added n-BuLi (336 L, 0.86 mmol, 2.5 M in hexanes) and the resulting mixture stirred for 30 min. The resulting solution was added to a suspension of [5-(2-ethylbenzoimidazol-1-yl)-7-morpholin-4-ylthiazolo [5,4-d]pyrimidin-2-ylmethyl]phosphonic acid dimethyl ester (375 mg, 0.77 mmol) in THE (6 mL) at -78 C. The resulting mixture was warmed to r.t. before a solution of 4-oxopiperidine-l-carboxylic acid benzyl ester (206 mg, 0.88 mmol) in THE (1 mL) was added. The resulting mixture was stirred at r.t. for 3 h then quenched with H20. The mixture was concentrated in vacuo and the residue was partitioned between EtOAc and H20. The organic phase was dried (MgSO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, EtOAc:pentane, 50-75%) affording 4-[5-(2-Ethylbenzoimidazol-1-yl)-7-morpholin-ylthiazolo[5,4-d]pyrimidin-2-ylmethylene]piperidine-l-carboxylic acid benzyl ester (300 mg, 66%). LCMS (method H): RT 3.98 min, [M+H]+ 596.4 [00451] Example 66f 5-(2-Ethylbenzoimidazol-1-yl)-7-morpholin-4-yl-2-piperidin-ylmethylthiazolo[5,4-d]pyrimidine CO) N I N
l S N!' N
_N
N
J
H

[00452] To a solution of 4-[5-(2-ethylbenzoimidazol-1-yl)-7-morpholin-4-ylthiazolo[5,4-d]pyrimidin-2-ylmethylene]piperidine-l-carboxylic acid benzyl ester (300 mg, 0.50 mmol) in AcOH (20 mL) was added 10% Pd(OH)2/C (200 mg) and the resulting mixture stirred under an atmosphere of H2 for 2 h. The reaction mixture was filtered through Celite , washing with EtOAc. The filtrate was loaded onto an Isolute SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH. The resulting residue was purified by column chromatography (Si-PCC, 2M NH3/MeOH:DCM, 0-10%) affording 5-(2-Ethylbenzoimidazol-1-yl)-7-morpholin-4-yl-2-piperidin-4-ylmethylthiazolo [5,4-d]pyrimidine (96 mg, 41%). 1H NMR (CDC13, 400 MHz): 6 7.99-7.98 (1 H, m), 7.74-7.73 (1 H, m), 7.30-7.26 (2 H, m), 4.43 (4 H, s), 3.88 (4 H, t, J = 4.74 Hz), 3.33 (2 H, q, J =
7.48 Hz), 3.12-3.08 (2 H, m), 2.99 (2 H, d, J = 7.14 Hz), 2.63 (2 H, td, J = 12.12, 2.54 Hz), 2.03-1.91 (1 H, m), 1.79 (2 H, brd d, J = 13.18 Hz), 1.42 (3 H, t, J = 7.48 Hz), 1.30-1.29 (2 H, m) [00453] Example 66g Acetic acid 2-{4-[5-(2-ethylbenzoimidazol-1-yl)-7-morpholin-4-ylthiazolo[5,4-d]pyrimidin-2-ylmethyl]piperidin-1-yl}-1,1-dimethyl-2-oxoethyl ester (0) NN
S Ni\N \
N e~N
O
O
O
[00454] A mixture of 5-(2-ethylbenzoimidazol-1-yl)-7-morpholin-4-yl-2-piperidin-4-ylmethylthiazolo[5,4-d]pyrimidine (96 mg, 0.21 mmol), acetic acid 1-chlorocarbonyl-l-methylethyl ester (40 L, 0.28 mmol) and NEt3 (40 L, 0.31 mmol) in DCM (1 mL) was allowed to stir at r.t. for 30 min then concentrated in vacuo. The resulting residue was loaded onto an Isolute SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH affording Acetic acid 2-{4-[5-(2-ethylbenzoimidazol-1-yl)-7-morpholin-4-ylthiazolo[5,4-d]pyrimidin-2-ylmethyl]piperidin-1-yl}-1,1-dimethyl-2-oxoethyl ester. LCMS
(method A): RT 3.19 min [M+H]+ 592.2 [00455] Formula I(ii) thiophenyl intermediates wherein (ii) X1 is CR7 and X2 is S
[00456] Example 70a 9-(2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-1-oxa-4,9-diazaspiro [5.5 ]undecan-3-one CO) N
S NZ N

N N CI
O

~N
O H

[00457] A solution of 6-bromomethyl-2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (500 mg, 1.43 mmol), 1-oxa-4,9-diaza-spiro[5.5]undecan-3-one (315 mg, 1.85 mmol) and potassium carbonate (450 mg, 3.26 mmol) in DMF (40 mL) was stirred at ambient temperature for 18 hours, then loaded onto an Isolute SCX-2 cartridge (10 g). The cartridge was washed with MeOH and the desired product was subsequently eluted using 2 M
NH3 in MeOH. The eluent was collected and concentrated in vacuo. The resultant residue was purified by flash chromatography (Si-PPC, DCM: MeOH 100:0 to 98:2 to 95:5) to afford 9-(2-Chloro-4-morpholin-4-yl-thieno [3,2-d]pyrimidin-6-ylmethyl)- l -oxa-4,9-diazaspiro[5.5]undecan-3-one as a white solid (515 mg, 82 %). LCMS (Method A):
RT= 2.51 min, [M+H]+ 438.1 [00458] Example 70b 2-[4-(4-Morpholin-4-yl-2-(tributylstannanyl)thieno[3,2-d]pyrimidin-6-ylmethyl)-piperazin- l -yl]isobutyramide (0) N
N N Sn NJ

>~_ NH2 O

[00459] A mixture of 2-[4-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-piperazin-1-yl]isobutyramide (1.0 g, 2.3 mmol), hexabutylditin (1.4 mL, 2.7 mmol), and PdC12 {PtBu2(Ph p-Nme2)}2 (161 mg, 0.2 mmol) in dioxane (10 mL) was degassed and then subjected to microwave irradiation at 150 C for 30 min. The reaction mixture was diluted with MeOH and loaded onto a Isolute SCX -2 cartridge (25 g). The cartridge was then washed with MeOH and the desired product was subsequently eluted using 2 M NH3 in MeOH. Appropriate fractions were combined and concentrated to give a residue which was subjected to flash chromatography (Si-PPC, MeOH:DCM, gradient 0:100 to 10:90). Appropriate fractions were combined and concentrated to give 2-[4-(4-Morpholin-4-yl-2-(tributylstannanyl)thieno[3,2-d]pyrimidin-6-ylmethyl)-piperazin-1-yl]isobutyramide as white foam (0.9 g, 56 %).-LCMS (Method C) RT= 3.88 min; [M + H]+ 693.1 (116Sn) 695.1 ("8Sn) [00460] Example 70c 2-[4-(2-Chloro-7-methyl-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)piperazin- l -yl]isobutyramide (0) N
S / N

(I) N CI
O

[00461] To a solution of 2-chloro-7-methyl-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde (1.00 g, 3.36 mmol) in DCE (50 mL) was added 2-(piperazin-l-yl)isobutyramide (630 mg, 3.69 mmol), trimethyl orthoformate (3.67 mL, 33.58 mmol) and acetic acid (0.19 mL, 3.36 mmol). After stirring at room temperature for 3 h sodium triacetoxyborohydride (1.10 g, 5.03 mmol) was added and the resulting mixture stirred for a further 17 h. The reaction mixture was loaded onto an Isolute SCX-2 cartridge, washed with MeOH then eluted with 2 M NH3 in MeOH/DCM. The resultant residue was triturated with MeOH to give 2-[4-(2-Chloro-7-methyl-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)piperazin-1-yl]isobutyramide as a white solid (1.12 g, 74 %). LCMS
(Method C):
RT = 2.88 min, [M+H]+ 453 [00462] Example 70d 2-[4-(7-Methyl-4-morpholin-4-yl-2-(tributylstannanyl)thieno [3,2-d]pyrimidin-6-ylmethyl)piperazin-1-yl]isobutyramide CO) N
S N
N \ N I Sn--111~
NJ

O

[00463] A mixture of 2-[4-(2-chloro-7-methyl-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)piperazin-1-yl]isobutyramide (194 mg, 0.43 mmol), hexabutylditin (373 mg, 0.64 mmol), PdC12 {PtBu2(Ph p-Nme2)}2 (30 mg, 10 mol %) in dioxane (2 mL) was purged with nitrogen gas then heated at 150 C, for 20 min, in a microwave reactor. The reaction mixture was loaded onto an Isolute SCX-2 cartridge, washed with MeOH
then eluted with 2M NH3 in MeOH. The resulting residue was purified by column chromatography (Si-PPC, MeOH:DCM, gradient 0:100 to 05:95) to afford 2-[4-(7-Methyl-4-morpholin-4-yl-2-(tributylstannanyl)thieno[3,2-d]pyrimidin-6-ylmethyl)piperazin-l-yl]isobutyramide as a colorless oil (192 mg, 63 %). LCMS (Method D): RT 2.92 min, [M+H]+ 705 (116Sn), 707 (118Sn) [00464] Example 70e 2-Chloro-4-morpholin-4-yl-6-(4-morpholin-4-yl-piperidin-l-ylmethyl)-thieno [3,2-d]pyrimidine (0) S N
N
N CI
N>
OJ

[00465] A mixture of 2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde (2.0 g, 7.1 mmol) and 4-piperidin-4-yl-morpholine (1.4 g, 8.5 mmol) in DCE
(40 mL) was stirred at room temperature for 1.5 hour then triacetoxyborohydride (2.2 g, 10.6 mmol) was added. The reaction mixture was stirred at room temperature for 18 hours then diluted with MeOH and loaded onto an Isolute SCX-2 cartridge (70 g). The cartridge was washed with MeOH/DCM (1/1 : v/v) and the desired product was eluted with (2M
NH3 in MeOH)/DCM (1/1 : v/v). The solvents were removed and the residue was triturated in hot IMS, filtered and dried at 60 C for 1 hour under vacuum to give 2-Chloro-4-morpholin-4-yl-6-(4-morpholin-4-yl-piperidin-l-ylmethyl)-thieno[3,2-d]pyrimidine as a white solid (2.6 g, 84%). LCMS (Method C): RT 0.34 min and 1.67 min; [M+H]+ 438 [00466] Example 70f 4-Morpholin-4-yl-6-(4-morpholin-4-yl-piperidin-1-ylmethyl)-2-(tributylstannanyl)thieno [3,2-d]pyrimidine (o) S

N NSn [00467] A mixture of 2-chloro-4-morpholin-4-yl-6-(4-morpholin-4-yl-piperidin-l-ylmethyl)thieno[3,2-d]pyrimidine (874 mg, 2.0 mmol), hexabutylditin (1.1 mL, 2.2 mmol), and PdCl2 {PtBuz(Ph p-Nme2)}2 (71 mg, 0.1 mmol) in dioxane (10 mL) was degassed and then subjected to microwave irradiation at 150 C for 20 min. The reaction mixture was diluted with MeOH and loaded onto a Isolute SCX -2 cartridge (10 g). The cartridge was then washed with MeOH and the desired product was subsequently eluted using 2 M NH3 in MeOH. Appropriate fractions were combined and concentrated to give a residue which was subjected to flash chromatography (Si-PPC, MeOH:EtOAc, gradient 0:100 to 40:60).
Appropriate fractions were combined and concentrated to give 4-Morpholin-4-yl-6-(4-morpholin-4-yl-piperidin- 1-ylmethyl)-2-(tributylstannanyl)thieno[3,2-d]pyrimidine as pale yellow oil (823 mg, 59 %). LCMS (Method C): RT = 2.72 min; [M + H]+ 692 (116Sn) 694 (118Sn) [00468] Example 70g [1-(2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)piperidin-4-yl] dimethylamine (0) S I N
N
N CI
P
-N

[00469] A mixture of 2-chloro-4-morpholin-4-ylthieno[3,2-d]pyrimidine-6-carbaldehyde (5.0 g, 17.7 mmol) and dimethylpiperidin-4-ylamine (2.7 g, 21.2 mmol) in DCE
(100 mL) was stirred at room temperature for 4 hours then triacetoxyborohydride (5.6 g, 26.5 mmol) was added. The reaction mixture was stirred at room temperature for 18 hours then diluted with MeOH and loaded onto an Isolute SCX-2 cartridge (2 x 70 g). The cartridge was washed with MeOH/DCM (1/1 : v/v) and the desired product was eluted with (2M NH3 in MeOH)/DCM (1/1 : v/v). The solvents were removed and the residue was precipitated from IMS to give [1-(2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)piperidin-4-yl]dimethylamine as a white solid (4.45 g, 64%). LCMS
(Method B):
RT 0.37 min and 1.85 min; [M+H]+ 396 [00470] Example 70h Dimethyl-[1-(4-morpholin-4-yl-2-(tributylstannanyl)thieno[3,2-d]pyrimidin-6-ylmethyl)piperidin-4-yl] amine (o) S I 'N

N NSn -N

[00471] A mixture of [1-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)piperidin-4-yl]dimethylamine (1.0 g, 2.5 mmol), hexabutylditin (1.5 mL, 3.0 mmol), and PdC12 {PtBuz(Ph p-Nme2)}2 (128 mg, 0.18 mmol) in dioxane (10 mL) was degassed and then subjected to microwave irradiation at 160 C for 20 min. The reaction mixture was diluted with MeOH and loaded onto a Isolute SCX -2 cartridge (25 g). The cartridge was then washed with MeOH and the desired product was subsequently eluted using 2 M NH3 in MeOH. Appropriate fractions were combined and concentrated to give a residue which was subjected to flash chromatography (Si-PPC, MeOH:DCM, gradient 0:100 to 40:60). Appropriate fractions were combined and concentrated to give Dimethyl-[1-(4-morpholin-4-yl-2-(tributylstannanyl)thieno [3,2-d]pyrimidin-6-ylmethyl)piperidin-4-yl] amine as pale yellow oil (879 mg, 54 %). LCMS (Method C): RT= 2.76 min; [M + H]+ 650 (116Sn) 652 (11sSn) [00472] Example 70i 1-[1-(2-Chloro-4-morpholin-4-ylthieno[3,2-d]pyrimidin-6-ylmethyl)azetidin-3-yl]piperidin-4-ol CO) 'N
N
N CI
P

Q
HO

[00473] A mixture of 2-chloro-4-morpholin-4-ylthieno[3,2-d]pyrimidine-6-carbaldehyde (136 mg, 0.48 mmol), 1-azetidin-3-ylpiperidin-4-ol (90 mg, 0.58 mmol) and 4A
powdered molecular sieves (260 mg) in DCE (15 mL) was stirred for 5 h before the addition of sodium triacetoxyborohydride (202 mg, 0.96 mmol). The resulting mixture was stirred for 18 h then filtered through Celite and the filtrate loaded onto an Isolute SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH/DCM. The resulting residue was purified by column chromatography (Si-PCC, MeOH:DCM, 0-10%) affording the title compound as a pale yellow oil (153 mg, 75 %). LCMS (method H): RT
1.88 min [M+H]+ 424.3 [00474] Example 70i 2-Chloro-6-(2,2-dimethyl-4-oxetan-3-ylpiperazin-1-ylmethyl)-4-morpholin-4-yl-thieno [3,2-d]pyrimidine Co) N
\I N ~ I
N CI
NJ

[00475] A mixture of 2-chloro-4-morpholin-4-ylthieno[3,2-d]pyrimidine-6-carbaldehyde (400 mg, 1.42 mmol), 3,3-dimethyl-l-oxetan-3-ylpiperazine (290 mg, 1.71 mmol) and 4A powdered molecular sieves (500 mg) in DCE (20 mL) were allowed to stir at r.t. 3 h before the addition of sodium triacetoxyborohydride (420 mg, 1.98 mmol). The resulting mixture was allowed to stir for 18 h then filtered through Celite .
The filtrate was loaded onto an Isolute SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH. The resulting residue was purified by column chromatography (Si-PCC, MeOH:EtOAc, 0-10%) affording the title compound as a cream solid (305 mg, 49%). LCMS (method H): RT 2.12 min, [M+H]+ 438.3 [00476] Example 70k 3-(2-Chloro-4-morpholin-4-ylthieno[3,2-d]pyrimidin-6-ylmethylene)azetidine-l-carboxylic acid tert-butyl ester CO) S ?N
N CI
N
O=<
O
[00477] To a suspension of (2-chloro-4-morpholin-4-ylthieno[3,2-d]pyrimidin-6-ylmethyl)phosphonic acid dimethyl ester (3.0 g, 7.94 mmol) in THE (150 mL) at -78 C was added LiHMDS (8.8 mL, 8.80 mmol, 1M solution in THF) and the resulting mixture stirred for 30 min then warmed to r.t. before the addition of a solution of 3-oxo-azetidine-l-carboxylic acid tert-butyl ester (1.51 g, 8.82 mmol) in THE (20 mL). The reaction mixture was stirred at r.t. for 16 h then quenched with H2O and MeOH and concentrated in vacuo.
The resulting residue was purified by column chromatography (Si-PCC, EtOAc:DCM, 5-100%) affording the title compound as a yellow solid (2.14 g, 63%). LCMS
(method A): RT
3.97 min [M+H]+ 423.3 [00478] Example 701 3-[2-(2-Ethylbenzoimidazol-1-yl)-4-morpholin-4-ylthieno[3,2-d]pyrimidin-6-ylmethylene]azetidine-l-carboxylic acid tert-butyl ester (o) S ~N
N N \ O=( N e N
O

[00479] A mixture of 3-(2-chloro-4-morpholin-4-ylthieno[3,2-d]pyrimidin-6-ylmethylene)azetidine-l-carboxylic acid tert-butyl ester (1.1 g, 2.51 mmol), 2-ethylbenzimidazole (400 mg, 2.74 mmol), tris(dibenzylideneacetone)dipalladium (115 mg, 0.13 mmol), XPhos (240 mg, 0.50 mmol) and Cs2CO3 (1.25 g, 3.84 mmol) in dioxane (25 mL) was purged with argon then heated at 110 C for 16 h. The reaction mixture was filtered through Celite , washing with DCM, and the filtrate concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, MeOH:DCM, 0-10%) affording the title compound as an orange solid (1.5 g, quant.). LCMS (method A): RT
3.40 min [M+H]+ 533.4 [00480] Example 70m 3-[2-(2-Ethylbenzoimidazol-1-yl)-4-morpholin-4-ylthieno[3,2-d]pyrimidin-6-ylmethyl]azetidine-1-carboxylic acid tert-butyl ester (o) S ~N
NN \ O=( N e N
O

[00481] To a solution of 3-[2-(2-ethylbenzoimidazol-1-yl)-4-morpholin-4-ylthieno[3,2-d]pyrimidin-6-ylmethylene]azetidine-l-carboxylic acid tert-butyl ester (1.5 g, 2.51 mmol) in EtOH (30 mL) was added 10% Pd/C (275 mg) and the resulting mixture stirred under an atmosphere of H2 for 65 h. The reaction mixture was filtered through Celite , washing with EtOH, and the filtrate concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, MeOH:DCM, 0-10%) affording the title compound as an orange oil (0.71 g, 53%). LCMS (method A): RT 3.22 min [M+H]+
535.4 [00482] Example 70n 6-Azetidin-3-ylmethyl-2-(2-ethylbenzoimidazol-1-yl)-4-morpholin-4-ylthieno [3,2-d]pyrimidine (0) S I -N _ \ N~N /
H N

[00483] To a solution of 3-[2-(2-ethylbenzoimidazol-1-yl)-4-morpholin-4-ylthieno[3,2-d]pyrimidin-6-ylmethyl]azetidine-l-carboxylic acid tert-butyl ester (700 mg, 1.31 mmol) in DCM (3 mL) was added TFA (0.5 mL) and the resulting mixture stirred for 18 h at r.t. The reaction mixture was concentrated in vacuo and the resulting residue loaded onto an Isolute SCX-2 cartridge which was washed with MeOH/DCM and the product eluted with 2M NH3/MeOH affording the title compound as an orange gum (522 mg, 91%).
LCMS
(method A): RT 1.80 min [M+H]+ 435.4 [00484] Formula I(iii) purine intermediates wherein (iii) X1 is N and X2 is [00485] Example 75a 2,6-dichloro-9-methyl-9H-purine 4 N

O CI

~ I N]~H PC15 /N NN
N H^0 reflux \N N" CI

[00486] The cyano group of 5-amino-l-methyl-IH-imidazole-4-carbonitrile 1 is hydrolyzed with sulfuric acid to give 5-amino-l-methyl-IH-imidazole-4-carboxamide 2.
Cyclization with urea gives 9-methyl-lH-purine-2,6(3H,9H)-dione 3.
Chlorination with phosphorus pentachloride and phosphorusoxychloride gives 2,6-dichloro-9-methyl-9H-purine 4 (CAS Registry 2382-10-7).
[00487] Example 75b 2-(1-((2-chloro-9-methyl-6-morpholino-9H-purin-8-yl)methyl)piperidin-4-yl)propan-2-ol OH CO) N
1I)N

N NCI

[00488] To 4-(2-chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)morpholine (100 g) in methanol (500 mL) at 50 C was added p-toluenesulfonic acid monohydrate (6 g). The reaction was stirred for 30 mins, whereupon white solid has crashed fully out of solution.
The solid is filtered and collected thru Buchner funnel, rinsed with Methanol and dried under vacuum to get 4-(2-chloro-9H-purin-6-yl)morpholine. Cesium carbonate (200 g) and iodomethane (30 mL) were subsequently added to a stirring solution of 4-(2-chloro-9H-purin-6-yl)morpholine in DMF at 50 C. The reaction was monitored by lc-ms until complete, about 30 minutes, whereupon the solvent was concentrated to dryness.
Subsequent suspension of the crude reaction in water precipitated 4-(2-chloro-9-methyl-9H-purin-6-yl)morpholine (72 g) as a white solid, which was filtered and dried under vacuum overnight.
(O) N
H N N
N \N~CI

[00489] To stirred solution of 4-(2-chloro-9-methyl-9H-purin-6-yl)morpholine (10 g) and N,N,N',N'-tetramethylethylenediamine (9.0 mL) in tetrahydrofuran (200 mL) at -78 C
was added 2.5 M of n-butyllithium in tetrahydrofuran (35 mL) . The solution was stirred at -40 C for 30 minutes, and then re-cooled to -78 C, whereupon DMF (8 mL) was added and the reaction stirred for another hour. The reaction was quenched into cold 0.25N HCl solution via l OmL serological pipet aliquots. Ice was added to keep quenching solution temperature below 5 C, to avoid formation of by-product during workup. 2-Chloro-9-methyl-6-morpholino-9H-purine-8-carbaldehyde (11 g) precipitated as a light yellow solid which was filtered, rinsed with water and dried under vacuum.
[00490] A solution of 2-chloro-9-methyl-6-morpholino-9H-purine-8-carbaldehyde (17.2 g) in MeOH (800 mL) at 0 C was treated portion wise with sodium borohydride (5 g).
The reaction was warmed to room temperature and stirred 15 minutes. The reaction mixture was quenched with saturated solution of sodium bicarbonate. The aqueous layer was extracted twice with ethyl acetate. The combined organic layers were dried over magnesium sulfate and concentrated in vacuo to yield crude 2-chloro-9-methyl-6-morpholino-9H-purin-8-yl)methanol (16.9 g) as a white solid.
CO) N
BrN I ~ N NI
CI
[00491] To a solution of crude 2-chloro-9-methyl-6-morpholino-9H-purin-8-yl)methanol (16.5 g) in a mixture of dichloroethane (600 mL) and THE (400 mL) at 0 C was added phosphorus tribromide (11 mL) dropwise. The reaction was stirred for 1 h whereupon the solid that precipitated was filtered, rinsed with water, collected and dried to give 4-(8-(bromomethyl)-2-chloro-9-methyl-9H-purin-6-yl)morpholine (15.6 g) as a white solid.
[00492] 2-(Piperidin-4-yl)propan-2-ol (0.73 g) was reacted with 4-(8-(bromomethyl)-2-chloro-9-methyl-9H-purin-6-yl)morpholine (1.6 g) via General Procedure C to yield 2-(1-((2-chloro-9-methyl-6-morpholino-9H-purin-8-yl)methyl)piperidin-4-yl)propan-2-ol (1.76 g) as a white solid.
[00493] Example 75c 9-Methyl-2-(2-methylbenzoimidazol-1-yl)-6-morpholin-4-yl-9H-purine-8-carbaldehyde CO) 0~ N I ~N
H
N~N
)--N

[00494] A mixture of Pd2(dba)3 (161 mg, 0.18 mmol), Xphos (CAS Reg. No. 564483-18-7, 336 mg, 0.72 mmol), 2-chloro-9-methyl-6-morpholin-4-yl-9H-purine-8-carbaldehyde (1.0 g, 3.52 mmol), 2-ethyl-lH-benzoimidazole (500 mg, 3.73 mmol), cesium carbonate (2.3 g, 7 mmol) in dioxane (15 mL) was degassed for 5 min and heated at 145 C for 30 min under microwave irradiation. The reaction mixture was filtered while still hot through a pad of celite, and the pad was washed with hot dioxane. The product precipitated immediately as a pale yellow solid. The solid was filtered and dried at 50 C under vacuum to give 9-Methyl-2-(2-methylbenzoimidazol- 1-yl)-6-morpholin-4-yl-9H-purine-8-carbaldehyde (650 mg, 50%).
Additional material could be recovered from the mother liquors. LCMS (Method H): RT 3.39 min; [M+MeOH]+ 410 [00495] Example 75d 2-(2-Ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine-8-carbaldehyde CO) O N ~

H1 N I NN '94' N

[00496] A mixture of Pd2(dba)3 (458 mg, 0.5 mmol), Xphos (954 mg, 2.0 mmol), 2-chloro-9-methyl-6-morpholin-4-yl-9H-purine-8-carbaldehyde (5.64 g, 20.0 mmol), 2-ethyl-1H-benzoimidazole (3.21 g, 22.0 mmol), cesium carbonate (9.78 g, 30.0 mmol) in dioxane (80 mL) was degassed for 5 min and heated at reflux for 18h. The reaction mixture was filtered through a pad of celite while still hot, and the pad was washed with hot dioxane. The combined filtrate was concentrated under reduced pressure to give a residue which was triturated in Et20 (ca 100 mL), filtered and dried at 50 C under vacuum to give 2-(2-Ethylbenzoimidazol- 1-yl)-9-methyl-6-morpholin-4-yl-9H-purine-8-carbaldehyde as a yellow solid (4.5 g). LCMS (Method H): RT 3.63 min; [M+MeOH]+ 424 [00497] Example 75e 2-(2-Cyclopropylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine-8-carbaldehyde CO) O\\ N ON

N NN
N

[00498] A mixture of 2-chloro-9-methyl-6-morpholin-4-yl-9H-purine-8-carbaldehyde (210 mg, 0.79 mmol), 2-cyclopropylbenzimidazole (150 mg, 0.95 mmol), tris(dibenzylideneacetone)dipalladium (44 mg, 0.05 mmol), Xphos (90 mg, 0.18 mmol) and Cs2CO3 (618 mg, 1.90 mmol) in dioxane (3 mL) and DMF (1 mL) was purged with argon then heated at 145 C for 45 min in a microwave reactor. The reaction mixture was filtered through a pad of celite, washing with EtOAc. The filtrate was concentrated in vacuo and purified by column chromatography (Si-PCC, EtOAc:cyclohexane, 0-75%) affording 2-(2-Cyclopropylbenzoimidazol- 1-yl)-9-methyl-6-morpholin-4-yl-9H-purine-8-carbaldehyde as an orange solid (282 mg, 89%). LCMS (Method H): RT 3.79 min, [M+H]+ 436.4 [00499] Example 75f 2-[2-(2-Hydroxyethyl)benzoimidazol-1-yl]-9-methyl-6-morpholin-4-yl-9H-purine-8-carbaldehyde (0) O\\ N I ~N

N NiN \
/ N
HO

[00500] A mixture of 2-chloro-9-methyl-6-morpholin-4-yl-9H-purine-8-carbaldehyde (500 mg, 1.78 mmol), 2-(1H-benzoimidazol-2-yl)ethanol (335 mg, 2.06 mmol), Pd2dba3 (40 mg, 0.043 mmol), Xphos (85 mg, 0.18 mmol) and cesium carbonate (840 mg, 2.58 mmol) in 1,4-dioxane (10 mL) was purged with argon gas then subjected to microwave irradiation at 145 C for 30 min. The reaction mixture was filtered through a pad of Celite and the filtrate was concentrated in vacuo. The resultant residue was purified by flash chromatography (Si-PPC, EtOAc: MeOH; 100:0 to 98:2 to 95:5 to 90:10) to afford 2-[2-(2-Hydroxyethyl)benzoimidazol-1-yl]-9-methyl-6-morpholin-4-yl-9H-purine-8-carbaldehyde as a yellow solid (487 mg, 67 %). 1H NMR (CDC13, 400MHz) 6 9.93 (s, 1 H); 8.16-8.12 (m, 1 H); 7.76-7.72 (m, 1 H); 7.35-7.29 (m, 2 H); 4.52 (m, 4 H); 4.20 (t, J = 5.3 Hz, 2 H); 4.14 (s,3H); 3.91 (m, 5H) and 3.57(t,J=5.3Hz,2H).
[00501] Example 75g 8-Chloromethyl-2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine (0) r--N I N
CI N!N
_ N

[00502] To a suspension of [2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-yl-9H-purin-8-yl]methanol (200 mg, 0.51 mmol) in DCM (6 mL) and DMF (100 L) was added oxalyl chloride (129 L, 1.52 mmol) and the resulting solution was stirred at room temperature for 19 h. The reaction mixture was concentrated in vacuo to an oil which was purified by column chromatography (Si-PCC, MeOH:DCM, 0-10%) affording 8-Chloromethyl-2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine as an impure mixture which was used directly in subsequent reactions.
[00503] Example 75h 2-Chloro-8-[3-(1,1-Dioxo-l-thiomorpholin-4-yl)azetidin-l-ylmethyl]-9-methyl-6-morpholin-4-yl-9H-purine (0) _/N I N
N/ N N CI
N>

i O

[00504] A mixture of 2-chloro-9-methyl-6-morpholin-4-yl-9H-purine-8-carbaldehyde (400 mg, 1.42 mmol), 4-azetidin-3-ylthiomorpholine- 1, 1 -dioxide (324 mg, 1.70 mmol) and 4A powdered molecular sieves (900 mg) in DCE (20 mL) was stirred at room temperature for 4 h before the addition of sodium triacetoxyborohydride (602 mg, 2.84 mmol).
The reaction mixture was stirred for 40 h then filtered through celite, washing with DCM.
The organic phase was washed with brine (x 1) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, MeOH:EtOAc, 0-15%) affording 2-Chloro-8-[3-(1,1-Dioxo- l -thiomorpholin-4-yl)azetidin-1-ylmethyl]-9-methyl-6-morpholin-4-yl-9H-purine as a cream solid (587 mg, 91%). LCMS (Method H): RT 2.25 min [M+H]+
456.3 [00505] Example 75i 2-Chloro-9-methyl-6-morpholin-4-yl-8-(3-morpholin-4-ylazetidin- l -ylmethyl)-9H-purine (o) N -N
N,,/N I N CI
C N

[00506] A mixture of 2-chloro-9-methyl-6-morpholin-4-yl-9H-purine-8-carbaldehyde (235 mg, 0.82 mmol), 4-azetidin-3-ylmorpholine (122 mg, 0.86 mmol) and 4A
powdered molecular sieves (300 mg) in DCE (8 mL) was stirred at room temperature for 3 h before the addition of sodium triacetoxyborohydride (346 mg, 1.63 mmol). The reaction mixture was stirred for 65 h then filtered through celite, washing with DCM. The organic phase was washed with brine and concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, MeOH:EtOAc, 0-20%) affording 2-Chloro-9-methyl-6-morpholin-4-yl-8-(3-morpholin-4-ylazetidin-1-ylmethyl)-9H-purine as a cream solid (165 mg, 49%).
LCMS (Method A): RT 2.22 min [M+H]+ 408.2 [00507] Example 75i 2-(2-Ethylbenzoimidazol-1-yl)-6-morpholin-4-yl-9-(tetrahydropyran-2-yl)-8-[3-(tetrahydropyran-4-yl)azetidin-1-ylmethyl]-9H-purine CO) N~N
NN ~NN

0 e~9 O

[00508] Step 1: 2-(2-Ethylbenzoimidazol-1-yl)-6-morpholin-4-yl-9-(tetrahydropyran-2-yl)-9H-purine-8-carbaldehyde CO) N
H N N

[00509] Step 1: A mixture of 2-chloro-6-morpholin-4-yl-9-(tetrahydropyran-2-yl)-9H-purine-8-carbaldehyde (0.8 g, 2.27 mmol), 2-ethyl-lH-benzoimidazole (0.4 g, 2.72 mmol), Xphos (0.216g, 0.45 mmol), Pd2(dba)3 (0.104 g, 0.11 mmol) and Cs2CO3 (1.48 g, 4.54 mmol) in dioxane (10 mL) was subjected to microwave irradiation at 145 C for 45 min.
The suspension was filtered through Celite and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography (Si-PPC, EtOAc : Cyclohexane, gradient 0:100 to 75:25) to give 2-(2-Ethylbenzoimidazol-1-yl)-6-morpholin-4-yl-9-(tetrahydropyran-2-yl)-8-[3-(tetrahydropyran-4-yl)azetidin-1-ylmethyl]-9H-purine as a yellow foam (0.444 g, 43 %).
LCMS (Method A): RT = 4.05min, [M+H]+ 494.4 [00510] Step 2: A 10 mL round-bottomed flask was charged with a solution of 2-(2-ethylbenzoimidazol-1-yl)-6-morpholin-4-yl-9-(tetrahydropyran-2-yl)-9H-purine-8-carbaldehyde (0.22 g, 0.48 mmol), 3-(tetrahydropyran-4-yl)azetidine hydrochloride (0.093 g, 0.53 mmol) in DCE (5 mL), trimethoxymethane (0.518 mL, 4.8 mmol) and acetic acid (0.03 mL, 0.48 mmol). The reaction mixture was stirred for 4 h at room temperature.
Sodium triacetoxyborohydride (0.152 g, 0.72 mmol) was added and the reaction mixture was stirred for a further 72 h at room temperature. The suspension was partitioned between DCM and water; the organic layer was separated and washed with brine, dried with sodium sulphate and concentrated to give 2-(2-Ethylbenzoimidazol-l-yl)-6-morpholin-4-yl-9-(tetrahydropyran-2-yl)-8-[3-(tetrahydropyran-4-yl)azetidin-1-ylmethyl]-9H-purine as an orange oil (0.356 g, 99%). LCMS (Method A): RT = 2.97min, [M+H]+ 587.4 [00511] Example 75k N-[9-Methyl-6-morpholin-4-yl-8-(4-oxetan-3-yl-piperidin-l-ylmethyl)-9H-purin-2-yl]benzene-1,2-diamine Co) 'N N N N"q O

[00512] A mixture of 2-chloro-9-methyl-6-morpholin-4-yl-8-(4-oxetan-3-yl-piperidin-1-ylmethyl)-9H-purine (0.2 g, 0.49 mmol), benzene-1,2-diamine (0.106 g, 0.98 mmol), Xphos (0.047g, 0.098 mmol), Pd2(dba)3 (0.022 g, 0.025 mmol) and Cs2CO3 (0.32 g, 0.98 mmol) in DMF (2 mL) was subjected to microwave irradiation at 150 C for 30 min. The suspension was filtered through Celite and the solution was concentrated in vacuo. The residue was purified by flash chromatography (Si-PPC, MEOH:DCM, gradient 0:100 to 10:90) to give N-[9-Methyl-6-morpholin-4-yl-8-(4-oxetan-3-yl-piperidin-1-ylmethyl)-9H-purin-2-yl]benzene-1,2-diamine as yellow foam (0.117 g, 50 %). LCMS (Method A): RT =
2.14min, [M+H]+ 479.2 [00513] Example 751 2-Chloro-9-methyl-6-morpholin-4-yl-8-[3-(tetrahydropyran-4-yl)azetidin- l -ylmethyl] -9H-purine CO) N

NN~
N N:, N CI
O

[00514] A 25 mL round-bottomed flask was charged with a solution of 2-chloro-9-methyl-6-morpholin-4-yl-9H-purine-8-carbaldehyde (0.173 g, 0.65 mmol), 3-(tetrahydropyran-4-yl)azetidine hydrochloride (0.138 g, 0.78 mmol) and 4 A
molecular sieves (0.9 g) in DCE (7 mL). The reaction mixture was stirred for 5 h at room temperature.
Sodium triacetoxyborohydride (0.274 g, 1.29 mmol) was added and the reaction mixture was stirred for 18 h at room temperature. The suspension was filtered through Celite and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography (Si-PPC, MeOH : EtOAc, gradient 0:100 to 10:90) to give 2-Chloro-9-methyl-6-morpholin-4-yl-8-[3-(tetrahydropyran-4-yl)azetidin- 1-ylmethyl]-9H-purine as a white foam (0.117 g, 45 %).
LCMS (Method A): RT = 2.40min, [M+H]+ 407.2 [00515] Example 75m N-{9-Methyl-6-morpholin-4-yl-8-[3-(tetrahydropyran-4-yl)azetidin- l -ylmethyl]-9H-purin-2-yl}benzene- 1,2-diamine (0) N

NCN
NNNN

O

[00516] A mixture of 2-chloro-9-methyl-6-morpholin-4-yl-8-[3-(tetrahydropyran-yl)azetidin-1-ylmethyl]-9H-purine (0.25 g, 0.61 mmol), benzene- 1,2-diamine (0.133 g, 1.23 mmol), Xphos (0.059g, 0.123 mmol), Pd2(dba)3 (0.028 g, 0.031 mmol) and Cs2CO3 (0.17 g, 1.23 mmol) in DMF (2.5 mL) was subjected to microwave irradiation at 150 C for 30 min.
The suspension was filtered through Celite and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography (Si-PPC, MEOH:DCM, gradient 0:100 to 10:90) to give the title compound as a brown foam (0.234 g, 80 %). LCMS
(Method A): RT =
2.20min, [M+H]+ 479.4 [00517] Example 75n 2-[1-(9-Methyl-6-morpholin-4-yl-2-(tributylstannanyl)-9H-purin-8-ylmethyl)piperidin-4-yl]propan-2-ol (0) N ~N
N N NSn HO

[00518] A mixture of 2-[1-(2-chloro-9-methyl-6-morpholin-4-yl-9H-purin-8-ylmethyl)-piperidin-4-yl]propan-2-ol (500 mg, 1.23 mmol), hexabutylditin (0.928 mL, 1.84 mmol), PdC12 {PtBu2(Ph p-Nme2)}2 (88 mg, 0.122 mmol) in dioxane (2.5 mL) and NMP (0.25 mL) was degassed and then subjected to microwave irradiation at 150 C for 45 min. The reaction mixture was filtered through Celite and the filtrate was concentrated in vacuo. The residue was dissolved in DCM (10 mL), washed with water (10 mL). The organic layer was separated, dried with sodium sulphate and concentrated in vacuo. The residue was diluted with MeOH and loaded onto a Isolute SCX -2 cartridge (10 g). The cartridge was then washed with MeOH and the desired product was subsequently eluted using 2 M NH3 in MeOH. The solution was concentrated to give a residue which was subjected to flash chromatography (Si-PPC, MEOH:DCM, gradient 0:100 to 7.5:92.5) followed by (Si-PPC, EtOAc : cyclohexane, gradient 0:100 to 100:0). Appropriate fractions were combined and concentrated to give the title compound as pale yellow oil (236 mg, 29 %).
LCMS (Method A) RT= 4.58 min; [M + H]+ 663.3 (116Sn) 665.3 (118Sn) [00519] Example 75o (2-Chloro-9-methyl-6-morpholin-4-yl-9H-purin-8-yl)acetaldehyde () O~N I ~N
NCI

[00520] To a stirred suspension of (methoxymethyl)triphenylphosphonium chloride (1.49 g, 4.35 mmol) in dry THE (10 mL) was added dropwise a 1 M solution of LiHMDS in THE (4.35 mL, 4.35 mmol) under an atmosphere of nitrogen, at 0 C. After 15 min a suspension of 2-chloro-9-methyl-6-morpholin-4-yl-9H-purine-8-carbaldehyde (1.02 g, 3.62 mmol) in dry THE (10 mL) was added. The mixture was allowed to warm to RT
after 30 min and stirred for a further 1 h then quenched with H20. The mixture was partitioned between EtOAc and 0.5 M HC1(aq), the organic layer separated and washed with water and then brine.
The organic layer was dried (Na2SO4) and evaporated to give a residue (2.2 g), which was dissolved in MeOH, loaded onto an Isolute SCX-2 cartridge, the cartridge was washed with MeOH then the desired product eluted with 2 M NH3 in MeOH to give a residue (860 mg) which was taken up in 37 wt. % HC1(,q) / THE (8:16 mL). The resulting mixture was stirred at 50 C for 2 h then allowed to cool, partitioned between EtOAc and saturated NaHCO3 (aq).
The organic layer was separated and washed with brine then dried (Na2SO4) and concentrated in vacuo. The resultant residue was purified by flash chromatography (Si-PCC, 0-100 %
EtOAc in cyclohexane) to give the title compound (451 mg, 42 % over 2 steps) as an orange solid. LCMS (Method H): RT 3.29 min, [M+H]+ 296.2 [00521] Example 75p 2-{1-[2-(2-Chloro-9-methyl-6-morpholin-4-yl-9H-purin-8-yl)ethyl]piperidin-4-yl}propan-2-ol CO) N
N-\`/N N
O
H ~~
N NCI

[00522] To a solution of (2-chloro-9-methyl-6-morpholin-4-yl-9H-purin-8-yl)acetaldehyde (150 mg, 0.51 mmol) in DCE (10 mL) was added 2-piperidin-4-ylpropan-2-ol (110 mg, 0.77 mmol), trimethyl orthoformate (0.55 mL, 5.02 mmol) and acetic acid (0.03 mL, 0.52 mmol). The reaction mixture was stirred at room temperature for 5 h, sodium triacetoxyborohydride (154 mg, 0.73 mmol) was added and the resulting mixture stirred for a further 2 h. The reaction mixture was loaded onto an Isolute SCX-2 cartridge, the cartridge was washed with MeOH then the desired product eluted with 2 M NH3 in MeOH. The resulting residue was purified by column chromatography (Si-PCC, 0-10 % MeOH
in DCM) to give the title compound as an off white solid (109 mg, 51 %). LCMS (Method H): RT =
2.54 min, [M+H]+ 423.5 [00523] Example 75q 2-{4-[2-(2-Chloro-9-methyl-6-morpholin-4-yl-9H-purin-8-yl)ethyl]piperazin- l -yl}isobutyramide CO) N
0=~ NH2 N 11 NCI

[00524] To a solution of (2-chloro-9-methyl-6-morpholin-4-yl-9H-purin-8-yl)acetaldehyde (110 mg, 0.37 mmol) in DCE (10 mL) was added 2-piperazin-l-ylisobutyramide (90 mg, 0.53 mmol), trimethyl orthoformate (0.20 mL, 1.86 mmol) and acetic acid (0.02 mL, 0.37 mmol). The reaction mixture was stirred at room temperature for 3 h, sodium triacetoxyborohydride (118 mg, 0.56 mmol) was added and the resulting mixture stirred for a further 2 days. The reaction mixture was loaded onto an Isolute cartridge, the cartridge was washed with MeOH then the desired product eluted with 2 M
NH3 in MeOH. The resulting residue was purified by column chromatography (Si-PCC, 0-20 % MeOH in EtOAc) to give the title compound as a pale yellow solid (71 mg, 42 %). LCMS
(Method H): RT = 2.40 min, [M+H]+ 451.5 [00525] Example 75r 2-Chloro-8-[2-(2,2-dimethylmorpholin-4-yl)ethyl]-9-methyl-morpholin-4-yl-9H-purine C) N
0 N-\ N I ~N
N N!CI

[00526] To a solution of (2-chloro-9-methyl-6-morpholin-4-yl-9H-purin-8-yl)acetaldehyde (116 mg, 0.39 mmol) in DCE (10 mL) was added 2,2-dimethylmorpholine (68 mg, 0.59 mmol), trimethyl orthoformate (0.22 mL, 1.96 mmol) and acetic acid (0.02 mL, 0.39 mmol). The reaction mixture was stirred at room temperature for 3 h, sodium triacetoxyborohydride (125 mg, 0.59 mmol) was added and the resulting mixture stirred for a further 18 h. The reaction mixture was loaded onto an Isolute SCX-2 cartridge, he cartridge was washed with MeOH then the desired product eluted with 2 M NH3 in MeOH. The resulting residue was purified by column chromatography (Si-PCC, 0-10 % MeOH
in EtOAc) to give the title compound as a pale yellow solid (100 mg, 65 %). LCMS
(Method H): RT = 2.51 min, [M+H]+ 395.4 [00527] Example 75s 2-{1-[2-(2-Chloro-9-methyl-6-morpholin-4-yl-9H-purin-8-yl)ethyl]azetidin-3-yl}propan-2-ol (0) N
N N
HO ~
N NNCI

[00528] To a solution of (2-chloro-9-methyl-6-morpholin-4-yl-9H-purin-8-yl)acetaldehyde (300 mg, 1.01 mmol) in DCE (20 mL) was added 2-azetidin-3-ylpropan-2-ol (118 mg, 1.02 mmol), trimethyl orthoformate (1.11 mL, 10.14 mmol) and acetic acid (0.06 mL, 1.01 mmol). The reaction mixture was stirred at room temperature for 6 h, sodium triacetoxyborohydride (323 mg, 1.52 mmol) was added and the resulting mixture stirred for a further 18 h. The reaction mixture was loaded onto an Isolute SCX-2 cartridge, the cartridge was washed with MeOH then the desired product eluted with 2 M NH3 in MeOH.
The resulting residue was purified by column chromatography (Si-PCC, 0-10 %
MeOH in DCM) to give the title compound as a pale yellow oil (90 mg, 23 %). LCMS
(Method A): RT
= 2.37 min, [M+H]+ 395.2 [00529] Example 75t 1-[2-(2-Chloro-9-methyl-6-morpholin-4-yl-9H-purin-8-yl)ethyl]-4-methylpiperidin-4-ol COJ
HO/~ N
( .N N

N NNCI

[00530] To a solution of (2-chloro-9-methyl-6-morpholin-4-yl-9H-purin-8-yl)acetaldehyde (200 mg, 0.68 mmol) in DCE (15 mL) was added 4-methylpiperidin-4-ol (117 mg, 1.01 mmol), trimethyl orthoformate (0.74 mL, 6.76 mmol) and acetic acid (0.04 mL, 0.68 mmol). The reaction mixture was stirred at room temperature for 1.5 h, sodium triacetoxyborohydride (187 mg, 1.35 mmol) was added and the resulting mixture stirred for a further 18 h. The reaction mixture was loaded onto an Isolute SCX-2 cartridge, washed with MeOH then the desired product eluted with 2 M NH3/MeOH in DCM. The resulting residue was purified by column chromatography (Si-PCC, 0-20 % 2 M NH3/MeOH in DCM) to give the title compound as a colourless oil (45 mg, 17 %). LCMS (Method H):
RT = 2.24 min, [M+H]+ 395.5 [00531] Example 75u 1-[2-(2-Chloro-9-methyl-6-morpholin-4-yl-9H-purin-8-yl)ethyl]-3-methyl-azetidin-3-ol (0) N
HO,> N N \ N

N N CI

[00532] To a solution of (2-chloro-9-methyl-6-morpholin-4-yl-9H-purin-8-yl)acetaldehyde (150 mg, 0.51 mmol) in DCE (10 mL) was added 3-methyl-azetidin-3-ol (65 mg, 0.75 mmol) and powdered 4 A molecular sieves. The reaction mixture was stirred at room temperature for 2 h, sodium triacetoxyborohydride (215 mg, 1.01 mmol) was added and the resulting mixture stirred for a further 17 h. The reaction mixture was loaded onto an Isolute SCX-2 cartridge, washed with MeOH then the desired product eluted with 2 M NH3 in MeOH. The resulting residue was purified by column chromatography (Si-PCC, 0-10 %
MeOH in DCM) to give the title compound as a pale yellow oil (83 mg, 45 %).
LCMS
(Method H): RT = 2.29 min, [M+H]+ 367.5 [00533] Example 75v 7-[2-(2-Chloro-9-methyl-6-morpholin-4-yl-9H-purin-8-yl)ethyl]-7-azaspiro[3.5]nonan-2-ol (0) N
HO-~~>( .N N N
N N CI

[00534] To a solution of (2-chloro-9-methyl-6-morpholin-4-yl-9H-purin-8-yl)acetaldehyde (157 mg, 0.53 mmol) in DCE (10 mL) was added 7-azaspiro[3.5]nonan-2-ol (109 mg, 0.77 mmol) and powdered 4 A molecular sieves. The reaction mixture was stirred at room temperature for 4 h, sodium triacetoxyborohydride (225 mg, 1.06 mmol) was added and the resulting mixture stirred for a further 16 h. The reaction mixture was loaded onto an Isolute SCX-2 cartridge, washed with MeOH then the desired product eluted with 2 M NH3 in MeOH. The resulting residue was purified by column chromatography (Si-PCC, 0-10 % 2 M NH3/MeOH in DCM) to give the title compound as a colourless oil (155 mg, 69 %).
LCMS (Method H): RT = 2.41 min, [M+H]+ 421.5 [00535] Example 75w 1-[2-(2-Chloro-9-methyl-6-morpholin-4-yl-9H-purin-8-yl)ethyl]-3-isopropyl-azetidin-3-ol (0) N
HO N -\_<N
N
N N CI

[00536] To a solution of (2-chloro-9-methyl-6-morpholin-4-yl-9H-purin-8-yl)acetaldehyde (69 mg, 0.23 mmol) in DCE (5 mL) was added 3-isopropyl-azetidin-3-ol (27 mg, 0.23 mmol) and powdered 4 A molecular sieves. The reaction mixture was stirred at room temperature for 2 h, sodium triacetoxyborohydride (99 mg, 0.47 mmol) was added and the resulting mixture stirred for a further 2 days. The reaction mixture was loaded onto an Isolute SCX-2 cartridge, washed with MeOH then the desired product eluted with 2 M NH3 in MeOH. The resulting residue was purified by column chromatography (Si-PCC, 0-10 % 2 M NH3/MeOH in DCM) to give the title compound as a pale yellow oil (30 mg, 33 %).
LCMS (Method H): RT = 2.65 min, [M+H]+ 395.5 [00537] Example 75x 4-[2-(2-Chloro-9-methyl-6-morpholin-4-yl-9H-purin-8-yl)ethyl]-1-isopropylpiperazin-2-one 0 (O) N
NN N

N N CI

[00538] To a solution of (2-chloro-9-methyl-6-morpholin-4-yl-9H-purin-8-yl)acetaldehyde (167 mg, 0.57 mmol) in DCE (10 mL) was added 1-isopropylpiperazin-2-one (87 mg, 0.61 mmol) and powdered 4 A molecular sieves. The reaction mixture was stirred at room temperature for 1 h, sodium triacetoxyborohydride (239 mg, 1.13 mmol) was added and the resulting mixture stirred for a further 16 h. The reaction mixture was filtered through Celite , loaded onto an Isolute SCX-2 cartridge, washed with MeOH then the desired product eluted with 2 M NH3 in MeOH. The resulting residue was purified by column chromatography (Si-PCC, 0-10 % 2 M NH3/MeOH in DCM) to give the title compound as a pale yellow oil (51 mg, 33 %). LCMS (Method H): RT = 3.31 min, [M+H]+ 422.5 [00539] Example 75xx 2-Chloro-9-methyl-6-morpholin-4-yl-8-[2-(3-oxa-8-azabicyclo[3.2.1 ]oct-8-yl)ethyl]-9H-purine (O) N
OON N N
N N CI

[00540] To a solution of (2-chloro-9-methyl-6-morpholin-4-yl-9H-purin-8-yl)acetaldehyde (117 mg, 0.40 mmol) in DCE (10 mL) was added 3-oxa-8-azabicyclo[3.2.1]octane (54 mg, 0.48 mmol) and powdered 4 A molecular sieves.
The reaction mixture was stirred at room temperature for 2 h, sodium triacetoxyborohydride (168 mg, 0.79 mmol) was added and the resulting mixture stirred for a further 16 h.
The reaction mixture was filtered through Celite , loaded onto an Isolute SCX-2 cartridge, washed with MeOH then the desired product eluted with 2 M NH3 in MeOH. The resulting residue was purified by column chromatography (Si-PCC, 0-10 % MeOH in DCM) to give the title compound as a pale yellow oil (80 mg, 51 %). LCMS (Method H): RT = 2.34 min, [M+H]+
393.5 [00541] Example 75X 4-[2-(2-Chloro-9-methyl-6-morpholin-4-yl-9H-purin-8-yl)ethyl]-6-isopropylpiperazin-2-one N

H NNNN NCI

[00542] To a solution of (2-chloro-9-methyl-6-morpholin-4-yl-9H-purin-8-yl)acetaldehyde (184 mg, 0.62 mmol) in DCE (15 mL) was added 6-isopropylpiperazin-2-one (106 mg, 0.75 mmol) and powdered 4 A molecular sieves. The reaction mixture was stirred at room temperature for 6 h, sodium triacetoxyborohydride (364 mg, 1.72 mmol) was added and the resulting mixture stirred for a further 18 h. The reaction mixture was filtered through Celite , loaded onto an Isolute SCX-2 cartridge, washed with MeOH then the desired product eluted with 2 M NH3/MeOH in DCM. The resulting residue was purified by column chromatography (Si-PCC, 0-10 % MeOH in DCM) to give the title compound as a pale yellow oil (93 mg, 35 %). LCMS (Method H): RT = 3.44 min, [M+H]+ 422.4 [00543] Example 75z 2-Chloro-8-[2-(3,3-dimethylmorpholin-4-yl)ethyl]-9-methyl-morpholin-4-yl-9H-purine (0) N
0N -\ N I N

N NICI

[00544] To a solution of (2-chloro-9-methyl-6-morpholin-4-yl-9H-purin-8-yl)acetaldehyde (119 mg, 0.40 mmol) in DCE (10 mL) was added 3,3-dimethylmorpholine.HC1(61 mg, 0.40mmol), triethylamine (0.06 mL, 0.40 mmol) and powdered 4 A molecular sieves. After stirring at room temperature for 4 h, sodium triacetoxyborohydride (171 mg, 0.80 mmol) was added and the resulting mixture stirred for a further 16 h. The reaction mixture was filtered through Celite , loaded onto an Isolute SCX-2 cartridge, the cartridge was washed with MeOH then the desired product eluted with 2 M NH3/MeOH in DCM. The resulting residue was purified by column chromatography (Si-PCC, 0-7 % MeOH in DCM) to give the title compound as a pale yellow oil (44 mg, 28 %).
LCMS (Method H): RT = 2.45 min, [M+H]+ 395.5 [00545] Example 75aa 2-Chloro-8-{2-[3-(1,1-dioxo-l-thiomorpholin-4-yl)azetidin-l-yl]-ethyl }-9-methyl-6-morpholin-4-yl-9H-purine (0) 0. N
S N <N N
IN
:: I
N N CI

[00546] To a solution of (2-chloro-9-methyl-6-morpholin-4-yl-9H-purin-8-yl)acetaldehyde (115 mg, 0.39 mmol) in DCE (10 mL) was added 4-azetidin-3-yl-thiomorpholine, l -1-dioxide (74 mg, 0.39 mmol) and powdered 4 A molecular sieves. The reaction mixture was stirred at room temperature for 4 h, sodium triacetoxyborohydride (165 mg, 0.78 mmol) was added and the resulting mixture stirred for a further 2 days. The reaction mixture was filtered through Celite , loaded onto an Isolute SCX-2 cartridge, washed with MeOH then the desired product eluted with 2 M NH3/MeOH in DCM. The resulting residue was purified by column chromatography (Si-PCC, 0-10 % 2 M NH3/MeOH in DCM) to give the title compound as a pale yellow oil (93 mg, 51 %). LCMS (Method H): RT =
2.25 min, [M+H]+ 470.3 [00547] Example 75bb 2-Chloro-8-[2-(4,4-difluoropiperidin-1-yl)ethyl]-9-methyl-6-morpholin-4-yl-9H-purine (0) F)/ N
N N
F ~
N ~ NNCI

[00548] To a solution of (2-chloro-9-methyl-6-morpholin-4-yl-9H-purin-8-yl)acetaldehyde (60 mg, 0.20 mmol) in DCE (10 mL) was added 4,4-difluoropiperidine.HC1 (42 mg, 0.26 mmol), triethylamine (0.04 mL, 0.26 mmol), powdered 4 A molecular sieves and sodium triacetoxyborohydride (86 mg, 0.41 mmol). The reaction mixture was stirred at room temperature for 5 h, the reaction mixture was loaded onto an Isolute SCX-2 cartridge, washed with MeOH then the desired product eluted with 2 M NH3/MeOH in DCM. The resulting residue was purified by column chromatography (Si-PCC, 0-5 % MeOH in DCM) to give the title compound as a pale yellow oil (30 mg, 37 %). LCMS (Method H): RT =
2.61min, [M+H]+ 401.5 [00549] Example 75cc 2-Chloro-9-methyl-6-morpholin-4-yl-8-{2-[4-(tetrahydropyran-4-yl)piperazin-l-yl]ethyl} -9H-purine (0) /~ N
O, - N\-/N N N
N N CI

[00550] To a solution of (2-chloro-9-methyl-6-morpholin-4-yl-9H-purin-8-yl)acetaldehyde (72 mg, 0.24 mmol) in DCE (15 mL) was added 1-(tetrahydropyran-yl)piperazine (60 mg, 0.35 mmol), powdered 4 A molecular sieves and sodium triacetoxyborohydride (103 mg, 0.49 mmol). The reaction mixture was stirred at room temperature for 17 h. The reaction mixture was loaded onto an Isolute SCX-2 cartridge, the cartridge was washed with MeOH then the desired product eluted with 2 M
NH3/MeOH in DCM. The resulting residue was purified by column chromatography (Si-PCC, 0-10 %
MeOH in DCM) to give the title compound as a yellow solid (37 mg, 34 %). LCMS
(Method H): RT = 2.46min, [M+H]+ 450.5 [00551] Example 75dd 2-[(1S,4S)-5-(2-Chloro-9-methyl-6-morpholin-4-yl-9H-purin-8-ylmethyl)-2,5-diazabicyclo [2.2.1 ]hept-2-yl]-2-methylpropan- l -ol (0) / I ~N
N N N,CI
\COH

[00552] A solution of 2-chloro-9-methyl-6-morpholin-4-yl-9H-purine-8-carbaldehyde (235 mg, 0.83 mmol), (2-(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl-2-methylpropan-l-ol (168 mg, 0.99 mmol) and molecular sieves (4 A, powdered, 1 g) in DCE (10 mL) was stirred at ambient temperature for 4 h. Sodium triacetoxyborohydride (265 mg, 1.25 mmol) was added and the mixture stirred for 18 h, then loaded onto an Isolute SCX-2 cartridge (25 g). The cartridge was then washed with methanol and the desired product was subsequently eluted using 2 M NH3 in MeOH. The product was collected and concentrated in vacuo.
The resultant residue was purified by flash chromatography (Si-PPC, DCM: MeOH;
90:10) to afford the title compound as a tan solid (50 mg, 14 %). LCMS (Method H): RT =
2.39 min, M+H+ = 436.
[00553] Example 75ee 2-Chloro-8-((1S,4S)-5-methanesulfonyl-2,5-diazabicyclo[2.2.1 ]hept-2-ylmethyl)-9-methyl-6-morpholin-4-yl-9H-purine C) N
N ~N
N N! CI
O=S

[00554] A solution of 2-chloro-9-methyl-6-morpholin-4-yl-9H-purine-8-carbaldehyde (227 mg, 0.81 mmol), (1S,4S)-2-methanesulfonyl-2,5-diazabicyclo[2.2.1]heptane (170 mg, 0.97 mmol) and molecular sieves (4 A, powdered, 1 g) in DCE (12 mL) was stirred at ambient temperature for 3 h. Sodium triacetoxyborohydride (255 mg, 1.20 mmol) was added and the mixture stirred for 17 h, then loaded onto an Isolute SCX-2 cartridge (25 g). The cartridge was then washed with methanol and the desired product was subsequently eluted using 2 M NH3 in MeOH. The product was collected and concentrated in vacuo.
The resultant residue was purified by flash chromatography (Si-PPC, DCM: MeOH;
98:2) to afford the title compound as a white solid (350 mg, 98 %). LCMS (Method H): RT
= 2.51 min, M+H+ = 442.
[00555] Example 75ff 2-Chloro-9-methyl-6-morpholin-4-yl-8-(4-oxetan-3-ylpiperidin-l-ylmethyl)-9H-purine CO) < -N
N,CI
N \N

O

[00556] A solution of 2-chloro-9-methyl-6-morpholin-4-yl-9H-purine-8-carbaldehyde (1.0 g, 3.55 mmol), 4-oxetan-3-ylpiperidine (600 mg, 4.25 mmol) and molecular sieves (4 A, powdered, 5 g) in anhydrous THE (25 mL) was stirred at ambient temperature for 5 h.
Sodium triacetoxyborohydride (1.5 g, 7.08 mmol) was added and the mixture stirred for 18 h, then loaded onto an Isolute SCX-2 cartridge (25 g). The cartridge was then washed with methanol and the desired product was subsequently eluted using 2 M NH3 in MeOH. The product was collected and concentrated in vacuo. The resultant residue was purified by flash chromatography (Si-PPC, DCM: MeOH; 100:0 to 99:1 to 98:2 to 95:5 to 90:10) to afford the title compound as a white foam (0.82 g, 57 %). LCMS (Method H): RT = 2.38 min, M+H+ _ 408.

[00557] Example 75" 2-Chloro-8-[2-(4-methanesulfonyl-3,3-dimethylpiperazin-l-yl)-ethyl]-9-methyl-6-morpholin-4-yl-9H-purine (0) ,S-N N-\_ N I -ICI

[00558] To a solution of (2-chloro-9-methyl-6-morpholin-4-yl-9H-purin-8-yl)acetaldehyde (137 mg, 0.46 mmol) in DCE (10 mL) was added 2,2-dimethylpiperazine-l-carboxylic acid tert-butyl ester (99 mg, 0.46 mmol), powdered 4 A molecular sieves and sodium triacetoxyborohydride (146 mg, 0.69 mmol). After stirring at rt for 20 h, the reaction mixture was filtered through Celite , loaded onto an Isolute SCX-2 cartridge, washed with MeOH then the desired product eluted with 2 M NH3/MeOH in DCM. The resulting residue was purified by column chromatography (Si-PCC, 0-10% MeOH in DCM) to give a residue, which was taken up in DCM (3 mL). TFA (1 mL) was then added and the reaction mixture stirred at RT for 2 h. The reaction mixture was loaded onto an Isolute SCX-2 cartridge, washed with MeOH then the desired product eluted with 2 M NH3 in MeOH. The resulting residue was purified by column chromatography (Si-PCC, 0-10% MeOH in DCM) to give a residue (28 mg), which was taken up in DCM (4 mL). The solution was cooled to 0 C and Net3 (0.03 mL, 0.21 mmol) and methanesulfonyl chloride (0.03 mL, 0.39 mmol) were added.
After 10 min the reaction mixture was allowed to warm to RT then stirred for 60 h. The reaction mixture was partitioned between DCM and sat. NaHCO3(aq), the organic layer separated and passed through a hydrophobic frit, then evaporated in vacuo.
This residue was taken up in MeOH/DCM, loaded onto an Isolute SCX-2 cartridge, washed with MeOH then eluted with 2 M NH3/MeOH in DCM ) to give 2-Chloro-8-[2-(4-methanesulfonyl-3,3-dimethylpiperazin- 1-yl)-ethyl]-9-methyl-6-morpholin-4-yl-9H-purine (35 mg, 16% over 3 steps) as a yellow oil. LCMS (Method H): RT = 2.82 min, [M+H]+ 472.4 [00559] Example 75hh [2-(2-Chloro-9-methyl-6-morpholin-4-yl-9H-purin-8-yl)-ethyl]-(1,1-dioxo-tetrahydro- l -thiophen-3-yl)amine O;S
Q (0) N
H-_<N :]I I N NCI

[00560] To a solution of (2-chloro-9-methyl-6-morpholin-4-yl-9H-purin-8-yl)acetaldehyde (118 mg, 0.40 mmol) in DCE (15 mL) was added 1,1-dioxo-tetrahydro-l-thiophen-3-ylamine (107 mg, 0.80 mmol) and powdered 4 A molecular sieves. The reaction mixture was stirred at room temperature for 30 min, sodium triacetoxyborohydride (169 mg, 0.80 mmol) was added and the resulting mixture stirred for a further 18 h. The reaction mixture was filtered through Celite , loaded onto an Isolute SCX-2 cartridge, washed with MeOH then the desired product eluted with 2 M NH3/MeOH in DCM. The resulting residue was purified by column chromatography (Si-PCC, 0-7% MeOH in DCM) to give [2-(2-Chloro-9-methyl-6-morpholin-4-yl-9H-purin-8-yl)-ethyl]-(1,1-dioxo-tetrahydro-l -thiophen-3-yl)amine as a yellow oil (45 mg, 27%). LCMS (Method H): RT = 2.38 min, [M+H]+ 415.4 [00561] Example 75ii 3-(2-Chloro-9-methyl-6-morpholin-4-yl-9H-purin-8-yl)-pyrrolidine-l-carboxylic acid tert-butyl ester (0) N

N N CI

[00562] Zinc activation: To a suspension of zinc powder (128 mg, 0.99 mmol) and Celpure P65 in anhydrous DMA (4 mL) was added a 7:5 (v:v) mixture of TMS-C1:1,2-dibromoethane (25 L). The reaction mixture was stirred at room temperature for 10 min.
[00563] Zinc insertion: A solution of 3-iodopyrrolidine-l-carboxylic acid tert-butyl ester (470 g, 1.58 mmol) in anhydrous DMA (2 mL) was added dropwise. The reaction mixture was stirred for 45 min at room temperature.
[00564] Coupling reaction: A mixture of 2-chloro-8-iodo-9-methyl-6-morpholin-4-yl-9H-purine (400 mg, 1.05 mmol), Pd(dppf)C12.DCM (42 mg, 5 mol%) and Cul (20 mg, mol%) in DMA (4 mL) was evacuated and back-filled with argon. The zincate mixture was quickly filtered (PTFE) and added onto the palladium-containing mixture. The resulting reaction mixture was stirred at 85 C for 18 hours then cooled to room temperature. The mixture was partitioned between EtOAc and a 1M aqueous solution of ammonium chloride, the organic layer separated, washed with water, brine and dried (Na2SO4). The resulting residue was purified by column chromatography (Si-PCC, 0-100% EtOAc in cyclohexane) to give 3-(2-Chloro-9-methyl-6-morpholin-4-yl-9H-purin-8-yl)-pyrrolidine-l-carboxylic acid tert-butyl ester as an orange oil (79 mg, 18%). LCMS (Method H): RT = 4.48 min, [M+H]+
423.5 [00565] Example 75jj. 4-(2-Chloro-9-methyl-6-morpholin-4-yl-9H-purin-8-ylmethyl)-3-isopropylpiperazin-2-one (0) N
N :]l N N NCI

O
NJ
H

[00566] A mixture of 2-chloro-9-methyl-6-morpholin-4-yl-9H-purine-8-carbaldehyde (212 mg, 0.75 mmol), 3-isopropylpiperazin-2-one (128 mg, 0.90 mmol) and powdered 4A
molecular sieves in DCE (18 mL) were stirred at RT. After 4 h, sodium triacetoxyborohydride (318 mg, 1.50 mmol) was added and the resulting mixture stirred for a further 17 h. The reaction mixture was filtered through Celite , loaded onto an Isolute SCX-2 cartridge, washed with MeOH then the desired product eluted with 2 M
NH3/MeOH
in DCM. Trituration of the resulting residue with EtOAc gave 4-(2-Chloro-9-methyl-6-morpholin-4-yl-9H-purin-8-ylmethyl)-3-isopropylpiperazin-2-one as a yellow oil (198 mg, 65%). LCMS (Method H): RT = 2.82 min, [M+H]+ 408.4 [00567] Example 75kk 2-Chloro-8-iodo-9-methyl-6-morpholin-4-yl-9H-purine (0) N
N

N NxCI

[00568] A suspension of 2-chloro-9-methyl-6-morpholin-4-yl-9H-purine (2.95 g, 11.7 mmol) and TMEDA (2.6 mL, 2.03 g, 17.5 mmol) in THE (80 mL) was cooled to -78 C
before the drop wise addition of n-BuLi (9.8 mL, 24.5 mmol, 2.5 M solution in hexanes). The resulting mixture was warmed to -40 C and stirred for 40 mins. The mixture was cooled back to -78 C before the addition of 1-chloro-2-iodoethane (3.7 mL, 7.8 g, 40.8 mmol). The resulting mixture was allowed to warm to r.t. over 2 h then quenched with NH4C1 and extracted with EtOAc (x 4). The combined organics were dried (Na2SO4) and concentrated in vacuo affording 2-Chloro-8-iodo-9-methyl-6-morpholin-4-yl-9H-purine as a yellow solid (4.02 g, 91 %). LCMS (method H): RT 4.09 min [M+H]+ 379.9 [00569] Example 7511 2-(2-Ethylbenzoimidazol-l-yl)-9-methyl-6-morpholin-4-yl-9H-purine ( ) N
H -</N
N NIN
N
[00570] A mixture of 2-chloro-9-methyl-6-morpholin-4-yl-9H-purine (4.0 g, 15.8 mmol), 2-ethylbenzimidazole (2.8 g, 19.0 mmol), tris(dibenzylideneacetone)dipalladium (724 mg, 0.79 mmol), Xphos (1.5 g, 3.16 mmol) and Cs2CO3 (10.3 g, 31.6 mmol) in dioxane (90 mL) was purged with argon then heated at 120 C for 16 h in a sealed reactor.
The reaction mixture was filtered through a pad of celite, washing with EtOAc. The filtrate was concentrated in vacuo and purified by column chromatography (Si-PCC, MeOH:EtOAc, 0-10%) affording 2-(2-Ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine as an orange solid (3.49 g, 96%). LCMS (method H): RT 3.46 min, [M+H]+ 364.5 [00571] Example 75mm 2-(2-Ethylbenzoimidazol-1-yl)-8-iodo-9-methyl-6-morpholin-4-yl-9H-purine CO) N
N
j N NN
N
[00572] A suspension of 2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine (1.67 g, 4.58 mmol) and TMEDA (1.0 mL, 799 mg, 6.88 mmol) in THE (25 mL) was cooled to -78 C before the drop wise addition of n-BuLi (2.8 mL, 6.88 mmol, 2.5 M
solution in hexanes). The resulting mixture was stirred for 40 mins before the addition of 1-chloro-2-iodoethane (629 L, 1.3 g, 6.88 mmol). The resulting mixture was stirred at -78 C
for 1 h then quenched with H2O and warmed to r.t.. The pale yellow precipitate was collected by filtration washing with further H2O and dried under vacuum at 50 C. 2-(2-Ethylbenzoimidazol- 1-yl)-8-iodo-9-methyl-6-morpholin-4-yl-9H-purine was afforded as a pale yellow powder (2.0 g, 90%). LCMS (method H): RT 2.74 min [M+H]+ 490.2 [00573] Example 75nn 2-Chloro-9-methyl-6-morpholin-4-yl-8-[4-(tetrahydropyran-4-yl)piperazin-1-ylmethyl]-9H-purine (0) , I ~N
~N>/ N NCI
NJ

[00574] A mixture of 2-chloro-9-methyl-6-morpholin-4-yl-9H-purine-8-carbaldehyde (165 mg, 0.59 mmol), 1-(tetrahydropyran-4-yl)piperazine (110 mg, 0.65 mmol) and molecular sieves (4 A, powdered, 750 mg) in DCE (10 mL) was stirred at ambient temperature for 4 h. Sodium triacetoxyborohydride (170 mg, 0.80 mmol) was added and the mixture stirred for 18 h, then loaded onto an Isolute SCX-2 cartridge (10 g).
The cartridge was then washed with methanol and the desired product was subsequently eluted using 2 M
NH3 in MeOH. The product was collected and concentrated in vacuo. The resultant residue was purified by flash chromatography (Si-PPC, DCM: MeOH, 100:0 to 98:2 to 95:5 to 90:10) to afford 2-Chloro-9-methyl-6-morpholin-4-yl-8-[4-(tetrahydropyran-4-yl)piperazin-l-ylmethyl]-9H-purine as a white solid (250 mg, 98%). 1H NMR (CDC13, 400MHz) 6 4.27 (m, 4 H), 4.01 (dd, J = 11.5, 4.2 Hz, 2 H), 3.81 (m, 7 H), 3.69 (s, 2 H), 3.36 (dd, J = 12.5, 10.9 Hz, 2 H), 2.55 (m, 8 H), 2.40 (m, 1 H), 1.75 (d, J = 12.5 Hz, 2 H) and 1.56 (m, 2 H) [00575] Example 76a (2-Chloro-9-methyl-6-morpholin-4-yl-9H-purin-8-ylmethyl)phosphonic acid dimethyl ester (0) N :N
O P` N I N'CI
O

[00576] A mixture of 8-bromomethyl-2-chloro-9-methyl-6-morpholin-4-yl-9H-purine (3.92 g, 11.3 mmol) and trimethylphosphite (20 mL, mmol) was heated to reflux (120 C) for 2 h. The reaction mixture was concentrated in vacuo to a fluorescent green solid which was triturated with H20. The resulting pale green solid was purified by column chromatography (Si-PCC, MeOH:EtOAc, 0-10%) affording the title compound as a green solid (3.36 g, 79%).
LCMS (method A): RT 3.45 min [M+H]+ 376.1 [00577] Example 76b 3-(2-Chloro-9-methyl-6-morpholin-4-yl-9H-purin-8-ylmethylene)azetidine-l-carboxylic acid tert-butyl ester CO) N ~-N
N NCI
di N /
O=<
O

[00578] To a solution of diisopropylamine (1.4 mL, 9.8 mmol) in THE (3 mL) at -C was added n-BuLi (3.9 mL, 9.8 mmol, 2.5 M in hexanes) and the resulting mixture allowed to stir for 20 min. The resulting solution was added to a pale green solution of (2-chloro-9-methyl-6-morpholin-4-yl-9H-purin-8-ylmethyl)phosphonic acid dimethyl ester (3.36 g, 8.9 mmol) in THE (80 mL) at -78 C. The resulting mixture was warmed to r.t.
before a solution of 3-oxo-azetidine-l-carboxylic acid tert-butyl ester (1.76 g, 10.2 mmol) in THE (10 mL) was added. The resulting pink mixture was stirred for 16 h then quenched with H20. The mixture was concentrated in vacuo and the residue was partitioned between DCM
and brine. The organic phase was dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, EtOAc:cyclohexane, 0-70%) affording the title compound as a green powder (3.46 g, 92%). 'H NMR (CDC13, 400 MHz):
6 6.33-6.32 (1 H, m), 4.91-4.90 (2 H, m), 4.71-4.70 (2 H, m), 4.28 (4 H, brd s), 3.81 (4 H, t, J
= 4.74 Hz), 3.71 (3 H, s), 1.48 (9 H, s).
[00579] Example 76c 3-[2-(2-Ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purin-8-ylmethylene]azetidine-1-carboxylic acid tert-butyl ester (0) N ~x~p N NO=< N N
O

[00580] A mixture of 3-(2-chloro-9-methyl-6-morpholin-4-yl-9H-purin-8-ylmethylene)azetidine-l-carboxylic acid tert-butyl ester (1.4 g, 3.33 mmol), 2-ethylbenzimidazole (584 mg, 3.99 mmol), tris(dibenzylideneacetone)dipalladium (152 mg, 0.17 mmol), XPhos (317 mg, 0.66 mmol) and Cs2CO3 (2.17 g, 6.65 mmol) in dioxane (15 mL) was purged with argon then heated at 120 C for 16 h in a sealed tube. The reaction mixture was filtered through Celite , washing with EtOAc, and the filtrate concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, EtOAc:cyclohexane, 0-100%) affording the title compound as a cream solid (1.1 g, 62%).
LCMS (method H): RT 3.20 min [M+H]+ 531.4 [00581] Example 76d 3-[2-(2-Ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purin-8-ylmethyl]azetidine-l-carboxylic acid tert-butyl ester (o) N I ~N
N NN
O=< N N
O

[00582] To a solution of 3-[2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purin-8-ylmethylene]azetidine-1-carboxylic acid tert-butyl ester (1.1 g, 2.07 mmol) in EtOH (40 mL) and AcOH (15 mL) was added 10% Pd/C (200 mg) and the resulting mixture stirred under an atmosphere of H2 for 65 h. The reaction mixture was filtered through Celite , washing with EtOAc, and the filtrate concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, EtOAc:cyclohexane, 70-100%) affording the title compound as an orange oil (0.92 g, 83%). LCMS (method H): RT 3.01 min [M+H]+
533.4 [00583] Example 76e 8-Azetidin-3-ylmethyl-2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine (0) N I ~N
i ~N NN 9 H e~N

[00584] To a solution of 3-[2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purin-8-ylmethyl]azetidine-l-carboxylic acid tert-butyl ester (917 mg, 1.72 mmol) in DCM (6 mL) was added TFA (3 mL) and the resulting mixture stirred for 3 h at r.t. The reaction mixture was loaded onto an Isolute SCX-2 cartridge which was washed with MeOH/DCM and the product eluted with 2M NH3/MeOH affording the title compound as a colourless oil (647 mg, 87%). LCMS (method H): RT 1.83 min [M+H]+ 433.3 [00585] Example 76f 4-[2-(2-Ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purin-8-ylmethyl]-2-isopropyl-3-oxopiperazine-l-carboxylic acid tert-butyl ester (o) N
NI
N N'N
N~
O

[00586] To a solution of 2-isopropyl-3-oxopiperazine-1-carboxylic acid tert-butyl ester (58 mg, 0.24 mmol) in DMF (1.5 mL) at 0 C was added NaH (11 mg, 0.29 mmol, 60%
dispersion in mineral oil) and the resulting mixture stirred at r.t. for 30 min before the addition of 8-bromomethyl-2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine (100 mg, 0.22 mmol) in DMF (1.5 mL). The resulting mixture was allowed to stir for 19 h then partitioned between EtOAc and H20. The organic phase was dried (MgSO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, MeOH:EtOAc, 0-10%) affording the title compound as a yellow oil (104 mg, 77%).
LCMS (method H): RT 3.03 min [M+H]+ 618.4 [00587] Example 76g [2-(2-Chloro-9-methyl-6-morpholin-4-yl-9H-purin-8-yl)ethyl]methyl-(3-methyl- l ,1-dioxotetrahydrothiophen-3-yl)amine CO) N--\~ N N
i O N NCI
O

[00588] A mixture of (2-chloro-9-methyl-6-morpholin-4-yl-9H-purin-8-yl)acetaldehyde (210 mg, 0.71 mmol), methyl-(3-methyl-1,1-dioxotetrahydrothiophen-3-yl)amine (116 mg, 0.71 mmol), sodium triacetoxyborohydride (301 mg, 1.42 mmol) and 4A
powdered molecular sieves (280 mg) in DCE (15 mL) was stirred for 23 h. The reaction mixture was filtered through Celite and the filtrate loaded onto an Isolute SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH/DCM. The resulting residue was purified by column chromatography (Si-PCC, MeOH:EtOAc, 0-10%) affording the title compound as a pale yellow solid (87 mg, 28%). LCMS (method H): RT
2.01 min [M+H]+ 443.2 [00589] Example 76h 4-(2-Chloro-9-methyl-6-morpholin-4-yl-9H-purin-8-ylmethyl)-3,3-dimethyl-piperazine-1-carboxylic acid tert-butyl ester CO) --iN I -N
N>/ N NCI
NJ

[00590] A mixture of 8-bromomethyl-2-chloro-9-methyl-6-morpholin-4-yl-9H-purine (400 mg, 1.16 mmol), 3,3-dimethylpiperazine-l-carboxylic acid tert-butyl ester (250 mg, 1.17 mmol) and K2C03 (176 mg, 1.28 mmol) in DMF (20 mL) was allowed to stir at r.t.
for 16 h.
The reaction mixture was loaded onto an Isolute SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH. The resulting residue was purified by column chromatography (Si-PCC, MeOH:DCM, 0-10%) affording the title compound (150 mg, 27%). 1H NMR (CDC13, 400 MHz): 6 4.26 (4 H, brd s), 3.82-3.80 (9 H, m), 3.33 (2 H, brd s), 3.22 (2 H, brd s), 2.42-2.35 (2 H, m), 1.45 (9 H, s), 1.15 (6 H, s).
[00591] Example 76i 2-Chloro-8-(2,2-dimethylpiperazin-1-ylmethyl)-9-methyl-6-morpholin-4-yl-9H-purine CO) N I - N
~N N N CI
NJ
H

[00592] To a solution of 4-(2-chloro-9-methyl-6-morpholin-4-yl-9H-purin-8-ylmethyl)-3,3-dimethyl-piperazine-l-carboxylic acid tert-butyl ester (288 mg, 0.60 mmol) in DCM (30 mL) was added TFA (3 mL) and the mixture stirred at r.t for 1 h. The reaction mixture was loaded onto an Isolute SCX-2 cartridge which was washed with MeOH
and the product eluted with 2M NH3/MeOH affording the title compound as a white solid (199 mg, 87%). 1H NMR (CDC13, 400 MHz): 6 4.26 (4 H, brd s), 3.84-3.77 (9 H, m), 2.84 (2 H, t, J =
4.87 Hz), 2.74 (2 H, s), 2.43 (2 H, t, J = 4.89 Hz), 1.21 (6 H, s).
[00593] Example 76i 2-Chloro-8-(2,2-dimethyl-4-oxetan-3-ylpiperazin-1-ylmethyl)-9-methyl-6-morpholin-4-yl-9H-purine (0) N I -N
~N>/ N N,CI
NJ

d [00594] A mixture of 2-chloro-8-(2,2-dimethylpiperazin-1-ylmethyl)-9-methyl-6-morpholin-4-yl-9H-purine (198 mg, 0.52 mmol), oxetan-3-one (42 mg, 0.58 mmol) and 4A
powdered molecular sieves in DCE (10 mL) was allowed to stir at r.t for 4 h before the addition of sodium triacetoxyborohydride (144 mg, 0.68 mmol). The resulting mixture was allowed to stir for 16 h then loaded onto an Isolute SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH affording the title compound (192 mg, 85%)._'H NMR (CDC13, 400 MHz): 6 4.63 (2 H, t, J = 6.48 Hz), 4.55 (2 H, t, J =
6.08 Hz), 4.27 (4 H, brd s), 3.84-3.80 (7 H, m), 3.49 (2 H, s), 3.38-3.37 (1 H, m), 2.50-2.40 (2 H, m), 2.23-2.04 (4 H, m), 1.20 (6 H, s) [00595] Example 76k (1-{4-[2-(2-Ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-yl-9H-purin-8-ylmethyl]-3,3-dimethylpiperazine-l-carbonyl}
cyclopropyl)carbamic acid tert-butyl ester (0) i--C'N I -N N N
NJ N
~O 1 ~N O

[00596] A mixture of 8-(2,2-dimethylpiperazin-l-ylmethyl)-2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine (140 mg, 0.29 mmol), 1-aminocyclopropanecarboxylic acid (64 mg, 0.32 mmol), HATU (120 mg, 0.32 mmol) and DIPEA (56 L, 0.32 mmol) in DCM (3 mL) was allowed to stir at r.t. for 60 h.
The reaction mixture was loaded onto an Isolute SCX-2 cartridge which was washed with MeOH
and the product eluted with 2M NH3/MeOH. The resulting residue was purified by column chromatography (Si-PCC, MeOH:DCM, 0-2%) affording the title compound. LCMS
(method H): RT 2.56 min, [M+H]+ 673.7 [00597] Example 761 2-(2-Cyclopropylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine-8-carboxylic acid (0) o\ /N I N
i N
HO N~N
N

[00598] To a suspension of 2-(2-cyclopropylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine-8-carbaldehyde (500 mg, 1.24 mmol) in EtOH (16 mL) was added AgNO3 (265 mg, 1.56 mmol) followed by a solution of NaOH (302 mg, 7.5 mmol) in H2O (5 mL). The resulting black suspension was allowed to stir at r.t. for 30 min then filtered through Celite and the resulting filtrate concentrated in vacuo. The resulting residue was dissolved in H2O and basified by the addition of aq. NaOH. The aqueous phase was extracted with DCM then acidified to pH 2 with HC1. The aqueous phase was concentrated in vacuo to half volume then cooled on ice. The resulting precipitate was collected by filtration and dried in vacuo affording the title compound (280 mg, 55%)._'H NMR (DMSO, 400 MHz): 6 8.12-8.11 (1 H, m), 7.72-7.68 (1 H, m), 7.44-7.43 (2 H, m), 4.60 (4 H, brd s), 4.04 (3 H, s), 3.90-3.70 (4 H, m), 3.06-3.00 (1 H, m), 1.33-1.31 (4 H, m) [00599] Example 76m 4- { 1-[2-Chloro-6-morpholin-4-yl-9-(tetrahydropyran-2-yl)-9H-purin-8-ylmethyl]azetidin-3-yl}piperazin-2-one CO) N I - N
N CI
pN NO

N
=0 H

[00600] A mixture of 2-chloro-6-morpholin-4-yl-9-(tetrahydropyran-2-yl)-9H-purine-8-carbaldehyde (1.06 g, 3.01 mmol) and 4-azetidin-3-ylpiperazin-2-one (560 mg, 3.61 mmol) in DCE (60 mL) and DMF (20 mL) was allowed to stir at r.t. for 10 min before the addition of 4A powdered molecular sieves (3.0 g) followed by sodium triacetoxyborohydride (1.28 g, 6.04 mmol). The resulting mixture was allowed to stir for 64 h then filtered through Celite which was washed with DCM. The filtrate was concentrated in vacuo and the resulting residue dissolved in EtOAc and washed with NaHCO3, H2O and brine. The organic phase was dried (Na2SO4) and concentrated in vacuo affording the title compound as a yellow gum (997 mg, 67%). LCMS (method A): RT 2.19 and 2.11 min [M-CSH90 +H]+ 407.3 [00601] Example 76n 4- { 1-[2-(2-Ethylbenzoimidazol- l -yl)-6-morpholin-4-yl-9-(tetrahydropyran-2-yl)-9H-purin-8-ylmethyl]azetidin-3-yl}piperazin-2-one CO) N -N

N

O =0 H

[00602] A mixture of 4- { 1- [2-chloro-6-morpholin-4-yl-9-(tetrahydropyran-2-yl)-9H-purin-8-ylmethyl]azetidin-3-yl}piperazin-2-one (990 mg, 2.00 mmol), 2-ethylbenzimidazole (322 mg, 2.20 mmol), tris(dibenzylideneacetone)dipalladium (46 mg, 0.05 mmol), XPhos (95 mg, 0.20 mmol) and Cs2CO3 (980 mg, 3.01 mmol) in dioxane (30 mL) was purged with argon then heated at 115 C for 6 h then stirred at r.t. for 16 h. The reaction mixture was filtered through Celite , washing with dioxane, and the filtrate concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, MeOH:DCM, 0-10%) affording the title compound (470 mg, 39%). LCMS (method A): RT 2.01 and 1.92 min [M+H]+ 601.6 [00603] Example 76o 2-Chloro-8-iodo-6-morpholin-4-yl-9-(tetrahydropyran-2-yl)-9H-purine CO) I_<N N
N NiCI
do [00604] A solution of 2-chloro-6-morpholin-4-yl-9-(tetrahydropyran-2-yl)-9H-purine (1.50 g, 4.63 mmol) and TMEDA (1.72 mL, 6.94 mmol) in THE (30 mL) was cooled to -78 C before the drop wise addition of n-BuLi (6.08 mL, 9.73 mmol, 1.6 M solution in hexanes).
The resulting mixture was allowed to stir at -78 C for 485 min before the addition of 1-chloro-2-iodoethane (902 L, 16.22 mmol). The resulting mixture was allowed to warm to 0 C over 2.5 h then quenched with H2O and extracted with DCM. The combined organics were washed with brine then dried (Na2SO4) and concentrated in vacuo. The residue was triturated with 1PrOAc and the resulting solid collected by filtration affording the title compound (1.80 g, 87%). LCMS (method A): RT 3.90 min [M+H]+ 450.3 [00605] Example 76p 3-[2-(2-Methylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purin-8-ylmethylene]azetidine-l-carboxylic acid tert-butyl ester (o) N ~x~p N N
O=<
O

[00606] A mixture of 3-(2-chloro-9-methyl-6-morpholin-4-yl-9H-purin-8-ylmethylene)azetidine-l-carboxylic acid tert-butyl ester (200 mg, 0.48 mmol), methylbenzimidazole (76 mg, 0.57 mmol), tris(dibenzylideneacetone)dipalladium (44 mg, 0.06 mmol), XPhos (58 mg, 0.10 mmol) and Cs2CO3 (320 mg, 0.95 mmol) in toluene (4 mL) was purged with argon then heated at 140 C for 2 h in a microwave reactor.
The reaction mixture was filtered through Celite , washing with MeOH, and the filtrate concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, EtOAc:cyclohexane, 0-100%) affording the title compound as an off-white solid (156 mg, 64%). LCMS (method A): RT 3.11 min [M+H]+ 517.3 [00607] Example 76q 3-[2-(2-Methylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purin-8-ylmethyl]azetidine-l-carboxylic acid tert-butyl ester (o) N xp 'N NN O=<

N O

[00608] To a solution of 3-[2-(2-methylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purin-8-ylmethylene]azetidine-l-carboxylic acid tert-butyl ester (205 mg, 0.40 mmol) in EtOH (10 mL) and AcOH (3 mL) was added 10% Pd/C (40 mg) and the resulting mixture stirred under an atmosphere of H2 for 65 h. The reaction mixture was filtered through Celite , washing with MeOH, and the filtrate concentrated in vacuo affording the title compound (207 mg, quant.). LCMS (method H): RT 2.92 min [M+H]+ 519.4 [00609] Example 76r 8-Azetidin-3-ylmethyl-2-(2-methylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-y1-9H-purine C0~

NN
N. N~N
H N

[00610] To a solution of 3-[2-(2-methylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purin-8-ylmethyl]azetidine-1-carboxylic acid tert-butyl ester (207 mg, 0.40 mmol) in DCM (5 mL) was added TFA (5 mL) and the resulting mixture stirred for 2 h at r.t. The reaction mixture was loaded onto an Isolute SCX-2 cartridge which was washed with MeOH/DCM and the product eluted with 2M NH3/MeOH affording the title compound as a white foam (131 mg, 80%). LCMS (method H): RT 1.81 min [M+H]+ 419.4 [00611] Example 76s Acetic acid 1,1-dimethyl-2-{3-[9-methyl-2-(2-methylbenzoimidazol-1-yl)-6-morpholin-4-yl-9H-purin-8-ylmethyl] azetidin- l -yl} -2-oxoethyl ester (0) NN
N,N
N N
O
\ ~O O

[00612] A mixture of 8-azetidin-3-ylmethyl-2-(2-methylbenzoimidazol-l-yl)-9-methyl-6-morpholin-4-y1-9H-purine (131 mg, 0.31 mmol), acetic acid 1-chlorocarbonyl-l-methylethyl ester (45 L, 0.31 mmol) and NEt3 (40 L, 0.31 mmol) in THE (3 mL) was allowed to stir at r.t. for 16 h then concentrated in vacuo. The resulting residue was partitioned between DCM and H20, the organic phase dried (Na2SO4) and concentrated in vacuo. The residue was purified by column chromatography (Si-PCC, MeOH:EtOAc, 0-10%) affording the title compound as a white solid (125 mg, 73%). LCMS (method H):
RT 2.50 min [M+H]+ 547.5 [00613] Example 76t 3-[2-(2-Isopropylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purin-8-ylmethylene]azetidine-l-carboxylic acid tert-butyl ester (0) 1/ 11 N ~N
N N~N \
N / N O=( O

[00614] A mixture of 3-(2-chloro-9-methyl-6-morpholin-4-yl-9H-purin-8-ylmethylene)azetidine-l-carboxylic acid tert-butyl ester (200 mg, 0.48 mmol), isopropylbenzimidazole (92 mg, 0.57 mmol), tris(dibenzylideneacetone)dipalladium (44 mg, 0.06 mmol), XPhos (58 mg, 0.10 mmol) and Cs2CO3 (310 mg, 0.95 mmol) in toluene (4 mL) was purged with argon then heated at 140 C for 45 min in a microwave reactor.
The reaction mixture was filtered through Celite , washing with MeOH, and the filtrate concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, EtOAc:cyclohexane, 0-100%) affording the title compound as an off-white solid (255 mg, 99%). LCMS (method A): RT 3.40 min [M+H]+ 545.3 [00615] Example 76u 3-[2-(2-Isopropylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purin-8-ylmethyl]azetidine-l-carboxylic acid tert-butyl ester (0) N I i ~~ N!' N
O=( N N
O

[00616] To a solution of 3-[2-(2-isopropylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purin-8-ylmethylene]azetidine-l-carboxylic acid tert-butyl ester (255 mg, 0.47 mmol) in EtOH (15 mL) and AcOH (5 mL) was added 10% Pd/C (55 mg) and the resulting mixture stirred under an atmosphere of H2 for 65 h. The reaction mixture was filtered through Celite , washing with MeOH, and the filtrate concentrated in vacuo affording the title compound (256 mg, quant.). LCMS (method A): RT 3.16 min [M+H]+ 547.4 [00617] Example 76v 8-Azetidin-3-ylmethyl-2-(2-isopropylbenzoimidazol-l-yl)-9-methyl-6-morpholin-4-yl-9H-purine C0~

N DI
~~ N!' N
N. N

[00618] To a solution of 3-[2-(2-isopropylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purin-8-ylmethyl]azetidine-l-carboxylic acid tert-butyl ester (256 mg, 0.47 mmol) in DCM (5 mL) was added TFA (5 mL) and the resulting mixture stirred for 2 h at r.t. The reaction mixture was loaded onto an Isolute SCX-2 cartridge which was washed with MeOH/DCM and the product eluted with 2M NH3/MeOH affording the title compound as an orange foam (205 mg, 97%). LCMS (method H): RT 1.91 min [M+H]+ 447.4 [00619] Example 76w Acetic acid 1,1-dimethyl-2-{3-[9-methyl-2-(2-methylbenzoimidazol-1-yl)-6-morpholin-4-yl-9H-purin-8-ylmethyl] azetidin- l -yl} -2-oxoethyl ester (0) NN
N,N

N N
O \~
O O

[00620] A mixture of 8-azetidin-3-ylmethyl-2-(2-isopropylbenzoimidazol-l-yl)-9-methyl-6-morpholin-4-yl-9H-purine (100 mg, 0.22 mmol), acetic acid 1-chlorocarbonyl-l-methylethyl ester (32 L, 0.22 mmol) and NEt3 (29 L, 0.22 mmol) in THE (3 mL) was allowed to stir at r.t. for 16 h then concentrated in vacuo. The resulting residue was partitioned between DCM and H20, the organic phase dried (Na2SO4) and concentrated in vacuo. The residue was purified by column chromatography (Si-PCC, MeOH:EtOAc, 0-7%) affording the title compound as a white foam (97 mg, 75%)._LCMS (method A): RT
2.65 min [M+H]+ 575.3 [00621] Example 77a 4-[2-(2-Ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine-8-carbonyl]piperidine-1-carboxylic acid tert-butyl ester CO) O N

N N!' N
N
N
O=( O
[00622] To a solution of 2-(2-ethylbenzoimidazol-l-yl)-9-methyl-6-morpholin-4-yl-9H-purine (500 mg, 1.38 mmol) and TMEDA (312 L, 2.07 mmol) in THE (10 mL) at -C was added n-BuLi (660 L, 1.65 mmol, 2.5M solution in hexanes) and the resulting mixture stirred for 30 min before the addition of a solution of 4-(methoxymethylcarbamoyl)piperidine-l-carboxylic acid tert-butyl ester (564 mg, 2.07 mmol) in THE (5 mL). The resulting mixture was stirred for 2 h then quenched with H2O and extracted with EtOAc. The combined organic phases were dried (MgSO4) and concentrated in vacuo. The resulting residue was triturated with EtOAc:cyclohexane and the mother liquors concentrated in vacuo affording the title compound as an oil (760 mg, 96%). LCMS
(method A): RT 3.67 min [M+H]+ 557.3 [00623] Example 77b 4-{l-[2-(2-Ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purin-8-yl]-l-hydroxyethyl}piperidine-l-carboxylic acid tert-butyl ester (0) OH N

3H,LN
O=<
O

[00624] To a solution of 4-[2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine-8-carbonyl]piperidine-l-carboxylic acid tert-butyl ester (177 mg, 0.31 mmol) in THE (3 mL) at 0 C was added methylmagnesium bromide (130 L, 0.37 mmol, 3M
solution in Et20) and the resulting mixture stirred for 1 h before further methylmagnesium bromide (130 L, 0.37 mmol) was added. The resulting mixture was warmed to r.t. and stirred for 16 h then concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, MeOH:EtOAc, 0-10%) affording the title compound as a clear oil (104 mg, 57%).
LCMS (method A): RT 3.09 min [M+H]+ 591.2 [00625] Example 77c 3-{2-[2-((R)-l-Hydroxyethyl)benzoimidazol-1-yl]-9-methyl-6-morpholin-4-yl-9H-purin-8-ylmethylene}azetidine-l-carboxylic acid tert-butyl ester (0) N ~N
,ON NN P
O HO_N
O

[00626] A mixture of 3-(2-chloro-9-methyl-6-morpholin-4-yl-9H-purin-8-ylmethylene)azetidine-l-carboxylic acid tert-butyl ester (180 mg, 0.43 mmol), (R)-1-(1H-benzoimidazol-2-yl)ethanol (84 mg, 0.52 mmol), tris(dibenzylideneacetone) dipalladium (40 mg, 0.04 mmol), XPhos (82 mg, 0.17 mmol) and Cs2CO3 (279 mg, 0.86 mmol) in toluene (3 mL) was purged with argon then heated at 140 C for 1 h in a microwave reactor. The reaction mixture was filtered through Celite , washing with EtOAc and the filtrate concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, MeOH:EtOAc, 0-15%) affording the title compound (167 mg, 72%). LCMS
(method A): RT 3.24 min [M+H]+ 547.4 [00627] Example 77d 3-{2-[2-((R)-l-Hydroxyethyl)benzoimidazol-1-yl]-9-methyl-6-morpholin-4-yl-9H-purin-8-ylmethyl}azetidine-l-carboxylic acid tert-butyl ester CO) N I -_ N N N
N
O HO_N
O

[00628] To a solution of 3-{2-[2-((R)-l-hydroxyethyl)benzoimidazol-1-yl]-9-methyl-6-morpholin-4-yl-9H-purin-8-ylmethylene}azetidine-l-carboxylic acid tert-butyl ester (167 mg, 0.31 mmol) in EtOAc (5 mL) and EtOH (5 mL) was added 20% Pd(OH)2/C (160 mg) and the resulting mixture stirred under an atmosphere of H2 for 16 h. The reaction mixture was filtered through Celite and the filtrate concentrated in vacuo affording the title compound (156 mg, 93%). LCMS (method A): RT 3.07 min [M+H]+ 549.4 [00629] Example 77e (R)-1-[l-(8-Azetidin-3-ylmethyl-9-methyl-6-morpholin-4-yl-9H-purin-2-yl)- 1H-benzoimidazol-2-yl]ethanol Cpl N ::I

~~ N!' N \
N. HON

[00630] To a solution of 3-{2-[2-((R)-l-hydroxyethyl)benzoimidazol-1-yl]-9-methyl-6-morpholin-4-yl-9H-purin-8-ylmethyl}azetidine-l-carboxylic acid tert-butyl ester (156 mg, 0.28 mmol) in DCM (5 mL) was added TFA (2 mL) and the resulting mixture stirred at r.t.
for 45 min. The reaction mixture was concentrated in vacuo and the resulting residue loaded onto an Isolute SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH affording the title compound (114 mg, 90%). LCMS (method A): RT
1.80 min [M+H]+ 449.4 [00631] Example 77f 3-{2-[2-((S)-l-Hydroxyethyl)benzoimidazol-1-yl]-9-methyl-6-morpholin-4-yl-9H-purin-8-ylmethylene}azetidine-l-carboxylic acid tert-butyl ester CO) N

N NN
HO,,.~N
O
O

[00632] A mixture of 3-(2-chloro-9-methyl-6-morpholin-4-yl-9H-purin-8-ylmethylene)azetidine-l-carboxylic acid tert-butyl ester (180 mg, 0.43 mmol), (S)-1-(1H-benzoimidazol-2-yl)ethanol (84 mg, 0.52 mmol), tris(dibenzylideneacetone) dipalladium (40 mg, 0.04 mmol), XPhos (82 mg, 0.17 mmol) and Cs2CO3 (279 mg, 0.86 mmol) in toluene (3 mL) was purged with argon then heated at 140 C for 1 h in a microwave reactor. Further tris(dibenzylideneacetone) dipalladium (40 mg, 0.04 mmol) and XPhos (82 mg, 0.17 mmol) were added and the mixture heated at 140 C for a further 1 h. The reaction mixture was filtered through Celite , washing with EtOAc and the filtrate concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, MeOH:EtOAc, 0-15%) affording the title compound (127 mg, 55%). LCMS (method A): RT 3.27 min [M+H]+ 547.4 [00633] Example 77g 3-{2-[2-((S)-l-Hydroxyethyl)benzoimidazol-1-yl]-9-methyl-6-morpholin-4-yl-9H-purin-8-ylmethyl}azetidine-l-carboxylic acid tert-butyl ester CO) N~N
~N
N,N
HO,,.~N
O
O

[00634] To a solution of 3-{ 2- [2-((S)-1 -hydroxyethyl)benzoimidazol-l-yl]-9-methyl-6-morpholin-4-yl-9H-purin-8-ylmethylene}azetidine-l-carboxylic acid tert-butyl ester (127 mg, 0.23 mmol) in EtOAc (5 mL) and EtOH (5 mL) was added 20% Pd(OH)2/C (130 mg) and the resulting mixture stirred under an atmosphere of H2 for 18 h. The reaction mixture was filtered through Celite and the filtrate concentrated in vacuo affording the title compound (109 mg, 86%). LCMS (method A): RT 3.06 min [M+H]+ 549.4 [00635] Example 77h (5)-1-[1-(8-Azetidin-3-ylmethyl-9-methyl-6-morpholin-4-yl-9H-purin-2-yl)-1H-benzoimidazol-2-yl]ethanol CO) NDN
~N N~N ~
H HO",N

[00636] To a solution of 3-{ 2- [2-((S)-1 -hydroxyethyl)benzoimidazol-l-yl]-9-methyl-6-morpholin-4-yl-9H-purin-8-ylmethyl}azetidine-l-carboxylic acid tert-butyl ester (109 mg, 0.20 mmol) in DCM (5 mL) was added TFA (2 mL) and the resulting mixture stirred at r.t.
for 45 min. The reaction mixture was concentrated in vacuo and the resulting residue loaded onto an Isolute SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH affording the title compound (70 mg, 80%). LCMS (method A): RT
1.87 min [M+H]+ 449.4 [00637]
[00638] Formula I(iv) furano intermediates wherein (iv) X1 is CR7 and X2 is 0 [00639] Example 80a 2-[4-(2-Chloro-4-morpholin-4-ylfuro[3,2-d]pyrimidin-6-ylmethyl)piperazin- l -yl]-isobutyramide CO) O 'N
N
CD N CI
N

--~NH
O

[00640] A solution of 2-chloro-4-morpholin-4-yl-furo[3,2-d]pyrimidine-6-carbaldehyde (300 mg, 1.12 mmol) and 2-piperazin-1-ylisobutyramide dihydrochloride (327 mg, 1.33 mmol) in DCE (12 mL) was stirred at ambient temperature for 1 h.
Sodium triacetoxyborohydride (358 mg, 1.69 mmol) was added and the mixture stirred for 6 h, then loaded onto an Isolute SCX-2 cartridge (25 g). The cartridge was then washed with methanol and the desired product was subsequently eluted using 2 M NH3 in MeOH. The product was collected and concentrated in vacuo. The resultant residue was purified by flash chromatography (Si-PPC, DCM: MeOH; gradient from 100:0 to 90:10) to afford the title compound as a tan solid (390 mg, 82 %). LCMS (Method H): RT = 2.39 min, M+H+ =

[00641] Example 80b 2-Chloro-4-morpholin-4-yl-6-(3-morpholin-4-ylazetidin-l-ylmethyl)furo[3,2-d]-pyrimidine C) N
O -N
N \ I N CI
OJ

[00642] A solution of 2-chloro-4-morpholin-4-ylfuro[3,2-d]pyrimidine-6-carbaldehyde (300 mg, 1.12 mmol) and 4-azetidin-3-yl-morpholine (191 mg, 1.34 mmol) in DCE
(12 mL) was stirred at ambient temperature for 1 h. Sodium triacetoxyborohydride (358 mg, 1.69 mmol) was added and the mixture stirred for 6 h, then loaded onto an Isolute cartridge (10 g). The cartridge was then washed with methanol and the desired product was subsequently eluted using 2 M NH3 in MeOH. The product was collected and concentrated in vacuo. The resultant residue was purified by flash chromatography (Si-PPC, DCM: MeOH;
gradient from 100:0 to 90:10) to afford the title compound as a tan solid (357 mg, 81 %).
LCMS (Method H): RT = 2.26 min, M+H+ = 394 [00643] Example 80c 2-[1-(2-Chloro-4-morpholin-4-ylfuro[3,2-d]pyrimidin-6-ylmethyl)piperidin-4-yl]-propan-2-ol (o) O 'N
N CI
OH

[00644] A solution of 2-chloro-4-morpholin-4-ylfuro[3,2-d]pyrimidine-6-carbaldehyde (78 mg, 0.29 mmol) and 2-piperidin-4-ylpropan-2-ol (50 mg, 0.35 mmol) in DCE
(3 mL) was stirred at ambient temperature for 45 min. Sodium triacetoxyborohydride (93 mg, 0.44 mmol) was added and the mixture stirred for 2 h, then loaded onto an Isolute SCX-2 cartridge (10 g). The cartridge was then washed with methanol and the desired product was subsequently eluted using 2 M NH3 in MeOH. The product was collected and concentrated in vacuo. The resultant residue was purified by flash chromatography (Si-PPC, DCM: MeOH;
100:0 to 98:2 to 95:5) to afford the title compound as a tan solid (110 mg, 96 %). LCMS
(Method H): RT =
2.33 min, M+H+ = 395.
[00645] Example 80d 2-[1-(4-Morpholin-4-yl-2-(tributylstannanyl)furo[3,2-d]pyrimidin-6-ylmethyl)-piperidin-4-yl]-propan-2-ol Co) 'N
N N Sn OH

[00646] A mixture of 2-[1-(2-chloro-4-morpholin-4-ylfuro[3,2-d]pyrimidin-6-ylmethyl)piperidin-4-yl]propan-2-ol (140 mg, 0.36 mmol), hexabutylditin (266 L, 0.53 mmol), and PdC12 {PtBuz(Ph p-Nme2)}2 (25 mg, 0.034 mmol) in 1,4-dioxane (1.6 mL) was purged with argon gas and then subjected to microwave irradiation at 150 C
for 30 min. The reaction mixture was diluted with MeOH and loaded onto an Isolute SCX -2 cartridge (10 g). The cartridge was then washed with MeOH and the desired product was subsequently eluted using 2 M NH3 in MeOH. The product was collected and concentrated in vacuo to afford the title compound which was used without further purification (147 mg, 54 %).
LCMS (Method H) RT= 3.72 min; [M + H]+ 649 (116Sn) 651 (118Sn) [00647] Example 80e 4-Morpholin-4-yl-6-(3-morpholin-4-yl-azetidin-1-ylmethyl)-(tributylstannanyl)furo [3,2-d]pyrimidine CO) O 'N
N N Sn 0>

[00648] A mixture of 2-chloro-4-morpholin-4-yl-6-(3-morpholin-4-ylazetidin-l-ylmethyl)furo[3,2-d]pyrimidine (200 mg, 0.51 mmol), hexabutylditin (380 L, 0.75 mmol), and PdC12 {PtBuz(Ph p-Nme2)}2 (36 mg, 0.051 mmol) in 1,4-dioxane (2.3 mL) was purged with argon gas and then subjected to microwave irradiation at 150 C for 30 min. The reaction mixture was diluted with MeOH and loaded onto a Isolute SCX -2 cartridge (10 g).
The cartridge was then washed with MeOH and the desired product was subsequently eluted using 2 M NH3 in MeOH. The product was collected and concentrated in vacuo.
The resultant residue was purified by flash chromatography (Si-PPC, DCM: MeOH;
100:0 to 98:2 to 95:5) to afford to afford the title compound as a yellow oil (227 mg, 69 %). LCMS
(Method H) RT= 3.72 min; [M + H]+ 648 (116Sn) 650 (118Sn) [00649] Example 81a 2-Chloro-6-((R)-3-methylmorpholin-4-yl)-9H-purine (0"1"
N
N :J NN
N CI

[00650] A mixture of 2,6-dichloro-9H-purine (2.18 g, 11.53 mmol), (R)-3-methylmorpholine (1.40 g, 13.84 mmol) and DIPEA (2.57 mL, 14.99 mmol) in IMS
(50 mL) were heated at 80 C for 8 h. The reaction mixture was concentrated in vacuo to a reduced volume and the residue partitioned between EtOAc and H20. The organic phase was dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, MeOH:EtOAc, 0-10%) affording the title compound as an off-white solid (914 mg, 31%). LCMS (method H): RT 2.53 min [M+H]+ 254.3 [00651] Example 81b 2-Chloro-9-methyl-6-((R)-3-methylmorpholin-4-yl)-9H-purine co ~
N
N], i N NxCI

[00652] A mixture of 2-chloro-6-((R)-3-methylmorpholin-4-yl)-9H-purine (635 mg, 2.50 mmol), methyl iodide (187 L, 3.00 mmol) and K2C03 (484 mg, 3.50 mmol) in THE
(15 mL) were stirred at r.t. for 18 h before further methyl iodide (187 L, 3.00 mmol) was added. The resulting mixture was allowed to stir for 65 h then concentrated in vacuo. The resulting residue was partitioned between EtOAc and H20, the organic phase washed with brine, then dried (Na2SO4) and concentrated in vacuo affording the title compound as an off-white solid (552 mg, 83%). LCMS (method H): RT 2.76 min [M+H]+ 268.3 [00653] Example 81c 2-Chloro-9-methyl-6-((R)-3-methylmorpholin-4-yl)-9H-purine-8-carbaldehyde CO
N
O N
~ I
N NICI

[00654] To a solution of 2-chloro-9-methyl-6-((R)-3-methylmorpholin-4-yl)-9H-purine (550 mg, 2.05 mmol) in THE (20 mL) at -78 C was added LiHMDS (3.1 mL, 3.08 mmol, 1M solution in THF). The resulting mixture was allowed to stir for 45 min before the addition of DMF (800 L, 10.33 mmol). The reaction mixture was warmed to r.t. over 1.5 h then poured onto 0.5M HC1. The resulting precipitate was collected by filtration and washed with H2O then Et20 affording the title compound as a yellow solid (406 mg, 67%).
LCMS
(method H): RT 3.35 min [M+H]+ 296.3 [00655] Example 8l d 2- { l -[2-Chloro-9-methyl-6-((R)-3-methylmorpholin-4-yl)-purin-8-ylmethyl]piperidin-4-yl}propan-2-ol N
N

N NICI
OH

[00656] A mixture of 2-chloro-9-methyl-6-((R)-3-methylmorpholin-4-yl)-9H-purine-8-carbaldehyde (279 mg, 0.94 mmol), 2-piperidin-4-ylpropan-2-ol (149 mg, 1.04 mmol) and 4A powdered molecular sieves (700 mg) in DCE (15 mL) was stirred for 5.5 h before the addition of sodium triacetoxyborohydride (400 mg, 1.89 mmol). The resulting mixture was allowed to stir for 17 h then filtered through Celite , washing with MeOH. The resulting filtrate was loaded onto an Isolute SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH/DCM. The resulting residue was purified by column chromatography (Si-PCC, MeOH:EtOAc, 0-15%) affording the title compound as a pale yellow solid (366 mg, 92%). LCMS (method H): RT 2.11 min [M+H]+ 423.4 [00657] Example 82a 2-Chloro-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-9H-purine O

d N
N I
N NCI
H

[00658] A mixture of 2,6-dichloro-9H-purine (527 Mg, 2.79 mmol), 3-Oxa-8-aza-bicyclo[3.2.1]octane hydrochloride (500 mg, 3.34 mmol) and DIPEA (1.2 mL, 6.98 mmol) in IMS (15 mL) were heated at 80 C for 3 h then stirred at r.t. for 18 h. The resulting precipitate was collected by filtration and washed with further IMS. The resulting solid was dried in vacuo affording the title compound (663 mg, 90%). 1H NMR (CDC13, 400 MHz): 6 8.14 (1 H, s), 5.60 (1 H, brd s), 4.80 (1 H, brd s), 3.66 (4 H, brd s), 2.00 (4 H, s) [00659] Example 82b 2-Chloro-9-methyl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-9H-purine O

N
<N31 N NxCI

[00660] A mixture of 2-chloro-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-9H-purine (650 mg, 2.45 mmol), methyl iodide (183 L, 2.94 mmol) and K2C03 (473 mg, 3.43 mmol) in THE (15 mL) was stirred at r.t. for 18 h before further methyl iodide (50 L, 0.80 mmol) was added. The resulting mixture was allowed to stir for 65 h then concentrated in vacuo. The resulting residue was partitioned between EtOAc and H20, the organic phase washed with brine, then dried (Na2SO4) and concentrated in vacuo affording the title compound as an off-white solid (673 mg, 98%). LCMS (method H): RT 2.63min [M+H]+ 280.3 [00661] Example 82c 2-Chloro-9-methyl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-9H-purine-8-carbaldehyde N
O N
~ I
N NICI

[00662] To a solution of 2-chloro-9-methyl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-9H-purine (620 mg, 2.22 mmol) and TMEDA (498 L, 3.33 mmol) in THE (11 mL) at -78 C
was added n-BuLi (1.3 mL, 3.33 mmol, 2.5M solution in hexanes). The resulting mixture was warmed to -40 C and allowed to stir for 30 min before cooling back to -78 C.
DMF (517 L, 6.65 mmol) was added and the resulting mixture was stirred at -78 C for 30 min then poured onto 1 M HC1. The aqueous layer was extracted with EtOAc and the organic phase washed with brine, then dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, MeOH:DCM, 0-10%) affording the title compound as a pale yellow solid (500 mg, 73%). 'H NMR (CDC13, 400 MHz): 6 9.88 (1 H, s), 5.79 (1 H, d, J = 6.14 Hz), 5.05 (1 H, d, J = 6.84 Hz), 4.05 (3 H, s), 3.80-3.78 (4 H, m), 2.29-2.01 (4 H, m) [00663] Example 82d 2-{l-[2-Chloro-9-methyl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-9H-purin-8-ylmethyl]piperidin-4-yl}propan-2-ol b N
N N
/--<" :: I -N NCI
OH

[00664] A mixture of 2-chloro-9-methyl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-purine-8-carbaldehyde (500 mg, 1.63 mmol), 2-piperidin-4-ylpropan-2-ol (256 mg, 1.79 mmol) and 4A powdered molecular sieves (500 mg) in DCE (11 mL) was stirred for 4 h before the addition of sodium triacetoxyborohydride (690 mg, 3.26 mmol). The resulting mixture was allowed to stir for 17 h then filtered through Celite , washing with MeOH. The resulting filtrate was loaded onto an Isolute SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH/DCM. The resulting residue was purified by column chromatography (Si-PCC, MeOH:DCM, 0-10%) affording the title compound as a pale yellow solid (577 mg, 82%). LCMS (method H): RT 0.30 and 2.00 min [M+H]+
435.4 [00665] Example 83a 2-Chloro-6-((S)-3-methylmorpholin-4-yl)-9H-purine C:).,. N ::l N NxCI

H
[00666] A mixture of 2,6-dichloro-9H-purine (5.2 g, 27.51 mmol), (S)-3-methylmorpholine (3.30 g, 32.62 mmol) and DIPEA (5.0 mL, 28.71 mmol) in IMS
(130 mL) were heated at 80 C for 3 h then stirred at r.t. for 17 h. The resulting white precipitate was collected by filtration and the filtrate concentrated in vacuo to a reduced volume and the resulting precipitate also collected by filtration. Both batches of solid were combined in DCM
and the organic phase washed with H2O and brine, then dried (MgSO4) and concentrated in vacuo affording the title compound as a white powder (5.3 g, 76%). LCMS
(method H): RT
2.54 min [M+H]+ 254.1 [00667] Example 83b 2-Chloro-9-methyl-6-((S)-3-methylmorpholin-4-yl)-9H-purine C:).,, N :]j N NxCI

[00668] A mixture of 2-chloro-6-((S)-3-methylmorpholin-4-yl)-9H-purine (5.3 g, 20.89 mmol), methyl iodide (1.6 mL, 25.70 mmol) and K2C03 (4.0 g, 28.94 mmol) in THE
(100 mL) were stirred at r.t. for 18 h then concentrated in vacuo. The resulting residue was partitioned between EtOAc and H20, the organic phase washed with brine, then dried (Na2SO4) and concentrated in vacuo affording the title compound (4.84 g, 87%).
LCMS
(method H): RT 2.74 min [M+H]+ 268.2 [00669] Example 83c 2-Chloro-9-methyl-6-((S)-3-methylmorpholin-4-yl)-9H-purine-8-carbaldehyde O
CND,', O N
~ I
N NICI

[00670] To a solution of 2-chloro-9-methyl-6-((S)-3-methylmorpholin-4-yl)-9H-purine (500 mg, 1.67 mmol) and TMEDA (419 L, 2.80 mmol) in THE (10 mL) at -78 C was added n-BuLi (1.12 mL, 2.80 mmol, 2.5M solution in hexanes). The resulting mixture was allowed to warm to -40 C and stir for 30 min then cooled back to -78 C
before the addition of DMF (435 L, 5.61 mmol). The reaction mixture was allowed to stir at -78 C
for 30 min then poured onto 1M HC1. The aqueous phase was extracted with EtOAc and the combined organic phases were washed with H2O and brine, then dried (MgSO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, EtOAc:cyclohexane, 0-50%) affording the title compound as a white solid (450 mg, 81%).
LCMS (method H): RT 3.28 min [M+H]+ 296.3 [00671] Example 83d 2-{l-[2-Chloro-9-methyl-6-((S)-3-methylmorpholin-4-yl)-9H-purin-8-ylmethyl]piperidin-4-yl}propan-2-ol COD,"
N

/--<"N :], N
i NCI
OH

[00672] A mixture of 2-chloro-9-methyl-6-((S)-3-methylmorpholin-4-yl)-9H-purine-8-carbaldehyde (450 mg, 1.52 mmol), 2-piperidin-4-ylpropan-2-ol (239 mg, 1.67 mmol) and 4A powdered molecular sieves (450 mg) in DCE (10 mL) was stirred for 6 h before the addition of sodium triacetoxyborohydride (644 mg, 3.04 mmol). The resulting mixture was allowed to stir for 17 h then filtered through Celite , washing with MeOH. The resulting filtrate was loaded onto an Isolute SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH/DCM. The resulting residue was purified by column chromatography (Si-PCC, MeOH:DCM, 0-4%) affording the title compound as a cream solid (538 mg, 84%). LCMS (method H): RT 2.02 min [M+H]+ 423.3 [00673] Example 101 4-(1-((2-(isoquinolin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-yl)morpholine 101 [00674] A sealable tube was charged with 2-chloro-4-morpholin-4-yl-6-(4-morpholin-4-yl-piperidin-1-ylmethyl)-thieno[3,2-d]pyrimidine (0.100 g, 0.229 mmol), isoquinoline-5-boronic acid (0.048 g, 0.275 mmol), dichlorobis(triphenylphosphine)palladium(II) (0.008 g, 0.012 mmol), 1 N aqueous sodium carbonate solution (1 mL) and acetonitrile (3 mL). The vessel was evacuated and back-filled with argon three times then sealed and heated at 130 C
for 90 min. The reaction mixture was cooled, concentrated, redissolved in ethyl acetate and filtered through celite. The filtrates were concentrated then purified by chromatography (silica, 10 to 20 % methanol in dichloromethane) to give 101 (0.033 g, 27 %) as a yellow solid. MS m/e 531 [M+H]+; 1H NMR (300 MHz, CDC13) 8 ppm 1.54 - 1.71 (m, 2 H) 1.87 (d, J=l 1.3 Hz, 2 H) 2.09 - 2.30 (m, 3 H) 2.52 - 2.63 (m, 4 H) 3.01 - 3.11 (m, 2 H) 3.70 -3.78 (m, 4 H) 3.85 (s, 2 H) 3.87 - 3.94 (m, 4 H) 4.03 - 4.12 (m,4H)7.35(s,1H)7.67-7.75 (m,1H)8.06(d,J=8.3Hz,1H)8.31-8.37(m,1H)8.52- 8.58 (m,1H)8.61-8.67(m,1 H) 9.30 (s, 1 H) [00675] Example 102 4-(6-((4-(cyclopropylmethyl)piperazin-1-yl)methyl)-2-(1H-pyrrolo[2,3-c]pyridin-4-yl)thieno[3,2-d]pyrimidin-4-yl)morpholine 102 [00676] Step 1: 6-(4-(Cyclopropylmethyl)piperazin-1-ylmethyl)-2-methylsulfanyl-morpholin-4-yl-thieno [3,2-d]pyrimidine (0) N
S / N
N S
U

00677] 2-Chloro-6-(4-(cyclopropylmethyl)piperazin-l-ylmethyl)-4-morpholin-4-[
ylthieno[3,2-d]pyrimidine (0.2 g, 0.49 mmol) in DMF (3 mL) was treated with sodium thiomethoxide (0.12 g, 1.71 mmol) in a sealed tube and the reaction mixture heated at 100 C
with stirring. After 2 hours the contents of the tube were diluted with EtOAc then washed with saturated aqueous NaHCO3 (x2) followed by brine and the organic phase was isolated, dried (Na2SO4), filtered and concentrated to afford 6-(4-(cyclopropylmethyl)piperazin-l-ylmethyl)-2-methylsulfanyl-4-morpholin-4-yl-thieno[3,2-d]pyrimidine as a pale yellow solid (0.2 g, 97%). LCMS (Method D): RT = 2.04 min, [M+H]+ 419 [00678] Step 2: A solution of 6-(4-cyclopropylmethylpiperazin-l-ylmethyl)-2-methylsulfanyl-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (46 mg, 0.11 mmol) and benzenesulfonyl-4-tributylstannanyl-lH-pyrrolo[2,3-c]pyridine (129 mg, 0.24 mmol) in DME (2 mL) was treated with copper (I) bromide-dimethyl sulfide complex (50 mg, 2.43 mmol) in a sealed tube then the solution was degassed with argon for 5 min.
Pd(PPh3)4 (20 mg, 0.016 mmol) was added and the reaction mixture heated at 100 C for 3 hours. The mixture was filtered through Celite , which was washed with DME and the combined filtrate was evaporated to give a yellow gum. The gum was purified by flash chromatography on silica, eluting with EtOAc to afford 2-(l-benzenesulfonyl-6-(4-cyclopropylmethylpiperazin-1-ylmethyl)-4-morpholin-4-yl-2-(1H-pyrrolo[2,3-c]pyridin-4-yl)thieno[3,2-d]pyrimidine (34 mg, 54%). This intermediate was dissolved in IMS (1 mL) and 1,4-dioxane (1 mL) and the stirring solution was treated with NaOH solution (0.1 mL from 2.5 g NaOH in 5 mL H20).
After 10 min the reaction mixture was treated with HC1(10 N) until at pH 7.
The reaction mixture was filtered to remove insoluble material. The solids were washed with 1,4-dioxane, and the filtrate was evaporated. The resulting residue was taken up in DCM and washed with brine; the isolated organic phase was dried (MgSO4), filtered and evaporated.
Purification was carried out by flash chromatography, eluting with 3-12% MeOH in DCM to afford 102 (22 mg, 41%). IH NMR (DMSO, 400 MHz): 6 11.76 (s, 1 H); 9.13 (s, 1 H); 8.81 (s, 1 H);
7.71 (d, J = 2.71 Hz, 1 H); 7.45 (s, 1 H); 7.40-7.36 (m, 1 H); 3.99 (t, J =
4.6 Hz, 4 H); 3.87 (s, 2 H); 3.83 (t, J = 4.65 Hz, 4 H); 3.30 (br s, 4H); 2.54 (br s, 4 H); 2.24 (br s, 2H); 0.89-0.77 (m, 1 H); 0.50-0.41 (m, 2 H); 0.12-0.04 (m, 2 H). LCMS (Method F): RT =
4.63 min, [M+H]+ 490.1 [00679] Example 103 4-((4-morpholino-2-(1H-pyrrolo[2,3-c]pyridin-4-yl)thieno[3,2-d]pyrimidin-6-yl)methyl)morpho line 103 [00680] Step 1: 2-Methylsulfanyl-4-morpholin-4-yl-6-morpholin-4-ylmethyl-thieno [3,2-d]pyrimidine (0) N
S / N
N> \
N S
O

O[00681] 2-Chloro-4-morpholin-4-yl-6-morpholin-4-ylmethyl-thieno[3,2-d]pyrimidine (0.2 g, 0.56 mmol) in DMF (3 mL) was treated with sodium thiomethoxide (0.12 g, 1.71 mmol) in a sealed tube and the reaction mixture heated at 100 C with stirring.
After 2 h the contents of the tube were diluted with EtOAc, washed with saturated aqueous NaHCO3 (x 2) then brine, and the organic phase was isolated, dried (Na2SO4), filtered and concentrated to afford the title compound as a light brown solid (0.205 g, 100%). LCMS (Method D): RT =
1.80 min, [M+H]+ 366.
[00682] Step 2: A solution of 2-methylsulfanyl-4-morpholin-4-yl-6-morpholin-4-ylmethyl-thieno[3,2-d]pyrimidine (40 mg, 0.11 mmol) and 1-benzenesulfonyl-4-(tributylstannanyl)-1H-pyrrolo[2,3-c]pyridine (129 mg, 0.24 mmol) in DME (2 mL) was treated with copper (I) bromide-dimethyl sulfide complex (50 mg, 2.43 mmol) in a sealed tube and the solution was degassed with argon for 5 min. Pd(PPh3)4 (19 mg, 0.016 mmol) was added and the reaction mixture heated at 100 C for 3 hours. The mixture was filtered through celite, which was washed with DME and the combined filtrate was evaporated to give a yellow gum. The gum was purified by flash chromatography on silica, eluting with EtOAc to afford 2-(1-benzenesulfonyl-lH-pyrrolo[2,3-c]pyridin-4-yl)-4-morpholin-4-yl-6-morpholin-4-ylmethyl-thieno[3,2-d]pyrimidine (34 mg, 54%). The sulfone intermediate was dissolved in IMS (1 mL) and 1,4-dioxane (1 mL) and the stirring solution was treated with NaOH solution (0.1 mL from 2.5 g NaOH in 5 mL H20). After 10 min the reaction mixture was treated with HC1(10 N) until at pH 7. The reaction mixture was filtered to remove insoluble material. The solids were washed with 1,4-dioxane, and the filtrate was evaporated.
The resulting residue was taken up in DCM and washed with brine; the isolated organic phase was dried (MgS04), filtered and evaporated. The resultant crude residue was purified by flash chromatography, (Si-PPC) eluting with 2-8% MeOH in DCM to afford 103 as a white solid (14 mg, 29%). IH NMR (MeOD, 400 MHz): 6 8.99 (s, 1 H); 8.75 (s, 1 H); 7.66 (d, J = 3.95 Hz, 1 H); 7.40-7.36 (m, 2 H); 4.14-4.05 (m, 4 H); 3.94-3.85 (m, 6 H); 3.73 (t, J
= 4.6 Hz, 4 H); 2.59 (t, J = 4.35 Hz, 4 H). LCMS (Method F): RT = 4.59min, [M+H]+ 437.2 [00683] Example 104 1-((2-(7-chloroquinolin-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-N,N-dimethylpiperidin-4-amine 104 [00684] A sealable tube was charged with [1-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-piperidin-4-yl]-dimethyl-amine (0.150 g, 0.380 mmol), chloroquinoline-4-boronic acid pinacol ester (0.132 g, 0.456 mmol), dichlorobis(triphenylphosphine) palladium(II) (0.013 g, 0.02 mmol), 1 N
aqueous sodium carbonate solution (1 mL) and acetonitrile (3 mL). The vessel was evacuated and back-filled with argon three times then sealed and heated at 130 C for 90 min. The reaction mixture was cooled, concentrated, redissolved in ethyl acetate and filtered through celite. The filtrates were concentrated then purified by chromatography (silica, 10 to 20 % methanol in dichloromethane) to give 104 (0.085 g, 43 %) as a yellow solid. MS m/e 531 [M+H]+; 1H

NMR (300 MHz, METHANOL-d4) 8 ppm 1.48 - 1.67 (m, 2 H) 1.82 - 1.96 (m, 2 H) 2.07 -2.26 (m, 3 H) 2.30 (s, 6 H) 3.07 (d, J=l 1.7 Hz, 2 H) 3.82 - 3.91 (m,6H)4.02-4.11 (m,4H) 7.36 (s, 1 H) 7.60 (dd, J=9.1, 2.3 Hz, 1 H) 7.95 (d, J=4.5 Hz, 1 H) 8.10 (d, J=2.3 Hz, 1 H) 8.67 (d, J=9.4 Hz, 1 H) 8.98 (d, J=4.9 Hz, 1 H) [00685] Example 105 2-methyl-2-(4-((4-morpholino-2-(1H-pyrrolo[2,3-c]pyridin-4-yl)thieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)propanamide 105 [00686] A mixture of 2-[4-(4-morpholin-4-yl-2-(tributlystannanyl)thieno[3,2-d]pyrimidin-6-ylmethyl)piperazin-1-yl]isobutyramide (1.17 g, 1.69 mmol), 4-bromo-lH-pyrrolo[2,3-c]pyridine (432 mg, 2.19 mmol), tetrakis(triphenylphosphine)palladium (194 mg, mol %) and Cul (385 mg, 2.02 mmol) in dioxane (20 mL) was purged with argon gas then heated at 140 C, for 20 min, in a microwave reactor. The reaction mixture was loaded onto an Isolute SCX-2 cartridge, washed with MeOH/DCM then eluted with 2 M NH3 in MeOH/DCM. The resulting residue was purified by column chromatography (Si-PPC, MeOH:DCM, gradient 0:100 to 20:80). The resulting solid was dissolved in MeOH, loaded onto an Isolute SCX-2 cartridge, washed with MeOH then eluted with 2 M NH3 in MeOH
to afford 105 as a pale yellow solid (242 mg, 39 %). LCMS (Method F): RT 4.51 min, [M+H]+ 521.2. IH NMR (DMSO, 400 MHz): 6 11.75 (s, 1 H); 9.13 (s, 1 H); 8.81 (s, 1 H);
7.71 (t, J = 2.7 Hz, 1 H); 7.45 (s, 1 H); 7.40-7.37 (m, 1 H); 7.07 (d, J = 3.5 Hz, 1 H); 6.95 (d, J = 3.5 Hz, 1 H); 4.01 (t, J = 4.6 Hz, 4 H); 3.87 (s, 2H); 3.83 (t, J = 4.6 Hz, 4 H); 2.58 (s, 4 H); 2.49 (s, 4 H); 1.10 (s, 6 H) [00687] Example 106 2-methyl-2-(4-((4-morpholino-2-(1H-pyrrolo[3,2-c]pyridin-4-yl)thieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)propanamide 106 [00688] A mixture of 2-[4-(4-morpholin-4-yl-2-(tributylstannanyl)thieno[3,2-d]pyrimidin-6-ylmethyl)piperazin-1-yl]isobutyramide (150 mg, 0.22 mmol), 1-benzenesulfonyl-4-bromo-lH-pyrrolo[3,2-c]pyridine (90 mg, 0.27 mmol), Pd(PPh3)4 (25 mg, 10 mol%) and Cul (50 mg, 0.25 mmol) in dioxane (2.5 mL) was purged with argon gas then heated at 140 C, for 20 min, in a microwave reactor. The reaction mixture was loaded onto an Isolute SCX-2 cartridge, washed with MeOH/DCM then eluted with 2 M NH3 in MeOH.
The resulting residue was dissolved in IMS/dioxane (1:1 mL) and 12.5 M aqueous NaOH
solution (0.1 mL) added. After stirring for 1 h the reaction mixture was loaded onto an Isolute SCX-2 cartridge, washed with MeOH/DCM then eluted with 2 M NH3 in MeOH/DCM. The resulting residue was purified by flash chromatography (Si-PPC, MeOH:DCM, gradient 0:100 to 05:95) to give 106 (28 mg, 24 %) as a pale yellow solid.

LCMS (Method F) RT 4.86 min; [M+H]+ 521.3. IH NMR (CDC13, 400 MHz): 6 9.11 (s, H); 8.54 (d, J = 5.6 Hz, 1 H); 7.45 (s, 1 H); 7.41 (dd, J = 3.3, 0.9 Hz, 1 H);
7.38 (dd, J =
5.6, 0.95 Hz, 1 H); 7.36 (d, J = 3.3 Hz, 1 H); 7.10 (d, J = 5.3 Hz, 1 H); 5.25 (d, J = 5.2 Hz, 1 H); 4.10 (t, J = 4.75 Hz, 4 H); 3.91 (t, J = 4.7 Hz, 4 H); 3.85 (s, 2 H); 2.60 (s, 8 H); 1.24 (s, 6 H) [00689] Example 107 1-((2-(isoquinolin-8-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-N,N-dimethylpiperidin-4-amine 107 [00690] A microwave vessel was charged with dimethyl-[1-(4-morpholin-4-yl-2-tributylstannanyl-thieno[3,2-d]pyrimidin-6-methyl)-piperidin-4-yl]-amine (0.106 g, 0.163 mmol), 8-bromoisoquinoline (0.041 g, 0.196 mmol), copper(I) iodine (0.037 g, 0.196 mmol), palladium tetrakis(triphenylphosphine) (0.019 g, 0.016 mmol) and tetrahydrofuran (2 mL).
The vessel was evacuated and back-filled with argon three times then sealed and heated at 140 C under microwave irradiation for 20 min. The reaction mixture was cooled to room temperature and filtered through celite. The filtrates were concentrated then purified by chromatography (silica, 1 to 20 % of a 49:1 McOH:NH4OH mixture in dichloromethane) to give a colorless residue. This residue was dissolved in dichloromethane (3 mL) then 1 N HC1 in ether (0.2 mL) added dropwise. The resulting precipitate was collected by filtration to furnish 107 (0.028 g, 29 %) as a pale yellow powder and as a tetrahydrochloride salt. MS
m/e 489 [M+H]+. 1H NMR (300 MHz, methanol-d4) 8 ppm 2.45 (br. s., 4 H) 2.94 (s, 6 H) 3.47 (br. s., 2 H) 3.64 - 4.09 (m, 7 H) 4.35 (br. s., 4 H) 4.98 (br. s., 2 H) 8.14 (br. s., 1 H) 8.45 (br. s., 1 H) 8.64 (d, J=7.9 Hz, 1 H) 8.70 (d, J=6.0 Hz, 1 H) 8.73 - 8.86 (m, 1 H) 10.37 (br. s., 1 H).
[00691] Example 108 2-(4-((2-(1-aminoisoquinolin-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-methylpropanamide 108 [00692] Step 1: 4-bromoisoquinolin-l-amine Br N--[00693] To a mixture of 4-bromoisoquinoline (1.102 g, 7.644 mmol), potassium bromide (0.9369 g, 7.873 mmol), and phosphomolybdic acid (70 mg) in acetic acid (23 mL) was added 30% of hydrogen peroxide in water (0.88 mL) over 5 min. The mixture formed a suspension and was stirred at room temperature for 2 h. Water (50 mL) was added. The suspension was extracted with EtOAc (2x100 mL). The combined EtOAc extracts were washed with water (2x50 mL), saturated NaHCO3 (2x50 mL), and brine (20 mL), and dried (Na2SO4). The crude (1.322 g) was purified with flash chromatography to give the product as off-white powder (71 mg, 65%). LCMS: M+H+ =223.
[00694] Step 2: A mixture of 4-bromoisoquinolin-l-amine (126 mg, 0.565 mmol), bispinacol ester boronate (358 mg, 1.41 mmol), and potassium acetate (333 mg, 3.39 mmol) in 1,4-dioxane (4.6 mL) was sparged with N2 for 10 min. [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium(II), complex with dichloromethane (1:1) (23.1 mg, 0.0282 mmol) was added. The mixture was sealed under N2 and heated at 80 C for 20 h, diluted with DCM, the contents were filtered, washed with DCM, and concentrated.
The crude product was mixed with 2-(4-((2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-methylpropanamide (124 mg, 0.282 mmol), a 1 M
solution of sodium carbonate (0.85 mL) and 1,4-dioxane (3.4 mL, 44 mmol). The mixture was sparged with N2 for 10 min. Palladium acetate (6.342 mg, 0.02825 mmol) and a 1.0 M
solution of tri-tert-butylphosphine in toluene (0.0565 mL) were added. The mixture was sealed under N2 and heated at 85 C for 6 h, diluted with DCM, the contents were filtered, and concentrated.
The residue was purified with flash chromatography. The fractions containing the desired product were collected, concentrated, and purified with reverse-phase HPLC to give 108 (25 mg, 16%). LCMS: M+H+ =467. 1H NMR (400 MHz, CDC13) 6 8.91 (d, J = 8.6, 1H), 8.67 (s, 1H), 7.85 (d, J = 8.3, 1H), 7.71 - 7.64 (m, 1H), 7.53 (t, J = 7.3, 1H), 7.34 (s, 1H), 7.10 (s, 1H), 5.29 (s, 2H), 5.20 (s, 1H), 4.10 - 3.99 (m, 4H), 3.87 (dd, J = 9.1, 4.6, 6H), 2.61 (s, 8H), 1.24 (s, 6H) [00695] Example 109 1-((2-(isoquinolin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-N,N-dimethylpiperidin-4-amine 109 [00696] A sealable tube was charged with [1-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-piperidin-4-yl]-dimethyl-amine (0.630 g, 1.59 mmol), isoquinoline-5-boronic acid (0.331 g, 1.91 mmol), dichlorobis(triphenylphosphine) palladium(II) (0.056 g, 0.08 mmol), 1 N aqueous sodium carbonate solution (2.5 mL) and acetonitrile (7.5 mL). The vessel was evacuated and back-filled with argon three times then sealed and heated at 130 C
for 90 min. The reaction mixture was cooled, concentrated, redissolved in methanol and filtered through celite. The filtrates were concentrated then purified by chromatography (C-18 reverse phase column, 5 to 95 % acetonitrile in water containing 0.1 %
TFA). The fractions containing the desired product were concentrated then dissolved in MeOH/dichloromethane, basified with solid sodium carbonate then filtered and concentrated to furnish 109 (0.386 g, 50 %) as a white foam. MS m/e 489 [M+H]; 1H NMR (300 MHz, McOH-d4) 8ppm1.61-1.91 (m, 2 H) 1.99 - 2.15 (m, 2 H) 2.17 - 2.36 (m, 2 H) 2.88 (s, 6 H) 3.04-3.28 (m, 3 H) 3.73 - 3.87 (m, 4 H) 3.91 (s, 2 H) 3.96 - 4.07 (m,4H)7.33(s,1H)7.69 - 7.83 (m, 1 H) 8.18 (d, J=8.3 Hz, 1 H) 8.30 (d, J=7.2 Hz, 1 H) 8.43 (d, J=6.4 Hz, 1 H) 8.57 (d, J=6.0 Hz, 1 H) 9.28 (s, 1 H) [00697] Example 110 1-((2-(1H-benzo[d]imidazol-1-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-N,N-dimethylpiperidin-4-amine 110 [00698] A mixture of [1-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-piperidin-4-yl]dimethylamine (50 mg, 0.13 mmol), benzimidazole (32 mg, 0.27 mmol) and concentrated HC1(53 L, 0.64 mmol) in 1,4-dioxane (1 mL) was subjected to microwave irradiation at 150 C for 40 min. The reaction mixture was cooled to ambient temperature and loaded onto an Isolute SCX-2 cartridge (2 g). The cartridge was then washed with MeOH and the desired product was subsequently eluted using 2 M NH3 in MeOH. The eluent was collected and concentrated in vacuo. The resultant residue was purified by flash chromatography (Si-PPC, DCM: 2 M NH3 in MeOH 100:0 to 98:2 to 95:5 to 90:10) to afford 110 as a white solid (38 mg, 63%). LCMS (Method F): RT =
5.12 min, [M+H]+ 478.2. IH NMR (CDC13, 400 MHz): 6 9.04 (s, 1 H); 8.61-8.57 (m, 1 H);
7.86-7.82 (m, 1 H); 7.43-7.31 (m, 2 H); 7.27 (s, 1H); 4.07 (t, J = 4.8 Hz, 4 H); 3.92 (t, J = 4.8 Hz, 4 H); 3.82 (s, 2 H); 3.08-2.99 (m, 2 H); 2.30 (s, 6 H); 2.20-2.10 (m, 3 H); 1.88-1.78 (m, 2 H); 1.66-1.54 (m, 2 H) [00699] Example 112 2-methyl-2-(4-((7-methyl-4-morpholino-2-(1H-pyrrolo[2,3-c]pyridin-4-yl)thieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)propanamide [00700] A mixture of 2-[4-(7-methyl-4-morpholin-4-yl-2-(tributylstannanyl)thieno[3,2-d]pyrimidin-6-ylmethyl)piperazin-1-yl]isobutyramide (109 mg, 0.15 mmol), 4-bromo-lH-pyrrolo[2,3-c]pyridine (39 mg, 0.20 mmol), tetrakis(triphenylphosphine)palladium (18 mg, 10 mol %) and Cul (32 mg, 0.17 mmol) in toluene (2 mL) was purged with argon gas, then heated at 150 C for 30 min in a microwave reactor. The reaction mixture was loaded onto an Isolute SCX-2 cartridge, washed with MeOH then eluted with 2 M NH3 in MeOH/DCM. The resulting residue was purified by column chromatography (Si-PPC, MeOH:DCM, gradient 0:100 to 05:95) followed by reverse phase HPLC (Phenomenex Gemini 5u C18, 20 mM triethylamine in water on a gradient of acetonitrile 80:20 to 2:98) to give 112 as an off-white solid (17 mg, 21%).
LCMS (Method F): RT 4.93 min, [M+H]+ 535.3. IH NMR (MeOD plus CDC13, 400 MHz): 6 9.17 (s, 1 H);
8.75 (s, 1 H); 7.61 (d, J = 3.0 Hz, 1 H); 7.56 (d, J = 3.0 Hz, 1 H); 4.11 (t, J = 4.7 Hz, 4 H);

3.94 (t, J = 4.7 Hz, 4 H); 3.88 (s, 2 H); 2.74-2.56 (m, 8 H); 2.53 (s, 3 H);
1.24 (s, 6 H) [00701] Example 114 4-(8-((4-tert-butylpiperidin-1-yl)methyl)-9-methyl-6-morpholino-9H-purin-2-yl)isoquinolin-l-amine 114 CO) N
N N

N NCI

[00702] 4-tert-butylpiperidine (0.45 g) was reacted with 4-(8-(bromomethyl)-2-chloro-9-methyl-9H-purin-6-yl)morpholine (1.0 g) via General Procedure C to yield 4-(8-((4-tert-butylpiperidin-l-yl)methyl)-2-chloro-9-methyl-9H-purin-6-yl)morpholine (0.80 g) as a white solid.
CO) N
N N

N
N n..... [00703] A mixture of 4-(8-((4-tert-butylpiperidin-1-yl)methyl)-2-chloro-9-methyl-9H-purin-6-yl)morpholine (697 mg), bis-tributyltin (1.71 mL) and PdC12[t-Bu2P(Ph p-Nme2)2]
(190 mg, in 1,4-dioxane (8.5 mL) was heated in a CEM microwave at 140 C for 40 minutes.
The reaction mixture was then concentrated and the crude product was then purified by flash chromatography (0-30% hexanes/ethyl acetate over 15 minutes) to give intermediate 4-(8-((4-tert-butylpiperidin-1-yl)methyl)-9-methyl-2-(tributylstannyl)-9H-purin-6-yl)morpholine (627 mg).
CO) N
N N

N P

[00704] 4-(8-((4-tert-butylpiperidin-l-yl)methyl)-9-methyl-2-(tributylstannyl)-purin-6-yl)morpholine (0.1 g)was reacted with 4-bromoisoquinolin-l-amine via General Procedure D to afford 114 (10 mg) following reverse phase purification. MS
(Ql) 515.3 (M)+. 'H NMR (500 MHz, CDC13) 6 9.02 (d, 1H), 7.94 - 7.45 (m, 6H), 4.35 (s, 4H), 4.02 -3.61 (m, 9H), 2.97 (s, 2H), 2.13 (s, 2H), 1.92 - 1.52 (m, 5H), 1.52 - 0.68 (m, 26H) [00705] Example 115 2-(1-((2-(1-aminoisoquinolin-4-yl)-9-methyl-6-morpholino-purin-8-yl)methyl)piperidin-4-yl)propan-2-o1115 [00706] 2-(1-((9-Methyl-6-morpholino-2-(tributylstannyl)-9H-purin-8-yl)methyl)piperidin-4-yl)propan-2-ol (0.1 g) was reacted with 4-bromoisoquinolin-l-amine via General Procedure G to afford 115 following reverse phase purification. MS
(Ql) 517.3 (M)+._'H NMR (400 MHz, DMSO) 6 9.01 (d, 1H), 8.56 (s, 1H), 8.25 (d, 1H), 7.67 (t, 1H), 7.49 (t, 1H), 7.07 (s, 2H), 4.23 (s, 4H), 4.02 (s, 1H), 3.87 - 3.66 (m, 1OH), 2.89 (d, 3H), 1.99 (t, 2H), 1.66 (d, 2H), 1.35 - 1.10 (m, 3H), 1.02 (s, 6H).
[00707] Example 116 1-((2-(1H-indazol-1-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-N,N-dimethylpiperidin-4-amine 116 [00708] A solution of indazole (0.118 g) in DMF (8 mL) was cooled to 0 C then sodium hydride (0.06 g) added. After 15 min, [1-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-piperidin-4-yl]-dimethyl-amine (0.395 g) was added and the reaction vessel sealed and heated at 150 C. After 1 h the reaction mixture was cooled to room temperature then diluted with water. The resulting precipitate was collected by filtration then purified by chromatography (silica, 0 to 20 % of a 49:1 McOH:NH4OH
mixture in dichloromethane) to furnish 116 (0.233 g, 49 %) as a white solid after trituration with ethyl acetate. MS m/e 478 [M+H]+; 1H NMR (300 MHz, DMSO-d6) 6 ppm 1.41 (dd, J=l 1.68, 3.39 Hz, 2 H) 1.73 (d, J=10.93 Hz, 2 H) 2.07 (t, J=10.74 Hz, 3 H) 2.17 (s, 6 H) 2.94 (d,J=11.68Hz,2H)3.75-3.90(m,6H)3.93-4.13(m,4H)7.31(t,J=7.54 Hz,1H)7.39 (s, 1 H) 7.56 (dd, J=7.91, 6.40 Hz, 1 H) 7.88 (d, J=7.91 Hz, 1 H) 8.39 (s, 1 H) 8.68 (d, J=8.67 Hz, 1 H).
[00709] Example 117 N,N-dimethyl-l-((2-(2-methyl-lH-benzo[d]imidazol-1-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-amine 117 [00710] A mixture of N-[6-(4-dimethylaminopiperidin-1-ylmethyl)-4-morpholin-4-yl-thieno [3,2-d]pyrimidin-2-yl]benzene-1,2-diamine (80 mg, 0.17 mmol) and triethyl orthoformate (1 mL, 6.0 mmol) in DMF (1 mL) was heated at 150 C for 6 h. The reaction mixture was cooled to ambient temperature and loaded onto an Isolute SCX-2 cartridge (10 g). The cartridge was then washed with MeOH and the desired product was subsequently eluted using 2 M NH3 in MeOH. The eluent was collected and concentrated in vacuo. The resultant residue was purified by flash chromatography (Si-PPC, DCM: 2 M NH3 in MeOH
100:0 to 98:2 to 95:5) followed by reverse phase HPLC (Phenomenex Luna C,8, 20 mM Et3N

in water on a gradient of 20 mM Et3N in acetonitrile 95:5 to 2:98) to afford 117 as a white solid (20 mg, 24%). LCMS (Method F): RT = 4.24 min, [M+H]+ 492.3. IH NMR
(CDC13, 400 MHz): 6 8.09-8.04 (m, 1 H); 7.74-7.68 (m, 1 H); 7.29-7.24 (m, 3 H); 4.08-4.02 (m, 4 H); 3.91-3.86 (m, 4 H); 3.83 (s, 2 H); 3.08-3.00 (m, 2 H); 2.93 (s, 3 H); 2.30 (s, 6 H);
2.21-2.10 (m, 3 H); 1.88-1.79 (m, 2 H); 1.68-1.53 (m, 2 H) [00711] Example 118 2-(1-((9-methyl-6-morpholino-2-(1H-pyrrolo[2,3-c]pyridin-4-yl)-9H-purin-8-yl)methyl)piperidin-4-yl)propan-2-o1118 [00712] 2-(1-((9-methyl-6-morpholino-2-(tributylstannyl)-9H-purin-8-yl)methyl)piperidin-4-yl)propan-2-ol (150 mg) was reacted with 4-bromo-6-azaindole via General Procedure G to afford 118 (31.8 mg) following reverse phase purification. MS (Ql) 491.2 (M)+. 'H NMR (400 MHz, DMSO) 6 11.70 (s, 1H), 9.14 (s, 1H), 8.79 (s, 1H), 7.70 (t, 1H), 7.43 (s, 1H), 4.30 (s, 4H), 4.02 (s, 1H), 3.89 (s, 3H), 3.83 - 3.76 (m, 4H), 3.73 (s, 2H), 2.92 (t, 2H), 1.97 (dd, 16.9, 2H), 1.69 (t, 2H), 1.40 - 1.09 (m, 3H), 1.02 (s, 6H) [00713] Example 119 2-(1-((9-methyl-6-morpholino-2-(1H-pyrrolo[3,2-c]pyridin-4-yl)-9H-purin-8-yl)methyl)piperidin-4-yl)propan-2-o1119 [00714] 2-(1-((9-Methyl-6-morpholino-2-(tributylstannyl)-9H-purin-8-yl)methyl)piperidin-4-yl)propan-2-ol (150 mg) was reacted with 4-bromo-5 -azaindole via General Procedure G to afford 119 (20 mg) following reverse phase purification. MS (Ql) 491.2 (M)+. 'H NMR (400 MHz, MeOD) 6 8.31 (d, 1H), 7.51 (d, 1H), 7.45 (d, 1H), 7.34 (d, 1H), 4.39 (s, 4H), 4.03 - 3.69 (m, 10H), 3.31 (d, 5H), 3.01 (d, 2H), 2.10 (t, 2H), 2.03 (s, 2H), 1.75 (d, 2H), 1.53 - 1.22 (m, 4H), 1.13 (s, 6H) [00715] Example 120 4-(6-((4-methylpiperazin-1-yl)methyl)-2-(quinolin-5-yl)thieno[3,2-d]pyrimidin-4-yl)morpholine 120 [00716] Following General Procedure L for reductive amination, 4-morpholino-2-(quinolin-5-yl)thieno[3,2-d]pyrimidine-6-carbaldehyde and 1-methylpiperazine were reacted to give 120. LCMS m/z: 461.6 (MH+) [00717] Example 121 2-(4-((2-(7-fluoro-lH-pyrrolo[3,2-c]pyridin-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-methylpropanamide 121 [00718] Following the procedures for 142, 2-[4-(4-morpholin-4-yl-2-(tributylstannanyl)thieno[3,2-d]pyrimidin-6-ylmethyl)piperazin-1-yl]isobutyramide was converted to 121. LCMS m/z: 539.2 (MH+) [00719] Example 123 4-((4-morpholino-2-(1H-pyrrolo[3,2-c]pyridin-4-yl)thieno[3,2-d]pyrimidin-6-yl)methyl)morpholine 123 [00720] Following General Procedure L for reductive amination, 4-morpholino-2-(1H-pyrrolo[3,2-c]pyridin-4-yl)thieno[3,2-d]pyrimidine-6-carbaldehyde and morpholine were reacted to give 123. LCMS: M+H+ = 437.5 [00721] Example 124 4-(1-((9-methyl-6-morpholino-2-(1H-pyrrolo[2,3-c]pyridin-4-yl)-9H-purin-8-yl)methyl)piperidin-4-yl)morpholine 124 [00722] Step 1: 4-(1-((9-methyl-6-morpholino-2-(tributylstannyl)-9H-purin-8-yl)methyl)piperidin-4-yl)morpholine CO) N

N
I
I
N / \NSnBu3 ~[00723] A mixture of 4-(1-((2-chloro-9-methyl-6-morpholino-9H-purin-8-yl)methyl)piperidin-4-yl)morpholine (593 mg, 1.36 mmol), bis(tributyltin) (1.36 mL, 2.72 mmol) and PdC12[t-Bu2P(Ph p-Nme2)2] (150 mg, 0.21 mmol) in 1,4-dioxane (5 mL) was heated in a microwave at 140 C for 40 minutes. The reaction mixture was then concentrated.
The crude product was then purified by flash chromatography (10% MeOH in DCM) to give the title compound (859 mg, 91.4%). LCMS: M+H+ = 691.4.
[00724] Step 2: To a degassed mixture of 4-(1-((9-methyl-6-morpholino-2-(tributylstannyl)-9H-purin-8-yl)methyl)piperidin-4-yl)morpholine (859 mg, 1.24 mmol), 4-bromo-l-(phenylsulfonyl)-1H-pyrrolo[2,3-c]pyridine (385 mg, 1.14 mmol), copper(I) iodide (326 mg, 1.71 mmol) in 1,4-dioxane (10 mL) was added Pd(PPh3)4 (100 mg, 0.09 mmol).
The reaction mixture was stirred at 110 C for 18 hours. The reaction mixture was concentrated and then dissolved in DCM and filtered through a column of silica gel (20%
MeOH in DCM). The elutant was concentrated to give a yellow paste which was taken up in ethanol (2 mL) and 1,4-dioxane (3 mL). A 12 M aqueous NaOH solution (0.5 mL) was then added and the resulting mixture was stirred at room temperature for 1 hour.
The reaction mixture was then concentrated and the crude product was purified by flash chromatography using a Biotage KP-NH column (10% MeOH in DCM) followed by RP-HPLC to give 124.
LCMS: M+H+ = 518.3. 'H-NMR (400 MHz, DMSO-d6): 6 11.70 (s, 1H), 9.14 (s, 1H), 8.79 (s, 1H), 7.70 (m, 1H), 7.43 (m, 1H), 4.30 (s, br, 4H), 3.88 (s, 3H), 3.78 (m, 4H), 3.70 (s, 2H), 3.54 (m, 4H), 2.86 (m, 2H), 2.43 (m, 4H), 2.09 (m, 2H), 1.75 (m, 2H), 1.36 (m, 3H).

[00725] Example 125 N,N-dimethyl-l-((4-morpholino-2-(1H-pyrrolo[3,2-c]pyridin-3-yl)thieno[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-amine 125 [00726] A microwave vessel was charged with dimethyl-[1-(4-morpholin-4-yl-2-tributylstannanyl-thieno[3,2-d]pyrimidin-6-methyl)-piperidin-4-yl]-amine(0.4g) in dioxane (8mL). The vessel was evacuated and back filled with argon. To this mixture was added 3-iodo-pyrrolo[3,2-c]pyridine-l-carboxylic acid tert-butyl ester (0.254 g), copper iodide (0.14 g) and tetrakistriphenylphosphine palladium(0.08 g). The vessel was evacuated and back filled with argon again, then the mixture was then irradiated with microwaves at 150 C for 35 min. The reaction mixture was cooled to room temperature then filtered through HPLC filter.
The filtrate was concentrated and the residue obtained was purified by chromatography (silica, 0 to 10 % of a 49:1 McOH:NH4OH mixture in dichloromethane). The residue obtained was dissolved in anhydrous methanol (2mL) and 4.0 N HC1 in dioxane (6 mL) was added. The mixture was stirred at room temperature overnight. The precipitated solid was collected by filtration and the residue obtained was dried at 50 C under vacuum overnight to furnish125 (0.086g, 22 %) as a white solid. MS m/e 478 [M+H]+. 'H NMR (300 MHz, DMSO-d6) ppm 2.19 - 2.34 (m, 4 H) 2.71 (s, 6 H) 3.06 (br. s., 2 H) 3.43 (br. s., 1 H) 3.50 - 3.57 (m, 2 H) 3.81-3.90(m,4H)4.01-4.11(m,4H)4.64(s,2H)7.93(s,1H) 8.07 (d, J=6.78 Hz,1H) 8.50 (d, J=6.78 Hz, 1 H) 8.75 (s, 1 H) 9.76 (s, 1 H) [00727] Example 126 2-methyl-2-(4-((7-methyl-4-morpholino-2-(1H-pyrrolo[3,2-c]pyridin-4-yl)thieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)propanamide [00728] A degassed solution of 2-[4-(7-methyl-4-morpholin-4-yl-2-(tributylstannanyl)thieno[3,2-d]pyrimidin-6-ylmethyl)piperazin-1-yl]isobutyramide (100 mg, 0.14 mmol), 1-benzenesulfonyl-4-bromo-lH-pyrrolo[3,2-c]pyridine (60 mg, 0.18 mmol), Pd(PPh3)4 (16 mg, 0.014 mmol) and Cul (33 mg, 0.17 mmol) in 1,4-dioxane (1.5 mL) was subjected to microwave irradiation at 140 C for 20 min. The reaction mixture was cooled to ambient temperature and loaded onto an Isolute SCX-2 cartridge (10 g). The cartridge was then washed with MeOH and the desired product was subsequently eluted using 2 M NH3 in MeOH. The eluent was collected and concentrated to give 2-{4-[2-(1-benzenesulfonyl-lH-pyrrolo [3,2-c]pyridin-4-yl)-7-methyl-4-morpholin-4-yl-thieno [3,2-d]pyrimidin-6-ylmethyl]-piperazin-l-yl}-isobutyramide as a crude oil. Aqueous NaOH (12.5 M, 0.2 mL) was added to a solution of this intermediate in 1,4-dioxane (2 mL) and IMS (2 mL). The reaction mixture was stirred at ambient temperature for 1 h, and then concentrated in vacuo.
The residue was dissolved in MeOH then loaded onto an Isolute SCX-2 cartridge (10 g). The cartridge was then washed with MeOH and the desired product was subsequently eluted using 2 M NH3 in MeOH. The eluent was collected and concentrated to afford a crude solid. The solid was purified by flash chromatography (Si-PPC, DCM: 2 M NH3 in MeOH, 100:0 to 99:1 to 98:2 to 95:5 to 90:0) to afford 126 as a cream solid (36 mg, 48%). LCMS (Method F):
RT = 5.04 min, [M+H]+ 535.2. IH NMR (CDC13, 400 MHz): 6 9.76 (s, 1 H); 8.46 (d, J = 5.6 Hz, 1 H);
7.49 (dd, J = 3.2, 1.0 Hz, 1 H); 7.34 (d, J = 3.25 Hz, 1 H); 7.31 (dd, J =
5.6, 1.0 Hz, 1 H);
7.12 (d, J = 5.3 Hz, 1 H); 5.35 (d, J = 5.25 Hz, 1 H); 4.08 (t, J = 4.7 Hz, 4 H); 3.86 (t, J =
4.7 Hz, 4 H); 3.82 (s, 2 H); 2.60 (s, 8 H); 2.58-2.45 (m, 3 H); 1.33-1.17 (m, 6 H) [00729] Example 127 4-(6-((4-(1-amino-2-methyl-l-oxopropan-2-yl)piperazin-l-yl)methyl)-4-morpholinothieno[3,2-d]pyrimidin-2-yl)-1H-pyrrolo[2,3-c]pyridine 6-oxide 127 [00730] A mixture of 2-[4-(4-morpholin-4-yl-2-(tributylstannanyl)thieno[3,2-d]pyrimidin-6-ylmethyl)piperazin-1-yl]isobutyramide (170 mg, 0.25 mmol), 4-bromo-6-oxy-pyrrolo[2,3-c]pyridine-l-carboxylic acid tert-butyl ester (100 mg, 0.32 mmol), tetrakis(triphenylphosphine)palladium (28 mg, 10 mol %) and Cul (55 mg, 0.28 mmol) in dioxane (2.5 mL) was purged with argon gas then heated at 140 C, for 20 min, in a microwave reactor. The reaction mixture was loaded onto an Isolute SCX-2 cartridge, washed with MeOH/DCM then eluted with 2 M NH3 in MeOH/DCM. The resulting residue was dissolved in DCM (3 mL) and trifluoroacetic acid (0.4 mL) added. After stirring for 3 h the reaction mixture was loaded onto an Isolute SCX-2 cartridge, washed with MeOH/DCM then eluted with 2 M NH3 in MeOH/DCM. The resulting residue was purified by column chromatography (Si-PPC, MeOH:DCM, gradient 0:100 to 15:85) to give 127 (30 mg, 17%) as a pale yellow solid. LCMS (Method F): RT 4.95 min, [M+H]+ 537.9.
IH NMR
(CDC13, 400 MHz): 6 12.52 (s, 1 H); 9.07 (s, 1 H); 8.79 (s, 1 H); 7.65 (d, J =
2.8 Hz, 1 H);
7.56 (d, J = 2.8 Hz, 1 H); 7.34 (s, 1 H); 7.09 (d, J = 5.3 Hz, 1 H); 5.38 (d, J = 5.3 Hz, 1 H);
4.05 (t, J = 4.6 Hz, 4 H); 3.89 (t, J = 4.7 Hz, 4 H); 3.84 (s, 2 H); 2.60 (s, 8 H); 1.24 (m, 6 H) [00731] Example 128 2-(4-((2-(benzofuran-3-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-methylpropanamide 128 [00732] Following the procedures for 140, 2-(benzofuran-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane was converted to 128. LCMS: M+H+ = 521.2. 'H-NMR (400 MHz, DMSO-d6): 6 8.73 (s, 1H), 8.52 (m, 1H), 7.66 (m, 1H), 7.39 (m, 3H), 7.05 (s, 1H), 6.93 (s, 1H), 3.99 (m, 4H), 3.86 (s, 2H), 2.83 (m, 4H), 2.39-2.61 (m, 8H), 1.08 (s, 6H) [00733] Example 129 2-(1-((2-(3-amino-lH-indazol-l-yl)-9-methyl-6-morpholino-9H-purin-8-yl)methyl)piperidin-4-yl)propan-2-o1129 [00734] Sodium hydride (1.5 eq) was added to 3-iodoindazole (0.5 g) in DMF (5 mL) and the reaction was stirred for 30 minutes at 0 C. 2-(1-((2-Chloro-9-methyl-6-morpholino-9H-purin-8-yl)methyl)piperidin-4-yl)propan-2-ol was subsequently added to the reaction mixture and heated in a Biotage microwave for 10 minutes at 180 C. The reaction was purified by flash column chromatography to afford 2-(1-((2-(3-iodo-IH-indazol-l-yl)-9-methyl-6-morpholino-9H-purin-8-yl)methyl)piperidin-4-yl)propan-2-ol (0.4 g) as a brown solid.
[00735] To a solution of 2-(1-((2-(3-iodo-1H-indazol-1-yl)-9-methyl-6-morpholino-9H-purin-8-yl)methyl)piperidin-4-yl)propan-2-ol (0.1 g), tris(dibenzylideneacetone)dipalladium(0) (3 mg) , 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (5.6 mg) and cesium carbonate (74 mg) in 1,4-dioxane (0.5 mL) was added benzophenone imine (40 L)..The reaction was heated at 120 C until complete, about 90 minutes. The crude reaction mixture was loaded onto silica and purified by flash column chromatography to afford 2-(1-((2-(3 -(diphenylmethyleneamino)-1H-indazol-l-yl)-9-methyl-6-morpholino-9H-purin-8-yl)methyl)piperidin-4-yl)propan-2-ol.
[00736] 2-(1-((2-(3 -(Diphenylmethyleneamino)-1H-indazol-l-yl)-9-methyl-6-morpholino-9H-purin-8-yl)methyl)piperidin-4-yl)propan-2-ol and hydroxylamine hydrochloride (12.4 mg) in MeOH (2 mL) were stirred overnight at room temperature. The crude was purified by reverse phase HPLC to give 129 as a white solid (32.6 mg). MS (Q1) 506.3 (M)+. 'H NMR (400 MHz, DMSO) 6 8.56 (d, 1H), 7.83 (d, 1H), 7.47 (t, 1H), 7.17 (t, 1H), 6.05 (s, 2H), 4.26 (s, 5H), 4.02 (s, 1H), 3.79 (s, 7H), 3.68 (s, 4H), 2.86 (t, 2H), 1.97 (t, J
= 2H), 1.66 (d, 2H), 1.33 - 1.11 (m, 4H), 1.02 (s, 6H).
[00737] Example 130 2-(1-((2-(1-aminoisoquinolin-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-yl)propan-2-o1130 [00738] Following the procedures for 108, 2-(1-((2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-yl)propan-2-ol and 4-bromoisoquinolin-l-amine were converted to 130. LCMS: M+H+ =519. 'H NMR (400 MHz, DMSO) 6 8.99 (d, J = 8.5, 1H), 8.58 (s, 1H), 8.26 (d, J = 8.5, 1H), 8.17 (s, 2H), 7.68 (t, J = 7.6, 1H), 7.50 (t, J = 7.5, 1H), 7.37 (s, 1H), 7.12 (s, 1H), 4.00 - 3.89 (m, 4H), 3.86 - 3.75 (m, 6H), 2.99 (d, J = 11.0, 2H), 1.97 (t, J = 11.2, 2H), 1.65 (t, J = 15.4, 2H), 1.37-1.11 (m, 3H), 1.04 (s, 6H) [00739] Example 131 2-methyl-2-(4-((7-morpholino-5-(1H-pyrrolo[2,3-c]pyridin-4-yl)thiazolo[5,4-d]pyrimidin-2-yl)methyl)piperazin-1-yl)propanamide 131 [00740] A mixture of 2-[4-(7-morpholin-4-yl-5-(tributylstannanyl)thiazolo[5,4-d]pyrimidin-2-ylmethyl)piperazin-1-yl]isobutyramide (167 mg, 0.24 mmol), 4-bromo-lH-pyrrolo[2,3-c]pyridine (62 mg, 0.31 mmol), tetrakis(triphenylphosphine)palladium (28 mg, mol %) and Cul (55 mg, 0.28 mmol) in dioxane (2.5 mL) was purged with argon gas then heated at 140 C, for 20 min, in a microwave reactor. The reaction mixture was loaded onto an Isolute SCX-2 cartridge, washed with MeOH/DCM then eluted with 2 M NH3 in MeOH/DCM. The resulting residue was purified by column chromatography (Si-PPC, MeOH:DCM, gradient 0:100 to 15:85) to give 131 as an pale yellow solid (12 mg, 10%).
LCMS (Method F): RT 4.70 min, [M+H]+ 522.2. IH NMR (DMSO, 400 MHz): 6 11.94 (s, 1 H); 9.10 (s, 1 H); 8.88 (s, 1 H); 7.82 (s, 1 H); 7.35 (s, 1 H); 7.15 (s, 1 H);
7.04 (s, 1 H);
4.37 (s, 4 H); 3.95 (s, 2 H); 3.82 (t, J = 4.6 Hz, 4 H); 2.68 (s, 4 H); 2.56 (s, 4 H); 1.13 (s, 6 H) [00741] Example 132 2-methyl-2-(4-((2-(7-methyl-lH-pyrrolo[2,3-c]pyridin-4-yl)-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)propanamide 132 [00742] A mixture of 2-[4-(4-morpholin-4-yl-2-(tributylstannanyl)thieno[3,2-d]pyrimidin-6-ylmethyl)-piperazin-1-yl]isobutyramide (197 mg, 0.28 mmol), 4-bromo-7-methyl-lH-pyrrolo[2,3-c]pyridine (60 mg, 0.28 mmol), copper(I) 2-thiophene carboxylate (11 mg, 0.056mmol), and Pd(PPh3)4 (32 mg, 0.028 mmol) in dioxane (3 mL) was placed in a microwave tube which was sealed and evacuated. The reaction vessel was degassed and purged with argon (x3). The reaction mixture was irradiated at 140 C for 20 min. The cooled mixture was then poured onto an Isolute SCX -II cartridge and the cartridge was washed with MeOH (100 mL). The product was eluted with 2 M NH3 in MeOH. The pooled fractions were evaporated and the product was further purified by chromatography on silica (Si-PPC), using MeOH in DCM (0-10%) as eluent. The pooled product-containing fractions were evaporated and the residue was crystallized from hot EtOAc to afford 132 as a white crystalline solid (70 mg, 46%). LCMS: (Method F): RT 5.02 min; [M+H]+ 535.2.
IH NMR
(DMSO, 400 MHz): 6 11.71 (s, 1 H); 9.02 (s, 1 H); 7.66 (t, J = 2.7 Hz, 1 H);
7.44 (s, 1H);
7.38 (dd, J = 2.9, 1.9 Hz, 1 H); 7.08 (d, J = 3.5 Hz, 1 H); 6.95 (d, J = 3.5 Hz, 1 H); 3.99 (t, J =
4.6 Hz, 4 H); 3.86 (s, 2 H); 3.85-3.80 (m, 4 H); 2.73 (s, 3 H); 2.62-2.53 (m, 4 H); 2.47 (s, 4 H); 1.08 (s, 6 H) [00743] Example 133 4-(1-((9-methyl-6-morpholino-2-(1H-pyrrolo[3,2-c]pyridin-4-yl)-9H-purin-8-yl)methyl)piperidin-4-yl)morpholine 133 [00744] Following the procedures to prepare 124, 4-(1-((9-Methyl-6-morpholino-(tributylstannyl)-9H-purin-8-yl)methyl)piperidin-4-yl)morpholine and 4-bromo-lH-pyrrolo[3,2-c]pyridine were reacted to give 133. LCMS: M+H+ = 518.3. 'H-NMR
(400 MHz, DMSO-d6): 6 11.55 (s, 1H), 8.30 (d, 1H), 7.51 (d, 1H), 7.48 (d, 1H), 7.20 (d, 1H), 4.30 (m, 4H), 3.80 (s, 3H), 3.78 (m, 6H), 3.55 (m, 4H), 2.88 (m, 2H), 2.44 (m, 4H), 2.09 (m, 2H), 1.77 (m, 2H), 1.40 (m, 3H) [00745] Example 134 1-((2-(1H-indazol-3-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-N,N-dimethylpiperidin-4-amine 134 [00746] A microwave vessel was charged with dimethyl-[1-(4-morpholin-4-yl-2-tributylstannanyl-thieno[3,2-d]pyrimidin-6-methyl)-piperidin-4-yl]-amine (0.400g, 0.615 mmol), 1-boc-3-bromo-lH-indazole (0.219 g, 0.737 mmol), tetrakis(triphenylpho'sphine)palladium (0.071 g, 0.061 mmol), copper iodide (0.140 g, 0.735 mmol), and THE (8 mL). The vessel was sealed, evacuated, and back filled with argon.
Then the mixture was heated at 140 C under microwave irradiation for 20 min.
The reaction mixture was cooled to room temperature, ethyl acetate (30 mL) was added, and the mixture was filterd through celite. The filtrate was concentrated then purified by chromatography (silica, 0 to 20 % of a 9:1 McOH:NH4OH mixture in dichloromethane) to yield a crude solid.
This solid was dissolved in dichloromethane (10 mL) and methanol (0.5 mL).
Then HC1 (0.80 mL, 1 N in ether) was added dropwise. After stirring for 1 hr at room temperature, the mixture was concentrated then purified by chromatography (C 18, 0 to 90% of a 0.1 %
aqueous TFA mixture in methanol). The fractions containing the title compound were combined and the volatile solvents were removed under reduced pressure. The remaining aqueous mixture was diluted with aqueous bicarbonate and extracted with ethyl acetate. The organic layer was dried on sodium sulfate, collected by filtration, and concentrated to give 134 (0.012 g, 9%) as a white solid. MS m/e 477 [M+H]+. 'H NMR (300 MHz, DMSO-d6) 8 ppm 1.45 (dd, J=12, 23 Hz, 2 H), 1.77 (d, J=12 Hz, 2 H), 2.04-2.11 (m, 3 H), 2.25 (s, 6 H), 2.96 (d, J=12 Hz, 2 H), 3.81-3.85 (m, 6 H), 3.99-4.02 (m, 4 H), 7.24 (t, J=9 Hz, 1 H), 7.40 (t, J=9 Hz, 1 H), 7.42 (s, 1 H), 7.62 (d, J=9 Hz, 1 H), 8.54 (d, J=9 Hz, 1 H), 13.37 (s, 1 H) [00747] Example 135 2-(4-((2-(isoquinolin-8-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-methylpropanamide 135 [00748] A microwave vessel was charged with 2-[4-(4-morpholin-4-yl-2-tributylstannanyl-thieno[3,2-d]pyrimidin-6-yl methyl)-piperazin-1-yl]-isobutyramide (0.200 g, 0.288 mmol), 5-bromoisoquinoline (0.072 g, 0.346 mmol), copper(I) iodine (0.066 g, 0.346 mmol), palladium tetrakis(triphenylphosphine) (0.033 g, 0.029 mmol) and dioxane (4 mL).
The vessel was evacuated and back-filled with argon three times then sealed and heated at 140 C under microwave irradiation for 20 min. The reaction mixture was cooled to room temperature and filtered through celite. The filtrates were concentrated then purified by chromatography (silica, 0 to 15 % of a 9:1 McOH:NH4OH mixture in dichloromethane) to give a yellow residue. This residue was dissolved in dichloromethane then 1 N
HC1 in ether (0.2 mL) added dropwise. The resulting precipitate was collected by filtration to furnish 135 (0.012 g, 6 %) as a pale yellow powder and as a tetrahydrochloride salt. MS
m/e 532 [M+H]+;
iH NMR (300 MHz, 360 K, DMSO-d6) 8 ppm 1.49 (s, 6 H) 2.96 - 3.33 (m, 8 H) 3.79 - 3.91 (m, 4 H) 3.97 - 4.09 (m, 4 H) 4.22 (br. s., 2 H) 6.00 (br. s., 2 H) 7.65 (s,1H)8.06-8.18(m, 1 H) 8.23 - 8.35 (m, 2 H) 8.54 (d, J=7.5 Hz, 1 H) 8.68 (br. s., 1 H) 10.57 (br. s., 1 H) [00749] Example 136 N,N-dimethyl-l-((4-morpholino-2-(1H-pyrrolo[2,3-b]pyridin-3-yl)thieno[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-amine 136 [00750] A microwave vessel was charged with dimethyl-[1-(4-morpholin-4-yl-2-tributylstannanyl-thieno[3,2-d]pyrimidin-6-methyl)-piperidin-4-yl]-amine(0.2g) in dioxane (8mL). The vessel was evacuated and back filled with argon. To this mixture was added 3-bromo-pyrrolo[2,3-b]pyridine-l-carboxylic acid tert-butyl ester (0.18 g), copper iodide (0.07g) and tetrakistriphenylphosphine palladium(0.04g). The vessel was evacuated and back filled with argon again, then the mixture was then irradiated with microwaves at 150 C for 30 min. The reaction mixture was cooled to room temperature then filtered through HPLC filter.
The filtrate was concentrated and the residue obtained was purified by chromatography (silica, 0 to 10 % of a 49:1 McOH:NH4OH mixture in dichloromethane) to furnish (0.026g, 17 %) as a light brown solid. MS m/e 478 [M+H]+. 1H NMR (400 MHz, DMSO-d6) 8 ppm 1.41 (d, J=9.09 Hz, 2 H) 1.74 (d, J=11.12 Hz, 2 H) 2.06 (t, J=10.61 Hz, 3 H) 2.18 (s, 6 H)2.94(d,J=11.12Hz,2H)3.75-3.88(m,6H)3.91-4.05(m,4H)7.21 (dd, J=8.08, 4.55 Hz, 1 H) 7.33 (s, 1 H) 8.12 - 8.35 (m, 2 H) 8.83 (dd, J=7.83, 1.77 Hz, 1 H) 12.09 (br. s., 1 H) [00751] Example 137 2-(1-((2-(1-(ethylamino)isoquinolin-4-yl)-4-morpholinothieno [3,2-d]pyrimidin-6-yl)methyl)piperidin-4-yl)propan-2-o1137 [00752] Step 1: 4-bromo-N-ethylisoquinolin-l-amine Br N--INH
[00753] To a suspension of 4-bromo-l chloroisoquinoline (0.831 g, 3.43 mmol) in MeOH (10.3 mL, 254 mmol) was added ethylamine (70% in water, 1.1 mL). The mixture was heated at 50 C for 16 h. The mixture was concentrated. The residue was partitioned between water (20 mL) and DCM (20 mL). DCM layer was separated. The aqueous layer was extracted with DCM (10 mL). The combined DCM solutions were dried (Na2SO4).
Filtration and concentration gave 4-bromo-N-ethylisoquinolin-l-amine (0.761 g, 88%).
LCMS: M+H+ =25 1.
[00754] Step 2: Following the procedures for 108, 2-(1-((2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-yl)propan-2-ol and 4-bromo-N-ethylisoquinolin-l-amine were converted to 137. LCMS: M+H+ =547. 1H NMR (400 MHz, DMSO) 6 9.03 (d, J = 8.5, 1H), 8.67 (s, 1H), 8.28 (d, J = 8.3, 1H), 7.68 (dd, J = 16.9, 6.5, 2H), 7.51 (t, J = 7.5, 1H), 7.37 (s, 1H), 4.04 (s, 1H), 3.93 (d, J = 4.8, 4H), 3.80 (d, J = 6.3, 6H), 3.65 - 3.54 (m, 2H), 2.99 (d, J = 10.9, 2H), 2.07 (s, 1H), 1.97 (t, J =
11.5, 2H), 1.67 (d, J
= 10.9, 2H), 1.36-1.12 (m, 6H), 1.04 (s, 6H) [00755] Example 138 2-(1-((2-(benzofuran-3-yl)-9-methyl-6-morpholino-9H-purin-yl)methyl)piperidin-4-yl)propan-2-o1138 [00756] Following the procedures for 140, 2-(1-((2-chloro-9-methyl-6-morpholino-9H-purin-8-yl)methyl)piperidin-4-yl)propan-2-ol and 2-(benzofuran-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane was converted to 138. LCMS: M+H+ = 491.2. 'H-NMR (400 MHz, DMSO-d6): 6 8.75 (s, 1H), 8.58 (m, 1H), 7.66 (m, 1H), 7.40 (m, 2H), 4.66 (s, 2H), 4.31 (m, 4H), 3.90 (s, 3H), 3.80 (m, 4H), 3.68 (s, br, 1H), 3.12 (m, 2H), 2.90 (m, 2H), 1.90 (m, 2H), 1.56 (m, 3H), 1.06 (s, 6H) [00757] Example 139 4-(9-methyl-6-morpholino-8-((4-morpholinopiperidin-l-yl)methyl)-9H-purin-2-yl)isoquinolin-l-amine 139 [00758] To a degassed suspension of 4-(1-((2-chloro-9-methyl-6-morpholino-9H-purin-8-yl)methyl)piperidin-4-yl)morpholine (84 mg, 0.19 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinolin-l-amine (52 mg, 0.19 mmol), 2 M Na2CO3 aqueous solution (0.19 mL, 0.38 mmol) in toluene (3 mL) and ethanol (1 mL) was added Pd(PPh3)4 (11 mg, 0.010 mmol). The suspension was then stirred under nitrogen at 100 C
for 18 hours.
The reaction mixture was then diluted with EtOAc and water. The aqueous layer was extracted three times with EtOAc. The combined organic extracts were washed with water, dried over Na2SO4, filtered and concentrated. The crude product was purified by flash chromatography (25% MeOH in DCM) to give 139 as a white solid (14.3 mg, 14%).
LCMS:
M+H+ = 544.3. 'H-NMR (400 MHz, DMSO-d6): 6 9.01 (d, 1H), 8.25 (d, 1H), 8.16 (s, 1H), 7.67 (t, 1H), 7.49 (t, 1H), 7.08 (s, 2H), 4.23 (s, br, 4H), 3.82 (s, 3H), 3.78 (m, 6H), 3.55 (m, 4H), 2.88 (m, 2H), 2.43 (m, 4H), 2.07 (m, 3H), 1.75 (m, 2H), 1.38 (m, 2H) [00759] Example 140 2-methyl-2-(4-((2-(2-methylbenzofuran-3-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)propanamide 140 [00760] To a degassed suspension of 2-(4-((2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-methylpropanamide (90.0 mg 0.205 mmol), 4,4,5,5-tetramethyl-2-(2-methylbenzofuran-3-yl)-1,3,2-dioxaborolane (120 mg, 0.46 mmol) in acetonitrile (2 mL) was added 2 M aqueous solution of sodium carbonate (0.20 mL) and 1 M aqueous solution of potassium acetate (0.2 mL). The mixture was then heated in a microwave at 140 C for 30 minutes. The reaction mixture was diluted with water and EtOAc. The aqueous layer was extracted with EtOAc. The combined extracts were washed with brine, dried over Na2SO4, filtered and concentrated. The crude product was purified by RP-HPLC to give 140 (33.6 mg, 30.6%). LCMS: M+H+ = 535.2. 'H-NMR (400 MHz, DMSO-d6): 6 8.45 (m, 1H), 7.55 (m, 1H), 7.42 (s, 1H), 7.31 (m, 2H), 7.05 (s, 1H), 6.93 (s, 1H), 3.95 (m, 4H), 3.86 (s, 2H), 3.83 (m, 4H), 2.84 (s, 3H), 2.42-2.63 (m, 8H), 1.08 (s, 6H) [00761] Example 141 2-(2-(1-aminoisoquinolin-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)propan-2-ol 141 [00762] To a solution of 2-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)propan-2-ol (63 mg, 0.20 mmol) in acetonitrile (3.6 ml) in a microwave reaction vessel was added 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinolin-l-amine (110 mg, 0.40 mmol), Bis(triphenylphosphine)palladium(II) chloride (7.02 mg, 0.010 mmol) and 1M
sodium carbonate in water (0.60 ml). The reaction vessel was sealed and heated in the microwave at 140 C for 20 minutes. LC-MS of the reaction mixture showed no more starting material. The solvent was evaporated and the resulting oil was purified on silica gel (0 to 20% of 2N NH3 in MeOH/DCM). The resulting oil was further purified by reversed phase HPLC to give 141 as an off-white solid (4.7 mg, 6%) 1H NMR (DMSO d6, 400MHz) 9.02 (d, 1H, J =
8.4 Hz), 8.26 (s, I H), 8.26 (d, I H, J = 8.4 Hz), 7.67 (t, I H, J = 7.6 Hz), 7.50 (t, I H, J = 7.6)m 7.33 (s, 1H), 7.11 (s, 2H), 5.84 (s, 1H), 3.98-3.94 (m, 4H), 3.81-3.78 (m, 4H), 1.61 (m, 6H). LCMS
m/z: 422 (MH+) [00763] Example 142 2-methyl-2-(4-((2-(2-methyl-lH-pyrrolo[2,3-c]pyridin-4-yl)-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)propanamide 142 [00764] Step 1: 2-{4-[2-(1-Benzenesulfonyl-2-methyl-lH-pyrrolo[2,3-c]pyridin-4-yl)-4-morpholin-4-yl-thieno [3,2-d]pyrimidin-6-ylmethyl]piperazine-1-yl}
isobutyramide CO) N
S N
S-Q
N
N O

O
[00765] A 5 mL microwave vial was charged with a suspension of 2-[4-(4-morpholin-4-yl-2-(tributylstannanyl)thieno [3,2-d]pyrimidin-6-ylmethyl)piperazin-1-yl]isobutyramide (0.22 g, 0.31 mmol), 1-benzenesulfonyl-4-bromo-2-methyl-lH-pyrrolo[2,3-c]pyridine (0.13 g, 0.37 mmol), copper(I) 2-thiophene carboxylate (0.012 g, 0.062 mmol) and Pd(PPh3)4 (0.036 g, 0.031 mmol) in dioxane (3 mL). The reaction mixture was heated in a microwave for 20 min at 140 C. The crude reaction mixture was loaded onto a SCX-2 cartridge treated with MeOH. The cartridge was washed with MeOH (I OOmL), then the product was recovered eluting with 2N ammonia in MeOH. The eluent was concentrated in vacuo, and the resultant residue was purified by flash chromatography (Si-PPC, 0% to 10% MeOH in DCM) to give the product as white foam (0.17 g, 82%). LCMS (Method C): RT = 3.36 min, [M+H]+ 675.1 [00766] Step 2: 2-{4-[2-(2-Methyl-lH-pyrrolo[2,3-c]pyridin-4-yl)-4-morpholin-4-yl-thieno [3,2-d]pyrimidin-6-ylmethyl]piperazin-1-yl} isobutyramide CO) N
S N
N ~N / NH

O

[00767] A 25 mL round-bottomed flask, under nitrogen, fitted with a condenser/inert gas bubbler (via a Claisen head), was charged with a solution of 2-{ 4-[2-(l-benzenesulfonyl-2-methyl-lH-pyrrolo[2,3-c]pyridin-4-yl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl]piperazine-l-yl}isobutyramide (0.17 g, 0.25 mmol) in dioxane (4 mL), IMS (4 mL) and NaOH 12.5M (0.4 mL). The resulting mixture was stirred at room temperature for 2.5 h.
The solution was concentrated in vacuo, the residue diluted with MeOH and loaded onto a Isolute SCX-2 cartridge treated with MeOH. The cartridge was washed with MeOH
(100 mL) and the product was recovered eluting with 2N NH3 in MeOH, the eluent concentrated, suspended in dioxane/water and freeze-dried overnight. The resultant solid was dissolved in DMSO and purified by preparative HPLC (C 18 column) gradient: (acetonitrile/20 mM
triethylamine) 10% to 98% in (water/20 mM triethylamine) over 20 min (flow rate 18m1/min). The product was freeze-dried overnight yielding 142 as a white powder (0.047 g, 35%). LCMS (Method E): RT = 5.27 min, [M+H]+ 535.2. IH NMR (DMSO, 400 MHz): 6 11.43 (s, 1 H); 8.22 (d, J = 5.4 Hz, 1 H); 7.43 (s, 1 H); 7.33 (dd, J = 6.3, 0.9 Hz, 1 H); 7.07 (d, J = 3.5 Hz, 1 H); 6.95 (d, J = 3.45 Hz, 1 H); 6.87 (s, 1 H); 3.98 (t, J =
4.6 Hz, 4 H); 3.87 (s, 2 H); 3.81 (t, J = 4.6 Hz, 4 H); 3.57 (s, 3 H); 2.61-2.53 (m, 2 H); 2.49-2.45 (m, 2H);
2.44 (s, 4H); 1.08 (s, 6 H) [00768] Example 143 2-methyl-2-(4-((2-(2-methyl-lH-pyrrolo[3,2-c]pyridin-4-yl)-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)propanamide 143 [00769] Step 1: 2-{4-[2-(1-Benzenesulfonyl-2-methyl-lH-pyrrolo[3,2-c]pyridin-4-yl)-4-morpholin-4-yl-thieno [3,2-d]pyrimidin-6-ylmethyl]piperazine-1-yl}
isobutyramide CO) N
S ' N
O
N,N

O
[00770] A 20 mL microwave vial was charged with a suspension of 2-[4-(4-morpholin-4-yl-2-(tributylstannanyl)thieno[3,2-d]pyrimidin-6-ylmethyl)piperazin-l-yl]isobutyramide (0.38 g, 0.54 mmol), 1-benzenesulfonyl-4-bromo-2-methyl-lH-pyrrolo[3,2-c]pyridine (0.21 g, 0.60 mmol), copper(I) 2-thiophene carboxylate (0.042g, 0.22 mmol) and Pd(PPh3)4 (0.126 g, 0.108 mmol) in dioxane (8 mL) and NMP (2 mL). The reaction mixture was heated in a microwave for 100 min at 140 C. The crude reaction mixture was loaded onto a Isolute SCX-2 cartridge treated with MeOH. The cartridge was washed with MeOH
(100 mL), then the product was recovered eluting with 2N NH3 in MeOH. The eluent was concentrated in vacuo and the resultant residue was purified by flash chromatography (Si-PPC, 0-10% MeOH in DCM) to give the product as yellow foam (0.24 g, 65 %).
LCMS
(Method A): RT = 3.53min, [M+H]+ 675.2 [00771] Step 2: A 25 mL round-bottomed flask, under nitrogen, fitted with a condenser and inert gas bubbler (via a Claisen head), was charged with a solution of 1-2- {4-[2-(1-benzenesulfonyl-2-methyl-1 H-pyrrolo [3,2-c]pyridin-4-yl)-4-morpholin-4-yl-thieno [3,2-d]pyrimidin-6-ylmethyl]piperazine-1-yl}isobutyramide (0.24 g, 0.35 mmol) in dioxane (5 mL), IMS (5 mL) and NaOH 12.5M (0.5 mL). The resulting mixture was stirred at room temperature for 2 h and was then concentrated in vacuo. The resultant residue was diluted with MeOH and loaded onto a Isolute SCX-2 cartridge pre-treated with MeOH.
The cartridge was washed with MeOH (100 mL) and the product was recovered eluting with 2N
ammonia in MeOH and concentrated in vacuo. The residue was purified by flash chromatography (Si-PPC, 0 to 100% EtOAc in cyclohexane) to give a yellow powder. The solid was dissolved in DMSO and purified by preparative HPLC (C 18 column, flow rate 18m1/min)) gradient: (acetonitrile / 20 mM triethylamine in water / 20 mM
triethylamine) 25-98% over 20 min. The product was freeze-dried overnight yielding 143 as a yellow powder (0.035 g, 21%). LCMS (Method E): RT = 5.60min, [M+H]+ 535.2. IH NMR (DMSO, 400 MHz): 6 11.43 (s, 1 H); 8.22 (d, J = 5.4 Hz, 1 H); 7.43 (s, 1 H); 7.33 (dd, J
= 6.3, 0.9 Hz, 1 H); 7.07 (d, J = 3.5 Hz, 1 H); 6.95 (d, J = 3.45 Hz, 1 H); 6.87 (s, 1 H); 3.98 (t, J = 4.6 Hz, 4 H); 3.87 (s, 2 H); 3.81 (t, J = 4.6 Hz, 4 H); 3.57 (s, 3 H); 2.61-2.53 (m, 2 H); 2.49-2.45 (m, 2H); 2.44 (s, 4H); 1.08 (s, 6 H) [00772] Example 144 2-(4-((2-(1-acetamidoisoquinolin-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-methylpropanamide 144 [00773] Step 1: N-acetyl-N-(4-bromoisoquinolin-1-yl)acetamide Br NI O\ NT0 [00774] To a solution of 4-bromoisoquinolin-l-amine (403 mg, 1.81 mmol) in methylene chloride (11 mL) at 0 C was added N,N-diisopropylethylamine (1.57 mL, 9.03 mmol), followed by acetyl chloride (0.321 mL, 4.52 mmol) dropwise. The mixture was stirred at 0 C for 10 min then at room temperature for 2 h. The mixture was diluted with DCM (10 mL). Water (20 mL) was added. The organic layer was separated. The aqueous solution was extracted with DCM (10 mL). The combined DCM solutions were dried (Na2SO4). After filtration and concentration, the crude was purified with flash chromatography to give the desired product (470 mg, 85%). 1H NMR (400 MHz, DMSO) 6 8.79 (s, I H), 8.23 (d, J = 8.4, I H), 8.13 (d, J = 8.4, I H), 8.05 (t, J =
7.7, I H), 7.87 (t, J = 7.6, I H), 2.23 (s, 6H).
[00775] Step 2: Following General Procedure B of Suzuki coupling, N-acetyl-N-(4-bromoisoquinolin-1-yl)acetamide (57 mg) was reacted with 2-(4-((2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-methylpropanamide (107 mg). After reaction completion, 1 M Na2CO3 (2 mL) and 1, 4-dioxane (2 mL) were added to the mixture. The suspension was heated at 60 C for 3 h. The reaction mixture was concentrated. Water (5 mL) was added. The contents were extracted with DCM
(2x10 mL).
The combined DCM solutions were dried (Na2SO4). The crude was purified with reverse-phase HPLC to give 144 (20 mg, 22%). LCMS: M+H+ =589. 1H NMR (400 MHz, CDC13) 8.86 (2H), 8.07 (, s, br, 2H), 7.75 (t, J = 7.7, I H), 7.64 (t, J = 7.6, I H), 7.36 (s, I H), 7.09 (s, 1H), 5.18 (s, 1H), 4.12 - 4.00 (m, 4H), 3.94 - 3.81 (m, 6H), 2.62 (s, 8H), 2.44 (s, 3H), 1.25 (s, 6H) [00776] Example 145 2-(1-((9-methyl-2-(2-methylbenzofuran-3-yl)-6-morpholino-9H-purin-8-yl)methyl)piperidin-4-yl)propan-2-o1145 [00777] Following the procedures for 140, 2-(1-((2-chloro-9-methyl-6-morpholino-9H-purin-8-yl)methyl)piperidin-4-yl)propan-2-ol was converted to 145. LCMS: M+H+
= 505.3.
1H-NMR (400 MHz, DMSO-d6): 6 8.49 (m, 1H), 7.54 (m, 1H), 7.31 (m, 2H), 4.26 (s, br, 4H), 4.05 (s, 1H), 3.86 (s, 3H), 3.77 (m, 4H), 3.68 (s, 2H), 2.94 (s, 3H), 2.90 (m, 2H), 2.01 (m, 2H), 1.66 (m, 2H), 1.21 (m, 3H), 0.94 (s, 6H).
[00778] Example 146 1-((2-(benzo[b]thiophen-3-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-N,N-dimethylpiperidin-4-amine 146 [00779] A microwave vessel was charged with [1-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-piperidin-4-yl]-dimethyl-amine (0.400 g, 1.01 mmol), benzo[b]thien-3-ylboronic acid (197 mg, 1.11 mmol), 1 N sodium carbonate solution (2.5 mL), acetonitrile (7.5 mL) and Pd(dppf)C12 (82.4 mg. 0.100 mmol), then the mixture was degassed, sealed, and heated at 140 C under microwave irradiation for 20 min.
The reaction mixture was diluted with dichloromethane (100 mL) and 1 N sodium carbonate solution (10 mL) then the phases were separated. The organic phase was washed with saturated aqueous sodium bicarbonate solution (15 mL) then dried (MgSO4) and concentrated in vacuo.
Purification by chromatography (silica, 0 to 15 % of a 9.5:0.5 McOH:NH4OH
solution in dichloromethane) to afford 146 (240 mg, 48.2 %) as a light brown solid. MS m/e [M+H]+'H NMR (300 MHz, CHLOROFORM-d) 8 ppm 1.47 - 1.68 (m, 2 H) 1.81 (d, J=12.43 Hz, 2 H) 2.03 - 2.20 (m, 3 H) 2.28 (s, 6 H) 3.02 (d, J=12.06 Hz, 2 H) 3.80 (s, 2 H) 3.85-3.95 (m, 4 H) 3.99 - 4.10 (m,4H)7.32(s,1H)7.34-7.42 (m,1H)7.43-7.53(m,1 H) 7.89 (d, J=7.91 Hz, 1 H) 8.44 (s, 1 H) 9.00-9.15 (m, 1 H).
[00780] Example 147 2-(1-((2-(1-aminoisoquinolin-5-yl)-9-methyl-6-morpholino-purin-8-yl)methyl)piperidin-4-yl)propan-2-o1147 [00781] Step 1: 2-(1-((9-methyl-6-morpholino-2-(tributylstannyl)-9H-purin-8-yl)methyl)piperidin-4-yl)propan-2-ol CO) N
ND
\ N
I I
N / N SnBu3 HO
[00782] A mixture of 2-(1-((2-chloro-9-methyl-6-morpholino-9H-purin-8-yl)methyl)piperidin-4-yl)propan-2-ol (235 mg, 0.575 mmol), bis(tributyltin) (0.58 mL, 1.15 mmol) and PdC12[t-Bu2P(Ph p-Nme2)2] (41 mg, 0.057 mmol) in 1,4-dioxane (3 mL) was heated in a microwave at 140 C for 40 minutes. The reaction mixture was then concentrated.
The crude product was purified by flash chromatography (0-100% gradient EtOAc-Heptane) to give the title compound (256 mg, 67.1%). LCMS: M+H+ = 663.2 [00783] Step 2: To a degassed mixture of 2-(1-((9-methyl-6-morpholino-2-(tributylstannyl)-9H-purin-8-yl)methyl)piperidin-4-yl)propan-2-ol (256 mg, 0.386 mmol), 5-bromoisoquinolin-l-amine (86 mg, 0.386 mmol), copper(I) thiophene-2-carboxylate (74 mg, 0.386 mmol) in 1,4-dioxane (4 mL) was added Pd(PPh3)4 (45 mg, 0.039 mmol). The reaction mixture was heated in the microwave at 140 C for 35 minutes. The reaction mixture was then loaded onto a Biotage Isolute SPE SCX-2 column. The column was first washed with MeOH. The product was eluted with 2 M NH3 in MeOH and concentrated. The crude was further purified by RP-HPLC to give 147 (36.3 mg, 18.2%). LCMS: M+H+ = 517.3.
'H-NMR (400 MHz, DMSO-d6): 6 8.28 (d, 1H), 8.11 (d, 1H), 7.79 (d, 1H), 7.70 (d, 1H), 7.53 (t, 1H), 6.80 (s, 2H), 4.23 (s, br, 4H), 4.09 (s, 1H), 3.81 (s, 3H), 3.73 (m, 6H), 2.90 (m, 2H), 2.02 (m, 2H), 1.66 (m, 2H), 1.19 (m, 3H), 1.02 (s, 6H) [00784] Example 149 N,N-dimethyl-l-((4-morpholino-2-(1H-pyrrolo[3,2-c]pyridin-1-yl)thieno[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-amine 149 [00785] Following General Procedure I for Buchwald coupling, 1-((2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-N,N-dimethylpiperidin-4-amine and 1H-pyrrolo[3,2-c]pyridine were reacted to give 149. MS m/e 478.6 [M+H]+
[00786] Example 150 1-((2-(isoquinolin-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-N,N-dimethylpiperidin-4-amine 150 [00787] A microwave vessel was charged with 2-[4-(4-morpholin-4-yl-2-tributylstannanyl-thieno[3,2-d]pyrimidin-6-yl methyl)-piperazin-l-yl]-isobutyramide (0.226 g, 0.347 mmol), 4-bromoisoquinoline (0.086 g, 0.416 mmol), copper(I) thiophene-2-carboxylate (Cu (TC)) (0.066 g, 0.347 mmol), palladium tetrakis(triphenylphosphine) (0.040 g, 0.034 mmol) and dioxane (2 mL). The vessel was degassed, sealed, and heated at 140 C
under microwave irradiation for 20 min. The reaction mixture was cooled to room temperature and filtered through celite. The filtrates were concentrated then purified twice by chromatography (silica, 0 to 15 % of a 9:1 McOH:NH4OH mixture in dichloromethane) to furnish 150 (0.026 g, 15.38 %) as an off-white foam. 1H NMR (400 MHz, CDC13-d) 8 ppm 1.60 (qd, J=12.04, 3.79 Hz, 2 H) 1.83 (d, J=12.63 Hz, 2 H) 2.08 - 2.22 (m, 3 H) 2.30 (s, 6 H) 3.05 (d, J=12.13 Hz, 2 H) 3.84 (s, 2 H) 3.86 - 3.92 (m, 4 H) 4.03 - 4.11 (m,4H)7.35(s, 1 H) 7.59 - 7.65 (m, 1 H) 7.69 - 7.77 (m, 1 H) 8.03 (d, J=8.59 Hz, 1 H) 8.82 (d, J=8.08 Hz, 1 H) 9.11 (s, 1 H) 9.30 (s, 1 H). MS m/e 489 [M+H]+
[00788] Example 151 2-(4-((2-(2-ethyl-lH-pyrrolo[2,3-c]pyridin-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-methylpropanamide 151 CO) S N~
N-g 0 N
o N~ N

NI~O

[00789] A mixture of 2-[4-(4-morpholin-4-yl-2-(tributylstannanyl)thieno[3,2-d]pyrimidin-6-ylmethyl)piperazin-1-yl]isobutyramide (0.241 g, 0.35 mmol), 1-benzenesulfonyl-4-bromo-2-ethyl-lH-pyrrolo[2,3-c]pyridine (0.14 g, 0.38 mmol), copper(I) 2-thiophene carboxylate (0.01g, 0.069 mmol) and Pd(PPh3)4 (0.040 g, 0.035 mmol) in dioxane (3 mL) was subjected to microwave irradiation at 150 C for 20 min. The reaction mixture was loaded onto an Isolute SCX-2 cartridge. The cartridge was washed with MeOH
and the desired product was eluted using 2 M NH3 in MeOH. The eluent was concentrated in vacuo and the residue was purified by flash chromatography (Si-PPC, MEOH:DCM, gradient 0:100 to 20:80) to give 2-{4-[2-(1-benzenesulfonyl-2-ethyl-lH-pyrrolo[2,3-c]pyridin-4-yl)-4-morpholin-4-ylthieno[3,2-d]pyrimidin-6-ylmethyl]piperazin-l-yl}isobutyramide as a yellow foam (0.15 g, 64 %). LCMS (Method A): RT = 3.53min, [M+H]+ 689.2 [00790] A mixture of 2-{4-[2-(1-benzenesulfonyl-2-ethyl-lH-pyrrolo[2,3-c]pyridin-4-yl)-4-morpholin-4-ylthieno[3,2-d]pyrimidin-6-ylmethyl]piperazin-l-yl}isobutyramide (0.15 g, 0.22 mmol) in dioxane (3 mL), IMS (3 mL) and NaOH 12.5M (0.34 mL) was stirred at room temperature for 3 h and was then concentrated in vacuo. The residue was loaded onto an Isolute SCX-2 cartridge. The cartridge was washed with MeOH and the desired product was eluted using 2 M NH3 in MeOH. The residue was purified by reverse phase HPLC
(Phenomenex Gemini 5u C18, 20 mM triethylamine in water on a gradient of acetonitrile 95:5 to 2:98) to give 151 as a white powder (0.034 g, 29%). LCMS (Method E):
RT = 5.87 min, [M+H]+ 549.2. 'H NMR (400 MHz, DMSO-d6 ): 6 11.56 (s, 1 H); 9.09 (s, 1 H); 8.65 (s, 1 H); 7.45 (s, 1 H); 7.14 (s, 1 H); 7.07 (d, J = 3.5 Hz, 1 H); 6.95 (d, J
= 3.5 Hz, 1 H);
3.99 (t, J = 4.6 Hz, 4 H); 3.86 (s, 2 H); 3.82 (t, J = 4.6 Hz, 4 H); 2.86 (q, J = 7.6 Hz, 2 H);
2.56-2.53 (m, 4 H); 2.51-2.45 (m, 4 H); 1.34 (t, J = 7.6 Hz, 3 H); 1.08 (s, 6 H) [00791] Example 152 4-(1-((7-morpholino-5-(1H-pyrrolo[3,2-c]pyridin-4-yl)thiazolo[5,4-d]pyrimidin-2-yl)methyl)azetidin-3-yl)morpholine 152 (0) N
N N S i P N SnBu3 N

OJ

[00792] A degassed solution of 5-chloro-7-morpholin-4-yl-2-(3-morpholin-4-yl-azetidin-1-ylmethyl)thiazolo[5,4-d]pyrimidine (1.0 g, 2.43 mmol), PdC12{PtBu2(Ph p-Nme2)}2 (170 mg, 0.24 mmol) and hexamethylditin (1.85 mL, 3.66 mmol) in 1,4-dioxane (10 mL) was subjected to microwave irradiation at 150 C for 30 minutes. The reaction mixture was cooled to ambient temperature and loaded onto an Isolute SCX-2 cartridge (25 g). The cartridge was then washed with MeOH and the desired product was subsequently eluted using 2 M NH3 in MeOH. The product was collected and concentrated to give a yellow oil.
The oil was purified by flash chromatography (Si-PPC, DCM: MeOH, 100:0 to 98:2 to 95:5) to afford 7-morpholin-4-yl-2-(3-morpholin-4-yl-azetidin-1-ylmethyl)-5-(tributylstannanyl)thiazolo[5,4-d]pyrimidine as a pale yellow oil (1.18 g, 73 %). NMR
(CDC13, 400MHz) 6 4.31 (m, 4 H), 3.97 (s, 2 H), 3.82 (t, J = 4.6 Hz, 4 H), 3.72 (m, 4 H), 3.65-3.59 (m, 2 H), 3.14-3.05 (m, 3 H), 2.34 (m, 4 H), 1.65-1.52 (m, 6 H), 1.39-1.26 (m, 6 H), 1.23-1.01 (m, 6 H), 0.93-0.84 (m, 9 H).
[00793] A degassed solution of 7-morpholin-4-yl-2-(3-morpholin-4-yl-azetidin-l-ylmethyl)-5-(tributylstannanyl)thiazolo[5,4-d]pyrimidine (200 mg, 0.30 mmol), benzenesulfonyl-4-bromo-lH-pyrrolo[3,2-c]pyridine (132 mg, 0.39 mmol), PdC12{PtBu2(Ph-p-Nme2)}2 (22 mg, 0.03 mmol) and copper(I) thiophene-2-carboxylate (12 mg, 0.06 mmol) in 1,4-dioxane (4 mL) was subjected to microwave irradiation at 140 C for 20 minutes. The reaction mixture was cooled to ambient temperature and loaded onto an Isolute cartridge (10 g). The cartridge was then washed with MeOH and the desired product was subsequently eluted using 2 M NH3 in MeOH. The product was collected and concentrated to give 5-(1-benzenesulfonyl-lH-pyrrolo[3,2-c]pyridin-4-yl)-7-morpholin-4-yl-2-(3-morpholin-4-yl-azetidin-1-ylmethyl)thioazolo[5,4-d]pyrimidine as a crude oil. Aqueous NaOH (12.5 M, 0.5 mL) was added to a solution of 5-(1-benzenesulfonyl-lH-pyrrolo[3,2-c]pyridin-4-yl)-7-morpholin-4-yl-2-(3-morpholin-4-yl-azetidin-1-ylmethyl)-thiazolo[5,4-d]pyrimidine in 1,4-dioxane (4 mL) and IMS (4 mL). The reaction mixture was stirred at ambient temperature for 45 min, then concentrated in vacuo. The residue was dissolved in MeOH then loaded onto an Isolute SCX-2 cartridge (10 g). The cartridge was then washed with MeOH and the desired product was subsequently eluted using 2 M NH3 in MeOH. The product was collected and concentrated to afford a solid. The solid was purified by flash chromatography (Si-PPC, DCM: MeOH, 100:0 to 98:2 to 96:4) to afford 152 as a yellow solid (56 mg, 38 %). LCMS
(Method E): RT = 4.34 min, M+H+ = 493.2. 1H NMR (CDC13, 400MHz) 6 8.72 (bs, 1 H), 8.56 (d, J = 5.7 Hz, 1 H), 7.41 (m, 2 H), 7.36 (d, J = 3.2 Hz, 1 H), 4.49-4.44 (m, 4 H), 4.02 (s, 2 H), 3.90 (t, J = 4.7 Hz, 4 H), 3.74-3.65 (m, 6 H), 3.16-3.07 (m, 3 H), 2.35 (m, 4 H) [00794] Example 153 2-methyl-2-(4-((2-(5-methyl-lH-pyrrolo[2,3-c]pyridin-4-yl)-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)propanamide 153 [00795] A mixture of 2-[4-(4-morpholin-4-yl-2-(tributylstannanyl)thieno[3,2-d]pyrimidin-6-ylmethyl)piperazin-l-yl]isobutyramide (72 mg, 0.10 mmol), 4-bromo-5-methyl- lH-pyrrolo[2,3-c]pyridine (22 mg, 0.10 mmol), Pd(PPh3)4 (12 mg, 10 mol %) and copper(I)-thiophene-2-carboxylate (4 mg, 20 mol %) in dioxane (1 mL) was purged with argon gas then heated at 150 C, for 20 min, in a microwave reactor. The reaction mixture was loaded onto an Isolute SCX-2 cartridge, the cartridge was washed with MeOH then the desired product eluted with 2 M NH3 in MeOH. The resulting residue was purified by column chromatography (Si-PCC, 0-20 % MeOH in DCM) to give 153 as a pale yellow solid (24 mg, 43 %). LCMS (Method E): RT = 4.19min, [M+H]+ 535.2. IH NMR (400 MHz, CHC13-d):

9.14 (s, 1 H), 8.73 (s, 1 H), 7.34-7.32 (m, 2 H), 7.11 (d, J = 5.3 Hz, 1 H), 6.67-6.65 (m, 1 H), 5.30 (d, J = 4.7 Hz, 1 H), 4.04 (t, J = 4.7 Hz, 4 H), 3.87 (d, J = 4.7 Hz, 4 H), 3.85 (s, 2 H), 2.76 (s, 3 H), 2.61 (m, 8 H), 1.28-1.22 (m, 6 H) [00796] Example 154 4-(1-((9-methyl-2-(2-methyl-lH-benzo[d]imidazol-1-yl)-6-morpholino-9H-purin-8-yl)methyl)piperidin-4-yl)morpholine 154 [00797] Following the procedures for 178, 4-(1-((2-chloro-9-methyl-6-morpholino-9H-purin-8-yl)methyl)piperidin-4-yl)morpholine and acetic acid were converted to 154. LCMS:
M+H+ = 532.3. 'H-NMR (400 MHz, DMSO-d6): 8 8.09 (m, 1H), 7.60 (m, 1H), 7.25 (m, 2H), 4.26 (s, br, 4H), 3.82 (s, 3H), 3.71 (m, 6H), 3.54 (m, 4H), 2.85 (m, 5), 2.43 (m, 4H), 2.08 (m, 3H), 1.76 (m, 2H), 1.39 (m, 2H).
[00798] Example 155 4-(8-((4-(2-methoxypropan-2-yl)piperidin-1-yl)methyl)-9-methyl-6-morpholino-9H-purin-2-yl)isoquinolin-l-amine 155 HO

Nu0 IOI
[00799] 2-(Piperidin-4-yl)propan-2-ol (1 g) was reacted with 1.1 eq of benzyl chloroformate and 1.3 eq of triethylamine in 30 mL of chloroform. The reaction was halted after 2 days at room temperature and purified by isco (0-60% Hexanes/Ethyl Acetate over 20 minutes) to afford 1.49 g benzyl 4-(2-hydroxypropan-2-yl)piperidine-1-carboxylate.

O
'--ON O I
Y
O
[00800] To a suspension of sodium hydride, 60% dispersion in mineral oil (0.322 g) and methyl iodide (1.00 mL) in 10 mL THE at room temp was carefully added portionwise benzyl 4-(2-hydroxypropan-2-yl)piperidine-l-carboxylate (1.49 g, 0.00537 mol) in 15 mL
THE The reaction was heated at 50 C for 18 hours and then it was cooled down to 0 C and carefully quenched by addition of sat NH4C1 solution, then extracted with EtOAc twice. The combined organics were washed with brine, dried over MgSO4 and concentrated in vacuo.
The residue was purified by flash chrom to get 1.2 g benzyl 4-(2-methoxypropan-yl)piperidine-1-carboxylate as a colorless oil.

~O

NH
[00801] The cbz protecting group was hydrogenated off using the H-cube with palladium on carbon-The product in a solution of methanol was then concentrated and run through an isolute scx-2 spe cartridge to yield 0.44 g of 4-(2-methoxypropan-2-yl)piperidine as a colorless oil.

O CO) N
N N xcI
N

[00802] 4-(2-methoxypropan-2-yl)piperidine (0.12 g) was reacted with 4-(8-(bromomethyl)-2-chloro-9-methyl-9H-purin-6-yl)morpholine (0.25 g) via General Procedure E to give 300 mg of crude 4-(2-chloro-8-((4-(2-methoxypropan-2-yl)piperidin-1-yl)methyl)-9-methyl-9H-purin-6-yl)morpholine, of which 0.78 g was reacted with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinolin-l-amine via General Procedure A to yield 12 mg of 155 as a white solid following reverse phase purification. MS (Q1) 531.3 (M)+
[00803] Example 156 1-(8-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)-9-methyl-6-morpholino-9H-purin-2-yl)-1H-benzo[d]imidazol-2(3H)-one 156 [00804] A mixture of 2-(1-((2-(2-aminophenylamino)-9-methyl-6-morpholino-9H-purin-8-yl)methyl)piperidin-4-yl)propan-2-ol (40 mg, 0.083 mmol) and N,N-carbonyldiimidazole (17 mg, 0.108 mmol) in acetonitrile (2 mL) was stirred at reflux for 15 hours. The reaction mixture was then filtered through paper and purified by RP-HPLC to give 156 (6.7 mg, 16%). LCMS: M+H+ = 507.2. 'H-NMR (400 MHz, DMSO-d6): 8 11.0 (s, 1H), 7.55 (d, 1H), 7.04 (m, 3H), 4.21 (s, br, 4H), 4.02 (s, 1H), 3.78 (s, 3H), 3.74 (m, 6H), 2.88 (m, 2H), 2.00 (m, 2H), 1.66 (m, 2H), 1.20 (m, 3H), 1.02 (s, 6H) [00805] Example 157 2-(1-((9-methyl-2-(2-methyl-lH-benzo[d]imidazol-1-yl)-6-morpholino-9H-purin-8-yl)methyl)piperidin-4-yl)propan-2-ol 157 CO) N
N / N I
~ II
N \N'% /
H

HO
[00806] Step 1: A mixture of 2-(1-((2-chloro-9-methyl-6-morpholino-9H-purin-8-yl)methyl)piperidin-4-yl)propan-2-ol (1.21 g, 2.96 mmol), benzene- 1,2-diamine (520 mg, 4.8 mmol), palladium acetate (66 mg, 0.29 mmol), bist(tri-t-butylphosphine)palladium (150 mg, 0.29 mmol) and sodium tert-butoxide (620 mg, 6.4 mmol) in toluene (30 mL) was stirred at DEMANDE OU BREVET VOLUMINEUX

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Claims (30)

1. A compound selected from Formulas Ia and Ib:

and stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, wherein (i) X1 is N and X2 is S, (ii) X1 is CR7 and X2 is S, (iii) X1 is N and X2 is NR2, or (iv) X1 is CR7 and X2 is O;

R1 is selected from C1-C12 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C6-C20 aryl, C2-C20 heterocyclyl, C3-C12 carbocyclyl, C1-C20 heteroaryl, -(C1-C12 alkylene)-(C3-C12 carbocyclyl), -(C1-C12 alkylene)-(C2-C20 heterocyclyl), -(C1-C12 alkylene)-(C2-C20 heterocyclyl)-(C2-C20 heterocyclyl), -(C1-C12 alkylene)-(C2-C20 heterocyclyl)-(C3-C12 carbocyclyl), -(C1-C12 alkylene)-(C2-C20 heterocyclyl)-C(=O)-(C2-C20 heterocyclyl), -(C1-C12 alkylene)-(C1-C20 heteroaryl), -(C1-C12 alkylene)-(C2-C20 heterocyclyl)-(C1-C12 alkyl), -(C1-C12 alkylene)-(C6-C20 aryl)-(C1-C12 alkyl), -(C1-C12 alkylene)-(C1-C20 heteroaryl)-(C1-C12 alkyl), -(C1-C12 alkylene)-C(=O)-(C2-C20 heterocyclyl), -(C1-C12 alkylene)-NHR2', -(C1-C12 alkylene)-NR2'-(C1-C12 alkyl), -(C1-C12 alkylene)-NR2'-(C3-C12 carbocyclyl), -(C1-C12 alkylene)-NR2'-(C2-C20 heterocyclyl), -(C1-C12 alkylene)-NR2'-(C1-C20 heteroaryl), -(C1-C12 alkylene)-NR2'-(C6-C20 aryl), -(C1-C12 alkylene)-NR2'-(C1-C12 alkylene)-(C3-C12 carbocyclyl), -(C1-C12 alkylene)-NR2'-(C1-C12 alkylene)-(C1-C20 heteroaryl), -(C1-C12 alkylene)-NR2'-(C1-C12 alkylene)-(C1-C20 heterocyclyl), -(C1-C12 alkylene)-NR2'-(C1-C12 alkylene)-(C6-C20 aryl), -(C1-C12 alkylene)-NR2'-(C1-C12 alkylene)-NHC(=O)-(C1-C20 heteroaryl), -(C1-C12 alkylene)-(C2-C20 heterocyclyl)-N(C1-C12 alkyl)R2', -(C1-C12 alkylene)-(C2-C20 heterocyclyl)-(C1-C12 alkyl)-N(C1-C12 alkyl)R2', -(C2-C12 alkenylene)-(C2-C20 heterocyclyl), -(C1-C20 heteroaryl)-(C2-C20 heterocyclyl), -(C1-C20 heteroaryl)-(C3-C12 carbocyclyl), -C(=O)-(C2-C20 heterocyclyl), -C(=O)-(C1-C20 heteroaryl), -C(=O)-(C2-C20 heterocyclyl)-(C2-C20 heterocyclyl), -C(=O)-(C2-C20 heterocyclyl)-(C1-C20 heteroaryl), -C(=O)-(C1-C12 alkyl), -C(=O)-NR2'-(C1-C12 alkyl), and -CR4=CR5R6 where R4 is selected from H, F, Cl, Br, I and C1-C12 alkyl, and R5 and R6 form C2-C20 heterocyclyl, C1-C20 heteroaryl, or C3-C12 carbocyclyl, where alkyl, alkenyl, alkynyl, alkylene, carbocyclyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more groups independently selected from F, Cl, Br, I, -CH3, -CH2CH3, -CH2CH(CH3)2, -CH2NH2, -CH2N(CH3)2, -CH2CH2NH2, -CH2CH2N(CH3)2, -CH2OH, -CH2OH, -CH2OCH3, -CH2CH2OH, -C(CH3)2OH, -CH2C(CH3)2OH, -CH(OH)CH(CH3)2, -C(CH3)2CH2OH, -CH2CH2SO2CH3, -CN, -CF3, -CO2H, -CHO, -COCH3, -CO2CH3, -CO2C(CH3)3, -COCH2OH, -COC(OH)(CH3)2, -COCH(OH)CH3, -CONH2, -CONHCH3, -CON(CH3)2, -CH2CONH2, -CH2CON(CH3)2, -C(CH3)2CONH2, -NO2, -NH2, -NHCH3, -N(CH3)2, -NHCOCH3, -N(CH3)COCH3, -NHS(O)2CH3, -N(CH3)C(CH3)2CONH2, -N(CH3)CH2CH2S(O)2CH3, =O, -OH, -OCH3, -S(O)2N(CH3)2, -SCH3, -CH2OCH3, -S(O)2CH3, -C(O)-cyclopropyl, cyclopropyl, cyclobutyl, oxetanyl, and morpholino;

R2 and R2' are independently selected from H, C1-C12 alkyl, C2-C8 alkenyl, C2-alkynyl, -(C1-C12 alkylene)-(C3-C12 carbocyclyl), -(C1-C12 alkylene)-(C2-C20 heterocyclyl), -(C1-C12 alkylene)-C(=O)-(C2-C20 heterocyclyl), -(C1-C12 alkylene)-(C6-C20 aryl), and -(C1-C12 alkylene)-(C1-C20 heteroaryl), where alkyl, alkenyl, alkynyl, alkylene, carbocyclyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more groups independently selected from F, Cl, Br, I, -CH3, -CH2OH, -CN, -CF3, -CO2H, -COCH3, -COC(CH3)3, -COCF3, -CO2CH3, -CONH2, -CONHCH3, -CON(CH3)2, -NO2, -NH2, -NHCH3, -NHCOCH3, -NHS(O)2CH3, -OH, -OCH35 -S(O)2N(CH3)2, -SCH3, -CH2OCH3, and -S(O)2CH3;

R3 is a bicyclic heteroaryl group selected from:

optionally substituted with one or more groups independently selected from C1-alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C12 carbocyclyl, C2-C20 heterocyclyl, C6-C20 aryl, C1-C20 heteroaryl, -(C1-C12 alkylene)-(C2-C20 heterocyclyl), -NH-(C1-C12 alkylene)-(C2-C20 heterocyclyl), -N(C1-C12 alkyl)-(C1-C12 alkylene)-(C2-C20 heterocyclyl), -NH-(C2-C20 heterocyclyl), -O-(C2-C20 heterocyclyl), -NH-(C3-C12 carbocyclyl), -O-(C3-carbocyclyl), F, Cl, Br, I, -CN, -CO2H, -CONH2, -CONH(C1-C12 alkyl), -CON(C1-alkyl)2, -CO(C1-C12 alkyl), -NO2, -NH2, -NH(C1-C12 alkyl), -N(C1-C12 alkyl)2, -NHCO(C1-C12 alkyl), -NHS(O)2(C1-C12 alkyl), -N(C1-C12 alkyl)S(O)2(C1-C12 alkyl), -OH, -O(C1-C12 alkyl), -NHC(=O)NH(C1-C12 alkyl), -SH, -S(C1-C12 alkyl), -S(O)(C1-C12 alkyl), -S(O)2(C1-C12 alkyl), -S(O)2NH2, -S(O)2NH(C1-C12 alkyl), and -S(O)2N(C1-C12 alkyl)2, where alkyl, alkenyl, alkynyl, alkylene, carbocyclyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more groups independently selected from F, Cl, Br, I, --CN, -CF3, -CO2H, -COCH3, -CO2CH3, -CONH2, -CONHCH3, -CON(CH3)2, -NO2, -NH2, -NHCH3, -NHCOCH3, -NHS(O)2CH3, =O, -OH, -OCH3, -S(O)2N(CH3)2, -SH, -SCH3, -CH2OCH3, and -S(O)2CH3;

R7 is selected from H, C1-C12 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, -(C1-C12 alkylene)-(C3-C12 carbocyclyl), -(C1-C12 alkylene)-(C2-C20 heterocyclyl), -(C1-alkylene)-C(=O)-(C2-C20 heterocyclyl), -(C1-C12 alkylene)-(C6-C20 aryl), and -(C1-C12 alkylene)-(C1-C20 heteroaryl), where alkyl, alkenyl, alkynyl, alkylene, carbocyclyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more groups independently selected from F, Cl, Br, I, -CH3, -CH2CH3, -CH2OH, -CN, -CF3, -CO2H, -COCH3, -CO2CH3, -CONH2, -CONHCH3, -CON(CH3)2, -NO2, -NH2, -NHCH3, -NHCOCH3, -NHS(O)2CH3, =O, -OH, -OCH3, -S(O)2N(CH3)2, -SCH3, -CH2OCH3, and -S(O)2CH3;
mor is a morpholine group or a bicyclic structure selected from:

optionally substituted with one or more groups selected from F, Cl, Br, I, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -C(CH3)3, -CH2OCH3, -CHF2, -CN, -CF3, -CH2OH, -CH2OCH3, -CH2CH2OH, -CH2C(CH3)2OH, -CH(CH3)OH, -CH(CH2CH3)OH, -CH2CH(OH)CH3, -C(CH3)2OH, -C(CH3)20CH3, -CH(CH3)F, -C(CH3)F2, -CH(CH2CH3)F, -C(CH2CH3)2F, -CO2H, -CONH2, -CON(CH2CH3)2, -COCH3, -CON(CH3)2, -NO2, -NH2, -NHCH3, -N(CH3)2, -NHCH2CH3, -NHCH(CH3)2, -NHCH2CH2OH, -NHCH2CH2OCH3, -NHCOCH3, -NHCOCH2CH3, -NHCOCH2OH, -NHS(O)2CH3, -N(CH3)S(O)2CH3, =O, -OH, -OCH3, -OCH2CH3, -OCH(CH3)2, -SH, -NHC(=O)NHCH3, -NHC(=O)NHCH2CH3, -S(O)CH3, -S(O)CH2CH3, -S(O)2CH3, -S(O)2NH2, -S(O)2NHCH3, -S(O)2N(CH3)2, -CH2S(O)2CH3;
and wherein the IC50 binding activity to p110 delta is ten or more times lower than the binding activity to p110 alpha;
with the proviso that a Formula Ib compound wherein (ii) X1 is CR7 and X2 is S, R1 is -(C1-C12 alkylene)-(C2-C20 heterocyclyl), R3 is optionally substituted benzo[d]imidazol-1-yl, and R7 is H, excludes the C2-C20 heterocyclyl of R1 substituted with -S(O)2CH3.

2. The compound of claim 1 selected from the structures:

3. The compound of claim 1 selected from the structures:

4. The compound of claim 1 selected from the structures:

5. The compound of claim 1 selected from the structures:

6. The compound of claim 1 wherein R1 is selected from the structures where the wavy line indicates the site of attachment.

7. The compound of claim 1 wherein R2 is C1-C12 alkyl optionally substituted with one or more groups independently selected from F, Cl, Br, I, -CH3, -CH2OH, -CN, -CF3, -CO2H, -COCH3, -CO2CH3, -CONH2, -CONHCH3, -CON(CH3)2, -NO2, -NH2, -NHCH3, -NHCOCH3, -NHS(O)2CH3, -OH, -OCH3, -S(O)2N(CH3)2, -SCH3, -CH2OCH3, and -S(O)2CH3.

8. The compound of claim 7 wherein R2 is CH3.

9. The compound of claim 1 wherein the R3 bicyclic heteroaryl is substituted with one or more groups independently selected from F, Cl, Br, I, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -C(CH3)3, -CH2OCH3, -CHF2, -CH2CN, -CN, -CF3, -CH2OH, -CH2OCH3, -CH2CH2OH, -CH2CH2CH2OH, -CH2C(CH3)2OH, -CH(CH3)OH, -CH(CH2CH3)OH, -CH2CH(OH)CH3, -CH2CH(OCH3)CH3, -C(CH3)2OH, -CH(CH3)OCH3, -C(CH3)2OCH3, -CH(CH3)F, -C(CH3)F2, -CH(CH2CH3)F, -C(CH2CH3)2F, -C(CH2CH3)F2, -CO2H, -CONH2, -CON(CH2CH3)2, -COCH3, -CON(CH3)2, -NO2, -NH2, -NHCH3, -N(CH3)2, -NHCH2CH3, -NHCH(CH3)2, -NHCH2CH2OH, -NHCH2CH2OCH3, -NHCOCH3, -NHCOCH2CH3, -NHCOCH2OH, -NHS(O)2CH3, -N(CH3)S(O)2CH3, =O, -OH, -OCH3, -OCH2CH3, -OCH(CH3)2, -SH, -NHC(=O)NHCH3, -NHC(=O)NHCH2CH3, -S(O)CH3, -S(O)CH2CH3, -S(O)2CH3, -S(O)2NH2, -S(O)2NHCH3, -S(O)2N(CH3)2, -CH2S(O)2CH3, and a group selected from

10. The compound of claim 1 wherein R3 is:

where R8 is selected from H, F, Cl, Br, I, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -C(CH3)3, -CH2OCH3, -CHF2, -CH2CN, -CN, -CF3, -CH2OH, -CH2OCH3, -CH2CH2OH, -CH2C(CH3)20H, -CH(CH3)OH, -CH(CH2CH3)OH, -CH2CH(OH)CH3, -CH2CH(OCH3)CH3, -C(CH3)20H, -C(CH3)2OCH3, -CH(CH3)F, -C(CH3)F2, -CH(CH2CH3)F, -C(CH2CH3)2F, -CO2H, -CONH2, -CON(CH2CH3)2, -COCH3, -CON(CH3)2, -NO2, -NH2, -NHCH3, -N(CH3)2, -NHCH2CH3, -NHCH(CH3)2, -NHCH2CH2OH, -NHCH2CH2OCH3, -NHCOCH3, -NHCOCH2CH3, -NHCOCH2OH, -NHS(O)2CH3, -N(CH3)S(O)2CH3, -OH, -OCH3, -OCH2CH3, -OCH(CH3)2, -SH, -NHC(=O)NHCH3, -NHC(=O)NHCH2CH3, -S(O)CH3, -S(O)CH2CH3, -S(O)2CH3, -S(O)2NH2, -S(O)2NHCH3, -S(O)2N(CH3)2, -CH2S(O)2CH3, and a group selected from R9 is independently selected from F, Cl, Br, I, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH(CH3)2, -CH2OH, -CH2CH2OH, -CN, -CF3, -CO2H, -COCH3, -CO2CH3, -CONH2, -CONHCH3, -CON(CH3)2, -NO2, -NH2, -NHCH3, -NHCOCH3, -NHS(O)2CH3, -OH, -OCH3, -S(O)2N(CH3)2, -SCH3, -CH2OCH3, and -S(O)2CH3; and n is 0, 1, 2, 3, or 4.

11. The compound of claim 10 having the structures:

12. The compound of claim 1 wherein R7 is H.

13. The compound of claim 1 wherein R7 is C1-C12 alkyl optionally substituted with one or more groups independently selected from F, Cl, Br, I, -CH3, -CH2OH, -CN, -CF3, -CO2H, -COCH3, -CO2CH3, -CONH2, -CONHCH3, -CON(CH3)2, -NO2, -NH2, -NHCH3, -NHCOCH3, -NHS(O)2CH3, -OH, -OCH3, -S(O)2N(CH3)2, -SCH3, -CH2OCH3, and -S(O)2CH3.

14. The compound of claim 13 wherein R7 is CH3.

15. The compound of claim 11 having the structure:
wherein R1 is -(C1-C12 alkylene)-(C2-C20 heterocyclyl) where C2-C20 heterocyclyl is optionally substituted with one or more groups independently selected from F, Cl, Br, I, -CH3, -CH2CH3, -CH2CH(CH3)2, -CH2OH, -CH2CH2OH, -C(CH3)2OH, -CH(OH)CH(CH3)2, -C(CH3)2CH2OH, -CH2CH2SO2CH3, -CN, -CF3, -CO2H, -COCH3, -CO2CH3, -CO2C(CH3)3, -COCH(OH)CH3, -CONH2, -CONHCH3, -CON(CH3)2, -C(CH3)2CONH2, -NO2, -NH2, -NHCH3, -N(CH3)2, -NHCOCH3, -N(CH3)COCH3, -NHS(O)2CH3, -N(CH3)C(CH3)2CONH2, -N(CH3)CH2CH2 S(O)2CH3, -OH, -OCH35 S(O)2N(CH3)2, -SCH3, -CH2OCH3, cyclopropyl, oxetanyl, and morpholino; and R7 is H or -CH3.

16. A compound having the structure:
and stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, wherein:

C1-C12 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C6-C20 aryl, C2-C20 heterocyclyl, C3-C12 carbocyclyl, C1-C20 heteroaryl, -(C1-C12 alkylene)-(C3-C12 carbocyclyl), -(C1-C12 alkylene)-(C2-C20 heterocyclyl), -(C1-C12 alkylene)-(C2-C20 heterocyclyl)-(C2-C20 heterocyclyl), -(C1-C12 alkylene)-(C2-C20 heterocyclyl)-(C3-C12 carbocyclyl), -(C1-C12 alkylene)-(C2-C20 heterocyclyl)-C(=O)-(C2-C20 heterocyclyl), -(C1-C12 alkylene)-(C1-C20 heteroaryl), -(C1-C12 alkylene)-(C2-C20 heterocyclyl)-(C1-C12 alkyl), -(C1-C12 alkylene)-(C6-C20 aryl)-(C1-C12 alkyl), -(C1-C12 alkylene)-(C1-C20 heteroaryl)-(C1-C12 alkyl), -(C1-C12 alkylene)-C(=O)-(C2-C20 heterocyclyl), -(C1-C12 alkylene)-NHR2', -(C1-C12 alkylene)-NR2'-(C1-C12 alkyl), -(C1-C12 alkylene)-NR2'-(C3-C12 carbocyclyl), -(C1-C12 alkylene)-NR2'-(C2-C20 heterocyclyl), -(C1-C12 alkylene)-NR2'-(C1-C20 heteroaryl), -(C1-C12 alkylene)-NR2'-(C6-C20 aryl), -(C1-C12 alkylene)-NR2'-(C1-C12 alkylene)-(C3-C12 carbocyclyl), -(C1-C12 alkylene)-NR2'-(C1-C12 alkylene)-(C1-C20 heteroaryl), -(C1-C12 alkylene)-NR2'-(C1-C12 alkylene)-(C1-C20 heterocyclyl), -(C1-C12 alkylene)-NR2'-(C1-C12 alkylene)-(C6-C20 aryl), -(C1-C12 alkylene)-NR2'-(C1-C12 alkylene)-NHC(=O)-(C1-C20 heteroaryl), -(C1-C12 alkylene)-(C2-C20 heterocyclyl)-N(C1-C12 alkyl)R2', -(C1-C12 alkylene)-(C2-C20 heterocyclyl)-(C1-C12 alkyl)-N(C1-C12 alkyl)R2', -(C2-C12 alkenylene)-(C2-C20 heterocyclyl), -(C1-C20 heteroaryl)-(C2-C20 heterocyclyl), -(C1-C20 heteroaryl)-(C3-C12 carbocyclyl), -C(=O)-(C2-C20 heterocyclyl), -C(=O)-(C1-C20 heteroaryl), -C(=O)-(C2-C20 heterocyclyl)-(C2-C20 heterocyclyl), -C(=O)-(C2-C20 heterocyclyl)-(C1-C20 heteroaryl), -C(=O)-(C1-C12 alkyl), -C(=O)-NR2'-(C1-C12 alkyl), and -CR4=CR5R6 where R4 is selected from H, F, Cl, Br, I and C1-C12 alkyl, and R5 and R6 form C2-C20 heterocyclyl, C1-C20 heteroaryl, or C3-C12 carbocyclyl, where alkyl, alkenyl, alkynyl, alkylene, carbocyclyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more groups independently selected from F, Cl, Br, I, -CH3, -CH2CH3, -CH2CH(CH3)2, -CH2NH2, -CH2N(CH3)2, -CH2CH2NH2, -CH2CH2N(CH3)2, -CH2OH, -CH2OH, -CH2OCH3, -CH2CH2OH, -C(CH3)20H, -CH2C(CH3)20H, -CH(OH)CH(CH3)2, -C(CH3)2CH2OH, -CH2CH2SO2CH3, -CN, -CF3, -CO2H, -CHO, -COCH3, -CO2CH3, -CO2C(CH3)3, -COCH2OH, -COC(OH)(CH3)2, -COCH(OH)CH3, -CONH2, -CONHCH3, -CON(CH3)2, -CH2CONH2, -CH2CON(CH3)2, -C(CH3)2CONH2, -NO2, -NH2, -NHCH3, -N(CH3)2, -NHCOCH3, -N(CH3)COCH3, -NHS(O)2CH3, -N(CH3)C(CH3)2CONH2, -N(CH3)CH2CH2S(O)2CH3, =O, -OH, -OCH3, -S(O)2N(CH3)2, -SCH3, -CH2OCH3, -S(O)2CH3, -C(O)-cyclopropyl, cyclopropyl, cyclobutyl, oxetanyl, and morpholino;

R2 and R2' are independently selected from H, C1-C12 alkyl, C2-CS alkenyl, C2-alkynyl, -(C1-C12 alkylene)-(C3-C1z carbocyclyl), -(C1-C12 alkylene)-(C2-C20 heterocyclyl), -(C1-C12 alkylene)-C(=O)-(C2-C20 heterocyclyl), -(C1-C12 alkylene)-(C6-C20 aryl), and -(C1-C12 alkylene)-(C1-C20 heteroaryl), where alkyl, alkenyl, alkynyl, alkylene, carbocyclyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more groups independently selected from F, Cl, Br, I, -CH3, -CH2OH, -CN, -CF3, -CO2H, -COCH3, -COC(CH3)3, -COCF3, -CO2CH3, -CONH2, -CONHCH3, -CON(CH3)2, -NO2, -NH2, -NHCH3, -NHCOCH3, -NHS(O)2CH3, -OH, -OCH35 -S(O)2N(CH3)2, -SCH3, -CH2OCH3, and -S(O)2CH3;

R8 is selected from H, F, Cl, Br, I, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -C(CH3)3, -CH2OCH3, -CHF2, -CN, -CF3, -CH2OH, -CH2OCH3, -CH2CH2OH, -CH2C(CH3)20H, -CH(CH3)OH, -CH(CH2CH3)OH, -CH2CH(OH)CH3, -CH2CH(OCH3)CH3, -C(CH3)2OH, -C(CH3)2OCH3, -CH(CH3)F, -C(CH3)F2, -CH(CH2CH3)F, -C(CH2CH3)2F, -CO2H, -CONH2, -CON(CH2CH3)2, -COCH3, -CON(CH3)2, -NO2, -NH2, -NHCH3, -N(CH3)2, -NHCH2CH3, -NHCH(CH3)2, -NHCH2CH2OH, -NHCH2CH2OCH3, -NHCOCH3, -NHCOCH2CH3, -NHCOCH2OH, -NHS(O)2CH3, -N(CH3)S(O)2CH3, =O, -OH5 -OCH3, -OCH2CH3, -OCH(CH3)2, -SH, -NHC(=O)NHCH3, -NHC(=O)NHCH2CH3, -S(O)CH3, -S(O)CH2CH3, -S(O)2CH3, -S(O)2NH2, -S(O)2NHCH3, -S(O)2N(CH3)2, -CH2S(O)2CH3, and a group selected from R9 is independently selected from F, Cl, Br, I, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH(CH3)2, -CH2OH, -CH2CH2OH, -CN, -CF3, -CO2H, -COCH3, -CO2CH3, -CONH2, -CONHCH3, -CON(CH3)2, -NO2, -NH2, -NHCH3, -NHCOCH3, -NHS(O)2CH3, -OH, -OCH3, -S(O)2N(CH3)2, -SCH3, -CH2OCH3, and -S(O)2CH3; and n is 0, 1, 2, 3, or 4.

17. The compound of claim 1 wherein R1 is selected from the structures where the wavy line indicates the site of attachment.

18. The compound of claim 16 wherein R2 is C1-C12 alkyl optionally substituted with one or more groups independently selected from F, Cl, Br, I, -CH3, -CH2OH, -CN, -CF3, -CO2H, -COCH3, -CO2CH3, -CONH2, -CONHCH3, -CON(CH3)2, -NO2, -NH2, -NHCH3, -NHCOCH3, -NHS(O)2CH3, =O, -OH, -OCH3, -S(O)2N(CH3)2, -SCH3, -CH2OCH3, and -S(O)2CH3.

19. The compound of claim 18 wherein R2 is CH3.

20. The compound of claim 1 selected from Table 1.

21. The compound of claim 1 selected from Table 2.

22. The compound of claim 1 selected from Table 3.

23. A pharmaceutical composition comprised of a compound of any one of claims 1 to 22, and a pharmaceutically acceptable carrier, glidant, diluent, or excipient.

24. The pharmaceutical composition of claim 23 further comprising a second therapeutic agent.

25. A process for making a pharmaceutical composition which comprises combining a compound of any one of claims 1 to 22 with a pharmaceutically acceptable carrier, glidant, diluent, or excipient.

26. Use of a compound of any one of claims 1 to 22 in the manufacture of a medicament for treating a disease or disorder selected from cancer, immune disorders, cardiovascular disease, viral infection, inflammation, metabolism/endocrine function disorders and neurological disorders, and mediated by the p110 delta isoform of PI3 kinase.

27. A method of treating a disease or disorder which method comprises administering a compound of any one of claims 1 to 22 to a patient with a disease or disorder selected from cancer, immune disorders, cardiovascular disease, viral infection, inflammation, metabolism/endocrine function disorders and neurological disorders, and mediated by the p110 delta isoform of PI3 kinase.

28. The method of claim 27 further comprising administering an additional therapeutic agent selected from a chemotherapeutic agent, an anti-inflammatory agent, an immunomodulatory agent, a neurotropic factor, an agent for treating cardiovascular disease, an agent for treating liver disease, an anti-viral agent, an agent for treating blood disorders, an agent for treating diabetes, and an agent for treating immunodeficiency disorders.

29. A kit for treating a condition mediated by the p110 delta isoform of PI3 kinase, comprising:
a) a first pharmaceutical composition comprising a compound of any one of claims 1 to 22; and b) instructions for use.

30. A compound of any one of claims 1 to 22 for use in a method of treatment of the human or animal body for use in treating a disease or disorder selected selected from cancer, immune disorders, cardiovascular disease, viral infection, inflammation, metabolism/endocrine function disorders and neurological disorders, and mediated by the p110 delta isoform of PI3 kinase.