WO2010120854A1

WO2010120854A1 - Chemical compounds

Info

Publication number: WO2010120854A1
Application number: PCT/US2010/030996
Authority: WO
Inventors: Jeffrey Michael Axten; Gerald Patrick Brady, Jr.; Timothy Francis Gallagher; Dirk A. Heerding; Jesus Raul Medina; Stuart Paul Romeril
Original assignee: Glaxosmithkline Llc
Priority date: 2009-04-15
Filing date: 2010-04-14
Publication date: 2010-10-21

Abstract

The invention is directed to to substituted indazole derivatives. Specifically, the invention is directed to compounds according to Formula I: wherein R¹ - R⁶ and X are defined herein. The compounds of the invention are inhibitors of PDK1 and can be useful in the treatment of disorders characterized by constitutively activated ACG kinases such as cancer and more specifically leukemia and cancers of the breast, colon, and lung. Accordingly, the invention is further directed to pharmaceutical compositions comprising a compound of the invention. The invention is still further directed to methods of inhibiting PDK1 activity and treatment of disorders associated therewith using a compound of the invention or a pharmaceutical composition comprising a compound of the invention.

Description

CHEMICAL COMPOUNDS

FIELD OF THE INVENTION

The present invention relates to substituted indazole compounds and their ability to inhibit the activity of the serine/threonine kinase, PDK1. The present invention also relates to pharmaceutical compositions comprising such compounds and methods of using such compounds in the treatment of cancer.

BACKGROUND OF THE INVENTION

The phosphoinositide-3 kinase (PI3K) pathway regulates critical cellular functions such as cell cycle progression, growth, survival, and differentiation as well as the metabolic actions of insulin (Hennessy et al. Nature Rev. Drug Dis. 4:988-1004 (2005)). Modulation of the activity of kinases downstream of PI3K is mediated by 3- phosphoinositide dependent kinase 1 (PDK1 ), a 63-kD serine/threonine kinase that is ubiquitously expressed in human tissues (Storz and Toker, Front. Biosci. 7:886-902 (2002). PDK1 contains an amino-terminal kinase domain, a linker region and a pleckstrin- homology (PH) domain at the carboxyl-terminus. The PH domain binds to the lipid products of PI3K (phosphatidylinositol 3,4,5-triphosphate, PIP3) with high affinity, and facilitates co-localization of the kinase with its PH-domain-containing substrates. Substrates of PDK1 include many of the AGC family of protein kinases (the cAMP- dependent, cGJVIP-dependent, and protein kinase C), including AKT/PKB, p70S6K, cyclic AMP-dependent protein kinase (PKA), protein kinase C (PKC), serum and glucocorticoid- inducible kinase (SGK), p90 ribosomal protein kinase (RSK), p21-activated kinase-1 (PAK1 ), PRK1/2, and others (Wick and Liu, Curr. Drug Targets Immune Endocr. Metabol. Disord. 1 :209-221 (2001 ); Mora et al., Semin. Cell Dev. Biol. 15:161-170 (2004)). Recent in vivo studies with PDK1 (-/-) and PDK1 (-/+) mice showed that AKT, p70S6K, RSK and protein kinase C are key mediators of PDK1 function, regulating diverse cellular functions (Lawlor et al EMBO J. 21 :3728-3738 (2002); Williams et al., Curr. Biol. 10:439-448 (2000); Storz and Toker, Front. Biosci. 7:886-902 (2002)). Activation of these substrates by PDK1 leads to an increase in glucose uptake, protein synthesis, and inhibition of pro-apoptotic proteins. Dysregulation of the PI-3 kinase pathway is seen in a variety of cancers. A significant number of cancers possess mutations in genes that result in elevation of cellular levels of PIP3. Increased levels of PIP3 leads to activation of AKT and p70S6K kinases, which promote the proliferation and enhanced survival of these tumor cells. For example, genetic alterations of the PI3K gene including amplifications and activating mutations have been observed in various cancers (Hennessey et al., Nature Rev. Cancer 4, 988-1004 (2005)). One of the most common mutations giving rise to elevated levels of PIP3 is in the PIP3 3-phosphatase PTEN gene (Leslie and Downes, Cell Signal. 14:285- 295 (2002); Cantley, Science 296:1655-1657 (2002)). Germline mutations of PTEN are responsible for human cancer syndromes such as Cowden disease (Liaw et al., Nature Genetics 16:64-67 (1997)). PTEN is deleted in a large percentage of human tumors and tumor cell lines without functional PTEN show elevated levels of activated AKT (Li et al. supra, Guldberg et al., Cancer Research 57:3660-3663 (1997), Risinger et al., Cancer Research 57:4736-4738 (1997)).

AKT/PKB (consisting of 3 family members, AKT1 , AKT2, AKT3) is a substrate for PDK1 and is an important mediator of the physiological effects of insulin and several growth factors including EGF, PDGF, and IGF-1 (Manning and Cantley, Cell 129:1261- 1274 (2007)). AKT is activated by phosphorylation events occurring in response to PI3K signaling. PI3K phosphorylates membrane inositol phospholipids, generating the second messengers Pl P3 and phosphatidylinositol 3,4-diphosphate, which have been shown to bind to the PH domain of AKT. The current model of AKT activation proposes recruitment of the enzyme to the membrane by Pl P3 through the PH domain of PDK1. Co-localization of AKT and PDK1 at the membrane allows for AKT modification and activation by PDK1 and possibly other kinases (Hemmings, Science 275:628-630 (1997); Hemmings, Science 276:534 (1997); Downward, Science 279:673-674(1998)). Phosphorylation of AKT1 occurs on two regulatory sites, Thr308 by PDK1 in the catalytic domain activation loop and Ser473 (most probably by TORC2 mTOR complex) near the carboxy terminus (Alessi et al., EMBO J. 15:6541-6551 (1996); Meier et al., J. Biol. Chem. 272:30491-30497 (1997)). Analysis of AKT levels in human tumors revealed that AKT is overexpressed in a significant number of ovarian (Cheung et al., Proc. Natl. Acad. Sci. U.S.A. 89:9267-9271 (1992)) and pancreatic cancers (Cheung et al., Proc. Natl. Acad. Sci. U.S.A. 93:3636- 3641 (1996)). AKT was also found to be overexpressed in breast and prostate cancer cell lines (Nakatani et al. J. Biol. Chem. 274:21528-21532 (1999)). More recently, a transforming mutation in the PH domain of AKT 1 was detected in human breast, colorectal and ovarian cancers (Carpten et al., Nature 448:439-444 (2007)). Specific inhibitors of PI3K or dominant negative AKT mutants abolish survival-promoting activities of growth factors or cytokines. It has been previously described that inhibitors of PI3K (LY294002 or wortmannin) blocked the activation of AKT. In addition, introduction of constitutively active PI3K or AKT mutants promotes cell survival under conditions in which cells normally undergo apoptotic cell death (Kulik et al., MoI. Cell Biol. 17(3):1595-1606 (1997); Dudek et al, Sc/eπce 275(5300):661-665 (1997)).

PDK1 modulates affects the activity of a variety of substrates besides AKT. These substrates lack the PH domain seen in AKT and are therefore not dependent on co- localization with PDK1 on cell membranes. Important PH-domain-independent substrates of PDK1 are PKC, RSK and p70 S6K. RSKs have been recently implicated in promoting FGFR3-mediated hematopoetic transformation (Kang et al., Cancer Cell 12:201-214 (2007)). PDK1 activates RSK by phosphorylating its amino terminal kinase domain in an ERK-dependent manner (Cohen et al., Nature Chem. Biol. 3(3): 156-160 (2007)). Also, recent studies revealed additional roles of PDK1 that could be important during tumorigenesis and metastasis, such as cell motility and migration (Primo et al., J. Cell Biol. 176(7): 1035-1047 (2007); Pinner and Sahai, Nature Cell Biol. 10(2): 127-137 (2008)).

Taken together, these observations suggest a beneficial role for an inhibitor of PDK1 in the treatment of cancer cells. Consistent with this, a hypomorphic mutation of

PDK1 suppresses tumorigenesis in PTEN+/- mice (Bayascas et al., Curr. Biol. 15, 1839-

1846 (2005)). Furthermore, antisense-based reduction of PDK1 levels in tumor cells leads to decreased tumor cell proliferation and increased apoptosis (Flynn et al. Curr. Biol.

10: 1439-1442 (2000)), and small molecule kinase inhibitors of PDK1 inhibit the growth of tumors cells in vitro and in vivo (Feldman et al., J. Biol. Chem. 280: 19867-19874 (2005);

Gopalsamy et al. {J. Med. Chem. 50, 5547-5549 (2007); Tamguney et al. Exp. Cell Res.

314:2299-2312 (2008)). Finally, since knockdown of PDK1 by siRNA was shown to sensitise breast cancer cells to tamoxifen (Irons et al., Biochem. J. 417:361-370 (2009)), inhibition of PDK1 may have a therapeutic benefit in combination with other anticancer treatments.

PDK1 is reported to be a mediator of T-cell activation through NF-kB activation

(Lee et al. Science 308: 114-1 18 (2005)) and also a regulator of T-cell development

(Hinton et. al. Nat. Immunol. 5(5), 539-545 (2004)). Literature data also suggests that a PDK1 inhibitor may be useful for the treatment of autoimmune disease and transplant rejection (e.g. Park et al. Nat. Immunol. 10(2), 158-666 (2009)). Given the close association of PDK1 with with the AKT and PI3K pathways, and inhibitor of PDK1 may have beneficial use in treating diseases related to metabolism and aging, for example through the downstream inhibition of S6K1 signaling (Selman et al. Science 326: 140-144 (2009)).

It is an object of the instant invention to provide novel compounds that are inhibitors of PDK1.

It is also an object of the present invention to provide pharmaceutical compositions that comprise a pharmaceutical carrier and compounds useful in the methods of the invention.

It is also an object of the present invention to provide a method for treating cancer, immune and metabolic diseases that comprises administering such inhibitors of PDK1 activity.

It is also an object of the present invention to provide a method for treating cancer that comprises administering such inhibitors of PDK1 activity.

SUMMARY OF THE INVENTION

The invention is directed to substituted indazole derivatives. Specifically, the invention is directed to compounds according to Formula I:

R is selected from: hydrogen, trifluoromethyl, fluoride, chloride, bromide, iodide,

C-i-Cβalkoxy,

C-i-Cβalkoxy substituted with from one to three substituents selected from halogen, trifluoromethyl, hydroxy, oxo, and methoxy, C-|-C4alkyl, and

C-|-C4alkyl substituted with form one to three substituents selected from halogen, trifluoromethyl, hydroxy, oxo, and methoxy;

2 3 4

R , R and R are each independently selected from: hydrogen, Ci-C6alkyl, substituted C-|.C6alkyl, C-|-C6alkoxy, substituted C-|.C6alkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl,

Cβ-Cδcylcoalkyl, substituted Cβ-Cscycloalkyl, heterocycloalkyl, substituted heterocycloalkyl,

-C(O)OR²⁰, formyl, nitro, cyano,

-NHC(O)NHR²⁰

-S(O)_nR²⁰,

-NR²⁵R²⁶,

-C(O)NR²⁵R²⁶, phosphonic acid, sulfonic acid, phosphinic acid,

-SO₂NR²⁵R²⁶, and halogen, where, n is 0-2,

R²⁰ is selected from: hydrogen, C-|.C6alkyl, Cβ-Cscycloalkyl, substituted C-|.C6alkyl, and substituted Cβ-Cscycloalkyl, and R²⁵ and R²⁶ are each independently selected from: hydrogen, Ci-C4alkyl, substituted Ci-C4alkyl, 03.Cs⁰Y⁰¹⁰³¹M- C-|-C-|2aryl, and -C(O)Ci-C6alkyl, or R²⁵ and R²⁶ taken together with the nitrogen to which they are attached represent a 5 to 6 member saturated ring containing up to one other heteroatom selected from oxygen and nitrogen, or either:

2 3

R and R form a 5 or 6 member saturated or unsaturated ring, optionally containing 1 or 2 heteroatoms selected from oxygen, nitrogen, and sulfur, and optionally substituted with 1 or 2 substituents selected from halogen, trifluoromethyl, C-|-C4alkyl, hydroxy, oxo, and methoxy, and

4 R is as described above, or,

3 4 R and R form a 5 or 6 member saturated or unsaturated ring, optionally containing 1 or 2 heteroatoms selected from oxygen, nitrogen, and sulfur, and optionally substituted with 1 or 2 substituents selected from halogen, trifluoromethyl, C-|-C4alkyl, hydroxy, oxo, and methoxy, and

2 R is as described above;

5 R is selected from: hydrogen, -NH2, and -N(H)C-|-C4alkyl;

R is selected from: aryl, substituted aryl, C3_C8cycloalkyl, substituted C3. C_βcycloalkyl, heteroaryl, substituted heteroaryl, C-|-C6alkyl, substituted C-|-C6alkyl, heterocycloalkyl, substituted heterocycloalkyl, C-|-C6alkoxy, substituted C-|-C6alkoxy, heteroaryloxy, aryloxy, -SC-|-C6alkylaryl, - SarylCi-Cβalkyl, and -NR³⁵R³⁶, where, R³⁵ and R³⁶ are each independently selected from: hydrogen, C-|-

Cβalkyl, substituted C-|-C6alkyl, C3_C8cycloalkyl, substituted C3. Cβcycloalkyl, heteroaryl, substituted heteroaryl, substituted C-i-C-^aryl and C-i-C^ary'! ^and

X is selected from: O, S, Ncyclopropyl, NH, NEt and NMe;

or a salt thereof.

This invention also relates to pharmaceutically acceptable salts of the compounds of Formula (I).

This invention relates to a method of treating cancer, which comprises administering to a subject in need thereof an effective amount of a PDK1 inhibiting compound of Formula (I). The present invention also relates to the discovery that the compounds of Formula (I) are active as inhibitors of PDK1.

In a further aspect of the invention there is provided novel processes and novel intermediates useful in preparing the presently invented PDK1 inhibiting compounds.

Included in the present invention are pharmaceutical compositions that comprise a pharmaceutical carrier and compounds useful in the methods of the invention.

Also included in the present invention are methods of co-administering the presently invented PDK1 inhibiting compounds with further active ingredients.

DETAILED DESCRIPTION OF THE INVENTION

This invention relates to compounds of Formula (I) as described above. The presently invented compounds of Formula (I) inhibit PDK1 activity

Included in the presently invented compounds of Formula (I) are compounds of Formula (II):

R is selected from: hydrogen, trifluoromethyl, fluoride, chloride, bromide, C-|- Cβalkoxy, and C-|-C4alkyl;

Cβ-Cδcylcoalkyl, substituted Cβ-Cscycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, -C(O)OR⁵⁰,

-NHC(O)NHR⁵⁰

-S(O)_nR⁵⁰,

-NR⁵⁵R⁵⁶,

-CONR⁵⁵R⁵⁶, -SO₂NR⁵⁵R⁵⁶, and halogen, where, n is 0-2,

R⁵⁰ is selected from: hydrogen, C-|.C6alkyl and substituted C-|- Cβalkyl, and

R⁵⁵ and R⁵⁶ are each independently selected from: hydrogen, C-|-C4alkyl, and substituted C-|-C4alkyl, or R⁵⁵ and R⁵⁶ taken together with the nitrogen to which they are attached represent a 5 to 6 member saturated ring containing up to one other heteroatom selected from oxygen, and nitrogen,

R is selected from: -NH2 and -N(H)C-|-C4alkyl;

12 R is selected from: aryl, substituted aryl, C3_C8cycloalkyl, substituted C3.

C_βcycloalkyl, heteroaryl, substituted heteroaryl, C-|-C6alkyl, substituted C-|-C6alkyl, heterocycloalkyl, substituted heterocycloalkyl, C-|-C6alkoxy, substituted C-|-C6alkoxy, aryloxy, heteroaryloxy, -SC-i-Cealkylaryl, -

SarylCi-Cβalkyl, and -NR⁶⁵R⁶⁶, where,

R⁶⁵ and R⁶⁶ are each independently selected from: hydrogen, C-|- Cβalkyl, substituted C-|-C6alkyl, C3_C8cycloalkyl, substituted C3.

C_βcycloalkyl, heteroaryl, substituted heteroaryl, substituted C-|-C-|2aryl and C-|-C-|2aryl; and X is selected from: O, S, Ncyclopropyl, NH, NEt and NMe;

or a salt thereof.

This invention also relates to pharmaceutically acceptable salts of the compounds of Formula (II).

Included in the presently invented compounds of Formula (I) are compounds of

Formula (III):

13 R is selected from: hydrogen, methoxy, fluoride, chloride, bromide, and C-|-

C₂alkyl; R , R and R are each independently selected from: hydrogen, C-|.C4alkyl,

C-|.C4alkoxy, aryl, heteroaryl, C3-C8^cyl^c°alkyl, heterocycloalkyl, -

C(O)OR⁸⁰, -NHC(O)NHR⁸⁰, -S(O)_nR⁸⁰, -NR⁸⁵R⁸⁶, -CONR⁸⁵R⁸⁶, - SO2NR⁸⁵R⁸⁶, and halogen, where, n is 0-2,

R80 js selected from: hydrogen and C-|.C6alkyl and R85 and R^6 are each independently selected from: hydrogen and Ci-C4alkyl, or R85 and R^6 taken together with the nitrogen to which they are attached represent a 5 to 6 member saturated ring containing up to one other heteroatom selected from oxygen and nitrogen;

R is selected from: -NH2 and -N(H)C-|-C4alkyl;

18 R is selected from: aryl, substituted aryl, heteroaryl, substituted heteroaryl,

C-|-C4alkyl, C-|-C4substituted alkyl, heterocycloalkyl, substituted heterocycloalkyl, C3_C8cycloalkyl, substituted C3_C8cycloalkyl, and - NR95R96, where, R95 and R^6 are each independently selected from: hydrogen, C-|-

C4alkyl, substituted C-|-C4alkyl, C3_C8cycloalkyl, substituted C3. Cβcycloalkyl, heteroaryl, substituted heteroaryl, substituted C-i-C-^aryl and C-i-C^ary'; ^and

X is selected from: O, S, Ncyclopropyl, NH, NEt and NMe;

or a salt thereof.

This invention also relates to pharmaceutically acceptable salts of the compounds of Formula (III).

Included among the compounds useful in the present invention are:

4-(10-Fluoro-1 ,2-dihydroindazolo[4,3-6c][1 ,5]benzoxazepin-4-yl)-6-(4-morpholinyl)- 2-pyrimidinamine;

4-(1 ,2-Dihydroindazolo[4,3-6c][1 ,5]benzoxazepin-4-yl)-6-[(2R)-2-ethyl-1- pyrrolidinyl]-2-pyrimidinamine;

4-(2-Cyclopropyl-1 -pyrrolidinyl)-6-(1 ,2-dihydroindazolo[4,3-6c][1 ,5]benzoxazepin-4- yl)-2-pyrimidinamine; 4-(1 ,2-Dihydroindazolo[4,3-6c][1 ,5]benzoxazepin-4-yl)-6-(2-methyl-1-piperidinyl)-2- pyrimidinamine;

4-(1 ,2-Dihydroindazolo[4,3-6c][1 ,5]benzoxazepin-4-yl)-6-[(3R)-3-ethyl-4- morpholinyl]-2-pyrimidinamine;

4-(2-Cyclopropyl-1 -piperidinyl)-6-(1 ,2-dihydroindazolo[4,3-6c][1 ,5]benzoxazepin-4- yl)-2-pyrimidinamine; 4-[2-Amino-6-(4-morpholinyl)-4-pyrimidinyl]-Λ/-methyl-1 ,2-dihydroindazolo[4,3-

6c][1 ,5]benzoxazepine-9-sulfonamide;

4-(1 ,2-Dihydroindazolo[4,3-6c][1 ,5]benzothiazepin-4-yl)-6-(4-morpholinyl)-2- pyrimidinamine;

4-(1 ,2-Dihydroindazolo[4,3-6c][1 ,5]benzoxazepin-4-yl)-6-(3-oxa-8- azabicycloβ^.iloct-δ-yl^-pyrimidinamine;

6-(1 ,2-dihydroindazolo[4,3-6c][1 ,5]benzoxazepin-4-yl)-Λ/⁴-(2-phenylethyl)-2,4- pyrimidinediamine;

4-(1 ,2-Dihydroindazolo[4,3-6c][1 ,5]benzoxazepin-4-yl)-6-[2-(methyloxy)phenyl]-2- pyrimidinamine; 4-(1 ,2-Dihydroindazolo[4,3-6c][1 ,5]benzoxazepin-4-yl)-6-(1 -pyrrolidinyl)-2- pyrimidinamine;

4-(1 ,2-Dihydroindazolo[4,3-6c][1 ,5]benzoxazepin-4-yl)-6-(2-methyl-1 -pyrrolidinyl)- 2-pyrimidinamine;

4-(1 ,2-Dihydroindazolo[4,3-6c][1 ,5]benzoxazepin-4-yl)-6-(1 -piperidinyl)-2- pyrimidinamine;

4-(1-Azetidinyl)-6-(1 ,2-dihydroindazolo[4,3-6c][1 ,5]benzoxazepin-4-yl)-2- pyrimidinamine;

Λ/⁴-Cyclohexyl-6-(1 ,2-dihydroindazolo[4,3-6c][1 ,5]benzoxazepin-4-yl)-2,4- pyrimidinediamine; Λ/⁴-Cyclopentyl-6-(1 ,2-dihydroindazolo[4,3-6c][1 ,5]benzoxazepin-4-yl)-2,4- pyrimidinediamine;

6-(1 ,2-Dihydroindazolo[4,3-6c][1 ,5]benzoxazepin-4-yl)-Λ/⁴-methyl-2,4- pyrimidinediamine;

6-(1 ,2-Dihydroindazolo[4,3-6c][1 ,5]benzoxazepin-4-yl)-Λ/⁴-ethyl-2,4- pyrimidinediamine;

6-(1 ,2-Dihydroindazolo[4,3-6c][1 ,5]benzoxazepin-4-yl)-Λ/⁴-(1 -methylethyl)-2,4- pyrimidinediamine;

6-(1 ,2-dihydroindazolo[4,3-6c][1 ,5]benzoxazepin-4-yl)-Λ/⁴,Λ/⁴-dimethyl-2,4- pyrimidinediamine; Λ/⁴-Cyclobutyl-6-(1 ,2-dihydroindazolo[4,3-6c][1 ,5]benzoxazepin-4-yl)-2,4- pyrimidinediamine; 6-(1 ,2-Dihydroindazolo[4,3-6c][1 ,5]benzoxazepin-4-yl)-Λ/⁴-methyl-Λ/⁴-(1- methylethyl)-2,4-pyrimidinediamine;

6-(1 ,2-Dihydroindazolo[4,3-6c][1 ,5]benzoxazepin-4-yl)-Λ/⁴-propyl-2,4- pyrimidinediamine;

6-(1 ,2-dihydroindazolo[4,3-6c][1 ,5]benzoxazepin-4-yl)-Λ/⁴-(2-methylpropyl)-2,4- pyrimidinediamine;

6-(1 ,2-dihydroindazolo[4,3-6c][1 ,5]benzoxazepin-4-yl)-Λ/⁴,Λ/⁴-diethyl-2,4- pyrimidinediamine;

4-(1 ,2-Dihydroindazolo[4,3-6c][1 ,5]benzoxazepin-4-yl)-6-(2-ethyl-1-piperidinyl)-2- pyrimidinamine; 1-[2-Amino-6-(1 ,2-dihydroindazolo[4,3-6c][1 ,5]benzoxazepin-4-yl)-4-pyrimidinyl]-L- prolinamide;

1-[2-Amino-6-(1 ,2-dihydroindazolo[4,3-6c][1 ,5]benzoxazepin-4-yl)-4-pyrimidinyl]- Λ/,Λ/-dimethyl-L-prolinamide;

4-(1 ,2-Dihydroindazolo[4,3-6c][1 ,5]benzoxazepin-4-yl)-6-[(3R)-3-methyl-4- morpholinyl]-2-pyrimidinamine;

4-(1 ,2-Dihydroindazolo[4,3-6c][1 ,5]benzoxazepin-4-yl)-6-(4-morpholinyl)-2- pyrimidinamine;

4-[2-Amino-6-(4-morpholinyl)-4-pyrimidinyl]-Λ/,Λ/-dimethyl-1 ,2-dihydroindazolo[4,3- 6c][1 ,5]benzoxazepine-8-sulfonamide; and 4-(2,6-Dihydro-1 /-/-indazolo[3,4-6c][1 ,5]benzodiazepin-4-yl)-6-(4-morpholinyl)-2- pyrimidinamine;

6-(1 ,2-Dihydroindazolo[4,3-6c][1 ,5]benzoxazepin-4-yl)-Λ/⁴-[1- (phenylmethyl)cyclopropyl]-2,4-pyrimidinediamine;

6-(1 ,2-Dihydroindazolo[4,3-6c][1 ,5]benzoxazepin-4-yl)-Λ/⁴-(1 , 1 -dimethyl-2- phenylethyl)-2,4-pyrimidinediamine;

4-(1 ,2-Dihydroindazolo[4,3-6c][1 ,5]benzoxazepin-4-yl)-6-[(2R)-2-methyl-1- pyrrolidinyl]-2-pyrimidinamine;

4-(1 ,2-Dihydroindazolo[4,3-6c][1 ,5]benzoxazepin-4-yl)-6-[2-(1-methylethyl)-1- pyrrolidinyl]-2-pyrimidinamine; 4-Cyclopentyl-6-(1 ,2-dihydroindazolo[4,3-6c][1 ,5]benzoxazepin-4-yl)-2- pyrimidinamine;

4-(1 ,2-Dihydroindazolo[4,3-6c][1 ,5]benzoxazepin-4-yl)-6-ethyl-2-pyrimidinamine; 4-(1 ,2-Dihydroindazolo[4,3-ιbc][1 ,5]benzoxazepin-4-yl)-6-propyl-2-pyrimidinamine;

4-Cyclobutyl-6-(1 ,2-dihydroindazolo[4,3-6c][1 ,5]benzoxazepin-4-yl)-2- pyrimidinamine;

4-(1 ,2-Dihydroindazolo[4,3-6c][1 ,5]benzoxazepin-4-yl)-6-(tetrahydro-2H-pyran-4- yl)-2-pyrimidinamine; 4-(1 ,2-Dihydroindazolo[4,3-6c][1 ,5]benzoxazepin-4-yl)-6-(phenylmethyl)-2- pyrimidinamine;

4-(1 ,2-Dihydroindazolo[4,3-6c][1 ,5]benzoxazepin-4-yl)-6-(1 , 1 -dimethylethyl)-2- pyrimidinamine;

4-Butyl-6-(1 ,2-dihydroindazolo[4,3-6c][1 ,5]benzoxazepin-4-yl)-2-pyrimidinamine;

4-(1 ,2-Dihydroindazolo[4,3-6c][1 ,5]benzoxazepin-4-yl)-6-(2-methylpropyl)-2- pyrimidinamine;

4-(1 ,2-Dihydroindazolo[4,3-όc][1 ,5]benzoxazepin-4-yl)-6-(2-phenylethyl)-2- pyrimidinamine;

4-(1 ,2-Dihydroindazolo[4,3-6c][1 ,5]benzoxazepin-4-yl)-6-[(ethyloxy)methyl]-2- pyrimidinamine;

4-(6-methyl-2,6-dihydro-1 H-indazolo[3,4-bc][1 ,5]benzodiazepin-4-yl)-6-(4- morpholinyl)-2-pyrimidinamine; 4-(2,6-dihydro-1 /-/-indazolo[3,4-6c][1 ,5]benzodiazepin-4-yl)-6-(3-oxa-8- azabicyclo^^.iloct-δ-yl^-pyrimidinamine;

4-[2-amino-6-(1 ,2-dihydroindazolo[4,3-6c][1 ,5]benzoxazepin-4-yl)-4-pyrimidinyl]-3- morpholinecarboxamide; 6-(1 ,2-dihydroindazolo[4,3-bc][1 ,5]benzoxazepin-4-yl)-N4-phenyl-2,4- pyrimidinediamine;

6-(1 ,2-dihydroindazolo[4,3-bc][1 ,5]benzoxazepin-4-yl)-N4-methyl-N4-phenyl-2,4- pyrimidinediamine;

6-(1 ,2-dihydroindazolo[4,3-bc][1 ,5]benzoxazepin-4-yl)-N4-(2,6-dimethylphenyl)- 2,4-pyrimidinediamine;

6-(1 ,2-dihydroindazolo[4,3-bc][1 ,5]benzoxazepin-4-yl)-N4-methyl-N4-(2- methylphenyl)-2,4-pyrimidinediamine;

6-(1 ,2-dihydroindazolo[4,3-bc][1 ,5]benzoxazepin-4-yl)-N4-(2-methylphenyl)-2,4- pyrimidinediamine;

6-(1 ,2-dihydroindazolo[4,3-bc][1 ,5]benzoxazepin-4-yl)-N4-(1-methyl-1 H-pyrazol-3- yl)-2,4-pyrimidinediamine; 4-(1 ,2-dihydroindazolo[4,3-bc][1 ,5]benzoxazepin-4-yl)-6-(2-methyl-4-morpholinyl)- 2-pyrimidinamine;

1-[2-amino-6-(1 ,2-dihydroindazolo[4,3-bc][1 ,5]benzoxazepin-4-yl)-4-pyrimidinyl]-2- azetidinecarboxamide;

1-[2-amino-6-(1 ,2-dihydroindazolo[4,3-bc][1 ,5]benzoxazepin-4-yl)-4-pyrimidinyl]-N- phenyl-3-piperidinecarboxamide; 1-[2-amino-6-(1 ,2-dihydroindazolo[4,3-bc][1 ,5]benzoxazepin-4-yl)-4-pyrimidinyl]-N- methyl-L-prolinamide;

1-[2-amino-6-(1 ,2-dihydroindazolo[4,3-6c][1 ,5]benzoxazepin-4-yl)-4-pyrimidinyl]-D- prolinamide; and

4-[(3R)-3-methyl-4-morpholinyl]-6-[10-(methyloxy)-2,6-dihydro-1 H-indazolo[3,4- bc][1 ,5]benzodiazepin-4-yl]-2-pyrimidinamine or a salt thereof including a pharmaceutically acceptable salt thereof.

Compounds of Formula (I) and pharmaceutically acceptable salts thereof, are included in the pharmaceutical compositions of the invention and used in the methods of the invention.

The salts of the compounds of the invention are readily prepared by those of skill in the art.

The pharmaceutically acceptable salts of the compounds of the invention are readily prepared by those of skill in the art.

Certain of the compounds described herein may contain one or more chiral atoms, or may otherwise be capable of existing as two enantiomers. Accordingly, the compounds of this invention include mixtures of enantiomers as well as purified enantiomers or enantiomerically enriched mixtures. Also, it is understood that all tautomers and mixtures of tautomers are included within the scope of the compounds of Formula (I).

The compounds according to Formula I may also contain double bonds or other centers of geometric asymmetry. Where the stereochemistry of a center of geometric asymmetry present in Formula I, or in any chemical structure illustrated herein, is not specified, the structure is intended to encompass the trans (E) geometric isomer, the cis

(Z) geometric isomer, and all mixtures thereof. Certain compounds described herein may form a solvate which is understood to be a complex of variable stoichiometry formed by a solute (in this invention, a compound of Formula I a salt thereof) and a solvent. Such solvents for the purpose of the invention may not interfere with the biological activity of the solute. Examples of suitable solvents include, but are not limited to, water, methanol, ethanol and acetic acid. Suitably the solvent used is a pharmaceutically acceptable solvent. Examples of suitable pharmaceutically acceptable solvents include, without limitation, water, ethanol and acetic acid. Suitably the solvent used is water. The invention includes all such solvates.

The skilled artisan will further appreciate that certain compounds of Formula I or salts, including pharmaceutically acceptable salts, thereof that exist in crystalline form, including the various solvates thereof, may exhibit polymorphism (i.e. the capacity to occur in different crystalline structures). These different crystalline forms are typically known as "polymorphs." The invention includes all such polymorphs. Polymorphs have the same chemical composition but differ in packing, geometrical arrangement, and other descriptive properties of the crystalline solid state. Polymorphs, therefore, may have different physical properties such as shape, density, hardness, deformability, stability, and dissolution properties. Polymorphs typically exhibit different melting points, IR spectra, and X-ray powder diffraction patterns, which may be used for identification. The skilled artisan will appreciate that different polymorphs may be produced, for example, by changing or adjusting the reaction conditions or reagents, used in making the compound. For example, changes in temperature, pressure, or solvent may result in polymorphs. In addition, one polymorph may spontaneously convert to another polymorph under certain conditions.

By the term "treating" and derivatives thereof as used herein, is meant therapeutic therapy. In reference to a particular condition, treating means: (1 ) to ameliorate or prevent the condition of one or more of the biological manifestations of the condition, (2) to interfere with (a) one or more points in the biological cascade that leads to or is responsible for the condition or (b) one or more of the biological manifestations of the condition, (3) to alleviate one or more of the symptoms or effects associated with the condition, or (4) to slow the progression of the condition or one or more of the biological manifestations of the condition. Prophylactic therapy is also contemplated thereby. The skilled artisan will appreciate that "prevention" is not an absolute term. In medicine, "prevention" is understood to refer to the prophylactic administration of a drug to substantially diminish the likelihood or severity of a condition or biological manifestation thereof, or to delay the onset of such condition or biological manifestation thereof. Prophylactic therapy is appropriate, for example, when a subject is considered at high risk for developing cancer, or when a subject has been exposed to a carcinogen.

As used herein, the term "effective amount" and derivatives thereof means that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal or human that is being sought, for instance, by a researcher or clinician. Furthermore, the term "therapeutically effective amount" and derivatives thereof means any amount which, as compared to a corresponding subject who has not received such amount, results in improved treatment, healing, prevention, or amelioration of a disease, disorder, or side effect, or a decrease in the rate of advancement of a disease or disorder. The term also includes within its scope amounts effective to enhance normal physiological function.

Compounds of Formula (I) are included in the pharmaceutical compositions of the invention and used in the methods of the invention. Where a -COOH or -OH group is present, pharmaceutically acceptable esters can be employed, for example methyl, ethyl, pivaloyloxymethyl, and the like for -COOH, and acetate maleate and the like for -OH, and those esters known in the art for modifying solubility or hydrolysis characteristics, for use as sustained release or prodrug formulations.

Definitions

"Alkyl" By the term "alkyl" and derivatives thereof and in all carbon chains as used herein, including alkyl chains defined by the term "-(CH2)_n" and the like, is meant a linear or branched, saturated or unsaturated hydrocarbon chain, and unless otherwise defined, the carbon chain will contain from 1 to 12 carbon atoms. Examples of alkyl as used herein include: -CH₃, -CH₂-CH₃, -CH₂-CH₂-CH₃, -CH(CH₃)₂, -CH₂-CH₂-C(CH₃)₃, -C≡C-C(CH₃)₃, -C(CH₃)3, -(CH₂)₃-CH₃, -CH₂-CH(CH₃)₂, -CH(CH₃)-CH₂-CH₃, - CH=CH₂, and -C=C-CH₃.

"Aryl" By the term "aryl", and derivatives thereof, used alone or as part of a larger moiety as in "-(CH₂)_maryl" as used herein, unless otherwise defined, is meant monocyclic, bicyclic, and tricyclic ring systems having a total of five to fourteen ring members, wherein at least one ring system is aromatic and wherein each ring in the system contains 3 to 7 members, such as phenyl, naphthalene, tetrahydronaphthalene and biphenyl. Suitably, by the term "aryl" is meant a monocyclic aromatic ring system having a total of 5 to 7 ring members.

"C5-Ci2aryl" By the term "C5-C-|2aryl", used alone or as part of a larger moiety as in "-(CH2)mC5-C-|2aryl", as used herein, is meant an aromatic group selected from: phenyl, naphthalene, tehrahydronaphthanlene and biphenyl.

"C3-C8Cycloalkyl" By the term "Cβ-Cscycloalkyl", and derivatives thereof, used alone or as part of a larger moiety as in "-(CH2)mcycloalkyl" as used herein, unless otherwise defined, is meant a non-aromatic, saturated or unsaturated, cyclic hydrocarbon ring having from three to eight carbon atoms. Exemplary "cycloalkyl" groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, and cyclohexenyl.

"Halogen" By the term "halogen" as used herein is meant a substituent selected from the radicals fluoro, chloro, bromo, and iodo.

"Heteroaryl" By the term "heteroaryl", and derivatives thereof, used alone or as part of a larger moiety as in "-(CH2)mheteroaryl" as used herein, unless otherwise defined, is meant an aromatic ring containing from 1 to 4 heteroatoms as member atoms in the ring. Heteroaryl groups containing more than one heteroatom may contain different heteroatoms. Heteroaryl groups are monocyclic ring systems or are fused bicyclic ring systems. Monocyclic heteroaryl rings have 5 or 6 member atoms. Bicyclic heteroaryl rings have from 8 to 11 member atoms. Bicyclic heteroaryl rings include those rings wherein a monocyclic heteroaryl ring and a phenyl, or a monocyclic cycloalkyl, cycloalkenyl, heterocycloalkyl, or heteroaryl ring are attached forming a fused bicyclic ring system. The point of attachment of a heteroaryl can be at a heteroatom or it can be at a carbon atom. Heteroaryl includes pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, furanyl, furazanyl, thienyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, tetrazinyl, indolyl, azaindolyl, isoindolyl, indolizinyl, indazolyl, purinyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, pteridinyl, benzimidazolyl, benopyranyl, benzoxazolyl, benzofuranyl, isobenzofuranyl, benzothiazolyl, benzothienyl, furopyridinyl, and napthyridinyl.

"Heteroatom" By the term "heteroatom" as used herein is meant nitrogen, sulfur, or oxygen atom.

"Heterocycloalkyl" By the term "heterocycloalkyl", and derivatives thereof, used alone or as part of a larger moiety as in "-(CH2)mheterocycloalkyl" as used herein, unless otherwise defined, is meant a non-aromatic, saturated or unsaturated ring containing from 1 to 4 heteroatoms as member atoms in the ring. Heterocycloalkyl groups containing more than one heteroatom may contain different heteroatoms. Heterocycloalkyl groups are monocyclic and polycyclic ring systems having from 4 to 8 member atoms, provided that at least one atom is a carbon atom. Heterocycloalkyl groups may be fused, spiro or bridged. In certain embodiments, heterocycloalkyl is saturated. In other embodiments, heterocycloalkyl is unsaturated but not aromatic. The point of attachment of a heterocycloalkyl can be at a heteroatom or it can be at a carbon atom. Heterocycloalkyl includes pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, pyranyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothienyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, piperidinyl, homopiperidinyl, piperazinyl, morpholinyl, thiamorpholinyl, 1 ,3-dioxolanyl, 1 ,3-dioxanyl, 1 ,4-dioxanyl, 1 ,3-oxathiolanyl, 1 ,3-oxathianyl, 1 ,3-dithianyl, azetidinyl, and 3-oxa-8- azabicyclo[3.2.1 ]oct-8-yl .

"Substituted" The term "substituted" as used herein, unless otherwise defined, is meant that the subject chemical moiety has from one to five substituents, suitably from one to three substituents, selected from the group consisting of: -CO2R¹2°, C-|-C4alkyl, hydroxyC-|-C₄alkyl, C-|-C₄alkyloxy, -OC(O)NHR³⁰⁰, -NHC(O)OR³⁰¹ , amino, C₁-

C4alkylamino, aminoC-|-C4alkyl, diC-|-C4alkylamino, aryl, heteroaryl, Cβ-Cscycloalkyl, - C(O)NR^⁰⁰RSOI ₁ hydroxy, nitro, cyano, oxo, halogen and trifluoromethyl; where R^ 20 j_s selected form hydrogen, C-_|-C4alkyl, and trifluoromethyl, R2°° and R2°1 are each independently selected from: hydrogen and C-|-C4alkyl,

R³⁰⁰ is selected from hydrogen, C-|-Cgalkyl, C3-C8cycloalkyl, phenyl and heteroaryl, and

R³°1 is selected from C-|-Cgalkyl and C3-C8cycloalkyl. Suitably, the term "substituted" as used herein is meant that the subject chemical moiety has from one to three substituents, selected from the group consisting of: C-|-

C₄alkyl, hydroxyC-_|-C₄alkyl, C-_|-C₄alkyloxy, -OC(O)NHRSOO₁ -NHC(O)OR³⁰¹ , amino,

C-_|-C4alkylamino, phenyl, heteroaryl, cyclopropyl, -C(O)NR200R201 _I aminoC-_|-C4alkyl, hydroxy, halogen and trifluoromethyl; where R^⁰⁰ _anc| R201 _{are eac}h independently selected from: hydrogen, C-_|-C4alkyl and phenyl,

R300 |_{S se}|_ec^_ec| f_rom hydrogen, C-_|-Cgalkyl, C3-C8cycloalkyl, phenyl and heteroaryl, and R³⁰¹ is selected from C-|-Cgalkyl and C3-C8cycloalkyl. Suitably, the term "substituted" as used herein is meant that the subject chemical moiety has from one to three substituents, selected from the group consisting of: halogen, phenyl, heteroaryl, C-|-C₄alkyl, C-|-C₄alkyloxy, -OC(O)NHR³⁰⁰, -NHC(O)OR³⁰¹ , - C(O)NH₂, -C(O)NHCH₃, -C(O)N(CH₃)₂ and trifluoromethyl;

Where R³⁰⁰ is selected from hydrogen, C-_|-Cgalkyl, C3-C8cycloalkyl, phenyl and heteroaryl, and

R³⁰¹ is selected from C-_|-Cgalkyl and C_β-Cscycloalkyl.

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

Compound Preparation The compounds according to Formula I are generally prepared as shown in

Schemes 1 and 2 below, or by analogous methods, provided the X and 'R' substituents in Formula (I) do not include any such substituents that render inoperative the processes of any of Schemes 1 and 2. All of the starting materials are commercially available or are readily made from commercially available starting materials by those of skill in the art unless otherwise noted in the experimental section.

The skilled artisan will appreciate that if a substituent described herein is not compatible with the synthetic methods described herein, the substituent may be protected with a suitable protecting group. The protecting group may be removed at a suitable point in the reaction sequence to provide a desired intermediate or target compound. Suitable protecting groups and the methods for protecting and de-protecting different substituents using such suitable protecting groups are well known to those skilled in the art.

Scheme 1

Bromoacid (II) and aniline (III) are commercially available or may be synthesized using techniques well known in the art. These intermediates may be advantageously reacted under amide coupling conditions to produce intermediate (IV), using an acid activating reagent such as EDCI, an additive such as HOBT, a base such as Hunig's base, and a solvent such as DMF. Alternatively, bromoacid (II) can be converted first to the respective acylchloride using techniques well known in the art, and reacted with aniline (II) in the presence of a suitable base such as triethylamine in a suitable solvent such as

CH₂CI₂. When X = OH, intermediate (IV) can be converted to intermediate (V) using a suitable base such as K₂CO₃ or Cs₂CO₃ in a suitable solvent such as DMF. This reaction is typically carried out at room temperature. When X = NR (R = H, alkyl), intermediate (IV) can be converted to intermediate (V) using a suitable base such as NaH in a suitable solvent such as THF at an elevated temperature (typically under reflux conditions). Reaction of intermediate (V) with Lawesson's reagent in a suitable solvent such as toluene at an elevated temperature (typically at 100 ⁰C) provides the respective thiolactam intermediate which, upon treatment with hydrazine monohydrate in a suitable solvent such as 1 ,4-dioxane at an elevated temperature (typically from about 80 to about 100 ⁰C), provides intermediate (Vl). This intermediate can be acetylated using techniques well known in the art. Reaction of intermediate (Vl) with acetic anhydride as the solvent at an elevated temperature (typically from about 100 to about 120 ⁰C) provides intermediate (VII). The product can be a mixture of mono-acetates as well as di-acetates. If additional substituents can be acetylated, then products containing more than two acetate groups can be observed. Reaction with bis-pinacolatodiboron forms the intermediate boronate ester (VIII). The reaction can be advantageously carried out at elevated temperatures (typically from about 80 to about 100 ⁰C) in the presence of a suitable base such as potassium acetate using a palladium catalyst such as Pd(dppf)CI₂ ^«CH₂CI₂ in a suitable solvent such as dioxane. Suzuki coupling with chloropyrimidine (IX), which is commercially available or may be synthesized using techniques well known in the art, provides final product (X). The Suzuki coupling can be advantageously carried out at elevated temperatures (typically from about 80 to about 100 ⁰C) in the presence of a suitable base such as saturated aqueous NaHCO₃ using a palladium catalyst such as Pd₂(dba)₃, a suitable ligand such as tricyclohexylphosphine, and a suitable solvent such as 1 ,4- dioxane. If acetyl groups are still present in intermediate (X) a final deprotection step is necessary. The removal of the acetyl groups can be carried out using HCI in a suitable solvent such as CH₃OH at an elevated temperature (typically from about 65 to about 100 ⁰C).

An alternative method for preparing intermediate (V) when X = S is illustrated in Scheme 2. Methylester (Xl) can be prepared using techniques well known in the art such as methylation of Bromoacid (II) using a suitable methylating agent such as methyl sulphate, a suitable base such as K₂CO₃, and a suitable solvent such as acetone. Reaction of Intermediate (Xl) with the corresponding aminothiophenol (III) using a suitable base such as K₂CO₃ in a suitable solvent such as DMF provides intermediate (XII). Cyclization under microwave conditions at an elevated temperature (-200 ⁰C) in a suitable solvent such as 1 ,4-dioxane in the presence of a suitable acid such as toluensulfonic acid provides the desired intermediate (V). Scheme 2

Methods of Use

The compounds according to Formula I and pharmaceutically acceptable salts thereof are inhibitors of PDK1. These compounds are useful in the treatment of conditions wherein the underlying pathology is attributable to (but not limited to) constitutively activated ACG kinases, for example, cancer and more specifically leukemias and cancers of the breast, colon, and lung. What is meant by constitutively activated ACG kinases is that one or more ACG kinases are being produced at a constant rate regardless of physiological demand or concentration. Accordingly, in another aspect the invention is directed to methods of treating such conditions.

Suitably, the present invention relates to a method for treating or lessening the severity of breast cancer, including inflammatory breast cancer, ductal carcinoma, and lobular carcinoma.

Suitably the present invention relates to a method for treating or lessening the severity of colon cancer. Suitably the present invention relates to a method for treating or lessening the severity of lung cancer including small cell lung cancer, non-small cell lung cancer, squamous cell carcinoma, adenocarcinoma, and large cell carcinoma.

Suitably the present invention relates to a method for treating or lessening the severity of leukaemia including Chronic myelogenous leukemia, Chronic lymphocytic leukemia, acute lymphoblastic leukemia and acute myelogenous leukemia.

Suitably the present invention relates to a method for treating or lessening the severity of cancers selected from the group consisting of: brain (gliomas), glioblastomas, Bannayan-Zonana syndrome, Cowden disease, Lhermitte-Duclos disease, breast, inflammatory breast cancer, Wilm's tumor, Ewing's sarcoma, Rhabdomyosarcoma, ependymoma, medulloblastoma, colon, head and neck, kidney, lung, liver, melanoma, ovarian, pancreatic, prostate, sarcoma, osteosarcoma, giant cell tumor of bone, thyroid, Lymphoblastic T cell leukemia, Chronic myelogenous leukemia, Chronic lymphocytic leukemia, Hairy-cell leukemia, acute lymphoblastic leukemia, acute myelogenous leukemia, Chronic neutrophilic leukemia, Acute lymphoblastic T cell leukemia, Plasmacytoma, lmmunoblastic large cell leukemia, Mantle cell leukemia, Multiple myeloma Megakaryoblastic leukemia, multiple myeloma, acute megakaryocyte leukemia, promyelocytic leukemia, Erythroleukemia, malignant lymphoma, hodgkins lymphoma, non-hodgkins lymphoma, lymphoblastic T cell lymphoma, Burkitt's lymphoma, follicular lymphoma, neuroblastoma, bladder cancer, urothelial cancer, lung cancer, vulval cancer, cervical cancer, endometrial cancer, renal cancer, mesothelioma, esophageal cancer, salivary gland cancer, hepatocellular cancer, gastric cancer, nasopharangeal cancer, buccal cancer, cancer of the mouth, GIST (gastrointestinal stromal tumor) and testicular cancer.

Suitably the present invention relates to a method for treating or lessening the severity of at least one disease related to metabolism, an immune disease and/or aging.

The methods of treatment of the invention comprise administering a save and effective amount of a compound according to Formula I or a pharmaceutically acceptable salt thereof to a patient in need thereof. The invention also provides a compound according to Formula I or a pharmaceutically-acceptable salt thereof for use in medical therapy, and particularly in cancer therapy. Thus, in further aspect, the invention is directed to the use of a compound according to Formula I or a pharmaceutically-acceptable salt thereof in the preparation of a medicament for the treatment of a disorder characterized by constitutively activated ACG kinases, such as cancer.

As used herein the terms, "patient" and "subject" and derivatives thereof, as used herein, unless otherwise defined, is meant a human or other mammal. Suitably the patient or subject is a human.

The compounds of Formula I and pharmaceutically acceptable salts thereof may be co-administered with at least one other active ingredient known to be useful in the treatment of cancer.

By the term "co-administration" as used herein is meant either simultaneous administration or any manner of separate sequential administration of a PDK1 inhibiting compound, as described herein, and a further active ingredient or ingredients, known to be useful in the treatment of cancer, including chemotherapy and radiation treatment. The term further active ingredient or ingredients, as used herein, includes any compound or therapeutic agent known to or that demonstrates advantageous properties when administered to a patient in need of treatment for cancer. Preferably, if the administration is not simultaneous, the compounds are administered in a close time proximity to each other. Furthermore, it does not matter if the compounds are administered in the same dosage form, e.g. one compound may be administered by injection and another compound may be administered orally.

Typically, any anti-neoplastic agent that has activity versus a susceptible tumor being treated may be co-administered in the treatment of cancer in the present invention. Examples of such agents can be found in Cancer Principles and Practice of Oncology by VT. Devita and S. Hellman (editors), 6^th edition (February 15, 2001 ), Lippincott Williams & Wilkins Publishers. A person of ordinary skill in the art would be able to discern which combinations of agents would be useful based on the particular characteristics of the drugs and the cancer involved. Typical anti-neoplastic agents useful in the present invention include, but are not limited to, anti-microtubule agents such as diterpenoids and vinca alkaloids; platinum coordination complexes; alkylating agents such as nitrogen mustards, oxazaphosphorines, alkylsulfonates, nitrosoureas, and triazenes; antibiotic agents such as anthracyclins, actinomycins and bleomycins; topoisomerase Il inhibitors such as epipodophyllotoxins; antimetabolites such as purine and pyrimidine analogues and anti-folate compounds; topoisomerase I inhibitors such as camptothecins; hormones and hormonal analogues; signal transduction pathway inhibitors; receptor tyrosine kinase inhibitors; serine-threonine kinase inhibitors; non-receptor tyrosine kinase inhibitors; angiogenesis inhibitors, immunotherapeutic agents; proapoptotic agents; and cell cycle signalling inhibitors.

Examples of a further active ingredient or ingredients (anti-neoplastic agent) for use in combination or co-administered with the presently invented PDK1 inhibiting compounds are chemotherapeutic agents.

Anti-microtubule or anti-mitotic agents are phase specific agents active against the microtubules of tumor cells during M or the mitosis phase of the cell cycle. Examples of anti-microtubule agents include, but are not limited to, diterpenoids and vinca alkaloids.

Diterpenoids, which are derived from natural sources, are phase specific anticancer agents that operate at the G₂/M phases of the cell cycle. It is believed that the diterpenoids stabilize the β-tubulin subunit of the microtubules, by binding with this protein. Disassembly of the protein appears then to be inhibited with mitosis being arrested and cell death following. Examples of diterpenoids include, but are not limited to, paclitaxel and its analog docetaxel.

Paclitaxel, 5β,20-epoxy-1 ,2α,4,7β, 10β, 13α-hexa-hydroxytax-1 1 -en-9-one 4,10- diacetate 2-benzoate 13-ester with (2R,3S)-N-benzoyl-3-phenylisoserine; is a natural diterpene product isolated from the Pacific yew tree Taxus brevifolia and is commercially available as an injectable solution TAXOL®. It is a member of the taxane family of terpenes. It was first isolated in 1971 by Wani et al. J. Am. Chem, Soc, 93:2325. 1971 ), who characterized its structure by chemical and X-ray crystallographic methods. One mechanism for its activity relates to paclitaxel's capacity to bind tubulin, thereby inhibiting cancer cell growth. Schiff et al., Proc. Natl, Acad, Sci. USA, 77:1561-1565 (1980); Schiff et al., Nature, 277:665-667 (1979); Kumar, J. Biol, Chem, 256: 10435-10441 (1981 ). For a review of synthesis and anticancer activity of some paclitaxel derivatives see: D. G. I. Kingston et al., Studies in Organic Chemistry vol. 26, entitled "New trends in Natural Products Chemistry 1986", Attaur-Rahman, P. W. Le Quesne, Eds. (Elsevier, Amsterdam, 1986) pp 219-235.

Paclitaxel has been approved for clinical use in the treatment of refractory ovarian cancer in the United States (Markman et al., Yale Journal of Biology and Medicine, 64:583, 1991 ; McGuire et al., Ann. Intern, Med., 1 11 :273,1989) and for the treatment of breast cancer (Holmes et al., J. Nat. Cancer Inst., 83:1797,1991.) It is a potential candidate for treatment of neoplasms in the skin (Einzig et. al., Proc. Am. Soc. Clin. Oncol., 20:46) and head and neck carcinomas (Forastire et. al., Sem. Oncol., 20:56, 1990). The compound also shows potential for the treatment of polycystic kidney disease (Woo et. al., Nature, 368:750. 1994), lung cancer and malaria. Treatment of patients with paclitaxel results in bone marrow suppression (multiple cell lineages, Ignoff, RJ. et. al, Cancer Chemotherapy Pocket Guide_A 1998) related to the duration of dosing above a threshold concentration (5OnM) (Kearns, CM. et. al., Seminars in Oncology, 3(6) p.16-23, 1995).

Docetaxel, (2R,3S)- N-carboxy-3-phenylisoserine,N-terf-butyl ester, 13-ester with 5β-20-epoxy-1 ,2α,4,7β,10β,13α-hexahydroxytax-1 1-en-9-one 4-acetate 2-benzoate, trihydrate; is commercially available as an injectable solution as TAXOTERE®. Docetaxel is indicated for the treatment of breast cancer. Docetaxel is a semisynthetic derivative of paclitaxel q.v., prepared using a natural precursor, 10-deacetyl-baccatin III, extracted from the needle of the European Yew tree. The dose limiting toxicity of docetaxel is neutropenia.

Vinca alkaloids are phase specific anti-neoplastic agents derived from the periwinkle plant. Vinca alkaloids act at the M phase (mitosis) of the cell cycle by binding specifically to tubulin. Consequently, the bound tubulin molecule is unable to polymerize into microtubules. Mitosis is believed to be arrested in metaphase with cell death following. Examples of vinca alkaloids include, but are not limited to, vinblastine, vincristine, and vinorelbine.

Vinblastine, vincaleukoblastine sulfate, is commercially available as VELBAN® as an injectable solution. Although, it has possible indication as a second line therapy of various solid tumors, it is primarily indicated in the treatment of testicular cancer and various lymphomas including Hodgkin's Disease; and lymphocytic and histiocytic lymphomas. Myelosuppression is the dose limiting side effect of vinblastine. Vincristine, vincaleukoblastine, 22-oxo-, sulfate, is commercially available as ONCOVIN® as an injectable solution. Vincristine is indicated for the treatment of acute leukemias and has also found use in treatment regimens for Hodgkin's and non-Hodgkin's malignant lymphomas. Alopecia and neurologic effects are the most common side effect of vincristine and to a lesser extent myelosupression and gastrointestinal mucositis effects occur.

Vinorelbine, 3',4'-didehydro -4'-deoxy-C'-norvincaleukoblastine [R-(R^*, R^*)-2,3- dihydroxybutanedioate (1 :2)(salt)], commercially available as an injectable solution of vinorelbine tartrate (NAVELBINE®), is a semisynthetic vinca alkaloid. Vinorelbine is indicated as a single agent or in combination with other chemotherapeutic agents, such as cisplatin, in the treatment of various solid tumors, particularly non-small cell lung, advanced breast, and hormone refractory prostate cancers. Myelosuppression is the most common dose limiting side effect of vinorelbine.

Platinum coordination complexes are non-phase specific anti-cancer agents, which are interactive with DNA. The platinum complexes enter tumor cells, undergo, aquation and form intra- and interstrand crosslinks with DNA causing adverse biological effects to the tumor. Examples of platinum coordination complexes include, but are not limited to, cisplatin and carboplatin.

Cisplatin, cis-diamminedichloroplatinum, is commercially available as PLATINOL® as an injectable solution. Cisplatin is primarily indicated in the treatment of metastatic testicular and ovarian cancer and advanced bladder cancer. The primary dose limiting side effects of cisplatin are nephrotoxicity, which may be controlled by hydration and diuresis, and ototoxicity.

Carboplatin, platinum, diammine [1 ,1-cyclobutane-dicarboxylate(2-)-O,O'], is commercially available as PARAPLATI N® as an injectable solution. Carboplatin is primarily indicated in the first and second line treatment of advanced ovarian carcinoma. Bone marrow suppression is the dose limiting toxicity of carboplatin.

Alkylating agents are non-phase anti-cancer specific agents and strong electrophiles. Typically, alkylating agents form covalent linkages, by alkylation, to DNA through nucleophilic moieties of the DNA molecule such as phosphate, amino, sulfhydryl, hydroxyl, carboxyl, and imidazole groups. Such alkylation disrupts nucleic acid function leading to cell death. Examples of alkylating agents include, but are not limited to, nitrogen mustards such as cyclophosphamide, melphalan, and chlorambucil; alkyl sulfonates such as busulfan; nitrosoureas such as carmustine; and triazenes such as dacarbazine.

Cyclophosphamide, 2-[bis(2-chloroethyl)amino]tetrahydro-2H-1 ,3,2- oxazaphosphorine 2-oxide monohydrate, is commercially available as an injectable solution or tablets as CYTOXAN®. Cyclophosphamide is indicated as a single agent or in combination with other chemotherapeutic agents, in the treatment of malignant lymphomas, multiple myeloma, and leukemias. Alopecia, nausea, vomiting and leukopenia are the most common dose limiting side effects of cyclophosphamide.

Melphalan, 4-[bis(2-chloroethyl)amino]-L-phenylalanine, is commercially available as an injectable solution or tablets as ALKERAN®. Melphalan is indicated for the palliative treatment of multiple myeloma and non-resectable epithelial carcinoma of the ovary. Bone marrow suppression is the most common dose limiting side effect of melphalan.

Chlorambucil, 4-[bis(2-chloroethyl)amino]benzenebutanoic acid, is commercially available as LEUKERAN® tablets. Chlorambucil is indicated for the palliative treatment of chronic lymphatic leukemia, and malignant lymphomas such as lymphosarcoma, giant follicular lymphoma, and Hodgkin's disease. Bone marrow suppression is the most common dose limiting side effect of chlorambucil.

Busulfan, 1 ,4-butanediol dimethanesulfonate, is commercially available as MYLERAN® TABLETS. Busulfan is indicated for the palliative treatment of chronic myelogenous leukemia. Bone marrow suppression is the most common dose limiting side effects of busulfan.

Carmustine, 1 ,3-[bis(2-chloroethyl)-1 -nitrosourea, is commercially available as single vials of lyophilized material as BiCNU®. Carmustine is indicated for the palliative treatment as a single agent or in combination with other agents for brain tumors, multiple myeloma, Hodgkin's disease, and non-Hodgkin's lymphomas. Delayed myelosuppression is the most common dose limiting side effects of carmustine.

Dacarbazine, 5-(3,3-dimethyl-1-triazeno)-imidazole-4-carboxamide, is commercially available as single vials of material as DTIC-Dome®. Dacarbazine is indicated for the treatment of metastatic malignant melanoma and in combination with other agents for the second line treatment of Hodgkin's Disease. Nausea, vomiting, and anorexia are the most common dose limiting side effects of dacarbazine.

Antibiotic anti-neoplasties are non-phase specific agents, which bind or intercalate with DNA. Typically, such action results in stable DNA complexes or strand breakage, which disrupts ordinary function of the nucleic acids leading to cell death. Examples of antibiotic anti-neoplastic agents include, but are not limited to, actinomycins such as dactinomycin, anthracyclins such as daunorubicin and doxorubicin; and bleomycins.

Dactinomycin, also know as Actinomycin D, is commercially available in injectable form as COSMEGEN®. Dactinomycin is indicated for the treatment of Wilm's tumor and rhabdomyosarcoma. Nausea, vomiting, and anorexia are the most common dose limiting side effects of dactinomycin.

Daunorubicin, (8S-cis-)-8-acetyl-10-[(3-amino-2,3,6-trideoxy-α-L-lyxo- hexopyranosyl)oxy]-7,8,9, 10-tetrahydro-6,8, 11 -trihydroxy-1 -methoxy-5, 12 naphthacenedione hydrochloride, is commercially available as a liposomal injectable form as DAUNOXOME® or as an injectable as CERUBIDINE®. Daunorubicin is indicated for remission induction in the treatment of acute nonlymphocytic leukemia and advanced HIV associated Kaposi's sarcoma. Myelosuppression is the most common dose limiting side effect of daunorubicin.

Doxorubicin, (8S, 10S)-10-[(3-amino-2,3,6-trideoxy-α-L-lyxo-hexopyranosyl)oxy]-8- glycoloyl, 7, 8, 9, 10-tetrahydro-6, 8, 11 -trihydroxy-1 -methoxy-5, 12 naphthacenedione hydrochloride, is commercially available as an injectable form as RUBEX® or

ADRIAMYCIN RDF®. Doxorubicin is primarily indicated for the treatment of acute lymphoblastic leukemia and acute myeloblasts leukemia, but is also a useful component in the treatment of some solid tumors and lymphomas. Myelosuppression is the most common dose limiting side effect of doxorubicin. Bleomycin, a mixture of cytotoxic glycopeptide antibiotics isolated from a strain of

Streptomyces verticillus, is commercially available as BLENOXANE®. Bleomycin is indicated as a palliative treatment, as a single agent or in combination with other agents, of squamous cell carcinoma, lymphomas, and testicular carcinomas. Pulmonary and cutaneous toxicities are the most common dose limiting side effects of bleomycin.

Topoisomerase Il inhibitors include, but are not limited to, epipodophyllotoxins.

Epipodophyllotoxins are phase specific anti-neoplastic agents derived from the mandrake plant. Epipodophyllotoxins typically affect cells in the S and G₂ phases of the cell cycle by forming a ternary complex with topoisomerase Il and DNA causing DNA strand breaks. The strand breaks accumulate and cell death follows. Examples of epipodophyllotoxins include, but are not limited to, etoposide and teniposide.

Etoposide, 4'-demethyl-epipodophyllotoxin 9[4,6-0-(R)-ethylidene-β-D- glucopyranoside], is commercially available as an injectable solution or capsules as VePESID® and is commonly known as VP-16. Etoposide is indicated as a single agent or in combination with other chemotherapy agents in the treatment of testicular and non- small cell lung cancers. Myelosuppression is the most common side effect of etoposide. The incidence of leucopenia tends to be more severe than thrombocytopenia.

Teniposide, 4'-demethyl-epipodophyllotoxin 9[4,6-0-(R)-thenylidene-β-D- glucopyranoside], is commercially available as an injectable solution as VUMON® and is commonly known as VM-26. Teniposide is indicated as a single agent or in combination with other chemotherapy agents in the treatment of acute leukemia in children. Myelosuppression is the most common dose limiting side effect of teniposide. Teniposide can induce both leucopenia and thrombocytopenia.

Antimetabolite neoplastic agents are phase specific anti-neoplastic agents that act at S phase (DNA synthesis) of the cell cycle by inhibiting DNA synthesis or by inhibiting purine or pyrimidine base synthesis and thereby limiting DNA synthesis. Consequently, S phase does not proceed and cell death follows. Examples of antimetabolite antineoplastic agents include, but are not limited to, fluorouracil, methotrexate, cytarabine, mecaptopurine, thioguanine, and gemcitabine. 5-fluorouracil, 5-fluoro-2,4- (1 H,3H) pyrimidinedione, is commercially available as fluorouracil. Administration of 5-fluorouracil leads to inhibition of thymidylate synthesis and is also incorporated into both RNA and DNA. The result typically is cell death. 5- fluorouracil is indicated as a single agent or in combination with other chemotherapy agents in the treatment of carcinomas of the breast, colon, rectum, stomach and pancreas. Myelosuppression and mucositis are dose limiting side effects of 5-fluorouracil. Other fluoropyrimidine analogs include 5-fluoro deoxyuridine (floxuridine) and 5- fluorodeoxyuridine monophosphate.

Cytarabine, 4-amino-1-β-D-arabinofuranosyl-2 (I H)-pyrimidinone, is commercially available as CYTOSAR-U® and is commonly known as Ara-C. It is believed that cytarabine exhibits cell phase specificity at S-phase by inhibiting DNA chain elongation by terminal incorporation of cytarabine into the growing DNA chain. Cytarabine is indicated as a single agent or in combination with other chemotherapy agents in the treatment of acute leukemia. Other cytidine analogs include 5-azacytidine and 2', 2'- difluorodeoxycytidine (gemcitabine). Cytarabine induces leucopenia, thrombocytopenia, and mucositis.

Mercaptopurine, 1 ,7-dihydro-6H-purine-6-thione monohydrate, is commercially available as PURINETHOL®. Mercaptopurine exhibits cell phase specificity at S-phase by inhibiting DNA synthesis by an as of yet unspecified mechanism. Mercaptopurine is indicated as a single agent or in combination with other chemotherapy agents in the treatment of acute leukemia. Myelosuppression and gastrointestinal mucositis are expected side effects of mercaptopurine at high doses. A useful mercaptopurine analog is azathioprine.

Thioguanine, 2-amino-1 ,7-dihydro-6H-purine-6-thione, is commercially available as TABLOID®. Thioguanine exhibits cell phase specificity at S-phase by inhibiting DNA synthesis by an as of yet unspecified mechanism. Thioguanine is indicated as a single agent or in combination with other chemotherapy agents in the treatment of acute leukemia. Myelosuppression, including leucopenia, thrombocytopenia, and anemia, is the most common dose limiting side effect of thioguanine administration. However, gastrointestinal side effects occur and can be dose limiting. Other purine analogs include pentostatin, erythrohydroxynonyladenine, fludarabine phosphate, and cladribine. Gemcitabine, 2'-deoxy-2', 2'-difluorocytidine monohydrochloride (β-isomer), is commercially available as GEMZAR®. Gemcitabine exhibits cell phase specificity at S- phase and by blocking progression of cells through the G1/S boundary. Gemcitabine is indicated in combination with cisplatin in the treatment of locally advanced non-small cell lung cancer and alone in the treatment of locally advanced pancreatic cancer. Myelosuppression, including leucopenia, thrombocytopenia, and anemia, is the most common dose limiting side effect of gemcitabine administration.

Methotrexate, N-[4[[(2,4-diamino-6-pteridinyl) methyl]methylamino] benzoyl]-L- glutamic acid, is commercially available as methotrexate sodium. Methotrexate exhibits cell phase effects specifically at S-phase by inhibiting DNA synthesis, repair and/or replication through the inhibition of dyhydrofolic acid reductase which is required for synthesis of purine nucleotides and thymidylate. Methotrexate is indicated as a single agent or in combination with other chemotherapy agents in the treatment of choriocarcinoma, meningeal leukemia, non-Hodgkin's lymphoma, and carcinomas of the breast, head, neck, ovary and bladder. Myelosuppression (leucopenia, thrombocytopenia, and anemia) and mucositis are expected side effect of methotrexate administration.

Camptothecins, including, camptothecin and camptothecin derivatives are available or under development as Topoisomerase I inhibitors. Camptothecins cytotoxic activity is believed to be related to its Topoisomerase I inhibitory activity. Examples of camptothecins include, but are not limited to irinotecan, topotecan, and the various optical forms of 7-(4-methylpiperazino-methylene)-10,1 1-ethylenedioxy-20-camptothecin described below.

Irinotecan HCI, (4S)-4,1 1-diethyl-4-hydroxy-9-[(4-piperidinopiperidino) carbonyloxy]-1 H-pyrano[3',4',6,7]indolizino[1 ,2-b]quinoline-3,14(4H,12H)-dione hydrochloride, is commercially available as the injectable solution CAMPTOSAR®.

Irinotecan is a derivative of camptothecin which binds, along with its active metabolite SN-38, to the topoisomerase I - DNA complex. It is believed that cytotoxicity occurs as a result of irreparable double strand breaks caused by interaction of the topoisomerase I : DNA : irintecan or SN-38 ternary complex with replication enzymes. Irinotecan is indicated for treatment of metastatic cancer of the colon or rectum. The dose limiting side effects of irinotecan HCI are myelosuppression, including neutropenia, and Gl effects, including diarrhea.

Topotecan HCI, (S)-10-[(dimethylamino)methyl]-4-ethyl-4,9-dihydroxy-1 H- pyrano[3',4',6,7]indolizino[1 ,2-b]quinoline-3,14-(4H,12H)-dione monohydrochloride, is commercially available as the injectable solution HYCAMTI N®. Topotecan is a derivative of camptothecin which binds to the topoisomerase I - DNA complex and prevents religation of singles strand breaks caused by Topoisomerase I in response to torsional strain of the DNA molecule. Topotecan is indicated for second line treatment of metastatic carcinoma of the ovary and small cell lung cancer. The dose limiting side effect of topotecan HCI is myelosuppression, primarily neutropenia.

Also of interest, is the camptothecin derivative of Formula A following, currently under development, including the racemic mixture (R,S) form as well as the R and S enantiomers:

known by the chemical name "7-(4-methylpiperazino-methylene)-10,1 1-ethylenedioxy- 20(R,S)-camptothecin (racemic mixture) or "7-(4-methylpiperazino-methylene)-10,11- ethylenedioxy-20(R)-camptothecin (R enantiomer) or "7-(4-methylpiperazino-methylene)- 10,11-ethylenedioxy-20(S)-camptothecin (S enantiomer). Such compound as well as related compounds are described, including methods of making, in U.S. Patent Nos. 6,063,923; 5,342,947; 5,559,235; 5,491 ,237 and 6,100,273.

Hormones and hormonal analogues are useful compounds for treating cancers in which there is a relationship between the hormone(s) and growth and/or lack of growth of the cancer. Examples of hormones and hormonal analogues useful in cancer treatment include, but are not limited to, adrenocorticosteroids such as prednisone and prednisolone which are useful in the treatment of malignant lymphoma and acute leukemia in children; aminoglutethimide and other aromatase inhibitors such as anastrozole, letrazole, vorazole, and exemestane useful in the treatment of adrenocortical carcinoma and hormone dependent breast carcinoma containing estrogen receptors; progestrins such as megestrol acetate useful in the treatment of hormone dependent breast cancer and endometrial carcinoma; estrogens, androgens, and anti-androgens such as flutamide, nilutamide, bicalutamide, cyproterone acetate and 5α-reductases such as finasteride and dutasteride, useful in the treatment of prostatic carcinoma and benign prostatic hypertrophy; anti-estrogens such as tamoxifen, toremifene, raloxifene, droloxifene, iodoxyfene, as well as selective estrogen receptor modulators (SERMS) such those described in U.S. Patent Nos. 5,681 ,835, 5,877,219, and 6,207,716, useful in the treatment of hormone dependent breast carcinoma and other susceptible cancers; and gonadotropin-releasing hormone (GnRH) and analogues thereof which stimulate the release of leutinizing hormone (LH) and/or follicle stimulating hormone (FSH) for the treatment prostatic carcinoma, for instance, LHRH agonists and antagagonists such as goserelin acetate and luprolide.

Signal transduction pathway inhibitors are those inhibitors, which block or inhibit a chemical process which evokes an intracellular change. As used herein this change is cell proliferation or differentiation. Signal tranduction inhibitors useful in the present invention include inhibitors of receptor tyrosine kinases, non-receptor tyrosine kinases, SH2/SH3 domain blockers, serine/threonine kinases, phosphotidylinositol-3 kinases, myoinositol signaling, and Ras oncogenes.

Several protein tyrosine kinases catalyse the phosphorylation of specific tyrosyl residues in various proteins involved in the regulation of cell growth. Such protein tyrosine kinases can be broadly classified as receptor or non-receptor kinases.

Receptor tyrosine kinases are transmembrane proteins having an extracellular ligand binding domain, a transmembrane domain, and a tyrosine kinase domain. Receptor tyrosine kinases are involved in the regulation of cell growth and are generally termed growth factor receptors. Inappropriate or uncontrolled activation of many of these kinases, i.e. aberrant kinase growth factor receptor activity, for example by over- expression or mutation, has been shown to result in uncontrolled cell growth. Accordingly, the aberrant activity of such kinases has been linked to malignant tissue growth. Consequently, inhibitors of such kinases could provide cancer treatment methods. Growth factor receptors include, for example, epidermal growth factor receptor (EGFr), platelet derived growth factor receptor (PDGFr), erbB2, erbB4, vascular endothelial growth factor receptor (VEGFr), tyrosine kinase with immunoglobulin-like and epidermal growth factor homology domains (TIE-2), insulin growth factor -I (IGFI) receptor, macrophage colony stimulating factor (cfms), BTK, ckit, cmet, fibroblast growth factor (FGF) receptors, Trk receptors (TrkA, TrkB, and TrkC), ephrin (eph) receptors, and the RET protooncogene. Several inhibitors of growth receptors are available or under development and include ligand antagonists, antibodies (cetuximab/Erbitux; panitumumab/Vectibix); trastuzumab/Herceptin), tyrosine kinase inhibitors (Gefitinib/lressa; erlotinib/Tarceva; lapatinib/Tykerb; sorafenib/Nexavar; sunitinib/Sutent) and anti-sense oligonucleotides. Growth factor receptors and agents that inhibit growth factor receptor function are described, for instance, in Kath, John C, Exp. Opin. Ther. Patents (2000) 10(6):803-818; Shawver et al DDT VoI 2, No. 2 February 1997; and Lofts, F. J. et al, "Growth factor receptors as targets", New Molecular Targets for Cancer Chemotherapy, ed. Workman, Paul and Kerr, David, CRC press 1994, London.

Tyrosine kinases, which are not growth factor receptor kinases are termed nonreceptor tyrosine kinases. Non-receptor tyrosine kinases for use in the present invention, which are targets or potential targets of anti-cancer drugs, include cSrc, Lck, Fyn, Yes, Jak, cAbl, FAK (Focal adhesion kinase), Brutons tyrosine kinase, and Bcr-Abl. Such non- receptor kinases and agents which inhibit non-receptor tyrosine kinase function are described in Sinh, S. and Corey, S. J., (1999) Journal of Hematotherapy and Stem Cell Research 8 (5): 465 - 80; and Bolen, J. B., Brugge, J. S., (1997) Annual review of Immunology. 15: 371-404.

SH2/SH3 domain blockers are agents that disrupt SH2 or SH3 domain binding in a variety of enzymes or adaptor proteins including, PI3-K p85 subunit, Src family kinases, adaptor molecules (She, Crk, Nek, Grb2) and Ras-GAP. SH2/SH3 domains as targets for anti-cancer drugs are discussed in Smithgall, T. E. (1995), Journal of Pharmacological and Toxicological Methods. 34(3) 125-32.

Inhibitors of Serine/Threonine Kinases including MAP kinase cascade blockers which include blockers of Raf kinases (rafk), Mitogen or Extracellular Regulated Kinase (MEKs), and Extracellular Regulated Kinases (ERKs); and Protein kinase C family member blockers including blockers of PKCs (alpha, beta, gamma, epsilon, mu, lambda, iota, zeta). IkB kinase family (IKKa, IKKb IKK epsilon), PKB family kinases, Akt kinase family members; TGF beta receptor kinases; and mammalian target of rapamycin (mTOR) inhibitors (temsirolimus/Torisel). Such Serine/Threonine kinases and inhibitors thereof are described in Yamamoto, T., Taya, S., Kaibuchi, K., (1999), Journal of Biochemistry. 126 (5) 799-803; Brodt, P, Samani, A., and Navab, R. (2000), Biochemical Pharmacology, 60. 1101-1 107; Massague, J., Weis-Garcia, F. (1996) Cancer Surveys. 27:41-64; Philip, P.A., and Harris, A.L. (1995), Cancer Treatment and Research. 78: 3-27, Lackey, K. et al Bioorganic and Medicinal Chemistry Letters, (10), 2000, 223-226; U.S. Patent No. 6,268,391 ; and Martinez-lacaci, L., et al, Int. J. Cancer (2000), 88(1 ), 44-52.

Inhibitors of Phosphotidylinositol-3 Kinase family members including blockers of PI3-kinase, ATM, ATR, DNA-PK, and Ku may also be useful in the present invention. Such kinases are discussed in Abraham, RT. (1996), Current Opinion in Immunology. 8 (3) 412-8; Canman, C. E., Lim, D.S. (1998), Oncogene 17 (25) 3301-3308; Jackson, S.P. (1997), International Journal of Biochemistry and Cell Biology. 29 (7):935-8; and Zhong, H. et al, Cancer res, (2000) 60(6), 1541-1545.

Also of interest in the present invention are Myo-inositol signaling inhibitors such as phospholipase C blockers and Myoinositol analogues. Such signal inhibitors are described in Powis, G., and Kozikowski A., (1994) New Molecular Targets for Cancer Chemotherapy ed., Paul Workman and David Kerr, CRC press 1994, London.

Another group of signal transduction pathway inhibitors are inhibitors of Ras Oncogene. Such inhibitors include inhibitors of farnesyltransferase (tipifarnib), geranyl- geranyl transferase, and CAAX proteases as well as anti-sense oligonucleotides, ribozymes and immunotherapy. Such inhibitors have been shown to block ras activation in cells containing wild type mutant ras, thereby acting as antiproliferation agents. Ras oncogene inhibition is discussed in Scharovsky, O. G., Rozados, V.R., Gervasoni, S.I. Matar, P. (2000), Journal of Biomedical Science. 7(4) 292-8; Ashby, M.N. (1998), Current Opinion in Lipidology. 9 (2) 99 - 102; and BioChim. Biophys. Acta, (19899) 1423(3):19-30.

As mentioned above, antibody antagonists to receptor kinase ligand binding may also serve as signal transduction inhibitors. This group of signal transduction pathway inhibitors includes the use of humanized antibodies to the extracellular ligand binding domain of receptor tyrosine kinases. For example lmclone C225 EGFR specific antibody(cetuximab/Erbitux) (see Green, M. C. et al, Monoclonal Antibody Therapy for Solid Tumors, Cancer Treat. Rev., (2000), 26(4), 269-286); Herceptin ® erbB2 antibody (see Tyrosine Kinase Signalling in Breast canceπerbB Family Receptor Tyrosine Kniases, Breast cancer Res., 2000, 2(3), 176-183); and 2CB VEGFR2 specific antibody (see Brekken, R.A. et al, Selective Inhibition of VEGFR2 Activity by a monoclonal Anti-VEGF antibody blocks tumor growth in mice, Cancer Res. (2000) 60, 5117-5124).

Non-receptor kinase angiogenesis inhibitors may also be useful in the present invention. Inhibitors of angiogenesis related VEGFR and TIE2 are discussed above in regard to signal transduction inhibitors (both receptors are receptor tyrosine kinases). Angiogenesis in general is linked to erbB2/EGFR signalling since inhibitors of erbB2 and EGFR have been shown to inhibit angiogenesis, primarily VEGF expression. Accordingly, non-receptor tyrosine kinase inhibitors may be used in combination with the compounds of the present invention. For example, anti-VEGF antibodies, which do not recognize VEGFR (the receptor tyrosine kinase), but bind to the ligand (aflibercept/VEGF Trap); small molecule inhibitors of integrin (alpha_v beta₃) that will inhibit angiogenesis; endostatin and angiostatin (non-RTK) may also prove useful in combination with the disclosed compounds. (See Bruns CJ et al (2000), Cancer Res., 60: 2926-2935; Schreiber AB, Winkler ME, and Derynck R. (1986), Science, 232: 1250-1253; Yen L et al. (2000), Oncogene 19: 3460-3469).

Agents used in immunotherapeutic regimens may also be useful in combination with the compounds of Formula (I). There are a number of immunologic strategies to generate an immune response. These strategies are generally in the realm of tumor vaccinations. The efficacy of immunologic approaches may be greatly enhanced through combined inhibition of signaling pathways using a small molecule inhibitor. Discussion of the immunologic/tumor vaccine approach against erbB2/EGFR are found in Reilly RT et al. (2000), Cancer Res. 60: 3569-3576; and Chen Y, Hu D, Eling DJ, Robbins J, and

Kipps TJ. (1998), Cancer Res. 58: 1965-1971.

Agents used in proapoptotic regimens (e.g., bcl-2 antisense oligonucleotides) may also be used in the combination of the present invention. Members of the Bcl-2 family of proteins block apoptosis. Upregulation of bcl-2 has therefore been linked to chemoresistance. Studies have shown that the epidermal growth factor (EGF) stimulates anti-apoptotic members of the bcl-2 family (i.e., mcl-1 ). Therefore, strategies designed to downregulate the expression of bcl-2 in tumors have demonstrated clinical benefit and are now in Phase I I/I 11 trials, namely Genta's oblimersen bcl-2 antisense oligonucleotide. Such proapoptotic strategies using the antisense oligonucleotide strategy for bcl-2 are discussed in Water JS et al. (2000), J. Clin. Oncol. 18: 1812-1823; and Kitada S et al. (1994), Antisense Res. Dev. 4: 71-79.

Cell cycle signalling inhibitors inhibit molecules involved in the control of the cell cycle. A family of protein kinases called cyclin dependent kinases (CDKs) and their interaction with a family of proteins termed cyclins controls progression through the eukaryotic cell cycle. The coordinate activation and inactivation of different cyclin/CDK complexes is necessary for normal progression through the cell cycle. Several inhibitors of cell cycle signalling are under development. For instance, examples of cyclin dependent kinases, including CDK2, CDK4, and CDK6 and inhibitors for the same are described in, for instance, Rosania et al, Exp. Opin. Ther. Patents (2000) 10(2):215-230.

In one embodiment, the cancer treatment method of the claimed invention includes the co-administration a compound of Formula (I) and/or a pharmaceutically acceptable salt thereof and at least one anti-neoplastic agent, such as one selected from the group consisting of anti-microtubule agents, platinum coordination complexes, alkylating agents, antibiotic agents, topoisomerase Il inhibitors, antimetabolites, topoisomerase I inhibitors, hormones and hormonal analogues, signal transduction pathway inhibitors, non-receptor tyrosine kinase angiogenesis inhibitors, immunotherapeutic agents, proapoptotic agents, and cell cycle signaling inhibitors.

Because the pharmaceutically active compounds of the present invention are active as PDK1 inhibitors they exhibit therapeutic utility in treating cancer.

Assays

PDK1 Scintillation Proximity (LEADseeker) and Time Resolved Fluorescence Resonance Energy Transfer (TR-FRET) Assays using AKT1 as the phosphoacceptor

Substrate phosphorylation assays are carried out as follows:

The source of substrate protein

Biotinylated-hAKTI : Human AKT1 (containing amino acid residues 136-480, as annotated by National Center for Biotechnology Information (NCBI) accession number AAL55732.1 , with a MetLysLysHisβ N-terminal addition) is purified to >90% from lysate of baculovirus expression by Nickel Chelating ProBond resin (InVitrogen), Q-Sepharose Fast Flow, and Superdex 200 size exclusion chromatography. Biotinylation is achieved using EZ-Link Sulfo-NHS-LC Biotin (Pierce). Samples, in 25 mM HEPES, pH 7.5, 200 mM NaCI, 2 mM DTT, and 30% glycerol are stored at -80C until use.

The source of enzyme:

PDK1 : Full-length human 3-Phosphoinositide Dependent protein Kinase-1 (hPDK1 ; National Center for Biotechnology Information (NCBI) accession number AAH39158.1 with a MetGlyHisβ N-terminal addition) is purified from baculovirus expression in Sf9 cells. Purity of approximately 80% is achieved by the use of chelation chromatography (Ni-NTA Superflow) and desalting columns. Samples, in 25 mM HEPES, 150 mM NaCI, 2.5 mM DTT, 0.05%Triton, 30% glycerol, pH 8.0, are stored at -80⁰C until use.

Scintillation Proximity (LEADseeker) Kinase assay of purified hPDK1 :

Assays are performed in 384-well microtiter plates (Greiner, Catalog No. 784075). The reaction volume (10 μl) contains, in final concentrations, 25mM MOPS (pH 7.5), 1OmM MgCI2, 5OmM KCI, 0.1 mg/ml BSA, 1 μM ATP, 3uCi/ml ³³PγATP, 5mM DTT, 1 mM CHAPS or 0.05% Tween20, 0.35μM AKT1 biotinylated protein, and 10 nM hPDKL

Compounds, titrated in DMSO, are evaluated at eleven concentrations ranging from 50 μM to 2 pM. Final assay concentrations of DMSO do not exceed 1%. No effect on activity relative to controls without DMSO is observed for hPDK1 at these DMSO amounts. hPDK1 is pre-incubated, 30 minutes at room temperature, with compounds before initiating phosphorylation of AKT1 by addition of substrate to hPDK1/compound. Reactions are stopped after 3 hours at room temperature by the addition of 50 mM EDTA, 5 mg/ml LEADseeker beads (GE Healthcare) in PBS (10 ul). Beads are allowed to settle overnight, and samples are imaged on Viewlux (PerkinElmer).

The data for compound concentration responses were plotted as % Inhibition, calculated with the data reduction formula 100^*(1-[(U1-C2)/(C1-C2)]), versus concentration of compound, where U is the unknown value,

C1 is the average control value obtained for DMSO only, and C2 is the average control value obtained for reactions stopped with EDTA at t=0. Data were fitted to the curve described by: y = ((Vmax ^* x) / (K + x)) where Vmax is the upper asymptote and

K is the IC50. The results for each compound were recorded as plC50 calculated as follows: plC50 = -Log10(K).

TR-FRET Kinase assay of purified hPDK1 : Assays are performed in 384-well microtiter plates (Greiner, Catalog No. 784076).

The reaction volume (10 μl) contains, in final concentrations, 25mM MOPS (pH 7.5), 1OmM MgCI₂, 5OmM KCI, 0.1 mg/ml BSA, 5μM ATP, 5mM DTT, 1 mM CHAPS, 0.35μM AKT1 biotinylated protein, and 0.6- 0.9 nM hPDKL

As previously described for the Scintillation Proximity protocol, hPDK1 is pre- incubated (30 minutes at room temperature) with compounds before initiating phosphorylation of AKT1 by addition of substrate to the hPDK1 and compound mix. Reactions are stopped after 4-6 hours at room temperature by the addition to final concentrations of 0.02 M EDTA, 0.0875μM Streptavidin APC (PerkinElmer), 0.03 μM AKT1 (phospho T308) antibody (Abeam Inc.), 0.00375 μM Lance Eu-labeled anti rabbit IgG Antibody (PerkinElmer). Antibody binding reaches equilibrium in 30 minutes before signal is read on an EnVision™ 2103 Multilabel Reader (PerkinElmer). APC Signals are normalized to Europium signal. Data processing is the same as described for the Scintillation Proximity assay with the exception of the generation of the "C2" control by addition of buffer without hPDK1 to control wells at t=0 instead of EDTA.

Scintillation Proximity (LEADseeker) Kinase assay of purified hPDK1 using biotinylated-PDKtide peptide:

Assays are performed in 384-well microtiter plates (Greiner, Catalog No. 784075). The reaction volume (10 μl) contains, in final concentrations, 25mM MOPS (pH 7.5), 1OmM MgCI2, 5OmM KCI, 0.1 mg/ml BSA, 1 μM ATP, 3uCi/ml ³³PγATP, 5mM DTT, 0.5mM CHAPS, 1 μM biotinylated-PDKtide peptide, and 0.5 nM hPDKL

Compounds, titrated in DMSO, are evaluated at eleven concentrations ranging from 25 μM to 0.4 pM. Final assay concentrations of DMSO do not exceed 1%. No effect on activity relative to controls without DMSO is observed for hPDK1 at these DMSO amounts. hPDK1 is pre-incubated, 30 minutes at room temperature, with compounds before initiating phosphorylation of biotinylated-PDKtide peptide by addition of substrate to hPDK1/compound. Reactions are stopped after 4 hours at room temperature by the addition of 50 mM EDTA, 5 mg/ml LEADseeker beads (GE Healthcare) in PBS (10 ul). Beads are allowed to settle overnight, and samples are imaged on Viewlux (PerkinElmer). The data for compound concentration responses were plotted as % Inhibition, calculated with the data reduction formula 100^*(1-[(U1-C2)/(C1-C2)]), versus concentration of compound, where

U is the unknown value,

K is the IC50.

The results for each compound were recorded as plC50 calculated as follows: plC50 = -Log10(K).

Abbreviations used:

APC, Allophycocyanin

ATP, adenosine triphosphate

BSA, bovine serum albumin CHAPS, 3-[3-Cholamidopropyl)Dimethylammonio] -1-Propanesulfonate

DMSO, dimethyl sulfoxide

DTT, Dithiothreitol

EDTA, ethylenediaminetetraacetic acid

Eu, Europium HEPES, N-(2-Hydroxyethyl)piperazine-N'-2-ethanesulfonic acid

HPLC, high performance/pressure liquid chromatography

KCI, Potassium chloride

M, molar mg, milligram MgC^, magnesium chloride ml, milliliter mM, millimolar

MOPS, 3-morpholinopropanesulfonic acid

NaCI, Sodium chloride NCBI, National Center for Biotechnology Information nM, nanomolar PBS, phosphate buffered saline

PDK1 , human 3-Phosphoinositide Dependent protein Kinase-1 pM, picomolar

Tris-HCI, Tris(hydroxymethyl)aminomethane hydrochloride μM, micromolar

Phospho-AKT (S473, T308, Total AKT) and phospho-RSK ELISA

PC3 cells (ATCC, Manassas, VA) were plated in 96-well flat bottom plates (Corning, Lowell, MA) at a density of 15,000 cells/well in RPMI 1640 medium supplemented with

10% FBS. Cells were incubated at 37°C, 5% CO₂ for 18-20 h. Compounds (dissolved in

100% DMSO) were diluted in an 1 1-point 3-fold dilution in DMSO. Compound dilution stocks were further diluted in RPMI 1640with 10% FBS and added to each cell well.

DMSO without compound was used in control wells. Final concentration of DMSO in each well was 0.15%. After 6 hours at 37°C cells were washed with cold PBS (without calcium or magnesium) and lysed in lysis buffer (Meso Scale Discovery, Gaithersburg, MD) supplemented with 1 protease inhibitor tablet/10 ml (Roche, Indianapolis, IN), 10 mM NaF, and 200 μl/10 ml Sigma phosphatase inhibitor 1 & 2 (Sigma Aldrich, St Louis, MO) for 30 min at 4⁰C. All washes were performed on a Bio Tek ELx405 plate washer (Bio Tek Instruments, Winooski, VT).

ELISA plates (Meso Scale Discovery; AKT Duplex, cat. N41 100B-1 ; phospho AKT, cat. N411 CAB-1 ; RSK, cat. N41ZB-1 ) were prepared by the addition of blocking buffer (3% Blocker A diluted in wash buffer (Meso Scale Discovery) for AKT duplex assay and phospho AKT assays; 5% Blocker A / 1% Blocker B in Tris-buffered saline for RSK) for 1 hour and washed with wash buffer. Lysates were transferred to assay wells and incubated overnight at 4°C. Following washing with wash buffer, detection buffer (1% Blocker A in wash buffer for AKT duplex and phospho AKT or 1% Blocker A in TBS for RSK) with appropriate antibodies was added. Detection of AKT duplex and phospho AKT was carried out using a sulfo-tagged detection antibodies (Meso Scale Discovery). Detection of phospho-RSK was carried out sequentially with anti phospho-RSK1 (S221 )/RSK2 (S227) (R&D systems, Minneapolis, MN, cat. AF892) and goat anti-rabbit sulfo-tag antibody (cat R32AB-1 ; Meso Scale Discovery). Plates were incubated for 1 hour at room temperature and washed with wash buffer. Plates were read on a SECTOR™ Imager 6000 (Meso Scale Discovery) using Workbench software (Meso Scale Discovery) following addition of read buffer (Meso Scale Discovery) to each well. For analysis, phospho-AKT (S473) signals were normalized to total AKT, while phospho-AKT (T308) and phospho-RSK signals were analyzed without normalization. All values were expressed as percent of the DMSO-treated controls. IC50S were determined from inhibition curves using XLfit4 software (IDBS, Guildford, UK).

Cell Proliferation Assays

Cells were plated at 5000 cells/well in complete growth medium in white, top-read capable, 96 well plates (Thermo-Fisher, Waltham, MA), and allowed to adhere overnight in an humidified incubator at 37⁰C supplemented with 5% CO₂. Duplicate plates were used for each cell line. Compounds were diluted in dimethylsulfoxide (DMSO) and added directly to each well to yield a final compound concentration range of 10 pM to 30μM in a 3-fold dilution series. The final concentration of DMSO was 0.3% per well. Cells were then returned to the incubator for 72 h. Cell Titer GIo reagent (Promega, Madison, Wl) was added to each well and the plates rocked gently for 2 min. The chemiluminescent signal was allowed to develop at room temperature for 10 minutes following which luminescence was measured using in an Envision plate reader (Wallac/ Perkin Elmer, Waltham, MA). Cell growth was expressed as a percentage of the cells in the DMSO control wells, and

IC50 for each compound was determined from the inhibition curves using the XLfit4 software (IDBS, Guildford, UK).

Compounds of the invention are tested for activity against PDK1 in one or more of the above assays.

The compounds of the Examples were tested generally according to the above PDK1 enzyme assays and in at least one experimental run exhibited a IC50 value: ≤ 100

(nM) against full length PDK1.

The compound of Example 1 was tested generally according to the above PDK1 enzyme assays and in at least one experimental run exhibited a IC50 value: equal to 7.6

(nM) against full length PDK1. The compound of Example 5 was tested generally according to the above PDK1 enzyme assays and in at least one experimental run exhibited a IC50 value: equal to 3.2

(nM) against full length PDK1.

The pharmaceutically active compounds within the scope of this invention are useful as PDK1 inhibitors in mammals, particularly humans, in need thereof. The present invention therefore provides a method of treating cancer and other conditions requiring PDK1 inhibition, which comprises administering an effective compound of Formula (I) or a pharmaceutically acceptable salt thereof. The compounds of Formula (I) and pharmaceutically acceptable salts thereof also provide for a method of treating the above indicated disease states because of their demonstrated ability to act as PDK1 inhibitors. The drug may be administered to a patient in need thereof by any conventional route of administration, including, but not limited to, intravenous, intramuscular, oral, subcutaneous, intradermal, and parenteral.

The pharmaceutically active compounds of the present invention are incorporated into convenient dosage forms such as capsules, tablets, or injectable preparations. Solid or liquid pharmaceutical carriers are employed. Solid carriers include, starch, lactose, calcium sulfate dihydrate, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid. Liquid carriers include syrup, peanut oil, olive oil, saline, and water. Similarly, the carrier or diluent may include any prolonged release material, such as glyceryl monostearate or glyceryl distearate, alone or with a wax. The amount of solid carrier varies widely but, suitably, will be from about 25 mg to about 1 g per dosage unit. When a liquid carrier is used, the preparation will be in the form of a syrup, elixir, emulsion, soft gelatin capsule, sterile injectable liquid such as an ampoule, or an aqueous or nonaqueous liquid suspension. The pharmaceutical preparations are made following conventional techniques of a pharmaceutical chemist involving mixing, granulating, and compressing, when necessary, for tablet forms, or mixing, filling and dissolving the ingredients, as appropriate, to give the desired oral or parenteral products.

Doses of the presently invented pharmaceutically active compounds in a pharmaceutical dosage unit as described above will be an efficacious, nontoxic quantity suitably selected from the range of 0.001 - 100 mg/kg of active compound, suitably 0.01 - 50 mg/kg, suitably 0.1 - 20mg/kg. When treating a human patient in need of a PDK1 inhibitor, the selected dose is administered preferably from 1-6 times daily, orally or parenterally. Preferred forms of parenteral administration include topically, rectally, transdermal^, by injection and continuously by infusion. Oral dosage units for human administration suitably contain from about 0.05 to 3500 mg of active compound, suitably 0.5 to 350 mg, suitably 5 to 200 mg. Oral administration, which uses lower dosages, is preferred. Parenteral administration, at high dosages, however, also can be used when safe and convenient for the patient. Optimal dosages to be administered may be readily determined by those skilled in the art, and will vary with the particular PDK1 inhibitor in use, the strength of the preparation, the mode of administration, and the advancement of the disease condition. Additional factors depending on the particular patient being treated will result in a need to adjust dosages, including patient age, weight, diet, and time of administration.

The method of this invention of inducing PDK1 inhibitory activity in mammals, including humans, comprises administering to a subject in need of such activity an effective PDK1 inhibiting amount of a pharmaceutically active compound of the present invention.

The invention also provides for the use of a compound of Formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use as a PDK1 inhibitor.

The invention also provides for the use of a compound of Formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in therapy.

The invention also provides for the use of a compound of Formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in treating cancer.

The invention also provides for a pharmaceutical composition for use as a PDK1 inhibitor which comprises a compound of Formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. The invention also provides for a pharmaceutical composition for use in the treatment of cancer which comprises a compound of Formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

In addition, the pharmaceutically active compounds of the present invention can be co-administered with further active ingredients, such as other compounds known to treat cancer, or compounds known to have utility when used in combination with a PDK1 inhibitor.

Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. The following Examples are, therefore, to be construed as merely illustrative and not a limitation of the scope of the present invention in any way.

EXAMPLES The compounds of Examples 1 to 33 are readily made according to Schemes 1 and 2 or by analogous methods. The following examples further illustrate the invention. These examples are not intended to limit the scope of the present invention, but rather to provide guidance to the skilled artisan to prepare and use the compounds, compositions, and methods of the present invention. While particular embodiments of the present invention are described, the skilled artisan will appreciate that various changes and modifications can be made without departing from the spirit and scope of the invention.

Intermediate 1 4-Bromo-2,6-difluoro-Λ/-(2-fluoro-6-hvdroxyphenyl)benzamide

To 4-bromo-2,6-difluorobenzoic acid (1.86 g, 7.87 mmol) was added thionyl chloride (8 ml_, 110 mmol), and the mixture was stirred overnight at 100 ⁰C. The solution was concentrated and the resulting residue was evaporated (2X) from toluene. The residue was dissolved in CH₂CI₂ (30 ml.) and the resulting solution was added slowly to a solution of 2-amino-3-fluorophenol (1.0 g, 7.9 mmol) in CH₂CI₂ (40 ml.) and triethylamine (Et₃N) (2.2 ml_, 15.7 mmol). The reaction mixture was stirred for 4 hours at room temperature, and then poured onto water. The organic layer was separated, and the aqueous layer was further extracted with CH₂CI₂. The combined organic layers were dried (MgSO₄), filtered, and concentrated to afford the title compound (2.96 g) as a brown solid. LC-MS (ES) m/z = 346, 348 [M+H]⁺.

Intermediate 2

3-Bromo-1 ,9-difluorodibenzorά,/iπ ,4loxazepin-1 1 (1 OHVone

To 4-bromo-2,6-difluoro-Λ/-(2-fluoro-6-hydroxyphenyl)benzamide (2.96 g, 8.55 mmol) in N,N-Dimethylformamide (DMF) (50 ml.) was added Cs₂CO₃ (6.6 g, 20.3 mmol), and the reaction mixture was stirred overnight at room temperature. Water was added (-150 ml_), and the resulting mixture was stirred for 15 minutes. The mixture was filtered and the solid was washed with water. The solid was dried under vacuum at 40 ⁰C to afford the title compound (1.87 g) as a tan solid. LC-MS (ES) m/z = 326, 328 [M+H]⁺.

Intermediate 3

4-Bromo-10-fluoro-1 ,2-dihydroindazolor4,3-άciπ ,51benzoxazepine

To 3-bromo-1 ,9-difluorodibenzo[b,f][1 ,4]oxazepin-11 (10H)-one (1.5 g, 4.60 mmol) in toluene (20 ml.) was added Lawesson's reagent (5.58 g, 13.80 mmol), and the reaction mixture was stirred overnight at 100 ⁰C. The mixture was filtered, and the solid was washed with toluene followed by hexanes. The solid was purified via flash chromatography on SiO₂ (gradient: 100%CHCl3 to 5% ethyl acetate (EtOAc)/ 95% CHCI3) to afford the thioamide intermediate. To this material in 1 ,4-dioxane (50 ml.) was added hydrazine monohydrate (2.26 ml_, 46 mmol), and the reaction mixture was stirred for 3 hours at 85 ⁰C (caution: vigorous release of gas). The reaction was allowed to cool to room temperature, and then filtered. To the filtrate was added water (-300 ml_), and a white precipitate was immediately observed. The precipitate was filtered and dried under vacuum at 40 ⁰C to afford the title compound (537 mg, 37%) as a white solid. LC-MS (ES) m/z = 320, 322 [M+H]⁺.

Intermediate 4

2-Acetyl-4-bromo-10-fluoro-1 ,2-dihvdroindazolor4,3-άciri ,51benzoxazepine

To 4-bromo-10-fluoro-1 ,2-dihydroindazolo[4,3-bc][1 ,5]benzoxazepine (0.4 g, 1.250 mmol) was added acetic anhydride (12 mL, 127 mmol) and the resulting mixture was stirred for 1 hour at 100 ⁰C. During this time, the starting material dissolved when the mixture was heated to 100 ⁰C. Eventually, a precipitate was observed. The amount of precipitate increased as the reaction mixture was allowed to cool to room temperature. The mixture was concentrated under vacuum, co-evaporating the resulting residue from ethanol (3 X 75 ml.) to afford the crude product (453 mg) as a yellow solid as a mixture of monoacetates. LC-MS (ES) m/z = 362, 364 [M+H]⁺.

Intermediate 5

2-Acetyl-10-fluoro-4-(4.4.5.5-tetramethyl-1 ,3.2-dioxaborolan-2-vn-1 ,2-dihvdroindazolor4.3- άciπ ,51benzoxazepine

A mixture of 2-acetyl-4-bromo-10-fluoro-1 ,2-dihydroindazolo[4,3-bc][1 ,5]benzoxazepine (453 mg, 1.25 mmol), bis(pinacolato)diboron (317 mg, 1.25 mmol), and potassium acetate (368 mg, 3.75 mmol) in 1 ,4-dioxane (15 ml.) was purged with N₂ for 10 minutes into a sealable tube. PdCI₂(dppf)-CH₂Cl2 adduct (51.0 mg, 0.063 mmol) was added, the tube was sealed, and the reaction mixture was stirred overnight at 100 ⁰C. The mixture was poured onto water and ethyl acetate. The organic layer was separated, and the aqueous layer was further extracted with EtOAc. The combined organic layers were washed with brine, dried (MgSO₄), filtered and concentrated. The resulting residue was dissolved in dichloromethane and treated with hexanes until the solution became cloudy. Sonication of the system precipitated a light brown solid which was filtered to afford crude product (213 mg). LC-MS (ES) m/z = 410 [M+H]⁺.

Example 1

4-(10-Fluoro-1 ,2-dihydroindazolo[4,3-άc1[1 ,51benzoxazepin-4-yl)-6-(4-morpholinyl)-2- pyrimidinamine

To 2-acetyl-10-fluoro-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 ,2- dihydroindazolo[4,3-bc][1 ,5]benzoxazepine (100 mg, 0.24 mmol), 4-chloro-6-(4- morpholinyl)-2-pyιϊmidinamine (53 mg, 0.24 mmol) and K₃PO₄ (104 mg, 0.49 mmol) were added 1 ,4-dioxane (5 ml.) and water (1.5 ml_), and the resulting mixture was purged with N₂ for 10 minutes into a sealable tube. Pd₂(dba)₃ (6.7 mg, 7.3 μmol) was added, and N₂ was bubbled through the mixture for an additional 5 minutes. Tricyclohexylphosphine (4.5 mg, 0.016 mmol) was added, the tube was sealed, and the reaction mixture was stirred overnight at 100 ⁰C. The mixture was poured onto water and EtOAc. The organic layer was separated, and the aqueous layer was further extracted with EtOAc. The combined organic layers were washed with brine, dried (MgSO₄), filtered and concentrated. Flash chromatography on SiO₂ (gradient: 100% CHCI₃ to 90:10:1 CHCI₃:CH₃OH:NH₄OH) afforded the title compound (25 mg, 24%) as a light brown solid. LC-MS (ES) m/z = 420 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 3.66 (m, 8H), 6.20 (s, 2H), 6.71 (s, 1 H), 6.91 (m, 1 H), 7.09 (m, 1 H) 7.12 - 7.18 (m, 1 H), 7.53 (s, 1 H), 7.90 (s, 1 H), 9.14 (d, J = 3.79 Hz, 1 H), 12.47 (s, 1 H).

Intermediate 6 4-Bromo-2,6-difluoro-Λ/-(2-hvdroxyphenyl)benzamide

4-Bromo-2,6-difluorobenzoic acid (20 g, 84 mmol) was treated with thionyl chloride (100 ml_), and the reaction mixture was heated to reflux for 3 hours. The reaction was then cooled and concentrated, and the resulting dark brown oil was azeotroped with toluene (3 x 50 ml_). The resulting acid chloride was dissolved in CH₂CI₂ (50 ml.) and added dropwise via addition funnel to a 500 ml. round bottom flask containing 2-aminophenol (9.21 g, 84 mmol) and Et₃N (1 1.8 ml_, 84 mmol) in CH₂CI₂ (100 ml_). The resulting reaction mixture was then allowed to stir for 2 days at room temperature. A precipitate was formed, which was filtered and washed with CH₂CI₂ to afford white fluffy crystals and a dark brown filtrate. Initial NMR of the crystals showed significant amount of Et₃N. This material was taken up in EtOAc (200 ml_), and the resulting organic layer was washed with 0.1 M HCI (2 x 200 ml_), brine (2 x 200 ml_), dried (Na₂SO₄), filtered and concentrated to afford the title compound (9.7 g) as an off-white solid. The dark brown filtrate was concentrated to dryness and re-dissolved in EtOAc (300 ml_). The resulting organic solution was extracted with 0.1% HCI (3 x 200 ml_), brine (2 x 200 ml_), dried (Na₂SO₄), filtered and concentrated. The resulting residue was taken up in CH₃OH (200 ml_), and treated with water was induce precipitation. This precipitate material was then filtered, washed with water and dried to afford another batch of the title compound (12.4 g) as an off-white solid. LC-MS (ES) m/z = 328, 330 [M+H]⁺.

Intermediate 7 3-Bromo-1-fluorodibenzorά,/iπ ,4loxazepin-1 1 (10/-/)-one

To 4-bromo-2,6-difluoro-Λ/-(2-hydroxyphenyl)benzamide (20.6 g, 62.8 mmol) in DMF (100 ml.) was added K₂CO₃ (17.4 g, 126 mmol), and the reaction mixture was stirred for 3 days at room temperature. The mixture was poured onto water (1 L), and a precipitate was formed. The pH of the resulting aqueous mixture was adjusted to -5-6 with addition of 2 M HCI, and the precipitate was filtered, washed with water, and dried. The crude material was triturated overnight with 200 mL of 1 :1 EtOAc/Hexanes, and the solid was filtered, washed with 2:1 Hexanes/EtOAc, and dried to afford the title compound (15.8 g) as a white solid. LC-MS (ES) m/z = 308, 310 [M+H]⁺. Intermediate 8

4-Bromo-1 ,2-dihydroindazolo[4,3-άc1[1 ,51benzoxazepine

To 3-bromo-1-fluorodibenzo[6,/][1 ,4]oxazepin-1 1 (10H)-one (15.4 g, 50.0 mmol) in toluene (150 mL) was added Lawesson's reagent (20.2 g, 50.0 mmol), and the reaction mixture was stirred for 2 hours at 100 ⁰C into a 350 mL sealed tube. The reaction was allowed to cool to room temperature and sit overnight. The resulting yellow crystals were filtered, washed with toluene, and briefly dried by air aspiration. This crude material was dissolved/suspended in dioxane (100 mL), treated with hydrazine monohydrate (4.90 mL, 100 mmol), and the reaction mixture was stirred for 3 hours at 85 ⁰C. More hydrazine monohydrate (4.90 mL, 100 mmol) was added, and the reaction mixture was stirred for an additional hour at 85 ⁰C. The reaction was allowed to cool to room temperature, and the grey precipitate in the reaction mixture was filtered, rinsed with 1 ,4-dioxane, and discarded. As the filtrate began to cool in the collection flask, a precipitate began to form. The filtrate mixture was re-heated to re-dissolve the solid, and allowed to cool to room temperature and sit overnight. The crystals that had formed overnight were filtered, rinsed with a small amount of 1 ,4-dioxane and dried to afford the title compound (10.4 g) as light yellow needles. A second crop of product was formed from the mother liquor to afford an additional 1.05 g of the title compound. LC-MS (ES) m/z = 302, 304 [M+H]⁺.

Intermediate 9 2-Acetyl-4-bromo-1 ,2-dihvdroindazolor4,3-άciπ ,5lbenzoxazepine

Acetic anhydride (100 mL, 1060 mmol) was added to 4-bromo-1 ,2-dihydroindazolo[4,3- 6c][1 ,5]benzoxazepine (10.4 g, 34.4 mmol) and the resulting mixture was stirred for 2 hours at 100 ⁰C. The reaction was allowed to cool to room temperature and concentrated to dryness. The crude material was azeotroped from ethanol (3 x 50 ml_), and dried under vacuum to afford crude title compound (10.4 g) as bright yellow needles. LCMS analysis of the crude material showed a single peak with the desired MW. By HPLC, the crude material contains two very closely eluting peaks. In the ¹H NMR of the crude material, there appears to be two acetyl peaks, and thus are probably two isomeric forms of this material. LC-MS (ES) m/z = 344, 346 [M+H]⁺.

Intermediate 10

2-Acetyl-4-(4.4.5.5-tetramethyl-1.3.2-dioxaborolan-2-vn-1.2-dihvdroindazolor4.3- άciπ ,51benzoxazepine

Into a 350 mL sealable tube were added 2-acetyl-4-bromo-1 ,2-dihydroindazolo[4,3- 6c][1 ,5]benzoxazepine (10.2 g, 29.6 mmol), bis(pinacolato)diboron (7.53 g, 29.6 mmol), and KOAc (7.27 g, 74.1 mmol) in 1 ,4-dioxane (150 mL), and the resulting mixture was degassed with N₂ for 10 minutes. PdCI₂(dppf)-CH₂CI₂ (1.21 g, 1.48 mmol) was added, and the reaction mixture was stirred for 40 hours at 95 ⁰C. The mixture was poured onto EtOAc (800 mL) and water (800 mL). The layers were separated, and the aqueous layer was further extracted with EtOAc (2 x 200 mL). The combined organic layers were washed with brine (2 x 400 mL), dried (Na₂SO₄), filtered and concentrated. The crude material was triturated with hot CH₂CI₂ (300 mL) to afford the title compound (4.2 g) as an off-white solid. The mother liquor was concentrated, and the resulting residue was triturated with hot ethanol to afford additional title compound (5.4 g) as a gray solid. LC- MS (ES) m/z = 392 [M+H]⁺. Intermediate 1 1

Phenylmethyl (2S)-2-({[(4-methylphenyl)sulfonyl1oxy}methyl)-1-pyrrolidinecarboxylate1

To phenylmethyl (2S)-2-(hydroxymethyl)-1-pyrrolidinecarboxylate (0.78 g, 3.32 mmol) in CH₂CI₂ (10 ml.) was added Et₃N (0.92 ml_, 6.63 mmol) followed by TsCI (0.664 g, 3.48 mmol) and the reaction mixture was stirred overnight at room temperature. The mixture was poured onto water and diethyl ether (Et₂O). The aqueous layer was separated and the organic layer was washed with saturated aqueous NaHCO₃ followed by brine, dried

(MgSO₄), filtered and concentrated. Flash chromatography on SiO₂ (gradient: 100% hexanes to 20% EtOAc/hexanes) afforded the title compound (0.85 g, 66%) as a colorless oil. LC-MS (ES) m/z = 390 [M+H]⁺.

Intermediate 12

Phenylmethyl (2/?)-2-ethyl-1-pyrrolidinecarboxvlate

To copper(l) iodide (1.25 g, 6.55 mmol) in Et₂O (25 ml.) was added methyllithium (8.2 ml_, 13.1 mmol) at 0 ⁰C. A solution of phenylmethyl (2S)-2-({[(4- methylphenyl)sulfonyl]oxy}methyl)-1-pyrrolidinecarboxylate (0.85 g, 2.182 mmol) in CH₂CI₂ (4 ml.) was added next, and the reaction mixture was stirred for 2 hours at O⁰C. The reaction was quenched with saturated aqueous NH₄CI, and extracted with CH₂CI₂ (3X). The combined organic layers were washed with brine, dried (MgSO₄), filtered and concentrated. Flash chromatography on SiO₂ (gradient: 100% hexanes to 20% EtOAc/hexanes) afforded the title compound (230 mg, 45%) as a colorless oil. LC-MS (ES) m/z = 234 [M+H]⁺. Intermediate 13 (2/?)-2-Ethylpyrrolidine

Into a sealable tube, phenylmethyl (2/?)-2-ethyl-1-pyrrolidinecarboxylate (230 mg, 0.99 mmol) was dissolved in a mixture of 1 ,4-dioxane (6 ml.) and concentrated HCI (4 ml_). The tube was sealed, and the reaction mixture was stirred for 5 hours at 90 ⁰C. The solution was concentrated, evaporating the resulting residue from toluene (-20 ml_). Et₂O was added, and the resulting mixture was sonicated and decanted. The resulting solid was dissolved in acetonitrile (CH₃CN) and treated with Et₂O until a precipitate was formed. The mixture was sonicated and decanted, and the solid was triturated with Et₂O to afford the HCI salt of the title compound (80 mg, 60%) as an off-white solid. ¹H NMR (400 MHz, CD₃OD): δ 1.07 (t, J = 7.5, 3H), 1.60 - 1.84 (m, 3H), 1.96 - 2.17 (m, 2H), 2.19 - 2.31 (m, 1 H), 3.30 (m, 2H), 3.38 - 3.52 (m, 1 H).

Intermediate 14

4-Chloro-6-r(2/?)-2-ethyl-1-pyrrolidinyll-2-pyrimidinamine

A mixture of (2/?)-2-ethylpyrrolidine (80 mg, 0.59 mmol), 4,6-dichloro-2-pyrimidinamine (1 19 mg, 0.726 mmol) and Et₃N (0.25 ml_, 1.77 mmol) in CH₃CN (6 ml.) was stirred overnight at 80 ⁰C. The mixture was poured onto water (-150 ml_), sonicated and filtered to afford the title compound (94 mg, 70%) as a white solid. LC-MS (ES) m/z = 227, 229 [M+H]⁺.

Example 2

4-(1.2-Dihvdroindazolor4.3-άciri .5lbenzoxazepin-4-vn-6-r(2/?V2-ethyl-1-pyrrolidinyll-2- pyrimidinamine To a mixture of 4-chloro-6-[(2/?)-2-ethyl-1-pyrrolidinyl]-2-pyrimidinamine (50 mg, 0.22 mmol), 2-acetyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 ,2-dihydroindazolo[4,3- bc][1 ,5]benzoxazepine (86 mg, 0.221 mmol), and K₃PO₄ (94 mg, 0.441 mmol) was added 1 ,4-dioxane (3 ml.) and water (1 ml_), and the resulting mixture was purged with N₂ for 10 minutes into a sealable tube. Pd₂(dba)₃ (6.06 mg, 6.62 μmol) was added, and the mixture was purged with N₂ for an additional 5 minutes. Tricyclohexylphosphine (4.08 mg, 0.015 mmol) was added, the tube was sealed, and the reaction mixture was stirred for 2 hours at 100 ⁰C. The reaction was poured onto water, sonicated, and filtered. LCMS analysis of the resulting solid indicated a mixture of desired product and acetylated desired product. The solid was transferred to a sealable tube and treated with CH₃OH (6ml_) and concentrated HCI (0.3 ml_, 3.6 mmol). The tube was sealed, and the reaction mixture was stirred for 2 hours at 100 ⁰C. The mixture was poured onto saturated aqueous NaHCO₃. A precipitate was formed, which was filtered and washed with water. The solid was pre-absorbed on SiO₂ and dry loaded onto a SiO₂ column. Flash chromatography (gradient: 100% CHCI₃ to 90:10:1 CHCI₃:CH₃OH:NH₄OH) afforded the title compound (46 mg, 50%) as a tan solid. LC-MS (ES) m/z = 414 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 0.91 (t, J = 7.3 Hz, 3H), 1.40 (m, 1 H), 1.81 (m, 2H), 1.87 - 2.07 (m, 3H), 3.40 (m, 1 H,) 3.48 - 3.60 (m, 1 H), 4.05 (m, 1 H), 6.00 (s, 2H), 6.30 (s, 1 H), 6.84 - 6.93 (m, 1 H), 7.02 - 7.1 1 (m, 1 H), 7.28 (m, 2H), 7.39 (s, 1 H), 7.77 (s, 1 H₁) 9.48 (s, 1 H), 12.25 (s, 1 H).

Intermediate 15

1-(Phenylmethyl)-2,5-pyrrolidinedione

To 2,5-pyrrolidinedione (2.5 g, 25.2 mmol) in DMF (50 ml.) was added K₂CO₃ (4.18 g, 30.3 mmol) followed by benzyl bromide (3.00 ml_, 25.2 mmol), and the reaction mixture was stirred overnight at 55 ⁰C. Water was added to the reaction mixture (-200 ml.) and a precipitate was immediately observed. The precipitate was filtered, and the white solid was washed with water and dried to afford the title compound (2.7 g, 57%). ¹H NMR (400 MHz, CDCI₃): δ 2.73 (s, 4H), 4.68 (s, 2H), 7.28 - 7.37 (m, 3H), 7.39 - 7.44 (m, 2H).

Intermediate 16 5-Cvclopropyl-5-hvdroxy-1-(phenylmethyl)-2-pyrrolidinone

To 1-(phenylmethyl)-2,5-pyrrolidinedione (1 g, 5.29 mmol) in THF (50 ml.) at -78 ⁰C was added cyclopropylmagnesium bromide (42.3 ml_, 21.1 mmol) dropwise. The reaction mixture was allowed to warm to 0 ⁰C and stirred for an additional 2 hours. The reaction was quenched with a saturated aqueous solution of ammonium chloride and transferred to a separatory funnel. EtOAc was added, and the organic phase was separated. The aqueous layer was further extracted with EtOAc, and the combined organic layers were washed with brine, dried (MgSO₄), filtered and concentrated. Flash chromatography on SiO₂ (gradient: 100% hexanes to 80% EtOAc/hexanes) afforded the title compound (400 mg, 33%) as a yellow solid. LC-MS (ES) m/z = 232 [M+H]⁺.

Intermediate 17 5-Cvclopropyl-1-(phenylmethyl)-2-pyrrolidinone

To 5-cyclopropyl-5-hydroxy-1-(phenylmethyl)-2-pyrrolidinone (400 mg, 1.73 mmol) in CH₂CI₂ (10 ml.) at -78 ⁰C was added a mixture of triethylsilane (2.76 ml_, 17.3 mmol) and

BF₃ ^«OEt₂ (0.88 ml_, 6.92 mmol) dropwise. The resulting reaction mixture was stirred for 2 hours at -78 ⁰C, then allowed to warm to room temperature and stirred overnight. The reaction was quenched by adding a saturated aqueous NaHCO₃ solution, and the aqueous layer was extracted with CH₂CI₂ (2X). The combined organic layers were dried (MgSO₄), filtered and concentrated. Flash chromatography on SiO₂ (gradient: 100% hexanes to 100% EtOAc) afforded the title compound (240 mg, 65%) as a colorless oil. LC-MS (ES) m/z = 216 [M+H]⁺.

Intermediate 18 2-Cvclopropyl-1-(phenylmethyl)pyrrolidine

To 5-cyclopropyl-1-(phenylmethyl)-2-pyrrolidinone (240 mg, 1.12 mmol) in THF (5 ml.) was added BH₃ ^«SMe₂ 2M in THF (5.6 ml_, 11.2 mmol), and the reaction mixture was stirred over the weekend at room temperature. The reaction was quenched with the dropwise addition of CH₃OH (~2 ml_, caution: vigorous H₂ evolution occurs). The solution was poured onto water (-50 ml.) and EtOAc (-50 ml_), and the mixture was stirred at 60 ⁰C for 3 hours. A saturated aqueous solution of NaHCO₃ (-25 ml.) and EtOAc (-50 ml.) were added, and the organic layer was separated, washed with brine, dried (MgSO₄), filtered and concentrated. Flash chromatography on SiO₂ (gradient: 100% hexanes to 75% EtOAc/hexanes) afforded the title compound (100 mg, 45%) as a yellow oil. LC-MS (ES) m/z = 202 [M+H]⁺.

Intermediate 19 2-Cvclopropylpyrrolidine

To a solution of 2-cyclopropyl-1-(phenylmethyl)pyrrolidine (100 mg, 0.50 mmol) in ethanol (5 mL) was added 1 N HCI_(aq) (0.50 mL, 0.50 mmol), and the resulting mixture was purged with N₂ for 10 minutes. Pd/C (10 mg, 10 wt%) was added and the reaction mixture was stirred overnight at room temperature under a H₂ atmosphere (balloon setup). LCMS analysis indicated -20% desired product and -70% starting material. More Pd/C was added (30 mg), and the reaction mixture was stirred under a H₂ atmosphere for an additional 24 hours. Additional 1 N HCI_(aq) (0.50 mL, 0.50 mmol) was added, and the mixture was filtered through an Acrodisk, washing with ethanol. The solution was evaporated, and the resulting residue was triturated with diethyl ether to afford the HCI salt of the title compound (74 mg) as a white solid. ¹H NMR (400 MHz, CD₃OD): δ 0.37 - 0.54 (m, 2H), 0.67 - 0.80 (m, 2H), 0.98 - 1.15 (m, 1 H), 1.77 - 1.93 (m, 1 H), 1.96 - 2.18 (m, 2H), 2.18 - 2.30 (m, 1 H), 2.84 - 2.98 (m, 1 H), 3.20 - 3.30 (m, 1 H), 3.30 - 3.43 (m, 1 H).

Intermediate 20 4-Chloro-6-(2-cvclopropyl-1-pyrrolidinyl)-2-pyrimidinamine

To 4,6-dichloro-2-pyrimidinamine (95 mg, 0.576 mmol) in CH₃CN (5 mL) was added Et₃N (0.25 mL, 1.75 mmol) followed by 2-cyclopropylpyrrolidine (74 mg, 0.50 mmol), and the reaction mixture was stirred for 4 hours at 80 ⁰C. The reaction was poured onto water (a precipitate was formed), and filtered. Flash chromatography SiO2 (gradient: EtOAc/hexanes) afforded the title compound (70 mg) as a white solid. LC-MS (ES) m/z = 239, 241 [M+H]⁺.

Example 3

4-(2-Cvclopropyl-1 -pyrrolidinyl)-6-(1 ,2-dihydroindazolor4,3-άciπ ,51benzoxazepin-4-yl)-2- pyrimidinamine

To 2-acetyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 ,2-dihydroindazolo[4,3- bc][1 ,5]benzoxazepine (57 mg, 0.15 mmol), 4-chloro-6-(2-cyclopropyl-1-pyrrolidinyl)-2- pyrimidinamine (35 mg, 0.15 mmol) and K₃PO₄ (62 mg, 0.29 mmol) were added 1 ,4- dioxane (4 mL) and water (1 mL), and the resulting mixture was purged with N₂ for 10 minutes into a sealable tube. Pd₂(dba)₃ (4.0 mg, 4.4 μmol) was added, and N₂ was bubbled through the mixture for an additional 5 minutes. Tricyclohexylphosphine (2.7 mg, 9.7 μmol) was added, the tube was sealed, and the reaction mixture was stirred overnight at 100 ⁰C. LCMS analysis showed a significant amount of the chloropyrimidine starting material. More 2-acetyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 ,2- dihydroindazolo[4,3-bc][1 ,5]benzoxazepine (57 mg, 0.15 mmol) and K₃PO₄ (62 mg, 0.29 mmol) were added, and the resulting mixture was degassed with N₂ for 10 minutes. Pd₂(dba)3 (4.0 mg, 4.4 μmol) was added, and N₂ was bubbled through the mixture for an additional 5 minutes. Tricyclohexylphosphine (2.7 mg, 9.7 μmol) was added, the tube was sealed, and the reaction mixture was stirred overnight at 100 ⁰C. The mixture was poured onto water and filtered. Flash chromatography on SiO₂ of the filtered solid (gradient: 100% CHCI₃ to 90:10:1 CHCI₃:CH₃OH:NH₄OH) afforded the title compound (10 mg, 16%) as a light brown solid. LC-MS (ES) m/z = 426 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 0.21 (m, 1 H), 0.31 - 0.42 (m, 1 H), 0.47 (m, 1 H), 0.72 (m, 1 H), 0.93 - 1.08 (m, 1 H), 1.77 - 2.00 (m, 3H) 2.08 (m, 1 H), 3.41 (m, 1 H), 3.58 (m, 1 H), 3.98 (m, 1 H), 6.03 (m, 2H), 6.37 (bs, 1 H), 6.83 - 6.93 (m, 1 H), 7.02 - 7.12 (m, 1 H), 7.28 (m, 2H), 7.39 (s, 1 H) 7.77 (s, 1 H), 9.50 (s, 1 H), 12.28 (s, 1 H).

Intermediate 21 4-Chloro-6-(2-methyl-1-piperidinyl)-2-pyrimidinamine

To 4,6-dichloro-2-pyrimidinamine (500 mg, 3.05 mmol) in CH₃CN (10 ml.) were added 2- methylpiperidine (0.47 ml_, 3.96 mmol) and Et₃N (1.7 ml_, 12.2 mmol), and the reaction mixture was heated in a microwave at 120 ⁰C for 2 hours. The solution was concentrated, and the resulting residue was partitioned between EtOAc and water. The organic layer was separated, and the aqueous layer was further extracted with EtOAc. The combined organic layers were dried (MgSO₄), filtered, and concentrated to afford the crude title compound (587 mg). LC-MS (ES) m/z = 227, 229 [M+H]⁺. Example 4

4-(1 ,2-Dihvdroindazolor4,3-άciri ,5lbenzoxazepin-4-yl)-6-(2-methyl-1-piperidinyl)-2- pyrimidinamine

To 2-acetyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 ,2-dihydroindazolo[4,3- bc][1 ,5]benzoxazepine (350 mg, 0.88 mmol), 4-chloro-6-(2-methyl-1-piperidinyl)-2- pyrimidinamine (139 mg, 0.61 mmol) and K₃PO₄ (221 mg, 1.04 mmol) were added 1 ,4- dioxane (6 ml.) and water (2 ml_), and the resulting mixture was purged with N₂ for 10 minutes into a sealable tube. Pd₂(dba)₃ (9.1 mg, 9.9 μmol) was added, and N₂ was bubbled through the mixture for an additional 5 minutes. Tricyclohexylphosphine (7.2 mg, 0.03 mmol) was added, the tube was sealed, and the reaction mixture was stirred overnight at 100 ⁰C. The mixture was poured onto water and EtOAc, the organic layer was separated, and the aqueous layer was further extracted with EtOAc. The combined organic layers were washed with brine, dried (MgSO₄), filtered and concentrated. The resulting material was purified on reversed-phase HPLC (C18, 15% to 80% CH₃CN in water with 0.1% TFA, 10 minute gradient). The CH₃CN was evaporated from the fractions containing the desired product, and sodium bicarbonate was added to the water layer. A precipitate was immediately observed which was filtered and dried under vacuum at 40 ⁰C to afford the title compound (24 mg, 9%) as a light green solid. LC-MS (ES) m/z = 414 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 1.16 (d, J = 6.8 Hz, 3H), 1.38 (m, 1 H), 1.52 - 1.80 (m, 5H), 2.81 - 2.97 (m, 1 H), 4.39 (m, 1 H), 4.85 (m, 1 H), 6.08 (bs, 2H), 6.62 (s, 1 H) 6.83 - 6.94 (m, 1 H₁) 7.01 - 7.11 (m, 1 H), 7.28 (m, 2H), 7.44 (s, 1 H), 7.82 (s, 1 H), 9.51 (s, 1 H), 12.28 (s, 1 H).

Intermediate 22 (5/?)-5-Ethyl-3-morpholinone

To NaH (1.51 g, 37.9 mmol) in dry toluene (10 mL) under nitrogen at 0 ⁰C was added a solution of (2/?)-2-amino-1-butanol (1.5 g, 16.8 mmol) in toluene (5 mL) dropwise, and the resulting mixture was stirred for 20 minutes allowing it to warm up to room temperature. A solution of chloroacetyl chloride (1.5 mL, 18.9 mmol) in toluene (5 mL) was then added dropwise while cooling the reaction flask with an ice bath, and the resulting reaction mixture was stirred overnight at 1 10 ⁰C. The reaction was cooled to room temperature, NH₄CI (5 g) was added portionwise, and the resulting mixture was stirred for 20 minutes, and then filtered. The filter cake was washed with toluene, and the filtrate was concentrated. Flash chromatography on SiO₂ of the resulting orange (gradient: 100% CH₂CI₂ to 90:10:1 CH₂CI₂:CH₃OH:NH₄OH) afforded the title compound (1.2 g, 52%) as a yellow solid. ¹H NMR (400 MHz, CDCI₃): δ 0.96 (t, J = 7.6 Hz, 3H), 1.52 - 1.63 (m, 2H), 3.40 - 3.51 (m, 2H), 3.85 - 3.94 (m, 1 H), 4.07 - 4.20 (m, 2H), 7.55 (bs, 1 H).

Intermediate 23 (3/?)-3-Ethylmorpholine

To a 1 M solution of LiAIH₄ in THF (7.7 mL, 7.7 mmol) at 0 ⁰C was added a solution of (5R)-5-ethyl-3-morpholinone (500 mg, 3.87 mmol) in THF (10 mL) dropwise, and the reaction mixture was stirred for 16 hours at 70 ⁰C. A thick white precipitate was formed during this time. The reaction mixture was cooled down to room temperature and carefully quenched sequentially with water (1 mL), 2M NaOH (1 mL) and water (4 mL). The resulting slurry was stirred at room temperature for 1 hour and then filtered through celite. The filter cake was washed with EtOAc, and the resulting filtrate was washed with brine, dried (MgSO₄), and filtered. HCI in ether (3.87 mL, 3.87 mmol) was then added to provide a cloudy solution. The solvent was evaporated to afford the HCI salt of the title compound (250 mg) as an orange solid. ¹H NMR (400 MHz, DMSO-d₆): δ 0.93 (t, J = 7.6 Hz, 3H), 1.46 - 1.72 (m, 2H), 2.91 - 3.18 (m, 3H), 3.46 (dd, J = 12.3, 10.2 Hz, 1 H), 3.71 (m, 1 H), 3.82 - 3.97 (m, 2 H), 9.68 (bs, 2H).

Intermediate 24 4-Chloro-6-r(3/?)-3-ethyl-4-morpholinyll-2-pyrimidinamine

To 2-amino-4,6-dichloropyrimidine (240 mg, 1.46 mmol) in CH₃CN (8 ml.) were added (3R)-3-ethylmorpholine (244 mg, 1.61 mmol) and Hunig's base (1 ml_, 5.8 mmol), and the reaction mixture was heated in a microwave at 140 ⁰C for 1.5 hours. The solution was concentrated and the resulting residue was partitioned between EtOAc and water. The organic layer was separated, and the aqueous layer was further extracted with EtOAc. The combined organic layers were dried (MgSO₄), filtered, and concentrated to afford the crude title compound (307 mg). LC-MS (ES) m/z = 243, 245 [M+H]⁺.

Example 5

4-(1.2-Dihvdroindazolor4.3-άciri .5lbenzoxazepin-4-vn-6-r(3/?V3-ethyl-4-morpholinyll-2- pyrimidinamine

To 2-acetyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 ,2-dihydroindazolo[4,3- bc][1 ,5]benzoxazepine (246 mg, 0.63 mmol), 4-chloro-6-[(3R)-3-ethyl-4-morpholinyl]-2- pyrimidinamine (153 mg, 0.63 mmol) and K₃PO₄ (227 mg, 1.07 mmol) were added 1 ,4- dioxane (5 ml.) and water (1.5 ml_), and the resulting mixture was purged with N₂ for 10 minutes into a sealable tube. Pd₂(dba)₃ (17.3 mg, 19 μmol) was added, and N₂ was bubbled through the mixture for an additional 5 minutes. Tricyclohexylphosphine (10.6 mg, 0.04 mmol) was added, the tube was sealed, and the reaction mixture was stirred overnight at 100 ⁰C. The mixture was poured onto water and EtOAc. The organic layer was separated, and the aqueous layer was further extracted with EtOAc. The combined organic layers were washed with brine, dried (MgSO₄), filtered and concentrated. The resulting material was purified on reversed-phase HPLC (C18, 15% to 80% CH₃CN in water with 0.1% TFA, 10 minute gradient). The CH₃CN was evaporated from the fractions containing the desired product, and sodium bicarbonate was added to the water layer. A precipitate was immediately observed which was filtered and dried under vacuum at 40 ⁰C to afford the title compound (1 1 mg, 4%) as a light green solid. LC-MS (ES) m/z = 430 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 0.88 (t, J = 7.3 Hz, 3H), 1.59 - 1.88 (m, 2H), 3.10 (m, 1 H), 3.39 (m, 1 H), 3.48 - 3.62 (m, 1 H), 3.76 - 3.99 (m, 2H), 4.2 - 4.5 (m, 2H), 6.13 (bs, 2H), 6.64 (s, 1 H₁), 6.88 (m, 1 H), 7.06 (m, 1 H), 7.14 - 7.38 (m, 2H), 7.45 (s, 1 H), 7.83 (s, 1 H,) 9.51 (s, 1 H) 12.30 (bs, 1 H).

Intermediate 25 2-Cvclopropylpyridine

2-Bromopyridine (6.2 ml_, 63.3 mmol), cyclopropylboronic acid (8.16 g, 95 mmol), and tricyclohexylphosphine (1.78 g, 6.33 mmol) were added to toluene (175 ml.) and stirred. A solution of potassium phosphate (47.0 g, 222 mmol) in water (35 ml.) was added, followed by palladium(ll) acetate (0.71 g, 3.16 mmol), and the reaction mixture was refluxed gently under N₂ overnight (-16 hours). Careful TLC with 10% Et₂O/hexanes indicated the complete conversion to the desired product (slightly lower Rf), along with a more polar product (2,2'-bipyridyl by-product). The organic layer was separated and washed with water. The combined aqueous layers were back-extracted with EtOAc (50 ml_), and the combined organics were further washed with water. The product was then extracted with 1 N HCI (2 x 150 ml_). The combined aqueous acidic fractions was washed with Et₂O (100 ml_), then cooled in an ice bath with stirring, and basified to pH 12 with 50% aqueous NaOH (dropwise addition). The product was then extracted with Et₂O (3 x 100 ml_), and the combined extracts were dried (Na₂SO₄) filtered and concentrated with minimal vacuum to give a yellow oil. The product was then purified by simple distillation. The fraction collected at 182-185 ⁰C (760 mm) afforded the title compound (5.32 g, 67%) as a colorless liquid. ¹H NMR (400 MHz, CDCI₃): δ 0.90 - 1.16 (m, 4H), 1.90 - 2.18 (m, 1 H), 6.97 - 7.10 (m, 1 H), 7.14 (d, J = 7.8 Hz, 1 H), 7.54 (td, J = 7.6, 1.9 Hz, 1 H), 8.46 (d, J = 4.8 Hz, 1 H).

Intermediate 26

2-Cvclopropyl-1 -(phenylmethyl)pyridinium bromide

2-Cyclopropylpyridine (1.02 g, 8.56 mmol) and benzyl bromide (1.07 ml_, 8.99 mmol) were mixed together and heated at 100 ⁰C for 4 hours. The reaction mixture was cooled to room temperature, and the solid mass was broken up, triturated with EtOAc, and filtered. The solid was washed with EtOAc followed by hexanes, and then dried to afford the title compound (2.42 g, 93%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆): δ 1.04 - 1.14 (m, 2H), 1.17 - 1.28 (m, 2H), 2.32 - 2.47 (m, 1 H), 6.10 (s, 2H), 7.15 - 7.36 (m, 2H), 7.36 - 7.52 (m, 3H), 7.86 (d, J = 8.3 Hz, 1 H), 7.95 - 8.09 (m, 1 H), 8.53 (t, J=7.8 Hz, 1 H), 9.18 (d, J = 6.3 Hz, 1 H).

Intermediate 27

6-Cvclopropyl-i -(phenylmethvD-1 ,2,3,6-tetrahydropyridine

2-Cyclopropyl-1-(phenylmethyl)pyridinium bromide (2.41 g, 8.30 mmol) was stirred in ethanol (30 ml.) under N₂ while cooling in an ice bath. Sodium borohydride (0.63 g, 16.6 mmol) was added portion-wise over 10 minutes and the mixture was allowed to warm to room temperature and stirred for 2 hours. The mixture was concentrated and partitioned between 1 N NaOH (50 ml.) and Et₂O (75 ml_), and stirred 1 hour. The aqueous layer was extracted with Et₂O (2 x 50 ml_), and the combined organic layers were washed with water, brine, dried (Na₂SO₄), filtered and evaporated. The product was purified by chromatography (Analogix SF40-80g SiO₂ column; gradient: 100% hexanes to 10% EtOAc/hexanes) to afford the title compound (1.25 g, 64%) as a pale yellow liquid. LC-MS (ES) m/z = 214 [M+H]⁺. ¹H NMR (400 MHz, CDCI₃): δ -0.06 - 0.14 (m, 1 H), 0.27 - 0.42 (m, 1 H), 0.42 - 0.58 (m, 1 H), 0.61 - 0.77 (m, 1 H), 0.94 - 1.00 (m, 1 H), 1.79 - 1.93 (m, 1 H), 2.13 - 2.27 (m, 1 H), 2.27 - 2.44 (m, 1 H), 2.86 (dt, J = 16.9, 2.7 Hz, 1 H), 3.10 - 3.24 (m, 1 H), 3.45 (d, J = 13.1 Hz, 1 H), 4.33 (d, J = 13.1 Hz, 1 H), 5.52 - 5.70 (m, 1 H), 5.70 - 5.88 (m, 1 H), 7.21 - 7.29 (m, 1 H), 7.29 - 7.37 (m, 2H), 7.37 - 7.47 (m, 2H).

Intermediate 28 2-Cvclopropylpiperidine

A mixture of 6-cyclopropyl-1-(phenylmethyl)-1 ,2,3,6-tetrahydropyridine (250 mg, 1.17 mmol), ethanol (5 ml.) and HCI (0.586 ml_, 1.172 mmol, 2M aqueous) was stirred and degassed with N₂. 10% Pd/C (50% wet, Degussa type E101 NE/W) (50 mg, 0.470 mmol) was added, and the reaction mixture was stirred under a hydrogen atmosphere (balloon setup) until the reaction was complete by TLC (~1 h). The mixture was degassed and filtered through a 0.2 μm disc, washing with minimal ethanol. The filtrate was evaporated to dryness and azeotroped with ethanol (3X) to afford the HCI salt of the title compound (183 mg, 92%) as a white solid. ¹H NMR 400 MHz, D₂O): δ 0.12 - 0.42 (m, 2H), 0.42 - 0.71 (m, 2H), 0.84 (m, 1 H), 1.29 - 1.59 (m, 3H), 1.73 (dd, J = 8.7, 3.2 Hz, 2H), 1.94 (d, J = 12.9 Hz, 1 H), 2.17 - 2.44 (m, 1 H), 2.79 (td, J = 12.8, 3.0 Hz, 1 H), 3.25 (d, J = 12.4 Hz, 1 H).

Intermediate 29 4-Chloro-6-(2-cvclopropyl-1-piperidinyl)-2-pyrimidinamine

Into a 10-20 ml. microwave vessel were added 2-cyclopropylpiperidine (175 mg, 1.08 mmol), CH₃CN (10 ml.) and Hunig's base (0.57 ml_, 3.25 mmol) followed by 2-amino-4,6- dichloropyrimidine (169 mg, 1.03 mmol). The reaction mixture was heated with stirring in a microwave reactor at 160 ⁰C for 45 minutes. The mixture was evaporated, and the resulting residue was purified by flash chromatography on SiO₂ (Analogix SF25-40g; gradient: 100% CHCI₃ to 10% EtOAc/CHCI₃) to afford the title compound (153 mg, 53%) as a white foam. LC-MS (ES) m/z = 253, 255 [M+H]⁺.

Example 6

4-(2-Cvclopropyl-1 -piperidinyl)-6-(1 ,2-dihydroindazolor4,3-άciπ ,51benzoxazepin-4-yl)-2- pyrimidinamine

4-Chloro-6-(2-cyclopropyl-1-piperidinyl)-2-pyrimidinamine (75 mg, 0.30 mmol), 2-acetyl-4- (4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 ,2-dihydroindazolo[4,3-6c] [1 ,5]benzoxazepine (139 mg, 0.36 mmol), and tricyclohexylphosphine (42 mg, 0.15 mmol) were placed in a 2-5 mL microwave vessel with 1 ,4-dioxane (3 ml.) and K₃PO₄ (3M aqueous) (0.30 mL, 0.89 mmol). Pd₂(dba)₃ ^«CHCI₃ (6.1 mg, 5.9 μmol) was added, the vessel was sealed, and the reaction mixture was heated in a microwave reactor for 40 minutes at 140 ⁰C. The mixture was diluted with water and EtOAc, the aqueous was back-extracted with EtOAc, and the combined organic layers were washed with brine, dried (Na₂SO₄), filtered and concentrated. The resulting crude material was dissolved in CH₃OH (5 mL), treated with cone. HCI (0.2 mL), and the resulting mixture was refluxed for 2 hours until all the remaining acetylated material was converted to the desired product. The mixture was evaporated and the product was purified on an automated reverse phase HPLC (Varian Polaris C18 5u, 100 x 300 mm, Product* A-2000, gradient: 15% CH₃CN/H₂O to 95% CH₃CN/H₂O w/0.1 % TFA). The fractions containing the desired product were combined, concentrated, then azeotroped with CH₃CN (2X). The resulting material was triturated with acetonitrile, filtered and dried to afford a TFA salt of the title compound (29 mg, 34%) as a pale yellow solid. LC-MS (ES) m/z = 440 [M+H]⁺ 1 H NMR (400 MHz, DMSO-d₆): δ (^* denotes rotamer peaks) 0.17 - 0.53 (m, 3H), 0.60 (bs, 1 H), 1.46 (bs, 1 H), 1.74 - 1.52 (m, 3H), 1.75 - 2.02 (m, 3H), 3.37 (bs, 1 H), ^*3.96 (bs, 0.5H), 4.43 (bs, 1 H), ^*4.92 (bs, 0.5H), 6.84 - 7.03 (m, 2H), 7.09 (td, J = 7.6, 1.3 Hz, 1 H), 7.22 (bs, 1 H), 7.25 - 7.36 (m, 2H), 7.59 (bs, 1 H), 8.31-7.00 (bs, 2H), 9.67 (s, 1 H), 12.18 (bs, 1 H), 12.71 (s, 1 H).

Intermediate 30 4-Bromo-2,6-difluoro-Λ/-{2-hvdroxy-5-r(methylamino)sulfonyllphenyl}benzamide

Into a 200 mL flask under argon were combined 4-bromo-2,6-difluorobenzoic acid (5.3 g, 22.4 mmol) and thionyl chloride (26 mL, 358 mmol), and the reaction mixture was refluxed for 4 hours in an 82 ⁰C oil bath. The reaction was concentrated, and toluene was evaporated from the system (3 X 50 mL). The resulting acid chloride was dissolved in CH₂CI₂ (25 mL), and added dropwise via addition funnel to a solution of 3-amino-4- hydroxy-Λ/-methylbenzenesulfonamide (4.52 g, 22.4 mmol) and Et₃N (3.27 mL, 23.5 mmol) in CH₂CI₂ (50 mL). The resulting mixture was allowed to stir at room temperature overnight (a precipitate was formed during this time). The reaction mixture was partitioned between CH₂CI₂ (300 ml.) and 0.1 N HCI_(aq) (100 ml_). The layers were separated, and the aqueous layer was further extracted with CH₂CI₂ (200 ml_). A significant amount of solid was present in the aqueous layer. The solids were filtered, washed with water, and dried under vacuum at 40 ⁰C to afford the title compound (7.69 g) as a light tan solid. LC-MS (ES) m/z = 421 , 423 [M+H]⁺.

Intermediate 31

3-Bromo-1-fluoro-Λ/-methyl-1 1-oxo-10,11-dihydrodibenzorά,/iri ,4loxazepine-8- sulfonamide

Into a 1 L flask under argon were combined 4-bromo-2,6-difluoro-Λ/-{2-hydroxy-5- [(methylamino)sulfonyl]phenyl}benzamide (7.69g, 18.3 mmol) and K₂Cθ3 (7.57 g, 54.8 mmol) in DMF (460 ml_), and the resulting mixture was stirred overnight at room temperature. LCMS analysis showed the formation of -15% desired product. The reaction mixture was stirred for 2 days at 35 ⁰C (-89% conversion), then for 3 hours at 40 ⁰C (-96% conversion). The reaction was allowed to cool to room temperature and poured onto water (3.5 L). Aqueous HCI (2N, 18 mL) was added to the aqueous mixture to adjust the pH to -7-8. After 15 minutes of gentle stirring, a precipitate formed. After an additional 30 minutes of gentle stirring, the mixture was filtered, and the resulting tan solid was dried under vacuum at 40 ⁰C to afford the title compound (5.26 g). LC-MS (ES) m/z = 401 , 403 [M+H]⁺.

Intermediate 32 4-Bromo-Λ/-methyl-1 ,2-dihydroindazolo[4,3-άc1[1 ,51benzoxazepine-9-sulfonamide

Into a 200 mL flask under argon were combined 3-bromo-1-fluoro-Λ/-methyl-11-oxo-10,11- dihydrodibenzo[b,f][1 ,4]oxazepine-8-sulfonamide (5.13 g, 12.8 mmol) and Lawesson's reagent (5.17 g, 12.8 mmol) in toluene (50 mL), and the reaction mixture was stirred for 3 hours at 100 ⁰C. The reaction was allowed to cool to room temperature and then sonicated. The resulting solid was filtered, washed with toluene (20 mL) and hexanes (100 mL), and air dried. The solid material was dissolved in 1 ,4-dioxane (34 mL), and treated with hydrazine monohydrate (6.3 mL, 128 mmol). The resulting mixture was stirred overnight under argon at 85 ⁰C (caution: vigorous release of H₂S). A yellow precipitate was formed. The reaction mixture was allowed to cool to room temperature, then diluted with water (10 mL) and filtered. The resulting white solid was washed with a 80/20 water/dioxane mixture (50 mL) followed by hexanes, then dried under vacuum at 40 ⁰C to afford the title compound (4.25 g). LC-MS (ES) m/z = 395, 397 [M+H]⁺.

Intermediate 33

Λ/-r(2,11-Diacetyl-4-bromo-2,1 1-dihvdroindazolor4,3-άciπ ,5lbenzoxazepin-9-yl)sulfonyll-Λ/- methylacetamide

To 4-bromo-Λ/-methyl-1 ,2-dihydroindazolo[4,3-bc][1 ,5]benzoxazepine-9-sulfonamide (4.19 g, 10.6 mmol) was added acetic anhydride (100 ml_), and the reaction mixture was stirred overnight at 100 ⁰C. LCMS analysis showed a mixture of mono, bis, and tris acetylated material. The reaction mixture was stirred for an additional 32 hours at 1 15 ⁰C when LCMS analysis showed complete product formation. The mixture was concentrated and the resulting solid were evaporated from Ethanol (50 mL). Flash chromatography on SiO2 (gradient: 100% CHCI₃ to 10% acetone in CHCI₃) afforded the title compound (4.73 g) as a light yellow solid. LC-MS (ES) m/z = 521 , 523 [M+H]⁺.

Intermediate 34

Λ/-{r2.11-diacetyl-4-(4.4.5.5-tetramethyl-1.3.2-dioxaborolan-2-vn-2.1 1-dihvdroindazolor4.3- άciri ,51benzoxazepin-9-yllsulfonyl}-Λ/-methylacetamide

A mixture of Λ/-[(2,11-diacetyl-4-bromo-2,11-dihydroindazolo[4,3-6c][1 ,5]benzoxazepin-9- yl)sulfonyl]-Λ/-methylacetamide (4.73 g, 9.07 mmol), potassium acetate (2.23 g, 22.7 mmol) and bis(pinacolato)diboron (2.42 g, 9.53 mmol) in 1 ,4-dioxane (80 mL) was degassed with argon for 10 minutes. PdCI₂(dppf)-CH₂Cl2 was added (0.33 g, 0.40 mmol), and the reaction mixture was stirred overnight at 90 ⁰C into a sealed tube. The reaction was poured onto EtOAc (300 mL) and water (400 mL), and the organic layer was washed with water followed by brine, dried (MgSO₄), filtered and concentrated. The resulting solids were dissolved in CH₂CI₂ (50 mL) and treated with hexanes (100 mL) to precipitate the product (4.16 g) as a tan solid. LC-MS (ES) m/z = 569 (boronate), 487 (boronic acid) [M+H]⁺. Example 7

4-[2-Amino-6-(4-morpholinyl)-4-pyrimidinyl1-/\/-methyl-1 ,2-dihvdroindazolo[4,3- άc1[1 ,51benzoxazepine-9-sulfonamide

A mixture of /V-{[2,11-diacetyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-2,1 1- dihydroindazolo[4,3-6c][1 ,5]benzoxazepin-9-yl]sulfonyl}-Λ/-methylacetamide (0.30 g, 0.53 mmol), 4-chloro-6-(4-morpholinyl)-2-pyrimidinamine (0.113 g, 0.53 mmol), and K₃PO₄ (0.190 g, 0.90 mmol) in 1 ,4-dioxane (2 ml.) and water (0.66 ml.) was degassed for 10 minutes with argon. Pd₂(dba)3 (4.83 mg, 5.28 μmol) and tricyclohexylphosphine (3.26 mg, 0.012 mmol) were added, and the reaction mixture was stirred overnight at 100 ⁰C into a sealed tube. LCMS analysis of the reaction mixture showed a mixture of mono, bis, and tris-acetylated product. The reaction was allowed to cool to room temperature, and the organic layer (1 ,4-dioxane) was separated and filtered through a 0.2μm filter followed by a 300mg C18 plug. The resulting filtrate was concentrated. Flash chromatography on SiO₂ (gradient: 25-100% (80/20/2 CHCI₃/CH₃OH/NH₄OH) in CHCI₃) afforded tris, bis- and mono-acetylated product fractions. The fractions were combined, concentrated, and treated with CH₃OH (10 ml.) and concentrated HCI (0.25 ml_, 2.96 mmol) into a sealable tube. The resulting mixture was stirred overnight at 90 ⁰C. The reaction was allowed to cool to room temperature and filtered. The resulting yellow solid was washed with Et₂O and dried under vacuum at 40 ⁰C to afford the title compound (1 18 mg) as an HCI salt. LC-MS (ES) m/z = 495 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 2.46 (d, J = 5.1 Hz, 3H), 3.74 (m, 4H), 3.91 (bs, 4H), 7.03 (s, 1 H), 7.26 (dd, J = 8.6, 2.3 Hz, 1 H), 7.38 (s, 1 H), 7.43 - 7.51 (m, 2H), 7.77 (s, 1 H), 7.82 (d, J = 2.3 Hz, 1 H), 10.16 (s, 1 H), 12.44 (bs, 1 H), 12.94 (s, 1 H). Intermediate 35

Methyl 4-bromo-2,6-difluorobenzoate

To a solution of 4-bromo-2,6-difluorobenzoic acid (2.0 g, 8.44 mmol) in acetone (42.2 mL) were added K₂CO₃ (1.75 g, 12.7 mmol) and dimethyl sulfate (0.89 mL, 9.3 mmol), and the resulting mixture was stirred for 16 hours at 50 ⁰C. The mixture was poured onto EtOAc

(100 mL) and water (100 mL). The organic layer was separated, washed with water followed by brine, dried (MgSO₄), filtered, and concentrated. The resulting yellow oil was purified by flash chromatography on SiO₂ (gradient: 100% hexanes to 20% EtOAc in hexanes) to afford the title compound (1.94 g) as a white solid. ¹H NMR (400 MHz,

DMSO-de): δ 3.89 (s, 3H), 7.68 (d, J = 7.8 Hz, 2H).

Intermediate 36

Methyl 2-r(2-aminophenyl)thiol-4-bromo-6-fluorobenzoate

To a solution of methyl 4-bromo-2,6-difluorobenzoate (1.75 g, 6.97 mmol) in DMF (35 mL) were added K₂CO₃ (1.16 g, 8.37 mmol) and 2-aminothiophenol (0.78 mL, 7.32 mmol), and the resulting mixture was stirred at room temperature under argon for 24 hours. The reaction was partitioned between EtOAc and water. The layers were separated, and the organic layer was washed with water followed by brine, dried (MgSO₄), filtered, and concentrated. Flash chromatography on SiO₂ of the resulting tan oil (gradient: 5% EtOAc in hexanes to 35% EtOAc in hexanes) afforded the title compound (1.4 g) as a clear oil. LC-MS (ES) m/z = 356, 358 [M+H]⁺. Intermediate 37 3-Bromo-1-fluorodibenzo[ά,/1[1 ,41thiazepin-1 1 (10/-/)-one

To a solution of methyl 2-[(2-aminophenyl)thio]-4-bromo-6-fluorobenzoate (1.28 g, 3.59 mmol) in 1 ,4-dioxane (10 ml.) was added tosic acid (0.684 g, 3.59 mmol), and the reaction mixture was heated in a microwave reactor for 2 hours at 200 ⁰C. The mixture was poured onto EtOAc (300 ml.) and water (100 ml_), and the organic layer was separated, washed with brine, dried (MgSO₄), filtered through a pad of Siθ₂, and concentrated. The resulting off-white solid was triturated with a 90/10 Hexanes/EtOAc mixture (30 ml.) to afford the title compound (720 mg) as a white solid. LC-MS (ES) m/z = 324, 326 [M+H]⁺.

Intermediate 38

4-Bromo-1 ,2-dihydroindazolor4,3-άciπ ,51benzothiazepine

Into a 25 ml. sealable tube under argon were combined 3-bromo-1- fluorodibenzo[6,/][1 ,4]thiazepin-11 (10/-/)-one (0.72 g, 2.22 mmol) and Lawesson's reagent (0.90 g, 2.22 mmol) in toluene (6.7 ml_). The tube was sealed, and the reaction mixture was stirred overnight at 100 ⁰C. LCMS analysis of the reaction mixture showed the presence of remaining starting material. An additional amount of Lawesson's reagent (0.90 g, 2.22 mmol) was added, and the reaction mixture was stirred at 100 ⁰C for an additional 4 hours. The reaction was allowed to cool to room temperature and filtered. The resulting solid material was washed with toluene (10 mL) followed by hexanes (50 mL). To the resulting material (thioamide intermediate) was added 1 ,4-dioxane (4.4 mL) followed by hydrazine monohydrate (1.09 mL, 22.2 mmol) under argon, and the reaction mixture was stirred for 2.5 hours at 85 ⁰C (caution: vigorous release of H₂S). The reaction was allowed to cool to room temperature and concentrated. The resulting yellow solid was diluted with 1 ,4-dioxane (5 mL), sonicated, and filtered. The remaining solid was discarded and the filtrate was retained. Flash chromatography on SiO₂ (gradient: 0-100% EtOAc in hexanes) of the filtrate afforded the title compound (185 mg) as an off-white solid. LC-MS (ES) m/z = 318, 320 [M+H]⁺.

Example 8

4-(1 ,2-Dihvdroindazolor4,3-άciri ,5lbenzothiazepin-4-yl)-6-(4-morpholinyl)-2- pyrimidinamine

Into a 25 ml. sealable tube were combined 4-bromo-1 ,2-dihydroindazolo[4,3- 6c][1 ,5]benzothiazepine (0.185 g, 0.58 mmol) and acetic anhydride (5.49 ml_, 58.1 mmol). The tube was sealed, and the reaction mixture was stirred overnight at 100 ⁰C. LCMS analysis of the reaction mixture showed the presence of a mixture of mono and bis- acetylated material. The reaction was concentrated, and the resulting solid was diluted with ethanol, and the mixture concentrated to afford a mixture of mono and bis-acetylated intermediates (0.203 g) as a yellow solid. To this material were added bis(pinacolato)diboron (0.150 g, 0.59 mmol) and potassium acetate (0.138 g, 1.41 mmol) in 1 ,4-dioxane (5 mL), and the resulting mixture was degassed with argon for 10 minutes into a sealable tube. PdCI₂(dppf)-CH₂CI₂ (0.023 g, 0.028 mmol) was added, the tube was sealed, and the reaction mixture was stirred overnight at 90 ⁰C. The reaction was allowed to cool to room temperature and partitioned between EtOAc (100 mL) and water (100 mL). The organic layer was separated, washed with brine, dried (MgSO₄), filtered and concentrated. The resulting tan solid was triturated with a mixture of EtOAc (10 mL) and hexanes (90 mL) to afford a mixture of mono- and bis-acetylated boronate esters (99 mg) as an off-white solid. This boronate ester mixture was combined with 4-chloro-6-(4- morpholinyl)-2-pyrimidinamine (0.051 g, 0.24 mmol) and K₃PO₄ (0.086 g, 0.41 mmol) in 1 ,4-dioxane (0.89 mL) and water (0.30 mL), and the resulting mixture was degassed with argon into a 10 mL sealable tube. Pd₂(dba)₃ (2.2 mg, 2.4 μmol) was added, and argon was bubble through the mixture for an additional 5 minutes. Tricyclohexylphosphine (1.5 mg, 5.2 μmol) was added, the tube was sealed, and the reaction mixture was stirred for 16 hours at 100 ⁰C. The organic layer was decanted and filtered. The resulting filtrate was treated with 5 drops of TFA and purified on a reverse phase HPLC (CH₃CN/H₂O w/0.1 %TFA) to afford a mixture of the title compound and acetylated title compound (37 mg, mixture is 83% mono-acetylated and 17% non-acetylated material. LC-MS (ES) m/z = 460 (acetylated), 418 (de-acetylated) [M+H]⁺). To a solution of this mixture in CH₃OH (5 mL) was added 12M HCI (0.13 mL, 1.61 mmol), and the resulting solution was stirred at room temperature under argon overnight (no reaction), then 9 hours at 80 ⁰C (50% complete by LCMS). Additional 12M HCI (0.13 mL, 1.61 mmol) was added, and the reaction mixture was stirred for 2 days at 90 ⁰C. The reaction was concentrated, and the resulting yellow solid was dissolved in water (1 mL) and treated with saturated aqueous NaHCO₃ (5 drops). The resulting precipitate was extracted into EtOAc (1 mL) and purified on SiO₂ (gradient: 10% to 100% EtOAc in hexanes) to afford the title compound (7 mg) as a light yellow solid. LC-MS (ES) m/z = 418 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 3.65 (m, 8H), 6.19 (s, 2H), 6.70 (s, 1 H), 6.93 (m, 1 H), 7.29 (m, 1 H), 7.34 - 7.40 (m, 1 H), 7.50 (dd, J = 7.7, 1.4 Hz, 1 H), 7.72 (s, 1 H), 7.96 (d, J = 1.26 Hz, 1 H), 9.15 (s, 1 H).

Intermediate 39 [1-(Phenylmethyl)-2,5-pyrrolidinediyl1dimethanol

A solution of diethyl 1-benzyl-2,5-pyrrolidinedicarboxylate (9.5 g, 31.1 mmol, mixture of cis and trans isomers) in THF (40 mL) was added dropwise to LAH (1.0 M in THF, 57.0 mL, 57.0 mmol), and the mixture was stirred at room temperature under N₂ for 20 hours. The reaction mixture was quenched by sequential dropwise addition of water (2.3 mL), 15% NaOH (2.3 mL), and water (7.0 mL). The slurry was diluted with ethyl acetate, dried (Na₂SO₄), and filtered, rinsing with copious amounts of EtOAc. The filtrate was concentrated to give the title compound (7.34 g, 96%) as a yellow oil, which is a mixture of cis and trans isomers (about 2:1 according to ¹H NMR, but it was not determined which was the major isomer). LC-MS (ES) m/z = 222 [M+H]⁺. Intermediate 40 δ-fPhenylmethylKS-oxa-δ-azabicvcloP^.I^'loct.ane

A mixture of [1-(phenylmethyl)-2,5-pyrrolidinediyl]dimethanol (7.34 g, 33.2 mmol) and sulfuric acid (66% in water, 26.8 ml_, 332 mmol) was stirred at 175 ⁰C in a sealed tube for 16 hours. The mixture was then cooled to room temperature, quenched by adding dropwise to a stirring solution of saturated Na₂CO3 (400 ml_), and extracted with CH₂CI₂. The extracts were dried (Na₂SO₄), filtered, and concentrated. The resulting residue was purified by flash chromatography on SiO₂ (gradient: 0-30% EtOAc in hexanes) to give the title compound (3.02 g, 45%) as a colorless oil. LC-MS (ES) m/z = 204 [M+H]⁺.

Intermediate 41 3-Oxa-8-azabicvclor3.2.1 loctane

A suspension of 8-(phenylmethyl)-3-oxa-8-azabicyclo[3.2.1]octane (1.056 g, 7.41 mmol), 10 wt.% Pd/C (308 mg), and hydrochloric acid (6.0 M, 1.25 ml_, 7.50 mmol) in ethanol (75 ml.) was stirred under an atmosphere of hydrogen for 7 hours. The mixture was filtered through celite, and the filtrate was concentrated to afford the HCI salt of the title compound (1.117 g, 96%) as a white solid. LC-MS (ES) m/z = 114 [M+H]⁺.

Intermediate 42 4-Chloro-6-(3-oxa-8-azabicvclor3.2.Hoct-8-yl)-2-pyrimidinamine

A mixture of 3-oxa-8-azabicyclo[3.2.1]octane hydrochloride (1.093 g, 7.31 mmol), 2- amino-4,6-dichloropyrimidine (1.003 g, 6.12 mmol), and Λ/,Λ/-diisopropylethylamine (3.2 ml_, 18.3 mmol) in CH₃CN (15 ml.) was stirred at 100 ⁰C into a sealed tube for 20 hours. Upon cooling a precipitate formed. Collection of the precipitate by vacuum filtration afforded the title compound (1.257 g, 85%) as a beige solid. LC-MS (ES) m/z = 241 , 243 [M+H]⁺.

Example 9

4-(1.2-Dihvdroindazolor4.3-άciπ .5lbenzoxazepin-4-vn-6-(3-oxa-8-azabicvclor3.2.1loct-8- vD-2-pyrimidinamine

A mixture of 4-chloro-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-2-pyrimidinamine (125 mg, 0.52 mmol), 2-acetyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 ,2-dihydroindazolo[4,3- bc][1 ,5]benzoxazepine (202 mg, 0.52 mmol), and K₃PO₄ (338 mg, 1.60 mmol) in 1 ,4- dioxane (4.5 ml.) and water (1.5 ml.) was degassed with N₂ for 10 minutes. Pd₂(dba)₃ (25 mg, 0.027 mmol) was added, and the mixture was degassed for an additional 5 minutes. Tricyclohexylphosphine (18 mg, 0.064 mmol) was then added, and the mixture was stirred at 100 ⁰C in a sealed tube for 2 hours. After cooling, the mixture was filtered, and the filtrate was poured into water (30 ml_). A precipitate formed, and it was collected by vacuum filtration to give a relatively pure 5 :1 mixture of desired product and monoacylated desired product. The residue was taken up in CH₃OH (10 ml_), treated with concentrated HCI (1.0 ml_), and the resulting mixture was stirred at 80 ⁰C overnight. The reaction was allowed to cool to room temperature, and the resulting precipitate was filtered to afford a HCI salt of the title compound (76 mg, 28%) as a brown solid. LC-MS (ES) m/z = 428 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 1.89-2.14 (m, 4H), 3.61-3.75 (m, 4H), 4.82-4.93 (m, 2H), 6.92 (m, 1 H), 6.98 (s, 1 H), 7.07-7.13 (m, 1 H), 7.25-7.33 (m, 3H), 7.70 (s, 1 H), 9.69 (s, 1 H), 12.31 (bs, 1 H), 12.77 (s, 1 H). Intermediate 43

6-Chloro-Λ/⁴-(2-phenylethyl)-2,4-pyrimidinediamine

H

NH₂

To 2-amino-4,6-dichloropyrimidine (0.5 g, 3.05 mmol) in CH₃CN (10 mL) was added Et₃N (1.28 mL, 9.15 mmol) followed by (2-phenylethyl)amine (0.40 mL, 3.20 mmol), and the reaction mixture was stirred overnight at 80 ⁰C. The mixture was poured onto EtOAc and water. The organic layer was separated, washed with brine, dried (MgSO₄), filtered and concentrated. The resulting residue was sonicated in the presence of 20% EtOAc in hexanes. The solution was decanted, and the solid was triturated again in 20% EtOAc in hexanes to afford the title compound (469 mg, 62%) as a tan solid. LC-MS (ES) m/z = 249, X [M+H]⁺.

Example 10

6-(1.2-dihvdroindazolor4.3-άciri .5lbenzoxazepin-4-vn-Λ/⁴-(2-phenylethvn-2.4- pyrimidinediamine

A solution of 2-acetyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 ,2- dihydroindazolo[4,3-6c][1 ,5]benzoxazepine (0.214 g, 0.55 mmol), 6-chloro-Λ/⁴-(2- phenylethyl)-2,4-pyrimidinediamine (0.136 g, 0.55 mmol), Pd₂(dba)₃ (5.0 mg, 5.5 μmol), and K₃PO₄ (0.197 g, 0.93 mmol) in 1 ,4-dioxane (1 mL) and water (1.5 mL) was degassed with N₂ for 5 minutes. Tricyclohexylphosphine (3.4 mg, 0.012 mmol) was added, the vial was sealed, and the reaction mixture was stirred overnight at 100 ⁰C. The reaction was cooled to room temperature and diluted with EtOAc and water. The phases were separated and the aqueous phase was further extracted with EtOAc. The combined organic layers were dried (Na₂SO₄) and concentrated. The resulting dark brown solid was taken up in CH₂CI₂ and precipitated with hexanes. The resulting solid was dry loaded (~1 g SiO₂) onto a 24-40g SiO₂ column. Flash chromatography (gradient: (5% CHCI₃/ 95% (90:10:1 CHCI₃:CH₃OH:NH₄OH)) to 90:10:1 CHCI₃:CH₃OH:NH₄OH) afforded the title compound (69 mg, 29%) as a tan solid. LC-MS (ES) m/z = 436 [M+H]⁺. ¹H NMR (400 MHz, DMSO-de): δ 2.87 (t, J = 7.3 Hz, 2H), 3.54 (m, 2H), 6.09 (bs, 2H), 6.35 (s, 1 H), 6.88 (m, 1 H), 7.06 (m,1 H), 7.17-7.24 (m, 1 H), 7.26 - 7.33 (m, 8H), 7.69 (bs, 1 H), 9.50 (s, 1 H), 12.28 (s, 1 H).

Intermediate 44 4-Chloro-6-r2-(methyloxy)phenyll-2-pyrimidinamine

To a flask charged with 2-amino-4,6-dichloropyrimidine (1.0 g, 6.10 mmol), 2- methoxybenzene boronic acid (0.93 g, 6.10 mmol), Na₂CO₃ (3.88 g, 36.6 mmol), tricyclohexylphosphane (0.513 g, 1.829 mmol), and Pd(OAc)₂ (0.205 g, 0.915 mmol), were added 1 ,2-dimethoxyethane (DME) (15 ml.) and water (3.75 ml_), and the resulting mixture was vigorously stirred under N₂ for 2 hours. The reaction mixture was diluted with EtOAc and filtered, and the orange filtrate was washed with water and concentrated. The resulting orange residue was dissolved in CH₂CI₂ and treated with hexanes until a precipitate was observed. The mixture was filtered, and the filtrate was concentrated. The resulting residue was dissolved in CH₃OH and dry loaded onto SiO₂. Flash chromatography (gradient: 100% hexanes to 25% EtOAc in hexanes) afforded the title compound (230 mg, 16%) as a yellow solid. LC-MS (ES) m/z = 236, 238 [M+H]⁺.

Example 1 1

4-(1 ,2-Dihvdroindazolo[4,3-άc1[1 ,51benzoxazepin-4-yl)-6-[2-(methyloxy)phenyl1-2- pyrimidinamine

A mixture of 2-acetyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 ,2- dihydroindazolo[4,3-6c][1 ,5]benzoxazepine (220 mg, 0.56 mmol), 4-chloro-6-[2- (methyloxy)phenyl]-2-pyrimidinamine (133 mg, 0.56 mmol), K₃PO₄ (203 mg, 0.96 mmol), and tricyclohexylphosphane (4 mg, 0.014 mmol) in 1 ,4-dioxane (1 ml.) and water (1.5 ml.) was degassed for 5 minutes. Pd₂(dba)₃ (5 mg, 5.5 μmol) was added, the vial was sealed, and the resulting mixture was stirred overnight at 100 ⁰C. The reaction mixture was cooled to room temperature, and diluted with EtOAc and water. The organic layer was separated, dried (Na₂SO₄), filtered, and concentrated. The resulting dark brown solid was taken up in CH₃OH and dry loaded onto SiO₂ (2 g). Flash chromatography on SiO₂ (gradient: 100% CHCI₃ to 90:10:1 CHCI₃:CH₃OH:NH₄OH) afforded the title compound (58 mg, 24%) as a tan solid. LC-MS (ES) m/z = 423 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 3.90 (s, 3H), 6.75 (s, 2H), 6.86 - 6.93 (m, 1 H), 7.05 - 7.12 (m, 2H), 7.19 (d, J = 8.3 Hz, 1 H), 7.29 - 7.33 (m, 2H), 7.44 - 7.50 (m, 2H), 7.61 (s, 1 H), 7.80 (dd, J = 7.6, 1.8 Hz, 1 H), 7.83 (s, 1 H), 9.54 (s, 1 H), 12.38 (s, 1 H).

Intermediate 45 4-Chloro-6-(1-pyrrolidinyl)-2-pyrimidinamine

In a 100 ml. flask were combined pyrrolidine (1.74 g, 24.4 mol) and 2-amino-4,6- dichloropyrimidine (1.0 g ,6.10 mmol) in CH₃OH (20 ml_), and the reaction mixture was stirred for 2 hours at 50 ⁰C. The mixture was concentrated to dryness, and the resulting solid was partitioned between EtOAc and water. The organic layer was separated, dried (Na₂SO₄), filtered, and concentrated to afford the title compound (969 mg) as a pale yellow solid. LC-MS (ES) m/z = 199, 201 [M+H]⁺.

Example 12

4-(1 ,2-Dihydroindazolo[4,3-άc1[1 ,51benzoxazepin-4-yl)-6-(1 -pyrrolidinyl)-2-pyrimidinamine

To a mixture of 4-chloro-6-(1-pyrrolidinyl)-2-pyrimidinamine (400 mg, 2.01 mmol), 2-acetyl- 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 ,2-dihydroindazolo[4,3- 6c][1 ,5]benzoxazepine_(1.02 g, 2.61 mmol), tricyclohexylphosphine (14 mg, 0.05 mmol), and K₂CO₃ (883 mg, 6.03 mmol) in 1 ,4-dioxane (4 ml.) and water (6 ml.) was added Pd₂(dba)3 (18 mg, 0.02 mmol) under nitrogen, and the reaction mixture was heated for 40 minutes at 140 ⁰C in a microwave reactor. The mixture was cooled to room temperature and filtered, and the resulting solid was washed with EtOAc and purified by reverse phase HPLC (gradient: 55% CH₃CN/H₂O to 95% CH₃CN/H₂O w/0.01 % NH₄HCO₃) to afford the title compound (133 mg, 17%) as a white solid. LC-MS (ES) m/z = 386 [M+H]⁺. ¹H NMR (400 MHz, DMSO-de): δ 1.93 (s, 4H), 3.47 (s, 4H), 6.06 (s, 2H), 6.34 (s, 1 H), 6.86 - 6.90 (m, 1 H), 7.03 - 7.07 (m, 1 H), 7.27 - 7.29 (m, 2H), 7.41 (s, 1 H), 7.80 (s, 1 H), 9.50 (s, 1 H), 12.28 (s, 1 H).

Intermediate 46 4-Chloro-6-(2-methyl-1-pyrrolidinyl)-2-pyrimidinamine

To 2-amino-4,6-dichloropyrimidine (518 mg, 3.16 mmol) in ethanol (5 mL) was added 2- methylpyrrolidine (1.13 g, 13.3 mmol), and the reaction mixture was heated for 20 minutes at 120 ⁰C in a microwave reactor. The mixture was concentrated, and the resulting solids were partitioned between EtOAc and water. The organic layer was separated, dried (Na₂SO₄), filtered, and concentrated to afford the title compound (580 mg) as brown oil, which solidified upon standing at room temperature overnight. LC-MS (ES) m/z = 213, 215 [M+H]⁺

Example 13

4-(1 ,2-Dihydroindazolor4,3-άciπ ,5lbenzoxazepin-4-yl)-6-(2-methyl-1 -pyrrolidinyl)-2- pyrimidinamine

To a mixture of 4-chloro-6-(2-methyl-1-pyrrolidinyl)-2-pyrimidinamine (410 mg, 1.93 mmol), 2-acetyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 ,2-dihydroindazolo[4,3- 6c][1 ,5]benzoxazepine (982 mg, 2.51 mmol), tricyclohexylphosphine (14 mg, 0.05 mmol), and K₂CO3 (800 mg, 5.79 mmol) in 1 ,4-dioxane (4 ml.) and water (6 ml.) was added Pd₂(dba)₃ (18 mg, 0.02 mmol) under nitrogen, and the reaction mixture was heated for 40 minutes at 140 ⁰C in a microwave reactor. The mixture was cooled to room temperature and filtered, and the resulting solid was washed with EtOAc and purified by reverse phase HPLC (gradient: 60% CH₃CN/H₂O to 95% CH₃CN/H₂O w/0.01 % NH₄HCO₃) to afford the title compound (288 mg, 37%) as a white solid. LC-MS (ES) m/z = 400 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 1.19 - 1.20 (d, J = 6.0 Hz , 3H), 1.65 (s, 1 H), 1.91 - 1.20 (m, 3H), 3.39 (m, 1 H), 3.56 (m, 1 H), 4.25 (bs, 1 H), 6.04 (s, 2H), 6.33 (s, 1 H), 6.87 - 6.90 (m, 1 H), 7.04 - 7.08 (m, 1 H), 7.28 - 7.30 (m, 2H), 7.41 (s, 1 H), 7.79 (s, 1 H), 9.51 (s, 1 H), 12.28 (s, 1 H).

Intermediate 47 4-Chloro-6-(1-piperidinyl)-2-pyrimidinamine

To a solution of 2-amino-4,6-dichloropyrimidine (1.0 g, 6.10 mmol) in CH₃OH (50 mL) was added piperidine (3.50 mL, 3.01 g, 35.4 mmol), and the reaction mixture was stirred for 1 hour at 70 ⁰C. The solution was concentrated, and the resulting residue was partitioned between EtOAc (100 ml.) and water (150 ml_). The organic layer was separated, and the aqueous layer was further extracted with EtOAc (2 x 100 ml_). The combined organic layers were dried (Na₂SO₄), filtered, and concentrated to afford the title compound (1.30 g) as a brown solid. LC-MS (ES) m/z = 213, 215 [M+H]⁺.

Example 14

4-(1 ,2-Dihydroindazolor4,3-ibciri ,5lbenzoxazepin-4-yl)-6-(1 -piperidinvD-2-pyrimidinamine

To a suspension of 4-chloro-6-(1-piperidinyl)-2-pyrimidinamine (0.5 g, 2.35 mmol), 2- acetyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 ,2-dihydroindazolo[4,3- 6c][1 ,5]benzoxazepine (1.38 g, 3.52 mmol), K₂CO₃ (0.81 g, 5.87 mmol), and tricyclohexylphosphine (16mg, 0.059mmol) in 1 ,4-dioxane (6 ml.) and water (4 ml.) was added Pd₂(dba)₃ (22 mg, 0.024 mmol) under nitrogen, and the reaction mixture was heated at 140 ⁰C under microwave conditions for 40 minutes. The mixture was poured onto water (150 ml.) and EtOAc (100 ml_), the organic layer was separated, and the aqueous layer was further extracted with EtOAc (2 x 150 ml_). The combined organic layers were washed with brine (150 ml_), dried (Na₂SO₄), filtered, and concentrated. The resulting residue was purified by reverse phase chromatography (gradient: 33% CH₃CN/H₂O to 40% CH₃CN/H₂O w/0.5% TFA) to afford a TFA salt of the title compound (451 mg) as a yellow solid. LC-MS (ES) m/z = 400 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 1.61 (bs, 4H), 1.69 (s, 2H), 3.87 (bs, 4H), 6.89 - 6.93 (m, 1 H), 6.98 (s, 1 H), 7.07 - 7.1 1 (m, 1 H), 7.25 - 7.32 (m, 3H), 7.63 (s, 1 H), 9.66 (s, 1 H), 12.19 (bs, 1 H), 12.69 (s, 1 H). Intermediate 48 4-(1-Azetidinyl)-6-chloro-2-pyrimidinamine

To 2-amino-4,6-dichloropyrimidine (610 mg, 3.72 mmol) in ethanol (2.5 mL) was added azetidine (850 mg,14.9 mmol), and the reaction mixture was heated for 20 minutes at 120 ⁰C in a microwave reactor. The mixture was cooled to room temperature and concentrated, and the resulting solid was partitioned between EtOAc and water. The organic layer was separated, dried (Na₂SO₄), filtered, and concentrated to afford the title compound (572 mg) as a white solid. LC-MS (ES) m/z = 185, 187 [M+H]⁺

Example 15 4-(1-Azetidinyl)-6-(1 ,2-dihvdroindazolo[4,3-άc1[1 ,51benzoxazepin-4-yl)-2-pyrimidinamine

To a mixture of 4-(1-azetidinyl)-6-chloro-2-pyrimidinamine (570 mg, 3.09 mmol), 2-acetyl- 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 ,2-dihydroindazolo[4,3- 6c][1 ,5]benzoxazepine (1.57 g, 4.02 mmol), tricyclohexylphosphine (22.4 mg, 0.08 mmol), and K₂CO₃ (1.28 g, 9.27 mmol) in 1 ,4-dioxane (4 mL) and water (6 mL) was added Pd₂(dba)3 (28 mg, 0.03 mmol) under nitrogen, and the reaction mixture was heated for 40 minutes at 140 ⁰C in a microwave reactor. The mixture was cooled to room temperature and filtered, and the resulting solid was washed with EtOAc and purified by reverse phase HPLC (gradient: 50% CH₃CN/H₂O to 95% CH₃CN/H₂O w/0.01 % NH₄HCO₃) to afford the title compound (72 mg, 6%) as a yellow solid. LC-MS (ES) m/z = 372 [M+H]⁺. ¹H NMR (400 MHz, DMSO-de): δ 2.30 - 2.35 (m, 2H), 4.02 - 4.06 (m, 4H), 6.19 (s, 1 H), 6.23 (s, 1 H), 6.86 - 6.90 (m, 1 H), 7.04 - 7.08 (m, 1 H), 7.28 - 7.29 (m, 2H), 7.40 (s, 1 H), 7.80 (s, 1 H), 9.51 (s, 1 H), 12.30 (s, 1 H). Intermediate 49 θ-Chloro-Λ^-cvclohexyl^^-pyrimidinediamine

To a solution of 2-amino-4,6-dichloropyrimidine (1.0 g, 6.10 mmol) in CH₃OH (50 mL) was added cyclohexylamine (3.50 mL, 30.5 mmol), and the reaction mixture was stirred for 1 hour at 70 ⁰C. The solution was concentrated, and the resulting residue was partitioned between EtOAc (100 mL) and water (150 mL). The organic layer was separated, and the aqueous layer was further extracted with EtOAc (2 x 100 mL). The combined organic layers were dried (Na₂SO₄), filtered, and concentrated to afford the title compound (1.20 g) as a brown solid. LC-MS (ES) m/z = 227, 229 [M+H]⁺.

Example 16

Λ/⁴-Cvclohexyl-6-(1 ,2-dihvdroindazolor4,3-άciri .5lbenzoxazepin-4-yl)-2,4- pyrimidinediamine

To a suspension of β-chloro-Λ^-cyclohexyl^^-pyrimidinediamine (0.5 g, 2.21 mmol), 2- acetyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 ,2-dihydroindazolo[4,3- 6c][1 ,5]benzoxazepine (1.04 g, 2.65 mmol), K₂CO₃ (0.76 g, 5.53 mmol), and tricyclohexylphosphine (15 mg, 0.055 mmol) in 1 ,4-dioxane (6.0 mL) and water (4.0 mL) was added Pd₂(dba)₃ (20 mg, 0.022 mmol) under nitrogen, and the reaction mixture was heated for 40 minutes at 140 ⁰C under microwave conditions. The mixture was poured onto water (150 mL) and EtOAc (100 mL), the organic layer was separated, and the aqueous layer was further extracted with EtOAc (2 x 150 mL). The combined organic layers were washed with brine (150 mL), dried (Na₂SO₄), filtered, and concentrated. The resulting residue was purified by reverse phase chromatography (gradient: 30%

CH₃CN/H₂O to 40% CH₃CN/H₂O w/0.5% TFA) to afford a TFA salt of the title compound (97 mg) as a yellow solid. LC-MS (ES) m/z = 414 [M+H]⁺. ¹H NMR (400 MHz, DMSOd₆): δ 1.25 - 1.31 (m, 4H), 1.60 - 1.62 (m, 1 H), 1.76 (s, 2H), 1.92 (bs, 2H), 3.96 (bs, 2H), 6.44 (s, 1 H), 6.88 - 6.93 (m, 1 H), 7.00 (s, 1 H), 7.07 - 7.12 (m, 1 H), 7.26 - 7.31 (m, 3H), 7.46 (2, 1 H), 8.70 (d, J = 8.0 Hz, 1 H), 9,66 (s, 1 H), 12.07 (bs, 1 H), 12.70 (s, 1 H).

Intermediate 50 e-Chloro-Λ^-cvclopentyl^^-pyrimidinediamine

To 2-amino-4,6-dichloropyrimidine (2.0 g, 12.2 mmol) in CH₃OH (40 mL) was added cycloplentylamine (4.15 g, 48.8 mmol), and the reaction mixture was stirred for 7.5 hours at 60 ⁰C. The mixture was concentrated, and the resulting solid was partitioned between EtOAc and water. The organic layer was separated, dried (Na₂SO₄), filtered, and concentrated to afford the title compound (2.46 g) as a brown solid. LC-MS (ES) m/z = 213, 215 [M+H]⁺

Example 17

Λ/⁴-Cvclopentyl-6-(1 ,2-dihvdroindazolor4,3-άciπ ,5lbenzoxazepin-4-yl)-2,4- pyrimidinediamine

To a mixture of β-chloro-Λ^-cyclopentyl^^-pyrimidinediamine (600 mg, 2.82 mmol), 2- acetyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 ,2-dihydroindazolo[4,3- 6c][1 ,5]benzoxazepine (1.44 g, 3.67 mmol), tricyclohexylphosphine (19.6 mg, 0.07 mmol), and K₂CO₃ (1.17 g, 8.46 mmol) in 1 ,4-dioxane (4 mL) and water (6 mL) was added Pd₂(dba)₃ (27.5 mg, 0.03 mmol) under nitrogen, and the reaction mixture was heated for 40 minutes at 140 ⁰C in a microwave reactor. The mixture was cooled to room temperature and filtered, and the resulting solid was washed with EtOAc and purified by reverse phase chromatography (gradient: 33% CH₃CN/H₂O to 45% CH₃CN/H₂O w/0.5% TFA) to afford a TFA salt of the title compound (108 mg, 10%) as a yellow solid. LC-MS (ES) m/z = 400 [M+H]⁺. ¹H NMR (400 MHz, DMSOd₆): δ 1.54 - 1.61 (m, 4H), 1.71 - 1.73 (s, 2H), 1.96 - 1.99 (m, 2H), 4.34 - 4.39 (m, 1 H), 6.44 (s, 1 H), 6.89 - 6.92 (m, 1 H), 7.00 (s, 1 H), 7.07 - 7.1 1 (m, 1 H), 7.25 - 7.31 (m, 3H), 7.45 (s, 1 H), 8.81 - 8.82 (m, 1 H), 9.64 (s, 1 H), 12.14 (bs, 1 H), 12.70 (s, 1 H).

Intermediate 51 e-Chloro-Λ^-methyl^^-pyrimidinediamine

H

.N Cl

NH,

To 2-amino-4,6-dichloropyrimidine (1.0 g, 6.1 mmol) in CH₃OH (20 ml.) was added methylamine (2.37 g, 24.4 mmol, 32% solution of methylamine in CH₃OH), and the reaction mixture was stirred for 2 hours at 50 ⁰C. The mixture was concentrated, and the resulting solid was partitioned between EtOAc and water. The organic layer was separated, dried (Na₂SO₄), filtered, and concentrated to afford the title compound (833 mg) as a pale yellow solid. LC-MS (ES) m/z = 159, 161 [M+H]⁺.

Example 18 6-(1 ,2-Dihvdroindazolor4,3-άciri ,5lbenzoxazepin-4-yl)-Λ/⁴-methyl-2,4-pyrimidinediamine

To a mixture of β-chloro-Λ^-methyl^^-pyrimidinediamine (500 mg, 3.15 mmol), 2-acetyl- 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 ,2-dihydroindazolo[4,3- 6c][1 ,5]benzoxazepine (1.60 g, 4.10 mmol), tricyclohexylphosphine (22 mg, 0.08 mmol), and K₂CO₃ (1.31 g, 9.45 mmol) in 1 ,4-dioxane (4 mL) and water (6 mL) was added Pd₂(dba)₃ (27 mg, 0.03 mmol) under nitrogen, and the reaction mixture was heated for 40 minutes at 140 ⁰C in a microwave reactor. The mixture was cooled to room temperature and filtered, and the resulting solid was washed with EtOAc and purified by reverse phase chromatography (gradient: 30% CH₃CN/H₂O to 40% CH₃CN/H₂O w/0.5% TFA) to afford a TFA salt of the title compound (169 mg, 16%) as a yellow solid. LC-MS (ES) m/z = 346 [M+H]⁺. ¹H NMR (400 MHz, DMSOd₆): δ 2.95 - 2.96 (d, J = 4.4 Hz, 3H), 6.46 (s, 1 H), 6.89 - 6.97 (m, 1 H), 7.03 (s, 1 H), 7.07 - 7.11 (m, 1 H), 7.26 - 7.30 (m, 2H), 7.47 (s, 1 H), 8.74 (bs, 1 H), 9.65 (s, 1 H), 12.14 (bs, 1 H), 12.68 (s, 1 H).

Intermediate 52 e-Chloro-Λ^-ethyl^^-pyrimidinediamine

Into a 100 ml. flask were combined ethylamine hydrochloride (3.98 g,48.8 mmol), 2- amino-4,6-dichloropyrimidine (2.0 g, 12.2 mmol) and triethylamine (6.1726 g,61 mmol) in CH₃OH (40.0 ml_), and the resulting mixture was stirred for 10 hours at 60 ⁰C. The mixture was concentrated, and the resulting solid was partitioned between EtOAc and water. The organic layer was separated, dried (Na₂SO₄), filtered, and concentrated to afford the title compound (1.75 g) as a yellow solid. LC-MS (ES) m/z = 173, 175 [M+H]⁺.

Example 19 δ-d ^-DihydroindazoloK.S-άcifi .δibenzoxazepin^-vD-Λ^-ethyl^^-pyrimidinediamine

To a mixture of β-chloro-Λ^-ethyl^^-pyrimidinediamine (500 mg, 2.90 mmol), 2-acetyl-4- (4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 ,2-dihydroindazolo[4,3- 6c][1 ,5]benzoxazepine (1.47 g, 3.77 mmol), tricyclohexylphosphine (20 mg, 0.07 mmol), and K₂CO₃ (1.20 g, 8.7 mmol) in 1 ,4-dioxane (4 mL) and water (6 mL) was added Pd₂(O¹Da)₃ (27.5 mg, 0.03 mmol) under nitrogen, and the reaction mixture was heated for 40 minutes at 140 ⁰C in a microwave reactor. The mixture was cooled to room temperature and filtered, and the resulting solid was washed with EtOAc and purified by reverse phase chromatography (gradient: 27% CH₃CN/H₂O to 35% CH₃CN/H₂O w/0.5% TFA) to afford a TFA salt of the title compound (153 mg, 15%) as a yellow solid. LC-MS (ES) m/z = 360 [M+H]⁺. ¹H NMR (400 MHz, DMSOd₆): δ 1.17 - 1.21 (t, J = 7.2 Hz, 3H), 3.42 - 3.49 (m, 2H), 6.44 (s, 1 H), 6.88 - 6.92 (m, 1 H), 7.02 (s, 1 H), 7.07 - 7.1 1 (m, 1 H), 7.26 - 7.31 (m, 3H), 7.46 (s, 1 H), 8.82 (bs, 1 H), 9.64 (s, 1 H), 12.16 (bs, 1 H), 12.69 (s, 1 H).

Intermediate 53 δ-Chloro-Λ^-d-methylethvD^^-pyrimidinediamine

Into a 100 ml. flask were combined isopropylamine (1.44 g, 24.4 mmol) and 2-amino-4,6- dichloropyrimidine (1.0 g, 6.1 mmol) in CH₃OH (20.0 ml_), and the resulting mixture was stirred overnight at 50 ⁰C. The mixture was concentrated, and the resulting solid was partitioned between EtOAc and water. The organic layer was separated, dried (Na₂SO₄), filtered, and concentrated to afford the title compound (1.06 g) as a pale yellow solid. LC- MS (ES) m/z = 187, 189 [M+H]⁺

Example 20

6-(1 ,2-Dihvdroindazolor4,3-άciri .δlbenzoxazepin-^vD-Λ^-d -methylethvD-2,4- pyrimidinediamine

To a mixture of 6-chloro-Λ/⁴-(1-methylethyl)-2,4-pyrimidinediamine (500 mg, 2.68 mmol), 2- acetyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 ,2-dihydroindazolo[4,3- 6c][1 ,5]benzoxazepine (1.36 g, 3.48 mmol), tricyclohexylphosphine, (20 mg, 0.07 mmol), and K₂CO₃ (1.11 g, 8.04 mmol) in 1 ,4-dioxane (4 ml.) and water (6 mL) was added Pd₂(dba)₃ (27 mg, 0.03 mmol) under nitrogen, and the reaction mixture was heated for 40 minutes at 140 ⁰C in a microwave reactor. The mixture was cooled to room temperature and poured onto water (150 mL) and EtOAc (100 mL). The organic layer was separated, and the aqueous layer was further extracted with EtOAc (2 x 150 mL). The combined organic layers were washed with brine (150 mL), dried (Na₂SO₄), filtered and concentrated. The resulting residue was purified by reverse phase HPLC (gradient: 45% CH₃CN/H₂O to 95% CH₃CN/H₂O w/0.01 % NH₄HCO₃) to afford the title compound (300 mg, 23%) as a yellow solid. LC-MS (ES) m/z = 374 [M+H]⁺. ¹H NMR (400 MHz, DMSO- cfe): δ 1.16 - 1.18 (d, J = 6.4 Hz, 6H), 4.14 - 4.15 (bs, 1 H), 6.03 (s, 2H), 6.32 (s, 1 H), 6.74 - 6.75 (bs, 1 H), 6.87 - 6.90 (m, 1 H), 7.05 - 7.08 (m, 1 H), 7.28 - 7.30 (bs, 3H), 7.68 (s, 1 H), 9.49 (s, 1 H), 12.28 (s, 1 H).

Intermediate 54 δ-Chloro-ΛΛΛ^-dimethyl^^-pyrimidinediamine

Into a 100 mL flask were combined dimethylamine hydrochloride (3.98 g, 48.8 mmol), 2- amino-4,6-dichloropyrimidine (2.0 g, 12.2 mmol) and triethylamine (6.17 g, 61 mmol) in CH₃OH (20.0 mL), and the resulting mixture was stirred for 2 hours at 50 ⁰C. The mixture was concentrated, and the resulting solid was partitioned between EtOAc and water. The organic layer was separated, dried (Na₂SO₄), filtered, and concentrated to afford the title compound (1.74 g) as a yellow solid. LC-MS (ES) m/z = 173, 175 [M+H]⁺.

Example 21

B-d ^-dihvdroindazoloK^-άcifi .δibenzoxazepin^-vD-Λ^.Λ^-dimethyl^^- pyrimidinediamine

To a mixture of θ-chloro-ΛΛΛ^-dimethyl^^-pyrimidinediamine (500 mg, 2.90 mmol), 2- acetyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 ,2-dihydroindazolo[4,3- 6c][1 ,5]benzoxazepine (1.47 g, 3.77 mmol), tricyclohexylphosphine (20 mg, 0.07 mmol), and K₂CO₃ (1.22 g, 8.7 mmol) in 1 ,4-dioxane (4 ml.) and water (6 ml.) was added Pd₂(dba)3 (26 mg, 0.03 mmol) under nitrogen, and the reaction mixture was heated for 40 minutes at 140 ⁰C in a microwave reactor. The mixture was cooled to room temperature and filtered, and the resulting solid was washed with EtOAc and purified by reverse phase HPLC (gradient: 20% CH₃CN/H₂O to 95% CH₃CN/H₂O w/0.04% NH₄OH) to afford the title compound (96 mg, 9%) as a pale yellow solid. LC-MS (ES) m/z = 360 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 3.1 1 (s, 6H), 6.12 (s, 2H), 6.55 (s, 1 H), 6.89 - 6.92 (m, 1 H), 7.06 - 7.10 (m, 1 H), 7.30 - 7.33 (m, 2H), 7.48 (s, 1 H), 7.87 (s, 1 H), 9.54 (s, 1 H).

Intermediate 55 e-Chloro-Λ^-cvclobutyl^^-pyrimidinediamine

To a solution of 2-amino-4,6-dichloropyrimidine (1.0 g, 6.10 mmol) in CH₃OH (50.0 mL) was added cyclobutanamine (3.50 mL, 41.0 mmol), and the reaction mixture was stirred for 1.0 hour at 70 ⁰C. The solution was concentrated, and the resulting residue was partitioned between EtOAc (100 mL) and water (150 mL). The organic layer was separated, and the aqueous layer was further extracted with EtOAc (2 x 100 mL). The combined organic layers were dried (Na₂SO₄), filtered, and concentrated to afford the title compound (1.44 g) as a brown solid. LC-MS (ES) m/z = 199, 201 [M+H]⁺. Example 22

Λ^-Cvclobutyl-B-d ^-dihvdroindazoloK^-άcifi .δibenzoxazepin^-yl)^^- pyrimidinediamine

To a suspension of β-chloro-Λ^-cyclobutyl^^-pyrimidinediamine (0.5 g, 2.52 mmol), 2- acetyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 ,2-dihydroindazolo[4,3- 6c][1 ,5]benzoxazepine (1.18 g, 3.02 mmol), K₂CO₃ (0.87 g, 6.30 mmol), and tricyclohexylphosphine (18 mg, 0.063 mmol) in 1 ,4-dioxane (6.0 ml.) and water (4.0 ml.) was added Pd₂(dba)₃ (22 mg, 0.025 mmol) under nitrogen, and the reaction mixture was heated at 140 ⁰C under microwave conditions for 40 minutes. The mixture was poured onto water (150 ml.) and EtOAc (100 ml_), the organic layer was separated, and the aqueous layer was further extracted with EtOAc (2 x 150 ml_). The combined organic layers were washed with brine (150 ml), dried (Na₂SO₄), filtered, and concentrated. The resulting residue was purified by reverse phase chromatography (gradient: 30% CH₃CN/H₂O to 40% CH₃CN/H₂O w/0.5% TFA) to afford a TFA salt of the title compound (240 mg) as a yellow solid. LC-MS (ES) m/z = 414 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 1.70 - 1.78 (m, 2H), 2.00 - 2.05 (m, 2H), 2.29 - 2.35 (m, 2H), 4.51 - 4.53 (m, 1 H), 6.38 (s, 1 H), 6.89 - 6.93 (m, 1 H), 7.01 (s, 1 H), 7.07 - 7.1 1 (m, 1 H), 7.26 - 7.31 (m, 3H), 7.45 (s, 1 H), 9.05 (d, J = 7.6 Hz, 1 H), 9.67 (s, 1 H), 12.08 (s, 1 H), 12.69 (s, 1 H).

Intermediate 56 δ-Chloro-Λ^-methyl-Λ^-d-methylethvD^^-pyrimidinediamine

To a solution of 2-amino-4,6-dichloropyrimidine (0.5 g, 3.05 mmol) in ethanol (3.0 ml.) was added Λ/-methyl-2-propanamine (2.0 ml_, 19.2 mmol), and the reaction mixture was heated for 20 minutes at 120 ⁰C under microwave conditions. The solution was concentrated, and the resulting residue was partitioned between EtOAc (100 ml.) and water (150 ml_). The organic layer was separated, and the aqueous layer was further extracted with EtOAc (2 x 100 ml_). The combined organic layers were dried (Na₂SO₄), filtered, and concentrated to afford the title compound (0.65 g) as a brown solid. LC-MS (ES) m/z = 201 , 203 [M+H]⁺.

Example 23

6-(1.2-Dihvdroindazolor4.3-άciri .5lbenzoxazepin-4-vn-Λ/⁴-methyl-Λ/⁴-(1-methylethvn-2.4- pyrimidinediamine

To a suspension of 6-chloro-Λ/⁴-methyl-Λ/⁴-(1-methylethyl)-2,4-pyrimidinediamine_(0.5 g, 2.49 mmol), 2-acetyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 ,2- dihydroindazolo[4,3-6c][1 ,5]benzoxazepine (1.17 g, 2.99 mmol), K₂CO₃ (0.86 g, 6.23 mmol), and tricyclohexylphosphine (17 mg, 0.062 mmol) in 1 ,4-dioxane (6.0 ml.) and water (4.0 ml.) was added Pd₂(dba)₃ (23mg, 0.025mmol) under nitrogen, and the reaction mixture was heated at 140 ⁰C under microwave conditions for 40 minutes. The mixture was poured onto water (150 ml.) and EtOAc (100 ml_), the organic layer was separated, and the aqueous layer was further extracted with EtOAc (2 x 150 ml_). The combined organic layers were washed with brine (150 ml_), dried (Na₂SO₄), filtered, and concentrated. The resulting residue was purified by reverse phase chromatography (gradient: 33% CH₃CN/H₂O to 40% CH₃CN/H₂O w/0.5% TFA) to afford a TFA salt of the title compound (170 mg) as a yellow solid. LC-MS (ES) m/z = 388 [M+H]⁺. ¹H NMR (400 MHz, DMSO-de): δ 1.21 (d, J = 5.6 Hz, 6H), 3.09 (s, 3H), 5.24 (s, 1 H), 6.76 (bs, 1 H), 6.89 - 6.93 (m, 1 H), 7.07 - 7.11 (m, 1 H), 7.07 - 7.11 (m, 1 H), 7.24 (s, 1 H), 7.26 - 7.32 (m, 2H), 7.62 (s, 1 H), 9.66 (s, 1 H), 12.27 (bs, 1 H), 12.70 (s, 1 H). Intermediate 57 θ-Chloro-Λ^-propyl^^-pyrimidinediamine

To a solution of 2-amino-4,6-dichloropyrimidine (1.0 g, 6.10 mmol) in CH₃OH (50 mL) was added propan-1-amine (3.50 mL, 42.5 mmol), and the reaction mixture was stirred for 1 hour at 70 ⁰C. The solution was concentrated, and the resulting residue was partitioned between EtOAc (100 mL) and water (150 mL). The organic layer was separated, and the aqueous layer was further extracted with EtOAc (2 x 100 mL). The combined organic layers were dried (Na₂SO₄), filtered, and concentrated to afford the title compound (1.03 g) as a brown solid. LC-MS (ES) m/z = 187, 189 [M+H]⁺.

Example 24 6-(1 ,2-Dihvdroindazolor4,3-άciri .5lbenzoxazepin-4-yl)-Λ/⁴-propyl-2,4-pyrimidinediamine

To a suspension of θ-chloro-Λ^-propyl^^-pyrimidinediamine (0.5 g, 2.68 mmol), 2-acetyl- 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 ,2-dihydroindazolo[4,3- bc][1 ,5]benzoxazepine (1.26 g, 3.21 mmol), K₂CO₃ (0.93 g, 6.7 mmol) and tricyclohexylphosphine (19 mg, 0.07 mmol) in 1 ,4-dioxane (6.0 mL) and water (4.0 mL) was added Pd₂(dba)₃ (25 mg, 0.027 mmol) under nitrogen, and the reaction mixture was heated at 140 ⁰C under microwave conditions for 40 minutes. The mixture was poured onto water (150 mL) and EtOAc (100 mL), the organic layer was separated, and the aqueous layer was further extracted with EtOAc (2 x 150 mL). The combined organic layers were washed with brine (150 mL), dried (Na₂SO₄), filtered, and concentrated. The resulting residue was purified by reverse phase chromatography (gradient: 30% CH₃CN/H₂O to 45% CH₃CN/H₂O w/0.5% TFA) to afford a TFA salt of the title compound (95 mg) as a yellow solid. LC-MS (ES) m/z = 374 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): δ θ.94 (t, J = 7.6 Hz 3H), 1.55 - 1.65 (m, 2H), 2.99 (bs, 2H), 6.46 (s, 1 H), 6.89 - 6.93 (m, 1 H), 7.02 (s, 1 H), 7.07 - 7.1 1 (m, 1 H), 7.26 - 7.31 (m, 3H), 7.47 (s, 1 H), 8.77 (bs, 1 H), 9.66 (s, 1 H), 12.02 (bs, 1 H), 12.68 (s, 1 H).

Intermediate 58 6-Chloro-Λ/⁴-(2-methylpropyl)-2,4-pyrimidinediamine

To a solution of 2-amino-4,6-dichloropyrimidine (1.0 g, 6.10 mmol) in CH₃OH (50 mL) was added 2-methylpropan-1 -amine (3.50 mL, 34.7 mmol), and the reaction mixture was stirred for 1 hour at 70 ⁰C. The solution was concentrated, and the resulting residue was partitioned between EtOAc (100 mL) and water (150 mL). The organic layer was separated, and the aqueous layer was further extracted with EtOAc (2 x 100 mL). The combined organic layers were dried (Na₂SO₄), filtered, and, concentrated to afford the title compound (1.20 g) as a brown solid. LC-MS (ES) m/z = 201 , 203 [M+H]⁺.

Example 25

6-(1 ,2-dihvdroindazolor4,3-άciri ,5lbenzoxazepin-4-yl)-Λ/⁴-(2-methylpropyl)-2,4- pyrimidinediamine

To a suspension of 6-chloro-Λ/⁴-(2-methylpropyl)-2,4-pyrimidinediamine

(0.5 g, 2.5 mmol), 2-acetyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 ,2- dihydroindazolo[4,3-6c][1 ,5]benzoxazepine (1.47 g, 3.75 mmol), K₂CO₃ (0.86 g, 6.25 mmol), and tricyclohexylphosphine (18 mg, 0.063 mmol) in 1 ,4-dioxane (6.0 mL) and water (4.0 mL) was added Pd₂(dba)₃ (23 mg, 0.025 mmol) under nitrogen, and the reaction mixture was heated for 40 minutes at 140 ⁰C under microwave conditions. The mixture was poured onto water (150 mL) and EtOAc (100 mL), the organic layer was separated, and the aqueous layer was further extracted with EtOAc (2 x 150 ml_). The combined organic layers were washed with brine (150 ml_), dried (Na₂SO₄), filtered, and concentrated. The resulting residue was purified by reverse phase chromatography (gradient: 30% CH₃CN/H₂O to 40% CH₃CN/H₂O w/0.5% TFA) to afford a TFA salt of the title compound (353 mg) as a yellow solid. LC-MS (ES) m/z = 388 [M+H]⁺. ¹H NMR (400 MHz, DMSO-de): δ 0.95 (d, J = 6.8 Hz, 6H), 1.87 - 1.94 (m, 1 H), 3.26 - 3.30 (m, 2H), 6.52 (s, 1 H), 6.89 - 6.93(m, 1 H), 7.03 (s, 1 H), 7.07 - 7.12 (m, 1 H), 7.26 - 7.31 (m, 3H), 7.47 (s, 1 H), 8.80 (bs, 1 H), 9.66 (s, 1 H), 12.16 (bs, 1 H), 12.71 (s, 1 H).

Intermediate 59 e-Chloro-ΛΛΛ^-diethyl^Λ-pyrimidinediamine

Into a 100 ml. flask were combined diethylamine (1.78 g, 24.4 mmol) and 2-amino-4,6- dichloropyrimidine (1.0 g, 6.10 mmol) in CH₃OH (20 ml_), and the resulting mixture was stirred for 7 hours at 60 ⁰C. The mixture was concentrated, and the resulting solid was partitioned between EtOAc and water. The organic layer was separated, dried (Na₂SO₄), filtered, and concentrated to afford the title compound (990 mg) as a pale yellow solid. LC-

MS (ES) m/z = 201 , 203 [M+H]⁺.

Example 26 e-d ^-dihydroindazoloK.S-άcifi .δibenzoxazepin^-vD-Λ^.Λ^-diethyl^^-pyrimidinediamine

To a mixture of β-chloro-Λ^^-diethyl^^-pyrimidinediamine (500 mg,2.49 mol), 2-acetyl- 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 ,2-dihydroindazolo[4,3-

6c][1 ,5]benzoxazepine (1.27 g, 3.24 mmol), tricyclohexylphosphine (17 mg, 0.06 mmol), and K₂CO₃ (1.0324 g, 7.47 mmol) in 1 ,4-dioxane (4 ml.) and water (6 mL) was added Pd₂(dba)₃ (18 mg, 0.02 mmol) under nitrogen, and the reaction mixture was heated for 40 minutes at 140 ⁰C in a microwave reactor. The mixture was cooled to room temperature and filtered, and the resulting solid was washed with EtOAc and purified by reverse phase HPLC (gradient: 60% CH₃CN/H₂O to 95% CH₃CN/H₂O w/0.01 % NH₄HCO₃) to afford the title compound (322 mg, 33%) as a pale yellow solid. LC-MS (ES) m/z = 388 [M+H]⁺. ¹H NMR (400 MHz, DMSO-Cf₆): δ 1.12 - 1.16 (t, J = 6.8 Hz, 6H), 3.54 - 3.55 (m, 4H), 6.03 (s, 2H), 6.45 (s, 1 H), 6.86 - 6.90 (m, 1 H), 7.04 - 7.07 (m, 1 H), 7.28 - 7.30 (m, 2H), 7.41 - 7.44 (m, 1 H), 7.79 - 7.82 (m, 1 H), 9.50 (s, 1 H), 12.25 (bs, 1 H).

Intermediate 60 4-Chloro-6-(2-ethyl-1-piperidinyl)-2-pyrimidinamine

To 2-amino-4,6-dichloropyrimidine (2.0 g, 12.2 mmol) in ethanol (10 mL) was added 2- ethylpiperidine (5.52 g, 48.8 mmol), and the reaction mixture was heated for 20 minutes at 120 ⁰C in a microwave reactor. The mixture was cooled to room temperature and concentrated, and the resulting solid was partitioned between EtOAc and water. The organic layer was separated, dried (Na₂SO₄), filtered, and concentrated to afford the title compound (2.21 g) as a yellow solid. LC-MS (ES) m/z = 241 , 243 [M+H]⁺

Example 27

4-(1 ,2-Dihydroindazolo[4,3-άc1[1 ,51benzoxazepin-4-yl)-6-(2-ethyl-1-piperidinyl)-2- pyrimidinamine

To a mixture of 4-chloro-6-(2-ethyl-1-piperidinyl)-2-pyrimidinamine (800 mg,3.32 mol), 2- acetyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 ,2-dihydroindazolo[4,3- 6c][1 ,5]benzoxazepine (1.69 g, 4.32 mmol), tricyclohexylphosphine (22 mg, 0.08 mmol), and K₂CO₃ (1.38 g, 9.96 mmol) in 1 ,4-dioxane (4 ml.) and water (6 ml.) was added Pd₂(dba)₃ (27 mg, 0.03 mmol) under nitrogen, and the reaction mixture was heated for 60 minures at 140 ⁰C in a microwave reactor. The mixture was poured onto water (200 ml.) and EtOAc (150 ml_), the organic layer was separated, and the aqueous layer was further extracted with EtOAc (3 x 100 ml_). The combined organic layers were washed with brine (150 ml_), dried (Na₂SO₄), filtered, and concentrated. The resulting residue was purified by reverse phase HPLC (gradient: 70% CH₃CN/H₂O to 95% CH₃CN/H₂O w/0.01% NH₄HCO₃) to afford the title compound as a yellow solid. This material was purified further by reverse phase chromatography (gradient: 68% CH₃CN/H₂O to 75% CH₃CN/H₂O w/0.08% NH₄HCO₃) to afford the title compound (109 mg, 8%) as a white solid. LC-MS (ES) m/z = 428 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 0.82 - 0.85 (t, J = 7.2 Hz, 3H), 1.34 - 1.37 (m, 1 H), 1.55 - 1.78 (m, 7H), 2.81 - 2.87 (m, 1 H), 4.47 (bs, 1 H), 4.62 (bs, 1 H), 6.02 (s, 2H), 6.63 (s, 1 H), 6.86 - 6.90 (m, 1 H), 7.04 - 7.08 (m, 1 H), 7.28 - 7.30 (m, 2H), 7.45 (s, 1 H), 7.83 (s, 1 H), 9.49 (s, 1 H), 12.27 (s, 1 H).

Intermediate 61

1-(2-Amino-6-chloro-4-pyrimidinyl)-L-prolinamide

To 2-amino-4,6-dichloropyrimidine (0.328 g, 2.0 mmol) and L-prolinamide (0.228 g, 2.0 mmol) in CH₃CN (6 mL) was added diethylaminomethyl-polystyrene (0.75 g, 2.4 mmol), and the reaction mixture was heated for 1 hour at 160 ⁰C under microwave conditions. The mixture was filtered to remove the polystyrene base and the solid was rinsed with

CH3CN. The filtrate was concentrated, and the resulting crude material was triturated with Et₂O, sonicated and decanted to afford the title compound (360 mg, 75%) as an off-white solid. LC-MS (ES) m/z = 242, 244 [M+H]⁺. Example 28 i-^-Amino-B-d ^-dihvdroindazoloK^-άcifi .δibenzoxazepin^-ylM-pyrimidinyli-L- prolinamide

A mixture of 2-acetyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 ,2- dihydroindazolo[4,3-6c][1 ,5]benzoxazepine (453 mg, 1.16 mmol), 1-(2-amino-6-chloro-4- pyrimidinyl)-L-prolinamide (280 mg, 1.16 mmol), and K₃PO₄ (418 mg, 1.97 mmol) in 1 ,4- dioxane (3 ml.) and water (1 ml.) was degassed with N₂ for 10 minutes into a microwave vial. Tricyclohexylphosphine (16.2 mg, 0.058 mmol) and Pd₂(dba)₃ (21.2 mg, 0.023 mmol) were added, and N₂ was bubbled through the resulting mixture for an additional 5 minutes. The vessel was sealed, and the reaction mixture was stirred overnight at 100 ⁰C. The reaction was allowed to cool to room temperature, and the 1 ,4-dioxane layer was separated and filtered. The filtrate was passed through a C-18 filter cartridge, and the filter cartridge was washed with CH₃CN (5 ml_). To the resulting filtrate mixture was added TFA, and the precipitate formed was filtered to afford a tan solid. This salt product was re- dissolved in DMSO (~ 2 ml.) and added dropwise to saturated aqueous NaHCO₃ (10 ml_). The resulting light tan solid was filtered, washed with water and dried. This material was triturated overnight with EtOAc (5 ml_), filtered and dried to afford the title compound (145 mg, 32%) as a light brown solid. LC-MS (ES) m/z = 429 [M+H]⁺. ¹H NMR (400 MHz, DMSO-de + D₂O): δ 1.65 - 2.40 (m, 4H), 3.40 - 3.60 (m, 1 H), 3.60 - 3.75 (m, 1 H), 4.13 - 4.65 (m, 1 H), 5.87 - 6.52 (m, 1 H), 6.82 - 6.96 (m, 1 H), 6.99 - 7.14 (m, 1 H), 7.15 - 7.47 (m, 1 H), 7.24 - 7.30 (m, 2H), 7.55 - 7.90 (m, 1 H).

Intermediate 62

1-(2-Amino-6-chloro-4-pyrimidinyl)-/\/,/\/-dimethyl-L-prolinamide

To 2-amino-4,6-dichloropyrimidine (0.328 g, 2.0 mmol) and Λ/,Λ/-dimethyl-L-prolinamide (0.284 g, 2.0 mmol) in CH₃CN (3 ml.) was added Hunig's base (1.05 ml_, 6.0 mmol), and the reaction mixture was heated for 1 hour at 160 ⁰C under microwave conditions. The mixture was concentrated, and the resulting material was partitioned between water (50 ml.) and CH₂CI₂ (50 ml_). The organic layer was separated, and the aqueous layer was further extracted with CH₂CI₂ (2 x 50 ml_). The combined organic layers were washed with water, brine, dried (Na₂SO₄), filtered and concentrated to afford the title compound (210 mg, 39%) as an off-white solid. LC-MS (ES) m/z = 270, 272 [M+H]⁺.

Example 29

1-r2-Amino-6-(1 ,2-dihvdroindazolor4,3-άciri ,5lbenzoxazepin-4-yl)-4-pyrimidinyll-Λ/,Λ/- dimethyl-L-prolinamide

A mixture of 2-acetyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 ,2- dihydroindazolo[4,3-6c][1 ,5]benzoxazepine (305 mg, 0.78 mmol), 1-(2-amino-6-chloro-4- pyrimidinyl)-Λ/,Λ/-dimethyl-L-prolinamide (210 mg, 0.78 mmol), and K₃PO₄ (281 mg, 1.32 mmol) in 1 ,4-dioxane (3 ml.) and water (1 ml.) was degassed with N₂ for 10 minutes into a microwave vial. Tricyclohexylphosphine (10.9 mg, 0.039 mmol) and Pd₂(dba)₃ (14.3 mg, 0.016 mmol) were added, and N₂ was bubbled through the resulting mixture for an additional 5 minutes. The vessel was sealed, and the reaction mixture was stirred overnight at 100 ⁰C. The reaction was cooled to room temperature, and the 1 ,4-dioxane layer was separated and filtered. Flash chromatography on SiO₂ (gradient: 100% CHCI₃ to 90:10:1 CHCI₃:CH₃OH:NH₄OH) afforded the title compound (132 mg, 36%) as a light brown solid. LC-MS (ES) m/z = 457 [M+H]⁺. ¹H NMR (400 MHz, DMSOd₆): δ 1.72 - 2.35 (m, 4H), 2.84 (bs, 3H), 3.18 (bs, 3H), 3.60 (m, 2H), 5.01 (dd, J = 8.3, 2.8 Hz, 1 H), 5.95 (bs, 2H), [6.13^*, 6.39 (bs, 1 H)], 6.88 (dd, J = 15.2, 1.5 Hz, 1 H), 7.06 (dd, J = 15.2, 1.5 Hz, 1 H), 7.28 (dd, J = 8.1 , 1.3 Hz, 2H), [7.28^*, 7.42 (bs, 1 H)], [7.62^*, 7.80 (bs, 1 H)], 9.51 (s, 1 H), 12.30 (s, 1 H). (^* Denotes minor rotamer).

Intermediate 63 (2/?)-2-[(Phenylmethyl)amino1-1-propanol

To (2/?)-2-amino-1-propanol (4.5 g, 60 mmol) in toluene (120 ml.) was added benzaldehyde (636 ml_). A Dean-Stark trap was placed on the flask, and the reaction mixture was heated to reflux until no further water evolved. The reaction was cooled down to room temperature and concentrated. The resulting residue was dissolved in ethanol (120 ml_), and treated with NaBH₄ (5.67 g, 150 mmol) at 0 ⁰C followed by sufficient 4N HCI in dioxane to adjust the pH to 2. The reaction mixture was stirred overnight at room temperature, and then concentrated in vaccuo. The resulting residue was dissolved in 1 N aq. HCI (200 ml.) and washed with CH₂CI₂ (2 X 100 ml_). The aqueous phase was then adjusted to pH > 13 with 6N aqueous NaOH and extracted with CH₂CI₂ (2 X 150 ml_). The combined organic phase was dried over anhydrous Na₂SO₄, filtered, and concentrated to afford the title compound (9.44 g, 95%) as a colorless oil which solidified under high vacuum. LC-MS (ES) m/z = 166.2 [M+H]⁺

Intermediate 64 (5/?)-5-Methyl-4-(phenylmethyl)-3-morpholinone

To (2/?)-2-[(phenylmethyl)amino]-1-propanol (8.43 g, 51 mmol) in THF (50 mL) was added a solution of K₂CO₃ (21.15 g, 153 mmol) in water (50 mL). To the resulting mixture at 0 ⁰C was added slowly via syringe chloroacetyl chloride (5.7 mL, 71.4 mmol) with vigorous stirring, and the reaction mixture was stirred for 1 hour at 0 ⁰C. A 50% aqueous NaOH solution was added to adjust the pH>13, and the resulting mixture was warmed up overnight to room temperature. The solution was extracted with CH₂CI₂ (2 X 200 mL), and the organic layer was dried (Na₂SO₄), filtered and concentrated to afford the title compound (100% crude yield) as a colorless oil. LC-MS (ES) m/z = 206 [M+H]⁺

Intermediate 65 (3/?)-3-Methyl-4-(phenylmethyl)morpholine

To a solution of (5R)-5-methyl-4-(phenylmethyl)-3-morpholinone (1 1.7 g, 57 mmol) in toluene (140 ml.) at 0 ⁰C was added sodium bis(2-methoxyethoxy)aluminumhydride (Red- Al) (35 ml_, 3 ml_/g of morpholinone) slowly via addition funnel, and the reaction mixture was stirred overnight at 60 ⁰C. The reaction was cooled down to 0 ⁰C and quenched by dropwise addition of 1 N aqueous NaOH (15 ml_). The resulting mixture was partitioned between Et₂O (100 ml.) and of 1 N aqueous NaOH (100 ml_). The organic layer was separated, and the aqueous layer was further extracted with Et₂O (50 ml_). The combined organic layers were dried (Na₂SO₄), filtered and concentrated. The resulting residue was azeotroped with CH₃OH (50 ml.) to afford the title compound (10.69 g) as a colorless oil. LC-MS (ES) m/z = 192 [M+H]⁺

Intermediate 66 (3/?)-3-Methylmorpholine

To (3R)-3-methyl-4-(phenylmethyl)morpholine (10.7 g, 56 mmol) in CH₃OH (1 10 mL) were added 6N aqueous HCI (9.3 mL) and Pd/C (1.07 g, 10 wt%), and the reaction mixture was stirred overnight at room temperature under a H₂ atmosphere (balloon setup). The mixture was filtered through a glass fiber filter, and the filter cake was washed with CH₃OH. The combined filtrate was concentrated and azeotroped with CH₃OH (4 X 100 mL) to afford the HCI salt of the title compound as a yellow oil that solidified under high vacuum (7.91 g). ¹H NMR (400 MHz, CD₃OD): δ 3.95 - 4.05 (m, 2H), 3.77 (m, 1 H), 3.47 - 3.54 (m, 1 H), 3.38 - 3.47 (m, 1 H), 3.30 - 3.34 (m, 1 H), 3.18 - 3.28 (m, 1 H), 1.29 (d, J = 6.3 Hz, 3H). Intermediate 67 4-Chloro-6-[(3/?)-3-methyl-4-morpholinyl1-2-pyrimidinamine

To 2-amino-4,6-dichloropyrimidine (400 mg, 2.44 mmol) and (3R)-3-methylmorpholine (369 mg, 2.68 mmol) in CH₃CN (10 ml.) was added Hunig's base (1.28 ml_, 7.32 mmol) into a sealable tube. The tube was sealed, and the reaction mixture was stirred for 3 days at 100 ⁰C. The mixture was poured onto EtOAc and water. The organic layer was separated, and the aqueous layer was further extracted with EtOAc. The combined organic layers were washed with brine, dried (MgSO₄), filtered and concentrated. Flash chromatography on SiO₂ (gradient: 100% CHCI₃ to 50% EtOAc in CHCI₃) afforded the title compound (410 mg, 74%) as a white solid. LC-MS (ES) m/z = 229, 231 [M+H]⁺.

Example 30

4-(1 ,2-Dihvdroindazolor4,3-άciri ,5lbenzoxazepin-4-yl)-6-r(3/?)-3-methyl-4-morpholinyll-2- pyrimidinamine

Into a sealable tube were placed 4-chloro-6-[(3R)-3-methyl-4-morpholinyl]-2- pyrimidinamine (200 mg, 0.875 mmol), 2-acetyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan- 2-yl)-1 ,2-dihydroindazolo[4,3-6c][1 ,5]benzoxazepine (513 mg, 1.31 mmol), and K₃PO₄ (650 mg, 3.06 mmol). 1 ,4-Dioxane (6 ml.) and water (3 ml.) were added, and N₂ gas was bubbled through the resulting mixture for 10 minutes. Pd₂(dba)₃ (48 mg, 0.05 mmol) was added, and N₂ gas was bubbled through the mixture for an additional 5 minutes. Tricyclohexylphosphine (29.4 mg, 0.105 mmol) was added, the tube was sealed, and the reaction mixture was heated under microwave conditions for 1 hour at 140 ⁰C. The mixture was filtered and the resulting filtrate was poured onto water. A precipitate was formed which was filtered. Flash chromatography on SiO₂ of the resulting solid (gradient: 1 :1 EtOAc/hexanes to 100% EtOAc) afforded the desired product (336 mg, -95% pure by HPLC and ¹H NMR) as an olive solid. A portion of this material (100 mg) was transferred to a submission vial. The rest of the material was treated with hot EtOAc (~5 ml.) and filtered to afford another batch of the desired product (60 mg, N7219-86-B1 , >99% pure by HPLC and ¹H NMR) as an off-white solid. LC-MS (ES) m/z = 416 [M+H]⁺. ¹H NMR (400 MHz, DMSO-de): δ 1.20 (d, J = 6.8 Hz, 3H), 3.12 (m, 1 H), 3.45 (m, 1 H), 3.55 - 3.66 (m, 1 H), 3.67 - 3.79 (m, 1 H), 3.93 (dd, J = 11.1 , 2.8 Hz, 1 H), 4.13 - 4.18 (m, 1 H), 4.52 (m, 1 H), 6.16 (s, 2H), 6.63 (s, 1 H), 6.82 - 6.95 (m, 1 H), 7.01 - 7.13 (m, 1 H), 7.27 (m, 2H), 7.46 (s, 1 H), 7.84 (s, 1 H), 9.51 (s, 1 H), 12.30 (s, 1 H).

Example 31 4-(1 ,2-Dihvdroindazolor4,3-άciπ ,5lbenzoxazepin-4-yl)-6-(4-morpholinyl)-2-pyrimidinamine

A mixture of 4-chloro-6-(4-morpholinyl)-2-pyrimidinamine (300 mg, 1.40 mmol), 2-acetyl-4- (4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 ,2-dihydroindazolo[4,3-

6c][1 ,5]benzoxazepine (601 mg, 1.54 mmol), and K₃PO₄ monohydrate (1.3 g, 5.6 mmol) in 1 ,4-dioxane (8 mL) and water (2 mL) was degassed with N₂ into a microwave vial. Pd₂(dba)₃ ^«CHCI₃ (28.9 mg, 0.028 mmol) and tricyclohexylphosphine tetrafluoroborate (257 mg, 0.70 mmol) were added, the vessel was sealed, and the reaction mixture was heated for 45 minutes at 140 ⁰C under microwave conditions. The upper 1 ,4-dioxane layer was separated and concentrated. The resulting residue was purified by flash chromatography on SiO₂ (gradient: 100% CHCI₃ to 90:10:1 CHCI₃:CH₃OH:NH₄OH). The pure fractions were and concentrated, and the resulting residue was stirred with CH₃OH (5 mL). The suspended product was filtered, washed with CH₃OH and dried to afford the title compound (310 mg, 53%) as a yellow powder. LC-MS (ES) m/z = 402 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 3.66 (m, 8H), 6.19 (bs, 2H), 6.70 (s, 1 H), 6.82 - 6.94 (m, 1 H), 7.01 - 7.14 (m, 1 H), 7.21 - 7.35 (m, 2H), 7.47 (s, 1 H), 7.85 (s, 1 H), 9.51 (s, 1 H), 12.31 (s, 1 H). Intermediate 68 4-Bromo-/V-{4-[(dimethylamino)sulfonyl1-2-hvdroxyphenyl}-2,6-difluorobenzamide

A mixture of 4-bromo-2,6-difluorobenzoic acid (5.0 g, 21.1 mmol) and thionyl chloride (25 ml_, 343 mmol) was stirred for 3 hours at 100 ⁰C. The reaction mixture was concentrated, and the resulting orange oil was taken up in CH₂CI₂ (20 ml_). The resulting mixture was added drop-wise via cannulation to a solution of 4-amino-3-hydroxy-Λ/,Λ/- dimethylbenzenesulfonamide (4.56 g, 21.1 mmol), and Et₃N (5.88 ml_, 42.2 mmol) in CH₂CI₂ (20 ml_). The reaction mixture was stirred overnight at room temperature, and then diluted with water. The phases were separated, and the aqueous phase was further extracted with CH₂CI₂ (3X). The combined organic layers were dried (Na₂SO₄), filtered and concentrated to afford the crude title compound (10.4 g) as a yellow/tan foam. LC-MS (ES) m/z = 435, 437 [M+H]⁺ .

Intermediate 69

3-Bromo-1 -fluoro-Λ/,Λ/-dimethyl-11 -oxo-10, 11 -dihvdrodibenzorά,/iri ,41oxazepine-7- sulfonamide

To a solution of 4-bromo-Λ/-{4-[(dimethylamino)sulfonyl]-2-hydroxyphenyl}-2,6- difluorobenzamide (10.4 g, 23.89 mmol) in DMF (300 ml.) was added K₂CO₃ (6.60 g, 47.8 mmol), and the resulting mixture was stirred overnight at room temperature. The reaction mixture was diluted with saturated aqueous NH₄CI, and the resulting precipitate was collected by vacuum filtration to afford the title compound (8.6 g, 87%) as an off-white solid. LC-MS (ES) m/z = 415, 417 [M+H]⁺. Intermediate 70 4-Bromo-Λ/,Λ/-dimethyl-1 ,2-dihvdroindazolo[4,3-άc1[1 ,51benzoxazepine-8-sulfonamide

To 3-bromo-1-fluoro-Λ/,Λ/-dimethyl-1 1-oxo-10,1 1-dihydrodibenzo[6,/][1 ,4]oxazepine-7- sulfonamide (0.2 g, 0.48 mmol) in toluene (4 ml.) was added Lawesson's reagent (0.4 g,

0.99 mmol), and the resulting mixture was stirred overnight at 100 ⁰C into a sealed tube.

The reaction mixture was filtered, and the solid was washed with toluene. This material

(thioamide intermediate) was taken up in 1 ,4-dioxane (10 ml.) and treated with hydrazine monohydrate (0.030 ml_). The resulting cloudy solution was stirred for 2 hours at 85 ⁰C. Upon cooling, a precipitate was formed which was filtered to afford the title compound (59 mg, 27%) as an off-white solid. LC-MS (ES) m/z = 409, 411 [M+H]⁺ .

Intermediate 71

2,1 1-Diacetyl-4-bromo-Λ/,Λ/-dimethyl-2,1 1-dihvdroindazolor4,3-άciπ ,5lbenzoxazepine-8- sulfonamide

To 4-bromo-Λ/,Λ/-dimethyl-1 ,2-dihydroindazolo[4,3-6c][1 ,5]benzoxazepine-8-sulfonamide (160 mg, 0.391 mmol) was added acetic anhydride (5 ml_, 53 mmol), and the reaction mixture was stirred for 3 days at 100 ⁰C into a sealed tube. The mixture was concentrated and co-evaporated with ethanol to afford a yellow solid. Flash chromatography on Siθ₂ (gradient: 100% CHCI₃ to 90:10 CHCI₃:acetone) afforded the title compound (140 mg, 72%) as a yellow solid. LC-MS (ES) m/z = 493, 495 [M+H]⁺. Intermediate 72

2,1 1-Diacetyl-Λ/,Λ/-dimethyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-2,1 1- dihydroindazolo[4,3-άc1[1 ,51benzoxazepine-8-sulfonamide

A mixture of 2,11-diacetyl-4-bromo-Λ/,Λ/-dimethyl-2,1 1-dihydroindazolo[4,3- 6c][1 ,5]benzoxazepine-8-sulfonamide (0.2 g, 0.41 mmol), bis(pinacolato)diboron (0.103 g, 0.405 mmol) and potassium acetate (0.139 g, 1.42 mmol) in 1 ,4-dioxane (3.5 ml.) was degassed with N₂ for -10 minutes. PdCI₂(dppf)-CH₂CI₂ (0.017 g, 0.020 mmol) was added, and the resulting mixture was degassed for an additional 2 minutes. The vial was sealed, and the reaction mixture was stirred overnight at 100 ⁰C. The reaction was cooled to room temperature and diluted with CH₂CI₂ and water. The organic layer was separated, the aqueous layer was further extracted with CH₂CI₂, and the combined organic layers were concentrated. The resulting dark residue was taken up in CH₂CI₂ and precipitated with hexanes to afford the title compound (0.5 g) as a gray solid. LC-MS (ES) m/z = 541 [M+H]⁺.

Example 32

4-[2-Amino-6-(4-morpholinyl)-4-pyrimidinyl1-Λ/,Λ/-dimethyl-1 ,2-dihvdroindazolo[4,3- άciπ ,51benzoxazepine-8-sulfonamide

A mixture of 2,1 1-diacetyl-/V,/V-dimethyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)- 2,1 1-dihydroindazolo[4,3-ιbc][1 ,5]benzoxazepine-8-sulfonamide (0.6 g, 1.1 1 mmol), 4- chloro-6-(4-morpholinyl)-2-pyrimidinamine (0.238 g, 1.1 1 mmol), and K₃PO₄ (0.471 g, 2.22 mmol) in 1 ,4-dioxane (8 ml.) and water (3 ml.) was degassed with N₂ for ~5 minutes into a sealable tube. Pd₂(dba)₃ (10.17 mg, 0.011 mmol) was added, and the resulting mixture was degassed for an additional 3 minutes. Tricyclohexylphosphine (6.85 mg, 0.024 mmol) was added and the solution was degassed for 3 additional minutes. The vial was sealed, and the reaction mixture was stirred overnight at 100 ⁰C. The reaction was diluted with CH₂CI₂ and water, the layers were separated, and the aqueous layer was further extracted with CH₂CI₂. The combined organic layers were concentrated, and the resulting dark residue was taken up in ethanol and precipitated with hexanes. The resulting solid was filtered and dry loaded onto ~1 g of SiO₂. Flash chromatography on SiO₂ (gradient: 100% CHCI₃ to 90:10:1 CHCI₃:CH₃OH:NH₄OH afforded the title compound (26 mg, 5%) as a tan solid. LC-MS (ES) m/z = 509 [M+H]⁺. ¹H NMR (400 MHz, DMSO- d₆): δ 2.62 (s, 6H), 3.66 (m, 8H), 6.20 (bs, 2H), 6.73 (s, 1 H), 7.41-7.49 (m, 2H), 7.60 (m, 2H), 7.95 (s, 1 H), 10.34 (s, 1 H), 12.60 (s, 1 H).

Intermediate 73 Λ/-(2-Aminophenyl)-4-bromo-2,6-difluorobenzamide

To 4-bromo-2,6-difluorobenzoic acid (15 g, 63.3 mmol) was added thionyl chloride (75 ml_), and the mixture was stirred for 3 h at 85 ⁰C. The mixture was concentrated, and the resulting residue was evaporated (2X) from toluene. The residue was dissolved in CH₂CI₂ (20 ml_), and the resulting solution was added slowly to a solution of 1 ,2-benzenediamine (6.84 g, 63.3 mmol) in CH₂CI₂ (60 ml.) and Et₃N (10 ml_, 72.1 mmol) at ⁰C. The reaction mixture was stirred overnight at ambient temperature, then diluted with a water/CH₂CI₂ mixture. The resulting wet paste was filtered and washed with EtOAc and TBME (tert- butylmethylether). The cake was dried under vacuum, washed with water, and dried under vacuum again. The dried solids were sonicated with TBME (250 ml.) and filtered. This was repeated 4X. The combined filtrates were concentrated, triturated in a mixture of TBME and hexane, and filtered to afford the title compound (4.58 g). The initial filtrates from various washes were combined, and the organic phase was separated, dried (Na₂SO₄), filtered, and concentrated. The resulting residue was triturated in TBME and hexane and filtered to afford another batch of the title compound (9.20 g) as a white solid. LC-MS (ES) m/z = 326, 328 [M+H]⁺.

Intermediate 74 3-Bromo-1-fluoro-5,10-dihvdro-11 H-dibenzorά,eiri ,4ldiazepin-1 1-one

To a stirred solution of Λ/-(2-aminophenyl)-4-bromo-2,6-difluorobenzamide (8.45 g, 25.8 mmol) in tetrahydrofuran (THF) (230 ml.) at room temperature was added portionwise sodium hydride (60% wt, 3.38 g, 85 mmol), and the reaction mixture was stirred overnight at reflux. The reaction was cooled to 0 ⁰C and quenched with the dropwise addition of 6N HCI dropwise until the pH reached -5-6. The resulting mixture was concentrated, and the resulting residue was taken up in a mixture of hexane and water. The suspension was briefly sonicated, followed by filtration. Drying under vacuum afforded the title compound (9.05 g) as a tan solid. LC-MS (ES) m/z = 306, 308 [M+H]⁺.

Intermediate 75

3-Bromo-1 -fluoro-5, 10-dihvdro-11 /-/-dibenzorά.eiπ ,4ldiazepine-11 -thione

To 3-bromo-1 -fluoro-5, 10-dihydro-1 1H-dibenzo[ό,e][1 ,4]diazepin-11 -one (12.47 g, 40.6 mmol) in propionitrile (130 mL) was added Lawesson's reagent (24.63 g, 60.9 mmol), and the reaction mixture was stirred for 3 hours at 100 ⁰C. The mixture was filtered, and the solid was washed with propionitrile and toluene. The solid and the filtrate were combined and purified via flash chromatography on SiO₂ (gradient: 100% CHCI₃ to 5% EtOAc/ 95%

CHCI3) to afford the title compound (3.00 g). The column was washed with 60% EtOAc in chloroform to elute off the rest of the material. The late eluting fractions were combined and concentrated to afford a solid, which was triturated in CHCI3 and filtered to afford additional title compound (5.0 g). The filtrate was purified by flash column to afford another 0.45 g of the title compound as a yellow solid. LC-MS (ES) m/z = 322, 324 [M+H]⁺.

Intermediate 76

4-Bromo-2,6-dihydro-1 /-/-indazolor3,4-άciπ ,51benzodiazepine

To 3-bromo-1-fluoro-5,10-dihydro-1 1 /-/-dibenzo[6,e][1 ,4]diazepine-1 1-thione (5.75 g, 17.79 mmol) in 1 ,4-dioxane (82 ml.) was added hydrazine monohydrate (2.2 ml_, 44.9 mmol), and the resulting mixture was stirred for 2 hours 80 ⁰C. The reaction was allowed to cool to room temperature, and then filtered. The filtrate was concentrated, and the resulting residue was taken up in water, sonicated briefly, and filtered. Drying under vacuum over P₂O₅ (phosphorous pentoxide) afforded the title compound (4.87) as a tan solid. LC-MS (ES) m/z = 300, 302 [M+H]⁺.

Intermediate 77

2,6,1 1-Triacetyl-4-bromo-6,1 1-dihydro-2/-/-indazolor3,4-άciri ,5lbenzodiazepine

A suspension of 4-bromo-2,6-dihydro-1 /-/-indazolo[3,4-6c][1 ,5]benzodiazepine (4.75 g, 15.8 mmol) in acetic anhydride (30 mL) was heated at 100 ⁰C for 18 hours. The mixture was cooled and concentrated, and the resulting residue was chased with ethanol and EtOAc, followed by drying under vacuum. The resulting residue was taken up in TBME (5 mL) and hexane (50 mL), resulting in a suspension. Filtration and drying under vacuum afforded the title compound (5.82 g) as a tan solid. LC-MS (ES) m/z = 426, 428 [M+H]⁺. Intermediate 78

2,6,1 1-Triacetyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-6,11-dihvdro-2/-/- indazolo[3,4-άc1[1 ,51benzodiazepine

A mixture of 2,6,1 1-triacetyl-4-bromo-6,11-dihydro-2/-/-indazolo[3,4-

6c][1 ,5]benzodiazepine (9.05 g, 21.2 mmol), bis(pinacolato)diboron (5.38 g, 21.2 mmol), KOAc (5.20 g, 53.0 mmol), and PdCI₂(dppf)-CH₂CI₂ adduct (1.21 g, 1.48 mmol) in 1 ,4- dioxane (135 ml.) was degassed and back flushed (4X) with N₂, and the reaction mixture was stirred overnight at 100 ⁰C. The mixture was cooled and concentrated, and the resulting residue was partitioned between EtOAc (300 ml.) and water (100 ml_). The resulting mixture was sonicated and filtered through celite, and the filtrate was partitioned between EtOAc and water. The organic layer was separated, and the aqueous layer was further extracted with EtOAc (150 ml_). The combined organic layers were dried (Na₂SO₄), filtered and concentrated. The resulting residue was dissolved in a mixture of CH₂CI₂ (10 ml.) and EtOAc (10 ml_), and the resulting solution was added dropwise to hexane (250 ml.) to precipitate the product. The precipitate was filtered and dried under vacuum to afford the desired boronate esters (4.65 g) as a mixture of triacetyl and diacetyl derivatives. The celite cake mentioned above was taken up in CH₂CI₂ (250 ml_), sonicated and filtered. The cake was further washed with CH₂CI₂ (100 ml_). The combined filtrate was concentrated in vacuo. The solids were triturated in a mixture of CH₂CI₂ (10 ml.) and hexane (80 ml_), and then filtered to afford the title compound (4.27 g) as a beige solid. LC-MS (ES) m/z = 475 [M+H]⁺.

Example 33 4-(2,6-Dihvdro-1 /-/-indazolor3,4-άciri ,51benzodiazepin-4-yl)-6-(4-morpholinyl)-2- pyrimidinamine

A mixture of 2,6,1 1-triacetyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-6,11-dihydro- 2H-indazolo[3,4-6c][1 ,5]benzodiazepine (2.0 g, 4.22 mmol), 4-chloro-6-(4-morpholinyl)-2- pyrimidinamine (0.91 g, 4.22 mmol), Pd₂(dba)₃ (0.19 g, 0.21 mmol), tricyclohexylphosphine (0.13 g, 0.46 mmol), and K₃PO₄ (1.52 g, 7.17 mmol) in 1 ,4-dioxane (30 ml.) and water (10 ml.) was degassed and back flushed with nitrogen (4X), and the reaction mixture was stirred for 24 hours at 100 ⁰C. The mixture was concentrated, and the residue was taken up in water (100 ml.) as a suspension. The mixture was filtered and dried under vacuum to afford the crude mono and diacetyl derivatives of the title compound (2.33 g). Flash chromatography on SiO₂ (eluent: 90:10:1 CHCl3:CH3θH:NH₄OH) provided a sample of the diacetyl derivative (430 mg). To this material were added CH₃OH (75 ml_), ethanol (25 ml.) and concentrated HCI (5 ml_), and the resulting mixture was refluxed for 2 hours. The reaction was concentrated, and the resulting residue was taken up in ethanol (45 ml_), isopropanol (45 ml_), and cone. HCI (6 ml_). The resulting mixture was refluxed for 16 h, and then concentrated. The residue was taken up in CH₃CN (30 ml.) as a suspension and filtered. Drying under vacuum over P₂O₅ gave the di-hydrochloride salt of the monohydrate title compound (243 mg) of as a brownish solid. LC-MS (ES) m/z = 401 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 3.72 (bs, 4H), 3.82 (bs, 2H), 3.91 (bs, 2H), 6.75 (m, 4H), 6.82 (s, 1 H), 6.95 (s, 1 H), 7.13 (m, 2H), 7.28 (s, 1 H), 9.14 (bs, 1 H), 9.22 (s, 1 H), 12.44 (bs, 1 H), 12.78 (s, 1 H).

Intermediate 79 1-(Phenylmethyl)cvclopropanamine

To a solution of phenylacetonitrile (3 g, 25.6 mmol) and tetraisopropylorthotitanate (8 ml_, 27.2 mmol) in Et₂O/THF (1/1 ,100 ml.) was added ethylmagnesiumbromide (7.85 g,58.9 mmol) dropwise at room temperature. The exothermic mixture was stirred at room temperature for 1 hour. Then BF₃ ^«Et₂0 (7.27 g, 51.2 mmol) was added dropwise and the mixture was stirred at room temperature for 1 hour. The mixture was poured into a cold aqueous solution of sodium hydroxide (10%) and diluted with EtOAc. The mixture was filtered, and the organic layer was washed with water and brine, dried (MgSO₄), filtered and concentrated in vacuum. The resulting solids were purified by reverse phase chromatography using CH₃CN in water (0.08% ammonium hydrogen carbonate) (gradient: from 37% to 47% in 7min; flowrate:40 mL/min). The pH of the solution was adjusted to 2 with concentrated HCI and concentrated in vacuum to afford the HCI salt of the title compound (700 mg) as a white solid. LC-MS (ES) m/z = 148 [M+H]⁺.

Intermediate 80 6-Chloro-Λ/⁴-ri-(phenylmethyl)cvclopropyll-2,4-pyrimidinediamine

A mixture of 1-(phenylmethyl)cyclopropanamine_hydrochloride (530 mg, 2.88 mmol), 4,6- dichloro-2-pyrimidinamine (295 mg, 1.80 mmol), Et₃N (91 1 mg, 9 mmol) and K₂CO₃ (249 mg ,1.80 mmol) in ethanol (6 ml.) was stirred and heated at 140 ⁰C for 4 hours in a Biotage Initiator microwave synthesizer. The mixture was cooled to room temperature and concentrated to dryness. The resulting solids were partitioned between EtOAc and water. The organic layer was separated, dried (Na₂SO₄ ), concentrated to dryness and purified by reverse phase chromatography using CH₃CN in water from 32% to 42% (0.05% trifluoroacetic acid in water) in 8 min to afford the title compound (204 mg) as a white solid. LC-MS (ES) m/z = 275 [M+H]⁺.

Example 34

B-d ^-DihvdroindazoloK^-άcifi .δibenzoxazepin-^vD-Λ^-fi-fphenylmethvDcvclopropyll-

2,4-pyrimidinediamine

To a mixture of ⁴6-chloro-Λ/⁴-[1-(phenylmethyl)cyclopropyl]-2,4-pyrimidinediamine (137 mg, 0.5 mmol), 2-acetyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 ,2- dihydroindazolo[4,3-6c][1 ,5]benzoxazepine (254 mg, 0.65 mmol), tricyclohexylphosphine (2.8 mg,10 μmol), K₂CO₃ (207 mg, 1.5 mmol) and Pd₂(dba)₃ (4.6 mg, 5 μmol) were added 1 ,4-dioxane (4 ml.) and water (6 ml_). The tube was sealed, and the reaction mixture was stirred at 140 ⁰C for 1 hour in a Biotage Initiator microwave synthesizer. The mixture was cooled to room temperature, and washed between water and EtOAc. The organic layer was separated, dried over Na₂SO₄, filtered, concentrated to dryness, and purified by SSGC using a gradient of 3:1 petroleum ether/EtOAc to 1 :1 petroleum ether/EtOAc to 1 :5 petroleum ether/EtOAc as eluent to afford the title compound (35.3 mg) as a brown solid. LC-MS (ES) m/z = 462 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): 5 0.81 (d, AH), 2.97 (s, 2H), 5.99 (s, 2H), 6.32 (s, 1 H), 6.87 - 6.91 (m, 1 H), 7.04 - 7.08 (m, 1 H), 7.18 - 7.21 (m, 3H), 7.26 - 7.31 (m, 6H), 7.65 (s, 1 H), 9.46 (s, 1 H), 12.26 (s, 1 H).

Intermediate 81 2,2-Dimethyl-3-phenylpropanoic acid

To a solution of diisopropylamine (48.91 g, 483 mmol) in THF (100 ml.) under nitrogen at 0 ⁰C was added a solution of 2.5M n-butyllithium in hexane (179 ml_, 447.5 mmol.) followed by the dropwise addition of isobutyric acid (15.77 grams, 179 mmols). The reaction mixture was stirred at room temperature for 1.5 hours, then cooled to -15 ⁰C. Benzyl chloride (22.66 g, 179 mmol) was added dropwise while maintaining the temperature below -5 ⁰C, and the resulting mixture was stirred at room temperature overnight. The reaction mixture was partitioned between Et₂O and water. The aqueous layer was acidified by the addition of concentrated HCI (36%, 50 ml_), and extracted with Et₂O (4 X 150 ml_), The organic layer was dried over MgSO₄ and concentrated to afford the title compound (21.36 g) as a colorless liquid. LC-MS (ES) m/z = 177 [M-H]^".

Intermediate 82

2-Methyl-1 -phenyl-2-propanamine

DPPA (16.87 g, 61.31 mmol) was added with external cooling to a stirred solution of 2,2- dimethyl-3-phenylpropanoic acid (10.21 g, 57.30 mmol) and triethylamine (6.20 g, 61.3 mmol) in dry toluene (100 ml_). A slightly exothermic reaction commenced and was completed after about 1 hour. The reaction mixture was stirred for an additional 1 hour at room temperature, followed by refluxing for 3 hours. The solution was cooled and washed with water (3 X 100 ml_), and the toluene phase was separated, dried over Na₂SO₄, and evaporated in vacuum. A mixture of 15% hydrochloric acid (20 ml.) and acetic acid (20 ml.) was added, and the resulting mixture was stirred at room temperature overnight. The mixture was partitioned between EtOAc and water. The aqueous layer was extracted with

EtOAc (4 X 50 ml_), and the aqueous was concentrated in vacuum to afford the HCI salt of the title compound (5.21 g) as a white solid. LC-MS (ES) m/z = 150 [M+H]⁺.

Intermediate 83 δ-Chloro-Λ^-d .i-dimethyl^-phenylethvD^^-pyrimidinediamine

A mixture of 2-methyl-1-phenyl-2-propanamine hydrochloride (742 mg, 4 mmol), 4,6- dichloro-2-pyrimidinamine (438 mg, 2.67 mmol) and Hunig's base (1.55 g, 12 mmol) in

CH₃CN (8 mL) was stirred and heated for 6 hours at 160 ⁰C in a Biotage Initiator microwave synthesizer. The mixture was cooled to room temperature and concentrated to dryness. The resulting solids were partitioned between EtOAc and water, and the organic layer was dried over Na₂SO₄, filtered and concentrated to dryness. Purification by reverse phase chromatography using CH₃CN in water from 45% to 65% (0.08% ammonium hydrogen carbonate) in 18 minutes, afforded the title compound (373 mg) as a white solid.

LC-MS (ES) m/z = 277 [M+H]⁺. Example 35

B-d ^-DihvdroindazoloK^-άcifi .δibenzoxazepin-^vD-Λ^-d .i-dimethyl^-phenylethyl)-

2,4-pyrimidinediamine

To a mixture of 6-chloro-Λ/⁴-(1 ,1-dimethyl-2-phenylethyl)-2,4-pyrimidinediamine (172 mg, 0.62 mol), 2-acetyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 ,2- dihydroindazolo[4,3-6c][1 ,5]benzoxazepine (317 mg, 0.81 mmol), tricyclohexylphosphine (5.6 mg, 20 μmol), K₂CO₃ (257 mg, 1.86 mmol), and Pd₂(dba)₃ (5.7 mg, 6.2 μmol) were added 1 ,4-dioxane (4 ml.) and water (6 ml_). The tube was sealed, and the reaction mixture was stirred at 140 ⁰C for 100 minutes in a Biotage Initiator microwave synthesizer. The mixture was cooled to room temperature and washed between water and EtOAc. The organic layer was dried over Na₂SO₄, filtered, concentrated to dryness, and purified by reverse phase chromatography using CH₃CN in water from 55% to 55% (0.08% ammonium hydrogen carbonate). The resulting material was freezed dried and purified further by reversed phase HPLC with CH₃CN in water (0.01 % ammonium hydrogen carbonate) (gradient: from 70% to 82%) to afford the title compound (34.1 mg) as a light yellow solid. LC-MS (ES) m/z = 464 [M+H]⁺. ¹H NMR (400 MHz,DMSO-d₆): δ 1.35 (s, 6H), 3.26 (s, 2H), 6.10 (s, 2H), 6.41 (s, 2H), 6.86 - 6.90 (m, 1 H), 7.04 - 7.08 (m, 1 H), 7.1 1 (d, 2H), 7.14 - 7.18 (m, 1 H), 7.22 - 7.29 (m, 5H), 7.66 (s, 1 H), 9.50 (s, 1 H), 12.29 (s, 1 H).

Intermediate 84 4-Chloro-6-r(2/?)-2-methyl-1-pyrrolidinyll-2-pyrimidinamine

A mixture of 4,6-dichloro-2-pyrimidinamine (680 mg, 4.17 mmol), (2/?)-2-methylpyrrolidine

(360mg, 4.23mmol) and Hunig's base (2 mL) in CH₃OH (3 mL) was heated at 100⁰C for 2 hours in a microwave synthesizer. The reaction mixture was evaporated and purified by silica column chromatography eluting with petroleum etheπTHF (1 :1 ) to afford the title compound (480 mg) as a yellow solid. LC-MS (ES) m/z = 213 [M+H]⁺.

Example 36

4-(1 ,2-Dihvdroindazolor4,3-άciri ,5lbenzoxazepin-4-yl)-6-r(2/?)-2-methyl-1-pyrrolidinyll-2- pyrimidinamine

A mixture of 4-chloro-6-[(2/?)-2-methyl-1-pyrrolidinyl]-2-pyrimidinamine (480 mg, 2.26 mmol), 2-acetyl-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)-1 ,2-dihydroindazolo [4,3-

6c][1 ,5]benzoxazepine (1.1 g, 2.9 mmol), tricyclohexylphosphine (15 mg, 0.057 mmol), and K₂CO₃ (935 mg, 6.78 mmol) in water (10 ml.) and 1 ,4-dioxane (15 ml.) was protected with nitrogen. Pd₂(dba)₂ (31 mg, 0.027 mmol) was added, and the reaction was heated to

140 ⁰C for 1 hour in a microwave synthesizer. Upon cooling, the solution was decanted away from solids and concentrated to dryness. The resulting oil was purified by reversed phase HPLC to afford the title compound (47 mg) as a yellow solid. LC-MS (ES) m/z = 400

[M+H]⁺. ¹H NMR (400 MHz, DMSOd₆): δ 1.20 (d, J = 6.4 Hz, 3H), 1.67 (s, 1 H), 1.92 - 2.02

(m, 3H), 3.39 - 3.58 (m, 2H), 4.26 (s, 1 H), 5.99 (s, 2H), 6.32 (s, 1 H), 6.88 (t, J = 8.0 Hz,

1 H), 7.06 (t, J = 8.4 Hz, 1 H), 7.28 (d, J = 8.4 Hz, 2H), 7.39 (s, 1 H), 7.78 (s, 1 H), 9.47 (s, 1 H), 12.24 (s, 1 H).

Intermediate 85 4-Chloro-6-[2-(1-methylethyl)-1-pyrrolidinyll-2-pyrimidinamine

To a suspension of 4,6-dichloro-2-pyrimidinamine (0.5 g, 3.05 mmol) and K₂CO₃ (1.05 g, 7.63 mmol) in ethanol (3.0ml) was added 2-(1-methylethyl)pyrrolidine hydrochloride (0.46 g, 6.10 mmol), and the reaction mixture was heated at 140 ⁰C under microwave conditions with stirring for 1 hour. The mixture was filtered and the solution was concentrated. The residue was dissolved in EtOAc (100 ml_), and the resulting solution was poured onto water (150 ml_). The organic layer was separated, and the aqueous layer was further extracted with EtOAc (2 X 100 ml_). The combined organic layers were dried (Na₂SO₄), filtered, and concentrated to afford the crude title compound (0.55 g) as a brown solid. LC- MS (ES) m/z = 241 [M+H]⁺.

Example 37

4-(1 ,2-Dihydroindazolor4,3-άciπ ,5lbenzoxazepin-4-yl)-6-r2-(1 -methylethvD-1 -pyrrolidinyll-

2-pyrimidinamine

To a suspension of 4-chloro-6-[2-(1-methylethyl)-1-pyrrolidinyl]-2-pyrimidinamine (0.35 g, 1.45 mmol), 2-acetyl-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 ,2-dihydroindazolo [4,3-_5c][1 ,5]benzoxazepine (0.68 g, 1.74 mmol), K₂CO₃ (0.60 g, 4.35 mmol) and tricyclohexylphosphine (10 mg, 0.04 mmol) in 1 ,4-dioxane (6.0ml) and water (4.0ml) was added Pd₂(dba)₃ (10 mg, 0.01 mmol) under nitrogen, and the mixture was heated at 140 ⁰C under microwave conditions with stirring for 1 hour. The mixture was poured onto water (150 ml.) and EtOAc (100 ml_). The organic layer was separated, and the aqueous layer was further extracted with EtOAc (2 X 150 ml_). The combined organic layers were washed with brine (150ml), dried (Na₂SO₄), filtered and concentrated. The resulting residue was purified by reverse chromatography using CH₃CN in water from 30% to 40% (0.5% ammonium hydrogen carbonate in water) to give the title compound (53 mg) as a yellow solid. LC-MS (ES) m/z = 428 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): δ θ.78 - 0.79 (d, J = 7.2 Hz, 3H), 0.92 (d, J = 6.8 Hz, 3H), 1.85 - 1.95 (m, 4H), 2.34 - 2.40 (m, 2H), 3.45 - 3.57 (m, 2H), 6.02 (s, 1 H), 6.35 (s, 2H), 6.85 - 6.90 (m, 1 H), 7.03 - 7.07 (m, 1 H), 7.38 (s, 1 H), 7.77 (s, 1 H), 9.49 (s, 1 H), 12.27 (s, 1 H).

Intermediate 86

Methyl 3-cvclopentyl-3-oxopropanoate

To a solution of cyclopentanecarboxylic acid (10.0 g, 87.6 mmol) and DMF (0.1 mL) in CH₂CI₂ (100 mL) was added oxalyl chloride (16.68 g, 131.42 mmol) dropwise slowly at 0 ⁰C. The reaction mixture was then stirred at ambient temperature for 2 hours and distilled in vacuo to afford cyclopentanecarbonyl chloride (6.71 g) as a pale yellow liquid.

To a stirring solution of 2,2-dimethyl-1 ,3-dioxane-4,6-dione (6.63 g, 46.01 mmol), pyridine (7.5 mL, 92.02 mmol) in CHCI₃ (150 mL) was added cyclopentanecarbonyl chloride (6.71 g, 50.61 mmol) in CHCI₃ (30 mL) dropwise slowly at 0 ⁰C and stirred for 1 hour. The reaction mixture was allowed to warm up to ambient temperature and stirred overnight. 1 N aqueous HCI (100 mL) was added, then extracted with CHCI₃ (3 X 60 mL), and the combined organic layers were washed with water (2 X 80 mL), dried with Na₂SO₄, filtered and concentrated. CH₃OH (250 mL) was added, and the solution was heated to 80 ⁰C and refluxed for 3h. Concentrating and distilling under reduced pressure afford the title compound (7.40 g) as brown oil.

Intermediate 87 4-Chloro-6-cvclopentyl-2-pyrimidinamine

To methyl methyl S-cyclopentyl-S-oxopropanoate (7.40 g, 43.48 mmol) and guanidine hydrochloride (4.99 g, 52.18 mmol) in CH₃OH (200 mL) was added potassium tert- butoxide (24.39 g, 217.40 mmol) at ambient temperature over 15 minutes under vigorous stirring. Then the reaction mixture was stirred overnight and filtered. The solution was concentrated to 20 mL, diluted with water (20 mL) and the pH was adjusted to 5 by addition of 6N HCI. The resulting white precipitate was collected by filtration and dessicated to afford 2-amino-6-cyclopentyl-4(1 /-/)-pyrimidinone (5.03 g). A mixture of 2-amino-6-cyclopentyl-4(1 H)-pyrimidinone (5.03 g, 28.07 mmol) in phosphorous oxychloride (55.0 ml_, 574.1 mmol) was heated to 120 ⁰C and refluxed for 2 hours. The mixture was evaporated, treated with ice-water, and filtered to obtain a mixture of the title compound and 4-chloro-6-cyclopentylpyrimidin-2-ylphosphoramidic acid (2.1 Og) as a black solid.

Example 38 4-Cvclopentyl-6-(1 ,2-dihvdroindazolor4,3-άciri ,5lbenzoxazepin-4-yl)-2-pyrimidinamine

A mixture of the crude 4-chloro-6-cyclopentyl-2-pyrimidinamine and 4-chloro-6- cyclopentylpyrimidin-2-ylphosphoramidic acid (0.35 g), 2-acetyl-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)-1 ,2-dihydroindazolo [4,3-6c][1 ,5]benzoxazepine (0.762 g, 1.95 mmol), Pd₂(dba)₃ (18 mg, 0.02 mmol), tricyclohexylphosphine (14 mg, 0.05 mmol) and K₂CO₃ (0.978 g, 7.08 mmol) in 1 ,4-dioxane (5.0 ml.) and water (2.5 ml.) was reacted in a Biotage Initiator microwave synthesizer at 140 ⁰C for 1 hour. Upon cooling, the mixture was concentrated, and water (30 ml.) was added. The resulting mixture was filtered, and the crude product was purified via reversed-phase flash column chromatography to afford the title compound (89 mg) as a yellow solid. LC-MS (ES) m/z = 385 [M+H]⁺. ¹H NMR (400 MHz, DMSOd₆): δ 1.66 (m, 2H), 1.81 (m, 4H), 1.99 (m, 2H), 3.04 (m, 1 H), 6.73 (s, 2H), 6.90 (m, 1 H), 7.08 (m, 1 H), 7.20 (s, 1 H), 7.28 (m, 2H), 7.48 (s, 1 H), 7.87 (s, 1 H), 9.55 (s, 1 H), 12.41 (s, 1 H).

Intermediate 88 Methyl 3-oxopentanoate

O O

O^'

To a solution of propionic acid (10.0 g, 135.0 mmol) and DMF (0.1 ml.) in CH₂CI₂ (100 ml.) was added oxalyl chloride (25.7 g, 202.5 mmol) dropwise slowly at 0 ⁰C. The reaction mixture was then stirred at ambient temperature for 2 hours, and distilled in vacuo to afford propionyl chloride (6.98 g) as a colorless liquid.

To a stirring solution of 2,2-dimethyl-1 ,3-dioxane-4,6-dione (9.89 g, 68.65 mmol) and pyridine (1 1.2 ml_, 137.3 mmol) in CHCI3 (150 ml.) was added propionyl chloride (6.98 g, 75.44 mmol) in CHCI₃ (30 ml.) dropwise slowly at 0 ⁰C and stirred for 1 hour. The reaction mixture was allowed to warm up to ambient temperature and stirred overnight. 1 N aqueous HCI (100 ml.) was added, and the resulting mixture was then extracted with

CHCI3 (3 X 60 ml_). The combined organic layers were washed with water (2 X 80 ml_), dried with Na₂SO₄, filtered and concentrated. CH₃OH (250 ml.) was added, and the solution was heated to 80 ⁰C and refluxed for 3 hours. Concentrating and distilling under reduced pressure afforded the title compound (6.82 g) as yellow oil.

Intermediate 89 4-Chloro-6-ethyl-2-pyrimidinamine

To a mixture of methyl 3-oxopentanoate (6.82 g, 52.41 mmol) and guanidine hydrochloride (6.01 g, 62.9 mmol) in CH₃OH (20OmL) was added potassium te/t-butoxide

(29.39bg, 262.0 mmol) at ambient temperature over 15 minutes under vigorous stirring.

Then the reaction mixture was stirred overnight and filtered. The solution was concentrated to 20 ml_, diluted with water (20 ml_), and the pH adjusted to 5 by addition of

6N HCI. The resulting white precipitate was collected by filtration and dessicated to afford

2-amino-6-ethyl-4(1 H)-pyrimidinone (4.2Og).

A mixture of 2-amino-6-ethyl-4(1 /-/)-pyrimidinone (4.20 g, 30.18 mmol) in phosphorous oxychloride (31.4 ml_, 328.0 mmol) was heated to 120 ⁰C and refluxed for 2 hours. The mixture was evaporated and treated with ice-water. The resulting mixture was filtered to obtain crude title compound as a yellow solid (7.0 g). The crude product also contains 4- chloro-β-ethylpyrimidin^-ylphosphoramidic acid. Example 39 4-(1 ,2-Dihvdroindazolo[4,3-ac1[1 ,51benzoxazepin-4-yl)-6-ethyl-2-pyrimidinamine

A mixture of the above crude 4-chloro-6-ethyl-2-pyrimidinamine (0.350 g, 2.22 mmol), 2- acetyl-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 ,2-dihydroindazolo [4,3-

6c][1 ,5]benzoxazepine (0.956 g, 2.45 mmol), Pd₂(dba)₃ (18 mg, 0.02 mmol), tricyclohexylphosphine (14 mg, 0.05 mmol) and K₂CO3 (1.227 g, 8.88 mmol) in 1 ,4- dioxane (5.0 ml.) and water (2.5 ml.) was reacted in a Biotage Initiator microwave synthesizer at 140 ⁰C for 1 hour. Upon cooling, the mixture was concentrated, and water (30 ml.) was added. The resulting mixture was filtered, and the crude product was purified via reversed-phase flash column chromatography to afford the title compound (45 mg) as a brown solid. LC-MS (ES) m/z = 345 [M+H]⁺. ¹H NMR (400 MHz, DMSOd₆): δ 1.26 (t, J = 7.6 Hz, 3H), 2.61 (m, 2H), 6.57 (s, 2H), 6.90 (m, 1 H), 7.07 (m, 1 H), 7.15 (s, 1 H), 7.27 (m, 2H), 7.46 (s, 1 H), 7.84 (s, 1 H), 9.49 (s, 1 H), 12.34 (s, 1 H).

Intermediate 90 Methyl 3-oxohexanoate

O O

CT

To a stirring solution of 2,2-dimethyl-1 ,3-dioxane-4,6-dione (22.14 g, 153.58 mmol) and pyridine (25.0 ml_, 307.2 mmol) in CHCI₃ (250 ml.) was added butyl chloride (18.0 g, 168.94 mmol) in CHCI3 (50 ml.) dropwise at 0 ⁰C and stirred for 1 hour. The reaction mixture was allowed to warm up to ambient temperature and stirred overnight. 1 N aqueous HCI (150 ml.) was added, and the resulting mixture was then extracted with CHCI₃ (3 X 150 ml_). The combined organic layers were washed with water (2 X 100 ml_), dried over Na₂SO₄, filtered and concentrated. CH₃OH (250 ml.) was added, and the solution was heated to 80 ⁰C and refluxed for 3 hour. Concentrating and distilling under reduced pressure afforded the title compound (17.6 g) as a yellow liquid. Intermediate 91 2-Amino-6-propyl-4(1 /-/)-pyrimidinone

To a mixture of methyl 3-oxohexanoate (17.6 g, 122.08 mmol) and guanidine hydrochloride (14.0 g, 146.49mmol) in CH₃OH (300 ml.) was added potassium tert- butoxide (74.52 g, 664.11 mmol) at ambient temperature over 15 minutes under vigorous stirring. Then the reaction mixture was stirred overnight and filtered. The solution was concentrated to 20 ml_, diluted with water (20 ml_), and the pH was adjusted to 5 by addition of 6N HCI. The resulting white precipitate was collected by filtration and dessicated to afford the title compound (12.8 g).

Intermediate 92

(4-Chloro-6-propyl-2-pyrimidinyl)phosphoramidic acid

A mixture of 2-amino-6-propyl-4(1 /-/)-pyrimidinone (12.8g, 83.562mmol) in phosphorous oxychloride (80.1 ml_, 835.6 mmol) was heated to 120 ⁰C and refluxed for 2 hours. The mixture was evaporated and treated with ice-water. The resulting mixture was filtered to obtain the title compound (8.3 g) as a yellow solid.

Example 40

4-(1 ,2-Dihvdroindazolo[4,3-άc1[1 ,51benzoxazepin-4-yl)-6-propyl-2-pyrimidinamine

A mixture of (4-chloro-6-propyl-2-pyrimidinyl)phosphoramidic acid (0.500 g, 1.99 mmol), 2- acetyl-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 ,2-dihydroindazolo [4,3- bc][1 ,5]benzoxazepine (0.855 g, 2.17 mmol), Pd₂(dba)₃ (18 mg, 0.020 mmol.), tricyclohexylphosphine (14 mg, 0.05 mmol) and K₂CO3 (1.098 g, 7.95 mmol) in 1 ,4- dioxane (5.0 ml.) and water (2.5 ml.) was reacted in a Biotage Initiator microwave synthesizer at 140 ⁰C for 1 hour. Upon cooling, the mixture was concentrated, and water (30 ml.) was added. The resulting mixture was filtered, and the crude product was purified via reversed-phase flash column chromatography to afford the title compound (131.8 mg). LC-MS (ES) m/z = 359 [M+H]⁺. ¹H NMR (400 MHz, DMSOd₆): δ θ.94 (t, J = 7.6 Hz, 3H), 1.72 (m, 2H), 2.56 (t, J = 7.6 Hz, 2H), 6.62 (s, 2H), 6.89 (t, J = 8.0 Hz, 1 H), 7.07 (t, J = 7.6 Hz, 1 H), 7.16 (s, 1 H), 7.28 (d, J = 7.6 Hz, 2H), 7.46 (s, 1 H), 7.85 (s, 1 H), 9.55 (s, 1 H), 12.40 (s, 1 H).

Intermediate 93 Methyl 3-cvclobutyl-3-oxopropanoate

Cyclobutanecarboxylic acid (10.0 g) was cooled to ⁰C, and then thionyl chloride (20 ml.) was added dropwise with stirring. Then the mixture was refluxed for 1.5 hours. The product was distilled to give 10 g of forerun and 9.5 g of the desired cyclobutanecarbonyl chloride (32 °C/20mmHg) as a colorless liquid. Reference: b.p. 130-140 ⁰C (760mmHg)

2,2-Dimethyl-1 ,3-dioxane-4,6-dione (10.5 g, 72.9 mmols) was dissolved in CHCI₃ (1 10 ml_), and pyridine (10.9 ml_, 133.4 mmols) was added. Then a solution of cyclobutanecarbonyl chloride (9.5 g, 80.1 mmols) in CHCI₃ (40 ml.) was added dropwise thereto at a temperature of 10 ⁰C or lower while cooling in an ice-bath. After completion of the dropwise addition, the reaction mixture was stirred for 1 hour at 0 ⁰C, then at room temperature for 1 hour. The mixture was cooled at 0 ⁰C, and 1 N aqueous HCI (100 ml.) was added thereto. The reaction product was extracted with CHCI₃, washed with water, and dried over anhydrous Na₂SO₄, followed by concentrating under reduced pressure. CH₃OH (100 ml.) was added thereto to dissolve the residue and the solution was heated for 3 hours under reflux. After cooling to room temperature, the mixture was concentrated under reduced pressure and the residue was distilled to afford the title compound (6.5 g) as a colorless liquid. Intermediate 94 2-Amino-6-cvclobutyl-4(1/-/)-pyrimidinone

To a solution of methyl S-cyclobutyl-S-oxopropanoate (6.5 g, 41.6 mmol) and guanidine hydrochloride (4.77 g, 49.9 mmol) in CH₃OH (80 ml.) at room temperature was added potassium te/t-butoxide (25.2 g) portionwise over 15 minutes with vigorous stirring and the reaction warmed automatically. Then the reaction was cooled to room temperature and stirred overnight. The precipitated salt was removed by filtration, and the filtrate was concentrated under reduce pressure to approximately 10 ml_, then diluted with 10 ml. of water and the pH adjusted to 5 by the addition of 6N HCI. The precipitate was separated by filtration to afford the title compound (6.6 g) as a white solid. ¹H NMR: δ 10.647 (br, 1

H), 6.5 (br, 2 H), 5.35 (s, 1 H), 3.11-3.20 (m, 1 H), 1.86-2.13 (m, 4 H), 1.71-1.77 (m, 2 H).

Intermediate 95 4-Chloro-6-cvclobutyl-2-pyrimidinamine

2-Amino-6-cyclobutylpyrimidin-4-ol (5.0 g, 30.2 mmol) and POCI₃ (20 ml.) were combined, and the resulting mixture was heated to reflux for 3 hours. The mixture was cooled and concentrated under reduced pressure, and the residue was treated with water carefully, and then neutralized with saturated Na₂CO₃ solution. The resulting mixture was filtered. Then it was concentrated under reduced pressure to approximately 10 ml_, and then filtered to afford the title compound (1.4 g) as a white solid. ¹H NMR: δ 7.01 1 (s, 2 H), 6.519 (s, 1 H), 3.360-3.425 (m, 1 H), 2.164-2.233 (m, 4 H), 1.927-1.999 (m, 1 H), 1.777- 1.825 (m, 1 H). Example 41 4-Cyclobutyl-6-(1 ,2-dihvdroindazolo[4,3-ibciri ,51benzoxazepin-4-yl)-2-pyrimidinamine

To a solution of 4-chloro-6-cyclobutyl-2-pyrimidinamine (250 mg, 1.36 mmol), 2-acetyl- (4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 ,2-dihydroindazolo [4,3-

6c][1 ,5]benzoxazepine (586 mg, 1.50 mmol), Pd₂(dba)₃ (12 mg, 0.014 mmol) and tricyclohexylphosphine (10 mg, 0.034 mmol) in 1 ,4-dioxane (8 ml.) and water (2 ml.) was added K₂CO₃ (751 mg, 5.44 mmol), and the reaction mixture was heated to 140 ⁰C in a microwave reactor for 1 hour. The mixture was cooled and filtered, and then the filtrate was concentrated under reduced pressure. The residue was purified by HPLC (A= 1 OmM NH₄HCO₃/ H₂O, B= CH₃CN) to afford the title compound (85 mg) as a yellow solid. Yield: 16.8%. ¹H NMR: δ 12.353 (br, 1 H), 9.514 (s, 1 H), 7.856 (s, 1 H), 7.469 (s, 1 H), 7.272- 7.301 (m, 2 H), 7.046-7.1 11 (m, 2 H), 6.871-6.912 (m, 1 H), 6.612(s, 2 H), 3.495-3.543 (m, 1 H), 2.238-2.364 (m, 4 H), 1.835-2.076 (m, 2 H).

Intermediate 96

Ethyl 3-oxo-3-(tetrahvdro-2/-/-pyran-4-yl)propanoate

To a stirring solution of lithium 6/s(trimethylsilyl)amide (1 M in THF, 71.5 ml_, 71.5 mmol) was added anhydrous ethyl acetate (6.1 1 g, 69.36 mmol) at -78 ⁰C dropwise, and the mixture was stirred for 30 minutes. To the reaction mixture was added methyl tetrahydro- 2H-pyran-4-carboxylate (5.00 g, 34.68 mmol) in THF (10 ml.) dropwise at -78 ⁰C. After for 4 hours under -78 ⁰C, the reaction was quenched with sat. NH₄CI solution, warmed to ambient temperature, and then extracted with EtOAc (3 X 60 ml_). The combined organic layers were washed with sat. NH₄CI soln., dried with Na₂SO₄, filtered and concentrated to afford crude title compound (6.8Og) as a yellow oil. Intermediate 97 2-Amino-6-(tetrahvdro-2/-/-pyran-4-yl)-4(1 /-/)-pyrimidinone

To the above crude ethyl 3-oxo-3-(tetrahydro-2H-pyran-4-yl)propanoate (6.80 g, 33.93 mmol) and guanidine hydrochloride (3.89 g ,40.72 mmol) in CH₃OH (80 ml.) was added potassium terf-butoxide (19.00 g ,169.65 mmol) at ambient temperature over 15 minutes under vigorous stirring. Then the reaction mixture was stirred overnight and filtered. The solution was concentrated to 20 ml_, diluted with water (2 OmL) and the pH adjusted to 5 by addition of 6N HCI. The white precipitate was collected by filtration and dessicated to afford the title compound (2.86 g).

Intermediate 98 4-Chloro-6-(tetrahvdro-2H-pyran-4-yl)-2-pyrimidinamine

A mixture of 2-amino-6-(tetrahydro-2H-pyran-4-yl)-4(1 /-/)-pyrimidinone (2.86 g, 14.65 mmol) in phosphorous oxychloride (28.1 ml_, 293.0 mmol) was heated to 120 ⁰C and refluxed for 2 hours. The mixture was evaporated and treated with ice-water. The resulting mixture was filtered to get a black solid as crude product (0.823 g). The crude product also contains [4-chloro-6-(tetrahydro-2H-pyran-4-yl)-2-pyrimidinyl]phosphoramidic acid .

Example 42

4-(1 ,2-Dihvdroindazolo[4,3-άc1[1 ,51benzoxazepin-4-yl)-6-(tetrahvdro-2/-/-pyran-4-yl)-2- pyrimidinamine

The mixture of above 4-chloro-6-(tetrahydro-2/-/-pyran-4-yl)-2-pyrimidinamine (0.350 g, 1.64 mmol), 2-acetyl-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 ,2-dihydroindazolo [4,3-_5c][1 ,5]benzoxazepine (0.70 6g, 1.81 mmol), Pd₂(dba)₃ (18 mg, 0.02 mmol), tricyclohexylphosphine (14 mg, 0.05 mmol) and K₂CO₃ (0.906g, 6.56mmol) in 1 ,4-dioxane (5.OmL) and water (2.5ml_) was reacted in a Biotage Initiator microwave synthesizer at 140 ⁰C for 1 hour. Upon cooling, the mixture was concentrated, and water (30 ml.) was added. The rwsulting mixture was filtered, and the crude product was purified via reversed-phase flash column chromatography to afford the title compound (62 mg) as an orange solid. LC-MS (ES) m/z = 401 [M+H]⁺. ¹H NMR (400 MHz, DMSOd₆): δ 1.86 (m, 4H), 2.88 (m, 1 H), 3.44 (m, 2H), 3.99 (d, J = 10.4 Hz, 2H), 6.90 (t, J = 6.8 Hz, 1 H), 7.08 (t, 1 H), 7.29 (m, 2H), 7.36 (s, 1 H), 7.53 (s, 1 H), 7.94 (s, 1 H), 9.58 (s, 1 H, br), 12.51 (s, 1 H, br).

Intermediate 99

Methyl 3-oxo-4-phenylbutanoate

To a solution of 2-phenylacetic acid (15.0 g, 110.17 mmol) and DMF (0.1 mL) in CH₂CI₂ (100 mL) was added oxalyl chloride (20.98 g, 165.26 mmol) dropwise slowly at 0 ⁰C. The reaction mixture was then stirred at ambient temperature for 2hours and distilled in vacuo to afford 2-phenylacetyl chloride (13.7 g) as a pink liquid.

To a stirring solution of 2,2-dimethyl-1 ,3-dioxane-4,6-dione (11.61 g, 80.57 mmol) and pyridine (13.1 mL, 161.13 mmol) in CHCI₃ (200 mL) was added 2-phenylacetyl chloride (13.7 g, 88.62 mmol) in CHCI₃ (50 mL) dropwise slowly at 0 ⁰C, and the reaction mixture was stirred for 1 hour. The reaction was allowed to warm up to ambient temperature and stirred overnight. 1 N aqueous HCI (100 mL) was added, and the resulting mixture was then extracted with CHCI₃ (3 X 60 mL). The combined organic layers were washed with water (2 X 80 mL), dried over Na₂SO₄, filtered and concentrated. CH₃OH (250 mL) was added, and the solution was heated to 80 ⁰C and refluxed for 3 hours. Concentrating and distilling under reduced pressure afforded the title compound (13.4 g) as a pink liquid.

Intermediate 100 2-Amino-6-(phenylmethyl)-4(1 /-/)-pyrimidinone

To methyl 3-oxo-4-phenylbutanoate (1 1.2 g, 58.21 mmol) and guanidine hydrochloride (6.68 g, 69.92 mmol) in CH₃OH (200 mL) was added potassium te/t-butoxide (35.57 g, 316.99 mmol) at ambient temperature over 15 minutes under vigorous stirring, and the reaction mixture was stirred overnight. The mixture was filtered, and the solution was concentrated to 20 mL, diluted with water (20 mL) and the pH adjusted to 5 by addition of 6N HCI. The white precipitate was collected by filtration and dessicated to afford the title compound (8.30 g).

Intermediate 101 4-Chloro-6-(phenylmethyl)-2-pyrimidinamine

A mixture of 2-amino-6-(phenylmethyl)-4(1 /-/)-pyrimidinone (3.30 g, 16.40 mmol) in phosphorous oxychloride (31.4 mL, 328.0 mmol) was heated to 120 ⁰C and refluxed for 2 hours. The mixture was evaporated and treated with ice-water, and the resulting mixture was filtered to afford the title compound (0.8Og, 22.2% yield) as a black solid. Example 43 4-(1 ,2-Dihvdroindazolo[4,3-ibciri ,51benzoxazepin-4-yl)-6-(phenylmethyl)-2-pyrimidinamine

A mixture of above crude 4-chloro-6-(phenylmethyl)-2-pyrimidinamine (0.350 g, 1.59 mmol), 2-acetyl-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 ,2-dihydroindazolo [4,3- 6c][1 ,5]benzoxazepine (0.685 g, 1.75 mmol), Pd₂(dba)₃ (18 mg, 0.02 mmol), tricyclohexylphosphine (14 mg, 0.05 mmol) and K₂CO3 (0.879g, 6.36mmol) in 1 ,4-dioxane (5.OmL) and water (2.5ml_) was reacted in a Biotage Initiator microwave synthesizer at 140 ⁰C for 1 hour. Upon cooling, the mixture was concentrated, and water (30 ml.) was added. The resulting mixture was filtered, and the crude product was purified via reversed- phase flash column chromatography to afford the title compound (71 mg) as a brown solid. LC-MS (ES) m/z = 407 [M+H]⁺. ¹H NMR (400 MHz, DMSOd₆): δ 3.97 (s, 2H), 6.89 (t, J = 7.2 Hz, 1 H), 7.07 (t, J = 8.0 Hz, 2H), 7.28 (m, 9H), 7.44 (s, 1 H), 7.83 (s, 1 H), 9.56 (s, 1 H, br), 12.45 (s, 1 H, br).

Intermediate 102

Methyl 4,4-dimethyl-3-oxopentanoate

NaH (6g) was suspended in dimethyl carbonate (45 mL) and hexamethyl phosphoric acid triamide (10 mL). Pinacolone (10 g) was added slowly at 45 ⁰C, and on completion of the addition, the reaction was stirred for 1 hour at 45 ⁰C. After cooling, alcohol, water and finally 1 N aqueous HCI were carefully added to the reaction mixture. The mixture was extracted by EtOAc (3 X 150 mL), and the organic layer was dried over MgSO₄ and evaporated to get a yellow oil as the crude product. This material was distilled to collect the fraction from 86-96 ⁰C under slight vacuum, affording the title compound (9.2 g) as a colorless oil. ¹H NMR (400 MHz, CDCI₃): δ 1.17 (s, 9H), 3.56 (s, 2H), 3.72 (s, 3H). Intermediate 103 2-Amino-6-(1 ,1-dimethylethyl)-4(1H)-pyrimidinone

To a solution of methyl 4,4-dimethyl-3-oxopentanoate (9.2 g, 58.16 mmol) and guanidine hydrochloride (6.67 g, 69.8 mmol) in CH₃OH (300 ml.) was added potassium terf-butoxide (32.63 g, 290.8 mmol) at ambient temperature over 30 minutes under vigorous stirring, and then the reaction mixture was stirred overnight. The mixture was filtered, and the solution was concentrated to 40 ml_, diluted with water (40 ml.) and the pH adjusted to 5 by addition of 6N aqueous HCI. The resulting white precipitate was collected by filtration and dessicated to afford the title compound (5.3 g).

Intermediate 104

4-Chloro-6-(1 , 1 -dimethylethyl)-2-pyrimidinamine

A solution of 2-amino-6-(1 ,1-dimethylethyl)-4(1 /-/)-pyrimidinone (4.3 g, 25.7 mmol) in phosphorous oxychloride (20 ml.) was heated to 120 ⁰C and refluxed for 2 hours. The mixture was evaporated and treated with ice-water. The resulting mixture was filtered to obtain the title compound (3.2 g) as white solid estimated to be ~ 27% pure.

Example 44

4-(1 ,2-Dihydroindazolor4,3-άciπ ,51benzoxazepin-4-yl)-6-(1 , 1 -dimethylethyl)-2- pyrimidinamine

A mixture of 4-chloro-6-(1 ,1-dimethylethyl)-2-pyrimidinamine,_(600mg, 3.23mmol), 2- acetyl-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 ,2-dihydroindazolo [4,3-

6c][1 ,5]benzoxazepine (703 mg, 1.80 mmol), Pd₂(dba)₃ (45 mg, 3%), tricyclohexylphosphine (25 mg, 6% ) and K₂CO3 (1.24 g, 4.5 mmol) in 1 ,4-dioxane (10 ml.) and water (2.5 ml.) were vacuumed and purged with N₂. Then the mixture was sealed and heated at 140 ⁰C for 40 minutes. When the reaction was completed, the organic layer was filtered through a pad of silica gel, eluting with THF. Then the solvents were removed under reduced pressure and the resulting residue was purified by HPLC (CH₃CN / water, 0.01% NH₄CO₃) to afford the title compound (54 mg) as a yellow powder. LC-MS (ES) m/z = 373 [M+H]⁺. ¹H NMR (400 MHz, DMSOd₆): δ 1.32 (s, 9H), 6.53 (s, 2H), 6.89 (t, J = 7.2 Hz, 1 H), 7.06 (t, J = 7.2 Hz, 1 H), 7.21 (s, 1 H), 7.29 (dd, J = 6.8, 1.2 Hz, 1 H), 7.47 (s, 1 H), 7.86 (s, 1 H), 9.50 (s, 1 H), 12.32 (s, 1 H).

Intermediate 105 Ethyl 3-oxoheptanoate

To a solution of NaH (1.8g, 44mmol) in THF (100 mL) at 0 ⁰C was added ethyl 3- oxobutonoate (5.2 g, 40 mmol), and the mixture was stirred at 0 ⁰C for 10 minutes. Then, n-BuLi in hexanes (17.6 mL, 44mmol) was added dropwise, and the solution was stirred at 0 ⁰C for another 10 minutes. Then, iodopropane (7.5 g, 44 mmol) was added dropwise, and the temperature was allowed to rise to room temperature and maintained for 2 hours. The reaction was quenched with 6N HCI, diluted with water, and extracted with EtOAc (3X). The combined organic layers were washed with brine, dried over MgSO₄, and concentrated in vacuo to afford the crude title compound (6.9 g) as a yellow oil.

Intermediate 106 2-Amino-6-butyl-4(1 /-/)-pyrimidinone

To a solution of ethyl 3-oxoheptanoate (6.9 g, 40 mmol) and guanidine hydrochloride (4.6g, 48 mmol) in CH₃OH (100 mL) at room temperature was added potassium tert- butoxide (24.2 g, 216 mmol ) over 5 minutes with vigorous stirring, and the reaction was warmed to 60 ⁰C, then slowly cooled to room temperature and stirred overnight. The precipitate salt was filtered and the filtrate was concentrated in vacuo. The resulting residue was diluted with 20 ml. of water, and the pH value adjusted to 5 with 6N HCI. The resulting solution was extracted with EtOAc, and the aqueous phase was purified via chromatography to afford the title compound (3.5 g) as a off-white solid. ¹H NMR (400 MHz, DMSOd₆): δ 0.90 (t, 3H), 1.36 - 1.27 (m, 2H), 1.58 - 1.50 (m, 2H), 2.41 (t, 2H), 5.74(s, 1 H), 8.18(s, 1 H), 8.53 (br, 1 H).

Intermediate 107 4-Butyl-6-chloro-2-pyrimidinamine

A solution of 2-amino-6-butyl-4(1 /-/)-pyrimidinone (3.0 g, 18 mmol) in POCI₃ (15 ml.) was stirred at 110 ⁰C for 3 hours. Upon cooling, the solvents were removed under reduce pressure. The resulting residue was diluted with 10 ml. of water, neutralized with Na₂CO₃ aqueous solution, and extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO₄, and concentrated in vacuo to afford the crude title compound (1.1 g) as a brown oil.

Example 45 4-Butyl-6-(1 ,2-dihvdroindazolor4,3-άciri ,5lbenzoxazepin-4-yl)-2-pyrimidinamine

A mixture of 4-butyl-6-chloro-2-pyrimidinamine (300 mg, 1.6 mmol), 2-acetyl-(4,4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 ,2-dihydroindazolo [4,3-6c][1 ,5]benzoxazepine (703 mg, 1.8 mmol), tricyclohexylphosphine (11 mg, 0.04 mmol) and K₂CO₃ (883 mg, 6.4 mmol) in 1 ,4-dioxane (8 ml.) and water (2 ml.) was purged with N₂ for 5 minutes, then treated with Pd₂(dba)₃ (15 mg, 0.016 mmol). The reaction mixture was heated to 140 ⁰C for 1 hour in a microwave synthesizer. Upon cooling, the mixture was poured onto water and extracted with EtOAc (2X). The combined organic layers were washed with water and brine, dried over MgSO₄ and concentrated in vacuo. The resulting residue was washed with EtOAc, and the solid material was dried under high vacuum to afford the title compound (309 mg) as an off-white solid. ¹H NMR (400 MHz, DMSO-c/₆): δ 12.37 (s, 1 H), 9.53 (s, 1 H), 7.84 (d, 1 H), 7.45 (d, 1 H), 7.29 - 7.26 (m, 2H), 7.16 (s, 1 H), 7.08 - 7.04 (m, 1 H), 6.91 - 6.87 (m, 1 H), 6.60 (s, 2H), 2.60 - 2.56 (t, 2H), 1.71 - 1.64 (m, 2H), 1.39 - 1.33 (m, 2H), 0.94 - 0.91 (t, 3H).

Intermediate 108

Ethyl 5-methyl-3-oxohexanoate

To a solution of NaH (3.5 g, 88 mmol) in THF (150 ml.) at 0 ⁰C was added ethyl 3- oxobutonoate (10.4 g, 80 mmol), and the mixture was stirred at 0 ⁰C for 10 minutes. Then, n-BuLi (35.2 ml_, 88 mmol) was added dropwise, and the solution was stirred at 0 ⁰C for another 10 minutes. Then, 2-iodopropane (15.0 g, 88 mmol) was added dropwise, and the temperature was allowed to rise to room temperature and maintained for 2 hours. The reaction was quenched with 6N HCI, diluted with water, and extracted with EtOAc (3X). The combined organic layers were washed with brine, dried over MgSO₄, and concentrated in vacuo to afford the crude title compound (13.8 g) as a yellow oil.

Intermediate 109

2-Amino-6-(2-methylpropyl)-4(1/-/)-pyrimidinone

To a solution of ethyl 5-methyl-3-oxohexanoate (13.8 g, 800 mmol) and guanidine hydrochloride (9.2 g, 96 mmol) in CH₃OH (200 ml.) at room temperature was added potassium terf-butoxide (48.4 g, 432 mmol) over 5 minutes with vigorous stirring. The reaction was warmed to 60 ⁰C, then slowly cooled to room temperature and stirred overnight. The resulting precipitate salt was filtered, and the filtrate was concentrated in vacuo. The residue was diluted with 20 ml. of water, and the pH value was adjusted to 5 with 6N HCI. The resulting solution was extracted with EtOAc, and the aqueous phase was purified via chromatography to afford the title compound (1.4 g) as a off-white solid. ¹H NMR (400 MHz, DMSO-d₆): δ 0.90 (d, 6H), 1.95 - 1.92 (m, 1 H), 2.28 (d, 2H), 4.13 (br, 1 H), 5.71 (s, 1 H), 8.17 (br, 2H). Intermediate 1 10 4-Chloro-6-(2-methylpropyl)-2-pyrimidinamine

A solution of 2-amino-6-(2-methylpropyl)-4(1 /-/)-pyrimidinone (1.4 g, 8.4 mmol) in POCI3 (10 mL) was stirred at 1 10 ⁰C for 3 hours. Upon cooling, the solvents were removed under reduce pressure. The resulting residue was diluted with 10 mL of water, neutralized with Na₂CO₃ aqueous solution, and extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO₄ and concentrated in vacuo to afford the crude title compound (0.8 g) as a brown oil.

Example 46

4-(1 ,2-Dihvdroindazolo[4,3-άc1[1 ,51benzoxazepin-4-yl)-6-(2-methylpropyl)-2- pyrimidinamine

A mixture of 4-chloro-6-(2-methylpropyl)-2-pyrimidinamine (300 mg, 1.6 mmol), 2-acetyl- (4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 ,2-dihydroindazolo [4,3-

6c][1 ,5]benzoxazepine (703 mg, 1.8 mmol), tricyclohexylphosphine (1 1 mg, 0.04 mmol) and K₂CO3 (883 mg, 6.4 mmol) in 1 ,4-dioxane (8 mL) and water (2 mL) was purged with N₂ for 5 minutes, and then treated with Pd₂(dba)₃ (15 mg, 0.016 mmol). The reaction mixture was heated to 140 ⁰C for 1 hour in a microwave synthesizer. Upon cooling, the mixture was poured onto water and extracted with EtOAc (2X). The combined organic layers were washed with water and brine, dried over MgSO₄, and concentrated in vacuo. The resulting residue was washed with EtOAc, and the solid material was dried under high vacuum to afford the title compound (178 mg) as an off-white solid. ¹H NMR (400 MHz, DMSO-de): δ 0.93 (d, 6H), 2.16 - 2.09 (m, 1 H), 2.45 (d, 2H), 6.60 (s, 2H), 6.91 - 6.87 (m, 1 H), 7.08 - 7.04 (m, 1 H), 7.13 (s, 1 H), 7.29 - 7.26 (m, 2H), 7.45 (d, 1 H), 7.84 (d, 1 H), 9.53(s, 1 H), 12.37 (s, 1 H).

Intermediate 1 11 Methyl 3-oxo-5-phenylpentanoate

To 3-phenylpropanoic acid (18.02 g, 120 mmol) and DMF (3 drops) in CH₂CI₂ was added oxalyl chloride (38.08 g, 300 mmol) dropwise, and the mixture was stirred for 3 hours at room temperature. The solution was concentrated to afford the crude 3-phenylpropanoyl chloride (20 g) as a yellow oil.

3-Phenylpropanoyl chloride (10.12 g, 60 mmol) was added dropwise into a mixture of 2,2- dimethyl-1 ,3-dioxane-4,6-dione (9.513 g, 66 mmol) and pyridine (1 1.87 g, 150 mmol) in CH₂CI₂ (100 ml.) for 1 hour. Then the mixture was stirred overnight. 10% HCI (100 ml.) was added into the mixture, and the aqueous was extracted with EtOAc (200 ml_). The combined organic layers were dried with Na₂SO₄ and filtered, and the filtrate was concentrated. To the resulting residue was added CH₃OH (150 ml.) and the mixture was refluxed for 3 hours. The mixture was cooled to room temperature and concentrated, and the resulting residue was purified by chloromatography (EtOAc/PE=1 :6) to obtain the title compound (6.6 g) as a yellow oil. LC-MS (ES) m/z = 207 [M+H]⁺. ¹H NMR (400 MHz, CDCIs-de): δ 2.96 (m, 4H), 3.44 (s, 2H), 3.71 (s, 3H), 7.19 (m, 3H), 7.28 (m, 2H).

Intermediate 1 12 2-Amino-6-(2-phenylethyl)-4(1/-/)-pyrimidinone

To a mixture of methyl 3-oxo-5-phenylpentanoate (6.6 g, 32 mmol) and guanidine (4.59 g, 48 mmol) in CH₃OH (100 ml.) at 20 ⁰C was added potassium-2-methylpropan-2-olate (19.75 g,176 mmol) over 20 minutes with vigorously stirring, and the reaction mixture was warmed to 60 ⁰C. Then the mixture was cooled to room temperature and stirred overnight. The resulting precipitate salt was removed by filtration. The filtrate was concentrated to approximately 10 ml_, and then diluted with water (10 ml.) and the pH adjusted to 5 by the addition of 6N HCI. The resulting precipitate was filtered and dried in vacuum to obtain the title compound (5.3 g) as a white solid . LC-MS (ES) m/z = 216 [M+H]⁺.

Intermediate 1 13 4-Chloro-6-(2-phenylethyl)-2-pyrimidinamine

A mixture of 2-amino-6-(2-phenylethyl)-4(1 /-/)-pyrimidinone (5.3 g, 24.6 mmol) and POCI₃ (25 ml.) was stirred at 130 ⁰C for 2 hours, then cooled to room temperature. The solution was poured into ice (200 g), and extracted with EtOAc (2 X 100 ml_). The combined organic layers were dried with MgSO₄ and concentrated to obtain the crude title compound (6 g) as a yellow oil. LC-MS (ES) m/z = 234 [M+H]⁺.

Example 47 4-(1 ,2-Dihvdroindazolor4,3-άciri ,5lbenzoxazepin-4-yl)-6-(2-phenylethyl)-2-pyrimidinamine

To 2-acetyl-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 ,2-dihydroindazolo [4,3-

6c][1 ,5]benzoxazepine (391 mg, 1 mmol), 4-chloro-6-(2-phenylethyl)-2-pyrimidinamine (467 mg, 2 mmol) and K₃CO₄ (553 mg, 4 mmol) were added 1 ,4-dioxane (4 mL) and water (1 mL), and the resulting mixture was purged with N₂ for 10 minutes into a sealable tube. Pd₂(dba)₃ (9 mg, 10 μmol) was added, and N₂ was bubbled through the mixture for an additional 5 minutes. Tricyclohexylphosphine (7 mg, 0.025 mmol) was added, the tube was sealed, and the reaction mixture was stirred for 1 h at 140 ⁰C in microwave. The mixture was poured onto water and EtOAc. The organic layer was separated, and the aqueous layer was further extracted with EtOAc. The combined organic layers were washed with brine, dried (MgSO₄), filtered and concentrated. Flash chromatography on SiO₂ (gradient: 100% CH₂CI₂ to 90:10:1 CH₂CI₂:CH₃OH:NH₄OH) afforded the title compound (150 mg) as a light brown solid. LC-MS (ES) m/z = 421 [M+H]⁺. ¹H NMR (400 MHz, DMSO-de): δ 2.89 (m, 2H), 3.03 (m, 2H), 6.63 (s, 2H), 6.88 (t, 1 H), 7.06 (t, 1 H) 7.26 (m, 2H), 7.42 (s, 6H), 7.88 (s, 1 H), 9.52 (s, 1 H).

Intermediate 1 14

Methyl 4-(ethyloxy)-3-oxobutanoate

To a solution of 2-ethoxyacetic acid (15.0 g, 144.23 mmol) and DMF (0.1 ml.) in CH₂CI₂ (200 ml.) was added oxalyl chloride (27.47 g, 216.35 mmol) dropwise slowly at 0 ⁰C. The reaction mixture was then stirred at ambient temperature for 2 hours, and distilled in vacuo to afford 2-ethoxyacetyl chloride (10.1 g) as a pale yellow liquid.

To a stirring solution of 2,2-dimethyl-1 ,3-dioxane-4,6-dione (9.90 g, 68.71 mmol) and pyridine (13.41 ml_, 164.92 mmol) in CHCI₃ (200 ml.) was added 2-ethoxyacetyl chloride (10.1 g, 82.45 mmol) in CHCI₃ (50 ml.) dropwise slowly at 0 ⁰C and stirred for 1 hour. The reaction mixture was allowed to warm up to ambient temperature and stirred overnight. 1 N aqueous HCI (80 ml.) was added, and the mixture was then extracted with CHCI₃ (3 X 50 ml_). The combined organic layers were washed with water (2 X 80 ml_), dried with Na₂SO₄, filtered and concentrated. CH₃OH (250 ml.) was added, and the solution was heated to 80 ⁰C and refluxed for 3 hours. Concentrating and distilling under reduced pressure afforded the title compound (6.0 g) as a yellow oil.

Intermediate 1 15 2-Amino-6-r(ethyloxy)methyll-4(1H)-pyrimidinone

,OH

⁰ Il

NH₂ To methyl 4-(ethyloxy)-3-oxobutanoate (6.0 g, 37.46 mmol) and guanidine hydrochloride (4.49 g, 44.95 mmol) in CH₃OH (150 ml.) was added potassium te/t-butoxide (23.12 g, 206.03 mmol) at ambient temperature over 15 minutes under vigorous stirring. Then the reaction mixture was stirred overnight and filtered. The solution was concentrated to 20 ml_, diluted with water (20 ml.) and the pH adjusted to 5 by addition of 6N HCI. The resulting white precipitate was collected by filtration and dessicated to afford the title compound (6.31g). Intermediate 1 16 4-Chloro-6-[(ethyloxy)methyl1-2-pyrimidinamine

A mixture of 2-amino-6-[(ethyloxy)methyl]-4(1 H)-pyrimidinone (3.00 g, 17.73 mmol) in phosphorous oxychloride (17.0 ml_, 177.30 mmol) was heated to 120 ⁰C and refluxed for 2 hours. The mixture was evaporated, treated with ice-water, and filtered to obtain the title compound (1.80 g) as a red solid.

Example 48

4-(1 ,2-Dihvdroindazolor4,3-άciπ ,5lbenzoxazepin-4-yl)-6-r(ethyloxy)methyll-2- pyrimidinamine

A mixture of the above crude 4-chloro-6-[(ethyloxy)methyl]-2-pyrimidinamine (0.350 g, 1.87 mmol), 2-acetyl-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 ,2-dihydroindazolo [4,3-_5c][1 ,5]benzoxazepine (0.803 g, 2.06 mmol), Pd₂(dba)₃ (18 mg, 0.02 mmol), tricyclohexylphosphine (14 mg, 0.05 mmol) and K₂CO₃ (1.031 g, 7.46 mmol) in 1 ,4- dioxane (5.0 ml.) and water (2.5 ml.) was reacted in a Biotage Initiator microwave synthesizer at 140 ⁰C for 1 hour. Upon cooling, the mixture was concentrated and water (30 ml.) was added. The resulting mixture was filtered, and the crude product was purified via reversed-phase chromatography to afford the title compound (210 mg) as a green solid. LC-MS (ES) m/z = 375 [M+H]⁺. ¹H NMR (400 MHz, DMSOd₆): δ 1.24 (t, J = 7.2 Hz, 3H), 3.61 (m, 2H), 4.40 (s, 2H), 6.90 (m, 1 H), 7.08 (m, 1 H), 7.20 (s, 1 H), 7.29 (m, 2H), 7.43 (s, 1 H), 7.82 (s, 1 H), 9.49 (s, 1 H). Intermediate 1 17 4-bromo-2,6-difluoro-N-r2-(methylamino)phenyllbenzamide

To a mixture of 4-bromo-2,6-difluorobenzoic acid (2 g, 8.44 mmol) with thionyl chloride (8 ml_, 1 10 mmol) in Toluene (15 ml.) was heated at 80 ⁰C for 1.5hr. The reaction was concentrated then diluted with 1 OmL of DCM and slowly added to a premixed solution of N-methyl-1 ,2-benzenediamine (1.237 g, 10.13 mmol) and DIEA (1.764 ml_, 10.13 mmol) in 20 ml. of DCM. The reaction was let stir for 18hr at room temperature. The reaction was diluted with 5OmL of DCM then washed with water (2OmL). The organic was dried over Na₂SO₄, filtered and concentrated. The oil was then purified on a 4Og KP-SiI column with Biotage SP1 in 0 to 40% gradient over 35 minutes to afford the title compound (450mg) as a white solid. LC-MS (ES) m/z = 340.7 [M+H]⁺.

Intermediate 1 18

3-bromo-1-fluoro-5-methyl-5,10-dihvdro-11 H-dibenzorb,eiπ ,4ldiazepin-11-one

To a solution of 4-bromo-2,6-difluoro-N-[2-(methylamino)phenyl]benzamide (200 mg, 0.586 mmol) with Tetrahydrofuran (THF) (5 mL) in a 20ml seal sealable vial was added NaH (60% in oil, 58.6 mg, 1.466 mmol). The vial was then capped and heated at 80 ⁰C overnight. The reaction wasn't completed and additional NaH (60% in oil, 20 mg, 0.5 mmol) was added and let stir overnight. The reaction was concentrated then dissolved with 3mL of DMF followed by 10ml of 1 N HCI. Solid crashed out of solution and was isolated by filtration. The solid was then washed with Hexane to afford the title compound (158mg). Without further purification it was brought onto next step. LC-MS (ES) m/z 320.6 [M+H]⁺.

Intermediate 1 19 4-bromo-6-methyl-2,6-dihvdro-1 H-indazolor3,4-bciπ ,5lbenzodiazepine

To 3-bromo-1 -fluoro-5-methyl-5, 10-dihydro-11 H-dibenzo[b,e][1 ,4]diazepin-11 -one (158 mg, 0.492 mmol) was added Toluene (5 ml.) then added Lawesson's reagent (199 mg, 0.492 mmol) the solution was capped in a sealable reaction tube and heated at 100 ⁰C overnight. The reaction was cooled in ice bath and 5ml_ of hexane was added. Solid crashed out of solution and was isolated by filtration. The solid was washed with hexane then dissolved with 1 ,4-Dioxane (4 ml.) in a sealable reaction tube. Hydrazine monohydrate (0.1 19 ml_, 2.460 mmol) was then added and the reaction was capped and heated at 85 ⁰C overnight. The reaction was concentrated the dissolved with 2ml_ of DMSO and purified on HPLC: (HPLC condition: Gilson HPLC using Trilution software with a phenomenex Luna 5u C18(2) 100A, AXIA. 50X30.00mm 5 micron. 7.3-minute run (47ml/min, 25%ACN/H2O, 0.1% TFA to 55%ACN/H₂O, 0.1% TFA) with UV detection at 254nm). The product fractions were pooled, concentrated and freeze-dried to afford the title compound (88mg). LC-MS (ES) m/z = 314.6 [M+H]⁺.

Intermediate 120 2,1 1-diacetyl-4-bromo-6-methyl-6,1 1-dihvdro-2H-indazolo[3,4-bc1[1 ,51benzodiazepine

To 4-bromo-6-methyl-2,6-dihydro-1 H-indazolo[3,4-bc][1 ,5]benzodiazepine (60 mg, 0.190 mmol) was added Toluene (5mL) in 2OmL sealable vial. Then added acetic anhydride (2 mL, 21.20 mmol) and heated at 1 10 ⁰C overnight. The reaction was concentrated then chased the toluene with EtOH then re-suspended the solid with 5mL of EtOH and isolated the title compound (48mg) by filtration. The yellowish solid was used as is without purification. LC-MS (ES) m/z = 398.8 [M+H]⁺.

Intermediate 121

4-(2.1 1-diacetyl-6-methyl-6.11-dihvdro-2H-indazolor3.4-bciri .5lbenzodiazepin-4-ylV6-(4- morpholinyl)-2-pyrimidinamine

To 2,1 i-diacetyM-bromo-β-methyl-βJ

(50 mg, 0.125 mmol), bis(pinacolato)diboron (38.2 mg, 0.150 mmol) in dioxane (1.5 ml.) were added potassium acetate (49.2 mg, 0.501 mmol), PdCI₂(dppf)-CH₂CI₂ adduct (10.23 mg, 0.013 mmol), in a 5ml_ microwave vial. The vial was capped and heated at at 80 ⁰C for 2hr on hotplate. After 4-chloro-6-(4-morpholinyl)-2-pyrimidinamine (29.6 mg, 0.138 mmol) and 2M K₂CO₃ (.75 ml.) were added. The reaction was capped and heat in microwave at 120⁰C for 20min.The reaction was concentrated then dissolved with DMF (5ml_) and filtered over PFTE filter. The filtrate was then concentrated and dissolved in 2ml_ of DMSO and purified on HPLC (HPLC condition: Gilson HPLC using Trilution software with a phenomenex Luna 5u C18(2) 100A, AXIA. 50X30.00mm 5 micron. 7.3- minute run (47ml/min, 25%ACN/H₂O, 0.1% TFA to 55%ACN/H₂O, 0.1% TFA) with UV detection at 254nm). The fractions with the desired product were pooled and then freeze- dried to isolate the title compound (22mg) as an off white solid. LC-MS (ES) m/z = 456.9 [M+H]⁺.

Example 49

4-(6-methyl-2,6-dihvdro-1 H-indazolo[3,4-bciri ,51benzodiazepin-4-yl)-6-(4-morpholinyl)-2- pyrimidinamine

To 4-(1 1-acetyl-6-methyl-6,11-dihydro-2H-indazolo[3,4-bc][1 ,5]benzodiazepin-4-yl)-6-(4- morpholinyl)-2-pyrimidinamine (22 mg, 0.048 mmol) was added Water (2 ml_), Methanol (200 μl_) and HCI (400 μl_, 13.16 mmol) in to a 5ml sealable vial. The reaction vial was capped and was heated in sand bath at 85 ⁰C overnight. The reaction was concentrated then purified on HPLC (HPLC condition: open-access Gilson using Trilution software with a X-Bridge C18 30X75.00mm 5 micron. 10-minute run (50ml/min, 10%ACN/H₂O, 0.1% NH₄OH to 50%ACN/H₂O, 0.1 % NH₄OH) with UV detection at 254nm). The fractions with the desired product were pooled and then freeze-dried to isolate the title compound (1 1 mg) as an off white solid. 1 H NMR (400 MHz, DMSO-d₆) d ppm 3.51 (s, 3 H) 3.60 - 3.72 (m, 8 H) 6.05 - 6.40 (m, 2 H) 6.63 (br. s., 1 H) 6.95 (dd, J=6.57, 3.03 Hz, 3 H) 7.16 - 7.26 (m, 2 H) 7.48 (s, 1 H) 8.80 (s, 1 H) 11.95 (br. s., 1 H). LC-MS (ES) m/z = 415.0 [M+H]⁺

Example 50

4-(2,6-dihvdro-1 H-indazolor3,4-άciπ ,5lbenzodiazepin-4-yl)-6-(3-oxa-8- azabicvclo[3.2.πoct-8-yl)-2-pyrimidinamine

A mixture of 4-chloro-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-2-pyrimidinamine (127 mg, 0.53 mmol), 2,6, 11 -Triacetyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-6, 11 -dihydro-2H- indazolo[3,4-6c][1 ,5]benzodiazepine (252 mg, 0.53 mmol), and K₃PO₄ (560 mg, 2.64 mmol) in 1 ,4-dioxane (4.5 ml.) and water (1.5 mL) was degassed with nitrogen for 15 minutes. Pd₂(dba)₃ (27 mg, 0.03 mmol) and tricyclohexylphosphine (18 mg, 0.06 mmol) were then added and the mixture was degassed for an additional 2 minutes. The sealed tube was capped and the mixture was stirred at 100 ⁰C for 16 hours. The mixture was then cooled and allowed to sit until two layers formed. The organic layer was filtered through a plug of silica gel (40 g), rinsing first with DCM (200 mL) then with 90/10/1 DCM/CH₃OH/NH₄OH (400 mL). The 90/10/1 DCM/CH₃OH/NH₄OH fractions were combined and concentrated in vacuo to give a mixture of mono- and diacylated desired products. That mixture was taken up in EtOH (10 mL), treated with cone. HCI (0.5 mL) and heated to 120 ⁰C in the microwave for 30 minutes. I twas then quenched with saturated aqueous NaHCOs (25 mL) and extracted with ethyl acetate (2 x 20 mL). The extracts were washed with brine (20 mL), dried (Na₂SO₄), filtered, and concentrated in vacuo. The dark residue was purified by flash chromatography (24 g SiO₂, DCM to 90/10/1 DCM/CH₃OH/NH₄OH gradient) to give the desired product in about 90% purity. It was recrystallized from ethyl acetate/hexanes to give the title compound (58 mg) as a brown solid. LC-MS (ES) m/z = 427 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 1.86-2.01 (m, 4H), 3.56 (d, J = 10.6 Hz, 2H), 3.65 (d, J = 10.8 Hz, 2H), 4.57 (bs, 2H), 6.08 (s, 2H), 6.49 (s, 1 H), 6.67-6.77 (m, 2H), 7.04-7.13 (m, 2H), 7.13 (s, 1 H), 7.39 (s, 1 H), 8.88 (s, 1 H), 9.08 (s, 1 H), 1 1.95 (s, 1 H).

Intermediate 122 3-morpholinecarboxamide

A mixture of 4-{[(1 ,1-dimethylethyl)oxy]carbonyl}-3-morpholinecarboxylic acid (2.86 g, 12.4 mmol), EDC (2.83 g, 14.7 mmol), and HOBt (1.25 g, 7.36 mmol) in DMF (50 mL) was stirred for about 5 minutes. Ammonium chloride (2.09 g, 39.1 mmol) and triethylamine (8.5 mL, 61.0 mmol) were then added, and the reaction was stirred at room temperature under nitrogen for 18 hours. The mixture was then poured into water (100 mL) and extracted with diethyl ether (3 x 50 mL). The extracts were washed with brine (50 mL), dried (Na₂SO₄), filtered, and concentrated in vacuo. The combined aqueous layers were further extracted with DCM (3 x 75 mL), and the extracts were dried (Na₂SO₄), filtered, combined with the ether extracts, and concentrated in vacuo. The residue was stirred in DCM (50 ml.) and TFA (10 ml.) at room temperature for one hour then concentrated in vacuo. Diethyl ether was added and the mixture was stirred vigorously for 3 days. The precipitate was collected by vacuum filtration to give a TFA salt of the title compound (2.31 g, ca. 90% pure) as a white solid. LC-MS (ES) m/z = 131 [M+H]⁺.

Intermediate 123

4-(2-amino-6-chloro-4-pyrimidinyl)-3-morpholinecarboxamide

A mixture of 3-morpholinecarboxamide (830 mg, 3.40 mmol), 2-amino-4,6- dichloropyrimidine (502 mg, 3.06 mmol), and DIPEA (1.6 ml_, 9.16 mmol) in acetonitrile

(12 ml.) was stirred at 100 ⁰C in a sealed tube for 40 hours. The mixture was diluted with ethyl acetate (100 ml_), and washed with saturated aqueous NaHCO₃ (2 x 50 ml.) and brine (50 ml_). The combined aqueous phases were back-extracted with DCM (3 * 50 ml.) and ethyl acetate (3 x 50 ml_). All of the organic phases were combined, dried (Na₂SO₄), filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (34 g SiO₂, DCM to 90/10/1 DCM/MeOH/NH₄OH gradient) to give the title compound (394 mg) as a white solid. LC-MS (ES) m/z = 258, 260 [M+H]⁺.

Example 51

4-r2-amino-6-(1 ,2-dihvdroindazolor4,3-άciri ,5lbenzoxazepin-4-yl)-4-pyrimidinyll-3- morpholinecarboxamide

A mixture of 4-(2-amino-6-chloro-4-pyrimidinyl)-3-morpholinecarboxamide (510 mg, 1.98 mmol), 2-acetyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 ,2-dihydroindazolo[4,3- 6c][1 ,5]benzoxazepine (774 mg, 1.98 mmol), Pd₂(dba)₃ (91 mg, 0.10 mmol), tricyclohexylphosphine (56 mg, 0.20 mmol), and K₃PO₄ (1.260 g, 5.94 mmol) in 1 ,4- dioxane (9 ml.) and water (3 mL) was degassed with nitrogen for 10 minutes. The vial was sealed and stirred at 100 ⁰C for 16 hours. The mixture was then cooled and poured into water (75 mL) and the precipitate was collected by vacuum filtration. Most of the solid was dissolved in 80/20/2 DCM/CH3OH/NH₄OH and filtered, and the filtrate was purified by flash chromatography (90 g SiO₂, 10-85% 80/20/2 DCM/CH3OH/NH₄OH in methylene chloride gradient). The product fractions were further purified by successive recrystallizations from hot ethyl acetate/CH₃OH to give the title compound (304 mg) as a yellow solid. LC-MS (ES) m/z = 445 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 3.30-3.41 (m, 1 H), 3.42-3.52 (m, 1 H), 3.62 (dd, J = 11.6, 3.5 Hz, 1 H), 3.85-3.94 (m, 1 H), 4.10 (bs, 1 H), 4.37 (d, J = 11.6 Hz, 1 H), 4.98 (bs, 1 H), 6.18 (bs, 2H), 6.64 (bs, 1 H), 6.86-6.92 (m, 1 H), 7.03-7.10 (m, 1 H), 7.20 (bs, 1 H), 7.24-7.31 (m, 2H), 7.36 (bs, 1 H), 7.45 (s, 1 H), 7.83 (s, 1 H), 9.52 (s, 1 H), 12.32 (s, 1 H).

Intermediate 124

6-Chloro-N4-phenyl-2,4-pyrimidinediamine

To 4,6-dichloro-2-pyrimidinamine (.2 g, 1.220 mmol) in ethanol (10 mL) was added aniline (0.111 mL, 1.220 mmol) and the reaction mixture was stirred overnight at 100 ⁰C. The mixture was poured onto ethyl acetate and saturated aqueous NaHCO₃. The layers were separated and the aqueous layer was further extracted with more ethyl acetate. The combined organic layers were washed with brine, dried (MgSO4), filtered and concentrated to afford the crude title compound (654 mg, 1.927 mmol, 158% yield). LC- MS (ES) m/z = 221 [M+H]⁺.

Example 52 6-(1 ,2-dihvdroindazolor4,3-bciri ,5lbenzoxazepin-4-yl)-N4-phenyl-2,4-pyrimidinediamine

6-Chloro-N4-phenyl-2,4-pyrimidinediamine (.300 g, 0.884 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.051 g, 0.044 mmol) were added to a 2.5 mL microwave vial and stirred under a blanket of N₂ for 10 min at room temperature. Then 4- (4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 ,2-dihydroindazolo[4,3- 6c][1 ,5]benzoxazepine (0.309 g, 0.884 mmol) was added, followed by potassium carbonate (1.767 ml_, 3.53 mmol) and ethanol (1.200 ml_). The reaction was sealed and irradiated at 130 ⁰C for 10 min. The reaction mixture was then diluted with water and extracted with EtOAc. The organics were dried and concentrated for purification via HPLC (25-55% ACN/H₂O, 0.1 % TFA). Product fractions were selected, combined and concentrated to afford the title compound (119.8 mg, 1.80 mmol, 20% yield ) as a yellow solid. LC-MS (ES) m/z = 408 [M+H]⁺. ¹H NMR (400 MHz, DMSOd₆): δ 6.66 - 6.72 (m, 1 H), 6.89 - 6.95 (m, 1 H), 7.07 - 7.11 (m, 2H), 7.1 1 - 7.14 (m, 1 H), 7.16 - 7.23 (m, 1 H), 7.27 - 7.33 (m, 2H), 7.43 (t, J = 7.71 Hz, 2H), 7.54 (s, 1 H), 7.82 (br. s., 2H), 9.69 (s, 1 H), 10.56 (br. s., 1 H), 12.47 (br. s., 1 H), 12.71 (s, 1 H)

Intermediate 124 6-Chloro-N4-methyl-N4-phenyl-2,4-pyrimidinediamine

To 4,6-dichloro-2-pyrimidinamine (.2 g, 1.220 mmol) in ethanol (5 mL) was added n- methylaniline (0.132 mL, 1.220 mmol) and the reaction mixture was stirred overnight at 100 ⁰C. The mixture was poured onto ethyl acetate and saturated aqueous NaHCO₃. The layers were separated and the aqueous layer was further extracted with more ethyl acetate. The combined organic layers were washed with brine, dried (MgSO₄), filtered and concentrated to afford the crude title compound (320.1 mg, 1.023 mmol, 84% yield). LC- MS (ES) m/z = 235 [M+H]⁺.

Example 53

6-(1 ,2-dihvdroindazolor4,3-bciri ,5lbenzoxazepin-4-yl)-N4-methyl-N4-phenyl-2,4- pyrimidinediamine

6-Chloro-N4-methyl-N4-phenyl-2,4-pyrimidinediamine (.160 mg, 0.51 1 μmol) and tetrakis(triphenylpnosphine)palladium(0) (0.030 mg, 0.026 μmol) were added to a 2.5 ml_ microwave vial and stirred under a blanket of N₂ for 10 min at room temperature. Then A- (4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 ,2-dihydroindazolo[4,3- 6c][1 ,5]benzoxazepine (0.179 mg, 0.511 μmol) was added, followed by potassium carbonate (1.023 μl_, 2.045 μmol) and ethanol (1.200 ml_). The reaction was sealed and irradiated at 130 ⁰C for 10 min. The reaction mixture was then diluted with water and extracted with EtOAc. The organics were dried and concentrated for HPLC purification (25-55% ACN/H₂O, 0.1 % TFA). Product fractions were selected, combined and concentrated to afford the title compound (0.0749 g, 0.133 mmol, 3% yield). LC-MS (ES) m/z = 422 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 3.55 (s, 3H), 6.85 - 6.92 (m, 1 H), 6.98 (br. s., 1 H), 7.04 - 7.11 (m, 1 H), 7.27 (s, 3H), 7.39 (br. s., 1 H), 7.48 (d, J = 7.58 Hz, 4H), 7.55 - 7.61 (m, 2H), 9.65 (s, 1 H), 12.39 (br. s., 1 H), 12.59 (s, 1 H). Intermediate 125 6-Chloro-N4-(2,6-dimethylphenyl)-2,4-pyrimidinediamine

To 4,6-dichloro-2-pyrimidinamine (.2 g, 1.220 mmol) in ethanol (5 mL) was added o- toluidine (0.131 g, 1.220 mmol) and the reaction mixture was stirred overnight at 100 ⁰C. The mixture was poured onto ethyl acetate and saturated aqueous NaHCO₃. The layers were separated and the aqueous layer was further extracted with more ethyl acetate. The combined organic layers were washed with brine, dried (MgSO₄), filtered and concentrated to afford the title compound (0.408 g, 1.050 mmol, 86% yield). LC-MS (ES) m/z = 249 [M+H]⁺.

Example 54

6-(1.2-dihvdroindazolor4.3-bciri .5lbenzoxazepin-4-vn-N4-(2.6-dimethylphenylV2.4- pyrimidinediamine

6-Chloro-N4-(2,6-dimethylphenyl)-2,4-pyrimidinediamine (.2 g, 0.460 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.027 g, 0.023 mmol) were added to a 2.5 mL microwave vial and stirred under a blanket of N₂ for 10 min at room temperature. Then 4- (4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 ,2-dihydroindazolo[4,3-

6c][1 ,5]benzoxazepine (0.161 g, 0.460 mmol) was added, followed by potassium carbonate (0.920 mL, 1.841 mmol) and ethanol (1.200 mL). The reaction was sealed and irradiated at 130 ⁰C for 10 min. The reaction mixture was then diluted with water and extracted with EtOAc. The organics were dried and concentrated for purification via HPLC (30-60% ACN/H₂O, 0.1 % TFA). Fractions were selected, combined and concentrated to afford the title compound (0.0196 g, 0.034 mmol, 7% yield) as a yellow solid. LC-MS (ES) m/z = 436 [M+H]⁺. ¹H NMR (400 MHz, DMSOd₆): δ 2.21 (s, 6H), 6.72 (s, 1 H), 6.88 - 6.97 (m, 2H), 7.05 - 7.15 (m, 2H), 7.18 (s, 2H), 7.23 - 7.34 (m, 2H), 7.56 (s, 1 H), 9.69 (br. s., 1 H), 10.12 (br. s., 1 H), 12.23 (br. s., 1 H), 12.54 (br. s., 1 H), 12.74 (br. s., 1 H).

Example 55

6-(1 ,2-dihvdroindazolor4,3-bciri ,5lbenzoxazepin-4-yl)-N4-methyl-N4-(2-methylphenyl)- 2,4-pyrimidinediamine

To 4,6-dichloro-2-pyrimidinamine (.2 g, 1.220 mmol) in 1 ,4-dioxane (6 mL) was added N- methyl-o-toluidine (0.150 mL, 1.220 mmol) and DIEA (0.213 mL, 1.220 mmol), the reaction mixture was stirred overnight at 100 ⁰C. The reaction mixture was cooled to room temperature and then transferred to a 20 mL microwave vessel followed by tetrakis(triphenylpnosphine)palladium(0) (0.070 g, 0.061 mmol), 4-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)-1 ,2-dihydroindazolo[4,3-6c][1 ,5]benzoxazepine (0.477 g, 1.220 mmol), and potassium carbonate (2.440 mL, 4.88 mmol). The vial was sealed and irradiated at 130 ⁰C for 10 minutes. The reaction mixture was then diluted with water and extracted with EtOAc. The organics were dried and concentrated for purification via HPLC. Fractions were selected, combined and concentrated to afford the title compound (0.114 g, 0.163 mmol, 13% yield). LC-MS (ES) m/z = 436 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 2.21 (s, 3H), 3.47 (s, 3H), 5.63 (s, 1 H), 6.84 - 6.93 (m, 2H), 7.03 - 7.13 (m, 2H), 7.21 - 7.36 (m, 4H), 7.35 - 7.51 (m, 4H), 9.64 (s, 1 H), 12.54 (s, 1 H). Intermediate 126 6-Chloro-N4-(2-methylphenyl)-2,4-pyrimidinediamine

To 4,6-dichloro-2-pyrimidinamine (.2 g, 1.220 mmol) in ethanol (5 mL) was added o- toluidine (0.131 g, 1.220 mmol) and HCI (1.853 μl_, 0.061 mmol), the reaction mixture was heated to 80 ⁰C overnight. The reaction mixture was concentrated to afford the crude title compound (286 mg, 1.158 mmol, 95% yield). LC-MS (ES) m/z = 235 [M+H]⁺.

Example 56

6-(1 ,2-dihydroindazolo[4,3-bc1[1 ,51benzoxazepin-4-yl)-N4-(2-methylphenyl)-2,4- pyrimidinediamine

6-Chloro-N4-(2-methylphenyl)-2,4-pyrimidinediamine (286 mg, 1.220 mmol) in ethanol (2 mL) was added to a 20 mL microwave vessel, followed by 4-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)-1 ,2-dihydroindazolo[4,3-6c][1 ,5]benzoxazepine (460 mg, 1.220 mmol), tetrakis(triphenylphosphine)palladium(0) (70.5 mg, 0.061 mmol) and potassium carbonate (2.440 mL, 4.88 mmol). Toluene (5.00 mL) was added and then the reaction was capped and irradiated for 30 min at 130 ⁰C. The reaction mixture was partitioned between EtOAc and H₂O. The organic layer was separated, dried and concentrated. The resulting residue was dissolved in ethanol followed by a few drops on cone. HCI. The reaction was left to stir at room temperature overnight and was then filtered to give a yellow solid that was purified via HPLC (20-50%, ACN/H₂O, 0.1% TFA). Fractions were selected, combined and dried to afford the title compound (145.5 mg, 0.213 mmol, 17% yield) as a yellow solid. LC-MS (ES) m/z = 422 [M+H]⁺. ¹H NMR (400 MHz, DMSOd₆): δ 2.27 (s, 3H), 6.89 - 6.95 (m, 2H), 7.07 - 7.13 (m, 3H), 7.22 - 7.33 (m, 4H), 7.35 (d, J = 6.82 Hz, 1 H), 7.44 (d, J = 6.82 Hz, 1 H), 7.53 (s, 1 H), 9.69 (s, 1 H), 10.16 (br. s., 1 H), 12.39 (br. s., 1 H), 12.71 (br. s., 1 H).

Intermediate 127 6-Chloro-N4-(1-methyl-1 H-pyrazol-3-yl)-2,4-pyrimidinediamine

To 4,6-dichloro-2-pyrimidinamine (.5 g, 3.05 mmol) in ethanol (10 ml.) was added 1- methyl-1 H-pyrazol-3-amine (0.296 g, 3.05 mmol) and TEA (1.062 ml_, 7.62 mmol). The reaction mixture was then stirred overnight at 80 ⁰C. The reaction mixture was concentrated to afford the crude title compound (0.200 g, 0.890 mmol, 95% yield). LC-MS (ES) m/z = 225 [M+H]⁺.

Example 57

6-(1.2-dihvdroindazolor4.3-bciri .5lbenzoxazepin-4-vn-N4-(1-methyl-1 H-pyrazol-3-ylV2.4- pyrimidinediamine

6-Chloro-N4-(1-methyl-1 H-pyrazol-3-yl)-2,4-pyrimidinediamine (.2 g, 0.890 mmol) was added to a microwave vial followed by 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 ,2- dihydroindazolo[4,3-6c][1 ,5]benzoxazepine (0.349 g, 0.890 mmol), tetrakis(triphenylphosphine)palladium(0) (0.051 g, 0.045 mmol), potassium carbonate (1.781 ml_, 3.56 mmol), toluene (2.5 ml.) and ethanol (1 ml_). The reaction was irradiated at 130 ⁰C for 10 min. The reaction mixture was diluted with H₂O and extracted with EtOAc. The organics were dried and concentrated and the resulting residue was purified via HPLC (20-40%, ACN/H₂O, 0.1 % TFA). Fractions were selected, combined and concentrated to afford the title compound (33 mg, 0.049 mmol, 6% yield) as a yellow solid. LC-MS (ES) m/z = 412 [M+H]⁺. ¹H NMR (400 MHz, DMSOd₆): δ 3.87 (s, 3H), 6.57 (s, 1 H), 6.89 - 6.95 (m, 1 H), 7.07 (s, 1 H), 7.08 - 7.13 (m, 1 H), 7.26 - 7.35 (m, 2H), 7.51 (s, 1 H), 7.79 (s, 1 H), 8.27 (s, 1 H), 8.53 (br. s., 1 H), 9.69 (s, 1 H), 10.91 (s, 1 H), 12.37 (br. s., 1 H), 12.73 (s, 1 H).

Intermediate 128 4-Chloro-6-(2-methyl-4-morpholinyl)-2-pyrimidinamine

To 4,6-dichloro-2-pyrimidinamine (.2 g, 1.220 mmol) in acetonitrile (5 mL) was added 2- methylmorpholine (0.123 g, 1.220 mmol) and TEA (0.357 mL, 2.56 mmol). The reaction mixture was heated to 80 ⁰C overnight. The reaction mixture was poured into H₂O and extracted with EtOAc. The organic layer was dried and concentrated to afford the crude title compound (0.279 g, 1.220 mmol, 95% yield). LC-MS (ES) m/z = 229 [M+H]⁺.

Example 58

4-(1 ,2-dihvdroindazolor4,3-bciπ ,5lbenzoxazepin-4-yl)-6-(2-methyl-4-morpholinyl)-2- pyrimidinamine

4-Chloro-6-(2-methyl-4-morpholinyl)-2-pyrimidinamine (0.279 g, 1.220 mmol) was added to a 20 ml. microwave vial followed by 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 ,2- dihydroindazolo[4,3-6c][1 ,5]benzoxazepine (0.479 g, 1.220 mmol), tetrakis(triphenylphosphine)palladium(0) (0.070 g, 0.061 mmol), potassium carbonate (2.440 ml_, 4.88 mmol), toluene (2.5 ml.) and ethanol (1 ml_). The reaction was irradiated at 130 ⁰C for 10 min. The reaction mixture was diluted with H₂O and extracted with EtOAc. The organics were dried and concentrated and the resulting residue was purified via HPLC (15-45%, ACN/H₂O, 0.1% TFA). Product fractions were selected, combined and concentrated to afford the title compound (0.0891 g, 0.132 mmol, 1 1% yield). LC-MS (ES) m/z = 416 [M+H]⁺. ¹H NMR (400 MHz, DMSOd₆): δ 1.18 (d, 3H), 2.54 (s, 1 H), 2.73 - 3.35 (m, 2H), 3.47 - 3.64 (m, 2H), 3.93 - 4.01 (m, 1 H), 4.43 (br. s., 1 H), 4.70 (br. s., 1 H), 6.88 - 6.96 (m, 1 H), 7.02 (s, 1 H), 7.06 - 7.13 (m, 1 H), 7.23 - 7.33 (m, 3H), 7.62 (s, 1 H), 9.70 (s, 1 H), 12.27 (br. s., 1 H), 12.75 (s, 1 H). Intermediate 129 1-(2-amino-6-chloro-4-pyrimidinyl)-2-azetidinecarboxamide

To 4,6-dichloro-2-pyrimidinamine (.2 g, 1.220 mmol) in acetonitrile (5 mL) was added azetidine -2-carboxylic acid amide (0.122 g, 1.220 mmol) and TEA (0.357 mL, 2.56 mmol), the reaction mixture was heated to 80 ⁰C overnight. The reaction mixture was poured into H₂O and extracted with EtOAc. The organic layer was dried and concentrated to afford the crude title compound (0.278 g, 1.220 mmol, 95% yield). LC-MS (ES) m/z = 228 [M+H]⁺.

Example 59

H2-amino-6-(1 ,2-dihvdroindazolor4,3-bciri ,51benzoxazepin-4-yl)-4-pyrimidinvπ-2- azetidinecarboxamide

1-(2-amino-6-chloro-4-pyrimidinyl)-2-azetidinecarboxamide (0.278 g, 1.220 mmol) was added to a microwave vial followed by 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 ,2- dihydroindazolo[4,3-6c][1 ,5]benzoxazepine (0.479 g, 1.220 mmol), tetrakis(triphenylphosphine)palladium(0) (0.070 g, 0.061 mmol), potassium carbonate (2.440 ml_, 4.88 mmol), toluene (2.5 ml.) and ethanol (1 ml_). The reaction was irradiated at 130 ⁰C for 10 min. The reaction mixture was diluted with H₂O and extracted with EtOAc. The organics were dried and concentrated and the resulting residue was purified via HPLC (10-40%, ACN/H₂O, 0.1% TFA). Product fractions were selected, combined and concentrated to afford the title compound (0.0714 g, 0.106 mmol, 9% yield). LC-MS (ES) m/z = 415 [M+H]⁺. ¹H NMR (400 MHz, DMSOd₆): 5 3.17 (s, 1 H), 4.14 (br. s., 1 H), 4.28 (br. s., 1 H), 4.87 (br. s., 1 H), 5.12 (br. s., 1 H), 6.38 (br. s., 1 H), 6.59 (br. s., 1 H), 6.86 - 6.94 (m, 1 H), 7.04 - 7.14 (m, 1 H), 7.22 (br. s., 1 H), 7.29 (s, 2H), 7.51 - 7.68 (m, 2H), 7.75 (br. s., 1 H), 9.69 (s, 1 H), 12.21 (br. s., 1 H), 12.71 (s, 1 H).

Intermediate 130 1 , 1 -dimethylethyl 3-r(phenylamino)carbonyll-1 -piperidinecarboxylate

In a 100 mL round-bottomed flask, to a solution of 1-{[(1 ,1-dimethylethyl)oxy]carbonyl}-3- piperidinecarboxylic acid (1.5 g, 6.54 mmol), EDC (1.380 g, 7.20 mmol), HOBT (1.002 g, 6.54 mmol) in DMF (30 ml.) was added aniline (0.656 ml_, 7.20 mmol). The mixture was stirred at room temperature overnight. LCMS showed reaction was completed. The reaction was poured into water and extracted with EtOAc (2XIOOmL). Organic layer was washed with brine and dried over MgSO4, filtered and evaporated to give the title compound as white solid (2g, 100%). LC-MS (ES) m/z = 305 [M+H]⁺.

Intermediate 131 N-phenyl-3-piperidinecarboxamide

1 , 1 -dimethylethyl 3-[(phenylamino)carbonyl]-1-piperidinecarboxylate (2g, 6.57 mmol) was dissolved in DCM (6mL) in a 100 mL round-bottomed flask, and 6 mL of TFA was carefully added followed by 3 drops of MeOH.. The mixture was stirred at room temperature for 3 hours. LCMS showed mainly desired product. The solvent was evaporated, and dried to give light brown oily title compound (1.342 g, 100%). LC-MS (ES) m/z = 205 [M+H]⁺.

Intermediate 132 1-(2-amino-6-chloro-4-pyrimidinyl)-N-phenyl-3-piperidinecarboxamide

4,6-dichloro-2-pyrimidinamine (0.538 g, 3.28 mmol), N-phenyl-3-piperidinecarboxamide (0.67 g, 3.28 mmol), and DIPEA (3.44 mL, 19.68 mmol) in 5 ml of ACN were heated in microwave reactor at 140⁰C for 50 min. LCMS showed mainly desired comound with some SM. It was cooled down to room temperature and solid started to crash out of solution. The formed solid was filtered to afford pure light yellow colored title compound (0.211 g, 19.4%). LC-MS (ES) m/z = 333 [M+H]⁺. Example 60 i-^-amino-B-d ^-dihvdroindazoloK^-bcifi .δibenzoxazepin-^ylM-pyrimidinyli-N-phenyl-

3-piperidinecarboxamide

In a sealable tube, 1-(2-amino-6-chloro-4-pyrimidinyl)-N-phenyl-3-piperidinecarboxamide (100 mg, 0.301 mmol), 2-acetyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 ,2- dihydroindazolo[4,3-bc][1 ,5]benzoxazepine (1 18 mg, 0.301 mmol) and sodium bicarbonate (25.3 mg, 0.301 mmol) in 10 ml of dioxane and 5 ml. of water were stirred for 10 min under nitrogen. Pd(Ph3P)4 (17.41 mg, 0.015 mmol) was added and the light yellow solution was heated at 95°C with stirring for overnight. LCMS showed no more starting material.

The reaction was poured into water (100 ml_), the formed solid was filtered, washed with water, hexane, ether, and dried. The solid was dissoved in CH3CN (1.5 ml.) at 50 oC with stirring. The solution was cooled to room temperature and allowed to stand overnight. The resulted yellow solid was filtered and washed by CH3CN, dried and afford the titled compound as yellow solid (20 mg, 12.9%). LC-MS (ES) m/z = 519 [M+H]⁺ 1 H NMR (400 MHz, MeOD-d₄): δ ppm 1.64 (m, 1 H), 1.85 - 1.91 (m, 1 H), 1.92-1.94 (m, 1 H), 1.96 (m, 1 H), 2.08 - 2.15 (m, 1 H), 2.61 - 2.68 (m, 1 H), 3.05 (m, 1 H), 3.08 (m, 1 H), 3.22 (m, 1 H), 3.37 (m, 1 H), 4.43 (m, 1 H), 4.74 (m, 1 H), 6.59 (s, 1 H), 6.88 - 6.95 (m, 1 H), 7.05 - 7.09 (m, 1 H), 7.10 - 7.13 (m, 1 H), 7.17 (m, 1 H), 7.25 (s, 1 H), 7.27 (m, 1 H), 7.29 - 7.35 (m, 2 H), 7.55 - 7.63 (m, 3 H). Intermediate 133 1-(2-amino-6-chloro-4-pyrimidinyl)-N-methyl-L-prolinamide

4,6-dichloro-2-pyrimidinamine (0.328 g, 2.000 mmol) and N-methyl-L-prolinamide (0.329 g, 2.000 mmol) were dissolved in 10 ml. of acetonitrile. Diethylaminomethyl-polystyrene

(0.75 g, 2.400 mmol) was added and the contents were heated in a microwave reactor at

160 C for 1 hr. The contents were filtered to remove the polystyrene base, rinsed with acetonitrile and the mother liquor and washings rotovapped to dryness. The crude material was briefly triturated with diethyl ether, sonicated and decanted, and the crude material was dried by vacuum to give the title compound (300 mg). LC-MS (ES) m/z =

256 [M+H]⁺.

Example 61 i-^-amino-e-d ^-dihvdroindazoloK^-bcifi .δibenzoxazepin^-ylM-pyrimidinyli-N-methyl- L-prolinamide

In a 5 ml. (max vol.) microwave vial, 2-acetyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)-1 ,2-dihydroindazolo[4,3-bc][1 ,5]benzoxazepine (153 mg, 0.391 mmol), 1-(2-amino-6- chloro-4-pyrimidinyl)-N-methyl-L-prolinamide (100 mg, 0.391 mmol), and potassium phosphate (141 mg, 0.665 mmol) were taken up in 4 ml. of 3:1 dioxane-water. The contents were degassed by bubbling nitrogen through for 10 min. tricyclohexylphosphine (5.48 mg, 0.020 mmol) and Pd₂(dba)₃ (7.16 mg, 7.82 μmol) were added, contents degassed an additional 5 min. The vessel was sealed and heated to 100 C overnight (16 hrs). The contents were cooled to room temperature. The dioxane layer was seperated from the water, passed through a C-18 filter cartridge, which was further washed with approx. 10 mL of acetonitrile. The eluent was rotovapped to dryness. The crude material was then purified by RP-HPLC (Gilson) using a 5-75% 0.1% TFA/ACN gradient over 10 min. The desired fractions were pooled and lyophilized to yield (45 mg) of the monotrifluoroacetate salt of the title compound as a yellow powder. LC-MS (ES) m/z = 443 [M+H]⁺. ¹H NMR (400 MHz, DMSOd₆): δ 1.79-2.37 (m, 4H), 2.57-2.63 (d, J = 4.55 Hz, 2H) major rotamer, 2.63-2.72 (d, J = 4.55 Hz, 1 H) minor rotamer, 3.64-3.90 (m, 2H), 4.60- 4.68 major rotamer 4.73-4.80 minor rotamer (m, 2H), 6.35 minor rotamer, 6.76 major rotamer (s, 1 H), 6.86-6.98 (m, 1 H), 7.03-7.15 (m, 1 H), 7.20-7.36 (m, 3H), 7.54 minor rotamer 7.67 major rotamer (s, 1 H), 7.83-7.95 major rotamer 8.16-8.25 (m, 1 H), 6.75-8.25 (bs, 1 H), 9.68 (s, 1 H), 12.21-12.53 (bs, 1 H), 12.75 (s, 1 H).

lntemediate 134 1-(2-amino-6-chloro-4-pyrimidinyl)-D-prolinamide

4,6-dichloro-2-pyrimidinamine (656 mg, 4.00 mmol) and D-prolinamide (457 mg, 4 mmol) were dissolved in 10 mL of acetonitrile, diethylaminomethyl-polystyrene (3000 mg, 9.60 mmol) was added and the contents were heated in the microwave at 160 C for 1 hr. By LCMS, reaction seems to be complete (no SM). The contents were filtered to remove the polystyrene base, rinsed with acetonitrile and the mother liquor and washings rotovapped to dryness. The crude material was briefly triturated with diethyl ether, sonicated and decanted, and dried by vacuum to give the title compound (690 mg). LC-MS (ES) m/z = 242 [M+H]⁺.

Example 62 i-^-amino-B-d ^-dihvdroindazoloK^-άcifi .δibenzoxazepin^-ylM-pyrimidinyli-D- prolinamide

In a 5 ml. (max vol.) microwave vial, 2-acetyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)-1 ,2-dihydroindazolo[4,3-bc][1 ,5]benzoxazepine (243 mg, 0.621 mmol), 1-(2-amino-6- chloro-4-pyrimidinyl)-D-prolinamide (150 mg, 0.621 mmol), and potassium phosphate (224 mg, 1.056 mmol) were taken up in 4 ml. of 3:1 dioxane-water. The contents were degassed by bubbling nitrogen through for 10 min. tricyclohexylphosphine (17.41 mg, 0.062 mmol) and Pd₂(dba)₃ (22.75 mg, 0.025 mmol) were added, contents degassed an additional 5 min. The vessel was sealed and heated to 100 C overnight (16 hrs). The contents were cooled to room temperature, and the dioxane layer was seperated from the aqueous portion. The solids were filtered off and the crude dioxane layer was passed through a C-18 filter cartridge. The filter cartridge was washed with 5 ml. of acetonitrile, and the washings were combined with the crude dioxane solution. The crude material was then purified by RP-HPLC using a 5-75% 0.1 % TFA/ACN gradient over 10 min. The desired fractions were pooled and lyophilized to yield a yellow powder which was still partially acetylated. The acetyl group was removed by dissolving in 10 ml. of methanol, adding 1 ml. of concentrated HCI and heating to 60 C overnight (16 hrs). The contents were then evaporated to remove the methanol, and sat. sodium bicarbonate was added until the pH was basic. The resulting very fine ppt. was filtered, washed with water and dried to give the title compound (110 mg) as a gray-green solid LC-MS (ES) m/z = 429 [M+H]⁺. ¹H NMR (400 MHz, DMSOd₆): δ 1.71-2.41 (m, 4H), 3.50-3.92 (m, 2H), 4.1 1-4.68 (m, 1 H), 5.87-6.54 (m, 3H), 6.76-8.00 (m, 8H), 9.51 (s, 1 H), 12.31 (s, 1 H). Intermediate 135 2-(methoxy)-6-nitroaniline

To 2-amino-3-nitrophenol (5.4 g, 35.0 mmol) dissolved in 50 mL acetone in a 100 mL rb flask, was added potassium carbonate (5.81 g, 42.0 mmol) and methyl iodide (2.6 mL, 42.0 mmol). The red solution was stirred at room temperature for 20 hours. The reaction mixture was concentrated in vacuo, and the residue taken up in ethyl acetate, washed with water (2x), saturated ammonium chloride solution (1x), and brine (1x), dried over MgSO4, filter, and concentrated in vacuo to afford a brick red solid. After drying overnight in vacuum oven at 35 ⁰C, 5.75 g of the title compound was obtained. ¹H NMR (400 MHz, CHLOROFORM-d) d ppm 3.92 (s, 3 H) 6.44 (br s, 2 H) 6.61 (dd, J=8.8, 0.8 Hz, 1 H) 6.89 (d, J=7.6 Hz, 1 H) 7.73 (dd, J=8.8, 1.2 Hz, 1 H).

Intermediate 136 4-bromo-2,6-difluorobenzoyl chloride

To the 4-bromo-2,6-difluorobenzoic acid (3.3075 g, 13.96 mmol) in a 50 mL rb flask was added 8 mL of thionyl chloride. After the mixture was heated for 2 h at reflux, LCMS (in MeOH) indicated the reaction was complete by observation of the methyl ester. The mixture was concentrated in vacuo and azeotroped 2x with toluene to afford 3.5826 g as a dark orange liquid (87% yield). 1 H NMR (CDCI3) is consistent with desired acid chloride structure and purity with toluene still present (singlet at 2.5 ppm). 1 H NMR (400 MHz, CHLOROFORM-d) d ppm 7.23 (m, 1 H) 7.25 (m, 1 H). Used without further purification. Intermediate 137 4-bromo-2,6-difluoro-N-[2-(methyloxy)-6-nitrophenyl]benzamide

To a solution of 2-(methoxy)-6-nitroaniline (1.226 g, 7.29 mmol) and triethylamine (928 uL, 6.66 mmol) in 10 ml. DCM at room temperature was added dropwise a solution of 4- bromo-2,6-difluorobenzoyl chloride (1.7 g, 6.66 mmol) in 2 ml. DCM. LCMS (after being stirred overnight) indicated: 50% bisacylated product, 34% aniline starting material, and

11 % desired monoacylated product. The reaction mixture was washed with 0.1 N HCI

(2x), sodium bicarbonate (2x) and brine, dried over MgSO4, filtered, and concentrated in vacuo to afford 2.8604 g crude red oil.

To the residue dissolved in 30 ml. 1 :1 MeOH/dioxane was added sodium hydroxide (140 mg, 3.5 mmol). The solution was stirred for 1 h at rt. LCMS shows 10% bisacylated product remaining, 45% desired product, and 35% aniline starting material. An additional 2 mmol NaOH was added to force reaction to completion after an additional hour. The mixture was quenched with saturated ammonium chloride solution, diluted with DCM, washed with saturated sodium bicarbonate solution, and brine, dried over MgSO4, filtered, and concentrated in vacuo to afford 3.0955 g of a dark orange oil which was purified on Combiflash using a 40 g silica column (0-100% EtOAc/Hex) by a liquid load to afford 1.0338 g of a tan solid which was dried overnight in vacuum oven at 35 ⁰C. (39% yield) LCMS 98% pure.. ¹H NMR (400 MHz, CHLOROFORM-d) d ppm 3.96 (s, 3 H) 7.22 (m, 3 H) 7.35 (t, J=8.21 Hz, 1 H) 7.59 (d, J=8.08 Hz, 1 H) 8.22 (br. s., 1 H). Intermediate 138 N-[2-amino-6-(methyloxy)phenyl]-4-bromo-2,6-difluorobenzamide

As a test reaction, 4-bromo-2,6-difluoro-N-[2-(methyloxy)-6-nitrophenyl]benzamide (0.1 g, 0.26 mmol) was dissolved in 5 ml. THF (0.05 M) and circulated through a Thales H-cube® using a Ni (Ra) catalyst cartridge at 10 bar pressure, room temperature. After 1 hour, the yellow solution turned colorless and the reaction was complete by LCMS. The remaining 933.8 mg was dissolved in 45 ml. THF and circulated through the H-cube using the same conditions. The solution was allowed to circulate overnight. LCMS (18 h) indicated the reaction was complete, and no starting material seen. The pale orange solution was concentrated in vacuo to afford a pale pink solid (1.0172 g, 100% yield). LCMS: 94% purity.. ¹H NMR (400 MHz, CHLOROFORM-d) d ppm 3.84 (s, 3 H) 4.22 (br. s., 2 H) 6.38 (dd, J=QA, 0.8 Hz, 1 H) 6.47 (dd, J=8.34, 1.01 Hz, 1 H) 7.07 (t, J=8.21 Hz, 1 H) 7.19 - 7.25 (m, 2 H) 7.64 (br. s., 1 H).

Intermediate 138 3-bromo-1-fluoro-9-(methyloxy)-5,10-dihydro-11 H-dibenzo[b,e][1 ,4]diazepin-11-one

As a test reaction, in a 4 mL vial was added Λ/-[2-amino-6-(methyloxy)phenyl]-4-bromo- 2,6-difluorobenzamide (100 mg, 0.28 mmol) and then dissolved in 1.5 mL THF (0.2 M). The sodium hydride (34 mg, 0.84 mmol) was then added. After all bubbling ceased the vial was capped and heated at 65 ⁰C. LCMS after 42h showed 23% desired, and no starting material remaining. The remaining amount of starting material in a 100 mL rb flask (917.2 mg, 2.57 mmol) was dissolved in 12 mL THF and treated with 3 eq NaH (308 mg, 7.70 mmol) and heated to 70 ⁰C ON. LCMS (18 h) shows very little product. 42% SM, 4% product, and an unknown byproduct 38%. An additional 10 mL THF and 3 eq NaH was added and the reaction continued to heat. The starting material was consumed within an additional 3h and the reaction was quenched with ammonium chloride and diluted with ethyl acetate. The two reactions were combined for workup. The aqueous layer was extracted 3x with ethyl acetate. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo to afford an orange solid (1.2 g). The crude material was dry-loaded onto celite and purified on silica gel via Combiflash (0-5% MeOH/DCM). The fractions which were enriched more than 50% with the desired product were combined and concentrated to afford 144.5 mg of a pale yellow solid (LCMS: 65% purity) and were used in the next step without further purification. (¹H NMR (CDCI3) suggests purity is higher than 65%. Spectral pattern is consistent with desired structure. ¹H NMR (400 MHz, CHLOROFORM-d) d ppm 3.87 (d, J=1.52 Hz, 3 H) 5.37 (br. s., 1 H) 6.47 (d, J=7.83 Hz, 1 H) 6.64 (d, J=8.08 Hz, 1 H) 6.81 (d, J=1.26 Hz, 1 H) 6.90 - 6.96 (m, 1 H) 7.00 (td, J=8.21 , 1.52 Hz, 1 H) 7.58 (br. s., 1 H).

Intermediate 139

4-bromo-10-(methyloxy)-2,6-dihydro-1 H-indazolo[3,4-bc][1 ,5]benzodiazepine

To the 3-bromo-1-fluoro-9-(methyloxy)-5,10-dihydro-1 1 H-dibenzo[b,e][1 ,4]diazepin-11-one (145 mg, 0.43 mmol) dissolved in 2 mL toluene was added Lawesson's reagent (173 mg, 0.43 mmol) and heated to 100 ⁰C overnight (16 h) in a sealed 2-5 mL microwave vessel. LCMS after 16 h indicated a 1 :1 ratio of starting material to desired product. An additional equivalent of Lawesson reagent was added and the mixture continued to heat at 100 ⁰C. No significant change by LCMS. The solvent was then evaporated under N2 stream to give the crude thione.

The yellow residue was taken up in 2 mL dioxane and treated with 104 uL hydrazine monohydrate. The mixture was capped and heated under N₂ at 85 ⁰C. LCMS (4h): 33% thioamide starting material, and, no desired product seen. An additional 5 equivalents of hydrazine was added and the reaction heated overnight. LCMS (22h): 32% desired product, 6% thioamide. An additional 5 eq hydrazine monohydrate was added and the reaction continued to heat in order to ensure complete conversion. After an additional 6 hours, the reaction looked complete by LCMS - no starting material or thioamide seen, 47% desired product. The yellow slurry was filtered through paper on a porcelain Buchner funnel and washed with dioxane to remove the white solid byproduct and produce a clear yellow filtrate which contains the product. LCMS: 54%. The filtrate was concentrated in vacuo to afford an orange solid (263.7 mg) which was taken on to the next step without further purification.

Intermediate 140

Tris(1 ,1-dimethylethyl) 4-bromo-10-(methyloxy)-2H-indazolo[3,4-bc][1 ,5]benzodiazepine- 2,6,1 1-tricarboxylate

To the 4-bromo-10-(methyloxy)-2,6-dihydro-1 H-indazolo[3,4-bc][1 ,5]benzodiazepine dissolved in 4 mL DCM was added DMAP (97 mg, 0.80 mmol), TEA (422 uL, 3.03 mmol), and BoC₂O (660 mg, 3.03 mmol). The yellow reaction mixture bubbled vigorously upon addition of the BoC₂O and became a brown solution. LCMS (90 min) showed no starting material remaining, 34% desired product. Let stir over the weekend at room temperature. No change by LCMS. The mixture was concentrated in vacuo to afford 685.5 g crude and purified by ISCO Combiflash (0-100% EtOAc/Hex) using a 12 g silica column. The desired fractions were combined and concentrated in vacuo to afford a yellow oil which was dried overnight in the vacuum oven at 35 ⁰C to afford 174.6 mg of a yellow oil (18% yield). LCMS purity: 51 % desired, 32% bisprotected product.

Intermediate 141

Tris(1 ,1-dimethylethyl) 10-(methyloxy)-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-2H- indazolo[3,4-bc][1 ,5]benzodiazepine-2,6, 11 -tricarboxylate

In a 2-5 mL microwave vial was placed potassium acetate (109 mg, 1.1 mmol), bis(pinacolato)diboron (70 mg, 0.276 mmol), PdCI₂(dppf)-CH₂CI₂ adduct (23 mg, 28 umol), and the benzodiazepine starting material (174.6 mg) dissolved in 1 ,4-dioxane (3 mL). The orange reaction mixture was sealed and heated at 100 ⁰C. LCMS (4h) shows the desired products: triboc (35%), diboc (20%) as well as some unreacted starting material, 8% and 5% triboc and diboc respectively. Continued heating overnight. LCMS (18 h): showed the desired products: triboc (30%), diboc (24%) and no residual starting material. The reaction mixture was concentrated in vacuo, and taken up in ethyl acetate and water, sonicated, and filtered through celite. The filtrate was partitioned between ethyl acetate and water. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo to afford a brown gum (217 mg) which was used without further purification. LCMS of the desired products: triboc (31%), diboc (24%). Example 63

4-r(3R)-3-methyl-4-morpholinyll-6-ri 0-(methyloxy)-2,6-dihvdro-1 H-indazolor3,4- bc1[1 ,51benzodiazepin-4-yl1-2-pyrimidinamine

To a 2-5 ml. microwave vial was added Pd2(dba)3 (14.6 mg, 16 umol), tricyclohexylphosphine (9.0 mg, 0.032 mmol), potassium phosphate tribasic monohydrate (125 mg, 0.54 mmol), and 4-chloro-6-[(3R)-3-methyl-4-morpholinyl]-2-pyrimidinamine (73 mg, 0.32 mmol) as solids, followed by tris(1 , 1 -dimethylethyl) 10-(methyloxy)-4-(4, 4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)-2H-indazolo[3,4-bc][1 ,5]benzodiazepine-2,6, 11- tricarboxylate (217 mg, 0.32 mmol) in 2.5 ml. dioxane. 800 uL water was added, and the mixture was capped and heated to 100 ⁰C overnight (18 h). LCMS: shows no starting boronate ester remaining, 61% starting starting chloropyrimidine, 12% Cy3P=O, 15% di- boc product, and 4% mono-boc product. The dark brown mixture was concentrated in the EZ2. The residue was taken up in ethyl acetate and water, sonicated, and filtered through celite. The celite was rinsed well with water and ethyl acetate. The phases were partitioned and the aqueous phase was extracted 3x with ethyl acetate. The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo to afford a black solid (267.6 mg) which was used without further purification.

The product was then treated with 4 ml. 4N HCI/dioxane and 1 ml. MeOH and monitored reaction progress by LCMS. After 18h, no Boc protected products remained. The black solution was concentrated in vacuo to afford 339.9 mg of a brown solid. LCMS: 15% desired. The product was dissolved in 2 mL DMSO and submitted for basic HPLC purification. Desired fractions were combined to afford 3.4 mg of product as a tan solid

(2% yield) after lyophilization. LCMS: 95% purity. 1 H NMR (CDCI3) consistent with desired structure and purity. 1 H NMR (400 MHz, CHLOROFORM-d) d ppm 1.33 (d, 3 H)

3.27 (td, J=12.82, 3.66 Hz, 1 H) 3.59 (td, J=11.81 , 2.91 Hz, 1 H) 3.71 - 3.77 (m, 1 H) 3.77 - 3.84 (m, 1 H) 3.94 (s, 3 H) 4.02 (dt, J=7.39, 3.76 Hz, 1 H) 4.09 (dt, J=12.13, 1.64 Hz, 1 H) 4.33 - 4.45 (m, 1 H) 4.86 (s, 2 H) 6.35 (s, 1 H) 6.37 (s, 1 H) 6.47 (dd, J=8.21 , 0.88 Hz, 1 H) 6.54 (dd, J=7.96, 1.14 Hz, 1 H) 6.77 (t, J=8.08 Hz, 1 H) 6.96 (d, J=0.76 Hz, 1 H) 7.39 (s, 1 H) 7.64 (s, 1 H) 9.30 (s, 1 H).

Example 64 - Capsule Composition

An oral dosage form for administering the present invention is produced by filing a standard two piece hard gelatin capsule with the ingredients in the proportions shown in Table I, below.

Table I

INGREDIENTS AMOUNTS

4-(10-Fluoro-1 ,2-dihydroindazolo[4,3-6c][1 ,5]benzoxazepin- 20 mg 4-yl)-6-(4-morpholinyl)-2-pyrimidinamine (Compound of Example 1 )

Lactose 50 mg

Talc 15 mg

Magnesium Stearate 4 mg

Example 65 - Injectable Parenteral Composition

An injectable form for administering the present invention is produced by stirring 1.5% by weight of 4-(1 ,2-Dihydroindazolo[4,3-6c][1 ,5]benzoxazepin-4-yl)-6-[(2R)-2- ethyl-1-pyrrolidinyl]-2-pyrimidinamine (Compound of Example 2) in 10% by volume propylene glycol in water.

Example 66 - Tablet Composition The sucrose, calcium sulfate dihydrate and an Akt inhibitor as shown in

Table Il below, are mixed and granulated in the proportions shown with a 10% gelatin solution. The wet granules are screened, dried, mixed with the starch, talc and stearic acid;, screened and compressed into a tablet.

Table Il

INGREDIENTS AMOUNTS

4-(2-Cyclopropyl-1-pyrrolidinyl)-6-(1 ,2- 25 mg dihydroindazolo[4,3-6c][1 ,5]benzoxazepin-4-yl)-2- pyrimidinamine (Compound of Example 3) calcium sulfate dihydrate 35 mg sucrose 4 mg starch 2 mg talc 1 mg stearic acid 0.5 mg

While the preferred embodiments of the invention are illustrated by the above, it is to be understood that the invention is not limited to the precise instructions herein disclosed and that the right to all modifications coming within the scope of the following claims is reserved.

Claims

What is claimed is:

1. A compound of Formula (I):

Ci-C3alkoxy,

Ci-C3alkoxy substituted with from one to three substituents selected from halogen, trifluoromethyl, hydroxy, oxo, and methoxy, Ci-C4alkyl, and

Ci-C4alkyl substituted with form one to three substituents selected from halogen, trifluoromethyl, hydroxy, oxo, and methoxy;

2 3 4

R , R and R are each independently selected from: hydrogen, Ci-Cβalkyl, substituted Ci-Cβalkyl, C-i-C_βalkoxy, substituted C-i-Cβalkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl,

C3-Cδcylcoalkyl, substituted C3-C8cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, -C(O)OR²⁰, formyl, nitro, cyano,

-NHC(O)NHR²O -S(O)_nR²O,

-NR²SR²B,

-C(O)NR²5R²6, phosphonic acid, sulfonic acid, phosphinic acid,

-SO₂NR²⁵R²⁶, and halogen, where, n is 0-2, R²O is selected from: hydrogen, C-i-Cβalkyl, C3-C8cycloalkyl, substituted Ci-Cβalkyl, and substituted C3-C8cycloalkyl, and

R²⁵ and R²⁶ are each independently selected from: hydrogen,

C-|-C4alkyl, substituted C-|-C4alkyl, C3_C8cycloalkyl, C-|-C-|2^ary'' and -C(O)Ci_C6alkyl, or R²⁵ and R²⁶ taken together with the nitrogen to which they are attached represent a 5 to 6 member saturated ring containing up to one other heteroatom selected from oxygen and nitrogen, or either:

2 3

4 R is as described above, or,

3 4

R and R form a 5 or 6 member saturated or unsaturated ring, optionally containing 1 or 2 heteroatoms selected from oxygen, nitrogen, and sulfur, and optionally substituted with 1 or 2 substituents selected from halogen, trifluoromethyl, Ci-C4alkyl, hydroxy, oxo, and methoxy, and

2 R is as described above;

5 R is selected from: hydrogen, -NH2, and -N(H)Ci-C4alkyl;

6 R is selected from: aryl, substituted aryl, C3_C8cycloalkyl, substituted C3. Cβcycloalkyl, heteroaryl, substituted heteroaryl, Ci-Cβalkyl, substituted

Ci-Cβalkyl, heterocycloalkyl, substituted heterocycloalkyl, Ci-Cβalkoxy, substituted Ci-Cβalkoxy, heteroaryloxy, aryloxy, -SCi-Cβalkylaryl, -

SarylCi-C6alkyl, and -NR³⁵R³⁶, where, R³⁵ and R³⁶ are each independently selected from: hydrogen, C-|-

Cβalkyl, substituted Ci-Cβalkyl, C3_C8cycloalkyl, substituted C3. Cβcycloalkyl, heteroaryl, substituted heteroaryl, substituted C-i-C-^aryl and C-i-C^ary'; ^and

X is selected from: O, S, Ncyclopropyl, NH, NEt and NMe; t thereof including a pharmaceutically acceptable salt thereof.

2. A compound of Formula (I) as described in claim 1 , having the following Formula (II):

R is selected from: hydrogen, trifluoromethyl, fluoride, chloride, bromide, C-|- C3alkoxy, and C-|-C4alkyl;

R , R and R are each independently selected from: hydrogen, Ci-C6alkyl, substituted Ci-Cβalkyl, Ci-Cβalkoxy, substituted Ci-Cβalkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl,

C3-Cδcylcoalkyl, substituted C3-Cδcycloalkyl, heterocycloalkyl, substituted heterocycloalkyl,

-C(O)OR⁵⁰,

-NHC(O)NHRSO

-S(O)_nRSO, -NR55R56, -CONR⁵⁵R⁵⁶, -SO₂NR⁵⁵R⁵⁶, and halogen, where, n is 0-2,

R⁵O is selected from: hydrogen, Ci-Cβalkyl and substituted C-|-

Cβalkyl, and

R⁵⁵ and R⁵⁶ are each independently selected from: hydrogen,

Ci-C4alkyl, and substituted C-|-C4alkyl, or R⁵⁵ and R⁵⁶ taken together with the nitrogen to which they are attached represent a 5 to 6 member saturated ring containing up to one other heteroatom selected from oxygen, and nitrogen,

R is selected from: -NH₂ and -N(H)Ci-C4alkyl;

12 R is selected from: aryl, substituted aryl, C3_C8cycloalkyl, substituted C3. Cβcycloalkyl, heteroaryl, substituted heteroaryl, Ci-Cβalkyl, substituted

Ci-Cβalkyl, heterocycloalkyl, substituted heterocycloalkyl, Ci-Cβalkoxy, substituted Ci-Cβalkoxy, aryloxy, heteroaryloxy, -SCi-Cβalkylaryl, -

SarylCi-C6alkyl, and -NR⁶⁵R⁶⁶, where, R⁶⁵ and R⁶⁶ are each independently selected from: hydrogen, C-|-

Cβalkyl, substituted Ci-Cβalkyl, C3_C8cycloalkyl, substituted C3.

C_βcycloalkyl, heteroaryl, substituted heteroaryl, substituted C-|-C-|₂aryl and C-|-C-|₂aryl; and

X is selected from: O, S, Ncyclopropyl, NH, NEt and NMe;

or a salt thereof including a pharmaceutically acceptable salt thereof.

3. A compound of Formula (I) as described in claim 1 , having the following Formula (III):

13 R is selected from: hydrogen, methoxy, fluoride, chloride, bromide, and Ci-

C2alkyl; R , R and R are each independently selected from: hydrogen, Ci-C4alkyl,

Ci-C4alkoxy, aryl, heteroaryl, C3-Cscylcoalkyl, heterocycloalkyl, - C(O)OR⁸⁰, -NHC(O)NHRSO₁ -S(O)_nR⁸⁰, -NR⁸SRSB₁ -CON R⁸5R⁸6, . Sθ2NR⁸⁵R⁸⁶, and halogen, where, n is 0-2,

R⁸⁰ is selected from: hydrogen and Ci-Cβalkyl and

R⁸S and R⁸^ are each independently selected from: hydrogen and

Ci-C4alkyl, or R⁸S and R⁸^ taken together with the nitrogen to which they are attached represent a 5 to 6 member saturated ring containing up to one other heteroatom selected from oxygen and nitrogen;

R is selected from: -NH2 and -N(H)Ci-C4alkyl;

R is selected from: aryl, substituted aryl, heteroaryl, substituted heteroaryl,

Ci-C4alkyl, Ci-C4substituted alkyl, heterocycloalkyl, substituted heterocycloalkyl, C3_C8cycloalkyl, substituted C3_C8cycloalkyl, and - NR95R96, where,

R95 and R^6 are each independently selected from: hydrogen, Ci-

C4alkyl, substituted Ci-C4alkyl, C3_C8cycloalkyl, substituted C3. Cβcycloalkyl, heteroaryl, substituted heteroaryl, substituted C-i-C-^aryl and C-i-C^ary'; ^ancl X is selected from: O, S, Ncyclopropyl, NH, NEt and NMe;

or a salt thereof including a pharmaceutically acceptable salt thereof.

4. A compound of claim 1 selected from:

4-(10-Fluoro-1 ,2-dihydroindazolo[4,3-6c][1 ,5]benzoxazepin-4-yl)-6-(4-morpholinyl)-

2-pyrimidinamine;

4-(1 ,2-Dihydroindazolo[4,3-6c][1 ,5]benzoxazepin-4-yl)-6-[(2R)-2-ethyl-1 - pyrrolidinyl]-2-pyrimidinamine;

4-(2-Cyclopropyl-1-pyrrolidinyl)-6-(1 ,2-dihydroindazolo[4,3-6c][1 ,5]benzoxazepin- 4-yl)-2-pyrimidinamine;

4-(1 ,2-Dihydroindazolo[4,3-6c][1 ,5]benzoxazepin-4-yl)-6-(2-methyl-1 -piperidinyl)-2- pyrimidinamine;

4-(1 ,2-Dihydroindazolo[4,3-όc][1 ,5]benzoxazepin-4-yl)-6-[(3/?)-3-ethyl-4- morpholinyl]-2-pyrimidinamine;

4-(2-Cyclopropyl-1-piperidinyl)-6-(1 ,2-dihydroindazolo[4,3-6c][1 ,5]benzoxazepin-4- yl)-2-pyrimidinamine;

4-[2-Amino-6-(4-morpholinyl)-4-pyrimidinyl]-Λ/-methyl-1 ,2-dihydroindazolo[4,3- 6c][1 ,5]benzoxazepine-9-sulfonamide;

4-(1 ,2-Dihydroindazolo[4,3-6c][1 ,5]benzoxazepin-4-yl)-6-(3-oxa-8- azabicycloβ^.ijoct-δ-yl^-pyrimidinamine;

4-(1 ,2-Dihydroindazolo[4,3-6c][1 ,5]benzoxazepin-4-yl)-6-[2-(methyloxy)phenyl]-2- pyrimidinamine; 4-(1 ,2-Dihydroindazolo[4,3-6c][1 ,5]benzoxazepin-4-yl)-6-(1-pyrrolidinyl)-2- pyrimidinamine;

4-(1 ,2-Dihydroindazolo[4,3-6c][1 ,5]benzoxazepin-4-yl)-6-(2-methyl-1-pyrrolidinyl)- 2-pyrimidinamine;

4-(1 ,2-Dihydroindazolo[4,3-6c][1 ,5]benzoxazepin-4-yl)-6-(1-piperidinyl)-2- pyrimidinamine;

4-(1-Azetidinyl)-6-(1 ,2-dihydroindazolo[4,3-όc][1 ,5]benzoxazepin-4-yl)-2- pyrimidinamine;

Λ/⁴-Cyclohexyl-6-(1 ,2-dihydroindazolo[4,3-6c][1 ,5]benzoxazepin-4-yl)-2,4- pyrimidinediamine;

Λ/⁴-Cyclopentyl-6-(1 ,2-dihydroindazolo[4,3-6c][1 ,5]benzoxazepin-4-yl)-2,4- pyrimidinediamine;

6-(1 ,2-Dihydroindazolo[4,3-6c][1 ,5]benzoxazepin-4-yl)-Λ/⁴-(1-methylethyl)-2,4- pyrimidinediamine;

6-(1 ,2-dihydroindazolo[4,3-6c][1 ,5]benzoxazepin-4-yl)-Λ/⁴,Λ/⁴-dimethyl-2,4- pyrimidinediamine;

Λ/⁴-Cyclobutyl-6-(1 ,2-dihydroindazolo[4,3-6c][1 ,5]benzoxazepin-4-yl)-2,4- pyrimidinediamine;

6-(1 ,2-Dihydroindazolo[4,3-6c][1 ,5]benzoxazepin-4-yl)-Λ/⁴-methyl-Λ/⁴-(1 - methylethyl)-2,4-pyrimidinediamine;

6-(1 ,2-dihydroindazolo[4,3-6c][1 ,5]benzoxazepin-4-yl)-Λ/⁴-(2-methylpropyl)-2,4- pyrimidinediamine; 6-(1 ,2-dihydroindazolo[4,3-6c][1 ,5]benzoxazepin-4-yl)-Λ/⁴,Λ/⁴-diethyl-2,4- pyrimidinediamine;

4-(1 ,2-Dihydroindazolo[4,3-6c][1 ,5]benzoxazepin-4-yl)-6-(2-ethyl-1 -piperidinyl)-2- pyrimidinamine;

1-[2-Amino-6-(1 ,2-dihydroindazolo[4,3-6c][1 ,5]benzoxazepin-4-yl)-4-pyrimidinyl]-L- prolinamide;

1-[2-Amino-6-(1 ,2-dihydroindazolo[4,3-6c][1 ,5]benzoxazepin-4-yl)-4-pyrimidinyl]-

Λ/,Λ/-dimethyl-L-prolinamide;

4-[2-Amino-6-(4-morpholinyl)-4-pyrimidinyl]-Λ/,Λ/-dimethyl-1 ,2-dihydroindazolo[4,3- 6c][1 ,5]benzoxazepine-8-sulfonamide; and

4-(2,6-Dihydro-1/-/-indazolo[3,4-6c][1 ,5]benzodiazepin-4-yl)-6-(4-morpholinyl)-2- pyrimidinamine;

6-(1 ,2-Dihydroindazolo[4,3-6c][1 ^benzoxazepin^-yO-Λ/⁴-^ -

(phenylmethyl)cyclopropyl]-2,4-pyrimidinediamine;

θ^i ^-Dihydroindazoloμ^-bclti ^lbenzoxazepin^-yO-Λ^^I J-dimethyl^- phenylethyl)-2,4-pyrimidinediamine;

4-(1 ,2-Dihydroindazolo[4,3-6c][1 ,5]benzoxazepin-4-yl)-6-[2-(1-methylethyl)-1- pyrrolidinyl]-2-pyrimidinamine;

4-Cyclopentyl-6-(1 ,2-dihydroindazolo[4,3-6c][1 ,5]benzoxazepin-4-yl)-2- pyrimidinamine;

4-(1 ,2-Dihydroindazolo[4,3-6c][1 ,5]benzoxazepin-4-yl)-6-(tetrahydro-2/-/-pyran-4- yl)-2-pyrimidinamine;

4-(1 ,2-Dihydroindazolo[4,3-6c][1 ,5]benzoxazepin-4-yl)-6-(phenylmethyl)-2- pyrimidinamine;

4-(1 ,2-Dihydroindazolo[4,3-6c][1 ,5]benzoxazepin-4-yl)-6-(1 ,1-dimethylethyl)-2- pyrimidinamine;

4-(1 ,2-Dihydroindazolo[4,3-6c][1 ,5]benzoxazepin-4-yl)-6-(2-phenylethyl)-2- pyrimidinamine;

4-(6-methyl-2,6-dihydro-1 H-indazolo[3,4-bc][1 ,5]benzodiazepin-4-yl)-6-(4- morpholinyl)-2-pyrimidinamine;

4-(2,6-dihydro-1 /-/-indazolo[3,4-6c][1 ,5]benzodiazepin-4-yl)-6-(3-oxa-8- azabicyclo^^.iloct-δ-yl^-pyrimidinamine;

6-(1 ,2-dihydroindazolo[4,3-bc][1 ,5]benzoxazepin-4-yl)-N4-(1 -methyl-1 H-pyrazol-3- yl)-2,4-pyrimidinediamine;

4-(1 ,2-dihydroindazolo[4,3-bc][1 ,5]benzoxazepin-4-yl)-6-(2-methyl-4-morpholinyl)-

2-pyrimidinamine;

1-[2-amino-6-(1 ,2-dihydroindazolo[4,3-bc][1 ,5]benzoxazepin-4-yl)-4-pyrimidinyl]-N- phenyl-3-piperidinecarboxamide;

1-[2-amino-6-(1 ,2-dihydroindazolo[4,3-bc][1 ,5]benzoxazepin-4-yl)-4-pyrimidinyl]-N- methyl-L-prolinamide;

1-[2-amino-6-(1 ,2-dihydroindazolo[4,3-6c][1 ,5]benzoxazepin-4-yl)-4-pyrimidinyl]-D- prolinamide; and 4-[(3R)-3-methyl-4-morpholinyl]-6-[10-(methyloxy)-2,6-dihydro-1 H-indazolo[3,4- bc][1 ,5]benzodiazepin-4-yl]-2-pyrimidinamine

or a salt thereof including a pharmaceutically acceptable salt thereof.

5. A pharmaceutical composition comprising a compound according to claim 1 , or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

6. A process for preparing a pharmaceutical composition containing a pharmaceutically acceptable carrier or diluent and an effective amount of a compound of Formula (I) as described in claim 1 or a pharmaceutically acceptable salt thereof, which process comprises bringing the compound of Formula (I) or a pharmaceutically acceptable salt thereof into association with a pharmaceutically acceptable carrier or diluent.

7. A method of treating or lessening the severity of cancer in a mammal in need thereof, which comprises administering to such mammal a therapeutically effective amount of a compound of Formula I, as described in claim 1 or a pharmaceutically acceptable salt thereof.

8. The method of claim 7 wherein the mammal is a human.

9. A method of treating or lessening the severity of cancer in a mammal in need thereof, which comprises administering to such mammal a therapeutically effective amount of a compound of claim 4 or a pharmaceutically acceptable salt thereof.

10. The method of claim 9 wherein the mammal is a human.

11. The method according to claim 7 wherein said cancer is selected from: brain (gliomas), glioblastomas, Bannayan-Zonana syndrome, Cowden disease, Lhermitte-Duclos disease, breast, colon, head and neck, leukemia, kidney, lung, liver, melanoma, ovarian, pancreatic, prostate, sarcoma and thyroid.

12. The method according to claim 9 wherein: said cancer is selected from brain (gliomas), glioblastomas, Bannayan-Zonana syndrome, Cowden disease, Lhermitte-Duclos disease, breast, colon, head and neck, leukemia, kidney, lung, liver, melanoma, ovarian, pancreatic, prostate, sarcoma and thyroid.

13. Use of a compound of Formula (I), as described in claim 1 or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in treating or lessening the severity of cancer.

14. The method of inhibiting PDK1 activity in a mammal in need thereof, which comprises administering to such mammal a therapeutically effective amount of a compound of Formula I, as described in claim 1 or a pharmaceutically acceptable salt thereof.

15. The method of claim 14 wherein the mammal is a human.

16. A method of treating cancer in a mammal in need thereof, which comprises: administering to such mammal a therapeutically effective amount of a) a compound of Formula (I), as described in claim 1 or a pharmaceutically acceptable salt thereof; and b) at least one anti-neoplastic agent.

17. The method claim 16, wherein the at least one anti-neoplastic agent is selected from the group consisting essentially of anti-microtubule agents, platinum coordination complexes, alkylating agents, antibiotic agents, topoisomerase Il inhibitors, antimetabolites, topoisomerase I inhibitors, hormones and hormonal analogues, signal transduction pathway inhibitors; non-receptor tyrosine kinase angiogenesis inhibitors; immunotherapeutic agents; proapoptotic agents; and cell cycle signaling inhibitors.

18. The method of claim 16, wherein the at least one anti-neoplastic agent is an anti-microtubule agent selected from diterpenoids and vinca alkaloids.

19. The method of claim 16, wherein the at least one anti-neoplastic agent is a diterpenoid.

20. The method of claim 16, wherein the at least one anti-neoplastic agent is a vinca alkaloid.

21. The method of claim 16, wherein the at least one anti-neoplastic agent is a platinum coordination complex.

22. The method of claim 16, wherein the at least one anti-neoplastic agent is paclitaxel, carboplatin, or vinorelbine.

23 The method of claim 16, wherein the at least one anti-neoplastic agent is paclitaxel.

24. The method of claim 16, wherein the at least one anti-neoplastic agent is carboplatin.

25. The method of claim 16, wherein the at least one anti-neoplastic agent is vinorelbine.

26. The method of claim 16, wherein the at least one anti-neoplatic agent is a signal transduction pathway inhibitor.

27. The method of claim 26, wherein the signal transduction pathway inhibitor is an inhibitor of a growth factor receptor kinase selected from the group consisting of VEGFR2, TIE2, PDGFR, BTK, IGFR-1 , TrkA, TrkB, TrkC, and c-fms.

28. The method of claim 26, wherein the signal transduction pathway inhibitor is an inhibitor of a serine/threonine/tyrosine kinase selected from the group consisting of Raf, MEK, Akt, and PKC family kinases.

29. The method of claim 26, wherein the signal transduction pathway inhibitor is an inhibitor of a serine/threonine kinase selected from the src family of kinases.

30. The method of claim 29, wherein the signal transduction pathway inhibitor is an inhibitor of c-src.

31. The method of claim 26, wherein the signal transduction pathway inhibitor is an inhibitor of Ras oncogene selected from inhibitors of farnesyl transferase and geranylgeranyl transferase.

32. The method of claim 26, wherein the signal transduction pathway inhibitor is an inhibitor of PI3K.

33. The method of claim 16, wherein the at least one anti-neoplastic agent is a cell cycle signaling inhibitor.

34. The method of claim 33, wherein the cell cycle signaling inhibitor is selected from inhibitors of the group CDK2, CDK4, CDK6 and CDK8.

35. A pharmaceutical combination as claimed in claim 16 for use in therapy.

36. The use of a pharmaceutical combination as claimed in claim 16 for the preparation of a medicament useful in the treatment of cancer.

37. The method according to claim 7 wherein said cancer is selected from: brain (gliomas), glioblastomas, Bannayan-Zonana syndrome, Cowden disease, Lhermitte-Duclos disease, breast, inflammatory breast cancer, Wilm's tumor, Ewing's sarcoma, Rhabdomyosarcoma, ependymoma, medulloblastoma, colon, head and neck, kidney, lung, liver, melanoma, ovarian, pancreatic, prostate, sarcoma, osteosarcoma, giant cell tumor of bone, thyroid,

Lymphoblastic T cell leukemia, Chronic myelogenous leukemia, Chronic lymphocytic leukemia, Hairy-cell leukemia, acute lymphoblastic leukemia, acute myelogenous leukemia, Chronic neutrophilic leukemia, Acute lymphoblastic T cell leukemia, Plasmacytoma, lmmunoblastic large cell leukemia, Mantle cell leukemia, Multiple myeloma Megakaryoblastic leukemia, multiple myeloma, acute megakaryocyte leukemia, promyelocytic leukemia, Erythroleukemia, malignant lymphoma, hodgkins lymphoma, non-hodgkins lymphoma, lymphoblastic T cell lymphoma, Burkitt's lymphoma, follicular lymphoma, neuroblastoma, bladder cancer, urothelial cancer, lung cancer, vulval cancer, cervical cancer, endometrial cancer, renal cancer, mesothelioma, esophageal cancer, salivary gland cancer, hepatocellular cancer, gastric cancer, nasopharangeal cancer, buccal cancer, cancer of the mouth, GIST (gastrointestinal stromal tumor) and testicular cancer.

38. The method of claim 37 wherein the mammal is a human.

39. A method of treating or lessening the severity of at least one disease or disorder related to metabolism, an immune disease and/or aging in a mammal in need thereof, which comprises administering to such mammal a therapeutically effective amount of a compound of Formula I, as described in any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof.

40. The method of claim 39 wherein said mammal is a human.

41. Use of a compound of Formula I, as described in any one of claims 1 to 4 for the manufacture of a medicament useful in the treatment of at least one disease or disorder related to metabolism, an immune disease and/or aging.