Piperidine substituted pyrazolopyrimidine derivatives as inhibitors of SGK1

Abstract

The present invention provides compounds of Formula (I): or stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, wherein all the variables are as defined herein. These compounds are selective SGK1 inhibitors. This invention also relates to pharmaceutical compositions comprising these compounds and methods of treating disorders associated with serum- and glucocorticoid-regulated kinase 1 (SGK1) activity, such as cardiovascular disorders, fibrotic diseases, metabolic diseases, immune and inflammatory diseases, neurological disorders, and cancer, by using the compounds and pharmaceutical compositions.

Description

[0001] PIPERIDINE SUBSTITUTED PYRAZOLOPYRIMIDINE DERIVATIVES AS INHIBITORS OF SGK1 CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Application No. 63 / 585,630 filed September 27, 2023, the disclosure of which are incorporated herein by reference in its entirety. FIELD OF THE INVENTION The present invention relates to novel amino-substituted pyrazolopyrimidine derivatives, compositions containing them, and methods of using them, for example, for the treatment or prophylaxis of disorders associated with aberrant serum and glucocorticoid-regulated kinase 1 (SGK1) activity. BACKGROUND OF THE INVENTION Serum and glucocorticoid regulated kinase 1 (SGK1) belongs to a subfamily of serine / threonine kinase family consisting of SGK1, SGK2 and SGK3. Despite sharing 80% sequence homology at the catalytic domain and general properties of regulating ion channels, transport, and transcription for all three isoforms, SGK1 exhibits distinct patho- physiological functions (Lang, F. at al., Physiol Rev, 86(4), 1151-1178 (2006)). SGK1 is expressed at low levels in most cells but is stimulated under a variety of pathological conditions such as excess glucocorticoid, mineralocorticoid, hypertension, inflammation, ischemia, and hyperglycemia (Lang, F. et al., Sci STKE, 108, re17 (2001)). Accumulating evidence suggests that over expression and excess activity of SGK1 may contribute to various diseases or disorders, such as cardiovascular and cerebrovascular diseases (including hypertension, heart failure, coronary artery disease, myocardial infarction, peripheral vascular disease, stroke and arrhythmia), fibrotic diseases (including diabetic nephropathy, glomerulonephritis, experimental nephrotic syndrome, obstructive nephropathy, lung fibrosis, liver cirrhosis, fibrotic pancreatitis, peritoneal fibrosis, Crohn’s disease and coeliac disease), metabolic disorders and complications (including diabetes, obesity, metabolic syndrome), immune / inflammatory diseases (including rheumatoid arthritis and osteoarthritis), neuronal diseases (including Alzheimer, Parkinson, Seizure, and Lafora progressive myoclonic epilepsy), and cancer (Lang, F. et al., Expert Opin Investg Drugs, 22, 701-714 (2013)). Thus, targeting SGK1 may represent a therapeutic option for treating these disease conditions. SGK1 activates tubular ion channels and transporters, and stimulates both Na+intake and renal Na+excretion. SGK1 is expected to influence blood pressure via regulation of salt balance. SGK1 is known to activate epithelial Na+channel (ENAC), a channel regulated by mineralocorticoids. It is important to note that stimulation of Na+reabsorption by mineralocorticoids is only partially mediated by SGK1. This is supported by the fact that gene deletion of SGK1 in mice had no effect on blood pressure under either normal conditions or after treatment with excess mineralocorticoids and excess salt (Wulff, P. et al., The Journal of Clinical Investigation, 110, 1263-1268 (2002)). However, under high-fructose or high-fat diet, hypertension induced by salt excess is attenuated in SGK1-deficient animals (Huang, D. Y. at al., Am J physiol Renal Physiol, 291, F1264-1273 (2006)). These data suggests that SGK1 also mediates insulin- dependent stimulation of renal Na+retention and might contributes to the secondary hypertension in type II diabetes. SGK1 is expressed in the heart and upregulated in heart failure (Das, S., et al., Circulation, 126, 2208-2219 (2012)). Substantial preclinical evidence suggests that SGK1, in response to aldosterone and other pathological stimuli, mediates multiple intracellular pathways which lead to cardiac hypertrophy, fibrosis and myocardial dysfunction. Aldosterone induces SGK1 gene expression in the heart, causing an increase of Na+in the cytosol of cardiomyocytes and cardiac fibroblasts with the subsequent increase in Ca2+through Na+ / Ca2+exchanger (Martin-Fernandez, B. et al., J Cardiovasc Pharmcol, 57, 114-121 (2011)). In addition to mediating aldosterone effect, a broader role of SGK1 in fibrosis is suggested by the fact that SGK1 is upregulated by TGFβ and is involved in Smad2 / 3- TGFβ−CTGF signaling pathway, which leads to pathological fibrosis and negative remodeling (Artunc, F. et al., Nephron Physiol, 128, 35-39 (2014)). In several heart failure animal models, cardiac fibrosis and hypertrophy induced by deoxycorticosterone acetate (DOCA), angiotensin II or pressure overload are attenuated in SGK1 knockout mice (Das, S., et al., Circulation, 126, 2208-2219 (2012) and Vallon, V. et al., J Mol Med (Berl), 4, 396-404 (2006)). Furthermore, SGK1 is highly expressed in other fibrotic tissues and may play a role in diabetic nephropathy, glomerulonephritis, experimental nephrotic syndrome, obstructive nephropathy, lung fibrosis, liver cirrhosis, fibrotic pancreatitis, peritoneal fibrosis, Crohn’s disease and coeliac disease (Lang, F. at al., Physiol Rev, 86(4), 1151-1178 (2006)). Therefore, inhibition of SGK1 kinase activity may provide benefit to other fibrotic diseases. SGK1 may play a role in cardiac arrhythmia. In the heart, SGK1 stimulates the activity of several channels (SCN5A, Kv4.3, Kv1.5, and KCNE1 / KCNQ1) affecting the shape and duration of the cardiac action potential. In fact, the E8CC / CT;I6CC gene variant of SGK1 is also reported to be associated with a shortened Q-T interval in humans (Busjahn, A. et al., Cell physiol Biochem, 14, 135-142 (2004)). Increased SGK1 expression and activity is also implicated in coagulation. SGK1 is stimulated by thrombin and oxidative stress, which in turn induces upregulation of tissue factor, a key trigger for extrinsic coagulation cascade (Belaiba, R. S. et al., Circ Res, 98, 828-836 (2006)). An association between genetic variants in SGK1 and ischemic stroke has been reported (Dahlberg, J. et al., J Hypertens, 29, 884-889 (2011)). SGK1 is expressed in glomerular podocytes and upregulated by aldosterone and oxidative stress. SGK1 phosphorylates nephrin and may participate in the development of proteinuria during mineralocorticoid excess, inflammation or other pathological stimuli (Ohashi, T. et al., Clin Exp Nephrol, 15, 688-693 (201)). SGK1 stimulates the Na+-coupled glucose transporter SGLT1, which accelerates the intestinal uptake of glucose and contributes to the development of obesity. SGK1 is expressed in white adipose and is shown to stimulate adipocyte differentiation and adipogenesis (Lang, F. et al., Expert Opin Ther Targets, 13, 1303-1311 (2009)). Furthermore, a SGK1 polymorphism is reported to be associated with insulin secretion and development of type 2 diabetes mellitus (Schwab, M. et al., Cell Physiol Biochem, 21, 151-160 (2008)). SGK1 appears to mediate the differentiation and maintenance of CD4+TH17 cells and is thus implicated in related disorders such as autoimmune and proinflammatory diseases (Kuchroo, V. K. et al., WO / 2011 / 014775). Furthermore, SGK1 is expressed in diseased osteoarthritic cartilage and is implicated in the pathogenesis of rheumatoid arthritis and osteoarthritis (Bartnik, E. et al., US 2008 / 0274487). SGk1 is expressed in the brain and may contribute to the pathological effect of glucocorticoids during cerebral injury such as stroke and seizure (Kaufer, D. et al., Nat Neurosci, 7, 947-953 (2004)). In addition, SGK1 phosphorylates several neural factors involved in neurodegenerative diseases, although the role of SGK1 in the neuronal function is not well understood. For example, SGK1 phosphorylates tau, an activity that may be relevant to the development of Alzheimer’s disease (Chuna, J. et al., Molecules& Cells (Springer Science &Business Media BV) 18 (3) (2004)). In addition, upregulation of SGK1 expression is shown to coincide with the onset of dopaminergic cell death in 1-year subacute MPTP model of Parkinson’s disease (Stichel, C. C. et al., Eur J Neurosci, 21, 301-316 (2005)). SGK1 is highly expressed in many tumor cells, these include but not limited to breast cancer, colon cancer, myeloma, medulloblastoma, non-small-cell lung cancer, ovarian cancer, and prostate cancer (Lang, F. at al., Physiol Rev, 86(4), 1151-1178 (2006)). As a down downstream regulator, SGK1 may mediate the effect of glucocorticoids on the invasiveness, motility and adhesiveness of breast cancer cells (Tangir, J. et al., Clin Exp Metastasis, 21, 477-483 (2004)). Furthermore, a potential role of SGK1 in immune-mediated tumor response is suggested (Heikamp, E. B. et al., Nat Immunol, 15, 457-464 (2014)). Overall, SGK1 is a stress-responsive protein kinase that is upregulated by various pathological stimuli. Excess SGK1 activity is involved in cellular mechanisms that contribute to many disease states as described above. As such, inhibitors of SGK1, such as the compounds in the present invention, can be used to treat disease states in which SGK-1 activity contributes to the pathogenesis of these diseases. SUMMARY OF THE INVENTION The present invention provides novel amino-substituted pyrazolopyrimidine derivatives including stereoisomers, tautomers, pharmaceutically acceptable salts, or solvates thereof, which are useful as selective inhibitors of serum- and glucocorticoid- regulated kinases 1 (SGK1). The present invention also provides processes and intermediates for making the compounds of the present invention. The present invention also provides pharmaceutical compositions comprising a pharmaceutically acceptable carrier and at least one of the compounds of the present invention or stereoisomers, tautomers, pharmaceutically acceptable salts, or solvates thereof. The compounds of the invention may be used in the treatment and / or prophylaxis of conditions associated with aberrant SGK1 activity. The compounds of the present invention may be used in therapy. The compounds of the present invention may be used for the manufacture of a medicament for the treatment and / or prophylaxis of a condition associated with aberrant SGK1 activity. The compounds of the invention can be used alone, in combination with other compounds of the present invention, or in combination with one or more, preferably one to two other agent(s). These and other features of the invention will be set forth in expanded form as the disclosure continues. DETAILED DESCRIPTION OF THE INVENTION The present application provides compounds, including all stereoisomers, solvates, prodrugs and pharmaceutically acceptable salts and solvate forms thereof, according to Formula (I). The present application also provides pharmaceutical compositions containing at least one compound according to Formula (I), or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt or a solvate thereof, and optionally at least one additional therapeutic agent. Additionally, the present application provides methods for treating a patient suffering from an SGK1-modulated diseases or disorders, for example, cardiovascular and cerebrovascular diseases (including hypertension, heart failure, coronary artery disease, myocardial infarction, peripheral vascular disease, stroke and arrhythmia), fibrotic diseases (including diabetic nephropathy, glomerulonephritis, experimental nephrotic syndrome, obstructive nephropathy, lung fibrosis, liver cirrhosis, fibrotic pancreatitis, peritoneal fibrosis, Crohn’s disease and coeliac disease), metabolic disorders and complications (including diabetes, obesity, metabolic syndrome), immune / inflammatory diseases (including rheumatoid arthritis and osteoarthritis), neuronal diseases (including Alzheimer, Parkinson, Seizure, and Lafora progressive myoclonic epilepsy) and cancer, by administering to a patient in need of such treatment a therapeutically effective amount of a compound of the present invention, or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt or a solvate thereof, and optionally in combination with at least one additional therapeutic agent. I. COMPOUNDS OF THE INVENTION In a first aspect, the present invention provides, inter alia, compounds of Formula (I): or stereoisomers, tautomers, pharmaceutically acceptable salts or solvates thereof, wherein: R1is selected from the group consisting of C6-10aryl and 5- to 10-membered heterocyclyl comprising carbon atoms and 1-5 heteroatoms selected from N, O, and S(=O)p, and substituted with 0-3 R4aand 1 R4b; R2is selected from the group consisting of C6-10aryl substituted with 1-5 R6and 5- to 9- membered heterocyclyl comprising carbon atoms and 1-5 heteroatoms selected from N, O, and S(=O)p, and substituted with 1-5 R6; R3, at each occurrence, is independently selected from the group consisting of H, halo, - ORb, -NRaRa, and C1-3alkyl; alternatively, R3and R3are taken together with the two adjacent carbon atoms, to which they are attached, to form C3-6cycloalkyl; R4a, at each occurrence, is independently selected from the group consisting of H, halo, and C1-4alkyl substituted with 1-3 Re; R4bis selected from the group consisting of -ORb, -O-(CRdRd)1-5NRaRa, -O-(CRdRd)1-5ORb, C3-12 carbocyclyl substituted with 1-5 R5, 3- to 10-membered heterocyclyl comprising carbon atoms and 1-4 heteroatoms selected from N, O, and S(=O)p, and substituted with 1-5 R5, -O-(CRdRd)r-C3-12carbocyclyl substituted with 1-5 R5, -O-(CRdRd)r-3- to 10-membered heterocyclyl comprising carbon atoms and 1-4 heteroatoms selected from N, O, and S(=O)p, and substituted with 1-5 R5; R5, at each occurrence, is independently selected from the group consisting of H, halo, CN, ORb, =O, -(CRdRd)r-NR7R7, C1-6alkyl substituted with 1-5 Re, C2-6alkenyl substituted with 1-5 Re, C2-6alkynyl substituted with 1-5 Re, C3-10carbocyclyl with 1-5 Re, and 3- to10-membered heterocyclyl comprising carbon atoms and 1-4 heteroatoms selected from N, O, and S(=O)p. and substituted with 1-5 Re; R6, at each occurrence, is independently selected from the group consisting of H, halo, CN, =O, -(CRdRd)rNRaRa, NO2, -ORb, -C(=O)NRaRa, -C(=O)NRa(CRdRd)rORb, - C(=O)Rb, -C(=O)(CRdRd)rORb, -NRaC(=O)ORb, -NRaC(=O)(CRdRd)rNRaRa, - S(=O)PRc, -NRaS(=O)PRc, and C1-6alkyl substituted with 1-5 Re; R7, at each occurrence, is independently selected from the group consisting of H, C1-7alkyl substituted with 1-5 Re, C3-10carbocyclyl substituted with 1-5 Re, and -3- to 10-membered heterocyclyl comprising carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(=O)p, and substituted with 1-5 Re; or R7and R7together with the nitrogen atom, to which they are both attached, form a 3- to 10-membered heterocyclyl comprising carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(=O)p, and substituted with 1-5 Re; Ra, at each occurrence, is independently selected from the group consisting of H, C1-6alkyl substituted with 1-5 Re, C3-10carbocyclyl substituted with 1-5 Re, and 3- to 10-membered heterocyclyl comprising carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(=O)p, and substituted with 1-5 Re; or Raand Ratogether with the nitrogen atom, to which they are both attached, form a 3- to 10-membered heterocyclyl comprising carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(=O)p, and substituted with 1-5 Re; Rb, at each occurrence, is independently selected from the group consisting of H, C1-6alkyl substituted with 1-5 Re, C3-10carbocyclyl substituted with 1-5 Re, and 3- to 10-membered heterocyclyl comprising carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(=O)p, and substituted with 1-5 Re; Rc, at each occurrence, is independently selected from the group consisting of C1-6alkyl substituted with 1-5 Re, C3-10carbocyclyl substituted with 1-5 Re, and 3- to 10- membered heterocyclyl comprising carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(=O)p, and substituted with 1-5 Re; Rd, at each occurrence, is independently selected from the group consisting of H, C1-6alkyl substituted with 1-5 Re, and C3-6cycloalkyl substituted with 1-5 Re; Reis independently selected from the group consisting of H, halo, CN, =O, C1-6alkyl substituted with 1-5 Rg, C2-6alkenyl substituted with 1-5 Rg, C2-6alkynyl substituted with 1-5 Rg, C3-10carbocyclyl substituted with 1-5 Rg, 3- to 10- membered heterocyclyl comprising carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(=O)p, and substituted with 1-5 Rg, - (CH2)rORf, -(CH2)rNRfRf, -(CH2)rC(=O)Rf, and -(CH2)rC(=O)ORf; Rf, at each occurrence, is independently selected from the group consisting of H, C1-6alkyl substituted with 1-5 Rg, C3-10carbocyclyl substituted with 1-5 Rg, 3- to 10- membered heterocyclyl comprising carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(=O)p, and substituted with 1-3 Rg; Rg, at each occurrence, is independently selected from the group consisting of H, halo, CN, -OH, -O(C1-5alkyl), NH2, NH(C1-5alkyl), NH(C1-5alkyl)2, and C1-5alkyl; p is an integer of zero, 1, or 2; and r is an integer of zero, 1, 2, 3, 4, or 5. In a second aspect within the scope of the first aspect, the present invention provides compounds of Formula (I), or stereoisomers, tautomers, pharmaceutically acceptable salts or solvates thereof, wherein: R1is 5- to 6-membered heterocyclyl comprising carbon atoms and 1-3 heteroatoms selected from N, O, and S(=O)p, and substituted with 0-2 R4aand 1 R4b; and R2is selected from the group consisting of phenyl substituted with 1-5 R6and 5- to 6- membered heterocyclyl comprising carbon atoms and 1-3 heteroatoms selected from N, O, and S(=O)p, and substituted with 1-5 R6. In a third aspect within the scope of the first or second aspect, the present invention provides compounds of Formula (I), or stereoisomers, tautomers, pharmaceutically acceptable salts or solvates thereof, wherein: R1is selected from the group consisting of R2is selected from the group consisting of R4ais selected from the group consisting of H and C1-3alkyl; R4bis selected from the group consisting of , -O-C1-4alkyl, -O-(CH2)1-5NRaRa, C3-12carbocyclyl substituted with 1-5 R5, 3- to 10-membered heterocyclyl comprising carbon atoms and 1-4 heteroatoms selected from N, O, and S(=O)p, and substituted with 1-5 R5, -O-C3-12carbocyclyl substituted with 1-5 R5, -O-3- to 10- membered heterocyclyl comprising carbon atoms and 1-4 heteroatoms selected from N, O, and S(=O)p, and substituted with 1-5 R5; R5, at each occurrence, is independently selected from the group consisting of H, halo, - NR7R7, and C1-6alkyl substituted with 1-5 Re; R6, at each occurrence, is independently selected from the group consisting of H, halo, CN, -ORb, C(=O)Rb, -C(=O)NRaRa, -S(=O)PRc, and C1-3alkyl substituted with 1-5 Re; R7, at each occurrence, is independently selected from the group consisting of H, C1-3 alkyl substituted with 1-5 Re, and C3-6carbocyclyl substituted with 1-5 Re; or R7 and R7together with the nitrogen atom, to which they are both attached, form 3- to 10-membered heterocyclyl comprising carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(=O)p, and substituted with 1-3 ReRa, at each occurrence, is independently selected from the group consisting of H and C1-4alkyl substituted with 1-5 Re; Rb, at each occurrence, is independently selected from the group consisting of H and C1-4alkyl substituted with 1-5 Re; Rcis C1-4alkyl substituted with 1-5 Re; Reis independently selected from the group consisting of H, halo, CN, C1-4alkyl, and - ORf; and Rfis selected from the group consisting of H and C1-4alkyl. In a fourth aspect within the scope of the third aspect, the present invention provides compounds of Formula (II): or stereoisomers, tautomers, pharmaceutically acceptable salts or solvates thereof, wherein:R2 is selected from the group consisting

[0002] R4ais C1-3alkyl; R4bis selected from the group consisting of -O(CH2)1-3NRaRa, C3-10carbocyclyl substituted with 1-4 R5, 4- to 10-membered heterocyclyl comprising carbon atoms and 1-4 heteroatoms selected from N, O, and S(=O)p, and substituted with 1-4 R5, -O-C3-10carbocyclyl substituted with 1-4 R5, and -O-4- to 10-membered heterocyclyl comprising carbon atoms and 1-4 heteroatoms selected from N, O, and S(=O)p, and substituted with 1-4 R5; R5, at each occurrence, is independently selected from the group consisting of H, halo, - NR7R7, and C1-5alkyl substituted with 1-3 Re; R6, at each occurrence, is independently selected from the group consisting of H, halo, CN, -ORb, -C(=O)Rb, -C(=O)NRaRa, -S(=O)2Rc, and C1-3alkyl substituted with 1- 3 Re; R7, at each occurrence, is independently selected from the group consisting of H, C1-5alkyl substituted with 1-3 Re, and C3-6cycloalkyl; or R7and R7together with the nitrogen atom, to which they are both attached, form 4- to 6-membered heterocyclyl comprising carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(=O)p, and substituted with 1-3 Re; Ra, at each occurrence, is independently selected from the group consisting of H and C1-3alkyl substituted with 1-5 Re; Rb, at each occurrence, is independently selected from the group consisting of H and C1-3alkyl substituted with 1-5 Re; Rcis C1-3alkyl; Reis independently selected from the group consisting of H, halo, CN, C1-3alkyl, and - ORf; and Rfis selected from the group consisting of H and C1-3alkyl. In a fifth aspect within the scope of the third aspect, the present invention provides compounds of Formula (III): or stereoisomers, tautomers, pharmaceutically acceptable salts or solvates thereof, wherein:R2 is selected from the group consisting R4a is C1-3 alkyl; R4bis selected from the group consisting of -O-C3-10carbocyclyl substituted with 1-4 R5, - O-4- to 10-membered heterocyclyl comprising carbon atoms and 1-4 heteroatoms selected from N, O, and S(=O)p, and substituted with 1-4 R5; R5, at each occurrence, is independently selected from the group consisting of H, halo, CN, ORb, -NR7R7, C1-5alkyl substituted with 1-3 Re, C3-6carbocyclyl with 1-3 Re, and 3- to 6- membered heterocyclyl comprising carbon atoms and 1-4 heteroatoms selected from N, O, and S(=O)p. and substituted with 1-4 Re; R6, at each occurrence, is independently selected from the group consisting of H, halo, CN, -NRaRa, -ORb, -C(=O)NRaRa, -C(=O)NRaORb, -C(=O)Rb, -S(=O)2Rc, - NRaS(=O)2Rc, C1-4 alkyl substituted with 1-5 Re, -(CH2)rC3-6carbocyclyl substituted with 1-5 R7, and 5- to 6-membered heterocyclyl comprising carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(=O)p, and substituted with 1-5 R7; R7, at each occurrence, is independently selected from the group consisting of H, C1-5alkyl substituted with 1-3 Re, and C3-6cycloalkyl; or R7and R7together with the nitrogen atom, to which they are both attached, form 4- to 6-membered heterocyclyl comprising carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(=O)p, and substituted with 1-5 Re; Ra, at each occurrence, is independently selected from the group consisting of H and C1-3alkyl substituted with 1-5 Re; Rb, at each occurrence, is independently selected from the group consisting of H and C1-3alkyl substituted with 1-5 Re; Rcis C1-3alkyl; Reis independently selected from the group consisting of H, halo, CN, C1-3alkyl, and - ORf; and Rfis selected from the group consisting of H and C1-3alkyl. In a sixth aspect within the scope of the fourth or fifth aspect, the present invention provides compounds of Formula (II), or stereoisomers, tautomers, pharmaceutically acceptable salts or solvates thereof, wherein: R4ais C1-2alkyl; R4bis selected from the group consisting

[0003] R5, at each occurrence, is independently selected from the group consisting of H, -NR7R7, and C1-3alkyl substituted with 1-5 Re; R7, at each occurrence, is independently selected from the group consisting of H, C1-5alkyl substituted with 1-3 Re, and C3-6cycloalkyl; or R7and R7together with the nitrogen atom, to which they are both attached, form 5- to 6-membered heterocyclyl comprising carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(=O)p, and substituted with 1-5 Re; Re, at each occurrence, is independently selected from the group consisting of H, halo, CN, C1-3alkyl, and -ORf; and Rfis selected from the group consisting of H and C1-3alkyl. In a seventh aspect within the scope of the sixth aspect, the present invention provides compounds of Formula (II) or (III), or stereoisomers, tautomers, pharmaceutically acceptable salts or solvates thereof, wherein: R5is selected from the group consisting of -NR7R7and C1-3alkyl substituted with 1-5 Re; R7, at each occurrence, is independently selected from the group consisting of H, C1-5alkyl substituted with 1-3 Re, and C3-6cycloalkyl; or R7and R7together with the nitrogen atom, to which they are both attached, form 3- to 10-membered heterocyclyl comprising carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(=O)p, and substituted with 1-3 Re; Re, at each occurrence, is independently selected from the group consisting of H, halo, CN, C1-2alkyl, and -ORf; Rfis selected from the group consisting of H and C1-2alkyl. In an eighth aspect within the scope of the seventh aspect, the present invention provides compounds of Formula (II), or stereoisomers, tautomers, pharmaceutically acceptable salts or solvates thereof, wherein: R5is -NR7R7; R7, at each occurrence, is independently selected from the group consisting of H, Me, Et, or R7and R7together with the nitrogen atom, to which they are both attached, form In a ninth aspect within the scope of the fourth or fifth aspect, the present invention provides compounds of Formula (II) or (III), or stereoisomers, tautomers, pharmaceutically acceptable salts or solvates thereof, wherein: R6, at each occurrence, is independently selected from the group consisting of H, halo, CN, -OC1-3alkyl, -C(=O)NH2, -S(=O)2C1-3alkyl, and C1-3alkyl. In a tenth aspect within the scope of the fourth or fifth aspect, the present invention provides compounds of Formula (III), or stereoisomers, tautomers, pharmaceutically acceptable salts or solvates thereof, wherein:R2 is selected from the group consisting R6, at each occurrence, is independently selected from the group consisting of H, - C(=O)C1-3alkyl, and C1-3alkyl. In an eleventh aspect within the scope of the third aspect, the present invention provides compounds of Formula (IV): or stereoisomers, tautomers, pharmaceutically acceptable salts or solvates thereof, wherein: R2is selected from the group consisting of

[0004] R4bis independently selected from the group consisting of -OC1-3alkyl, C3-12carbocyclyl substituted with 1-5 R5and 3- to 10-membered heterocyclyl comprising carbon atoms and 1-4 heteroatoms selected from N, O, and S(=O)p, and substituted with 1-5 R5; R5, at each occurrence, is independently selected from the group consisting of H, -NR7R7, and C1-5alkyl substituted with 1-5 Re; R6, at each occurrence, is independently selected from the group consisting of H, halo, CN, ORb, C(=O)Rb, -C(=O)NRaRa, -S(=O)2Rc, and C1-3alkyl substituted with 1-5 Re; R7, at each occurrence, is independently selected from the group consisting of H, C1-3alkyl substituted with 1-5 Re, and C3-6carbocyclyl substituted with 1-5 Re; Ra, at each occurrence, is independently selected from the group consisting of H and C1-3alkyl; Rb, at each occurrence, is independently selected from the group consisting of H and C1-3alkyl substituted with 1-4 Re, C3-10carbocyclyl substituted with 1-5 Re, and 5- to 6- membered heterocyclyl comprising carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(=O)p, and substituted with 1-4 Re; Rcis C1-3alkyl; Re, at each occurrence, is independently selected from the group consisting of H, halo, CN, C1-3alkyl, and ORf; and Rfis selected from the group consisting of H and C1-3alkyl. In a twelfth aspect within the scope of the eleventh aspect, the present invention provides compounds of Formula (IV), or stereoisomers, tautomers, pharmaceutically acceptable salts or solvates thereof, wherein: R4bis selected from the group consisting R5is selected from the group consisting of H, and C1-4alkyl; and R7, at each occurrence, is independently selected from the group consisting of H and C1-3

[0005] In another embodiment of the compounds of Formula (I) or (III), R1is with the nitrogen atom, to which they are both attached, form

[0006] In another embodiment of the compounds of Formula (I) or (III), R1is In another embodiment of the compounds of Formula (I) or (II), R1is In another embodiment of the compounds of Formula (I) or (III), R1is NR7R7is -NHC(CH3)2, -N(CH3)2, -N(CH2CH3)2, -NHC(CH3)CH2OH, - NHC(CH2CH3)CH2OH, -NHC(CH3)CH2OCH3, -NH-cyclobutyl, N N O , or . R S4aN In one embodiment of the compounds of Formula (I) or (III), R1isR4b; NHC(CH3)CH2OH, -NHC(CH2CH3)CH2OH, -NHC(CH3)CH2OCH3, -NH-cyclobutyl, In one embodiment of the compounds of Formula In another embodiment of the compounds of Formula (I), R1 is In one embodiment of the compounds of Formula For a compound of Formulae (I)-(IV), the scope of any instance of a variable substituent, including R1, R2, R3, R4a, R4bR5, R6, R7, Ra, Ra, Rb, Rc, Rd, Re, Rf, and Rg, can be used independently with the scope of any other instance of a variable substituent. As such, the invention includes combinations of the different aspects. In one embodiment, the compounds of the present invention have SGK1 IC50values ≤ 0.1 µM. In another embodiment, the compounds of the present invention have SGK1 IC50values ≤ 0.05 µM. In another embodiment, the compounds of the present invention have SGK1 IC50 values ≤ 0.01 µM. II. OTHER EMBODIMENTS OF THE INVENTION In another embodiment, the present invention provides a pharmaceutical composition, comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one of the compounds of the present invention or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, or a solvate thereof. In another embodiment, the present invention provides a process for making a compound of the present invention. In another embodiment, the present invention provides an intermediate for making a compound of the present invention. In another embodiment, the present invention provides a pharmaceutical composition further comprising additional therapeutic agent(s). In another embodiment, the present invention provides a method for the treatment and / or prophylaxis of a condition associated with aberrant SGK1 activity comprising administering to a patient in need of such treatment and / or prophylaxis a therapeutically effective amount of at least one of the compounds of the present invention or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, or a solvate thereof. As used herein, the term "patient" encompasses all mammalian species. The term "treating" or "treatment" as used herein refers to an approach for obtaining beneficial or desired results, including clinical results, by using a compound or a composition of the present invention. For purposes of this invention, beneficial or desired clinical results include, but are not limited to, one or more of the following: decreasing the severity and / or frequency one or more symptoms resulting from the disease, disorder, or condition; diminishing the extent of or causing regression of the disease, disorder, or condition; stabilizing the disease, disorder, or condition (e.g., preventing or delaying the worsening of the disease, disorder, or condition); delay or slowing the progression of the disease, disorder, or condition; ameliorating the disease, disorder, or condition state; decreasing the dose of one or more other medications required to treat the disease, disorder, or condition; and / or increasing the quality of life. As used herein, "prophylaxis" is the protective treatment of a disease state to reduce and / or minimize the risk and / or reduction in the risk of recurrence of a disease state by administering to a patient a therapeutically effective amount of at least one of the compounds of the present invention or a or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, or a solvate thereof. Patients may be selected for prophylaxis therapy based on factors that are known to increase risk of suffering a clinical disease state compared to the general population. For prophylaxis treatment, conditions of the clinical disease state may or may not be presented yet. "Prophylaxis" treatment can be divided into (a) primary prophylaxis and (b) secondary prophylaxis. Primary prophylaxis is defined as treatment to reduce or minimize the risk of a disease state in a patient that has not yet presented with a clinical disease state, whereas secondary prophylaxis is defined as minimizing or reducing the risk of a recurrence or second occurrence of the same or similar clinical disease state. As used herein, "prevention" covers the preventive treatment of a subclinical disease-state in a mammal, particularly in a human, aimed at reducing the probability of the occurrence of a clinical disease-state. Patients are selected for preventative therapy based on factors that are known to increase risk of suffering a clinical disease state compared to the general population. The present invention may be embodied in other specific forms without departing from the spirit or essential attributes thereof. This invention encompasses all combinations of preferred aspects of the invention noted herein. It is understood that any and all embodiments of the present invention may be taken in conjunction with any other embodiment or embodiments to describe additional embodiments. It is also to be understood that each individual element of the embodiments is its own independent embodiment. Furthermore, any element of an embodiment is meant to be combined with any and all other elements from any embodiment to describe an additional embodiment. III. CHEMISTRY Throughout the specification and the appended claims, a given chemical formula or name shall encompass all stereo and optical isomers and racemates thereof where such isomers exist. Unless otherwise indicated, all chiral (enantiomeric and diastereomeric) and racemic forms are within the scope of the invention. Many geometric isomers of C=C double bonds, C=N double bonds, ring systems, and the like can also be present in the compounds, and all such stable isomers are contemplated in the present invention. Cis- and trans- (or E- and Z-) geometric isomers of the compounds of the present invention are described and may be isolated as a mixture of isomers or as separated isomeric forms. The present compounds can be isolated in optically active or racemic forms. Optically active forms may be prepared by resolution of racemic forms or by synthesis from optically active starting materials. All processes used to prepare compounds of the present invention and intermediates made therein are considered to be part of the present invention. When enantiomeric or diastereomeric products are prepared, they may be separated by conventional methods, for example, by chromatography or fractional crystallization. Depending on the process conditions the end products of the present invention are obtained either in free (neutral) or salt form. Both the free form and the salts of these end products are within the scope of the invention. If so desired, one form of a compound may be converted into another form. A free base or acid may be converted into a salt; a salt may be converted into the free compound or another salt; a mixture of isomeric compounds of the present invention may be separated into the individual isomers. Compounds of the present invention, free form and salts thereof, may exist in multiple tautomeric forms, in which hydrogen atoms are transposed to other parts of the molecules and the chemical bonds between the atoms of the molecules are consequently rearranged. It should be understood that all tautomeric forms, insofar as they may exist, are included within the invention. As used herein, "a compound of the invention" or "compounds of the invention" means one or more compounds encompassed by Formulae (I)-(VII), and any subgenus and exemplified species thereof. The term "stereoisomer" refers to isomers of identical constitution that differ in the arrangement of their atoms in space. Enantiomers and diastereomers are examples of stereoisomers. The term "enantiomer" refers to one of a pair of molecular species that are mirror images of each other and are not superimposable. The term "diastereomer" refers to stereoisomers that are not mirror images. The term "racemate" or "racemic mixture" refers to a composition composed of equimolar quantities of two enantiomeric species, wherein the composition is devoid of optical activity. The symbols "R" and "S" represent the configuration of substituents around a chiral carbon atom(s). The isomeric descriptors "R" and "S" are used as described herein for indicating atom configuration(s) relative to a core molecule and are intended to be used as defined in the literature (IUPAC Recommendations 1996, Pure and Applied Chemistry, 68:2193-2222 (1996)). The term "chiral" refers to the structural characteristic of a molecule that makes it impossible to superimpose it on its mirror image. The term "homochiral" refers to a state of enantiomeric purity. The term "optical activity" refers to the degree to which a homochiral molecule or nonracemic mixture of chiral molecules rotates a plane of polarized light. In accordance with a convention used in the art, a bond pointing to a wave line, such as used in structural formulas herein, depicts the bond that is the point of attachment of the moiety or substituent to the core or backbone structure. As used herein, the term "alkyl" or "alkylene" is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. For example, "C1-10alkyl" (or alkylene), is intended to include C1, C2, C3, C4, C5, C6, C7, C8, C9, and C10alkyl groups. Alkyl group can be unsubstituted or substituted with at least one hydrogen being replaced by another chemical group. Example alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, t-butyl), and pentyl (e.g., n-pentyl, isopentyl, neopentyl). “Heteroalkyl” refers to an alkyl group where one or more carbon atoms have been replaced with a heteroatom, such as, O, N, or S. For example, if the carbon atom of the alkyl group which is attached to the parent molecule is replaced with a heteroatom (e.g., O, N, or S) the resulting heteroalkyl groups are, respectively, an alkoxy group (e.g., -OCH3, etc.), an amine (e.g., -NHCH3, -N(CH3)2, etc.), or a thioalkyl group (e.g., -SCH3). If a non-terminal carbon atom of the alkyl group which is not attached to the parent molecule is replaced with a heteroatom (e.g., O, N, or S) and the resulting heteroalkyl groups are, respectively, an alkyl ether (e.g., -CH2CH2-O-CH3, etc.), an alkyl amine (e.g., -CH2NHCH3, -CH2N(CH3)2, etc.), or a thioalkyl ether (e.g.,-CH2-S-CH3). If a terminal carbon atom of the alkyl group is replaced with a heteroatom (e.g., O, N, or S), the resulting heteroalkyl groups are, respectively, a hydroxyalkyl group (e.g., -CH2CH2-OH), an aminoalkyl group (e.g., -CH2NH2), or an alkyl thiol group (e.g., -CH2CH2-SH). A heteroalkyl group can have, for example, 1 to 20 carbon atoms, 1 to 10 carbon atoms, or 1 to 6 carbon atoms. A C1-C6heteroalkyl group means a heteroalkyl group having 1 to 6 carbon atoms. "Alkenyl" or "alkenylene" is intended to include hydrocarbon chains of either straight or branched configuration having the specified number of carbon atoms and one or more, preferably one to two, carbon-carbon double bonds that may occur in any stable point along the chain. For example, "C2-6alkenyl" (or alkenylene), is intended to includeC2, C3, C4, C5, and C6alkenyl groups. Examples of alkenyl include, but are not limitedto, ethenyl, 1-propenyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3, pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl, and 4-methyl-3-pentenyl. "Alkynyl" or "alkynylene" is intended to include hydrocarbon chains of either straight or branched configuration having one or more, preferably one to three, carbon-carbon triple bonds that may occur in any stable point along the chain. Forexample, "C2-6alkynyl" (or alkynylene), is intended to include C2, C3, C4, C5, and C6alkynyl groups; such as ethynyl, propynyl, butynyl, pentynyl, and hexynyl. As used herein, “arylalkyl” refers to an acyclic alkyl radical in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp3carbon atom, is replaced with an aryl radical. Typical arylalkyl groups include, but are not limited to, benzyl, 2-phenylethan-1-yl, naphthylmethyl, 2-naphthylethan-1-yl, naphthobenzyl, 2-naphthophenylethan-1-yl and the like. The arylalkyl group can comprise 7 to 20 carbon atoms, e.g., the alkyl moiety is 1 to 6 carbon atoms and the aryl moiety is 6 to 14 carbon atoms. The term "benzyl", as used herein, refers to a methyl group on which one of the hydrogen atoms is replaced by a phenyl group, wherein said phenyl group may optionallybe substituted with 1 to 5 groups, preferably 1 to 3 groups, OH, OCH3, Cl, F, Br, I, CN,NO2, NH2, N(CH3)H, N(CH3)2, CF3, OCF3, C(=O)CH3, SCH3, S(=O)CH3,S(=O)2CH3, CH3, CH2CH3, CO2H, and CO2CH3. “Benzyl” can also be represented byformula “Bn”. The term “lower alkoxy”, "alkoxy" or "alkyloxy", “aryloxy” or “aralkoxy” refersto any of the above alkyl, aralkyl or aryl groups linked to an oxygen atom. "C1to C6alkoxy" or "C1-6alkoxy" (or alkyloxy), is intended to include C1, C2, C3, C4, C5, andC6alkoxy groups. Example alkoxy groups include, but are not limited to, methoxy,ethoxy, propoxy (e.g., n-propoxy and isopropoxy), and t-butoxy. Similarly, “lower alkylthio”, "alkylthio", "thioalkoxy", “arylthio”, or “aralkylthio” represents an alkyl, aryl, or aralkyl group as defined above with the indicated number of carbon atoms attached through a sulphur bridge; for example methyl-S- and ethyl-S-. The term “halogen” or “halo” as used herein alone or as part of another group refers to chlorine, bromine, fluorine, and iodine, with chlorine or fluorine being preferred. "Haloalkyl" is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, substitutedwith one or more halogens. "C1to C6haloalkyl" or "C1-6haloalkyl" (or haloalkyl), isintended to include C1, C2, C3, C4, C5, and C6haloalkyl groups. Examples of haloalkylinclude, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl, 2,2,2-trifluoroethyl, heptafluoropropyl, and heptachloropropyl. Examples of haloalkyl also include "fluoroalkyl" that is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, substituted with 1 or more fluorine atoms. The term “polyhaloalkyl” as used herein refers to an “alkyl” group as defined above which includes from 2 to 9, preferably from 2 to 5, halo substituents, such as F or Cl, preferably F, such as polyfluoroalkyl, for example, CF3CH2, CF3or CF3CF2CH2. "Haloalkoxy" or "haloalkyloxy" represents a haloalkyl group as defined above with the indicated number of carbon atoms attached through an oxygen bridge. Forexample, "C1-6haloalkoxy", is intended to include C1, C2, C3, C4, C5, and C6haloalkoxy groups. Examples of haloalkoxy include, but are not limited to, trifluoromethoxy, 2,2,2-trifluoroethoxy, and pentafluorothoxy. Similarly, "haloalkylthio" or "thiohaloalkoxy" represents a haloalkyl group as defined above with the indicated number of carbon atoms attached through a sulphur bridge; for example trifluoromethyl-S-, and pentafluoroethyl-S-. The term “polyhaloalkyloxy” as used herein refers to an “alkoxy” or “alkyloxy” group as defined above which includes from 2 to 9, preferably from 2 to 5, halo substituents, such as F or Cl, preferably F, such as polyfluoroalkoxy, for example, CF3CH2O, CF3O or CF3CF2CH2O. "Hydroxyalkyl" is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, substituted with 1 or more hydroxyl (OH). For example, “C1-6hydroxyalkyl" (or hydroxyalkyl), isintended to include C1, C2, C3, C4, C5, and C6hydroxyalkyl groups.The term "cycloalkyl" refers to cyclized alkyl groups, including mono-, bi- orpoly-cyclic ring systems. "C3to C7cycloalkyl" or "C3-7cycloalkyl" is intended toinclude C3, C4, C5, C6, and C7cycloalkyl groups. Example cycloalkyl groups include,but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and norbornyl. Branched cycloalkyl groups such as 1-methylcyclopropyl and 2-methylcyclopropyl are included in the definition of "cycloalkyl". As used herein, "carbocycle", "carbocyclyl", or "carbocyclic " is intended to mean any stable 3-, 4-, 5-, 6-, 7-, or 8-membered monocyclic or 5-, 6-, 7-, 8-, 9-, 10-, 11-, 12-, or 13-membered polycyclic (including bicyclic or tricyclic) hydrocarbon ring, any of which may be saturated or partially unsaturated. That is, the term "carbocycle", "carbocyclyl", or "carbocyclic" includes, without limitation, cycloalkyl and cycloalkenyl. Examples of such carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cycloheptenyl, cycloheptyl, cycloheptenyl, adamantyl, cyclooctyl, cyclooctenyl, cyclooctadienyl, [3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane (decalin), [2.2.2]bicyclooctane, fluorenyl, indanyl, adamantyl, and tetrahydronaphthyl (tetralin). As shown above, bridged rings are also included in the definition of carbocycle (e.g., [2.2.2]bicyclooctane). Preferred carbocycles, unless otherwise specified, are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, indanyl, and tetrahydronaphthyl. A bridged ring occurs when one or more, preferably one to three, carbon atoms link two non-adjacent carbon atoms. Preferred bridges are one or two carbon atoms. It is noted that a bridge always converts a monocyclic ring into a tricyclic ring. When a ring is bridged, the substituents recited for the ring may also be present on the bridge. Furthermore, the term “carbocyclyl”, including “cycloalkyl” and “cycloalkenyl”, as employed herein alone or as part of another group includes saturated or partially unsaturated (containing 1 or 2 double bonds) cyclic hydrocarbon groups containing 1 to 3 rings, including monocyclicalkyl, bicyclicalkyl and tricyclicalkyl, containing a total of 3 to 20 carbons forming the rings, preferably 3 to 10 carbons, forming the ring and which may be fused to 1 or 2 aromatic rings as described for aryl, which include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl and cyclododecyl, cyclohexenyl, any of which groups may be optionally substituted with 1 to 4 substituents such as halogen, alkyl, alkoxy, hydroxy, aryl, aryloxy, arylalkyl, cycloalkyl, alkylamido, alkanoylamino, oxo, acyl, arylcarbonylamino, nitro, cyano, thiol and / or alkylthio and / or any of the alkyl substituents. As used herein, the term "bicyclic carbocycle" or "bicyclic carbocyclic group" is intended to mean a stable 9- or 10-membered carbocyclic ring system that contains two fused rings and consists of carbon atoms. Of the two fused rings, one ring is a benzo ring fused to a second ring, and the second ring is a 5- or 6-membered carbon ring which is saturated or partially unsaturated. The bicyclic carbocyclic group may be attached to its pendant group at any carbon atom which results in a stable structure. The bicyclic carbocyclic group described herein may be substituted on any carbon if the resulting compound is stable. Examples of a bicyclic carbocyclic group are, but not limited to, 1,2-dihydronaphthyl, 1,2,3,4-tetrahydronaphthyl, and indanyl. As used herein, the term "aryl", as employed herein alone or as part of another group, refers to monocyclic or polycyclic (including bicyclic and tricyclic) aromatic hydrocarbons, including, for example, phenyl, naphthyl, anthracenyl, and phenanthranyl. Aryl moieties are well known and described, for example, in Lewis, R.J., ed., Hawley's Condensed Chemical Dictionary, 13th Edition, John Wiley & Sons, Inc., New York (1997). In one embodiment, the term “aryl” denotes monocyclic and bicyclic aromatic groups containing 6 to 10 carbons in the ring portion (such as phenyl or naphthylincluding 1-naphthyl and 2-naphthyl). For example, "C6or C10aryl" refers to phenyl andnaphthyl. As used herein, the term "heterocycle", "heterocyclyl", or "heterocyclic group" is intended to mean a stable 3-, 4-, 5-, 6-, or 7-membered monocyclic or 5-, 6-, 7-, 8-, 9-, 10-, 11-, 12-, 13-, or 18-membered polycyclic (including bicyclic and tricyclic) heterocyclic ring that is saturated, or partially unsaturated, and that contains carbon atoms and 1, 2, 3 or 4 heteroatoms independently selected from N, O and S, and including any polycyclic group in which any of the above-defined heterocyclic rings is fused to a carbocyclic or an aryl (e.g., benzene) ring. That is, the term "heterocycle", "heterocyclyl", or "heterocyclic group" includes non-aromatic ring systems, such as heterocycloalkyl and heterocycloalkenyl. The nitrogen and sulfur heteroatoms mayoptionally be oxidized (i.e., N→O and S(O)p, wherein p is 0, 1 or 2). The nitrogen atommay be substituted or unsubstituted (i.e., N or NR wherein R is H or another substituent, if defined). The heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure. The heterocyclic rings described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable. A nitrogen in the heterocycle may optionally be quaternized. It is preferred that when the total number of S and O atoms in the heterocycle exceeds 1, then these heteroatoms are not adjacent to one another. It is preferred that the total number of S and O atoms in the heterocycle is not more than 1. Examples of hetercyclyl include, without limitation, azetidinyl, piperazinyl, piperidinyl, piperidonyl, piperonyl, pyranyl, morpholinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, morpholinyl, dihydrofuro[2,3-b]tetrahydrofuran. As used herein, the term "bicyclic heterocycle" or "bicyclic heterocyclic group" is intended to mean a stable 9- or 10-membered heterocyclic ring system which contains two fused rings and consists of carbon atoms and 1, 2, 3, or 4 heteroatoms independently selected from N, O and S. Of the two fused rings, one ring is a 5- or 6-membered monocyclic aromatic ring comprising a 5-membered heteroaryl ring, a 6-membered heteroaryl ring or a benzo ring, each fused to a second ring. The second ring is a 5- or 6-membered monocyclic ring which is saturated, partially unsaturated, or unsaturated, and comprises a 5-membered heterocycle, a 6-membered heterocycle or a carbocycle (provided the first ring is not benzo when the second ring is a carbocycle). The bicyclic heterocyclic group may be attached to its pendant group at any heteroatom or carbon atom which results in a stable structure. The bicyclic heterocyclic group described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable. It is preferred that when the total number of S and O atoms in the heterocycle exceeds 1, then these heteroatoms are not adjacent to one another. It is preferred that the total number of S and O atoms in the heterocycle is not more than 1. Examples of a bicyclic heterocyclic group are, but not limited to, 1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, 5,6,7,8-tetrahydro-quinolinyl, 2,3-dihydro-benzofuranyl, chromanyl, 1,2,3,4-tetrahydro-quinoxalinyl, and 1,2,3,4-tetrahydro-quinazolinyl. Bridged rings are also included in the definition of heterocycle. A bridged ring occurs when one or more, preferably one to three, atoms (i.e., C, O, N, or S) link two non-adjacent carbon or nitrogen atoms. Examples of bridged rings include, but are not limited to, one carbon atom, two carbon atoms, one nitrogen atom, two nitrogen atoms, and a carbon-nitrogen group. It is noted that a bridge always converts a monocyclic ring into a tricyclic ring. When a ring is bridged, the substituents recited for the ring may also be present on the bridge. As used herein, the term "heteroaryl" is intended to mean stable monocyclic and polycyclic (including bicyclic and tricyclic) aromatic hydrocarbons that include at least one heteroatom ring member such as sulfur, oxygen, or nitrogen. Heteroaryl groups include, without limitation, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furyl, quinolyl, isoquinolyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrroyl, oxazolyl, benzofuryl, benzothienyl, benzthiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1,2,4-thiadiazolyl, isothiazolyl, purinyl, carbazolyl, benzimidazolyl, indolinyl, benzodioxolanyl, and benzodioxane. Heteroaryl groups are substituted or unsubstituted. The nitrogen atom is substituted or unsubstituted (i.e., N or NR wherein R is H or another substituent, if defined). The nitrogen and sulfur heteroatoms may optionally be oxidized(i.e., N→O and S(O)p, wherein p is 0, 1 or 2).Examples of heteroaryl include, but are not limited to, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, imidazolopyridinyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isatinoyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isothiazolopyridinyl, isoxazolyl, isoxazolopyridinyl, methylenedioxyphenyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolopyridinyl, oxazolidinylperimidinyl, oxindolyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathianyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolopyridinyl, pyrazolyl, pyridazinyl, pyridooxazolyl, pyridoimidazolyl, pyridothiazolyl, pyridinyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2-pyrrolidonyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrazolyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thiazolopyridinyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, and xanthenyl. Examples of 5- to 10-membered heteroaryl include, but are not limited to, pyridinyl, furanyl, thienyl, pyrazolyl, imidazolyl, imidazolidinyl, indolyl, tetrazolyl, isoxazolyl, oxazolyl, oxadiazolyl, oxazolidinyl, thiadiazinyl, thiadiazolyl, thiazolyl, triazinyl, triazolyl, benzimidazolyl, 1H-indazolyl, benzofuranyl, benzothiofuranyl, benztetrazolyl, benzotriazolyl, benzisoxazolyl, benzoxazolyl, oxindolyl, benzoxazolinyl, benzthiazolyl, benzisothiazolyl, isatinoyl, isoquinolinyl, octahydroisoquinolinyl, isoxazolopyridinyl, quinazolinyl, quinolinyl, isothiazolopyridinyl, thiazolopyridinyl, oxazolopyridinyl, imidazolopyridinyl, and pyrazolopyridinyl. Examples of 5- to 6-membered heterocycles include, but are not limited to, pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, pyrazinyl, imidazolyl, imidazolidinyl, indolyl, tetrazolyl, isoxazolyl, oxazolyl, oxadiazolyl, oxazolidinyl, thiadiazinyl, thiadiazolyl, thiazolyl, triazinyl, and triazolyl. It is understood herein that if a carbocyclic or heterocyclic moiety may be bonded or otherwise attached to a designated substrate through differing ring atoms without denoting a specific point of attachment, then all possible points are intended, whether through a carbon atom or, for example, a trivalent nitrogen atom. For example, the term “pyridyl” means 2-, 3- or 4-pyridyl, the term “thienyl” means 2- or 3-thienyl, and so forth. When a dotted ring is used within a ring structure, this indicates that the ring structure may be saturated, partially saturated or unsaturated. When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, then such substituent may be bonded to any atom on the ring. For example, when the ring has a bicyclic or tricyclic structure, then such substituent may be bonded to any ring-member atom of the bicyclic or tricyclic structure. When a substituent is listed without indicating the atom in which such substituent is bonded to the rest of the compound of a given formula, then such substituent may be bonded via any atom in such substituent. Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds. One skilled in the art will recognize that substituents and other moieties of the compounds of the present invention should be selected in order to provide a compound which is sufficiently stable to provide a pharmaceutically useful compound which can be formulated into an acceptably stable pharmaceutical composition. Compounds of the present invention which have such stability are contemplated as falling within the scope of the present invention. The term "counter ion" is used to represent a negatively charged species such as chloride, bromide, hydroxide, acetate, and sulfate. The term “metal ion” refers to alkali metal ions such as sodium, potassium or lithium and alkaline earth metal ions such as magnesium and calcium, as well as zinc and aluminum. As referred to herein, the term "substituted" means that at least one hydrogen atom is replaced with a non-hydrogen group, provided that normal valencies are maintained and that the substitution results in a stable compound. When a substituent is keto, also known as “oxo” which is a substituent oxygen atom connected to another atom by a double bond (i.e., =O), then 2 hydrogens on the atom are replaced. Keto substituents are not present on aromatic moieties. When a ring system (e.g., carbocyclic or heterocyclic) is said to be substituted with a carbonyl group or a double bond, it is intended that the carbonyl group or double bond be part (i.e., within) of the ring. Ring double bonds, as used herein, are double bonds that are formed between two adjacent ring atoms (e.g., C=C, C=N, or N=N). In cases wherein there are nitrogen atoms (e.g., amines) on compounds of the present invention, these may be converted to N-oxides by treatment with an oxidizing agent (e.g., mCPBA and / or hydrogen peroxides) to afford other compounds of this invention. Thus, shown and claimed nitrogen atoms are considered to cover both the shown nitrogen and its N-oxide (N→O) derivative. When any variable occurs more than one time in any constituent or formula for a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with 0, 1, 2, or 3 R groups, then said group be unsubstituted when it is substituted with 0 R group, or be substituted with up to three R groups, and at each occurrence R is selected independently from the definition of R. Also, combinations of substituents and / or variables are permissible only if such combinations result in stable compounds. As used herein, the term “tautomer” refers to each of two or more isomers of a compound that exist together in equilibrium, and are readily interchanged by migration of an atom or group within the molecule For example, one skilled in the art would readily understand that a 1,2,3-triazole exists in two tautomeric forms as defined above: 1H-1,2,3-triazole 2H-1,2,3-triazole.Thus, this disclosure is intended to cover all possible tautomers even when a structure depicts only one of them. The phrase "pharmaceutically acceptable" is employed herein to refer to those compounds, materials, compositions, and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, and / or other problem or complication, commensurate with a reasonable benefit / risk ratio. The compounds of the present invention can be present as salts, which are also within the scope of this invention. Pharmaceutically acceptable salts are preferred. As used herein, "pharmaceutically acceptable salts" refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound that contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 18th Edition, Mack Publishing Company, Easton, PA (1990), the disclosure of which is hereby incorporated by reference. If the compounds of the present invention have, for example, at least one basic center, they can form acid addition salts. These are formed, for example, with strong inorganic acids, such as mineral acids, for example sulfuric acid, phosphoric acid or a hydrohalic acid, with organic carboxylic acids, such as alkanecarboxylic acids of 1 to 4 carbon atoms, for example acetic acid, which are unsubstituted or substituted, for example, by halogen as chloroacetic acid, such as saturated or unsaturated dicarboxylic acids, for example oxalic, malonic, succinic, maleic, fumaric, phthalic or terephthalic acid, such as hydroxycarboxylic acids, for example ascorbic, glycolic, lactic, malic, tartaric or citric acid, such as amino acids, (for example aspartic or glutamic acid or lysine or arginine), or benzoic acid, or with organic sulfonic acids, such as (C1-C4) alkyl or arylsulfonic acids which are unsubstituted or substituted, for example by halogen, for example methyl- or p-toluene- sulfonic acid. Corresponding acid addition salts can also be formed having, if desired, an additionally present basic center. The compounds of the present invention having at least one acid group (for example COOH) can also form salts with bases. Suitable salts with bases are, for example, metal salts, such as alkali metal or alkaline earth metal salts, for example sodium, potassium or magnesium salts, or salts with ammonia or an organic amine, such as morpholine, thiomorpholine, piperidine, pyrrolidine, a mono, di or tri-lower alkylamine, for example ethyl, tert-butyl, diethyl, diisopropyl, triethyl, tributyl or dimethyl-propylamine, or a mono, di or trihydroxy lower alkylamine, for example mono, di or triethanolamine. Corresponding internal salts may furthermore be formed. Salts which are unsuitable for pharmaceutical uses but which can be employed, for example, for the isolation or purification of free compounds of Formula (I) or their pharmaceutically acceptable salts, are also included. Preferred salts of the compounds of Formula (I) which contain a basic group include monohydrochloride, hydrogensulfate, methanesulfonate, phosphate, nitrate or acetate. Preferred salts of the compounds of Formula (I) which contain an acid group include sodium, potassium and magnesium salts and pharmaceutically acceptable organic amines. In addition, the compounds of the present invention may have prodrug forms. Any compound that will be converted in vivo to provide the bioactive agent, i.e., a compound of formula (I), is a prodrug within the scope and spirit of the invention. Preparation of prodrugs is well known in the art and described in, for example, King, F.D., ed., Medicinal Chemistry: Principles and Practice, The Royal Society of Chemistry, Cambridge, UK (1994); Testa, B. et al., Hydrolysis in Drug and Prodrug Metabolism. Chemistry, Biochemistry and Enzymology, VCHA and Wiley-VCH, Zurich, Switzerland (2003); Wermuth, C.G., ed., The Practice of Medicinal Chemistry, Academic Press, San Diego, CA (1999). The present invention is intended to include all isotopes of atoms occurring in the present compounds. Isotopes include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes ofhydrogen include deuterium and tritium. Isotopes of carbon include13C and14C.Isotopically-labeled compounds of the invention can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described herein, using an appropriate isotopically-labeled reagent in place of the non-labeled reagent otherwise employed. Such compounds have a variety of potential uses, e.g., as standards and reagents in determining the ability of a potential pharmaceutical compound to bind to target proteins or receptors, or for imaging compounds of this invention bound to biological receptors in vivo or in vitro. "Stable compound" and "stable structure" are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent. It is preferred thatcompounds of the present invention do not contain a N-halo, S(O)2H, or S(O)H group.The term "solvate" means a physical association of a compound of this invention with one or more solvent molecules, whether organic or inorganic. This physical association includes hydrogen bonding. The solvent molecules in the solvate may be present in a regular arrangement and / or a non-ordered arrangement. The solvate may comprise either a stoichiometric or nonstoichiometric amount of the solvent molecules. "Solvate" encompasses both solution-phase and isolable solvates. Exemplary solvates include, but are not limited to, hydrates, ethanolates, methanolates, and isopropanolates. Methods of solvation are generally known in the art. Abbreviations as used herein, are defined as follows: “1 x” for once, “2 x” for twice, “3 x” for thrice, “ºC” for degrees Celsius, “eq” for equivalent or equivalents, “g” for gram or grams, “mg” for milligram or milligrams, “L” for liter or liters, “mL” for milliliter or milliliters, “μL” for microliter or microliters, “N” for normal, “M” for molar, “mmol” for millimole or millimoles, “min” for minute or minutes, “h” for hour or hours, “rt” for room temperature, “RT” for retention time, “atm” for atmosphere, “psi” for pounds per square inch, “conc.” for concentrate, “sat” or “saturated” for saturated, “MW” for molecular weight, “mp” for melting point, “ee” for enantiomeric excess, “MS” or “Mass Spec” for mass spectrometry, “ESI” for electrospray ionization mass spectroscopy, “HR” for high resolution, “HRMS” for high resolution mass spectrometry, “LCMS” for liquid chromatography mass spectrometry, “HPLC” for high pressure liquid chromatography, “RP HPLC” for reverse phase HPLC, “TLC” or “tlc” for thin layer chromatography, “NMR” for nuclear magnetic resonance spectroscopy, “nOe” for nuclear Overhauser effect spectroscopy, “1H” for proton, “δ” for delta, “s” for singlet, “d” for doublet, “t” for triplet, “q” for quartet, “m” for multiplet, “br” for broad, “Hz” for hertz, and “α”, “β”, “R”, “S”, “E”, and “Z” are stereochemical designations familiar to one skilled in the art. Me Methyl Et Ethyl Pr Propyl i-Pr Isopropyl Bu Butyl i-Bu Isobutyl t-Bu tert-butyl Ph Phenyl Bn Benzyl Boc tert-butyloxycarbonyl ACN acetonitrile AcOH or HOAc acetic acid BOP reagent benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate CBz Carbobenzyloxy CH2Cl2Dichloromethane CH3CN or ACN Acetonitrile CDCl3deutero-chloroform CHCl3Chloroform mCPBA or m-CPBA meta-chloroperbenzoic acid Cs2CO3cesium carbonate Cu(OAc)2copper (II) acetate DCE 1,2 dichloroethane DCM dichloromethane DIEA, or Hunig's base diisopropylethylamine DMA or DMAc dimethylacetamide DMAP 4-dimethylaminopyridine DME 1,2-dimethoxyethane DMF dimethyl formamide DMSO dimethyl sulfoxide dppf 1,1′-Ferrocenediyl-bis(diphenylphosphine) EDTA ethylenediaminetetraacetic acid EtOAc ethyl acetate Et2O diethyl ether EtOH Ethanol HCl hydrochloric acid HATU O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate H2SO4sulfuric acid K2CO3potassium carbonate LiOH lithium hydroxide MeCN acetonitrile MeOH methanol NaOH sodium hydroxide Na2SO4sodium sulfate Pd / C palladium on carbon Pet ether petroleum ether i-PrOH or IPA isopropanol SFC supercritical fluid chromatography TEA triethylamine TFA trifluoroacetic acid THF tetrahydrofuran IV. BIOLOGY The inhibitory activity of compounds in SGK1 was determined by the following assay. Potencies of SGK inhibitors are determined in homogeneous time-resolved fluorescence (HTRF assay), a time resolved FRET-based competition binding assay. A GST-tagged form of SGK1 produced at BMS at a concentration of 1 nM was incubated with 0.2 nM Tb-labeled anti-GST detection antibody (Cis-Bio, MA), test compound, and fluorescein-labeled ATP competitive probe at a concentration corresponding to the probe’s equilibrium dissociation constant for one hour. Fluorescence at 495 nm and 520 nm was measured using an EnVision microplate reader to quantify FRET between Tb- labeled detection antibody and fluorescein-labeled probe (specially designed for SGK1 served as energy transfer acceptor). Background subtracted FRET ratios were normalized to the maximum signal obtained in the absence of test compound. These values were converted to a percent inhibition. Percent inhibition was determined for test compounds at 11 concentrations. The IC50, defined as the concentration of competing test compound needed to reduce specific binding of the probe by 50%, was derived by fitting data to the 4-parameter logistic equation y = A+((B-A) / (1+((C / x)^D))), where A and B denotes minimal and maximal % inhibition, respectively, C is the IC50, D is hill slope and x represents compound concentration. Representative Examples were tested in the SGK1 assay described above and found having SGK1 inhibitory activity. The IC50values are shown in Table A below.

[0007] Table A Example No. SGK1 IC50Example No. SGK1 IC50(µM) (µM)1 0.006 26 0.012 2 0.007 27 0.018 3 0.005 28 0.015 4 0.007 29 0.014 5 0.006 30 0.016 6 0.006 31 0.009 7 0.006 32 0.012 8 0.006 33 0.009 9 0.008 34 0.005 10 (Iso-1) 0.015 35 0.017 10 (Iso-2) 0.005 36 0.009 11 0.017 37 0.139 12 0.005 38 0.070 13 0.015 39 0.007 14 0.005 40 0.005 15 0.011 16 0.005 17 0.011 18 0.005 19 0.005 20 0.004 21 0.003 22 0.004 23 0.016 24 0.007 25 0.005 V. PHARMACEUTICAL COMPOSITIONS, FORMULATIONS AND COMBINATIONS The compounds of this invention can be administered in such oral dosage forms as tablets, capsules (each of which includes sustained release or timed release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions. They may also be administered in intravenous (bolus or infusion), intraperitoneal, subcutaneous, or intramuscular form, using dosage forms well known to those of ordinary skill in the pharmaceutical arts. They can be administered alone, but generally will be administered with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice. The term "pharmaceutical composition" means a composition comprising a compound of the invention in combination with at least one additional pharmaceutically acceptable carrier. A "pharmaceutically acceptable carrier" refers to media generally accepted in the art for the delivery of biologically active agents to animals, in particular, mammals, including, i.e., adjuvant, excipient or vehicle, such as diluents, preserving agents, fillers, flow regulating agents, disintegrating agents, wetting agents, emulsifying agents, suspending agents, sweetening agents, flavoring agents, perfuming agents, antibacterial agents, antifungal agents, lubricating agents and dispensing agents, depending on the nature of the mode of administration and dosage forms. Pharmaceutically acceptable carriers are formulated according to a number of factors well within the purview of those of ordinary skill in the art. These include, without limitation: the type and nature of the active agent being formulated; the patient to which the agent-containing composition is to be administered; the intended route of administration of the composition; and the therapeutic indication being targeted. Pharmaceutically acceptable carriers include both aqueous and non-aqueous liquid media, as well as a variety of solid and semi-solid dosage forms. Such carriers can include a number of different ingredients and additives in addition to the active agent, such additional ingredients being included in the formulation for a variety of reasons, e.g., stabilization of the active agent, binders, etc., well known to those of ordinary skill in the art. Descriptions of suitable pharmaceutically acceptable carriers, and factors involved in their selection, are found in a variety of readily available sources such as, for example, Remington's Pharmaceutical Sciences, 18th Edition (1990). The dosage regimen for the compounds of the present invention will, of course, vary depending upon known factors, such as the pharmacodynamic characteristics of the particular agent and its mode and route of administration; the species, age, sex, health, medical condition, and weight of the recipient; the nature and extent of the symptoms; the kind of concurrent treatment; the frequency of treatment; the route of administration, the renal and hepatic function of the patient, and the effect desired. A physician or veterinarian can determine and prescribe the effective amount of the drug required to prevent, counter, or arrest the progress of the disorder. By way of general guidance, the daily oral dosage of each active ingredient, when used for the indicated effects, will range between about 0.001 to about 1000 mg / kg of body weight, preferably between about 0.01 to about 100 mg / kg of body weight per day, and most preferably between about 0.1 to about 20 mg / kg / day. Intravenously, the most preferred doses will range from about 0.001 to about 10 mg / kg / minute during a constant rate infusion. Compounds of this invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three, or four times daily. Compounds of this invention can also be administered by parenteral administration (e.g., intra-venous, intra-arterial, intramuscularly, or subcutaneously. When administered intra-venous or intra-arterial, the dose can be given continuously or intermittent. Furthermore, formulation can be developed for intramuscularly and subcutaneous delivery that ensure a gradual release of the active pharmaceutical ingredient. Compounds of this invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using transdermal skin patches. When administered in the form of a transdermal delivery system, the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen. The compounds are typically administered in admixture with suitable pharmaceutical diluents, excipients, or carriers (collectively referred to herein as pharmaceutical carriers) suitably selected with respect to the intended form of administration, e.g., oral tablets, capsules, elixirs, and syrups, and consistent with conventional pharmaceutical practices. For instance, for oral administration in the form of a tablet or capsule, the active drug component can be combined with an oral, non-toxic, pharmaceutically acceptable, inert carrier such as lactose, starch, sucrose, glucose, methyl cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like; for oral administration in liquid form, the oral drug components can be combined with any oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like. Moreover, when desired or necessary, suitable binders, lubricants, disintegrating agents, and coloring agents can also be incorporated into the mixture. Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth, or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, and the like. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like. Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum, and the like. The compounds of the present invention can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine, or phosphatidylcholines. Compounds of the present invention may also be coupled with soluble polymers as targetable drug carriers. Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethylaspartamidephenol, or polyethyleneoxide-polylysine substituted with palmitoyl residues. Furthermore, the compounds of the present invention may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacylates, and crosslinked or amphipathic block copolymers of hydrogels. Dosage forms (pharmaceutical compositions) suitable for administration may contain from about 1 milligram to about 1000 milligrams of active ingredient per dosage unit. In these pharmaceutical compositions the active ingredient will ordinarily be present in an amount of about 0.1-95% by weight based on the total weight of the composition. Gelatin capsules may contain the active ingredient and powdered carriers, such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like. Similar diluents can be used to make compressed tablets. Both tablets and capsules can be manufactured as sustained release products to provide for continuous release of medication over a period of hours. Compressed tablets can be sugar coated or film coated to mask any unpleasant taste and protect the tablet from the atmosphere, or enteric coated for selective disintegration in the gastrointestinal tract. Liquid dosage forms for oral administration can contain coloring and flavoring to increase patient acceptance. In general, water, a suitable oil, saline, aqueous dextrose (glucose), and related sugar solutions and glycols such as propylene glycol or polyethylene glycols are suitable carriers for parenteral solutions. Solutions for parenteral administration preferably contain a water soluble salt of the active ingredient, suitable stabilizing agents, and if necessary, buffer substances. Antioxidizing agents such as sodium bisulfite, sodium sulfite, or ascorbic acid, either alone or combined, are suitable stabilizing agents. Also used are citric acid and its salts and sodium EDTA. In addition, parenteral solutions can contain preservatives, such as benzalkonium chloride, methyl-or propyl-paraben, and chlorobutanol. The compounds of the present invention can be administered alone or in combination with one or more additional therapeutic agents. By "administered in combination" or "combination therapy" it is meant that the compound of the present invention and one or more additional therapeutic agents are administered concurrently to the mammal being treated. When administered in combination, each component may be administered at the same time or sequentially in any order at different points in time. Thus, each component may be administered separately but sufficiently closely in time so as to provide the desired therapeutic effect. The compounds of the present invention are also useful as standard or reference compounds, for example, as a quality standard or control, in tests or assays involving the inhibition of SGK1. Such compounds may be provided in a commercial kit, for example, for use in pharmaceutical research involving SGK1. For example, a compound of the present invention could be used as a reference in an assay to compare its known activity to a compound with an unknown activity. This would ensure the experimentor that the assay was being performed properly and provide a basis for comparison, especially if the test compound was a derivative of the reference compound. When developing new assays or protocols, compounds according to the present invention could be used to test their effectiveness. The present invention also encompasses an article of manufacture. As used herein, article of manufacture is intended to include, but not be limited to, kits and packages. The article of manufacture of the present invention, comprises: (a) a first container; (b) a pharmaceutical composition located within the first container, wherein the composition, comprises: a first therapeutic agent, comprising: a compound of the present invention or a pharmaceutically acceptable salt form thereof; and, (c) a package insert stating that the pharmaceutical composition can be used for the treatment of a cardiovascular and / or inflammatory disorder (as defined previously). In another embodiment, the package insert states that the pharmaceutical composition can be used in combination (as defined previously) with a second therapeutic agent to treat cardiovascular and / or inflammatory disorder. The article of manufacture can further comprise: (d) a second container, wherein components (a) and (b) are located within the second container and component (c) is located within or outside of the second container. Located within the first and second containers means that the respective container holds the item within its boundaries. The first container is a receptacle used to hold a pharmaceutical composition. This container can be for manufacturing, storing, shipping, and / or individual / bulk selling. First container is intended to cover a bottle, jar, vial, flask, syringe, tube (e.g., for a cream preparation), or any other container used to manufacture, hold, store, or distribute a pharmaceutical product. The second container is one used to hold the first container and, optionally, the package insert. Examples of the second container include, but are not limited to, boxes (e.g., cardboard or plastic), crates, cartons, bags (e.g., paper or plastic bags), pouches, and sacks. The package insert can be physically attached to the outside of the first container via tape, glue, staple, or another method of attachment, or it can rest inside the second container without any physical means of attachment to the first container. Alternatively, the package insert is located on the outside of the second container. When located on the outside of the second container, it is preferable that the package insert is physically attached via tape, glue, staple, or another method of attachment. Alternatively, it can be adjacent to or touching the outside of the second container without being physically attached. The package insert is a label, tag, marker, etc. that recites information relating to the pharmaceutical composition located within the first container. The information recited will usually be determined by the regulatory agency governing the area in which the article of manufacture is to be sold (e.g., the United States Food and Drug Administration). Preferably, the package insert specifically recites the indications for which the pharmaceutical composition has been approved. The package insert may be made of any material on which a person can read information contained therein or thereon. Preferably, the package insert is a printable material (e.g., paper, plastic, cardboard, foil, adhesive-backed paper or plastic, etc.) on which the desired information has been formed (e.g., printed or applied). Other features of the invention will become apparent in the course of the following descriptions of exemplary embodiments that are given for illustration of the invention and are not intended to be limiting thereof. The following Examples have been prepared, isolated and characterized using the methods disclosed herein. VI. GENERAL SYNTHESIS INCLUDING SCHEMES The compounds of the present invention can be prepared in a number of ways known to one skilled in the art of organic synthesis. General synthetic schemes for preparing compounds of the present invention are described below. These schemes are illustrative and are not meant to limit the possible techniques one skilled in the art may use to prepare the compounds disclosed herein. As illustrated in Scheme 1, the reaction of tert-butyl (R)-piperidin-3-ylcarbamate I with 2-(bis(methylthio)methylene)malononitrile in the presence of suitable solvent such as EtOH provides the malononitrile intermediate II. Reaction of II with hydrazine in a suitable solvent such as acetic acid provides the pyrazole derivative III. Pyrazole derivative III can lead to piperidine derivative IV on reaction with formimidamide acetate. Reaction of IV with appropriate boronic acid or halides via Chan-Lam coupling or Buchwald-Hartwig amination, or other suitable coupling conditions, and using a suitable solvent can lead to formation of V. Boc-deprotection using acid such as HCl can lead to VI which on coupling with appropriate acid under standard amide coupling conditions can provide VII. This can be further derivatized depending on the nature of R1, e.g., if R1contains an amine, reductive amination using appropriate aldehydes or ketones can provide corresponding aminoalkylated derivatives. Scheme 1 Alternatively, intermediate V can be prepared from 3-bromo-1H-pyrazolo[3,4- d]pyrimidin-4-amine (VIII) as shown in Scheme 2. SNAr reaction between VIII and R2-X using a suitable base such as Cs2CO3affords intermediate IX. Alternatively, VIII can be N-arylated via Chan-Lam coupling or Buchwald-Hartwig coupling to afford intermediate IX. Reaction of intermediate IX with tert-butyl (R)-piperidin-3-ylcarbamate I in a solvent such as NMP at elevated temperature affords Intermediate V. Intermediate V can be further elaborated as described in Scheme 1 to provide VII. Scheme 2 The compounds of the present invention can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or by variations thereon as appreciated by those skilled in the art. Preferred methods include, but are not limited to, those described below. The reactions are performed in a solvent or solvent mixture appropriate to the reagents and materials employed and suitable for the transformations being effected. It will be understood by those skilled in the art of organic synthesis that the functionality present on the molecule should be consistent with the transformations proposed. This will sometimes require a judgment to modify the order of the synthetic steps or to select one particular process scheme over another in order to obtain a desired compound of the invention. It will also be recognized that another major consideration in the planning of any synthetic route in this field is the judicious choice of the protecting group used for protection of the reactive functional groups present in the compounds described in this invention. An authoritative account describing the many alternatives to the trained practitioner is Greene et al. (Protective Groups in Organic Synthesis, 5th Edition, Wiley- Interscience (2015)). LCMS conditions: Method A: Column: XBridge BEH XP C18 (50x2.1) mm, 2.5 μm; Mobile phase A: 10 mM NH4OAc, Acetonitrile (95:5); Mobile phase B: 10 mM NH4OAc: Acetonitrile (5:95); Gradient = 0-100% B over 3 minutes; Temperature: 50 °C; Flow rate: 1.1 mL / min; Detection: UV at 220 nm. Method B: Column: XBridge BEH XP C18 (50x2.1) mm, 2.5 μm; Mobile phase A: 0.1% TFA in water, Acetonitrile (95:5); Mobile phase B: 0.1% TFA in water, Acetonitrile (5:95); Gradient = 0-100% B over 3 minutes; Temperature: 50 °C; Flow rate: 1.1 mL / min; Detection: UV at 220 nm. Intermediate 1. Preparation of lithium 4-(((1S,4S)-4-((tert- butoxycarbonyl)amino)cyclohexyl)oxy)-2-methylthiazole-5-carboxylate Intermediate 1A. Ethyl 4-(((1S,4S)-4-((tert-butoxy carbonyl) amino) cyclohexyl) oxy)-2- methylthiazole-5-carboxylate To a stirred solution of ethyl 4-hydroxy-2-methylthiazole-5-carboxylate (10 g, 53.4 mmol), tert-butyl ((1R,4R)-4-hydroxycyclohexyl)carbamate (11.50 g, 53.4 mmol) and triphenylphosphine (21.0 g, 80 mmol) in THF (100 mL) was added DIAD (23.9 mL, 123 mmol). After stirring for 2 h at rt, it was concentrated and the residue obtained was purified by silica gel chromatography (330 g column, eluting with 0-100% EtOAc in Pet. Ether,compound eluted at 28-30%) to afford Intermediate 1A (13.5 g, 42 % yield) as a white solid. MS: [M+H]+= 385.15.1H NMR (400 MHz, CHLOROFORM-d) δ ppm 5.19 - 5.14 (m, 1H), 4.32 - 4.25 (m, 2H), 2.62 (s, 3H), 2.10 - 1.98 (m, 2H), 1.84 - 1.78 (m, 2H), 1.72 - 1.65 (m, 3H), 1.46 (s, 9H), 1.35 (d, J = 7.0 Hz, 6H). Intermediate 1. Lithium 4-(((1S,4S)-4-((tert-butoxycarbonyl)amino)cyclohexyl)oxy)-2- methylthiazole-5-carboxylate To a stirred solution of Intermediate 1A (6.0 g, 15.6 mmol) in a mixture of ethanol (20 mL), THF (30 mL) and water (10 mL), was added LiOH.H2O (1.12 g, 46.8 mmol). After stirring for 5 h at rt, the mixture was evaporated to afford Intermediate 1 (6.7 g, 95 % yield) as an off-white solid. MS: [M-H]+= 355.0. Intermediate 2. Preparation of lithium 5-(difluoromethyl)-3-(((1R,3s,5S)-8-methyl-8- azabicyclo[3.2.1]octan-3-yl)oxy)thiophene-2-carboxylate Intermediate 2A. Methyl 5-(difluoromethyl)-3-(((1R,3s,5S)-8-methyl-8- azabicyclo[3.2.1]octan-3-yl)oxy)thiophene-2-carboxylate Analogous to the preparation of Intermediate 1A, reaction of methyl 5- (difluoromethyl)-3-hydroxythiophene-2-carboxylate (1.5 g, 7.21 mmol), (1R,3r,5S)-8- methyl-8-azabicyclo[3.2.1]octan-3-ol (1.017 g, 7.21 mmol), triphenylphosphine (2.457 g, 9.37 mmol) and diethyl azodicarboxylate (1.26 mL, 7.93 mmol) afforded Intermediate 2A (2 g, 84 % yield) as a yellow solid. MS: [M+H]+= 332.1. Intermediate 2. Lithium 5-(difluoromethyl)-3-(((1R,3s,5S)-8-methyl-8- azabicyclo[3.2.1]octan-3-yl)oxy)thiophene-2-carboxylate Analogous to the preparation of Intermediate 1, reaction of methyl 5- (difluoromethyl)-3-(((1R,3s,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl)oxy)thiophene-2- carboxylate (900 mg, 2.72 mmol) and LiOH (130 mg, 5.43 mmol) afforded Intermediate 2 (800 mg, 93% yield) as a pale yellow solid. MS: [M+H]+= 318.3. Intermediate 3. Preparation of lithium 4-((4-(azetidin-1-yl)cyclohexyl)oxy)-2- methylthiazole-5-carboxylate Intermediate 3A. Ethyl 4-((4-(azetidin-1-yl)cyclohexyl)oxy)-2-methylthiazole-5- carboxylate To a stirred solution of ethyl 2-methyl-4-((4-oxocyclohexyl)oxy)thiazole-5- carboxylate (2.0 g, 7.06 mmol) in THF (5 mL), was added azetidine (2.38 mL, 35.3 mmol) followed by titanium(IV) isopropoxide (4.18 mL, 14.1 mmol). After stirring for 16 h at rt, NaBH4(0.401 g, 10.6 mmol) was added to the reaction mixture and stirring was continued for another 2 h. The mixture was concentrated and purified by flash chromatography (120 g silica gel column, 0-20% Methanol in DCM). Separation by SFC afforded Intermediate 3A ethyl 4-((4-(azetidin-1-yl)cyclohexyl)oxy)-2-methylthiazole-5-carboxylate (Isomer-1, 500 mg, 22 % yield) as a yellow gummy solid, MS: [M+H]+= 325.1 and ethyl 4-((4- (azetidin-1-yl)cyclohexyl)oxy)-2-methylthiazole-5-carboxylate (Isomer-2, 120 mg, 5% yield) as a yellow gummy solid, MS: [M+H]+= 325.1. Isomer-1 was taken to the next step. Intermediate 3. lithium 4-((4-(azetidin-1-yl)cyclohexyl)oxy)-2-methylthiazole-5- carboxylate Analogous to the preparation of Intermediate 1, reaction of ethyl 4-((4-(azetidin- 1-yl)cyclohexyl)oxy)-2-methylthiazole-5-carboxylate (500 mg, 1.541 mmol) and lithium hydroxide hydrate (129 mg, 3.08 mmol) afforded lithium 4-((4-(azetidin-1- yl)cyclohexyl)oxy)-2-methylthiazole-5-carboxylate (420 mg, 90 % yield) as a white solid. MS: [M+H]+= 297.1. Intermediate 4. Preparation of lithium 5-chloro-3-(2-(dimethylamino)ethoxy)thiophene-2- carboxylate Intermediate 4A. Methyl 5-chloro-3-(2-(dimethylamino)ethoxy)thiophene-2-carboxylate Analogous to the preparation of Intermediate 1A, reaction of methyl 5-chloro-3- hydroxythiophene-2-carboxylate (1.5 g, 7.79 mmol), 2-(dimethylamino)ethan-1-ol (0.694 g, 7.79 mmol), triphenylphosphine (2.45 g, 9.35 mmol) and DIAD (1.67 mL, 8.57 mmol) afforded Intermediate 4A (1.0 g, 49 % yield) as a yellow solid. MS: [M+H]+= 264.2.1H NMR (500 MHz, DMSO-d6) δ ppm 7.42 (s, 1H), 4.53-4.47 (m, 2H), 3.76-3.70 (m, 3H), 3.55-3.49 (m, 2H), 2.92 (s, 6H). Intermediate 4. lithium 5-chloro-3-(2-(dimethylamino)ethoxy)thiophene-2-carboxylate Analogous to the preparation of Intermediate 1, reaction of methyl 5-chloro-3-(2- (dimethylamino)ethoxy)thiophene-2-carboxylate (460 mg, 1.74 mmol) and LiOH (3.5 mL of 1M aq. Solution, 3.49 mmol) afforded Intermediate 4 (420 mg, 96 % yield) as an off- white solid. MS: [M+H]+= 250.2. Intermediate 5. Preparation of lithium 2-methyl-4-(((1s,4s)-4-(pentan-3- ylamino)cyclohexyl)oxy)thiazole-5-carboxylate Intermediate 5A. Ethyl 4-(((1s,4s)-4-aminocyclohexyl)oxy)-2-methylthiazole-5- carboxylate.HCl To a stirred solution of ethyl 4-(((1s,4s)-4-((tert- butoxycarbonyl)amino)cyclohexyl)oxy)-2-methylthiazole-5-carboxylate (7.6 g, 19.8 mmol) in DCM (20 mL) was added 4N HCl in dioxane (24.7 mL, 99 mmol). After stirring at rt for 2 h, the mixture was evaporated to afford Intermediate 5A (6.3 g, 99 % yield). MS: [M+H]+= 285.2. Intermediate 5B. Ethyl 2-methyl-4-(((1s,4s)-4-(pentan-3- ylamino)cyclohexyl)oxy)thiazole-5-carboxylate To a stirred solution of ethyl 4-(((1s,4s)-4-aminocyclohexyl)oxy)-2- methylthiazole-5-carboxylate, HCl (6.3 g, 19.6 mmol) in MeOH (50 mL) were added sodium cyanoborohydride (7.40 g, 118 mmol), acetic acid (1.12 mL, 19.64 mmol) and pentan-3-one (33.8 g, 393 mmol). After stirring for 3h at rt, the mixture was partitioned between water (200 mL) and ethyl acetate (250 mL). The organic layer was dried over sodium sulphate and concentrated. The crude product was purified by flash chromatography (40 g column; 1-20% MeOH in DCM as eluent) to afford Intermediate 5B (5.5 g, 79 % yield) as a light yellow oil. MS: [M+H]+= 355.1. Intermediate 5. lithium 2-methyl-4-(((1s,4s)-4-(pentan-3- ylamino)cyclohexyl)oxy)thiazole-5-carboxylate Analogous to the preparation of Intermediate 1, reaction of ethyl 2-methyl-4- (((1s,4s)-4-(pentan-3-ylamino)cyclohexyl)oxy)thiazole-5- carboxylate (5.5 g, 15.5 mmol) and LiOH (1.12 g, 46.5 mmol) afforded Intermediate 5 (5 g, 90 % yield). MS: [M+H]+= 327.1. Example 1 Preparation of N-((R)-1-(4-amino-1-(4-(methylsulfonyl)phenyl)-1H-pyrazolo[3,4- d]pyrimidin-3-yl)piperidin-3-yl)-4-(((1S,4S)-4-(dimethylamino)cyclohexyl)oxy)-2- methylthiazole-5-carboxamide Example 1A. tert-butyl (R)-(1-(2,2-dicyano-1-(methylthio)vinyl)piperidin-3-yl)carbamate To a stirred soliution of tert-butyl (R)-piperidin-3-ylcarbamate (11.8 g, 58.7 mmol) in anhydrous ethanol (100 mL), was added 2-(bis(methylthio)methylene)malononitrile (10 g, 58.7 mmol) at rt. The reaction mixture was heated to 85 °C for 6 h. It was cooled to rt and evaporated to afford Example 1A (20 g, 99 % yield) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ ppm 3.99 - 3.92 (m, 1H), 3.86 - 3.79 (m, 1H), 3.52 - 3.36 (m, 3H), 2.58 (s, 3H), 1.93 - 1.81 (m, 2H), 1.65 - 1.48 (m, 2H), 1.40 (s, 9H). MS: [M+H]+= 345.2. Example 1B. tert-butyl (R)-(1-(3-amino-4-cyano-1H-pyrazol-5-yl)piperidin-3- yl)carbamate To a stirred solution of tert-butyl (R)-(1-(2,2-dicyano-1- (methylthio)vinyl)piperidin-3-yl)carbamate (19 g, 58.9 mmol) in anhydrous ethanol (60 mL), was added hydrazine monohydrate (9.25 mL, 295 mmol) at rt. After stirring for 4 h, the reaction mixture was evaporated. The residue was diluted with water and the resultant suspension was stirred for 5 min. The mixture was filtered, and the collected solid was dried under vacuum to afford Example 1B (18.0 g, 90 % yield) as off-white solid.1H NMR (400 MHz, DMSO-d6) δ ppm 11.12 - 10.88 (m, 1H), 6.81 (br d, J = 7.5 Hz, 1H), 6.20 - 5.95 (m, 1H), 3.57 (br d, J = 12.5 Hz, 2H), 3.42 (br d, J = 7.0 Hz, 1H), 2.62 (br d, J = 10.0 Hz, 1H), 2.44 (s, 1H), 1.83 - 1.62 (m, 2H), 1.59 - 1.45 (m, 1H), 1.39 (s, 9H), 1.33 - 1.22 (m, 1H). MS: [M+H]+= 305.3. Example 1C. tert-butyl (R)-(1-(4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)piperidin-3- yl)carbamate To a stirred solution of tert-butyl (R)-(1-(3-amino-4-cyano-1H-pyrazol-5- yl)piperidin-3-yl)carbamate (4.9 g, 16.0 mmol) in anhydrous ethanol (100 mL), was added formamidine acetate salt (16.65 g, 160 mmol) at rt. The reaction mixture was heated to 80 °C. After stirring for 16 h, the mixture was allowed to cool to rt and then was diluted with water. The resulting suspension was stirred for 5 min. The suspension was filtered and the solid obtained was washed with water and dried under vacuum to afford Example 1C (5.2 g, 98 % yield).1H NMR (400 MHz, DMSO-d6) δ ppm 8.09 (s, 1H), 7.03 (br d, J = 8.0 Hz, 1H), 6.80 (br d, J = 8.5 Hz, 1H), 3.78 - 3.58 (m, 1H), 3.13 - 3.02 (m, 1H), 2.92 - 2.62 (m, 2H), 1.93 - 1.58 (m, 4H), 1.39 (s, 9H). MS: [M+H]+= 334.3. Example 1D. tert-butyl (R)-(1-(4-amino-1-(4-(methylsulfonyl)phenyl)-1H-pyrazolo[3,4- d]pyrimidin-3-yl)piperidin-3-yl)carbamate To a stirred solution of tert-butyl (R)-(1-(4-amino-1H-pyrazolo[3,4-d]pyrimidin-3- yl)piperidin-3-yl)carbamate (500 mg, 1.50 mmol) and (4-(methylsulfonyl)phenyl)boronic acid (510 mg, 2.55 mmol) in anhydrous DCM (20 mL) were added pyridine (0.364 mL, 4.50 mmol) and copper (II) acetate (545 mg, 3.00 mmol) at rt. The reaction mixture was stirred under open air for 16 h. The suspension was filtered through a celite bed and the filtrate was concentrated. The crude product which was purified by flash chromatography (55% ethyl acetate in pet. ether as eluent) to afford Example 1D (730 mg, 80 % yield) as a pale yellow solid. MS: [M+H]+= 488.1. Example 1E. (R)-3-(3-aminopiperidin-1-yl)-1-(4-(methylsulfonyl)phenyl)-1H- pyrazolo[3,4-d]pyrimidin-4-amine To a stirred solution of tert-butyl (R)-(1-(4-amino-1-(4-(methylsulfonyl)phenyl)- 1H-pyrazolo[3,4-d]pyrimidin-3-yl)piperidin-3-yl)carbamate (730 mg, 1.50 mmol) in anhydrous DCM (15 mL), was added 4N HCl in dioxane (10 mL, 40.0 mmol). After stirring for 2h, the reaction mixture was concentrated to afford Example 1E (580 mg, 90 % yield) as a brown solid. MS: [M+H]+= 388.2. Example 1F. tert-butyl ((1S,4S)-4-((5-(((R)-1-(4-amino-1-(4-(methylsulfonyl)phenyl)-1H- pyrazolo[3,4-d]pyrimidin-3-yl)piperidin-3-yl)carbamoyl)-2-methylthiazol-4- yl)oxy)cyclohexyl)carbamate To a stirred solution of (R)-3-(3-aminopiperidin-1-yl)-1-(4- (methylsulfonyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (530 mg, 1.37 mmol) in anhydrous DMF (8 mL), were added BOP (1.03 g, 2.33 mmol), DIPEA (1.43 mL, 8.21 mmol) and 4-(((1S,4S)-4-((tert-butoxycarbonyl)amino)cyclohexyl)oxy)-2-methylthiazole- 5-carboxylic acid (585 mg, 1.64 mmol) at rt. After stirring for 16h at rt, the resultant suspension was filtered through a celite bed, and the filtrate was concentrated. The crude product which was purified by flash chromatography (5% methanol in chloroform as eluent) to afford Example 1F (990 mg, 80 % yield) as a pale yellow semisolid. MS: [M+H]+= 726.5. Example 1G. N-((R)-1-(4-amino-1-(4-(methylsulfonyl)phenyl)-1H-pyrazolo[3,4- d]pyrimidin-3-yl)piperidin-3-yl)-4-(((1S,4S)-4-aminocyclohexyl)oxy)-2-methylthiazole- 5-carboxamide To a stirred solution of tert-butyl ((1S,4S)-4-((5-(((R)-1-(4-amino-1-(4- (methylsulfonyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)piperidin-3-yl)carbamoyl)-2- methylthiazol-4 yl)oxy)cyclohexyl)carbamate (300 mg, 0.413 mmol) in anhydrous DCM (3 mL), was added 4N HCl in dioxane (3 mL, 12 mmol). The reaction mixture was stirred for 2 h, then was concentrated to afford Example 1G (260 mg, 60 % yield) as a brown solid, which was used without additional purification. MS: [M+H]+= 626.3.

[0008] Example 1. To a stirred solution of N-((R)-1-(4-amino-1-(4-(methylsulfonyl)phenyl)-1H- pyrazolo[3,4-d]pyrimidin-3-yl)piperidin-3-yl)-4-(((1S,4S)-4-aminocyclohexyl)oxy)-2- methylthiazole-5-carboxamide (80 mg, 0.128 mmol) in anhydrous methanol (2 mL) at rt, were added formaldehyde (0.021 mL, 0.767 mmol) and sodium cyanoborohydride (48.2 mg, 0.767 mmol). After stirring for 16 h, the suspension was filtered through a celite pad, and the filtrate was concentrated. The crude product was purified by preparative HPLC to afford Example 1 (9.5 mg, 11 % yield). LC-MS Method B: RT = 0.99 min, [M+H]+= 654.3.1H NMR (400 MHz, DMSO-d6) δ ppm 8.55 - 8.45 (m, 2H), 8.35 (s, 1H), 8.12 - 8.00 (m, 2H), 7.40 (br d, J = 8.5 Hz, 1H), 5.02 (br s, 1H), 4.28 (br s,1H), 3.55 - 3.49 (m, 1H), 3.25 - 3.18 (m, 6H), 2.61 (s, 3H), 2.21 (br s, 1H), 2.04 (br s, 10H), 1.73 - 1.51 (m, 4H), 1.49 - 1.32 (m, 3H). Analogous to synthesis of Example 1, the following Examples 2-9 in Table 1 were prepared.

[0009] Table 1

[0010] -22- 5.. 8 J,4, ,J- ,4,,08834-.9., ) 6 ) ,20d. s0 0.7 4dH8 .2m(H3 d2.8 rb 4,(6.12, ,) rb, - 57, rb 5.8-(0.16. ,)=m6)H(m1.m( (68 22 Jp0H4( 7. 1 20 9. ,H,tp.8δ, 1 1, 5.1 2- 12),zm(3, 2.,)10.8.m 10p .,p 8 4, =)2H,d(),) )J sH,7(0) H1 H 5)3H H- 1 .2 -7 HδHt1 1,, d( 19 7.0d6- ,0s.82.71 7,s ,) 3. 3,)6 ,m2 m(.1,)O ( S4 =- ,s2.( 4H3 1,zd-s((3J 7rb3 7. ,)42.61 ,)H7HHM.8 ,d43 OS43 3.4,.3H3,s(.7(,3) 2,s( 4, .4M.8 7 )-,s(D,,)9 ,) 2.H4)H1 sr=.)D ,) -H z H3.H4, 26. b(JH1 1 9r42.3 ,zH4. ,z 2. b(1.)RH2, 7,1,,) z ,s2,8,d ,H2, 7H3,7 ,)H6MMm()HmHH(1r,0.b)(H5.r1bz,( HMm()H5.)H9.1H6 ,zN 0 1 s 1 1 ,30 231 ,,sH H084( 4.,48m( 3.r 177b( =1., )3m(H 468..4 080=4( 4., =,8m( J z ) rHH3b( 4.7,).dnoi62266298ht m(3.1 0.3.1 1.eT:1::1MRABA:B+) H+ 3.3.M8(66696-n- ini-dire-di2i 3r-ena- p - p)ptn 5-)-lyiHyxp) eelplo-o3)e ( -lydi-y- zamH-3-4-) iht -1-4)n xea-1-)n S)(-l1yi-ndiho xlob4(-lyindi 4,Sy1xooenhmir- ip)ml y4cy rp-c ac1-oehmir(()(ly] ))- So5-nip)l yp-]4-xeha y-nd4 o- 4, nSieloma y-ndlo -yh ole( f -l4,31[1m (al zai4( fl4,3[te cycdi-uslol((-ypht-ul1- slolm-)omae)mRyha((-t oez4a- r)olrp yh)Ryht oz2-)nixoyy-os te((- earlyy- mabrN Nm( p 3i(m Nm( p 3lyacH N NRelpmaxE 2 3 -,4s( =rb,s 8,5.J1 ,) , -7960 rb,55- 2 ,),t(832.,(r .3m(Hm5( 45 .7.5 (m(.240 7.1H418d(02.b( ,40)27.,m13..8-,7)95.032.-.2,,) , 7.0m36H2 (10H, 3 4)Hm(,pp,) 3δH .17,).,H34,-1 - .)mp .81,)-6.H5, )9H )1 ,,) )s(388. 4H3p,) zH1 42, 1,m(1.1H,H32.2 1 - 4. ,z δ)HH0, 2.)Hm0 1 ,zd6 s( 2 sr1, .3,)51,H d61, .8 m( 3,3( 8. -H - O4,b(z,)H0.S3. m(6 HH1,2 )5,H. -s(=91 ) ,H031 -43 9.)5 6 OS4 J,.41 m(.2 5 .1 31M889. 0.2, zH,=3M.8d-,z21-9. ,),8.)D,) 9.4, 7 srH 3 m(J,D ,()682H.311,H.6H ,zH72 - ) ,RH3 b(0. ,s( 6d(,H3. .45-4.)5=3,H,8 1.47 51 4.7zH27, ,).082, H1,mJ zMMm0. ,N (08,z=2. =J6. 18.,HJ3m)H11.) ,,,Hm ( ,dt Hd2, -0, M(H2 1,=3, 4(05 (4.7H0614( 4.)8H1 8., ) r )67ddH1b(H2 7.)0061H24( 4.,srJ) ,68m(b(,dH5m( 9. .112-1.1=J,).dnoi131 1 0t 29 535hm.9. .9.e (1:0 1 0MTR A:B:A:B +)H+ 2.3M4.8(8696- -)e-)eH- -d3i- -di- S4 2- mH-3S4 2- m -1- n,4)( l is)-1 -yxa1x- -) -lni ,s)1yxax1y-ndi(( oe(2-o)o 4nhmilb (- yndi(((-2o)olbr-4nip)l yp -a yr)lpoxac1- ehmir -4-n yrxacre -5onip)yp -)latue -5ma y]- nd-y- phyol-ellmy]nd-y- bhyol-el4o(f4,3-- l1u nxocy oza-4 of4,3-nxocy ozs3[ idi rdc)oai(- lus3[ idi rdc) aie -)lmRy olre yh nihtl1- ly olre yhonihtla(h(-t oeza pi -1 y )( mhtR(ht oza pi -1myhtmry p)l(- a)le(- emry p)l((- a)leN N( p y 4 ym N( p y 4 ym H O H O H N H NRelpmaxE 4 5 -77 5-3 - 4 , 3, r4 , ,,59..87 0.1 0 ) .d b3 ) z3662- 50,6.318.2H ).3,).2,)5 6((.,=947HH .2m(.1.).92,)1,8.-1- H3m8p0H,)H,)Hm(J, 8.8s 48.,Hr77 124,zp.81δ,),H z1 6,H4, 2 d(m)2, b(=J .2 -.1H) HH,m(2,m(5.0 ppH1z20 ,d ,)60,)3.10.m(51m5 1-8.0 δ ,s H .(85 rH.2H6d6- ,s 82 .( 5O(=1.3.)24 - 29 3 ,63.8 ,)b(9,,)5,=J.- 7.)dH- 3. =H1 95mH3 m,S43J., -522 561,2 OS 8, J ,z.3( (d1,srM D8d,(03.3- .2 ) ,m M) ,Hd H ,) 1.(35. b(,)8z H3.4,)70,)H5(D 2( 35.H1306.138RH2 .,7,,)H MMm)H1 .,3H ,)1, 8,m( 1.,z,z 0. 7,- - 1.)HH8= s2.0r42. ,)57. ,)N 0(H1,m(H m(3 -HH0514( 42.,sr28m(b( 5 3.28. 5 3 M8, 0.,)J,b( 3H 08 H1dr1 ,)21H ,,)2,3 ,s( 7.2 1-3.1 zH4(=J,sb( 2.4H1m(H5m(,).dni0 6 8o5480810ht m. . .0.e (1:1 1 1MTR A:B:A:B +)H+ 3.38.M(94686- -)e-eH-S-2 di- -)S-2 di-13-4) -n 4,- s -)ymHa13-) -n 4,- s)yma(l-1yidi 1( 2- xoxo-4lyidi 1(-2xoxo-n( oenhmipi (r- na )lbr(-1 n( emi (- -n)lbr)y 4-)py aox c- -o hp ry 4-apyxac- mlp] ly reay-ndph 5-ni)lp)] l- -yore3ph 5- 4o-yoxlcelma ynd- -3o-y lcel(f- l41 u,nios3[o di hytcoze)oa-i4 ofl4,nh(-ui xo ycozs3[o di rd )oaihe -)lRylho rzepim-ni tl1my-)lRylho rze ypih-ni tlmyma((-tear1(ht ( t a 1(htN(y p)pl(y- a) e( 4ym- e rp) (a) eNm lNm(yply-4lym H O OHNHNRelpmaxE 6 7,d,(d ,z23,z ,s,) , -69 ,) ,)62- 56,), ( 93 H .4HrbHm5( 65 .7H1H1 .360.2Hm5(4.80. 88.m, 7 ,) 5.=H11(, 91860.8-,z ,,).3,) , 22. m( .1m01H m(H1 ,)H1 m( .1 .p)pHJδ1, ,,d s =26rJ,,) 8. -.)p11p.80. 8,zH3 , 0-)H 4H3δ,)8 1.)4H, m(8.1 533d6s( rb b(d-4(1rH -.1,z )H 0b(7,60, 1 = -3.s( 3 - .1,z)H d6 ,s J,4237.24 ,)HO3. 53.50 m(.2H4. - (d3. 1,1.- 0.H5.S 8.,7,) 6.4,)5 7 OS43 rb48.3,18 25 6M),)H3,,DH ,2H z,z2 3,, )0.H.H3 3,m(=JM8(,) 2, =).2,) ,m=Jzs(1,- s( 6t(D ,,)8z H3H1JH6,)H4( ,2.7 ,s ,d ,H, 7d(RHHMH 2 m421 4.1 37H,,)r dm( 2,m( 4.1 08N M850.8 8..86 (.,3 6.2H0 ) 8- .0 ,0Mm(Hb),)(rb4 ,)0 42(,6 m - .5 61.(545. 40,)14(=J=JH.14-H1H1 7.1H054( 4.8m( 0.5 5.33-9.2 2-7.1H2,).dni3373512oht m(1.1 0.4. 60.eT:1: 1:1MRABA:B +)H+ 3.3.M8(98696- -)H-e-)e-di- - -di-13-- Sn4,2- 4)( ls)ymHa13S- -n 4,2- s)ma-1yidi 1( -xoxo-4)lyidi 1(-2 yx xo-n( oenhm(-2-)lbr(-1 n( em(- -n o)lbripir)y 4-nayxac- -o hpiry 4-apyxac- mlp)] lytueh 5-ni)lp)] lyoreay-ndph 5-- -3b o4o-y lcelma ynd- -3 yoxlcel(f- l41 u,ni xos3[o di rydco)z -4 ofl4, -nio ycozoaih(-us3[di hte)oaihe -)lRylho rze ypih-ni tl1- my )lRy olho rzepim-ni tlyma((-tea 1(ht ( t a 1( mhtmry p)l(- a)le(- emry p)l(- a)leN N( p y 4 ym N( p y 4 ym O H H NO HNRelpmaxE 8 9 Example 10. Preparation of N-((R)-1-(4-amino-1-(4-(methylsulfonyl)phenyl)-1H- pyrazolo[3,4-d]pyrimidin-3-yl)piperidin-3-yl)-4-((4-(azetidin-1-yl)cyclohexyl)oxy)-2- methylthiazole-5-carboxamide Example 10A. (R)-N-(1-(4-amino-1-(4-(methylsulfonyl)phenyl)-1H-pyrazolo[3,4- d]pyrimidin-3-yl)piperidin-3-yl)-2-methyl-4-((4-oxocyclohexyl)oxy)thiazole-5- carboxamide To a stirred solution of (R)-3-(3-aminopiperidin-1-yl)-1-(4- (methylsulfonyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (275 mg, 0.710 mmol) in anhydrous DMF (1.5 mL) at rt, were added 2-methyl-4-((4-oxocyclohexyl)oxy)thiazole-5- carboxylic acid (272 mg, 1.07 mmol), BOP (534 mg, 1.21 mmol) and DIPEA (0.372 mL, 2.13 mmol). After stirring for 4 h at rt, the mixture was diluted with ice water (5 mL). The resultant precipitate was filtered and the solid was collected and dried under vacuum to afford Example 10A (380 mg, 43 % yield) as a brown solid. MS: [M+H]+= 625.3. Example 10 To a stirred solution of (R)-N-(1-(4-amino-1-(4-(methylsulfonyl)phenyl)-1H- pyrazolo[3,4-d]pyrimidin-3-yl)piperidin-3-yl)-2-methyl-4-((4- oxocyclohexyl)oxy)thiazole-5-carboxamide (80 mg, 0.128 mmol) in anhydrous methanol (3 mL) at rt, was added azetidine (36.6 mg, 0.640 mmol) and sodium borohydride (24.2 mg, 0.640 mmol). The reaction mixture was stirred at room temperature for 12 h, then concentrated. The residue was purified by preparative HPLC to afford two isomers. Example 10 (Iso-1): (3.8 mg, 4 % yield). LC-MS Method A: 1.276, Method B: RT = 1.03 min, [M+H]+= 663.3.1H NMR (400 MHz, DMSO-d6) δ ppm 8.55 - 8.48 (m, 2H), 8.37 (s, 1H), 8.12 - 8.01 (m, 2H), 7.50 (d, J = 7.8 Hz, 1H), 4.81 - 4.68 (m, 1H), 4.22 (br s, 1H), 3.47 (br s, 1H), 3.24 - 3.16 (m, 5H), 2.82 (br t, J = 7.4 Hz, 4H), 2.59 (s, 3H), 2.10 - 1.98 (m, 4H), 1.97 - 1.70 (m, 8H), 1.53 (br s, 1H), 1.46 - 1.35 (m, 2H), 1.32 - 1.12 (m, 3H), 0.95 - 0.78 (m, 2H). Example 10 (Iso-2) (4.5 mg, 5 % yield). LC-MS Method A: 1.288, Method B: RT = 1.00 min, [M+H]+= 663.3. (400 MHz, DMSO-d6) δ ppm 8.56 - 8.46 (m, 2H), 8.35 (s, 1H), 8.11 - 7.96 (m, 2H), 7.52 (br d, J = 8.0 Hz, 1H), 5.07 - 4.88 (m, 1H), 4.33 (br s, 1H), 3.45 (br s, 1H), 3.29 - 3.26 (m, 1H), 3.22 (s, 3H), 2.78 (t, J = 6.8 Hz, 4H), 2.60 (s, 3H), 1.99 - 1.70 (m, 8H), 1.68 - 1.48 (m, 4H), 1.38 - 1.17 (m, 4H). Analogous to synthesis of Example 10, the following Examples 11-18 in Table 2 were prepared. Table-2

[0011] -893122,z ,)15 rb-8999 rb J,2,7m,8.. . .H.( 6. .(d .(m587-5,4H ),) 0. 1, 1s,)7957 4..8-,)92.rb2 (( - 77 13.m0p1H1H121rbH70,m90H14, 8 98 ..11 -p.8,z ,,3.(8, )Hpp.8,z ) 2H.3 2, - 4δ,)H m(2 8.2m(2, δ,)H 1,,) )54H0. .1)H1 3.276.=J,)2 m)6H1 3.mH1 52,).)d6- ,s =4,dH6.(19d,8s =(2, ,s(,)HH2O(J, -1dr4,-1.- ( OJ, 6. m(2 H33, ,S63. d8. b(m(61 - S53. d4 -12. ,sm(m(M D8 r,,)b( 4,0zH7)7 7 .26M8 rb4(2 .3 3, ( 8 61H4.1.24.3,) 3.1D ,)89.- )H164.1.1713,,- H,),zH24.4, 051 .2 - -RH,,))mH523,H H, 7,))H.3,z,)5792MMm( H(1N 062, 78,.3s(2,.)Mm( H1,,)HH.1.1.s ,)9 s H207 2,s H1 5. 2,,),)H04( 4.8m(4r-b(H1 5.r2b(,0s4( 4.8mr(b(,6s =m(H6H2,).dnoi66926080ht m(5.1 0.8.1 0.eT:1::1MRABA:B+) H+ 2.2.M4(84686-o- si os,Ie,-d-eH-3i-- mH-d3i-- m -1-)n3( a1-)n3( a4( l i-1y di -4x( -o- -n b4( lyidi -4x( -oboehmi (r-nip42-)ra-1-ne mi (-42-)ra)y-)l-yxc-5onhp r)y-)l-yxc- mlay p]- nd y-1-o) -ei ly p]y-1-o 5) -e4 o-43-ni lyloma- ndo-43-ni lylo(f- l ,3 nidi1us t xeza 4(fl ,3 nidit xezal[o dir ez h ih-1 usl [o dir ez h ihe -) yloep aoolctly-) yloeaoolctlymRa(h(-te zar ip)ro yc) htRe(h(te za piro y htpy f ym1 - rp)c) eN Nm(y l ul lNm(yplyulflym2F F N NRelpmaxE1121 -493r3, , -40r2 , , ,-91 -,5,592b(2mm9 1b( 2 ) ) d 93s 066m..7.52 .3 ( ( 06..7.50 .3H4H2 dr 55 .7.572.rb(.2.1 (8 -,) 2. ,) 77 5.2. 8-,) 5. ,),s ,mb(..)8-,) 4,4 ,) -32.m0p1H p.814, , H z)1 11 -m80H .13,)H2 ((91H m01H .1) 4.H617.1 -H,z- 0 pp 8,zH,s 16. 54. .13,pp 8,zH13,) ,s1, 9δ,)H0 1,H 70.4.1 δ,)H 1, rb( 2,1 -,)s( δ,)H,mHrb)H3.1)H1.8 m(8. 2,) )H1 0.8 sr9)0H2 41H5.)1.7(1,s(6,,).)d6- ,s =19=,)Hd6- ,s =b( 2.H26.1,z 1d6- ,s =76r86mHH2O( 6J,6.J H32,.)O( 5J,63,) ,s ,)H ,)O(J, .4 b(.2 (2, ,S 3. dr4,d , m(H2S 3. d2r.4HrH3.H2S63. d - 94,)77. srm(M D8 -,b( 6 r s( 9,sM8, b(,)1,b( 7,6 ,zM8 rb(77.3H31b(98,)zH1 7.b(0424.6.1 rD74,)05.2 -b(,)zH4Hz324. 2,H09. m(=28 J,H D ,3.,)zH2 .4,) ,24. ,)Hs- (405.5..01 -RH,,)H.3,)4730H, 7,)m.2 ,6. dr8,H, 7,)H 2,22 2,,)70MMm( H1N 0,,)H .1.1Mm( H(9 1 )H1 -b(0.Mm( H1,m(.3 ).HH 0642,srH1 3,),)00142,7. = J3 105 3 0062, sr4 ,)3 11,,)H4(.8m(b(,s ,s(H6H44(.8m(4-,d ,s(.2 3.1=J4( 4.8m(b( 0.4H2 ,s(m(H2,).dn 5 8 2 3oiht m82. 1022.3. 00462. 99e (1 1 1.1 1.0MTR:A:B:A:B:A:B+) H+ 2.6 3.6 2.M 9692( 686-y-o -y- - xo srI x osI osI-d,oerd,e,eH-y di-y di-di13- h- mH- 13- h- mH- 13- - m - -)ni 3( a- -)n3( a- -)n3( a4( l-1y-ndi -4x( -ob4( l i-y di -4x( -ob4( l i-y di -4x( -oboehmi (r-nip4-2-)ra 1-ne mi (-4-2-)ra 1-ne mi (-4-2-)ra)y-)l1-yxc- onhp r)y-)l1-y c- onhp r)y-)l1-y c- mlay p]y-nio 5) -- nd-34 o-dit lei ly p]yyloma-ni xo 5) -- nd-3-dit lei ly p]yyloma-ni xo 5) -- nd-3-dit leylo(f- l4,3 niez x zoa 4(fl4,3 niez x zoa 4(fl4,3 nie1 us z x zal[o dialeh ih-1 usl [o dialeh ih-1 usl [o dia eyh ihe -)Rylho rzeypi ht olectlyy-)Rylho rzeypi ht olectly-)Rylho rzepix oolctlyma((-teary p) ht ( teay ht ( tea ry htplm y- c)3le( y m1 - rN(y p)plmc) e( y3 ym2 - rp) dc) eN Nm(m - lNm(yplyyhlym1H H H O O O N N NRelpmaxE314151 -6659.. 8,87 0. s5.,)9784J,=,)84,)20- -5r,) b 1(1 H4.1.1d(J,H1 .3H2 .29 150.18=,s - -d315(,z,) ,s ,).1,,)m2p1H p.81,2z.4J,( 220.6..8 50HH1rbH1)H2, d2.2,1, .).m88.7,s(6,H5,δ,)H)r3 ) )Hb,HHHpp,)=rb( 6. m(,mm( ) H1 5.d6- ,7 1 (s =,s 6)4H1. 2,1s,4, δH1 Jmm,32, 13 (71( )6 ,s d2.)H.2 96.1.)O (J,rb 3 ,srb((46 d-(7rb4, 4-.1- H S53M. d (,)r8rbb76.1. O3.(7)H,s(2 - 634,(7 H1(4.1 - 1 - S 8,4. 1,24.23 .1 zD,)69.4,s82 2, 5 5M D) 7, m2. ,9).1,)H,zH24. ,)( .3 ) 7.4. ,H2) ( 3,H,)H8.6RH, 7, H 19,)H31,1,zH,zH2 56.)3 H 2,=MMm()H1.3H,s) )(HHMH,z 4H3,s(2m(JN 0062,,s,)1, 0 6,2,08.H - 7,s 9 ,s2,dH4( 4.8mr(b(H1 zH6.2m(m0(48( =0.9 7.r4b( 5.r2b( 4.r1b(,).dni8608432oht m(2.1 9.3. 70.eT:0 1:1MRA:B A:B+) H+ 2.2.M2(80686-osI,-1-ed- - -n- H- -13-- -iH-3 4-l id 5- n3ma1- -y itel4)( l-1yi(di -4xo-4)lnyidhiteezoza-n( oenhmipi (r--2-br(a-1 ne mima-lyih)y 4- -t)1)-y c- -o hp ry 2-)hte )y1- mlay p] l- nd-y-n3i xo 5-ni)l4o-di )le y p] ly mxoosIylomand- -3- ) -3(l,e(f- l4u,3[ni tedz xeza-i4 o(f- l4u,3[ni -y4- xe di1sloiahh 1so di)hme -) ylo re yx olctly-)lylo re S4 olcaxmRa(h(te zarpipo)rd yc) htRe(h(te zarpip,)s1 yco)brN - Nm(yplyyhlym2 -Nm(yply(((lyacH O N NRelpmaxE6171 -1=,)-,6.J8,H d1 0 s 651- (,z. r3b.(21 562,.z1H, ,)7).1,H,)3.)H6m4p0. H3H0.31H2,=p8.1,s 6 Jδ,)6=,s ,)Hr ,m(,d) H1 Jd6 ,rb 3b(m(72 rb-,s d ( ,s( 4496.1( O (rS5 bM3.(92.. 22 .1-88742. ,)- 14..0D8,4.,) 3, H3 10 1,),) 7zH,)H1) ,,Hs .(2,,)H H2H2Hs 1 0)2,R ,2MMm, r,bm6. H1 ,m(N 0( z( (2m034H 07954,),s ( 6r340..1)H4(.8.9.4.3H2b(.1 -H4,).dni1 5o836ht m( .1 0.eT:1MRA:B+) H+ 2.M0(86- - -1- - H-3 4-ni5-ly di-e-1-4)( lni htt-eelzoz1y-ndia aoenhmim r-lyihip)y 2-ht t)y2- mlp) ]lyemxoosa y-nd- -3- ) 4o-3l I,e(f- l4-u,3[ni(-yd 4- xe di1sly ol ire)S holmae) o p 4,c xmRa(h(-te zar ip)s1 ycob(p y() rN Nmy l((lyacNRelpmaxE81 Example 19 Preparation of N-((R)-1-(4-amino-1-(4-carbamoyl-3-fluorophenyl)-1H-pyrazolo[3,4- d]pyrimidin-3-yl)piperidin-3-yl)-4-(((1S,4S)-4-(isopropylamino)cyclohexyl)oxy)-2- methylthiazole-5-carboxamide Example 19A. tert-butyl (R)-(1-(4-amino-1-(4-cyano-3-fluorophenyl)-1H- pyrazolo[3,4-d]pyrimidin-3-yl)piperidin-3-yl)carbamate To a stirred solution of tert-butyl (R)-(1-(4-amino-1H-pyrazolo[3,4-d]pyrimidin-3- yl)piperidin-3-yl)carbamate (600 mg, 1.80 mmol) and (4-cyano-3-fluorophenyl)boronic acid (505 mg, 3.06 mmol) in anhydrous DCE (15 mL) at rt, were added pyridine (0.437 mL, 5.40 mmol) and copper (II) acetate (654 mg, 3.60 mmol). The reaction mixture was stirred under open air for 16 h. The suspension was filtered through a celite bed. The filtrate was concentrated. The crude product was purified by flash chromatography (5% methanol in chloroform as eluent) to afford Example 19A (610 mg, 75 % yield) as a brown solid.1H NMR (400 MHz, DMSO-d6) δ ppm 8.42 - 8.34 (m, 2H), 8.04 (dd, J = 7.5, 8.5 Hz, 1H), 7.85 - 7.41 (m, 2H), 7.11 - 6.99 (m, 1H), 3.79 (br dd, J = 3.0, 8.0 Hz, 1H), 3.45 (br d, J = 12.0 Hz, 1H), 3.26 - 3.19 (m, 1H), 3.11 - 2.83 (m, 2H), 1.98 - 1.69 (m, 4H), 1.39 (s, 9H). MS: [M+H]+= 453.3. Example 19B. (R)-4-(4-amino-3-(3-aminopiperidin-1-yl)-1H-pyrazolo[3,4- d]pyrimidin-1-yl)-2-fluorobenzonitrile.HCl To a stirred solution of tert-butyl (R)-(1-(4-amino-1-(4-cyano-3-fluorophenyl)-1H- pyrazolo[3,4-d]pyrimidin-3-yl)piperidin-3-yl)carbamate (610 mg, 1.35 mmol) in anhydrous DCM (10 mL) at rt, was added 4N HCl in dioxane (5 mL, 20.0 mmol). After stirring for 2 h, the reaction mixture was concentrated to afford Example 19B (600 mg) as a brown solid. MS: [M+H]+= 353.1. Example 19C. tert-butyl ((1S,4S)-4-((5-(((R)-1-(4-amino-1-(4-cyano-3-fluorophenyl)- 1H-pyrazolo[3,4-d]pyrimidin-3-yl)piperidin-3-yl)carbamoyl)-2-methylthiazol-4- yl)oxy)cyclohexyl)carbamate To a stirred solution of (R)-4-(4-amino-3-(3-aminopiperidin-1-yl)-1H- pyrazolo[3,4-d]pyrimidin-1-yl)-2-fluorobenzonitrile (600 mg, 1.70 mmol) in anhydrous DMF (8 mL) at rt, were added BOP (1.28 g, 2.89 mmol), DIPEA (1.78 mL, 10.2 mmol), and 4-(((1S,4S)-4-((tert-butoxycarbonyl)amino)cyclohexyl)oxy)-2-methylthiazole-5- carboxylic acid (728 mg, 2.04 mmol). After stirring for 16 h, mixture was filtered through a celite bed. The filtrate was concentrated, then the crude product was purified by flash chromatography (5% methanol in chloroform as eluent) to afford Example 19C (850 mg, 54 % yield) as a pale yellow semisolid. MS: [M+H]+= 691.5. Example 19D. tert-butyl ((1S,4s)-4-((5-(((R)-1-(4-amino-1-(4-carbamoyl-3- fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)piperidin-3-yl)carbamoyl)-2- methylthiazol-4-yl)oxy)cyclohexyl)carbamate To a stirred solution of tert-butyl ((1S,4s)-4-((5-(((R)-1-(4-amino-1-(4-cyano-3- fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)piperidin-3-yl)carbamoyl)-2- methylthiazol-4-yl)oxy)cyclohexyl)carbamate (270 mg, 0.391 mmol) in DMSO (3 mL) at rt, were added 0.3 mL of aq. NaOH and 30% hydrogen peroxide (0.44 mL, 3.91 mmol) slowly. After stirring for 2 h, water (10 mL) was added to afford a suspension, which was filtered to afford Example 19D (270 mg, 88 % yield) as a solid. MS: [M+H]+= 709.3. Example 19E. N-((R)-1-(4-amino-1-(4-carbamoyl-3-fluorophenyl)-1H-pyrazolo[3,4- d]pyrimidin-3-yl)piperidin-3-yl)-4-(((1s,4S)-4-aminocyclohexyl)oxy)-2- methylthiazole-5-carboxamide.HCl To a stirred solution of tert-butyl ((1S,4s)-4-((5-(((R)-1-(4-amino-1-(4-carbamoyl- 3-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)piperidin-3-yl)carbamoyl)-2- methylthiazol-4-yl)oxy)cyclohexyl)carbamate (270 mg, 0.381 mmol) in anhydrous DCM (2 mL) ar rt was added 4N HCl in dioxane (2.5 mL, 10.00 mmol). After stirring for 2h, the reaction mixture was concentrated and the residue triturated with diethyl ether to afford Example 19E (230 mg, 99 % yield). MS: [M+H]+= 609.3. Example 19. N-((R)-1-(4-amino-1-(4-carbamoyl-3-fluorophenyl)-1H-pyrazolo[3,4- d]pyrimidin-3-yl)piperidin-3-yl)-4-(((1S,4S)-4-(isopropylamino)cyclohexyl)oxy)-2- methylthiazole-5-carboxamide Analogous to the preparation of Example 1, reaction of N-((R)-1-(4-amino-1-(4- carbamoyl-3-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)piperidin-3-yl)-4-(((1s,4S)- 4-aminocyclohexyl)oxy)-2-methylthiazole-5-carboxamide (75 mg, 0.123 mmol), propan- 2-one (71.6 mg, 1.23 mmol) and sodium cyanoborohydride (46.5 mg, 0.739 mmol) afforded Example 19 (1.1 mg, 1 % yield). LC-MS Method A: RT = 1.155 min, Method B: RT = 0.961 min, [M+H]+= 651.3.1H NMR (400 MHz, DMSO-d6) δ ppm 8.34 (s, 1H), 8.21 - 8.12 (m, 2H), 7.85 (t, J = 8.6 Hz, 1H), 7.64 (br s, 2H), 7.37 (br d, J = 7.3 Hz, 1H), 4.89 (br s, 1H), 4.21 (br s, 1H), 3.60 - 3.49 (m, 1H), 3.27 (s, 2H), 2.87 (br s, 1H), 2.60 (s, 3H), 2.13 - 1.89 (m, 6H), 1.86 - 1.54 (m, 3H), 1.46 - 1.27 (m, 2H), 0.93 (br s, 6H). Analogous to synthesis of Example 1, the following Examples 20-26 in Table 3 were prepared.

[0012] Table-3

[0013] ,s( , ,s 3 8 ,) ,13 ,s(=rb,s ,)- ,) ,s,s(= = - ,)2m( rb0.5 4.3Hm3(.1 4J, (rH1 70Hrb5J,J,63H 4.88( 0.,) - ,s 9m836 7 -3.t(83.b( , .23, (3.t(d(.41, p.H25 (.164848 732 z,)m(27. 8 484 ,)m(p-71, .316.-.1mp .7,).4H3 Hδ) 2 ,) z 8 0mp .7 4.7H8H,) 220,) p,)H2,) .23,4.,) p,),)1,4.62.H1 3d8-,, .H,81).,2H4δ)H s H4 ,) ,d6O)m(=r -2,,srH1 s( 1H1δ)Hs2Hr 3b1, =06-,s d6- ,2,sb( -SH17 b,sHm1(Om((sJ,.237.(6Om((1 15.7J, (9rb( ,74 S7 36. rbd ,) 1 8.S026.0.5 3M D,,s.(7d-rb2(.45 m(.1M0.8 7, ( rbH,) 0,M1.87,, ,),2. 9-D2 ,z - )4H9. ( 2,H4)DH,- ) )HH1R zH43883) 3,0.7. .)H321475sr,4zH4H 21 1,M.8.7 4.H1)H2-1H.8,z,).3 b(m(,s .8,z,zm(N M0 ,),7),) ,s 1 ,8)3 M0 ,)HH ,()2 84.)M0 ,HH8H04(H1H2Hr2b, 1(m(.H 22, 01m(4(H81.18,sH21.73.21.1H0 )64(H81.38.18.4,).dn 3 9 05 3 1oiht m1(19.8. 104. 808.2. 99.eT 1:1:1 1:0MRA:B A:B A:B+) H3+.733 3M( 6.9.73636- - -)- yed-elo- - H4- x iH - H41-)-) o)m1- -4-zai1- -)-l4y3- Sn4,lyaxx )ly3- lh- ny)ht)ly3- Sn4,(n-e id s1hi 1(eohbr-4(ne id teyx-4(ne id s1(-pooni rm( i(r-olc ac- -1hipmm- -3- o)l -1hipm((-oy 4-)yc5- -oor iry 2-) nay-xoor iry 4- mual p- f] l4 -d-y-)3oelnioul p] lytneh nioul p)] ly-niozmaf-d- -3e-poledimaf-d- -3(3- -l4,3[nimaai -lh-t 4(3- -l4,3[ni(-4c-ycm-a4(3- -l4, -3ni1y o diyl1 y o di) ) x y[die)omlo re ht yht-)omlo re S4ono1b-)oomlo remR(abza pipeme R(abza pip,simraR(abza pia( N- rNarcy)pliydm ( - ( 2- rNarcy)pl1y((a(lcy- ( 5- rNarcy p)plyH NNH NRelpmaxE021222. 42m( 6-,.s(=J114 4J,, ,) ,dHm =6,1 (J, 7.2m(25. 0,1 8. s(803 7. 0.,d ,578 d m( 5-,.)250H -683 -.13.t(d( ,35d(,) 4 -, 3. -=0..25 Jrb(65 -.25,3 7,)83883sr .34H5.2 4)7H8 8,3 .35 ,)m(, -.)51H m H4. ,)4,p .p7.,7 b),)(-1. 2,- .7 93, m413m8.,7d( 2.- 6.2H ),. pp,)63 4, 2 , 1, 944,2z,H )7 m(δ)HH0.5.) (H66.Hm( )HδH.7 ) 6.) .3Hm 1HH, 62,2, 5 3, 39.2,5), 6362,,)H1 ,)5( -3 m24d.-ms(,) )H, 2 - )m1.,zd-mH,sH,m532.36,( s1OS(2Hm1 1(7H1(1- H OS(2, rb 1(.2 7.1=(208.-146.)M0D1.6.87,,6,zm(1.03.3,,z0H8.12 4.36M80s( (,z90 -,, D .82 60H .334 )J, 6.-.1H,z - )HH 7- )0-.1 4. ,z - 6. .54. -.2H5Rd2,)9 ,)7,H2 1 8. 1. 5H3.64 ,) 2H37, ,)7 6 ,) ,MrbH9.N(311,H1 m2(M.5 08,,z7H,428. ,.-z=0.H= 2.)HH,42.Hm(13,HJ2, 5J, M08, 1 1 .3 3, 4H2., )3m(H, 11m(.0 )14(H61.3 38 =.)4H51., )2q(H, d 0 )4m(d(4(H,,1m( zH=) ,08JH1m(.1,).dni1 6 3 3o0ht m(3. 9192.2. 59.eR :0 1 0MTA:B:A:B+) H+ 3.3.M1(81686-)yxoe )l di- -4e- -4eyxm H ea 1-)- -)-d3S4 2-iH1- - -)-dihxm)3S4 2- oo llb-y -nni ,s)1yxa lx -y -nni ,s)m 1yxaxcrya4(-eh di(((- cc 2 o)o 4lbr(-eh di(((o)olb) -o51-poo mir -4 -nyxac1-po mir -4-2 yracn-ielnmoi royup -)l apeh-5onrioyp -)l-nxaeh-5azmlf]d-y- orol-eulmlf]d-y- tuol-ellayia- -3 3thu t-4, -l4(- lnpycy oy 3za- -3 3[i-4dx c , -nbycy ozio ) ai4(- ly 3[ idi xoc) aie byoml h1t-)oolre htoenihtl1-)oolre rdonihtlace Rmym(ao-(-bzra pimmyhmtR(aobza pi yhmyhtary p)l-1 a()le(- rary p)l-1 a()leNc( 2Nc p y ( ym Nc p y ( ym H O O H N H NRelpmaxE3242,m,(s(873 7. = --,)57J,8232H 627,.) ,s(01 H23 82.3 ,s ,z77.7 rbH5-,.)257H2. 3.8-dr.4.3,,, ) ,3.8- - (3.-.1,,08- m8b(,) )m(H6 m(.)397432.11 66 )m(.)6p .75H 7.p,) 3. 1H ,1, 3 ,5H3mp .7.7 4 ,.0δs 6.m( 2. ,p,),),)5. 2H64H31 ,) ,2.,,)H )d6H -27,, s)rr2 91-zHδ)H2HH1 =Hm(1zH Hb( b( -7.1036.d,2, ,5J,4 - 3.5,OSm(2 2 8 477,s0.5.m3.-426. 6-0 1Om(s, ,5 S7rsbr, m(8. 83. 6(b(dd 81- 1,3( M0.(25,,),).2 ).H1M0. 2 5 r0. 2 ,).28D,8 - 6.)HH6 ,)5=D,8 - 6.0.b(3 - 0.H=R 0.zM1H27-2. ,H )1 1,, ,H zmm3,,mJ,z37,5, 7 32, 6,J,s( ddH2.)H) 5H.N M3 2.)Hmdd9. 08,H1H ((7( 05(M08, 1 1 ,3, 5 ((H3.)1H0 )34(H, 81 01m(.17.14.6.3.21 38 0 ) , , ) ) ,0408-.04(H1m(m(H1H1m(.1.0,).dni229 829oht m(1. 918.1. 98.eT:0 1:0MRA:B A:B+) H+ 2.2.M7(67666-o- - - -sIH4 ,1- eH4 ,e-)-)-dli1- - -)-di-4y3- Sn4,2- s)yma)ly3- Sn4,2- s)ma(n-e idi 1(1h( -xoxo-4(ne idi 1y((xoxo-poonrmi (r- 2- )lbyra-1hpmi (- -2- )lbrioy 4-)naxec- -oorry 4-)nyaxaec- mual p] ly-poho5-nioul p] ly poho5--f 4 -d-3-rplcelomaf-d- -3-rplcelo(3- -l4,niy1 yxyc zo3[a-4(3-l4,niyo di xyc zar or)o ih-1 yo3[o dir or)o ihe -) mloz ep dynitly-) mloz ep dynitlymRa((a-brar ip)h- m 1a) ht1e-R((ab aip h- maht(ymoI - r r )Nc p y1) eN Nacyply(l s a y l((lym2H H O O H N H NRelpmaxE5262 Example 27 Preparation of N-((R)-1-(4-amino-1-(2-methoxypyrimidin-4-yl)-1H-pyrazolo[3,4- d]pyrimidin-3-yl)piperidin-3-yl)-4-(((1S,4S)-4-(dimethylamino)cyclohexyl)oxy)-2- Example 27A. tert-butyl (R)-(1-(4-amino-1-(2-methoxypyrimidin-4-yl)-1H- pyrazolo[3,4-d]pyrimidin-3-yl)piperidin-3-yl)carbamate To a stirred solution of tert-butyl (R)-(1-(4-amino-1H-pyrazolo[3,4-d]pyrimidin-3- yl)piperidin-3-yl)carbamate (1.0 g, 3.00 mmol) in anhydrous DMF (20 mL) at rt, were added Cs2CO3(1.96 g, 6.0 mmol) and 4-chloro-2-methoxypyrimidine (0.650 g, 4.50 mmol). The reaction mixture was stirred at 70 °C for 16 h. After cooling, the mixture was diluted with water and extracted with ethyl acetate. The organic layer was collected, dried over anhydrous Na2SO4, filtered and concentrated to afford Example 27A (1.1 g, 50 % yield) as a brown solid. MS: [M+H]+= 442.5. Example 27B. (R)-3-(3-aminopiperidin-1-yl)-1-(2-methoxypyrimidin-4-yl)-1H- pyrazolo[3,4-d]pyrimidin-4-amine.HCl To a stirred solution of tert-butyl (R)-(1-(4-amino-1-(2-methoxypyrimidin-4-yl)- 1H-pyrazolo[3,4-d]pyrimidin-3-yl)piperidin-3-yl)carbamate (1.1 g, 2.49 mmol) in DCM (10 mL) at rt, was added 4N HCl in dioxane (6.23 mL, 24.9 mmol). After stirring for 1 h, the mixture was concentrated, then triturated with diethyl ether to afford Example 27B (850 mg, 50 % yield) as a pale yellow semi-solid. MS: [M+H]+= 342.2. Example 27C. tert-butyl (4-((5-(((R)-1-(4-amino-1-(2-methoxypyrimidin-4-yl)-1H- pyrazolo[3,4-d]pyrimidin-3-yl)piperidin-3-yl)carbamoyl)-2-methylthiazol-4- yl)oxy)cyclohexyl)carbamate To a stirred solution of (R)-3-(3-aminopiperidin-1-yl)-1-(2-methoxypyrimidin-4- yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (400 mg, 1.17 mmol) in anhydrous DMF (8 mL) at rt, were added 4-((4-((tert-butoxycarbonyl)amino)cyclohexyl)oxy)-2-methylthiazole-5- carboxylic acid (501 mg, 1.41 mmol), BOP (881 mg, 1.99 mmol) and DIPEA (0.614 mL, 3.52 mmol). After stirring for 16 h, ice cold water was added dropwise affording a suspension. The mixture was stirred for 5 min, and then was filtered. The solid collected was dried under vacuum to afford Example 27C (400 mg, 25 % yield) as a brown semi- solid. MS : [M+H]+= 680.6. Example 27D. N-((R)-1-(4-amino-1-(2-methoxypyrimidin-4-yl)-1H-pyrazolo[3,4- d]pyrimidin-3-yl)piperidin-3-yl)-4-(((1S,4S)-4-aminocyclohexyl)oxy)-2- methylthiazole-5-carboxamide.HCl To a stirred solution of tert-butyl ((1S,4S)-4-((5-(((R)-1-(4-amino-1-(2- methoxypyrimidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)piperidin-3-yl)carbamoyl)-2- methylthiazol-4 yl)oxy)cyclohexyl)carbamate (350 mg, 0.515 mmol) in anhydrous DCM (2 mL) at rt, was added 4N HCl in dioxane (3 mL, 12 mmol). After 2 h, the mixture was concentrated, then triturated with diethyl ether to afford Example 27D (300 mg, 70 % yield) as a pale yellow semi-solid. MS: [M+H]+= 580.3. Example 27 Analogous to the preparation of Example 1, reaction of N-((R)-1-(4-amino-1-(2- methoxypyrimidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)piperidin-3-yl)-4-(((1S,4S)-4- aminocyclohexyl)oxy)-2-methylthiazole-5-carboxamide (75 mg, 0.13 mmol), formaldehyde (0.018 mL, 0.65 mmol) and sodium cyanoborohydride (8.1 mg, 0.13 mmol) afforded Example 27 (4.1 mg, 5 % yield). LC-MS Method B: RT = 0.957 min, [M+H]+= 608.3.1H-NMR (400 MHz, DMSO-d6) δ ppm 8.62 (d, J = 5.8 Hz, 1H), 8.36 (s, 1H), 8.05 (d, J = 5.8 Hz, 1H), 7.39 (br d, J = 7.5 Hz, 1H), 5.00 (br s, 1H), 4.24 (br s, 1H), 3.97 (s, 3H), 3.51 (br s, 1H), 3.26 - 3.12 (m, 7H), 2.60 (s, 3H), 2.20 (br s, 1H), 2.09 - 1.93 (m, 8H), 1.85 (br s, 1H), 1.73 - 1.51 (m, 4H), 1.49 - 1.29 (m, 3H). Analogous to synthesis of Example 1, the following Examples 28-30 in Table 4 were prepared. Table 4

[0014] ,z rHb(,)6H .18,.)- 2 H7 1 = ,r, ,,- 5Jzb,H( 6.z2sH(05 4.,z r77 H b(,)0H16..)2H8 753.,7s ,) ,.1d 5 53 =36. = 804 ,,0,rHm(,) r .b5 .7 J,.9 .2 1J.. s)1, ,) ,t 57 rH,=J)bH(5,s 08H (=,3 6 J) d=Ht(J)(=,HH1 3 J)b 1 mH( ,s(,d(1 0,2.r.b1 , 8.,0d(1, 02 ,d 1, ,s7.,d(1 3,25.r 2.2z 4 (-m6 H ,)7 8(,) 2 z.H4,rb s r0(r b( ,) 2 zH4, b)( 14 -.8 8.H12.0 23.25.H62.85. )bH6(6H67.85.H11.326.m5p =,pJ s ,),)1-,5 1,rHHmm 6 (p =,pJ,s5.r347,.8.1 ,5)2, mm (p =,pJ sr,) 1H,)δ)d b(1 363 d b(,) )6,d b(1H96(75,9s,.rs(1 2.δ1 )6 (H 743HH 240.δ (1 )68 6,9sr ,d- 0. .84,b(0 ,6)- Hd- 0.98.,4s( , ,m -d- 0. . m84,b( (OS,) )H45.21 8,3. OS,),)H7 m9( (6 O62 4.S,) )H2 556.MH D1 1 . ,,3,,,) 1Hm(,)MH1 1 .,3,1.39.11,)MH1 1 .,3 1, -zs( zH)H2, 8H.RH6 1)D,,zs( zH)H - - HD,,zs( zH)H40.MM3.5.73,s m(6.1,H6- mN(,H6zM3.8. 17, 5z27 4.03.,.2m)H7HM3.0.83, 2s,)08,= ( 66H08,=H, ,(68,= (H H0 )4(HJ1, 7d9..32 8-7. 014.1 8.0 )54(HJ1,d 8.)4H)1H 135. ,1z00 ) J7H4(H1,d 9. 33,s(,).dni958 959 7 8o 220 451036ht m( . . . . .0.eT 1:1 1:1 1:1MRA:B A:B A:B+) H+ 3.3.3.M2(20654636- -)- -)4yxed eilyo-4xoed- H- -) o3)- Sl- m - 4ya H-4z3a- -))lim --l ih H-3S4yx a-1-2) (-lni ,s1xe xo1b- -)lniyhtt)y-1- - )ni ,se x1h ob1y--do4i((h-mi ( ol ra2(- y-di em-xo 2(-ly-di((o(lcrar-n4 cy c-51- 4-mir -2 3-)nly 1- 4-mir -4yccini)-5dy-p)l c)-eoninidy-p)latxe onini y-p)l o -emia-m]d-y- o3ni loi ]zmymd- -n3ehoedmim]d-y-ni loz4i(r4, --y1p3[nim dalaia-4 ir4, -pn(-lcdia-ir4,3- m nalaiyhtl(-yp3[ id 4-y m 4)c)a(-yp3[ id ythtle -) yxol irmR e po yh1-) yxol ire S oxno1-) yxol ireubyha( o(hoz-tearpi rp te R( ohoza pi4,sibraR( ohoza piolteyp)losm- (-te ry p)l1( malc- (-te ry p)clym N N mp yi( 2N mp y(( y 5N mp yc(-2HHH NNN RelpmaxE829203 Example 31 Preparation of (R)-N-(1-(4-amino-1-(6-cyanopyridin-3-yl)-1H-pyrazolo[3,4- d]pyrimidin-3-yl)piperidin-3-yl)-5-chloro-3-(2-(dimethylamino)ethoxy)thiophene-2- carboxamide Example 31A. tert-butyl (R)-(1-(4-amino-1-(6-cyanopyridin-3-yl)-1H-pyrazolo[3,4- d]pyrimidin-3-yl)piperidin-3-yl)carbamate To the stirred solution of 5-fluoropicolinonitrile (0.439 g, 3.60 mmol) and tert-butyl (R)-(1-(4- amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)piperidin-3-yl)carbamate (1.0 g, 3.0 mmol) in DMF (20 mL), was added K2CO3(1.66 g, 12.0 mmol). The reaction mixture was heated at 70 °C for 8 h. After cooling, the mixture was partitioned between water (50 mL) and ethyl acetate (2 X 50 mL). The organic layer was dried over sodium sulphate and concentrated to afford Example 31A (1.2 g, 92 % yield). MS: [M+H]+= 436.2. Example 31B. (R)-5-(4-amino-3-(3-aminopiperidin-1-yl)-1H-pyrazolo[3,4- d]pyrimidin-1-yl)picolinonitrile Analogous to the procedure for the preparation of Example19B, the reaction of tert- butyl (R)-(1-(4-amino-1-(6- cyanopyridin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-3- yl)piperidin-3-yl)carbamate (300 mg, 0.689 mmol) and 4N HCl in dioxane (1.72 mL, 6.89 mmol) afforded Example 31B (200 mg, 86 % yield). The product was used in the following step without additional purification. MS: [M+H]+= 336.3. Example 31 Analogous to the procedure for the preparation of Example 19C, reaction of 5- chloro-3-(2- (dimethylamino)ethoxy)thiophene-2-carboxylic acid (37.2 mg, 0.149 mmol) and (R)-5-(4-amino-3-(3-aminopiperidin-1-yl)-1H-pyrazolo[3,4-d]pyrimidin-1- yl)picolinonitrile (50 mg, 0.149 mmol) afforded Example 31 (12.9 mg, 14 % yield). LC- MS Method A: RT = 1.686 min, [M+H]+= 567.1;1H NMR (400 MHz, DMSO-d6) δ ppm 9.68 - 9.53 (m, 1H), 8.88 - 8.77 (m, 1H), 8.36 (s, 1H), 8.25 - 8.05 (m, 1H), 7.80 - 7.52 (m, 1H), 7.32 (s, 1H), 4.44 - 4.10 (m, 3H), 3.78 - 3.59 (m, 1H), 3.56 - 3.46 (m, 1H), 3.18 - 2.92 (m, 2H), 2.74 - 2.66 (m, 2H), 2.38 - 2.10 (m, 6H), 2.08 - 1.83 (m, 3H), 1.68 - 1.47 (m, 1H). Example 32 Preparation of (N-((R)-1-(4-amino-1-(6-cyanopyridin-3-yl)-1H-pyrazolo[3,4- d]pyrimidin-3-yl)piperidin-3-yl)-5-(difluoromethyl)-3-(((1R,3s,5S)-8-methyl-8- azabicyclo[3.2.1]octan-3-yl)oxy)thiophene-2-carboxamide Analogous to the procedure for the preparation of Example 19C, reaction of 5- (difluoromethyl)-3-(((1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl)oxy)thiophene-2- carboxylic acid (47.3 mg, 0.149 mmol) and (R)-5-(4-amino-3-(3-aminopiperidin-1-yl)-1H- pyrazolo[3,4-d]pyrimidin-1-yl)picolinonitrile (50 mg, 0.149 mmol) afforded Example 32 (18.6 mg, 18 % yield). LC-MS Method A: RT = 1.341 min, [M+H]+= 635.3; LC-MS Method B: RT = 1.217 min, [M+H]+=635.3.1H NMR (400 MHz, DMSO-d6) δ ppm 9.74 - 9.65 (m, 1H), 9.59 (d, J = 2.5 Hz, 1H), 8.80 (dd, J = 2.6, 8.6 Hz, 1H), 8.35 (s, 1H), 8.16 (d, J = 8.5 Hz, 1H), 7.73 - 7.55 (m, 1H), 7.37 - 6.96 (m, 3H), 4.86 - 4.75 (m, 1H), 4.28 - 4.19 (m, 1H), 3.97 - 3.89 (m, 3H), 3.69 (br dd, J = 2.9, 11.6 Hz, 1H), 3.16- 3.01 (m, 2H), 2.69 (d, J = 5.0 Hz, 3H), 2.36 - 2.29 (m, 2H), 2.25 - 2.00 (m, 6H), 1.99 - 1.82 (m, 4H), 1.63 - 1.53 (m, 1H), 1.19 - 1.04 (m, 2H). Example 33. Preparation of N-((R)-1-(4-amino-1-(5-oxo-2,5-dihydrofuran-3-yl)-1H-pyrazolo[3,4- d]pyrimidin-3-yl)piperidin-3-yl)-2-methyl-4-(((1s,4S)-4-(pentan-3- ylamino)cyclohexyl)oxy)thiazole-5-carboxamide Example 33A. tert-butyl (R)-(1-(4-amino-1-(5-oxo-2,5-dihydrofuran-3-yl)-1H- pyrazolo[3,4-d]pyrimidin-3-yl)piperidin-3-yl)carbamate To a solution of tert-butyl (R)-(1-(4-amino-1H-pyrazolo[3,4-d]pyrimidin-3- yl)piperidin-3-yl)carbamate (500 mg, 1.50 mmol) and 5-oxo-2,5-dihydrofuran-3-yl trifluoromethanesulfonate (696 mg, 3.00 mmol) in DMF (5 mL), was added K2CO3(415 mg, 3.00 mmol). The mixture was stirred at 80oC for 16 h. The reaction mixture was evaporated and the residue was purified by flash chromatography (eluting with 0-100% EtOAc in hexane) to afford Example 33A (110 mg, 18 % yield) as a yellow solid. MS: [M+H]+= 416.15.1H NMR (400 MHz, DMSO-d6) δ ppm 8.37 (s, 1H), 7.06 (br d, J = 7.5 Hz, 1H), 6.15 (s, 1H), 5.44 (s, 2H), 3.74 (br s, 1H), 3.01 (br s, 1H), 2.94 - 2.83 (m, 2H), 2.76 - 2.68 (m, 1H), 1.89 (br d, J = 16.5 Hz, 1H), 1.77 (br s, 3H), 1.46 (br d, J = 12.0 Hz, 2H), 1.38 (s, 9H). Example 33B. (R)-4-(4-amino-3-(3-aminopiperidin-1-yl)-1H-pyrazolo[3,4- d]pyrimidin-1-yl)furan-2(5H)-one.HCl Analogous to the procedure for the preparation of Example 19B, reaction of Example 33A (110 mg, 0.265 mmol) and 4N HCl (0.993 mL, 3.97 mmol) afforded Example 33B (80 mg, 86 % yield) as a yellow solid. MS: [M+H]+= 316.05. Example 33 Analogous to the procedure for the preparation of Example 19C, reaction of Example 33B (31.8 mg, 0.090 mmol), lithium 2-methyl-4-(((1s,4s)-4-(pentan-3- ylamino)cyclohexyl)oxy)thiazole-5-carboxylate (30 mg, 0.090 mmol), BOP (59.9 mg, 0.135 mmol) and DIPEA (0.047 mL, 0.271 mmol) afforded Example 33 (8.8 mg, 16 % yield) as a pale-yellow solid. LCMS Method A: RT = 1.490 min, [M+H]+= 624.3; LC-MS Method B: RT = 1.199 min, [M+H]+= 624.3.1H NMR (400 MHz, DMSO-d6) δ ppm 8.34 (s, 1H), 8.09 (br s, 2H), 7.19 (d, J = 7.3 Hz, 1H), 6.08 (s, 1H), 5.55 - 5.29 (m, 2H), 4.89 (br s, 1H), 4.17 -4.03 (m, 1H), 3.62 (br d, J = 10.0 Hz, 1H), 3.26 - 3.12 (m, 3H), 3.09 - 2.97 (m, 1H), 2.60 (s, 3H), 2.30 - 2.12 (m, 2H), 2.08 - 1.89 (m, 3H), 1.87 -1.45 (m, 11H), 0.89 (dt, J = 3.1, 7.4 Hz, 6H). Example 34. N-((R)-1-(4-amino-1-(5-oxo-2,5-dihydrofuran-3-yl)-1H-pyrazolo[3,4- d]pyrimidin-3-yl)piperidin-3-yl)-2-methyl-4-(((1s,4S)-4-(pentan-3- ylamino)cyclohexyl)oxy)thiazole-5-carboxamide Analogous to the preparation of Example 19C, reaction of Example 33B (31.8 mg, 0.090 mmol) and lithium 4-((4-(azetidin-1-yl)cyclohexyl)oxy)-2-methylthiazole-5- carboxylate (30 mg, 0.099 mmol) afforded Example 34 (37.2 mg, 63 % yield) as a pale- yellow solid. LCMS Method A: RT = 1.178 min, [M+H]+= 594.3; LC-MS Method B: RT = 0.991 min, [M+H]+= 594.3.1H NMR (400 MHz, DMSO-d6) δ ppm 8.36 (s, 1H), 7.42 (br d, J = 8.3 Hz, 1H), 6.12 (s, 1H), 5.42 (s, 2H), 5.00 (br d, J = 1.8 Hz, 1H), 4.34 - 4.16 (m,1H), 3.48 (br s, 2H), 3.18 (br s, 3H), 2.89 (br s, 4H), 2.60 (s, 3H), 2.01 - 1.65 (m, 11H), 1.64 - 1.50 (m, 2H), 1.46 - 1.29 (m, 2H), 1.28 - 1.07 (m, 3H). Example 35. Preparation of 1-(1-(1-acetyl-2,5-dihydro-1H-pyrrol-3-yl)-4- amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)piperidin-3-yl)-2-methyl-4-(((1s,4S)-4- (pentan-3-ylamino)cyclohexyl)oxy)thiazole-5-carboxamide Example 35A. tert-butyl (R)-(1-(1-(1-acetyl-2,5-dihydro-1H-pyrrol-3-yl)-4-amino- 1H-pyrazolo[3,4-d]pyrimidin-3-yl)piperidin-3-yl)carbamate To a stirred solution of tert-butyl (R)-(1-(4-amino-1H-pyrazolo[3,4-d]pyrimidin-3- yl)piperidin-3-yl)carbamate (600 mg, 1.80 mmol) and 1-(3-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-2,5-dihydro-1H-pyrrol-1-yl)ethan-1-one (853 mg, 3.60 mmol) in DCE (5 mL), were added pyridine (0.437 mL, 5.40 mmol) and copper (II) acetate (327 mg, 1.80 mmol). After stirring for 16 h at rt, the mixture was diluted with DCM (10 mL), then filtered through a ceilte bed. The filtrate was evaporated. The residue was purified by flash chromatography (eluting with 0-100% EtOAc in DCM) to afford Example 35A (500 mg, 3 % yield) as a yellow solid. MS: [M+H]+= 443.3. Example 35B. (R)-1-(3-(4-amino-3-(3-aminopiperidin-1-yl)-1H-pyrazolo[3,4- d]pyrimidin-1-yl)-2,5-dihydro-1H-pyrrol-1-yl)ethan-1-one.HCl Analogous to the preparation of Example 19B, reaction of Example 35A (300 mg) and 4N HCl afforded Example 35B (280 mg, 96 % yield) as a yellow solid. MS: [M+H]+= 343.2. Example 35. N-((R)-1-(1-(1-acetyl-2,5-dihydro-1H-pyrrol-3-yl)-4-amino-1H- pyrazolo[3,4-d]pyrimidin-3-yl)piperidin-3-yl)-2-methyl-4-(((1s,4S)-4-(pentan-3- ylamino)cyclohexyl)oxy)thiazole-5-carboxamide Analogous to the preparation of Example 19C, reaction of Example 35B (37.6 mg, 0.099 mmol) and lithium 2-methyl-4-(((1s,4s)-4-(pentan-3- ylamino)cyclohexyl)oxy)thiazole-5-carboxylate (30 mg, 0.090 mmol) afforded Example 35 (6.8 mg, 11 % yield) as a pale-yellow solid. LCMS Method A: RT = 1.395 min, [M+H]+= 651.3; LC-MS Method B: RT = 1.072 min, [M+H]+= 651.3.1H NMR (400 MHz, DMSO- d6) δ ppm 8.96 (br s, 1H), 8.25 (d, J = 4.5 Hz, 1H), 7.40 (br d, J = 7.8 Hz, 1H), 6.26 - 6.12 (m, 1H), 5.10 (br d, J = 1.0 Hz,1H), 4.86 (br d, J = 1.3 Hz, 1H), 4.65 (br s, 1H), 4.41 (br s, 1H), 4.21 (br d, J = 2.8 Hz, 2H), 3.50 - 3.45 (m, 1H), 3.26 - 3.20 (m, 1H), 3.14 - 2.96 (m, 2H), 2.60 (s, 3H), 2.32 - 2.23 (m, 1H), 2.12 - 2.07 (m, 1H), 2.03 (d, J = 16.8 Hz, 3H), 1.98 - 1.80 (m, 5H), 1.70 - 1.48 (m, 5H), 1.35 - 1.14 (m, 6H), 0.78 - 0.68 (m, 6H). Example 36. (R)-N-(1-(1-(1-acetyl-2,5-dihydro-1H-pyrrol-3-yl)-4-amino-1H- pyrazolo[3,4-d]pyrimidin-3-yl)piperidin-3-yl)-4-((4-(azetidin-1-yl)cyclohexyl)oxy)-2- methylthiazole-5-carboxamide

[0015] Analogous to the preparation of Example 19C, reaction of Example 35B (37.6 mg, 0.099 mmol) and lithium 4-((4-(azetidin-1-yl)cyclohexyl)oxy)-2-methylthiazole-5- carboxylate (30 mg, 0.099 mmol) afforded Example 36 (14.1 mg, 22 % yield) as a pale- yellow solid. LCMS Method A: RT = 1.129 min, [M+H]+= 621.3; LC-MS Method B: RT = 1.129 min, [M+H]+= 621.3.1H NMR (400 MHz, DMSO-d6) δ ppm 8.26 (d, J = 4.0 Hz, 1H), 7.50 (br t, J = 8.4 Hz, 1H), 6.26 - 6.07 (m, 1H), 5.02 (br s, 1H), 4.86 (br d, J = 2.0 Hz, 1H), 4.66 (dd, J = 1.5, 4.0 Hz, 1H), 4.41 (br d, J = 2.0 Hz, 1H), 4.33 - 4.14 (m, 2H), 3.23 - 3.17 (m, 3H), 2.84 (td, J = 7.4, 10.3 Hz, 4H), 2.60 (s, 3H), 2.08 - 1.97 (m, 4H), 1.96 - 1.64 (m, 11H), 1.62 - 1.47 (m, 2H), 1.39 - 1.18 (m, 4H). Example 37. Preparation of N-((3R)-1-(1-(1-acetylpyrrolidin-3-yl)-4-amino-1H- pyrazolo[3,4-d]pyrimidin-3-yl)piperidin-3-yl)-2-methyl-4-(((1s,4S)-4-(pentan-3- ylamino)cyclohexyl)oxy)thiazole-5-carboxamide Example 37A. tert-butyl ((3R)-1-(1-(1-acetylpyrrolidin-3-yl)-4-amino-1H- pyrazolo[3,4-d]pyrimidin-3-yl)piperidin-3-yl)carbamate To a solution of Example 35A (80 mg, 0.181 mmol) in Methanol (2 mL), was added 50% wet Pd / C (192 mg). The reaction mixture was stirred at room temperature under H2for 20 h, then was filtered through celite. The filtrate was concentrated to afford Example 37A (40 mg, 50 % yield) as a yellow gummy solid. MS: [M+H]+= 445.3. Example 37B.1-(3-(4-amino-3-((R)-3-aminopiperidin-1-yl)-1H-pyrazolo[3,4- d]pyrimidin-1-yl)pyrrolidin-1-yl)ethan-1-one, HCl Analogous to the preparation of Example 19B, reaction of Example 37A (40 mg) and 4N HCl in 1,4-dioxane afforded Example 37B (34 mg, 99 % yield) as a yellow solid. MS: [M+H]+= 345.3.

[0016] Example 37. Analogous to the preparation of Example 19C, reaction of Example 37B (34 mg) and lithium 2-methyl-4-(((1s,4s)-4-(pentan-3-ylamino)cyclohexyl)oxy)thiazole-5- carboxylate (30 mg, 0.090 mmol) afforded Example 37 (7.5 mg, 12 % yield) as a pale- yellow solid. LCMS Method A: RT = 1.386 min, [M+H]+= 615.3; LC-MS Method B: RT = 1.115 min, [M+H]+= 615.3.1H NMR (400 MHz, DMSO-d6) δ ppm 8.87 (s, 1H), 8.14 (d, J = 3.8 Hz, 1H), 7.36 (br d, J = 7.3 Hz, 1H), 5.36 - 5.20 (m, 1H), 5.08 (br s, 1H), 4.78 (td, J = 6.3, 12.5 Hz, 1H), 4.24 - 4.11 (m, 1H), 3.91 - 3.68 (m, 3H), 3.63 - 3.57 (m, 2H), 3.39 (br d, J = 7.3 Hz, 2H), 3.26 - 3.20 (m, 2H), 3.03 - 2.86 (m, 2H), 2.76 - 2.65 (m, 1H), 2.61 (s, 3H), 2.37 - 2.19 (m, 2H), 2.05 - 1.89 (m, 4H), 1.83 (br s, 2H), 1.71 - 1.50 (m, 5H), 1.46 - 1.24 (m, 5H), 1.19 (d, J = 6.3 Hz, 5H), 0.83 - 0.72 (m, 5H). Example 38. (R)-N-(1-(4-amino-1-(4-(methylsulfonyl)phenyl)-1H-pyrazolo[3,4- d]pyrimidin-3-yl)piperidin-3-yl)benzamide, TFA To a solution of (R)-3-(3-aminopiperidin-1-yl)-1-(4-(methylsulfonyl)phenyl)-1H- pyrazolo[3,4-d]pyrimidin-4-amine, 2 TFA (8 mg, 0.013 mmol) in THF (1 mL), were added TEA (9 µl, 0.065 mmol) and benzoyl chloride (10% solution in THF) (0.018 mL, 0.016 mmol). The mixture was stirred at rt for 30 min, then was quenched with MeOH and evaporated. The residue was purified by preparative HPLC to afford Example 38 (3.7 mg, 46 % yield). LCMS Method A: RT = 1.62 min, [M+H]+= 492.28; LC-MS Method B: RT = 1.29 min, [M+H]+= 492.56.1H NMR (500 MHz, DMSO-d6) δ 8.48 (br d, J=8.8 Hz, 2H), 8.44 (br d, J=7.6 Hz, 1H), 8.32 (s, 1H), 8.02 (br d, J=8.8 Hz, 2H), 7.82 (br d, J=7.1 Hz, 2H), 7.55 - 7.48 (m, 1H), 7.47 - 7.40 (m, 2H), 4.26 (br dd, J=7.4, 4.1 Hz, 2H), 3.20 (s, 3H), 3.03 - 2.90 (m, 2H), 2.03 - 1.85 (m, 3H), 1.71 - 1.53 (m, 2H). Example 39. (R)-N-(1-(4-amino-1-(4-(methylsulfonyl)phenyl)-1H-pyrazolo[3,4- d]pyrimidin-3-yl)piperidin-3-yl)-5-methylthiophene-2-carboxamide, TFA To a solution of (R)-3-(3-aminopiperidin-1-yl)-1-(4-(methylsulfonyl)phenyl)-1H- pyrazolo[3,4-d]pyrimidin-4-amine, 2 TFA (8 mg, 0.013 mmol) in DMF (0.5 mL), were added 5-methylthiophene-2-carboxylic acid (2.8 mg, 0.019 mmol), DIEA (0.011 mL, 0.065 mmol) and HATU (7.4 mg, 0.019 mmol). The mixture was stirred at rt for 5.5 h, then was purified by preparative HPLC to afford Example 39 (3.7 mg, 46 % yield). LCMS Method A: RT = 1.63 min, [M+H]+= 512.10; LC-MS Method B: RT = 1.42 min, [M+H]+= 511.96.1H NMR (500 MHz, DMSO-d6) δ 8.48 (d, J=8.9 Hz, 2H), 8.33 (s, 1H), 8.30 (br d, J=7.6 Hz, 1H), 8.02 (d, J=8.8 Hz, 2H), 7.59 (d, J=3.7 Hz, 1H), 6.85 - 6.78 (m, 1H), 4.23 - 4.11 (m, 1H), 3.68 - 3.60 (m, 1H), 3.20 (s, 3H), 2.90 (br t, J=10.8 Hz, 2H), 2.44 (s, 3H), 2.01 - 1.91 (m, 1H), 1.91 - 1.81 (m, 2H), 1.66 - 1.53 (m, 1H) Example 40. (R)-N-(1-(4-amino-1-(4-(methylsulfonyl)phenyl)-1H-pyrazolo[3,4- d]pyrimidin-3-yl)piperidin-3-yl)-2-methoxyisonicotinamide To a solution of (R)-3-(3-aminopiperidin-1-yl)-1-(4-(methylsulfonyl)phenyl)-1H- pyrazolo[3,4-d]pyrimidin-4-amine, 2 TFA (8 mg, 0.013 mmol) in DMF (0.5 mL), were added 2-methoxyisonicotinic acid (3 mg, 0.019 mmol), DIEA (0.011 mL, 0.065 mmol) and HATU (7.4 mg, 0.019 mmol). The mixture was stirred at rt for 5.5 h, then was purified by preparative HPLC to afford Example 40 (2.2 mg, 32 % yield). LCMS Method A: RT = 1.49 min, [M+H]+= 522.89; LC-MS Method B: RT = 1.35 min, [M+H]+= 523.16.1H NMR (500 MHz, DMSO-d6) δ 8.65 (br d, J=7.3 Hz, 1H), 8.46 (d, J=8.9 Hz, 2H), 8.30 (s, 1H), 8.23 (d, J=5.2 Hz, 1H), 8.00 (d, J=8.9 Hz, 2H), 7.32 - 7.26 (m, 1H), 7.13 (s, 1H), 4.29 - 4.16 (m, 1H), 3.85 (s, 3H), 3.43 (br dd, J=12.7, 3.8 Hz, 1H), 3.19 (s, 3H), 3.04 - 2.92 (m, 2H), 1.99 - 1.79 (m, 4H), 1.68 - 1.57 (m, 1H). The embodiments described above are intended to be merely exemplary, and those skilled in the art will recognize, or will be able to ascertain using no more than routine experimentation, numerous equivalents of specific compounds, materials, and procedures. All such equivalents are considered to be within the scope of the claimed subject matter and are encompassed by the appended claims.

Claims

WHAT IS CLAIMED IS:

1. A compound according to Formula (I):or a pharmaceutically acceptable salt thereof, wherein: R1 is selected from the group consisting of C6-10 aryl and 5- to 10-membered heterocyclyl comprising carbon atoms and 1-5 heteroatoms selected from N, O, and S(=O)p, and substituted with 0-3 R4aand 1 R4b; R2is selected from the group consisting of C6-10aryl substituted with 1-5 R6and 5- to 9- membered heterocyclyl comprising carbon atoms and 1-5 heteroatoms selected from N, O, and S(=O)p, and substituted with 1-5 R6; R3, at each occurrence, is independently selected from the group consisting of H, halo, - ORb, -NRaRa, and C1-3alkyl; alternatively, R3and R3are taken together with the two adjacent carbon atoms, to which they are attached, to form C3-6cycloalkyl; R4a, at each occurrence, is independently selected from the group consisting of H, halo, and C1-4 alkyl substituted with 1-3 Re; R4bis selected from the group consisting of -ORb, -O-(CRdRd)1-5NRaRa, -O-(CRdRd)1-5ORb, C3-12carbocyclyl substituted with 1-5 R5, 3- to 10-membered heterocyclyl comprising carbon atoms and 1-4 heteroatoms selected from N, O, and S(=O)p, and substituted with 1-5 R5, -O-(CRdRd)r-C3-12carbocyclyl substituted with 1-5 R5, -O-(CRdRd)r-3- to 10-membered heterocyclyl comprising carbon atoms and 1-4 heteroatoms selected from N, O, and S(=O)p, and substituted with 1-5 R5; R5, at each occurrence, is independently selected from the group consisting of H, halo, CN, ORb, =O, -(CRdRd)r-NR7R7, C1-6alkyl substituted with 1-5 Re, C2-6alkenyl substituted with 1-5 Re, C2-6alkynyl substituted with 1-5 Re, C3-10carbocyclyl with 1-5 Re, and 3- to10-membered heterocyclyl comprising carbon atoms and 1-4 heteroatoms selected from N, O, and S(=O)p. and substituted with 1-5 Re;R6, at each occurrence, is independently selected from the group consisting of H, halo, CN, =O, -(CRdRd)rNRaRa, NO2, -ORb, -C(=O)NRaRa, -C(=O)NRa(CRdRd)rORb, - C(=O)Rb, -C(=O)(CRdRd)rORb, -NRaC(=O)ORb, -NRaC(=O)(CRdRd)rNRaRa, - S(=O)PRc, -NRaS(=O)PRc, and C1-6alkyl substituted with 1-5 Re; R7, at each occurrence, is independently selected from the group consisting of H, C1-7alkyl substituted with 1-5 Re, C3-10carbocyclyl substituted with 1-5 Re, and -3- to 10-membered heterocyclyl comprising carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(=O)p, and substituted with 1-5 Re; or R7and R7together with the nitrogen atom, to which they are both attached, form a 3- to 10-membered heterocyclyl comprising carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(=O)p, and substituted with 1-5 Re; Ra, at each occurrence, is independently selected from the group consisting of H, C1-6alkyl substituted with 1-5 Re, C3-10carbocyclyl substituted with 1-5 Re, and 3- to 10-membered heterocyclyl comprising carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(=O)p, and substituted with 1-5 Re; or Raand Ratogether with the nitrogen atom, to which they are both attached, form a 3- to 10-membered heterocyclyl comprising carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(=O)p, and substituted with 1-5 Re; Rb, at each occurrence, is independently selected from the group consisting of H, C1-6alkyl substituted with 1-5 Re, C3-10carbocyclyl substituted with 1-5 Re, and 3- to 10-membered heterocyclyl comprising carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(=O)p, and substituted with 1-5 Re; Rc, at each occurrence, is independently selected from the group consisting of C1-6alkyl substituted with 1-5 Re, C3-10carbocyclyl substituted with 1-5 Re, and 3- to 10- membered heterocyclyl comprising carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(=O)p, and substituted with 1-5 Re; Rd, at each occurrence, is independently selected from the group consisting of H, C1-6alkyl substituted with 1-5 Re, and C3-6cycloalkyl substituted with 1-5 Re; Reis independently selected from the group consisting of H, halo, CN, =O, C1-6alkyl substituted with 1-5 Rg, C2-6alkenyl substituted with 1-5 Rg, C2-6alkynylsubstituted with 1-5 Rg, C3-10carbocyclyl substituted with 1-5 Rg, 3- to 10- membered heterocyclyl comprising carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(=O)p, and substituted with 1-5 Rg, - (CH2)rORf, -(CH2)rNRfRf, -(CH2)rC(=O)Rf, and -(CH2)rC(=O)ORf; Rf, at each occurrence, is independently selected from the group consisting of H, C1-6alkyl substituted with 1-5 Rg, C3-10carbocyclyl substituted with 1-5 Rg, 3- to 10- membered heterocyclyl comprising carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(=O)p, and substituted with 1-3 Rg; Rg, at each occurrence, is independently selected from the group consisting of H, halo, CN, -OH, -O(C1-5alkyl), NH2, NH(C1-5alkyl), NH(C1-5alkyl)2, and C1-5alkyl; p is an integer of zero, 1, or 2; and r is an integer of zero, 1, 2, 3, 4, or 5.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein: R1is 5- to 6-membered heterocyclyl comprising carbon atoms and 1-3 heteroatoms selected from N, O, and S(=O)p, and substituted with 0-2 R4aand 1 R4b; and R2is selected from the group consisting of phenyl substituted with 1-5 R6and 5- to 6- membered heterocyclyl comprising carbon atoms and 1-3 heteroatoms selected from N, O, and S(=O)p, and substituted with 1-5 R6.

3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein: R1is selected from the group consisting ofR2is selected from the group consisting ofR4ais selected from the group consisting of H and C1-3alkyl; R4bis selected from the group consisting of , -O-C1-4alkyl, -O-(CH2)1-5NRaRa, C3-12carbocyclyl substituted with 1-5 R5, 3- to 10-membered heterocyclyl comprising carbon atoms and 1-4 heteroatoms selected from N, O, and S(=O)p, and substituted with 1-5 R5, -O-C3-12carbocyclyl substituted with 1-5 R5, -O-3- to 10- membered heterocyclyl comprising carbon atoms and 1-4 heteroatoms selected from N, O, and S(=O)p, and substituted with 1-5 R5; R5, at each occurrence, is independently selected from the group consisting of H, halo, - NR7R7, and C1-6alkyl substituted with 1-5 Re; R6, at each occurrence, is independently selected from the group consisting of H, halo, CN, -ORb, C(=O)Rb, -C(=O)NRaRa, -S(=O)PRc, and C1-3alkyl substituted with 1-5 Re; R7, at each occurrence, is independently selected from the group consisting of H, C1-3alkyl substituted with 1-5 Re, and C3-6carbocyclyl substituted with 1-5 Re; or R7and R7together with the nitrogen atom, to which they are both attached, form 3- to 10-membered heterocyclyl comprising carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(=O)p, and substituted with 1-3 ReRa, at each occurrence, is independently selected from the group consisting of H and C1-4alkyl substituted with 1-5 Re; Rb, at each occurrence, is independently selected from the group consisting of H and C1-4alkyl substituted with 1-5 Re;Rcis C1-4alkyl substituted with 1-5 Re; Reis independently selected from the group consisting of H, halo, CN, C1-4alkyl, and - ORf; and Rfis selected from the group consisting of H and C1-4alkyl.

4. The compound of claim 3, having Formula (II):or a pharmaceutically acceptable salt thereof, wherein:R2 is selected from the group consistingR4ais C1-3alkyl; R4bis selected from the group consisting of -O(CH2)1-3NRaRa, C3-10carbocyclyl substituted with 1-4 R5, 4- to 10-membered heterocyclyl comprising carbon atoms and 1-4 heteroatoms selected from N, O, and S(=O)p, and substituted with 1-4 R5, -O-C3-10carbocyclyl substituted with 1-4 R5, and -O-4- to 10-membered heterocyclyl comprising carbon atoms and 1-4 heteroatoms selected from N, O, and S(=O)p, and substituted with 1-4 R5; R5, at each occurrence, is independently selected from the group consisting of H, halo, - NR7R7, and C1-5alkyl substituted with 1-3 Re;R6, at each occurrence, is independently selected from the group consisting of H, halo, CN, -ORb, -C(=O)Rb, -C(=O)NRaRa, -S(=O)2Rc, and C1-3alkyl substituted with 1- 3 Re; R7, at each occurrence, is independently selected from the group consisting of H, C1-5alkyl substituted with 1-3 Re, and C3-6cycloalkyl; or R7and R7together with the nitrogen atom, to which they are both attached, form 4- to 6-membered heterocyclyl comprising carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(=O)p, and substituted with 1-3 Re; Ra, at each occurrence, is independently selected from the group consisting of H and C1-3alkyl substituted with 1-5 Re; Rb, at each occurrence, is independently selected from the group consisting of H and C1-3alkyl substituted with 1-5 Re; Rcis C1-3alkyl; Reis independently selected from the group consisting of H, halo, CN, C1-3alkyl, and - ORf; and Rfis selected from the group consisting of H and C1-3alkyl.

5. The compound of claim 3, having Formula (III):or a pharmaceutically acceptable salt thereof, wherein:R2 is selected from the group consistingR4ais C1-3alkyl; R4bis selected from the group consisting of -O-C3-10carbocyclyl substituted with 1-4 R5, - O-4- to 10-membered heterocyclyl comprising carbon atoms and 1-4 heteroatoms selected from N, O, and S(=O)p, and substituted with 1-4 R5; R5, at each occurrence, is independently selected from the group consisting of H, halo, CN, ORb, -NR7R7, C1-5alkyl substituted with 1-3 Re, C3-6carbocyclyl with 1-3 Re, and 3- to 6- membered heterocyclyl comprising carbon atoms and 1-4 heteroatoms selected from N, O, and S(=O)p. and substituted with 1-4 Re; R6, at each occurrence, is independently selected from the group consisting of H, halo, CN, -NRaRa, -ORb, -C(=O)NRaRa, -C(=O)NRaORb, -C(=O)Rb, -S(=O)2Rc, - NRaS(=O)2Rc, C1-4alkyl substituted with 1-5 Re, -(CH2)rC3-6carbocyclyl substituted with 1-5 R7, and 5- to 6-membered heterocyclyl comprising carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(=O)p, and substituted with 1-5 R7; R7, at each occurrence, is independently selected from the group consisting of H, C1-5alkyl substituted with 1-3 Re, and C3-6cycloalkyl; or R7and R7together with the nitrogen atom, to which they are both attached, form 4- to 6-membered heterocyclyl comprising carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(=O)p, and substituted with 1-5 Re; Ra, at each occurrence, is independently selected from the group consisting of H and C1-3alkyl substituted with 1-5 Re;Rb, at each occurrence, is independently selected from the group consisting of H and C1-3alkyl substituted with 1-5 Re; Rcis C1-3alkyl; Reis independently selected from the group consisting of H, halo, CN, C1-3alkyl, and - ORf; and Rfis selected from the group consisting of H and C1-3alkyl.

6. The compound of claim 4 or 5, or a pharmaceutically acceptable salt thereof, wherein: R4ais C1-2alkyl; R4bis selected from the group consisting,R5, at each occurrence, is independently selected from the group consisting of H, -NR7R7, and C1-3alkyl substituted with 1-5 Re; R7, at each occurrence, is independently selected from the group consisting of H, C1-5alkyl substituted with 1-3 Re, and C3-6cycloalkyl; or R7and R7together with the nitrogen atom, to which they are both attached, form 5- to 6-memberedheterocyclyl comprising carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(=O)p, and substituted with 1-5 Re; Re, at each occurrence, is independently selected from the group consisting of H, halo, CN, C1-3alkyl, and -ORf; and Rfis selected from the group consisting of H and C1-3alkyl.

7. The compound of claim 6, or a pharmaceutically acceptable salt thereof, wherein:R5is selected from the group consisting of -NR7R7and C1-3alkyl substituted with 1-5 Re; R7, at each occurrence, is independently selected from the group consisting of H, C1-5alkyl substituted with 1-3 Re, and C3-6cycloalkyl; or R7and R7together with the nitrogen atom, to which they are both attached, form 3- to 10-membered heterocyclyl comprising carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(=O)p, and substituted with 1-3 Re; Re, at each occurrence, is independently selected from the group consisting of H, halo, CN, C1-2alkyl, and -ORf; Rfis selected from the group consisting of H and C1-2alkyl.

8. The compound of claim 7, or a pharmaceutically acceptable salt thereof, wherein: R5is -NR7R7; R7, at each occurrence, is independently selected from the group consisting of H, Me, Et,or R7and R7together with the nitrogen atom, to which they are both attached, form9. The compound of claim 4 or 5, or a pharmaceutically acceptable salt thereof, wherein:R6, at each occurrence, is independently selected from the group consisting of H, halo, CN, -OC1-3alkyl, -C(=O)NH2, -S(=O)2C1-3alkyl, and C1-3alkyl.

10. The compound of claim 4 or 5, or a pharmaceutically acceptable salt thereof, wherein:R2 is selected from the group consistingR6, at each occurrence, is independently selected from the group consisting of H, - C(=O)C1-3alkyl, and C1-3alkyl.

11. The compound of claim 3, having Formula (IV):or a pharmaceutically acceptable salt thereof, wherein:R2is selected from the group consisting ofR4bis independently selected from the group consisting of -O-C1-3alkyl, C3-12carbocyclyl substituted with 1-5 R5, and 3- to 10-membered heterocyclyl comprising carbon atoms and 1-4 heteroatoms selected from N, O, and S(=O)p, and substituted with 1-5 R5; R5, at each occurrence, is independently selected from the group consisting of H, -NR7R7, and C1-5alkyl substituted with 1-5 Re; R6, at each occurrence, is independently selected from the group consisting of H, halo, CN, ORb, C(=O)Rb, -C(=O)NRaRa, -S(=O)2Rc, and C1-3alkyl substituted with 1-5 Re; R7, at each occurrence, is independently selected from the group consisting of H, C1-3alkyl substituted with 1-5 Re, and C3-6carbocyclyl substituted with 1-5 Re; Ra, at each occurrence, is independently selected from the group consisting of H and C1-3alkyl; Rb, at each occurrence, is independently selected from the group consisting of H and C1-3alkyl substituted with 1-4 Re, C3-10carbocyclyl substituted with 1-5 Re, and 5- to 6- membered heterocyclyl comprising carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(=O)p, and substituted with 1-4 Re; Rcis C1-3alkyl; Re, at each occurrence, is independently selected from the group consisting of H, halo, CN, C1-3alkyl, and ORf; and Rfis selected from the group consisting of H and C1-3alkyl.

12. The compound of claim 11, or a pharmaceutically acceptable salt thereof, wherein: R4bis independently selected from the group consisting; R5, at each occurrence, is independently selected from the group consisting of H, and C1-4alkyl; and R7, at each occurrence, is independently selected from the group consisting of H and C1-3alkyl.

13. The compound of claim 1, which is selected from any one of the examples as described in the specification, or a pharmaceutically acceptable salt thereof.

14. A pharmaceutical composition comprising one or more compounds according to any one of claims 1 to 12 and a pharmaceutically acceptable carrier or diluent.

15. A compound according to any one of claims 1 to 12 for use in therapy.

16. Use of a compound according to any one of claims 1 to 12 for prophylaxis and / or treatment of disorders associated with serum- and glucocorticoid-regulated kinase 1 (SGK1) activity.

17. The use of claim 16, wherein said disorder is selected from cardiovascular and cerebrovascular diseases (including hypertension, heart failure, coronary artery disease, myocardial infarction, peripheral vascular disease, stroke and arrhythmia), fibrotic diseases (including diabetic nephropathy, glomerulonephritis, experimental nephrotic syndrome, obstructive nephropathy, lung fibrosis, liver cirrhosis, fibrotic pancreatitis, peritoneal fibrosis, Crohn’s disease and coeliac disease), metabolic disorders and complications (including diabetes, obesity, metabolic syndrome),immune / inflammatory diseases (including rheumatoid arthritis and osteoarthritis), neuronal diseases (including Alzheimer, Parkinson, seizure, and Lafora progressive myoclonic epilepsy) and cancer.

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