Piperidine-substituted pyrazolopyrimidine derivatives as SGK1 inhibitors

Abstract

The present invention relates to formula (I): The present invention provides compounds represented by TIFF2026534475000154.tif58164 (wherein all variables are as defined herein), or their stereoisomers, tautomers, or pharmaceutically acceptable salts. These compounds are selective SGK1 inhibitors. The present invention also relates to pharmaceutical compositions comprising these compounds, and to methods for treating disorders related to serum and glucocorticoid-regulated kinase 1 (SGK1) activity (e.g., cardiovascular disorders, fibrosis, metabolic diseases, immune and inflammatory diseases, neurological disorders, and cancer) using these compounds and pharmaceutical compositions.

Description

[Technical Field]

[0001] (Cross-reference of related applications) This application claims priority to U.S. Provisional Application No. 63 / 585,630 filed on 27 September 2023, the entirety of which is incorporated herein by reference.

[0002] (Technical field) The present invention relates to novel amino-substituted pyrazolopyrimidine derivatives, compositions comprising them, and methods for using them, for example, for the treatment or prevention of disorders associated with abnormal activity of serum and glucocorticoid-regulating kinase 1 (SGK1). [Background technology]

[0003] Serum and glucocorticoid-regulating kinase 1 (SGK1) belongs to a subfamily of serine / threonine kinases, consisting of SGK1, SGK2, and SGK3. Despite all three isoforms sharing 80% sequence homology in the catalytic domain, as well as general properties of ion channel, transport, and transcriptional regulation, SGK1 exhibits distinct pathophysiological functions (Lang, F. at al., Physiol Rev, 86(4), 1151-1178 (2006)).

[0004] SGK1 is expressed at low levels in most cells, but is stimulated under a variety of pathological conditions, including excessive glucocorticoids, mineralocorticoids, hypertension, inflammation, ischemia, and hyperglycemia (Lang, F. et al., Sci STKE, 108, re17 (2001)). Evidence is accumulating suggesting that SGK1 overexpression and overactivity contribute to a variety of diseases or disorders, including cardiovascular and cerebrovascular diseases (including hypertension, heart failure, coronary artery disease, myocardial infarction, peripheral vascular disease, stroke, and arrhythmias), fibrosis (including diabetic nephropathy, glomerulonephritis, experimental nephrotic syndrome, obstructive nephropathy, pulmonary fibrosis, cirrhosis, fibrotic pancreatitis, peritoneal fibrosis, Crohn's disease, and celiac disease), metabolic disorders and complications (including diabetes, obesity, and metabolic syndrome), immune / inflammatory diseases (including rheumatoid arthritis and osteoarthritis), neurological disorders (including Alzheimer's disease, Parkinson's disease, epileptic seizures, and Lafora progressive myoclonus epilepsy), and cancer (Lang, F. et al., Expert Opin Investing Drugs, 22, 701-714 (2013)). Therefore, targeting SGK1 could be a potential treatment option for these conditions.

[0005] SGK1 activates tubular ion channels and transporters, and Na + Na uptake and kidney Na + It stimulates both the excretion of sodium. SGK1 is thought to influence blood pressure through the regulation of salt balance. SGK1 stimulates epithelial sodium + It is known to activate channels (ENAC) that are regulated by mineralocorticoids. +It is important to note that SGK1 is only partially involved in reabsorption. This is supported by the fact that genetic deletion of SGK1 in mice had no effect on blood pressure, either under healthy 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 a high-fructose or anti-lipid diet, salt overload-induced hypertension was mitigated in SGK1-deficient animals (Huang, D. Y. et al., Am J Physiol Renal Physiol, 291, F1264-1273 (2006)). These data indicate that SGK1 is associated with renal Na + It also mediates the insulin-dependent stimulation of retention, suggesting that it may be a cause of secondary hypertension in type II diabetes.

[0006] SGK1 is expressed in the heart and its expression is upregulated in heart failure (Das, S., et al., Circulation, 126, 2208-2219 (2012)). A substantial body of preclinical evidence suggests that SGK1 mediates multiple intracellular pathways in response to aldosterone and other pathological stimuli, leading to cardiac hypertrophy, fibrosis, and myocardial dysfunction. Aldosterone induces SGK1 gene expression in the heart, increasing Na in the cytosol of cardiomyocytes and cardiac fibroblasts + and subsequently, via the Na + / Ca 2+ exchanger, increases Ca 2+ (Martin-Fernandez, B. et al., J Cardiovasc Pharmacol, 57, 114-121 (2011)).

[0007] In addition to its aldosterone-mediated influence, the broad role of SGK1 in fibrosis is suggested by the fact that SGK1 expression is upregulated by TGFβ, is involved in the Smad2 / 3-TGFβ CTGF signaling pathway, and leads to pathological fibrosis and negative remodeling (Artunc, F. et al., Nephron Physiol, 128, 35-39 (2014)). In several animal models of heart failure, cardiomyopathy 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 fibrous tissues and may play a role in diabetic nephropathy, glomerulonephritis, experimental nephrotic syndrome, obstructive nephropathy, pulmonary fibrosis, cirrhosis, fibrous pancreatitis, peritoneal fibrosis, Crohn's disease, and celiac disease (Lang, F. at al., Physiol Rev, 86(4), 1151-1178 (2006)). Therefore, inhibition of SGK1 kinase activity may offer benefits for other fibrotic diseases.

[0008] SGK1 may play a role in cardiac arrhythmias. In the heart, SGK1 stimulates the activity of several channels (SCN5A, Kv4.3, Kv1.5, and KCNE1 / KCNQ1), influencing the state and duration of cardiac action potentials. In fact, the E8CC / CT;I6CC gene variant of SGK1 has been reported to be associated with shortening of the QT interval in humans (Busjahn, A. et al., Cell physiol Biochem, 14, 135-142 (2004)). Increased SGK1 expression and activity are also involved in coagulation. SGK1 is stimulated by thrombin and oxidative stress, which in turn induces increased expression of tissue factor, a key trigger in the extrinsic coagulation cascade (Belaiba, RS et al., Circ Res, 98, 828-836 (2006)). A link between SGK1 gene mutations and ischemic stroke has been reported (Dahlberg, J. et al., J Hypertens, 29, 884-889 (2011)).

[0009] SGK1 is expressed in glomerular podocytes and its expression is upregulated by aldosterone and oxidative stress. SGK1 phosphorylates nephrin and may be involved in the development of proteinuria in response to mineralocorticoid excess, inflammation, and other pathological stimuli (Ohashi, T. et al., Clin Exp Nephrol, 15, 688-693 (201)).

[0010] SGK1 is Na + SGK1 stimulates the glucose cotransporter SGLT1, promoting intestinal glucose uptake and contributing to the development of obesity. SGK1 is expressed in white adipose tissue and has been shown to stimulate adipocyte differentiation and adipogenesis (Lang, F. et al., Expert Opin Ther Targets, 13, 1303-1311 (2009)). Furthermore, SGK1 polymorphisms have been reported to be associated with insulin secretion and type II diabetes (Schwab, M. et al., Cell Physiol Biochem, 21, 151-160 (2008)).

[0011] SGK1 is CD4 + SGK1 is involved in the differentiation and maintenance of TH17 cells and is therefore involved in related diseases (e.g., autoimmune diseases and inflammatory diseases) (Kuchroo, VK et al., International Publication No. 2011 / 014775). Furthermore, SGK1 is expressed in osteoarthritis cartilage and is involved in the pathogenesis of rheumatoid arthritis and osteoarthritis (Bartnik, E. et al., U.S. Patent Application No. 2008 / 0274487).

[0012] SGK1 is expressed in the brain and may be involved in the pathological effects of glucocorticoids during brain injury (e.g., stroke and epileptic seizures) (Kaufer, D. et al., Nat Neurosci, 7, 947-953 (2004)). Furthermore, although the role of SGK1 in neuronal function is not fully understood, SGK1 phosphorylates several neuronal factors associated with neurodegenerative diseases. For example, SGK1 phosphorylates tau, an activity that may be linked to the development of Alzheimer's disease (Chuna, J. et al., Molecules & Cells (Springer Science & Business Media BV) 18 (3) (2004)). Furthermore, elevated SGK1 expression has been shown to coincide with the onset of dopaminergic cell death in a one-year subacute MPTP model of Parkinson's disease (Stichel, CC et al., Eur J Neurosci, 21, 301-316 (2005)).

[0013] SGK1 is highly expressed in many tumor cells, including, but not limited to, breast cancer, colon cancer, myeloma, medulloblastoma, non-small cell lung cancer, ovarian cancer, and prostate cancer (Lang, F. et al., Physiol Rev, 86(4), 1151-1178 (2006)). As a downstream regulator, SGK1 may mediate the effects of glucocorticoids on the invasiveness, motility, and adhesion of breast cancer cells (Tangir, J. et al., Clin Exp Metastasis, 21, 477-483 (2004)). Furthermore, it has been suggested that SGK1 may play a role in immune-mediated tumor responses (Heikamp, ​​EB et al., Nat Immunol, 15, 457-464 (2014)).

[0014] Generally, SGK1 is a stress-responsive protein kinase whose expression is upregulated by various pathological stimuli. Excessive SGK1 activity is associated with cellular mechanisms that cause many of the aforementioned pathological conditions. Therefore, SGK1 inhibitors, such as the compounds of the present invention, can be used to treat conditions in which SGK1 activity contributes to the pathogenesis of these diseases. [Prior art documents] [Patent Documents]

[0015] [Patent Document 1] International Publication No. 2011 / 014775 [Patent Document 2] U.S. Patent Application No. 2008 / 0274487 [Non-patent literature]

[0016] [Non-Patent Document 1] Lang, F. at al., Physiol Rev, 86(4), 1151-1178 (2006) [Non-Patent Document 2] Lang, F. et al., Sci STKE, 108, re17 (2001) [Non-licensed document 3] Lang, F. et al., Expert Opin Investg Drugs, 22, 701-714 (2013)

Non-licensed Document 4

Non-licensed Document 5

Non-licensed Document 6

Non-licensed Document 7

Non-licensed literature 9

Non-licensed literature 10

Non-licensed Document 11

Non-licensed Document 12

Non-licensed Document 13

Non-licensed Document 14

Non-licensed Document 15

Non-licensed Document 16

Non-licensed Document 17

Non-licensed Document 18

Non-licensed Document 19

Non-licensed Document 20

Non-licensed Document 21

Non-licensed Document 22

Non-licensed Document 23

[0017] The present invention provides novel amino-substituted pyrazolopyrimidine derivatives (including their stereoisomers, tautomers, pharmaceutically acceptable salts, or solvates) that are useful as selective inhibitors of serum and mineralocorticoid regulatory kinase 1 (SGK1).

[0018] The present invention also provides a method for producing the compound of the present invention and intermediates.

[0019] The present invention also provides a pharmaceutically acceptable carrier and a pharmaceutical composition comprising at least one compound of the present invention, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof.

[0020] The compounds of the present invention may be used to treat and / or prevent symptoms associated with abnormal activity of SGK1.

[0021] The compounds of the present invention may be used for therapeutic purposes.

[0022] The compounds of the present invention may be used for the manufacture of pharmaceuticals for the treatment and / or prevention of symptoms associated with abnormal SGK1 activity.

[0023] The compounds of the present invention may be used alone, in combination with other compounds of the present invention, or in combination with one or more, preferably one to two, other agents.

[0024] These and other features of the present invention will be described in more detail as the disclosure progresses. [Modes for carrying out the invention]

[0025] This application provides the compound described in formula (I) (including all stereoisomers, solvates, prodrugs, and pharmaceutically acceptable salts and solvates). This application also provides a pharmaceutical composition comprising at least one compound described in formula (I), or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof, and optionally at least one additional therapeutic agent. Furthermore, the present invention provides a method for treating patients suffering from SGK1 regulated disorders or disorders, such as cardiovascular and cerebrovascular diseases (including hypertension, heart failure, coronary artery disease, myocardial infarction, peripheral vascular disease, stroke, and arrhythmias), fibrosis (including diabetic nephropathy, glomerulonephritis, experimental nephrotic syndrome, obstructive nephropathy, pulmonary fibrosis, cirrhosis, fibrotic pancreatitis, peritoneal fibrosis, Crohn's disease, and celiac disease), metabolic disorders and complications (including diabetes, obesity, and metabolic syndrome), immune / inflammatory diseases (including rheumatoid arthritis and osteoarthritis), neurological diseases (including Alzheimer's disease, Parkinson's disease, epileptic seizures, and Lafora progressive myoclonus epilepsy), and cancer, by administering a therapeutically effective amount of the compound of the present invention, or its stereoisomers, tautomers, or pharmaceutically acceptable salts or solvates, in combination with at least one additional therapeutic agent as appropriate, to patients in need of such treatment.

[0026] (I. Compounds of the present invention) In a first embodiment, the present invention particularly relates to formula (I): [ka] [In the formula, R1 is C 6-10 Aryls, as well as carbon atoms, and N, O, and S (=O) p It contains 1 to 5 heteroatoms selected from and 0 to 3 R 4a and one R 4b Selected from a group consisting of 5-10 member heterocyclines that have been substituted; R2 is a C that has been replaced by 1 to 5 R6s. 6-10 Aryls, as well as carbon atoms, and N, O, and S (=O) pSelected from the group consisting of 5- to 9-membered heterocyclines containing 1 to 5 heteroatoms selected from and substituted with 1 to 5 R6 groups; R3 is independent in each presence: H, halogen, -OR b , -NR a R a , and C 1-3 Selected from the group consisting of alkyl groups; or, R3 and R3 together with the two adjacent carbon atoms to which they are bonded, C 3-6 Forms a cycloalkyl group; R 4a In each presence, independently, H, halogen, and 1-3 R atoms are present. e C replaced by 1-4 Selected from the group consisting of alkyl groups; R 4b is -OR b ,-O-(CR d R d ) 1-5 NR a R a ,-O-(CR d R d ) 1-5 Ure b , C substituted with 1 to 5 R5 3-12 Carbocyclyl, carbon atom, and N, O, and S (=O) p 3-10 membered heterocyclyl containing 1-4 heteroatoms selected from and substituted with 1-5 R5 atoms, -O-(CR) substituted with 1-5 R5 atoms d R d ) r -C 3-12 Carbocyclyl, as well as carbon atoms, and N, O, and S (=O) p -O-(CR) containing 1 to 4 heteroatoms selected from and substituted with 1 to 5 R5 atoms d R d ) r - Selected from a group consisting of 3- to 10-membered heterocyclines; R5 is independent for each presence: H, halogen, CN, OR b ,=O,-(CR d R d ) r -NR7R7, 1 to 5 R's e C replaced by1-6 alkyl, 1 to 5 R e substituted C 2-6 alkenyl, 1 to 5 R e substituted C 2-6 alkynyl, 1 to 5 R e substituted C 3-10 carbocyclyl, and 3- to 10-membered heterocyclyl containing 1 to 4 heteroatoms selected from carbon atoms and N, O, and S(=O) p selected from the group consisting of 1 to 5 R e substituted 3- to 10-membered heterocyclyl; R6 is, at each occurrence, independently selected from H, halogen, CN, =O, -(CR d R d ) r NR a R a , NO2, -OR b , -C(=O)NR a R a , -C(=O)NR a (CR d R d ) r OR b , -C(=O)R b , -C(=O)(CR d R d ) r OR b , -NR a C(=O)OR b , -NR a C(=O)(CR d R d ) r NR a R a , -S(=O) p R c , -NR a S(=O) p R c , and 1 to 5 R e substituted C 1-6 alkyl; R7 is, at each occurrence, independently H, 1 to 5 R e substituted C 1-7 alkyl, 1 to 5 R e substituted C 3-10Carbocyclyl, as well as carbon atoms, and N, O, and S (=O) p It contains 1 to 4 heteroatoms selected from the group consisting of 1 to 5 R e Selected from the group consisting of 3- to 10-membered heterocyclines substituted with; or R7 and R7 together with the nitrogen atom to which they are bonded, a carbon atom, and N, O, and S (=O) p It contains 1 to 4 heteroatoms selected from the group consisting of 1 to 5 R e Forms 3-10 member heterocyclines substituted with; R a Each entity independently has H and 1 to 5 R e C replaced by 1-6 Alkyl, 1 to 5 R e C replaced by 3-10 Carbocyclyl, as well as carbon atoms, and N, O, and S (=O) p It contains 1 to 4 heteroatoms selected from the group consisting of 1 to 5 R e Selected from the group consisting of 3- to 10-membered heterocyclines substituted with; or R a and R a This includes the nitrogen atom to which both are bonded, as well as the carbon atom, and N, O, and S (=O) p It contains 1 to 4 heteroatoms selected from the group consisting of 1 to 5 R e Forms 3-10 member heterocyclines substituted with; R b Each entity independently has H and 1 to 5 R e C replaced by 1-6 Alkyl, 1 to 5 R e C replaced by 3-10 Carbocyclyl, as well as carbon atoms, and N, O, and S (=O) p It contains 1 to 4 heteroatoms selected from the group consisting of 1 to 5 R e Selected from a group consisting of 3- to 10-membered heterocyclines substituted with; R c Each entity independently has 1 to 5 R e C replaced by 1-6 Alkyl, 1 to 5 R e C replaced by3-10 Carbocyclyl, as well as carbon atoms, and N, O, and S (=O) p It contains 1 to 4 heteroatoms selected from the group consisting of 1 to 5 R e Selected from a group consisting of 3- to 10-membered heterocyclines substituted with; R d Each entity independently has H and 1 to 5 R e C replaced by 1-6 Alkyl and 1-5 R e C replaced by 3-6 Selected from the group consisting of cycloalkyl groups; R e These are independently H, halogen, CN, =O, and 1 to 5 R g C replaced by 1-6 Alkyl, 1 to 5 R g C replaced by 2-6 Alkenyl, 1-5 R g C replaced by 2-6 Alkinyl, 1 to 5 R g C replaced by 3-10 Carbocyclyl, carbon atom, and N, O, and S (=O) p It contains 1 to 4 heteroatoms selected from the group consisting of 1 to 5 R g A 3-10 member heterocyclyl substituted with -(CH2) r Ure f ,-(CH2) r NR f R f ,-(CH2) r C(=O)R f , and -(CH2) r C(=O)OR f Selected from the group consisting of; R f Each entity independently has H and 1 to 5 R g C replaced by 1-6 Alkyl, 1 to 5 R g C replaced by 3-10 Carbocyclyl, carbon atom, and N, O, and S (=O) p It contains 1 to 4 heteroatoms selected from the group consisting of 1 to 3 R gSelected from a group consisting of 3- to 10-membered heterocyclines substituted with; R g In each of these entities, independently, H, halogen, CN, -OH, -O(C) 1-5 Alkyl), NH2, NH(C 1-5 Alkyl), NH(C 1-5 Alkyl)2, and C 1-5 Selected from the group consisting of alkyl groups; p is an integer, either 0, 1, or 2; and r is an integer of 0, 1, 2, 3, 4, or 5. The present invention provides the compound represented by, or its stereoisomers, tautomers, pharmaceutically acceptable salts, or solvates.

[0027] In a second embodiment that falls within the scope of the first embodiment, the present invention is described as follows: R1 is a carbon atom, and N, O, and S (=O) p It contains 1 to 3 heteroatoms selected from and 0 to 2 R 4a and one R 4b It is a 5-6 member heterocycline substituted with; and R2 is substituted with 1 to 5 R6 atoms in phenyl, as well as carbon atoms, and N, O, and S (=O) p Selected from the group consisting of 5-6 membered heterocyclines containing 1-3 heteroatoms selected from and substituted with 1-5 R6 groups, The present invention provides a compound represented by formula (I), or its stereoisomers, tautomers, pharmaceutically acceptable salts, or solvates.

[0028] In a third embodiment that falls within the scope of the first or second embodiment, the present invention is: R1 [ka] Selected from the group consisting of; R2 [ka] Selected from the group consisting of; R 4a H and C 1-3 Selected from the group consisting of alkyl groups; R 4b ga-OC 1-4 Alkyl, -O-(CH2) 1-5 NR a R a , C substituted with 1 to 5 R5 3-12 Carbocyclyl, carbon atom, and N, O, and S (=O) p 3-10 membered heterocyclyl containing 1-4 heteroatoms selected from and substituted with 1-5 R5 atoms, -OC substituted with 1-5 R5 atoms 3-12 Carbocyclyl, carbon atom, and N, O, and S (=O) p Selected from the group consisting of -O-3 to 10-membered heterocyclines containing 1 to 4 heteroatoms selected from and substituted with 1 to 5 R5 atoms; R5 independently contains H, halogen, -NR7R7, and 1 to 5 R e C replaced by 1-6 Selected from the group consisting of alkyl groups; R6 is independent in each presence: H, halogen, CN, -OR b , C(=O)R b -C(=O)NR a R a -S(=O) p R c , and 1 to 5 R e C replaced by 1-3 Selected from the group consisting of alkyl groups; R7 independently in each existence, H, 1 to 5 R e C replaced by 1-3 Alkyl and 1-5 R e C replaced by 3-6 Selected from the group consisting of carbocyclyl; or R7 and R7 together with the nitrogen atom to which they are bonded, carbon atoms, and N, O, and S (=O) p It contains 1 to 4 heteroatoms selected from the group consisting of 1 to 3 R e Forms 3-10 member heterocyclines substituted with; Ra However, each entity independently contains H and 1 to 5 R e C replaced by 1-4 Selected from the group consisting of alkyl groups; R b However, each entity independently contains H and 1 to 5 R e C replaced by 1-4 Selected from the group consisting of alkyl groups; R c 1 to 5 R e C replaced by 1-4 It is alkyl; R e These are independently H, halogen, CN, and C 1-4 Alkyl and -OR f Selected from the group consisting of; and R f H and C 1-4 Selected from the group consisting of alkyl groups, The present invention provides a compound represented by formula (I), or its stereoisomers, tautomers, pharmaceutically acceptable salts, or solvates.

[0029] In a fourth embodiment, which falls within the scope of the third embodiment, the present invention relates to formula (II): [ka] [In the formula, R2 [ka] Selected from the group consisting of; R 4a C 1-3 It is alkyl; R 4b However, -O(CH2) 1-3 NR a R a , C substituted with 1 to 4 R5 3-10 Carbocyclyl, carbon atom, and N, O, and S (=O) p 4-10 membered heterocyclyl containing 1-4 heteroatoms selected from, substituted with 1-4 R5 atoms, and -OC substituted with 1-4 R5 atoms.3-10 Carbocyclyl, as well as carbon atoms, and N, O, and S (=O) p Selected from the group consisting of -O-4 to 10 membered heterocyclines containing 1 to 4 heteroatoms and substituted with 1 to 4 R5 atoms; R5 independently contains H, halogen, -NR7R7, and 1-3 R e C replaced by 1-5 Selected from the group consisting of alkyl groups; R6 is independent in each presence: H, halogen, CN, -OR b -C(=O)R b -C(=O)NR a R a -S(=O)2R c , and 1 to 3 R e C replaced by 1-3 Selected from the group consisting of alkyl groups; R7 independently in each existence, H, 1 to 3 R e C replaced by 1-5 Alkyl, and C 3-6 Selected from the group consisting of cycloalkyl groups; or R7 and R7 together with the nitrogen atom to which they are bonded, carbon atoms, and N, O, and S (=O) p It contains 1 to 4 heteroatoms selected from the group consisting of 1 to 3 R e Forms a 4-6 member heterocycline by substitution; R a However, each entity independently contains H and 1 to 5 R e C replaced by 1-3 Selected from the group consisting of alkyl groups; R b However, each entity independently contains H and 1 to 5 R e C replaced by 1-3 Selected from the group consisting of alkyl groups; R c C 1-3 It is alkyl; R e These are independently H, halogen, CN, and C 1-3 Alkyl and -OR f Selected from the group consisting of; and Rf H and C 1-3 Selected from the group consisting of alkyl groups. The present invention provides the compound represented by, or its stereoisomers, tautomers, pharmaceutically acceptable salts, or solvates.

[0030] In a fifth embodiment, which falls within the scope of the third embodiment, the present invention relates to formula (III): [ka] [In the formula, R2 [ka] Selected from the group consisting of; R 4a C 1-3 It is alkyl; R 4b However, -OC was replaced with 1 to 4 R5s. 3-10 Carbocyclyl, carbon atom, and N, O, and S (=O) p Selected from the group consisting of -O-4 to 10-membered heterocyclines containing 1 to 4 heteroatoms and substituted with 1 to 4 R5 atoms; R5 is independent in each presence: H, halogen, CN, OR b -NR7R7, 1 to 3 R e C replaced by 1-5 Alkyl, 1-3 R e C replaced by 3-6 Carbocyclyl, as well as carbon atoms, and N, O, and S (=O) p It contains 1 to 4 heteroatoms selected from and 1 to 4 R e Selected from a group consisting of 3- to 6-membered heterocyclines substituted with; R6 is independent in each presence: H, halogen, CN, -NR a R a , -OR b -C(=O)NR a R a -C(=O)NR a Ure b -C(=O)Rb -S(=O)2R c , -NR a S(=O)2R c , 1 to 5 R e C replaced by 1-4 Alkyl, -(CH2) substituted with 1-5 R7 groups r C 3-6 Carbocyclyl, as well as carbon atoms, and N, O, and S (=O) p Selected from the group consisting of 5-6 membered heterocyclyls comprising 1-4 heteroatoms selected from the group consisting of 1-5 R7 substituted; R7 independently in each existence, H, 1 to 3 R e C replaced by 1-5 Alkyl, and C 3-6 Selected from the group consisting of cycloalkyl groups; or R7 and R7 together with the nitrogen atom to which they are bonded, carbon atoms, and N, O, and S (=O) p It contains 1 to 4 heteroatoms selected from the group consisting of 1 to 5 R e Forms a 4-6 member heterocycline by substitution; R a However, each entity independently contains H and 1 to 5 R e C replaced by 1-3 Selected from the group consisting of alkyl groups; R b However, each entity independently contains H and 1 to 5 R e C replaced by 1-3 Selected from the group consisting of alkyl groups; R c C 1-3 It is alkyl; R e These are independently H, halogen, CN, and C 1-3 Alkyl and -OR f Selected from the group consisting of; and R f However, H and C 1-3 Selected from the group consisting of alkyl groups. The present invention provides the compound represented by, or its stereoisomers, tautomers, pharmaceutically acceptable salts, or solvates.

[0031] In a sixth embodiment that falls within the scope of the fourth or fifth embodiment, the present invention R 4a C 1-2 It is alkyl; R 4b but [ka] Selected from the group consisting of; R5 independently in each existence, H, -NR7R7, and 1 to 5 R e C replaced by 1-3 Selected from the group consisting of alkyl groups; R7 independently in each existence, H, 1 to 3 R e C replaced by 1-5 Alkyl, and C 3-6 Selected from the group consisting of cycloalkyl groups; or R7 and R7 together with the nitrogen atom to which they are bonded, carbon atoms, as well as N, O, and S(=O) p It contains 1 to 4 heteroatoms selected from the group consisting of 1 to 5 R e Forms a 5-6 member heterocycline by substitution; R e However, each entity independently contains H, halogen, CN, and C. 1-3 Alkyl and -OR f Selected from the group consisting of; and R f However, H and C 1-3 Selected from the group consisting of alkyl groups, A compound represented by formula (II), or its stereoisomers, tautomers, pharmaceutically acceptable salts, or solvates are provided.

[0032] In the seventh embodiment, which falls within the scope of the sixth embodiment, the present invention is R 4b but [ka] and; R5 is -NR7R7, and 1 to 5 R e C replaced by1-3 Selected from the group consisting of alkyl groups; R7 independently in each existence, H, 1 to 3 R e C replaced by 1-5 Alkyl, and C 3-6 Selected from the group consisting of cycloalkyl groups; or R7 and R7 together with the nitrogen atom to which they are bonded, carbon atoms, and N, O, and S (=O) p It contains 1 to 4 heteroatoms selected from the group consisting of 1 to 3 R e Forms 3-10 member heterocyclines substituted with; R e However, each entity independently contains H, halogen, CN, and C. 1-2 Alkyl and -OR f Selected from the group consisting of; R f However, H and C 1-2 Selected from the group consisting of alkyl groups, The present invention provides compounds represented by formula (II) or (III), or their stereoisomers, tautomers, pharmaceutically acceptable salts, or solvates.

[0033] In the eighth embodiment, which falls within the scope of the seventh embodiment, the present invention is R5 is -NR7R7; R7 independently in each entity, H, Me, Et, [ka] Selected from the group consisting of; or, R7 and R7 together with the nitrogen atom to which they are bonded, [ka] to form The present invention provides the compound represented by formula (II), or its stereoisomers, tautomers, pharmaceutically acceptable salts, or solvates.

[0034] In the ninth embodiment, which falls within the scope of the fourth or fifth embodiment, the present invention is described as follows: R2 [ka] and R6 independently comprises H, halogen, CN, and -OC in each presence. 1-3 Alkyl, -C(=O)NH2, -S(=O)2C 1-3 Alkyl, and C 1-3 Selected from the group consisting of alkyl groups, The present invention provides compounds represented by formula (II) or (III), or their stereoisomers, tautomers, pharmaceutically acceptable salts, or solvates.

[0035] In a tenth embodiment that falls within the scope of the fourth or fifth embodiment, the present invention is R2 [ka] Selected from the group consisting of; and R6 independently has H, -C(=O)C in each existence. 1-3 Alkyl, and C 1-3 Selected from the group consisting of alkyl groups, The present invention provides a compound represented by formula (III), or its stereoisomers, tautomers, pharmaceutically acceptable salts, or solvates.

[0036] In an eleventh embodiment, which falls within the scope of the third embodiment, the present invention relates to formula (IV): [ka] [In the formula, R2 [ka] Selected from the group consisting of; R 4b -OC 1-3 Alkyl, C substituted with 1-5 R5 groups 3-12 Carbocyclyl, as well as carbon atoms, and N, O, and S (=O)p Selected from the group consisting of 3-10 membered heterocyclines containing 1-4 heteroatoms selected from and substituted with 1-5 R5 groups; R5 independently in each existence, H, -NR7R7, and 1 to 5 R e C replaced by 1-5 Selected from the group consisting of alkyl groups; R6 is independent in each presence: H, halogen, CN, OR b , C(=O)R b -C(=O)NR a R a -S(=O)2R c , and 1 to 5 R e C replaced by 1-3 Selected from the group consisting of alkyl groups; R7 independently in each existence, H, 1 to 5 R e C replaced by 1-3 Alkyl and 1-5 R e C replaced by 3-6 Selected from the group consisting of carbocyclyls; R a However, in each existence independently, H and C 1-3 Selected from the group consisting of alkyl groups; R b However, each entity independently contains H and 1 to 4 R e C replaced by 1-3 Alkyl, 1 to 5 R e C replaced by 3-10 Carbocyclyl, as well as carbon atoms, and N, O, and S (=O) p It contains 1 to 4 heteroatoms selected from and 1 to 4 R e Selected from a group consisting of 5-6 member heterocyclines substituted with; R c C 1-3 It is alkyl; R e However, each entity independently contains H, halogen, CN, and C. 1-3 Alkyl and OR f Selected from the group consisting of; and R f However, H and C 1-3Selected from the group consisting of alkyl groups. The present invention provides the compound represented by, or its stereoisomers, tautomers, pharmaceutically acceptable salts, or solvates.

[0037] In a twelfth embodiment, which falls within the scope of the eleventh embodiment, the present invention is: R 4b but, [ka] Selected from the group consisting of; R5 is H, and C 1-4 Selected from the group consisting of alkyl groups; and R7 independently in each existence, H and C 1-3 Selected from the group consisting of alkyl groups, The present invention provides the compound represented by formula (IV), or its stereoisomers, tautomers, pharmaceutically acceptable salts, or solvates.

[0038] In some embodiments of the compound represented by formula (I) or (III), R1 is [ka] And; R2 is [ka] R6 is S(=O)2CH3; R 4a is H, CH3, CHF2, Et, iPr, or c-Pr; R 4b is -O(CH2) 1-3 N(CH3)2, [ka] R5 is NR7R7; and NR7R7 is -NHC(CH3)2, -N(CH3)2, -N(CH2CH3)2, -NHC(CH3)CH2OH, -NHC(CH2CH3)CH2OH, or -NHC(CH3)CH2OCH3.

[0039] In another embodiment of the compound represented by formula (I) or (III), R1 is

化

化

化

化

[0040] In another embodiment of the compound represented by formula (I) or (III), R1 is

化

化

化

[0041] In another embodiment of the compound represented by formula (I) or (III), R1 is [ka] And; R2 is [ka] And; R6 is -OCH3; R 4a R is H, CH3, CHF2, Et, iPr, or c-Pr; R 4b teeth [ka] R5 is NR7R7; and NR7R7 is -NHC(CH3)2, -N(CH3)2, -N(CH2CH3)2, -NHC(CH3)CH2OH, -NHC(CH2CH3)CH2OH, -NHC(CH3)CH2OCH3, or -NH-cyclobutyl.

[0042] In some embodiments of the compound represented by formula (I) or (II), R1 is [ka] And; R2 is [ka] And; R 4a is F, Cl, or CH3; R 4b is -O(CH2) 1-3 N(CH3)2 is CN; and R6 is CN.

[0043] In another embodiment of the compound represented by formula (I) or (II), R1 is [ka] And; R2 is [ka] and is; R 4a is H, F, Cl, CH3, or CHF2; R 4b is

Chemical formula

[0044] In another embodiment of the compound represented by formula (I) or (III), R1 is

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0045] In a certain embodiment of the compound represented by formula (I) or (III), R1 is

Chemical formula

Chemical formula

Chemical formula

[0046] In some embodiments of the compound represented by formula (I) or (III), R1 is [ka] And; R2 is [ka] R6 is -S(=O)2CH3 or C(=O)CH3; R 4a is F, Cl, or CH3; R 4b teeth [ka] R5 is NR7R7; NR7R7 is -NHC(CH3)2, -N(CH3)2, -N(CH2CH3)2, -NHC(CH3)CH2OH, -NHC(CH2CH3)CH2OH, -NHC(CH3)CH2OCH3, -NH-cyclobutyl, [ka] That is the case.

[0047] In some embodiments of the compound represented by formula (I) or (II), R1 is [ka] And; R2 is [ka] Therefore, R6 is S(=O)2CH3.

[0048] In another embodiment of the compound represented by formula (I), R1 is [ka] And; R2 is [ka] And; R 4a is H, CH3, CHF2, or Et; and R6 is S(=O)2CH3.

[0049] In some embodiments of the compound represented by formula (I) or (IV), R1 is [ka] And; R2 is [ka] And; R 4b R6 is -OCH3; and R6 is S(=O)2CH3.

[0050] For the compounds represented by formulas (I) to (IV), R1, R2, R3, R 4a , R 4b R5, R6, R7, R a , R a , R b , R c , R d , R e , R f , and R g The range of presence of any of the variable substituents can be used independently of the range of presence of any other variable substituent. Therefore, the present invention includes combinations of different embodiments.

[0051] In one embodiment, the compound of the present invention is SGK1 IC 50 The value is ≤ 0.1 μM.

[0052] In another embodiment, the compound of the present invention is SGK1 IC 50 The value is ≤ 0.05 μM.

[0053] In another embodiment, the compound of the present invention is SGK1 IC 50 The value is ≤ 0.01 μM.

[0054] (II. Other Embodiments of the Invention) In another embodiment, the present invention provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and at least one therapeutically effective amount of the compound of the present invention, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof.

[0055] In another embodiment, the present invention provides a method for producing the compound of the present invention.

[0056] In another embodiment, the present invention provides an intermediate for the production of the compound of the present invention.

[0057] In another embodiment, the present invention provides a pharmaceutical composition comprising further additional therapeutic agents.

[0058] In another embodiment, the present invention provides a method for the treatment and / or prevention of symptoms associated with SGK1 abnormal activity, comprising administering to a patient in need of such treatment and / or prevention at least one therapeutically effective amount of the compound of the present invention, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof. The term “patient” as used herein includes all mammalian species.

[0059] As used herein, the terms “treating” or “treatment” refer to means of using the compounds or compositions of the present invention to obtain a benefit or desired outcome (including clinical outcomes). For the purposes of the present invention, the benefit or desired clinical outcome includes, but is not limited to, a reduction in the severity and / or frequency of one or more symptoms resulting from a disease, disorder, or condition; a reduction in the degree of the disease, disorder, or condition or progression of regression; stabilization of the disease, disorder, or condition (e.g., prevention or delay of the worsening of the disease, disorder, or condition); delay or slowing the progression of the disease, disorder, or condition; improvement of the disease, disorder, or condition; a reduction in the dosage of one or more other medicines required to treat the disease, disorder, or condition; and / or an improvement in quality of life.

[0060] As used in this specification, “prophylaxis” refers to protective treatment of a disease state, which involves administering to a patient at least one therapeutically effective amount of one of the compounds of the present invention, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, to reduce and / or minimize the risk of a disease state, and / or reduce the risk of recurrence of a disease state. In prophylactic treatment, the clinical symptoms of the disease state may or may not be present. “Prophylactic” treatment can be divided into primary and secondary prevention. Primary prevention is defined as treatment to reduce or minimize the risk of a disease state in a patient who does not yet present with a clinical disease state. Secondary prevention, on the other hand, is defined as minimizing or reducing the risk of recurrence or a second occurrence of the same or similar clinical disease state.

[0061] As used herein, “prevention” encompasses the prophylactic treatment of asymptomatic disease conditions in mammals (particularly humans) aimed at reducing the probability of developing a clinical disease condition. Patients are selected for prophylactic treatment based on factors known to increase their risk of developing a clinical disease condition compared to the general population.

[0062] The present invention may be embodied in other specific forms without departing from its essence or essential attributes. The present invention encompasses all combinations of preferred embodiments of the present invention described herein. It is understood that any and all embodiments of the present invention may be construed in combination with any other embodiment or a plurality of embodiments to illustrate additional embodiments. It should also be understood that the individual elements of each embodiment are themselves independent embodiments. Furthermore, any element of a given embodiment is intended to be combined with any other element from any embodiment to illustrate additional embodiments.

[0063] (III.Chemistry) Throughout this specification and the appended claims, a given chemical formula or name shall encompass all stereoisomers, optical isomers, and racemates, if isomers exist. Unless otherwise specified, all chiral (enantiomers and diastereomers) and racemates are included in the scope of the present invention. Numerous geometric isomers, such as C=C double bonds, C=N double bonds, and cyclic systems, may also be included in the compounds, and all such stable isomers are considered to belong to 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 isomer mixtures or divided isomers. The compounds may be isolated in the form of optically active or racemates. Optically active compounds may be prepared by dividing a racemate or by synthesis from optically active starting materials. All methods used to prepare the compounds of the present invention and their intermediates are considered to be part of the present invention. When enantiomer or diastereomer products are prepared, they may be separated by conventional methods (e.g., chromatography or fractional crystallization). Depending on the conditions of the method, the final product of the present invention may be obtained in either a free (neutral) or salt form. Both the free form and the salt of these final products are included within the scope of the present invention. If desired, one form of the compound may be transformed into another form. A free base or acid may be transformed into a salt; a salt may be transformed into a free compound or another salt; a mixture of isomer compounds of the present invention may be separated into individual isomers. The compounds of the present invention, their free forms and salts may exist in multiple tautomers in which hydrogen atoms are transferred to other parts of the molecule, resulting in a rearrangement of the interatomic chemical bonds of the molecule. It should be understood that all tautomers, insofar as they exist, are included within the present invention. As used herein, “a compound of the invention” or “compounds of the invention” means one or more compounds encompassed by formulas (I) to (VII), as well as any subspecies and exemplary species thereof.

[0064] The term "stereoisomer" refers to an isomer of the same composition but with different arrangements of 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 but cannot be superimposed. The term "diastereomer" refers to a stereoisomer that is not a mirror image of each other. The term "racemate" or "racemic mixture" refers to a composition consisting of equimolar amounts of two enantiomer species that does not possess optical activity.

[0065] The symbols "R" and "S" represent the arrangement of substituents around a chiral carbon atom. The isomer descriptors "R" and "S" are used as described herein to indicate the atomic arrangement relative to the core molecule and are intended to be used as defined in the literature (IUPAC recommendations 1996, Pure and Applied Chemistry, 68:2193-2222 (1996)).

[0066] The term "chiral" refers to a molecular structural characteristic that makes it impossible to superimpose its mirror image onto another molecule. The term "homochiraral" refers to the state of enantiomer purity. The term "optical activity" refers to the degree to which a homochiral molecule or a non-racemic mixture of chiral molecules rotates plane-polarized light.

[0067] In accordance with the conventions used in this art, the structural formulas used herein [ka] Bonds pointing towards the wavy line, as shown above, indicate bonds that are attachment points of a partial or substituent to the core or main chain structure.

[0068] As used herein, the terms “alkyl” or “alkylene” are intended to include both branched and linear saturated aliphatic hydrocarbon groups having a specific number of carbon atoms. For example, “C 1-10 Alkyl (or alkylene) is C1, C2, C3, C4, C5, C6, C7, C8, C9, and C 10The term is intended to include alkyl groups. Alkyl groups may be unsubstituted or substituted, with at least one hydrogen atom being replaced by another chemical group. Examples of 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).

[0069] A "heteroalkyl group" is an alkyl group in which one or more carbon atoms are replaced by heteroatoms such as O, N, or S. For example, when the carbon atoms of an alkyl group bonded to a parent molecule are replaced by heteroatoms (e.g., O, N, or S), the resulting heteroalkyl group is an alkoxy group (e.g., -OCH3), an amine (e.g., -NHCH3, -N(CH3)2), or a thioalkyl group (e.g., -SCH3), respectively. When the non-terminal carbon atoms of an alkyl group not bonded to a parent molecule are replaced by heteroatoms (e.g., O, N, or S), the resulting heteroalkyl group is an alkyl ether (e.g., -CH2CH2-O-CH3), an alkylamine (e.g., -CH2NHCH3, -CH2N(CH3)2), or a thioalkyl ether (e.g., -CH2-S-CH3), respectively. When the terminal carbon atoms of an alkyl group are replaced by heteroatoms (e.g., O, N, or S), the resulting heteroalkyl groups are, respectively, hydroxyalkyl groups (e.g., -CH2CH2-OH), aminoalkyl groups (e.g., -CH2NH2), or alkylthiol groups (e.g., -CH2CH2-SH). Heteroalkyl groups can have, for example, 1 to 20 carbon atoms, 1 to 10 carbon atoms, or 1 to 6 carbon atoms. A C1-C6 heteroalkyl group refers to a heteroalkyl group having 1 to 6 carbon atoms.

[0070] "Alkenyl" or "alkenylene" is intended to represent a hydrocarbon chain, either linear or branched, having a specific number of carbon atoms and one or more, preferably 1-2, carbon-carbon double bonds that may occur at any stable point along the chain. For example, "C 2-6 An "alkenyl" (or alkenylene) is intended to contain C2, C3, C4, C5, and C6 alkenyl groups. Examples of alkenyls include, but are not limited to, 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.

[0071] "Alkynyl" or "Alkynylene" is intended to include a hydrocarbon chain in either a linear or branched configuration, having one or more, preferably 1 to 3, carbon-carbon triple bonds, which may occur at any stable point along the chain. For example, "C 2-6 "Alkynyl" (or alkynylene) is intended to include C2, C3, C4, C5, and C6 alkynyl groups; for example, ethynyl, propynyl, butynyl, pentynyl, and hexynyl.

[0072] As used herein, "arylalkyl" refers to carbon atoms (typically terminal or sp). 3 An acyclic alkyl group is defined as a group in which one of the hydrogen atoms bonded to a carbon atom is replaced by an aryl group. Typical arylalkyl groups include, but are not limited to, benzyl, 2-phenylethane-1-yl, naphthylmethyl, 2-naphthylethane-1-yl, naphthobenzyl, and 2-naphthophenylethane-1-yl. An arylalkyl group can contain 7 to 20 carbon atoms; for example, the alkyl group may have 1 to 6 carbon atoms and the aryl group may have 6 to 14 carbon atoms.

[0073] As used herein, the term "benzyl" refers to a methyl group in which one hydrogen atom is replaced by a phenyl group, and the phenyl group can be appropriately substituted with groups having 1 to 5 phenyl groups, preferably 1 to 3 phenyl 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 by the formula "Bn".

[0074] The terms "lower alkoxy," "alkoxy," or "alkyloxy," "aryloxy," or "aralkoxy" refer to any of the alkyl, aralkyl, or aryl groups bonded to an oxygen atom. "C1-C6 alkoxy" or "C 1-6 "Alkoxy" (or alkyloxy) is intended to include C1, C2, C3, C4, C5, and C6 alkoxy groups. Examples of 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" represent the alkyl, aryl, or aralkyl groups defined above, in which the indicated number of carbon atoms are bonded via sulfur bridges; for example, methyl-S- and ethyl-S-.

[0075] As used herein, the terms "halogen" or "halo," either alone or as part of another group, refer to chlorine, bromine, fluorine, and iodine, with chlorine or fluorine being preferred.

[0076] "Haloalkyl" is intended to include both branched and straight saturated aliphatic hydrocarbon groups having a specific number of carbon atoms, substituted with one or more halogens. "C1-C6 haloalkyl" or "C 1-6"Haloalkyl" (or "haloalkyl") is intended to include C1, C2, C3, C4, C5, and C6 haloalkyl groups. Examples of haloalkyl groups include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl, 2,2,2-trifluoroethyl, heptafluoropropyl, and heptachloropropyl. Another example of a haloalkyl group is "fluoroalkyl," which is intended to include both branched and linear saturated aliphatic hydrocarbon groups having a specific number of carbon atoms, substituted with one or more fluorine atoms. As used herein, "polyhaloalkyl" means a polyfluoroalkyl group, e.g., CF3CH2, CF3, or CF3CF2CH2, as defined above, substituted with 2 to 9, preferably 2 to 5, halo substituents, e.g., F or Cl, preferably F.

[0077] A "haloalkoxy" or "haloalkyloxy" refers to a haloalkyl group as defined above, in which the indicated number of carbon atoms are bonded via oxygen crosslinks. For example, "C 1-6 "Haloalkoxy" is intended to include C1, C2, C3, C4, C5, and C6 haloalkoxy groups. Examples of haloalkoxys include, but are not limited to, trifluoromethoxy, 2,2,2-trifluoroethoxy, and pentafluoroethoxy. Similarly, "haloalkylthio" or "thiohaloalkoxy" refers to the haloalkyl groups defined above, in which the indicated number of carbon atoms are bonded via sulfur bridges; for example, trifluoromethyl-S- and pentafluoroethyl-S-. As used herein, the term "polyhaloalkyloxy" refers to the "alkoxy" or "alkyloxy" groups defined above, such as polyfluoroalkoxys, e.g., CF3CH2O, CF3O, or CF3CF2CH2O, which are substituted with 2 to 9, preferably 2 to 5, halo substituents, e.g., F or Cl, preferably F.

[0078] "Hydroxyalkyl" is intended to include both branched and linear saturated aliphatic hydrocarbon groups having a specific number of carbon atoms, substituted with one or more hydroxyl (OH) groups. For example, "C 1-6 "Hydroxyalkyl" (or hydroxyalkyl) is intended to include C1, C2, C3, C4, C5, and C6 hydroxyalkyl groups.

[0079] The term "cycloalkyl" refers to a cyclic alkyl group, including monocyclic, bicyclic, or polycyclic systems. It can also refer to "C3-C7 cycloalkyl" or "C 3-7 The term "cycloalkyl" is intended to include C3, C4, C5, C6, and C7 cycloalkyl groups. Examples of 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".

[0080] As used herein, “carbocyclic,” “carbocyclyl,” or “carbocyclic formula” 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 dicyclic or tricyclic) hydrocarbon ring, which may be saturated or partially unsaturated. That is, the terms “carbocyclic,” “carbocyclyl,” or “carbocyclic formula” include, but are not limited to, cycloalkyl and cycloalkenyl. Examples of such carbocyclic compounds 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, crosslinking rings are also included in the definition of carbocyclic compounds (e.g., [2.2.2]bicyclooctane). Preferred carbocyclic compounds are, unless otherwise specified, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, indanyl, and tetrahydronaphthyl. Crosslinking rings are formed when one or more carbon atoms, preferably 1 to 3 carbon atoms, are bonded to two non-adjacent carbon atoms. Preferred bridges consist of one or two carbon atoms. It should be noted that bridges always transform a monocyclic ring into a tricyclic ring. When a ring is bridged, substituents described for the ring may also be included in the bridge.

[0081] Furthermore, the terms "carbocyclyl" as used herein, including "cycloalkyl" and "cycloalkenyl," either alone or as part of another group, include a saturated or partially unsaturated (containing one or two double bonds) cyclic hydrocarbon group comprising one to three rings, including monocyclic alkyl, bicyclic alkyl, and tricyclic alkyl groups, with a total of 3 to 20 carbon atoms forming the rings, preferably 3 to 10 carbon atoms forming the rings, and including cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, and cyclododecyl, and cyclohexenyl, any of which may be appropriately substituted with one to four substituents (e.g., halogen, alkyl, alkoxy, hydroxy, aryl, aryloxy, arylalkyl, cycloalkyl, alkylamide, alkanoylamino, oxo, acyl, arylcarbonylamino, nitro, cyano, thiol, and / or alkylthio, and / or any alkyl substituent).

[0082] As used herein, the term “bicyclic carbocyclic” or “bicyclic carbocyclic group” is intended to mean a stable nine- or ten-membered carbocyclic ring system consisting of two fused rings and carbon atoms. Of the two fused rings, the first ring is a benzo ring fused to the second ring; and the second ring is a saturated or partially unsaturated five- or six-membered carbocyclic ring. The bicyclic carbocyclic group can be bonded to its side chain group at any carbon atom that results in a stable structure. The bicyclic carbocyclic groups described herein can be substituted on any carbon if the resulting compound is stable. Examples of bicyclic carbocyclic groups include, but are not limited to, 1,2-dihydronaphthyl, 1,2,3,4-tetrahydronaphthyl, and indanyl.

[0083] As used herein, the term “aryl,” either 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 phenantranyl. The aryl portion is well known and is described, for example, in Lewis, RJ, ed., Hawley's Condensed Chemical Dictionary, 13th Edition, John Wiley & Sons, Inc., New York (1997). In some embodiments, the term “aryl” means monocyclic and bicyclic aromatic groups (e.g., phenyl, or naphthyl including 1-naphthyl and 2-naphthyl) containing 6 to 10 carbon atoms in the ring portion. For example, “C6 or C 10 "Aryl" refers to phenyl and naphthyl compounds.

[0084] As used herein, the terms “heterocycle,” “heterocyclyl,” or “heterocyclic group” are intended to mean stable 3-, 4-, 5-, 6-, or 7-membered monocycles or 5-, 6-, 7-, 8-, 9-, 10-, 11-, 12-, 13-, or 18-membered polycyclic (including dicyclic and tricyclic) heterocycles that are saturated or partially unsaturated and contain a carbon atom and one, two, three, or four heteroatoms independently selected from N, O, and S, and include any polycyclic group in which any of the heterocyclic rings defined above is fused to a carbocyclic or aryl (e.g., benzene) ring. That is, the terms “heterocycle,” “heterocyclyl,” or “heterocyclic group” include non-aromatic ring systems such as heterocycloalkyls and heterocycloalkenyls. The nitrogen and sulfur heteroatoms may be oxidized as appropriate (i.e., N → O and S(O)p, where p is 0, 1, or 2). The nitrogen atom may be substituted or unsubstituted (i.e., N or NR, where R is H or another substituent, if defined). The heterocycle may be bonded to its side chain group with any heteroatom or carbon atom that results in a stable structure. The heterocycles described herein may be substituted with carbon or nitrogen atoms if the resulting compound is stable. The nitrogen of the heterocycle may be quaternized as appropriate. If the total number of S and O atoms in the heterocycle is greater than 1, it is preferable that these heteroatoms are not adjacent to each other. It is preferable that the total number of S and O atoms in the heterocycle is 1 or less. Examples of heterocyclils include, but are not limited to, azetidinyl, piperazinyl, piperidinyl, piperidonyl, piperonyl, pyranyl, morpholinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, morpholinyl, and dihydroflu[2,3-b]tetrahydrofuranyl.

[0085] As used herein, the terms “bicyclic heterocycle” or “bicyclic heterocyclic group” are intended to mean a stable nine- or ten-membered heterocyclic system comprising two fused rings, consisting of a carbon atom and one, two, three, or four heteroatoms independently selected from N, O, and S. Of the two fused rings, one ring is a five- or six-membered monocyclic aromatic ring containing a five-membered heteroaryl ring, a six-membered heteroaryl ring, or a benzo ring, each fused to the second ring. The second ring is saturated, partially unsaturated, or unsaturated, and is a five- or six-membered monocyclic ring containing a five-membered heterocycle, a six-membered heterocycle, or a carbocyclic ring (provided that if the second ring is a carbocyclic ring, the first ring is not benzo).

[0086] Bicyclic heterocyclic groups can be bonded to their side chain groups with any heteroatom or carbon atom that results in a stable structure. Bicyclic heterocyclic groups described herein may be substituted on carbon or nitrogen atoms if the resulting compound is stable. If the total number of S and O atoms in the heterocycle is greater than 1, it is preferable that these heteroatoms are not adjacent to each other. It is preferable that the total number of S and O atoms in the heterocycle is 1 or less. Examples of bicyclic heterocyclic groups include, but are not limited to, 1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, 5,6,7,8-tetrahydro-quinolinyl, 2,3-dihydro-benzofuranyl, chromanil, 1,2,3,4-tetrahydro-quinoxalinyl, and 1,2,3,4-tetrahydro-quinazolinyl.

[0087] A bridging ring is also included in the definition of a heterocycle. A bridging ring occurs when one or more atoms, preferably 1 to 3 atoms (i.e., C, O, N, or S), bond to two non-adjacent carbon or nitrogen atoms. Examples of bridging 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 should be noted that bridging always transforms a monocycle into a tricycle. When a ring is bridging, substituents described for the ring may also be included in the bridging.

[0088] As used herein, the term “heteroaryl” is intended to mean stable monocyclic and polycyclic (including bicyclic and tricyclic) aromatic hydrocarbons containing at least one heteroatom ring member (e.g., sulfur, oxygen, or nitrogen). Heteroaryl groups include, but are not limited to, pyridyl, pyrimidinyl, pyrazinyl, pyridadinyl, triazinyl, furyl, quinolyl, isoquinolyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrroyl, oxazolyl, benzofuryl, benzothienyl, benzthiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1,2,4-thiadiazolyl, isothiazolyl, prinyl, carbazolyl, benzimidazolyl, indolinyl, benzodioxolanil, and benzodioxane. Heteroaryl groups may be substituted or unsubstituted. The nitrogen atom is substituted or unsubstituted (i.e., N or NR, where R is H, or another substituent, if defined). The nitrogen and sulfur heteroatoms may be oxidized as appropriate (i.e., N → O and S(O)p, where p is 0, 1, or 2).

[0089] Examples of heteroaryls include, but are not limited to, acridinil, azosinil, benzimidazolyl, benzofuranil, benzothiofuranil, benzothiophenyl, benzoxazolyl, benzoxazolinil, benzthiazolyl, benztriazolyl, benztetrazolyl, benzoisoxazolyl, benzisothiazolyl, benzimidazolinil, carbazolyl, 4aH-carbazolyl, carborinil, chromanil, clomenil, sinnolinil, decahydroquinolinil, 2H,6H-1,5,2-dithiadinyl. Furacil, Flazanil, Imidazolidinil, Imidazolinil, Imidazolyl, 1H-Indazolyl, Imidazolopyridinil, Indrenyl, Indolinyl, Indolidinil, Indolyl, 3H-Indolyl, Isatinoyl, Isobenzofuranil, Isochromanil, Isoindazolyl, Isoindolinyl, Isoindolyl, Isoquinolinil, Isothiazolyl, Isothiazolopyridinil, Isoxazolyl, Isoxazolopyridinil, Methylenedioxyphenyl, Naphthyridinil, Octahydroisoquinolinil, Oxad Azolyl, 1,2,3-Oxadiazolyl, 1,2,4-Oxadiazolyl, 1,2,5-Oxadiazolyl, 1,3,4-Oxadiazolyl, Oxazolidinyl, Oxazolyl, Oxazolopyridinyl, Oxazolidinylperimidinyl, Oxioindolyl, Pyrimidinyl, Phenanthrolinyl, Phenanthrolinyl, Phenadinyl, Phenothiazinyl, Phenoxathiazinyl, Phenoxadinyl, Phthalazinyl, Pteridinyl, Prinyl, Pyrazinyl, Pyrazolidinyl, Pyrazolinyl, Pyrazolopyridinyl, Pyrazoli Pyridazinyl, pyridooxazolyl, pyridoimidazolyl, pyridothiazolyl, pyridinyl, pyrimidinyl, pyrrolidinyl, pyrrolidinyl, 2-pyrrolidonyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolidinyl, quinoxalinyl, quinuclidinyl, tetrazolyl, tetrahydrofuranil, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-1,2,5-thiadiadinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,Examples include 4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thiazolopyridinyl, thienothiazolyl, thienoxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, and xanthenyl.

[0090] Examples of 5-10 member heteroaryls include, but are not limited to, pyridinyl, furanil, thienyl, pyrazolyl, imidazolyl, imidazolidinyl, indolyl, tetrazolyl, isoxazolyl, oxazolyl, oxadiazolyl, oxazolidinyl, thiadiadinyl, thiadiazolyl, thiazolyl, triazinyl, triazolyl, benzimidazolyl, 1H-indazolyl, benzofuranil, benzothiofuranil, benztetrazolyl, benzotriazolyl, benzoisoxazolyl, benzoxazolyl, oxyindolyl, benzoxazolinil, benzthiazolyl, benzisothiazolyl, isatinoyl, isoquinolinil, octahydroisoquinolinil, isoxazolopyridinyl, quinazolinil, quinolinil, isothiazolopyridinyl, thiazolopyridinyl, oxazolopyridinyl, imidazolopyridinyl, and pyrazolopyridinyl. Examples of 5-6 member heterocycles include, but are not limited to, pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, pyrazinyl, imidazolyl, imidazolidinyl, indolyl, tetrazolyl, isoxazolyl, oxazolyl, oxadiazolyl, oxazolidinyl, thiadiadinyl, thiadiazolyl, thiazolyl, triazinyl, and triazolyl.

[0091] When a carbocyclic or heterocyclic portion can bond to a specified substrate via different ring atoms without explicitly indicating a specific bonding site, or otherwise connect in any way, it is understood that all possible points, including carbon atoms or, for example, trivalent nitrogen atoms, are intended. For example, the term "pyridyl" means 2-, 3-, or 4-pyridyl, and the term "thienyl" means 2-, or 3-thienyl, etc.

[0092] When a dotted ring is used within a ring structure, this indicates that the ring structure may be saturated, partially saturated, or unsaturated.

[0093] If the bond to a substituent is shown to traverse a bond connecting two atoms in the ring, such substituent may bond to any atom in the ring. For example, if the ring has a bicyclic or tricyclic structure, such substituent may bond to any ring member atom of the bicyclic or tricyclic structure. If a substituent is listed without indicating which atom to which the substituent bonds to the rest of the compound in a given formula, such substituent may bond via any atom of the substituent. A combination of substituents and / or variable groups is permissible only if such combination results in a stable compound.

[0094] Those skilled in the art will recognize that substituents and other parts of the compounds of the present invention should be selected to provide compounds that are sufficiently stable to provide pharmaceutically useful compounds that can be formulated into pharmaceutical compositions that are stable to an acceptable degree. Compounds of the present invention having such stability are intended to be within the scope of the present invention.

[0095] The term "counterion" is used to describe negatively charged species such as chlorides, bromides, hydroxides, acetates, and sulfates. The term "metal ion" refers to alkali metal ions such as sodium, potassium, or lithium, as well as alkaline earth metal ions such as magnesium and calcium, and zinc and aluminum.

[0096] As used herein, the term “substitution” means that at least one hydrogen atom is replaced by a non-hydrogen group, provided that the normal valence is maintained and the substitution results in a stable compound. If the substituent is a keto (i.e., =O), also known as an “oxo,” which is a substituted oxygen atom bonded to another atom by a double bond, then two hydrogens on the atom are replaced. Keto substituents are not present in aromatic moieties. When a ring system (e.g., a carbocyclic or heterocyclic) is described as being substituted by a carbonyl group or a double bond, it means that the carbonyl group or double bond is part of the ring (i.e., intra-ring). As used herein, a ring double bond means a double bond formed between two adjacent ring atoms (e.g., C=C, C=N, or N=N).

[0097] If a nitrogen atom (e.g., an amine) is present in the compound of the present invention, it can be converted to an N-oxide by treatment with an oxidizing agent (e.g., mCPBA and / or hydrogen peroxide) to obtain other compounds of the present invention. Therefore, the indicated and claimed nitrogen atom is considered to include both the indicated nitrogen and its N-oxide (N→O) derivative.

[0098] If any variable group is present two or more times in any component or formula of a compound, the definition in each presence is independent of the definitions of all other presences. Therefore, for example, if a group is shown to be substituted with 0, 1, 2, or 3 R groups, the group is unsubstituted if it is substituted with 0 R groups, or if it is substituted with up to 3 R groups, and in each presence, R is independently selected from the definition of R.

[0099] Furthermore, combinations of substituents and / or variable groups are only permitted if such combinations result in a stable compound.

[0100] As used herein, the term "tautomer" refers to each of two or more isomers of a compound that exist in equilibrium and can be readily interchanged by the movement of atoms or groups within the molecule. For example, 1,2,3-triazole has two tautomer forms as defined above: [ka] Those skilled in the art will readily understand that it exists.

[0101] Therefore, this disclosure is intended to include all possible tautomers, even when only one structure is depicted.

[0102] The phrase “medically acceptable” means, as used herein, a compound, substance, composition, and / or dosage form that, within the bounds of sound medical judgment, is suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic response, and / or other problems or complications, and has a reasonable benefit / risk ratio.

[0103] The compounds of the present invention may exist as salts, and this is also within the scope of the invention. pharmaceutically acceptable salts are preferred. As used herein, “pharmaceutically acceptable salt” means a derivative of the disclosed compound in which the parent compound is modified by the formation of an acid or base salt thereof. pharmaceutically acceptable salts of the present invention can be synthesized from parent compounds containing a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base form of these compounds with an equivalent amount of a suitable base or acid in water, an organic solvent, or a mixture thereof; generally, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. A list of suitable salts is provided herein by reference in Remington's Pharmaceutical Sciences, 18th Edition, Mack Publishing Company, Easton, PA (1990).

[0104] If the compounds of the present invention have, for example, at least one basic center, they can form acid addition salts. These can be formed with, for example, inorganic strong acids such as mineral acids (e.g., sulfuric acid, phosphoric acid, or hydrohalic acid), unsubstituted or substituted (e.g., halogen-substituted, such as chloroacetic acid) 1-4 carbon atom alkane carboxylic acids (e.g., acetic acid), saturated or unsaturated dicarboxylic acids (e.g., oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, phthalic acid, or terephthalic acid), hydroxycarboxylic acids (e.g., ascorbic acid, glycolic acid, lactic acid, malic acid, tartaric acid, or citric acid), amino acids (e.g., aspartic acid or glutamic acid or lysine or arginine), or organic carboxylic acids such as benzoic acid, or unsubstituted or substituted (e.g., halogen-substituted) (C1-C4) alkyl or aryl sulfonic acids (e.g., methyl- or p-toluenesulfonic acid). If desired, corresponding acid addition salts having an additional basic center can also be formed. Compounds of the present invention having at least one acidic group (e.g., COOH) can also form salts with bases. Suitable salts with bases include, for example, metal salts such as alkali metal or alkaline earth metal salts (e.g., sodium, potassium, or magnesium salts), or salts with ammonia or organic amines such as morpholine, thiomorpholine, piperidine, pyrrolidine, mono, di, or tri lower alkylamines (e.g., ethyl, tert-butyl, diethyl, diisopropyl, triethyl, tributyl, or dimethyl-propylamine), or mono, di, or trihydroxy lower alkylamines (e.g., mono, di, or triethanolamine). Corresponding intramolecular salts may be further formed. Salts that are not suitable for pharmaceutical use may also be used, for example, for the isolation or purification of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof.

[0105] Preferred salts of the compound represented by formula (I) containing a basic group include monohydrochloride, bisulfate, methanesulfonate, phosphate, nitrate, or acetate.

[0106] Preferred salts of compounds represented by formula (I) containing an acidic group include sodium salts, potassium salts, and magnesium salts, as well as pharmaceutically acceptable organic amines.

[0107] Furthermore, the compounds of the present invention may have a prodrug form. Any compound that is converted in vivo to provide a bioactive agent, i.e., a compound represented by formula (I), is a prodrug that falls within the scope and essence of the present invention. The manufacture of prodrugs is well known in the art and is described, for example, in King, FD, 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, CG, ed., The Practice of Medicinal Chemistry, Academic Press, San Diego, CA (1999).

[0108] This invention is intended to include all isotopes of the atoms present in the compound. Isotopes include atoms with the same atomic number but different mass numbers. Common examples include, but are not limited to, deuterium and tritium as isotopes of hydrogen. The isotopes of carbon are 13 C and 14Contains C. The isotope-labeled compounds of the present invention can be prepared by methods similar to those of the prior art generally known to those skilled in the art or by methods described herein, using a suitable isotope-labeled reagent instead of the unlabeled reagent used in other cases. Such compounds have diverse potential uses, for example, as a reference or reagent for measuring the ability of a promising pharmaceutical compound to bind to a target protein or receptor, or for imaging of the compounds of the present invention bound to a biological receptor in vivo or in vitro.

[0109] "Stable compound" and "stable structure" refer to a compound that is robust enough to remain in the reaction mixture at a useful level of purity and in the formulation of an effective therapeutic agent. The compounds of the present invention preferably do not contain N-halo, S(O)2H, or S(O)H groups.

[0110] The term "solvate" refers to the physical association of a compound of the present invention with one or more solvent molecules, whether organic or inorganic. This physical association includes hydrogen bonding. The solvent molecules of a solvate may be in a regular and / or irregular arrangement. A solvate may contain equivalent or non-equivalent amounts of solvent molecules. "Solvate" encompasses both the solution phase and the isolateable solvate. Examples of solvates include, but are not limited to, hydrates, ethanolates, methanolates, and isopropanolates. Methods of solvation are generally known in the art.

[0111] The abbreviations used in this specification are as follows: "1×" means once, "2×" means twice, "3×" means three times, "℃" means degrees Celsius, "eq" means equivalent, "g" means gram, "mg" means milligram, "L" means liter, "mL" means milliliter, "μL" means microliter, "N" means normality, "M" means molar concentration, "mmol" means millimoles, "min" means minutes, "h" means hours, "rt" means room temperature, "RT" means retention time, "atm" means atmospheric pressure, "psi" means pounds per square inch, "concentrate" means concentrated, "sat" or "saturated" means saturated, "MW" means molecular weight, "mp" means melting point, "ee" means enantiomer excess, "MS" or "Mass Spec" means mass spectrometry, "ESI" means electrospray ionization mass spectrometry, "HR" means high resolution, "HRMS" means high resolution mass spectrometry, "LCMS" means liquid chromatography mass spectrometry, "HPLC" means high-performance liquid chromatography, "RP" means high-performance liquid chromatography. "HPLC" is reverse-phase HPLC, "TLC" or "tlc" is thin-layer chromatography, "NMR" is nuclear magnetic resonance spectroscopy, "nOe" is nuclear Overhauser effect spectroscopy, 1 "H" is defined as a proton, "δ" as a delta, "s" as a singlet, "d" as a doublet, "t" as a triplet, "q" as a quadrant, "m" as a multiplet, "br" as a broadband, "Hz" as Hertz, and "α", "β", "R", "S", "E", and "Z" as defined in stereochemical specifications well known to those skilled in the art. [Table 1] [Table 2]

[0112] (IV.Biology) The inhibitory activity of compounds against SGK1 was measured using the following assays. The potency of SGK inhibitors was measured using homogeneous time-resolved fluorescence (HTRF) assays and time-resolved FRRT-based competitive binding assays. SGK1 in a 1 nM GST-tagged form, manufactured by BMS, was incubated for 1 hour with a 0.2 nM Tb-labeled anti-GST detection antibody (Cis-Bio, MA), the test compound, and a fluorescein-labeled ATP antagonist probe at a concentration corresponding to the probe's equilibrium dissociation constant. Fluorescence at 495 nm and 520 nm was measured using an EnVision microplate reader to quantify the FRET between the Tb-labeled detection antibody and the fluorescein-labeled probe (specifically designed for SGK1 as an energy transfer receptor). The FRET ratio, excluding background noise, was normalized to the maximum signal obtained in the absence of the test compound. These values ​​were converted to inhibition rates. Inhibition rates were measured for 11 different concentrations of the test compound. IC was defined as the concentration of the competing test compound required to reduce the probe's specific binding by 50%. 50 This was calculated by fitting the data to the four-variable logistic equation y = A + ((BA) / (1 + ((C / x)^D))). Here, A and B represent the minimum and maximum inhibition rates, respectively, and C is IC. 50 D represents the hill slope, and x represents the concentration of the compound.

[0113] Representative examples were tested using the SGK1 assay described above, and it was found that they possess SGK1 inhibitory activity. 50 The values ​​are shown in Table A below. [Table 3] [Table 4]

[0114] (V. Pharmaceutical compositions, formulations, and combinations) The compounds of the present invention can be administered in oral dosage forms such as tablets, capsules (including sustained-release or time-controlled-release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions. They can also be administered intravenously (bolus or infusion), intraperitoneally, subcutaneously, or intramuscularly using dosage forms well known to those skilled in the pharmaceutical art. They can be administered alone, but are generally administered with a pharmaceutical carrier selected based on the chosen route of administration and standard formulation techniques.

[0115] The term “pharmaceutical composition” means a composition comprising the compound of the present invention in combination with at least one additional pharmaceutically acceptable carrier. “pharmaceutically acceptable carrier” means a medium generally accepted in the art for delivering a biological agent to an animal, in particular a mammal, depending on the method of administration and dosage form, i.e., a medium containing an adjuvant, excipient, or vehicle (e.g., diluents, preservatives, fillers, flow regulators, disintegrants, wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, fragrances, antibacterial agents, antifungal agents, lubricants, and dispersants).

[0116] Medicinally acceptable carriers are formulated based on many factors well within the knowledge of those skilled in the art. These include, but are not limited to, the type and nature of the activator being formulated; the patients to whom the drug-containing composition is administered; the intended route of administration of the composition; and the targeted therapeutic indication. Medicinally acceptable carriers include both aqueous and non-aqueous liquid media, as well as a variety of solid and semi-solid dosage forms. Such carriers may contain many different components and excipients added to the activator, and such additional components are included in the formulation for a variety of reasons, such as activator stabilization, binding, etc., which are well known to those skilled in the art. Suitable pharmaceutically acceptable carriers and the factors relating to their selection are described in various readily available sources, such as Remington's Pharmaceutical Sciences, 18th Edition (1990).

[0117] The administration regimen of the compounds of the present invention will naturally vary depending on known factors such as the pharmacodynamic characteristics of the particular drug and its method and route of administration; the recipient's species, age, sex, health status, medical condition, and weight; the nature and severity of the symptoms; the type of current treatment; the frequency of treatment; the route of administration, the patient's renal and hepatic function, and the desired effect. A physician or veterinarian can determine and prescribe the effective amount of drug necessary to prevent, treat, or halt the progression of the disorder.

[0118] As a general guideline, the daily oral dose of each active ingredient, when used for the indicated effect, is about 0.001 to about 1000 mg / kg body weight, preferably about 0.01 to about 100 mg / kg body weight per day, and most preferably about 0.1 to about 20 mg / kg / day. Intravenously, the most preferred dose is in the range of about 0.001 to about 10 mg / kg / min via constant-rate infusion. The compounds of the present invention can be administered in a once-daily dose, or the total daily dose can be administered in two, three, or four divided doses per day.

[0119] The compounds of the present invention can also be administered parenterally (e.g., intravenously, intra-arterially, intramuscularly, or subcutaneously). In the case of intravenous or intra-arterial administration, the dose may be administered continuously or intermittently. Furthermore, formulations may be developed for intramuscular and subcutaneous delivery to ensure the gradual release of the active pharmaceutical ingredient.

[0120] The compounds of the present invention can be administered intranasally by topical use of a suitable intranasal medium, or via a transdermal route using a transdermal skin patch. When administered via a transdermal delivery system, the dosage is, of course, continuous rather than intermittent through the administration regimen.

[0121] The compounds are typically administered in a mixture with a suitable pharmaceutical diluent, excipient, or carrier (collectively referred to herein as pharmaceutical carrier) selected with respect to the intended dosage form, such as oral tablets, capsules, elixirs, and syrups, and in accordance with conventional pharmaceutical practices.

[0122] For example, for oral administration in tablet or capsule form, the active drug component may be combined with an orally and non-toxic, pharmaceutically acceptable inert carrier (e.g., lactose, starch, sucrose, glucose, methylcellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol, etc.); for oral administration in liquid form, the oral drug component may be combined with any orally and non-toxic, pharmaceutically acceptable inert carrier (e.g., ethanol, glycerol, water, etc.). Furthermore, if desired or necessary, suitable binders, lubricants, disintegrants, and colorants may 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, wax, etc. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, etc. The disintegrants include, but are not limited to, starch, methylcellulose, agar, bentonite, and xanthan gum.

[0123] The compounds of the present invention may also be administered in the form of liposome delivery systems such as small monolayer vesicles, macrolayer vesicles, and multilayer vesicles. Liposomes may be formed from various phospholipids such as cholesterol, stearylamine, or phosphatidylcholine.

[0124] The compounds of the present invention can be bound to soluble polymers as targetable drug carriers. Such polymers may include polyvinylpyrrolidone, pyran copolymers, polyhydroxypropyl methacrylamide-phenol, polyhydroxyethyl aspartamidophenol, or polyethylene oxide-polylysine substituted with palmitoyl residues. Furthermore, the compounds of the present invention can be bound to a class of biodegradable polymers useful for achieving controlled drug release, such as polylactic acid, polyglycolic acid, copolymers of polylactic acid and polyglycolic acid, polyepsilon caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacillates, and crosslinked or amphiphilic block copolymers of hydrogels.

[0125] Suitable dosage forms (pharmaceutical compositions) may contain approximately 1 milligram to 1000 milligrams of the active ingredient per dose unit. In these pharmaceutical compositions, the active ingredient is typically present in an amount of approximately 0.1 to 95% by weight based on the total weight of the composition.

[0126] Gelatin capsules may contain an active ingredient and a powder carrier (e.g., lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, etc.). Similar diluents may be used in the manufacture of compressed tablets. Both tablets and capsules may be manufactured as sustained-release products to provide sustained release of the drug over a period of time. Compressed tablets may be coated with a sugar or film to mask any unpleasant taste and protect the tablet from the atmosphere, or with an enteric coating for selective disintegration in the gastrointestinal tract.

[0127] Liquid dosage forms for oral administration may contain colorants and flavorings to enhance patient acceptance.

[0128] Generally, water, suitable oils, saline solutions, aqueous dextrose (glucose), and related sugar solutions and glycols (e.g., propylene glycol or polyethylene glycol) are suitable carriers for parenteral solutions. Solutions for parenteral administration preferably contain a water-soluble salt of the active ingredient, a suitable stabilizer, and, if necessary, a buffer. Antioxidants such as sodium bisulfite, sodium sulfite, or ascorbic acid are suitable stabilizers, either alone or in combination. Citric acid and its salts and sodium EDTA are also used. Furthermore, parenteral solutions may contain preservatives such as benzalkonium chloride, methyl- or propyl-paraben, and chlorobutanol.

[0129] The compounds of the present invention may be administered alone or in combination with one or more additional therapeutic agents. “Combined administration” or “combination therapy” means that the compounds of the present invention and one or more additional therapeutic agents are administered simultaneously to the mammal being treated. When administered in combination, each component may be administered simultaneously or sequentially at different time points in any order. Therefore, each component may be administered at sufficiently close, albeit at a distance, to provide the desired therapeutic effect.

[0130] The compounds of the present invention are also useful as reference compounds, such as quality standards or controls, in tests or assays related to SGK1 inhibition. Such compounds may be provided, for example, in commercially available kits for use in pharmaceutical research related to SGK1. For example, the compounds of the present invention can be used as a reference in an assay to compare compounds with known and unknown activities. This allows the experimenter to verify the proper conduct of the assay, and provides a standard for comparison, especially when the test compound is a derivative of a reference compound. When developing a new assay or protocol, the compounds of the present invention can be used to test its efficacy.

[0131] The present invention also encompasses products. Products as used herein are intended to include, but are not limited to, kits and packages. A product of the present invention includes (a) a first container; (b) a pharmaceutical composition disposed within the first container (where the composition comprises a first therapeutic agent comprising the 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 cardiovascular and / or inflammatory disorders (as defined above). In other embodiments, the package insert states that the pharmaceutical composition can be used in combination with a second therapeutic agent (as defined above) for the treatment of cardiovascular and / or inflammatory disorders. The product may further include (d) a second container, in which components (a) and (b) are disposed within the second container and component (c) is disposed within or outside the second container. Disposed within the first and second containers means that each container holds the item within its boundaries.

[0132] The first container is a container used for holding a pharmaceutical composition. This container may be for manufacturing, storage, transport, and / or individual / bulk sales. The first container is intended to include bottles, jars, vials, flasks, syringes, tubes (e.g., for cream formulations), or any other container used for manufacturing, holding, or distributing pharmaceuticals.

[0133] The second container is used to hold the first container and, as appropriate, the accompanying documentation. 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 accompanying documentation may be physically attached to the outside of the first container by tape, glue, staples, or other means of attachment, or it may be placed in the second container without any physical means of attachment to the first container. Alternatively, the accompanying documentation may be placed on the outside of the second container. When placed on the outside of the second container, it is preferable that the accompanying documentation is physically attached by tape, glue, staples, or other means of attachment. Alternatively, it may be adjacent to or in contact with the outside of the second container without physical attachment.

[0134] The package insert is a label, tag, marker, etc., that contains information relating to the pharmaceutical composition placed inside the first container. The information to be included is usually determined by the regulatory authority that has jurisdiction over the region where the product is sold (e.g., the U.S. Food and Drug Administration). Preferably, the package insert includes information on the indications for which the pharmaceutical composition is approved. The package insert may be made of any material on which a person can read the information contained therein. Preferably, the package insert is made of a printable material (e.g., paper, plastic, corrugated cardboard, foil, adhesive paper, or plastic) on which the desired information is formed (e.g., printed or transferred).

[0135] Other characteristics of the present invention will become apparent through the following description of the examples presented to illustrate the invention and not limiting it. The following examples were prepared, isolated, and characterized using the methods disclosed herein.

[0136] (VI. General synthesis including schemes) The compounds of the present invention can be prepared by numerous methods known to those skilled in the art of organic synthesis. General synthetic schemes for preparing the compounds of the present invention are described below. These schemes are for illustrative purposes only and are not intended to limit the techniques that those skilled in the art may use to prepare the compounds of this disclosure.

[0137] As illustrated in Scheme 1, tert-butyl (R)-piperidine-3-ylcarbamate I is reacted with 2-(bis(methylthio)methylene)malononitrile in the presence of a suitable solvent (e.g., EtOH) to obtain a malononitrile intermediate II. II is reacted with hydrazine in a suitable solvent (e.g., acetic acid) to obtain pyrazole derivative III. By reacting pyrazole derivative III with formimidamide acetate, piperidine derivative IV can be obtained. V can be obtained by reacting IV with a suitable boronic acid or halide in a suitable solvent using Chan-Lam coupling, Buchwald-Hartwig amination, or other suitable coupling conditions. VI can be obtained by Boc-deprotection with an acid (e.g., HCl), and VII can be obtained by coupling this with a suitable acid under standard amide coupling conditions. This may be further derivatized depending on the properties of R1. For example, if R1 contains an amine, the corresponding aminoalkylated derivative can be obtained by reductive amination using a suitable aldehyde or ketone. [ka]

[0138] Alternatively, intermediate V may be prepared from 3-bromo-1H-pyrazolo[3,4-d]pyrimidine-4-amine (VIII) as shown in Scheme 2. VIII and R2-X are reacted with a suitable base (e.g., Cs2CO3) in a SNAr reaction to obtain intermediate IX. Alternatively, intermediate IX can be obtained by N-arylation of VIII via Chan-Lam coupling or Buchwald-Hartwig coupling. Intermediate IX is reacted with tert-butyl(R)-piperidine-3-ylcarbamate I at high temperature in a solvent (e.g., NMP) to obtain intermediate V. Intermediate V can be further synthesized to obtain VII as described in Scheme 1. [ka]

[0139] The compounds of the present invention can be synthesized by using the following methods in conjunction with synthetic methods known in the field of synthetic organic chemistry, or by modifications thereof as recognized by those skilled in the art. Preferred methods include, but are not limited to, those described below. The reaction is carried out in a solvent or solvent mixture suitable for the reagents and substances used and suitable for the transformation to be carried out. It is understood by those skilled in organic synthesis that the functional groups contained in the molecule should match the proposed transformation. This may require judgment to modify the order of the synthetic steps or to select a particular method scheme rather than another method scheme in order to obtain the desired compound of the present invention.

[0140] Another major concern in planning any synthetic route in this field is the wise selection of protecting groups to be used to protect the reactive functional groups contained in the compounds described herein. An authoritative book that explains many options to trained practitioners is Greene et al. (Protective Groups in Organic Synthesis, 4th Edition, Wiley-Interscience (2006)).

[0141] 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 for 3 minutes; Temperature: 50°C; Flow rate: 1.1 mL / min; Detection: 220 nm UV. Method B: Column: XBridge BEH XP C18 (50x2.1) mm, 2.5 μm; Mobile phase A: 0.1% TFA / water, acetonitrile (95:5); Mobile phase B: 0.1% TFA / water, acetonitrile (5:95); Gradient = 0-100% B for 3 minutes; Temperature: 50°C; Flow rate: 1.1 mL / min; Detection: 220 nm UV.

[0142] Preparation of intermediate 1. Lithium 4-(((1S,4S)-4-((tert-butoxycarbonyl)amino)cyclohexyl)oxy)-2-methylthiazole-5-carboxylate [ka]

[0143] Intermediate 1A. Ethyl 4-(((1S,4S)-4-((tert-butoxycarbonyl)amino)cyclohexyl)oxy)-2-methylthiazole-5-carboxylate [ka] 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) / THF (100 mL) were stirred together, and DIAD (23.9 mL, 123 mmol) was added. After stirring at room temperature for 2 hours, the mixture was concentrated, and the resulting residue was purified by silica gel chromatography (330 g column, eluted using 0-100% siRNA / petroleum ether; compounds eluted at 28-30%) to obtain intermediate 1A (13.5 g, 42% yield) as a white solid. MS:[M+H] + = 385.15. 1 ¹H NMR (400MHz, 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=7.0Hz, 6H).

[0144] Intermediate 1. Lithium 4-(((1S,4S)-4-((tert-butoxycarbonyl)amino)cyclohexyl)oxy)-2-methylthiazole-5-carboxylate [ka] Intermediate 1A (6.0 g, 15.6 mmol) was mixed with ethanol (20 mL), THF (30 mL), and water (10 mL). LiOH.H2O (1.12 g, 46.8 mmol) was added to this stirred solution. After stirring at room temperature for 5 hours, the mixture was evaporated to obtain intermediate 1 (6.7 g, 95% yield) as an off-white solid. MS:[MH] + =355.0.

[0145] Preparation of Intermediate 2. Lithium 5-(difluoromethyl)-3-(((1R,3s,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl)oxy)thiophene-2-carboxylate [ka]

[0146] Intermediate 2A. Methyl 5-(difluoromethyl)-3-(((1R,3s,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl)oxy)thiophene-2-carboxylate [ka] Similar to the preparation of intermediate IA, intermediate 2A (2 g, 84% yield) was obtained as a yellow solid by the 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). MS:[M+H] + = 332.1.

[0147] Intermediate 2. Lithium 5-(difluoromethyl)-3-(((1R,3s,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl)oxy)thiophene-2-carboxylate [ka] Similar to the preparation of intermediate 1, intermediate 2 (800 mg, 93% yield) was obtained as a pale yellow solid by the 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). MS:[M+H] + = 318.3.

[0148] Intermediate 3. Preparation of lithium 4-((4-(azetidine-1-yl)cyclohexyl)oxy)-2-methylthiazole-5-carboxylate [ka]

[0149] Intermediate 3A. Ethyl 4-((4-(azetidine-1-yl)cyclohexyl)oxy)-2-methylthiazole-5-carboxylate [ka] To a stirred solution of ethyl 2-methyl-4-((4-oxocyclohexyl)oxy)thiazole-5-carboxylate (2.0 g, 7.06 mmol) / THF (5 mL), azetidine (2.38 mL, 35.3 mmol) was added, followed by titanium(IV) isopropoxide (4.18 mL, 14.1 mmol). After stirring at room temperature for 16 hours, NaBH4 (0.401 g, 10.6 mmol) was added to the reaction mixture, and stirring was continued for a further 2 hours. The mixture was concentrated and purified by flash chromatography (120 g silica gel column, 0-20% methanol / DCM). SFC separation yielded the intermediate 3A ethyl 4-((4-(azetidine-1-yl)cyclohexyl)oxy)-2-methylthiazole-5-carboxylate (isomer-1, 500 mg, 22% yield) as a yellow viscous solid (MS: [M+H]). + =325.1) and ethyl 4-((4-(azetidine-1-yl)cyclohexyl)oxy)-2-methylthiazole-5-carboxylate (isomer-2, 120 mg, 5% yield) as a yellow viscous solid (MS:[M+H] + =325.1) was obtained. Isomer-1 was used in the next step.

[0150] Intermediate 3. Lithium 4-((4-(azetidine-1-yl)cyclohexyl)oxy)-2-methylthiazole-5-carboxylate [ka] Similar to the preparation of intermediate 1, lithium 4-((4-(azetidine-1-yl)cyclohexyl)oxy)-2-methylthiazole-5-carboxylate (420 mg, 90% yield) was obtained as a white solid by the reaction of ethyl 4-((4-(azetidine-1-yl)cyclohexyl)oxy)-2-methylthiazole-5-carboxylate (420 mg, 90% yield) with lithium hydroxide hydrate (129 mg, 3.08 mmol). MS:[M+H] + =297.1.

[0151] Intermediate 4. Preparation of lithium 5-chloro-3-(2-(dimethylamino)ethoxy)thiophene-2-carboxylate [ka]

[0152] Intermediate 4A. Methyl 5-chloro-3-(2-(dimethylamino)ethoxy)thiophene-2-carboxylate [ka] Similar to the preparation of intermediate 1A, intermediate 4A (1.0 g, 49% yield) was obtained as a yellow solid by the reaction of methyl 5-chloro-3-hydroxythiophene-2-carboxylate (1.5 g, 7.79 mmol), 2-(dimethylamino)ethane-1-ol (0.694 g, 7.79 mmol), triphenylphosphine (2.45 g, 9.35 mmol), and DIAD (1.67 mL, 8.57 mmol). MS:[M+H] + = 264.2. 1 H NMR (500MHz, 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).

[0153] Intermediate 4. Lithium 5-chloro-3-(2-(dimethylamino)ethoxy)thiophene-2-carboxylate [ka] Similar to the preparation of intermediate 1, intermediate 4 (420 mg, 96% yield) was obtained as an off-white solid by the reaction of methyl 5-chloro-3-(2-(dimethylamino)ethoxy)thiophene-2-carboxylate (460 mg, 1.74 mmol) and LiOH (3.5 mL, 1 M aqueous solution, 3.49 mmol). MS:[M+H] + = 250.2.

[0154] Intermediate 5. Preparation of lithium 2-methyl-4-(((1s,4s)-4-(pentan-3-ylamino)cyclohexyl)oxy)thiazole-5-carboxylate [ka]

[0155] Intermediate 5A. Ethyl 4-(((1s,4s)-4-aminocyclohexyl)oxy)-2-methylthiazole-5-carboxylate.HCl [ka] 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) / DCM (20 mL), 4N HCl / dioxane (24.7 mL, 99 mmol) was added. After stirring at room temperature for 2 hours, the mixture was evaporated to obtain intermediate 5A (6.3 g, 99% yield). MS:[M+H] + = 285.2.

[0156] Intermediate 5B. Ethyl 2-methyl-4-(((1s,4s)-4-(pentan-3-ylamino)cyclohexyl)oxy)thiazole-5-carboxylate [ka] To a stirred solution of ethyl 4-(((1s,4s)-4-aminocyclohexyl)oxy)-2-methylthiazole-5-carboxylate, HCl (6.3 g, 19.6 mmol) / MeOH (50 mL), sodium borohydride (7.40 g, 118 mmol), acetic acid (1.12 mL, 19.64 mmol), and pentane-3-one (33.8 g, 393 mmol) were added. After stirring at room temperature for 3 hours, the mixture was partitioned between water (200 mL) and ethyl acetate (250 mL). The organic layer was dried over sodium sulfate and concentrated. The crude product was purified by flash chromatography (40 g column; eluent: 1-20% MeOH / DCM) to obtain intermediate 5B (5.5 g, 79% yield) as a pale yellow oil. MS:[M+H] + = 355.1.

[0157] Intermediate 5. Lithium 2-methyl-4-(((1s,4s)-4-(pentan-3-ylamino)cyclohexyl)oxy)thiazole-5-carboxylate [ka] Similar to the preparation of intermediate 1, intermediate 5 (5 g, 90% yield) was obtained by the reaction of ethyl 2-methyl-4-(((1s,4s)-4-(pentan-3-ylamino)cyclohexyl)oxy)thiazole-5-carboxylate (5.5 g, 15.5 mmol) with LiOH (1.12 g, 46.5 mmol). MS:[M+H] + = 327.1.

[0158] Example 1 Preparation of N-((R)-1-(4-amino-1-(4-(methylsulfonyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidine-3-yl)piperidine-3-yl)-4-(((1S,4S)-4-(dimethylamino)cyclohexyl)oxy)-2-methylthiazole-5-carboxamide [ka]

[0159] Example 1A. tert-butyl (R)-(1-(2,2-dicyano-1-(methylthio)vinyl)piperidine-3-yl)carbamate [ka] To a stirred solution of tert-butyl (R)-piperidine-3-ylcarbamate (11.8 g, 58.7 mmol) / anhydrous ethanol (100 mL), 2-(bis(methylthio)methylene)malononitrile (10 g, 58.7 mmol) was added at room temperature. The reaction mixture was heated at 85 °C for 6 hours. After cooling to room temperature and evaporating, Example 1A (20 g, 99% yield) was obtained as a yellow solid. 1 H NMR(400MHz,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.

[0160] Example 1B. tert-butyl (R)-(1-(3-amino-4-cyano-1H-pyrazole-5-yl)piperidine-3-yl)carbamate [ka] To a stirred solution of tert-butyl (R)-(1-(2,2-dicyano-1-(methylthio)vinyl)piperidine-3-yl)carbamate (19 g, 58.9 mmol) / anhydrous ethanol (60 mL), hydrazine monohydrate (9.25 mL, 295 mmol) was added at room temperature. After stirring for 4 hours, the reaction mixture was evaporated. The residue was diluted with water, and the resulting suspension was stirred for 5 minutes. The mixture was filtered, and the collected solid was dried under vacuum to obtain Example 1B (18.0 g, 90% yield) as an off-white solid. 1H NMR(400MHz,DMSO-d6)δ ppm 11.12-10.88(m,1H),6.81(br d,J=7.5Hz,1H),6.20-5.95(m,1H),3.57(br d,J=12.5Hz,2H),3.42(br d,J=7.0Hz,1H),2.62(br d,J=10.0Hz,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.

[0161] Example 1: C.tert-butyl (R)-(1-(4-amino-1H-pyrazolo[3,4-d]pyrimidine-3-yl)piperidine-3-yl)carbamate [ka] To a stirred solution of tert-butyl (R)-(1-(3-amino-4-cyano-1H-pyrazole-5-yl)piperidine-3-yl)carbamate (4.9 g, 16.0 mmol) / anhydrous ethanol (100 mL), formamidine acetate (16.65 g, 160 mmol) was added at room temperature. The reaction mixture was heated at 80 °C. After stirring for 16 hours, the mixture was cooled to room temperature and then diluted with water. The resulting suspension was stirred for 5 minutes. The suspension was filtered, the resulting solid was washed with water, and dried under vacuum to obtain Example 1C (5.2 g, 98% yield). 1 H NMR(400MHz,DMSO-d6)δ ppm 8.09(s,1H),7.03(br d,J=8.0Hz,1H),6.80(br d,J=8.5Hz,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.

[0162] Example 1: D. tert-butyl (R)-(1-(4-amino-1-(4-(methylsulfonyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidine-3-yl)piperidine-3-yl)carbamate [ka] To a stirred solution of tert-butyl (R)-(1-(4-amino-1H-pyrazolo[3,4-d]pyrimidine-3-yl)piperidine-3-yl)carbamate (500 mg, 1.50 mmol) and (4-(methylsulfonyl)phenyl)boronic acid (510 mg, 2.55 mmol) / anhydrous DCM (20 mL), pyridine (0.364 mL, 4.50 mmol) and copper(II)acetic acid (545 mg, 3.00 mmol) were added at room temperature. The reaction mixture was stirred under open air for 16 hours. The suspension was filtered through Celite, and the filtrate was concentrated. The crude product was purified by flash chromatography (with 55% ethyl acetate / petroleum ether as eluent) to obtain Example 1D (730 mg, 80% yield) as a pale yellow solid. MS:[M+H] + = 488.1.

[0163] Example 1E.(R)-3-(3-aminopiperidine-1-yl)-1-(4-(methylsulfonyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidine-4-amine [ka] To a stirred solution of tert-butyl (R)-(1-(4-amino-1-(4-(methylsulfonyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidine-3-yl)piperidine-3-yl)carbamate (730 mg, 1.50 mmol) / anhydrous DCM (15 mL), 4N HCl / dioxane (10 mL, 40.0 mmol) was added. After stirring for 2 hours, the reaction mixture was concentrated to obtain Example 1E (580 mg, 90% yield) as a brown solid. MS:[M+H] + = 388.2.

[0164] Example 1 F. tert-butyl ((1S,4S)-4-((5-(((R)-1-(4-amino-1-(4-(methylsulfonyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidine-3-yl)piperidine-3-yl)carbamoyl)-2-methylthiazole-4-yl)oxy)cyclohexyl)carbamate [ka] (R)-3-(3-aminopiperidine-1-yl)-1-(4-(methylsulfonyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidine-4-amine (530 mg, 1.37 mmol) / anhydrous DMF (8 mL) was stirred, to which 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) were added at room temperature. After stirring at room temperature for 16 hours, the resulting suspension was filtered by Celite, and the filtrate was concentrated. The crude product was purified by flash chromatography (with 5% methanol / chloroform as an eluent) to obtain Example 1F (990 mg, 80% yield) as a pale yellow semi-solid. MS:[M+H] + = 726.5.

[0165] Example 1: G.N-((R)-1-(4-amino-1-(4-(methylsulfonyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidine-3-yl)piperidine-3-yl)-4-(((1S,4S)-4-aminocyclohexyl)oxy)-2-methylthiazole-5-carboxamide [ka] To a stirred solution of tert-butyl ((1S,4S)-4-((5-(((R)-1-(4-amino-1-(4-(methylsulfonyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidine-3-yl)piperidine-3-yl)carbamoyl)-2-methylthiazole-4-yl)oxy)cyclohexyl)carbamate (300 mg, 0.413 mmol) / anhydrous DCM (3 mL), 4N HCl / dioxane (3 mL, 12 mmol) was added. The reaction mixture was stirred for 2 hours, then concentrated to obtain Example 1 G (260 mg, 60% yield) as a brown solid, which was used without further purification. MS:[M+H] + = 626.3.

[0166] Example 1 [ka] N-((R)-1-(4-amino-1-(4-(methylsulfonyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidine-3-yl)piperidine-3-yl)-4-(((1S,4S)-4-aminocyclohexyl)oxy)-2-methylthiazole-5-carboxamide (80 mg, 0.128 mmol) / anhydrous methanol (2 mL) was stirred, and formaldehyde (0.021 mL, 0.767 mmol) and sodium borohydride cyanohydride (48.2 mg, 0.767 mmol) were added at room temperature. After stirring for 16 hours, the suspension was filtered by Celite and the filtrate was concentrated. The crude product was purified by preparative HPLC to obtain Example 1 (9.5 mg, 11% yield). LC-MS method B: RT=0.99 min, [M+H] + = 654.3. 1 H NMR(400MHz,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=8.5Hz,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).

[0167] Examples 2 to 9 in Table 1 below were prepared in the same manner as the synthesis in Example 1. [Table 5] [Table 6] [Table 7] [Table 8]

[0168] Example 10. Preparation of N-((R)-1-(4-amino-1-(4-(methylsulfonyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidine-3-yl)piperidine-3-yl)-4-((4-(azetidine-1-yl)cyclohexyl)oxy)-2-methylthiazole-5-carboxamide [ka]

[0169] Example 10 A.R)-N-(1-(4-amino-1-(4-(methylsulfonyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidine-3-yl)piperidine-3-yl)-2-methyl-4-((4-oxocyclohexyl)oxy)thiazole-5-carboxamide [ka] (R)-3-(3-aminopiperidine-1-yl)-1-(4-(methylsulfonyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidine-4-amine (275 mg, 0.710 mmol) / anhydrous DMF (1.5 mL) was stirred and then 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) were added at room temperature. After stirring at room temperature for 4 hours, the mixture was diluted with ice water (5 mL). The resulting precipitate was filtered, the solid was collected and dried under vacuum to obtain Example 10A (380 mg, 43% yield) as a brown solid. MS:[M+H] + = 625.3.

[0170] Example 10 [ka] (R)-N-(1-(4-amino-1-(4-(methylsulfonyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidine-3-yl)piperidine-3-yl)-2-methyl-4-((4-oxocyclohexyl)oxy)thiazole-5-carboxamide (80 mg, 0.128 mmol) / anhydrous methanol (3 mL) was stirred, and azetidine (36.6 mg, 0.640 mmol) and sodium borohydride (24.2 mg, 0.640 mmol) were added at room temperature. The reaction mixture was stirred at room temperature for 12 hours and then concentrated. The residue was purified by preparative HPLC to obtain two isomers.

[0171] Example 10 (Isomer-1): (3.8 mg, 4% yield). LC-MS method A: 1.276, method B: RT=1.03min, [M+H] + = 663.3. 1H NMR (400MHz, DMSO-d6)δ ppm 8.55-8.48(m,2H),8.37(s,1H),8.12-8.01(m,2H),7.50(d,J=7.8Hz,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=7.4Hz,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).

[0172] Example 10 (opposite sex body-2) (4.5 mg, 5% yield). LC-MS Method A: 1.288, Method B: RT = 1.00 min, [M+H] + =663.3. (400MHz, 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=8.0Hz,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=6.8Hz,4H),2.60(s,3H),1.99-1.70(m,8H),1.68-1.48(m,4H),1.38-1.17(m,4H).

[0173] The synthesis method of Example 10 is the same as the preparation method of Examples 11 to 18 in Table 2 below.

[0174] Table 9 Table 10 Table 11 Table 12

[0175] Example 19 Preparation of N-((R)-1-(4-amino-1-(4-carbamoyl-3-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidine-3-yl)piperidine-3-yl)-4-(((1S,4S)-4-(isopropylamino)cyclohexyl)oxy)-2-methylthiazole-5-carboxamide [ka]

[0176] Example 19 A. tert-butyl (R)-(1-(4-amino-1-(4-cyano-3-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidine-3-yl)piperidine-3-yl)carbamate [ka] To a stirred solution of tert-butyl (R)-(1-(4-amino-1H-pyrazolo[3,4-d]pyrimidine-3-yl)piperidine-3-yl)carbamate (600 mg, 1.80 mmol) and (4-cyano-3-fluorophenyl)boronic acid (505 mg, 3.06 mmol) / anhydrous DCE (15 mL), pyridine (0.437 mL, 5.40 mmol) and copper(II)acetic acid (654 mg, 3.60 mmol) were added at room temperature. The reaction mixture was stirred under open air for 16 hours. The suspension was filtered through Celite. The filtrate was concentrated. The crude product was purified by flash chromatography (with 5% methanol / chloroform as eluent) to obtain Example 19A (610 mg, 75% yield) as a brown solid. 1H NMR(400MHz,DMSO-d6)δ ppm 8.42-8.34(m,2H),8.04(dd,J=7.5,8.5Hz,1H),7.85-7.41(m,2H),7.11-6.99(m,1H),3.79(br dd,J=3.0,8.0Hz,1H),3.45(br d,J=12.0Hz,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.

[0177] Example 19B. (R)-4-(4-amino-3-(3-aminopiperidine-1-yl)-1H-pyrazolo[3,4-d]pyrimidine-1-yl)-2-fluorobenzonitrile.HCl [ka] To a stirred solution of tert-butyl (R)-(1-(4-amino-1-(4-cyano-3-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidine-3-yl)piperidine-3-yl)carbamate (610 mg, 1.35 mmol) / anhydrous DCM (10 mL), 4N HCl / dioxane (5 mL, 20.0 mmol) was added at room temperature. After stirring for 2 hours, the reaction mixture was concentrated to obtain Example 19B (600 mg) as a brown solid. MS:[M+H] + = 353.1.

[0178] Example 19 C. tert-butyl ((1S,4S)-4-((5-(((R)-1-(4-amino-1-(4-cyano-3-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidine-3-yl)piperidine-3-yl)carbamoyl)-2-methylthiazole-4-yl)oxy)cyclohexyl)carbamate [ka] (R)-4-(4-amino-3-(3-aminopiperidine-1-yl)-1H-pyrazolo[3,4-d]pyrimidine-1-yl)-2-fluorobenzonitrile (600 mg, 1.70 mmol) / anhydrous DMF (8 mL) was stirred and at room temperature, to which 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) were added. After stirring for 16 hours, the mixture was filtered by Celite. The filtrate was concentrated, and the crude product was then purified by flash chromatography (with 5% methanol / chloroform as an eluent) to obtain Example 19C (850 mg, 54% yield) as a pale yellow semi-solid. MS:[M+H] + = 691.5.

[0179] Example 19 D. tert-butyl ((1S,4s)-4-((5-(((R)-1-(4-amino-1-(4-carbamoyl-3-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidine-3-yl)piperidine-3-yl)carbamoyl)-2-methylthiazole-4-yl)oxy)cyclohexyl)carbamate [ka] 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]pyrimidine-3-yl)piperidine-3-yl)carbamoyl)-2-methylthiazole-4-yl)oxy)cyclohexyl)carbamate (270 mg, 0.391 mmol) / DMSO (3 mL), 0.3 mL of aqueous NaOH solution and 30% hydrogen peroxide (0.44 mL, 3.91 mmol) were slowly added at room temperature. After stirring for 2 hours, water (10 mL) was added to obtain a suspension, which was filtered to obtain Example 19D (270 mg, 88% yield) as a solid. MS:[M+H] + = 709.3.

[0180] Example 19: E.N-((R)-1-(4-amino-1-(4-carbamoyl-3-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidine-3-yl)piperidine-3-yl)-4-(((1s,4S)-4-aminocyclohexyl)oxy)-2-methylthiazole-5-carboxamide.HCl [ka] 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]pyrimidine-3-yl)piperidine-3-yl)carbamoyl)-2-methylthiazole-4-yl)oxy)cyclohexyl)carbamate (270 mg, 0.381 mmol) / anhydrous DCM (2 mL), 4N HCl / dioxane (2.5 mL, 10.00 mmol) was added at room temperature. After stirring for 2 hours, the reaction mixture was concentrated, and the residue was triturated with diethyl ether to obtain Example 19E (230 mg, 99% yield). MS:[M+H] + = 609.3.

[0181] Example 19. N-((R)-1-(4-amino-1-(4-carbamoyl-3-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidine-3-yl)piperidine-3-yl)-4-(((1S,4S)-4-(isopropylamino)cyclohexyl)oxy)-2-methylthiazole-5-carboxamide [ka] Similar to the preparation in Example 1, Example 19 (1.1 mg, 1% yield) was obtained by reacting N-((R)-1-(4-amino-1-(4-carbamoyl-3-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidine-3-yl)piperidine-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 borohydride (46.5 mg, 0.739 mmol). LC-MS Method A: RT = 1.155 min, Method B: RT = 0.961 min, [M+H] + = 651.3. 1 H NMR(400MHz,DMSO-d6)δ ppm 8.34(s,1H),8.21-8.12(m,2H),7.85(t,J=8.6Hz,1H),7.64(br s,2H),7.37(br d,J=7.3Hz,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).

[0182] Examples 20-26 in Table 3 below were prepared in the same manner as the synthesis in Example 1.

[0183] [Table 13] [Table 14] [Table 15] [Table 16]

[0184] Example 27 Preparation of N-((R)-1-(4-amino-1-(2-methoxypyrimidine-4-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-yl)piperidine-3-yl)-4-(((1S,4S)-4-(dimethylamino)cyclohexyl)oxy)-2-methylthiazole-5-carboxamide [ka]

[0185] Example 27 A. tert-butyl (R)-(1-(4-amino-1-(2-methoxypyrimidine-4-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-yl)piperidine-3-yl)carbamate [ka] To a stirred solution of tert-butyl (R)-(1-(4-amino-1H-pyrazolo[3,4-d]pyrimidine-3-yl)piperidine-3-yl)carbamate (1.0 g, 3.00 mmol) / anhydrous DMF (20 mL), Cs2CO3 (1.96 g, 6.0 mmol) and 4-chloro-2-methoxypyrimidine (0.650 g, 4.50 mmol) were added at room temperature. The reaction mixture was stirred at 70°C for 16 hours. 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 obtain Example 27A (1.1 g, 50% yield) as a brown solid. MS:[M+H] + = 442.5.

[0186] Example 27B. (R)-3-(3-aminopiperidine-1-yl)-1-(2-methoxypyrimidine-4-yl)-1H-pyrazolo[3,4-d]pyrimidine-4-amine.HCl [ka] To a stirred solution of tert-butyl (R)-(1-(4-amino-1-(2-methoxypyrimidine-4-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-yl)piperidine-3-yl)carbamate (1.1 g, 2.49 mmol) / DCM (10 mL), 4N HCl / dioxane (6.23 mL, 24.9 mmol) was added at room temperature. After stirring for 1 hour, the mixture was concentrated and then triturated with diethyl ether to obtain Example 27B (850 mg, 50% yield) as a pale yellow semi-solid. MS:[M+H] + = 342.2.

[0187] Example 27 C. tert-butyl (4-((5-(((R)-1-(4-amino-1-(2-methoxypyrimidine-4-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-yl)piperidine-3-yl)carbamoyl)-2-methylthiazole-4-yl)oxy)cyclohexyl)carbamate [ka] (R)-3-(3-aminopiperidine-1-yl)-1-(2-methoxypyrimidine-4-yl)-1H-pyrazolo[3,4-d]pyrimidine-4-amine (400 mg, 1.17 mmol) / anhydrous DMF (8 mL) was stirred and then 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) were added at room temperature. After stirring for 16 hours, well-chilled water was added dropwise to obtain a suspension. The mixture was stirred for 5 minutes and then filtered. The collected solid was dried under vacuum to obtain Example 27C (400 mg, 25% yield) as a brown semi-solid. MS:[M+H] + = 680.6.

[0188] Example 27D.N-((R)-1-(4-amino-1-(2-methoxypyrimidine-4-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-yl)piperidine-3-yl)-4-(((1S,4S)-4-aminocyclohexyl)oxy)-2-methylthiazole-5-carboxamide.HCl [ka] To a stirred solution of tert-butyl ((1S,4S)-4-((5-(((R)-1-(4-amino-1-(2-methoxypyrimidine-4-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-yl)piperidine-3-yl)carbamoyl)-2-methylthiazole-4-yl)oxy)cyclohexyl)carbamate (350 mg, 0.515 mmol) / anhydrous DCM (2 mL), 4N HCl / dioxane (3 mL, 12 mmol) was added at room temperature. After 2 hours, the mixture was concentrated and then triturated with diethyl ether to obtain Example 27D (300 mg, 70% yield) as a pale yellow semi-solid. MS:[M+H] + = 580.3.

[0189] Example 27 [ka] Similar to the preparation in Example 1, Example 27 (4.1 mg, 5% yield) was obtained by reacting N-((R)-1-(4-amino-1-(2-methoxypyrimidine-4-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-yl)piperidine-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 borohydride (8.1 mg, 0.13 mmol). LC-MS method B: RT = 0.957 min, [M + H] + = 608.3. 1H NMR(400MHz,DMSO-d6)δ ppm 8.62(d,J=5.8Hz,1H),8.36(s,1H),8.05(d,J=5.8Hz,1H),7.39(br d,J=7.5Hz,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).

[0190] Examples 28-30 in Table 4 below were prepared in the same manner as the synthesis in Example 1.

[0191] [Table 17]

[0192] Example 31 Preparation of (R)-N-(1-(4-amino-1-(6-cyanopyridine-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-yl)piperidine-3-yl)-5-chloro-3-(2-(dimethylamino)ethoxy)thiophene-2-carboxamide [ka]

[0193] Example 31 A. tert-butyl (R)-(1-(4-amino-1-(6-cyanopyridine-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-yl)piperidine-3-yl)carbamate [ka] 5-Fluoropicolinonitrile (0.439 g, 3.60 mmol) and tert-butyl (R)-(1-(4-amino-1H-pyrazolo[3,4-d]pyrimidine-3-yl)piperidine-3-yl)carbamate (1.0 g, 3.0 mmol) / DMF (20 mL) were stirred together, and K2CO3 (1.66 g, 12.0 mmol) was added. The reaction mixture was heated at 70 °C for 8 hours. After cooling, the mixture was partitioned between water (50 mL) and ethyl acetate (2 x 50 mL). The organic layer was dried over sodium sulfate and concentrated to obtain Example 31A (1.2 g, 92% yield). MS:[M+H] + = 436.2.

[0194] Example 31B. (R)-5-(4-amino-3-(3-aminopiperidine-1-yl)-1H-pyrazolo[3,4-d]pyrimidine-1-yl)picolinonitrile [ka] Similar to the preparation procedure for Example 19B, Example 31B (200 mg, 86% yield) was obtained by reacting tert-butyl (R)-(1-(4-amino-1-(6-cyanopyridine-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-yl)piperidine-3-yl)carbamate (300 mg, 0.689 mmol) with 4N HCl / dioxane (1.72 mL, 6.89 mmol). The product was used in the next step without further purification. MS:[M+H] + = 336.3.

[0195] Example 31 [ka] Example 31 (12.9 mg, 14% yield) was obtained by the 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-aminopiperidine-1-yl)-1H-pyrazolo[3,4-d]pyrimidine-1-yl)picolinonitrile (50 mg, 0.149 mmol), similar to the preparation procedure for Example 19C. LC-MS method A: RT = 1.686 min, [M + H] + =567.1; 1 H NMR(400MHz,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).

[0196] Example 32 Preparation of (N-((R)-1-(4-amino-1-(6-cyanopyridine-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-yl)piperidine-3-yl)-5-(difluoromethyl)-3-(((1R,3s,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl)oxy)thiophene-2-carboxamide [ka] Example 32 (18.6 mg, 18% yield) was obtained by the 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-aminopiperidine-1-yl)-1H-pyrazolo[3,4-d]pyrimidine-1-yl)picolinonitrile (50 mg, 0.149 mmol), similar to the preparation procedure for Example 19C. LC-MS method A: RT = 1.341 min, [M + H] + =635.3;LC-MS method B: RT=1.217min, [M+H] + = 635.3. 1 H NMR(400MHz,DMSO-d6)δ ppm 9.74-9.65(m,1H),9.59(d,J=2.5Hz,1H),8.80(dd,J=2.6,8.6Hz,1H),8.35(s,1H),8.16(d,J=8.5Hz,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=2.9,11.6Hz,1H),3.16- 3.01(m,2H),2.69(d,J=5.0Hz,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).

[0197] Example 33 Preparation of N-((R)-1-(4-amino-1-(5-oxo-2,5-dihydrofuran-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-yl)piperidine-3-yl)-2-methyl-4-(((1s,4S)-4-(pentan-3-ylamino)cyclohexyl)oxy)thiazole-5-carboxamide [ka]

[0198] Example 33 A. tert-butyl (R)-(1-(4-amino-1-(5-oxo-2,5-dihydrofuran-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-yl)piperidine-3-yl)carbamate [ka] To a solution of tert-butyl (R)-(1-(4-amino-1H-pyrazolo[3,4-d]pyrimidine-3-yl)piperidine-3-yl)carbamate (500 mg, 1.50 mmol) and 5-oxo-2,5-dihydrofuran-3-yl trifluoromethanesulfonate (696 mg, 3.00 mmol) / DMF (5 mL), K2CO3 (415 mg, 3.00 mmol) was added. The mixture was stirred at 80°C for 16 hours. The reaction mixture was evaporated, and the residue was purified by flash chromatography (eluted with 0-100% Â / hexane) to obtain Example 33A (110 mg, 18% yield) as a yellow solid. MS:[M+H] + = 416.15. 1 H NMR(400MHz,DMSO-d6)δ ppm 8.37(s,1H),7.06(br d,J=7.5Hz,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=16.5Hz,1H),1.77(br s,3H),1.46(br d,J=12.0Hz,2H),1.38(s,9H).

[0199] Example 33B. (R)-4-(4-amino-3-(3-aminopiperidine-1-yl)-1H-pyrazolo[3,4-d]pyrimidine-1-yl)furan-2(5H)-one.HCl [ka] Similar to the preparation procedure for Example 19B, Example 33B (80 mg, 86% yield) was obtained as a yellow solid by reacting Example 33A (110 mg, 0.265 mmol) with 4N HCl (0.993 mL, 3.97 mmol). MS:[M+H]+ = 316.05.

[0200] Example 33 [ka] Similar to the preparation procedure for Example 19C, Example 33 (8.8 mg, 16% yield) was obtained as a pale yellow solid by reacting 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). LCMS method A: RT = 1.490 min, [M + H] + =624.3;LC-MS method B: RT=1.199min, [M+H] + = 624.3. 1 H NMR(400MHz,DMSO-d6)δ ppm 8.34(s,1H),8.09(br s,2H),7.19(d,J=7.3Hz,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=10.0Hz,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=3.1,7.4Hz,6H).

[0201] Example 34. N-((R)-1-(4-amino-1-(5-oxo-2,5-dihydrofuran-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-yl)piperidine-3-yl)-2-methyl-4-(((1s,4S)-4-(pentan-3-ylamino)cyclohexyl)oxy)thiazole-5-carboxamide [ka] Similar to the preparation of Example 19C, Example 34 (37.2 mg, 63% yield) was obtained as a pale yellow solid by the reaction of Example 33B (31.8 mg, 0.090 mmol) and lithium 4-((4-(azetidine-1-yl)cyclohexyl)oxy)-2-methylthiazole-5-carboxylate (30 mg, 0.099 mmol). LCMS method A: RT = 1.178 min, [M + H] + =594.3;LC-MS method B: RT=0.991min, [M+H] + = 594.3. 1 H NMR(400MHz,DMSO-d6)δ ppm 8.36(s,1H),7.42(br d,J=8.3Hz,1H),6.12(s,1H),5.42(s,2H),5.00(br d,J=1.8Hz,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).

[0202] Example 35. Preparation of N-((R)-1-(1-(1-acetyl-2,5-dihydro-1H-pyrrole-3-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidine-3-yl)piperidine-3-yl)-2-methyl-4-(((1s,4S)-4-(pentan-3-ylamino)cyclohexyl)oxy)thiazole-5-carboxamide [ka]

[0203] Example 35 A. tert-butyl (R)-(1-(1-(1-acetyl-2,5-dihydro-1H-pyrrole-3-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidine-3-yl)piperidine-3-yl)carbamate [ka] To a stirred solution of tert-butyl (R)-(1-(4-amino-1H-pyramido[3,4-d]pyrimidine-3-yl)piperidine-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-pyrrole-1-yl)ethane-1-one (853 mg, 3.60 mmol) / DCE (5 mL), pyridine (0.437 mL, 5.40 mmol) and copper(II)acetic acid (327 mg, 1.80 mmol) were added. After stirring at room temperature for 16 hours, the mixture was diluted with DCM (10 mL) and then filtered by Celite. The filtrate was evaporated. The residue was purified by flash chromatography (eluted using 0-100% Â / DCM) to obtain Example 35A (500 mg, 3% yield) as a yellow solid. MS:[M+H] + = 443.3.

[0204] Example 35B. (R)-1-(3-(4-amino-3-(3-aminopiperidine-1-yl)-1H-pyrazolo[3,4-d]pyrimidine-1-yl)-2,5-dihydro-1H-pyrrole-1-yl)ethane-1-one.HCl [ka] Similar to the preparation of Example 19B, Example 35B (280 mg, 96% yield) was obtained as a yellow solid by reacting Example 35A (300 mg) with 4N HCl. MS: [M+H] + = 343.2.

[0205] Example 35. N-((R)-1-(1-(1-acetyl-2,5-dihydro-1H-pyrrole-3-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidine-3-yl)piperidine-3-yl)-2-methyl-4-(((1s,4S)-4-(pentan-3-ylamino)cyclohexyl)oxy)thiazole-5-carboxamide [ka] Similar to the preparation of Example 19C, Example 35 (6.8 mg, 11% yield) was obtained as a pale yellow solid by the 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). LCMS method A: RT = 1.395 min, [M + H] + =651.3;LC-MS method B: RT=1.072min, [M+H] + = 651.3. 1 H NMR(400MHz,DMSO-d6)δ ppm 8.96(br s,1H),8.25(d,J=4.5Hz,1H),7.40(br d,J=7.8Hz,1H),6.26-6.12(m,1H),5.10(br d,J=1.0Hz,1H),4.86(br d,J=1.3Hz,1H),4.65(br s,1H),4.41(br s,1H),4.21(br d,J=2.8Hz,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=16.8Hz,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).

[0206] Example 36. (R)-N-(1-(1-(1-acetyl-2,5-dihydro-1H-pyrrole-3-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidine-3-yl)piperidine-3-yl)-4-((4-(azetidine-1-yl)cyclohexyl)oxy)-2-methylthiazole-5-carboxamide [ka] Similar to the preparation of Example 19C, Example 36 (14.1 mg, 22% yield) was obtained as a pale yellow solid by the reaction of Example 35B (37.6 mg, 0.099 mmol) and lithium 4-((4-(azetidine-1-yl)cyclohexyl)oxy)-2-methylthiazole-5-carboxylate (30 mg, 0.099 mmol). LCMS method A: RT = 1.129 min, [M + H] + =621.3;LC-MS method B: RT=1.129min, [M+H] + = 621.3. 1 H NMR(400MHz,DMSO-d6)δ ppm 8.26(d,J=4.0Hz,1H),7.50(br t,J=8.4Hz,1H),6.26-6.07(m,1H),5.02(br s,1H),4.86(br d,J=2.0Hz,1H),4.66(dd,J=1.5,4.0Hz,1H),4.41(br d,J=2.0Hz,1H),4.33-4.14(m,2H),3.23-3.17(m,3H),2.84(td,J=7.4,10.3Hz,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).

[0207] Example 37. Preparation of N-((3R)-1-(1-(1-acetylpyrrolidine-3-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidine-3-yl)piperidine-3-yl)-2-methyl-4-(((1s,4S)-4-(pentan-3-ylamino)cyclohexyl)oxy)thiazole-5-carboxamide [ka]

[0208] Example 37 A. tert-butyl ((3R)-1-(1-(1-acetylpyrrolidine-3-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidine-3-yl)piperidine-3-yl)carbamate [ka] To a solution of Example 35A (80 mg, 0.181 mmol) in methanol (2 mL), 192 mg of 50% wet Pd / C was added. The reaction mixture was stirred under H2 at room temperature for 20 hours and then filtered by Celite. The filtrate was concentrated to obtain Example 37A (40 mg, 50% yield) as a yellow viscous solid. MS:[M+H] + = 445.3.

[0209] Example 37B. 1-(3-(4-amino-3-((R)-3-aminopiperidine-1-yl)-1H-pyrazolo[3,4-d]pyrimidine-1-yl)pyrrolidine-1-yl)ethane-1-one,HCl [ka] Similar to the preparation of Example 19B, Example 37B (34 mg, 99% yield) was obtained as a yellow solid by reacting Example 37A (40 mg) with 4N HCl / 1,4-dioxane. [M+H] + = 345.3.

[0210] Example 37 [ka] Similar to the preparation of Example 19C, Example 37 (7.5 mg, 12% yield) was obtained as a pale yellow solid by the 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). LCMS method A: RT = 1.386 min, [M + H] + =615.3;LC-MS method B: RT=1.115min, [M+H] + = 615.3. 1H NMR(400MHz,DMSO-d6)δ ppm 8.87(s,1H),8.14(d,J=3.8Hz,1H),7.36(br d,J=7.3Hz,1H),5.36-5.20(m,1H),5.08(br s,1H),4.78(td,J=6.3,12.5Hz,1H),4.24-4.11(m,1H),3.91-3.68(m,3H),3.63-3.57(m,2H),3.39(br d,J=7.3Hz,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=6.3Hz,5H),0.83-0.72(m,5H).

[0211] Example 38. (R)-N-(1-(4-amino-1-(4-(methylsulfonyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidine-3-yl)piperidine-3-yl)benzamide, TFA [ka] (R)-3-(3-aminopiperidine-1-yl)-1-(4-(methylsulfonyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidine-4-amine,2 was mixed with TEA (9 μl, 0.065 mmol) and benzoyl chloride (10% solution / THF) (0.018 mL, 0.016 mmol) in a solution of TFA (8 mg, 0.013 mmol) / THF (1 mL). The mixture was stirred at room temperature for 30 minutes, then quenched with MeOH and evaporated. The residue was purified by preparative HPLC to obtain Example 38 (3.7 mg, 46% yield). LCMS method A: RT = 1.62 min, [M+H] + =492.28;LC-MS method B: RT=1.29min, [M+H] + = 492.56. 1H NMR(500MHz,DMSO-d6)δ 8.48(br d,J=8.8Hz,2H),8.44(br d,J=7.6Hz,1H),8.32(s,1H),8.02(br d,J=8.8Hz,2H),7.82(br d,J=7.1Hz,2H),7.55-7.48(m,1H),7.47-7.40(m,2H),4.26(br dd,J=7.4,4.1Hz,2H),3.20(s,3H),3.03-2.90(m,2H),2.03-1.85(m,3H),1.71-1.53(m,2H).

[0212] Example 39. (R)-N-(1-(4-amino-1-(4-(methylsulfonyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidine-3-yl)piperidine-3-yl)-5-methylthiophene-2-carboxamide, TFA [ka] (R)-3-(3-aminopiperidine-1-yl)-1-(4-(methylsulfonyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidine-4-amine,2 was added to a solution of TFA (8 mg, 0.013 mmol) / DMF (0.5 mL) with 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 room temperature for 5.5 hours and then purified by preparative HPLC to obtain Example 39 (3.7 mg, 46% yield). LCMS method A: RT = 1.63 min, [M + H] + =512.10;LC-MS method B: RT=1.42min, [M+H] + = 511.96. 1H NMR(500MHz,DMSO-d6)δ 8.48(d,J=8.9Hz,2H),8.33(s,1H),8.30(br d,J=7.6Hz,1H),8.02(d,J=8.8Hz,2H),7.59(d,J=3.7Hz,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=10.8Hz,2H),2.44(s,3H),2.01-1.91(m,1H),1.91-1.81(m,2H),1.66-1.53(m,1H)

[0213] Example 40. (R)-N-(1-(4-amino-1-(4-(methylsulfonyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidine-3-yl)piperidine-3-yl)-2-methoxyisonicotinamide [ka] (R)-3-(3-aminopiperidine-1-yl)-1-(4-(methylsulfonyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidine-4-amine,2 was added to a solution of TFA (8 mg, 0.013 mmol) / DMF (0.5 mL) with 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 room temperature for 5.5 hours and then purified by preparative HPLC to obtain Example 40 (2.2 mg, 32% yield). LCMS method A: RT = 1.49 min, [M+H] + =522.89;LC-MS method B: RT=1.35min, [M+H] + = 523.16. 1H NMR(500MHz,DMSO-d6)δ 8.65(br d,J=7.3Hz,1H),8.46(d,J=8.9Hz,2H),8.30(s,1H),8.23(d,J=5.2Hz,1H),8.00(d,J =8.9Hz,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=12.7,3.8Hz,1H),3.19(s,3H),3.04-2.92(m,2H),1.99-1.79(m,4H),1.68-1.57(m,1H).

[0214] The embodiments described above are intended to be illustrative only, and those skilled in the art will be able to recognize or identify many specific compounds, substances, and procedure equivalents without using anything beyond routine experiments. All such equivalents are considered to be within the scope of the claims and are encompassed by the attached claims.

Claims

1. Equation (I): 【Chemistry 1】 [In the formula, R １ C ６－１０ Aryl atoms, as well as carbon atoms, and N, O, and S (=O) ｐ It contains 1 to 5 heteroatoms selected from and 0 to 3 R ４ａ and one R ４ｂ Selected from a group consisting of 5- to 10-membered heterocyclines substituted with; R ２ is selected from the group consisting of C substituted with 1 to 5 R ６ ; aryl, which is substituted with 1 to 5 R ６－１０ ; and 5- to 9-membered heterocyclyl which contains 1 to 5 heteroatoms selected from carbon atoms, N, O, and S(=O) ｐ and is substituted with 1 to 5 R ６ ; selected from the group consisting of 5-9 membered heterocyclyl substituted with R ３ In each entity, H, halogen, -OR ｂ , -NR ａ R ａ , and C １－３ Selected from the group consisting of alkyl groups; or, R ３ and R ３ Together with the two adjacent carbon atoms to which it is bonded, C ３－６ Forms a cycloalkyl group; R ４ａ In each presence, independently, H, halogen, and 1 to 3 R atoms are present. ｅ C replaced by １－４ Selected from the group consisting of alkyl groups; R ４ｂ is, -OR ｂ ,-O-(CR ｄ R ｄ ) １－５ NR ａ R ａ ,-O-(CR ｄ R ｄ ) １－５ OR ｂ , 1 to 5 R ５ C replaced by ３－１２ Carbocyclyl, carbon atom, and N, O, and S (=O) ｐ It contains 1 to 4 heteroatoms selected from and 1 to 5 R ５ A 3- to 10-membered heterocycline substituted with 1-5 R ５ -O-(CR) ｄ R ｄ ) ｒ -C ３－１２ Carbocyclyl, carbon atom, and N, O, and S (=O) ｐ It contains 1 to 4 heteroatoms selected from and 1 to 5 R ５ -O-(CR) ｄ R ｄ ) ｒ - Selected from a group consisting of 3 to 10-membered heterocyclines; R ５ In each of these entities, H, halogen, CN, OR are independent. ｂ , = O, - (CR ｄ R ｄ ) ｒ -NR ７ R ７ , 1 to 5 R ｅ C replaced by １－６ Alkyl, 1 to 5 R ｅ C replaced by ２－６ Alkenil, 1 to 5 R ｅ C replaced by ２－６ Alkinyl, 1 to 5 R ｅ C replaced by ３－１０ Carbocyclyl, as well as carbon atoms, and N, O, and S (=O) ｐ It contains 1 to 4 heteroatoms selected from and 1 to 5 R ｅ Selected from a group consisting of 3- to 10-membered heterocyclines substituted with; R ６ is, independently at each occurrence, selected from H, halogen, CN, =O, -(CR ｄ R ｄ ) ｒ NR ａ R ａ , NO ２ , -OR ｂ , -C(=O)NR ａ R ａ , -C(=O)NR ａ (CR ｄ R ｄ ) ｒ OR ｂ , -C(=O)R ｂ , -C(=O)(CR ｄ R ｄ ) ｒ OR ｂ , -NR ａ C(=O)OR ｂ , -NR ａ C(=O)(CR ｄ R ｄ ) ｒ NR ａ R ａ , -S(=O) ｐ R ｃ , -NR ａ S(=O) ｐ R ｃ , and C substituted with 1 to 5 R ｅ groups １－６ alkyl; R ７ Each entity independently contains H and 1 to 5 R ｅ C replaced by １－７ Alkyl, 1 to 5 R ｅ C replaced by ３－１０ Carbocyclyl, as well as carbon atoms, and N, O, and S (=O) ｐ It contains 1 to 4 heteroatoms selected from the group consisting of 1 to 5 R ｅ Selected from the group consisting of 3- to 10-membered heterocyclines substituted with; or R ７ and R ７ This includes the nitrogen atom to which both are bonded, as well as the carbon atom, and N, O, and S (=O) ｐ It contains 1 to 4 heteroatoms selected from the group consisting of 1 to 5 R ｅ Forms 3- to 10-membered heterocyclines substituted with; R ａ Each entity independently contains H and 1 to 5 R ｅ C replaced by １－６ Alkyl, 1 to 5 R ｅ C replaced by ３－１０ Carbocyclyl, as well as carbon atoms, and N, O, and S (=O) ｐ It contains 1 to 4 heteroatoms selected from the group consisting of 1 to 5 R ｅ Selected from the group consisting of 3- to 10-membered heterocyclines substituted with; or R ａ and R ａ Both are bonded together with the nitrogen atom, carbon atoms, and N, O, and S (=O) ｐ It contains 1 to 4 heteroatoms selected from the group consisting of 1 to 5 R ｅ Forms a 3- to 10-membered heterocycline substituted with; R ｂ Each entity independently contains H and 1 to 5 R ｅ C replaced by １－６ Alkyl, 1 to 5 R ｅ C replaced by ３－１０ Carbocyclyl, as well as carbon atoms, and N, O, and S (=O) ｐ It contains 1 to 4 heteroatoms selected from the group consisting of 1 to 5 R ｅ Selected from a group consisting of 3- to 10-membered heterocyclines substituted with; R ｃ Each entity independently has 1 to 5 R ｅ C replaced by １－６ Alkyl, 1 to 5 R ｅ C replaced by ３－１０ Carbocyclyl, as well as carbon atoms, and N, O, and S (=O) ｐ It contains 1 to 4 heteroatoms selected from the group consisting of 1 to 5 R ｅ Selected from a group consisting of 3- to 10-membered heterocyclines substituted with; R ｄ Each entity independently contains H and 1 to 5 R ｅ C replaced by １－６ Alkyl and 1 to 5 R ｅ C replaced by ３－６ Selected from the group consisting of cycloalkyl groups; R ｅ These are independently H, halogen, CN, =O, and 1 to 5 R ｇ C replaced by １－６ Alkyl, 1 to 5 R ｇ C replaced by ２－６ Alkenil, 1 to 5 R ｇ C replaced by ２－６ Alkinyl, 1 to 5 R ｇ C replaced by ３－１０ Carbocyclyl, carbon atom, and N, O, and S (=O) ｐ It contains 1 to 4 heteroatoms selected from the group consisting of 1 to 5 R ｇ A 3- to 10-membered heterocyclyl substituted with -(CH ２ ) ｒ OR ｆ ,-(CH ２ ) ｒ NR ｆ R ｆ ,-(CH ２ ) ｒ C(=O)R ｆ , and - (CH ２ ) ｒ C (=O) OR ｆ Selected from the group consisting of; R ｆ Each entity independently contains H and 1 to 5 R ｇ C replaced by １－６ Alkyl, 1 to 5 R ｇ C replaced by ３－１０ Carbocyclyl, as well as carbon atoms, and N, O, and S (=O) ｐ It contains 1 to 4 heteroatoms selected from the group consisting of 1 to 3 R ｇ Selected from a group consisting of 3- to 10-membered heterocyclines substituted with; R ｇ In each of these entities, H, halogen, CN, -OH, -O(C) １－５ Alkyl), NH ２ NH(C １－５ Alkyl), NH(C １－５ Alkyl) ２ , and C １－５ Selected from the group consisting of alkyl groups; p is an integer of 0, 1, or 2; and r is an integer of 0, 1, 2, 3, 4, or 5. The compound indicated by or a pharmaceutically acceptable salt thereof.

2. R １ However, carbon atoms, and N, O, and S (=O) ｐ It contains 1 to 3 heteroatoms selected from the group consisting of and 0 to 2 R ４ａ and one R ４ｂ It is a 5-6 member heterocycline substituted with; and R ２ However, 1 to 5 R ６ Phenyl substituted with, as well as carbon atoms, and N, O, and S (=O) ｐ It contains 1 to 3 heteroatoms selected from the group consisting of 1 to 5 R ６ Selected from a group consisting of 5-6 member heterocyclines substituted with The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

3. R １ but, 【Chemistry 2】 Selected from the group consisting of; R ２ but 【Transformation 3】 Selected from the group consisting of; R ４ａ However, H and C １－３ Selected from the group consisting of alkyl groups; R ４ｂ However, -O-C １－４ Alkyl, -O-(CH ２ ) １－５ NR ａ R ａ , 1 to 5 R ５ C replaced by ３－１２ Carbocyclyl, carbon atom, and N, O, and S (=O) ｐ It contains 1 to 4 heteroatoms selected from and 1 to 5 R ５ A 3- to 10-membered heterocycline substituted with 1-5 R ５ -O-C substituted ３－１２ Carbocyclyl, carbon atom, and N, O, and S (=O) ｐ It contains 1 to 4 heteroatoms selected from and 1 to 5 R ５ Selected from the group consisting of -O-3 to 10-membered heterocyclines substituted with; R ５ However, each entity independently produces H, halogen, and -NR ７ R ７ , and 1 to 5 R ｅ C replaced by １－６ Selected from the group consisting of alkyl groups; R ６ However, each entity independently contains H, halogen, CN, -OR ｂ , C(=O)R ｂ , -C(=O)NR ａ R ａ , -S (=O) ｐ R ｃ , and 1 to 5 R ｅ C replaced by １－３ Selected from the group consisting of alkyl groups; R ７ However, each entity independently has H and 1 to 5 R ｅ C replaced by １－３ Alkyl and 1 to 5 R ｅ C replaced by ３－６ Selected from the group consisting of carbocyclyl; or R ７ and R ７ However, along with the nitrogen atom to which both are bonded, carbon atoms, and N, O, and S (=O) ｐ It contains 1 to 4 heteroatoms selected from the group consisting of 1 to 3 R ｅ Forms 3- to 10-membered heterocyclines substituted with; R ａ However, each entity independently contains H and 1 to 5 R ｅ C replaced by １－４ Selected from the group consisting of alkyl groups; R ｂ However, each entity independently contains H and 1 to 5 R ｅ C replaced by １－４ Selected from the group consisting of alkyl groups; R ｃ However, 1 to 5 R ｅ C replaced by １－４ It is alkyl; R ｅ These are independently H, halogen, CN, and C. １－４ Alkyl and -OR ｆ Selected from the group consisting of; and R ｆ However, H and C １－４ Selected from the group consisting of alkyl groups, A compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof.

4. Formula (II): 【Chemistry 4】 [In the formula, R ２ but 【Transformation 5】 Selected from the group consisting of; R ４ａ C １－３ It is alkyl; R ４ｂ However, -O(CH ２ ) １－３ NR ａ R ａ , 1 to 4 R ５ C replaced by ３－１０ Carbocyclyl, carbon atom, and N, O, and S (=O) ｐ It contains 1 to 4 heteroatoms selected from and 1 to 4 R ５ A 4-10 member heterocycline substituted with 1-4 R ５ -O-C substituted ３－１０ Carbocyclyl, as well as carbon atoms, and N, O, and S (=O) ｐ It contains 1 to 4 heteroatoms selected from and 1 to 4 R ５ Selected from the group consisting of -O-4 to 10-membered heterocyclines substituted with; R ５ However, each entity independently produces H, halogen, and -NR ７ R ７ , and 1 to 3 R ｅ C replaced by １－５ Selected from the group consisting of alkyl groups; R ６ However, each entity independently contains H, halogen, CN, -OR ｂ , -C(=O)R ｂ , -C(=O)NR ａ R ａ , -S (=O) ２ R ｃ , and 1 to 3 R ｅ C replaced by １－３ Selected from the group consisting of alkyl groups; R ７ However, each entity independently has H and 1 to 3 R ｅ C replaced by １－５ Alkyl and C ３－６ Selected from the group consisting of cycloalkyl groups; or R ７ and R ７ However, along with the nitrogen atom to which both are bonded, carbon atoms, and N, O, and S (=O) ｐ It contains 1 to 4 heteroatoms selected from the group consisting of and 1 to 3 R ｅ Forms a 4-6 member heterocycline substituted with; R ａ However, each entity independently contains H and 1 to 5 R ｅ C replaced by １－３ Selected from the group consisting of alkyl groups; R ｂ However, each entity independently contains H and 1 to 5 R ｅ C replaced by １－３ Selected from the group consisting of alkyl groups; R ｃ C １－３ It is alkyl; R ｅ These are independently H, halogen, CN, and C. １－３ Alkyl and -OR ｆ Selected from the group consisting of; and R ｆ However, H and C １－３ Selected from the group consisting of alkyl groups. The compound according to claim 3 or a pharmaceutically acceptable salt thereof, as shown in [the provided symbol].

5. Formula (III): 【Transformation 6】 [In the formula, R ２ but 【Transformation 7】 Selected from the group consisting of; R ４ａ C １－３ It is alkyl; R ４ｂ However, 1 to 4 R ５ -O-C substituted ３－１０ Carbocyclyl, carbon atom, and N, O, and S (=O) ｐ It contains 1 to 4 heteroatoms selected from and 1 to 4 R ５ Selected from the group consisting of -O-4 to 10-membered heterocyclines substituted with; R ５ However, each entity independently contains H, halogen, CN, OR ｂ , -NR ７ R ７ , 1 to 3 R ｅ C replaced by １－５ Alkyl, 1 to 3 R ｅ C replaced by ３－６ Carbocyclyl, as well as carbon atoms, and N, O, and S (=O) ｐ It contains 1 to 4 heteroatoms selected from and 1 to 4 R ｅ Selected from a group consisting of 3- to 6-membered heterocyclines substituted with; R ６ However, each element independently contains H, halogen, CN, and -NR ａ R ａ , -OR ｂ , -C(=O)NR ａ R ａ , -C(=O)NR ａ OR ｂ , -C(=O)R ｂ , -S (=O) ２ R ｃ , -NR ａ S (=O) ２ R ｃ , 1 to 5 R ｅ C replaced by １－４ Alkyl, 1 to 5 R ７ Substituted with - (CH ２ ) ｒ C ３－６ Carbocyclyl, as well as carbon atoms, and N, O, and S (=O) ｐ It contains 1 to 4 heteroatoms selected from the group consisting of 1 to 5 R ７ Selected from a group consisting of 5-6 member heterocyclines substituted with; R ７ However, each entity independently has H and 1 to 3 R ｅ C replaced by １－５ Alkyl and C ３－６ Selected from the group consisting of cycloalkyl groups; or R ７ and R ７ However, along with the nitrogen atom to which both are bonded, carbon atoms, and N, O, and S (=O) ｐ It contains 1 to 4 heteroatoms selected from the group consisting of 1 to 5 R ｅ Forms a 4-6 member heterocycline substituted with; R ａ However, each entity independently contains H and 1 to 5 R ｅ C replaced by １－３ Selected from the group consisting of alkyl groups; R ｂ However, each entity independently contains H and 1 to 5 R ｅ C replaced by １－３ Selected from the group consisting of alkyl groups; R ｃ C １－３ It is alkyl; R ｅ These are independently H, halogen, CN, and C. １－３ Alkyl and -OR ｆ Selected from the group consisting of; and R ｆ H and C １－３ Selected from the group consisting of alkyl groups. The compound according to claim 3 or a pharmaceutically acceptable salt thereof, as shown in [the provided symbol].

6. R ４ａ C １－２ It is alkyl; R ４ｂ but 【Transformation 8】 Selected from the group consisting of; R ５ However, in each entity independently, H, -NR ７ R ７ , and 1 to 5 R ｅ C replaced by １－３ Selected from the group consisting of alkyl groups; R ７ However, each entity independently has H and 1 to 3 R ｅ C replaced by １－５ Alkyl and C ３－６ Selected from the group consisting of cycloalkyl groups; or, R ７ and R ７ However, along with the nitrogen atom to which both are bonded, carbon atoms, and N, O, and S (=O) ｐ It contains 1 to 4 heteroatoms selected from the group consisting of 1 to 5 R ｅ Forms a 5-6 member heterocycline substituted with; R ｅ However, each element independently contains H, halogen, CN, and C. １－３ Alkyl and -OR ｆ Selected from the group consisting of; and R ｆ H and C １－３ Selected from the group consisting of alkyl groups, The compound according to claim 4 or 5 or a pharmaceutically acceptable salt thereof.

7. R ４ｂ but 【Chemistry 9】 And; R ５ However, -NR ７ R ７ , and 1 to 5 R ｅ C replaced by １－３ Selected from the group consisting of alkyl groups; R ７ However, each entity independently has H and 1 to 3 R ｅ C replaced by １－５ Alkyl and C ３－６ Selected from the group consisting of cycloalkyl groups; or R ７ and R ７ However, along with the nitrogen atom to which both are bonded, carbon atoms, and N, O, and S (=O) ｐ It contains 1 to 4 heteroatoms selected from the group consisting of 1 to 3 R ｅ Forms 3- to 10-membered heterocyclines substituted with; R ｅ However, each element independently contains H, halogen, CN, and C. １－２ Alkyl and -OR ｆ Selected from the group consisting of; R ｆ H and C １－２ Selected from the group consisting of alkyl groups, The compound according to claim 6 or a pharmaceutically acceptable salt thereof.

8. R ５ ga-NR ７ R ７ And; R ７ However, each entity independently possesses H, Me, Et, 【Chemistry 10】 Selected from the group consisting of; or, R ７ and R ７ However, along with the nitrogen atom to which both are bonded, 【Chemistry 11】 to form The compound according to claim 7 or a pharmaceutically acceptable salt thereof.

9. R ２ but 【Chemistry 12】 and R ６ However, in each entity independently, H, halogen, CN, -OC １－３ Alkyl, -C(=O)NH ２ , -S (=O) ２ C １－３ Alkyl and C １－３ Selected from the group consisting of alkyl groups, The compound according to claim 4 or 5 or a pharmaceutically acceptable salt thereof.

10. R ２ but 【Chemistry 13】 Selected from the group consisting of; and R ６ However, in each existence independently, H, -C (=O)C １－３ Alkyl and C １－３ Selected from the group consisting of alkyl groups, The compound according to claim 4 or 5 or a pharmaceutically acceptable salt thereof.

11. Formula (IV): 【Chemistry 14】 [In the formula, R ２ but 【Chemistry 15】 Selected from the group consisting of; R ４ｂ -O-C １－３ Alkyl, 1 to 5 R ５ C replaced by ３－１２ Carbocyclyl, as well as carbon atoms, and N, O, and S (=O) ｐ It contains 1 to 4 heteroatoms selected from and 1 to 5 R ５ Selected from a group consisting of 3- to 10-membered heterocyclines substituted with; R ５ However, in each entity independently, H, -NR ７ R ７ , and 1 to 5 R ｅ C replaced by １－５ Selected from the group consisting of alkyl groups; R ６ However, each entity independently contains H, halogen, CN, OR ｂ , C(=O)R ｂ , -C(=O)NR ａ R ａ , -S (=O) ２ R ｃ , and 1 to 5 R ｅ C replaced by １－３ Selected from the group consisting of alkyl groups; R ７ However, each entity independently has H and 1 to 5 R ｅ C replaced by １－３ Alkyl and 1 to 5 R ｅ C replaced by ３－６ Selected from the group consisting of carbocyclyls; R ａ However, in each existence independently, H and C １－３ Selected from the group consisting of alkyl groups; R ｂ However, each entity independently contains H and 1 to 4 R ｅ C replaced by １－３ Alkyl, 1 to 5 R ｅ C replaced by ３－１０ Carbocyclyl, as well as carbon atoms, and N, O, and S (=O) ｐ It contains 1 to 4 heteroatoms selected from the group consisting of 1 to 4 R ｅ Selected from a group consisting of 5-6 member heterocyclines substituted with; R ｃ C １－３ It is alkyl; R ｅ However, each element independently contains H, halogen, CN, and C. １－３ Alkyl and OR ｆ Selected from the group consisting of; and R ｆ However, H and C １－３ Selected from the group consisting of alkyl groups. The compound according to claim 3 or a pharmaceutically acceptable salt thereof, as shown in [the provided symbol].

12. R ４ｂ They became independent 【Chemistry 16】 Selected from the group consisting of; R ５ However, in each existence independently, H and C １－４ Selected from the group consisting of alkyl groups; and R ７ However, in each existence independently, H and C １－３ Selected from the group consisting of alkyl groups, The compound according to claim 11 or a pharmaceutically acceptable salt thereof.

13. A compound according to claim 1 or a pharmaceutically acceptable salt thereof, selected from any one of the examples described in the specification.

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 therapeutic purposes.

16. Use of the compound according to any one of claims 1 to 12 for the prevention and / or treatment of disorders related to serum and glucocorticoid-regulating kinase 1 (SGK1) activity.

17. The disorder is selected from cardiovascular and cerebrovascular diseases (including hypertension, heart failure, coronary artery disease, myocardial infarction, peripheral vascular disease, stroke, and arrhythmias), fibrosis (including diabetic nephropathy, glomerulonephritis, experimental nephrotic syndrome, obstructive nephropathy, pulmonary fibrosis, cirrhosis, fibrotic pancreatitis, peritoneal fibrosis, Crohn's disease, and celiac disease), metabolic disorders and complications (including diabetes, obesity, and metabolic syndrome), immune / inflammatory diseases (including rheumatoid arthritis and osteoarthritis), neurological disorders (including Alzheimer's disease, Parkinson's disease, epileptic seizures, and Lafora progressive myoclonus epilepsy), and cancer. The use described in claim 16.

Images