Thiazolo tetrahydroquinoline compounds as class II phosphoinositide 3-kinase inhibitors

Abstract

The present invention relates to chemical compounds useful as inhibitors of class II phosphoinositide 3-kinase (PI3K) signaling. The invention further relates to the medical use of inhibitors of class II phosphoinositide 3-kinase (PI3K) signaling in the treatment of medical conditions associated with defective and / or pathological class II phosphoinositide 3-kinase (PI3K) signaling, such as stroke, cardiovascular diseases associated with endothelial cell dysfunction, cancer, cancerometastasis, myopathy and diabetes.

Description

Technical Field

[0001] This invention belongs to the fields of biochemistry and medicine, and relates to chemical compounds used as inhibitors of type II phosphoinositol 3-kinase (PI3K) signaling. The invention further relates to the medical use of inhibitors of PI3K signaling in the treatment of medical conditions associated with defective and / or pathological type II phosphoinositol 3-kinase (PI3K) signaling, such as stroke, cardiovascular disease associated with endothelial cell dysfunction, cancer, cancer metastasis, myopathy, and diabetes. The invention further relates to the medical use of inhibitors of the β-isoform (PI3K-2b) signaling of type II phosphoinositol 3-kinase in the treatment of medical conditions associated with defective and / or pathological type II phosphoinositol 3-kinase β-isoform (PI3K-C2b) signaling. Background Technology

[0002] Phosphoinositol 3-kinases (PI3Ks) are the most important family of lipid kinases regulating a wide range of vital intracellular processes. PI3Ks coordinate cellular responses, including mitotic signaling, cell survival and growth, metabolic control, vesicle transport, degranulation, cytoskeleton rearrangement, and migration. PI3Ks catalyze the phosphorylation of the 3'-OH group on the inositol ring of phosphatidylinositol. Based on substrate preference, amino acid sequence, and structure, three classes of PI3Ks have been identified.

[0003] Type I PI3Ks were the first PI3Ks discovered. They form heterodimers through the combination of catalytic and regulatory subunits, producing PI(3,4,5)P3. Type I PI3Ks are further classified into type IA (p110α, β, and δ) and type IB (p110γ) based on different regulatory subunits. Figure 1 The structural similarity between class I PI3K and the kinase domains of protein kinases suggests that PI3K possesses protein kinase activity in addition to lipid kinase activity.

[0004] Class II phosphoinositol 3-kinases (PI3Ks) control a wide range of cellular functions, from membrane and actin dynamics to cell signaling, via the synthesis of 3'-phosphorylated inositol phospholipids. Less is known about class II PI3Ks compared to class I. Class II PI3Ks produce PI(3)P or PI(3,4)P2 at varying efficiency levels, which can be correlated with subtype and cell type. Three class II PI3K subtypes (PI3KC2α, PI3KC2β, and PI3KC2γ) exist in vertebrates, but only one member is found in worms and flies. Similar to the catalytic subunits of class I PI3Ks, all class II subtypes contain a Ras-binding domain (RBD), a C2 domain (C2), a helical domain (HD), and a kinase domain, but possess a unique disordered region at their N-terminus and two lipid-binding domains (PX and C2 domains) extending from their C-terminus. Unlike class I PI3Ks, class II PI3K kinases lack regulatory subunits and act as monomers.

[0005] Class II PI3K isoforms have been shown to couple signal transduction with membrane transport. This suggests that different mechanisms are used to recruit PI3KII, and that their lipid products have unique roles [PI(3)P and / or PI(3,4)P2]. Recently, the α isoform has been shown to synthesize PI(3,4)P2 at endocytic pits on the plasma membrane, where PI(3,4)P2 is essential for pre-vesicle mitotic membrane contraction (Posor et al., Nature, 2013, 499, 233–237) and is essential for the internalization of VEGF receptors in endothelial cells (Yoshioka et al., Nat. Med., 2012, 18, 1560). 1569). In addition, PI3KC2α knockdown impairs the maturation of autophagy and endocytic vesicles in at least some cells. PI3KC2α can also generate PI(3)P and regulate the formation of PI(3)P pools at the pericentriole recirculating endosome (PRE) required for Rab11 and Shh pathway activation and primary ciliation.

[0006] The activity of the β isoform of class II PI3K (PI3KC2β, also known as PI3K-C2b) is associated with endocytosis, proliferation, and glucose metabolism. Furthermore, the β isoform regulates nutrient signaling by inhibiting mTORC1 signaling through the local production of PI(3,4)P2 at late endosomes or lysosomes (Marat et al, Science, 2017, 356, 968-972).

[0007] Endothelial-specific PI3KC2α knockout mice exhibit vascular barrier dysfunction, indicating that PI3KC2α is involved in angiogenesis (Yoshioka et al., Endothelial PI3K-C2alpha, a class II PI3K, has anessential role in angiogenesis and vascular barrier function. Nat. Med. 2012, 18, 1560-1569). Furthermore, the liver-specific C2γ subtype has recently been shown to produce an endosomal PI(3,4)P2 pool required for sustained Akt2 activation following insulin stimulation (Braccini et al., Nat. Commun. 2015, 6, 7400). Based on currently accumulated data, class II PI3K appears to be associated with cancer, cardiovascular disease, myopathy, diabetes, and other diseases (Falasca et al., J. Med. Chem. 2016, 60, 47-65).

[0008] Cell-permeable small molecule inhibitors of kinases are excellent tools for directly and rapidly revealing the functional consequences of kinase inactivity and represent useful medical agents. A key challenge in generating such inhibitors is their specificity. For PI3K, the two most widely used and readily available major pharmacological tools, wortmannin and LY294002, have off-target effects on other members of this family. Therefore, over the past decade, a wider variety of chemically diverse small molecule inhibitors have been developed to specifically target specific PI3K isoforms.

[0009] Different chemotypes were observed for a range of PI3K inhibitors with varying degrees of selectivity. The most selective compounds included quinazolinone purine inhibitors for PI3K δ (e.g., TGX-115, TGX286, and PIK-108) and imidazopyridine inhibitors for PI3K α (e.g., PIK75). Figure 2 A). These compounds exhibited >100-fold selectivity between their primary target and other class I PI3Ks. Other chemotype inhibitors (i.e., arylthiazolidinones, pyridinylfuranopyrimidines, phenylthiazolides, and imidazoquinazolinides) were found to inhibit multiple PI3Ks to varying degrees. Additional class I PI3K inhibitors are described in Falasca et al, J. Med. Chem. 2016, 60, 47-65.

[0010] Recently, class III PI3K (Vps34) specific inhibitors, SAR304 / VPS34IN1 and SAR405, have been developed. These have been shown to affect the late endosome / lysosome compartment, inhibit autophagy, and rescue defective endosome exocytosis in the absence of PI(3)P phosphatase MTM1 (Ketel et al, Nature, 2016, 529, 408-412).

[0011] Compared to class I and class III PI3K, there are almost no specific inhibitors for class II PI3K, also due to a lack of structural information. Currently, there are no specific inhibitors described for PI3K-C2b.

[0012] Mountford et al. (ACS Medicinal Chemistry Letters, 2015, 6, 3-6) and Falasca et al. J. Med. Chem. 2016, 60, 47-65) are review articles presenting comments on inhibitors of phosphoinositol 3-kinase (PI3K) signaling and the development prospects of PI3K as a potential drug target. The chemical structures disclosed therein differ from those of the present invention.

[0013] WO 2019 / 234237 A1 discloses compounds for inhibiting type II phosphoinositol 3-kinase, particularly type II phosphoinositol 3-kinase α (PI3KC2a). The disclosed chemical structure differs from the chemical structure of this invention.

[0014] Pemberton et al. (“Discovery of Highly Isoform Selective Orally Bioavailable Phosphoinositide 3-Kinase (PI3K) - [gamma] Inhibitors”, JOURNALOF Medicinal Chemistry, 2018) disclosed various isoform-selective PI3Kγ inhibitors. Compound 15 (AZD3458) exhibited high selectivity for PI3Kγ inhibition compared to PI3Kα and PI3Kβ. Inhibition of class II and III PI3Ks, such as PI3K-C2β, was also investigated, with AZD3458 also showing inhibition of PI3K-C2β, however, less than that of PI3Kγ. The disclosed chemical structures differ from those of the present invention.

[0015] WO 2009 / 017822 A2 discloses various molecules for inhibiting PI3K, particularly PI3Kα, which can be used to treat PI3K-regulated diseases, such as cancer.

[0016] WO 2020 / 210379 A1 discloses various molecules for inhibiting PI3K, particularly PI3Kγ, for the treatment of PI3K-regulated diseases such as allergic reactions, inflammatory diseases, autoimmune diseases, asthma, emphysema, respiratory diseases, or cancer.

[0017] Carnevalli et al. (“Macrophage Activation Status Rather than Repolarization Is Associated with Enhanced Checkpoint Activity in Combination with P13K[gamma]Inhibition”, Molecular Cancer Therapeutics, 2021) investigated the PI3Kγ inhibitor AZD3458 for cancer treatment and its effects on tumor-associated macrophage phenotypes.

[0018] Sadiq et al. (“Characterisation of pharmacokinetics, safety and tolerability in a first-in-human study for AZD8154, a novel inhaled selective selective PI3K[gamma][delta]dual inhibitor targeting airway inflammatory disease”, British Journal of Clinical Pharmacology, 2021) disclosed the selective dual PI3Kγδ inhibitor AZD8154. This inhibitor is designed for inhalation use for anti-inflammatory treatment of respiratory diseases such as asthma.

[0019] WO 2010 / 037765 A2 discloses various molecules with a 4-morpholino-pyrido[3,2-d]pyrimidine backbone for inhibiting PI3K, which are used to treat PI3K-regulated diseases such as autoimmune diseases, inflammatory diseases, multiple sclerosis and cancer.

[0020] CN 115 611 883 A discloses various molecules for treating cancer by inhibiting PI3K, particularly PI3Kα.

[0021] WO 2012 / 148540 A1 and WO 2014 / 151147 A1 disclose different molecules for inhibiting PI3K, particularly PI3Kα, and / or mTOR, in combination for the treatment of cancer.

[0022] EP 2 944 637 A1 discloses various molecules for inhibiting PI3K, particularly PI3Kα, for the treatment of cancer, allergic diseases, autoimmune diseases, neurodegenerative diseases, circulatory disorders, inflammatory diseases, endocrine disorders, and metabolic diseases. WO 2017 / 153527 A1 discloses various molecules for inhibiting PI3K, particularly PI3Kγ, for the treatment of respiratory diseases such as asthma and COPD.

[0023] Apart from WO 2019 / 234237 A1 and Pemberton et al., none of these studies disclose the inhibition of class II PI3K.

[0024] Given the lack of established class II PI3K inhibitors, this invention seeks to develop class II PI3K inhibitors, particularly specific inhibitors of PI3K-C2b, to provide novel compounds for research and medical treatment. Given the prior art and considering the relevance of class II PI3K in a variety of medical conditions, there remains a significant need in the art to provide compounds for inhibiting class II PI3K. Summary of the Invention

[0025] In view of the prior art, the fundamental technical problem of the present invention is to provide a method for suppressing class II PI3K (including the β subtype (PIK3-2b) of class II PIK3).

[0026] This problem is solved by the features of the independent claims. Preferred embodiments of the invention are provided by the dependent claims.

[0027] Therefore, the present invention relates to a compound according to Formula 1 for use in treating medical conditions associated with defective and / or pathological type II phosphoinositol 3-kinase (PI3K) signaling. Formula 1 in n is 1 or 2. A is a 5- or 6-membered heteroaryl group and -N (R4R5) is attached to the C atom adjacent to the N atom of ring A. R1 is C, S, O, or N. R2 is C or N. R3 is H, C1 to C5 alkyl (preferably C1 to C3 alkyl), C3 to C6 cycloalkyl, C1 to C5 haloalkyl (preferably C1 to C3 haloalkyl, including Cl, Br or F), -CN, carbonyl, carboxyl, carboxylic acid ester, alkoxy, aldehyde, primary amine, secondary or tertiary amine, amide, imide, carbamate, formamide, nitro, sulfide, sulfinyl, sulfonyl, sulfinyl or sulfonamide R4 and R5 may be the same or different, and are H, C1 to C5 alkyl (preferably C1 to C3 alkyl), C2 to C5 alkenyl, C3 to C6 cycloalkyl, C3 to C6 heterocycloalkyl (preferably including N, S and / or O), C1 to C5 haloalkyl (preferably C1 to C3 haloalkyl, preferably including Cl, Br or F), C4 to C6 aryl, sulfide, sulfinyl, sulfonyl, sulfinyl, sulfonamide, carboxyl, carboxylic acid ester, carbonyl C=OR, wherein R is C1 to C10 alkyl (preferably C1 to C5 alkyl), C1 to C3 haloalkyl (preferably including Cl, Br or F), C4 to C6 aryl, wherein R is optionally substituted with a urethane group or urethane. Alternatively, R4 and R5 form a 4, 5, or 6-membered heterocyclic alkyl group comprising N and optionally one or more additional heteroatoms (preferably N, O, and / or S), wherein the heterocyclic alkyl group is optionally substituted with an alkoxy group. R6 is absent, or R1 is C and R6 forms a carbonyl group (C=O) with R1, or R1 is S and R6 forms a sulfoxide group (S=O) with R1. Whether R7, R8, and R9 are the same or different, they are C or N. R10 is H, C1 to C5 alkyl (preferably C1 to C3 alkyl), C3 to C6 cycloalkyl, C1 to C5 haloalkyl (preferably C1 to C3 haloalkyl, including Cl, Br or F), -CN, carbonyl, carboxyl, carboxylic acid ester, alkoxy, aldehyde, primary amine, secondary or tertiary amine, amide, imide, carbamate, formamide, nitro, sulfide, sulfinyl, sulfonyl, sulfinyl or sulfonamide R11 is H, C3 to C6 cycloalkyl, C4 to C6 heterocycloalkyl (preferably including N, S and / or O), halogen (preferably F, Cl or Br), sulfide, sulfinyl, sulfonyl, sulfinyl, sulfonamide, carboxyl, carboxylic acid ester, formamide, alkoxy or aryloxy. Alternatively, R10 and R11, together with the atoms they are attached to, form a 5- to 8-membered cycloalkyl or aryl ring structure D comprising two carbon atoms of B, forming a fused bicyclic group with B, optionally including one or more heteroatoms (preferably N, O, and / or S), and R14 is H, a C1 to C5 alkyl group (preferably C1 to C3 alkyl), a primary amine, a secondary amine, a tertiary amine, or an alkylamine. Alternatively, R11 and R14, together with the atoms they are attached to, form a 5- to 8-membered cycloalkyl or aryl ring structure C comprising two carbon atoms of B, forming a fused cyclic group with B, optionally including one or more heteroatoms (preferably N, O, and / or S), and R12 is a C1 to C5 alkyl (preferably C1 to C3 alkyl), carbonyl C=O, sulfide, sulfinyl, or sulfonyl. R13 is a C1 to C5 alkyl (preferably C1 to C3 alkyl), C2 to C5 alkenyl, C3 to C6 cycloalkyl, C5 or C6 aryl, alkylaryl, C5 or C6 heteroaryl (preferably including N, S and / or O), bicyclic group (preferably including one or two aromatic rings), optionally including one or more heteroatoms (preferably N, O and / or S). Alternatively, R11 may be hydrogen or a halogen, or may not form a ring structure with R10 or R14, or R11 and R14 may form a 5- to 8-membered cycloalkyl or aryl ring structure with the atoms they are attached to, and R15 and R16 may be present, in which case R12 and R13 may not be present. R15 is a C1 to C5 alkyl group (preferably C1 to C3 alkyl group), carbonyl group (C=O), sulfide, sulfinyl group, or sulfonyl group. R16 is a C1 to C5 alkyl (preferably C1 to C3 alkyl), C2 to C5 alkenyl, C3 to C6 cycloalkyl, C5 or C6 aryl, alkylaryl, C5 or C6 heteroaryl (preferably including N, S and / or O), bicyclic group (preferably including one or two aromatic rings), optionally including one or more heteroatoms (preferably N, O and / or S). Alternatively, R15 and R16 may not exist when R14 is H, or when R10 and R11 together with the atoms to which they are attached form a 5- to 8-membered cycloalkyl or aryl ring structure D, or when R11 and R14 together with the atoms to which they are attached form a 5- to 8-membered cycloalkyl or aryl ring structure C and R12 and R13 are present.

[0028] The compounds of the present invention are unexpectedly effective in inhibiting class II phosphoinositol 3-kinase (PI3K), particularly PI3K-C2b. Class II phosphoinositol 3-kinase (PI3K) controls a wide range of cellular functions, from membrane and actin dynamics to cell signaling, via the synthesis of 3'-phosphorylated inositol phospholipids. The activity of the β isoform of class II PI3K (PI3K-C2b) is associated with endocytosis, proliferation, and glucose metabolism. To the inventors' knowledge, no specific inhibitors of PI3K-C2b have been described to date. Therefore, the compounds described herein represent a novel and unexpected class of compounds that exhibit specific inhibition of PI3K-C2b. Those skilled in the art will not derive this invention from any indications or suggestions in the prior art. Therefore, this invention encompasses a novel family of thiazo[a]tetrahydroquinoline-based compounds that specifically inhibit class II PI3Ks (including PI3K-C2b), and these compounds have potential use in various clinical settings for inhibiting class II PI3Ks, such as for the treatment of diseases including cancer, cancer metastasis, cardiovascular diseases associated with endothelial cell dysfunction, stroke, diabetes, or myotubular myopathy. This invention is based on an unexpected and beneficial discovery, as no thiazo[a]tetrahydroquinoline-derived class II PI3K inhibitors have been previously described.

[0029] In one embodiment, the present invention relates to a compound according to Formula 1 for use in treating medical conditions associated with defective and / or pathological type II phosphoinositol 3-kinase (PI3K) signaling. Formula 1 in n is 1 or 2. A is a 5- or 6-membered heteroaryl group and -N (R4R5) is attached to the C atom adjacent to the N atom of ring A. R1 is C, S, O, or N. R2 is C or N. R3 is H, C1 to C5 alkyl (preferably C1 to C3 alkyl), C3 to C6 cycloalkyl, C1 to C5 haloalkyl (preferably C1 to C3 haloalkyl, including Cl, Br or F), -CN, carbonyl, carboxyl, carboxylic acid ester, alkoxy, aldehyde, primary amine, secondary or tertiary amine, amide, imide, carbamate, formamide, nitro, sulfide, sulfinyl, sulfonyl, sulfinyl or sulfonamide R4 and R5 may be the same or different, and are H, C1 to C5 alkyl (preferably C1 to C3 alkyl), C2 to C5 alkenyl, C3 to C6 cycloalkyl, C3 to C6 heterocycloalkyl (preferably including N, S and / or O), C1 to C5 haloalkyl (preferably C1 to C3 haloalkyl, preferably including Cl, Br or F), C4 to C6 aryl, C5 to C6 heteroaryl (preferably including N, S and / or O and optionally substituted with C3 to C6 heterocycloyl (preferably including N, S and / or O)), sulfide, sulfinyl, sulfonyl, sulfinyl, sulfonamide, carboxyl, carboxylic acid ester, carbonyl C=OR, wherein R is C1 to C10 alkyl (preferably C1 to C5 alkyl), C1 to C3 haloalkyl (preferably including Cl, Br or F), C3 to C6 cycloalkyl, alkoxy, C4 to C6 aryl, wherein R is optionally substituted with urethane or urethane, or R4 and R5 form a 4, 5, or 6-membered heterocyclic alkyl group comprising N and optionally one or more additional heteroatoms (preferably N, O, and / or S), wherein the heterocyclic alkyl group is optionally substituted with an alkoxy group. R6 is absent, or R1 is C and R6 forms a carbonyl group (C=O) with R1, or R1 is S and R6 forms a sulfoxide group (S=O) with R1. Whether R7, R8, and R9 are the same or different, they are C or N. R10 is H, C1 to C5 alkyl (preferably C1 to C3 alkyl), C3 to C6 cycloalkyl, C1 to C5 haloalkyl (preferably C1 to C3 haloalkyl, including Cl, Br or F), -CN, carbonyl, carboxyl, carboxylic acid ester, alkoxy, aldehyde, primary amine, secondary or tertiary amine, amide, imide, carbamate, formamide, nitro, sulfide, sulfinyl, sulfonyl, sulfinyl or sulfonamide R11 is H, C3 to C6 cycloalkyl, C4 to C6 heterocycloalkyl (preferably including N, S and / or O), halogen (preferably F, Cl or Br), sulfide, sulfinyl, sulfonyl, sulfinyl, sulfonamide, carboxyl, carboxylic acid ester, formamide, alkoxy or aryloxy. Alternatively, R10 and R11, together with the atoms they are attached to, form a 5- to 8-membered cycloalkyl or aryl ring structure D comprising two carbon atoms of B, forming a fused bicyclic group with B, optionally including one or more heteroatoms (preferably N, O, and / or S), and R14 is H, a C1 to C5 alkyl group (preferably C1 to C3 alkyl), a primary amine, a secondary amine, a tertiary amine, or an alkylamine. Alternatively, R11 and R14, together with the atoms they are attached to, form a 5- to 8-membered cycloalkyl or aryl ring structure C comprising two carbon atoms of B, forming a fused cyclic group with B, optionally including one or more heteroatoms (preferably N, O, and / or S), and R12 is a C1 to C5 alkyl (preferably C1 to C3 alkyl), carbonyl C=O, sulfide, sulfinyl, or sulfonyl. R13 is a C1 to C5 alkyl (preferably C1 to C3 alkyl), C2 to C5 alkenyl, C3 to C6 cycloalkyl, C5 or C6 aryl, alkylaryl, C5 or C6 heteroaryl (preferably including N, S and / or O), bicyclic group (preferably including one or two aromatic rings), optionally including one or more heteroatoms (preferably N, O and / or S). Alternatively, R11 may be hydrogen or a halogen, or may not form a ring structure with R10 or R14, or R11 and R14 may form a 5- to 8-membered cycloalkyl or aryl ring structure with the atoms they are attached to, and R15 and R16 may be present, in which case R12 and R13 may not be present. R15 is a C1 to C5 alkyl group (preferably C1 to C3 alkyl group), carbonyl group (C=O), sulfide, sulfinyl group, or sulfonyl group. R16 is a C1 to C5 alkyl (preferably C1 to C3 alkyl), C2 to C5 alkenyl, C3 to C6 cycloalkyl, C5 or C6 aryl, alkylaryl, C5 or C6 heteroaryl (preferably including N, S and / or O), C3 to C6 heterocycloalkyl (preferably including N, S and / or O and preferably including at least one double bond), bicyclic group (preferably including one or two aromatic rings), optionally including one or more heteroatoms (preferably N, O and / or S), or R15 and R16 are absent when R14 is H, or when R10 and R11 together with the atoms to which they are attached form a 5 to 8-membered cycloalkyl or aryl ring structure D, or when R11 and R14 together with the atoms to which they are attached form a 5 to 8-membered cycloalkyl or aryl ring structure C and R12 and R13 are present.

[0030] In one embodiment, the compound according to Formula 1 is characterized in that, n is 1 or 2. A is a 5- or 6-membered heteroaryl group and -N (R4R5) is attached to the C atom adjacent to the N atom of ring A. R1 is C, S, O, or N. R2 is C or N. R3 is H, C1 to C3 alkyl, C3 to C6 cycloalkyl, or CX3, where X is Cl, Br, or F. R4 and R5 may be the same or different, and are H, C1 to C3 alkyl, C2 to C5 alkenyl, C3 to C6 cycloalkyl, C3 to C6 heterocycloalkyl (preferably including N, S and / or O), C1 to C3 haloalkyl (preferably including Cl, Br or F), C4 to C6 aryl, sulfonyl or one of the following:

[0031]

[0032] Alternatively, R4 and R5, together with the atoms they are attached to, form a 4, 5, or 6-membered heterocyclic alkyl group comprising N and optionally one or more additional heteroatoms (preferably N, O, and / or S), wherein the heterocyclic alkyl group is optionally substituted with an alkoxy group, such as...

[0033] R6 is absent, or R1 is C and R6 forms a carbonyl group (C=O) with R1, or R1 is S and R6 forms a sulfoxide group (S=O) with R1. Whether R7, R8, and R9 are the same or different, they are C or N. R10 is H or a C1 to C3 alkyl group. R11 is H, C3 to C6 cycloalkyl, C4 to C6 heterocycloalkyl (preferably including N, S and / or O), halogen (preferably F, Cl or Br), sulfide, sulfinyl, sulfonyl, carboxylic acid ester, formamide or alkoxy-CH2OR, wherein R is C1 to C3 alkyl or benzyl. Alternatively, R10 and R11, together with the atoms they are attached to, form a 5- to 7-membered cycloalkyl or aryl ring structure D comprising two carbon atoms of B, forming a fused bicyclic group with B, optionally comprising one or more heteroatoms (preferably N, O, and / or S). R14 is H, a C1 to C3 alkyl group, a secondary or tertiary amine, or an alkylamine; or R11 and R14 together with the atoms to which they are attached form a 5 to 7-membered cycloalkyl or aryl ring structure C including two carbon atoms of B, forming a fused cyclic group with B, optionally including one or more heteroatoms (preferably N, O, and / or S). R12 is a C1 to C3 alkyl, carbonyl C=O, or sulfonyl group. R13 is a C1 to C3 alkyl, C2 to C5 alkenyl, C3 to C6 cycloalkyl, C5 or C6 aryl, benzyl, C5 or C6 heteroaryl (preferably including N, S and / or O), bicyclic group (preferably including one or two aromatic rings), optionally including one or more heteroatoms (preferably N, O and / or S). Alternatively, R11 may be hydrogen or a halogen, or may not form a ring structure with R10 or R14, or R11 and R14 may form a 5- to 7-membered cycloalkyl or aryl ring structure with the atoms they are attached to, and R15 and R16 may be present, in which case R12 and R13 may not be present. R15 is a C1 to C3 alkyl, carbonyl C=O, or sulfonyl group. R16 is a C1 to C3 alkyl, C2 to C5 alkenyl, C3 to C6 cycloalkyl, C5 or C6 aryl, benzyl, C5 or C6 heteroaryl (preferably including N, S and / or O), bicyclic group (preferably including one or two aromatic rings), optionally including one or more heteroatoms (preferably N, O and / or S). Alternatively, R15 and R16 may not exist when R14 is H, or when R10 and R1 together with the atoms to which they are attached form a 5- to 7-membered cycloalkyl or aryl ring structure D, or when R11 and R14 together with the atoms to which they are attached form a 5- to 7-membered cycloalkyl or aryl ring structure C and R12 and R13 are present.

[0034] In one embodiment, the compound according to Formula 1 is characterized in that, R4 and R5 may be the same or different, and are H, C1 to C3 alkyl, C2 to C5 alkenyl, C3 to C6 cycloalkyl, C3 to C6 heterocycloalkyl (preferably including N, S and / or O), C1 to C3 haloalkyl (preferably including Cl, Br or F), C4 to C6 aryl, sulfonyl or one of the following:

[0035]

[0036]

[0037] Where X is C or O. Furthermore, Boc is a tert-butoxycarbonyl group. Alternatively, R4 and R5, together with the atoms they are attached to, form a 4, 5, or 6-membered heterocyclic alkyl group comprising N and optionally one or more additional heteroatoms (preferably N, O, and / or S), wherein the heterocyclic alkyl group is optionally substituted with an alkoxy group, such as... .

[0038] In one embodiment, the compound according to Formula 1 is characterized in that R16 is a C1 to C3 alkyl, C2 to C5 alkenyl, C3 to C6 cycloalkyl, C5 or C6 aryl, benzyl, C5 or C6 heteroaryl (preferably including N, S and / or O), C3 to C6 heterocycloalkyl (preferably including N, S and / or O and preferably including at least one double bond), bicyclic group (preferably including one or two aromatic rings), optionally including one or more heteroatoms (preferably N, O and / or S), or when R14 is H, or R10 and R1 together with the atoms to which they are attached form a 5 to 7-membered cycloalkyl or aryl ring structure D, or when R11 and R14 together with the atoms to which they are attached form a 5 to 7-membered cycloalkyl or aryl ring structure C and R12 and R13 are present, R15 and R16 are absent.

[0039] In one embodiment, the present invention relates to a compound according to formula 1a for use in treating medical conditions associated with defective and / or pathological type II phosphoinositol 3-kinase (PI3K) signaling. Formula 1a in n is 1 or 2. A is a 5- or 6-membered heteroaryl group and -N (R4R5) is attached to the C atom adjacent to the N atom of ring A. R1 is C, S, O, or N. R2 is C or N. R3 is H, C1 to C5 alkyl (preferably C1 to C3 alkyl), C3 to C6 cycloalkyl, C1 to C5 haloalkyl (preferably C1 to C3 haloalkyl, including Cl, Br or F), -CN, carbonyl, carboxyl, carboxylic acid ester, alkoxy, aldehyde, primary amine, secondary or tertiary amine, amide, imide, carbamate, formamide, nitro, sulfide, sulfinyl, sulfonyl, sulfinyl or sulfonamide R4 and R5 may be the same or different, and are H, C1 to C5 alkyl (preferably C1 to C3 alkyl), C2 to C5 alkenyl, C3 to C6 cycloalkyl, C3 to C6 heterocycloalkyl (preferably including N, S and / or O), C1 to C5 haloalkyl (preferably C1 to C3 haloalkyl, preferably including Cl, Br or F), C4 to C6 aryl, sulfide, sulfinyl, sulfonyl, sulfinyl, sulfonamide, carboxyl, carboxylic acid ester, carbonyl C=OR, wherein R is C1 to C10 alkyl (preferably C1 to C5 alkyl), C1 to C3 haloalkyl (preferably including Cl, Br or F), C4 to C6 aryl, wherein R is optionally substituted with a urethane group or urethane. Alternatively, R4 and R5 form a 4, 5, or 6-membered heterocyclic alkyl group comprising N and optionally one or more additional heteroatoms (preferably N, O, and / or S), wherein the heterocyclic alkyl group is optionally substituted with an alkoxy group. R6 is absent, or R1 is C and R6 forms a carbonyl group (C=O) with R1, or R1 is S and R6 forms a sulfoxide group (S=O) with R1. R7, R8, and R9 may be the same or different; they may be C or N. R9 is C. R10 is H, C1 to C5 alkyl (preferably C1 to C3 alkyl), C3 to C6 cycloalkyl, C1 to C5 haloalkyl (preferably C1 to C3 haloalkyl, including Cl, Br or F), -CN, carbonyl, carboxyl, carboxylic acid ester, alkoxy, aldehyde, primary amine, secondary or tertiary amine, amide, imide, carbamate, formamide, nitro, sulfide, sulfinyl, sulfonyl, sulfinyl or sulfonamide R11 is H, C3 to C6 cycloalkyl, C4 to C6 heterocycloalkyl (preferably including N, S and / or O), halogen (preferably F, Cl or Br), sulfide, sulfinyl, sulfonyl, sulfinyl, sulfonamide, carboxyl, carboxylic acid ester, formamide, alkoxy or aryloxy. R14 is H, C1 to C5 alkyl (preferably C1 to C3 alkyl), primary amine, secondary amine, tertiary amine, or alkylamine. Alternatively, R11 and R14, together with the atoms they are attached to, form a 5- to 8-membered cycloalkyl or aryl ring structure C comprising two carbon atoms of B, forming a fused cyclic group with B, optionally including one or more heteroatoms (preferably N, O, and / or S). R15 is a C1 to C5 alkyl group (preferably C1 to C3 alkyl group), carbonyl group (C=O), sulfide, sulfinyl group, or sulfonyl group. R16 is a C1 to C5 alkyl (preferably C1 to C3 alkyl), C2 to C5 alkenyl, C3 to C6 cycloalkyl, C5 or C6 aryl, alkylaryl, C5 or C6 heteroaryl (preferably including N, S and / or O), bicyclic group (preferably including one or two aromatic rings), optionally including one or more heteroatoms (preferably N, O and / or S). Or, when R14 is H, R15 and R16 do not exist.

[0040] In one embodiment, the compound according to formula 1a is characterized in that R4 and R5 may be the same or different, and are H, C1 to C5 alkyl (preferably C1 to C3 alkyl), C2 to C5 alkenyl, C3 to C6 cycloalkyl, C3 to C6 heterocycloalkyl (preferably including N, S and / or O), C1 to C5 haloalkyl (preferably C1 to C3 haloalkyl, preferably including Cl, Br or F), C4 to C6 aryl, C5 to C6 heteroaryl (preferably including N, S and / or O and optionally substituted with C3 to C6 heterocyclic groups (preferably including N, S and / or O)). The compounds are sulfides, sulfinyl groups, sulfonyl groups, sulfinyl groups, sulfonamides, carboxyl groups, carboxylic acid esters, and carbonyl groups (C=OR), wherein R is a C1 to C10 alkyl group (preferably C1 to C5 alkyl group), a C1 to C3 haloalkyl group (preferably including Cl, Br, or F), a C3 to C6 cycloalkyl group, an alkoxy group, or a C4 to C6 aryl group, wherein R is optionally substituted with a urethane group or a urethane ester, or R4 and R5 form a 4, 5, or 6-membered heterocyclic alkyl group including N and optionally one or more additional heteroatoms (preferably N, O, and / or S), wherein the heterocyclic alkyl group is optionally substituted with an alkoxy group.

[0041] In one embodiment, the compound according to formula 1a is characterized in that R16 is a C1 to C5 alkyl (preferably C1 to C3 alkyl), C2 to C5 alkenyl, C3 to C6 cycloalkyl, C5 or C6 aryl, alkylaryl, C5 or C6 heteroaryl (preferably including N, S and / or O), C3 to C6 heterocycloalkyl (preferably including N, S and / or O and preferably including at least one double bond), bicyclic group (preferably including one or two aromatic rings), optionally including one or more heteroatoms (preferably N, O and / or S), or when R14 is H, R15 and R16 are absent.

[0042] In one embodiment, the compound according to formula 1a is characterized in that, n is 1 or 2. A is a 5- or 6-membered heteroaryl group and -N (R4R5) is attached to the C atom adjacent to the N atom of ring A. R1 is C, S, O, or N. R2 is C or N. R3 is H, C1 to C3 alkyl, C3 to C6 cycloalkyl, or CX3, where X is Cl, Br, or F. R4 and R5 may be the same or different, and are H, C1 to C3 alkyl, C2 to C5 alkenyl, C3 to C6 cycloalkyl, C3 to C6 heterocycloalkyl (preferably including N, S and / or O), C1 to C3 haloalkyl (preferably including Cl, Br or F), C4 to C6 aryl, sulfonyl or one of the following:

[0043]

[0044] Alternatively, R4 and R5, together with the atoms they are attached to, form a 4, 5, or 6-membered heterocyclic alkyl group comprising N and optionally one or more additional heteroatoms (preferably N, O, and / or S), wherein the heterocyclic alkyl group is optionally substituted with an alkoxy group, such as...

[0045] R6 is absent, or R1 is C and R6 forms a carbonyl group (C=O) with R1, or R1 is S and R6 forms a sulfoxide group (S=O) with R1. R7, R8, and R9 may be the same or different; they may be C or N. R9 is C. R10 is H or a C1 to C3 alkyl group. R11 is H, C3 to C6 cycloalkyl, C4 to C6 heterocycloalkyl (preferably including N, S and / or O), halogen (preferably F, Cl or Br), sulfide, sulfinyl, sulfonyl, carboxylic acid ester, formamide or alkoxy-CH2OR, wherein R is C1 to C3 alkyl or benzyl. R14 is H, a C1 to C3 alkyl group, a secondary or tertiary amine, or an alkylamine; or R11 and R14 together with the atoms to which they are attached form a 5 to 7-membered cycloalkyl or aryl ring structure C including two carbon atoms of B, forming a fused cyclic group with B, optionally including one or more heteroatoms (preferably N, O, and / or S). R15 is a C1 to C3 alkyl, carbonyl C=O, or sulfonyl group. R16 is a C1 to C3 alkyl, C2 to C5 alkenyl, C3 to C6 cycloalkyl, C5 or C6 aryl, benzyl, C5 or C6 heteroaryl (preferably including N, S and / or O), bicyclic group (preferably including one or two aromatic rings), optionally including one or more heteroatoms (preferably N, O and / or S). Or, when R14 is H, R15 and R16 do not exist.

[0046] In one embodiment, the compound according to formula 1a is characterized in that, R4 and R5 may be the same or different, and are H, C1 to C3 alkyl, C2 to C5 alkenyl, C3 to C6 cycloalkyl, C3 to C6 heterocycloalkyl (preferably including N, S and / or O), C1 to C3 haloalkyl (preferably including Cl, Br or F), C4 to C6 aryl, sulfonyl or one of the following:

[0047]

[0048]

[0049] Where X is C or O. Furthermore, Boc is a tert-butoxycarbonyl group. Alternatively, R4 and R5, together with the atoms they are attached to, form a 4, 5, or 6-membered heterocyclic alkyl group comprising N and optionally one or more additional heteroatoms (preferably N, O, and / or S), wherein the heterocyclic alkyl group is optionally substituted with an alkoxy group, such as... .

[0050] In one embodiment, the compound according to formula 1a is characterized in that R16 is a C1 to C3 alkyl, C2 to C5 alkenyl, C3 to C6 cycloalkyl, C5 or C6 aryl, benzyl, C5 or C6 heteroaryl (preferably including N, S and / or O), C3 to C6 heterocycloalkyl (preferably including N, S and / or O and preferably including at least one double bond), bicyclic group (preferably including one or two aromatic rings), optionally including one or more heteroatoms (preferably N, O and / or S).

[0051] In one embodiment, the present invention relates to a compound according to Formula 2 for use in treating medical conditions associated with defective and / or pathological type II phosphoinositol 3-kinase (PI3K) signaling. Formula 2 in R1 is C, S, O, or N. R2 is C or N. R3 is H, C1 to C5 alkyl (preferably C1 to C3 alkyl), C3 to C6 cycloalkyl, C1 to C5 haloalkyl (preferably C1 to C3 haloalkyl, including Cl, Br or F), -CN, carbonyl, carboxyl, carboxylic acid ester, alkoxy, aldehyde, primary amine, secondary or tertiary amine, amide, imide, carbamate, formamide, nitro, sulfide, sulfinyl, sulfonyl, sulfinyl or sulfonamide R4 and R5 may be the same or different, and are H, C1 to C5 alkyl (preferably C1 to C3 alkyl), C2 to C5 alkenyl, C3 to C6 cycloalkyl, C3 to C6 heterocycloalkyl (preferably including N, S and / or O), C1 to C5 haloalkyl (preferably C1 to C3 haloalkyl, preferably including Cl, Br or F), C4 to C6 aryl, sulfide, sulfinyl, sulfonyl, sulfinyl, sulfonamide, carboxyl, carboxylic acid ester, carbonyl C=OR, wherein R is C1 to C10 alkyl (preferably C1 to C5 alkyl), C1 to C3 haloalkyl (preferably including Cl, Br or F), C4 to C6 aryl, wherein R is optionally substituted with a urethane group or urethane. Alternatively, R4 and R5 form a 4, 5, or 6-membered heterocyclic alkyl group comprising N and optionally one or more additional heteroatoms (preferably N, O, and / or S), wherein the heterocyclic alkyl group is optionally substituted with an alkoxy group. R6 is absent, or R1 is C and R6 forms a carbonyl group (C=O) with R1, or R1 is S and R6 forms a sulfoxide group (S=O) with R1. Whether R7, R8, and R9 are the same or different, they are C or N. R10 is H, C1 to C5 alkyl (preferably C1 to C3 alkyl), C3 to C6 cycloalkyl, C1 to C5 haloalkyl (preferably C1 to C3 haloalkyl, including Cl, Br or F), -CN, carbonyl, carboxyl, carboxylic acid ester, alkoxy, aldehyde, primary amine, secondary or tertiary amine, amide, imide, carbamate, formamide, nitro, sulfide, sulfinyl, sulfonyl, sulfinyl or sulfonamide R11 is H, C3 to C6 cycloalkyl, C4 to C6 heterocycloalkyl (preferably including N, S and / or O), halogen (preferably F, Cl or Br), sulfide, sulfinyl, sulfonyl, sulfinyl, sulfonamide, carboxyl, carboxylic acid ester, formamide, alkoxy or aryloxy. Alternatively, R10 and R11, together with the atoms they are attached to, form a 5- to 8-membered cycloalkyl or aryl ring structure D comprising two carbon atoms of B, forming a fused bicyclic group with B, optionally including one or more heteroatoms (preferably N, O, and / or S), and R14 is H, a C1 to C5 alkyl group (preferably C1 to C3 alkyl), a primary amine, a secondary amine, a tertiary amine, or an alkylamine. Alternatively, R11 and R14, together with the atoms they are attached to, form a 5- to 8-membered cycloalkyl or aryl ring structure C comprising two carbon atoms of B, forming a fused cyclic group with B, optionally including one or more heteroatoms (preferably N, O, and / or S), and R12 is a C1 to C5 alkyl (preferably C1 to C3 alkyl), carbonyl C=O, sulfide, sulfinyl, or sulfonyl. R13 is a C1 to C5 alkyl (preferably C1 to C3 alkyl), C2 to C5 alkenyl, C3 to C6 cycloalkyl, C5 or C6 aryl, alkylaryl, C5 or C6 heteroaryl (preferably including N, S and / or O), bicyclic group (preferably including one or two aromatic rings), optionally including one or more heteroatoms (preferably N, O and / or S). Alternatively, R11 may be hydrogen or a halogen, or may not form a ring structure with R10 or R14, or R11 and R14 may form a 5- to 8-membered cycloalkyl or aryl ring structure with the atoms they are attached to, and R15 and R16 may be present, in which case R12 and R13 may not be present. R15 is a C1 to C5 alkyl group (preferably C1 to C3 alkyl group), carbonyl group (C=O), sulfide, sulfinyl group, or sulfonyl group. R16 is a C1 to C5 alkyl (preferably C1 to C3 alkyl), C2 to C5 alkenyl, C3 to C6 cycloalkyl, C5 or C6 aryl, alkylaryl, C5 or C6 heteroaryl (preferably including N, S and / or O), bicyclic group (preferably including one or two aromatic rings), optionally including one or more heteroatoms (preferably N, O and / or S). Alternatively, R15 and R16 may not exist when R14 is H, or when R10 and R11 together with the atoms to which they are attached form a 5- to 8-membered cycloalkyl or aryl ring structure D, or when R11 and R14 together with the atoms to which they are attached form a 5- to 8-membered cycloalkyl or aryl ring structure C and R12 and R13 are present.

[0052] In one embodiment, the compound according to Formula 2 is characterized in that R4 and R5 may be the same or different, and are H, C1 to C5 alkyl (preferably C1 to C3 alkyl), C2 to C5 alkenyl, C3 to C6 cycloalkyl, C3 to C6 heterocycloalkyl (preferably including N, S and / or O), C1 to C5 haloalkyl (preferably C1 to C3 haloalkyl, preferably including Cl, Br or F), C3 to C6 cycloalkyl, alkoxy, C4 to C6 aryl, C5 to C6 heteroaryl (preferably including N, S and / or O and optionally surrounded by C3 to C6 heterocycloyl (preferably Including N, S and / or O substitution), sulfides, sulfinyl, sulfonyl, sulfinyl, sulfonamide, carboxyl, carboxylic acid ester, carbonyl C=OR, wherein R is C1 to C10 alkyl (preferably C1 to C5 alkyl), C1 to C3 haloalkyl (preferably including Cl, Br or F), C4 to C6 aryl, wherein R is optionally substituted with urethane or urethane, or R4 and R5 form a 4, 5 or 6-membered heterocyclic alkyl group including N and optionally one or more additional heteroatoms (preferably N, O and / or S), wherein the heterocyclic alkyl group is optionally substituted with alkoxy.

[0053] In one embodiment, the compound according to Formula 2 is characterized in that R16 is a C1 to C5 alkyl (preferably C1 to C3 alkyl), C2 to C5 alkenyl, C3 to C6 cycloalkyl, C5 or C6 aryl, alkylaryl, C5 or C6 heteroaryl (preferably including N, S and / or O), C3 to C6 heterocycloalkyl (preferably including N, S and / or O and preferably including at least one double bond), bicyclic group (preferably including one or two aromatic rings), optionally including one or more heteroatoms (preferably N, O and / or S), or when R14 is H, or when R10 and R11 together with the atoms to which they are attached form a 5 to 8-membered cycloalkyl or aryl ring structure D, or when R11 and R14 together with the atoms to which they are attached form a 5 to 8-membered cycloalkyl or aryl ring structure C and R12 and R13 are present, R15 and R16 are absent.

[0054] In one embodiment, the compound according to Formula 2 is characterized in that, R1 is C, S, O, or N. R2 is C or N. R3 is H, C1 to C3 alkyl, C3 to C6 cycloalkyl, or CX3, where X is Cl, Br, or F. R4 and R5 may be the same or different, and are H, C1 to C3 alkyl, C2 to C5 alkenyl, C3 to C6 cycloalkyl, C3 to C6 heterocycloalkyl (preferably including N, S and / or O), C1 to C3 haloalkyl (preferably including Cl, Br or F), C4 to C6 aryl, sulfonyl or one of the following:

[0055]

[0056] Alternatively, R4 and R5, together with the atoms they are attached to, form a 4, 5, or 6-membered heterocyclic alkyl group comprising N and optionally one or more additional heteroatoms (preferably N, O, and / or S), wherein the heterocyclic alkyl group is optionally substituted with an alkoxy group, such as...

[0057] R6 is absent, or R1 is C and R6 forms a carbonyl group (C=O) with R1, or R1 is S and R6 forms a sulfoxide group (S=O) with R1. Whether R7, R8, and R9 are the same or different, they are C or N. R10 is H or a C1 to C3 alkyl group. R11 is H, C3 to C6 cycloalkyl, C4 to C6 heterocycloalkyl (preferably including N, S and / or O), halogen (preferably F, Cl or Br), sulfide, sulfinyl, sulfonyl, carboxylic acid ester, formamide or alkoxy-CH2OR, wherein R is C1 to C3 alkyl or benzyl. Alternatively, R10 and R11, together with the atoms they are attached to, form a 5- to 7-membered cycloalkyl or aryl ring structure D comprising two carbon atoms of B, forming a fused bicyclic group with B, optionally comprising one or more heteroatoms (preferably N, O, and / or S). R14 is H, a C1 to C3 alkyl group, a secondary or tertiary amine, or an alkylamine; or R11 and R14 together with the atoms to which they are attached form a 5 to 7-membered cycloalkyl or aryl ring structure C including two carbon atoms of B, forming a fused cyclic group with B, optionally including one or more heteroatoms (preferably N, O, and / or S). R12 is a C1 to C3 alkyl, carbonyl C=O, or sulfonyl group. R13 is a C1 to C3 alkyl, C2 to C5 alkenyl, C3 to C6 cycloalkyl, C5 or C6 aryl, benzyl, C5 or C6 heteroaryl (preferably including N, S and / or O), bicyclic group (preferably including one or two aromatic rings), optionally including one or more heteroatoms (preferably N, O and / or S). Alternatively, R11 may be hydrogen or a halogen, or may not form a ring structure with R10 or R14, or R11 and R14 may form a 5- to 7-membered cycloalkyl or aryl ring structure with the atoms they are attached to, and R15 and R16 may be present, in which case R12 and R13 may not be present. R15 is a C1 to C3 alkyl, carbonyl C=O, or sulfonyl group. R16 is a C1 to C3 alkyl, C2 to C5 alkenyl, C3 to C6 cycloalkyl, C5 or C6 aryl, benzyl, C5 or C6 heteroaryl (preferably including N, S and / or O), bicyclic group (preferably including one or two aromatic rings), optionally including one or more heteroatoms (preferably N, O and / or S). Alternatively, R15 and R16 may not exist when R14 is H, or when R10 and R11 together with the atoms to which they are attached form a 5- to 7-membered cycloalkyl or aryl ring structure D, or when R11 and R14 together with the atoms to which they are attached form a 5- to 7-membered cycloalkyl or aryl ring structure C and R12 and R13 are present.

[0058] In one embodiment, the compound according to Formula 2 is characterized in that, R4 and R5 may be the same or different, and are H, C1 to C3 alkyl, C2 to C5 alkenyl, C3 to C6 cycloalkyl, C3 to C6 heterocycloalkyl (preferably including N, S and / or O), C1 to C3 haloalkyl (preferably including Cl, Br or F), C4 to C6 aryl, sulfonyl or one of the following:

[0059]

[0060] Where X is C or O. Furthermore, Boc is a tert-butoxycarbonyl group. Alternatively, R4 and R5, together with the atoms they are attached to, form a 4, 5, or 6-membered heterocyclic alkyl group comprising N and optionally one or more additional heteroatoms (preferably N, O, and / or S), wherein the heterocyclic alkyl group is optionally substituted with an alkoxy group, such as... .

[0061] In one embodiment, the compound according to Formula 2 is characterized in that R16 is a C1 to C3 alkyl, C2 to C5 alkenyl, C3 to C6 cycloalkyl, C5 or C6 aryl, benzyl, C5 or C6 heteroaryl (preferably including N, S and / or O), C3 to C6 heterocycloalkyl (preferably including N, S and / or O and preferably including at least one double bond), bicyclic group (preferably including one or two aromatic rings), optionally including one or more heteroatoms (preferably N, O and / or S), or when R14 is H, or when R10 and R11 together with the atoms to which they are attached form a 5 to 7-membered cycloalkyl or aryl ring structure D, or when R11 and R14 together with the atoms to which they are attached form a 5 to 7-membered cycloalkyl or aryl ring structure C and R12 and R13 are present, R15 and R16 are absent.

[0062] In one embodiment, the present invention relates to a compound according to formula 2a for use in treating medical conditions associated with defective and / or pathological type II phosphoinositol 3-kinase (PI3K) signaling. Equation 2a in R1 is C, S, O, or N. R2 is C or N. R3 is H, C1 to C5 alkyl (preferably C1 to C3 alkyl), C3 to C6 cycloalkyl, C1 to C5 haloalkyl (preferably C1 to C3 haloalkyl, including Cl, Br or F), -CN, carbonyl, carboxyl, carboxylic acid ester, alkoxy, aldehyde, primary amine, secondary or tertiary amine, amide, imide, carbamate, formamide, nitro, sulfide, sulfinyl, sulfonyl, sulfinyl or sulfonamide R4 and R5 may be the same or different, and are H, C1 to C5 alkyl (preferably C1 to C3 alkyl), C2 to C5 alkenyl, C3 to C6 cycloalkyl, C3 to C6 heterocycloalkyl (preferably including N, S and / or O), C1 to C5 haloalkyl (preferably C1 to C3 haloalkyl, preferably including Cl, Br or F), C4 to C6 aryl, sulfide, sulfinyl, sulfonyl, sulfinyl, sulfonamide, carboxyl, carboxylic acid ester, carbonyl C=OR, wherein R is C1 to C10 alkyl (preferably C1 to C5 alkyl), C1 to C3 haloalkyl (preferably including Cl, Br or F), C4 to C6 aryl, wherein R is optionally substituted with a urethane group or urethane. Alternatively, R4 and R5 form a 4, 5, or 6-membered heterocyclic alkyl group comprising N and optionally one or more additional heteroatoms (preferably N, O, and / or S), wherein the heterocyclic alkyl group is optionally substituted with an alkoxy group. R6 is absent, or R1 is C and R6 forms a carbonyl group (C=O) with R1, or R1 is S and R6 forms a sulfoxide group (S=O) with R1. R7, R8, and R9 may be the same or different; they may be C or N. R9 is C. R10 is H, C1 to C5 alkyl (preferably C1 to C3 alkyl), C3 to C6 cycloalkyl, C1 to C5 haloalkyl (preferably C1 to C3 haloalkyl, including Cl, Br or F), -CN, carbonyl, carboxyl, carboxylic acid ester, alkoxy, aldehyde, primary amine, secondary or tertiary amine, amide, imide, carbamate, formamide, nitro, sulfide, sulfinyl, sulfonyl, sulfinyl or sulfonamide R11 is H, C3 to C6 cycloalkyl, C4 to C6 heterocycloalkyl (preferably including N, S and / or O), halogen (preferably F, Cl or Br), sulfide, sulfinyl, sulfonyl, sulfinyl, sulfonamide, carboxyl, carboxylic acid ester, formamide, alkoxy or aryloxy. R14 is H, C1 to C5 alkyl (preferably C1 to C3 alkyl), primary amine, secondary amine, tertiary amine, or alkylamine. Alternatively, R11 and R14, together with the atoms they are attached to, form a 5- to 8-membered cycloalkyl or aryl ring structure C comprising two carbon atoms of B, forming a fused cyclic group with B, optionally including one or more heteroatoms (preferably N, O, and / or S). R15 is a C1 to C5 alkyl (preferably C1 to C3 alkyl), carbonyl C=O, sulfide, sulfinyl or sulfonyl, and R16 is a C1 to C5 alkyl (preferably C1 to C3 alkyl), C2 to C5 alkenyl, C3 to C6 cycloalkyl, C5 or C6 aryl, alkylaryl, C5 or C6 heteroaryl (preferably including N, S and / or O), bicyclic group (preferably including one or two aromatic rings), optionally including one or more heteroatoms (preferably N, O and / or S). Or, when R14 is H, R15 and R16 do not exist.

[0063] In one embodiment, the compound according to formula 2a is characterized in that R4 and R5 may be the same or different, and are H, C1 to C5 alkyl (preferably C1 to C3 alkyl), C2 to C5 alkenyl, C3 to C6 cycloalkyl, C3 to C6 heterocycloalkyl (preferably including N, S and / or O), C1 to C5 haloalkyl (preferably C1 to C3 haloalkyl, preferably including Cl, Br or F), C3 to C6 cycloalkyl, alkoxy, C4 to C6 aryl, C5 to C6 heteroaryl (preferably including N, S and / or O and optionally surrounded by C3 to C6 heterocycloyl group (preferably This includes N, S and / or O (substituted), sulfides, sulfinyl, sulfonyl, sulfinyl, sulfonamide, carboxyl, carboxylic acid ester, carbonyl C=OR, wherein R is C1 to C10 alkyl (preferably C1 to C5 alkyl), C1 to C3 haloalkyl (preferably including Cl, Br or F), C4 to C6 aryl, wherein R is optionally substituted with urethane or urethane, or R4 and R5 form a 4, 5 or 6-membered heterocyclic alkyl group including N and optionally one or more additional heteroatoms (preferably N, O and / or S), wherein the heterocyclic alkyl group is optionally substituted with an alkoxy group.

[0064] In one embodiment, the compound according to formula 2a is characterized in that R16 is a C1 to C5 alkyl (preferably C1 to C3 alkyl), C2 to C5 alkenyl, C3 to C6 cycloalkyl, C5 or C6 aryl, alkylaryl, C5 or C6 heteroaryl (preferably including N, S and / or O), C3 to C6 heterocycloalkyl (preferably including N, S and / or O and preferably including at least one double bond), bicyclic group (preferably including one or two aromatic rings), optionally including one or more heteroatoms (preferably N, O and / or S), or when R14 is H, R15 and R16 are absent.

[0065] In one embodiment, the compound according to formula 2a is characterized in that, R1 is C, S, O, or N. R2 is C or N. R3 is H, C1 to C3 alkyl, C3 to C6 cycloalkyl, or CX3, where X is Cl, Br, or F. R4 and R5 may be the same or different, and are H, C1 to C3 alkyl, C2 to C5 alkenyl, C3 to C6 cycloalkyl, C3 to C6 heterocycloalkyl (preferably including N, S and / or O), C1 to C3 haloalkyl (preferably including Cl, Br or F), C4 to C6 aryl, sulfonyl or one of the following:

[0066]

[0067] Alternatively, R4 and R5, together with the atoms they are attached to, form a 4, 5, or 6-membered heterocyclic alkyl group comprising N and optionally one or more additional heteroatoms (preferably N, O, and / or S), wherein the heterocyclic alkyl group is optionally substituted with an alkoxy group, such as...

[0068] R6 is absent, or R1 is C and R6 forms a carbonyl group (C=O) with R1, or R1 is S and R6 forms a sulfoxide group (S=O) with R1. R7, R8, and R9 may be the same or different; they may be C or N. R9 is C. R10 is H or a C1 to C3 alkyl group. R11 is H, C3 to C6 cycloalkyl, C4 to C6 heterocycloalkyl (preferably including N, S and / or O), halogen (preferably F, Cl or Br), sulfide, sulfinyl, sulfonyl, carboxylic acid ester, formamide or alkoxy-CH2OR, wherein R is C1 to C3 alkyl or benzyl. R14 is H, a C1 to C3 alkyl group, a secondary or tertiary amine, or an alkylamine; or R11 and R14 together with the atoms to which they are attached form a 5 to 7-membered cycloalkyl or aryl ring structure C including two carbon atoms of B, forming a fused cyclic group with B, optionally including one or more heteroatoms (preferably N, O, and / or S). R15 is a C1 to C3 alkyl, carbonyl C=O, or sulfonyl group, and R16 is a C1 to C3 alkyl, C2 to C5 alkenyl, C3 to C6 cycloalkyl, C5 or C6 aryl, benzyl, C5 or C6 heteroaryl (preferably including N, S and / or O), bicyclic group (preferably including one or two aromatic rings), optionally including one or more heteroatoms (preferably N, O and / or S). Or, when R14 is H, R15 and R16 do not exist.

[0069] In one embodiment, the compound according to formula 2a is characterized in that, R4 and R5 may be the same or different, and are H, C1 to C3 alkyl, C2 to C5 alkenyl, C3 to C6 cycloalkyl, C3 to C6 heterocycloalkyl (preferably including N, S and / or O), C1 to C3 haloalkyl (preferably including Cl, Br or F), C4 to C6 aryl, sulfonyl or one of the following:

[0070]

[0071] Where X is C or O. Furthermore, Boc is a tert-butoxycarbonyl group. Alternatively, R4 and R5, together with the atoms they are attached to, form a 4, 5, or 6-membered heterocyclic alkyl group comprising N and optionally one or more additional heteroatoms (preferably N, O, and / or S), wherein the heterocyclic alkyl group is optionally substituted with an alkoxy group, such as... .

[0072] In one embodiment, the compound according to formula 2a is characterized in that R16 is a C1 to C3 alkyl, C2 to C5 alkenyl, C3 to C6 cycloalkyl, C5 or C6 aryl, benzyl, C5 or C6 heteroaryl (preferably including N, S and / or O), C3 to C6 heterocycloalkyl (preferably including N, S and / or O and preferably including at least one double bond), bicyclic group (preferably including one or two aromatic rings), optionally including one or more heteroatoms (preferably N, O and / or S), or when R14 is H, R15 and R16 are absent.

[0073] In one embodiment, the compound according to formula 1, 1a, 2, 2a, 3, 4, 5, 6 or 7 is characterized in that R1 is C, S or O. In one embodiment, the compound according to formula 1, 1a, 2, 2a, 3, 4, 5, 6 or 7 is characterized in that R3 is H, C1 to C2 alkyl, C3 cycloalkyl, or CF3.

[0074] In one embodiment, the compound according to formula 1, 1a, 2, 2a, 3, 4, 5 or 6 is characterized in that R4 and R5 may be the same or different, and are H, CH3, C3 alkenyl, C4 heterocyclic alkyl (preferably including O), -CH2CF3, C6 aryl, sulfonyl or one of the following:

[0075]

[0076] Alternatively, R4 and R5, together with the atoms they are attached to, form a 4- to 6-membered heterocyclic alkyl group comprising N and optionally one or more additional heteroatoms (preferably O), wherein the heterocyclic alkyl group is optionally substituted with an alkoxy group, such as... .

[0077] In one embodiment, the compound according to formula 1, 1a, 2, 2a, 3, 4, 5 or 6 is characterized in that R4 and R5 may be the same or different, and are H, CH3, C3 alkenyl, C4 heterocyclic alkyl (preferably including O), -CH2CF3, C6 aryl, sulfonyl or one of the following:

[0078]

[0079] Where X is C or O. Furthermore, Boc is a tert-butoxycarbonyl group. Alternatively, R4 and R5, together with the atoms they are attached to, form a 4- to 6-membered heterocyclic alkyl group comprising N and optionally one or more additional heteroatoms (preferably O), wherein the heterocyclic alkyl group is optionally substituted with an alkoxy group, such as... .

[0080] In one embodiment, the compound according to formula 1 or 2 is characterized in that R10 is H or CH3, and R11 is H, C3 cycloalkyl, C5 heterocycloalkyl (preferably including N), F, sulfide, sulfinyl, sulfonyl, carboxylic acid ester, formamide, or alkoxy-CH2OR, wherein R is CH3 or benzyl, or R10 and R11 together with the atoms to which they are attached form a 6-membered cycloalkyl or aryl ring structure D including two carbon atoms of B, forming a fused bicyclic group with B, optionally including a heteroatom (preferably N).

[0081] In one embodiment, the compound according to formula 1, 1a, 2 or 2a is characterized in that R14 is H, C1 to C2 alkyl, secondary or tertiary amine or alkylamine, or R11 and R14 together with the atoms to which they are attached form a 5 to 7-membered cycloalkyl or aryl ring structure C including two carbon atoms of B, forming a fused cyclic group with B, optionally including one or more heteroatoms (preferably N, O and / or S).

[0082] In one embodiment, the compound according to formula 1 or 2 is characterized in that R12 is sulfonyl and R13 is C6 aryl, or R12 and R13 are absent when R11 is H or F, or does not form a ring structure with R10 or R14, or when R11 and R14 together with the atoms to which they are attached form a 5 to 7-membered cycloalkyl or aryl ring structure C and R15 and R16 are present.

[0083] In one embodiment, the compound according to formula 1, 1a, 2 or 2a is characterized in that R15 is CH3, carbonyl C=O or sulfonyl, and R16 is CH3, C3 alkenyl, C3 cycloalkyl, C6 cycloalkyl, C6 cycloalkyl, C6 aryl, C5 or C6 heteroaryl (preferably including N and / or S), a bicyclic group comprising at least one aromatic ring, optionally comprising one or more heteroatoms (preferably N, O and / or S), or when R14 is H, or when R10 and R11 together with the atoms to which they are attached form a 5 to 7-membered cycloalkyl or aryl ring structure D, or when R11 and R14 together with the atoms to which they are attached form a 5 to 7-membered cycloalkyl or aryl ring structure C and R12 and R13 are present, R15 and R16 are absent.

[0084] In one embodiment, the compound according to formula 1, 1a, 2 or 2a is characterized in that R15 is CH3, carbonyl C=O or sulfonyl, and R16 is CH3, C3 alkenyl, C3 cycloalkyl, C6 cycloalkyl, C6 cycloalkyl, C6 aryl, C5 or C6 heteroaryl (preferably including N and / or S), C3 to C6 heterocycloalkyl (preferably including N, S and / or O and preferably including at least one double bond), a bicyclic group including at least one aromatic ring, optionally including one or more heteroatoms (preferably N, O and / or S), or when R14 is H, or when R10 and R11 together with the atoms to which they are attached form a 5 to 7-membered cycloalkyl or aryl ring structure D, or when R11 and R14 together with the atoms to which they are attached form a 5 to 7-membered cycloalkyl or aryl ring structure C and R12 and R13 are present, R15 and R16 are absent.

[0085] In one embodiment, the compound according to formula 1 or 2 is characterized in that, R11 and R14, together with the atoms they are attached to, form a 5- to 7-membered ring or aryl ring structure C, which forms a fused bicyclic group with B, wherein B and C are one of the following:

[0086]

[0087] as well as Whether R7, R8, and R9 are the same or different, they are C or N. R12 is a C1 to C5 alkyl group (preferably C1 to C3 alkyl group), carbonyl group (C=O), sulfide, sulfinyl group, or sulfonyl group. R13 is a C1 to C5 alkyl (preferably C1 to C3 alkyl), C2 to C5 alkenyl, C3 to C6 cycloalkyl, C5 or C6 aryl, alkylaryl, C5 or C6 heteroaryl (preferably including N, S and / or O), bicyclic group (preferably including one or two aromatic rings), optionally including one or more heteroatoms (preferably N, O and / or S). R15 is a C1 to C5 alkyl group (preferably C1 to C3 alkyl group), carbonyl group (C=O), sulfide, sulfinyl group, or sulfonyl group. R16 is a C1 to C5 alkyl (preferably C1 to C3 alkyl), C2 to C5 alkenyl, C3 to C6 cycloalkyl, C5 or C6 aryl, alkylaryl, C5 or C6 heteroaryl (preferably including N, S and / or O), bicyclic group (preferably including one or two aromatic rings), optionally including one or more heteroatoms (preferably N, O and / or S). X and Y may be the same or different, and are C, N, S, and / or O. R17 can be the same or different, and can be absent (electron pair of X), H, hydroxyl, halogen (preferably F, Cl, or Br), alkoxy, C1 to C5 alkyl (preferably C1 to C3 alkyl), C1 to C5 haloalkyl (preferably C1 to C3 haloalkyl, including Cl, Br, or F), C3 to C6 cycloalkyl, C3 to C6 heterocycloalkyl (preferably including N, O, and / or S and optionally substituted with alkoxy), C4 to C6 aryl, carbonyl C(=O)R, where R is a C1 to C5 alkyl. (Preferably C1 to C3 alkyl), carboxyl, carboxylic acid ester, alkoxy (preferably -OCH3, -OCH2CH3 or C3 to C6 cycloalkylalkoxy), aldehyde, primary amine, secondary or tertiary amine, amide, imide, carbamate, formamide, nitro, sulfide (preferably -SCH3, -SCH2CH3), sulfinyl, sulfonyl, sulfinyl or sulfonamide, or when X is C, forming a carbonyl C=O with X, or when X is S, forming a sulfoxide S=O or a sulfonyl S(=O)2 with X. Alternatively, two R17 atoms may form a 4, 5, or 6-membered cycloalkyl group, optionally including one or more heteroatoms (preferably N, O, and / or S). R18 can be the same or different, and can be H, alkoxy, or one R18 can form a carbonyl group (C=O) with the attached C atom. Alternatively, an R17 and an R18 form a 5- or 6-membered cyclic ring structure comprising two carbon atoms of C, forming a fused cyclic group with C, optionally including one or more heteroatoms (preferably N, O, and / or S), wherein the 5- or 6-membered cyclic ring structure is optionally substituted with a C1 to C3 alkyl or alkoxy carbonyl group (preferably at the heteroatom position), and R19 can be the same or different, and is H, C1 to C6 alkyl (preferably C1 to C3 alkyl).

[0088] In one embodiment, the compound according to formula 1 or 2 is characterized in that R11 and R14 together with the atoms to which they are attached form a 5 to 7-membered ring or aryl ring structure C, forming a fused bicyclic group with B, wherein B and C are as disclosed above, and R12 is a sulfonyl group and R13 is a C6 aryl group.

[0089] In one embodiment, the compound according to Formula 1 or 2 is characterized in that R11 and R14 together with the atoms to which they are attached form a 5- to 7-membered ring or aryl ring structure C, forming a fused bicyclic group with B, wherein B and C are as disclosed above, and R15 is CH3, carbonyl C=O or sulfonyl, and R16 is CH3, C3 alkenyl, C3 cycloalkyl, C6 cycloalkyl, C6 cycloalkyl, C6 aryl, C5 or C6 heteroaryl (preferably including N and / or S), a bicyclic group comprising at least one aromatic ring, optionally comprising one or more heteroatoms (preferably N, O and / or S).

[0090] In one embodiment, the compound according to Formula 1 or 2 is characterized in that R11 and R14, together with the atoms to which they are attached, form a 5- to 7-membered ring or aryl ring structure C, forming a fused bicyclic group with B, wherein B and C are as disclosed above, and R17 may be the same or different, and is absent (electron pair of X), H, hydroxyl, F, CH3, C4 to C6 heterocyclic alkyl (preferably including N and / or O and optionally substituted with alkoxy), -C(=O)CH3, carboxylic acid ester, alkoxy (preferably -OCH3 or C4 cycloalkylalkoxy), tertiary amine, -SCH2CH3, or when X is C, forming a carbonyl C=O with X, or when X is S, forming a alkyl group with X. The R17 may be sulfone S=O or sulfonyl S(=O)2, or two R17 may form a 4-membered cycloalkyl group, optionally including one or more heteroatoms (preferably O), and R18 may be the same or different, being H, alkoxy, or one R18 may form a carbonyl C=O with the attached C atom, or one R17 and one R18 may form a 5 or 6-membered cyclic ring structure including two carbon atoms of C, forming a fused cyclic group with C, optionally including one or more heteroatoms (preferably N and / or O), wherein the 5 or 6-membered cyclic ring structure is optionally substituted by a C1 to C3 alkyl or alkoxy carbonyl group (preferably at the heteroatom position), and R19 may be the same or different, being H or CH3.

[0091] In one embodiment, the compound according to formula 1a or 2a is characterized in that, R11 and R14, together with the atoms they are attached to, form a 5- to 7-membered ring or aryl ring structure C, which forms a fused bicyclic group with B, wherein B and C are one of the following:

[0092] as well as Whether R7 and R8 are the same or different, and whether they are C or N. R9 is C. R15 is a C1 to C5 alkyl group (preferably C1 to C3 alkyl group), carbonyl group (C=O), sulfide, sulfinyl group, or sulfonyl group. R16 is a C1 to C5 alkyl (preferably C1 to C3 alkyl), C2 to C5 alkenyl, C3 to C6 cycloalkyl, C5 or C6 aryl, alkylaryl, C5 or C6 heteroaryl (preferably including N, S and / or O), bicyclic group (preferably including one or two aromatic rings), optionally including one or more heteroatoms (preferably N, O and / or S). X and Y may be the same or different, and are C, N, S, and / or O. R17 can be the same or different, and can be absent (electron pair of X), H, hydroxyl, halogen (preferably F, Cl, or Br), alkoxy, C1 to C5 alkyl (preferably C1 to C3 alkyl), C1 to C5 haloalkyl (preferably C1 to C3 haloalkyl, including Cl, Br, or F), C3 to C6 cycloalkyl, C3 to C6 heterocycloalkyl (preferably including N, O, and / or S and optionally substituted with alkoxy), C4 to C6 aryl, carbonyl C(=O)R, where R is a C1 to C5 alkyl. (Preferably C1 to C3 alkyl), carboxyl, carboxylic acid ester, alkoxy (preferably -OCH3, -OCH2CH3 or C3 to C6 cycloalkylalkoxy), aldehyde, primary amine, secondary or tertiary amine, amide, imide, carbamate, formamide, nitro, sulfide (preferably -SCH3, -SCH2CH3), sulfinyl, sulfonyl, sulfinyl or sulfonamide, or when X is C, forming a carbonyl C=O with X, or when X is S, forming a sulfoxide S=O or a sulfonyl S(=O)2 with X. Alternatively, two R17 atoms may form a 4, 5, or 6-membered cycloalkyl group, optionally including one or more heteroatoms (preferably N, O, and / or S). R18 can be the same or different, and can be H, alkoxy, or one R18 can form a carbonyl group (C=O) with the attached C atom. Alternatively, an R17 and an R18 form a 5- or 6-membered cyclic ring structure comprising two carbon atoms of C, forming a fused cyclic group with C, optionally including one or more heteroatoms (preferably N, O, and / or S), wherein the 5- or 6-membered cyclic ring structure is optionally substituted with a C1 to C3 alkyl or alkoxy carbonyl group (preferably at the heteroatom position), and R19 can be the same or different, and is H, C1 to C6 alkyl (preferably C1 to C3 alkyl).

[0093] In one embodiment, the compound according to formula 1a or 2a is characterized in that R11 and R14 together with the atoms to which they are attached form a 5- to 7-membered ring or aryl ring structure C, forming a fused bicyclic group with B, wherein B and C are as disclosed above, and R15 is CH3, carbonyl C=O or sulfonyl, and R16 is CH3, C3 alkenyl, C3 cycloalkyl, C6 cycloalkyl, C6 cycloalkyl, C6 aryl, C5 or C6 heteroaryl (preferably including N and / or S), a bicyclic group comprising at least one aromatic ring, optionally comprising one or more heteroatoms (preferably N, O and / or S).

[0094] In one embodiment, the compound according to formula 1a or 2a is characterized in that R11 and R14 together with the atoms to which they are attached form a 5- to 7-membered ring or aryl ring structure C, forming a fused bicyclic group with B, wherein B and C are as disclosed above, and R17 may be the same or different, and is absent (electron pair of X), H, hydroxyl, F, CH3, C4 to C6 heterocyclic alkyl (preferably including N and / or O and optionally substituted with alkoxy), -C(=O)CH3, carboxylic ester, alkoxy (preferably -OCH3 or C4 cycloalkylalkoxy), tertiary amine, -SCH2CH3, or when X is C, forming a carbonyl C=O with X, or when X is S, forming a The sulfoxide S=O or sulfonyl S(=O)2, or two R17s forming a 4-membered cycloalkyl group, optionally including one or more heteroatoms (preferably O), and R18 may be the same or different, being H, alkoxy, or one R18 forming a carbonyl C=O with the attached C atom, or one R17 and one R18 forming a 5 or 6-membered cyclic ring structure including two carbon atoms of C, forming a fused cyclic group with C, optionally including one or more heteroatoms (preferably N and / or O), wherein the 5 or 6-membered cyclic ring structure is optionally substituted by a C1 to C3 alkyl or alkoxy carbonyl group (preferably at the heteroatom position), and R19 may be the same or different, being H, CH3.

[0095] In one embodiment, the present invention relates to a compound according to Formula 3 for use in treating medical conditions associated with defective and / or pathological type II phosphoinositol 3-kinase (PI3K) signaling. Formula 3 in R1 is C, S, O, or N. R2 is C or N. R3 is H, C1 to C5 alkyl (preferably C1 to C3 alkyl), C3 to C6 cycloalkyl, C1 to C5 haloalkyl (preferably C1 to C3 haloalkyl, including Cl, Br or F), -CN, carbonyl, carboxyl, carboxylic acid ester, alkoxy, aldehyde, primary amine, secondary or tertiary amine, amide, imide, carbamate, formamide, nitro, sulfide, sulfinyl, sulfonyl, sulfinyl or sulfonamide R4 and R5 may be the same or different, and are H, C1 to C5 alkyl (preferably C1 to C3 alkyl), C2 to C5 alkenyl, C3 to C6 cycloalkyl, C3 to C6 heterocycloalkyl (preferably including N, S and / or O), C1 to C5 haloalkyl (preferably C1 to C3 haloalkyl, preferably including Cl, Br or F), C4 to C6 aryl, sulfide, sulfinyl, sulfonyl, sulfinyl, sulfonamide, carboxyl, carboxylic acid ester, carbonyl C=OR, wherein R is C1 to C10 alkyl (preferably C1 to C5 alkyl), C1 to C3 haloalkyl (preferably including Cl, Br or F), C4 to C6 aryl, wherein R is optionally substituted with a urethane group or urethane. Alternatively, R4 and R5 form a 4, 5, or 6-membered heterocyclic alkyl group comprising N and optionally one or more additional heteroatoms (preferably N, O, and / or S), wherein the heterocyclic alkyl group is optionally substituted with an alkoxy group. R6 is absent, or R1 is C and R6 forms a carbonyl group (C=O) with R1, or R1 is S and R6 forms a sulfoxide group (S=O) with R1. Whether R7, R8, and R9 are the same or different, they are C or N. R10 is H, C1 to C5 alkyl (preferably C1 to C3 alkyl), C3 to C6 cycloalkyl, C1 to C5 haloalkyl (preferably C1 to C3 haloalkyl, including Cl, Br or F), -CN, carbonyl, carboxyl, carboxylic acid ester, alkoxy, aldehyde, primary amine, secondary or tertiary amine, amide, imide, carbamate, formamide, nitro, sulfide, sulfinyl, sulfonyl, sulfinyl or sulfonamide R11 is H, C3 to C6 cycloalkyl, C4 to C6 heterocycloalkyl (preferably including N, S and / or O), halogen (preferably F, Cl or Br), sulfide, sulfinyl, sulfonyl, sulfinyl, sulfonamide, carboxyl, carboxylic acid ester, formamide, alkoxy or aryloxy. R14 is H, C1 to C5 alkyl (preferably C1 to C3 alkyl), primary amine, secondary amine, tertiary amine, or alkylamine. Alternatively, R11 and R14, together with the atoms they are attached to, form a 5- to 8-membered cycloalkyl or aryl ring structure C comprising two carbon atoms of B, forming a fused cyclic group with B, optionally including one or more heteroatoms (preferably N, O, and / or S). R16 is a C1 to C5 alkyl (preferably C1 to C3 alkyl), C2 to C5 alkenyl, C3 to C6 cycloalkyl, C5 or C6 aryl, alkylaryl, C5 or C6 heteroaryl (preferably including N, S and / or O), bicyclic group (preferably including one or two aromatic rings), optionally including one or more heteroatoms (preferably N, O and / or S).

[0096] In one embodiment, the compound according to Formula 3 is characterized in that R4 and R5 may be the same or different, and are H, C1 to C5 alkyl (preferably C1 to C3 alkyl), C2 to C5 alkenyl, C3 to C6 cycloalkyl, C3 to C6 heterocycloalkyl (preferably including N, S and / or O), C1 to C5 haloalkyl (preferably C1 to C3 haloalkyl, preferably including Cl, Br or F), C3 to C6 cycloalkyl, alkoxy, C4 to C6 aryl, C5 to C6 The compounds include heteroaryl groups (preferably including N, S, and / or O and optionally substituted with C3 to C6 heterocyclic groups (preferably including N, S, and / or O)), sulfides, sulfinyl groups, sulfonyl groups, sulfinyl groups, sulfonamides, carboxyl groups, carboxylic acid esters, and carbonyl groups (C=OR), wherein R is a C1 to C10 alkyl group (preferably C1 to C5 alkyl group), a C1 to C3 haloalkyl group (preferably including Cl, Br, or F), or a C4 to C6 aryl group, wherein R is optionally substituted with a urethane group or a urethane ester. Alternatively, R4 and R5 form a 4, 5, or 6-membered heterocyclic alkyl group comprising N and optionally one or more additional heteroatoms (preferably N, O, and / or S), wherein the heterocyclic alkyl group is optionally substituted with an alkoxy group.

[0097] In one embodiment, the compound according to Formula 3 is characterized in that R16 is a C1 to C5 alkyl (preferably C1 to C3 alkyl), C2 to C5 alkenyl, C3 to C6 cycloalkyl, C5 or C6 aryl, alkylaryl, C5 or C6 heteroaryl (preferably including N, S and / or O), C3 to C6 heterocycloalkyl (preferably including N, S and / or O and preferably including at least one double bond), bicyclic group (preferably including one or two aromatic rings), optionally including one or more heteroatoms (preferably N, O and / or S).

[0098] In one embodiment, the compound according to Formula 3 is characterized in that, R1 is C, S, O, or N. R2 is C or N. R3 is H, C1 to C3 alkyl, C3 to C6 cycloalkyl, or CX3, where X is Cl, Br, or F. R4 and R5 may be the same or different, and are H, C1 to C3 alkyl, C2 to C5 alkenyl, C3 to C6 cycloalkyl, C3 to C6 heterocycloalkyl (preferably including N, S and / or O), C1 to C3 haloalkyl (preferably including Cl, Br or F), C4 to C6 aryl, sulfonyl or one of the following:

[0099]

[0100] Alternatively, R4 and R5, together with the atoms they are attached to, form a 4, 5, or 6-membered heterocyclic alkyl group comprising N and optionally one or more additional heteroatoms (preferably N, O, and / or S), wherein the heterocyclic alkyl group is optionally substituted with an alkoxy group, such as...

[0101] R6 is absent, or R1 is C and R6 forms a carbonyl group (C=O) with R1, or R1 is S and R6 forms a sulfoxide group (S=O) with R1. Whether R7, R8, and R9 are the same or different, they are C or N. R10 is H or a C1 to C3 alkyl group. R11 is H, C3 to C6 cycloalkyl, C4 to C6 heterocycloalkyl (preferably including N, S and / or O), halogen (preferably F, Cl or Br), sulfide, sulfinyl, sulfonyl, carboxylic acid ester, formamide or alkoxy-CH2OR, wherein R is C1 to C3 alkyl or benzyl. R14 is H, a C1 to C3 alkyl group, a secondary or tertiary amine, or an alkylamine; or R11 and R14 together with the atoms to which they are attached form a 5 to 7-membered cycloalkyl or aryl ring structure C including two carbon atoms of B, forming a fused cyclic group with B, optionally including one or more heteroatoms (preferably N, O, and / or S). R16 is a C1 to C3 alkyl, C2 to C5 alkenyl, C3 to C6 cycloalkyl, C5 or C6 aryl, benzyl, C5 or C6 heteroaryl (preferably including N, S and / or O), bicyclic group (preferably including one or two aromatic rings), optionally including one or more heteroatoms (preferably N, O and / or S).

[0102] In one embodiment, the compound according to Formula 3 is characterized in that, R4 and R5 may be the same or different, and are H, C1 to C3 alkyl, C2 to C5 alkenyl, C3 to C6 cycloalkyl, C3 to C6 heterocycloalkyl (preferably including N, S and / or O), C1 to C3 haloalkyl (preferably including Cl, Br or F), C4 to C6 aryl, sulfonyl or one of the following:

[0103]

[0104] Where X is C or O. Furthermore, Boc is a tert-butoxycarbonyl group. Alternatively, R4 and R5, together with the atoms they are attached to, form a 4, 5, or 6-membered heterocyclic alkyl group comprising N and optionally one or more additional heteroatoms (preferably N, O, and / or S), wherein the heterocyclic alkyl group is optionally substituted with an alkoxy group, such as... .

[0105] In one embodiment, the compound according to Formula 3 is characterized in that R16 is a C1 to C3 alkyl, C2 to C5 alkenyl, C3 to C6 cycloalkyl, C5 or C6 aryl, benzyl, C5 or C6 heteroaryl (preferably including N, S and / or O), C3 to C6 heterocycloalkyl (preferably including N, S and / or O and preferably including at least one double bond), bicyclic group (preferably including one or two aromatic rings), optionally including one or more heteroatoms (preferably N, O and / or S).

[0106] In one embodiment, the present invention relates to a compound according to Formula 4 for use in treating medical conditions associated with defective and / or pathological type II phosphoinositol 3-kinase (PI3K) signaling. Formula 4 in R1 is C, S, O, or N. R2 is C or N. R3 is H, C1 to C5 alkyl (preferably C1 to C3 alkyl), C3 to C6 cycloalkyl, C1 to C5 haloalkyl (preferably C1 to C3 haloalkyl, including Cl, Br or F), -CN, carbonyl, carboxyl, carboxylic acid ester, alkoxy, aldehyde, primary amine, secondary or tertiary amine, amide, imide, carbamate, formamide, nitro, sulfide, sulfinyl, sulfonyl, sulfinyl or sulfonamide R6 is absent, or R1 is C and R6 forms a carbonyl group (C=O) with R1, or R1 is S and R6 forms a sulfoxide group (S=O) with R1. Whether R7, R8, and R9 are the same or different, they are C or N. R10 is H, C1 to C5 alkyl (preferably C1 to C3 alkyl), C3 to C6 cycloalkyl, C1 to C5 haloalkyl (preferably C1 to C3 haloalkyl, including Cl, Br or F), -CN, carbonyl, carboxyl, carboxylic acid ester, alkoxy, aldehyde, primary amine, secondary or tertiary amine, amide, imide, carbamate, formamide, nitro, sulfide, sulfinyl, sulfonyl, sulfinyl or sulfonamide R11 is H, C3 to C6 cycloalkyl, C4 to C6 heterocycloalkyl (preferably including N, S and / or O), halogen (preferably F, Cl or Br), sulfide, sulfinyl, sulfonyl, sulfinyl, sulfonamide, carboxyl, carboxylic acid ester, formamide, alkoxy or aryloxy. R14 is H, C1 to C5 alkyl (preferably C1 to C3 alkyl), primary amine, secondary amine, tertiary amine, or alkylamine. Alternatively, R11 and R14, together with the atoms they are attached to, form a 5- to 8-membered cycloalkyl or aryl ring structure C comprising two carbon atoms of B, forming a fused cyclic group with B, optionally including one or more heteroatoms (preferably N, O, and / or S). R16 is a C1 to C5 alkyl (preferably C1 to C3 alkyl), C2 to C5 alkenyl, C3 to C6 cycloalkyl, C5 or C6 aryl, alkylaryl, C5 or C6 heteroaryl (preferably including N, S and / or O), bicyclic group (preferably including one or two aromatic rings), optionally including one or more heteroatoms (preferably N, O and / or S).

[0107] In one embodiment, the compound according to Formula 4 is characterized in that, R1 is C, S, O, or N. R2 is C or N. R3 is H, C1 to C3 alkyl, C3 to C6 cycloalkyl, or CX3, where X is Cl, Br, or F. R6 is absent, or R1 is C and R6 forms a carbonyl group (C=O) with R1, or R1 is S and R6 forms a sulfoxide group (S=O) with R1. Whether R7, R8, and R9 are the same or different, they are C or N. R10 is H or a C1 to C3 alkyl group. R11 is H, C3 to C6 cycloalkyl, C4 to C6 heterocycloalkyl (preferably including N, S and / or O), halogen (preferably F, Cl or Br), sulfide, sulfinyl, sulfonyl, carboxylic acid ester, formamide or alkoxy-CH2OR, wherein R is C1 to C3 alkyl or benzyl. R14 is H, a C1 to C3 alkyl group, a secondary or tertiary amine, or an alkylamine; or R11 and R14 together with the atoms to which they are attached form a 5 to 7-membered cycloalkyl or aryl ring structure C including two carbon atoms of B, forming a fused cyclic group with B, optionally including one or more heteroatoms (preferably N, O, and / or S). R16 is a C1 to C3 alkyl, C2 to C5 alkenyl, C3 to C6 cycloalkyl, C5 or C6 aryl, benzyl, C5 or C6 heteroaryl (preferably including N, S and / or O), bicyclic group (preferably including one or two aromatic rings), optionally including one or more heteroatoms (preferably N, O and / or S).

[0108] According to Formula 4 of the present invention, combinations of various preferred embodiments are themselves considered preferred embodiments.

[0109] In one embodiment, the compound according to Formula 4 is characterized in that R16 is a C1 to C3 alkyl, C2 to C5 alkenyl, C3 to C6 cycloalkyl, C5 or C6 aryl, benzyl, C5 or C6 heteroaryl (preferably including N, S and / or O), C3 to C6 heterocycloalkyl (preferably including N, S and / or O and preferably including at least one double bond), bicyclic group (preferably including one or two aromatic rings), optionally including one or more heteroatoms (preferably N, O and / or S).

[0110] In one embodiment, the compound according to formula 3 or 4 is characterized in that R7 and R8 are the same or different, are C or N, and R9 is C.

[0111] In one embodiment, the compound according to formula 3 or 4 is characterized in that R10 is H or CH3, and R11 is H, C3 cycloalkyl, C5 heterocycloalkyl (preferably including N), F, sulfide, sulfinyl, sulfonyl, carboxylic acid ester, formamide or alkoxy-CH2OR, wherein R is CH3 or benzyl.

[0112] In one embodiment, the compound according to formula 3 or 4 is characterized in that R14 is H, C1 to C2 alkyl, secondary or tertiary amine or alkylamine, or R11 and R14 together with the atoms to which they are attached form a 5 to 7-membered cycloalkyl or aryl ring structure C including two carbon atoms of B, forming a fused cyclic group with B, optionally including one or more heteroatoms (preferably N, O and / or S).

[0113] In one embodiment, the compound according to formula 3, 4, 5, 6 or 7 is characterized in that R16 is a CH3, C3 alkenyl, C3 cycloalkyl, C6 cycloalkyl, C6 cycloalkyl, C6 aryl, C5 or C6 heteroaryl (preferably including N and / or S), a bicyclic group comprising at least one aromatic ring, optionally comprising one or more heteroatoms (preferably N, O and / or S).

[0114] In one embodiment, the compound according to formula 3 or 4 is characterized in that, R11 and R14, together with the atoms they are attached to, form a 5- to 7-membered ring or aryl ring structure C, which forms a fused bicyclic group with B, wherein B and C are one of the following:

[0115] as well as Whether R7, R8, and R9 are the same or different, they are C or N. R16 is a C1 to C5 alkyl (preferably C1 to C3 alkyl), C2 to C5 alkenyl, C3 to C6 cycloalkyl, C5 or C6 aryl, alkylaryl, C5 or C6 heteroaryl (preferably including N, S and / or O), bicyclic group (preferably including one or two aromatic rings), optionally including one or more heteroatoms (preferably N, O and / or S). X and Y may be the same or different, and are C, N, S, and / or O. R17 can be the same or different, and can be absent (electron pair of X), H, hydroxyl, halogen (preferably F, Cl, or Br), alkoxy, C1 to C5 alkyl (preferably C1 to C3 alkyl), C1 to C5 haloalkyl (preferably C1 to C3 haloalkyl, including Cl, Br, or F), C3 to C6 cycloalkyl, C3 to C6 heterocycloalkyl (preferably including N, O, and / or S and optionally substituted with alkoxy), C4 to C6 aryl, carbonyl C(=O)R, where R is a C1 to C5 alkyl. (Preferably C1 to C3 alkyl), carboxyl, carboxylic acid ester, alkoxy (preferably -OCH3, -OCH2CH3 or C3 to C6 cycloalkylalkoxy), aldehyde, primary amine, secondary or tertiary amine, amide, imide, carbamate, formamide, nitro, sulfide (preferably -SCH3, -SCH2CH3), sulfinyl, sulfonyl, sulfinyl or sulfonamide, or when X is C, forming a carbonyl C=O with X, or when X is S, forming a sulfoxide S=O or a sulfonyl S(=O)2 with X. Alternatively, two R17 atoms may form a 4, 5, or 6-membered cycloalkyl group, optionally including one or more heteroatoms (preferably N, O, and / or S). R18 can be the same or different, and can be H, alkoxy, or one R18 can form a carbonyl group (C=O) with the attached C atom. Alternatively, an R17 and an R18 form a 5- or 6-membered cyclic ring structure comprising two carbon atoms of C, forming a fused cyclic group with C, optionally including one or more heteroatoms (preferably N, O, and / or S), wherein the 5- or 6-membered cyclic ring structure is optionally substituted with a C1 to C3 alkyl or alkoxy carbonyl group (preferably at the heteroatom position), and R19 can be the same or different, and is H, C1 to C6 alkyl (preferably C1 to C3 alkyl).

[0116] In one embodiment, the compound according to formula 3 or 4 is characterized in that R11 and R14 together with the atoms to which they are attached form a 5- to 7-membered ring or aryl ring structure C, forming a fused bicyclic group with B, wherein B and C are as disclosed above, and R16 is a CH3, C3 alkenyl, C3 cycloalkyl, C6 cycloalkyl, C6 cycloalkyl, C6 aryl, C5 or C6 heteroaryl (preferably including N and / or S), a bicyclic group comprising at least one aromatic ring, optionally comprising one or more heteroatoms (preferably N, O and / or S).

[0117] In one embodiment, the compound according to formula 3 or 4 is characterized in that R11 and R14 together with the atoms to which they are attached form a 5- to 7-membered ring or aryl ring structure C, forming a fused bicyclic group with B, wherein B and C are as disclosed above, and R16 is CH3, C3 alkenyl, C3 cycloalkyl, C6 cycloalkyl, C6 cycloalkyl, C6 aryl, C5 or C6 heteroaryl (preferably including N and / or S), C3 to C6 heterocycloalkyl (preferably including N, S and / or O and preferably including at least one double bond), a bicyclic group including at least one aromatic ring, optionally including one or more heteroatoms (preferably N, O and / or S).

[0118] In one embodiment, the compound according to formula 3 or 4 is characterized in that R11 and R14 together with the atoms to which they are attached form a 5- to 7-membered ring or aryl ring structure C, forming a fused bicyclic group with B, wherein B and C are as disclosed above, and R17 may be the same or different, and is absent (electron pair of X), H, hydroxyl, F, CH3, C4 to C6 heterocyclic alkyl (preferably including N and / or O and optionally substituted with alkoxy), -C(=O)CH3, carboxylic acid ester, alkoxy (preferably -OCH3 or C4 cycloalkylalkoxy), tertiary amine, -SCH2CH3, or when X is C, forming a carbonyl C=O with X, or when X is S, forming a alkyl group with X. The R17 may be sulfone S=O or sulfonyl S(=O)2, or two R17 may form a 4-membered cycloalkyl group, optionally including one or more heteroatoms (preferably O), and R18 may be the same or different, being H, alkoxy, or one R18 may form a carbonyl C=O with the attached C atom, or one R17 and one R18 may form a 5 or 6-membered cyclic ring structure including two carbon atoms of C, forming a fused cyclic group with C, optionally including one or more heteroatoms (preferably N and / or O), wherein the 5 or 6-membered cyclic ring structure is optionally substituted by a C1 to C3 alkyl or alkoxy carbonyl group (preferably at the heteroatom position), and R19 may be the same or different, being H or CH3.

[0119] In one embodiment, the compound according to formula 1, 1a, 2, 2a, 3, 4, 5, 6 or 7 is characterized in that R16 is one of the following:

[0120] in R20 may be the same or different, and is H, C1 to C5 alkyl (preferably C1 to C3 alkyl), halogen (preferably F, Cl and / or Br), alkoxy or E, wherein E is one of the following:

[0121] R21 can be the same or different, and is H, C1 to C5 alkyl (preferably C1 to C3 alkyl), halogen (preferably F, Cl and / or Br), alkoxy, primary amine, secondary or tertiary amine, sulfide, sulfinyl, sulfonyl, sulfinyl, sulfonamide, carboxyl, carboxylic acid ester, secondary hydroxyl group C(-OH)CH3, carbonyl C=OR (wherein R is C1 to C10 alkyl (preferably C1 to C5 alkyl), C1 to C3 haloalkyl (preferably including Cl, Br or F)), imide, urethane group, formamide, amide N=OR (wherein R is C1 to C3 alkyl, C1 to C3 alkenyl, C1 to C3 haloalkyl (preferably including Cl, Br or F)), nitro or E, R22 can be the same or different, and is H or a C1 to C5 alkyl group (preferably a C1 to C3 alkyl group). R23 is an H, carbonyl, carboxyl, or carboxylic acid ester. R24 is H or a C1 to C5 alkyl group (preferably a C1 to C3 alkyl group), and R25 can be the same or different, and can be H, C1 to C4 alkyl, C1 to C4 heteroalkyl, C3 to C6 cycloalkyl, or C2 to C6 heterocycloalkyl.

[0122] In one embodiment, the compound according to formula 1, 1a, 2, 2a, 3, 4, 5, 6 or 7 is characterized in that R16 is one of the following:

[0123] X and Y can be the same or different, and can be C, O, S or N. R20 may be the same or different, and is H, C1 to C5 alkyl (preferably C1 to C3 alkyl), halogen (preferably F, Cl and / or Br), alkoxy or E, wherein E is one of the following:

[0124] R21 can be the same or different, and is H, C1 to C5 alkyl (preferably C1 to C3 alkyl), halogen (preferably F, Cl and / or Br), alkoxy, primary amine, secondary or tertiary amine, sulfide, sulfinyl, sulfonyl, sulfinyl, sulfonamide, carboxyl, carboxylic acid ester, secondary hydroxyl group C(-OH)CH3, carbonyl C=OR (wherein R is C1 to C10 alkyl (preferably C1 to C5 alkyl), C1 to C3 haloalkyl (preferably including Cl, Br or F)), imide, urethane group, formamide, amide N=OR (wherein R is C1 to C3 alkyl, C1 to C3 alkenyl, C1 to C3 haloalkyl (preferably including Cl, Br or F)), nitro or E, R22 can be the same or different, and is H or a C1 to C5 alkyl group (preferably a C1 to C3 alkyl group). R23 is an H, carbonyl, carboxyl, or carboxylic acid ester. R24 is H or a C1 to C5 alkyl group (preferably a C1 to C3 alkyl group), and R25 can be the same or different, and can be H, C1 to C4 alkyl, C1 to C4 heteroalkyl, C3 to C6 cycloalkyl, or C2 to C6 heterocycloalkyl.

[0125] In one embodiment, the compounds according to formula 1, 1a, 2, 2a, 3, 4, 5, 6 or 7 are characterized in that R20 may be the same or different, and is H, CH3, F, Cl or alkoxy.

[0126] In one embodiment, the compounds according to formula 1, 1a, 2, 2a, 3, 4, 5, 6 or 7 are characterized in that R21 may be the same or different and is H, CH3, F, Cl, Br, alkoxy, tertiary amine, sulfonyl, carboxyl, carboxylic acid ester, secondary hydroxyl group C(-OH)CH3, carbonyl C=OR (wherein R is CH3 or C2 haloalkyl (preferably including Br)), amide N=OR (wherein CH3, C2 alkenyl or C2 haloalkyl (preferably including Cl)) or nitro.

[0127] In one embodiment, the compounds according to formula 1, 1a, 2, 2a, 3, 4, 5, 6, or 7 are characterized in that R22 may be the same or different, and is H or CH3. In one embodiment, the compounds according to formula 1, 1a, 2, 2a, 3, 4, 5, 6, or 7 are characterized in that R23 is H or a carboxylic acid ester. In one embodiment, the compounds according to formula 1, 1a, 2, 2a, 3, 4, 5, 6, or 7 are characterized in that R24 is H or CH3.

[0128] In one embodiment, the compound according to formula 1, 1a, 2, 2a, 3, 4, 5, 6 or 7 is characterized in that R16 is one of the following:

[0129] X and Y can be the same or different, and can be C, O, S or N. R20 may be the same or different, and is H, C1 to C5 alkyl (preferably C1 to C3 alkyl), halogen (preferably F, Cl and / or Br), alkoxy or E, wherein E is one of the following:

[0130]

[0131] R21 can be the same or different, and is H, C1 to C5 alkyl (preferably C1 to C3 alkyl), halogen (preferably F, Cl and / or Br), alkoxy, primary amine, secondary or tertiary amine, sulfide, sulfinyl, sulfonyl, sulfinyl, sulfonamide, carboxyl, carboxylic acid ester, secondary hydroxyl group C(-OH)CH3, carbonyl C=OR (wherein R is C1 to C10 alkyl (preferably C1 to C5 alkyl), C1 to C3 haloalkyl (preferably including Cl, Br or F)), imide, urethane group, formamide, amide N=OR (wherein R is C1 to C3 alkyl, C1 to C3 alkenyl, C1 to C3 haloalkyl (preferably including Cl, Br or F)), nitro or E, R22 can be the same or different, and is H or a C1 to C5 alkyl group (preferably a C1 to C3 alkyl group). R23 is an H, carbonyl, carboxyl, or carboxylic acid ester. R24 is H or a C1 to C5 alkyl group (preferably a C1 to C3 alkyl group). R25 can be the same or different, and can be H, C1 to C4 alkyl, C1 to C4 heteroalkyl, C3 to C6 cycloalkyl, or C2 to C6 heterocycloalkyl. R26, R27, and R28 may be the same or different, and are H, C1 to C3 alkyl groups, halogens (preferably Cl, Br, or F), and R29 is H or a C1 to C3 alkyl group (preferably a C1 alkyl group).

[0132] In one embodiment, the present invention relates to a compound according to Formula 5 for use in treating medical conditions associated with defective and / or pathological type II phosphoinositol 3-kinase (PI3K) signaling. Formula 5 in R1 is C, S, O, or N. R2 is C or N. R3 is H, C1 to C5 alkyl (preferably C1 to C3 alkyl), C3 to C6 cycloalkyl, C1 to C5 haloalkyl (preferably C1 to C3 haloalkyl, including Cl, Br or F), -CN, carbonyl, carboxyl, carboxylic acid ester, alkoxy, aldehyde, primary amine, secondary or tertiary amine, amide, imide, carbamate, formamide, nitro, sulfide, sulfinyl, sulfonyl, sulfinyl or sulfonamide R4 and R5 may be the same or different, and are H, C1 to C5 alkyl (preferably C1 to C3 alkyl), C2 to C5 alkenyl, C3 to C6 cycloalkyl, C3 to C6 heterocycloalkyl (preferably including N, S and / or O), C1 to C5 haloalkyl (preferably C1 to C3 haloalkyl, preferably including Cl, Br or F), C4 to C6 aryl, sulfide, sulfinyl, sulfonyl, sulfinyl, sulfonamide, carboxyl, carboxylic acid ester, carbonyl C=OR, wherein R is C1 to C10 alkyl (preferably C1 to C5 alkyl), C1 to C3 haloalkyl (preferably including Cl, Br or F), C4 to C6 aryl, wherein R is optionally substituted with a urethane group or urethane. Alternatively, R4 and R5 form a 4, 5, or 6-membered heterocyclic alkyl group comprising N and optionally one or more additional heteroatoms (preferably N, O, and / or S), wherein the heterocyclic alkyl group is optionally substituted with an alkoxy group. R6 is absent, or R1 is C and R6 forms a carbonyl group (C=O) with R1, or R1 is S and R6 forms a sulfoxide group (S=O) with R1. Whether R7, R8, and R9 are the same or different, they are C or N. R10 is H, C1 to C5 alkyl (preferably C1 to C3 alkyl), C3 to C6 cycloalkyl, C1 to C5 haloalkyl (preferably C1 to C3 haloalkyl, including Cl, Br or F), -CN, carbonyl, carboxyl, carboxylic acid ester, alkoxy, aldehyde, primary amine, secondary or tertiary amine, amide, imide, carbamate, formamide, nitro, sulfide, sulfinyl, sulfonyl, sulfinyl or sulfonamide R15 is a C1 to C5 alkyl group (preferably C1 to C3 alkyl group), carbonyl group (C=O), sulfide, sulfinyl group, or sulfonyl group. R16 is a C1 to C5 alkyl (preferably C1 to C3 alkyl), C2 to C5 alkenyl, C3 to C6 cycloalkyl, C5 or C6 aryl, alkylaryl, C5 or C6 heteroaryl (preferably including N, S and / or O), bicyclic group (preferably including one or two aromatic rings), optionally including one or more heteroatoms (preferably N, O and / or S). R17 can be the same or different, and can be absent (electron pair of X), H, hydroxyl, halogen (preferably F, Cl, or Br), alkoxy, C1 to C5 alkyl (preferably C1 to C3 alkyl), C1 to C5 haloalkyl (preferably C1 to C3 haloalkyl, including Cl, Br, or F), C3 to C6 cycloalkyl, C3 to C6 heterocycloalkyl (preferably including N, O, and / or S and optionally substituted with alkoxy), C4 to C6 aryl, carbonyl C(=O)R, where R is a C1 to C5 alkyl. (Preferably C1 to C3 alkyl), carboxyl, carboxylic acid ester, alkoxy (preferably -OCH3, -OCH2CH3 or C3 to C6 cycloalkylalkoxy), aldehyde, primary amine, secondary or tertiary amine, amide, imide, carbamate, formamide, nitro, sulfide (preferably -SCH3, -SCH2CH3), sulfinyl, sulfonyl, sulfinyl or sulfonamide, or when X is C, forming a carbonyl C=O with X, or when X is S, forming a sulfoxide S=O or a sulfonyl S(=O)2 with X. Alternatively, two R17 atoms may form a 4, 5, or 6-membered cycloalkyl group, optionally including one or more heteroatoms (preferably N, O, and / or S). R18 can be the same or different, and can be H, alkoxy, or one R18 can form a carbonyl group (C=O) with the attached C atom. Alternatively, an R17 and an R18 form a 5- or 6-membered cyclic ring structure comprising two carbon atoms of C, forming a fused cyclic group with C, optionally including one or more heteroatoms (preferably N, O, and / or S), wherein the 5- or 6-membered cyclic ring structure is optionally substituted with a C1 to C3 alkyl or alkoxy carbonyl group (preferably at the heteroatom position), and R19 can be the same or different, and is H, C1 to C6 alkyl (preferably C1 to C3 alkyl).

[0133] In one embodiment, the compound according to Formula 5 is characterized in that R4 and R5 may be the same or different, and are H, C1 to C5 alkyl (preferably C1 to C3 alkyl), C2 to C5 alkenyl, C3 to C6 cycloalkyl, C3 to C6 heterocycloalkyl (preferably including N, S and / or O), C1 to C5 haloalkyl (preferably C1 to C3 haloalkyl, preferably including Cl, Br or F), C3 to C6 cycloalkyl, alkoxy, C4 to C6 aryl, C5 to C6 heteroaryl (preferably including N, S and / or O and optionally surrounded by C3 to C6 heterocycloyl (preferably including) The group includes N, S and / or O (substituted), sulfides, sulfinyl, sulfonyl, sulfinyl, sulfonamide, carboxyl, carboxylic acid ester, carbonyl C=OR, wherein R is C1 to C10 alkyl (preferably C1 to C5 alkyl), C1 to C3 haloalkyl (preferably including Cl, Br or F), C4 to C6 aryl, wherein R is optionally substituted with urethane or urethane, or R4 and R5 form a 4, 5 or 6-membered heterocyclic alkyl group including N and optionally one or more additional heteroatoms (preferably N, O and / or S), wherein the heterocyclic alkyl group is optionally substituted with alkoxy.

[0134] In one embodiment, the compound according to Formula 5 is characterized in that R16 is a C1 to C5 alkyl (preferably C1 to C3 alkyl), C2 to C5 alkenyl, C3 to C6 cycloalkyl, C5 or C6 aryl, alkylaryl, C5 or C6 heteroaryl (preferably including N, S and / or O), C3 to C6 heterocycloalkyl (preferably including N, S and / or O and preferably including at least one double bond), bicyclic group (preferably including one or two aromatic rings), optionally including one or more heteroatoms (preferably N, O and / or S).

[0135] In one embodiment, the present invention relates to a compound according to Formula 6 for use in treating medical conditions associated with defective and / or pathological type II phosphoinositol 3-kinase (PI3K) signaling. Formula 6 in R1 is C, S, O, or N. R2 is C or N. R3 is H, C1 to C5 alkyl (preferably C1 to C3 alkyl), C3 to C6 cycloalkyl, C1 to C5 haloalkyl (preferably C1 to C3 haloalkyl, including Cl, Br or F), -CN, carbonyl, carboxyl, carboxylic acid ester, alkoxy, aldehyde, primary amine, secondary or tertiary amine, amide, imide, carbamate, formamide, nitro, sulfide, sulfinyl, sulfonyl, sulfinyl or sulfonamide R4 and R5 may be the same or different, and are H, C1 to C5 alkyl (preferably C1 to C3 alkyl), C2 to C5 alkenyl, C3 to C6 cycloalkyl, C3 to C6 heterocycloalkyl (preferably including N, S and / or O), C1 to C5 haloalkyl (preferably C1 to C3 haloalkyl, preferably including Cl, Br or F), C4 to C6 aryl, sulfide, sulfinyl, sulfonyl, sulfinyl, sulfonamide, carboxyl, carboxylic acid ester, carbonyl C=OR, wherein R is C1 to C10 alkyl (preferably C1 to C5 alkyl), C1 to C3 haloalkyl (preferably including Cl, Br or F), C4 to C6 aryl, wherein R is optionally substituted with a urethane group or urethane. Alternatively, R4 and R5 form a 4, 5, or 6-membered heterocyclic alkyl group comprising N and optionally one or more additional heteroatoms (preferably N, O, and / or S), wherein the heterocyclic alkyl group is optionally substituted with an alkoxy group. R6 is absent, or R1 is C and R6 forms a carbonyl group (C=O) with R1, or R1 is S and R6 forms a sulfoxide group (S=O) with R1. Whether R7, R8, and R9 are the same or different, they are C or N. R10 is H, C1 to C5 alkyl (preferably C1 to C3 alkyl), C3 to C6 cycloalkyl, C1 to C5 haloalkyl (preferably C1 to C3 haloalkyl, including Cl, Br or F), -CN, carbonyl, carboxyl, carboxylic acid ester, alkoxy, aldehyde, primary amine, secondary or tertiary amine, amide, imide, carbamate, formamide, nitro, sulfide, sulfinyl, sulfonyl, sulfinyl or sulfonamide R16 is a C1 to C5 alkyl (preferably C1 to C3 alkyl), C2 to C5 alkenyl, C3 to C6 cycloalkyl, C5 or C6 aryl, alkylaryl, C5 or C6 heteroaryl (preferably including N, S and / or O), bicyclic group (preferably including one or two aromatic rings), optionally including one or more heteroatoms (preferably N, O and / or S). R17 can be the same or different, and can be absent (electron pair of X), H, hydroxyl, halogen (preferably F, Cl, or Br), alkoxy, C1 to C5 alkyl (preferably C1 to C3 alkyl), C1 to C5 haloalkyl (preferably C1 to C3 haloalkyl, including Cl, Br, or F), C3 to C6 cycloalkyl, C3 to C6 heterocycloalkyl (preferably including N, O, and / or S and optionally substituted with alkoxy), C4 to C6 aryl, carbonyl C(=O)R, where R is a C1 to C5 alkyl. (Preferably C1 to C3 alkyl), carboxyl, carboxylic acid ester, alkoxy (preferably -OCH3, -OCH2CH3 or C3 to C6 cycloalkylalkoxy), aldehyde, primary amine, secondary or tertiary amine, amide, imide, carbamate, formamide, nitro, sulfide (preferably -SCH3, -SCH2CH3), sulfinyl, sulfonyl, sulfinyl or sulfonamide, or when X is C, forming a carbonyl C=O with X, or when X is S, forming a sulfoxide S=O or a sulfonyl S(=O)2 with X. Alternatively, two R17 atoms may form a 4, 5, or 6-membered cycloalkyl group, optionally including one or more heteroatoms (preferably N, O, and / or S). R18 can be the same or different, and can be H, alkoxy, or one R18 can form a carbonyl group (C=O) with the attached C atom. Alternatively, an R17 and an R18 form a 5- or 6-membered cyclic ring structure comprising two carbon atoms of C, forming a fused cyclic group with C, optionally including one or more heteroatoms (preferably N, O, and / or S), wherein the 5- or 6-membered cyclic ring structure is optionally substituted with a C1 to C3 alkyl or alkoxy carbonyl group (preferably at the heteroatom position), and R19 can be the same or different, and is H, C1 to C6 alkyl (preferably C1 to C3 alkyl).

[0136] In one embodiment, the compound according to Formula 6 is characterized in that R4 and R5 may be the same or different, and are H, C1 to C5 alkyl (preferably C1 to C3 alkyl), C2 to C5 alkenyl, C3 to C6 cycloalkyl, C3 to C6 heterocycloalkyl (preferably including N, S and / or O), C1 to C5 haloalkyl (preferably C1 to C3 haloalkyl, preferably including Cl, Br or F), C3 to C6 cycloalkyl, alkoxy, C4 to C6 aryl, C5 to C6 heteroaryl (preferably including N, S and / or O and optionally surrounded by C3 to C6 heterocycloyl (preferably including) The group includes N, S and / or O (substituted), sulfides, sulfinyl, sulfonyl, sulfinyl, sulfonamide, carboxyl, carboxylic acid ester, carbonyl C=OR, wherein R is C1 to C10 alkyl (preferably C1 to C5 alkyl), C1 to C3 haloalkyl (preferably including Cl, Br or F), C4 to C6 aryl, wherein R is optionally substituted with urethane or urethane, or R4 and R5 form a 4, 5 or 6-membered heterocyclic alkyl group including N and optionally one or more additional heteroatoms (preferably N, O and / or S), wherein the heterocyclic alkyl group is optionally substituted with alkoxy.

[0137] In one embodiment, the compound according to Formula 6 is characterized in that R16 is a C1 to C5 alkyl (preferably C1 to C3 alkyl), C2 to C5 alkenyl, C3 to C6 cycloalkyl, C5 or C6 aryl, alkylaryl, C5 or C6 heteroaryl (preferably including N, S and / or O), C3 to C6 heterocycloalkyl (preferably including N, S and / or O and preferably including at least one double bond), bicyclic group (preferably including one or two aromatic rings), optionally including one or more heteroatoms (preferably N, O and / or S).

[0138] In one embodiment, the present invention relates to a compound according to formula 7 for use in treating medical conditions associated with defective and / or pathological type II phosphoinositol 3-kinase (PI3K) signaling. Formula 7 in R1 is C, S, O, or N. R2 is C or N. R3 is H, C1 to C5 alkyl (preferably C1 to C3 alkyl), C3 to C6 cycloalkyl, C1 to C5 haloalkyl (preferably C1 to C3 haloalkyl, including Cl, Br or F), -CN, carbonyl, carboxyl, carboxylic acid ester, alkoxy, aldehyde, primary amine, secondary or tertiary amine, amide, imide, carbamate, formamide, nitro, sulfide, sulfinyl, sulfonyl, sulfinyl or sulfonamide R6 is absent, or R1 is C and R6 forms a carbonyl group (C=O) with R1, or R1 is S and R6 forms a sulfoxide group (S=O) with R1. Whether R7, R8, and R9 are the same or different, they are C or N. R10 is H, C1 to C5 alkyl (preferably C1 to C3 alkyl), C3 to C6 cycloalkyl, C1 to C5 haloalkyl (preferably C1 to C3 haloalkyl, including Cl, Br or F), -CN, carbonyl, carboxyl, carboxylic acid ester, alkoxy, aldehyde, primary amine, secondary or tertiary amine, amide, imide, carbamate, formamide, nitro, sulfide, sulfinyl, sulfonyl, sulfinyl or sulfonamide R16 is a C1 to C5 alkyl (preferably C1 to C3 alkyl), C2 to C5 alkenyl, C3 to C6 cycloalkyl, C5 or C6 aryl, alkylaryl, C5 or C6 heteroaryl (preferably including N, S and / or O), bicyclic group (preferably including one or two aromatic rings), optionally including one or more heteroatoms (preferably N, O and / or S). R17 can be the same or different, and can be absent (electron pair of X), H, hydroxyl, halogen (preferably F, Cl, or Br), alkoxy, C1 to C5 alkyl (preferably C1 to C3 alkyl), C1 to C5 haloalkyl (preferably C1 to C3 haloalkyl, including Cl, Br, or F), C3 to C6 cycloalkyl, C3 to C6 heterocycloalkyl (preferably including N, O, and / or S and optionally substituted with alkoxy), C4 to C6 aryl, carbonyl C(=O)R, where R is a C1 to C5 alkyl. (Preferably C1 to C3 alkyl), carboxyl, carboxylic acid ester, alkoxy (preferably -OCH3, -OCH2CH3 or C3 to C6 cycloalkylalkoxy), aldehyde, primary amine, secondary or tertiary amine, amide, imide, carbamate, formamide, nitro, sulfide (preferably -SCH3, -SCH2CH3), sulfinyl, sulfonyl, sulfinyl or sulfonamide, or when X is C, forming a carbonyl C=O with X, or when X is S, forming a sulfoxide S=O or a sulfonyl S(=O)2 with X. Alternatively, two R17 atoms may form a 4, 5, or 6-membered cycloalkyl group, optionally including one or more heteroatoms (preferably N, O, and / or S). R18 can be the same or different, and can be H, alkoxy, or one R18 can form a carbonyl group (C=O) with the attached C atom. Alternatively, an R17 and an R18 form a 5- or 6-membered cyclic ring structure comprising two carbon atoms of C, forming a fused cyclic group with C, optionally including one or more heteroatoms (preferably N, O, and / or S), wherein the 5- or 6-membered cyclic ring structure is optionally substituted with a C1 to C3 alkyl or alkoxy carbonyl group (preferably at the heteroatom position), and R19 can be the same or different, and is H, C1 to C6 alkyl (preferably C1 to C3 alkyl).

[0139] In one embodiment, the compound according to formula 5, 6 or 7 is characterized in that R7 and R8 and R9 are the same or different, are C or N, and R9 is C.

[0140] In one embodiment, the compound according to Formula 6 is characterized in that R16 is a C1 to C5 alkyl (preferably C1 to C3 alkyl), C2 to C5 alkenyl, C3 to C6 cycloalkyl, C5 or C6 aryl, alkylaryl, C5 or C6 heteroaryl (preferably including N, S and / or O), C3 to C6 heterocycloalkyl (preferably including N, S and / or O and preferably including at least one double bond), bicyclic group (preferably including one or two aromatic rings), optionally including one or more heteroatoms (preferably N, O and / or S).

[0141] In one embodiment, the compound according to formula 5, 6 or 7 is characterized in that R10 is H or CH3.

[0142] In one embodiment, the compound according to formula 5, 6, or 7 is characterized in that R17 can be the same or different, and is absent (electron pair of X), H, hydroxyl, F, CH3, C4 to C6 heterocyclic alkyl (preferably including N and / or O and optionally substituted with alkoxy), -C(=O)CH3, carboxylic ester, alkoxy (preferably -OCH3 or C4 cycloalkylalkoxy), tertiary amine, -SCH2CH3, or when X is C, forms a carbonyl C=O with X, or when X is S, forms a sulfoxide S=O or a sulfonyl S(=O)2 with X, or the two R17 form a 4-membered cycloalkane. The group, optionally comprising one or more heteroatoms (preferably O), and R18 may be the same or different, being H, alkoxy, or one R18 forming a carbonyl C=O with the attached C atom, or one R17 and one R18 forming a 5 or 6-membered ring structure comprising two carbon atoms of C, forming a fused cyclic group with C, optionally comprising one or more heteroatoms (preferably N and / or O), wherein the 5 or 6-membered ring structure is optionally substituted by a C1 to C3 alkyl or alkoxy carbonyl group (preferably at the heteroatom position), and R19 may be the same or different, being H or CH3.

[0143] According to formulas 1, 1a, 2, 2a, 3, 4, 5, 6 or 7 of the present invention, combinations of various preferred embodiments are themselves considered preferred embodiments.

[0144] In a preferred embodiment, the compound according to one of Formula 1 or 5 is selected from the group consisting of: N-(4-methyl-5-(1-(phenylsulfonyl)-1H-indol-5-yl)thiazolyl-2-yl)acetamide, N-(4-methyl-5-(1-(phenylsulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)thiazolyl-2-yl)acetamide, N-(4-methyl-5-(1-(phenylsulfonyl)indololine-5-yl)thiazolyl-2-yl)acetamide, N-(4-methyl-5-(4-(phenylsulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)thiazolyl-2-yl)acetamide, N-(5-(1-(phenylsulfonyl)-2,3,4,5- Tetrahydro-1H-benzo[b]azacycloheptan-7-yl)thiazo-2-yl)acetamide, N-(4-methyl-5-(5-(phenylsulfonyl)-5,6,7,8-tetrahydronaphthio-2-yl)thiazo-2-yl)acetamide, N-(5-(4-methoxy-1-(phenylsulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)-4-methylthiazo-2-yl)acetamide, N-(4-methyl-5-(4-(phenylsulfonyl)-3,4-dihydro-2H-benzo[b][1,4]thiazin-7-yl)thiazo-2-yl)acetamide, N-(4-methyl-5-(1-oxy-4-(phenylsulfonyl)-3,4-dihydro-2H-benzo[b][1,4]thiazin-7-yl)thiazo-2-yl)acetamide, N-(4-methyl-5-(1-oxo-4-(phenylsulfonyl)-3,4-dihydro-2H-benzo[b][1,4]thiazin-7-yl)thiazo-2-yl)acetamide, N-(5-(1,1-dioxo-4-(phenylsulfonyl)-3,4-dihydro-2H-benzo[b][1,4]thiazin-7-yl)-4-methylthiazol-2-yl)acetamide, N-(4-methyl-5-(8-(phenylsulfonyl)-5,6,7,8-tetrahydro-1,8-naphthidin-3-yl)thiazol-2-yl)acetamide, N-(4-methyl-5-(4-oxoylide-1-(phenylsulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)thiazol-2-yl)acetamide, N-(5-(4-hydroxy-1-(phenylsulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)-4-methylthiazol-2-yl)acetamide, N-(4-methyl-5-(2-methyl-1-(phenylsulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)thiazolyl-2-yl)acetamide, N-(5-(1-(phenylsulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)thiazolyl-2-yl)acetamide, N-(4-methyl-5-(5-(phenylsulfonyl)-5,6,7,8-tetrahydro-1,5-naphthidin-2-yl)thiazolyl)acetamide, N-(4-methyl-5-(1-(phenylsulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)oxazol-2-yl)acetamide, N-(4-methyl-5-(5-(phenylsulfonyl)-2,3,3a,4,5,9b-hexahydrofurano[3,2-c]quinoline-8-yl)thiazolyl)acetamide, (R)-N-(5-(4-methoxy-1-(phenylsulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)-4-methylthiazolyl)acetamide, 6-((4-methyl-5-(1-(phenylsulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)thiazolyl)amino)-6-oxylidenehexyl)tert-butyl carbamate, N-(5-(4-acetyl-1-(phenylsulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)-4-methylthiazolyl)acetamide, N-(4-methyl-5-(4-methyl-3-oxylidene-1-(phenylsulfonyl)-1,2) 3,4-Tetrahydroquinoxalin-6-yl)thiazolyl)acetamide, N-(5-(3-methoxy-1-(phenylsulfonyl)-1,2,3,4-tetrahydroquinoxalin-6-yl)-4-methylthiazolyl)acetamide, N-(5-(4-methoxy-4-methyl-1-(phenylsulfonyl)-1,2,3,4-tetrahydroquinoxalin-6-yl)-4-methylthiazolyl)acetamide, N-(4-methyl-5-(4-morpholino-1-(phenylsulfonyl)-1,2,3,4-tetrahydroquinoxalin-6-yl)thiazolyl)acetamide, N-(4-methyl-5-(6-(phenylsulfonyl)-3,4,4a,5,6,10b-hexahydro-2H- Pyrano[3,2-c]quinoline-9-yl)thiazoline-2-yl)acetamide, N-(4-methyl-5-(1-(o-tolylsulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)thiazoline-2-yl)acetamide, N-(4-methyl-5-(1-(naphthyl-1-ylsulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)thiazoline-2-yl)acetamide, N-(5-(1-(cyclohexylsulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)-4-methylthiazoline-2-yl)acetamide, N-(4-methyl-5-(1-(pyridin-3-ylsulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)thiazoline-2-yl)acetamide, N-(4 N-(4-methyl-5-(1-(methylsulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)thiazoline-2-yl)acetamide, N-(5-(1-((4-fluorophenyl)sulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)-4-methylthiazoline-2-yl)acetamide, N-(5-(1-((2,4-dichlorophenyl)sulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)-4-methylthiazoline-2-yl)acetamide, N-(4-methyl-5-(1-(naphthyl-2-yl ...4-Tetrahydroquinoline-6-yl)thiazoline-2-yl)acetamide, (S)-N-(5-(4-methoxy-1-(phenylsulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)-4-methylthiazoline-2-yl)acetamide, N-(4-methyl-5-(1-toluenesulfonyl-1,2,3,4-tetrahydroquinoline-6-yl)thiazoline-2-yl)acetamide, N-(5-(1-((2,3-dichlorophenyl)sulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)-4-methylthiazoline-2-yl)acetamide, N-(5-( 1-((2,3-dihydrobenzofuran-5-yl)sulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)-4-methylthiazolyl-2-yl)acetamide, (4-methyl-5-(1-(phenylsulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)thiazolyl)tert-butyl carbamate, 4-methyl-5-(1-(phenylsulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)thiazolyl-2-amine, N-(4-ethyl-5-(1-(phenylsulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)thiazolyl-2-yl)acetamide, N-(5-(1-(cyclopropylsulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)-4-methylthiazolyl- 2-yl)acetamide, N-(5-(2,2-dimethyl-1-(phenylsulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)-4-methylthiazol-2-yl)acetamide, N-(4-methyl-5-(1'-(phenylsulfonyl)-2',3'-dihydro-1'H-spiro[oxetane-3,4'-quinoline]-6'-yl)thiazol-2-yl)acetamide, N-(5-(1-((3-methoxyphenyl)sulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)-4-methylthiazol-2-yl)acetamide, N-(4-methyl-5-(5-methyl-1-(phenylsulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)thiazol-2-yl)acetamide Amide, 5-methyl-4-(1-(phenylsulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)-N-(2,2,2-trifluoroethyl)thiazol-2-amine, N-(5-(4,4-difluoro-1-(phenylsulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)-4-methylthiazol-2-yl)acetamide, N-(5-(1-(allylsulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)-4-methylthiazol-2-yl)acetamide, N-allyl-5-methyl-4-(1-(phenylsulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)thiazol-2-amine, N,5-dimethyl-4-(1-(phenylsulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)thiazol-2-amine, N,5-dimethyl-4-(1-(phenylsulfonyl)-1,2,3,4-Tetrahydroquinoline-6-yl)thiazol-2-amine, N-(5-(1-((3-bromophenyl)sulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)-4-methylthiazol-2-yl)acetamide, 3-((6-(2-acetamido-4-methylthiazol-5-yl)-3,4-dihydroquinoline-1(2H)-yl)sulfonyl)benzenesulfonyl fluoride, N-(5-(1-((3-acetylphenyl)sulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)-4-methylthiazol-2-yl)acetamide, N-(5-(1-((3-(2-bromoacetyl)phenyl)sulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)-4-methylthiazol-2-yl)acetamide, 2,2,2-tris( Fluoro-N-(4-methyl-5-(1-(phenylsulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)thiazolyl-2-yl)acetamide, N-(5-(1-((3-(1-hydroxyethyl)phenyl)sulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)-4-methylthiazolyl-2-yl)acetamide, 4-methyl-N-phenyl-5-(1-(phenylsulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)thiazolyl-2-amine, N-(5-(1-((3-aminophenyl)sulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)-4-methylthiazolyl-2-yl)acetamide, N-(3-((6-(2-acetamamido-4-methylthiazolyl)-3,4-dihydro) Quinoline-1(2H)-yl)sulfonyl)phenyl)acetamide, N-(5-(1-((3-(dimethylamino)phenyl)sulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)-4-methylthiazol-2-yl)acetamide, N-(5-(1-((2-chlorophenyl)sulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)-4-methylthiazol-2-yl)acetamide, N-(5-(1-((3,4-dimethoxyphenyl)sulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)-4-methylthiazol-2-yl)acetamide, N-(5-(1-((3,4-dimethoxyphenyl)sulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)-4-methylthiazol-2-yl)acetamide, N-(5-(1-((2,3-dimethoxyphenyl)sulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)-4-methylthiazol-2-yl)acetamide 3-((6-(2-acetamido-4-methylthiazolyl-5-yl)-3,4-dihydroquinoline-1(2H)-yl)sulfonyl)thiophene-2-carboxylic acid methyl ester, N-(4-methyl-5-(1-((3-nitrophenyl)sulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)thiazolyl-2-yl)acetamide, N-(4-methyl-5-(1-((2-oxomylidene-2,3-dihydrobenzo[d]oxazol-7-yl)sulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)thiazolyl-2-yl)acetamide, N-(4-methyl-5-(1-((3-oxomylidene-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)sulfonyl)-1,2,3,4-Tetrahydroquinoline-6-yl)thiazolyl)acetamide, N-(5-(1-((2,5-difluorophenyl)sulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)-4-methylthiazolyl)acetamide, 3-((6-(2-acetamido-4-methylthiazolyl)-3,4-dihydroquinoline-1(2H)-yl)sulfonyl)methyl benzoate, N-(5-(1-((5-chloro-2-fluorophenyl)sulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)-4-methylthiazolyl)acetamide, N-(5-(1-((2-chloro-5-fluorophenyl)sulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)-4-methylthiazolyl)acetamide, N-(5-(1-(benzo[d][1,3]dioxane-5-ylsulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)-4-methylthiazoline-2-yl)acetamide, N-(4-methyl-5-(1-((1-methyl-1H-indol-5-yl)sulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)thiazoline-2-yl)acetamide, N-(5-(1-((2,3-dihydro-1H-indole-5-yl)sulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)-4-methylthiazoline-2-yl)acetamide, N-(5-(1-((2,3-dihydro-1H-indole-5-yl)sulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)-4-methylthiazoline-2-yl)acetamide, N-(5-(1-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)sulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl) N-(4-methyl-5-(1-((5,6,7,8-tetrahydronaphthyl-2-yl)sulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)thiazol-2-yl)acetamide, N-(5-(1-(benzofuran-2-ylsulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)-4-methylthiazol-2-yl)acetamide, N-(5-(1-(benzofuran-6-ylsulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)-4-methylthiazol-2-yl)acetamide, N-(5-(1-(benzofuran-6-ylsulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)-4-methylthiazol-2-yl)acetamide, N-(5-(1-(benzofuran-6-ylsulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)-4-methylthiazol-2-yl)acetyl)acetamide Amine, N-(5-(1-((2,6-dichlorophenyl)sulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)-4-methylthiazol-2-yl)acetamide, N-((5-(1-((2,6-difluorophenyl)sulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)-4-methylthiazol-2-yl)acetamide, N-(4-methyl-5-(1-((3-oxomyne-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)sulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)thiazol-2-yl)acetamide, N-(4-methyl-5-(1-((2-oxomyne-2,3-dihydrobenzo[d]oxazol-5-yl)sulfonyl)-1,2,3,4-Tetrahydroquinoline-6-yl)thiazoline-2-yl)acetamide, N-(4-methyl-5-(1-(((4-nitrophenyl)sulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)thiazoline-2-yl)acetamide, 3-((6-(2-acetamido-4-methylthiazoline-5-yl)-3,4-dihydroquinoline-1(2H)-yl)sulfonyl)benzoic acid, N-(3-((6-(2-acetamido-4-methylthiazoline-5-yl)-3,4-dihydroquinoline-1(2H)-yl)sulfonyl)phenyl)acrylamide, N-(3-((6-(2-acetamido-4-methylthiazoline-5-yl)-3,4-dihydroquinoline-1(2H)-yl)sulfonyl)phenyl)2-chloroacetamide, 7-(2-acetamido-4-methylthiazolyl-5-yl)-4-(phenylsulfonyl)-3,4-dihydroquinoxalin-1(2H)-carboxylic acid tert-butyl ester, N-(4-methyl-5-(1-(phenylsulfonyl)-1,2,3,4-tetrahydroquinoxalin-6-yl)thiazolyl)acetamide, N-(4-methyl-5-(4-methyl-1-(phenylsulfonyl)-1,2,3,4-tetrahydroquinoxalin-6-yl)thiazolyl)acetamide, N-(5-(5-(phenylsulfonyl)-5,6,7,8-tetrahydro-1,5-naphthidin-2-yl)thiazolyl)acetamide, N-(5-(1-(phenylsulfonyl)-1,2,3,4-tetrahydroquinoxalin-6-yl)-1,3,4 -thiadiazole-2-yl)acetamide, N-(5-(1-((4-aminophenyl)sulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)-4-methylthiazol-2-yl)acetamide, N-(4-((6-(2-acetamamido-4-methylthiazol-5-yl)-3,4-dihydroquinoline-1(2H)-yl)sulfonyl)phenyl)acrylamide, N-(4-((6-(2-acetamamido-4-methylthiazol-5-yl)-3,4-dihydroquinoline-1(2H)-yl)sulfonyl)phenyl)-2-chloroacetamide, N-(5-(1-((4-acetylphenyl)sulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)-4-methylthiazol-2-yl)acetamide, N-(5 -(1-((4-(dimethylamino)phenyl)sulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)-4-methylthiazol-2-yl)acetamide, N-(5-(1-((4-(2-bromoacetyl)phenyl)sulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)-4-methylthiazol-2-yl)acetamide, N-(5-(1-((4-(1-hydroxyethyl)phenyl)sulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)-4-methylthiazol-2-yl)acetamide, N-(5-(5-((2,3-dichlorophenyl)sulfonyl)-5,6,7,8-tetrahydro-1,5-naphthidin-2-yl)thiazol-2-yl)acetamide, N-(5-(5-((2,3-dichlorophenyl)sulfonyl)-5,6,7,8-tetrahydro-1,5-naphthidin-2-yl)thiazol-2-yl)acetamide, N-(5-(5-(2,3-Dichlorophenyl)sulfonyl)-5,6,7,8-tetrahydro-1,5-naphthidin-2-yl)-4-methylthiazolyl)acetamide, N-(5-(5-((5-chloro-2-fluorophenyl)sulfonyl)-5,6,7,8-tetrahydro-1,5-naphthidin-2-yl)thiazolyl)acetamide, N-(5-(5-((5-chloro-2-fluorophenyl)sulfonyl)-5,6,7,8-tetrahydro-1,5-naphthidin-2-yl)-4-methylthiazolyl)acetamide, N-(5-(1-benzoyl-1,2,3,4-tetrahydroquinoline-6-yl)- 4-Methylthiazol-2-yl)acetamide, N-(5-(1-benzyl-1,2,3,4-tetrahydroquinoline-6-yl)-4-methylthiazol-2-yl)acetamide, 9-(2-acetamyl-4-methylthiazol-5-yl)-6-(phenylsulfonyl)-3,4,4a,5,6,10b-hexahydrobenzo[h][1,6]naphthyl-1(2H)-carboxylic acid tert-butyl ester, N-(4-methyl-5-(6-(phenylsulfonyl)-1,2,3,4,4a,5,6,10b-octahydrobenzo[h][1,6]naphthyl-9-yl)thiazol-2-yl)acetamide, N-(4-methyl-5-(1-methyl-6-(phenylsulfonyl)-1,2,3,4,4a,5,6,10b-octahydrobenzo[h][1,6]naphthidin-9-yl)thiazolyl)acetamide, N-(5-(4-ethylthio)-1-(phenylsulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)-4-methylthiazolyl)acetamide, N-(5-(1-((3-chloro-2-fluorophenyl)sulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)-4-methylthiazolyl)acetamide, N-(4-methyl-5-(1-( N-(5-(4-(3-isopropoxyazino-1-yl)-1,2,3,4-tetrahydroquinoline-6-yl)thiazoline-2-yl)acetamide, N-(5-(4-(3-isopropoxyazino-1-yl)-1-(phenylsulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)-4-methylthiazoline-2-yl)acetamide, N-(5-(4-(dimethylamino)-1-(phenylsulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)-4-methylthiazoline-2-yl)acetamide, N-(5-(4-cyclobutoxy-1-(phenylsulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)-4-methylthiazoline-2-yl)acetamide, N-(5-(4-cyclobutoxy-1-(phenylsulfonyl)-1,2,3,4-Tetrahydroquinoline-6-yl)-4-methylthiazolyl-2-yl)acetamide, N-(4-methyl-5-(3-(methylsulfonyl)-4-(phenylsulfonamido)phenyl)thiazolyl-2-yl)acetamide, N-(5-(4-((2-chlorophenyl)sulfonamido)-3-(methylsulfonyl)phenyl)-4-methylthiazolyl-2-yl)acetamide, N-(4-methyl-5-(3-(methylsulfonyl)-4-(naphthal-1-sulfonamido)phenyl)thiazolyl-2-yl)acetamide, N-(4-methyl-5-(2-(phenylsulfonyl)isoindoline-5-yl)thiazolyl-2-yl)acetamide, N-(5-(2 -((2-chlorophenyl)sulfonyl)isoindoline-5-yl)-4-methylthiazol-2-yl)acetamide, N-(5-(3-fluoro-4-(phenylsulfonylmethyl)phenyl)-4-methylthiazol-2-yl)acetamide, N-(4-methyl-5-(3-(methylsulfonyl)-4-(phenylsulfonylmethyl)phenyl)thiazol-2-yl)acetamide, N-(5-(3-fluoro-4-((phenylsulfonyl)methyl)phenyl)-4-methylthiazol-2-yl)acetamide, N-(4-methyl-5-(3-(methylsulfonyl)-4-((phenylsulfonyl)methyl)phenyl)thiazol-2-yl)acetamide, N-(4-methyl-5-(4-(N-methylphenylsulfonamido)-3-(methylsulfonyl)phenyl)thiazo-2-yl)acetamide, N-(4-methyl-5-(3-(methylthio)-4-(phenylsulfonamido)phenyl)thiazo-2-yl)acetamide, N-(4-methyl-5-(3-(methylsulfinyl)-4-(phenylsulfonamido)phenyl)thiazo-2-yl)acetamide, N-(4-methyl-5-(4-(phenylsulfonamido)-3-(pyrrolidone-1-yl)phenyl)thiazo-2-yl)acetamide, 5-(2-acetamiprido-4-methylthiazo-5-yl)-2-(phenylsulfonamido) Methyl benzoate, N-(5-(3-(benzyloxy)-4-(phenylsulfonamido)phenyl)-4-methylthiazol-2-yl)acetamide, N-(5-(3-fluoro-4-(phenylsulfonamido)phenyl)-4-methylthiazol-2-yl)acetamide, N-(5-(3-cyclopropyl-4-(phenylsulfonamido)phenyl)-4-methylthiazol-2-yl)acetamide, N-(5-(3-acetamido-4-(phenylsulfonamido)phenyl)-4-methylthiazol-2-yl)acetamide, N-(5-(3-(methoxymethyl)-4-(phenylsulfonamido)phenyl)-4-methylthiazol-2-yl)acetamide,

[0145] In a preferred embodiment, the compound according to one of Formula 1 or 5 is selected from the group consisting of: N-(4-methyl-5-(1-(phenylsulfonyl)-1H-indol-5-yl)thiazo-2-yl)acetamide, N-(4-methyl-5-(1-(phenylsulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)thiazo-2-yl)acetamide, N-(4-methyl-5-(1-(phenylsulfonyl)indololine-5-yl)thiazo-2-yl)acetamide, N-(4-methyl-5-(4-(phenylsulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)thiazo-2-yl)acetamide, N-(5-(1-(phenylsulfonyl)-2,3,4-tetrahydroquinoline-6-yl)thiazo-2-yl)acetamide, N-(4-methyl-5-(1-(phenylsulfonyl)-1H-indol-5 ... ,5-Tetrahydro-1H-benzo[b]azacycloheptan-7-yl)thiazolyl)acetamide, N-(4-methyl-5-(5-(phenylsulfonyl)-5,6,7,8-tetrahydronaphthyl)thiazolyl)acetamide, N-(5-(4-methoxy-1-(phenylsulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)-4-methylthiazolyl)acetamide, N-(4-methyl-5-(4-(phenylsulfonyl)-3,4-dihydro-2H-benzo[b][1,4]thiazine-7-yl)thiazolyl)acetamide, N-(4-methyl-5-(1-oxy-4-(phenylsulfonyl)-3,4-dihydro-2H-benzo[b][1,4]thiazine N-(5-(1,1-dioxy-4-(phenylsulfonyl)-3,4-dihydro-2H-benzo[b][1,4]thiazin-7-yl)-4-methylthiazol-2-yl)acetamide, N-(4-methyl-5-(8-(phenylsulfonyl)-5,6,7,8-tetrahydro-1,8-naphthidin-3-yl)thiazol-2-yl)acetamide, N-(4-methyl-5-(4-oxoylide-1-(phenylsulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)thiazol-2-yl)acetamide, N-(5-(4-hydroxy-1-(phenylsulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)thiazol-2-yl)acetamide N-(4-methyl-5-(2-methyl-1-(phenylsulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)thiazolyl-2-yl)acetamide, N-(5-(1-(phenylsulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)thiazolyl-2-yl)acetamide, N-(4-methyl-5-(5-(phenylsulfonyl)-5,6,7,8-tetrahydro-1,5-naphthidin-2-yl)thiazolyl-2-yl)acetamide, N-(4-methyl-5-(1-(phenylsulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)oxazol-2-yl)acetamide, N-(4-methyl-5-(5-(phenylsulfonyl)-2,3,3a,4,5,9b-hexahydrofurano[3,2-c]quinoline-8-yl)thiazolyl)acetamide, (R)-N-(5-(4-methoxy-1-(phenylsulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)-4-methylthiazolyl)acetamide, 6-((4-methyl-5-(1-(phenylsulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)thiazolyl)amino)-6-oxylidenehexyl)tert-butyl carbamate, N-(5-(4-acetyl-1-(phenylsulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)-4-methylthiazolyl)acetamide, N-(4-methyl-5-(4-methyl-3-oxylidene-1-(phenylsulfonyl)-1,2) 3,4-Tetrahydroquinoxalin-6-yl)thiazolyl)acetamide, N-(5-(3-methoxy-1-(phenylsulfonyl)-1,2,3,4-tetrahydroquinoxalin-6-yl)-4-methylthiazolyl)acetamide, N-(5-(4-methoxy-4-methyl-1-(phenylsulfonyl)-1,2,3,4-tetrahydroquinoxalin-6-yl)-4-methylthiazolyl)acetamide, N-(4-methyl-5-(4-morpholino-1-(phenylsulfonyl)-1,2,3,4-tetrahydroquinoxalin-6-yl)thiazolyl)acetamide, N-(4-methyl-5-(6-(phenylsulfonyl)-3,4,4a,5,6,10b-hexahydro-2H- Pyrano[3,2-c]quinoline-9-yl)thiazoline-2-yl)acetamide, N-(4-methyl-5-(1-(o-tolylsulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)thiazoline-2-yl)acetamide, N-(4-methyl-5-(1-(naphthyl-1-ylsulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)thiazoline-2-yl)acetamide, N-(5-(1-(cyclohexylsulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)-4-methylthiazoline-2-yl)acetamide, N-(4-methyl-5-(1-(pyridin-3-ylsulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)thiazoline-2-yl)acetamide, N-(4 N-(4-methyl-5-(1-(methylsulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)thiazoline-2-yl)acetamide, N-(5-(1-((4-fluorophenyl)sulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)-4-methylthiazoline-2-yl)acetamide, N-(5-(1-((2,4-dichlorophenyl)sulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)-4-methylthiazoline-2-yl)acetamide, N-(4-methyl-5-(1-(naphthyl-2-yl ...4-Tetrahydroquinoline-6-yl)thiazoline-2-yl)acetamide, (S)-N-(5-(4-methoxy-1-(phenylsulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)-4-methylthiazoline-2-yl)acetamide, N-(4-methyl-5-(1-toluenesulfonyl-1,2,3,4-tetrahydroquinoline-6-yl)thiazoline-2-yl)acetamide, N-(5-(1-((2,3-dichlorophenyl)sulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)-4-methylthiazoline-2-yl)acetamide, N-(5-( 1-((2,3-dihydrobenzofuran-5-yl)sulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)-4-methylthiazolyl-2-yl)acetamide, (4-methyl-5-(1-(phenylsulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)thiazolyl)tert-butyl carbamate, 4-methyl-5-(1-(phenylsulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)thiazolyl-2-amine, N-(4-ethyl-5-(1-(phenylsulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)thiazolyl-2-yl)acetamide, N-(5-(1-(cyclopropylsulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)-4-methylthiazolyl- 2-yl)acetamide, N-(5-(2,2-dimethyl-1-(phenylsulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)-4-methylthiazol-2-yl)acetamide, N-(4-methyl-5-(1'-(phenylsulfonyl)-2',3'-dihydro-1'H-spiro[oxetane-3,4'-quinoline]-6'-yl)thiazol-2-yl)acetamide, N-(5-(1-((3-methoxyphenyl)sulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)-4-methylthiazol-2-yl)acetamide, N-(4-methyl-5-(5-methyl-1-(phenylsulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)thiazol-2-yl)acetamide Amide, 5-methyl-4-(1-(phenylsulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)-N-(2,2,2-trifluoroethyl)thiazol-2-amine, N-(5-(4,4-difluoro-1-(phenylsulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)-4-methylthiazol-2-yl)acetamide, N-(5-(1-(allylsulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)-4-methylthiazol-2-yl)acetamide, N-allyl-5-methyl-4-(1-(phenylsulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)thiazol-2-amine, N,5-dimethyl-4-(1-(phenylsulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)thiazol-2-amine, N,5-dimethyl-4-(1-(phenylsulfonyl)-1,2,3,4-Tetrahydroquinoline-6-yl)thiazol-2-amine, N-(5-(1-((3-bromophenyl)sulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)-4-methylthiazol-2-yl)acetamide, 3-((6-(2-acetamido-4-methylthiazol-5-yl)-3,4-dihydroquinoline-1(2H)-yl)sulfonyl)benzenesulfonyl fluoride, N-(5-(1-((3-acetylphenyl)sulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)-4-methylthiazol-2-yl)acetamide, N-(5-(1-((3-(2-bromoacetyl)phenyl)sulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)-4-methylthiazol-2-yl)acetamide, 2,2,2-tris( Fluoro-N-(4-methyl-5-(1-(phenylsulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)thiazolyl-2-yl)acetamide, N-(5-(1-((3-(1-hydroxyethyl)phenyl)sulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)-4-methylthiazolyl-2-yl)acetamide, 4-methyl-N-phenyl-5-(1-(phenylsulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)thiazolyl-2-amine, N-(5-(1-((3-aminophenyl)sulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)-4-methylthiazolyl-2-yl)acetamide, N-(3-((6-(2-acetamamido-4-methylthiazolyl)-3,4-dihydro) Quinoline-1(2H)-yl)sulfonyl)phenyl)acetamide, N-(5-(1-((3-(dimethylamino)phenyl)sulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)-4-methylthiazol-2-yl)acetamide, N-(5-(1-((2-chlorophenyl)sulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)-4-methylthiazol-2-yl)acetamide, N-(5-(1-((3,4-dimethoxyphenyl)sulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)-4-methylthiazol-2-yl)acetamide, N-(5-(1-((3,4-dimethoxyphenyl)sulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)-4-methylthiazol-2-yl)acetamide, N-(5-(1-((2,3-dimethoxyphenyl)sulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)-4-methylthiazol-2-yl)acetamide 3-((6-(2-acetamido-4-methylthiazolyl-5-yl)-3,4-dihydroquinoline-1(2H)-yl)sulfonyl)thiophene-2-carboxylic acid methyl ester, N-(4-methyl-5-(1-((3-nitrophenyl)sulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)thiazolyl-2-yl)acetamide, N-(4-methyl-5-(1-((2-oxomylidene-2,3-dihydrobenzo[d]oxazol-7-yl)sulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)thiazolyl-2-yl)acetamide, N-(4-methyl-5-(1-((3-oxomylidene-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)sulfonyl)-1,2,3,4-Tetrahydroquinoline-6-yl)thiazolyl)acetamide, N-(5-(1-((2,5-difluorophenyl)sulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)-4-methylthiazolyl)acetamide, 3-((6-(2-acetamido-4-methylthiazolyl)-3,4-dihydroquinoline-1(2H)-yl)sulfonyl)methyl benzoate, N-(5-(1-((5-chloro-2-fluorophenyl)sulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)-4-methylthiazolyl)acetamide, N-(5-(1-((2-chloro-5-fluorophenyl)sulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)-4-methylthiazolyl)acetamide, N-(5-(1-(benzo[d][1,3]dioxane-5-ylsulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)-4-methylthiazoline-2-yl)acetamide, N-(4-methyl-5-(1-((1-methyl-1H-indol-5-yl)sulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)thiazoline-2-yl)acetamide, N-(5-(1-((2,3-dihydro-1H-indole-5-yl)sulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)-4-methylthiazoline-2-yl)acetamide, N-(5-(1-((2,3-dihydro-1H-indole-5-yl)sulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)-4-methylthiazoline-2-yl)acetamide, N-(5-(1-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)sulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl) N-(4-methyl-5-(1-((5,6,7,8-tetrahydronaphthyl-2-yl)sulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)thiazol-2-yl)acetamide, N-(5-(1-(benzofuran-2-ylsulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)-4-methylthiazol-2-yl)acetamide, N-(5-(1-(benzofuran-6-ylsulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)-4-methylthiazol-2-yl)acetamide, N-(5-(1-(benzofuran-6-ylsulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)-4-methylthiazol-2-yl)acetamide, N-(5-(1-(benzofuran-6-ylsulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)-4-methylthiazol-2-yl)acetyl)acetamide Amine, N-(5-(1-((2,6-dichlorophenyl)sulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)-4-methylthiazol-2-yl)acetamide, N-((5-(1-((2,6-difluorophenyl)sulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)-4-methylthiazol-2-yl)acetamide, N-(4-methyl-5-(1-((3-oxomyne-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)sulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)thiazol-2-yl)acetamide, N-(4-methyl-5-(1-((2-oxomyne-2,3-dihydrobenzo[d]oxazol-5-yl)sulfonyl)-1,2,3,4-Tetrahydroquinoline-6-yl)thiazoline-2-yl)acetamide, N-(4-methyl-5-(1-(((4-nitrophenyl)sulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)thiazoline-2-yl)acetamide, 3-((6-(2-acetamido-4-methylthiazoline-5-yl)-3,4-dihydroquinoline-1(2H)-yl)sulfonyl)benzoic acid, N-(3-((6-(2-acetamido-4-methylthiazoline-5-yl)-3,4-dihydroquinoline-1(2H)-yl)sulfonyl)phenyl)acrylamide, N-(3-((6-(2-acetamido-4-methylthiazoline-5-yl)-3,4-dihydroquinoline-1(2H)-yl)sulfonyl)phenyl)2-chloroacetamide, 7-(2-acetamido-4-methylthiazolyl-5-yl)-4-(phenylsulfonyl)-3,4-dihydroquinoxalin-1(2H)-carboxylic acid tert-butyl ester, N-(4-methyl-5-(1-(phenylsulfonyl)-1,2,3,4-tetrahydroquinoxalin-6-yl)thiazolyl)acetamide, N-(4-methyl-5-(4-methyl-1-(phenylsulfonyl)-1,2,3,4-tetrahydroquinoxalin-6-yl)thiazolyl)acetamide, N-(5-(5-(phenylsulfonyl)-5,6,7,8-tetrahydro-1,5-naphthidin-2-yl)thiazolyl)acetamide, N-(5-(1-(phenylsulfonyl)-1,2,3,4-tetrahydroquinoxalin-6-yl)-1,3,4 -thiadiazole-2-yl)acetamide, N-(5-(1-((4-aminophenyl)sulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)-4-methylthiazol-2-yl)acetamide, N-(4-((6-(2-acetamamido-4-methylthiazol-5-yl)-3,4-dihydroquinoline-1(2H)-yl)sulfonyl)phenyl)acrylamide, N-(4-((6-(2-acetamamido-4-methylthiazol-5-yl)-3,4-dihydroquinoline-1(2H)-yl)sulfonyl)phenyl)-2-chloroacetamide, N-(5-(1-((4-acetylphenyl)sulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)-4-methylthiazol-2-yl)acetamide, N-(5 -(1-((4-(dimethylamino)phenyl)sulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)-4-methylthiazol-2-yl)acetamide, N-(5-(1-((4-(2-bromoacetyl)phenyl)sulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)-4-methylthiazol-2-yl)acetamide, N-(5-(1-((4-(1-hydroxyethyl)phenyl)sulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)-4-methylthiazol-2-yl)acetamide, N-(5-(5-((2,3-dichlorophenyl)sulfonyl)-5,6,7,8-tetrahydro-1,5-naphthidin-2-yl)thiazol-2-yl)acetamide, N-(5-(5-((2,3-dichlorophenyl)sulfonyl)-5,6,7,8-tetrahydro-1,5-naphthidin-2-yl)thiazol-2-yl)acetamide, N-(5-(5-(2,3-Dichlorophenyl)sulfonyl)-5,6,7,8-tetrahydro-1,5-naphthidin-2-yl)-4-methylthiazolyl)acetamide, N-(5-(5-((5-chloro-2-fluorophenyl)sulfonyl)-5,6,7,8-tetrahydro-1,5-naphthidin-2-yl)thiazolyl)acetamide, N-(5-(5-((5-chloro-2-fluorophenyl)sulfonyl)-5,6,7,8-tetrahydro-1,5-naphthidin-2-yl)-4-methylthiazolyl)acetamide, N-(5-(1-benzoyl-1,2,3,4-tetrahydroquinoline-6-yl)- 4-Methylthiazol-2-yl)acetamide, N-(5-(1-benzyl-1,2,3,4-tetrahydroquinoline-6-yl)-4-methylthiazol-2-yl)acetamide, 9-(2-acetamyl-4-methylthiazol-5-yl)-6-(phenylsulfonyl)-3,4,4a,5,6,10b-hexahydrobenzo[h][1,6]naphthyl-1(2H)-carboxylic acid tert-butyl ester, N-(4-methyl-5-(6-(phenylsulfonyl)-1,2,3,4,4a,5,6,10b-octahydrobenzo[h][1,6]naphthyl-9-yl)thiazol-2-yl)acetamide, N-(4-methyl-5-(1-methyl-6-(phenylsulfonyl)-1,2,3,4,4a,5,6,10b-octahydrobenzo[h][1,6]naphthidin-9-yl)thiazolyl)acetamide, N-(5-(4-ethylthio)-1-(phenylsulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)-4-methylthiazolyl)acetamide, N-(5-(1-((3-chloro-2-fluorophenyl)sulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)-4-methylthiazolyl)acetamide, N-(4-methyl-5-(1-( N-(5-(4-(3-isopropoxyazino-1-yl)-1,2,3,4-tetrahydroquinoline-6-yl)thiazoline-2-yl)acetamide, N-(5-(4-(3-isopropoxyazino-1-yl)-1-(phenylsulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)-4-methylthiazoline-2-yl)acetamide, N-(5-(4-(dimethylamino)-1-(phenylsulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)-4-methylthiazoline-2-yl)acetamide, N-(5-(4-cyclobutoxy-1-(phenylsulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)-4-methylthiazoline-2-yl)acetamide, N-(5-(4-cyclobutoxy-1-(phenylsulfonyl)-1,2,3,4-Tetrahydroquinoline-6-yl)-4-methylthiazoline-2-yl)acetamide, N-(4-methyl-5-(3-(methylsulfonyl)-4-(phenylsulfonamido)phenyl)thiazoline-2-yl)acetamide, N-(5-(4-((2-chlorophenyl)sulfonamido)-3-(methylsulfonyl)phenyl)-4-methylthiazoline-2-yl)acetamide, N-(4-methyl-5-(3-(methylsulfonyl)-4-(naphth-1-sulfonamido)phenyl)thiazoline-2-yl)acetamide, N-(4-methyl-5-(2-(phenylsulfonyl)isoindoline-5-yl)thiazoline-2-yl)acetamide, N-(5-(2-((2-chlorophenyl)sulfonyl)isoindoline-5-yl)-4-methyl) Thiazol-2-yl)acetamide, N-(5-(3-fluoro-4-(phenylsulfonamidomethyl)phenyl)-4-methylthiazol-2-yl)acetamide, N-(4-methyl-5-(3-(methylsulfonyl)-4-(phenylsulfonamidomethyl)phenyl)thiazol-2-yl)acetamide, N-(5-(3-fluoro-4-((phenylsulfonyl)methyl)phenyl)-4-methylthiazol-2-yl)acetamide, N-(4-methyl-5-(3-(methylsulfonyl)-4-((phenylsulfonyl)methyl)phenyl)thiazol-2-yl)acetamide, N-(4-methyl-5-(4-(N-methylphenylsulfonamido)-3-(methylsulfonyl)phenyl)thiazol-2-yl)acetamide, N-(4- Methyl-5-(3-(methylthio)-4-(phenylsulfonamido)phenyl)thiazol-2-yl)acetamide, N-(4-methyl-5-(3-(methylsulfinyl)-4-(phenylsulfonamido)phenyl)thiazol-2-yl)acetamide, N-(4-methyl-5-(4-(phenylsulfonamido)-3-(pyrrolidone-1-yl)phenyl)thiazol-2-yl)acetamide, methyl 5-(2-acetamido-4-methylthiazol-5-yl)-2-(phenylsulfonamido)benzoate, N-(5-(3-(benzyloxy)-4-(phenylsulfonamido)phenyl)-4-methylthiazol-2-yl)acetamide, N-(5-(3-fluoro-4-(phenylsulfonamido)phenyl)-4-methylthiazol- 2-yl)acetamide, N-(5-(3-cyclopropyl-4-(phenylsulfonamido)phenyl)-4-methylthiazol-2-yl)acetamide, N-(5-(3-acetamido-4-(phenylsulfonamido)phenyl)-4-methylthiazol-2-yl)acetamide, N-(5-(3-(methoxymethyl)-4-(phenylsulfonamido)phenyl)-4-methylthiazol-2-yl)acetamide, N-(5-(1-((2,6-dimethylphenyl)sulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)-4-methylthiazol-2-yl)acetamide, N-(5-(1-((3,4-dihydro-2H-benzo[b][1,4]dioxohepane-7-yl)sulfonyl)-1,2,3,4-Tetrahydroquinoline-6-yl)-4-methylthiazol-2-yl)acetamide, N-(5-(1-(furan-2-ylsulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)-4-methylthiazol-2-yl)acetamide, N-(5-(1-((1H-imidazol-2-yl)sulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)-4-methylthiazol-2-yl)acetamide, N-(5-(4-((2,3-dichlorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]thiazin-7-yl)-4-methylthiazol-2-yl)acetamide, N-(5-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)sulfonyl)-3,4 -dihydro-2H-benzo[b][1,4]oxazin-7-yl)-4-methylthiazol-2-yl)acetamide, N-(5-(1'-(cyclopropylsulfonyl)-2',3'-dihydro-1'H-spiro[oxacyclobutane-3,4'-quinoline]-6'-yl)-4-methylthiazol-2-yl)acetamide, N-(5-(1-(cyclopropanecarbonyl)-1,2,3,4-tetrahydroquinoline-6-yl)-4-methylthiazol-2-yl)acetamide, N-(5-(1-(cyclopropylsulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)-4-methylthiazol-2-yl)cyclopropaneformamide, N-(5-(1-(cyclopropylsulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)-4-methylthiazol-2-yl)cyclopropaneformamide, N-(5-(1-(cyclopropylsulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)-4 N-(5-(1-(cyclopropylsulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)-4-methylthiazol-2-yl)isobutyramide, N-(5-(1-(cyclopropylsulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)-4-methylthiazol-2-yl)cyclopentaneformamide, N-(5-(4-((2,3-dichlorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-4-methylthiazol-2-yl)acetamide, N-(5-(4-((2,3-dichlorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)thiazol-2-yl)acetamide, N-(5-(1-((4H-1,2,4-triazol-3-yl)sulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)-4-methylthiazol-2-yl)acetamide, 1-(6-((5-(1-((2,3-dichlorophenyl)sulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)-4-methylthiazol-2-yl)amino)pyridin-2-yl)pyrrolidone, N-(5-(1-((2,6-dioxonyl-1,2,3,6-tetrahydropyrimidin-4-yl)sulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)-4-methylthiazol-2-yl)acetamide, N-(4-methyl-5-(1-((5-methyl-2,6-dioxonyl ...6-Tetrahydropyrimidin-4-yl)sulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)thiazoline-2-yl)acetamide, N-(5-(1-((1H-pyrazol-4-yl)sulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)-4-methylthiazoline-2-yl)acetamide, N-(4-methyl-5-(1-((1-methyl-1H-1,2,3-triazol-5-yl)sulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)thiazoline-2-yl)acetamide, N-(4-methyl-5-(1-((1-methyl-1H-imidazol-2-yl)sulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)thiazoline-2-yl)acetamide, 6-(6-((5-(1-(( 2,3-Dichlorophenyl)sulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)-4-methylthiazolyl)amino)pyridin-2-yl)-7-oxylidene-2,6-diazaspiro[3,4]octane-2-carboxylic acid tert-butyl ester, N-(4-methyl-5-(1-((1-methyl-1H-pyrazol-5-yl)sulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)thiazolyl)acetamide, N-(4-methyl-5-(1-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)thiazolyl)acetamide, N-(4-methyl-5-(1-((1-methyl-1H-pyrazol-3-yl)sulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)thiazolyl)acetamide, N-(4-methyl-5-(1-((1-methyl-1H-pyrazol-3-yl)sulfonyl)-1,2, 3,4-Tetrahydroquinoline-6-yl)thiazolyl)acetamide, N-(5-(1-(isothiazolyl-5-ylsulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)-4-methylthiazolyl)acetamide, N-(5-(1-((4-chloro-1-methyl-1H-pyrazol-5-yl)sulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)-4-methylthiazolyl)acetamide, N-(5-(1-((4-chloro-1-methyl-1H-imidazol-5-yl)sulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)-4-methylthiazolyl)acetamide, N-(4-methyl-5-(1-((3-(prop-2-yn-1-ylamino)phenyl)sulfonyl) N-(5-(1-((3-((cyanomethyl)amino)phenyl)sulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)-4-methylthiazol-2-yl)acetamide, N-(5-(1-((6-cyanopyridin-2-yl)sulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)-4-methylthiazol-2-yl)acetamide, N-(5-(1-((3-cyanamidophenyl)sulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)-4-methylthiazol-2-yl)acetamide, N-(5-(1-((3-cyanamidophenyl)sulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)-4-methylthiazol-2-yl)acetamide, N-(4-methyl-5-(1-((3-(vinylsulfonamido)phenyl)sulfonyl)-1,2,3,4-Tetrahydroquinoline-6-yl)thiazoline-2-yl)acetamide, N-(3-((6-(2-acetamido-4-methylthiazoline-5-yl)-3,4-dihydroquinoline-1(2H)-yl)sulfonyl)phenyl)propyneamide, N-(4-methyl-5-(1-((2-(methylsulfonyl)benzo[d]thiazoline-6-yl)sulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)thiazoline-2-yl)acetamide, 1-(6-((5-(1 -(cyclopropylsulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)-4-methylthiazolyl-2-yl)amino)pyridin-2-yl)pyrrolidone, N-(5-(1-(cyclopropylsulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)-4-methylthiazolyl)cyclobutanecarboxamide, N-(5-(1-(cyclopropylsulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)-4-methylthiazolyl)-1-methyl 2-Cyclopropyl-1-carboxamide, N-(5-(1-(cyclopropylsulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)-4-methylthiazoline-2-yl)-2-methoxyacetamide, 2-cyclopropyl-N-(5-(1-(cyclopropylsulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)-4-methylthiazoline-2-yl)acetamide, N-(4-methyl-5-(1-((1-methylcyclopropyl)sulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)-4-methylthiazoline-2-yl)acetamide (Hydroquinoline-6-yl)thiazoline-2-yl)acetamide, 1-(6-((5-(1-(cyclopropylsulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)-4-methylthiazoline-2-yl)amino)pyridin-2-yl)piperidin-2-one, and 3-(6-((5-(1-(cyclopropylsulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)-4-methylthiazoline-2-yl)amino)pyridin-2-yl)-1,3-oxazinane-2-one.

[0146] As described in more detail herein, the present invention relates to the compounds themselves and their use in treating one or more of the medical indications described herein. Compounds of Formula 2 according to the embodiments described below, as represented by the exemplary compounds listed in Table 2, are considered novel in themselves and exhibit previously undisclosed structures. These compounds also exhibit the beneficial properties of the invention and are intended for use in the medical applications disclosed herein, but are not limited thereto.

[0147] In one embodiment, the present invention relates to compounds according to formula 2. Formula 2 in R1 is C, S, O, or N. R3 is a C1 to C5 alkyl (preferably C1 to C3 alkyl), C3 to C6 cycloalkyl, C1 to C5 haloalkyl (preferably C1 to C3 haloalkyl, including Cl, Br or F), -CN, carbonyl, carboxyl, carboxylic acid ester, alkoxy, aldehyde, primary amine, secondary or tertiary amine, amide, imide, carbamate, formamide, nitro, sulfide, sulfinyl, sulfonyl, sulfinyl or sulfonamide R4 and R5 may be the same or different, and are H, C1 to C5 alkyl (preferably C1 to C3 alkyl), C2 to C5 alkenyl, C3 to C6 cycloalkyl, C3 to C6 heterocycloalkyl (preferably including N, S and / or O), C1 to C5 haloalkyl (preferably C1 to C3 haloalkyl, preferably including Cl, Br or F), C4 to C6 aryl, sulfide, sulfinyl, sulfonyl, sulfinyl, sulfonamide, carboxyl, carboxylic acid ester, carbonyl C=OR, wherein R is C1 to C10 alkyl (preferably C1 to C5 alkyl), C1 to C3 haloalkyl (preferably including Cl, Br or F), C4 to C6 aryl, wherein R is optionally substituted with a urethane group or urethane, wherein when R10 and R11 or R11 and R14 do not form a ring structure, at least one of R4 and R5 is a carbonyl C=OR. Alternatively, R4 and R5 form a 4, 5, or 6-membered heterocyclic alkyl group comprising N and optionally one or more additional heteroatoms (preferably N, O, and / or S), wherein the heterocyclic alkyl group is optionally substituted with an alkoxy group. R6 is absent, or R1 is C and R6 forms a carbonyl group (C=O) with R1, or R1 is S and R6 forms a sulfoxide group (S=O) with R1. Whether R7, R8, and R9 are the same or different, they are C or N. R10 is H, C1 to C5 alkyl (preferably C1 to C3 alkyl), C3 to C6 cycloalkyl, C1 to C5 haloalkyl (preferably C1 to C3 haloalkyl, including Cl, Br or F), -CN, carbonyl, carboxyl, carboxylic acid ester, alkoxy, aldehyde, primary amine, secondary or tertiary amine, amide, imide, carbamate, formamide, nitro, sulfide, sulfinyl, sulfonyl, sulfinyl or sulfonamide R11 is a C3 to C6 cycloalkyl, C4 to C6 heterocycloalkyl (preferably including N, S and / or O), halogen (preferably F, Cl or Br), sulfide, sulfinyl, sulfonyl, sulfinyl, sulfonamide, carboxyl, carboxylic acid ester, formamide, alkoxy or aryloxy. Alternatively, R10 and R11, together with the atoms they are attached to, form a 5- to 8-membered cycloalkyl or aryl ring structure D comprising two carbon atoms of B, forming a fused cyclic group with B, optionally including one or more heteroatoms (preferably N, O, and / or S). R14 is H, C1 to C5 alkyl (preferably C1 to C3 alkyl), primary amine, secondary amine, tertiary amine, or alkylamine. Alternatively, R11 and R14, together with the atoms they are attached to, form a 5- to 8-membered cycloalkyl or aryl ring structure C comprising two carbon atoms of B, forming a fused bicyclic group with B, optionally comprising one or more heteroatoms (preferably N, O, and / or S), wherein B and C are one of the following:

[0148] R12 is a C1 to C5 alkyl group (preferably C1 to C3 alkyl group), carbonyl group (C=O), sulfide, sulfinyl group, or sulfonyl group. R13 is a C1 to C5 alkyl (preferably C1 to C3 alkyl), C2 to C5 alkenyl, C3 to C6 cycloalkyl, C5 or C6 aryl, alkylaryl, C5 or C6 heteroaryl (preferably including N, S and / or O), bicyclic group (preferably including one or two aromatic rings), optionally including one or more heteroatoms (preferably N, O and / or S). Alternatively, R11 may be a halogen, or not form a ring structure with R10 or R14, or R11 and R14 may form a 5- to 8-membered cycloalkyl or aryl ring structure with the atoms they are attached to, and R15 and R16 may be present, in which case R12 and R13 may not be present. When R11 and R14 do not form a ring structure, or when R11 and R14 form a 5, 7, or 8-membered ring structure, R15 is a C1 to C5 alkyl (preferably C1 to C3 alkyl), carbonyl C=O, sulfide, sulfinyl or sulfonyl, or When R11 and R14 form a 6-membered ring structure, R15 is a C1 to C5 alkyl (preferably C1 to C3 alkyl), sulfide, sulfinyl, or sulfonyl. R16 is a C1 to C5 alkyl (preferably C1 to C3 alkyl), C2 to C5 alkenyl, C3 to C6 cycloalkyl, C5 or C6 aryl, alkylaryl, C5 or C6 heteroaryl (preferably including N, S and / or O), bicyclic group (preferably including one or two aromatic rings), optionally including one or more heteroatoms (preferably N, O and / or S). Alternatively, R14 is H, or R10 and R11 together with the atoms they are attached to form a 5- to 8-membered cycloalkyl or aryl ring structure D, or R11 and R14 together with the atoms they are attached to form a 5- to 8-membered cycloalkyl or aryl ring structure C and R12 and R13 are present, in which case R15 and R16 are absent. X is C, S, and / or O. Y is C, N, S and / or O, R17 can be the same or different, and can be absent (electron pair of X), H, hydroxyl, halogen (preferably F, Cl, or Br), alkoxy, C1 to C5 alkyl (preferably C1 to C3 alkyl), C1 to C5 haloalkyl (preferably C1 to C3 haloalkyl, including Cl, Br, or F), C3 to C6 cycloalkyl, C3 to C6 heterocycloalkyl (preferably including N, O, and / or S and optionally substituted with alkoxy), C4 to C6 aryl, carbonyl C(=O)R, where R is a C1 to C5 alkyl. (Preferably C1 to C3 alkyl), carboxyl, carboxylic acid ester, alkoxy (preferably -OCH3, -OCH2CH3 or C3 to C6 cycloalkylalkoxy), aldehyde, primary amine, secondary or tertiary amine, amide, imide, carbamate, formamide, nitro, sulfide (preferably -SCH3, -SCH2CH3), sulfinyl, sulfonyl, sulfinyl or sulfonamide, or when X is C, forming a carbonyl C=O with X, or when X is S, forming a sulfoxide S=O or a sulfonyl S(=O)2 with X. Alternatively, two R17 atoms may form a 4, 5, or 6-membered cycloalkyl group, optionally including one or more heteroatoms (preferably N, O, and / or S). R18 can be the same or different, and can be H or alkoxy. Alternatively, an R17 and an R18 form a 5- or 6-membered cyclic ring structure comprising two carbon atoms of C, forming a fused cyclic group with C, optionally including one or more heteroatoms (preferably N, O, and / or S), wherein the 5- or 6-membered cyclic ring structure is optionally substituted with a C1 to C3 alkyl or alkoxy carbonyl group (preferably at the heteroatom position), and R19 can be the same or different, and is H, C1 to C6 alkyl (preferably C1 to C3 alkyl).

[0149] In one embodiment, the compound according to Formula 2 is characterized in that R4 and R5 may be the same or different, and are H, C1 to C5 alkyl (preferably C1 to C3 alkyl), C2 to C5 alkenyl, C3 to C6 cycloalkyl, C3 to C6 heterocycloalkyl (preferably including N, S and / or O), C1 to C5 haloalkyl (preferably C1 to C3 haloalkyl, preferably including Cl, Br or F), C3 to C6 cycloalkyl, alkoxy, C4 to C6 aryl, C5 to C6 heteroaryl (preferably including N, S and / or O and optionally substituted by C3 to C6 heterocycloyl (preferably including N, S and / or O)), sulfide, sulfinyl The compounds are alkyl, sulfonyl, sulfinyl, sulfonamide, carboxyl, carboxylic acid ester, carbonyl C=OR, wherein R is a C1 to C10 alkyl (preferably C1 to C5 alkyl), C1 to C3 haloalkyl (preferably including Cl, Br or F), C4 to C6 aryl, wherein R is optionally substituted with a urethane group or urethane, wherein when R10 and R11 or R11 and R14 do not form a ring structure, at least one of R4 and R5 is a carbonyl C=OR, or R4 and R5 form a 4, 5 or 6-membered heterocyclic alkyl group including N and optionally one or more additional heteroatoms (preferably N, O and / or S), wherein the heterocyclic alkyl group is optionally substituted with an alkoxy group.

[0150] In one embodiment, the compound according to Formula 2 is characterized in that R16 is a C1 to C5 alkyl (preferably C1 to C3 alkyl), C2 to C5 alkenyl, C3 to C6 cycloalkyl, C5 or C6 aryl, alkylaryl, C5 or C6 heteroaryl (preferably including N, S and / or O), C3 to C6 heterocycloalkyl (preferably including N, S and / or O and preferably including at least one double bond), bicyclic group (preferably including one or two aromatic rings), optionally including one or more heteroatoms (preferably N, O and / or S), or when R14 is H, or when R10 and R11 together with the atoms to which they are attached form a 5 to 8-membered cycloalkyl or aryl ring structure D, or when R11 and R14 together with the atoms to which they are attached form a 5 to 8-membered cycloalkyl or aryl ring structure C and R12 and R13 are present, R15 and R16 are absent.

[0151] In one embodiment, the present invention relates to compounds according to formula 2. R10 and R11, together with the atoms they are attached to, form a 5- to 7-membered ring or aryl ring structure D, which forms a fused bicyclic group with B, wherein B and D are

[0152] And R7, R8, R9, R12 and R13 are as described in claim 10.

[0153] In one embodiment, the present invention relates to compounds according to formula 2a. Equation 2a in R1 is C, S, O, or N. R3 is a C1 to C5 alkyl (preferably C1 to C3 alkyl), C3 to C6 cycloalkyl, C1 to C5 haloalkyl (preferably C1 to C3 haloalkyl, including Cl, Br or F), -CN, carbonyl, carboxyl, carboxylic acid ester, alkoxy, aldehyde, primary amine, secondary or tertiary amine, amide, imide, carbamate, formamide, nitro, sulfide, sulfinyl, sulfonyl, sulfinyl or sulfonamide R4 and R5 may be the same or different, and are H, C1 to C5 alkyl (preferably C1 to C3 alkyl), C2 to C5 alkenyl, C3 to C6 cycloalkyl, C3 to C6 heterocycloalkyl (preferably including N, S and / or O), C1 to C5 haloalkyl (preferably C1 to C3 haloalkyl, preferably including Cl, Br or F), C4 to C6 aryl, sulfide, sulfinyl, sulfonyl, sulfinyl, sulfonamide, carboxyl, carboxylic acid ester, carbonyl C=OR, wherein R is C1 to C10 alkyl (preferably C1 to C5 alkyl), C1 to C3 haloalkyl (preferably including Cl, Br or F), C4 to C6 aryl, wherein R is optionally substituted with a urethane group or urethane, wherein when R11 and R14 do not form a ring structure, at least one of R4 and R5 is a carbonyl C=OR. Alternatively, R4 and R5 form a 4, 5, or 6-membered heterocyclic alkyl group comprising N and optionally one or more additional heteroatoms (preferably N, O, and / or S), wherein the heterocyclic alkyl group is optionally substituted with an alkoxy group. R6 is absent, or R1 is C and R6 forms a carbonyl group (C=O) with R1, or R1 is S and R6 forms a sulfoxide group (S=O) with R1. Whether R7 and R8 are the same or different, and whether they are C or N. R9 is C. R10 is H, C1 to C5 alkyl (preferably C1 to C3 alkyl), C3 to C6 cycloalkyl, C1 to C5 haloalkyl (preferably C1 to C3 haloalkyl, including Cl, Br or F), -CN, carbonyl, carboxyl, carboxylic acid ester, alkoxy, aldehyde, primary amine, secondary or tertiary amine, amide, imide, carbamate, formamide, nitro, sulfide, sulfinyl, sulfonyl, sulfinyl or sulfonamide R11 is a C3 to C6 cycloalkyl, C4 to C6 heterocycloalkyl (preferably including N, S and / or O), halogen (preferably F, Cl or Br), sulfide, sulfinyl, sulfonyl, sulfinyl, sulfonamide, carboxyl, carboxylic acid ester, formamide, alkoxy or aryloxy. R14 is H, C1 to C5 alkyl (preferably C1 to C3 alkyl), primary amine, secondary amine, tertiary amine, or alkylamine. Alternatively, R11 and R14, together with the atoms they are attached to, form a 5- to 8-membered cycloalkyl or aryl ring structure C comprising two carbon atoms of B, forming a fused bicyclic group with B, optionally comprising one or more heteroatoms (preferably N, O, and / or S), wherein B and C are one of the following:

[0154] When R11 and R14 do not form a ring structure, or when R11 and R14 form a 5, 7, or 8-membered ring structure, R15 is a C1 to C5 alkyl (preferably C1 to C3 alkyl), carbonyl C=O, sulfide, sulfinyl or sulfonyl, or When R11 and R14 form a 6-membered ring structure, R15 is a C1 to C5 alkyl (preferably C1 to C3 alkyl), sulfide, sulfinyl, or sulfonyl. R16 is a C1 to C5 alkyl (preferably C1 to C3 alkyl), C2 to C5 alkenyl, C3 to C6 cycloalkyl, C5 or C6 aryl, alkylaryl, C5 or C6 heteroaryl (preferably including N, S and / or O), bicyclic group (preferably including one or two aromatic rings), optionally including one or more heteroatoms (preferably N, O and / or S). Alternatively, when R14 is H, R15 and R16 do not exist. X is C, S, and / or O. Y is C, N, S and / or O, R17 can be the same or different, and can be absent (electron pair of X), H, hydroxyl, halogen (preferably F, Cl, or Br), alkoxy, C1 to C5 alkyl (preferably C1 to C3 alkyl), C1 to C5 haloalkyl (preferably C1 to C3 haloalkyl, including Cl, Br, or F), C3 to C6 cycloalkyl, C3 to C6 heterocycloalkyl (preferably including N, O, and / or S and optionally substituted with alkoxy), C4 to C6 aryl, carbonyl C(=O)R, where R is a C1 to C5 alkyl. (Preferably C1 to C3 alkyl), carboxyl, carboxylic acid ester, alkoxy (preferably -OCH3, -OCH2CH3 or C3 to C6 cycloalkylalkoxy), aldehyde, primary amine, secondary or tertiary amine, amide, imide, carbamate, formamide, nitro, sulfide (preferably -SCH3, -SCH2CH3), sulfinyl, sulfonyl, sulfinyl or sulfonamide, or when X is C, forming a carbonyl C=O with X, or when X is S, forming a sulfoxide S=O or a sulfonyl S(=O)2 with X. Alternatively, two R17 atoms may form a 4, 5, or 6-membered cycloalkyl group, optionally including one or more heteroatoms (preferably N, O, and / or S). R18 can be the same or different, and can be H or alkoxy. Alternatively, an R17 and an R18 form a 5- or 6-membered cyclic ring structure comprising two carbon atoms of C, forming a fused cyclic group with C, optionally including one or more heteroatoms (preferably N, O, and / or S), wherein the 5- or 6-membered cyclic ring structure is optionally substituted with a C1 to C3 alkyl or alkoxy carbonyl group (preferably at the heteroatom position), and R19 can be the same or different, and is H, C1 to C6 alkyl (preferably C1 to C3 alkyl).

[0155] In one embodiment, the compound according to formula 2a is characterized in that R4 and R5 may be the same or different, and are H, C1 to C5 alkyl (preferably C1 to C3 alkyl), C2 to C5 alkenyl, C3 to C6 cycloalkyl, C3 to C6 heterocycloalkyl (preferably including N, S and / or O), C1 to C5 haloalkyl (preferably C1 to C3 haloalkyl, preferably including Cl, Br or F), C3 to C6 cycloalkyl, alkoxy, C4 to C6 aryl, C5 to C6 heteroaryl (preferably including N, S and / or O and optionally substituted with C3 to C6 heterocycloyl (preferably including N, S and / or O)), sulfide The compounds are sulfinyl, sulfonyl, sulfinyl, sulfonamide, carboxyl, carboxylic acid ester, carbonyl C=OR, wherein R is a C1 to C10 alkyl (preferably C1 to C5 alkyl), C1 to C3 haloalkyl (preferably including Cl, Br or F), C4 to C6 aryl, wherein R is optionally substituted with a urethane group or urethane, wherein when R11 and R14 do not form a ring structure, at least one of R4 and R5 is a carbonyl C=OR, or R4 and R5 form a 4, 5 or 6-membered heterocyclic alkyl group including N and optionally one or more additional heteroatoms (preferably N, O and / or S), wherein the heterocyclic alkyl group is optionally substituted with an alkoxy group.

[0156] In one embodiment, the compound according to formula 2a is characterized in that R16 is a C1 to C5 alkyl (preferably C1 to C3 alkyl), C2 to C5 alkenyl, C3 to C6 cycloalkyl, C5 or C6 aryl, alkylaryl, C5 or C6 heteroaryl (preferably including N, S and / or O), C3 to C6 heterocycloalkyl (preferably including N, S and / or O and preferably including at least one double bond), bicyclic group (preferably including one or two aromatic rings), optionally including one or more heteroatoms (preferably N, O and / or S).

[0157] In one embodiment, the present invention relates to compounds according to formula 2 or 2a. R16 is one of the following:

[0158] in R20 may be the same or different, and is H, C1 to C5 alkyl (preferably C1 to C3 alkyl), halogen (preferably F, Cl and / or Br), alkoxy or E, wherein E is one of the following:

[0159] R21 can be the same or different, and is H, C1 to C5 alkyl (preferably C1 to C3 alkyl), halogen (preferably F, Cl and / or Br), alkoxy, primary amine, secondary or tertiary amine, sulfide, sulfinyl, sulfonyl, sulfinyl, sulfonamide, carboxyl, carboxylic acid ester, secondary hydroxyl group C(-OH)CH3, carbonyl C=OR (wherein R is C1 to C10 alkyl (preferably C1 to C5 alkyl), C1 to C3 haloalkyl (preferably including Cl, Br or F)), imide, urethane group, formamide, amide N=OR (wherein R is C1 to C3 alkyl, C1 to C3 alkenyl, C1 to C3 haloalkyl (preferably including Cl, Br or F)), nitro or E, R22 can be the same or different, and is H or a C1 to C5 alkyl group (preferably a C1 to C3 alkyl group). R23 is an H, carbonyl, carboxyl, or carboxylic acid ester. R24 is H or a C1 to C5 alkyl group (preferably a C1 to C3 alkyl group), and R25 can be the same or different, and can be H, C1 to C4 alkyl, C1 to C4 heteroalkyl, C3 to C6 cycloalkyl, or C2 to C6 heterocycloalkyl.

[0160] In one embodiment, the present invention relates to compounds according to formula 2 or 2a. R16 is one of the following:

[0161] in X and Y may be the same or different, and X may be one of O, S, or N. R20 may be the same or different, and is H, C1 to C5 alkyl (preferably C1 to C3 alkyl), halogen (preferably F, Cl and / or Br), alkoxy or E, wherein E is one of the following:

[0162] R21 can be the same or different, and is H, C1 to C5 alkyl (preferably C1 to C3 alkyl), halogen (preferably F, Cl and / or Br), alkoxy, primary amine, secondary or tertiary amine, sulfide, sulfinyl, sulfonyl, sulfinyl, sulfonamide, carboxyl, carboxylic acid ester, secondary hydroxyl group C(-OH)CH3, carbonyl C=OR (wherein R is C1 to C10 alkyl (preferably C1 to C5 alkyl), C1 to C3 haloalkyl (preferably including Cl, Br or F)), imide, urethane group, formamide, amide N=OR (wherein R is C1 to C3 alkyl, C1 to C3 alkenyl, C1 to C3 haloalkyl (preferably including Cl, Br or F)), nitro or E, R22 can be the same or different, and is H or a C1 to C5 alkyl group (preferably a C1 to C3 alkyl group). R23 is an H, carbonyl, carboxyl, or carboxylic acid ester. R24 is H or a C1 to C5 alkyl group (preferably a C1 to C3 alkyl group), and R25 can be the same or different, and can be H, C1 to C4 alkyl, C1 to C4 heteroalkyl, C3 to C6 cycloalkyl, or C2 to C6 heterocycloalkyl.

[0163] In one embodiment, the present invention relates to compounds according to formula 2 or 2a. R16 is one of the following:

[0164] in X and Y may be the same or different, and X is one of C, O, S, or N. R20 may be the same or different, and is H, C1 to C5 alkyl (preferably C1 to C3 alkyl), halogen (preferably F, Cl and / or Br), alkoxy or E, wherein E is one of the following:

[0165] R21 can be the same or different, and is H, C1 to C5 alkyl (preferably C1 to C3 alkyl), halogen (preferably F, Cl and / or Br), alkoxy, primary amine, secondary or tertiary amine, sulfide, sulfinyl, sulfonyl, sulfinyl, sulfonamide, carboxyl, carboxylic acid ester, secondary hydroxyl group C(-OH)CH3, carbonyl C=OR (wherein R is C1 to C10 alkyl (preferably C1 to C5 alkyl), C1 to C3 haloalkyl (preferably including Cl, Br or F)), imide, urethane group, formamide, amide N=OR (wherein R is C1 to C3 alkyl, C1 to C3 alkenyl, C1 to C3 haloalkyl (preferably including Cl, Br or F)), nitro or E, R22 can be the same or different, and is H or a C1 to C5 alkyl group (preferably a C1 to C3 alkyl group). R23 is an H, carbonyl, carboxyl, or carboxylic acid ester. R24 is H or a C1 to C5 alkyl group (preferably a C1 to C3 alkyl group). R25 can be the same or different, and can be H, C1 to C4 alkyl, C1 to C4 heteroalkyl, C3 to C6 cycloalkyl, or C2 to C6 heterocycloalkyl. R26, R27, and R28 may be the same or different, and are H, C1 to C3 alkyl groups, halogens (preferably Cl, Br, or F), and R29 is H or a C1 to C3 alkyl group (preferably a C1 alkyl group).

[0166] In one embodiment, the present invention relates to compounds according to any one of formulas 1, 1a, 2, 2a, 3, 4, 5, 6, and 7 for use as a medicament in treating medical conditions associated with defective and / or pathological type II phosphoinositol 3-kinase (PI3K) signaling. In another embodiment, the present invention relates to compounds according to any one of formulas 1, 1a, 2, 2a, 3, 4, 5, 6, and 7 for use as a medicament in treating medical conditions associated with defective and / or pathological signaling of the β subtype (PI3K-C2b) of type II phosphoinositol 3-kinase.

[0167] In one embodiment, the present invention relates to a compound according to any one of 1, 1a, 2, 2a, 3, 4, 5, 6 and 7 for use as a medicament in treating medical conditions associated with defective and / or pathological type II phosphoinositol 3-kinase (PI3K) signaling, preferably with defective and / or pathological signaling of the β subtype of type II phosphoinositol 3-kinase (PI3K-C2b), wherein the medical condition is selected from the group consisting of: stroke, cardiovascular disease associated with endothelial cell dysfunction, cancer, cancer metastasis, myopathy (preferably myotubular myopathy) and diabetes.

[0168] In one embodiment, the present invention relates to a compound according to any one of 1, 1a, 2, 2a, 3, 4, 5, 6 and 7 for use in treating a subject suffering from a medical condition associated with defective and / or pathological signaling of the β subtype of phosphoinositol 3-kinase (PI3K), preferably β-type phosphoinositol 3-kinase (PI3K-C2b), wherein the medical condition is selected from the group consisting of: stroke, cardiovascular disease associated with endothelial cell dysfunction, cancer, cancer metastasis, myopathy (preferably myotubular myopathy) and diabetes.

[0169] In one embodiment, the medical condition to be treated is myopathy, preferably myotubular myopathy, more preferably X-linked central nucleus myopathy. Preferred embodiments relate to myopathy associated with defective and / or pathological phosphoinositol 3-kinase (PI3K) signaling. For example, it has been shown that the X-linked central nucleus myopathy phenotype in mouse models can be rescued by the deletion of class II PI3K-C2b and partially improved by administration of the non-selective PI3K inhibitor womanpem.

[0170] In one embodiment, the medical condition to be treated is cancer and / or cancer metastasis, preferably a solid tumor, and more preferably wherein the compound targets pathological tumor angiogenesis. Preferred embodiments relate to cancers associated with defective and / or pathological class II phosphoinositol 3-kinase (PI3K) signaling.

[0171] In one embodiment, the medical condition to be treated is diabetes. A preferred embodiment involves a subject suffering from diabetes, wherein the condition may be shown to be associated with defective and / or pathological type II phosphoinositol 3-kinase (PI3K) signaling.

[0172] In one embodiment, the medical condition to be treated is stroke and / or cardiovascular disease associated with endothelial cell dysfunction. Preferred embodiments relate to cardiovascular disease associated with defective and / or pathological class II phosphoinositol 3-kinase (PI3K) signaling.

[0173] In one embodiment, the present invention relates to a method for treating and / or preventing medical conditions associated with defective and / or pathological type II phosphoinositol 3-kinase (PI3K) signaling, preferably defective and / or pathological signaling of the β subtype of type II phosphoinositol 3-kinase (PI3K-C2b), wherein the medical condition is selected from the group consisting of: stroke, cardiovascular disease associated with endothelial cell dysfunction, cancer, cancer metastasis, myopathy (preferably myotubular myopathy), and diabetes, the method comprising administering to a subject in need of the above compounds or compounds falling into the above formulas, particularly one or more of compounds of formulas 1, 1a, 2, 2a, 3, 4, 5, 6, and 7, and preferred embodiments and combinations thereof.

[0174] In one embodiment, the present invention relates to a method for treating or preventing, in a subject with a need, a medical condition associated with defective and / or pathological type II phosphoinositol 3-kinase (PI3K) signaling, preferably defective and / or pathological signaling of the β subtype of type II phosphoinositol 3-kinase (PI3K-C2b), wherein the medical condition is selected from the group consisting of: stroke, cardiovascular disease associated with endothelial cell dysfunction, cancer, cancer metastasis, myopathy (preferably myotubular myopathy), and diabetes, the method comprising: (a) Identify the subject as having a medical condition associated with defective and / or pathological type II phosphoinositol 3-kinase (PI3K) signaling, or defective and / or pathological signaling of the β-isoform of type II phosphoinositol 3-kinase (PI3K-C2b). (b) By administering to a subject a compound according to any one of formulas 1, 1a, 2, 2a, 3, 4, 5, 6 and 7, selectively inhibiting defective and / or pathological type II phosphoinositol 3-kinase (PI3K) signaling in the subject, preferably defective and / or pathological signaling of the β isoform of type II phosphoinositol 3-kinase (PI3K-C2b).

[0175] In one embodiment, a compound according to any one of formulas 1, 1a, 2, 2a, 3, 4, 5, 6, and 7 selectively inhibits type II phosphoinositol 3-kinase (PI3K) signaling, preferably the signaling of the β isoform of type II phosphoinositol 3-kinase (PI3K-C2b). In embodiments, the compounds described herein may be referred to as PIK3 inhibitors. In embodiments, the compounds described herein may be referred to as PI3K-C2b inhibitors. In embodiments, the compounds according to the invention exhibit the desired properties of inhibiting PIK3. In embodiments, the compounds according to the invention exhibit the desired properties of inhibiting PI3K-C2b. Those skilled in the art can determine whether any given compound exhibits the desired properties of the invention.

[0176] In embodiments, the compounds of the present invention are defined by the presence of a functional property (i.e., inhibition of PIK3, preferably inhibition of PI3K-C2b). This inhibition may be apparent when using one or more in vitro (or other) assays described in detail in the examples. Those skilled in the art can determine, with minimal effort, whether any given compound according to the invention exhibits the desired property, using the guidance provided herein and their common general knowledge.

[0177] In one aspect, the present invention relates to a pharmaceutical composition for use as a medicament in treating a medical condition associated with defective and / or pathological signaling of the β subtype of phosphoinositol 3-kinase (PI3K), preferably PI3K-C2b, the pharmaceutical composition comprising one or more compounds according to any one of the preceding claims with a pharmaceutically acceptable carrier.

[0178] In one aspect, the present invention relates to an in vitro method for modulating (preferably inhibiting) type II phosphoinositol 3-kinase (PI3K) signaling, preferably the signaling of the β isoform of type II phosphoinositol 3-kinase (PI3K-C2b), the in vitro method comprising administering to cells in which PI3K signaling, preferably the signaling of the β isoform of type II phosphoinositol 3-kinase (PI3K-C2b), is to be modulated, a compound according to any one of the preceding claims or a composition comprising said compound.

[0179] Table 1 shows many exemplary compounds of the present invention suitable for the medical uses described herein. Any structure may represent an embodiment of the invention and / or be used in any aspect or embodiment of the invention described herein.

[0180] Table 1: Preferred compounds of the present invention

[0181] All features described in this specification may be used to define any other embodiment or aspect of the invention. For example, a feature used to describe the medical use of one compound may be used to describe the medical use of another compound, and vice versa. Features used to describe any one or more compounds may be combined with any one or more medical uses of the invention. Similarly, as understood by those skilled in the art, structural features of compounds may be used to describe the methods of the invention, other compounds of the invention, or pharmaceutical compositions of the invention, and vice versa.

[0182] Detailed description This invention relates to chemical compounds used as inhibitors of type II phosphoinositol 3-kinase (PI3K) signaling. The invention further relates to the medical use of inhibitors of type II phosphoinositol 3-kinase (PI3K) signaling in the treatment of medical conditions associated with defective and / or pathological type II phosphoinositol 3-kinase (PI3K) signaling, such as stroke, cardiovascular disease associated with endothelial cell dysfunction, cancer, cancer metastasis, myopathy (preferably myotubular myopathy), and diabetes.

[0183] Medical uses: According to the present invention, "medical condition associated with defective and / or pathological type II phosphoinositol 3-kinase (PI3K) signaling" or "associated with defective and / or pathological signaling of the β subtype of type II phosphoinositol 3-kinase (PKI3-C2b)" refers to any medical condition, disease, illness, or other medical state in which type II phosphoinositol 3-kinase (PI3K) signaling is abnormal or associated with signaling defects (such as reduced signaling, enhanced signaling, and / or any changes in signaling associated with or responsible for the cause of the medical condition).

[0184] The term "phosphoinositol 3-kinase (PI3K) signaling" refers to a signaling pathway as understood by those skilled in the art, and in a preferred embodiment, to an abnormality in PI3K activity that results in disruption of the associated signaling pathway. A review of PI3K signaling is provided in Vanhaesebroeck et al. (Nat. Rev.Mol. Cell Biol. 2010, 11, 329-341).

[0185] In preferred embodiments, but not limited to this, "defective and / or pathological type II phosphoinositol 3-kinase (PI3K) signaling" refers to elevated activity, gene copy number, or expression of type II phosphoinositol 3-kinase. In preferred embodiments, but not limited to this, "defective and / or pathological signaling of the β isoform of type II phosphoinositol 3-kinase (PKI3-C2b)" refers to elevated activity, gene copy number, or expression of the β isoform of type II phosphoinositol 3-kinase. The established assay can be used by a technician to determine whether type II PI3K signaling is disrupted, for example by obtaining pathological cells, such as cancer cells, and assessing said signaling in these cells, or by directly assessing elevated activity, gene copy number, or expression of type II phosphoinositol 3-kinase in tumors or other biological samples, depending on the disease being tested.

[0186] PIK3-C2b, also known as "PI3KC2β," is a subtype of PIK3 and plays a role in signaling pathways involved in cell proliferation, oncogenic transformation, cell survival, cell migration, and intracellular protein transport. PIK3-C2b is associated with endocytosis, proliferation, and glucose metabolism, and further regulates nutrient signaling by inhibiting mTORC1 signaling through the local production of PI(3,4)P2 at late endosomes or lysosomes (Marat et al, Science, 2017, 356, 968-972). Based on currently available data, class II PI3Ks such as PIK3-C2b appear to be associated with cancer, cardiovascular disease, diabetes, and other diseases (Falasca et al, J. Med. Chem. 2016, 60, 47-65).

[0187] diabetes: Numerous PIK3-C2b-deficient mouse models have been developed to date. Therefore, a mouse model with combined deficiency of both PI3K-C2α and PI3K-C2b has been described, demonstrating that at least some key functions of these two highly related enzymes do not overlap (Fyffe et al., Curr. Pharm. Des., 2013, 19, 680-686). The first significant phenotype observed in PI3KC2β-deficient mice indicates the role of PI3KC2β in insulin sensitivity and glucose tolerance. Furthermore, PI3KC2βD1212A / D1212A mice were protected from high-fat diet-induced steatosis, suggesting that this regulatory role in insulin signaling is particularly important in the liver (Alliouachene et al., Cell Rep., 2015, 13, 1881-1894). These results suggest that PI3K-C2b may be a potential drug target for the treatment of type 2 diabetes and other insulin resistance conditions, such as non-alcoholic fatty liver disease.

[0188] cancer: Thorpe et al. (Nat. Rev. Cancer, 2015, 15, 7-24) provided a broad review of potential cancer targets in PI3K signaling.

[0189] Genes encoding PI3K-C2b and PIK3C2B have been reported to amplify in several tumor types (such as histological sections of glioblastoma multiforme and glioblastoma), and a similarly significant increase in PIK3C2B copy number was observed in 90 ovarian cancer specimens. The increased expression of PI3K-C2b observed in ovarian cancer cells was significantly higher than that of other PI3K classes. PIK3C2B, along with MDM4 amplification, was also detected in oligodendrogliomas. Overexpression of PI3K-C2b was observed in various cancer cell lines and specimens, such as acute myeloid leukemia, medulloblastoma, and glioblastoma multiforme. PIK3C2B was identified as one of the mutated genes in non-small cell lung cancer samples compared to non-tumoric tissues. Overexpression of negative PI3K-C2b significantly inhibited the growth of small cell lung cancer and growth factor-induced Akt activation. Increased PI3K-C2b expression has also been confirmed in myeloid leukemia and acute lymphoblastic leukemia. Its inhibition exhibits high antiproliferative activity, particularly in AML cell lines, where reduced proliferation and significantly increased apoptosis are observed.

[0190] In summary, these observations suggest that PI3K-C2b inhibition is a valuable therapeutic strategy for treating cancers, including solid tumors, with PI3K-C2b serving as a drug target for reducing pathological tumor metastasis, angiogenesis, and growth / survival.

[0191] In a preferred embodiment, the present invention relates to cancer and / or cancer metastasis as a disease to be treated. Cancer according to the invention refers to all types of cancer or growths or malignant tumors found in mammals, including leukemia, lymphoma, sarcoma, melanoma, and carcinoma. Examples of cancers are breast cancer, pancreatic cancer, colon cancer, lung cancer, non-small cell lung cancer, ovarian cancer, and prostate cancer.

[0192] In the context of this invention, leukemia includes, but is not limited to, acute non-lymphocytic leukemia, chronic lymphocytic leukemia, acute myeloid leukemia, chronic myeloid leukemia, acute promyelocytic leukemia, adult T-cell leukemia, non-leukemic leukemia, leukocythemotic leukemia, basophylic leukemia, blastic leukemia, bovine leukemia, chronic myelocytic leukemia, cutaneous leukemia, embryonal leukemia, eosinophilic leukemia, Gross' leukemia, hairy cell leukemia, hemoblastic leukemia, and hemocytoblastic leukemia. Leukemia, histiocytic leukemia, stem cell leukemia, acute monocytic leukemia, leukopenic leukemia, lymphocytic leukemia, lymphoblastic leukemia, lymphocytic leukemia, lymphogenous leukemia, lymphoid leukemia, lymphosarcoma cell leukemia, mast cell leukemia, megakaryocytic leukemia, micromyeloblastic leukemia Leukemia, monocytic leukemia, myeloblasticle leukemia, myeloid leukemia, myeloid granulocytic leukemia, myelomonocytic leukemia, Naegeli leukemia, plasma cell leukemia, plasma cell leukemia, promyelocytic leukemia, Rieder cell leukemia, Schilling's leukemia, stem cell leukemia, subleukemic leukemia, and undifferentiated cell leukemia.

[0193] According to the present invention, lymphomas include Hodgkin's lymphoma and non-Hodgkin's lymphoma (B-cell and T-cell lymphomas), including but not limited to diffuse large B-cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma, follicular lymphoma, chronic lymphocytic leukemia, small lymphocytic lymphoma, mantle cell lymphoma, marginal zone B-cell lymphoma, extranodal marginal zone B-cell lymphoma (also known as mucosa-associated lymphoid tissue (MALT) lymphoma), intranodal marginal zone B-cell lymphoma and splenic marginal zone B-cell lymphoma, Burkitt lymphoma, and lymphoplasmacytic lymphoma (Waldenstrom macroglobulinemia). macroglobulinemia, hairy cell leukemia, primary central nervous system (CNS) lymphoma, precursor T-cell lymphoblastic lymphoma / leukemia, peripheral T-cell lymphoma, cutaneous T-cell lymphoma (mycosis fungoides, Sezary syndrome, etc.), adult T-cell leukemia / lymphoma (including smoldering, chronic, acute and lymphoma subtypes), angioimmunoblastic T-cell lymphoma, extranodal natural killer / T-cell lymphoma, nasal type, enteropathy-associated intestinal T-cell lymphoma (EATL), anaplastic large cell lymphoma (ALCL), and nonspecific peripheral T-cell lymphoma.

[0194] Sarcomas defined in the context of this invention include, but are not limited to, chondrosarcoma, fibrosarcoma, lymphosarcoma, melanosarcoma, myxosarcoma, osteosarcoma, Abernethy's sarcoma, adipose sarcoma, liposarcoma, alveolar soft tissue sarcoma, ameloblastic sarcoma, botryoid sarcoma, chloroma sarcoma, choriocarcinoma, embryonal sarcoma, and Wilms' tumor. Sarcoma, endometrial sarcoma, stromal sarcoma, Ewing's sarcoma, fascial sarcoma, fibroblastic sarcoma, giant cell sarcoma, granulocyte sarcoma, Hodgkin's sarcoma, idiopathic multiple pigmented hemorrhagic sarcoma, B-cell immunoblastic sarcoma, lymphoma, T-cell immunoblastic sarcoma, Jensen's sarcoma, Kaposi's sarcoma, Kupffer cell sarcoma, angiosarcoma, leukemic sarcoma, malignant mesenchymal sarcoma, periosteal sarcoma, reticulocytic sarcoma, Rous sarcoma, serocystic sarcoma, synovial sarcoma, and capillary angiotensin-constricting sarcoma.

[0195] The melanomas according to the present invention include, but are not limited to, for example, acral lentigines melanoma, amelanoma, benign juvenile melanoma, Cloudman's melanoma, S91 melanoma, Harding-Passey melanoma, juvenile melanoma, malignant lentigines melanoma, malignant melanoma, nodular melanoma, subungual melanoma, and superficial diffuse melanoma.

[0196] The cancers defined in this invention include, but are not limited to, acinar carcinoma, acinar carcinoma, adenoid cystic carcinoma, adenoid cystic carcinoma, adenomatous carcinoma, adrenocortical carcinoma, alveolar carcinoma, alveolar cell carcinoma, basal cell carcinoma, basal cell carcinoma, basal cell-like carcinoma, basal squamous cell carcinoma, bronchioloalveolar carcinoma, bronchiolar carcinoma, bronchial carcinoma, cerebriform carcinoma, cholangiocarcinoma, choriocarcinoma, colloid carcinoma, comedo carcinoma, uterine cancer, cribriform carcinoma, armored carcinoma, cutaneous carcinoma, columnar carcinoma, columnar cell carcinoma, ductal carcinoma, sclerosing carcinoma, embryonal carcinoma, encephaloid carcinoma, epidermoid carcinoma, and adenoid epithelial carcinoma. adenoides, exophytic carcinoma, ulcerative carcinoma, fibrous carcinoma, gelatiniform carcinoma, gelatinous carcinoma, giant cell carcinoma, gigantocellular carcinoma, glandular carcinoma, granular cell carcinoma, pilonidal carcinoma, hematoid carcinoma, hepatocellular carcinoma, Hurthle cell carcinoma, hyaline carcinoma, hypernephroid carcinoma, infantile embryonal carcinoma, carcinoma in situ, intraepithelial carcinoma, intraepithelial carcinoma, Krompecher's carcinoma, Kulchitzky-cell carcinoma, large cell carcinoma, lenticular carcinoma, lenticular carcinoma, lipomatous carcinoma Carcinoma, lymphoepithelial carcinoma, medullary carcinoma, melanoma, molluscum carcinoma, mucinous carcinomaCarcinoma, mucinous carcinoma, mucocellular carcinoma, mucoepidermoid carcinoma, mucinous carcinoma, mucous carcinoma, myxomatodes, nasopharyngeal carcinoma, oat cell carcinoma, ossificans carcinoma, osteoid carcinoma, papillary carcinoma, periportal carcinoma, preinvasive carcinoma, acanthosis pilaris, pultaceous carcinoma, renal cell carcinoma, reserve cell carcinoma, sarcomatodes, Schneiderian carcinoma, scirrhous carcinoma, scrotal carcinoma, signet ring cell carcinoma, simple carcinoma, small cell carcinoma, and potato-shaped carcinoma. Carcinoma, spherical cell carcinoma, spindle cell carcinoma, cavernous carcinoma (carcinoma spongiosum), squamous carcinoma, squamous cell carcinoma, string carcinoma, telangiectatic carcinoma, telangiectodes carcinoma, transitional cell carcinoma, tuberosum carcinoma, tuberous carcinoma, verrucous carcinoma, and villosum carcinoma.

[0197] Other cancers according to the present invention include, but are not limited to, multiple myeloma, neuroblastoma, breast cancer, ovarian cancer, lung cancer, rhabdomyosarcoma, essential thrombocytosis, essential macroglobulinemia, small cell lung tumor, primary brain tumor, gastric cancer, colon cancer, malignant pancreatic insulinoma, malignant carcinoid tumor, urobladder cancer, precancerous skin lesions, testicular cancer, lymphoma, thyroid cancer, esophageal cancer, urogenital tract cancer, malignant hypercalcemia, cervical cancer, endometrial cancer, adrenocortical carcinoma, and prostate cancer.

[0198] Cardiovascular diseases: The term "cardiovascular disease" (CVD) or "cardiovascular disease associated with endothelial cell dysfunction" refers to a class of diseases involving the heart or blood vessels. CVD includes, but is not limited to, coronary artery disease (CAD), such as angina and myocardial infarction (commonly known as a heart attack). Other CVDs include stroke, heart failure, hypertensive heart disease, rheumatic heart disease, cardiomyopathy, arrhythmias, congenital heart disease, valvular heart disease, carditis, aortic aneurysms, peripheral artery disease, thromboembolic diseases, and venous thrombosis.

[0199] Myopathy: The term "myopathy" refers to a class of diseases involving structural changes and / or functional impairment of muscles, and is associated with defective and / or pathological phosphoinositol 3-kinase (PI3K) signaling. Preferably, the term "myopathy" refers to myotubular myopathy, more preferably X-linked central nucleus myopathy.

[0200] It has been demonstrated that PIK3-C2b inhibition improves function and prolongs survival in animal models of myotubular myopathy (Sabha et al., J Clin Invest. 2016, 126, 3613-3625). Myotubular myopathy (MTM) is a pediatric neuromuscular disorder caused by mutations in the PIP phosphatase MTM1, and there is currently no established treatment. Targeting class II and III PI3 kinases (PI3Ks) in MTM1-deficient mouse models resulted in muscle-specific ablation of Pik3c2b, rather than Pik3c3, leading to complete prevention of the MTM phenotype, and post-symptomatic targeting significantly rescued the disease. The PI3K inhibitor wollampenine also improved motor function and prolonged lifespan in MTM1-deficient mice. This evidence strongly demonstrates the therapeutic efficacy of PIK3 inhibitors in treating myopathy, muscular dystrophy, etc.

[0201] Chemical compounds Regarding the chemical compounds described herein, the term "alkyl" refers to a branched or unbranched saturated hydrocarbon group, preferably with 1 to 5 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, pentyl, etc. Preferred alkyl groups have 1 to 5 carbon atoms, more preferably 1 to 4, 1 to 3, 2, or 1 carbon atom. Any or more alkyl groups described herein may be "substituted alkyl," wherein one or more hydrogen atoms are substituted by a substituent such as a halogen, cycloalkyl, alkoxy, hydroxyl, aryl, or carboxyl group.

[0202] The term "heteroalkyl" refers to a branched or unbranched saturated alkyl group in which one or more carbon atoms are replaced by heteroatoms such as nitrogen, oxygen, or sulfur, wherein further heteroatoms may be oxidized, for example, N=O, S=O, SO2. Any or more heteroalkyl groups described herein may be "substituted heteroalkyl" in which one or more hydrogen atoms are replaced by substituents such as halogen, cycloalkyl, alkoxy, hydroxyl, aryl, or carboxyl groups.

[0203] The term "cycloalkyl" refers to a configuration derived from cycloalkanes by removing hydrogen atoms, preferably forming cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl groups. Any or more cycloalkyl groups described herein can be "substituted cycloalkyl," where one or more hydrogen atoms are replaced by substituents such as halogens, cycloalkyl groups, alkoxy groups, hydroxyl groups, aryl groups, or carboxyl groups. Any or more cycloalkyl groups described herein may include one or more double bonds without forming an aromatic aryl group.

[0204] The term "alkoxy group" refers to a straight-chain, branched, or cyclic hydrocarbon configuration and combinations thereof, preferably with 1-7 carbon atoms, more preferably 1-6, 1-5, 1-4, or 1-3 carbon atoms, which includes an oxygen atom (such as an O-alkyl group) at the junction. Examples of "alkoxy groups" are represented by the formula -OR or -ROR (such as -CH2OR), where R can be an alkyl group, optionally substituted with a halogen, aryl (also called aryloxy), cycloalkyl, or haloalkyl. Suitable alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, cyclohexyloxy, etc.

[0205] The term "aryl" refers to any carbonyl aromatic group, including but not limited to benzene, naphthalene, etc. The term "aromatic" also includes "heteroaryl group," which is defined as an aromatic group having at least one heteroatom bonded to its ring. Examples of heteroatoms include, but are not limited to, nitrogen, oxygen, and sulfur. An aryl group may be substituted with one or more groups, including but not limited to alkyl, aryl, halogen, nitro, hydroxyl, carboxylic acid, or alkoxy groups, or the aryl group may be unsubstituted.

[0206] The term “heteroaryl” is understood to mean a saturated (heterocyclic alkyl), partially unsaturated (heterocyclic alkenyl), or unsaturated (heteroaryl) hydrocarbon ring containing 3 to 15 carbon atoms in a monocyclic or bicyclic, fused, bridged, or spirocyclic ring, wherein 1 to 5 of the 3 to 15 ring carbon atoms are replaced by heteroatoms, such as nitrogen, oxygen, or sulfur, wherein further heteroatoms may be oxidized, for example, N=O, S=O, SO2. Non-restricted examples of heterocycles include acridine, azaindole (1H-pyrrolopyridyl), azabenzimidazolyl, azaspirodecyl, azacycloheptanyl, azacyclobutyl, azacyclopropyl, benzimidazolyl, benzofuranyl, dihydrobenzofuranyl, benzothiofuranyl, benzothiophene, benzooxazolyl, benzothiazolyl, benzotriazolyl, benzotetrazole, benzoisooxazolyl, benzoisothiazolyl, carbazole, 4aH-carbazole, carbolinyl, chromanyl, and chromenyl. Crazolinyl, decahydroquinolinyl, 4,5-dihydrooxazolinyl, dioxazolyl, dioxazinyl, 1,3-dioxopentyl, 1,3-dioxolanedienyl, 3,3-dioxanedi[1,3,4]oxathiazinyl, 6H-1,5,2-dithiazinyl, dihydrofurano[2,3-b]-tetrahydrofuranyl, furanyl, furazanyl, imidazoalkyl, imidazolinyl, imidazolyl, 1H-indazoleyl, indololinyl, indole Zinyl, indolyl, 3H-indolyl, isobenzofuranyl, isochoryl, isoindolinyl, isoindolyl, isoquinolinyl (benzimidazolyl), isothiazolyl, isothiazolinyl, isoxazolyl, isoxazolinyl, isoxazolyl, 2-isooxazolinyl, ketopiperazinyl, morpholinyl, naphthidyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2-oxa-thiepanyl, 1,2-oxathiolanyl, 1,4-oxazepanyl, 1,4-oxazepinyl, 1,2-oxazinyl, 1,3-oxazinyl, 1,4-Oxazinyl, oxazolyl, oxazolinyl, oxazolyl, oxetaneyl, oxetaneyl, oxetaneyloctyl, phenanthidyl, phenanthrolineyl, phenazinyl, phenothiazinyl, phenothiazinyl, phenothiazinyl, phthalazinyl, piperazinyl, piperidinyl, pteridinyl, purine, pyranyl, pyrazinyl, pyrazolylyl, pyrazolylylalkyl, pyrazolylyl, pyrazolyl, pyridazinyl, pyridooxazolyl, pyridoimidazolyl, pyridothiazolyl, pyridinyl, pyrimidinyl, pyrrolylyl, pyrrolidone, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinazinyl, quinoxolinyl, quininecycloyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyridinyl, tetrahydrothiophenyl, tetraazinyl Tetrazolyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazinyl, 1,2,4-thiadiazinyl, 1,2,5-thiadiazinyl, 1,3,4-thiadiazinyl, thiaanthryl, 1,2-thiazinyl, 1,3-thiazinyl, 1,4-thiazinyl, 1,3-thiazolyl, thiazolyl, thiazolyl, thiazolinyl, thiophene, thiohexacyclic butyl, thiophene-thiazolyl Thiophene-oxazolyl, thienenoimidazolyl, thiomorpholinyl, thiophenoly, thienyl, thiaranyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1,2,3-triazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, and xanthonyl.

[0207] The term "amine" refers to a group of the formula -NRR', where R and R' can independently be hydrogen or one of the aforementioned alkyl, alkenyl, ynyl, aryl, aralkyl, cycloalkyl, haloalkyl, or heterocyclic alkyl groups. The term "primary amine" refers to a group of the formula -NH2. The term "secondary amine" refers to a group of the formula -NRH, where R can be one of the aforementioned alkyl, alkenyl, ynyl, aryl, aralkyl, cycloalkyl, haloalkyl, or heterocyclic alkyl groups. The term "secondary amine" refers to a group of the formula -NRR', where R and R' can independently be one of the aforementioned alkyl, alkenyl, ynyl, aryl, aralkyl, cycloalkyl, haloalkyl, or heterocyclic alkyl groups.

[0208] The term "amide" or "amido" is represented by the formula -C(O)NRR', where R and R' can independently be hydrogen, the aforementioned alkyl, alkenyl, alkynyl, aryl, aralkyl, cycloalkyl, haloalkyl, or heterocyclic alkyl groups. A suitable amide group is acetamido.

[0209] "Carbonyl" refers to a group of the formula -C(O)-. Carbonyl groups include any substituents containing a carbon-oxygen double bond (C=O), including acyl groups, amides, carboxyl groups, esters, ureas, urethanes, carbamates, carbonates, formamides, imides, ketones, and aldehydes, such as substituents based on -COR or -RCHO, where R is aliphatic, heteroaliphatic, alkyl, heteroalkyl, hydroxyl or secondary amine, tertiary or quaternary amine, phenyl, substituted phenyl (substituted by, for example, halogens, C1-C3 alkyl, alkoxy, amine), carboxyl, alkoxycarbonyl, amine, or aryl.

[0210] The term "alkylamino" refers to an alkyl group as defined above, wherein at least one hydrogen atom is replaced by an amino group.

[0211] The term "carboxyl group" refers to the -COOH group. A substituted carboxyl group is -COOR, where R is aliphatic, heteroaliphatic, alkyl, heteroalkyl, or carboxylic acid or ester. The term carboxylic acid ester refers to -COOR, where R is an alkyl group.

[0212] The term "hydroxyl group" is represented by the formula -OH.

[0213] The term "hydroxyalkyl" refers to an alkyl group having at least one hydrogen atom replaced by a hydroxyl group. The term "alkoxyalkyl" is defined as an alkyl group having at least one hydrogen atom replaced by an alkoxy group.

[0214] The term "aralkyl" or "alkylaryl" refers to an aryl group having an alkyl group attached to an aryl group as defined above. An example of an aralkyl group is a benzyl group.

[0215] Optionally substituted groups, such as “optionally substituted alkyl”, refer to groups that, when substituted, have 1 to 5 substituents, typically 1, 2 or 3 substituents, such as alkyl groups, with substituents selected from alkoxy, optionally substituted alkoxy, acyl, amide, acyloxy, amino, aminoacyl, aminoacyloxy, aryl, carboxyalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, halogen, optionally substituted heteroaryl, optionally substituted heterocyclic, hydroxyl, sulfonyl, mercapto and thioalkoxy.

[0216] In particular, the optionally substituted alkyl groups include, for example, haloalkyl groups, such as fluoroalkyl groups, including but not limited to trifluoromethyl groups. These potential optional substituents apply to any group of the formula disclosed herein in which optional substituents are described. Preferred optional substituents are hydroxyl, alkyl, alkoxy, carbonyl, alkoxycarbonyl, NO2, and amine.

[0217] The term "aldehyde" is represented by the formula -CHO, which consists of a carbonyl center (carbon double bonded to oxygen), wherein the carbon atom is also bonded to hydrogen and R groups, preferably the main chain of this formula.

[0218] The term "carboxylic acid ester" is represented by the formula -C(O)-OR.

[0219] The term "formamide" is represented by the formula -C(O)-N(R)-R.

[0220] The terms "primary amine, secondary amine, or tertiary amine" are represented by the formula -N(R)-R.

[0221] The term "carbamate" is represented by the formula -NR-C(O)-OR.

[0222] The term "imide" is represented by the formula -C(O)-N(R)-C(O)-R'.

[0223] The term "sulfide" is represented by the formula -SR.

[0224] The term "sulfinyl" is represented by the formula -S(O)R.

[0225] The term "sulfonyl" is represented by the formula -SO2R.

[0226] The term "sulfonyl" is represented by the formula -SO2H.

[0227] The term "sulfonyl" is represented by the formula -SO3H.

[0228] The term "sulfone" or "sulfone" is preferably selected from the group -SO r -R, where r is 1-3, preferably selected from the groups -S(O)R, -SO2R, -SO2H and -SO3H.

[0229] The terms "amine sulfoxide," "sulfonamide," and "sulfonamide amine" are preferably selected from groups -N(R)-S(O). u -R, where u is 1 or 2, or -S(O) v -N(R)-R, where v is 1 or 2, preferably selected from the groups -NHSO2CH3, -SO2NHCH3, and -NHSO2N(CH3)2.

[0230] For the above definitions, preferably, the terms R and R' are independently selected from the following groups: H, alkyl, alkyl halogen, alkoxy, amine, or any of the groups described in the above embodiments, wherein X is a halogen. The terms R and R' also include the possibility of any given group attached to R.

[0231] The term "nitro" refers to the NO2 group.

[0232] Optionally substituted groups, such as “optionally substituted”, refer to groups that have 1 to 5 substituents when substituted, typically 1, 2 or 3 substituents, such as alkyl groups.

[0233] The term "4, 5, or 6-membered heterocyclic alkyl" refers to a configuration comprising a 4, 5, or 6-membered heterocyclic structure, preferably one or more of C and N, O, and / or S. The term "5 to 8-membered cycloalkyl or aryl ring structure" refers to a configuration comprising a 5, 6, 7, or 8-membered cyclic optionally aromatic ring structure, optionally comprising one or more heteroatoms, such as one or more of N, O, and / or S.

[0234] The term "fused bicyclic group" refers to a configuration comprising two optional aromatic ring structures of 4 to 8 members, optionally including one or more heteroatoms, such as N, O and / or S, wherein the two ring structures are connected to each other by two of their adjacent atoms.

[0235] When referring to "C1 to C7, C1 to C5, C1 to C3" alkyl, cycloalkyl, alkoxy, aryl, etc., the number of carbon atoms of C1 to C7 preferably refers to each of the substituents mentioned, although in some embodiments, the shorter substituents of C1 to C5 or C1 to C3 are applicable to alkyl, cycloalkyl and / or alkoxy groups, whereby the aryl group can preferably remain C3 to C6, such as C6 phenyl.

[0236] Protected derivatives of the disclosed compounds, for example, used in the synthesis of the disclosed compounds, are also considered. Various suitable protecting groups for use with the disclosed compounds are disclosed in Greene and Wuts Protective Groups in Organic Synthesis; 3rd Ed.; John Wiley & Sons, New York, 1999. Generally, the protecting groups are removed under conditions that will not affect the remaining portion of the molecule. These methods are well known in the art and include acid hydrolysis, hydrogenolysis, etc.

[0237] Specific examples of the compounds disclosed herein include one or more asymmetric centers; therefore, these compounds can exist in different stereoisomeric forms. Consequently, the compounds and compositions can be provided as individual pure enantiomers or as mixtures of stereoisomers (including racemic mixtures).

[0238] The compounds of the present invention can also exist in various polymorphic forms, such as amorphous and crystalline polymorphic forms. All polymorphic forms of the compounds of the present invention are within the scope of the present invention and are further aspects of the present invention.

[0239] The compounds of the present invention may also include deuterium replacing hydrogen. In some cases, such substitution can lead to improved metabolic stability (Nature Reviews Drug Discovery 15, 219-221 (2016)).

[0240] It should be understood that the substituents and substitution modes of the compounds described herein can be selected by those skilled in the art to provide chemically stable compounds that can be readily synthesized using techniques known in the art and further by the methods set forth in this disclosure.

[0241] Composition and treatment method: This invention further relates to pharmaceutically acceptable salts of the compounds described herein. The term "pharmaceutically acceptable salt" refers to a salt or ester of the compounds described herein prepared by conventional methods, including basic salts of inorganic and organic acids. "Pharmaceutically acceptable salt" also includes free acid, base, and zwitterionic forms. A description of suitable pharmaceutically acceptable salts can be found in the Handbook of Pharmaceutical Salts, Properties, Selection and Use, Wiley VCH (2002). For therapeutic uses, the salt of the compound is a salt in which the anti-charge ion is pharmaceutically acceptable. However, salts of non-pharmaceutically acceptable acids and bases may also be used, for example, in the preparation or purification of pharmaceutically acceptable compounds.

[0242] Another aspect of this disclosure includes the preparation of pharmaceutical compositions for administration to a subject, and these pharmaceutical compositions include therapeutically effective amounts of one or more of the compounds disclosed herein. In some embodiments, the pharmaceutical compositions are used to treat medical conditions such as myopathy, cancer, diabetes, and cardiovascular disease associated with defective and / or pathological signaling of the β-isomer of phosphoinositol 3-kinase (PI3K), preferably the β-isomer of phosphoinositol 3-kinase (PIK3-C2b).

[0243] The therapeutically effective amount of the disclosed compound will depend on the route of administration, the type of subject, and the physical characteristics of the subject to be treated. Specific factors that may be considered include disease severity and stage, weight, diet, and concomitant medications. Those skilled in the art understand the relationship between these factors in determining the therapeutically effective amount of the disclosed compound.

[0244] In addition to the selected molecules, pharmaceutical compositions for administration to a subject may include at least one additional pharmaceutically acceptable additive, such as a carrier, thickener, diluent, buffer, preservative, surfactant, etc. Pharmaceutical compositions may also include one or more additional active ingredients, such as antimicrobial agents, anti-inflammatory agents, anesthetics, etc. Pharmaceutically acceptable carriers used in these formulations are conventional. Remington's Pharmaceutical Sciences, by EW Martin, Mack Publishing Co., Easton, PA, 19th Edition (1995), describes compositions and formulations suitable for the drug delivery of the compounds disclosed herein.

[0245] Generally, the nature of the carrier will depend on the specific route of administration employed. For example, parenteral preparations typically contain injectable fluids, including pharmaceutically and physiologically acceptable fluids such as water, physiological saline, balanced salt solutions, aqueous dextran, glycerol, etc., as the carrier. For solid compositions (e.g., powders, pills, tablets, or capsules), conventional non-toxic solid carriers may include, for example, pharmaceutical-grade mannitol, lactose, starch, or magnesium stearate. In addition to biologically neutral carriers, the pharmaceutical composition to be administered may contain small amounts of non-toxic excipients, such as wetting agents or emulsifiers, preservatives, and pH buffers, such as sodium acetate or sorbitol monolaurate.

[0246] The pharmaceutical composition can be administered to the subject via various mucosal routes of administration, including oral, rectal, intraocular, intranasal, intrapulmonary, or percutaneous delivery, or topical delivery to other surfaces. Optionally, the composition can be administered via non-mucosal routes, including intramuscular, intraocular, subcutaneous, intravenous, intra-articular, intra-articular, intraperitoneal, intrathecal, intraventricular, or parenteral routes.

[0247] The compositions disclosed herein may alternatively include pharmaceutically acceptable carrier substances to approximate physiological conditions, such as pH adjusters and buffers, tonicants, wetting agents, etc., for example, sodium acetate, sodium lactate, sodium chloride, potassium chloride, calcium chloride, sorbitol monolaurate, and triethanolamine oleate. For solid compositions, conventional, non-toxic, pharmaceutically acceptable supports may be used, including, for example, pharmaceutical-grade mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose, glucose, sucrose, magnesium carbonate, etc.

[0248] In a preferred embodiment, the present invention includes topical and / or local administration to a subject of compounds described herein and / or compositions comprising compounds described herein. The term "topical administration" refers to the delivery of a pharmacologically active agent to the skin or mucous membranes of a patient. Topical administration may provide local rather than systemic effects. The terms "topical administration" and "transdermal administration" are used interchangeably, referring to the administration of a pharmacologically active agent to the skin or mucous membranes of a patient to achieve a therapeutic effect in treating or preventing a medical condition of the present invention or discomfort at the site of topical or transdermal administration. Preferred administration modalities involve topical solutions, lotions, shake lotions, creams, ointments, gels, foams, transdermal patches, powders, solid forms, sponges, tapes, pastes, or tinctures. Preferred embodiments involve creams, foams, gels, lotions, and ointments.

[0249] Various additives known to those skilled in the art may be included in the topical compositions of this disclosure. For example, solvents, including relatively small amounts of alcohol, may be used to dissolve the compounds of the invention. Other optional additives include antioxidants, fragrances, colorants, gelling agents, emulsifiers, thickeners, stabilizers, surfactants, buffers, coolants (e.g., menthol), etc. Other agents, such as antimicrobial agents, may also be added to prevent spoilage during storage, i.e., to inhibit the growth of microorganisms such as yeasts and molds. Examples of suitable antimicrobial agents include methyl and propylparabens of para-hydroxybenzoic acid (i.e., methylparaben and propylparaben), sodium benzoate, sorbic acid, imidazole urea, etc. When applied to the skin, the topical compositions of this disclosure may be covered with an occlusive or non-occlusive dressing, which may be porous or non-porous, to protect the composition from mechanical removal during the treatment period, such as plastic film food packaging or other non-absorbent films. Various inert coverings may be employed. Nonwoven or woven coverings, particularly elastomeric coverings, may be employed, which allow heat and vapor transport. These covers allow cooling of the affected area, which can provide greater comfort, while protecting the composition from mechanical removal.

[0250] According to the various treatment methods disclosed herein, the compound can be delivered to a subject in a manner consistent with the routine methods associated with the management of a disease for which treatment or prevention is sought. As disclosed herein, preventive or therapeutically effective amounts of the compound and / or other bioactive agents are administered to subjects in need of such treatment at times and under conditions sufficient to prevent, inhibit, and / or improve the selected disease or condition or one or more symptoms thereof.

[0251] The terms "administration of" and "administering" should be understood to mean providing the compound described herein, a prodrug of the compound, or a pharmaceutical composition thereof. The compound or composition may be administered to the subject by another person (e.g., via intravenous, gel, cream, spray), or may be self-administered by the subject (e.g., tablet, gel, cream, spray).

[0252] The dosage can be adjusted by the attending clinician to maintain the desired concentration at the target site (e.g., the lungs or systemic circulation). Higher or lower concentrations can be selected based on the delivery modality, such as transdermal, rectal, oral, pulmonary, or nasal delivery compared to intravenous or subcutaneous delivery. The dosage can also be adjusted based on the release rate of the administered formulation, such as intrapulmonary inhalers versus powders, sustained-release oral formulations versus injectable granules, or transdermal delivery formulations.

[0253] The term "subject" includes both human and veterinary subjects. The term "treatment" refers to a therapeutic intervention that improves the signs or symptoms of a disease or pathological condition after it has begun to develop.

[0254] As used herein, the term “improvement” in relation to a disease or pathological condition refers to any given beneficial effect of treatment. For example, a beneficial effect can be demonstrated by a delayed onset of clinical symptoms of the disease in a subject, a reduction in the severity of some or all of the clinical symptoms of the disease, a slowing of disease progression, an improvement in the overall health or well-being of the subject, or by other parameters well known in the art to be specific to a particular disease.

[0255] This invention encompasses both therapeutic and preventative treatment of subjects. "Preventative" treatment is the administration of a compound to a subject who does not exhibit signs of a medical condition or preferably shows indications for the development or further development of any given medical condition, with the aim of reducing the risk of developing pathological or clinical symptoms. Preventative administration may include administering the compound before the development of symptoms, thereby avoiding or reducing the subsequent occurrence of the disease. This invention also relates to methods of treating subjects suffering from the various medical conditions disclosed herein. Treatment methods preferably involve administering a therapeutically effective amount of the compounds disclosed herein to the subject in need.

[0256] "Therapeutic effective amount" means an amount of the agent sufficient to achieve the desired effect in a subject treated with the specific agent. For example, this could be an amount of the disclosed compound used to relieve symptoms of one or more medical conditions described herein in a subject. The therapeutically effective or diagnostically effective amount of the agent will depend on the subject being treated, the severity of the condition, and the route of administration of the therapeutic composition. Dosing regimens can be adjusted to provide an optimal preventative or therapeutic response. Therapeutic effective amount is also the amount in which any toxic or adverse side effects of the compound and / or other bioactive agents are clinically offset by the beneficial therapeutic effect. In the methods and formulations of this disclosure, the non-limiting range for the therapeutically effective amount of the compound and / or other bioactive agents is from about 0.001 mg / kg body weight to 50 mg / kg body weight, from 0.01 mg / kg body weight to about 20 mg / kg body weight, such as from about 0.05 mg / kg to about 5 mg / kg body weight, or from about 0.2 mg / kg to about 2 mg / kg body weight.

[0257] This disclosure also includes kits, packaging materials, and multi-container units containing the pharmaceutical compositions described herein, active ingredients, and / or devices for administration thereto, for the prevention and treatment of diseases and other conditions in mammalian subjects. Attached Figure Description

[0258] The invention is further described with reference to the following accompanying drawings. These are not intended to limit the scope of the invention, but rather to illustrate preferred embodiments of aspects of the invention and to provide for a better explanation of the invention described herein.

[0259] Brief description of the attached figures Figure 1 : PI3-kinase domain organization.

[0260] Figure 2 Expression and purification of PI3KC2β Δ1-298, KKT mutant.

[0261] Figure 3 Purified PI3KC2β ΔN KKT kinase activity.

[0262] Figure 4 Cellular activity of example compounds 036, 40, 90 and 96.

[0263] Figure 5 Kinobeda pull-down assay of example compounds 47 and 91.

[0264] Detailed description of the attached figures Figure 1PI3-kinase domain organization. PI3-kinases are classified by the diversity of their primary sequences and domain architecture. Class I (PI3Kα, β, δ) and Class III (VPS34) kinases form heterodimers with their respective regulatory subunits, such as p85 or p55 for PI3Kα, β, δ; p101 or p87 for PI3K; and VPS15 for VPS34. All PI3-kinases contain a PI3K core region, including the C2, helical, and kinase domains. Class I PI3Kα, β, δ contains an ABD domain (adaptor-binding domain) for binding to the regulatory subunit. Class II PI3-kinases contain a unique N-terminal disordered region for protein-protein interactions, an HBD (helical bundle domain) for scaffold function, and two C-terminal lipid-binding domains (Phox and C-C2 domains) for binding to phosphatidylinositol.

[0265] Figure 2 Expression and purification of PI3KC2β Δ1-298, KKT mutant. His expression was performed using a baculovirus insect cell expression system. 10 PI3KC2β Δ1-298; KKT mutant (PI3KC2β) ΔN KKT). (A)PI3KC2β ΔN KKT size exclusion chromatography. Peak fractions are shown as indicated by the arrows. (B) Purified PI3KC2β ΔN SDS-PAGE validation of KKT. Estimation of PI3KC2β ΔN KKT has a purity of over 90%.

[0266] Figure 3 Purified PI3KC2β ΔN KKT kinase activity. (A) Using 100 µM ATP and 200 µM PI as substrates, via ADP-Glo TM Kinase assay to measure purified PI3KC2β ΔN KKT activity. Purified PI3KC2β was titrated. ΔN KKT was used in experiments using a triplicate method. In the established concentration series, purified PI3KC2β... ΔN The activity and concentration of KKT showed a linear correlation. (B) For PI3KC2β ΔN Km of KKT ATP, purified with 10 ng / µl of PI3KC2b ΔN KKT and titrated ATP were tested in triplicate. The curves were fitted using the Michaelis-Menten equation. The Km of ATP was 63.7 µM.

[0267] Figure 4 Cellular activity of example compounds 36, 40, 90, and 96. (A) Cellular regulatory protocol for PI3KC2β. PKN2 prevents PI3KC2β from being recruited to lysosomes. The catalytic activity of PI3KC2β downregulates the activity of mTOR for S6K phosphorylation. (B) Assay protocol specified for validating compound activity in cells. Notably, treatment with PKN1 / 2 inhibitors increases basal PI3KC2β activity, resulting in much lower basal p-S6K levels. (C) Cells treated with 1 µM of example compounds 36, 40, 90, and 96. Representative Western blot results of p-S6K and total S6K levels under compound treatment. The inhibition of PI3KC2β by example compounds 36, 40, 90, and 96 was determined by a significant increase in pS6K levels.

[0268] Figure 5 Example: Kinobeda pull-down assay of compounds 47 and 91. This assay was performed on HEK293 cell lysates at 10 different concentrations of the compounds, with the hit criterion being IC50. 50 <10 μM. For example compounds 47 and 91, no hits were observed other than the desired target PI3KC2B.

[0269] Example The invention is further described by way of the following examples. These are not intended to limit the scope of the invention, but rather to illustrate preferred embodiments of aspects of the invention and to provide for a better explanation of the invention described herein.

[0270] Example 1: Development and structural characterization of an inhibitor of PI3KC2β.

[0271] Functional genetic data suggest that PI3KC2β is a potential pharmacological target for the treatment of X-linked myotubular myopathy (XLMTM). To date, the structure of PI3KC2β remains undetermined. Furthermore, no potent and selective inhibitors targeting PI3KC2β have been described. Therefore, the object of this invention is to develop novel small molecule inhibitors to structurally reveal the pharmacological target site in PI3KC2β and for use in the treatment of XLMTM.

[0272] Example 2: PI3KC2β ΔN KKT expression and purification Overcoming limitations regarding the availability of pure recombinant PI3KC2β and the poor activity of PI3KC2β against PIs as substrates, the inventors, based on prior experience in purifying PI3KC2β, engineered human PI3KC2β with a truncated AA 1-297. 1248 DPK 1250 Mutation 1248 KKT1250 PI3KC2β ΔN KKT is labeled with 10x histidine at its N-terminus. PI3KC2β was detected in insect cells infected with baculovirus. ΔN KKT expression was observed. Cells were grown to a density of 1.5 million cells / ml and infected with a 1:50 (v / v) viral stock solution. PI3KC2β expression occurred within 48 hours post-infection. ΔN KKT expression. PI3KC2β ΔN KKT was purified using Ni-NTA beads, followed by size exclusion chromatography. The presence of PI3KC2β was confirmed by SDS-PAGE and Coomassie blue staining. ΔN Peak fractionation of KKT. Purified PI3KC2β ΔN KKT was concentrated to a protein concentration of 0.4 mg / ml. The sample was then rapidly frozen with liquid nitrogen and stored at -80°C.

[0273] Example 3: Purified PI3KC2β ΔN Development of KKT enzyme activity and assay via ADP-Glo TM Kinase assay to measure purified PI3KC2β ΔN KKT kinase activity. To determine the range of linear correlation between the signal and different amounts of the kinase, the concentration of PI3KC2β was first titrated. ΔN KKT and fixed concentrations of PI (200 µM) and ATP (100 µM) were used to measure kinase activity. Activity curves showed a wide range of linear correlations in the setup. To measure kinase activity for PI3KC2β... ΔN The Km of ATP from KKT was measured using a triplicate method, with the activity of the purified kinase at 10 ng / µl, along with 200 µM PI and titrated concentrations of ATP. The titration curves were fitted to the Michaelis-Menten equation to obtain the Km of PI3KC2β. ΔN The Km value of ATP from KKT is 63.7 µM. Therefore, PI3KC2β purified at 10 ng / µl... ΔN KKT, PI (200 µM), and ATP (40 µM) were used to establish IC50 values ​​for chemical compounds.

[0274] Example 4: Cellular activity of chemical compounds Four PI3KC2β inhibitors (DC-03-036, -040, -090, and -096) were selected for cell viability measurements. Since PI3KC2β kinase activity is a negative regulator of mTOR1-mediated S6K phosphorylation, PI3KC2β cell viability can be reported by pS6K levels. PKN2 is a known negative regulator of basal PI3KC2β activity. Therefore, a cell treatment protocol was established in which HEK cells were incubated with the compounds overnight at a concentration of 1 µM, followed by PKN1 / 2 inhibition for 2 hours. Treatment with DC-03-036, -040, -090, and -096 showed a significant increase in pS6K levels, indicating that DC-03-036, -040, -090, and -096 can inhibit PI3KC2β activity in cells.

[0275] Example 4: Kinase selectivity of chemical compounds Five PI3KC2β inhibitors (example compounds 2, 18, 19, 47, and 91) were selected and their kinase selectivity was measured in the extended panel. The results for each compound are shown in Tables 2 through 6.

[0276] SelectScreen kinase profile analysis at ThermoFisher Scientific followed the protocols described below (Tables 2-6): Kashem et al. J. Biomol. Screen. 2007, 12, 70-83 (Adapta); Lebakkenet al. J. Biomol. Screen. 2009, 14; 924-935 (lanthascreen); Kleman-Leyer et al. Drug Disc. Devel. 2003, 6, 81-82. (zlyte).

[0277] Kinopead spectral analysis was performed by adjusting the procedures described below: Reinecke et al. ACS Chem.Biol. 2019, 14, 655-664 and Klaeger et al., Science 2017, 358, eaan4368.

[0278] Kinobed pull-down assays were performed using 5 mg / mL HEK293 cell lysates in buffer 32 containing IGEPA CA-630. Briefly, for spectroscopic analysis of each compound, 12 wells of a 96-well plate were filled with lysates (2.5 mg total protein per well) and incubated at 4°C for 45 min in an end-over-end shaker with 0 nM (DMSO control), 30 nM, 100 nM, 300 nM, 1 μM, 3 μM, 10 μM, 30 μM, 100 μM, 300 μM, and 1 mM solutions of the compound dissolved in DMSO. Subsequently, the treated lysates were incubated with Kinobeds-ε at 4°C for 30 min in a 96-well filter plate on the end-over-end shaker. The beads were then washed, followed by denaturation of the bound proteins and alkylation with chloroacetamide. Trypsin (300 ng per well) was added to initiate overnight bead digestion. The acidified peptide eluent was then desalted using the C18 StageTip for LC-MS / MS analysis on an Orbitrap Fusion Lumos Tribrid (ThermoFisher Scientific) mass spectrometer coupled with an online Dionex Ultimate 3000 (ThermoFisher Scientific) equipped with a microflow Vanquish pump UHPLC. MaxQuant (v.1.5.3.30.) / Andromeda was used to quantify proteins using the Swissprot reference database, which contains all typical protein sequences with standard settings. A set of R scripts was used to export dose-response curves, Kdapps, and kinase tree from the proteinGroup.txt file.

[0279] Abbreviations: Km: Michaelis constant; Km app: Apparent Km value.

[0280] Table 2—Kinetic Selectivity—Kinetic Inhibition %, tested at an exemplary compound 2 at a concentration of 1 μM.

[0281]

[0282] Table 3—Kinetic Selectivity—Kinetic Inhibition %, tested at a concentration of exemplary compound 18 at 10 μM.

[0283]

[0284] Table 4—Kinetic Selectivity—Kinetic Inhibition %, tested at a concentration of 10 μM for Exemplary Compound 19.

[0285]

[0286] Table 5—Kinetic Selectivity—Kinetic Inhibition %, tested at a concentration of 10 μM for Exemplary Compound 47.

[0287]

[0288] Table 6—Kinetic Selectivity—Kinetic Inhibition %, tested at an exemplary compound 91 at a concentration of 10 μM.

[0289]

[0290] Evaluations of kinase selectivity (Tables 2 to 6) and inhibitory concentration (IC50) (Table 1) show that the compounds of the present invention exhibit selectivity for PIK3C2 kinase and significantly lower IC50 for inhibition of PI3K-C2b (PI3KC2β) compared to PI3Kγ. 50 (See Table 1, for example, compound 2: PI3KC2β IC50 [nM] = 18 and PI3Kγ IC50 [nM] = 1024; compound 18: PI3KC2β IC50 [nM] = 42 and PI3Kγ IC50 [nM] => 5000; compound 19: PI3KC2β IC50 [nM] = 22 and PI3Kγ IC50 [nM] = 3570; compound 47: PI3KC2β IC50 [nM] = 56 and PI3Kγ IC50 [nM] => 10000; and compound 91: PI3KC2β IC50 [nM] = 48 and PI3Kγ IC50 [nM] => 10000) Therefore, the compounds of the present invention are particularly effective in inhibiting PIK3C2 kinase, especially PI3K-C2b.

[0291] Compounds were further screened using a kinobead pull-down assay at ten different concentrations on HEK293 cell lysates. The hit criterion was IC50 < 10 μM. Results are shown in... Figure 5 In, for example, compounds 47 and 91 were found to be untargeted, except for the desired target PI3KC2b. This further confirms that the compounds of the present invention are particularly effective in inhibiting PIK3C2 kinase, especially PI3K-C2b.

[0292] Methods for protein expression and ADP-Glo ​​kinase assay: Protein purification Using SF900-II serum-free medium (ThermoFisher) Sf 21. His expression in insect cells 10 -Tagged PI3KC2β ΔN KKT. Infected with 16 ml of baculovirus encoding the desired construct, grown to 1.5–2 x 10⁻⁶ cells / mL. 6 density of cells / ml Sf 21 cells (800 ml). Cells were harvested 48 h post-infection. The cell pellet was frozen and stored at -20°C until purification. For purification, the cell pellet from each 200 ml culture was resuspended in 30 ml lysis buffer (50 mM Tris pH 7.2, 300 mM NaCl, 10 mM imidazole, 1 mM DTT, 0.5% Triton X-100, 1 tablet / 50 ml protease inhibitor mixture), sonicated for 1 min (pulse on 1 s, pulse off 5 s), and centrifuged at 27 krpm for 20 min. 50 ml of the supernatant was incubated on a rotary disc with 0.25 ml of nickel NTA beads (Sigma Inc.) for 1 h. The beads were collected in an open column, washed with 10 ml lysis buffer, and then washed three times with 10 ml wash buffer (50 mM Tris pH 7.5, 300 mM NaCl, 20 mM imidazole, 1 mM DTT). Protein was eluted with 8 ml of elution buffer (20 mM Tris pH 7.5, 300 mM NaCl, 300 mM imidazole, 5 mM DTT). PI3KC2β ΔN KKT was immediately purified further using a Superdex 200 gel filter column at 4°C with SEC buffer (20 mM Tris pH 7.5, 300 mM NaCl, 5 mM DTT). PI3KC2β ΔN KKT was concentrated to 0.4 mg / ml. The sample was rapidly frozen in liquid nitrogen and stored at -80°C.

[0293] ADP-Glo ​​kinase assay Natural hepatic phosphatidylinositol (PI) was dissolved to a concentration of 400 μM in kinase buffer [5 mM HEPES / KOH, pH 7.2, 25 mM KCl, 2.5 mM Mg(OAc)2, 150 mM K glutamate, 10 mM CaCl2, 0.2% CHAPS] by water bath sonication, followed by the addition of 200 μM ATP. For kinase titration, a titration amount of purified PI3KC2β was added. ΔNKKT was used to initiate the kinase reaction. To measure the Km of ATP, titratable ATP was prepared in a PI solution. The reaction was initiated by mixing 5 μl of protein stock solution with 5 μl of substrate solution and incubating at room temperature for 20 min. The reaction was stopped by adding 10 μl of ADP-Glo ​​reagent (Promega). After incubation for 40 min, 20 μl of kinase assay reagent was added. After incubation for 20 min, the luminescence was read using a TECAN plate reader. A series of compounds at different concentrations were used, along with 10 ng / μl PI3KC2β. ΔN IC50 analysis of chemical compounds was performed using KKT, 200 μM PI, and 40 μM ATP. 50 Measurement.

[0294] Cell processing and Western blotting 400,000 HEK cells per well were seeded into polylysine-coated 6-well plates. Ten hours post-seeding, DSMO or a chemical compound was applied to the cells at a final concentration of 0.1% DMSO or 1 μM each. After overnight treatment, cells were treated with a PKN1 / 2 inhibitor mixture for 2 hours. To collect cell lysates, cells were washed three times in ice-cold PBS and collected in TBS containing 1% CHAPS, 1 tablet / 10 ml protease inhibitor mixture mini (Roch), and phosphatase inhibitors (mixtures 2 and 3, Sigma-Aldrich). Protein levels were quantified using Bradford reagent (Sigma-Aldrich). Iso-concentrated lysates in Laemmli sample buffer were boiled for 5 min; proteins between 10 and 30 μg were separated by SDS-PAGE and analyzed via immunoblotting using LI-COR 800CW infrared secondary antibody.

[0295] Synthetic and analytical chemistry: abbreviation AcOH = acetic acid, CH3Li = methyllithium, Cs2CO3 = cesium carbonate, CuBr2 = copper(II) bromide, DMF = N , N -Dimethylformamide, ESI = electrospray ionization, EtOAc = ethyl acetate, h = hours, H2O = water, HCl = hydrogen chloride, HPLC = high performance liquid chromatography, KOH = potassium hydroxide, min = minutes, mL = milliliters, MS = mass spectrometry, NaH = sodium hydride, NaHCO3 = sodium bicarbonate, NaOH = sodium hydroxide, Na2CO3 = sodium carbonate, Na2SO4 = sodium sulfate, Na2S2O3 = sodium thiosulfate, NMR = Nuclear magnetic resonance Pd(OAc)2 = palladium(II) acetate, TFA = trifluoroacetic acid, THF = tetrahydrofuran.

[0296] Example Compound 1: N - (4-methyl-5- (1- (phenylsulfonyl) -1 H - indol-5-yl) thiazol-2-yl) acetamide Step 1: 5-Bromo-1-(phenylsulfonyl)-1 H -Indole

[0297] 5-bromo-1 H -Indole (207 mg, 1.06 mmol) was dissolved in 2 mL of toluene. Then, a solution of benzenesulfonyl chloride (1.1 equivalent, 205 mg, 1.16 mmol) in 1 mL of toluene was added to the mixture, followed by tetrabutylammonium hydrogen sulfate (0.07 equivalent, 18 mg, 74 µmol) and 3 mL of 6 M KOH aqueous solution. The reaction mixture was stirred at room temperature for 45 minutes, and after the reaction was complete, the crude mixture was transferred to a separatory funnel containing EtOAc and a diluted aqueous solution of HCl at pH 1. The aqueous phase was extracted three times with EtOAc. The combined organic phases were then dried over Na₂SO₄ and concentrated under reduced pressure. The crude product was then finally purified by silica gel chromatography using a gradient of cyclohexane and EtOAc as eluents. The product was obtained as a white solid.

[0298] Yield: 180 mg (51%).

[0299] MS(ES+) [M+H) + m / e = 333.7, 335.7 (bromine isotope mode).

[0300] 1 H NMR (300 MHz, CDCl3): δ 7.90 – 7.82 (m, 3H), 7.66 (d, J = 2.0 Hz,1H), 7.59 – 7.53 (m, 2H), 7.48 – 7.38 (m, 3H), 6.61 (dd, J = 3.7, 0.8 Hz, 1H).

[0301] 13 C NMR (75 MHz, CDCl3): δ 137.93, 134.06, 133.53, 132.45, 129.37, 127.55, 127.50, 126.71, 124.08, 116.87, 114.92, 108.49.

[0302] Step 2: N-(4-Methyl-5-(1-(phenylsulfonyl)-1 H -indol-5-yl)thiazo-2-yl)acetamide

[0303] 5-bromo-1-(phenylsulfonyl)-1 H -Indole (180 mg, 535 µmol), N 1,4-(4-methylthiazolyl-2-yl)acetamide (1.2 equivalents, 100 mg, 642 µmol), tri-tert-butylphosphonium tetrafluoroborate (0.2 equivalents, 31 mg, 107 µmol), Pd(OAc)₂ (0.1 equivalents, 12 mg, 53 µmol), and Cs₂CO₃ (3 equivalents, 523 mg, 1.61 mmol) were suspended in 2 mL of DMF. The suspension was sonicated for 5 min, washed with nitrogen, heated to 110 °C, and stirred overnight. The solvent was then removed under reduced pressure, and the crude product was purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1% TFA). The product was lyophilized to obtain an amorphous white solid.

[0304] Yield: 101 mg (46%).

[0305] MS (ES+) [M+H) + m / e = 411.7.

[0306] 1 H NMR (600 MHz, DMSO-d6): δ 12.07 (s, 1H), 8.03 – 7.97 (m, 3H), 7.85(d, J = 3.7 Hz, 1H), 7.72 – 7.66 (m, 2H), 7.63 – 7.58 (m, 2H), 7.42 (dd, J = 8.6, 1.8 Hz, 1H), 6.88 (d, J = 3.5 Hz, 1H), 2.31 (s, 3H), 2.13 (s, 3H).

[0307] 13C NMR (151 MHz, DMSO-d6): δ 168.39, 155.13, 141.69, 137.12, 134.79,133.11, 131.03, 129.96, 127.82, 127.58, 126.75, 125.56, 123.86, 121.59,113.49, 109.67, 22.47, 15.95.

[0308] Example Compound 2: N - (4-methyl-5-(l-(phenylsulfonyl)-l,2,3,4-tetrahydroquinolin-6-yl)thiazol-2- Acetamide Step 1: 6-Bromo-1-(phenylsulfonyl)-1,2,3,4-tetrahydroquinoline

[0309] 6-Bromo-1,2,3,4-Tetrahydroquinoline (234 mg, 1.10 mmol) was dissolved in 3 mL of pyridine. Then, benzenesulfonyl chloride (1.1 equivalent, 214 mg, 1.21 mmol, 0.155 mL) was added to the mixture. The reaction mixture was stirred at room temperature for three hours. The solvent was then removed under reduced pressure, and the crude product was finally purified by silica gel chromatography using a gradient of cyclohexane and EtOAc as eluents. The product was obtained as a white solid.

[0310] Yield: 320 mg (82%).

[0311] MS (ES+) [M+H) + m / e = 351.6, 353.8 (bromine isotope mode).

[0312] 1 H NMR (300 MHz, CDCl3): δ 7.70 (d, J = 8.8 Hz, 1H), 7.63 – 7.51 (m,3H), 7.47 – 7.39 (m, 2H), 7.33 – 7.28 (m, 1H), 7.15 (dt, J = 2.2, 1.0 Hz, 1H),3.83 – 3.71 (m, 2H), 2.40 (t, J = 6.7 Hz, 2H), 1.63 – 1.56 (m, 2H).

[0313] 13C NMR (75 MHz, CDCl3): δ 139.27, 135.88, 132.93, 132.68, 131.76, 129.59, 129.09, 127.02, 126.60, 118.29, 46.40, 26.40, 21.11.

[0314] Step 2: N -(4-Methyl-5-(1-(phenylsulfonyl)-1,2,3,4-tetrahydroquinolin-6-yl)thiazo-2-yl)acetamide

[0315] 6-Bromo-1-(phenylsulfonyl)-1,2,3,4-tetrahydroquinoline (160 mg, 454 µmol), N 1,2-(4-methylthiazolyl-2-yl)acetamide (1.2 equivalents, 85 mg, 545 µmol), tri-tert-butylphosphonium tetrafluoroborate (0.2 equivalents, 26 mg, 91 µmol), Pd(OAc)₂ (0.1 equivalents, 10 mg, 45 µmol), and Cs₂CO₃ (3 equivalents, 443 mg, 1.36 mmol) were suspended in 2 mL of DMF. The suspension was sonicated for 5 min, washed with nitrogen, heated to 110 °C, and stirred overnight. The solvent was then removed under reduced pressure, and the crude product was purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1% TFA). The product was lyophilized to obtain an amorphous white solid.

[0316] Yield: 139 mg (71%).

[0317] MS (ES+) [M+H) + m / e = 427.7.

[0318] 1 H NMR (300 MHz, DMSO-d6): δ 12.09 (s, 1H), 7.66 (ddd, J = 8.1, 2.9, 1.8Hz, 4H), 7.61 – 7.51 (m, 2H), 7.28 (dd, J = 8.6, 2.3 Hz, 1H), 7.15 (d, J = 2.2Hz, 1H), 3.87 – 3.69 (m, 2H), 2.33 (s, 3H), 2.13 (s, 3H), 1.65 – 1.52 (m, 2H).

[0319] 13 C NMR (75 MHz, DMSO-d6): δ 168.35, 154.99, 141.89, 138.91, 135.34,133.48, 130.81, 129.58, 129.20, 128.46, 126.80, 126.34, 123.81, 123.20,46.31, 26.05, 22.47, 20.94, 16.15.

[0320] Example Compound 3: N - (4-methyl-5-(1 -(phenylsulfonyl)indolin-5-yl)thiazol-2-yl)acetamide Step 1: 5-Bromo-1-(phenylsulfonyl)indoline

[0321] 5-Bromoindoline (234 mg, 1.18 mmol) was dissolved in 2 mL of pyridine. Then, benzenesulfonyl chloride (1.1 equivalent, 230 mg, 1.30 mmol, 0.166 mL) was added to the mixture. The reaction mixture was stirred at room temperature for three hours. The solvent was then removed under reduced pressure, and the crude product was purified by silica gel chromatography using a gradient of cyclohexane and EtOAc as eluents. The product was obtained as a yellow oil.

[0322] Yield: 388 mg (97%).

[0323] MS (ES+) [M+H) + m / e = 337.7, 339.7 (bromine isotope mode).

[0324] 1 H NMR (300 MHz, CDCl3): δ 7.81 – 7.74 (m, 2H), 7.62 – 7.42 (m, 4H), 7.31 (dd, J = 8.5, 2.1 Hz, 1H), 7.19 (t, J = 1.1 Hz, 1H), 3.92 (t, J = 8.5 Hz, 2H), 2.87 (t, J = 8.4 Hz, 2H).

[0325] 13 C NMR (75 MHz, CDCl3): δ 141.31, 136.79, 134.20, 133.55, 130.83, 129.32, 128.38, 127.38, 116.64.

[0326] Step 2: N -(4-Methyl-5-(1-(phenylsulfonyl)indololin-5-yl)thiazo-2-yl)acetamide

[0327] 5-bromo-1-(phenylsulfonyl)indoline (130 mg, 384 µmol), N 1,2-(4-methylthiazolyl-2-yl)acetamide (1.2 equivalents, 72 mg, 461 µmol), tri-tert-butylphosphonium tetrafluoroborate (0.2 equivalents, 11.1 mg, 38 µmol), Pd(OAc)₂ (0.1 equivalents, 4.3 mg, 19 µmol), and Cs₂CO₃ (3 equivalents, 375 mg, 1.15 mmol) were suspended in 2 mL of DMF. The suspension was sonicated for 5 min, washed with nitrogen, heated to 120 °C, and stirred overnight. The solvent was then removed under reduced pressure, and the crude product was purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1% TFA). The product was lyophilized to obtain an amorphous white solid.

[0328] Yield: 132 mg (83%).

[0329] MS (ES+) [M+H) + m / e = 413.7.

[0330] 1 H NMR (300 MHz, DMSO-d6): δ 12.07 (s, 1H), 7.89 – 7.82 (m, 2H), 7.74 – 7.66 (m, 1H), 7.64 – 7.56 (m, 2H), 7.52 (d, J = 8.3 Hz, 1H), 7.30 – 7.22 (m,2H), 3.94 (t, J = 8.4 Hz, 2H), 2.96 (t, J = 8.4 Hz, 2H), 2.29 (s, 3H), 2.12 (s, 3H).

[0331] 13C NMR (75 MHz, DMSO-d6): δ 168.29, 154.76, 141.53, 140.36, 136.02,133.91, 133.00, 129.60, 127.96, 127.58, 127.18, 125.58, 123.51, 114.15,50.17, 27.16, 22.45, 16.04.

[0332] Example compound 4: N -(4-Methyl-5-(4-(phenylsulfonyl)-3,4-dihydro-2 H -benzo[ b [1,4]oxazin-7-yl)thiazo-2-yl)acetamide

[0333] 7-bromo-3,4-dihydro-2 H -benzo[ b [1,4]Oxazine (150 mg, 701 µmol) was dissolved in 2 mL of pyridine. Then, benzenesulfonyl chloride (1.1 equivalent, 136 mg, 771 µmol) was added to the mixture. The reaction mixture was stirred at room temperature for three hours. After the reaction was complete, the crude product was poured into a separatory funnel containing DCM and a 1 M aqueous solution of NaOH. The aqueous phase was extracted three times with DCM. Then, the combined organic phases were dried over Na₂SO₄ and concentrated under reduced pressure. The crude mixture, N 1,2-(4-methylthiazolyl-2-yl)acetamide (1.2 equivalents, 131 mg, 841 µmol), tri-tert-butylphosphonium tetrafluoroborate (0.2 equivalents, 41 mg, 140 µmol), Pd(OAc)₂ (0.1 equivalents, 16 mg, 70 µmol), and Cs₂CO₃ (3 equivalents, 684 mg, 2.10 mmol) were suspended in 2 mL of DMF. The suspension was sonicated for 5 min, washed with nitrogen, heated to 120 °C, and stirred overnight. The solvent was then removed under reduced pressure, and the crude product was purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1% TFA). The product was lyophilized to obtain an amorphous white solid.

[0334] Yield: 82 mg (27%).

[0335] MS (ES+) [M+H) + m / e = 429.7.

[0336] 1H NMR (300 MHz, DMSO-d6): δ 12.11 (s, 1H), 7.78 – 7.67 (m, 4H), 7.65– 7.56 (m, 2H), 7.04 (dd, J = 8.6, 2.2 Hz, 1H), 6.88 (d, J = 2.1 Hz, 1H), 3.92(dd, J = 5.3, 3.8 Hz, 2H), 3.74 (dd, J = 5.2, 3.7 Hz, 2H), 2.32 (s, 3H), 2.13 (s, 3H).

[0337] 13 C NMR (75 MHz, DMSO-d6): δ 168.37, 155.12, 146.40, 142.24, 137.73,134.00, 130.01, 129.84, 127.08, 124.16, 122.76, 122.57, 120.94, 116.81,62.77, 43.93, 22.45, 16.18.

[0338] Example Compound 5: N - (5-(l-(phenylsulfonyl)-2,3,4,5-tetrahydro-lH-benzo[ ]azepin-7- (2-yl)thiazolyl)acetamide Step 1: 7-Bromo-1-(phenylsulfonyl)-2,3,4,5-tetrahydro-1 H -benzo[ b [Azacyclohepta ...

[0339] 2,3,4,5-tetrahydro-1 H -benzo[ bAzacycloheptanine (255 mg, 1.73 mmol) was dissolved in 3 mL of acetonitrile. Then, 1-bromopyrrolidine-2,5-dione (1.0 equivalent, 308 mg, 1.73 mmol) was added to the mixture, and the reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete, the crude reaction mixture was poured into a separatory funnel containing DCM and an aqueous solution of 1 M Na₂S₂O₃. The aqueous phase was extracted three times with DCM. The combined organic phases were then dried over Na₂SO₄ and concentrated under reduced pressure. The crude product was then dissolved in 3 mL of pyridine. Subsequently, benzenesulfonyl chloride (1.1 equivalent, 336 mg, 1.90 mmol, 0.243 mL) was added to the mixture. The reaction mixture was stirred at room temperature for three hours. The solvent was then removed under reduced pressure, and the crude product was purified by silica gel chromatography using a gradient of cyclohexane and EtOAc as eluents. The product was obtained as a yellow oil.

[0340] Yield: 370 mg (58%).

[0341] MS (ES+) [M+H) + m / e = 365.7, 367.7 (bromine isotope mode).

[0342] 1 H NMR (300 MHz, DMSO-d6): δ 12.13 (s, 1H), 7.80 – 7.66 (m, 3H), 7.65– 7.55 (m, 2H), 7.33 – 7.23 (m, 2H), 7.21 – 7.14 (m, 1H), 3.63 (s, 2H), 2.44– 2.36 (m, 2H), 2.35 (s, 3H), 2.13 (s, 3H), 1.80 – 1.65 (m, 2H), 1.51 (s, 2H).

[0343] 13 C NMR (75 MHz, DMSO-d6): δ 168.44, 155.32, 142.39, 142.15, 141.22,138.67, 133.09, 131.84, 129.98, 129.61, 129.13, 126.78, 126.75, 123.06,50.53, 33.36, 29.30, 25.23, 22.48, 16.24.

[0344] Step 2: N -(5-(1-(phenylsulfonyl)-2,3,4,5-tetrahydro-1H -benzo[ b [Aza-hepta-7-yl)thiazolyl)acetamide]

[0345] 7-Bromo-1-(phenylsulfonyl)-2,3,4,5-tetrahydro-1 H -benzo[ b Azacycloheptamethrin (120 mg, 328 µmol), N 1,2-(4-methylthiazolyl-2-yl)acetamide (1.2 equivalents, 61 mg, 393 µmol), tri-tert-butylphosphonium tetrafluoroborate (0.2 equivalents, 19 mg, 66 µmol), Pd(OAc)₂ (0.1 equivalents, 7.4 mg, 33 µmol), and Cs₂CO₃ (3 equivalents, 320 mg, 983 µmol) were suspended in 2 mL of DMF. The suspension was sonicated for 5 min, rinsed with nitrogen, heated to 120 °C, and stirred overnight. The solvent was then removed under reduced pressure, and the crude product was purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1% TFA). The product was lyophilized to obtain an amorphous white solid.

[0346] Yield: 66 mg (47%).

[0347] MS (ES+) [M+H) + m / e = 441.7.

[0348] 1 H NMR (300 MHz, DMSO-d6) δ 12.13 (s, 1H), 7.80 – 7.66 (m, 3H), 7.65 –7.55 (m, 2H), 7.33 – 7.23 (m, 2H), 7.21 – 7.14 (m, 1H), 3.63 (s, 2H), 2.44 –2.36 (m, 2H), 2.35 (s, 3H), 2.13 (s, 3H), 1.80 – 1.65 (m, 2H), 1.51 (s, 2H).

[0349] 13C NMR (75 MHz, DMSO-d6) δ 168.44, 155.32, 142.39, 142.15, 141.22,138.67, 133.09, 131.84, 129.98, 129.61, 129.13, 126.78, 126.75, 123.06,50.53, 33.36, 29.30, 25.23, 22.48, 16.24.

[0350] Example Compound 6: N - (4-methyl-5-(5-(phenylsulfonyl)-5, 6,7, 8-tetrahydronaphthalen-2-yl)thiazol-2- Acetamide Step 1: 6-Bromo-1-(phenylsulfonyl)-1,2,3,4-tetrahydronaphthalene

[0351] 6-Bromo-1,2,3,4-Tetrahydronaphthalene-1-ol (90 mg, 396 µmol) was dissolved in 2 mL of DCM. TMSCl (1.2 equivalents, 52 mg, 476 µmol), sodium benzenesulfinate (1.5 equivalents, 98 mg, 594 µmol), and FeCl3 (0.15 equivalents, 9.6 mg, 59 µmol) were added to this solution, followed by the addition of TMSCl (1.2 equivalents, 52 mg, 476 µmol), sodium benzenesulfinate (1.5 equivalents, 98 mg, 594 µmol), and FeCl3 (0.15 equivalents, 9.6 mg, 59 µmol). The reaction mixture was refluxed overnight. The solvent was then removed under reduced pressure, and the crude product was purified by silica gel chromatography using a gradient of cyclohexane and EtOAc as eluents. The product was obtained as a yellow oil.

[0352] Yield: 70 mg (50%).

[0353] MS (ES+) [M+Na) + m / e = 372.6, 374.6 (bromine isotope mode).

[0354] 1 H NMR (300 MHz, CDCl3): δ 7.72 – 7.59 (m, 3H), 7.50 (dd, J = 8.3, 6.9Hz, 2H), 7.25 (d, J = 8.1 Hz, 2H), 7.13 (d, J = 8.1 Hz, 1H), 4.34 (dd, J = 6.4, 3.7Hz, 1H), 2.70 – 2.54 (m, 2H), 2.43 – 2.31 (m, 1H), 2.14 – 1.94 (m, 2H), 1.68 – 1.52 (m, 1H).

[0355] 13 C NMR (75 MHz, CDCl3): δ 142.12, 137.52, 133.89, 133.27, 132.22,129.34, 129.11, 128.86, 126.00, 122.86, 63.95, 28.56, 23.61, 18.80.

[0356] Step 2: N -(4-Methyl-5-(5-(phenylsulfonyl)-5,6,7,8-tetrahydronaphthyl-2-yl)thiazolyl)acetamide

[0357] 6-Bromo-1-(phenylsulfonyl)-1,2,3,4-tetrahydronaphthalene (70 mg, 199 µmol), N 1,4-(4-methylthiazolyl-2-yl)acetamide (1.2 equivalents, 37 mg, 239 µmol), tri-tert-butylphosphonium tetrafluoroborate (0.2 equivalents, 12 mg, 40 µmol), Pd(OAc)₂ (0.1 equivalents, 4.5 mg, 20 µmol), and Cs₂CO₃ (3 equivalents, 195 mg, 598 µmol) were suspended in 1 mL of DMF. The suspension was sonicated for 5 min, rinsed with nitrogen, heated to 120 °C, and stirred overnight. The solvent was then removed under reduced pressure, and the crude product was purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1% TFA). The product was lyophilized to obtain an amorphous white solid.

[0358] Yield: 22 mg (26%).

[0359] MS (ES+) [M+H) + m / e = 426.7.

[0360] 1 H NMR (600 MHz, DMSO-d6): δ 12.09 (s, 1H), 7.81 – 7.71 (m, 3H), 7.68– 7.61 (m, 2H), 7.31 (t, J= 5.5 Hz, 1H), 7.26 – 7.21 (m, 2H), 4.84 – 4.80 (m,1H), 2.70 – 2.59 (m, 2H), 2.36 (s, 3H), 2.14 (s, 3H), 2.10 – 2.00 (m, 2H), 1.97 – 1.89 (m, 1H), 1.60 – 1.51 (m, 1H).

[0361] 13 C NMR (151 MHz, DMSO-d6): δ 168.31, 155.18, 142.23, 140.25, 137.69,133.94, 132.17, 132.06, 129.28, 128.77, 128.66, 125.61, 125.22, 123.36,62.13, 28.02, 23.19, 22.41, 18.28, 16.12.

[0362] Example Compound 7: N - (5-(4-methoxy-l-(phenylsulfonyl)-l,2,3,4-tetrahydroquinolin-6-yl)-4- (2-yl)-thiazolyl acetamide Step 1: 6-Bromo-1-(phenylsulfonyl)-2,3-dihydroquinoline-4(1 H )-ketone

[0363] 2,3-dihydroquinoline-4(1 H 1-Bromopyrrolidine-2,5-dione (317 mg, 2.15 mmol) was dissolved in 4 mL of acetonitrile. Then, 1-bromopyrrolidine-2,5-dione (1.0 equivalent, 383 mg, 2.15 mmol) was added to the mixture, and the reaction was stirred at room temperature for 16 hours. After the reaction was complete, the crude reaction mixture was poured into a separatory funnel containing DCM and an aqueous solution of 1 M Na₂S₂O₃. The aqueous phase was extracted three times with DCM. The combined organic phases were then dried over Na₂SO₄ and concentrated under reduced pressure. The residue was then dissolved in 3 mL of pyridine. Subsequently, benzenesulfonyl chloride (1.1 equivalent, 418 mg, 2.37 mmol, 0.303 mL) was added to the mixture. The reaction mixture was stirred at room temperature for three hours. The solvent was then removed under reduced pressure, and the crude product was purified by silica gel chromatography using a gradient of cyclohexane and EtOAc as eluents. The product was obtained as a yellow oil.

[0364] Yield: 630 mg (80%).

[0365] MS (ES+) [M+H) +m / e = 365.7, 367.8 (bromine isotope mode).

[0366] 1 H NMR (300 MHz, CDCl3): δ 8.05 (d, J = 2.5 Hz, 1H), 7.78 (d, J = 8.8 Hz,1H), 7.72 – 7.65 (m, 3H), 7.64 – 7.56 (m, 1H), 7.52 – 7.43 (m, 2H), 4.28 –4.15 (m, 2H), 2.42 – 2.30 (m, 2H).

[0367] 13 C NMR (75 MHz, CDCl3): δ 191.40, 141.26, 139.58, 137.57, 133.93, 130.62, 129.82, 126.96, 126.94, 126.45, 119.61, 46.22, 36.30.

[0368] Step 2: 6-Bromo-4-methoxy-1-(phenylsulfonyl)-1,2,3,4-tetrahydroquinoline

[0369] 6-bromo-1-(phenylsulfonyl)-2,3-dihydroquinoline-4(1 H The ketone (100 mg, 271 µmol) was dissolved in 1 mL of MeOH. Then, NaBH4 (4 equivalents, 41 mg, 1.09 mmol) was added to the mixture. The reaction mixture was kept at room temperature for 30 minutes. After the reaction was complete, the crude product was poured into a separatory funnel containing DCM and water. The aqueous phase was extracted three times with DCM. The combined organic phases were then dried over Na2SO4 and concentrated under reduced pressure. The residue was then dissolved in dry THF (2 mL) and brought to 0 °C. Then, 60% NaH (2 equivalents, 22 mg, 546 µmol) and CH3I (2 equivalents, 77 mg, 546 µmol) were added to the mixture. The reaction mixture was then brought to room temperature and stirred for 1 hour. The reaction mixture was then slowly quenched with acetic acid and poured into a separatory funnel containing DCM and water. The aqueous phase was extracted three times with DCM. The combined organic phases were then dried over Na2SO4 and concentrated under reduced pressure. The crude product was then purified by silica gel chromatography using a gradient of cyclohexane and EtOAc as eluents. The product obtained was a yellow oil.

[0370] Yield: 80 mg (77%).

[0371] MS (ES+) [M+Na) + m / e = 403.7, 405.7 (bromine isotope mode).

[0372] 1 H NMR (300 MHz, CDCl3): δ 7.80 (d, J = 8.9 Hz, 1H), 7.63 – 7.58 (m,2H), 7.57 – 7.49 (m, 1H), 7.46 – 7.36 (m, 3H), 7.33 (d, J = 2.4 Hz, 1H), 4.02 –3.88 (m, 2H), 3.70 (ddd, J = 12.9, 11.3, 4.1 Hz, 1H), 3.04 (s, 3H), 1.94 (dq, J =13.6, 4.4 Hz, 1H), 1.65 (dddd, J = 14.0, 11.3, 4.9, 3.6 Hz, 1H).

[0373] 13 C NMR (75 MHz, CDCl3): δ 138.52, 135.55, 133.12, 132.31, 131.93,131.17, 129.11, 127.24, 125.62, 117.69, 73.34, 55.87, 42.31, 26.79.

[0374] Step 3: N -(5-(4-methoxy-1-(phenylsulfonyl)-1,2,3,4-tetrahydroquinolin-6-yl)-4-methylthiazolyl-2-yl)acetamide

[0375] 6-Bromo-4-methoxy-1-(phenylsulfonyl)-1,2,3,4-tetrahydroquinoline (40 mg, 105 µmol), N1,4-(4-methylthiazolyl-2-yl)acetamide (1.2 equivalents, 20 mg, 126 µmol), tri-tert-butylphosphonium tetrafluoroborate (0.2 equivalents, 6 mg, 21 µmol), Pd(OAc)₂ (0.1 equivalents, 2.3 mg, 10 µmol), and Cs₂CO₃ (3 equivalents, 102 mg, 314 µmol) were suspended in 1 mL of DMF. The suspension was sonicated for 5 min, rinsed with nitrogen, heated to 110 °C, and stirred overnight. The solvent was then removed under reduced pressure, and the crude product was purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1% TFA). The product was lyophilized to obtain an amorphous white solid.

[0376] Yield: 31 mg (65%).

[0377] MS (ES+) [M+H) + m / e = 457.7 (bromine isotope mode).

[0378] 1 H NMR (300 MHz, DMSO-d6): δ 12.11 (s, 1H), 7.77 (d, J = 8.6 Hz, 1H),7.70 – 7.62 (m, 3H), 7.60 – 7.50 (m, 2H), 7.41 (dd, J = 8.7, 2.3 Hz, 1H), 7.32(d, J = 2.3 Hz, 1H), 4.15 (t, J = 4.1 Hz, 1H), 3.98 (dt, J = 12.7, 4.6 Hz, 1H), 3.66 (td, J = 12.0, 3.8 Hz, 1H), 3.05 (s, 3H), 2.33 (s, 3H), 2.13 (s, 3H), 1.95(dq, J = 13.4, 4.3 Hz, 1H), 1.76 – 1.61 (m, 1H).

[0379] 13C NMR (75 MHz, DMSO-d6): δ 168.37, 155.00, 142.01, 138.13, 134.85,133.53, 129.83, 129.49, 129.22, 128.52, 127.69, 126.89, 122.95, 122.59,72.45, 55.13, 42.20, 26.11, 22.47, 16.10.

[0380] Example Compound 8: N - (4-cyclopropyl-5-(l-(phenylsulfonyl)-l,2,3,4-tetrahydroquinolin-6-yl)thiazol- 2-yl)acetamide Step 1: N -(4-Cyclopropylthiazolyl-2-yl)acetamide

[0381] 4-Cyclopropylthiazol-2-amine (350 mg, 2.5 mmol) was dissolved in dry DCM (5 mL). Acetic anhydride (1.5 equivalent, 383 mg, 3.7 mmol) and triethylamine (1.5 equivalent, 380 mg, 3.7 mmol) were then added to the mixture. The reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete, the crude product was poured into a separatory funnel containing DCM and water. The aqueous phase was extracted three times with DCM. The combined organic phases were then dried over Na₂SO₄ and concentrated under reduced pressure. The product was obtained as a yellow oil.

[0382] Yield: 287 mg (73%).

[0383] MS (ES+) [M+H) + m / e = 182.9.

[0384] 1 H NMR (300 MHz, CD3OD): δ 6.58 (s, 1H), 2.16 (s, 3H), 1.94 (tt, J =8.2, 5.1 Hz, 1H), 0.89 – 0.72 (m, 4H).

[0385] 13 C NMR (151 MHz, CD3OD): δ 170.58, 159.01, 154.58, 106.11, 22.53, 12.77, 7.94.

[0386] Step 2: N-(4-Cyclopropyl-5-(1-(phenylsulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)thiazolyl-2-yl)acetamide

[0387] 6-Bromo-1-(phenylsulfonyl)-1,2,3,4-tetrahydroquinoline (42 mg, 119 µmol), N -(4-Cyclopropylthiazolyl-2-yl)acetamide (1.5 equivalents, 33 mg, 179 µmol), tri-tert-butylphosphonium tetrafluoroborate (0.2 equivalents, 6.9 mg, 24 µmol), Pd(OAc)₂ (0.1 equivalents, 2.7 mg, 12 µmol), and Cs₂CO₃ (3 equivalents, 117 mg, 358 µmol) were suspended in 1 mL of DMF. The suspension was sonicated for 5 min, rinsed with nitrogen, heated to 110 °C, and stirred overnight. The solvent was then removed under reduced pressure, and the crude product was purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1% TFA). The product was lyophilized to obtain an amorphous white solid.

[0388] Yield: 9 mg (17%).

[0389] MS (ES+) [M+H) + m / e = 453.8.

[0390] 1 H NMR (300 MHz, DMSO-d6): δ 12.07 (s, 1H), 7.72 – 7.64 (m, 4H), 7.61– 7.53 (m, 2H), 7.35 (dd, J = 8.6, 2.2 Hz, 1H), 7.21 (d, J = 2.2 Hz, 1H), 3.83 –3.75 (m, 2H), 2.11 (s, 3H), 2.09 – 1.99 (m, 1H), 1.66 – 1.54 (m, 2H), 0.96 –0.81 (m, 4H).

[0391] 13C NMR (75 MHz, DMSO-d6): δ 168.38, 155.43, 146.71, 138.90, 135.37,133.47, 130.86, 129.58, 129.49, 128.31, 126.78, 126.64, 123.90, 121.97,46.29, 26.04, 22.37, 20.91, 10.60, 8.16.

[0392] Example Compound 9: N - (4-methyl-5- (4- (phenylsulfonyl) -3, 4-dihydro-2 H - benzo[ b ][1,4] thiazine- 7-yl)thiazolyl)acetamide Step 1: 7-Bromo-4-(phenylsulfonyl)-3,4-dihydro-2 H -benzo[ b [1,4]thiazide

[0393] 7-bromo-3,4-dihydro-2 H -benzo[ b [1,4]Thiazine (225 mg, 977 µmol) was dissolved in 3 mL of pyridine. Subsequently, benzenesulfonyl chloride (1.1 equivalent, 189 mg, 1.08 mmol) was added to the mixture. The reaction mixture was stirred at room temperature for three hours. The solvent was then removed under reduced pressure, and the crude product was purified by silica gel chromatography using a gradient of cyclohexane and EtOAc as eluents. The product was obtained as a yellow oil.

[0394] Yield: 351 mg (97%).

[0395] MS (ES+) [M+Na) + m / e = 391.6, 393.6 (bromine isotope mode).

[0396] 1 H NMR (300 MHz, CDCl3): δ 7.64 – 7.53 (m, 4H), 7.49 – 7.41 (m, 2H), 7.24 – 7.18 (m, 2H), 4.00 – 3.93 (m, 2H), 2.86 – 2.79 (m, 2H).

[0397] 13C NMR (75 MHz, CDCl3): δ 140.06, 133.43, 133.29, 130.38, 129.56, 129.48, 129.20, 127.82, 127.19, 120.06, 44.55, 25.56.

[0398] Step 2: N -(4-Methyl-5-(4-(phenylsulfonyl)-3,4-dihydro-2 H -benzo[ b [1,4]thiazin-7-yl)thiazolyl)acetamide

[0399] 7-bromo-4-(phenylsulfonyl)-3,4-dihydro-2 H -benzo[ b [1,4]Thiazide (350 mg, 945 µmol), N 1,4-(4-methylthiazolyl-2-yl)acetamide (1.2 equivalents, 177 mg, 1.13 mmol), tri-tert-butylphosphonium tetrafluoroborate (0.2 equivalents, 55 mg, 189 µmol), Pd(OAc)₂ (0.1 equivalents, 21 mg, 95 µmol), and Cs₂CO₃ (3 equivalents, 924 mg, 2.84 mmol) were suspended in 4 mL of DMF. The suspension was sonicated for 5 min, washed with nitrogen, heated to 110 °C, and stirred overnight. The solvent was then removed under reduced pressure, and the crude product was purified by silica gel chromatography using a gradient of cyclohexane and EtOAc as eluents. The product was obtained as a white solid.

[0400] Yield: 144 mg (34%).

[0401] MS (ES+) [M+H) + m / e = 445.7.

[0402] 1 H NMR (300 MHz, CD3CN): δ 9.87 (s, 1H), 7.69 – 7.58 (m, 4H), 7.54 –7.45 (m, 2H), 7.19 (dd, J = 8.5, 2.1 Hz, 1H), 7.14 (d, J = 2.1 Hz, 1H), 4.01 –3.92 (m, 2H), 2.94 – 2.84 (m, 2H), 2.31 (s, 3H), 2.16 (s, 3H).

[0403] 13 C NMR (75 MHz, CD3CN): δ 169.28, 156.30, 143.94, 140.92, 134.39,134.02, 131.91, 130.42, 129.85, 128.73, 128.00, 127.32, 125.79, 124.42, 45.54, 26.32, 23.06, 16.45.

[0404] Example compounds 10, 11 and 12: N - (4-methyl-5- (1-oxido-4- (phenylsulfonyl) -3, 4-dihydro-2 H - benzene and b [1,4]thiazin-7-yl)thiazol-2-yl)acetamide, N - (5-(1,1 -dioxido-4-(phenylsulfonyl)-3,4-dihydro- Hydrogen-2 H - benzo[ b ] [1,4] thiazin-7-yl) -4-methylthiazol-2-yl) acetamide and N - (4-methyl-1 -oxido-5- (1 -oxido-5- Hydro-4-(phenylsulfonyl)-3,4-dihydro-2 H - benzo[ b ][1,4]thiazin-7-yl)thiazol-2-yl)acetamide

[0405] At 0℃ N -(4-Methyl-5-(4-(phenylsulfonyl)-3,4-dihydro-2 H -benzo[ b [1,4]Thiazin-7-yl)thiazolyl-2-yl)acetamide (100 mg, 224 µmol) was dissolved in 1 mL of DCM. Subsequently, m-chloroperbenzoic acid (1.7 equivalents, 66 mg, 382 µmol) was added to the mixture, and the reaction mixture was maintained at 0 °C for 45 min, then at room temperature for one hour. The solvent was then removed under reduced pressure, and the crude product was purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1% TFA). Lyophilization yielded all separated products as pure, amorphous white solids.

[0406] Compound 10: N -(4-Methyl-5-(1-O-4-(phenylsulfonyl)-3,4-dihydro-2- H -benzo[ b [1,4]thiazin-7-yl)thiazolyl)acetamide Yield: 23 mg (22%).

[0407] MS (ES+) [M+H) + m / e = 461.7.

[0408] 1H NMR (600 MHz, DMSO-d6): δ 12.16 (s, 1H), 7.84 – 7.77 (m, 3H), 7.75– 7.70 (m, 1H), 7.69 – 7.64 (m, 2H), 7.63 – 7.59 (m, 2H), 4.40 (ddd, J = 14.0,5.9, 4.1 Hz, 1H), 4.01 (ddd, J = 11.5, 9.2, 4.2 Hz, 1H), 3.24 – 3.13 (m, 2H), 2.35 (s, 3H), 2.15 (s, 3H).

[0409] 13 C NMR (151 MHz, DMSO-d6): δ 168.48, 155.53, 143.04, 137.84, 134.09,133.48, 132.74, 131.97, 129.81, 129.46, 129.19, 126.96, 124.21, 121.76,45.24, 37.46, 22.43, 16.07.

[0410] Compound 11: N -(5-(1,1-dioxide-4-(phenylsulfonyl)-3,4-dihydro-2 H -benzo[ b [1,4]thiazin-7-yl)-4-methylthiazol-2-yl)acetamide Yield: 7 mg (6%).

[0411] MS (ES+) [M+H) + m / e = 477.7.

[0412] 1 H NMR (600 MHz, DMSO-d6): δ 12.20 (s, 1H), 7.87 – 7.82 (m, 2H), 7.81 – 7.71 (m, 3H), 7.71 – 7.67 (m, 1H), 7.65 (t, J = 7.7 Hz, 2H), 4.49 – 4.40 (m,2H), 3.63 – 3.57 (m, 2H), 2.35 (s, 3H), 2.15 (s, 3H).

[0413] 13C NMR (151 MHz, DMSO-d6): δ 168.57, 155.72, 143.54, 138.05, 134.38,133.88, 132.95, 131.51, 130.02, 129.91, 127.02, 124.38, 122.74, 121.21,49.32, 44.95, 22.43, 16.03.

[0414] Compound 12: N -(4-methyl-1-oxy-5-(1-oxy-4-(phenylsulfonyl)-3,4-dihydro-2- H -benzo[ b [1,4]thiazin-7-yl)thiazolyl)acetamide Yield: 6 mg (5%).

[0415] MS (ES+) [M+H) + m / e = 477.7.

[0416] 1 H NMR (600 MHz, DMSO-d6): δ 7.87 (d, J = 8.7 Hz, 1H), 7.84 – 7.79 (m,3H), 7.75 – 7.71 (m, 2H), 7.62 (t, J = 7.8 Hz, 2H), 4.43 (dt, J = 14.0, 4.7 Hz,1H), 4.03 (ddd, J = 13.8, 8.5, 5.1 Hz, 1H), 3.24 – 3.17 (m, 2H), 2.36 (s, 3H), 2.28 (s, 3H).

[0417] 13 C NMR (151 MHz, DMSO-d6) δ 158.37, 158.13, 137.80, 136.01, 134.19,134.17, 133.44, 131.97, 129.85, 127.04, 126.98, 124.09, 117.61, 116.42, 44.97, 37.34, 22.62, 11.25.

[0418] Example Compound 13: N - (4-methyl-5-(8-(phenylsulfonyl)-5,6,7,8-tetrahydro-l,8-naphthyridin-3-yl) Thiazol-2-yl)acetamide Step 1:6-Bromo-1-(phenylsulfonyl)-1,2,3,4-tetrahydro-1,8-naphthidine

[0419] 6-bromo-3,4-dihydro-1,8-naphthidine-2 ( 1H )-ketone (290 mg, 1.28 mmol) was dissolved in 3 mL of dry THF and brought to 0 °C. Then, 2 M LiAlH4 solution (3 equivalents, 145 mg, 3.83 mmol, 1.92 mL) was added dropwise to the solution, and the reaction mixture was maintained at 0 °C for one hour. After completion, the reaction mixture was quenched with an aqueous solution of Na2CO3, and the crude product was then poured into a separatory funnel containing DCM and water. The aqueous phase was extracted three times with DCM. The combined organic phases were then dried over Na2SO4 and concentrated under reduced pressure. The residue was then dissolved in 3 mL of pyridine. Subsequently, benzenesulfonyl chloride (1.5 equivalents, 338 mg, 1.91 mmol, 0.245 mL) was added to the mixture. The reaction mixture was stirred at room temperature for three hours. The solvent was then removed under reduced pressure, and the crude product was purified by silica gel chromatography using a gradient of cyclohexane and EtOAc as eluents. The product was obtained as a yellow oil.

[0420] Yield: 153 mg (34%).

[0421] MS (ES+) [M+H) + m / e = 352.7, 354.7 (bromine isotope mode).

[0422] 1 H NMR (300 MHz, CDCl3): δ 8.10 – 8.00 (m, 3H), 7.59 – 7.40 (m, 4H), 4.13 – 4.03 (m, 2H), 2.78 (t, J = 6.5 Hz, 2H), 2.07 (dt, J = 12.3, 6.3 Hz, 2H).

[0423] 13 C NMR (75 MHz, CDCl3): δ 149.05, 146.17, 141.09, 139.70, 132.84, 128.57, 128.37, 122.98, 113.64, 46.30, 26.90, 22.21.

[0424] Step 2: N-(4-Methyl-5-(8-(phenylsulfonyl)-5,6,7,8-tetrahydro-1,8-naphthidin-3-yl)thiazolyl)acetamide

[0425] 6-Bromo-1-(phenylsulfonyl)-1,2,3,4-tetrahydro-1,8-naphthidine (100 mg, 283 µmol), N 1,4-(4-methylthiazolyl-2-yl)acetamide (1.2 equivalents, 53 mg, 340 µmol), tri-tert-butylphosphonium tetrafluoroborate (0.2 equivalents, 16 mg, 57 µmol), Pd(OAc)₂ (0.1 equivalents, 6.4 mg, 28 µmol), and Cs₂CO₃ (3 equivalents, 276 mg, 849 µmol) were suspended in 1 mL of DMF. The suspension was sonicated for 5 min, rinsed with nitrogen, heated to 110 °C, and stirred overnight. The solvent was then removed under reduced pressure, and the crude product was purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1% TFA). The product was lyophilized to obtain an amorphous white solid.

[0426] Yield: 44 mg (36%).

[0427] MS (ES+) [M+H) + m / e = 428.8.

[0428] 1 H NMR (300 MHz, DMSO-d6): δ 12.13 (s, 1H), 8.06 – 7.96 (m, 3H), 7.68– 7.52 (m, 4H), 4.09 – 3.98 (m, 2H), 2.83 (t, J = 6.4 Hz, 2H), 2.27 (s, 3H), 2.12 (s, 3H), 1.99 (p, J = 6.2 Hz, 2H).

[0429] 13 C NMR (75 MHz, DMSO-d6): δ 168.39, 155.37, 148.64, 143.73, 142.60,141.06, 137.35, 132.84, 128.79, 127.67, 122.83, 121.67, 119.97, 46.18, 25.91,22.44, 21.85, 15.84.

[0430] Example Compound 14: N - (4-methyl-5-(4-oxo-1-(phenylsulfonyl)-1,2,3,4-tetrahydroquinolin-6- (2-yl)thiazolyl)acetamide Step 1: 6-Bromo-1-(phenylsulfonyl)-2,3-dihydro-1 H -spiro[quinoline-4,2'-[1,3]dioxolane]

[0431] 6-bromo-1-(phenylsulfonyl)-2,3-dihydroquinoline-4(1 H )-ketone (160 mg, 437 µmol) and tetrabutylammonium bromide (0.01 equivalent, 1.4 mg, 4.4 µmol) were dissolved in 2 mL of ethane-1,2-diol. The mixture was then heated at 110 °C for 72 hours. After completion, the crude product was poured into a separatory funnel containing DCM and water. The aqueous phase was extracted three times with DCM. The combined organic phases were then dried over Na2SO4 and concentrated under reduced pressure, and the crude product was then purified by silica gel chromatography using a gradient of cyclohexane and EtOAc as eluents. The product was obtained as a yellow oil.

[0432] Yield: 55 mg (31%).

[0433] MS (ES+) [M+H) + m / e = 409.6, 411.6 (bromine isotope mode).

[0434] 1 H NMR (300 MHz, CDCl3): δ 7.81 – 7.73 (m, 1H), 7.71 – 7.60 (m, 2H), 7.59 – 7.51 (m, 1H), 7.51 – 7.35 (m, 4H), 4.14 – 3.84 (m, 6H), 1.81 – 1.68(m, 2H).

[0435] 13 C NMR (75 MHz, CDCl3): δ 138.86, 136.36, 133.32, 132.56, 129.46, 129.24, 127.23, 126.94, 124.84, 118.05, 65.18, 44.78, 31.89.

[0436] Step 2: N -(4-methyl-5-(4-oxoylidene-1-(phenylsulfonyl)-1,2,3,4-tetrahydroquinolin-6-yl)thiazolyl)acetamide

[0437] 6-bromo-1-(phenylsulfonyl)-2,3-dihydro-1 H -spiro[quinoline-4,2'-[1,3]dioxolane] (55 mg, 134 µmol), N 1,4-(4-methylthiazolyl-2-yl)acetamide (1.2 equivalents, 25 mg, 161 µmol), tri-tert-butylphosphonium tetrafluoroborate (0.2 equivalents, 8 mg, 27 µmol), Pd(OAc)₂ (0.1 equivalents, 3.0 mg, 13 µmol), and Cs₂CO₃ (3 equivalents, 131 mg, 402 µmol) were suspended in 1 mL of DMF. The suspension was sonicated for 5 min, rinsed with nitrogen, heated to 110 °C, and stirred overnight. The crude product was poured into a separatory funnel containing DCM and water. The aqueous phase was extracted three times with DCM. The combined organic phases were then dried over Na₂SO₄ and concentrated under reduced pressure. Subsequently, the crude product was dissolved in 1 mL of acetone and 1 mL of 1 M HCl aqueous solution. The mixture was then heated to 60 °C for 1 hour. After completion, NaHCO₃ aqueous solution was added until the pH reached 7. The solvent was then removed under reduced pressure, and the product was purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1% TFA). The product was then lyophilized to obtain an amorphous white solid.

[0438] Yield: 29 mg (49%).

[0439] MS (ES+) [M+H) + m / e = 441.7.

[0440] 1 H NMR (300 MHz, DMSO-d6): δ 12.18 (s, 1H), 7.84 – 7.69 (m, 6H), 7.66– 7.58 (m, 2H), 4.26 (t, J = 6.3 Hz, 2H), 2.46 (t, J = 6.4 Hz, 18H), 2.35 (s, 3H), 2.14 (s, 3H).

[0441] 13C NMR (75 MHz, DMSO-d6): δ 192.01, 168.53, 155.41, 142.89, 140.43,138.81, 134.20, 134.07, 129.99, 129.24, 126.87, 126.19, 125.32, 123.93,122.10, 45.72, 36.46, 22.47, 16.13.

[0442] Example Compound 15: N - (5-(4-hydroxy-l-(phenylsulfonyl)-l,2,3,4-tetrahydroquinolin-6-yl)-4- (2-yl)-thiazolyl acetamide

[0443] Will N 24 mg, 54 µmol of 4-methyl-5-(4-oxoylide-1-(phenylsulfonyl)-1,2,3,4-tetrahydroquinolin-6-yl)thiazolyl-2-yl)acetamide was dissolved in 1 mL of MeOH. Subsequently, NaBH4 (2 equivalents, 4.1 mg, 109 µmol) was added to the mixture, and the reaction mixture was stirred at room temperature for 1 hour. The solvent was then removed under reduced pressure, and the crude product was purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1% TFA). The product was obtained by lyophilization as an amorphous white solid.

[0444] Yield: 17 mg (71%).

[0445] MS (ES+) [M+H) + m / e = 443.7.

[0446] 1 H NMR (300 MHz, DMSO-d6): δ 12.09 (s, 1H), 7.75 – 7.63 (m, 4H), 7.62– 7.53 (m, 2H), 7.41 (d, J = 2.3 Hz, 1H), 7.34 (dd, J = 8.6, 2.3 Hz, 1H), 5.51(d, J = 5.3 Hz, 1H), 4.31 (q, J = 5.0 Hz, 1H), 3.99 (ddd, J = 13.0, 7.0, 4.1 Hz,1H), 3.77 (ddd, J= 12.9, 8.7, 3.8 Hz, 1H), 2.34 (s, 3H), 2.13 (s, 3H), 1.83 –1.56 (m, 2H).

[0447] 13 C NMR (75 MHz, DMSO-d6): δ 168.36, 154.96, 141.85, 138.72, 134.32,133.57, 133.21, 129.61, 128.87, 127.90, 127.47, 126.80, 123.22, 122.12,63.19, 42.86, 30.24, 22.48, 16.16.

[0448] Example Compound 16: N - (4-methyl-5-(2-methyl-l-(phenylsulfonyl)-l,2,3,4-tetrahydroquinolin-6- (2-yl)thiazolyl)acetamide Step 1: 6-Bromo-2-methyl-1-(phenylsulfonyl)-1,2,3,4-tetrahydroquinoline

[0449] 2-Methyl-1,2,3,4-tetrahydroquinoline (291 mg, 1.98 mmol) was dissolved in 3 mL of acetonitrile. Then, 1-bromopyrrolidine-2,5-dione (1.0 equivalent, 352 mg, 1.98 mmol) was added to the mixture, and the reaction was stirred at room temperature for 16 hours. After the reaction was complete, the crude product was poured into a separatory funnel containing DCM and an aqueous solution of 1 M Na₂S₂O₃. The aqueous phase was extracted three times with DCM. The combined organic phases were then dried over Na₂SO₄ and concentrated under reduced pressure. The residue was then dissolved in 3 mL of pyridine. Subsequently, benzenesulfonyl chloride (1.1 equivalent, 384 mg, 2.17 mmol, 0.278 mL) was added to the mixture. The reaction mixture was stirred at room temperature for three hours. The solvent was then removed under reduced pressure, and the crude product was purified by silica gel chromatography using a gradient of cyclohexane and EtOAc as eluents. The product was obtained as a yellow oil.

[0450] Yield: 558 mg (77%).

[0451] MS (ES+) [M+Na) + m / e = 387.7, 389.7 (bromine isotope mode).

[0452] 1H NMR (300 MHz, DMSO-d6): δ 12.10 (s, 1H), 7.71 – 7.59 (m, 2H), 7.58– 7.48 (m, 4H), 7.33 (dd, J = 8.5, 2.2 Hz, 1H), 7.14 (d, J = 2.2 Hz, 1H), 4.37(q, J = 6.4 Hz, 1H), 2.48 – 2.42 (m, 1H), 2.35 (s, 3H), 2.13 (s, 3H), 1.76 (tq, J = 11.6, 5.6 Hz, 2H), 1.41 – 1.27 (m, 1H), 1.21 (d, J = 6.5 Hz, 3H).

[0453] 13 C NMR (75 MHz, DMSO-d6): δ 168.35, 155.02, 142.02, 138.38, 133.59,133.44, 133.35, 129.41, 129.21, 128.12, 126.72, 126.53, 126.51, 123.23,52.04, 29.02, 23.72, 22.47, 21.29, 16.23.

[0454] Step 2: N -(4-Methyl-5-(2-methyl-1-(phenylsulfonyl)-1,2,3,4-tetrahydroquinolin-6-yl)thiazolyl-2-yl)acetamide

[0455] 6-bromo-2-methyl-1-(phenylsulfonyl)-1,2,3,4-tetrahydroquinoline (105 mg, 287 µmol), N1,4-(4-methylthiazolyl-2-yl)acetamide (1.2 equivalents, 54 mg, 344 µmol), tri-tert-butylphosphonium tetrafluoroborate (0.2 equivalents, 17 mg, 57 µmol), Pd(OAc)₂ (0.1 equivalents, 6 mg, 29 µmol), and Cs₂CO₃ (3 equivalents, 280 mg, 860 µmol) were suspended in 1 mL of DMF. The suspension was sonicated for 5 min, rinsed with nitrogen, heated to 110 °C, and stirred overnight. The solvent was then removed under reduced pressure, and the crude product was purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1% TFA). The product was lyophilized to obtain an amorphous white solid.

[0456] Yield: 32 mg (25%).

[0457] MS (ES+) [M+H) + m / e = 441.7.

[0458] 1 H NMR (300 MHz, DMSO-d6): δ 12.10 (s, 1H), 7.71 – 7.59 (m, 2H), 7.58– 7.48 (m, 4H), 7.33 (dd, J = 8.5, 2.2 Hz, 1H), 7.14 (d, J = 2.2 Hz, 1H), 4.37(q, J = 6.4 Hz, 1H), 2.48 – 2.42 (m, 1H), 2.35 (s, 3H), 2.13 (s, 3H), 1.76 (tq, J = 11.6, 5.6 Hz, 2H), 1.41 – 1.27 (m, 1H), 1.21 (d, J = 6.5 Hz, 3H).

[0459] 13 C NMR (75 MHz, DMSO-d6): δ 168.35, 155.02, 142.02, 138.38, 133.59,133.44, 133.35, 129.41, 129.21, 128.12, 126.72, 126.53, 126.51, 123.23,52.04, 29.02, 23.72, 22.47, 21.29, 16.23.

[0460] Example Compound 17: N - (5-(1-(phenylsulfonyl)-1,2,3,4-tetrahydroquinolin-6-yl)-4- Thiazol-2-yl)acetamide Step 1: N -(4-(trifluoromethyl)thiazo-2-yl)acetamide

[0461] 4-(trifluoromethyl)thiazol-2-amine (144 mg, 856 µmol) was dissolved in dry DCM (3 mL). Acetyl chloride (2 equivalents, 134 mg, 1.71 mmol) and triethylamine (2 equivalents, 173 mg, 1.71 mmol) were then added to the mixture. The reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete, the crude product was poured into a separatory funnel containing DCM and water. The aqueous phase was extracted three times with DCM. The combined organic phases were then dried over Na₂SO₄ and concentrated under reduced pressure. The crude product was then purified by silica gel chromatography using a gradient of cyclohexane and EtOAc as eluents. The product was obtained as a yellow oil.

[0462] Yield: 40 mg (22%).

[0463] MS (ES+) [M+H) + m / e = 182.9.

[0464] 1 H NMR (300 MHz, CD3OD): δ 7.61 (s, 1H), 4.88 (s, 1H), 2.22 (s, 3H).

[0465] 13 C NMR (75 MHz, CD3OD): δ 171.24, 161.25, 140.45 (q, J = 37.2 Hz), 122.26 (q, J = 268.9 Hz), 116.45 (q, J = 3.6 Hz), 22.47.

[0466] Step 2: N -(5-(1-(phenylsulfonyl)-1,2,3,4-tetrahydroquinolin-6-yl)-4-(trifluoromethyl)thiazolyl-2-yl)acetamide

[0467] 6-Bromo-1-(phenylsulfonyl)-1,2,3,4-tetrahydroquinoline (30 mg, 85 µmol), N-(4-(trifluoromethyl)thiazolyl-2-yl)acetamide (1.2 equivalents, 21 mg, 102 µmol), tri-tert-butylphosphonium tetrafluoroborate (0.2 equivalents, 4.9 mg, 17 µmol), Pd(OAc)₂ (0.1 equivalents, 1.9 mg, 9 µmol), and Cs₂CO₃ (3 equivalents, 83 mg, 255 µmol) were suspended in 1 mL of DMF. The suspension was sonicated for 5 min, rinsed with nitrogen, heated to 130 °C, and stirred overnight. The solvent was then removed under reduced pressure, and the crude product was purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1% TFA). The product was lyophilized to obtain an amorphous white solid.

[0468] Yield: 30 mg (73%).

[0469] MS (ES+) [M+H) + m / e = 481.7.

[0470] 1 H NMR (600 MHz, DMSO-d6): δ 12.60 (s, 1H), 7.74 – 7.63 (m, 4H), 7.60– 7.52 (m, 2H), 7.30 – 7.25 (m, 1H), 7.21 – 7.17 (m, 1H), 3.86 – 3.79 (m,2H), 2.56 – 2.51 (m, 2H), 2.18 (s, 3H), 1.63 (p, J = 6.1 Hz, 2H).

[0471] 13 C NMR (151 MHz, DMSO-d6): δ 169.31, 156.98, 138.77, 137.22, 136.49, 133.51, 132.49, 130.39, 129.52, 127.45, 126.70, 124.53, 123.12, 46.30, 25.99, 22.28, 20.85. (CF3 missing).

[0472] Example Compound 18: N - (5-(1-(phenylsulfonyl)-1,2,3,4-tetrahydroquinolin-6-yl)thiazol-2-yl)eth amide

[0473] 6-Bromo-1-(phenylsulfonyl)-1,2,3,4-tetrahydroquinoline (82 mg, 233 µmol), N1,46 mg (326 µmol) of thiazolyl-2-yl)acetamide, tri-tert-butylphosphonium tetrafluoroborate (0.2 mg, 47 µmol), Pd(OAc)₂ (0.1 mg, 23 µmol), and Cs₂CO₃ (3 mg, 698 µmol) were suspended in 1 mL of DMF. The suspension was sonicated for 5 min, rinsed with nitrogen, heated to 130 °C, and stirred overnight. The solvent was then removed under reduced pressure, and the crude product was purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1% TFA). The product was lyophilized to obtain an amorphous white solid.

[0474] Yield: 22 mg (22%).

[0475] MS (ES+) [M+H) + m / e = 413.7.

[0476] 1 H NMR (300 MHz, DMSO-d6): δ 12.15 (s, 1H), 7.80 (s, 1H), 7.71 – 7.60 (m, 4H), 7.60 – 7.51 (m, 2H), 7.46 (dd, J = 8.6, 2.2 Hz, 1H), 7.32 (d, J = 2.2Hz, 1H), 3.82 – 3.73 (m, 2H), 2.49 – 2.42 (m, 2H), 2.15 (s, 3H), 1.62 – 1.49(m, 2H).

[0477] 13 C NMR (75 MHz, DMSO-d6): δ 168.40, 156.92, 138.78, 135.50, 133.73,133.47, 131.21, 130.20, 129.58, 128.05, 126.78, 126.35, 124.28, 123.54,46.30, 26.00, 22.47, 20.83.

[0478] Example Compound 19: N - (4-methyl-5-(5-(phenylsulfonyl)-5,6,7,8-tetrahydro-1,5-naphthyridin-2-yl) Thiazol-2-yl)acetamide Step 1: 6-Bromo-1-(phenylsulfonyl)-1,2,3,4-tetrahydro-1,5-naphthidine

[0479] 6-Bromo-1,2,3,4-Tetrahydro-1,5-naphthidine (108 mg, 507 µmol) was dissolved in 2 mL of pyridine. Then, benzenesulfonyl chloride (1.2 equivalents, 107 mg, 608 µmol) was added to the mixture. The reaction mixture was stirred at room temperature for three hours. The solvent was then removed under reduced pressure, and the crude product was purified by silica gel chromatography using a gradient of cyclohexane and EtOAc as eluents. The product was obtained as a yellow oil.

[0480] Yield: 75 mg (42%).

[0481] MS (ES+) [M+H) + m / e = 352.6, 354.7 (bromine isotope mode).

[0482] 1 H NMR (300 MHz, DMSO-d6): δ 7.95 (d, J = 8.7 Hz, 1H), 7.77 – 7.55 (m,5H), 7.49 (d, J = 8.7 Hz, 1H), 3.84 – 3.70 (m, 2H), 2.62 (t, J = 6.7 Hz, 2H), 1.54 (p, J = 6.4 Hz, 2H).

[0483] 13 C NMR (151 MHz, DMSO-d6): δ 151.22, 138.09, 135.40, 133.89, 133.75, 132.97, 129.81, 126.87, 125.69, 45.66, 29.10, 19.71.

[0484] Step 2: N -(4-Methyl-5-(5-(phenylsulfonyl)-5,6,7,8-tetrahydro-1,5-naphthidin-2-yl)thiazolyl)acetamide

[0485] 6-Bromo-1-(phenylsulfonyl)-1,2,3,4-tetrahydro-1,5-naphthidine (75 mg, 212 µmol), N1,4-(4-methylthiazolyl-2-yl)acetamide (1.2 equivalents, 40 mg, 254 µmol), tri-tert-butylphosphonium tetrafluoroborate (0.2 equivalents, 6 mg, 21 µmol), Pd(OAc)₂ (0.1 equivalents, 6 mg, 29 µmol), and Cs₂CO₃ (3 equivalents, 280 mg, 860 µmol) were suspended in 1 mL of DMF. The suspension was sonicated for 5 min, rinsed with nitrogen, heated to 110 °C, and stirred overnight. The solvent was then removed under reduced pressure, and the crude product was purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1% TFA). The product was lyophilized to obtain an amorphous white solid.

[0486] Yield: 60 mg (66%).

[0487] MS (ES+) [M+H) + m / e = 428.7.

[0488] 1 H NMR (300 MHz, DMSO-d6): δ 12.11 (s, 1H), 8.04 (d, J = 8.8 Hz, 1H),7.74 – 7.64 (m, 3H), 7.63 – 7.55 (m, 2H), 7.53 (d, J = 8.8 Hz, 1H), 3.86 – 3.72(m, 2H), 2.62 (t, J = 6.7 Hz, 2H), 2.52 (s, 3H), 2.13 (s, 3H), 1.65 – 1.52 (m, 2H).

[0489] 13 C NMR (75 MHz, DMSO-d6): δ 168.50, 156.67, 149.50, 147.33, 144.43,138.38, 133.76, 131.41, 130.64, 129.77, 126.88, 124.69, 118.62, 45.91, 29.48,22.54, 20.16, 17.54.

[0490] Example Compound 20: N - (4-methyl-5-(l-(phenylsulfonyl)-l,2,3,4-tetrahydroquinolin-6-yl)oxazol- 2-yl)acetamide

[0491] 4-Methyloxazol-2-amine (20 mg, 204 µmol) was dissolved in dry DCM (1 mL). Acetic anhydride (2 equivalents, 42 mg, 407 µmol) and triethylamine (2 equivalents, 41 mg, 407 µmol) were then added to the mixture. The reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete, the crude product was poured into a separatory funnel containing DCM and water. The aqueous phase was extracted three times with DCM. The combined organic phases were then dried over Na₂SO₄ and concentrated under reduced pressure. The crude product, 6-bromo-1-(phenylsulfonyl)-1,2,3,4-tetrahydroquinoline (50 mg, 142 µmol), tri-tert-butylphosphonium tetrafluoroborate (0.2 equivalents, 8 mg, 28 µmol), Pd(OAc)₂ (0.1 equivalents, 3.2 mg, 14 µmol), and Cs₂CO₃ (3 equivalents, 139 mg, 426 µmol) were suspended in 1 mL of DMF. The suspension was sonicated for 5 min, washed with nitrogen, heated to 130 °C, and stirred overnight. The solvent was then removed under reduced pressure, and the crude product was purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1% TFA). The product was lyophilized to obtain an amorphous white solid.

[0492] Yield: 7 mg (12%).

[0493] MS (ES+) [M+H) + m / e = 411.8.

[0494] 1 H NMR (300 MHz, DMSO-d6): δ 11.24 (s, 1H), 7.73 (d, J = 8.7 Hz, 1H),7.70 – 7.61 (m, 3H), 7.60 – 7.49 (m, 2H), 7.37 (dd, J = 8.7, 2.2 Hz, 1H), 7.22(d, J = 2.2 Hz, 1H), 3.86 – 3.73 (m, 2H), 2.49 – 2.42 (m, 2H), 2.29 (s, 3H), 2.11 (s, 3H), 1.63 – 1.54 (m, 2H).

[0495] 13C NMR (75 MHz, DMSO-d6) δ 169.23, 158.51, 151.34, 140.12, 138.73,135.32, 133.49, 131.03, 129.58, 126.78, 125.10, 124.17, 122.52, 46.30, 26.13,23.40, 20.84, 13.12.

[0496] Example compound 21: 4-(4-methyl-5-(1-(phenylsulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)thiazole- 2-yl)morpholine Step 1: 4-(4-methylthiazolyl-2-yl)morpholine

[0497] 2-Bromo-4-methylthiazole (150 mg, 842 µmol) and morpholine (4 equivalents, 294 mg, 3.37 mmol) were dissolved in 1 mL of DMF, and the mixture was heated to 130 °C for 16 hours. The solvent was then removed under reduced pressure, and the crude product was purified by silica gel chromatography using a gradient of cyclohexane and EtOAc as eluents. The product was obtained as a yellow oil.

[0498] Yield: 55 mg (35%).

[0499] MS (ES+) [M+H) + m / e = 185.1.

[0500] 1 H NMR (300 MHz, CDCl3): δ 6.13 (q, J = 1.1 Hz, 1H), 3.83 – 3.71 (m,4H), 3.47 – 3.35 (m, 4H), 2.23 (d, J = 1.1 Hz, 3H).

[0501] 13 C NMR (75 MHz, CDCl3): δ 171.57, 149.50, 101.92, 66.23, 48.59, 17.66.

[0502] Step 2: 4-(4-methyl-5-(1-(phenylsulfonyl)-1,2,3,4-tetrahydroquinolin-6-yl)thiazo-2-yl)morpholine

[0503] 6-Bromo-1-(phenylsulfonyl)-1,2,3,4-tetrahydroquinoline (55 mg, 156 µmol), 4-(4-methylthiazolyl-2-yl)morpholine (1.2 equivalents, 35 mg, 187 µmol), tri-tert-butylphosphonium tetrafluoroborate (0.2 equivalents, 9 mg, 31 µmol), Pd(OAc)₂ (0.1 equivalents, 3.5 mg, 16 µmol), and Cs₂CO₃ (3 equivalents, 152 mg, 468 µmol) were suspended in 1 mL of DMF. The suspension was sonicated for 5 min, rinsed with nitrogen, heated to 110 °C, and stirred overnight. The solvent was then removed under reduced pressure, and the crude product was purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1% TFA). The lyophilized powder was poured into a separatory funnel containing DCM and a saturated aqueous solution of Na₂CO₃. The aqueous phase was extracted three times with DCM. The combined organic phases were then dried over Na2SO4 and concentrated under reduced pressure. The product was obtained as an amorphous white solid.

[0504] Yield: 16 mg (22%).

[0505] MS (ES+) [M+H) + m / e = 456.1.

[0506] 1 H NMR (300 MHz, CDCl3): δ 7.78 (d, J = 8.6 Hz, 1H), 7.68 – 7.60 (m,2H), 7.58 – 7.50 (m, 1H), 7.47 – 7.36 (m, 2H), 7.19 (dd, J = 8.6, 2.2 Hz, 1H), 7.00 (d, J = 2.5 Hz, 1H), 3.87 – 3.75 (m, 6H), 3.47 (t, J = 4.9 Hz, 4H), 2.46 (t, J = 6.7 Hz, 2H), 2.33 (s, 3H), 1.70 – 1.58 (m, 2H).

[0507] 13C NMR (75 MHz, CDCl3): δ 168.71, 144.12, 139.70, 135.57, 132.95,130.73, 129.46, 129.17, 127.16, 126.91, 124.94, 119.67, 66.25, 48.54, 46.68,26.78, 21.60, 16.51.

[0508] Example Compound 22: N - (4-methyl-5-(5-(phenylsulfonyl)-2,3,3a,4,5,9b-hexahydrofuro[3, 2- c ]quinolin-8-yl)thiazol-2-yl)acetamide Step 1: 8-Bromo-2,3,3a,4,5,9b-hexahydrofurano[3,2- c Quinoline

[0509] 4-Bromoaniline (200 mg, 1.16 mmol) and 37% formaldehyde in water (1 equivalent, 94 mg, 1.16 mmol) were dissolved in 2 mL of acetonitrile at 0 °C. Yb(OTf)3 (0.05 equivalent, 36 mg, 58 µmol) was then added to the mixture, followed by dropwise addition of 2,3-dihydrofuran (1 equivalent, 81 mg, 1.16 mmol) dissolved in 1 mL of acetonitrile. The reaction mixture was maintained at 0 °C for 20 min. The crude product was then purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1% TFA). The lyophilized powder was poured into a separatory funnel containing DCM and a saturated aqueous solution of Na₂CO₃. The aqueous phase was extracted three times with DCM. The combined organic phases were then dried over Na₂SO₄ and concentrated under reduced pressure. The product was obtained as an amorphous white solid.

[0510] Yield: 95 mg (32%).

[0511] MS (ES+) [M+H) + m / e = 252.0, 254.0 (bromine isotope mode).

[0512] 1H NMR (300 MHz, CDCl3): δ 7.43 (d, J = 2.4 Hz, 1H), 7.15 (dd, J = 8.6, 2.4 Hz, 1H), 6.48 (d, J = 8.6 Hz, 1H), 4.51 (d, J = 5.4 Hz, 1H), 3.94 (td, J= 8.5, 5.8 Hz, 1H), 3.81 (td, J = 8.8, 6.2 Hz, 1H), 3.15 (dd, J = 11.3, 5.1 Hz, 1H), 2.81 (t, J = 11.1 Hz, 1H), 2.42 (ddtd, J = 10.7, 8.2, 5.3, 2.9 Hz, 1H), 2.23(dddt, J = 14.2, 7.4, 5.9, 3.7 Hz, 1H), 1.75 (dddd, J = 15.1, 10.0, 6.5, 3.3 Hz, 1H).

[0513] 13 C NMR (75 MHz, CDCl3): δ 144.25, 133.90, 131.58, 122.68, 116.59, 109.77, 74.98, 65.52, 43.00, 35.85, 29.71.

[0514] Step 2: 8-Bromo-5-(phenylsulfonyl)-2,3,3a,4,5,9b-hexahydrofurano[3,2- c Quinoline

[0515] 8-Bromo-2,3,3a,4,5,9b-hexahydrofurano[3,2- c Quinoline (95 mg, 374 µmol) was dissolved in 1 mL of pyridine. Subsequently, benzenesulfonyl chloride (1.1 equivalent, 53 mg, 411 µmol) was added to the mixture. The reaction mixture was stirred at room temperature for three hours. The solvent was then removed under reduced pressure, and the crude product was purified by silica gel chromatography using a gradient of cyclohexane and EtOAc as eluents. The product was obtained as a yellow oil.

[0516] Yield: 80 mg (54%).

[0517] MS (ES+) [M+Na) + m / e = 416.0, 418.0 (bromine isotope mode).

[0518] 1H NMR (300 MHz, CDCl3): δ 7.65 – 7.52 (m, 5H), 7.48 – 7.38 (m, 3H), 4.25 (dd, J = 13.9, 5.3 Hz, 1H), 4.05 (d, J = 6.1 Hz, 1H), 3.91 – 3.75 (m, 1H), 3.66 (ddd, J = 8.7, 7.7, 6.8 Hz, 1H), 2.86 (dd, J = 14.0, 12.1 Hz, 1H), 2.26 –1.97 (m, 2H), 1.53 (dddd, J = 12.4, 10.3, 6.9, 2.4 Hz, 1H).

[0519] 13 C NMR (75 MHz, CDCl3): δ 139.94, 135.42, 133.27, 132.97, 131.80,131.52, 129.39, 127.00, 126.40, 119.29, 73.93, 66.22, 47.88, 35.38, 30.30.

[0520] Step 3: N -(4-methyl-5-(5-(phenylsulfonyl)-2,3,3a,4,5,9b-hexahydrofurano[3,2- c Quinoline-8-yl)thiazolyl)acetamide

[0521] 8-Bromo-5-(phenylsulfonyl)-2,3,3a,4,5,9b-hexahydrofurano[3,2- c Quinoline (75 mg, 190 µmol), N1,4-(4-methylthiazolyl-2-yl)acetamide (1.2 equivalents, 36 mg, 228 µmol), tri-tert-butylphosphonium tetrafluoroborate (0.2 equivalents, 11 mg, 42 µmol), Pd(OAc)₂ (0.1 equivalents, 4 mg, 19 µmol), and Cs₂CO₃ (3 equivalents, 186 mg, 571 µmol) were suspended in 1 mL of DMF. The suspension was sonicated for 5 min, rinsed with nitrogen, heated to 110 °C, and stirred overnight. The solvent was then removed under reduced pressure, and the crude product was purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1% TFA). The product was lyophilized to obtain an amorphous white solid.

[0522] Yield: 30 mg (34%).

[0523] MS (ES+) [M+H) + m / e = 470.1.

[0524] 1 H NMR (300 MHz, DMSO-d6): δ 12.13 (s, 1H), 7.76 – 7.65 (m, 3H), 7.64– 7.53 (m, 3H), 7.46 – 7.37 (m, 2H), 4.22 (d, J = 6.3 Hz, 1H), 4.17 (dd, J =13.8, 5.2 Hz, 1H), 3.75 (td, J = 8.0, 5.3 Hz, 1H), 3.59 (q, J = 7.8 Hz, 1H), 2.95(dd, J = 13.9, 11.8 Hz, 1H), 2.34 (s, 3H), 2.27 – 2.01 (m, 5H), 1.66 – 1.50 (m, 1H).

[0525] 13 C NMR (75 MHz, DMSO-d6): δ 168.41, 155.15, 142.18, 139.39, 134.87,133.62, 130.27, 129.76, 129.74, 128.97, 128.10, 126.71, 123.53, 122.91,73.51, 65.41, 47.28, 35.10, 29.63, 22.47, 16.11.

[0526] Example Compound 23: N - (6-methyl-5-(l-(phenylsulfonyl)-l,2,3,4-tetrahydroquinolin-6-yl)pyridin- 2-yl)acetamide

[0527] Will N 1,4-Dioxane was dissolved in 1 mL of 1,4-dioxane. The 1,4-(5-bromo-6-methylpyridin-2-yl)acetamide (106 mg, 462 µmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxane) (1.5 equivalents, 176 mg, 694 µmol), potassium acetate (3 equivalents, 136 mg, 1.39 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]dichloropalladium(II) (0.05 equivalents, 17 mg, 23 µmol) were sonicated for 5 min, rinsed with nitrogen, heated to 100 °C, and stirred for 2 h. After completion, 6-bromo-1-(phenylsulfonyl)-1,2,3,4-tetrahydroquinoline (1 equivalent, 42 mg, 119 µmol) and 1 mL of water were added to the crude product, and the suspension was sonicated for 5 minutes, washed with nitrogen, heated to 100 °C, and stirred overnight. The solvent was then removed under reduced pressure, and the crude product was purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1% TFA). The product was lyophilized to obtain an amorphous white solid.

[0528] Yield: 37 mg (74%).

[0529] MS (ES+) [M+H) + m / e = 422.2.

[0530] 1 H NMR (300 MHz, DMSO-d6): δ 10.56 (s, 1H), 7.95 (d, J = 8.4 Hz, 1H),7.72 – 7.63 (m, 4H), 7.63 – 7.51 (m, 3H), 7.21 (dd, J = 8.5, 2.2 Hz, 1H), 7.10(d, J = 2.2 Hz, 1H), 3.85 – 3.77 (m, 2H), 2.49 – 2.46 (m, 2H), 2.37 (s, 3H), 2.09 (s, 3H), 1.68 – 1.57 (m, 2H).

[0531] 13C NMR (75 MHz, DMSO-d6): δ 169.33, 153.17, 150.34, 139.43, 138.96,135.45, 135.34, 133.44, 130.85, 130.33, 129.94, 129.54, 127.02, 126.77,123.30, 110.75, 46.34, 26.07, 23.89, 22.57, 21.00.

[0532] Example Compound 24: R N - (5-(4-methoxy-1-(phenylsulfonyl)-1,2,3,4-tetrahydroquinolin-6-​ 4-methylthiazolyl-2-yl)acetamide Step 1: ( R 6-Bromo-1-(phenylsulfonyl)-1,2,3,4-tetrahydroquinoline-4-ol

[0533] 6-bromo-1-(phenylsulfonyl)-2,3-dihydroquinoline-4(1 H )-ketone (25 mg, 68 µmol), [ N -[(1 R ,2 R )-2-(amino-κ) N )-1,2-diphenylethyl]-4-methylbenzenesulfonamide-κ N Ruthenium chloride [(1,2,3,4,5,6-η)-1-methyl-4-(1-methylethyl)benzene]-ruthenium (0.01 equivalents, 0.4 mg, 0.68 µmol) was dissolved in 0.5 mL of formic acid and 0.5 mL of triethylamine and stirred at room temperature for 72 hours. Afterward, the solvent was removed under reduced pressure, and the crude product was purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1% TFA). The product was lyophilized to obtain an amorphous white solid.

[0534] Yield: 22 mg (88%).

[0535] ee: >99%.

[0536] Following steps 2 and 3 of example compound 7, example 24 is obtained.

[0537] Example compound 25: 2-(3-isopropoxyazacyclobutane-1-yl)-4-methyl-5-(1-(phenylsulfonyl)- 1,2,3,4-Tetrahydroquinoline-6-yl)thiazole Step 1: 2-(3-Isopropoxyazacyclobutane-1-yl)-4-methylthiazole

[0538] 2-bromo-4-methylthiazole (113 mg, 635 µmol), 3-isopropoxyazacyclobutane hydrochloride (2 equivalents, 192 mg, 1.27 mmol) and N 1-Ethyl diisopropylamine (4 equivalents, 328 mg, 2.54 mmol, 0.442 mL) was dissolved in 2 mL of DMF, and the mixture was heated to 130 °C for 16 hours. The solvent was then removed under reduced pressure, and the crude product was purified by silica gel chromatography using a gradient of cyclohexane and EtOAc as eluents. The product was obtained as a yellow oil.

[0539] Yield: 53 mg (39%).

[0540] MS (ES+) [M+H) + m / e = 213.1.

[0541] 1 H NMR (300 MHz, CDCl3): δ 6.09 (q, J = 1.1 Hz, 1H), 4.55 – 4.44 (m,1H), 4.31 – 4.20 (m, 2H), 3.93 (ddd, J = 8.3, 4.9, 1.1 Hz, 2H), 3.62 (hept, J =6.2 Hz, 1H), 2.24 (d, J = 1.1 Hz, 3H), 1.15 (d, J = 6.1 Hz, 6H).

[0542] 13 C NMR (75 MHz, CDCl3): δ 171.34, 149.40, 102.45, 71.55, 67.18, 61.87, 22.51, 17.49.

[0543] Step 2: 2-(3-Isopropoxyazacyclobutane-1-yl)-4-methyl-5-(1-(phenylsulfonyl)-1,2,3,4-tetrahydroquinolin-6-yl)thiazole

[0544] 6-Bromo-1-(phenylsulfonyl)-1,2,3,4-tetrahydroquinoline (70 mg, 199 µmol), 2-(3-isopropoxyazacyclobutane-1-yl)-4-methylthiazole (1.2 equivalents, 50 mg, 238 µmol), tri-tert-butylphosphonium tetrafluoroborate (0.2 equivalents, 12 mg, 40 µmol), Pd(OAc)₂ (0.1 equivalents, 4.5 mg, 20 µmol), and Cs₂CO₃ (3 equivalents, 194 mg, 596 µmol) were suspended in 1 mL of DMF. The suspension was sonicated for 5 min, rinsed with nitrogen, heated to 110 °C, and stirred overnight. The solvent was then removed under reduced pressure, and the crude product was purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1% TFA). The lyophilized powder was poured into a separatory funnel containing DCM and a saturated aqueous solution of Na₂CO₃. The aqueous phase was extracted three times with DCM. The combined organic phases were then dried over Na₂SO₄ and concentrated under reduced pressure. The product was obtained as a white solid.

[0545] Yield: 26 mg (27%).

[0546] MS (ES+) [M+H) + m / e = 484.1.

[0547] 1 H NMR (300 MHz, CDCl3): δ 7.77 (d, J = 8.6 Hz, 1H), 7.67 – 7.60 (m,2H), 7.58 – 7.50 (m, 1H), 7.47 – 7.37 (m, 2H), 7.17 (dd, J = 8.6, 2.3 Hz, 1H), 6.98 (dd, J = 2.1, 1.1 Hz, 1H), 4.52 (tt, J = 6.5, 4.8 Hz, 1H), 4.37 – 4.21 (m,2H), 4.04 – 3.93 (m, 2H), 3.85 – 3.76 (m, 2H), 3.64 (hept, J = 6.1 Hz, 1H), 2.45 (t, J = 6.7 Hz, 2H), 2.33 (s, 3H), 1.69 – 1.57 (m, 2H), 1.17 (d, J = 6.1 Hz, 6H).

[0548] 13C NMR (75 MHz, CDCl3): δ 168.45, 143.72, 139.69, 135.58, 132.95,130.74, 129.45, 129.18 (2C), 127.17, 126.90, 124.95, 120.23, 71.65, 67.12,61.98, 46.69, 26.78, 22.52, 21.59, 16.28.

[0549] Example compound 26: 6-((4-methyl-5-(1-(phenylsulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)thiazole- 2-yl)amino)-6-oxoylide)tert-butyl carbamate Step 1: (6-((4-methylthiazo-2-yl)amino)-6-oxoylide)tert-butyl carbamate

[0550] 6-((tert-butoxycarbonyl)amino)hexanoic acid (120 mg, 519 µmol) and N 1-Ethyl diisopropylamine (3 equivalents, 202 mg, 1.55 mol) was dissolved in 2 mL of dry DMF. Subsequently, 1-[bis(dimethylamino)methylene]-1 H -1,2,3-triazolo[4,5- b Pyridinium 3-oxide hexafluorophosphate (1.2 equivalents, 240 mg, 623 µmol) was added to the mixture, and the suspension was stirred at room temperature for 30 minutes. Then, 4-methylthiazol-2-amine (1.2 equivalents, 71 mg, 623 µmol) was added to the solution. After 16 hours at room temperature, the solvent was removed under reduced pressure, and the crude product was then purified by silica gel chromatography using a gradient of cyclohexane and EtOAc as eluents. The product was obtained as a yellow oil.

[0551] Yield: 112 mg (66%).

[0552] MS (ES+) [M+H) + m / e = 328.4.

[0553] 1 H NMR (300 MHz, DMSO-d6): δ 11.96 (s, 1H), 6.77 (t, J = 5.7 Hz, 1H), 6.71 (d, J = 1.2 Hz, 1H), 2.88 (q, J = 6.6 Hz, 2H), 2.37 (t, J= 7.4 Hz, 2H), 2.24(d, J = 1.1 Hz, 3H), 1.56 (p, J = 7.5 Hz, 2H), 1.44 – 1.10 (m, 13H).

[0554] 13 C NMR (151 MHz, DMSO-d6): δ 171.01, 157.24, 155.54, 146.45, 107.33,77.26, 40.06, 34.84, 29.19, 28.23, 25.81, 24.43, 16.83.

[0555] Step 2: 6-((4-methyl-5-(1-(phenylsulfonyl)-1,2,3,4-tetrahydroquinolin-6-yl)thiazo-2-yl)amino)-6-oxoylide)tert-butyl carbamate

[0556] 6-Bromo-1-(phenylsulfonyl)-1,2,3,4-tetrahydroquinoline (60 mg, 169 µmol), (6-((4-methylthiazolyl-2-yl)amino)-6-oxoylidelhexyl)carbamate tert-butyl ester (1 equivalent, 55 mg, 169 µmol), tri-tert-butylphosphonium tetrafluoroborate (0.2 equivalent, 10 mg, 34 µmol), Pd(OAc)₂ (0.1 equivalent, 3.8 mg, 17 µmol), and Cs₂CO₃ (3 equivalent, 166 mg, 507 µmol) were suspended in 1 mL of DMF. The suspension was sonicated for 5 min, washed with nitrogen, heated to 110 °C, and stirred overnight. The solvent was then removed under reduced pressure, and the crude product was purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1% TFA). The product was lyophilized to obtain an amorphous white solid.

[0557] Yield: 29 mg (30%).

[0558] MS (ES+) [M+H) + m / e = 599.1.

[0559] 1 H NMR (300 MHz, DMSO-d6): δ 12.06 (s, 1H), 7.73 – 7.63 (m, 4H), 7.62– 7.53 (m, 2H), 7.28 (dd, J= 8.6, 2.3 Hz, 1H), 7.15 (d, J = 2.2 Hz, 1H), 6.84 –6.72 (m, 1H), 3.84 – 3.74 (m, 2H), 2.89 (q, J = 6.4 Hz, 2H), 2.40 (t, J = 7.3 Hz, 2H), 2.32 (s, 3H), 1.65 – 1.52 (m, 4H), 1.46 – 1.18 (m, 14H).

[0560] 13 C NMR (151 MHz, DMSO-d6): δ 171.17, 155.55, 154.89, 141.85, 138.90,135.31, 133.40, 130.73, 129.51, 129.15, 128.42, 126.72, 126.29, 123.70,123.12, 77.27, 46.25, 40.06, 34.84, 29.19, 28.24, 26.00, 25.80, 24.45, 20.93,16.05.

[0561] Example compound 27: (2-(2-(2-((4-methyl-5-(1-(phenylsulfonyl)-1,2,3,4-tetrahydroquinoline-6- 2-(2-)thiazolyl)amino)-2-oxo-2-oxyethoxy)ethoxy)ethyl)tert-butyl carbamate Step 1: (2-(2-(2-(((4-methylthiazo-2-yl)amino)-2-oxo-ethylene)ethoxy)ethyl)tert-butyl carbamate

[0562] 150 mg (337 µmol) of 2,2-dimethyl-4-oxoylide-3,8,11-trioxa-5-azatridecane-13-acid dicyclohexylamine salt was dissolved in 2 mL of dry DMF. Subsequently, 1-[bis(dimethylamino)methylene]-1 H -1,2,3-triazolo[4,5- b Pyridinium 3-oxide hexafluorophosphate (1.2 equivalents, 46 mg, 405 µmol) was added to the mixture, and the suspension was stirred at room temperature for 30 minutes. Then, 4-methylthiazol-2-amine (1.2 equivalents, 156 mg, 405 µmol) was added to the solution. After 16 hours at room temperature, the solvent was removed under reduced pressure, and the crude product was then purified by silica gel chromatography using a gradient of cyclohexane and EtOAc as eluents. The product was obtained as a yellow oil.

[0563] Yield: 60 mg (50%).

[0564] MS (ES+) [M+H) + m / e = 360.4.

[0565] 1 H NMR (300 MHz, DMSO-d6): δ 11.59 (s, 1H), 6.95 – 6.87 (m, 1H), 6.79(d, J = 1.3 Hz, 1H), 4.20 (s, 2H), 3.65 (dd, J = 5.8, 3.0 Hz, 2H), 3.56 (dd, J =5.7, 3.0 Hz, 2H), 3.46 – 3.38 (m, 2H), 3.12 (q, J = 5.9 Hz, 2H), 2.26 (d, J = 1.0Hz, 3H), 1.36 (s, 9H).

[0566] 13 C NMR (151 MHz, DMSO-d6): δ 162.27, 156.63, 155.55, 146.61, 107.92,77.57, 70.46, 69.46, 69.36, 69.16, 52.22, 38.22, 28.18.

[0567] Step 2: (2-(2-(2-((4-methyl-5-(1-(phenylsulfonyl)-1,2,3,4-tetrahydroquinolin-6-yl)thiazolyl-2-yl)amino)-2-oxo-ethylene)ethoxy)ethyl)tert-butyl carbamate)

[0568] 6-Bromo-1-(phenylsulfonyl)-1,2,3,4-tetrahydroquinoline (60 mg, 169 µmol), (2-(2-(2-((4-methylthiazol-2-yl)amino)-2-oxylideneethoxy)ethoxy)ethyl)carbamate tert-butyl ester (60 mg, 169 µmol), tri-tert-butylphosphonium tetrafluoroborate (0.2 equivalents, 10 mg, 34 µmol), Pd(OAc)₂ (0.1 equivalents, 3.8 mg, 17 µmol), and Cs₂CO₃ (3 equivalents, 166 mg, 507 µmol) were suspended in 1 mL of DMF. The suspension was sonicated for 5 min, washed with nitrogen, heated to 110 °C, and stirred overnight. The solvent was then removed under reduced pressure, and the crude product was purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1% TFA). The product obtained after freeze-drying is an amorphous white solid.

[0569] Yield: 50 mg (47%).

[0570] MS (ES+) [M+H) + m / e = 631.1.

[0571] 1 H NMR (300 MHz, DMSO-d6): δ 11.73 (s, 1H), 7.74 – 7.63 (m, 4H), 7.61– 7.53 (m, 2H), 7.30 (dd, J = 8.6, 2.3 Hz, 1H), 7.17 (d, J = 2.2 Hz, 1H), 6.88(t, J = 5.6 Hz, 1H), 3.84 – 3.77 (m, 2H), 3.66 (dd, J = 5.9, 3.0 Hz, 2H), 3.57(dd, J = 5.7, 3.0 Hz, 2H), 3.43 (t, J = 5.9 Hz, 2H), 3.12 (q, J = 5.8 Hz, 2H), 2.55– 2.51 (m, 2H), 2.34 (s, 3H), 1.66 – 1.54 (m, 2H), 1.36 (s, 9H).

[0572] 13C NMR (151 MHz, DMSO-d6): δ 168.61, 155.55, 154.27, 141.96, 138.89,135.46, 133.41, 130.78, 129.53, 129.21, 128.15, 126.73, 126.35, 123.71,123.65, 77.59, 70.49, 69.42, 69.37, 69.19, 46.26, 40.06, 28.19, 26.01, 20.93,15.95.

[0573] Example compound 28: N -(5-(4-acetyl-1-(phenylsulfonyl)-1,2,3,4-tetrahydroquinoxalin-6-yl)- 4-Methylthiazo-2-yl)acetamide Step 1: 7-Bromo-4-(phenylsulfonyl)-3,4-dihydroquinoxaline-2(1 H )-ketone

[0574] 7-bromo-3,4-dihydroquinoxaline-2(1 H )-ketone (250 mg, 1.10 mmol) was dissolved in 3 mL of pyridine. Subsequently, benzenesulfonyl chloride (1.1 equivalent, 213 mg, 1.21 mmol, 0.155 mL) was added to the mixture. The reaction mixture was stirred at room temperature for three hours. The solvent was then removed under reduced pressure, and the crude product was purified by silica gel chromatography using a gradient of cyclohexane and EtOAc as eluents. The product was obtained as a yellow oil.

[0575] Yield: 372 mg (92%).

[0576] MS (ES+) [M+H) + m / e = 367.0, 369.0 (bromine isotope mode).

[0577] 1 H NMR (300 MHz, CDCl3): δ 7.65 (s, 1H), 7.62 (d, J = 8.6 Hz, 1H), 7.57– 7.46 (m, 3H), 7.43 – 7.35 (m, 2H), 7.31 – 7.26 (m, 1H), 6.81 (d, J = 2.1 Hz, 1H), 4.35 (s, 2H).

[0578] 13C NMR (75 MHz, CDCl3): δ 165.58, 136.84, 133.88, 133.30, 129.36, 129.33, 127.16, 127.15, 123.66, 121.67, 118.94, 49.18.

[0579] Step 2: 6-Bromo-1-(phenylsulfonyl)-1,2,3,4-tetrahydroquinoxaline

[0580] 7-bromo-4-(phenylsulfonyl)-3,4-dihydroquinoxaline-2(1 H The ketone (156 mg, 424 µmol) was dissolved in 2 mL of dry THF and brought to 0 °C. Subsequently, 2 M LiAlH4 solution (3 equivalents, 48 ​​mg, 1.27 mmol, 0.673 mL) was added dropwise to the solution, and the reaction mixture was maintained at 0 °C for one hour. After completion, the reaction mixture was quenched with an aqueous solution of Na2CO3, and the crude product was then poured into a separatory funnel containing DCM and water. The aqueous phase was extracted three times with DCM. The combined organic phases were then dried over Na2SO4 and concentrated under reduced pressure.

[0581] Yield: 127 mg (84%).

[0582] MS (ES+) [M+H) + m / e = 353.0, 355.0 (bromine isotope mode).

[0583] 1 H NMR (300 MHz, CDCl3): δ 7.65 – 7.46 (m, 4H), 7.41 (t, J = 7.7 Hz, 2H), 6.76 (dd, J = 8.7, 2.2 Hz, 1H), 6.59 (d, J = 2.2 Hz, 1H), 3.72 (t, J = 5.2 Hz,2H), 3.35 (s, 1H), 2.84 (t, J = 5.2 Hz, 2H).

[0584] 13C NMR (75 MHz, CDCl3): δ 139.21, 139.01, 133.15, 129.27, 127.66, 127.24, 120.46, 119.92, 119.73, 116.97, 43.43, 38.50.

[0585] Step 3: 1-(7-bromo-4-(phenylsulfonyl)-3,4-dihydroquinoxaline-1(2 H )-yl)ethane-1-one

[0586] 6-Bromo-1-(phenylsulfonyl)-1,2,3,4-tetrahydroquinoxaline (41 mg, 116 µmol) was dissolved in 1 mL of dry acetone. Acetyl chloride (1.1 equivalent, 12 mg, 127 µmol) and triethylamine (2 equivalent, 23 mg, 232 µmol) were then added to the mixture. The reaction mixture was stirred at room temperature for one hour. After the reaction was complete, the crude product was poured into a separatory funnel containing DCM and water. The aqueous phase was extracted three times with DCM. The combined organic phases were then dried over Na₂SO₄ and concentrated under reduced pressure. The crude product was then purified by silica gel chromatography using a gradient of cyclohexane and EtOAc as eluents. The product was obtained as a yellow oil.

[0587] Yield: 34 mg (74%).

[0588] MS (ES+) [M+Na) + m / e = 416.9, 418.9 (bromine isotope mode).

[0589] 1 H NMR (300 MHz, CDCl3): δ 7.75 (d, J = 8.8 Hz, 1H), 7.60 – 7.50 (m,3H), 7.50 – 7.40 (m, 2H), 7.37 (dd, J = 8.8, 2.2 Hz, 1H), 7.29 – 7.18 (m, 1H), 3.90 (t, J = 6.1 Hz, 2H), 3.73 (t, J = 6.3 Hz, 2H), 1.66 (s, 3H).

[0590] 13C NMR (75 MHz, CDCl3): δ 168.40, 137.88, 136.05, 133.55, 130.69,129.55, 129.41, 127.91, 127.57, 127.09, 119.16, 48.07, 43.67, 22.01.

[0591] Step 4: N -(5-(4-acetyl-1-(phenylsulfonyl)-1,2,3,4-tetrahydroquinoxalin-6-yl)-4-methylthiazolyl-2-yl)acetamide

[0592] 1-(7-bromo-4-(phenylsulfonyl)-3,4-dihydroquinoxaline-1(2 H )-yl)ethane-1-one (34 mg, 86 µmol), N 1,4-(4-methylthiazolyl-2-yl)acetamide (1.2 equivalents, 16 mg, 103 µmol), tri-tert-butylphosphonium tetrafluoroborate (0.2 equivalents, 5 mg, 17 µmol), Pd(OAc)₂ (0.1 equivalents, 1.9 mg, 8.6 µmol), and Cs₂CO₃ (3 equivalents, 84 mg, 258 µmol) were suspended in 1 mL of DMF. The suspension was sonicated for 5 min, rinsed with nitrogen, heated to 110 °C, and stirred overnight. The solvent was then removed under reduced pressure, and the crude product was purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1% TFA). The product was lyophilized to obtain an amorphous white solid.

[0593] Yield: 20 mg (49%).

[0594] MS (ES+) [M+H) + m / e = 471.1.

[0595] 1 H NMR (300 MHz, DMSO-d6): δ 12.14 (s, 1H), 7.74 – 7.47 (m, 7H), 7.32(dd, J = 8.4, 2.1 Hz, 1H), 3.90 (t, J = 6.2 Hz, 2H), 3.67 (t, J = 6.2 Hz, 2H), 2.34(s, 3H), 2.14 (s, 3H), 1.74 (s, 3H).

[0596] 13 C NMR (75 MHz, DMSO-d6): δ 168.43, 168.13, 158.56, 158.07, 155.33,148.95, 142.60, 137.64, 133.74, 129.58, 126.74, 125.71, 125.67, 124.64,122.77, 47.59, 28.61, 22.46, 22.12, 16.09.

[0597] Example compound 29: N -(4-Methyl-5-(4-methyl-3-oxoylide-1-(phenylsulfonyl)-1,2,3,4-tetrahydro Quinoxalo-6-yl)thiazo-2-yl)acetamide Step 1: 7-Bromo-1-methyl-4-(phenylsulfonyl)-3,4-dihydroquinoxaline-2(1 H )-ketone

[0598] 7-bromo-4-(phenylsulfonyl)-3,4-dihydroquinoxal...

Claims

1. A compound according to Formula 1 for use in treating medical conditions associated with defective and / or pathological class II phosphoinositol 3-kinase (PI3K) signaling. Formula 1 in n is 1 or 2. A is a 5- or 6-membered heteroaryl group and -N (R4R5) is attached to the C atom adjacent to the N atom of ring A. R1 is C, S, O, or N. R2 is C or N. R3 is H, C1 to C5 alkyl (preferably C1 to C3 alkyl), C3 to C6 cycloalkyl, C1 to C5 haloalkyl (preferably C1 to C3 haloalkyl, including Cl, Br or F), -CN, carbonyl, carboxyl, carboxylic acid ester, alkoxy, aldehyde, primary amine, secondary or tertiary amine, amide, imide, carbamate, formamide, nitro, sulfide, sulfinyl, sulfonyl, sulfinyl or sulfonamide R4 and R5 may be the same or different, and are H, C1 to C5 alkyl (preferably C1 to C3 alkyl), C2 to C5 alkenyl, C3 to C6 cycloalkyl, C3 to C6 heterocycloalkyl (preferably including N, S and / or O), C1 to C5 haloalkyl (preferably C1 to C3 haloalkyl, preferably including Cl, Br or F), C4 to C6 aryl, sulfide, sulfinyl, sulfonyl, sulfinyl, sulfonamide, carboxyl, carboxylic acid ester, carbonyl C=OR, wherein R is C1 to C10 alkyl (preferably C1 to C5 alkyl), C1 to C3 haloalkyl (preferably including Cl, Br or F), C4 to C6 aryl, wherein R is optionally substituted with a urethane group or urethane. Alternatively, R4 and R5 form a 4, 5, or 6-membered heterocyclic alkyl group comprising N and optionally one or more additional heteroatoms (preferably N, O, and / or S), wherein the heterocyclic alkyl group is optionally substituted with an alkoxy group. R6 is absent, or R1 is C and R6 forms a carbonyl group (C=O) with R1, or R1 is S and R6 forms a sulfoxide group (S=O) with R1. Whether R7, R8, and R9 are the same or different, they are C or N. R10 is H, C1 to C5 alkyl (preferably C1 to C3 alkyl), C3 to C6 cycloalkyl, C1 to C5 haloalkyl (preferably C1 to C3 haloalkyl, including Cl, Br or F), -CN, carbonyl, carboxyl, carboxylic acid ester, alkoxy, aldehyde, primary amine, secondary or tertiary amine, amide, imide, carbamate, formamide, nitro, sulfide, sulfinyl, sulfonyl, sulfinyl or sulfonamide R11 is H, C3 to C6 cycloalkyl, C4 to C6 heterocycloalkyl (preferably including N, S and / or O), halogen (preferably F, Cl or Br), sulfide, sulfinyl, sulfonyl, sulfinyl, sulfonamide, carboxyl, carboxylic acid ester, formamide, alkoxy or aryloxy. Alternatively, R10 and R11, together with the atoms they are attached to, form a 5- to 8-membered cycloalkyl or aryl ring structure D comprising two carbon atoms of B, forming a fused bicyclic group with B, optionally comprising one or more heteroatoms (preferably N, O, and / or S). R14 is H, C1 to C5 alkyl (preferably C1 to C3 alkyl), primary amine, secondary amine, tertiary amine, or alkylamine. Alternatively, R11 and R14, together with the atoms they are attached to, form a 5- to 8-membered cycloalkyl or aryl ring structure C comprising two carbon atoms of B, forming a fused cyclic group with B, optionally including one or more heteroatoms (preferably N, O, and / or S). R12 is a C1 to C5 alkyl group (preferably C1 to C3 alkyl group), carbonyl C=O group, sulfide, sulfinyl group, or sulfonyl group. R13 is a C1 to C5 alkyl (preferably C1 to C3 alkyl), C2 to C5 alkenyl, C3 to C6 cycloalkyl, C5 or C6 aryl, alkylaryl, C5 or C6 heteroaryl (preferably including N, S and / or O), bicyclic group (preferably including one or two aromatic rings), optionally including one or more heteroatoms (preferably N, O and / or S). Alternatively, R11 may be hydrogen or a halogen, or may not form a ring structure with R10 or R14, or R11 and R14 may form a 5- to 8-membered cycloalkyl or aryl ring structure with the atoms they are attached to, and R15 and R16 may be present, in which case R12 and R13 may not be present. R15 is a C1 to C5 alkyl group (preferably C1 to C3 alkyl group), carbonyl group (C=O), sulfide, sulfinyl group, or sulfonyl group. R16 is a C1 to C5 alkyl (preferably C1 to C3 alkyl), C2 to C5 alkenyl, C3 to C6 cycloalkyl, C5 or C6 aryl, alkylaryl, C5 or C6 heteroaryl (preferably including N, S and / or O), bicyclic group (preferably including one or two aromatic rings), optionally including one or more heteroatoms (preferably N, O and / or S). Alternatively, R15 and R16 may not exist when R14 is H, or when R11 and R10 together with the atoms to which they are attached form a 5- to 8-membered cycloalkyl or aryl ring structure D, or when R11 and R14 together with the atoms to which they are attached form a 5- to 8-membered cycloalkyl or aryl ring structure C and R12 and R13 are present.

2. The compound for the use according to claim 1, according to formula 1 Formula 1 in n is 1 or 2. A is a 5- or 6-membered heteroaryl group and -N (R4R5) is attached to the C atom adjacent to the N atom of ring A. R1 is C, S, O, or N, and R2 is C or N. R3 is H, C1 to C3 alkyl, C3 to C6 cycloalkyl, or CX3, where X is Cl, Br, or F. R4 and R5 may be the same or different, and are H, C1 to C3 alkyl, C2 to C5 alkenyl, C3 to C6 cycloalkyl, C3 to C6 heterocycloalkyl (preferably including N, S and / or O), C1 to C3 haloalkyl (preferably including Cl, Br or F), C4 to C6 aryl, sulfonyl or one of the following: Alternatively, R4 and R5, together with the atoms they are attached to, form a 4, 5, or 6-membered heterocyclic alkyl group comprising N and optionally one or more additional heteroatoms (preferably N, O, and / or S), wherein the heterocyclic alkyl group is optionally substituted with an alkoxy group, such as... R6 is absent, or R1 is C and R6 forms a carbonyl group (C=O) with R1, or R1 is S and R6 forms a sulfoxide group (S=O) with R1. Whether R7, R8, and R9 are the same or different, they are C or N. R10 is H or a C1 to C3 alkyl group. R11 is H, C3 to C6 cycloalkyl, C4 to C6 heterocycloalkyl (preferably including N, S and / or O), halogen (preferably F, Cl or Br), sulfide, sulfinyl, sulfonyl, carboxylic acid ester, formamide or alkoxy-CH2OR, wherein R is C1 to C3 alkyl or benzyl. Alternatively, R10 and R11, together with the atoms they are attached to, form a 5- to 7-membered cycloalkyl or aryl ring structure D comprising two carbon atoms of B, forming a fused bicyclic group with B, optionally comprising one or more heteroatoms (preferably N, O, and / or S). R14 is H, a C1 to C3 alkyl group, a secondary or tertiary amine, or an alkylamine; or R11 and R14 together with the atoms to which they are attached form a 5 to 7-membered cycloalkyl or aryl ring structure C including two carbon atoms of B, forming a fused cyclic group with B, optionally including one or more heteroatoms (preferably N, O, and / or S). R12 is a C1 to C3 alkyl, carbonyl C=O, or sulfonyl group. R13 is a C1 to C3 alkyl, C2 to C5 alkenyl, C3 to C6 cycloalkyl, C5 or C6 aryl, benzyl, C5 or C6 heteroaryl (preferably including N, S and / or O), bicyclic group (preferably including one or two aromatic rings), optionally including one or more heteroatoms (preferably N, O and / or S). Alternatively, R11 may be hydrogen or a halogen, or may not form a ring structure with R10 or R14, or R11 and R14 may form a 5- to 7-membered cycloalkyl or aryl ring structure with the atoms they are attached to, and R15 and R16 may be present, in which case R12 and R13 may not be present. R15 is a C1 to C3 alkyl, carbonyl C=O, or sulfonyl group. R16 is a C1 to C3 alkyl, C2 to C5 alkenyl, C3 to C6 cycloalkyl, C5 or C6 aryl, benzyl, C5 or C6 heteroaryl (preferably including N, S and / or O), bicyclic group (preferably including one or two aromatic rings), optionally including one or more heteroatoms (preferably N, O and / or S). Alternatively, R15 and R16 may not exist when R14 is H, or when R10 and R11 together with the atoms to which they are attached form a 5- to 7-membered cycloalkyl or aryl ring structure D, or when R11 and R14 together with the atoms to which they are attached form a 5- to 7-membered cycloalkyl or aryl ring structure C and R12 and R13 are present.

3. The compound for use according to any one of the preceding claims, according to Formula 2 Formula 2 in R1 to R16 are as described in claim 1.

4. The compound for use according to any one of the preceding claims, wherein, R11 and R14, together with the atoms they are attached to, form a 5- to 7-membered ring or aryl ring structure C, which forms a fused bicyclic group with B, wherein B and C are one of the following: And among them R7, R8, R9, R12, R13, R15, and R16 are as described in claim 1. X and Y may be the same or different, and are C, N, S, and / or O. R17 can be the same or different, and can be absent (electron pair of X), H, hydroxyl, halogen (preferably F, Cl, or Br), alkoxy, C1 to C5 alkyl (preferably C1 to C3 alkyl), C1 to C5 haloalkyl (preferably C1 to C3 haloalkyl, including Cl, Br, or F), C3 to C6 cycloalkyl, C3 to C6 heterocycloalkyl (preferably including N, O, and / or S and optionally substituted with alkoxy), C4 to C6 aryl, carbonyl C(=O)R, where R is a C1 to C5 alkyl. (Preferably C1 to C3 alkyl), carboxyl, carboxylic acid ester, alkoxy (preferably -OCH3, -OCH2CH3 or C3 to C6 cycloalkylalkoxy), aldehyde, primary amine, secondary or tertiary amine, amide, imide, carbamate, formamide, nitro, sulfide (preferably -SCH3, -SCH2CH3), sulfinyl, sulfonyl, sulfinyl or sulfonamide, or when X is C, forming a carbonyl C=O with X, or when X is S, forming a sulfoxide S=O or a sulfonyl S(=O)2 with X. Alternatively, two R17 atoms may form a 4, 5, or 6-membered cycloalkyl group, optionally including one or more heteroatoms (preferably N, O, and / or S). R18 can be the same or different, and can be H, alkoxy, or one R18 can form a carbonyl group (C=O) with the attached C atom. Alternatively, an R17 and an R18 form a 5- or 6-membered cyclic ring structure comprising two carbon atoms of C, forming a fused cyclic group with C, optionally including one or more heteroatoms (preferably N, O, and / or S), wherein the 5- or 6-membered cyclic ring structure is optionally substituted with a C1 to C3 alkyl or alkoxy carbonyl group (preferably at the heteroatom position), and R19 can be the same or different, and is H, C1 to C6 alkyl (preferably C1 to C3 alkyl).

5. The compound for use according to any one of the preceding claims, wherein, R10 and R11, together with the atoms they are attached to, form a 5- to 7-membered ring or aryl ring structure D, which forms a fused bicyclic group with B, wherein B and D are And R7, R8, R9, R12 and R13 are as described in claim 1.

6. The compound for use according to any one of the preceding claims, wherein, R16 is one of the following: in R20 may be the same or different, and is H, C1 to C5 alkyl (preferably C1 to C3 alkyl), halogen (preferably F, Cl and / or Br), alkoxy or E, wherein E is one of the following: R21 can be the same or different, and is H, C1 to C5 alkyl (preferably C1 to C3 alkyl), halogen (preferably F, Cl and / or Br), alkoxy, primary amine, secondary or tertiary amine, sulfide, sulfinyl, sulfonyl, sulfinyl, sulfonamide, carboxyl, carboxylic acid ester, secondary hydroxyl group C(-OH)CH3, carbonyl C=OR (wherein R is C1 to C10 alkyl (preferably C1 to C5 alkyl), C1 to C3 haloalkyl (preferably including Cl, Br or F)), imide, urethane group, formamide, amide N=OR (wherein R is C1 to C3 alkyl, C1 to C3 alkenyl, C1 to C3 haloalkyl (preferably including Cl, Br or F)), nitro or E, R22 can be the same or different, and is H or a C1 to C5 alkyl group (preferably a C1 to C3 alkyl group). R23 is an H, carbonyl, carboxyl, or carboxylic acid ester. R24 is H or a C1 to C5 alkyl group (preferably a C1 to C3 alkyl group), and R25 can be the same or different, and can be H, C1 to C4 alkyl, C1 to C4 heteroalkyl, C3 to C6 cycloalkyl, or C2 to C6 heterocycloalkyl.

7. The compound for use according to any one of the preceding claims, according to Formula 5 Formula 5 in R1 to R10, R15 and R16 are as described in claim 1, and R17 to R19 are as described in claim 4.

8. The compound for use according to any one of the preceding claims, according to formula 6 Formula 6 in R1 to R10 and R16 are as described in claim 1, and R17 to R19 are as described in claim 4.

9. The compound for use according to any one of the preceding claims, selected from the group consisting of: N -(4-Methyl-5-(1-(phenylsulfonyl)-1 H -indol-5-yl)thiazo-2-yl)acetamide, N -(4-methyl-5-(1-(phenylsulfonyl)-1,2,3,4-tetrahydroquinolin-6-yl)thiazolyl-2-yl)acetamide, N -(4-methyl-5-(1-(phenylsulfonyl)indololin-5-yl)thiazo-2-yl)acetamide, N -(4-Methyl-5-(4-(phenylsulfonyl)-3,4-dihydro-2 H -benzo[ b [1,4]oxazin-7-yl)thiazo-2-yl)acetamide, N -(5-(1-(phenylsulfonyl)-2,3,4,5-tetrahydro-1 H -benzo[ b [Azacycloheptan-7-yl)thiazo-2-yl)acetamide, N -(4-methyl-5-(5-(phenylsulfonyl)-5,6,7,8-tetrahydronaphthyl-2-yl)thiazolyl)acetamide, N -(5-(4-methoxy-1-(phenylsulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)-4-methylthiazolyl-2-yl)acetamide, N -(4-Methyl-5-(4-(phenylsulfonyl)-3,4-dihydro-2 H -benzo[ b [1,4]thiazin-7-yl)thiazolyl)acetamide, N -(4-Methyl-5-(1-O-4-(phenylsulfonyl)-3,4-dihydro-2- H -benzo[ b [1,4]thiazin-7-yl)thiazolyl)acetamide, N -(5-(1,1-dioxide-4-(phenylsulfonyl)-3,4-dihydro-2 H -benzo[ b [1,4]thiazin-7-yl)-4-methylthiazol-2-yl)acetamide, N -(4-methyl-5-(8-(phenylsulfonyl)-5,6,7,8-tetrahydro-1,8-naphthidin-3-yl)thiazolyl)acetamide, N -(4-methyl-5-(4-oxoylidene-1-(phenylsulfonyl)-1,2,3,4-tetrahydroquinolin-6-yl)thiazolyl-2-yl)acetamide, N -(5-(4-hydroxy-1-(phenylsulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)-4-methylthiazolyl-2-yl)acetamide, N -(4-methyl-5-(2-methyl-1-(phenylsulfonyl)-1,2,3,4-tetrahydroquinolin-6-yl)thiazolyl-2-yl)acetamide, N -(5-(1-(phenylsulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)thiazolyl-2-yl)acetamide, N -(4-methyl-5-(5-(phenylsulfonyl)-5,6,7,8-tetrahydro-1,5-naphthidin-2-yl)thiazolyl)acetamide, N -(4-methyl-5-(1-(phenylsulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)oxazol-2-yl)acetamide, N -(4-methyl-5-(5-(phenylsulfonyl)-2,3,3a,4,5,9b-hexahydrofurano[3,2- c Quinoline-8-yl)thiazolyl)acetamide, ( R )- N -(5-(4-methoxy-1-(phenylsulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)-4-methylthiazolyl-2-yl)acetamide, 6-((4-methyl-5-(1-(phenylsulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)thiazolyl-2-yl)amino)-6-oxoylidelhexyl)carbamate tert-butyl carbamate, N -(5-(4-acetyl-1-(phenylsulfonyl)-1,2,3,4-tetrahydroquinoxalin-6-yl)-4-methylthiazolyl-2-yl)acetamide, N -(4-methyl-5-(4-methyl-3-oxoylide-1-(phenylsulfonyl)-1,2,3,4-tetrahydroquinoxalin-6-yl)thiazolyl-2-yl)acetamide, N -(5-(3-methoxy-1-(phenylsulfonyl)-1,2,3,4-tetrahydroquinolin-6-yl)-4-methylthiazolyl-2-yl)acetamide, N -(5-(4-methoxy-4-methyl-1-(phenylsulfonyl)-1,2,3,4-tetrahydroquinolin-6-yl)-4-methylthiazolyl-2-yl)acetamide, N -(4-methyl-5-(4-morpholino-1-(phenylsulfonyl)-1,2,3,4-tetrahydroquinolino-6-yl)thiazolyl)acetamide, N -(4-Methyl-5-(6-(phenylsulfonyl)-3,4,4a,5,6,10b-hexahydro-2 H -pyrano[3,2- c Quinoline-9-yl)thiazolyl-2-yl)acetamide, N -(4-methyl-5-(1-(o-tolylsulfonyl)-1,2,3,4-tetrahydroquinolin-6-yl)thiazolyl-2-yl)acetamide, N -(4-methyl-5-(1-(naphthyl-1-ylsulfonyl)-1,2,3,4-tetrahydroquinolin-6-yl)thiazolyl-2-yl)acetamide, N -(5-(1-(cyclohexylsulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)-4-methylthiazoline-2-yl)acetamide, N -(4-methyl-5-(1-(pyridin-3-ylsulfonyl)-1,2,3,4-tetrahydroquinolin-6-yl)thiazolyl-2-yl)acetamide, N -(4-methyl-5-(1-(methylsulfonyl)-1,2,3,4-tetrahydroquinolin-6-yl)thiazo-2-yl)acetamide, N -(4-methyl-5-(1-(thiophene-2-ylsulfonyl)-1,2,3,4-tetrahydroquinolin-6-yl)thiazolyl)acetamide, N -(5-(1-((4-fluorophenyl)sulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)-4-methylthiazoline-2-yl)acetamide, N -(5-(1-((2,4-dichlorophenyl)sulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)-4-methylthiazoline-2-yl)acetamide, N -(4-methyl-5-(1-(naphthyl-2-ylsulfonyl)-1,2,3,4-tetrahydroquinolin-6-yl)thiazolyl-2-yl)acetamide, ( S )- N -(5-(4-methoxy-1-(phenylsulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)-4-methylthiazolyl-2-yl)acetamide, N -(4-methyl-5-(1-toluenesulfonyl-1,2,3,4-tetrahydroquinolin-6-yl)thiazolyl-2-yl)acetamide, N -(5-(1-((2,3-dichlorophenyl)sulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)-4-methylthiazoline-2-yl)acetamide, N -(5-(1-(benzylsulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)-4-methylthiazoline-2-yl)acetamide, N -(5-(1-((2,3-dihydrobenzofuran-5-yl)sulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)-4-methylthiazoline-2-yl)acetamide, (4-methyl-5-(1-(phenylsulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)thiazoline-2-yl)tert-butyl carbamate, 4-methyl-5-(1-(phenylsulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)thiazoline-2-amine, N -(4-ethyl-5-(1-(phenylsulfonyl)-1,2,3,4-tetrahydroquinolin-6-yl)thiazolyl-2-yl)acetamide, N -(5-(1-(cyclopropylsulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)-4-methylthiazoline-2-yl)acetamide, N -(5-(2,2-dimethyl-1-(phenylsulfonyl)-1,2,3,4-tetrahydroquinolin-6-yl)-4-methylthiazolyl-2-yl)acetamide, N -(4-Methyl-5-(1'-(phenylsulfonyl)-2',3'-dihydro-1' H -spiro[oxetane-3,4'-quinoline]-6'-yl)thiazo-2-yl)acetamide, N -(5-(1-((3-methoxyphenyl)sulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)-4-methylthiazoline-2-yl)acetamide, N -(4-methyl-5-(5-methyl-1-(phenylsulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)thiazoline-2-yl)acetamide, 5-methyl-4-(1-(phenylsulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)- N -(2,2,2-trifluoroethyl)thiazole-2-amine N -(5-(4,4-difluoro-1-(phenylsulfonyl)-1,2,3,4-tetrahydroquinolin-6-yl)-4-methylthiazo-2-yl)acetamide, N -(5-(1-(allylsulfonyl)-1,2,3,4-tetrahydroquinolin-6-yl)-4-methylthiazo-2-yl)acetamide, N -Allyl-5-methyl-4-(1-(phenylsulfonyl)-1,2,3,4-tetrahydroquinolin-6-yl)thiazolyl-2-amine N 5-Dimethyl-4-(1-(phenylsulfonyl)-1,2,3,4-tetrahydroquinolin-6-yl)thiazolyl-2-amine N -(5-(1-((3-bromophenyl)sulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)-4-methylthiazoline-2-yl)acetamide, 3-((6-(2-acetamido-4-methylthiazoline-5-yl)-3,4-dihydroquinoline-1(2 H )-yl)sulfonyl)benzenesulfonyl fluoride, N -(5-(1-((3-acetylphenyl)sulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)-4-methylthiazoline-2-yl)acetamide, N -(5-(1-((3-(2-bromoacetyl)phenyl)sulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)-4-methylthiazolyl-2-yl)acetamide, 2,2,2-trifluoro- N -(4-methyl-5-(1-(phenylsulfonyl)-1,2,3,4-tetrahydroquinolin-6-yl)thiazolyl-2-yl)acetamide, N -(5-(1-((3-(1-hydroxyethyl)phenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-6-yl)-4-methylthiazolyl-2-yl)acetamide, 4-methyl- N -Phenyl-5-(1-(phenylsulfonyl)-1,2,3,4-tetrahydroquinolin-6-yl)thiazolyl-2-amine, N -(5-(1-((3-aminophenyl)sulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)-4-methylthiazoline-2-yl)acetamide, N -(3-((6-(2-acetamido-4-methylthiazo-5-yl)-3,4-dihydroquinoline-1(2 H )-yl)sulfonyl)phenyl)acetamide, N- (5-(1-((3-(dimethylamino)phenyl)sulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)-4-methylthiazoline-2-yl)acetamide, N -(5-(1-((2-chlorophenyl)sulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)-4-methylthiazoline-2-yl)acetamide, N -(5-(1-((3,4-dimethoxyphenyl)sulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)-4-methylthiazoline-2-yl)acetamide, N -(5-(1-((2,3-dimethoxyphenyl)sulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)-4-methylthiazoline-2-yl)acetamide, 3-((6-(2-acetamido-4-methylthiazoline-5-yl)-3,4-dihydroquinoline-1(2 H methyl 2-carboxylic acid sulfonyl thiophene N -(4-methyl-5-(1-((3-nitrophenyl)sulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)thiazolyl-2-yl)acetamide, N -(4-methyl-5-(1-((2-oxo-2,3-dihydrobenzo[] d [Oxazol-7-yl)sulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)thiazolyl)acetamide, N -(4-Methyl-5-(1-((3-oxo-3,4-dihydro-2-) H -benzo[ b [1,4]oxazin-7-yl)sulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)thiazolyl)acetamide, N -(5-(1-((2,5-difluorophenyl)sulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)-4-methylthiazoline-2-yl)acetamide, 3-((6-(2-acetamido-4-methylthiazoline-5-yl)-3,4-dihydroquinoline-1(2 H methyl benzoate (-yl)sulfonyl)benzoate N -(5-(1-((5-chloro-2-fluorophenyl)sulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)-4-methylthiazoline-2-yl)acetamide, N -(5-(1-((2-chloro-5-fluorophenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-6-yl)-4-methylthiazolyl-2-yl)acetamide, N -(5-(1-(benzo[ d [1,3]dioxacyclopenten-5-ylsulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)-4-methylthiazolyl-2-yl)acetamide, N -(4-methyl-5-(1-((1-methyl-1) H -indol-5-yl)sulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)thiazolyl)acetamide, N -(5-(1-((2,3-dihydro-1) H -inden-5-yl)sulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)-4-methylthiazolyl)acetamide, N -(5-(1-((2,3-dihydrobenzo[ b [1,4]Dioxin-6-yl)sulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)-4-methylthiazolyl)acetamide, N -(4-methyl-5-(1-((5,6,7,8-tetrahydronaphthyl-2-yl)sulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)thiazolyl)acetamide, N -(5-(1-(benzofuran-2-ylsulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)-4-methylthiazolyl-2-yl)acetamide, N -(5-(1-(benzo[ b Thiophene-3-ylsulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)-4-methylthiazolyl-2-yl)acetamide, N -(5-(1-(benzofuran-6-ylsulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)-4-methylthiazolyl-2-yl)acetamide, N -(5-(1-((2,6-dichlorophenyl)sulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)-4-methylthiazoline-2-yl)acetamide, N -((5-(1-((2,6-difluorophenyl)sulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)-4-methylthiazoline-2-yl)acetamide, N -(4-Methyl-5-(1-((3-oxo-3,4-dihydro-2-) H -benzo[ b [1,4]Thiazin-6-yl)sulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)thiazolyl)acetamide, N -(4-methyl-5-(1-((2-oxo-2,3-dihydrobenzo[] d [Oxazol-5-yl)sulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)thiazolyl)acetamide, N -(4-methyl-5-(1-((4-nitrophenyl)sulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)thiazoline-2-yl)acetamide, 3-((6-(2-acetamido-4-methylthiazoline-5-yl)-3,4-dihydroquinoline-1(2 H )-yl)sulfonyl)benzoic acid, N -(3-((6-(2-acetamido-4-methylthiazo-5-yl)-3,4-dihydroquinoline-1(2 H )-yl)sulfonyl)phenyl)acrylamide, N -(3-((6-(2-acetamido-4-methylthiazo-5-yl)-3,4-dihydroquinoline-1(2 H )-yl)sulfonyl)phenyl)-2-chloroacetamide, 7-(2-acetamido-4-methylthiazolyl-5-yl)-4-(phenylsulfonyl)-3,4-dihydroquinoxaline-1(2 H )-tert-butyl formate, N -(4-methyl-5-(1-(phenylsulfonyl)-1,2,3,4-tetrahydroquinoxalin-6-yl)thiazolyl-2-yl)acetamide, N -(4-methyl-5-(4-methyl-1-(phenylsulfonyl)-1,2,3,4-tetrahydroquinoxalin-6-yl)thiazolyl-2-yl)acetamide, N -(5-(5-(phenylsulfonyl)-5,6,7,8-tetrahydro-1,5-naphthidin-2-yl)thiazolyl)acetamide, N -(5-(1-(phenylsulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)-1,3,4-thiadiazol-2-yl)acetamide, N -(5-(1-((4-aminophenyl)sulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)-4-methylthiazoline-2-yl)acetamide, N -(4-((6-(2-acetamido-4-methylthiazo-5-yl)-3,4-dihydroquinoline-1(2 H )-yl)sulfonyl)phenyl)acrylamide, N -(4-((6-(2-acetamido-4-methylthiazo-5-yl)-3,4-dihydroquinoline-1(2 H )-yl)sulfonyl)phenyl)-2-chloroacetamide, N -(5-(1-((4-acetylphenyl)sulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)-4-methylthiazoline-2-yl)acetamide, N -(5-(1-((4-(dimethylamino)phenyl)sulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)-4-methylthiazoline-2-yl)acetamide, N -(5-(1-((4-(2-bromoacetyl)phenyl)sulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)-4-methylthiazoline-2-yl)acetamide, N -(5-(1-((4-(1-hydroxyethyl)phenyl)sulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)-4-methylthiazoline-2-yl)acetamide, N -(5-(5-((2,3-dichlorophenyl)sulfonyl)-5,6,7,8-tetrahydro-1,5-naphthidin-2-yl)thiazolyl)acetamide, N -(5-(5-((2,3-dichlorophenyl)sulfonyl)-5,6,7,8-tetrahydro-1,5-naphthidin-2-yl)-4-methylthiazolyl)acetamide, N -(5-(5-((5-chloro-2-fluorophenyl)sulfonyl)-5,6,7,8-tetrahydro-1,5-naphthidin-2-yl)thiazolyl)acetamide, N -(5-(5-((5-chloro-2-fluorophenyl)sulfonyl)-5,6,7,8-tetrahydro-1,5-naphthidin-2-yl)-4-methylthiazolyl)acetamide, N -(5-(1-benzoyl-1,2,3,4-tetrahydroquinoline-6-yl)-4-methylthiazolyl-2-yl)acetamide, N -(5-(1-benzyl-1,2,3,4-tetrahydroquinolin-6-yl)-4-methylthiazolyl-2-yl)acetamide, 9-(2-acetamyl-4-methylthiazolyl-5-yl)-6-(phenylsulfonyl)-3,4,4a,5,6,10b-hexahydrobenzo[ h [1,6]Naphthyl-1(2 H )-tert-butyl formate, N -(4-Methyl-5-(6-(phenylsulfonyl)-1,2,3,4,4a,5,6,10b-octahydrobenzo[ h [1,6]Naphthidin-9-yl)thiazolyl)acetamide, N -(4-Methyl-5-(1-methyl-6-(phenylsulfonyl)-1,2,3,4,4a,5,6,10b-octahydrobenzo[ h [1,6]Naphthidin-9-yl)thiazolyl)acetamide, N -(5-(4-ethylthio)-1-(phenylsulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)-4-methylthiazoline-2-yl)acetamide, N -(5-(1-((3-chloro-2-fluorophenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-6-yl)-4-methylthiazolyl-2-yl)acetamide, N -(4-methyl-5-(1-(phenylsulfonyl)-4-(piperidin-1-yl)-1,2,3,4-tetrahydroquinolin-6-yl)thiazolyl-2-yl)acetamide, N -(5-(4-(3-isopropoxyazacyclobutane-1-yl)-1-(phenylsulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)-4-methylthiazolyl-2-yl)acetamide, N -(5-(4-(dimethylamino)-1-(phenylsulfonyl)-1,2,3,4-tetrahydroquinolin-6-yl)-4-methylthiazolyl-2-yl)acetamide, N -(5-(4-cyclobutoxy-1-(phenylsulfonyl)-1,2,3,4-tetrahydroquinoline-6-yl)-4-methylthiazoline-2-yl)acetamide, N -(4-methyl-5-(3-(methylsulfonyl)-4-(phenylsulfonamido)phenyl)thiazo-2-yl)acetamide, N -(5-(4-((2-chlorophenyl)sulfonamido)-3-(methylsulfonyl)phenyl)-4-methylthiazo-2-yl)acetamide, N -(4-methyl-5-(3-(methylsulfonyl)-4-(naphthyl-1-sulfonamido)phenyl)thiazo-2-yl)acetamide, N -(4-methyl-5-(2-(phenylsulfonyl)isoindololin-5-yl)thiazo-2-yl)acetamide, N -(5-(2-((2-chlorophenyl)sulfonyl)isoindoline-5-yl)-4-methylthiazo-2-yl)acetamide, N -(5-(3-fluoro-4-(phenylsulfonamidomethyl)phenyl)-4-methylthiazo-2-yl)acetamide, N -(4-methyl-5-(3-(methylsulfonyl)-4-(phenylsulfonamidomethyl)phenyl)thiazo-2-yl)acetamide, N -(5-(3-fluoro-4-((phenylsulfonyl)methyl)phenyl)-4-methylthiazo-2-yl)acetamide, N -(4-methyl-5-(3-(methylsulfonyl)-4-((phenylsulfonyl)methyl)phenyl)thiazo-2-yl)acetamide, N -(4-methyl-5-(4-( N -Methylphenylsulfonamide)-3-(methylsulfonyl)phenyl)thiazo-2-yl)acetamide, N -(4-methyl-5-(3-(methylthio)-4-(phenylsulfonamido)phenyl)thiazo-2-yl)acetamide, N -(4-Methyl-5-(3-(methylsulfinyl)-4-(phenylsulfonamido)phenyl)thiazo-2-yl)acetamide, N -(4-methyl-5-(4-(phenylsulfonamido)-3-(pyrrolidone-1-yl)phenyl)thiazo-2-yl)acetamide, methyl 5-(2-acetamido-4-methylthiazo-5-yl)-2-(phenylsulfonamido)benzoate, N -(5-(3-(benzyloxy)-4-(phenylsulfonamido)phenyl)-4-methylthiazo-2-yl)acetamide, N -(5-(3-fluoro-4-(phenylsulfonamido)phenyl)-4-methylthiazo-2-yl)acetamide, N -(5-(3-Cyclopropyl-4-(phenylsulfonamido)phenyl)-4-methylthiazo-2-yl)acetamide, N -(5-(3-acetamido-4-(phenylsulfonamido)phenyl)-4-methylthiazo-2-yl)acetamide, N -(5-(3-(methoxymethyl)-4-(phenylsulfonamide)phenyl)-4-methylthiazolyl-2-yl)acetamide.

10. A compound according to formula 2, Formula 2 in R1 is C, S, O, or N. R3 is a C1 to C5 alkyl (preferably C1 to C3 alkyl), C3 to C6 cycloalkyl, C1 to C5 haloalkyl (preferably C1 to C3 haloalkyl, including Cl, Br or F), -CN, carbonyl, carboxyl, carboxylic acid ester, alkoxy, aldehyde, primary amine, secondary or tertiary amine, amide, imide, carbamate, formamide, nitro, sulfide, sulfinyl, sulfonyl, sulfinyl or sulfonamide R4 and R5 may be the same or different, and are H, C1 to C5 alkyl (preferably C1 to C3 alkyl), C2 to C5 alkenyl, C3 to C6 cycloalkyl, C3 to C6 heterocycloalkyl (preferably including N, S and / or O), C1 to C5 haloalkyl (preferably C1 to C3 haloalkyl, preferably including Cl, Br or F), C4 to C6 aryl, sulfide, sulfinyl, sulfonyl, sulfinyl, sulfonamide, carboxyl, carboxylic acid ester, carbonyl C=OR, wherein R is C1 to C10 alkyl (preferably C1 to C5 alkyl), C1 to C3 haloalkyl (preferably including Cl, Br or F), C4 to C6 aryl, wherein R is optionally substituted with a urethane group or urethane, wherein when R10 and R11 or R11 and R14 do not form a ring structure, at least one of R4 and R5 is a carbonyl C=OR. Alternatively, R4 and R5 form a 4, 5, or 6-membered heterocyclic alkyl group comprising N and optionally one or more additional heteroatoms (preferably N, O, and / or S), wherein the heterocyclic alkyl group is optionally substituted with an alkoxy group. R6 is absent, or R1 is C and R6 forms a carbonyl group (C=O) with R1, or R1 is S and R6 forms a sulfoxide group (S=O) with R1. Whether R7, R8, and R9 are the same or different, they are C or N. R10 is H, C1 to C5 alkyl (preferably C1 to C3 alkyl), C3 to C6 cycloalkyl, C1 to C5 haloalkyl (preferably C1 to C3 haloalkyl, including Cl, Br or F), -CN, carbonyl, carboxyl, carboxylic acid ester, alkoxy, aldehyde, primary amine, secondary or tertiary amine, amide, imide, carbamate, formamide, nitro, sulfide, sulfinyl, sulfonyl, sulfinyl or sulfonamide R11 is a C3 to C6 cycloalkyl, C4 to C6 heterocycloalkyl (preferably including N, S and / or O), halogen (preferably F, Cl or Br), sulfide, sulfinyl, sulfonyl, sulfinyl, sulfonamide, carboxyl, carboxylic acid ester, formamide, alkoxy or aryloxy. Alternatively, R10 and R11, together with the atoms they are attached to, form a 5- to 8-membered cycloalkyl or aryl ring structure D comprising two carbon atoms of B, forming a fused cyclic group with B, optionally including one or more heteroatoms (preferably N, O, and / or S). R14 is H, C1 to C5 alkyl (preferably C1 to C3 alkyl), primary amine, secondary amine, tertiary amine, or alkylamine. Alternatively, R11 and R14, together with the atoms they are attached to, form a 5- to 8-membered cycloalkyl or aryl ring structure C comprising two carbon atoms of B, forming a fused bicyclic group with B, optionally comprising one or more heteroatoms (preferably N, O, and / or S), wherein B and C are one of the following: R12 is a C1 to C5 alkyl group (preferably C1 to C3 alkyl group), carbonyl C=O group, sulfide, sulfinyl group, or sulfonyl group. R13 is a C1 to C5 alkyl (preferably C1 to C3 alkyl), C2 to C5 alkenyl, C3 to C6 cycloalkyl, C5 or C6 aryl, alkylaryl, C5 or C6 heteroaryl (preferably including N, S and / or O), bicyclic group (preferably including one or two aromatic rings), optionally including one or more heteroatoms (preferably N, O and / or S). Alternatively, R11 may be a halogen, or not form a ring structure with R10 or R14, or R11 and R14 may form a 5- to 8-membered cycloalkyl or aryl ring structure with the atoms they are attached to, and R15 and R16 may be present, in which case R12 and R13 may not be present. When R11 and R14 do not form a ring structure, or when R11 and R14 form a 5, 7, or 8-membered ring structure, R15 is a C1 to C5 alkyl (preferably C1 to C3 alkyl), carbonyl C=O, sulfide, sulfinyl or sulfonyl, or When R11 and R14 form a 6-membered ring structure, R15 is a C1 to C5 alkyl (preferably C1 to C3 alkyl), sulfide, sulfinyl, or sulfonyl. R16 is a C1 to C5 alkyl (preferably C1 to C3 alkyl), C2 to C5 alkenyl, C3 to C6 cycloalkyl, C5 or C6 aryl, alkylaryl, C5 or C6 heteroaryl (preferably including N, S and / or O), bicyclic group (preferably including one or two aromatic rings), optionally including one or more heteroatoms (preferably N, O and / or S). Alternatively, R14 is H, or R10 and R11 together with the atoms they are attached to form a 5- to 8-membered cycloalkyl or aryl ring structure D, or R11 and R14 together with the atoms they are attached to form a 5- to 8-membered cycloalkyl or aryl ring structure C and R12 and R13 are present, in which case R15 and R16 are absent. X is C, S, and / or O. Y is C, N, S and / or O, R17 can be the same or different, and can be absent (electron pair of X), H, hydroxyl, halogen (preferably F, Cl, or Br), alkoxy, C1 to C5 alkyl (preferably C1 to C3 alkyl), C1 to C5 haloalkyl (preferably C1 to C3 haloalkyl, including Cl, Br, or F), C3 to C6 cycloalkyl, C3 to C6 heterocycloalkyl (preferably including N, O, and / or S and optionally substituted with alkoxy), C4 to C6 aryl, carbonyl C(=O)R, where R is a C1 to C5 alkyl. (Preferably C1 to C3 alkyl), carboxyl, carboxylic acid ester, alkoxy (preferably -OCH3, -OCH2CH3 or C3 to C6 cycloalkylalkoxy), aldehyde, primary amine, secondary or tertiary amine, amide, imide, carbamate, formamide, nitro, sulfide (preferably -SCH3, -SCH2CH3), sulfinyl, sulfonyl, sulfinyl or sulfonamide, or when X is C, forming a carbonyl C=O with X, or when X is S, forming a sulfoxide S=O or a sulfonyl S(=O)2 with X. Alternatively, two R17 atoms may form a 4, 5, or 6-membered cycloalkyl group, optionally including one or more heteroatoms (preferably N, O, and / or S). R18 can be the same or different, and can be H or alkoxy. Alternatively, an R17 and an R18 form a 5- or 6-membered cyclic ring structure comprising two carbon atoms of C, forming a fused cyclic group with C, optionally including one or more heteroatoms (preferably N, O, and / or S), wherein the 5- or 6-membered cyclic ring structure is optionally substituted with a C1 to C3 alkyl or alkoxy carbonyl group (preferably at the heteroatom position), and R19 can be the same or different, and is H, C1 to C6 alkyl (preferably C1 to C3 alkyl).

11. The compound according to claim 10, wherein, R10 and R11, together with the atoms they are attached to, form a 5- to 7-membered ring or aryl ring structure D, which forms a fused bicyclic group with B, wherein B and D are And R7, R8, R9, R12 and R13 are as described in claim 10.

12. The compound according to any one of claims 10 or 11, wherein, R16 is one of the following: in R20 may be the same or different, and is H, C1 to C5 alkyl (preferably C1 to C3 alkyl), halogen (preferably F, Cl and / or Br), alkoxy or E, wherein E is one of the following: R21 can be the same or different, and is H, C1 to C5 alkyl (preferably C1 to C3 alkyl), halogen (preferably F, Cl and / or Br), alkoxy, primary amine, secondary or tertiary amine, sulfide, sulfinyl, sulfonyl, sulfinyl, sulfonamide, carboxyl, carboxylic acid ester, secondary hydroxyl group C(-OH)CH3, carbonyl C=OR (wherein R is C1 to C10 alkyl (preferably C1 to C5 alkyl), C1 to C3 haloalkyl (preferably including Cl, Br or F)), imide, urethane group, formamide, amide N=OR (wherein R is C1 to C3 alkyl, C1 to C3 alkenyl, C1 to C3 haloalkyl (preferably including Cl, Br or F)), nitro or E, R22 can be the same or different, and is H or a C1 to C5 alkyl group (preferably a C1 to C3 alkyl group). R23 is an H, carbonyl, carboxyl, or carboxylic acid ester. R24 is H or a C1 to C5 alkyl group (preferably a C1 to C3 alkyl group), and R25 can be the same or different, and can be H, C1 to C4 alkyl, C1 to C4 heteroalkyl, C3 to C6 cycloalkyl, or C2 to C6 heterocycloalkyl.

13. The compound according to any one of the preceding claims, for use as a medicament in treating medical conditions associated with defective and / or pathological signaling of the β subtype (PI3K-C2b) of class II phosphoinositol 3-kinase.

14. The compound according to any one of the preceding claims, for use as a medicament in treating medical conditions associated with defective and / or pathological class II phosphoinositol 3-kinase (PI3K) signaling, said medical conditions being selected from the group consisting of: stroke, cardiovascular disease associated with endothelial cell dysfunction, cancer, cancer metastasis, myopathy (preferably myotubular myopathy) and diabetes.

15. A pharmaceutical composition for use as a medicament in treating a medical condition associated with defective and / or pathological class II phosphoinositol 3-kinase (PI3K) signaling, said pharmaceutical composition comprising one or more compounds according to any one of the preceding claims and a pharmaceutically acceptable carrier.

16. An in vitro method for modulating (preferably inhibiting) type II phosphoinositol 3-kinase (PI3K) signaling, said in vitro method comprising administering to cells in which PI3K signaling is to be modulated a compound according to any one of the preceding claims or a composition comprising said compound.

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