WO2025003330A1

WO2025003330A1 - Thiazolo tetrahydrochinoline compounds as class ii phosphoinositide 3-kinase inhibitors

Info

Publication number: WO2025003330A1
Application number: PCT/EP2024/068134
Authority: WO
Inventors: Davide CIRILLO; Wen-Ting Lo; Volker HAUCKE; Marc Nazare
Original assignee: Forschungsverbund Berlin FVB eV
Current assignee: Forschungsverbund Berlin FVB eV
Priority date: 2023-06-30
Filing date: 2024-06-27
Publication date: 2025-01-02
Anticipated expiration: 2025-12-30

Abstract

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

Description

THIAZOLO TETRAHYDROCHINOLINE COMPOUNDS AS CLASS II PHOSPHOINOSITIDE 3-KINASE INHIBITORS

DESCRIPTION

The invention is in the field of biochemistry and medicine relates to chemical compounds useful as inhibitors of class II phosphoinositide 3-kinase (PI3K) signalling. The invention further relates to the medical use of inhibitors of class II phosphoinositide 3-kinase (PI3K) signalling in the treatment of medical conditions associated with defective and/or pathologic class II phosphoinositide 3-kinase (PI3K) signaling such as stroke, a cardiovascular disease related to endothelial cell dysfunction, cancer, cancer metastasis, myopathy and diabetes. The invention further relates to the medical use of inhibitors of signalling of the beta isoform of class II phosphoinositide 3-kinase (PI3K-2b) in the treatment of medical conditions associated with defective and/or pathologic signaling of the beta isoform of class II phosphoinositide 3-kinase (PI3K-C2b).

BACKGROUND OF THE INVENTION

The phosphoinositide 3-kinases (PI3Ks) are a family of lipid kinases central to regulating a wide range of important intracellular processes. PI3Ks orchestrate cell responses including mitogenic signaling, cell survival and growth, metabolic control, vesicular trafficking, degranulation, cytoskel- etal 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 are identified.

Class I PI3Ks are the earliest discovered PI3Ks. They form hetero-dimers by association of a catalytic subunit and a regulatory subunit that produce P I (3 ,4,5)P3. Class I PI3Ks are further classified into class IA (p110a, p, and 5) and class IB (p110y), based on distinct regulatory subunits (Figure 1). The structural similarity between kinase domains of class I PI3Ks and protein kinases implies that PI3Ks have protein kinase activity in addition to lipid kinase activity.

Class II phosphoinositide 3-kinases (PI3Ks) control multiple cellular functions ranging from membrane and actin dynamics to cell signaling via synthesis of 3'-phosphorylated inositol phospholipids. In contrast to class I, relatively little is known about class II PI3K. Class II PI3Ks produce PI(3)P or PI(3,4)P2, with varying levels of efficiency that may be related to isoform and cell type. There are three class II PI3K isoforms (PI3KC2oc, PI3KC2P, and PI3KC2y) in vertebrates, but only one member exists in worm and fly. Similar to the catalytic subunit of class I PI3Ks, all class II isoforms contain a Ras binding domain (RBD), a C2 domain (C2), a helical domain (HD), and a kinase domain, but have unique disordered regions in their N-terminus and are extended by two lipid binding domains (PX and C2 domain) at their C-terminus. Unlike class I PI3K, class II PI3K kinases lack regulatory subunits and act as monomers.

Class II PI3K isoforms have been demonstrated to couple signaling to membrane traffic. This indicates that distinct mechanisms serve to recruit PI3KII and that their lipid product has unique roles [PI(3)P and/or PI(3,4)P2]. Recently, the a isoform has been shown to synthesize PI(3,4)P2 on endocytic pits at the plasma membrane, where PI(3,4)P2 is required for membrane constriction prior to vesicle fission (Posor et al, Nature, 2013, 499, 233-237) and is required to internalize VEGF receptor in endothelial cells (Yoshioka et al., Nat. Med., 2012, 18, 1560-1569). Besides, PI3KC2oc knock-down impairs autophagy at least in some cells and the maturation of endocytic vesicles. PI3KC2oc can also generate PI(3)P and regulate the formation of a PI(3)P pool at peri- centriolar recycling endosomes (PRE) required for Rabi 1 and Shh pathway activation and primary cilia formation.

The activity of the beta isoform of class II PI3K (PI3KC2P, also termed PI3K-C2b) is associated with endocytosis, proliferation and glucose metabolism. Moreover, the beta isoform regulates nutrient signaling by suppressing mTORCI signaling via local production of PI(3,4)P2 at late endosomes or lysosomes (Marat et al, Science, 2017, 356, 968-972).

Endothelial-specific PI3KC2a knock-out mice display a vascular barrier function defect indicating that PI3KC2a is involved in angiogenesis (Yoshioka et al., Endothelial PI3K-C2alpha, a class II PI3K, has an essential role in angiogenesis and vascular barrier function. Nat. Med. 2012, 18, 1560-1569). In addition, the liver-specific C2y isoform has recently been shown to produce an endosomal PI(3,4)P2 pool needed for sustained Akt2 activation following insulin stimulation (Braccini et al., Nat. Commun. 2015, 6, 7400). Based on data accumulated to this point in time, class II PI3Ks appear to be involved in cancer, cardiovascular disease, myopathy and diabetes, amongst other diseases (Falasca et al, J. Med. Chem. 2016, 60, 47-65).

Cell permeable small-molecule inhibitors of kinases are excellent tools to directly and quickly unravel the functional consequences of kinase inactivity and represent useful medical agents. A key challenge for the generation of such inhibitors is their specificity. For PI3Ks, the two widely used primary pharmacological tools available, wortmannin and LY294002, have off-target effects on other members of this family. Therefore, during the past decade more chemotypically diverse small molecule inhibitors have been developed in order to specifically target specific PI3K isoforms.

For a spectrum of PI3K inhibitors with different degrees of selectivity, different chemotypes have been observed. The most selective compounds include the quinazolinone purine inhibitors (e.g. TGX-115, TGX286, and PIK-108) for PI3K 8 and imidazopyridine inhibitors (e.g. PIK75) for PI3K a (Figure 2A). These compounds exhibit > 100-fold selectivity between their primary targets and other class I PI3Ks. Other chemotypes of inhibitors (i.e. aryl thiazolidinones, pyridinylfuranopyrim- idines, phenylthiazoles, and imidazoquinazolines) were found to inhibit multiple PI3Ks to a variable extent. Additional class I PI3K inhibitors are described in Falasca et al, J. Med. Chem. 2016, 60, 47-65.

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

In contrast to class I and III PI3Ks, for class II PI3Ks few specific inhibitors exist, also because of the lack of structural information. At present no specific inhibitors of PI3K-C2b have been described. 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 that present comments on prospects for the development of inhibitors of class II phosphoinositide 3-kinase (PI3K) signalling and class II phosphoinositide 3- kinases as potential drug targets. The chemical structures disclosed therein are distinct from those of the present invention.

WO 2019/234237 A1 discloses compounds for inhibition of class II phosphoinositide 3-kinases, in particular class II phosphoinositide 3-kinase alpha (PI3KC2a). The chemical structures disclosed are distinct from those of the present invention.

Pemberton et al. ("Discovery of Highly Isoform Selective Orally Bioavail-able Phosphoinositide 3- Kinase (PI3K) - [gamma] Inhibitors", JOURNAL OF Medicinal Chemistry, 2018) discloses various isoform-selective PI3Ky inhibitors. Compound 15 (AZD3458) shows a high selectivity of inhibition of PI3Ky over PI3Ka and PI3Kp. The inhibition of class II and III PI3Ks such as PI3K-C2P is also investigated, whereby AZD3458 also shows inhibition of PI3K-C2P, which is, however, lower than that of PI3Ky. The chemical structures disclosed are distinct from those of the present invention.

WO 2009/017822 A2 discloses various molecules for the inhibition of PI3K, in particular PI3Ka, which can be used for the treatment of PI3K-modulated diseases such as cancer.

WO 2020/210379 A1 discloses various molecules for the inhibition of PI3K, in particular PI3Ky for the treatment of PI3K-modulated diseases such as allergic reactions, inflammatory diseases, autoimmune diseases, asthma, emphysema, respiratory diseases or cancer.

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) investigates the PI3Ky inhibitor AZD3458 for the treatment of cancer and the influence of the inhibitor on the phenotype of tumour-associated macrophages.

Sadiq et al. ("Characterisation of pharmacokinetics, safety and tolerability in a first-in-human study for AZD8154, a novel inhaled selective P13K[gamma][delta] dual inhibitor targeting airway inflammatory disease", British Journal of Clinical Pharmacology, 2021) discloses the selective, dual PI3Kyb inhibitor AZD8154. The inhibitor is intended to be used inhalational for the anti-inflammatory treatment of respiratory diseases such as asthma.

WO 2010/037765 A2 discloses various molecules with a 4-morpholino-pyrido[3,2-d]pyrimidine backbone for the inhibition of PI3K for the treatment of PI3K-modulated diseases such as autoimmune diseases, inflammatory diseases, multiple sclerosis and cancers.

CN 115 611 883 A discloses various molecules for the inhibition of PI3K, in particular PI3Ka for the treatment of cancer.

WO 2012/148540 A1 and WO 2014/151147 A1 disclose different molecules for the inhibition of PI3K, in particular PI3Ka, and/or mTOR, which are used in combination for the treatment of cancer.

EP 2 944 637 A1 discloses various molecules for the inhibition of PI3K, in particular PI3Ka for the treatment of cancers, allergic diseases, autoimmune diseases, neurodegenerative diseases, circulatory disorders, inflammatory diseases, endocrine diseases and metabolic diseases. WO 2017/153527 A1 discloses various molecules for the inhibition of PI3K, in particular PI3Ky for the treatment of respiratory diseases such as asthma and COPD.

None of these documents besides WO 2019/234237 A1 and Pemberton et al. discloses the inhibition of class II PI3K.

In light of the lack of established class II PI3K inhibitors, the present invention sought the development of class II PI3Ks inhibitors, in particular specific inhibitors of PI3K-C2b, in order to provide novel compounds useful in research and medical treatment. In light of the prior art, and considering the relevance of class II PI3Ks in multiple medical conditions, there remains a significant need in the art to provide compounds for the inhibition of class II PI3Ks.

SUMMARY OF THE INVENTION

In light of the prior art the technical problem underlying the present invention is to provide means for the inhibition of class II PI3Ks, including the beta isoform of class II PIK3 (PIK3-2b).

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

The present invention therefore relates to a compound for use in the treatment of a medical condition associated with defective and/or pathologic class II phosphoinositide 3-kinase (PI3K) signaling, according to Formula 1

n is 1 or 2,

A is a 5-membered or 6-membered heteroaryl and -N(R4R5) is attached to the C atom adjacent to the N 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 comprising Cl, Br, or F), -CN, carbonyl, carboxyl, carboxy ester, alkoxy, aldehyde, primary, secondary or tertiary amine, amide, imide, carbamate, carboxamide, nitro, sulfide, sulfinyl, sulfonyl, sulfino or sulfonamide, R4 and R5 can be the same or different, H, C1 to C5 alkyl (preferably C1 to C3 alkyl), C2 to C5 alkenyl, C3 to C6 cycloalkyl, C3 to C6 hetero cycloalkyl (preferably comprising N, S and/or O), C1 to C5 haloalkyl (preferably C1 to C3 haloalkyl, preferably comprising Cl, Br or F), C4 to C6 aryl, sulfide, sulfinyl, sulfonyl, sulfino, sulfonamide, carboxyl, carboxy ester, carbonyl C=OR, wherein R is C1 to C10 alkyl (preferably C1 to C5 alkyl), C1 to C3 haloalkyl (preferably comprising Cl, Br or F), C4 to C6 aryl, wherein R is optionally substituted with a carbamate or a carbamate ester, or R4 and R5 form a 4-, 5- or 6-membered hetero cycloalkyl comprising N and optionally one or more further heteroatoms (preferably N, O and/or S), wherein said hetero cycloalkyl is optionally substituted by alkoxy,

R6 is absent or, R1 is C and R6 forms a carbonyl C=O with R1 or, R1 is S and R6 forms a sulfoxide S=O with R1 ,

R7, R8 and R9 are the same or different, 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 comprising Cl, Br, or F), -CN, carbonyl -, carboxyl, carboxy ester, alkoxy, aldehyde, primary, secondary or tertiary amine, amide, imide, carbamate, carboxamide, nitro, sulfide, sulfinyl, sulfonyl, sulfino or sulfonamide,

R11 is H, C3 to C6 cycloalkyl, C4 to C6 hetero cycloalkyl (preferably comprising N, S and/or O), halogen (preferably F, Cl, or Br), sulfide, sulfinyl, sulfonyl, sulfino, sulfonamide, carboxyl, carboxyl ester, carboxamide, alkoxy or aryloxy, or R10 and R11 form together with the atoms they are attached to a 5- to 8-membered cycloalkyl or aryl ring structure D comprising two carbon atoms of B, forming a condensed 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), a primary, secondary or tertiary amine or alkyl amine, or R11 and R14 form together with the atoms they are attached to a 5- to 8-membered cycloalkyl or aryl ring structure C comprising two carbon atoms of B, forming a condensed cyclic group with B, optionally comprising one or more heteroatoms (preferably N, O and/or S), R12 is C1 to C5 alkyl (preferably C1 to C3 alkyl), carbonyl C=O, sulfide, sulfinyl or sulfonyl,

R13 is C1 to C5 alkyl (preferably C1 to C3 alkyl), C2 to C5 alkenyl, C3 to C6 cycloalkyl, C5 or C6 aryl, alkyl aryl, C5 or C6 hetero aryl (preferably comprising N, S and/or O), a bicyclic group (preferably comprising one or two aromatic rings), optionally comprising one or more heteroatoms (preferably N, O and/or S), or R12 and R13 are absent when R11 is H or halogen, or not forming a ring structure with R10 or R14, or when R11 and R14 form together with the atoms they are attached to a 5- to 8-mem- bered cycloalkyl or aryl ring structure C and R15 and R16 are present,

R15 is C1 to C5 alkyl (preferably C1 to C3 alkyl), carbonyl C=O, sulfide, sulfinyl or sulfonyl, R16 is C1 to C5 alkyl (preferably C1 to C3 alkyl), C2 to C5 alkenyl, C3 to C6 cycloalkyl, C5 or C6 aryl, alkyl aryl, C5 or C6 hetero aryl (preferably comprising N, S and/or O), a bicyclic group (preferably comprising one or two aromatic rings), optionally comprising one or more heteroatoms (preferably N, O and/or S), or R15 and R16 are absent when R14 is H, or R10 and R11 form together with the atoms they are attached to a 5- to 8-membered cycloalkyl or aryl ring structure D, or when R11 and R14 form together with the atoms they are attached to a 5- to 8-membered cycloalkyl or aryl ring structure C and R12 and R13 are present.

The compounds of the invention are surprisingly effective in the inhibition of class II phosphoinositide 3-kinases (PI3Ks), in particular PI3K-C2b. Class II phosphoinositide 3-kinases (PI3Ks) control multiple cellular functions ranging from membrane and actin dynamics to cell signaling via synthesis of 3’-phosphorylated inositol phospholipids. The activity of the beta isoform of class II PI3K (PI3K-C2b) is associated with endocytosis, proliferation and glucose metabolism. According to the knowledge of the inventors, no specific inhibitors of PI3K-C2b have been described to date. The compounds described herein therefore represent a novel and unexpected class of compounds that exhibit specific inhibition of PI3K-C2b. A skilled person would not have arrived at the invention from any indication or suggestion in the prior art. The present invention therefore covers a novel series of compounds based on a thiazolo tetrahydroquinoline scaffold that specifically inhibit class II PI3K, including PI3K-C2b, that are of potential use to inhibit class II PI3K in various clinical settings, for example to treat diseases ranging including cancer, cancer metastasis, a cardiovascular disease related to endothelial cell dysfunction, stroke, diabetes, or myotubular myopathy. The present invention is based on an unexpected and beneficial finding, as no thiazolo tetrahydroquinoline derived class II PI3K inhibitors have been previously described.

In one embodiment the invention relates to compound for use in the treatment of a medical condition associated with defective and/or pathologic class II phosphoinositide 3-kinase (PI3K) signaling, according to Formula 1

Formula 1 wherein n is 1 or 2,

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 comprising Cl, Br, or F), -CN, carbonyl, carboxyl, carboxy ester, alkoxy, aldehyde, primary, secondary or tertiary amine, amide, imide, carbamate, carboxamide, nitro, sulfide, sulfinyl, sulfonyl, sulfino or sulfonamide,

R4 and R5 can be the same or different, H, C1 to C5 alkyl (preferably C1 to C3 alkyl), C2 to C5 alkenyl, C3 to C6 cycloalkyl, C3 to C6 hetero cycloalkyl (preferably comprising N, S and/or O), C1 to C5 haloalkyl (preferably C1 to C3 haloalkyl, preferably comprising Cl, Br or F), C4 to C6 aryl, C5 to C6 heteroaryl (preferably comprising N, S and/or O and optionally substituted with C3 to C6 hetero cyclyl (preferably comprising N, S and/or O)), sulfide, sulfinyl, sulfonyl, sulfino, sulfonamide, carboxyl, carboxy ester, carbonyl C=OR, wherein R is C1 to C10 alkyl (preferably C1 to C5 alkyl), C1 to C3 haloalkyl (preferably comprising Cl, Br or F), C3 to C6 cycloalkyl, alkoxy, C4 to C6 aryl, wherein R is optionally substituted with a carbamate or a carbamate ester, or

R4 and R5 form a 4-, 5- or 6-membered hetero cycloalkyl comprising N and optionally one or more further heteroatoms (preferably N, O and/or S), wherein said hetero cycloalkyl is optionally substituted by alkoxy

R7, R8 and R9 are the same or different, C or N,

R15 is C1 to C5 alkyl (preferably C1 to C3 alkyl), carbonyl C=O, sulfide, sulfinyl or sulfonyl,

R16 is C1 to C5 alkyl (preferably C1 to C3 alkyl), C2 to C5 alkenyl, C3 to C6 cycloalkyl, C5 or C6 aryl, alkyl aryl, C5 or C6 hetero aryl (preferably comprising N, S and/or O), C3 to C6 heterocycloalkyl (preferably comprising N, S and/or O and preferably comprising at least one double bond), a bicyclic group (preferably comprising one or two aromatic rings), optionally comprising one or more heteroatoms (preferably N, O and/or S), or

R15 and R16 are absent when R14 is H, or R10 and R11 form together with the atoms they are attached to a 5- to 8-membered cycloalkyl or aryl ring structure D, or when R11 and R14 form together with the atoms they are attached to a 5- to 8-membered cycloalkyl or aryl ring structure C and R12 and R13 are present.

In one embodiment the compound according to Formula 1 is characterized in that, n is 1 or 2,

A is a 5-membered or 6-membered heteroaryl and -N(R4R5) is attached to the C atom adjacent to N 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, CX3, wherein X is Cl, Br, or F,

R4 and R5 can be the same or different, H, C1 to C3 alkyl, C2 to C5 alkenyl, C3 to C6 cycloalkyl, C3 to C6 hetero cycloalkyl (preferably comprising N, S and/or O), C1 to C3 haloalkyl (preferably comprising Cl, Br or F), C4 to C6 aryl, sulfonyl, or one of

or R4 and R5 form together with the atoms they are attached to a 4-, 5- or 6-membered hetero cycloalkyl comprising N and optionally one or more further heteroatoms (preferably N, O and/or S), wherein said hetero cycloalkyl is optionally substituted by alkoxy, such as

R6 is absent, or R1 is C and R6 forms a carbonyl C=O with R1 or, R1 is S and R6 forms a sulfoxide S=O with R1 ,

R7, R8 and R9 are the same or different, C or N,

R10 is H or C1 to C3 alkyl,

R11 is H, C3 to C6 cycloalkyl, C4 to C6 hetero cycloalkyl (preferably comprising N, S and/or O), halogen (preferably F, Cl, or Br), sulfide, sulfinyl, sulfonyl, carboxyl ester, carboxamide or alkoxy - CH2OR wherein R C1 to C3 alkyl or benzyl, or R10 and R11 form together with the atoms they are attached to a 5- to 7-membered cycloalkyl or aryl ring structure D comprising two carbon atoms of B, forming a condensed bicyclic group with B, optionally comprising one or more heteroatoms (preferably N, O and/or S),

R14 is H, C1 to C3 alkyl, a secondary or tertiary amine or alkyl amine, or R11 and R14 form together with the atoms they are attached to a 5- to 7-membered cycloalkyl or aryl ring structure C comprising two carbon atoms of B, forming a condensed cyclic group with B, optionally comprising one or more heteroatoms (preferably N, O and/or S),

R12 is C1 to C3 alkyl, carbonyl C=O or sulfonyl,

R13 is C1 to C3 alkyl, C2 to C5 alkenyl, C3 to C6 cycloalkyl, C5 or C6 aryl, benzyl, C5 or C6 hetero aryl (preferably comprising N, S and/or O), a bicyclic group (preferably comprising one or two aromatic rings), optionally comprising one or more heteroatoms (preferably N, O and/or S), or R12 and R13 are absent when R11 is H or halogen, or not forming a ring structure with R10 or R14, or when R11 and R14 form together with the atoms they are attached to a 5- to 7-mem- bered cycloalkyl or aryl ring structure C and R15 and R16 are present,

R15 is C1 to C3 alkyl, carbonyl C=O or sulfonyl,

R16 is C1 to C3 alkyl, C2 to C5 alkenyl, C3 to C6 cycloalkyl, C5 or C6 aryl, benzyl, C5 or C6 hetero aryl (preferably comprising N, S and/or O), a bicyclic group (preferably comprising one or two aromatic rings), optionally comprising one or more heteroatoms (preferably N, O and/or S), or R15 and R16 are absent when R14 is H, or R10 and R1 form together with the atoms they are attached to a 5- to 7-membered cycloalkyl or aryl ring structure D, or when R11 and R14 form together with the atoms they are attached to a 5- to 7-membered cycloalkyl or aryl ring structure C and R12 and R13 are present.

In one embodiment the compound according to Formula 1 is characterized in that R4 and R5 can be the same or different, H, C1 to C3 alkyl, C2 to C5 alkenyl, C3 to C6 cycloalkyl, C3 to C6 hetero cycloalkyl (preferably comprising N, S and/or O), C1 to C3 haloalkyl (preferably comprising Cl, Br or F), C4 to C6 aryl, sulfonyl, or one of

wherein X is C or O, and wherein Boc is tert-butyloxycarbonyl, or R4 and R5 form together with the atoms they are attached to a 4-, 5- or 6-membered hetero cycloalkyl comprising N and optionally one or more further heteroatoms (preferably N, O and/or S), wherein said hetero cycloalkyl is optionally substituted by alkoxy, such as

In one embodiment the compound according to Formula 1 is characterized in that R16 is C1 to C3 alkyl, C2 to C5 alkenyl, C3 to C6 cycloalkyl, C5 or C6 aryl, benzyl, C5 or C6 hetero aryl (preferably comprising N, S and/or O), C3 to C6 heterocycloalkyl (preferably comprising N, S and/or O and preferably comprising at least one double bond), a bicyclic group (preferably comprising one or two aromatic rings), optionally comprising one or more heteroatoms (preferably N, O and/or S), or R15 and R16 are absent when R14 is H, or R10 and R1 form together with the atoms they are attached to a 5- to 7-membered cycloalkyl or aryl ring structure D, or when R11 and R14 form together with the atoms they are attached to a 5- to 7-membered cycloalkyl or aryl ring structure C and R12 and R13 are present. In one embodiment the present invention relates to a compound for use in the treatment of a medical condition associated with defective and/or pathologic class II phosphoinositide 3-kinase (PI3K) signaling, according to Formula 1a

Formula 1a wherein n is 1 or 2,

R1 is C, S, O or N,

R2 is C or N,

R4 and R5 can be the same or different, H, C1 to C5 alkyl (preferably C1 to C3 alkyl), C2 to C5 alkenyl, C3 to C6 cycloalkyl, C3 to C6 hetero cycloalkyl (preferably comprising N, S and/or O), C1 to C5 haloalkyl (preferably C1 to C3 haloalkyl, preferably comprising Cl, Br or F), C4 to C6 aryl, sulfide, sulfinyl, sulfonyl, sulfino, sulfonamide, carboxyl, carboxy ester, carbonyl C=OR, wherein R is C1 to C10 alkyl (preferably C1 to C5 alkyl), C1 to C3 haloalkyl (preferably comprising Cl, Br or F), C4 to C6 aryl, wherein R is optionally substituted with a carbamate or a carbamate ester, or R4 and R5 form a 4-, 5- or 6-membered hetero cycloalkyl comprising N and optionally one or more further heteroatoms (preferably N, O and/or S), wherein said hetero cycloalkyl is optionally substituted by alkoxy,

R7 and R8 and R9 are the same or different, C or N,

R9 is C,

R11 is H, C3 to C6 cycloalkyl, C4 to C6 hetero cycloalkyl (preferably comprising N, S and/or O), halogen (preferably F, Cl, or Br), sulfide, sulfinyl, sulfonyl, sulfino, sulfonamide, carboxyl, carboxyl ester, carboxamide, alkoxy or aryloxy,

R14 is H, C1 to C5 alkyl (preferably C1 to C3 alkyl), a primary, secondary or tertiary amine or alkyl amine, or R11 and R14 form together with the atoms they are attached to a 5- to 8-membered cycloalkyl or aryl ring structure C comprising two carbon atoms of B, forming a condensed cyclic group with B, optionally comprising one or more heteroatoms (preferably N, O and/or S),

R16 is C1 to C5 alkyl (preferably C1 to C3 alkyl), C2 to C5 alkenyl, C3 to C6 cycloalkyl, C5 or C6 aryl, alkyl aryl, C5 or C6 hetero aryl (preferably comprising N, S and/or O), a bicyclic group (preferably comprising one or two aromatic rings), optionally comprising one or more heteroatoms (preferably N, O and/or S), or R15 and R16 are absent when R14 is H.

In one embodiment the compound according to Formula 1a is characterized in that, R4 and R5 can be the same or different, H, C1 to C5 alkyl (preferably C1 to C3 alkyl), C2 to C5 alkenyl, C3 to C6 cycloalkyl, C3 to C6 hetero cycloalkyl (preferably comprising N, S and/or O), C1 to C5 haloalkyl (preferably C1 to C3 haloalkyl, preferably comprising Cl, Br or F), C4 to C6 aryl, C5 to C6 heteroaryl (preferably comprising N, S and/or O and optionally substituted with c3 to c6 hetero cyclyl (preferably comprising N, S and/or O)), sulfide, sulfinyl, sulfonyl, sulfino, sulfonamide, carboxyl, carboxy ester, carbonyl C=OR, wherein R is C1 to C10 alkyl (preferably C1 to C5 alkyl), C1 to C3 haloalkyl (preferably comprising Cl, Br or F), C3 to C6 cycloalkyl, alkoxy, C4 to C6 aryl, wherein R is optionally substituted with a carbamate or a carbamate ester, or R4 and R5 form a 4-, 5- or 6-membered hetero cycloalkyl comprising N and optionally one or more further heteroatoms (preferably N, O and/or S), wherein said hetero cycloalkyl is optionally substituted by alkoxy.

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

In one embodiment the compound according to Formula 1a is characterized in that, n is 1 or 2,

R1 is C, S, O or N, R2 is C or N,

R3 is H, C1 to C3 alkyl, C3 to C6 cycloalkyl, CX3, wherein X is Cl, Br, or F,

R7 and R8 and R9 are the same or different, C or N,

R9 is C,

R10 is H or C1 to C3 alkyl,

R11 is H, C3 to C6 cycloalkyl, C4 to C6 hetero cycloalkyl (preferably comprising N, S and/or O), halogen (preferably F, Cl, or Br), sulfide, sulfinyl, sulfonyl, carboxyl ester, carboxamide or alkoxy - CH2OR wherein R C1 to C3 alkyl or benzyl,

R15 is C1 to C3 alkyl, carbonyl C=O or sulfonyl,

R16 is C1 to C3 alkyl, C2 to C5 alkenyl, C3 to C6 cycloalkyl, C5 or C6 aryl, benzyl, C5 or C6 hetero aryl (preferably comprising N, S and/or O), a bicyclic group (preferably comprising one or two aromatic rings), optionally comprising one or more heteroatoms (preferably N, O and/or S), or R15 and R16 are absent when R14 is H.

In one embodiment the compound according to Formula 1a is characterized in that

In one embodiment the compound according to Formula 1a is characterized in that R16 is C1 to C3 alkyl, C2 to C5 alkenyl, C3 to C6 cycloalkyl, C5 or C6 aryl, benzyl, C5 or C6 hetero aryl (preferably comprising N, S and/or O), C3 to C6 heterocycloalkyl (preferably comprising N, S and/or O and preferably comprising at least one double bond), a bicyclic group (preferably comprising one or two aromatic rings), optionally comprising one or more heteroatoms (preferably N, O and/or S). In one embodiment the present invention relates to a compound for use in the treatment of a medical condition associated with defective and/or pathologic class II phosphoinositide 3-kinase (PI3K) signaling, according to Formula 2,

Formula 2 wherein

R1 is C, S, O or N,

R2 is C or N,

R7, R8 and R9 are the same or different, C or N,

R16 is C1 to C5 alkyl (preferably C1 to C3 alkyl), C2 to C5 alkenyl, C3 to C6 cycloalkyl, C5 or C6 aryl, alkyl aryl, C5 or C6 hetero aryl (preferably comprising N, S and/or O), a bicyclic group (preferably comprising one or two aromatic rings), optionally comprising one or more heteroatoms (preferably N, O and/or S), or R15 and R16 are absent when R14 is H, or R10 and R11 form together with the atoms they are attached to a 5- to 8-membered cycloalkyl or aryl ring structure D, or when R11 and R14 form together with the atoms they are attached to a 5- to 8-membered cycloalkyl or aryl ring structure C and R12 and R13 are present.

In one embodiment the compound according to Formula 2 is characterized in that R4 and R5 can be the same or different, H, C1 to C5 alkyl (preferably C1 to C3 alkyl), C2 to C5 alkenyl, C3 to C6 cycloalkyl, C3 to C6 hetero cycloalkyl (preferably comprising N, S and/or O), C1 to C5 haloalkyl (preferably C1 to C3 haloalkyl, preferably comprising Cl, Br or F), C3 to C6 cycloalkyl, alkoxy , C4 to C6 aryl, C5 to C6 heteroaryl (preferably comprising N, S and/or O and optionally substituted with C3 to C6 hetero cyclyl (preferably comprising N, S and/or O)), sulfide, sulfinyl, sulfonyl, sulfino, sulfonamide, carboxyl, carboxy ester, carbonyl C=OR, wherein R is C1 to C10 alkyl (preferably C1 to C5 alkyl), C1 to C3 haloalkyl (preferably comprising Cl, Br or F), C4 to C6 aryl, wherein R is optionally substituted with a carbamate or a carbamate ester, or R4 and R5 form a 4-, 5- or 6-membered hetero cycloalkyl comprising N and optionally one or more further heteroatoms (preferably N, O and/or S), wherein said hetero cycloalkyl is optionally substituted by alkoxy,

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

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, CX3, wherein X is Cl, Br, or F,

R7, R8 and R9 are the same or different, C or N,

R10 is H or C1 to C3 alkyl,

R12 is C1 to C3 alkyl, carbonyl C=O or sulfonyl,

R15 is C1 to C3 alkyl, carbonyl C=O or sulfonyl,

R16 is C1 to C3 alkyl, C2 to C5 alkenyl, C3 to C6 cycloalkyl, C5 or C6 aryl, benzyl, C5 or C6 hetero aryl (preferably comprising N, S and/or O), a bicyclic group (preferably comprising one or two aromatic rings), optionally comprising one or more heteroatoms (preferably N, O and/or S), or R15 and R16 are absent when R14 is H, or R10 and R11 form together with the atoms they are attached to a 5- to 7-membered cycloalkyl or aryl ring structure D, or when R11 and R14 form together with the atoms they are attached to a 5- to 7-membered cycloalkyl or aryl ring structure C and R12 and R13 are present.

In one embodiment the compound according to Formula 2 is characterized in that

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

In one embodiment the present invention relates to a compound for use in the treatment of a medical condition associated with defective and/or pathologic class II phosphoinositide 3-kinase (PI3K) signaling, according to Formula 2a,

Formula 2a wherein

R1 is C, S, O or N,

R2 is C or N,

R7 and R8 and R9 are the same or different, C or N,

R9 is C,

R15 is C1 to C5 alkyl (preferably C1 to C3 alkyl), carbonyl C=O, sulfide, sulfinyl or sulfonyl, and

In one embodiment the compound according to Formula 2a is characterized in that R4 and R5 can be the same or different, H, C1 to C5 alkyl (preferably C1 to C3 alkyl), C2 to C5 alkenyl, C3 to C6 cycloalkyl, C3 to C6 hetero cycloalkyl (preferably comprising N, S and/or O), C1 to C5 haloalkyl (preferably C1 to C3 haloalkyl, preferably comprising Cl, Br or F), C3 to C6 cycloalkyl, alkoxy , C4 to C6 aryl, C5 to C6 heteroaryl (preferably comprising N, S and/or O and optionally substituted with c3 to c6 hetero cyclyl (preferably comprising comprising N, S and/or O)), sulfide, sulfinyl, sulfonyl, sulfino, sulfonamide, carboxyl, carboxy ester, carbonyl C=OR, wherein R is C1 to C10 alkyl (preferably C1 to C5 alkyl), C1 to C3 haloalkyl (preferably comprising Cl, Br or F), C4 to C6 aryl, wherein R is optionally substituted with a carbamate or a carbamate ester, or R4 and R5 form a 4-, 5- or 6-membered hetero cycloalkyl comprising N and optionally one or more further heteroatoms (preferably N, O and/or S), wherein said hetero cycloalkyl is optionally substituted by alkoxy,

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

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, CX3, wherein X is Cl, Br, or F,

R7 and R8 and R9 are the same or different, C or N,

R9 is C,

R10 is H or C1 to C3 alkyl,

R15 is C1 to C3 alkyl, carbonyl C=O or sulfonyl, and

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

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, CF3.

In one embodiment the compound according to Formula 1 , 1a, 2, 2a, 3, 4, 5 or 6 is characterized in that R4 and R5 can be the same or different, H, CH3, C3 alkenyl, C4 hetero cycloalkyl (preferably comprising O), -CH2CF3, C6 aryl, sulfonyl, or one of

or R4 and R5 form together with the atoms they are attached to a 4- to 6-membered hetero cycloalkyl comprising N and optionally one or more further heteroatoms (preferably O), wherein said hetero cycloalkyl is optionally substituted by alkoxy, such as

wherein X is C or O, and wherein Boc is tert-butyloxycarbonyl, or R4 and R5 form together with the atoms they are attached to a 4- to 6-membered hetero cycloalkyl comprising N and optionally one or more further heteroatoms (preferably O), wherein said hetero cycloalkyl is optionally substituted by alkoxy, such as

In one embodiment the compound according to Formula 1 or 2 is characterized in that R10 is H or CHs and R11 is H, C3 cycloalkyl, C5 hetero cycloalkyl (preferably comprising N), F, sulfide, sulfinyl, sulfonyl, carboxyl ester, carboxamide or alkoxy -CH2OR wherein R is CH3 or benzyl, or R10 and R11 form together with the atoms they are attached to a 6-membered cycloalkyl or aryl ring structure D comprising two carbon atoms of B, forming a condensed bicyclic group with B, optionally comprising one heteroatom (preferably N).

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

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 not forming a ring structure with R10 or R14, orwhen R11 and R14 form together with the atoms they are attached to a 5- to 7-membered cycloalkyl or aryl ring structure C and R15 and R16 are present.

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 hetero aryl (preferably comprising N and/or S), a bicyclic group comprising at least one aromatic rings, optionally comprising one or more heteroatoms (preferably N, O and/or S), or R15 and R16 are absent when R14 is H, or R10 and R11 form together with the atoms they are attached to a 5- to 7-membered cycloalkyl or aryl ring structure D, or when R11 and R14 form together with the atoms they are attached to a 5- to 7-membered cycloalkyl or aryl ring structure C and R12 and R13 are present.

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 hetero aryl (preferably comprising N and/or S), C3 to C6 heterocycloalkyl (preferably comprising N, S and/or O and preferably comprising at least one double bond), a bicyclic group comprising at least one aromatic rings, optionally comprising one or more heteroatoms (preferably N, O and/or S), or R15 and R16 are absent when R14 is H, or R10 and R11 form together with the atoms they are attached to a 5- to 7-membered cycloalkyl or aryl ring structure D, or when R11 and R14 form together with the atoms they are attached to a 5- to 7- membered cycloalkyl or aryl ring structure C and R12 and R13 are present. In one embodiment the compound according to Formula 1 or 2 is characterized in that,

R11 and R14 form together with the atoms they are attached to a 5- to 7-membered cyclic or aryl ring structure C forming a condensed bicyclic group with B, wherein B and C are one of

and

R7, R8 and R9 are the same or different, C or N,

R12 is C1 to C5 alkyl (preferably C1 to C3 alkyl), carbonyl C=O, sulfide, sulfinyl or sulfonyl,

R13 is C1 to C5 alkyl (preferably C1 to C3 alkyl), C2 to C5 alkenyl, C3 to C6 cycloalkyl, C5 or C6 aryl, alkyl aryl, C5 or C6 hetero aryl (preferably comprising N, S and/or O), a bicyclic group (preferably comprising one or two aromatic rings), optionally comprising one or more heteroatoms (preferably N, O and/or S),

R16 is C1 to C5 alkyl (preferably C1 to C3 alkyl), C2 to C5 alkenyl, C3 to C6 cycloalkyl, C5 or C6 aryl, alkyl aryl, C5 or C6 hetero aryl (preferably comprising N, S and/or O), a bicyclic group (preferably comprising one or two aromatic rings), optionally comprising one or more heteroatoms (preferably N, O and/or S),

X and Y are the same or different, C, N, S and/or O,

R17 may be the same or different, absent (electron pair of X), H, hydroxy, 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 comprising Cl, Br, or F), C3 to C6 cycloalkyl, C3 to C6 hetero cycloalkyl (preferably comprising N,0 and/or S and optionally substituted with alkoxy), C4 to C6 aryl, carbonyl C(=O)R, wherein R is C1 to C5 alkyl (preferably C1 to C3 alkyl), carboxyl, carboxy ester, alkoxy (preferably 1

-OCH3, -OCH2CH3or C3 to C6 cycloalkyl alkoxy), aldehyde, primary, secondary or tertiary amine, amide, imide, carbamate, carboxamide, nitro, sulfide (preferably -SCH3, -SCH2CH3), sulfinyl, sulfonyl, sulfino or sulfonamide or when X is C forming a carbonyl C=O with X or when X is S forming sulfoxide S=O or sulfonyl S(=O)2 with X, or two R17 are forming a 4-, 5- or 6-membered cycloalkyl, optionally comprising one or more hetero atoms (preferably N, O and/or S),

R18 may be the same or different, H, alkoxy or one R18 is forming a carbonyl C=O with the C atom attached to, or one R17 and one R18 form a 5- or 6-membered cyclic ring structure comprising two carbon atoms of C, forming a condensed cyclic group with C, optionally comprising one or more heteroatoms (preferably N, O and/or S), wherein the 5- or 6-membered cyclic ring structure is optionally substituted with C1 to C3 alkyl or alkoxy carbonyl (preferably at the position of the heteroatom), and

R19 may be the same or different, H, C1 to C6 alkyl (preferably C1 to C3 alkyl).

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

In one embodiment the compound according to Formula 1 or 2 is characterized in that, R11 and R14 form together with the atoms they are attached to a 5- to 7-membered cyclic or aryl ring structure C forming a condensed 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 hetero aryl (preferably comprising N and/or S), a bicyclic group comprising at least one aromatic rings, optionally comprising one or more heteroatoms (preferably N, O and/or S).

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

and

R7 and R8 are the same or different, C or N,

R9 is C,

X and Y are the same or different, C, N, S and/or O,

R17 may be the same or different, absent (electron pair of X), H, hydroxy, 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 comprising Cl, Br, or F), C3 to C6 cycloalkyl, C3 to C6 hetero cycloalkyl (preferably comprising N,0 and/or S and optionally substituted with alkoxy), C4 to C6 aryl, carbonyl C(=O)R, wherein R is C1 to C5 alkyl (preferably C1 to C3 alkyl), carboxyl, carboxy ester, alkoxy (preferably -OCH3, -OCH2CH3or C3 to C6 cycloalkyl alkoxy), aldehyde, primary, secondary or tertiary amine, amide, imide, carbamate, carboxamide, nitro, sulfide (preferably -SCH3, -SCH2CH3), sulfinyl, sulfonyl, sulfino or sulfonamide or when X is C forming a carbonyl C=O with X or when X is S forming sulfoxide S=O or sulfonyl S(=O)2 with X, or two R17 are forming a 4-, 5- or 6-membered cycloalkyl, optionally comprising one or more hetero atoms (preferably N, O and/or S),

In one embodiment the compound according to Formula 1a or 2a is characterized in that, R11 and R14 form together with the atoms they are attached to a 5- to 7-membered cyclic or aryl ring structure C forming a condensed 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 hetero aryl (preferably comprising N and/or S), a bicyclic group comprising at least one aromatic rings, optionally comprising one or more heteroatoms (preferably N, O and/or S).

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

In one embodiment the present invention relates to a compound for use in the treatment of a medical condition associated with defective and/or pathologic class II phosphoinositide 3-kinase (PI3K) signaling, according to Formula 3

Formula 3 wherein R1 is C, S, O or N,

R2 is C or N,

R7, R8 and R9 are the same or different, C or N,

In one embodiment the compound according to Formula 3 is characterized in that, R4 and R5 can be the same or different, H, C1 to C5 alkyl (preferably C1 to C3 alkyl), C2 to C5 alkenyl, C3 to C6 cycloalkyl, C3 to C6 hetero cycloalkyl (preferably comprising N, S and/or O), C1 to C5 haloalkyl (preferably C1 to C3 haloalkyl, preferably comprising Cl, Br or F), C3 to C6 cycloalkyl, alkoxy, C4 to C6 aryl, C5 to C6 heteroaryl (preferably comprising N, S and/or O and optionally substituted with c3 to c6 hetero cyclyl (preferably comprising comprising N, S and/or O)), sulfide, sulfinyl, sulfonyl, sulfino, sulfonamide, carboxyl, carboxy ester, carbonyl C=OR, wherein R is C1 to C10 alkyl (preferably C1 to C5 alkyl), C1 to C3 haloalkyl (preferably comprising Cl, Br or F), C4 to C6 aryl, wherein R is optionally substituted with a carbamate or a carbamate ester, or R4 and R5 form a 4-, 5- or 6-membered hetero cycloalkyl comprising N and optionally one or more further heteroatoms (preferably N, O and/or S), wherein said hetero cycloalkyl is optionally substituted by alkoxy,

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

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, CX3, wherein X is Cl, Br, or F,

R7, R8 and R9 are the same or different, C or N,

R10 is H or C1 to C3 alkyl,

R16 is C1 to C3 alkyl, C2 to C5 alkenyl, C3 to C6 cycloalkyl, C5 or C6 aryl, benzyl, C5 or C6 hetero aryl (preferably comprising N, S and/or O), a bicyclic group (preferably comprising one or two aromatic rings), optionally comprising one or more heteroatoms (preferably N, O and/or S).

In one embodiment the compound according to Formula 3 is characterized in that,

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

In one embodiment the present invention relates to a compound for use in the treatment of a medical condition associated with defective and/or pathologic class II phosphoinositide 3-kinase (PI3K) signaling, according to Formula 4

Formula 4 wherein

R1 is C, S, O or N,

R2 is C or N,

R7, R8 and R9 are the same or different, 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 comprising Cl, Br, or F), -CN, carbonyl -, carboxyl, carboxy ester, alkoxy, aldehyde, primary, secondary or tertiary amine, amide, imide, carbamate, carboxamide, nitro, sulfide, sulfinyl, sulfonyl, sulfino or sulfonamide, R11 is H, C3 to C6 cycloalkyl, C4 to C6 hetero cycloalkyl (preferably comprising N, S and/or O), halogen (preferably F, Cl, or Br), sulfide, sulfinyl, sulfonyl, sulfino, sulfonamide, carboxyl, carboxyl ester, carboxamide, alkoxy or aryloxy,

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, CX3, wherein X is Cl, Br, or F,

R7, R8 and R9 are the same or different, C or N,

R10 is H or C1 to C3 alkyl,

R16 is C1 to C3 alkyl, C2 to C5 alkenyl, C3 to C6 cycloalkyl, C5 or C6 aryl, benzyl, C5 or C6 hetero aryl (preferably comprising N, S and/or O), a bicyclic group (preferably comprising one or two aromatic rings), optionally comprising one or more heteroatoms (preferably N, O and/or S).,

Combinations of the various preferred embodiments are themselves considered preferred embodiments according to Formula 4 of the present invention.

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

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

In one embodiment the compound according to Formula 3 or 4 is characterized in that R10 is H or CHs and R11 is H, C3 cycloalkyl, C5 hetero cycloalkyl (preferably comprising N), F, sulfide, sulfinyl, sulfonyl, carboxyl ester, carboxamide or alkoxy -CH2OR wherein R is CH3 or benzyl.

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

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

In one embodiment the compound according to Formula 3 or 4 is characterized in that,

and

R7, R8 and R9 are the same or different, C or N,

R16 is C1 to C5 alkyl (preferably C1 to C3 alkyl), C2 to C5 alkenyl, C3 to C6 cycloalkyl, C5 or C6 aryl, alkyl aryl, C5 or C6 hetero aryl (preferably comprising N, S and/or O), a bicyclic group (preferably comprising one or two aromatic rings), optionally comprising one or more heteroatoms (preferably N, O and/or S), X and Y are the same or different, C, N, S and/or O,

In one embodiment the compound according to Formula 3 or 4 is characterized in that, R11 and R14 form together with the atoms they are attached to a 5- to 7-membered cyclic or aryl ring structure C forming a condensed 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 hetero aryl (preferably comprising N and/or S), a bicyclic group comprising at least one aromatic rings, optionally comprising one or more heteroatoms (preferably N, O and/or S).

In one embodiment the compound according to Formula 3 or 4 is characterized in that, R11 and R14 form together with the atoms they are attached to a 5- to 7-membered cyclic or aryl ring structure C forming a condensed 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 hetero aryl (preferably comprising N and/or S), C3 to C6 heterocycloalkyl (preferably comprising N, S and/or O and preferably comprising at least one double bond), a bicyclic group comprising at least one aromatic rings, optionally comprising one or more heteroatoms (preferably N, O and/or S).

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

wherein

R20 may be the same or different, 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

R21 may be the same or different, H, C1 to C5 alkyl (preferably C1 to C3 alkyl), halogen (preferably F, Cl and/or Br), alkoxy, primary, secondary or tertiary amine, sulfide, sulfinyl, sulfonyl, sulfino, sulfonamide, carboxyl, carboxy ester, a 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 comprising Cl, Br or F)), imide, carbamate, carboxamide, amide N=OR (wherein R is C1 to C3 alkyl, C1 to C3 alkenyl, C1 to C3 haloalkyl (preferably comprising Cl, Br or F)), nitro or E,

R22 may be the same or different, H or C1 to C5 alkyl (preferably C1 to C3 alkyl),

R23 is H, carbonyl, carboxyl or carboxy ester, R24 is H or C1 to C5 alkyl (preferably C1 to C3 alkyl), and

R25 may be the same or different, H, C1 to C4 alkyl, C1 to C4 heteroalkyl, C3 to C6 cycloalkyl, C2 to C6 heterocycloalkyl.

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

wherein X and Y may be the same or different, C, O, S or N, R20 may be the same or different, 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

R21 may be the same or different, H, C1 to C5 alkyl (preferably C1 to C3 alkyl), halogen (preferably F, Cl and/or Br), alkoxy, primary, secondary or tertiary amine, sulfide, sulfinyl, sulfonyl, sulfino, sulfonamide, carboxyl, carboxy ester, a 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 comprising Cl, Br or F)), imide, carbamate, carboxamide, amide N=OR (wherein R is C1 to C3 alkyl, C1 to C3 alkenyl, C1 to C3 haloalkyl (preferably comprising Cl, Br or F)), nitro or E, R22 may be the same or different, H or C1 to C5 alkyl (preferably C1 to C3 alkyl),

R23 is H, carbonyl, carboxyl or carboxy ester,

R24 is H or C1 to C5 alkyl (preferably C1 to C3 alkyl), and

In one embodiment the compound according to Formula 1, 1a, 2, 2a, 3, 4, 5, 6 or 7 is characterized in that R20 may be the same or different, H, CH3, F, Cl or alkoxy.

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

In one embodiment the compound according to Formula 1, 1a, 2, 2a, 3, 4, 5, 6 or 7 is characterized in that R22 may be the same or different, H or CH3. In one embodiment the compound according to Formula 1, 1a, 2,2a, 3, 4, 5, 6 or 7 is characterized in that R23 is H or carboxy ester.

In one embodiment the compound according to Formula 1, 1a, 2, 2a, 3, 4, 5, 6 or 7 is characterized in that R24 is H or CH3.

wherein X and Y may be the same or different, C, O, S or N,

R20 may be the same or different, H, C1 to C5 alkyl (preferably C1 to C3 alkyl), halogen (prefera- bly F, Cl and/or Br), alkoxy or E, wherein E is one of

R22 may be the same or different, H or C1 to C5 alkyl (preferably C1 to C3 alkyl), R23 is H, carbonyl, carboxyl or carboxy ester,

R24 is H or C1 to C5 alkyl (preferably C1 to C3 alkyl),

R25 may be the same or different, H, C1 to C4 alkyl, C1 to C4 heteroalkyl, C3 to C6 cycloalkyl, C2 to C6 heterocycloalkyl,

R26, R27 and R28 may be the same or differen, H, C1 to C3 alkyl, halogen (preferably Cl, Br or F), and wherein R29 is H or C1 to C3 alkyl (preferably C1 alkyl).

In one embodiment the present invention relates to a compound for use in the treatment of a medical condition associated with defective and/or pathologic class II phosphoinositide 3-kinase (PI3K) signaling, according to Formula 5

Formula 5 wherein

R1 is C, S, O or N,

R2 is C or N,

R6 is absent or, R1 is C and R6 forms a carbonyl C=O with R1 or, R1 is S and R6 forms a sulfoxide S=O with R1 , R7, R8 and R9 are the same or different, C or N,

In one embodiment the compound according to Formula 5 is characterized in that R4 and R5 can be the same or different, H, C1 to C5 alkyl (preferably C1 to C3 alkyl), C2 to C5 alkenyl, C3 to C6 cycloalkyl, C3 to C6 hetero cycloalkyl (preferably comprising N, S and/or O), C1 to C5 haloalkyl (preferably C1 to C3 haloalkyl, preferably comprising Cl, Br or F), C3 to C6 cycloalkyl, alkoxy, C4 to C6 aryl, C5 to C6 heteroaryl (preferably comprising N, S and/or O and optionally substituted with c3 to c6 hetero cyclyl (preferably comprising comprising N, S and/or O)), sulfide, sulfinyl, sulfonyl, sulfino, sulfonamide, carboxyl, carboxy ester, carbonyl C=OR, wherein R is C1 to C10 alkyl (preferably C1 to C5 alkyl), C1 to C3 haloalkyl (preferably comprising Cl, Br or F), C4 to C6 aryl, wherein R is optionally substituted with a carbamate or a carbamate ester, or R4 and R5 form a 4-, 5- or 6-membered hetero cycloalkyl comprising N and optionally one or more further heteroatoms (preferably N, O and/or S), wherein said hetero cycloalkyl is optionally substituted by alkoxy,

In one embodiment the compound according to Formula 5 is characterized in that R16 is C1 to C5 alkyl (preferably C1 to C3 alkyl), C2 to C5 alkenyl, C3 to C6 cycloalkyl, C5 or C6 aryl, alkyl aryl, C5 or C6 hetero aryl (preferably comprising N, S and/or O), C3 to C6 heterocycloalkyl (preferably comprising N, S and/or O and preferably comprising at least one double bond), a bicyclic group (preferably comprising one or two aromatic rings), optionally comprising one or more het- eroa-toms (preferably N, O and/or S).

In one embodiment the present invention relates to a compound for use in the treatment of a medical condition associated with defective and/or pathologic class II phosphoinositide 3-kinase (PI3K) signaling, according to Formula 6

Formula 6 wherein

R1 is C, S, O or N,

R2 is C or N,

R6 is absent or R1 is C and R6 forms a carbonyl C=O with R1 or, R1 is S and R6 forms a sulfoxide S=O with R1 , R7, R8 and R9 are the same or different, C or N,

In one embodiment the compound according to Formula 6 is characterized in that R4 and R5 can be the same or different, H, C1 to C5 alkyl (preferably C1 to C3 alkyl), C2 to C5 alkenyl, C3 to C6 cycloalkyl, C3 to C6 hetero cycloalkyl (preferably comprising N, S and/or O), C1 to C5 haloalkyl (preferably C1 to C3 haloalkyl, preferably comprising Cl, Br or F), C3 to C6 cycloalkyl, alkoxy, C4 to C6 aryl, C5 to C6 heteroaryl (preferably comprising N, S and/or O and optionally substituted with c3 to c6 hetero cyclyl (preferably comprising comprising N, S and/or O)), sulfide, sulfinyl, sulfonyl, sulfino, sulfonamide, carboxyl, carboxy ester, carbonyl C=OR, wherein R is C1 to C10 alkyl (preferably C1 to C5 alkyl), C1 to C3 haloalkyl (preferably comprising Cl, Br or F), C4 to C6 aryl, wherein R is optionally substituted with a carbamate or a carbamate ester, or R4 and R5 form a 4-, 5- or 6-membered hetero cycloalkyl comprising N and optionally one or more further heteroatoms (preferably N, O and/or S), wherein said hetero cycloalkyl is optionally substituted by alkoxy, In one embodiment the compound according to Formula 6 is characterized in that R16 is C1 to C5 alkyl (preferably C1 to C3 alkyl), C2 to C5 alkenyl, C3 to C6 cycloalkyl, C5 or C6 aryl, alkyl aryl, C5 or C6 hetero aryl (preferably comprising N, S and/or O), C3 to C6 heterocycloalkyl (preferably comprising N, S and/or O and preferably comprising at least one double bond), a bicyclic group (preferably comprising one or two aromatic rings), optionally comprising one or more heteroatoms (preferably N, O and/or S),

In one embodiment the present invention relates to a compound for use in the treatment of a medical condition associated with defective and/or pathologic class II phosphoinositide 3-kinase (PI3K) signaling, according to Formula 7

Formula 7 wherein

R1 is C, S, O or N,

R2 is C or N,

R7, R8 and R9 are the same or different, C or N,

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, C or N, and R9 is C.

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

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

In one embodiment the compound according to Formula 5, 6 or 7 is characterized in that R17 may be the same or different, absent (electron pair of X), H, hydroxy, F, CH3, C4 to C6 hetero cycloalkyl (preferably comprising N and/or O and optionally substituted with alkoxy), -C(=O)CH3, carboxy ester, alkoxy (preferably -OCH3 or C4 cycloalkyl alkoxy), tertiary amine, -SCH2CH3, or when X is C forming a carbonyl C=O with X or when X is S forming sulfoxide S=O or sulfonyl S(=O)₂ with X, or two R17 are forming a 4-membered cycloalkyl, optionally comprising one or more hetero atoms (preferably O ), and R18 may be the same or different, H, alkoxy or one R18 is forming a carbonyl C=O with the C atom attached to or one R17 and one R18 form a 5- or e- membered cyclic ring structure comprising two carbon atoms of C, forming a condensed cyclic group with C, optionally comprising one or more heteroatoms (preferably N and/or O), wherein the 5- or 6-membered cyclic ring structure is optionally substituted with C1 to C3 alkyl or alkoxy carbonyl (preferably at the position of the heteroatom), and R19 may be the same or different, H, CH₃. Combinations of the various preferred embodiments are themselves considered preferred embodiments according to Formulas, 1, 1a, 2, 2a, 3, 4, 5, 6 or 7 of the present invention.

In one preferred embodiment the compound according to and one of Formulas 1 or 5 is selected from the group of N-(4-methyl-5-(1-(phenylsulfonyl)-1 H-indol-5-yl)thiazol-2-yl)acetamide, N-(4- methyl-5-(1-(phenylsulfonyl)-1 ,2,3,4-tetrahydroquinolin-6-yl)thiazol-2-yl)acetamide, N-(4-methyl-5- (1-(phenylsulfonyl)indolin-5-yl)thiazol-2-yl)acetamide, N-(4-methyl-5-(4-(phenylsulfonyl)-3,4-dihy- dro-2H-benzo[b][1 ,4]oxazin-7-yl)thiazol-2-yl)acetamide, N-(5-(1-(phenylsulfonyl)-2,3,4,5-tetrahy- dro-1 H-benzo[b]azepin-7-yl)thiazol-2-yl)acetamide, N-(4-methyl-5-(5-(phenylsulfonyl)-5,6,7,8-tet- rahydronaphthalen-2-yl)thiazol-2-yl)acetamide, N-(5-(4-methoxy-1-(phenylsulfonyl)-1 ,2,3,4-tetra- hydroquinolin-6-yl)-4-methylthiazol-2-yl)acetamide, N-(4-methyl-5-(4-(phenylsulfonyl)-3,4-dihydro- 2H-benzo[b][1 ,4]thiazin-7-yl)thiazol-2-yl)acetamide, N-(4-methyl-5-(1-oxido-4-(phenylsulfonyl)- 3,4-dihydro-2H-benzo[b][1 ,4]thiazin-7-yl)thiazol-2-yl)acetamide, N-(5-(1 ,1-dioxido-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-naphthyridin-3-yl)thiazol-2-yl)acetamide, N-(4- methyl-5-(4-oxo-1-(phenylsulfonyl)-1 ,2,3,4-tetrahydroquinolin-6-yl)thiazol-2-yl)acetamide, N-(5-(4- hydroxy-1-(phenylsulfonyl)-1 ,2,3,4-tetrahydroquinolin-6-yl)-4-methylthiazol-2-yl)acetamide, N-(4- methyl-5-(2-methyl-1-(phenylsulfonyl)-1 ,2,3,4-tetrahydroquinolin-6-yl)thiazol-2-yl)acetamide, N-(5- (1-(phenylsulfonyl)-1 ,2,3,4-tetrahydroquinolin-6-yl)thiazol-2-yl)acetamide, N-(4-methyl-5-(5- (phenylsulfonyl)-5,6,7,8-tetrahydro-1 ,5-naphthyridin-2-yl)thiazol-2-yl)acetamide, N-(4-methyl-5-(1- (phenylsulfonyl)-1 ,2,3,4-tetrahydroquinolin-6-yl)oxazol-2-yl)acetamide, N-(4-methyl-5-(5- (phenylsulfonyl)-2,3,3a,4,5,9b-hexahydrofuro[3,2-c]quinolin-8-yl)thiazol-2-yl)acetamide, (R)-N-(5- (4-methoxy-1-(phenylsulfonyl)-1 ,2,3,4-tetrahydroquinolin-6-yl)-4-methylthiazol-2-yl)acetamide, tert-butyl 6-((4-methyl-5-(1-(phenylsulfonyl)-1 ,2,3,4-tetrahydroquinolin-6-yl)thiazol-2-yl)amino)-6- oxohexyl)carbamate,N-(5-(4-acetyl-1-(phenylsulfonyl)-1 ,2,3,4-tetrahydroquinoxalin-6-yl)-4-methyl- thiazol-2-yl)acetamide, N-(4-methyl-5-(4-methyl-3-oxo-1-(phenylsulfonyl)-1 ,2,3,4-tetrahydro- quinoxalin-6-yl)thiazol-2-yl)acetamide, N-(5-(3-methoxy-1-(phenylsulfonyl)-1 ,2,3,4-tetrahydroquin- olin-6-yl)-4-methylthiazol-2-yl)acetamide, N-(5-(4-methoxy-4-methyl-1-(phenylsulfonyl)-1 ,2,3,4- tetrahydroquinolin-6-yl)-4-methylthiazol-2-yl)acetamide, N-(4-methyl-5-(4-morpholino-1- (phenylsulfonyl)-1 ,2,3,4-tetrahydroquinolin-6-yl)thiazol-2-yl)acetamide, N-(4-methyl-5-(6- (phenylsulfonyl)-3,4,4a,5,6,10b-hexahydro-2H-pyrano[3,2-c]quinolin-9-yl)thiazol-2-yl)acetamide, N-(4-methyl-5-(1-(o-tolylsulfonyl)-1 ,2,3,4-tetrahydroquinolin-6-yl)thiazol-2-yl)acetamide, N-(4-me- thyl-5-(1 -(naphthalen-1 -ylsulfonyl)-1 ,2,3,4-tetrahydroquinolin-6-yl)thiazol-2-yl)acetamide, N-(5-(1- (cyclohexylsulfonyl)-l ,2,3,4-tetrahydroquinolin-6-yl)-4-methylthiazol-2-yl)acetamide, N-(4-methyl- 5-(1-(pyridin-3-ylsulfonyl)-1 ,2,3,4-tetrahydroquinolin-6-yl)thiazol-2-yl)acetamide, N-(4-methyl-5-(1- (methylsulfonyl)-1 ,2,3,4-tetrahydroquinolin-6-yl)thiazol-2-yl)acetamide, N-(4-methyl-5-(1-(thio- phen-2-ylsulfonyl)-1 ,2,3,4-tetrahydroquinolin-6-yl)thiazol-2-yl)acetamide, N-(5-(1-((4-fluoro- phenyl)sulfonyl)-1 ,2,3,4-tetrahydroquinolin-6-yl)-4-methylthiazol-2-yl)acetamide, N-(5-(1 -((2,4-di- chlorophenyl)sulfonyl)-1 ,2,3,4-tetrahydroquinolin-6-yl)-4-methylthiazol-2-yl)acetamide, N-(4-me- thyl-5-(1-(naphthalen-2-ylsulfonyl)-1 ,2,3,4-tetrahydroquinolin-6-yl)thiazol-2-yl)acetamide, (S)-N-(5- (4-methoxy-1-(phenylsulfonyl)-1 ,2,3,4-tetrahydroquinolin-6-yl)-4-methylthiazol-2-yl)acetamide, N- (4-methyl-5-(1-tosyl-1 ,2,3,4-tetrahydroquinolin-6-yl)thiazol-2-yl)acetamide, N-(5-(1-((2,3-dichloro- phenyl)sulfonyl)-1 ,2,3,4-tetrahydroquinolin-6-yl)-4-methylthiazol-2-yl)acetamide, N-(5-(1 -(benzyl- sulfonyl)-1 ,2,3,4-tetrahydroquinolin-6-yl)-4-methylthiazol-2-yl)acetamide, N-(5-(1-((2,3-dihydro- benzofuran-5-yl)sulfonyl)-1 ,2,3,4-tetrahydroquinolin-6-yl)-4-methylthiazol-2-yl)acetamide, tert-bu- tyl (4-methyl-5-(1-(phenylsulfonyl)-1 ,2,3,4-tetrahydroquinolin-6-yl)thiazol-2-yl)carbamate, 4-me- thyl-5-(1 -(phenylsulfonyl)- 1 ,2,3,4-tetrahydroquinolin-6-yl)thiazol-2-amine, N-(4-ethyl-5-(1- (phenylsulfonyl)-1 ,2,3,4-tetrahydroquinolin-6-yl)thiazol-2-yl)acetamide, N-(5-(1-(cyclopropyl- sulfonyl)-1 ,2,3,4-tetrahydroquinolin-6-yl)-4-methylthiazol-2-yl)acetamide, N-(5-(2,2-dimethyl-1- (phenylsulfonyl)-1 ,2,3,4-tetrahydroquinolin-6-yl)-4-methylthiazol-2-yl)acetamide, N-(4-methyl-5- (r-(phenylsulfonyl)-2',3'-dihydro-rH-spiro[oxetane-3,4'-quinolin]-6'-yl)thiazol-2-yl)acetamide, N- (5-(1-((3-methoxyphenyl)sulfonyl)-1 ,2,3,4-tetrahydroquinolin-6-yl)-4-methylthiazol-2-yl)acetamide, N-(4-methyl-5-(5-methyl-1-(phenylsulfonyl)-1 ,2,3,4-tetrahydroquinolin-6-yl)thiazol-2-yl)acetamide,

5-methyl-4-(1-(phenylsulfonyl)-1 ,2,3,4-tetrahydroquinolin-6-yl)-N-(2,2,2-trifluoroethyl)thiazol-2- amine, N-(5-(4,4-difluoro-1-(phenylsulfonyl)-1 ,2,3,4-tetrahydroquinolin-6-yl)-4-methylthiazol-2- yl)acetamide, N-(5-(1-(allylsulfonyl)-1 ,2,3,4-tetrahydroquinolin-6-yl)-4-methylthiazol-2-yl)acetam- ide, N-allyl-5-methyl-4-(1-(phenylsulfonyl)-1 ,2,3,4-tetrahydroquinolin-6-yl)thiazol-2-amine, N,5- dimethyl-4-(1-(phenylsulfonyl)-1 ,2,3,4-tetrahydroquinolin-6-yl)thiazol-2-amine, N-(5-(1-((3-bromo- phenyl)sulfonyl)-1 ,2,3,4-tetrahydroquinolin-6-yl)-4-methylthiazol-2-yl)acetamide, 3-((6-(2-acetam- ido-4-methylthiazol-5-yl)-3,4-dihydroquinolin-1 (2H)-yl)sulfonyl)benzenesulfonyl fluoride, N-(5-(1- ((3-acetylphenyl)sulfonyl)-1 ,2,3,4-tetrahydroquinolin-6-yl)-4-methylthiazol-2-yl)acetamide, N-(5-(1- ((3-(2-bromoacetyl)phenyl)sulfonyl)-1 ,2,3,4-tetrahydroquinolin-6-yl)-4-methylthiazol-2-yl)acetam- ide, 2,2,2-trifluoro-N-(4-methyl-5-(1-(phenylsulfonyl)-1 ,2,3,4-tetrahydroquinolin-6-yl)thiazol-2- yl)acetamide, N-(5-(1 -((3-(1 -hydroxyethyl)phenyl)sulfonyl)-1 ,2,3,4-tetrahydroquinolin-6-yl)-4-me- thylthiazol-2-yl)acetamide, 4-methyl-N-phenyl-5-(1-(phenylsulfonyl)-1 ,2,3,4-tetrahydroquinolin-6- yl)thiazol-2-amine, N-(5-(1-((3-aminophenyl)sulfonyl)-1 ,2,3,4-tetrahydroquinolin-6-yl)-4-methylthi- azol-2-yl)acetamide, N-(3-((6-(2-acetamido-4-methylthiazol-5-yl)-3,4-dihydroquinolin-1 (2H)-yl)sul- fonyl)phenyl)acetamide, N-(5-(1-((3-(dimethylamino)phenyl)sulfonyl)-1 ,2,3,4-tetrahydroquinolin-6- yl)-4-methylthiazol-2-yl)acetamide, N-(5-(1-((2-chlorophenyl)sulfonyl)-1 ,2,3,4-tetrahydroquinolin-

6-yl)-4-methylthiazol-2-yl)acetamide, N-(5-(1-((3,4-dimethoxyphenyl)sulfonyl)-1 ,2,3,4-tetrahydro- quinolin-6-yl)-4-methylthiazol-2-yl)acetamide, N-(5-(1-((2,3-dimethoxyphenyl)sulfonyl)-1 ,2,3,4-tet- rahydroquinolin-6-yl)-4-methylthiazol-2-yl)acetamide, Methyl 3-((6-(2-acetamido-4-methylthiazol- 5-yl)-3,4-dihydroquinolin-1 (2H)-yl)sulfonyl)thiophene-2-carboxylate, N-(4-methyl-5-(1-((3-nitro- phenyl)sulfonyl)-1 ,2,3,4-tetrahydroquinolin-6-yl)thiazol-2-yl)acetamide, N-(4-methyl-5-(1-((2-oxo- 2,3-dihydrobenzo[d]oxazol-7-yl)sulfonyl)-1 ,2,3,4-tetrahydroquinolin-6-yl)thiazol-2-yl)acetamide, N- (4-methyl-5-(1-((3-oxo-3,4-dihydro-2H-benzo[b][1 ,4]oxazin-7-yl)sulfonyl)-1 ,2,3,4-tetrahydroquino- lin-6-yl)thiazol-2-yl)acetamide, N-(5-(1-((2,5-difluorophenyl)sulfonyl)-1 ,2,3,4-tetrahydroquinolin-6- yl)-4-methylthiazol-2-yl)acetamide, methyl 3-((6-(2-acetamido-4-methylthiazol-5-yl)-3,4-dihydro- qu i no I in- 1 (2H)-yl)sulfonyl)benzoate, N-(5-(1 -((5-chloro-2-fluorophenyl)sulfonyl)-1 ,2,3,4-tetrahydro- quinolin-6-yl)-4-methylthiazol-2-yl)acetamide, N-(5-(1-((2-chloro-5-fluorophenyl)sulfonyl)-1 , 2,3,4- tetrahydroquinolin-6-yl)-4-methylthiazol-2-yl)acetamide, N-(5-(1-(benzo[d][1 ,3]dioxol-5-ylsulfonyl)- 1 ,2,3,4-tetrahydroquinolin-6-yl)-4-methylthiazol-2-yl)acetamide, N-(4-methyl-5-(1 -((1 -methyl-1 H- indol-5-yl)sulfonyl)-1 ,2,3,4-tetrahydroquinolin-6-yl)thiazol-2-yl)acetamide, N-(5-(1-((2,3-dihydro- 1 H-inden-5-yl)sulfonyl)-1 ,2,3,4-tetrahydroquinolin-6-yl)-4-methylthiazol-2-yl)acetamide, N-(5-(1- ((2,3-dihydrobenzo[b][1 ,4]dioxin-6-yl)sulfonyl)-1 ,2,3,4-tetrahydroquinolin-6-yl)-4-methylthiazol-2- yl)acetamide, N-(4-methyl-5-(1 -((5,6,7, 8-tetrahydronaphthalen-2-yl)sulfonyl)-1 , 2,3, 4-tetrahydro- quinolin-6-yl)thiazol-2-yl)acetamide, N-(5-(1-(benzofuran-2-ylsulfonyl)-1 ,2,3,4-tetrahydroquinolin- 6-yl)-4-methylthiazol-2-yl)acetamide, N-(5-(1-(benzo[b]thiophen-3-ylsulfonyl)-1 ,2,3,4-tetrahydro- quinolin-6-yl)-4-methylthiazol-2-yl)acetamide, N-(5-(1-(benzofuran-6-ylsulfonyl)-1 ,2,3,4-tetrahy- droquinolin-6-yl)-4-methylthiazol-2-yl)acetamide, N-(5-(1-((2,6-dichlorophenyl)sulfonyl)-1 ,2,3,4- tetrahydroquinolin-6-yl)-4-methylthiazol-2-yl)acetamide, N-((5-(1-((2,6-difluorophenyl)sulfonyl)-

1.2.3.4-tetrahydroquinolin-6-yl)-4-methylthiazol-2-yl)acetamide, N-(4-methyl-5-(1-((3-oxo-3,4-dihy- dro-2H-benzo[b][1 ,4]thiazin-6-yl)sulfonyl)-1 ,2,3,4-tetrahydroquinolin-6-yl)thiazol-2-yl)acetamide, N-(4-methyl-5-(1-((2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)sulfonyl)-1 ,2,3,4-tetrahydroquinolin-6- yl)thiazol-2-yl)acetamide, N-(4-methyl-5-(1-((4-nitrophenyl)sulfonyl)-1 ,2,3,4-tetrahydroquinolin-6- yl)thiazol-2-yl)acetamide, 3-((6-(2-acetamido-4-methylthiazol-5-yl)-3,4-dihydroquinolin-1 (2H)- yl)sulfonyl)benzoic acid, N-(3-((6-(2-acetamido-4-methylthiazol-5-yl)-3,4-dihydroquinolin-1 (2H)- yl)sulfonyl)phenyl)acrylamide, N-(3-((6-(2-acetamido-4-methylthiazol-5-yl)-3,4-dihydroquinolin- 1 (2H)-yl)sulfonyl)phenyl)-2-chloroacetamide, tert-butyl 7-(2-acetamido-4-methylthiazol-5-yl)-4- (phenylsulfonyl)-3,4-dihydroquinoxaline-1 (2H)-carboxylate, N-(4-methyl-5-(1-(phenylsulfonyl)-

1 .2.3.4-tetrahydroquinoxalin-6-yl)thiazol-2-yl)acetamide, N-(4-methyl-5-(4-methyl-1 - (phenylsulfonyl)-1 ,2,3,4-tetrahydroquinoxalin-6-yl)thiazol-2-yl)acetamide, N-(5-(5-(phenylsulfonyl)- 5,6,7,8-tetrahydro-1 ,5-naphthyridin-2-yl)thiazol-2-yl)acetamide, N-(5-(1 -(phenylsulfonyl)-l ,2,3,4- tetrahydroquinolin-6-yl)-1 ,3,4-thiadiazol-2-yl)acetamide, N-(5-(1 -((4-aminophenyl)sulfonyl)-

1.2.3.4-tetrahydroquinolin-6-yl)-4-methylthiazol-2-yl)acetamide, N-(4-((6-(2-acetamido-4-methyl- thiazol-5-yl)-3,4-dihydroquinolin-1 (2H)-yl)sulfonyl)phenyl)acrylamide, N-(4-((6-(2-acetamido-4-me- thylthiazol-5-yl)-3,4-dihydroquinolin-1 (2H)-yl)sulfonyl)phenyl)-2-chloroacetamide, N-(5-(1-((4- acetylphenyl)sulfonyl)-1 ,2,3,4-tetrahydroquinolin-6-yl)-4-methylthiazol-2-yl)acetamide, N-(5-(1-((4- (dimethylamino)phenyl)sulfonyl)-1 ,2,3,4-tetrahydroquinolin-6-yl)-4-methylthiazol-2-yl)acetamide, N-(5-(1-((4-(2-bromoacetyl)phenyl)sulfonyl)-1 ,2,3,4-tetrahydroquinolin-6-yl)-4-methylthiazol-2- yl)acetamide, N-(5-(1 -((4-(1 -hydroxyethyl)phenyl)sulfonyl)-1 ,2,3,4-tetrahydroquinolin-6-yl)-4-me- thylthiazol-2-yl)acetamide, N-(5-(5-((2,3-dichlorophenyl)sulfonyl)-5,6,7,8-tetrahydro-1 ,5-naphthy- ridin-2-yl)thiazol-2-yl)acetamide, N-(5-(5-((2,3-dichlorophenyl)sulfonyl)-5,6,7,8-tetrahydro-1 ,5- naphthyridin-2-yl)-4-methylthiazol-2-yl)acetamide, N-(5-(5-((5-chloro-2-fluorophenyl)sulfonyl)- 5,6,7,8-tetrahydro-1 ,5-naphthyridin-2-yl)thiazol-2-yl)acetamide, N-(5-(5-((5-chloro-2-fluoro- phenyl)sulfonyl)-5,6,7,8-tetrahydro-1 ,5-naphthyridin-2-yl)-4-methylthiazol-2-yl)acetamide, N-(5-(1- benzoyl-1 ,2,3,4-tetrahydroquinolin-6-yl)-4-methylthiazol-2-yl)acetamide, N-(5-(1 -benzyl-1 , 2,3,4- tetrahydroquinolin-6-yl)-4-methylthiazol-2-yl)acetamide, tert-butyl 9-(2-acetamido-4-methylthiazol- 5-yl)-6-(phenylsulfonyl)-3,4,4a,5,6,10b-hexahydrobenzo[h][1 ,6]naphthyridine-1 (2H)-carboxylate, N-(4-methyl-5-(6-(phenylsulfonyl)-1 ,2,3,4,4a,5,6,10b-octahydrobenzo[h][1 ,6]naphthyridin-9-yl)thi- azol-2-yl)acetamide, N-(4-methyl-5-(1-methyl-6-(phenylsulfonyl)-1 ,2,3,4,4a,5,6,10b-octahydro- benzo[h][1 ,6]naphthyridin-9-yl)thiazol-2-yl)acetamide, N-(5-(4-ethylthio)-1-(phenylsulfonyl)-

1 ,2,3,4-tetrahydroquinolin-6-yl)-4-methylthiazol-2-yl)acetamide, N-(5-(1-((3-chloro-2-fluoro- phenyl)sulfonyl)-1 ,2,3,4-tetrahydroquinolin-6-yl)-4-methylthiazol-2-yl)acetamide, N-(4-methyl-5-(1- (phenylsulfonyl)-4-(piperidin-1-yl)-1 ,2,3,4-tetrahydroquinolin-6-yl)thiazol-2-yl)acetamide, N-(5-(4- (3-isopropoxyazetidin-1-yl)-1-(phenylsulfonyl)-1 ,2,3,4-tetrahydroquinolin-6-yl)-4-methylthiazol-2- yl)acetamide, N-(5-(4-(dimethylamino)-1-(phenylsulfonyl)-1 ,2,3,4-tetrahydroquinolin-6-yl)-4-me- thylthiazol-2-yl)acetamide, N-(5-(4-cyclobutoxy-1-(phenylsulfonyl)-1 ,2,3,4-tetrahydroquinolin-6-yl)- 4-methylthiazol-2-yl)acetamide, N-(4-methyl-5-(3-(methylsulfonyl)-4-(phenylsulfonamido)phe- nyl)thiazol-2-yl)acetamide, N-(5-(4-((2-chlorophenyl)sulfonamido)-3-(methylsulfonyl)phenyl)-4-me- thylthiazol-2-yl)acetamide, N-(4-methyl-5-(3-(methylsulfonyl)-4-(naphthalene-1-sulfonamido)phe- nyl)thiazol-2-yl)acetamide, N-(4-methyl-5-(2-(phenylsulfonyl)isoindolin-5-yl)thiazol-2-yl)acetamide, N-(5-(2-((2-chlorophenyl)sulfonyl)isoindolin-5-yl)-4-methylthiazol-2-yl)acetamide N-(5-(3-fluoro-4- (phenylsulfonamidomethyl)phenyl)-4-methylthiazol-2-yl)acetamide, N-(4-methyl-5-(3-(methyl- sulfonyl)-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-(methyl- sulfonyl)-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-(me- thylthio)-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-(pyr- rolidin-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-acetam- ido-4-(phenylsulfonamido)phenyl)-4-methylthiazol-2-yl)acetamide, N-(5-(3-(methoxymethyl)-4- (phenylsulfonamido)phenyl)-4-methylthiazol-2-yl)acetamide.

In one preferred embodiment the compound according to and one of Formulas 1 or 5 is selected from the group consisting of N-(4-methyl-5-(1-(phenylsulfonyl)-1 H-indol-5-yl)thiazol-2-yl)acetam- ide, N-(4-methyl-5-(1-(phenylsulfonyl)-1 ,2,3,4-tetrahydroquinolin-6-yl)thiazol-2-yl)acetamide, N-(4- methyl-5-(1-(phenylsulfonyl)indolin-5-yl)thiazol-2-yl)acetamide, N-(4-methyl-5-(4-(phenylsulfonyl)-

3.4-dihydro-2H-benzo[b][1 ,4]oxazin-7-yl)thiazol-2-yl)acetamide, N-(5-(1-(phenylsulfonyl)-2, 3,4,5- tetrahydro-1 H-benzo[b]azepin-7-yl)thiazol-2-yl)acetamide, N-(4-methyl-5-(5-(phenylsulfonyl)- 5,6,7,8-tetrahydronaphthalen-2-yl)thiazol-2-yl)acetamide, N-(5-(4-methoxy-1-(phenylsulfonyl)-

1.2.3.4-tetrahydroquinolin-6-yl)-4-methylthiazol-2-yl)acetamide, N-(4-methyl-5-(4-(phenylsulfonyl)-

3.4-dihydro-2H-benzo[b][1 ,4]thiazin-7-yl)thiazol-2-yl)acetamide, N-(4-methyl-5-(1 -oxido-4- (phenylsulfonyl)-3,4-dihydro-2H-benzo[b][1 ,4]thiazin-7-yl)thiazol-2-yl)acetamide, N-(5-(1 ,1-diox- ido-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-naphthyridin-3-yl)thiazol-2-yl)acetamide, N-(4-methyl-5-(4-oxo-1-(phenylsulfonyl)-1 ,2,3,4-tetrahydroquinolin-6-yl)thiazol-2-yl)acetamide, N- (5-(4-hydroxy-1-(phenylsulfonyl)-1 ,2,3,4-tetrahydroquinolin-6-yl)-4-methylthiazol-2-yl)acetamide, N-(4-methyl-5-(2-methyl-1-(phenylsulfonyl)-1 ,2,3,4-tetrahydroquinolin-6-yl)thiazol-2-yl)acetamide, N-(5-(1-(phenylsulfonyl)-1 ,2,3,4-tetrahydroquinolin-6-yl)thiazol-2-yl)acetamide, N-(4-methyl-5-(5- (phenylsulfonyl)-5,6,7,8-tetrahydro-1 ,5-naphthyridin-2-yl)thiazol-2-yl)acetamide, N-(4-methyl-5-(1- (phenylsulfonyl)-1 ,2,3,4-tetrahydroquinolin-6-yl)oxazol-2-yl)acetamide, N-(4-methyl-5-(5- (phenylsulfonyl)-2,3,3a,4,5,9b-hexahydrofuro[3,2-c]quinolin-8-yl)thiazol-2-yl)acetamide, (R)-N-(5- (4-methoxy-1-(phenylsulfonyl)-1 ,2,3,4-tetrahydroquinolin-6-yl)-4-methylthiazol-2-yl)acetamide, tert-butyl 6-((4-methyl-5-(1-(phenylsulfonyl)-1 ,2,3,4-tetrahydroquinolin-6-yl)thiazol-2-yl)amino)-6- oxohexyl)carbamate,N-(5-(4-acetyl-1-(phenylsulfonyl)-1 ,2,3,4-tetrahydroquinoxalin-6-yl)-4-methyl- thiazol-2-yl)acetamide, N-(4-methyl-5-(4-methyl-3-oxo-1-(phenylsulfonyl)-1 ,2,3,4-tetrahydro- quinoxalin-6-yl)thiazol-2-yl)acetamide, N-(5-(3-methoxy-1-(phenylsulfonyl)-1 ,2,3,4-tetrahydroquin- olin-6-yl)-4-methylthiazol-2-yl)acetamide, N-(5-(4-methoxy-4-methyl-1-(phenylsulfonyl)-1 ,2,3,4- tetrahydroquinolin-6-yl)-4-methylthiazol-2-yl)acetamide, N-(4-methyl-5-(4-morpholino-1- (phenylsulfonyl)-1 ,2,3,4-tetrahydroquinolin-6-yl)thiazol-2-yl)acetamide, N-(4-methyl-5-(6- (phenylsulfonyl)-3,4,4a,5,6, 10b-hexahydro-2H-pyrano[3,2-c]quinolin-9-yl)thiazol-2-yl)acetamide, N-(4-methyl-5-(1-(o-tolylsulfonyl)-1 ,2,3,4-tetrahydroquinolin-6-yl)thiazol-2-yl)acetamide, N-(4-me- thyl-5-(1 -(naphthalen-1 -ylsulfonyl)-1 ,2,3,4-tetrahydroquinolin-6-yl)thiazol-2-yl)acetamide, N-(5-(1- (cyclohexylsulfonyl)-l ,2,3,4-tetrahydroquinolin-6-yl)-4-methylthiazol-2-yl)acetamide, N-(4-methyl- 5-(1-(pyridin-3-ylsulfonyl)-1 ,2,3,4-tetrahydroquinolin-6-yl)thiazol-2-yl)acetamide, N-(4-methyl-5-(1- (methylsulfonyl)-1 ,2,3,4-tetrahydroquinolin-6-yl)thiazol-2-yl)acetamide, N-(4-methyl-5-(1-(thio- phen-2-ylsulfonyl)-1 ,2,3,4-tetrahydroquinolin-6-yl)thiazol-2-yl)acetamide, N-(5-(1-((4-fluoro- phenyl)sulfonyl)-1 ,2,3,4-tetrahydroquinolin-6-yl)-4-methylthiazol-2-yl)acetamide, N-(5-(1 -((2,4-di- chlorophenyl)sulfonyl)-1 ,2,3,4-tetrahydroquinolin-6-yl)-4-methylthiazol-2-yl)acetamide, N-(4-me- thyl-5-(1-(naphthalen-2-ylsulfonyl)-1 ,2,3,4-tetrahydroquinolin-6-yl)thiazol-2-yl)acetamide, (S)-N-(5- (4-methoxy-1-(phenylsulfonyl)-1 ,2,3,4-tetrahydroquinolin-6-yl)-4-methylthiazol-2-yl)acetamide, N- (4-methyl-5-(1-tosyl-1 ,2,3,4-tetrahydroquinolin-6-yl)thiazol-2-yl)acetamide, N-(5-(1-((2,3-dichloro- phenyl)sulfonyl)-1 ,2,3,4-tetrahydroquinolin-6-yl)-4-methylthiazol-2-yl)acetamide, N-(5-(1-(benzyl- sulfonyl)-1 ,2,3,4-tetrahydroquinolin-6-yl)-4-methylthiazol-2-yl)acetamide, N-(5-(1-((2,3-dihydro- benzofuran-5-yl)sulfonyl)-1 ,2,3,4-tetrahydroquinolin-6-yl)-4-methylthiazol-2-yl)acetamide, tert-bu- tyl (4-methyl-5-(1-(phenylsulfonyl)-1 ,2,3,4-tetrahydroquinolin-6-yl)thiazol-2-yl)carbamate, 4-me- thyl-5-(1 -(phenylsulfonyl)- 1 ,2,3,4-tetrahydroquinolin-6-yl)thiazol-2-amine, N-(4-ethyl-5-(1- (phenylsulfonyl)-1 ,2,3,4-tetrahydroquinolin-6-yl)thiazol-2-yl)acetamide, N-(5-(1-(cyclopropyl- sulfonyl)-1 ,2,3,4-tetrahydroquinolin-6-yl)-4-methylthiazol-2-yl)acetamide, N-(5-(2,2-dimethyl-1- (phenylsulfonyl)-1 ,2,3,4-tetrahydroquinolin-6-yl)-4-methylthiazol-2-yl)acetamide, N-(4-methyl-5- (r-(phenylsulfonyl)-2',3'-dihydro-rH-spiro[oxetane-3,4'-quinolin]-6'-yl)thiazol-2-yl)acetamide, N- (5-(1-((3-methoxyphenyl)sulfonyl)-1 ,2,3,4-tetrahydroquinolin-6-yl)-4-methylthiazol-2-yl)acetamide, N-(4-methyl-5-(5-methyl-1-(phenylsulfonyl)-1 ,2,3,4-tetrahydroquinolin-6-yl)thiazol-2-yl)acetamide,

6-yl)-4-methylthiazol-2-yl)acetamide, N-(5-(1-((3,4-dimethoxyphenyl)sulfonyl)-1 ,2,3,4-tetrahydro- quinolin-6-yl)-4-methylthiazol-2-yl)acetamide, N-(5-(1-((2,3-dimethoxyphenyl)sulfonyl)-1 ,2,3,4-tet- rahydroquinolin-6-yl)-4-methylthiazol-2-yl)acetamide, Methyl 3-((6-(2-acetamido-4-methylthiazol- 5-yl)-3,4-dihydroquinolin-1 (2H)-yl)sulfonyl)thiophene-2-carboxylate, N-(4-methyl-5-(1-((3-nitro- phenyl)sulfonyl)-1 ,2,3,4-tetrahydroquinolin-6-yl)thiazol-2-yl)acetamide, N-(4-methyl-5-(1-((2-oxo- 2,3-dihydrobenzo[d]oxazol-7-yl)sulfonyl)-1 ,2,3,4-tetrahydroquinolin-6-yl)thiazol-2-yl)acetamide, N- (4-methyl-5-(1-((3-oxo-3,4-dihydro-2H-benzo[b][1 ,4]oxazin-7-yl)sulfonyl)-1 ,2,3,4-tetrahydroquino- lin-6-yl)thiazol-2-yl)acetamide, N-(5-(1-((2,5-difluorophenyl)sulfonyl)-1 ,2,3,4-tetrahydroquinolin-6- yl)-4-methylthiazol-2-yl)acetamide, methyl 3-((6-(2-acetamido-4-methylthiazol-5-yl)-3,4-dihydro- qu i no I in- 1 (2H)-yl)sulfonyl)benzoate, N-(5-(1 -((5-chloro-2-fluorophenyl)sulfonyl)-1 ,2,3,4-tetrahydro- quinolin-6-yl)-4-methylthiazol-2-yl)acetamide, N-(5-(1-((2-chloro-5-fluorophenyl)sulfonyl)-1 , 2,3,4- tetrahydroquinolin-6-yl)-4-methylthiazol-2-yl)acetamide, N-(5-(1-(benzo[d][1 ,3]dioxol-5-ylsulfonyl)-

1 ,2,3,4-tetrahydroquinolin-6-yl)-4-methylthiazol-2-yl)acetamide, N-(4-methyl-5-(1 -((1 -methyl-1 H- indol-5-yl)sulfonyl)-1 ,2,3,4-tetrahydroquinolin-6-yl)thiazol-2-yl)acetamide, N-(5-(1-((2,3-dihydro- 1 H-inden-5-yl)sulfonyl)-1 ,2,3,4-tetrahydroquinolin-6-yl)-4-methylthiazol-2-yl)acetamide, N-(5-(1- ((2,3-dihydrobenzo[b][1 ,4]dioxin-6-yl)sulfonyl)-1 ,2,3,4-tetrahydroquinolin-6-yl)-4-methylthiazol-2- yl)acetamide, N-(4-methyl-5-(1 -((5,6,7, 8-tetrahydronaphthalen-2-yl)sulfonyl)-1 , 2,3, 4-tetrahydro- quinolin-6-yl)thiazol-2-yl)acetamide, N-(5-(1-(benzofuran-2-ylsulfonyl)-1 ,2,3,4-tetrahydroquinolin- 6-yl)-4-methylthiazol-2-yl)acetamide, N-(5-(1-(benzo[b]thiophen-3-ylsulfonyl)-1 ,2,3,4-tetrahydro- quinolin-6-yl)-4-methylthiazol-2-yl)acetamide, N-(5-(1-(benzofuran-6-ylsulfonyl)-1 ,2,3,4-tetrahy- droquinolin-6-yl)-4-methylthiazol-2-yl)acetamide, N-(5-(1-((2,6-dichlorophenyl)sulfonyl)-1 ,2,3,4- tetrahydroquinolin-6-yl)-4-methylthiazol-2-yl)acetamide, N-((5-(1-((2,6-difluorophenyl)sulfonyl)-

1.2.3.4-tetrahydroquinolin-6-yl)-4-methylthiazol-2-yl)acetamide, N-(4-((6-(2-acetamido-4-methyl- thiazol-5-yl)-3,4-dihydroquinolin-1 (2H)-yl)sulfonyl)phenyl)acrylamide, N-(4-((6-(2-acetamido-4-me- thylthiazol-5-yl)-3,4-dihydroquinolin-1 (2H)-yl)sulfonyl)phenyl)-2-chloroacetamide, N-(5-(1-((4- acetylphenyl)sulfonyl)-1 ,2,3,4-tetrahydroquinolin-6-yl)-4-methylthiazol-2-yl)acetamide, N-(5-(1-((4- (dimethylamino)phenyl)sulfonyl)-1 ,2,3,4-tetrahydroquinolin-6-yl)-4-methylthiazol-2-yl)acetamide, N-(5-(1-((4-(2-bromoacetyl)phenyl)sulfonyl)-1 ,2,3,4-tetrahydroquinolin-6-yl)-4-methylthiazol-2- yl)acetamide, N-(5-(1 -((4-(1 -hydroxyethyl)phenyl)sulfonyl)-1 ,2,3,4-tetrahydroquinolin-6-yl)-4-me- thylthiazol-2-yl)acetamide, N-(5-(5-((2,3-dichlorophenyl)sulfonyl)-5,6,7,8-tetrahydro-1 ,5-naphthy- ridin-2-yl)thiazol-2-yl)acetamide, N-(5-(5-((2,3-dichlorophenyl)sulfonyl)-5,6,7,8-tetrahydro-1 ,5- naphthyridin-2-yl)-4-methylthiazol-2-yl)acetamide, N-(5-(5-((5-chloro-2-fluorophenyl)sulfonyl)- 5,6,7,8-tetrahydro-1 ,5-naphthyridin-2-yl)thiazol-2-yl)acetamide, N-(5-(5-((5-chloro-2-fluoro- phenyl)sulfonyl)-5,6,7,8-tetrahydro-1 ,5-naphthyridin-2-yl)-4-methylthiazol-2-yl)acetamide, N-(5-(1- benzoyl-1 ,2,3,4-tetrahydroquinolin-6-yl)-4-methylthiazol-2-yl)acetamide, N-(5-(1 -benzyl-1 , 2,3,4- tetrahydroquinolin-6-yl)-4-methylthiazol-2-yl)acetamide, tert-butyl 9-(2-acetamido-4-methylthiazol- 5-yl)-6-(phenylsulfonyl)-3,4,4a,5,6,10b-hexahydrobenzo[h][1 ,6]naphthyridine-1 (2H)-carboxylate, N-(4-methyl-5-(6-(phenylsulfonyl)-1 ,2,3,4,4a,5,6,10b-octahydrobenzo[h][1 ,6]naphthyridin-9-yl)thi- azol-2-yl)acetamide, N-(4-methyl-5-(1-methyl-6-(phenylsulfonyl)-1 ,2,3,4,4a,5,6,10b-octahydro- benzo[h][1 ,6]naphthyridin-9-yl)thiazol-2-yl)acetamide, N-(5-(4-ethylthio)-1-(phenylsulfonyl)- 1 ,2,3,4-tetrahydroquinolin-6-yl)-4-methylthiazol-2-yl)acetamide, N-(5-(1-((3-chloro-2-fluoro- phenyl)sulfonyl)-1 ,2,3,4-tetrahydroquinolin-6-yl)-4-methylthiazol-2-yl)acetamide, N-(4-methyl-5-(1- (phenylsulfonyl)-4-(piperidin-1-yl)-1 ,2,3,4-tetrahydroquinolin-6-yl)thiazol-2-yl)acetamide, N-(5-(4- (3-isopropoxyazetidin-1-yl)-1-(phenylsulfonyl)-1 ,2,3,4-tetrahydroquinolin-6-yl)-4-methylthiazol-2- yl)acetamide, N-(5-(4-(dimethylamino)-1-(phenylsulfonyl)-1 ,2,3,4-tetrahydroquinolin-6-yl)-4-me- thylthiazol-2-yl)acetamide, N-(5-(4-cyclobutoxy-1-(phenylsulfonyl)-1 ,2,3,4-tetrahydroquinolin-6-yl)- 4-methylthiazol-2-yl)acetamide, N-(4-methyl-5-(3-(methylsulfonyl)-4-(phenylsulfonamido)phe- nyl)thiazol-2-yl)acetamide, N-(5-(4-((2-chlorophenyl)sulfonamido)-3-(methylsulfonyl)phenyl)-4-me- thylthiazol-2-yl)acetamide, N-(4-methyl-5-(3-(methylsulfonyl)-4-(naphthalene-1-sulfonamido)phe- nyl)thiazol-2-yl)acetamide, N-(4-methyl-5-(2-(phenylsulfonyl)isoindolin-5-yl)thiazol-2-yl)acetamide, N-(5-(2-((2-chlorophenyl)sulfonyl)isoindolin-5-yl)-4-methylthiazol-2-yl)acetamide N-(5-(3-fluoro-4- (phenylsulfonamidomethyl)phenyl)-4-methylthiazol-2-yl)acetamide, N-(4-methyl-5-(3-(methyl- sulfonyl)-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-(methyl- sulfonyl)-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-(me- thylthio)-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-(pyr- rolidin-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-acetam- ido-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)sul- fonyl)-1 ,2,3,4-tetrahydroquinolin-6-yl)-4-methylthiazol-2-yl)acetamide, N-(5-(1-((3,4-Dihydro-2H- benzo[b][1 ,4]dioxepin-7-yl)sulfonyl)-1 ,2,3,4-tetrahydroquinolin-6-yl)-4-methylthiazol-2-yl)acetam- ide, N-(5-(1-(Furan-2-ylsulfonyl)-1 ,2,3,4-tetrahydroquinolin-6-yl)-4-methylthiazol-2-yl)acetamide, N-(5-(1-((1 H-lmidazol-2-yl)sulfonyl)-1 ,2,3,4-tetrahydroquinolin-6-yl)-4-methylthiazol-2-yl)acetam- ide, N-(5-(4-((2,3-Dichlorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1 ,4]thiazin-7-yl)-4-methylthia- zol-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'-dihy- dro-1 'H-spiro[oxetane-3,4'-quinolin]-6'-yl)-4-methylthiazol-2-yl)acetamide, N-(5-(1 -(Cyclopropane- carbonyl)-! ,2,3,4-tetrahydroquinolin-6-yl)-4-methylthiazol-2-yl)acetamide, N-(5-(1-(Cyclopropyl- sulfonyl)-1 ,2,3,4-tetrahydroquinolin-6-yl)-4-methylthiazol-2-yl)cyclopropanecarboxamide, N-(5-(1- (Cyclopropylsulfonyl)-1 ,2,3,4-tetrahydroquinolin-6-yl)-4-methylthiazol-2-yl)propionamide, N-(5-(1- (Cyclopropylsulfonyl)-1 ,2,3,4-tetrahydroquinolin-6-yl)-4-methylthiazol-2-yl)isobutyramide, N-(5-(1- (Cyclopropylsulfonyl)-1 ,2,3,4-tetrahydroquinolin-6-yl)-4-methylthiazol-2-yl)cyclopentanecarbox- amide, N-(5-(4-((2,3-Dichlorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1 ,4]oxazin-7-yl)-4-methyl- thiazol-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-tetrahydroquinolin-6- yl)-4-methylthiazol-2-yl)acetamide, 1-(6-((5-(1-((2,3-Dichlorophenyl)sulfonyl)-1 ,2,3,4-tetrahydro- quinolin-6-yl)-4-methylthiazol-2-yl)amino)pyridin-2-yl)pyrrolidin-2-one, N-(5-(1-((2,6-Dioxo-1 ,2,3,6- tetrahydropyrimidin-4-yl)sulfonyl)-1 ,2,3,4-tetrahydroquinolin-6-yl)-4-methylthiazol-2-yl)acetamide, N-(4-Methyl-5-(1-((5-methyl-2,6-dioxo-1 ,2,3,6-tetrahydropyrimidin-4-yl)sulfonyl)-1 ,2,3,4-tetrahy- droquinolin-6-yl)thiazol-2-yl)acetamide, N-(5-(1-((1 H-Pyrazol-4-yl)sulfonyl)-1 ,2,3,4-tetrahydroquin- olin-6-yl)-4-methylthiazol-2-yl)acetamide, N-(4-Methyl-5-(1 -((1 -methyl-1 H-1 ,2 , 3-triazol-5-y l)su I- fonyl)-1 ,2,3,4-tetrahydroquinolin-6-yl)thiazol-2-yl)acetamide, N-(4-Methyl-5-(1 -((1 -methyl-1 H-imid- azol-2-yl)sulfonyl)-1 ,2,3,4-tetrahydroquinolin-6-yl)thiazol-2-yl)acetamide, tert-Butyl 6-(6-((5-(1- ((2,3-dichlorophenyl)sulfonyl)-1 ,2,3,4-tetrahydroquinolin-6-yl)-4-methylthiazol-2-yl)amino)pyridin- 2-yl)-7-oxo-2,6-diazaspiro[3.4]octane-2-carboxylate, N-(4-Methyl-5-(1 -((1 -methyl-1 H-pyrazol-5- yl)sulfonyl)-1 ,2,3,4-tetrahydroquinolin-6-yl)thiazol-2-yl)acetamide, N-(4-Methyl-5-(1-((1 -methyl-1 H- pyrazol-4-yl)sulfonyl)-1 ,2,3,4-tetrahydroquinolin-6-yl)thiazol-2-yl)acetamide, N-(4-Methyl-5-(1-((1- methyl-1 H-pyrazol-3-yl)sulfonyl)-1 ,2,3,4-tetrahydroquinolin-6-yl)thiazol-2-yl)acetamide, N-(5-(1- (lsothiazol-5-ylsulfonyl)-1 ,2,3,4-tetrahydroquinolin-6-yl)-4-methylthiazol-2-yl)acetamide, N-(5-(1- ((4-Chloro-1 -methyl-1 H-pyrazol-5-yl)sulfonyl)-1 ,2,3,4-tetrahydroquinolin-6-yl)-4-methylthiazol-2- yl)acetamide, N-(5-(1 -((4-Chloro-1 -methyl-1 H-imidazol-5-yl)sulfonyl)-1 ,2,3,4-tetrahydroquinolin-6- yl)-4-methylthiazol-2-yl)acetamide, N-(4-Methyl-5-(1-((3-(prop-2-yn-1-ylamino)phenyl)sulfonyl)-

1.2.3.4-tetrahydroquinolin-6-yl)thiazol-2-yl)acetamide, N-(5-(1-((3-((Cyanomethyl)amino)phe- nyl)sulfonyl)-1 ,2,3,4-tetrahydroquinolin-6-yl)-4-methylthiazol-2-yl)acetamide, N-(5-(1-((6-Cyano- pyridin-2-yl)sulfonyl)-1 ,2,3,4-tetrahydroquinolin-6-yl)-4-methylthiazol-2-yl)acetamide, N-(5-(1-((3- Cyanamidophenyl)sulfonyl)-1 ,2,3,4-tetrahydroquinolin-6-yl)-4-methylthiazol-2-yl)acetamide, N-(4- Methyl-5-(1-((3-(vinylsulfonamido)phenyl)sulfonyl)-1 ,2,3,4-tetrahydroquinolin-6-yl)thiazol-2-yl)ac- etamide, N-(3-((6-(2-Acetamido-4-methylthiazol-5-yl)-3,4-dihydroquinolin-1 (2H)-yl)sulfonyl)phe- nyl)propiolamide, N-(4-Methyl-5-(1-((2-(methylsulfonyl)benzo[d]thiazol-6-yl)sulfonyl)-1 ,2,3,4-tetra- hydroquinolin-6-yl)thiazol-2-yl)acetamide, 1-(6-((5-(1-(Cyclopropylsulfonyl)-1 ,2,3,4-tetrahydroquin- olin-6-yl)-4-methylthiazol-2-yl)amino)pyridin-2-yl)pyrrolidin-2-one, N-(5-(1-(Cyclopropylsulfonyl)-

1.2.3.4-tetrahydroquinolin-6-yl)-4-methylthiazol-2-yl)cyclobutanecarboxamide, N-(5-(1-(Cyclo- propylsulfonyl)-1 ,2,3,4-tetrahydroquinolin-6-yl)-4-methylthiazol-2-yl)-1-methylcyclopropane-1 -carboxamide, N-(5-(1-(Cyclopropylsulfonyl)-1 ,2,3,4-tetrahydroquinolin-6-yl)-4-methylthiazol-2-yl)-2- methoxyacetamide, 2-Cyclopropyl-N-(5-(1-(cyclopropylsulfonyl)-1 ,2,3,4-tetrahydroquinolin-6-yl)-4- methylthiazol-2-yl)acetamide, N-(4-Methyl-5-(1-((1-methylcyclopropyl)sulfonyl)-1 ,2,3,4-tetrahydro- quinolin-6-yl)thiazol-2-yl)acetamide, 1-(6-((5-(1-(Cyclopropylsulfonyl)-1 ,2,3,4-tetrahydroquinolin-6- yl)-4-methylthiazol-2-yl)amino)pyridin-2-yl)piperidin-2-one and 3-(6-((5-(1-(Cyclopropylsulfonyl)-

1.2.3.4-tetrahydroquinolin-6-yl)-4-methylthiazol-2-yl)amino)pyridin-2-yl)-1 ,3-oxazinan-2-one.

As described in more detail herein, the invention relates to the following compounds as such, and their use in treating one or more of the medical indications described herein. The compounds of the Formula 2 according to the following embodiments, as represented by the exemplary compounds listed in Table 2, are considered novel as such and exhibit structures not previously disclosed. These compounds also exhibit the benefical properties of the invention and are intended for the medical use disclosed herein, but are not limited thereto.

In one embodiment the invention trelates to a compound according to Formula 2

Formula 2 wherein

R1 is C, S, O or N,

R3 is C1 to C5 alkyl (preferably C1 to C3 alkyl), C3 to C6 cycloalkyl, C1 to C5 haloalkyl (preferably C1 to C3 haloalkyl comprising Cl, Br, or F), -CN, carbonyl, carboxyl, carboxy ester, alkoxy, aldehyde, primary, secondary or tertiary amine, amide, imide, carbamate, carboxamide, nitro, sulfide, sulfinyl, sulfonyl, sulfino or sulfonamide,

R4 and R5 can be the same or different, H, C1 to C5 alkyl (preferably C1 to C3 alkyl), C2 to C5 alkenyl, C3 to C6 cycloalkyl, C3 to C6 hetero cycloalkyl (preferably comprising N, S and/or O), C1 to C5 haloalkyl (preferably C1 to C3 haloalkyl, preferably comprising Cl, Br or F), C4 to C6 aryl, sulfide, sulfinyl, sulfonyl, sulfino, sulfonamide, carboxyl, carboxy ester, carbonyl C=OR, wherein R is C1 to C10 alkyl (preferably C1 to C5 alkyl), C1 to C3 haloalkyl (preferably comprising Cl, Br or F), C4 to C6 aryl, wherein R is optionally substituted with a carbamate or a carbamate ester, wherein when R10 and R11 or R11 and R14 do not form a ring structure, at least one of R4 and R5 is carbonyl C=OR, or R4 and R5 form a 4-, 5- or 6-membered hetero cycloalkyl comprising N and optionally one or more further heteroatoms (preferably N, O and/or S), wherein said hetero cycloalkyl is optionally substituted by alkoxy,

R7, R8 and R9 are the same or different, C or N,

R11 is C3 to C6 cycloalkyl, C4 to C6 hetero cycloalkyl (preferably comprising N, S and/or O), halogen (preferably F, Cl, or Br), sulfide, sulfinyl, sulfonyl, sulfino, sulfonamide, carboxyl, carboxyl ester, carboxamide, alkoxy or aryloxy, or R10 and R11 form together with the atoms they are attached to a 5- to 8-membered cycloalkyl or aryl ring structure D comprising two carbon atoms of B, forming a condensed cyclic 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), a primary, secondary or tertiary amine or alkyl amine, or R11 and R14 form together with the atoms they are attached to a 5- to 8-membered cycloalkyl or aryl ring structure C comprising two carbon atoms of B, forming a condensed bicyclic group with B, optionally comprising one or more heteroatoms (preferably N, O and/or S), wherein B and C is one of

R13 is C1 to C5 alkyl (preferably C1 to C3 alkyl), C2 to C5 alkenyl, C3 to C6 cycloalkyl, C5 or C6

aryl, alkyl aryl, C5 or C6 hetero aryl (preferably comprising N, S and/or O), a bicyclic group (preferably comprising one or two aromatic rings), optionally comprising one or more heteroatoms (preferably N, O and/or S), or R12 and R13 are absent when R11 is halogen, or not forming a ring structure with R10 or R14, or when R11 and R14 form together with the atoms they are attached to a 5- to 8-membered cycloalkyl or aryl ring structure C and R15 and R16 are present,

R15 is C1 to C5 alkyl (preferably C1 to C3 alkyl), carbonyl C=O, sulfide, sulfinyl or sulfonyl, when R11 and R14 are not forming a ring structure, or when R11 and R14 form a 5-, 7- or 8-membered ring structure, or

R15 is C1 to C5 alkyl (preferably C1 to C3 alkyl), sulfide, sulfinyl or sulfonyl, when R11 and R14 form a 6- membered ring structure, R16 is C1 to C5 alkyl (preferably C1 to C3 alkyl), C2 to C5 alkenyl, C3 to C6 cycloalkyl, C5 or C6 aryl, alkyl aryl, C5 or C6 hetero aryl (preferably comprising N, S and/or O), a bicyclic group (preferably comprising one or two aromatic rings), optionally comprising one or more heteroatoms (preferably N, O and/or S), or R15 and R16 are absent when R14 is H, or R10 and R11 form together with the atoms they are attached to a 5- to 8-membered cycloalkyl or aryl ring structure D, or when R11 and R14 form together with the atoms they are attached to a 5- to 8-membered cycloalkyl or aryl ring structure C and R12 and R13 are present,

X is C, S and/or O,

Y is C, N, S and/or O,

R18 may be the same or different, H, alkoxy, or one R17 and one R18 form a 5- or 6-membered cyclic ring structure comprising two carbon atoms of C, forming a condensed cyclic group with C, optionally comprising one or more heteroatoms (preferably N, O and/or S), wherein the 5- or 6-membered cyclic ring structure is optionally substituted with C1 to C3 alkyl or alkoxy carbonyl (preferably at the position of the heteroatom), and

In one embodiment the compound according to Formula 2 is characterized in that R4 and R5 can be the same or different, H, C1 to C5 alkyl (preferably C1 to C3 alkyl), C2 to C5 alkenyl, C3 to C6 cycloalkyl, C3 to C6 hetero cycloalkyl (preferably comprising N, S and/or O), C1 to C5 haloalkyl (preferably C1 to C3 haloalkyl, preferably comprising Cl, Br or F), C3 to C6 cycloalkyl, alkoxy, C4 to C6 aryl, C5 to C6 heteroaryl (preferably comprising N, S and/or O and optionally substituted with c3 to c6 hetero cyclyl (preferably comprising comprising N, S and/or O)), sulfide, sulfinyl, sulfonyl, sulfino, sulfonamide, carboxyl, carboxy ester, carbonyl C=OR, wherein R is C1 to C10 alkyl (preferably C1 to C5 alkyl), C1 to C3 haloalkyl (preferably comprising Cl, Br or F), C4 to C6 aryl, wherein R is optionally substituted with a carbamate or a carbamate ester, wherein when R10 and R11 or R11 and R14 do not form a ring structure, at least one of R4 and R5 is carbonyl C=OR, or R4 and R5 form a 4-, 5- or 6-membered hetero cycloalkyl comprising N and optionally one or more further heteroatoms (preferably N, O and/or S), wherein said hetero cycloalkyl is optionally substituted by alkoxy,

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

In one embodiment the invention trelates to a compound according to Formula 2 wherein R10 and R11 form together with the atoms they are attached to a 5- to 7-membered cyclic or aryl ring structure D forming a condensed bicyclic group with B, wherein B and D is

and wherein R7, R8, R9, R12 and R13 are according to claim 10.

In one embodiment the invention trelates to a compound according to Formula 2a

Formula 2a wherein

R1 is C, S, O or N,

R4 and R5 can be the same or different, H, C1 to C5 alkyl (preferably C1 to C3 alkyl), C2 to C5 alkenyl, C3 to C6 cycloalkyl, C3 to C6 hetero cycloalkyl (preferably comprising N, S and/or O), C1 to C5 haloalkyl (preferably C1 to C3 haloalkyl, preferably comprising Cl, Br or F), C4 to C6 aryl, sulfide, sulfinyl, sulfonyl, sulfino, sulfonamide, carboxyl, carboxy ester, carbonyl C=OR, wherein R is C1 to C10 alkyl (preferably C1 to C5 alkyl), C1 to C3 haloalkyl (preferably comprising Cl, Br or F), C4 to C6 aryl, wherein R is optionally substituted with a carbamate or a carbamate ester, wherein when R11 and R14 do not form a ring structure, at least one of R4 and R5 is carbonyl C=OR, or R4 and R5 form a 4-, 5- or 6-membered hetero cycloalkyl comprising N and optionally one or more further heteroatoms (preferably N, O and/or S), wherein said hetero cycloalkyl is optionally substituted by alkoxy,

R7 and R8 are the same or different, C or N,

R9 is C,

R11 is C3 to C6 cycloalkyl, C4 to C6 hetero cycloalkyl (preferably comprising N, S and/or O), halogen (preferably F, Cl, or Br), sulfide, sulfinyl, sulfonyl, sulfino, sulfonamide, carboxyl, carboxyl ester, carboxamide, alkoxy or aryloxy,

R15 is C1 to C5 alkyl (preferably C1 to C3 alkyl), sulfide, sulfinyl or sulfonyl, when R11 and R14 form a 6- membered ring structure,

R16 is C1 to C5 alkyl (preferably C1 to C3 alkyl), C2 to C5 alkenyl, C3 to C6 cycloalkyl, C5 or C6 aryl, alkyl aryl, C5 or C6 hetero aryl (preferably comprising N, S and/or O), a bicyclic group (preferably comprising one or two aromatic rings), optionally comprising one or more heteroatoms (preferably N, O and/or S), or R15 and R16 are absent when R14 is H,

X is C, S and/or O,

Y is C, N, S and/or O,

In one embodiment the compound according to Formula 2a is characterized in that R4 and R5 can be the same or different, H, C1 to C5 alkyl (preferably C1 to C3 alkyl), C2 to C5 alkenyl, C3 to C6 cycloalkyl, C3 to C6 hetero cycloalkyl (preferably comprising N, S and/or O), C1 to C5 haloalkyl (preferably C1 to C3 haloalkyl, preferably comprising Cl, Br or F), C3 to C6 cycloalkyl, alkoxy, C4 to C6 aryl, C5 to C6 heteroaryl (preferably comprising N, S and/or O and optionally substituted with c3 to c6 hetero cyclyl (preferably comprising comprising N, S and/or O)), sulfide, sulfinyl, sulfonyl, sulfino, sulfonamide, carboxyl, carboxy ester, carbonyl C=OR, wherein R is C1 to C10 alkyl (preferably C1 to C5 alkyl), C1 to C3 haloalkyl (preferably comprising Cl, Br or F), C4 to C6 aryl, wherein R is optionally substituted with a carbamate or a carbamate ester, wherein when R11 and R14 do not form a ring structure, at least one of R4 and R5 is carbonyl C=OR, or R4 and R5 form a 4-, 5- or 6-membered hetero cycloalkyl comprising N and optionally one or more further heteroatoms (preferably N, O and/or S), wherein said hetero cycloalkyl is optionally substituted by alkoxy,

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

In one embodiment the invention trelates to a compound according to Formula 2 or 2a wherein R16 is one of

wherein

wherein

X and Y are the same or different, one of O, S or N,

wherein

X and Y are the same or different, one of C, O, S or N,

R23 is H, carbonyl, carboxyl or carboxy ester,

R24 is H or C1 to C5 alkyl (preferably C1 to C3 alkyl),

In one embodiment the invention relates to the compound according to any one of Formulas 1, 1a, 2, 2a, 3, 4, 5, 6 and 7 for use as a medicament in the treatment of a medical condition associated with defective and/or pathologic class II phosphoinositide 3-kinase (PI3K) signaling. In one embodiment the invention relates to the compound according to any one of Formulas 1, 1a, 2, 2a, 3, 4, 5, 6 and 7 for use as a medicament in the treatment of a medical condition associated with defective and/or pathologic signaling of the beta isoform of class II phosphoinositide 3-kinase (PI3K-C2b).

In one embodiment the invention relates to the compound according to any one of 1, 1a, 2, 2a, 3, 4, 5, 6 and 7 for use as a medicament in the treatment of a medical condition associated with defective and/or pathologic class II phosphoinositide 3-kinase (PI3K) signaling, preferably defective and/or pathologic signaling of the beta isoform of class II phosphoinositide 3-kinase (PI3K-C2b), wherein the medical condition is selected from the group consisting of stroke, a cardiovascular disease related to endothelial cell dysfunction, cancer, cancer metastasis, myopathy (preferably myotubular myopathy) and diabetes.

In one embodiment the invention relates to the compound according to any one of 1, 1a, 2, 2a, 3, 4, 5, 6 and 7 for use in the treatment of a subject suffering from a medical condition associated with defective and/or pathologic class II phosphoinositide 3-kinase (PI3K) signaling, preferably defective and/or pathologic signaling of the beta isoform of class II phosphoinositide 3-kinase (PI3K-C2b), wherein the medical condition is selected from the group consisting of stroke, a cardiovascular disease related to endothelial cell dysfunction, cancer, cancer metastasis, myopathy (preferably myotubular myopathy) and diabetes.

In one embodiment, the medical condition to be treated is myopathy, preferably myotubular myopathy, more preferably X-linked centronuclear myopathy. Preferred embodiments relate to myopathies associated with defective and/or pathologic phosphoinositide 3-kinase (PI3K) signaling. For example, it has been shown that X-linked centronuclear myopathy phenotypes in mouse models are rescued by deletion of class II PI3K-C2b and partially ameliorated by application of the non-selective PI3K inhibitor wortmannin.

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

In one embodiment, the medical condition to be treated is diabetes. Preferred embodiments relate to subjects with diabetes in which it can be shown the disease is associated with defective and/or pathologic class II phosphoinositide 3-kinase (PI3K) signaling.

In one embodiment, the medical condition to be treated is stroke and/or a cardiovascular disease related to endothelial cell dysfunction. Preferred embodiments relate to cardiovascular diseases associated with defective and/or pathologic class II phosphoinositide 3-kinase (PI3K) signaling.

In one embodiment the invention relates to a method of treating and/or preventing a medical condition associated with defective and/or pathologic class II phosphoinositide 3-kinase (PI3K) signaling, preferably defective and/or pathologic signaling of the beta isoform of class II phosphoinositide 3-kinase (PI3K-C2b), wherein the medical condition is selected from the group consisting of stroke, a cardiovascular disease related to endothelial cell dysfunction, cancer, cancer metastasis, myopathy (preferably myotubular myopathy) and diabetes, said method comprising the administration of one or more of the above compounds or compounds falling under the formulae described above to a subject in need thereof, in particular the compounds of Formulas 1, 1a, 2, 2a, 3, 4, 5, 6 and 7, and preferred embodiments and combinations thereof described above.

In one embodiment the invention relates to a method of treatment of preventing a medical condition associated with defective and/or pathologic class II phosphoinositide 3-kinase (PI3K) signaling, preferably defective and/or pathologic signaling of the beta isoform of class II phosphoinositide 3-kinase (PI3K-C2b), in a subject in need thereof, wherein the medical condition is selected from the group consisting of stroke, a cardiovascular disease related to endothelial cell dysfunction, cancer, cancer metastasis, myopathy (preferably myotubular myopathy) and diabetes, comprising

(a) identifying the subject as having a a medical condition associated with defective and/or pathologic class II phosphoinositide 3-kinase (PI3K) signaling, defective and/or pathologic signaling of the beta isoform of class II phosphoinositide 3-kinase (PI3K- C2b),

(b) selectively inhibiting defective and/or pathologic class II phosphoinositide 3-kinase (PI3K) signaling, preferably defective and/or pathologic signaling of the beta isoform of class II phosphoinositide 3-kinase (PI3K-C2b), in the subject by administering to the subject a compound according to any one of Formulas 1, 1a, 2, 2a, 3, 4, 5, 6 and 7.

In one embodiment the compound according to any one of Formulas 1, 1a, 2, 2a, 3, 4, 5, 6 and 7 selectively inhibits class II phosphoinositide 3-kinase (PI3K) signaling, preferably signaling of the beta isoform of class II phosphoinositide 3-kinase (PI3K-C2b). In embodiments the compounds described herein may be termed PIK3 inhibitors. In embodiments the compounds described herein may be termed PI3K-C2b inhibitors. In embodiments the compounds according to the present invention exhibit the desired property of inhibiting PIK3. In embodiments the compounds according to the present invention exhibit the desired property of inhibiting PI3K-C2b. A skilled person is capable of determining whether any given compound exhibits the desired properties of the invention.

In embodiments, the compounds of the present invention are defined by the presence of a functional property, namely the inhibition of PIK3, preferably the inhibition of PI3K-C2b. Said inhibition may be evident when using one or more of the in vitro (or other) assays described in detail in the examples. A skilled person is capable, without undue effort, of ascertaining whether any given compound within the compounds according to the present invention exhibits the desired properties using the guidance provided herein and their common general knowledge.

In one aspect the invention relates to a pharmaceutical composition for use as a medicament in the treatment of a medical condition associated with defective and/or pathologic class II phosphoinositide 3-kinase (PI3K) signaling, preferably defective and/or pathologic signaling of the beta isoform of class II phosphoinositide 3-kinase (PI3K-C2b), comprising one or more compounds according to any one of the preceding claims with a pharmaceutically acceptable carrier. In one aspect the invention relates to an in vitro method for modulating (preferably inhibiting) class II phosphoinositide 3-kinase (PI3K) signaling, preferably signaling of the beta isoform of class II phosphoinositide 3-kinase (PI3K-C2b), comprising the administration of a compound according to any one of the preceding claims, or a composition comprising said compound, to a cell in which PI3K signaling, preferably signaling of the beta isoform of class II phosphoinositide 3-kinase (PI3K-C2b), is to be modulated.

Table 1 shows a number of exemplary compounds of the invention, suitable for the medical use described herein. Any structure may represent an embodiment of the invention and/or be employed in any of the aspects or embodiments of the invention described herein. Table 1 : Preferred compounds of the invention

All features described in the present specification may be employed to define any other embodiment or aspect of the invention, for example, features used to describe the medical use of one compound may be used to describe a medical use of another compound, and vice versa. Ill

Features used to describe any one or more compounds may be combined with any one or more of the medical uses of the invention. Similarly, structural features of the compounds may be used to describe the methods of the invention, other compounds of the invention or pharmaceutical composition and vice versa, according to the understanding of a skilled person.

DETAILED DESCRIPTION

The invention relates to chemical compounds useful as inhibitors of class II phosphoinositide 3- kinase (PI3K) signalling. The invention further relates to the medical use of inhibitors of class II phosphoinositide 3-kinase (PI3K) signalling in the treatment of medical conditions associated with defective and/or pathologic class II phosphoinositide 3-kinase (PI3K) signaling, such as stroke, a cardiovascular disease related to endothelial cell dysfunction, cancer, cancer metastasis, myopathy (preferably myotubular myopathy) and diabetes.

Medical Use:

According to the invention, “medical conditions associated with defective and/or pathologic class II phosphoinositide 3-kinase (PI3K) signaling” or “associated with defective and/or pathologic signaling of the beta isoform of class II phosphoinositide 3-kinase (PKI3-C2b)” relate to any medical condition, illness, disease or other medical state in which class II phosphoinositide 3- kinase (PI3K) signaling is aberrant or associated with a defect in signaling, such as reduced signaling, enhanced signaling and/or any change in signaling associated with or responsible for the cause of a medical condition.

The term “class II phosphoinositide 3-kinase (PI3K) signaling” relates to a signaling pathway as understood by a skilled person, in preferred embodiments relating to aberrations in class II phosphoinositide 3-kinase (PI3K) activity, thereby leading to disruptions in associated signaling pathways. A review of PI3K signaling is provided in Vanhaesebroeck et al (Nat. Rev. Mol. Cell Biol. 2010, 11 , 329-341).

In preferred embodiments, without limitation thereto, the “defective and/or pathologic class II phosphoinositide 3-kinase (PI3K) signaling” or relates to elevated activity, gene copy number, or expression of class II phosphoinositide 3-kinases. In preferred embodiment, without limitation, the “defective and/or pathologic signaling of the beta isoform of class II phosphoinositide 3-kinase (PKI3-C2b)” relates to elevated activity, gene copy number, or expression of the beta isoform of class II phosphoinositide 3-kinases. Established tests are available for a skilled person to determine whether class II PI3K signaling is disrupted, for example by obtaining pathologic cells, such as cancer cells, and assessing these for said signaling, or directly assessing elevated activity, gene copy number, or expression of class II phosphoinositide 3-kinases in tumor or other biological samples, depending on the disease to be tested.

PIK3-C2b also termed “PI3KC2P” is an isoform of class PIK3 and plays a role in in signaling pathways involved in cell proliferation, oncogenic transformation, cell survival, cell migration, and intracellular protein trafficking. PIK3-C2b is associated with endocytosis, proliferation and glucose metabolism and further regulates nutrient signaling by suppressing mTORCI signaling via local production of PI(3,4)P2 at late endosomes or lysosomes (Marat et al, Science, 2017, 356, 968- 972). Based on data accumulated to this point in time, class II PI3Ks such as PIK3-C2b appear to be involved in cancer, cardiovascular disease, and diabetes, amongst other diseases (Falasca et al, J. Med. Chem. 2016, 60, 47-65).

Diabetes:

A number of PIK3-C2b deficient mouse models have been developed to date. Thereby, a mouse model in which there is combined deficiency of both PI3K-C2a and PI3K-C2b has been described, and suggests that at least some of the 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 PI3KC2P- deficient mice points to a role for PI3KC2P in insulin sensitivity and glucose tolerance. Furthermore, PI3KC2PD1212A/ D1212A mice were protected from high- fat diet-induced steatosis, indicating that this regulatory role of insulin signalling 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, as well as other insulin-resistant conditions such as nonalcoholic fatty liver diseases.

Cancer:

Thorpe et al, (Nat. Rev. Cancer, 2015, 15, 7-24) provides an extensive review of potential cancer targets in PI3K signaling.

Amplification of the gene encoding PI3K-C2b, PIK3C2B, has been reported in several tumors, such as glioblastoma multiforme and glioblastoma histological sections, and in 90 ovarian cancer specimens pointed to a similar, significant increase in PIK3C2B copy number in these cells. The observed increase in PI3K-C2b expression in ovarian cancer cells was significantly higher than of other PI3K classes. Amplification of PIK3C2B, together with MDM4, was also detected in oligodendroglia tumors. Overexpression of PI3K-C2b has been observed in different cancer cell lines and specimens, such as acute myeloid leukemia, medulloblastoma, glioblastoma multiforme. PIK3C2B was identified as one of the genes mutated in non-small-cell lung cancer samples, compared to nontumorigenic tissues. Overexpression of negative PI3K-C2b considerably inhibited growth and growth factor-induced Akt activation in small cell lung cancer. Increased expression of PI3K-C2b was also demonstrated in myeloid leukemia and acute lymphocytic leukemia. Its inhibition showed high antiproliferative activity, especially in AML cell lines, in which reduced proliferation, as well as considerable increase in apoptosis, was observed.

Taken together, these observations suggest that PI3K-C2b inhibition has value as a therapeutic strategy for the treatment of cancer, including solid tumors, with PI3K-C2b as a drug target for reducing pathologic tumor metastasis, angiogenesis and growth/ survival.

In a preferred embodiment the present invention relates to cancer and/or cancer metastasis as a disease to be treated. Cancer according to the present invention refers to all types of cancer or neoplasm or malignant tumors found in mammals, including leukemias, lymphomas, sarcomas, melanomas and carcinomas. Examples of cancers are cancer of the breast, pancreas, colon, lung, non-small cell lung, ovary, and prostate.

In the context of the present invention, leukemias include, but are not limited to acute non- lymphocytic leukemia, chronic lymphocytic leukemia, acute granulocytic leukemia, chronic granulocytic leukemia, acute promyelocytic leukemia, adult T-cell leukemia, aleukemic leukemia, a leukocythemic leukemia, basophylic leukemia, blast cell leukemia, bovine leukemia, chronic myelocytic leukemia, leukemia cutis, embryonal leukemia, eosinophilic leukemia, Gross' leukemia, hairy-cell leukemia, hemoblastic leukemia, hemocytoblastic leukemia, histiocytic leukemia, stem cell leukemia, acute monocytic leukemia, leukopenic leukemia, lymphatic leukemia, lymphoblastic leukemia, lymphocytic leukemia, lymphogenous leukemia, lymphoid leukemia, lymphosarcoma cell leukemia, mast cell leukemia, megakaryocytic leukemia, micromyeloblastic leukemia, monocytic leukemia, myeloblastic leukemia, myelocytic leukemia, myeloid granulocytic leukemia, myelomonocytic leukemia, Naegeli leukemia, plasma cell leukemia, plasmacytic leukemia, promyelocytic leukemia, Rieder cell leukemia, Schilling's leukemia, stem cell leukemia, subleukemic leukemia, and undifferentiated cell leukemia.

According to the present invention, lymphomas include Hodgkin and non-Hodgkin lymphoma (13- cell and T-cell lymphoma) 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 lymphomas, Extranodal marginal zone B-cell lymphomas, also known as mucosa-associated lymphoid tissue (MALT) lymphomas, Nodal marginal zone B-cell lymphoma and Splenic marginal zone B-cell lymphoma, Burkitt lymphoma, Lymphoplasmacytic lymphoma (Waldenstrom macroglobulinemia), Hairy cell leukemia Primary central nervous system (CNS) lymphoma, Precursor T-lymphoblastic lymphoma/leukemia, Peripheral T-cell lymphomas, Cutaneous T-cell lymphomas (mycosis fungoides, Sezary syndrome, and others), Adult T-cell leukemia/lymphoma including the smoldering, the chronic, the acute and the lymphoma subtype, 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 unspecified Peripheral T-cell lymphoma.

Sarcomas as defined in the context of the present invention include, but are not limited to a chondrosarcoma, fibrosarcoma, lymphosarcoma, melanosarcoma, myxosarcoma, osteosarcoma, Abernethy's sarcoma, adipose sarcoma, liposarcoma, alveolar soft part sarcoma, ameloblastic sarcoma, botryoid sarcoma, chloroma sarcoma, chorio carcinoma, embryonal sarcoma, Wilms' tumor sarcoma, endometrial sarcoma, stromal sarcoma, Ewing's sarcoma, fascial sarcoma, fibroblastic sarcoma, giant cell sarcoma, granulocytic sarcoma, Hodgkin's sarcoma, idiopathic multiple pigmented hemorrhagic sarcoma, immunoblastic sarcoma of B cells, lymphoma, immunoblastic sarcoma of T-cells, Jensen's sarcoma, Kaposi's sarcoma, Kupffer cell sarcoma, angiosarcoma, leukosarcoma, malignant mesenchymoma sarcoma, parosteal sarcoma, reticulocytic sarcoma, Rous sarcoma, serocystic sarcoma, synovial sarcoma, and telangiectaltic sarcoma.

Melanomas according to the present invention include, but are not limited to include, for example, acral-lentiginous melanoma, amelanotic melanoma, benign juvenile melanoma, Cloudman's melanoma, S91 melanoma, Harding-Passey melanoma, juvenile melanoma, lentigo maligna melanoma, malignant melanoma, nodular melanoma, subungal melanoma, and superficial spreading melanoma.

Carcinomas as defined by the present invention include, but are not limited to acinar carcinoma, acinous carcinoma, adenocystic carcinoma, adenoid cystic carcinoma, carcinoma adenomatosum, carcinoma of adrenal cortex, alveolar carcinoma, alveolar cell carcinoma, basal cell carcinoma, carcinoma basocellulare, basaloid carcinoma, basosquamous cell carcinoma, bronchioalveolar carcinoma, bronchiolar carcinoma, bronchogenic carcinoma, cerebriform carcinoma, cholangiocellular carcinoma, chorionic carcinoma, colloid carcinoma, comedo carcinoma, corpus carcinoma, cribriform carcinoma, carcinoma en cuirasse, carcinoma cutaneum, cylindrical carcinoma, cylindrical cell carcinoma, duct carcinoma, carcinoma durum, embryonal carcinoma, encephaloid carcinoma, epiermoid carcinoma, carcinoma epitheliale adenoides, exophytic carcinoma, carcinoma exulcere, carcinoma fibrosum, gelatiniform carcinoma, gelatinous carcinoma, giant cell carcinoma, carcinoma gigantocellulare, glandular carcinoma, granulosa cell carcinoma, hair-matrix carcinoma, hematoid carcinoma, hepatocellular carcinoma, Hurthle cell carcinoma, hyaline carcinoma, hypernephroid carcinoma, infantile embryonal carcinoma, carcinoma in situ, intraepidermal carcinoma, intraepithelial carcinoma, Krompecher's carcinoma, Kulchitzky-cell carcinoma, large-cell carcinoma, lenticular carcinoma, carcinoma lenticulare, lipomatous carcinoma, lymphoepithelial carcinoma, carcinoma medullare, medullary carcinoma, melanotic carcinoma, carcinoma molle, mucinous carcinoma, carcinoma muciparum, carcinoma mucocellulare, mucoepidermoid carcinoma, carcinoma mucosum, mucous carcinoma, carcinoma myxomatodes, nasopharyngeal carcinoma, oat cell carcinoma, carcinoma ossificans, osteoid carcinoma, papillary carcinoma, periportal carcinoma, preinvasive carcinoma, prickle cell carcinoma, pultaceous carcinoma, renal cell carcinoma of kidney, reserve cell carcinoma, carcinoma sarcomatodes, Schneiderian carcinoma, scirrhous carcinoma, carcinoma scroti, signet-ring cell carcinoma, carcinoma simplex, small-cell carcinoma, solanoid carcinoma, spheroidal cell carcinoma, spindle cell carcinoma, carcinoma spongiosum, squamous carcinoma, squamous cell carcinoma, string carcinoma, carcinoma telangiectaticurn, carcinoma telangiectodes, transitional cell carcinoma, carcinoma tuberosum, tuberous carcinoma, verrucous carcinoma, and carcinoma villosum.

Additional cancers according to the present invention include, but are not limited to multiple myeloma, neuroblastoma, breast cancer, ovarian cancer, lung cancer, rhabdomyosarcoma, primary thrombocytosis, primary macroglobulinemia, small-cell lung tumors, primary brain tumors, stomach cancer, colon cancer, malignant pancreatic insulanoma, malignant carcinoid, urinary bladder cancer, premalignant skin lesions, testicular cancer, lymphomas, thyroid cancer, esophageal cancer, genitourinary tract cancer, malignant hypercalcemia, cervical cancer, endometrial cancer, adrenal cortical cancer, and prostate cancer.

Cardiovascular diseases:

The term “cardiovascular disease” (CVD) or “cardiovascular disease related to endothelial cell disfunction” is a class of diseases that involve the heart or blood vessels. Cardiovascular disease includes, but is not limited to, coronary artery diseases (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, heart arrhythmia, congenital heart disease, valvular heart disease, carditis, aortic aneurysms, peripheral artery disease, thromboembolic disease, and venous thrombosis.

Myopathy: The term “myopathy” refers to a class of diseases that involve structural changes and/or functional impairments of the muscles and that are associated with defective and/or pathologic phosphoinositide 3-kinase (PI3K) signaling. Preferably the term “myopathy” refers to a mytotubular myopathy, more preferably an X-linked centronuclear myopathy.

It has been demonstrated that PIK3-C2b inhibition improves function and prolongs survival in myotubular myopathy animal models (Sabha et al, J Clin Invest. 2016,126, 3613-3625). Myotubular myopathy (MTM) is a pediatric neuromuscular disorder of phosphoinositide (PIP) metabolism resulting from mutations of the PIP phosphatase MTM1 for which there are presently no established treatments. Class II and III PI3 kinases were targeted (PI3Ks) in an MTM1- deficient mouse model. Muscle-specific ablation of Pik3c2b, but not Pik3c3, resulted in complete prevention of the MTM phenotype, and postsymptomatic targeting promoted a striking rescue of disease. The PI3K inhibitor wortmannin also improved motor function and prolonged lifespan of the Mtm1 -deficient mice. This evidence speaks strongly for a therapeutic effect of PIK3 inhibitors in treating myopathy. Muscular dystrophies such as

Chemical compounds

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

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

The term “cycloalkyl” refers to a configuration derived from a cycloalkane by removal of an atom of hydrogen, thereby forming preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, or the like. Any one or more of the cycloalkyl groups described herein may be "substituted cycloalkyls", wherein one or more hydrogen atoms are substituted with a substituent such as halogen, cycloalkyl, alkoxy, hydroxyl, aryl, or carboxyl. Any of the or more of the cycloalkyl groups described herein may comprise one or more double bonds without forming an aromatic aryl group.

The term "alkoxy" refers to a straight, branched or cyclic hydrocarbon configuration and combinations thereof, including preferably 1-7 carbon atoms, more preferably 1-6, 1-5, 1-4 or 1-3 carbon atoms, that include an oxygen atom at the point of attachment (such as O-alkyl). An example of an "alkoxy group" is represented by the formula -OR, or-ROR (such as -CH2OR), where R can be an alkyl group, optionally substituted with halogen, aryl (also referred to as aryl oxy), cycloalkyl, halogenated alkyl. Suitable alkoxy groups include methoxy, ethoxy, n-propoxy, i- propoxy, n-butoxy, i-butoxy, sec-butoxy, cyclohexyloxy, and the like. The term "aryl" refers to any carbon-based aromatic group including, but not limited to, benzene, naphthalene, and the like. The term "aromatic" also includes "heteroaryl group," which is defined as an aromatic group that has at least one heteroatom incorporated within the ring of the aromatic group. Examples of heteroatoms include, but are not limited to, nitrogen, oxygen, sulfur. The aryl group can be substituted with one or more groups including, but not limited to, alkyl, aryl, halogen, nitro, hydroxy, carboxylic acid, or alkoxy, or the aryl group can be unsubstituted.

The term “heteroaryl” is understood to mean saturated (heterocycloalkyl), partly unsaturated (heterocycloalkenyl) or unsaturated (heteroaryl) hydrocarbon rings containing from 3 to 15 carbon atoms in a mono- or bicyclic, fused, bridged or spirocyclic ring in which 1 to 5 carbon atoms of the 3 to 15 ring carbon atoms are replaced by heteroatoms such as nitrogen, oxygen or sulfur in which further the heteroatoms can be oxidized, for example N=O, S=O, SO2. Non-limiting examples of heterocycles are acridinyl, azaindole (1 H-pyrrolopyridinyl), azabenzimidazolyl, azaspirodecanyl, azepinyl, azetidinyl, aziridinyl, benzimidazolyl, benzofuranyl, dihydrobenzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydrochinolinyl, 4,5-dihydrooxazolinyl, dioxazolyl, dioxazinyl, 1 ,3-dioxolanyl, 1 ,3-dioxolenyl, 3,3-dioxo[1 ,3,4]oxathiazinyl, 6H-1 ,5,2- dithiazinyl, dihydrofuro[2,3-b]-tetrahydrofuranyl, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1 H-indazolyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl (benzimidazolyl), isothiazolyl, isothiazolidinyl, isothiazolinyl, isoxazolyl, isoxazolinyl, isoxazolidinyl, 2-isoxazolinyl, ketopiperazinyl, morpholinyl, naphthyridinyl, 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, oxazolidinyl, oxazolinyl, oxazolyl, oxetanyl, oxocanyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazolyl, pyridoimidazolyl, pyridothiazolyl, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolidinonyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyridinyl, tetrahydrothiophenyl, tetrazinyl, tetrazolyl, 6H-1 ,2,5-thiadiazinyl, 1 ,2,3- thiadiazolyl, 1 ,2,4-thiadiazolyl, 1 ,2,5-thiadiazolyl, 1 ,3,4-thiadiazolyl, thianthrenyl, 1 ,2-thiazinyl, 1 ,3- thiazinyl, 1 ,4-thiazinyl, 1 ,3-thiazolyl, thiazolyl, thiazolidinyl, thiazolinyl, thienyl, thietanyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiomorpholinyl, thiophenolyl, thiophenyl, thiopyranyl, 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 xanthenyl.

The term "amine" refers to a group of the formula -NRR', where R and R' can be, independently, hydrogen or an alkyl, alkenyl, alkynyl, aryl, aralkyl, cycloalkyl, halogenated alkyl, or hetero cycloalkyl group described above. The term primary amine refers to a group of the formula -NH2. The term secondary amine refers to a group of the formula -NRH, wherein R can be an alkyl, alkenyl, alkynyl, aryl, aralkyl, cycloalkyl, halogenated alkyl, or hetero cycloalkyl group described above. The term secondary amine refers to a group of the formula -NRR', wherein R and R’ can be, independently an alkyl, alkenyl, alkynyl, aryl, aralkyl, cycloalkyl, halogenated alkyl, or hetero cycloalkyl group described above.

The term "amide" or "amido" is represented by the formula -C(O)NRR', where R and R' independently can be a hydrogen, alkyl, alkenyl, alkynyl, aryl, aralkyl, cycloalkyl, halogenated alkyl, or heterocycloalkyl group described above. A suitable amido group is acetamido.

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

The term "alkyl amino" refers to alkyl groups as defined above where at least one hydrogen atom is replaced with an amino group.

"Carboxyl" refers to a -COOH radical. Substituted carboxyl refers to -COOR where R is aliphatic, heteroaliphatic, alkyl, heteroalkyl, or a carboxylic acid or ester. The term carboxy ester refers to - COOR where R is alkyl.

The term "hydroxyl" is represented by the formula -OH.

The term "hydroxyalkyl" refers to an alkyl group that has at least one hydrogen atom substituted with a hydroxyl group. The term "alkoxyalkyl group" is defined as an alkyl group that has at least one hydrogen atom substituted with an alkoxy group described above.

The term "aralkyl" or “alkyl aryl” refers to an aryl group having an alkyl group, as defined above, attached to the aryl group, as defined above. An example of an aralkyl group is a benzyl group.

Optionally substituted groups, such as "optionally substituted alkyl," refers to groups, such as an alkyl group, that when substituted, have from 1-5 substituents, typically 1 , 2 or 3 substituents, selected from alkoxy, optionally substituted alkoxy, acyl, acylamino, acyloxy, amino, aminoacyl, aminoacyloxy, aryl, carboxyalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, halogen, optionally substituted heteroaryl, optionally substituted heterocyclyl, hydroxy, sulfonyl, thiol and thioalkoxy.

In particular, optionally substituted alkyl groups include, by way of example, haloalkyl groups, such as fluoroalkyl groups, including, without limitation, trifluoromethyl groups. These potential optional substituents apply to any group of the formula disclosed herein where an optional substituent is recited. Preferable optional substituents are hydroxyl, alkyl, alkoxy, carbonyl, alkoxycarbonyl, NO2, amine.

The term "aldehyde" is represented by the formula -CHO, consisting of a carbonyl center (a carbon double-bonded to oxygen) with the carbon atom also bonded to hydrogen and to an R group, preferably the backbone of the formula.

The term "carboxyester" is represented by the formula -C(O)-O-R.

The term "carboxamide” is represented by the formula -C(O)-N(R)-R.

The term "primary, secondary or tertiary amine” is represented by the formula -N(R)-R. The term "carbamate" is represented by the formula -NR-C(O)-O-R.

The term "imide" is represented by the formula -C(O)-N(R)-C(O)-R’.

The term "sulfide" is represented by the formula -S-R.

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

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

The term "sulfino" is represented by the formula -SO2H.

The term "sulfo" is represented by the formula -SO3H.

The terms "sulfoxide” or “sulfone are preferably selected from the groups -SO_rR, wherein r is 1-3, preferably from the groups -S(O)R, -SO2R, -SO2H, and -SO3H.

The terms “amine sulfoxide”, “sulfonamide”, “sulfonamide amine” are preferably selected from the groups -N(R)-S(O)_U-R, wherein u is 1 or 2, or -S(0)_v-N(R)-R, wherein v is 1 or 2, preferably from the groups -NHSO2CH3, -SO2NHCH3, -NHSO₂N(CH₃)2).

For the definitions above, preferably the terms R, R’ are independently selected from the group of H, alkyl, alkylhalo, alkoxy, amine or any of the embodiments described above, and wherein X is halogen. The terms R, R’ also comprise the possibility of any given group being appended to R.

The term “nitro” refers to an NO2 group.

Optionally substituted groups, such as "optionally substituted" refers to groups, such as an alkyl group, that when substituted, have from 1-5 substituents, typically 1 , 2 or 3 substituents.

The term “4-, 5- or 6-membered hetero cycloalkyl” refers to a configuration comprising a 4-, 5- or 6-membered heterocyclic ring structure, comprising preferably C and one or more of 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.

The term “condensed bicyclic group” refers to a configuration comprising two 4- to 8-membered cyclic optionally aromatic ring structures, optionally comprising one or more heteroatoms such as one or more of N, O and/or S, wherein the two ring structures are attached to each other by two of their adjacent atoms.

Where reference is made to “C1 to C7, C1 to C5, C1 to C3” alkyl, cycloalkyl, alkoxy, aryl, or the like, the number of carbon atoms 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 apply to the alkyl, cycloalkyl and/or alkoxy groups, whereby aryl may remain preferably C3 to C6, such as C6 phenyl.

Protected derivatives of the disclosed compound also are contemplated, for example for use in the synthesis of the disclosed compounds. A variety of 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. In general, protecting groups are removed under conditions which will not affect the remaining portion of the molecule. These methods are well known in the art and include acid hydrolysis, hydrogenolysis and the like.

Particular examples of the presently disclosed compounds include one or more asymmetric centers; thus these compounds can exist in different stereoisomeric forms. Accordingly, compounds and compositions may be provided as individual pure enantiomers or as stereoisomeric mixtures, including racemic mixtures.

The compounds of the invention may also exist in various polymorphous forms, for example as amorphous and crystalline polymorphous forms. All polymorphous forms of the compounds of the invention belong within the framework of the invention and are a further aspect of the invention.

The compound of the invention may also comprise deuterium replacing hydrogen. This replacement may in some circumstances lead to improved metabolic stability (Nature Reviews Drug Discovery 15, 219-221 (2016)).

It is understood that substituents and substitution patterns of the compounds described herein can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by techniques known in the art and further by the methods set forth in this disclosure.

Compositions and modes of treatment:

The present invention relates further to pharmaceutically acceptable salts of the compounds described herein. The term "pharmaceutically acceptable salt" refers to salts or esters of the compounds described herein prepared by conventional means that include basic salts of inorganic and organic acids. "Pharmaceutically acceptable salts" are also inclusive of the free acid, base, and zwitterionic forms. Descriptions of suitable pharmaceutically acceptable salts can be found in Handbook of Pharmaceutical Salts, Properties, Selection and Use, Wiley VCH (2002). For therapeutic use, salts of the compounds are those wherein the counter-ion is pharmaceutically acceptable. However, salts of acids and bases which are non-pharmaceutically acceptable may also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound.

Another aspect of the disclosure includes pharmaceutical compositions prepared for administration to a subject and which include a therapeutically effective amount of one or more of the compounds disclosed herein. In certain embodiments, the pharmaceutical compositions are useful for treating medical conditions associated with defective and/or pathologic class II phosphoinositide 3-kinase (PI3K) signaling, preferably defective and/or pathologic signaling of the beta isoform of class II phosphoinositide 3-kinase (PIK3-C2b), such as myopathy, cancer, diabetes and cardiovascular disease.

The therapeutically effective amount of a disclosed compound will depend on the route of administration, the species of subject and the physical characteristics of the subject being treated. Specific factors that can be taken into account include disease severity and stage, weight, diet and concurrent medications. The relationship of these factors to determining a therapeutically effective amount of the disclosed compounds is understood by those of skill in the art. Pharmaceutical compositions for administration to a subject can include at least one further pharmaceutically acceptable additive such as carriers, thickeners, diluents, buffers, preservatives, surface active agents and the like in addition to the molecule of choice. Pharmaceutical compositions can also include one or more additional active ingredients such as antimicrobial agents, anti-inflammatory agents, anesthetics, and the like. The pharmaceutically acceptable carriers useful for these formulations are conventional. Remington's Pharmaceutical Sciences, by E. W. Martin, Mack Publishing Co., Easton, PA, 19th Edition (1995), describes compositions and formulations suitable for pharmaceutical delivery of the compounds herein disclosed.

In general, the nature of the carrier will depend on the particular mode of administration being employed. For instance, parenteral formulations usually contain injectable fluids that include pharmaceutically and physiologically acceptable fluids such as water, physiological saline, balanced salt solutions, aqueous dextrose, glycerol or the like as a vehicle. For solid compositions (for example, powder, pill, tablet, or capsule forms), conventional non-toxic solid carriers can include, for example, pharmaceutical grades of mannitol, lactose, starch, or magnesium stearate. In addition to biologically-neutral carriers, pharmaceutical compositions to be administered can contain minor amounts of non-toxic auxiliary substances, such as wetting or emulsifying agents, preservatives, and pH buffering agents and the like, for example sodium acetate or sorbitan monolaurate.

The pharmaceutical compositions can be administered to subjects by a variety of mucosal administration modes, including by oral, rectal, intraocular, intranasal, intrapulmonary, or transdermal delivery, or by topical delivery to other surfaces. Optionally, the compositions can be administered by non-mucosal routes, including by intramuscular, intraocular, subcutaneous, intravenous, intra-arterial, intra-articular, intraperitoneal, intrathecal, intracerebroventricular, or parenteral routes.

The compositions of the disclosure can alternatively contain as pharmaceutically acceptable carrier substances as required to approximate physiological conditions, such as pH adjusting and buffering agents, tonicity adjusting agents, wetting agents and the like, for example, sodium acetate, sodium lactate, sodium chloride, potassium chloride, calcium chloride, sorbitan monolaurate, and triethanolamine oleate. For solid compositions, conventional nontoxic pharmaceutically acceptable vehicles can be used which include, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talcum, cellulose, glucose, sucrose, magnesium carbonate, and the like.

In a preferred embodiment the invention comprise the topical and/or local administration of a compound as described herein and/or a composition comprising a compound as described herein to a subject. The term “topical administration” refers to the delivery of a pharmacologically active agent to the skin or mucosa of a patient. Topical administration can provide a local rather than a systemic effect. The terms “topical administration” and “transdermal administration” are used interchangeably to mean administration of a pharmacologically active agent to the skin or mucosa of a patient to achieve a therapeutic effect in treating or preventing a medical disorder of the invention or discomfort at the site of topical or transdermal administration. Preferred administration modes relate to a topical solution, lotion, shake lotion, cream, ointment, gel, foam, transdermal patch, powder, solid form, sponge, tape, paste or tincture. Preferred embodiments relate to creams, foams, gels, lotions, and ointments.

Various additives, known to those skilled in the art, may be included in topical compositions of the present disclosure. For example, solvents, including relatively small amounts of alcohol, may be used to solubilize a compound of the invention. Other optional additives include antioxidants, fragrances, colorant, gelling agents, emulsifiers, thickening agents, stabilizers, surfactants, buffers, cooling agents (e.g., menthol) and the like. Other agents may also be added, such as antimicrobial agents, to prevent spoilage upon storage, i.e., to inhibit growth of microbes such as yeasts and molds. Examples of suitable antimicrobial agents include methyl and propyl esters of p-hydroxybenzoic acid (i.e., methyl and propyl paraben), sodium benzoate, sorbic acid, imidurea, and the like. When applied to skin, a topical composition of the present disclosure can be covered with an occlusive or non-occlusive dressing, which may be porous or non-porous, so as to protect the composition from mechanical removal during the period of treatment, e.g. a plastic film food wrap or other non-absorbent film. Various inert coverings may be employed. Non-woven or woven coverings may be employed, particularly elastomeric coverings, which allow for heat and vapor transport. These coverings can allow for cooling of the diseased site, which can provide for greater comfort, while protecting the composition from mechanical removal.

In accordance with the various treatment methods of the disclosure, the compound can be delivered to a subject in a manner consistent with conventional methodologies associated with management of the disorder for which treatment or prevention is sought. In accordance with the disclosure herein, a prophylactically or therapeutically effective amount of the compound and/or other biologically active agent is administered to a subject in need of such treatment for a time and under conditions sufficient to prevent, inhibit, and/or ameliorate a selected disease or condition or one or more symptom(s) thereof.

"Administration of' and "administering a" compound should be understood to mean providing a compound, a prodrug of a compound, or a pharmaceutical composition as described herein. The compound or composition can be administered by another person to the subject (e.g., intravenously, gel, cream, spray) or it can be self-administered by the subject (e.g., tablets, gel, cream, spray).

Dosage can be varied by the attending clinician to maintain a desired concentration at a target site (for example, the lungs or systemic circulation). Higher or lower concentrations can be selected based on the mode of delivery, for example, trans-epidermal, rectal, oral, pulmonary, or intranasal delivery versus intravenous or subcutaneous delivery. Dosage can also be adjusted based on the release rate of the administered formulation, for example, of an intrapulmonary spray versus powder, sustained release oral versus injected particulate or transdermal delivery formulations, and so forth.

The term "subject" includes both human and veterinary subjects. The term "treatment" refers to a therapeutic intervention that ameliorates a sign or symptom of a disease or pathological condition after it has begun to develop.

As used herein, the term "ameliorating", with reference to a disease or pathological condition, refers to any given beneficial effect of the treatment. The beneficial effect can be evidenced, for example, by a delayed onset of clinical symptoms of the disease in a subject, a reduction in severity of some or all clinical symptoms of the disease, a slower progression of the disease, an improvement in the overall health or well-being of the subject, or by other parameters well known in the art that are specific to the particular disease.

The present invention encompasses both therapeutic treatment and prophylactic treatment of a subject. A "prophylactic" treatment is a treatment administered to a subject, who does not exhibit signs of the medical condition or who preferably exhibits indications of developing or developing further any given medical condition, for the purpose of decreasing the risk of developing pathology or clinical symptoms. A prophylactic administration may comprise the administration of the compounds in advance of developing symptoms, thereby avoiding or reducing the subsequent occurrence of a disease. The present invention also relates to a method of treatment of subjects suffering from the various medical conditions disclosed herein. The method of treatment comprises preferably the administration of a therapeutically effective amount of a compound disclosed herein to a subject in need thereof.

A "therapeutically effective amount" refers to a quantity of a specified agent sufficient to achieve a desired effect in a subject being treated with that agent. For example, this may be the amount of a compound disclosed herein useful in alleviating the symptoms of one or more of the medical conditions described herein in a subject. The therapeutically effective amount or diagnostically effective amount of an agent will be dependent on the subject being treated, the severity of illness, and the manner of administration of the therapeutic composition. Dosage regimens can be adjusted to provide an optimum prophylactic or therapeutic response. A therapeutically effective amount is also one in which any toxic or detrimental side effects of the compound and/or other biologically active agent is outweighed in clinical terms by therapeutically beneficial effects. A non-limiting range for a therapeutically effective amount of a compound and/or other biologically active agent within the methods and formulations of the disclosure is about 0.001 mg/kg body weight to 50 mg/kg body weight, 0.01 mg/kg body weight to about 20 mg/kg body weight, such as about 0.05 mg kg to about 5 mg/kg body weight, or about 0.2 mg/kg to about 2 mg/kg body weight.

The instant disclosure also includes kits, packages and multi-container units containing the herein described pharmaceutical compositions, active ingredients, and/or means for administering the same for use in the prevention and treatment of diseases and other conditions in mammalian subjects.

FIGURES

The invention is further described by the following figures. These are not intended to limit the scope of the invention, but represent preferred embodiments of aspects of the invention provided for greater illustration of the invention described herein.

Brief description of the figures

Fig.1 : Domain organization of PI3-kinases. Fig.2: Expression and purification of PI3KC2P A1-298, KKT mutant.

Fig.3: Kinase activity of purified PI3KC2P ^AN KKT.

Fig.4 : Cellular activity of example compounds 036, 40, 90 and 96.

Fig.5 : Kinobead pulldown assay of example compounds 47 and 91.

Detailed description of the figures

Fig.1 : Domain organization of PI3-kinases. PI3-kinases are classified by their diversity of primary sequence and domain architectures. The catalytic subunit of class I (PI3K a, p, y, 5) and class III (VPS34) kinase form heterodimers with their respective regulator subunit, e.g., p85 or p55 for PI3K a, p, 5; p101 or p87 for PI3Ky, and VPS15 for VPS34. All PI3-kinases contain PI3K core region, including C2, helical and kinase domain. Class I PI3K a, p, y, 5 contains an ABD domain (adaptor binding domain) for regulatory subunit binding. Class II PI3-kinases contains unique N- terminal disorder region for protein-protein interaction, a HBD (helical bundle domain) for scaffold function, and two C-terminal lipid binding domains (Phox and C-C2 domain) for phosphoinositide binding.

Fig.2: Expression and purification of PI3KC2P A1-298, KKT mutant. His -tagged PI3KC2P A1- 298; KKT mutant (PI3KC2P ^AN KKT) was expressed by baculovirus-insect cell expression system.

(A) Size exclusion chromatography of PI3KC2P ^AN KKT. The peak fractions as indicated by arrow.

(B) SDS-PAGE validation of purified PI3KC2P ^AN KKT. The purity of PI3KC2P ^AN KKT was estimated to be more than 90%.

Fig.3: Kinase activity of purified PI3KC2P ^AN KKT. (A) Activity of purified PI3KC2P ^AN KKT was measure by ADP-Glo™ kinase assay with 100 pM ATP and 200 pM PI as substrates. The triplicate experiments were performed with titrated amount of purified PI3KC2P ^AN KKT. The activity and concentration of the purified PI3KC2P ^AN KKT displayed a linear correlation in the established concentration series. (B) Km of ATP for PI3KC2P ^AN KKT was performed in triplicate experiment with 10 ng/pl of purified PI3KC2b ^AN KKT and titrated amount of ATP. The curve was fitted using Michaelis-Menten equation. The Km of ATP is 63.7 pM.

Fig.4 : Cellular activity of example compounds 36, 40, 90 and 96. (A) Scheme of cellular regulation of PI3KC2p. PKN2 prevent PI3KC2P recruitment to lysosome. Catalytic activity of PI3KC2P down-regulates the mTOR activity on phosphorylation of S6K. (B) Scheme of assay designation for validation of compound activity in the cells. Of note that treatment of PKN1/2 inhibitor will elevate the basal activity of PI3KC2P, leading to much lower basal p-S6K level. (C) Cells were treated with 1 pM of example compounds 36, 40, 90 and 96. A representative western bot result for p-S6K level and total S6K level under compound treatments. The inhibition of PI3KC2P with example compounds 36, 40, 90 and 96 was determined by significant increase of pS6K levels.

Fig.5 : Kinobead pulldown assay of example compounds 47 and 91 . The assay was performed on HEK293 cell lysates at 10 different concentrations of the compounds, Hit criteria in the assay are IC⁵⁰ < 10 pM. No hit except the desired target PI3KC2B was observed for the example compounds 47 and 91 . EXAMPLES

The invention is further described by the following examples. These are not intended to limit the scope of the invention but represent preferred embodiments of aspects of the invention provided for greater illustration of the invention described herein.

Example 1 : Inhibitor development and structural characterization of PI3KC2p.

Functional genetic data indicate that PI3KC2P is a potential drug target forX-linked myotubular myopathy (XLMTM) treatment. So far, the structure of PI3KC2P is still unresolved. Besides, no potent and selective inhibitors against PI3KC2P have been described. The object of this invention is therefore the development of novel small molecular inhibitor for structurally unveiling the pharmacological target sites in PI3KC2P and for XLMTM treatment.

Example 2: Expression and purification of PI3KC2p ^AN KKT

To overcome limitations with respect to the availability of pure recombinant PI3KC2P and the poor activity of PI3KC2P against PI as substrate. The inventors engineer the human PI3KC2P with truncation of AA 1-297 and mutation of ¹²⁴⁸DPK¹²⁵⁰ _to 1248^1-1250 according to previous experiences on the purification PI3KC2o. The PI3KC2P ^AN KKT was tagged with 10x histidine at its N-termini. The expression of PI3KC2P ^AN KKT was performed by baculovirus-infected insect cells. The cells were grown to a cell density at 1 .5 million cells/ml and infected with 1 :50 (volume ratio) of virus stock. The expression of PI3KC2p ^AN KKT takes place for 48-hours post infection. PI3KC2P ^AN KKT was purified with Ni-NTA beads and followed by size exclusion chromatography. The peak fractions containing PI3KC2P ^AN KKT were validated by SDS-PAGE and Coomassie blue staining. Purified PI3KC2P ^AN KKT was concentrated to a protein concentration at 0.4 mg/ml. The sample was snap frozen by liquid nitrogen and stored at -80 °C freezer.

Example 3: Enzymatic activity and assay development for purified PI3KC2p ^AN KKT

The kinase activity of purified PI3KC2 ^AN KKT was measured by ADP-Glo™ kinase assay. To determine the linear correlation rage of the signal with different amount of kinase, the kinase activity was first measured with titrated concentration of PI3KC2P ^AN KKT and fixed concentration of PI (200 pM) and ATP (100 pM). The activity curve displays a broad range of linear correlation in the setup. To measure the Km of ATP for PI3KC2P ^AN KKT, the activity of 10 ng/pl purified kinase together with 200 pM of PI and titrated concentration of ATP were used for triplicated measurement. The titration curve was fit into Michaelis-Menten equation to obtain the Km value of ATP for PI3KC2 ^AN KKT is 63.7 pM. Therefore, the IC50 measurements for chemical compounds were established with 10 ng/pl purified PI3KC2P ^AN KKT, PI (200 pM), and ATP (40 pM).

Example 4: Cellular activity of chemical compounds

Four PI3KC2P inhibitors (DC-03-036, -040, -090, -096) were selected for cellular activity measurement. Because PI3KC2P kinase activity is the negative regulator of mTOR1 activity on phosphorylation of S6K, the cellular activity of PI3KC2P can be reported by pS6K level. PKN2 is the known negative regulator for basal PI3KC2P activity. Therefore, the protocol for cellular treatment was established with overnight incubation of compounds with HEK cell at 1 pM concentration and followed by 2-hours PKN1/2 inhibition. With DC-03-036, -040, -090, -096 treatment, pS6K level showed significant increase indicating DC-03-036, -040, -090, -096 can inhibit PI3KC2P activity in the cell.

Example 4: Kinase selectivity of chemical compounds

Five PI3KC2P inhibitors (example compounds 2, 18, 19, 47 and 91) were selected for the measurement of kinase selectivity in an extended panel. The results for the respective compounds are shown in tables 2 to 6.

SelectScreen Kinase Profiling was performed at ThermoFisher Scientific (Table 2-6) following protocols described by Kashem et al. J. Biomol. Screen. 2007, 12, 70-83 (Adapta); Lebakken et al. J. Biomol. Screen. 2009, 14; 924-935 (lanthascreen); Kleman-Leyer et al. Drug Disc. Devel. 2003, 6, 81-82. (zlyte)

Kinobead profiling was performed by adapting procedures described by Reinecke et al. ACS Chem. Biol. 2019, 14, 655-664 and Klaeger et al., Science 2017, 358, eaan4368

Kinobead pulldown assays were performed using 5 mg/mL HEK293 cell lysates in IGEPAL CA- 630-containing buffer 32. Briefly, for profiling each compound, 12 wells of a 96-well plate were filled with lysate (2.5 mg of total proteins per well) and incubated for 45 min at 4 °C in an end- over-end shaker with 0 nM (DMSO control), 30 nM, 100 nM, 300 nM, 1 pM, 3 pM, 10 pM, 30 pM, 100 pM, 300 pM and 1 mM of compound dissolved in DMSO. Subsequently, the treated lysates were incubated with Kinobeads-E for 30 min at 4 °C in a 96-well filter plate on an end-over-end shaker. The beads were then washed before the bound proteins were denatured and alkylated with chloroacetamide. Addition of trypsin (300 ng per well) started overnight on-bead digestion. Acidified peptide eluates were then subjected to C18 StageTip desalting for LC-MS/MS analysis on an Orbitrap Fusion Lumos Tribrid (ThermoFisher Scientific) mass spectrometer coupled to an online Dionex Ultimate3000 equipped with a micro flow Vanquish pump UHPLC (ThermoFisherScientific). MaxQuant (v.1.5.3.30.)/Andromeda was used to quantify proteins using the Swissprot reference database containing all canonical protein sequences with standard settings. Dose-response curves, Kdapps and the kinome tree were derived from the proteinGroup.txt file using a set of R scripts.

Abbreviations: Km: Michaelis-Menten constant; Km app: apparent Km value

Table 2 - Kinase selectivity - % of inhibition of the kinase, tested at a concentration of 1 pM of exemplary compound 2

Table 3 - Kinase selectivity - % of inhibition of the kinase, tested at a concentration of 10 pM of exemplary compound 18

Table 4 - Kinase selectivity - % of inhibition of the kinase, tested at a concentration of 10 pM of exemplary compound 19

Table 5 - Kinase selectivity - % of inhibition of the kinase, tested at a concentration of 10 pM of exemplary compound 47

Table 6 - Kinase selectivity - % of inhibition of the kinase, tested at a concentration of 10 pM of exemplary compound 91

Km app MARK3 11

Km app MET (cMet) 26

Km app MKNK1 (MNK1) 7

The evaluation on kinase selectivity (Tables 2 to 6) and inhibitory concentration (IC50) (Table 1) shows that the compounds of the present invention show a selectivity for the PIK3C2 kinases, having a substantially lower IC50 for the inhibition of PI3K-C2b (PI3KC2P) compared to PI3Ky (see for in table 1 for example compound 2: PI3KC2P IC50 [nM] = 18 and PI3Ky IC50 [nM] = 1024; compound 18: PI3KC2 IC50 [nM] = 42 and PI3Ky IC50 [nM] = > 5000; compound 19: PI3KC2P IC50 [nM] = 22 and PI3Ky IC50 [nM] = 3570; compound 47: PI3KC2 IC50 [nM] = 56 and PI3Ky IC50 [nM] = > 10000 and compound 91 : PI3KC2 IC50 [nM] = 48 and PI3Ky IC50 [nM] = > 10000) The compounds of the present invention are thus particularly effective for inhibiting PIK3C2 kinases, in particular PI3K-C2b.

The compounds were further screened by a kinobead pulldown assay performed on HEK293 cell lysates at ten different concentrations. Hit criteria were an IC50 < 10 pM. The results are shown in Figure 5. For example compounds 47 and 91 no hit except the desired target PI3KC2b was found. This further confirms that the compounds of the present invention are particularly effective for inhibiting PIK3C2 kinases, in particular PI3K-C2b.

Methods employed for protein expression and ADP-Glo kinase assay:

Protein purification

His -tagged PI3KC2P ^AN KKT was expressed in Sf21 insect cells, using SF900-II serum-free media (ThermoFisher). S/21 cells (800 ml) grown to a density of 1 .5-2 x 10⁶ cells/ ml were infected with 16 ml amplified baculovirus encoding the desired construct. Cells were harvested at 48h post-infection. Cell pellets were frozen and stored at -20 °C until purification. For purification, cell pellets from each 200 ml culture were resuspended in 30 ml lysis buffer (50 mM Tris pH 7.2, 300 mM NaCI, 10 mM imidazole, 1 mM DTT, 0.5% Triton X-100, 1 tablet/ 50ml protease inhibitor cocktail), sonicated for 1 min (1s pulse on, 5 s pulse off) and centrifuged for 20 min at 27k rpm 50 ml supernatant were incubated with 0.25 ml Nickel NTA beads (Sigma Inc.) on a rotating wheel for 1 h. Beads were collected in an open column, washed with 10 ml lysis buffer, then 3 times with 10 ml wash buffer (50 mM Tris pH 7.5, 300 mM NaCI, 20 mM imidazole, 1 mM DTT). Protein was eluted with 8 ml elution buffer (20 mM Tris pH 7.5, 300 mM NaCI, 300 mM imidazole, 5 mM DTT). PI3KC2P ^AN KKT was immediately further purified by a Superdex 200 gel filtration column at 4°C with SEC buffer (20 mM Tris pH 7.5, 300 mM NaCI, 5 mM DTT). PI3KC2P ^AN KKT were concentrated to 0.4 mg/ ml. The sample were flash frozen in liquid nitrogen and stored at -80°C.

ADP-Glo kinase assay

Native liver phosphatidylinositol (PI) were dissolved to a concentration of 400 pM with kinase buffer [5 mM HEPES/KOH, pH 7.2, 25 mM KCI, 2.5 mM Mg (OAc)₂, 150 mM K-glutamate, 10 mM CaCh, 0.2% CHAPS] by water-bath sonification and then supplied with 200 pM ATP. To do the kinase titration, the kinase reaction was initiated by adding titrated amount of purified PI3KC2P ^AN KKT. For measurement of Km of ATP, the titrated amount of ATP in PI solution was prepared. Reactions were started by mixing 5 pl of protein stock with 5 pl of substrate solution and incubated for 20 m at room temperature. The reactions were stopped by adding 10 pl of ADP-Glo reagent (Promega). After 40 min incubation, 20 pl Kinase Detection Reagent were added. After 20 min incubation, luminescence was read with a TECAN plate reader. IC50 measurements of chemical compound were carried out using concentration series of compounds, and 10 ng/pl PI3KC2p ^AN KKT, 200 pM PI, and 40 pM ATP.

Cell treatment and Western blot

0.4 million HEK cells per well were seeded to poly-Lys coated 6-wells plate. 10- hours after seeding, DSMO or chemical compounds were applied to the cell af final concentration of 0.1 % DMSO or 1 pM in respect. After overnight treatment, cells were treated with PKN1/2 inhibitor cocktail for 2-hours. To collect the cell lysate, cells were washed three times in ice-cold PBS and collected in TBS with 1% CHAPS, 1 tablet/ 10ml of protease inhibitor cocktail mini (Roch) and phosphatase inhibitors (cocktails 2 and 3, Sigma-Aldrich). Protein levels were quantified using Bradford reagent (Sigma-Aldrich). Equal concentration lysates in Laemmli sample buffer were boiled for 5 min; between 10 and 30 pg protein was resolved by SDS-PAGE and analysed via immunoblot using LI-COR 800CW infrared secondary antibodies.

Synthesis and analytical Chemistry:

Abbreviations

AcOH = acetic acid, CHsLi = methyllithium, Cs2CC>3 = cesium carbonate, CuBr2 = copper(ll) bromide, DMF = A/,A/-dimethylformamide, ESI = electrospray ionization, EtOAc = ethyl acetate, h = hour(s), H2O = water, HCI = hydrogen chloride, HPLC = high performance liquid chromatography, KOH = potassium hydroxide, min = minute(s), mL = milliliter, MS = mass spectrum, NaH = sodium hydride, NaHCOa = sodium hydrogen carbonate, NaOH = sodium hydroxide, Na2COa = sodium carbonate, Na2SO4 = sodium sulfate, Na2S2O3= sodium thiosulfate, NMR = nuclear magnetic resonance, Pd(OAc)2 = palladium(ll) acetate, TFA = trifl uroacetic acid, THF = tetrahydrofuran.

Example compound 1 : A/-(4-Methyl-5-(1-(phenylsulfonyl)-1H-indol-5-yl)thiazol-2- vDacetamide

Step 1 : 5-Bromo-1 -(phenylsulfonyl)-l /-/-indole

5-Bromo-1 /-/-indole (207 mg, 1 .06 mmol) was dissolved in 2 mL of toluene. A solution of benzenesulfonyl chloride (1.1 eq., 205 mg, 1.16 mmol) in 1 mL of toluene was then added to the mixture, followed by the addition of tetrabutylammonium hydrogen sulfate (0.07 eq., 18 mg, 74 pmol) and a 3 mL of 6 M solution of KOH in water. The reaction mixture was stirred at room temperature for 45 minutes, and upon completion of the reaction the crude mixture was transferred in a separatory funnel containing EtOAc and a water solution of diluted HCI of pH 1 . The water phase was extracted 3 times with EtOAc. Then, the combined organic phases were 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 eluent. The product was obtained as a white solid.

Yield: 180 mg (51 %). MS (ES+) [M+H]⁺ m/e = 333.7, 335.7 (bromine isotopic pattern).

¹H NMR (300 MHz, CDCI₃): 5 7.90 - 7.82 (m, 3H), 7.66 (d, J = 2.0 Hz, 1 H), 7.59 - 7.53 (m, 2H), 7.48 - 7.38 (m, 3H), 6.61 (dd, J = 3.7, 0.8 Hz, 1 H).

¹³C NMR (75 MHz, CDCI3): 5 137.93, 134.06, 133.53, 132.45, 129.37, 127.55, 127.50, 126.71 , 124.08, 116.87, 114.92, 108.49.

Step 2: A/-(4-Methyl-5-(1 -(phenylsulfonyl)-l H-indol-5-yl)thiazol-2-yl)acetamide

5-Bromo-1-(phenylsulfonyl)-1 /7-indole (180 mg, 535 pmol), A/-(4-methylthiazol-2-yl)acetamide (1.2 eq., 100 mg, 642 pmol), tri-tert-butylphosphonium tetrafluoroborate (0.2 eq., 31 mg, 107 pmol), Pd(OAc)2, (0.1 eq., 12 mg, 53 pmol) and CS2CO3 (3 eq., 523 mg, 1.61 mmol) were suspended in 2 mL of DMF. The suspension was sonicated for 5 minutes, flushed with nitrogen, heated up to 110 °C and stirred overnight. The solvent was then removed under reduced pressure and the crude product purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1% TFA). The product was obtained after lyophilization as an amorphous white solid.

Yield: 101 mg (46%).

MS (ES+) [M+H]⁺ m/e = 411.7.

¹H NMR (600 MHz, DMSO-d₆): 5 12.07 (s, 1 H), 8.03 - 7.97 (m, 3H), 7.85 (d, J = 3.7 Hz, 1 H), 7.72 - 7.66 (m, 2H), 7.63 - 7.58 (m, 2H), 7.42 (dd, J = 8.6, 1 .8 Hz, 1 H), 6.88 (d, J = 3.5 Hz, 1 H), 2.31 (s, 3H), 2.13 (s, 3H).

¹³C NMR (151 MHz, DMSO-d₆): 5 168.39, 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.

Example compound 2: / -(4-Methyl-5-(1-(phenylsulfonyl)-1,2,3,4-tetrahydroquinolin-6- yl)thiazol-2-yl)acetamide

Step 1 : 6-Bromo-1 -(phenylsulfonyl)-l ,2,3,4-tetrahydroquinoline

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

Yield: 320 mg (82%).

MS (ES+) [M+H]⁺ m/e = 351.6, 353.8 (bromine isotopic pattern). ¹H NMR (300 MHz, CDCI₃): 6 7.70 (d, J = 8.8 Hz, 1 H), 7.63 - 7.51 (m, 3H), 7.47 - 7.39 (m, 2H), 7.33 - 7.28 (m, 1 H), 7.15 (dt, J = 2.2, 1.0 Hz, 1 H), 3.83 - 3.71 (m, 2H), 2.40 (t, J = Q.7 Hz, 2H), 1.63 - 1.56 (m, 2H).

¹³C NMR (75 MHz, CDCI3): 5 139.27, 135.88, 132.93, 132.68, 131.76, 129.59, 129.09, 127.02, 126.60, 118.29, 46.40, 26.40, 21.11.

Step 2: A/-(4-Methyl-5-(1 -(phenylsulfonyl)-l ,2,3,4-tetrahydroquinolin-6-yl)thiazol-2- yl)acetamide

6-Bromo-1-(phenylsulfonyl)-1 ,2,3,4-tetrahydroquinoline (160 mg, 454 pmol), A/-(4-methylthiazol-2- yl)acetamide (1.2 eq., 85 mg, 545 pmol), tri-tert-butylphosphonium tetrafluoroborate (0.2 eq., 26 mg, 91 pmol), Pd(OAc)2, (0.1 eq., 10 mg, 45 pmol) and CS2CO3 (3 eq., 443 mg, 1.36 mmol) were suspended in 2 mL of DMF. The suspension was sonicated for 5 minutes, flushed with nitrogen, heated up to 110 °C and stirred overnight. The solvent was then removed under reduced pressure and the crude product purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1% TFA). The product was obtained after lyophilization as an amorphous white solid.

Yield: 139 mg (71 %).

MS (ES+) [M+H]⁺ m/e = 427.7.

¹H NMR (300 MHz, DMSO-d₆): 5 12.09 (s, 1 H), 7.66 (ddd, J = 8.1 , 2.9, 1.8 Hz, 4H), 7.61 - 7.51 (m, 2H), 7.28 (dd, = 8.6, 2.3 Hz, 1 H), 7.15 (d, J = 2.2 Hz, 1 H), 3.87 - 3.69 (m, 2H), 2.33 (s, 3H), 2.13 (s, 3H), 1.65 - 1.52 (m, 2H).

¹³C NMR (75 MHz, DMSO-d₆): 6 168.35, 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.

Example compound 3: A/-(4-Methyl-5-(1-(phenylsulfonyl)indolin-5-yl)thiazol-2-yl)acetamide

Step 1 : 5-Bromo-1 -(phenylsulfonyl)indoline

5-Bromoindoline (234 mg, 1.18 mmol) was dissolved in 2 mL pyridine. Afterwards, benzenesulfonyl chloride (1.1 eq., 230 mg, 1 .30 mmol, 0.166 mL) was added to the mixture. The reaction mixture was stirred for three hours at room temperature. The solvent was then removed under reduced pressure and the crude product was then purified by silica gel chromatography using a gradient of cyclohexane and EtOAc as eluent. The product was obtained as a yellow oil.

Yield: 388 mg (97%).

MS (ES+) [M+H]⁺ m/e = 337.7, 339.7 (bromine isotopic pattern).

¹H NMR (300 MHz, CDCI3): 5 7.81 - 7.74 (m, 2H), 7.62 - 7.42 (m, 4H), 7.31 (dd, J = 8.5, 2.1 Hz, 1 H), 7.19 (t, J = 1.1 Hz, 1 H), 3.92 (t, = 8.5 Hz, 2H), 2.87 (t, = 8.4 Hz, 2H). ¹³C NMR (75 MHz, CDCI₃): 5 141.31 , 136.79, 134.20, 133.55, 130.83, 129.32, 128.38, 127.38, 116.64,

Step 2: A/-(4-Methyl-5-(1-(phenylsulfonyl)indolin-5-yl)thiazol-2-yl)acetamide

5-Bromo-1-(phenylsulfonyl)indoline (130 mg, 384 pmol), A/-(4-methylthiazol-2-yl)acetamide (1.2 eq., 72 mg, 461 pmol), tri-te/Y-butylphosphonium tetrafluoroborate (0.2 eq., 11.1 mg, 38 pmol), Pd(OAc)2, (0.1 eq., 4.3 mg, 19 pmol) and CS2CO3 (3 eq., 375 mg, 1.15 mmol) were suspended in 2 mL of DMF. The suspension was sonicated for 5 minutes, flushed with nitrogen, heated up to 120 °C and stirred overnight. The solvent was then removed under reduced pressure and the crude product purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1% TFA). The product was obtained after lyophilization as an amorphous white solid.

Yield: 132 mg (83%).

MS (ES+) [M+H]⁺ m/e = 413.7.

¹H NMR (300 MHz, DMSO-d₆): 5 12.07 (s, 1 H), 7.89 - 7.82 (m, 2H), 7.74 - 7.66 (m, 1 H), 7.64 - 7.56 (m, 2H), 7.52 (d, J = 8.3 Hz, 1 H), 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).

¹³C NMR (75 MHz, DMSO-d₆): 6 168.29, 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.

Example comopund 4: A/-(4-Methyl-5-(4-(phenylsulfonyl)-3,4-dihydro-2H- benzo[b][1 ,4]oxazin-7-yl)thiazol-2-yl)acetamide

7-Bromo-3,4-dihydro-2/7-benzo[b][1 ,4]oxazine (150 mg, 701 pmol) was dissolved in 2 mL pyridine. Afterwards, benzenesulfonyl chloride (1.1 eq., 136 mg, 771 pmol) was added to the mixture. The reaction mixture was stirred for three hours at room temperature. Upon completion of the reaction, the crude was poured in a separatory funnel, containing DCM and 1 M solution of NaOH in water. The water phase was extracted 3 times with DCM. Then, the combined organic phases were dried over Na2SC>4 and concentrated under reduced pressure. The crude mixture, A/-(4-methylthiazol-2-yl)acetamide (1.2 eq., 131 mg, 841 pmol), tri-tert-butylphosphonium tetrafluoroborate (0.2 eq., 41 mg, 140 pmol), Pd(OAc)2, (0.1 eq., 16 mg, 70 pmol) and CS2CO3 (3 eq., 684 mg, 2.10 mmol) were suspended in 2 mL of DMF. The suspension was sonicated for 5 minutes, flushed with nitrogen, heated up to 120 °C and stirred overnight. The solvent was then removed under reduced pressure and the crude product purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1 % TFA). The product was obtained after lyophilization as an amorphous white solid.

Yield: 82 mg (27%). MS (ES+) [M+H]⁺ m/e = 429.7.

¹H NMR (300 MHz, DMSO-d₆): 6 12.11 (s, 1 H), 7.78 - 7.67 (m, 4H), 7.65 - 7.56 (m, 2H), 7.04 (dd, J = 8.6, 2.2 Hz, 1 H), 6.88 (d, J = 2.1 Hz, 1 H), 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).

¹³C NMR (75 MHz, DMSO-d₆): 6 168.37, 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.

Example compound 5: A/-(5-(1-(Phenylsulfonyl)-2,3,4,5-tetrahvdro-1H-benzorblazepin-7- yl)thiazol-2-yl)acetamide

Step 1 : 7-Bromo-1 -(phenylsulfonyl)-2,3,4,5-tetrahydro-1 H-benzo[b]azepine

2,3,4,5-Tetrahydro-1/7-benzo[b]azepine (255 mg, 1.73 mmol) was dissolved in 3 mL of acetonitrile. Afterwards, 1 -bromopyrrolidine-2, 5-dione (1.0 eq., 308 mg, 1 .73 mmol) was added to the mixture and the reaction mixture was sitrred at room temperature for 16 hours. Upon completion of the reaction, the crude reaction mixture was poured in a separatory funnel, containing DCM and 1 M solution of Na2S2C>3 in water. The water phase was extracted 3 times with DCM. Then, the combined organic phases were dried over Na2SC>4 and concentrated under reduced pressure. The crude product was then dissolved in 3 mL pyridine. Afterwards, benzenesulfonyl chloride (1.1 eq., 336 mg, 1 .90 mmol, 0.243 mL) was added to the mixture. The reaction mixture was stirred for three hours at room temperature. The solvent was then removed under reduced pressure and the crude product was then purified by silica gel chromatography using a gradient of cyclohexane and EtOAc as eluent. The product was obtained as a yellow oil.

Yield: 370 mg (58%).

MS (ES+) [M+H]⁺ m/e = 365.7, 367.7 (bromine isotopic pattern).

¹H NMR (300 MHz, DMSO-d₆): 5 12.13 (s, 1 H), 7.80 - 7.66 (m, 3H), 7.65 - 7.55 (m, 2H), 7.33 - 7.23 (m, 2H), 7.21 - 7.14 (m, 1 H), 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).

¹³C NMR (75 MHz, DMSO-d₆): 6 168.44, 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.

2 A/-(5-(1 -(Phenylsulfonyl )-2, 3, 4, 5-tetrahydro-1H-benzo[b]azepin-7-yl)thiazol-2- yl)acetamide

7-Bromo-1-(phenylsulfonyl)-2,3,4,5-tetrahydro-1/7-benzo[b]azepine (120 mg, 328 pmol), A/-(4- methylthiazol-2-yl)acetamide (1.2 eq., 61 mg, 393 pmol), tri-tert-butylphosphonium tetrafluoroborate (0.2 eq., 19 mg, 66 pmol), Pd(OAc)2, (0.1 eq., 7.4 mg, 33 pmol) and CS2CO3 (3 eq., 320 mg, 983 pmol) were suspended in 2 mL of DMF. The suspension was sonicated for 5 minutes, flushed with nitrogen, heated up to 120 °C and stirred overnight. The solvent was then removed under reduced pressure and the crude product purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1 % TFA). The product was obtained after lyophilization as an amorphous white solid.

Yield: 66 mg (47%).

MS (ES+) [M+H]⁺ m/e = 441.7.

¹H NMR (300 MHz, DMSO-d₆) 5 12.13 (s, 1 H), 7.80 - 7.66 (m, 3H), 7.65 - 7.55 (m, 2H), 7.33 - 7.23 (m, 2H), 7.21 - 7.14 (m, 1 H), 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).

¹³C NMR (75 MHz, DMSO-d₆) 6 168.44, 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.

Example compound 6: /V-(4-Methyl-5-(5-(phenylsulfonyl)-5,6,7,8-tetrahydronaphthalen-2- yl)thiazol-2-yl)acetamide

Step 1 : 6-Bromo-1 -(phenylsulfonyl)-l ,2,3,4-tetrahydronaphthalene

6-Bromo-1 ,2,3,4-tetrahydronaphthalen-1-ol (90 mg, 396 pmol) was dissolved in 2 mL of DCM. To the solution, TMSCI (1.2 eq., 52 mg, 476 pmol), sodium benzenesulfinate (1.5 eq., 98 mg, 594 pmol) and FeCh (0.15 eq., 9.6 mg, 59 pmol) were then added to the mixture. The reaction mixture was reflux overnight. The solvent was then removed under reduced pressure and the crude product was then purified by silica gel chromatography using a gradient of cyclohexane and EtOAc as eluent. The product was obtained as a yellow oil.

Yield: 70 mg (50%).

MS (ES+) [M+Na]⁺ m/e = 372.6, 374.6 (bromine isotopic pattern).

¹H NMR (300 MHz, CDCI₃): 5 7.72 - 7.59 (m, 3H), 7.50 (dd, J = 8.3, 6.9 Hz, 2H), 7.25 (d, J = 8.1 Hz, 2H), 7.13 (d, = 8.1 Hz, 1 H), 4.34 (dd, = 6.4, 3.7 Hz, 1 H), 2.70 - 2.54 (m, 2H), 2.43 - 2.31 (m, 1 H), 2.14 - 1.94 (m, 2H), 1.68 - 1.52 (m, 1 H).

¹³C NMR (75 MHz, CDCI3): 5 142.12, 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.

Step 2: A/-(4-Methyl-5-(5-(phenylsulfonyl)-5,6,7,8-tetrahydronaphthalen-2-yl)thiazol-2- yl)acetamide

6-Bromo-1-(phenylsulfonyl)-1 ,2,3,4-tetrahydronaphthalene (70 mg, 199 pmol), A/-(4- methylthiazol-2-yl)acetamide (1.2 eq., 37 mg, 239 pmol), tri-tert-butylphosphonium tetrafluoroborate (0.2 eq., 12 mg, 40 pmol), Pd(OAc)2, (0.1 eq., 4.5 mg, 20 pmol) and CS2CO3 (3 eq., 195 mg, 598 pmol) were suspended in 1 mL of DMF. The suspension was sonicated for 5 minutes, flushed with nitrogen, heated up to 120 °C and stirred overnight. The solvent was then removed under reduced pressure and the crude product purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1 % TFA). The product was obtained after lyophilization as an amorphous white solid.

Yield: 22 mg (26%).

MS (ES+) [M+H]⁺ m/e = 426.7.

¹H NMR (600 MHz, DMSO-d₆): 5 12.09 (s, 1 H), 7.81 - 7.71 (m, 3H), 7.68 - 7.61 (m, 2H), 7.31 (t, J = 5.5 Hz, 1 H), 7.26 - 7.21 (m, 2H), 4.84 - 4.80 (m, 1 H), 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, 1 H), 1.60 - 1.51 (m, 1 H).

¹³C NMR (151 MHz, DMSO-d₆): 5 168.31 , 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.

Example compound 7: A/-(5-(4-Methoxy-1-(phenylsulfonyl)-1,2,3,4-tetrahydroquinolin-6-yl)- 4-methylthiazol-2-yl)acetamide

Step 1 : 6-Bromo-1 -(phenylsulfonyl)-2,3-dihydroquinolin-4(1 H)-one

2,3-Dihydroquinolin-4(1 /7)-one (317 mg, 2.15 mmol) was dissolved in 4 mL of acetonitrile. Afterwards, 1 -bromopyrrolidine-2, 5-dione (1 .0 eq., 383 mg, 2.15 mmol) was added to the mixture and the reaction was stirred at room temperature for 16 hours. Upon completion of the reaction, the crude reaction mixture was poured in a separatory funnel, containing DCM and 1 M solution of Na2S2C>3 in water. The water phase was extracted 3 times with DCM. Then, the combined organic phases were dried over Na2SC>4 and concentrated under reduced pressure. The residue was then dissolved in 3 mL pyridine. Afterwards, benzenesulfonyl chloride (1.1 eq., 418 mg, 2.37 mmol, 0.303 mL) was added to the mixture. The reaction mixture was stirred for three hours at room temperature. The solvent was then removed under reduced pressure and the crude product was then purified by silica gel chromatography using a gradient of cyclohexane and EtOAc as eluent. The product was obtained as a yellow oil.

Yield: 630 mg (80%).

MS (ES+) [M+H]⁺ m/e = 365.7, 367.8 (bromine isotopic pattern).

¹H NMR (300 MHz, CDCI₃): 5 8.05 (d, J = 2.5 Hz, 1 H), 7.78 (d, J = 8.8 Hz, 1 H), 7.72 - 7.65 (m, 3H), 7.64 - 7.56 (m, 1 H), 7.52 - 7.43 (m, 2H), 4.28 - 4.15 (m, 2H), 2.42 - 2.30 (m, 2H).

¹³C NMR (75 MHz, CDCI3): 5 191.40, 141.26, 139.58, 137.57, 133.93, 130.62, 129.82, 126.96, 126.94, 126.45, 119.61 , 46.22, 36.30.

Step 2: 6-Bromo-4-methoxy-1 -(phenylsulfonyl)-l ,2,3,4-tetrahydroquinoline

6-Bromo-1-(phenylsulfonyl)-2,3-dihydroquinolin-4(1/7)-one (100 mg, 271 pmol) was dissolved in 1 mL of MeOH. Afterwards, NaBH4 (4 eq., 41 mg, 1 .09 mmol) was added to the mixture. The reaction mixture was kept for 30 minutes at room temperature. Upon completion of the reaction, the crude was poured in a separatory funnel, containing DCM and water. The water phase was extracted 3 times with DCM. Then, the combined organic phases were dried over Na2SC>4 and concentrated under reduced pressure. The residue was then dissolved in dry THF (2 mL) and brought to 0 °C. Afterwards, NaH 60% (2 eq., 22 mg, 546 pmol) and CH3I (2 eq., 77 mg, 546 pmol) were added to the mixture. The reaction mixture was then brought to room temprature and stirred for 1 hour. The reaction mixture was then slowly quenched with acetic acid and poured in a separatory funnel, containing DCM and water. The water phase was extracted 3 times with DCM. Then, the combined organic phases were 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 eluent. The product was obtained as a yellow oil.

Yield: 80 mg (77%).

MS (ES+) [M+Na]⁺ m/e = 403.7, 405.7 (bromine isotopic pattern).

¹H NMR (300 MHz, CDCI3): 5 7.80 (d, J = 8.9 Hz, 1 H), 7.63 - 7.58 (m, 2H), 7.57 - 7.49 (m, 1 H), 7.46 - 7.36 (m, 3H), 7.33 (d, J = 2.4 Hz, 1 H), 4.02 - 3.88 (m, 2H), 3.70 (ddd, J = 12.9, 11 .3, 4.1 Hz, 1 H), 3.04 (s, 3H), 1.94 (dq, J = 13.6, 4.4 Hz, 1 H), 1.65 (dddd, J = 14.0, 11.3, 4.9, 3.6 Hz, 1 H).

¹³C NMR (75 MHz, CDCI3): 5 138.52, 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.

Step 3: A/-(5-(4-Methoxy-1-(phenylsulfonyl)-1,2,3,4-tetrahydroquinolin-6-yl)-4-methylthiazol- 2-yl)acetamide

6-Bromo-4-methoxy-1-(phenylsulfonyl)-1 ,2,3,4-tetrahydroquinoline (40 mg, 105 pmol), A/-(4- methylthiazol-2-yl)acetamide (1.2 eq., 20 mg, 126 pmol), tri-tert-butylphosphonium tetrafluoroborate (0.2 eq., 6 mg, 21 pmol), Pd(OAc)2, (0.1 eq., 2.3 mg, 10 pmol) and CS2CO3 (3 eq., 102 mg, 314 pmol) were suspended in 1 mL of DMF. The suspension was sonicated for 5 minutes, flushed with nitrogen, heated up to 110 °C and stirred overnight. The solvent was then removed under reduced pressure and the crude product purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1 % TFA). The product was obtained after lyophilization as an amorphous white solid.

Yield: 31 mg (65%).

MS (ES+) [M+H]⁺ m/e = 457.7 (bromine isotopic pattern).

¹H NMR (300 MHz, DMSO-d₆): 5 12.11 (s, 1 H), 7.77 (d, = 8.6 Hz, 1 H), 7.70 - 7.62 (m, 3H), 7.60 - 7.50 (m, 2H), 7.41 (dd, J = 8.7, 2.3 Hz, 1 H), 7.32 (d, = 2.3 Hz, 1 H), 4.15 (t, J = 4.1 Hz, 1 H), 3.98 (dt, J = 12.7, 4.6 Hz, 1 H), 3.66 (td, J = 12.0, 3.8 Hz, 1 H), 3.05 (s, 3H), 2.33 (s, 3H), 2.13 (s, 3H), 1.95 (dq, J = 13.4, 4.3 Hz, 1 H), 1.76 - 1.61 (m, 1 H).

¹³C NMR (75 MHz, DMSO-d₆): 6 168.37, 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.

8: A/-(4-< -1 ,2,3,44 in-6- Step 1 : A/-(4-Cyclopropylthiazol-2-yl)acetamide

4-Cyclopropylthiazol-2-amine (350 mg, 2.5 mmol) was dissolved in dry DCM (5 mL). Afterwards, acetic anhydride (1 .5 eq., 383 mg, 3.7 mmol) and triethylamine (1 .5 eq., 380 mg, 3.7 mmol) were added tot he mixture. The reaction mixture was stirred at room temperature for 16 hours. Upon completion of the reaction, the crude was poured in a separatory funnel, containing DCM and water. The water phase was extracted 3 times with DCM. Then, the combined organic phases were dried over Na2SO4 and concentrated under reduced pressure. The product was obtained as a yellow oil.

Yield: 287 mg (73%).

MS (ES+) [M+H]⁺ m/e = 182.9.

¹H NMR (300 MHz, CD₃OD): 56.58 (s, 1 H), 2.16 (s, 3H), 1 .94 (tt, J = 8.2, 5.1 Hz, 1 H), 0.89 - 0.72 (m, 4H).

¹³C NMR (151 MHz, CD₃OD): 5 170.58, 159.01 , 154.58, 106.11 , 22.53, 12.77, 7.94.

Step 2: A/-(4-Cyclopropyl-5-(1 -(phenylsulfonyl)-l ,2,3,4-tetrahydroquinolin-6-yl)thiazol-2- yl)acetamide

6-Bromo-1-(phenylsulfonyl)-1 ,2,3,4-tetrahydroquinoline (42 mg, 119 pmol), A/-(4- cyclopropylthiazol-2-yl)acetamide (1.5 eq., 33 mg, 179 pmol), tri-tert-butylphosphonium tetrafluoroborate (0.2 eq., 6.9 mg, 24 pmol), Pd(OAc)2, (0.1 eq., 2.7 mg, 12 pmol) and CS2CO3 (3 eq., 117 mg, 358 pmol) were suspended in 1 mL of DMF. The suspension was sonicated for 5 minutes, flushed with nitrogen, heated up to 110 °C and stirred overnight. The solvent was then removed under reduced pressure and the crude product purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1 % TFA). The product was obtained after lyophilization as an amorphous white solid.

Yield: 9 mg (17%).

MS (ES+) [M+H]⁺ m/e = 453.8.

¹H NMR (300 MHz, DMSO-d₆): 5 12.07 (s, 1 H), 7.72 - 7.64 (m, 4H), 7.61 - 7.53 (m, 2H), 7.35 (dd, J = 8.6, 2.2 Hz, 1 H), 7.21 (d, J = 2.2 Hz, 1 H), 3.83 - 3.75 (m, 2H), 2.11 (s, 3H), 2.09 - 1 .99 (m, 1 H), 1 .66 - 1 .54 (m, 2H), 0.96 - 0.81 (m, 4H).

¹³C NMR (75 MHz, DMSO-d₆): 6 168.38, 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.

Example compound 9: A/-(4-Methyl-5-(4-(phenylsulfonyl)-3,4-dihydro-2H- benzofblH ,41thiazin-7-yl)thiazol-2-yl)acetamide Step 1 : 7-Bromo-4-(phenylsulfonyl)-3,4-dihydro-2H-benzo[b][1,4]thiazine

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

Yield: 351 mg (97%).

MS (ES+) [M+Na]⁺ m/e = 391 .6, 393.6 (bromine isotopic pattern).

¹H NMR (300 MHz, CDCI₃): 5 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).

¹³C NMR (75 MHz, CDCI3): 5 140.06, 133.43, 133.29, 130.38, 129.56, 129.48, 129.20, 127.82, 127.19, 120.06, 44.55, 25.56.

Step 2: A/-(4-Methyl-5-(4-(phenylsulfonyl)-3,4-dihydro-2H-benzo[b][1,4]thiazin-7-yl)thiazol-2- yl)acetamide

7-Bromo-4-(phenylsulfonyl)-3,4-dihydro-2/7-benzo[b][1 ,4]thiazine (350 mg, 945 pmol), A/-(4- methylthiazol-2-yl)acetamide (1.2 eq., 177 mg, 1.13 mmol), tri-tert-butylphosphonium tetrafluoroborate (0.2 eq., 55 mg, 189 pmol), Pd(OAc)2, (0.1 eq., 21 mg, 95 pmol) and CS2CO3 (3 eq., 924 mg, 2.84 mmol) were suspended in 4 mL of DMF. The suspension was sonicated for 5 minutes, flushed with nitrogen, heated up to 110 °C and stirred overnight. The solvent was then removed under reduced pressure and the crude product was then purified by silica gel chromatography using a gradient of cyclohexane and EtOAc as eluent. The product was obtained as a white solid.

Yield: 144 mg (34%).

MS (ES+) [M+H]⁺ m/e = 445.7

¹H NMR (300 MHz, CD3CN): 5 9.87 (s, 1 H), 7.69 - 7.58 (m, 4H), 7.54 - 7.45 (m, 2H), 7.19 (dd, J = 8.5, 2.1 Hz, 1 H), 7.14 (d, = 2.1 Hz, 1 H), 4.01 - 3.92 (m, 2H), 2.94 - 2.84 (m, 2H), 2.31 (s, 3H), 2.16 (s, 3H).

¹³C NMR (75 MHz, CD3CN): 5 169.28, 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. Example compounds 10, 11 and 12: A/-(4-Methyl-5-(1-oxido-4-(phenylsulfonyl)-3,4-dihydro- 2/7-benzo[bin ,41thiazin-7-yl)thiazol-2-yl)acetamide, /V-(5-(1 ,1-Dioxido-4-(phenylsulfonyl)- 3.4-dihydro-2H-benzorbiri ,41thiazin-7-yl)-4-methylthiazol-2-yl)acetamide, and A/-(4-Methyl-1 - oxido-5-(1-oxido-4-(phenylsulfonyl)-3,4-dihydro-2H-benzorbiri,4lthiazin-7-yl)thiazol-2- vDacetamide

A/-(4-Methyl-5-(4-(phenylsulfonyl)-3,4-dihydro-2/7-benzo[b][1 ,4]thiazin-7-yl)thiazol-2-yl)acetamide (100 mg, 224 pmol) was dissolved in 1 mL of DCM at 0 °C. Afterwards, mefa-chloroperbenzoic acid (1 .7 eq., 66 mg, 382 pmol) was added to the mixture, and the reaction mixture was kept at 0 °C for 45 minutes, then at room temperature for one hour. The solvent was then removed under reduced pressure and the crude product purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1% TFA). All separated products were obtained after lyophilization as amorphous white solids in pure form.

Compound 10: A/-(4-Methyl-5-(1-oxido-4-(phenylsulfonyl)-3,4-dihydro-2/7-benzo[b][1 ,4]thiazin-7- yl)thiazol-2-yl)acetamide

Yield: 23 mg (22%).

MS (ES+) [M+H]⁺ m/e = 461.7.

¹H NMR (600 MHz, DMSO-d₆): 5 12.16 (s, 1 H), 7.84 - 7.77 (m, 3H), 7.75 - 7.70 (m, 1 H), 7.69 - 7.64 (m, 2H), 7.63 - 7.59 (m, 2H), 4.40 (ddd, J = 14.0, 5.9, 4.1 Hz, 1 H), 4.01 (ddd, J = 11 .5, 9.2, 4.2 Hz, 1 H), 3.24 - 3.13 (m, 2H), 2.35 (s, 3H), 2.15 (s, 3H).

¹³C NMR (151 MHz, DMSO-d₆): 5 168.48, 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.

Compound 11 : A/-(5-(1 ,1-Dioxido-4-(phenylsulfonyl)-3,4-dihydro-2/7-benzo[b][1 ,4]thiazin-7-yl)-4- methylthiazol-2-yl)acetamide

Yield: 7 mg (6%).

MS (ES+) [M+H]⁺ m/e = 477.7.

¹H NMR (600 MHz, DMSO-d₆): 5 12.20 (s, 1 H), 7.87 - 7.82 (m, 2H), 7.81 - 7.71 (m, 3H), 7.71 - 7.67 (m, 1 H), 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).

¹³C NMR (151 MHz, DMSO-d₆): 5 168.57, 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.

Compound 12: A/-(4-Methyl-1-oxido-5-(1-oxido-4-(phenylsulfonyl)-3,4-dihydro-2/7- benzo[b][1 ,4]thiazin-7-yl)thiazol-2-yl)acetamide

Yield: 6 mg (5%).

MS (ES+) [M+H]⁺ m/e = 477.7.

¹H NMR (600 MHz, DMSO-d₆): 5 7.87 (d, J = 8.7 Hz, 1 H), 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, 1 H), 4.03 (ddd, J = 13.8, 8.5, 5.1 Hz, 1 H), 3.24 - 3.17 (m, 2H), 2.36 (s, 3H), 2.28 (s, 3H). ¹³C NMR (151 MHz, DMSO-d₆) 5 158.37, 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.

Example compound 13: A/-(4-Methyl-5-(8-(phenylsulfonyl)-5,6,7,8-tetrahydro-1,8- naphthyridin-3-yl)thiazol-2-yl)acetamide

Step 1 : 6-bromo-1 -(Phenylsulfonyl)-1 ,2,3,4-tetrahydro-1 ,8-naphthyridine

6-Bromo-3,4-dihydro-1 ,8-naphthyridin-2(7/7)-one (290 mg, 1.28 mmol) was dissolved in 3 mL of dry THF and brought to 0 °C. Afterwards, a 2 M solution of LiAIH4 (3 eq., 145 mg, 3.83 mmol, 1 .92 mL) was added dropwise to the solution and the reaction mixture was kept at 0 °C for one hour. Upon completion, the reaction mixture was quenched with a water solution of a solution of Na2CC>3 and then the crude was poured in a separatory funnel, containing DCM and water. The water phase was extracted 3 times with DCM. Then, the combined organic phases were dried over Na2SC>4 and concentrated under reduced pressure. The residue was then dissolved in 3 mL pyridine. Afterwards, benzenesulfonyl chloride (1.5 eq., 338 mg, 1.91 mmol, 0.245 mL) was added to the mixture. The reaction mixture was stirred for three hours at room temperature. The solvent was then removed under reduced pressure and the crude product was then purified by silica gel chromatography using a gradient of cyclohexane and EtOAc as eluent. The product was obtained as a yellow oil.

Yield: 153 mg (34%).

MS (ES+) [M+H]⁺ m/e = 352.7, 354.7 (bromine isotopic pattern).

¹H NMR (300 MHz, CDCI₃): 5 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).

¹³C NMR (75 MHz, CDCI3): 5 149.05, 146.17, 141.09, 139.70, 132.84, 128.57, 128.37, 122.98, 113.64, 46.30, 26.90, 22.21.

Step 2: A/-(4-Methyl-5-(8-(phenylsulfonyl)-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)thiazol-2- yl)acetamide

6-Bromo-1-(phenylsulfonyl)-1 ,2,3,4-tetrahydro-1 ,8-naphthyridine (100 mg, 283 pmol), A/-(4- methylthiazol-2-yl)acetamide (1.2 eq., 53 mg, 340 pmol), tri-te/Y-butylphosphonium tetrafluoroborate (0.2 eq., 16 mg, 57 pmol), Pd(OAc)2, (0.1 eq., 6.4 mg, 28 pmol) and CS2CO3 (3 eq., 276 mg, 849 pmol) were suspended in 1 mL of DMF. The suspension was sonicated for 5 minutes, flushed with nitrogen, heated up to 110 °C and stirred overnight. The solvent was then removed under reduced pressure and the crude product purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1 % TFA). The product was obtained after lyophilization as an amorphous white solid.

Yield: 44 mg (36%). MS (ES+) [M+H]⁺ m/e = 428.8.

¹H NMR (300 MHz, DMSO-d₆): 6 12.13 (s, 1 H), 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).

¹³C NMR (75 MHz, DMSO-d₆): 6 168.39, 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.

Example compound 14: A/-(4-Methyl-5-(4-oxo-1-(phenylsulfonyl)-1,2,3,4-tetrahydroquinolin- 6-yl)thiazol-2-yl)acetamide

Step 1 : 6-Bromo-1 -(phenylsulfonyl)-2,3-dihydro-1 H-spiro[quinoline-4,2'-[1 ,3]dioxolane]

6-Bromo-1-(phenylsulfonyl)-2,3-dihydroquinolin-4(1/7)-one (160 mg, 437 pmol) and Tetrabutylammonium bromide (0.01 eq., 1.4 mg, 4.4 pmol) were dissolved in 2 mL ethane-1 ,2- diol. The mixture was then heated at 110 °C for 72 hours. Upon completion, the crude was poured in a separatory funnel, containing DCM and water. The water phase was extracted 3 times with DCM. Then, the combined organic phases were dried over Na2SC>4 and concentrated under reduced pressure and the crude product was then purified by silica gel chromatography using a gradient of cyclohexane and EtOAc as eluent. The product was obtained as a yellow oil.

Yield: 55 mg (31%).

MS (ES+) [M+H]⁺ m/e = 409.6, 411.6 (bromine isotopic pattern).

¹H NMR (300 MHz, CDCI₃): 5 7.81 - 7.73 (m, 1 H), 7.71 - 7.60 (m, 2H), 7.59 - 7.51 (m, 1 H), 7.51 - 7.35 (m, 4H), 4.14 - 3.84 (m, 6H), 1.81 - 1 .68 (m, 2H).

¹³C NMR (75 MHz, CDCI₃): 5 138.86, 136.36, 133.32, 132.56, 129.46, 129.24, 127.23, 126.94, 124.84, 118.05, 65.18, 44.78, 31.89.

Step 2: A/-(4-Methyl-5-(4-oxo-1 -(phenylsulfonyl)-l ,2,3,4-tetrahydroquinolin-6-yl)thiazol-2- yl)acetamide

6-Bromo-1-(phenylsulfonyl)-2,3-dihydro-1 /7-spiro[quinoline-4,2'-[1 ,3]dioxolane] (55 mg, 134 pmol), A/-(4-methylthiazol-2-yl)acetamide (1.2 eq., 25 mg, 161 pmol), tri-tert-butylphosphonium tetrafluoroborate (0.2 eq., 8 mg, 27 pmol), Pd(OAc)2, (0.1 eq., 3.0 mg, 13 pmol) and CS2CO3 (3 eq., 131 mg, 402 pmol) were suspended in 1 mL of DMF. The suspension was sonicated for 5 minutes, flushed with nitrogen, heated up to 110 °C and stirred overnight. The crude was poured in a separatory funnel, containing DCM and water. The water phase was extracted 3 times with DCM. Then, the combined organic phases were dried over Na2SO4 and concentrated under reduced pressure. Afterwards, the crude was dissolved in 1 mL of Acetone and 1 mL of a 1 M solution of HCI in water. The mixture was then warmed up to 60 °C for 1 hour. Upon completion, a water solution of NaHCO₃ was added until the pH reached 7. The solvent was then removed under reduced pressure purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1% TFA). The product was obtained after lyophilization as an amorphous white solid. Yield: 29 mg (49%).

MS (ES+) [M+H]⁺ m/e = 441.7.

¹H NMR (300 MHz, DMSO-d₆): 6 12.18 (s, 1 H), 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).

¹³C NMR (75 MHz, DMSO-d₆): 6 192.01 , 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.

Example compound 15: A/-(5-(4-Hvdroxy-1-(phenylsulfonyl)-1 ,2,3,4-tetrahydroquinolin-6- yl)-4-methylthiazol-2-yl)acetamide

A/-(4-Methyl-5-(4-oxo-1-(phenylsulfonyl)-1 ,2,3,4-tetrahydroquinolin-6-yl)thiazol-2-yl)acetamide (24 mg, 54 pmol) was dissolved in 1 mL of MeOH. Afterwards, NaBH4 (2 eq., 4.1 mg, 109 pmol) 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 purified by reversed- phase preparative HPLC (5% to 99% acetonitrile with 0.1 % TFA). The product was obtained after lyophilization as an amorphous white solid.

Yield: 17 mg (71%).

MS (ES+) [M+H]⁺ m/e = 443.7.

¹H NMR (300 MHz, DMSO-d₆): 5 12.09 (s, 1 H), 7.75 - 7.63 (m, 4H), 7.62 - 7.53 (m, 2H), 7.41 (d, J = 2.3 Hz, 1 H), 7.34 (dd, J = 8.6, 2.3 Hz, 1 H), 5.51 (d, J = 5.3 Hz, 1 H), 4.31 (q, J = 5.0 Hz, 1 H), 3.99 (ddd, J = 13.0, 7.0, 4.1 Hz, 1 H), 3.77 (ddd, J = 12.9, 8.7, 3.8 Hz, 1 H), 2.34 (s, 3H), 2.13 (s, 3H), 1.83 - 1.56 (m, 2H).

¹³C NMR (75 MHz, DMSO-d₆): 6 168.36, 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.

Example compound 16: A/-(4-Methyl-5-(2-methyl-1-(phenylsulfonyl)-1 ,2,3,4- tetrahydroquinolin-6-yl)thiazol-2-yl)acetamide

Step 1 : 6-Bromo-2-methyl-1 -(phenylsulfonyl)-l ,2,3,4-tetrahydroquinoline

2-Methyl-1 ,2,3,4-tetrahydroquinoline (291 mg, 1.98 mmol) was dissolved in 3 mL of acetonitrile. Afterwards, 1 -bromopyrrolidine-2, 5-dione (1 .0 eq., 352 mg, 1 .98 mmol) was added to the mixture and the reaction was stirred at room temperature for 16 hours. Upon completion of the reaction, the crude was poured in a separatory funnel, containing DCM and 1 M solution of Na2S2C>3 in water. The water phase was extracted 3 times with DCM. Then, the combined organic phases were dried over Na2SC>4 and concentrated under reduced pressure. The residue was then dissolved in 3 mL pyridine. Subsequently, benzenesulfonyl chloride (1.1 eq., 384 mg, 2.17 mmol, 0.278 mL) was added to the mixture. The reaction mixture was stirred for three hours at room temperature. The solvent was then removed under reduced pressure and the crude product was then purified by silica gel chromatography using a gradient of cyclohexane and EtOAc as eluent. The product was obtained as a yellow oil.

Yield: 558 mg (77%).

MS (ES+) [M+Na]⁺ m/e = 387.7, 389.7 (bromine isotopic pattern).

¹H NMR (300 MHz, DMSO-d₆): 5 12.10 (s, 1 H), 7.71 - 7.59 (m, 2H), 7.58 - 7.48 (m, 4H), 7.33 (dd, J = 8.5, 2.2 Hz, 1 H), 7.14 (d, J = 2.2 Hz, 1 H), 4.37 (q, J = 6.4 Hz, 1 H), 2.48 - 2.42 (m, 1 H), 2.35 (s, 3H), 2.13 (s, 3H), 1.76 (tq, J = 11.6, 5.6 Hz, 2H), 1.41 - 1.27 (m, 1 H), 1.21 (d, J = 6.5 Hz, 3H).

¹³C NMR (75 MHz, DMSO-d₆): 6 168.35, 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.

Step 2: A/-(4-Methyl-5-(2-methyl-1 -(phenylsulfonyl)-l ,2,3,4-tetrahydroquinolin-6-yl)thiazol-2- yl)acetamide

6-Bromo-2-methyl-1-(phenylsulfonyl)-1 ,2,3,4-tetrahydroquinoline (105 mg, 287 pmol), A/-(4- methylthiazol-2-yl)acetamide (1.2 eq., 54 mg, 344 pmol), tri-tert-butylphosphonium tetrafluoroborate (0.2 eq., 17 mg, 57 pmol), Pd(OAc)2, (0.1 eq., 6 mg, 29 pmol) and CS2CO3 (3 eq., 280 mg, 860 pmol) were suspended in 1 mL of DMF. The suspension was sonicated for 5 minutes, flushed with nitrogen, heated up to 110 °C and stirred overnight. The solvent was then removed under reduced pressure and the crude product purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1 % TFA). The product was obtained after lyophilization as an amorphous white solid.

Yield: 32 mg (25%).

MS (ES+) [M+H]⁺ m/e = 441.7.

Example compound 17: A/-(5-(1-(Phenylsulfonyl)-1,2,3,4-tetrahydroquinolin-6-yl)-4- (trifluoromethyl)thiazol-2-yl)acetamide

Step 1 : /V-(4-(T rifluoromethyl)thiazol-2-yl)acetamide

4-(Trifluoromethyl)thiazol-2-amine (144 mg, 856 pmol) was dissolved in dry DCM (3 mL). Afterwards, acetyl chloride (2 eq., 134 mg, 1.71 mmol) and triethylamine (2 eq., 173 mg, 1.71 mmol) were added to the mixture. The reaction mixture was stirred at room temperature for 16 hours. Upon completion of the reaction, the crude was poured in a separatory funnel, containing DCM and water. The water phase was extracted 3 times with DCM. Then, the combined organic phases were dried over Na2SC>4 and concentrated under reduced pressure. The crude product was then purified by silica gel chromatography using a gradient of cyclohexane and EtOAc as eluent. The product was obtained as a yellow oil.

Yield: 40 mg (22%).

MS (ES+) [M+H]⁺ m/e = 182.9.

¹H NMR (300 MHz, CD₃OD): 5 7.61 (s, 1 H), 4.88 (s, 1 H), 2.22 (s, 3H).

¹³C NMR (75 MHz, CD₃OD): 5 171.24, 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.

Step 2: Af-(5-(d -(Phenylsulfonyl)-1 ,2,3,4-tetrahydroquinolin-6-yl)-4-(trifluoromethyl)thiazol-2- yl)acetamide

6-Bromo-1-(phenylsulfonyl)-1 ,2,3,4-tetrahydroquinoline (30 mg, 85 pmol), A/-(4- (trifluoromethyl)thiazol-2-yl)acetamide (1.2 eq., 21 mg, 102 pmol), tri-tert-butylphosphonium tetrafluoroborate (0.2 eq., 4.9 mg, 17 pmol), Pd(OAc)2, (0.1 eq., 1.9 mg, 9 pmol) and CS2CO3 (3 eq., 83 mg, 255 pmol) were suspended in 1 mL of DMF. The suspension was sonicated for 5 minutes, flushed with nitrogen, heated up to 130 °C and stirred overnight. The solvent was then removed under reduced pressure and the crude product purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1 % TFA). The product was obtained after lyophilization as an amorphous white solid.

Yield: 30 mg (73%).

MS (ES+) [M+H]⁺ m/e = 481 .7.

¹H NMR (600 MHz, DMSO-d₆): 5 12.60 (s, 1 H), 7.74 - 7.63 (m, 4H), 7.60 - 7.52 (m, 2H), 7.30 - 7.25 (m, 1 H), 7.21 - 7.17 (m, 1 H), 3.86 - 3.79 (m, 2H), 2.56 - 2.51 (m, 2H), 2.18 (s, 3H), 1.63 (p, J = 6.1 Hz, 2H).

¹³C NMR (151 MHz, DMSO-d₆): 5 169.31 , 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. (missing the CF₃)

Example compound 18: A/-(5-(1-(Phenylsulfonyl)-1,2,3,4-tetrahydroquinolin-6-yl)thiazol-2- vDacetamide

6-Bromo-1-(phenylsulfonyl)-1 ,2,3,4-tetrahydroquinoline (82 mg, 233 pmol), A/-(thiazol-2- yl)acetamide (1.4 eq., 46 mg, 326 pmol), tri-tert-butylphosphonium tetrafluoroborate (0.2 eq., 14 mg, 47 pmol), Pd(OAc)2, (0.1 eq., 5 mg, 23 pmol) and CS2CO3 (3 eq., 228 mg, 698 pmol) were suspended in 1 mL of DMF. The suspension was sonicated for 5 minutes, flushed with nitrogen, heated up to 130 °C and stirred overnight. The solvent was then removed under reduced pressure and the crude product purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1% TFA). The product was obtained after lyophilization as an amorphous white solid.

Yield: 22 mg (22%).

MS (ES+) [M+H]⁺ m/e = 413.7.

¹H NMR (300 MHz, DMSO-d₆): 5 12.15 (s, 1 H), 7.80 (s, 1 H), 7.71 - 7.60 (m, 4H), 7.60 - 7.51 (m, 2H), 7.46 (dd, J = 8.6, 2.2 Hz, 1 H), 7.32 (d, J = 2.2 Hz, 1 H), 3.82 - 3.73 (m, 2H), 2.49 - 2.42 (m, 2H), 2.15 (s, 3H), 1.62 - 1.49 (m, 2H).

¹³C NMR (75 MHz, DMSO-d₆): 6 168.40, 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.

Example compound 19: A/-(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)-l ,2,3,4-tetrahydro-1 ,5-naphthyridine

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

Yield: 75 mg (42%).

MS (ES+) [M+H]⁺ m/e = 352.6, 354.7 (bromine isotopic pattern)

¹H NMR (300 MHz, DMSO-d₆): 5 7.95 (d, J = 8.7 Hz, 1 H), 7.77 - 7.55 (m, 5H), 7.49 (d, J = 8.7 Hz, 1 H), 3.84 - 3.70 (m, 2H), 2.62 (t, J = 6.7 Hz, 2H), 1 .54 (p, J = 6.4 Hz, 2H).

¹³C NMR (151 MHz, DMSO-d₆): 5 151.22, 138.09, 135.40, 133.89, 133.75, 132.97, 129.81 , 126.87, 125.69, 45.66, 29.10, 19.71.

Step 2: A/-(4-Methyl-5-(5-(phenylsulfonyl)-5,6,7,8-tetrahydro-1,5-naphthyridin-2-yl)thiazol-2- yl)acetamide

6-Bromo-1-(phenylsulfonyl)-1 ,2,3,4-tetrahydro-1 ,5-naphthyridine (75 mg, 212 pmol), A/-(4- methylthiazol-2-yl)acetamide (1.2 eq., 40 mg, 254 pmol), tri-tert-butylphosphonium tetrafluoroborate (0.2 eq., 6 mg, 21 pmol), Pd(OAc)2, (0.1 eq., 6 mg, 29 pmol) and CS2CO3 (3 eq., 280 mg, 860 pmol) were suspended in 1 mL of DMF. The suspension was sonicated for 5 minutes, flushed with nitrogen, heated up to 110 °C and stirred overnight. The solvent was then removed under reduced pressure and the crude product purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1 % TFA). The product was obtained after lyophilization as an amorphous white solid.

Yield: 60 mg (66%).

MS (ES+) [M+H]⁺ m/e = 428.7.

¹H NMR (300 MHz, DMSO-d₆): 5 12.11 (s, 1 H), 8.04 (d, = 8.8 Hz, 1 H), 7.74 - 7.64 (m, 3H), 7.63 - 7.55 (m, 2H), 7.53 (d, J = 8.8 Hz, 1 H), 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).

¹³C NMR (75 MHz, DMSO-d₆): 5 168.50, 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.

Example compound 20: A/-(4-Methyl-5-(1-(phenylsulfonyl)-1 ,2,3,4-tetrahydroquinolin-6- yl)oxazol-2-yl)acetamide

4-Methyloxazol-2-amine (20 mg, 204 pmol) was dissolved in dry DCM 1 mL). Afterwards, acetic anhydride (2 eq., 42 mg, 407 pmol) and triethylamine (2 eq., 41 mg, 407 pmol) were added to the mixture. The reaction mixture was stirred at room temperature for 16 hours. Upon completion of the reaction, the crude was poured in a separatory funnel, containing DCM and water. The water phase was extracted 3 times with DCM. Then, the combined organic phases were dried over Na2SO4 and concentrated under reduced pressure. The crude, 6-bromo-1-(phenylsulfonyl)- 1 ,2,3,4-tetrahydroquinoline (50 mg, 142 pmol), tri-tert-butylphosphonium tetrafluoroborate (0.2 eq., 8 mg, 28 pmol), Pd(OAc)2, (0.1 eq., 3.2 mg, 14 pmol) and CS2CO3 (3 eq., 139 mg, 426 pmol) were suspended in 1 mL of DMF. The suspension was sonicated for 5 minutes, flushed with nitrogen, heated up to 130 °C and stirred overnight. The solvent was then removed under reduced pressure and the crude product purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1% TFA). The product was obtained after lyophilization as an amorphous white solid.

Yield: 7 mg (12%).

MS (ES+) [M+H]⁺ m/e = 411.8

¹H NMR (300 MHz, DMSO-d₆): 5 11 .24 (s, 1 H), 7.73 (d, J = 8.7 Hz, 1 H), 7.70 - 7.61 (m, 3H), 7.60

- 7.49 (m, 2H), 7.37 (dd, J = 8.7, 2.2 Hz, 1 H), 7.22 (d, J = 2.2 Hz, 1 H), 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).

¹³C NMR (75 MHz, DMSO-d₆) 6 169.23, 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.

Example compound 21 : 4-(4-Methyl-5-(1-(phenylsulfonyl)-1 ,2,3,4-tetrahydroquinolin-6- yl)thiazol-2-yl)morpholine

1 4-(4-Methylthiazol-2-yl)morpholine

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

Yield: 55 mg (35%).

MS (ES+) [M+H]⁺ m/e = 185.1.

¹H NMR (300 MHz, CDCI₃): 5 6.13 (q, J = 1.1 Hz, 1 H), 3.83 - 3.71 (m, 4H), 3.47 - 3.35 (m, 4H), 2.23 (d, J = 1.1 Hz, 3H).

¹³C NMR (75 MHz, CDCI3): 5 171.57, 149.50, 101.92, 66.23, 48.59, 17.66.

Step 2: 4-(4-Methyl-5-(1 -(phenylsulfonyl)-l ,2,3,4-tetrahydroquinolin-6-yl)thiazol-2- yl)morpholine

6-Bromo-1-(phenylsulfonyl)-1 ,2,3,4-tetrahydroquinoline (55 mg, 156 pmol), 4-(4-methylthiazol-2- yl)morpholine (1.2 eq., 35 mg, 187 pmol), tri-tert-butylphosphonium tetrafluoroborate (0.2 eq., 9 mg, 31 pmol), Pd(OAc)2, (0.1 eq., 3.5 mg, 16 pmol) and CS2CO3 (3 eq., 152 mg, 468 pmol) were suspended in 1 mL of DMF. The suspension was sonicated for 5 minutes, flushed with nitrogen, heated up to 110 °C and stirred overnight. The solvent was then removed under reduced pressure and the crude product purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1% TFA). The lyophilized powder was poured in an separatory funnel containing DCM and a saturated solution of Na2COs in water. The water phase was extracted 3 times with DCM. Then, the combined organic phases were dried over Na2SC>4 and concentrated under reduced pressure. The product was obtained as an amorphous white solid.

Yield: 16 mg (22%).

MS (ES+) [M+H]⁺ m/e = 456.1 .

¹H NMR (300 MHz, CDCI3): 5 7.78 (d, J = 8.6 Hz, 1 H), 7.68 - 7.60 (m, 2H), 7.58 - 7.50 (m, 1 H), 7.47 - 7.36 (m, 2H), 7.19 (dd, J = 8.6, 2.2 Hz, 1 H), 7.00 (d, J = 2.5 Hz, 1 H), 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).

¹³C NMR (75 MHz, CDCI3): 5 168.71 , 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.

Example compound 22: A/-(4-Methyl-5-(5-(phenylsulfonyl)-2,3,3a,4,5,9b-hexahydrofuror3,2- clquinolin-8-yl)thiazol-2-yl)acetamide

Step 1 : 8-Bromo-2,3,3a,4,5,9b-hexahydrofuro[3,2-c]quinoline

4-Bromoaniline (200 mg, 1.16 mmol) and formaldehyde 37% in water (1 eq., 94 mg, 1.16 mmol) were dissolved in 2 mL of acetonitrile at 0°C. Afterwards, Yb(OTf)3 (0.05 eq., 36 mg, 58 pmol) was added tot he mixture, followed by the dropwise addition of 2,3-dihydrofurane (1 eq., 81 mg, 1.16 mmol) dissolved in 1 mL of acetonitrile. The reaction mixture was kept at 0° C for 20 minutes. Afterwards, the crude product purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1% TFA). The lyophilized powder was poured in an separatory funnel containing DCM and a saturated solution of Na2CO₃ in water. The water phase was extracted 3 times with DCM. Then, the combined organic phases were dried over Na2SC>4 and concentrated under reduced pressure. The product was obtained as an amorphous white solid.

Yield: 95 mg (32%).

MS (ES+) [M+H]⁺ m/e = 252.0, 254.0 (bromine isotopic pattern).

1 H NMR (300 MHz, CDCI₃): 6 7.43 (d, J = 2.4 Hz, 1 H), 7.15 (dd, J = 8.6, 2.4 Hz, 1 H), 6.48 (d, J = 8.6 Hz, 1 H), 4.51 (d, J = 5.4 Hz, 1 H), 3.94 (td, J = 8.5, 5.8 Hz, 1 H), 3.81 (td, J = 8.8, 6.2 Hz, 1 H), 3.15 (dd, J = 11.3, 5.1 Hz, 1 H), 2.81 (t, J = 11.1 Hz, 1 H), 2.42 (ddtd, J = 10.7, 8.2, 5.3, 2.9 Hz, 1 H), 2.23 (dddt, J = 14.2, 7.4, 5.9, 3.7 Hz, 1 H), 1.75 (dddd, J = 15.1 , 10.0, 6.5, 3.3 Hz, 1 H).

¹³C NMR (75 MHz, CDCI₃): 5 144.25, 133.90, 131.58, 122.68, 116.59, 109.77, 74.98, 65.52, 43.00, 35.85, 29.71.

Step 2: 8-Bromo-5-(phenylsulfonyl)-2,3,3a,4,5,9b-hexahydrofuro[3,2-c]quinoline

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

Yield: 80 mg (54%).

MS (ES+) [M+Na]⁺ m/e = 416.0, 418.0 (bromine isotopic pattern)

¹H NMR (300 MHz, CDCI3): 5 7.65 - 7.52 (m, 5H), 7.48 - 7.38 (m, 3H), 4.25 (dd, J = 13.9, 5.3 Hz, 1 H), 4.05 (d, J = 6.1 Hz, 1 H), 3.91 - 3.75 (m, 1 H), 3.66 (ddd, J = 8.7, 7.7, 6.8 Hz, 1 H), 2.86 (dd, J = 14.0, 12.1 Hz, 1 H), 2.26 - 1.97 (m, 2H), 1.53 (dddd, J = 12.4, 10.3, 6.9, 2.4 Hz, 1 H).

¹³C NMR (75 MHz, CDCI3): 5 139.94, 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.

Step 3: A/-(4-Methyl-5-(5-(phenylsulfonyl)-2,3,3a,4,5,9b-hexahydrofuro[3,2-c]quinolin-8- yl)thiazol-2-yl)acetamide

8-Bromo-5-(phenylsulfonyl)-2,3,3a,4,5,9b-hexahydrofuro[3,2-c]quinoline (75 mg, 190 pmol), A/-(4- methylthiazol-2-yl)acetamide (1.2 eq., 36 mg, 228 pmol), tri-tert-butylphosphonium tetrafluoroborate (0.2 eq., 11 mg, 42 pmol), Pd(OAc)2, (0.1 eq., 4 mg, 19 pmol) and CS2CO3 (3 eq., 186 mg, 571 pmol) were suspended in 1 mL of DMF. The suspension was sonicated for 5 minutes, flushed with nitrogen, heated up to 110 °C and stirred overnight. The solvent was then removed under reduced pressure and the crude product purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1 % TFA). The product was obtained after lyophilization as an amorphous white solid.

Yield: 30 mg (34%).

MS (ES+) [M+H]⁺ m/e = 470.1

¹H NMR (300 MHz, DMSO-d₆): 5 12.13 (s, 1 H), 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, 1 H), 4.17 (dd, J = 13.8, 5.2 Hz, 1 H), 3.75 (td, J = 8.0, 5.3 Hz, 1 H), 3.59 (q, J = 7.8 Hz, 1 H), 2.95 (dd, 13.9, 11.8 Hz, 1 H), 2.34 (s, 3H), 2.27 - 2.01 (m, 5H), 1.66 - 1.50 (m, 1 H).

¹³C NMR (75 MHz, DMSO-d₆): 6 168.41 , 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.

Example compound 23: A/-(6-Methyl-5-(1-(phenylsulfonyl)-1 ,2,3,4-tetrahydroquinolin-6- yl)pyridin-2-yl)acetamide

A/-(5-Bromo-6-methylpyridin-2-yl)acetamide (106 mg, 462 pmol), 4,4,4',4',5,5,5',5'-octamethyl- 2,2'-bi(1 ,3,2-dioxaborolane) (1.5 eq., 176 mg, 694 pmol), potassium acetate (3 eq., 136 mg, 1.39 mmol) and [1 ,1 '-Bis(diphenylphosphino)ferrocene]dichloropalladium(ll) (0.05 eq., 17 mg, 23 pmol) were dissolved in 1 mL of 1 ,4-dioxane. The suspension was sonicated for 5 minutes, flushed with nitrogen, heated up to 100 °C and stirred for 2 hours. Upon completion, 6-bromo-1- (phenylsulfonyl)-1 ,2,3,4-tetrahydroquinoline (1 eq., 42 mg, 119 pmol) and 1 mL of water was added to the crude and the suspension was sonicated for 5 minutes, flushed with nitrogen, heated up to 100 °C and stirred overnight. The solvent was then removed under reduced pressure and the crude product purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1% TFA). The product was obtained after lyophilization as an amorphous white solid.

Yield: 37 mg (74%).

MS (ES+) [M+H]⁺ m/e = 422.2.

¹H NMR (300 MHz, DMSO-d₆): 5 10.56 (s, 1 H), 7.95 (d, J = 8.4 Hz, 1 H), 7.72 - 7.63 (m, 4H), 7.63 - 7.51 (m, 3H), 7.21 (dd, J = 8.5, 2.2 Hz, 1 H), 7.10 (d, J = 2.2 Hz, 1 H), 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).

¹³C NMR (75 MHz, DMSO-d₆): 6 169.33, 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.

Example compound 24: (/?)-A/-(5-(4-methoxy-1-(phenylsulfonyl)-1 ,2,3,4-tetrahydroquinolin- 6-yl)-4-methylthiazol-2-yl)acetamide Step 1 : (/?)-6-Bromo-1 -(phenylsulfonyl)-l ,2,3,4-tetrahydroquinolin-4-ol

6-Bromo-1-(phenylsulfonyl)-2,3-dihydroquinolin-4(1/7)-one (25 mg, 68 pmol), [A/-[(1 R,2R)-2- (Amino-K /)-1 ,2-diphenylethyl]-4-methylbenzenesulfonamidato-KA/]chloro[(1 ,2,3,4,5,6-q)-1-methyl- 4-(1-methylethyl)benzene]-ruthenium (0.01 eq., 0.4 mg, 0.68 pmol) were dissolved in 0.5 mL of formic acid and 0.5 mL of triethylamine and stirred at room temperature for 72 hours. Upon completion, the solvents were then removed under reduced pressure. The solvent was then removed under reduced pressure and the crude product purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1 % TFA). The product was obtained after lyophilization as an amorphous white solid.

Yield: 22 mg (88%). ee: >99%

Step 2 and step 3 of example compound 7 have been followed to obtain example 24

Example compound 25: 2-(3-lsopropoxyazetidin-1-yl)-4-methyl-5-(1-(phenylsulfonyl)- 1 ,2,3,4-tetrahydroquinolin-6-yl)thiazole

Step 1 : 2-(3-lsopropoxyazetidin-1 -yl)-4-methylthiazole

2-Bromo-4-methylthiazole (113 mg, 635 pmol), 3-isopropoxyazetidine hydrochloride (2 eq., 192 mg, 1 .27 mmol) and A/-ethyldiisopropylamine (4 eq., 328 mg, 2.54 mmol, 0.442 mL) were dissolved in 2 mL of DMF and the mixture was heated up to 130 °C for 16 hours. The solvent was then removed under reduced pressure and the crude product was then purified by silica gel chromatography using a gradient of cyclohexane and EtOAc as eluent. The product was obtained as a yellow oil.

Yield: 53 mg (39%).

MS (ES+) [M+H]⁺ m/e = 213.1

¹H NMR (300 MHz, CDCI₃): 5 6.09 (q, J = 1.1 Hz, 1 H), 4.55 - 4.44 (m, 1 H), 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, 1 H), 2.24 (d, J = 1.1 Hz, 3H), 1.15 (d, J = 6.1 Hz, 6H).

¹³C NMR (75 MHz, CDCI3): 5 171.34, 149.40, 102.45, 71.55, 67.18, 61.87, 22.51 , 17.49.

Step 2: 2-(3-lsopropoxyazetidin-1 -yl)-4-methyl-5-(1 -(phenylsulfonyl)-l ,2,3,4- tetrahydroquinolin-6-yl)thiazole

6-Bromo-1-(phenylsulfonyl)-1 ,2,3,4-tetrahydroquinoline (70 mg, 199 pmol), 2-(3- isopropoxyazetidin-1-yl)-4-methylthiazole (1.2 eq., 50 mg, 238 pmol), tri-tert-butylphosphonium tetrafluoroborate (0.2 eq., 12 mg, 40 pmol), Pd(OAc)2, (0.1 eq., 4.5 mg, 20 pmol) and CS2CO3 (3 eq., 194 mg, 596 pmol) were suspended in 1 mL of DMF. The suspension was sonicated for 5 minutes, flushed with nitrogen, heated up to 110 °C and stirred overnight. The solvent was then removed under reduced pressure and the crude product purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1 % TFA). The lyophilized powder was poured in an separatory funnel containing DCM and a saturated solution of Na2COs in water. The water phase was extracted 3 times with DCM. Then, the combined organic phases were dried over Na2SC>4 and concentrated under reduced pressure, product was obtained as a white solid.

Yield: 26 mg (27%).

MS (ES+) [M+H]⁺ m/e = 484.1

¹H NMR (300 MHz, CDCI3): 5 7.77 (d, J = 8.6 Hz, 1 H), 7.67 - 7.60 (m, 2H), 7.58 - 7.50 (m, 1 H), 7.47 - 7.37 (m, 2H), 7.17 (dd, J = 8.6, 2.3 Hz, 1 H), 6.98 (dd, J = 2.1 , 1.1 Hz, 1 H), 4.52 (tt, J = 6.5, 4.8 Hz, 1 H), 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, 1 H), 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).

¹³C NMR (75 MHz, CDCI3): 5 168.45, 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.

Example compound 26: Tert-butyl 6-((4-methyl-5-(1-(phenylsulfonyl)-1 ,2,3,4- tetrahvdroquinolin-6-yl)thiazol-2-yl)amino)-6-oxohexyl)carbamate

Step 1 : Tert-butyl (6-((4-methylthiazol-2-yl)amino)-6-oxohexyl)carbamate

6-((Te/t-butoxycarbonyl)amino)hexanoic acid (120 mg, 519 pmol) and A/-ethyldiisopropylamine (3 eq., 202 mg, 1.55 mol) were dissolved in 2 mL of dry DMF. Afterwards, 1- [bis(dimethylamino)methylene]-1 /7-1 ,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (1 .2 eq., 240 mg, 623 pmol) was added to the mixture and the suspension was stirred at room temperature for 30 minutes. 4-Methylthiazol-2-amine (1.2 eq., 71 mg, 623 pmol) was then added to the 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 eluent. The product was obtained as a yellow oil.

Yield: 112 mg (66%).

MS (ES+) [M+H]⁺ m/e = 328.4.

¹H NMR (300 MHz, DMSO-d₆): 5 11 .96 (s, 1 H), 6.77 (t, J = 5.7 Hz, 1 H), 6.71 (d, J = 1 .2 Hz, 1 H), 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).

¹³C NMR (151 MHz, DMSO-d₆): 5 171.01 , 157.24, 155.54, 146.45, 107.33, 77.26, 40.06, 34.84, 29.19, 28.23, 25.81 , 24.43, 16.83. Step 2: Tert-butyl 6-((4-methyl-5-(1 -(phenylsulfonyl)-l ,2,3,4-tetrahydroquinolin-6-yl)thiazol- 2-yl)amino)-6-oxohexyl)carbamate

6-Bromo-1-(phenylsulfonyl)-1 ,2,3,4-tetrahydroquinoline (60 mg, 169 pmol), tert-butyl (6-((4- methylthiazol-2-yl)amino)-6-oxohexyl)carbamate (1 eq., 55 mg, 169 pmol), tri-tert- butylphosphonium tetrafluoroborate (0.2 eq., 10 mg, 34 pmol), Pd(OAc)2, (0.1 eq., 3.8 mg, 17 pmol) and CS2CO3 (3 eq., 166 mg, 507 pmol) were suspended in 1 mL of DMF. The suspension was sonicated for 5 minutes, flushed with nitrogen, heated up to 110 °C and stirred overnight. The solvent was then removed under reduced pressure and the crude product purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1% TFA). The product was obtained after lyophilization as an amorphous white solid.

Yield: 29 mg (30%).

MS (ES+) [M+H]⁺ m/e = 599.1.

¹H NMR (300 MHz, DMSO-d₆): 5 12.06 (s, 1 H), 7.73 - 7.63 (m, 4H), 7.62 - 7.53 (m, 2H), 7.28 (dd, J = 8.6, 2.3 Hz, 1 H), 7.15 (d, J = 2.2 Hz, 1 H), 6.84 - 6.72 (m, 1 H), 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).

¹³C NMR (151 MHz, DMSO-d₆): 5 171.17, 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.

Example compound 27: Tert-butyl (2-(2-(2-((4-methyl-5-(1-(phenylsulfonyl)-1 ,2,3,4- tetrahvdroquinolin-6-yl)thiazol-2-yl)amino)-2-oxoethoxy)ethoxy)ethyl)carbamate

Step 1 : Tert-butyl (2-(2-(2-((4-methylthiazol-2-yl)amino)-2-

oxoethoxy)ethoxy)ethyl)carbamate

Dicyclohexylamine 2,2-dimethyl-4-oxo-3,8,11-trioxa-5-azatridecan-13-oate (150 mg, 337 pmol) was dissolved in 2 mL of dry DMF. Afterwards, 1-[bis(dimethylamino)methylene]-1 /7-1 ,2,3- triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (1.2 eq., 46 mg, 405 pmol) was added to the mixture and the suspension was stirred at room temperature for 30 minutes. 4-Methylthiazol- 2-amine (1 .2 eq., 156 mg, 405 pmol) was then added to the 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 eluent. The product was obtained as a yellow oil.

Yield: 60 mg (50%).

MS (ES+) [M+H]⁺ m/e = 360.4.

¹H NMR (300 MHz, DMSO-d₆): 6 11.59 (s, 1 H), 6.95 - 6.87 (m, 1 H), 6.79 (d, J = 1 .3 Hz, 1 H), 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 .0 Hz, 3H), 1 .36 (s, 9H). ¹³C NMR (151 MHz, DMSO-d₆): 5 162.27, 156.63, 155.55, 146.61 , 107.92, 77.57, 70.46, 69.46, 69.36, 69.16, 52.22, 38.22, 28.18.

Step 2: Tert -butyl (2-(2-(2-((4-methyl-5-(1 -(phenylsulfonyl)-l ,2,3,4-tetrahydroquinolin-6- yl)thiazol-2-yl)amino)-2-oxoethoxy)ethoxy)ethyl)carbamate

6-Bromo-1-(phenylsulfonyl)-1 ,2,3,4-tetrahydroquinoline (60 mg, 169 pmol), tert-butyl (2-(2-(2-((4- methylthiazol-2-yl)amino)-2-oxoethoxy)ethoxy)ethyl)carbamate (60 mg, 169 pmol), tri-tert- butylphosphonium tetrafluoroborate (0.2 eq., 10 mg, 34 pmol), Pd(OAc)2, (0.1 eq., 3.8 mg, 17 pmol) and CS2CO3 (3 eq., 166 mg, 507 pmol) were suspended in 1 mL of DMF. The suspension was sonicated for 5 minutes, flushed with nitrogen, heated up to 110 °C and stirred overnight. The solvent was then removed under reduced pressure and the crude product purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1% TFA). The product was obtained after lyophilization as an amorphous white solid.

Yield: 50 mg (47%).

MS (ES+) [M+H]⁺ m/e = 631.1.

¹H NMR (300 MHz, DMSO-d₆): 6 11.73 (s, 1 H), 7.74 - 7.63 (m, 4H), 7.61 - 7.53 (m, 2H), 7.30 (dd, J = 8.6, 2.3 Hz, 1 H), 7.17 (d, J = 2.2 Hz, 1 H), 6.88 (t, J = 5.6 Hz, 1 H), 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).

¹³C NMR (151 MHz, DMSO-d₆): 5 168.61 , 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.

Example compound 28: A/-(5-(4-Acetyl-1-(phenylsulfonyl)-1 ,2,3,4-tetrahydroquinoxalin-6- yl)-4-methylthiazol-2-yl)acetamide

Step 1 : 7-Bromo-4-(phenylsulfonyl)-3,4-dihydroquinoxalin-2(1 H)-one

7-Bromo-3,4-dihydroquinoxalin-2(1/7)-one (250 mg, 1.10 mmol) was dissolved in 3 mL of pyridine. Afterwards, benzenesulfonyl chloride (1.1 eq., 213 mg, 1.21 mmol, 0.155 mL) was added to the mixture. The reaction mixture was stirred for three hours at room temperature. The solvent was then removed under reduced pressure and the crude product was then purified by silica gel chromatography using a gradient of cyclohexane and EtOAc as eluent. The product was obtained as a yellow oil.

Yield: 372 mg (92%).

MS (ES+) [M+H]⁺ m/e = 367.0, 369.0 (bromine isotopic pattern)

¹H NMR (300 MHz, CDCI3): 5 7.65 (s, 1 H), 7.62 (d, J = 8.6 Hz, 1 H), 7.57 - 7.46 (m, 3H), 7.43 - 7.35 (m, 2H), 7.31 - 7.26 (m, 1 H), 6.81 (d, J = 2.1 Hz, 1 H), 4.35 (s, 2H). ¹³C NMR (75 MHz, CDCI₃): 5 165.58, 136.84, 133.88, 133.30, 129.36, 129.33, 127.16, 127.15, 123.66, 121.67, 118.94, 49.18.

Step 2: 6-Bromo-1 -(phenylsulfonyl)-l ,2,3,4-tetrahydroquinoxaline

7-Bromo-4-(phenylsulfonyl)-3,4-dihydroquinoxalin-2(1 /7)-one (156 mg, 424 pmol) was dissolved in 2 mL of dry THF and brought to 0 °C. Afterwards, a 2 M solution of LiAl H4 (3 eq., 48 mg, 1 .27 mmol, 0.673 mL) was added dropwise to the solution and the reaction mixture was kept at 0 °C for one hour. Upon completion, the reaction mixture was quenched with a water solution of a solution of Na2CC>3 and then the crude was poured in a separatory funnel, containing DCM and water. The water phase was extracted 3 times with DCM. Then, the combined organic phases were dried over Na2SC>4 and concentrated under reduced pressure.

Yield: 127 mg (84%).

MS (ES+) [M+H]⁺ m/e = 353.0, 355.0 (bromine isotopic pattern).

¹H NMR (300 MHz, CDCI3): 5 7.65 - 7.46 (m, 4H), 7.41 (t, J = 7.7 Hz, 2H), 6.76 (dd, J = 8.7, 2.2 Hz, 1 H), 6.59 (d, J = 2.2 Hz, 1 H), 3.72 (t, J = 5.2 Hz, 2H), 3.35 (s, 1 H), 2.84 (t, J = 5.2 Hz, 2H).

¹³C NMR (75 MHz, CDCI3): 5 139.21 , 139.01 , 133.15, 129.27, 127.66, 127.24, 120.46, 119.92, 119.73, 116.97, 43.43, 38.50.

Step 3: 1 -(7-Bromo-4-(phenylsulfonyl)-3,4-dihydroquinoxalin-1 (2H)-yl)ethan-1 -one

6-Bromo-1-(phenylsulfonyl)-1 ,2,3,4-tetrahydroquinoxaline (41 mg, 116 pmol) was dissolved in 1 mL of dry acetone. Afterwards, acetyl chloride (1.1 eq., 12 mg, 127 pmol) and triethylamine (2 eq., 23 mg, 232 pmol) were added to the mixture. The reaction mixture was stirred at room temperature for one hour. Upon completion of the reaction, the crude was poured in a separatory funnel, containing DCM and water. The water phase was extracted 3 times with DCM. Then, the combined organic phases were 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 eluent. The product was obtained as a yellow oil.

Yield: 34 mg (74%).

MS (ES+) [M+Na]⁺ m/e = 416.9, 418.9 (bromine isotopic pattern).

¹H NMR (300 MHz, CDCI3): 5 7.75 (d, J = 8.8 Hz, 1 H), 7.60 - 7.50 (m, 3H), 7.50 - 7.40 (m, 2H), 7.37 (dd, J = 8.8, 2.2 Hz, 1 H), 7.29 - 7.18 (m, 1 H), 3.90 (t, = 6.1 Hz, 2H), 3.73 (t, J = 6.3 Hz, 2H), 1.66 (s, 3H).

¹³C NMR (75 MHz, CDCI3): 5 168.40, 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.

A/-(5-(4-Acetyl-1 -(phenylsulfonyl)-l ,2,3,4-tetrahydroquinoxalin-6-yl)-4-methylthiazol-

2-yl)acetamide

1-(7-Bromo-4-(phenylsulfonyl)-3,4-dihydroquinoxalin-1 (2/7)-yl)ethan-1-one (34 mg, 86 pmol), A/- (4-methylthiazol-2-yl)acetamide (1.2 eq., 16 mg, 103 pmol), tri-tert-butylphosphonium tetrafluoroborate (0.2 eq., 5 mg, 17 pmol), Pd(OAc)2, (0.1 eq., 1.9 mg, 8.6 pmol) and CS2CO3 (3 eq., 84 mg, 258 pmol) were suspended in 1 mL of DMF. The suspension was sonicated for 5 minutes, flushed with nitrogen, heated up to 110 °C and stirred overnight. The solvent was then removed under reduced pressure and the crude product purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1 % TFA). The product was obtained after lyophilization as an amorphous white solid.

Yield: 20 mg (49%).

MS (ES+) [M+H]⁺ m/e = 471.1.

¹H NMR (300 MHz, DMSO-d₆): 5 12.14 (s, 1 H), 7.74 - 7.47 (m, 7H), 7.32 (dd, = 8.4, 2.1 Hz, 1 H), 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).

¹³C NMR (75 MHz, DMSO-d₆): 6 168.43, 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.

Example compound 29: A/-(4-Methyl-5-(4-methyl-3-oxo-1-(phenylsulfonyl)-1 ,2,3,4- tetrahydroquinoxalin-6-yl)thiazol-2-yl)acetamide

Step 1 : 7-Bromo-1 -methyl-4-(phenylsulfonyl)-3,4-dihydroquinoxalin-2(1 H)-one

7-Bromo-4-(phenylsulfonyl)-3,4-dihydroquinoxalin-2(1 /7)-one (41 mg, 112 pmol) was dissolved in 1 mL of dry acetone. Afterwards, CS2CO3 (4 eq., 146 mg, 467 pmol) and iodomethane (2 eq., 32 mg, 223 pmol) were added to the mixture. The reaction mixture was stirred at 60 °C for two hours. Upon completion of the reaction, the crude was poured in a separatory funnel, containing DCM and water. The water phase was extracted 3 times with DCM. Then, the combined organic phases were dried over Na2SC>4 and concentrated under reduced pressure. The crude product was then purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1% TFA). The product was obtained as a yellow oil.

Yield: 12 mg (28%).

MS (ES+) [M+H]⁺ m/e = 380.9, 382.9 (bromine isotopic pattern).

¹H NMR (300 MHz, CDCI3): 5 7.60 (d, J = 8.5 Hz, 1 H), 7.58 - 7.50 (m, 1 H), 7.47 - 7.36 (m, 4H), 7.35 - 7.28 (m, 1 H), 6.96 (d, J = 2.1 Hz, 1 H), 4.37 (s, 2H), 2.66 (s, 3H).

¹³C NMR (75 MHz, CDCI3): 5 164.37, 136.78, 136.66, 133.70, 129.71 , 129.14, 127.20, 126.94, 125.31 , 122.14, 118.64, 49.73, 28.67. 2 A/-(4-Methyl-5-(4-methyl-3-oxo-1-(phenylsulfonyl)-1,2,3,4-tetrahydroquinoxalin-6- yl)thiazol-2-yl)acetamide

7-Bromo-1-methyl-4-(phenylsulfonyl)-3,4-dihydroquinoxalin-2(1/7)-one (11 mg, 29 pmol), A/-(4- methylthiazol-2-yl)acetamide (1.2 eq., 5.4 mg, 35 pmol), tri-tert-butylphosphonium tetrafluoroborate (0.2 eq., 1.7 mg, 5.8 pmol), Pd(OAc)2, (0.1 eq., 0.7 mg, 2.9 pmol) and CS2CO3 (3 eq., 28 mg, 87 mol) were suspended in 1 mL of DMF. The suspension was sonicated for 5 minutes, flushed with nitrogen, heated up to 110 °C and stirred overnight. The solvent was then removed under reduced pressure and the crude product purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1 % TFA). However, A/-(4-methyl-5-(4-methyl-3-oxo-3,4- dihydroquinoxalin-6-yl)thiazol-2-yl)acetamide was obtained instead of the desired compound. NaBH4 (4 eq., 4.4 mg, 115 mol) was added to a stirred solution of the product in 1 mL of MeOH. After one hour at room temperature, the crude wass poured in a separatory funnel, containing DCM and water. The water phase was extracted 3 times with DCM. Then, the combined organic phases were dried over Na2SC>4 and concentrated under reduced pressure. The residue was then dissolved in 1 mL pyridine, followed by the addition of benzenesulfonyl chloride (2 eq., 10 mg, 58 mol) to the mixture. The reaction mixture was stirred for three hours at room temperature. The solvent was then removed under reduced pressure and the crude product purified by reversed- phase preparative HPLC (5% to 99% acetonitrile with 0.1 % TFA). The product was obtained after lyophilization as an amorphous white solid.

Yield: 2.5 mg (20%).

MS (ES+) [M+H]⁺ m/e = 457.0.

¹H NMR (600 MHz, CDCI3): 5 7.86 (d, J = 8.2 Hz, 1 H), 7.59 - 7.54 (m, 1 H), 7.51 - 7.48 (m, 2H), 7.42 (dd, J = 8.3, 7.3 Hz, 2H), 7.22 (dd, J = 8.2, 1 .9 Hz, 1 H), 6.80 (d, J = 1 .9 Hz, 1 H), 4.42 (s, 2H), 2.75 (s, 3H), 2.52 (s, 3H), 2.44 (s, 3H).

¹³C NMR (151 MHz, CDCI3) 6 169.63, 164.26, 160.40, 136.97, 136.60, 133.84, 133.58, 129.26, 129.20, 127.27, 127.21 , 124.25, 124.08, 115.69, 49.69, 28.71 , 23.24, 13.15.

Example compound 30: A/-Methyl-A/-(4-methyl-5-(1-(phenylsulfonyl)-1 ,2,3,4- tetrahydroquinolin-6-yl)thiazol-2-yl)acetamide

A/-(4-Methyl-5-(1 -(phenylsulfonyl)-l ,2,3,4-tetrahydroquinolin-6-yl)thiazol-2-yl)acetamide (30 mg, 70 mol) was dissolved in 1 mL of DMF. Afterwards, CS2CO3 (2 eq., 46 mg, 140 mol) and iodomethane (1.5 eq., 15 mg, 105 mol) were added to the mixture. The reaction mixture was stirred at 60 °C for two hours. The solvent was then removed under reduced pressure and the crude product purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1% TFA). The product was obtained after lyophilization as an amorphous white solid.

Yield: 14 mg (43%).

MS (ES+) [M+H]⁺ m/e = 442.1 .

¹H NMR (600 MHz, DMSO-d₆): 5 7.72 - 7.63 (m, 4H), 7.57 (dd, J = 8.5, 7.1 Hz, 2H), 7.28 (dd, J = 8.6, 2.3 Hz, 1 H), 7.15 (d, J = 2.2 Hz, 1 H), 3.83 - 3.76 (m, 2H), 3.63 (s, 3H), 2.53 - 2.51 (m, 2H), 2.38 (s, 3H), 2.35 (s, 3H), 1 .65 - 1 .55 (m, 2H).

¹³C NMR (151 MHz, DMSO-d₆): 5 170.34, 156.03, 141.10, 138.89, 135.38, 133.40, 130.75, 129.52, 129.18, 128.33, 126.73, 126.35, 124.77, 123.72, 46.25, 34.72, 25.99, 22.85, 20.93, 16.25.

Example compound 31: A/-(5-(3-Methoxy-1-(phenylsulfonyl)-1,2,3,4-tetrahydroquinolin-6- yl)-4-methylthiazol-2-yl)acetamide

Step 1 : 6-Bromo-1 -(phenylsulfonyl)-l ,2,3,4-tetrahydroquinolin-3-ol

1 ,2,3,4-Tetrahydroquinolin-3-ol (260 mg, 1 .74 mmol) was dissolved in 3 mL of acetonitrile. Afterwards, 1 -bromopyrrolidine-2, 5-dione (1 .0 eq., 310 mg, 1 .74 mmol) was added to the mixture and the reaction was stirred at room temperature for 16 hours. Upon completion of the reaction, the crude was poured in a separatory funnel, containing DCM and 1 M solution of Na2S2C>3 in water. The water phase was extracted 3 times with DCM. Then, the combined organic phases were dried over Na2SC>4 and concentrated under reduced pressure. The residue was then dissolved in 3 mL pyridine. Afterwards, benzenesulfonyl chloride (1.1 eq., 338 mg, 1.91 mmol, 0.245 mL) was added to the mixture. The reaction mixture was stirred for three hours at room temperature. The solvent was then removed under reduced pressure and the crude product was then purified by silica gel chromatography using a gradient of cyclohexane and EtOAc as eluent. The product was obtained as a yellow oil.

Yield: 554 mg (86%).

MS (ES+) [M+Na]⁺ m/e = 389.9, 392.0 (bromine isotopic pattern).

¹H NMR (300 MHz, CDCI₃): 5 7.63 (dt, J = 7.2, 1 .4 Hz, 2H), 7.56 - 7.46 (m, 2H), 7.44 - 7.33 (m, 2H), 7.22 (dd, J = 8.9, 2.4 Hz, 1 H), 7.10 (d, J = 2.4 Hz, 1 H), 4.03 - 3.84 (m, 2H), 3.50 (dd, J = 13.0, 6.9 Hz, 1 H), 3.24 (s, 1 H), 2.70 - 2.56 (m, 1 H), 2.40 (dd, J = 16.5, 6.9 Hz, 1 H).

¹³C NMR (75 MHz, CDCI3): 5 138.94, 135.07, 133.16, 132.34, 130.13, 129.73, 129.18, 126.89, 124.82, 118.16, 63.20, 51.86, 35.38. Step 2: A/-(5-(3-Methoxy-1-(phenylsulfonyl)-1,2,3,4-tetrahydroquinolin-6-yl)-4-methylthiazol- 2-yl)acetamide

6-Bromo-1-(phenylsulfonyl)-1 ,2,3,4-tetrahydroquinolin-3-ol (150 mg, 407 pmol) was dissolved in 3 mL of dry THF. Afterwards, NaH 60% (3 eq., 49 mg, 1.22 mmol) and CH3I (3 eq., 173 mg, 1 .22 mmol) were added to the mixture at 0°C. The reaction mixture was then brought to room temprature and stirred for 1 hour. The reaction mixture was then slowly quenched with acetic acid and then the crude was poured in a separatory funnel, containing DCM and water. The water phase was extracted 3 times with DCM. Then, the combined organic phases were dried over Na2SC>4 and concentrated under reduced pressure. The crude, A/-(4-methylthiazol-2-yl)acetamide (1.2 eq., 76 mg, 488 pmol), tri-tert-butylphosphonium tetrafluoroborate (0.2 eq., 24 mg, 81 pmol), Pd(OAc)2, (0.1 eq., 9 mg, 41 pmol) and CS2CO3 (3 eq., 398 mg, 1 .22 mmol) were suspended in 2 mL of DMF. The suspension was sonicated for 5 minutes, flushed with nitrogen, heated up to 110 °C and stirred overnight. The solvent was then removed under reduced pressure and the crude product purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1% TFA). The product was obtained after lyophilization as an amorphous white solid.

Yield: 55 mg (30%).

MS (ES+) [M+H]⁺ m/e = 458.1 .

¹H NMR (300 MHz, DMSO-d₆): 5 12.09 (s, 1 H), 7.79 - 7.72 (m, 2H), 7.72 - 7.64 (m, 1 H), 7.63 - 7.51 (m, 3H), 7.26 (dd, = 8.6, 2.3 Hz, 1 H), 7.19 (d, J = 2.2 Hz, 1 H), 3.96 (dd, J = 13.4, 3.7 Hz, 1 H), 3.79 (dd, J = 13.4, 5.7 Hz, 1 H), 3.66 - 3.54 (m, 1 H), 3.24 (s, 3H), 2.73 (dd, J = 16.6, 4.9 Hz, 1 H), 2.60 (dd, J = 16.5, 5.8 Hz, 1 H), 2.31 (s, 3H), 2.13 (s, 3H).

¹³C NMR (75 MHz, DMSO-d₆): 6 168.32, 154.97, 141.85, 138.97, 134.98, 133.49, 129.63, 129.53, 128.32, 128.17, 126.86, 126.53, 123.10, 122.09, 71.89, 55.55, 48.80, 31.90, 22.45, 16.10.

Example compound 32: A/-(5-(4-Methoxy-4-methyl-1-(phenylsulfonyl)-1 ,2,3,4- tetrahydroquinolin-6-yl)-4-methylthiazol-2-yl)acetamide

Step 1 : 6-Bromo-4-methyl-1 -(phenylsulfonyl)-l ,2,3,4-tetrahydroquinolin-4-ol

6-Bromo-1-(phenylsulfonyl)-2,3-dihydroquinolin-4(1/7)-one (100 mg, 273 pmol) was dissolved in 2 mL of dry THF. Afterwards, the solution was brought to -78 °C and a solution 1 .6 M of CH3U in THF (1.10 eq., 6.60 mg, 300 pmol, 0.187 mL) was added dropwise to the stirring solution. The reaction mixture was slowly brought to 0 °C and stirred for one hour. The reaction mixture was then slowly quenched with acetic acid and then the crude was poured in a separatory funnel, containing DCM and water. The water phase was extracted 3 times with DCM. Then, the combined organic phases were 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 eluent. The product was obtained as a yellow oil. Yield: 44 mg (42%).

MS (ES+) [M+H]⁺ m/e = 381.0, 382.9 (bromine isotopic pattern).

¹H NMR (300 MHz, CDCI₃): 5 7.64 - 7.52 (m, 2H), 7.49 - 7.36 (m, 4H), 7.31 (dd, J = 6.9, 1 .6 Hz, 1 H), 7.22 (d, J = 2.3 Hz, 1 H), 4.33 (dq, J = 3.6, 1 .7 Hz, 2H), 4.01 - 3.75 (m, 1 H), 3.67 (s, 1 H), 1 .76 - 1 .56 (m, 1 H), 1 .56 - 1 .49 (m, 3H).

¹³C NMR (75 MHz, CDCI3): 5 138.88, 132.85, 130.83, 129.36, 128.98, 128.62, 127.44, 127.17, 126.50, 121.61 , 45.32, 43.75, 36.69, 17.74.

Step 2: 6-Bromo-4-methoxy-4-methyl-1 -(phenylsulfonyl)-l ,2,3,4-tetrahydroquinoline

6-Bromo-4-methyl-1-(phenylsulfonyl)-1 ,2,3,4-tetrahydroquinolin-4-ol (40 mg, 104 pmol) was dissolved in 2 mL of dry THF. Afterwards, NaH 60% (3 eq., 13 mg, 314 pmol) and CH3I (3 eq., 45 mg, 314 pmol) were added to the mixture at 0°C. The reaction mixture was then brought to room temprature and stirred for 1 hour. The reaction mixture was then slowly quenched with acetic acid and then the crude was poured in a separatory funnel, containing DCM and water. The water phase was extracted 3 times with DCM. Then, the combined organic phases were dried over Na2SC>4 and concentrated under reduced pressure. The crude product was then purified by silica gel chromatography using a gradient of cyclohexane and EtOAc as eluent. The product was obtained as a yellow oil.

Yield: 5 mg (12%).

MS (ES+) [M+Na]⁺ m/e = 418.0, 420.0 (bromine isotopic pattern).

¹H NMR (300 MHz, CD3OD): 5 7.80 (d, J = 8.7 Hz, 1 H), 7.69 - 7.57 (m, 3H), 7.54 - 7.39 (m, 4H), 4.04 (ddd, J = 13.9, 7.9, 4.1 Hz, 1 H), 3.81 (ddd, J = 13.9, 8.3, 3.8 Hz, 1 H), 2.58 (s, 3H), 1.93 (ddd, J = 14.0, 8.3, 4.1 Hz, 1 H), 1 .48 (ddd, J = 14.1 , 8.0, 3.8 Hz, 1 H), 1 .20 (s, 3H).

¹³C NMR (75 MHz, CD3OD): 5 140.55, 137.49, 136.79, 134.52, 132.16, 131.27, 130.50, 128.48, 127.28, 119.56, 74.18, 50.30, 45.49, 31.82, 28.90.

Step 3: A/-(5-(4-Methoxy-4-methyl-1 -(phenylsulfonyl)-l ,2,3,4-tetrahydroquinolin-6-yl)-4- methylthiazol-2-yl)acetamide

6-Bromo-4-methoxy-4-methyl-1-(phenylsulfonyl)-1 ,2,3,4-tetrahydroquinoline (5 mg, 13 pmol) N- (4-methylthiazol-2-yl)acetamide (1.2 eq., 2.4 mg, 15 pmol), tri-tert-butylphosphonium tetrafluoroborate (0.2 eq., 0.7 mg, 2.5 pmol), Pd(OAc)2, (0.1 eq., 0.3 mg, 1.3 pmol) and CS2CO3 (3 eq., 12 mg, 38 pmol) were suspended in 1 mL of DMF. The suspension was sonicated for 5 minutes, flushed with nitrogen, heated up to 110 °C and stirred overnight. The solvent was then removed under reduced pressure and the crude product purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1 % TFA). The product was obtained after lyophilization as an amorphous white solid.

Yield: 3 mg (50%). MS (ES+) [M+H]⁺ m/e = 472.1 .

¹H NMR (600 MHz, DMSO-d₆): 6 12.09 (s, 1 H), 7.79 (d, = 8.6 Hz, 1 H), 7.69 - 7.64 (m, 3H), 7.58

- 7.54 (m, 2H), 7.40 (dd, J = 8.6, 2.3 Hz, 1 H), 7.34 (d, J = 2.3 Hz, 1 H), 3.99 (ddd, J = 13.7, 7.7, 4.0 Hz, 1 H), 3.81 (ddd, J = 13.7, 8.6, 3.6 Hz, 1 H), 2.54 (s, 3H), 2.34 (s, 3H), 2.14 (s, 3H), 1.91 (ddd, J = 13.2, 8.6, 4.1 Hz, 1 H), 1.51 (ddd, J = 13.9, 7.6, 3.6 Hz, 1 H), 1.24 (s, 3H).

¹³C NMR (151 MHz, DMSO-d₆): 5 168.32, 154.97, 142.08, 138.62, 135.27, 133.51 , 133.03, 129.56, 128.62, 127.92, 126.92 (2C), 123.65, 123.07, 72.53, 49.16, 44.03, 30.40, 28.25, 22.42, 16.04.

Example compound 33: A/,A/.4-Trimethyl-5-(1-(phenylsulfonyl)-1,2,3,4-tetrahydroquinolin-6- yl)thiazol-2-amine

6-Bromo-1-(phenylsulfonyl)-1 ,2,3,4-tetrahydroquinoline (44 mg, 125 pmol), A/,A/,4-trimethylthiazol- 2-amine (1.2 eq., 21 mg, 150 pmol), tri-te/Y-butylphosphonium tetrafluoroborate (0.2 eq., 7 mg, 25 pmol), Pd(OAc)2, (0.1 eq., 2.8 mg, 13 pmol) and CS2CO3 (3 eq., 122 mg, 375 pmol) were suspended in 1 mL of DMF. The suspension was sonicated for 5 minutes, flushed with nitrogen, heated up to 110 °C and stirred overnight. The solvent was then removed under reduced pressure and the crude product purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1% TFA). The lyophilized powder was poured in a separatory funnel containing DCM and a saturated solution of Na2COs in water. The water phase was extracted 3 times with DCM. Then, the combined organic phases were dried over Na2SC>4 and concentrated under reduced pressure. The product was obtained as an amorphous white solid.

Yield: 17 mg (33%).

MS (ES+) [M+H]⁺ m/e = 414.1.

¹H NMR (300 MHz, CDCI3): 5 7.78 (d, J = 8.6 Hz, 1 H), 7.68 - 7.60 (m, 2H), 7.58 - 7.51 (m, 1 H), 7.47 - 7.37 (m, 2H), 7.19 (dd, J = 8.6, 2.3 Hz, 1 H), 7.01 - 6.97 (m, 1 H), 3.88 - 3.74 (m, 2H), 3.13 (s, 6H), 2.45 (t, J = 6.7 Hz, 2H), 2.36 (s, 3H), 1 .69 - 1 .58 (m, 2H).

¹³C NMR (75 MHz, CDCI3): 5 168.34, 143.89, 139.74, 135.35, 132.93, 130.76, 129.75, 129.17, 129.03, 127.19, 126.80, 124.98, 118.64, 46.70, 40.55, 26.79, 21.64, 16.48.

Example compound 34: A/-(4-Methyl-5-(4-morpholino-1-(phenylsulfonyl)-1 ,2,3,4- tetrahydroquinolin-6-yl)thiazol-2-yl)acetamide

Step 1 : 4,6-Dibromo-1 -(phenylsulfonyl)-l ,2,3,4-tetrahydroquinoline

6-Bromo-1-(phenylsulfonyl)-1 ,2,3,4-tetrahydroquinolin-4-ol (120 mg, 326 pmol) was dissolved in 2 mL of dry THF. Afterwards, PBrs (1.5 eq., 97 mg, 358 pmol) was added dropwise to the mixture at 0°C. The reaction mixture was then brought to room temprature and stirred for two hours. Upon completion of the reaction, the crude was poured in a separatory funnel, containing DCM and 1 M solution of Na2S2C>3 in water. The water phase was extracted 3 times with DCM. Then, the combined organic phases were 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 eluent. The product was obtained as a yellow oil.

Yield: 127 mg (90%).

A/o MS since it hydrolyzes in water

¹H NMR (300 MHz, CDCI₃): 5 7.77 (d, J = 8.9 Hz, 1 H), 7.69 - 7.62 (m, 2H), 7.61 - 7.52 (m, 1 H), 7.49 - 7.38 (m, 3H), 7.36 (dd, J = 8.9, 2.4 Hz, 1 H), 5.16 (t, J = 3.2 Hz, 1 H), 4.31 (dtd, J = 13.6, 3.8, 1.2 Hz, 1 H), 3.90 (ddd, J = 13.6, 12.3, 2.9 Hz, 1 H), 2.18 (dq, J = 15.2, 3.1 Hz, 1 H), 1.94 (ddt, J = 15.2, 12.3, 4.1 Hz, 1 H).

¹³C NMR (75 MHz, CDCI3): 5 138.93, 134.96, 133.53 (2C), 132.48, 130.79, 129.43, 127.25, 125.08, 117.74, 45.11 , 42.89, 30.96.

Step 2: A/-(4-Methyl-5-(4-morpholino-1 -(phenylsulfonyl)-l ,2,3,4-tetrahydroquinolin-6- yl)thiazol-2-yl)acetamide

4,6-Dibromo-1-(phenylsulfonyl)-1 ,2,3,4-tetrahydroquinoline (15 mg, 35 pmol) was dissolved in 1 mL of DCM. Afterwards, morpholine (4 eq., 12 mg, 139 pmol) was added to the mixture. The reaction mixture was stirred at room temprature and for 1 hour. The residue was then poured in a separatory funnel, containing DCM and water. The water phase was extracted 3 times with DCM. Then, the combined organic phases were dried over Na2SO4 and concentrated under reduced pressure. Then, the crude, A/-(4-methylthiazol-2-yl)acetamide (1.2 eq., 7 mg, 42 pmol), tri-tert- butylphosphonium tetrafluoroborate (0.2 eq., 2.0 mg, 7.0 pmol), Pd(OAc)2, (0.1 eq., 0.8 mg, 3.5 pmol) and CS2CO3 (3 eq., 34 mg, 104 pmol) were suspended in 2 mL of DMF. The suspension was sonicated for 5 minutes, flushed with nitrogen, heated up to 110 °C and stirred overnight. The solvent was then removed under reduced pressure and the crude product purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1% TFA). The lyophilized powder was poured in an separatory funnel containing DCM and a saturated solution of Na2COs in water. The water phase was extracted 3 times with DCM. Then, the combined organic phases were dried over Na2SO4 and concentrated under reduced pressure. The product was obtained as an amorphous white solid.

Yield: 8 mg (45%).

MS (ES+) [M+H]⁺ m/e = 414.1.

¹H NMR (600 MHz, CDCI3): 5 7.94 (d, J = 8.6 Hz, 1 H), 7.73 - 7.66 (m, 2H), 7.55 (td, J = 7.4, 2.9 Hz, 2H), 7.43 (t, J = 7.8 Hz, 2H), 7.33 (dd, J = 8.6, 2.3 Hz, 1 H), 4.13 (ddd, J = 12.6, 7.3, 4.0 Hz, 1 H), 3.69 (ddd, J = 12.7, 8.6, 3.7 Hz, 1 H), 3.57 - 3.38 (m, 5H), 2.41 (s, 3H), 2.36 - 2.22 (m, 5H), 2.10 (s, 2H), 1.85 (s, 1 H).

¹³C NMR (151 MHz, CDCI₃): 5 167.54, 155.49, 141.66, 139.46, 136.87, 133.12, 132.26, 129.88, 129.25, 128.71 , 128.52, 127.52, 125.65, 124.63, 67.07, 60.73, 49.14, 44.87, 23.44, 20.80, 16.27.

Example compound 35: A/-(4-Methyl-5-(6-(phenylsulfonyl)-3,4,4a,5,6,10b-hexahydro-2H- pyrano[3,2-c1quinolin-9-yl)thiazol-2-yl)acetamide Step 1 : 9-Bromo-6-(phenylsulfonyl)-3,4,4a,5,6,10b-hexahydro-2H-pyrano[3,2-c]quinoline

4-Bromoaniline (200 mg, 1.16 mmol) and formaldehyde 37% in water (1 eq., 94 mg, 1.16 mmol) were dissolved in 2 mL of acetonitrile at 0°C. Afterwards, Yb(0Tf)3 (0.05 eq., 36 mg, 58 pmol) was added tot he mixture, followed by the dropwise addition of 3,4-dihydro-2/7-pyran (1.1 eq., 107 mg, 1.28 mmol) dissolved in 1 mL of acetonitrile. The reaction mixture was kept at 0° C for 20 minutes. Afterwards, the crude product purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1% TFA). The lyophilized powder was poured in a separatory funnel containing DCM and a saturated solution of Na2COs in water. The water phase was extracted 3 times with DCM. Then, the combined organic phases were dried over Na2SC>4 and concentrated under reduced pressure. The product was then dissolved in 1 mL of pyridine, followed by the addition of benzenesulfonyl chloride (1.1 eq., 226 mg, 1.28 mmol) to the mixture. The reaction mixture was stirred for three hours at room temperature. The solvent was then removed under reduced pressure and the crude product purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1% TFA). The product was obtained after lyophilization as an amorphous white solid.

Yield: 12 mg (2.5%).

MS (ES+) [M+Na]⁺ m/e = 429.9, 432.0 (bromine isotopic pattern).

¹H NMR (300 MHz, CDCI₃): 5 7.74 - 7.65 (m, 3H), 7.60 - 7.51 (m, 1 H), 7.49 - 7.40 (m, 3H), 7.35 (dd, = 9.0, 2.5 Hz, 1 H), 4.17 (d, = 3.1 Hz, 1 H), 4.05 (ddd, J = 13.2, 3.4, 1.2 Hz, 1 H), 3.92 - 3.76 (m, 2H), 3.54 (td, J = 11 .2, 2.6 Hz, 1 H), 1 .82 - 1 .58 (m, 4H), 1 .46 - 1 .37 (m, 1 H).

¹³C NMR (75 MHz, CDCI3): 5 139.73, 135.86, 133.88, 133.28, 131.98, 130.12, 129.38, 127.05, 123.91 , 117.62, 72.69, 67.88, 46.42, 31.36, 25.05, 21.67.

Step 2: A/-(4-Methyl-5-(6-(phenylsulfonyl)-3,4,4a,5,6,10b-hexahydro-2H-pyrano[3,2- c]quinolin-9-yl)thiazol-2-yl)acetamide

9-Bromo-6-(phenylsulfonyl)-3,4,4a,5,6,10b-hexahydro-2/7-pyrano[3,2-c]quinoline (12 mg, 29 pmol), A/-(4-methylthiazol-2-yl)acetamide (1.2 eq., 5 mg, 32 pmol), tri-tert-butylphosphonium tetrafluoroborate (0.2 eq., 1.7 mg, 5.9 pmol), Pd(OAc)2, (0.1 eq., 0.7 mg, 2.9 pmol) and CS2CO3 (3 eq., 29 mg, 88 pmol) were suspended in 1 mL of DMF. The suspension was sonicated for 5 minutes, flushed with nitrogen, heated up to 120 °C and stirred overnight. The solvent was then removed under reduced pressure and the crude product purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1 % TFA). The product was obtained after lyophilization as an amorphous white solid.

Yield: 4 mg (28%).

MS (ES+) [M+H]⁺ m/e = 484.1 . ¹H NMR (600 MHz, DMSO-d₆): 6 12.12 (s, 1 H), 7.85 - 7.79 (m, 2H), 7.72 - 7.67 (m, 2H), 7.63 - 7.55 (m, 2H), 7.37 (dd, J = 8.8, 2.4 Hz, 1 H), 7.31 (d, J = 2.4 Hz, 1 H), 4.34 (d, J = 2.7 Hz, 1 H), 4.05 (dd, J = 13.3, 2.9 Hz, 1 H), 3.81 (dd, J = 13.0, 10.8 Hz, 1 H), 3.72 (dt, J = 11.4, 3.7 Hz, 1 H), 3.51 (td, J = 11.2, 2.6 Hz, 1 H), 2.31 (s, 3H), 2.12 (s, 3H), 1.82 - 1.69 (m, 3H), 1.65 - 1.51 (m, 1 H), 1.40 - 1.32 (m, 1 H).

¹³C NMR (151 MHz, DMSO-d₆): 5 168.41 , 154.97, 141.96, 138.99, 135.10, 133.72, 131.13, 129.76, 128.54, 128.29, 127.65, 126.86, 122.89, 121.03, 71.79, 66.70, 46.03, 30.83, 24.31 , 22.52, 21.30, 16.14. in-6-

Tert-butyl 6-(2-acetamido-4-methylthiazol-5-yl)-3,4-dihydroquinoline-1(2H)- carboxylate

Tert-butyl 6-bromo-3,4-dihydroquinoline-1 (2/7)-carboxylate (956 mg, 3.06 mmol), A/-(4- methylthiazol-2-yl)acetamide (1.2 eq., 574 mg, 3.67 mmol), tri-tert-butylphosphonium tetrafluoroborate (0.2 eq., 177 mg, 612 pmol), Pd(OAc)2, (0.1 eq., 69 mg, 31 pmol) and CS2CO3 (3 eq., 2.99 g, 9.19 mmol) were suspended in 10 mL of DMF. The suspension was sonicated for 5 minutes, flushed with nitrogen, heated up to 110 °C and stirred overnight. Upon completion of the reaction, the crude was poured in a separatory funnel, containing DCM and water. The water phase was extracted 3 times with DCM. Then, the combined organic phases were 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 eluent. The product was obtained as a yellow oil.

Yield: 910 mg (77%).

MS (ES+) [M+H]⁺ m/e = 388.1.

¹H NMR (300 MHz, DMSO-d₆): 5 12.06 (s, 1 H), 7.65 (d, J = 8.3 Hz, 1 H), 7.23 - 7.14 (m, 2H), 3.69 - 3.60 (m, 2H), 2.76 (t, J = 6.5 Hz, 2H), 2.33 (s, 3H), 2.13 (s, 3H), 1.84 (p, J = 6.4 Hz, 2H), 1.47 (s, 9H). ,3,4-tetrahydroquinolin-6-yl)thiazol-2-yl)acetamide

Tert-butyl 6-(2-acetamido-4-methylthiazol-5-yl)-3,4-dihydroquinoline-1 (2/7)-carboxylate (910 mg, 2.35 mmol) was dissolved in 10 mL of DCM and 1 mL of TFA was slowly added to the solution at room temperature. After one hour, a 1 M solution of a solution of Na2COs in water was added to the solution until the the pH reached 8-9. The residue was then poured in a separatory funnel, containing DCM and water. The water phase was extracted 3 times with DCM. Then, the combined organic phases were dried over Na2SC>4 and concentrated under reduced pressure.

The product was obtained as a yellow oil.

Yield: 574 mg (85%).

MS (ES+) [M+H]⁺ m/e = 288.1.

¹H NMR (300 MHz, DMSO-d₆): 5 11 .92 (s, 1 H), 6.95 - 6.82 (m, 2H), 6.46 (d, J = 8.1 Hz, 1 H), 5.88 (s, 1 H), 3.19 (dq, = 6.0, 2.6 Hz, 2H), 2.68 (t, = 6.3 Hz, 2H), 2.27 (s, 3H), 2.10 (s, 3H), 1.79 (p, J = 6.1 Hz, 2H).

¹³C NMR (151 MHz, DMSO-d₆): 5 167.90, 153.47, 144.77, 139.29, 129.22, 126.94, 125.31 , 120.04, 118.17, 113.32, 40.69, 26.64, 22.40, 21.31 , 15.87.

Step 3: A/-(4-Methyl-5-(1 -(o-tolylsulfonyl)-l ,2,3,4-tetrahydroquinolin-6-yl)thiazol-2- yl)acetamide

A/-(4-Methyl-5-(1 ,2,3,4-tetrahydroquinolin-6-yl)thiazol-2-yl)acetamide (20 mg, 70 pmol) was dissolved in 1 mL of pyridine, followed by the addition of 2-methylbenzenesulfonyl chloride (1 .5 eq., 20 mg, 104 pmol) to the mixture. The reaction mixture was stirred for three hours at room temperature. The solvent was then removed under reduced pressure and the crude product purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1% TFA). The product was obtained after lyophilization as an amorphous white solid.

Yield: 18 mg (59%).

MS (ES+) [M+H]⁺ m/e = 442.1 .

¹H NMR (300 MHz, DMSO-d₆): 5 12.08 (s, 1 H), 7.86 (dd, = 8.2, 1.4 Hz, 1 H), 7.58 (td, J = 7.5, 1.4 Hz, 1 H), 7.47 - 7.39 (m, 2H), 7.37 - 7.31 (m, 1 H), 7.24 - 7.18 (m, 2H), 3.79 - 3.70 (m, 2H), 2.70 (t, = 6.7 Hz, 2H), 2.36 (s, 3H), 2.31 (s, 3H), 2.13 (s, 3H), 1.78 - 1.66 (m, 2H).

13C NMR (75 MHz, DMSO-d₆) 6 168.30, 154.93, 141.80, 138.21 , 136.89, 135.90, 133.34, 133.10, 130.25, 129.31 , 129.03, 128.07, 126.83, 126.14, 123.26, 123.21 , 45.80, 26.06, 22.44, 21.34, 19.81 , 16.05.

Example compound 37: A/-(4-Methyl-5-(1-(naphthalen-1-ylsulfonyl)-1 ,2,3,4- tetrahydroquinolin-6-yl)thiazol-2-yl)acetamide

A/-(4-Methyl-5-(1 ,2,3,4-tetrahydroquinolin-6-yl)thiazol-2-yl)acetamide (20 mg, 70 pmol) was dissolved in 1 mL of pyridine, followed by the addition of naphthalene-1 -sulfonyl chloride (1 .5 eq., 24 mg, 104 pmol) to the mixture. The reaction mixture was stirred for three hours at room temperature. The solvent was then removed under reduced pressure and the crude product purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1% TFA). The product was obtained after lyophilization as an amorphous white solid.

Yield: 18 mg (54%).

MS (ES+) [M+H]⁺ m/e = 478.2.

¹H NMR (300 MHz, DMSO-d₆): 5 12.09 (s, 1 H), 8.33 - 8.19 (m, 2H), 8.15 - 8.03 (m, 2H), 7.69 (dd, J = 8.2, 7.4 Hz, 1 H), 7.60 (ddd, J = 8.1 , 6.9, 1 .2 Hz, 1 H), 7.54 (d, J = 8.5 Hz, 1 H), 7.42 (ddd, J = 8.5, 6.9, 1 .4 Hz, 1 H), 7.29 (dd, J = 8.5, 2.2 Hz, 1 H), 7.08 (d, J = 2.2 Hz, 1 H), 3.89 - 3.74 (m, 2H), 2.39 (t, J = 6.6 Hz, 2H), 2.32 (s, 3H), 2.13 (s, 3H), 1.58 - 1.41 (m, 2H).

¹³C NMR (75 MHz, DMSO-d₆): 6 168.31 , 154.98, 141.85, 135.63, 134.64 (2C), 134.01 , 131.02, 129.70, 129.10, 129.03, 128.50, 127.71 , 127.64, 127.07, 126.27, 124.82, 124.20, 124.06, 123.24, 45.85, 25.79, 22.45, 21.20, 16.01.

Example compound 38: A/-(5-(1-(Cvclohexylsulfonyl)-1 ,2,3,4-tetrahydroquinolin-6-yl)-4- methylthiazol-2-yl)acetamide

A/-(4-Methyl-5-(1 ,2,3,4-tetrahydroquinolin-6-yl)thiazol-2-yl)acetamide (20 mg, 70 pmol) was dissolved in 1 mL of pyridine, followed by the addition of cyclohexanesulfonyl chloride (1.5 eq., 19 mg, 104 pmol) to the mixture. The reaction mixture was stirred for three hours at room temperature. The solvent was then removed under reduced pressure and the crude product purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1% TFA). The product was obtained after lyophilization as an amorphous white solid.

Yield: 2 mg (6%).

MS (ES+) [M+H]⁺ m/e = 434.2.

¹H NMR (300 MHz, DMSO-d₆): 5 12.06 (s, 1 H), 7.28 - 7.07 (m, 3H), 4.23 - 4.02 (m, 1 H), 3.31 - 3.16 (m, 1 H), 2.87 - 2.68 (m, 2H), 2.44 - 2.19 (m, 4H), 2.13 (s, 4H), 2.05 - 1.87 (m, 4H), 1.85 - 1.47 (m, 6H), 1.39 - 1.18 (m, 1 H).

¹³C NMR (75 MHz, DMSO-d₆): 6 168.24, 154.65, 141.24, 140.30, 129.72, 126.83, 126.42, 125.39, 123.56, 118.11 , 33.19, 32.52, 26.36, 23.99, 22.45, 21.96, 21.51 , 21.03, 15.95. Example compound 39: A/-(4-Methyl-5-(1-(pyridin-3-ylsulfonyl)-1 ,2,3,4-tetrahydroquinolin-6- yl)thiazol-2-yl)acetamide

A/-(4-Methyl-5-(1 ,2,3,4-tetrahydroquinolin-6-yl)thiazol-2-yl)acetamide (20 mg, 70 pmol) was dissolved in 1 mL of pyridine, followed by the addition of pyridine-3-sulfonyl chloride (1.5 eq., 19 mg, 104 pmol) to the mixture. The reaction mixture was stirred for three hours at room temperature. The solvent was then removed under reduced pressure and the crude product purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1% TFA). The product was obtained after lyophilization as an amorphous white solid.

Yield: 10 mg (34%).

MS (ES+) [M+H]⁺ m/e = 429.1 .

¹H NMR (300 MHz, DMSO-d₆): 5 12.10 (s, 1 H), 8.84 (dd, J = 4.8, 1.6 Hz, 1 H), 8.82 (dd, J = 2.4, 0.8 Hz, 1 H), 8.07 (ddd, J = 8.1 , 2.4, 1 .6 Hz, 1 H), 7.68 (d, J = 8.6 Hz, 1 H), 7.62 (ddd, J = 8.1 , 4.8, 0.8 Hz, 1 H), 7.31 (dd, = 8.6, 2.3 Hz, 1 H), 7.18 (d, J = 2.2 Hz, 1 H), 3.90 - 3.78 (m, 2H), 2.55 - 2.51 (m, 2H), 2.33 (s, 3H), 2.13 (s, 3H), 1 .73 - 1 .51 (m, 2H).

¹3C NMR (75 MHz, DMSO-d₆): 5 168.34, 155.02, 153.96, 147.02, 142.01 , 135.33, 134.87, 134.72, 131.10, 129.25, 128.84, 126.50, 124.63, 123.82, 123.05, 46.43, 25.96, 22.45, 21.18, 16.14.

Example compound 40: A/-(4-Methyl-5-(1-(methylsulfonyl)-1,2,3,4-tetrahydroquinolin-6- yl)thiazol-2-yl)acetamide

A/-(4-Methyl-5-(1 ,2,3,4-tetrahydroquinolin-6-yl)thiazol-2-yl)acetamide (20 mg, 70 pmol) was dissolved in 1 mL of pyridine, followed by the addition of methanesulfonyl chloride (1 .5 eq., 12 mg, 104 pmol) to the mixture. The reaction mixture was stirred for three hours at room temperature. The solvent was then removed under reduced pressure and the crude product purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1% TFA). The product was obtained after lyophilization as an amorphous white solid.

Yield: 19 mg (75%).

MS (ES+) [M+H]⁺ m/e = 366.1 .

¹H NMR (300 MHz, DMSO-d₆): 5 12.09 (s, 1 H), 7.67 - 7.57 (m, 1 H), 7.30 - 7.20 (m, 2H), 3.84 - 3.54 (m, 2H), 2.84 (t, J = 6.6 Hz, 2H), 2.34 (s, 3H), 2.13 (s, 3H), 2.01 - 1 .83 (m, 2H). ¹³C NMR (75 MHz, DMSO-d₆): 6 168.29, 154.89, 141.69, 135.96, 129.96, 129.44, 127.65, 126.43, 123.30, 122.44, 45.95, 38.46, 26.49, 22.45, 21.67, 16.06.

Example compound 41 : A/-(4-Methyl-5-(1-(thiophen-2-ylsulfonyl)-1 ,2,3,4-tetrahydroquinolin-

6-yl)thiazol-2-yl)acetamide

A/-(4-Methyl-5-(1 ,2,3,4-tetrahydroquinolin-6-yl)thiazol-2-yl)acetamide (20 mg, 70 pmol) was dissolved in 1 mL of pyridine, followed by the addition of thiophene-2-sulfonyl chloride (1.5 eq., 19 mg, 104 pmol) to the mixture. The reaction mixture was stirred for three hours at room temperature. The solvent was then removed under reduced pressure and the crude product purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1% TFA). The product was obtained after lyophilization as an amorphous white solid.

Yield: 15 mg (50%).

MS (ES+) [M+H]⁺ m/e = 434.0.

¹H NMR (300 MHz, DMSO-d₆): 5 12.10 (s, 1 H), 7.97 (dd, J = 5.0, 1.4 Hz, 1 H), 7.70 (d, J = 8.6 Hz, 1 H), 7.58 (dd, = 3.8, 1.4 Hz, 1 H), 7.31 (dd, J = 8.6, 2.3 Hz, 1 H), 7.22 - 7.15 (m, 2H), 3.83 - 3.75 (m, 2H), 2.57 - 2.51 (m, 2H), 2.34 (s, 3H), 2.13 (s, 3H), 1.68 - 1.55 (m, 2H).

¹³C NMR (75 MHz, DMSO-d₆): 6 168.34, 155.00, 141.98, 138.25, 134.83, 134.37, 132.90, 131.43, 129.13, 128.87, 127.96, 126.34, 124.47, 123.13, 46.54, 26.10, 22.45, 20.69, 16.16.

Example compound 42: A/-(5-(1-((4-Fluorophenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-6-yl)- 4-methylthiazol-2-yl)acetamide

A/-(4-Methyl-5-(1 ,2,3,4-tetrahydroquinolin-6-yl)thiazol-2-yl)acetamide (20 mg, 70 pmol) was dissolved in 1 mL of pyridine, followed by the addition of 4-fluorobenzenesulfonyl chloride (1 .5 eq., 20 mg, 104 pmol) to the mixture. The reaction mixture was stirred for three hours at room temperature. The solvent was then removed under reduced pressure and the crude product purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1% TFA). The product was obtained after lyophilization as an amorphous white solid.

Yield: 16 mg (52%).

MS (ES+) [M+H]⁺ m/e = 446.1 . ¹H NMR (300 MHz, CDCI₃): 6 7.87 (d, J = 8.6 Hz, 1 H), 7.73 - 7.62 (m, 2H), 7.23 (dd, J = 8.6, 2.3 Hz, 1 H), 7.17 - 7.04 (m, 3H), 3.88 - 3.75 (m, 2H), 2.56 (t, J = Q.7 Hz, 2H), 2.46 (s, 3H), 2.37 (s, 3H), 1.78 - 1.62 (m, 2H).

¹³C NMR (75 MHz, CDCI3): 5 169.03, 165.41 (d, = 255.8 Hz), 158.83, 137.35, 135.63 (d, 7 = 3.3 Hz), 134.90, 131.20, 129.86 (d, 7 = 9.3 Hz), 129.77, 127.15, 126.29, 125.12, 124.92, 116.61 (d, 7 = 22.6 Hz), 46.76, 26.94, 23.25, 21.54, 13.93.

Example compound 43: A/-(5-(1-((2,4-Dichlorophenyl)sulfonyl)-1 ,2,3,4-tetrahydroquinolin-6- yl)-4-methylthiazol-2-yl)acetamide

A/-(4-Methyl-5-(1 ,2,3,4-tetrahydroquinolin-6-yl)thiazol-2-yl)acetamide (20 mg, 70 pmol) was dissolved in 1 mL of pyridine, followed by the addition of 2,4-dichlorobenzenesulfonyl chloride (1.5 eq., 26 mg, 104 pmol) to the mixture. The reaction mixture was stirred for three hours at room temperature. The solvent was then removed under reduced pressure and the crude product purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1% TFA). The product was obtained after lyophilization as an amorphous white solid.

Yield: 13 mg. (38%).

MS (ES+) [M+H]⁺ m/e = 496.0.

¹H NMR (300 MHz, DMSO-d₆): 5 12.08 (s, 1 H), 8.10 (d, 7 = 8.6 Hz, 1 H), 7.94 (d, 7 = 2.1 Hz, 1 H), 7.69 (dd, 7 = 8.6, 2.1 Hz, 1 H), 7.28 (d, 7 = 8.5 Hz, 1 H), 7.25 - 7.13 (m, 2H), 3.90 - 3.80 (m, 2H), 2.78 (t, 7 = 6.6 Hz, 2H), 2.31 (s, 3H), 2.12 (s, 3H), 1.89 - 1.76 (m, 2H).

¹³C NMR (75 MHz, DMSO-d₆): 6 168.30, 154.94, 141.82, 138.97, 136.40, 135.41 , 132.89, 132.12, 131.91 , 130.04, 129.35, 128.35, 128.00, 126.22, 123.14, 122.10, 46.39, 26.22, 22.44, 21.90, 16.06.

Example compound 44: A/-(4-Methyl-5-(1-(naphthalen-2-ylsulfonyl)-1 ,2,3,4- tetrahydroquinolin-6-yl)thiazol-2-yl)acetamide

A/-(4-Methyl-5-(1 ,2,3,4-tetrahydroquinolin-6-yl)thiazol-2-yl)acetamide (20 mg, 70 pmol) was dissolved in 1 mL of pyridine, followed by the addition of naphthalene-2-sulfonyl chloride (1 .5 eq., 24 mg, 104 pmol) to the mixture. The reaction mixture was stirred for three hours at room temperature. The solvent was then removed under reduced pressure and the crude product purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1% TFA). The product was obtained after lyophilization as an amorphous white solid.

Yield: 13 mg (39%).

MS (ES+) [M+H]⁺ m/e = 478.1 .

¹H NMR (300 MHz, DMSO-d₆): 5 12.08 (s, 1 H), 8.46 (d, J = 1.9 Hz, 1 H), 8.19 - 8.12 (m, 1 H), 8.08 (d, J = 8.8 Hz, 1 H), 8.05 - 8.00 (m, 1 H), 7.77 - 7.63 (m, 3H), 7.57 (dd, J = 8.7, 2.0 Hz, 1 H), 7.29 (dd, J = 8.6, 2.3 Hz, 1 H), 7.13 (d, J = 2.2 Hz, 1 H), 3.89 - 3.81 (m, 2H), 2.49 - 2.43 (m, 2H), 2.31 (s, 3H), 2.13 (s, 3H), 1.70 - 1.50 (m, 2H).

¹³C NMR (75 MHz, DMSO-d₆): 6 168.32, 154.95, 141.87, 136.01 , 135.40, 134.42, 131.69, 130.76, 129.66, 129.38, 129.23, 129.19, 128.38, 128.26, 127.89, 127.85, 126.37, 123.69, 123.19, 121.93, 46.39, 26.06, 22.45, 21.12, 16.11.

Example compound 45: (S)-A/-(5-(4-methoxy-1-(phenylsulfonyl)-1,2,3,4-tetrahydroquinolin- 6-yl)-4-methylthiazol-2-yl)acetamide

Step 1 : (S)-6-Bromo-1 -(phenylsulfonyl)-l ,2,3,4-tetrahydroquinolin-4-ol

6-Bromo-1-(phenylsulfonyl)-2,3-dihydroquinolin-4(1/7)-one (25 mg, 68 pmol), [A/-[(1 S,2S)-2- (amino-K /)-1 ,2-diphenylethyl]-4-methylbenzenesulfonamidato-K /]chloro[(1 ,2,3,4,5,6-r|)-1-methyl- 4-(1-methylethyl)benzene]-ruthenium (0.01 eq., 0.4 mg, 0.68 pmol) were dissolved in 0.5 mL of formic acid and 0.5 mL of triethylamine and stirred at room temperature for 72 hours. Upon completion, the solvents were then removed under reduced pressure. The solvent were then removed under reduced pressure and the crude product purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1 % TFA). The product was obtained after lyophilization as an amorphous white solid.

Yield: 22 mg (88%). ee: >99%

Reaction step 2 and step 3 described in example compound 7 have been followed to obtain example 45 (S)-A/-(5-(4-methoxy-1-(phenylsulfonyl)-1 ,2,3,4-tetrahydroquinolin-6-yl)-4- methylthiazol-2-yl)acetamide Example compound 46: A/-(4-Methyl-5-(1-tosyl-1,2,3,4-tetrahydroquinolin-6-yl)thiazol-2- vDacetamide

A/-(4-Methyl-5-(1 ,2,3,4-tetrahydroquinolin-6-yl)thiazol-2-yl)acetamide (20 mg, 70 pmol) was dissolved in 1 mL of pyridine, followed by the addition of 4-methylbenzenesulfonyl chloride (1 .5 eq., 20 mg, 104 pmol) to the mixture. The reaction mixture was stirred for three hours at room temperature. The solvent was then removed under reduced pressure and the crude product purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1% TFA). The product was obtained after lyophilization as an amorphous white solid.

Yield: 13 mg (39%).

MS (ES+) [M+H]⁺ m/e = 442.1 .

¹H NMR (300 MHz, DMSO-d₆): 5 12.08 (s, 1 H), 7.67 (d, = 8.6 Hz, 1 H), 7.58 - 7.51 (m, 2H), 7.36 (d, J = 8.1 Hz, 2H), 7.27 (dd, J = 8.6, 2.3 Hz, 1 H), 7.15 (d, J = 2.2 Hz, 1 H), 3.86 - 3.70 (m, 2H), 2.55 - 2.51 (m, 2H), 2.36 (s, 3H), 2.33 (s, 3H), 2.13 (s, 3H), 1 .66 - 1 .47 (m, 2H).

¹³C NMR (75 MHz, DMSO-d₆): 6 168.33, 154.94, 143.90, 141.83, 136.09, 135.42, 130.67, 129.98, 129.18, 128.29, 126.84, 126.29, 123.70, 123.20, 46.26, 26.11 , 22.46, 21.01 , 20.91 , 16.13.

Example compound 47: A/-(5-(1-((2,3-Dichlorophenyl)sulfonyl)-1 ,2,3,4-tetrahydroquinolin-6- yl)-4-methylthiazol-2-yl)acetamide

A/-(4-Methyl-5-(1 ,2,3,4-tetrahydroquinolin-6-yl)thiazol-2-yl)acetamide (20 mg, 70 pmol) was dissolved in 1 mL of pyridine, followed by the addition of 2,3-dichlorobenzenesulfonyl chloride (1.5 eq., 26 mg, 104 pmol) to the mixture. The reaction mixture was stirred for three hours at room temperature. The solvent was then removed under reduced pressure and the crude product purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1% TFA). The product was obtained after lyophilization as an amorphous white solid.

Yield: 20 mg (58%).

MS (ES+) [M+H]⁺ m/e = 496.0. ¹H NMR (300 MHz, DMSO-d₆): 6 12.09 (s, 1 H), 8.11 (dd, = 8.0, 1.5 Hz, 1 H), 8.00 (dd, = 8.1 ,

1 .5 Hz, 1 H), 7.63 (t, J = 8.1 Hz, 1 H), 7.28 - 7.12 (m, 3H), 3.93 - 3.82 (m, 2H), 2.81 (t, J = 6.6 Hz, 2H), 2.30 (s, 3H), 2.12 (s, 3H), 1 .95 - 1 .79 (m, 2H).

¹³C NMR (75 MHz, DMSO-d₆): 6 168.31 , 154.95, 141.81 , 139.71 , 135.50, 135.31 , 134.72, 130.23, 129.88, 129.42, 129.09, 129.03, 127.93, 126.23, 123.13, 121.83, 46.53, 26.25, 22.44, 22.04, 16.04.

Example compound 48: A/-(5-(1-(Benzylsulfonyl)-1 ,2,3,4-tetrahydroquinolin-6-yl)-4- methylthiazol-2-yl)acetamide

A/-(4-Methyl-5-(1 ,2,3,4-tetrahydroquinolin-6-yl)thiazol-2-yl)acetamide (20 mg, 70 pmol) was dissolved in 1 mL of pyridine, followed by the addition of phenylmethanesulfonyl chloride (1 .5 eq., 20 mg, 104 pmol) to the mixture. The reaction mixture was stirred for three hours at room temperature. The solvent was then removed under reduced pressure and the crude product purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1% TFA). The product was obtained after lyophilization as an amorphous white solid.

Yield: 19 mg (62%).

MS (ES+) [M+H]⁺ m/e = 442.1 .

¹H NMR (300 MHz, DMSO-d₆): 5 12.08 (s, 1 H), 7.41 - 7.26 (m, 6H), 7.19 (d, J = 2.2 Hz, 1 H), 7.15 (dd, J = 8.6, 2.3 Hz, 1 H), 4.67 (s, 2H), 3.55 - 3.43 (m, 2H), 2.76 (t, J = 6.6 Hz, 2H), 2.33 (s, 3H), 2.13 (s, 3H), 1 .78 (p, J = 6.5 Hz, 2H).

¹³C NMR (75 MHz, DMSO-d₆): 6 168.29, 154.84, 141.61 , 135.99, 131.05, 129.38, 129.25, 129.04, 128.46, 128.43, 127.19, 126.22, 123.35, 121 .81 , 57.13, 46.37, 26.35, 22.45, 22.06, 16.03.

Example compound 49: A/-(5-(1-((2,3-Dihvdrobenzofuran-5-yl)sulfonyl)-1,2,3,4- tetrahydroquinolin-6-yl)-4-methylthiazol-2-yl)acetamide

A/-(4-Methyl-5-(1 ,2,3,4-tetrahydroquinolin-6-yl)thiazol-2-yl)acetamide (20 mg, 70 pmol) was dissolved in 1 mL of pyridine, followed by the addition of 2,3-dihydrobenzofuran-5-sulfonyl chloride (1.5 eq., 23 mg, 104 pmol) to the mixture. The reaction mixture was stirred for three hours at room temperature. The solvent was then removed under reduced pressure and the crude product purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1% TFA). The product was obtained after lyophilization as an amorphous white solid.

Yield: 15 mg (46%).

MS (ES+) [M+H]⁺ m/e = 470.1 .

¹H NMR (300 MHz, DMSO-d₆): 5 12.08 (s, 1 H), 7.66 (d, = 8.6 Hz, 1 H), 7.53 (d, J = 2.0 Hz, 1 H), 7.41 (dd, J = 8.5, 2.1 Hz, 1 H), 7.26 (dd, J = 8.6, 2.3 Hz, 1 H), 7.16 (d, J = 2.2 Hz, 1 H), 6.88 (d, J = 8.5 Hz, 1 H), 4.63 (t, J = 8.8 Hz, 2H), 3.79 - 3.71 (m, 2H), 3.20 (t, J = 8.8 Hz, 2H), 2.55 (t, J = 6.5 Hz, 2H), 2.33 (s, 3H), 2.13 (s, 3H), 1 .72 - 1 .57 (m, 2H).

¹³C NMR (75 MHz, DMSO-d₆): 6 168.29, 163.64, 154.90, 141.78, 135.61 , 130.58, 130.44, 129.20, 129.17, 128.32, 128.08, 126.25, 124.22, 123.63, 123.24, 109.30, 72.34, 46.18, 28.36, 26.17, 22.44, 20.97, 16.10.

Example compound 50: Tert-butyl (4-methyl-5-(1-(phenylsulfonyl)-1 ,2,3,4- tetrahydroquinolin-6-yl)thiazol-2-yl)carbamate

6-Bromo-1-(phenylsulfonyl)-1 ,2,3,4-tetrahydroquinoline (80 mg, 227 pmol), tert-butyl (4- methylthiazol-2-yl)carbamate (1.2 eq., 61 mg, 272 pmol), tri-te/t-butylphosphonium tetrafluoroborate (0.2 eq., 14 mg, 45 pmol), Pd(OAc)2, (0.1 eq., 5 mg, 23 pmol) and CS2CO3 (3 eq., 222 mg, 682 pmol) were suspended in 1 mL of DMF. The suspension was sonicated for 5 minutes, flushed with nitrogen, heated up to 110 °C and stirred overnight. The solvent was then removed under reduced pressure and the crude product purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1 % TFA). The product was obtained after lyophilization as an amorphous white solid.

Yield: 33 mg (30%).

MS (ES+) [M+H]⁺ m/e = 486.1 .

¹H NMR (600 MHz, DMSO-d₆): 6 11.38 (s, 1 H), 7.70 - 7.63 (m, 4H), 7.57 (dd, J = 8.5, 7.2 Hz, 2H), 7.26 (dd, J = 8.6, 2.3 Hz, 1 H), 7.14 (d, J = 2.3 Hz, 1 H), 3.85 - 3.72 (m, 2H), 2.49 - 2.48 (m, 2H), 2.29 (s, 3H), 1 .65 - 1 .58 (m, 2H), 1 .48 (s, 9H).

¹³C NMR (151 MHz, DMSO-d₆): 5 156.69, 152.76, 142.13, 138.90, 135.23, 133.39, 130.72, 129.51 , 129.08, 128.40, 126.72, 126.17, 123.70, 122.87, 81.15, 46.25, 27.88, 25.99, 20.92, 16.04. Example compound 51 : 4-Methyl-5-(1-(phenylsulfonyl)-1,2,3,4-tetrahydroquinolin-6- yl)thiazol-2-amine

Terf-butyl (4-methyl-5-(1-(phenylsulfonyl)-1 ,2,3,4-tetrahydroquinolin-6-yl)thiazol-2-yl)carbamate (20 mg, 41 pmol) was dissolved in 1 mL of DCM and 0.2 mL of TFA was slowly added to the solution at room temperature. After one hour, the solvent was then removed under reduced pressure and the crude product purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1% TFA). The lyophilized powder was poured in an separatory funnel containing DCM and a saturated solution of Na2COs in water. The water phase was extracted 3 times with DCM. Then, the combined organic phases were dried over Na2SO4 and concentrated under reduced pressure, product was obtained as a white solid.

Yield: 9 mg (57%).

MS (ES+) [M+H]⁺ m/e = 386.1 .

¹H NMR (300 MHz, DMSO-d₆): 5 7.75 - 7.48 (m, 5H), 7.15 (dd, J = 8.6, 2.3 Hz, 1 H), 7.04 - 6.92 (m, 2H), 3.83 - 3.70 (m, 2H), 2.45 (t, J = 6.5 Hz, 2H), 2.17 (s, 2H), 1 .64 - 1 .53 (m, 2H).

¹³C NMR (151 MHz, DMSO-d₆): 5 165.56, 143.08, 138.92, 134.30, 133.35, 130.63, 129.48, 128.39, 126.72, 125.73, 123.74, 116.73, 115.62, 46.22, 25.98, 20.96, 16.29.

Example compound 52: A/-(4-Methyl-5-(1-(phenylsulfonyl)-1 ,2,3,4-tetrahydroquinolin-6- yl)thiazol-2-yl)methanesulfonamide

Step 1 : A/-(4-Methylthiazol-2-yl)methanesulfonamide

4-Methylthiazol-2-amine (140 mg, 1 .23 mmol) was dissolved in 2 mL of pyridine, followed by the addition of methanesulfonyl chloride (1.1 eq., 155 mg, 1.35 mmol) to the mixture. The reaction mixture was stirred for three hours at room temperature. The solvent was then removed under reduced pressure and the crude product was then purified by silica gel chromatography using a gradient of cyclohexane and EtOAc as eluent. The product was obtained as a yellow oil.

Yield: 91 mg (37%).

MS (ES+) [M+H]⁺ m/e = 193.2.

¹H NMR (600 MHz, DMSO-d₆): 5 12.39 (s, 1 H), 6.36 (d, J = 1.5 Hz, 1 H), 2.86 (s, 3H), 2.10 (d, J = 1.3 Hz, 3H).

¹³C NMR (151 MHz, DMSO-d₆): 5 168.52, 133.29, 101.70, 40.36, 13.27. Step 2: A/-(4-Methyl-5-(1 -(phenylsulfonyl)-l ,2,3,4-tetrahydroquinolin-6-yl)thiazol-2- yl)methanesulfonamide

6-Bromo-1-(phenylsulfonyl)-1 ,2,3,4-tetrahydroquinoline (18 mg, 51 pmol), A/-(4-methylthiazol-2- yl)methanesulfonamide (1.2 eq., 12 mg, 61 pmol), tri-tert-butylphosphonium tetrafluoroborate (0.2 eq., 3.0 mg, 10 pmol), Pd(OAc)2, (0.1 eq., 1.6 mg, 5.1 pmol) and CS2CO3 (3 eq., 50 mg, 153 pmol) were suspended in 1 mL of DMF. The suspension was sonicated for 5 minutes, flushed with nitrogen, heated up to 110 °C and stirred overnight. The solvent was then removed under reduced pressure and the crude product purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1% TFA). The product was obtained after lyophilization as an amorphous white solid.

Yield: 3.4 mg (14%).

MS (ES+) [M+H]⁺ m/e = 464.1 .

¹H NMR (300 MHz, DMSO-d₆): 5 12.57 (s, 1 H), 7.73 - 7.62 (m, 4H), 7.62 - 7.50 (m, 2H), 7.25 (dd, J = 8.7, 2.3 Hz, 1 H), 7.13 (d, J = 2.3 Hz, 1 H), 3.84 - 3.75 (m, 2H), 2.92 (s, 3H), 2.21 (s, 3H), 1 .64 - 1 .53 (m, 2H). 2H hidden behind the DMSO peak.

¹³C NMR (151 MHz, DMSO-d₆): 5 165.70, 138.81 , 135.88, 133.45, 130.92, 129.54, 128.81 , 128.72, 126.87, 126.72, 125.82, 123.73, 115.49, 46.25, 40.58, 25.98, 20.86, 12.43.

Example compound 53: A/-(4-Ethyl-5-(1-(phenylsulfonyl)-1,2,3,4-tetrahydroquinolin-6- yl)thiazol-2-yl)acetamide

Step 1 : A/-(4-Ethylthiazol-2-yl)acetamide

4-Ethylthiazol-2-amine (50 mg, 390 pmol) was dissolved in dry DCM (1 mL). Afterwards, acetic anhydride (1 .5 eq., 60 mg, 585 pmol) and triethylamine (1 .5 eq., 59 mg, 585 pmol) were added tot he mixture. The reaction mixture was stirred at room temperature for 16 hours. Upon completion of the reaction, the crude was poured in a separatory funnel, containing DCM and water. The water phase was extracted 3 times with DCM. Then, the combined organic phases were dried over Na2SO4 and concentrated under reduced pressure. The product was obtained as a yellow oil.

Yield: 62 mg (93%).

MS (ES+) [M+H]⁺ m/e = 171.2.

¹H NMR (300 MHz, DMSO-d₆): 5 12.02 (s, 1 H), 6.72 (d, J = 1.1 Hz, 1 H), 2.59 (qd, J = 7.5, 1.0 Hz, 2H), 2.10 (s, 3H), 1.18 (t, J = 7.5 Hz, 3H).

¹³C NMR (151 MHz, DMSO-d₆): 5 168.16, 157.38, 152.57, 106.15, 24.23, 22.43, 13.24. Step 2: A/-(4-Ethyl-5-(1 -(phenylsulfonyl)-l ,2,3,4-tetrahydroquinolin-6-yl)thiazol-2- yl)acetamide

6-Bromo-1-(phenylsulfonyl)-1 ,2,3,4-tetrahydroquinoline (80 mg, 227 pmol), A/-(4-ethylthiazol-2- yl)acetamide (1.1 eq., 43 mg, 250 pmol), tri-tert-butylphosphonium tetrafluoroborate (0.2 eq., 13 mg, 45 pmol), Pd(OAc)2, (0.1 eq., 5 mg, 23 pmol) and CS2CO3 (3 eq., 225 mg, 682 pmol) were suspended in 1 mL of DMF. The suspension was sonicated for 5 minutes, flushed with nitrogen, heated up to 110 °C and stirred overnight. The solvent was then removed under reduced pressure and the crude product purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1% TFA). The product was obtained after lyophilization as an amorphous white solid.

Yield: 62 mg (62%).

MS (ES+) [M+H]⁺ m/e = 442.1 .

¹H NMR (300 MHz, DMSO-d₆): 5 12.13 (s, 1 H), 7.72 - 7.62 (m, 4H), 7.61 - 7.52 (m, 2H), 7.24 (dd, J = 8.6, 2.3 Hz, 1 H), 7.11 (d, J = 2.2 Hz, 1 H), 3.85 - 3.73 (m, 2H), 2.64 (q, J = 7.5 Hz, 2H), 2.13 (s, 3H), 1 .65 - 1 .54 (m, 2H), 1 .20 (t, J = 7.5 Hz, 3H). 2H hidden behind the DMSO peak.

¹³C NMR (151 MHz, DMSO-d₆): 5 168.29, 155.35, 147.34, 138.90, 135.49, 133.41 , 130.75, 129.52, 129.47, 128.20, 126.73, 126.57, 123.72, 122.79, 46.26, 26.01 , 22.40, 22.37, 20.92, 13.92.

Example compound 54: A/-(5-(1-(cvclopropylsulfonyl)-1 ,2,3,4-tetrahydroquinolin-6-yl)-4- methylthiazol-2-yl)acetamide

Step 1 : 6-Bromo-1 -(cyclopropylsulfonyl)-l ,2,3,4-tetrahydroquinoline

6-Bromo-1 ,2,3,4-tetrahydroquinoline (67 mg, 316 pmol) was dissolved in 1 mL of pyridine, followed by the addition of methanesulfonyl chloride (2 eq., 89 mg, 632 pmol) to the mixture. The reaction mixture was stirred for three hours at room temperature. The solvent was then removed under reduced pressure and the crude product was then purified by silica gel chromatography using a gradient of cyclohexane and EtOAc as eluent. The product was obtained as a yellow oil.

Yield: 50 mg (50%).

MS (ES+) [M+Na]⁺ m/e = 338.0, 339.9 (bromine isotopic pattern).

¹H NMR (300 MHz, CDCI3); 5 7.64 - 7.53 (m, 1 H), 7.29 - 7.21 (m, 2H), 3.82 - 3.72 (m, 2H), 2.84 (t, = 6.8 Hz, 2H), 2.39 (tt, = 8.0, 4.9 Hz, 1 H), 2.10 - 1.95 (m, 2H), 1.21 - 1.12 (m, 2H), 0.99 - 0.88 (m, 2H). ¹³C NMR (75 MHz, CDCI₃): 5 136.46, 132.25, 131.86, 129.67, 125.42, 117.80, 46.69, 29.93, 26.96, 22.29, 5.64.

Step 2: Af-(5-(d -(Cyclopropylsulfonyl)-1 ,2,3,4-tetrahydroquinolin-6-yl)-4-methylthiazol-2- yl)acetamide

6-Bromo-1-(cyclopropylsulfonyl)-1 ,2,3,4-tetrahydroquinoline (50 mg, 158 pmol), A/-(4- methylthiazol-2-yl)acetamide (1.2 eq., 30 mg, 190 pmol), tri-tert-butylphosphonium tetrafluoroborate (0.2 eq., 9 mg, 32 pmol), Pd(OAc)2, (0.1 eq., 3.6 mg, 16 pmol) and CS2CO3 (3 eq., 155 mg, 474 pmol) were suspended in 1 mL of DMF. The suspension was sonicated for 5 minutes, flushed with nitrogen, heated up to 110 °C and stirred overnight. The solvent was then removed under reduced pressure and the crude product purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1 % TFA). The product was obtained after lyophilization as an amorphous white solid.

Yield: 24 mg (39%).

MS (ES+) [M+H]⁺ m/e = 392.1.

¹H NMR (300 MHz, DMSO-d₆): 5 12.09 (s, 1 H), 7.64 - 7.57 (m, 1 H), 7.27 - 7.21 (m, 2H), 3.77 - 3.66 (m, 2H), 2.87 (t, J = 6.7 Hz, 2H), 2.77 (tt, J = 7.2, 5.7 Hz, 1 H), 2.34 (s, 3H), 2.13 (s, 3H), 2.03 - 1 .92 (m, 2H), 1 .01 - 0.89 (m, 4H).

¹³C NMR (75 MHz, DMSO-d₆): 6 168.33, 154.92, 141.73, 136.11 , 130.41 , 129.40, 127.98, 126.25, 123.44, 123.34, 46.25, 28.59, 26.32, 22.47, 21.84, 16.09, 5.07.

Example compound 55: A/-(5-(2,2-Dimethyl-1-(phenylsulfonyl)-1 ,2,3,4-tetrahydroquinolin-6- yl)-4-methylthiazol-2-yl)acetamide

6-Bromo-2,2-dimethyl-1 ,2,3,4-tetrahydroquinoline (100 mg, 416 pmol) was then dissolved in 3 mL of pyridine, followed by the addition of benzenesulfonyl chloride (1 .5 eq., 110 mg, 624 pmol) to the mixture. The reaction mixture was stirred for three hours at room temperature. The solvent was then removed under reduced pressure and the residue was then poured in a separatory funnel, containing DCM and 1 M solution of a solution of Na2COs in water. The water phase was extracted 3 times with DCM. Then, the combined organic phases were dried over Na2SC>4 and concentrated under reduced pressure. Afterwards, the crude, A/-(4-methylthiazol-2-yl)acetamide (1.2 eq., 78 mg, 500 pmol), tri-tert-butylphosphonium tetrafluoroborate (0.2 eq., 24 mg, 83 pmol), Pd(OAc)2, (0.1 eq., 9 mg, 42 pmol) and CS2CO3 (3 eq., 407 mg, 1 .25 mmol) were suspended in 2 mL of DMF. The suspension was sonicated for 5 minutes, flushed with nitrogen, heated up to 110 °C and stirred overnight. The solvent was then removed under reduced pressure and the crude product purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1% TFA). The product was obtained after lyophilization as an amorphous white solid.

Yield: 27 mg (14%).

MS (ES+) [M+H]⁺ m/e = 456.1 .

¹H NMR (600 MHz, DMSO-d₆): 5 12.08 (s, 1 H), 7.66 (td, J = 7.2, 1.5 Hz, 1 H), 7.64 - 7.61 (m, 2H), 7.59 - 7.55 (m, 2H), 7.53 (dd, J = 8.3, 1 .5 Hz, 1 H), 7.27 (dd, J = 8.4, 2.3 Hz, 1 H), 7.22 (d, J = 2.2 Hz, 1 H), 2.59 (t, J = 7.0 Hz, 2H), 2.37 (s, 3H), 2.14 (s, 3H), 1 .63 (t, J = 7.0 Hz, 2H), 1 .36 (s, 6H).

¹³C NMR (151 MHz, DMSO-d₆): 5 168.29, 154.96, 148.26, 141.98, 136.23, 133.59, 132.90, 129.39, 129.21 , 128.22, 127.91 , 126.70, 125.57, 123.25, 59.92, 35.36, 28.47, 23.75, 22.42, 16.19.

Example compound 56: A/-(4-Methyl-5-(T-(phenylsulfonyl)-2',3'-dihydro-TH-spiroroxetane- 3,4'-quinolinl-6'-yl)thiazol-2-yl)acetamide

Step 1 : 2',3'-dihydro-1 'H-spiro[oxetane-3,4'-quinoline]

Methyl 2-(oxetan-3-ylidene)acetate (700 mg, 5.46 mmol), 2-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)aniline hydrochloride (2 eq., 2.79 g, 10.93 mmol), potassium carbonate (2 eq., 1.51 g, 10.93 mmol) and hydroxy(cyclooctadiene)rhodium(l) dimer (2 eq., 125 mg, 273 pmol) were suspended in a 2% solution of TPGS-750-M in water (7 mL). The mixture was stirred vigorously at room temperature for 16 hours The residue was then poured in a separatory funnel, containing EtOAc and water. The water phase was extracted 3 times with EtOAc. Then, the combined organic phases were dried over Na2SC>4 and concentrated under reduced pressure. The crude intermediate was then purified by silica gel chromatography using a gradient of cyclohexane and EtOAc as eluent. The intermediate product was obtained as an impured black oil then dissolved in dy THF (7 mL) and brought to 0 °C. Afterwards, a 2 M solution of LiAIH4 (3 eq., 622 mg, 16.4 mmol, 8.19 mL) was added dropwise to the solution and the reaction mixture was kept at 0 °C for one hour. Upon completion, the reaction mixture was quenched with a water solution of a solution of Na2COs and then the crude was poured in a separatory funnel, containing DCM and water. The water phase was extracted 3 times with DCM. Then, the combined organic phases were dried over Na2SC>4 and concentrated under reduced pressure. The product was obtained as a colourless oil and used without further purification.

Yield: 70 mg (7%).

MS (ES+) [M+H]⁺ m/e = 176.1.

¹H NMR (300 MHz, CDCI₃): 6 7.73 (dd, J = 7.8, 1 .5 Hz, 1 H), 7.06 (ddd, J = 8.0, 7.2, 1 .5 Hz, 1 H), 6.82 (td, J = 7.5, 1 .3 Hz, 1 H), 6.51 (dd, J = 8.0, 1 .3 Hz, 1 H), 4.92 (d, J = 5.8 Hz, 2H), 4.55 (d, J = 5.8 Hz, 2H), 3.95 (s, 1 H), 3.28 - 3.15 (m, 2H), 2.35 - 2.26 (m, 2H).

¹³C NMR (75 MHz, CDCI₃): 5 144.32, 127.96, 127.14, 123.55, 118.12, 114.73, 85.11 , 40.28, 38.82, 34.10. Step 2: 6'-Bromo-1 '-(phenylsulfonyl)-2',3'-dihydro-1 'H-spiro[oxetane-3,4'-quinoline]

2',3'-Dihydro-1'/7-spiro[oxetane-3,4'-quinoline] (70 mg, 399 pmol) was dissolved in 2 mL of acetonitrile. Afterwards, 1 -bromopyrrolidine-2, 5-dione (1.0 eq., 71 mg, 399 pmol) was added to the mixture and the reaction was stirred at room temperature for 16 hours. Upon completion of the reaction, the crude was poured in a separatory funnel, containing DCM and 1 M solution of Na2S2C>3 in water. The water phase was extracted 3 times with DCM. Then, the combined organic phases were dried over Na2SC>4 and concentrated under reduced pressure. The residue was then dissolved in 2 mL pyridine. Afterwards, benzenesulfonyl chloride (1.2 eq., 85 mg, 479 pmol) was added to the mixture. The reaction mixture was stirred for three hours at room temperature. The solvent was then removed under reduced pressure and the crude product was then purified by silica gel chromatography using a gradient of cyclohexane and EtOAc as eluent. The product was obtained as a yellow oil.

Yield: 57 mg (36%).

MS (ES+) [M+H]⁺ m/e = 394.0, 396.0 (bromine isotopic pattern).

¹H NMR (300 MHz, CDCI₃): 5 7.97 (d, J = 2.3 Hz, 1 H), 7.70 (d, J = 8.9 Hz, 1 H), 7.61 - 7.51 (m, 3H), 7.48 - 7.32 (m, 3H), 4.53 (d, J = 6.1 Hz, 2H), 4.35 (d, J = 6.1 Hz, 2H), 3.76 - 3.69 (m, 2H), 1.94 - 1.86 (m, 2H).

¹³C NMR (75 MHz, CDCI3): 5 139.25, 135.04, 134.46, 133.35, 130.90, 129.68, 129.30, 127.05, 126.16, 119.38, 84.35, 43.77, 40.48, 32.25.

Step 3: A/-(4-Methyl-5-(1 '-(phenylsulfonyl)-2',3'-dihydro-1 'H-spirofoxetane-S^'-quinolinJ-e'- yl)thiazol-2-yl)acetamide

6'-Bromo-T-(phenylsulfonyl)-2',3'-dihydro-T/7-spiro[oxetane-3,4'-quinoline] (57 mg, 145 pmol), N- (4-methylthiazol-2-yl)acetamide (1.2 eq., 27 mg, 173 pmol), tri-tert-butylphosphonium tetrafluoroborate (0.2 eq., 8 mg, 29 pmol), Pd(OAc)2, (0.1 eq., 3.2 mg, 14 pmol) and CS2CO3 (3 eq., 141 mg, 433 pmol) were suspended in 1 mL of DMF. The suspension was sonicated for 5 minutes, flushed with nitrogen, heated up to 100 °C and stirred overnight. The solvent was then removed under reduced pressure and the crude product purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1 % TFA). The product was obtained after lyophilization as an amorphous white solid.

Yield: 15 mg (22%).

MS (ES+) [M+H]⁺ m/e = 470.1 . ¹H NMR (600 MHz, DMSO-d₆): 5 12.11 (s, 1 H), 7.87 (d, J = 2.3 Hz, 1 H), 7.70 - 7.65 (m, 4H), 7.60 - 7.54 (m, 2H), 7.39 (dd, J = 8.6, 2.2 Hz, 1 H), 4.49 (d, J = 6.2 Hz, 2H), 4.37 (d, J = 6.2 Hz, 2H), 3.81 - 3.72 (m, 2H), 2.38 (s, 3H), 2.15 (s, 3H), 2.00 - 1 .96 (m, 2H).

¹³C NMR (151 MHz, DMSO-d₆): 5 168.35, 155.08, 142.17, 138.80, 134.46, 133.57, 132.74, 129.59, 129.21 , 127.40, 126.72, 126.51 , 123.31 , 123.10, 83.27, 43.46, 40.06, 31.81 , 22.43, 16.10.

Example compound 57: A/-(5-(1-((3-Methoxyphenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-6- yl)-4-methylthiazol-2-yl)acetamide

A/-(4-Methyl-5-(1 ,2,3,4-tetrahydroquinolin-6-yl)thiazol-2-yl)acetamide (20 mg, 70 pmol) was dissolved in 1 mL of pyridine, followed by the addition of 2,3-dihydrobenzofuran-5-sulfonyl chloride (1.5 eq., 22 mg, 104 pmol) to the mixture. The reaction mixture was stirred for three hours at room temperature. The solvent was then removed under reduced pressure and the crude product purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1% TFA). The product was obtained after lyophilization as an amorphous white solid.

Yield: 20 mg (63%).

MS (ES+) [M+H]⁺ m/e = 458.1 .

¹H NMR (300 MHz, DMSO-d₆): 5 12.10 (s, 1 H), 7.69 (d, J = 8.6 Hz, 1 H), 7.49 (t, J = 8.0 Hz, 1 H), 7.30 (dd, J = 8.6, 2.3 Hz, 1 H), 7.27 - 7.11 (m, 4H), 6.97 (dd, J = 2.6, 1 .7 Hz, 1 H), 3.83 - 3.76 (m, 2H), 3.68 (s, 3H), 2.48 - 2.43 (m, 2H), 2.33 (s, 3H), 2.13 (s, 3H), 1 .65 - 1 .52 (m, 2H).

¹³C NMR (75 MHz, DMSO-d₆): 6 168.35, 159.38, 155.01 , 141.90, 139.90, 135.35, 131.20, 130.80, 129.17, 128.63, 126.39, 124.07, 123.17, 119.56, 118.81 , 111.30, 55.49, 46.42, 26.04, 22.47, 20.84, 16.07.

Example compound 58: A/-(4-Methyl-5-(5-methyl-1-(phenylsulfonyl)-1 ,2,3,4- tetrahydroquinolin-6-yl)thiazol-2-yl)acetamide

Step 1 : 6-Bromo-5-methyl-1 -(phenylsulfonyl)-l ,2,3,4-tetrahydroquinoline

5-Methyl-1 ,2,3,4-tetrahydroquinoline (100 mg, 679 pmol) was dissolved in 2 mL of acetonitrile. Afterwards, 1 -bromopyrrolidine-2, 5-dione (1 .0 eq., 121 mg, 679 pmol) was added to the mixture and the reaction was stirred at room temperature for 16 hours. Upon completion of the reaction, the crude was poured in a separatory funnel, containing DCM and 1 M solution of Na2S2C>3 in water. The water phase was extracted 3 times with DCM. Then, the combined organic phases were dried over Na2SC>4 and concentrated under reduced pressure. The residue was then dissolved in 2 mL pyridine. Subsequently, benzenesulfonyl chloride (1.1 eq., 132 mg, 747 pmol) was added to the mixture. The reaction mixture was stirred for three hours at room temperature. The solvent was then removed under reduced pressure and the crude product was then purified by silica gel chromatography using a gradient of cyclohexane and EtOAc as eluent. The product was obtained as a yellow oil.

Yield: 111 mg (45%).

MS (ES+) [M+Na]⁺ m/e = 387.9, 390.0 (bromine isotopic pattern).

¹H NMR (300 MHz, CDCI₃): 5 7.63 - 7.57 (m, 2H), 7.56 - 7.48 (m, 2H), 7.45 - 7.34 (m, 3H), 3.80 - 3.68 (m, 2H), 2.39 (t, J = 6.9 Hz, 2H), 2.23 (s, 3H), 1 .65 - 1 .52 (m, 2H).

¹³C NMR (75 MHz, CDCI₃): 5 139.77, 136.23, 136.15, 132.92, 130.78, 129.99, 129.13, 127.03, 124.18, 121.90, 45.66, 25.26, 21.03, 19.23.

Step 2: A/-(4-Methyl-5-(5-methyl-1 -(phenylsulfonyl)-l ,2,3,4-tetrahydroquinolin-6-yl)thiazol-2- yl)acetamide

6-Bromo-5-methyl-1-(phenylsulfonyl)-1 ,2,3,4-tetrahydroquinoline (50 mg, 137 pmol), A/-(4- methylthiazol-2-yl)acetamide (1.2 eq., 26 mg, 164 pmol), tri-tert-butylphosphonium tetrafluoroborate (0.2 eq., 8 mg, 27 pmol), Pd(OAc)2, (0.1 eq., 3.1 mg, 14 pmol) and CS2CO3 (3 eq., 133 mg, 410 pmol) were suspended in 1 mL of DMF. The suspension was sonicated for 5 minutes, flushed with nitrogen, heated up to 110 °C and stirred overnight. The solvent was then removed under reduced pressure and the crude product purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1 % TFA). The product was obtained after lyophilization as an amorphous white solid.

Yield: 24 mg (40%).

MS (ES+) [M+H]⁺ m/e = 442.1 .

¹H NMR (300 MHz, DMSO-d₆): 5 12.07 (s, 1 H), 7.72 - 7.64 (m, 3H), 7.61 - 7.53 (m, 2H), 7.50 (d, J = 8.6 Hz, 1 H), 7.10 (d, = 8.6 Hz, 1 H), 3.83 - 3.71 (m, 2H), 2.46 (t, = 6.7 Hz, 2H), 2.13 (s, 3H), 2.01 (s, 3H), 1 .97 (s, 3H), 1 .72 - 1 .54 (m, 2H).

¹³C NMR (75 MHz, DMSO-d₆): 6 168.29, 155.85, 142.82, 139.50, 136.86, 136.58, 133.40, 129.57, 129.15, 128.68, 127.40, 126.76, 122.75, 121 .01 , 45.50, 24.14, 22.45, 20.79, 16.36, 15.30. Example compound 59: 5-Methyl-4-(1-(phenylsulfonyl)-1,2,3,4-tetrahydroquinolin-6-yl)-A/- (2,2,2-trifluoroethyl)thiazol-2-amine

TTert-butyl (5-methyl-4-(1-(phenylsulfonyl)-1 ,2,3,4-tetrahydroquinolin-6-yl)thiazol-2-yl)carbamate (30 mg, 62 pmol), CS2CO3 (3 eq., 60 mg, 185 pmol) and 1 ,1 ,1-trifluoro-2-iodoethane (2 eq., 26 mg, 124 pmol) were dissolved in 1 mL of DMF and heated for one hour at 100 °C. The solvent was then removed under reduced pressure and the residue was then poured in a separatory funnel, containing DCM and water. The water phase was extracted 3 times with DCM. Then, the combined organic phases were dried over Na2SC>4 and concentrated under reduced pressure. Afterwards, the crude was dissolved in 1 mL of DCM and 0.2 mL of TFA was slowly added to the solution at room temperature. After one hour, the solvent was then removed under reduced pressure and the crude product purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1% TFA). The lyophilized powder was poured in an separatory funnel containing DCM and a saturated solution of Na2COs in water. The water phase was extracted 3 times with DCM. Then, the combined organic phases were dried over Na2SO4 and concentrated under reduced pressure. The product was obtained as a white solid.

Yield: 15 mg (52%).

MS (ES+) [M+H]⁺ m/e = 468.1 .

¹H NMR (600 MHz, CDCI3): 5 7.79 (d, J = 8.5 Hz, 1 H), 7.67 - 7.63 (m, 2H), 7.57 - 7.52 (m, 1 H), 7.43 (t, J = 7.9 Hz, 2H), 7.19 (dd, J = 8.5, 2.3 Hz, 1 H), 7.00 (d, J = 2.2 Hz, 1 H), 5.27 (s, 1 H), 4.02 (q, J = 8.9 Hz, 2H), 3.85 - 3.79 (m, 2H), 2.47 (t, J = 6.7 Hz, 2H), 2.30 (s, 3H), 1 .69 - 1 .63 (m, 2H).

¹³C NMR (151 MHz, CDCI3): 5 165.08, 143.87, 139.80, 135.84, 132.97, 130.78, 129.37, 129.20, 127.22, 127.08, 125.29 (q, J = 237.9 Hz), 124.95, 120.42, 46.73, 46.57 (q, J = 34.8 Hz), 26.83, 21.69, 16.46.

Example compound 60: A/-(5-(4,4-difluoro-1-(phenylsulfonyl)-1,2,3,4-tetrahydroquinolin-6- yl)-4-methylthiazol-2-yl)acetamide

Step 1 : 6-Bromo-4,4-difluoro-1-(phenylsulfonyl)-1 ,2,3,4-tetrahydroquinoline

6-Bromo-1-(phenylsulfonyl)-2,3-dihydroquinolin-4(1/7)-one (80 mg, 218 pmol) was dissolved in 0.4 mL of a 50% solution of bis(2-methoxyethyl)aminosulfur trifluoride in THF. The solution was flushed with nitrogen for 10 minutes and then heated for 16 hours at 100 °C. After evaporation of the sovent under reduced pressure the crude product was then purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1% TFA). The product was obtained after lyophilization as an amorphous white solid.

Yield: 12 mg (14%).

MS (ES+) [M+Na]⁺ m/e = 409.8, 411 .7 (bromine isotopic pattern).

¹H NMR (300 MHz, CDCI₃): 5 7.79 (dt, J = 9.0, 1 .2 Hz, 1 H), 7.73 - 7.42 (m, 7H), 4.12 - 3.96 (m, 2H), 2.12 - 1.92 (m, 2H).

¹³C NMR (75 MHz, CDCI3): 5 139.07, 136.15 (t, J = 5.0 Hz), 134.46 (t, J = 1.7 Hz), 133.86, 129.67, 129.43 (t, = 3.6 Hz), 127.02, 126.27 (t, J = 26.3 Hz), 125.11 , 118.71 (d, J = 1.9 Hz), 116.22 (t, J = 239.5 Hz), 44.13 (t, J = 4.7 Hz), 31 .28 (t, J = 24.5 Hz).

¹⁹F NMR (282 MHz, CDCI3): 5 -8.82.

Step 2: A/-(5-(4,4-Difluoro-1 -(phenylsulfonyl)-l ,2,3,4-tetrahydroquinolin-6-yl)-4- methylthiazol-2-yl)acetamide

6-Bromo-4,4-difluoro-1-(phenylsulfonyl)-1 ,2,3,4-tetrahydroquinoline (12 mg, 137 pmol), A/-(4- methylthiazol-2-yl)acetamide (1.2 eq., 5.8 mg, 37 pmol), tri-tert-butylphosphonium tetrafluoroborate (0.2 eq., 1.8 mg, 6.2 pmol), Pd(OAc)2, (0.1 eq., 0.7 mg, 3.1 pmol) and CS2CO3 (3 eq., 30 mg, 93 pmol) were suspended in 1 mL of DMF. The suspension was sonicated for 5 minutes, flushed with nitrogen, heated up to 110 °C and stirred overnight. The solvent was then removed under reduced pressure and the crude product purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1 % TFA). The product was obtained after lyophilization as an amorphous white solid.

Yield: 5 mg (35%).

MS (ES+) [M+H]⁺ m/e = 464.1 .

¹H NMR (600 MHz, DMSO-d₆): 5 12.15 (s, 1 H), 7.82 - 7.78 (m, 3H), 7.75 - 7.71 (m, 1 H), 7.64 - 7.60 (m, 3H), 7.56 (d, J = 2.2 Hz, 1 H), 4.09 - 4.06 (m, 2H), 2.34 (s, 3H), 2.22 (ttd, J = 12.0, 5.8, 2.9 Hz, 2H), 2.14 (s, 3H).

¹³C NMR (151 MHz, DMSO-d₆): 5 155.36, 142.79, 138.33, 135.39, 134.08, 131.48, 129.02, 126.83, 125.27, 123.84 (t, J = 24.8 Hz), 122.66, 121.98, 117.03 (t, = 237.9 Hz), 43.75, 40.06, 30.98 (t, 7 = 24.1 Hz), 22.41 , 15.98. Example compound 61 : A/-(5-(1-(Allylsulfonyl)-1,2,3,4-tetrahydroquinolin-6-yl)-4- methylthiazol-2-yl)acetamide

A/-(4-Methyl-5-(1 ,2,3,4-tetrahydroquinolin-6-yl)thiazol-2-yl)acetamide (20 mg, 70 pmol) was dissolved in 1 mL of pyridine, followed by the addition of prop-2-ene-1 -sulfonyl chloride (1 .5 eq., 15 mg, 104 pmol) to the mixture. The reaction mixture was stirred for three hours at room temperature. The solvent was then removed under reduced pressure and the crude product purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1% TFA). The product was obtained after lyophilization as an amorphous white solid.

Yield: 18 mg (66%).

MS (ES+) [M+H]⁺ m/e = 392.1.

¹H NMR (300 MHz, CDCI₃): 5 7.78 (d, J = 8.6 Hz, 1 H), 7.21 (dd, J = 8.6, 2.4 Hz, 1 H), 7.15 (d, J = 2.2 Hz, 1 H), 5.89 (ddt, J = 17.3, 10.1 , 7.3 Hz, 1 H), 5.43 (dd, J = 10.1 , 1.1 Hz, 1 H), 5.31 (dd, J = 17.1 , 1 .2 Hz, 1 H), 3.90 (dt, J = 7.2, 1 .0 Hz, 2H), 3.86 - 3.76 (m, 2H), 2.87 (t, J = 6.6 Hz, 2H), 2.49 (s, 3H), 2.41 (s, 3H), 2.05 (p, J = 6.5 Hz, 2H).

¹³C NMR (75 MHz, CDCI3): 5 169.62, 159.91 , 138.26, 132.58, 130.22, 129.63, 127.36, 125.00, 124.80, 124.78, 124.29, 122.20, 56.63, 47.29, 27.48, 23.19, 22.61 , 13.07.

Example compound 62: A/-Allyl-5-methyl-4-(1-(phenylsulfonyl)-1 ,2,3,4-tetrahydroquinolin-6- yl)thiazol-2-amine

Tert-butyl (5-methyl-4-(1-(phenylsulfonyl)-1 ,2,3,4-tetrahydroquinolin-6-yl)thiazol-2-yl)carbamate (30 mg, 62 pmol), CS2CO3 (3 eq., 60 mg, 185 pmol) and bromocyclopropane (2 eq., 15 mg, 124 pmol) were dissolved in 1 mL of DMF and heated for 16 hours at 110 °C. The solvent was then removed under reduced pressure and the residue was then poured in a separatory funnel, containing DCM and water. The water phase was extracted 3 times with DCM. Then, the combined organic phases were dried over Na2SC>4 and concentrated under reduced pressure. Afterwards, the residue was dissolved in 1 mL of DCM and 0.2 mL of TFA was slowly added to the solution at room temperature. After one hour, the solvent was then removed under reduced pressure and the crude product purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1% TFA). The lyophilized powder was poured in an separatory funnel containing DCM and a saturated solution of Na2COs in water. The water phase was extracted 3 times with DCM. Then, the combined organic phases were dried over Na2SO4 and concentrated under reduced pressure. The product was obtained as a white amorphous solid. Yield: 12 mg (46%).

MS (ES+) [M+H]⁺ m/e = 468.1 .

¹H NMR (300 MHz, CDCI₃): 6 7.78 (d, J = 8.6 Hz, 1 H), 7.66 - 7.61 (m, 2H), 7.58 - 7.51 (m, 1 H), 7.49 - 7.37 (m, 2H), 7.20 (dd, J = 8.6, 2.3 Hz, 1 H), 7.00 (d, J = 2.2 Hz, 1 H), 5.94 (ddt, J = 17.1 , 10.6, 5.5 Hz, 1 H), 5.40 - 5.28 (m, 1 H), 5.27 - 5.19 (m, 1 H), 3.90 (d, = 5.4 Hz, 2H), 3.85 - 3.77 (m, 2H), 2.45 (t, J = 6.7 Hz, 2H), 2.31 (s, 3H), 1 .76 (s, 1 H), 1 .69 - 1 .58 (m, 2H).

¹³C NMR (151 MHz, CDCI3): 5 167.09, 143.94, 139.82, 135.43, 133.72, 132.93, 130.76, 129.85, 129.18, 129.13, 127.23, 126.90, 124.99, 119.06, 117.40, 48.39, 46.74, 26.82, 21.70, 16.50.

Example compound 63: 5-Methyl-A/-(oxetan-3-yl)-4-(1-(phenylsulfonyl)-1 ,2,3,4- tetrahydroquinolin-6-yl)thiazol-2-amine

Tert-butyl (5-methyl-4-(1-(phenylsulfonyl)-1 ,2,3,4-tetrahydroquinolin-6-yl)thiazol-2-yl)carbamate (30 mg, 62 pmol), CS2CO3 (3 eq., 60 mg, 185 pmol) and 3-iodooxetane (2 eq., 23 mg, 124 pmol) were dissolved in 1 mL of DMF and heated for one hour at 100 °C. The solvent was then removed under reduced pressure and the residue was then poured in a separatory funnel, containing DCM and water. The water phase was extracted 3 times with DCM. Then, the combined organic phases were dried over Na2SC>4 and concentrated under reduced pressure. Afterwards, the crude residue was dissolved in 1 mL of DCM and 0.2 mL of TFA was slowly added to the solution at room temperature. After one hour, the solvent was then removed under reduced pressure and the crude product purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1% TFA). The lyophilized powder was poured in an separatory funnel containing DCM and a saturated solution of Na2COs in water. The water phase was extracted 3 times with DCM. Then, the combined organic phases were dried over Na2SO4 and concentrated under reduced pressure. The product was obtained as a white solid.

Yield: 7 mg (26%).

MS (ES+) [M+H]⁺ m/e = 442.1 .

¹H NMR (300 MHz, CDCI3): 5 7.74 (d, J = 8.6 Hz, 1 H), 7.65 - 7.59 (m, 2H), 7.59 - 7.50 (m, 1 H), 7.46 - 7.36 (m, 2H), 7.08 (dd, J = 8.6, 2.2 Hz, 1 H), 6.88 (d, J = 2.2 Hz, 1 H), 4.60 (s, 1 H), 3.99 - 3.72 (m, 5H), 3.60 (d, J = 11 .0 Hz, 1 H), 2.42 (t, J = 6.7 Hz, 2H), 2.14 (s, 3H), 1 .69 - 1 .51 (m, 2H).

¹³C NMR (75 MHz, CDCI3): 5 167.49, 139.63, 135.69, 133.00, 130.91 , 129.45, 129.21 , 128.36, 127.35, 127.14, 126.00, 124.96, 111.02, 77.36, 46.65, 31.08, 26.76, 21.53, 13.16. Example compound 64: A/,5-Dimethyl-4-(1-(phenylsulfonyl)-1,2,3,4-tetrahydroquinohn-6- yl)thiazol-2-amine

Terf-butyl (5-methyl-4-(1-(phenylsulfonyl)-1 ,2,3,4-tetrahydroquinolin-6-yl)thiazol-2-yl)carbamate (30 mg, 62 pmol), CS2CO3 (3 eq., 60 mg, 185 pmol) and CH3I (2 eq., 18 mg, 124 pmol) were dissolved in 1 mL of DMF and heated for one hour at 100 °C. The solvent was then removed under reduced pressure and the residue was then poured in a separatory funnel, containing DCM and water. The water phase was extracted 3 times with DCM. Then, the combined organic phases were dried over Na2SC>4 and concentrated under reduced pressure. Afterwards, the residue was dissolved in 1 mL of DCM and 0.2 mL of TFA was slowly added to the solution at room temperature. After one hour, the solvent was then removed under reduced pressure and the crude product purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1% TFA). The lyophilized powder was poured in an separatory funnel containing DCM and a saturated solution of Na2COs in water. The water phase was extracted 3 times with DCM. Then, the combined organic phases were dried over Na2SO4 and concentrated under reduced pressure. The product was obtained as a white solid.

Yield: 10 mg (41%).

MS (ES+) [M+H]⁺ m/e = 400.1 .

¹H NMR (600 MHz, CDCI3): 5 7.78 (d, J = 8.6 Hz, 1 H), 7.67 - 7.62 (m, 2H), 7.57 - 7.51 (m, 1 H), 7.47 - 7.39 (m, 2H), 7.20 (dd, J = 8.6, 2.3 Hz, 1 H), 7.00 (d, J = 2.5 Hz, 1 H), 3.85 - 3.78 (m, 2H), 2.98 (s, 3H), 2.46 (t, J = 6.6 Hz, 2H), 2.31 (s, 3H), 1 .68 - 1 .60 (m, 2H).

¹³C NMR (151 MHz, CDCI3): 5 168.39, 144.17, 139.81 , 135.35, 132.92, 130.76, 129.98, 129.17, 129.09, 127.22, 126.86, 124.98, 118.83, 46.73, 32.29, 26.81 , 21.69, 16.56.

Example compound 65: A/-(5-(1-((3-Bromophenyl)sulfonyl)-1 ,2,3,4-tetrahydroquinolin-6-yl)- 4-methylthiazol-2-yl)acetamide

A/-(4-Methyl-5-(1 ,2,3,4-tetrahydroquinolin-6-yl)thiazol-2-yl)acetamide (60 mg, 209 pmol) was dissolved in 1 mL of pyridine, followed by the addition of 3-bromobenzenesulfonyl chloride (1.5 eq., 80 mg, 313 pmol) to the mixture. The reaction mixture was stirred for three hours at room temperature. The solvent was then removed under reduced pressure and the crude product purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1% TFA). The product was obtained after lyophilization as an amorphous white solid. Yield: 64 mg (61%).

MS (ES+) [M+H]⁺ m/e = 506.0, 508.0 (bromine isotopic pattern).

¹H NMR (300 MHz, CD₂CI₂): 5 7.86 (d, J = 8.6 Hz, 1 H), 7.79 (t, J = 1 .8 Hz, 1 H), 7.72 (ddd, J = 8.0, 1 .9, 1 .0 Hz, 1 H), 7.58 (ddd, J = 7.9, 1 .8, 1 .1 Hz, 1 H), 7.36 (t, J = 8.0 Hz, 1 H), 7.31 - 7.25 (m, 1 H), 7.14 (dt, J = 2.1 , 1 .0 Hz, 1 H), 3.87 - 3.80 (m, 2H), 2.56 (t, J = 6.7 Hz, 2H), 2.48 (s, 3H), 2.37 (s, 3H), 1.78 - 1.66 (m, 2H).

¹³C NMR (75 MHz, CDCI₃): 5 171.84, 162.33, 143.44, 139.81 , 138.47, 134.65, 134.04, 133.20, 132.22, 132.18, 129.38, 127.92, 127.76, 127.18, 126.94, 125.37, 49.22, 29.07, 25.13, 23.79, 14.94.

Example compound 66: 3-((6-(2-Acetamido-4-methylthiazol-5-yl)-3,4-dihydroquinolin-1(2H)- vDsulfonvDbenzenesulfonyl fluoride

A/-(5-(1-((3-Bromophenyl)sulfonyl)-1 ,2,3,4-tetrahydroquinolin-6-yl)-4-methylthiazol-2-yl)acetamide (25 mg, 49 pmol), bis(di-te/Y-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(ll) (0.4 eq., 14 mg, 20 pmol), 1 ,4-diazabicyclo[2.2.2]octane bis(sulfur dioxide) adduct (2.4 eq., 29 mg, 118 pmol), triethylamine (3 eq., 15 mg, 148 pmol) were suspended in 1 mL of dry isopropanol in a microwave vial. The suspension was sonicated for 5 minutes, flushed with nitrogen, heated up to 110 °C and stirred overnight. Afterwards, A/-fluoro-A/-(phenylsulfonyl)benzenesulfonamide (3 eq., 47 mg, 148 pmol) was added to the mixture, which was then stirred for three hours at room temperature. The solvent was then removed under reduced pressure and the crude product purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1% TFA). The product was obtained after lyophilization as an amorphous white solid.

Yield: 12 mg (48%).

MS (ES+) [M+H]⁺ m/e = 510.0.

¹H NMR (600 MHz, CDCI₃): 5 8.21 - 8.16 (m, 2H), 8.05 (dt, J = 7.9, 1 .5 Hz, 1 H), 7.88 (d, J = 8.5 Hz, 1 H), 7.76 (t, J = 8.2 Hz, 1 H), 7.30 (dd, = 8.5, 2.3 Hz, 1 H), 7.10 (d, J = 2.2 Hz, 1 H), 3.91 - 3.85 (m, 2H), 2.52 (t, J = 6.6 Hz, 2H), 2.46 (s, 3H), 2.36 (s, 3H), 1 .78 - 1 .70 (m, 2H).

¹³C NMR (151 MHz, CDCI3): 5 168.68, 158.24, 141.72, 136.22, 134.56, 134.38, 133.35, 132.17, 131.43, 130.86, 129.85, 127.61 , 127.00, 125.09, 124.54, 47.08, 26.64, 23.12, 21.58, 14.00.

¹⁹F NMR (564 MHz, CDCI3): 5 -75.98. Example compound 67: A/-(5-(1-((3-Acetylphenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-6-yl)- 4-methylthiazol-2-yl)acetamide

A/-(4-Methyl-5-(1 ,2,3,4-tetrahydroquinolin-6-yl)thiazol-2-yl)acetamide (40 mg, 139 pmol) was dissolved in 1 mL of pyridine, followed by the addition of 3-acetylbenzenesulfonyl chloride (1.5 eq., 46 mg, 209 pmol) to the mixture. The reaction mixture was stirred for three hours at room temperature. The solvent was then removed under reduced pressure and the crude product purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1% TFA). The product was obtained after lyophilization as an amorphous white solid.

Yield: 38 mg (58%).

MS (ES+) [M+H]⁺ m/e = 470.1 .

¹H NMR (300 MHz, DMSO-d₆): 5 12.10 (s, 1 H), 8.22 (dt, J = 7.8, 1.4 Hz, 1 H), 7.99 (t, J = 1.7 Hz, 1 H), 7.91 (ddd, J = 7.9, 2.0, 1.1 Hz, 1 H), 7.78 - 7.67 (m, 2H), 7.32 (dd, J = 8.6, 2.3 Hz, 1 H), 7.16 (d, J = 2.2 Hz, 1 H), 3.86 - 3.77 (m, 2H), 2.53 (s, 3H), 2.46 (t, J = 6.5 Hz, 2H), 2.32 (s, 3H), 2.13 (s, 3H), 1.65 - 1.52 (m, 2H).

¹³C NMR (75 MHz, DMSO-d₆): 6 196.62, 168.35, 155.05, 141.99, 139.37, 137.37, 135.04, 132.97, 131.29, 130.75, 130.40, 129.26, 128.86, 126.50, 125.86, 124.10, 123.12, 46.50, 26.78, 25.94, 22.47, 20.95, 16.07.

Example compound 68: A/-(5-(1-((2,2-Dimethylchroman-6-yl)sulfonyl)-1,2,3,4- tetrahydroquinolin-6-yl)-4-methylthiazol-2-yl)acetamide

A/-(4-Methyl-5-(1 ,2,3,4-tetrahydroquinolin-6-yl)thiazol-2-yl)acetamide (20 mg, 70 pmol) was dissolved in 1 mL of pyridine, followed by the addition of 2,2-dimethylchromane-6-sulfonyl chloride (1.5 eq., 27 mg, 104 pmol) to the mixture. The reaction mixture was stirred for three hours at room temperature. The solvent was then removed under reduced pressure and the crude product purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1% TFA). The product was obtained after lyophilization as an amorphous white solid.

Yield: 18 mg (51%). MS (ES+) [M+H]⁺ m/e = 512.1.

¹H NMR (300 MHz, CDCI₃): 5 7.86 (d, J = 8.6 Hz, 1 H), 7.42 (d, J = 2.4 Hz, 1 H), 7.35 (dd, J = 8.7, 2.4 Hz, 1 H), 7.22 (dd, J = 8.6, 2.3 Hz, 1 H), 7.07 (d, J = 2.3 Hz, 1 H), 6.77 (d, J = 8.6 Hz, 1 H), 3.86 - 3.75 (m, 2H), 2.74 (t, J = 6.7 Hz, 2H), 2.59 (t, J = 6.6 Hz, 2H), 2.46 (s, 3H), 2.36 (s, 3H), 1 .85 - 1.67 (m, 4H), 1.33 (s, 6H).

¹³C NMR (75 MHz, CDCI3): 5 168.97, 158.50, 158.33, 137.85, 135.20, 130.90, 130.00, 129.66, 129.21 , 127.00, 126.72, 125.83, 125.19, 124.86, 121.67, 118.11 , 75.97, 46.61 , 32.27, 27.09, 26.97, 23.26, 22.44, 21.61 , 14.03.

Example compound 69: A/-(5-(1-((3-(2-Bromoacetyl)phenyl)sulfonyl)-1 ,2,3,4- tetrahydroquinolin-6-yl)-4-methylthiazol-2-yl)acetamide

A/-(5-(1-((3-Acetylphenyl)sulfonyl)-1 ,2,3,4-tetrahydroquinolin-6-yl)-4-methylthiazol-2-yl)acetamide (14 mg, 30 pmol) and CuBr2 (1.5 eq., 10 mg, 45 pmol) were suspended in 1 mL of EtOAc and stirred for 16 hours. The solvent was then removed under reduced pressure and the crude product purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1% TFA). The product was obtained after lyophilization as an amorphous white solid.

Yield: 4 mg (24%).

MS (ES+) [M+H]⁺ m/e = 548.0, 550.0 (bromine isotopic pattern).

¹H NMR (300 MHz, DMSO-d₆): 5 12.09 (s, 1 H), 8.26 (dt, J = 7.8, 1.4 Hz, 1 H), 8.12 (t, J = 1.8 Hz, 1 H), 7.92 (dt, J = 8.0, 1 .3 Hz, 1 H), 7.76 (t, J = 7.8 Hz, 1 H), 7.69 (d, J = 8.6 Hz, 1 H), 7.31 (dd, J = 8.6, 2.3 Hz, 1 H), 7.16 (d, J = 2.2 Hz, 1 H), 4.92 (s, 2H), 3.87 - 3.79 (m, 2H), 2.33 (s, 3H), 2.13 (s, 3H), 1 .61 (p, J = 6.5 Hz, 3H). 2H hidden behind the DMSO-d6 peak.

¹³C NMR (151 MHz, DMSO-d₆): 5 198.06, 168.28, 158.12, 154.98, 141.96, 139.44, 135.35, 132.41 , 131.77, 130.82, 130.33, 129.20, 128.75, 126.43, 125.47, 123.89, 123.09, 65.55, 46.44, 25.92, 22.41 , 21.00, 16.04.

Example compound 70: 2,2,2-Trifluoro-A/-(4-methyl-5-(1-(phenylsulfonyl)-1 ,2,3,4- tetrahydroquinolin-6-yl)thiazol-2-yl)acetamide

4-Methyl-5-(1-(phenylsulfonyl)-1 ,2,3,4-tetrahydroquinolin-6-yl)thiazol-2-amine (15 mg, 39 pmol) was dissolved in 1 mL pf pyridine. Afterwards, 2,2,2-trifluoroacetic anhydride (3 eq., 25 mg, 117 pmol) was dropwise added to the solution and stirred for 30 minutes at room temperature. The solvent was then removed under reduced pressure and the crude product purified by reversed- phase preparative HPLC (5% to 99% acetonitrile with 0.1 % TFA). The product was obtained after lyophilization as an amorphous white solid.

Yield: 12 mg (64%).

MS (ES+) [M+H]⁺ m/e = 482.1 .

¹H NMR (300 MHz, DMSO-d₆): 5 7.76 - 7.64 (m, 4H), 7.62 - 7.51 (m, 2H), 7.33 (dd, J = 8.6, 2.3 Hz, 1 H), 7.22 (d, J = 2.3 Hz, 1 H), 3.84 - 3.75 (m, 2H), 2.57 - 2.51 (m, 2H), 1 .68 - 1 .52 (m, 2H).

¹³C NMR (75 MHz, DMSO-d₆): 6 138.83, 136.37, 133.56, 131.00, 129.64, 129.24, 126.80, 126.53, 126.31 , 123.78, 121.45, 119.01 , 115.21 , 46.33, 26.09, 20.89. The carbon that couples with F disapperead.

¹⁹F NMR (282 MHz, DMSO-d₆): 6 4.02.

Example compound 71 : A/-(4-Methyl-5-(1-(phenylsulfonyl)-1 ,2,3,4-tetrahydroquinolin-6- yl)thiazol-2-yl)benzamide

4-Methyl-5-(1-(phenylsulfonyl)-1 ,2,3,4-tetrahydroquinolin-6-yl)thiazol-2-amine (15 mg, 39 pmol) was dissolved in 1 mL pf pyridine. Afterwards, benzoyl chloride (3 eq., 16 mg, 117 pmol) was dropwise added to the solution and stirred for 30 minutes at room temperature. The solvent was then removed under reduced pressure and the crude product purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1% TFA). The product was obtained after lyophilization as an amorphous white solid.

Yield: 11 mg (58%).

MS (ES+) [M+H]⁺ m/e = 482.1 .

¹H NMR (300 MHz, DMSO-d₆): 5 12.66 (s, 1 H), 8.14 - 8.06 (m, 2H), 7.73 - 7.50 (m, 9H), 7.33 (dd, J = 8.6, 2.3 Hz, 1 H), 7.21 (d, J = 2.2 Hz, 1 H), 3.81 (dd, J = 4.7, 3.0 Hz, 2H), 2.56 - 2.51 (m, 2H), 2.39 (s, 3H), 1 .70 - 1 .51 (m, 2H).

¹³C NMR (75 MHz, DMSO-d₆): 6 169.60, 138.91 , 135.47, 133.50, 132.64, 132.05, 130.83, 129.61 , 129.30, 128.65, 128.31 , 128.14, 126.80, 126.43, 126.18, 123.81 , 123.71 , 118.11 , 46.31 , 26.08, 20.95. Example compound 72: A/-(5-(1-((3-(1-Hydroxyethyl)phenyl)sulfonyl)-1 ,2,3,4- tetrahydroquinolin-6-yl)-4-methylthiazol-2-yl)acetamide

A/-(5-(1-((3-Acetylphenyl)sulfonyl)-1 ,2,3,4-tetrahydroquinolin-6-yl)-4-methylthiazol-2-yl)acetamide (5 mg, 11 pmol) was dissolved in 1 mL of MeOH. Afterwards, NaBH4 (4 eq., 1 .6 mg, 43 pmol) was added to the solution and the reaction was stirred at room temperature for one hour. The solvent was then removed under reduced pressure and the crude product purified by reversed- phase preparative HPLC (5% to 99% acetonitrile with 0.1 % TFA). The product was obtained after lyophilization as an amorphous white solid.

Yield: 3.5 mg (70%).

MS (ES+) [M+H]⁺ m/e = 472.1 .

¹H NMR (300 MHz, DMSO-d₆): 5 12.09 (s, 1 H), 7.68 (d, = 8.6 Hz, 1 H), 7.61 (dt, J = 6.3, 2.2 Hz, 1 H), 7.55 - 7.45 (m, 3H), 7.29 (dd, J = 8.6, 2.3 Hz, 1 H), 7.14 (d, J = 2.2 Hz, 1 H), 4.72 (q, J = 6.4 Hz, 1 H), 3.85 - 3.68 (m, 2H), 2.45 (t, J = 6.6 Hz, 2H), 2.32 (s, 3H), 2.13 (s, 3H), 1 .65 - 1 .48 (m, 2H), 1.19 (d, J = 6.5 Hz, 3H).

Example compound 73: 4-Methyl-A/-phenyl-5-(1-(phenylsulfonyl)-1 ,2,3,4- tetrahydroquinolin-6-yl)thiazol-2-amine

4-Methyl-5-(1-(phenylsulfonyl)-1 ,2,3,4-tetrahydroquinolin-6-yl)thiazol-2-amine (30 mg, 78 pmol), bromobenzene (1 eq., 12 mg, 78 pmol), (BrettPhos) palladium(ll) phenethylamine chloride (0.1 eq. 7 mg) and CS2CO3 (1.4 eq., 35 mg, 109 pmol) ) were dissolved in 1 mL of DMF. The suspension was sonicated for 5 minutes, flushed with nitrogen, heated up to 80 °C and stirred overnight. The solvent was then removed under reduced pressure and the crude product purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1 % TFA). The lyophilized powder was poured in an separatory funnel containing DCM and a saturated solution of Na2COs in water. The water phase was extracted 3 times with DCM. Then, the combined organic phases were dried over Na2SO4 and concentrated under reduced pressure. The product was obtained as an amorphous white solid.

Yield: 16 mg (46%).

MS (ES+) [M+H]⁺ m/e = 462.1 . ¹H NMR (300 MHz, CDCI₃): 6 7.81 (d, J = 8.6 Hz, 1 H), 7.68 - 7.61 (m, 2H), 7.59 - 7.51 (m, 1 H), 7.48 - 7.29 (m, 6H), 7.24 (dd, J = 8.5, 2.2 Hz, 1 H), 7.11 - 6.99 (m, 2H), 3.89 - 3.77 (m, 2H), 2.47 (t, J = 6.7 Hz, 2H), 2.37 (s, 3H), 1 .64 (tt, J = 7.7, 5.4 Hz, 2H), 1 .25 (s, 1 H).

¹³C NMR (75 MHz, CDCI3): 5 162.54, 143.55, 140.40, 139.68, 135.66, 132.97, 130.80, 129.65, 129.33, 129.30, 129.19, 127.19, 126.98, 125.02, 123.27, 119.70, 118.59, 46.71 , 26.80, 21.60, 16.50.

Example compound 74: A/-(5-(1-((3-Aminophenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-6-yl)- 4-methylthiazol-2-yl)acetamide

A/-(4-methyl-5-(1-((3-nitrophenyl)sulfonyl)-1 ,2,3,4-tetrahydroquinolin-6-yl)thiazol-2-yl)acetamide (160 mg, 339 pmol) was dissolved in 2 mL of MeOH and 1 mL of a 5% solution of ammonium chloride in water. Afterwards, zinc dust (10 eq., 221 mg, 3.39 mmol) was added to the mixture. The reaction mixture was stirred for 1 hour at room temperature. The crude product was then filtered and purified by silica gel chromatography using a gradient of cyclohexane and EtOAc as eluent. The product was obtained as a yellow oil.

Yield: 121 mg (81 %).

MS (ES+) [M+H]⁺ m/e = 443.1

¹H NMR (300 MHz, CD3OD): 5 7.76 (d, J = 8.6 Hz, 1 H), 7.23 (dd, J = 8.5, 2.2 Hz, 1 H), 7.19 - 7.10 (m, 2H), 6.94 (t, J = 2.1 Hz, 1 H), 6.84 (dddd, J = 7.6, 6.6, 2.1 , 1 .0 Hz, 2H), 3.85 - 3.76 (m, 2H), 2.53 (t, J = 6.7 Hz, 2H), 2.35 (s, 3H), 2.21 (s, 3H), 1 .73 - 1 .60 (m, 2H), 1 .29 (s, 2H).

¹³C NMR (75 MHz, CD3OD): 5 170.68, 157.07, 150.52, 143.21 , 141.27, 137.64, 132.66, 130.78, 130.57, 130.21 , 127.78, 126.14, 126.06, 120.01 , 116.39, 113.44, 47.66, 27.61 , 22.54, 22.44, 16.05.

Example compound 75: A/-(3-((6-(2-Acetamido-4-methylthiazol-5-yl)-3,4-dihydroquinolin- 1(2H)-yl)sulfonyl)phenyl)acetamide

A/-(5-(1-((3-Aminophenyl)sulfonyl)-1 ,2,3,4-tetrahydroquinolin-6-yl)-4-methylthiazol-2-yl)acetamide (20 mg, 45 pmol) was dissolved in 1 mL pf pyridine. Afterwards, acetyl chloride (3 eq., 11 mg, 136 pmol) was dropwise added to the solution and stirred for 30 minutes at room temperature. The solvent was then removed under reduced pressure and the crude product purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1% TFA). The product was obtained after lyophilization as an amorphous white solid.

Yield: 12 mg (55%).

MS (ES+) [M+H]⁺ m/e = 485.1

¹H NMR (300 MHz, DMSO-d₆): 5 12.09 (s, 1 H), 10.26 (s, 1 H), 8.06 (t, J = 1.9 Hz, 1 H), 7.77 (ddd, J = 8.3, 2.1 , 1 .0 Hz, 1 H), 7.63 (d, J = 8.6 Hz, 1 H), 7.47 (t, J = 8.0 Hz, 1 H), 7.34 - 7.22 (m, 2H), 7.15 (d, J = 2.2 Hz, 1 H), 3.82 - 3.74 (m, 2H), 2.58 - 2.51 (m, 2H), 2.32 (s, 3H), 2.13 (s, 3H), 2.03 (s, 3H), 1.65 (p, = 6.5 Hz, 2H).

¹³C NMR (75 MHz, DMSO-d₆): 5 168.85, 168.32, 154.95, 141.87, 140.13, 139.31 , 135.32, 130.70, 129.99, 129.24, 128.37, 126.36, 123.57, 123.22, 123.05, 120.99, 116.62, 46.37, 26.06, 24.04, 22.47, 21.01 , 16.08.

Example compound 76: A/-(5-(1-((3-(Dimethylamino)phenyl)sulfonyl)-1 ,2,3,4- tetrahydroquinolin-6-yl)-4-methylthiazol-2-yl)acetamide

A/-(5-(1-((3-Aminophenyl)sulfonyl)-1 ,2,3,4-tetrahydroquinolin-6-yl)-4-methylthiazol-2-yl)acetamide (20 mg, 45 pmol) was dissolved in 1 mL of MeOH and 0.1 mL of acetic acid. Afterwards, formaldehyde 37% in water (3 eq., 11 mg, 136 pmol) was added to the solution and stirred for 30 minutes at room temperature. NaBHsCN (5 eq., 14 mg, 226 pmol) was also added tot he stirring solution. After one hour at room temperature, the solvent was removed under reduced pressure and the residue was purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1% TFA). The lyophilized powder was poured in an separatory funnel containing DCM and a saturated solution of Na2COs in water. The water phase was extracted 3 times with DCM. Then, the combined organic phases were dried over Na2SO4 and concentrated under reduced pressure. The product was obtained as an amorphous white solid.

Yield: 14 mg (66%).

MS (ES+) [M+H]⁺ m/e = 471.1

¹H NMR (300 MHz, CDCI₃): 6 9.71 (s, 1 H), 7.88 (d, J = 8.6 Hz, 1 H), 7.29 - 7.21 (m, 2H), 7.08 (d, J = 2.2 Hz, 1 H), 7.03 - 6.94 (m, 1 H), 6.85 - 6.77 (m, 1 H), 6.75 - 6.69 (m, 1 H), 3.86 - 3.78 (m, 2H), 2.84 (s, 6H), 2.48 (t, J = 6.7 Hz, 2H), 2.39 (s, 3H), 2.26 (s, 3H), 1.71 - 1 .57 (m, 2H).

¹³C NMR (75 MHz, CDCI₃): 5 167.58, 155.53, 150.45, 141.65, 139.99, 136.69, 131.27, 129.70, 129.63, 128.72, 127.05, 125.68, 125.30, 116.20, 114.23, 109.98, 46.81 , 40.31 , 26.92, 23.43, 21.41 , 16.14.

Example compound 77: A/-(5-(1-((2-Chlorophenyl)sulfonyl)-1 ,2,3,4-tetrahydroquinolin-6-yl)- 4-methylthiazol-2-yl)acetamide

A/-(4-Methyl-5-(1 ,2,3,4-tetrahydroquinolin-6-yl)thiazol-2-yl)acetamide (20 mg, 70 pmol) was dissolved in 1 mL of pyridine, followed by the addition of 2-chlorobenzenesulfonyl chloride (1.5 eq., 22 mg, 104 pmol) to the mixture. The reaction mixture was stirred for three hours at room temperature. The solvent was then removed under reduced pressure and the crude product purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1% TFA). The product was obtained after lyophilization as an amorphous white solid.

Yield: 25 mg (78%).

MS (ES+) [M+H]⁺ m/e = 462.0

¹H NMR (300 MHz, DMSO-d₆): 5 12.08 (s, 1 H), 8.11 (dt, J = 7.7, 1.1 Hz, 1 H), 7.74 - 7.68 (m, 2H), 7.65 - 7.57 (m, 1 H), 7.29 (d, J = 8.5 Hz, 1 H), 7.21 (d, = 2.1 Hz, 1 H), 7.17 (dd, J = 8.6, 2.3 Hz, 1 H), 3.91 - 3.80 (m, 2H), 2.78 (t, = 6.6 Hz, 2H), 2.30 (s, 3H), 2.12 (s, 3H), 1.91 - 1.76 (m, 2H).

¹³C NMR (151 MHz, DMSO-d₆): 5 168.25, 154.88, 141.73, 137.33, 135.60, 134.94, 132.37, 131.52, 130.79, 129.81 , 129.32, 128.13, 127.75, 126.13, 123.16, 121.88, 46.28, 26.25, 22.41 , 21.82, 16.00.

Example compound 78: A/-(5-(1-((3,4-Dimethoxyphenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin- 6-yl)-4-methylthiazol-2-yl)acetamide

A/-(4-Methyl-5-(1 ,2,3,4-tetrahydroquinolin-6-yl)thiazol-2-yl)acetamide (20 mg, 70 pmol) was dissolved in 1 mL of pyridine, followed by the addition of 3,4-dimethoxybenzenesulfonyl chloride (1.5 eq., 25 mg, 104 pmol) to the mixture. The reaction mixture was stirred for three hours at room temperature. The solvent was then removed under reduced pressure and the crude product purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1% TFA). The product was obtained after lyophilization as an amorphous white solid.

Yield: 12 mg (34%).

MS (ES+) [M+H]⁺ m/e = 488.1

¹H NMR (300 MHz, DMSO-d₆): 5 12.10 (s, 1 H), 7.73 (d, J = 8.6 Hz, 1 H), 7.30 (dt, J = 8.5, 2.6 Hz, 2H), 7.16 (d, J = 2.2 Hz, 1 H), 7.11 (d, J = 8.6 Hz, 1 H), 6.82 (d, J = 2.2 Hz, 1 H), 3.81 (s, 3H), 3.79 - 3.72 (m, 2H), 3.58 (s, 3H), 2.46 (t, = 6.5 Hz, 2H), 2.32 (s, 3H), 2.13 (s, 3H), 1.62 - 1.49 (m, 2H).

¹³C NMR (151 MHz, DMSO-d₆): 5 168.29, 154.97, 152.58, 148.49, 141.81 , 135.57, 131.32, 130.05, 129.07, 128.52, 126.31 , 124.30, 123.19, 120.58, 111.35, 109.13, 55.84, 55.45, 46.32, 26.07, 22.41 , 20.67, 15.98.

Example compound 79: A/-(5-(1-((2,3-Dimethoxyphenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin- 6-yl)-4-methylthiazol-2-yl)acetamide

A/-(4-Methyl-5-(1 ,2,3,4-tetrahydroquinolin-6-yl)thiazol-2-yl)acetamide (20 mg, 70 pmol) was dissolved in 1 mL of pyridine, followed by the addition of 2,3-dimethoxybenzenesulfonyl chloride (1.5 eq., 25 mg, 104 pmol) to the mixture. The reaction mixture was stirred for three hours at room temperature. The solvent was then removed under reduced pressure and the crude product purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1% TFA). The product was obtained after lyophilization as an amorphous white solid.

Yield: 14 mg (41%).

MS (ES+) [M+H]⁺ m/e = 488.1

¹H NMR (300 MHz, DMSO-d₆): 5 12.06 (s, 1 H), 7.83 (d, = 8.5 Hz, 1 H), 7.43 (d, = 8.4 Hz, 1 H), 7.21 - 7.08 (m, 2H), 6.72 - 6.60 (m, 2H), 3.88 (s, 3H), 3.83 (s, 3H), 3.81 - 3.72 (m, 2H), 3.63 (s, 3H), 2.72 (t, J = 6.5 Hz, 2H), 2.30 (s, 3H), 2.12 (s, 3H), 1 .74 (p, J = 6.3 Hz, 2H).

¹³C NMR (151 MHz, DMSO-d₆): 5 168.22, 164.80, 158.25, 154.73, 141.41 , 136.45, 132.46, 129.06, 128.85, 126.61 , 125.95, 123.42, 121.43, 119.25, 105.25, 99.36, 55.87, 55.84, 46.15, 26.61 , 22.41 , 21.38, 15.97.

Example compound 80: Methyl 3-((6-(2-acetamido-4-methylthiazol-5-yl)-3,4- dihvdroquinolin-1(2H)-yl)sulfonyl)thiophene-2-carboxylate

A/-(4-Methyl-5-(1 ,2,3,4-tetrahydroquinolin-6-yl)thiazol-2-yl)acetamide (20 mg, 70 pmol) was dissolved in 1 mL of pyridine, followed by the addition of methyl 3-(chlorosulfonyl)thiophene-2- carboxylate (1 .5 eq., 25 mg, 104 pmol) to the mixture. The reaction mixture was stirred for three hours at room temperature. The solvent was then removed under reduced pressure and the crude product purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1% TFA). The product was obtained after lyophilization as an amorphous white solid. Yield: 29 mg (85%).

MS (ES+) [M+H]⁺ m/e = 492.0

¹H NMR (600 MHz, DMSO-d₆): 5 12.06 (s, 1 H), 8.00 (d, = 5.2 Hz, 1 H), 7.42 (d, = 5.3 Hz, 1 H), 7.39 - 7.35 (m, 1 H), 7.24 - 7.18 (m, 2H), 3.90 - 3.87 (m, 2H), 3.72 (s, 3H), 2.73 (t, = 6.6 Hz, 2H), 2.32 (s, 3H), 2.13 (s, 3H), 1 .83 - 1 .78 (m, 2H).

¹³C NMR (151 MHz, DMSO-d₆): 5 168.26, 159.81 , 154.90, 141.74, 141.34, 135.70, 133.57, 131.96, 130.15, 130.04, 129.28, 127.87, 126.18, 123.20, 122.60, 53.04, 46.30, 26.15, 22.41 , 21.69, 16.01.

Example compound 81 : A/-(4-Methyl-5-(1-((3-nitrophenyl)sulfonyl)-1 ,2,3,4- tetrahydroquinolin-6-yl)thiazol-2-yl)acetamide

A/-(4-Methyl-5-(1 ,2,3,4-tetrahydroquinolin-6-yl)thiazol-2-yl)acetamide (150 mg, 522 p mo I) was dissolved in 2 mL of pyridine, followed by the addition of 3-nitrobenzenesulfonyl chloride (1 .5 eq., 173 mg, 783 pmol) to the mixture. The reaction mixture was stirred for three hours at room temperature. The solvent was then removed under reduced pressure and the crude product was then purified by silica gel chromatography using a gradient of cyclohexane and EtOAc as eluent. The product was obtained as a yellow solid.

Yield: 144 mg (57%).

MS (ES+) [M+H]⁺ m/e = 473.0

¹H NMR (300 MHz, DMSO-d₆): 5 12.11 (s, 1 H), 8.50 (ddd, J = 8.2, 2.3, 1.0 Hz, 1 H), 8.21 (t, J = 2.0 Hz, 1 H), 8.08 (ddd, J = 7.8, 1 .8, 1 .0 Hz, 1 H), 7.87 (t, J = 8.1 Hz, 1 H), 7.69 (d, J = 8.6 Hz, 1 H), 7.34 (dd, = 8.6, 2.2 Hz, 1 H), 7.18 (d, J = 2.2 Hz, 1 H), 3.88 - 3.78 (m, 2H), 2.49 - 2.43 (m, 2H), 2.33 (s, 3H), 2.13 (s, 3H), 1 .68 - 1 .53 (m, 2H).

¹³C NMR (151 MHz, DMSO-d₆): 5 168.32, 155.07, 147.89, 142.06, 140.08, 134.65, 132.57, 131.70, 131.54, 129.28, 129.15, 127.99, 126.58, 124.09, 123.04, 121.44, 46.60, 25.84, 22.42, 21.14, 16.01.

Example compound 82: A/-(4-Methyl-5-(1-((2-oxo-2,3-dihvdrobenzorcfloxazol-7-yl)sulfonyl)- 1 ,2,3,4-tetrahydroquinolin-6-yl)thiazol-2-yl)acetamide

A/-(4-Methyl-5-(1 ,2,3,4-tetrahydroquinolin-6-yl)thiazol-2-yl)acetamide (20 mg, 70 pmol) was dissolved in 1 mL of pyridine, followed by the addition of 2-oxo-2,3-dihydrobenzo[d]oxazole-7- sulfonyl chloride (1.5 eq., 24 mg, 104 pmol) to the mixture. The reaction mixture was stirred for three hours at room temperature. The solvent was then removed under reduced pressure and the crude product purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1% TFA). The product was obtained after lyophilization as an amorphous white solid.

Yield: 13 mg (39%).

MS (ES+) [M+H]⁺ m/e = 485.1

¹H NMR (300 MHz, DMSO-d₆): 5 12.19 (s, 1 H), 12.09 (s, 1 H), 7.68 (d, J = 8.6 Hz, 1 H), 7.57 (d, J = 1 .7 Hz, 1 H), 7.46 (dd, J = 8.3, 1 .8 Hz, 1 H), 7.28 (dd, J = 8.6, 2.3 Hz, 1 H), 7.22 (d, J = 8.2 Hz, 1 H), 7.15 (d, J = 2.2 Hz, 1 H), 3.85 - 3.71 (m, 2H), 2.57 - 2.51 (m, 2H), 2.33 (s, 3H), 2.13 (s, 3H), 1.70 - 1.52 (m, 2H).

¹³C NMR (151 MHz, DMSO-d₆): 5 168.33, 154.95, 154.06, 143.02, 141.88, 135.32, 134.93, 132.11 , 130.82, 129.18, 128.38, 126.33, 123.72, 123.66, 123.20, 110.06, 108.16, 46.32, 26.10, 22.44, 21.03, 16.11.

Example compound 83: A/-(4-Methyl-5-(1-((3-oxo-3,4-dihydro-2H-benzorbiri,4loxazin-7- yl)sulfonyl)-1 ,2,3,4-tetrahydroquinolin-6-yl)thiazol-2-yl)acetamide

A/-(4-Methyl-5-(1 ,2,3,4-tetrahydroquinolin-6-yl)thiazol-2-yl)acetamide (20 mg, 70 pmol) was dissolved in 1 mL of pyridine, followed by the addition of 3-oxo-3,4-dihydro-2/7- benzo[b][1 ,4]oxazine-7-sulfonyl chloride (1.5 eq., 26 mg, 104 pmol) to the mixture. The reaction mixture was stirred for three hours at room temperature. The solvent was then removed under reduced pressure and the crude product purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1% TFA). The product was obtained after lyophilization as an amorphous white solid.

Yield: 3.5 mg (10%).

MS (ES+) [M+H]⁺ m/e = 499.0

¹H NMR (600 MHz, DMSO-d₆): 5 12.07 (s, 1 H), 10.87 (s, 1 H), 7.64 (d, J = 8.6 Hz, 1 H), 7.27 (d, J = 8.6 Hz, 1 H), 7.22 - 7.19 (m, 2H), 7.18 (s, 1 H), 7.07 (d, J = 8.8 Hz, 1 H), 4.68 (s, 2H), 3.75 (t, J = 5.9 Hz, 2H), 2.57 (t, J = 6.7 Hz, 2H), 2.33 (s, 3H), 2.13 (s, 3H), 1 .66 (p, J = 6.3 Hz, 2H).

¹³C NMR (151 MHz, DMSO-d₆): 5 168.36, 164.03, 154.96, 146.87, 141.90, 135.37, 132.31 , 130.73, 129.24, 128.39, 127.76, 126.33, 123.70, 123.25, 122.33, 116.82, 114.19, 66.69, 46.30, 26.13, 22.46, 21.00, 16.16. Example compund 84: A/-(5-(1-((2,5-Difluorophenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-6- yl)-4-methylthiazol-2-yl)acetamide

A/-(4-Methyl-5-(1 ,2,3,4-tetrahydroquinolin-6-yl)thiazol-2-yl)acetamide (30 mg, 104 pmol) was dissolved in 1 mL of pyridine, followed by the addition 2,5-difluorobenzenesulfonyl chloride (1.5 eq., 33 mg, 156 pmol) to the mixture. The reaction mixture was stirred for three hours at room temperature. The solvent was then removed under reduced pressure and the crude product purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1% TFA). The product was obtained after lyophilization as an amorphous white solid.

Yield: 45 mg (93%).

MS (ES+) [M+H]⁺ m/e = 464.1

¹H NMR (300 MHz, DMSO-d₆): 5 12.09 (s, 1 H), 7.75 (ddd, J = 8.0, 5.3, 3.2 Hz, 1 H), 7.64 (ddt, J = 9.0, 7.3, 3.5 Hz, 1 H), 7.58 - 7.43 (m, 2H), 7.28 - 7.16 (m, 2H), 3.92 - 3.76 (m, 2H), 2.71 (t, J = 6.6 Hz, 2H), 2.31 (s, 3H), 2.13 (s, 3H), 1.85 - 1.69 (m, 2H).

¹³C NMR (151 MHz, DMSO-d₆): 5 168.31 , 157.40 (d, = 254.6 Hz), 155.01 , 154.33 (d, 7 = 251.2 Hz), 141.85, 134.86, 130.22, 129.30, 128.32, 128.31 (dd, 7 = 17.5, 6.8 Hz), 126.32, 123.13, 122.97 (dd, 7 = 24.0, 8.9 Hz), 122.65, 119.69 (dd, 7 = 24.6, 8.3 Hz), 117.11 (d, 7 = 27.3 Hz), 46.33, 26.16, 22.42, 21 .57, 16.02.

Example compound 85: Methyl 3-((6-(2-acetamido-4-methylthiazol-5-yl)-3,4- dihvdroquinolin-1(2H)-yl)sulfonyl)benzoate

A/-(4-Methyl-5-(1 ,2,3,4-tetrahydroquinolin-6-yl)thiazol-2-yl)acetamide (150 mg, 522 pmol) was dissolved in 2 mL of pyridine, followed by the addition of 3-nitrobenzenesulfonyl chloride (1 .5 eq., 183 mg, 783 pmol) to the mixture. The reaction mixture was stirred for three hours at room temperature. The solvent was then removed under reduced pressure and the crude product was then purified by silica gel chromatography using a gradient of cyclohexane and EtOAc as eluent. The product was obtained as a yellow solid.

Yield: 224 mg (88%).

MS (ES+) [M+H]⁺ m/e = 486.1 ¹H NMR (300 MHz, DMSO-d₆): 6 12.10 (s, 1 H), 8.21 (dt, J = 7.9, 1.3 Hz, 1 H), 8.05 (t, J = 1.8 Hz, 1 H), 7.92 (ddd, J = 7.9, 1 .9, 1 .1 Hz, 1 H), 7.74 (t, J = 7.8 Hz, 1 H), 7.68 (d, J = 8.6 Hz, 1 H), 7.32 (dd, J = 8.6, 2.2 Hz, 1 H), 7.15 (d, J = 2.2 Hz, 1 H), 3.84 (s, 3H), 3.83 - 3.76 (m, 2H), 2.45 (t, J = 6.6 Hz, 2H), 2.33 (s, 3H), 2.13 (s, 3H), 1.67 - 1.50 (m, 2H).

¹³C NMR (151 MHz, DMSO-d₆): 5 168.29, 164.71 , 155.00, 141.97, 139.40, 134.92, 133.68, 131.29, 131.04, 130.67, 130.50, 129.20, 128.90, 127.03, 126.47, 124.08, 123.09, 66.91 , 52.65, 31.28, 22.41 , 20.96, 16.00.

Example compound 86: A/-(5-(1-((5-Chloro-2-fluorophenyl)sulfonyl)-1 ,2,3,4- tetrahydroquinolin-6-yl)-4-methylthiazol-2-yl)acetamide

A/-(4-Methyl-5-(1 ,2,3,4-tetrahydroquinolin-6-yl)thiazol-2-yl)acetamide (20 mg, 70 pmol) was dissolved in 1 mL of pyridine, followed by the addition of 5-chloro-2-fluorobenzenesulfonyl chloride (1.5 eq., 24 mg, 104 pmol) to the mixture. The reaction mixture was stirred for three hours at room temperature. The solvent was then removed under reduced pressure and the crude product purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1% TFA). The product was obtained after lyophilization as an amorphous white solid.

Yield: 27 mg (81%).

MS (ES+) [M+H]⁺ m/e = 480.1

¹H NMR (300 MHz, DMSO-d₆): 5 12.09 (s, 1 H), 7.93 - 7.78 (m, 2H), 7.54 (dd, = 9.9, 8.7 Hz, 1 H), 7.48 (d, J = 8.5 Hz, 1 H), 7.26 (dd, J = 8.6, 2.2 Hz, 1 H), 7.21 (d, J = 2.2 Hz, 1 H), 3.91 - 3.77 (m, 2H), 2.70 (t, J = 6.6 Hz, 2H), 2.32 (s, 3H), 2.13 (s, 3H), 1 .84 - 1 .69 (m, 2H).

¹³C NMR (151 MHz, DMSO-d₆): 5 168.28, 156.76 (d, = 255.1 Hz), 154.97, 141.88, 136.02 (d, J = 8.8 Hz), 134.76, 130.38, 129.61 , 129.28, 129.02 (d, 7 = 3.2 Hz), 128.56 (d, 7 = 16.6 Hz), 128.42, 126.32, 123.08, 122.83, 119.82 (d, 7 = 23.4 Hz), 46.32, 26.09, 22.41 , 21.51 , 16.02.

Example compound 87: A/-(5-(1-((2-Chloro-5-fluorophenyl)sulfonyl)-1 ,2,3,4- tetrahydroquinolin-6-yl)-4-methylthiazol-2-yl)acetamide

A/-(4-Methyl-5-(1 ,2,3,4-tetrahydroquinolin-6-yl)thiazol-2-yl)acetamide (20 mg, 70 pmol) was dissolved in 1 mL of pyridine, followed by the addition of 2-chloro-5-fluorobenzenesulfonyl chloride (1.5 eq., 24 mg, 104 pmol) to the mixture. The reaction mixture was stirred for three hours at room temperature. The solvent was then removed under reduced pressure and the crude product purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1% TFA). The product was obtained after lyophilization as an amorphous white solid.

Yield: 25 mg (75%).

MS (ES+) [M+H]⁺ m/e = 480.1

¹H NMR (300 MHz, DMSO-d₆): 5 12.09 (s, 1 H), 7.94 (dd, = 8.3, 3.0 Hz, 1 H), 7.78 (dd, = 8.8, 4.8 Hz, 1 H), 7.63 (ddd, J = 8.8, 7.8, 3.0 Hz, 1 H), 7.31 (d, J = 8.4 Hz, 1 H), 7.25 - 7.16 (m, 2H), 3.92 - 3.84 (m, 2H), 2.78 (t, J = 6.6 Hz, 2H), 2.31 (s, 3H), 2.12 (s, 3H), 1 .93 - 1 .74 (m, 2H).

¹³C NMR (151 MHz, DMSO-d₆): 5 168.29, 160.17 (d, = 249.9 Hz), 154.94, 141.82, 139.00 (d, J = 6.5 Hz), 135.38, 134.41 (d, 7 = 8.0 Hz), 130.10, 129.32, 128.08, 126.31 (d, 7 = 3.4 Hz), 126.25, 123.14, 122.23, 122.11 (d, 7 = 22.5 Hz), 118.68 (d, 7 = 26.5 Hz), 46.43, 26.17, 22.42, 21 .88, 16.01.

Example compound 88: A/-(5-(1-(Benzorcfiri,3ldioxol-5-ylsulfonyl)-1 ,2,3,4- tetrahvdroquinolin-6-yl)-4-methylthiazol-2-yl)acetamide

A/-(4-Methyl-5-(1 ,2,3,4-tetrahydroquinolin-6-yl)thiazol-2-yl)acetamide (20 mg, 70 pmol) was dissolved in 1 mL of pyridine, followed by the addition of benzo[d][1 ,3]dioxole-5-sulfonyl chloride (1.5 eq., 23 mg, 104 pmol) to the mixture. The reaction mixture was stirred for three hours at room temperature. The solvent was then removed under reduced pressure and the crude product purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1% TFA). The product was obtained after lyophilization as an amorphous white solid.

Yield: 28 mg (85%).

MS (ES+) [M+H]⁺ m/e = 472.1

¹H NMR (600 MHz, DMSO-d₆): 5 12.06 (s, 1 H), 7.66 (d, 7 = 8.6 Hz, 1 H), 7.27 (dd, 7 = 8.6, 2.3 Hz, 1 H), 7.22 (dd, 7 = 8.2, 1 .9 Hz, 1 H), 7.16 (d, 7 = 2.2 Hz, 1 H), 7.09 (d, 7 = 1 .8 Hz, 1 H), 7.05 (d, 7 = 8.2 Hz, 1 H), 6.15 (s, 2H), 3.78 - 3.75 (m, 2H), 2.56 (t, 7 = 6.6 Hz, 2H), 2.33 (s, 3H), 2.13 (s, 3H), 1.68 - 1.58 (m, 2H).

¹³C NMR (151 MHz, DMSO-d₆): 5 168.31 , 154.94, 151.44, 147.99, 141.85, 135.41 , 132.06, 130.74, 129.17, 128.30, 126.29, 123.70, 123.21 , 122.74, 108.54, 106.58, 102.68, 46.28, 26.16, 22.43, 21.01 , 16.09. Example compound 89: A/-(4-Methyl-5-(1-((1-methyl-1H-indol-5-yl)sulfonyl)-1 ,2,3,4- tetrahydroquinolin-6-yl)thiazol-2-yl)acetamide

/

A/-(4-Methyl-5-(1 ,2,3,4-tetrahydroquinolin-6-yl)thiazol-2-yl)acetamide (20 mg, 70 pmol) was dissolved in 1 mL of pyridine, followed by the addition of 1-methyl-1/7-indole-5-sulfonyl chloride (1.5 eq., 24 mg, 104 pmol) to the mixture. The reaction mixture was stirred for three hours at room temperature. The solvent was then removed under reduced pressure and the crude product purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1% TFA). The product was obtained after lyophilization as an amorphous white solid.

Yield: 18 mg (54%).

MS (ES+) [M+H]⁺ m/e = 481.1

¹H NMR (300 MHz, DMSO-d₆): 5 12.08 (s, 1 H), 7.98 (d, J = 1.8 Hz, 1 H), 7.75 (d, = 8.6 Hz, 1 H), 7.58 (d, J = 8.7 Hz, 1 H), 7.51 (d, J = 3.1 Hz, 1 H), 7.34 (dd, J = 8.7, 1 .9 Hz, 1 H), 7.27 (dd, J = 8.7, 2.3 Hz, 1 H), 7.11 (d, J = 2.3 Hz, 1 H), 6.61 (dd, J = 3.2, 0.8 Hz, 1 H), 3.85 - 3.75 (m, 5H), 2.46 (t, J = 6.5 Hz, 2H), 2.32 (s, 3H), 2.13 (s, 3H), 1 .60 - 1 .44 (m, 2H).

¹³C NMR (151 MHz, DMSO-d₆): 5 168.27, 154.87, 141.72, 137.99, 135.87, 132.44, 130.44, 129.34, 129.10, 127.95, 127.21 , 126.19, 123.73, 123.28, 120.66, 119.03, 110.54, 102.16, 46.18, 32.78, 26.18, 22.42, 20.80, 16.07.

Example compound 90: A/-(5-(1-((2,3-Dihvdro-1H-inden-5-yl)sulfonyl)-1 ,2,3,4- tetrahydroquinolin-6-yl)-4-methylthiazol-2-yl)acetamide

A/-(4-Methyl-5-(1 ,2,3,4-tetrahydroquinolin-6-yl)thiazol-2-yl)acetamide (20 mg, 70 pmol) was dissolved in 1 mL of pyridine, followed by the addition of 2,3-dihydro-1/7-indene-5-sulfonyl chloride (1.5 eq., 23 mg, 104 pmol) to the mixture. The reaction mixture was stirred for three hours at room temperature. The solvent was then removed under reduced pressure and the crude product purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1% TFA). The product was obtained after lyophilization as an amorphous white solid.

Yield: 13 mg (40%). MS (ES+) [M+H]⁺ m/e = 468.1

¹H NMR (300 MHz, DMSO-d₆): 6 12.08 (s, 1 H), 7.66 (d, = 8.6 Hz, 1 H), 7.51 (d, J = 1.7 Hz, 1 H), 7.46 - 7.34 (m, 2H), 7.26 (dd, J = 8.6, 2.3 Hz, 1 H), 7.15 (d, J = 2.2 Hz, 1 H), 3.82 - 3.72 (m, 2H), 2.88 (q, J = 7.9 Hz, 4H), 2.57 - 2.51 (m, 2H), 2.32 (s, 3H), 2.13 (s, 3H), 2.07 - 1 .96 (m, 2H), 1 .72 - 1.53 (m, 2H).

¹³C NMR (151 MHz, DMSO-d₆): 5 168.38, 154.96, 150.09, 145.41 , 141.85, 136.98, 135.59, 130.60, 129.23, 128.16, 126.33, 125.12, 125.10, 123.49, 123.28, 122.60, 46.33, 32.33, 32.08, 26.21 , 24.87, 22.47, 21 .09, 16.08.

Example compound 91 : W-(5-(1-((2,3-Dihvdrobenzorbiri,4ldioxin-6-yl)sulfonyl)-1 ,2,3,4- tetrahydroquinolin-6-yl)-4-methylthiazol-2-yl)acetamide

A/-(4-Methyl-5-(1 ,2,3,4-tetrahydroquinolin-6-yl)thiazol-2-yl)acetamide (20 mg, 70 pmol) was dissolved in 1 mL of pyridine, followed by the addition of 2,3-dihydrobenzo[b][1 ,4]dioxine-6- sulfonyl chloride (1.5 eq., 24 mg, 104 pmol) to the mixture. The reaction mixture was stirred for three hours at room temperature. The solvent was then removed under reduced pressure and the crude product purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1% TFA). The product was obtained after lyophilization as an amorphous white solid.

Yield: 30 mg (89%).

MS (ES+) [M+H]⁺ m/e = 486.1

¹H NMR (300 MHz, DMSO-d₆): 5 12.09 (s, 1 H), 7.66 (d, = 8.6 Hz, 1 H), 7.27 (dd, = 8.6, 2.3 Hz, 1 H), 7.18 - 7.06 (m, 3H), 7.01 (d, = 8.5 Hz, 1 H), 4.28 (ddt, J = 8.5, 6.6, 3.1 Hz, 4H), 3.81 - 3.70 (m, 2H), 2.62 - 2.52 (m, 2H), 2.33 (s, 3H), 2.13 (s, 3H), 1.71 - 1.50 (m, 2H).

¹³C NMR (151 MHz, DMSO-d₆): 5 168.31 , 154.93, 147.60, 143.42, 141.84, 135.48, 131.21 , 130.66, 129.18, 128.25, 126.27, 123.63, 123.21 , 120.43, 117.87, 115.76, 64.42, 64.04, 46.27, 26.17, 22.43, 20.96, 16.08.

Example compound 92: /V-(4-Methyl-5-(1-((5,6,7,8-tetrahvdronaphthalen-2-yl)sulfonyl)- 1 ,2,3,4-tetrahydroquinolin-6-yl)thiazol-2-yl)acetamide

A/-(4-Methyl-5-(1 ,2,3,4-tetrahydroquinolin-6-yl)thiazol-2-yl)acetamide (20 mg, 70 pmol) was dissolved in 1 mL of pyridine, followed by the addition of 5,6,7, 8-tetrahydronaphthalene-2-sulfonyl chloride (1.5 eq., 24 mg, 104 pmol) to the mixture. The reaction mixture was stirred for three hours at room temperature. The solvent was then removed under reduced pressure and the crude product purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1% TFA). The product was obtained after lyophilization as an amorphous white solid.

Yield: 29 mg (87%).

MS (ES+) [M+H]⁺ m/e = 482.1

¹H NMR (600 MHz, DMSO-d₆): 5 12.06 (s, 1 H), 7.66 (d, = 8.6 Hz, 1 H), 7.36 - 7.31 (m, 2H), 7.26 (dd, = 8.6, 2.3 Hz, 1 H), 7.22 (d, = 8.0 Hz, 1 H), 7.16 (d, J = 2.2 Hz, 1 H), 3.80 - 3.74 (m, 2H), 2.78 - 2.68 (m, 4H), 2.56 - 2.51 (m, 3H), 2.32 (s, 3H), 2.13 (s, 3H), 1.71 (p, J = 3.2 Hz, 4H), 1.68 - 1.62 (m, 2H).

¹³C NMR (151 MHz, DMSO-d₆): 5 168.28, 154.92, 142.85, 141.77, 138.13, 135.99, 135.53, 130.58, 129.93, 129.16, 128.13, 127.19, 126.28, 123.61 , 123.44, 123.22, 46.28, 28.70, 28.56, 26.15, 22.41 , 22.10, 22.02, 21.04, 16.03.

Example compound 93: A/-(5-(1-(Benzofuran-2-ylsulfonyl)-1 ,2,3,4-tetrahydroquinolin-6-yl)- 4-methylthiazol-2-yl)acetamide

A/-(4-Methyl-5-(1 ,2,3,4-tetrahydroquinolin-6-yl)thiazol-2-yl)acetamide (20 mg, 70 pmol) was dissolved in 1 mL of pyridine, followed by the addition of benzofuran-2-sulfonyl chloride (1 .5 eq., 23 mg, 104 pmol) to the mixture. The reaction mixture was stirred for three hours at room temperature. The solvent was then removed under reduced pressure and the crude product purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1% TFA). The product was obtained after lyophilization as an amorphous white solid.

Yield: 22 mg (68%).

MS (ES+) [M+H]⁺ m/e = 468.0

¹H NMR (300 MHz, DMSO-d₆): 5 12.10 (s, 1 H), 7.83 - 7.62 (m, 4H), 7.53 (ddd, = 8.5, 7.2, 1.4 Hz, 1 H), 7.44 - 7.36 (m, 1 H), 7.30 (dd, J = 8.6, 2.3 Hz, 1 H), 7.20 (d, J = 2.2 Hz, 1 H), 3.93 - 3.82 (m, 2H), 2.65 (t, J = 6.7 Hz, 2H), 2.32 (s, 3H), 2.13 (s, 3H), 1 .85 - 1 .68 (m, 2H).

¹³C NMR (151 MHz, DMSO-d₆): 5 168.29, 155.10, 155.01 , 148.72, 141.96, 134.67, 131.02, 129.16, 128.85, 128.32, 126.33, 125.57, 124.59, 123.55, 123.43, 123.05, 113.93, 112.19, 46.53, 25.91 , 22.41 , 21.63, 16.07. Example compound 94: A/-(5-(1-(Benzorblthiophen-3-ylsulfonyl)-1 ,2,3,4-tetrahydroquinolin- 6-yl)-4-methylthiazol-2-yl)acetamide

A/-(4-Methyl-5-(1 ,2,3,4-tetrahydroquinolin-6-yl)thiazol-2-yl)acetamide (20 mg, 70 pmol) was dissolved in 1 mL of pyridine, followed by the addition of benzo[b]thiophene-3-sulfonyl chloride (1.5 eq., 24 mg, 104 pmol) to the mixture. The reaction mixture was stirred for three hours at room temperature. The solvent was then removed under reduced pressure and the crude product purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1% TFA). The product was obtained after lyophilization as an amorphous white solid.

Yield: 27 mg (80%).

MS (ES+) [M+H]⁺ m/e = 484.1

¹H NMR (600 MHz, DMSO-d₆): 5 12.08 (s, 1 H), 8.66 (s, 1 H), 8.09 (d, J = 8.1 Hz, 1 H), 7.72 (d, J = 8.5 Hz, 1 H), 7.49 (d, J = 8.2 Hz, 1 H), 7.42 (ddd, J = 8.3, 7.1 , 1 .2 Hz, 1 H), 7.33 (dd, J = 8.5, 2.3 Hz, 1 H), 7.25 (ddd, J = 8.2, 7.0, 1.1 Hz, 1 H), 7.05 (d, J = 2.2 Hz, 1 H), 3.93 - 3.72 (m, 2H), 2.36 - 2.29 (m, 5H), 2.13 (s, 3H), 1.57 - 1.50 (m, 2H).

¹³C NMR (151 MHz, DMSO-d₆): 5 168.28, 155.01 , 141.91 , 139.81 , 137.04, 135.05, 133.21 , 132.26, 131.67, 128.96, 128.89, 126.32, 125.61 , 125.24, 124.84, 123.42, 123.19, 122.58, 46.04, 25.79, 22.41 , 21.01 , 15.96.

Example compound 95: A/-(5-(1-(Benzofuran-6-ylsulfonyl)-1 ,2,3,4-tetrahydroquinolin-6-yl)- 4-methylthiazol-2-yl)acetamide

A/-(4-Methyl-5-(1 ,2,3,4-tetrahydroquinolin-6-yl)thiazol-2-yl)acetamide (20 mg, 70 pmol) was dissolved in 1 mL of pyridine, followed by the addition of benzofuran-6-sulfonyl chloride (1 .5 eq., 24 mg, 104 pmol) to the mixture. The reaction mixture was stirred for three hours at room temperature. The solvent was then removed under reduced pressure and the crude product purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1% TFA). The product was obtained after lyophilization as an amorphous white solid.

Yield: 28 mg (86%).

MS (ES+) [M+H]⁺ m/e = 468.1 ¹H NMR (300 MHz, DMSO-d₆): 6 12.09 (s, 1 H), 8.18 (d, J = 2.2 Hz, 1 H), 8.09 (d, J = 1.9 Hz, 1 H), 7.78 (d, J = 9.0 Hz, 1 H), 7.71 (d, J = 8.6 Hz, 1 H), 7.56 (dd, J = 8.7, 2.0 Hz, 1 H), 7.28 (dd, J = 8.6, 2.3 Hz, 1 H), 7.17 - 7.08 (m, 2H), 3.87 - 3.75 (m, 2H), 2.47 (t, = 6.6 Hz, 2H), 2.32 (s, 3H), 2.13 (s, 3H), 1.64 - 1.51 (m, 2H).

¹³C NMR (151 MHz, DMSO-d₆): 5 168.27, 156.15, 154.92, 148.51 , 141.82, 135.44, 133.88, 130.71 , 129.14, 128.31 , 127.75, 126.28, 123.76, 123.18, 122.96, 121.27, 112.41 , 107.42, 46.27, 26.04, 22.41 , 20.95, 16.07.

Example compound 96: A/-(5-(1-((2,6-Dichlorophenyl)sulfonyl)-1 ,2,3,4-tetrahydroquinolin-6- yl)-4-methylthiazol-2-yl)acetamide

A/-(4-Methyl-5-(1 ,2,3,4-tetrahydroquinolin-6-yl)thiazol-2-yl)acetamide (20 mg, 70 pmol) was dissolved in 1 mL of pyridine, followed by the addition of 2,6-dichlorobenzenesulfonyl chloride (1.5 eq., 26 mg, 104 pmol) to the mixture. The reaction mixture was stirred for three hours at room temperature. The solvent was then removed under reduced pressure and the crude product purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1% TFA). The product was obtained after lyophilization as an amorphous white solid.

Yield: 16 mg (46%).

MS (ES+) [M+H]⁺ m/e = 496.0

¹H NMR (600 MHz, DMSO-d₆): 5 12.06 (s, 1 H), 7.71 (d, = 8.0 Hz, 2H), 7.63 (dd, J = 8.7, 7.4 Hz, 1 H), 7.23 (d, J = 2.0 Hz, 1 H), 7.20 - 7.15 (m, 2H), 2.81 (t, = 6.6 Hz, 2H), 2.30 (s, 3H), 2.12 (s, 3H), 1 .92 - 1 .85 (m, 2H). 2H hidden behind DMSO-D6 peak.

¹³C NMR (151 MHz, DMSO-d₆): 5 168.29, 154.93, 141.81 , 135.58, 135.44, 134.43, 134.33, 132.31 , 129.80, 129.43, 127.91 , 126.12, 123.13, 121.45, 46.18, 26.15, 22.42, 21.82, 16.02.

Example compound 97: A/-((5-(1-((2,6-Difluorophenyl)sulfonyl)-1 ,2,3,4-tetrahydroquinolin-6- yl)-4-methylthiazol-2-yl)acetamide

A/-(4-Methyl-5-(1 ,2,3,4-tetrahydroquinolin-6-yl)thiazol-2-yl)acetamide (30 mg, 104 pmol) was dissolved in 1 mL of pyridine, followed by the addition of 2,6-difluorobenzenesulfonyl chloride (1.5 eq., 33 mg, 157 pmol) to the mixture. The reaction mixture was stirred for three hours at room temperature. The solvent was then removed under reduced pressure and the crude product purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1% TFA). The product was obtained after lyophilization as an amorphous white solid.

Yield: 17 mg (35%).

MS (ES+) [M+H]⁺ m/e = 464.0

¹H NMR (600 MHz, DMSO-d₆): 5 12.06 (s, 1 H), 7.77 (tt, J = 8.5, 6.0 Hz, 1 H), 7.46 (d, = 8.5 Hz, 1 H), 7.33 (t, J = 9.1 Hz, 2H), 7.26 - 7.19 (m, 2H), 3.92 - 3.84 (m, 2H), 2.74 (t, J = 6.6 Hz, 2H), 2.31 (s, 3H), 2.13 (s, 3H), 1 .89 - 1 .80 (m, 2H).

¹³C NMR (151 MHz, DMSO-d₆): 5 168.27, 158.78 (dd, = 257.3, 3.9 Hz), 154.94, 141.86, 136.57 (t, J = 11.1 Hz), 134.85, 129.76, 129.39, 128.09, 126.28, 123.06, 121.60, 116.97 (t, J = 16.5 Hz), 113.83 (dd, J = 23.3, 3.5 Hz), 46.34, 26.25, 22.41 , 21 .47, 16.03.

Example compound 98: A/-(4-Methyl-5-(1-((3-oxo-3,4-dihydro-2H-benzorbiri,4lthiazin-6- yl)sulfonyl)-1 ,2,3,4-tetrahydroquinolin-6-yl)thiazol-2-yl)acetamide

A/-(4-Methyl-5-(1 ,2,3,4-tetrahydroquinolin-6-yl)thiazol-2-yl)acetamide (20 mg, 70 pmol) was dissolved in 1 mL of pyridine, followed by the addition of 3-oxo-3,4-dihydro-2/7- benzo[b][1 ,4]thiazine-6-sulfonyl chloride (1.5 eq., 28 mg, 104 pmol) to the mixture. The reaction mixture was stirred for three hours at room temperature. The solvent was then removed under reduced pressure and the crude product purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1% TFA). The product was obtained after lyophilization as an amorphous white solid.

Yield: 15 mg (42%).

MS (ES+) [M+H]⁺ m/e = 515.0

¹H NMR (300 MHz, DMSO-d₆): 5 12.09 (s, 1 H), 10.79 (s, 1 H), 7.62 (d, 7 = 8.6 Hz, 1 H), 7.50 (d, 7 = 8.2 Hz, 1 H), 7.34 (d, 7 = 2.0 Hz, 1 H), 7.27 (dd, 7 = 8.6, 2.3 Hz, 1 H), 7.22 - 7.14 (m, 2H), 3.82 - 3.71 (m, 2H), 3.55 (s, 2H), 2.59 (t, 7 = 6.6 Hz, 2H), 2.33 (s, 3H), 2.13 (s, 3H), 1.77 - 1.60 (m, 2H).

¹³C NMR (151 MHz, DMSO-d₆): 5 168.27, 164.72, 154.92, 141.86, 137.85, 137.14, 135.22, 130.60, 129.23, 128.35, 128.09, 126.31 , 125.70, 123.37, 123.17, 120.58, 114.72, 46.34, 28.13, 26.10, 22.41 , 21.14, 16.11. Example compound 99: A/-(4-Methyl-5-(1-((2-oxo-2,3-dihvdrobenzorcfloxazol-5-yl)sulfonyl)- 1,2,3,4-tetrahydroquinolin-6-yl)thiazol-2-yl)acetamide

A/-(4-Methyl-5-(1 ,2,3,4-tetrahydroquinolin-6-yl)thiazol-2-yl)acetamide (20 mg, 70 pmol) was dissolved in 1 mL of pyridine, followed by the addition of 2-oxo-2,3-dihydrobenzo[c/]oxazole-5- sulfonyl chloride (1.5 eq., 24 mg, 104 pmol) to the mixture. The reaction mixture was stirred for three hours at room temperature. The solvent was then removed under reduced pressure and the crude product purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1% TFA). The product was obtained after lyophilization as an amorphous white solid.

Yield: 17 mg (50%).

MS (ES+) [M+H]⁺ m/e = 485.0

¹H NMR (300 MHz, DMSO-d₆): 5 12.10 (s, 1 H), 11.99 (s, 1 H), 7.69 (d, J = 8.6 Hz, 1 H), 7.50 - 7.37 (m, 2H), 7.29 (dd, J = 8.6, 2.3 Hz, 1 H), 7.18 (dd, J = 6.3, 2.0 Hz, 2H), 3.87 - 3.72 (m, 2H), 2.34 (s, 3H), 2.13 (s, 3H), 1 .67 - 1 .48 (m, 2H).

¹³C NMR (151 MHz, DMSO-d₆): 5 168.30, 154.96, 153.87, 146.48, 141.91 , 135.25, 134.28, 131.20, 130.99, 129.17, 128.57, 126.30, 123.95, 123.15, 121.56, 110.14, 107.84, 46.30, 26.02, 22.42, 20.91 , 16.13.

Example compound 100: A/-(4-Methyl-5-(1-((4-nitrophenyl)sulfonyl)-1 ,2,3,4- tetrahydroquinolin-6-yl)thiazol-2-yl)acetamide

A/-(4-Methyl-5-(1 ,2,3,4-tetrahydroquinolin-6-yl)thiazol-2-yl)acetamide (250 mg, 897 pmol) was dissolved in 3 mL of pyridine, followed by the addition of 4-nitrobenzenesulfonyl chloride (1.5 eq., 289 mg, 1.30 mmol) to the mixture. The reaction mixture was stirred for three hours at room temperature. The solvent was then removed under reduced pressure and the crude product was then purified by silica gel chromatography using a gradient of cyclohexane and EtOAc as eluent. The product was obtained as a yellow solid.

Yield: 116 mg (28%). MS (ES+) [M+H]⁺ m/e = 473.0

¹H NMR (300 MHz, DMSO-d₆): 5 12.11 (s, 1 H), 8.41 - 8.33 (m, 2H), 7.98 - 7.87 (m, 2H), 7.67 (d, J = 8.6 Hz, 1 H), 7.32 (dd, J = 8.6, 2.3 Hz, 1 H), 7.20 (d, J = 2.2 Hz, 1 H), 3.89 - 3.78 (m, 2H), 2.55 (t, J = 6.5 Hz, 2H), 2.34 (s, 3H), 2.14 (s, 3H), 1 .70 - 1 .60 (m, 2H).

¹³C NMR (151 MHz, DMSO-d₆): 5 168.34, 155.03, 150.11 , 144.18, 142.05, 134.70, 131.15, 129.29, 128.97, 128.42, 126.47, 124.85, 123.78, 123.06, 46.52, 25.91 , 22.43, 21.19, 16.13.

Example compound 101 : 3-((6-(2-Acetamido-4-methylthiazol-5-yl)-3,4-dihydroquinolin- 1(2/7)-yl)sulfonyl)benzoic acid

Methyl 3-((6-(2-acetamido-4-methylthiazol-5-yl)-3,4-dihydroquinolin-1 (2/7)-yl)sulfonyl)benzoate (150 mg, 309 pmol) was dissolved in 1 mL of THF and 1 mL of water. Afterwards, lithium hydroxide monohydrate (2 eq., 26 mg, 618 pmol) was added to the solution. The reaction was stirred at room temperature for 16 hours. The mixture was then poured in an separatory funnel containing DCM and a 1 M solution HCI in water. The water phase was extracted 3 times with DCM. Then, the combined organic phases were dried over Na2SC>4 and concentrated under reduced pressure. The crude product was then purified by silica gel chromatography using a gradient of cyclohexane and EtOAc as eluent. The product was obtained as an amorphous white solid.

Yield: 112 mg (77%).

MS (ES+) [M+H]⁺ m/e = 472.0

¹H NMR (300 MHz, DMSO-d₆): 5 12.09 (s, 1 H), 8.19 (dt, J = 7.7, 1.4 Hz, 1 H), 8.05 (t, J = 1.8 Hz, 1 H), 7.90 (ddd, J = 7.9, 2.0, 1.2 Hz, 1 H), 7.75 - 7.64 (m, 2H), 7.31 (dd, = 8.6, 2.3 Hz, 1 H), 7.15 (d, J = 2.2 Hz, 1 H), 2.48 - 2.42 (m, 2H), 2.32 (s, 3H), 2.13 (s, 3H), 1 .59 (p, J = 6.5 Hz, 2H). 2H hidden behind the water peak.

¹³C NMR (75 MHz, DMSO-d₆): 6 168.35, 165.78, 155.03, 142.04, 139.29, 135.00, 133.89, 131.94, 131.25, 130.74, 130.36, 129.26, 128.88, 127.24, 126.51 , 124.11 , 123.14, 46.49, 25.91 , 22.47, 20.95, 16.09.

A/-(5-(1-((3-Aminophenyl)sulfonyl)-1 ,2,3,4-tetrahydroquinolin-6-yl)-4-methylthiazol-2-yl)acetamide (20 mg, 45 pmol) was dissolved in 1 mL pf pyridine. Afterwards, acryloyl chloride (3 eq., 13 mg, 136 pmol) was dropwise added to the solution and stirred for 30 minutes at room temperature. The solvent was then removed under reduced pressure and the crude product purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1% TFA). The product was obtained after lyophilization as an amorphous white solid.

Yield: 7 mg (31%).

MS (ES+) [M+H]⁺ m/e = 485.1

¹H NMR (600 MHz, CDCI₃): 5 7.98 (s, 1 H), 7.88 (d, J = 8.5 Hz, 1 H), 7.78 (dt, J = 5.4, 2.6 Hz, 1 H), 7.46 - 7.41 (m, 2H), 7.37 (s, 1 H), 7.22 (dd, J = 8.6, 2.3 Hz, 1 H), 7.06 (d, J = 2.2 Hz, 1 H), 6.44 (d, J = 17.2 Hz, 1 H), 6.22 (dd, J = 16.8, 10.3 Hz, 1 H), 5.83 (d, J = 9.9 Hz, 1 H), 3.92 - 3.86 (m, 2H), 2.61 (t, J = 6.7 Hz, 2H), 2.48 (s, 3H), 2.40 (s, 3H), 2.18 (s, 1 H), 1.83 - 1.76 (m, 2H).

¹³C NMR (151 MHz, CDCI3): 5 169.65, 163.68, 160.08, 140.45, 138.75, 137.99, 132.48, 131.29, 130.57, 130.11 , 129.87, 129.25, 127.24, 125.13, 124.91 , 124.80, 124.26, 122.87, 118.43, 46.94, 27.08, 23.16, 21.74, 12.97.

etamide

A/-(5-(1-((3-Aminophenyl)sulfonyl)-1 ,2,3,4-tetrahydroquinolin-6-yl)-4-methylthiazol-2-yl)acetamide

(20 mg, 45 pmol) was dissolved in 1 mL pf pyridine. Afterwards, 2-chloroacetyl chloride (3 eq., 15 mg, 136 pmol) was dropwise added to the solution and stirred for 30 minutes at room temperature. The solvent was then removed under reduced pressure and the crude product purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1% TFA). The product was obtained after lyophilization as an amorphous white solid.

Yield: 8 mg (34%).

MS (ES+) [M+H]⁺ m/e = 519.0 ¹H NMR (600 MHz, DMSO-d₆): 6 12.06 (s, 1 H), 10.61 (s, 2H), 8.07 (t, J = 2.0 Hz, 1 H), 7.80 (ddd, J = 8.2, 2.2, 0.9 Hz, 1 H), 7.64 (d, J = 8.6 Hz, 1 H), 7.53 (t, J = 8.0 Hz, 1 H), 7.35 (ddd, J = 7.8, 1 .9, 1 .0 Hz, 1 H), 7.27 (dd, J = 8.6, 2.3 Hz, 1 H), 7.16 (d, J = 2.2 Hz, 1 H), 4.25 (s, 2H), 3.82 - 3.77 (m, 2H), 2.54 (t, J = 6.6 Hz, 2H), 2.33 (s, 3H), 2.13 (s, 3H), 1.70 - 1.58 (m, 2H).

¹³C NMR (151 MHz, DMSO-d₆): 5 168.27, 165.15, 154.93, 141.89, 139.50, 139.30, 135.24, 130.71 , 130.20, 129.22, 128.42, 126.35, 123.54 (2C), 123.17, 121.82, 117.08, 46.36, 43.42, 26.02, 22.42, 21.04, 16.06.

Example compound 104: Tert-butyl 7-(2-acetamido-4-methylthiazol-5-yl)-4- (phenylsulfonyl)-3,4-dihydroquinoxaline-1 (2/7)-carboxylate

Step 1 : Tert-butyl 7-bromo-4-(phenylsulfonyl)-3,4-dihydroquinoxaline-1(2H)-carboxylate

6-Bromo-1-(phenylsulfonyl)-1 ,2,3,4-tetrahydroquinoxaline (370 mg, 1.05 mmol) was dissolved in dry DCM (5 mL). Afterwards, di-fert-butyl dicarbonate (2 eq., 457 mg, 2.09 mmol) and N,N- dimethylpyridin-4-amine (0.2 eq., 26 mg, 209 pmol) were added to the mixture. The reaction mixture was stirred at room temperature for 16 hours. Upon completion of the reaction, the crude mixture was poured in a separatory funnel, containing DCM and water. The water phase was extracted 3 times with DCM. Then, the combined organic phases were 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 eluent. The product was obtained as a yellow oil.

Yield: 220 mg (46%).

MS (ES+) [M+Na]⁺ m/e = 475.0, 477.0

¹H NMR (300 MHz, CDCI₃): 6 7.90 (d, J = 2.2 Hz, 1 H), 7.63 - 7.48 (m, 4H), 7.46 - 7.37 (m, 2H), 7.19 (dd, J = 8.7, 2.3 Hz, 1 H), 3.91 - 3.77 (m, 2H), 3.48 - 3.38 (m, 2H), 1 .38 (s, 9H).

¹³C NMR (75 MHz, CDCI₃): 5 151.73, 138.70, 134.06, 133.20, 129.02, 127.85, 126.96, 126.83, 126.44, 126.35, 119.10, 81.91 , 45.95, 43.69, 27.97.

Step 2: Tert-butyl 7-(2-acetamido-4-methylthiazol-5-yl)-4-(phenylsulfonyl)-3,4- dihydroquinoxa line-1 (2H) -carboxylate

Tert-butyl 7-bromo-4-(phenylsulfonyl)-3,4-dihydroquinoxaline-1 (2/7)-carboxylate (135 mg, 298 pmol), A/-(4-methylthiazol-2-yl)acetamide (1.2 eq., 56 mg, 357 pmol), tri-tert-butylphosphonium tetrafluoroborate (0.2 eq., 17 mg, 60 pmol), Pd(OAc)2, (0.1 eq., 7 mg, 30 pmol) and CS2CO3 (3 eq., 291 mg, 893 pmol) were suspended in 2 mL of DMF. The suspension was sonicated for 5 minutes, flushed with nitrogen, heated up to 110 °C and stirred overnight. The solvent was then removed under reduced pressure and the crude product was then purified by silica gel chromatography using a gradient of cyclohexane and EtOAc as eluent. The product was obtained as a yellow oil.

Yield: 70 mg (44%).

MS (ES+) [M+H]⁺ m/e = 529.1

¹H NMR (300 MHz, DMSO-d₆): 5 12.12 (s, 1 H), 7.75 - 7.50 (m, 7H), 7.22 (dd, J = 8.5, 2.1 Hz, 1 H), 3.86 (t, J = 6.0 Hz, 2H), 3.44 (t, J = 6.0 Hz, 2H), 2.36 (s, 3H), 2.13 (s, 3H), 1 .34 (s, 9H).

¹³C NMR (75 MHz, DMSO-d₆): 5 168.40, 159.22, 155.15, 151.68, 142.28, 138.30, 133.79, 133.01 , 129.55, 127.68, 126.75, 125.30, 123.49, 123.36, 123.12, 54.95, 46.05, 43.69, 27.80, 22.45, 16.21.

Example compound 105: A/-(4-Methyl-5-(1-(phenylsulfonyl)-1,2,3,4-tetrahydroquinoxalin-6- yl)thiazol-2-yl)acetamide

Tert-butyl 7-(2-acetamido-4-methylthiazol-5-yl)-4-(phenylsulfonyl)-3,4-dihydroquinoxaline-1 (2H)- carboxylate (70 mg, 132 pmol) was dissolved in 1 mL of DCM and 0.1 mL of TFA. The solution was stirred for 3 hours at room temperature. The solvent was then removed under reduced pressure and the crude product purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1% TFA). The lyophilized powder was poured in an separatory funnel containing DCM and a saturated solution of Na2COs in water. The water phase was extracted 3 times with DCM. Then, the combined organic phases were dried over Na2SO4 and concentrated under reduced pressure. The product was obtained as an amorphous white solid.

Yield: 55 mg (97%).

MS (ES+) [M+H]⁺ m/e = 429.1

¹H NMR (300 MHz, CD₃OD): 5 7.66 - 7.55 (m, 4H), 7.54 - 7.42 (m, 2H), 6.65 (dd, J = 8.4, 2.1 Hz, 1 H), 6.57 (d, J = 2.0 Hz, 1 H), 3.81 - 3.69 (m, 2H), 3.35 (s, 1 H), 2.92 - 2.77 (m, 2H), 2.34 (s, 3H), 2.21 (s, 3H).

¹³C NMR (75 MHz, CD₃OD): 5 170.64, 156.89, 142.86, 140.79, 140.36, 134.24, 131.89, 130.31 , 128.42, 127.33, 126.77, 121.56, 117.43, 115.69, 44.84, 39.22, 22.56, 16.16.

Example compound 106: A/-(4-Methyl-5-(4-methyl-1-(phenylsulfonyl)-1 ,2,3,4- tetrahydroquinoxalin-6-yl)thiazol-2-yl)acetamide

A/-(4-Methyl-5-(1 -(phenylsulfonyl)-l ,2,3,4-tetrahydroquinoxalin-6-yl)thiazol-2-yl)acetamide (20 mg, 47 pmol) was dissolved in 1 mL of MeOH and 0.1 mL of acetic acid. Afterwards, and formaldehyde 37% in water (3 eq., 11 mg, 140 pmol) was added to the solution and stirred for 30 minutes at room temperature. NaBHsCN (5 eq., 15 mg, 233 pmol) was also added tot he stirring solution. After one hour at room temperature, 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 lyophilized powder was poured in an separatory funnel containing DCM and a saturated solution of Na2CO₃ in water. The water phase was extracted 3 times with DCM. Then, the combined organic phases were dried over Na2SC>4 and concentrated under reduced pressure. The product was obtained as an amorphous white solid.

Yield: 11 mg (53%).

MS (ES+) [M+H]⁺ m/e = 443.0.

¹H NMR (300 MHz, CDCI₃): 5 10.47 (s, 1 H), 7.64 (d, J = 8.3 Hz, 1 H), 7.61 - 7.49 (m, 3H), 7.48 - 7.37 (m, 2H), 6.78 (dd, J = 8.3, 2.0 Hz, 1 H), 6.59 (d, J = 1 .9 Hz, 1 H), 3.91 - 3.78 (m, 2H), 2.85 (t, J = 5.4 Hz, 2H), 2.66 (s, 3H), 2.44 (s, 3H), 2.26 (s, 3H).

¹³C NMR (75 MHz, CDCI₃): 5 167.80, 155.99, 141.41 , 140.18, 139.47, 133.04, 130.85, 129.01 , 127.38, 126.46, 126.26, 121.87, 117.11 , 111.82, 47.15, 43.88, 38.22, 23.35, 16.39.

Example compound 107: A/-(5-(5-(Phenylsulfonyl)-5,6,7,8-tetrahvdro-1,5-naphthyridin-2- yl)thiazol-2-yl)acetamide

6-Bromo-1-(phenylsulfonyl)-1 ,2,3,4-tetrahydro-1 ,5-naphthyridine (80 mg, 226 pmol), A/-(thiazol-2- yl)acetamide (1.2 eq., 39 mg, 272 pmol), tri-tert-butylphosphonium tetrafluoroborate (0.2 eq., 13 mg, 45 pmol), Pd(OAc)2, (0.1 eq., 5.0 mg, 23 pmol) and CS2CO3 (3 eq., 221 mg, 679 pmol) were suspended in 1 mL of DMF. The suspension was sonicated for 5 minutes, flushed with nitrogen, heated up 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 obtained after lyophilization as an amorphous white solid.

Yield: 43 mg (46%).

MS (ES+) [M+H]⁺ m/e = 415.0.

¹H NMR (300 MHz, DMSO-d₆): 5 12.18 (s, 1 H), 8.08 (s, 1 H), 8.01 (d, J = 8.7 Hz, 1 H), 7.81 - 7.64 (m, 4H), 7.63 - 7.54 (m, 2H), 3.83 - 3.76 (m, 2H), 2.60 (t, J = 6.7 Hz, 2H), 2.16 (s, 3H), 1 .65 - 1.47 (m, 2H).

¹³C NMR (75 MHz, DMSO-d₆): 6 169.02, 159.63, 150.07, 147.30, 138.76, 136.42, 134.23, 132.14, 132.00, 131.70, 130.23, 127.34, 117.38, 46.33, 29.82, 22.98, 20.52.

Example compound 108: A/-(5-(1-(Phenylsulfonyl)-1,2,3,4-tetrahydroquinolin-6-yl)-1,3,4- thiadiazol-2-yl)acetamide

Step 1 : A/-(d ,3,4-Thiadiazol-2-yl)acetamide

1 ,3,4-Thiadiazol-2-amine (100 mg, 999 pmol) was dissolved in 2 mL of dry DCM. Aferwards, acetic anhydride (1.1 eq., 112 mg, 1.1 mmol) and triethylamine (1.1 eq., 111 mg, 1.1 mmol) were slowly added to the solution and the reaction mixture was stirred at room temperature for one hour. Upon completion of the reaction, the crude mixture was poured in a separatory funnel, containing DCM and water. The water phase was extracted 3 times with DCM. Then, the combined organic phases were dried over Na2SC>4 and concentrated under reduced pressure. The crude product was then purified by silica gel chromatography using a gradient of cyclohexane and EtOAc as eluent. The product was obtained as a yellow oil.

Yield: 44 mg (63%).

MS (ES+) [M+H]⁺ m/e = 144.0.

¹H NMR (600 MHz, DMSO-d₆): 5 12.52 (s, 1 H), 9.14 (s, 1 H), 2.19 (s, 3H).

¹³C NMR (151 MHz, DMSO-d₆): 5 168.62, 158.48, 148.46, 22.41.

Step 2: Af-(5-(d -(Phenylsulfonyl)-1 ,2,3,4-tetrahydroquinolin-6-yl)-1 ,3,4-thiadiazol-2- yl)acetamide

6-Bromo-1-(phenylsulfonyl)-1 ,2,3,4-tetrahydroquinoline (33 mg, 94 pmol), A/-(1 ,3,4-thiadiazol-2- yl)acetamide (1 .2 eq., 16 mg, 112 pmol), tri-tert-butylphosphonium tetrafluoroborate (0.2 eq., 5.4 mg, 19 pmol), Pd(OAc)2, (0.1 eq., 2.1 mg, 9.4 pmol) and CS2CO3 (3 eq., 92 mg, 281 pmol) were suspended in 1 mL of DMF. The suspension was sonicated for 5 minutes, flushed with nitrogen, heated up 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 obtained after lyophilization as an amorphous white solid.

Yield: 7 mg (18%).

MS (ES+) [M+H]⁺ m/e = 415.0.

¹H NMR (300 MHz, CDCI3): 5 7.95 (d, J = 8.7 Hz, 1 H), 7.77 - 7.49 (m, 5H), 7.49 - 7.39 (m, 2H), 3.92 - 3.80 (m, 2H), 2.57 (t, J = 6.6 Hz, 2H), 2.47 (s, 3H).

¹³C NMR (189 MHz, CDCI3): 5 168.38, 162.85, 159.78, 139.51 , 133.22, 131.33, 129.34, 128.04, 127.19, 126.27, 125.70, 124.96, 46.88, 27.04, 23.39, 21.54.

Example 109: A/-(5-(1-((4-Aminophenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-6-yl)-4- methylthiazol-2-yl)acetamide

A/-(4-Methyl-5-(1-((4-nitrophenyl)sulfonyl)-1 ,2,3,4-tetrahydroquinolin-6-yl)thiazol-2-yl)acetamide (164 mg, 347 pmol) was dissolved in 2 mL of MeOH and 1 mL of a 5% solution of ammonium chloride in water. Afterwards, zinc dust (10 eq., 226 mg, 3.47 mmol) was added to the mixture. The reaction mixture was stirred for 1 hour at room temperature. The crude product was then filtered and purified by silica gel chromatography using a gradient of cyclohexane and EtOAc as eluent. The product was obtained as a yellow oil.

Yield: 132 mg (86%).

MS (ES+) [M+H]⁺ m/e = 443.0.

¹H NMR (300 MHz, CDCI₃): 6 11.26 (s, 1 H), 7.80 (d, J = 8.6 Hz, 1 H), 7.43 - 7.33 (m, 2H), 7.22 (dd, J = 8.6, 2.2 Hz, 1 H), 7.06 (d, J = 2.2 Hz, 1 H), 6.62 - 6.52 (m, 2H), 4.24 (s, 2H), 3.83 - 3.69 (m, 2H), 2.51 (t, J = 6.7 Hz, 2H), 2.40 (s, 3H), 2.24 (s, 3H), 1 .73 - 1 .57 (m, 2H).

¹³C NMR (75 MHz, CDCI3): 5 168.02, 156.35, 150.82, 141.01 , 136.42, 130.56, 129.40, 129.04, 128.10, 127.28, 126.67, 125.43, 124.76, 113.89, 46.31 , 26.70, 23.12, 21.19, 16.14.

Example compound 110: A/-(4-((6-(2-Acetamido-4-methylthiazol-5-yl)-3,4-dihydroquinolin- 1(2H)-yl)sulfonyl)phenyl)acrylamide

A/-(5-(1-((4-Aminophenyl)sulfonyl)-1 ,2,3,4-tetrahydroquinolin-6-yl)-4-methylthiazol-2-yl)acetamide (20 mg, 45 pmol) was dissolved in 1 mL pf pyridine. Afterwards, acryloyl chloride (3 eq., 13 mg, 136 pmol) was dropwise added to the solution and stirred for 30 minutes at room temperature. The solvent was then removed under reduced pressure and the crude product purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1% TFA). The product was obtained after lyophilization as an amorphous white solid.

Yield: 9 mg (40%).

MS (ES+) [M+H]⁺ m/e = 497.1 .

¹H NMR (600 MHz, DMSO-d₆): 5 12.06 (s, 1 H), 10.53 (s, 1 H), 7.84 - 7.79 (m, 1 H), 7.66 (d, J = 8.6 Hz, 1 H), 7.64 - 7.60 (m, 1 H), 7.27 (dd, J = 8.6, 2.3 Hz, 1 H), 7.15 (d, J = 2.2 Hz, 1 H), 6.42 (dd, J = 16.9, 10.1 Hz, 1 H), 6.29 (dd, J = 17.0, 1.9 Hz, 1 H), 5.81 (dd, J = 10.1 , 1.8 Hz, 1 H), 3.80 - 3.76 (m, 2H), 2.53 (t, J = 6.6 Hz, 3H), 2.33 (s, 3H), 2.13 (s, 2H), 1 .70 - 1 .56 (m, 2H).

¹³C NMR (151 MHz, DMSO-d₆): 5 168.26, 163.69, 158.22, 154.90, 143.28, 141.81 , 135.42, 132.82, 131.32, 130.67, 129.12, 128.25, 128.11 (2C), 126.26, 123.70, 123.20, 119.16, 46.19, 26.07, 22.41 , 20.94, 16.09. Example compound 111 : A/-(4-((6-(2-Acetamido-4-methylthiazol-5-yl)-3,4-dihydroquinohn- 1(2/7)-yl)sulfonyl)phenyl)acetamide

A/-(5-(1-((4-Aminophenyl)sulfonyl)-1 ,2,3,4-tetrahydroquinolin-6-yl)-4-methylthiazol-2-yl)acetamide (20 mg, 45 pmol) was dissolved in 1 mL pf pyridine. Afterwards, acetyl chloride (3 eq., 11 mg, 136 pmol) was dropwise added to the solution and stirred for 30 minutes at room temperature. The solvent was then removed under reduced pressure and the crude product purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1% TFA). The product was obtained after lyophilization as an amorphous white solid.

Yield: 14 mg (64%).

MS (ES+) [M+H]⁺ m/e = 485.1 .

¹H NMR (300 MHz, DMSO-d₆): 5 12.09 (s, 1 H), 10.35 (s, 1 H), 7.77 - 7.69 (m, 2H), 7.66 (d, J = 8.6 Hz, 1 H), 7.62 - 7.53 (m, 2H), 7.27 (dd, J = 8.6, 2.3 Hz, 1 H), 7.15 (d, J = 2.2 Hz, 1 H), 3.93 - 3.59 (m, 2H), 2.33 (s, 3H), 2.13 (s, 3H), 2.06 (s, 3H), 1 .67 - 1 .52 (m, 2H). 2H hidden behind the DMSO peak.

¹³C NMR (75 MHz, DMSO-d₆): 6 169.16, 168.33, 154.94, 143.62, 141.84, 135.47, 132.27, 130.71 , 129.16, 128.27, 128.14, 126.29, 123.82, 123.24, 118.67, 46.21 , 26.11 , 24.18, 22.47, 20.91 , 16.16.

Example compound 112: A/-(4-((6-(2-Acetamido-4-methylthiazol-5-yl)-3,4-dihydroquinolin- 1(2H)-yl)sulfonyl)phenyl)-2-chloroacetamide

A/-(5-(1-((3-Aminophenyl)sulfonyl)-1 ,2,3,4-tetrahydroquinolin-6-yl)-4-methylthiazol-2-yl)acetamide (20 mg, 45 pmol) was dissolved in 1 mL pf pyridine. Afterwards, 2-chloroacetyl chloride (3 eq., 15 mg, 136 pmol) was dropwise added to the solution and stirred for 30 minutes at room temperature. The solvent was then removed under reduced pressure and the crude product purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1% TFA). The product was obtained after lyophilization as an amorphous white solid. Yield: 8 mg (34%).

MS (ES+) [M+H]⁺ m/e = 519.0

¹H NMR (300 MHz, CDCI₃): 5 8.41 (s, 1 H), 7.91 (d, J = 8.6 Hz, 1 H), 7.73 - 7.65 (m, 3H), 7.22 (dd, J = 8.6, 2.3 Hz, 1 H), 7.10 - 7.03 (m, 1 H), 4.20 (s, 2H), 3.92 - 3.78 (m, 2H), 2.57 (t, J = 6.7 Hz, 2H), 2.50 (s, 2H), 2.41 (s, 2H), 1 .76 - 1 .67 (m, 2H), 1 .25 (s, 1 H).

Example compound 113: A/-(5-(1-((4-Acetylphenyl)sulfonyl)-1 ,2,3,4-tetrahydroquinolin-6-yl)- 4-methylthiazol-2-yl)acetamide

A/-(5-(1-((4-Aminophenyl)sulfonyl)-1 ,2,3,4-tetrahydroquinolin-6-yl)-4-methylthiazol-2-yl)acetamide (20 mg, 70 pmol) was dissolved in 1 mL pf pyridine. Afterwards, 4-acetylbenzenesulfonyl chloride (1.5 eq., 23 mg, 136 pmol) was dropwise added to the solution and stirred for 3 hours at room temperature. The solvent was then removed under reduced pressure and the crude product purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1% TFA). The product was obtained after lyophilization as an amorphous white solid.

Yield: 18 mg (55%).

MS (ES+) [M+H]⁺ m/e = 470.1 .

¹H NMR (300 MHz, CDCI3): 5 8.06 - 7.97 (m, 2H), 7.90 (d, J = 8.6 Hz, 1 H), 7.82 - 7.71 (m, 2H), 7.24 (dd, J = 8.6, 2.3 Hz, 1 H), 7.11 - 7.03 (m, 1 H), 3.93 - 3.78 (m, 2H), 2.62 (s, 3H), 2.55 (t, J = 6.7 Hz, 2H), 2.49 (s, 3H), 2.40 (s, 3H), 1 .77 - 1 .62 (m, 2H).

¹³C NMR (75 MHz, CDCI3): 5 196.78, 169.63, 160.02, 143.30, 140.37, 137.58, 132.63, 131.33, 129.81 , 129.11 , 127.46, 127.19, 125.56, 125.10, 124.59, 46.85, 26.98, 26.92, 23.15, 21.56, 13.07.

Example compound 114: A/-(5-(1-((4-(Dimethylamino)phenyl)sulfonyl)-1 ,2,3,4- tetrahydroquinolin-6-yl)-4-methylthiazol-2-yl)acetamide

A/-(5-(1-((4-Aminophenyl)sulfonyl)-1 ,2,3,4-tetrahydroquinolin-6-yl)-4-methylthiazol-2-yl)acetamide (20 mg, 45 pmol) was dissolved in 1 mL of MeOH and 0.1 mL of acetic acid. Afterwards, formaldehyde 37% in water (3 eq., 11 mg, 136 pmol) was added to the solution and stirred for 30 minutes at room temperature. NaBHaCN (5 eq., 14 mg, 226 pmol) was also added tot he stirring solution. After one hour at room temperature, the solvent was removed under reduced pressure and the residue was purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1% TFA). The lyophilized powder was poured in an separatory funnel containing DCM and a saturated solution of Na2COs in water. The water phase was extracted 3 times with DCM. Then, the combined organic phases were dried over Na2SC>4 and concentrated under reduced pressure. The product was obtained as an amorphous white solid.

Yield: 15 mg (71%).

MS (ES+) [M+H]⁺ m/e = 471.1.

¹H NMR (300 MHz, CDCI₃): 5 7.86 (d, J = 8.6 Hz, 1 H), 7.50 - 7.42 (m, 2H), 7.24 (dd, J = 8.5, 2.3 Hz, 1 H), 7.06 (d, J = 2.2 Hz, 1 H), 6.62 - 6.51 (m, 2H), 3.85 - 3.75 (m, 2H), 3.02 (s, 6H), 2.54 (t, J = 6.7 Hz, 2H), 2.41 (s, 3H), 2.28 (s, 3H), 1 .75 - 1 .62 (m, 3H).

¹³C NMR (75 MHz, CDCI₃): 5 167.78, 155.93, 152.99, 143.93, 137.11 , 130.63, 129.63, 129.00, 127.73, 126.93, 125.71 , 125.03, 124.94, 110.94, 46.52, 40.17, 27.05, 23.40, 21.45, 15.79.

Example compound 115: A/-(5-(1-((4-(2-Bromoacetyl)phenyl)sulfonyl)-1 ,2,3,4- tetrahydroquinolin-6-yl)-4-methylthiazol-2-yl)acetamide

A/-(5-(1-((4-Acetylphenyl)sulfonyl)-1 ,2,3,4-tetrahydroquinolin-6-yl)-4-methylthiazol-2-yl)acetamide (14 mg, 30 pmol) and CuBr₃ (1.5 eq., 10 mg, 45 pmol) were suspended in 1 mL of EtOAc and stirred for 16 hours. The solvent was then removed under reduced pressure and the crude product purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1% TFA). The product was obtained after lyophilization as an amorphous white solid.

Yield: 4 mg (24%).

MS (ES+) [M+H]⁺ m/e = 548.0, 550.0 (bromine isotope pattern).

¹H NMR (600 MHz, DMSO-d₆) 5 12.07 (s, 1 H), 8.08 - 8.02 (m, 2H), 7.82 - 7.79 (m, 2H), 7.66 (d, J = 8.5 Hz, 1 H), 7.29 (dd, J = 8.6, 2.3 Hz, 1 H), 7.17 (d, J = 2.3 Hz, 1 H), 4.79 (s, 2H), 2.55 - 2.52 (m, 2H), 2.33 (s, 3H), 2.13 (s, 3H), 1.68 - 1.59 (m, 2H). 2H was hidden behind the water peak.

¹³C NMR (151 MHz, DMSO-d₆): 5 197.72, 168.28, 158.34, 154.96, 142.57, 142.26, 134.99, 130.82, 129.23, 129.17, 128.74, 127.16, 126.37, 123.56, 123.07, 65.68, 46.40, 25.99, 22.41 , 21.10, 16.11. Example compound 116: A/-(5-(1-((4-(1-Hydroxyethyl)phenyl)sulfonyl)-1 ,2,3,4- tetrahydroquinolin-6-yl)-4-methylthiazol-2-yl)acetamide

A/-(5-(1-((4-Acetylphenyl)sulfonyl)-1 ,2,3,4-tetrahydroquinolin-6-yl)-4-methylthiazol-2-yl)acetamide (30 mg, 64 pmol) was dissolved in 1 mL of MeOH. Afterwards, NaBH4 (4 eq., 10 mg, 256 pmol) was added to the solution and the reaction was stirred at room temperature for one hour. The solvent was then removed under reduced pressure and the crude product purified by reversed- phase preparative HPLC (5% to 99% acetonitrile with 0.1 % TFA). The product was obtained after lyophilization as an amorphous white solid.

Yield: 17 mg (56%).

MS (ES+) [M+H]⁺ m/e = 472.1 .

¹H NMR (600 MHz, DMSO-d₆): 5 12.06 (s, 1 H), 7.67 (d, = 8.6 Hz, 1 H), 7.64 - 7.60 (m, 2H), 7.54 - 7.50 (m, 2H), 7.27 (dd, J = 8.6, 2.3 Hz, 1 H), 7.16 (d, J = 2.3 Hz, 1 H), 4.77 (q, J = 6.5 Hz, 1 H), 3.81 - 3.77 (m, 2H), 2.53 (t, J = 6.6 Hz, 2H), 2.33 (s, 3H), 2.13 (s, 3H), 1.68 - 1.55 (m, 2H), 1.30 (d, = 6.5 Hz, 3H).

¹³C NMR (151 MHz, DMSO-d₆): 5 168.29, 154.91 , 153.11 , 141.82, 137.06, 135.42, 130.55, 129.17, 128.22, 126.73, 126.29, 126.25, 123.50, 123.18, 67.43, 46.25, 26.10, 25.63, 22.42, 20.99, 16.09.

Example compound 117: A/-(5-(5-((2,3-Dichlorophenyl)sulfonyl)-5,6,7,8-tetrahydro-1,5- naphthyridin-2-yl)thiazol-2-yl)acetamide

Step 1 : 6-Bromo-1 -((2,3-dichlorophenyl)sulfonyl)-1 ,2,3,4-tetrahydro-1 ,5-naphthyridine

6-Bromo-1 , 2, 3, 4-tetrahydro-1 ,5-naphthyridine (75 mg, 352 pmol) was dissolved in 1 mL pf pyridine. Afterwards, 2,3-dichlorobenzenesulfonyl chloride (1.5 eq., 130 mg, 528 pmol) was dropwise added to the solution and stirred for 3 hours at room temperature. The solvent was then removed under reduced pressure and the crude product purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1 % TFA). The product was obtained after lyophilization as an amorphous white solid.

Yield: 78 mg (53%).

MS (ES+) [M+H]⁺ m/e = 422.9. ¹H NMR (300 MHz, CDCI₃): 6 8.08 (dd, J = 8.0, 1 .6 Hz, 1 H), 7.78 - 7.66 (m, 2H), 7.40 (t, J = 8.0 Hz, 1 H), 7.22 (d, J = 8.7 Hz, 1 H), 3.90 - 3.75 (m, 2H), 2.94 (t, J = 6.8 Hz, 2H), 1 .98 - 1 .84 (m, 2H).

¹³C NMR (75 MHz, CDCI3): 5 150.26, 139.26, 136.44, 135.79, 135.30, 133.79, 132.35, 130.95, 130.63, 127.70, 125.78, 46.31 , 29.94, 21.37.

Step 2: A/-(5-(5-((2,3-Dichlorophenyl)sulfonyl)-5,6,7,8-tetrahydro-1,5-naphthyridin-2- yl)thiazol-2-yl)acetamide

6-Bromo-1-((2,3-dichlorophenyl)sulfonyl)-1 ,2,3,4-tetrahydro-1 ,5-naphthyridine (21 mg, 50 pmol), A/-(thiazol-2-yl)acetamide (1.2 eq., 8 mg, 60 pmol), tri-te/Y-butylphosphonium tetrafluoroborate (0.2 eq., 2.9 mg, 9.9 pmol), Pd(OAc)2, (0.1 eq., 1.1 mg, 5.0 pmol) and CS2CO3 (3 eq., 49 mg, 149 pmol) were suspended in 1 mL of DMF. The suspension was sonicated for 5 minutes, flushed with nitrogen, heated up 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 obtained after lyophilization as an amorphous white solid.

Yield: 3 mg (12%).

MS (ES+) [M+H]⁺ m/e = 482.9

¹H NMR (600 MHz, CDCI3): 5 8.14 (dd, J = 8.0, 1 .5 Hz, 1 H), 7.90 (d, J = 8.7 Hz, 1 H), 7.73 (dd, J = 8.1 , 1 .5 Hz, 1 H), 7.67 (s, 1 H), 7.42 (t, J = 8.0 Hz, 1 H), 7.34 (d, J = 8.7 Hz, 1 H), 3.92 - 3.83 (m, 2H), 2.98 (t, J = 6.7 Hz, 2H), 2.42 (s, 3H), 2.03 - 1 .95 (m, 2H).

¹³C NMR (151 MHz, CDCI3): 5 169.43, 162.71 , 149.60, 143.18, 139.37, 136.49, 135.34, 134.24, 133.71 , 131.01 , 130.76, 130.03, 127.73, 122.85, 117.11 , 46.65, 30.29, 23.24, 21.59.

Example compound 118: A/-(5-(5-((2,3-Dichlorophenyl)sulfonyl)-5,6,7,8-tetrahydro-1,5- naphthyridin-2-yl)-4-methylthiazol-2-yl)acetamide

6-Bromo-1-((2,3-dichlorophenyl)sulfonyl)-1 ,2,3,4-tetrahydro-1 ,5-naphthyridine (21 mg, 50 pmol), A/-(4-methylthiazol-2-yl)acetamide (1.2 eq., 9 mg, 60 pmol), tri-tert-butylphosphonium tetrafluoroborate (0.2 eq., 2.9 mg, 9.9 pmol), Pd(OAc)2, (0.1 eq., 1.1 mg, 5.0 pmol) and CS2CO3 (3 eq., 49 mg, 149 pmol) were suspended in 1 mL of DMF. The suspension was sonicated for 5 minutes, flushed with nitrogen, heated up to 120 °C and stirred overnight. The solvent was then removed under reduced pressure and the residue was purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1 % TFA). The product was obtained after lyophilization as an amorphous white solid.

Yield: 3.5 mg (14%).

MS (ES+) [M+H]⁺ m/e = 497.0. ¹H NMR (600 MHz, CDCI₃): 6 8.14 (dd, J = 8.1 , 1 .5 Hz, 1 H), 7.92 (d, J = 8.7 Hz, 1 H), 7.73 (dd, J = 8.1 , 1 .5 Hz, 1 H), 7.42 (t, J = 8.0 Hz, 1 H), 7.30 (d, J = 8.7 Hz, 1 H), 3.93 - 3.84 (m, 2H), 2.99 (t, J = 6.7 Hz, 2H), 2.66 (s, 3H), 2.41 (s, 3H), 2.04 - 1 .96 (m, 2H).

¹³C NMR (151 MHz, CDCI3): 5 169.65, 161.09, 149.65, 143.82, 139.37, 136.49, 135.35, 133.66, 133.34, 131.01 , 130.75, 129.88, 127.74, 126.45, 118.72, 46.65, 30.34, 23.25, 21.59, 14.14.

Example compound 119: A/-(5-(5-((5-Chloro-2-fluorophenyl)sulfonyl)-5,6,7,8-tetrahydro-1,5- naphthyridin-2-yl)thiazol-2-yl)acetamide

Step 1 : 6-Bromo-1 -((5-chloro-2-fluorophenyl)sulfonyl)-1 ,2,3,4-tetrahydro-1 ,5-naphthyridine

6-Bromo-1 ,2,3,4-tetrahydro-1 ,5-naphthyridine (75 mg, 352 pmol) was dissolved in 1 mL pf pyridine. Afterwards, 5-chloro-2-fluorobenzenesulfonyl chloride (1.5 eq., 121 mg, 528 pmol) was dropwise added to the solution and stirred for 3 hours at room temperature. The solvent was then removed under reduced pressure and the crude product purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1 % TFA). The product was obtained after lyophilization as an amorphous white solid.

Yield: 83 mg (58%).

MS (ES+) [M+H]⁺ m/e = 406.9.

¹H NMR (300 MHz, CDCI3): 5 8.00 (d, J = 8.8 Hz, 1 H), 7.92 (dd, J = 5.9, 2.7 Hz, 1 H), 7.57 (ddd, J = 8.8, 4.2, 2.7 Hz, 1 H), 7.38 (d, J = 8.8 Hz, 1 H), 7.14 (t, J = 9.1 Hz, 1 H), 3.97 - 3.74 (m, 2H), 2.97 (t, J = 6.8 Hz, 2H), 1 .97 - 1 .80 (m, 2H).

¹³C NMR (75 MHz, CDCI3): 5 157.29 (d, J = 256.9 Hz), 150.02, 136.04 (d, J = 8.5 Hz), 134.65, 134.35 (d, J = 1.5 Hz), 133.77, 130.61 , 130.49 (d, J = 3.7 Hz), 128.21 (d, J = 16.3 Hz), 126.87, 119.21 (d, J = 23.2 Hz), 46.17, 28.49, 20.66.

Step 2: A/-(5-(5-((5-Chloro-2-fluorophenyl)sulfonyl)-5,6,7,8-tetrahydro-1,5-naphthyridin-2- yl)thiazol-2-yl)acetamide

6-Bromo-1-((5-chloro-2-fluorophenyl)sulfonyl)-1 ,2,3,4-tetrahydro-1 ,5-naphthyridine (42 mg, 104 pmol), A/-(thiazol-2-yl)acetamide (1.2 eq., 18 mg, 124 pmol), tri-tert-butylphosphonium tetrafluoroborate (0.2 eq., 6 mg, 21 pmol), Pd(OAc)2, (0.1 eq., 2.3 mg, 10 pmol) and CS2CO3 (3 eq., 101 mg, 310 pmol) were suspended in 1 mL of DMF. The suspension was sonicated for 5 minutes, flushed with nitrogen, heated up 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 obtained after lyophilization as an amorphous white solid.

Yield: 5 mg (10%). MS (ES+) [M+H]⁺ m/e = 467.0.

¹H NMR (600 MHz, CDCI₃): 6 12.08 (s, 1 H), 7.97 (d, J = 8.6 Hz, 1 H), 7.93 (dd, J = 5.8, 2.7 Hz, 1 H), 7.78 (s, 1 H), 7.53 (ddd, J = 8.8, 4.1 , 2.7 Hz, 1 H), 7.39 (d, J = 8.7 Hz, 1 H), 7.11 (t, J = 9.0 Hz, 1 H), 3.94 - 3.85 (m, 2H), 2.90 (t, 7 = 6.7 Hz, 2H), 2.37 (s, 4H), 1.94 (ddd, J = 10.7, 8.6, 5.1 Hz, 2H).

¹³C NMR (151 MHz, CDCI3): 5 169.27, 158.36 (d, = 257.1 Hz), 150.70, 146.77, 136.55 (d, J = 8.4 Hz), 133.20, 131.74 (d, 7 = 5.3 Hz), 131.61 , 131.27 (d, 7 = 3.5 Hz), 129.85 (d, 7 = 16.5 Hz), 128.52, 127.19, 121.92, 120.05 (d, 7 = 23.4 Hz), 118.24, 47.70, 31.31 , 24.40, 22.56.

Example compound 120: A/-(5-(5-((5-Chloro-2-fluorophenyl)sulfonyl)-5,6,7,8-tetrahydro-1,5- naphthyridin-2-yl)-4-methylthiazol-2-yl)acetamide

6-Bromo-1-((5-chloro-2-fluorophenyl)sulfonyl)-1 ,2,3,4-tetrahydro-1 ,5-naphthyridine (42 mg, 104 pmol), A/-(4-methylthiazol-2-yl)acetamide (1.2 eq., 19 mg, 124 pmol), tri-tert-butylphosphonium tetrafluoroborate (0.2 eq., 6 mg, 21 pmol), Pd(OAc)2, (0.1 eq., 2.3 mg, 10 pmol) and CS2CO3 (3 eq., 101 mg, 310 pmol) were suspended in 1 mL of DMF. The suspension was sonicated for 5 minutes, flushed with nitrogen, heated up to 120 °C and stirred overnight. The solvent was then removed under reduced pressure and the crude poduct was purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1% TFA). The product was obtained after lyophilization as an amorphous white solid.

Yield: 18 mg (36%).

MS (ES+) [M+H]⁺ m/e = 481 .0.

¹H NMR (600 MHz, DMSO-d₆): 5 12.09 (s, 1 H), 7.93 (dd, 7 = 5.8, 2.7 Hz, 1 H), 7.91 - 7.84 (m, 2H), 7.54 (t, 7 = 9.3 Hz, 1 H), 7.50 (d, 7 = 8.8 Hz, 1 H), 3.89 - 3.79 (m, 2H), 2.80 (t, 7 = 6.7 Hz, 2H), 2.51 (s, 3H), 2.14 (s, 3H), 1 .83 - 1 .72 (m, 2H).

¹³C NMR (151 MHz, DMSO-d₆): 5 168.44, 156.77 (d, 7 = 255.2 Hz), 156.64, 149.17, 147.32, 144.40, 136.32 (d, 7 = 8.7 Hz), 130.71 , 130.25, 129.71 , 129.18 (d, 7 = 2.6 Hz), 128.04 (d, 7 = 16.5 Hz), 124.61 , 119.90 (d, 7 = 23.4 Hz), 118.49, 45.95, 29.50, 22.48, 20.75, 17.43.

Example compound 121 : A/-(5-(1-Benzoyl-1,2,3,4-tetrahvdroquinolin-6-yl)-4-methylthiazol-2- vDacetamide

A/-(5-(1-((4-Aminophenyl)sulfonyl)-1 ,2,3,4-tetrahydroquinolin-6-yl)-4-methylthiazol-2-yl)acetamide (20 mg, 70 pmol) was dissolved in 1 mL pf pyridine. Afterwards, benzoyl chloride (1.5 eq., 15 mg, 104 pmol) was dropwise added to the solution and stirred for 3 hours at room temperature. The solvent was then removed under reduced pressure and the crude product purified by reversed- phase preparative HPLC (5% to 99% acetonitrile with 0.1 % TFA). The product was obtained after lyophilization as an amorphous white solid.

Yield: 17 mg (62%).

MS (ES+) [M+H]+ m/e = 392.1.

¹H NMR (300 MHz, DMSO-d₆): 5 12.08 (s, 1 H), 7.48 - 7.34 (m, 5H), 7.27 (d, J = 2.1 Hz, 1 H), 7.00 (dd, J = 8.4, 2.1 Hz, 1 H), 6.92 (d, J = 8.6 Hz, 1 H), 3.84 - 3.58 (m, 2H), 2.86 (t, J = 6.6 Hz, 2H), 2.29 (s, 3H), 2.12 (s, 3H), 1 .95 (p, J = 6.6 Hz, 2H).

¹³C NMR (75 MHz, DMSO-d₆): 5 169.48, 168.32, 154.87, 141.70, 137.89, 136.48, 131.59, 130.16, 128.50, 128.30, 128.08, 127.91 , 125.46, 125.15, 123.47, 44.90, 26.30, 23.39, 22.47, 16.09.

Example compound 122: A/-(5-(1-Benzyl-1,2,3,4-tetrahvdroquinolin-6-yl)-4-methylthiazol-2- vDacetamide

A/-(5-(1-((4-Aminophenyl)sulfonyl)-1 ,2,3,4-tetrahydroquinolin-6-yl)-4-methylthiazol-2-yl)acetamide (20 mg, 70 pmol) was dissolved in 1 mL of MeOH and 0.1 mL of acetic acid. Afterwards, benzaldehyde (3 eq., 22 mg, 208 pmol) was added to the solution and stirred for 30 minutes at room temperature. NaBHsCN (5 eq., 22 mg, 348 pmol) was also added to the stirring solution. After one hour at room temperature, the solvent was removed under reduced pressure and the crude poduct was purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1% TFA). The lyophilized powder was poured in an separatory funnel containing DCM and a saturated solution of Na2COs in water. The water phase was extracted 3 times with DCM. Then, the combined organic phases were dried over Na2SO4 and concentrated under reduced pressure. The product was obtained as an amorphous white solid.

Yield: 16 mg (61%).

MS (ES+) [M+H]+ m/e = 378.2.

¹H NMR (300 MHz, CDCI₃): 6 7.41 - 7.33 (m, 2H), 7.31 - 7.25 (m, 3H), 7.10 - 7.02 (m, 2H), 6.54 (d, J = 8.4 Hz, 1 H), 4.54 (s, 2H), 3.50 - 3.41 (m, 2H), 2.87 (t, J = 6.3 Hz, 2H), 2.43 (s, 3H), 2.30 (s, 3H), 2.14 - 2.01 (m, 2H).

¹³C NMR (75 MHz, CDCI₃): 5 168.32, 156.42, 145.50, 138.40, 136.56, 129.62, 128.83, 127.99, 127.09, 126.99, 126.57, 122.60, 118.02, 111.04, 55.14, 50.07, 28.28, 23.27, 22.24, 15.17.

Example compound 123: Tert-Butyl 9-(2-acetamido-4-methylthiazol-5-yl)-6- (phenylsulfonyl)-3,4,4a,5,6,10b-hexahydrobenzo[/7l[1 ,6]naphthyridine-1 (2/7)-carboxylate

Step 1 : Tert-Butyl 9-bromo-6-(phenylsulfonyl)-3,4,4a,5,6,10b- hexahydrobenzo[/?][1 ,6]naphthyridine-1 (2H) -carboxy late

4-Bromoaniline (350 mg, 2.03 mmol) and formaldehyde 37% in water (1 eq., 165 mg, 2.03 mmol) were dissolved in 3 mL of acetonitrile at 0 °C. Afterwards, Yb(OTf)3 (0.05 eq., 63 mg, 102 pmol) was added tot he mixture, followed by the dropwise addition of tert-butyl 3,4-dihydropyridine- 1 (2/-/)-carboxylate (1.1 eq., 410 mg, 2.24 mmol) dissolved in 1 mL of acetonitrile. The reaction mixture was kept at 0° C for 20 minutes. Afterwards, the crude product purified by reversed- phase preparative HPLC (5% to 99% acetonitrile with 0.1 % TFA). The lyophilized powder was poured in a separatory funnel containing DCM and a saturated solution of Na2COs in water. The water phase was extracted 3 times with DCM. Then, the combined organic phases were dried over Na2SC>4 and concentrated under reduced pressure. The product was then dissolved in 3 mL of pyridine, followed by the addition of benzenesulfonyl chloride (1.1 eq., 395 mg, 2.24 mmol) to the mixture. The reaction mixture was stirred for three hours at room temperature. The solvent was then removed under reduced pressure and the crude product purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1% TFA). The product was obtained after lyophilization as an amorphous white solid.

Yield: 393 mg (38%).

MS (ES+) [M+Na]⁺ m/e = 529.0, 531 .0 (bromine isotopic pattern).

¹H NMR (300 MHz, CDCI₃): 5 7.80 (dd, J = 7.3, 1 .9 Hz, 2H), 7.64 - 7.55 (m, 1 H), 7.55 - 7.45 (m, 3H), 7.23 (dd, = 9.0, 2.4 Hz, 1 H), 7.11 (s, 1 H), 5.26 (d, J = 61.1 Hz, 1 H), 4.33 (dd, J = 12.8, 3.0 Hz, 1 H), 4.12 - 3.81 (m, 1 H), 3.74 - 3.51 (m, 1 H), 2.53 - 2.33 (m, 1 H), 2.22 - 2.10 (m, 1 H), 1.74 (d, J = 11.9 Hz, 1 H), 1.50 (s, 12H).

Step 2: Tert-Butyl 9-(2-acetamido-4-methylthiazol-5-yl)-6-(phenylsulfonyl)-3,4,4a,5,6,10b- hexahydrobenzo[h][1 ,6]naphthyridine-1 (2/-/) -carboxy late

Tert-butyl 9-bromo-6-(phenylsulfonyl)-3,4,4a,5,6,10b-hexahydrobenzo[/?][1 ,6]naphthyridine-1 (2/7)- carboxylate (220 mg, 434 pmol), A/-(4-methylthiazol-2-yl)acetamide (1.2 eq., 81 mg, 520 pmol), tri-tert-butylphosphonium tetrafluoroborate (0.2 eq., 25 mg, 87 pmol), Pd(OAc)2, (0.1 eq., 9.7 mg, 43 pmol) and CS2CO3 (3 eq., 424 mg, 1 .30 mmol) were suspended in 3 mL of DMF. The suspension was sonicated for 5 minutes, flushed with nitrogen, heated up to 120 °C and stirred overnight. The solvent was then removed under reduced pressure and the crude product purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1 % TFA). The product was obtained after lyophilization as an amorphous white solid.

Yield: 180 mg (71 %).

MS (ES+) [M+H]⁺ m/e = 583.2.

¹H NMR (300 MHz, CDCI3): 5 7.85 (d, J = 7.1 Hz, 2H), 7.69 - 7.48 (m, 4H), 7.16 (dd, J = 8.7, 2.3 Hz, 1 H), 7.02 (s, 1 H), 5.60 - 5.18 (m, 1 H), 4.46 (dd, J = 12.9, 3.0 Hz, 1 H), 4.09 - 3.87 (m, 1 H), 3.67 (d, J = 12.7 Hz, 1 H), 2.41 (s, 3H), 2.37 (s, 3H), 2.29 - 2.15 (m, 1 H), 1.80 (d, J = 12.1 Hz, 1 H), 1.61 - 1.40 (m, 12H). ¹³C NMR (75 MHz, CDCI₃): 5 169.51 , 159.86, 139.92, 138.19, 133.50, 132.01 , 129.57, 128.05, 127.74, 126.82, 125.74, 124.79, 123.97, 120.12, 117.67, 81.15, 51.21 , 51.05, 39.68, 31.70, 28.52, 24.73, 23.59, 23.03, 12.78.

Example compound 124: A/-(4-Methyl-5-(6-(phenylsulfonyl)-1 ,2,3,4,4a,5,6,10b- octahydrobenzolhin ,61naphthyridin-9-yl)thiazol-2-yl)acetamide

Tert-butyl 9-(2-acetamido-4-methylthiazol-5-yl)-6-(phenylsulfonyl)-3,4,4a,5,6,10b- hexahydrobenzo[/7][1 ,6]naphthyridine-1 (2/-/)-carboxylate (180 mg, 308 pmol) was dissolved in 10 mL of DCM and 1 mL of TFA was slowly added to the solution at room temperature. Afterwards, the solvent was evaporated and the crude product purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1% TFA). The lyophilized powder was poured in a separatory funnel containing DCM and a saturated solution of Na2COs in water. The water phase was extracted 3 times with DCM. Then, the combined organic phases were dried over Na2SO4 and concentrated under reduced pressure. The product was obtained after lyophilization as an amorphous white solid.

Yield: 133 mg (89%).

MS (ES+) [M+H]⁺ m/e = 483.1 .

¹H NMR (300 MHz, CDCI3): 5 7.86 - 7.79 (m, 1 H), 7.78 - 7.72 (m, 2H), 7.59 - 7.51 (m, 1 H), 7.50 - 7.42 (m, 2H), 7.30 - 7.24 (m, 2H), 4.08 - 3.99 (m, 2H), 3.77 - 3.61 (m, 2H), 2.94 (dt, J = 11 .9, 3.9 Hz, 1 H), 2.73 (ddd, J = 11 .9, 9.8, 3.7 Hz, 1 H), 2.38 (s, 3H), 2.23 (s, 3H), 1 .89 - 1 .77 (m, 1 H), 1 .78 - 1 .64 (m, 2H), 1 .55 - 1 .42 (m, 2H).

¹³C NMR (75 MHz, CDCI3): 5 168.07, 156.47, 141.27, 139.70, 135.72, 133.08, 130.88, 130.02, 129.23, 128.38, 128.06, 127.08, 125.23, 122.42, 54.99, 46.01 , 31.52, 29.78, 26.46, 23.26, 22.07, 16.25.

1-1 ,2, 3, 4, 4a, 5,6,10b-

A/-(4-methyl-5-(6-(phenylsulfonyl)-1 ,2,3,4,4a,5,6,10b-octahydrobenzo[rt][1 ,6]naphthyridin-9- yl)thiazol-2-yl)acetamide (10 mg, 20.7 pmol) was dissolved in 1 mL of MeOH and 0.1 mL of acetic acid. Afterwards, formaldehyde 37% in water (2 eq., 3.4 mg, 41 pmol) was added to the solution and stirred for 30 minutes at room temperature. NaBHsCN (2 eq., 2.6 mg, 41 pmol) was also added to the stirring solution. After one hour at room temperature, the solvent was removed under reduced pressure and the residue was purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1% TFA). The lyophilized powder was poured in an separatory funnel containing DCM and a saturated solution of Na2CO₃ in water. The water phase was extracted 3 times with DCM. Then, the combined organic phases were dried over Na2SC>4 and concentrated under reduced pressure. The product was obtained as an amorphous white solid.

Yield: 7.2 mg (70%).

MS (ES+) [M+H]⁺ m/e = 497.2

¹H NMR (300 MHz, CDCI₃): 5 10.25 (s, 1 H), 7.94 (d, J = 8.6 Hz, 1 H), 7.71 (d, J = 7.7 Hz, 2H), 7.53 - 7.44 (m, 1 H), 7.37 (dd, J = 8.3, 6.9 Hz, 2H), 7.32 (dd, J = 8.6, 2.3 Hz, 1 H), 7.05 (d, J = 2.3 Hz, 1 H), 4.05 (t, J = 11 .7 Hz, 1 H), 3.70 (s, 1 H), 2.71 (s, 1 H), 2.58 (d, J = 11 .1 Hz, 1 H), 2.39 (s, 3H), 2.25 (s, 3H), 2.15 - 2.03 (m, 1 H), 2.00 - 1.86 (m, 1 H), 1.84 - 1.64 (m, 3H), 1.63 (s, 3H), 1.53 - 1.43 (m, 1 H).

¹³C NMR (75 MHz, CDCI₃): 5 167.78, 155.94, 141.49, 138.20, 135.86, 132.70, 131.66, 131.42, 128.99, 128.59, 127.82, 127.29, 125.54, 124.18, 65.59, 56.78, 46.67, 43.68, 33.98, 26.00, 23.41 , 20.95, 16.31.

Example compound 126: A/-(5-(4-(ethylthio)-1-(phenylsulfonyl)-1,2,3,4-tetrahydroquinolin-6- yl)-4-methylthiazol-2-yl)acetamide

Step 1 : 6-Bromo-4-(ethylthio)-1 -(phenylsulfonyl)-l ,2,3,4-tetrahydroquinoline

4-Bromoaniline (350 mg, 2.03 mmol) and formaldehyde 37% in water (1 eq., 165 mg, 2.03 mmol) were dissolved in 3 mL of acetonitrile at 0 °C. Afterwards, Yb(OTf)3 (0.05 eq., 63 mg, 102 pmol) was added tot he mixture, followed by the dropwise addition of ethyl(vinyl)sulfane (1.1 eq., 197 mg, 2.24 mmol) dissolved in 1 mL of acetonitrile. The reaction mixture was kept at 0° C for 20 minutes. Afterwards, the crude product purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1% TFA). The lyophilized powder was poured in a separatory funnel containing DCM and a saturated solution of Na2CO₃ in water. The water phase was extracted 3 times with DCM. Then, the combined organic phases were dried over Na2SO4 and concentrated under reduced pressure. The product was then dissolved in 3 mL of pyridine, followed by the addition of benzenesulfonyl chloride (1.1 eq., 395 mg, 2.24 mmol) to the mixture. The reaction mixture was stirred for three hours at room temperature. The solvent was then removed under reduced pressure and the crude product purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1% TFA). The product was obtained after lyophilization as an amorphous white solid.

Yield: 72 mg (8%).

MS (ES+) [M+Na]⁺ m/e = 434.0, 436.0 (bromine isotopic pattern).

¹H NMR (300 MHz, CDCI3): 5 7.76 (d, J = 8.9 Hz, 1 H), 7.67 - 7.61 (m, 2H), 7.58 - 7.51 (m, 1 H), 7.47 - 7.38 (m, 3H), 7.31 (dd, J = 8.9, 2.5 Hz, 1 H), 4.03 (dt, J = 13.5, 4.7 Hz, 1 H), 3.91 (ddd, J = 13.6, 8.8, 4.9 Hz, 1 H), 3.78 (t, J = 4.7 Hz, 1 H), 2.29 (q, J = 7.4 Hz, 2H), 1.87 - 1.79 (m, 2H), 1.15 (t, J = 7.4 Hz, 3H). ¹³C NMR (75 MHz, CDCI3): 5 139.05, 135.86, 133.22, 133.05, 131.38, 130.92, 129.25, 127.33, 125.48, 117.80, 43.47, 40.71 , 27.11 , 24.95, 14.48.

Step 2: A/-(5-(4-(Ethy Ith io)-1 -(phenylsulfonyl)-l ,2,3,4-tetrahydroquinolin-6-yl)-4- methylthiazol-2-yl)acetamide

6-bromo-4-(ethylthio)-1-(phenylsulfonyl)-1 ,2,3,4-tetrahydroquinoline (60 mg, 145 pmol), A/-(4- methylthiazol-2-yl)acetamide (1.2 eq., 27 mg, 175 pmol), tri-tert-butylphosphonium tetrafluoroborate (0.2 eq., 8.4 mg, 29 pmol), Pd(OAc)2, (0.1 eq., 3.3 mg, 15 pmol) and CS2CO3 (3 eq., 142 mg, 436 pmol) were suspended in 1 mL of DMF. The suspension was sonicated for 5 minutes, flushed with nitrogen, heated up to 120 °C and stirred overnight. The solvent was then removed under reduced pressure and the crude product purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1 % TFA). The product was obtained after lyophilization as an amorphous white solid.

Yield: 38 mg (53%).

MS (ES+) [M+H]⁺ m/e = 488.1 .

¹H NMR (300 MHz, CDCI₃): 5 7.94 (d, J = 8.7 Hz, 1 H), 7.76 - 7.67 (m, 2H), 7.61 - 7.53 (m, 1 H), 7.47 (dd, J = 8.3, 6.8 Hz, 2H), 7.38 (d, = 2.3 Hz, 1 H), 7.22 (dd, J = 8.7, 2.3 Hz, 1 H), 4.13 (dt, J = 13.4, 4.4 Hz, 1 H), 4.02 - 3.89 (m, 2H), 2.48 (s, 3H), 2.44 - 2.31 (m, 5H), 1 .99 - 1 .88 (m, 2H), 1.19 (t, = 7.4 Hz, 3H).

¹³C NMR (75 MHz, CDCI3): 5 169.64, 160.00, 139.20, 137.82, 133.39, 132.56, 131.07, 129.86, 129.37, 128.08, 127.28, 124.59, 124.57, 123.93, 43.30, 40.96, 27.12, 25.17, 23.15, 14.53, 13.00. i-1.2.3.4-

A/-(4-Methyl-5-(1 ,2,3,4-tetrahydroquinolin-6-yl)thiazol-2-yl)acetamide (20 mg, 70 pmol) was dissolved in 1 mL of pyridine, followed by the addition of 3-chloro-2-fluorobenzenesulfonyl chloride (2 eq., 32 mg, 140 pmol) to the mixture. The reaction mixture was stirred for three hours at room temperature. The solvent was then removed under reduced pressure and the crude product purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1% TFA). The product was obtained after lyophilization as an amorphous white solid.

Yield: 30 mg (89%).

MS (ES+) [M+H]⁺ m/e = 480.0 ¹H NMR (300 MHz, DMSO-d₆): 6 12.09 (s, 1 H), 8.04 - 7.79 (m, 2H), 7.54 - 7.39 (m, 2H), 7.33 - 7.18 (m, 2H), 3.86 (t, J = 5.8 Hz, 2H), 2.71 (t, J = 6.6 Hz, 2H), 2.31 (s, 3H), 2.13 (s, 3H), 1.80 (p, J = 6.3 Hz, 2H).

¹³C NMR (151 MHz, DMSO-d₆): 5 168.33, 154.99, 153.49 (d, = 255.9 Hz), 141.92, 136.27, 134.83, 130.25, 129.36 (2C), 128.79 (d, J = 14.2 Hz), 128.34, 126.31 , 126.21 (d, 7 = 4.6 Hz), 123.10, 122.53, 121.84 (d, 7 = 17.5 Hz), 46.38, 26.14, 22.44, 21.65, 16.04.

Example compound 128: A/-(4-Methyl-5-(1-(phenylsulfonyl)-4-(piperidin-1-yl)-1 ,2,3,4- tetrahydroquinolin-6-yl)thiazol-2-yl)acetamide

Step 1 : A/-(5-(4-Bromo-1 -(phenylsulfonyl)-l ,2,3,4-tetrahydroquinolin-6-yl)-4-methylthiazol-2- yl)acetamide

A/-(5-(4-Hydroxy-1-(phenylsulfonyl)-1 ,2,3,4-tetrahydroquinolin-6-yl)-4-methylthiazol-2- yl)acetamide (140 mg, 316 pmol) was dissolved in 2 mL of dry THF, followed by the addition at 0 °C of phosphorus tribromide (1 .5 eq., 128 mg, 474 pmol). The reaction mixture was stirred for two hours at room temperature. The solvent was then removed under reduced pressure and the crude was used for other reactions without further purification.

MS (ES+) [M+H]⁺ m/e = 506.6, 508.6 (bromine isotopic pattern).

¹H NMR (300 MHz, CDCI₃): 8 7.91 (d, 7 = 8.6 Hz, 1 H), 7.77 - 7.69 (m, 2H), 7.65 - 7.53 (m, 1 H), 7.48 (dd, 7 = 8.3, 6.8 Hz, 2H), 7.32 - 7.23 (m, 2H), 4.38 (dtd, 7 = 13.3, 3.8, 1.1 Hz, 1 H), 4.13 - 4.09 (m, 1 H), 3.73 - 3.65 (m, 1 H), 2.43 (s, 3H), 2.36 (s, 3H), 2.02 - 1 .97 (m, 2H).

Step 2: A/-(4-Methyl-5-(1 -(phenylsulfonyl)-4-(piperidin-1 -y I )-1 ,2,3,4-tetrahydroquinolin-6- yl)thiazol-2-yl)acetamide

A/-(5-(4-Bromo-1-(phenylsulfonyl)-1 ,2,3,4-tetrahydroquinolin-6-yl)-4-methylthiazol-2-yl)acetamide (50 mg, 98 pmol) was dissolved in 1 mL of dry DCM, followed by the addition of 1 mL of piperidine. The reaction mixture was stirred for one hour at room temperature. The solvent was then removed under reduced pressure and the crude product purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1% TFA). The lyophilized powder was poured in an separatory funnel containing DCM and a saturated solution of Na2COs in water. The water phase was extracted 3 times with DCM. Then, the combined organic phases were dried over Na2SO4 and concentrated under reduced pressure. The product was obtained as an amorphous white solid. Yield: 19 mg (37%).

MS (ES+) [M+H]⁺ m/e = 513.1

¹H NMR (600 MHz, DMSO-d₆): 5 12.08 (s, 1 H), 7.75 (d, = 8.6 Hz, 1 H), 7.68 - 7.64 (m, 1 H), 7.64 - 7.60 (m, 2H), 7.59 (d, J = 2.4 Hz, 1 H), 7.54 (t, J = 7.9 Hz, 2H), 7.34 (dd, J = 8.6, 2.3 Hz, 1 H), 4.12 (dt, J = 13.5, 4.7 Hz, 1 H), 3.64 - 3.53 (m, 2H), 2.34 (s, 3H), 2.16 - 2.07 (m, 5H), 2.02 - 1.92 (m, 2H), 1 .65 - 1 .57 (m, 1 H), 1 .56 - 1 .45 (m, 1 H), 1 .39 - 1 .21 (m, 6H).

¹³C NMR (151 MHz, DMSO-d₆): 5 168.31 , 154.90, 141.78, 138.71 , 135.88, 133.34, 131.88, 129.50, 128.57, 128.20, 126.94, 126.92, 123.96, 123.40, 59.95, 48.75, 45.28, 25.94, 24.06, 22.42, 18.44, 16.13.

Example compound 129: A/-(5-(4-(3-lsopropoxyazetidin-1-yl)-1-(phenylsulfonyl)-1 ,2,3,4- tetrahydroquinolin-6-yl)-4-methylthiazol-2-yl)acetamide

A/-(5-(4-Bromo-1-(phenylsulfonyl)-1 ,2,3,4-tetrahydroquinolin-6-yl)-4-methylthiazol-2-yl)acetamide (50 mg, 98 pmol) was dissolved in 1 mL of dry DCM, followed by the addition of 3- isopropoxyazetidine hydrochloride (2 eq., 30 mg, 196 pmol) and CS2CO3 (6 eq. ,195 mg, 588 pmol). The reaction mixture was stirred for one hour at room temperature. The solvent was then removed under reduced pressure and the crude product purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1 % TFA). The lyophilized powder was poured in an separatory funnel containing DCM and a saturated solution of Na2COs in water. The water phase was extracted 3 times with DCM. Then, the combined organic phases were dried over Na2SO4 and concentrated under reduced pressure. The product was obtained as an amorphous white solid.

Yield: 30 mg (55%).

MS (ES+) [M+H]⁺ m/e = 541.2

¹H NMR (600 MHz, DMSO-d₆): 5 12.06 (s, 1 H), 7.77 (d, = 8.6 Hz, 1 H), 7.68 - 7.62 (m, 3H), 7.55 (t, J = H Hz, 2H), 7.34 (dd, = 8.7, 2.3 Hz, 1 H), 7.22 (s, 1 H), 3.81 (s, 1 H), 3.73 - 3.63 (m, 2H), 3.53 - 3.45 (m, 1 H), 3.38 (s, 1 H), 3.17 (s, 1 H), 2.80 (s, 1 H), 2.67 (s, 1 H), 2.59 (s, 1 H), 2.32 (s, 3H), 2.13 (s, 3H), 1.93 - 1.84 (m, 1 H), 1.63 - 1.50 (m, 1 H), 1.01 (t, = 6.1 Hz, 6H).

¹³C NMR (151 MHz, DMSO-d₆): 5 168.29, 154.90, 141.85, 137.80, 134.73, 133.18, 130.06, 129.06, 128.00, 127.27, 127.00 (2C), 123.11 , 122.80, 70.22, 65.33, 59.83, 59.33, 42.52, 31.29, 24.61 , 22.42, 22.37, 22.33, 16.05. Example compound 130: A/-(5-(4-(Dimethylamino)-1-(phenylsulfonyl)-1 ,2,3,4- tetrahydroquinolin-6-yl)-4-methylthiazol-2-yl)acetamide

A/-(5-(4-Bromo-1-(phenylsulfonyl)-1 ,2,3,4-tetrahydroquinolin-6-yl)-4-methylthiazol-2-yl)acetamide (50 mg, 98 pmol) was dissolved in 1 mL of dry DCM, followed by the addition of 1 mL of dimethylamine 2 M in THF. The reaction mixture was stirred for one hour at room temperature. The solvent was then removed under reduced pressure and the crude product purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1% TFA). The lyophilized powder was poured in an separatory funnel containing DCM and a saturated solution of Na2COs in water. The water phase was extracted 3 times with DCM. Then, the combined organic phases were dried over Na2SO4 and concentrated under reduced pressure. The product was obtained as an amorphous white solid.

Yield: 37 mg (72%).

MS (ES+) [M+H]⁺ m/e = 471.1

¹H NMR (300 MHz, DMSO-d₆) 5 12.10 (s, 1 H), 7.75 (d, = 8.6 Hz, 1 H), 7.68 - 7.59 (m, 3H), 7.58 - 7.49 (m, 2H), 7.46 (d, J = 2.3 Hz, 1 H), 7.37 (dd, J = 8.6, 2.3 Hz, 1 H), 4.07 (dt, J = 11 .4, 5.3 Hz, 1 H), 3.62 (dt, J = 12.9, 6.2 Hz, 1 H), 3.56 - 3.43 (m, 1 H), 2.33 (s, 3H), 2.13 (s, 3H), 1.83 (s, 6H), 1.68 - 1.53 (m, 2H).

¹³C NMR (151 MHz, DMSO-d₆) 5 168.34, 154.87, 141.90, 138.51 , 135.58, 133.31 , 132.21 , 129.38, 128.67, 128.44, 127.22, 126.95, 123.97, 123.24, 59.62, 44.57, 40.34, 22.43, 18.95, 16.10.

Example compound 131 : A/-(5-(4-Cyclobutoxy-1-(phenylsulfonyl)-1 ,2,3,4- tetrahydroquinolin-6-yl)-4-methylthiazol-2-yl)acetamide

A/-(5-(4-Bromo-1-(phenylsulfonyl)-1 ,2,3,4-tetrahydroquinolin-6-yl)-4-methylthiazol-2-yl)acetamide (20 mg, 39 pmol) was dissolved in 1 mL of dry DCM, followed by the addition of 1 mL of cyclobutanol. The reaction mixture was stirred for one hour at room temperature. The solvent was then removed under reduced pressure and the crude product purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1% TFA). The lyophilized powder was poured in an separatory funnel containing DCM and a saturated solution of Na2COs in water. The water phase was extracted 3 times with DCM. Then, the combined organic phases were dried over Na2SO4 and concentrated under reduced pressure. The product was obtained as an amorphous white solid. Yield: 9 mg (46%).

MS (ES+) [M+H]⁺ m/e = 498.1

¹H NMR (600 MHz, CDCI₃): 6 7.98 (d, J = 8.7 Hz, 1 H), 7.76 - 7.71 (m, 2H), 7.61 - 7.56 (m, 1 H), 7.47 (t, J = 7.9 Hz, 2H), 7.29 (dd, J = 8.6, 2.3 Hz, 1 H), 7.26 - 7.25 (m, 1 H), 4.19 - 4.12 (m, 1 H), 4.08 (dt, J = 12.8, 4.9 Hz, 1 H), 3.96 - 3.89 (m, 1 H), 3.81 (ddd, J = 12.8, 10.7, 3.7 Hz, 1 H), 2.49 (s, 3H), 2.43 (s, 3H), 2.20 - 2.11 (m, 1 H), 2.08 - 2.00 (m, 1 H), 1 .98 - 1 .92 (m, 1 H), 1 .92 - 1 .82 (m, 1 H), 1.82 - 1.74 (m, 1 H), 1.74 - 1.68 (m, 1 H), 1.64 (q, J = 10.1 Hz, 1 H), 1.51 - 1.40 (m, 1 H).

¹³C NMR (151 MHz, CDCI3): 5 169.39, 153.76, 142.11 , 139.15, 134.55, 133.38, 130.33, 130.14, 129.36, 129.06, 127.29, 124.87, 124.25, 123.63, 70.20, 42.77, 31.46, 31.21 , 27.77, 23.33, 13.07, 12.80.

Example compounds 132 to 134:

Step 1 : 4-Bromo-2-(methylsulfonyl)-1 -nitrobenzene

A solution of 2,2,2-trifluoroacetic anhydride (20 eq., 6.38 g, 30.39 mmol, 4. 28 mL) in 5 mL of DCM was added to a 35% solution of H2O2 in water (17.5 eq., 2.58 g, 26.59 mmol, 2.33 mL) at 0 °C. Afterwards, a solution of 4-bromo-2-(methylsulfonyl)aniline (380 mg, 1.52 mmol) in 5 mL of DCM was added to the mixture at the reaction mixture was let to warm up to room temperature. The reaction reached full conversion after 16 hours and the mixture was extracted three times with DCM and the combined organic phases were dried over Na2SO4 and concentrated under reduced pressure. The product was obtained as a beige amorphous solid.

Yield: 410 mg (96%).

MS (ES+) [M+H]⁺ m/e = 279.7, 281.7 (bromine isotopic pattern).

¹H NMR (300 MHz, CD₃OD): 5 8.31 (dd, J = 2.1 , 1 .0 Hz, 1 H), 8.03 (dd, J = 8.5, 2.1 Hz, 1 H), 7.83 (dd, J = 8.5, 1 .0 Hz, 1 H), 3.47 (d, J = 1 .0 Hz, 3H).

¹³C NMR (75 MHz, CD3OD): 5 148.24, 138.68, 138.12, 135.93, 134.68, 127.82, 127.21 , 78.44, 78.01 , 77.58, 49.85, 49.57, 49.28, 49.00, 48.72, 48.43, 48.15, 46.84, 45.16, 1 .29.

Step 2: A/-(4-Methvl-5-(3-(methvlsulfonvl)-4-nitrophenvl)thiazol-2-vl)acetamide

4-Bromo-2-(methylsulfonyl)-1-nitrobenzene (385 mg, 1.37 mmol), A/-(4-methylthiazol-2- yl)acetamide (1.2 eq., 258 mg, 1.65 mmol), tri-tert-butylphosphonium tetrafluoroborate (0.2 eq., 80 mg, 275 pmol), Pd(OAc)2, (0.1 eq., 31 mg, 137 pmol) and CS2CO3 (3 eq., 1.34 g, 4.12 mmol) were suspended in 5 mL of DMF. The suspension was sonicated for 5 minutes, flushed with nitrogen, heated up to 110 °C and stirred overnight. The solvent was then removed under reduced pressure and the residue extracted three times with DCM from water. The combined organic phases were dried over Na2SO4 and concentrated under reduced pressure. The product was obtained as a beige amorphous solid.

Yield: 236 mg (48%).

MS (ES+) [M+H]⁺ m/e = 355.7. ¹H NMR (300 MHz, DMSO-d₆): 6 12.36 (s, 1 H), 8.14 (d, = 8.3 Hz, 1 H), 8.08 (d, J = 1.9 Hz, 1 H), 8.04 (dd, J = 8.3, 2.0 Hz, 1 H), 3.57 (s, 3H), 2.45 (s, 3H), 2.18 (s, 3H).

¹³C NMR (75 MHz, CD₃OD): 5 170.64, 156.70, 148.02, 142.88, 136.67, 130.26, 129.86, 122.28, 121.96, 119.06, 42.34, 22.54, 15.80.

Step 3: /V-(5-(4-Amino-3-(methvlsulfonvl)phenvl)-4-methvlthiazol-2-vl)acetamide

A/-(4-Methyl-5-(3-(methylsulfonyl)-4-nitrophenyl)thiazol-2-yl)acetamide (190 mg, 535 pmol) was dissolved in 3 mL of MeOH and 1 mL of a 5% solution of ammonium chloride in water.

Afterwards, zinc dust (10 eq., 350 mg, 5.35 mmol) was added to the mixture. The reaction mixture was heated up to 50 °C and stirred overnight. The crude product was then filtered and purified by silica gel chromatography using a gradient of cyclohexane and EtOAc as eluent. The product was obtained as a beige oil.

Yield: 48 mg (28%).

MS (ES+) [M+H]⁺ m/e = 325.8.

¹H NMR (300 MHz, Pyridine-d₅): 5 8.17 (d, J = 2.2 Hz, 1 H), 7.51 (dd, J = 8.5, 2.2 Hz, 1 H), 7.14 (d, J = 8.5 Hz, 1 H), 6.90 (s, 2H), 3.30 (s, 3H), 2.45 (s, 3H), 2.33 (s, 3H).

¹³C NMR (75 MHz, Pyridine-d₅): 6 168.93, 156.33, 147.59, 142.66, 136.16, 130.01 , 124.61 , 122.36, 121.82, 118.73, 42.53, 23.32, 16.63.

Step 4: Example compound 132: /V-(4-Methyl-5-(3-(methylsulfonyl)-4- (phenylsulfonamido)phenyl)thiazol-2-yl)acetamide

A/-(5-(4-Amino-3-(methylsulfonyl)phenyl)-4-methylthiazol-2-yl)acetamide (20 mg, 61.5 pmol) was dissolved in 1 mL pyridine. Afterwards, benzenesulfonyl chloride (1.5 eq., 16 mg, 92.2 pmol) was added to the mixture. The reaction mixture was heated up to 100 °C and stirred for one hour. The solvent was then removed under reduced pressure and and purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1% TFA). The product was obtained after lyophilization as an amorphous white solid.

Yield: 7 mg (24%).

MS (ES+) [M+H]⁺ m/e = 465.7.

¹H NMR (600 MHz, CDCI3): 5 9.23 (s, 1 H), 8.00 - 7.95 (m, 2H), 7.88 (d, J = 2.2 Hz, 1 H), 7.80 (d, J = 8.6 Hz, 1 H), 7.67 - 7.63 (m, 1 H), 7.59 - 7.55 (m, 3H), 4.08 (s, 1 H), 2.96 (s, 3H), 2.45 (s, 3H), 2.40 (s, 3H). ¹³C NMR (151 MHz, CDCI3): 5 169.39, 160.08, 139.32, 136.98, 135.43, 135.01 , 133.94, 130.06, 129.66, 128.12, 127.20, 125.59, 122.37, 121.10, 44.33, 23.01 , 13.13.

4 Example compound 133: /V-(5-(4-((2-Chlorophenyl)sulfonamido)-3-

(methylsulfonyl)phenyl)-4-methylthiazol-2-yl)acetamide

A/-(5-(4-Amino-3-(methylsulfonyl)phenyl)-4-methylthiazol-2-yl)acetamide (20 mg, 61.5 pmol) was dissolved in 1 mL pyridine. Afterwards, 2-chlorobenzenesulfonyl chloride (2.0 eq., 26 mg, 122.9 pmol) was added to the mixture. The reaction mixture was heated up to 100 °C and stirred for one hour. The solvent was then removed under reduced pressure and and purified by reversed- phase preparative HPLC (5% to 99% acetonitrile with 0.1 % TFA). The product was obtained after lyophilization as an amorphous white solid.

Yield: 10 mg (33%).

MS (ES+) [M+H]⁺ m/e = 499.6.

¹H NMR (600 MHz, CDCI3): 5 9.65 (s, 1 H), 8.28 (dd, J = 7.9, 1 .6 Hz, 1 H), 7.93 (d, J = 2.2 Hz, 1 H), 7.63 - 7.47 (m, 5H), 4.81 (s, 1 H), 3.20 (s, 3H), 2.43 (s, 3H), 2.38 (s, 3H).

¹³C NMR (151 MHz, CDCI3): 5 169.21 , 159.70, 136.67, 136.52, 135.61 , 135.37, 134.89, 132.44, 132.37, 131.31 , 130.20, 127.76, 127.48, 125.43, 122.43, 119.31 , 44.15, 23.02, 13.32.

Example compound 134: A/-(4-Methyl-5-(3-(methylsulfonyl)-4-(naphthalene-1- sulfonamido)phenyl)thiazol-2-yl)acetamide

A/-(5-(4-Amino-3-(methylsulfonyl)phenyl)-4-methylthiazol-2-yl)acetamide (20 mg, 61.5 pmol) was dissolved in 1 mL pyridine. Afterwards, 2 naphthalene-1 -sulfonyl chloride (2.0 eq., 28 mg, 122.9 pmol) was added to the mixture. The reaction mixture was heated up to 100 °C and stirred for one hour. The solvent was then removed under reduced pressure and and purified by reversed- phase preparative HPLC (5% to 99% acetonitrile with 0.1 % TFA). The product was obtained after lyophilization as an amorphous white solid.

Yield: 2 mg (6%).

MS (ES+) [M+H]⁺ m/e = 515.6.

¹H NMR (750 MHz, CDCI₃): 5 9.60 (s, 1 H), 8.69 (d, J = 8.7 Hz, 1 H), 8.43 (d, J = 7.4 Hz, 1 H), 8.14

(d, J = 8.2 Hz, 1 H), 7.97 (d, J = 8.2 Hz, 1 H), 7.81 (d, J = 2.2 Hz, 1 H), 7.80 - 7.75 (m, 1 H), 7.72 (d, J = 8.7 Hz, 1 H), 7.65 (t, J = 7.5 Hz, 1 H), 7.61 (t, J = 7.8 Hz, 1 H), 7.49 (dd, J = 8.7, 2.2 Hz, 1 H), 2.88 (s, 3H), 2.40 (s, 3H), 2.39 (s, 3H).

¹³C NMR (189 MHz, CDCI₃): 5 169.41 , 160.09, 137.13, 135.64, 135.38, 134.69, 134.37, 133.95, 130.38, 130.10, 129.40, 129.26, 127.84, 127.64, 127.56, 125.05, 124.16, 124.11 , 122.36, 120.25, 44.29, 23.00, 13.02.

Example compound 135: A/-(4-Methyl-5-(2-(phenylsulfonyl)isoindolin-5-yl)thiazol-2- vDacetamide

5-Bromo-2-(phenylsulfonyl)isoindoline (28 mg, 82.8 pmol), A/-(4-methylthiazol-2-yl)acetamide (1.2 eq., 16 mg, 99.3 pmol), tri-te/Y-butylphosphonium tetrafluoroborate (0.2 eq., 4.8 mg, 16.6 pmol), Pd(OAc)2, (0.1 eq., 2 mg, 8.3 pmol) and CS2CO3 (3 eq., 81 mg, 248 pmol) were suspended in 1 mL of DMF. The suspension was sonicated for 5 minutes, flushed with nitrogen, heated up to 110 °C and stirred overnight. The solvent was then removed under reduced pressure and the crude poduct was purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1 % TFA). The product was obtained after lyophilization as an amorphous white solid.

Yield: 18 mg (53%).

MS (ES+) [M+H]⁺ m/e = 413.7.

¹H NMR (300 MHz, CDCI3) 6 12.43 (s, 1 H), 7.94 - 7.88 (m, 2H), 7.64 - 7.50 (m, 3H), 7.32 - 7.20 (m, 3H), 4.68 (s, 4H), 2.40 (s, 3H), 2.33 (s, 3H).

¹³C NMR (75 MHz, CDCI3) 6 168.54, 157.99, 137.26, 137.05, 136.57, 136.52, 133.01 , 130.17, 129.29, 128.68, 127.53, 124.89, 123.37, 123.17, 53.50, 23.12, 14.19.

Example compound 136: A/-(5-(2-((2-Chlorophenyl)sulfonyl)isoindolin-5-yl)-4-methylthiazol- 2-yl)acetamide

Step 1 : 5-Bromo-2-((2-chloroohenvl)sulfonvl)isoindoline

5-Bromoisoindoline hydrochloride (200 mg, 856 pmol) was dissolved in 2 mL pyridine. Afterwards, 2-chlorobenzenesulfonyl chloride (1.25 eq., 225 mg, 1.07 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 and and purified by silica gel chromatography using a gradient of cyclohexane and EtOAc as eluent. The product was obtained as a white solid.

Yield: 38 mg (12%).

MS (ES+) [M+H]⁺ m/e = 371.6, 373.7 (bromine isotopic pattern).

¹H NMR (600 MHz, DMSO-d₆): 5 7.99 (dd, J = 8.0, 1 .6 Hz, 1 H), 7.73 - 7.65 (m, 2H), 7.60 - 7.53 (m, 2H), 7.49 (dd, J = 8.0, 1 .9 Hz, 1 H), 7.28 (d, J = 8.1 Hz, 1 H), 4.71 (t, J = 2.0 Hz, 2H), 4.66 (t, J = 2.2 Hz, 2H). ¹³C NMR (151 MHz, DMSO-d₆): 5 138.58, 135.74, 135.32, 134.60, 132.33, 131.16, 130.84, 130.49, 127.96, 125.95, 125.04, 120.51 , 52.94.

Step 2: /V-(5-(2-((2-Chlorophenvl)sulfonvl)isoindolin-5-vl)-4-methvlthiazol-2-vl)acetamide

5-Bromo-2-((2-chlorophenyl)sulfonyl)isoindoline (25 mg, 67.1 pmol), A/-(4-methylthiazol-2- yl)acetamide (1.2 eq., 13 mg, 80.5 pmol), tri-tert-butylphosphonium tetrafluoroborate (0.2 eq., 3.9 mg, 13.4 pmol), Pd(OAc)2, (0.1 eq., 1.5 mg, 6.7 pmol) and CS2CO3 (3 eq., 66 mg, 201 pmol) were suspended in 1 mL of DMF. The suspension was sonicated for 5 minutes, flushed with nitrogen, heated up to 110 °C and stirred overnight. The solvent was then removed under reduced pressure and the crude product purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1% TFA). The product was obtained after lyophilization as an amorphous white solid.

Yield: 16 mg (53%).

MS (ES+) [M+H]⁺ m/e = 447.6.

¹H NMR (600 MHz, DMSO-d₆): 5 12.08 (s, 1 H), 8.01 (dd, = 7.9, 1.6 Hz, 1 H), 7.73 - 7.65 (m, 2H), 7.58 (td, = 7.6, 1.5 Hz, 1 H), 7.41 (s, 1 H), 7.38 (d, = 1.1 Hz, 2H), 4.74 (q, J = 2.4 Hz, 4H), 2.32 (s, 3H), 2.13 (s, 3H).

¹³C NMR (151 MHz, DMSO-d₆): 5 168.35, 155.13, 142.09, 136.74, 135.84, 134.83, 134.55, 132.35, 131.63, 131.16, 130.89, 128.04, 127.96, 123.50, 123.39, 122.97, 53.26, 53.18, 22.42, 15.97.

Example compound 137: A/-(4-Methyl-5-(2-(naphthalen-1-ylsulfonyl)isoindolin-5-yl)thiazol- 2-yl)acetamide

Step 1 : 5-Bromo-2-(naphthalen-1-vlsulfonvl)isoindoline

5-Bromoisoindoline hydrochloride (110 mg, 555 pmol) was dissolved in 1 mL pyridine. Afterwards, 2 naphthalene-1-sulfonyl chloride (2.0 eq., 252 mg, 1.11 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 and and purified by silica gel chromatography using a gradient of cyclohexane and EtOAc as eluent. The product was obtained as a white solid.

Yield: 44 mg (20%).

MS (ES+) [M+H]⁺ m/e = 409.6, 411.7 (bromine isotopic pattern).

¹H NMR (600 MHz, DMSO-d₆): 5 8.73 (dd, J = 8.6, 1.1 Hz, 1 H), 8.28 (d, J = 8.3 Hz, 1 H), 8.14 (dd, J = 7.3, 1 .2 Hz, 1 H), 8.11 (dt, J = 8.0, 0.8 Hz, 1 H), 7.75 (ddd, J = 8.5, 6.8, 1 .4 Hz, 1 H), 7.71 - 7.64 (m, 2H), 7.50 (d, J = 1 .8 Hz, 1 H), 7.44 (dd, J = 8.1 , 1 .9 Hz, 1 H), 7.24 (d, J = 8.1 Hz, 1 H), 4.67 (s, 2H), 4.63 (s, 2H).

¹³C NMR (151 MHz, DMSO- d₆): 5 138.57, 135.32, 134.57, 134.10, 132.85, 130.50, 129.11 , 129.08, 128.39, 128.17, 127.08, 125.97, 125.04, 124.74, 124.42, 120.52, 52.74. Step 2: /V-(4-Methvl-5-(2-(naphthalen-1 -vlsulfonvl)isoindolin-5-vl)thiazol-2-vl)acetamide

5-Bromo-2-(naphthalen-1-ylsulfonyl)isoindoline (44 mg, 113 pmol), A/-(4-methylthiazol-2- yl)acetamide (1.2 eq., 21 mg, 136 pmol), tri-tert-butylphosphonium tetrafluoroborate (0.2 eq., 6.6 mg, 22.6 pmol), Pd(OAc)2, (0.1 eq. ,2.5 mg, 11 .3 pmol) and CS2CO3 (3 eq., 111 mg, 340 pmol) were suspended in 1 mL of DMF. The suspension was sonicated for 5 minutes, flushed with nitrogen, heated up to 110 °C and stirred overnight. The solvent was then removed under reduced pressure and the crude product purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1% TFA). The product was obtained after lyophilization as an amorphous white solid.

Yield: 25 mg (47%).

MS (ES+) [M+H]⁺ m/e = 463.7.

¹H NMR (600 MHz, DMSO-d₆): 5 12.07 (s, 1 H), 8.77 (d, = 8.7 Hz, 1 H), 8.28 (d, J = 8.2 Hz, 1 H), 8.17 (dd, J = 7.3, 1.2 Hz, 1 H), 8.10 (d, J = 8.2 Hz, 1 H), 7.76 (ddd, J = 8.6, 6.9, 1.4 Hz, 1 H), 7.72 - 7.65 (m, 2H), 7.36 (s, 1 H), 7.33 (d, J = 1.2 Hz, 2H), 4.70 (s, 4H), 2.29 (s, 3H), 2.12 (s, 3H).

¹³C NMR (151 MHz, DMSO-d₆): 5 168.77, 155.57, 142.49, 137.16, 135.25, 134.94, 134.54, 133.37, 132.06, 129.53, 129.52, 128.79, 128.66, 128.47, 127.49, 125.17, 124.94, 123.91 , 123.80, 123.39, 53.47, 53.38, 22.84, 16.36.

Example compound 138: A/-(4-Methyl-5-(1-oxo-2-(phenylsulfonyl)isoindolin-5-yl)thiazol-2- vDacetamide

Step 1 : 5-Bromo-2-(phenvlsulfonvl)isoindolin-1-one

5-Bromoisoindolin-1-one (165 mg, 778 pmol) was dissolved in dry THF (3 mL) and the solution was brought to 0 °C. Afterwards, NaH 60% (2 eq., 62 mg, 1.56 mmol) and benzenesulfonyl chloride (2 eq., 275 mg, 1 .56 mmol, 0.2 mL) were added to the mixture, which was then warmed up to 50 °C. After 2 hours, the reaction mixture was quenched with acetic acid and the crude mixture was extracted three times with DCM. Then, the combined organic phases were dried over Na2SC>4 and concentrated under reduced pressure. The crude product was then finally purified by silica gel chromatography using a gradient of cyclohexane and EtOAc as eluent. The product was obtained as a white solid.

Yield: 204 mg (74%).

MS (ES+) [M+H]⁺ m/e = 351.6, 353.7 (bromine isotopic pattern).

¹H NMR (300 MHz, DMSO-d₆): 5 8.13 - 8.02 (m, 2H), 7.94 (d, J = 1 .0 Hz, 1 H), 7.83 - 7.57 (m, 5H), 5.10 (s, 2H).

¹³C NMR (75 MHz, DMSO-d₆): 6 164.95, 144.31 , 137.88, 134.53, 132.06, 129.48, 128.34, 128.09, 127.82, 127.46, 126.09, 49.82. Step 2: /V-(4-Methvl-5-(1 -oxo-2-(phenvlsulfonvl)isoindolin-5-vl)thiazol-2-vl)acetamide

5-Bromo-2-(phenylsulfonyl)isoindolin-1-one (45 mg, 128 pmol), A/-(4-methylthiazol-2-yl)acetamide (1.2 eq., 24 mg, 153 pmol), tri-te/Y-butylphosphonium tetrafluoroborate (0.2 eq., 7.4 mg, 25.6 pmol), Pd(OAc)2, (0.1 eq., 2.9 mg, 12.8 pmol) and CS2CO3 (3 eq., 125 mg, 383 pmol) were suspended in 1 mL of DMF. The suspension was sonicated for 5 minutes, flushed with nitrogen, heated up to 110 °C and stirred overnight. The solvent was then removed under reduced pressure and the crude product purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1% TFA). The product was obtained after lyophilization as an amorphous white solid.

Yield: 16 mg (28%).

MS (ES+) [M+H]⁺ m/e = 427.7.

¹H NMR (600 MHz, DMSO-d₆): 5 12.22 (s, 1 H), 8.09 - 8.06 (m, 2H), 7.79 - 7.74 (m, 3H), 7.68 - 7.64 (m, 2H), 7.62 (dd, J = 8.2, 1 .5 Hz, 1 H), 5.13 (s, 2H), 2.40 (s, 3H), 2.15 (s, 3H).

¹³C NMR (151 MHz, DMSO-d₆): 5 168.60, 165.28, 156.19, 144.12, 142.99, 138.17, 138.04, 134.36, 129.41 , 128.81 , 127.68, 127.30, 124.69, 123.62, 122.75, 50.14, 22.42, 16.37.

Example compound 139: A/-(5-(2-((2-Chlorophenyl)sulfonyl)-1-oxoisoindolin-5-yl)-4- methylthiazol-2-yl)acetamide

Step 1 : 5-Bromo-2-((2-chlorophenvl)sulfonvl)isoindolin-1 -one

5-Bromoisoindolin-1-one (200 mg, 943 pmol) was dissolved in dry THF (3 mL) and the solution was brought to 0 °C. Afterwards, NaH 60% (2 eq., 75 mg, 1 .89 mmol) and 2- chlorobenzenesulfonyl chloride (2 eq., 398 mg, 1.89 mmol) were added to the mixture, which was then warmed up to 50 °C. After 2 hours, the reaction mixture was quenched with acetic acid and the mixture was extracted three times with DCM. Then, the combined organic phases were dried over Na2SC>4 and concentrated under reduced pressure. The crude product was then finally purified by silica gel chromatography using a gradient of cyclohexane and EtOAc as eluent. The product was obtained as a white solid.

Yield: 157 mg. (43%).

MS (ES+) [M+H]⁺ m/e = 385.6, 387.6 (bromine isotopic pattern).

¹H NMR (600 MHz, DMSO-d₆): 5 8.27 (dd, J = 8.0, 1 .6 Hz, 1 H), 7.99 (d, J = 1 .6 Hz, 1 H), 7.79 - 7.75 (m, 2H), 7.72 - 7.64 (m, 3H), 5.21 (s, 2H).

¹³C NMR (151 MHz, DMSO-d₆): 5 164.79, 144.25, 135.98, 135.31 , 132.92, 132.16, 131.95, 130.84, 128.30, 128.04, 127.83, 127.64, 126.12, 49.81. Step 2: A/-(5-(2-((2-Chlorophenvl)sulfonvl)-1 -oxoisoindolin-5-yl)-4-methylthiazol-2- yl)acetamide

5-Bromo-2-((2-chlorophenyl)sulfonyl)isoindolin-1-one (45 mg, 116 pmol), A/-(4-methylthiazol-2- yl)acetamide (1.2 eq., 22 mg, 140 pmol), tri-tert-butylphosphonium tetrafluoroborate (0.2 eq., 6.7 mg, 23.3 pmol), Pd(OAc)2, (0.1 eq., 2.6 mg, 11.6 pmol) and CS2CO3 (3 eq., 114 mg, 349 pmol) were suspended in 1 mL of DMF. The suspension was sonicated for 5 minutes, flushed with nitrogen, heated up to 110 °C and stirred overnight. The solvent was then removed under reduced pressure and the crude product purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1% TFA). The product was obtained after lyophilization as an amorphous white solid.

Yield: 15 mg (28%).

MS (ES+) [M+H]⁺ m/e = 461.6.

¹H NMR (600 MHz, DMSO-d₆): 5 12.24 (s, 1 H), 8.28 (dd, = 8.0, 1.6 Hz, 1 H), 7.81 (s, 1 H), 7.80 - 7.74 (m, 2H), 7.74 - 7.62 (m, 3H), 5.25 (s, 2H), 2.43 (s, 3H), 2.16 (s, 3H).

¹³C NMR (151 MHz, DMSO-d₆): 5 168.63, 165.14, 156.24, 144.26, 143.02, 138.37, 135.85, 135.50, 132.87, 131.90, 130.82, 128.82, 127.99, 126.76, 124.75, 123.74, 122.74, 50.16, 22.43, 16.47.

Example compound 140: A/-(4-Methyl-5-(2-(naphthalen-1-ylsulfonyl)-1-oxoisoindolin-5- yl)thiazol-2-yl)acetamide

Step 1 : 5-Bromo-2-(naphthalen-1 -ylsulfonyl)isoindolin-1 -one

5-Bromoisoindolin-1-one (200 mg, 943 pmol) was dissolved in dry THF (3 mL) and the solution was brought to 0 °C. Afterwards, NaH 60% (2 eq., 75 mg, 1.89 mmol) and naphthalene-1 -sulfonyl chloride (2 eq., 427 mg, 1 .89 mmol) were added to the mixture, which was then warmed up to 50 °C. After 2 hours, the reaction mixture was quenched with acetic acid and the mixture was extracted three times with DCM. Then, the combined organic phases were dried over Na2SC>4 and concentrated under reduced pressure. The crude product was then finally purified by silica gel chromatography using a gradient of cyclohexane and EtOAc as eluent. The product was obtained as a white solid.

Yield: 365 mg (96%).

MS (ES+) [M+H]⁺ m/e = 401.6, 403.6 (bromine isotopic pattern).

¹H NMR (300 MHz, DMSO-d₆): 5 8.57 (dd, J = 8.6, 1 .2 Hz, 1 H), 8.46 (dd, J = 7.5, 1 .2 Hz, 1 H), 8.37 (d, J = 8.2 Hz, 1 H), 8.13 (dd, = 8.0, 1.5 Hz, 1 H), 7.93 (d, J = 1.6 Hz, 1 H), 7.81 - 7.62 (m, 4H), 7.58 (d, J = 8.2 Hz, 1 H), 5.23 (s, 2H). ¹³C NMR (151 MHz, DMSO-d₆): 5 168.63, 165.14, 156.24, 144.26, 143.02, 138.37, 135.85, 135.50, 132.87, 131.90, 130.82, 128.82, 127.99, 126.76, 124.75, 123.74, 122.74, 50.16, 22.43, 16.47.

Step 2: A/-(4-Methvl-5-(2-(naphthalen-1-vlsulfonvl)-1 -oxoisoindolin-5-yl)thiazol-2- yl)acetamide

5-Bromo-2-(naphthalen-1-ylsulfonyl)isoindolin-1-one (50 mg, 124 pmol), A/-(4-methylthiazol-2- yl)acetamide (1.2 eq., 23 mg, 149 pmol), tri-tert-butylphosphonium tetrafluoroborate (0.2 eq., 7.2 mg, 24.9 pmol), Pd(OAc)2, (0.1 eq., 2.8 mg, 12.4 pmol) and CS2CO3 (3 eq., 121 mg, 373 pmol) were suspended in 1 mL of DMF. The suspension was sonicated for 5 minutes, flushed with nitrogen, heated up to 110 °C and stirred overnight. The solvent was then removed under reduced pressure and the crude product purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1% TFA). The product was obtained after lyophilization as an amorphous white solid.

Yield: 10 mg (17%).

MS (ES+) [M+H]⁺ m/e = 477.6.

¹H NMR (600 MHz, DMSO-d₆): 5 12.22 (s, 1 H), 8.60 (dd, = 8.6, 1.0 Hz, 1 H), 8.46 (dd, = 7.4, 1.2 Hz, 1 H), 8.38 (d, J = 8.2 Hz, 1 H), 8.14 (dd, = 8.2, 1.4 Hz, 1 H), 7.80 - 7.73 (m, 3H), 7.72 - 7.66 (m, 2H), 7.60 (dd, J = 8.1 , 1 .6 Hz, 1 H), 5.25 (s, 2H), 2.39 (s, 3H), 2.15 (s, 3H).

¹³C NMR (151 MHz, DMSO-d₆): 5 168.61 , 165.11 , 156.21 , 144.16, 142.62, 138.20, 135.80, 133.74, 132.91 , 131.70, 129.40, 129.04, 128.83, 127.52, 127.18, 127.12, 124.73, 124.65, 123.68, 123.32, 122.73, 49.91 , 22.42, 16.40.

Example compounds 141 and 142

Step 1 : /V-(4-Bromo-2-fluorobenzvl)benzenesulfonamide

(4-Bromo-2-fluorophenyl)methanamine (590 mg, 2.89 mmol) was dissolved in 6 mL pyridine. Afterwards, 2 benzenesulfonyl chloride (2.0 eq., 1.02 g, 5.78 mmol, 0.738 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 residue purified by silica gel chromatography using a gradient of cyclohexane and EtOAc as eluent. The product was obtained as a yellow oil.

Yield: 496 mg (50%).

MS (ES-) [M-H]' m/e = 341.7, 343.7 (bromine isotopic pattern).

¹H NMR (600 MHz, CDCI3): 5 7.83 - 7.78 (m, 2H), 7.58 - 7.53 (m, 1 H), 7.49 - 7.43 (m, 2H), 7.19 (dd, J = 8.2, 1 .9 Hz, 1 H), 7.16 - 7.09 (m, 2H), 4.90 (t, J = 6.5 Hz, 1 H), 4.19 (d, J = 6.5 Hz, 2H). ¹³C NMR (151 MHz, CDCI₃): 5 160.38 (d, = 251.3 Hz), 139.89, 132.74, 131.20 (d, 7 = 4.7 Hz), 129.10, 127.63 (d, 7 = 3.6 Hz), 126.97, 122.82, 122.20 (d, 7 = 9.6 Hz), 119.05 (d, 7 = 24.4 Hz), 40.94 (d, 7 = 3.6 Hz).

Step 2: Example compound 141 : A/-(5-(3-Fluoro-4-(phenylsulfonamidomethyl)phenyl)-4- methylthiazol-2-yl)acetamide

A/-(4-Bromo-2-fluorobenzyl)benzenesulfonamide (245 mg, 712 pmol), A/-(4-methylthiazol-2- yl)acetamide (1.2 eq., 133 mg, 854 pmol), tri-te/Y-butylphosphonium tetrafluoroborate (0.2 eq., 41 mg, 142 pmol), Pd(OAc)2, (0.1 eq., 16 mg, 71 pmol) and CS2CO3 (3 eq., 696 mg, 2.14 mmol) were suspended in 3 mL of DMF. The suspension was sonicated for 5 minutes, flushed with nitrogen, heated up to 110 °C and stirred overnight. The solvent was then removed under reduced pressure and the crude product purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1% TFA). The product was obtained after lyophilization as an amorphous white solid.

Yield: 175 mg (59%).

MS (ES+) [M+H]⁺ m/e = 419.7.

¹H NMR (600 MHz, DMSO-d₆): 5 12.13 (s, 1 H), 8.22 (t, 7 = 6.2 Hz, 1 H), 7.79 - 7.75 (m, 2H), 7.62 - 7.58 (m, 1 H), 7.57 - 7.52 (m, 2H), 7.36 (t, 7 = 8.0 Hz, 1 H), 7.19 - 7.13 (m, 2H), 4.06 (d, 7 = 6.1 Hz, 2H), 2.32 (s, 3H), 2.14 (s, 3H).

¹³C NMR (75 MHz, DMSO-d₆): 6 168.49, 159.83 (d, 7 = 246.3 Hz), 155.51 , 142.88, 140.57, 133.51 (d, 7 = 8.7 Hz), 132.40, 130.82 (d, 7 = 4.9 Hz), 129.15, 126.45, 124.40 (d, 7 = 3.1 Hz), 123.12 (d, 7 = 14.9 Hz), 122.37 (d, 7 = 2.0 Hz), 114.78 (d, 7 = 22.8 Hz), 22.47, 16.06. CH₂ was covered by the solvent peak

Step 2: Example compound 142: A/-(4-methyl-5-(3-(methylsulfonyl)-4- (phenylsulfonamidomethyl)phenyl)thiazol-2-yl)acetamide

A/-(5-(3-Fluoro-4-(phenylsulfonamidomethyl)phenyl)-4-methylthiazol-2-yl)acetamide (78 mg, 186 pmol), NaSCHs (2 eq., 26 mg, 372 pmol) and CS2CO3 (2 eq., 73 mg, 372 pmol) were dissolved in 1 mL of DMF. The suspension was flushed with nitrogen, heated up to 140 °C and stirred overnight. The solvent was then removed under reduced pressure and the residue was used for the following reaction without further purification. The solid was resuspended in 1 mL of DCM and brought to 0 °C. Afterwards, mefa-chloroperbenzoic acid (3 eq., 96 mg, 558 pmol) was added to the mixture, which was kept at 0 °C for 45 minutes. The solvent was then removed under reduced pressure and the crude product purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1% TFA). The product was obtained after lyophilization as an amorphous white solid.

Yield: 10 mg (11%). MS (ES+) [M+H]⁺ m/e = 479.7.

¹H NMR (600 MHz, DMSO-d₆): 5 12.19 (s, 1 H), 8.37 (t, 7 = 6.3 Hz, 1 H), 7.88 (d, 7 = 2.0 Hz, 1 H), 7.84 - 7.81 (m, 2H), 7.75 (dd, 7 = 8.1 , 2.0 Hz, 1 H), 7.70 (d, 7 = 8.1 Hz, 1 H), 7.66 - 7.62 (m, 1 H), 7.61 - 7.57 (m, 2H), 4.49 (d, 7 = 6.3 Hz, 2H), 3.28 (s, 3H), 2.36 (s, 3H), 2.15 (s, 3H).

¹³C NMR (151 MHz, DMSO-d₆): 5 168.65, 155.81 , 143.52, 140.44, 138.48, 135.67, 133.10, 132.65, 132.11 , 130.97, 129.34, 128.20, 126.50, 121.84, 40.06, 22.48, 16.09, 8.67.

Example compound 143: A/-(5-(3-Fluoro-4-((phenylsulfonyl)methyl)phenyl)-4-methylthiazol- 2-yl)acetamide

4-Bromo-2-fluoro-1-((phenylsulfonyl)methyl)benzene (135 mg, 410 pmol), A/-(4-methylthiazol-2- yl)acetamide (1.2 eq., 77 mg, 492 pmol), tri-tert-butylphosphonium tetrafluoroborate (0.2 eq., 24 mg, 82 pmol), Pd(OAc)2, (0.1 eq., 9 mg, 41 pmol) and CS2CO3 (3 eq., 401 mg, 1.23 mmol) were suspended in 2 mL of DMF. The suspension was sonicated for 5 minutes, flushed with nitrogen, heated up to 110 °C and stirred overnight. The solvent was then removed under reduced pressure and the crude product purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1% TFA). The product was obtained after lyophilization as an amorphous white solid.

Yield: 80 mg (48%).

MS (ES+) [M+H]⁺ m/e = 405.1 .

¹H NMR (300 MHz, DMSO-d₆): 5 12.18 (s, 1 H), 7.81 - 7.70 (m, 3H), 7.67 - 7.56 (m, 2H), 7.35 - 7.17 (m, 3H), 4.71 (s, 2H), 2.34 (s, 3H), 2.14 (s, 3H).

¹³C NMR (151 MHz, DMSO-d₆): 5 168.61 , 160.84 (d, = 249.6 Hz), 155.74, 143.46, 138.34, 135.09 (d, 7 = 8.8 Hz), 134.20, 133.66 (d, 7 = 3.9 Hz), 129.34, 128.10, 124.38, 122.16, 114.86 (d, 7 = 22.9 Hz), 114.53 (d, 7 = 15.2 Hz), 54.57, 22.48, 16.22.

Example compound 144: A/-(4-Methyl-5-(3-(methylsulfonyl)-4- ((phenylsulfonyl)methyl)phenyl)thiazol-2-yl)acetamide

A/-(5-(3-Fluoro-4-((phenylsulfonyl)methyl)phenyl)-4-methylthiazol-2-yl)acetamideacetamide (70 mg, 173 pmol), NaSCHs (2 eq., 24 mg, 346 pmol) and CS2CO3 (2 eq., 113 mg, 346 pmol) were dissolved in 1 mL of DMF. The suspension was flushed with nitrogen, heated up to 140 °C and stirred overnight. The solvent was then removed under reduced pressure and the crude poduct was used for the following reaction without further purification. The solid was resuspended in 1 mL of DCM and brought to 0 °C. Afterwards, mefa-chloroperbenzoic acid (3 eq., 90 mg, 519 pmol) was added to the mixture, which was kept at 0 °C for 45 minutes. The solvent was then removed under reduced pressure and the crude product purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1 % TFA). The product was obtained after lyophilization as an amorphous white solid.

Yield: 12 mg (15%).

MS (ES+) [M+H]⁺ m/e = 464.6.

¹H NMR (600 MHz, DMSO-d₆): 5 12.22 (s, 1 H), 8.04 (d, J = 1.9 Hz, 1 H), 7.88 - 7.85 (m, 2H), 7.83

- 7.78 (m, 2H), 7.69 (t, J = 7.7 Hz, 2H), 7.50 (d, J = 8.1 Hz, 1 H), 5.28 (s, 2H), 3.38 (s, 3H), 2.40 (s, 3H), 2.16 (s, 3H).

¹³C NMR (151 MHz, DMSO-d₆): 5 168.76, 156.12, 144.18, 140.85, 138.80, 134.86, 134.45, 133.95, 132.73, 129.70, 129.63, 128.06, 125.27, 121.62, 56.54, 44.91 , 22.51 , 16.27. l-4-(2-

4-Bromo-2-(methylsulfonyl)-1 -vinyl benzene

Methyltriphenylphosphonium bromide (1.2 eq., 652 mg, 1.82 mmol) was suspended in 7 mL of dry TH F. Afterwards, potassium tert-butoxide, 12% in THF, (1.2 eq., 205 mg, 1.82 mmol, 1.82 mL) was added to the mixture and left stirring at room temperature for 30 minutes. Then, the reaction mixture was brought at 0 °C and 4-bromo-2-(methylsulfonyl)benzaldehyde (400 mg, 1 .52 mmol) was added to the mixture. After 30 min at 0°C, the rection was slowly quenched with AcOH. The solvent was evaporated and the crude poduct was purified by silica gel chromatography using a gradient of cyclohexane and EtOAc as eluent. The product was obtained as a yellow oil.

Yield: 150 mg (38%).

¹H NMR (300 MHz, CDCI₃): 5 8.21 (d, J = 2.1 Hz, 1 H), 7.77 - 7.69 (m, 1 H), 7.64 - 7.49 (m, 2H), 5.79 (dd, J = 17.3, 1.0 Hz, 1 H), 5.58 (dd, J = 11.0, 1.0 Hz, 1 H), 3.07 (s, 3H).

¹³C NMR (75 MHz, CDCI₃): 5 138.71 , 136.89, 136.69, 132.32, 131.70, 129.77, 120.57, 77.42, 77.00, 76.58, 43.79. (methylsulfonyl)-4-vinylphenyl)thiazol-2-yl)acetamide

4-Bromo-2-(methylsulfonyl)-1-vinylbenzene (150 mg, 574 pmol), A/-(4-methylthiazol-2- yl)acetamide (1.2 eq., 108 mg, 689 pmol), tri-tert-butylphosphonium tetrafluoroborate (0.2 eq., 33 mg, 114 pmol), Pd(OAc)2, (0.1 eq., 13 mg, 57 pmol) and CS2CO3 (3 eq., 561 mg, 1 .72 mmol) were suspended in 2 mL of DMF. The suspension was sonicated for 5 minutes, flushed with nitrogen, heated up to 110 °C and stirred overnight. The solvent was then removed under reduced pressure and the crude product purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1% TFA). The product was obtained after lyophilization as an amorphous white solid.

Yield: 35 mg (13%).

MS (ES+) [M+H]⁺ m/e = 337.1. ¹H NMR (300 MHz, CDCI3): 6 8.15 (d, J = 1.8 Hz, 1 H), 7.75 - 7.56 (m, 3H), 5.83 (dd, J = 17.3, 1.1 Hz, 1 H), 5.58 (dd, J = 11 .0, 1 .1 Hz, 1 H), 3.11 (s, 3H), 2.43 (s, 3H), 2.28 (s, 3H).

¹³C NMR (75 MHz, CDCI3): 6 167.99, 157.02, 142.94, 137.66, 136.35, 133.81 , 132.61 , 132.54, 128.71 , 128.63, 123.86, 120.25, 43.89, 23.21 , 16.23.

Step 3: A/-(4-Methvl-5-(3-(methvlsulfonvl)-4-(2-(phenvlsulfonvl)ethvl)phenvl)thiazol-2- yl)acetamide

A/-(4-Methyl-5-(3-(methylsulfonyl)-4-vinylphenyl)thiazol-2-yl)acetamide (35 mg, 104 pmol), benzenethiol (1.5 eq., 17 mg, 156 pmol) were dissolved in 1 mL of acetonitrile. The solution was flushed with nitrogen, heated up to reflux and stirred overnight. The solvent was then removed under reduced pressure and the residue was used for the following reaction without further purification. The solid was resuspended in 1 mL of DCM and brought to 0 °C. Afterwards, meta- chloroperbenzoic acid (3 eq., 54 mg, 312 pmol) was added to the mixture, which was kept at 0 °C for 45 minutes. The solvent was then removed under reduced pressure and the crude product purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1% TFA). The product was obtained after lyophilization as an amorphous white solid.

Yield: 8 mg (16%).

MS (ES+) [M+H]⁺ m/e = 479.1 .

¹H NMR (300 MHz, CDCI3): 5 8.05 (d, J = 1 .8 Hz, 1 H), 8.00 - 7.92 (m, 2H), 7.73 - 7.55 (m, 5H), 3.58 - 3.40 (m, 4H), 3.07 (s, 3H), 2.50 (s, 3H), 2.43 (s, 3H).

¹³C NMR (151 MHz, DMSO-d₆): 6 168.68, 155.77, 143.45, 139.49, 138.79, 135.60, 134.04, 133.21 , 132.89, 131.79, 129.54, 128.27, 127.83, 121.88, 55.19, 43.98, 25.44, 22.49, 16.09.

Example compound 146: A/-(4-Methyl-5-(4-(A/-methylphenylsulfonamido)-3- (methylsulfonyl)phenyl)thiazol-2-yl)acetamide

A/-(4-Methyl-5-(3-(methylsulfonyl)-4-(phenylsulfonamido)phenyl)thiazol-2-yl)acetamide (30 mg, 64 pmol) was dissolved in 1 mL of DMF. Afterwards, CH3I (2 eq., 18 mg, 129 pmol) and CS2CO3 (2 eq., 42 mg, 129 pmol) were added tot he mixture. The reaction mixture was warmed up to 45 °C and stirred for one hour. Upon completion of the reaction, the solvent was removed under reduced pressure and the crude product purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1% TFA). The product was obtained after lyophilization as an amorphous white solid.

Yield: 12 mg (39%). MS (ES+) [M+H]⁺ m/e = 479.7.

¹H NMR (600 MHz, DMSO-D6): 6 12.25 (s, 1 H), 8.05 (d, J = 2.3 Hz, 1 H), 7.92 - 7.88 (m, 2H), 7.87 - 7.82 (m, 1 H), 7.78 (dd, J = 8.3, 2.3 Hz, 1 H), 7.75 (t, J = 7.8 Hz, 2H), 6.89 (d, J = 8.2 Hz, 1 H), 3.52 (s, 3H), 3.17 (s, 3H), 2.39 (s, 3H), 2.16 (s, 3H).

¹³C NMR (151 MHz, DMSO-D6): 5 168.66, 156.14, 144.21 , 140.63, 138.11 , 137.09, 134.11 , 133.94, 133.79, 129.77, 129.46, 129.20, 128.09, 121.27, 44.19, 40.56, 28.59, 22.42, 16.20.

Example compounds 147 and 148:

Step 1 : (5-Bromo-2-nitrophenvl)(methvl)sulfane

4-Bromo-2-fluoro-1 -nitrobenzene (456 mg, 2.07 mmol), NaSCHs (3 eq., 436 mg, 6.22 mmol) and CS2CO3 (3 eq., 2.03 g, 6.22 mmol) were dissolved in 5 mL of acetonitrile and the reaction mixture was stirred for 16 hours at room temperature. Upon completion of the reaction, the mixture was poured in a separatory funnel, containing DCM and Water. The water phase was extracted 3 times with DCM. Then, the combined organic phases were dried over Na2SC>4 and concentrated under reduced pressure. The crude product was then finally purified by silica gel chromatography using a gradient of cyclohexane and EtOAc as eluent. The product was obtained as a yellow solid.

Yield: 243 mg (47%).

¹H NMR (300 MHz, DMSO-d₆): 5 8.15 (d, J = 8.8 Hz, 1 H), 7.69 (d, J = 2.0 Hz, 1 H), 7.59 (dd, J = 8.8, 2.0 Hz, 1 H), 2.57 (s, 3H).

¹³C NMR (75 MHz, DMSO-d₆): 6 144.03, 140.89, 129.08, 128.64, 127.83, 127.69, 15.35.

Step 2: A/-(4-Bromo-2-(methvlthio)phenvl)benzenesulfonamide

(5-Bromo-2-nitrophenyl)(methyl)sulfane (200 mg, 806 pmol) was dissolved in 3 mL of MeOH and 1 mL of a 5% solution of ammonium chloride in water. Afterwards, zinc dust (10 eq., 527 mg, 8.06 mmol) was added to the mixture. The reaction mixture was and stirred at room temperature for 30 minutes. The crude intermediate was then used for the following reaction without further purification. The product was dissolved in 1 mL pyridine. Afterwards, benzenesulfonyl chloride (2 eq., 142 mg, 806 pmol, 0.103 mL) was added to the mixture. The reaction mixture was stirred for three hours at room temperature. The solvent was then removed under reduced pressure and the crude product was then finally purified by silica gel chromatography using a gradient of cyclohexane and EtOAc as eluent. The product was obtained as a white solid.

Yield: 97 mg (67%).

MS (ES+) [M+H]⁺ m/e = 357.7, 359.6 (bromine isotopic pattern).

¹H NMR (300 MHz, CDCI3): 5 7.81 - 7.72 (m, 2H), 7.58 - 7.38 (m, 6H), 7.32 (dd, J = 8.7, 2.3 Hz, 1 H), 2.16 (s, 3H).

¹³C NMR (75 MHz, CDCI3): 5 138.79, 135.67, 134.49, 133.25, 131.42, 130.25, 129.06, 127.12, 122.54, 118.16, 18.56. Step 3: Example compound 147: A/-(4-Methyl-5-(3-(methylthio)-4- (phenylsulfonamido)phenyl)thiazol-2-yl)acetamide

A/-(4-Bromo-2-(methylthio)phenyl)benzenesulfonamide (95 mg, 265 pmol), A/-(4-methylthiazol-2- yl)acetamide (1.2 eq., 50 mg, 318 pmol), tri-tert-butylphosphonium tetrafluoroborate (0.2 eq., 15 mg, 53 pmol), Pd(OAc)2, (0.1 eq., 6 mg, 27 pmol) and CS2CO3 (3 eq., 259 mg, 796 pmol) were suspended in 2 mL of DMF. The suspension was sonicated for 5 minutes, flushed with nitrogen, heated up to 130 °C and stirred overnight. The solvent was then removed under reduced pressure and the crude product purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1% TFA). The product was obtained after lyophilization as an amorphous white solid.

Yield: 22 mg (19%).

MS (ES+) [M+H]⁺ m/e = 433.7.

¹H NMR (600 MHz, DMSO-d₆): 5 12.10 (s, 1 H), 9.70 (s, 1 H), 7.80 - 7.75 (m, 2H), 7.68 - 7.63 (m, 1 H), 7.61 - 7.56 (m, 2H), 7.22 (d, = 2.1 Hz, 1 H), 7.12 (dd, J = 8.2, 2.1 Hz, 1 H), 6.91 (d, J = 8.2 Hz, 1 H), 2.33 (s, 3H), 2.32 (s, 3H), 2.13 (s, 3H).

¹³C NMR (151 MHz, DMSO-d₆): 5 168.83, 155.76, 143.02, 141.47, 138.19, 133.23, 131.81 , 129.63, 127.87, 127.18, 126.56, 125.71 , 124.56, 123.34, 22.90, 16.58, 15.49.

Step 3: Example compound 148: A/-(4-Methyl-5-(3-(methylsulfinyl)-4- (phenylsulfonamido)phenyl)thiazol-2-yl)acetamide

A/-(4-Methyl-5-(3-(methylthio)-4-(phenylsulfonamido)phenyl)thiazol-2-yl)acetamide (10 mg, 23 pmol) was dissolved in 1 mL of DCM and brought to 0 °C. Afterwards, mefa-chloroperbenzoic acid (2 eq., 8.0 mg, 46.1 pmol) was added portionwise (2 mg every 10 minutes) to the mixture, which was kept at 0 °C for 45 minutes. The solvent was then removed under reduced pressure and the crude product purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1% TFA). The product was obtained after lyophilization as an amorphous white solid.

Yield: 7 mg (68%).

MS (ES+) [M+H]⁺ m/e = 449.7.

¹H NMR (600 MHz, DMSO-d₆): 5 12.16 (s, 1 H), 10.26 (s, 1 H), 7.79 (d, J = 2.2 Hz, 1 H), 7.78 - 7.75 (m, 2H), 7.72 - 7.68 (m, 1 H), 7.62 (t, J = 7.7 Hz, 2H), 7.52 (dd, J = 8.3, 2.2 Hz, 1 H), 6.93 (d, J = 8.4 Hz, 1 H), 2.74 (s, 3H), 2.34 (s, 3H), 2.14 (s, 3H). ¹³C NMR (151 MHz, DMSO-d₆): 5 168.49, 155.58, 143.58, 143.20, 139.70, 133.28, 131.95, 131.74, 131.12, 129.45, 128.79, 126.76, 124.03, 122.14, 42.19, 22.41 , 16.20.

Example compound 149: A/-(4-Methyl-5-(4-(phenylsulfonamido)-3-(pyrrolidin-1- yl)phenyl)thiazol-2-yl)acetamide

Step 1 : A/-(4-Methvl-5-(4-nitro-3-(pyrrolidin-1-vl)phenvl)thiazol-2-vl)acetamide

4-Bromo-2-fluoro-1 -nitrobenzene (61 mg, 277 pmol), pyrrolidine (1.5 eq., 29.6 mg, 416 pmol) and CS2CO3 (2 eq., 180 mg, 554 pmol) were suspended in 2 mL of DMF and irradiated with microwaved for 2 hours at 100 °C. Afterwards, A/-(4-methylthiazol-2-yl)acetamide (1.2 eq., 52 mg, 332 pmol), tri-tert-butylphosphonium tetrafluoroborate (0.2 eq., 16 mg, 55 pmol), Pd(OAc)2, (0.1 eq., 6 mg, 28 pmol) and again CS2CO3 (2 eq., 180 mg, 554 pmol) were added to the crude mixture. The suspension was sonicated for 5 minutes, flushed with nitrogen, heated up to 130 °C and stirred overnight. The solvent was then removed under reduced pressure and the crude product purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1% TFA). The product was obtained after lyophilization as an amorphous white solid.

Yield: 33 mg (34%).

MS (ES+) [M+H]⁺ m/e = 346.9.

¹H NMR (300 MHz, CDCI3): 5 7.82 (d, J = 8.4 Hz, 1 H), 6.85 (d, J = 1 .8 Hz, 1 H), 6.71 (dd, J = 8.5, 1.8 Hz, 1 H), 3.31 - 3.16 (m, 4H), 2.53 (s, 3H), 2.42 (s, 3H), 2.08 - 1.94 (m, 4H).

¹³C NMR (75 MHz, CDCI3): 5 169.45, 160.35, 142.64, 136.84, 133.72, 133.42, 127.83, 124.13, 116.02, 115.35, 50.54, 25.71 , 23.08, 13.11.

Step 2: A/-(4-Methvl-5-(4-(phenvlsulfonamido)-3-(pyrrolidin-1 -vl)phenvl)thiazol-2- yl)acetamide

A/-(4-Methyl-5-(4-nitro-3-(pyrrolidin-1-yl)phenyl)thiazol-2-yl)acetamide (33 mg, 95 pmol) was dissolved in 1 mL of MeOH and 0.5 mL of a 5% solution of ammonium chloride in water. Afterwards, zinc dust (10 eq., 62 mg, 953 pmol) was added to the mixture. The reaction mixture was and stirred at room temperature for 30 minutes. The crude product was then used fort he following reaction without fourther purification. The product was dissolved in 1 mL pyridine. Afterwards, benzenesulfonyl chloride (2 eq., 34 mg, 191 pmol) was added to the mixture which was stirred at room temperature for 3 hours. The solvent was then removed under reduced pressure and and purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1% TFA). The lyophilized powder was poured in an separatory funnel containing DCM and a saturated solution of Na2COs in water. The water phase was extracted 3 times with DCM. Then, the combined organic phases were dried over Na2SO4 and concentrated under reduced pressure. The product was obtained as an amorphous white solid.

Yield: 16 mg (37%). MS (ES+) [M+H]⁺ m/e = 456.8.

¹H NMR (600 MHz, DMSO-d₆): 5 12.04 (s, 1 H), 9.33 (s, 1 H), 7.75 - 7.70 (m, 2H), 7.68 - 7.63 (m, 1 H), 7.61 - 7.53 (m, 2H), 6.74 (s, 1 H), 6.61 - 6.56 (m, 2H), 3.34 - 3.25 (m, 4H), 2.31 (s, 3H), 2.12 (s, 3H), 1.85 - 1.77 (m, 4H).

¹³C NMR (151 MHz, DMSO-d₆): 5 168.23, 154.90, 146.07, 141.83, 140.98, 132.55, 131.42, 129.08, 129.00, 126.71 , 123.81 , 122.03, 117.68, 115.82, 50.37, 24.89, 22.40, 16.13.

Example compound 150: Methyl 5-(2-acetamido-4-methylthiazol-5-yl)-2- (phenylsulfonamido)benzoate

Step 1 : Methyl 5-bromo-2-(phenylsulfonamido)benzoate

Methyl 2-amino-5-bromobenzoate (371 mg, 1 .61 mmol) was dissolved in 4 mL pyridine. Afterwards, benzenesulfonyl chloride (1.1 eq., 313 mg, 1.77 mmol, 0.227 mL) was added to the mixture. The reaction mixture was stirred for three hours at room temperature. The solvent was then removed under reduced pressure and the crude product was then purified by silica gel chromatography using a gradient of cyclohexane and EtOAc as eluent. The product was obtained as a yellow oil.

Yield: 283 mg (47%).

MS (ES+) [M+Na]⁺ m/e = 391 .6, 393.7 (bromine isotopic pattern).

¹H NMR (300 MHz, DMSO-d₆): 5 10.33 (s, 1 H), 7.90 (d, J = 2.5 Hz, 1 H), 7.82 - 7.72 (m, 3H), 7.71 - 7.63 (m, 1 H), 7.62 - 7.53 (m, 2H), 7.39 (d, J = 8.8 Hz, 1 H), 3.79 (s, 3H).

¹³C NMR (75 MHz, DMSO-d₆): 6 166.07, 138.55, 137.33, 136.77, 133.64, 133.13, 129.53, 126.88, 123.00, 121.18, 116.12, 52.91.

Step 2: Methyl 5-(2-acetamido-4-methylthiazol-5-yl)-2-(phenylsulfonamido)benzoate

Methyl 5-bromo-2-(phenylsulfonamido)benzoate (80 mg, 216 pmol), A/-(4-methylthiazol-2- yl)acetamide (1.2 eq., 40 mg, 259 pmol), tri-tert-butylphosphonium tetrafluoroborate (0.2 eq., 12 mg, 43 pmol), Pd(OAc)2, (0.1 eq., 4.8 mg, 21 pmol) and CS2CO3 (3 eq., 211 mg, 648 pmol) were suspended in 1 mL of DMF. The suspension was sonicated for 5 minutes, flushed with nitrogen, heated up to 130 °C and stirred overnight. The solvent was then removed under reduced pressure and the crude product purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1% TFA). The product was obtained after lyophilization as an amorphous white solid.

Yield: 11 mg (11%).

MS (ES+) [M+H]⁺ m/e = 445.7.

¹H NMR (600 MHz, DMSO-d₆): 5 12.13 (s, 1 H), 10.41 (s, 1 H), 7.85 - 7.82 (m, 3H), 7.69 - 7.64 (m, 2H), 7.61 - 7.56 (m, 2H), 7.52 (d, = 8.6 Hz, 1 H), 3.82 (s, 3H), 2.29 (s, 3H), 2.13 (s, 3H).

¹³C NMR (151 MHz, DMSO-d₆): 5 168.43, 167.04, 155.25, 142.68, 138.79, 136.96, 133.85, 133.56, 130.32, 129.49, 127.93, 126.86, 121.85, 120.93, 118.96, 52.79, 22.40, 15.94.

Example compound 151 : A/-(5-(3-(Benzyloxy)-4-(phenylsulfonamido)phenyl)-4- methylthiazol-2-yl)acetamide

Step 1 : A/-(2-(Benzvloxv)-4-bromophenvl)benzenesulfonamide

2-Amino-5-bromophenol (500 mg, 2.66 mmol), (bromomethyl)benzene (1.05 eq., 476 mg, 2.79 mmol) and CS2CO3 (1 .5 eq., 1 .30 g, 3.9 mmol) were suspended in 5 mL of acetonitrile. The reaction mixture was stirred at 40 °C for one hour. Upon completion of the reaction, the mixture was poured in a separatory funnel, containing DCM and water. The water phase was extracted 3 times with DCM. Then, the combined organic phases were dried over Na2SC>4 and concentrated under reduced pressure. The residue was then dissolved in 5 mL pyridine. Afterwards, benzenesulfonyl chloride (1.1 eq., 517 mg, 2.93 mmol, 0.375 mL) was added to the mixture. The reaction mixture was stirred for three hours at room temperature. The solvent was then removed under reduced pressure and the crude product was then purified by silica gel chromatography using a gradient of cyclohexane and EtOAc as eluent. The product was obtained as a yellow oil.

Yield: 376 mg (34%).

MS (ES+) [M+Na]⁺ m/e = 439.7, 441 .6 (bromine isotopic pattern).

¹H NMR (300 MHz, CDCI3): 5 7.76 - 7.63 (m, 2H), 7.59 - 7.51 (m, 1 H), 7.48 (d, J = 8.5 Hz, 1 H), 7.44 - 7.32 (m, 5H), 7.20 - 7.11 (m, 2H), 7.07 (dd, J = 8.5, 2.0 Hz, 1 H), 6.93 (d, J = 2.1 Hz, 1 H), 6.89 (s, 1 H), 4.81 (s, 2H).

¹³C NMR (75 MHz, CDCI3): 5 149.45, 139.00, 134.98, 133.01 , 128.91 , 128.81 , 128.69, 127.62, 127.12, 125.10, 124.38, 123.20, 118.28, 115.29, 70.94.

Step 2: A/-(5-(3-(Benzvloxv)-4-(phenvlsulfonamido)phenvl)-4-methvlthiazol-2-vl)acetamide

A/-(2-(Benzyloxy)-4-bromophenyl)benzenesulfonamide (100 mg, 239 pmol), A/-(4-methylthiazol-2- yl)acetamide (1.2 eq., 45 mg, 287 pmol), tri-tert-butylphosphonium tetrafluoroborate (0.2 eq., 14 mg, 48 pmol), Pd(OAc)2, (0.1 eq., 5.4 mg, 24 pmol) and CS2CO3 (3 eq., 234 mg, 717 pmol) were suspended in 1 mL of DMF. The suspension was sonicated for 5 minutes, flushed with nitrogen, heated up to 130 °C and stirred overnight. The solvent was then removed under reduced pressure and the crude product purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1% TFA). The product was obtained after lyophilization as an amorphous white solid.

Yield: 43 mg (36%).

MS (ES+) [M+H]⁺ m/e = 493.7.

¹H NMR (600 MHz, DMSO-d₆): 5 12.05 (s, 1 H), 9.69 (s, 1 H), 7.77 - 7.72 (m, 2H), 7.61 - 7.57 (m, 1 H), 7.47 (t, J = 7.9 Hz, 2H), 7.36 - 7.32 (m, 2H), 7.31 - 7.25 (m, 4H), 6.93 (dd, J = 8.1 , 1 .9 Hz, 1 H), 6.91 (d, J = 1.9 Hz, 1 H), 5.00 (s, 2H), 2.16 (s, 3H), 2.12 (s, 3H).

¹³C NMR (151 MHz, DMSO-d₆): 5 168.27, 155.03, 150.98, 142.03, 140.71 , 136.62, 132.58, 130.24, 128.93, 128.23, 127.59, 127.16, 126.56, 125.41 , 124.54, 123.32, 120.71 , 113.05, 69.34, 22.39, 15.91.

Example compound 152: A/-(5-(3-Fluoro-4-(phenylsulfonamido)phenyl)-4-methylthiazol-2- vDacetamide

Step 1 : /V-(4-Bromo-2-fluorophenvl)benzenesulfonamide

4-Bromo-2-fluoroaniline (200 mg, 1 .05 mmol) was dissolved in 2 mL pyridine. Afterwards, benzenesulfonyl chloride (1.1 eq., 204 mg, 1.16 mmol, 0.148 mL) was added to the mixture. The reaction mixture was stirred for three hours at room temperature. The solvent was then removed under reduced pressure and the crude product was then purified by silica gel chromatography using a gradient of cyclohexane and EtOAc as eluent. The product was obtained as a yellow oil.

Yield: 143 mg (41 %).

¹H NMR (300 MHz, DMSO-D6): 5 10.32 (s, 1 H), 7.86 - 7.81 (m, 1 H), 7.74 - 7.69 (m, 2H), 7.67 - 7.61 (m, 1 H), 7.60 - 7.48 (m, 3H), 7.35 (ddd, J = 8.6, 2.2, 1.1 Hz, 1 H), 7.19 (t, J = 8.5 Hz, 1 H).

¹³C NMR (75 MHz, DMSO-D6): 5 155.88 (d, J = 252.3 Hz), 140.08, 133.61 , 129.78, 128.39 (d, J = 9.5 Hz), 128.26 (d, J = 1.7 Hz), 127.01 , 124.50 (d, J = 12.9 Hz), 119.92 (d, J = 23.2 Hz), 118.73 (d, J = 8.7 Hz)

Step 2: A/-(5-(3-Fluoro-4-(phenvlsulfonamido)phenvl)-4-methvlthiazol-2-vl)acetamide

A/-(4-Bromo-2-fluorophenyl)benzenesulfonamide (100 mg, 303 pmol), A/-(4-methylthiazol-2- yl)acetamide (1.2 eq., 57 mg, 363 pmol), tri-tert-butylphosphonium tetrafluoroborate (0.2 eq., 18 mg, 61 pmol), Pd(OAc)2, (0.1 eq., 6.8 mg, 30 pmol) and CS2CO3 (3 eq., 296 mg, 908 pmol) were suspended in 1 mL of DMF. The suspension was sonicated for 5 minutes, flushed with nitrogen, heated up to 130 °C and stirred overnight. The solvent was then removed under reduced pressure and the crude product purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1% TFA). The product was obtained after lyophilization as an amorphous white solid.

Yield: 15 mg (12%).

¹H NMR (600 MHz, DMSO-d₆): 5 12.12 (s, 1 H), 10.28 (s, 1 H), 7.79 - 7.75 (m, 2H), 7.67 - 7.63 (m, 1 H), 7.58 (t, J = H Hz, 2H), 7.29 (t, 7 = 8.4 Hz, 1 H), 7.25 (dd, J = 11 .4, 2.1 Hz, 1 H), 7.20 (dd, J = 8.4, 2.1 Hz, 1 H), 2.31 (s, 3H), 2.13 (s, 3H).

¹³C NMR (151 MHz, DMSO-d₆): 5 168.89, 155.90, 155.74 (d, = 248.0 Hz), 143.38, 140.49, 133.49, 131.70 (d, 7 = 8.0 Hz), 129.73, 127.02, 126.92, 125.17, 123.61 (d, 7 = 13.3 Hz), 122.48, 116.08 (d, 7 = 21.0 Hz), 22.88, 16.56.

Example compound 153: A/-(5-(3-Cvclopropyl-4-(phenylsulfonamido)phenyl)-4- methylthiazol-2-yl)acetamide

Step 1 : A/-(4-Bromo-2-cvclopropylphenvl)benzenesulfonamide

4-Bromo-2-cyclopropylaniline (52 mg, 245 pmol) was dissolved in 1 mL pyridine. Afterwards, benzenesulfonyl chloride (1.1 eq., 47 mg, 269 pmol) was added to the mixture. The reaction mixture was stirred for three hours at room temperature. The solvent was then removed under reduced pressure and the crude product was then purified by silica gel chromatography using a gradient of cyclohexane and EtOAc as eluent. The product was obtained as a yellow oil.

Yield: 51 mg (59%).

MS (ES+) [M+Na]⁺ m/e = 373.7, 375.7 (bromine isotopic pattern).

¹H NMR (300 MHz, CDCI₃): 5 7.81 - 7.72 (m, 2H), 7.60 - 7.51 (m, 1 H), 7.50 - 7.36 (m, 3H), 7.28 (dd, 7 = 8.7, 2.3 Hz, 1 H), 7.10 (dd, 7 = 2.3, 0.8 Hz, 1 H), 6.96 (s, 1 H), 1.34 (tt, 7 = 8.3, 5.3 Hz, 1 H), 0.91 - 0.81 (m, 2H), 0.44 - 0.36 (m, 2H).

¹³C NMR (75 MHz, CDCI3): 5 139.23, 135.64, 135.37, 133.23, 131.22, 130.22, 129.13, 127.01 , 122.99, 118.36, 10.86, 6.16.

Step 2: A/-(5-(3-Cvclopropyl-4-(phenvlsulfonamido)phenvl)-4-methvlthiazol-2-vl)acetamide

A/-(4-Bromo-2-cyclopropylphenyl)benzenesulfonamide (60 mg, 170 pmol), A/-(4-methylthiazol-2- yl)acetamide (1.2 eq., 32 mg, 204 pmol), tri-tert-butylphosphonium tetrafluoroborate (0.2 eq., 10 mg, 32 pmol), Pd(OAc)2, (0.1 eq., 3.8 mg, 17 pmol) and CS2CO3 (3 eq., 166 mg, 511 pmol) were suspended in 1 mL of DMF. The suspension was sonicated for 5 minutes, flushed with nitrogen, heated up to 130 °C and stirred overnight. The solvent was then removed under reduced pressure and the crude product purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1% TFA). The product was obtained after lyophilization as an amorphous white solid.

Yield: 7 mg (9%). MS (ES+) [M+H]⁺ m/e = 427.7

¹H NMR (600 MHz, DMSO-d₆): 6 12.06 (s, 1 H), 9.76 (s, 1 H), 7.74 - 7.70 (m, 2H), 7.67 - 7.62 (m, 1 H), 7.57 (dd, J = 8.4, 7.1 Hz, 2H), 7.14 (dd, J = 8.3, 2.1 Hz, 1 H), 7.07 (d, J = 8.2 Hz, 1 H), 6.76 (d, = 2.1 Hz, 1 H), 2.27 (s, 3H), 2.12 (s, 3H), 1.99 (td, J = 8.5, 4.3 Hz, 1 H), 0.75 - 0.69 (m, 2H), 0.44 - 0.38 (m, 2H).

¹³C NMR (151 MHz, DMSO-d₆): 5 168.27, 155.00, 142.00, 140.66, 139.63, 134.17, 132.69, 130.37, 129.15, 126.63, 126.45, 125.80, 124.29, 123.29, 22.40, 16.00, 10.58, 8.73.

Example compound 154: A/-(5-(3-Acetamido-4-(phenylsulfonamido)phenyl)-4- methylthiazol-2-yl)acetamide

Step 1 : /V-(5-Bromo-2-(phenvlsulfonamido)phenvl)acetamide

A/-(5-Bromo-2-nitrophenyl)acetamide (480 mg, 806 pmol) was dissolved in 5 mL of MeOH and 2 mL of a 5% solution of ammonium chloride in water. Afterwards, Zinc dust (10 eq., 1.21 g, 18.5 mmol) was added to the mixture. The reaction mixture was and stirred at room temperature for 30 minutes. The crude product was then used for the following reaction without further purification. The product was dissolved in 5 mL pyridine. Afterwards, benzenesulfonyl chloride (1 eq., 327 mg, 1.85 mmol, 0.237 mL) was added to the mixture. The reaction mixture was stirred for three hours at room temperature. The solvent was then removed under reduced pressure and the crude product was then purified by silica gel chromatography using a gradient of cyclohexane and EtOAc as eluent. The product was obtained as a yellow oil.

Yield: 151 mg (22%).

MS (ES+) [M+H]⁺ m/e = 368.7, 370.5 (bromine isotopic pattern).

¹H NMR (300 MHz, DMSO-d₆): 5 9.59 (s, 1 H), 9.22 (s, 1 H), 7.83 (d, J = 2.3 Hz, 1 H), 7.69 - 7.59 (m, 3H), 7.58 - 7.48 (m, 2H), 7.25 (dd, J = 8.6, 2.4 Hz, 1 H), 7.05 (d, J = 8.6 Hz, 1 H), 1.91 (s, 3H).

¹³C NMR (75 MHz, DMSO-d₆): 6 168.54, 139.40, 134.21 , 133.13, 129.25, 128.13, 127.23, 126.61 , 125.60, 118.53, 23.63. henylsulfonamido)phenyl)-4-methylthiazol-2-yl)acetamide

A/-(5-Bromo-2-(phenylsulfonamido)phenyl)acetamide (75 mg, 203 pmol), A/-(4-methylthiazol-2- yl)acetamide (1.2 eq., 38 mg, 244 pmol), tri-tert-butylphosphonium tetrafluoroborate (0.2 eq., 12 mg, 41 pmol), Pd(OAc)2, (0.1 eq., 4.6 mg, 20 pmol) and CS2CO3 (3 eq., 199 mg, 609 pmol) were suspended in 1 mL of DMF. The suspension was sonicated for 5 minutes, flushed with nitrogen, heated up to 130 °C and stirred overnight. The solvent was then removed under reduced pressure and the crude product purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1% TFA). The product was obtained after lyophilization as an amorphous white solid.

Yield: 12 mg (13%).

MS (ES+) [M+H]⁺ m/e = 444.7.

¹H NMR (600 MHz, DMSO-d₆) 5 12.09 (s, 1 H), 9.50 (s, 1 H), 9.23 (s, 1 H), 7.71 - 7.60 (m, 4H), 7.55 (t, J = 7.8 Hz, 2H), 7.21 - 7.16 (m, 2H), 2.31 (s, 3H), 2.13 (s, 3H), 1.93 (s, 3H).

¹³C NMR (189 MHz, DMSO-d₆) 5 168.70, 168.37, 155.13, 142.33, 139.62, 133.09, 132.71 , 130.28, 129.24, 126.59, 126.55, 126.33, 124.52, 123.25, 122.84, 23.58, 22.42, 16.15.

Example compound 155: A/-(5-(3-(Methoxymethyl)-4-(phenylsulfonamido)phenyl)-4- methylthiazol-2-yl)acetamide

Step 1 : 4-Bromo-2-(methoxvmethvl)aniline

(2-Amino-5-bromophenyl)methanol (193 mg, 955 pmol) was dissolved in 3 mL of dry THF. Afterwards, potassium tert-butoxide, 12% in THF, (1.1 eq., 118 mg, 1.05 mmol, 1.05 mL) was added at 0 °C to the mixture and left stirring for 30 minutes. Then, iodomethane (1.1 eq., 149 mg, 1 .05 mmol) was added to the mixture. After 1 hour at room temperature, the rection was slowly quenched with AcOH. Upon completion of the reaction, the mixture was poured in a separatory funnel, containing DCM and water. The water phase was extracted 3 times with DCM. Then, the combined organic phases were dried over Na2SC>4 and concentrated under reduced pressure. The product was obtained as a yellow oil.

Yield: 200 mg (97%).

MS (ES+) [M-OCHa]⁺ m/e = 183.8, 185.8 (bromine isotopic pattern).

¹H NMR (300 MHz, CDCI₃): 6 7.23 - 7.15 (m, 2H), 6.55 (d, J = 8.3 Hz, 1 H), 4.41 (s, 2H), 3.32 (s, 3H).

¹³C NMR (75 MHz, CDCI₃): 5 145.26, 132.33, 131.77, 123.84, 117.16, 109.21 , 72.92, 57.48.

Step 2: A/-(4-Bromo-2-(methoxvmethvl)phenvl)benzenesulfonamide

4-Bromo-2-(methoxymethyl)aniline (200 mg, 286 pmol) was dissolved in 2 mL pyridine. Afterwards, benzenesulfonyl chloride (1.1 eq., 180 mg, 1.02 mmol, 0.130 mL) was added to the mixture. The reaction mixture was stirred for three hours at room temperature. The solvent was then removed under reduced pressure and the crude product was then finally purified by silica gel chromatography using a gradient of cyclohexane and EtOAc as eluent. The product was obtained as a yellow oil.

Yield: 102 mg (31 %).

MS (ES+) [M+Na]⁺ m/e = 377.7, 379.7 (bromine isotopic pattern). ¹H NMR (300 MHz, CDCI₃): 6 7.97 (s, 1 H), 7.78 - 7.70 (m, 2H), 7.60 - 7.50 (m, 1 H), 7.48 - 7.36 (m, 4H), 7.17 (d, J = 2.3 Hz, 1 H), 4.01 (s, 2H), 3.26 (s, 3H).

Step 3: A/-(5-(3-(Methoxvmethvl)-4-(phenvlsulfonamido)phenvl)-4-methvlthiazol-2- yl)acetamide

A/-(4-Bromo-2-(methoxymethyl)phenyl)benzenesulfonamide (102 mg, 286 pmol), A/-(4- methylthiazol-2-yl)acetamide (1.2 eq., 54 mg, 344 pmol), tri-tert-butylphosphonium tetrafluoroborate (0.2 eq., 8.3 mg, 29 pmol), Pd(OAc)2, (0.1 eq., 3.2 mg, 14 pmol) and CS2CO3 (3 eq., 280 mg, 859 pmol) were suspended in 1 mL of DMF. The suspension was sonicated for 5 minutes, flushed with nitrogen, heated up to 130 °C and stirred overnight. The solvent was then removed under reduced pressure and the crude product purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1 % TFA). The product was obtained after lyophilization as an amorphous white solid.

Yield: 15 mg (12%).

MS (ES+) [M+H]⁺ m/e = 431 .8.

¹H NMR (300 MHz, DMSO-d₆): 5 12.11 (s, 1 H), 9.65 (s, 1 H), 7.75 - 7.63 (m, 3H), 7.62 - 7.53 (m, 2H), 7.37 (d, J = 2.2 Hz, 1 H), 7.28 (dd, J = 8.3, 2.3 Hz, 1 H), 6.98 (d, J = 8.3 Hz, 1 H), 4.32 (s, 2H), 3.18 (s, 3H), 2.30 (s, 3H), 2.13 (s, 3H).

¹³C NMR (75 MHz, DMSO-d₆): 6 168.41 , 155.12, 142.20, 140.06, 134.97, 132.98, 132.71 , 130.26, 129.33, 127.80, 127.63, 126.70, 126.31 , 123.09, 69.31 , 57.78, 22.47, 16.15.

Example compound 156: A/-(4-Methyl-5-(1-(phenylsulfonyl)-1,2,3,4-tetrahydroquinolin-7- yl)thiazol-2-yl)acetamide

Step 1 : 7-bromo-1 -(phenylsulfonyl)-l ,2,3,4-tetrahydroquinoline

7-bromo-1 ,2,3,4-tetrahydroquinoline (120 mg, 565 pmol) was dissolved in 2 mL of pyridine. Afterwards, benzenesulfonyl chloride (2 eq., 201 mg, 1.14 mmol) was added to the mixture. The reaction mixture was stirred for three hours at room temperature. The solvent was then removed under reduced pressure and the crude product purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1% TFA). The product was obtained after lyophilization as an amorphous white solid.

Yield: 167 mg (84%).

MS (ES+) [M+Na]⁺ m/e = 373.9, 375.9 (bromine isotopic pattern) ¹H NMR (300 MHz, CDCI₃): 6 7.99 (d, J = 2.0 Hz, 1 H), 7.66 - 7.62 (m, 2H), 7.58 - 7.52 (m, 1 H), 7.43 (t, J = 7.9 Hz, 2H), 7.19 (dd, J = 8.1 , 2.0 Hz, 1 H), 6.87 (d, J = 8.2 Hz, 1 H), 3.81 - 3.76 (m, 2H), 2.39 (t, J = 6.7 Hz, 2H), 1 .65 - 1 .59 (m, 2H).

¹³C NMR (151 MHz, CDCI3): 5 139.47, 138.14, 133.11 , 130.51 , 129.46, 129.23, 128.11 , 127.54, 127.25, 119.73, 46.56, 26.44, 21.45

Step 2: A/-(4-Methyl-5-(1 -(phenylsulfonyl)-l ,2,3,4-tetrahydroquinolin-7-yl)thiazol-2- yl)acetamide

7-bromo-1-(phenylsulfonyl)-1 ,2,3,4-tetrahydroquinoline (80 mg, 227 pmol), A/-(4-methylthiazol-2- yl)acetamide (1.2 eq., 43 mg, 272 pmol), tri-tert-butylphosphonium tetrafluoroborate (0.2 eq., 13 mg, 45 pmol), Pd(OAc)2, (0.1 eq., 5.2 mg, 23 pmol) and CS2CO3 (3 eq., 225 mg, 681 pmol) were suspended in 2 mL of DMF. The suspension was sonicated for 5 minutes, flushed with nitrogen, heated up to 110 °C and stirred overnight. The solvent was then removed under reduced pressure and the crude product purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1% TFA). The product was obtained after lyophilization as an amorphous white solid.

Yield: 66 mg (44%).

MS (ES+) [M+H]⁺ m/e = 428.1 .

¹H NMR (600 MHz, DMSO-d₆): 5 12.09 (s, 1 H), 7.70 - 7.63 (m, 4H), 7.59 - 7.56 (m, 2H), 7.17 - 7.13 (m, 2H), 3.84 - 3.79 (m, 2H), 2.51 - 2.46 (m, 7H), 2.33 (s, 3H), 2.14 (s, 3H), 1 .65 - 1 .58 (m, 2H).

¹³C NMR (151 MHz, DMSO-d₆): 5 168.38, 155.07, 141.99, 139.00, 136.61 , 133.46, 130.05, 129.94, 129.60, 129.23, 126.70, 124.67, 123.48, 123.12, 46.25, 25.77, 22.44, 20.95, 15.96.

Example compound 157: A/-(4-Methyl-5-(2-(phenylsulfonyl)-1,2,3,4-tetrahydroisoquinolin-6- yl)thiazol-2-yl)acetamide

Step 1 : 6-bromo-2-(phenylsulfonyl)-1 ,2,3,4-tetrahydroisoquinoline

7-bromo-1 ,2,3,4-tetrahydroquinoline hydrochloeide (120 mg, 482 pmol) was dissolved in 2 mL of pyridine. Afterwards, benzenesulfonyl chloride (2 eq., 170 mg, 964 mmol) was added to the mixture. The reaction mixture was stirred for three hours at room temperature. The solvent was then removed under reduced pressure and the crude product purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1% TFA). The product was obtained after lyophilization as an amorphous white solid.

Yield: 126 mg (74%).

MS (ES+) [M+Na]⁺ m/e = 373.9, 375.9 (bromine isotopic pattern) ¹H NMR (300 MHz, CDCI₃): 6 7.93 - 7.78 (m, 2H), 7.70 - 7.47 (m, 3H), 7.36 - 7.21 (m, 2H), 6.93 (d, J = 8.2 Hz, 1 H), 4.23 (s, 2H), 3.38 (t, J = 5.9 Hz, 2H), 2.92 (t, J = 5.9 Hz, 2H).

¹³C NMR (151 MHz, CDCI3): 5 136.52, 135.46, 133.11 , 131.78, 130.75, 129.66, 129.31 , 128.10, 127.78, 120.57, 47.32, 43.49, 28.75.

Step 2: A/-(4-Methyl-5-(2-(phenylsulfonyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)thiazol-2- yl)acetamide

6-bromo-2-(phenylsulfonyl)-1 ,2,3,4-tetrahydroisoquinoline (80 mg, 227 pmol), A/-(4-methylthiazol- 2-yl)acetamide (1.2 eq., 43 mg, 272 pmol), tri-tert-butylphosphonium tetrafluoroborate (0.2 eq., 13 mg, 45 pmol), Pd(OAc)2, (0.1 eq., 5.2 mg, 23 pmol) and CS2CO3 (3 eq., 225 mg, 681 pmol) were suspended in 2 mL of DMF. The suspension was sonicated for 5 minutes, flushed with nitrogen, heated up to 110 °C and stirred overnight. The solvent was then removed under reduced pressure and the crude product purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1% TFA). The product was obtained after lyophilization as an amorphous white solid.

Yield: 71 mg (72%).

MS (ES+) [M+H]⁺ m/e = 428.1 .

¹H NMR (300 MHz, DMSO-d₆): 5 12.09 (s, 1 H), 7.87 - 7.80 (m, 2H), 7.75 - 7.59 (m, 3H), 7.25 - 7.15 (m, 3H), 4.23 (s, 2H), 3.32 (t, J = 5.9 Hz, 2H), 2.89 (t, J = 6.0 Hz, 2H), 2.30 (s, 3H), 2.12 (s, 3H).

¹³C NMR (151 MHz, DMSO-d₆): 6 168.27, 155.00, 141.84, 135.98, 133.72, 133.20, 130.70, 130.48, 129.41 , 128.58, 127.37, 126.97, 126.28, 123.48, 47.04, 43.42, 27.93, 22.40, 15.94.

Example compound 158: A/-(4-Methyl-5-(1-(phenylsulfonyl)-1,2,3,4-tetrahydroquinolin-5- yl)thiazol-2-yl)acetamide

Step 1 : 5-bromo-1 -(phenylsulfonyl)-l ,2,3,4-tetrahydroquinoline

5-bromo-1 ,2,3,4-tetrahydroquinoline (400 mg, 1 .89 mmol) was dissolved in 6 mL of pyridine.

Afterwards, benzenesulfonyl chloride (2 eq., 668 mg, 3.78 mmol) was added to the mixture. The reaction mixture was stirred for three hours at room temperature. The solvent was then removed under reduced pressure and the crude product was then purified by silica gel chromatography using a gradient of cyclohexane and EtOAc as eluent. The product was obtained as a yellow oil. Yield: 303 mg (46%).

MS (ES+) [M+Na]⁺ m/e = 373.9, 375.9 (bromine isotopic pattern)

¹H NMR (600 MHz, CDCI₃): 5 7.78 (dd, J = 8.3, 1 .2 Hz, 1 H), 7.63 - 7.60 (m, 2H), 7.58 - 7.53 (m, 1 H), 7.46 - 7.41 (m, 2H), 7.38 (dd, J = 8.0, 1.1 Hz, 1 H), 7.07 (t, J = 8.2 Hz, 1 H), 3.82 - 3.75 (m, 2H), 2.50 (t, J = 6.9 Hz, 2H), 1 .66 - 1 .59 (m, 2H).

¹³C NMR (151 MHz, CDCI3): 5 139.95, 138.66, 133.10, 130.09, 129.40, 129.28, 127.31 , 127.19, 125.23, 124.44, 46.19, 27.82, 21.33.

Step 2: A/-(4-Methyl-5-(1 -(phenylsulfonyl)-l ,2,3,4-tetrahydroquinolin-5-yl)thiazol-2- yl)acetamide

5-bromo-1-(phenylsulfonyl)-1 ,2,3,4-tetrahydroquinoline (65 mg, 200 pmol), A/-(4-methylthiazol-2- yl)acetamide (1.2 eq., 36 mg, 240 pmol), tri-tert-butylphosphonium tetrafluoroborate (0.2 eq., 11 mg, 40 pmol), Pd(OAc)2, (0.1 eq., 4.2 mg, 20 pmol) and CS2CO3 (3 eq., 186 mg, 600 pmol) were suspended in 2 mL of DMF. The suspension was sonicated for 5 minutes, flushed with nitrogen, heated up to 110 °C and stirred overnight. The solvent was then removed under reduced pressure and the crude product purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1% TFA). The product was obtained after lyophilization as an amorphous white solid.

Yield: 59 mg (73%).

MS (ES+) [M+H]⁺ m/e = 428.1 .

¹H NMR (300 MHz, DMSO-d₆): 5 12.07 (s, 1 H), 7.71 - 7.60 (m, 2H), 7.57 - 7.50 (m, 4H), 7.30 (t, J = 7.9 Hz, 1 H), 7.11 (dd, J = 7.6, 1 .3 Hz, 1 H), 3.75 (dd, J = 6.9, 5.6 Hz, 2H), 2.11 (s, 3H), 1 .97 (t, J = 6.5 Hz, 2H), 1 .86 (s, 3H), 1 .55 (p, J = 6.4 Hz, 2H).

¹³C NMR (75 MHz, DMSO-d₆): 6 168.32, 156.02, 143.12, 138.51 , 136.77, 133.37, 132.54, 130.99, 129.44, 128.35, 126.70, 126.09, 125.44, 121.20, 46.06, 24.24, 22.41 , 21.84, 15.15.

Example compound 159: A/-(4-Methvl-5-(5-(ohenvlsulfonvl)-5.6.7,8-tetrahvdroovridor3.2- c/]pyrimidin-2-yl)thiazol-2-yl)acetamide

Step 1 : 5-Bromo-1 -(phenylsulfonyl)-l ,2,3,4-tetrahydroquinoline

tert-Butyl 2-chloro-7,8-dihydropyrido[3,2-d]pyrimidine-5(6/7)-carboxylate (40 mg, 148 pmol), A/-(4- methylthiazol-2-yl)acetamide (1.2 eq., 28 mg, 178 pmol), tri-tert-butylphosphonium tetrafluoroborate (0.2 eq., 8.6 mg, 30 pmol), Pd(OAc)2, (0.1 eq., 3.3 mg, 15 pmol) and CS2CO3 (3 eq., 145 mg, 445 pmol) were suspended in 2 mL of DMF. The suspension was sonicated for 5 minutes, flushed with nitrogen, heated up to 110 °C and stirred overnight. The solvent was then removed under reduced pressure and the crude product purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1 % TFA). The product was obtained after lyophilization as an amorphous white solid.

Yield: 25 mg (43%).

MS (ES+) [M+H]⁺ m/e = 390.1

¹H NMR (300 MHz, CDCI₃): 5 9.15 (s, 1 H), 4.84 (s, 1 H), 3.84 - 3.69 (m, 2H), 2.94 (t, J = 6.6 Hz, 2H), 2.86 (s, 3H), 2.41 (s, 3H), 2.11 - 1 .97 (m, 2H), 1 .55 (s, 9H).

¹³C NMR (75 MHz, CDCI3): 5 169.68, 161.13, 156.62, 152.93, 152.80, 150.64, 137.93, 132.51 , 124.47, 82.86, 44.63, 30.49, 28.40, 23.25, 21.73, 14.15.

Step 2: A/-(4-Methyl-5-(5-(phenylsulfonyl)-5,6,7,8-tetrahydropyrido[3,2-cf]pyrimidin-2- yl)thiazol-2-yl)acetamide

5-Bromo-1-(phenylsulfonyl)-1 ,2,3,4-tetrahydroquinoline (25 mg, 64 pmol) was dissolved in 1 mL of DCM and 1 mL of TFA was slowly added to the solution at room temperature. After one hour, a 1 M solution of a solution of Na2COs in water was added to the solution until the the pH reached 8-9. The residue was then poured in a separatory funnel, containing DCM and water. The water phase was extracted 3 times with DCM. Then, the combined organic phases were dried over Na2SO4 and concentrated under reduced pressure. The crude was dissolved in 1 mL of pyridine. Afterwards, benzenesulfonyl chloride (2 eq., 23 mg, 128 pmol) was added to the mixture. The reaction mixture was stirred for three hours at room temperature. The solvent was then removed under reduced pressure and the crude product purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1% TFA). The product was obtained after lyophilization as an amorphous white solid.

Yield: 13 mg (47%).

MS (ES+) [M+H]⁺ m/e = 430.1

¹H NMR (600 MHz, CDCh): 5 9.14 (s, 1 H), 7.71 (dt, J = 8.7, 1 .4 Hz, 1 H), 7.62 (td, J = 7.3, 1 .2 Hz, 1 H), 7.51 (td, J = 8.1 , 1 .6 Hz, 2H), 3.87 - 3.76 (m, 2H), 2.83 (s, 3H), 2.71 (t, J = 6.7 Hz, 2H), 2.36 (s, 3H), 2.36 (s, 3H), 1.74 - 1.60 (m, 2H).

¹³C NMR (151 MHz, CDCh): 5 168.72, 160.08, 157.62, 155.78, 151.37, 143.13, 138.67, 133.80, 130.28, 129.73, 127.32, 124.49, 46.25, 29.64, 23.39, 20.04, 15.77.

Example compound 160: A/-(5-(4-((2.3-Dihvdrobenzorbiri.41dioxin-6-vl)sulfonvl)-3.4- dihydro-2H-benzo[b][1 ,4]thiazin-7-yl)-4-methylthiazol-2-yl)acetamide

Step 1 : 7-Bromo-4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)sulfonyl)-3,4-dihydro-2H- benzo[b][1 ,4]thiazine

7-Bromo-3,4-dihydro-2/7-benzo[b][1 ,4]thiazine (85 mg, 369 pmol) was dissolved in 2 mL pyridine. Afterwards, 2,3-dihydrobenzo[b][1 ,4]dioxine-6-sulfonyl chloride (1.8 eq., 156 mg, 664 pmol) was added to the mixture. The reaction mixture was stirred for three hours at room temperature The solvent was then removed under reduced pressure and the crude product purified by reversed- phase preparative HPLC (5% to 99% acetonitrile with 0.1 % TFA). The product was obtained after lyophilization as an amorphous white solid.

Yield: 83 mg (52%).

MS (ES+) [M+Na]⁺ m/e = 450.0, 452.0 (bromine isotopic pattern).

Step 2: A/-(5-(4-((2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)sulfonyl)-3,4-dihydro-2H- benzo[b][1 ,4]thiazin-7-yl)-4-methylthiazol-2-yl)acetamide

7-Bromo-4-((2,3-dihydrobenzo[b][1 ,4]dioxin-6-yl)sulfonyl)-3,4-dihydro-2/7-benzo[b][1 ,4]thiazine (35 mg, 82 pmol), A/-(4-methylthiazol-2-yl)acetamide (1.2 eq., 15 mg, 98 pmol), tri-tert- butylphosphonium tetrafluoroborate (0.2 eq., 4.7 mg, 16 pmol), Pd(OAc)2, (0.1 eq., 1.8 mg, 8 pmol) and CS2CO3 (3 eq., 80 mg, 245 pmol) were suspended in 1 mL of DMF. The suspension was sonicated for 5 minutes, flushed with nitrogen, heated up to 110 °C and stirred overnight. The solvent was then removed under reduced pressure and the crude product purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1% TFA). The product was obtained after lyophilization as an amorphous white solid.

Yield: 25 mg (61%).

MS (ES+) [M+H]⁺ m/e = 504.1

¹H NMR (600 MHz, CDCI3): 5 7.82 - 7.73 (m, 1 H), 7.22 - 7.17 (m, 2H), 7.17 - 7.11 (m, 2H), 6.93 (d, J = 8.5 Hz, 1 H), 4.34 (dt, J = 4.6, 2.9 Hz, 2H), 4.30 (qt, J = 3.9, 2.4 Hz, 2H), 4.05 - 3.89 (m, 2H), 3.04 - 2.92 (m, 2H), 2.53 (s, 3H), 2.44 (s, 3H).

¹³C NMR (151 MHz, CDCI3): 5 169.38, 160.07, 148.03, 143.75, 135.27, 132.70, 132.27, 129.28, 128.33, 126.89, 126.59, 124.79, 124.19, 120.85, 118.08, 116.74, 64.56, 64.15, 44.31 , 25.72, 23.06, 12.89.

161 : A/-(5-(4-((2,3-Dichlorophenyl)sulfonyl)-1 ,1 -dioxido-3,4-dihydro-2H- benzo[b][1 ,4]thiazin-7-yl)-4-methylthiazol-2-yl)acetamide

A/-(5-(4-((2,3-Dichlorophenyl)sulfonyl)-3,4-dihydro-2/7-benzo[b][1 ,4]thiazin-7-yl)-4-methylthiazol-2- yl)acetamide (25 mg, 48 pmol) was dissolved in 1 mL of DCM at 0 °C. Afterwards, meta- chloroperbenzoic acid (2.0 eq., 17 mg, 97 pmol) was added to the mixture, and the reaction mixture was kept at 0 °C for 45 minutes, then at room temperature for one hour. The solvent was then removed under reduced pressure and the crude product purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1% TFA). The product was obtained after lyophilization as amorphous white solids in pure form.

Yield: 8 mg (30%).

MS (ES+) [M+H]⁺ m/e = 545.9

¹H NMR (600 MHz, DMSO-d₆): 5 12.22 (s, 1 H), 8.21 (dd, = 8.0, 1.5 Hz, 1 H), 8.08 (dd, = 8.1 , 1 .5 Hz, 1 H), 7.78 (d, J = 2.2 Hz, 1 H), 7.72 - 7.62 (m, 2H), 7.42 (d, J = 8.8 Hz, 1 H), 4.56 - 4.45 (m, 2H), 3.89 - 3.79 (m, 2H), 2.35 (s, 3H), 2.16 (s, 3H).

¹³C NMR (151 MHz, DMSO-d₆): 5 169.06, 156.23, 144.03, 139.18, 136.41 , 135.48, 134.74, 133.43, 132.09, 130.50, 130.37, 129.83, 129.65, 124.37, 123.37, 121.68, 51.01 , 45.90, 22.90, 16.46.

Example compound 162: A/-(5-(4-((2.3-Dihvdrobenzorbiri ,4]dioxin-6-yl)sulfonyl)-1 ,1 - dioxido-3,4-dihydro-2/-/-benzo[b][1 ,4]thiazin-7-yl)-4-methylthiazol-2-yl)acetamide

A/-(5-(4-((2,3-Dihydrobenzo[b][1 ,4]dioxin-6-yl)sulfonyl)-3,4-dihydro-2/7-benzo[b][1 ,4]thiazin-7-yl)-4- methylthiazol-2-yl)acetamide (27 mg, 54 pmol) was dissolved in 1 mL of DCM at 0 °C.

Afterwards, mefa-chloroperbenzoic acid (2.2 eq., 20 mg, 118 pmol) was added to the mixture, and the reaction mixture was kept at 0 °C for 3 hours, then at room temperature for one hour. The solvent was then removed under reduced pressure and the crude product purified by reversed- phase preparative HPLC (5% to 99% acetonitrile with 0.1 % TFA). The product was obtained after lyophilization as amorphous white solids in pure form.

Yield: 11 mg (38%).

MS (ES+) [M+H]⁺ m/e = 536.0 Example compound 163: A/-(5-(1-((2.6-Dimethvlphenvl)sulfonvl)-1.2.3.4-tetrahvdroquinolin- 6-yl)-4-methylthiazol-2-yl)acetamide

A/-(4-Methyl-5-(1 ,2,3,4-tetrahydroquinolin-6-yl)thiazol-2-yl)acetamide (17 mg, 59 pmol) was dissolved in 1 mL of pyridine. Afterwards, 2,6-dimethylbenzenesulfonyl chloride (2 eq., 24 mg, 118 pmol) was added dropwise to the solution and stirred for 3 hours at room temperature. The solvent was then removed under reduced pressure and the crude product purified by reversed- phase preparative HPLC (5% to 99% acetonitrile with 0.1 % TFA). The product was obtained after lyophilization as an amorphous white solid.

Yield: 26 mg (99%).

MS (ES+) [M+H]⁺ m/e = 456.1

¹H NMR (300 MHz, DMSO d₆): 6 12.08 (s, 1 H), 7.54 - 6.99 (m, 6H), 3.67 - 3.65 (m, 2H), 2.78 (t, J = 6.7 Hz, 2H), 2.52 (s, 6H) 2.31 (s, 3H), 2.13 (s, 3H), 1.89 - 1.73 (m, 2H).

¹³C NMR (151 MHz, DMSO-d₆): 5 168.28, 154.92, 141.78, 139.08, 137.23, 136.27, 132.72, 131.71 , 130.40, 129.51 , 128.07, 126.08, 123.22, 122.72, 44.98, 40.06, 26.02, 22.42, 21.25, 16.02.

Example compound 164: A/-(5-(1-((3.4-Dihvdro-2H-benzorbiri ,4ldioxepin-7-vl)sulfonvl)-

1 ,2,3,4-tetrahydroquinolin-6-yl)-4-methylthiazol-2-yl)acetamide

A/-(4-Methyl-5-(1 ,2,3,4-tetrahydroquinolin-6-yl)thiazol-2-yl)acetamide (30 mg, 104 pmol) was dissolved in 1 mL of pyridine. Afterwards, 3,4-dihydro-2/7-benzo[b][1 ,4]dioxepine-7-sulfonyl chloride (2 eq., 52 mg, 208 pmol) was added dropwise to the solution and stirred overnight at room temperature. The solvent was then removed under reduced pressure and the crude product purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1% TFA). The product was obtained after lyophilization as an amorphous white solid.

Yield: 46 mg (88%).

MS (ES+) [M+H]⁺ m/e = 500.1

¹H NMR (300 MHz, DMSO-d₆): 5 12.10 (s, 1 H), 7.65 (d, J = 8.6 Hz, 1 H), 7.34 - 7.03 (m, 5H), 4.19 (dt, J = 19.1 , 5.6 Hz, 4H), 3.81 - 3.67 (m, 2H), 2.54 (d, J = 6.7 Hz, 2H), 2.33 (s, 3H), 2.17 - 2.06 (m, 5H), 1.67 - 1.55 (m, 2H).

¹³C NMR (151 MHz, DMSO-d₆): 5 168.28, 158.11 , 154.94, 154.85, 150.55, 141.86, 135.37, 133.03, 130.88, 129.15, 128.42, 126.29, 123.81 , 123.18, 122.32, 120.29, 70.69, 70.47, 46.26, 30.46, 26.05, 22.42, 20.92, 16.07. Example compound 165: A/-(5-(1-(Furan-2-vlsulfonvl)-1.2.3.4-tetrahvdroquinolin-6-vl)-4- methylthiazol-2-yl)acetamide

A/-(4-Methyl-5-(1 ,2,3,4-tetrahydroquinolin-6-yl)thiazol-2-yl)acetamide (50 mg, 174 pmol) was dissolved in 1 mL of pyridine. Afterwards, furan-2-sulfonyl chloride (2 eq., 58 mg, 348 pmol) was added dropwise to the solution and stirred overnight at room temperature. The solvent was then removed under reduced pressure and the crude product purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1 % TFA). The product was obtained after lyophilization as an amorphous white solid.

Yield: 64 mg (88%).

MS (ES+) [M+H]⁺ m/e = 418.0

¹H NMR (600 MHz, DMSO-d₆): 5 12.07 (s, 1 H), 7.99 (dd, J = 1.8, 0.8 Hz, 1 H), 7.61 (d, J = 8.6 Hz, 1 H), 7.36 - 7.13 (m, 3H), 6.70 (dd, J = 3.5, 1.8 Hz, 1 H), 3.82 - 3.74 (m, 2H), 2.65 (t, = 6.7 Hz, 2H), 2.33 (s, 3H), 2.13 (s, 3H), 1 .73 - 1 .63 (m, 2H).

¹³C NMR (151 MHz, DMSO-d₆): 5 168.30, 154.99, 147.99, 146.67, 141.91 , 134.86, 130.92, 129.11 , 128.72, 126.23, 123.81 , 123.11 , 118.02, 111.97, 46.27, 25.92, 22.42, 21.33, 16.08.

Example compound 166: A/-(5-(1-((1H-lmidazol-2-vl)sulfonvl)-1.2.3.4-tetrahvdroquinolin-6- yl)-4-methylthiazol-2-yl)acetamide

A/-(4-Methyl-5-(1 ,2,3,4-tetrahydroquinolin-6-yl)thiazol-2-yl)acetamide (20 mg, 70 pmol) was dissolved in 1 mL of pyridine. Afterwards, 1 /7-imidazole-2-sulfonyl chloride (1.1 eq., 13 mg, 77 pmol) was added dropwise to the solution and stirred overnight at room temperature. The solvent was then removed under reduced pressure and the crude product purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1% TFA). The product was obtained after lyophilization as an amorphous white solid.

Yield: 73 mg (21%).

MS (ES+) [M+H]⁺ m/e = 418.0

¹H NMR (300 MHz, CDCI₃): 5 7.81 (d, J = 8.2 Hz, 1 H), 7.24 - 7.01 (m, 4H), 3.94 (d, J = 6.1 Hz, 2H), 2.70 (t, J = 6.4 Hz, 2H), 2.46 (s, 3H), 2.40 (s, 3H), 1 .89 (s, 2H).

¹³C NMR (151 MHz, CDCI3): 5 169.60, 164.02, 160.06, 137.19, 132.55, 132.23, 129.75, 127.11 , 125.80, 125.09, 124.72, 116.99, 115.06, 47.20, 26.84, 23.19, 22.15, 13.04. 167 A/-(5-(4-((2,3-Dichlorophenyl)sulfonyl)-3,4-dihydro-2H- benzo[b][1 ,4]thiazin-7-yl)-4-methylthiazol-2-yl)acetamide

Step 1 : 7-Bromo-4-((2,3-dichlorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]thiazine

7-Bromo-3,4-dihydro-2/7-benzo[b][1 ,4]thiazine (100 mg, 0.44 mmol) was dissolved in 2 mL pyridine. Afterwards, 2,3-dichlorobenzenesulfonyl chloride (2 eq., 216 mg, 0.88 mmol) was added to the mixture. The reaction mixture was stirred for three hours at room temperature The solvent was then removed under reduced pressure and the crude product purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1% TFA). The product was obtained after lyophilization as an amorphous white solid.

Yield: 65 mg (34%).

MS (ES+) [M+H]⁺ m/e = 398.8

¹H NMR (600 MHz, DMSO-d₆): 5 8.05 (ddd, J = 17.3, 8.0, 1.5 Hz, 2H), 7.63 (t, J = 8.0 Hz, 1 H), 7.47 (d, J = 2.3 Hz, 1 H), 7.22 (dd, J = 8.7, 2.3 Hz, 1 H), 7.02 (d, J = 8.7 Hz, 1 H), 4.06 - 3.90 (m, 2H), 3.16 - 3.01 (m, 2H).

¹³C NMR (151 MHz, DMSO-d₆): 5 139.61 , 135.59, 134.87, 133.78, 130.48, 129.97, 129.16, 129.09, 128.76, 127.50, 127.22, 118.54, 44.63, 26.72.

Step 2: A/-(5-(4-((2,3-Dichlorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]thiazin-7-yl)-4- methylthiazol-2-yl)acetamide

7-Bromo-4-((2,3-dichlorophenyl)sulfonyl)-3,4-dihydro-2/7-benzo[b][1 ,4]thiazine (50 mg, 114 pmol), A/-(4-methylthiazol-2-yl)acetamide (1.5 eq., 27 mg, 171 pmol), tri-tert-butylphosphonium tetrafluoroborate (0.2 eq., 6.6 mg, 23 pmol), Pd(OAc)2, (0.1 eq., 2.6 mg, 11 pmol) and CS2CO3 (3 eq., 111 mg, 342 pmol) were suspended in 1 mL of DMF. The suspension was sonicated for 5 minutes, flushed with nitrogen, heated up to 110 °C and stirred overnight. The solvent was then removed under reduced pressure and the crude product purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1 % TFA). The product was obtained after lyophilization as an amorphous white solid.

Yield: 32 mg (55%).

MS (ES+) [M+H]⁺ m/e = 513.9

Example compound 168: A/-(5-(4-((2.3-Dihvdrobenzorbiri,41dioxin-6-vl)sulfonvl)-3.4- dihydro-2H-benzo[b][1 ,4]oxazin-7-yl)-4-methylthiazol-2-yl)acetamide

7-Bromo-3,4-dihydro-2/7-benzo[b][1 ,4]oxazine (65 mg, 303 pmol) was dissolved in 2 mL pyridine. Afterwards, 2,3-dihydrobenzo[b][1 ,4]dioxine-6-sulfonyl chloride (2 eq., 142 mg, 607 pmol) was added to the mixture. The reaction mixture was stirred for three hours at room temperature The solvent was then removed under reduced pressure and the crude used for the followng reaction. The crude, A/-(4-methylthiazol-2-yl)acetamide (1.2 eq., 62 mg, 395 pmol), tri-tert- butylphosphonium tetrafluoroborate (0.2 eq., 19 mg, 65 pmol), Pd(OAc)2, (0.1 eq., 7.4 mg, 33 pmol) and CS2CO3 (3 eq., 321 mg, 985 pmol) were suspended in 2 mL of DMF. The suspension was sonicated for 5 minutes, flushed with nitrogen, heated up to 110 °C and stirred overnight. The solvent was then removed under reduced pressure and the crude product purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1% TFA). The product was obtained after lyophilization as an amorphous white solid.

Yield: 16 mg (10%).

MS (ES+) [M+H]⁺ m/e = 488.1

¹H NMR (300 MHz, DMSO-d₆) 5 12.13 (s, 1 H), 7.75 (d, = 8.6 Hz, 1 H), 7.16 (dd, J = 6.1 , 2.4 Hz, 2H), 7.12 - 6.97 (m, 2H), 6.90 (d, J = 2.1 Hz, 1 H), 4.44 - 4.11 (m, 4H), 3.90 (t, J = 4.5 Hz, 2H), 3.81 (t, J = 4.6 Hz, 2H), 2.33 (s, 3H), 2.14 (s, 3H).

¹³C NMR (75 MHz, DMSO-d₆) 6 168.82, 164.04, 155.55, 148.55, 146.88, 144.12, 142.68, 130.33, 124.65, 123.24, 123.21 , 121.36, 121.21 , 118.59, 117.26, 116.51 , 64.91 , 64.50, 63.29, 44.37, 22.91 , 16.64.

Example compound 169: A/-(5-(T-(Cvclopropvlsulfonvl)-2',3'-dihvdro-TH-spiroroxetane- 3,4'-quinolin]-6'-yl)-4-methylthiazol-2-yl)acetamide

Step 1 : 6'-Bromo-1 '-(cyclopropylsulfonyl)-2',3'-dihydro-1 'H-spiro[oxetane-3,4'-quinoline]

2',3'-Dihydro-1'/7-spiro[oxetane-3,4'-quinoline] (50 mg, 285 pmol) was dissolved in 2 mL of acetonitrile. Afterwards, 1 -bromopyrrolidine-2, 5-dione (1.0 eq., 51 mg, 285 pmol) was added to the mixture and the reaction was stirred at room temperature for 16 hours. Upon completion of the reaction, the crude was poured in a separatory funnel, containing DCM and 1 M solution of Na2S2C>3 in water. The water phase was extracted 3 times with DCM. Then, the combined organic phases were dried over Na2SC>4 and concentrated under reduced pressure. The residue was then dissolved in 2 mL pyridine. Afterwards, cyclopropanesulfonyl chloride (1.2 eq., 48 mg, 342 pmol) was added to the mixture. The reaction mixture was stirred for three hours at 70 °C. The solvent was then removed under reduced pressure and the crude product purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1% TFA). The product was obtained after lyophilization as an amorphous white solid.

Yield: 57 mg (56 %).

MS (ES+) [M+Na]⁺ m/e = 358.0, 359.9 (bromine isotopic pattern).

Step 2: /V-(5-(1'-(Cyclopropylsulfonyl)-2',3'-dihydro-1'/-/-spiro[oxetane-3,4'-quinolin]-6'-yl)-4- methylthiazol-2-yl)acetamide

6'-Bromo-T-(cyclopropylsulfonyl)-2',3'-dihydro-TH-spiro[oxetane-3,4'-quinoline] (10 mg, 28 pmol) A/-(4-methylthiazol-2-yl)acetamide (2 eq., 8.8 mg, 56 pmol), tri-tert-butylphosphonium tetrafluoroborate (0.2 eq., 1.6 mg, 5.6 pmol), Pd(OAc)2, (0.1 eq., 0.6 mg, 2.8 pmol) and CS2CO3 (3 eq., 27 mg, 84 pmol) were suspended in 1 mL of DMF. The suspension was sonicated for 5 minutes, flushed with nitrogen, heated up to 110 °C and stirred overnight. The solvent was then removed under reduced pressure and the crude product purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1 % TFA). The product was obtained after lyophilization as an amorphous white solid.

Yield: 4 mg (33%).

MS (ES+) [M+H]⁺ m/e = 434.0

¹H NMR (600 MHz, CDCI3): 5 8.05 (d, J = 2.3 Hz, 1 H), 7.82 (dd, J = 8.6, 2.2 Hz, 1 H), 7.34 (dd, J = 8.6, 2.2 Hz, 1 H), 4.90 (d, J = 6.1 Hz, 2H), 4.71 (d, J = 6.1 Hz, 2H), 3.85 - 3.74 (m, 2H), 2.54 - 2.44 (m, 6H), 2.33 (d, J = 2.1 Hz, 3H), 1 .35 - 1 .27 (m, 2H), 1 .02 (qd, J = 5.7, 1 .2 Hz, 2H).

¹³C NMR (151 MHz, CDCI3): 5 167.56, 155.82, 141.01 , 135.79, 131.61 , 128.82, 128.39, 127.76, 125.10, 122.94, 85.10, 43.97, 40.93, 34.16, 30.52, 29.09, 23.28, 15.72, 5.77.

Example compound 170: A/-(5-(1-(Cvclopropanecarbonvl)-1 ,2.3.4-tetrahvdroquinolin-6-vl)- 4-methylthiazol-2-yl)acetamide

A/-(4-Methyl-5-(1 ,2,3,4-tetrahydroquinolin-6-yl)thiazol-2-yl)acetamide (20 mg, 70 pmol) was dissolved in 1 mL of pyridine. Afterwards, cyclopropanecarbonyl chloride (1.5 eq., 11 mg, 104 pmol) was added dropwise to the solution and stirred for 3 hours at room temperature. The solvent was then removed under reduced pressure and the crude product purified by reversed- phase preparative HPLC (5% to 99% acetonitrile with 0.1 % TFA). The product was obtained after lyophilization as an amorphous white solid.

Yield: 17 mg (58%). MS (ES+) [M+H]⁺ m/e = 356.0

¹H NMR (600 MHz, CDCI₃): 5 7.49 (d, J = 8.1 Hz, 1 H), 7.27 (d, J = 9.0 Hz, 2H), 3.87 (t, J = 6.6 Hz, 2H), 2.81 (t, = 6.6 Hz, 2H), 2.45 (s, 3H), 2.31 (s, 3H), 2.12 - 1.94 (m, 3H), 1.24 - 1.13 (m, 2H), 0.86 (dq, J = 7.1 , 3.8 Hz, 2H).

¹³C NMR (151 MHz, CDCI3): 5 173.45, 167.63, 156.08, 140.24, 138.75, 133.35, 128.98, 128.04, 126.50, 125.60, 124.81 , 43.42, 27.14, 23.99, 23.27, 15.71 , 13.78, 9.27.

Example compound 171 : A/-(5-(1-(Cvclopropanecarbonvl)-1.2.3.4-tetrahvdroquinolin-6-vl)- 4-methylthiazol-2-yl)acetamide

Step 1 : 5-(1-(Cvclopropvlsulfonvl)-1.2.3.4-tetrahvdroquinolin-6-vl)-4-methvlthiazol-2-amine

A/-(5-(1-(Cyclopropylsulfonyl)-1 ,2,3,4-tetrahydroquinolin-6-yl)-4-methylthiazol-2-yl)acetamide (190 mg, 383 pmol) and lithium hydroxide monohydride (25 eq., 419 mg, 9.98 mmol) were dissolved in 4 mL of H2O, 4 mL of THF and 1 mL of MeOH. The reaction was heated for 3 hours at 100 °C in the microwave reactor. Upon completion of the reaction, the crude was poured in a separatory funnel, containing DCM and water. The water phase was extracted 3 times with DCM. The solvent was then removed under reduced pressure and the crude product purified by reversed- phase preparative HPLC (5% to 99% acetonitrile with 0.1 % TFA). The product was obtained after lyophilization as an amorphous white solid.

Yield: 152 mg (90%).

MS (ES+) [M+H]⁺ m/e = 350.1

¹H NMR (600 MHz, CDCI3): 5 7.73 (d, J = 8.5 Hz, 1 H), 7.15 (dd, J = 8.6, 2.2 Hz, 1 H), 7.11 - 7.09 (m, 1 H), 5.37 (s, 2H), 3.84 - 3.80 (m, 2H), 2.88 (t, J = 6.7 Hz, 2H), 2.45 (tdd, J = 8.3, 5.3, 4.4 Hz, 1 H), 2.30 (s, 3H), 2.10 - 2.04 (m, 2H), 1.23 - 1.19 (m, 2H), 0.98 - 0.93 (m, 2H).

³C NMR (151 MHz, CDCI₃): 5 167.14, 165.37, 141.97, 136.27, 129.71 , 129.64, 128.38, 127.00, 123.59, 120.21 , 46.75, 29.93, 27.11 , 22.49, 15.66, 5.54.

Step 2: Af-(5-(d -(Cyclopropylsulfonyl)-1 ,2,3,4-tetrahydroquinolin-6-yl)-4-methylthiazol-2- yl)cyclopropanecarboxamide

5-(1-(Cyclopropylsulfonyl)-1 ,2,3,4-tetrahydroquinolin-6-yl)-4-methylthiazol-2-amine (20 mg, 57 pmol) and trietylamine (3 eq., 17 mg, 172 pmol) are dissolved in 1 mL of DCM. Afterwards, cyclopropanecarbonyl chloride (1 .5 eq., 9 mg, 86 pmol) is added to the mixture and the reaction is stirred at room temperature for 30 minutes. The solvent was then removed under reduced pressure and the crude product purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1% TFA). The product was obtained after lyophilization as an amorphous white solid.

Yield: 12 mg (50%).

MS (ES+) [M+H]⁺ m/e = 418.1

¹H NMR (600 MHz, CDCI3): 5 7.80 (d, J = 8.6 Hz, 1 H), 7.25 (dd, J = 8.6, 2.2 Hz, 1 H), 7.20 (d, J = 2.3 Hz, 1 H), 3.91 - 3.77 (m, 2H), 2.91 (t, J = 6.7 Hz, 2H), 2.49 (tt, J = 8.1 , 4.8 Hz, 1 H), 2.44 (s, 3H), 2.14 - 2.03 (m, 2H), 1 .68 (tt, J = 8.1 , 4.5 Hz, 1 H), 1 .28 - 1 .20 (m, 4H), 1 .08 - 0.93 (m, 4H).

¹³C NMR (151 MHz, CDCI3): 5 171.59, 156.09, 140.27, 136.77, 129.97, 129.80, 127.86, 127.03, 125.16, 123.60, 46.78, 29.97, 27.12, 26.71 , 22.44, 15.68, 15.08, 9.34, 5.56.

Example compound 172: A/-(5-(1-(Cyclopropylsulfonyl)-1,2,3,4-tetrahydroquinolin-6-yl)-4- methylthiazol-2-yl)propionamide

5-(1-(Cyclopropylsulfonyl)-1 ,2,3,4-tetrahydroquinolin-6-yl)-4-methylthiazol-2-amine (20 mg, 57 pmol) and trietylamine (3 eq., 17 mg, 172 pmol) are dissolved in 1 mL of DCM. Afterwards, propionyl chloride (1 .5 eq., 8 mg, 86 pmol) is added to the mixture and the reaction is stirred at room temperature for 30 minutes. The solvent was then removed under reduced pressure and the crude product purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1% TFA). The product was obtained after lyophilization as an amorphous white solid.

Yield: 10 mg (43%).

MS (ES+) [M+H]⁺ m/e = 406.1

H NMR (600 MHz, CDCI₃): 5 7.81 (d, J = 8.6 Hz, 1 H), 7.24 (dd, J = 8.6, 2.3 Hz, 1 H), 7.20 (d, J = 2.1 Hz, 1 H), 3.90 - 3.82 (m, 2H), 2.92 (t, J = 6.8 Hz, 2H), 2.57 (q, J = 7.5 Hz, 2H), 2.50 (td, J = 8.0, 4.1 Hz, 1 H), 2.42 (s, 3H), 2.10 (qd, J = 6.6, 3.9 Hz, 2H), 1.34 - 1.27 (m, 3H), 1.27 - 1.22 (m, 2H), 1.02 - 0.95 (m, 2H).

¹³C NMR (151 MHz, CDCI3): 5 171.73, 166.47, 156.95, 137.04, 130.00, 129.88, 127.29, 127.08, 124.96, 123.64, 46.78, 29.99, 29.56, 27.17, 22.43, 14.95, 9.00, 5.57.

173 A/-(5-(1-(Cyclopropylsulfonyl)-1,2,3,4-tetrahydroquinolin-6-yl)-4- methylthiazol-2-yl)isobutyramide

5-(1-(Cyclopropylsulfonyl)-1 ,2,3,4-tetrahydroquinolin-6-yl)-4-methylthiazol-2-amine (20 mg, 57 pmol) and trietylamine (3 eq., 17 mg, 172 pmol) are dissolved in 1 mL of DCM. Afterwards, isobutyryl chloride (1 .5 eq., 9 mg, 86 pmol) is added to the mixture and the reaction is stirred at room temperature for 30 minutes. The solvent was then removed under reduced pressure and the crude product purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1% TFA). The product was obtained after lyophilization as an amorphous white solid.

Yield: 13 mg (54%).

MS (ES+) [M+H]⁺ m/e = 420.1

¹H NMR (600 MHz, CDCI₃): 5 7.80 (d, J = 8.5 Hz, 1 H), 7.25 (dd, J = 8.5, 2.3 Hz, 1 H), 7.21 (d, J = 2.2 Hz, 1 H), 3.87 - 3.84 (m, 2H), 2.92 (t, J = 6.8 Hz, 2H), 2.68 (hept, J = 6.9 Hz, 1 H), 2.50 (tt, J = 8.0, 4.8 Hz, 1 H), 2.42 (s, 3H), 2.14 - 2.06 (m, 2H), 1 .32 (d, J = 6.9 Hz, 6H), 1 .25 (tt, J = 5.5, 3.0 Hz, 2H), 1 .00 (pd, J = 6.2, 1 .8 Hz, 2H).

¹³C NMR (151 MHz, CDCI3): 5 174.39, 155.58, 140.94, 136.69, 130.00, 129.78, 128.05, 127.08, 125.34, 123.59, 46.78, 35.61 , 29.96, 27.12, 22.45, 19.13, 15.68, 5.56.

Example compound 174: A/-(5-(1-(Cyclopropylsulfonyl)-1,2,3,4-tetrahydroquinolin-6-yl)-4- methylthiazol-2-yl)cyclopentanecarboxamide

5-(1-(Cyclopropylsulfonyl)-1 ,2,3,4-tetrahydroquinolin-6-yl)-4-methylthiazol-2-amine (20 mg, 57 pmol) and trietylamine (3 eq., 17 mg, 172 pmol) are dissolved in 1 mL of DCM. Afterwards, cyclopentanecarbonyl chloride (1 .5 eq., 11 mg, 86 pmol) is added to the mixture and the reaction is stirred at room temperature for 30 minutes. The solvent was then removed under reduced pressure and the crude product purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1% TFA). The product was obtained after lyophilization as an amorphous white solid.

Yield: 12 mg (47%).

MS (ES+) [M+H]⁺ m/e = 446.1

H NMR (600 MHz, CDCI3): 5 7.85 (dd, J = 8.5, 3.0 Hz, 1 H), 7.25 - 7.21 (m, 1 H), 7.18 (d, J = 2.3 Hz, 1 H), 3.86 (td, J = 6.2, 3.3 Hz, 2H), 3.05 - 2.97 (m, 1 H), 2.93 (t, J = 6.7 Hz, 2H), 2.54 - 2.48 (m, 4H), 2.14 - 2.02 (m, 4H), 1.92 (dq, J = 12.3, 8.0 Hz, 2H), 1.81 (tdd, J = 12.8, 9.1 , 5.0 Hz, 2H), 1 .71 (qt, J = 7.1 , 3.2 Hz, 2H), 1 .27 (qt, J = 5.1 , 2.1 Hz, 2H), 1 .05 - 0.95 (m, 2H).

¹³C NMR (151 MHz, CDCI3): 5 175.32, 158.58, 137.80, 130.08, 129.97, 128.81 , 127.02, 125.74, 124.78, 123.75, 46.77, 45.42, 30.23, 30.07, 27.19, 26.06, 22.36, 13.79, 5.59.

Example compound 175: A/-(5-(4-((2,3-Dichlorophenvl)sulfonvl)-3.4-dihvdro-2H- benzo[b][1 ,4]oxazin-7-yl)-4-methylthiazol-2-yl)acetamide

A/-(5-(3,4-Dihydro-2H-benzo[b][1,4]oxazin-7-yl)-4-methylthiazol-2-yl)acetamide

7-Bromo-3,4-dihydro-2/7-benzo[b][1 ,4]oxazine (50 mg, 223 pmol) A/-(4-methylthiazol-2- yl)acetamide (1.5 eq., 55 mg, 350 pmol), tri-tert-butylphosphonium tetrafluoroborate (0.2 eq., 14 mg, 47 pmol), Pd(OAc)2, (0.1 eq., 5.2 mg, 23 pmol) and CS2CO3 (3 eq., 228 mg, 700 pmol) were suspended in 2 mL of DMF. The suspension was sonicated for 5 minutes, flushed with nitrogen, heated up to 110 °C and stirred overnight. The solvent was then removed under reduced pressure and the crude product purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1% TFA). The product was obtained after lyophilization as an amorphous white solid.

Yield: 20 mg (30%).

MS (ES+) [M+H]⁺ m/e = 290.0

Step 2: A/-(5-(4-((2,3-Dichlorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-4- methylthiazol-2-yl)acetamide

A/-(5-(3,4-Dihydro-2/7-benzo[b][1 ,4]oxazin-7-yl)-4-methylthiazol-2-yl)acetamide (20 mg, 70 pmol) was dissolved in 1 mL of pyridine. Afterwards, 2,3-dichlorobenzenesulfonyl chloride (2 eq., 34 mg, 140 pmol) was added dropwise to the solution and stirred overnight hours at room temperature. The solvent was then removed under reduced pressure and the crude product purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1% TFA). The product was obtained after lyophilization as an amorphous white solid.

Yield: 10 mg (28%).

MS (ES+) [M+H]⁺ m/e = 499.0

¹H NMR (600 MHz, DMSO-d₆): 5 12.09 (s, 1 H), 8.18 (dd, J = 8.0, 1.5 Hz, 1 H), 8.04 (dd, J = 8.1 , 1 .5 Hz, 1 H), 7.66 (t, J = 8.1 Hz, 1 H), 7.32 (d, J = 8.5 Hz, 1 H), 6.97 (d, J = 2.1 Hz, 1 H), 6.94 (dd, J = 8.5, 2.2 Hz, 1 H), 4.19 (dd, J = 5.2, 3.8 Hz, 2H), 4.01 (dd, J = 5.2, 3.7 Hz, 2H), 2.31 (s, 3H), 2.13 (s, 3H).

¹³C NMR (151 MHz, DMSO-d₆): 5 168.79, 155.57, 146.37, 142.63, 139.18, 136.20, 135.35, 131 .08, 129.88, 129.67, 129.63, 123.47, 123.19, 122.63, 121 .31 , 117.42, 65.07, 44.59, 22.89, 16.52.

Example compound 176: A/-(5-(4-((2,3-Dichlorophenvl)sulfonvl)-3.4-dihvdro-2H- benzo[b][1 ,4]oxazin-7-yl)thiazol-2-yl)acetamide

Step 1 : A/-(5-(3,4-Dihydro-2H-benzo[b][1,4]oxazin-7-yl)thiazol-2-yl)acetamide IT.

7-Bromo-3,4-dihydro-2/7-benzo[b][1 ,4]oxazine (50 mg, 223 pmol) A/-(thiazol-2-yl)acetamide (1 .5 eq., 50 mg, 350 pmol), tri-tert-butylphosphonium tetrafluoroborate (0.2 eq., 14 mg, 47 pmol), Pd(OAc)2, (0.1 eq., 5.2 mg, 23 pmol) and CS2CO3 (3 eq., 228 mg, 700 pmol) were suspended in 2 mL of DMF. The suspension was sonicated for 5 minutes, flushed with nitrogen, heated up to 110 °C and stirred overnight. The solvent was then removed under reduced pressure and the crude product purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1% TFA). The product was obtained after lyophilization as an amorphous white solid.

Yield: 11 mg (17%).

MS (ES+) [M+H]⁺ m/e = 276.1

Step 2: A/-(5-(4-((2,3-Dichlorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7- yl)thiazol-2-yl)acetamide

A/-(5-(3,4-Dihydro-2/7-benzo[b][1 ,4]oxazin-7-yl)thiazol-2-yl)acetamide (11 mg, 39 pmol) was dissolved in 1 mL of pyridine. Afterwards, 2,3-dichlorobenzenesulfonyl chloride (2 eq., 20 mg, 78 pmol) was added dropwise to the solution and stirred overnight hours at room temperature. The solvent was then removed under reduced pressure and the crude product purified by reversed- phase preparative HPLC (5% to 99% acetonitrile with 0.1 % TFA). The product was obtained after lyophilization as an amorphous white solid.

Yield: 2.6 mg (34%).

MS (ES+) [M+H]⁺ m/e = 484.9

¹H NMR (600 MHz, CDCI₃): 6 8.17 (dd, J = 8.0, 1.6 Hz, 1 H), 7.75 (dd, = 8.0, 1.6 Hz, 1 H), 7.65 - 7.53 (m, 1 H), 7.44 (t, J = 8.0 Hz, 1 H), 7.39 (d, J = 8.6 Hz, 1 H), 7.11 (d, J = 2.0 Hz, 1 H), 7.02 (dd, J = 8.6, 2.1 Hz, 1 H), 4.27 (dd, J = 5.2, 3.8 Hz, 2H), 4.07 (dd, J = 5.2, 3.7 Hz, 2H), 2.36 (s, 3H).

¹³C NMR (151 MHz, CDCI3): 5 167.75, 146.43, 139.52, 136.35, 135.16, 132.72, 130.89, 130.57, 130.52, 130.43, 128.52, 127.63, 124.13, 122.51 , 118.75, 115.24, 64.79, 44.55, 23.25.

177 Af-(5-(d -( (4/7-1 ,2,4-T riazol-3-yl)sulfonyl)-1 ,2,3,4-tetrahydroquinolin-

6-yl)-4-methylthiazol-2-yl)acetamide 1 >

A/-(4-Methyl-5-(1 ,2,3,4-tetrahydroquinolin-6-yl)thiazol-2-yl)acetamide (20 mg, 70 pmol) was dissolved in 1 mL of pyridine. Afterwards, 4/7-1 ,2,4-triazole-3-sulfonyl chloride (3 eq., 32 mg, 209 pmol) was added dropwise to the solution and stirred for 2 hours at 70 °C. The solvent was then removed under reduced pressure and the crude product purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1 % TFA). The product was obtained after lyophilization as an amorphous white solid.

Yield: 10 mg (34%).

MS (ES+) [M+H]⁺ m/e = 419.0

¹H NMR (600 MHz, DMSO-d₆): 5 12.06 (s, 1 H), 8.82 (s, 1 H), 7.63 (d, J = 8.6 Hz, 1 H), 7.23 (dd, J = 8.6, 2.3 Hz, 1 H), 7.19 (d, J = 2.2 Hz, 1 H), 3.90 - 3.79 (m, 2H), 2.70 (t, J = 6.6 Hz, 2H), 2.32 (s, 3H), 2.13 (s, 3H), 1.89 - 1.72 (m, 2H).

¹³C NMR (151 MHz, DMSO-d₆): 5 168.75, 160.89, 155.39, 146.47, 142.26, 135.72, 130.91 , 129.57, 128.58, 126.66, 123.65, 123.07, 47.08, 26.66, 22.90, 22.18, 16.53.

Example compound 178: 1 -(6-((5-(d -((2,3-Dichlorophenyl)sulfonyl)-1 ,2,3,4- tetrahydroquinolin-6-yl)-4-methylthiazol-2-yl)amino)pyridin-2-yl)pyrrolidin-2-one

Step 1 : 1 -(6-Bromopyridin-2-yl)pyrrolidin-2-one

2,6-Dibromopyridine (100 mg, 422 pmol), pyrrolidin-2-one (1.0 eq., 36 mg, 422 pmol), (9,9- dimethyl-9/7-xanthene-4,5-diyl)bis(diphenylphosphane) (0.2 eq., 49 mg, 84 pmol), Pd(OAc)2, (0.1 eq., 9.5 mg, 42 pmol) and CS2CO3 (3 eq., 412 mg, 1 .27 mmol) were suspended in 3 mL of 1 ,4- dioxane. The suspension was sonicated for 5 minutes, flushed with nitrogen, heated in a micowave reactor to 60 °C for 2 hours. The solvent was then removed under reduced pressure and the crude product purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1% TFA). The product was obtained after lyophilization as an amorphous white solid.

Yield: 38 mg (37%).

MS (ES+) [M+Na]⁺ m/e = 241 .0, 242.9 (bromine isotopic pattern).

¹H NMR (300 MHz, CDCI3): 5 8.39 (dd, J = 8.3, 0.7 Hz, 1 H), 7.55 (dd, J = 8.3, 7.6 Hz, 1 H), 7.22 (dd, J = 7.6, 0.7 Hz, 1 H), 4.19 - 3.86 (m, 2H), 2.68 (dd, J = 8.5, 7.7 Hz, 2H), 2.36 - 2.01 (m, 2H)

¹³C NMR (75 MHz, CDCI3): 5 175.17, 151.93, 139.89, 139.19, 123.26, 112.97, 47.54, 33.78, 17.68.

Step 2: 5-(1-((2.3-Dichlorophenvl)sulfonvl)-1.2.3.4-tetrahvdroquinolin-6-vl)-4-methvlthiazol- 2 -amine

A/-(5-(1-((2,3-Dichlorophenyl)sulfonyl)-1 ,2,3,4-tetrahydroquinolin-6-yl)-4-methylthiazol-2- yl)acetamide (200 mg, 403 pmol) and lithium hydroxide monohydride (25 eq., 423 mg, 4.03 mmol) were dissolved in 4 mL of H2O, 4 mL of THF and 1 mL of MeOH. The reaction was heated for 3 hours at 65 °C in the microwave reactor. Upon completion of the reaction, the crude was poured in a separatory funnel, containing DCM and water. The water phase was extracted 3 times with DCM. The solvent was then removed under reduced pressure and the crude product purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1% TFA). The product was obtained after lyophilization as an amorphous white solid.

Yield: 149 mg (81 %).

MS (ES+) [M+H]⁺ m/e = 454.0

Step 3: 1 -(6-((5-(1 -((2,3-Dichlorophenyl)sulfonyl)-1 ,2,3,4-tetrahydroquinolin-6-yl)-4- methylthiazol-2-yl)amino)pyridin-2-yl)pyrrolidin-2-one

1-(6-Bromopyridin-2-yl)pyrrolidin-2-one (11 mg, 44 pmol), 5-(1-((2,3-dichlorophenyl)sulfonyl)-

1.2.3.4-tetrahydroquinolin-6-yl)-4-methylthiazol-2-amine (1.0 eq., 20 mg, 44 pmol), [(4,5- bis(diphenylphosphino)-9,9-dimethylxanthene)-2-(2'-amino-1 ,1 '-biphenyl)]palladium(ll) methanesulfonate (0.1 eq., 3.9 mg, 4.4 pmol), and CS2CO3 (2 eq., 29 mg, 88 pmol) were suspended in 1 mL of DMF. The suspension was sonicated for 5 minutes, flushed with nitrogen, heated in a micowave reactor to 110 °C for 2 hours. The solvent was then removed under reduced pressure and the crude product purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1% TFA). The product was obtained after lyophilization as an amorphous white solid.

Yield: 5.5 mg (20%).

MS (ES+) [M+H]⁺ m/e = 615.0

Example compound 179: A/-(5-(1-((2.6-Dioxo-1 ,2.3.6-tetrahvdropvrimidin-4-vl)sulfonvl)-

1.2.3.4-tetrahydroquinolin-6-yl)-4-methylthiazol-2-yl)acetamide 1

A/-(4-Methyl-5-(1 ,2,3,4-tetrahydroquinolin-6-yl)thiazol-2-yl)acetamide (20 mg, 70 pmol) was dissolved in 1 mL of pyridine. Afterwards, 2,6-dioxo-1 ,2,3,6-tetrahydropyrimidine-4-sulfonyl chloride (3 eq., 44 mg, 209 pmol) was added dropwise to the solution and stirred for 2 hours at 70 °C. The solvent was then removed under reduced pressure and the crude product purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1% TFA). The product was obtained after lyophilization as an amorphous white solid.

Yield: 8 mg (25%).

MS (ES+) [M+H]⁺ m/e = 462.0

¹H NMR (600 MHz, DMSO-d₆): 5 12.05 (s, 1 H), 11.89 (d, J = 6.7 Hz, 1 H), 11.63 (s, 1 H), 8.22 (d, J = 6.3 Hz, 1 H), 7.63 - 7.45 (m, 1 H), 7.19 (dd, J = 6.4, 2.6 Hz, 2H), 3.91 - 3.83 (m, 2H), 2.76 (t, J = 6.5 Hz, 2H), 2.32 (s, 3H), 2.13 (s, 3H), 1.93 (p, J = 6.3 Hz, 2H).

¹³C NMR (151 MHz, DMSO-d₆): 5 168.72, 159.16, 155.24, 150.81 , 149.62, 142.01 , 135.96, 129.84, 129.61 , 127.33, 126.69, 123.83, 121.60, 111.84, 47.05, 27.21 , 22.90, 22.52, 16.54.

Example compound 180: A/-(4-Methvl-5-(1-((5-methvl-2.6-dioxo-1.2.3.6-tetrahvdropyrimidin- 4-yl)sulfonyl)-1 ,2,3,4-tetrahydroquinolin-6-yl)thiazol-2-yl)acetamide

A/-(4-Methyl-5-(1 ,2,3,4-tetrahydroquinolin-6-yl)thiazol-2-yl)acetamide (20 mg, 70 pmol) was dissolved in 1 mL of pyridine. Afterwards, 5-methyl-2,6-dioxo-1 ,2,3,6-tetrahydropyrimidine-4- sulfonyl chloride (3 eq., 47 mg, 209 pmol) was added dropwise to the solution and stirred for 2 hours at 70 °C. The solvent was then removed under reduced pressure and the crude product purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1% TFA). The product was obtained after lyophilization as an amorphous white solid.

Yield: 9 mg (27%).

MS (ES+) [M+H]⁺ m/e = 476.0

¹H NMR (600 MHz, DMSO-d₆): 5 12.04 (s, 1 H), 11.69 (s, 1 H), 11.48 (s, 1 H), 7.36 (d, J = 8.6 Hz, 1 H), 7.21 (dd, J = 8.6, 2.3 Hz, 1 H), 7.18 (d, J = 2.2 Hz, 1 H), 3.92 - 3.83 (m, 2H), 2.76 (t, J = 6.4 Hz, 2H), 2.54 (s, 3H), 2.32 (s, 3H), 2.13 (s, 3H), 1 .92 (p, J = 6.3 Hz, 2H).

¹³C NMR (151 MHz, DMSO-d₆): 5 168.69, 161.15, 160.14, 155.17, 150.09, 141.86, 136.62,

129.54, 129.27, 126.79, 126.74, 123.95, 120.39, 110.74, 47.33, 27.30, 22.90, 22.58, 19.63,

16.54. Example compound 181 : A/-(5-(1-((1H-Pvrazol-4-vl)sulfonvl)-1.2.3.4-tetrahvdroquinolin-6- yl)-4-methylthiazol-2-yl)acetamide

A/-(4-Methyl-5-(1 ,2,3,4-tetrahydroquinolin-6-yl)thiazol-2-yl)acetamide (20 mg, 70 pmol) was dissolved in 1 mL of pyridine. Afterwards, 1 /7-pyrazole-4-sulfonyl chloride (3 eq., 35 mg, 209 pmol) was added dropwise to the solution and stirred for 2 hours at 70 °C. The solvent was then removed under reduced pressure and the crude product purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1 % TFA). The product was obtained after lyophilization as an amorphous white solid.

Yield: 17 mg (59%).

MS (ES+) [M+H]⁺ m/e = 418.0

¹H NMR (600 MHz, DMSO-d₆): 5 12.06 (s, 1 H), 8.31 (s, 1 H), 7.70 (s, 2H), 7.27 (dd, = 8.6, 2.3 Hz, 1 H), 7.17 (d, J = 2.3 Hz, 1 H), 3.83 - 3.71 (m, 2H), 2.60 (t, J = 6.6 Hz, 2H), 2.34 (s, 3H), 2.14 (s, 3H), 1.80 - 1.63 (m, 2H).

¹³C NMR (151 MHz, DMSO-d₆): 5 168.74, 155.36, 142.22, 138.36, 135.96, 131.68, 130.87, 129.63, 128.38, 126.78, 123.73, 123.64, 120.22, 46.66, 26.81 , 22.90, 21.48, 16.56.

Example compound 182: A/-(4-Methvl-5-(1 -((1 -methyl-1 H-1 ,2,3-triazol-5-yl)sulfonyl)-1 ,2,3,4- tetrahydroquinolin-6-yl)thiazol-2-yl)acetamide

A/-(4-Methyl-5-(1 ,2,3,4-tetrahydroquinolin-6-yl)thiazol-2-yl)acetamide (20 mg, 70 pmol) was dissolved in 1 mL of pyridine. Afterwards, 1 -methyl-1 /7-1 ,2, 3-triazole-5-sulfonyl chloride (3 eq., 38 mg, 209 pmol) was added dropwise to the solution and stirred for 2 hours at 70 °C. The solvent was then removed under reduced pressure and the crude product purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1% TFA). The product was obtained after lyophilization as an amorphous white solid.

Yield: 8 mg (27%).

MS (ES+) [M+H]⁺ m/e = 433.1

¹H NMR (600 MHz, DMSO-d₆): 5 12.10 (s, 1 H), 8.36 (d, J = 2.7 Hz, 1 H), 7.61 - 7.54 (m, 1 H), 7.34 (d, J = 8.7 Hz, 1 H), 7.28 (s, 1 H), 3.89 (d, J = 3.0 Hz, 5H), 2.61 (t, J = 7.1 Hz, 2H), 2.38 - 2.33 (m, 3H), 2.15 (d, = 2.6 Hz, 3H), 1.72 (q, J = 6.6 Hz, 2H). ¹³C NMR (151 MHz, DMSO-d₆): 5 168.82, 155.63, 142.74, 137.59, 135.83, 134.31 , 132.45, 130.15, 129.75, 127.03, 124.91 , 123.38, 47.09, 37.06, 26.23, 22.91 , 21.94, 16.58.

Example compound 183: A/-(4-Methvl-5-(1 -((1 -methyl-1 H-imidazol-2-yl)sulfonyl)-1 ,2,3,4- tetrahydroquinolin-6-yl)thiazol-2-yl)acetamide

A/-(5-(1-((1/7-imidazol-2-yl)sulfonyl)-1 ,2,3,4-tetrahydroquinolin-6-yl)-4-methylthiazol-2- yl)acetamide (6 mg, 14 pmol) was dissolved in 1 mL of ACN. Afterwards, CS2CO3 (3 eq., 14 mg, 43 pmol) and iodomethane (1.1 eq., 2.2 mg, 16 pmol) were added to the mixture and the reaction was stirred for 3 hours at room temperature . The solvent was then removed under reduced pressure and the crude product purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1% TFA). The product was obtained after lyophilization as an amorphous white solid.

Yield: 3 mg (48%).

MS (ES+) [M+H]⁺ m/e = 432.1

¹H NMR (600 MHz, DMSO-d₆): 5 12.08 (s, 1 H), 7.57 (d, = 8.5 Hz, 1 H), 7.46 (d, J = 1.0 Hz, 1 H), 7.27 (dd, = 8.6, 2.3 Hz, 1 H), 7.22 (d, J = 2.2 Hz, 1 H), 7.10 (d, J = 1.0 Hz, 1 H), 3.90 - 3.83 (m, 2H), 3.64 (s, 3H), 2.64 (t, J = 6.6 Hz, 2H), 2.33 (s, 3H), 2.14 (s, 3H), 1.81 - 1 .72 (m, 2H).

¹³C NMR (151 MHz, DMSO-d₆): 5 168.78, 155.47, 142.41 , 141.59, 135.50, 131.94, 129.51 , 129.22, 128.83, 127.50, 126.68, 124.31 , 123.60, 47.07, 35.14, 26.40, 22.90, 22.04, 16.54.

Example compound 184: tert-Butvl 6-(6-((5-(1 -((2,3-dichlorophenyl)sulfonyl)-1 ,2,3,4- tetrahydroquinolin-6-yl)-4-methylthiazol-2-yl)amino)pyridin-2-yl)-7-oxo-2,6- diazaspiro[3.4]octane-2-carboxylate

Step 1 : tert-Butyl 6-(6-bromopyridin-2-yl)-7-oxo-2,6-diazaspiro[3.4]octane-2-carboxylate

2,6-Dibromopyridine (100 mg, 422 pmol), tert-butyl 7-oxo-2,6-diazaspiro[3.4]octane-2-carboxylate (1.0 eq., 95 mg, 422 pmol), (9,9-dimethyl-9/7-xanthene-4,5-diyl)bis(diphenylphosphane) (0.2 eq., 49 mg, 84 pmol), Pd(OAc)2, (0.1 eq., 9.5 mg, 42 pmol) and CS2CO3 (3 eq., 412 mg, 1.27 mmol) were suspended in 3 mL of 1 ,4-dioxane. The suspension was sonicated for 5 minutes, flushed with nitrogen, heated in a micowave reactor to 60 °C for 2 hours. The solvent was then removed under reduced pressure and the crude product purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1% TFA). The product was obtained after lyophilization as an amorphous white solid.

Yield: 115 mg (71 %).

MS (ES+) [M+Na]⁺ m/e = 404.0, 406.0 (bromine isotopic pattern). ¹H NMR (300 MHz, DMSO-d₆): 6 8.24 (dd, J = 8.3, 0.7 Hz, 1 H), 7.83 - 7.67 (m, 1 H), 7.39 (dd, J = 7.6, 0.7 Hz, 1 H), 4.13 (s, 2H), 3.89 (dd, J = 18.1 , 7.3 Hz, 4H), 2.93 (s, 2H), 1.38 (d, J = 1.4 Hz, 9H).

Step 2: tert-Butvl 6-(6-((5-(d -((2,3-dichlorophenyl)sulfonyl)-1 ,2,3,4-tetrahydroquinolin-6-yl)- 4-methylthiazol-2-yl)amino)pyridin-2-yl)-7 -oxo-2, 6-diazaspiro[3.4]octane-2 -carboxylate

tert-Butyl 6-(6-bromopyridin-2-yl)-7-oxo-2,6-diazaspiro[3.4]octane-2-carboxylate (8.4 mg, 22 pmol), 5-(1-((2,3-dichlorophenyl)sulfonyl)-1 ,2,3,4-tetrahydroquinolin-6-yl)-4-methylthiazol-2-amine (1.0 eq., 10 mg, 22 pmol), [(4,5-bis(diphenylphosphino)-9,9-dimethylxanthene)-2-(2'-amino-1 ,1 biphenyl)]palladium(ll) methanesulfonate (0.1 eq., 2.0 mg, 2.2 pmol), and CS2CO3 (2 eq., 14 mg, 44 pmol) were suspended in 1 mL of DMF. The suspension was sonicated for 5 minutes, flushed with nitrogen, heated in a micowave reactor to 110 °C for 2 hours. The solvent was then removed under reduced pressure and the crude product purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1% TFA). The product was obtained after lyophilization as an amorphous white solid.

Yield: 2.8 mg (17%).

MS (ES+) [M+H]⁺ m/e = 755.0

Example compound 185: A/-(4-Methvl-5-(1 -((1 -methyl-1 H-pyrazol-5-yl)sulfonyl)-1 ,2,3,4- tetrahydroquinolin-6-yl)thiazol-2-yl)acetamide

A/-(4-Methyl-5-(1 ,2,3,4-tetrahydroquinolin-6-yl)thiazol-2-yl)acetamide (20 mg, 70 pmol) was dissolved in 1 mL of pyridine. Afterwards, 1 -methyl-1 /7-pyrazole-5-sulfonyl chloride (1.1 eq., 14 mg, 77 pmol) was added dropwise to the solution and stirred for 2 hours at 70 °C. The solvent was then removed under reduced pressure and the crude product purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1% TFA). The product was obtained after lyophilization as an amorphous white solid.

Yield: 15 mg (49%).

MS (ES+) [M+H]⁺ m/e = 432.1 1

¹H NMR (600 MHz, DMSO-d₆): 6 12.09 (s, 1 H), 7.61 (d, J = 2.0 Hz, 1 H), 7.56 (d, J = 8.5 Hz, 1 H), 7.31 (dd, J = 8.6, 2.3 Hz, 1 H), 7.24 (d, J = 2.3 Hz, 1 H), 6.87 (d, J = 2.1 Hz, 1 H), 3.86 - 3.76 (m, 2H), 3.67 (s, 3H), 2.59 (t, J = 6.6 Hz, 2H), 2.33 (s, 3H), 2.13 (s, 3H), 1.71 - 1 .60 (m, 2H).

¹³C NMR (151 MHz, DMSO-d₆): 5 168.34, 155.09, 142.12, 138.13, 134.48, 131.79, 129.34, 129.26, 129.16, 126.37, 124.43, 123.00, 111 .76, 46.32, 38.35, 25.76, 22.43, 21.17, 16.08.

Example compound 185: A/-(4-Methvl-5-(1 -((1 -methyl-1 H-pyrazol-4-yl)sulfonyl)-1 ,2,3,4- tetrahydroquinolin-6-yl)thiazol-2-yl)acetamide

A/-(4-Methyl-5-(1 ,2,3,4-tetrahydroquinolin-6-yl)thiazol-2-yl)acetamide (20 mg, 70 pmol) was dissolved in 1 mL of pyridine. Afterwards, 1 -methyl-1 /7-pyrazole-4-sulfonyl chloride (1.1 eq., 14 mg, 77 pmol) was added dropwise to the solution and stirred for 2 hours at 70 °C. The solvent was then removed under reduced pressure and the crude product purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1% TFA). The product was obtained after lyophilization as an amorphous white solid.

Yield: 21 mg (70%).

MS (ES+) [M+H]⁺ m/e = 432.0

¹H NMR (600 MHz, DMSO-d₆): 5 12.06 (s, 1 H), 8.30 (s, 1 H), 7.77 - 7.59 (m, 2H), 7.31 - 7.07 (m, 2H), 3.84 (s, 3H), 3.79 - 3.74 (m, 2H), 2.62 (t, J = 6.5 Hz, 2H), 2.33 (s, 3H), 2.13 (s, 3H), 1 .80 - 1.72 (m, 2H).

¹³C NMR (151 MHz, DMSO-d₆): 5 168.29, 154.89, 141.76, 137.93, 135.42, 132.90, 130.35, 129.21 , 127.90, 126.32, 123.25, 123.02, 119.92, 46.19, 39.06, 26.36, 22.43, 21.08, 16.08.

Example compound 187: A/-(4-Methvl-5-(1 -((1 -methyl-1 H-pyrazol-3-yl)sulfonyl)-1 ,2,3,4- tetrahydroquinolin-6-yl)thiazol-2-yl)acetamide

X

A/-(4-Methyl-5-(1 ,2,3,4-tetrahydroquinolin-6-yl)thiazol-2-yl)acetamide (20 mg, 70 pmol) was dissolved in 1 mL of pyridine. Afterwards, 1 -methyl-1 /7-pyrazole-3-sulfonyl chloride (1.1 eq., 14 mg, 77 pmol) was added dropwise to the solution and stirred for 2 hours at 70 °C. The solvent was then removed under reduced pressure and the crude product purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1% TFA). The product was obtained after lyophilization as an amorphous white solid.

Yield: 18 mg (60%).

MS (ES+) [M+H]⁺ m/e = 432.1

¹H NMR (600 MHz, DMSO-d₆) 5 12.07 (s, 1 H), 7.89 (q, J = 2.4 Hz, 1 H), 7.66 (d, J = 8.5 Hz, 1 H), 7.24 (dd, = 8.6, 2.4 Hz, 1 H), 7.18 (s, 1 H), 6.60 (q, J = 2.4 Hz, 1 H), 3.91 (d, J = 1.7 Hz, 3H), 3.84 - 3.76 (m, 2H), 2.67 (t, J = 6.7 Hz, 2H), 2.34 (d, J = 2.0 Hz, 3H), 2.14 (d, J = 1 .7 Hz, 3H), 1 .79 (dq, J = 13.0, 5.8 Hz, 2H).

¹³C NMR (151 MHz, DMSO-d₆): 5 168.74, 155.35, 148.92, 142.20, 136.04, 133.78, 130.84, 129.57, 128.36, 126.62, 123.74, 123.45, 107.73, 46.75, 26.70, 22.90, 21.87, 16.54.

Example compound 188: A/-(5-(1-(lsothiazol-5-vlsulfonvl)-1.2.3.4-tetrahvdroquinolin-6-vl)-4- methylthiazol-2-yl)acetamide

A/-(4-Methyl-5-(1 ,2,3,4-tetrahydroquinolin-6-yl)thiazol-2-yl)acetamide (20 mg, 70 pmol) was dissolved in 1 mL of pyridine. Afterwards, isothiazole-5-sulfonyl chloride (1.1 eq., 14 mg, 77 pmol) was added dropwise to the solution and stirred for 2 hours at 70 °C. The solvent was then removed under reduced pressure and the crude product purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1 % TFA). The product was obtained after lyophilization as an amorphous white solid.

Yield: 9 mg (29%).

MS (ES+) [M+H]⁺ m/e = 435.0

¹H NMR (600 MHz, DMSO-d₆): 5 12.19 - 12.01 (m, 1 H), 8.69 (d, J = 1.8 Hz, 1 H), 7.83 (d, J = 1.8 Hz, 1 H), 7.69 (d, J = 8.5 Hz, 1 H), 7.36 (dd, J = 8.6, 2.3 Hz, 1 H), 7.24 (d, J = 2.3 Hz, 1 H), 3.91 - 3.83 (m, 2H), 2.57 - 2.53 (m, 2H), 2.35 (s, 3H), 2.14 (s, 3H), 1 .74 - 1 .65 (m, 2H).

¹³C NMR (151 MHz, DMSO-d₆): 5 168.34, 161.82, 159.09, 155.12, 142.20, 133.92, 131.89, 129.56, 129.32, 127.26, 126.59, 124.32, 122.93, 46.96, 25.96, 22.42, 20.88, 16.12.

Example compound 189: -((4-Chloro-1 -methyl-1 H-pyrazol-5-yl)sulfonyl)-1 ,2,3,4-tetra- hydroquinolin-6-yl)-4-methylthiazol-2-yl)acetamide

A/-(4-Methyl-5-(1 ,2,3,4-tetrahydroquinolin-6-yl)thiazol-2-yl)acetamide (20 mg, 70 pmol) was dissolved in 1 mL of pyridine. Afterwards, 4-chloro-1 -methyl-1 /7-pyrazole-5-sulfonyl chloride (2 eq., 30 mg, 140 pmol) was added dropwise to the solution and stirred for 2 hours at 70 °C. The solvent was then removed under reduced pressure and the crude product purified by reversed- phase preparative HPLC (5% to 99% acetonitrile with 0.1 % TFA). The product was obtained after lyophilization as an amorphous white solid.

Yield: 4.6 mg (14%).

MS (ES+) [M+H]⁺ m/e = 466.0

¹H NMR (300 MHz, DMSO-d₆): 6 12.12 (s, 1 H), 7.84 (s, 1 H), 7.50 (d, J = 8.5 Hz, 1 H), 7.37 - 7.16 (m, 2H), 3.96 - 3.78 (m, 2H), 3.74 (s, 3H), 2.63 (t, J = Q.7 Hz, 2H), 2.33 (s, 3H), 2.13 (s, 3H), 1.69 (p, J = 6.6 Hz, 2H).

¹³C NMR (151 MHz, DMSO-d₆): 5 168.37, 155.13, 142.21 , 137.81 , 134.58, 134.12, 131.98, 129.70, 129.20, 126.39, 124.74, 122.98, 112.97, 46.13, 40.55, 25.65, 22.44, 21 .09, 16.08.

190 Af-(5-(d -((4-Chloro-1 -methyl-1 H-imidazol-5-yl)sulfonyl)-1 ,2,3,4- tetrahydroquinolin-6-yl)-4-methylthiazol-2-yl)acetamide

A/-(4-Methyl-5-(1 ,2,3,4-tetrahydroquinolin-6-yl)thiazol-2-yl)acetamide (20 mg, 70 pmol) was dissolved in 1 mL of pyridine. Afterwards, 4-chloro-1 -methyl-1 /7-imidazole-5-sulfonyl chloride (2 eq., 30 mg, 140 pmol) was added dropwise to the solution and stirred for 2 hours at 70 °C. The solvent was then removed under reduced pressure and the crude product purified by reversed- phase preparative HPLC (5% to 99% acetonitrile with 0.1 % TFA). The product was obtained after lyophilization as an amorphous white solid.

Yield: 16 mg (49%).

MS (ES+) [M+H]⁺ m/e = 466.0

¹H NMR (300 MHz, DMSO-d₆): 5 12.08 (s, 1 H), 7.94 (s, 1 H), 7.65 (d, J = 8.5 Hz, 1 H), 7.34 - 6.99 (m, 2H), 3.91 - 3.73 (m, 2H), 3.60 (s, 3H), 2.69 (t, = 6.6 Hz, 2H), 2.31 (s, 3H), 2.13 (s, 3H), 1.84 (t, = 6.0 Hz, 2H). ¹³C NMR (75 MHz, DMSO-d₆): 6 168.76, 155.32, 142.15, 139.02, 136.09, 133.24, 130.50, 129.61 , 128.18, 126.54, 123.74, 122.99, 121.92, 46.91 , 32.57, 26.81 , 22.91 , 22.01 , 16.52.

Example compound 191 : A/-(4-Methvl-5-(1-((3-(prop-2-vn-1-vlamino)phenvl)sulfonvl)- 1 ,2,3,4-tetrahydroquinolin-6-yl)thiazol-2-yl)acetamide

A/-(5-(1-((3-Aminophenyl)sulfonyl)-1 ,2,3,4-tetrahydroquinolin-6-yl)-4-methylthiazol-2-yl)acetamide (76 mg, 173 pmol) was dissolved in 2 mL of DMF. Afterwards, NaHCOa (4.1 eq., 58 mg, 699 pmol), pyridine (3 eq., 41 mg, 518 pmol) and propargyl bromide (80% in toluene, 6 eq., 124 mg, 1 .04 mmol) were added to the solution and the mixture stirred overnight at 50 °C. The solvent was then removed under reduced pressure and the crude product purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1% TFA). The product was obtained after lyophilization as an amorphous white solid.

Yield: 5 mg (6%).

MS (ES+) [M+H]⁺ m/e = 481.1

¹H NMR (600 MHz, DMSO-d₆) 5 12.07 (s, 2H), 7.66 (d, = 8.6 Hz, 1 H), 7.31 - 7.23 (m, 2H), 7.16 (d, J = 2.2 Hz, 1 H), 6.90 - 6.85 (m, 2H), 6.84 (dt, J = 7.7, 1 .2 Hz, 1 H), 6.55 (t, J = 6.0 Hz, 1 H), 3.81 (dd, J = 5.9, 2.5 Hz, 2H), 3.79 - 3.73 (m, 2H), 2.54 (t, J = 6.7 Hz, 2H), 2.34 (s, 3H), 2.14 (s, 3H), 1.67 - 1.58 (m, 2H).

¹³C NMR (151 MHz, DMSO-d₆): 5 168.73, 155.36, 148.79, 142.26, 139.96, 136.10, 131.16, 130.22, 129.60, 128.66, 126.68, 124.15, 123.73, 117.75, 114.76, 110.21 , 81.62, 73.84, 46.73, 32.25, 26.61 , 22.90, 21 .38, 16.50.

Example compound 192: A/-(5-(1-((3-((Cvanomethvl)amino)phenvl)sulfonvl)-1.2,3,4- tetrahydroquinolin-6-yl)-4-methylthiazol-2-yl)acetamide

A/-(5-(1-((3-Aminophenyl)sulfonyl)-1 ,2,3,4-tetrahydroquinolin-6-yl)-4-methylthiazol-2-yl)acetamide (25 mg, 56 pmol) was dissolved in 1 mL of DMF. Afterwards, NaHCOa (4.1 eq., 38.8 mg, 233 pmol), pyridine (3 eq., 14 mg, 233 pmol) and 2-chloroacetonitrile (14 eq., 30 mg, 394 pmol) were added to the solution and the mixture stirred overnight at 50 °C. The solvent was then removed under reduced pressure and the crude product purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1% TFA). The product was obtained after lyophilization as an amorphous white solid.

Yield: 13 mg (48%).

MS (ES+) [M+H]⁺ m/e = 482.0 ¹H NMR (600 MHz, CDCI₃): 6 7.81 (d, J = 8.5 Hz, 1 H), 7.24 (d, J = 2.4 Hz, 1 H), 7.19 (t, J = 7.9 Hz, 1 H), 7.10 (s, 1 H), 6.99 (d, J = 9.3 Hz, 1 H), 6.92 (s, 1 H), 6.80 (dd, J = 8.0, 3.0 Hz, 1 H), 5.16 (s, 2H), 3.87 - 3.79 (m, 2H), 2.57 - 2.49 (m, 5H), 2.43 (s, 3H), 1 .72 (h, J = 7.3 Hz, 2H).

¹³C NMR (151 MHz, CDCI3): 5 168.16, 154.35, 147.05, 141.75, 140.44, 136.51 , 130.76, 130.01 , 129.61 , 128.40, 127.04, 124.78, 120.83, 119.02, 116.76, 114.72, 112.76, 46.58, 35.33, 26.78, 22.71 , 21.54, 16.23.

Example compound 193: A/-(5-(1-((6-Cvanopvridin-2-vl)sulfonvl)-1.2.3.4-tetrahvdroquinolin- 6-yl)-4-methylthiazol-2-yl)acetamide

A/-(4-Methyl-5-(1 ,2,3,4-tetrahydroquinolin-6-yl)thiazol-2-yl)acetamide (24 mg, 82 pmol) was dissolved in 1 mL of pyridine. Afterwards, 6-cyanopyridine-2-sulfonyl chloride (3 eq., 50 mg, 147 pmol) was added dropwise to the solution and stirred at room temperature ovenight. The solvent was then removed under reduced pressure and the crude product purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1% TFA). The product was obtained after lyophilization as an amorphous white solid.

Yield: 11 mg (30%).

MS (ES+) [M+H]⁺ m/e = 454.1

¹H NMR (600 MHz, CDCI3): 5 8.22 (dd, J = 8.0, 1 .0 Hz, 1 H), 8.09 (t, J = 7.9 Hz, 1 H), 7.85 (dd, J = 7.8, 1.0 Hz, 1 H), 7.76 (d, = 8.5 Hz, 1 H), 7.16 - 7.11 (m, 2H), 4.08 - 4.02 (m, 2H), 2.84 (t, J = 6.6 Hz, 2H), 2.47 (s, 3H), 2.41 (s, 3H), 2.10 (p, J = 6.6 Hz, 2H).

³C NMR (151 MHz, CDCI3): 5 169.23, 164.05, 159.87, 158.97, 139.70, 137.61 , 133.95, 131.97, 131.05, 129.89, 127.08, 125.80, 124.74, 124.62, 123.03, 115.62, 47.85, 27.05, 23.12, 22.55, 12.87.

Example compound 194: A/-(5-(1-((3-Cvanamidoohenvl)sulfonvl)-1.2.3.4-tetrahvdroquinolin- 6-yl)-4-methylthiazol-2-yl)acetamide

A/-(5-(1-((3-Aminophenyl)sulfonyl)-1 ,2,3,4-tetrahydroquinolin-6-yl)-4-methylthiazol-2-yl)acetamide (49 mg, 111 pmol) was dissolved in 5 mL of a solvent mixture MeOH and H2O (9:1). Afterwards, 1-chloropyrrolidine-2, 5-dione (2.1 eq., 30 mg, 231 pmol) and Zn(CN)2 (2 eq., 26 mg, 222 pmol) were added to the solution and the mixture stirred overnight at room temperature. The solvent was then removed under reduced pressure and the crude product purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1% TFA). The product was obtained after lyophilization as an amorphous white solid.

Yield: 10 mg (20%).

MS (ES+) [M+H]⁺ m/e = 468.1

¹H NMR (600 MHz, DMSO-d₆): 5 12.06 (d, = 6.4 Hz, 1 H), 7.63 (dd, J = 14.2, 8.6 Hz, 1 H), 7.54 (t, = 8.0 Hz, 1 H), 7.30 (td, = 8.4, 1.8 Hz, 1 H), 7.24 (ddd, J = 10.6, 8.3, 2.3 Hz, 1 H), 7.18 - 7.11 (m, 2H), 3.80 - 3.74 (m, 2H), 2.33 (d, J = 3.4 Hz, 3H), 2.13 (d, J = 1 .4 Hz, 3H), 1 .99 (s, 2H), 1 .69 - 1.59 (m, 2H).

195 A/-(4-Methyl-5-(1-((3-(vinylsulfonamido)phenyl)sulfonyl)-1, 2,3,4- tetrahydroquinolin-6-yl)thiazol-2-yl)acetamide

A/-(5-(1-((3-Aminophenyl)sulfonyl)-1 ,2,3,4-tetrahydroquinolin-6-yl)-4-methylthiazol-2-yl)acetamide (51 mg, 114 pmol) was dissolved in 5 mL of a diethylether and 2 mL of DMF. Afterwards, trietyhlamine (3 eq., 112 mg, 343 pmol) and 2-chloroethane-1 -sulfonyl chloride (6 eq., 26 mg, 689 pmol) were added to the solution and the mixture stirred overnight at room temperature. The solvent was then removed under reduced pressure and the crude product purified by reversed- phase preparative HPLC (5% to 99% acetonitrile with 0.1 % TFA). The product was obtained after lyophilization as an amorphous white solid.

Yield: 3 mg (5%).

MS (ES+) [M+H]⁺ m/e = 533.0

Example compound 196: A/-(3-((6-(2-Acetamido-4-methvlthiazol-5-vl)-3,4-dihvdroquinolin- 1(2H)-yl)sulfonyl)phenyl)propiolamide

A/-(5-(1-((3-Aminophenyl)sulfonyl)-1 ,2,3,4-tetrahydroquinolin-6-yl)-4-methylthiazol-2-yl)acetamide (48 mg, 109 pmol) was dissolved in 2 mL of DCM. Afterwards, A/,A/-dimethylpyridin-4-amine (0.2 eq., 2.4 mg, 19 pmol) is added to the solution and the mixture stirred overnight at room temperature. A/,A/'-Dicyclohexylcarbodiimide (6 eq., 134 mg, 654 pmol) and propiolic acid (10 eq., 77 mg, 1.1 mmol) are also dissolved in 2 mL of DCM and this latter solution is added dropwise to the first solution and the reaction is stirred at room temperature overnight. The solvent was then removed under reduced pressure and the crude product purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1 % TFA). The product was obtained after lyophilization as an amorphous white solid.

Yield: 6 mg (11%).

MS (ES+) [M+H]⁺ m/e = 495.0

¹H NMR (600 MHz, DMSO-d₆): 5 12.06 (s, 1 H), 11.10 (s, 1 H), 8.05 (t, = 2.1 Hz, 1 H), 7.79 (dd, J = 8.3, 2.1 Hz, 1 H), 7.62 (d, J = 8.6 Hz, 1 H), 7.52 (t, J = 8.0 Hz, 1 H), 7.37 (dt, J = 7.9, 1 .2 Hz, 1 H), 7.26 (dd, = 8.6, 2.3 Hz, 1 H), 7.15 (d, J = 2.2 Hz, 1 H), 4.47 (s, 1 H), 3.79 - 3.76 (m, 2H), 2.53 (d, J = 6.6 Hz, 2H), 2.32 (s, 3H), 2.13 (s, 3H), 1 .68 - 1 .64 (m, 2H).

¹³C NMR (151 MHz, DMSO-d₆): 5 168.27, 156.61 , 154.93, 149.88, 141.89, 138.97, 135.21 , 130.73, 130.16, 129.21 , 128.42, 126.36, 123.84, 123.51 , 123.19, 122.18, 117.46, 47.49, 46.38, 33.33, 26.02, 22.42, 21 .05, 16.04.

Example compound 197: A/-(4-Methvl-5-(1-((2-(methvlsulfonvl)benzorcflthiazol-6- yl)sulfonyl)-1 ,2,3,4-tetrahydroquinolin-6-yl)thiazol-2-yl)acetamide

Step 1 : A/-(4-methvl-5-(1-((2-(methvlthio)benzorcflthiazol-6-vl)sulfonvl)-1.2,3,4- tetrahydroquinolin-6-yl)thiazol-2-yl)acetamide

A/-(4-Methyl-5-(1 ,2,3,4-tetrahydroquinolin-6-yl)thiazol-2-yl)acetamide (25 mg, 87 pmol) was dissolved in 2 mL of pyridine. Afterwards, 2-(methylthio)benzo[d]thiazole-6-sulfonyl chloride (2 eq., 49 mg, 175 pmol) was added dropwise to the solution and stirred at 70 °C for 2 hours. The solvent was then removed under reduced pressure and the crude product purified by reversed- phase preparative HPLC (5% to 99% acetonitrile with 0.1 % TFA). The product was obtained after lyophilization as an amorphous white solid.

Yield: 13 mg (28%).

MS (ES+) [M+H]⁺ m/e = 531.0

¹H NMR (600 MHz, CDCI₃): 5 8.13 (d, J = 1 .9 Hz, 1 H), 7.93 (d, J = 8.6 Hz, 1 H), 7.86 (d, J = 8.6 Hz, 1 H), 7.66 - 7.62 (m, 1 H), 7.24 (dd, J = 8.6, 2.3 Hz, 1 H), 7.05 (d, J = 2.2 Hz, 1 H), 3.89 - 3.85 (m, 2H), 2.81 (s, 3H), 2.53 (q, J = 6.0 Hz, 2H), 2.49 (s, 3H), 2.41 (s, 3H), 1 .74 - 1 .68 (m, 3H).

¹³C NMR (151 MHz, CDCI3): 5 173.81 , 169.06, 159.72, 156.16, 138.34, 135.85, 134.84, 131.41 , 129.84, 128.68, 127.21 , 125.21 , 124.87, 121.84, 121.31 , 120.88, 119.62, 46.83, 27.04, 23.42, 21.59, 16.16, 13.07.

Step 2: A/-(4-Methvl-5-(1 -((2-(methvlsulfonvl)benzorcflthiazol-6-vl)sulfonvl)-1 ,2,3.4-tetrahvd- roquinolin-6-yl)thiazol-2-yl)acetamide

A/-(4-methyl-5-(1 -((2-(methylthio)benzo[c/]thiazol-6-yl)sulfonyl)-1 ,2,3,4-tetrahydroquinolin-6- yl)thiazol-2-yl)acetamide (11 mg, 21 pmol) was dissolved in 1 mL of DCM at 0 °C. Afterwards, mefa-chloroperbenzoic acid (2.2 eq., 7.9 mg, 46 pmol) was added to the mixture, and the reaction mixture was kept at 0 °C for 1 hour and then at room temperature for 48 hours. The solvent was then removed under reduced pressure and the crude product purified by reversed- phase preparative HPLC (5% to 99% acetonitrile with 0.1 % TFA). All separated products were obtained after lyophilization as amorphous white solids in pure form.

Yield: 4 mg (35%).

MS (ES+) [M+H]⁺ m/e = 563.0

¹H NMR (600 MHz, DMSO-d₆): 5 12.07 (s, 1 H), 8.94 (d, J = 1.9 Hz, 1 H), 8.39 (d, J = 8.7 Hz, 1 H), 7.85 (dd, J = 8.7, 2.0 Hz, 1 H), 7.69 (d, J = 8.6 Hz, 1 H), 7.30 (dd, J = 8.6, 2.3 Hz, 1 H), 7.16 (d, J = 2.3 Hz, 1 H), 3.88 - 3.85 (m, 2H), 3.60 (s, 3H), 2.33 (s, 3H), 2.13 (s, 3H), 2.08 (s, 2H), 1.69 - 1.62 (m, 2H).

Example compound 198: 1 -(6-((5-(d -(Cyclopropylsulfonyl)-1 ,2,3,4-tetrahydroquinolin-6-yl)- 4-methylthiazol-2-yl)amino)pyridin-2-yl)pyrrolidin-2-one

1-(6-Bromopyridin-2-yl)pyrrolidin-2-one (13 mg, 55 pmol), 5-(1-(cyclopropylsulfonyl)-1 , 2,3,4- tetrahydroquinolin-6-yl)-4-methylthiazol-2-amine (1.0 eq., 19 mg, 55 pmol), [(2-di- cyclohexylphosphino-3,6-dimethoxy-2',4',6'- triisopropyl-1 ,1 '-biphenyl)-2-(2'-amino-1 ,1 ' - biphenyl)]palladium(ll) methanesulfonate (0.1 eq., 5.0 mg, 5.7 pmol), and CS2CO3 (2 eq., 37 mg, 112 pmol) were suspended in 1 mL of 2-methyl-2-propanol. The suspension was sonicated for 5 minutes, flushed with nitrogen and heated in at 100 °C for 2 hours. The solvent was then removed under reduced pressure and the crude product purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1 % TFA). The product was obtained after lyophilization as an amorphous white solid.

Yield: 11 mg (38%).

MS (ES+) [M+H]⁺ m/e = 510.1

¹H NMR (600 MHz, DMSO-d₆): 6 11.27 (s, 1 H), 7.80 (d, J = 8.0 Hz, 1 H), 7.68 (t, J = 8.0 Hz, 1 H), 7.63 - 7.59 (m, 1 H), 7.26 - 7.22 (m, 2H), 6.73 (d, J = 7.9 Hz, 1 H), 4.19 (t, J = 7.1 Hz, 2H), 3.75 - 3.70 (m, 2H), 2.91 - 2.86 (m, 2H), 2.78 (tt, = 7.5, 5.3 Hz, 1 H), 2.57 (t, J = 8.1 Hz, 2H), 2.33 (s, 2H), 2.08 (s, 3H), 2.02 - 1 .98 (m, 2H), 1 .25 (d, J = 23.4 Hz, 2H), 1 .01 - 0.97 (m, 4H).

¹³C NMR (151 MHz, DMSO-d₆): 5 175.02, 163.47, 156.79, 153.82, 150.35, 139.82, 136.20, 130.77, 129.64, 129.07, 126.62, 123.90, 106.28, 105.96, 105.36, 48.75, 46.68, 33.53, 31.15, 29.91 , 26.81 , 22.35, 17.84, 16.57, 5.56.

Example compound 199: A/-(5-(1-(Cyclopropylsulfonyl)-1,2,3,4-tetrahydroquinolin-6-yl)-4- methylthiazol-2-yl)cyclobutanecarboxamide

5-(1-(Cyclopropylsulfonyl)-1 ,2,3,4-tetrahydroquinolin-6-yl)-4-methylthiazol-2-amine (20 mg, 57 pmol) and trietylamine (12 eq., 87 mg, 670 pmol) are dissolved in 1 mL of DCM. Afterwards, cyclobutanecarbonyl chloride (7.5 eq., 51 mg, 427 pmol) is added to the mixture and the reaction is stirred at room temperature for 1 hour. The solvent was then removed under reduced pressure and the crude product purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1% TFA). The product was obtained after lyophilization as an amorphous white solid.

Yield: 2 mg (8%).

MS (ES+) [M+H]⁺ m/e = 432.0

¹H NMR (600 MHz, DMSO-d₆): 5 11 .94 (s, 1 H), 7.64 - 7.59 (m, 1 H), 7.25 - 7.23 (m, 2H), 3.74 - 3.71 (m, 2H), 2.87 (t, J = 6.7 Hz, 2H), 2.78 (tt, J = 7.6, 5.1 Hz, 1 H), 2.33 (s, 3H), 2.22 (dq, J = 11.6, 9.1 Hz, 2H), 2.16 - 2.11 (m, 2H), 2.02 - 1.93 (m, 3H), 0.99 - 0.96 (m, 4H).

¹³C NMR (151 MHz, DMSO-d₆): 5 173.22, 155.47, 142.25, 136.58, 130.85, 130.11 , 129.86, 128.45, 126.73, 123.85, 46.70, 38.73, 31.16, 29.86, 26.79, 24.95, 22.31 , 18.23, 16.50, 5.52.

Example compound 200: A/-(5-(1-(Cyclopropylsulfonyl)-1,2,3,4-tetrahydroquinolin-6-yl)-4- methylthiazol-2-yl)-1 -methylcyclopropane-1 -carboxamide

5-(1-(Cyclopropylsulfonyl)-1 ,2,3,4-tetrahydroquinolin-6-yl)-4-methylthiazol-2-amine (20 mg, 57 pmol) and trietylamine (14 eq., 79 mg, 778 pmol) are dissolved in 1 mL of DCM. Afterwards, 1- methylcyclopropane-1 -carbonyl chloride (5 eq., 33 mg, 279 pmol) is added to the mixture and the reaction is stirred at room temperature for 1 hour. The solvent was then removed under reduced pressure and the crude product purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1% TFA). The product was obtained after lyophilization as an amorphous white solid.

Yield: 13 mg (53%). MS (ES+) [M+H]⁺ m/e = 432.0

¹H NMR (600 MHz, DMSO-d₆): 6 11 .55 (s, 1 H), 7.64 - 7.59 (m, 1 H), 7.26 - 7.21 (m, 2H), 3.75 - 3.70 (m, 2H), 2.87 (t, J = 6.7 Hz, 2H), 2.77 (tt, J = 7.6, 5.2 Hz, 1 H), 2.35 (s, 3H), 2.02 - 1 .96 (m, 2H), 1 .40 (s, 3H), 1 .19 (q, J = 3.8 Hz, 2H), 0.97 (ddt, J = 7.6, 4.2, 2.6 Hz, 4H), 0.74 (q, J = 4.0 Hz, 2H).

¹³C NMR (151 MHz, DMSO-d₆): 5 173.81 , 155.98, 142.10, 136.59, 130.84, 129.87, 128.44, 126.73, 124.02, 123.85, 46.70, 29.86, 26.79, 22.31 , 20.23, 19.65, 16.67, 16.41 , 5.52.

Example compound 201 : A/-(5-(1-(Cyclopropylsulfonyl)-1,2,3,4-tetrahydroquinolin-6-yl)-4- methylthiazol-2-yl)-2 -methoxyacetamide

5-(1-(Cyclopropylsulfonyl)-1 ,2,3,4-tetrahydroquinolin-6-yl)-4-methylthiazol-2-amine (23 mg, 65 pmol) and trietylamine (13 eq., 86 mg, 848 pmol) are dissolved in 1 mL of DCM. Afterwards, 2- methoxyacetyl chloride (5 eq., 35 mg, 326 pmol) is added to the mixture and the reaction is stirred at room temperature for 1 hour. The solvent was then removed under reduced pressure and the crude product purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1% TFA). The product was obtained after lyophilization as an amorphous white solid.

Yield: 17 mg (62%).

MS (ES+) [M+H]⁺ m/e = 422.1

¹H NMR (600 MHz, DMSO-d₆): 5 12.04 (s, 1 H), 7.63 - 7.60 (m, 1 H), 7.25 (d, J = 6.8 Hz, 2H), 4.14 (s, 3H), 3.93 (s, 2H), 3.75 - 3.69 (m, 2H), 2.87 (t, J = 6.7 Hz, 2H), 2.77 (tt, J = 7.6, 5.1 Hz, 1 H), 2.50 (p, J = 1.9 Hz, 2H), 2.35 (s, 3H), 1.99 (ddd, J = 10.8, 8.7, 5.2 Hz, 2H), 0.96 (d, = 5.1 Hz, 2H).

¹³C NMR (151 MHz, DMSO-d₆) 5 171.98, 168.75, 154.74, 142.32, 136.68, 130.88, 129.90, 128.25, 126.75, 123.85, 71.00, 69.33, 59.21 , 46.70, 29.86, 26.77, 22.30, 16.47, 5.52.

Example compound 202: 2-Cyclopropyl-A/-(5-(1 -(cyclopropylsulfonyl)-l ,2,3,4- tetrahydroquinolin-6-yl)-4-methylthiazol-2-yl)acetamide

5-(1-(Cyclopropylsulfonyl)-1 ,2,3,4-tetrahydroquinolin-6-yl)-4-methylthiazol-2-amine (21 mg, 60 pmol) and trietylamine (12 eq., 72 mg, 714 pmol) are dissolved in 1 mL of DCM. Afterwards, cyclopropanecarbonyl chloride (3.5 eq., 25 mg, 209 pmol) is added to the mixture and the reaction is stirred at room temperature for 1 hour. The solvent was then removed under reduced pressure and the crude product purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1% TFA). The product was obtained after lyophilization as an amorphous white solid.

Yield: 9.5 mg (37%).

MS (ES+) [M+H]⁺ m/e = 432.1

¹H NMR (600 MHz, CDCI₃): 5 9.22 (s, 1 H), 7.77 (d, J = 8.5 Hz, 1 H), 7.24 (dd, J = 8.6, 2.3 Hz, 1 H), 7.19 (d, J = 2.2 Hz, 1 H), 3.86 - 3.80 (m, 2H), 2.90 (t, J = 6.7 Hz, 2H), 2.47 (tt, J = 8.0, 4.8 Hz, 1 H), 2.42 (d, J = 7.2 Hz, 2H), 2.41 (s, 3H), 2.11 - 2.04 (m, 2H), 1 .22 (qd, J = 5.2, 2.4 Hz, 2H), 1.07 (ddt, J = 10.3, 7.6, 3.8 Hz, 1 H), 0.99 - 0.93 (m, 2H), 0.77 - 0.71 (m, 2H), 0.31 (dt, = 6.0, 4.7 Hz, 2H).

¹³C NMR (151 MHz, CDCI3): 5 169.81 , 154.86, 141.75, 136.58, 130.01 , 129.75, 128.34, 127.11 , 125.52, 123.57, 77.23, 77.01 , 76.80, 46.78, 41.25, 29.94, 27.12, 22.48, 15.98, 6.65, 5.54, 4.90.

Example compound 203: A/-(4-Methyl-5-(1 -((1 -methylcyclopropyl)sulfonyl)-1 ,2,3,4- tetrahydroquinolin-6-yl)thiazol-2-yl)acetamide

A/-(4-Methyl-5-(1 ,2,3,4-tetrahydroquinolin-6-yl)thiazol-2-yl)acetamide (21 mg, 74 pmol) was dissolved in 1 mL of pyridine. Afterwards, 1-methylcyclopropane-1 -sulfonyl chloride (30 eq., 341 mg, 2.21 mmol) was added dropwise to the solution and stirred at 100 °C overnight. The solvent was then removed under reduced pressure and the crude product purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1% TFA). The product was obtained after lyophilization as an amorphous white solid.

Yield: 2 mg (7%).

MS (ES+) [M+H]⁺ m/e = 406.0 ¹H NMR (600 MHz, CDCI3): 5 7.69 (d, J = 8.7 Hz, 1 H), 7.28 - 7.22 (m, 1 H), 7.21 - 7.16 (m, 1 H), 3.87 - 3.77 (m, 2H), 2.90 (t, J = 6.8 Hz, 2H), 2.40 (s, 3H), 2.34 - 2.24 (m, 3H), 2.14 - 2.07 (m, 2H), 1 .54 (s, 2H), 1 .44 (s, 3H), 0.95 - 0.82 (m, 2H).

³C NMR (151 MHz, CDCI3): 5 167.36, 155.35, 141.35, 137.41 , 129.90, 129.43, 127.85, 126.86, 125.53, 123.43, 47.15, 37.38, 27.01 , 23.24, 22.83, 18.67, 15.91 , 13.70.

Example compound 204: 1 -(6-((5-(1 -(Cyclopropylsulfonyl)-1 ,2,3,4-tetrahydroquinolin-6-yl)- 4-methylthiazol-2-yl)amino)pyridin-2-yl)piperidin-2-one

Step 1 : 1 -(6-Bromopyridin-2-yl)piperidin-2-one

2,6-Dibromopyridine (400 mg, 1.7 mmol), piperidin-2-one (1.0 eq., 170 mg, 1.7 mmol), (9,9- dimethyl-9/7-xanthene-4,5-diyl)bis(diphenylphosphane) (0.2 eq., 196 mg, 338 pmol), Pd(OAc)2, (0.1 eq., 38 mg, 171 pmol) and CS2CO3 (3 eq., 1 .66 g, 5.1 mmol) were suspended in 20 mL of 1 ,4-dioxane. The suspension was sonicated for 5 minutes, flushed with nitrogen, heated in a micowave reactor to 60 °C for 2 hours. Upon completion of the reaction, the crude was poured in a separatory funnel, containing DCM and water. The water phase was extracted 3 times with DCM. Then, the combined organic phases were dried over Na2SC>4 and concentrated under reduced pressure. The crude product was then purified by silica gel chromatography using a gradient of cyclohexane and EtOAc as eluent. The product was obtained as a yellow oil.

Yield: 119 mg (28%).

MS (ES+) [M+Na]⁺ m/e = 255.0, 257.0 (bromine isotopic pattern).

¹H NMR (300 MHz, CDCI₃): 6 7.85 (dd, J = 8.2, 0.7 Hz, 1 H), 7.51 (t, J = 7.9 Hz, 1 H), 7.29 - 7.19 (m, 1 H), 4.01 - 3.88 (m, 2H), 2.65 - 2.53 (m, 2H), 2.01 - 1 .79 (m, 4H).

¹³C NMR (75 MHz, CDCI₃): 5 171.17, 154.27, 139.17, 139.03, 124.25, 118.89, 47.62, 33.81 , 23.06, 20.87.

Step 2: 1 -(6-((5-(1 -(Cyclopropylsulfonyl)-1 ,2,3,4-tetrahydroquinolin-6-yl)-4-methylthiazol-2- yl)amino)pyridin-2-yl)piperidin-2-one

1-(6-Bromopyridin-2-yl)piperidin-2-one (17 mg, 66 pmol), 5-(1-(cyclopropylsulfonyl)-1 ,2,3,4- tetrahydroquinolin-6-yl)-4-methylthiazol-2-amine (1.0 eq., 23 mg, 66 pmol), [(2-di- cyclohexylphosphino-3,6-dimethoxy-2',4',6'- triisopropyl-1 ,1 '-biphenyl)-2-(2'-amino-1 ,1 ' - biphenyl)]palladium(ll) methanesulfonate (0.1 eq., 5.8 mg, 6.5 pmol), and CS2CO3 (2 eq., 43 mg, 132 pmol) were suspended in 1 mL of 2-methyl-2-propanol. The suspension was sonicated for 5 minutes, flushed with nitrogen and heated in at 100 °C for 1 hour. The solvent was then removed under reduced pressure and the crude product purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1% TFA). The product was obtained after lyophilization as an amorphous white solid.

Yield: 28 mg (82%).

MS (ES+) [M+H]⁺ m/e = 524.1

¹H NMR (600 MHz, CDCI3): 5 7.78 (d, J = 8.5 Hz, 1 H), 7.62 (t, J = 8.0 Hz, 1 H), 7.43 (d, J = 7.9 Hz, 1 H), 7.23 (dd, J = 8.6, 2.2 Hz, 1 H), 7.19 (d, J = 2.2 Hz, 1 H), 6.63 (d, J = 7.9 Hz, 1 H), 4.07 (t, J = 5.8 Hz, 2H), 3.86 - 3.82 (m, 2H), 2.92 (t, J = 6.8 Hz, 2H), 2.63 (t, J = 6.6 Hz, 2H), 2.50 (tt, J = 8.0, 4.9 Hz, 1 H), 2.39 (s, 3H), 2.12 - 2.07 (m, 2H), 2.01 - 1 .92 (m, 4H), 1 .25 (qd, J = 5.2, 2.4 Hz, 2H), 1.01 - 0.96 (m, 2H).

¹³C NMR (151 MHz, CDCI3): 5 171.01 , 168.78, 157.94, 152.41 , 149.71 , 140.42, 138.93, 136.35, 129.77, 128.72, 127.12, 123.66, 122.23, 112.92, 106.85, 48.33, 46.76, 33.70, 30.07, 27.16, 23.27, 22.54, 20.89, 15.57, 5.60.

205 3-(6-((5-(1-(Cyclopropylsulfonyl)-1,2,3,4-tetrahydroquinolin-6-yl)-

4-methylthiazol-2-yl)amino)pyridin-2-yl)-1 ,3-oxazinan-2-one Step 1 : 3-(6-Bromopyridin-2-yl)-1 ,3-oxazinan-2-one

2,6-Dibromopyridine (400 mg, 1.7 mmol), 1 ,3-oxazinan-2-one (1.0 eq., 171 mg, 1.7 mmol), (9,9- dimethyl-9/7-xanthene-4,5-diyl)bis(diphenylphosphane) (0.2 eq., 196 mg, 338 pmol), Pd(OAc)2, (0.1 eq., 38 mg, 171 pmol) and CS2CO3 (3 eq., 1 .66 g, 5.1 mmol) were suspended in 20 mL of 1 ,4-dioxane. The suspension was sonicated for 5 minutes, flushed with nitrogen, heated in a micowave reactor to 60 °C for 2 hours. Upon completion of the reaction, the crude was poured in a separatory funnel, containing DCM and water. The water phase was extracted 3 times with DCM. Then, the combined organic phases were dried over Na2SC>4 and concentrated under reduced pressure. The crude product was then purified by silica gel chromatography using a gradient of cyclohexane and EtOAc as eluent. The product was obtained as a yellow oil.

Yield: 135 mg (31 %).

MS (ES+) [M+H]⁺ m/e = 257.0, 259.0 (bromine isotopic pattern).

¹H NMR (300 MHz, CDCI3): 5 8.02 (dd, J = 8.3, 0.7 Hz, 1 H), 7.55 (dd, J = 8.2, 7.6 Hz, 1 H), 7.31 - 7.21 (m, 1 H), 4.42 (dd, J = 6.0, 4.8 Hz, 2H), 4.07 (t, J = 6.3 Hz, 2H), 2.29 - 2.15 (m, 2H).

¹³C NMR (75 MHz, CDCI3): 5 153.98, 152.07, 139.59, 138.64, 123.84, 117.36, 67.32, 44.91 , 22.27.

Step 2: 3-(6-((5-(1-(Cvclopropvlsulfonvl)-1.2.3.4-tetrahvdroguinolin-6-vl)-4-methvlthiazol-2- yl)amino)pyridin-2-yl)-1 ,3-oxazinan-2-one

3-(6-Bromopyridin-2-yl)-1 ,3-oxazinan-2-one (16 mg, 62 pmol), 5-(1-(cyclopropylsulfonyl)-1 , 2,3,4- tetrahydroquinolin-6-yl)-4-methylthiazol-2-amine (1.0 eq., 22 mg, 62 pmol), [(2-di- cyclohexylphosphino-3,6-dimethoxy-2',4',6'- triisopropyl-1 ,1 '-biphenyl)-2-(2'-amino-1 ,1 ' - biphenyl)]palladium(ll) methanesulfonate (0.1 eq., 5.7 mg, 6.4 pmol), and CS2CO3 (2 eq., 41 mg, 126 pmol) were suspended in 1 mL of 2-methyl-2-propanol. The suspension was sonicated for 5 minutes, flushed with nitrogen and heated in at 100 °C for 1 hour. The solvent was then removed under reduced pressure and the crude product purified by reversed-phase preparative HPLC (5% to 99% acetonitrile with 0.1% TFA). The product was obtained after lyophilization as an amorphous white solid.

Yield: 16 mg (48%).

MS (ES+) [M+H]⁺ m/e = 526.1 ¹H NMR (600 MHz, CDCI₃): 6 7.77 (d, J = 8.5 Hz, 1 H), 7.63 (t, J = 8.0 Hz, 1 H), 7.53 (d, J = 8.0 Hz, 1 H), 7.22 (dd, J = 8.5, 2.2 Hz, 1 H), 7.19 (d, J = 2.2 Hz, 1 H), 6.65 (d, = 7.9 Hz, 1 H), 4.44 (t, J = 5.5 Hz, 2H), 4.15 (t, J = 6.2 Hz, 2H), 3.86 - 3.81 (m, 2H), 2.92 (t, J = 6.8 Hz, 2H), 2.50 (tt, J = 8.0, 4.8 Hz, 1 H), 2.39 (s, 3H), 2.27 - 2.21 (m, 2H), 2.12 - 2.05 (m, 2H), 1 .25 (qd, J = 5.6, 1.1 Hz, 2H), 1.03 - 0.96 (m, 2H).

¹³C NMR (151 MHz, CDCI3): 5 168.56, 158.00, 152.46, 152.19, 149.49, 140.33, 139.35, 136.48, 129.86, 129.82, 128.49, 127.21 , 123.68, 122.06, 111.68, 106.72, 67.26, 46.75, 45.81 , 30.12, 27.15, 22.55, 15.38, 5.62.

Claims

1 . A compound for use in the treatment of a medical condition associated with defective and/or pathologic class II phosphoinositide 3-kinase (PI3K) signaling, according to Formula 1

Formula 1 wherein n is 1 or 2,

R1 is C, S, O or N,

R2 is C or N,

R7, R8 and R9 are the same or different, 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 comprising Cl, Br, or F), -CN, carbonyl -, carboxyl, carboxy ester, alkoxy, aldehyde, primary, secondary or tertiary amine, amide, imide, carbamate, carboxamide, nitro, sulfide, sulfinyl, sulfonyl, sulfino or sulfonamide,

R11 is H, C3 to C6 cycloalkyl, C4 to C6 hetero cycloalkyl (preferably comprising N, S and/or O), halogen (preferably F, Cl, or Br), sulfide, sulfinyl, sulfonyl, sulfino, sulfonamide, carboxyl, carboxyl ester, carboxamide, alkoxy or aryloxy, or R10 and R11 form together with the atoms they are attached to a 5- to 8-membered cycloalkyl or aryl ring structure D comprising two carbon atoms of B, forming a condensed bicyclic group with B, optionally comprising one or more heteroatoms (preferably N, O and/or S),

R13 is C1 to C5 alkyl (preferably C1 to C3 alkyl), C2 to C5 alkenyl, C3 to C6 cycloalkyl, C5 or C6 aryl, alkyl aryl, C5 or C6 hetero aryl (preferably comprising N, S and/or O), a bicyclic group (preferably comprising one or two aromatic rings), optionally comprising one or more heteroatoms (preferably N, O and/or S), or R12 and R13 are absent when R11 is H or halogen, or not forming a ring structure with R10 or R14, or when R11 and R14 form together with the atoms they are attached to a 5- to 8-membered cycloalkyl or aryl ring structure C and R15 and R16 are present,

R16 is C1 to C5 alkyl (preferably C1 to C3 alkyl), C2 to C5 alkenyl, C3 to C6 cycloalkyl, C5 or C6 aryl, alkyl aryl, C5 or C6 hetero aryl (preferably comprising N, S and/or O), a bicyclic group (preferably comprising one or two aromatic rings), optionally comprising one or more heteroatoms (preferably N, O and/or S), or R15 and R16 are absent when R14 is H, or R11 and R10 form together with the atoms they are attached to a 5- to 8-membered cycloalkyl or aryl ring structure D, or when R11 and R14 form together with the atoms they are attached to a 5- to 8-membered cycloalkyl or aryl ring structure C and R12 and R13 are present. The compound for use according to claim 1 , according to Formula 1

Formula 1 wherein n is 1 or 2,

R1 is C, S, O or N, R2 is C or N,

R3 is H, C1 to C3 alkyl, C3 to C6 cycloalkyl, CX3, wherein X is Cl, Br, or F,

R6 is absent, forms a carbonyl C=O with R1 or, R1 is S and R6 forms a sulfoxide S

R7, R8 and R9 are the same or different, C or N, R10 is H or C1 to C3 alkyl,

R11 is H, C3 to C6 cycloalkyl, C4 to C6 hetero cycloalkyl (preferably comprising N, S and/or O), halogen (preferably F, Cl, or Br), sulfide, sulfinyl, sulfonyl, carboxyl ester, carboxamide or alkoxy -CH2OR wherein R C1 to C3 alkyl or benzyl, or R10 and R11 form together with the atoms they are attached to a 5- to 7-membered cycloalkyl or aryl ring structure D comprising two carbon atoms of B, forming a condensed bicyclic group with B, optionally comprising one or more heteroatoms (preferably N, O and/or S),

R12 is C1 to C3 alkyl, carbonyl C=O or sulfonyl,

R13 is C1 to C3 alkyl, C2 to C5 alkenyl, C3 to C6 cycloalkyl, C5 or C6 aryl, benzyl, C5 or C6 hetero aryl (preferably comprising N, S and/or O), a bicyclic group (preferably comprising one or two aromatic rings), optionally comprising one or more heteroatoms (preferably N, O and/or S), or R12 and R13 are absent when R11 is H or halogen, or not forming a ring structure with R10 or R14, or when R11 and R14 form together with the atoms they are attached to a 5- to 7-membered cycloalkyl or aryl ring structure C and R15 and R16 are present,

R15 is C1 to C3 alkyl, carbonyl C=O or sulfonyl,

3. The compound for use according to any one of the preceding claims, according to Formula 2

Formula 2 wherein

R1 to R16 are according to claim 1.

4. The compound for use according to any one of the preceding claims, wherein R11 and R14 form together with the atoms they are attached to a 5- to 7-membered cyclic or aryl ring structure C forming a condensed bicyclic group with B, wherein B and C are one of

and wherein

R7, R8, R9, R12, R13, R15 and R16 are according to claim 1 ,

X and Y are the same or different, C, N, S and/or O,

R17 may be the same or different, absent (electron pair of X), H, hydroxy, 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 comprising Cl, Br, or F), C3 to C6 cycloalkyl, C3 to C6 hetero cycloalkyl (preferably comprising N,0 and/or S and optionally substituted with alkoxy), C4 to C6 aryl, carbonyl C(=O)R, wherein R is C1 to C5 alkyl (preferably C1 to C3 alkyl), carboxyl, carboxy ester, alkoxy (preferably -OCH3, -OCFhCHs or C3 to C6 cycloalkyl alkoxy), aldehyde, primary, secondary or tertiary amine, amide, imide, carbamate, carboxamide, nitro, sulfide (preferably -SCH3, -SCH2CH3), sulfinyl, sulfonyl, sulfino or sulfonamide or when X is C forming a carbonyl C=O with X or when X is S forming sulfoxide S=O or sulfonyl S(=O)2 with X, or two R17 are forming a 4-, 5- or 6-membered cycloalkyl, optionally comprising one or more hetero atoms (preferably N, O and/or S),

5. The compound for use according to any one of the preceding claims, wherein R10 and R11 form together with the atoms they are attached to a 5- to 7-membered cyclic or aryl ring structure D forming a condensed bicyclic group with B, wherein B and D is

and wherein R7, R8, R9, R12 and R13 are according to claim 1 .

6. The compound for use according to any one of the preceding claims wherein R16 is one of

wherein

R21 may be the same or different, H, C1 to C5 alkyl (preferably C1 to C3 alkyl), halogen (preferably F, Cl and/or Br), alkoxy, primary, secondary or tertiary amine, sulfide, sulfinyl, sulfonyl, sulfino, sulfonamide, carboxyl, carboxy ester, a secondary hydroxyl group C(- OH)CHs, carbonyl C=OR (wherein R is C1 to C10 alkyl (preferably C1 to C5 alkyl), C1 to C3 haloalkyl (preferably comprising Cl, Br or F)), imide, carbamate, carboxamide, amide N=OR (wherein R is C1 to C3 alkyl, C1 to C3 alkenyl, C1 to C3 haloalkyl (preferably comprising Cl, Br or F)), nitro or E,

R23 is H, carbonyl, carboxyl or carboxy ester,

R24 is H or C1 to C5 alkyl (preferably C1 to C3 alkyl), and

7. The compound for use according to any one of the preceding claims, according to

Formula 5

Formula 5 wherein

R1 to R10, R15 and R16 are according to claim 1 , and

R17 to R19 are according to claim 4.

8. The compound for use according to any one of the preceding claims, according to

Formula 6

Formula 6 wherein

R1 to R10 and R16 are according to claim 1 , and

R17 to R19 are according to claim 4.

9. The compound for use according to any one of the preceding claims, selected from the group consisting of: A/-(4-methyl-5-(l-(phenylsulfonyl)-lH-indol-5-yl)thiazol-2-yl)acetamide, A/-(4- methyl-5-(l-(phenylsulfonyl)-l,2,3,4-tetrahydroquinolin-6-yl)thiazol-2-yl)acetamide, A/-(4-methyl- 5-(l-(phenylsulfonyl)indolin-5-yl)thiazol-2-yl)acetamide, A/-(4-methyl-5-(4-(phenylsulfonyl)-3,4- dihydro-2H-benzo[b][l,4]oxazin-7-yl)thiazol-2-yl)acetamide, A/-(5-(l-(phenylsulfonyl)-2, 3,4,5- tetrahydro-lH-benzo[b]azepin-7-yl)thiazol-2-yl)acetamide, A/-(4-methyl-5-(5-(phenylsulfonyl)- 5,6,7,8-tetrahydronaphthalen-2-yl)thiazol-2-yl)acetamide, A/-(5-(4-methoxy-l-(phenylsulfonyl)-

1.2.3.4-tetrahydroquinolin-6-yl)-4-methylthiazol-2-yl)acetamide, A/-(4-methyl-5-(4-

(phenylsulfonyl)-3,4-dihydro-2H-benzo[b][l,4]thiazin-7-yl)thiazol-2-yl)acetamide, A/-(4-methyl-5- (l-oxido-4-(phenylsulfonyl)-3,4-dihydro-2H-benzo[b][l,4]thiazin-7-yl)thiazol-2-yl)acetamide, A/-(5- (l,l-dioxido-4-(phenylsulfonyl)-3,4-dihydro-2H-benzo[b][l,4]thiazin-7-yl)-4-methylthiazol-2- yl)acetamide, A/-(4-methyl-5-(8-(phenylsulfonyl)-5,6,7,8-tetrahydro-l,8-naphthyridin-3-yl)thiazol-2- yl)acetamide, A/-(4-methyl-5-(4-oxo-l-(phenylsulfonyl)-l,2,3,4-tetrahydroquinolin-6-yl)thiazol-2- yl)acetamide, A/-(5-(4-hydroxy-l-(phenylsulfonyl)-l,2,3,4-tetrahydroquinolin-6-yl)-4- methylthiazol-2-yl)acetamide, A/-(4-methyl-5-(2-methyl-l-(phenylsulfonyl)-l, 2,3,4- tetrahydroquinolin-6-yl)thiazol-2-yl)acetamide, A/-(5-(l-(phenylsulfonyl)-l, 2,3,4- tetrahydroquinolin-6-yl)thiazol-2-yl)acetamide, A/-(4-methyl-5-(5-(phenylsulfonyl)-5, 6,7,8- tetrahydro-l,5-naphthyridin-2-yl)thiazol-2-yl)acetamide, A/-(4-methyl-5-(l-(phenylsulfonyl)-

1.2.3.4-tetrahydroquinolin-6-yl)oxazol-2-yl)acetamide, A/-(4-methyl-5-(5-(phenylsulfonyl)-

2,3,3a,4,5,9b-hexahydrofuro[3,2-c]quinolin-8-yl)thiazol-2-yl)acetamide, (/?)-/V-(5-(4-methoxy-l- (phenylsulfonyl)-l,2,3,4-tetrahydroquinolin-6-yl)-4-methylthiazol-2-yl)acetamide, tert-butyl 6-((4- methyl-5-(l-(phenylsulfonyl)-l,2,3,4-tetrahydroquinolin-6-yl)thiazol-2-yl)amino)-6- oxohexyl)carbamate,A/-(5-(4-acetyl-l-(phenylsulfonyl)-l,2,3,4-tetrahydroquinoxalin-6-yl)-4- methylthiazol-2-yl)acetamide, A/-(4-methyl-5-(4-methyl-3-oxo-l-(phenylsulfonyl)-l,2,3,4- tetrahydroquinoxalin-6-yl)thiazol-2-yl)acetamide, A/-(5-(3-methoxy-l-(phenylsulfonyl)-l, 2,3,4- tetrahydroquinolin-6-yl)-4-methylthiazol-2-yl)acetamide, A/-(5-(4-methoxy-4-methyl-l-

(phenylsulfonyl)-l,2,3,4-tetrahydroquinolin-6-yl)-4-methylthiazol-2-yl)acetamide, A/-(4-methyl-5-

(4-morpholino-l-(phenylsulfonyl)-l,2,3,4-tetrahydroquinolin-6-yl)thiazol-2-yl)acetamide, A/-(4- methyl-5-(6-(phenylsulfonyl)-3,4,4a,5,6,10b-hexahydro-2H-pyrano[3,2-c]quinolin-9-yl)thiazol-2- yl)acetamide, A/-(4-methyl-5-(l-(o-tolylsulfonyl)-l,2,3,4-tetrahydroquinolin-6-yl)thiazol-2- yl)acetamide, A/-(4-methyl-5-(l-(naphthalen-l-ylsulfonyl)-l,2,3,4-tetrahydroquinolin-6-yl)thiazol-

2-yl)acetamide, A/-(5-(l-(cyclohexylsulfonyl)-l,2,3,4-tetrahydroquinolin-6-yl)-4-methylthiazol-2- yl)acetamide, A/-(4-methyl-5-(l-(pyridin-3-ylsulfonyl)-l,2,3,4-tetrahydroquinolin-6-yl)thiazol-2- yl)acetamide, A/-(4-methyl-5-(l-(methylsulfonyl)-l,2,3,4-tetrahydroquinolin-6-yl)thiazol-2- yl)acetamide, A/-(4-methyl-5-(l-(thiophen-2-ylsulfonyl)-l,2,3,4-tetrahydroquinolin-6-yl)thiazol-2- yl)acetamide, A/-(5-(l-((4-fluorophenyl)sulfonyl)-l,2,3,4-tetrahydroquinolin-6-yl)-4-methylthiazol-

2-yl)acetamide, A/-(5-(l-((2,4-dichlorophenyl)sulfonyl)-l,2,3,4-tetrahydroquinolin-6-yl)-4- methylthiazol-2-yl)acetamide, A/-(4-methyl-5-(l-(naphthalen-2-ylsulfonyl)-l,2,3,4- tetrahydroquinolin-6-yl)thiazol-2-yl)acetamide, (S)-/V-(5-(4-methoxy-l-(phenylsulfonyl)-l, 2,3,4- tetrahydroquinolin-6-yl)-4-methylthiazol-2-yl)acetamide, A/-(4-methyl-5-(l-tosyl-l, 2,3,4- tetrahydroquinolin-6-yl)thiazol-2-yl)acetamide, A/-(5-(l-((2, 3-dichlorophenyl)sulfonyl)-l, 2,3,4- tetrahydroquinolin-6-yl)-4-methylthiazol-2-yl)acetamide, A/-(5-(l-(benzylsulfonyl)-l, 2,3,4- tetrahydroquinolin-6-yl)-4-methylthiazol-2-yl)acetamide, A/-(5-(l-((2,3-dihydrobenzofuran-5- yl)sulfonyl)-l,2,3,4-tetrahydroquinolin-6-yl)-4-methylthiazol-2-yl)acetamide, tert-butyl (4-methyl-

5-(l-(phenylsulfonyl)-l,2,3,4-tetrahydroquinolin-6-yl)thiazol-2-yl)carbamate, 4-methyl-5-(l- (phenylsulfonyl)-l,2,3,4-tetrahydroquinolin-6-yl)thiazol-2-amine, A/-(4-ethyl-5-(l-(phenylsulfonyl)-

1.2.3.4-tetrahydroquinolin-6-yl)thiazol-2-yl)acetamide, A/-(5-(l-(cyclopropylsulfonyl)-l, 2,3,4- tetrahydroquinolin-6-yl)-4-methylthiazol-2-yl)acetamide, A/-(5-(2,2-dimethyl-l-(phenylsulfonyl)-

1.2.3.4-tetrahydroquinolin-6-yl)-4-methylthiazol-2-yl)acetamide, A/-(4-methyl-5-(l'-

(phenylsulfonyl)-2^,,3^,-dihydro-l^,/-/-spiro[oxetane-3,4^,-quinolin]-6'-yl)thiazol-2-yl)acetamide, A/-(5- (l-((3-methoxyphenyl)sulfonyl)-l,2,3,4-tetrahydroquinolin-6-yl)-4-methylthiazol-2-yl)acetamide, A/-(4-methyl-5-(5-methyl-l-(phenylsulfonyl)-l,2,3,4-tetrahydroquinolin-6-yl)thiazol-2- yl)acetamide, 5-methyl-4-(l-(phenylsulfonyl)-l,2,3,4-tetrahydroquinolin-6-yl)-A/-(2,2,2- trifluoroethyl)thiazol-2-amine, A/-(5-(4,4-difluoro-l-(phenylsulfonyl)-l,2,3,4-tetrahydroquinolin-6- yl)-4-methylthiazol-2-yl)acetamide, A/-(5-(l-(allylsulfonyl)-l,2,3,4-tetrahydroquinolin-6-yl)-4- methylthiazol-2-yl)acetamide, A/-allyl-5-methyl-4-(l-(phenylsulfonyl)-l,2,3,4-tetrahydroquinolin-

6-yl)thiazol-2-amine, A/,5-dimethyl-4-(l-(phenylsulfonyl)-l,2,3,4-tetrahydroquinolin-6-yl)thiazol-2- amine, A/-(5-(l-((3-bromophenyl)sulfonyl)-l,2,3,4-tetrahydroquinolin-6-yl)-4-methylthiazol-2- yl)acetamide, 3-((6-(2-acetamido-4-methylthiazol-5-yl)-3,4-dihydroquinolin-l(2H)- yl)sulfonyl)benzenesulfonyl fluoride, A/-(5-(l-((3-acetylphenyl)sulfonyl)-l, 2,3,4- tetrahydroquinolin-6-yl)-4-methylthiazol-2-yl)acetamide, A/-(5-(l-((3-(2- bromoacetyl)phenyl)sulfonyl)-l,2,3,4-tetrahydroquinolin-6-yl)-4-methylthiazol-2-yl)acetamide, 2,2,2-trifluoro-/V-(4-methyl-5-(l-(phenylsulfonyl)-l,2,3,4-tetrahydroquinolin-6-yl)thiazol-2- yl)acetamide, A/-(5-(l-((3-(l-hydroxyethyl)phenyl)sulfonyl)-l,2,3,4-tetrahydroquinolin-6-yl)-4- methylthiazol-2-yl)acetamide, 4-methyl-A/-phenyl-5-(l-(phenylsulfonyl)-l, 2,3,4- tetrahydroquinolin-6-yl)thiazol-2-amine, A/-(5-(l-((3-aminophenyl)sulfonyl)-l, 2,3,4- tetrahydroquinolin-6-yl)-4-methylthiazol-2-yl)acetamide, A/-(3-((6-(2-acetamido-4-methylthiazol- 5-yl)-3,4-dihydroquinolin-l(2H)-yl)sulfonyl)phenyl)acetamide, A/-(5-(l-((3-

(dimethylamino)phenyl)sulfonyl)-l,2,3,4-tetrahydroquinolin-6-yl)-4-methylthiazol-2-yl)aceamide, A/-(5-(l-((2-chlorophenyl)sulfonyl)-l,2,3,4-tetrahydroquinolin-6-yl)-4-methylthiazol-2- yl)acetamide, A/-(5-(l-((3,4-dimethoxyphenyl)sulfonyl)-l,2,3,4-tetrahydroquinolin-6-yl)-4- methylthiazol-2-yl)acetamide, A/-(5-(l-((2,3-dimethoxyphenyl)sulfonyl)-l, 2,3,4- tetrahydroquinolin-6-yl)-4-methylthiazol-2-yl)acetamide, Methyl 3-((6-(2-acetamido-4- methylthiazol-5-yl)-3,4-dihydroquinolin-l(2H)-yl)sulfonyl)thiophene-2-carboxylate, A/-(4-methyl- 5-(l-((3-nitrophenyl)sulfonyl)-l,2,3,4-tetrahydroquinolin-6-yl)thiazol-2-yl)acetamide, A/-(4-methyl- 5-(l-((2-oxo-2,3-dihydrobenzo[d]oxazol-7-yl)sulfonyl)-l,2,3,4-tetrahydroquinolin-6-yl)thiazol-2- yl)acetamide, A/-(4-methyl-5-(l-((3-oxo-3,4-dihydro-2H-benzo[b] [l,4]oxazin-7-yl)sulfonyl)-l, 2,3,4- tetrahydroquinolin-6-yl)thiazol-2-yl)acetamide, A/-(5-(l-((2, 5-difluorophenyl)sulfonyl)-l, 2,3,4- tetrahydroquinolin-6-yl)-4-methylthiazol-2-yl)acetamide, methyl 3-((6-(2-acetamido-4- methylthiazol-5-yl)-3,4-dihydroquinolin-l(2H)-yl)sulfonyl)benzoate, A/-(5-(l-((5-chloro-2- fluorophenyl)sulfonyl)-l,2,3,4-tetrahydroquinolin-6-yl)-4-methylthiazol-2-yl)acetamide, A/-(5-(l- ((2-chloro-5-fluorophenyl)sulfonyl)-l,2,3,4-tetrahydroquinolin-6-yl)-4-methylthiazol-2- yl)acetamide, A/-(5-(l-(benzo[d][l,3]dioxol-5-ylsulfonyl)-l,2,3,4-tetrahydroquinolin-6-yl)-4- methylthiazol-2-yl)acetamide, A/-(4-methyl-5-(l-((l-methyl-lH-indol-5-yl)sulfonyl)-l, 2,3,4- tetrahydroquinolin-6-yl)thiazol-2-yl)acetamide, A/-(5-(l-((2,3-dihydro-lH-inden-5-yl)sulfonyl)- l,2,3,4-tetrahydroquinolin-6-yl)-4-methylthiazol-2-yl)acetamide, A/-(5-(l-((2,3- dihydrobenzo[b][l,4]dioxin-6-yl)sulfonyl)-l,2,3,4-tetrahydroquinolin-6-yl)-4-methylthiazol-2- yl)acetamide, A/-(4-methyl-5-(l-((5, 6,7, 8-tetrahydronaphthalen-2-yl)sulfonyl)-l, 2,3,4- tetrahydroquinolin-6-yl)thiazol-2-yl)acetamide, A/-(5-(l-(benzofuran-2-ylsulfonyl)-l, 2,3,4- tetrahydroquinolin-6-yl)-4-methylthiazol-2-yl)acetamide, A/-(5-(l-(benzo[b]thiophen-3-ylsulfonyl)-

1.2.3.4-tetrahydroquinolin-6-yl)-4-methylthiazol-2-yl)acetamide, A/-(5-(l-(benzofuran-6- ylsulfonyl)-l,2,3,4-tetrahydroquinolin-6-yl)-4-methylthiazol-2-yl)acetamide, A/-(5-(l-((2,6- dichlorophenyl)sulfonyl)-l,2,3,4-tetrahydroquinolin-6-yl)-4-methylthiazol-2-yl)acetamide, A/-((5- (l-((2,6-difluorophenyl)sulfonyl)-l,2,3,4-tetrahydroquinolin-6-yl)-4-methylthiazol-2-yl)acetamide, A/-(4-methyl-5-(l-((3-oxo-3,4-dihydro-2H-benzo[b] [l,4]thiazin-6-yl)sulfonyl)-l, 2,3,4- tetrahydroquinolin-6-yl)thiazol-2-yl)acetamide, A/-(4-methyl-5-(l-((2-oxo-2,3- dihydrobenzo[d]oxazol-5-yl)sulfonyl)-l,2,3,4-tetrahydroquinolin-6-yl)thiazol-2-yl)acetamide, A/-(4- methyl-5-(l-((4-nitrophenyl)sulfonyl)-l,2,3,4-tetrahydroquinolin-6-yl)thiazol-2-yl)acetamide, 3- ((6-(2-acetamido-4-methylthiazol-5-yl)-3,4-dihydroquinolin-l(2H)-yl)sulfonyl)benzoic acid, A/-(3- ((6-(2-acetamido-4-methylthiazol-5-yl)-3,4-dihydroquinolin-l(2H)-yl)sulfonyl)phenyl)acrylamide, A/-(3-((6-(2-acetamido-4-methylthiazol-5-yl)-3,4-dihydroquinolin-l(2H)-yl)sulfonyl)phenyl)-2- chloroacetamide, tert-butyl 7-(2-acetamido-4-methylthiazol-5-yl)-4-(phenylsulfonyl)-3,4- dihydroquinoxaline-l(2H)-carboxylate, A/-(4-methyl-5-(l-(phenylsulfonyl)-l, 2,3,4- tetrahydroquinoxalin-6-yl)thiazol-2-yl)acetamide, A/-(4-methyl-5-(4-methyl-l-(phenylsulfonyl)-

1.2.3.4-tetrahydroquinoxalin-6-yl)thiazol-2-yl)acetamide, A/-(5-(5-(phenylsulfonyl)-5, 6,7,8- tetrahydro-1, 5-naphthyridin-2-yl)thiazol-2-yl)acetamide, A/-(5-(l-(phenylsulfonyl)-l, 2,3,4- tetrahydroquinolin-6-yl)-l,3,4-thiadiazol-2-yl)acetamide, /V-(5-(l-((4-aminophenyl)sulfonyl)-

1.2.3.4-tetrahydroquinolin-6-yl)-4-methylthiazol-2-yl)acetamide, A/-(4-((6-(2-acetamido-4- methylthiazol-5-yl)-3,4-dihydroquinolin-l(2H)-yl)sulfonyl)phenyl)acrylamide, A/-(4-((6-(2- acetamido-4-methylthiazol-5-yl)-3,4-dihydroquinolin-l(2/7)-yl)sulfonyl)phenyl)-2- chloroacetamide, A/-(5-(l-((4-acetylphenyl)sulfonyl)-l,2,3,4-tetrahydroquinolin-6-yl)-4- methylthiazol-2-yl)acetamide, A/-(5-(l-((4-(dimethylamino)phenyl)sulfonyl)-l, 2,3,4- tetrahydroquinolin-6-yl)-4-methylthiazol-2-yl)acetamide, A/-(5-(l-((4-(2- bromoacetyl)phenyl)sulfonyl)-l,2,3,4-tetrahydroquinolin-6-yl)-4-methylthiazol-2-yl)acetamide, N- (5-(l-((4-(l-hydroxyethyl)phenyl)sulfonyl)-l,2,3,4-tetrahydroquinolin-6-yl)-4-methylthiazol-2- yl)acetamide, A/-(5-(5-((2,3-dichlorophenyl)sulfonyl)-5,6,7,8-tetrahydro-l,5-naphthyridin-2- yl)thiazol-2-yl)acetamide, A/-(5-(5-((2,3-dichlorophenyl)sulfonyl)-5,6,7,8-tetrahydro-l,5- naphthyridin-2-yl)-4-methylthiazol-2-yl)acetamide, A/-(5-(5-((5-chloro-2-fluorophenyl)sulfonyl)- 5,6,7,8-tetrahydro-l,5-naphthyridin-2-yl)thiazol-2-yl)acetamide, A/-(5-(5-((5-chloro-2- fluorophenyl)sulfonyl)-5,6,7,8-tetrahydro-l,5-naphthyridin-2-yl)-4-methylthiazol-2-yl)acetamide, A/-(5-(l-benzoyl-l,2,3,4-tetrahydroquinolin-6-yl)-4-methylthiazol-2-yl)acetamide, A/-(5-(l-benzyl- l,2,3,4-tetrahydroquinolin-6-yl)-4-methylthiazol-2-yl)acetamide, tert-butyl 9-(2-acetamido-4- methylthiazol-5-yl)-6-(phenylsulfonyl)-3,4,4a,5,6,10b-hexahydrobenzo[h][l,6]naphthyridine- l(2H)-carboxylate, /V-(4-methyl-5-(6-(phenylsulfonyl)-l,2,3,4,4a,5,6,10b- octahydrobenzo[h][l,6]naphthyridin-9-yl)thiazol-2-yl)acetarnide, /V-(4-methyl-5-(l-methyl-6- (phenylsulfonyl)-l,2,3,4,4a,5,6,10b-octahydrobenzo[h][l,6]naphthyridin-9-yl)thiazol-2- yl)acetamide, A/-(5-(4-ethylthio)-l-(phenylsulfonyl)-l,2,3,4-tetrahydroquinolin-6-yl)-4- methylthiazol-2-yl)acetamide, A/-(5-(l-((3-chloro-2-fluorophenyl)sulfonyl)-l, 2,3,4- tetrahydroquinolin-6-yl)-4-methylthiazol-2-yl)acetamide, A/-(4-methyl-5-(l-(phenylsulfonyl)- 4-(piperidin-l-yl)-l,2,3,4-tetrahydroquinolin-6-yl)thiazol-2-yl)acetamide, A/-(5-(4-(3- isopropoxyazetidin-l-yl)-l-(phenylsulfonyl)-l,2,3,4-tetrahydroquinolin-6-yl)-4-methylthiazol- 2-yl)acetamide, /V-(5-(4-(dimethylamino)-l-(phenylsulfonyl)-l,2,3,4-tetrahydroquinolin-6-yl)- 4-methylthiazol-2-yl)acetamide, A/-(5-(4-cyclobutoxy-l-(phenylsulfonyl)-l,2,3,4- tetrahydroquinolin-6-yl)-4-methylthiazol-2-yl)acetamide, A/-(4-methyl-5-(3-(methylsulfonyl)-

4-(phenylsulfonamido)phenyl)thiazol-2-yl)acetamide, A/-(5-(4-((2- chlorophenyl)sulfonamido)-3-(methylsulfonyl)phenyl)-4-methylthiazol-2-yl)acetamide, A/- (4-methyl-5-(3-(methylsulfonyl)-4-(naphthalene-1-sulfonamido)phenyl)thiazol-2- yl)acetamide, A/-(4-methyl-5-(2-(phenylsulfonyl)isoindolin-5-yl)thiazol-2-yl)acetamide, A/- (5-(2-((2-chlorophenyl)sulfonyl)isoindolin-5-yl)-4-methylthiazol-2-yl)acetamide A/-(5-(3- fluoro-4-(phenylsulfonamidomethyl)phenyl)-4-methylthiazol-2-yl)acetamide, A/-(4-methyl-

5-(3-(methylsulfonyl)-4-(phenylsulfonamidomethyl)phenyl)thiazol-2-yl)acetamide, A/-(5-(3- fluoro-4-((phenylsulfonyl)methyl)phenyl)-4-methylthiazol-2-yl)acetamide, A/-(4-methyl-5-(3- (methylsulfonyl)-4-((phenylsulfonyl)methyl)phenyl)thiazol-2-yl)acetamide, A/-(4-methyl-5- (4-(A/-methylphenylsulfonamido)-3-(methylsulfonyl)phenyl)thiazol-2-yl)acetamide, A/-(4- methyl-5-(3-(methylthio)-4-(phenylsulfonamido)phenyl)thiazol-2-yl)acetamide, A/-(4- methyl-5-(3-(methylsulfinyl)-4-(phenylsulfonamido)phenyl)thiazol-2-yl)acetamide, A/-(4- methyl-5-(4-(phenylsulfonamido)-3-(pyrrolidin-1-yl)phenyl)thiazol-2-yl)acetamide, Methyl 5-(2-acetamido-4-methylthiazol-5-yl)-2-(phenylsulfonamido)benzoate, A/-(5-(3-

(benzyloxy)-4-(phenylsulfonamido)phenyl)-4-methylthiazol-2-yl)acetamide, A/-(5-(3-fluoro- 4-(phenylsulfonamido)phenyl)-4-methylthiazol-2-yl)acetamide, A/-(5-(3-cyclopropyl-4- (phenylsulfonamido)phenyl)-4-methylthiazol-2-yl)acetamide, A/-(5-(3-acetamido-4- (phenylsulfonamido)phenyl)-4-methylthiazol-2-yl)acetamide, A/-(5-(3-(methoxymethyl)-4- (phenylsulfonamido)phenyl)-4-methylthiazol-2-yl)acetamide.

10. A compound according to Formula 2

Formula 2 wherein

R1 is C, S, O or N,

R7, R8 and R9 are the same or different, C or N,

R13 is C1 to C5 alkyl (preferably C1 to C3 alkyl), C2 to C5 alkenyl, C3 to C6 cycloalkyl, C5 or C6 aryl, alkyl aryl, C5 or C6 hetero aryl (preferably comprising N, S and/or O), a bicyclic group (preferably comprising one or two aromatic rings), optionally comprising one or more heteroatoms (preferably N, O and/or S), or R12 and R13 are absent when R11 is halogen, or not forming a ring structure with R10 or R14, or when R11 and R14 form together with the atoms they are attached to a 5- to 8- membered cycloalkyl or aryl ring structure C and R15 and R16 are present,

R16 is C1 to C5 alkyl (preferably C1 to C3 alkyl), C2 to C5 alkenyl, C3 to C6 cycloalkyl, C5 or C6 aryl, alkyl aryl, C5 or C6 hetero aryl (preferably comprising N, S and/or O), a bicyclic group (preferably comprising one or two aromatic rings), optionally comprising one or more heteroatoms (preferably N, O and/or S), or R15 and R16 are absent when R14 is H, or R10 and R11 form together with the atoms they are attached to a 5- to 8-membered cycloalkyl or aryl ring structure D, or when R11 and R14 form together with the atoms they are attached to a 5- to 8-membered cycloalkyl or aryl ring structure C and R12 and R13 are present,

X is C, S and/or O,

Y is C, N, S and/or O,

11. The compound according to claim 10, wherein R10 and R11 form together with the atoms they are attached to a 5- to 7-membered cyclic or aryl ring structure D forming a condensed bicyclic group with B, wherein B and D is

and wherein R7, R8, R9, R12 and R13 are according to claim 10.

12. The compound according to any one of claims 10 or 11 , wherein R16 is one of

wherein R20 may be the same or different, 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

R21 may be the same or different, H, C1 to C5 alkyl (preferably C1 to C3 alkyl), halogen (preferably F, Cl and/or Br), alkoxy, primary, secondary or tertiary amine, sulfide, sulfinyl, sulfonyl, sulfino, sulfonamide, carboxyl, carboxy ester, a 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 comprising Cl, Br or F)), imide, carbamate, carboxamide, amide N=OR (wherein R is C1 to C3 alkyl, C1 to C3 alkenyl, C1 to C3 haloalkyl (preferably comprising Cl, Br or F)), nitro or E,

R23 is H, carbonyl, carboxyl or carboxy ester,

R24 is H or C1 to C5 alkyl (preferably C1 to C3 alkyl), and

13. The compound according to any one of the preceding claims for use as a medicament in the treatment of a medical condition associated with defective and/or pathologic signaling of the beta isoform of class II phosphoinositide 3-kinase (PI3K-C2b).

14. The compound according to any one of the preceding claims for use as a medicament in the treatment of a medical condition associated with defective and/or pathologic class II phosphoinositide 3-kinase (PI3K) signaling, wherein the medical condition is selected from the group consisting of stroke, a cardiovascular disease related to endothelial cell dysfunction, cancer, cancer metastasis, myopathy (preferably myotubular myopathy) and diabetes.

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

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