New acylsulfonamide derivatives and their use for the treatment of cancer

Abstract

The present disclosure describes acylsulfonamide compounds of Formula (I), and pharmaceutically acceptable salts thereof, compositions, methods, and uses thereof. Such compounds are believed to be therapeutically useful as inhibitors of KAT6A with improved selectivity particularly in the treatment and / or prevention of diseases and disorders mediated by KAT6A in a subject.

Description

[0001] New acylsulfonamide derivatives and their use for the treatment of cancer

[0002] FIELD OF THE INVENTION

[0003] [1] The present invention relates to the field of pharmaceuticals and concerns compounds capable of modulating KAT6 activity and / or KAT6-signaling, including their synthesis methods and therapeutic applications. In addition, the invention relates to incorporation of these compounds into a pharmaceutical formulation, and its application as a KAT6 inhibitor in the development of therapeutic agents for the treatment and / or prevention of cancer.

[0004] BACKGROUND OF THE INVENTION

[0005] [2] KAT6A, also designated as MYST3 or MOZ, is a member of the MYST family of histone acetyltransferases (HATs) that play a role in the regulation of gene expression and chromatin modification. KAT6A functions as an epigenetic regulator by acetylating histone H3 at lysine 9 (H3K9) and lysine 14 (H3K14), post-translational modifications associated with transcriptionally active chromatin. Through these modifications, KAT6A modulates chromatin structure and accessibility, thereby influencing the transcription of genes involved in key cellular processes such as differentiation, proliferation, and survival (Lv, D. et a!., 2017).

[0006] [3] Beyond its role in normal cellular function, KAT6A has been implicated in oncogenesis. Alterations in KAT6A activity, including mutations, chromosomal translocations, and aberrant expression, are associated with the initiation and progression of various cancers. Notably, chromosomal translocations involving KAT6A, such as t(8; 16)(p11 ;p13), result in fusion proteins like KAT6A-CREBBP, which are linked to acute myeloid leukemia (AML) (Coenen, E.A. et al., 2013). Additionally, overexpression of KAT6A has been observed in solid tumors, including breast and colon cancers, where it contributes to increased cellular proliferation and survival (Hu, Z. et al., 2019).

[0007] [4] The oncogenic potential of KAT6A is mediated through its capacity to modify the transcriptional landscape in a manner that supports tumor progression. KAT6A, as a histone acetyltransferase, acetylates histone H3 at lysine residues K9, K14, and K23, thereby facilitating the expression of genes involved in cellular proliferation and survival while repressing those associated with differentiation and apoptosis. Additionally, KAT6A seems to interact with other epigenetic regulators, including the NuA4 complex and the p300 / CBP coactivator, to modulate the expression of oncogenes and tumor suppressor genes. These interactions collectively contribute to the establishment of a transcriptional environment that promotes oncogenic processes. Thus, targeting KAT6A presents a viable therapeutic strategy for cancers characterized by KAT6A dysregulation. Inhibition of KAT6A’s acetyltransferase activity has the potential to disrupt the transcriptional programs that drive cancer progression (Weber, L.M. et al., 2023).

[0008] [5] Cancers driven by KAT6A dysregulation, including AML, breast cancer, and colon cancer, frequently present aggressive phenotypes and exhibit resistance to conventional treatments like chemotherapy and radiation. Compounds such as WM-1119 demonstrate moderate efficacy in vitro but lack sufficient potency in vivo to achieve robust therapeutic outcomes due to issues such as low bioavailability, or poor pharmacokinetic properties (Sharma S. et al., 2023). A primary challenge in developing KAT6A inhibitors is achieving selectivity due to structural homology with other MYST family members, including KAT6B (MORF), KAT5 (Tip60), and KAT7 (HBO1). This similarity, particularly within the acetyl- CoA binding pocket, complicates the design of inhibitors that specifically target KAT6A without affecting other HATs, which are essential for normal cellular functions. Indeed, non-selective inhibition may lead to off-target effects and toxicity, thereby narrowing the therapeutic window. The development of novel KAT6A inhibitors with enhanced selectivity and potency could provide new therapeutic options for these cancers, particularly those resistant to existing treatments. Additionally, such inhibitors could be integrated into combination therapies to improve treatment efficacy and mitigate drug resistance.

[0009] [6] Recent advancements include the discovery of CTx-648 (PF-9363), a highly potent, and orally bioavailable inhibitor of KAT6A / B histone acetyltransferases. CTx-648 has demonstrated antitumor activity in breast cancer models with high KAT6A expression and estrogen receptor positivity (ER+). By specifically inhibiting KAT6A / B, CTx-648 reduces the acetylation of histone H3 at lysine 23 (H3K23Ac), thereby suppressing tumor growth. The efficacy of CTx-648 in preclinical trials highlights the potential of targeted KAT6A inhibition as a therapeutic approach for cancers with KAT6A dysregulation. However, in the phase 1 clinical trial of PF-07248144 for ER+HER2- metastatic breast cancer, neutropenia and anemia were among the most frequently reported treatment- related adverse events. These occurred in 59.8% and 48.6% of patients, respectively, with 35.5% and 13.1% experiencing grade 3 or 4 severity (Mukohara T. et al., 2024). This high incidence stresses the critical role of the KAT families in hematopoiesis and in particular KAT6 and KAT7. KAT6A / B enzymes are involved in the regulation of gene expression for the proliferation and differentiation of hematopoietic stem cells (HSC) and show a high degree of cooperation in the regulation of hematopoiesis. Like KAT6A / B and KAT7 also have a critical role in maintaining HSC function as it confers differentiation down the erythroid or alternative lineages. However, KAT6A / B, but not KAT7, regulates B cell development. The inhibition of KAT6B and KAT7 alongside KAT6A disrupts normal blood cell development, leading to adverse effects such as anemia and neutropenia (Bergamasco M.l. et al., 2024). The occurrence of neutropenia and anemia emphasizes the necessity for developing compounds with greater specificity to minimize adverse effects while maintaining therapeutic efficacy.

[0010] [7] Recently, a class of acylsulfonamide compounds has been introduced, disclosing their potential as inhibitors specifically targeting the KAT6A protein (WO2024189598). These compounds are suggested to have therapeutic value in conditions associated with KAT6A activity, including various cancers and proliferative disorders. However, the patent does not provide details regarding their specificity toward KAT6A or differentiate between KAT6A and its close relative, KAT6B. This raises questions about the selectivity of these compounds, such specificity is crucial for the development of cancer-specific inhibitors with high therapeutic index that can precisely target KAT6A-driven malignancies.

[0011] [8] In summary, KAT6A is involved in normal gene regulation and cancer pathogenesis through its histone acetyltransferase activity. While existing inhibitors have laid important groundwork, there remains a pressing need for more selective and potent inhibitors that target KAT6A-driven cancers with a selective inhibition of KAT6A in preference to KAT6B.

[0012] SUMMARY OF THE INVENTION

[0013] [9] The invention aims to address these drawbacks and in particular aims at developing compounds with a better therapeutic index. The following provides a simplified summary of selected aspects, embodiments, and examples of the present invention to offer a basic understanding of it. However, this summary is not intended to provide a comprehensive overview of all aspects, embodiments, and examples of the invention. Its sole purpose is to present selected aspects, embodiments, and examples in a concise manner, serving as an introduction to the more detailed description of the aspects, embodiments, and examples that follow this summary.

[0014]

[0010] The present disclosure aims to provide a compound of formula (I): or a pharmaceutically acceptable salt thereof, wherein:

[0015] A represents an aryl group or a heteroaryl group, such as a benzo-fused alicyclic group, preferably a benzo-fused heterocyclic group; wherein A is optionally substituted by one or more members selected from the group consisting of: alkoxy groups, such as a C1-C4 alkoxy group; alkyl groups such as a C1-C4 alkyl group, optionally substituted by 1 to 3 fluorine atoms; halogens; unsubstituted or substituted amino groups, such as dialkylamino groups, such as a dimethylamino group (-N(CH3)2); cycloalkyl groups optionally substituted by one or more alkyl groups and / or halogens, such as a C3-C5 cycloalkyl group optionally substituted by 1 to 2 fluorine atoms; heterocyclyl groups, preferably a 4- to 6-member heterocycloalkyl group, such as azetidine or pyrrolidine, optionally substituted by one or more alkyl groups, oxo groups and / or halogens; and phenyl groups, optionally substituted by one or more alkyl groups and / or halogens; and

[0016] B represents a substituted benzo-fused oxygen containing heterocyclic group; wherein B is substituted by one or more members selected from the group consisting of: heteroaryl groups, preferably a 5- or 6-member heteroaryl group, connected to the benzo-fused oxygen containing heterocyclic group through a spacer, preferably said spacer being chosen from a C1-C4 alkylene chain or a single oxygen atom; halogens; and alkyl groups such as a C1-C4 alkyl group, optionally substituted by 1 to 3 fluorine atoms.

[0017]

[0011] As it is shown in the examples, the compound of formula (I) shows a better selectivity against KAT6A compared to compounds from the prior art.

[0018]

[0012] Indeed, the compounds according to the invention are effective in modulating or inhibiting the KAT6 signaling pathway. Moreover, the compounds of the invention show selective inhibition of KAT6A in preference to KAT6B.

[0019]

[0013] As demonstrated, the compounds of the invention display a significantly lower human plasma protein binding and a higher human blood to plasma ratio which should result in a better tumor exposure. The effect is expected to be further enhanced when antitumor efficacy in solid tumor cancers is considered.

[0020]

[0014] At last, compared to acylsulfonamide previously described in W02020216701 and WO2024189589, the compound of formula (I) displays a significantly lower P-Glycoprotein (P-gp) efflux ratio which could be critical for tumor exposure since most of cancer cell lines overexpress P-gp to efflux xenobiotics.

[0021]

[0015] According to other optional features of the compound of the invention, it may optionally include one or more of the following features, either individually or in combination:

[0022] - A represents a phenyl group or a benzo-fused cycloalkyl group or a benzo-fused heterocyclic group; when A represents a phenyl group or a benzo-fused cycloalkyl group it is substituted by an alkoxy group, such as a C1-C4 alkoxy group; when A represents a benzo-fused heterocyclic group, the benzo-fused heterocyclic group comprises a heterocyclic group comprising at least one oxygen atom and being fused to a benzene ring; and

[0023] A is optionally substituted, or further substituted on the benzene ring by one or more members selected from the group consisting of: alkoxy groups, such as a C1-C4 alkoxy group; and

[0024] 4- to 6-member heterocyclyl groups, such as azetidine or pyrrolidine, optionally substituted by one or more alkyl groups, oxo groups and / or halogens. the benzo-fused oxygen containing heterocyclic group of B comprises a benzene ring being substituted by a heteroaryl group, preferably a 5- or 6-member heteroaryl group, connected to the benzene ring through a C1-C4 alkylene chain spacer, preferably through a Ci alkylene spacer; wherein B is optionally further substituted by one or more members selected from the group consisting of: halogens; and alkyl groups, such as a C1-C4 alkyl group, optionally substituted by 1 to 3 fluorine atoms.

[0025] This specific embodiment, due to the presence of the heteroaryl group on the benzene ring of B, leads to a marked enhancement of KAT6A inhibitory activity.

[0026] Preferably, the group B is directly bonded, via a carbon atom of the benzene ring of group B, to the carbonyl carbon atom of the carboxamide group. the compound is of formula (II): or a pharmaceutically acceptable salt thereof, wherein:

[0027] R1, R2, R3, R4, and R5each independently represent H; an alkyl group, such as a C1-C4 alkyl group, optionally substituted by 1 to 3 fluorine atoms; a cycloalkyl group, optionally substituted by one or more alkyl groups and / or halogens; a 4- to 6-member heterocyclyl group, optionally substituted by one or more alkyl groups, oxo groups and / or halogens; a halogen; an alkoxy group, such as a C1-C4 alkoxy group; a cycloakyloxy group, optionally substituted by one or more alkyl groups and / or halogens; a phenyl group, optionally substituted by one or more alkyl groups and / or halogens; or a substituted or unsubstituted amino group, such as dialkylamino groups, such as a dimethylamino group (-N(CH3)2); alternatively, any one pair selected from R1and R3, R2and R4, R4and R5, or R3and R5, taken together, form a cycloalkyl group, a 5- or 6-member heterocycloalkyl group or an heteroaromatic group, optionally substituted by one or more alkyl groups and / or halogens, while the remaining R1, R2, R3, R4, and R5, each independently, represent H; an alkyl group, optionally substituted by 1 to 3 fluorine atoms; a cycloalkyl group, optionally substituted by one or more alkyl groups and / or halogens; a 4- to 6-member heterocyclyl group, optionally substituted by one or more alkyl groups, oxo groups and / or halogens; a halogen; an alkoxy group, such as a C1-C4 alkoxy group; a cycloakyloxy group, optionally substituted by one or more alkyl groups and / or halogens; a phenyl group, optionally substituted by one or more alkyl groups and / or halogens; or a substituted or unsubstituted amino group, such as dialkylamino groups, such as a dimethylamino group (-N(CH3)2). the compound is of formula (III): or a pharmaceutically acceptable salt thereof, wherein: n and m each independently represent 0 or 1 ;

[0028] R6and R7, each independently represent hydrogen; halogen; Ci-Ce alkyl group, optionally substituted by one or more halogens; C2-C6 alkenyl group, optionally substituted by one or more halogens; or Ci-Ce alkoxy group, optionally substituted by one or more halogens; alternatively, one of R6and R7taken together with any of R8, R9, R10or R11form a cyclic group, such as a 3- to 6-cycloalkyl group, optionally substituted by one or more alkyl groups and / or halogens; while the other one of R6and R7, when not involved in the cyclic group, represents hydrogen or halogen;

[0029] R8and R9, when not involved in a cyclic group with R6or R7, each independently represent hydrogen; halogen; Ci-Ce alkyl group, optionally substituted by one or more halogens; C2-C6 alkenyl group, optionally substituted by one or more halogens; or Ci-Ce alkoxy group, optionally substituted by one or more halogens; alternatively, R8and R9taken together, or one of R8and R9taken together with any of R10or R11, form a cyclic group such as a 3- to 6-cycloalkyl group, optionally substituted by one or more alkyl groups and / or halogens; while the other one of R8and R9, when not involved in the cyclic group, represents hydrogen or halogen; R10and R11, taken together form a cyclic group such as a 3- to 6-cycloalkyl group, optionally substituted by one or more alkyl groups and / or halogens; or R10and R11, when not involved in a cyclic group, each independently represent hydrogen; halogen; Ci-Ce alkyl group, optionally substituted by one or more halogens; C2-C6 alkenyl group, optionally substituted by one or more halogens; or Ci-Ce alkoxy group, optionally substituted by one or more halogens;

[0030] X1represents an oxygen atom, a sulfur atom or CR15R16, wherein R15and R16each independently represent a hydrogen, an alkyl group, or a halogen such as fluorine; alternatively, R15taken together with any R10or R11form a cyclic group, such as a 3- to 6-cycloalkyl group, optionally substituted by one or more alkyl groups and / or halogens; alternatively, when X1represents CR15R16, R15and R16taken together form a cyclic group, such as a 3- to 6-cycloalkyl group, optionally substituted by one or more alkyl groups and / or halogens;

[0031] R12and R13each independently represent a hydrogen or an alkyl group; and

[0032] R14represents -CH2-heteroaryl group or -O-heteroaryl group in which the heteroaryl group is preferably a 5- or 6- member heteroaryl group such as pyrazole, oxazole, isoxazole, thiazole or pyridine.

[0033] The compounds of formula (III) exhibit higher selectivity against KAT6A vs KAT6B, reduced lower human plasma protein binding, a higher blood-to-plasma ratio, and decreased P-glycoprotein efflux in Caco-2 cells. the compound is of formula (IV): or a pharmaceutically acceptable salt thereof, wherein:

[0034] R1, R2, R3, R4, and R5each independently represent H; an alkyl group, such as a C1-C4 alkyl group, optionally substituted by 1 to 3 fluorine atoms; a cycloalkyl group, optionally substituted by one or more alkyl groups and / or halogens; a 4- to 6-member heterocyclyl group, optionally substituted by one or more alkyl groups, oxo groups and / or halogens; a halogen; an alkoxy group such as a C1-C4 alkoxy group; a cycloakyloxy group, optionally substituted by one or more alkyl groups and / or halogens; a phenyl group, optionally substituted by one or more alkyl groups and / or halogens; or a substituted or unsubstituted amino group, such as dialkylamino groups, such as a dimethylamino group (-N(CH3)2); alternatively, any one pair selected from R1and R3, R2and R4, R4and R5, or R3and R5, taken together, form a cycloalkyl group, a 5- or 6-member heterocycloalkyl group or an heteroaromatic group, optionally substituted by one or more alkyl groups and / or halogens, while the remaining R1, R2, R3, R4, and R5, each independently, represent H; an alkyl group, optionally substituted by 1 to 3 fluorine atoms; a cycloalkyl group, optionally substituted by one or more alkyl groups and / or halogens; a 4- to 6-member heterocyclyl group, optionally substituted by one or more alkyl groups, oxo groups and / or halogens; a halogen; an alkoxy group such as a C1-C4 alkoxy group; a cycloakyloxy group, optionally substituted by one or more alkyl groups and / or halogens; a phenyl group, optionally substituted by one or more alkyl groups and / or halogens; or a substituted or unsubstituted amino group, such as dialkylamino groups, such as a dimethylamino group (-N(CH3)2); n and m each independently represent 0 or 1 ;

[0035] R6and R7, each independently represent hydrogen; halogen; Ci-Ce alkyl group, optionally substituted by one or more halogens; C2-C6 alkenyl group, optionally substituted by one or more halogens; or Ci-Ce alkoxy group, optionally substituted by one or more halogens; alternatively, one of R6and R7taken together with any of R8, R9, R10or R11form a cyclic group such as a 3- to 6-cycloalkyl group, optionally substituted by one or more alkyl groups and / or halogens; while the other one of R6and R7, when not involved in the cyclic group, represents hydrogen or halogen;

[0036] R8and R9, when not involved in a cyclic group with R6or R7, each independently represent hydrogen; halogen; Ci-Ce alkyl group, optionally substituted by one or more halogens; C2-C6 alkenyl group, optionally substituted by one or more halogens; or Ci-Ce alkoxy group, optionally substituted by one or more halogens; alternatively, R8and R9taken together, or one of R8and R9taken together with any of R10or R11, form a cyclic group such as a 3- to 6-cycloalkyl group, optionally substituted by one or more alkyl groups and / or halogens; while the other one of R8and R9, when not involved in the cyclic group, represents hydrogen or halogen; R10and R11, taken together form a cyclic group such as a 3- to 6-cycloalkyl group, optionally substituted by one or more alkyl groups and / or halogens; or R10and R11, when not involved in a cyclic group, each independently represent hydrogen; halogen; Ci-Ce alkyl group, optionally substituted by one or more halogens; C2-C6 alkenyl group, optionally substituted by one or more halogens; or Ci-Ce alkoxy group, optionally substituted by one or more halogens; X1represents an oxygen atom, a sulfur atom, or CR15R16, wherein R15and R16each independently represent a hydrogen, an alkyl group, or a halogen such as fluorine; alternatively, R15taken together with any R10or R11form a cyclic group, such as a 3- to 6-cycloalkyl group, optionally substituted by one or more alkyl groups and / or halogens; alternatively, when X1represents CR15R16, R15and R16taken together form a cyclic group, such as a 3- to 6-cycloalkyl group, optionally substituted by one or more alkyl groups and / or halogens;

[0037] R12and R13each independently represent a hydrogen or an alkyl group; and

[0038] R14represents -CH2-heteroaryl group or -O-heteroaryl group in which the heteroaryl group is preferably a 5- or 6- member heteroaryl group such as pyrazole, oxazole, isoxazole, thiazole or pyridine.

[0039] The compounds according to formula (IV) exhibit higher selectivity against KAT6A vs KAT6B, and reduced lower human plasma protein binding, a higher blood-to- plasma ratio, and decreased P-glycoprotein efflux in Caco-2 cells. the compound is of formula (111 b): or a pharmaceutically acceptable salt thereof, wherein:

[0040] R6and R7, each independently represent hydrogen; halogen; Ci-Ce alkyl group, optionally substituted by one or more halogens; C2-C6 alkenyl group, optionally substituted by one or more halogens; or Ci-Ce alkoxy group, optionally substituted by one or more halogens; alternatively, one of R6and R7taken together with any of R8, R9, R10or R11form a cyclic group such as a 3- to 6-cycloalkyl group, optionally substituted by one or more alkyl groups and / or halogens; while the other one of R6and R7, when not involved in the cyclic group, represents hydrogen or halogen;

[0041] R8and R9, when not involved in a cyclic group with R6or R7, each independently represent hydrogen; halogen; Ci-Ce alkyl group, optionally substituted by one or more halogens; C2-C6 alkenyl group, optionally substituted by one or more halogens; or Ci-Ce alkoxy group, optionally substituted by one or more halogens; alternatively, R8and R9taken together, or one of R8and R9taken together with any of R10or R11, form a cyclic group such as a 3- to 6-cycloalkyl group, optionally substituted by one or more alkyl groups and / or halogens; while the other one of R8and R9, when not involved in the cyclic group, represents hydrogen or halogen; R10and R11, taken together form a cyclic group such as a 3- to 6-cycloalkyl group, optionally substituted by one or more alkyl groups and / or halogens; or R10and R11, when not involved in a cyclic group, each independently represent hydrogen; halogen; Ci-Ce alkyl group, optionally substituted by one or more halogens; C2-C6 alkenyl group, optionally substituted by one or more halogens; or Ci-Ce alkoxy group, optionally substituted by one or more halogens;

[0042] X1represents an oxygen atom, a sulfur atom, or CR15R16, wherein R15and R16each independently represent a hydrogen, an alkyl group, or a halogen such as fluorine; alternatively, R15taken together with any R10or R11form a cyclic group, such as a 3- to 6-cycloalkyl group, optionally substituted by one or more alkyl groups and / or halogens; alternatively, when X1represents CR15R16, R15and R16taken together form a cyclic group, such as a 3- to 6-cycloalkyl group, optionally substituted by one or more alkyl groups and / or halogens; the compound is of formula (I Vf) :

[0043] or a pharmaceutically acceptable salt thereof, wherein:

[0044] R2, R3, R4, and R5each independently represent H; an alkyl group, such as a Ci- 04 alkyl group, optionally substituted by 1 to 3 fluorine atoms; a cycloalkyl group, optionally substituted by one or more alkyl groups and / or halogens; a 4- to 6- member heterocyclyl group, optionally substituted by one or more alkyl groups, oxo groups and / or halogens; a halogen; an alkoxy group, such as a C1-C4 alkoxy group; a cycloakyloxy group, optionally substituted by one or more alkyl groups and / or halogens; a phenyl group, optionally substituted by one or more alkyl groups and / or halogens; or a substituted or unsubstituted amino group, such as dialkylamino groups, such as a dimethylamino group (-N(CH3)2); alternatively, any one pair selected from R2and R4, R4and R5, or R3and R5, taken together, form a cycloalkyl group, a 5- or 6-member heterocycloalkyl group or an heteroaromatic group, optionally substituted by one or more alkyl groups and / or halogens, while the remaining R2, R3, R4, and R5, each independently, represent H; an alkyl group, optionally substituted by 1 to 3 fluorine atoms; a cycloalkyl group, optionally substituted by one or more alkyl groups and / or halogens; a 4- to 6-member heterocyclyl group, optionally substituted by one or more alkyl groups, oxo groups and / or halogens; a halogen; an alkoxy group, such as a C1-C4 alkoxy group; a cycloakyloxy group, optionally substituted by one or more alkyl groups and / or halogens; a phenyl group, optionally substituted by one or more alkyl groups and / or halogens; or a substituted or unsubstituted amino group, such as dialkylamino groups, such as a dimethylamino group (- N(CH3)2); n and m each independently represent 0 or 1 ;

[0045] R6and R7, each independently represent hydrogen; halogen; Ci-Ce alkyl group, optionally substituted by one or more halogens; C2-C6 alkenyl group, optionally substituted by one or more halogens; or Ci-Ce alkoxy group, optionally substituted by one or more halogens; alternatively, one of R6and R7taken together with any of R8, R9, R10or R11form a cyclic group such as a 3- to 6-cycloalkyl group, optionally substituted by one or more alkyl groups and / or halogens; while the other one of R6and R7, when not involved in the cyclic group, represents hydrogen or halogen;

[0046] R8and R9, when not involved in a cyclic group with R6or R7, each independently represent hydrogen; halogen; Ci-Ce alkyl group, optionally substituted by one or more halogens; C2-C6 alkenyl group, optionally substituted by one or more halogens; or Ci-Ce alkoxy group, optionally substituted by one or more halogens; alternatively, R8and R9taken together, or one of R8and R9taken together with any of R10or R11, form a cyclic group such as a 3- to 6-cycloalkyl group, optionally substituted by one or more alkyl groups and / or halogens; while the other one of R8and R9, when not involved in the cyclic group, represents hydrogen or halogen;

[0047] R10and R11, taken together form a cyclic group such as a 3- to 6-cycloalkyl group, optionally substituted by one or more alkyl groups and / or halogens; or R10and R11, when not involved in a cyclic group, each independently represent hydrogen; halogen; Ci-Ce alkyl group, optionally substituted by one or more halogens; C2-C6 alkenyl group, optionally substituted by one or more halogens; or Ci-Ce alkoxy group, optionally substituted by one or more halogens;

[0048] X1represents an oxygen atom, a sulfur atom or CR15R16, wherein R15and R16each independently represent a hydrogen, an alkyl group, or a halogen such as fluorine; alternatively, R15taken together with any R10or R11form a cyclic group, such as a 3- to 6-cycloalkyl group, optionally substituted by one or more alkyl groups and / or halogens; and alternatively, when X1represents CR15R16, R15and R16taken together form a cyclic group, such as a 3- to 6-cycloalkyl group, optionally substituted by one or more alkyl groups and / or halogens.

[0049] The compounds of formula IVd allow for an enhanced affinity as well as selectivity for KAT6A compared to other KATs, and represent lower protein plasma binding and higher blood to plasma ratio as well as lower P-gp efflux in caco-2 cells.

[0050] R6, R7, R8, R9, R10, and R11are hydrogen. at least one of n or m equal 0, preferably both equal 0 and X1is oxygen. the compound of general formula (I) or a pharmaceutically acceptable salt thereof has a structure selected from:

[0051]

[0052] the compound of general formula (I) or a pharmaceutically acceptable salt thereof has the structure:

[0053]

[0016] According to another aspect, the invention relates to a pharmaceutical composition comprising a compound according to the invention, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

[0017] According to another aspect, the invention relates to a compound according to the invention or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to the invention, for use in the treatment or prophylaxis of a disease, preferably wherein the disease is a hyperproliferative disorder.

[0054]

[0018] The compounds of the invention are particularly effective for use in the treatment or prophylaxis of a disease at modulating or inhibiting the KAT6 activity or KAT6 signalling pathway, particularly KAT6A.

[0055]

[0019] The invention can in particular relate to the compound, the pharmaceutically acceptable salt or the pharmaceutical composition for use according to the invention, wherein it is for use in combination with a selective estrogen receptor degrader (SERD) such as fulvestrant or oral alternatives like camizestrant; immune checkpoint inhibitors targeting PD-1, PD-L1, or CTLA-4 and / or a cyclin-dependent kinase (CDK) inhibitor, including CDK2, CDK4, CDK6 or dual CDK2 / 4 or CDK4 / 6 inhibitors, such as palbociclib, ribociclib, or abemaciclib, for enhanced therapeutic efficacy in estrogen receptor-positive cancer. The compounds of the invention are particularly effective for use in combination with a selective estrogen receptor degrader (SERD) inhibitor; immune checkpoint inhibitors targeting PD-1, PD-L1 , or CTLA-4 inhibitor and / or a cyclin-dependent kinase (CDK) inhibitor.

[0056]

[0020] According to another aspect, the invention relates to a method for treating or prophylaxis of a disease, preferably wherein the disease is a hyperproliferative disorder, comprising administering to a patient in need thereof a compound of general formula (I), or a pharmaceutically acceptable salt thereof, according to the invention, or a pharmaceutically acceptable composition according to the invention.

[0057]

[0021] The method of the invention is particularly effective for use in the treatment or prophylaxis of a disease at modulating or inhibiting the KAT6 activity or KAT6 signalling pathway. The invention can in particular relate to the method for treating or prophylaxis of a disease according to the invention, wherein it further comprises administering to the patient in need thereof a Selective Estrogen Receptor Degrader (SERD) such as fulvestrant or oral alternatives like camizestrant; immune checkpoint inhibitors targeting PD-1 , PD-L1, or CTI.A-4 and / or a cyclin-dependent kinase (CDK) inhibitor, including such as CDK2, CDK4, CDK6 or dual CDK2 / 4 or, CDK4 / 6 inhibitors, such as palbociclib, ribociclib, or abemaciclib.

[0058]

[0022] The method of the invention is particularly effective for use in combination with a selective estrogen receptor degrader (SERD) inhibitor and / or a cyclin-dependent kinase (CDK) inhibitor.

[0059] DETAILED DESCRIPTION AND ADDITIONAL EMBODIMENTS

[0023] Below, we provide a summary of the invention and its associated terminology, followed by a discussion of the drawbacks of the prior art. Finally, we will detail how the invention effectively addresses these issues.

[0060]

[0024] Unless otherwise stated, a reference to a physical measurement value in the form of an interval shall be understood to include the limits.

[0061]

[0025] As used herein, the singular form "a", "an", and "the" include plural references unless indicated otherwise. For example, "a" substituent includes one or more substituents.

[0062]

[0026] The expression “hyperproliferative disorders” within the meaning of the invention can refer to any diseases characterized by excessive and uncontrolled cell proliferation in humans or animals. This includes a wide range of conditions where abnormal cell growth leads to the formation of tumors or other tissue anomalies. Examples encompass various forms of cancer such as carcinomas, sarcomas, leukemias, lymphomas, and melanomas.

[0063]

[0027] The term “cancer” within the meaning of the invention, can refer to a diverse group of diseases or disorders characterized by the uncontrolled growth and spread of abnormal cells. Cancer can manifest in various tissues and organs, presenting as solid tumors or affecting blood-forming tissues, such as in leukemia. This term encompasses a wide range of malignancies, including but not limited to carcinomas, sarcomas, leukemias, lymphomas, and melanomas. Specifically, it includes primary cancers as well as metastatic diseases, wherein cancer cells spread from the original (primary) site to other parts of the body. Examples of cancers covered by this term include lung, breast, colorectal, prostate, pancreatic, liver, stomach, esophageal, ovarian, cervical, bladder, and skin carcinomas; osteosarcoma, chondrosarcoma, liposarcoma, and rhabdomyosarcoma sarcomas; acute and chronic lymphoblastic and myeloid leukemias; Hodgkin and non-Hodgkin lymphomas; central nervous system cancers such as glioblastoma and medulloblastoma; melanomas; germ cell tumors including testicular and ovarian cancers; neuroendocrine tumors; multiple myeloma; thyroid cancers; mesotheliomas; head and neck cancers; gastrointestinal stromal tumors (GIST); Kaposi’s sarcoma; and vulvar, vaginal, and penile cancers. Additionally, the term includes rare and mixed types of cancers, as well as metastatic cancers. Furthermore, it encompasses KATs overexpressing cancers, particularly those exhibiting elevated levels of KAT6, which contribute to the malignancy’s progression and resistance to conventional therapies.

[0064]

[0028] The term “tumor” within the meaning of the invention, can refer to an abnormal mass of tissue that arises from excessive and uncontrolled cell proliferation. Tumors can be classified as either benign or malignant. A benign tumor is non-cancerous and does not invade surrounding tissues or metastasize to other parts of the body. In contrast, a malignant tumor, also known as a cancerous tumor, possesses the potential to invade nearby tissues and spread (metastasize) to distant sites within the body. Hence, the term “tumor” preferably refers to solid masses that may develop in various organs or tissues, as well as neoplastic growths affecting any part of the body, including soft tissues, bones, and blood-forming organs.

[0065]

[0029] The expression “KATs overexpressing cancer” within the meaning of the invention, can refer to cancers in which one or more lysine acetyltransferases (KATs) are produced at abnormally high levels compared to normal tissue counterparts. Specifically, this includes cancers that exhibit overexpression of KAT6, a member of the KAT family involved in chromatin remodeling and the regulation of gene expression. Overexpression of KAT6 and other KATs can drive oncogenic processes such as enhanced cell proliferation, resistance to apoptosis, metastasis, and the maintenance of stem cell-like properties in cancer cells. Examples of KATs overexpressing cancers include certain subtypes of leukemia, such as acute myeloid leukemia (AML) with KAT6A or KAT6B rearrangements, as well as solid tumors like specific forms of breast cancer, colorectal cancer, and pancreatic cancer that display elevated KAT6 expression. The expression “KAT6A overexpressing cancer” within the meaning of the invention, can refer to cancers in which KAT6A is produced at higher levels compared to normal tissue counterparts. In breast cancer, KAT6A was found to be amplified in 12-15% of tumors as part of the 8p11-12 amplicon, and is associated with poor outcomes for primary breast cancer patients, mostly of luminal subtype (Turner-Ivey B. et al. 2017). Additionally, neuroendocrine tumors and other malignancies where KAT6 overexpression contributes to tumor progression and therapy resistance are encompassed within this definition.

[0066]

[0030] The terms “patient” or “subject” within the meaning of the invention, can refer to any individual, whether human or non-human, who is undergoing treatment, diagnosis, or observation related to a medical condition or therapeutic intervention. This includes individuals currently diagnosed with a disease, disorder, or condition, as well as those who are at risk of developing such conditions. Additionally, it encompasses individuals participating in clinical trials or research studies, those receiving preventive care, and those undergoing monitoring for potential health issues. Both symptomatic and asymptomatic individuals fall within this definition.

[0067]

[0031] The expressions “patient in need thereof” or “subject in need thereof” within the meaning of the invention, can refer to any individual, whether human or non-human, who requires therapeutic intervention, diagnosis, or monitoring for a specific medical condition or disease addressed by the invention. This includes individuals who are diagnosed with the targeted disease or condition and require treatment, as well as those who are at elevated risk of developing the disease and thus require preventive measures. Additionally, it encompasses individuals undergoing therapy or intervention aimed at managing, mitigating, or curing the targeted disease or condition, as well as those participating in diagnostic or monitoring procedures related to the disease. Furthermore, it includes individuals who may benefit from improved therapeutic outcomes, enhanced disease management, or reduced side effects through the use of the invention.

[0068]

[0032] The terms “treatment” or “treating” within the meaning of the invention, can refer to any medical intervention aimed at managing, alleviating, reducing, or eliminating symptoms of a disease, disorder, or condition, as well as preventing its progression or recurrence. This may include the administration of pharmaceutical compounds, therapeutic agents, medical procedures, or other interventions that directly or indirectly modify the course of the condition. The terms may encompass both curative approaches, aimed at eradicating the condition, and palliative approaches, intended to relieve symptoms without necessarily curing the underlying disease. Treatment can also involve preventive measures to inhibit the onset of a disease in individuals at risk.

[0069]

[0033] The terms “prophylaxis” within the meaning of the invention, can refer to the use of a compound that, in a statistical sample, reduces the occurrence of the disorder or condition in the treated sample relative to an untreated control sample, or delays the onset or reduces the severity of one or more symptoms of the disorder or condition relative to the untreated control sample, when administered prior to the onset of the disorder or condition.

[0070]

[0034] The expression “pharmaceutical composition” within the meaning of the invention, can refer to a formulation that contains one or more active therapeutic agents selected from the compounds described herein, their pharmaceutically acceptable salts, prodrugs, or derivatives thereof, in combination with pharmaceutically acceptable excipients, carriers, adjuvants, or other chemical components. These compositions are prepared in a form suitable for administration to a patient and are designed to deliver the active ingredient effectively while ensuring stability, bioavailability, and eventually controlled release. The pharmaceutical composition encompasses a variety of dosage forms, including but not limited to solid forms such as tablets, capsules, granules, and powders; liquid forms such as solutions, suspensions, emulsions, and syrups; parenteral forms including injectable solutions or suspensions; topical forms like creams, ointments, gels, and lotions; and inhalable forms such as aerosols and dry powders. Additionally, these compositions are formulated for multiple routes of administration, including oral, intravenous (IV), intramuscular (IM), subcutaneous (SC), transdermal, and inhalation.

[0071]

[0035] The expression “pharmaceutically acceptable” within the meaning of the invention, can refer to substances, compounds, or compositions that are suitable for use in humans or animals without producing significant adverse effects, toxicity, or undesirable reactions. These acceptable components are compatible with the active pharmaceutical ingredients and other formulation components, ensuring safety and efficacy in therapeutic applications. Characteristics of pharmaceutically acceptable substances include being non-toxic and non-irritating at the concentrations used, chemically and physically compatible with active ingredients and other excipients, and not adversely affecting the stability of the pharmaceutical composition.

[0072]

[0036] The expression “pharmaceutically acceptable salt” within the meaning of the invention, can refer to a salt form of an active pharmaceutical compound that is suitable for therapeutic use in humans or animals. These salts are derived from the reaction of the active compound with pharmaceutically acceptable inorganic or organic acids or bases, enhancing properties such as solubility, stability, or bioavailability without introducing significant toxicity. Examples of pharmaceutically acceptable salts include those formed by reacting the active compound with inorganic acids like hydrochloric acid or sulfuric acid, organic acids such as citric acid or acetic acid, inorganic bases like sodium hydroxide or potassium hydroxide, and organic bases including ammonia or triethylamine. These salts may be prepared through direct neutralization during the final stages of purification or via solvent-based methods that facilitate salt formation during crystallization or precipitation. The pharmaceutically acceptable salts described herein are further detailed in Stahl, P. H., & Wermuth, C. G. (Eds.). (2011). Handbook of Pharmaceutical Salts: Properties, Selection, and Use. Wiley-VCH which is incorporated by reference.

[0073]

[0037] The term “excipients”, within the meaning of the invention, can refer to pharmaceutically acceptable inert substances that are incorporated into a pharmaceutical composition alongside the active compound described herein. Excipients serve various essential functions in the formulation, including but not limited to facilitating the manufacturing process, enhancing the stability and shelf-life of the active ingredient, aiding in the delivery and absorption of the active compound, improving the taste or appearance of the pharmaceutical formulation, and ensuring uniformity and proper dosage.

[0074]

[0038] The expression “pharmaceutically acceptable excipient, carrier, adjuvant, or vehicle” within the meaning of the invention, can refer to any substance that facilitates the delivery, administration, stability, absorption, or effectiveness of an active pharmaceutical ingredient (API) without causing significant adverse effects or negatively interacting with the API. Carriers provide a medium for the API, ensuring uniform distribution within the dosage form, while excipients serve various functions such as fillers, binders, disintegrants, lubricants, and preservatives. Adjuvants may enhance the therapeutic effect of the API, and vehicles act as solvents or dispersing agents to deliver the API in liquid or semi-solid formulations. Characteristics of pharmaceutically acceptable carriers, adjuvants, or vehicles include biocompatibility, ensuring they are non-toxic and nonirritating to the patient; compatibility, meaning they do not react adversely with the API or other formulation components; and stability, maintaining the integrity and efficacy of the pharmaceutical composition over its intended shelf life.

[0075]

[0039] The term "halogen," as used here, refers to either the elemental forms fluorine, chlorine, bromine, or iodine, as well as their corresponding radicals when acting as substituents in chemical compounds. Specifically, it encompasses fluoro (F), chloro (Cl), bromo (Br), or iodo (I) groups that can be incorporated into the compounds of the invention.

[0076]

[0040] The expression “alkyl group”, within the meaning of the invention, can refer to saturated monovalent hydrocarbon radicals. It is derived from an alkane by removing one hydrogen atom, resulting in a structure with the general formula CnH2n+i. Alkyl groups can vary in size and structure, ranging from simple methyl (CH3-) and ethyl (C2H5-) groups to larger, more complex chains such as propyl (C3H7-), butyl (C4H9-), pentyl (C5H11-), and hexyl (C6H13-) groups. Alkyl groups may also include branched or ramified structures like isopropyl (CH(CH3)2~) and isobutyl (CH2CH(CH3)2-). The terms “C1-4 alkyl group” or “C1-C4 alkyl group” refer to both linear and branched alkyl groups containing between one and four carbon atoms. Similarly, “C1-6 alkyl group” or“Ci-Ce alkyl group” encompasses alkyl groups with one to six carbon atoms. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, and isobutyl groups.

[0077]

[0041] The expression "alkoxy group", as used herein, refers to an alkyl radical bonded to an oxygen atom, represented as alkyl-O-. The alkoxy radical is attached to a molecule through the oxygen atom. Alkoxy groups can vary in size and structure, encompassing both straight and branched alkyl moieties. The terms "C1-C4 alkoxy" and "C1-C3 alkoxy" denote alkoxy radicals containing from one to four carbon atoms and from one to three carbon atoms, respectively. Examples of alkoxy groups include, but are not limited to, methoxy (CH3O-), ethoxy (C2H5O-), propoxy (C3H7O-), isopropoxy ((CHs^CHO-), and butoxy (C4H9O-) groups.

[0078]

[0042] The expression “amino group” within the meaning of the invention, can refer to a functional group consisting of a nitrogen atom bonded to one or more substituents.

[0079] Specifically, it can denote primary amino group (-NH2), secondary amino group (-NHR) where a nitrogen atom is bonded to one hydrogen atom and one alkyl or aryl group, or a tertiary amino group (-NR2) where a nitrogen atom is bonded to two alkyl or aryl groups. In particular, an amino group according to the invention can comprise a dialkylamino group, such as a dimethylamino group (-N(CH3)2).

[0080]

[0043] The expression “phenyl group” within the meaning can refer to a functional group derived from benzene, an aromatic hydrocarbon, by the removal of one hydrogen atom, resulting in the formula (-CH5). It comprises a six-carbon aromatic ring, specifically a benzene ring, which can be attached to other atoms or functional groups in a molecule through the position where the hydrogen atom was removed. The phenyl group can be substituted at different positions on the ring, leading to derivatives such as ortho-, meta-, and para-substituted phenyl compounds. Examples of compounds containing a phenyl group include, but are not limited to, 1,3-dimethoxybenzene, where the phenyl group is attached to two methoxy group; 1-methoxy-4-(trifluoromethyl)benzene, where it is attached to a methoxy and a trifluoromethyl.

[0081]

[0044] The expression “cyclic group” within the meaning of the invention can refer to a functional group comprising one or more ring structures formed by atoms connected in a closed loop. These rings can be saturated or unsaturated, aromatic or non-aromatic, and can consist of carbon atoms alone (carbocyclic) or a combination of carbon and heteroatoms such as nitrogen, oxygen, or sulfur (heterocyclic).

[0082]

[0045] The expression “ring system” within the meaning of the invention, can refer to a cyclic structure composed of one or more connected rings. Ring systems can be monocyclic (a single ring) or polycyclic (multiple rings fused together or linked). Ring systems can be carbocyclic, consisting entirely of carbon atoms, or heterocyclic, containing one or more heteroatoms such as nitrogen, oxygen, or sulfur. Ring systems include, but are not limited to, saturated monocyclic rings, saturated polycyclic rings, aromatic monocyclic rings or aromatic polycyclic rings.

[0083]

[0046] The term "carbocyclic ring system" refers to a ring composed exclusively of carbon atoms. Carbocyclic ring systems can be monocyclic or polycyclic, and can comprise saturated (alicyclic), as in cycloalkyl groups, and / or aromatic, as in aryl groups.

[0084]

[0047] The expression “cycloalkyl group” within the meaning of the invention, can refer to saturated cyclic hydrocarbon radical derived from cycloalkanes by the removal of one hydrogen atom, resulting in a structure with the general formula CnH2n-i, where n typically ranges from three to six. Examples of cycloalkyl group include, but are not limited to, C3- C6 cycloalkyl.

[0085]

[0048] The expression “cycloalkyloxy group” within the meaning of the invention, can refer to an alkoxy group in which the alkyl moiety is a cycloalkyl group. It is represented as cycloalkyl-O-, where the cycloalkyl portion is a saturated cyclic hydrocarbon group.

[0086] Examples of cycloalkyloxy groups include, but are not limited to, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, or cyclohexyloxy.

[0087]

[0049] The expression “aryl group” within the meaning of the invention, can refer to a functional group derived from an aromatic hydrocarbon. It comprises an aromatic ring, typically a benzene ring (CeHs-), which can be attached to other atoms or functional groups in a molecule. The term "Ce-C aryl" encompasses aryl groups containing from six to ten carbon atoms. Examples of aryl groups include, but are not limited to, phenyl (CeHs-), naphthyl (C10H7-), anthracyl (C14H10-), and their respective isomers such as 1- naphthyl and 2-anthracyl. Additionally, "aryl" includes fused polycyclic aromatic ring systems, such as bicyclic group, where an aromatic ring is fused to one or more additional rings, aromatic or not, such as heterocyclic rings containing heteroatoms, whether saturated or partially saturated. Examples include, but are not limited to, chromanyl, indanyl (2,3-dihydro-1H-indene) and tetrahydronaphthyl (1,2,3,4-tetrahydronaphthyl), where the point of attachment is on the aromatic ring.

[0088]

[0050] The expression "heterocyclic ring system" refers to a ring system containing at least one heteroatom (nitrogen, oxygen, or sulfur) within the ring. Heterocyclic ring systems can be monocyclic or polycyclic, and can be saturated, partially saturated, or aromatic. The ring size can vary, typically containing 3 to 7 ring atoms per ring.

[0089]

[0051] The term “heteroatom” within the meaning of the invention, can refer to an atom within a molecule that is not carbon or hydrogen. Specifically, it includes atoms such as nitrogen (N), oxygen (O), sulfur (S), phosphorus (P), silicon (Si), and other elements that can substitute for carbon in organic compounds.

[0090]

[0052] The expression “heterocyclyl group” within the meaning of the invention, can refer to a substituent derived from a heterocycle by the removal of one hydrogen atom, resulting in a group that can be attached to other atoms or functional groups within a molecule. A heterocycle refers to a cyclic structure, saturated, partially saturated, or aromatic ring, in which one or more of the atoms in the ring are elements other than carbon, such as nitrogen, oxygen, or sulfur. Heterocycles can be aromatic or non-aromatic and may contain various numbers of heteroatoms within the ring. Examples of heterocyclyl group include, but are not limited to, 4- to 6-member heterocyclyl group, such as azetidine (derived from azetidine, a four-membered ring containing one nitrogen atom), imidazolyl (derived from imidazole, a five-membered ring containing two nitrogen atoms), pyrrolidinyl (derived from pyrrolidine, a five-membered ring containing one nitrogen atom), or thiazolyl (derived from thiazole, a five-membered ring containing both nitrogen and sulfur atoms). These heterocyclyl groups may be optionally substituted by an alkyl group, oxo group or a halogen, allowing for further diversification of the compound's structure, optionally substituted by an alkyl group or a halogen.

[0091]

[0053] The expression “heteroaryl group” within the meaning of the invention, can refer to an aryl group in which one or more carbon atoms in the aromatic ring are replaced by heteroatoms such as nitrogen, oxygen, or sulfur. These heteroatoms can be incorporated into the aromatic ring in various positions, leading to structures such as pyridyl (where a nitrogen replaces a carbon in a benzene ring), thiophenyl (an aryl group with sulfur substitution in the aromatic ring), furanyl (an aryl group with oxygen substitution in the aromatic ring) groups, or indolyl (an aryl group derived from indole, containing both nitrogen and fused aromatic rings). Heteroaryl groups maintain the aromatic character of the ring. Additionally, "heteroaryl" includes fused polycyclic aromatic ring systems where an aromatic ring comprising one or more heteroatoms is fused to one or more additional rings, aromatic or not.

[0092]

[0054] The expression “heterocycloalkyl group” within the meaning of the invention, can refer to a cycloalkyl group in which one or more carbon atoms are replaced by heteroatoms such as nitrogen, oxygen, or sulfur, thereby forming a heterocyclic ring. Examples of heterocycloalkyl groups include, but are not limited to, a 4- to 6-member heterocycloalkyl group such as azetidinyl (a four-membered ring containing one nitrogen atom, derived from azetidine), morpholinyl (a six-membered ring containing both nitrogen and oxygen atoms, derived from morpholine), piperidinyl (a six-membered ring containing one nitrogen atom, derived from piperidine) or thiazolidinyl (a five-membered ring containing both nitrogen and sulfur atoms, derived from thiazolidine). Heterocycloalkyl groups may be optionally substituted by an alkyl group, oxo group or a halogen, allowing for further structural diversification and modulation of the compound's pharmacological properties.

[0093]

[0055] The expression "bicyclic ring" can refer to a ring system composed of two fused rings, which can be both carbocyclic, both heterocyclic, or a combination of carbocyclic and heterocyclic rings. The rings can be saturated, partially saturated, or aromatic. Bicyclic ring can be homocyclic (both rings of the same type) or heterocyclic (rings of different types). Bicyclic ring can be further substituted by cyclic group.

[0094]

[0056] The expression "polycyclic ring" can refer to a ring system composed of at least two fused rings, which can be both carbocyclic, both heterocyclic, or a combination of carbocyclic and heterocyclic rings. The rings can be saturated, partially saturated, or aromatic. Polycyclic ring can be homocyclic (both rings of the same type) or heterocyclic (rings of different types). Polycyclic ring can be further substituted by cyclic group.

[0095]

[0057] The expression “benzo-fused alicyclic group” refers to a polycyclic ring system formed by the fusion of a benzene ring with a heterocycloalkyl ring or a cycloalkyl ring. The heterocycloalkyl or cycloalkyl portion are a saturated or partially saturated ring. Such expression encompasses the benzo-fused heterocycloalkyl group and benzo-fused cycloalkyl group. Examples include di hydro benzofuran (a partially saturated furan ring fused to a benzene ring).

[0096]

[0058] The expression "benzo-fused heterocyclic group" can refer to a polycyclic ring comprising a benzene ring which is fused to a heterocyclic ring containing at least one heteroatom. The heterocyclic ring can be five- to seven-membered; it is partially saturated. Examples include indoline (benzene fused to a pyrrolidine ring), di hydro benzofuran (benzene fused to a tetra hydrofuran ring), and dihydrobenzothiophene (benzene fused to a tetrahydrothiophene ring). A "benzo-fused heterocyclic group" can comprise more than two ring systems with for example a ring system fused to the heterocyclic ring such as fused cycloalkyl or spirocyclic systems.

[0097]

[0059] The expression "benzo-fused oxygen containing heterocyclic group" can refer to a polycyclic ring comprising a benzene ring which is fused to a heterocyclic ring containing at least one oxygen atom. These polycyclic ring systems can be fused, bridged or spirocyclic systems; They preferably consist in a 9 to 15 atom polycyclic ring system containing at least one oxygen atom and in which one ring is a phenyl. The heterocyclic ring can be five- to seven-membered, fully or partially saturated. Examples include dihydro benzodioxepine, tetrahydro-2-benzoxepine and dihydrobenzofuran. A "benzo-fused oxygen containing heterocyclic group" can comprise more than two ring systems with for example a ring system fused to the heterocyclic ring such-as 3-Oxabicyclo[4.1.0]heptane or 2-Oxabicyclo [3.1.0]hexane or a spirocyclic systems such as 5-Oxaspiro[2.4]heptane or 6-Oxaspiro[2.5]octane.

[0098]

[0060] The expression "benzo-fused heterocycloalkyl group" refers to a polycyclic ring system formed by the fusion of a benzene ring with a heterocycloalkyl ring. The heterocycloalkyl portion is a saturated or partially saturated ring that contains one or more heteroatoms such as nitrogen, oxygen, or sulfur. This fused ring system can be saturated or partially saturated. Examples of benzo-fused heterocycloalkyl groups include di hydro benzofuran (benzene fused to a partially saturated oxygen-containing ring).

[0099]

[0061] The expression "benzo-fused cycloalkyl group" refers to a polycyclic ring system formed by the fusion of a benzene ring with a cycloalkyl ring. The cycloalkyl portion is a saturated or partially saturated cyclic hydrocarbon ring. This fused ring system can be saturated or partially saturated and includes both carbocyclic ring. Examples of benzo- fused cycloalkyl groups include indane (benzene fused to cyclopentane) and tetralin (benzene fused to cyclohexane).

[0100]

[0062] The expression “partially saturated” within the meaning of the invention, can refer to a molecule, a molecular fragment, or a group that contains both single bonds and multiple bonds (such as double or triple bonds) within its structure. This means that while part of the molecule retains full saturation (i.e. , single bonds between atoms), certain regions of the molecule exhibit unsaturation, often involving carbon-carbon or carbonheteroatom double or triple bonds

[0101]

[0063] The term “unsaturated” within the meaning of the invention, can refer to a group or functional group that contains one or more double or triple bonds between carbon atoms or between carbon and heteroatoms (such as nitrogen, oxygen, or sulfur) within its structure.

[0064] The term “substituted” within the meaning of the invention, can refer to a molecule, a molecular fragment or a group in which one or more hydrogen atoms have been replaced by other atoms or functional groups. The expression “optionally substituted” within the meaning of the invention, can refer to a molecule, a molecular fragment or a group that may or may not contain one or more substituent groups attached to its core structure.

[0102]

[0065] The term "solvate" is used herein to describe a molecular complex comprising a compound described herein and one or more pharmaceutically acceptable solvent molecules, for example, ethanol.

[0103] Compounds of the Invention

[0104]

[0066] In some embodiments, a compound of the present disclosure is represented by general formula (I): or a pharmaceutically acceptable salt thereof, wherein:

[0105] A represents an aryl group or a heteroaryl group, such as a benzo-fused alicyclic group, preferably a benzo-fused heterocyclic group; optionally, A being substituted by one or more members selected from the group consisting of: alkoxy groups such as a C1-C4 alkoxy group; alkyl groups, such as a C1-C4 alkyl group, optionally substituted by 1 to 3 fluorine atoms; halogens; substituted or unsubstituted amino groups, such as dialkylamino groups, such as a dimethylamino group (-N(CH3)2); cycloalkyl groups optionally substituted by one or more alkyl groups and / or halogens, such as a C3-C5 cycloalkyl group optionally substituted by 1 to 2 fluorine atoms; heterocyclyl groups, preferably a 4- to 6-member heterocycloalkyl group, such as azetidine or pyrrolidine, optionally substituted by one or more alkyl groups, oxo groups and / or halogens; and phenyl groups, optionally substituted by one or more alkyl groups and / or halogens; and

[0106] B represents a substituted benzo-fused oxygen containing heterocyclic group; B being further substituted by one or more members selected from the group consisting of: heteroaryl groups, preferably a 5- or 6-member heteroaryl group, connected to the benzo-fused oxygen containing heterocyclic group through a spacer, preferably said spacer being chosen from a C1-C4 alkylene chain or a single oxygen atom; halogens; and alkyl groups, such as a C1-C4 alkyl group, optionally substituted by 1 to 3 fluorine atoms.

[0107]

[0067] In some embodiments, the invention relates to a compound of general formula (I) or formula (III), or a pharmaceutically acceptable salt thereof, wherein:

[0108] A represents an aryl group or a heteroaryl group, such as a benzo-fused alicyclic group, preferably a benzo-fused heterocyclic group;

[0109] A being substituted by an alkoxy group such as a C1-C4 alkoxy group or an alkyl group, such as a C1-C4 alkyl group, optionally substituted by 1 to 3 fluorine atoms; wherein A is optionally substituted, or further substituted by one or more members selected from the group consisting of: alkoxy groups such as a C1-C4 alkoxy group; alkyl groups, such as a C1-C4 alkyl group, optionally substituted by 1 to 3 fluorine atoms; halogens; substituted or unsubstituted amino groups, such as dialkylamino groups, such as a dimethylamino group (-N(CH3)2);

[0110] 4- to 6-member heterocyclyl groups, such as azetidine or pyrrolidine, optionally substituted by one or more alkyl groups, oxo groups and / or halogens; phenyl groups optionally substituted by alkyl groups and / or halogens; and cycloalkyl groups optionally substituted by alkyl groups and / or halogens, such as a C3-C5 cycloalkyl group optionally substituted by 1 to 2 fluorine atoms.

[0068] In preferred embodiments, the invention relates to a compound of general formula (I) or formula (III), or a pharmaceutically acceptable salt thereof, wherein:

[0111] A represents a phenyl group or a benzo-fused cycloalkyl group or a benzofused heterocycloalkyl group; wherein when A represents a phenyl group or a benzo-fused cycloalkyl group, it is substituted by an alkoxy group such as a C1-C4 alkoxy group; wherein when A represents a benzo-fused heterocyclic group, the benzo- fused heterocyclic group comprises a heterocyclic group comprising at least one oxygen atom and being fused to the benzene ring; wherein A is optionally substituted, or further substituted by one or more members selected from the group consisting of: alkoxy groups such as a C1-C4 alkoxy group; alkyl groups, such as a C1-C4 alkyl group, optionally substituted by 1 to 3 fluorine atoms; halogens; substituted or unsubstituted amino groups, such as dialkylamino groups, such as a dimethylamino group (-N(CH3)2);

[0112] 4- to 6-member heterocyclyl groups, such as azetidine or pyrrolidine, optionally substituted by one or more alkyl groups, oxo groups and / or halogens; and cycloalkyl groups optionally substituted by alkyl groups and / or halogens, such as a C3-C5 cycloalkyl group optionally substituted by 1 to 2 fluorine atoms.

[0113]

[0069] In more preferred embodiments, the invention relates to a compound of general formula (I) or formula (III), or a pharmaceutically acceptable salt thereof, wherein:

[0114] A represents a phenyl group or a benzo-fused cycloalkyl group or a benzo-fused oxygen containing heterocycloalkyl group; when A represents a phenyl group or a benzo-fused cycloalkyl group, it is substituted by an alkoxy group such as a C1-C4 alkoxy group; wherein A is optionally substituted, or further substituted by one or more members selected from the group consisting of: alkoxy groups such as a C1-C4 alkoxy group; alkyl groups, such as a C1-C4 alkyl group, optionally substituted by 1 to 3 fluorine atoms; halogens; substituted or unsubstituted amino groups, such as dialkylamino groups, such as a dimethylamino group (-N(CH3)2);

[0115] 4- to 6-member heterocyclyl groups, such as azetidine or pyrrolidine, optionally substituted by one or more alkyl groups, oxo groups and / or halogens; and cycloalkyl groups optionally substituted one or more alkyl groups and / or halogens, such as a C3-C5 cycloalkyl group optionally substituted by 1 to 2 fluorine atoms.

[0116]

[0070] In even more preferred embodiments, the invention relates to a compound of general formula (I) or formula (III), or a pharmaceutically acceptable salt thereof, wherein:

[0117] A represents a benzo-fused oxygen containing heterocycloalkyl group; wherein A is optionally substituted by one or more members selected from the group consisting of: alkoxy groups such as a C1-C4 alkoxy group; alkyl groups, such as a C1-C4 alkyl group, optionally substituted by 1 to 3 fluorine atoms; halogens; substituted or unsubstituted amino groups, such as dialkylamino groups, such as a dimethylamino group (-N(CH3)2);

[0118] 4- to 6-member heterocyclyl groups, such as azetidine or pyrrolidine, optionally substituted by one or more alkyl groups, oxo groups and / or halogens; and cycloalkyl groups optionally substituted by alkyl groups and / or halogens, such as a C3-C5 cycloalkyl group optionally substituted by 1 to 2 fluorine atoms.

[0119]

[0071] In some embodiments, the invention relates to a compound of general formula (I) or formula (II), or a pharmaceutically acceptable salt thereof, wherein:

[0120] B represents a substituted benzo-fused oxygen containing heterocyclic group, substituted by a heteroaryl group, preferably a 5- or 6-member heteroaryl group, connected to the benzo-fused oxygen containing heterocyclic group through a spacer, preferably said spacer being chosen from a C1-C4 alkylene chain, or a single oxygen atom; wherein B is optionally further substituted by one or more members selected from the group consisting of: halogens; alkyl groups, such as a C1-C4 alkyl group, optionally substituted by 1 to 3 fluorine atoms.

[0121]

[0072] In preferred embodiments, the invention relates to a compound of general formula (I) or formula (II), or a pharmaceutically acceptable salt thereof, wherein:

[0122] B represents a substituted benzo-fused oxygen containing heterocyclic group; the benzo-fused heterocyclic group comprising a benzene ring being substituted by a heteroaryl group, preferably a 5- or 6-member heteroaryl group connected to the benzo-fused oxygen containing heterocyclic group through a spacer, preferably said spacer being chosen from a C1-C4 alkylene chain, or a single oxygen atom; wherein B is optionally further substituted by one or more members selected from the group consisting of: halogens; and alkyl groups, such as a C1-C4 alkyl group, optionally substituted by 1 to 3 fluorine atoms.

[0123]

[0073] In more preferred embodiments, the invention relates to a compound of general formula (I) or formula (II), or a pharmaceutically acceptable salt thereof, wherein:

[0124] B represents a substituted benzo-fused oxygen containing heterocyclic group; the benzo-fused heterocyclic group comprising a benzene ring being substituted by a heteroaryl group, preferably a 5- or 6-member heteroaryl group, connected to the benzo-fused oxygen containing heterocyclic group through a C1-C4 alkylene chain spacer, preferably through a Ci alkylene spacer; the benzo-fused heterocyclic group comprising heterocyclic ring fused to the benzene ring and comprising at least one oxygen atom; wherein B is optionally substituted by one or more members selected from the group consisting of: halogens; and alkyl groups, such as a C1-C4 alkyl group, optionally substituted by 1 to 3 fluorine atoms.

[0125]

[0074] In even more preferred embodiments, the invention relates to a compound of general formula (I) or formula (II), or a pharmaceutically acceptable salt thereof, wherein:

[0126] B represents a substituted benzo-fused oxygen containing heterocyclic group; the benzo-fused oxygen containing heterocyclic group comprising a benzene ring being substituted by a heteroaryl group, preferably a 5- or 6-member heteroaryl group, connected to the benzene ring through a C1-C4 alkylene chain spacer, preferably through a Ci alkylene spacer; the benzo-fused heterocyclic group further comprising a cycloalkyl ring fused to the heterocyclic ring or sharing a single common atom with the heterocyclic ring; wherein B is optionally further substituted by one or more members selected from the group consisting of: halogens; and alkyl groups, such as a C1-C4 alkyl group, optionally substituted by 1 to 3 fluorine atoms.

[0127]

[0075] In some embodiments, the invention relates to a compound of general formula (I) or a pharmaceutically acceptable salt thereof, wherein:

[0128] A represents an aryl group or a heteroaryl group such as a benzo-fused alicyclic group, preferably a benzo-fused heterocyclic group;

[0129] A being substituted by an alkoxy group such as a C1-C4 alkoxy group or an alkyl group, such as a C1-C4 alkyl group, optionally substituted by 1 to 3 fluorine atoms; A being further substituted by one or more members selected from the group consisting of: alkoxy groups such as a C1-C4 alkoxy group; alkyl groups, such as a C1-C4 alkyl group, optionally substituted by 1 to 3 fluorine atoms; halogens; substituted or unsubstituted amino groups, such as dialkylamino groups, such as a dimethylamino group (-N(CH3)2);

[0130] 4- to 6-member heterocyclyl groups, such as azetidine or pyrrolidine, optionally substituted by one or more one or more alkyl groups, oxo groups and / or halogens; phenyl groups optionally substituted by alkyl groups and / or halogens; and cycloalkyl groups optionally substituted by alkyl groups and / or halogens such as a C3-C5 cycloalkyl group, optionally substituted by 1 to 2 fluorine atoms; and

[0131] B represents a substituted benzo-fused oxygen containing heterocyclic group, the benzo-fused oxygen containing heterocyclic group comprising a benzene ring being substituted by a heteroaryl group, preferably a 5- or 6-member heteroaryl group, connected to the benzene ring through a spacer chosen from a C1-C4 alkylene chain, or a single oxygen atom; wherein B is optionally further substituted by one or more members selected from the group consisting of: halogens; and alkyl groups, such as a C1-C4 alkyl group, optionally substituted by 1 to 3 fluorine atoms.

[0132]

[0076] In preferred embodiments, the invention relates to a compound of general formula (I) or a pharmaceutically acceptable salt thereof, wherein:

[0133] A represents an aryl group or a heteroaryl group, such as a benzo-fused alicyclic group, preferably a benzo-fused heterocyclic group; A being substituted by an alkoxy group such as a C1-C4 alkoxy group;

[0134] A being further substituted by one or more members selected from the group consisting of: alkoxy groups such as a C1-C4 alkoxy group; an alkyl groups, such as a C1-C4 alkyl group, optionally substituted by 1 to 3 fluorine atoms; halogens; substituted or unsubstituted amino groups, such as dialkylamino groups, such as a dimethylamino group (-N(CH3)2);

[0135] 4- to 6-member heterocyclyl groups, such as azetidine or pyrrolidine, optionally substituted by one or more alkyl groups, oxo groups and / or halogens; and cycloalkyl groups optionally substituted by alkyl groups and / or halogens such as a C3-C5 cycloalkyl group, optionally substituted by 1 to 2 fluorine atoms; and

[0136] B represents a substituted benzo-fused oxygen containing heterocyclic group; the benzo-fused heterocyclic group comprising a benzene ring being substituted by a heteroaryl group, preferably a 5- or 6-member heteroaryl group, connected to the benzene ring through a spacer chosen from a C1-C4 alkylene chain, or a single oxygen atom; wherein B is optionally further substituted by one or more members selected from the group consisting of: halogens; alkyl groups, such as a C1-C4 alkyl group, optionally substituted by 1 to 3 fluorine atoms.

[0077] In more preferred embodiments, the invention relates to a compound of general formula (I) or a pharmaceutically acceptable salt thereof, wherein:

[0137] A represents a phenyl group or a benzo-fused alicyclic group; A being substituted by an alkoxy group such as a C1-C4 alkoxy group; when A represents a benzo-fused alicyclic group, the benzo-fused alicyclic group comprises a benzene ring being substituted by the alkoxy group;

[0138] A being further substituted by one or more members selected from the group consisting of: alkoxy groups such as a C1-C4 alkoxy group; alkyl groups, such as a C1-C4 alkyl group, optionally substituted by 1 to 3 fluorine atoms;

[0139] 4- to 6-member heterocyclyl groups, such as azetidine or pyrrolidine, optionally substituted by one or more alkyl groups, oxo groups and / or halogens; halogens; and substituted or unsubstituted amino groups, such as dialkylamino groups, such as a dimethylamino group (-N(CH3)2); and

[0140] B represents a substituted benzo-fused oxygen containing heterocyclic group; the benzo-fused heterocyclic group comprising a benzene ring being substituted by a heteroaryl group, preferably a 5- or 6-member heteroaryl group, connected to the benzene ring through a C1-C4 alkylene chain spacer, preferably through a Ci alkylene spacer; wherein B is optionally further substituted by one or more members selected from the group consisting of: halogens; and alkyl groups, such as a C1-C4 alkyl group, optionally substituted by 1 to 3 fluorine atoms.

[0141]

[0078] In even more preferred embodiments, the invention relates to a compound of general formula (I) or a pharmaceutically acceptable salt thereof, wherein:

[0142] A represents a phenyl group or a benzo-fused cycloalkyl group or a benzo-fused heterocyclic group ; when A represents a phenyl group or a benzo-fused cycloalkyl group it is substituted by an alkoxy group such as a C1-C4 alkoxy group; when A represents a benzo-fused heterocyclic group, the benzo-fused heterocyclic group comprises a heterocyclic group comprising at least one oxygen atom and being fused to the benzene ring; wherein A is optionally substituted, or further substituted on the benzene ring by one or more members selected from the group consisting of: alkoxy groups such as a C1-C4 alkoxy group; and

[0143] 4- to 6-member heterocyclyl groups, such as azetidine or pyrrolidine, optionally substituted by one or more alkyl groups, oxo groups and / or halogens; and

[0144] B represents a substituted benzo-fused oxygen containing heterocyclic group; the benzo-fused oxygen containing heterocyclic group comprising a benzene ring being substituted by a heteroaryl group, preferably a 5- or 6-member heteroaryl group, connected to the benzene ring through a C1-C4 alkylene chain spacer, preferably through a Ci alkylene spacer; the benzo-fused heterocyclic group comprising heterocyclic ring comprising at least one oxygen atom; the benzo-fused heterocyclic group further comprising a cycloalkyl ring fused to the heterocyclic ring or sharing a single common atom with the heterocyclic ring; wherein B is optionally further substituted by one or more members selected from the group consisting of: halogens; and alkyl groups, such as a C1-C4 alkyl group, optionally substituted by 1 to 3 fluorine atoms.

[0145]

[0079] In some embodiments, a compound of Formula (I), or pharmaceutically acceptable salt thereof, is a compound of Formula (II): or a pharmaceutically acceptable salt thereof, wherein:

[0146] B is selected as previously described; R1, R2, R3, R4, and R5each independently represent H; an alkyl group, such as a C1-C4 alkyl group, optionally substituted by 1 to 3 fluorine atoms; a cycloalkyl group, optionally substituted by one or more alkyl groups and / or halogens; a 4- to 6-member heterocyclyl group, optionally substituted by one or more alkyl groups, oxo groups and / or halogens; a halogen; an alkoxy group such as a C1-C4 alkoxy group; a cycloakyloxy group, optionally substituted by one or more alkyl groups and / or halogens; a phenyl group, optionally substituted by one or more alkyl groups and / or halogens; or a substituted or unsubstituted amino group, such as dialkylamino groups, such as a dimethylamino group (-N(CH3)2); alternatively, any one pair selected from R1and R3, R2and R4, R4and R5, or R3and R5, taken together, form a cycloalkyl group, a 5- or 6-member heterocycloalkyl group or an heteroaromatic group, optionally substituted by one or more alkyl groups and / or halogens, while the remaining R1, R2, R3, R4, and R5, each independently, represent H; an alkyl group, optionally substituted by 1 to 3 fluorine atoms; a cycloalkyl group, optionally substituted by one or more alkyl groups and / or halogens; a 4- to 6-member heterocyclyl group, optionally substituted by one or more alkyl groups, oxo groups and / or halogens; a halogen; an alkoxy group such as a C1-C4 alkoxy group; a cycloakyloxy group, optionally substituted by one or more alkyl groups and / or halogens; a phenyl group, optionally substituted by one or more alkyl groups and / or halogens; a substituted or unsubstituted amino groups, such as dialkylamino groups, such as a dimethylamino group (-N(CH3)2).

[0147]

[0080] In some embodiments, a compound of Formula (I), or pharmaceutically acceptable salt thereof, is a compound of Formula (III): or a pharmaceutically acceptable salt thereof, wherein: A is selected as previously described; n and m each independently represent 0 or 1 ;

[0148] R6and R7, each independently represent hydrogen; halogen; Ci-Ce alkyl group, optionally substituted by one or more halogens; alternatively, one of R6and R7taken together with any of R8, R9, R10or R11form a cyclic group such as a 3- to 6-cycloalkyl group, optionally substituted by one or more alkyl groups and / or halogens; while the other one of R6and R7, when not involved in the cyclic group, represents hydrogen or halogen;

[0149] R8and R9, when not involved in a cyclic group with R6or R7, each independently represent hydrogen; halogen; Ci-Ce alkyl group, optionally substituted by one or more halogens; C2-C6 alkenyl group, optionally substituted by one or more halogens; or Ci-Ce alkoxy group, optionally substituted by one or more halogens; alternatively, R8and R9taken together, or one of R8and R9taken together with any of R10or R11, form a cyclic group such as a 3- to 6-cycloalkyl group, optionally substituted by one or more alkyl groups and / or halogens; while the other one of R8and R9, when not involved in the cyclic group, represents hydrogen or halogen, alternatively, R8and R9taken together form a cyclic group such as a 3- to 6- cycloalkyl group, optionally substituted by one or more alkyl groups and / or halogens; alternatively, R10and R11taken together form a cyclic group such as a 3- to 6- cycloalkyl group, optionally substituted by one or more alkyl groups and / or halogens; or R10and R11, when not involved in a cyclic group, each independently represent hydrogen; halogen; Ci-Ce alkyl group, optionally substituted by one or more halogens;

[0150] X1represents an oxygen atom, a sulfur atom or CR15R16, wherein R15and R16each independently represent a hydrogen, an alkyl group, or a halogen such as fluorine; alternatively, R15taken together with any R10or R11form a cyclic group, such as a 3- to 6-cycloalkyl group, optionally substituted by one or more alkyl groups and / or halogens; alternatively, when X1represents CR15R16, R15and R16taken together form a cyclic group, such as a 3- to 6-cycloalkyl group, optionally substituted by one or more alkyl groups and / or halogens;

[0151] R12and R13each independently represent a hydrogen or an alkyl group; and R14represents -CH2-heteroaryl group or -O-heteroaryl group in which the heteroaryl group is preferably a 5- or 6-member heteroaryl group such as pyrazole, oxazole, isoxazole, thiazole or pyridine.

[0081] In some embodiments, a compound of Formula (I), or pharmaceutically acceptable salt thereof, is a compound of Formula (IV): or a pharmaceutically acceptable salt thereof, wherein:

[0152] R1, R2, R3, R4, and R5each independently represent H; an alkyl group, such as a C1-C4 alkyl group, optionally substituted by 1 to 3 fluorine atoms; a cycloalkyl group, optionally substituted by one or more alkyl groups and / or halogens; a 4- to 6-member heterocyclyl group, optionally substituted by one or more alkyl groups, oxo groups and / or halogens; a halogen; an alkoxy group such as a C1-C4 alkoxy group; a cycloakyloxy group, optionally substituted by one or more alkyl groups and / or halogens; a phenyl group, optionally substituted by one or more alkyl groups and / or halogens; a substituted or unsubstituted amino groups, such as dialkylamino groups, such as a dimethylamino group (-N(CH3)2); alternatively, any one pair selected from R1and R3, R2and R4, R4and R5, or R3and R5, taken together, form a cycloalkyl group such as a 5- or 6-member cycloalkyl group, a 5- or 6-member heterocycloalkyl group or an heteroaromatic group, optionally substituted by one or more alkyl groups and / or halogens; while the remaining R1, R2, R3, R4, and R5, each independently, represent H; an alkyl group, optionally substituted by 1 to 3 fluorine atoms; a cycloalkyl group, optionally substituted by one or more alkyl groups and / or halogens; a 4- to 6-member heterocyclyl group, optionally substituted by one or more alkyl groups, oxo groups and / or halogens; a halogen; an alkoxy group such as a C1-C4 alkoxy group; a cycloakyloxy group, optionally substituted by one or more alkyl groups and / or halogens; a phenyl group, optionally substituted by one or more alkyl groups and / or halogens; a substituted or unsubstituted amino groups, such as dialkylamino groups, such as a dimethylamino group (-N(CH3)2); n and m each independently represent 0 or 1 ; R6and R7, each independently represent hydrogen; halogen; Ci-Ce alkyl group, optionally substituted by one or more halogens; C2-C6 alkenyl group, optionally substituted by one or more halogens; or Ci-Ce alkoxy group, optionally substituted by one or more halogens; alternatively, one of R6and R7taken together with any of R8, R9, R10or R11form a cyclic group such as a 3- to 6-cycloalkyl group, optionally substituted by one or more alkyl groups and / or halogens; while the other one of R6and R7, when not involved in the cyclic group, represents hydrogen or halogen;

[0153] R8and R9, when not involved in a cyclic group with R6or R7, each independently represent hydrogen; halogen; Ci-Ce alkyl group, optionally substituted by one or more halogens; C2-C6 alkenyl group, optionally substituted by one or more halogens; or Ci-Ce alkoxy group, optionally substituted by one or more halogens; alternatively, R8and R9taken together, or one of R8and R9taken together with any of R10or R11, form a cyclic group such as a 3- to 6-cycloalkyl group, optionally substituted by one or more alkyl groups and / or halogens; while the other one of R8and R9, when not involved in the cyclic group, represents hydrogen or halogen, alternatively, R8and R9taken together form a cyclic group such as a 3- to 6- cycloalkyl group, optionally substituted by one or more alkyl groups and / or halogens; alternatively, R10and R11taken together form a cyclic group such as a 3- to 6- cycloalkyl group, optionally substituted by one or more alkyl groups and / or halogens; or R10and R11, when not involved in a cyclic group, each independently represent hydrogen; halogen; Ci-Ce alkyl group, optionally substituted by one or more halogens; C2-C6 alkenyl group, optionally substituted by one or more halogens; or Ci-Ce alkoxy group, optionally substituted by one or more halogens;

[0154] X1represents an oxygen atom, a sulfur atom or CR15R16, wherein R15and R16each independently represent a hydrogen, an alkyl group, or a halogen such as fluorine; alternatively, R15taken together with any R10or R11form a cyclic group, such as a 3- to 6-cycloalkyl group, optionally substituted by one or more alkyl groups and / or halogens; alternatively, when X1represents CR15R16, R15and R16taken together form a cyclic group, such as a 3- to 6-cycloalkyl group, optionally substituted by one or more alkyl groups and / or halogens;

[0155] R12and R13each independently represent a hydrogen or an alkyl group; and R14represents -CH2-heteroaryl group or -O-heteroaryl group in which the heteroaryl group is preferably a 5- or 6- member heteroaryl group such as pyrazole, oxazole, isoxazole, thiazole or pyridine.

[0156]

[0082] In some embodiments, the present invention provides compounds of formula (II) or (IV), supra, or a pharmaceutically acceptable salt thereof, in which R1is selected from H; an alkyl group, such as a C1-C4 alkyl group, optionally substituted by 1 to 3 fluorine atoms; a cycloalkyl group, optionally substituted by one or more alkyl groups and / or halogens; a 4- to 6-member heterocyclyl group, optionally substituted by one or more alkyl groups, oxo groups and / or halogens; a halogen; an alkoxy group, such as a C1-C4 alkoxy group; a cycloakyloxy group, optionally substituted by one or more alkyl groups and / or halogens; a phenyl group, optionally substituted by one or more alkyl groups and / or halogens; or a substituted or unsubstituted amino group, such as dialkylamino groups, such as a dimethylamino group (-N(CH3)2.

[0157]

[0083] In a particular embodiment, the present invention provides compounds of formula (II) or (IV), supra, or a pharmaceutically acceptable salt thereof, in which R1is selected from a hydrogen atom; a halogen; an alkoxy group; or a cycloakyloxy group, optionally substituted by one or more alkyl groups and / or halogens. Preferably, R1is selected from a hydrogen atom; a halogen; or an alkoxy group. More preferably, R1is selected from a hydrogen atom; or an alkoxy group. Even more preferably, R1is selected from an alkoxy group, such as a methoxy or ethoxy group.

[0158]

[0084] In some embodiments, the present invention provides compounds of formula (II) or (IV), supra, or a pharmaceutically acceptable salt thereof, in which R2is selected from H; an alkyl group, such as a C1-C4 alkyl group, optionally substituted by 1 to 3 fluorine atoms; a cycloalkyl group, optionally substituted by one or more alkyl groups and / or halogens; a 4- to 6-member heterocyclyl group, optionally substituted by one or more alkyl groups, oxo groups and / or halogens; a halogen; an alkoxy group, such as a C1-C4 alkoxy group; a cycloakyloxy group, optionally substituted by one or more alkyl groups and / or halogens; a phenyl group, optionally substituted by one or more alkyl groups and / or halogens; or a substituted or unsubstituted amino group, such as dialkylamino groups, such as a dimethylamino group (-N(CH3)2.

[0159]

[0085] In a particular embodiment, the present invention provides compounds of formula (II) or (IV), supra, or a pharmaceutically acceptable salt thereof, in which R2is selected from a hydrogen atom; a halogen; an alkoxy group; or a cycloakyloxy group, optionally substituted by one or more alkyl groups and / or halogens. Preferably, R2is selected from a hydrogen atom; a halogen; or an alkoxy group. More preferably, R2is selected from a hydrogen atom; or an alkoxy group. Even more preferably, R2is selected from an alkoxy group, such as a methoxy or ethoxy group.

[0160]

[0086] In some embodiments, the present invention provides compounds of formula (II) or (IV), supra, or a pharmaceutically acceptable salt thereof, in which R1and R2each independently represent an alkoxy group, such as a methoxy or ethoxy group.

[0161]

[0087] In some embodiments, the present invention provides compounds of formula (II) or (IV), supra, or a pharmaceutically acceptable salt thereof, in which R3is selected from H; an alkyl group, such as a C1-C4 alkyl group, optionally substituted by 1 to 3 fluorine atoms; a cycloalkyl group, optionally substituted by one or more alkyl groups and / or halogens; a 4- to 6-member heterocyclyl group, optionally substituted by one or more alkyl groups, oxo groups and / or halogens; a halogen; an alkoxy group such as a C1-C4 alkoxy group; a cycloakyloxy group, optionally substituted by one or more alkyl groups and / or halogens; a phenyl group, optionally substituted by one or more alkyl groups and / or halogens; or a substituted or unsubstituted amino group, such as dialkylamino groups, such as a dimethylamino group (-N(CH3)2.

[0162]

[0088] In a particular embodiment, the present invention provides compounds of formula (II) or (IV), supra, or a pharmaceutically acceptable salt thereof, in which R3is selected from a hydrogen atom; an alkyl group, such as a C1-C4 alkyl group, optionally substituted by 1 to 3 fluorine atoms; a cycloalkyl group, optionally substituted by one or more alkyl groups and / or halogens; a 4- to 6-member heterocyclyl group, optionally substituted by one or more alkyl groups, oxo groups and / or halogens; a cycloakyloxy group, optionally substituted by one or more alkyl groups and / or halogens; a phenyl group, optionally substituted by one or alkyl groups and / or halogens; or a substituted or unsubstituted amino group, such as dialkylamino groups, such as a dimethylamino group (-N(CH3)2). Preferably, R3is selected from a hydrogen atom and a C1-C4 alkyl group substituted by 1 to 3 fluorine atoms; a heterocyclyl group substituted by one or more alkyl groups and / or halogens. More preferably, R3is selected from a hydrogen atom and a C1-C4 alkyl group substituted by 1 to 3 fluorine atoms. Even more preferably, R3represents a hydrogen atom.

[0163]

[0089] In some embodiments, the present invention provides compounds of formula (II) or (IV), supra, or a pharmaceutically acceptable salt thereof, in which R4is selected from H; an alkyl group, such as a C1-C4 alkyl group, optionally substituted by 1 to 3 fluorine atoms; a cycloalkyl group, optionally substituted by one or more alkyl groups and / or halogens; a 4- to 6-member heterocyclyl group, optionally substituted by one or more alkyl groups, oxo groups and / or halogens; a halogen; an alkoxy group such as a C1-C4 alkoxy group; a cycloakyloxy group, optionally substituted by one or more alkyl groups and / or halogens; a phenyl group, optionally substituted by one or more alkyl groups and / or halogens; or a substituted or unsubstituted amino group, such as dialkylamino groups, such as a dimethylamino group (-N(CH3)2.

[0164]

[0090] In a particular embodiments, the present invention provides compounds of formula (II) or (IV), supra, or a pharmaceutically acceptable salt thereof, in which R4is selected from a hydrogen atom; an alkyl group, such as a C1-C4 alkyl group, optionally substituted by 1 to 3 fluorine atoms; a cycloalkyl group, optionally substituted by one or more alkyl groups and / or halogens; a 4- to 6-member heterocyclyl group, optionally substituted by one or more alkyl groups, oxo groups and / or halogens; a cycloakyloxy group, optionally substituted by one or more alkyl groups and / or halogens; a phenyl group, optionally substituted by one or more alkyl groups and / or halogens; or a substituted or unsubstituted amino group, such as dialkylamino groups, such as a dimethylamino group (-N(CH3)2). Preferably, R4is selected from a hydrogen atom and a C1-C4 alkyl group substituted by 1 to 3 fluorine atoms; or a heterocyclyl group substituted by one or more alkyl groups and / or halogens. More preferably, R4is selected from a hydrogen atom and a C1-C4 alkyl group substituted by 1 to 3 fluorine atoms. Even more preferably, R4represents a hydrogen atom.

[0165]

[0091] In some embodiments, the present invention provides compounds of formula (II) or (IV), supra, or a pharmaceutically acceptable salt thereof, in which R5is selected from H; an alkyl group, such as a C1-C4 alkyl group, optionally substituted by 1 to 3 fluorine atoms; a cycloalkyl group, optionally substituted by one or more alkyl groups and / or halogens; a 4- to 6-member heterocyclyl group, optionally substituted by one or more alkyl groups, oxo groups and / or halogens; a halogen; an alkoxy group, such as a C1-C4 alkoxy group; a cycloakyloxy group, optionally substituted by one or more alkyl groups and / or halogens; a phenyl group, optionally substituted by one or more alkyl groups and / or halogens; or a substituted or unsubstituted amino group, such as dialkylamino groups, such as a dimethylamino group (-N(CH3)2.

[0166]

[0092] In a particular embodiment, the present invention provides compounds of formula (II) or (IV), supra, or a pharmaceutically acceptable salt thereof, in which R5is selected from a hydrogen atom and a halogen atom. Preferably, R5represents a hydrogen atom.

[0167]

[0093] In some embodiments, the present invention provides compounds of formula (II) or (IV), supra, or a pharmaceutically acceptable salt thereof, in which R1and R3taken together, form a cycloalkyl group, a heterocycloalkyl group such as a 5- or 6-member heterocycloalkyl group or an heteroaromatic ring or a cycloalkyl group such as a 5- or 6- member cycloalkyl group, optionally substituted by one or more alkyl groups and / or halogens; while the remaining R2, R4, and R5, each independently, represent H; an alkyl group, optionally substituted by 1 to 3 fluorine atoms; a cycloalkyl group, optionally substituted by one or more alkyl groups and / or halogens; a 4- to 6-member heterocyclyl group, optionally substituted by one or more alkyl groups, oxo groups and / or halogens; a halogen; an alkoxy group such as a C1-C4 alkoxy group; a cycloakyloxy group, optionally substituted by one or more alkyl groups and / or halogens; a phenyl group, optionally substituted by one or more alkyl groups and / or halogens; or a substituted or unsubstituted amino group, such as dialkylamino groups, such as a dimethylamino group (-N(CH3)2).

[0168]

[0094] In some embodiments, the present invention provides compounds of formula (II) or (IV), supra, or a pharmaceutically acceptable salt thereof, in which R2and R4taken together, form a cycloalkyl group, a heterocycloalkyl group such as a 5- or 6-member heterocycloalkyl group or an heteroaromatic ring or a cycloalkyl group such as a 5- or 6- member cycloalkyl group, optionally substituted by one or more alkyl groups and / or halogens; while the remaining R1, R3, and R5, each independently, represent H; an alkyl group, optionally substituted by 1 to 3 fluorine atoms; a cycloalkyl group, optionally substituted by one or more alkyl groups and / or halogens; a 4- to 6-member heterocyclyl group, optionally substituted by one or more alkyl groups, oxo groups and / or halogens; a halogen; an alkoxy group, such as a C1-C4 alkoxy group; a cycloakyloxy group, optionally substituted by one or more alkyl groups and / or halogens; a phenyl group, optionally substituted by one or more alkyl groups and / or halogens; or a substituted or unsubstituted amino group, such as dialkylamino groups, such as a dimethylamino group (-N(CH3)2).

[0169]

[0095] In some embodiments, the present invention provides compounds of formula (II) or (IV), supra, or a pharmaceutically acceptable salt thereof, in which R4and R5taken together, form a cycloalkyl group, a heterocycloalkyl group such as a 5- or 6-member heterocycloalkyl group or an heteroaromatic ring or a cycloalkyl group such as a 5- or 6- member cycloalkyl group, optionally substituted by one or more alkyl groups and / or halogens; while the remaining R1, R2, and R3, each independently, represent H; an alkyl group, optionally substituted by 1 to 3 fluorine atoms; a cycloalkyl group, optionally substituted by one or more alkyl groups and / or halogens; a 4- to 6-member heterocyclyl group, optionally substituted by one or more alkyl groups, oxo groups and / or halogens; a halogen; an alkoxy group such as a C1-C4 alkoxy group; a cycloakyloxy group, optionally substituted by one or more alkyl groups and / or halogens; a phenyl group, optionally substituted by one or alkyl groups and / or halogens; or a substituted or unsubstituted amino group, such as dialkylamino groups, such as a dimethylamino group (-N(CH3)2).

[0170]

[0096] In some embodiments, the present invention provides compounds of formula (II) or (IV), supra, or a pharmaceutically acceptable salt thereof, in which R3and R5taken together, form a cycloalkyl group, a heterocycloalkyl group such as a 5- or 6-member heterocycloalkyl group or an heteroaromatic ring or a cycloalkyl group, such as a 5- or 6- member cycloalkyl group, optionally substituted by one or more alkyl groups and / or halogens; while the remaining R1, R2, and R4, each independently, represent H; an alkyl group, optionally substituted by 1 to 3 fluorine atoms; a cycloalkyl group, optionally substituted by one or more alkyl groups and / or halogens; a 4- to 6-member heterocyclyl group, optionally substituted by one or more alkyl groups, oxo groups and / or halogens; a halogen; an alkoxy group, such as a C1-C4 alkoxy group; a cycloakyloxy group, optionally substituted by one or more alkyl groups and / or halogens; a phenyl group, optionally substituted by one or more alkyl groups and / or halogens; or a substituted or unsubstituted amino group, such as dialkylamino groups, such as a dimethylamino group (-N(CH3)2).

[0171]

[0097] In some embodiments, the present invention provides compounds of formula (III) or (IV), supra, or a pharmaceutically acceptable salt thereof, in which n and m each independently represent 0 or 1. For example, n represents 1 and m represents 0. Preferably, n represents 1 and m represents 1. More preferably, n represents 0 and m represents 0. Even more preferably, n represents 0 and m represents 1.

[0172]

[0098] In some embodiments, the present invention provides compounds of formula (III) or (IV), supra, or a pharmaceutically acceptable salt thereof, in which one of R6and R7taken together with any of R8, R9, R10or R11form a cyclic group such as a 3- to 6- cycloalkyl group, optionally substituted by one or more alkyl groups and / or halogens; while the other one of R6and R7, when not involved in the cyclic group, represents hydrogen or halogen. Preferably, R6and R7, each independently represent hydrogen; halogen; Ci-Ce alkyl group, optionally substituted by one or more halogens; C2-C6 alkenyl group, optionally substituted by one or more halogens; or Ci-Ce alkoxy group, optionally substituted by one or more halogens. More preferably, R6and R7, represent hydrogen.

[0173]

[0099] In some embodiments, the present invention provides compounds of formula (III) or (IV), supra, or a pharmaceutically acceptable salt thereof, in which R8and R9taken together, or one of R8and R9taken together with any of R10or R11, form a cyclic group, such as a 3- to 6-cycloalkyl group, optionally substituted by one or more alkyl groups and / or halogens; while the other one of R8and R9, when not involved in the cyclic group, represents hydrogen or halogen. Preferably, R8and R9, each independently, represent hydrogen; halogen; Ci-Ce alkyl group, optionally substituted by one or more halogens; C2- Ce alkenyl group, optionally substituted by one or more halogens; or Ci-Ce alkoxy group, optionally substituted by one or more halogens. More preferably, R8and R9, represent hydrogen.

[0174]

[0100] In some embodiments, the present invention provides compounds of formula (III) or (IV), supra, or a pharmaceutically acceptable salt thereof, in which R8and R9, when not involved in a cyclic group with R6or R7, each independently represent hydrogen; halogen; Ci-Ce alkyl group, optionally substituted by one or more halogens; C2-C6 alkenyl group, optionally substituted by one or more halogens; or Ci-Ce alkoxy group, optionally substituted by one or more halogens. In some embodiments, the present invention provides compounds of formula (III) or (IV), supra, in which one of R10and R11taken together with any of R15or R16form a cyclic group such as a 3- to 6-cycloalkyl group, optionally substituted by one or more alkyl groups and / or halogens; while the other one of R10and R11, when not involved in the cyclic group, represents hydrogen or halogen. Preferably, R10and R11, each independently, represent hydrogen; halogen; Ci-Ce alkyl group, optionally substituted by one or more halogens; C2-C6 alkenyl group, optionally substituted by one or more halogens; or Ci-Ce alkoxy group, optionally substituted by one or more halogens. More preferably, R10and R11, represent hydrogen.

[0175]

[0101] In some embodiments, the present invention provides compounds of formula (III) or (IV), supra, or a pharmaceutically acceptable salt thereof, in which R10and R11, taken together form a cyclic group such as a 3- to 6-cycloalkyl group, optionally substituted by one or more alkyl groups and / or halogens; or R10and R11, when not involved in a cyclic group, each independently represent hydrogen; halogen; Ci-Ce alkyl group, optionally substituted by one or more halogens; C2-C6 alkenyl group, optionally substituted by one or more halogens; or Ci-Ce alkoxy group, optionally substituted by one or more halogens.

[0176]

[0102] In some embodiments, the present invention provides compounds of formula (III) or (IV), supra, or a pharmaceutically acceptable salt thereof, in which X1represents CR15R16, wherein R15taken together with any R10or R11form a cyclic group such as a 3- to 6-cycloalkyl group, optionally substituted by one or more alkyl groups and / or halogens, while R16represents a hydrogen, an alkyl group, or a halogen such as fluorine. Preferably, X1represents an oxygen atom or a sulfur atom or CR15R16, wherein R15and R16each independently represent a hydrogen, an alkyl group, or a halogen such as fluorine. More preferably, X1represents CR15R16, wherein R15and R16each independently represent a hydrogen, an alkyl group, or a halogen such as fluorine.

[0177]

[0103] In some embodiments, the present invention provides compounds of formula (III) or (IV), supra, or a pharmaceutically acceptable salt thereof, in which X1represents CR15R16, R15and R16taken together form a cyclic group such as a 3- to 6-cycloalkyl group, optionally substituted by one or more alkyl groups and / or halogens.

[0178]

[0104] In some embodiments, the present invention provides compounds of formula (III) or (IV), supra, or a pharmaceutically acceptable salt thereof, in which R12and R13each independently represent a hydrogen or an alkyl group.

[0179]

[0105] In some embodiments, the present invention provides compounds of formula (III) or (IV), supra, or a pharmaceutically acceptable salt thereof, in which R14represents a hydrogen; a halogen; a Ci-Ce alkyl group, optionally substituted by one or more halogens; a Ci-Ce alkoxy group, optionally substituted by one or more halogens; or a heteroaryl group, preferably a 5- or 6-member heteroaryl group, connected to the substituted benzofused oxygen containing heterocyclic group of B through a spacer chosen from a C1-C4 alkylene chain, or a single oxygen atom. Preferably, R14represents a hydrogen; a halogen; or a heteroaryl group, such as a 5- or 6-member heteroaryl group, connected to the substituted benzo-fused oxygen containing heterocyclic group of B through a spacer chosen from a C1-C4 alkylene chain, or a single oxygen atom. More preferably, R14represents a heteroaryl group, such as a 5- or 6-member heteroaryl group, connected to the benzene ring of the substituted benzo-fused oxygen containing heterocyclic group of B through a spacer chosen from a C1-C4 alkylene chain, or a single oxygen atom. Even more preferably, R14represents a 5- or 6-member heteroaryl group, such as a pyrazole, connected to the benzene ring of the substituted benzo-fused oxygen containing heterocyclic group of B through -CH2-.

[0180]

[0106] In a particular embodiment, the present invention provides compounds of formula (III) or (IV), supra, or a pharmaceutically acceptable salt thereof, in which R14represents - CH2-heteroaryl group or -O-heteroaryl group in which the heteroaryl group is preferably a 5- to 6- member heteroaryl such as pyrazole, oxazole, isoxazole, thiazole or pyridine.

[0181]

[0107] In some embodiments, a compound of Formula (I) or Formula (II), or pharmaceutically acceptable salt thereof, is a compound of Formula (Ila): or a pharmaceutically acceptable salt thereof, wherein B, R2, R4, and R5, are selected as previously described; and R22and R23, each independently, represent H; or an alkyl group.

[0182]

[0108] In some embodiments, a compound of Formula (I) or Formula (II), or pharmaceutically acceptable salt thereof, is a compound of Formula (lib): or a pharmaceutically acceptable salt thereof, wherein B, R2, R3, R4, and R5, are selected as previously described; and wherein R17represents an alkyl group or a cycloalkyl group.

[0109] In some embodiments, a compound of Formula (I) or Formula (II), or pharmaceutically acceptable salt thereof, is a compound of Formula (llb-1): or a pharmaceutically acceptable salt thereof, wherein B, R2, R3, R4, and R5, are selected as previously described.

[0183]

[0110] In some embodiments, a compound of Formula (I) or Formula (II), or pharmaceutically acceptable salt thereof, is a compound of Formula (He): or a pharmaceutically acceptable salt thereof, wherein B and R4, are selected as previously described; and wherein R17represents an alkyl group or a cycloalkyl. Preferably, R4represents a hydrogen atom; or a C1-C4 alkyl group substituted by 1 to 3 fluorine atoms; or a heterocyclyl group substituted by one or more alkyl groups and / or halogens.

[0184]

[0111] In some embodiments, a compound of Formula (I) or Formula (II), or pharmaceutically acceptable salt thereof, is a compound of Formula (llc-1): or a pharmaceutically acceptable salt thereof, wherein B and R4are selected as previously described.

[0112] In some embodiments, a compound of Formula (I) or Formula (II), or pharmaceutically acceptable salt thereof, is a compound of Formula (lid): or a pharmaceutically acceptable salt thereof, wherein B, R3, R4, and R5, are selected as previously described; and wherein R17and R18represents, each independently, an alkyl group or a cycloalkyl group.

[0185]

[0113] In some embodiments, a compound of Formula (I) or Formula (II), or pharmaceutically acceptable salt thereof, is a compound of Formula (He): or a pharmaceutically acceptable salt thereof, wherein B is selected as previously described; and wherein R17and R18represents, each independently, an alkyl group or a cycloalkyl group.

[0186]

[0114] In some embodiments, a compound of Formula (I) or Formula (II), or pharmaceutically acceptable salt thereof, is a compound of Formula (lle-1): or a pharmaceutically acceptable salt thereof, wherein B is selected as previously described.

[0187]

[0115] In some embodiments, a compound of Formula (I) or Formula (II), or pharmaceutically acceptable salt thereof, is a compound of Formula (Ilf): or a pharmaceutically acceptable salt thereof, wherein B, R1, R2, R3, and R5, are selected as previously described; and wherein Y represents a substituted or unsubstituted amino group, such as dialkylamino groups, such as a dimethylamino group (-N(CH3)2); or a 4- to 6-member heterocyclyl group, such as azetidine or pyrrolidine, optionally substituted by one or more alkyl groups, oxo groups and / or halogens.

[0188]

[0116] In some embodiments, a compound of Formula (I) or Formula (II), or pharmaceutically acceptable salt thereof, is a compound of Formula (llf-1): or a pharmaceutically acceptable salt thereof, wherein B, R1, R2, R3, and R5, are selected as previously described; and wherein R19and R20represents, each independently, an alkyl group.

[0189]

[0117] In some embodiments, a compound of Formula (I) or Formula (II), or pharmaceutically acceptable salt thereof, is a compound of Formula (llf-2): or a pharmaceuticall are selected as previously described; R21represents a halogen or an oxo group, and p is 0, 1 , 2, or 3; q is 1 or 2.

[0118] In some embodiments, a compound of Formula (I) or Formula (II), or pharmaceutically acceptable salt thereof, is a compound of Formula (llg): or a pharmaceutically acce are selected as previously described; X2represents an oxygen atom or a CH2 group.

[0190]

[0119] In some embodiments, a compound of Formula (I) or Formula (II), or pharmaceutically acceptable salt thereof, is a compound of Formula (llh): or a pharmaceutically acceptable salt thereof, wherein B, R1, R2, and R3, are selected as previously described; X3and X4each independently represent an oxygen atom or a -CH2-.

[0191]

[0120] In some embodiments, a compound of Formula (I) or Formula (II), or pharmaceutically acceptable salt thereof, is a compound of Formula (Hi): or a pharmaceutically acceptable salt thereof, wherein B, R1, R2, and R3, are selected as previously described; X3and X4each independently represent an oxygen atom or -CH2-.

[0192]

[0121] In some embodiments, a compound of Formula (I) or Formula (III), or pharmaceutically acceptable salt thereof, is a compound of Formula (Illa): or a pharmaceutically acceptable salt thereof, wherein A, X1, R6, R7, R8, R9, R10, R11, and

[0193] R14, are selected as previously described; n and m each independently represent 0 or 1.

[0194]

[0122] In some embodiments, a compound of Formula (I) or Formula (III), or pharmaceutically acceptable salt thereof, is a compound of Formula (lllb): or a pharmaceutically acceptable salt thereof, wherein A, X1, R6, R7, R8, R9, R10, and R11are selected as previously described; n and m each independently represent 0 or 1.

[0195]

[0123] In some embodiments, a compound of Formula (I) or Formula (III), or pharmaceutically acceptable salt thereof, is a compound of Formula (lllc): or a pharmaceutically acceptable salt thereof, wherein A, and R14, are selected as previously described; n and m each independently represent 0 or 1.

[0196]

[0124] In some embodiments, a compound of Formula (I) or Formula (III), or pharmaceutically acceptable salt thereof, is a compound of Formula (Hid): or a pharmaceutically acceptable salt thereof, wherein A, R8, R9, R10, R11, and R14, are selected as previously described; n and m each independently represent 0 or 1.

[0197]

[0125] In some embodiments, a compound of Formula (I) or Formula (III), or pharmaceutically acceptable salt thereof, is a compound of Formula (Hie): or a pharmaceutically acceptable salt thereof, wherein A, R6, R7, R8, R9, R10, R11, and R14, are selected as previously described; n and m each independently represent 0 or 1.

[0198]

[0126] In some embodiments, a compound of Formula (I) or Formula (III), or pharmaceutically acceptable salt thereof, is a compound of Formula (lllf): or a pharmaceutically acceptable salt thereof, wherein A, X1, and R14are selected as previously described.

[0199]

[0127] In some embodiments, a compound of Formula (I) or Formula (III), or pharmaceutically acceptable salt thereof, is a compound of Formula (lllf-1): or a pharmaceutically acceptable salt thereof, wherein A and R14, are selected as previously described.

[0200]

[0128] In some embodiments, a compound of Formula (I) or Formula (III), or pharmaceutically acceptable salt thereof, is a compound of Formula (lllf-2): or a pharmaceutically acceptable salt thereof, wherein A and R14, are selected as previously described.

[0201]

[0129] In some embodiments, a compound of Formula (I) or Formula (IV), or pharmaceutically acceptable salt thereof, is a compound of Formula (IVa): or a pharmaceutically acceptable salt thereof, wherein R2, R4, R5, R6, R7, R8, R9, R10, R11, R22, R23, and X1, are selected as previously described; n and m each independently represent 0 or 1.

[0130] In some embodiments, a compound of Formula (I) or Formula (IV), or pharmaceutically acceptable salt thereof, is a compound of Formula (IVb): or a pharmaceutically acceptable salt thereof, wherein R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R18and X1, are selected as previously described; n and m each independently represent 0 or 1.

[0202]

[0131] In some embodiments, a compound of Formula (I) or Formula (IV), or pharmaceutically acceptable salt thereof, is a compound of Formula (IVc): or a pharmaceutically acceptable salt thereof, wherein R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R17, R18and X1, are selected as previously described; n and m each independently represent 0 or 1.

[0203]

[0132] In some embodiments, a compound of Formula (I) or Formula (IV), or pharmaceutically acceptable salt thereof, is a compound of Formula (IVd): or a pharmaceutically acceptable salt thereof, wherein R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R18and X1, are selected as previously described; n and m each independently represent 0 or 1.

[0204]

[0133] In some embodiments, a compound of Formula (I) or Formula (IV), or pharmaceutically acceptable salt thereof, is a compound of Formula (IVe): or a pharmaceutically acceptable salt thereof, wherein R3, R4, R5, R6, R7, R8, R9, R10, R11, R17, R18and X1, are selected as previously described; n and m each independently represent 0 or 1.

[0205]

[0134] In some embodiments, a compound of Formula (I) or Formula (IV), or pharmaceutically acceptable salt thereof, is a compound of Formula (IVf): or a pharmaceutically acceptable salt thereof, wherein R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, and X1, are selected as previously described; n and m each independently represent

[0206] 0 or 1.

[0207]

[0135] In some embodiments, a compound of Formula (I), (II), (III), and / or (IV), or a pharmaceutically acceptable salt thereof, is a compound wherein the compound has the structure of a compound shown in Table 1 , or a pharmaceutically acceptable salt thereof.

[0208] Table 1

[0209] Pharmaceutical Compositions

[0210]

[0136] The present invention relates to pharmaceutical compositions comprising at least one active compound of Formula (I), (II), (Ila), (lib), (llb-1), (lie), (llc-1), (lid), (He), (lle-1), (Ilf), (Hf-1), (llf-2), (llg), (llh), (Hi), (HI), (Illa), (Illb), (lllc), (Hid), (Hie), (Hlf), (Hlf-1), (Hlf-2), (IV), (IVa), (IVb), (IVc), (IVd), (IVe), (IVf) or a pharmaceutically acceptable salt thereof. These compositions are formulated with one or more pharmaceutically acceptable excipients suitable for human or animal use, aiming to provide effective treatment for cancer and related disorders.

[0211]

[0137] The compounds of the present invention may be administered alone or in combination with various pharmaceutically acceptable carriers, adjuvants, diluents, fillers, buffers, stabilizers, preservatives, lubricants, or other materials commonly used in pharmaceutical formulations. These excipients are typically approved by regulatory authorities or are generally regarded as safe for human or animal use.

[0212]

[0138] Pharmaceutically acceptable excipients include, but are not limited to, carriers such as lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, and starch; diluents like water or other solvents; glidants and lubricants such as talc, magnesium stearate, and stearic acid; preservatives like methylparaben and propylparaben; buffering agents; chelating agents; polymers; gelling agents; viscosifying agents; and solvents. Auxiliary agents may also be included, such as wetting agents, suspending agents, sweetening agents, flavoring agents, colorants, and any combination thereof.

[0213]

[0139] The pharmaceutical compositions can be prepared in various conventional forms, including tablets, capsules (soft or hard gelatin), dragees, troches, lozenges, solutions, suspensions, injectables, ointments, pastes, creams, lotions, powders, eye or ear drops, impregnated textiles, and products for topical application. These compositions may also be formulated to provide a desired release profile, such as immediate or controlled release.

[0214]

[0140] In particular, the dosage forms for these compositions can take various conventional forms, including but not limited to: solid dosage forms, liquid dosage forms, injectable preparations, transdermal forms, rectal and vaginal formulations and powders and sprays.

[0215]

[0141] Solid dosage forms can for example be selected among: tablets, capsules (soft or hard gelatin), dragees, troches, and lozenges. Tablets can be prepared by compression or molding techniques and may contain binders (e.g., povidone, gelatin), fillers or diluents (e.g., lactose, microcrystalline cellulose), lubricants (e.g., magnesium stearate), disintegrants (e.g., sodium starch glycolate), and preservatives. Capsules can be filled with the active compound in powder or pellet form along with appropriate excipients. The active compounds can also be formulated into microencapsulated forms with excipients. Solid dosage forms may have coatings such as enteric coatings or release-controlling coatings to modify the release profile of the active compound. Buffering agents may be included to maintain the stability of the active compound.

[0216]

[0142] Liquid dosage forms can for example include emulsions, microemulsions, solutions, and suspensions designed for oral administration. These formulations may contain inert diluents like water, solubilizing agents, and emulsifiers such as ethyl alcohol, isopropyl alcohol, and various oils (e.g., cottonseed, olive, castor oils). Adjuvants like wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents, and perfuming agents may also be included

[0217]

[0143] Injectable preparations such as sterile aqueous or oleaginous suspensions are generally formulated using dispersing, wetting, or suspending agents. Sterile injectable solutions, suspensions, or emulsions can be prepared in nontoxic, parenterally acceptable diluents or solvents like water, Ringer's solution, or isotonic sodium chloride solution.

[0218] Fixed oils such as synthetic mono- or diglycerides and fatty acids like oleic acid may be used as solvents or suspending media.

[0219]

[0144] Topical and transdermal forms comprise compositions such as ointments, pastes, creams, lotions, gels, solutions, sprays, and transdermal patches. These may be formulated with suitable fats, oils, waxes, or polymers to achieve desired topical or transdermal absorption rates. Patches may also employ rate-controlling membranes or polymer matrices to control the release of the active compounds.

[0220]

[0145] Rectal and vaginal formulations may be in the form of suppositories or gels, incorporating the active compounds into bases such as cocoa butter, polyethylene glycol, or other suitable non-irritating materials.

[0221]

[0146] Powders and Sprays, for topical or inhalation use, may be prepared as powders or aerosol sprays. Propellants like chlorofluorohydrocarbons may be used for spray formulations.

[0222]

[0147] The formulation process for these compositions follows conventional pharmaceutical techniques, ensuring uniform mixing of the active compound with the chosen excipients. Manufacturing steps may include granulation, encapsulation, or coating, depending on the desired release characteristics of the final product. Controlled- release formulations can be achieved through the application of suitable coatings or matrix systems that modulate the release profile of the active ingredient.

[0223] Administration and dosage

[0224]

[0148] The compounds of the present invention, including their pharmaceutically acceptable salts, may be administered to patients using various routes, depending on the nature of the disease, the desired therapeutic effect, and the formulation of the pharmaceutical composition. The choice of administration route and dosage form ensures that the active compounds are delivered effectively to the intended site of action with an appropriate pharmacokinetic profile, taking into consideration factors like bioavailability, absorption rate, and patient compliance. Suitable routes of administration include oral, nasal, buccal, dermal, intradermal, transdermal, parenteral (including intravenous, intramuscular, and subcutaneous), rectal, intraurethral, and topical applications.

[0225]

[0149] The compound described herein may be administered to a subject in an effective amount to achieve the desired therapeutic effect. The appropriate dosage and dosing regimen can vary based on several factors, including the activity of the compound, the route and timing of administration, the rate of excretion, the duration of treatment, any concurrent medications, the severity of the condition being treated, and characteristics of the patient such as species, sex, age, weight, general health, and medical history. Determining the optimal dosage involves balancing the therapeutic benefits against potential risks or side effects and is ultimately at the discretion of the treating physician.

[0226]

[0150] Administration of the compound can be performed in a single dose or multiple doses, either continuously or intermittently throughout the course of treatment. The compound may be administered via any convenient route, whether systemically or at the site of desired action. Routes of administration include, but are not limited to, oral ingestion; topical application (such as transdermal, intranasal, ocular, buccal, and sublingual routes); pulmonary delivery via inhalation or insufflation therapy using an aerosol through the mouth or nose; rectal or vaginal administration; and parenteral routes, including various forms of injection such as subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intraarticular, subarachnoid, intravitreal, and intrasternal injections. Additionally, the compound may be administered through the implantation of a depot, for example, subcutaneously, intramuscularly, or intravitreally.

[0227]

[0151] The dosing frequency may vary depending on the needs of the patient and the judgment of the physician. A single dose may be administered hourly, daily, or weekly. For instance, administration may occur once every 1 hour, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 12 hours, 16 hours, or once every 24 hours. Alternatively, the compound may be administered once every 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, or once every 7 days. In some cases, the compound may be administered once every week, every two weeks, every three weeks, or once every four weeks. In certain embodiments, administration may occur once every month. The dosage and frequency may be adjusted over the course of treatment based on the patient's response and any side effects experienced.

[0228]

[0152] Therapeutically effective amounts of the compound generally range from about 0.00001 mg / kg to about 10 mg / kg of body weight per day. More specific dosage ranges include from about 0.0001 mg / kg to about 10 mg / kg per day, from about 0.001 mg / kg to about 1 mg / kg per day, from about 0.01 mg / kg to about 1 mg / kg per day, and from about 0.05 mg / kg to about 0.5 mg / kg per day. Alternatively, the compound may be administered in doses ranging from about 0.01 mg to about 1000 mg per dose. Examples of therapeutically effective amounts include doses from about 0.01 mg to about 100 mg, from about 0.1 mg to about 100 mg, from about 1 mg to about 100 mg, from about 1 mg to about 50 mg, and from about 1 mg to about 10 mg per dose. Specific dose amounts may be about 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, or about 100 mg per dose. Higher doses may include about 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 350 mg, 400 mg, 450 mg, or about 500 mg per dose.

[0229]

[0153] In specific embodiments, the compound may be administered to a human patient according to the following dosage regimens: about 5 mg or about 10 mg administered three or four times daily; about 20 mg or about 40 mg administered three or four times daily; about 50 mg or about 75 mg administered three or four times daily; about 100 mg or about 125 mg administered twice daily; about 100 mg administered three times daily; about 150 mg administered twice daily; or about 200 mg administered twice daily.

[0230]

[0154] The duration of treatment may vary depending on the condition being treated and the patient's response. Treatment may be administered for at least about one week, at least about two weeks, at least about three weeks, one month, at least about two months, at least about three months, at least about six months, at least about twelve months, or potentially extending for the lifetime of the individual. The dosage or dosing frequency may be adjusted over the course of treatment based on the patient's response and the judgment of the administering physician.

[0231]

[0155] In some cases, the active compounds of the present invention may be administered in combination with other therapeutic agents, such as chemotherapeutic drugs, immunotherapy agents, or radiation therapy, for a synergistic effect in treating diseases such as cancer. The combination therapy may be administered concurrently, sequentially, or as a fixed-dose combination, with careful consideration given to potential interactions and the pharmacokinetics of the combined agents.

[0232] Methods and uses

[0233]

[0156] The present invention relates to methods and uses concerning the treatment of diseases and disorders, for example hyperproliferative disorders, particularly cancer, by administering therapeutically effective amounts of compounds of Formula (I), (II), (Ila), (lib), (llb-1), (He), (llc-1), (lid), (lie), (lle-1), (Ilf), (llf-1), (llf-2), (llg), (llh), (Hi), (HI), (Illa), (Illb), (lllc), (Hid), (Hie), (Hlf), (Hlf-1), (Hlf-2), (IV), (IVa), (IVb), (IVc), (IVd), (IVe), (IVf) or their pharmaceutically acceptable salts. These compounds are valuable as medicaments for treating conditions mediated by KAT6A, a histone acetyltransferase implicated in cancer progression.

[0234]

[0157] The pharmaceutical compositions of the present invention are intended for use as medicaments for example in the treatment of hyperproliferative disorders, in particular in cancer and related disorders. The active compounds may be formulated to provide a therapeutically effective amount sufficient to achieve the desired therapeutic benefit without causing unwanted side effects. Dosages and modes of administration can be determined and adjusted by healthcare professionals based on factors like the type and severity of the disease, patient characteristics, and preliminary evidence from clinical studies.

[0235]

[0158] The compounds of the present invention effectively inhibit KAT6A activity, thereby modulating pathological processes associated with KAT6A-mediated diseases. Inhibition of KAT6A can suppress cancer cell growth and proliferation, making these compounds significant therapeutic agents in oncology.

[0236]

[0159] Cancers that can be treated using these compounds encompass a wide range, including but not limited to brain gliomas, glioblastomas, astrocytomas, multiforme, Bannayan-Zonana syndrome, Cowden disease, Lhermitte-Duclos disease, breast cancer (such as estrogen receptor-positive [ER+] breast cancer, ER+ HER2- breast cancer, and locally advanced or metastatic ER+ HER2- breast cancer), colon cancer, head and neck cancer, kidney cancer, liver cancer, lung cancer (including non-small cell lung cancer and locally advanced or metastatic non-small cell lung cancer), bone cancer, colorectal cancer, germ cell cancer, melanoma, ovarian cancer, pancreatic cancer, adenocarcinomas (including ductal and adenosquamous carcinoma), acinar cell carcinoma, glucagonoma, insulinoma, prostate cancer (including castration-resistant forms and locally advanced or metastatic cases), sarcoma, thyroid cancer, various leukemias (such as lymphoblastic T cell leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia, hairy-cell leukemia, acute lymphoblastic leukemia, acute myelogenous leukemia, chronic neutrophilic leukemia, plasmacytoma, mantle cell leukemia, megakaryoblastic leukemia, multiple myeloma, promyelocytic leukemia, erythroleukemia), malignant lymphomas (including Hodgkin’s and non-Hodgkin’s lymphoma, Burkitt’s lymphoma, follicular lymphoma), neuroblastoma, bladder cancer, urothelial cancer, vulval cancer, uterine cancer, cervical cancer, endometrial cancer, renal cancer, mesothelioma, esophageal cancer, salivary gland cancer, hepatocellular cancer, gastric cancer, nasopharyngeal cancer, buccal cancer, cancers of the mouth, gastrointestinal stromal tumors (GIST), neuroendocrine cancers, testicular cancer, and virus-related cancers.

[0237]

[0160] Moreover, the compounds may be used in treating other disorders associated with abnormal cell growth, such as benign proliferative diseases including psoriasis, benign prostatic hypertrophy, or restenosis. They may also be applied in methods of treating disorders associated with angiogenesis, such as age-related macular degeneration, proliferative diabetic retinopathy, rheumatoid arthritis, osteoporosis, Paget's disease, humoral hypercalcemia of malignancy, coronary restenosis, and certain microbial infections.

[0238]

[0161] In more preferred embodiment, the compounds of the invention are used in treating or preventing a disease selected among: breast cancer(such as estrogen receptor-positive [ER+] breast cancer, ER+ HER2- breast cancer, and locally advanced or metastatic ER+ HER2- breast cancer), prostate cancer, ovarian cancer, cervical cancer, lung adenocarcinoma, colon and rectal adenocarcinomas, medulloblastoma, glioblastoma and blood cancer such as acute myeloid leukaemia. In more preferred embodiment, the invention relates to a method for treating or prophylaxis of a disease selected from a KATs overexpressing cancer.

[0239]

[0162] One embodiment of the invention provides a pharmaceutical composition comprising a compound of any of the aforementioned formulas, or a pharmaceutically acceptable salt thereof, for use in the treatment, management, or prophylaxis of a disease, disorder, or condition in a subject.

[0240]

[0163] The subject is typically a human in need of such treatment. The diseases or disorders targeted include those mediated by KAT6A, with a particular focus on various forms of cancer.

[0241]

[0164] One embodiment of the invention provides a method of treating, managing, or preventing a disease, disorder, or condition in a subject by administering a therapeutically effective amount of a compound of any of the aforementioned formulas, or a pharmaceutically acceptable salt thereof.

[0242] Combination therapy

[0243]

[0165] Compounds of Formula (I), (II), (Ila), (lib), (llb-1), (He), (llc-1), (lid), (lie), (lle-1), (Ilf), (llf-1), (llf-2), (llg), (llh), (Hi), (III), (Illa), (lllb), (lllc), (Hid), (Hie), (lllf), (Hlf-1), (Hlf-2), (IV), (IVa), (IVb), (IVc), (IVd), (IVe), (IVf) or their pharmaceutically acceptable salts described herein may be used in combination with other therapeutic agents for the treatment of diseases such as cancer. These compounds can be administered alongside additional therapeutic agents, including chemotherapeutic agents, biological agents, targeted therapies, or agents that alleviate symptoms associated with the disease. The combination therapy may involve administering the compounds and additional agents either in a single pharmaceutical formulation or in separate formulations, delivered simultaneously or sequentially.

[0244]

[0166] The compounds may act synergistically with chemotherapy, radiotherapy, or targeted therapies, enhancing the overall therapeutic effect. For instance, they can be combined with fibroblast growth factor receptor 1 (FGFR1) inhibitors, nuclear hormone receptor-targeting therapies, or immune checkpoint inhibitors. Notably, the compounds may be used in conjunction with bromodomain and extraterminal domain (BET) inhibitors, which reversibly bind to the bromodomains of BET proteins BRD2, BRD3, BRD4, and BRDT.

[0245]

[0167] Inhibition of histone acetyltransferase (KAT) proteins of the MYST family by these compounds reduces lysine acetylation of histones and other nuclear proteins. This action sensitizes tumor cells to chemotherapy and radiotherapy by attenuating DNA damage repair processes, such as the repair of DNA double-strand breaks, thereby increasing the efficacy of cancer cell eradication induced by these therapies. Consequently, the compounds are expected to combine effectively with low-dose chemotherapy or radiotherapy.

[0246]

[0168] The compounds may be administered in conjunction with radiotherapeutic or chemotherapeutic regimens. Suitable chemotherapeutic agents include, but are not limited to, platinum compounds (e.g., cisplatin, carboplatin, oxaliplatin), alkylating agents (e.g., cyclophosphamide, ifosfamide), antitumor antibiotics (e.g., doxorubicin, bleomycin), taxanes (e.g., paclitaxel, docetaxel), antimetabolites (e.g., 5-fluorouracil, methotrexate), nucleoside analogues (e.g., fludarabine), and topoisomerase inhibitors (e.g., irinotecan). Suitable biological agents include monoclonal antibodies (e.g., rituximab, trastuzumab, bevacizumab), enzymes (e.g., L-asparaginase), cytokines (e.g., interferons, interleukins), growth factors, cancer vaccines, and gene therapy vectors.

[0247]

[0169] In scenarios where the compounds are used to abrogate regulatory T cell (Treg) suppression, they may be combined with immune checkpoint inhibitors, such as those targeting PD-1, PD-L1, or CTI.A-4, to enhance anti-tumor immunity. Additionally, combining these compounds with radiotherapy may further diminish Treg function within tumors, potentially improving therapeutic outcomes.

[0170] These treatment methods may be applied to subjects for whom other treatments have failed or have had limited success, such as those with cancers refractory to standard-of-care treatments. The compounds can be administered prior to, simultaneously with, or after other therapeutic modalities, including chemotherapy, surgery, hormone therapy, or radiation. The combinations described are illustrative and not limiting, and the compounds may be used with one or more additional agents to achieve the desired therapeutic effect.

[0248]

[0171] Combination therapies may involve co-administering the compounds with estrogen receptor antagonists or partial antagonists, aromatase inhibitors (e.g., letrozole), Selective Estrogen Receptor Modulators (SERMs) such as tamoxifen, endoxifene, raloxifene, toremifene, lasofoxifene, ospemifene, elacestrant, or bazedoxifene, and Selective Estrogen Receptor Degraders (SERDs) like fulvestrant, camizestrant, palazestrant, imlunestrant, elacestrant, or giredestrant. Complete Estrogen Receptor Antagonists (CERANs) such as fulvestrant or palazestrant can also be used in combination.

[0249]

[0172] Additionally, the compounds may be combined with other anti-cancer agents, including HER2 inhibitors (e.g., tucatinib, trastuzumab, pertuzumab, ado-trastuzumab emtansine, trastuzumab deruxtecan, lapatinib, neratinib), mTOR inhibitors (e.g., everolimus, sirolimus, temsirolimus, LY3023414), CDK4 / 6 inhibitors (e.g., palbociclib, abemaciclib, ribociclib, lerociclib, trilaciclib, SHR6390), CDK2 inhibitors (e.g., PF- 07104091), CDK4-selective inhibitors (e.g., PF-07220060), PI3 kinase inhibitors (e.g., perifosine, CAL101, BEZ235, XL147, XL765, GDC-0941 , IPI-145), PIK3CA inhibitors (e.g., alpelisib, taselisib, LY3023414, inavolisib, STX-478, RLY-2608, LOXO-783, OKI- 219, TOS-358), aromatase inhibitors (e.g., aminoglutethimide, testolactone, anastrozole, letrozole, exemestane, vorozole, formestane, fadrozole, 4-hydroxyandrostenedione, 1 ,4,6- androstatrien-3, 17-dione, 4-androstene-3,6, 17-trione), antibodies or inhibitors targeting PD-1 , PD-L1, or CTI.A-4, and inhibitors of EGFR, PGFR, or IGFR (e.g., erlotinib, gefitinib). LISP1 inhibitors and AKT inhibitors such as capivasertib are also suitable for combination therapy.

[0250]

[0173] The examples and preparations presented herein further illustrate and exemplify the compounds described, along with the methods for their preparation. It should be noted that the scope of the embodiments described is not limited in any way by these examples and preparations.

[0251]

[0174] In the following examples, unless otherwise specified, molecules with a single chiral center are provided as racemic mixtures. Molecules with two or more chiral centers are also presented as racemic mixtures of diastereomers unless stated otherwise. Methods for obtaining single enantiomers or diastereomers are well-known to those skilled in the art.

[0175] Unless otherwise explicitly stated, all atoms described in any formula or structure of this specification may exist in any of their stable isotopic forms or isotopic variant. In particular, any hydrogen (H) atom may be substituted by deuterium (2H) or tritium (3H). The term “isotopic variant,” as used herein, encompasses compounds in which one or more atoms are replaced by an atom having the same atomic number but a different atomic mass. All such isotopic variants are contemplated as included within the scope of the present invention and are expressly incorporated within the definition of the claimed compounds. In light of the descriptions provided herein, the compounds described herein can be prepared by processes known in the chemical arts. Specific processes for the manufacture of these compounds are included as additional features of the embodiments and are illustrated in the reaction schemes provided below and in the experimental section.

[0252] EXAMPLES

[0253]

[0176] The following examples are provided to illustrate specific embodiments of the invention and are not intended to limit the scope thereof. Variations and modifications will become apparent to those skilled in the art upon reading this specification. The full scope of the invention should be determined by the claims and their equivalents.

[0254] I. Synthesis of Sulfonamide Intermediates

[0255] Intermediate INTA-I : 2,6-dimethoxybenzenesulfonamide (Intermediate INTA-I)

[0256] Scheme SCHINTAI

[0257]

[0177] To a solution of 2,6-dimethoxybenzenesulfonyl chloride (2.62 g, 11.07 mmol) in DCM (25 mL) at room temperature was added 4M ammonia solution in MeOH (27.68 mL, 110.7 mmol). The reaction mixture was stirred at room temperature for 30 min. The solvent was removed under reduced pressure and water was added. The reaction mixture was filtered and the resulting solid was washed with acetonitrile. The solid was suspended in dry toluene and evaporated to dryness under reduced pressure to afford 2,6- dimethoxybenzenesulfonamide (Intermediate INTA-I) (1.80 g, 74 % yield) as a white solid. LCMS (ES, m / z): 218.1 [M+H]+.

[0258] Intermediate INTA-2: 2-methoxybenzenesulfonamide (Intermediate INTA-2) Scheme SCHINTA2. ,

[0259]

[0178] To a mixture of 2-methoxybenzenesulfonyl chloride (3.00 g, 14.51 mmol) in DCM (20 mL) at room temperature was added 4M ammonia solution in MeOH (18.14 mL, 72.59 mmol). The reaction mixture was stirred at room temperature for 16 h. The precipitate was filtered and washed with DCM. Water was added to the filtrate. After separation, the organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with cyclohexane / (ethyl acetate / ethanol 3:1) as eluent from 100 / 0 to 0 / 100 to afford 2-methoxybenzenesulfonamide (Intermediate INTA-2) (2.8 g, 98 % yield) as a beige solid. LCMS (ES, m / z): 188.2 [M+H]+.

[0260] Intermediate INTA-S: 2-methoxy-5-(trifluoromethyl)benzenesulfonamide (Intermediate IN TA-S )

[0261] Scheme SCH INTA3-

[0262]

[0179] To a mixture of 2-methoxy-5-(trifluoromethyl)benzenesulfonyl chloride (2.50 g, 9.10 mmol) in DCM (30 mL) at room temperature was added 4M ammonia solution in MeOH (22.8 mL, 91 mmol). The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated to dryness under reduced pressure then diluted with water. The suspension was stirred for 10 min then filtered and dried to afford 2- methoxy-5-(trifluoromethyl)benzenesulfonamide (Intermediate INTA^S) (2.0 g, 82 % yield) as a white solid. LCMS (ES, m / z): 255.0 [M-H]+.

[0263] Intermediate INTA^: 5-(3-fluoroazetidin-1-yl)-2-methoxybenzenesulfonamide TFA salt (Intermediate INTA^I)

[0264] Scheme SCHINTA4

[0265]

[0180] Step 1 : To a mixture of 5-bromo-2-methoxybenzenesulfonyl chloride (4.83 g, 16.9 mmol) in DCM (84.6 mL) at room temperature was added 4M ammonia solution in MeOH (42.3 mL, 169 mmol). The reaction mixture was stirred at room temperature for 30 min. The reaction mixture was concentrated under reduced pressure then diluted with water. The suspension was stirred for 10 min then filtered and dried to afford 5-bromo-2- methoxybenzenesulfonamide (4.41 g, 93 % yield) as a white solid. LCMS (ES, m / z): 266.1-268.1 [M+H]+.

[0266]

[0181] Step 2: To a solution of 5-bromo-2-methoxybenzenesulfonamide (425 mg, 1.59 mmol) in DCM (15.9 mL) was added Et3N (668 pL, 4.79 mmol) and BOC2O (440 pL, 1.91 mmol). The reaction mixture was stirred at room temperature for 16 h. Water was added and the layers were separated. The organic one was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford tert- butyl ((5-bromo-2-methoxyphenyl)sulfonyl)carbamate (810 mg, Qte yield) as a clear oil which was engaged in the next step without further purification. LCMS (ES, m / z): 364.1- 366.1 [M-H]+.

[0267]

[0182] Step 3: A mixture of tert-butyl ((5-bromo-2-methoxyphenyl)sulfonyl)carbamate (585 mg, 1.59 mmol), 3-fluoroazetidine hydrochloride (712 mg, 6.38 mmol) and cesium carbonate (4.16 g, 12.7 mmol) in dioxane (15.9 mL) at room temperature was degassed with argon for 5 min. XPhos Pd G3 (202 mg, 239 pmol) was added. The reaction mixture was stirred at 110 °C for 6 h under MW irradiations. The reaction mixture was filtered, a saturated NH4CI aqueous solution and ethyl acetate were added and the resulting suspension was stirred for 30 min. The pH of the aqueous phase was adjusted to 2 by addition of 1 N HCI aqueous solution. After separation, the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated under pressure. The residue was purified by silica gel column chromatography eluting with cyclohexane / ethyl acetate from 100 / 0 to 50 / 50 to afford tert-butyl ((5-(3-fluoroazetidin-1-yl)-2-methoxyphenyl)sulfonyl)carbamate (400 mg, 69.5 % yield) as a yellowish oil. LCMS (ES, m / z): 361.2 [M+H]+.

[0268]

[0183] Step 4: To a mixture of tert-butyl ((5-(3-fluoroazetidin-1-yl)-2-methoxyphenyl) sulfonyl)carbamate (150 mg, 416 pmol) in DCM (8.3 mL) at 0°C was added TFA (274 pL, 4.16 mmol) portion wise. The reaction mixture was stirred at room temperature for 16 min. The reaction mixture was concentrated under reduced pressure and dried to afford 5-(3- fluoroazetidin-1-yl)-2-methoxybenzenesulfonamide TFA salt (Intermediate INTA-4) (185 mg, Qte yield) as a brown oil which was used in the next step without purification. LCMS (ES, m / z): 261.2 [M+H]+.

[0269] Intermediate INTA^: 5-(3-fluoroazetidin-1-yl)-2-methoxybenzenesulfonamide trifluoroacetic acid salt (Intermediate INTA^b)

[0270] Scheme SCHINTA -

[0271] Step 1 : A suspension of tert-butyl ((5-bromo-2-methoxyphenyl)sulfonyl)carbamate (Intermediate INTA-23) (585 mg, 1.59 mmol), 3-fluoroazetidine hydrochloride (712 mg, 6.38 mmol) and cesium carbonate (4.16 g, 12.7 mmol) in dioxane (15.9 mL) was degassed with argon for 5min. Then, XPhos Pd G3 (2.02 g, 239 pmol) was added. The reaction mixture was stirred at 110 °C for 6 h. The reaction mixture was filtered then saturated NH4CI aqueous solution and ethyl acetate were added. The resulting suspension was stirred at room temperature for 30 min. The pH of the aqueous phase was adjusted to 2 by addition of 1 N HCI aqueous solution. After separation, the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with cyclohexane / ethyl acetate from 100 / 0 to 50 / 50 to afford tert- butyl ((5-(3-fluoroazetidin-1-yl)-2-methoxyphenyl)sulfonyl)carbamate (400 mg, 69 % yield) as a yellow oil.

[0272] LCMS (ES, m / z): 361.2 [M-H]+.

[0273] Step 2: To a mixture of tert-butyl ((5-(3-fluoroazetidin-1-yl)-2-methoxyphenyl) sulfonyl)carbamate (150 mg, 416 pmol) in dichloromethane (8.3 mL) at 0°C was added TFA (274 pL, 4.16 mmol) portionwise. The reaction mixture was stirred at room temperature for 16 h. The solvent was removed under reduced pressure to afford 5-(3-fluoroazetidin-1-yl)- 2-methoxybenzenesulfonamide trifluoroacetic acid salt (Intermediate INTA^b) (145 mg, 93 % yield) as a brown oil.

[0274] LCMS (ES, m / z): 261.1 [M-H]+.

[0275] Intermediate INTA-S: 2-chloro-6-methoxyquinoline-7-sulfonamide (Intermediate INTA-

[0276] 5)

[0277] Scheme SCHINTAS

[0278]

[0184] To a mixture of 2-chloro-6-methoxyquinoline-7-sulfonyl chloride (1.0 g, 3.42 mmol) in DCM (17.1 mL) at room temperature was added 2M ammonia solution in MeOH (17.12 mL, 34.23 mmol). The reaction mixture was stirred at room temperature for 6 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by reverse phase Cis column chromatography eluted with water / acetonitrile from 100 / 0 to 25 / 75 to afford 2-chloro-6-methoxyquinoline-7-sulfonamide (Intermediate INTA-S) (920 mg, 98 % yield) as a white solid. LCMS (ES, m / z): 273.0 [M+H]+.

[0279] Intermediate INTA-6: 6-methoxyquinoline-7-sulfonamide (Intermediate INTA-B) Scheme SCHINTA6.

[0280]

[0185] Step 1 : To a solution of 2-chloro-6-methoxyquinoline-7-sulfonamide (Intermediate INTA-5) (410 mg, 1.28 mmol) in THF (12.8 mL) at room temperature under argon was added Pd / C 10% (136 mg, 128 pmol). The reaction mixture was stirred at room temperature for 16 h under hydrogen atmosphere. The reaction mixture was filtered over a pad of Celite. The filtrate was diluted in ethyl acetate and water. After separation, the organic phase was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was triturated with DCM, filtered and dried to afford 6-methoxy-1 ,2,3,4-tetrahydroquinoline-7-sulfonamide (50 mg, 15 % yield) as a grey solid. LCMS (ES, m / z): 243.2 [M+H]+.

[0281]

[0186] Step 2: To a solution of 6-methoxy-1 ,2,3,4-tetrahydroquinoline-7-sulfonamide (130 mg, 537 pmol) in THF (5.4 mL) at room temperature was added DDQ (244 mg, 1.07 mmol). The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was filtered over a pad of Celite. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with DCM / MeOH from 100 / 0 to 97 / 3. The resulting compound was triturated with a mixture of DCM / MeOH, filtered and dried to afford 6-methoxyquinoline-7-sulfonamide (50 mg, 37 % yield) as a white solid. LCMS (ES, m / z): 239.1 [M+H]+.

[0282] Intermediate INTA-?: 2,3-dihydrobenzofuran-7-sulfonamide (Intermediate INTA-?) Scheme SCH INTA7.

[0283]

[0187] To a mixture of 2,3-dihydrobenzofuran-7-sulfonyl chloride (2.00 g, 9.15 mmol) in DCM (15 mL) at room temperature was added 4M ammonia solution in MeOH (22.9 mL, 91.5 mmol). The reaction mixture was stirred at room temperature for 30 min. The crude mixture was purified by reverse phase C18 column chromatography eluted with H2O / acetonitrile from 100 / 0 to 20 / 80 to afford 2,3-dihydrobenzofuran-7-sulfonamide (Intermediate INTA-?) (1.46 g, 80 % yield) as a white solid. LCMS (ES, m / z): 200.1 [M+H]+.

[0284] Intermediate INTA-S: 4-methoxy-2,3-dihydro-1H-indene-5-sulfonamide (Intermediate

[0285]

[0188] To a mixture of 4-methoxy-2,3-dihydro-1 H-indene-5-sulfonyl chloride (1.00 g, 4.05 mmol) in dichloromethane (10 mL) at room temperature was added 4M ammonia solution in MeOH (10.1 mL, 0.54 mmol). The reaction mixture was stirred at room temperature for 30 min. Dichloromethane was added and the reaction mixture was filtered. The filtrate was concentrated under reduced pressure to afford 4-methoxy-2,3-dihydro-1H-indene-5- sulfonamide (Intermediate INTA-S) (1.03 g, Qt. yield) as a white solid.

[0286]

[0189] LCMS (ES, m / z): 227.2 [M+H]+.

[0287] Intermediate INTA-9: 5-(3,3-difluoropyrrolidin-1 -yl)-2-methoxybenzenesulfonamide hydrochloride (Intermediate INTA-S) Scheme SCHINTA9.

[0288]

[0190] Step 1 : A suspension of tert-butyl ((5-bromo-2-methoxyphenyl)sulfonyl)carbamate (Intermediate INTA-23) (1.25 g, 2.73 mmol), 3,3-difluoropyrrolidine hydrochloride (1.17 g, 8.19 mmol), cesium carbonate (4.44 g, 13.6 mmol) and XPhos (520 mg, 1.09 mmol) in toluene (20 mL) at room temperature was degassed with argon for 10 min then palladium^ I) acetate (122 mg, 546 pmol) was added . The reaction mixture was stirred at 90 °C for 24 h. The reaction mixture was dissolved in water and ethyl acetate then acetic acid was added until pH=3. After separation, the organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by silica gel column chromatography eluted with cyclohexane / ethyl acetate from 100 / 0 to 60 / 40 to afford tert-butyl ((5-(3,3- difluoropyrrolidin-1-yl)-2-methoxyphenyl) sulfonyl)carbamate (678 mg, 63 % yield) as a brown varnish. LCMS (ES, m / z): 393.4 [M-H]+.

[0289]

[0191] Step 2: To a solution of terf-butyl ((5-(3,3-difluoropyrrolidin-1-yl)-2-methoxyphenyl) sulfonyl)carbamate (60 mg, 0.15 mmol) in concentrated 12M HCI solution (0.25 mL, 3.1 mmol). The reaction mixture was stirred at 60 °C for 10 min then concentrated under reduced pressure and dried to afford 5-(3,3-difluoropyrrolidin-1-yl)-2- methoxybenzenesulfonamide hydrochloride (Intermediate INTA-S) (56 mg, 100 % yield) as a brown solid. LCMS (ES, m / z): 293.2 [M-H]+.

[0290] Intermediate INTA-IO: 3-methoxy-5,6,7,8-tetrahydronaphthalene-2-sulfonamide

[0291] (Intermediate INT A-IO)

[0292] Scheme SCHINTA- O-

[0293] Step 1

[0294]

[0192] Step 1 : To a mixture of 6-methoxy-1,2,3,4-tetrahydronaphthalene (1.00 g, 6.16 mmol) in dichloromethane (30.8 mL) at 0 °C was added chlorosulfonic acid (1.23 mL). After the addition, the reaction mixture was allowed to warm-up to room temperature and stirred for 1 h. The reaction mixture was poured into water and extracted with dichloromethane. The organic layer was washed with saturated NaHCCh aqueous solution, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to afford 3-methoxy-5,6,7,8-tetrahydronaphthalene-2-sulfonyl chloride (2.4 g, Qt. yield) as a white solid. LCMS (ES, m / z): 241.2 [M-H]+. Sulfonyl chloride was quenched by water and the reported mass corresponding to sulfonic acid.

[0295]

[0193] Step 2: To a mixture of 3-methoxy-5,6,7,8-tetrahydronaphthalene-2-sulfonyl chloride (1.60 g, 6.13 mmol) in dichloromethane (30.6 mL) at room temperature was added 4M ammonia in MeOH (15.3 mL, 61.3 mmol). The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The resulting product was triturated in water, filtered and dried to afford 3-methoxy-5,6,7,8-tetrahydronaphthalene-2-sulfonamide (Intermediate INTA-IO) (688 mg, 44 % yield) as a white solid. LCMS (ES, m / z): 242.1 [M- H]+.

[0296] Intermediate INTA-H : 7-methoxychromane-6-sulfonamide (Intermediate INTA-H) Scheme SCHINTM

[0297] Step 1 Step 2

[0298]

[0194] Step 1 : To a mixture of 7-methoxychromane (100 mg, 609 pmol) in dichloromethane (3.05 mL) at 0 °C was added chlorosulfonic acid (122 pL, 1.83 mmol). After the addition, the reaction mixture was allowed to warm-up and stirred at room temperature for 16 h. The crude material was poured into water and extracted with dichloromethane. The organic layer was washed with saturated NaHCCh aqueous solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford 7-methoxychromane-6-sulfonyl chloride (110 mg, 53 % yield) as a dark oil.1H NMR (400 MHz, CDCI3) 6 7.67 (t, J=0.9 Hz, 1 H), 6.48 (s, 1 H), 4.31 - 4.27 (m, 2H), 3.99 (s, 3H), 2.78 (t , J=6.4 Hz, 2H), 2.07-2.01 (m, 2H).

[0299]

[0195] Step 2: To a mixture of 7-methoxychromane-6-sulfonyl chloride (78 mg, 0.23 mmol) in dichloromethane (1.1 mL) at room temperature was added ammonia (4M solution in MeOH) (0.57 mL, 2.3 mmol). The reaction mixture was stirred at room temperature for 2 h. The crude material was concentrated to dryness. The resulting solid was suspended in water, filtered, rinsed with water then dried under reduced pressure to afford 7-methoxychromane-6-sulfonamide (Intermediate INTA-H) (33 mg, 59 % yield) as an off-white solid. LCMS (ES, m / z): 245.1[M-H]+.

[0300] Intermediate INTA-12: 7-methoxy-2,3-dihydrobenzo[b][1,4]dioxine-6-sulfonamide

[0301] (Intermediate INTA-12)

[0302] Scheme SCHINTAI2 chlorosulfonic acid

[0303] Ammonia 4M in MeOH

[0304] DOM, O’C to RT

[0305]

[0196] To 1,4-benzodioxin, 2,3-dihydro-6-methoxy- (420 mg, 2.52 mmol) in dichloromethane (8.42 mL) at 0°C was added slowly chlorosulfonic acid (507 pL, 7.58 mmol) in dichloromethane (4.21 mL). The reaction mixture allowed to warm up to room temperature and stirred for 1 h. The reaction mixture was cooled down to 0°C and 4M ammonia solution in MeOH (18.9 mL, 75.8 mmol) was added dropwise. The reaction was allowed to warm up to room temperature and stirred for 2 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to afford 7-methoxy-2,3- dihydrobenzo[b][1,4]dioxine-6-sulfonamide (Intermediate INTA12) (1.47 g, Qt. yield) as a white solid which was used in the next step without further purification. LCMS (ES, m / z): 246.1 [M-H]+.

[0306] Intermediate INTA-16: 6-methoxy-2,3-dihydrobenzofuran-5-sulfonamide (Intermediate

[0307] INTA-16)

[0308] Scheme SCHINTMB-

[0309]

[0197] Step 1 : To a mixture of 6-methoxy-2,3-dihydrobenzofuran (217 mg, 1.44 mmol) in dichloromethane (7.24 mL) at 0 °C was added chlorosulfonic acid (290 pL, 4.33 mmol). The reaction mixture was allowed to warm-up to room temperature and stirred for 1 h. The reaction mixture was poured into water and extracted with dichloromethane. The organic layer was washed with saturated NaHCCh aqueous solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford 6-methoxy-2,3- dihydrobenzofuran-5-sulfonyl chloride (260 mg, 72 % yield) as a green solid which was used without further purifications.

[0310]

[0198] Step 2: To a mixture of 6-methoxy-2,3-dihydrobenzofuran-5-sulfonyl chloride (350 mg, 1.40 mmol) in dichloromethane (7 mL) at room temperature was added 4M ammonia solution in MeOH (7.03 mL, 14.1 mmol). The reaction mixture was stirred at room temperature for 30 min. Dichloromethane was added and the reaction mixture was filtered. The filtrate was concentrated to dryness under reduced pressure to afford 6- methoxy-2,3-dihydrobenzofuran-5-sulfonamide (Intermediate INTA-IB) (375 mg, Qt. yield) as a yellow solid. LCMS (ES, m / z): 231.1 [M+H]+.

[0311] Intermediate INTA-I?: 2-methyl-2,3-dihydrobenzofuran-7-sulfonamide (Intermediate INTA-17)

[0312] Scheme SCHINTA-VT-

[0313]

[0199] To a mixture of 2-methyl-2,3-dihydrobenzofuran-7-sulfonyl chloride (500 mg, 2.14 mmol) in DCM (8.6 mL) at room temperature was added 4M ammonia solution in MeOH (5.37 mL, 21.4 mmol). The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated to dryness under reduced pressure. The resulting insoluble was suspended in water then filtered, rinsed with water and dried to afford 2- methyl-2,3-dihydrobenzofuran-7-sulfonamide (Intermediate INTA-I?) (385 mg, 80 % yield) as an off-white solid. LCMS (ES, m / z): 213.2 [M+H]+.

[0314] Intermediate INT A-IS: 5-isopropyl-2-methoxybenzenesulfonamide (Intermediate INTA- 18)

[0315] Scheme SCHINTAIS-

[0316]

[0200] To a mixture of 5-isopropyl-2-methoxybenzenesulfonyl chloride (1.48 g, 5.95 mmol) in DCM (10 mL) at room temperature was added 4M ammonia solution in MeOH (14.8 mL, 59.5 mmol). The reaction mixture was stirred at room temperature for 30 min. DCM was added and the resulting precipitate was filtered. The filtrate was concentrated to dryness under reduced pressure to afford 5-isopropyl-2-methoxybenzenesulfonamide (Intermediate INTA-IS) (1.59 g, Qt. yield) as a white solid witch was used in the next step without further purification. LCMS (ES, m / z): 230.1 [M+H]+.

[0317] Intermediate INTA-IS: 6-methoxychromane-7-sulfonamide (Intermediate INT A-19)

[0318] Scheme SCH INT -IS-

[0319] Ste l Step 2

[0320]

[0201] Step 1 : To a mixture of 6-methoxychromane (550 mg, 3.35 mmol) in DCM (16.7 mL) at 0 °C was added chlorosulfonic acid (1.17 g, 10 mmol). The reaction mixture was allowed to warm-up to room temperature and stirred for 1 h. The reaction mixture was poured into water and extracted with dichloromethane. The organic layer was washed with saturated NaHCOs aqueous solution, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by silica gel column chromatography eluted with cyclohexane / ethyl acetate from 100 / 0 to 50 / 50 to afford 6- methoxychromane-7-sulfonyl chloride (60 mg, 6.5 % yield) as a white solid.1H-NMR (400 MHz, CDCI3) 5 7.43 (s, 1H), 6.80 (s, 1H), 4.23 - 4.19 (m, 2H), 3.99 (s, 3H), 2.89 (t, J=6.4 Hz, 2H), 2.09 - 2.02 (m, 2H).

[0321]

[0202] Step 2: To a mixture of 6-methoxychromane-7-sulfonyl chloride (60 mg, 0.23 mmol) in DCM (1.1 mL) at room temperature was added 4M ammonia solution in methanol (39 mg, 2.3 mmol). The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure. The resulting solid was triturated in water, filtered and dried to afford 6-methoxychromane-7-sulfonamide (Intermediate INT A-19) (40 mg, 68 % yield) as a white solid. LCMS (ES, m / z): 244.1[M- H]+.

[0322] Intermediate INTA-2O: 5-(1 -hydroxy-1 -methyl-ethyl)-2-methoxy-benzenesulfonamide (Intermediate INT A-20)

[0323] Scheme SCHINTP O-

[0324]

[0203] Step 1 : To a mixture of chlorosulfonic acid (4.4 mL, 66 mmol) was added 4- methoxybenzoic acid (2.0 g, 13 mmol). After the addition, the reaction mixture was stirred at 60 °C for 4 h. After cooling to room temperature, the reaction mixture was added carefully to cold water and the resulting precipitate was filtered and washed with water to afford 3-(chlorosulfonyl)-4-methoxybenzoic acid (2.02 g, 58 % yield) as a white solid.1H- NMR (400 MHz, DMSO) 5 13.90 - 13.80 (m, 2H), 8.30 (d, J=2.3 Hz, 1 H), 7.90 (dd, J=2.4, 8.6 Hz, 1 H), 7.06 (d, J=8.7 Hz, 1 H), 3.83 (s, 1 H).

[0325]

[0204] Step 2: To a mixture of 3-(chlorosulfonyl)-4-methoxybenzoic acid (2.00 g, 7.98 mmol) in dichloromethane (40 mL) at room temperature was added ammonia (4M solution in MeOH) (19.9 mL, 79.8 mmol). The reaction mixture was stirred at room temperature for 1 h. The solvent was removed under reduced pressure then 1 N HCI aqueous solution was added. The resulting precipitate was filtered and dried to afford 4-methoxy-3- sulfamoylbenzoic acid (2.00 g, 100 % yield) as a white solid. LCMS (ES, m / z): 232. OEM- HIT

[0326]

[0205] Step 3: A mixture of 4-methoxy-3-sulfamoylbenzoic acid (1.85 g, 8.0 mmol) and H2SO4 (853 pL, 16.0 mmol) in methanol (40 mL) was heated at 60°C for 16 h. The solvent was removed under reduced pressure. The crude material was dissolved in water. The resulting precipitate was formed filtered and washed with water to afford methyl 4- methoxy-3-sulfamoylbenzoate (900 mg, 44 % yield) as a pink solid. LCMS (ES, m / z): 246.1[M-H]+.

[0327]

[0206] Step 4: To a mixture of methyl 4-methoxy-3-sulfamoylbenzoate (100 mg, 408 pmol) in THF (2 mL) at 0 °C was added magnesium-bromomethyl (3M solution in 2- MeTHF) (408 pL). The reaction mixture was stirred at room temperature for 2 h. Extra magnesium-bromomethyl (3M solution in 2-MeTHF) (408 pL) was added and the reaction mixture was stirred at room temperature for 16 h. The crude material was dissolved in water and ethyl acetate. After separation, the organic one was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with cyclohexane / ethyl acetate from 100 / 0 to 00 / 100 afford 5-(2-hydroxypropan-2-yl)-2-methoxybenzenesulfonamide (Intermediate INTA-2O) (50 mg, 47 % yield) as a white solid.

[0328] Intermediate INTA-21 : 2,4-dimethoxy-6-methyl-pyridine-3-sulfonamide (Intermediate

[0329] INTA-21 )

[0330] Scheme SCHINTAZI-

[0331]

[0207] Step 1 : To a mixture of 2,4-dichloro-6-methyl-3-nitropyridine (7.50 g, 36.2 mmol) in methanol (20 mL) was added sodium methoxide (25.2 mL, 25% Wt, 109 mmol). The reaction mixture was stirred at 60°C for 2 h. The solvent was removed under reduced pressure. The crude material was dissolved in water and ethyl acetate. The layers were separated and the organic one was dried with sodium sulfate, filtered and concentrated under reduced pressure to afford 2,4-dimethoxy-6-methyl-3-nitropyridine (7.46 g, 99 % yield) as a yellow solid. LCMS (ES, m / z): 199.1[M-H]+.

[0332]

[0208] Step 2: To a mixture of 2,4-dimethoxy-6-methyl-3-nitropyridine (7.46 g, 37.6 mmol) in ethanol (200 mL) and water (10 mL) at room temperature was added iron (10.5 g, 188 mmol) and hydrochloric acid (19 mL, 37% Wt, 226 mmol). The reaction mixture was stirred at 60 °C for 24 h. The crude material was dissolved in ethyl acetate and a saturated aqueous solution of NaHCOs then filtered over a pad of Celite. The layers were separated and extracted with ethyl acetate. The organic phase was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with cyclohexane / ethyl acetate 100 / 0 to 50 / 50 to afford 2,4-dimethoxy-6-methylpyridin-3- amine (4.6 g, 69 % yield) as a red oil. LCMS (ES, m / z): 169.1[M-H]+.

[0333]

[0209] Step 3: To a mixture of 2,4-dimethoxy-6-methylpyridin-3-amine (1.00 g, 5.95 mmol) in acetonitrile (10 mL) was added dibenzyl disulfide (2.93 g, 11.9 mmol) and isoascorbic acid (524 mg, 2.97 mmol). The reaction mixture was stirred at 0°C then isoamyl nitrite (3.18 mL, 23.8 mmol) was added. The reaction mixture was stirred at room temperature for 12 h. The crude material was dissolved in ethyl acetate and water. The layers were separated and the organic one was dried with sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with cyclohexane / CPME 100 / 0 to 75 / 25 afford 3-(benzylthio)-2,4- dimethoxy-6-methylpyridine (610 mg, 35 % yield) as a yellow oil. LCMS (ES, m / z): 276.1[M-H]+.

[0334]

[0210] Step 4: To a mixture of 3-(benzylthio)-2,4-dimethoxy-6-methylpyridine (200 mg, 726 pmol) in acetonitrile (5.2 mL), water (1 .3 mL) and acetic acid (0.8 mL) at -10°C was added 1 ,3-dichloro-5,5-dimethylhydantoin (253 mg, 68% Wt, 872 pmol). The reaction mixture was stirred at -10 °C for 30 min. The reaction mixture was diluted with water and extracted with dichloromethane. The organic phase was washed with water, brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford 2,4-dimethoxy-6-methylpyridine-3-sulfonyl chloride (400 mg, 98 % yield) as a yellowish solid which was engaged in the next step without further purification. LCMS (ES, m / z): 252.0[M-H]+.

[0335]

[0211] Step 5: To a mixture of 2,4-dimethoxy-6-methylpyridine-3-sulfonyl chloride (470 mg, 45% Wt, 840 pmol) in dichloromethane (4.2 mL) at room temperature was added ammonia (4M solution in MeOH) (10.5 mL, 42.0 mmol). The reaction mixture was stirred at room temperature for 16 h. The solvent was removed under reduced pressure and water was added. The resulting precipitate was filtered and dried to afford 2,4-dimethoxy- 6-methylpyridine-3-sulfonamide (Intermediate INTA-21) (115 mg, 56 % yield) as a white solid. LCMS (ES, m / z): 233.1 [M-H]+.

[0336] Intermediate INTA-22: 5-bromo-2-methoxybenzenesulfonamide (Intermediate INTA-22) Scheme SCHINT 22-

[0337]

[0212] To a mixture of 5-bromo-2-methoxybenzenesulfonyl chloride (5.0 g, 17.51 mmol) in dichloromethane (80 mL) at room temperature was added 4M ammonia solution in MeOH (43.7 mL, 175.1 mmol). The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure. The residue was diluted in water and stirred for 10 min then filtered and dried to afford 5-bromo-2- methoxybenzenesulfonamide (Intermediate INTA-22) (4.70 g, 96 % yield) as a white solid. LCMS (ES, m / z): 265-9-267.9 [M+H]+.

[0338] Intermediate INTA-23: tert-butyl ((5-bromo-2-methoxyphenyl)sulfonyl)carbamate

[0339] (Intermediate INTA-23)

[0340] Scheme SCHINTP Z-

[0341]

[0213] To a mixture of 5-bromo-2-methoxybenzenesulfonamide (Intermediate INTA-22) (4.70 g, 17.66 mmol), triethylamine (7.39 mL, 52.9 mmol) and DMAP (215 mg, 1.76 mmol) in dichloromethane (150 mL) was added BOC2O (4.46 mL, 19.4 mmol). The reaction mixture was stirred at room temperature for 16 h. Water was added and the layers were separated. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with cyclohexane / ethyl acetate from 100 / 0 to 50 / 50. The resulting product was triturated in acetonitrile / diethyl ether (9 / 1), filtered and dried to afford to afford tert-butyl ((5-bromo-2-methoxyphenyl)sulfonyl)carbamate (Intermediate INTA-23) (5.50 mg, 85 % yield) as a white solid. LCMS (ES, m / z): 364.1- 366.1 [M-H]+.

[0342] Intermediate INTA-24: 7-(pyrazol-1-ylmethyl)-1,1a,2,7b- tetrahydrocyclopropa[c]chromene-4-carboxylic acid (Intermediate INTA-24) Scheme SCHINTPM-

[0343]

[0214] Step 1 : To a mixture of 3-chloro-2-iodophenol (1.8 g, 7.07 mmol) in chloroform (100 mL) was added diisopropylamine (2.00 mL, 14.15 mmol). The reaction mixture was cooled down to -50 °C and NBS (1.25 g, 7.07 mmol) was added portionwise. The reaction mixture was stirred at -50 °C for 2 h. The reaction mixture was poured in iced water (100 mL). The resulting precipitate was filtered and the solid was stirred for 1 h in 1 N HCI aqueous solution (50 mL). The reaction mixture was filtered and dried to afford 6-bromo-3- chloro-2-iodophenol (2.1 g, 85 % yield) as a white solid. LCMS (ES, m / z): 334.9[M-H]+.

[0344]

[0215] Step 2: To a mixture of 6-bromo-3-chloro-2-iodophenol (2.1 g, 6.3 mmol) in acetonitrile (20 mL) was added CS2CO3 (4.10 g, 12.6 mmol) and 3-bromoprop-1-ene (654 pL, 7.56 mmol). The reaction mixture was stirred at 90 °C for 1 h. The reaction mixture was poured into water then ethyl acetate was added. After separation, the organic layer was washed with water, was dried over anhydrous sodium sulfate, filtered then concentrated under reduced pressure to afford 2-(allyloxy)-1-bromo-4-chloro-3- iodobenzene (2.3 g, 93 % yield) as a colorless oil. LCMS (ES, m / z): 374.0[M-H]+.

[0345]

[0216] Step 3: 2-(allyloxy)-1-bromo-4-chloro-3-iodobenzene (2.2 mg, 5.89 mmol) and silver carbonate (3.24 g, 11.7 mmol) were added to a sealable pressure tube containing degassed DMF (15 mL) then PdP(Ph3)4 (680 mg, 589 pmol) was added. The reaction mixture was flushed with argon then sealed and the reaction mixture stirred at 70 °C for 2 h. The reaction mixture was poured into water then diethyl ether was added. After separation, the organic layer was washed with water, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with cyclohexane / ethyl acetate from 100 / 0 to 90 / 10 to afford 7-bromo-4-chloro-3-methylene-2,3-dihydrobenzofuran (500 mg, 33 % yield) as a colorless solid.1H NMR (400 MHz, DMSO) 5 7.47 (1H, d, J=8.6 Hz), 6.95 (1 H, d, J=8.5 Hz), 5.99 (1H, dd, J=3.2, 3.2 Hz), 5.34 (1H, dd, J=2.8, 2.8 Hz), 5.29 (2H, dd, J=3.0, 3.0 Hz).

[0346]

[0217] Step 4: To a mixture of 1M diethylzinc solution in hexane (3.26 mL, 3.26 mmol) in dichloromethane (6.5 mL) under argon at 0°C was added TFA (251 pL, 3.26 mmol). The reaction mixture was stirred for 15 min then diiodomethane (524 pL, 6.52 mmol) was added. The reaction mixture was stirred at 0 °C for 1 h and a solution of 7-bromo-4-chloro- 3-methylene-2,3-dihydrobenzofuran (400 mg, 1.63 mmol) in dichloromethane (26. mL) was added. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was poured into iced saturated NH4CI aqueous solution (50 mL). After separation, the organic layer was washed with water then brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with cyclohexane / ethyl acetate from 100 / 0 to 70 / 30 to afford 7-bromo-4-chloro-2H-spiro[benzofuran-3,1'-cyclopropane] (150 mg, 23 % yield) as a colorless oil.1H NMR (400 MHz, DMSO) 5 7.30 (1 H, d, J=8.5 Hz), 6.78 (1H, d, J=8.7 Hz), 4.56 (2H, s), 1.64 (2H, dd, J=4.6, 6.8 Hz), 1.03 (2H, dd, J=4.6, 6.7 Hz).

[0347]

[0218] Step 5: To a solution of 7-bromo-4-chloro-2H-spiro[benzofuran-3,1'-cyclopropane] (150 mg, 578 pmol) in dioxane (3 mL) was added DMAP (70.6 mg, 578 pmol), 2,6- dimethoxybenzenesulfonamide (Intermediate INTA-I) (251 mg, 1.16 mmol), carbon monooxide-molybdenum (6:1) (153 mg, 578 pmol) , tri-terf-butylphosphonium tetrafluoroborate (33.5 mg, 116 pmol) trans-b / s(acetato)b / s[2-[bis(2- methylphenyl)phosphino]benzyl]dipalladium(ll) (54.2 mg, 57.8 pmol) and DBU (261 pL, 1.73 mmol). The reaction mixture was stirred at 110 °C for 2 h under microwave irradiations. The reaction mixture was diluted with dichloromethane and water then acetic acid (1 mL) was added. After separation, the organic layer was washed with water, dried over anhydrous sodium sulfate, filtered then concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with cyclohexane / (ethyl acetate / ethanol 3 / 1) from 100 / 0 to 0 / 100 to afford 4-chloro- / V-((2,6- dimethoxyphenyl)sulfonyl)-2H-spiro[benzofuran-3,1'-cyclopropane]-7-carboxamide (Intermediate INTA-24) (65 mg, 24 % yield) as beige solid. LCMS (ES, m / z): 424.3[M-H]+.

[0348] Intermediate INTA-2S: 6-methoxy-2,3-dihydrobenzofuran-7-sulfonamide (Intermediate

[0349] INTA-25)

[0350] Scheme SCHINTA-25-

[0351]

[0219] Step 1 : To a mixture of 2,3-dihydrobenzofuran-6-ol (2.4 g, 17.62 mmol) in acetonitrile (176 mL) was added potassium carbonate (7.30 g, 52.8 mmol) and methyl iodide (9.60 mL, 148 mmol). The reaction mixture was stirred at room temperature for 4 h. The reaction mixture was filtered then the solvent was removed under reduced pressure. The mixture was purified by silica gel column chromatography eluted with cyclohexane / ethyl acetate from 100 / 0 to 80 / 20 to afford 6-methoxy-2,3-dihydrobenzofuran (2.08 g, 71 % yield) as an yellow oil. LCMS (ES, m / z): 151.1 [M+H]+.

[0352]

[0220] Step 2: To a mixture of 6-methoxy-2,3-dihydrobenzofuran (2.06 g, 12.7 mmol) in THF (85 mL) at room temperature was slowly added 2.5M n-butyllithium solution in hexane (7.65 mL, 19.14 mmol). The reaction mixture was stirred at room temperature for 30 min. Then, a solution of iodine (3.56 g, 14.0 mmol) in THF (42.5 mL) was slowly added. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was dissolved in ethyl acetate and saturated Na2SO2 aqueous solution. After separation, the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with cyclohexane / ethyl acetate from 100 / 0 to 70 / 30 to afford 7-iodo-6-methoxy-2,3- di hydro benzofuran (2.24 g, 60 % yield) as a white solid. LCMS (ES, m / z): 277.0[M+H]+.

[0221] Step 3: 7-iodo-6-methoxy-2,3-dihydrobenzofuran (1.1 g, 3.98 mmol) and DI PEA (1.39 mL, 7.96 mmol) were dissolved in dioxane (39.9 mL) at room temperature and the reaction mixture was degassed with argon for 10 min. Then (4- methoxyphenyl)methanethiol (666 pL, 4.78 mmol) and Pd2(dba)3 (182 mg, 199 pmol) were added. The reaction mixture was stirred at 100°C for 16 h. The reaction mixture was dissolved in ethyl acetate and water. After separation, the aqueous layer was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by silica gel column chromatography eluted with cyclohexane / ethyl acetate from 100 / 0 to 50 / 50 to afford 6- methoxy-7-((4-methoxybenzyl)thio)-2,3-dihydrobenzofuran (670 mg, 55 % yield) as a yellow oil. LCMS (ES, m / z): 303.1[M+H]+.

[0353]

[0222] Step 4: To a mixture of 6-methoxy-7-((4-methoxybenzyl)thio)-2,3- di hydro benzofuran (250 mg, 827 pmol) in acetonitrile (6.0 mL), water (1.5 mL) and acetic acid (0.8 mL) at -10°C was added 1 ,3-dichloro-5,5-dimethylhydantoin (287 mg, 992 pmol). The reaction mixture was stirred at 0 °C for 30 min. The reaction mixture was diluted with water and extracted with dichloromethane. Combined organic phases were concentrated under reduced pressure. 4M solution ammonia in methanol (1.79 mL, 82.7 mmol) was added to the residue. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was dissolved in water and ethyl acetate. After separation, the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was triturated in methanol, filtered and dried to afford 6-methoxy-2,3- dihydrobenzofuran-7-sulfonamide (Intermediate INTA-2S) (25 mg, 7.6 % yield) as a white powder. LCMS (ES, m / z): 230.1 [M+H]+.

[0354] Intermediate INTA-26: 7-chloro-N-((2,6 dimethoxyphenyl)sulfonyl)benzo[d][1,3]dioxole-2,2-d2-4-carboxamide (Intermediate INTA-26)

[0355] Scheme SCHINTA-26-

[0356]

[0223] Step 1 : To a mixture of 3-bromobenzene-1 ,2-diol (5.13 g, 27.1 mmol) in toluene (540 mL) was added dimethylamine hydrochloride (111 mg, 1.36 mmol). The reaction mixture was cooled down to 0°C and 1 ,3-dichloro-5,5-dimethylimidazolidine-2, 4-dione (4.28 g, 21.7 mmol) was portion wise added. The reaction mixture was stirred at 0°C for 16 h in absence of light. The reaction mixture was quenched with a few drops of water and the solvent was removed under reduced pressure. Water was added then 1 N aqueous solution of HCI was slowly added until pH=1. Aqueous layer was extracted with ethyl acetate. Then, the organic phase was washed with a 10% Na2S20s aqueous solution, brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by Cis reverse phase column chromatography eluted with water / acetonitrile from 100 / 0 to 70 / 30 to afford 3-bromo-6-chlorobenzene-1,2-diol (4.0 g, 66% yield) as a dark purple solid. LCMS (ES, m / z): 221.0[M-H]+.

[0357]

[0224] Step 2: In a sealed tube to 3-bromo-6-chlorobenzene-1,2-diol (1.5 g, 6.7 mmol) in DMF (15 mL) at room temperature was added cesium carbonate (6.6 g, 20 mmol) and dibromomethane-d2 (1.4 mL, 20 mmol). The reaction mixture was stirred at 110 °C for 16 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The crude material was purified by silica gel column chromatography eluted with cyclohexane to afford 4-bromo-7-chlorobenzo[d][1,3]dioxole-2,2-d2 (400 mg, 25% yield) as a yellowish oil.1H N MR (400 MHz, DMSO) 5 7.14 - 7.04 (m, 1H), 7.04 - 6.89 (m, 1 H) ppm.

[0358]

[0225] Step 3: To a solution of 4-bromo-7-chlorobenzo[d][1,3]dioxole-2,2-d2 (340 mg, 1.43 mmol) in dioxane (9 mL) was added DMAP (175 mg, 1.43 mmol), 2,6- dimethoxybenzenesulfonamide (Intermediate INTA-I) (622 mg, 2.86 mmol), carbon monooxide-molybdenum (6:1) (378 mg, 1.43 mmol), tr / -terf-butylphosphonium tetrafluoroborate (83 mg, 286 pmol) trans-b / s(acetato)bis[2-[bis(2- methylphenyl)phosphino]benzyl]dipalladium(ll) (134 mg, 143 pmol) and DBU (pL, 4.30 mmol). The reaction mixture was stirred at 110°C for 2.5 h under microwave irradiations. The reaction mixture was diluted with water and washed with ethyl acetate. Then, the aqueous phase was slowly acidified with 1N HCI aqueous solution until pH=3. The resulting solid was filtered, washed with water and dried by toluene azeotrope under reduced pressure to afford 7-chloro-N-((2,6- dimethoxyphenyl)sulfonyl)benzo[d][1 ,3]dioxole-2,2-d2-4-carboxamide (Intermediare INTA- 26) (130 mg, 19 % yield) as a yellowish solid. LCMS (ES, m / z): 402.1[M+H]+.

[0359] Intermediates INTA-I to INTA-26

[0360]

[0226] Intermediates I NTA-I to I NTA-24, as listed in Table 2, were synthesized by methods analogous to those described above for Intermediates I NTA-I , I NTA-2, I NTA-3, I NTA-4, I NTA-S I NTA-6, I NTA-7, I NTA-8, I NTA-9, I NTA-10, I NTA-11 , I NTA-12, I NTA-16, I NTA-17, I NTA-18, I NTA-19, I NTA- 20, I NTA-21 , I NTA-22, I NTA-23, I NTA-24 , I NTA-25 and I NTA-26 utilizing suitable starting materials and standard procedures familiar to those skilled in the art. In some cases, commercially available sulfonyl chloride building blocks were employed directly. Table 2. Intermediates A

[0361] II. Synthesis Benzoic Acid Intermediates

[0362] Intermediate INTB-O: 1 -(methylsulfonyl )-1H-pyrazole (Intermediate INTB-O)

[0363] Scheme SCHINTBO-

[0364] DCM, RT

[0365]

[0227] To a solution of 1 H-pyrazole (1.50 g, 22.03 mmol) in DCM (60 mL) under argon at 0°C was added triethylamine (3.07 mL, 22.03 mmol) followed by the addition of methanesulfonyl chloride (1.71 mL, 22.03 mmol). The reaction was allowed to warm at room temperature and stirred for 16 h. The reaction mixture was quenched with saturated NH4CI aqueous solution and diluted with water. Organic layer was successively washed with water and brine, dried over anhydrous sodium sulfate, filtered and passed through SPE NH2 column to afford 1 -(methylsulfonyl)- 1 H-pyrazole (Intermediate INTB-O) (3.0 g, 93 % yield) as a colorless oil. LCMS (ES, m / z): 147.0 [M+H]+.

[0366] Intermediate INTB-I : 5-((1H-pyrazol-1-yl)methyl)chromane-8-carboxylic acid (Intermediate INTB-I) Scheme SCHINTBI.

[0367]

[0228] Step 1 : To a mixture of 4-bromo-2-hydroxybenzonitrile (3.67 mg, 18.5 mmol) in acetonitrile (70 mL) was added CS2CO3 (12.1 g, 37.1 mmol) and 3-bromoprop-1-ene (2.41 mL, 27.8 mmol). The reaction mixture was stirred at 90 °C for 1 h then diluted with water and extracted with ethyl acetate. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford 2-(allyloxy)-4-bromobenzonitrile (4.23 g, 91 % yield) as a yellowish solid which was used without any further purification. LCMS (ES, m / z): 236.3 [M-H]+.

[0368]

[0229] Step 2: A mixture of 2-(allyloxy)-4-bromobenzonitrile (1.83 g, 7.68 mmol) in dichlorobenzene (15.3 mL) was stirred at 220 °C for 2 h under MW irradiations. After cooling, the reaction mixture was filtered and the precipitate was washed with cyclohexane and dried to afford 3-allyl-4-bromo-2-hydroxybenzonitrile (750 mg, 39 % yield) as a beige solid. LCMS (ES, m / z): 236.2-238-.1 [M-H]+.

[0369]

[0230] Step 3: To a solution of 3-allyl-4-bromo-2-hydroxybenzonitrile (1.50 g, 6.30 mmol) in THF (95.4 mL) at 0°C was added dropwise 1M solution of borane tetrahydrofuran complex (18.9 mL, 18.9 mmol). The reaction mixture was stirred at room temperature for 3 h. Water (9.55 mL) was then cautiously added to the reaction mixture followed by addition of 1N NaOH aqueous solution (18.9 mL, 18.9 mmol). Then a solution of hydrogen peroxide (707 pL, 30% Wt, 6.93 mmol) was added dropwise and the resulting mixture was stirred at room temperature for 1 h. The reaction mixture was poured in a saturated NH4CI aqueous solution then extracted with ethyl acetate and washed with water and brine. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with cyclohexane / ethyl acetate 100 / 0 to 50 / 50 to afford 4-bromo-2-hydroxy-3-(3- hydroxypropyl)benzonitrile (935 mg, 46 % yield) as a yellowish oil. LCMS (ES, m / z): 236.2-238.1 [M-H]+.

[0370]

[0231] Step 4: To a mixture of 4-bromo-2-hydroxy-3-(3-hydroxypropyl)benzonitrile (935 mg, 2.92 mmol) in THF (29.2 mL) was added triphenylphosphine (919 mg, 3.5 mmol) and DIAD (681 pL, 3.50 mmol). The reaction mixture was stirred at room temperature for 16 h. The crude material was dissolved in EtOAc and saturated NH4CI aqueous solution. The layers were separated and the organic one was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with cyclohexane / ethyl acetate from 100 / 0 to 50 / 50 to afford 5-bromochromane-8-carbonitrile (350 mg, 48 % yield) as a white solid. LCMS (ES, m / z): 238.1-240.1 [M-H]+.

[0371]

[0232] Step 5: A mixture of 5-bromochromane-8-carbonitrile (340 mg, 1.42 mmol), potassium trifluoro(vinyl)borate(1-) (382 mg, 2.85 mmol) and potassium phosphate tribasic (384 pL, 4.28 mmol) in dioxane (12.8 mL) and water (1.42 mL) was degassed with argon for 10 min and [1,1'-B / s(diphenylphosphino)ferrocene]dichloropalladium(ll) (complex with DCM) (116 mg, 142 pmol) was added. The reaction mixture was stirred at 110 °C for 16 h. The reaction mixture was filtered on a Celite pad then concentrated under pressure. The residue was purified by silica gel column chromatography eluted with cyclohexane / CPME from 100 / 0 to 80 / 20 to afford 5-vinylchromane-8-carbonitrile (185 mg, 66% yield) as an orange oil. LCMS (ES, m / z): 186.2 [M+H]+.

[0372]

[0233] Step 6: To a solution of 5-vinylchromane-8-carbonitrile (150 mg, 809 pmol) in THF (7.2 mL) and water (1.8 mL) at 0°C was added sodium metaperiodate (108 L, 2.02 mmol) and potassiumosmate(VI)dihydrate (14.9 mg, 40.4 pmol). The reaction mixture was allowed to warm up to room temperature and stirred for 1 h. The reaction mixture was diluted with ethyl acetate and washed with water. After separation, the organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with cyclohexane / ethyl acetate 100 / 0 to 50 / 50 to afford 5-formylchromane-8-carbonitrile (122 mg, 76 % yield) as a white solid. LCMS (ES, m / z): 188.3 [M+H]+.

[0373]

[0234] Step 7: To a mixture of 5-formylchromane-8-carbonitrile (120 mg, 641 pmol) in methanol (3.21 mL) at 0 °C was added NaBH4 (29.1 mg, 769 pmol). The reaction mixture was stirred at 0 °C for 30 min. The solvent was removed under reduced pressure. The crude material was dissolved in ethyl acetate and a saturated NH4CI aqueous solution. After separation, the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford 5-(hydroxymethyl)chromane-8-carbonitrile (115 mg, 90 % yield) as a white solid which was used in the next step without any further purification. LCMS (ES, m / z): 190.1 [M+H]+.

[0374]

[0235] Step 8: To a mixture of 5-(hydroxymethyl)chromane-8-carbonitrile (110 mg, 581 pmol) in acetonitrile (2.9 mL) at room temperature was added 1-(methylsulfonyl)-1H- pyrazole (127 mg, 872 pmol) and cesium carbonate (568 mg, 1.74 mmol). The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was filtered on a Celite pad and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography eluted with cyclohexane / ethyl acetate 100 / 0 to 50 / 50 to afford 5-((1 H-pyrazol-1-yl)methyl)chromane-8-carbonitrile (138 mg, 94 % yield) as a colorless oil. LCMS (ES, m / z): 240.2 [M+H]+.

[0375]

[0236] Step 9: A mixture of 5-((1 H-pyrazol-1-yl)methyl)chromane-8-carbonitrile (130 mg, 543 pmol) in 1N NaOH aqueous solution (5.43 mL, 5.43 mmol) was stirred at 100

[0376] °C for 16 h. The reaction mixture was acidified with 1N HCI aqueous solution. The resulting precipitate was filtered, washed with water and dried to afford 5-((1H-pyrazol-1- yl)methyl)chromane-8-carboxylic acid (Intermediate INTB-I) (120 mg, 81 % yield) as a white solid which was used in the next step without any purification. LCMS (ES, m / z): 259.2 [M+H]+.

[0377] Intermediate INTB-2: 4-((1H-pyrazol-1-yl)methyl)-2,3-dihydrobenzofuran-7-carboxylic acid (Intermediate INTB-2)

[0378] Scheme SCHINTB2

[0379]

[0237] Step 1 : To a mixture of methyl 4-bromo-2,3-dihydrobenzofuran-7-carboxylate (500 mg, 1.94 mmol), potassium trifluoro(vinyl)borate(1-) (782 mg, 5.83 mmol) and potassium phosphate tribasic (524 pL, 5.83 mmol) in dioxane (50 mL) and water (5.6 mL) was degassed with argon for 10 min then [1,1'-B / s(diphenylphosphino) ferrocene]dichloropalladium(ll) (complex with dichloromethane) (159 mg, 194 pmol) was added. The reaction mixture was stirred at 100 °C for 24 h then poured in water and ethyl acetate was added. After separation, the organic phase was washed with water, dried over anhydrous sodium sulfate, filtered then concentrated under reduced pressure to afford methyl 4-vinyl-2,3-dihydrobenzofuran-7-carboxylate (420 mg, 92 % yield) as black oil. LCMS (ES, m / z): 205.3 [M+H]+.

[0380]

[0238] Step 2: To methyl 4-vinyl-2,3-dihydrobenzofuran-7-carboxylate (400 mg, 1.96 mmol) in THF (22.4 mL) and water (5.6 mL) at 0°C was added sodium metaperiodate (262 pL, 4.90 mmol) and potassium osmate(VI)dihydrate (36.1 mg, 97.9 pmol). The reaction mixture was allowed to warm up to room temperature and stirred for 2 h. The crude material was diluted with ethyl acetate and the mixture was filtered on a Celite pad and the solvent was evaporated under reduced pressure. The crude material was partitioned between water and ethyl acetate. After separation, the organic phase was washed with water, dried over anhydrous sodium sulfate, filtered then concentrated under reduced pressure to afford methyl 4-formyl-2,3-dihydrobenzofuran-7-carboxylate (400 mg, 94 % yield) as a brown powder. LCMS (ES, m / z): 207.1 [M+H]+.

[0381]

[0239] Step 3: To a mixture of methyl 4-formyl-2,3-dihydrobenzofuran-7-carboxylate (300 mg, 1.45 mmol) in THF (10 mL) and methanol (10 mL) at 0 °C was slowly added NaBH4 (110 mg, 2.91 mmol). The reaction mixture was allowed to warm up to room temperature and stirred for 2 h. The crude material was dissolved in water and ethyl acetate. After separation, the organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with cyclohexane / (ethyl acetate / ethanol 3 / 1) as eluent from 100 / 0 to 70 / 30 to afford methyl 4-(hydroxymethyl)-2,3-dihydrobenzofuran-7-carboxylate (200 mg, 63 % yield) as a brown oil. LCMS (ES, m / z): 209.3 [M+H]+.

[0382]

[0240] Step 4: To a mixture of methyl 4-(hydroxymethyl)-2,3-dihydrobenzofuran-7- carboxylate (200 mg, 961 pmol) in acetonitrile (20 mL) at room temperature was added 1- (methylsulfonyl)-IH-pyrazole (183 mg, 1.25 mmol) and CS2CO3 (939 mg, 2.88 mmol). The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was filtered on a Celite pad and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography eluted with cyclohexane / ethyl acetate 100 / 0 to 50 / 50 to afford methyl 4-((1 H-pyrazol-1-yl)methyl)-2,3- dihydrobenzofuran-7-carboxylate (135 mg, 47 % yield) as a yellow oil. LCMS (ES, m / z): 209.3 [M+H]+.

[0383]

[0241] Step 5: To a mixture of methyl 4-((1H-pyrazol-1-yl)methyl)-2,3-dihydrobenzofuran- 7-carboxylate (135 mg, 523 pmol) in THF (5 mL) and water (5 mL) at room temperature was added LiOH (44.7 mg, 1.05 mmol). The reaction mixture was stirred at room temperature for 5 h then diluted with water and ethyl acetate. Aqueous layer was acidified to pH = 5 with 1M HCI aqueous solution then ethyl acetate was added. After separation, the organic phase was washed with water, dried over anhydrous sodium sulfate, filtered then concentrated under reduced pressure to afford 4-((1 H-pyrazol-1- yl)methyl)-2,3-dihydrobenzofuran-7-carboxylic acid (Intermediate INTB-2) (120 mg, 89 % yield) as a colorless solid. LCMS (ES, m / z): 245.3 [M+H]+.

[0384] Intermediate INTB-S: 7-(pyrazol-1-ylmethyl)-1,1a,2,7b- tetrahydrocyclopropa[c]chromene-4-carboxylic acid (Intermediate INT B-S) Scheme SCHINTBB-

[0385]

[0386]

[0242] Step 1 : To a mixture of 2-fluoro-4-(hydroxymethyl)benzonitrile (3.00 g, 19.8 mmol) in acetonitrile (99.2 mL) at room temperature was added 1 -(methylsulfonyl)- 1H-pyrazole (Intermediate INTB-O) (4.35 g, 29.8 mmol) and CS2CO3 (19.4 g, 59.5 mmol). The reaction mixture was stirred at room temperature for 4 h. The reaction mixture was filtered on a Celite pad and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography eluted with cyclohexane / ethyl acetate from 100 / 0 to 50 / 50 to afford 4-((1H-pyrazol-1-yl)methyl)-2-fluorobenzonitrile (4.20 g, 95 % yield) as a yellow oil. LCMS (ES, m / z): 202.2[M-H]+.

[0387]

[0243] Step 2: To a solution of prop-2-yn-1-ol (836 mg, 14.9 mmol) in THF (25 mL) at 0 °C under argon was added sodium hydride (60% dispersion in mineral oil) (795 mg, 19.9 mmol). The suspension was stirred at this 0°C for 20 min then 4-((1 H-pyrazol-1-yl)methyl)- 2-fluorobenzonitrile (2.00 g, 9.94 mmol) in THF (25 mL) was added slowly at 0°C. The reaction mixture was allowed to warm up at room temperature and stirred for 16 h. The reaction mixture was diluted in NH4CI and ethyl acetate. After separation, the organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with cyclohexane / ethyl acetate from 100 / 0 to 50 / 50 to afford 4-((1 H-pyrazol-1-yl)methyl)-2- (prop-2-yn-1-yloxy)benzonitrile (1.51 g, 61 % yield) as an orange solid. LCMS (ES, m / z): 238.3[M-H]+.

[0388]

[0244] Step 3: A mixture of 5-((1 H-pyrazol-1-yl)methyl)-2H-chromene-8-carbonitrile (1.26 g, 5.0 mmol) in dichlorobenzene (11.8 mL) was stirred under MW irradiations at 220°C for 2 h. The reaction mixture was directly purified by silica gel column chromatography eluted with cyclohexane / ethyl acetate from 100 / 0 to 50 / 50 to afford 5- ((1 H-pyrazol-1-yl)methyl)-2H-chromene-8-carbonitrile (1.26 g, 85 % yield) as an orange solid. LCMS (ES, m / z): 238.3[M-H]+.

[0245] Step 4: To a mixture of 5-((1 H-pyrazol-1-yl)methyl)-2H-chromene-8-carbonitrile (1.00 g, 4.21 mmol) in DMA (6.5 mL) and ethylene glycol (1.3 mL) was added potassium carbonate (1.08 g, 7.84 mmol) and trifluoro(iodomethyl)-l4-borane potassium salt (583 mg, 2.35 mmol). The reaction mixture was degassed with argon for 5 min then cataCXium® C (147 mg, 156 pmol) was added. The reaction mixture was stirred at 120 °C for 8 h under MW irradiations. The reaction mixture was filtered and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography eluted with cyclohexane / ethyl acetate from 100 / 0 to 50 / 50 to afford 7-((1 H-pyrazol-1-yl)methyl)- 1 ,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carbonitrile (520 mg, 47% yield) as an orange oil. LCMS (ES, m / z): 252.3[M-H]+.

[0389]

[0246] Step 5: A mixture of 7-((1 H-pyrazol-1-yl)methyl)-1 ,1a,2,7b-tetrahydrocyclopropa[c] chromene-4-carbonitrile (520 mg, 2.07 mmol) in 1 N NaOH aqueous solution (20.7 mL, 20.7 mmol) was stirred at 100 °C for 16 h. The reaction mixture was acidified with 1 N HCI aqueous solution. The resulting precipitate was filtered and dried to afford 7-((1 H-pyrazol- 1-yl)methyl)-1 ,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid (Intermediate INTB-5) (408 mg, 69 % yield) as a yellow solid which was used in the next step without any further purification. LCMS (ES, m / z): 271.2[M-H]+.

[0390] Intermediate INTB-H : 6-((1 H-pyrazol-1-yl)methyl)-2,3,4,5-tetrahydrobenzo[b]oxepine-

[0391] 9-carboxylic acid (Intermediate INT B-H)

[0392] Scheme SCHINTB- -

[0393]

[0247] Step 1 : To a mixture of 4-bromo-2-hydroxybenzonitrile (4.08 g, 20.6 mmol) in acetonitrile (80 mL) was added CS2CO3 (13.4 g, 41.2 mmol) and 3-bromoprop-1-ene (2.67 mL, 30.9 mmol). The reaction mixture was stirred at 90 °C for 1 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford 2-(allyloxy)-4-bromobenzonitrile (4.95 g, 96 % yield) as a yellow solid. LCMS (ES, m / z): 236.0-238.0[M-H]+.

[0394]

[0248] Step 2: A solution of 2-(allyloxy)-4-bromobenzonitrile (2.5 g, 10.5 mmol) in dichlorobenzene (21 mL) was stirred under microwave irradiations at 220 °C for 2 h. The reaction mixture was cooled to 0°C. The resulting precipitate was filtered, washed with cyclohexane and dried to afford 3-allyl-4-bromo-2-hydroxybenzonitrile (2.60 g, 99 % yield) as a yellow solid. LCMS (ES, m / z): 236.0-238.0[M-H]+.

[0395]

[0249] Step 3: To a mixture of 3-allyl-4-bromo-2-hydroxybenzonitrile (1.1 g, 4.62 mmol) in acetonitrile (23.1 mL) was added CS2CO3 (3.01 g, 9.24 mmol) and 3-bromoprop-1-ene (599 pL, 6.93 mmol). The reaction mixture was stirred at 90 °C for 1 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford 3-allyl-2-(allyloxy)-4-bromobenzonitrile (1.33 g, 98 % yield) as a yellow oil which was engaged without any purification. LCMS (ES, m / z): 278.1 -280.1[M+H]+.

[0396]

[0250] Step 4: To a mixture of 3-allyl-2-(allyloxy)-4-bromobenzonitrile (1.3 g, 4.67 mmol) in dichloromethane (93.5 mL) was added dichloro(1,3-dimesityl-2-imidazolidinylidene)(2- isopropoxybenzylidene)ruthenium (146 mg, 233 pmol). The reaction mixture was stirred at room temperature for 2 h. The solvent was removed under reduced pressure. The mixture was purified by silica gel column chromatography eluted with cyclohexane / ethyl acetate from 100 / 0 to 50 / 50 to afford 6-bromo-2,5-dihydrobenzo[b]oxepine-9-carbonitrile (1.05 g, 85 % yield) as a yellow solid. LCMS (ES, m / z): 250.1-252.0 [M+H]+.

[0397]

[0251] Step 5: To a mixture of 6-bromo-2,5-dihydrobenzo[b]oxepine-9-carbonitrile (620 mg, 2.48 mmol) in ethyl acetate (24 mL) was added Rh / C 5% (253 mg, 124 pmol) The reaction mixture was stirred at room temperature for 4 h under H2 atmosphere. The reaction mixture was filtered and concentrated under reduce pressure to afford 6-bromo- 2,3,4,5-tetrahydrobenzo[b]oxepine-9-carbonitrile (530 mg, 76 % yield) as a yellow oil. LCMS (ES, m / z): 252.1-254.1 [M+H]+.

[0398]

[0252] Step 6: To a mixture of 6-bromo-2,3,4,5-tetrahydrobenzo[b]oxepine-9-carbonitrile (500 mg, 1.78 mmol), potassium ((1 H-pyrazol-1-yl)methyl)trifluoroborate (402 mg, 2.14 mmol) and cesium carbonate (1.74 g, 5.35 mmol) in CPME (7.1 mL) and water (1.8 mL) degassed with argon for 10 min was added allylpalladium(ll)chloride dimer (32.6 mg, 89.2 pmol) followed by sodium 2'-(dicyclohexylphosphino)-2,6-dimethoxy-[1 ,1'-biphenyl]-3- sulfonate hydrate (94.7 mg, 178 pmol). The reaction mixture was stirred at 110 °C for 24 h. The reaction mixture was concentrated under reduced pressure. The reaction mixture was diluted with 1 N HCI aqueous solution then extracted with ethyl acetate. The organic layer was washed with water and brine then dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by silica gel column chromatography eluted with cyclohexane / ethyl acetate from 100 / 0 to 50 / 50 to afford 6- ((1H-pyrazol-1-yl)methyl)-2,3,4,5-tetrahydrobenzo[b]oxepine-9-carbonitrile (240 mg, 50 % yield) as a yellow solid. LCMS (ES, m / z): 254.2 [M+H]+.

[0399]

[0253] Step 7: A mixture of 6-((1 H-pyrazol-1-yl)methyl)-2, 3,4,5- tetrahydrobenzo[b]oxepine-9-carbonitrile (240 mg, 947 pmol) in 1 N NaOH aqueous solution (9.47 mL, 9.47 mmol) was stirred at 100 °C for 16 h. The reaction mixture was acidified with 1N HCI aqueous solution. The resulting precipitate was filtered and dried to afford 6-((1 H-pyrazol-1-yl)methyl)-2,3,4,5-tetrahydrobenzo[b]oxepine-9-carboxylic acid (Intermediate INTB-H) (160 mg, 59 % yield) as a yellow solid which was used in the next step without any purification. LCMS (ES, m / z): 273.2 [M+H]+.

[0400] Intermediate INTB-IS: 9-((1H-pyrazol-1-yl)methyl)-3,4-dihydro-2H- benzo[b][1,4]dioxepine-6-carboxylic acid (Intermediate INT B-13) Scheme SCHINTBIS

[0401]

[0254] To a mixture of ethyl 4-bromo-2,3-dihydroxybenzoate (500 mg, 1.92 mmol) in acetone (100 mL) was added CS2CO3 (2.50 g, 7.66 mmol) and 1,3-dibromopropane (214 pL, 2.11 mmol). The reaction mixture was stirred at 80 °C for 16 h. The reaction mixture was poured into water and extracted with ethyl acetate. After separation, the organic layer was washed with water, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford ethyl 9-bromo-3,4-dihydro-2H- benzo[b][1 ,4]dioxepine-6-carboxylate (505 mg, 83 % yield) as a colorless oil. LCMS (ES, m / z): 301.0-303.0[M+H]+.

[0402]

[0255] To a mixture of ethyl 9-bromo-3,4-dihydro-2H-benzo[b][1,4]dioxepine-6- carboxylate (500 mg, 1.66 mmol), potassium ((1 H-pyrazol-1-yl)methyl)trifluoroborate (374 mg, 1.99 mmol) and cesium carbonate (1.62 g, 4.98 mmol) in CPME (6 mL) and water (2 mL) degassed with argon for 10 min were added allylpalladium(l l)chloride dimer (30.3 mg, 83 pmol) followed by sodium 2'-(dicyclohexylphosphino)-2,6-dimethoxy-[1 ,1'-biphenyl]-3- sulfonate hydrate (88.1 mg, 166 pmol). The reaction mixture was stirred at 110 °C for 24 h. The reaction mixture was diluted with ethyl acetate washed with water, brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica column chromatography eluted with cyclohexane / ethyl acetate from 100 / 0 to 30 / 70 to afford ethyl 9-((1H-pyrazol-1-yl)methyl)-3,4-dihydro-2H-benzo[b] [1 ,4]dioxepine-6-carboxylate (320 mg, 61 % yield) as a colorless oil. LCMS (ES, m / z): 303.2 [M+H]+.

[0256] To a mixture of ethyl 9-((1 H-pyrazol-1-yl)methyl)-3,4-dihydro-2H- benzo[b][1 ,4]dioxepine-6-carboxylate (320 mg, 1.06 mmol) in THF (5 mL) and water (5 mL) at room temperature was added LiOH (90.5 mg, 2.12 mmol). The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with water and ethyl acetate. The aqueous layer was acidified with 1 N HCI aqueous solution until pH = 3 then extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford 9- ((1 H-pyrazol-1-yl)methyl)-3,4-dihydro-2H-benzo[b][1 ,4]dioxepine-6-carboxylic acid (Intermediate INT B-13) (270 mg, 88 % yield) as a yellow gum. LCMS (ES, m / z): 275.1 [M+H]+.

[0403] Intermediate INTB-IS: 8-((1 H-pyrazol-1-yl)methyl)-2,3-dihydrobenzo[b][1,4]dioxine-5- carboxylic acid (Intermediate INTB-IS) Scheme SCH INTB-IS

[0404]

[0257] Step 1 : To a solution of ethyl 4-bromo-2,3-dihydroxybenzoate (425 mg, 1.62 mmol) in DMF (32.5 mL) at room temperature was added K2CO3 (449mg, 3.25 mmol) and 1 ,2-dibromoethane (281 pL, 3.25 mmol). The reaction mixture was stirred at 80°C for 1 h. The reaction mixture was washed with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford ethyl 8-bromo-2,3- dihydrobenzo[b][1 ,4]dioxine-5-carboxylate (520 mg, Qt. yield) as a brown solid. LCMS (ES, m / z): 287.0-289.0[M+H]+.

[0405]

[0258] Step 2: To a mixture of ethyl 8-bromo-2,3-dihydrobenzo[b][1 ,4]dioxine-5- carboxylate (250 mg, 783 pmol), potassium ((1 H-pyrazol-1-yl)methyl)trifluoroborate (176 mg, 940 pmol) and cesium carbonate (766 mg, 2.35 mmol) in CPME (3.1 mL) and water (783 pL) degassed with argon for 10 min was added allylpalladium(ll)chloride dimer (14.3 mg, 9.18 pmol) followed by sodium 2'-(dicyclohexylphosphino)-2,6-dimethoxy-[1 ,T- biphenyl]-3-sulfonate hydrate (41.5 mg, 78.3 pmol). The reaction mixture was stirred at 110 °C for 24 h. The reaction mixture was concentrated then diluted with 1 N HCI aqueous solution and extracted with ethyl acetate. The reaction mixture was washed with water, brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with cyclohexane / ethyl acetate from 100 / 0 to 50 / 50 to afford ethyl 8-((1 H-pyrazol-1- yl)methyl)-2,3-dihydrobenzo[b][1 ,4]dioxine-5-carboxylate (136 mg, 60 %) as a white solid. LCMS (ES, m / z): 289.1 [M+H]+.

[0406]

[0259] Step 3: To a mixture of ethyl 8-((1H-pyrazol-1-yl)methyl)-2,3- dihydrobenzo[b][1,4]dioxine-5-carboxylate (130 mg, 450 pmol) in THF (1.1 mL) and water (1.1 mL), was added LiOH (21.6 mg, 901 pmol). The reaction mixture was stirred at room temperature for 16 h. The reaction mixture diluted with water and acidified with 1 N HCI aqueous solution until pH=2-3. The aqueous phase was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford 8-((1H-pyrazol-1-yl)methyl)- 2,3-dihydrobenzo[b][1,4]dioxine-5-carboxylic acid (Intermediate INTB-IS) (73 mg, 62 % yield) as a pale yellow solid. LCMS (ES, m / z): 261.1 [M+H]+.

[0407] Intermediate INTB-16: 7-((1H-pyrazol-1-yl)methyl)benzo[d][1,3]dioxole-4-carboxylic acid (Intermediate INT B-IS) Scheme SCHINTB- B-

[0408]

[0260] Step 1 : To a mixture of ethyl 7-bromobenzo[d][1 ,3]dioxole-4-carboxylate (500 mg, 1.83 mmol), potassium ((1 H-pyrazol-1-yl)methyl)trifluoroborate (516 mg, 2.74 mmol) and cesium carbonate (1.79 g, 5.49 mmol) in CPME (7.3 mL) and water (1.8 mL) degassed with argon for 10 min was added allylpalladium(ll)chloride dimer (33.5 mg, 91.5 pmol) followed by sodium 2'-(dicyclohexylphosphino)-2,6-dimethoxy-[1 ,1'-biphenyl]-3- sulfonate hydrate (97.1 mg, 183 pmol). The reaction mixture was stirred at 110 °C for 24 h. The reaction mixture was concentrated under reduced pressure then diluted with 1N HCI aqueous solution and extracted with ethyl acetate. The organic phase washed with water, brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with cyclohexane / ethyl acetate from 100 / 0 to 50 / 50 to afford ethyl 7-((1 H-pyrazol-1- yl)methyl)benzo[d][1,3]dioxole-4-carboxylate (370 mg, 73 % yield) as a white solid. LCMS (ES, m / z): 275.1 [M+H]+.

[0409]

[0261] Step 2: To a mixture of ethyl 7-((1H-pyrazol-1-yl)methyl)benzo[d][1,3]dioxole-4- carboxylate (360 mg, 1.31 mmol) in THF (6.5 mL) and water (6.5 mL) was added LiOH (62.8 mg, 2.62 mmol). The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with water and acidified with 1 N HCI aqueous solution until pH=2-3. The resulting precipitate was filtered, rinsed with water then dried under reduced pressure to afford 7-((1 H-pyrazol-1-yl)methyl) benzo[d][1,3]dioxole-4-carboxylic acid (Intermediate INT B-IB) (227 mg, 70 % yield) as a pale yellow solid. LCMS (ES, m / z): 247.2 [M+H]+.

[0410] Intermediate INTB-I?: methyl 5-hydroxychromane-8-carboxylate (Intermediate INT B-

[0411] 17)

[0412] Scheme SCHINTBI

[0413] Step l Step 2

[0414]

[0262] Step 1 : A mixture of 5-bromochromane-8-carboxylic acid (500 mg, 1.94 mmol), KOH (655 mg, 11.7 mmol) in dioxane (9.8 mL) and water (9.8 mL) was degassed under argon then Pd2dba3 (17.8 mg, 19.4 pmol) and t-BuXPhos (16.5 mg, 38.9 pmol) were added. The reaction mixture was stirred at 80 °C for 16 h. Dichloromethane and 1N HCI aqueous solution were added until pH=1. After separation, aqueous phase was extracted with dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford 5-hydroxychromane-8- carboxylic acid (360 mg, 86 % yield) as an orange solid. LCMS (ES, m / z): 195.1[M-H]+.

[0415]

[0263] Step 2: A mixture of 5-hydroxychromane-8-carboxylic acid (600 mg, 3.09 mmol) and H2SO4 (606 mg, 6.18 mmol) in methanol (31 mL) was stirred at 110°C for 16 h. The reaction mixture was diluted with ethyl acetate, washed with water and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford methyl 5-hydroxychromane-8-carboxylate (Intermediate INTB-I?) (620 mg, 96 % yield) as a yellow solid. LCMS (ES, m / z): 209.1[M-H]+.

[0416] Intermediate INTB-IS: 5-(thiazol-2-yloxy)chromane-8-carboxylic acid (Intermediate

[0417] INT B-18)

[0418] Scheme SCHINTB B-

[0419] Step 1 Step 2

[0420]

[0264] Step 1 : To a mixture of methyl 5-hydroxychromane-8-carboxylate (Intermediate INT B-17) (400 mg, 1.92 mmol) in DMSO (9.6 mL) was added potassium carbonate (797 mg, 5.76 mmol) and 2-bromo-thiazole (473 mg, 2.88 mmol). The reaction mixture was stirred at 120 °C for 72 h. The reaction mixture was dissolved with water and ethyl acetate. After separation, the aqueous phase was extracted with ethyl acetate. Combined organic layers were washed with water, brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with cyclohexane / ethyl acetate / ethanol from 100 / 0 / 0 to 60 / 30 / 10 to afford methyl 5-(thiazol-2-yl oxy)chromane-8-carboxylate (200 mg, 34 % yield) as a brown oil. LCMS (ES, m / z): 292.1[M-H]+.

[0421]

[0265] Step 2: To a solution of methyl 5-(thiazol-2-yloxy)chromane-8-carboxylate (200 mg, 645 pmol) in THF (4.8 mL) and water (1.6 mL) was added lithium hydroxide monohydrate (53.8 pL, 1.94 mmol). The reaction mixture was stirred at room temperature for 18 h. The solvent was removed under reduced pressure and the residue was dissolved in water and dichloromethane then 1N HCI aqueous solution was added until pH=3. After separation, the aqueous layer was extracted with dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford 5-(thiazol-2-yloxy)chromane-8-carboxylic acid (Intermediate INTB-IS) (165 mg, 90 % yield) as a clear oil. LCMS (ES, m / z): 278.1[M-H]+.

[0422] Intermediate INT B-19: 5-(oxazol-2-yloxy)chromane-8-carboxylic acid (Intermediate

[0423] INT B-19)

[0424] Scheme SCH INTB-IS-

[0425] Step l Step 2

[0426]

[0266] Step 1 : To a mixture of methyl 5-hydroxychromane-8-carboxylate (Intermediate INT B-17) (200 mg, 961 pmol) in DMSO (4.8 mL) was added 2-bromooxazole (213 mg, 1.44 mmol) and potassium carbonate (398 mg, 2.88 mmol). The reaction mixture was stirred at 120 °C for 3 h. The reaction mixture was dissolved in water and ethyl acetate. After separation, aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water, brine, dried over anhydrous sodium sulfate, filtered and concentrated under pressure to afford methyl 5-(oxazol-2-yloxy)chromane-8-carboxylate (220 mg, 79 % yield) as a yellow solid. LCMS (ES, m / z): 276.1[M-H]+.

[0427]

[0267] Step 2: To a solution of methyl 5-(oxazol-2-yloxy)chromane-8-carboxylate (220 mg, 799 pmol) in THF (12 mL) and water (4 mL) was added lithium hydroxide monohydrate (101 mg, 2.4 mmol). The reaction mixture was stirred at room temperature for 18 h. The solvent was removed under reduced pressure and the residue was dissolved in water and dichloromethane. 1 N HCI aqueous solution was added until pH=3. After separation, aqueous layer was extracted with dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford 5-(oxazol-2-yloxy)chromane-8-carboxylic acid (Intermediate INTB-IS) (230 mg, 95 % yield) as a white solid. LCMS (ES, m / z): 262.1[M-H]+.

[0428] Intermediate INTB-2O: 5-(thiazol-2-yloxy)chromane-8-carboxylic acid (Intermediate

[0429] INT B-20)

[0430] Scheme SCHINTB2O-

[0431]

[0268] Step 1 : A mixture of 5-bromochromane-8-carboxylic acid (1.08 g, 4.21 mmol), potassium hydroxide (1.42 g, 25.3 mmol) in dioxane (21 mL) and water (21 mL) were degassed for 5 min. Then Pd2dba3 (38.6 mg, 42.1 pmol) and t-BuXPhos (35.8 mg, 84.3 pmol) were added. The reaction mixture was stirred at 80°C for 16 h. Dichloromethane and 1N HCI aqueous solution were added until pH=1. After separation, the aqueous phase was extracted with dichloromethane. The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford 5- hydroxychromane-8-carboxylic acid (870 mg, 100 % yield) as an orange solid. LCMS (ES, m / z): 195.1[M+H]+.

[0432]

[0269] Step 2: A mixture of 5-hydroxychromane-8-carboxylic acid (1.45 g, 7.467 mmol) and H2SO4 (796.0 pL, 14.93 mmol) in methanol (75 mL) was heated at 110°C for 16 h. The reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified on silica gel column chromatography eluted with cyclohexane / ethyl acetate from 100 / 0 to 80 / 20 to afford methyl 5-hydroxychromane- 8-carboxylate (470 mg, 30 % yield) as a brown solid. LCMS (ES, m / z): 209.2[M+H]+.

[0433]

[0270] Step 3: To a mixture of methyl 5-hydroxychromane-8-carboxylate (105 mg, 504 pmol) in DMSO (2.5 mL) was added 2-bromothiazole (67.6 pL, 756 pmol), potassium carbonate (209 mg, 1.51 mmol). The reaction mixture was stirred at 150 °C for 12 h under MW irradiations. The crude material was dissolved in water and ethyl acetate. After separation, the aqueous phase was extracted ethyl acetate. The combined organic phases were washed with water, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with cyclohexane / (ethyl acetate / ethanol 3:1) from 100 / 0 to 70 / 30 to afford methyl 5-(thiazol-2-yloxy)chromane-8-carboxylate (230 mg, 39 % yield) as a yellow oil. LCMS (ES, m / z): 292.2[M-H]+.

[0434]

[0271] Step 4: To a solution of methyl 5-(thiazol-2-yloxy)chromane-8-carboxylate (230 mg, 790 pmol) in THF (5.9 mL) and water (2.0 mL) was added lithium hydroxide monohydrate (99.4 mg, 2.37 mmol). The reaction mixture was stirred at room temperature for 18 h. The solvent was removed under reduced pressure. The residue was dissolved in water and dichloromethane then aqueous 1 N HCI aqueous solution was added until pH=3. After separation, the aqueous phase was extracted with dichloromethane. The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford 5-(thiazol-2-yloxy)chromane-8-carboxylic acid (Intermediate INTB-2o) (230 mg, 100 % yield) as a clear oil. LCMS (ES, m / z): 278.1[M-H]+.

[0435] Intermediate INT B-21 : 2-(chloromethyl)thiazole (Intermediate INT B-21 ) Scheme SCHINTB2 -

[0436] Step 1 Step 2

[0437]

[0272] Step 1 : To thiazole-2-carbaldehyde (1.55 mL, 17.7 mmol) in methanol (50 mL) at 0°C was added NaBhL (669 mg, 17.7 mmol). The reaction mixture was stirred at 0°C for 2 h. Few drops of a saturated NH4CI aqueous solution were added. The solvent was removed under reduced pressure. The crude material was dissolved in water and ethyl acetate. The layers were separated and the organic one was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford thiazol-2- ylmethanol (1.3 g, 64 % yield) as a colorless oil. LCMS (ES, m / z): 116.0[M+H]+.

[0438]

[0273] Step 2: To thiazol-2-ylmethanol (800 mg, 6.94 mmol) in dichloromethane (20 mL) at 0°C was added thionyl chloride (1.01 mL, 13.89 mmol). The reaction mixture was stirred at 40 °C for 16 h. The solvent was removed under reduced pressure to afford 2- (chloromethyl)thiazole (Intermediate INTB-21) (1.1 g, 100 % yield) as an orange solid. LCMS (ES, m / z): 134.1[M+H]+.

[0439] Intermediate INT B-22: 5-(thiazol-2-ylmethyl)chromane-8-carboxylic acid (Intermediate

[0440] INT B-22)

[0441] Scheme SCHINTB22-

[0442]

[0274] Step 1 : A mixture of 5-bromochromane-8-carboxylic acid (1.57 g, 6.11 mmol) and H2SO4 (651 pL, 12.2 mmol) in methanol (30 mL) was heated at 90°C for 16 h. The reaction mixture was diluted with ethyl acetate, washed with water and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford methyl 5-bromochromane-8-carboxylate (1.58 g, 95 % yield) as a yellow pale oil. LCMS (ES, m / z): 271.0[M+H]+.

[0443]

[0275] Step 2: To methyl 5-bromochromane-8-carboxylate (125.00 mg, 461 pmol) were added potassium acetate (135 mg, 1.38 mmol) and b / s(pinacolato)diborane (175 mg, 691 pmol). The reaction mixture was degassed with argon for 10 min. and Pd(dppf)Ch complex (18.8 mg, 23 pmol) was added. The reaction mixture was stirred at 130°C for 25 min under microwave irradiations. The reaction material was filtered over a pad of silica, sodium sulfate and Celite. The filtrate was evaporated under reduced pressure to afford methyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)chromane-8-carboxylate (260 mg, 100 % yield) as a brown oil which was engaged in the next step without further purification. LCMS (ES, m / z): 319.1 [M+H]+.

[0444]

[0276] Step 3: In a sealed tube, 2-(chloromethyl)thiazole (Intermediate INTB-21) (623 mg, 3.92 mmol), methyl 5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)chromane-8- carboxylate (1.60 g, 57% Wt, 0.615 mmol), cesium carbonate (1.70 g, 5.23 mmol) in dioxane (8.7 mL) at room temperature were degassed for 5 min with argon. Then, Pd(dppf)Ch complex (213 mg, 261 pmol) was added. The reaction mixture was stirred at 130 °C for 30 min under microwave irradiations. Water and ethyl acetate were added. After separation, the organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted cyclohexane / CPME from 100 / 0 to 40 / 60 to afford methyl 5-(thiazol-2-ylmethyl)chromane-8-carboxylate (376 mg, 39 % yield) as a brown oil. LCMS (ES, m / z): 290.2[M+H]+.

[0445]

[0277] Step 4: To methyl 5-(thiazol-2-ylmethyl)chromane-8-carboxylate (376 mg, 1.03 mmol) in THF (2.0 mL) and water (2.0 mL) at room temperature was added LiOH (49.2 mg, 2.05 mmol). The reaction mixture was stirred at room temperature for 16 h. Then aqueous 1 N HCI aqueous solution was added slowly until pH=3. The aqueous layer was extracted with ethyl acetate / IPA. The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford 5-(thiazol-2-ylmethyl)chromane-8-carboxylic acid (Intermediate INTB-22) (182 mg, 50 % yield) as a white solid. LCMS (ES, m / z): 276.2[M+H]+.

[0446] Intermediate INTB-23: 7-(thiazol-2-yloxy)benzo[d][1,3]dioxole-4-carboxylic acid

[0447] (Intermediate INTB-23)

[0448] Scheme SCHINTB-23-

[0449]

[0278] Step 1 : To ethyl 7-bromobenzo[d][1 ,3]dioxole-4-carboxylate (800mg, 2.92 mmol) in dioxane (7.3 mL) and water (7.3 mL) was added potassium hydroxide (821 mg, 14.6 mmol) and tBu-XPhos (124 mg, 292 pmol). The reaction mixture was degassed with argon for 10 min and Pd2(dba)s (134 mg, 146 pmol) was added. The reaction mixture was stirred at 80 °C for 16 h under argon atmosphere. Water and ethyl acetate were added. After separation, 1N HCI aqueous solution was added to the aqueous phase and extracted with ethyl acetate. The combined organic layers were washed with a brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford 7-hydroxybenzo[d][1 ,3]dioxole-4-carboxylic acid (486 mg, 75 % yield) as a yellow solid which was engaged in the next step without further purification. LCMS (ES, m / z): 183.1[M+H]+.

[0450]

[0279] Step 2: A mixture of 7-hydroxybenzo[d][1 ,3]dioxole-4-carboxylic acid (446 mg, 2.45 mmol) and H2SO4 (261 pL, 4.9 mmol) in methanol (12.2 mL) was heated at 90°C for 20 h. The reaction mixture was diluted with ethyl acetate, washed with water and brine then dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford methyl 7-hydroxybenzo[d][1 ,3]dioxole-4-carboxylate (380 mg, 67 % yield) as an orange solid. LCMS (ES, m / z): 197.1[M+H]+.

[0451]

[0280] Step 3: To a mixture of methyl 7-hydroxybenzo[d][1,3]dioxole-4-carboxylate (330 mg, 1.68 mmol) in DMSO (8.4 mL) was added 2-bromothiazole (303 pL, 3.36 mmol), potassium carbonate (697 mg, 5.04 mmol). The reaction mixture was stirred at 120°C for 90 h. The crude material was dissolved in water and ethyl acetate. The organic phase was washed with water and after separation, the organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with cyclohexane / CPME from 100 / 0 to 50 / 50 to afford methyl 7-(thiazol-2-yloxy) benzo[d][1 ,3]dioxole-4-carboxylate (88 mg, 18 % yield) as a yellow pale oil. LCMS (ES, m / z): 280.1[M+H]+.

[0452]

[0281] Step 4: To methyl 7-(thiazol-2-yloxy)benzo[d][1,3]dioxole-4-carboxylate (88 mg, 0.32 mmol) in THF (1.0 mL) and water (1.0 mL) at room temperature was added lithium hydroxide (15 mg, 0.63 mmol). The reaction mixture was stirred at room temperature for 16 h. 1 N HCI aqueous solution was added slowly until pH=3. Then, the aqueous layer was extracted with ethyl acetate / IPA. The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford 7-(thiazol-2-yloxy)benzo[d][1 ,3]dioxole-4-carboxylic acid (Intermediate INTB-23) (74 mg, 89 % yield) as a white solid. LCMS (ES, m / z): 266.1[M+H]+.

[0453] Intermediates INTB-I to INTB-23

[0454]

[0282] The following intermediates from Intermediate INTB-I to Intermediate INTB-23listed in Table 3 were prepared by following similar procedures described above for Intermediate INTB-I and INTB-23 using appropriate reagents with suitable modifications known to the one skilled in the art.

[0455] Table 3. Intermediates B

[0456] Compounds of the present invention can be synthesized following the processes outlined here after.

[0457] Example EXAi: 5-((1H-pyrazol-1-yl)methyl)- / V-((2,6- dimethoxyphenyl)sulfonyl)chromane-8-carboxamide (Example EXAi - Compound 4) Scheme SCHEXAI

[0458]

[0283] To a mixture of 5-((1 H-pyrazol-1 -yl)methyl)chromane-8-carboxylic acid (Intermediate INTB-I) (60 mg, 0.23 mmol) in DMF (1 mL) at 50 °C was added GDI (49 mg, 0.30 mmol). The reaction mixture was stirred at 50 °C for 1 h then 2,6- dimethoxybenzenesulfonamide (Intermediate INTA-I) (61 mg, 0.28 mmol) and DBU (0.11 mL, 0.70 mmol) were sequentially added at room temperature. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was purified by reverse phase Cis column chromatography eluting with water / acetonitrile 100 / 0 to 0 / 100 to afford 5-((1 H- pyrazol-1-yl)methyl)- / \ / -((2,6-dimethoxyphenyl)sulfonyl)chromane-8-carboxamide (Example EXA1 - Compound 4) (8 mg, 7 % yield) as a white solid. LCMS (ES, m / z): 458.3 [M+H]+.

[0459] 1H NMR (400 MHz, DMSO) 511.25-11.16 (br. s, 1 H), 7.80-7.75 (m, 1 H), 7.56-7.47 (m, 2H), 7.37-7.27 (m, 1 H), 6.83-6.77 (m, 2H), 6.36 (d, J = 8.25 Hz, 1 H), 6.30 (t, J = 2.14 Hz, 1 H), 5.35 (s, 2H), 4.35-4.26 (m, 2H), 3.80 (s, 6H), 2.80-2.75 (m, 2H), 2.05-1.95 (m, 2H).

[0460] Example EXA2: 4-((1 H-pyrazol-1 -yl)methyl)- / V-((2,6-dimethoxyphenyl)sulfonyl)-2,3- dihydrobenzofuran-7-carboxamide (Example EXA2 - Compound 5)

[0461] Scheme SCHEXA2

[0462]

[0284] To a mixture of 4-((1 H-pyrazol-1 -yl)methyl)-2,3-dihydrobenzofuran-7-carboxylic acid (Intermediate INTB-2) (110 mg, 450 pmol) in THF (3 mL) at 50 °C was added GDI (94 mg, 585 pmol). The reaction mixture was stirred at 50 °C for 1 h then 2,6- dimethoxybenzenesulfonamide (Intermediate INTA-I) (88 mg, 405 pmol) and DBU (204 pL, 1.35 mmol) were sequentially added at room temperature. The mixture was stirred at room temperature for 16 h. The reaction mixture was purified by reverse phase C18 column chromatography eluting water / acetonitrile from 100 / 0 to 30 / 70 to afford 4-((1H- pyrazol-1-yl)methyl)- / \ / -((2,6-dimethoxyphenyl)sulfonyl)-2,3-dihydrobenzofuran-7- carboxamide (Example EXA2 - Compound 5) (16 mg, 7.6 % yield) as a colorless gum. LCMS (ES, m / z): 444.3 [M+H]+.

[0463] 1H NMR (400 MHz, DMSO) 5 10.60 (1 H, s), 7.84 (1H, d, J=1.1 Hz), 7.52 (1H, bs), 7.49 (1H, d, J=1.9 Hz), 7.46 (1H, d, J=8.1 Hz), 6.78 (2H, d, J=6.3 Hz), 6.59 (1 H, d, J=8.4 Hz), 6.30 (1H, dd, J=2.0, 2.0 Hz), 5.36 (2H, s), 4.85 - 4.82 (2H, m), 3.78 (6H, s), 3.17 - 3.13 (2H, m).

[0464] Example EXA3: A / -[(2-chloro-5-methoxy-6-quinolyl)sulfonyl]-5-(pyrazol-1- ylmethyl)chromane-8-carboxamide (Example EXA3 - Compound 2) Scheme SCHEXA3-

[0465]

[0285] A solution of 5-((1 H-pyrazol-1-yl)methyl)chromane-8-carboxylic acid (Intermediate INTB-I) (50 mg, 194 pmol) and GDI (44 mg, 271 pmol) in DMF (1 mL) was stirred at 50°C for 1 h. The reaction mixture was allowed to cool down to room temperature then 2-chloro- 6-methoxyquinoline-7-sulfonamide (Intermediate INTA-5) (63 mg, 232 pmol) and DBU (87.5 pL, 581 pmol) were added. The reaction mixture was stirred at 50°C for 16 h. The crude mixture was directly purified by preparative HPLC to afford 5-((1H-pyrazol-1- yl)methyl)- / V-((2-chloro-6-methoxyquinolin-7-yl)sulfonyl) chromane-8-carboxamide (Example EXA3 - Compound 2) (11 mg, 11 % yield) as a white solid. LCMS (ES, m / z): 513.3 [M+H]+.

[0466] 1H NMR (400 MHz, DMSO) 511.94 (1H, s), 8.45 - 8.41 (2H, m), 7.78 - 7.70 (3H, m), 7.48 (1H, d, J=1.3 Hz), 7.19 (1H, d, J=8.6 Hz), 6.37 (1H, d, J=8.1 Hz), 6.29 (1 H, t, J=2.0 Hz), 5.33 (2H, s), 4.24 (2H, s), 4.01 (3H, s), 2.74 (2H, t, J=6.3 Hz), 2.01 - 1.95 (2H, m).

[0467] Example EXA4: A / -(2,3-dihydrobenzofuran-7-ylsulfonyl)-5-(pyrazol-1- ylmethyl)chromane-8-carboxamide (Example EXA4 - Compound 1) Scheme SCHEXA4-

[0468]

[0286] To a solution of 5-((1 H-pyrazol-1-yl)methyl)chromane-8-carboxylic acid (Intermediate INTB-I) (80 mg, 310 pmol) and GDI (70 mg, 434 pmol) in DMF (1.55 mL) was stirred at 60°C for 1 h. The reaction mixture was allowed to cool down to room temperature then 2,3-dihydrobenzofuran-7-sulfonamide (Intermediate INTA-?) (74 mg, 372 pmol) and DBU (140 pL, 929 pmol) were added. The reaction mixture was stirred at room temperature for 16 h. The crude mixture was directly purified by preparative HPLC to afford 5-((1 H-pyrazol-1-yl)methyl)- / V-((2,3-dihydrobenzofuran-7-yl)sulfonyl) chromane-8- carboxamide (Example EXA4 - Compound 1) (14 mg, 10 % yield) as a white solid. LCMS (ES, m / z): 440.3 [M+H]+.

[0469] 1H NMR (400 MHz, DMSO) 511.71 (1 H, s), 7.77 (1 H, d, J=1 .9 Hz), 7.59 - 7.48 (3H, m), 7.19 (1 H, d, J=7.2 Hz), 6.99 (1 H, t, J=7.6 Hz), 6.38 (1 H, d, J=7.0 Hz), 6.30 (1 H, t, J=2.1 Hz), 5.34 (2H, d), 4.69 (2H, t, J=8.3 Hz), 4.22 (2H, t, J=4.6 Hz), 3.26 (2H, t, J= 9.0 Hz), 2.75 (2H, t, J=6.5 Hz), 2.01 - 1.94 (2H, m).

[0470] Example EXA5: A / -(2-methoxyphenyl)sulfonyl-5-(pyrazol-1-ylmethyl)chromane-8- carboxamide (Example EXAs - Compound 3) Scheme SCHEXAS.

[0471]

[0287] To a mixture of 5-((1 H-pyrazol-1-yl)methyl)chromane-8-carboxylic acid (Intermediate INTB-I) (100 mg, 387 pmol) in DMF (1.94 mL) at 60°C was added GDI (81.6 mg, 503 pmol). The reaction mixture was stirred at 60°C under Argon for 1 h then 2- methoxybenzenesulfonamide (Intermediate INTA-2) (87 mg, 465 pmol) and DBU (175 pL, 1.16 mmol) were sequentially added at 60°C. The reaction mixture was stirred at 60°C under argon for 16 h. The crude material was dissolved in ethyl acetate and saturated aqueous NH4CI solution. The layers were separated and the organic one was dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with cyclohexane / ethyl acetate / ethanol 100 / 0 / 0 to 60 / 30 / 10 to afford 5-((1H-pyrazol-1-yl)methyl)- / V-((2- methoxyphenyl)sulfonyl)chromane-8-carboxamide (Example EXA5 - Compound 3) (95 mg, 55 % yield) as a white solid. LCMS (ES, m / z): 428.4 [M+H]+.

[0472] 1H-NMR (400 MHz, DMSO) 5 11.53 (s, 1H), 7.88 (dd, J=1.7, 8.0 Hz, 1H), 7.78 (d, J=2.1 Hz, 1 H), 7.68 (t, J=7.7 Hz, 1H), 7.50 (d, J=1.3 Hz, 1H), 7.25 (d, J=8.4 Hz, 1H), 7.22 (d, J=8.2 Hz, 1 H), 7.14 (t, J=7.5 Hz, 1H), 6.37 (d, J=8.0 Hz, 1 H), 6.30 (t, J=2.1 Hz, 1 H), 5.35 - 5.34 (m, 2H), 4.27 (t, J=5.0 Hz, 2H), 3.90 - 3.89 (m, 3H), 2.76 (t, J=6.5 Hz, 2H), 2.03 - 1.96 (m, 2H).

[0473] Example EXAs: 5-((1 H-pyrazol-1 -yl)methyl)- / V-((6-methoxyquinolin-7- yl)sulfonyl)chromane-8-carboxamide (Example EXAS- Compound 6) Scheme SCHEXA6-

[0474]

[0288] A mixture of 5-((1 H-pyrazol-1-yl)methyl)chromane-8-carboxylic acid (Intermediate INTB-I) (50 mg, 194 pmol) and GDI (43 mg, 271 pmol) in DMF (1 mL) was stirred at 60°C for 1 h. The reaction mixture was allowed to cool down to RT then 6-methoxyquinoline-7- sulfonamide (Intermediate INTA-B) (50 mg, 210 pmol) and DBU (87.5 pL, 581 pmol) were added. The reaction mixture was stirred at 60°C for 16 h. The crude mixture was directly purified by preparative HPLC to afford 5-((1 H-pyrazol-1-yl)methyl)- / V-((6-methoxyquinolin- 7-yl)sulfonyl)chromane-8-carboxamide (Example EXA6- Compound 6) (35 mg, 36 % yield) as a white solid.

[0475] LCMS (ES, m / z): 479.2 [M+H]+.1H NMR (400 MHz, DMSO) 611.88 (1 H, s), 8.92 (1 H, dd, J=1.5, 4.2 Hz), 8.54 (1 H, s), 8.37 (1 H, dd, J=0.9, 8.6 Hz), 7.77 (1 H, dd, J=0.6, 2.3 Hz), 7.69 - 7.64 (2H, m), 7.49 (1 H, dd, J=0.7, 1.8 Hz), 7.19 (1 H, d, J=7.9 Hz), 6.36 (1 H, d, J=8.0 Hz), 6.30 - 6.29 (1 H, m), 5.34 (2H, s), 4.26 (2H, t, J=5.0 Hz), 4.01 (3H, s), 2.76 (2H, t, J=6.4 Hz), 2.03 - 1.95 (2H, m).

[0476] Example EXA?: 5-((1H-pyrazol-1-yl)methyl)-N-((5-(3,3-difluoropyrrolidin-1-yl)-2- methoxyphenyl)sulfonyl)chromane-8-carboxamide (Example EXA7- compound 21) Scheme SCH EXA7.

[0477]

[0289] To a mixture of 5-((1 H-pyrazol-1-yl)methyl)chromane-8-carboxylic acid (Intermediate INTB-I) (40 mg, 0.15 mmol) in DMF (0.5 mL) at 80 °C was added GDI (33 mg, 0.20 mmol). The reaction mixture was stirred at 80°C under argon for 1 h. Then 5- (3,3-difluoropyrrolidin-1-yl)-2-methoxy benzenesulfonamide hydrochloride (Intermediate INTA-9) (56 mg, 0.17 mmol) and DBU (70 pL, 0.46 mmol) were sequentially added at room temperature. The reaction mixture was stirred at room temperature under argon for 16 h. The reaction mixture was purified by preparative HPLC and the resulting product was triturated in a mixture diethyl of ether / acetonitrile 9:1 , filtered and dried to afford 5-((1 H- pyrazol-1-yl)methyl)-N-((5-(3,3-difluoropyrrolidin-1-yl)-2-methoxyphenyl)sulfonyl) chromane-8-carboxamide (Example EXA7- compound 21) (2.3 mg, 2.6 % yield) as a beige solid. LCMS (ES, m / z): 533.2 [M+H]+.

[0478] 1H NMR (400 MHz, CDCI3) 6 10.54 (1 H, s), 7.88 (1 H, d, J=8.2 Hz), 7.60 - 7.58 (1 H, m), 7.36 - 7.33 (2H, m), 6.95 (1 H, d, J=8.9 Hz), 6.73 (1 H, dd, J=2.8, 9.0 Hz), 6.63 (1 H, d, J=8.2 Hz), 6.34 - 6.32 (1 H, m), 5.32 (2H, s), 4.47 - 4.43 (2H, m), 3.86 (3H, s), 3.70 (2H, t, J=13.1 Hz), 3.56 (2H, t, J=7.1 Hz), 2.77 - 2.73 (2H, m), 2.57 - 2.46 (2H, m), 2.20 - 2.12 (2H, m).

[0479] Example EXAs: 5-((1 H-pyrazol-1 -yl)methyl)-N-((5-(3-fluoroazetidin-1 -y I )-2- methoxyphenyl) sulfonyl)chromane-8-carboxamide (Example EXAs - compound 29) Scheme SCH EXA8-

[0480]

[0290] A mixture of 5-((1 H-pyrazol-1 -yl)methyl)chromane-8-carboxylic acid (Intermediate INTB-I) (100 mg, 387 pmol) and GDI (87.8 mg, 542 pmol) in DMF (1.9 mL) was stirred at 60°C for 1 h. The mixture was allowed to cool down to room temperature and 5-(3- fluoroazetidin-1-yl)-2-methoxybenzenesulfonamide TFA salt (Intermediate INTA^I) (145 mg, 557 pmol) and DBU (198 L, 1.31 mmol) were added. The reaction mixture was stirred at 60°C for 4 h. The crude was directly purified by preparative HPLC to afford 5- ((1 H-pyrazol-1-yl)methyl)-N-((5-(3-fluoroazetidin-1-yl)-2- methoxyphenyl)sulfonyl)chromane-8-carboxamide (Example EXAs - compound 29) (21 mg, 10 % yield) as a white solid. LCMS (ES, m / z): 501.2 [M+H]+.

[0481] 1H NMR (400 MHz, DMSO) 511.48 (1 H, s), 7.78 (1 H, d, J=2.1 Hz), 7.50 (1 H, dd, J=0.7, 1.8 Hz), 7.25 - 7.22 (1 H, m), 7.16 - 7.13 (1 H, m), 6.92 (1 H, d, J=3.0 Hz), 6.82 - 6.78 (1 H, m), 6.36 (1 H, d, J=8.2 Hz), 6.31 - 6.29 (1 H, m), 5.59 - 5.54 (0.5H, m), 5.44 - 5.38 (0.5H, m), 5.35 (2H, s), 4.27 (2H, t, J=4.5 Hz), 4.21 - 4.10 (2H, m), 3.93 - 3.83 (2H, m), 3.79 (3H, m), 2.76 (2H, t, J=6.4 Hz), 2.03 - 1.91 (2H, m).

[0482] Example EXA9: 6-(( 1 H-pyrazol-1 -yl)methyl)-N-((2,6-dimethoxyphenyl)sulfonyl)- 2,3,4,5-tetrahydrobenzo[b]oxepine-9-carboxamide (Example EXA9 - compound 15) Scheme SCH EXA9.

[0291] To a mixture of 6-((1 H-pyrazol-1 -yl)methyl)-2, 3, 4, 5-tetrahydrobenzo[b]oxepine-9- carboxylic acid (Intermediate INTB-H) (100 mg, 367 pmol) in DMF (1.8 mL) at 80 °C was added GDI (77 mg, 477 pmol). The reaction mixture was stirred at 80 °C under argon for 1 h. Then 2,6-dimethoxy benzenesulfonamide (Intermediate INTA-I) (95 mg, 441 pmol) and DBU (166 pL, 1.10 mmol) were sequentially added at room temperature. The reaction mixture was stirred at room temperature under argon for 3 h. The reaction mixture was concentrated under reduced pressure then diluted with 1 N HCI aqueous solution and extracted with ethyl acetate. The organic layer was washed with water, brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by reverse phase Cis column chromatography eluted with water / acetonitrile from 100 / 0 to 0 / 100 to afford 6-((1H-pyrazol-1-yl)methyl)-N-((2,6- dimethoxyphenyl)sulfonyl)-2,3,4,5-tetrahydro benzo[b]oxepine-9-carboxamide (Example EXA9- compound 15) (45 mg, 25 % yield) as a white solid. LCMS (ES, m / z): 472.2 [M+H]+.

[0483] 1H NMR (400 MHz, DMSO) 5 7.63 - 7.60 (1H, m), 7.44 (1H, dd, J=0.6, 1.9 Hz), 7.32 - 7.21 (1 H, m), 7.21 - 7.16 (1 H, m), 6.75 (1 H, d, J=8.1 Hz), 6.67 - 6.61 (2H, m), 6.24 (1H, t, J=1.9 Hz), 5.33 (2H, s), 3.84 - 3.77 (2H, m), 3.73 (6H, s), 2.80 - 2.74 (2H, m), 1.81 - 1.72 (2H, m), 1.45 - 1.36 (2H, m). Note: NH not visible.

[0484] Example EXA10: 5-((1 H-pyrazol-1 -yl)methyl)-N-((7-methoxy-2,3-dihydrobenzo [b][1,4]dioxin-6-yl)sulfonyl)chromane-8-carboxamide (Example EXA10 - compound 20)

[0485] Scheme SCH EXA10.

[0486]

[0292] A solution of 5-((1 H-pyrazol-1 -yl)methyl)chromane-8-carboxylic acid (Intermediate INTB-I) (70 mg, 271 pmol) and GDI (65 mg, 407 pmol) in DMF (1.9 mL) was stirred at 60°C for 1 h. The reaction mixture was allowed to cool down to room temperature then 7- methoxy-2,3-dihydrobenzo[b][1 ,4]dioxine-6-sulfonamide (Intermediate INTA-12) (70 mg, 271 pmol) and DBU (123 pL, 813 pmol) were added. The reaction mixture was stirred at 60°C for 16 h. The crude was purified by preparative HPLC to afford 5-((1H-pyrazol-1- yl)methyl)-N-((7-methoxy-2,3-dihydrobenzo[b][1,4]dioxin-6-yl) sulfonyl)chromane-8- carboxamide (Example EXA10 - compound 20) (51 mg, 37 % yield) as a white solid. LCMS (ES, m / z): 486.2 [M+H]+.

[0487] 1H NMR (400 MHz, DMSO) 5 11.43 (1 H, s), 7.77 (1 H, d, J=1.9 Hz), 7.49 (1 H, d, J=1.1 Hz), 7.30 (1 H, s), 7.24 - 7.21 (1 H, m), 6.75 (1 H, s), 6.36 (1 H, d, J=8 Hz) 6.31 - 6.29 (1 H, m), 5.34 (2H, s), 4.36 - 4.32 (2H, m), 4.27 - 4.24 (4H, m), 3.79 (3H, s), 2.75 (2H, t, J=6.3 Hz), 2.02 - 1.91 (2H, m).

[0488] Example EXAn : 5-((1 H-pyrazol-1 -yl)methyl)-N-((3-methoxy-5, 6,7,8- tetrahydronaphthalen-2-yl)sulfonyl)chromane-8-carboxamide (Example EXAn - compound 23)

[0489] Scheme SCH EXAII .

[0490]

[0293] To a mixture of 5-((1 H-pyrazol-1 -yl)methyl)chromane-8-carboxylic acid (Intermediate INTB-I) (110 mg, 426 pmol) in DMF (2.1 mL) at 60 °C was added GDI (89 mg, 554 pmol). The reaction mixture was stirred at 60 °C under argon for 1 h then 3- methoxy-5,6,7,8-tetrahydronaphthalene-2-sulfonamide (Intermediate INTA-IO) (113 mg, 468 pmol) and DBU (193 pL, 1.28 mmol) were added. The reaction mixture was stirred at 60 °C under argon for 16 h. The reaction mixture was concentrated then diluted with 1 N HCI aqueous solution and extracted with ethyl acetate. The organic layer was washed with water, brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with cyclohexane / ethyl acetate / ethanol from 100 / 0 / 00 to 60 / 30 / 10 to afford 5-((1 H-pyrazol- 1-yl)methyl)-N-((3-methoxy-5,6,7,8-tetrahydro naphthalen-2-yl)sulfonyl)chromane-8- carboxamide (Example EXAn - compound 23) (106 mg, 49 % yield) as a white solid. LCMS (ES, m / z): 482.2 [M+H]+.

[0491] 1H-NMR (400 MHz, DMSO) 5 11.40 (s, 1 H), 7.78 (d, J=1.5 Hz, 1 H), 7.54 (s, 1 H), 7.50 (dd, J=0.8, 1 .9 Hz, 1 H), 7.27 - 7.22 (m, 1 H), 6.92 (s, 1 H), 6.36 (d, J=8.0 Hz, 1 H), 6.30 (dd, J=1 .9, 2.3 Hz, 1 H), 5.35 (s, 2H), 4.29 - 4.25 (m, 2H), 3.82 (s, 3H), 2.79 - 2.69 (m, 6H), 2.03 - 1.97 (m, 2H), 1.75 - 1.72 (m, 4H). Example EXA12: 5-(( 1 H-pyrazol-1 -yl)methyl)-N-((6-methoxy-2,3-dihydro-1 H-indene-5- yl)sulfonyl)chromane-8-carboxamide (Example EXA12 - compound 22)

[0492] Scheme SCH EXA12.

[0493]

[0294] To a mixture of 5-((1 H-pyrazol-1 -yl)methyl)chromane-8-carboxylic acid (Intermediate INTB-I) (110 mg, 426 pmol) in DMF (2.1 mL) at 60 °C was added GDI (89 mg, 554 pmol). The reaction mixture was stirred at 60 °C under argon for 1 h then 4- methoxy-2,3-dihydro-1H-indene-5-sulfonamide (Intermediate INTA-S) (113 mg, 468 pmol) and DBU (193 pL, 1.28 mmol) were added. The reaction mixture was stirred at 60 °C under argon for 16 h. The reaction mixture was concentrated then diluted with 1 N HCI aqueous solution and extracted with ethyl acetate. The organic layer was washed with water, brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with cyclohexane / ethyl acetate / ethanol from 100 / 0 / 00 to 60 / 30 / 10 to afford 5-((1 H-pyrazol- 1-yl)methyl)-N-((6-methoxy-2,3-dihydro-1H-indene-5-yl)sulfonyl)chromane-8-carboxamide (Example EXA12 - compound 22) (106 mg, 49 % yield) as a white solid. LCMS (ES, m / z): 482.2 [M+H]+.

[0494] 1H-NMR (400 MHz, DMSO) 5 11.40 (s, 1 H), 7.78 (d, J=1.5 Hz, 1H), 7.54 (s, 1H), 7.50 (dd, J=0.8, 1.9 Hz, 1 H), 7.27 - 7.22 (m, 1 H), 6.92 (s, 1 H), 6.36 (d, J=8.0 Hz, 1 H), 6.30 (dd, J=1.9, 2.3 Hz, 1H), 5.35 (s, 2H), 4.29 - 4.25 (m, 2H), 3.82 (s, 3H), 2.79 - 2.69 (m, 6H), 2.03 - 1.97 (m, 2H), 1.75 - 1.72 (m, 4H).

[0495] Example EXA13: 9-((1 H-pyrazol-1 -yl)methyl)-N-((2,6-dimethoxyphenyl)sulfonyl)-3,4- dihydro-2H-benzo[b][1,4]dioxepine-6-carboxamide (Example EXA13 - compound 16) Scheme SCH EXA13.

[0496]

[0295] To a mixture of 9-((1 H-pyrazol-1 -yl)methyl)-3,4-dihydro-2H-benzo[b][1 ,4]dioxepine- 6-carboxylic acid (Intermediate INTB-IS) (100 mg, 365 pmol) in DMF (1 mL) at 80 °C was added GDI (76 mg, 474 pmol). The reaction mixture was stirred at 80 °C under argon for 1 h then 2,6-dimethoxybenzenesulfonamide (Intermediate INTA-I) (87 mg, 401 pmol) and DBU (165 pL, 1.09 mmol) were sequentially added at room temperature. The reaction mixture was stirred at room temperature under argon for 16 h. The reaction mixture was directly purified by preparative HPLC to afford 9-((1 H-pyrazol-1 -yl)methyl)-N- ((2,6-dimethoxyphenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1 ,4] dioxepine-6-carboxamide (Example EXA13 - compound 16) (105 mg, 58 % yield) as a white solid. LCMS (ES, m / z): 474.2 [M+H]+.

[0497] 1H NMR (400 MHz, DMSO) 5 11.65 (1 H, s), 7.79 (1 H, d, J=1.7 Hz), 7.54 (1 H, dd, J=8.4, 8.4 Hz), 7.46 (1 H, dd, J=0.7, 1.8 Hz), 7.03 (1 H, d, J=8.0 Hz), 6.81 (2H, d, J=8.5 Hz), 6.63 (1 H, d, J=8.2 Hz), 6.28 (1 H, dd, J=1 .9, 2.3 Hz), 5.33 (2H, s), 4.18 (2H, dd, J=5.1 , 5.1 Hz), 4.11 (2H, dd, J=5.4, 5.4 Hz), 3.82 (6H, s), 2.19 - 2.13 (2H, m).

[0498] Example EXA14: 8-(( 1 H-pyrazol-1 -yl)methyl)-N-((2,6-dimethoxyphenyl)sulfonyl)-2,3- dihydrobenzo[b][1,4]dioxine-5-carboxamide (Example EXA14 - compound 27) Scheme SCH EXA14.

[0499]

[0296] To a mixture of 8-((1 H-pyrazol-1 -yl)methyl)-2,3-dihydrobenzo[b][1 ,4]dioxine- 5- carboxylic acid (Intermediate INTB-IS) (70 mg, 269 pmol) in DMF (0.8 mL) at 80 °C was added GDI (56 mg, 350 pmol). The reaction mixture was stirred at 80 °C under argon for 1 h then 2,6-dimethoxybenzenesulfonamide (Intermediate INTA-I) (70 mg, 323 pmol) and DBU (122 pL, 807 pmol) were sequentially added at room temperature. The reaction mixture was stirred at room temperature under argon for 16 h then at 60°C for 72 h. Additional GDI (56.7 mg, 1.3 Eq, 350 pmol) was added and the reaction mixture was stirred at 60°C for 16 h. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography eluted with dichloromethane / methanol from 100 / 0 to 96 / 4 to afford 8-((1 H-pyrazol-1 -yl)methyl)-N-((2, 6- dimethoxyphenyl)sulfonyl)-2,3-dihydrobenzo[b][1,4]dioxine-5-carboxamide (Example EXA14 - compound 27) (13 mg, 10 % yield) as white solid. LCMS (ES, m / z): 474.2 [M+H]+.

[0500] 1H NMR (400 MHz, DMSO) 5 11.35 (1 H, s), 7.79 (1H, d, J=1.7 Hz), 7.56 - 7.48 (2H, m), 7.00 - 6.97 (1H, m), 6.82 - 6.78 (2H, m), 6.38 - 6.35 (1 H, m), 6.29 (1 H, t, J=2.0 Hz), 5.31 (2H, s), 4.45 - 4.38 (4H, m), 3.81 - 3.80 (6H, m).

[0501] Example EXA15: 5-((1 H-pyrazol-1 -yl)methyl)-N-((6-methoxy-2,3-dihydrobenzofuran-5- yl) sulfonyl)chromane-8-carboxamide (Example EXA15 - compound 8) Scheme SCH EXA15.

[0502]

[0297] To a mixture of 5-((1 H-pyrazol-1 -yl)methyl)chromane-8-carboxylic acid (Intermediate INTB-I) (120 mg, 465 pmol) in DMF (2 mL) at 60 °C was added GDI (97.9 mg, 604 pmol). The reaction mixture was stirred at 60 °C under argon for 1 h then 6- methoxy-2,3-dihydrobenzofuran-6-sulfonamide (Intermediate INTA-IB) (128 mg, 558 pmol) and DBU (210 pL, 1.39 mmol) were sequentially added at 60 °C. The reaction mixture was stirred at 60 °C under argon for 16 h. The reaction mixture was diluted with 1N HCI aqueous solution and extracted with ethyl acetate. The organic layer was washed with water, brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by reverse phase C18 column chromatography eluted with water / acetonitrile from 100 / 0 to 30 / 70 to afford 5-((1H-pyrazol-1-yl)methyl)-N-((6- methoxy-2,3-dihydrobenzofuran-5-yl)sulfonyl) chromane-8-carboxamide (Example EXA15 - compound 8) (42 mg, 18 % yield) as a white solid. LCMS (ES, m / z): 470.3 [M+H]+.1H NMR (400 MHz, DMSO) 6 7.68 (1 H, s), 7.63 (1 H, s), 7.47 (1 H, d, J=1 .1 Hz), 7.03 (1 H, br s), 6.48 (1 H, br s), 6.35 (1 H, d, J=7.8 Hz), 6.27 (1 H, t, J=2.0 Hz), 5.27 (2H, s), 4.58 (2H, t, J=8.6 Hz), 4.03 (2H, br s), 3.73 (3H, s), 3.11 (2H, t, J=9.3 Hz), 2.70 - 2.65 (2H, m), 1.92 - 1.88 (2H, m). Note: NH sulfonamide signal not visible.

[0503] Example EXAis: 7-((1H-pyrazol-1-yl)methyl)-N-((2,6- dimethoxyphenyl)sulfonyl)benzo[d][1,3] dioxole-4-carboxamide (Example EXA16 - compound 30)

[0504] Scheme SCH EXA16.

[0505]

[0298] To a mixture of 7-((1 H-pyrazol-1-yl)methyl)benzo[d][1 ,3]dioxole-4-carboxylic acid (Intermediate INTB-IB) (100 mg, 406 pmol) in DMF (2 mL) at 60 °C was added GDI (85.6 mg, 528 pmol). The reaction mixture was stirred at 60 °C under argon for 1 h then 2,6- dimethoxy benzenesulfonamide (Intermediate INTA-I) (105 mg, 487 pmol) and DBU (183 L1 .21 mmol) were sequentially added at room temperature. The reaction mixture was stirred at 60 °C under argon for 16 h. The reaction mixture was concentrated to dryness under reduced pressure and purified by preparative HPLC to afford 7-((1 H-pyrazol-1- yl)methyl)-N-((2,6-dimethoxy phenyl)sulfonyl) benzo[d][1 ,3]dioxole -4-carboxamide (Example EXA16 - compound 30) (34 mg, 18 % yield) as a white solid. LCMS (ES, m / z): 446.3 [M+H]+.

[0506] 1H NMR (400 MHz, DMSO) 5 11.37 (1 H, s), 7.84 (1 H, dd, J=0.6, 2.3 Hz), 7.54 - 7.47 (2H, m), 7.14 - 7.11 (1 H, m), 6.82 - 6.78 (2H, m), 6.61 - 6.54 (1 H, m), 6.29 (1 H, t, J=2.1 Hz), 6.22 (2H, s), 5.34 (2H, s), 3.33 (6H, s).

[0507] Example EXAi7a: N-(2,6-dimethoxyphenyl)sulfonyl-7-(pyrazol-1-ylmethyl)-1,1a,2,7b- tetrahydro cyclopropa[c]chromene-4-carboxamide (Example EXAi?a- compound 10) and Example EXAi?b: N-(2,6-dimethoxyphenyl)sulfonyl-7-(pyrazol-1-ylmethyl)- 1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxamide (Example EXAi?b - compound 11) Scheme SCH EX17.

[0508] Isomer 1 Isomer 2

[0509]

[0299] To a mixture of 7-((1 H-pyrazol-1-yl)methyl)-1 ,1a,2,7b- tetrahydrocyclopropa[c]chromene-4-carboxylic acid (Intermediate INTB-S) (110 mg, 407 pmol) in DMF (2.0 mL) at 60 °C was added GDI (85.8 mg, 529 pmol). The reaction mixture was stirred at 60 °C under argon for 1 h. Then 2,6-dimethoxybenzenesulfonamide (Intermediate INTA-I) (106 mg, 488 pmol) and DBU (184 pL, 1.22 mmol) were sequentially added at 60 °C. The reaction mixture was stirred at 60°C under argon for 2 h. The reaction mixture was diluted with 1 N HCI aqueous solution, extracted with ethyl acetate. The organic layer was washed with water, brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by Cis reverse column chromatography eluted with water / acetonitrile from 100 / 0 to 00 / 100 to afford 7-((1 H-pyrazol-1-yl)methyl)-N-((2,6-dimethoxyphenyl)sulfonyl)-1 ,1a,2,7b- tetrahydrocyclopropa[c]chromene-4-carboxamide (mixture of Isomer 1 and Isomer 2) (57 mg, 28 % yield) as a white solid.

[0510]

[0300] The mixture of diastereoisomers was separated by chiral preparative HPLC eluted with heptane / (methanol / DCM) 50 / 50 to afford 7-((1 H-pyrazol-1-yl)methyl)-N-((2,6- dimethoxyphenyl) sulfonyl)-1 ,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxamide (Isomer 1) (Example EXAi?a- compound 10 or 11) (19 mg) as a white solid. LCMS (ES, m / z): 470.2[M-H]+.

[0511] 1H NMR (400 MHz, DMSO-d6) 5 11.30 (s, 1 H), 7.82 (d, J=1 .9 Hz, 1 H), 7.53 (t, J=8.5 Hz, 1 H), 7.50 (dd, J=0.7, 1.8 Hz, 1 H), 7.25 (d, J=8.1 Hz, 1 H), 6.80 (d, J=8.9 Hz, 2H), 6.54 (d, J=8.1 Hz, 1 H), 6.30 (dd, J=1.9, 2.2 Hz, 1 H), 5.57 - 5.47 (m, 2H), 4.39 (d, J=10.7 Hz, 1 H), 4.12 (d, J=11.2 Hz, 1 H), 3.80 (s, 6H), 2.33 (dt, J=4.6, 8.6 Hz, 1 H), 1.93 - 1.87 (m, 1 H), 1.19 - 1.13 (m, 1 H), 0.89 - 0.85 (m, 1 H).

[0512]

[0301] and 7-((1 H-pyrazol-1-yl)methyl)-N-((2,6-dimethoxyphenyl)sulfonyl)-1 ,1a,2,7b- tetrahydrocyclopropa [c]chromene-4-carboxamide (Isomer 2) (Example EXAi?b - compound 10 or 11) (15 mg) as a white solid. LCMS (ES, m / z): 470.2[M-H]+.

[0513] 1H NMR (400 MHz, DMSO-d6) 5 11.30 (s, 1 H), 7.82 (d, J=1 .9 Hz, 1 H), 7.53 (t, J=8.5 Hz, 1 H), 7.50 (dd, J=0.7, 1.8 Hz, 1 H), 7.25 (d, J=8.1 Hz, 1 H), 6.80 (d, J=8.9 Hz, 2H), 6.54 (d, J=8.1 Hz, 1 H), 6.30 (dd, J=1.9, 2.2 Hz, 1 H), 5.57 - 5.47 (m, 2H), 4.39 (d, J=10.7 Hz, 1 H), 4.12 (d, J=11.2 Hz, 1 H), 3.80 (s, 6H), 2.33 (dt, J=4.6, 8.6 Hz, 1 H), 1.93 - 1.87 (m, 1 H), 1.19 - 1.13 (m, 1 H), 0.89 - 0.85 (m, 1 H).

[0514] Example EXAis: 7-((1H-pyrazol-1-yl)methyl)-N-((5-isopropyl-2- methoxyphenyl)sulfonyl)benzo [d][1,3]dioxole-4-carboxamide (Example EXAis - compound 31)

[0515] Scheme SCH EXA18.

[0516]

[0302] To a mixture of 7-((1 H-pyrazol-1-yl)methyl)benzo[d][1 ,3]dioxole-4-carboxylic acid (Intermediate INTB-IB) (105 mg, 426 pmol) in DMF (2 mL) at 60 °C was added GDI (89.9 mg, 554 pmol). The reaction mixture was stirred at 60 °C under argon for 1 h then 5- isopropyl-2-methoxybenzenesulfonamide (Intermediate INTA-IS) (117 mg, 511 pmol) and DBU (192 pL, 1.27 mmol) were sequentially added at 60 °C. The reaction mixture was stirred at 60 °C under argon for 16 h. The crude mixture was washed with water and extracted with ethyl acetate. The aqueous layer was concentrated to dryness. The residue was purified by Cis reverse phase column chromatography eluted with water / acetonitrile from 100 / 0 to 0 / 100 to afford 7-((1 H-pyrazol-1-yl)methyl)-N-((5- isopropyl-2-methoxyphenyl)sulfonyl)benzo[d][1 ,3]dioxole-4-carboxamide (Example EXAis - compound 31) (14 mg, 7% yield) as a white solid. LCMS (ES, m / z): 458.2 [M+H]+.

[0517] 1H NMR (400 MHz, DMSO) 7.77 (1 H, d, J=1 .7 Hz), 7.68 (1 H, d, J=2.5 Hz), 7.45 (1 H, d, J=1 .1 Hz), 7.24 - 7.20 (2H, m), 6.92 - 6.89 (1 H, m), 6.50 - 6.47 (1 H, m), 6.26 (1 H, t, J=2.0 Hz), 6.02 (2H, s), 5.26 (2H, s), 3.67 (3H, s), 2.90 - 2.74 (1 H, m), 1.19 (6H, d, J=6.8 Hz). Note: 1 H not visible on spectra.

[0518] Example EXA19: N-((2,6-dimethoxyphenyl)sulfonyl)-5-(thiazol-2-yloxy)chromane-8- carboxamide (Example EXA19 - compound 32)

[0519] Scheme SCH EXA19.

[0520]

[0303] To a suspension of 5-(thiazol-2-yloxy)chromane-8-carboxylic acid (Intermediate INTB-20) (80 mg, 289 pmol) and GDI (79.5 mg, 490 pmol) in DMF (1.9 mL) was stirred at 60°C for 1 h. The reaction mixture was allowed to cool down to room temperature and 2,6- dimethoxybenzenesulfonamide (Intermediate INTA-I) (81.5 mg, 375 pmol) and DBU (132 mg, 866 pmol) were added. The reaction mixture was stirred at 60°C for 16 h. The crude was directly purified by preparative HPLC to afford N-((2,6-dimethoxyphenyl)sulfonyl)-5- (thiazol-2-yloxy)chromane-8-carboxamide (Example EXA19 - compound 32) (18.8 mg, 13 % yield) as a white solid. LCMS (ES, m / z): 477.1 [M-H]+.

[0521] 1H NMR (400 MHz, DMSO) 5 11.24 (1 H, s), 7.57 - 7.46 (2H, m), 7.31 - 7.31 (2H, m), 6.92 - 6.89 (1 H, m), 6.83 - 6.80 (2H, m), 4.37 (2H, t, J=4.9 Hz), 3.83 - 3.82 (6H, m), 2.71 - 2.66 (2H, m), 2.01 - 1.95 (2H, m).

[0522] Example EXA20: N-((2,6-dimethoxyphenyl)sulfonyl)-5-(oxazol-2-yloxy)chromane-8- carboxamide (Example EXA20 - compound 33)

[0523] Scheme SCH EXA20-

[0524]

[0304] A solution of 5-(oxazol-2-yloxy)chromane-8-carboxylic acid (Intermediate INTB-IS) (115 mg, 440 pmol) and GDI (112 mg, 691 pmol) in DMF (4.40 mL) was stirred at 60°C for 1 h. The reaction mixture was allowed to cool down to room temperature then 2,6- dimethoxybenzenesulfonamide (Intermediate INTA-I) (124 mg, 572 pmol) and DBU (201 mg, 1.32 mmol) were added. The reaction mixture was stirred at 60°C for 16 h. The crude was directly purified by preparative HPLC to afford N-((2,6-dimethoxyphenyl)sulfonyl)-5- (oxazol-2-yloxy)chromane-8-carboxamide (Example EXA20 - compound 33) (52 mg, 25 % yield) as a white solid. LCMS (ES, m / z): 461.2[M-H]+.1H NMR (400 MHz, DMSO) 6 11.26 (1 H, s), 7.87 (1 H, s), 7.55 - 7.45 (2H, m), 7.06 (1 H, d, J=1.1 Hz), 6.97 (1 H, s), 6.82 (2H, s), 4.36 (2H, dd, J=3.1 , 4.5 Hz), 3.83 - 3.82 (6H, m), 2.70 - 2.67 (2H, m), 2.01 - 1.95 (2H, m).

[0525] Example EXA21 : 5-((1 H-pyrazol-1 -yl)methyl)-N-((6-methoxychroman-7- yl)sulfonyl)chromane-8-carboxamide (Example EXA21 - compound 34) Scheme SCH EXA21 ■

[0526]

[0305] To a mixture of 5-((1 H-pyrazol-1 -yl)methyl)chromane-8-carboxylic acid (Intermediate INTB-I) (35 mg, 0.140 mmol) in DMF (1.0 mL) at 60 °C was added GDI (29 mg, 0.18 mmol). The reaction mixture was stirred at 60 °C under argon for 1 h then 2,6- dimethoxybenzenesulfonamide (Intermediate INTA-IS) (40 mg, 0.16 mmol) and DBU (184 pL, 0.41 mmol) were sequentially added at 60 °C. The reaction mixture was stirred at 60°C under argon for 2 h. The reaction mixture was diluted with 1 N HCI aqueous solution, extracted with ethyl acetate then washed with water, brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative HPLC to afford 5-((1 H-pyrazol-1-yl)methyl)-N-((6-methoxychroman-7- yl)sulfonyl)chromane-8-carboxamide (Example EXA21 - compound 34) (27 mg, 39 % yield) as a white solid. LCMS (ES, m / z): 484.1 [M-H]+.

[0527] 1H-NMR (400 MHz, DMSO) 5 11.46 (s, 1 H), 7.78 (d, J=2.0 Hz, 1 H), 7.50 (dd, J=0.7, 1.8 Hz, 1 H), 7.23 (d, J=8.1 Hz, 1 H), 7.18 (s, 1 H), 6.97 (s, 1 H), 6.36 (d, J=7.8 Hz, 1 H), 6.30 (t, J=2.0 Hz, 1 H), 5.35 (s, 2H), 4.26 (t, J=5.3 Hz, 2H), 4.14 (t, J=4.9 Hz, 2H), 3.79 (s, 3H), 2.81 (t, J=6.4 Hz, 2H), 2.76 (t, J=6.5 Hz, 2H), 2.02 - 1.96 (m, 2H), 1.95 - 1.89 (m, 2H).

[0528] Example EXA22: 5-((1 H-pyrazol-1 -yl)methyl)-N-((2-methyl-2,3-dihydrobenzofuran-7- yl) sulfonyl)chromane-8-carboxamide (Example EXA22 - compound 35) Scheme SCH EXA22.

[0529]

[0306] To a mixture of 5-((1 H-pyrazol-1-yl)methyl)chromane-8-carboxylic acid (Intermediate INTB-I) (100 mg, 387 pmol) in DMF (20 mL) at 60 °C was added GDI (81.6 mg, 503 pmol). The reaction mixture was stirred at 60 °C under argon for 1 h then 2- methyl-2,3-dihydrobenzofuran-7-sulfonamide (Intermediate INTA-I?) (99 mg, 464 pmol) and DBU (175 pL, 1.16 mmol) were sequentially added at 60 °C. The mixture was stirred at 60 °C under argon for 1 h. The crude mixture was washed with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica column chromatography eluted with cyclohexane / ethyl acetate from 100 / 0 to 30 / 70. The resulting solid was recrystallized in a mixture of methanol and ethanolto afford 5-((1H-pyrazol-1-yl)methyl)-N-((2-methyl-2,3- dihydrobenzofuran-7-yl)sulfonyl)chromane-8-carboxamide (mixture of enantiomers 1 and 2) as a white solid.

[0530]

[0307] The mixture of enantiomers was separated by chiral preparative HPLC eluted with heptane / isopropylamine 55 / 45 to afford 5-((1H-pyrazol-1-yl)methyl)-N-((2-methyl-2,3- dihydrobenzofuran-7-yl)sulfonyl)chromane-8-carboxamide (Isomer 1) (Example EXA22a - compound 35a or 35b) (2.1 mg) as a white solid. n LCMS (ES, m / z): 454.2[M-H]+.

[0531] 1H NMR (400 MHz, DMSO) 5 11.66 (1 H, s), 7.77 (1H, d, J=2.1 Hz), 7.59 - 7.49 (3H, m), 7.24 - 7.21 (1H, m), 6.99 (1 H, t, J=7.7 Hz), 6.37 - 6.29 (2H, m), 5.35 (2H, s), 5.11 - 5.05 (1 H, m), 4.24 (2H, t, J=4.8 Hz), 3.43 - 3.36 (1 H, m), 2.87 - 2.73 (3H, m), 2.01 - 1.95 (2H, m), 1.35 - 1.33 (3H, m). and 5-((1 H-pyrazol-1-yl)methyl)-N-((2-methyl-2,3-dihydrobenzofuran-7- yl)sulfonyl)chromane-8-carboxamide (Isomer 2) (Example EXA22b - compound 35a or 35b) (5.7 mg) as a white solid.

[0532] LCMS (ES, m / z): 454.2[M-H]+.

[0533] 1H NMR (400 MHz, DMSO) 5 11.66 (1 H, s), 7.77 (1H, d, J=2.1 Hz), 7.59 - 7.49 (3H, m), 7.24 - 7.21 (1H, m), 6.99 (1 H, t, J=7.7 Hz), 6.37 - 6.29 (2H, m), 5.35 (2H, s), 5.11 - 5.05 (1 H, m), 4.24 (2H, t, J=4.8 Hz), 3.43 - 3.36 (1 H, m), 2.87 - 2.73 (3H, m), 2.01 - 1.95 (2H, m), 1.35 - 1.33 (3H, m).

[0534] Example EXA23: 4-((1 H-pyrazol-1 -yl)methyl)-N-((2,6-dimethoxyphenyl)sulfonyl)-2H- spiro [benzofuran-3,1'-cyclopropane]-7-carboxamide (Example EXA23 - compound 14)

[0535] Scheme SCH EXA23.

[0536] Cs2C03, allylpalladium(ll)chloride Dimer sodium 2'-(dicvclohexylphosphino )-

[0537] 2 6-dimethoxy-[1 1 '-biphenyl]-3-sulfonate hydrate CPME, water, 110“C

[0538]

[0308] In a sealed tube, a mixture of 4-chloro-N-((2,6-dimethoxyphenyl)sulfonyl)-2H- spiro[benzofuran-3,1'-cyclopropane]-7-carboxamide (Intermediate INTA-24) (65 mg, 153 pmol), potassium((1 H-pyrazol-1-yl)methyl) trifluoroborate (31 mg, 169 pmol) and cesium carbonate (200 mg, 613 pmol) in CPME (2 mL) and water (0.5 mL) was degassed with argon for 10 min. Allylpalladium(ll)chloridedimer (2.81 mg, 7.67 pmol) followed by sodium 2'-(dicyclohexylphosphino)-2,6-dimethoxy-[1,1'-biphenyl]-3-sulfonate hydrate (8.1 mg, 15.3 pmol) were added. The reaction mixture was stirred at 100 °C for 16 h. The reaction mixture was filtered then diluted with ethyl acetate and water and acetic acid was added. The reaction mixture was extracted with ethyl acetate and the organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative HPLC to afford 4-((1 H-pyrazol-1 - yl)methyl)-N-((2,6-dimethoxyphenyl) sulfonyl)-2H-spiro[benzofuran-3,1'-cyclopropane]-7- carboxamide (Example EXA23 - compound 14) (7 mg, 9 % yield) as a white solid LCMS (ES, m / z): 470.2 [M+H]+.

[0539] 1H NMR (400 MHz, DMSO) 5 10.76 (1 H, s), 7.81 (1H, d, J=1.7 Hz), 7.53 (1H, t, J=8.6 Hz), 7.50 (1H, dd, J=0.7, 1.8 Hz), 7.37 (1H, d, J=8.4 Hz), 6.80 (2H, d, J=8.5 Hz), 6.37 (1H, d, J=8.4 Hz), 6.30 (1H, dd, J=1.8, 2.2 Hz), 5.17 (2H, s), 4.67 (2H, s), 3.80 (6H, s), 1.69 - 1.65 (2H, m), 1.12 - 1.09 (2H, m).

[0540] Example EXA24: 5-((1 H-pyrazol-1 -yl)methyl)-N-((7-methoxychroman-6- yl)sulfonyl)chromane-8-carboxamide (Example EXA24 - compound 24) Scheme SCH EXA24.

[0541]

[0309] To a mixture of 5-((1 H-pyrazol-1-yl)methyl)chromane-8-carboxylic acid (Intermediate INTB-I) (30.0 mg, 116 pmol) in DMF (1.16 mL) at 60 °C was added GDI (24.5 mg, 151 pmol). The reaction mixture was stirred at 60 °C under argon for 1 h and 7- methoxychromane-6-sulfonamide (Intermediate INTA-H) (33 mg, 136 pmol) and DBU (52.5 pL, 348 pmol) were sequentially added at 60 °C. The reaction mixture was stirred at 60 °C under argon for 16 h. The crude mixture was quenched with water then directly adsorbed with Celite and purified by silica gel column chromatography eluted with dichloromethane / methanol from 100 / 0 to 97 / 3 to afford 5-((1 H-pyrazol-1 -yl)methyl)-N-((7- methoxychroman-6-yl)sulfonyl)chromane-8-carboxamide (Example EXA24 - compound 24) (7.5 mg, 13 % yield) as an off-white solid. LCMS (ES, m / z): 484.2[M+H]+.

[0542] 1H NMR (400 MHz, DMSO) 5 11.33 - 11.31 (1 H, m), 7.78 (1 H, d, J=1.7 Hz), 7.56 (1 H, s), 7.50 - 7.49 (1 H, m), 7.26 - 7.22 (1 H, m), 6.56 - 6.55 (1 H, m), 6.37 - 6.30 (2H, m), 5.34 (2H, s), 4.29 - 4.19 (4H, m), 3.80 (3H, s), 2.79 - 2.71 (4H, m), 2.02 - 1.89 (4H, m).

[0543] Example EXA25: 5-((1 H-pyrazol-1 -yl)methyl)-N-((5-(2-hydroxypropan-2-yl)-2- methoxyphenyl) sulfonyl)chromane-8-carboxamide (Example EXA25 - compound 36)

[0544] Scheme SCH EXA25.

[0545]

[0310] To a mixture of 5-((1 H-pyrazol-1 -yl)methyl)chromane-8-carboxylic acid (Intermediate INTB-I) (40 mg, 0.15 mmol) in DMF (1 mL) at 60°C was added GDI (33 mg, 0.20 mmol). The reaction mixture was stirred at 60°C under argon for 1 h and 4-(2- hydroxypropan-2-yl)-2-methoxybenzenesulfonamide (Intermediate INTA-2O) (46 mg, 0.19 mmol) and DBU (70 pL, 0.46 mmol) were sequentially added at room temperature. The reaction mixture was stirred at 50 °C under argon for 16 h. The crude material was purified by preparative HPLC to afford 5-((1 H-pyrazol-1-yl)methyl)-N-((5-(2- hydroxypropan-2-yl)-2-methoxyphenyl)sulfonyl)chromane-8-carboxamide (Example EXA25 - compound 36) (17 mg, 21 % yield) as a white solid. LCMS (ES, m / z): 484.2[M- H]+.

[0546] 1H NMR (400 MHz, DMSO) 5 11.47 (1 H, s), 8.00 (1 H, d, J=2.3 Hz), 7.78 (1 H, d, J=2.1 Hz), 7.70 (1 H, dd, J=2.5, 8.6 Hz), 7.50 (1 H, dd, J=0.6, 1.9 Hz), 7.24 (1 H, d, J=7.5 Hz), 7.17 (1 H, d, J=8.9 Hz), 6.36 (1 H, d, J=8.1 Hz), 6.30 (1 H, t, J=2.1 Hz), 5.35 (2H, s), 5.23 (1 H, s), 4.32 - 4.25 (2H, m), 3.87 (3H, s), 2.79 - 2.75 (2H, m), 2.05 - 1.96 (2H, m), 1.43 (6H, s).

[0547] Example EXA26: 5-(( 1 H-pyrazol-1 -yl)methyl)-N-((2,4-dimethoxy-6-methylpyridin-3- yl)sulfonyl)chromane-8-carboxamide (Example EXA26 - compound 37) Scheme SCH EXA26-

[0548]

[0311] To a mixture of 5-((1 H-pyrazol-1 -yl)methyl)chromane-8-carboxylic acid (Intermediate INTB-I) (20 mg, 77 pmol) in DMF (1 mL) at 60°C was added GDI (16 mg, 0.10 mmol). The reaction mixture was stirred at 60°C under argon for 1 h and 2,4- dimethoxy-6-methylpyridine-3-sulfonamide (Intermediate INTA-21) (22 mg, 93 pmol) and DBU (35 pL, 0.23 mmol) were sequentially added at room temperature. The reaction mixture was stirred at 60°C under argon for 16 h. The crude material was directly purified by reverse phase C18 column chromatography eluted with water / acetonitrile from 100 / 0 to 00 / 100 to afford 5-((1 H-pyrazol-1-yl)methyl)-N-((2,4-dimethoxy-6-methylpyridin-3-yl) sulfonyl)chromane-8-carboxamide (Example EXA26 - compound 37) (12 mg, 31 % yield) as a white solid. LCMS (ES, m / z): 473.3[M+H]+.1H NMR (400 MHz, DMSO) 6 7.68 (d, J=1.8 Hz, 1 H), 7.47 (dd, J=0.7, 1.8 Hz, 1 H), 7.08 (d, J=7.7 Hz, 1 H), 6.64 - 6.58 (m, 1 H), 6.36 (d, J=7.8 Hz, 1 H), 6.27 (t, J=2.1 Hz, 1 H), 5.26 (s, 2H), 4.07 - 3.99 (m, 2H), 3.78 (s, 3H), 3.76 (s, 3H), 2.69 - 2.65 (m, 2H), 2.33 (s, 3H), 1.94

[0549] - 1.86 (m, 2H).

[0550] Example EXA27: N-((2,4-dimethoxy-6-methylpyridin-3-yl)sulfonyl)-5-(thiazol-2-yloxy) chromane-8-carboxamide (Example EXA27 - compound 38)

[0551] Scheme SCH EXA27.

[0552]

[0312] A mixture of 5-(thiazol-2-yloxy)chromane-8-carboxylic acid (Intermediate INTB-IS) (55 mg, 198 pmol) and GDI (57.9 mg, 357 pmol) in DMF (1.32 mL) were stirred at 60°C for 1 h. the reaction mixture was allowed to cool down to room temperature and 2,4- dimethoxy-6-methylpyridine-3-sulfonamide (Intermediate INTA-21) (55.0 mg, 237 pmol) and DBU (89.7 L, 595 pmol) were added. The reaction mixture was stirred at 60°C for 16 h. The crude was directly purified by preparative HPLC to afford N-((2,4-dimethoxy-6- methylpyridin-3-yl)sulfonyl)-5-(thiazol-2-yloxy)chromane-8-carboxamide (Example EXA27 - compound 38) (12.4 mg, 12 % yield) as a white foam. LCMS (ES, m / z): 492.1[M+H]+.1H NMR (400 MHz, DMSO) 5 11.41 (1 H, s), 7.45 - 7.40 (1 H, m), 7.31 (2H, s), 6.91 - 6.85 (2H, m), 4.33 - 4.32 (2H, m), 3.90 - 3.88 (6H, m), 2.69 - 2.66 (2H, m), 2.40 (3H, s), 2.00 - 1.93 (2H, m).

[0553] Example EXA28: N-((2,6-dimethoxyphenyl)sulfonyl)-5-(thiazol-2-ylmethyl)chromane-8 carboxamide (Example EXA28 - compound 39) Scheme SCH EXA28.

[0554]

[0313] To a mixture of 5-(thiazol-2-ylmethyl)chromane-8-carboxylic acid (Intermediate INTB-22) (90.0 mg, 326 pmol) in DMF (1.5 mL) at 60°C was added GDI (68.9 mg, 425 pmol). The reaction mixture was stirred at 60 °C under argon for 1 h. Then 2,6- dimethoxybenzenesulfonamide (Intermediate INTA-I) (85.2 mg, 392 pmol) and DBU (147 pL, 980 pmol) were sequentially added at room temperature. The reaction mixture was stirred at 60 °C under argon for 16 h. Water was added then 1N HCI aqueous solution was added slowly until pH=3. The aqueous layer was extracted with ethyl acetate / IPA. The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by reverse phase column chromatography eluted with water / acetonitrile from 100 / 0 to 70 / 30 to afford N-((2,6-dimethoxyphenyl)sulfonyl)-5-(thiazol-2-ylmethyl)chromane-8- carboxamide (Example EXA28 - compound 39) (15 mg, 8.3 % yield) as a white solid. LCMS (ES, m / z): 475.3[M+H]+.

[0555] 1H NMR (400 MHz, DMSO) 5 7.69 (d, J = 3.3 Hz, 1H), 7.51 (d, J = 3.3 Hz, 1 H), 7.33 - 7.21 (m, 2H), 6.77 - 6.73 (m, 2H), 6.68 (d, 1 H), 4.26 (s, 2H), 4.08 (br s, 2H), 3.77 (s, 6H), 2.70 (t, J = 6.7 Hz, 2H), 1.92 (t, J = 5.8 Hz, 2H).

[0556] Example EXA29: N-((2,6-dimethoxyphenyl)sulfonyl)-7-(thiazol-2- yloxy)benzo[d][1,3]dioxole-4-carboxamide (Example EXA29 - compound 40) Scheme SCH EXA29-

[0557]

[0314] To a mixture of 7-(thiazol-2-yloxy)benzo[d][1 ,3]dioxole-4-carboxylic acid (Intermediate INTB-23) (90.0 mg, 339 pmol) in DMF (1.5 mL) at 60°C was added GDI (71.5 mg, 441 pmol). The reaction mixture was stirred at 60°C under argon for 1 h. Then 2,6- dimethoxybenzenesulfonamide (Intermediate INTA-I) (88.4 mg, 407 pmol) and DBU (153 pL, 1.01 mmol) were sequentially added at room temperature. The reaction mixture was stirred at 60°C under argon for 16 h. Water was added then 1 N HCI aqueous solution was added slowly until pH=3. The aqueous layer was extracted with ethyl acetate / IPA. The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by reverse phase column chromatography eluted with water / acetonitrile from 100 / 0 to 50 / 50 to afford N-((2,6-dimethoxyphenyl)sulfonyl)-7-(thiazol-2-yloxy)benzo[d][1 ,3]dioxole-4-carboxamide (Example EXA29 - compound 40) (4 mg, 2 % yield) as a white solid. LCMS (ES, m / z): 465.2[M+H]+.

[0558] 1H NMR (400 MHz, DMSO) 5 7.37 (d, J = 8.8 Hz, 1 H), 7.29 - 7.23 (m, 2H), 7.19 (d, J = 3.8 Hz, 1 H), 6.79 (d, J = 3.9 Hz, 1 H), 6.65 (d, J = 8.3 Hz, 2H), 6.05 (s, 2H), 3.73 (s, 6H).

[0559] Example EXA30: A / -((6-methoxy-2,3-dihydrobenzofuran-7-yl)sulfonyl)-5-(thiazol-2- yloxy) chromane-8-carboxamide (Example EXA30- compound 41)

[0560]

[0315] 5-(thiazol-2-yloxy)chromane-8-carboxylic acid (Intermediate INTB-20) (25 mg, 90 pmol) and GDI (26 mg, 162 pmol) in DMF (600 pL) were stirred at 60°C for 1 h. The reaction mixture was allowed to cool down to room temperature then 6-methoxy-2,3- dihydrobenzofuran-7-sulfonamide (Intermediate INTA-2S) (25 mg, 109 pmol) and DBU (40.8 pL, 270 pmol) were added. The reaction mixture was stirred at 60°C for 3 h. The crude mixture was directly purified by preparative HPLC to afford / V-((6-methoxy-2,3- dihydrobenzofuran-7-yl)sulfonyl)-5-(thiazol-2-yloxy)chromane-8-carboxamide (Example EXA30- compound 41) (15.5 mg, 33 % yield) as a white powder. LCMS (ES, m / z): 489.1[M+H]+.

[0561] 1H NMR (400 MHz, DMSO) 5 11.35 (1 H, s), 7.44 (1 H, d, J=8.9 Hz), 7.40 (1 H, d, J=9.1 Hz), 7.31 - 7.30 (2H, m), 6.90 (1 H, d, J=9.2 Hz), 6.60 (1 H, d, J=8.5 Hz), 4.65 (2H, t, J=8.5 Hz), 4.35 - 4.32 (2H, m), 3.80 (3H, s), 3.15 (2H, t, J=8.8 Hz), 2.68 (2H, t, J=6.6 Hz), 2.00 - 1.94 (2H, m).

[0562] Example EXA31 : A / -((6-methoxy-2,3-dihydrobenzofuran-7-yl)sulfonyl)-5-(thiazol-2- ylmethyl) chromane-8-carboxamide (Example EXA31- compound 42) Scheme SCHEXA3I-

[0563]

[0316] To a mixture of 5-(thiazol-2-ylmethyl)chromane-8-carboxylic acid (Intermediate INTB-22) (110 mg, 399 pmol) in DMF (2 mL) at 60°C was added GDI (84.2 mg, 519 pmol). The reaction mixture was stirred at 60°C under argon for 1 h. Then 6-methoxy-2,3- dihydrobenzofuran-7-sulfonamide (Intermediate INTA-2S) (100 mg, 439 pmol) and DBU (180 pL, 1.19 mmol) were sequentially added at room temperature. The reaction mixture was stirred at 60°C under argon for 16 h. Water was added and a 1 N HCI aqueous solution was slowly added until pH=3. The aqueous layer was extracted with ethyl acetate / IPA. The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with cyclohexane / (ethyl acetate / ethanol) (3:1) from 100 / 0 to 50 / 50 to afford / V-((6-methoxy-2,3-dihydrobenzofuran- 7-yl)sulfonyl)-5-(thiazol-2-ylmethyl)chromane-8-carboxamide (Example EXA31 - compound 42) (71 mg, 35 % yield) as a brown solid. LCMS (ES, m / z): 487.1[M+H]+.

[0564] 1H NMR (400 MHz, DMSO) 5 11.26 (1 H, s), 7.72 (1 H, d, J=3.4 Hz), 7.61 (1 H, d, J=3.4 Hz), 7.41 - 7.35 (2H, m), 6.91 (1 H, d, J=7.9 Hz), 6.58 (1 H, d, J=8.4 Hz), 4.65 (2H, t, J=8.8 Hz), 4.35 (2H, s), 4.28 (2H, t, J=5.0 Hz), 3.79 (3H, s), 3.15 (2H, t, J=8.8 Hz), 2.76 (2H, t, J=5.6 Hz), 2.01 - 1.94 (2H, m).

[0565] Example EXA32: 7-((1 H-pyrazol-1 -yl)methyl)- / V-((2,6-dimethoxyphenyl)sulfonyl)benzo

[0566] [d][1,3]dioxole-2,2-d2-4-carboxamide (Example EXA32- compound 43)

[0567] Scheme SCHEXA32-

[0568] Cs;CO,. ally Ipalladi um ( lljchlonde Dimer sodium 2'-(dicyclohexylphosphino)- 2,6-dimethoxy-[1 -1'-biphenyl]-3-sulfonate hydrate CPME, water, 110°C

[0569]

[0317] In a sealed vial, to a mixture of 7-chloro- / V-((2,6-dimethoxyphenyl)sulfonyl) benzo[d][1 ,3]dioxole-2,2-d2-4-carboxamide (Intermediate INTA-26) (130 mg, 324 mol), potassium ((1H-pyrazol-1-yl)methyl)trifluoroborate (69 mg, 372 mol) and cesium carbonate (422 mg, 1.29 mmol) in CPME (2.5 mL) and water (0.6 mL) degassed with argon for 10 min was added allylpalladium(ll)chloride dimer (5.9 mg, 16 mol) followed by sSPhos (17 mg, 32 mol). The reaction mixture was stirred at 110 °C for 16 h. The reaction mixture was diluted with water and washed with ethyl acetate. Then, the aqueous phase was slowly acidified with 1 N HCI aqueous solution until pH=3 and extracted with ethyl acetate / IPA. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with cyclohexane / (ethyl acetate / ethanol) (3:1) from 100 / 0 to 60 / 40. The tubes containing the product were collected and the solvent was concentrated to dryness to afford 7-((1 H-pyrazol-1-yl)methyl)- / V-((2,6- dimethoxyphenyl)sulfonyl)benzo[d][1 ,3]dioxole-2,2-d2-4-carboxamide (Example EXA32 - compound 43) (24 mg, 16% yield) as a white solid. LCMS (ES, m / z): 448.2[M+H]+.

[0570] 1H NMR (400 MHz, DMSO) 5 11.37 (1H, s), 7.83 (1 H, d, J=2.0 Hz), 7.53 (1H, t, J=8.2 Hz), 7.48 (1H, d, J=1.5 Hz), 7.12 (1H, d, J=8.3 Hz), 6.80 (2H, d, J=8.5 Hz), 6.59 (1 H, d, J=8.3 Hz), 6.29 (1H, t, J=2.0 Hz), 5.34 (2H, s), 3.80 (6H, s).

[0571] Example EXA33: A / -((6-methoxy-2,3-dihydrobenzofuran-7-yl)sulfonyl)-5-(oxazol-2- yloxy) chromane-8-carboxamide (Example EXA33- compound 44)

[0572]

[0318] A mixture of 5-(oxazol-2-yloxy)chromane-8-carboxylic acid (Intermediate INTB-IS) (65 mg, 249 pmol) and GDI (72 mg, 448 pmol) in DMF (1.66 mL) was stirred at 60°C for 1 h. The reaction mixture was allowed to cool down to room temperature then 6-methoxy- 2,3-dihydrobenzofuran-7-sulfonamide (Intermediate INTA-2S) (114 mg, 299 pmol) and DBU (113 pL, 746 pmol) were added. The reaction mixture was stirred at 60°C for 16 h. The reaction mixture was evaporated under reduced pressure and the residue was purified by preparative HPLC to afford / V-((6-methoxy-2,3-dihydrobenzofuran-7- yl)sulfonyl)-5-(oxazol-2-yloxy)chromane-8-carboxamide (Example EXA33- compound 44) (17 mg, 14 % yield) as a white solid. LCMS (ES, m / z): 473.2[M+H]+.

[0573] 1H NMR (400 MHz, DMSO) 5 11.37 (1H, s), 7.87 (1 H, d, J=0.9 Hz), 7.45 - 7.38 (2H, m), 7.06 - 7.06 (1 H, m), 6.99 - 6.96 (1 H, m), 6.60 (1 H, d, J=8.2 Hz), 4.65 (2H, t, J=8.3 Hz), 4.34 (2H, t, J=4.9 Hz), 3.80 (3H, s), 3.15 (2H, t, J=8.5 Hz), 2.68 (2H, t, J=6.4 Hz), 2.00 - 1.94 (2H, m).

[0574] IL Biological Examples Abbreviations:

[0575]

[0319] Acetyl coenzyme A : AcetylCoA or AC-Coa

[0576] Bovine serum albumin : BSA

[0577] Dithiothreitol : DTT

[0578] Ethylenediaminetetraacetic acid : EDTA Trizma Hydrochloride : Tris-HCL

[0579] KAT6A, KAT7 - Enzyme Activity Assay (AlphaScreen Method)

[0580] Materials and Instruments

[0581]

[0320] Active KAT6A / MOZ protein: Active motif # 81223 > lot. 2122003

[0582] Active KAT7: Active motif # 31489_ lot. 24321003 H4 peptide: Upstate Biotechnology # 12-405 lot 3743857 - 100 pg AcetylCoA: Sigma # A2056 lot 0000303137 - 5 mg Anti-Histone H4 (acetyl K8) antibody:

[0583] Cell Signaling # 2594S lot 11 (a-H4AcK8-1) 73 pg / mL Abeam # ab15823 lot 1029174-1 (a-H4AcK8-2) 0.9 mg / mL Trizma Hydrochloride solution pH8 (Sigma # T3038 lot SLBL2857V) 100 mM NaCI (Sigma # S5150 lot SLBH4802V) 15 mM EDTA (Sigma # E7889 lot SLBD5434V) 1 mM Tween-20 (Sigma # P7949 lot SZBC2920V) 0.01% BSA (Jackson v 001-000-173) 0.02% (= 0.2 mg / mL) DTT (Sigma # 43816) 1mM 384-well plate: AlphaPlate (PerkinElmer # 6005350) TopSeal-A PLUS (PerkinElmer # 6050185)

[0584] AlphaLISA beads :

[0585] Protein A acceptor (PerkinElmer # AL101 C lot 3178960)

[0586] Streptavidin donor beads (PerkinElmer # 6760002S lot 3082282)

[0587] Assay preparation:

[0588]

[0321] Assay Buffer with DTT: Composed of 100 mM Tris-HCI (pH 8), 15 mM NaCI, 1 mM EDTA, 0.01% Tween-20, 0.02% BSA, 1 mM DTT.

[0589]

[0322] Compounds Solutions: Compounds solutions 3x were prepared in the assay buffer with DTT from solution comprising different concentrations of compounds in DMSO.

[0590]

[0323] KAT6A Enzyme Solution 3x: Prepared a 60 nM for a use at a final concentration of 20 nM in the 3* assay buffer with DTT.

[0591]

[0324] KAT7 Enzyme Solution 3x: Prepared a 60 nM for a use at a final concentration of 20 nM in the 3* assay buffer with DTT.

[0592]

[0325] H4 peptide, antibodies, Ac-Coa 3X: Contains 150nM H4 peptide; 3 pM Ac-CoA and 1 / 1167 Cell signaling # 2594S and 1 / 1000 Abeam # ab15823 in the 1* assay buffer with DTT.

[0593]

[0326] Detection Reagent AlphaLisa beads 2.2X: Consists of AlphaScreen Protein A Acceptor Beads and AlphaScreen Streptavidin Donor Beads (2.93 or 8.8 pg / mL (final concentration, all prepared in the 1 * assay buffer.

[0594] Cellular Assay ZR75-1 H3K23ac

[0595] Materials and reagents:

[0596]

[0327] • Cell line: ZR-75-1 (Human breast ductal carcinoma, ECACC #87012601)

[0597] • Cell line passage number: P'13

[0598] • Medium: RPMI 1640 (Gibco #41965062) supplemented with: o 10% Fetal Bovine Serum (FBS, Pan Biotech #P30-3306) o 1% Glutamax (Gibco #35050038) o 1% Sodium pyruvate (Gibco #11360-039) o 4.5 g / L glucose

[0599] • Plates: 96-well Nunc™ Edge™ Nunclon Delta surface plates

[0600] (ThermoFisher #167425)

[0601] • Histone H3 Monoclonal Antibody (6D3B9), ThermoFisher # MA5-31759 lot XG3638535

[0602] • Acetyl-Histone H3 (Lys23) (D6Y7M) rabbit mAb, Cell Signaling # 14932

[0603] • Gio Substrate Reagent Pack DY993: R&D Systems lot P392320 • HRP secondary antibodies Jackson Immuno Research Laboratories HRP

[0604] DONKEY IGG ANTI RABBIT IGG (H+(lnterchim # 711-035-152)

[0605] • Envision luminometer in luminescent reading mode

[0606] Cell Seeding

[0607]

[0328] ZR-75-1 cells (passage 13) are seeded into two 96-well plates. Each well receives 25,000 cells in 200 pL of RPMI 1640 medium supplemented with 10% FBS, 1% Glutamax, 1% sodium pyruvate, and 4.5 g / L glucose. The plates are incubated for 24 hours at 37°C and 5% CO2 to allow the cells to adhere and reach an appropriate confluence for treatment.

[0608] Compound Treatment

[0609]

[0329] The compounds are prepared for treatment. Stock solutions of the compounds are diluted in DMSO. The final working concentrations for treatment are achieved by diluting the compounds dilutions in the medium. After aspirating the culture medium from each well, 180 pL of fresh incubation medium is added. Then, 20 pL of the compound solutions are added to each well, bringing the final volume to 200 pL per well. The plates are incubated for another 24 hours under the same conditions (37°C, 5% CO2).

[0610] Cell Lysis and Preparation for ELISA

[0611]

[0330] After 24 hours of compound incubation, the medium is aspirated from the wells, and the cells are lysed. The lysis buffer is prepared by combining 0.4 N HCI with 2 mM sodium butyrate. Each well receives 100 pL of this lysis buffer and is then agitated for 1 hour at 4°C. After lysis, the lysates are neutralized by adding 75 pL of neutralization buffer (1 N sodium phosphate dibasic pH 12.5 + 2 mM sodium butyrate + 1 protease inhibitor tablet). The plate is then agitated for 5 minutes at room temperature, and the entire plate is frozen at -80°C for 1 hour before further processing.

[0612] ELISA Assay for Histone H3 Acetylation (Lys23) - ELISA plate preparation

[0613]

[0331] The ELISA procedure begins with coating the ELISA plate. A half-area 96-well white OptiPlate is coated with Histone H3 monoclonal antibody (6D3B9) at 2 pg / mL in coating buffer (10 mM Tris-HCI pH 8.0, 10 mM NaCI). The antibody is diluted from its stock solution and distributed at 25 pL per well in the ELISA plate. The plate is sealed and incubated overnight at 4°C.

[0332] After overnight incubation, the ELISA plate is washed three times with 200 pL of PBS + 0.05% Tween20. The plate is then blocked by adding 100 pL per well of blocking buffer (PBS + 0.05% Tween20 + 1% BSA), and it is incubated for 1 hour at room temperature. After blocking, the plate is washed three more times with 200 pL of the wash buffer.

[0614] ELISA Assay for Histone H3 Acetylation (Lys23) - HRP Substrate Addition and Plate Reading

[0615]

[0333] The previously prepared cell lysates are thawed on ice and added to the ELISA plate. Each well receives 50 pL of cell lysate, and the plate is incubated for 1.5 hours at room temperature. In parallel, blanks are prepared using hydrochloric acid and sodium phosphate dibasic buffers containing sodium butyrate. After incubation, the plate is washed three times with the wash buffer.

[0616]

[0334] Next, the primary antibody, Acetyl-Histone H3 (Lys23) rabbit mAb (D6Y7M), is diluted to 0.1 pg / mL in the blocking buffer and 25 pL is added to each well. The plate is sealed and incubated for 1.5 hours at room temperature. The plate is washed again, and then a secondary HRP-conjugated antibody (Donkey IgG anti-Rabbit IgG, diluted to 0.4 pg / mL in blocking buffer) is added at 50 pL per well. The plate is incubated for 1 hour at room temperature, followed by three washes with the wash buffer.

[0617]

[0335] The HRP substrate is prepared by mixing Gio Reagent A and Gio Reagent B in a 1:2 ratio to produce 7 mL of luminescent substrate. Fifty microliters of this substrate mixture are added to each well, and the plate is incubated at room temperature for 10 minutes in the dark.

[0618]

[0336] Finally, the luminescence is measured using the Envision luminometer in luminescent reading mode. The luminescence readings provide a quantitative measure of histone acetylation at Lys23, which is used to assess the inhibition of KAT6A activity. The IC50 values for each compound are determined by plotting the luminescence data against the compound concentrations and fitting the data to a four-parameter logistic model to calculate the concentration at which 50% inhibition of KAT6A activity occurs.

[0619] Materials and reagents:

[0620]

[0337] • Cell line: ZR-75-1 (Human breast ductal carcinoma, ECACC #87012601)

[0621] • Cell line passage number: P'13

[0622] • Medium: RPMI 1640 (Gibco #41965062) supplemented with: o 10% Fetal Bovine Serum (FBS, Pan Biotech #P30-3306) o 1% Glutamax (Gibco #35050038) o 1% Sodium pyruvate (Gibco #11360-039) o 4.5 g / L glucose

[0623] • Plates: 96-well Nunc™ Edge™ Nunclon Delta surface plates (ThermoFisher

[0624] #167425)

[0625] • Histone H3 Monoclonal Antibody (6D3B9), ThermoFisher # MA5-31759 lot

[0626] XG3638535

[0627] • Acetyl-Histone H3 (Lys23) (D6Y7M) rabbit mAb, Cell Signaling # 14932

[0628] • Gio Substrate Reagent Pack DY993: R&D Systems lot P392320

[0629] • HRP secondary antibodies Jackson Immuno Research Laboratories HRP

[0630] DONKEY IGG ANTI RABBIT IGG (H+(lnterchim # 711-035-152)

[0631] • Envision luminometer in luminescent reading mode

[0632] Cell Seeding

[0633]

[0338] ZR-75-1 cells (passage 13) are seeded into two 96-well plates. Each well receives 25,000 cells in 200 pL of RPMI 1640 medium supplemented with 10% FBS, 1% Glutamax, 1% sodium pyruvate, and 4.5 g / L glucose. The plates are incubated for 24 hours at 37°C and 5% CO2 to allow the cells to adhere and reach an appropriate confluence for treatment.

[0634] Compound Treatment

[0635]

[0339] The compounds are prepared for treatment. Stock solutions of the compounds are diluted in DMSO. The final working concentrations for treatment are achieved by diluting the compound's dilutions in the medium. After aspirating the culture medium from each well, 180 pL of fresh incubation medium is added. Then, 20 pL of the compound solutions are added to each well, bringing the final volume to 200 pL per well. The plates are incubated for another 24 hours under the same conditions (37°C, 5% CO2).

[0636] Cell Lysis and Preparation for ELISA

[0637]

[0340] After 24 hours of compound incubation, the medium is aspirated from the wells, and the cells are lysed. The lysis buffer is prepared by combining 0.4 N HCI with 2 mM sodium butyrate. Each well receives 100 pL of this lysis buffer and is then agitated for 1 hour at 4°C. After lysis, the lysates are neutralized by adding 75 pL of neutralization buffer (1 N sodium phosphate dibasic pH 12.5 + 2 mM sodium butyrate + 1 protease inhibitor tablet). The plate is then agitated for 5 minutes at room temperature, and the entire plate is frozen at -80°C for 1 hour before further processing. ELISA Assay for Histone H3 Acetylation (Lys23) - ELISA plate preparation

[0638]

[0341] The ELISA procedure begins with coating the ELISA plate. A half-area 96-well white OptiPlate is coated with Histone H3 monoclonal antibody (6D3B9) at 2 pg / mL in coating buffer (10 mM Tris-HCI pH 8.0, 10 mM NaCI). The antibody is diluted from its stock solution and distributed at 25 pL per well in the ELISA plate. The plate is sealed and incubated overnight at 4°C.

[0639]

[0342] After overnight incubation, the ELISA plate is washed three times with 200 pL of PBS + 0.05% Tween20. The plate is then blocked by adding 100 pL per well of blocking buffer (PBS + 0.05% Tween20 + 1% BSA), and it is incubated for 1 hour at room temperature. After blocking, the plate is washed three more times with 200 pL of the wash buffer.

[0640] ELISA Assay for Histone H3 Acetylation (Lys23) - HRP Substrate Addition and Plate Reading

[0641]

[0343] The previously prepared cell lysates are thawed on ice and added to the ELISA plate. Each well receives 50 pL of cell lysate, and the plate is incubated for 1.5 hours at room temperature. In parallel, blanks are prepared using hydrochloric acid and sodium phosphate dibasic buffers containing sodium butyrate. After incubation, the plate is washed three times with the wash buffer.

[0642]

[0344] Next, the primary antibody, Acetyl-Histone H3 (Lys23) rabbit mAb (D6Y7M), is diluted to 0.1 pg / mL in the blocking buffer and 25 pL is added to each well. The plate is sealed and incubated for 1.5 hours at room temperature. The plate is washed again, and then a secondary HRP-conjugated antibody (Donkey IgG anti-Rabbit IgG, diluted to 0.4 pg / mL in blocking buffer) is added at 50 pL per well. The plate is incubated for 1 hour at room temperature, followed by three washes with the wash buffer.

[0643]

[0345] The HRP substrate is prepared by mixing Gio Reagent A and Gio Reagent B in a 1:2 ratio to produce 7 mL of luminescent substrate. Fifty microliters of this substrate mixture are added to each well, and the plate is incubated at room temperature for 10 minutes in the dark.

[0644]

[0346] Finally, the luminescence is measured using the Envision luminometer in luminescent reading mode. The luminescence readings provide a quantitative measure of histone acetylation at Lys23, which is used to assess the inhibition of KAT6A activity. The IC50 values for each compound are determined by plotting the luminescence data against the compound concentrations and fitting the data to a four-parameter logistic model to calculate the concentration at which 50% inhibition of KAT6A activity occurs. Comparative compounds

[0645]

[0347] The compounds of the invention have been compared to two well known inhibitors of KAT6A activity: CTX-3648 and PF07248144.

[0646]

[0348] The compounds of the invention have also been compared to an alternative acylsulfonamide derivative named “compound A” which is a comparative example. The compound A has the following structure:

[0647] Assay Procedure

[0648]

[0349] The prepared enzyme solution was added to a 384-well plate distribute of 4pL compounds 3x or DMSO and 4 pL KAT6A or KAT7 enzyme 3x, then vortexed and incubated 15 minutes at 30°C.

[0649]

[0350] 4 pL Mix antibodies + AcetylCoA + H4 peptide 3x or 4 pL (Mix antibodies + H4 peptide) 3x (condition w / o AcetylCoA) is added, then the plate is vertically centrifugated, vortexed and incubated 1h at 30°C with a film.

[0650]

[0351] 10 pL mix AlphaLISA beads 2.2 x in Assay buffer with DTT is added, and the plate is vortexed and incubated 5h at 23 °C protected from light before reading results with Envison.

[0651] Results

[0652] Table 4: IC50Values for the Inhibition of the enzymatic activity of Human KAT6A and KAT7 by the Compounds and control compounds CTX-3648, PF07248144 and compound A using both an enzymatic assay and a cellular assay. Values are reported in pM.

[0653]

[0352] As shown by the results in Table 4, the compounds according to the invention exhibit activity against KAT6A at very low concentrations. For example, the majority of compounds evaluated according to the invention, including compounds 3, 4, 14, 22, 27, 31, 32, 35, 36, 37, and 39, exhibited KAT6A mean enzymatic assay values below 0.1 pM, with activity further confirmed by cellular assays.

[0654]

[0353] Moreover, they exhibit a high specificity for KAT6A compared to other enzymes of the same family such as KAT7. For example, compounds 1 , 2, 3, 4 and 5 which were evaluated for selectivity, exhibited a KAT6A / KAT7 selectivity fold-change higher than 1000, whereas comparative compounds CTX-3648, PF07248144 and Compound A have all a selectivity fold change KAT6A / KAT7 lower than 500.

[0655]

[0354] Such specificity for KAT6A compared to KAT7 is an asset for the molecules according to the present invention and suggests a therapeutic potential superior to the molecules of the state of the technique.

[0656]

[0355] The cellular activity of the reported inhibitors was also characterized in ZR-75-1 compound screening assays and showed activity within the same range of the enzymatic assay, showed activity within the same range of the enzymatic assay.

[0657] Radiometric evaluation for KAT6A, KAT6B and KAT7

[0658]

[0356] Histone acetyltransferase assays performed at Reaction Biology are radiometric activity assays using tritiated acetyl-Coenzyme A as a cofactor.

[0659] Materials and reagents:

[0660]

[0357] • KAT6A assay: Histone H3, 5 pM.

[0661] • KAT6B assay: Histone H4, 2.5 pM.

[0662] • KAT7 assay: Histone H3, 2.5 pM.

[0663] • [3H]-acetyl-CoA for KAT6A and KAT7 and [4H]-acetyl-CoA for KAT6B at a final concentration of 0.5 pM.

[0664] • Assay buffer: 50 mM Tris-HCI, pH 8.0, 100 mM NaCI, 0.1 mM EDTA, 0.1 mM

[0665] DTT, 10% glycerol.

[0666] • Liquid scintillation counter or microplate scintillation reader.

[0667] Procedure

[0668]

[0358] Enzymes KAT6A, KAT6B and KAT7 are diluted in an appropriate assay buffer.

[0669]

[0359] The tritiated acetyl-CoA ([3H]-acetyl-CoA) for KAT6A and KAT7 and [4H]-acetyl- CoA for KAT6B are prepared at a final concentration of 0.5 pM.

[0670]

[0360] Test compounds are prepared by serial dilution to create 10-dose IC50 curves, starting from 10 pM. Each reaction well in the plate receives histone substrate, enzyme, and the test compound or control. The reaction is initiated by adding the acetyl-CoA.

[0361] For reaction conditions, the assay is incubated at 30°C to 37°C for 30-60 minutes. Upon completion, the reaction is stopped by adding a stop solution, such as 2% SDS or acetic acid.

[0671]

[0362] Filtration and detection involve transferring the reaction mixture to GF / B filter plates for radioisotope-based filtration. The unincorporated acetyl-CoA is removed by washing the plates three to five times with a cold buffer, leaving only the acetylated histone bound to the filter. The filter plates are then air-dried, and scintillation fluid is added to each well for detection. A scintillation counter measures the incorporation of the radioactive acetyl group into the histone substrate, with counts per minute (cpm) serving as the readout.

[0672]

[0363] Data analysis starts by calculating the percentage inhibition of acetylation for each test compound relative to a vehicle control (DMSO). The IC50 is determined by plotting the percentage inhibition against the compound concentration on a logarithmic scale. A four-parameter logistic curve is fitted to the data to calculate the concentration of the compound required to inhibit 50% of the enzyme activity.

[0673] Results

[0674] Table 5: IC50Values for the inhibition of Human KAT6A,KAT6B and KAT7 by the compounds of the invention and control compounds PF07248144 and compound A in radiometric assay

[0675]

[0364] As shown by the results in Table 5, the compounds according to the invention exhibit activity against KAT6A at very low concentrations as measured by radiometric assay.

[0676]

[0365] Moreover, they exhibit a high specificity for KAT6A compared to other enzymes of the same family such as KAT6B and KAT7. For example, compounds 4, 5 and 27 have a KAT6A / KAT6B ratio higher than 170 whereas comparative compounds PF07248144 and Compound A all have a KAT6A / KAT6B ratio lower than 108. Moreover, most compounds of the invention do not inhibit KAT7 at 100 pM, while PF07248144 and Compound A inhibits KAT7 at 3 pM and 22 pM, respectively.

[0677]

[0366] Such specificity for KAT6A compared to KAT6B, combined with the specificity for KAT6A over KAT7 confirm the strong therapeutic potential of the compounds according to the invention. Efflux ratio

[0678] Materials and reagents:

[0679]

[0367] • Cells: Caco-2 / TC7 cells

[0680] • Culture medium: Provided with the Caco-2 / TC7 kit.

[0681] • HBSS (+Ca, +Mg): Fisher Scientific, ref. 14025050.

[0682] • HEPES (1M): Fisher Scientific, ref. 15630056.

[0683] • Bovine Serum Albumin (BSA): SIGMA, ref. A7979-50ML (35%).

[0684] • HCI 1M: For pH adjustment of the apical medium.

[0685] • NaOH 1M: For pH adjustment of the basolateral medium.

[0686] • Verapamil: P-gp inhibitor (final concentration: 100 pM), Sigma V4629.

[0687] • Lucifer Yellow: Fluorescence assay.

[0688] • HPLC reagents: ACN + 0.1% formic acid, water + 0.1% formic acid.

[0689] • 96-well deep well plates: For LC-MS samples (DOMINIQUE DUTSCHER ref.

[0690] 353925).

[0691] • Fluorescence plate reader: TECAN SAFI RE II.

[0692] Preparation and acclimatation of cells:

[0693]

[0368] The acclimation process can be initiated by replacing the provided medium with fresh culture medium under sterile conditions.

[0694]

[0369] The culture medium should be refreshed the next day, and every two days subsequently. If the assay extends over a weekend, the medium should be changed on Friday afternoon and then again on Monday morning.

[0695] Pre-incubation:

[0370] For pre-incubation, two types of media are used: a common medium (A), which consists of HBSS containing calcium, magnesium, 10 mM HEPES, and 0.1% bovine serum albumin, and two specialized media with adjusted pH. The apical medium (B) is prepared by adding 0.16 mL of 1M HCI to 250 mL of medium A to achieve a pH of 6.8, while the basolateral medium (D) is adjusted to pH 7.4 by adding 0.65 mL of 1M NaOH to 250 mL of medium A.

[0696]

[0371] The pre-incubation procedure begins with removing the current medium from both compartments. Following this, 320 pL of the apical medium (B) is dispensed into the basolateral compartment, and 100 pL of common medium (A) is added to the apical compartment of the transwell system. The cells are then incubated for 30 minutes at 37°C in a 5% CO2 atmosphere.

[0697] Incubation (with or without P-gp inhibitor):

[0698]

[0372] For cases where inhibition of P-glycoprotein is required, verapamil is added to the media at a final concentration of 100 pM. During the incubation step, the apical medium (medium B) may be supplemented with Lucifer Yellow (LY) at a concentration of 200 pM. The test compounds are diluted to a final concentration of 10 pM.

[0699]

[0373] Depending on the assay direction, whether from apical to basolateral (A > B) or vice versa (B > A), the compounds are diluted in the appropriate media (medium B for the apical side and medium D for the basolateral side). The apical compartment is filled with 100 pL of the selected medium, and 320 pL is added to the basolateral compartment.

[0700] Transport experiment:

[0701]

[0374] The incubation is conducted at 37°C in a 5% CO2 incubator for a duration of 2 hours. Samples from the apical compartment are collected at both T5' and T125'. To measure fluorescence, the donor samples are diluted 1:10 with water, then transferred to a NUNC 96-well plate.

[0702]

[0375] Fluorescence readings are performed using the TECAN SAFI RE II plate reader. The settings for fluorescence measurement include an excitation wavelength of 430 nm, an emission wavelength of 540 nm, a gain of 100, and an integration time of 40 ps.

[0703]

[0376] For LC-MS / MS quantification, the donor samples collected at T5' and T125' are processed by adding 20 pL of the donor solution to 180 pL of medium D. Proteins are precipitated using 400 pL of acetonitrile containing an internal standard (100 ng / mL). The receiver samples collected at T125' are treated with 140 pL of the acetonitrile / internal standard solution. Before LC-MS injection, the samples are centrifuged at 4000 rpm for 10 minutes. Fluorescence reading:

[0704]

[0377] The diluted donor samples (50 pL) are placed into a flat-bottom NUNC 96-well plate for fluorescence measurement. For blanks, 50 pL of water is used. Fluorescence is measured with the TECAN SAFI RE II plate reader at an excitation wavelength of 430 nm and emission wavelength of 540 nm. The gain is set to 100, with an integration time of 40 ps, and the Z-position is fixed at 5400 pm.

[0705] LC-MS Sample Preparation:

[0706]

[0378] For LC-MS analysis, a C18 column (dimensions: 50x2.1 mm, particle size: 2.7 pm) is used. The flow rate is maintained at 0.5 mL / min with a gradient elution method. Mobile phase A consists of water with 0.1% formic acid, while mobile phase B consists of acetonitrile with 0.1% formic acid. The injection volume is set to 1 pL, and the column temperature is maintained at 50°C. The gradient program begins at 2% mobile phase B, increases to 98% by 1.2 minutes, holds at 98% until 2.0 minutes, and returns to 2% by 3.5 minutes.

[0707] Results

[0708] Table 6: IC50Efflux ratio from 0 to 125’ by the compounds of the invention and the control compound s: CTX-3648, PF07248144 and “compound A”

[0709]

[0379] The results of table 6 show that the control “compound A” with a value higher than 20 will be extensively pumped out of cells, potentially reducing its intracellular concentration and, as a result, its therapeutic efficacy.

[0710]

[0380] In contrast, the compounds of the invention with efflux ratios of 2.3 and 4.8 will face lower efflux activity, similar to PF07248144. Hence, compounds of the invention are more likely to be retained within the cells, allowing for greater intracellular concentrations and potentially enhanced efficacy in targeting cancer cells.

[0711] Microscale metabolic stability assay protocol

[0712] Preparations

[0381] Stock solution: 2mM in DMSO

[0713] Daughter solution: 50|JM in DMSO / water (25 / 75). [Final] = 0.5|JM (0.25% DMSO) Preparation of Microsomes in PBS Buffer: dilution at 0.625mg of proteins / ml. [Final] =0.5mg / ml.

[0714] NADPH: 10mg in 5.4ml NaHCO3 2% buffer. [Final] = 0.44mM.

[0715] Incubations (with Robot Tecan)

[0716]

[0382] Pre-warm 7min at 37°C: 5pl of daughter solution in 395pl microsomes Incubation starts with addition of 10OpI NADPH

[0717] Sampling 50pl at 0, 5, 10, 20, 45min in analytical plate Precipitation with 150pl acetonitrile (with IS)

[0718] Centrifuge plate (4600rpm / min, 15min) before injection

[0719] Analysis in LC / MS / MS

[0720]

[0383] The HPLC conditions are as follows: the column used is an Ascentis Express C18, with dimensions of 50 x 2.1 mm and a particle size of 2.7 pm. The flow rate is set to 0.5 mL / min, operating in gradient mode. The mobile phase consists of two components: mobile phase A is water with 0.1% formic acid (HCOOH), and mobile phase B is acetonitrile (ACN) with 0.1% formic acid. The injection volume is 2 pL, and the column temperature is maintained at 50°C. The gradient starts with 98% A and 2% B, maintained until 0.30 minutes. It then shifts to 2% A and 98% B by 1.50 minutes, held until 2.00 minutes, before reverting to 98% A and 2% B at 2.01 minutes, and held until 3.00 minutes. Results

[0721]

[0384] The microsomal intrinsic clearance for the compounds of the invention, tested in mouse, rat, and human liver microsomes is less than 5 pL / min / mg protein for each species. Such a low intrinsic clearance suggests that the compounds of the invention exhibit low metabolic turnover in the microsomal preparations of all three species (mouse, rat, and human). Hence, the compounds of the invention are stable in the liver microsomes and are likely to have a longer half-life in vivo, as they are not rapidly metabolized by liver enzymes, particularly cytochrome P450 enzymes.

[0722] Blood to plasma ratio assay

[0723]

[0385] Materials and Instruments

[0724] Fresh whole blood (1 pM final concentration of test compound) DMSO (0.5% as co-solvent)

[0725] Acetonitrile / Solvent S solution (quenching agent) LC-MS / MS system for compound quantification Gentle orbital shaker (150 rpm)

[0726] Assay Procedure

[0727]

[0386] Compounds are added to fresh whole blood at a final concentration of 1 pM, using 0.5% DMSO as a co-solvent. The mixture is gently vortexed and aliquots (n=3) are immediately quenched at time 0 (tO) in acetonitrile / Solvent S solution. The remaining blood-compound mixture is incubated at 20°C for 1 hour under gentle orbital shaking (150 rpm).

[0728]

[0387] After the 1-hour incubation, aliquots (n=3) of the incubated blood sample are quenched (t1h) in acetonitrile / Solvent S solution. The remaining whole blood is centrifuged to obtain plasma, and aliquots of plasma are similarly quenched.

[0729]

[0388] Compound concentrations in both blood (t1h) and plasma (t1h) are determined via LC-MS / MS. The blood-to-plasma ratio (Cb / Cp) is calculated from these concentrations. Results

[0730] Table 7. Blood-to-Plasma Ratio (B / P) of compounds according to the invention and comparative compounds across different species (Human, Rat, Mouse)

[0731]

[0389] The results according to Table 6 show that the compounds according to the invention (e.g. 4 and 5) have a higher B / P ratio than known compounds. A high B / P ratio indicates greater partitioning into blood cells which can correlate with an extended halflife, a better delivery to cells and a better tissue distribution in particular for solid tumours. Hence, these results confirm that the compounds according to the invention exhibit a higher therapeutic potential compared to known compounds.

[0732] REFERENCES

[0733] Bergamasco, M.I., Ranathunga, N., Abeysekera, W., et al. The histone acetyltransferase KAT6B is required for hematopoietic stem cell development and function. Stem Cell Reports. 2024 Apr 9;19(4):469-485. doi: 10.1016 / j.stemcr.2024.02.005. Epub 2024 Mar 21. PMID: 38518784; PMCID: PMC1 1096436.

[0734] Coenen, Eva A et al. Pediatric acute myeloid leukemia with t(8; 16)(p11 ;p13), a distinct clinical and biological entity: a collaborative study by the International-Berlin- Frankfurt-Munster AM L-study group. Blood vol. 122,15 (2013): 2704-13 Hu, Z. et al. Genomic characterization of genes encoding histone acetylation modulator proteins identifies therapeutic targets for cancer treatment. Nat Commun 10, 733 (2019).

[0735] Lv, D., et al. "Histone Acetyltransferase KAT6A Upregulates PI3K / AKT Signaling through TRIM24 Binding." Cancer Research, vol. 77 (22) (2017): 6190-620 IMukohara T. et al. Inhibition of lysine acetyltransferase KAT6 in ER+HER2- metastatic breast cancer: a phase 1 trial. Nat Med 30, 2242-2250 (2024).

[0736] Mukohara, T., Park, Y.H., Sommerhalder, D. et al. Inhibition of lysine acetyltransferase KAT6 in ER+HER2- metastatic breast cancer: a phase 1 trial. Nat Med 30, 2242-2250 (2024).

[0737] Shikhar S. et al. Discovery of a highly potent, selective, orally bioavailable inhibitor of KAT6A / B histone acetyltransferases with efficacy against KAT6A-high ER+ breast cancer. Cell Chemical Biology, Volume 30, Issue 10, 2023, 1191-1210. e20

[0738] Stahl, P. H., & Wermuth, C. G. (Eds.). (2011). Handbook of Pharmaceutical Salts: Properties, Selection, and Use.

[0739] Turner-Ivey B. et al. KAT6A, a Chromatin Modifier from the 8p11-p12 Amplicon is a Candidate Oncogene in Luminal Breast Cancer. Neoplasia, 16 (2014), pp. 644-655

[0740] Weber L.M. et al. The Histone Acetyltransferase KAT6A is Recruited to Unmethylated CpG Islands via a DNA Binding Winged Helix Domain. Nucleic Acids Research, vol. 51 , no. 2, 25 Jan. 2023, pp. 574-594

Claims

CLAIMS1. A compound of general formula (III):or a pharmaceutically acceptable salt thereof, wherein:A represents an aryl group or a heteroaryl group, such as a benzo-fused alicyclic group, preferably a benzo-fused heterocyclic group; wherein A is optionally substituted by one or more members selected from the group consisting of: alkoxy groups, such as a C1-C4 alkoxy group; alkyl groups, such as a C1-C4 alkyl group, optionally substituted by 1 to 3 fluorine atoms; halogens; unsubstituted or substituted amino groups, such as dialkylamino groups, such as a dimethylamino group (-N(CH3)2); cycloalkyl groups optionally substituted by one or more alkyl groups and / or halogens, such as a C3-C5 cycloalkyl group optionally substituted by 1 to 2 fluorine atoms; heterocyclyl groups, preferably a 4- to 6-member heterocycloalkyl group, such as azetidine or pyrrolidine, optionally substituted by one or more alkyl groups, oxo groups and / or halogens; and phenyl groups, optionally substituted by one or more alkyl groups and / or halogens; and n and m each independently represent 0 or 1 ;R6and R7, each independently represent hydrogen; halogen; Ci-Ce alkyl group, optionally substituted by one or more halogens; C2-C6 alkenyl group, optionally substituted by one or more halogens; or Ci-Ce alkoxy group, optionally substituted by one or more halogens; alternatively, one of R6and R7taken together with any of R8, R9, R10or R11form a cyclic group such as a 3- to 6-cycloalkyl group, optionally substituted by one or more alkyl groups and / or halogens; while the other one of R6and R7, when not involved in the cyclic group, represents hydrogen or halogen;R8and R9, when not involved in a cyclic group with R6or R7, each independently represent hydrogen; halogen; Ci-Ce alkyl group, optionally substituted by one or more halogens; C2-C6 alkenyl group, optionally substituted by one or more halogens; or Ci-Ce alkoxy group, optionally substituted by one or more halogens; alternatively, R8and R9taken together, or one of R8and R9taken together with any of R10or R11, form a cyclic group such as a 3- to 6-cycloalkyl group, optionally substituted by one or more alkyl groups and / or halogens; while the other one of R8and R9, when not involved in the cyclic group, represents hydrogen or halogen; R10and R11, taken together form a cyclic group such as a 3- to 6-cycloalkyl group, optionally substituted by one or more alkyl groups and / or halogens; or R10and R11, when not involved in a cyclic group, each independently represent hydrogen; halogen; Ci-Ce alkyl group, optionally substituted by one or more halogens; C2-C6 alkenyl group, optionally substituted by one or more halogens; or Ci-Ce alkoxy group, optionally substituted by one or more halogens;X1represents an oxygen atom, a sulfur atom or CR15R16, wherein R15and R16each independently represent a hydrogen, an alkyl group, or a halogen such as fluorine; alternatively, R15taken together with any R10or R11form a cyclic group, such as a 3- to 6-cycloalkyl group, optionally substituted by one or more alkyl groups and / or halogens; alternatively, when X1represents CR15R16, R15and R16taken together form a cyclic group, such as a 3- to 6-cycloalkyl group, optionally substituted by one or more alkyl groups and / or halogens;R12and R13each independently represent a hydrogen or an alkyl group; and R14represents -CH2-heteroaryl group or -O-heteroaryl group in which the heteroaryl group is preferably a 5- or 6- member heteroaryl group such as pyrazole, oxazole, isoxazole, thiazole or pyridine; more preferably the heteroaryl group is a pyrazole, or a thiazole.

2. The compound according to the claim 1 , wherein the compound is of formula (IV):or a pharmaceutically acceptable salt thereof, wherein:R1, R2, R3, R4, and R5each independently represent H; an alkyl group, such as a C1-C4 alkyl group, optionally substituted by 1 to 3 fluorine atoms; a cycloalkyl group, optionally substituted by one or more alkyl groups and / or halogens; a 4- to 6-member heterocyclyl group, optionally substituted by one or more alkyl groups, oxo groups and / or halogens; a halogen; an alkoxy group, such as a C1-C4 alkoxy group; a cycloakyloxy group, optionally substituted by one or more alkyl groups and / or halogens; a phenyl group, optionally substituted by one or more alkyl groups and / or halogens; or a substituted or unsubstituted amino group, such as dialkylamino groups, such as a dimethylamino group (-N(CH3)2); alternatively, any one pair selected from R1and R3, R2and R4, R4and R5, or R3and R5, taken together, form a cycloalkyl group, a 5- or 6-member heterocycloalkyl group or an heteroaromatic group, optionally substituted by one or more alkyl groups and / or halogens, while the remaining R1, R2, R3, R4, and R5, each independently, represent H; an alkyl group, optionally substituted by 1 to 3 fluorine atoms; a cycloalkyl group, optionally substituted by one or more alkyl groups and / or halogens; a 4- to 6-member heterocyclyl group, optionally substituted by one or more alkyl groups, oxo groups and / or halogens; a halogen; an alkoxy group, such as a C1-C4 alkoxy group; a cycloakyloxy group, optionally substituted by one or more alkyl groups and / or halogens; a phenyl group, optionally substituted by one or more alkyl groups and / or halogens; or a substituted or unsubstituted amino group, such as dialkylamino groups, such as a dimethylamino group (-N(CH3)2); n and m each independently represent 0 or 1 ;R6and R7, each independently represent hydrogen; halogen; Ci-Ce alkyl group, optionally substituted by one or more halogens; C2-C6 alkenyl group, optionally substituted by one or more halogens; or Ci-Ce alkoxy group, optionally substituted by one or more halogens; alternatively, one of R6and R7taken together with any of R8, R9, R10or R11form a cyclic group such as a 3- to 6-cycloalkyl group, optionally substituted by one or more alkyl groups and / or halogens; while the other one of R6and R7, when not involved in the cyclic group, represents hydrogen or halogen;R8and R9, when not involved in a cyclic group with R6or R7, each independently represent hydrogen; halogen; Ci-Ce alkyl group, optionally substituted by one or more halogens; C2-C6 alkenyl group, optionally substituted by one or more halogens; or Ci-Ce alkoxy group, optionally substituted by one or more halogens; alternatively, R8and R9taken together, or one of R8and R9taken together with any of R10or R11, form a cyclic group such as a 3- to 6-cycloalkyl group, optionally substituted by one or more alkyl groups and / or halogens; while the other one of R8and R9, when not involved in the cyclic group, represents hydrogen or halogen;R10and R11, taken together form a cyclic group such as a 3- to 6-cycloalkyl group, optionally substituted by one or more alkyl groups and / or halogens; or R10and R11, when not involved in a cyclic group, each independently represent hydrogen; halogen; Ci-Ce alkyl group, optionally substituted by one or more halogens; C2-C6 alkenyl group, optionally substituted by one or more halogens; or Ci-Ce alkoxy group, optionally substituted by one or more halogens;X1represents an oxygen atom, a sulfur atom or CR15R16, wherein R15and R16each independently represent a hydrogen, an alkyl group, or a halogen such as fluorine; alternatively, R15taken together with any R10or R11form a cyclic group, such as a 3- to 6-cycloalkyl group, optionally substituted by one or more alkyl groups and / or halogens; alternatively, when X1represents CR15R16, R15and R16taken together form a cyclic group, such as a 3- to 6-cycloalkyl group, optionally substituted by one or more alkyl groups and / or halogens;R12and R13each independently represent a hydrogen or an alkyl group; and R14represents -CH2-heteroaryl group or -O-heteroaryl group in which the heteroaryl group is preferably a 5- or 6- member heteroaryl group such as pyrazole, oxazole, isoxazole, thiazole or pyridine.

3. The compound according to the claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R6, R7, R8, R9, R10, and R11are hydrogen.

4. The compound according to any one of the claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein at least one of n or m equal 0, preferably both equal 0 and X1is oxygen.

5. The compound according to any one of claims 1 , 3 or 4, wherein the compound is of formula (I lib):or a pharmaceutically acceptable salt thereof, wherein,R6and R7, each independently represent hydrogen; halogen; Ci-Ce alkyl group, optionally substituted by one or more halogens; C2-C6 alkenyl group, optionally substituted by one or more halogens; or Ci-Ce alkoxy group, optionally substituted by one or more halogens; alternatively, one of R6and R7taken together with any of R8, R9, R10or R11form a cyclic group such as a 3- to 6-cycloalkyl group, optionally substituted by one or more alkyl groups and / or halogens; while the other one of R6and R7, when not involved in the cyclic group, represents hydrogen or halogen;R8and R9, when not involved in a cyclic group with R6or R7, each independently represent hydrogen; halogen; Ci-Ce alkyl group, optionally substituted by one or more halogens; C2-C6 alkenyl group, optionally substituted by one or more halogens; or Ci-Ce alkoxy group, optionally substituted by one or more halogens; alternatively, R8and R9taken together, or one of R8and R9taken together with any of R10or R11, form a cyclic group such as a 3- to 6-cycloalkyl group, optionally substituted by one or more alkyl groups and / or halogens; while the other one of R8and R9, when not involved in the cyclic group, represents hydrogen or halogen;R10and R11, taken together form a cyclic group such as a 3- to 6-cycloalkyl group, optionally substituted by one or more alkyl groups and / or halogens; or R10and R11, when not involved in a cyclic group, each independently represent hydrogen; halogen; Ci-Ce alkyl group, optionally substituted by one or more halogens; C2-C6 alkenyl group, optionally substituted by one or more halogens; or Ci-Ce alkoxy group, optionally substituted by one or more halogens;X1represents an oxygen atom, a sulfur atom or CR15R16, wherein R15and R16each independently represent a hydrogen, an alkyl group, or a halogen such as fluorine; alternatively, R15taken together with any R10or R11form a cyclic group, such as a 3- to 6-cycloalkyl group, optionally substituted by one or more alkyl groups and / or halogens; alternatively, when X1represents CR15R16, R15and R16taken together form a cyclic group, such as a 3- to 6-cycloalkyl group, optionally substituted by one or more alkyl groups and / or halogens.

6. The compound according to any one of claims 1 to 5, wherein the compound is of formula (I Vf):or a pharmaceutically acceptable salt thereof, wherein:R2, R3, R4, and R5each independently represent H; an alkyl group, such as a Ci- 04 alkyl group, optionally substituted by 1 to 3 fluorine atoms; a cycloalkyl group, optionally substituted by one or more alkyl groups and / or halogens; a 4- to 6- member heterocyclyl group, optionally substituted by one or more alkyl groups, oxo groups and / or halogens; a halogen; an alkoxy group, such as a C1-C4 alkoxy group; a cycloakyloxy group, optionally substituted by one or more alkyl groups and / or halogens; a phenyl group, optionally substituted by one or more alkylgroups and / or halogens; or a substituted or unsubstituted amino group, such as dialkylamino groups, such as a dimethylamino group (-N(CH3)2); alternatively, any one pair selected from R2and R4, R4and R5, or R3and R5, taken together, form a cycloalkyl group, a 5- or 6-member heterocycloalkyl group or an heteroaromatic group, optionally substituted by one or more alkyl groups and / or halogens, while the remaining R2, R3, R4, and R5, each independently, represent H; an alkyl group, optionally substituted by 1 to 3 fluorine atoms; a cycloalkyl group, optionally substituted by one or more alkyl groups and / or halogens; a 4- to 6-member heterocyclyl group, optionally substituted by one or more alkyl groups, oxo groups and / or halogens; a halogen; an alkoxy group, such as a C1-C4 alkoxy group; a cycloakyloxy group, optionally substituted by one or more alkyl groups and / or halogens; a phenyl group, optionally substituted by one or more alkyl groups and / or halogens; or a substituted or unsubstituted amino group, such as dialkylamino groups, such as a dimethylamino group (- N(CH3)2); n and m each independently represent 0 or 1 ;R6and R7, each independently represent hydrogen; halogen; Ci-Ce alkyl group, optionally substituted by one or more halogens; C2-C6 alkenyl group, optionally substituted by one or more halogens; or Ci-Ce alkoxy group, optionally substituted by one or more halogens; alternatively, one of R6and R7taken together with any of R8, R9, R10or R11form a cyclic group such as a 3- to 6-cycloalkyl group, optionally substituted by one or more alkyl groups and / or halogens; while the other one of R6and R7, when not involved in the cyclic group, represents hydrogen or halogen;R8and R9, when not involved in a cyclic group with R6or R7, each independently represent hydrogen; halogen; Ci-Ce alkyl group, optionally substituted by one or more halogens; C2-C6 alkenyl group, optionally substituted by one or more halogens; or Ci-Ce alkoxy group, optionally substituted by one or more halogens; alternatively, R8and R9taken together, or one of R8and R9taken together with any of R10or R11, form a cyclic group such as a 3- to 6-cycloalkyl group, optionally substituted by one or more alkyl groups and / or halogens; while the other one of R8and R9, when not involved in the cyclic group, represents hydrogen or halogen;R10and R11, taken together form a cyclic group such as a 3- to 6-cycloalkyl group, optionally substituted by one or more alkyl groups and / or halogens; or R10and R11, when not involved in a cyclic group, each independently represent hydrogen; halogen; Ci-Ce alkyl group, optionally substituted by one or morehalogens; C2-C6 alkenyl group, optionally substituted by one or more halogens; or C1-C6 alkoxy group, optionally substituted by one or more halogens;X1represents an oxygen atom, a sulfur atom or CR15R16, wherein R15and R16each independently represent a hydrogen, an alkyl group, or a halogen, such as fluorine; alternatively, R15taken together with any R10or R11form a cyclic group, such as a 3- to 6-cycloalkyl group, optionally substituted by one or more alkyl groups and / or halogens; and alternatively, when X1represents CR15R16, R15and R16taken together form a cyclic group, such as a 3- to 6-cycloalkyl group, optionally substituted by one or more alkyl groups and / or halogens.

7. The compound according to any one of claims 2, 3, 4 or 6, or a pharmaceutically acceptable salt thereof, wherein R2and R4taken together, form a 5- or 6-member heterocycloalkyl group, optionally substituted, preferably by one or more alkyl groups and / or halogens.

8. A compound of general formula (I) or a pharmaceutically acceptable salt thereof according to any of claims 1 to 7, wherein the compound has a structure selected from:

9. A compound of general formula (I) or a pharmaceutically acceptable salt thereof according to any of claims 1 to 8, wherein the compound has a structure selected from:

10. A pharmaceutical composition comprising a compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

11. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 9, or the pharmaceutical composition according to claim 10, for use in the treatment or prophylaxis of a disease, preferably wherein the disease is a hyperproliferative disorder.

12. The compound, the pharmaceutically acceptable salt or the pharmaceutical composition for use according to claim 11, wherein it is for use in combination with a selective estrogen receptor degrader (SERD) such as fulvestrant or oral alternatives like camizestrant, immune checkpoint inhibitors targeting PD-1, PD- L1, or CTLA-4 and / or a cyclin-dependent kinase (CDK) inhibitor, including CDK2, CDK4, CDK6 or dual CDK2 / 4 or CDK4 / 6 inhibitors, such as palbociclib, ribociclib, or abemaciclib.

13. A method for treating or prophylaxis of a disease, preferably wherein the disease is a hyperproliferative disorder, comprising administering to a patient in need thereof a compound of general formula (I), or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 9, or a pharmaceutically acceptable composition according to claim 10.

14. A method for treating or prophylaxis of a disease according to claim 13, wherein it further comprises administering to the patient in need thereof a Selective Estrogen Receptor Degrader (SERD) such as fulvestrant or oral alternatives like camizestrant, immune checkpoint inhibitors targeting PD-1, PD-L1 , or CTLA-4 and / or a cyclin-dependent kinase (CDK) inhibitor, including CDK2, CDK4, CDK6 or dual CDK2 / 4 or CDK4 / 6 inhibitors, such as palbociclib, ribociclib, or abemaciclib.

Images