Sulfonylurea derivatives and their use for the treatment of cancer

Abstract

The present disclosure describes sulfonylurea derivatives 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] Sulfonylurea 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 KAT6A activity and / or KAT6A-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 KAT6A 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 al., 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 specifically 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 invention relates to a compound of general formula (I): or a pharmaceutically acceptable salt thereof, wherein:

[0015] A represents an aryl group, such as a phenyl group or a benzo-fused cycloalkyl group, or a heteroaryl group, such as 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 C1-C4 alkoxy groups; alkyl groups, such as C1-C4 alkyl groups, 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); 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; phenyl groups, optionally substituted by one or more alkyl groups and / or halogens; and 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; and

[0016] B represents a partially saturated nitrogen containing bicyclic ring system, such as tetrahydro-isoquinoline or isoindoline, substituted by one or more members selected from the group consisting of: halogens; 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; alkoxy groups such as a C1-C4 alkoxy group;

[0017] 3- to 6-member cycloalkyloxy groups, such as cyclopropyloxy group, optionally substituted by one or more alkyl groups and / or halogens;

[0018] 4- to 6-member heterocycloalkyl groups, optionally substituted by one or more alkyl groups and / or halogens, which is directly bonded to the bicyclic ring system via a covalent bond or linked through a spacer, preferably chosen from a C1-C4 alkylene chain, or a single oxygen atom; for example a 4- to 6-member heterocyclyl group, such as azetidine, optionally substituted by one or more alkyl groups and / or halogens;

[0019] 5- or 6-member heteroaryl groups, optionally substituted by one or more alkyl groups and / or halogens, which is directly bonded to the bicyclic ring system via a covalent bond or linked through a spacer, preferably chosen from a C1-C4 alkylene chain, or a single oxygen atom; for example a 5- or

[0020] 6-member heteroaryl group, such as pyrazole, isoxazole, thiazole, pyridine or oxazole, optionally substituted by one or more alkyl groups and / or halogens; and alkyl groups, such as a C1-C4 alkyl group, optionally substituted by 1 to 3 fluorine atoms.

[0021]

[0011] As it is shown in the examples, the compounds of formula (I) 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.

[0022]

[0012] Preferably, the invention relates to a compound of general formula (III) or a pharmaceutically acceptable salt thereof, wherein:

[0023] A represents an aryl group, such as a phenyl group or a benzo fused cycloalkyl group, or a heteroaryl group, such as 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 C1-C4 alkoxy groups; alkyl groups, such as C1-C4 alkyl groups, 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); 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; phenyl groups, optionally substituted by one or more alkyl groups and / or halogens; and 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; and wherein:

[0024] R6, R7, R8, and R9each independently represent H; or an alkyl group; n and m each independently represent 0 or 1 ;

[0025] R10and R13each independently represent H; a halogen; an alkoxy group; a 4- to 6-member heterocycloalkyl group or a 5- or 6-member heteroaryl group, optionally substituted by one or more alkyl groups and / or halogens; a cycloalkyl group, optionally substituted by one or more alkyl groups and / or halogens; or an alkyl group, optionally substituted by 1 to 3 fluorine atoms; and

[0026] R11and R12each independently represent H; a halogen; a dialkylamino group, such as a dimethylamino group (-N(CH3)2); a cycloalkyl group, optionally substituted by one or more alkyl groups and / or halogens; a 4- to 6-member heterocycloalkyl group, optionally substituted by one or more alkyl groups and / or halogens, such as azetidine, optionally substituted by one or more alkyl groups and / or halogens; or a 4- to 6-member heteroaryl group, optionally substituted by one or more alkyl groups and / or halogens, which is directly bonded to the aryl via a covalent bond or linked through a spacer such as an alkyl chain; such as pyrazole or oxazole, optionally substituted by one or more alkyl groups and / or halogens.

[0027]

[0013] 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:

[0028] - A represents an aryl group, such as a phenyl group or a benzo-fused cycloalkyl group, or a heteroaryl group, such as a benzo-fused heterocyclic group; substituted by one or more alkoxy groups such as a C1-C4 alkoxy group, and / or alkyl groups, such as a C1-C4 alkyl group, optionally substituted by 1 to 3 fluorine atoms; wherein A is optionally 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; unsubstituted or substituted amino groups, such as dialkylamino groups, such as a dimethylamino group (-N(CH3)2); 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; phenyl groups, optionally substituted by one or more alkyl groups and / or halogens; and 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.

[0029] B represents a partially saturated nitrogen containing bicyclic ring system, such as tetrahydro-isoquinoline or isoindoline, comprising an aryl part substituted by a 5- or 6-member heteroaryl group, which is directly bonded to the aryl part of the bicyclic ring system via a covalent bond or linked through a spacer, said spacer being preferably 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; 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; alkoxy groups, such as a C1-C4 alkoxy group;

[0030] 3- to 6-member cycloalkyloxy groups, such as cyclopropyloxy, optionally substituted by one or more alkyl groups and / or halogens; and alkyl groups, such as a C1-C4 alkyl group, optionally substituted by 1 to 3 fluorine atoms. the compound is of formula (II): or a pharmaceutically acceptable salt thereof, wherein:

[0031] 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 heterocyclyl group, preferably 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 5- or 6-member heterocycloalkyl group or an heteroaromatic ring or a 5- or 6-member cycloalkyl 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 heterocyclyl group, preferably 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 compounds of formula (II) allow for an enhanced affinity towards the target the compound is of formula (III): or a pharmaceutically acceptable salt thereof, wherein:

[0032] R6, R7, R8, and R9each independently represent H; or an alkyl group; n and m each independently represent 0 or 1 ;

[0033] R10and R13each independently represent H; a halogen; an alkoxy group; a 4- to 6-member heterocycloalkyl group or a 5- or 6-member heteroaryl group, optionally substituted by one or more alkyl groups and / or halogens; a cycloalkyl group, optionally substituted by one or more alkyl groups and / or halogens; or an alkyl group, optionally substituted by 1 to 3 fluorine atoms; and

[0034] R11and R12each independently represent H; a halogen; a dialkylamino group, such as a dimethylamino group (-N(CH3)2); a cycloalkyl group, optionally substituted by one or more alkyl groups and / or halogens; a 4- to 6-member heterocycloalkyl group, optionally substituted by one or more alkyl groups and / or halogens, such as azetidine, optionally substituted by one or more alkyl groups and / or halogens; or a 4- to 6-member heteroaryl group, optionally substituted by one or more alkyl groups and / or halogens, which is directly bonded to the aryl via a covalent bond or linked through a spacer, such as an alkyl chain; such as pyrazole or oxazole, optionally substituted by one or more alkyl groups and / or halogens.

[0035] The compounds of formula (III) exhibit higher selectivity against KAT6A vs KAT6B as well as KAT7. the compound is of formula (Illa): or a pharmaceutically acceptable salt thereof, wherein A, R10, R11, R12and R13are as previously described. the compound is of formula (111 b): or a pharmaceutically acceptable salt thereof, wherein A, R6, R7, R8, R9, R10, R11and R12are as previously described. the compound is of formula (I I Ic) : or a pharmaceutically acceptable salt thereof, wherein A, R6, R7, R8, R9, R11, R12and R13are as previously described. the compound is of formula (Hid): or a pharmaceutically acceptable salt thereof, wherein A, R10, R11, and R12are as previously described. the compound is of formula (Hie): or a pharmaceutically acceptable salt thereof, wherein:

[0036] Z represents a halogen

[0037] A, R11, R12and R13are as previously described. the compound is of formula (lllf-1):

[0038] or a pharmaceutically acceptable salt thereof, wherein:

[0039] A, R11and R12are as previously described. the compound is of formula (Illg): or a pharmaceutically acceptable salt thereof, wherein R21represents an alkyl group and wherein A, R11and R12are as previously described. the compound is of formula (lllg-1): or a pharmaceutically acceptable salt thereof, wherein A, R11and R12are as previously described the compound is of formula (111 h): or a pharmaceutically acceptable salt thereof, wherein R22represents an alkyl group or a hydrogen atom or a halogen; and wherein A, R10, R12and R13are as previously described. the compound is of formula (Illi): or a pharmaceutically acceptable salt thereof, wherein A, R11and R12are as previously described. the compound is of formula (lllj): or a pharmaceutically acceptable salt thereof, wherein A, R11and R12are as previously described. the compound is of formula (111 k) : or a pharmaceutically acceptable salt thereof, wherein A, R11and R12are as previously described. the compound is of formula (I I If): or a pharmaceutically acceptable salt thereof, wherein Z represents a halogen; an alkyl group optionally substituted by 1 to 3 fluorine atoms; an alkoxy group; or a cycloalkyl group optionally substituted by one or more alkyl groups and / or halogens. the compound is of formula (IV):

[0040] or a pharmaceutically acceptable salt thereof, wherein:

[0041] 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 heterocyclyl group, preferably 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 5- or 6-member heterocycloalkyl group or an heteroaromatic ring or a 5- or 6-member cycloalkyl 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 heterocyclyl group, preferably 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);

[0042] R6, R7, R8, and R9each independently represent H; or an alkyl group; n and m each independently represent 0 or 1 ; R10and R13each independently represent H; a halogen; an alkoxy group; a 4- to 6-member heterocycloalkyl group or a 5- or 6-member heteroaryl group, optionally substituted by one or more alkyl groups and / or halogens; a cycloalkyl group, optionally substituted by one or more alkyl groups and / or halogens; an alkyl group, optionally substituted by 1 to 3 fluorine atoms; and

[0043] R11and R12each independently represent H; a halogen; a dialkylamino group, such as a dimethylamino group (-N(CH3)2); a cycloalkyl group, optionally substituted by one or more alkyl groups and / or halogens; a 4- to 6-member heterocycloalkyl group, optionally substituted by one or more alkyl groups and / or halogens, such as azetidine, optionally substituted by one or more alkyl groups and / or halogens; or a 4- to 6-member heteroaryl group, optionally substituted by one or more alkyl groups and / or halogens, which is directly bonded to the aryl via a covalent bond or linked through a spacer such as an alkyl chain; such as pyrazole or oxazole, optionally substituted by one or more alkyl groups and / or halogens.

[0044] The compounds according to formula (IV) exhibit higher selectivity against KAT6A vs KAT6B, as well as KAT7, KAT5 and KAT8.

[0045] B is a tetrahydro-isoquinoline substituted on its aryl part of the bicyclic ring system by a 5- or 6-member heteroaryl group, which is directly bonded to the aryl part via a covalent bond or linked through a spacer such as an alkyl chain; wherein B is optionally further substituted by one or more members selected from the group consisting of: halogens; 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; alkoxy groups, such as a C1-C4 alkoxy group;

[0046] 3- to 6-member cycloalkyloxy groups, such as cyclopropyloxy, optionally substituted by one or more alkyl groups and / or halogens; and alkyl groups, such as a C1-C4 alkyl group, optionally substituted by 1 to 3 fluorine atoms. The compound or a pharmaceutically acceptable salt thereof which is selected from:

[0047]

[0048] The compound or a pharmaceutically acceptable salt thereof which is selected from:

[0049]

[0050]

[0051]

[0014] 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.

[0052]

[0015] According to another aspect, the invention relates to a compound according to the invention or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to the invention, for use in the treatment or prophylaxis of a disease, preferably wherein the disease is a hyperproliferative disorder.

[0053]

[0016] 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 signaling pathway, particularly KAT6A.

[0054]

[0017] 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) inhibitor such as fulvestrant or oral alternatives like camizestrant; an immune checkpoint inhibitor targeting PD1, PDL1 , or CTLA4 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, preferably 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; an immune checkpoint inhibitor targeting PD1 , PDL1, or CTLA4 inhibitor; and / or a cyclin-dependent kinase (CDK) inhibitor.

[0055]

[0018] 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) inhibitor such as fulvestrant or oral alternatives like camizestrant; an immune checkpoint inhibitor targeting PD1, PDL1 , or CTLA4 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; and / or a menin inhibitor, such as revumenib, 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 PD1, PDL1, or CTLA4 inhibitor; a cyclin-dependent kinase (CDK) inhibitor; and / or a menin inhibitor. Menin inhibitors can for example be found in the following article : Combined inhibition of KAT6A / B and Menin reverses estrogen receptor-driven gene expression programs in breast cancer. Cells reports Medecine. Volume 6, Issue 7, 15 July 2025, 102192.

[0056]

[0019] 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. 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 signaling pathway, particularly KAT6A.

[0057]

[0020] 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) inhibitor such as fulvestrant or oral alternatives like elacestrant or camizestrant; immune checkpoint inhibitors targeting PD1, PDL1 , or CTLA4 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, PD1, PDL1 , CTLA4 and / or a Cyclin-Dependent Kinase (CDK) inhibitor, such as CDK2, CDK4, CDK6 or dual CDK2 / 4, CDK4 / 6 inhibitors, such as palbociclib, ribociclib, or abemaciclib.

[0058]

[0021] 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) inhibitor such as fulvestrant or oral alternatives like elacestrant or camizestrant; immune checkpoint inhibitors targeting PD1, PDL1 , or CTLA4 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; and / or a menin inhibitor such as revumenib. Preferably, for enhanced therapeutic efficacy in estrogen receptor-positive cancer.

[0059]

[0022] The method of the invention is particularly effective for use in combination with a selective estrogen receptor degrader (SERD) such as fulvestrant or oral alternatives like elacestrant or camizestrant; immune checkpoint inhibitors targeting PD1, PDL1 , or CTLA4 inhibitor 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, for enhanced therapeutic efficacy in estrogen receptor-positive cancer, PD1, PDL1 , CTI.A4 inhibitor and / or a Cyclin-Dependent Kinase (CDK) inhibitor, such as CDK2, CDK4, CDK6 or dual CDK2 / 4, CDK4 / 6 inhibitors, such as palbociclib, ribociclib, or abemaciclib, for enhanced therapeutic efficacy in estrogen receptor-positive cancer.

[0060]

[0023] The method of the invention is particularly effective for use in combination with a selective estrogen receptor degrader (SERD) such as fulvestrant or oral alternatives like elacestrant or camizestrant; immune checkpoint inhibitors targeting PD1, PDL1 , or CTLA4 inhibitor 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; and / or a menin inhibitor, such as revumenib, for enhanced therapeutic efficacy in estrogen receptor-positive cancer.

[0061] DETAILED DESCRIPTION AND ADDITIONAL EMBODIMENTS

[0062]

[0024] 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.

[0063]

[0025] Unless otherwise stated, a reference to a physical measurement value in the form of an interval shall be understood to include the limits.

[0064]

[0026] 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.

[0065]

[0027] 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.

[0066] Examples encompass various forms of cancer such as carcinomas, sarcomas, leukemias, lymphomas, and melanomas.

[0067]

[0028] 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.

[0068]

[0029] 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.

[0069]

[0030] 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.

[0070]

[0031] 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.

[0071]

[0032] 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.

[0072]

[0033] 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.

[0073]

[0034] 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.

[0074]

[0035] 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.

[0036] 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.

[0075]

[0037] 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), which is incorporated by reference.

[0076]

[0038] 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.

[0077]

[0039] 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.

[0078]

[0040] 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.

[0079]

[0041] 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.

[0080]

[0042] 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.

[0043] The expression “amino group” or the expression “substituted or unsubstituted 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. 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).

[0081]

[0044] 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.

[0082]

[0045] 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).

[0083]

[0046] 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.

[0084]

[0047] 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.

[0048] 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]

[0049] 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. Examples of cycloalkyloxy groups include, but are not limited to, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, or cyclohexyloxy.

[0086]

[0050] 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, indanyl (2,3- dihydro-1 H-indene) and tetrahydronaphthyl (1,2,3,4-tetrahydronaphthyl), where the point of attachment is on the aromatic ring.

[0087]

[0051] 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.

[0088]

[0052] 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.

[0089]

[0053] 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, an oxo group or a halogen, allowing for further diversification of the compound's structure, optionally substituted by an alkyl group and / or a halogen.

[0090]

[0054] 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.

[0091]

[0055] 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 one or more alkyl groups, oxo groups and / or halogens, allowing for further structural diversification and modulation of the compound's pharmacological properties.

[0056] 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.

[0092] 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.

[0093]

[0057] 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.

[0094]

[0058] 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).

[0095]

[0059] 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 quinoline (benzene fused to a pyridine ring), indoline (benzene fused to a pyrrolidine ring), di hydrobenzofuran (benzene fused to a tetrahydrofuran 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.

[0096]

[0060] 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.

[0097]

[0061] 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).

[0098]

[0062] 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).

[0099]

[0063] 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

[0100]

[0064] 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.

[0101]

[0065] 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]

[0066] 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]

[0067] 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, such as a phenyl group or a benzo-fused cycloalkyl group, or a heteroaryl group, such as 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); 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; phenyl groups, optionally substituted by one or more alkyl groups and / or halogens; and cycloalkyl group, 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; and

[0106] B represents a partially saturated nitrogen containing bicyclic ring system, such as tetrahydro-isoquinoline or isoindoline, substituted by one or more from: halogens; 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; alkoxy groups such as a C1-C4 alkoxy group;

[0107] 3- to 6-member cycloalkyloxy groups, such as cyclopropyloxy, optionally substituted by one or more alkyl groups and / or halogens;

[0108] 4- to 6-member heterocycloalkyl groups, optionally substituted by one or more alkyl groups and / or halogens, which is directly bonded to the bicyclic ring system via a covalent bond or linked through a spacer, preferably chosen from a C1-C4 alkylene chain, or a single oxygen atom; for example a 4- to 6-member heterocyclyl group, such as azetidine, optionally substituted by one or more alkyl groups and / or halogens;

[0109] 5- or 6-member heteroaryl groups, optionally substituted by one or more alkyl groups and / or halogens, which is directly bonded to the bicyclic ring system via a covalent bond or linked through a spacer, preferably chosen from a C1-C4 alkylene chain, or a single oxygen atom; for example a 5- or

[0110] 6-member heteroaryl group, such as pyrazole, isoxazole, thiazole, pyridine or oxazole, optionally substituted by one or more alkyl groups and / or halogens; and alkyl groups, such as a C1-C4 alkyl group, optionally substituted by 1 to 3 fluorine atoms.

[0111]

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

[0112] A represents an aryl group or a heteroaryl group, substituted by one or more alkoxy groups, such as a C1-C4 alkoxy group, and / or alkyl groups, such as a C1-C4 alkyl group, optionally substituted by 1 to 3 fluorine atoms; wherein A is optionally 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; unsubstituted or substituted amino groups, such as dialkylamino groups, such as a dimethylamino group (-N(CH3)2); 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; phenyl groups, optionally substituted by one or more alkyl groups and / or halogens; and 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.

[0113]

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

[0114] A represents an aryl group or a heteroaryl group; wherein A is optionally substituted by one or more members selected from the group consisting of: halogens; 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; unsubstituted or substituted amino groups, such as dialkylamino groups, such as a dimethylamino group (-N(CH3)2); 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 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.

[0115]

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

[0116] A represents a phenyl group substituted by an alkoxy group such as a C1-C4 alkoxy group; wherein A is 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; and unsubstituted or substituted amino groups, such as dialkylamino groups, such as a dimethylamino group (-N(CH3)2).

[0117]

[0071] 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:

[0118] A represents a benzo-fused heterocyclic group, optionally 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;

[0119] 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 one or more alkyl groups and / or halogens, such as a C3-C5 cycloalkyl group optionally substituted by 1 to 2 fluorine atoms.

[0120]

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

[0121] B represents a partially saturated nitrogen containing bicyclic ring system, such as tetrahydro-isoquinoline or isoindoline, comprising an aryl part substituted by a 5- or 6- member heteroaryl group, which is directly bonded to the aryl part of the bicyclic ring system via a covalent bond or linked through a spacer, said spacer being preferably chosen from a C1-C4 alkylene chain or a single oxygen atom; wherein B is further substituted by one or more members selected from the group consisting of: halogens; 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; alkoxy groups such as a C1-C4 alkoxy group;

[0122] 3- to 6-member cycloalkyloxy groups, such as cyclopropyloxy, optionally substituted by one or more alkyl groups and / or halogens; and alkyl groups, such as a C1-C4 alkyl group, optionally substituted by 1 to 3 fluorine atoms.

[0123]

[0073] In 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 partially saturated nitrogen containing heterocycloalkyl-fused aryl substituted by a 5- or 6-member heteroaryl group, which is directly bonded to the aryl part of the heterocycloalkyl-fused aryl through a covalent bond or linked through a spacer, said spacer being preferably chosen from a C1-C4 alkylene chain or a single oxygen atom; wherein B is further substituted by one or more members selected from the group consisting of: halogens; 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; alkoxy groups, such as a C1-C4 alkoxy group;

[0125] 3- to 6-member cycloalkyloxy groups, such as cyclopropyloxy, optionally substituted by one or more alkyl groups and / or halogens; and alkyl groups, such as a C1-C4 alkyl group, optionally substituted by 1 to 3 fluorine atoms.

[0126]

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

[0127] B represents a partially saturated nitrogen containing heterocycloalkyl-fused aryl substituted by a 5- or 6-member heteroaryl group, which is directly bonded to the aryl part of the heterocycloalkyl-fused aryl through a covalent bond; wherein B is optionally further substituted by one or more members selected from the group consisting of: halogens; 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; and alkoxy groups, such as a C1-C4 alkoxy group;

[0075] 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:

[0128] B represents a partially saturated nitrogen containing heterocycloalkyl-fused aryl substituted by a pyrazole which is directly bonded to the aryl part of the heterocycloalkyl-fused aryl; wherein B is optionally further substituted by one or more members selected from the group consisting of: halogens; 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; and alkoxy groups, such as a C1-C4 alkoxy group.

[0129]

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

[0130] B is a tetrahydro-isoquinoline substituted on its aryl part of the bicyclic ring system by a 5- or 6-member heteroaryl group, which is directly bonded to the aryl part via a covalent bond or linked through a spacer such as an alkyl chain; wherein B is optionally further substituted by one or more members selected from the group consisting of: halogens; 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; alkoxy groups, such as a C1-C4 alkoxy group;

[0131] 3- to 6-member cycloalkyloxy groups, such as cyclopropyloxy, optionally substituted by one or more alkyl groups and / or halogens; and alkyl groups, such as a C1-C4 alkyl group, optionally substituted by 1 to 3 fluorine atoms.

[0132]

[0077] 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; 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; unsubstituted or substituted amino groups, such as dialkylamino groups, such as a dimethylamino group (-N(CH3)2); phenyl groups, optionally substituted by one or more alkyl groups and / or halogens; 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 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; and

[0134] B represents a partially saturated nitrogen containing heterocycloalkyl-fused aryl substituted by a 5- or 6-member heteroaryl group, which is directly bonded to the aryl part of the heterocycloalkyl-fused aryl via a covalent bond or linked through a spacer, said spacer being preferably 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; 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; alkoxy groups such as a C1-C4 alkoxy group;

[0135] 3- to 6-member cycloalkyloxy groups, such as cyclopropyloxy, optionally substituted by one or more alkyl groups and / or halogens; and alkyl groups, such as a C1-C4 alkyl group, optionally substituted by 1 to 3 fluorine atoms.

[0136]

[0078] 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 substituted by an alkoxy group such as a C1-C4 alkoxy group; wherein A is further substituted by one or several from: 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; and unsubstituted or substituted amino groups, such as dialkylamino groups, such as a dimethylamino group (-N(CH3)2); and

[0138] B represents a partially saturated nitrogen containing heterocycloalkyl-fused aryl substituted by a 5- or 6-member heteroaryl group, which is directly bonded to the aryl part of the heterocycloalkyl-fused aryl via a covalent bond; wherein B is optionally further substituted by one or more members selected from the group consisting of: halogens; 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; and alkoxy groups, such as a C1-C4 alkoxy group.

[0139]

[0079] In even more preferred embodiments, the invention relates to a compound of general formula (I), or a pharmaceutically acceptable salt thereof, wherein:

[0140] A represents a phenyl group substituted by an alkoxy group such as a C1-C4 alkoxy group; wherein A is 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;

[0141] 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 one or more alkyl groups and / or halogens, such as a C3-C5 cycloalkyl group optionally substituted by 1 to 2 fluorine atoms; and

[0142] B represents a partially saturated nitrogen containing heterocycloalkyl-fused aryl substituted by a pyrazole which is directly bonded to the aryl part of the heterocycloalkyl-fused aryl; wherein B is further substituted by one or more members selected from the group consisting of: halogens; 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; and alkoxy groups, such as a C1-C4 alkoxy group.

[0143]

[0080] 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:

[0144] B is selected as previously described;

[0145] 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 heterocyclyl group, preferably a 4- to 6-member heterocycloalkyl 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 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 5- or 6-member heterocycloalkyl group or an heteroaromatic ring or a 5- or 6-member cycloalkyl 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 heterocyclyl group, preferably a 4- to 6-member heterocycloalkyl 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 group, such as a dimethylamino group (-N(CH3)2).

[0146]

[0081] 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:

[0147] A is selected as previously described;

[0148] R6, R7, R8, and R9each independently represent H; or an alkyl group; n and m each independently represent 0 or 1 ; R10and R13each independently represent H; a halogen; an alkoxy group; a 4- to 6-member heterocycloalkyl group or a 5- or 6-member heteroaryl group, optionally substituted by one or more alkyl groups and / or halogens; a cycloalkyl group, optionally substituted by one or more alkyl groups and / or halogens; or an alkyl group, optionally substituted by 1 to 3 fluorine atoms; and

[0149] R11and R12each independently represent H; a halogen; a dialkylamino group, such as a dimethylamino group (-N(CH3)2); a cycloalkyl group optionally substituted by one or more alkyl groups and / or halogens; a 4- to 6-member heterocycloalkyl group, optionally substituted by one or more alkyl groups and / or halogens, such as azetidine, optionally substituted by one or more alkyl groups and / or halogens; or a 5- or 6-member heteroaryl group, optionally substituted by one or more alkyl groups and / or halogens, which is directly bonded to the aryl via a covalent bond or linked through a spacer such as an alkyl chain; such as pyrazole or oxazole, optionally substituted by one or more alkyl groups and / or halogens.

[0150]

[0082] 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:

[0151] 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 heterocyclyl group, preferably a 4- to 6-member heterocycloalkyl 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 5- or 6-member heterocycloalkyl group or an heteroaromatic ring or a 5- or 6-member cycloalkyl 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 heterocyclyl group, preferably a 4- to 6-member heterocycloalkyl 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);

[0152] R6, R7, R8, and R9each independently represent H; or an alkyl group; n and m each independently represent 0 or 1 ;

[0153] R10and R13each independently represent H; a halogen; an alkoxy group; a 4- to 6-member heterocycloalkyl group or a 4- to 6-member heteroaryl group, optionally substituted by one or more alkyl groups and / or halogens; a cycloalkyl group, optionally substituted by one or more alkyl groups and / or halogens; or an alkyl group, optionally substituted by 1 to 3 fluorine atoms; and

[0154] R11and R12each independently represent H; a halogen; a dialkylamino group, such as a dimethylamino group (-N(CH3)2); a cycloalkyl group, optionally substituted by one or more alkyl groups and / or halogens; a 4- to 6-member heterocycloalkyl group, optionally substituted by one or more alkyl groups and / or halogens, such as azetidine, optionally substituted by one or more alkyl groups and / or halogens; or a 4- to 6-member heteroaryl group, optionally substituted by one or more alkyl groups and / or halogens, which is directly bonded to the aryl via a covalent bond or linked through a spacer such as an alkyl chain; such as pyrazole or oxazole, optionally substituted by one or more alkyl groups and / or halogens.

[0155]

[0083] 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 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 heterocyclyl group, preferably 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).

[0156]

[0084] 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 a hydrogen atom; a halogen; an alkoxy group; 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 group or ethoxy group.

[0157]

[0085] 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 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 heterocyclyl group, preferably 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).

[0158]

[0086] 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 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 group or ethoxy group.

[0159]

[0087] 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 group or ethoxy group.

[0160]

[0088] 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 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 heterocyclyl group, preferably 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).

[0161]

[0089] 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 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 heterocyclyl group, preferably 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 group, 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.

[0162]

[0090] 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 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 heterocyclyl group, preferably 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).

[0163]

[0091] 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 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 heterocyclyl group, preferably 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; 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.

[0164]

[0092] 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 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 heterocyclyl group, preferably 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).

[0165]

[0093] 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 a hydrogen atom and a halogen atom. Preferably, R5represents a hydrogen atom.

[0094] 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 5- or 6-member heterocycloalkyl group or an heteroaromatic ring or a 5- or 6-member cycloalkyl group, optionally substituted by one or more alkyl groups and / or halogens while R2, R4, and R5each 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 heterocyclyl group, optionally substituted by one or more alkyl groups and / or halogens; a halogen; an alkoxy group; or a cycloakyloxy group, optionally substituted by one or more alkyl groups and / or halogens.

[0166]

[0095] 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 5- or 6-member heterocycloalkyl group or an heteroaromatic ring or a 5- or 6-member cycloalkyl group, optionally substituted by one or more alkyl groups and / or halogens while R1, R3, and R5each 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 heterocyclyl group, optionally substituted by one or more alkyl groups and / or halogens; a halogen; an alkoxy group; or a cycloakyloxy group, optionally substituted by one or more alkyl groups and / or halogens.

[0167]

[0096] 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 5- or 6-member heterocycloalkyl group or an heteroaromatic ring or a 5- or 6-member cycloalkyl group, optionally substituted by one or more alkyl groups and / or halogens while R1, R2, and R3each 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 heterocyclyl group, optionally substituted by one or more alkyl groups and / or halogens; a halogen; an alkoxy group; or a cycloakyloxy group, optionally substituted by one or more alkyl groups and / or halogens.

[0168]

[0097] 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 5- or 6-member heterocycloalkyl group or an heteroaromatic ring or a 5- or 6-member cycloalkyl group, optionally substituted by one or more alkyl groups and / or halogens while R1, R2, and R4each 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 heterocyclyl group, optionally substituted by one or more alkyl groups and / or halogens; a halogen; an alkoxy group; or a cycloakyloxy group, optionally substituted by one or more alkyl groups and / or halogens.

[0169]

[0098] In some embodiments, the present invention provides compounds of formula (III) or (IV), supra, or a pharmaceutically acceptable salt thereof, in which R6, R7, R8, and R9each independently represent H; or an alkyl group; n represents 1 and m represents 0.

[0170]

[0099] Preferably, R6and R8represent H and R7and R9each independently represent H; or an alkyl group; n represents 1 and m represents 0. More preferably, R6, R7, R8, and R9represent H; n represents 1 and m represents 0.

[0171]

[0100] In some embodiments, the present invention provides compounds of formula (III) or (IV), supra, or a pharmaceutically acceptable salt thereof, in which R10represents H; a halogen; an alkoxy group; a 4- to 6-member heterocycloalkyl group or a 5- or 6-member heteroaryl group, optionally substituted by one or more alkyl groups and / or halogens; a cycloalkyl group, optionally substituted by one or more alkyl groups and / or halogens; or an alkyl group, optionally substituted by 1 to 3 fluorine atoms.

[0172]

[0101] In some embodiments, the present invention provides compounds of formula (III) or (IV), supra, or a pharmaceutically acceptable salt thereof, in which R10represents H; a halogen; an alkoxy group; a 4- to 6-member heterocycloalkyl group; a cycloalkyl group, optionally substituted by one or more alkyl groups and / or halogens; an alkyl group, optionally substituted by 1 to 3 fluorine atoms. Preferably, R10represents H; a halogen; an alkoxy group; a 4- to 6-member heterocycloalkyl group; a cycloalkyl group, optionally substituted by one or more alkyl groups and / or halogens; or an alkyl group, substituted by 1 to 3 fluorine atoms. More preferably, R10represents a halogen; an alkoxy group; a 4- to 6-member heterocycloalkyl group; a cycloalkyl group, optionally substituted by one or more alkyl groups and / or halogens. Even more preferably, R10represents a halogen; an alkoxy group; or a cycloalkyl group.

[0173]

[0102] In some embodiments, the present invention provides compounds of formula (III) or (IV), supra, or a pharmaceutically acceptable salt thereof, in which R11represent H; a halogen; a dialkylamino group, such as a dimethylamino group (-N(CH3)2); a cycloalkyl group, optionally substituted by one or more alkyl groups and / or halogens; a 4- to 6- member heterocycloalkyl group, optionally substituted by an alkyl group or a halogen, such as azetidine, optionally substituted by one or more alkyl groups and / or halogens; or a 4- to 6-member heteroaryl group, optionally substituted by one or more alkyl groups and / or halogens, which is directly bonded to the aryl via a covalent bond or linked through a spacer such as an alkyl chain; such as pyrazole or oxazole, optionally substituted by one or more alkyl groups and / or halogens. Preferably, R11represents H; a halogen; a dialkylamino group, such as a dimethylamino group (-N(CH3)2); a cycloalkyl group, optionally substituted by one or more alkyl groups and / or halogens. More preferably, R11represents H; a halogen; a dialkylamino group, such as a dimethylamino group (-N(CH3)2). Even more preferably, R11represents a hydrogen atom.

[0174]

[0103] In some embodiments, the present invention provides compounds of formula (III) or (IV), supra, or a pharmaceutically acceptable salt thereof, in which R12represents H; a halogen; a dialkylamino group, such as a dimethylamino group (-N(CH3)2); a cycloalkyl group, optionally substituted by one or more alkyl groups and / or halogens; a 4- to 6- member heterocycloalkyl group, optionally substituted by one or more alkyl groups and / or halogens, such as azetidine, optionally substituted by one or more alkyl groups and / or halogens; or a 4- to 6-member heteroaryl group, optionally substituted by one or more alkyl groups and / or halogens, which is directly bonded to the aryl via a covalent bond or linked through a spacer such as an alkyl chain; such as pyrazole or oxazole, optionally substituted by one or more alkyl groups and / or halogens. Preferably, R12represent H; a halogen; a dialkylamino group, such as a dimethylamino group (-N(CH3)2); a cycloalkyl group optionally substituted by one or more alkyl groups and / or halogens. More preferably, R12represents H; a halogen; a dialkylamino group, such as a dimethylamino group (-N(CH3)2). Even more preferably, R12represents a hydrogen atom.

[0175]

[0104] In some embodiments, the present invention provides compounds of formula (III) or (IV), supra, or a pharmaceutically acceptable salt thereof, in which R13represents H; a halogen; an alkoxy group; a 4- to 6-member heterocycloalkyl group or a 5- or 6-member heteroaryl group, optionally substituted by one or more alkyl groups and / or halogens; a cycloalkyl group, optionally substituted by one or more alkyl groups and / or halogens; or an alkyl group, optionally substituted by 1 to 3 fluorine atoms.

[0176]

[0105] In some embodiments, the present invention provides compounds of formula (III), or (IV), in which R13represents H; a halogen; a 4- to 6-member heterocycloalkyl group or a 4- to 6-member heteroaryl group, optionally substituted by one or more alkyl groups and / or halogens; or a cycloalkyl group, optionally substituted by one or more alkyl groups and / or halogens. Preferably, R13represents H; a halogen; a 4- to 6-member heteroaryl group, optionally substituted by one or more alkyl groups and / or halogens. More preferably, R13a halogen or a 4- to 6-member heteroaryl group, optionally substituted by one or more alkyl groups and / or halogens. Even more preferably, R13represent a 4- to 6- member heteroaryl group, such as a pyrazol.

[0177]

[0106] 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.

[0178]

[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 R14and R15, each independently, represent H or an alkyl group, preferably R14and R15represent H.

[0179]

[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 R16represents an alkyl group or cycloalkyl group.

[0180]

[0109] In some embodiments, a compound of Formula (I) or Formula (II), or pharmaceutically acceptable salt thereof, is a compound of Formula (llb-1):

[0181] (llb-1) or a pharmaceutically acceptable salt thereof, wherein B, R2, R3, R4, and R5, are selected as previously described.

[0182]

[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 R4are selected as previously described; and wherein R16represents an alkyl group or a cycloalkyl group.

[0183]

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

[0184]

[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 R18represent, 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 R18represent, 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 (Ilf): or a pharmaceutically acceptable salt thereof, wherein B, R1, R2, R3, and R5, are selected as previously described; and wherein X represents an amino group, such as substituted amino group, such as dialkylamino groups, such as a dimethylamino group (-N(CH3)2); or a heterocyclyl group, 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.

[0187]

[0115] 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 R20represent, each independently, an alkyl group or taken together can form an azetidine or a pyrrolidine, substituted or not.

[0188]

[0116] 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 pharmaceutically acceptable salt thereof, wherein B, R1, R2, R3, and R5, are selected as previously described.

[0117] In some embodiments, a compound of Formula (I) or Formula (II), or pharmaceutically acceptable salt thereof, is a compound of Formula (llf-3): or a pharmaceutically acceptable salt thereof, wherein B, R1, R2, R3, and R5, are selected as previously described.

[0189]

[0118] In some embodiments, a compound of Formula (I) or Formula (II), or pharmaceutically acceptable salt thereof, is a compound of Formula (llf-4): or a pharmaceutically acceptable salt thereof, wherein B, R1, R2, R3, and R5, are selected as previously described.

[0190]

[0119] In some embodiments, a compound of Formula (I) or Formula (II), or pharmaceutically acceptable salt thereof, is a compound of Formula (Ilf- 5):

[0191] or a pharmaceutically acceptable salt thereof, wherein B, R1, R2, R3, and R5, are selected as previously described.

[0192]

[0120] 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, R10, R11, R12, and R13, are selected as previously described.

[0193]

[0121] 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, R6, R7, R8, R9, R10, R11, and R12, are selected as previously described.

[0194]

[0122] 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, R6, R7, R8, R9, R11, R12, and R13, are selected as previously described.

[0195]

[0123] 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, R10, R11, and R12, are selected as previously described.

[0196]

[0124] In some embodiments, a compound of Formula (I) or Formula (III), or pharmaceutically acceptable salt thereof, is a compound of Formula (Hie):

[0197] or a pharmaceutically acceptable salt thereof, wherein A, R11, R12, and R13, are selected as previously described; Z represents an halogen.

[0198]

[0125] 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, is selected as previously described; and wherein Z represents a halogen; an alkyl group optionally substituted by 1 to 3 fluorine atoms; an alkoxy group; or a cycloalkyl group optionally substituted by one or more alkyl groups and / or halogens.

[0199]

[0126] 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, R11and R12, are selected as previously described.

[0200]

[0127] In some embodiments, a compound of Formula (I) or Formula (III), or pharmaceutically acceptable salt thereof, is a compound of Formula (Illg): or a pharmaceutically acceptable salt thereof, wherein A, R11and R12, are selected as previously described; and wherein R21represents an alkyl group.

[0201]

[0128] In some embodiments, a compound of Formula (I) or Formula (III), or pharmaceutically acceptable salt thereof, is a compound of Formula (lllg-1): or a pharmaceutically acceptable salt thereof, wherein A, R11and R12, are selected as previously described.

[0202]

[0129] In some embodiments, a compound of Formula (I) or Formula (III), or pharmaceutically acceptable salt thereof, is a compound of Formula (lllh):

[0203] or a pharmaceutically acceptable salt thereof, wherein A, R10, R12and R13, are selected as previously described; and wherein R22represents an alkyl group or a hydrogen atom or a halogen.

[0204]

[0130] In some embodiments, a compound of Formula (I) or Formula (III), or pharmaceutically acceptable salt thereof, is a compound of Formula (Illi): or a pharmaceutically acceptable salt thereof, wherein A, R11and R12, are selected as previously described.

[0205]

[0131] In some embodiments, a compound of Formula (I) or Formula (III), or pharmaceutically acceptable salt thereof, is a compound of Formula (lllj): or a pharmaceutically acceptable salt thereof, wherein A, R11and R12, are selected as previously described.

[0132] In some embodiments, a compound of Formula (I) or Formula (III), or pharmaceutically acceptable salt thereof, is a compound of Formula (lllk): or a pharmaceutically acceptable salt thereof, wherein A, R11and R12, are selected as previously described.

[0206]

[0133] 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. Pharmaceutical Compositions

[0207]

[0135] The present invention relates to pharmaceutical compositions comprising at least one active compound of Formula (I), (II), (Ila), (lib), (llb-1), (lie), (lid), (He), (Ilf), (llf-1), (llf- 2), (llf-3), (llf-4), (llf-5), (III), (Illa), (lllb), (lllc), (Hid), (Hie), (Hlf), (Hlf-1), (Illg), (Hlg-1), (Hlh), (Illi), (I I Ij), (111 k) and / or (IV), 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.

[0208]

[0136] 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.

[0209]

[0137] 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.

[0210]

[0138] 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.

[0211]

[0139] 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.

[0212]

[0140] 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.

[0213]

[0141] 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

[0214]

[0142] 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.

[0215] Fixed oils such as synthetic mono- or diglycerides and fatty acids like oleic acid may be used as solvents or suspending media.

[0216]

[0143] 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.

[0217]

[0144] 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.

[0218]

[0145] 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.

[0219]

[0146] 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.

[0220] Administration and dosage

[0221]

[0147] 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.

[0222]

[0148] 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.

[0223]

[0149] 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.

[0224]

[0150] 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.

[0225]

[0151] 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.

[0226]

[0152] 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.

[0227]

[0153] 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.

[0228]

[0154] 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.

[0229] Methods and uses

[0230]

[0155] 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), (lid), (He), (Ilf), (Hf-1), (Hf-2), (Hf-3), (Hf-4), (Hf-5), (HI), (Illa), (Illb), (lllc), (Hid), (Hie), (Hlf), (lllf-1), (Illg), (lllg-1), (Hlh), (Illi), (Illj), (I I Ik) and / or (IV), or their pharmaceutically acceptable salts. These compounds are valuable as medicaments for treating conditions mediated by KAT6A, a histone acetyltransferase implicated in cancer progression.

[0231]

[0156] 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.

[0232]

[0157] 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.

[0158] 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.

[0233]

[0159] 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.

[0234]

[0160] 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 method for treating or prophylaxis of a disease selected from a KATs overexpressing cancer.

[0235]

[0161] 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.

[0236]

[0162] 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.

[0237]

[0163] 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.

[0238] Combination therapy

[0239]

[0164] Compounds of Formula (I), (II), (Ila), (lib), (llb-1), (He), (lid), (lie), (Ilf), (llf-1), (llf-2), (llf-3), (llf-4), (llf-5), (III), (Illa), (lllb), (lllc), (Hid), (Hie), (Hlf), (Hlf-1), (Illg), (Hlg-1), (Hlh), (Illi), (Illj), (lllk) and / or (IV), described herein, or their pharmaceutically acceptable salts, 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.

[0240]

[0165] 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.

[0241]

[0166] 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.

[0242]

[0167] 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.

[0243]

[0168] 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.

[0244]

[0169] 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.

[0245]

[0170] 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.

[0246]

[0171] 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.

[0247]

[0172] Further, the compounds may be combined with Menin inhibitors. Advantageously, Menin inhibitors can be revumenib.

[0248]

[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.

[0249]

[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.

[0250]

[0175] 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.

[0251]

[0176] 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]

[0177] 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 sulfonyl isocyanate or sulfonyl carbamate Intermediates

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

[0256] Scheme SCHINTAI step 1 step!

[0257]

[0178] Step 1 : 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 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 resulting precipitate was filtered and washed with ACN. The solid was suspended in toluene and evaporated to dryness under reduced pressure to afford 2,6- dimethoxybenzenesulfonamide (1.80 g, 74 % yield) as a white solid. LCMS (ES, m / z): 218.1 [M+H]+.

[0179] Step 2: To a solution of 2,6-dimethoxybenzenesulfonamide (180 mg, 828 pmol) and oxalyl chloride (326 pL, 3.72 mmol) in toluene (3 mL) at room temperature under argon was added DABCO (9.29 mg, 82.85 pmol). The reaction mixture was stirred at 60°C for 1 h then at 110°C for 5 h. The reaction mixture was filtered and washed with toluene then concentrated to dryness under reduced pressure to afford 2,6- dimethoxybenzenesulfonyl isocyanate (Intermediate INTA-I) as an orange oil which was used without further purification. LCMS (ES, m / z): 276.1 [M+H]+. (Compound quenched with MeOH to follow carbamate formation)

[0258] Intermediate INTA-2: 5-isopropyl-2-methoxybenzenesulfonyl isocyanate (Intermediate INTA-2)

[0259] Scheme SCHINTA2- step 1 step 2

[0260]

[0180] Step 1 : To a mixture of 5-isopropyl-2-methoxybenzenesulfonyl chloride (1.00 g, 4.02 mmol) in DCM (15 mL) at room temperature was added 4M ammonia solution in MeOH (10.1 mL, 40.2 mmol). The reaction mixture was stirred at room temperature for 30 min. The reaction mixture was filtered and the precipitate was dried under reduced pressure to afford 5-isopropyl-2-methoxybenzenesulfonamide (980 mg, 96 % yield) as a white solid. LCMS (ES, m / z): 230.2 [M+H]+.

[0261]

[0181] Step 2: To a mixture of 5-isopropyl-2-methoxybenzenesulfonamide (600 mg, 2.62 mmol) and oxalyl chloride (1.01 mL, 11.8 mmol) in toluene (6 mL) at room temperature was added DABCO (29.4 mg, 262 pmol). The reaction mixture was stirred at 60°C for 1 h then at 110°C for 4 h. The reaction mixture was filtered, rinsed with anhydrous toluene and concentrated under reduced pressure to dryness to afford 5-isopropyl-2- methoxybenzenesulfonyl isocyanate (Intermediate INTA-2) (660 mg, 74 % yield) as a brown oil which was used without further purification. LCMS (ES, m / z): 288.1 [M+H]+. (Compound quenched with MeOH to follow carbamate formation)

[0262] Intermediate INTA-S: 5-(tert-butyl)-2-methoxybenzenesulfonyl isocyanate (Intermediate INTA-S)

[0263] Scheme SCH INTA3- ste 1 step 2

[0264]

[0182] Step 1 : To a mixture of 5-(tert-butyl)-2-methoxybenzenesulfonyl chloride (2.00 g, 7.61 mmol) in DCM (30 mL) at room temperature was added 4M ammonia solution in methanol (9.51 mL, 38.05 mmol). The reaction mixture was stirred at room temperature for 16h. The reaction mixture was filtered and washed with DCM. The filtrate was concentrated to dryness under reduced pressure to afford 5-(terf-butyl)-2- methoxybenzenesulfonamide (1.75 g, 90 % yield) as a white solid. LCMS (ES, m / z): 244.2 [M+H]+.

[0265]

[0183] Step 2: To a mixture of 5-(terf-butyl)-2-methoxybenzenesulfonamide (227 mg, 932 pmol) and oxalyl chloride (0.36 mL, 4.19 mmol) in toluene (2 mL) at room temperature under argon was added DABCO (10.4 mg, 93 pmol). The reaction mixture was stirred at 60°C for 1 h then at 110°C for 3 h. The reaction mixture was filtered, rinsed with toluene and the filtrate was concentrated to dryness to afford 5-(terf-butyl)-2- methoxybenzenesulfonyl isocyanate (Intermediate INTA-S) as an orange oil which was used without further purification. LCMS (ES, m / z): 302.1 [M+H]+. (Compound quenched with MeOH to follow carbamate formation)

[0266] Intermediate INTA^: 5-chloro-2-methoxybenzenesulfonyl isocyanate (Intermediate INTA^)

[0267] Scheme SCHINTA4 step 1 ste 2

[0268]

[0184] 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]+.

[0269]

[0185] Step 1 : To a mixture of 5-chloro-2-methoxybenzenesulfonyl chloride (1.5 g, 6.22 mmol) in DCM (10 mL) at room temperature was added 4M ammonia solution in MeOH (15.5 mL, 62.2 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-chloro-2-methoxybenzenesulfonamide (1.49 g, Qt.) as a white solid. LCMS (ES, m / z): 222.0 [M+H]+.

[0270]

[0186] Step 2: To a solution of 5-chloro-2-methoxybenzenesulfonamide (227 mg, 1.02 mmol) and oxalyl chloride (0.39 mL, 4.60 mmol) in toluene (2 mL) at room temperature under argon was added DABCO (11.4 mg, 102.4 pmol). The reaction mixture was stirred at 60°C for 1 h then at 110°C for 3 h. The reaction mixture was filtered and rinsed with toluene. The filtrate was concentrated to dryness to afford 5-chloro-2- methoxybenzenesulfonyl isocyanate (Intermediate INTA-4) as an orange oil which was used without further purification. LCMS (ES, m / z): 280.0 [M+H]+. (Compound quenched with MeOH to follow carbamate formation).

[0271] Intermediate INTA-S: 5-fluoro-2-methoxybenzenesulfonyl isocyanate (Intermediate INTA-5)

[0272] Scheme SCHINTAS step 1 step 2

[0273]

[0187] Step 1 : To a solution of 5-chloro-2-methoxybenzenesulfonyl chloride (1.5 g, 6.22 mmol) in DCM (10 mL) at room temperature was added 4M ammonia in methanol (15.5 mL, 62.2 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-chloro-2-methoxybenzenesulfonamide (1.49 g, Qt. yield) as a white solid. LCMS (ES, m / z): 206.0 [M+H]+.

[0274]

[0188] Step 2: To a solution of 5-fluoro-2-methoxybenzenesulfonamide (200 mg, 974 pmol) and oxalyl chloride (0.37 mL, 4.38 mmol) in toluene (2 mL) at room temperature under argon was added DABCO (10.9 mg, 97.4 pmol). The reaction mixture was stirred at 60°C for 1 h then at 110°C for 3 h. The solution was filtered, rinsed with toluene and the filtrate was concentrated to dryness under reduced pressure to afford 5-fluoro-2- methoxybenzenesulfonyl isocyanate (Intermediate INTA-S) as an orange oil which was used without further purification. LCMS (ES, m / z): 264.0 [M+H]+. (Compound quenched with MeOH to follow carbamate formation)

[0275] Intermediate INTA-6: 2-methoxybenzenesulfonyl isocyanate (Intermediate INTA-B)

[0276] Scheme SCHINTA6. ste 1 step 2

[0277]

[0189] To a mixture of 2-methoxybenzenesulfonyl chloride (2.74 g, 13.3 mmol) in DCM (44.2 mL) at room temperature was added 4M ammonia solution in MeOH (33.1 mL, 133 mmol). The reaction mixture was stirred at room temperature for 30 min. The reaction mixture was filtered and the filtrate was evaporated to dryness under reduced pressure to afford 2-methoxybenzenesulfonamide hydrochloride (3.05 g, 98 % yield) as a white solid. LCMS (ES, m / z): 188.1 [M+H]+.

[0278]

[0190] Step 2: To a mixture of 2-methoxybenzenesulfonamide (720 mg, 3.84 mmol) and oxalyl chloride (8.65 mL, 17.307 mmol) in toluene (8 mL) at room temperature was added DABCO (43 mg, 384 pmol). The reaction mixture was stirred at 60°C for 1 h then at 110°C for 3 h. The reaction mixture was filtered and rinsed with toluene. The filtrate was concentrated to dryness under reduced pressure to afford 2-methoxybenzenesulfonyl isocyanate (Intermediate INTA-B) as an orange oil which was used without further purification. LCMS (ES, m / z): 246.2 [M+H]+. (Compound quenched with MeOH to follow carbamate formation)

[0279] Intermediate INTA-?: 2-ethoxybenzenesulfonyl isocyanate (Intermediate INTA.?) Scheme SCH INTA7. ste 1 step 2

[0280]

[0191] Step 1 : To a mixture of 2-ethoxybenzenesulfonyl chloride (2.00 g, 9.06 mmol) in DCM (15 mL) at room temperature was added 4M ammonia solution in methanol (22.7 mL, 90.6 mmol). The reaction mixture was stirred at room temperature for 30 min. The reaction mixture was filtered and the filtrate was concentrated to dryness under reduced pressure to afford 2-ethoxybenzenesulfonamide (2.13 g, Qt. yield) as a white solid. LCMS (ES, m / z): 202.1 [M+H]+.

[0281]

[0192] Step 2: To a mixture of 2-ethoxybenzenesulfonamide (200 mg, 994 pmol) and oxalyl chloride (384 pL, 4.47 mmol) in toluene (4 mL) at room temperature was added DABCO (11.1 mg, 99.4 pmol). The reaction mixture was stirred at 60°C for 1 h then at 110°C for 4 h. The solution was filtered, rinsed with toluene and concentrated under reduced pressure to dryness to afford 2-ethoxybenzenesulfonyl isocyanate (Intermediate INTA-?) (199 mg, 88 % yield) as a brown oil which was used without further purification. LCMS (ES, m / z): 258.1 [M+H]-. (Compound quenched with MeOH to follow carbamate formation).

[0282] Intermediate INTA-S: ethyl ((2,4-dichlorophenyl)sulfonyl)carbamate (Intermediate INTA^)

[0283] Scheme SCHINTAS step 1st0P2

[0284]

[0193] Step 1 : To a mixture of 2,4-dichlorobenzenesulfonyl chloride (5.00 g, 20.4 mmol) in DCM (100 mL) at room temperature was added 4M ammonia solution in MeOH (50.9 mL, 204 mmol). The reaction mixture was stirred at room temperature for 30 min. The reaction mixture was filtered and the filtrate was concentrated to dryness under reduced pressure to afford 2,4-dichlorobenzenesulfonamide (4.94 g, 97 % yield) as a white solid. LCMS (ES, m / z): 224.0-226.0 [M+H]-.

[0194] Step 2: To a mixture of 2,4-dichlorobenzenesulfonamide (400 mg, 1.76 mmol) and potassium carbonate (635 mg, 4.60 mmol) in acetone (4.4 mL) at room temperature was added ethyl chloroformate (220 pL, 2.30 mmol). The reaction mixture was stirred at 70 °C for 16 h. The reaction mixture was filtered and rinsed with water. The filtrate was acidified with HCI 12N until pH=1 then diluted with ethyl acetate. After separation, the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford ethyl ((2,4-dichlorophenyl)sulfonyl)carbamate (Intermediate INTA-S) (424 mg, 80 % yield) as a yellow solid. LCMS (ES, m / z): 296.2-298.2 [M+H]’.

[0285] Intermediate INTA-S: ethyl ((5-bromo-2-methoxyphenyl)sulfonyl)carbamate (Intermediate INTA-S)

[0286] Scheme SCHINTAQ

[0287] Ethyl Chloroform ate K2CO3 DCM, RT Acetone, 70°C step 1steP2

[0288]

[0195] Step 1 : To a mixture of 5-bromo-2-methoxybenzenesulfonyl chloride (5.00 g, 17.5 mmol) in DCM (87.6 mL) at room temperature was added 4M ammonia solution in MeOH (43.8 mL, 175 mmol). The reaction mixture was stirred at room temperature for 30 min. The reaction mixture was filtered and the filtrate was concentrated to dryness under reduced pressure to afford 5-bromo-2-methoxybenzenesulfonamide (4.80 g, 98 % yield) as a white solid. LCMS (ES, m / z): 265.0-267.1 [M+H]+.

[0289]

[0196] Step 2: To a mixture of 5-bromo-2-methoxybenzenesulfonamide (200 mg, 751 pmol) and potassium carbonate (270 mg, 1.95 mmol) in acetone (7.5 mL) at room temperature was added ethyl chloroformate (93.8 pL, 977 pmol). The reaction mixture was stirred at 70 °C for 16 h. The reaction mixture was filtered and rinsed with water. The filtrate was acidified with HCI 12N until pH=1 then diluted with ethyl acetate. After separation, the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford ethyl ((5-bromo-2-methoxyphenyl)sulfonyl)carbamate (Intermediate INTA-S) (220 mg, 76 % yield) as a yellow solid. LCMS (ES, m / z): 338.0- 340.0 [M+H]+. Intermediate INTA-IO: ethyl ((4-chloro-2-methoxyphenyl)sulfonyl)carbamate (Intermediate INTA-IO)

[0290] Scheme SCHINTAIO step 1 step 2

[0291]

[0197] Step 1 : To a mixture of 4-chloro-2-methoxybenzene-1 -sulfonyl chloride (1.21 g, 5.04 mmol) in DCM (25.2 mL) at room temperature was added 4M ammonia solution in MeOH (12.6 mL, 50.4 mmol). The reaction mixture was stirred at room temperature for 30 min. The reaction mixture was filtered and the filtrate was concentrated to dryness under reduced pressure to afford 4-chloro-2-methoxybenzenesulfonamide (1.06 g, 94 % yield) as a white solid. LCMS (ES, m / z): 222.1 [M+H]+.

[0292]

[0198] Step 2: To a mixture of 4-chloro-2-methoxybenzenesulfonamide (150 mg, 676 pmol) and potassium carbonate (243 mg, 1.75 mmol) in acetone (6.7 mL) at room temperature was added ethyl chloroformate (84 pL, 879 pmol). The reaction mixture was stirred at 70 °C for 16 h. The reaction mixture was filtered and rinsed with water. The filtrate was acidified with HCI 1 N until pH=1 then diluted with ethyl acetate. 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 to afford ethyl ((4-chloro-2-methoxyphenyl)sulfonyl)carbamate (Intermediate INTA-IO) (160 mg, 76 % yield) as a white solid. LCMS (ES, m / z): 294.0 [M+H]+.

[0293] Intermediate INTA-H : ethyl ((3-(dimethylamino)phenyl)sulfonyl)carbamate (Intermediate INTA-H)

[0294] Scheme SCHINTAH

[0295] Ethyl Chloroformate

[0296] K2CO3 DCM, RT Acetone, 70°C step 1 st 2

[0297]

[0199] Step 1 : To a mixture of 3-(dimethylamino)benzenesulfonyl chloride (1.00 g, 4.55 mmol) in DCM (20 mL) at room temperature was added 4M ammonia solution in MeOH (5.69 mL, 22.76 mmol). The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was filtered, washed with DCM then water was added. After separation, the organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with cyclohexane / (ethyl acetate / EtOH 3:1) from 100 / 0 to 0 / 100 to afford 3-(dimethylamino)benzenesulfonamide (600 mg, 63 % yield) as a beige solid. LCMS (ES, m / z): 201.2 [M+H]+.

[0298]

[0200] Step 2: To a mixture of 3-(dimethylamino)benzenesulfonamide (600 mg, 2.99 mmol) and potassium carbonate (1.07 g, 7.78 mmol) in acetone (20 mL) at room temperature was added ethyl chloroformate (374 pL, 3.89 mmol). The reaction mixture was stirred at 70 °C for 16 h. The reaction mixture was filtered and rinsed with acetone. The filtrate was poured into water then ethyl acetate was added. The aqueous phase was acidified with HCI 1N until pH=1 and ethyl acetate was added. The organic layer was washed with water then brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford ethyl ((3- (dimethylamino)phenyl)sulfonyl)carbamate (Intermediate INTA-H) (300 mg, 35 % yield) as a colorless oil. LCMS (ES, m / z): 273.2 [M+H]+.

[0299] Intermediate INTA-12: ethyl ((5-(3-fluoroazetidin-1-yl)-2- methoxyphenyl)sulfonyl)carbamate (Intermediate INTA-12)

[0300] Scheme SCHINTAI2 ,

[0301]

[0201] To a suspension of ethyl ((5-bromo-2-methoxyphenyl)sulfonyl)carbamate (280 mg, 827 pmol), 3-fluoroazetidine hydrochloride (369 mg, 3.31 mmol) and cesium carbonate (2.15 g, 6.62 mmol) at room temperature in dioxane (8.27 mL). The reaction mixture was degassed with argon for 5 min then XPhos Pd G3 (105 mg, 124.2 pmol) was added. The reaction mixture tube was sealed and stirred at 110 °C for 6 h under MW irradiations. The reaction mixture was filtered then evaporated 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 suspended in saturated NH4CI aqueous solution and ethyl acetate and stirred at room temperature for 30 min. After separation, the aqueous phase was acidified with HCI 1 N until pH=2. The aqueous phase was extracted twice with ethyl acetate. The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford ethyl ((5-(3- fluoroazetidin-1-yl)-2-methoxyphenyl)sulfonyl)carbamate (Intermediate INTA-12) (140 mg, 48 % yield) as a yellow oil. LCMS (ES, m / z): 333.2 [M+H]+.

[0302] Intermediate INTA-IS: ethyl ((4-bromo-2-methoxyphenyl)sulfonyl)carbamate (Intermediate INTA-IS)

[0303] Scheme SCHINTAIS mate C step 1 step 2

[0304]

[0202] Step 1 : To a mixture of 4-bromo-2-methoxybenzenesulfonyl chloride (2.00 g, 7.0 mmol) in DCM (35 mL) at room temperature was added 4M ammonia solution in MeOH (17.5 mL, 70 mmol). The reaction mixture was stirred at room temperature for 30 min. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was suspended in water and stirred for 10 min then filtered and dried to afford 4-bromo-2-methoxybenzenesulfonamide (1.46 g, 73 % yield) as a white solid. LCMS (ES, m / z): 266.0-268.0 [M+H]+.

[0305]

[0203] Step 2: To a mixture of 4-bromo-2-methoxybenzenesulfonamide (150 mg, 564 pmol) and potassium carbonate (203 mg, 1.47 mmol) in acetone (5.6 mL) at room temperature was added ethyl chloroformate (70 pL, 733 pmol). The reaction mixture was stirred at 70 °C for 16 h. The reaction mixture was filtered and rinsed with water. The filtrate was acidified with HCI 12N until pH=1 then diluted with ethyl acetate. 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 to afford ethyl ((4-bromo-2-methoxyphenyl)sulfonyl)carbamate (Intermediate INTA-IS) (130 mg, 56 % yield) as a white solid. LCMS (ES, m / z): 338.0- 340.0 [M+H]+. Intermediate INTA-U: ethyl ((3-(pyrrolidin-1-yl)phenyl)sulfonyl)carbamate (Intermediate INTA-U)

[0306] Scheme SCHINTAI4 s ep

[0307]

[0204] Step 1 : To a mixture of 3-(pyrrolidin-1-yl)benzenesulfonyl chloride (1.00 g, 4.07 mmol) in DCM (20 mL) at room temperature was added 4M ammonia solution in MeOH (10.2 mL, 40.7 mmol). The reaction mixture was stirred at room temperature for 30 min. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to afford 3-(pyrrolidin-1-yl)benzenesulfonamide (960 mg, Qt. yield) as a white solid. LCMS (ES, m / z): 227.1 [M+H]+.

[0308]

[0205] Step 2: To a mixture of 3-(pyrrolidin-1-yl)benzenesulfonamide (200 mg, 883 pmol) and potassium carbonate (317 mg, 2.29 mmol) in acetone (8.8 mL) at room temperature was added ethyl chloroformate (127 pL, 1.32 mmol). The reaction mixture was stirred at 70 °C for 16 h. The reaction mixture was filtered and rinsed with water. The filtrate was acidified with HCI 1N until pH=1 then diluted with ethyl acetate. After separation, the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford ethyl ((3-(pyrrolidin-1-yl)phenyl)sulfonyl)carbamate (Intermediate INTA- 14) (226 mg, 60 % yield) as a clear oil. LCMS (ES, m / z): 299.2 [M+H]+.

[0309] Intermediate INTA-IS: 2-methoxy-5-(trifluoromethyl)benzenesulfonyl isocyanate (Intermediate INTA-IS)

[0310] Scheme SCHINTA-IS step 1 step 2

[0311]

[0206] Step 1 : 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, 91.0 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 resulting suspension was stirred for 10 min then filtered and dried to afford 2-methoxy-5-(trifluoromethyl)benzenesulfonamide (2.0 g, 82 % yield) as a white solid. LCMS (ES, m / z): 255.0 [M+H .

[0312]

[0207] Step 2: Under argon, to a mixture of 2-methoxy-5- (trifluoromethyl)benzenesulfonamide (170 mg, 666 pmol) and oxalyl chloride (262 pL, 2.99 mmol) in toluene (3 mL) at room temperature was added DABCO (7.47 mg, 66.6 pmol). The reaction mixture was stirred at 60 °C for 1 h then at 110 °C for 3 h. The reaction mixture was filtered, rinsed with anhydrous toluene and concentrated to dryness under reduced pressure to afford 2-methoxy-5-(trifluoromethyl)benzenesulfonyl isocyanate (Intermediate INTA-IS) as an orange oil which was used without further purification. LCMS (ES, m / z): 314.1 [M+H]+. (Compound quenched with MeOH to follow carbamate formation)

[0313] Intermediate INTA-IB: tert-butyl ((5-(3-fluoroazetidin-1-yl)-2- methoxyphenyl)sulfonyl)carbamate (Intermediate INTA-IB)

[0314] Scheme SCHINTAI6- step 1steP2

[0315]

[0208] Step 1 : To a mixture of 5-bromo-2-methoxybenzenesulfonyl chloride (4.83 g, 16.9 mmol) in DCM (84 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. The residue was diluted in water, stirred 10 min at room temperature 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]+.

[0316]

[0209] Step 2: To a solution of 5-bromo-2-methoxybenzenesulfonamide (500 mg, 1.87 mmol) in dichloromethane (18.8 mL) was added Et3N (786 pL, 5.63 mmol) and BOC2O (518 pL, 2.25 mmol). The reaction mixture was stirred at room temperature for 16 h. Water was added and the layers were separated. Then, the organic one was washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to afford tert-butyl ((5-bromo-2-methoxyphenyl)sulfonyl)carbamate (Intermediate INTAIB) (1.1 g, Qte yield) as a clear oil which was used in the next step without further purification. LCMS (ES, m / z): 364.2-366.1 [M+H]+.

[0317] Intermediate INTA-I?: tert-butyl ((5-(3-fluoroazetidin-1-yl)-2- methoxyphenyl)sulfonyl)carbamate (Intermediate INT A-17)

[0318] Scheme SCHINTAI - Dioxane, 1 10 C

[0319]

[0210] To a suspension of tert-butyl ((5-bromo-2-methoxyphenyl)sulfonyl)carbamate (1.1 g, 2.10 mmol), 3-fluoroazetidine hydrochloride (938 mg, 8.41 mmol) and cesium carbonate (5.48 g, 16.82 mmol) in dioxane (21 mL) at room temperature under argon was added XPhos Pd G3 (267 mg, 315 pmol). The reaction mixture was stirred at 110 °C for 6 h under MW irradiations. The reaction mixture was dissolved in saturated NH4CI aqueous solution and ethyl acetate and 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 phase was extracted with ethyl acetate. The combined organic phases were 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 tert-butyl ((5-(3-fluoroazetidin- 1-yl)-2-methoxyphenyl)sulfonyl)carbamate (Intermediate INTA-I?) (261 mg, 34 % yield) as a yellow solid. LCMS (ES, m / z): 361.2 [M+H]+.

[0320] Intermediate INTA-IS: tert-butyl ((4'-fluoro-4-methoxy-[1,T-biphenyl]-3- yl)sulfonyl)carbamate (Intermediate INTA-IS)

[0321] Scheme SCHINTAIS-

[0322]

[0211] To a mixture of tert-butyl ((5-bromo-2-methoxyphenyl)sulfonyl)carbamate (I NTA-IS) (415 mg, 906 pmol), 2-(4-fluorophenyl)-4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane (241 mg, 1.08 mmol) and cesium carbonate (886 mg, 2.71 mmol) in DME (8 mL) and water (0.9 mL) under nitrogen at room temperature was added PdP(Pha)4 (104 mg, 90.6 pmol). The reaction mixture was stirred at 90 °C for 16 h. The reaction mixture was poured into water and ethyl acetate then acetic acid (5 mL) was added. Organic layer was washed with water, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by silica column chromatography eluted with cyclohexane / ethyl acetate from 100 / 0 to 70 / 30 to afford tert-butyl ((4'-fluoro-4-methoxy-[1 ,1'-biphenyl]-3- yl)sulfonyl)carbamate (Intermediate INTA-IS) (170 mg, 59 % yield) as a beige solid. LCMS (ES, m / z): 380.2 [M-H]+.

[0323] Intermediate INTA-IS: 4-methoxy-[1,1'-biphenyl]-3-sulfonyl isocyanate (Intermediate

[0324] INTA-19)

[0325] Scheme SCHINTAIQ-

[0326]

[0212] Step 1 : To a mixture of tert-butyl ((5-bromo-2-methoxyphenyl)sulfonyl)carbamate (I NTA-16) (400 mg, 873 pmol), phenylboronic acid (127 mg, 1.04 mmol) and cesium carbonate (854 mg, 2.62 mmol) in DME (8 mL) and water (0.9 mL) under argon was added PdP(Pha)4 (100 mg, 87 pmol). The reaction mixture was stirred at 90 °C for 16 h. The reaction mixture was dissolved in water and ethyl acetate. Then, acetic acid was added until pH=3. The layers were separated and the organic one 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 70 / 30 to afford ferf-butyl ((4-methoxy-[1 ,T-biphenyl]-3-yl)sulfonyl)carbamate (306 mg, 96% yield) as a brown solid. LCMS (ES, m / z): 362.2 [M-H]+.

[0327]

[0213] Step 2: To a solution of terf-butyl ((4-methoxy-[1 ,1'-biphenyl]-3- yl)sulfonyl)carbamate (306 mg, 749 pmol) in dioxane (2 mL) was added 4M hydrogen chloride solution in dioxane (1.87, 7.49 mmol). The reaction mixture was stirred at room temperature for 16 h. The solvent was evaporated under reduced pressure to afford 4- methoxy-[1 ,1'-biphenyl]-3-sulfonamide (180 mg, 80 % yield) as a yellowish solid. LCMS (ES, m / z): 264.3 [M+H]+.

[0328]

[0214] Step 3: To a mixture of 4-methoxy-[1 ,1'-biphenyl]-3-sulfonamide (180 mg, 683 pmol) and oxalyl chloride (269 pL, 3.07 mmol) in toluene (4 mL) at room temperature was added DABCO (7.66 mg, 68.3 pmol). The reaction mixture was stirred at 60 °C for 1 h then at 110 °C for 3 h. The solution was filtered, rinsed with anhydrous dichloromethane and concentrated to dryness under reduced pressure to afford 4-methoxy-[1 ,1'-biphenyl]-3- sulfonyl isocyanate (Intermediate INTA-IS) (Purity 200 mg, 58 % yield) as an orange oil which was engaged in the next step of the synthesis without purification. LCMS (ES, m / z): 264.3 [M+H]+. (quenched with methanol to observe carbamate mass)

[0329] Intermediate INTA-2O: 2,3-dihydrobenzofuran-7-sulfonyl isocyanate (Intermediate

[0330] INTA-20)

[0331] Scheme SCHINTAZO

[0332]

[0215] Step 1 : 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 in MeOH (22.9 mL, 91.5 mmol). The reaction mixture was stirred at room temperature for 30 min. The solvent was removed under reduced pressure. The residue was purified by reverse phase Cis column chromatography eluted with water / acetonitrile 100 / 0 to 20 / 80 to afford 2,3- dihydrobenzofuran-7-sulfonamide (1.46 g, 80 % yield) as a white solid. LCMS (ES, m / z): 200.1 [M+H]+.

[0333]

[0216] Step 2: To a mixture of 2,3-dihydrobenzofuran-7-sulfonamide (300 mg, 1.51 mmol) and oxalyl chloride (593 pL, 6.78 mmol) in toluene (4 mL) at room temperature under argon was added DABCO (16.9 mg, 151 pmol). The reaction mixture was stirred at 60 °C for 1 h then at 110 °C for 3 h. The solution was filtered, rinsed with anhydrous toluene and concentrated to dryness under reduced pressure to afford 2,3-dihydrobenzofuran-7- sulfonyl isocyanate (Intermediate INTA-2O) (250 mg, 1.11 mmol, 73.7 %) as an yellow oil which was used in the next step without any further purification. LCMS (ES, m / z): 258.1 [M+H]+. (Compound quenched with MeOH to follow carbamate formation)

[0334] Intermediate INTA-21 : tert-butyl ((7-methoxyquinolin-8-yl) sulfonyl)carbamate (Intermediate INTA-21)

[0335] Scheme SCHINTAZI

[0336]

[0217] To a mixture of 7-methoxyquinoline-8-sulfonamide (500 mg, 2.10 mmol), triethylamine (877 pL, 6.30 mmol) and DMAP (25.6 mg, 210 pmol) in DCM (8.0 mL) was added BOC2O (530 pL, 2.31 mmol). The reaction mixture was stirred at room temperature for 16 h. Water was added and the layers were separated. The organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford tert-butyl ((7-methoxyquinolin-8-yl) sulfonyl)carbamate (Intermediate INTB-SS) (409 mg, 57 % yield) as a yellow solid. LCMS (ES, m / z): 339.1 [M+H]+.

[0337] Intermediates INTA-I to INTA-21

[0338]

[0218] Intermediates INTA-I to INTA-21 , as listed in Table 2, were synthesized by methods analogous to those described above for Intermediates INTA-I , to INTA-21 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.

[0339] Table 2. Intermediates A

[0340] II. Synthesis of isoquinoline Intermediates

[0341] Intermediate INTB-I : tert-butyl 8-methoxy-5-(1H-pyrazol-1-yl)-3,4- dihydroisoquinoline-2(1 H)-carboxylate (Intermediate INTB-I)

[0342] Scheme SCHINTBI- step 1 step 2

[0343]

[0219] Step 1 : To a solution of 5-bromo-8-methoxy-1 ,2,3,4-tetrahydroisoquinoline (946 mg, 3.90 mmol) in DCM (7 mL) was added Et3N (1.63 mL, 11.7 mmol) and BOC2O (1.08 mL, 4.68 mmol). The reaction mixture was stirred at room temperature for 16 h. Water was added and the layers were separated. The organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford tert-butyl 5-bromo-8-methoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate (1.35 g, Qt. yield) which was used without further purification. LCMS (ES, m / z): 286.1-288.1 [M+H- tBu]+.

[0344]

[0220] Step 2: A mixture of 1H-pyrazole (537 mg, 7.88 mmol), tert-butyl 5-bromo-8- methoxy-3,4-dihydroisoquinoline-2(1 H)-carboxylate (1.35 g, 3.94 mmol), potassium carbonate (1.63 g, 11.83 mmol) and trans-(1R,2R)-N1 ,N2-bismethyl-1 ,2- cyclohexanediamine (622 pL, 3.94 mmol) in DMF (10 mL) was stirred at room temperature under argon for 5 min then copper(l) iodide (751 mg, 3.94 mmol) was added and the reaction mixture was stirred at 120 °C for 48 h. Ethyl acetate (EtOAc) and a saturated NH4CI aqueous solution were added. The reaction mixture was filtered over a pad of Celite. 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 / Ethyl acetate from 100 / 0 to 50 / 50 to afford tert-butyl 8-methoxy-5-(1H-pyrazol-1-yl)-3,4- dihydroisoquinoline-2(1H)-carboxylate (Intermediate INTB-I) (1.00 g, 73 % yield) as a dark oil. LCMS (ES, m / z): 330.1 [M+H]+.

[0345] Intermediate INTB-2: 8-methoxy-5-(1H-pyrazol-1-yl)-1,2,3,4-tetrahydroisoquinoline hydrochloride (Intermediate INTB-2)

[0346] Scheme SCHINTB2-

[0347]

[0221] To a solution of tert-butyl 8-methoxy-5-(1 H-pyrazol-1-yl)-3,4-dihydroisoquinoline- 2(1 H)-carboxylate (Intermediate INTB-I) (335 mg, 1.01 mmol) in dioxane (2 mL) was added 4M HCI solution in dioxane (3.81 mL, 15.2 mmol). The reaction mixture was stirred at room temperature for 16 h. The solvent was removed under reduced pressure and diethyl ether was added. The resulting precipitate was filtered and dried to afford 8- methoxy-5-(1 H-pyrazol-1-yl)-1 ,2,3,4-tetrahydroisoquinoline hydrochloride (Intermediate INTB-2) (262 mg, 96 % yield) as a yellow solid. LCMS (ES, m / z): 230.3 [M+H]+.

[0348] Intermediate INTB-S: 8-cyclopropyl-5-(1H-pyrazol-1-yl)-1,2,3,4-tetrahydroisoquinoline hydrochloride (Intermediate INTB-S)

[0349] Scheme SCHINTBS-

[0350]

[0222] Step 1 : To a mixture of tert-butyl 8-methoxy-5-(1 H-pyrazol-1-yl)-3,4- dihydroisoquinoline-2(1H)-carboxylate (Intermediate INTB-I) (596 mg, 1.80 mmol) in DCM (10 mL) at -78°C was slowly added 1M BBr3solution in DCM (9.04 mL, 9.04 mmol). The reaction mixture was allowed to warm up at room temperature and stirred for 16 h. A saturated aqueous solution of NaHCO3was added to the reaction mixture until pH=8. The aqueous layer was extracted with a mixture of DCM / IPA (9 / 1). The organic layers were combined and washed with brine then dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford 5-(1H-pyrazol-1-yl)-1 , 2,3,4- tetrahydroisoquinolin-8-ol (240 mg, 40 % yield) as a brown oil. LCMS (ES, m / z): 216.3 [M+H]+.

[0351]

[0223] Step 2: To 5-(1H-pyrazol-1-yl)-1,2,3,4-tetrahydroisoquinolin-8-ol (240 mg, 1.11 mmol) in DCM (3 mL) was added Et3N (466 pL, 3.34 mmol) and BOC2O (307 pL, 1.33 mmol). The reaction mixture was stirred at room temperature for 16 h. Methanol (8 mL) and K2CO3 (231 mg, 1.67 mmol) were added. The reaction mixture was stirred at room temperature for 5 h. Water and AcOH were added until pH=5. The aqueous layer was extracted with ethyl acetate. The combined organic phases were washed with brine and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford tert-butyl 8-hydroxy-5-(1 H-pyrazol-1-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (274 mg, 77 % yield) as a brown oil. LCMS (ES, m / z): 316.2 [M+H]+.

[0224] Step 3: To tert-butyl 8-hydroxy-5-(1 H-pyrazol-1-yl)-3,4-dihydroisoquinoline-2(1H)- carboxylate (454 mg, 1.43 mmol) in DCM (7 mL) was added trifluoromethanesulfonic anhydride (291 pL, 1.72 mmol) and pyridine (233 pL, 2.87 mmol). The reaction mixture was stirred at room temperature for 16 h. Water and ethyl acetate were added and the layers were separated. 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 from 100 / 0 to 70 / 30 to afford tert-butyl 5-(1H-pyrazol-1-yl)-8-(((trifluoromethyl)sulfonyl)oxy)-3,4- dihydroisoquinoline-2(1H)-carboxylate (492 mg, 76 % yield) as a clear oil. LCMS (ES, m / z): 392.1 [M+H-tBu]+.

[0352]

[0225] Step 4: To a mixture of tert-butyl 5-(1H-pyrazol-1-yl)-8- (((trifluoromethyl)sulfonyl)oxy)-3,4-dihydroisoquinoline-2(1 H)-carboxylate (492 mg, 1.09 mmol), cyclopropylboronic acid (188 mg, 2.19 mmol), potassium phosphate tribasic (455 pL, 5.49 mmol) and potassium bromide (130 mg, 1.09 mmol) in toluene (5 mL) and water (0.6 mL) was degassed with argon for 10 min then PdP(Ph3)4 (127 mg, 109 pmol). The reaction mixture was stirred at 100 °C for 16 h. Water and ethyl acetate were added. After separation, the aqueous layer was 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 gel column chromatography eluted with cyclohexane / CPME from 100 / 0 to 30 / 70 to afford tert-butyl 8- cyclopropyl-5-(1 H-pyrazol-1-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (142 mg, 38 % yield) as a yellow pale oil. LCMS (ES, m / z): 338.2 [M+H]+.

[0353]

[0226] Step 5: To a solution of tert-butyl 8-cyclopropyl-5-(1H-pyrazol-1-yl)-3,4- dihydroisoquinoline-2(1H)-carboxylate (142 mg, 418 pmol) in dioxane (1 mL) was added 4M HCI solution in dioxane (1.04 mL, 4.18 mmol). The reaction mixture was stirred at room temperature for 16 h. The solvent was evaporated under reduced pressure to afford 8-cyclopropyl-5-(1 H-pyrazol-1-yl)-1 ,2,3,4-tetrahydroisoquinoline hydrochloride (Intermediate INTB-S) (114 mg, 98 % yield) as a brown solid. LCMS (ES, m / z): 240.2 [M+H]+.

[0354] Intermediate INTB^: tert-butyl 7-bromo-5-fluoro-3,4-dihydroisoquinoline-2(1H)- carboxylate (Intermediate INTB^)

[0355] Scheme SCHINTB4

[0356]

[0227] Step 1 : To 7-bromo-5-fluoro-1,2,3,4-tetrahydroisoquinoline hydrochloride (520 mg, 1.95 mmol) in DCM (8.0 mL) was added BOC2O (538 pL, 2.34 mmol) and Et3N (816 pL, 5.85 mmol). The reaction mixture was stirred at room temperature for 16 h. Water was added and the layers were separated. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford tert-butyl 7- bromo-5-fluoro-3,4-dihydroisoquinoline-2(1H)-carboxylate (Intermediate INTB^) (698 mg, Qt. yield) which was used without further purification. LCMS (ES, m / z): 273-9-275.9 [M+H- tBu]+.

[0357] Intermediate INTB-S: 5-fluoro-N,N-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-amine hydrochloride (Intermediate INTB-S)

[0358] Scheme SCH INTBS- step 1 step 2

[0359]

[0228] Step 1 : To a mixture of tert-butyl 7-bromo-5-fluoro-3,4-dihydroisoquinoline-2(1 H)- carboxylate (INTB-4) (52 mg, 1.44 mmol), sodium te / t-butoxide (691 mg, 7.2 mmol) and RuPhos (67 mg, 144 pmol) in dioxane (7 mL) at room temperature was stirred under argon for 5 min then 2M solution dimethylamine in MeOH (3.6 mL, 7.2 mmol) and Pd2(dba)3 (65 mg, 72 pmol) were added. The reaction mixture was stirred at 110°C for 2 h. The reaction mixture was directly absorbed with a pad of Celite and concentrated to dryness. The residue was purified by silica gel column chromatography eluted with cyclohexane / CPME from 100 / 0 to 50 / 50 to afford tert-butyl 7-(dimethylamino)-5-fluoro-3,4- dihydroisoquinoline-2(1H)-carboxylate (446 mg, 100 % yield) as a brown oil. LCMS (ES, m / z): 295.1 [M+H]+.

[0360]

[0229] Step 2: To a solution of tert-butyl 7-(dimethylamino)-5-fluoro-3,4- dihydroisoquinoline-2(1H)-carboxylate (446 mg, 1.52 mmol) in dioxane (5 mL) was added 4M HCI solution in dioxane (3.79 mL, 15.2 mmol). The reaction mixture was stirred at room temperature for 16 h. The solvent was removed under reduced pressure. The resulting residue was suspended in diethyl ether, filtered and dried to afford 5-fluoro-A / , / - dimethyl-1 ,2,3,4-tetrahydroisoquinolin-7-amine hydrochloride (Intermediate INTB-S) (378 mg, Qt. yield) as a brown solid. LCMS (ES, m / z): 295.1 [M+H]+.

[0361] Intermediate INTB-6: A / , / V-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-amine hydrochloride (Intermediate INTB-B)

[0362] Scheme SCHINTB6- step l step 2

[0363]

[0230] Step 1 : In a sealed tube, a mixture of tert-butyl 7-bromo-3,4-dihydroisoquinoline- 2(1 H)-carboxylate hydrochloride (1.00 g, 2.86 mmol), sodium fe / t-butoxide (1.37 g, 14.3 mmol) and RuPhos (133 mg, 286 pmol) in dioxane (14 mL) at room temperature under argon was stirred for 5 min then 2M dimethylamine solution in MeOH (7.17 mL, 14.34 mmol) and Pd2(dba)3 (131 mg, 143.4 pmol) were added. The reaction mixture was stirred at 110°C for 2 h. The reaction mixture was directly absorbed with a pad of Celite and concentrated to dryness. The residue was purified by silica gel column chromatography eluted with cyclohexane / CPME from 100 / 0 to 50 / 50 to afford tert-butyl 7-(dimethylamino)- 3,4-dihydroisoquinoline-2(1 H)-carboxylate (900 mg, Qt. yield) as a brown oil. LCMS (ES, m / z): 277.1 [M+H]+.

[0364]

[0231] Step 2: To a solution of tert-butyl 7-(dimethylamino)-3,4-dihydroisoquinoline- 2(1 H)-carboxylate (900 mg, 3.26 mmol) in dioxane (8 mL) was added 4 HCI solution in dioxane (18.14 mL, 32.6 mmol). The reaction mixture was stirred at room temperature for 16 h. The solvent was removed under reduced pressure and diethyl ether was added. The resulting solid was filtered and dried to afford / V, / V-dimethyl-1 ,2,3,4-tetrahydroisoquinolin- 7-amine hydrochloride (Intermediate INTB-B) (545 mg, 78 % yield) as a brown solid. 1 H NMR (400 MHz, DMSO) 59.46 (2H, br s), 7.24 - 6.96 (1 H, m), 4.25 - 4.21 (2H, m), 4.19 - 3.93 (2H, m), 3.36 - 3.31 (2H, m), 2.99 - 2.94 (8H, br s).

[0365] Intermediate INTB-?: 7-cyclopropyl-1,2,3,4-tetrahydroisoquinoline hydrochloride (Intermediate INTB-?)

[0366] Scheme SCHINTBT- step 1 step 2

[0367]

[0232] Step 1 : In a sealed tube, to a mixture of terf-butyl 7-bromo-3,4- dihydroisoquinoline-2(1H)-carboxylate (1.00 g, 3.20 mmol) in toluene (12 mL) and water (1.2 mL) was added cyclopropylboronic acid (412 mg, 4.80 mmol), tricyclohexylphosphine, (100 pL, 320 pmol) and potassium phosphate, tribasic (795 pL, 9.60 mmol). The reaction mixture was flushed under argon for 5 min and palladium diacetate (35.95 mg, 160 pmol) was added. The reaction mixture was stirred at 100°C for 2 h. Water and ethyl acetate were added. The layers were separated and 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 / CPME from 100 / 0 to 70 / 30 to afford terf-butyl 7-cyclopropyl-3,4- dihydroisoquinoline-2(1H)-carboxylate (830 mg, 90 % yield) as a brown oil. LCMS (ES, m / z): 218.1 [M+H-fBu]+.

[0368]

[0233] Step 2: To a solution of terf-butyl 7-cyclopropyl-3,4-dihydroisoquinoline-2(1H)- carboxylate (830 mg, 3.04 mmol) in dioxane (8 mL) was added 4M HCI solution in dioxane (7.59 mL, 30.4 mmol). The reaction mixture was stirred at room temperature for 16 h. The solvent was removed under reduced pressure and diethyl ether was added. The resulting solid was filtered and dried to afford 7-cyclopropyl-1,2,3,4-tetrahydroisoquinoline hydrochloride (Intermediate INTB-?) (600 mg, 90 % yield) as a white solid. LCMS (ES, m / z): 174.1 [M+H]+.

[0369] Intermediate INTB-S: 5-fluoro-7-(3-fluoroazetidin-1-yl)-1,2,3,4-tetrahydroisoquinoline (Intermediate INTB-S)

[0370] Scheme SCHINTBS-

[0371]

[0234] Step 1 : To a solution of terf-butyl 7-bromo-5-fluoro-3,4-dihydroisoquinoline-2(1 H)- carboxylate (INTB-4) (48 mg, 145 pmol), 3-fluoroazetidine hydrochloride (81 mg, 726 pmol) and cesium carbonate (378 mg, 1.16 mmol) in dioxane (1 mL) under argon was added XPhos Pd G3 (12 mg, 4.54 pmol). The reaction mixture was stirred at 110 °C for 2 h. The reaction mixture was 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 tert-butyl 5-fluoro-7-(3-fluoroazetidin-1-yl)-3,4-dihydroisoquinoline-2(1H)- carboxylate (125 mg, 76 % yield) as a colorless oil. LCMS (ES, m / z): 325.2 [M+H]+.

[0372]

[0235] Step 2: To a solution of tert-butyl 5-fluoro-7-(3-fluoroazetidin-1-yl)-3,4- dihydroisoquinoline-2(1H)-carboxylate (125 mg, 385 pmol) in DCM (2 mL) was added TFA (296 pL, 3.85 mmol). The reaction mixture was stirred at room temperature for 16 h. A saturated Na2COs aqueous solution was added until pH=11. The aqueous layer was extracted with a mixture of DCM / IPA. The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford 5-fluoro-7-(3-fluoroazetidin-1-yl)-1,2,3,4-tetrahydroisoquinoline (Intermediate INTB-S) (100 mg, Qt. yield) as a yellow oil. LCMS (ES, m / z): 225.2 [M+H]+.

[0373] Intermediate INTB-S: 7-(azetidin-1-yl)-5-fluoro-1,2,3,4-tetrahydroisoquinoline (Intermediate INTB-S)

[0374] Scheme SCHINTBQ-

[0375]

[0236] Step 1 : In a sealed tube, a mixture of tert-butyl 7-bromo-5-fluoro-3,4- dihydroisoquinoline-2(1H)-carboxylate (INTB-4) (740 mg, 2.24 mmol), sodium tert-butoxide (1.72 g, 17.9 mmol), azetidine hydrochloride (1.04 g, 11.20 mmol) and RuPhos (104.5 mg, 224 pmol) in dioxane (10 mL) at room temperature was stirred under argon for 5 min then Pd2(dba)3 (102 mg, 112 pmol) was added. The reaction mixture was stirred at 110°C for 4 h. The reaction mixture was absorbed with a pad of Celite and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography eluted with cyclohexane / CPME from 100 / 0 to 70 / 30 to afford tert-butyl 7-(azetidin-1-yl)-5- fluoro-3,4-dihydroisoquinoline-2(1H)-carboxylate (215 mg, 27 % yield) as a yellow oil. LCMS (ES, m / z): 307.2 [M+H]+.

[0376]

[0237] Step 2: To a solution of tert-butyl 7-(azetidin-1-yl)-5-fluoro-3,4-dihydroisoquinoline- 2(1H)-carboxylate (150 mg, 489.5 pmol) in DCM (3 mL) was added TFA (377 pL, 4.89 mmol). The reaction mixture was stirred at room temperature for 16 h. A saturated Na2CC>3 aqueous solution of was added until pH=11. The aqueous layer was extracted with DCM / IPA. The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford 7- (azetidin-1-yl)-5-fluoro-1 ,2,3,4-tetrahydroisoquinoline (Intermediate INTB-S) (100 mg, 99 % yield) as a yellow oil. LCMS (ES, m / z): 207.2 [M+ H]+.

[0377] Intermediate INTB-IO: tert-butyl 7-bromo-4-methyl-3,4-dihydroisoquinoline-2(1H)- carboxylate (Intermediate INTB-IO)

[0378] Scheme SCHINTBIO-

[0379]

[0238] To 7-bromo-4-methyl-1,2,3,4-tetrahydroisoquinoline hydrochloride (1.62 g, 6.16 mmol) in DCM (15 mL) were added BOC2O (1.7 mL, 7.40 mmol) and Et3N (2.58 mL, 18.5 mmol). The reaction mixture was stirred at room temperature for 4 h. Water was added and the layers were separated. The organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford tert- butyl 7-bromo-4-methyl-3,4-dihydroisoquinoline-2(1 H)-carboxylate (Intermediate INTB-IO) (2.19 g, Qt. yield). LCMS (ES, m / z): 270.0-272.0 [M+H-tBu]+.

[0380] Intermediate INTB-H : A / , / V,4-trimethyl-1,2,3,4-tetrahydroisoquinolin-7-amine hydrochloride (Intermediate INTB-H)

[0381] Scheme SCHINTBH- di meth

[0382] Pd

[0383] D step 1 step 2

[0384] Step 1 : In a sealed tube, a mixture of tert-butyl 7-bromo-4-methyl-3,4- dihydroisoquinoline-2(1H)-carboxylate (INTB- ) (409 mg, 1.12 mmol), sodium tert-butoxide (650 mg, 6.76 mmol) and RuPhos (52 mg, 112 pmol) in dioxane (7 mL) at room temperature was stirred under argon for 5 min then 2M dimethylamine solution (1.69 mL, 3.38 mmol) and Pd2(dba)3 (51 mg, 56.3 pmol) were added. The reaction mixture was stirred at 110°C for 16 h. The reaction mixture was filtered and the filtrate was absorbed with a pad of Celite and concentrated under reduced pressure to dryness. The residue was purified by silica gel column chromatography eluted with cyclohexane / CPME from 100 / 0 to 80 / 20 to afford terf-butyl 7-(dimethylamino)-4-methyl-3,4-dihydroisoquinoline- 2(1 H)-carboxylate (186 mg, 50 % yield) as a colorless oil. LCMS (ES, m / z): 291.3 [M+H]+.

[0385]

[0239] Step 2: To a solution of terf-butyl 7-(dimethylamino)-4-methyl-3,4- dihydroisoquinoline-2(1 H)-carboxylate (180 mg, 620 pmol) in dioxane (1 mL) was added 4M HCI solution in dioxane (1.55 mL, 6.20 mmol). The reaction mixture was stirred at room temperature for 16 h. The solvent was removed under reduced pressure and diethyl ether was added. The resulting solid was filtered and dried to afford / V, / V,4-trimethyl- 1 ,2,3,4-tetrahydroisoquinolin-7-amine hydrochloride (Intermediate INTB-H) (150 mg, Qt. yield) as a brown solid. LCMS (ES, m / z): 191.3 [M+H]+.

[0386] Intermediate INTB-12: 8-fluoro-5-methoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride (Intermediate INTB-12)

[0387] Scheme SCHINTBI2-

[0388]

[0240] Step 1 : To a solution of 8-fluoro-1 ,2,3,4-tetrahydroisoquinolin-5-ol hydrobromide (320 mg, 1.28 mmol) in DCM (3 mL) was added BOC2O (356 pL, 1.54 mmol) and Et3N (539 pL, 3.86 mmol). The reaction mixture was stirred at room temperature for 16 h. Water was added and the layers were separated. The organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford terf-butyl 8-fluoro-5-hydroxy-3,4-dihydroisoquinoline-2(1H)-carboxylate (370 mg, Qt. yield). LCMS (ES, m / z): 268.1 [M+H]+.

[0389]

[0241] Step 2: To terf-butyl 8-fluoro-5-hydroxy-3,4-dihydroisoquinoline-2(1 H)-carboxylate (255 mg, 953 pmol) and potassium carbonate (395 mg, 2.86 mmol) in DMF (5 mL) at room temperature was added iodomethane (89 pL, 1.43 mmol). The reaction mixture was stirred at room temperature for 4 h. The reaction mixture was directly absorbed with a pad of Celite and concentrated under reduced pressure to dryness. The residue was purified by silica gel column chromatography eluted with cyclohexane / ethyl acetate from 100 / 0 to 80 / 20 to afford terf-butyl 8-fluoro-5-methoxy-3,4-dihydroisoquinoline-2(1 H)-carboxylate (234 mg, 83 % yield) as a white solid. LCMS (ES, m / z): 282.2 [M+H]+.

[0242] Step 3: To a solution of terf-butyl 8-fluoro-5-methoxy-3,4-dihydroisoquinoline- 2(1 H)-carboxylate (267 mg, 949 pmol) in dioxane (1 mL) was added 4M HCI solution in dioxane (346 mg, 2.37 mL, 9.49 mmol). The reaction mixture was stirred at room temperature for 16 h. The solvent was removed under reduced pressure and diethyl ether was added. The resulting solid was filtered and dried to afford 8-fluoro-5-methoxy-1, 2,3,4- tetrahydroisoquinoline hydrochloride (Intermediate INTB-12) (202 mg, 97 % yield) as a white solid. LCMS (ES, m / z): 182.1 [M+H]+.

[0390] Intermediate INTB-IS: 7-((1H-pyrazol-1-yl)methyl)-4-methyl-1, 2,3,4- tetrahydroisoquinoline hydrochloride (Intermediate INTB-IS)

[0391] Scheme SCHINTBIS-

[0392]

[0243] Step 1 : To a mixture of terf-butyl 7-bromo-4-methyl-3,4-dihydroisoquinoline-2(1 H)- carboxylate (I NTB- ) (1.00 g, 3.07 mmol), potassium trifluoro(vinyl)borate(1-) (821 mg, 6.13 mmol) and K3PO4 (826 pL, 9.2 mmol) in dioxane (8 mL) and water (0.9 mL) was stirred under argon for 10 min then was added [1,1'- Bis(diphenylphosphino)ferrocene]dichloropalladium(ll) complex with DCM (125 mg, 153 pmol). The reaction mixture was stirred at 110°C for 16 h. Water and ethyl acetate were added. After separation, the aqueous layer was extracted with ethyl acetate. The combined organic layers were 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 / CPME from 100 / 0 to 80 / 20 to afford tert- butyl 4-methyl-7-vinyl-3,4-dihydroisoquinoline-2(1H)-carboxylate (633 mg, 57 % yield) as a colorless oil. LCMS (ES, m / z): 274.2 [M+H]+.

[0393]

[0244] Step 2: To terf-butyl 4-methyl-7-vinyl-3,4-dihydroisoquinoline-2(1 H)-carboxylate (633 mg, 1.75 mmol) in THF (6 mL) and water (2 mL) at 0°C was added sodium metaperiodate (235 pL, 4.39 mmol) and osmium tetraoxide (35.19 pL, 87.98 pmol). The reaction mixture was allowed to warm up to room temperature and stirred for 1 h. Ethyl acetate and water were added. The layers were separated and 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 / CPME from 100 / 0 to 70 / 30 to afford tert-butyl 7-formyl-4-methyl-3,4- dihydroisoquinoline-2(1 H)-carboxylate (391 mg, 77 % yield) as a colorless oil. LCMS (ES, m / z): 176.1 [M+H-Boc]+.

[0394]

[0245] Step 3: To a mixture of tert-butyl 7-formyl-4-methyl-3,4-dihydroisoquinoline-2(1 H)- carboxylate (300 mg, 849.8 pmol) in MeOH (5 mL) at 0°C was slowly added NaBH4 (64.3 mg, 1.69 mmol). The reaction mixture was allowed to warm up to room temperature and stirred for 2 h. The solvent was removed under reduced pressure. The crude material was dissolved in ethyl acetate and water. The layers were separated and 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 from 100 / 0 to 50 / 50 to afford tert-butyl 7-(hydroxymethyl)-4- methyl-3,4-dihydroisoquinoline-2(1 H)-carboxylate (325 mg, Qt. yield) as a colorless oil. LCMS (ES, m / z): 178.1 [M+H-Boc]+.

[0395]

[0246] Step 4: To a mixture of tert-butyl 7-(hydroxymethyl)-4-methyl-3,4- dihydroisoquinoline-2(1 H)-carboxylate (268 mg, 966.2 pmol) in ACN (5 mL) at room temperature was added 1-(methylsulfonyl)-1 H-pyrazole (169 mg, 1.15 mmol) then CS2CO3 (944 mg, 2.89 mmol). The reaction mixture was stirred at room temperature for 48 h. The reaction mixture material was dissolved in water and ethyl acetate then extracted with ethyl acetate. The layers were separated and 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 tert-butyl 7-((1 H-pyrazol-1-yl)methyl)-4-methyl-3,4- dihydroisoquinoline-2(1 H)-carboxylate (248 mg, 78 % yield) as a colorless oil. LCMS (ES, m / z): 328.2 [M+H]+.

[0396]

[0247] Step 5: To a solution of tert-butyl 7-((1 H-pyrazol-1-yl)methyl)-4-methyl-3,4- dihydroisoquinoline-2(1 H)-carboxylate (240 mg, 733 pmol) in dioxane (1 mL) was added 4M HCI solution in dioxane (1.83 mL, 7.33 mmol). The reaction mixture was stirred at room temperature for 16 h. The solvent was removed under reduced pressure. The residue was supspended in diethyl ether, filtered and dried to afford 7-((1 H-pyrazol-1- yl)methyl)-4-methyl-1 ,2,3,4-tetrahydroisoquinoline hydrochloride (Intermediate INTB-IS) (220 mg, 100 % yield) as a brown solid. LCMS (ES, m / z): 228.2 [M+H]+. Intermediate INTB- 8-fluoro-5-(1 H-pyrazol-1-yl)-1,2,3,4-tetrahydroisoquinoline hydrochloride (Intermediate INTB-U)

[0397] Scheme SCHINTBI4-

[0398]

[0248] Step 1 : A mixture of 1 H-pyrazole (206 mg, 3.02 mmol) terf-butyl 5-bromo-8-fluoro- 3,4-dihydroisoquinoline-2(1 H)-carboxylate (500 mg, 1.51 mmol), potassium carbonate (627 mg, 4.54 mmol), trans-(1 R,2R)- / V, / V'-bismethyl-1 ,2-cyclohexanediamine (239 L, 1.51 mmol) in DMF (7 mL) was stirred under argon for 5 min then copper(l) iodide (288 mg, 1 .51 mmol) was added. The reaction mixture was stirred at 120°C for 48 h then filtered over a pad of Celite. Water and ethyl acetate were added. After separation, the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with 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 terf-butyl 8-fluoro-5-(1 H-pyrazol- 1-yl)-3,4-dihydroisoquinoline-2(1 H)-carboxylate (366 mg, 51 % yield) as a brown oil. LCMS (ES, m / z): 318.2 [M+H]+.

[0399]

[0249] Step 2: To a solution of terf-butyl 8-fluoro-5-(1 H-pyrazol-1-yl)-3,4- dihydroisoquinoline-2(1 H)-carboxylate (366 mg, 1.15 mmol) in dioxane (2 mL) was added 4M HCI in dioxane (4.32 mL, 17.3 mmol). The reaction mixture was stirred at room temperature for 16 h. The solvent was evaporated under reduced pressure then diethyl ether was added. The resulting solid was filtered and dried to afford 8-fluoro-5-(1 H- pyrazol-1-yl)-1 ,2,3,4-tetrahydroisoquinoline hydrochloride (Intermediate INTB-U) (293 mg, 100 % yield) as a brown solid. LCMS (ES, m / z): 218.1 [M+H]+.

[0400] Intermediate INTB-IS: 2-(8-fluoro-1,2,3,4-tetrahydroisoquinolin-5-yl)oxazole hydrochloride (Intermediate INTB-IS)

[0401] Scheme SCHINTBIS-

[0402]

[0250] Step 1 : To a solution of tert-butyl 5-bromo-8-fluoro-3,4-dihydroisoquinoline-2(1 H)- carboxylate (365 mg, 1.10 mmol) in dioxane (6 mL) was added potassium acetate (207 pL, 3.31 mmol) and B / s(pinacolato)diboron (421 mg, 1.65 mmol). This reaction mixture was degassed with argon for 10 min then PdCh(dppf) (40.4 mg, 55.2 pmol) was added and the reaction mixture was stirred at 90°C for 18 h under argon. The reaction mixture was filtered over a Celite pad and water and ethyl acetate were added. After separation, the aqueous layer 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 tert-butyl 8-fluoro-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)-3,4-dihydroisoquinoline-2(1 H)-carboxylate (637 mg, Qt. yield) as a dark oil. LCMS (ES, m / z): 378.2 [M+H]+.

[0403]

[0251] Step 2: In a sealed tube, tert-butyl 8-fluoro-5-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)-3,4-dihydroisoquinoline-2(1 H)-carboxylate (525 mg, 1.39 mmol), 2- bromooxazole (308 mg, 2.08 mmol) and K3PO4 (345.6 pL, 4.17 mmol) in dioxane (10 mL) and water (3 mL) was stirred under argon for 10 min then XPhos Pd G3 (58.8 mg, 69.5 pmol) was added. The reaction mixture was stirred at 100°C for 16 h. Water and Ethyl acetate were added. The layers were separated and 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 from 100 / 0 to 50 / 50 to afford tert-butyl 8-fluoro-5-(oxazol-2-yl)- 3,4-dihydroisoquinoline-2(1 H)-carboxylate (295 mg, 63 % yield) as a white solid. LCMS (ES, m / z): 319.2 [M+H]+.

[0404]

[0252] Step 3: To a solution of tert-butyl 8-fluoro-5-(oxazol-2-yl)-3,4-dihydroisoquinoline- 2(1 H)-carboxylate (295 mg, 927 pmol) in dioxane (1 mL) was added 4M HCI in dioxane (2.32 mL, 9.27 mmol). The reaction mixture was stirred at room temperature for 16 h. The solvent was evaporated under reduced pressure and diethyl ether was added. The resulting solid was filtered and dried to afford 2-(8-fluoro-1,2,3,4-tetrahydroisoquinolin-5- yl)oxazole hydrochloride (Intermediate INTB-IS) (250 mg, Qt. yield) as a brown solid. LCMS (ES, m / z): 219.2 [M+H]+.

[0405] Intermediate INTB-16: 8-methyl-5-(1H-pyrazol-1-yl)-1,2,3,4-tetrahydroisoquinoline hydrochloride (Intermediate INTB-IB)

[0406] Scheme SCHINTBIG-

[0407]

[0253] Step 1 : A mixture of 1H-pyrazole (417 mg, 6.13 mmol) tert-butyl 5-bromo-8- methyl-3,4-dihydroisoquinoline-2(1 H)-carboxylate (1.00 g, 3.06 mmol), potassium carbonate (1.27 g, 9.19 mmol), Trans-^ R,2R)- / V, / V\'-bismethyl-1,2-cyclohexanediamine (483 pL, 3.06 mmol) in DMF (8 mL) was degassed under argon for 5 min then copper(l) iodide (583 mg, 3.06 mmol) was added. The reaction mixture was stirred at 120 °C for 48 h. The reaction mixture was filtered over a pad of Celite. Water and Ethyl acetate were added. After separation, the aqueous layer was extracted with Ethyl acetate. The combined organic layers were 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 50 / 50 to afford tert-butyl 8-methyl-5-(1 H-pyrazol-1-yl)-3,4-dihydroisoquinoline-2(1 H)-carboxylate (870 mg, 90 % yield) as a colorless oil. LCMS (ES, m / z): 314.2 [M+H]+.

[0408]

[0254] Step 2: To a solution of tert-butyl 8-methyl-5-(1H-pyrazol-1-yl)-3,4- dihydroisoquinoline-2(1H)-carboxylate (870 mg, 2.77 mmol) in dioxane (5 mL) was added 4M hydrogen chloride in dioxane (6.94 mL, 27.7 mmol). The reaction mixture was stirred at room temperature for 16 h. The solvent was evaporated under reduced pressure then diethyl ether was added. The resulting solid was filtered and dried to afford 8-methyl-5- (1H-pyrazol-1-yl)-1 ,2,3,4-tetrahydroisoquinoline hydrochloride (Intermediate INTB-IB) (618 mg, 89 % yield) as a white solid. LCMS (ES, m / z): 214.3 [M+H]+.

[0409] Intermediate INTB-I?: tert-butyl 8-amino-5-(1H-pyrazol-1-yl)-3,4-dihydroisoquinoline- 2(1 H)-carboxylate (Intermediate INTB-I?)

[0410] Scheme SCHINTBI - step 1 step 2 step 3

[0411]

[0255] Step 1 : To a mixture of 5-bromo-8-nitro-1 ,2,3,4-tetrahydroisoquinoline (1.50 g,

[0412] 5.83 mmol) in DCM (20 mL) was added diisopropylethylamine (3.0 mL, 17.50 mmol) and BOC2O (1.61 mL, 7.00 mmol). The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was quenched with water and extracted with Ethyl acetate. The organic phase was dried over anhydrous magnesium sulfate, filtered, evaporated under reduced pressure. The residue was purified by silica gel column chromatography eluted with cyclohexane / Ethyl acetate from 100 / 0 to 80 / 20 to afford tert-butyl 5-bromo-8-nitro- 3,4-dihydroisoquinoline-2(1 H)-carboxylate (1.67 g, 80 % yield) as a yellow solid. LCMS (ES, m / z): 357.1-359.1 [M+H]+.

[0413]

[0256] Step 2: To a solution of tert-butyl 5-bromo-8-nitro-3,4-dihydroisoquinoline-2(1 H)- carboxylate (1.00 g, 2.80 mmol) in acetic Acid (20 mL) was added iron (1.25 g, 22.4 mmol). The reaction mixture was stirred at 50 °C for 6 h. The reaction mixture was filtered on a pad of Celite and the filtrate was concentrated under reduced pressure. Water was added and pH was adjusted to 8 using a solution of NaHCCh then extracted with ethyl acetate. The organic phase 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 60 / 40 to afford tert- butyl 8-amino-5-bromo-3,4-dihydroisoquinoline-2(1 H)-carboxylate (673 mg, 73 % yield) as a pale-yellow solid. LCMS (ES, m / z): 327.1-329.1 [M+H]+.

[0414]

[0257] Step 3: A mixture of 1 H-pyrazole (499 mg, 7.33 mmol) tert-butyl 8-amino-5-bromo- 3,4-dihydroisoquinoline-2(1 H)-carboxylate (600 mg, 1.83 mmol), potassium carbonate (760 mg, 5.50 mmol), Trans- R,2R)- / V, / V\'-bismethyl-1 ,2-cyclohexanediamine (289 pL,

[0415] 1 .83 mmol) in DMF (8 mL) was degassed under argon for 5 min then copper(l) iodide (349 mg, 1.83 mmol) was added and the mixture was stirred at 120 °C for 16 h. The reaction mixture was filtered over a pad of Celite. Then, water and ethyl acetate were added. After separation, the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with 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 40 / 60 to afford tert- butyl 8-amino-5-(1 H-pyrazol-1-yl)-3,4-dihydroisoquinoline-2(1 H)-carboxylate (Intermediate INTB-I?) (430 mg, 74 % yield) as a yellow oil. LCMS (ES, m / z): 315.3 [M+H]+. Intermediate INTB-IS: 8-bromo-5-(1H-pyrazol-1-yl)-1,2,3,4-tetrahydroisoquinoline hydrochloride (Intermediate INTB-IS) Scheme SCHINTBIS-

[0416]

[0258] Step 1 : In a three-necked round bottom flask under N2 atmosphere, terf-butyl 8- amino-5-(1 H-pyrazol-1-yl)-3,4-dihydroisoquinoline-2(1 H)-carboxylate (400 mg, 1.27 mmol) and copper(ll) bromide (341 mg, 1.53 mmol) were suspended in acetonitrile (10 mL) . The reaction mixture was cooled at -10°C then terf-butyl nitrite (227 pL, 1.91 mmol) was slowly added over a period of 5 min maintaining the internal temperature at -10°C. At the end of the addition, the reaction mixture was allowed to warm up to room temperature and stirred for 3 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography eluted with cyclohexane / AcOEt from 100 / 0 to 90 / 10 to afford terf-butyl 8-bromo-5-(1 H-pyrazol-1-yl)-3,4-dihydroisoquinoline- 2(1 H)-carboxylate (162 mg, 33 % yield) as a light brown oil. LCMS (ES, m / z): 378.1-380.1 [M+H]+.

[0417]

[0259] Step 2: To a solution of terf-butyl 8-bromo-5-(1 H-pyrazol-1-yl)-3,4- dihydroisoquinoline-2(1 H)-carboxylate (160 mg, 423 pmol) in dioxane (2 mL) was added 4M hydrogen chloride in dioxane (1.06 mL, 4.23 mmol). The reaction mixture was stirred at room temperature for 16 h. The solvent was removed under reduced pressure to afford 8-bromo-5-(1 H-pyrazol-1-yl)-1 ,2,3,4-tetrahydroisoquinoline hydrochloride (Intermediate INTB-18) (150 mg, 100 % yield) as a brown solid. LCMS (ES, m / z): 278.0-280.0 [M+H]+.

[0418] Intermediate INTB-IS: 8-chloro-5-(1 H-pyrazol-1-yl)-1,2,3,4-tetrahydroisoquinoline hydrochloride (Intermediate INTB-IS)

[0419] Scheme SCHINTBIQ-

[0420]

[0260] Step 1 : To a mixture of 8-chloro-5-nitro-1,2,3,4-tetrahydroisoquinoline hydrochloride (1.00 g, 4.01 mmol) in DCM (20 mL) was added Et3N (2.24 mL16.1 mmol) and BOC2O (1.11 mL, 4.82 mmol). The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic phase was dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with cyclohexane / ethyl acetate from 100 / 0 to 80 / 20 to afford tert-butyl 8-chloro-5- nitro-3,4-dihydroisoquinoline-2(1 H)-carboxylate (1.20 g, 96 % yield) as a yellow solid. LCMS (ES, m / z): 313.1 [M+H]+.

[0421]

[0261] Step 2: To a solution of tert-butyl 8-chloro-5-nitro-3,4-dihydroisoquinoline-2(1 H)- carboxylate (1.20 g, 3.84 mmol) in AcOH (20 mL) was added iron (1.71 g, 30.7 mmol) . The reaction mixture was stirred at 50 °C for 6 h. The reaction mixture was filtered over a pad of Celite and the filtrate was concentrated under reduced pressure. Water was added and the pH was adjusted to 8 using a solution of NaHCCh then extracted with ethyl acetate. The solvent was evaporated under reduced pressure and 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-amino-8-chloro-3,4-dihydroisoquinoline-2(1 H)- carboxylate (870 mg, 80 % yield) as a pale-yellow solid. LCMS (ES, m / z): 283.1 [M+H]+.

[0422]

[0262] Step 3: To a suspension of tert-butyl 5-amino-8-chloro-3,4-dihydroisoquinoline- 2(1H)-carboxylate (780 mg, 2.76 mmol) and copper(ll) bromide (739 mg, 3.31 mmol) were suspended in acetonitrile (10 mL) under N2 atmosphere. The reaction mixture was cooled to -10°C then tert-butyl nitrite (492 pL, 4.14 mmol) was slowly added over a period of 5 min maintaining the internal temperature at -10°C. At the end of the addition, the reaction mixture was allowed to warm to room temperature and stirred for 2 h. Water and ethyl acetate were added. After the separation, the organic phase was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by reverse phase C18 column chromatography eluted with water / ACN 95 / 5 to 40 / 60 to afford tert-butyl 5-bromo- 8-chloro-3,4-dihydro-1 H-isoquinoline-2-carboxylate (465 mg, 46 % yield) as a pale brown oil. LCMS (ES, m / z): 346.1-348.1 [M+H]+.

[0423]

[0263] Step 4: A mixture of 1H-pyrazole (440 mg, 6.46 mmol) tert-butyl 5-bromo-8-chloro- 3,4-dihydroisoquinoline-2(1H)-carboxylate (560 mg, 1.62 mmol), potassium carbonate (670 mg, 4.85 mmol), Trans-f R,2R)- / V, / V\'-bismethyl-1,2-cyclohexanediamine (255 pL,

[0424] 1.62 mmol) in DMF (6 mL) was degassed under argon for 5 min then copper(l) iodide (308 mg, 1.62 mmol) was added and the reaction mixture was stirred at 120 °C for 16 h. The mixture was filtrated over a pad of Celite. Water and ethyl acetate were added. After separation, the aqueous layer was 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 gel column chromatography eluted with cyclohexane / ethyl acetate from 100 / 0 to 80 / 20 to afford tert- butyl 8-chloro-5-(1 H-pyrazol-1-yl)-3,4-dihydroisoquinoline-2(1 H)-carboxylate (183 mg, 33 % yield) as a yellow oil. LCMS (ES, m / z): 334.2 [M+H]+.

[0425]

[0264] Step 5: To a solution of tert-butyl 8-chloro-5-(1 H-pyrazol-1-yl)-3,4- dihydroisoquinoline-2(1H)-carboxylate (180 mg, 539 pmol) in dioxane (2 mL) was added 4M hydrogen chloride in dioxane (1.35 mL, 5.39 mmol). The reaction mixture was stirred at room temperature for 16 h. The solvent was removed under reduced pressure to afford 8-chloro-5-(1 H-pyrazol-1-yl)-1 ,2,3,4-tetrahydroisoquinoline hydrochloride (Intermediate INTB-19) (127 mg, 87 % yield) as a pale-yellow solid. LCMS (ES, m / z): 234.3 [M+H]+.

[0426] I ntermed i ate I NTB-2O : 5-(1 H-pyrazol- 1 -yl)-8-(trifluoromethyl)-1 ,2, 3,4- tetrahydroisoquinoline hydrochloride (Intermediate INTB-20)

[0427] Scheme SCHINTB2O-

[0428]

[0265] Step 1 : In a three-necked round bottom flask under N2 atmosphere at room temperature, tert-butyl 8-amino-5-(1 H-pyrazol-1-yl)-3,4-dihydroisoquinoline-2(1 H)- carboxylate (I NTB-I?) (810 mg, 2.58 mmol) and tert-butyl nitrite (460 pL, 3.86 mmol) were suspended in acetonitrile (10 mL) . The reaction mixture was cooled at -10 °C then Cui (638 mg, 3.35 mmol) was slowly added maintaining the internal temperature at -10 °C. At the end of the addition, the reaction mixture was allowed to warm at room teperature and strirred for 1 h. Water was added followed by an extraction with ethyl acetate. The organic layer 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 tert-butyl 8-iodo-5-(1 H-pyrazol-1-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (330 mg, 30 % yield) as a brown oil. LCMS (ES, m / z): 426.2 [M-H]+.

[0429]

[0266] Step 2: To a mixture of tert-butyl 8-iodo-5-(1 H-pyrazol-1-yl)-3,4- dihydroisoquinoline-2(1H)-carboxylate (150 mg, 353 pmol) in DMF (1.5 mL) was added (1,10-phenanthroline)(trifluoromethyl) copper (331 mg, 1.06 mmol). The reaction mixture was stirred at 100 °C for 72 h. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography eluted with cyclohexane / ethyl acetate 100 / 0 to 50 / 50 to afford tert-butyl 5-(1 H-pyrazol-1-yl)-8-(trifluoromethyl)-3,4- dihydroisoquinoline-2(1H)-carboxylate (120 mg, 92 % yield) as a colorless oil. LCMS (ES, m / z): 366.3 [M-H]+.

[0430]

[0267] Step 3: To a solution of tert-butyl 5-(1H-pyrazol-1-yl)-8-(trifluoromethyl)-3,4- dihydroisoquinoline-2(1H)-carboxylate (120 mg, 327 pmol) in dioxane (2 mL) was added 4M hydrogen chloride solution in dioxane (817 pL, 3.27 mmol). The reaction mixture was stirred at room temperature for 16 h. The solvent was removed under reduced pressure to afford 5-(1 H-pyrazol-1-yl)-8-(trifluoromethyl)-1 ,2,3,4-tetrahydroisoquinoline hydrochloride (Intermediate INTB-2O) (99 mg, 100 % yield) as a pale-yellow solid. LCMS (ES, m / z): 268.1 [M+H]+.

[0431] Intermediate INTB-21 : 8-isopropoxy-5-(1H-pyrazol-1-yl)-1,2,3,4-tetrahydroisoquinoline hydrochloride (Intermediate INTB-21)

[0432] Scheme SCHINTBZI-

[0433]

[0268] Step 1 : To a mixture of tert-butyl 8-methoxy-5-(1 H-pyrazol-1-yl)-3,4- dihydroisoquinoline-2(1H)-carboxylate (Intermediate INTB-I) (7.7 g, 23.3 mmol) in DCM (80 mL) at -78°C was slowly added BBra (70.1 mL, 70.1 mmol). The reaction mixture was allowed to warm up at room temperature and stirred for 16 h. A saturated NaHCOs aqueous solution was added until pH=8. The aqueous layer was extracted with a mix of DCM / IPA (9 / 1). The organic layers were combined, washed with brine and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford 5- (1H-pyrazol-1-yl)-1 ,2,3,4-tetrahydroisoquinolin-8-ol (15 g, Qt. yield) as a brown solid which was used without further purification. LCMS (ES, m / z): 216.3 [M+H]+.

[0434]

[0269] Step 2: To 5-(1H-pyrazol-1-yl)-1,2,3,4-tetrahydroisoquinolin-8-ol (5.07 g, 23.6 mmol) in DCM (50 mL) was added BOC2O (6.49 mL, 28.3 mmol) and triethylamine (16.4 mL, 118 mmol). The reaction mixture was stirred at room temperature for 16 h. MeOH (10 mL) and potassium carbonate (4.88 g, 35.3 mmol) were added. The reaction mixture was stirred at 60 °C for 24 h. Water and acetic acid were added until pH=5. The aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with brine and 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 tert-butyl 8-hydroxy-5-(1H- pyrazol-1-yl)-3,4-dihydroisoquinoline-2(1 H)-carboxylate (3.94 g, 53 % yield) as a white solid. LCMS (ES, m / z): 316.2 [M+H]+.

[0435]

[0270] Step 3: To tert-butyl 8-hydroxy-5-(1 H-pyrazol-1-yl)-3,4-dihydroisoquinoline-2(1H)- carboxylate (253 mg, 802 pmol) in DMF (6 mL) at room temperature was added 2- bromopropane (226 pL, 2.40 mmol), potassium iodide (13.3 mg, 80.2 pmol) and cesium carbonate (1.30 g, 4.01 mmol). The reaction mixture was stirred at 80 °C for 2 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with cyclohexane / CPME from 100 / 0 to 70 / 30 to afford tert-butyl 8-isopropoxy-5-(1 H-pyrazol-1- yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (328 mg, 85 % yield) as a colorless oil. LCMS (ES, m / z): 302.3 [M+H-tBu]+.Step 4: To a solution of tert-butyl 8-isopropoxy-5-(1 H- pyrazol-1-yl)-3,4-dihydroisoquinoline-2(1 H)-carboxylate (328 mg, 844 pmol) in dioxane (2 mL) was added 4M hydrogen chloride solution in dioxane (2.11 mL, 8.44 mmol). The reaction mixture was stirred at room temperature for 16 h. The solvent was removed under reduced pressure then diethyl ether was added and the resulting precipitate was filtered and dried to afford 8-isopropoxy-5-(1H-pyrazol-1-yl)-1,2,3,4-tetrahydroisoquinoline hydrochloride (Intermediate INTB-21) (279 mg, 84 % yield) as a yellow solid. LCMS (ES, m / z): 258.3 [M+H]+.

[0436] III. Synthesis of isoindoline Intermediates Intermediate INTB-SI : tert-butyl 5-bromoisoindoline-2-carboxylate (Intermediate INTB- 51 )

[0437] Scheme SCHINTBSI-

[0438]

[0271] To a mixture of 5-bromoisoindoline (1.0 g, 5.04 mmol) and N,N- diisopropylethylamine (2.6 mL, 15.15 mmol) in dichloromethane (20 mL) was added di- tert-butyldicarbonate (1.32 g, 6.05 mmol). The reaction mixture was stirred at room temperature for 3 h. The reaction mixture was quenched with water and extracted with dichloromethane. 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 from 100 / 0 to 70 / 30 to afford tert- butyl 5-bromoisoindoline-2-carboxylate (Intermediate INTB-SI) (1.22 g, 81 % yield) as a colorless oil. LCMS (ES, m / z): 242.1-244.1 [M+H-tBu]+.

[0439] Intermediate INTB-52: tert-butyl 6-bromo-4-fluoroisoindoline-2-carboxylate (Intermediate INTB-52)

[0440] Scheme SCHINTBS2-

[0441]

[0272] To a mixture of 6-bromo-4-fluoroisoindoline hydrochloride (500 mg, 1.98 mmol) and / V, / V-diisopropylethylamine (1.0 mL, 5.94 mmol) in dichloromethane (20 mL) was added di-tert-butyl dicarbonate (519 mg, 2.38 mmol). The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with water and extracted with dichloromethane. 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 from 100 / 0 to 70 / 30 to afford tert-butyl 6-bromo-4-fluoroisoindoline-2-carboxylate (Intermediate INTB-52) (660 mg, 100 % yield) as a colorless oil. LCMS (ES, m / z): 259.9-261.9 [M+H-tBu]+.

[0442] Intermediate INTB-SS: A / , / V-dimethylisoindolin-5-amine hydrochloride (Intermediate INTB-53)

[0443] Scheme SCHINTBSS-

[0444] Step 1 Step 2:

[0445]

[0273] Step 1 : To a mixture of terf-butyl 5-bromoisoindoline-2-carboxylate (INTB-SI) (300 mg, 1.01 mmol), sodium terf-butoxide (483 mg, 5.03 mmol), RuPhos (46.9 mg, 100 pmol) in dioxane (3 mL) at room temperature under argon was added dimethylamine (2.51 mL, 5.03 mmol) and Pd2(dba)s (46 mg, 50.3 pmol). The reaction mixture was stirred at 100°C for 16 h. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography eluted with cyclohexane / ethyl acetate from 100 / 0 to 70 / 30 to afford terf-butyl 5-(dimethylamino)isoindoline-2-carboxylate (227 mg, 82 % yield) as a white solid. LCMS (ES, m / z): 263.1 [M+H]+.

[0446]

[0274] Step 2: To a mixture of terf-butyl 5-(dimethylamino)isoindoline-2-carboxylate (227 mg, 865 pmol) in dioxane (2 mL) was added a solution of 4M HCI in dioxane (2.16 mL, 8.65 mmol) . The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated to dryness under reduced pressure to afford / V, / V- dimethylisoindolin-5-amine hydrochloride (Intermediate INTB-SS) (170 mg, 94 % yield) as a brown solid which was used in the next step without any further purification. LCMS (ES, m / z): 163.2 [M+H]+.

[0447] Intermediate INTB-54: 6-cyclopropyl-4-fluoroisoindoline hydrochloride (Intermediate INTB-54)

[0448] Scheme SCHINTBS4-

[0449] Step l Step 2

[0450]

[0275] Step 1 : To a mixture of terf-butyl 6-bromo-4-fluoroisoindoline-2-carboxylate (INTB- 52) (300 mg, 948 pmol) in toluene (4.7 mL) and water (200 pL) was added cyclopropylboronic acid (407 mg, 4.74 mmol), Pd(dppf)Ch (69.4 mg, 94.8 pmol) and K3PO4 (235 pL, 2.84 mmol). The reaction mixture was stirred at 100 °C for 8 h. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography eluted with cyclohexane / ethyl acetate from 100 / 0 to 70 / 30 to afford terf-butyl 6-cyclopropyl-4-fluoroisoindoline-2-carboxylate (140 mg, 51 % yield) as an off-white solid. LCMS (ES, m / z): 278.2 [M+H]+.

[0276] Step 2: To a mixture of terf-butyl 6-cyclopropyl-4-fluoroisoindoline-2-carboxylate (140 mg, 504 pmol) in dioxane (3 mL) was added a solution of 4M HCI in dioxane (1.26 mL, 4 molar, 5.04 mmol). The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated to dryness under reduced pressure to afford 6- cyclopropyl-4-fluoroisoindoline hydrochloride (Intermediate INTB-54) (105 mg, 97 % yield) as a brown solid which was used in the next step without any further purification. LCMS (ES, m / z): 178.2 [M+H]+.

[0451] Intermediate INTB-SS: 7-fluoro-A / ,A / -dimethylisoindolin-5-amine hydrochloride (Intermediate INTB-SS)

[0452] Scheme SCHINTBSS p

[0453] Cyclopropyl boronic acid JL?Q VM 4M HCI in dioxane — — — * Toluene, Water, 10O“C V \ Dioxane, RT

[0454] Step l Step 2

[0455]

[0277] Step 1 : To a mixture of terf-butyl 6-bromo-4-fluoroisoindoline-2-carboxylate (300 mg, 948 pmol), sodium terf-butoxide (455 mg, 4.74 mmol), Pd2(dba)s (43.4 mg, 47.4 pmol) in dioxane (4 mL) at room temperature under argon was added dimethylamine (2.37 mL, 4.74 mmol) and RuPhos (44.2 mg, 94.8 pmol). The reaction mixture was stirred at 100°C for 16 h. 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 70 / 30 to afford terf-butyl 6-(dimethylamino)-4-fluoroisoindoline-2-carboxylate (209 mg, 75 % yield) as a white solid. LCMS (ES, m / z): 281.2 [M+H]+.

[0456]

[0278] Step 2: To a mixture of terf-butyl 6-(dimethylamino)-4-fluoroisoindoline-2- carboxylate (209 mg, 746 pmol) in dioxane (4 mL) was added a solution 4M HCI in dioxane (1.86 mL, 7.46 mmol). The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated to dryness under reduced pressure to afford 7-fluoro- / V, / V-dimethylisoindolin-5-amine hydrochloride (Intermediate INTB-SS) (134 mg, 82 % yield) as a brown solid which was used in the next step without any further purification. LCMS (ES, m / z): 176.4 [M+H]+. 1 H NMR (400 MHz, DMSO) 5 10.06 (s, 1 H), 6.62 (s, 1 H), 6.57 (d, J = 13.0 Hz, 1 H), 4.89 (bs, 4H), 2.93 (s, 6H).

[0457] Intermediate INTB-GG: 5-(azetidin-1-yl)isoindoline (Intermediate INTB-SG)

[0458] Scheme SCHINTBS6 Azetidine hydrochlori

[0459] Pd-(dbal?fBuOHa Ru TFA Dioxane, 100°C DCM, RT

[0460] Step 1 Step 2

[0461]

[0279] Step 1: To a mixture of tert-butyl 5-bromoisoindoline-2-carboxylate (I NTB-SI) (400 mg, 1.34 mmol), sodium tert-butoxide (644 mg, 6.70 mmol), RuPhos (62.6 mg, 134 pmol) in dioxane (6 mL) at room temperature under argon was added azetidine hydrochloride (2.34 mL, 4.69 mmol) and Pd2(dba)3 (61.4 mg, 67.1 pmol). The reaction mixture was stirred at 100°C for 16 h. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography eluted with cyclohexane / ethyl acetate from 100 / 0 to 70 / 30 to afford tert-butyl 5-(azetidin-1-yl)isoindoline-2-carboxylate (113 mg, 30 % yield) as a yellow solid. LCMS (ES, m / z): 275.2 [M+H]+.

[0462]

[0280] Step 2: To a solution of tert-butyl 5-(azetidin-1-yl)isoindoline-2-carboxylate (50 mg, 182 pmol) in DCM (0.5 mL) was added TFA (140 pL, 1.82 mmol). The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with NaHCCh aqueous solution until pH = 8 and ethyl acetate was added. After separation, the solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography eluted with DCM / MeOH from 95 / 5 to 90 / 10 to afford 5-(azetidin-1- yl)isoindoline (Intermediate INTB-56) (35 mg, 99 % yield) as a pale brown oil. LCMS (ES, m / z): 175.3 [M+H]+.

[0463] Intermediate INTB-5?: 5-(3-fluoroazetidin-1-yl)isoindoline (Intermediate INTB-5?)

[0464] Scheme SCHINTBST-

[0465] 3-fluoroazEtidine hydrochloride XPIhos Pd G3 , MW, 110°C F

[0466] Step 1 Step 2

[0467]

[0281] Step 1 : To a suspension of tert-butyl 5-bromoisoindoline-2-carboxylate (INTB-SI) (250 mg, 838 pmol), cesium carbonate (2.18 g, 6.70 mmol) in dioxane (4 mL) under argon was added 3-fluoroazetidine hydrochloride (467 mg, 4.19 mmol) and XPhos Pd G3 (70.9 mg, 83.8 pmol). The reaction mixture was sealed and stirred at 110°C for 2 h under MW irradiations. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography eluted with cyclohexane / (ethyl acetate / ethanol (3:1)) from 100 / 0 to 60 / 40 to afford tert-butyl 5-(3-fluoroazetidin-1- yl)isoindoline-2-carboxylate (170 mg, 69 % yield) as a brown solid. LCMS (ES, m / z): 293.3 [M+H]+.

[0282] Step 2: To a solution of terf-butyl 5-(3-fluoroazetidin-1-yl)isoindoline-2-carboxylate (216 mg, 739 pmol) in DCM (1 mL) was added TFA (569 pL, 7.39 mmol). The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with NaHCOs aqueous solution until pH = 8 and ethyl acetate was added. After separation, the solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography eluted with dichloromethane / methanol from 95 / 5 to 90 / 10 to afford 5-(3-fluoroazetidin-1-yl)isoindoline (Intermediate INTB-5?) (120 mg, 84.5 % yield) as a pale brown oil. LCMS (ES, m / z): 193.1 [M+H]+.

[0468] Intermediate INTB-SS: tert-butyl 8-chloro-5-thiazol-2-yl-3,4-dihydro-lH-isoquinoline-2- carboxylate (Intermediate INTB-SS)

[0469] Scheme SCHINTBSS-

[0470]

[0283] Step 1 : To a mixture of 5-bromo-8-chloro-1,2,3,4-tetrahydroisoquinoline (1.0 g, 4.05 mmol) in dichloromethane (20 mL) at room temperature was added DIPEA (2.12 mL, 12.17 mmol) and BOC2O (1.06 g, 4.86 mmol). The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was evaporated to dryness under reduced pressure and purified by silica gel column chromatography eluted with cyclohexane / ethyl acetate from 100 / 0 to 50 / 50 to afford terf-butyl 5-bromo-8-chloro-3,4-dihydroisoquinoline- 2(1 H)-carboxylate (1.36 g, 96 % yield) as a colorless oil.

[0471] LCMS (ES, m / z): 348.0 [M+H]+.

[0472]

[0284] Step 2: In a sealed tube, terf-butyl 5-bromo-8-chloro-3,4-dihydroisoquinoline- 2(1 H)-carboxylate (1.36 g, 3.92 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1 ,3,2- dioxaborolane) (1.99 g, 7.85 mmol) and potassium acetate (1.54 g, 15.7 mmol) were suspended in dioxane (10 mL). The suspension was degassed with argon for 5 min then Pd(dppf)Ch (160 mg, 196 pmol) was added. The reaction mixture was heated at 100°C for 16 h. The reaction mixture was filtered thought a pad of Celite and purified by silica gel column chromatography eluted with cyclohexane / ethyl acetate from 100 / 00 to 80 / 20 to afford terf-butyl 8-chloro-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-3,4-dihydro isoquinoline-2(1 H)-carboxylate (1.6 g, 95 % yield) as a yellow oil. LCMS (ES, m / z): 394.2 [M+H]+.

[0285] Step 3: To a mixture of terf-butyl 8-chloro-5-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-3,4-dihydroisoquinoline-2(1 H)-carboxylate (1.30 g, 3.30 mmol) in toluene (10 mL) and water (800 pL) was added potassium phosphate (2.10 g, 9.90 mmol). The reaction mixture was degassed with argon for 5 min then 2-bromothiazole (0.60 mL,6.60 mmol) and Pd(dppf)Ch (241 mg, 330 pmol) were added. The reaction mixture was stirred at 110 °C for 16 h. The reaction mixture was filtered thought a pad of Celite and purified by silica gel column chromatography eluted with cyclohexane / ethyl acetate from 100 / 00 to 80 / 20 to afford terf-butyl 8-chloro-5-(thiazol-2-yl)-3,4-dihydroisoquinoline- 2(1 H)-carboxylate (Intermediate INTB-SS) (700 mg, 60 % yield) as a yellow oil.

[0473] 1H NMR (400 MHz, DMSO) 5 8.03 - 7.98 (m, 1 H), 7.96 - 7.89 (m, 2H), 7.63 (d, J = 7.8 Hz, 1H), 7.50 (d, J = 8.4 Hz, 1 H), 4.58 (s, 2H), 3.56 (s, 2H), 3.05 (d, J = 5.5 Hz, 2H), 1.45 (dd, J = 4.1, 1.9 Hz, 9H).

[0474] Intermediate INTB-5S>: 2-(8-chloro-l,2,3,4-tetrahydroisoquinolin-5-yl)thiazole, HCl(Intermediate INTB-SS

[0475] Scheme SCHINTBS

[0476]

[0286] Step 1 : To a solution of terf-butyl 8-chloro-5-(thiazol-2-yl)-3,4-dihydroisoquinoline- 2(1 H)-carboxylate (Intermediate INTB-SS) (230 mg, 656 pmol) in dioxane (2 mL) was added 4M HCI solution in dioxane (1.64 mL, 6.56 mmol). The reaction mixture was stirred at room temperature for 16 h. The solvent was removed under reduced pressure to afford 2-(8-chloro-1,2,3,4-tetrahydroisoquinolin-5-yl) thiazole hydrochloride (Intermediate INTB- 59) (190 mg, 95 % yield) as a pale yellow solid.

[0477] Intermediate INTB-SO: 2-(8-cyclopropyl-l,2,3,4-tetrahydroisoquinolin-5-yl)thiazole hydrochloride (Intermediate INT B-SO)

[0478] Scheme SCHINTBM

[0287] Step 1 : To a mixture of terf-butyl 8-chloro-5-(thiazol-2-yl)-3,4-dihydroisoquinoline- 2(1H)-carboxylate (Intermediate INTB-SS) (650 mg, 1.85 mmol) in toluene (7.0 mL,) and water (350 pL) was added cyclopropylboronic acid (239 mg, 2.78 mmol) and potassium phosphate tribasic (1.38 g, 6.48 mmol). The reaction mixture was degassed under argon for 5 min and palladium diacetate (20 mg, 92 pmol) and tricyclohexyl-phosphine (52 mg, 185 pmol) were added. The reaction mixture was stirred at 100 °C for 5 h. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography eluted with cyclohexane / ethyl acetate from 100 / 0 to 70 / 30 to afford tert- butyl 8-cyclopropyl-5-(thiazol-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (525 mg, 79 % yield) as a yellow oil. LCMS (ES, m / z): 357.3 [M+H]+.

[0479]

[0288] Step 2: To a solution of terf-butyl 8-cyclopropyl-5-(thiazol-2-yl)-3,4- dihydroisoquinoline-2(1H)-carboxylate (525 mg, 1.47 mmol) in dioxane (5 mL) was added 4M HCI solution in dioxane (3.68 mL, 14.7 mmol). The reaction mixture was stirred at room temperature for 16 h. The solvent was removed under reduced pressure to afford 2- (8-cyclopropyl-1 ,2,3,4-tetrahydroisoquinolin-5-yl)thiazole hydrochloride (Intermediate INTB-60) (430 mg, 99 % yield) as a white solid. LCMS (ES, m / z): 257.1 [M+H]+.

[0480] 'HNMR (400 MHz, DMSO) 59.48 (s, 1H), 8.04 (d, J = 3.4 Hz, 1H), 7.95 (d, J = 3.4 Hz, 1H), 7.74 (d, J = 8.4 Hz, 1H), 7.59 (d, J = 8.4 Hz, 1H), 4.38 - 4.31 (m, 2H), 3.45 - 3.33 (m, 2H), 3.33 - 3.24 (m, 2H).

[0481] Intermediates INTB-I to INTB-21 and INTB-SI to INTB-6O

[0482]

[0289] The following intermediates from Intermediate INTB-I to Intermediate INTB-21 and Intermediate INTB-SI to Intermediate INTB-6O listed in Table 3 were prepared by following similar procedures described above for using appropriate reagents with suitable modifications known to the one skilled in the art.

[0483] Table 3. Intermediates B

[0484]

[0290] Compounds of the present invention can be synthesized following the processes outlined here after. Example Compound A - Comparative example: A / -((2-ethoxyphenyl)sulfonyl)-3,4- dihydroisoquinoline-2(1 H)-carboxamide (Example Compound A - Comparative example)

[0485] Scheme SCHcomp-A.

[0486]

[0291] To a mixture of 1 ,2,3,4-tetrahydroisoquinoline hydrochloride (150 mg, 884 pmol) and DIPEA (1.54 mL, 8.84 mmol) in DCM (2 mL) at 0°C was added slowly a solution of 2- ethoxybenzenesulfonyl isocyanate (Intermediate INTA-?) (341 mg, 1.50 mmol) in DCM (2 mL). The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was directly purified by silica gel column chromatography eluted with cyclohexane / ethyl acetate from 100 / 0 to 0 / 100 to afford / \ / -((2-ethoxyphenyl)sulfonyl)-3,4- dihydroisoquinoline-2(1 H)-carboxamide (Example Compound A - Comparative example) (101 mg, 30 % yield) as a white solid.

[0487] LCMS (ES, m / z): 361.3 [M+H]+.

[0488] 1H NMR (400 MHz, DMSO) 5 7.76 (d, J = 8.6 Hz, 1 H), 7.45 (s, 1 H), 7.19-7.00 (m, 5H), 6.94 (d, J = 22.8 Hz, 1 H), 4.52 (s, 2H), 4.09 (dd, J = 13.6, 6.7 Hz, 2H), 3.60 (s, 2H), 2.73 (s, 2H), 1.31-1.15 (m, 3H). Note: NH not visible.

[0489] Example EXAi : 8-fluoro- / V-((2-methoxyphenyl)sulfonyl)-5-(1 H-pyrazol-1 -yl)-3,4- dihydroisoquinoline-2(1 H)-carboxamide (Example EXAi)

[0490] Scheme SCHEXAI-

[0292] To a mixture of 8-fluoro-5-(1H-pyrazol-1-yl)-1,2,3,4-tetrahydroisoquinoline hydrochloride (Intermediate INTB-U) (100 mg, 394 pmol) and DIPEA (687 pL, 3.94 mmol) in DCM (2 mL) at room temperature was added dropwise a solution of 2- methoxybenzenesulfonyl isocyanate (Intermediate INTA-B) (142 mg, 670 pmol). The reaction mixture was stirred at room temperature for 30 min. The reaction mixture was directly absorbed with a Celite pad and concentrated to dryness. The residue was purified by silica gel column chromatography eluted with cyclohexane / acetone from 100 / 0 to 30 / 70. The resulting product was triturated in diethyl ether, filtered and dried to afford 8- fluoro- / V-((2-methoxyphenyl)sulfonyl)-5-(1 H-pyrazol-1-yl)-3,4-dihydroisoquinoline-2(1H)- carboxamide (Example EXAi) (63 mg, 35 % yield) as a white solid.

[0491] LCMS (ES, m / z): 431.2 [M+H]+.

[0492] 1H NMR (400 MHz, DMSO) 5 8.00 (1H, d, J=2.3 Hz), 7.77 - 7.74 (1 H, m), 7.72 (1 H, d, J=1.5 Hz), 7.59 - 7.39 (1H, m), 7.33 - 7.28 (1H, m), 7.21 (1 H, t, J=8.9 Hz), 7.13 - 6.97 (2H, m), 6.50 (1 H, t, J=2.0 Hz), 4.60 (2H, br s), 3.79 (3H, br s), 3.66 - 3.59 (1 H, m), 3.53 (2H, br s), 3.18 - 3.12 (1H, m). Note: NH sulfonylurea signal non-visible.

[0493] Example EXA2: A / -((5-(tert-butyl)-2-methoxyphenyl)sulfonyl)-8-fluoro-5-(1 H-pyrazol- 1-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (Example EXA2)

[0494] Scheme SCHEXA2

[0495]

[0293] To a mixture of 8-fluoro-5-(1H-pyrazol-1-yl)-1,2,3,4-tetrahydroisoquinoline hydrochloride (Intermediate INTB-U) (98 mg, 386 pmol) and DIPEA (673 pL, 3.86 mmol) in DCM (2 mL) at room temperature was added dropwise a solution of 5-(terf-butyl)-2- methoxybenzenesulfonyl isocyanate (Intermediate INTA-S) (176 mg, 656 pmol). The reaction mixture was stirred at room temperature for 30 min. The reaction mixture was directly absorbed with a Celite pad and concentrated to dryness. The residue was purified by silica gel column chromatography eluted with cyclohexane / acetone from 100 / 0 to 30 / 70. The resulting product was triturated in diethyl ether, filtered and dried to afford N- ((5-(tert-butyl)-2-methoxyphenyl)sulfonyl)-8-fluoro-5-(1 H-pyrazol-1-yl)-3,4- dihydroisoquinoline-2(1 H)-carboxamide (Example EXA2) (20 mg, 10 % yield) as a white solid. LCMS (ES, m / z): 487.1 [M+H]+.

[0496] 1H NMR (400 MHz, DMSO) 8.00 (1 H, s), 7.75 (1 H, d, J=2.3 Hz), 7.72 (1 H, d, J=1 .5 Hz), 7.61 - 7.39 (1 H, m), 7.33 - 7.28 (1 H, m), 7.23 - 7.19 (1 H, m), 7.10 - 6.93 (1 H, m), 6.51 - 6.49 (1 H, m), 4.61 (2H, s), 3.76 (3H, s), 3.63 (1 H, s), 3.53 (2H, s), 3.14 (1 H, s), 1.25 (9H, s). NH sulfonylurea signal not visible.

[0497] Example EXA3: A / -((2,6-dimethoxyphenyl)sulfonyl)-8-fluoro-5-(1 H-pyrazol-1-yl)-3,4- dihydroisoquinoline-2(1 H)-carboxamide (Example EXA3)

[0498] Scheme SCHEXA3

[0499]

[0294] To a mixture of 8-fluoro-5-(1 H-pyrazol-1-yl)-1 ,2,3,4-tetrahydroisoquinoline hydrochloride (Intermediate INTB-U) (130 mg, 512 pmol) and DIPEA (893 pL, 5.12 mmol) in DCM (2 mL) at room temperature was added dropwise a solution of 2,6- dimethoxybenzenesulfonyl isocyanate (Intermediate INTA-I) (211 mg, 871 pmol). The reaction mixture was stirred at room temperature for 30 min. The reaction mixture was directly absorbed with a Celite pad and concentrated to dryness. The residue was purified by silica gel column chromatography eluted with cyclohexane / acetone from 100 / 0 to 50 / 50 to afford / V-((2,6-dimethoxyphenyl)sulfonyl)-8-fluoro-5-(1 H-pyrazol-1-yl)-3,4- dihydroisoquinoline-2(1 H)-carboxamide (Example EXA3) (8 mg, 3 % yield) as a white solid. LCMS (ES, m / z): 461.0 [M+H]+.

[0500] 1H NMR (400 MHz, DMSO) 5 10.81 (1 H, br s), 8.03 (1 H, dd, J=0.7, 2.3 Hz), 7.74 (1 H, dd, J=0.6, 1.7 Hz), 7.47 (1 H, t, J=8.4 Hz), 7.35 (1 H, dd, J=5.3, 8.7 Hz), 7.25 (1 H, t, J=9.0 Hz), 6.77 (2H, d, J=8.5 Hz), 6.52 - 6.50 (1 H, m), 4.63 (2H, br s), 3.78 (6H, s), 3.59 - 3.56 (2H, m), 2.60 (2H, t, J=5.7 Hz).

[0501] Example EXA4: A / -((5-chloro-2-methoxyphenyl)sulfonyl)-8-fluoro-5-(1 H-pyrazol-1-yl)- 3,4-dihydroisoquinoline-2(1 H)-carboxamide (Example EXA4) Scheme SCHEXA4-

[0502]

[0295] To a mixture of 8-fluoro-5-(1H-pyrazol-1-yl)-1,2,3,4-tetrahydroisoquinoline hydrochloride (Intermediate INTB-U) (90 mg, 333 pmol) and DIPEA (580 pL, 3.33 mmol) in DCM (1.5 mL) at room temperature was added dropwise a solution of 5-chloro-2- methoxybenzenesulfonyl isocyanate (Intermediate INTA-4) (140 mg, 566 pmol). The reaction mixture was stirred at room temperature for 30 min. The reaction mixture was directly absorbed with a pad of Celite and concentrated to dryness. The residue was purified by silica gel column chromatography eluted with cyclohexane / acetone from 100 / 0 to 40 / 60 to afford / V-((5-chloro-2-methoxyphenyl)sulfonyl)-8-fluoro-5-(1 H-pyrazol-1-yl)-3,4- dihydroisoquinoline-2(1H)-carboxamide (Example EXA4) (46 mg, 28 % yield) as a white solid. LCMS (ES, m / z): 465.1 [M+H]+.

[0503] 1H NMR (400 MHz, DMSO) 5 7.98 (1H, d, J=2.3 Hz), 7.72 - 7.69 (2H, m), 7.40 (1 H, br s), 7.30 - 7.25 (1H, m), 7.19 (1 H, t, J=8.9 Hz), 7.02 (1H, br s), 6.49 (1 H, t, J=2.1 Hz), 4.60 (2H, br s), 3.73 (3H, br s), 3.50 (2H, br s). Note: one CH2under DMSO signal and NH sulfonamide non-visible.

[0504] Example EXA5: 8-cyclopropyl-N-((5-(3-fluoroazetidin-1-yl)-2- methoxyphenyl)sulfonyl)-5-( 1 H-pyrazol-1-yl)-3,4-dihydroisoquinoline-2( 1 H)- carboxamide (Example EXA5) Scheme SCHEXAS.

[0505]

[0296] To a mixture of ethyl ((5-(3-fluoroazetidin-1-yl)-2- methoxyphenyl)sulfonyl)carbamate (Intermediate INTA-12) (130 mg, 360 pmol) and triethylamine (181 L, 1.08 mmol) in dioxane (3.60 mL) at room temperature was added 8-cyclopropyl-5-(1H-pyrazol-1-yl)-1,2,3,4-tetrahydroisoquinoline hydrochloride (Intermediate INTB-S) (129 mg, 468 pmol). The reaction mixture was stirred at 110°C for 16 h. The residue was purified by silica gel column chromatography eluted with cyclohexane / acetone from 100 / 0 to 50 / 50 to afford 8-cyclopropyl- / V-((5-(3-fluoroazetidin-1- yl)-2-methoxyphenyl)sulfonyl)-5-(1H-pyrazol-1-yl)-3,4-dihydroisoquinoline-2(1 H)- carboxamide (Example EXA5) (26 mg, 13 % yield) as a beige solid. LCMS (ES, m / z): 526.2 [M+H]+

[0506] 1H NMR (400 MHz, CDCI3) 6 7.72 - 7.70 (1 H, m), 7.56 - 7.54 (1 H, m), 7.19 - 7.15 (2H, m), 7.06 - 6.93 (2H, m), 6.67 - 6.62 (1 H, m), 6.46 - 6.44 (1 H, m), 5.52 - 5.46 (0.5H, m), 5.38 - 5.32 (0.5H, m), 4.78 (2H, s), 4.25 - 4.16 (2H, m), 4.02 - 3.99 (2H, m), 3.93 (3H, s), 3.57 (2H, t, J=5.7 Hz), 2.70 - 2.65 (2H, m), 0.95 - 0.89 (2H, m), 0.64 (2H, q, J=5.2 Hz).

[0507] Note : NH not visible

[0508] Example EXAs: 8-chloro-A / -((5-(3-fluoroazetidin-1 -yl)-2-methoxyphenyl)sulfonyl)-5-

[0509] (1H-pyrazol-1-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (Example EXAs)

[0510] Scheme SCHEXA6 methoxyphenyl)sulfonyl)carbamate (Intermediate INTA-12) (260 mg, 721 pmol) and triethylamine (484 pL, 2.89 mmol) in dioxane (7.2 mL) at room temperature was added 8-chloro-5-(1 H-pyrazol-1-yl)-1 ,2,3,4-tetrahydroisoquinoline hydrochloride

[0511] (Intermediate INTB-IS) (253 mg, 938 pmol). The reaction mixture was stirred at 110°C for 16 h. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography eluted with cyclohexane / acetone from 100 / 0 to 70 / 30 to afford 8-chloro- / V-((5-(3-fluoroazetidin-1-yl)-2-methoxyphenyl)sulfonyl)-5-(1H-pyrazol-1-yl)- 3,4-dihydroisoquinoline-2(1H)-carboxamide (Example EXAs) (15.8 mg, 4.2 % yield) as a grey solid. LCMS (ES, m / z): 520.3 [M+H]+

[0512] 1H NMR (400 MHz, DMSO) 5 8.01 (d, J = 1.9 Hz, 1H), 7.73 (d, J = 1.4 Hz, 1H), 7.47 (d, J = 8.4 Hz, 1H), 7.29 (d, J = 8.2 Hz, 1 H), 6.94 (bs, 1 H), 6.88 (d, J = 2.4 Hz, 1H), 6.56 (bs, 1H), 6.51 (t, J = 2.0 Hz, 1H), 5.46 (d, J = 56.3 Hz, 1H), 4.60 (s, 2H), 4.18 - 3.94 (m, 2H), 3.86 - 3.72 (m, 2H), 3.67 (s, 3H), 3.52 (s, 2H), 2.57 - 2.52 (m, 2H). Note: NH not visible

[0513] Example EXA7: 8-fluoro- / V-((5-(3-fluoroazetidin-1 -yl)-2-methoxyphenyl)sulfonyl)-5- (1H-pyrazol-1-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (Example EXA7) Scheme SCHEXA?

[0514]

[0298] To a mixture of 8-fluoro-5-(1H-pyrazol-1-yl)-1,2,3,4-tetrahydroisoquinoline hydrochloride (Intermediate INTB-U) (139 mg, 548 pmol) and triethylamine (212 pL, 1.26 mmol) in dioxane (4.2 mL) at room temperature was added ethyl / \ / -[5-(3-fluoroazetidin-1- yl)-2-methoxy-phenyl] sulfonylcarbamate (Intermediate INTA-12) (139 mg, 548 pmol). The reaction mixture was stirred at 110°C for 16 h. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography eluted with cyclohexane / acetone from 100 / 0 to 50 / 50 to afford 8-fluoro- / V-((5-(3-fluoroazetidin-1-yl)-2- methoxyphenyl)sulfonyl)-5-(1 H-pyrazol-1-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (Example EXA7) (32 mg, 14 % yield) as a yellow solid. LCMS (ES, m / z): 504.3 [M+H]+1H NMR (400 MHz, DMSO) 6 7.91 - 7.89 (1 H, m), 7.70 (1 H, d, J=1.7 Hz), 7.33 - 7.27 (1 H, m), 7.17 (1 H, q, J=6.0 Hz), 7.10 (0.3H, d, J=8.9 Hz), 7.02 - 6.99 (0.7H, m), 6.93 - 6.87 (1 H, m), 6.71 - 6.62 (1 H, m), 6.48 (1 H, t, J=2.1 Hz), 5.56 - 5.51 (0.5H, m), 5.41 - 5.37 (0.5H, m), 4.64 (2H, s), 4.20 - 4.08 (2H, m), 3.94 - 3.80 (2H, m), 3.74 (3H, s), 3.58 (2H, t, J=5.8 Hz), 2.62 - 2.57 (2H, m). Note: NH not visible.

[0515] Example EXAs: 8-cyclopropyl- / V-((2-methoxy-5-(trifluoromethyl)phenyl)sulfonyl)-5- (1 H-pyrazol-1 -yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (Example EXAs) Scheme SCHEXAS.

[0516]

[0299] To a mixture of 8-cyclopropyl-5-(1 H-pyrazol-1 -yl)-1 , 2, 3, 4-tetrahydroisoquinoline hydrochloride (Intermediate INTB-S) (95 mg, 344 pmol) and DIPEA (600 pL, 3.44 mmol) in DCM (2 mL) at room temperature was added dropwise a solution of 2-methoxy- 5-(trifluoromethyl)benzenesulfonyl isocyanate (Intermediate INTA-IS) (164 mg, 585 pmol). The reaction mixture was stirred at room temperature for 30 min. The reaction mixture was directly absorbed with a Celite pad and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography eluted with cyclohexane / acetone from 100 / 0 to 50 / 50. The resulting solid was triturated in diethyl ether, filtered and dried to afford 8-cyclopropyl- / V-((2-methoxy-5- (trifluoromethyl)phenyl)sulfonyl)-5-(1 H-pyrazol-1-yl)-3,4-dihydroisoquinoline-2(1 H)- carboxamide (Example EXAs) (6.9 mg, 3.7 % yield) as a white solid. LCMS (ES, m / z): 521.3 [M+H]+

[0517] 1H NMR (400 MHz, DMSO) 5 11.38 (1 H, br s), 8.04 (1 H, d, J=2.3 Hz), 8.03 - 7.97 (1 H, m), 7.96 (1 H, d, J=2.3 Hz), 7.70 (1 H, d, J=1.3 Hz), 7.43 (1 H, br s), 7.16 (1 H, d, J=8.1 Hz), 7.02 (1 H, d, J=8.5 Hz), 6.48 (1 H, t, J=2.0 Hz), 4.72 (2H, br s), 3.97 (3H, br s), 3.54 (2H, br s), 1 .90 (1 H, br s), 0.98 - 0.96 (2H, m), 0.67 - 0.66 (2H, m).

[0518] Example EXA9: 8-chloro- / V-((2,6-dimethoxyphenyl)sulfonyl)-5-(1 H-pyrazol-1 -yl)-3,4- dihydroisoquinoline-2(1 H)-carboxamide (Example EXA9) Scheme SCHEXAQ

[0519]

[0300] To a mixture of 8-chloro-5-(1 H-pyrazol-1-yl)-1 ,2,3,4-tetrahydroisoquinoline hydrochloride (Intermediate INTB-IS) (127 mg, 470 pmol) and DIPEA (819 L, 4.70 mmol) in DCM (2 mL) at room temperature was dropwise 2,6-dimethoxybenzenesulfonyl isocyanate (Intermediate INTA-I) (194 mg, 799 pmol). The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was directly absorbed with a pad of Celite and concentrated to dryness. The residue was purified by silica gel column chromatography eluted with cyclohexane / acetone from 100 / 0 to 0 / 100 to afford 8-chloro- / \ / -((2,6-dimethoxyphenyl)sulfonyl)-5-(1 H-pyrazol-1 -yl)-3,4-dihydroisoquinoline-2(1 H)- carboxamide (Example EXA9) (15 mg, 6.4 % yield) as a white solid. LCMS (ES, m / z): 477.3 [M+H]+.

[0520] 1H NMR (400 MHz, DMSO) 5 10.86 (s, 1 H), 8.08 - 8.03 (dd, J = 2.4, 0.5 Hz 1 H), 7.76 (dd, J = 1.8, 0.6 Hz, 1 H), 7.51 (d, J = 8.5 Hz, 1 H), 7.46 (t, J = 8.2 Hz, 1 H), 7.34 (d, J = 8.6 Hz, 1 H), 6.77 (d, J = 8.5 Hz, 2H), 6.53 (dd, J = 2.4, 1.9 Hz, 1 H), 4.61 (s, 2H), 3.78 (s, 6H), 3.57 (t, J = 5.1 Hz, 2H), 2.63 (t, J = 5.7 Hz, 2H).

[0521] Example EXA10: 8-bromo-A / -((2,6-dimethoxyphenyl)sulfonyl)-5-(1 H-pyrazol-1 -yl)-3,4- dihydroisoquinoline-2(1 H)-carboxamide (Example EXA10)

[0522] Scheme SCHEXAW

[0301] To a mixture of 8-bromo-5-(1 H-pyrazol-1-yl)-1,2,3,4-tetrahydroisoquinoline hydrochloride (Intermediate INTB-IS) (150 mg, 477 pmol) and DIPEA (831 pL, 4.77 mmol) in DCM (2 mL) at room temperature was added dropwise of 2,6- dimethoxybenzenesulfonyl isocyanate (Intermediate INTA-I) (197 mg, 811 pmol). The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was directly absorbed with a Celite pad and concentrated to dryness. The residue was purified by silica gel column chromatography eluted with cyclohexane / acetone from 100 / 0 to 0 / 100. The resulting product was triturated with acetone then filtered and washed with dichloromethane, acetonitrile and ethyl acetate to afford 8-bromo- / V-((2,6- dimethoxyphenyl)sulfonyl)-5-(1H-pyrazol-1-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (Example EXA10) (24 mg, 9.2 % yield) as a white solid.

[0523] LCMS (ES, m / z): 521.2-523.2 [M+H]+.

[0524] 1H NMR (400 MHz, DMSO) 5 10.89 (s, 1H), 8.06 (d, J = 2.2 Hz, 1 H), 7.76 (s, 1 H), 7.67 (d, J = 8.6 Hz, 1H), 7.48 (t, J = 8.4 Hz, 1H), 7.27 (d, J = 8.4 Hz, 1 H), 6.77 (d, J = 8.5 Hz, 2H), 6.53 (s, 1 H), 4.55 (s, 2H), 3.79 (s, 6H), 3.57 (s, 2H), 2.63 (s, 2H).

[0525] Example EXAn: A / -((2,6-dimethoxyphenyl)sulfonyl)-5-(1H-pyrazol-1-yl)-8- (trifluoromethyl)-3,4-dihydroisoquinoline-2(1 H)-carboxamide (Example EXAn) Scheme SCHEXAU

[0526]

[0302] To a mixture of 5-(1 H-pyrazol-1-yl)-8-(trifluoromethyl)-1, 2,3,4- tetrahydroisoquinoline hydrochloride (Intermediate INTB-2O) (100 mg, 329 pmol) and DI PEA (574 pL, 3.29 mmol) in DCM (2 mL) at room temperature was added dropwise a solution of 2,6-dimethoxybenzenesulfonyl isocyanate (Intermediate INTA-I) (136 mg, 560 pmol). The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was directly absorbed with a Celite pad and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography eluted with cyclohexane / acetone from 100 / 0 to 50 / 50 to afford of A / -((2,6- dimethoxyphenyl)sulfonyl)-5-(1H-pyrazol-1-yl)-8-(trifluoromethyl)-3,4-dihydroisoquinoline- 2(1 H)-carboxamide (Example EXAn) (9.1 mg, 5.% yield) as a white solid. LCMS (ES, m / z): 511.3 [M+H]+

[0527] 1H NMR (400 MHz, DMSO) 5 1 H NMR (400 MHz, DMSO) 5 10.84 (s, 1 H), 8.17 - 8.13 (dd, J = 2.5, 0.6 Hz, 1 H), 7.84 - 7.80 (dd, J = 1.8, 0.5 Hz, 1 H), 7.78 (d, J = 8.3 Hz, 1 H), 7.55 - 7.43 (m, 2H), 6.77 (d, J = 8.5 Hz, 2H), 6.58 (dd, J = 2.4, 1.8 Hz, 1 H), 4.77 (s, 2H), 3.78 (s, 6H), 3.63 (t, J = 5.9 Hz, 2H), 2.78 (t, J = 5.9 Hz, 2H).

[0528] Example EXA12: A / -((2,6-dimethoxyphenyl)sulfonyl)-8-methyl-5-(1 H-pyrazol-1 -yl)-3,4- dihydroisoquinoline-2(1 H)-carboxamide (Example EXA12)

[0529] Scheme SCHEXAI2

[0530]

[0303] To a mixture of 8-methyl-5-(1 H-pyrazol-1-yl)-1 ,2,3,4-tetrahydroisoquinoline hydrochloride (Intermediate INTB-IB) (100 mg, 400 pmol) and DIPEA (697 pL, 4.00 mmol) in DCM (2 mL) at room temperature was added dropwise a solution of 2,6- dimethoxybenzenesulfonyl isocyanate (Intermediate INTA-I) (165 mg, 680 pmol). The reaction mixture was stirred at room temperature for 30 min. The reaction mixture was directly absorbed with a pad of Celite and concentrated to dryness. The residue was purified by silica gel column chromatography eluted with cyclohexane / acetone from 100 / 0 to 50 / 50 to afford / V-((2,6-dimethoxyphenyl)sulfonyl)-8-methyl-5-(1 H-pyrazol-1-yl)-3,4- dihydroisoquinoline-2(1 H)-carboxamide (Example EXA12) (27 mg, 14 % yield) as a white solid. LCMS (ES, m / z): 457.4 [M+H]+.

[0531] 1H NMR (400 MHz, DMSO) 5 10.73 (1 H, s), 7.97 (1 H, d, J=1.9 Hz), 7.71 (1 H, d, J=0.9 Hz), 7.47 (1 H, t, J=8.7 Hz), 7.19 (2H, q, J=7.7 Hz), 6.77 (2H, d, J=8.8 Hz), 6.49 (1 H, t, J=2.0 Hz), 4.52 (2H, s), 3.79 (6H, s), 3.54 - 3.51 (2H, m), 2.29 (3H, s).

[0532] Example EXA13: A / -((4-chloro-2-methoxyphenyl)sulfonyl)-8-fluoro-5-(1 H-pyrazol-1-yl)-

[0533] 3,4-dihydroisoquinoline-2(1 H)-carboxamide (Example EXA13)

[0534] Scheme SCHEXAI3

[0535]

[0304] To a mixture of 8-fluoro-5-(1H-pyrazol-1-yl)-1,2,3,4-tetrahydroisoquinoline hydrochloride (Intermediate INTB-U) (179 mg, 708 pmol) and triethylamine (274 pL, 1.63 mmol) in dioxane (5.4 mL) at room temperature was added ethyl ((4-chloro-2- methoxyphenyl)sulfonyl)carbamate (Intermediate INTA-IO) (160 mg, 544 pmol). The reaction mixture was stirred at 110°C for 16 h. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography eluting with cyclohexane / acetone from 100 / 0 to 50 / 50 to afford / \ / -((4-chloro-2- methoxyphenyl)sulfonyl)-8- fluoro- 5-(1H-pyrazol-1-yl)-3,4-dihydroisoquinoline-2(1H)- carboxamide (Example EXA13) (41 mg, 15 % yield) as a white foam. LCMS (ES, m / z): 465.2 [M+H]+.

[0536] 1H NMR (400 MHz, DMSO) 5 11.22 (1 H, s), 8.00 (1H, d, J=2.1 Hz), 7.76 (1H, d, J=8.9 Hz), 7.72 (1H, d, J=1.7Hz), 7.32 (1 H, dd, J=5.2, 8.6 Hz), 7.22 (2H, t, J=9.1 Hz), 7.11 (1 H, s), 6.51 - 6.49 (1H, m), 4.64 - 4.60 (2H, m), 3.85 (3H, s), 3.58 - 3.53 (2H, m), 2.58 - 2.53 (2H, m).

[0537] Example EXA14: 8-chloro- / V-((4-methoxy-[1,1'-biphenyl]-3-yl)sulfonyl)-5-(1H-pyrazol- 1-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (Example EXA14)

[0538] Scheme SCHEXAI4

[0539]

[0305] To a mixture of 8-chloro-5-(1H-pyrazol-1-yl)-1,2,3,4-tetrahydroisoquinoline hydrochloride (Intermediate INTB-IS) (130 mg, 394 pmol) and DIPEA (687 pL, 3.94 mmol) in DCM (2 mL) at room temperature was added dropwise a solution of 4-methoxy- [1 ,1'-biphenyl]-3-sulfonyl isocyanate (Intermediate INTA-IS) (194 mg, 670 pmol). The reaction mixture was stirred at room temperature for 30 min. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography eluted with cyclohexane / acetone from 100 / 0 to 50 / 50 to afford 8-chloro- / V-((4-methoxy-[1 , 1 biphenyl]-3-yl)sulfonyl)-5-(1 H-pyrazol-1-yl)-3,4-dihydroisoquinoline-2(1 H)-carboxamide (Example EXA14) (20 mg, 9.2 % yield) as a white solid. LCMS (ES, m / z): 523.2 [M+H]+1H NMR (400 MHz, DMSO) 5 8.04 - 7.99 (2H, m), 7.75 - 7.73 (2H, m), 7.60 - 7.56 (2H, m), 7.49 - 7.43 (3H, m), 7.36 - 7.28 (2H, m), 7.21 - 7.08 (1 H, m), 6.52 - 6.50 (1 H, m), 4.60 (2H, s), 3.82 (3H, s), 3.53 (2H, s).

[0540] Example EXA15: 8-chloro- / V-((4'-fluoro-4-methoxy-[1,T-biphenyl]-3-yl)sulfonyl)-5-(1 H- pyrazol-1 -yl)-3,4-dihydroisoquinoline-2(1 H)-carboxamide (Example EXA15)

[0541] Scheme SCHEXAIS

[0542]

[0306] To a mixture of tert- butyl ((4'-fluoro-4-methoxy-[1 ,1'-biphenyl]-3- yl)sulfonyl)carbamate (Intermediate INTA-IS) (150 mg, 393 pmol) and triethylamine (198 pL, 1.18 mmol) in dioxane (2.0 mL) at room temperature was added 8-chloro-5-(1 H-pyrazol-1- yl)-1 ,2,3,4-tetrahydroisoquinoline hydrochloride (Intermediate INTB-IS) (138 mg, 511 pmol). The reaction mixture was stirred at 110°C for 16 h. The crude was purified by silica gel column chromatography eluted with cyclohexane / acetone from 100 / 0 to 0 / 100 to afford 8- chloro- / V-((4'-fluoro-4-methoxy-[1 ,T-biphenyl]-3-yl)sulfonyl)-5-(1 H-pyrazol-1-yl)-3,4- dihydroisoquinoline-2(1 H)-carboxamide (Example EXA15) (24 mg, 11 % yield) as a beige foam. LCMS (ES, m / z): 541.3 [M+H]+

[0543] 1H NMR (400 MHz, DMSO) 5 11.27 (1 H, s), 8.04 (1 H, d, J=2.1 Hz), 7.99 (1 H, d, J=2.5 Hz), 7.87 - 7.87 (1 H, m), 7.75 (1 H, dd, J=0.6, 1.9 Hz), 7.66 (2H, dd, J=5.4, 8.6 Hz), 7.50 (1 H, d, J=8.4 Hz), 7.35 - 7.27 (4H, m), 6.52 (1 H, dd, J=1.8, 2.4 Hz), 4.61 - 4.57 (2H, m), 3.90 (3H, s), 3.60 - 3.55 (2H, m), 2.60 - 2.56 (2H, m).

[0544] Example EXAis: 7-bromo-N-((2-ethoxyphenyl)sulfonyl)-4-methyl-3,4- dihydroisoquinoline-2(1 H)-carboxamide (Example EXAis) Scheme SCHEXAI6

[0545]

[0307] To a mixture of 7-bromo-4-methyl-1 ,2,3,4-tetrahydroisoquinoline hydrochloride (100 mg, 380 pmol) and DIPEA (663 L, 3.80 mmol) in DCM (2 mL) at room temperature was added dropwise a solution of 2-ethoxybenzenesulfonyl isocyanate (Intermediate INTA-?) (129 mg, 571 pmol). The reaction mixture was stirred at room temperature for 30 min. The reaction mixture was directly absorbed with a Celite pad and concentrated to dryness. The residue was purified by silica gel column chromatography eluted with cyclohexane / acetone from 100 / 0 to 80 / 20. The resulting solid was triturated in diethyl, filtered and dried to afford 7-bromo- / V-((2-ethoxyphenyl)sulfonyl)-4-methyl-3,4- dihydroisoquinoline-2(1 H)-carboxamide (Example EXAis) (74 mg, 41 % yield) as a white solid. LCMS (ES, m / z): 453.0-455.0 [M+H]+.

[0546] 1H NMR (400 MHz, DMSO) 5 10.80 (1 H, s), 7.79 (1 H, dd, J=1 .5, 7.9 Hz), 7.59 - 7.53 (1 H, m), 7.38 (1 H, dd, J=2.1 , 8.2 Hz), 7.32 (1 H, d, J=2.1 Hz), 7.21 (1 H, d, J=8.4 Hz), 7.17 (1 H, d, J=8.0 Hz), 7.06 (1 H, t, J=7.1 Hz), 4.65 - 4.57 (1 H, m), 4.46 (1 H, d, J=17.5 Hz), 4.15 (2H, q, J=7.0 Hz), 3.60 (1 H, br s), 3.41 (1 H, dd, J=6.8, 13.3 Hz), 2.89 (1 H, q, J=6.3 Hz), 1.26 (3H, t, J=6.9 Hz), 1.14 (3H, d, J=6.8 Hz).

[0547] Example EXA17: A / -((2,6-dimethoxyphenyl)sulfonyl)-8-methoxy-5-(1H-pyrazol-1-yl)-

[0548] 3,4-dihydroisoquinoline-2(1 H)-carboxamide (Example EXA17)

[0549] Scheme SCHEXAI

[0550]

[0308] To a mixture of 8-methoxy-5-(1 H-pyrazol-1-yl)-1 ,2,3,4-tetrahydroisoquinoline hydrochloride (Intermediate INTB-2) (120 mg, 451 pmol) and DIPEA (787 L, 4.51 mmol) in DCM (2 mL) at room temperature was dropwise a solution of 2,6- dimethoxybenzenesulfonyl isocyanate (Intermediate INTA-I) (186 mg, 767 pmol). The reaction mixture was stirred at room temperature for 30 min. The reaction mixture was directly absorbed with a Celite pad and concentrated to dryness. The residue was purified by silica gel column chromatography eluted with cyclohexane / acetone from 100 / 0 to 50 / 50 to afford / \ / -((2,6-dimethoxyphenyl)sulfonyl)-8-methoxy-5-(1 H-pyrazol-1-yl)-3,4- dihydroisoquinoline-2(1 H)-carboxamide (Example EXA17) (21 mg, 9.3 % yield) as a brown solid. LCMS (ES, m / z): 473.1 [M+H]+.

[0551] 1H NMR (400 MHz, DMSO) 5 10.71 (1 H, br s), 7.93 (1 H, dd, J=0.6, 2.3 Hz), 7.69 (1 H, dd, J=0.5, 1.8 Hz), 7.46 (1 H, t, J=8.5 Hz), 7.25 (1 H, d, J=8.7 Hz), 6.99 (1 H, d, J=8.8 Hz), 6.75 (2H, d, J=8.5 Hz), 6.47 (1 H, t, J=2.1 Hz), 4.48 (2H, br s), 3.88 (3H, s), 3.77 (6H, s), 3.54 - 3.51 (2H, m).

[0552] Example EXAis: 8-cyclopropyl- / V-((2,6-dimethoxyphenyl)sulfonyl)-5-(1H-pyrazol-1- yl)-3,4-dihydroisoquinoline-2(1 H)-carboxamide (Example EXAis)

[0553] Scheme SCHEXAIS

[0309] To a mixture of 8-cyclopropyl-5-(1H-pyrazol-1-yl)-1 ,2,3,4-tetrahydroisoquinoline hydrochloride (Intermediate INTB-S) (115 mg, 417 pmol) and DIPEA (726 pL, 4.17 mmol) in DCM (2 mL) at room temperature was added dropwise a solution of 2,6- dimethoxybenzenesulfonyl isocyanate (Intermediate INTA-I) (172 mg, 708 pmol). The reaction mixture was stirred at room temperature for 30 min. The reaction mixture was directly absorbed with a pad of Celite and concentrated to dryness. The residue was purified by silica gel column chromatography eluted with cyclohexane / acetone from 100 / 0 to 40 / 60 to afford 8-cyclopropyl- / V-((2,6-dimethoxyphenyl)sulfonyl)-5-(1H-pyrazol-1-yl)-3,4- dihydro isoquinoline-2(1H)-carboxamide (Example EXAis) (24 mg, 11 % yield) as a grey solid. LCMS (ES, m / z): 483.3 [M+H]+.

[0554] 1H NMR (400 MHz, DMSO) 5 10.75 (1 H, s), 7.97 (1H, dd, J=0.7, 2.4 Hz), 7.71 (1 H, dd, J=0.7, 1.8 Hz), 7.48 (1 H, t, J=8.4 Hz), 7.17 (1 H, d, J=8.1 Hz), 7.03 (1 H, d, J=8.5 Hz), 6.78 (2H, d, J=8.6 Hz), 6.49 - 6.48 (1H, m), 4.74 (2H, s), 3.79 (6H, s), 3.58 - 3.54 (2H, m), 2.57 (2H, t, J=5.6 Hz), 1.95 - 1.91 (1 H, m), 1.01 - 0.95 (2H, m), 0.70 - 0.65 (2H, m).

[0555] Example EXA19: A / -((5-bromo-2-methoxyphenyl)sulfonyl)-8-fluoro-5-(1 H-pyrazol-1 - yl)-3,4-dihydroisoquinoline-2(1 H)-carboxamide (Example EXA19)

[0556] Scheme SCHEXAI9

[0557]

[0310] To a mixture of 8-fluoro-5-(1H-pyrazol-1-yl)-1,2,3,4-tetrahydroisoquinoline hydrochloride (Intermediate INTB-U) (218 mg, 859 pmol) and triethylamine (288 pL, 1.72 mmol) in dioxane (5.7 mL) at room temperature was added ethyl ((5-bromo-2- methoxyphenyl)sulfonyl)carbamate (Intermediate INTA-S) (220 mg, 572 pmol). The reaction mixture was stirred at 110°C for 16 h. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography eluting with cyclohexane / acetone from 100 / 0 to 50 / 50 to afford / V-((5-bromo-2- methoxyphenyl)sulfonyl)-8- fluoro- 5-(1H-pyrazol-1-yl)-3,4-dihydroisoquinoline-2(1H)- carboxamide (Example EXA19) (74 mg, 24 % yield) as a yellow powder. LCMS (ES, m / z): 511.2 [M+H]+.

[0558] 1H NMR (400 MHz, DMSO) 5 7.94 - 7.93 (0.2H, m), 7.92 (0.8H, dd, J=0.8, 2.4 Hz), 7.87 (0.8H, d, J=2.5 Hz), 7.83 (0.2H, d, J=2.5 Hz), 7.74 - 7.71 (0.3H, m), 7.70 (0.7H, dd, J=0.6, 1.9 Hz), 7.63 - 7.58 (0.8H, m), 7.40 - 7.35 (0.2H, m), 7.31 - 7.24 (1 H, m), 7.22 - 7.14 (1 H, m), 7.10 - 7.03 (1 H, m), 6.52 - 6.50 (0.2H, m), 6.48 (0.8H, dd, J=1.8, 2.4 Hz), 4.63 (1.6H, s), 4.24 (0.4H, s), 3.93 (0.5H, s), 3.80 (2.5H, s), 3.56 (1.6H, t, J=6.4 Hz), 3.23 - 3.19 (0.4H, m), 2.78 - 2.72 (0.4H, m), 2.56 (1 ,6H, t, J=6.6 Hz). Note : NH not visible

[0559] Example EXA20: A / -((5-(tert-butyl)-2-methoxyphenyl)sulfonyl)-8-methoxy-5-(1 H- pyrazol-1 -yl)-3,4-dihydroisoquinoline-2(1 H)-carboxamide (Example EXA20)

[0560] Scheme SCHEXAZO.

[0561]

[0311] To a mixture of 8-methoxy-5-(1 H-pyrazol-1-yl)-1 ,2,3,4-tetrahydroisoquinoline hydrochloride (Intermediate INTB-2) (135 mg, 508 pmol) and DIPEA (885 L, 5.08 mmol) in DCM (2 mL) at room temperature was added dropwise a solution of 5-(terf-butyl)-2- methoxybenzenesulfonyl isocyanate (Intermediate INTA-S) (232 mg, 863 pmol). The reaction mixture was stirred at room temperature for 30 min. The reaction mixture was directly absorbed with a Celite pad and concentrated to dryness. The residue was purified by silica gel column chromatography eluted with cyclohexane / acetone from 100 / 0 to 50 / 50 to afford / V-((5-(tert-butyl)-2-methoxyphenyl)sulfonyl)-8-methoxy-5-(1 H-pyrazol-1-yl)-3,4- dihydroisoquinoline-2(1 H)-carboxamide (Example EXA20) (81 mg, 30 % yield) as a white solid. LCMS (ES, m / z): 499.2 [M+H]+.

[0562] 1H NMR (400 MHz, DMSO) 5 11.01 (1 H, s), 7.92 (1 H, d, J=2.1 Hz), 7.75 (1 H, d, J=2.5 Hz), 7.69 (1 H, d, J=1 .3 Hz), 7.66 - 7.63 (1 H, m), 7.25 (1 H, d, J=8.7 Hz), 7.13 (1 H, d, J=8.7 Hz), 6.99 (1 H, d, J=9.0 Hz), 6.47 (1 H, t, J=2.1 Hz), 4.45 (2H, br s), 3.87 (3H, s), 3.83 (3H, s), 3.52 (2H, br s), 1.28 (9H, s). 2 protons under DMSO signal. Example EXA21: 8-fluoro-A / -((5-fluoro-2-methoxyphenyl)sulfonyl)-5-(1H-pyrazol-1-yl)-

[0563] 3,4-dihydroisoquinoline-2(1 H)-carboxamide (Example EXA21)

[0564] Scheme SCHEXAZI

[0565]

[0312] To a mixture of 8-fluoro-5-(1H-pyrazol-1-yl)-1,2,3,4-tetrahydroisoquinoline hydrochloride (Intermediate INTB-U) (90 mg, 354 pmol) and DIPEA (618 L, 3.54 mmol) in DCM (1.5 mL) at room temperature was added dropwise a solution of 5-fluoro-2- methoxybenzenesulfonyl isocyanate (Intermediate INTA-S) (139 mg, 603 pmol). The reaction mixture was stirred at room temperature for 30 min. The reaction mixture was directly absorbed with a pad of Celite and concentrated to dryness. The residue was purified by silica gel column chromatography eluted with cyclohexane / acetone from 100 / 0 to 40 / 60. The resulting product was triturated in diethyl ether, filtered and dried to afford 8- fluoro- / V-((5-fluoro-2-methoxyphenyl)sulfonyl)-5-(1H-pyrazol-1-yl)-3,4-dihydroisoquinoline- 2(1H)-carboxamide (Example EXA21) (43 mg, 26 % yield) as a white solid. LCMS (ES, m / z): 449.1 [M+H]+.

[0566] 1H NMR (400 MHz, DMSO) 5 7.98 (1H, d, J=1.9 Hz), 7.71 (1 H, d, J=1.3 Hz), 7.51 - 7.47 (1H, m), 7.31 - 7.26 (1 H, m), 7.22 - 7.17 (2H, m), 7.02 (1 H, br s), 6.49 (1H, t, J=2.1 Hz), 4.61 (2H, br s), 3.71 (3H, br s), 3.51 (2H, br s). Note: one CH2under DMSO signal and NH sulfonamide non-visible.

[0567] Example EXA22: A / -((3-(dimethylamino)phenyl)sulfonyl)-8-fluoro-5-(1H-pyrazol-1-yl)-

[0568] 3,4-dihydroisoquinoline-2(1 H)-carboxamide (Example EXA22)

[0569] Scheme SCHEXA22

[0570]

[0313] To a mixture of 8-fluoro-5-(1H-pyrazol-1-yl)-1,2,3,4-tetrahydroisoquinoline hydrochloride (Intermediate INTB-U) (383 mg, 1.51 mmol) and triethylamine (554 L, 3.30 mmol) in dioxane (11 mL) at room temperature was added ethyl ((3- (dimethylamino)phenyl)sulfonyl)carbamate (Intermediate INTA-H) (300 mg, 1.10 mmol). The reaction mixture was stirred at 110°C for 16 h. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography eluted with cyclohexane / acetone from 100 / 0 to 0 / 100 to afford / \ / -((3- (dimethylamino)phenyl)sulfonyl)-8-fluoro-5-(1H-pyrazol-1-yl)-3,4-dihydroisoquinoline- 2(1 H)-carboxamide (Example EXA22) (28 mg, 5.4 % yield) as a beige solid. LCMS (ES, m / z): 444.3 [M+H]+.

[0571] 1H NMR (400 MHz, DMSO) 5 7.90 (1H, d, J=1.9 Hz), 7.69 (1 H, dd, J=0.6, 1.9 Hz), 7.27 (1H, dd, J=6.1 , 8.3 Hz), 7.21 - 7.10 (4H, m), 6.76 (1H, dd, J=2.0, 8.3 Hz), 6.47 (1H, dd, J=2.1 , 2.1 Hz), 4.65 (2H, s), 3.57 - 3.54 (2H, m), 2.90 (6H, s), 2.56 - 2.53 (2H, m). Note: NH sulfonamide not visible

[0572] Example EXA23: A / -((2,6-dimethoxyphenyl)sulfonyl)-8-isopropoxy-5-(1H-pyrazol-1-yl)-

[0573] 3,4-dihydroisoquinoline-2(1 H)-carboxamide (Example EXA23)

[0574] Scheme SCHEXA23

[0575]

[0314] To a mixture of 8-isopropoxy-5-(1H-pyrazol-1-yl)-1,2,3,4-tetrahydroisoquinoline hydrochloride (Intermediate INTB-21) (120 mg, 408 pmol) and DIPEA (711 pL, 4.08 mmol) in DCM (2 mL) at room temperature was added dropwise a solution of 2,6- dimethoxybenzenesulfonyl isocyanate (Intermediate INTA-I) (168 mg, 694 pmol). The reaction mixture was stirred at room temperature for 30 min. The reaction mixture was directly absorbed with a Celite pad and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography eluted with cyclohexane / acetone from 100 / 0 to 50 / 50. The resulting solid was triturated in diethyl ether, filtered and dried to afford / V-((2,6-dimethoxyphenyl)sulfonyl)-8-isopropoxy-5-(1H- pyrazol-1-yl)-3,4-dihydro isoquinoline-2(1H)-carboxamide (Example EXA23) (34 mg, 16 % yield) as a white solid. LCMS (ES, m / z): 501.4 [M+H]+

[0576] 1H NMR (400 MHz, DMSO) 5 10.73 (1 H, s), 7.93 (1H, d, J=1.7 Hz), 7.68 (1H, d, J=1.3 Hz), 7.49 - 7.42 (1H, m), 7.21 (1H, d, J=8.4 Hz), 7.00 (1H, d, J=8.6 Hz), 6.77 - 6.75 (2H, m), 6.47 (1H, t, J=2.1 Hz), 4.75 - 4.68 (1 H, m), 4.43 (2H, s), 3.78 (6H, s), 3.55 - 3.51 (2H, m), 1.32 (6H, d, J=6.1 Hz).

[0577] Example EXA24: A / -((4-bromo-2-methoxyphenyl)sulfonyl)-8-fluoro-5-(1 H-pyrazol-1 - yl)-3,4-dihydroisoquinoline-2(1 H)-carboxamide (Example EXA24)

[0578] Scheme SCHEXAM

[0579]

[0315] To a mixture of ethyl ((4-bromo-2-methoxyphenyl)sulfonyl)carbamate (Intermediate INTA-IS) (130 mg, 384 pmol) and triethylamine (193 pL, 1.15 mmol) in 1 ,4- dioxane (3.84 mL) at room temperature was added 8-fluoro-5-(1 H-pyrazol-1-yl)-1, 2,3,4- tetrahydroisoquinoline hydrochloride (Intermediate INTB-U) (130 mg, 512 pmol). The reaction mixture was stirred at 110°C for 16 h. The reaction mixture was purified by silica gel column chromatography eluted with cyclohexane / acetone from 100 / 0 to 50 / 50 to afford / V-((4-bromo-2-methoxyphenyl)sulfonyl)-8-fluoro-5-(1 H-pyrazol-1-yl)-3,4- dihydroisoquinoline-2(1H)-carboxamide (Example EXA24) (10.6 mg, 5.1 % yield) as a yellow solid. LCMS (ES, m / z): 509.2-511.2 [M+H]+

[0580] 1H NMR (400 MHz, DMSO) 5 7.91 (1 H, d, J=1.7 Hz), 7.72 - 7.69 (2H, m), 7.30 - 7.27 (2H, m), 7.21 - 7.13 (2H, m), 6.48 (1 H, t, J=2.1 Hz), 4.63 (1.6H, s), 4.13 (0.4H, s), 3.96 (0.4H, s), 3.83 (2.6H, s), 3.56 - 3.55 (1.6H, m), 3.10 (0.4H, s), 2.66 (0.4H, s), 2.59 - 2.55 (1.6H, m). Note: NH not visible.

[0581] Example EXA25: 7-(dimethylamino)- / V-((2-ethoxyphenyl)sulfonyl)-5-fluoro-3,4- dihydro isoquinoline-2(1H)-carboxamide (Example EXA25)

[0582] Scheme SCHEXA25-

[0583]

[0316] To a mixture of 5-fluoro- / V, / V-dimethyl-1 ,2,3,4-tetrahydroisoquinolin-7-amine hydrochloride (Intermediate INTB-S) (90 mg, 390 pmol) and DIPEA (680 L, 3.901 mmol) in DCM (2 mL) at room temperature was added dropwise a solution of 2- ethoxybenzenesulfonyl isocyanate (Intermediate INTA-?) (150 mg, 663 pmol). The reaction mixture was stirred at room temperature for 30 min. The reaction mixture was directly absorbed with Celite pad and concentrated to dryness then purified by silica gel column chromatography eluted with cyclohexane / ethyl acetate from 100 / 0 to 0 / 100. The resulting product was triturated in diethyl ether, filtered and dried to afford 7- (dimethylamino)- / \ / -((2-ethoxyphenyl)sulfonyl)-5-fluoro-3,4-dihydroisoquinoline-2(1 H)- carboxamide (Example EXA25) (88 mg, 51 % yield) as a brown solid. LCMS (ES, m / z): 422.2 [M+H]+.

[0584] 1H NMR (400 MHz, DMSO) 5 7.75 (1 H, d, J=7.6 Hz), 7.44 (1 H, br s), 7.07 (1 H, br s), 6.97 (1 H, br s), 6.38 (1 H, dd, J=1 .9, 13.1 Hz), 6.28 (1 H, s), 4.48 (2H, br s), 4.12 - 4.03 (2H, m), 3.60 (2H, br s), 2.85 (6H, s), 2.54 (2H, br s), 1.25 (3H, t, J=6.4 Hz). Note: NH proton non- visible.

[0585] Example EXA26: A / -((2,6-dimethoxyphenyl)sulfonyl)-7-(dimethylamino)-5-fluoro-3,4- dihydro isoquinoline-2(1H)-carboxamide (Example EXA26)

[0586] Scheme SCHEXA26-

[0587]

[0317] To a mixture of 5-fluoro- / V, / \ / -dimethyl-1,2,3,4-tetrahydroisoquinolin-7-amine hydrochloride (Intermediate INTB-S) (100mg, 433 pmol) and DIPEA (755 pL, 4.33 mmol) in DCM (2 mL) at room temperature was added slowly a solution of 2,6- dimethoxybenzenesulfonyl isocyanate (Intermediate INTA-I) (179.2 mg, 736.8 pmol). The reaction mixture was stirred at room temperature for 30 min. The reaction mixture was directly absorbed with a Celite pad and concentrated to dryness then purified by silica gel column chromatography eluted with cyclohexane / ethyl acetate from 100 / 0 to 0 / 100 to afford / V-((2,6-dimethoxyphenyl)sulfonyl)-7-(dimethylamino)-5-fluoro-3,4- dihydroisoquinoline-2(1H)-carboxamide (Example EXA26) (20 mg, 10 % yield) as a white solid. LCMS (ES, m / z): 438.2 [M+H]+.

[0588] 1H NMR (400 MHz, CDCI3) 6 8.04 (1 H, br s), 7.45 (1H, t, J=8.4 Hz), 6.67 (2H, d, J=8.7 Hz), 6.41 (1 H, br s), 6.26 (1 H, br s), 4.56 (2H, s), 3.94 (6H, s), 3.65 (2H, t, J=5.9 Hz), 2.94 (6H, s), 2.76 (2H, t, J=6.2 Hz).

[0589] Example EXA27: 7-(dimethylamino)-5-fluoro- / V-((5-isopropyl-2- methoxyphenyl)sulfonyl)-3,4-dihydroisoquinoline-2(1 H)-carboxamide (Example

[0590] EXA27)

[0591] Scheme SCHEXA27-

[0592]

[0318] To a mixture of 5-fluoro- / V, / \ / -dimethyl-1,2,3,4-tetrahydroisoquinolin-7-amine hydrochloride (Intermediate INTB-S) (90 mg, 390 pmol) and DIPEA (680 pL, 3.901 mmol) in DCM (2 mL) at room temperature was added slowly a solution of 5-isopropyl-2- methoxybenzenesulfonyl isocyanate (Intermediate INTA-2) (in toluene) (169 mg, 663 pmol). The reaction mixture was stirred at room temperature for 30 min. The reaction mixture was directly absorbed with a Celite pad and concentrated to dryness then purified by silica gel column chromatography eluted with cyclohexane / ethyl acetate from 100 / 0 to 0 / 100. The resulting product was triturated in diethyl ether, filtered and dried to afford 7- (dimethylamino)-5- fluoro- / V-((5-isopropyl-2-methoxyphenyl)sulfonyl)-3, 4- dihydroisoquinoline-2(1H)-carboxamide (Example EXA27) (5 mg, 3 % yield) as a brown solid. LCMS (ES, m / z): 432.3 [M+H]+.

[0593] 1H NMR (400 MHz, CDCh) 6 7.93 (1 H, br s), 7.43 (1H, br s), 6.95 (1 H, br s), 6.31 (1H, d, J=13.4 Hz), 6.14 (1 H, br s), 4.55 (2H, br s), 3.92 (3H, br s), 3.63 (2H, br s), 2.94 (1 H, br s), 2.90 (6H, br s), 2.74 (2H, br s), 1.29 (6H, br s). Note: NH proton non-visible

[0594] Example EXA28: 5-fluoro-7-(3-fluoroazetidin-1-yl)- / V-((5-isopropyl-2- methoxyphenyl)sulfonyl)-3,4-dihydroisoquinoline-2(1 H)-carboxamide (Example

[0595] EXA28)

[0596] Scheme SCHEXA28-

[0597]

[0319] To a mixture of 5-fluoro-7-(3-fluoroazetidin-1-yl)-1 ,2,3,4-tetrahydroisoquinoline hydrochloride (Intermediate INTB-S) (100 mg, 383 pmol) and DIPEA (334 pL, 1.91 mmol) in DCM (2 mL) at room temperature was added dropwise a solution of 5-isopropyl-2- methoxybenzenesulfonyl isocyanate (Intermediate INTA-2) (166 mg, 652 pmol). The reaction mixture was stirred at room temperature for 30 min. The reaction mixture was directly absorbed with a Celite pad and concentrated to dryness. The residue was purified by silica gel column chromatography eluted with cyclohexane / acetone from 100 / 0 to 50 / 50. The resulting product was triturated in diethyl ether, filtered and dried to afford 5- fluoro-7-(3-fluoroazetidin-1-yl)- / V-((5-isopropyl-2-methoxyphenyl)sulfonyl)-3,4- dihydroisoquinoline-2(1 H)-carboxamide (Example EXA28) (53 mg, 27 % yield) as a white solid. LCMS (ES, m / z): 480.2 [M+H]+.

[0598] 1 H NMR (400 MHz, DMSO) 5 10.88 (1 H, s), 7.60 (1 H, d, J=2.1 Hz), 7.45 (1 H, s), 7.09 (1 H, s), 6.21 (1 H, dd, J=1.9, 11.4 Hz), 6.07 (1 H, d, J=1.7 Hz), 5.56 - 5.37 (1 H, d sept, J=57.5 Hz, 3.1 Hz), 4.45 (2H, s), 4.16 - 4.06 (2H, m), 3.84 (2H, dt, J=3.0, 11.9 Hz), 3.79 (3H, s), 3.61 (2H, s), 2.94 - 2.87 (1 H, m), 2.58 (2H, t, J=6.1 Hz), 1.19 (6H, d, J=7.1 Hz).

[0599] Example EXA29: 7-(azetidin-1-yl)-5-fluoro- / V-((5-isopropyl-2- methoxyphenyl)sulfonyl)-3,4-dihydroisoquinoline-2(1 H)-carboxamide (Example EXA29)

[0600] Scheme SCHEXA29-

[0601]

[0320] To a mixture of 7-(azetidin-1-yl)-5-fluoro-1 ,2,3,4-tetrahydroisoquinoline hydrochloride (Intermediate INTB-9) (120 mg, 494 pmol) and DIPEA (431 pL, 2.47 mmol) in DCM (2 mL) at room temperature was added dropwise a solution of 5-isopropyl-2- methoxybenzenesulfonyl isocyanate (Intermediate INTA-2) (214 mg, 840 pmol). The reaction mixture was stirred at room temperature for 30 min. The reaction mixture was directly absorbed with a Celite pad and concentrated to dryness. The residue was purified by silica gel column chromatography eluted with cyclohexane / acetone from 100 / 0 to 70 / 30. The resulting product was triturated in acetonitrile, filtered and dried to afford 7- (azetidin-1-yl)-5-fluoro- / V-((5-isopropyl-2-methoxyphenyl)sulfonyl)-3,4-dihydroisoquinoline- 2(1 H)-carboxamide (Example EXA29) (13 mg, 5.4 % yield) as a white solid. LCMS (ES, m / z): 462.2 [M+H]+.

[0602] 1H NMR (400 MHz, DMSO) 5 10.87 (1 H, s), 7.61 (1 H, d, J=2.3 Hz), 7.48 (1 H, dd, J=1 .9, 8.4 Hz), 7.11 (1 H, d, J=8.3 Hz), 6.10 (1 H, dd, J=1.7, 11.8 Hz), 5.99 (1 H, s), 4.44 (2H, s), 3.80 (3H, s), 3.75 (4H, t, J=7.2 Hz), 3.61 (2H, t, J=5.5 Hz), 2.91 (1 H, quint), 2.58 (2H, t, J=5.7 Hz), 2.27 (2H, quint), 1.19 (6H, d, J=6.7 Hz). Example EXA30: 7-(dimethylamino)- / V-((2-ethoxyphenyl)sulfonyl)-3,4- dihydroisoquinoline-2(1 H)-carboxamide (Example EXAs)

[0603] Scheme SCHEXASO-

[0604]

[0321] To a mixture of A / , / V-dimethyl-1 ,2,3,4-tetrahydroisoquinolin-7-amine hydrochloride (Intermediate INTB-6) (90 mg, 423 pmol) and DI PEA (737 pL, 4.23 mmol) in DCM (2 mL) at room temperature was added dropwise a solution of 2-ethoxybenzenesulfonyl isocyanate (Intermediate INTA-?) (163 mg, 719 pmol). The reaction mixture was stirred at room temperature for 30 min. The reaction mixture was directly absorbed with a Celite pad and concentrated to dryness. The residue was purified by silica gel column chromatography eluted with cyclohexane / acetone from 100 / 0 to 50 / 50. The resulting product was triturated in diethyl ether filtered and dried to afford 7-(dimethylamino)- / V-((2- ethoxyphenyl)sulfonyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (Example EXA30) (45 mg, 25 % yield) as a brown solid. LCMS (ES, m / z): 404.2 [M+H]+.

[0605] 1H NMR (400 MHz, DMSO) 5 10.71 (1 H, br s), 7.78 (1H, dd, J=1.7, 7.8 Hz), 7.57 (1 H, t, J=7.6 Hz), 7.18 (1H, d, J=8.4 Hz), 7.06 (1H, t, J=7.2 Hz), 6.96 (1 H, d, J=8.7 Hz), 6.59 (1 H, dd, J=2.5, 8.4 Hz), 6.43 (1 H, d, J=2.3 Hz), 4.45 (2H, br s), 4.17 (2H, q, J=7.0 Hz), 3.58 (2H, br s), 2.84 (6H, s), 2.64 (2H, t, J=6.0 Hz), 1.28 (3H, t, J=6.9 Hz).

[0606] Example EXA31: 7- cyclopropyl- / V-((2-ethoxyphenyl)sulfonyl)-3,4- dihydroisoquinoline-2(1 H)-carboxamide (Example EXA31)

[0607] Scheme SCHEXASI.

[0608]

[0322] To a mixture of 7-cyclopropyl-1 ,2,3,4-tetrahydroisoquinoline hydrochloride (Intermediate INTB-T) (90 mg, 429 pmol) and DIPEA (748 pL, 4.29 mmol) in DCM (2 mL) at room temperature was added dropwise a solution of 2-ethoxybenzenesulfonyl isocyanate (Intermediate INTA-?) (165 mg, 729 pmol). The reaction mixture was stirred at room temperature for 30 min. The reaction mixture was directly absorbed with a Celite pad and concentrated to dryness. The residue was purified by silica column chromatography eluted with DCM / ethyl acetate from 100 / 0 to 90 / 10. The resulting product was triturated in diethyl ether, filtered and dried to afford 7-cyclopropyl- / V-((2- ethoxyphenyl)sulfonyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (Example EXA31) (75 mg, 41 % yield) as a white solid. LCMS (ES, m / z): 401.1 [M+H]+.

[0609] 1H NMR (400 MHz, DMSO) 5 10.77 (1 H, s), 7.78 (1H, dd, J=1.7, 7.8 Hz), 7.57 (1 H, ddd, J=7.9, 7.9, 1.4 Hz), 7.18 (1H, d, J=8.3 Hz), 7.07 (1 H, t, J=7.6 Hz), 7.02 (1H, d, J=7.8 Hz), 6.88 (1H, dd, J=1.8, 7.9 Hz), 6.80 (1H, s), 4.46 (2H, br s), 4.16 (2H, q, J=6.9 Hz), 3.58 (2H, br s), 2.71 (2H, t, J=5.8 Hz), 1.90 - 1.82 (1 H, m), 1.27 (3H, t, J=6.9 Hz), 0.93 - 0.87 (2H, m), 0.63 - 0.59 (2H, m).

[0610] Example EXA32: A / -((2-ethoxyphenyl)sulfonyl)-4-methyl-3,4-dihydroisoquinoline- 2(1 H)-carboxamide (Example EXA32) Scheme SCHEXA32

[0611]

[0323] To a mixture of 4-methyl-1,2,3,4-tetrahydroisoquinoline hydrochloride (119 mg, 647 pmol) and DI PEA (564 pL, 3.23 mmol) in DCM (2 mL) at room temperature was added dropwise a solution of 2-ethoxybenzenesulfonyl isocyanate (Intermediate INTA-?) (220 mg, 971 pmol). The reaction mixture was stirred at room temperature for 30 min. The reaction mixture was directly absorbed with a Celite pad and concentrated to dryness. The residue was purified by silica gel column chromatography eluted with DCM / ethyl acetate from 100 / 0 to 90 / 10. The resulting product was triturated in diethyl ether, filtered and dried to afford / V-((2-ethoxyphenyl)sulfonyl)-4-methyl-3,4-dihydroisoquinoline-2(1 H)- carboxamide (Example EXA32) (89 mg, 35 % yield) as a white solid. LCMS (ES, m / z): 375.1 [M+H]+.1H NMR (400 MHz, DMSO) 610.74 (1H, s), 7.80 (1H, dd, J=1.7, 8.0 Hz), 7.60 - 7.54 (1H, m), 7.26-7.21 (1H, m), 7.21 - 7.15 (3H, m), 7.11 - 7.04 (2H, m), 4.65-4.61 (1H, m), 4.50 -4.43 (1H, m), 4.19-4.12 (2H, m), 3.60 (1H, brs), 3.42 (1H, dd, J=7.1, 13.0 Hz), 2.93 (1H, q, J=6.2 Hz), 1.27 (3H, t, J=7.0 Hz), 1.16 (3H, d, J=6.8 Hz).

[0612] Example EXA33: (R)-A / -((2-ethoxyphenyl)sulfonyl)-4-methyl-3,4-dihydroisoquinoline-

[0613] 2(1 H)-carboxamide (Example EXA33)

[0614] Scheme SCHEXA33-

[0615]

[0324] To a mixture of (R)-4-methyl-1,2,3,4-tetrahydroisoquinoline hydrochloride (117 mg, 636 pmol) and DI PEA (555 pL, 3.18 mmol) in DCM (2 mL) at room temperature was added dropwise a solution of 2-ethoxybenzenesulfonyl isocyanate (Intermediate INTA-?) (246 mg, 1.08 mmol). The reaction mixture was stirred at room temperature for 30 min. The reaction mixture was directly absorbed with a Celite pad and concentrated to dryness. The residue was purified by silica gel column chromatography eluted with cyclohexane / acetone from 100 / 0 to 50 / 50 to afford (R)- / V-((2-ethoxyphenyl)sulfonyl)-4- methyl-3,4-dihydroisoquinoline-2(1H)-carboxamide (Example EXA33) (74 mg, 29 % yield) as a white solid. LCMS (ES, m / z): 375.1 [M+H]+.

[0616] 1H NMR (400 MHz, DMSO) 510.75 (1H, s), 7.79 (1H, dd, J=1.7, 7.8 Hz), 7.57 (1H, t, J=7.6 Hz), 7.26-7.21 (1H, m), 7.21 - 7.15 (3H, m), 7.11 - 7.03 (2H, m), 4.65-4.61 (1H, m), 4.49-4.42 (1H, m), 4.14 (2H, q, J=6.8 Hz), 3.60 (1H, brs), 3.43 (1H, dd, J=6.6, 12.9 Hz), 2.92 (1H, q, J=5.9 Hz), 1.26 (3H, t, J=7.0 Hz), 1.16 (3H, d, J=6.7 Hz).

[0617] Example EXA34: A / -((5-(tert-butyl)-2-methoxyphenyl)sulfonyl)-7-(dimethylamino)-4- methyl-3,4-dihydroisoquinoline-2(1 H)-carboxamide (Example EXA34)

[0618] Scheme SCHEXA34

[0619]

[0325] To a mixture of / V, / V,4-trimethyl-1,2,3,4-tetrahydroisoquinolin-7-amine hydrochloride (Intermediate INTB-H) (100 mg, 441 pmol) and DIPEA (768 pL, 4.41 mmol) in DCM (2 mL) at room temperature was added dropwise a solution of 5-(terf-butyl)-2- methoxybenzenesulfonyl isocyanate (Intermediate INTA-S) (201 mg, 749 pmol). The reaction mixture was stirred at room temperature for 30 min. The reaction mixture was directly absorbed with a Celite pad and concentrated to dryness. The residue was purified by silica gel column chromatography eluted with DCM / ethyl acetate from 100 / 0 to 60 / 40. The resulting product was triturated in diethyl ether, filtered and dried to afford / \ / -((5-(tert- butyl)-2-methoxyphenyl)sulfonyl)-7-(dimethylamino)-4-methyl-3,4-dihydroisoquinoline- 2(1H)-carboxamide (Example EXA34) (54 mg, 25 % yield) as a white solid. LCMS (ES, m / z): 460.3 [M+H]+.

[0620] 1H NMR (400 MHz, DMSO) 5 10.75 (1 H, s), 7.75 (1H, d, J=2.5 Hz), 7.63 (1H, dd, J=2.3, 8.9 Hz), 7.08 (2H, dd, J=8.8, 26.5 Hz), 6.61 (1 H, dd, J=2.7, 8.5 Hz), 6.42 (1H, d, J=2.7 Hz), 4.55 - 4.50 (1H, m), 4.43 - 4.39 (1H, m), 3.81 (3H, s), 3.62 (1 H, br s), 3.32 - 3.29 (1 H, m), 2.84 (6H, s), 2.82 - 2.79 (1H, m), 1.28 (9H, s), 1.12 (3H, d, J=6.7 Hz).

[0621] Example EXA35: 8-fluoro-5-methoxy- / V-((2-methoxyphenyl)sulfonyl)-3,4- dihydroisoquinoline-2(1H)-carboxamide (Example EXA35)

[0622] Scheme SCHEXA35

[0623]

[0326] To a mixture of 8-fluoro-5-methoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride (Intermediate INTB-12) (100 mg, 459 pmol) and DIPEA (800 pL, 4.59 mmol) in DCM (2 mL) at room temperature was added dropwise a solution of 2-methoxybenzenesulfonyl isocyanate (Intermediate INTA-B) (166 mg, 781 pmol). The reaction mixture was stirred at room temperature for 30 min. The reaction mixture was directly absorbed with a Celite pad and concentrated to dryness. The residue was purified by silica gel column chromatography eluted with DCM / ethyl acetate from 100 / 0 to 0 / 100. The resulting product was triturated in diethyl ether, filtered and dried to afford 8-fluoro-5-methoxy- / V-((2- methoxyphenyl)sulfonyl)-3,4-dihydroisoquinoline-2(1 H)-carboxamide (Example EXA35) (141 mg, 74 % yied) as a white solid. LCMS (ES, m / z): 395.1 [M+H]+.

[0624] 1H NMR (400 MHz, DMSO) 5 11.07 (1 H, s), 7.76 (1H, d, J=7.9 Hz), 7.55 (1H, br s), 7.14 (1 H, br s), 7.01 (2H, t, J=8.8 Hz), 6.83 (1H, dd, J=4.1, 9.1 Hz), 4.41 (2H, br s), 3.81 (3H, br s), 3.78 (3H, br s), 3.60 (2H, s), 2.65 (2H, br s).

[0625] Example EXA36: 8-fluoro- / V-((2-methoxyphenyl)sulfonyl)-5-(oxazol-2-yl)-3,4-dihydro isoquinoline-2(1 H)-carboxamide (Example EXA3B) Scheme SCHEXA36

[0626]

[0327] To a mixture of 2-(8-fluoro-1,2,3,4-tetrahydroisoquinolin-5-yl)oxazole hydrochloride (Intermediate INTB-IS) (140 mg, 549 pmol) and DIPEA (958 pL, 5.49 mmol) in DCM (2 mL) at room temperature was added dropwise a solution of 2-methoxybenzenesulfonyl isocyanate (Intermediate INTA-B) (199 mg, 9 934 pmol). The reaction mixture was stirred at room temperature for 30 min. The reaction mixture was directly absorbed with a Celite pad and concentrated to dryness. The residue was purified by silica gel column chromatography eluted with cyclohexane / acetone from 100 / 0 to 50 / 50 to afford 8-fluoro- / V- ((2-methoxyphenyl)sulfonyl)-5-(oxazol-2-yl)-3,4-dihydro isoquinoline-2(1H)-carboxamide (Example EXA36) (73 mg, 29 % yield) as a white solid. LCMS (ES, m / z): 432.1 [M+H]+.

[0627] 1H NMR (400 MHz, DMSO) 5 11.14 (1 H, s), 8.26 (1H, s), 7.90 - 7.86 (1 H, m), 7.79 (1 H, d, J=6.6 Hz), 7.61 (1H, t, J=7.4 Hz), 7.44 (1 H, s), 7.26 (1 H, t, J=8.8 Hz), 7.18 (1H, d, J=8.7 Hz), 7.09 (1 H, t, J=7.8 Hz), 4.59 (2H, br s), 3.85 (3H, s), 3.66 (2H, br s), 3.21 - 3.16 (2H, m).

[0628] Example EXA37: 7-((1 H-pyrazol-1 -yl)methyl)- / V-((2,6-dimethoxyphenyl)sulfonyl)-4- methyl-3,4-dihydroisoquinoline-2(1 H)-carboxamide (Example EXA37)

[0629] Scheme SCHEXA37

[0630]

[0328] To a mixture of 7-((1 H-pyrazol-1-yl)methyl)-4-methyl-1 ,2,3,4-tetrahydroisoquinoline hydrochloride (Intermediate INTB-IS) (190 mg, 720 pmol) and DIPEA (1 mL, 5.76 mmol) in DCM (1 mL) at room temperature added was slowly a solution of 2,6- dimethoxybenzenesulfonyl isocyanate (Intermediate INTA-I) (298 mg, 1.22 mmol) in DCM (2 mL). The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was evaporated to dryness and purified by silica gel column chromatography eluted with cyclohexane / acetone from 100 / 0 to 50 / 50 to afford 7-((1 H-pyrazol-1-yl)methyl)- / V-((2,6- dimethoxyphenyl)sulfonyl)-4-methyl-3,4-dihydroisoquinoline-2(1 H)-carboxamide (Example EXA37) (92 mg, 26 % yield) as a white solid. LCMS (ES, m / z): 471.3 [M+H]+.

[0631] 1H NMR (400 MHz, DMSO) 5 10.55 (1 H, s), 7.81 (1 H, dd, J=0.7, 2.2 Hz), 7.48 - 7.43 (2H, m), 7.22 (1 H, d, J=8.1 Hz), 7.07 (1 H, dd, J=1 .5, 8.0 Hz), 6.95 (1 H, s), 6.74 (2H, d, J=8.6 Hz), 6.26 (1 H, t, J=2.1 Hz), 5.28 (2H, s), 4.59 (1 H, d, J=16.7 Hz), 4.46 (1 H, d, J=16.7 Hz), 3.73 (6H, s), 3.59 (1 H, d, J=11.4 Hz), 3.38 (1 H, dd, J=6.6, 13.1 Hz), 2.91 (1 H, sext, J=6.0 Hz), 1.15 (3H, d, J=6.8 Hz).

[0632] Example EXA33: A / -((2,4-dichlorophenyl)sulfonyl)-8-fluoro-5-(1 H-pyrazol-1-yl)-3,4- dihydroisoquinoline-2(1 H)-carboxamide (Example EXAss)

[0633] Scheme SCHEXA38

[0634]

[0329] To a mixture of 8-fluoro-5-(1 H-pyrazol-1-yl)-1,2,3,4-tetrahydroisoquinoline hydrochloride (Intermediate INTB-U) (320 mg, 1.26 mmol) and triethylamine (422 L, 2.52 mmol) in dioxane (8.4 mL) at room temperature was added ethyl ((2,4- dichlorophenyl)sulfonyl)carbamate (Intermediate INTA-S) (250 mg, 0.839 mmol). The reaction mixture was stirred at 110°C for 16 h. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography eluting with cyclohexane / acetone from 100 / 0 to 50 / 50 to afford / \ / -((2,4-dichlorophenyl)sulfonyl)-8- fluoro-5-(1 H-pyrazol-1-yl)-3,4-dihydroisoquinoline-2(1 H)-carboxamide (Example EXAss) (85 mg, 21 % yield) as a yellow solid. LCMS (ES, m / z): 469.1-471.1 [M+H]+.

[0635] 1H NMR (400 MHz, DMSO) 5 8.00 (0.3H, d, J= 8.5 Hz), 7.97 (0.7H, d, J= 8.5 Hz), 7.95 (0.2H, dd ,J= 2.4, 0.6 Hz), 7.91 (0.8H, dd, J= 2.4, 0.6 Hz), 7.77 (0.2H, d, J= 2.1 Hz), 7.74 (0.3H, dd, J=1 .9, 0.7 Hz), 7.74 (0.7H, dd, J=1 .9, 0.6 Hz), 7.61 (0.2H, dd, J= 8.4, 2.1 Hz),

[0636] 7.51 - 7.49 (0.8H, m), 7.44 - 7.40 (1 H, m), 7.32 - 7.24 (1 H, m), 7.15 (0.8H, t, J= 9 Hz),

[0637] 6.52 (0.2H, dd, J=2.4, 1.9 Hz), 6.47 (0.8H, t, J=2.4, 1.9 Hz), 4.61 (1.6H, s), 4.34 (0.4H, s), 3.54 (1.6H, t, J= 6.1 Hz), 3.32 (0.4H, t, J= 6.0 Hz), 2.84 (0.4H, t, J= 6.0 Hz), 2.55 - 2.52 (1.6H, m). Note: NH not visible

[0638] Example EXA39: 8-fluoro-5-(1H-pyrazol-1-yl)-N-((3-(pyrrolidin-1-yl)phenyl)sulfonyl)-

[0639] 3,4-dihydroisoquinoline-2(1 H)-carboxamide (Example EXA39)

[0640] Scheme SCHEXA39

[0641]

[0330] To a mixture of ethyl ((3-(pyrrolidin-1-yl)phenyl)sulfonyl)carbamate (Intermediate INTA-U) (226 mg, 530 pmol) and triethylamine (267 L, 1.59 mmol) in 1 ,4-dioxane (5.3 mL) at room temperature was added 8-fluoro-5-(1 H-pyrazol-1-yl)-1 , 2,3,4- tetrahydroisoquinoline hydrochloride (Intermediate INTB-U) (250 mg, 985 pmol). The reaction mixture was stirred at 110°C for 16 h. The reaction mixture was purified by silica gel column chromatography eluted with cyclohexane / acetone from 100 / 0 to 50 / 50 to afford 8-fluoro-5-(1 H-pyrazol-1-yl)-N-((3-(pyrrolidin-1-yl)phenyl)sulfonyl)-3,4- dihydroisoquinoline-2(1 H)-carboxamide (Example EXA39) (47 mg, 18 %, yield) as a beige powder. LCMS (ES, m / z): 470.3 [M+H]+

[0642] 1H NMR (400 MHz, DMSO) 5 7.91 - 7.89 (1 H, m), 7.71 - 7.68 (1 H, m), 7.31 - 7.00 (5H, m), 6.66 - 6.62 (1 H, m), 6.49 - 6.46 (1 H, m), 4.64 (1.6H, s), 4.10 (0.4H, s), 3.57 (1.6H, t, J=5.57 Hz), 3.25 - 3.19 (4H, m), 3.09 - 3.03 (0.4H, m), 2.63 (0.4H, t, J=6.2 Hz), 2.57 (1.6H, t, J=6.0 Hz), 2.01 - 1.95 (4H, m).

[0643] Note: NH not visible

[0644] Example EXA45: A / -((5-(tert-butyl)-2-methoxyphenyl)sulfonyl)-7-(dimethylamino)-5- fluoro-3,4-dihydroisoquinoline-2(1 H)-carboxamide (Example EXA45)

[0645] Scheme SCHEXA45

[0646]

[0331] To a mixture of 5-fluoro- / V, / V-dimethyl-1 ,2,3,4-tetrahydroisoquinolin-7-amine hydrochloride (Intermediate INTB-S) (94 mg, 0.41 mmol) and DIPEA (0.71 mL, 4.1 mmol) in DCM (1 mL) was added slowly a solution of 5-(terf-butyl)-2-methoxybenzenesulfonyl isocyanate (Intermediate INTA^) (190 mg, 0.69 mmol) in DCM (2.3 mL). The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was purified by silica gel column chromatography eluted with cyclohexane / ethyl acetate 100 / 0 to 0 / 100. The resulting product was triturated in diethyl ether, filtered and dried to afford / V-((5-(terf- butyl)-2-methoxyphenyl)sulfonyl)-7-(dimethylamino)-5-fluoro-3,4-dihydroisoquinoline- 2(1 H)-carboxamide (60 mg, 30 % yield) as a white solid. LCMS (ES, m / z): 464.2 [M+H]+. 1 H NMR (400 MHz, DMSO) 5 10.88 (1 H, s), 7.75 - 7.74 (1 H, d, J = 2.4 Hz), 7.64 - 7.61 (1 H, d, J = 8.8 Hz), 7.12 - 7.10 (1 H, d, J = 8.4 Hz), 6.42 - 6.39 (1 H, dd, J = 1.6 Hz, J = 12.8 Hz), 6.282 - 6.278 (1 H, d, J = 1.6 Hz), 4.46 (2H, s), 3.81 (3H, s), 3.62 (2H, t, J = 5.6 Hz), 2.85 (6H, s), 2.60 - 2.571 (2H, t, J = 12.4 Hz), 1.27 (9H, s).

[0647] Example EXA46: A / -((2-ethoxyphenyl)sulfonyl)isoindoline-2-carboxamide (Example EXA42)

[0648] Scheme SCHEXA46

[0649]

[0332] To a mixture of isoindoline (45 mg, 377 pmol) and DI PEA (658 pL, 3.77 mmol) in DCM (2 mL) at 0°C was slowly added a solution of 2-ethoxybenzenesulfonyl isocyanate (Intermediate INTA-?) (145 mg, 641 pmol) in DCM (2 mL). The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was purified by silica gel column chromatography eluted with dichloromethane / methanol 100 / 0 to 95 / 5 to afford / \ / -((2- ethoxyphenyl)sulfonyl)isoindoline-2-carboxamide (Example EXA46) (20.2 mg, 15 % yield) as a white powder. LCMS (ES, m / z): 347.3 [M+H]+

[0650] 1 H NMR (400 MHz, DMSO) 5 10.77 (s, 1 H), 7.83 (dd, J = 7.9, 1.7 Hz, 1 H), 7.60 (ddd, J = 8.4, 7.4, 1.8 Hz, 1 H), 7.36 - 7.26 (m, 4H), 7.21 (d, J = 7.8 Hz, 1 H), 7.14 - 7.04 (m, 1 H), 4.78 (s, 2H), 4.54 (s, 2H), 4.21 (q, J = 7.0 Hz, 2H), 1.31 (t, J = 7.0 Hz, 3H).

[0651] Example EXA47: (S)- / V-((2-methoxyphenyl)sulfonyl)-1-methylisoindoline-2- carboxamide (Example EXA47) Scheme SCHEXA47

[0652]

[0333] To a mixture of (1S)-1-methyl-2,3-dihydro-1 H-isoindole hydrochloride (75 mg, 442 pmol) and DIPEA (385 pL, 2.21 mmol) in DCM (2 mL) at room temperature was added dropwise a solution of 2-methoxybenzenesulfonyl isocyanate (Intermediate INTA-B) (151 mg, 707 pmol). The reaction mixture was stirred at room temperature for 30 min. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography eluted with cyclohexane / ethyl acetate from 100 / 0 to 80 / 20 to afford (S)-N- ((2-methoxyphenyl)sulfonyl)-1-methylisoindoline-2-carboxamide (Example EXA47) (32 mg, 20 % yield) as a brown powder. LCMS (ES, m / z): 347.1 [M+H]+

[0653] 1H NMR (400 MHz, DMSO) 5 7.80 - 7.74 (1 H, m), 7.47 (1 H, s), 7.29 - 7.24 (4H, m), 7.10 (1 H, s), 6.99 - 6.95 (1 H, m), 5.10 - 4.90 (1 H, m), 4.63 (2H, s), 3.81 - 3.79 (3H, m), 1.41 - 1.36 (3H, m). Note: NH not visible

[0654] Example EXA48: (R)-A / -((2-methoxyphenyl)sulfonyl)-1-methylisoindoline-2- carboxamide (Example EXA48)

[0655] Scheme SCHEXA48

[0656]

[0334] To a mixture of (1 R)-1-methyl-2,3-dihydro-1 H-isoindole hydrochloride (75 mg, 442 pmol) and DI PEA (385 pL, 2.21 mmol) in DCM (2 mL) at room temperature was dropwise a solution of 2-methoxybenzenesulfonyl isocyanate (Intermediate INTA-B) (151 mg, 707 pmol). The reaction mixture was stirred at room temperature for 30 min. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography eluted with dichloromethane / ethyl acetate from 100 / 0 to 70 / 30. The resulting product was triturated in cyclohexane, filtered and dried to afford (R)- / V-((2- methoxyphenyl)sulfonyl)-1-methylisoindoline-2-carboxamide (Example EXA48) (11 mg, 7 % yield) as a brown powder. LCMS (ES, m / z): 347.2 [M+H]+

[0657] 1H NMR (400 MHz, DMSO) 5 7.79 - 7.75 (1 H, m), 7.41 - 7.37 (1 H, m), 7.24 (4H, s), 7.07 - 6.91 (2H, m), 4.98 (1 H,s), 4.63 (1 H, s), 4.41 (1 H, s), 3.76 (3H, s), 1.37 - 1.24 (3H, m).

[0658] Example EXA49: 5-cyclopropyl- / V-((2-ethoxyphenyl)sulfonyl)isoindoline-2- carboxamide (Example EXA49)

[0659] Scheme SCHEXA49-

[0660]

[0335] To a mixture of 5-cyclopropylisoindoline hydrochloride (100 mg, 511 pmol) and DIPEA (890 pL, 5.11 mmol) in DCM (2 mL) at 0°C was slowly added a solution of 2- ethoxybenzenesulfonyl isocyanate (Intermediate INTA-?) (174 mg, 766 pmol) in DCM (2 mL). The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was purified by silica gel column chromatography eluted with cyclohexane / ethyl acetate from 30 / 70 to 0 / 100. The resulting product was triturated in acetonitrile, filtered and dried to afford 5-cyclopropyl- / V-((2-ethoxyphenyl)sulfonyl) isoindoline-2-carboxamide (Example EXA49) (26 mg, 13 % yield) as a white powder. LCMS (ES, m / z): 387.2 [M+H]+

[0661] 1 H NMR (400 MHz, DMSO) 5 10.73 (s, 1 H), 7.82 (dd, J = 7.9, 1.7 Hz, 1 H), 7.66 - 7.55 (m, 1 H), 7.19 (dd, J = 12.1 , 8.1 Hz, 2H), 7.12 - 7.05 (m, 1 H), 7.01 (s, 2H), 4.60 (d, J = 101.2 Hz, 4H), 4.21 (q, J = 6.9 Hz, 2H), 1.92 (td, J = 7.3, 4.6 Hz, 1 H), 1.31 (t, J = 7.0 Hz, 3H), 0.98 - 0.87 (m, 2H), 0.66 (d, J = 3.6 Hz, 2H).

[0662] Example EXA50: 5-(dimethylamino)- / V-((2-ethoxyphenyl)sulfonyl)isoindoline-2- carboxamide (Example EXA50) Scheme SCHEXASO

[0663]

[0336] To a mixture of / V, / V-dimethylisoindolin-5-amine hydrochloride (Intermediate INTB- 53) (60 mg, 302 pmol) and DI PEA (526 pL, 3.02 mmol) in DCM (1 mL) at 0°C was slowly added a solution of 2-ethoxybenzenesulfonyl isocyanate (Intermediate INTA-?) (103 mg, 453 pmol) in DCM (2 mL). The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was purified by silica gel column chromatography eluted with cyclohexane / (ethyl acetate / ethanol 3:1) from 100 / 0 to 50 / 50. The resulting product was triturated in acetonitrile, filtered and dried to afford 5-(dimethylamino)- / V-((2- ethoxyphenyl)sulfonyl)isoindoline-2-carboxamide (Example EXA50) (15 mg, 12 % yield) as a white powder. LCMS (ES, m / z): 390.2 [M+H]+

[0664] 1 H NMR (400 MHz, DMSO) 5 10.69 (s, 1 H), 7.82 (d, J = 6.3 Hz, 1 H), 7.60 (t, J = 7.8 Hz, 1 H), 7.21 (d, J = 8.3 Hz, 1 H), 7.09 (dd, J = 13.7, 7.9 Hz, 2H), 6.73 - 6.60 (m, 2H), 4.55 (d, J = 82.0 Hz, 4H), 4.21 (q, J = 7.0 Hz, 2H), 2.88 (s, 6H), 1.31 (t, J = 7.0 Hz, 3H).

[0665] Example EXA51 : 5-bromo-A / -((5-(tert-butyl)-2-methoxyphenyl)sulfonyl)isoindoline-2- carboxamide (Example EXA51) Scheme SCHEXASI

[0666]

[0337] To a mixture of 5-bromoisoindoline hydrochloride (200 mg, 852 pmol) and DI PEA (1.19 mL, 6.82 mmol) in DCM (1 mL) at 0°C was slowly added a solution of 5-(terf-butyl)-2- methoxybenzenesulfonyl isocyanate (Intermediate INTA-S) (390 mg, 1.45 mmol) in DCM (2 mL). The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was purified by silica gel column chromatography eluted with cyclohexane / (ethyl acetate / ethanol (3 / 1)) from 100 / 0 to 50 / 50 to afford 5-bromo- / V-((5-(tert-butyl)-2- methoxyphenyl)sulfonyl)isoindoline-2-carboxamide (Example EXA51) (31 mg, 7.4 % yield) as an off-white solid. LCMS (ES, m / z): 467.1-469.1 [M+H]+

[0667] 1 H NMR (400 MHz, DMSO) 5 10.75 (s, 1 H), 7.78 (d, J = 2.5 Hz, 1 H), 7.58 - 7.47 (m, 2H), 7.45 (d, J = 8.1 Hz, 1 H), 7.28 (d, J = 8.0 Hz, 1 H), 7.05 (d, J = 8.7 Hz, 1 H), 4.53 (m, 4H), 3.79 (s, 3H), 1.27 (s, 9H).

[0668] Example EXA52: 5-cyclopropyl- / V-((5-isopropyl-2- methoxyphenyl)sulfonyl)isoindoline-2-carboxamide (Example EXA52) Scheme SCHEXAS2

[0669]

[0338] To a mixture of 5-cyclopropylisoindoline hydrochloride (100 mg, 511 pmol) and DIPEA (890 pL, 5.11 mmol) in DCM (2 mL) at 0°C was slowly added a solution of 5- isopropyl-2-methoxybenzenesulfonyl isocyanate (Intermediate INTA-2) (221 mg, 868 pmol) in DCM (2 mL). The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was purified by silica gel column chromatography eluted with cyclohexane / (ethyl acetate / ethanol 3:1) from 100 / 0 to 50 / 50. The resulting product was triturated in acetonitrile, filtered and dried to afford 5-cyclopropyl- / V-((5-isopropyl-2- methoxyphenyl)sulfonyl)isoindoline-2-carboxamide (Example EXA52) (26 mg, 12 % yield) as a white powder. LCMS (ES, m / z): 415.2 [M+H]+

[0670] 1 H NMR (400 MHz, DMSO) 5 10.76 (s, 1 H), 7.65 (d, J = 2.3 Hz, 1 H), 7.50 (dd, J = 8.6, 2.2 Hz, 1 H), 7.16 (dd, J = 13.2, 8.5 Hz, 2H), 7.01 (s, 2H), 4.60 (d, J = 85.7 Hz, 4H), 3.86 (s, 3H), 2.94 (dt, J = 13.5, 6.8 Hz, 1 H), 1.93 (s, 1 H), 1.21 (d, J = 6.9 Hz, 6H), 0.98 - 0.88 (m, 2H), 0.65 (d, J = 5.0 Hz, 2H).

[0671] Example EXA53: 5-(dimethylamino)- / V-((5-isopropyl-2- methoxyphenyl)sulfonyl)isoindoline-2-carboxamide (Example EXA53) Scheme SCHEXAS3

[0672]

[0339] To a mixture of / V, / V-dimethylisoindolin-5-amine hydrochloride (Intermediate INTB- 53) (60 mg, 302 pmol) and DI PEA (526 L, 3.02 mmol) in DCM (1 mL) at 0°C was slowly added a solution of 5-isopropyl-2-methoxybenzenesulfonyl isocyanate (Intermediate INTA-2) (131 mg, 513 pmol) in DCM (2 mL). The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was purified by silica gel column chromatography eluted cyclohexane / (ethyl acetate / ethanol) from 100 / 0 to 50 / 50. The resulting product was triturated in acetonitrile, filtered and dried to afford 5- (dimethylamino)- / \ / -((5-isopropyl-2-methoxyphenyl)sulfonyl)isoindoline-2-carboxamide (Example EXA53) (60 mg, 45 % yield) as a white powder.

[0673] LCMS (ES, m / z): 418.2 [M+H]+

[0674] 1 H NMR (400 MHz, DMSO) 5 10.73 (s, 1 H), 7.65 (d, J = 2.4 Hz, 1 H), 7.50 (dd, J = 8.7, 2.4 Hz, 1 H), 7.14 (d, J = 8.7 Hz, 1 H), 7.10 (d, J = 8.6 Hz, 1 H), 6.68 (dd, J = 8.5, 2.4 Hz, 1 H), 6.63 (s, 1 H), 4.56 (d, J = 83.6 Hz, 4H), 3.86 (s, 3H), 2.94 (dt, J = 13.7, 6.9 Hz, 1 H), 2.88 (s, 6H), 1.21 (d, J = 6.9 Hz, 6H).

[0675] Example EXA54: 6-(dimethylamino)-4-fluoro- / V-((5-isopropyl-2- methoxyphenyl)sulfonyl) isoindoline-2-carboxamide (Example EXA54) Scheme SCHEXAM

[0676]

[0340] To a mixture of 7-fluoro- / V, / V-dimethylisoindolin-5-amine hydrochloride (Intermediate INTB-SS) (180 mg, 830 pmol) and DIPEA (1.45 mL, 8.30 mmol) in DCM (1 mL) at 0°C was slowly added a solution of 5-isopropyl-2-methoxybenzenesulfonyl isocyanate (Intermediate INTA-2) (296 mg, 1.16 mmol) in DCM (2 mL). The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was purified by silica gel column chromatography eluted with cyclohexane / (ethyl acetate / ethanol 3:1) from 100 / 0 to 50 / 50. The resulting product was triturated in acetonitrile, filtered and dried to afford 6-(dimethylamino)-4-fluoro- / \ / -((5-isopropyl-2-methoxyphenyl)sulfonyl) isoindoline-2- carboxamide (Example EXA54) (35 mg, 9 % yield) as a white powder.

[0677] LCMS (ES, m / z): 436.1 [M+H]+

[0678] 1 H NMR (400 MHz, DMSO) 5 10.81 (s, 1 H), 7.65 (d, J = 2.4 Hz, 1 H), 7.51 (dd, J = 8.4, 2.4 Hz, 1 H), 7.15 (d, J = 8.7 Hz, 1 H), 6.44 (d, J = 13.2 Hz, 2H), 4.60 (d, J = 86.8 Hz, 4H), 3.86 (s, 3H), 2.95 (q, 6.6 Hz, 1 H), 2.90 (s, 6H), 1.21 (d, J = 6.9 Hz, 6H).

[0679] Example EXA55: A / -((5-(tert-butyl)-2-methoxyphenyl)sulfonyl)-5- (dimethylamino)isoindoline-2-carboxamide (Example EXA55) Scheme SCHEXASS

[0680]

[0341] To a mixture of / V, / V-dimethylisoindolin-5-amine hydrochloride (Intermediate INTB- 53) (100 mg, 503 pmol) and DIPEA (877 pL, 5.03 mmol) in DCM (1 mL) was slowly added a solution of 5-(terf-butyl)-2-methoxybenzenesulfonyl isocyanate (Intermediate INTA-S) (230 mg, 855 pmol) in DCM (2.85 mL). The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was purified by silica gel column chromatography eluted with cyclohexane / ethyl acetate from 100 / 0 to 0 / 100. The resulting product was triturated in acetonitrile, filtered and dried to afford / V-((5-(terf-butyl)-2- methoxyphenyl)sulfonyl)-5-(dimethylamino)isoindoline-2-carboxamide (Example EXA55) (144 mg, 63 % yield) as a white powder.

[0681] LCMS (ES, m / z): 432.2 [M+H]+

[0682] 1 H NMR (400 MHz, DMSO) 5 10.71 (1 H, s), 7.79 - 7.78 (1 H, d, J = 2.4 Hz), 7.58 (1 H, s), 7.11 - 7.09 (2H, d, J = 8.4 Hz), 6.68 - 6.66 (1 H, dd, J = 2.4 Hz, J = 8.8 Hz), 6.64 (1 H, s), 4.61 - 4.46 (4H, d), 3.84 (3H, s), 2.88 (6H, s), 1.29 (9H, s). Example EXAss: 6-cyclopropyl-4-fluoro- / V-((5-isopropyl-2-methoxyphenyl) sulfonyl)isoindoline-2-carboxamide (Example EXAse)

[0683] Scheme SCHEXAS6

[0684]

[0342] To a mixture of 6-cyclopropyl-4-fluoroisoindoline hydrochloride (Intermediate INTB- 54) (105 mg, 491 pmol) and DIPEA (856 pL, 4.91 mmol) in DCM (1 mL) at 0°C was slowly added a solution of 5-isopropyl-2-methoxybenzenesulfonyl isocyanate (Intermediate INTA- 2) (175 mg, 687 pmol) in DCM (2 mL). The reaction mixture was purified by silica gel column chromatography eluted with cyclohexane / (ethyl acetate / ethanol 3:1) from 100 / 0 to 50 / 50. The resulting product was triturated in diethyl ether, filtered and dried to afford 6- cyclopropyl-4-fluoro- / \ / -((5-isopropyl-2-methoxyphenyl) sulfonyl)isoindoline-2-carboxamide (Example EXAss) (15 mg, 6 % yield) as a pale pink powder. LCMS (ES, m / z): 433.1 [M+H]+1 H NMR (400 MHz, DMSO) 5 10.85 (s, 1 H), 7.65 (d, J = 2.4 Hz, 1 H), 7.51 (dd, J = 8.6, 2.3 Hz, 1 H), 7.14 (d, J = 8.7 Hz, 1 H), 6.90 (s, 1 H), 6.84 (d, J - 10.8 Hz, 1 H), 4.65 (d, J = 92.7 Hz, 4H), 3.86 (s, 3H), 2.94 (dt, J = 13.9, 6.9 Hz, 1H), 1.96 (m, 1 H), 1.21 (d, J = 6.9 Hz, 6H), 0.99 - 0.91 (m, 2H), 0.70 (d, J = 5.0 Hz, 2H).

[0685] Example EXA57: 5-(azetidin-1-yl)- / V-((5-isopropyl-2- methoxyphenyl)sulfonyl)isoindoline-2-carboxamide (Example EXA57)

[0686] Scheme SCHEXAS

[0687]

[0343] To a mixture of 5-(azetidin-1-yl)isoindoline (Intermediate INTB-SS) (70 mg, 402 pmol) and DI PEA (700 pL, 4.02 mmol) in DCM (1 mL) at 0°C was slowly added a solution of 5-isopropyl-2-methoxybenzenesulfonyl isocyanate (Intermediate INTA-2) (174 mg, 683 pmol) in DCM (2 mL). The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was purified by silica gel column chromatography eluted with cyclohexane / (ethyl acetate / ethanol 3:1) from 100 / 0 to 50 / 50 to afford 5-(azetidin-1-yl)- / V- ((5-isopropyl-2-methoxyphenyl)sulfonyl)isoindoline-2-carboxamide (Example EXA57) (27 mg, 15 % yield) as an off-white powder.

[0688] LCMS (ES, m / z): 430.2 [M+H]+

[0689] 1 H NMR (400 MHz, DMSO) 5 10.72 (s, 1 H), 7.65 (d, J = 2.4 Hz, 1 H), 7.48 (d, J = 7.3 Hz, 1 H), 7.11 (dd, J = 15.8, 8.2 Hz, 2H), 6.33 (d, J = 7.3 Hz, 2H), 4.52 (d, J = 93.2 Hz, 4H), 3.85 (s, 3H), 3.77 (t, J = 7.2 Hz, 4H), 2.93 (dt, J = 13.6, 6.8 Hz, 1 H), 2.34 - 2.24 (m, 2H), 1.20 (d, J = 6.9 Hz, 6H).

[0690] Example EXAss: 5-(3-fluoroazetidin-1-yl)- / V-((5-isopropyl-2- methoxyphenyl)sulfonyl)isoindoline-2-carboxamide (Example EXAss) Scheme SCH EXASS

[0691]

[0344] To a mixture of 5-(3-fluoroazetidin-1-yl)isoindoline (Intermediate INTB-5?) (75 mg, 390 pmol) and DIPEA (680 pL, 3.90 mmol) in DCM (1 mL) at 0°C was slowly added a solution of 5-isopropyl-2-methoxybenzenesulfonyl isocyanate (Intermediate INTA-2) (169 mg, 663 pmol) in DCM (2 mL). The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was purified by silica gel column chromatography eluted with cyclohexane / (ethyl acetate / ethanol 3:1) from 100 / 0 to 70 / 30. The resulting product was triturated in diethylether, filtered and dried to afford 5-(3-fluoroazetidin-1-yl)- / V-((5- isopropyl-2-methoxyphenyl)sulfonyl)isoindoline-2-carboxamide (Example EXAss) (2.3 mg, 1.3 % yield) as an off-white powder.

[0692] LCMS (ES, m / z): 448.2 [M+H]+1 H NMR (400 MHz, DMSO) 5 10.76 (s, 1 H), 7.64 (d, J = 1.9 Hz, 1 H), 7.45 (s, 1 H), 7.12 (d, J = 8.0 Hz, 2H), 6.42 (s, 2H), 5.48 (d, J = 57.3 Hz, 1 H), 4.52 (m, 4H), 4.13 (m, 2H), 3.96 - 3.79 (m, 5H), 3.00 - 2.82 (m, 1 H), 1.20 (d, J = 6.9 Hz, 6H). Example EXA59: A / -((5-(tert-butyl)-2-methoxyphenyl)sulfonyl)-6-(dimethylamino)-4- fluoroiso indoline-2-carboxamide (Example EXA59) Scheme SCHEXAS9

[0693]

[0345] To a mixture of 7-fluoro- / V, / V-dimethylisoindolin-5-amine (Intermediate INTB-SS) (109 mg, 604 pmol) and DIPEA (1.05 mL, 6.05 mmol) in DCM (1 mL) at 0°C was slowly added a solution of 5-(terf-butyl)-2-methoxybenzenesulfonyl isocyanate (Intermediate INTA^S) (276 mg, 1.02 mmol) in DCM (2 mL). The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was purified by silica gel column chromatography eluted with cyclohexane / (ethyl acetate / ethanol 3:1) from 100 / 0 to 50 / 50 to afford / V-((5-(terf-butyl)-2-methoxyphenyl)sulfonyl)-6-(dimethylamino)-4-fluoroiso indoline-2-carboxamide (Example EXA59) (16 mg, 4 5 % yield) as pink powder. LCMS (ES, m / z): 450.2 [M+H]+

[0694] 1 H NMR (400 MHz, DMSO) 5 10.80 (s, 1 H), 7.78 (d, J = 2.6 Hz, 1 H), 7.60 (s, 1 H), 7.11 (d, J = 8.7 Hz, 1 H), 6.47 (s, 1 H), 6.44 (d, J = 13.2 Hz, 1 H), 4.58 (d, J = 68.9 Hz, 4H), 3.84 (s, 3H), 2.90 (s, 6H), 1.29 (s, 9H).

[0695] Example EXAss: 8-chloro-A / -((7-methoxyquinolin-8-yl)sulfonyl)-5-(1 H-pyrazol-1 -yl)- 3,4-dihydroisoquinoline-2(1 H)-carboxamide (Example EXASs) Scheme SCHEXA63

[0696]

[0346] To a mixture of tert-butyl ((7-methoxyquinolin-8-yl)sulfonyl)carbamate (Intermediate INTA-21) (200 mg, 531 pmol) and triethylamine (267 pL, 1.59 mmol) in dioxane (3 mL) at room temperature was added 8-chloro-5-(1 H-pyrazol-1-yl)- 1,2,3,4-tetrahydroisoquinoline hydrochloride (Intermediate INTB-IS) (186 mg, 691 pmol). The reaction mixture was stirred at 110°C for 16 h. The reaction mixture was directly absorbed with a Celite pad and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography eluted with dichloromethane / acetone from 90 / 10 to 0 / 100 to afford 8-chloro- / V-((7-methoxyquinolin-8- yl)sulfonyl)-5-(1 H-pyrazol-1-yl)-3,4-dihydroisoquinoline-2(1 H)-carboxamide (Example EXA63) (6 mg, 2.2 % yield) as a yellow solid. LCMS (ES, m / z): 498.2 [M+H]+

[0697] 1H NMR (400 MHz, DM SO) 58.88 (m, 1 H), 8.44 (m, 1H), 8.18 (m, 1 H), 7.92 - 7.73 (m, 1H), 7.68 (m, 1H), 7.61 - 7.45 (m, 1H), 7.43 - 7.34 (m, 2H), 7.25 (m, 1 H), 6.51 - 6.38 (m, 1 H), 4.65 (s, 2H), 4.10 -3.98 (m, 3H), 3.56 (t, J = 5.6 Hz, 2H), 2.57 - 2.52 (m, 2H) (Rotamers). NH not visible.

[0698] Example EXA70: 8-chloro-A / -((2,6-dimethoxyphenyl)sulfonyl)-5-(thiazol-2-yl)-3,4- dihydro isoquinoline-2(1H)-carboxamide (Example EXA70)

[0699] Scheme SCHEXA O

[0700]

[0347] To a mixture of 2-(8-chloro-1,2,3,4-tetrahydroisoquinolin-5-yl)thiazole hydrochloride (Intermediate INTB-SS) (190 mg, 662 pmol) and DIPEA (1.15 mL, 6.62 mmol) in dichloromethane (2 mL) at room temperature was added dropwise a solution of 2,6-dimethoxybenzenesulfonyl isocyanate (Intermediate INTA-I) (257 mg, 1.06 mmol). The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was directly absorbed with a Celite pad and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography eluted with cyclohexane / acetone from 100 / 0 to 50 / 50 to afford 8-chloro- / V-((2,6- dimethoxyphenyl)sulfonyl)-5-(thiazol-2-yl)-3,4-dihydroisoquinoline-2(1 H)-carboxamide (Example EXA70) (54 mg, 16 % yield) as a white solid.

[0701] LCMS (ES, m / z): 494.1 [M+H]+1H NMR (400 MHz, CDCI3) 5 8.10 (s, NH), 7.94 (d, J = 3.3 Hz, 1H), 7.54 (d, J = 8.3 Hz, 1H), 7.50 - 7.43 (m, 2H), 7.35 (d, J = 8.3 Hz, 1H), 6.68 (d, J = 8.5 Hz, 2H), 4.67 (s, 2H), 3.98 (s, 6H), 3.64 (t, J = 5.9 Hz, 2H), 3.19 (t, J = 5.8 Hz, 2H).

[0702] Example EXA71 : 8-cyclopropyl-A / -((2,6-dimethoxyphenyl)sulfonyl)-5-(thiazol-2-yl)-3,4- dihydro isoquinoline-2(1H)-carboxamide (Example EXA71)

[0703] Scheme SCHEXA I

[0348] To a mixture of 2-(8-cyclopropyl-1 ,2,3,4-tetrahydroisoquinolin-5-yl)thiazole hydrochloride (Intermediate INTB-6O) (190 mg, 577 pmol) and DIPEA (1.01 mL, 5.77 mmol) in dichloromethane (2 mL) at room temperature was added dropwise a solution of 2,6-dimethoxybenzenesulfonyl isocyanate (Intermediate INTA-I) (225 mg, 923 pmol). The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was directly absorbed with a Celite pad and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography eluted with cyclohexane / acetone from 100 / 0 to 50 / 50. The resulting product was triturated with acetonitrile, filtered and dried to afford 8-cyclopropyl- / V-((2,6-dimethoxyphenyl)sulfonyl)-5- (thiazol-2-yl)-3,4-dihydro isoquinoline-2(1H)-carboxamide (Example EXA71) (18 mg, 5.9 % yield) as a white solid. LCMS (ES, m / z): 500.2 [M+H]+

[0704] 1H NMR (400 MHz, DMSO) 5 10.75 (s, 1 H), 7.97 (d, J = 3.3 Hz, 1 H), 7.84 (d, J = 3.3 Hz, 1H), 7.56 - 7.43 (m, 2H), 7.02 (d, J = 8.1 Hz, 1 H), 6.77 (d, J = 8.5 Hz, 2H), 4.75 (s, 2H), 3.78 (s, 6H), 3.62 (m, 2H), 3.05 (m, 2H), 1.94 (s, 1H), 1.08 - 0.93 (m, 2H), 0.69 (d, J = 5.2 Hz, 2H).

[0705] Example EXA72: 8-cyclopropyl-N-((2,3-dihydrobenzofuran-7-yl) sulfonyl)-5-(1H- pyrazol-1 -yl)-3,4-dihydroisoquinoline-2(1 H)-carboxamide (Example EXA72)

[0706] Scheme SCHEXA72

[0707]

[0349] To a mixture of 8-cyclopropyl-5-(1H-pyrazol-1-yl)-1,2,3,4-tetrahydroisoquinoline hydrochloride (Intermediate INTB-S) (100 mg, 363 pmol) and DIPEA (632 pL, 3.63 mmol) in DCM (2 mL) at room temperature was added dropwise a solution of 2,3- dihydrobenzofuran-7-sulfonyl isocyanate (Intermediate INTA-20) (139 mg, 616 pmol). The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was directly absorbed with a Celite pad and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography eluted with cyclohexane / acetone from 100 / 0 to 50 / 50 to afford 8-cyclopropyl-N-((2,3- dihydrobenzofuran-7-yl)sulfonyl)-5-(1H-pyrazol-1-yl)-3,4-dihydroisoquinoline-2(1 H)- carboxamide (Example EXA72) (11 mg, 6 % yield) as a white solid.

[0708] LCMS (ES, m / z): 465.4 [M+H]+

[0709] 1H NMR (400 MHz, DMSO) 57.93 (s, 1 H), 7.69 (d, J = 1.5 Hz, 1H), 7.46 (d, J = 7.9 Hz, 1H), 7.28 (s, 1H), 7.12 (d, J = 8.1 Hz, 1 H), 6.99 (d, J = 7.6 Hz, 1H), 6.82 (s, 1 H), 6.47 (t, J = 2.1 Hz, 1H), 4.71 (s, 2H), 4.55 (s, 2H), 3.52 (s, 2H), 3.17 (t, J = 8.2 Hz, 2H), 2.48 (s, 2H), 1.87 (s, 1 H), 0.97 (m, 2H), 0.66 (m, 2H). NH not visible.

[0710]

[0350] 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.

[0711]

[0351] 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.

[0712] Methods for obtaining single enantiomers or diastereomers are well-known to those skilled in the art.

[0713]

[0352] 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.

[0714] IL Biological Examples

[0715] Abbreviations:

[0716]

[0353] Acetyl coenzyme A : AcetylCoA or AC-Coa Bovine serum albumin : BSA Dithiothreitol : DTT

[0717] Ethylenediaminetetraacetic acid : EDTA Trizma Hydrochloride : Tris-HCL

[0718] KAT6A, KAT7 - Enzyme Activity Assay (AlphaScreen Method) Materials and Instruments

[0719]

[0354] Active KAT6A / M0Z protein: Active motif # 81223 > lot. 2122003

[0720] Active KAT7: Active motif # 31489_ lot. 24321003

[0721] H4 peptide: Upstate Biotechnology # 12-405 lot 3743857 - 100 pg

[0722] AcetylCoA: Sigma # A2056 lot 0000303137 - 5 mg

[0723] Anti-Histone H4 (acetyl K8) antibody:

[0724] Cell Signaling # 2594S lot 11 (a-H4AcK8-1) 73 pg / mL

[0725] Abeam # ab15823 lot 1029174-1 (a-H4AcK8-2) 0.9 mg / mL

[0726] Trizma Hydrochloride solution pH8 (Sigma # T3038 lot SLBL2857V) 100 mM

[0727] NaCI (Sigma # S5150 lot SLBH4802V) 15 mM

[0728] EDTA (Sigma # E7889 lot SLBD5434V) 1 mM

[0729] Tween-20 (Sigma # P7949 lot SZBC2920V ) 0.01%

[0730] BSA (Jackson v 001-000-173) 0.02% (= 0.2 mg / mL)

[0731] DTT (Sigma # 43816) 1mM

[0732] 384-well plate: AlphaPlate (PerkinElmer # 6005350)

[0733] TopSeal-A PLUS (PerkinElmer # 6050185)

[0734] AlphaLISA beads :

[0735] Protein A acceptor (PerkinElmer # AL101 C lot 3178960)

[0736] Streptavidin donor beads (PerkinElmer # 6760002S lot 3082282)

[0737] Assay preparation:

[0738]

[0355] 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.

[0739]

[0356] Compounds Solutions: Compounds solutions 3x were prepared in the assay buffer with DTT from solution comprising different concentrations of compounds in DMSO.

[0740]

[0357] 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.

[0741]

[0358] 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.

[0742]

[0359] 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.

[0360] 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.

[0743] Assay Procedure

[0744]

[0361] 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.

[0745]

[0362] 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.

[0746]

[0363] 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.

[0747] Cellular Assay ZR75-1 H3K23ac

[0748] Materials and reagents:

[0749]

[0364] Cell line: ZR-75-1 (Human breast ductal carcinoma, ECACC #87012601) Cell line passage number: P'13

[0750] 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

[0751] Plates: 96-well Nunc™ Edge™ Nunclon Delta surface plates (ThermoFisher #167425)

[0752] Histone H3 Monoclonal Antibody (6D3B9), ThermoFisher # MA5-31759 lot XG3638535

[0753] Acetyl- Histone H3 (Lys23) (D6Y7M) rabbit mAb, Cell Signaling # 14932

[0754] Gio Substrate Reagent Pack DY993: R&D Systems lot P392320

[0755] HRP secondary antibodies Jackson Immuno Research Laboratories HRP DONKEY IGG ANTI RABBIT IGG (H+(lnterchim # 711-035-152) Envision luminometer in luminescent reading mode

[0756] Cell Seeding

[0757]

[0365] 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.

[0758] Compound Treatment

[0759]

[0366] 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, b...

Claims

CLAIMS1. A compound of general formula (III)or a pharmaceutically acceptable salt thereof, wherein:A represents an aryl group, such as a phenyl group or a benzo fused cycloalkyl group, or a heteroaryl group, such as 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 C1-C4 alkoxy groups; alkyl groups, such as C1-C4 alkyl groups, 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); 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; phenyl groups, optionally substituted by one or more alkyl groups and / or halogens; and 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;and wherein:R6, R7, R8, and R9each independently represent H; or an alkyl group; n and m each independently represent 0 or 1 ;R10and R13each independently represent H; a halogen; an alkoxy group; a 4- to 6-member heterocycloalkyl group or a 5- or 6-member heteroaryl group, optionally substituted by one or more alkyl groups and / or halogens; a cycloalkyl group, optionally substituted by one or more alkyl groups and / or halogens; or an alkyl group, optionally substituted by 1 to 3 fluorine atoms; andR11and R12each independently represent H; a halogen; a dialkylamino group, such as a dimethylamino group (-N(CH3)2); a cycloalkyl group, optionally substituted by one or more alkyl groups and / or halogens; a 4- to 6-member heterocycloalkyl group, optionally substituted by one or more alkyl groups and / or halogens, such as azetidine, optionally substituted by one or more alkyl groups and / or halogens; or a 4- to 6-member heteroaryl group, optionally substituted by one or more alkyl groups and / or halogens, which is directly bonded to the aryl via a covalent bond or linked through a spacer such as an alkyl chain; such as pyrazole or oxazole, optionally substituted by one or more alkyl groups and / or halogens.

2. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein:A represents an aryl group, such as a phenyl group or a benzo-fused cycloalkyl group, or a heteroaryl group, such as a benzo-fused heterocyclic group; substituted by one or more alkoxy groups, such as a C1-C4 alkoxy group, and / or alkyl groups, such as a C1-C4 alkyl group, optionally substituted by 1 to 3 fluorine atoms; wherein A is optionally 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; unsubstituted or substituted amino groups, such as dialkylamino groups, such as a dimethylamino group (-N(CH3)2);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; phenyl groups, optionally substituted by one or more alkyl groups and / or halogens; and 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.

3. The compound according to any one of claim 1 or 2, wherein the compound is of formula (Illa):or a pharmaceutically acceptable salt thereof, wherein A, R10, R11, R12and R13are according to claim 1.

4. The compound according to any one of claim 1 or 2, wherein the compound is of formula (I I lb):or a pharmaceutically acceptable salt thereof, wherein A, R6, R7, R8, R9, R10, R11and R12are according to claim 1.

5. The compound according to any one of claim 1 or 2, wherein the compound is of formula (I I Ic):or a pharmaceutically acceptable salt thereof, wherein A, R6, R7, R8, R9, R11, R12and R13are according to claim 1.

6. The compound according to any one of claim 1 or 2, wherein the compound is of formula (Hid):or a pharmaceutically acceptable salt thereof, wherein A, R10, R11, and R12are according to claim 1.

7. The compound according to any one of claim 1 or 2, wherein the compound is of formula (Hie):or a pharmaceutically acceptable salt thereof, wherein:Z represents a halogenA, R11, R12and R13are according to claim 1.

8. The compound according to any one of claim 1 or 2, wherein the compound is of formula (lllf-1):or a pharmaceutically acceptable salt thereof, wherein:A, R11and R12are according to claim 1.

9. The compound according to any one of claim 1 or 2, wherein the compound is of formula (Illg):or a pharmaceutically acceptable salt thereof, wherein R21represents an alkyl group and wherein A, R11and R12are according to claim 1.

10. The compound according to any one of claim 1 or 2, wherein the compound is of formula (lllg-1):or a pharmaceutically acceptable salt thereof, wherein A, R11and R12are according to claim 1.

11. The compound according to any one of claim 1 or 2, wherein the compound is of formula (I I Ih):or a pharmaceutically acceptable salt thereof, wherein R22represents an alkyl group or a hydrogen atom or a halogen; and wherein A, R10, R12and R13are according to claim 1.

12. The compound according to any one of claim 1 or 2, wherein the compound is of formula (Illi):or a pharmaceutically acceptable salt thereof, wherein A, R11and R12are according to claim 1.

13. The compound according to any one of claim 1 or 2, wherein the compound is of formula (lllj):or a pharmaceutically acceptable salt thereof, wherein A, R11and R12are according to claim 1.

14. The compound according to any one of claim 1 or 2, wherein the compound is of formula (I I Ik):or a pharmaceutically acceptable salt thereof, wherein A, R11and R12are according to claim 1.

15. The compound according to any one of claim 1 or 2, wherein the compound is of formula (lllf):or a pharmaceutically acceptable salt thereof, wherein Z represents a halogen; an alkyl group optionally substituted by 1 to 3 fluorine atoms; an alkoxy group; or a cycloalkyl group optionally substituted by one or more alkyl groups and / or halogens.

16. The compound according to any one of claim 1 or 2, 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 heterocyclyl group, preferably 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 5- or 6-member heterocycloalkyl group or an heteroaromatic ring or a 5- or 6-member cycloalkyl 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 heterocyclyl group, preferably 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);R6, R7, R8, and R9each independently represent H; or an alkyl group; n and m each independently represent 0 or 1 ;R10and R13each independently represent H; a halogen; an alkoxy group; a 4- to 6-member heterocycloalkyl group or a 5- or 6-member heteroaryl group, optionally substituted by one or more alkyl groups and / or halogens; a cycloalkyl group, optionally substituted by one or more alkyl groups and / or halogens; an alkyl group, optionally substituted by 1 to 3 fluorine atoms; andR11and R12each independently represent H; a halogen; a dialkylamino group, such as a dimethylamino group (-N(CH3)2); a cycloalkyl group, optionally substituted by one or more alkyl groups and / or halogens; a 4- to 6-member heterocycloalkyl group, optionally substituted by one or more alkyl groups and / or halogens, such as azetidine, optionally substituted by one or more alkyl groups and / or halogens; or a 4- to 6-member heteroaryl group, optionally substituted by one or more alkyl groups and / or halogens, which is directly bonded to the aryl via a covalent bond or linked through a spacer such as an alkyl chain; such as pyrazole or oxazole, optionally substituted by one or more alkyl groups and / or halogens.

17. A compound of general formula (III) or a pharmaceutically acceptable salt thereof according to claim 1, which is selected from:

18. A compound of general formula (III) or a pharmaceutically acceptable salt thereof according to claim 1, which is selected from:

19. A pharmaceutical composition comprising a compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

20. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 18, or the pharmaceutical composition according to claim 19, for use in the treatment or prophylaxis of a disease, preferably wherein the disease is a hyperproliferative disorder.

21. The compound, the pharmaceutically acceptable salt or the pharmaceutical composition for use according to claim 20, wherein it is for use in combination with a selective estrogen receptor degrader (SERD) inhibitor; an immune checkpoint inhibitor targeting PD1, PDL1 , or CTLA4; a cyclin-dependent kinase (CDK) inhibitor; and / or a menin inhibitor22. 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 18, or a pharmaceutically acceptable composition according to claim 19.

23. A method for treating or prophylaxis of a disease according to claim 22, wherein it further comprises administering to the patient in need thereof a Selective Estrogen Receptor Degrader (SERD) inhibitor; an immune checkpoint inhibitor targeting PD1, PDL1 , or CTLA4; a Cyclin-Dependent Kinase (CDK) inhibitor; and / or a menin inhibitor.

Images