Smarca2 and smarca4 inhibitors for the treatment of diseases

Abstract

The present invention discloses compounds according to Formula (I) wherein A, B, X, Y, L1, L2, R1, R2, R3, R4a, R4b, R5, R6, and n are as defined herein. The present invention relates to compounds, methods for their production, pharmaceutical compositions comprising the same, and methods of treatment using the same, for the prophylaxis and / or treatment of proliferative diseases by administering a compound of the invention.

Description

SMARCA2 AND SMARCA4 INHIBITORS FOR THE TREATMENT OF DISEASESFIELD OF THE INVENTION

[0001] The present invention relates to compounds, methods for the production of the compounds of the invention, pharmaceutical compositions comprising the compounds of the invention, uses and methods for the prophylaxis and / or treatment of proliferative diseases by administering the compounds of the invention. In particular, the compounds of the invention may inhibit SMARCA2 and / or SMARCA4.BACKGROUND OF THE INVENTION

[0002] The mammalian SWItch / Sucrose Non-Fermentable (SWI / SNF) complexes are large, ATP dependent chromatin remodelers with vital roles in various cellular processes, including transcription, DNA repair, and replication, achieved by regulating DNA accessibility.

[0003] Approximately 20% of all human cancers exhibit mutations in the genes encoding the nearly 20 canonical SWI / SNF subunits (Kadoch et al. 2013). These mutations are most frequently found in rhabdoid tumors, female-specific cancers (such as ovarian, uterine, cervical, and endometrial cancers), lung adenocarcinoma, gastric adenocarcinoma, melanoma, esophageal cancer, and renal clear cell carcinoma.

[0004] Within these SWI / SNF complexes, SWI / SNF-related, Matrix-associated, Actin-dependent Regulator of Chromatin, subfamily A member 2 (SMARCA2, Brahma, or BRM) and SWI / SNF-related, Matrix-associated, Actin-dependent Regulator of Chromatin, subfamily A, member 4 (SMARCA4 or BRG1) stand out as subunits that contain catalytic ATPase domains, essential for the SWI / SNF complex function. They perturb histone-DNA contacts, thereby providing access points for transcription factors and DNA elements that regulate gene activation and repression.

[0005] SMARCA2 and SMARCA4 share a high degree of similarity, up to 75%, and both contain a DNA-stimulated, conserved ATPase domain driving chromatin-remodeling activity. In primary tumors, SMARCA4 is frequently mutated, particularly in lung, melanoma, liver, and pancreatic cancers. In SMARCA4-deleted cancer cells, SMARCA2's ATPase activity becomes critical for chromatin remodeling, which is essential for functions like cell proliferation, survival, and growth. Consequently, targeting SMARCA2 may hold promise as a therapeutic approach for SMARCA4-deleted or deficient cancers, e.g. non-small cell lung carcinoma, Burkitt lymphoma, childhood medulloblastoma, pancreatic adenocarcinoma, ovarian clear cell carcinoma, and melanoma (Wilson et al. 2014). Conversely, inhibition of SMARCA4 represents a therapeutic strategy for the treatment of SMARCA2-deficient cancers (Ehrenhöfer-Wölfer et al. 2019).

[0006] Hence, there is a need for therapeutic compounds that can inhibit SMARCA2 and / or SMARCA4 for the prophylaxis and / or treatment of the above mentioned diseases.SUMMARY OF THE INVENTION

[0007] The present invention is based on the identification of novel compounds, and their use in the prophylaxis and / or treatment of proliferative diseases. In particular, the compounds of the invention may be ATPase inhibitors, and more particularly SMARCA2 and / or SMARCA4 inhibitors. The present invention also provides methods for the production of these compounds, pharmaceutical compositions comprising these compounds and methods for the prophylaxis and / or treatment of proliferative diseases by administering the compounds of the invention.

[0008] Accordingly, in a first aspect of the invention, the compounds of the invention are provided having a Formula I:Iwherein,A is 6-10 membered monocyclic or bicyclic aryl, or 5-10 membered monocyclic or bicyclic heteroaryl comprising one, two or three heteroatoms independently selected from N, O, and S;R\ N.O,,0 N.0RzV's's / Y is independently selected from' ', ' ' and ' ';Ryand Rzare each independently hydrogen or C1.3 alkyl;X is N or CH;R1is Ci-6 alkyl, C1.3 alkoxy(Ci.3)alkyl, -N(CI-3 alkyl)2or hydroxy(Ci.4)alkyl, wherein said alkyl and alkoxy groups are optionally substituted with one or more halogen;n is 0, 1, or 2;each R2is independently selected from halogen and C1-6alkyl, which alkyl is optionally substituted with halo or C1-4alkoxy;or R1and one R2together with the atoms onto which they are attached form a fused 5-8 membered monocyclic cycloalkyl, or a fused 5-8 membered monocyclic heterocycloalkyl- comprising Y in formula I and zero, one, or two additional heteroatoms independently selected from N, O, and S, wherein the cycloalkyl or heterocycloalkyl is optionally substituted with one or more independently selected halogens (preferably fluoro) or C1-4 alkyl;R3is hydrogen or C1-6 alkyl;R4aand R4bare each independently hydrogen or C1-6 alkyl optionally substituted with one or more independently selected halo or C1.4 alkoxy;or R4aand R4b, together with the carbon to which they are attached, form a C3-6 cycloalkyl or 4-6 membered heterocycloalkyl comprising one or two heteroatoms independently selected from N, O, and S, which cycloalkyl or heterocycloalkyl is optionally substituted with one or more halo or C1-4 alkoxy;Li is a bond, Ce-io aryl, or 5-6 membered monocyclic heteroaryl comprising one, two or three heteroatoms independently selected from N, O, and S, which aryl or heteroaryl is optionally substituted with one or more independently selected halo, C1.4 alkyl, C1.4 haloalkyl, -NH2, -NH(CI-4 alkyl), or -N(CI-4 alkyl)2, morpholine, -CH=CHCO2R9a, C1.4 alkoxy, C1.4 haloalkoxy or oxetane;B is Ce-io aryl, 5-10 membered monocyclic or bicyclic heteroaryl comprising one, two, three or four heteroatoms independently selected from N, O, and S, or a 5-10 membered monocyclic or bicyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S, each of which is optionally substituted with one or more independently selected R7;L2is a bond or C1-6 alkyl, which alkyl is optionally substituted with one or more halo, -OH, -CN, or C1-4 alkoxy;R5is independently selected from- hydrogen,- oxo,- -OH,- -CN,- -P(O)(C1-4alkyl)2,- halo,- -S(=O)2-Ci.4 alkyl,- -NR8aR8b,- -CH=CHCO2R9a,- -S(=O)2NHC(O)C1-2alkyl,- -S(=O)2NH2,- -C(O)NHS(=O)2C1-2alkyl,- -CONR9aR9b,- -CO2R9a,- C1-4 alkyl optionally substituted with one or more independently selected halo, -OH, -CN, -CO2R9aor C1.4 alkoxy,- C1-4 alkoxy optionally substituted with one or more independently selected halo, -OH, -CN, -CO2R9a, C1.4 alkoxy, or C3-6 cycloalkyl,- C3-6 cycloalkyl, which cycloalkyl is optionally substituted with one or more independently selected oxo, halo, -OH, -CN, C1-4 alkyl, or C1-4 alkoxy,- 4-8 membered monocyclic or spirocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is optionally substituted with one or more independently selected oxo, halo, -OH, -CN, C1-4 alkyl, C1-4 alkoxy, -S(=O)2Ci-4 alkyl, - C(=O)Ci.4 alkyl, or -CO2R9a,- -Si(Ci-4 alkyl)3, and- Q1;R6is hydrogen, halo, or Ci-6 alkyl;each R7is independently selected from- oxo,- -OH,- -CN,- -P(O)(C1-4alkyl)2,- halo,- -S(=O)2-Ci.4 alkyl,- -NR8aR8b,- -CH=CHCO2R9a,- -S(=O)2NHC(O)CI-2alkyl,- -S(=O)2NH2,- -C(O)NHS(=O)2C1-2alkyl,- -CONR9aR9b,- -CO2R9a,- Ci-4 alkyl optionally substituted with one or more independently selected halo, -OH, -CN, -CO2R9aor Ci -4 alkoxy,- Ci-4 alkoxy optionally substituted with one or more independently selected halo, -OH, -CN, or Ci-4 alkoxy,- C3-6 cycloalkyl, which cycloalkyl is optionally substituted with one or more independently selected oxo, halo, -OH, -CN, C1-4 alkyl, or C1-4 alkoxy, and- 4-8 membered monocyclic or spirocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is optionally substituted with one or more independently selected oxo, halo, -OH, -CN, C1-4 alkyl, or C1-4 alkoxy, and- Q2;Q1is selected from phenyl and 5-10 membered monocyclic or bicyclic heteroaryl comprising one, two, or three heteroatoms independently selected from N, O, and S, which phenyl and heteroaryl is optionally substituted with one or more R10a;Q2is selected from phenyl and 5-10 membered monocyclic or bicyclic heteroaryl comprising one, two, or three heteroatoms independently selected from N, O, and S, which phenyl and heteroaryl is optionally substituted with one or more R10b;each R8ais independently hydrogen or C1-4 alkyl;each R8bis independently hydrogen, C1.4 alkyl or -C(O)Ci.2alkyl;each R9ais independently selected from hydrogen and C1.4 alkyl;R9bis hydrogen, C1.4 alkyl or C1.4 alkoxy, or R9aand R9btogether with the atoms onto which they are attached form a 4-7 membered monocyclic heterocycloalkyl comprising one, two or three heteroatomsindependently selected from N, O, and S, which heterocycloalkyl is optionally substituted with one or more independently selected oxo, halo, OH, CN, C1-4 alkyl;R10aand R10bare each independently selected from halo, OH, -NR11aR11b, CN, C1-4 alkyl, C1-4 haloalkyl, Ci-4alkoxy, C1.4 alkoxy (Ci.4)alkyl, C1.4 hydroxyalkyl, -CONR12aR12b, -CO2R12a, and -L3-Q3;-L3- is a bond, -O-, or C1.4 alkylene;Q3is selected from C3-6 cycloalkyl, 4-8 membered monocyclic heterocycloalkyl comprising one, two, or three heteroatoms independently selected from N, O, and S, 6-10 membered bicyclic fused, bridged, or spiro heterocycloalkyl comprising one, two, or three heteroatoms independently selected from N, O, and S, which cycloalkyl or heterocycloalkyl is optionally substituted with one or more independently selected oxo, halo, -OH, -CN, C1-4 alkyl, or C1-4 alkoxy;each R11ais independently hydrogen or C1-4 alkyl;each R11bis independently hydrogen, C1-4 alkyl or -C(O)C1-2alkyl;each R12ais independently selected from hydrogen and C1-4 alkyl; andR12bis hydrogen, C1-4 alkyl or C 1-4 alkoxy, or R12aand R12btogether with the atoms onto which they are attached form a 4-7 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is optionally substituted with one or more independently selected oxo, halo, OH, CN, C1-4 alkyl;or a pharmaceutically acceptable salt and / or solvate thereof.

[0009] Accordingly, in a further aspect, the invention concerns a compound according to Formula (I):R5wherein,A is 6-10 membered monocyclic or bicyclic aryl, or 5-10 membered monocyclic or bicyclic heteroaryl comprising one, two or three heteroatoms independently selected from N, O, and S;Ry0.,o N O* / / \\ / / Y is independently selected from' ', ' ' andRyand Rzare each independently hydrogen or C1-3 alkyl;X is N or CH;R1is C1-6alkyl, C1-3alkoxy(C1-3)alkyl, -N(C1-3alkyl)2or hydroxy(C1-4)alkyl, wherein said alkyl and alkoxy groups are optionally substituted with one or more halogen;n is 0, 1, or 2;each R2is independently selected from halogen and C1-6 alkyl, which alkyl is optionally substituted with halo, OH, or C1-4 alkoxy;or R1and one R2together with the atoms onto which they are attached form a fused 5-8 membered monocyclic cycloalkyl, or a fused 5-8 membered monocyclic heterocycloalkyl comprising Y in formula I and zero, one, or two additional heteroatoms independently selected from N, O, and S, wherein the cycloalkyl or heterocycloalkyl is optionally substituted with one or more independently selected halogens (preferably fluoro) or C1.4 alkyl;R3is hydrogen or C1-6alkyl;R4aand R4bare each independently hydrogen or Ci-e alkyl optionally substituted with one or more independently selected halo or C1-4 alkoxy;or R4aand R4b, together with the carbon to which they are attached, form a C3-6 cycloalkyl or 4-6 membered heterocycloalkyl comprising one or two heteroatoms independently selected from N, O, and S, which cycloalkyl or heterocycloalkyl is optionally substituted with one or more halo or C1-4 alkoxy;Li is a bond, Ce-io aryl, or 5-6 membered monocyclic heteroaryl comprising one, two or three heteroatoms independently selected from N, O, and S, which aryl or heteroaryl is optionally substituted with one or more independently selected halo, C1-4 alkyl, C1-4 haloalkyl, -NH2, -NH(CI-4 alkyl), or -N(CI-4 alkyl)2, morpholine, -CH=CHCO2R9a, C1-4 alkoxy, C1-4 haloalkoxy or oxetane;B is Ce-io aryl, 5-10 membered monocyclic or bicyclic heteroaryl comprising one, two, three or four heteroatoms independently selected from N, O, and S, or a 5-10 membered monocyclic or bicyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S, each of which is optionally substituted with one or more independently selected R7;L2 is a bond, Ci-e alkyl or C3-6 cycloalkyl, which alkyl or cycloalkyl is optionally substituted with one or more halo, -OH, -CN, or C1-4 alkoxy;R5is independently selected from- hydrogen,- oxo,- -OH,- -CN,- -P(O)(C1-4alkyl)2,- halo,- -S(=O)2-Ci.4 alkyl,- -NR8aR8b,- -CH=CHCO2R9a,- -S(=O)2NHC(O)C1-2alkyl,- -S(=O)2NH2,- -C(O)NHS(=O)2C1-2alkyl,- -CONR9aR9b,- -CO2R9a,- C1.4 alkyl optionally substituted with one or more independently selected halo, -OH, -CN, -CO2R9a, Ci -4 alkyl, or C1-4 alkoxy,- Ci-4 alkoxy optionally substituted with one or more independently selected halo, -OH, -CN, -CO2R9a, Ci -4 alkoxy, or C3-6 cycloalkyl,- C3-6 cycloalkyl, which cycloalkyl is optionally substituted with one or more independently selected oxo, halo, -OH, -CN, C1-4 alkyl, or C1-4 alkoxy,- 4-8 membered monocyclic or spirocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is optionally substituted with one or more independently selected oxo, halo, -OH, -CN, C1-4 alkyl, C1-4 alkoxy, -S(=O)2Ci-4 alkyl, - C(=O)Ci-4alkyl, or -CO2R9a,- -Si(Ci-4alkyl)3, and- Q1;R6is hydrogen, halo, or C1-6 alkyl;each R7is independently selected from- oxo,- -OH,- -CN,- -P(O)(C1-4alkyl)2,- halo,- -S(=O)2-Ci-4alkyl,- -NR8aR8b,- -CH=CHCO2R9a,- -S(=O)2NHC(O)CI-2alkyl,- -S(=O)2NH2,- -C(O)NHS(=O)2C1-2alkyl,- -CONR9aR9b,- -CO2R9a,- C1-4 alkyl optionally substituted with one or more independently selected halo, -OH, -CN, -CO2R9aor Ci -4 alkoxy,- C1-4 alkoxy optionally substituted with one or more independently selected halo, -OH, -CN, or C1-4 alkoxy,- C3-6 cycloalkyl, which cycloalkyl is optionally substituted with one or more independently selected oxo, halo, -OH, -CN, C1-4 alkyl, C1-4 alkoxy, or C1-4 alkyl, optionally substituted with OH;- 4-8 membered monocyclic or spirocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is optionally substituted with one or more independently selected oxo, halo, -OH, -CN, C1-4 alkyl, C1-4 alkoxy, or C1-4 alkyl, optionally substituted with OH; and- Q2;Q1is selected from phenyl and 5-12 membered monocyclic or bicyclic heteroaryl comprising one, two, or three heteroatoms independently selected from N, O, and S, which phenyl and heteroaryl is optionally substituted with one or more R10a;Q2is selected from phenyl and 5-10 membered monocyclic or bicyclic heteroaryl comprising one, two, or three heteroatoms independently selected from N, O, and S, which phenyl and heteroaryl is optionally substituted with one or more R10b;each R8ais independently hydrogen or C1.4 alkyl;each R8bis independently hydrogen, C1-4 alkyl or -C(O)Ci-2 alkyl;each R9ais independently selected from hydrogen and C1-4 alkyl;R9bis hydrogen, C1-4 alkyl or C1-4 alkoxy, or R9aand R9btogether with the atoms onto which they are attached form a 4-7 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is optionally substituted with one or more independently selected oxo, halo, -OH, -CN, C1-4 alkyl;R10aand R10bare each independently selected from halo, -OH, -NR11aR11b, -CN, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 alkoxy (Ci-4)alkyl, C1-4 hydroxyalkyl, -CONR12aR12b, -CO2R12a, -L3-Q3, and C1-4 alkoxy, optionally substituted by OH;-L3- is a bond, -O-, or C1-4 alkylene;Q3is selected from C3-6 cycloalkyl, 4-8 membered monocyclic heterocycloalkyl comprising one, two, or three heteroatoms independently selected from N, O, and S, 6-10 membered bicyclic fused, bridged, or spiro heterocycloalkyl comprising one, two, or three heteroatoms independently selected from N, O, and S, which cycloalkyl or heterocycloalkyl is optionally substituted with one or more independently selected oxo, halo, -OH, -CN, C1.4 alkyl, or C1.4 alkoxy;each R11ais independently hydrogen or C1-4 alkyl;each R11bis independently hydrogen, C1-4 alkyl or -C(O)C1-2 alkyl;each R12ais independently selected from hydrogen and C1.4 alkyl; andR12bis hydrogen, C1-4 alkyl or C 1-4 alkoxy, or R12aand R12btogether with the atoms onto which they are attached form a 4-7 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is optionally substituted with one or more independently selected oxo, halo, -OH, -CN, C1-4 alkyl;or a pharmaceutically acceptable salt and / or solvate thereof.

[0010] In a particular aspect, the compounds of the invention are provided for use in the prophylaxis and / or treatment of proliferative diseases.

[0011] Certain compounds according to the invention may also exhibit one or more benefits including, inter alia, advantageous levels of biological activity which may be useful in the prophylaxis and / or treatment of one or more disease, improved safety characteristics (e.g. relating to hERG inhibition, drugdrug interaction (DDI) or CYP-interaction characteristics, etc), improved selectivity for one or more disease-associated biological target (e.g. reduced off-target effects, etc), improved pharmacokinetic properties (e.g. relating to dosing, solubility, absorption, etc), improved pharmacodynamic properties (e.g.relating to permeability, efflux, etc) or superior properties for use as pharmaceutical active ingredients alone or in pharmaceutical compositions (e.g. stability), or advantageous physico-chemical properties useful in the manufacturability of such aforementioned pharmaceutical compositions.

[0012] In a further aspect, the present invention provides pharmaceutical compositions comprising a compound of the invention, and a pharmaceutical carrier, excipient or diluent. In a particular aspect, the pharmaceutical composition may additionally comprise further therapeutically active ingredients suitable for use in combination with the compounds of the invention. In a more particular aspect, the further therapeutically active ingredient is an agent for the treatment of proliferative diseases.

[0013] Moreover, the compounds of the invention, useful in the pharmaceutical compositions and treatment methods disclosed herein, are pharmaceutically acceptable as prepared and used.

[0014] In a further aspect of the invention, this invention provides a method of treating a mammal, in particular humans, afflicted with a condition selected from among those listed herein, and particularly proliferative diseases, which method comprises administering an effective amount of the pharmaceutical composition or compounds of the invention as described herein.

[0015] The present invention also provides pharmaceutical compositions comprising a compound of the invention, and a suitable pharmaceutical carrier, excipient or diluent for use in medicine. In a particular aspect, the pharmaceutical composition is for use in the prophylaxis and / or treatment of proliferative diseases.

[0016] In additional aspects, this invention provides methods for synthesizing the compounds of the invention, with representative synthetic protocols and pathways disclosed later on herein.

[0017] Certain compounds according to the invention may exhibit one or more benefits including, inter alia, advantageous levels of biological activity which may be useful in the prophylaxis and / or treatment of one or more disease, improved safety characteristics (e.g. relating to hERG inhibition, drug-drug interaction (DDI) or CYP -interaction characteristics, etc), improved selectivity for one or more disease -associated biological target (e.g. reduced off-target effects, etc), improved pharmacokinetic properties (e.g. relating to dosing, solubility, absorption, etc), improved pharmacodynamic properties (e.g. relating to permeability, efflux, etc) or superior properties for use as pharmaceutical active ingredients alone or in pharmaceutical compositions (e.g. stability), or advantageous physico-chemical properties useful in the manufacturability of such aforementioned pharmaceutical compositions.

[0018] Other objects and advantages will become apparent to those skilled in the art from a consideration of the ensuing detailed description.

[0019] It will be appreciated that compounds of the invention may be metabolized to yield biologically active metabolites.DETAILED DESCRIPTION OF THE INVENTIONDefinitions

[0020] The following terms are intended to have the meanings presented therewith below and are useful in understanding the description and intended scope of the present invention.

[0021] When describing the invention, which may include compounds, pharmaceutical compositions containing such compounds and methods of using such compounds and compositions, the following terms, if present, have the following meanings unless otherwise indicated. It should also be understood that when described herein any of the moieties defined forth below may be substituted with a variety of substituents, and that the respective definitions are intended to include such substituted moieties within their scope as set out below. Unless otherwise stated, the term “substituted” is to be defined as set out below. It should be further understood that the terms “groups” and “radicals” can be considered interchangeable when used herein.

[0022] The articles ‘a’ and ‘an’ may be used herein to refer to one or to more than one (i.e. at least one) of the grammatical objects of the article. By way of example ‘an analogue’ means one analogue or more than one analogue.

[0023] A dashthat is not between two letters or symbols is used to indicate a point of attachment for a substituent. For example, -CONH2 is attached through the carbon atom. A dash at the front or end of a chemical group is a matter of convenience; chemical groups may be depicted with or without one or more dashes without losing their ordinary meaning.

[0024] A wavy line drawn through a line in a structure indicates a point of attachment of a group. Similarly, a squiggly line on a chemical group as shown, for example, indicates a point of attachment, i.e., it shows the broken bond by which the group is connected to another described group.

[0025] The prefix “Cu-v” indicates that the following group has from u to v carbon atoms. For example, “C1-8 alkyl” indicates that the alkyl group has from 1 to 8 carbon atoms.

[0026] Reference to “about” a value or parameter herein includes (and describes) embodiments that are directed to that value or parameter per se. In certain embodiments, the term “about” includes the indicated amount ± 10%. In other embodiments, the term “about” includes the indicated amount ± 5%. In certain other embodiments, the term “about” includes the indicated amount ± 1%. Also, to the term “about X” includes description of “X”. Also, the singular forms "a" and "the" include plural references unless the context clearly dictates otherwise. Thus, e.g., reference to "the compound" includes a plurality of such compounds and reference to "the assay" includes reference to one or more assays and equivalents thereof known to those skilled in the art.

[0027] Unless indicated explicitly otherwise, where combinations of groups are referred to herein as one moiety, e.g. arylalkyl, the last-mentioned group contains the atom by which the moiety is attached to the rest of the molecule.

[0028] ‘Alkyl’ means straight or branched aliphatic hydrocarbon having the specified number of carbon atoms. Particular alkyl groups have 1 to 6 carbon atoms or 1 to 4 carbon atoms. Branched means that one or more alkyl groups such as methyl, ethyl or propyl is attached to a linear alkyl chain. Particular alkyl groups are methyl (-CH3), ethyl (-CH2-CH3), n-propyl (-CH2-CH2-CH3), isopropyl (-CH(CH3)2), n-butyl (-CH2-CH2-CH2-CH3), tert-butyl (-C(CH3)3), sec-butyl (-CH(CH3)-CH2CH3), isobutyl (-CH2-CH(CH3)2), n-pentyl (-CH2-CH2-CH2-CH2-CH3), n-hexyl (-CH2-CH2-CH2-CH2-CH2-CH3), and 1,2-dimethylbutyl (-CH(CH3)-CH(CH3)-CH2-CH3). Particular alkyl groups have between 1 and 4 carbon atoms.

[0029] ‘hydroxyalkyl’ refers to an alkyl group with the number of carbon atoms specified, substituted with an -OH group. For example, hydroxy (Ci-4)alkyl refers to carbon chain straight or branched wherein one carbon atom is substituted with an -OH group. Examples of such hydroxyalkyl include without limitation -CH2-OH, -CH(CH3)-OH, -CH2-CH2CH2-OH, or -C(CH3)2-OH.

[0030] ‘Alkylene’ refers to divalent alkene radical groups having the number of carbon atoms specified, in particular having 1 to 6 carbon atoms and more particularly 1 to 4 carbon atoms which can be straight-chained or branched. This term is exemplified by groups such as methylene (-CH2-), ethylene (-CH2-CH2-), or -CH(CH3)- and the like.

[0031] ‘Alkoxy’ refers to the group O-alkyl, where the alkyl group has the number of carbon atoms specified. In particular the term refers to the group -O-Ci e alkyl. Particular alkoxy groups are methoxy, ethoxy, w-propoxy. isopropoxy, w-butoxy. tert-butoxy, scc-butoxy. w-pcntoxy. w-hcxoxy. and 1,2-dimethylbutoxy. Particular alkoxy groups are lower alkoxy, i.e. with between 1 and 6 carbon atoms. Further particular alkoxy groups have between 1 and 4 carbon atoms.

[0032] ‘ Amino’ refers to the radical -NH2.

[0033] ‘Aryl’ refers to a monovalent aromatic hydrocarbon group derived by the removal of one hydrogen atom from a single carbon atom of a parent aromatic ring system. In particular aryl refers to an aromatic ring structure, monocyclic or fused polycyclic, with the number of ring atoms specified. Specifically, the term includes groups that include from 6 to 10 ring members. Particular aryl groups include phenyl, and naphthyl.

[0034] “Aryl” also covers partially aromatic bi- or polycyclic ring systems wherein at least one ring is an aromatic ring and one or more of the other ring(s) is a non -aromatic, saturated or partially saturated ring. Partially aromatic aryl bicyclic ring systems can be vicinally fused, i.e., where the rings are linked to each other through two adjacent carbon atoms. Examples of partially aromatic heteroaryl groups include for example:

[0035] ‘Cycloalkyl’refers to a non-aromatic hydrocarbyl ring structure, monocyclic, fused polycyclic, bridged polycyclic, or spirocyclic, with the number of ring atoms specified. A cycloalkyl may have from 3 to 12 carbon atoms, in particular from 3 to 10, and more particularly from 3 to 7 carbon atoms. Such cycloalkyl groups include, by way of example, single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

[0036] ‘Cyano’ refers to the radical -CN.

[0037] ‘Halo’ or ‘halogen’ refers to fluoro (F), chloro (Cl), bromo (Br) and iodo (I). Particular halo groups are either fluoro or chloro.

[0038] As used herein, term ‘polycyclic’ refers to chemical groups featuring several closed rings of atoms. In particular it refers to groups featuring two, three or four rings of atoms, more particularly two or three rings of atoms, most particularly two rings of atoms.

[0039] ‘Hetero’ when used to describe a compound or a group present on a compound means that one or more carbon atoms in the compound or group have been replaced by a nitrogen, oxygen, or sulfur heteroatom. Hetero may be applied to any of the hydrocarbyl groups described previously such as alkyl, e.g. heteroalkyl, cycloalkyl, e.g. heterocycloalkyl, aryl, e.g. heteroaryl, and the like having from 1 to 4, and particularly from 1 to 3 heteroatoms, more typically 1 or 2 heteroatoms, for example a single heteroatom.

[0040] ‘Heteroaryl’ means an aromatic ring structure, monocyclic or fused polycyclic, that includes one or more heteroatoms independently selected from O, N and S and the number of ring atoms specified. In particular, the aromatic ring structure may have from 5 to 9 ring members. The heteroaryl group can be, for example, a five membered or six membered monocyclic ring or a fused bicyclic structure formed from fused five and six membered rings or two fused six membered rings or, by way of a further example, two fused five membered rings. Each ring may contain up to four heteroatoms typically selected from nitrogen, sulfur and oxygen. Typically the heteroaryl ring will contain up to 4 heteroatoms, more typically up to 3 heteroatoms, more usually up to 2, for example a single heteroatom. In one embodiment, the heteroaryl ring contains at least one ring nitrogen atom. The nitrogen atoms in the heteroaryl rings can be basic, as in the case of an imidazole or pyridine, or essentially non-basic as in the case of an indole or pyrrole nitrogen. In general the number of basic nitrogen atoms present in the heteroaryl group, including any amino group substituents of the ring, will be less than five.

[0041] Examples of five membered monocyclic heteroaryl groups include but are not limited to pyrrolyl, furanyl, thiophenyl, imidazolyl, furazanyl, oxazolyl, oxadiazolyl, oxatriazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl and tetrazolyl groups.

[0042] “Heteroaryl” also covers partially aromatic bi- or polycyclic ring systems wherein at least one ring is an aromatic ring and one or more of the other ring(s) is a non-aromatic, saturated or partially saturated ring, provided at least one ring contains one or more heteroatoms selected from nitrogen, oxygen or sulfur. Partially aromatic heteroaryl bicyclic ring systems can be vicinally fused, i.e., where the rings are linked to each other through two adjacent carbon and / or nitrogen atoms. Examples of partially aromatic heteroaryl groups include for example, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 2-oxo-l, 2,3,4-tetrahydroquinolinyl, dihydrobenzthienyl, dihydrobenzfuranyl, 1,3-dihydroisobenzofuran, 2,3-dihydro-benzo[l,4]dioxinyl, benzo[l,3]dioxolyl, 2,2-dioxo-l,3-dihydro-2-benzothienyl, 4, 5,6,7-tetrahydrobenzofuranyl, indolinyl, l,2,3,4-tetrahydro-l,8-naphthyridinyl, l.2.3.4-tctrahydropyrido|2.3- / ?| pyrazinyl and 3.4-dihydro-2 / / -pyrido|3.2- / ?|| l,4]oxazinyl.

[0043] Examples of five membered monocyclic heteroaryl groups include but are not limited to pyrrolyl, furanyl, thiophenyl, imidazolyl, furazanyl, oxazolyl, oxadiazolyl, oxatriazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl and tetrazolyl groups.

[0044] Examples of six membered monocyclic heteroaryl groups include but are not limited to pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl and triazinyl.

[0045] Particular examples of bicyclic heteroaryl groups containing a five membered ring fused to another five-membered ring include but are not limited to imidazothiazolyl and imidazoimidazolyl.

[0046] Particular examples of bicyclic heteroaryl groups containing a six membered ring fused to a five membered ring include but are not limited to benzofuranyl, benzothiophenyl, benzoimidazolyl, benzoxazolyl, isobenzoxazolyl, benzisoxazolyl, benzothiazolyl, benzoisothiazolyl, isobenzofuranyl, indolyl, isoindolyl, indolizinyl, purinyl (e.g. adenine, guanine), indazolyl, pyrazolopyrimidinyl, triazolopyrimidinyl, and pyrazolopyridinyl groups.

[0047] Particular examples of bicyclic heteroaryl groups containing two fused six membered rings include but are not limited to quinolinyl, isoquinolinyl, pyridopyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, naphthyridinyl, and pteridinyl groups. Particular heteroaryl groups are those derived from thiophenyl, pyrrolyl, benzothiophenyl, benzofuranyl, indolyl, pyridinyl, quinolinyl, imidazolyl, oxazolyl and pyrazinyl.

[0048] Examples of representative heteroaryls include the following:wherein each Y is selected from > C=O, NH, O and S.

[0049] ‘Heterocycloalkyl’ means a non-aromatic fully saturated ring structure, monocyclic, fused polycyclic, spirocyclic, or bridged polycyclic, that includes one or more heteroatoms independently selected from O, N and S and the number of ring atoms specified. The heterocycloalkyl ring structure may have from 4 to 12 ring members, in particular from 4 to 10 ring members and more particularly from 4 to 7 ring members. Each ring may contain up to four heteroatoms typically selected from nitrogen, sulfur and oxygen. Typically the heterocycloalkyl ring will contain up to 4 heteroatoms, more typically up to 3 heteroatoms, more usually up to 2, for example a single heteroatom. Examples of heterocyclic rings include, but are not limited to azetidinyl, oxetanyl, thietanyl, pyrrolidinyl (e.g. 1-pyrrolidinyl, 2-pyrrolidinyl and 3-pyrrolidinyl), tetrahydrofuranyl (e.g. 1 -tetrahydrofuranyl, 2 -tetrahydrofuranyl and 3 -tetrahydrofuranyl), tetrahydrothiophenyl (e.g. 1 -tetrahydrothiophenyl, 2-tetrahydrothiophenyl and 3 -tetrahydrothiophenyl), piperidinyl (e.g. 1-piperidinyl, 2-piperidinyl, 3-piperidinyl and 4-piperidinyl), tetrahydropyranyl (e.g. 4-tetrahydropyranyl), tetrahydrothiopyranyl (e.g. 4-tetrahydrothiopyranyl), morpholinyl, thiomorpholinyl, dioxanyl, or piperazinyl.

[0050] Particular examples of monocyclic rings are shown in the following illustrative examples:wherein each W and Y is independently selected from -CH2-, -NH-, -O- and -S-.

[0051] Particular examples of fused bicyclic rings are shown in the following illustrative examples:wherein each W and Y is independently selected from -CH2-, -NH-, -O- and -S-.

[0052] Particular examples of bridged bicyclic rings are shown in the following illustrative examples:wherein each W and Y is independently selected from -CH2-. -NH-, -O- and -S- and each Z is selected from N or CH.

[0053] Particular examples of spirocyclic rings are shown in the following illustrative examples:wherein each Y is selected from -CH2-, -NH-, -O- and -S-.

[0054] ‘Hydroxyl’ refers to the radical -OH.

[0055] ‘ Oxo’ refers to the radical =0.

[0056] ‘ Substituted’ refers to a group in which one or more hydrogen atoms are each independently replaced with the same or different substituent(s).

[0057] As used herein, term ‘substituted with one or more’ refers to one to four substituents. In particular, it refers to one to three substituents. More particularly, it refers to one or two substituents. Most particularly, it refers to one substituent.

[0058] One having ordinary skill in the art of organic synthesis will recognize that the maximum number of heteroatoms in a stable, chemically feasible heterocyclic ring, whether it is aromatic or non-aromatic, is determined by the size of the ring, the degree of unsaturation and the valence of the heteroatoms. In general, a heterocyclic ring may have one to four heteroatoms so long as the heteroaromatic ring is chemically feasible and stable.

[0059] ‘Pharmaceutically acceptable’ means approved or approvable by a regulatory agency of the Federal or a state government or the corresponding agency in countries other than the United States, or that is listed in the U. S. Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, and more particularly, in humans.

[0060] ‘Pharmaceutically acceptable salt’ refers to a salt of a compound of the invention that is pharmaceutically acceptable and that retains the biological activity of the given compound, and which are is not biologically or otherwise undesirable. In particular, such salts may be inorganic or organic acid addition salts and base addition salts. For example, pharmaceutically acceptable salts are described in Handbook of Pharmaceutical Salts: Properties, Selection, and Use (Stahl & Wermuth 2011). The salts can be prepared in situ during the final isolation and purification of the compounds described herein or separately, e.g., by reacting the free base group with a suitable inorganic or organic acid. The compounds of the invention may have ionizable groups so as to be capable of preparation as pharmaceuticallyacceptable salts. These salts may be acid addition salts involving inorganic or organic acids or the salts may, in the case of acidic forms of the compounds of the invention be prepared from inorganic or organic bases. Frequently, the compounds are prepared or used as pharmaceutically acceptable salts prepared as addition products of pharmaceutically acceptable acids or bases. Suitable pharmaceutically acceptable acids and bases are well known in the art, such as, e.g., hydrochloric acid for forming acid addition salts, and such as, e.g., sodium hydroxide for forming basic salts. The term ‘pharmaceutically acceptable cation’ refers to an acceptable cationic counter-ion of an acidic functional group. Such cations are exemplified by sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium cations, and the like.

[0061] ‘Pharmaceutically acceptable vehicle’ refers to a diluent, adjuvant, excipient or carrier with which a compound of the invention is administered.

[0062] ‘Prodrugs’ refers to compounds, including derivatives of the compounds of the invention, which have cleavable groups and become by solvolysis or under physiological conditions the compounds of the invention which are pharmaceutically active in vivo. Such examples include, but are not limited to, choline ester derivatives and the like, N-alkylmorpholine esters and the like.

[0063] ‘ Solvate’ refers to forms of the compound that are associated with a solvent, usually by a solvolysis reaction. This physical association includes hydrogen bonding. Conventional solvents include water, EtOH, acetic acid and the like. The compounds of the invention may be prepared e.g. in crystalline form and may be solvated or hydrated. Suitable solvates include pharmaceutically acceptable solvates, such as hydrates, and further include both stoichiometric solvates and non-stoichiometric solvates. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. ‘Solvate’ encompasses both solution-phase and isolable solvates. Representative solvates include hydrates, ethanolates and methanolates.

[0064] ‘Subject’ includes humans. The terms ‘human’, ‘patient’ and ‘subject’ are used interchangeably herein.

[0065] ‘ Effective amount’ means the amount of a compound of the invention that, when administered to a subject for treating a disease, is sufficient to effect such treatment for the disease. The “effective amount” can vary depending on the compound, the disease and its severity, and the age, weight, etc., of the subject to be treated.

[0066] ‘Preventing’ or ‘prevention’ refers to a reduction in risk of acquiring or developing a disease or disorder (i.e. causing at least one of the clinical symptoms of the disease not to develop in a subject that may be exposed to a disease-causing agent, or predisposed to the disease in advance of disease onset.

[0067] The term ‘prophylaxis’ is related to ‘prevention’, and refers to a measure or procedure the purpose of which is to prevent, rather than to treat or cure a disease. Non-limiting examples of prophylactic measures may include the administration of vaccines; the administration of low molecular weight heparin to hospital patients at risk for thrombosis due, for example, to immobilization; and the administration of an anti-malarial agent such as chloroquine, in advance of a visit to a geographical region where malaria is endemic or the risk of contracting malaria is high.

[0068] ‘Treating’ or ‘treatment’ of any disease or disorder refers, in one embodiment, to ameliorating the disease or disorder (i.e. arresting the disease or reducing the manifestation, extent or severity of at least one of the clinical symptoms thereof). In another embodiment ‘treating’ or ‘treatment’ refers to ameliorating at least one physical parameter, which may not be discernible by the subject. In yet another embodiment, ‘treating’ or ‘treatment’ refers to modulating the disease or disorder, either physically, (e.g. stabilization of a discernible symptom), physiologically, (e.g. stabilization of a physical parameter), or both. In a further embodiment, “treating” or “treatment” relates to slowing the progression of the disease.

[0069] As used herein the term ‘proliferative disease(s)’ refers to diseases associated with excessive proliferation of cells and turnover of cellular matrix. In particular, the term refers to conditions such as cancer (e.g. uterine leiomyosarcoma or prostate cancer), myeloproliferative disorders (e.g. polycythemia vera, essential thrombocytosis and myelofibrosis), leukemia (e.g. acute myeloid leukemia, acute and chronic lymphoblastic leukemia), multiple myeloma, psoriasis, restenosis, scleroderma or fibrosis. In particular, the term refers to cancer, leukemia, and multiple myeloma.

[0070] Certain compounds of formula (I), or a pharmaceutically acceptable salt thereof, selectively target SMARCA2. For example, certain compounds of formula (I), or a pharmaceutically acceptable salt thereof, selectively target SMARCA2 over SMARCA4. For example, certain compounds of formula (I), or a pharmaceutically acceptable salt thereof, are at least about 3 fold (e.g. at least about 4-, 5-, 6-, 7-, 8-, 9-, 10-, 15-, 20-, 30-, 40-, 50-fold, or more) more selective for SMARCA2 than for SMARCA4.

[0071] As used herein, the term "selectivity" of a compound refers to the compound having more potent activity at the first target than the second target. A fold selectivity can be calculated by any method known in the art. For example, a fold selectivity can be calculated by dividing the IC50 value of a compound for the second target (e.g., SMARCA4) by the IC50 value of the same compound for the first target (e.g., SMARCA2). An IC50 value can be determined by any method known in the art. For example, an IC50 value can be determined as described in the assays below.

[0072] As used herein, the term ‘cancer’ refers to a malignant or benign growth of cells in skin or in body organs, for example but without limitation, breast, prostate, lung, kidney, pancreas, stomach or bowel. A cancer tends to infiltrate into adjacent tissue and spread (metastasize) to distant organs, for example to bone, liver, lung or the brain. As used herein the term cancer includes both metastatic tumour cell types (such as but not limited to, melanoma, lymphoma, leukemia, fibrosarcoma, rhabdomyosarcoma, and mastocytoma) and types of tissue carcinoma (such as but not limited to, colorectal cancer, prostate cancer, small cell lung cancer and non-small cell lung cancer, breast cancer, pancreatic cancer, bladder cancer, renal cancer, gastric cancer, glioblastoma, primary liver cancer, ovarian cancer, and uterine leiomyosarcoma). In particular, the term ‘cancer’ refers to acute lymphoblastic leukemia, acute myeloid leukemia, adrenocortical carcinoma, anal cancer, appendix cancer, astrocytomas, atypical teratoid / rhabdoid tumor, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer (osteosarcoma and malignant fibrous histiocytoma), brain stem glioma, brain tumors, brain and spinal cord tumors, breast cancer, bronchial tumors, Burkitt lymphoma, cervical cancer, chronic lymphocytic leukemia, chronic myelogenous leukemia, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, embryonal tumors, endometrial cancer,ependymoblastoma, ependymoma, esophageal cancer, Ewing sarcoma family of tumors, eye cancer, retinoblastoma, gallbladder cancer, gastric (stomach) cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST), gastrointestinal stromal cell tumor, germ cell tumor, glioma, hairy cell leukemia, head and neck cancer, hepatocellular (liver) cancer, hypopharyngeal cancer, intraocular melanoma, islet cell tumors (endocrine pancreas), Kaposi’s sarcoma, kidney cancer, Langerhans cell histiocytosis, laryngeal cancer, leukemia, hairy cell leukemia, liver cancer, non-small cell lung cancer, small cell lung cancer, Hodgkin lymphoma, non-Hodgkin lymphoma, lymphoma, Waldenstrom macroglobulinemia, medulloblastoma, medulloepithelioma, melanoma, mesothelioma, mouth cancer, myeloid leukemia, multiple myeloma, nasopharyngeal cancer, neuroblastoma, oral cancer, oropharyngeal cancer, osteosarcoma, malignant fibrous histiocytoma of bone, ovarian cancer, ovarian epithelial cancer, ovarian germ cell tumor, ovarian low malignant potential tumor, pancreatic cancer, papillomatosis, parathyroid cancer, penile cancer, pharyngeal cancer, pineal parenchymal tumors of intermediate differentiation, pineoblastoma and supratentorial primitive neuroectodermal tumors, pituitary tumor, plasma cell neoplasm / multiple myeloma, pleuropulmonary blastoma, primary central nervous system lymphoma, prostate cancer, rectal cancer, renal cell (kidney) cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcoma, Ewing sarcoma family of tumors, sarcoma, Sezary syndrome, skin cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, squamous cell carcinoma, stomach (gastric) cancer, supratentorial primitive neuroectodermal tumors, testicular cancer, throat cancer, thymoma and thymic carcinoma, thyroid cancer, urethral cancer, uterine cancer, uterine sarcoma, vaginal cancer, vulvar cancer, and Wilms tumor.

[0073] As used herein the term ‘leukemia’ refers to neoplastic diseases of the blood and blood forming organs. Such diseases can cause bone marrow and immune system dysfunction, which renders the host highly susceptible to infection and bleeding. In particular the term leukemia refers to acute myeloid leukemia (AML), and acute lymphoblastic leukemia (ALL) and chronic lymphoblastic leukemia (CLL).

[0074] ‘Compound(s) of the invention’, and equivalent expressions, are meant to embrace compounds of the Formula(e) as herein described, which expression includes the pharmaceutically acceptable salts, and the solvates, e.g. hydrates, and the solvates of the pharmaceutically acceptable salts where the context so permits. Similarly, reference to intermediates, whether or not they themselves are claimed, is meant to embrace their salts, and solvates, where the context so permits.

[0075] When ranges are referred to herein, for example but without limitation, C1-8alkyl, the citation of a range should be considered a representation of each member of said range.

[0076] Other derivatives of the compounds of this invention have activity in both their acid and acid derivative forms, but in the acid sensitive form often offers advantages of solubility, tissue compatibility, or delayed release in the mammalian organism (Bundgaard 1985). Prodrugs include acid derivatives well know to practitioners of the art, such as, for example, esters prepared by reaction of the parent acid with a suitable alcohol, or amides prepared by reaction of the parent acid compound with a substituted or unsubstituted amine, or acid anhydrides, or mixed anhydrides. Simple aliphatic or aromatic esters, amides and anhydrides derived from acidic groups pendant on the compounds of this invention are particularlyuseful prodrugs. In some cases it is desirable to prepare double ester type prodrugs such as (acyloxy)alkyl esters or ((alkoxycarbonyl)oxy)alkylesters. Particular such prodrugs are the C1-8alkyl, C2-8 alkenyl, Ce-io optionally substituted aryl, and (Ce-io aryl)-(Ci-4 alkyl) esters of the compounds of the invention.

[0077] The present disclosure includes all isotopic forms of the compounds of the invention provided herein, whether in a form (i) wherein all atoms of a given atomic number have a mass number (or mixture of mass numbers) which predominates in nature (referred to herein as the “natural isotopic form”) or (ii) wherein one or more atoms are replaced by atoms having the same atomic number, but a mass number different from the mass number of atoms which predominates in nature (referred to herein as an “unnatural variant isotopic form”). It is understood that an atom may naturally exists as a mixture of mass numbers. The term “unnatural variant isotopic form” also includes embodiments in which the proportion of an atom of given atomic number having a mass number found less commonly in nature (referred to herein as an “uncommon isotope”) has been increased relative to that which is naturally occurring e.g. to the level of >20%, >50%, >75%, >90%, >95% or> 99% by number of the atoms of that atomic number (the latter embodiment referred to as an "isotopically enriched variant form"). The term “unnatural variant isotopic form” also includes embodiments in which the proportion of an uncommon isotope has been reduced relative to that which is naturally occurring. Isotopic forms may include radioactive forms (i.e. they incorporate radioisotopes) and non-radioactive forms. Radioactive forms will typically be isotopically enriched variant forms.

[0078] An unnatural variant isotopic form of a compound may thus contain one or more artificial or uncommon isotopes such as deuterium (2H or D), carbon-11 (11C), carbon-13 (13C), carbon-14 (14C), nitrogen-13 (13N), nitrogen-15 (15N), oxygen-15 (15O), oxygen-17 (17O), oxygen-18 (18O), phosphorus-32 (32P), sulfur-35 (35S), chlorine-36 (36C1), chlorine-37 (37C1), fluorine-18 (18F) iodine-123 (123I), iodine-125 (125I) in one or more atoms or may contain an increased proportion of said isotopes as compared with the proportion that predominates in nature in one or more atoms.

[0079] Unnatural variant isotopic forms comprising radioisotopes may, for example, be used for drug and / or substrate tissue distribution studies. The radioactive isotopes tritium, i.e.3H, and carbon- 14, i.e.14C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection. Unnatural variant isotopic forms which incorporate deuterium i.e2H or D may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances. Further, unnatural variant isotopic forms may be prepared which incorporate positron emitting isotopes, such as11C,18F,15O and13N, and would be useful in Positron Emission Tomography (PET) studies for examining substrate receptor occupancy.

[0080] The selective replacement of hydrogen with deuterium in a compound may modulate the metabolism of the compound, the PK / PD properties of the compound and / or the toxicity of the compound. For example, deuteration may increase the half-life or reduce the clearance of the compound in vivo. Deuteration may also inhibit the formation of toxic metabolites, thereby improving safety and tolerability. It is to be understood that the invention encompasses deuterated derivatives of compounds of any offormulae I-XVIII. As used herein, the term deuterated derivative refers to compounds of the invention where in a particular position at least one hydrogen atom is replaced by deuterium. Accordingly, in a compound of the invention one or more hydrogen atom is optionally replaced by deuterium. For example, one or more hydrogen atoms in a Ci-4-alkyl group may be replaced by deuterium to form a deuterated C1-4-alkyl group. By way of example, if any of Ry, Rz, R1, R2, R3, R4a, R4b, R5, R6, R7, R8a, R8b, R9a, R9b, R10, R10a, R10b, R11a, R11b, R12a, or R12b, is methyl, the invention also encompasses -CD3, -CHD2and -CH2D. Similarly Ry, Rz, R3, R4a, R4b, R5, R6, R8a, R8b, R9a, R9b, R11a, R11b, R12a, or R12bmay be D.

[0081] It is also to be understood that compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed ‘isomers’. Isomers that differ in the arrangement of their atoms in space are termed ‘stereoisomers’.

[0082] Stereoisomers that are not mirror images of one another are termed ‘diastereomers’ and those that are non-superimposable mirror images of each other are termed ‘enantiomers’. When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible. An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R- and S-sequencing rules of Cahn, Ingold and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e. as (+) or (-)-isomers respectively). A chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a ‘racemic mixture’.

[0083] ‘ Tautomers’ refer to compounds that are interchangeable forms of a particular compound structure, and that vary in the displacement of hydrogen atoms and electrons. Thus, two structures may be in equilibrium through the movement of 71 electrons and an atom (usually H). For example, enols and ketones are tautomers because they are rapidly interconverted by treatment with either acid or base. Another example of tautomerism is the aci- and nitro- forms of phenylnitromethane that are likewise formed by treatment with acid or base.

[0084] Tautomeric forms may be relevant to the attainment of the optimal chemical reactivity and biological activity of a compound of interest.

[0085] The compounds of the invention may possess one or more asymmetric centers; such compounds can therefore be produced as individual (R)- or (S)- stereoisomers or as mixtures thereof.

[0086] An optical isomer with unknown absolute configuration may be depicted with an asterix (*) at thechiral center, e.g.,and / or and / or '111and / or '. Likewise, when a chemical structure possessing one or more asymmetric centers is described using its chemical name, stereocenters with unknown absolute configuration may be depicted with an asterix (*), e.g. R* and / or S*. Alternatively, if stereochemistry has been depicted but the phrase “stereochemistry arbitrary assigned”, or something to that effect, is present then this indicates an optical isomer with unknown absolute configuration.

[0087] Unless indicated otherwise, the description or naming of a particular compound in the specification and claims is intended to include both individual enantiomers and mixtures, racemic or otherwise, thereof.The methods for the determination of stereochemistry and the separation of stereoisomers are well-known in the art.

[0088] It will be appreciated that compounds of the invention may be metabolized to yield biologically active metabolites.THE INVENTION

[0089] The present invention is based on the identification of novel compounds, and their use in the prophylaxis and / or treatment of proliferative diseases. In particular, the compounds of the invention may be SMARCA2 and / or SMARCA4 inhibitors, and more particularly SMARCA2 inhibitors.

[0090] The present invention also provides methods for the production of these compounds, pharmaceutical compositions comprising these compounds and methods for the prophylaxis and / or treatment of proliferative diseases by administering the compounds of the invention.

[0091] Accordingly, in a first aspect of the invention, the compounds of the invention are provided having a Formula I:Iwherein,A is 6-10 membered monocyclic or bicyclic aryl, or 5-10 membered monocyclic or bicyclic heteroaryl comprising one, two or three heteroatoms independently selected from N, O, and S;RyO..0 N OV'SC / V'S'x / Y is independently selected from' ', ' ' andRyand Rzare each independently hydrogen or C1.3 alkyl;X is N or CH;R1is C1-6alkyl, C1-3alkoxy(C1-3)alkyl, -N(C1-3alkyl)2or hydroxy(C1-4)alkyl, wherein said alkyl and alkoxy groups are optionally substituted with one or more halogen;n is 0, 1, or 2;each R2is independently selected from halogen and C1-6alkyl, which alkyl is optionally substituted with halo or C1-4alkoxy;or R1and one R2together with the atoms onto which they are attached form a fused 5-8 membered monocyclic cycloalkyl, or a fused 5-8 membered monocyclic heterocycloalkyl comprising Y in formula I and zero, one, or two additional heteroatoms independently selected from N, O, and S, wherein the cycloalkyl or heterocycloalkyl is optionally substituted with one or more independently selected halogens (preferably fluoro) or C1.4 alkyl;R3is hydrogen or C1-6alkyl;R4aand R4bare each independently hydrogen or Ci-6 alkyl optionally substituted with one or more independently selected halo or C1-4 alkoxy;or R4aand R4b, together with the carbon to which they are attached, form a C3-6 cycloalkyl or 4-6 membered heterocycloalkyl comprising one or two heteroatoms independently selected from N, O, and S, which cycloalkyl or heterocycloalkyl is optionally substituted with one or more halo or C1.4 alkoxy;Li is a bond, Ce-io aryl, or 5-6 membered monocyclic heteroaryl comprising one, two or three heteroatoms independently selected from N, O, and S, which aryl or heteroaryl is optionally substituted with one or more independently selected halo, C1-4 alkyl, C1-4 haloalkyl, -NH2, -NH(CI-4 alkyl), or -N(CI-4 alkyl)2, morpholine, -CH=CHCO2R9a, C1-4 alkoxy, C1-4 haloalkoxy or oxetane;B is Ce-io aryl, 5-10 membered monocyclic or bicyclic heteroaryl comprising one, two, three or four heteroatoms independently selected from N, O, and S, or a 5-10 membered monocyclic or bicyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S, each of which is optionally substituted with one or more independently selected R7;L2 is a bond or C1-6 alkyl, which alkyl is optionally substituted with one or more halo, -OH, -CN, or C1-4 alkoxy;R5is independently selected from- hydrogen,- oxo,- -OH,- -CN,- -P(O)(C1-4alkyl)2,- halo,- -S(=O)2-Ci.4 alkyl,- -NR8aR8b,- -CH=CHCO2R9a,- -S(=O)2NHC(O)C1-2alkyl,- -S(=O)2NH2,- -C(O)NHS(=O)2C1-2alkyl,- -CONR9aR9b,- -CO2R9a,- C1-4 alkyl optionally substituted with one or more independently selected halo, -OH, -CN, -CO2R9aor Ci -4 alkoxy,- C1-4 alkoxy optionally substituted with one or more independently selected halo, -OH, -CN, -CO2R9a, Ci -4 alkoxy, or C3-6 cycloalkyl,- C3-6 cycloalkyl, which cycloalkyl is optionally substituted with one or more independently selected oxo, halo, -OH, -CN, C1-4 alkyl, or C1-4 alkoxy,- 4-8 membered monocyclic or spirocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is optionally substituted with oneor more independently selected oxo, halo, -OH, -CN, C1-4 alkyl, C1-4 alkoxy, -S(=O)2Ci-4 alkyl, - C(=O)Ci.4alkyl, or -CO2R9a,- -Si(Ci-4alkyl)3, and- Q1;R6is hydrogen, halo, or C1-6 alkyl;each R7is independently selected from- oxo,- -OH,- -CN,- -P(O)(C1-4alkyl)2,- halo,- -S(=O)2-Ci.4 alkyl,- -NR8aR8b,- -CH=CHCO2R9a,- -S(=O)2NHC(O)C1-2alkyl,- -S(=O)2NH2,- -C(O)NHS(=O)2C1-2alkyl,- -CONR9aR9b,- -CO2R9a,- C1-4 alkyl optionally substituted with one or more independently selected halo, -OH, -CN, -CO2R9aor Ci -4 alkoxy,- C1-4 alkoxy optionally substituted with one or more independently selected halo, -OH, -CN, or C1-4 alkoxy,- C3-6 cycloalkyl, which cycloalkyl is optionally substituted with one or more independently selected oxo, halo, -OH, -CN, C1-4 alkyl, or C1-4 alkoxy, and- 4-8 membered monocyclic or spirocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is optionally substituted with one or more independently selected oxo, halo, -OH, -CN, C1-4 alkyl, or C1-4 alkoxy, and- Q2;Q1is selected from phenyl and 5-10 membered monocyclic or bicyclic heteroaryl comprising one, two, or three heteroatoms independently selected from N, O, and S, which phenyl and heteroaryl is optionally substituted with one or more R10a;Q2is selected from phenyl and 5-10 membered monocyclic or bicyclic heteroaryl comprising one, two, or three heteroatoms independently selected from N, O, and S, which phenyl and heteroaryl is optionally substituted with one or more R10b;each R8ais independently hydrogen or C1.4 alkyl;each R8bis independently hydrogen, C1.4 alkyl or -C(O)Ci.2alkyl;each R9ais independently selected from hydrogen and C1.4 alkyl;R9bis hydrogen, C1-4 alkyl or C1-4 alkoxy, or R9aand R9btogether with the atoms onto which they are attached form a 4-7 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is optionally substituted with one or more independently selected oxo, halo, -OH, -CN, C1.4 alkyl;R10aand R10bare each independently selected from halo, -OH, -NR11aR11b, -CN, C1.4 alkyl, C1.4 haloalkyl, C1.4 alkoxy, C1.4 alkoxy(Ci.4)alkyl, C1.4 hydroxyalkyl, -CONR12aR12b, -CO2R12a, and -L3-Q3;-L3- is a bond, -O-, or C1.4 alkylene;Q3is selected from C3-6 cycloalkyl, 4-8 membered monocyclic heterocycloalkyl comprising one, two, or three heteroatoms independently selected from N, O, and S, 6-10 membered bicyclic fused, bridged, or spiro heterocycloalkyl comprising one, two, or three heteroatoms independently selected from N, O, and S, which cycloalkyl or heterocycloalkyl is optionally substituted with one or more independently selected oxo, halo, -OH, -CN, C1-4 alkyl, or C1-4 alkoxy;each R11ais independently hydrogen or C1-4 alkyl;each R11bis independently hydrogen, C1-4 alkyl or -C(O)C1-2alkyl;each R12ais independently selected from hydrogen and C1-4 alkyl; andR12bis hydrogen, C1-4 alkyl or C 1-4 alkoxy, or R12aand R12btogether with the atoms onto which they are attached form a 4-7 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is optionally substituted with one or more independently selected oxo, halo, -OH, -CN, C1-4 alkyl;

[0092] Certain compounds according to the invention may exhibit one or more benefits including, inter alia, advantageous levels of biological activity which may be useful in the prophylaxis and / or treatment of one or more disease, improved safety characteristics (e.g. relating to hERG inhibition, drug -drug interaction (DDI) or CYP -interaction characteristics, etc), improved selectivity for one or more disease -associated biological target (e.g. reduced off-target effects, etc), improved pharmacokinetic properties (e.g. relating to dosing, solubility, absorption, etc), improved pharmacodynamic properties (e.g. relating to permeability, efflux, etc) or superior properties for use as pharmaceutical active ingredients alone or in pharmaceutical compositions (e.g. stability), or advantageous physico-chemical properties useful in the manufacturability of such aforementioned pharmaceutical compositions.

[0093] In one embodiment, the compound of the compound of the invention is according to formula (I) wherein R5is selected from:- hydrogen,- C1.4 alkyl optionally substituted with one or more independently selected halo, -OH, -CN, -CO2R9aor C1-4 alkoxy,- C1.4 alkoxy optionally substituted with one or more independently selected halo, -OH, -CN, -CO2R9a, C1-4 alkoxy, or C3-6 cycloalkyl,- C3-6 cycloalkyl, which cycloalkyl is optionally substituted with one or more independently selected oxo, halo, -OH, -CN, C1.4 alkyl, or C1-4 alkoxy,- 4-8 membered monocyclic or spirocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is optionally substituted with one or more independently selected oxo, halo, -OH, -CN, C1-4 alkyl, C1-4 alkoxy, or -CO2R9a,- -Si(Ci-4alkyl)3, and- Q1;

[0094] In certain embodiments, the compound of the formula (I) is a compound of the formula (II):(II)wherein A, Y, B, R1, R2, R3, R4a, R4b, R5, R6, Li, L2, and n are as defined for formula (I).

[0095] In certain embodiments, the compound of the formula (I) is a compound of the formula (III):wherein A, Y, B, R1, R2, R3, R4a, R4b, R5, R6, L2, and n are as defined for formula (I).

[0096] In certain embodiments, the compound of the formula (I) is a compound of the formula (IV):wherein p is 0, 1, or 2, andA, Y, R1, R2, R3, R4a, R4b, R5, R6, R7, L2, and n are as defined for formula (I).

[0097] In certain embodiments, the compound of the formula (I) is a compound of the formula (V):wherein A, Y, R1, R2, R3, R4a, R4b, R5, R6, R7, L2, and n are as defined for formula (I).

[0098] In certain embodiments, the compound of the formula (I) is a compound of the formula (VI):wherein A, Y, R1, R2, R3, R4a, R4b, R6, R7, Q1, and n are as defined for formula (I).

[0099] In certain embodiments, the compound of the formula (I) is a compound of the formula (VII):(VII)wherein A, B, R1, R2, R3, R4a, R4b, R5, R6, Li, L2, and n are as defined for formula (I).

[0100] In certain embodiments, the compound of the formula (I) is a compound of the formula (VIII):wherein B, R1, R2, R3, R4a, R4b, R5, R6, Li, L2, and n are as defined for formula (I).

[0101] In certain embodiments, the compound of the formula (I) is a compound of the formula (VIII):(VIII)wherein B, R1, R2, R3, R4a, R4b, R5, R6, Li, L2, and n are as defined for formula (I).

[0102] In certain embodiments, the compound of the formula (I) is a compound of the formula (IX):(IX)whereinnl is 0 or 1;n2 is 0, 1, 2, 3, or 4;R2ais selected from halogen (preferably fluoro) and C1-4 alkyl; andB, R2, R3, R4a, R4b, R5, R6, Li, and L2are as defined for formula (I).

[0103] In certain embodiments, the compound of the formula (I) is a compound of the formula (X):(X)wherein A, B, R1, R2, R3, R4a, R4b, R5, R6, Rz, Li, L2, and n are as defined for formula (I).

[0104] In certain embodiments, the compound of the formula (I) is a compound of the formula (XI):(XI) whereinn3 is 0 or 1;n4 is 0, 1, 2, 3, or 4;R2ais selected from halogen (preferably fluoro) and C1-4 alkyl; andR2, R3, R4a, R4b, R5, R6, R7, Li, and L2are as defined for formula (I).

[0105] In certain embodiments, the compound of the formula (I) is a compound of the formula (XII):(XII)wherein R1, R2, R3, R4a, R4b, R6, R7, Q1, and n are as defined for formula (I).

[0106] In certain embodiments, the compound of the formula (I) is a compound of the formula (XIII):(XIII)wherein R1, R2, R3, R4a, R4b, R6, R7, Q1, and n are as defined for formula (I).

[0107] In certain embodiments, the compound of the formula (I) is a compound of the formula (XIV):whereinnl is 0 or 1;n2 is 0, 1, 2, 3, or 4;R2ais selected from halogen (preferably fluoro) and Ci-4 alkyl; andR2, R3, R4a, R4b, R6, R7, and Q1are as defined for formula (I).

[0108] In certain embodiments, the compound of the formula (I) is a compound of the formula (XV):wherein R1, R2, R3, R4a, R4b, R6, R7, Rz, Q1, and n are as defined for formula (I).

[0109] In certain embodiments, the compound of the formula (I) is a compound of the formula (XVI):whereinn3 is 0 or 1;n4 is 0, 1, 2, 3, or 4;R2ais selected from halogen (preferably fluoro) and Ci-4 alkyl; andR2, R3, R4a, R4b, R6, R7, Rz, and Q1are as defined for formula (I).

[0110] In certain embodiments, the compound of the formula (I) is a compound of the formula (XVIb):whereinnl is 0 or 1;n2 is 0, 1, 2, 3, or 4;R2ais selected from halogen (preferably fluoro) and Ci-4 alkyl; andR2, R3, R4a, R4b, R6, R7, and Q1are as defined for formula (I).

[0111] In certain embodiments, the compound of Formula (I) is a compound according to Formula (XII), (XIV) or (XlVb):(XlVb)whereinn is 0, 1, or 2;nl is 0 or 1;n2 is 0 or 1;R1is selected from CHF2or CHFCH2OH;each R2is independently selected from halogen, preferably chloro or fluoro, and CHF2;each R2ais independently selected from halogen, preferably fluoro, and C1.4 alkyl.

[0112] The following embodiments apply to compounds of any of Formulae I-XVI. These embodiments are independent and interchangeable. Any one embodiment may be combined with any other embodiment, where chemically allowed. In other words, any of the features described in the following embodiments may (where chemically allowable) may be combined with the features described in one or more other embodiments. In particular, where a compound is exemplified or illustrated in this specification, any two or more of the embodiments listed below, expressed at any level of generality, which encompass that compound may be combined to provide a further embodiment which forms part of the present disclosure.

[0113] In some embodiments, the compound is according to any one of Formulae I-XVI, wherein R3is hydrogen.

[0114] In some embodiments, the compound is according to any one of Formulae I-XVI, wherein R4aand R4bare hydrogen.

[0115] In some embodiments, the compound is according to any one of Formulae I-XVI, wherein R3, R4aand R4bare hydrogen.

[0116] In some embodiments, the compound is according to any one of Formulae I-XVI, wherein R6is hydrogen.

[0117] In some embodiments, the compound is according to any one of Formulae I-XVI, wherein R3, R4a, R4b, and R6are hydrogen.

[0118] In some embodiments, A is 6-10 membered monocyclic or bicyclic aryl. In some embodiments, A is phenyl. In some embodiments, A is 9-10 membered bicylic aryl.is selected from:is selected from:

[0121] In some embodiments, A is 5-10 membered monocyclic or bicyclic heteroaryl comprising one, two or three heteroatoms independently selected from N, O, and S.

[0122] In some embodiments, A is 5-membered monocyclic heteroaryl. In some embodiments, A is 6-membered monocyclic heteroaryl. In some embodiments, A is 9-membered bicyclic heteroaryl. In some embodiments, A is 10-membered bicyclic heteroaryl.

[0125] In some embodiments, Y is independently selected from

[0126] In some embodiments,Y is

[0127] In some embodiments, Y is. In some embodiments, Ryis hydrogen. In some embodiments, Ryis methyl. In some embodiments, Ryis ethyl.

[0128] In some embodiments, Y is. In some embodiments, Rzis hydrogen. In some embodiments, Rzis methyl. In some embodiments, Rzis ethyl.

[0129] In some embodiments, R1is C1-3 alkyl, C1-3 alkoxy(Ci-3)alkyl, -N(C1-3 alkyl)2 or hydroxy(C1-3)alkyl, wherein said alkyl and alkoxy groups are optionally substituted with one or more halogen.

[0130] In some embodiments, R1is C1-3 alkyl, C1-3 alkoxy(C1-3)alkyl, or hydroxy(C1-3)alkyl, wherein said alkyl and alkoxy groups are optionally substituted with one or more halogen.

[0131] In some embodiments, R1is C1-3 alkyl or C1-3 alkoxy (C1-3)alkyl, wherein said alkyl and alkoxy groups are optionally substituted with one or more halogen.

[0132] In some embodiments, R1is C1-3 alkyl, wherein said alkyl group is optionally substituted with one or more halogen. In some embodiments, R1is C1-3 alkyl, wherein said alkyl group is optionally substituted with one or more fluoro.

[0133] In some embodiments, R1is methyl.

[0134] In some embodiments, R1is C1-3 alkoxy(C1-3)alkyl, wherein said alkyl and alkoxy groups are optionally substituted with one or more halogen. In some embodiments, R1is C1-3 alkoxy(C1-3)alkyl, wherein said alkyl and alkoxy groups are optionally substituted with one or more fluoro.

[0135] In some embodiments, R1is -N(C1-3 alkyl)2.

[0136] In some embodiments, R1is hydroxy(C1-3)alkyl.

[0137] In some embodiments,is selected from:

[0138] In some embodiments,

[0139] In some embodiments,

[0140] In some embodiments,

[0141] In some embodiments,

[0142] In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2.

[0143] In some embodiments, R2is independently selected from halogen and C1-3 alkyl, which alkyl is optionally substituted with halo or C1-4 alkoxy.

[0144] In some embodiments, R2is halogen. In some embodiments, R2is fluoro. In some embodiments, R2is chloro.

[0145] In some embodiments, R2is C1-3 alkyl, which alkyl is optionally substituted with halo or C1-4 alkoxy.

[0146] In some embodiments, R2is C1-3 alkyl, which alkyl is optionally substituted with halo. In some embodiments, R2is C1-3 alkyl, which alkyl is optionally substituted with fluoro.

[0147] In some embodiments, R2is methyl, which methyl is optionally substituted with halo. In some embodiments, R2is methyl, which alkyl is optionally substituted with fluoro.

[0148] In some embodiments, R2is methyl.

[0149] In some embodiments, R1and one R2together with the atoms onto which they are attached form a fused 5-8 membered monocyclic cycloalkyl, or a fused 5-8 membered monocyclic heterocycloalkyl comprising Y in formula I and zero, one, or two additional heteroatoms independently selected from N, O, and S, wherein the cycloalkyl or heterocycloalkyl is optionally substituted with one or more independently selected halogens (preferably fluoro) or Ci-4 alkyl.

[0150] In some embodiments, Y isand R1and one R2together with the atoms onto which they are attached form a fused 5-8 membered monocyclic cycloalkyl, or a fused 5-8 membered monocyclic heterocycloalkyl comprising one or two heteroatoms independently selected from N, O, and S, wherein the cycloalkyl or heterocycloalkyl is optionally substituted with one or more independently selected halogens (preferably fluoro-) or Ci-4 alkyl.

[0151] In some embodiments, Y isand R1and one R2together with the atoms onto which they are attached form a fused 5-8 membered monocyclic heterocycloalkyl comprising one or two heteroatoms independently selected from N, O, and S, wherein the heterocycloalkyl is optionally substituted with one or more independently selected halogens (preferably fluoro-) or Ci-4 alkyl.

[0152] In some embodiments,; wherein n3 is 0 or 1, n4 is 0, 1, 2, 3, or 4 and R2ais selected from halogen (preferably fluoro) and Ci-4 alkyl.1, 2, 3, or 4 and R2ais selected from halogen (preferably fluoro) and Ci-4 alkyl.

[0154] In some embodiments,; wherein n3 is 0 or 1, n4 is 0, 1, 2, 3, or 4 and R2ais selected from halogen (preferably fluoro) and Ci-4 alkyl.R1

[0155] In some embodiments,; wherein n3 is 0 or 1, n4 is 0, 1, 2, 3, or 4 and R2ais selected from halogen (preferably fluoro) and Ci-4 alkyl.

[0156] In some embodiments,is 0 or 1, n4 is 0, 1, 2, 3, or 4 and R2ais selected from halogen (preferably fluoro) and Ci-4 alkyl.

[0157] In some embodiments,wherein n3 is 0 or 1, n4 is 0, 1, 2, 3, or 4 and R2ais selected from halogen (preferably fluoro) and Ci-4 alkyl.

[0158] In some embodiments,Y is and R1and one R2together with the atoms onto which they are attached form a fused 5-8 membered monocyclic heterocycloalkyl comprising the S atom of Y and zero, one, or two additional heteroatoms independently selected from N, O, and S, wherein theheterocycloalkyl is optionally substituted with one or more independently selected halogens (preferably fluoro-) or C1-4 alkyl.

[0159] In some embodiments, Y is [image] and R1and one R2together with the atoms onto which they are attached form a fused 5-8 membered monocyclic heterocycloalkyl comprising the S atom ofY and zero, one, or two additional heteroatoms independently selected from N, O, and S, wherein the heterocycloalkyl is optionally substituted with one or more independently selected halogens (preferably fluoro-) or C1-4 alkyl.OJ / S, R2a

[0160] In some embodiments,; wherein n1 is 0 or 1, n2 is 0, 1, 2, 3, or 4 and R2ais selected from halogen (preferably fluoro) and C1-4 alkyl.[R2a

[0161] In some embodiments,; wherein n1 is 0 or 1, n2 is 0, 1, 2, 3, or 4 and R2ais selected from halogen (preferably fluoro) and C1-4 alkyl.

[0162] In some embodiments,1, 2, 3, or 4 and R2ais selected from halogen (preferably fluoro) and C1-4 alkyl.OH^-0R1R2

[0163] In some embodiments,; wherein n1 is 0 or 1, n5 is 0, 1, 2, 3, or 4 and R2ais selected from halogen (preferably fluoro) and C1-4 alkyl.

[0164] In some embodiments,; wherein n1 is 0 or 1, n6 is 0, 1, 2, 3, or 4 and R2ais selected from halogen (preferably fluoro) and C1-4 alkyl.1, 2, 3, or 4 and R2ais selected from halogen (preferably fluoro) and C1-4 alkyl.is 0, 1, 2, 3, or 4 and R2ais selected from halogen (preferably fluoro) and C1-4 alkyl.is 0, 1, 2, 3, or 4 and R2ais selected from halogen (preferably fluoro) and C1-4 alkyl.is 0, 1, 2, 3, or 4 and R2ais selected from halogen (preferably fluoro) and C1-4 alkyl.n8 is 0, 1, 2, 3, or 4 and R2ais selected from halogen (preferably fluoro) and C1-4 alkyl.

[0170] In some embodiments nl is 0. In some embodiments nl is 1

[0171] In some embodiments n2 is 0. In some embodiments n2 is 1

[0172] In some embodiments n3 is 0. In some embodiments n3 is 1

[0173] In some embodiments n4 is 0. In some embodiments n4 is 1

[0174] In some embodiments n5 is 0. In some embodiments n5 is 1

[0175] In some embodiments n6 is 0. In some embodiments n6 is 1

[0176] In some embodiments n7 is 0. In some embodiments n7 is 1

[0177] In some embodiments n8 is 0. In some embodiments n8 is 1

[0178] In some embodiments, R2ais fluoro.

[0179] In some embodiments, R2ais methyl. In such embodiments, R2amay be a substituent on nitrogen within the ring, e.g., where, the -N(H)- may be -N(R2a)-.

[0187] In some embodiments,

[0188] In some embodiments,

[0189] In some embodiments,

[0190] In some embodiments,

[0191] In some embodiments,F2HC

[0192] In some embodiments,is

[0193] In some embodiments,is selected from:

[0207] In some embodiments,

[0208] In some embodiments,

[0209] In some embodiments,

[0210] In some embodiments,

[0211] In some embodiments,

[0212] In some embodiments,

[0213] In some embodiments,

[0214] In some embodiments, R3is hydrogen.

[0215] In some embodiments, R3is Ci-6 alkyl. In some embodiments, R3is methyl. In some embodiments, R3is ethyl.

[0216] In some embodiments, R4ais hydrogen.

[0217] In some embodiments, R4ais Ci-e alkyl. In another embodiment, R4ais -CH3, -CH2CH3, -CH(CH3)2, -C(CH3)3, -CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)CH2CH3, -CH2C(CH3)3, -CH(CH3)CH(CH3)2, -C(CH3)2CH2CH3, -CH(CH3)C(CH3)3, or -C(CH3)2C(CH3)2.

[0218] In some embodiments, R4ais -CH3, -CH2CH3, -CH(CH3)2, -CH2CH2CH3, -CH2CH(CH3)2, or -CH(CH3)CH2CH3. In a most particular embodiment, R4ais -CH3.

[0219] In some embodiments, R4bis hydrogen.

[0220] In some embodiments, R4bis C1-6 alkyl. In another embodiment, R4bis -CH3, -CH2CH3, -CH(CH3)2, -C(CH3)3, -CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)CH2CH3, -CH2C(CH3)3, -CH(CH3)CH(CH3)2, -C(CH3)2CH2CH3, -CH(CH3)C(CH3)3, or -C(CH3)2C(CH3)2.

[0221] In some embodiments, R4bis -CH3, -CH2CH3, -CH(CH3)2, -CH2CH2CH3, -CH2CH(CH3)2, or -CH(CH3)CH2CH3. In a most particular embodiment, R4bis -CH3.

[0222] In some embodiments, R4aand R4bare each hydrogen.

[0223] In some embodiments, R4aand R4btogether with the carbon to which they are attached, form a C3-e cycloalkyl or 4-6 membered heterocycloalkyl comprising one or two heteroatoms independently selected from N, O, and S, which cycloalkyl or heterocycloalkyl is optionally substituted with one or more halo or C1.4 alkoxy.

[0224] In some embodiments, R4aand R4btogether with the carbon to which they are attached, form the structure:; wherein C is a C3-6 cycloalkyl or 4-6 membered heterocycloalkyl comprising one or two heteroatoms independently selected from N, O, and S; p is 0, 1, or 2; and R4cis independently selected from halo or C1.4 alkoxy.

[0225] In some embodiments, C is C3-6 cycloalkyl. In some embodiments, C is cyclopropyl. In some embodiments, C is cyclobutyl. In some embodiments, C is cyclopentyl.

[0226] In some embodiments, C is 4-6 membered heterocycloalkyl comprising one or two heteroatoms independently selected from N, O, and S. In some embodiments, C is 4-membered heterocycloalkyl comprising one heteroatom independently selected from N, O, and S. In some embodiments, C is 5-membered heterocycloalkyl comprising one or two heteroatoms independently selected from N, O, and S.

[0227] In some embodiments, C is selected from:

[0228] In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 0.

[0229] In some embodiments, R4cis halo. In some embodiments, R4cis fluoro.

[0230] In some embodiments, R4cis C1.4 alkoxy. In some embodiments, R4cis -O-methyl. In some embodiments, R4cis -O-ethyl.

[0231] In some embodiments, C is selected from:

[0232] In some embodiments, C is

[0233] In some embodiments, X is N. In some embodiments, X is CH.

[0234] In some embodiments, R6is hydrogen.

[0235] In some embodiments, R6is halo. In some embodiments, R6is fluoro.

[0236] In some embodiments, R6is Ci-6 alkyl. In some embodiments, R6is C1-3 alkyl. In some embodiments, R6is methyl.

[0237] In some embodiments, Li is a bond.

[0238] In some embodiments, L1is Ce-io aryl, which aryl is optionally substituted with one or more independently selected halo, C1.4 alkyl, C1.4 haloalkyl, -NH2, -NH(CI-4 alkyl), or -N(CI-4 alkyl)2, morpholine, -CH=CHCO2R9a, C1-4 alkoxy, C1-4 haloalkoxy or oxetane.

[0239] In some embodiments, Li is 5-6 membered monocyclic heteroaryl comprising one, two or three heteroatoms independently selected from N, O, and S, which heteroaryl is optionally substituted with one or more independently selected halo, C1-4 alkyl, C1.4 haloalkyl, -NH2, -NH(Ci-4 alkyl), or -N(CI-4 alkyl)2, morpholine, -CH=CHCO2R9a, C1-4 alkoxy, C1-4 haloalkoxy or oxetane.

[0240] In some embodiments, B is Ce-io aryl, which aryl is optionally substituted with one or more independently selected R7. In some embodiments, Li is a bond and B is Ce-io aryl, which aryl is optionally substituted with one or more independently selected R7.

[0241] In some embodiments, B is phenyl, which is optionally substituted with one or more independently selected R7. In some embodiments, B is phenyl, which is optionally substituted with one independently selected R7.>

[0242] In some embodiments, B is1R7]J r, wherein r is 0, 1, 2, 3, or 4.

[0243] In some embodiments,B is ' *.

[0244] In some embodiments, B is 5-10 membered monocyclic or bicyclic heteroaryl comprising one, two, three or four heteroatoms independently selected from N, O, and S which heteroaryl is optionally substituted with one or more independently selected R7. In some embodiments, Li is a bond and B is 5-10 membered monocyclic or bicyclic heteroaryl comprising one, two, three or four heteroatoms independently selected from N, O, and S which heteroaryl is optionally substituted with one or more independently selected R7.

[0245] In some embodiments, B is 5-6 membered monocyclic heteroaryl comprising one, two, or three heteroatoms independently selected from N, O, and S, which heteroaryl is optionally substituted with one or more independently selected R7.

[0246] In some embodiments, B is pyridyl, optionally substituted with one or more R7.

[0247] In some embodiments, B is selected from:

[0248] In some embodiments, r is 0.

[0249] In some embodiments, r is 2.

[0250] In some embodiments, r is 3.

[0251] In some embodiments, r is 4.

[0252] In some embodiments, r is 1.

[0253] In some embodiments, B is 9-10 membered bicyclic heteroaryl comprising one, two, or three heteroatoms independently selected from N, O, and S, which heteroaryl is optionally substituted with one or more independently selected R7.

[0254] In some embodiments, B is 9-membered bicyclic heteroaryl comprising one, two, or three heteroatoms independently selected from N, O, and S, which heteroaryl is optionally substituted with one or more independently selected R7.

[0255] In some embodiments, B is 10-membered bicyclic heteroaryl comprising one, two, or three heteroatoms independently selected from N, O, and S, which heteroaryl is optionally substituted with one or more independently selected R7.

[0256] In some embodiments, B is a 5-10 membered monocyclic or bicyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is optionally substituted with one or more independently selected R7. In some embodiments, Li is a bond and B is a 5-10 membered monocyclic or bicyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is optionally substituted with one or more independently selected R7.

[0257] In some embodiments, R7is selected from:oxo,- -OH,- -CN,- -P(O)(C1-4alkyl)2,halo,- -S(=O)2-Ci.4 alkyl,- -NR8aR8b,- -CH=CHCO2R9a,- -S(=O)2NHC(O)CI-2alkyl,- -S(=O)2NH2,- -C(O)NHS(=O)2C1-2alkyl,- -CONR9aR9b,- -CO2R9a,Ci-4 alkyl optionally substituted with one or more independently selected halo, -OH, -CN, -CO2R9aor C 1.4 alkoxy,Ci-4 alkoxy optionally substituted with one or more independently selected halo, -OH, -CN, or Ci.4 alkoxy,C3-6 cycloalkyl, which cycloalkyl is optionally substituted with one or more independently selected oxo, halo, -OH, -CN, C1-4 alkyl, or C1-4 alkoxy, and4-8 membered monocyclic or spirocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is optionally substituted with one or more independently selected oxo, halo, -OH, -CN, C1-4 alkyl, or C1-4 alkoxy, and- Q2

[0258] In some embodiments, R7is selected from:- -OH,- -CN,halo,Ci -4 alkyl optionally substituted with one or more independently selected halo, -OH, -CN, -CO2R9aor Ci -4 alkoxy,Ci -4 alkoxy optionally substituted with one or more independently selected halo, -OH, -CN, or Ci- 4 alkoxy,C3-6 cycloalkyl, which cycloalkyl is optionally substituted with one or more independently selected oxo, halo, -OH, -CN, C1.4 alkyl, or C1.4 alkoxy, and4-8 membered monocyclic or spirocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is optionally substituted with one or more independently selected oxo, halo, -OH, -CN, C1-4 alkyl, or C1-4 alkoxy, and- Q2

[0259] In some embodiments, R7is selected from:- -CN,halo,Ci -4 alkoxy optionally substituted with one or more independently selected halo, -OH, -CN, or Ci- 4 alkoxy, and4-8 membered monocyclic or spirocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is optionally substituted with one or more independently selected oxo, halo, -OH, -CN, C1.4 alkyl, or C1.4 alkoxy.

[0260] In some embodiments, R7is -CN.

[0261] In some embodiments, R7is halo. In some embodiments, R7is fluoro. In some embodiments, R7is chloro.

[0262] In some embodiments, R7is Ci-4 alkoxy optionally substituted with one or more independently selected halo, -OH, -CN, or C1.4 alkoxy.

[0263] In some embodiments, R7is C1.4 alkoxy optionally substituted with one or more independently selected -OH or C1.4 alkoxy.

[0264] In some embodiments, R7is C1.4 alkoxy optionally substituted with one or more independently selected -OH or C1-2 alkoxy.

[0265] In some embodiments, R7is C1-2 alkoxy optionally substituted with one or more independently selected -OH or C1-2 alkoxy.

[0266] In some embodiments, R7is -OCH3. In some embodiments, R7is -OCH2CH3. In some embodiments, R7is -OCH2CH2OH. In some embodiments, R7is -OCH2CH2OCH3.and

[0269] In some embodiments, R7is 4-8 membered monocyclic or spirocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is optionally substituted with one or more independently selected oxo, halo, -OH, -CN, C1.4 alkyl, or C1.4 alkoxy.

[0270] In some embodiments, R7is 4-membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is optionally substituted with one or more independently selected oxo, halo, -OH, -CN, C1-4 alkyl, or C1.4 alkoxy.

[0271] In some embodiments, R7is 5 -membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is optionally substituted with one or more independently selected oxo, halo, -OH, -CN, C1-4 alkyl, or C1.4 alkoxy.

[0272] In some embodiments, R7is 6-membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is optionally substituted with one or more independently selected oxo, halo, -OH, -CN, C1.4 alkyl, or C1.4 alkoxy.

[0273] In some embodiments, R7is 4-membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is optionally substituted with one or more independently selected halo, -OH, -CN, or C1-2 alkyl.

[0274] In some embodiments, R7is 5 -membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is optionally substituted with one or more independently selected halo, -OH, -CN, or C1-2 alkyl.

[0275] In some embodiments, R7is 6-membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is optionally substituted with one or more independently selected halo, -OH, -CN, or C1-2 alkyl.

[0276] In some embodiments, R7is selected from:wherein R7is optionally substituted with one or more independently selected halo, -OH, -CN, or C1-2 alkyl.

[0277] In some embodiments, Q2is selected from 5-10 membered monocyclic or bicyclic heteroaryl comprising one, two, or three heteroatoms independently selected from N, O, and S, which heteroaryl is optionally substituted with one or more R10b.

[0278] In some embodiments, Q2is selected from 5- or 6-membered monocyclic heteroaryl comprising one, two, or three heteroatoms independently selected from N, O, and S, which heteroaryl is optionally substituted with one or more R10b.

[0279] In some embodiments, Q2is 5 -membered monocyclic heteroaryl comprising one, two, or three heteroatoms independently selected from N, O, and S, which heteroaryl is optionally substituted with one or more R10b.

[0280] In some embodiments, Q2is 5 -membered monocyclic heteroaryl comprising one, two, or three heteroatoms independently selected from N, O, and S, which heteroaryl is optionally substituted with one or more C1.4 alkyl.

[0281] In some embodiments, Q2isH, optionally substituted with one or more C1.4 alkyl.N

[0282] In some embodiments, Q2isH, optionally substituted with one or more independently selected halo, -OH, -CN, C1-4 alkyl, or C1-4 alkoxy, preferably substituted with one or more C1-4 alkyl.

[0283] In some embodiments, L2 is a bond.

[0284] In some embodiments, L2 is C1-6 alkyl, which alkyl is optionally substituted with one or more halo, -OH, -CN, or C1.4 alkoxy.

[0285] In some embodiments, L2is C1.3 alkyl, which alkyl is optionally substituted with one or more halo, -OH, -CN, or C1.4 alkoxy.

[0286] In some embodiments, L2is -CH2-. In some embodiments, L2is -CH2CH2-.

[0287] In some embodiments, R5is independently selected from- hydrogen,- C1.4 alkyl optionally substituted with one or more independently selected halo, -OH, -CN, -CO2R9aor C1.4 alkoxy,- C3-6 cycloalkyl, which cycloalkyl is optionally substituted with one or more independently selected oxo, halo, -OH, -CN, C1.4 alkyl, or C1.4 alkoxy,- 4-8 membered monocyclic or spirocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is optionally substituted with one or more independently selected oxo, halo, -OH, -CN, C1.4 alkyl, C1.4 alkoxy, or -CO2R9a,- -Si(Ci.4alkyl)3, and- Q1

[0288] In some embodiments, R5is independently selected from- hydrogen,- C1.4 alkyl optionally substituted with one or more independently selected halo, -OH, -CN, -CO2R9aor C1-4 alkoxy,- C3-6 cycloalkyl, which cycloalkyl is optionally substituted with one or more independently selected oxo, halo, -OH, -CN, C1.4 alkyl, or C1-4 alkoxy,- 4-8 membered monocyclic or spirocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is optionally substituted with one or more independently selected oxo, halo, -OH, -CN, C1-4 alkyl, C1.4 alkoxy, or -CO2R9a, and - Q1

[0289] In some embodiments, R5is hydrogen.

[0290] In some embodiments, R5is C1.4 alkyl optionally substituted with one or more independently selected halo, -OH, -CN, -CO2R9aor C1.4 alkoxy.

[0291] In some embodiments, R5is C1-4 alkyl optionally substituted with one or more independently selected halo, -OH, or -CN.

[0292] In some embodiments, R5is Ci-4 alkyl optionally substituted with one or more -OH.

[0293] In some embodiments, R5is 4-8 membered monocyclic or spirocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is optionally substituted with one or more independently selected oxo, halo, -OH, -CN, C1.4 alkyl, C1.4 alkoxy, or -CO2R9a.

[0294] In some embodiments, R5is 4-6 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is optionally substituted with one or more independently selected oxo, halo, -OH, -CN, C1-4 alkyl, C1-4 alkoxy, or -CO2R9a.

[0295] In some embodiments, R5is Q1.

[0296] In some embodiments, Q1is selected from 5-10 membered monocyclic or bicyclic heteroaryl comprising one, two, or three heteroatoms independently selected from N, O, and S, which heteroaryl is optionally substituted with one or more independently selected halo, -OH, -CN, C1-4 alkyl, or C1-4 alkoxy.

[0297] In some embodiments, Q1is selected from 5-6 membered monocyclic heteroaryl comprising one, two, or three heteroatoms independently selected from N, O, and S, which heteroaryl is optionally substituted with one or more R10a.

[0298] In some embodiments, Q1is 6-membered monocyclic heteroaryl comprising one, two, or three heteroatoms independently selected from N, O, and S, which heteroaryl is optionally substituted with one or more R10a.

[0299] In some embodiments, Q1is 6-membered monocyclic heteroaryl comprising one, two, or three heteroatoms independently selected from N, O, and S, which heteroaryl is optionally substituted with one or more R10a, wherein R10ais C1.4 alkyl.

[0300] In some embodiments, Q1is 5-membered monocyclic heteroaryl comprising one, two, or three heteroatoms independently selected from N, O, and S, which heteroaryl is optionally substituted with one or more independently selected R10a.

[0301] In some embodiments, Q1is 5-membered monocyclic heteroaryl comprising one, two, or three heteroatoms independently selected from N, O, and S, which heteroaryl is optionally substituted with one or more R10a, wherein R10ais C1.4 alkyl.

[0302] In some embodiments, Q1is selected from:HandN, wherein Q1is optionally substituted with one or more R10b.ftN

[0303] In some embodiments, Q1isH, optionally substituted with one or more R10a.

[0304] In some embodiments, Q1is selected from:HandH, wherein Q1is optionally substituted with one or more R10a.

[0305] In some embodiments, Q1is selected from:

[0306] In some embodiments, Q1isH, optionally substituted with one or more R10a.

[0307] In some embodiments, Q1is selected from:H and N, wherein Q1is optionally substituted with one or more R10a.

[0308] In some embodiments, Q1is selected from:

[0309] In some embodiments, Q1is oN, optionally substituted with one or more R10a.

[0310] In some embodiments, Q1is selected from:

[0311] In some embodiments, Q1is N, wherein Q1is optionally substituted with one or more R10a.

[0312] In some embodiments, Q1is R10a, wherein Q1is optionally substituted with one or more R10b.

[0313] In some embodiments, R10ais independently selected from halo, -OH, -NR11aR11b, -CN, C1-2 alkyl, C1-2 haloalkyl, C1-2 alkoxy, C1-2 alkoxy(Ci-2)alkyl, C1-2 hydroxyalkyl, -CONR12aR12b, -CO2R12a, and -L3-Q3.

[0314] In some embodiments, R10ais independently selected from halo, -OH, -CN, C1.2 alkyl, C1.2 haloalkyl, C1.2 alkoxy, C1.2 hydroxyalkyl, and -L3-Q3.

[0315] In some embodiments, R10ais halo. In some embodiments, R10ais fluoro. In some embodiments, R10ais chloro.

[0316] In some embodiments, R10ais C1-4 alkyl. In some embodiments, R10ais C1-2 alkyl. In some embodiments, R10ais methyl. In some embodiments, R10ais ethyl.

[0317] In some embodiments, R10ais -L3-Q3.

[0318] In some embodiments, -L3- is a bond.

[0319] In some embodiments, -L3- is -O-.

[0320] In some embodiments, -L3- is C1-4 alkylene. In some embodiments, -L3- is C1-2 alkylene. In some embodiments, -L3- is C2 alkylene. In some embodiments, -L3- is Ci alkylene.

[0321] In some embodiments, Q3is C3-6 cycloalkyl, which cycloalkyl is optionally substituted with one or more independently selected oxo, halo, -OH, -CN, C1-4 alkyl, or C1-4 alkoxy.

[0322] In some embodiments, Q3is C3 cycloalkyl, which cycloalkyl is optionally substituted with one or more independently selected halo, -OH, -CN, C1-2 alkyl, or C1-2 alkoxy.

[0323] In some embodiments, Q3is 4-8 membered monocyclic heterocycloalkyl comprising one, two, or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is optionally substituted with one or more independently selected oxo, halo, -OH, -CN, C1.4 alkyl, or C1.4 alkoxy.

[0324] In some embodiments, Q3is 4-6 membered monocyclic heterocycloalkyl comprising one, two, or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is optionally substituted with one or more independently selected oxo, halo, -OH, -CN, C1.4 alkyl, or C1.4 alkoxy.

[0325] In some embodiments, Q3is 5 -membered monocyclic heterocycloalkyl comprising one, two, or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is optionally substituted with one or more independently selected oxo, halo, -OH, -CN, C1-4 alkyl, or C1.4 alkoxy.

[0326] In some embodiments, Q3is 6-membered monocyclic heterocycloalkyl comprising one, two, or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is optionally substituted with one or more independently selected oxo, halo, -OH, -CN, C1-4 alkyl, or C1.4 alkoxy.

[0327] In some embodiments, Q3is 6-membered monocyclic heterocycloalkyl comprising one, two, or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is optionally substituted with one or more independently selected halo, -OH, -CN, or C1.4 alkyl.

[0328] In some embodiments, Q3is 6-membered monocyclic heterocycloalkyl comprising one, two, or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is optionally substituted with one or more C1.4 alkyl.

[0329] In some embodiments, Q3is 6-membered monocyclic heterocycloalkyl comprising one, two, or three heteroatoms independently selected from N, O, and S.

[0330] In some embodiments, R10bis independently selected from halo, -OH, -NR11aR11b, -CN, C1.2 alkyl, Ci-2 haloalkyl, C1.2 alkoxy, C1.2 alkoxy(Ci.2)alkyl, C1.2 hydroxyalkyl, -CONR12aR12b, -CO2R12a, and -L3-Q3.

[0331] In some embodiments, R10bis independently selected from halo, -OH, -CN, C1.2 alkyl, C1.2 haloalkyl, C1.2 alkoxy, C1.2 hydroxyalkyl, and -L3-Q3.

[0332] In some embodiments, R10bis halo. In some embodiments, R10bis fluoro. In some embodiments, R10bis chloro.

[0333] In some embodiments, R10bis C1.4 alkyl. In some embodiments, R10bis C1-2 alkyl. In some embodiments, R10bis methyl. In some embodiments, R10bis ethyl.

[0334] In some embodiments, R8ais hydrogen. In some embodiments, R8ais C1-4 alkyl. In some embodiments, R8ais methyl. In some embodiments, R8ais ethyl.

[0335] In some embodiments, R8bis hydrogen. In some embodiments, R8bis -C(O)Ci-2 alkyl. In some embodiments, R8bis C1-4 alkyl. In some embodiments, R8bis methyl. In some embodiments, R8bis ethyl.

[0336] In some embodiments, R9ais hydrogen. In some embodiments, R9ais C1-4 alkyl. In some embodiments, R9ais methyl. In some embodiments, R9ais ethyl.

[0337] In some embodiments, R9bis hydrogen. In some embodiments, R9bis C1.4 alkyl. In some embodiments, R9bis methyl. In some embodiments, R9bis ethyl. In some embodiments, R9bis C1.4 alkoxy. In some embodiments, R9bis C1.2 alkoxy. In some embodiments, R9bis -OCH3. In some embodiments, R9bis -OCH2CH3.

[0338] In some embodiments, Rllais hydrogen. In some embodiments, Rllais C1-4 alkyl. In some embodiments, Rllais methyl. In some embodiments, Rllais ethyl.

[0339] In some embodiments, Rllbis hydrogen. In some embodiments, Rllbis -C(O)Ci-2 alkyl. In some embodiments, Rllbis C1-4 alkyl. In some embodiments, Rllbis methyl. In some embodiments, Rllbis ethyl.

[0340] In some embodiments, R12ais hydrogen. In some embodiments, R12ais C1-4 alkyl. In some embodiments, R12ais methyl. In some embodiments, R12ais ethyl.

[0341] In some embodiments, R12bis hydrogen. In some embodiments, R12bis C1.4 alkyl. In some embodiments, R12bis methyl. In some embodiments, R12bis ethyl. In some embodiments, R12bis C1.4 alkoxy.In some embodiments, R12bis C1-2 alkoxy. In some embodiments, R12bis -OCH3. In some embodiments, R9bis -OCH2CH3.

[0342] In some embodiments, R1and one R2together with the atoms onto which they are attached form a a 1,1 -dioxidotetrahydrothiophenyl, 1, 1 -dioxidotetrahydro-2H-thiopy rany 1, 1, 1 -dioxidothiomorpholinyl, 4,4-dioxido-l,4-oxathianyl, l,l-dioxido-l,4-dithianyl, 1,1-dioxidothiepanyl, 4,4-dioxido-l,4-oxathiepanyl, l,l-dioxido-l,4-thiazepanyl, or l,l-dioxido-l,4-dithiepanyl; optionally substituted with 0, 1, 2, 3, or 4 R2a.

[0343] In some embodiments, R1and one R2together with the atoms onto which they are attached form

[0344] In one embodiment, B is 5-10 membered monocyclic or bicyclic heteroaryl comprising one, two or three heteroatoms independently selected from N, O, and S. In another embodiment, B is pyrrolyl, furanyl, thiophenyl, imidazolyl, furazanyl, oxazolyl, oxadiazolyl, oxatriazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, triazinyl, imidazothiazolyl, benzofuranyl, benzothiophenyl, benzimidazolyl, benzoxazolyl, isobenzoxazolyl, benzisoxazolyl, benzothiazolyl, benzoisothiazolyl, isobenzofuranyl, indolyl, isoindolyl, indolizinyl, purinyl, indazolyl, pyrazolopyridinyl, 3,4-dihydro-2H-l,4-benzoxazinyl, 2,3-dihydro-lH-pyrido[2,3-b] [ 1,4] oxazinyl, 2,3 -dihydro- IH-pyrido [3,4-b] [ 1,4] oxazinyl, 3,4-dihydro-2H-pyrido [3,2-b] [ 1,4] oxazinyl, 3,4-dihydro-2H-pyrido[4,3 -b] [ 1,4]oxazinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydro- 1,5-naphthyridinyl, 1,2,3,4-tetrahydro- 1,6-naphthyridinyl, 1,2,3,4-tetrahydro- 1,7-naphthyridinyl, 1,2,3,4-tetrahydro-l,8-naphthyridinyl, l,2,3,4-tetrahydro-2,6-naphthyridinyl, l,2,3,4-tetrahydro-2,7-naphthyridinyl, 5,6,7,8-tetrahydro-l,6-naphthyridinyl, 5,6,7,8-tetrahydro-l,7-naphthyridinyl, or 1,2,3,4-tetrahydroquinolinyl. In another embodiment, B is pyridinyl, pyrazolyl, indolyl, 1, 2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, 3,4-dihydro-2H-pyrido[3,2-b] [1,4] oxazinyl. Inanother embodiment, B is or

[0345] In one embodiment, B is 5-10 membered monocyclic or bicyclic heteroaryl comprising one, two or three heteroatoms independently selected from N, O, and S, which heteroaryl is substituted with one or more independently selected R7. In another embodiment, B is pyrrolyl, furanyl, thiophenyl, imidazolyl, furazanyl, oxazolyl, oxadiazolyl, oxatriazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, triazinyl, imidazothiazolyl, benzofuranyl, benzothiophenyl, benzimidazolyl, benzoxazolyl, isobenzoxazolyl, benzisoxazolyl, benzothiazolyl, benzoisothiazolyl, isobenzofuranyl, indolyl, isoindolyl, indolizinyl, purinyl, indazolyl, pyrazolopyridinyl, 3,4-dihydro-2H-l,4-benzoxazinyl, 2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazinyl, 2,3-dihydro-lH-pyrido[3,4-b][l,4]oxazinyl, 3,4-dihydro-2H-pyrido[3,2-b][l,4]oxazinyl, 3,4-dihydro-2H-pyrido[4,3-b] [1,4] oxazinyl, 1,2,3,4-tetrahydroisoquinolinyl, l,2,3,4-tetrahydro-l,5-naphthyridinyl, 1,2,3,4-tetrahydro-1,6-naphthyridinyl, l,2,3,4-tetrahydro-l,7-naphthyridinyl, l,2,3,4-tetrahydro-l,8-naphthyridinyl, 1, 2,3,4-tetrahydro-2,6-naphthyridinyl, l,2,3,4-tetrahydro-2,7-naphthyridinyl, 5,6,7,8-tetrahydro-l,6-naphthyridinyl, 5,6,7,8-tetrahydro-l,7-naphthyridinyl, or 1,2,3,4-tetrahydroquinolinyl, each of which is substituted with one or more independently selected R7. In another embodiment, B is 5-10 membered monocyclic or bicyclic heteroaryl comprising one, two or three heteroatoms independently selected from N, O, and S, which heteroaryl is substituted with one, two, or three independently selected R7. In another embodiment, B is pyrrolyl, furanyl, thiophenyl, imidazolyl, furazanyl, oxazolyl, oxadiazolyl, oxatriazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, triazinyl, imidazothiazolyl, benzofuranyl, benzothiophenyl, benzimidazolyl, benzoxazolyl, isobenzoxazolyl, benzisoxazolyl, benzothiazolyl, benzoisothiazolyl, isobenzofuranyl, indolyl, isoindolyl, indolizinyl, purinyl, indazolyl, pyrazolopyridinyl, 3,4-dihydro-2H-l,4-benzoxazinyl, 2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazinyl, 2,3-dihydro-lH-pyrido[3,4-b][l,4]oxazinyl, 3,4-dihydro-2H-pyrido[3,2-b][ 1,4] oxazinyl, 3,4-dihydro-2H-pyrido[4,3-b][l,4]oxazinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1, 2,3,4-tetrahydro- 1,5 -naphthyridinyl, 1,2,3,4-tetrahydro- 1,6-naphthyridinyl, 1,2,3,4-tetrahydro- 1,7-naphthyridinyl, l,2,3,4-tetrahydro-l,8-naphthyridinyl, l,2,3,4-tetrahydro-2,6-naphthyridinyl, 1, 2,3,4-tetrahydro-2,7-naphthyridinyl, 5,6,7,8-tetrahydro-l,6-naphthyridinyl, 5,6,7,8-tetrahydro-l,7-naphthyridinyl, or 1,2,3,4-tetrahydroquinolinyl, each of which is substituted with one, two, or three independently selected R7.

[0346] In one embodiment, B is 5-6 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S. In another embodiment, B is pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, dioxanyl, or piperazinyl.

[0347] In one embodiment, B is 5-6 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is substituted with one or more independently selected R7. In another embodiment, B is pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, dioxanyl, or piperazinyl, each of which is substituted with one or more independently selected R7. In another embodiment, B is 5-6 membered monocyclic heterocycloalkyl comprising one, twoor three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is substituted with one, two, or three independently selected R7. In another embodiment, B is pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, dioxanyl, or piperazinyl, each of which is substituted with one, two, or three independently selected R7. In another embodiment, B is piperidinyl, piperazinyl, or morpholinyl, each of which is substituted with one, two, or three independently selected R7.

[0348] In one embodiment, B is Ce-io aryl, 5-10 membered monocyclic or bicyclic heteroaryl comprising one, two or three heteroatoms independently selected from N, O, and S, or 5-6 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S, which aryl, heteroaryl, or heterocycloalkyl is substituted with one or more independently selected R7, and R7is oxo, -OH, -CN, halo, or -S(=O)2-Ci-4 alkyl. In another embodiment, R7is oxo, -OH, -CN, F, Cl, Br, -S(=O)2-CH3, -S(=O)2-CH2CH3, or -S(=O)2-CH(CH3)2. In another embodiment, R7is oxo, -OH, -CN, F, Cl, Br, or -S(=O)2-CH3.

[0349] In one embodiment, B is Ce-io aryl, 5-10 membered monocyclic or bicyclic heteroaryl comprising one, two or three heteroatoms independently selected from N, O, and S, or 5-6 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S, which aryl, heteroaryl, or heterocycloalkyl is substituted with one or more independently selected R7, R7is -NR8aR8b, and R8aand R8bare independently H or Ci_4alkyl. In another embodiment, R8aand R8bare both H. In another embodiment, one of R8aand R8bis H, and the other is Ci-4alkyl. In yet another embodiment, R8aand R8bare both independently C1.4 alkyl. In another embodiment, one of R8aand R8bis H, and the other is -CH3, -CH2CH3, or -CH(CH3)2. In another embodiment, R8aand R8bare both independently -CH3, -CH2CH3, or -CH(CH3)2. In another embodiment, R8aand R8bare both -CH3.

[0350] In one embodiment, B is Ce-io aryl, 5-10 membered monocyclic or bicyclic heteroaryl comprising one, two or three heteroatoms independently selected from N, O, and S, or 5-6 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S, which aryl, heteroaryl, or heterocycloalkyl is substituted with one or more independently selected R7, and R7is C1-4 alkyl. In another embodiment, R7is -CH3, -CH2CH3, -CH(CH3)2. In another embodiment, R7is -CH3.

[0351] In one embodiment, B is Ce-io aryl, 5-10 membered monocyclic or bicyclic heteroaryl comprising one, two or three heteroatoms independently selected from N, O, and S, or 5-6 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S, which aryl, heteroaryl, or heterocycloalkyl is substituted with one or more independently selected R7, and R7is C1-4 alkyl substituted with one or more independently selected halo, -CN, or C1-4 alkoxy. In another embodiment, R7is -CH3, -CH2CH3, -CH(CH3)2, each of which is substituted with one or more independently selected halo, -CN, or C1.4 alkoxy. In another embodiment, R7is C1.4 alkyl substituted with one, two, or three independently selected halo, -CN, or C1.4 alkoxy. In yet another embodiment, R7is C1.4 alkyl substituted with one or more independently selected F, Cl, Br, -CN, -O-CH3, -O-CH2CH3, or -O-CH(CH3)2. In another embodiment, R7is -CH3, -CH2CH3, -CH(CH3)2, each of which is substitutedwith one, two, or three independently selected F, Cl, Br, -CN, -O-CH3, -O-CH2CH3, or -O-CH(CH3)2. In another embodiment, R7is -CH3 or -CH2CH3, each of which is substituted with one, two, or three independently selected F, -CN, or -O-CH3. In yet another embodiment, R7is -CHF2, -CF3, -CH2CN, or -CH2CH2CN.

[0352] In one embodiment, B is Ce-io aryl, 5-10 membered monocyclic or bicyclic heteroaryl comprising one, two or three heteroatoms independently selected from N, O, and S, or 5-6 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S, which aryl, heteroaryl, or heterocycloalkyl is substituted with one or more independently selected R7, and R7is C1-4 alkoxy. In another embodiment, R7is -O-CH3, -O-CH2CH3, -O-CH(CH3)2. In another embodiment, R7is -O-CH3.

[0353] In one embodiment, B is Ce-io aryl, 5-10 membered monocyclic or bicyclic heteroaryl comprising one, two or three heteroatoms independently selected from N, O, and S, or 5-6 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S, which aryl, heteroaryl, or heterocycloalkyl is substituted with one or more independently selected R7, and R7is C1-4 alkoxy substituted with one or more independently selected halo, -CN, or C1.4 alkoxy. In another embodiment, R7is -O-CH3, -O-CH2CH3, -O-CH(CH3)2, each of which is substituted with one or more independently selected halo, -CN, or C1-4 alkoxy. In another embodiment, R7is C1-4 alkoxy substituted with one, two, or three independently selected halo, -CN, or C1-4 alkoxy. In yet another embodiment, R7is C1.4 alkoxy substituted with one or more independently selected F, Cl, Br, -CN, -O-CH3, -O-CH2CH3, or -O-CH(CH3)2. In another embodiment, R7is -O-CH3, -O-CH2CH3, -O-CH(CH3)2, each of which is substituted with one, two, or three independently selected F, Cl, Br, -CN, -O-CH3, -O-CH2CH3, or -O-CH(CH3)2. In another embodiment, R7is -O-CH3 or -O-CH2CH3, each of which is substituted with one, two, or three independently selected F, -CN, or -O-CH3. In another embodiment, R7is -O-CHF2, -O-CF3, or -O-CH2CH2-O-CH3.

[0354] In one embodiment, B is Ce-io aryl, 5-10 membered monocyclic or bicyclic heteroaryl comprising one, two or three heteroatoms independently selected from N, O, and S, or 5-6 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S, which aryl, heteroaryl, or heterocycloalkyl is substituted with one or more independently selected R7, and R7is 4-8 membered monocyclic or spirocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S. In another embodiment, R7is azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, dioxanyl, piperazinyl, 5-azaspiro[2.3]hexanyl, 4-azaspiro[2.3]hexanyl, 5-thiaspiro[2.3]hexanyl, 4-thiaspiro[2.3]hexanyl, 5-oxaspiro[2.3]hexanyl, 4-oxaspiro[2.3]hexanyl, 1 -azaspiro [3.3 ]heptanyl, 2-azaspiro[3.3]heptanyl, 5-azaspiro[2.4]heptanyl, 4-azaspiro[2.4]heptanyl, l-thiaspiro[3.3]heptanyl, 2-thiaspiro[3.3]heptanyl, 5-thiaspiro[2.4]heptanyl, 4-thiaspiro[2.4]heptanyl, l-oxaspiro[3.3]heptanyl, 2-oxaspiro[3.3]heptanyl, 5-oxaspiro[2.4]heptanyl, or 4-oxaspiro[2.4]heptanyl. In another embodiment, R7is azetidinyl, oxetanyl, morpholinyl, thiomorpholinyl, piperazinyl, or 2-oxaspiro[3.3]heptanyl.

[0355] In one embodiment, B is Ce-io aryl, 5-10 membered monocyclic or bicyclic heteroaryl comprising one, two or three heteroatoms independently selected from N, O, and S, or 5-6 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S, which aryl, heteroaryl, or heterocycloalkyl is substituted with one or more independently selected R7, and R7is 4-8 membered monocyclic or spirocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is optionally substituted with one or more independently selected oxo, halo, -OH, -CN, C1.4 alkyl, or C1.4 alkoxy. In another embodiment, R7is azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, dioxanyl, piperazinyl, 5-azaspiro[2.3]hexanyl, 4-azaspiro[2.3]hexanyl, 5-thiaspiro[2.3]hexanyl, 4-thiaspiro[2.3]hexanyl, 5-oxaspiro[2.3]hexanyl, 4-oxaspiro[2.3]hexanyl, l-azaspiro[3.3]heptanyl, 2-azaspiro[3.3]heptanyl, 5-azaspiro[2.4]heptanyl, 4-azaspiro[2.4]heptanyl, l-thiaspiro[3.3]heptanyl, 2-thiaspiro[3.3]heptanyl, 5-thiaspiro[2.4]heptanyl, 4-thiaspiro[2.4]heptanyl, l-oxaspiro[3.3]heptanyl, 2-oxaspiro[3.3]heptanyl, 5-oxaspiro[2.4]heptanyl, or 4-oxaspiro[2.4]heptanyl, each of which is substituted with one or more independently selected oxo, halo, -OH, -CN, C1-4 alkyl, or C1.4 alkoxy. In another embodiment, R7is 4-8 membered monocyclic or spirocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is substituted with one, two, or three independently selected oxo, halo, -OH, -CN, C1-4 alkyl, or C1-4 alkoxy. In yet another embodiment, R7is 4-8 membered monocyclic or spirocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is substituted with one or more independently selected oxo, F, Cl, Br, -OH, -CN, -CH3, -CH2CH3, -CH(CH3)2, -O-CH3, -O-CH2CH3, or -O-CH(CH3)2. In another embodiment, R7is azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, dioxanyl, piperazinyl, 5-azaspiro[2.3]hexanyl, 4-azaspiro[2.3]hexanyl, 5-thiaspiro[2.3]hexanyl, 4-thiaspiro[2.3]hexanyl, 5-oxaspiro[2.3]hexanyl, 4-oxaspiro[2.3]hexanyl, 1-azaspiro[3.3]heptanyl, 2-azaspiro[3.3]heptanyl, 5 -azaspiro [2.4]heptanyl, 4-azaspiro[2.4]heptanyl, 1-thiaspiro[3.3]heptanyl, 2-thiaspiro[3.3]heptanyl, 5 -thiaspiro [2.4]heptanyl, 4-thiaspiro[2.4]heptanyl, 1-oxaspiro[3.3]heptanyl, 2-oxaspiro[3.3]heptanyl, 5 -oxaspiro [2.4]heptanyl, or 4-oxaspiro[2.4]heptanyl, each of which is substituted with one, two, or three independently selected oxo, F, Cl, Br, -OH, -CN, -CH3, -CH2CH3, -CH(CH3)2, -O-CH3, -O-CH2CH3, or -O-CH(CH3)2. In another embodiment, R7is azetidinyl, oxetanyl, morpholinyl, thiomorpholinyl, piperazinyl, or 2-oxaspiro[3.3]heptanyl, each of which is substituted with one, two, or three independently selected oxo, F, Cl, Br, -OH, -CN, -CH3, -CH2CH3, -CH(CH3)2, -O-CH3, -O-CH2CH3, or -O-CH(CH3)2.

[0356] In one embodiment, a compound of the invention is provided in a natural isotopic form.

[0357] In one embodiment, a compound of the invention is provided in an unnatural variant isotopic form. In a specific embodiment, the unnatural variant isotopic form is a form in which deuterium (i.e.2H or D) is incorporated where hydrogen is specified in the chemical structure in one or more atoms of a compound of the invention. In one embodiment, the atoms of the compounds of the invention are in an isotopic formwhich is not radioactive. In one embodiment, one or more atoms of the compounds of the invention are in an isotopic form which is radioactive. Suitably radioactive isotopes are stable isotopes. Suitably, the unnatural variant isotopic form is a pharmaceutically acceptable form.

[0358] In one embodiment, a compound of the invention is provided whereby a single atom of the compound exists in an unnatural variant isotopic form. In another embodiment, a compound of the invention is provided whereby two or more atoms exist in an unnatural variant isotopic form.

[0359] Unnatural isotopic variant forms can generally be prepared by conventional techniques known to those skilled in the art or by processes described herein e.g. processes analogous to those described in the accompanying Examples for preparing natural isotopic forms. Thus, unnatural isotopic variant forms could be prepared by using appropriate isotopically variant (or labelled) reagents in place of the normal reagents employed in the illustrative example as examples.

[0360] In one aspect a compound of the invention according to any one of the embodiments herein described is present as the free base.

[0361] In one aspect a compound of the invention according to any one of the embodiments herein described is a pharmaceutically acceptable salt of the compound.

[0362] In one aspect a compound of the invention according to any one of the embodiments herein described is a solvate of the compound.

[0363] In one aspect a compound of the invention according to any one of the embodiments herein described is a solvate of a pharmaceutically acceptable salt of the compound.

[0364] While specified groups for each embodiment have generally been listed above separately, a compound of the invention includes one in which several or each embodiment in the above Formula, as well as other formulae presented herein, is selected from one or more of particular members or groups designated respectively, for each variable. Therefore, this invention is intended to include all combinations of such embodiments within its scope.

[0365] While specified groups for each embodiment have generally been listed above separately, a compound of the invention may be one for which one or more variables (for example, R groups) is selected from one or more embodiments according to any of the Formula(e) listed above. Therefore, the present invention is intended to include all combinations of variables from any of the disclosed embodiments within its scope.

[0366] Alternatively, the exclusion of one or more of the specified variables from a group or an embodiment, or combinations thereof is also contemplated by the present invention.

[0367] In certain aspects, the present invention provides prodrugs and derivatives of the compounds according to the formulae above. Prodrugs are derivatives of the compounds of the invention, which have metabolically cleavable groups and become by solvolysis or under physiological conditions the compounds of the invention, which are pharmaceutically active, in vivo. Such examples include, but are not limited to, choline ester derivatives and the like, N-alkylmorpholine esters and the like.

[0368] Other derivatives of the compounds of this invention have activity in both their acid and acid derivative forms, but the acid sensitive form often offers advantages of solubility, tissue compatibility, ordelayed release in the mammalian organism (Bundgaard 1985). Prodrugs include acid derivatives well known to practitioners of the art, such as, for example, esters prepared by reaction of the parent acid with a suitable alcohol, or amides prepared by reaction of the parent acid compound with a substituted or unsubstituted amine, or acid anhydrides, or mixed anhydrides. Simple aliphatic or aromatic esters, amides and anhydrides derived from acidic groups pendant on the compounds of this invention are preferred prodrugs. In some cases it is desirable to prepare double ester type prodrugs such as (acyloxy)alkyl esters or ((alkoxycarbonyl)oxy)alkylesters. Particularly useful are the Ci to Cs alkyl, C2-C8 alkenyl, aryl, C7-C12 substituted aryl, and C7-C12 arylalkyl esters of the compounds of the invention.

[0369] A further aspect of the invention concerns a compound according to Formula (I):(I)wherein,A is 6-10 membered monocyclic or bicyclic aryl, or 5-10 membered monocyclic or bicyclic heteroaryl comprising one, two or three heteroatoms independently selected from N, O, and S;R< N,0.,0 N O RzV'S's / V'sx / Y is independently selected from' *, ' ' and ' *;Ryand Rzare each independently hydrogen or C1-3 alkyl;X is N or CH;R1is C1-6alkyl, C1-3alkoxy(C1-3)alkyl, -N(C1-3alkyl)2or hydroxy(C1-4)alkyl, wherein said alkyl and alkoxy groups are optionally substituted with one or more halogen;n is 0, 1, or 2;each R2is independently selected from halogen and Ci-e alkyl, which alkyl is optionally substituted with halo, OH, or C1.4 alkoxy;or R1and one R2together with the atoms onto which they are attached form a fused 5-8 membered monocyclic cycloalkyl, or a fused 5-8 membered monocyclic heterocycloalkyl comprising Y in formula I and zero, one, or two additional heteroatoms independently selected from N, O, and S, wherein the cycloalkyl or heterocycloalkyl is optionally substituted with one or more independently selected halogens (preferably fluoro) or C1-4 alkyl;R3is hydrogen or C1-6 alkyl;R4aand R4bare each independently hydrogen or C1-6 alkyl optionally substituted with one or more independently selected halo or C1-4 alkoxy;or R4aand R4b, together with the carbon to which they are attached, form a C3-6 cycloalkyl or 4-6 membered heterocycloalkyl comprising one or two heteroatoms independently selected from N, O, and S, which cycloalkyl or heterocycloalkyl is optionally substituted with one or more halo or C1-4 alkoxy;Li is a bond, Ce-io aryl, or 5-6 membered monocyclic heteroaryl comprising one, two or three heteroatoms independently selected from N, O, and S, which aryl or heteroaryl is optionally substituted with one or more independently selected halo, C1-4 alkyl, C1-4 haloalkyl, -NH2, -NH(CI-4 alkyl), or -N(CI-4 alkyl)2, morpholine, -CH=CHCO2R9a, C1.4 alkoxy, C1.4 haloalkoxy or oxetane;B is Ce-io aryl, 5-10 membered monocyclic or bicyclic heteroaryl comprising one, two, three or four heteroatoms independently selected from N, O, and S, or a 5-10 membered monocyclic or bicyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S, each of which is optionally substituted with one or more independently selected R7;L2 is a bond, Ci-e alkyl or C3-6 cycloalkyl, which alkyl or cycloalkyl is optionally substituted with one or more halo, -OH, -CN, or C1-4 alkoxy;R5is independently selected from- hydrogen,- oxo,- -OH,- -CN,- -P(O)(C1-4alkyl)2,- halo,- -S(=O)2-Ci.4 alkyl,- -NR8aR8b,- -CH=CHCO2R9a,- -S(=O)2NHC(O)C1-2alkyl,- -S(=O)2NH2,- -C(O)NHS(=O)2C1-2alkyl,- -CONR9aR9b,- -CO2R9a,- C1.4 alkyl optionally substituted with one or more independently selected halo, -OH, -CN, -CO2R9a, C1.4 alkyl, or C1.4 alkoxy,- C1.4 alkoxy optionally substituted with one or more independently selected halo, -OH, -CN, -CO2R9a, C1.4 alkoxy, or C3-6 cycloalkyl,- C3-6 cycloalkyl, which cycloalkyl is optionally substituted with one or more independently selected oxo, halo, -OH, -CN, C1.4 alkyl, or C1.4 alkoxy,- 4-8 membered monocyclic or spirocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is optionally substituted with one or more independently selected oxo, halo, -OH, -CN, C1-4 alkyl, C1-4 alkoxy, -S(=O)2Ci-4 alkyl, - C(=O)Ci.4 alkyl, or -CO2R9a,- -Si(Ci-4alkyl)3, and- Q1;R6is hydrogen, halo, or Ci-e alkyl;each R7is independently selected from- oxo,- -OH,- -CN,- -P(O)(C1-4alkyl)2,- halo,- -S(=O)2-Ci.4 alkyl,- -NR8aR8b,- -CH=CHCO2R9a,- -S(=O)2NHC(O)CI-2alkyl,- -S(=O)2NH2,- -C(O)NHS(=O)2C1-2alkyl,- -CONR9aR9b,- -CO2R9a,- Ci-4 alkyl optionally substituted with one or more independently selected halo, -OH, -CN, -CO2R9aor Ci -4 alkoxy,- Ci-4 alkoxy optionally substituted with one or more independently selected halo, -OH, -CN, or Ci-4 alkoxy,- C3-6 cycloalkyl, which cycloalkyl is optionally substituted with one or more independently selected oxo, halo, -OH, -CN, C1-4 alkyl, C1-4 alkoxy, or C1-4 alkyl, optionally substituted with OH;- 4-8 membered monocyclic or spirocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is optionally substituted with one or more independently selected oxo, halo, -OH, -CN, C1-4 alkyl, C1-4 alkoxy, or C1-4 alkyl, optionally substituted with OH; and- Q2;Q1is selected from phenyl and 5-12 membered monocyclic or bicyclic heteroaryl comprising one, two, or three heteroatoms independently selected from N, O, and S, which phenyl and heteroaryl is optionally substituted with one or more R10a;Q2is selected from phenyl and 5-10 membered monocyclic or bicyclic heteroaryl comprising one, two, or three heteroatoms independently selected from N, O, and S, which phenyl and heteroaryl is optionally substituted with one or more R10b;each R8ais independently hydrogen or C1-4 alkyl;each R8bis independently hydrogen, C1-4 alkyl or -C(O)C1-2alkyl;each R9ais independently selected from hydrogen and C1-4 alkyl;R9bis hydrogen, C1-4 alkyl or C1-4 alkoxy, or R9aand R9btogether with the atoms onto which they are attached form a 4-7 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is optionally substituted with one or more independently selected oxo, halo, -OH, -CN, C1-4 alkyl;R10aand R10bare each independently selected from halo, -OH, -NR11aR11b, -CN, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 alkoxy (Ci-4)alkyl, C1-4 hydroxyalkyl, -CONR12aR12b, -CO2R12a, -L3-Q3, and C1-4 alkoxy, optionally substituted by OH;-L3- is a bond, -O-, or C1.4 alkylene;Q3is selected from C3-6 cycloalkyl, 4-8 membered monocyclic heterocycloalkyl comprising one, two, or three heteroatoms independently selected from N, O, and S, 6-10 membered bicyclic fused, bridged, or spiro heterocycloalkyl comprising one, two, or three heteroatoms independently selected from N, O, and S, which cycloalkyl or heterocycloalkyl is optionally substituted with one or more independently selected oxo, halo, -OH, -CN, C1-4 alkyl, or C1-4 alkoxy;each R11ais independently hydrogen or C1-4 alkyl;each R11bis independently hydrogen, C1-4 alkyl or -C(O)C1-2alkyl;each R12ais independently selected from hydrogen and C1-4 alkyl; andR12bis hydrogen, C1-4 alkyl or C 1-4 alkoxy, or R12aand R12btogether with the atoms onto which they are attached form a 4-7 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is optionally substituted with one or more independently selected oxo, halo, -OH, -CN, C1-4 alkyl;or a pharmaceutically acceptable salt and / or solvate thereof.

[0370] The compound, or a pharmaceutically acceptable salt and / or solvate thereof, according to claim 16,

[0380] In some embodiments,

[0381] In some embodiments,R1

[0383] In some embodiments,R1

[0384] In some embodiments,R1

[0385] In some embodiments,R1

[0386] In some embodiments,R1

[0387] In some embodiments,R1

[0388] In some embodiments,R1

[0389] In some embodiments,

[0390] In some embodiments,

[0391] In some embodiments,

[0392] In certain embodiments, the compound of Formula (I) of this aspect is according to any of the embodiments of the first aspect, as far as they are chemically allowed.PHARMACEUTICAL COMPOSITIONS

[0393] When employed as a pharmaceutical, a compound of the invention is typically administered in the form of a pharmaceutical composition. Such compositions can be prepared in a manner well known in the pharmaceutical art and comprise at least one active compound of the invention according to Formula I. Generally, a compound of the invention is administered in a pharmaceutically effective amount. The amount of compound of the invention actually administered will typically be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound of the invention administered, the age, weight, and response of the individual patient, the severity of the patient’s symptoms, and the like.

[0394] In one embodiment, the present invention provides pharmaceutical compositions comprising a compound of the invention and another therapeutic agent.

[0395] In one embodiment, the present invention provides pharmaceutical compositions comprising a compound of the invention and another therapeutic agent, which other therapeutic agent is a proliferative diseases treatment agent. In particular, the term proliferative diseases refers to cancer, myeloproliferative disorders, leukemia, multiple myeloma, psoriasis, restenosis, scleroderma or fibrosis. More particularly, the term refers to cancer, leukemia, and multiple myeloma.

[0396] In a particular embodiment, the present invention provides pharmaceutical compositions comprising a compound of the invention and another therapeutic agent, which other therapeutic agent is a cancer treatment agent. In particular, the term refers to both metastatic tumour cell types (such as but not limited to, melanoma, lymphoma, leukemia, fibrosarcoma, rhabdomyosarcoma, and mastocytoma) and types of tissue carcinoma (such as but not limited to, colorectal cancer, prostate cancer, small cell lung cancer and non-small cell lung cancer, breast cancer, pancreatic cancer, bladder cancer, renal cancer, gastric cancer, glioblastoma, primary liver cancer, ovarian cancer, and uterine leiomyosarcoma). More particularly, the term refers to acute lymphoblastic leukemia, acute myeloid leukemia, adrenocortical carcinoma, anal cancer, appendix cancer, astrocytomas, atypical teratoid / rhabdoid tumor, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer (osteosarcoma and malignant fibrous histiocytoma), brain stem glioma,brain tumors, brain and spinal cord tumors, breast cancer, bronchial tumors, Burkitt lymphoma, cervical cancer, chronic lymphocytic leukemia, chronic myelogenous leukemia, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, embryonal tumors, endometrial cancer, ependymoblastoma, ependymoma, esophageal cancer, Ewing sarcoma family of tumors, eye cancer, retinoblastoma, gallbladder cancer, gastric (stomach) cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST), gastrointestinal stromal cell tumor, germ cell tumor, glioma, hairy cell leukemia, head and neck cancer, hepatocellular (liver) cancer, hypopharyngeal cancer, intraocular melanoma, islet cell tumors (endocrine pancreas), Kaposi’s sarcoma, kidney cancer, Langerhans cell histiocytosis, laryngeal cancer, leukemia, hairy cell leukemia, liver cancer, non-small cell lung cancer, small cell lung cancer, Hodgkin lymphoma, non-Hodgkin lymphoma, lymphoma, Waldenstrom macroglobulinemia, medulloblastoma, medulloepithelioma, melanoma, mesothelioma, mouth cancer, myeloid leukemia, multiple myeloma, nasopharyngeal cancer, neuroblastoma, oral cancer, oropharyngeal cancer, osteosarcoma, malignant fibrous histiocytoma of bone, ovarian cancer, ovarian epithelial cancer, ovarian germ cell tumor, ovarian low malignant potential tumor, pancreatic cancer, papillomatosis, parathyroid cancer, penile cancer, pharyngeal cancer, pineal parenchymal tumors of intermediate differentiation, pineoblastoma and supratentorial primitive neuroectodermal tumors, pituitary tumor, plasma cell neoplasm / multiple myeloma, pleuropulmonary blastoma, primary central nervous system lymphoma, prostate cancer, rectal cancer, renal cell (kidney) cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcoma, Ewing sarcoma family of tumors, sarcoma, Sezary syndrome, skin cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, squamous cell carcinoma, stomach (gastric) cancer, supratentorial primitive neuroectodermal tumors, testicular cancer, throat cancer, thymoma and thymic carcinoma, thyroid cancer, urethral cancer, uterine cancer, uterine sarcoma, vaginal cancer, vulvar cancer, and Wilms tumor. Most particularly, the term refers to non-small cell lung cancer, Burkitt lymphoma, medulloblastoma, pancreatic cancer, ovarian cancer, and melanoma

[0397] In a further particular embodiment, the present invention provides pharmaceutical compositions comprising a compound of the invention and another therapeutic agent, which other therapeutic agent is a leukemia treatment agent. In particular, the term refers to neoplastic diseases of the blood and blood forming organs. More particularly, the term refers to acute myeloid leukemia (AML), and acute lymphoblastic leukemia (ALL) and chronic lymphoblastic leukemia (CLL).

[0398] The pharmaceutical compositions of this invention can be administered by a variety of routes including oral, rectal, transdermal, subcutaneous, intra-articular, intravenous, intramuscular, and intranasal. Depending on the intended route of delivery, a compound of the invention is preferably formulated as either injectable or oral compositions or as salves, as lotions or as patches all for transdermal administration.

[0399] The compositions for oral administration can take the form of bulk liquid solutions or suspensions, or bulk powders. More commonly, however, the compositions are presented in unit dosage forms to facilitate accurate dosing. The term ‘unit dosage forms’ refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceuticalexcipient, vehicle or carrier. Typical unit dosage forms include prefilled, premeasured ampules or syringes of the liquid compositions or pills, tablets, capsules or the like in the case of solid compositions. In such compositions, the compound of the invention according to Formula I is usually a minor component (from about 0.1 to about 50% by weight or preferably from about 1 to about 40% by weight) with the remainder being various vehicles or carriers and processing aids helpful for forming the desired dosing form.

[0400] Liquid forms suitable for oral administration may include a suitable aqueous or non-aqueous vehicle with buffers, suspending and dispensing agents, colorants, flavors and the like. Solid forms may include, for example, any of the following ingredients, or compound of the inventions of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or com starch; a lubricant such as magnesium stearate; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint or orange flavoring.

[0401] Injectable compositions are typically based upon injectable sterile saline or phosphate -buffered saline or other injectable carriers known in the art. As before, the active compound of the invention according to Formula I in such compositions is typically a minor component, often being from about 0.05 to 10% by weight with the remainder being the injectable carrier and the like.

[0402] Transdermal compositions are typically formulated as a topical ointment or cream containing the active ingredient(s), generally in an amount ranging from about 0.01 to about 20% by weight, preferably from about 0.1 to about 20% by weight, preferably from about 0.1 to about 10% by weight, and more preferably from about 0.5 to about 15% by weight. When formulated as an ointment, the active ingredients will typically be combined with either a paraffinic or a water-miscible ointment base. Alternatively, the active ingredients may be formulated in a cream with, for example an oil-in-water cream base. Such transdermal formulations are well-known in the art and generally include additional ingredients to enhance the dermal penetration or stability of the active ingredients or the formulation. All such known transdermal formulations and ingredients are included within the scope of this invention.

[0403] A compound of the invention can also be administered by a transdermal device. Accordingly, transdermal administration can be accomplished using a patch either of the reservoir or porous membrane type, or of a solid matrix variety.

[0404] The above-described components for orally administrable, injectable or topically administrable compositions are merely representative. Other materials as well as processing techniques and the like are set forth in Part 8 of Remington’s Pharmaceutical Sciences, 17th edition, 1985, Mack Publishing Company, Easton, Pennsylvania, which is incorporated herein by reference.

[0405] A compound of the invention can also be administered in sustained release forms or from sustained release drug delivery systems. A description of representative sustained release materials can be found in Remington’s Pharmaceutical Sciences (Remington & Gennaro 1985).

[0406] The following formulation examples illustrate representative pharmaceutical compositions that may be prepared in accordance with this invention. The present invention, however, is not limited to the following pharmaceutical compositions.Formulation 1 - Tablets

[0407] A compound of the invention according to Formula I may be admixed as a dry powder with a dry gelatin binder in an approximate 1:2 weight ratio. A minor amount of magnesium stearate may be added as a lubricant. The mixture may be formed into 240-270 mg tablets (80-90 mg of active compound of the invention according to Formula I per tablet) in a tablet press.Formulation 2 - Capsules

[0408] A compound of the invention according to Formula I may be admixed as a dry powder with a starch diluent in an approximate 1:1 weight ratio. The mixture may be fdled into 250 mg capsules (125 mg of active compound of the invention according to Formula I per capsule).Formulation 3 - Liquid

[0409] A compound of the invention according to Formula I (125 mg), may be admixed with sucrose (1.75 g) and xanthan gum (4 mg) and the resultant mixture may be blended, passed through a No. 10 mesh U. S. sieve, and then mixed with a previously made solution of microcrystalline cellulose and sodium carboxymethyl cellulose (11:89, 50 mg) in water. Sodium benzoate (10 mg), flavor, and color may be diluted with water and added with stirring. Sufficient water may then be added with stirring. Further sufficient water may be then added to produce a total volume of 5 mL.Formulation 4 - Tablets

[0410] A compound of the invention according to Formula I may be admixed as a dry powder with a dry gelatin binder in an approximate 1:2 weight ratio. A minor amount of magnesium stearate may be added as a lubricant. The mixture may be formed into 450-900 mg tablets (150-300 mg of active compound of the invention according to Formula I) in a tablet press.Formulation 5 - Injection

[0411] A compound of the invention according to Formula I may be dissolved or suspended in a buffered sterile saline injectable aqueous medium to a concentration of approximately 5 mg / mL.Formulation 6 - Topical

[0412] Stearyl alcohol (250 g) and a white petrolatum (250 g) may be melted at about 75 °C and then a mixture of a compound of the invention according to Formula I (50 g) methylparaben (0.25 g), propylparaben (0.15 g), sodium lauryl sulfate (10 g), and propylene glycol (120 g) dissolved in water (about 370 g) may be added and the resulting mixture may be stirred until it congeals.METHODS OF TREATMENT

[0413] In one embodiment, the present invention provides compounds of the invention, or pharmaceutical compositions comprising a compound of the invention, for use in medicine.

[0414] In one embodiment, the present invention provides compounds of the invention or pharmaceutical compositions comprising a compound of the invention, for use in the prophylaxis and / or treatment of proliferative diseases. In particular, the term proliferative diseases refers to cancer, myeloproliferative disorders, leukemia, multiple myeloma, psoriasis, restenosis, scleroderma or fibrosis. More particularly, the term refers to cancer, leukemia, and multiple myeloma.

[0415] In another embodiment, the present invention provides the use of compounds of the invention or pharmaceutical compositions comprising a compound of the invention in the manufacture of a medicament for the prophylaxis and / or treatment of proliferative diseases. In particular, the term proliferative diseases refers to cancer, myeloproliferative disorders, leukemia, multiple myeloma, psoriasis, restenosis, scleroderma or fibrosis. More particularly, the term refers to cancer, leukemia, and multiple myeloma.

[0416] In additional methods of treatment aspects, this invention provides methods of prophylaxis and / or treatment of a mammal afflicted with proliferative diseases, which methods comprise the administration of an effective amount of a compound of the invention or one or more of the pharmaceutical compositions herein described for the treatment or prophylaxis of said condition. In particular, the term proliferative diseases refers to cancer, myeloproliferative disorders, leukemia, multiple myeloma, psoriasis, restenosis, scleroderma or fibrosis. More particularly, the term refers to cancer, leukemia, and multiple myeloma.

[0417] In a particular embodiment, the present invention provides compounds of the invention or pharmaceutical compositions comprising a compound of the invention, for use in the prophylaxis and / or treatment of cancer. In particular, the term refers to both metastatic tumour cell types (such as but not limited to, melanoma, lymphoma, leukemia, fibrosarcoma, rhabdomyosarcoma, and mastocytoma) and types of tissue carcinoma (such as but not limited to, colorectal cancer, prostate cancer, small cell lung cancer and non-small cell lung cancer, breast cancer, pancreatic cancer, bladder cancer, renal cancer, gastric cancer, glioblastoma, primary liver cancer, ovarian cancer, and uterine leiomyosarcoma). More particularly, the term refers to acute lymphoblastic leukemia, acute myeloid leukemia, adrenocortical carcinoma, anal cancer, appendix cancer, astrocytomas, atypical teratoid / rhabdoid tumor, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer (osteosarcoma and malignant fibrous histiocytoma), brain stem glioma, brain tumors, brain and spinal cord tumors, breast cancer, bronchial tumors, Burkitt lymphoma, cervical cancer, chronic lymphocytic leukemia, chronic myelogenous leukemia, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, embryonal tumors, endometrial cancer, ependymoblastoma, ependymoma, esophageal cancer, Ewing sarcoma family of tumors, eye cancer, retinoblastoma, gallbladder cancer, gastric (stomach) cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST), gastrointestinal stromal cell tumor, germ cell tumor, glioma, hairy cell leukemia, head and neck cancer, hepatocellular (liver) cancer, hypopharyngeal cancer, intraocular melanoma, islet cell tumors (endocrine pancreas), Kaposi’s sarcoma, kidney cancer, Langerhans cell histiocytosis, laryngeal cancer, leukemia, hairy cell leukemia, liver cancer, non-small cell lung cancer, small cell lung cancer, Hodgkin lymphoma, non-Hodgkin lymphoma, lymphoma, Waldenstrom macroglobulinemia, medulloblastoma, medulloepithelioma, melanoma, mesothelioma, mouth cancer, myeloid leukemia, multiple myeloma, nasopharyngeal cancer, neuroblastoma, oral cancer, oropharyngealcancer, osteosarcoma, malignant fibrous histiocytoma of bone, ovarian cancer, ovarian epithelial cancer, ovarian germ cell tumor, ovarian low malignant potential tumor, pancreatic cancer, papillomatosis, parathyroid cancer, penile cancer, pharyngeal cancer, pineal parenchymal tumors of intermediate differentiation, pineoblastoma and supratentorial primitive neuroectodermal tumors, pituitary tumor, plasma cell neoplasm / multiple myeloma, pleuropulmonary blastoma, primary central nervous system lymphoma, prostate cancer, rectal cancer, renal cell (kidney) cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcoma, Ewing sarcoma family of tumors, sarcoma, Sezary syndrome, skin cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, squamous cell carcinoma, stomach (gastric) cancer, supratentorial primitive neuroectodermal tumors, testicular cancer, throat cancer, thymoma and thymic carcinoma, thyroid cancer, urethral cancer, uterine cancer, uterine sarcoma, vaginal cancer, vulvar cancer, and Wilms tumor. Most particularly, the term refers to non-small cell lung cancer, Burkitt lymphoma, medulloblastoma, pancreatic cancer, ovarian cancer, and melanoma.

[0418] In another embodiment, the present invention provides the use of compounds of the invention or pharmaceutical compositions comprising a compound of the invention in the manufacture of a medicament for the prophylaxis and / or treatment of cancer. In particular, the term refers to both metastatic tumour cell types (such as but not limited to, melanoma, lymphoma, leukemia, fibrosarcoma, rhabdomyosarcoma, and mastocytoma) and types of tissue carcinoma (such as but not limited to, colorectal cancer, prostate cancer, small cell lung cancer and non-small cell lung cancer, breast cancer, pancreatic cancer, bladder cancer, renal cancer, gastric cancer, glioblastoma, primary liver cancer, ovarian cancer, and uterine leiomyosarcoma). More particularly, the term refers to acute lymphoblastic leukemia, acute myeloid leukemia, adrenocortical carcinoma, anal cancer, appendix cancer, astrocytomas, atypical teratoid / rhabdoid tumor, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer (osteosarcoma and malignant fibrous histiocytoma), brain stem glioma, brain tumors, brain and spinal cord tumors, breast cancer, bronchial tumors, Burkitt lymphoma, cervical cancer, chronic lymphocytic leukemia, chronic myelogenous leukemia, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, embryonal tumors, endometrial cancer, ependymoblastoma, ependymoma, esophageal cancer, Ewing sarcoma family of tumors, eye cancer, retinoblastoma, gallbladder cancer, gastric (stomach) cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST), gastrointestinal stromal cell tumor, germ cell tumor, glioma, hairy cell leukemia, head and neck cancer, hepatocellular (liver) cancer, hypopharyngeal cancer, intraocular melanoma, islet cell tumors (endocrine pancreas), Kaposi’s sarcoma, kidney cancer, Langerhans cell histiocytosis, laryngeal cancer, leukemia, hairy cell leukemia, liver cancer, non-small cell lung cancer, small cell lung cancer, Hodgkin lymphoma, non-Hodgkin lymphoma, lymphoma, Waldenstrom macroglobulinemia, medulloblastoma, medulloepithelioma, melanoma, mesothelioma, mouth cancer, myeloid leukemia, multiple myeloma, nasopharyngeal cancer, neuroblastoma, oral cancer, oropharyngeal cancer, osteosarcoma, malignant fibrous histiocytoma of bone, ovarian cancer, ovarian epithelial cancer, ovarian germ cell tumor, ovarian low malignant potential tumor, pancreatic cancer, papillomatosis, parathyroid cancer, penile cancer, pharyngeal cancer, pineal parenchymal tumors of intermediate differentiation, pineoblastoma and supratentorial primitive neuroectodermal tumors, pituitarytumor, plasma cell neoplasm / multiple myeloma, pleuropulmonary blastoma, primary central nervous system lymphoma, prostate cancer, rectal cancer, renal cell (kidney) cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcoma, Ewing sarcoma family of tumors, sarcoma, Sezary syndrome, skin cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, squamous cell carcinoma, stomach (gastric) cancer, supratentorial primitive neuroectodermal tumors, testicular cancer, throat cancer, thymoma and thymic carcinoma, thyroid cancer, urethral cancer, uterine cancer, uterine sarcoma, vaginal cancer, vulvar cancer, and Wilms tumor. Most particularly, the term refers to non-small cell lung cancer, Burkitt lymphoma, medulloblastoma, pancreatic cancer, ovarian cancer, and melanoma.

[0419] In additional method of treatment aspects, this invention provides methods of prophylaxis and / or treatment of a mammal afflicted with cancer, which methods comprise the administration of an effective amount of a compound of the invention or one or more of the pharmaceutical compositions herein described for the treatment or prophylaxis of said condition. In particular, the term refers to both metastatic tumour cell types (such as but not limited to, melanoma, lymphoma, leukemia, fibrosarcoma, rhabdomyosarcoma, and mastocytoma) and types of tissue carcinoma (such as but not limited to, colorectal cancer, prostate cancer, small cell lung cancer and non-small cell lung cancer, breast cancer, pancreatic cancer, bladder cancer, renal cancer, gastric cancer, glioblastoma, primary liver cancer, ovarian cancer, and uterine leiomyosarcoma). More particularly, the term refers to acute lymphoblastic leukemia, acute myeloid leukemia, adrenocortical carcinoma, anal cancer, appendix cancer, astrocytomas, atypical teratoid / rhabdoid tumor, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer (osteosarcoma and malignant fibrous histiocytoma), brain stem glioma, brain tumors, brain and spinal cord tumors, breast cancer, bronchial tumors, Burkitt lymphoma, cervical cancer, chronic lymphocytic leukemia, chronic myelogenous leukemia, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, embryonal tumors, endometrial cancer, ependymoblastoma, ependymoma, esophageal cancer, Ewing sarcoma family of tumors, eye cancer, retinoblastoma, gallbladder cancer, gastric (stomach) cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST), gastrointestinal stromal cell tumor, germ cell tumor, glioma, hairy cell leukemia, head and neck cancer, hepatocellular (liver) cancer, hypopharyngeal cancer, intraocular melanoma, islet cell tumors (endocrine pancreas), Kaposi’s sarcoma, kidney cancer, Langerhans cell histiocytosis, laryngeal cancer, leukemia, hairy cell leukemia, liver cancer, non-small cell lung cancer, small cell lung cancer, Hodgkin lymphoma, non-Hodgkin lymphoma, lymphoma, Waldenstrom macroglobulinemia, medulloblastoma, medulloepithelioma, melanoma, mesothelioma, mouth cancer, myeloid leukemia, multiple myeloma, nasopharyngeal cancer, neuroblastoma, oral cancer, oropharyngeal cancer, osteosarcoma, malignant fibrous histiocytoma of bone, ovarian cancer, ovarian epithelial cancer, ovarian germ cell tumor, ovarian low malignant potential tumor, pancreatic cancer, papillomatosis, parathyroid cancer, penile cancer, pharyngeal cancer, pineal parenchymal tumors of intermediate differentiation, pineoblastoma and supratentorial primitive neuroectodermal tumors, pituitary tumor, plasma cell neoplasm / multiple myeloma, pleuropulmonary blastoma, primary central nervous system lymphoma, prostate cancer, rectal cancer, renal cell (kidney) cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcoma, Ewing sarcoma family of tumors, sarcoma, Sezarysyndrome, skin cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, squamous cell carcinoma, stomach (gastric) cancer, supratentorial primitive neuroectodermal tumors, testicular cancer, throat cancer, thymoma and thymic carcinoma, thyroid cancer, urethral cancer, uterine cancer, uterine sarcoma, vaginal cancer, vulvar cancer, and Wilms tumor. Most particularly, the term refers to non-small cell lung cancer, Burkitt lymphoma, medulloblastoma, pancreatic cancer, ovarian cancer, and melanoma.

[0420] In a particular embodiment, the present invention provides compounds of the invention or pharmaceutical compositions comprising a compound of the invention, for use in the prophylaxis and / or treatment of leukemia. In particular, the term refers to neoplastic diseases of the blood and blood forming organs. More particularly, the term refers to acute myeloid leukemia (AML), and acute lymphoblastic leukemia (ALL) and chronic lymphoblastic leukemia (CLL).

[0421] In another embodiment, the present invention provides the use of compounds of the invention or pharmaceutical compositions comprising a compound of the invention in the manufacture of a medicament for the prophylaxis and / or treatment of leukemia. In particular, the term refers to neoplastic diseases of the blood and blood forming organs. More particularly, the term refers to acute myeloid leukemia (AML), and acute lymphoblastic leukemia (ALL) and chronic lymphoblastic leukemia (CLL).

[0422] In additional method of treatment aspects, this invention provides methods of prophylaxis and / or treatment of a mammal afflicted with leukemia, which methods comprise the administration of an effective amount of a compound of the invention or one or more of the pharmaceutical compositions herein described for the treatment or prophylaxis of said condition. In particular, the term refers to neoplastic diseases of the blood and blood forming organs. More particularly, the term refers to acute myeloid leukemia (AML), and acute lymphoblastic leukemia (ALL) and chronic lymphoblastic leukemia (CLL).

[0423] Injection dose levels range from about 0.1 mg / kg / h to at least 10 mg / kg / h, all for from about 1 to about 120 h and especially 24 to 96 h. A preloading bolus of from about 0.1 mg / kg to about 10 mg / kg or more may also be administered to achieve adequate steady state levels. The maximum total dose is not expected to exceed about 1 g / day for a 40 to 80 kg human patient.

[0424] For the prophylaxis and / or treatment of long-term conditions, such as degenerative conditions, the regimen for treatment usually stretches over many months or years so oral dosing is preferred for patient convenience and tolerance. With oral dosing, one to four (1-4) regular doses daily, especially one to three (1-3) regular doses daily, typically one to two (1-2) regular doses daily, and most typically one (1) regular dose daily are representative regimens. Alternatively for long lasting effect drugs, with oral dosing, once every other week, once weekly, and once a day are representative regimens. In particular, dosage regimen can be every 1-14 days, more particularly 1-10 days, even more particularly 1-7 days, and most particularly 1-3 days.

[0425] Using these dosing patterns, each dose provides from about 1 to about 1000 mg of a compound of the invention, with particular doses each providing from about 10 to about 500 mg and especially about 30 to about 250 mg.

[0426] Transdermal doses are generally selected to provide similar or lower blood levels than are achieved using injection doses.

[0427] When used to prevent the onset of a condition, a compound of the invention will be administered to a patient at risk for developing the condition, typically on the advice and under the supervision of a physician, at the dosage levels described above. Patients at risk for developing a particular condition generally include those that have a family history of the condition, or those who have been identified by genetic testing or screening to be particularly susceptible to developing the condition.

[0428] A compound of the invention can be administered as the sole active agent or it can be administered in combination with other therapeutic agents, including other compound of the inventions that demonstrate the same or a similar therapeutic activity and that are determined to be safe and efficacious for such combined administration. In a specific embodiment, co-administration of two (or more) agents allows for significantly lower doses of each to be used, thereby reducing the side effects seen.

[0429] In one embodiment, a compound of the invention or a pharmaceutical composition comprising a compound of the invention is administered as a medicament. In a specific embodiment, said pharmaceutical composition additionally comprises a further active ingredient.

[0430] In one embodiment, a compound of the invention is co-administered with another therapeutic agent for the treatment and / or prophylaxis of proliferative disorders, particular agents include but are not limited to: methotrexate, leucovorin, adriamycin, prednisone, bleomycin, cyclophosphamide, 5 -fluorouracil, paclitaxel, docetaxel, vincristine, vinblastine, vinorelbine, doxorubicin, tamoxifen, toremifene, megestrol acetate, anastrozole, goserelin, anti-HER2 monoclonal antibody (e.g. Herceptin®), capecitabine, raloxifene hydrochloride, EGFR inhibitors (e.g. Iressa®, Tarceva®, Erbitux®), VEGF inhibitors (e.g. Avastin®), proteasome inhibitors (e.g. Velcade®), Glivec® and hsp90 inhibitors (e.g. 17-AAG). Additionally, the compound of the invention according to Formula I may be administered in combination with other therapies including, but not limited to, radiotherapy or surgery. In a specific embodiment the proliferative disorder is selected from cancer, myeloproliferative disease or leukemia.

[0431] By co-administration is included any means of delivering two or more therapeutic agents to the patient as part of the same treatment regime, as will be apparent to the skilled person. Whilst the two or more agents may be administered simultaneously in a single formulation, i. e. as a single pharmaceutical composition, this is not essential. The agents may be administered in different formulations and at different times.CHEMICAL SYNTHETIC PROCEDURESGeneral

[0432] The compound of the invention can be prepared from readily available starting materials using the following general methods and procedures. It will be appreciated that where typical or preferred process conditions (i.e. reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures.

[0433] Additionally, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions. The choice of a suitable protecting group for a particular functional group as well as suitable conditions for protection and deprotection are well known in the art (Wuts & Greene 2006).

[0434] The following methods are presented with details as to the preparation of a compound of the invention as defined hereinabove and the comparative examples. A compound of the invention may be prepared from known or commercially available starting materials and reagents by one skilled in the art of organic synthesis.

[0435] All reagents are of commercial grade and are used as received without further purification, unless otherwise stated. Commercially available anhydrous solvents are used for reactions conducted under inert atmosphere. Reagent grade solvents are used in all other cases, unless otherwise specified. Column chromatography is performed on silica gel 60 (35-70 pm) or with Biotage® Sfar KP -Amino D, Biotage® Sfar HC D, or Interchim® PuriFlash® Si HC flash chromatography cartridges. Thin layer chromatography is carried out using pre-coated silica gel F-254 plates (thickness 0.25 mm). Biotage® ISOLUTE® phase separators (e.g., Cat# 120-1907-E) are used for aqueous phase separation. ’HNMR spectra are recorded on a Bruker Avance NEO 400 NMR spectrometer (400 MHz), a Bruker Avance 400 NMR spectrometer (400 MHz), a Bruker Avance III HD NMR spectrometer (400 MHz), or a Bruker Avance DRX 500 spectrometer (500 MHz). Chemical shifts (5) for ’H NMR spectra are reported in parts per million (ppm) relative to tetramethylsilane (50.00) or the appropriate residual solvent peak, e.g. CHCL (57.26), MeOH (53.31), or DMSO (5 2.50 ppm), as internal reference. Multiplicities are given as singlet (s), doublet (d), triplet (t), multiplet (m) and broad (br). Electrospray MS spectra are obtained on a Waters Acquity H-Class UPLC system coupled to a UV PDA detector and to a Waters SQD or SQD2 mass spectrometer. Columns used: Waters Acquity UPLC BEH C18 1.7 pm, 2.1 mm ID x 30 / 50 mm L; Waters Acquity UPLC CSH C18 1.7 pm, 2.1 mm ID x 50 / 100 mm L; Waters Acquity UPLC CSH PhenylHexyl 1.7 pm, 2.1 mm ID x 100 mm L; Waters Acquity UPLC HSS PFP 1.8 pm, 2.1 mm ID x 100 mm L. The methods are using ACN / water or MeOH / water gradients with either 0.1% formic acid in both mobile phases, 0.05% NFLOH in both mobile phases, or 10 mM NH4HCO3 in water (adjusted to pH 10 with ammonia). Preparative HPLC is performed on a Waters AutoPurification system with UV and MS detection using Waters XBridge BEH C18 OBD 30 mm ID x 100 / 150 mm L columns and ACN / water gradients with either 0.1% formic acid in both mobile phases, 0.1% diethylamine in both mobile phases, 0.1% formic acid in water, or 10 mM NH4HCO3 in water (adjusted to pH 10 with ammonia), or on a Buchi® Pure C-850 Flash with UV and ESDL detection using Buchi® C18 AQ 100 A 250 x 20 mm column and using ACN / water gradients with either 0.1% formic acid in both mobile phases or 0.05% NH4OH in both mobile phases.Table I. List of abbreviations used in the experimental section:Abbreviation Definition Abbreviation Definition ACN acetonitrile aq. aqueous AcOK potassium acetate atm atmosphereAbbreviation Definition Abbreviation Definition Boc tert-butyloxy-carbonyl NBS N-bromosuccinimide Cpd compound P(Cy)3 Tricyclohexylphosphine d doublet [1,1 '-bis(diphenylphosphino)Pd(dppf)Cl2- ferrocene] dichloropalladium(I DCM dichloromethaneDCM I) complex with dichloro dd doublet of doubletsmethane (CAS# 95464-05-4) N, A'-diisopropylcthylamincDIPEA Pd(OAc)2Palladium(II) acetate (CAS# 7087-68-5)Tetrakis(triphenylphosphine) DMF N, A'-di m ethyl form am i de Pd(PPh3)4palladium(O) DMSO dimethylsulfoxide Bis(triphenylphosphine)pallad Pd(PPh3)2Cl21,1 '-bis(diphenylphosphino) ium(II) dichloride dppfferrocene (CAS# 12150-46-8)PPm parts-per-million dt doublet of tripletsq quartet eq- equivalentRT room temperature EtOAc ethyl acetates singlet h hourt triplet1 -[bis(dimethylamino)metd triplet of doublets thylene]-lH-l,2,3-triazoloTEA triethylamine HATE [4,5-b]pyridinium 3-oxidhexafluorophosphate TFA trifluoroacetic acid (CAS# 148893-10-1) THF tetrahydrofuran high-performance liquidHPLC TBAF Tetrabutylammonium fluoride chromatography2,4,6-tripropyl-l,3,5,2,4,6- Int intermediateT3P trioxatriphosphorinane-2,4,6- m multiplet trioxyde (CAS# 68957-94-8) MeOH methanol / BuXPhos-Pd-G3. [(2-Di-ferf- butylphosphino-2',4',6'- min minutetBuXPhos Pd triisopropyl- 1, 1 '-biphenyl)-2- mmol millimoleG3 (2'-amino- 1, 1 '-biphenyl)] MS mass spectrometry palladium(II) methanesulfo Mtd method nate (CAS# 1447963-75-8) MW molecular weight 4,5 -Bis(diphenylphosphino)- XantPhos 9,9-dimethylxanthene MW (calcd) molecular weight calculated(CAS# 161265-03-8) MW (obsd) molecular weight observedAbbreviation Definition(2-Dicyclohexylphosphino- 2',4',6'-triisopropyl-l,l'- biphenyl) [2-(2'-amino- 1,1'- Xphos Pd G3biphenyl)]palladium(II)methanesulfonate(CAS# 1445085-55-1)SYNTHETIC PREPARATION OF THE COMPOUNDS OF THE INVENTIONExample 1. Example 1. General synthetic methods1.1. Synthetic methods overviewGeneral method Al: Amide coupling with HATUGeneral method A2: Amide coupling with T3PGeneral method A3: Amide coupling with EDCI / HOBtGeneral method A4: One-pot Boc removal with HCl / amide coupling with T3P General method B: Miyaura borylationGeneral method Cl: Suzuki couplingGeneral method C2: Suzuki couplingGeneral method C3: Suzuki couplingGeneral method C4: Suzuki couplingGeneral method C5: Suzuki couplingGeneral method DI: Sonogashira coupling General method DI: Sonogashira couplingGeneral method D2: Sonogashira couplingGeneral method D3: Sonogashira couplingGeneral method D4: Sonogashira couplingGeneral method D5: Sonogashira couplingGeneral method D6: Sonogashira couplingGeneral method D7: Sonogashira couplingGeneral method D8: Sonogashira couplingGeneral method E: Boc removal with HC1 General method E2: Boc removal with TFAGeneral method F: CarbonylationGeneral method F2: CarbonylationGeneral method G: Deprotection of trimethylsilyl groupGeneral method Hl: Thioalkyl Nucleophilic substitutionGeneral method H2: Nucleophilic substitution pyrazoleGeneral method II: Oxidation with oxone®General method 12: Oxidation with m-cpbaGeneral method 13: Oxidation with RuC13 / NaIO4General method J: Reduction via triethylsilaneGeneral method K: Nucleophilic SubstitutionGeneral method L: Buchwald couplingGeneral method Ml: Thiol alkylationGeneral method M2: 3-mercaptobenzoic acid alkylationGeneral method M3: 2-hydroxythiophenol alkylationGeneral method Nl: Ester hydrolysis in acidic mediumGeneral method N2: Ester hydrolysis in basic mediumGeneral method Ol: Bromination with l,3-dibromo-5,5-dimethylhydantoinGeneral method 02: Bromination with Pyridinium perbromideGeneral method 03: Iodination with NISGeneral method QI: acetylation of alcoholGeneral method Rl: Deacetylation of alcoholGeneral method SI: Sonogashira libraryGeneral method S2: Sonogashira libraryGeneral method Tl: N-alkylationGeneral method Pl: Fluoro-ester reduction via NaBFh1.2. General methods1.2.1. General method Al: Amide coupling with HATU

[0436] To a solution of carboxylic acid (1.0 eq.) and amine (1.0 to 1.4 eq.) in DMF or in DCM is added HATU (1.2 to 1.9 eq.) at 0 °C or RT. The reaction mixture is stirred at 0 °C or RT for 10 min and DIPEA (2.0 to 5.0 eq.) is then added. The reaction is stirred at RT for 30 min to 18 h. The crude is evaporated to dryness and purified either by column chromatography on silica gel and / or if needed, by preparative HPLC to afford the desired amide.1.2.1.1. Illustrative synthesis ofInt-28lnt-28

[0437] To a solution of 3-methoxymethanesulfonyl-4-methylbenzoic acid (CAS# 1490760-54-7; 786 mg, 2.45 mmol, 1.0 eq.) and HATU (1.79 g, 4.70 mmol, 1.92 eq.) in DCM (24.0 mb) was added DIPEA (1.64mb, 9.4 mmol, 3.84 eq.) at 0 °C. The resulting mixture was stirred at 0 °C for 15 min, then l-(4-bromopyridin-2-yl)methanamine (CAS# 865156-50-9; 645 mg, 3.45 mmol, 1.41 eq.) was added and the reaction mixture was allowed to warm up to RT and stirred for 2 h. Water was added and the mixture was extracted with DCM (2x). The combined organic layers were washed with water, brine, dried over MgSO4, filtered and evaporated to dryness. The residue was purified by column chromatography on silica gel (eluting with DCM / EtOAc from 80 / 20 to 10 / 90) to afford Int-28.1.2.1.2. Illustrative synthesis of Int-12Int-12

[0438] To a solution of l,l-dioxo-3,5-dihydro-2H-4,lbenzoxathiepine-8-carboxylic acid (CAS# 2771132-16-0; 1 g, 4.13 mmol, 1.0 eq.) and HATU (2.35 g, 6.19 mmol, 1.5 eq.) in DCM (12.0 mb) was added DIPEA (2.16 mL, 12.38 mmol, 3.0 eq.) at 0 °C. The resulting mixture was stirred at 0 °C for 15 min, then l-(4-bromopyridin-2-yl)methanamine (CAS# 865156-50-9; 0.85 g, 4.54 mmol, 1.1 eq.) was added and the reaction mixture was allowed to warm up to RT and stirred for 2 h. Water was added and the mixture was extracted with DCM (2x). The combined organic layers were washed with water, brine, dried over MgSO4, filtered and evaporated to dryness. The residue was purified by column chromatography on silica gel (eluting with DCM / EtOAc from 100 / 0 to 0 / 100) to afford Int-12.1.2.2. General method A2: Amide coupling with T3PO O R A1OH H2N'RRAN-”H2

[0439] To a solution of carboxylic acid (1.0 to 1.1 eq.), amine salt or free base (1.1 to 1.2 eq.) and DIPEA (4.0 to 5.0 eq.) in DCM is added T3P (50%) in EtOAc (1.2 to 1.3 eq.). The reaction mixture is stirred at RT for 1 h to 73 h. Water and DCM are added, the organic layer was separated with hydrophobic frit and evaporated to dryness. The crude is purified either by column chromatography on silica gel then, if needed by preparative HPLC to afford the desired amide.1.2.2.1. Illustrative synthesis of Cpd-45

[0440] To a solution of 4-methyl-3- (propane-2-sulfonyl)benzoic acid (CAS# 1152497-12-5; 25.28 mg, 0.104 mmol, 1.0 eq.), Int-34 (70 mg, 0.13 mmol, 1.2 eq.) and DIPEA (0.073 mb, 0.42 mmol, 4.0 eq.) in DCM (0.5 mb) was added dropwise T3P (50%) in EtOAc (0.081 mb, 0.14 mmol, 1.3 eq.). The reactionmixture was stirred at RT for 73 h. Water and DCM were added, the organic layer was separated and evaporated to dryness. The crude was purified by column chromatography on silica gel (eluting with DCM / MeOH from 100 / 0 to 96 / 4), then by preparative HPLC to afford Cpd-45.1.2.3. General method A3: Amide coupling with EDCI / HOBto nR^OH + H2N'R2- - R1^N'RH

[0001] HOBt (1.1 eq) followed by amine (1 eq) were added to a solution of carboxylic acid (1 eq.), DIPEA (5 eq.) and EDCI. HC1 (1.1 eq.) in DCM at rt. The reaction mixture was stirred at rt for 20 h. Water and DCM were added. The mixture was extracted with DCM (3 times). The organics layer were combined, washed with water, dried over MgSO4, filtered and the solvent was evaporated in vacuo. The crude was purified by normal phase flash chromatography (eluent: gradient DCM / MeOH) The fractions containing compound were combined and the solvent was evaporated in vacuo to give the expected compound1.2.3.1. Illustrative synthesis of Cpd-242

[0002] HOBt (1.1 eq., 36.04 mg, 0.27 mmol) followed by Int-239 (1 eq., 168 mg, 0.24 mmol) were added to a solution of (4R)-4.9-difluoro-5.5-dioxo-3.4-dihydro-2H-l.5' / / ’-bcnzoxathicpinc-7- carboxylic acid CAS#[3008582-46-2] (1 eq., 67.46 mg, 0.24 mmol), DIPEA (5 eq., 156.69 mg, 0.21 mL, 1.21 mmol) and EDCI. HC1 (1.1 eq., 51.13 mg, 0.27 mmol) in DCM (1.18 mL) at rt. The reaction mixture was stirred at rt for 20 h. Water and DCM were added. The mixture was extracted with DCM (3 times). The organics layer were combined, washed with water, dried over MgSO4, filtered and the solvent was evaporated in vacuo. The crude was purified by normal phase flash chromatography (irregular SiOH, 30-60 pm, 12 g, Agela, liquid loading (DCM), mobile phase: first isocratic 100% DCM for 2 CV then gradient from 100% DCM to 96% DCM, 4% MeOH for 15 CV and isocratic 96% DCM, 4% MeOH for 4 CV). The fractions containing compound were combined and the solvent was evaporated in vacuo. The residue was taken-up with ACN (1 mL) extended with water (4 mL) then freeze-dried to give Cpd-242 as white solid (71 mg, 0.12 mmol, 48%).1.2.4. General method A4: One-pot Boc removal with HCl / amide coupling with T3POjlR1OH OR2 _ _ R2_ _ IIR2BocHN' H2N R1^N'H

[0003] To a solution of the Boc-protected amine (1.0 eq.) in DCM is added a HC1 (4 M) in 1,4- Dioxane (10 eq.). The reaction mixture is stirred at RT for 2 h. The reaction mixture is evaporated to dryness. The crude amine is taken into DCM and DIPEA (6.0 eq.), carboxylic acid (2.0 eq.) and T3P (50%) in EtOAc (2.0 eq.) are added. The reaction mixture is stirred at RT for 18 h and evaporated to dryness. The crude is purified either by column chromatography on silica gel then, if needed by preparative HPLC to afford the desired amide.1.2.4.1. Illustrative synthesis of Int-13

[0004] To a solution of Int-293 (1 eq., 77.3 mg, 0.09 mmol) in DCM (1 mL) was added HC1 (4N in dioxane) (10 eq., 0.22 mL, 0.9 mmol). The mixture was stirred at rt for 2 h. The reaction mixture was concentrated under reduced pressure, then dissolved in DCM (1 mL), DIPEA (6 eq., 0.094 mL, 0.54 mmol), (4R)-9-chloro-4-fluoro-5,5-dioxo-3,4-dihydro-2H-l,5X6-benzoxathiepine-7-carboxylic acid (CAS# 3008582-64-4; 2 eq., 52.8 mg, 0.18 mmol) and T3P (50% in EtOAc) (2 eq., 0.107 mL, 0.18 mmol) were added, and the mixture was stirred at rt for 18 h. The reaction mixture was concentrated under reduced pressure then directly purified by reverse phase chromatography, stationary phase: Column YMC -Actus Triart Prep C18-S 250*35mm 15 pm, mobile phase: focused gradient MeCN / aq. NH4HCO3 0.2% pH=7.9 from 40 / 60 to 60 / 40. Pure fractions were combined and concentrated in vacuo then the concentrated was taken-up in MeCN, extended with water and freeze- dried to give Cpd-331 (32 mg, 0.049 mmol, 55%) as a white solid.1.2.5. General method B: Miyaura borylationR1- "

[0005] To a stirred solution of the bromo substrate (1.0 eq.) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (CAS# 73183-34-3; 1.3 to 1.8 eq.) in 1,4-dioxane is added AcOK (2.0 to 3.0 eq.). The mixture is degassed with argon for 5 min. Pd(dppf)C12'DCM (0.05 to 0.1 eq.) is then added and the reaction is stirred at 90 °C to 100 °C for 18 to 65 h. The reaction mixture is filtered over a pad of Celite®, the celite® is washed with EtOAc. The filtrate is evaporated to dryness. The crude is purified by column chromatography on silica gel to afford the desired compound.1.2.5.1. Illustrative synthesis of Int-13Int-12 Int-13

[0006] To a stirred solution of the Int-12 (850 mg, 2.07 mmol, 1.0 eq.) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (CAS# 73183-34-3; 1135 mg, 3.1 mmol, 1.5 eq.) in 1,4-dioxane (21.0 mL) was added AcOK (609 mg, 6.2 mmol, 3.0 eq.). The mixture was degassed with argon for 5 min. Pd(dppf)C12'DCM (169 mg, 0.207 mmol, 0.1 eq.) was then added and the reaction was stirred at 90 °C for 18 h. The reaction mixture was filtered over a pad of Celite® and the Celite® was washed with EtOAc. The filtrate was evaporated to dryness. The crude was purified by column chromatography on silica gel (eluting with DCM / MeOH from 100 / 0 to 96 / 4) to afford Int-13.1.2.5.2. Illustrative synthesis of Int-32

[0007] To a stirred solution of the tert-Butyl ((4-bromopyridin-2-yl)methyl)carbamate (CAS# 1060813-12-8; 2 g, 6.96 mmol, 1.0 eq.) and 4,4,5,5-tetraethyl-2-(4,4,5,5-tetraethyl-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane (CAS# 2247367-07-1; 3.57 g, 9.75 mmol, 1.4 eq.) in 1,4-dioxane (71.6 mL) was added AcOK (2.05 g, 20.89 mmol, 3.0 eq.). The mixture was degassed with nitrogen for 5 min. Pd(dppf)C12'DCM (0.57 g, 0.7 mmol, 0.1 eq.) was then added and the reaction was stirred at 90 °C for 24 h. The reaction mixture was filtered over a pad of Celite® and the Celite® was washed with EtOAc. The filtrate was evaporated to dryness. The crude was purified by column chromatography on silica gel (eluting with Heptane / EtOAc from 90 / 10 to 20 / 80) to afford Int-32.1.2.6. General method Cl: Suzuki couplingR1R4-X+R2B R3- * R4— R1'O' 'O'

[0008] To a stirred solution of the iodo or bromo derivative (1.0 to 1.1 eq.) and the boronic acid or ester derivative (1.0 to 1.1 eq.) in 1,4-dioxane is added Cs2CO3(2.0 eq.) previously diluted in water at RT. The mixture is degassed either with argon or nitrogen for 5 min. Pd(dppf)C12'DCM (0.05 to 0.1 eq.) is then added, and the reaction is stirred at 80 to 100 °C for 1 h to 3 days. The reaction mixture is either directly evaporated to dryness and purified or poured onto H2O, extracted EtOAc, dried over MgSO4, filtered and the solvent was evaporated then purified by column chromatography on silica gel and / or if needed, by preparative HPLC to afford the desired compound. Alternatively, the purification is done by crystallization.1.2.6.1. Illustrative synthesis of Cpd-10lnt-2

[0009] To a stirred solution of Int-2 (30.0 mg, 0.062 mmol, 1.0 eq.) and 4-(2-(3-bromophenyl)ethynyl)pyridine (CAS# 918540-89-3; 15.92 mg, 0.062 mmol, 1.0 eq.) in 1,4-dioxane (0.54 mL) was added Cs2CO3(40.19 mg, 0.12 mmol, 2.0 eq.) in water (0.054 mL) at RT. The reaction mixture was degassed with nitrogen for 5 min. Pd(dppf)C12'DCM (2.52 mg, 0.0031 mmol, 0.05 eq.) was added and the reaction mixture was stirred at 80 °C for 23 h. The reaction mixture was evaporated to dryness. The residue was purified by column chromatography on a Biotage Sfär HC chromatography cartridge (eluting with DCM / MeOH from 100 / 0 to 90 / 10) to afford Cpd-10.1.2.6.2. Illustrative synthesis of Int-33

[0010] To a stirred solution of Int-32 (1.48 g, 3.78 mmol, 1.0 eq.) and Int-38 (4-((5-bromo-2-methoxyphenyl)ethynyl)-l -methyl- IH-pyrazole, CAS# 2530116-75-5) (1.1 g, 3.78 mmol, 1.0 eq.) in 1,4- Dioxane (30.8 mL) was added Cs2CO3(2.46 g, 7.56 mmol, 2.0 eq.) in water (3.1 mL) at RT. The reaction mixture was degassed with nitrogen for 5 min. Pd(dppf)C12'DCM (0.15 g, 0.19 mmol, 0.05 eq.) was added and the reaction mixture was stirred at 90 °C for 18 h. SiliaMetS thiol silica (Silicycle, 40-63 pm) (0.5 g) was added. The resulting suspension was stirred at rt for 1 h and the mixture was filtered over a pad of Celite® and then evaporated to dryness. The residue was purified by column chromatography on silica gel (eluting with DCM / MeOH from 100 / 0 to 96 / 4) to afford Int-33.1.2.6.3. Illustrative synthesis of Cpd-38

[0011] To a stirred solution of Int-13 (40 mg, 0.078 mmol, 1.0 eq.) and Int-7 (25.1 mg, 0.078 mmol, 1 eq.) in 1,4-Dioxane (0.68 mL) was added Cs2CO3(50.67 mg, 0.16 mmol, 2.0 eq.) in water (0.08 mL) at RT. The reaction mixture was degassed with nitrogen for 5 min. Pd(dppf)C12'DCM (3.17 mg, 3.9 pmol, 0.05 eq.) was added and the reaction mixture was stirred at 90 °C for 1 h. The mixture was evaporated to dryness. The residue was purified by preparative HPLC to afford Cpd-38.1.2.7. General method C2: Suzuki couplingR1

[0012] To a stirred solution of the bromo derivative (1.0 to 1.1 eq.) and the boronic ester derivative (1.0 or 1.1 eq.) in 1,4-Dioxane is added either Cs2CO3(2.0 eq.) previously diluted in water or K2CO3 (2 M) aqueous solution (3.0 eq.). The mixture is degassed either with argon or nitrogen for 5 min. Pd(dppf)C12-DCM (0.05 eq. to 0.1 eq) or XPhos Pd G3 (0.1 eq) is then added, and the reaction is stirred at 120 °C using one single mode microwave (Anton Paar) with a power output ranging from 0 to 850 W for 25 min to 50 min. The mixture is filtered over a pad of Celite®, then evaporated to dryness and purified by column chromatography on silica gel then by preparative HPLC to afford the desired compound.Alternatively, at the end of reaction, SiliaMetS thiol silica (Silicycle, 40-63 pm) (50 mg) is added and stirred at RT for 30 min to 1 h. Then this mixture is filtered over a pad of Celite®. Filtrate is evaporated to dryness and the residue is purified by column chromatography on silica gel then by preparative HPLC to afford the desired compound.1.2.7.1. Illustrative synthesis of Cpd-33

[0013] To a stirred solution of Int-13 (92.71 mg, 0.18 mmol, 1.0 eq.) and Int-15 (55 mg, 0.18 mmol, 1.0 eq.) in 1,4-Dioxane (1.47 mL) was added Cs2CO3(117 mg, 0.36 mmol 2.0 eq.) previously diluted in water (0.15 mL). The mixture was degassed with nitrogen for 5 min. Pd(dppf)C12'DCM (7.36 mg, 0.009 mmol, 0.05 eq.) was then added, and the reaction was stirred at 120 °C using one single mode microwave (Anton Paar) with a power output ranging from 0 to 850 W for 25 min. SiliaMetS thiol silica (Silicycle, 40-63 pm) (50.0 mg) was added. The resulting suspension was stirred at RT for 1 h and the mixture was filtered over a pad of Celite®, then evaporated to dryness and purified by column chromatography on silica gel (eluting with DCM / MeOH from 100 / 0 to 96 / 4) then by preparative HPLC to afford Cpd-33.1.2.8. General method C3: Suzuki couplingR1R4-X R2, R3R4— R1O O

[0014] To a stirred solution of the chloro or bromo derivative (1.0 eq.) and the boronic acid or ester derivative (1.0 eq.) in 1,4-Dioxane is added Cs2CO3(2.0 eq.) previously diluted in water. The mixture is degassed either with argon or nitrogen for 5 min. Pd(dppf)C12'DCM (0.05 to 0.1 eq.) is then added and the reaction is stirred at 85 °C to 90 °C for 18 h. XPhos Pd G3 (0.1 eq.) or Pd(PPh3)4 (0.05 eq.) is added and the mixture was purged with nitrogen and then the resulting mixture is heated at 120 °C using one single mode microwave (Anton Paar) with a power output ranging from 0 to 850 W for 30 min. SiliaMetS Imidazole (Silicycle, 40-63 pm) is added. The resulting suspension is stirred at RT for 1 h and the mixture is filtered over a pad of Celite® and then evaporated to dryness. The crude is purified either by column chromatography on silica gel and / or if needed, by preparative HPLC to afford the desired compound.1.2.8.1. Illustrative synthesis of Cpd-35

[0015] To a stirred solution of 5-bromo-2-methoxy-3-[2-(l- methyl-lH-pyrazol-4-yl)ethynyl]pyridine (CAS# 2626157-55-7; 39.75 mg, 0.14 mmol, 1.0 eq.) and Int-13 (70 mg, 0.14 mmol, 1.0 eq.) in 1,4-Dioxane (1.11 mL) was added Cs2CO3(88.67 mg, 0.27 mmol, 2.0 eq.) previously diluted in water (0.11 mL). The mixture was degassed with nitrogen for 5 min. Pd(dppf)C12'DCM (5.56 mg, 6.8 pmol, 0.05 eq.) was then added and the reaction was stirred at 90 °C for 18 h. XPhos Pd G3 (11.52 mg, 0.014 mmol, 0.1 eq.) was added and the mixture was purged with nitrogen for 5 min and then the resulting mixture was heated at 120 °C using one single mode microwave (Anton Paar) with a power output ranging from 0 to 850 W for 30 min. SiliaMetS Imidazole (Silicycle, 40-63 pm) (50 mg) was added. The resulting suspension was stirred at RT for 1 h and the mixture was filtered over a pad of Celite® and then evaporated to dryness. The crude was purified either by column chromatography on silica gel (eluting with DCM / MeOH from 100 / 0 to 96 / 4) to afford Cpd-35.1.2.9. General method C4: Suzuki couplingR1R4-X+R2B R3- - R4— R1'O' 'O'

[0016] To a stirred solution of the bromo derivative (1.0 eq.) and the boronic ester derivative (1.0 eq.) in 1,4-Dioxane is added Cs2CO3(2.0 eq.) previously diluted in water. The mixture is degassed either with argon or nitrogen for 5 min. Pd(dppf)C12'DCM (0.05 eq.) is then added and the reaction is stirred at 85 °C to 90 °C for 2 h. XPhosPdG3 (0.1 eq.) is added and the mixture is purged with nitrogen and then the resulting mixture is heated at 90 °C for 18 h. SiliaMetS thiol silica (Silicycle, 40-63 pm) (50 mg) is added. The resulting suspension is stirred at RT for 1 h and the mixture was filtered over a pad of Celite® and thenevaporated to dryness. The crude is purified either by column chromatography on silica gel and / or if needed, by preparative HPLC to afford the desired compound.1.2.9.1. Illustrative synthesis of Cpd-43

[0017] In a sealed tube, to a mixture of Int-13 (47.18 mg, 0.092 mmol, 1.0 eq.), Int-18 (30 mg, 0.092 mmol, 1 eq.), Cs2CO3(59.76 mg, 0.18 mmol, 2.0 eq.) and Pd(dppf)C12'DCM (3.74 mg, 0.0046 mmol, 0.05 eq.) were added 1,4-Dioxane (0.75 mL) and water (0.075 mL). The resulting mixture was stirred at 90 °C for 2 h. XPhosPdG3 (3.88 mg, 0.0046 mmol, 0.05 eq.) was added and the mixture was stirred at 90 °C for 18 h. SiliaMetS thiol silica (Silicycle, 40-63 pm) (50 mg) was added. The resulting suspension was stirred at RT for 1 h and the mixture was filtered over a pad of Celite® and then evaporated to dryness. The crude was purified by preparative HPLC to afford Cpd-43.1.2.10. General method C5: Suzuki couplingR2-B(OH)2Cl

[0018] Aryl chloride (1 eq.), boronic acid or boronate (3 eq.), K3PO4 (3 eq.), Pd 118 (0.1 eq.) are dissolved in dioxane or dioxane / water. The reaction mixture was stirred for 16 to 23 h at a temperature between 90 °C- 100 °C. It’s possible to add some additional amont of boronic acid if the reaction isn’t full. The reaction mixture was cooled to rt, filtered on a pad of celite, concentrated under reduced pressure and directly purified by normal phase flash chromatography (eluent: heptane / EtOAc). After evaporation of pure fraction to give the expected compound.1.2.10.1. Illustrative synthesis of Cpd-282

[0019] In a vial under N2, Cpd-151 (1 eq., 50 mg, 0.084 mmol), cyclopropylboronic acid (3 eq., 21.65 mg, 0.25 mmol), K3PO4(3 eq., 53.509 mg, 0.25 mmol), Pd 118 (0.1 eq., 5.48 mg, 0.0084 mmol) are dissolved in dioxane (2.5 mL). The reaction mixture was stirred for 19 hours at 90 °C. cyclopropylboronic acid (3 eq., 21.65 mg, 0.25 mmol) and Pd 118 (0.1 eq., 5.48 mg, 0.0084 mmol)were added to the mixture, after degassed with N2 gas, the mixture was stirred for 4 hours at100 °C. The reaction mixture was cooled to rt, filtered on a pad of celite, concentrated under reduced pressure and directly purified by normal phase flash chromatography (irregular SiOH, 20 g Agela, liquid injection (DCM), mobile phase gradient: heptane / EtOAc 100:0 to 0: 100 over 10 CV, then 100% EtOAc over 25 CV). Pure fractions were combined and concentrated in vacuo then the concentrated was taken-up in MeCN, extended with water and freeze-dried to give Cpd-282 (18 mg, 0.03 mmol, 36%) as a white solid.1.2.11. General method DI: Sonogashira couplingR2R1-X - ► R1-^=— R2

[0020] To a stirred solution of the bromo derivative (1.0 eq.) in THF is added TEA (3.0 eq.), Pd(PPhs)4 (0.05 eq.) and Cui (0.1 eq.) at RT. The mixture is degassed with argon for 5 min. The alkyne (2.0 eq.) is added, and the reaction is stirred at 50 °C for 16 h. Pd(dppf)C12-DCM (0.1 eq.) is then added. The mixture is degassed with argon for 5 min. The reaction is stirred at 90 °C for 3 h. The crude is evaporated to dryness and purified either by column chromatography on silica gel to afford the desired compound.1.2.11.1. Illustrative synthesis of Cpd-1lnt-4 Cpd-1

[0021] To a stirred solution of Int-4 (30 mg, 0.07 mmol, 1.0 eq.) in THF (1.0 mL) were added TEA (27 µL, 0.2 mmol, 3.0 eq.), Pd(PPh3)4 (3.77 mg, 3.3 µmol, 0.05 eq.) and CuI (1.24 mg, 6.5 µmol, 0.1 eq.) at RT. The reaction mixture was degassed with argon for 5 min. 4-(prop-2-yn-l- yl)morpholine (CAS# 5799- 76-8; 16.35 mg, 0.13 mmol, 2.0 eq.) was added and the reaction mixture was stirred at 50 °C for 16 h. Pd(dppf)Cl2·DCM (5.33 mg, 6.5 µmol, 0.1 eq.) was added, the reaction mixture was degassed with argon for 5 min and stirred at 90 °C for 3 h. The product fraction was evaporated to dryness. The residue was purified by column chromatography on a Biotage® Sfar HC chromatography cartridge (eluting with DCM / MeOH from 100 / 0 to 96 / 4), then repurified by column chromatography on a Biotage® Sfar Amino chromatography cartridge (eluting with DCM / MeOH from 100 / 0 to 99 / 1), to afford Cpd-1.1.2.12. General method D2: Sonogashira coupling^-R2R1-X - ► R1-^=— R2

[0022] To a stirred solution of the bromo or iodo derivative (1.0 to 1.1 eq.) in THF or DMF is added TEA (3.0 eq.), Cui (0.1 eq.), Pd(dppf)C12'DCM (0.1 eq.) or Pd(PPh3)2C12 (0.1 eq.) atRT. The mixture is degassed either with argon or nitrogen for 5 min. The alkyne (1.0 to 2.0 eq) is added and the reaction is stirred at 90 °C for 45 min to 20 h or at RT for 3 to 23 h. The crude is either filtered over a pad of Celite®, the Celite® is washed with EtOAc then evaporated or directly evaporated to dryness. The residue is purified either bycolumn chromatography on silica gel and / or if needed, by preparative HPLC to afford the desired compound.1.2.12.1. Illustrative synthesis of Cpd-4

[0023] To a stirred solution of Int-4 (50.0 mg, 0.11 mmol, 1.0 eq.) in THF (1.5 mL) were added TEA (45.0 pL, 0.33 mmol, 3.0 eq.), Pd(dppf)Cl2·DCM (8.89 mg, 10.9 µmol, 0.1 eq.) and CuI (2.07 mg, 10.9 µmol, 0.1 eq.) at RT. The reaction mixture was degassed with nitrogen for 5 min. 4-ethynyl-l-methyl-lH-pyrazole (CAS#: 39806-89-8; 11.55 mg, 0.11 mmol, 1.0 eq.) was added and the reaction mixture was stirred at 90 °C overnight. The product fraction was evaporated to dryness. The residue was purified by column chromatography on a Biotage® Sfar HC chromatography cartridge (eluting with DCM / MeOH from 100 / 0 to 95 / 5) to afford Cpd-4.1.2.13. General method D3: Sonogashira coupling^^-R2R1-X - ►R1^^R2

[0024] To a stirred solution of the bromo derivative (1.0 eq.) in DMF is added the alkyne (2.0 to 2.1 eq.), TEA (3.0 eq.), Pd(PPh3)2C12 (0.1 to 0.15 eq.) at RT. The mixture is degassed either with argon or nitrogen for 5 min. The reaction is stirred at 80 to 90 °C for 1 to 48 h. The crude is evaporated to dryness and purified either by column chromatography on silica gel and / or if needed, by preparative HPLC to afford the desired compound.1.2.13.1. Illustrative synthesis of Cpd- 7

[0025] To a stirred solution of Int-4 (30.0 mg, 65 pmol, 1.0 eq.) in DMF (1.0 mL) was added 3-ethynylpyridine (CAS# 2510-23-8, 13.5 mg, 0.13 mmol, 2.0 eq.), TEA (27.0 pL, 0.2 mmol, 3.0 eq.), Pd(PPh3)2Cl2 (4.58 mg, 6.5 µmol, 0.1 eq.) at RT. The reaction mixture was degassed with nitrogen for 5 min and stirred at 80 °C for 1 h. The reaction mixture was evaporated to dryness and purified by column chromatography on silica gel (eluting with DCM / MeOH from 100 / 0 to 96 / 4) to afford Cpd-7.1.2.14. General method D4: Sonogashira couplingR2R1-X - ►R1^^R2

[0026] To a stirred solution of the bromo or iodo derivative (1.0 to 1.1 eq.) and alkyne or TMS alkyne derivated (1.0 eq. to 20.0 eq.) in TEA (13.8 to 22.4 eq.) is added Pd(PPh₃)₂Cl₂ (0.05 to 0.15 eq), Cui (0.06 to 0.16 eq.) at RT. The mixture is degassed with nitrogen for 5 min. The reaction is stirred at RT for 1 to 20 h or at 50, 80 or 90 °C for 45 min to 24 h. The reaction mixture is filtered over a pad of Celite® and the Celite ® is washed with EtOAc then the filtrate is evaporated to dryness. The residue is purified by column chromatography on silica gel and / or if needed, by preparative HPLC to afford the desired compound.1.2.14.1. Illustrative synthesis of Cpd-28

[0027] To a stirred solution of Int-4 (50 mg, 0.11 mmol, 1.0 eq.) and 4-(5-ethynylpyridin-2-yl)morpholine (CAS# 454685-29-1; 30.73 mg, 0.16 mmol, 1.5 eq.) in TEA (0.25 mL, 1.78 mmol, 16.32 eq.) was added PdC12(PPh3)2 (3.82 mg, 5.4 μmol, 0.05 eq.) and Cui (1.24 mg, 6.5 μmol, 0.06 eq.) at RT. The reaction mixture was degassed with argon for 5 min then stirred at 90 °C for 1 h. The crude was filtered on a pad of silica gel (eluting with DCM / MeOH 95 / 5) then purified by preparative HPLC to afford Cpd-28.1.2.15. General method D5: Sonogashira couplingR2R1-X - ►R1^=_R2

[0028] To a stirred solution of the bromo derivative (1.0 eq.) and the alkyne (2.5 to 5.0 eq.) in TEA (3.0 to 6.0 eq.) is added XPhosPdG3 (0.05 to 0.2 eq.) in DMF or neat at RT. The mixture is degassed with nitrogen for 5 min. The reaction is heated at 100 or 120 °C using one single mode microwave (Anton Paar) with a power output ranging from 0 to 850 W for 20 min to 45 min. The reaction mixture was either filtered over a pad of Celite®, filtrate is evaporated then purified by column chromatography on silica gel and / or if needed, by preparative HPLC or poured onto water, extracted with EtOAc (2x). The organic layer is washed with water, brine, dried over MgSO4, filtered and evaporated to dryness. The residue is purified by column chromatography on silica gel and / or if needed, by preparative HPLC to afford the desired compound. Alternatively, at the end of reaction and before aqueous treatment, SiliaMetS thiol silica (silicylce, 40- 63pm) was added and stirred 30 min at RT then was filtered over Celite®.1.2.15.1. Illustrative synthesis of Cpd-47lnt-14 Cpd-47

[0029] To a stirred solution of Int-14 (93.0 mg, 0.19 mmol, 1.0 eq.) 4-ethynyl-l -methyl- IH-pyrazole (CAS# 39806-89-8; 50.53 mg, 0.48 mmol, 2.5 eq.) and TEA (0.079 mL, 0.57 mmol, 3.0 eq.) in DMF (2.81 mL) was added Xphos Pd G3 (16.1 mg, 0.019 mmol, 0.1 eq.) at RT. The reaction mixture was degassed with nitrogen for 5 min then heated at 120 °C using one single mode microwave (Anton Paar) with a power output ranging from 0 to 850 W for 20 min. Water was added to the mixture. The layers were separated, and the aqueous one was extracted with EtOAc (2x). The combined organic extracts were washed with water, brine, dried over MgSO₄, filtered and evaporated to dryness. The crude was purified by column chromatography on silica gel (eluting with Heptane to Heptane / EtOAc 70:30), then by repurified via reverse phase to afford Cpd-47.1.2.16. General method D6: Sonogashira couplingR2R1-X - - Ri— ==— R2

[0030] A mixture of aryl bromide or iodo derivated (1.0 eq.), alkyne or TMS alkyne derivative (3.0 to 5.9 eq.), Xphos Pd G3 (0.1 to 0.2 eq.), DMF, TEA (5.0 to 6.0 eq.) and CsF (4.0 to 6.0 eq.) is degassed with nitrogen. Then the reaction mixture is heated at 120 °C using one single mode microwave (Biotage Initiator EXP 60) with a power output ranging from 0 to 400 W for 30 min. The reaction mixture is directly filtered over a pad of Celite® then filtrate is evaporated, and the residue is purified by column chromatography on silica gel and / or if needed, by preparative HPLC to afford the desired compound.Alternatively, the reaction mixture is diluted with EtOAc and SiliaMetS thiol silica (Silicycle, 40-63 pm) was added. After stirring for 30 min at RT, the reaction mixture is filtered over a pad of Celite®, washed with EtOAc. The filtrate is washed with water twice and then with brine, dried over Na2SO4, filtered and evaporated to dryness. The crude is purified by column chromatography on silica gel and / or if needed, by preparative HPLC to afford the desired compound.1.2.16.1. Illustrative synthesis of Cpd- 70

[0031] A mixture of Int-48 (70.0 mg, 0.12 mmol, 1.0 eq.), Int-52 (85.0 mg, 0.408 mmol, 3.55 eq.), Xphos Pd G3 (19.45 mg, 0.023 mmol, 0.2 eq.), DMF (1.2 mL), TEA (58.19 mg, 0.08 mL, 0.58 mmol, 5.0 eq.) and CsF (87.34 mg, 0.58 mmol, 5.0 eq.) was degassed with nitrogen for 5 min then heated at 120 °C using one single mode microwave (Anton Parr) for 30 min. The reaction mixture was diluted with EtOAc and SiliaMetS thiol silica (Silicycle, 40-63 pm) (60 mg) was added. After stirring for 30 min at RT, the reaction mixture was filtered over a pad of Celite®, washed with EtOAc. The filtrate was washed with water twiceand then with sat brine, dried over Na2SC>4, filtered and evaporated to dryness. The crude was purified by column chromatography on silica gel to afford Cpd-70.1.2.16.2. Illustrative synthesis of Cpd-170

[0032] To a degassed mixture of Int-103 (1 eq., 43.84 mg, 0.075 mmol), Int-131 (3 eq., 58 mg, 0.22 mmol), TEA (5 eq., 37.75 mg, 0.052 mL, 0.37 mmol) and CsF (1 eq., 11.33 mg, 0.075 mmol) in DMF (0.8 mL) was added XPhos Pd G3 (0.05 eq., 3.15 mg, 0.0037 mmol). The resulting mixture was stirred at 120 °C using one single mode microwave (Anton Paar) with a power output ranging from 0 to 850 W for 45 min. The mixture was filtered over a pad of celite and then concentrated under reduced pressure and purified by normal phase preparative LC (irregular SiOH, 40-60 pm, 12 g Agela, liquid injection (DCM), mobile phase gradient: DCM / MeOH from 100:0 to 90: 10 over 12 CV). The fractions containing product were combined, evaporated under vacuum. The residue was purified by Reverse phase (Column YMC -Actus Triart Prep C18-S 150*30mm 5 pm Flow rate 50ml / min-Focused gradient MeCN / aq. NH4HCO3 0.2% pH=7.9 Focused gradient from 40 / 60 to 75 / 25). The fraction containing product were combined and evaporated under vacuum to give a residue. The residue was taken-up with MeCN (2 mL), extended with water (4 mL) then freeze-dried to give Cpd-170 (15 mg, 0.023 mmol, 31.38%) as a white fluffy solid.1.2.17. General method D7: Sonogashira couplingTMS =— R2R1-X - - R1= R2

[0033] A mixture of aryl / heteroaryl bromo or iodo derivated (1.0 to 1.05 eq.), TMS alkyne derivative (1.0 to 1.05 eq.), Cui (0.06 to 0.1 eq.), Pd(PPh3)2Cl2(0.05 eq.), TEA (4 to 6 eq.), THF or DMF and CsF (1.0 to 2.5 eq.) is degassed with nitrogen. Then the reaction mixture is heated to 65 to 70 °C for 2.5 to 18 h. The reaction mixture was either fdtered over a pad of Celite®, filtrate is evaporated then purified by column chromatography on silica gel and / or if needed, by preparative HPLC or the mixture is diluted with H2O and extracted with DCM. The organic layer is dried over MgSO4, filtered and evaporated to dryness. The crude is purified by column chromatography on silica gel and / or if needed, by preparative HPLC to afford the desired compound.1.2.17.1. Illustrative synthesis of Int-293lnt-221 Int-293

[0034] Under N2, to a stirred solution of 2-iodo-3-methyl-5H,6H,8H-imidazo[2,l-c][l,4]oxazine (CAS# 3076989-90-4; 1 eq., 47 mg, 0.18 mmol) and Int-221 (1.05 eq., 91.4 mg, 0.19 mmol) in Et₃N (6 eq., 0.15 mL, 1.07 mmol) were added Cui (0.1 eq., 3.4 mg, 0.018 mmol) and PdC12(PPh3)2 (0.05 eq., 6.3 mg, 0.0089 mmol) at rt. The reaction mixture was degassed with N2 for 2 min then heated to 65 °C for 18 h. The mixture was diluted with H2O and DCM, then extracted with DCM. The organic layer was dried over MgSO4, filtered and evaporated to dryness then directly purified by normal phase flash chromatography (irregular SiOH, 12 g Agela, liquid injection (DCM), mobile phase gradient: DCM / MeOH 100:0 to 95:5 over 10 CV to give Int-293 (77.3 mg, 0.09 mmol, 50%) as a light brown sticky solid.1.2.18. General method D8: Sonogashira couplingR2R1-X - ►R1^^_R2

[0035] A mixture of aryl / heteroaryl chloro, bromo or iodo derivated (1.0 eq), alkyne derivative (2.0 eq.), XantPhos (0.1 eq.), Pd(PPh3)2C12 (0.1 eq.), TMG (2.0 eq.) and THF is degassed with nitrogen. Then the reaction mixture is heated to 90 °C for 1 h. The mixture is diluted with H2O and extracted with EtOAc. The organic layer is dried over MgSO₄, filtered and evaporated to dryness. The crude is purified by column chromatography on silica gel and / or if needed, by preparative HPLC to afford the desired compound.1.2.18.1. Illustrative synthesis of lnt-321BocHNInt-221 lnt-321

[0036] A solution of Int-322 (1 eq., 68 mg, 0.21 mmol), 4-ethynyl-l -methyl- IH-pyrazole (CAS#39806-89-8; 2 eq., 45 mg, 0.42 mmol) and TMG (2 eq., 0.054 mL, 0.42 mmol) in THF (0.96 mL) was degassed through N2 bubbling at rt. xantphos (0.1 eq., 12.3 mg, 0.021 mmol) and PdC^PPlp^ (0.1 eq., 14.9 mg, 0.021 mmol) were then added at rt, and the resulting mixture was stirred under N2 atmosphere at 90 °C for 1 h. The reaction mixture was cooled down to rt and diluted with water and minimum of EtOAc. The layers were separated and the aqueous layer was extracted three times with EtOAc. The combined organic layers were concentrated under vacuum. The crude residue was purified by Flash Chromatography (irregular SiOH 50 pm, interchim, liquid injection, mobile phase gradient: from Hept 100 % over 3 CV in isocratic to DCM / MeOH 95 / 5 over 18 CV and then 10 CV in isocratic, then DCM / MeOH 9 / 1 in isocratic for 10 CV). The fractions containing compound were combined and concentrated under vacuum to give lnt-321 (51 mg, 0.11 mmol, 52%) as a brown oil.1.2.19. General method E: Boc removal with HClR2R-N'H

[0037] To a solution of the Boc-protected amine (1.0 eq.) in DCM is added a HC1 (4 M) in 1,4-Dioxane (7.8 to 18.4 eq.). The reaction mixture is stirred at RT for 2 to 16 h. The reaction mixture is evaporated to dryness to afford the crude desired compound as HC1 salt. Or the reaction mixture is evaporated to dryness and the residue is purified on column chromatography on silica gel and if needed, by preparative HPLC to afford the desired compound.1.2.19.1. Illustrative synthesis of Cpd-23

[0038] To a solution of Int-9 (25.0 mg, 0.044 mmol, 1.0 eq.) in DCM (2.0 mL) was added HCl (4 M) in 1,4-Dioxane (0.2 mL, 0.8 mmol, 18.4 eq.). The mixture was stirred at RT for 2 h. The reaction mixture was evaporated to dryness and was purified by preparative HPLC to afford Cpd-23.1.2.20. General method E2: Boc removal with TFAR2R2

[0039] To a solution of the Boc-protected amine (1.0 eq.) in DCM is added TFA (20 to 30 eq.). The reaction mixture is stirred at RT for 1 to 16 h. The reaction mixture is evaporated to dryness to afford the crude desired compound as TFA salts. Or the reaction mixture is evaporated to dryness, the residue taken-up with aq. K2CO3 (10%) and extracted with DCM. The combined organic layers are washed with brine, dried over MgSO4, filtered, concentrated under vacuum and purified on column chromatography on silica gel to give the desired amine as free base.1.2.20.1. Illustrative synthesis oflnt-128TFA BocHN

[0040] To a solution of Int-129 (1 eq., 208 mg, 0.404 mmol) in dichloromethane (4.04 mL) was added TFA (20 eq., 921 mg, 0.6 mL, 8.077 mmol). The reaction mixture was stirred at rt for 16 h and concentrated in vacuo to give Int-128 (397 mg, 0.39 mmol, 95.5%) as TFA salts (6 eq.) as a sticky yellow oil.1.2.21. General method F: CarbonylationR1-Br R1-COOH

[0041] In a sealed bomb are added a bromo derivative (1.0 eq.) and TEA (6.0 eq.) in H2O and 1,4-Dioxane then Pd(dppf)C12. DCM (0.1 eq.). The sealed bomb is filled with CO (5 bars). The mixture is stirred at 120 °C for 18 h. HC1 (I M) aqueous solution is added and the mixture is extracted with EtOAc (3x). The combined organic layers are washed with brine, dried over MgSO4 then filtered. The solvent is evaporated to dryness to afford the desired carboxylic acid.1.2.21.1. Illustrative synthesis of lnt-35lnt-35

[0042] In a sealed bomb were added 4-bromo-2-methanesulfonyl-l-(methoxymethyl)benzene (CAS# 1203655-79-1; 276 mg, 0.99 mmol, 1.0 eq.) and TEA (0.83 mL, 5.93 mmol, 6.0 eq.) in H2O (1.64 mL) and 1,4-Dioxane (10.2 mL) then Pd(dppf)C12. DCM (80.7 mg, 0.099 mmol, 0.1 eq.). The sealed bomb was filled with CO (5 bars). The mixture was heated at 120 °C for 18 h. HC1 (1 M) was added and the mixture was extracted with EtOAc (3x). The combined organic layers were washed with brine, dried over MgSO4, filtered and evaporated to dryness to afford lnt-35.1.2.22. General method F2: CarbonylationR1-Br - ► R1-COOH

[0043] In a sealed bomb are added a bromo derivative (1.0 eq.) and K2CO3 (3.0 eq.) in H2O and DMSO then l,3-bis(diphenylphosphino)propane (0.1 eq.) or l,3-bis(dicyclohexylphosphino)propane bis(tetrafluoroborate) (0.2 eq) and Pd(OAc)2 (0.1 eq.). The sealed bomb is filled with CO (5 bars). The mixture is stirred at 100 to 110 °C for 4 to 18 h. The reaction mixture is filtered over celite. The cake is eluted with water and the filtrate extracted with EtOAc. The aqueous layer is acidified with HC1 (I M) aqueous solution and extracted with EtOAc or 10:1 DCM / MeOH (3x). The combined organic layers are dried over MgSO4 or Na2SO4 then filtered. The solvent is evaporated to dryness to afford the desired carboxylic acid. Alternatively, the reaction mixture is quenched with sat aq NaHCO3and extracted twice with EtOAc. The aqueous layer is acidified to pH = 1 with aq HC1 (I M) and extracted three times with EtOAc or DCM. The combined organic layers are washed with 0.1 M aq HC1 and with sat brine, dried over NaSO4, filtered and concentrated under vacuum to give the desired carboxylic acid.1.2.22.1. Illustrative synthesis oflnt-112Flnt-113

[0044] In a sealed bomb were added Int-113 (1 eq., 72 mg, 0.23 mmol) and K2CO3 (3 eq., 96.6 mg, 0.7 mmol) in H2O (84 pL) and DMSO (2.32 mL) then l,3-bis(diphenylphosphino)propane (0.1 eq., 9.606 mg,0.023 mmol) and Pd(0Ac)2 (0.1 eq., 5.23 mg, 0.023 mmol). The sealed bomb is filled with CO (5 bars). The mixture is stirred at 110 °C for 18 h. The reaction mixture is filtered over celite. The cake is eluted with water and the filtrate extracted with EtOAc. The aqueous layer is acidified with HC1 (I M) aqueous solution and extracted with 10:1 DCM / MeOH (3x). The combined organic layers are dried over Na2SO4 then filtered. The solvent is evaporated to dryness to afford Int-112 (46 mg, 0.17 mmol, 72%).1.2.23. General method G: Deprotection of trimethylsilyl group of an alkyne / R— — Si— - ► R— =\

[0045] To a stirred solution of TMS-alkyne (1.0 eq.) in THF at 0 °C or at RT is added dropwise TBAF (1 M) in THF (1.5 eq.). The reaction mixture is stirred at 0 °C or at RT for 0.5 to 1 h. H2O is added, and the mixture is extracted twice with EtOAc. The combined organic layers are dried over Na2SO4, filtered and evaporated to dryness. The residue is purified by column chromatography on silica gel and / or if needed, by preparative HPLC to afford the desired compound.1.2.23.1. Illustrative synthesis of Cpd-3lnt-8 Cpd-3

[0046] To a stirred solution of Int-8 (94.0 mg, 0.2 mmol, 1.0 eq.) in THF (3.0 mL) at 0 °C was added dropwise TBAF (1 M) in THF (0.3 mL, 0.3 mmol, 1.5 eq.). The reaction mixture was stirred at 0 °C for 30 min. Water was added and the mixture was extracted twice with EtOAc. The combined organic layer was dried over Na2SO4, filtered and evaporated to dryness. The residue was purified by column chromatography on a Biotage® Star HC chromatography cartridge (eluting with DCM / MeOH from 100 / 0 to 97 / 3) to afford Cpd-3.1.2.24. General method H: “thioalkyl” introductionF" RKONa - * R2RI1 _sR2

[0047] To a mixture of aryl fluoride (1.0 eq.) in ACN or DMF is added sodium methylsulfanide or sodium ethylsulfanide (1.5 to 2.0 eq). The reaction mixture is stirred at RT for 16 to 24 h or at 70 °C for 23 h or 100 °C for 1 to 2 h. The reaction is poured onto water and extracted with EtOAc. The organic layer is dried and the solvent is evaporated to dryness. The residue is purified by column chromatography on silica gel to afford the desired compound.1.2.24.1. Illustrative synthesis ofInt-67Int-67

[0048] 5-bromo-7-fluoro-2,3-dihydro-lH-inden-l-one (CAS# 1242157-14-7; 2 g, 8.73 mmol; 1.0 eq.) was dissolved in DMF (30.0 mL), and sodium ethylsulfanide (CAS# 811-51-8; 1.102 g, 13.09 mmol; 1.5 eq.) was added, and the reaction mixture was stirred at RT for 16 h. The reaction system was diluted with water, extracted twice with EtOAc (25 mL) and the organic phases were combined, washed once with NaCl saturated aqueous solution, dried over anhydrous MgSO4, filtered, and evaporated to dryness. The residue was purified by column chromatography on silica gel (eluting with Heptane / EtOAc from 100 / 0 to 60 / 40) to afford Int-67.1.2.24.2. Illustrative synthesis oflnt- 75Na+

[0049] A mixture of methyl 3-fluoro-4-(trifluoromethyl)benzoate (CAS# 773873-89-5; 164 mg, 0.74 mmol; 1.0 eq.) and MeSNa (CAS# 5188-07-8; 51.74 mg, 0.74 mmol, 1.0 eq.) in ACN (3.0 mL) was stirred at RT for 16 h then was stirred at 70 °C for 2 h. An extra amount of MeSNa (CAS# 5188-07-8; 51.74 mg, 0.74 mmol; 1.0 eq.) was added and the reaction mixture was stirred at 70 °C for 5 h. The reaction was cooled down to RT. H2O and EtOAc were added. The layers were separated and the aqueous layer was extracted once again with EtOAc. The combined organic layers were dried over MgSO4, filtered and the solvent was evaporated to dryness. The residue was purified by column chromatography on silica gel (eluting with Heptane / EtOAc from 100 / 0 to 60 / 40) to afford Int-75.1.2.25. General method II: Oxydation with oxoneR< 'R2o- K+Rl^s°o=s=o

[0050] To a mixture of aryl -alkylsulfanyl (1.0 eq.) in ACN and water is added oxone® monopersulfate (CAS# 70693-62-8; 3.0 to 6.0 eq.). The reaction mixture is stirred at RT or 60 °C for 1 h to 18 h, then is concentrated, diluted into H20 and EtOAc. The aqueous layer is extracted with EtOAc and the organic layers are combined, washed once with H20, once with brine and the solvent is evaporated to dryness to afford the desired compound.1.2.25.1. Illustrative synthesis of Int- 73O’ K+o=s=olnt-72 lnt-73

[0051] 6 -bromo-4-(ethylsulfanyl)-l,3-dihydro-2-benzofuran lnt-72 (0.9 g, 3.47 mmol, 1.0 eq.) was dissolved in acetonitrile (33.8 mL) and water (33.8 mL), and oxone® monopersulfate (CAS# 70693-62-8; 6.34 g, 10.42 mmol, 3.0 eq.) was added. The reaction mixture was stirred at 60 °C for 1 h then was concentrated, diluted with EtOAc (30 mL) and water (30 mL), and the aqueous layer was extracted once with EtOAc (30 mL). The organic layers were combined, washed once with water and once with brine, dried over MgSO4, filtered, and evaporated to dryness to afford lnt-73.1.2.25.2. Illustrative synthesis of Int-69

[0052] 6-bromo-4-(ethylsulfanyl)-2,3-dihydro-lH-indene Int-68 (1.9 g, 5.25 mmol, 1.0 eq.) was dissolved in acetonitrile (51.0 mL) and water (51.0 mL), and oxone® monopersulfate (CAS# 70693-62-8; 9.58 g, 15.74 mmol, 3.0 eq.) was added. The reaction mixture was stirred at RT for 18 h. The reaction was concentrated, diluted with EtOAc (30 mL) and water (30 mL), and the aqueous layer was extracted once with EtOAc (30 mL). The organic phases were combined, washed once with water and once with brine, dried over MgSO4, filtered, and the solvent was evaporated to dryness to afford Int-69.1.2.26. General method 12: Oxydation with m-CPBAo \\S / oRi R2Ri R2

[0053] To a solution of benzothiazine (1.0 eq.) in DCM at 0 °C is added m-CPBA (2.1 eq.). The reaction mixture is stirred at RT for 16 to 18 h. The reaction is quenched with NaHCCh solution and DCM. The organic layer is separated via hydrophobic frit then the solvent is evaporated. The residue is purified by column chromatography on silica gel to afford the desired compound.1.2.26.1. Illustrative synthesis oflnt-81Int 80

[0054] To a solution of Int-80 (122 mg, 0.5 mmol, 1.0 eq.) in DCM (2.59 mL) cooled at 0 °C was added m-CPBA (258.68 mg, 1.049 mmol, 2.1 eq.), then the mixture was stirred at RT for 16 h. The reaction was quenched with NaHCO3saturated aqueous solution and DCM was added. The organic layer was separatedvia hydrophobic frit and evaporated to dryness. The residue was purified by column chromatography on silica gel (eluting with Heptane / EtOAc from 100 / 0 to 50 / 50) to afford Int-81.1.2.27. General method 13: Oxidation with RuClfNalORi^ R2

[0055] At 0 °C, ruthenium trichloride (5 mol%) is added to a solution of aryl -alkylsulfanyl (1 eq.), NaIO4(3.3 eq.) in DCE, CH3CN and water (2 / 1 / 1). The reaction mixture is stirred at rt for 3 h. The reaction is diluted with DCM. The salts are filtered over a pad of celite and the filtrate are washed with water (twice). The organics layers are combined, dried over Na2SO4. filtered and the solvent are evaporated under vacuo to give the sulfone derivative.1.2.27.1. Illustrative synthesis of Int-203Int-204 Int-203

[0056] At 0 °C, ruthenium trichloride (0.05 eq., 5.16 mg, 0.025 mmol) was added to a solution of Int-204 (1 eq., 148 mg, 0.5 mmol), NaIO4(3.3 eq., 351.44 mg, 1.64 mmol) in DCE (0.92 mL), CH3CN (0.73 mL) and water (0.59 mL). The reaction mixture was stirred at rt for 3 h. The reaction was diluted with DCM. The salts was filtered over a pad of celite and the filtrate was washed with water (2X). The organics layers were combined, dried over Na2SO4, filtered and the solvent was evaporated under vacuo to give Int-203 (123 mg, 0.43 mmol, 86.8%) as a grey residue.1.2.28. General method J: Reduction via triethylsilaneRi. F11 \ / SiH - ► H-kO^R2HR2

[0057] To a solution of ketone (1.0 eq.) in TFA is added triethylsilane (5.0 eq.). The reaction is stirred at RT for 18 h then the reaction is concentrated. The residue is taken up into EtOAc and H2O. The organic layer is washed with NaHCO₃ then brine and is dried over MgSO and fdtered. The solvent is evaporated to dryness and the residue is purified by column chromatography on silica gel to afford the desired compound.1.2.28.1. Illustrative synthesis of Int-64lnt-63 Int-64

[0058] To a solution of Int-63 (280 mg, 1.089 mmol, 1.0 eq.) in TFA (7.68 mL) was added triethylsilane (CAS# 617-86-7; 633.057 mg, 0.88 mL, 5.44 mmol, 5.0 eq.). The reaction mixture was stirred at RT for 18 h, then was concentrated and EtOAc (30 mL) and water (30.0 mL) were added. The organic layer was washed once with NaHCO3saturated aqueous solution (10.0 mL) and once with brine, dried over MgSO4, filtered. The solvent was evaporated to dryness. The residue was purified by column chromatography on silica gel (eluting with Heptane / EtOAc from 100 / 0 to 70 / 30) to afford Int-64.1.2.28.2. Illustrative synthesis of Int-68Int-67 Int-68

[0059] To a solution of Int-67 (1.43 g, 5.27 mmol, 1.0 eq.) in TFA (37.2 mL) was added triethylsilane (CAS# 617-86-7; 3.066 g, 4.26 mL, 26.37 mmol, 5.0 eq.). The reaction mixture was stirred at RT for 18 h, then evaporated. EtOAc (50.0 mL) and water (30.0 mL) were added, and the organic layer was decanted, washed once with NaHCO3saturated aqueous solution (10.0 mL) and once with brine, dried over MgSO4, filtered, and the solvent was evaporated to dryness. The residue was purified by column chromatography on siliga gel (eluting with Heptane / EtOAc from 100 / 0 to 70 / 30) to afford Int-68.1.2.29. General method K: Substitution nucleophile

[0060] To a mixture of aniline (1.0 eq) in DMSO is added NaH (60%) dispersion in mineral oil (4.0 eq.) at RT and this reaction mixture is stirred for 15 min. 1-bromo-2-(2-bromoethoxy)ethane (CAS# 5414-19-7; 1.0 eq) is added and the reaction mixture is stirred at RT for 2 h or 80 °C for 8 h. The reaction is quenched with H2O and extracted with EtOAc. The organic layer is decanted, washed with brine and dried over MgSO4 then filtered. The filtrate is evaporated and the residue is purified by column chromatography on silica gel to afford the desired compound.1.2.29.1. Illustrative synthesis of Int-20BrInt-20

[0061] To a mixture of 4-bromo-2-iodoaniline (CAS# 66416-72-6; 300 mg, 1.01 mmol, 1.0 eq.) in DMSO (12.0 mL) was added NaH (60%) dispersion in mineral oil (161 mg, 4.03 mmol, 4.0 eq.) at RT and the suspension was stirred for 15 min. 1-bromo-2-(2-bromoethoxy)ethane (CAS# 5414-19-7; 0.13 mL, 1.007 mmol, 1.0 eq.) was added and the reaction mixture was stirred at 80 °C for 8 h. The reaction mixture was quenched with water and diluted with EtOAc. The layers were separated, and the aqueous layer was extracted twice with EtOAc. The combined organic layers were washed with brine (3x), dried over MgSO4,filtered and evaporated to dryness. The crude was purified by column chromatography on silica gel (eluting with Heptane / EtOAc from 100 / 0 to 90 / 10) to afford Int-20.1.2.29.2. Illustrative synthesis of Int-90Br >Int-90

[0062] To a mixture of 4-iodopyridin-3-amine (300 mg, 1.36 mmol, 1.0 eq.) in DMSO (16.25 mL) was added NaH (60%) dispersion in mineral oil (218.15 mg, 5.45 mmol, 4.0 eq.) at RT and the suspension was stirred for 15 min. 1-bromo-2-(2-bromoethoxy)ethane (316.23 mg, 0.13 mL, 1.36 mmol, 1.0 eq.) was added and the reaction mixture was stirred at RT for 2 h. The reaction mixture was quenched with water and diluted with EtOAc. The layers were separated and the aqueous layer was extracted twice with EtOAc. The combined organic layers were washed with brine (3x), dried over MgSO4, filtered and the solvent was evaporated to dryness. The residue was purified by column chromatography on silica gel (eluting with DCM / MeOH from 100 / 0 to 97 / 3) to afford Int-90.1.2.30. General method L: Buchwald couplingTo a mixture of aryl chloride (1.0 eq.), amine (2.0 eq.), Cs2CO3(2.0 eq.) is added tBuXPhos Pd G3 (0.3 eq.) and 1,4-Dioxane. The reaction mixture is degazed with bubbling nitrogen then stirred at 100 °C for 3 h. The mixture is fdtered on a pad of Celite® then the fdtrate is diluted into H2O and EtOAc. The organic layer is decanted, dried over MgSO4and the residue is purified by preparative HPLC to afford the desired compound.1.2.30.1. Illustrative synthesis of Cpd-127

[0063] A solution of Cpd-39 (60.0 mg, 0.11 mmol, 1.0 eq.), azetidin-3-ol hydrochloride (CAS# 18621-18-6; 24.03 mg, 0.22 mmol, 2.0 eq.), Cs2CO3(178.68 mg, 0.55 mmol, 5.0 eq.), tBuXPhos Pd G3 (26.14 mg, 0.033 mmol, 0.3 eq.) in 1,4-Dioxane (4.0 mL) were degazed by bubbling nitrogen for 15 min at RT. The solutions were stirred to 100 °C for 3 h. The reaction mixture was cooled down to RT and filtered over a pad of Celite®. The filtrate was diluted in EtOAc and H2O. The organic layer was dried over MgSO4, filtered and evaporated to dryness. The residue was directly purified by preparative HPLC and directly freeze-dried to afford Cpd-127.1.2.30.2. Illustrative synthesis of Cpd-131

[0064] A solution of Cpd-39 (60.0 mg, 0.11 mmol, 1.0 eq.), pyrrolidin-3-ol (CAS# 40499-83-0; 19.11 mg, 0.22 mmol, 2.0 eq.), Cs2CO3(107.2 mg, 0.33 mmol, 3.0 eq.), tBuXPhos Pd G3 (26.14 mg, 0.033 mmol, 0.3 eq.) in 1,4-Dioxane (4.44 mL) was degased by bubbling nitrogen for 5 min. The reaction mixture was stirred at 100 °C for 3 h then was filtered over a pad of Celite®. The filtrate was diluted in EtOAc and H2O, the organic layer was dried over MgSO4, filtered and evaporated to dryness. The residue was directly purified by preparative HPLC twice then the compound was freeze-dried to afford Cpd-131.1.2.31. General method Ml: Thiol alkylationR Xe _H'' RI R22Base solvent

[0065] To a mixture of thiol derivative (1 eq) in THF, MeCN or DMF were added NaH 60% in mineral oil (1.1 to 3.0 eq.) or K2CO3 (2 eq.) or TEA (3eq.) and alkylhalogenure neat or in solution (1.2 to 2 eq.) then the mixture is stirred at rt until completion of the reaction (1 to 18 h). The reaction is treated by water or sat brine or IN aq HC1 then 2 extractions are performed with DCM or EtOAc. The combined organic layers are dried over MgSO4 or Na2SO4, filtered and the solvent are removed in vacuo to give sulfide derivative.1.2.31.1. Illustrative synthesis of Int-204CF2HIInt-204

[0066] To a mixture of methyl 4-chloro-3-sulfanylbenzoate (1 eq., 109 mg, 0.54 mmol) in THF (4.72 mL) were added NaH 60% in mineral oil (1.1 eq., 23.66 mg, 0.59 mmol) and difluoro(iodo)methane 10% in THF (2 eq., 1913.97 mg, 2.15 mL, 1.076 mmol) then the mixture was stirred at rt for 2 h. Brine and EtOAc were added. The layers were separated and the aqueous layer was extracted once again with EtOAc. The combined organic layers were dried over Na2SO4, filtered and the solvent was removed in vacuo to give Int-204 (134 mg, 0.53 mmol, 98.6%).1.2.32. General method M2: 3-mercaptobenzoic acid alkylationO O

[0067] A solution of 3-mercaptobenzoic acid derivative (1 eq.) and DIPEA or TEA (1.6 eq. to 3 eq.) in DCM or in DMF was cooled at 0°C, then bromoalkyl (1.5eq. to 1.8 eq.) was added dropwise, then the reaction mixture was left to warmed up at rt for 18 h. The mixture was quenched with 3N aqueous solution of NaOH and extracted with DCM (3 times). These extracts were discarded. The aqueous layer was acidified to pH = 2 with 3 M aq HC1 and the precipitate was filtered and dried under vacuo to give expect product. Alternative work-up, add 0.2 M aqHCl was added then product was extracted with EtOAc (twice). The combined organic layers were washed with 0.2M aqHCl, brine then dried over MgSO4, filtered and concentrated in vacuo then the product was purified by chromatography.1.2.32.1. Illustrative synthesis ofInt-157Int-157

[0068] A 40 mL reaction vial equipped with a magnetic stirring bar was charged with 4-methyl-3-sulfanylbenzoic acid (1 eq., 250 mg, 1.49 mmol) & DMF (10 mL). The reaction mixture was cooled to 0°C and Et3N (3 eq., 451.19 mg, 0.62 mL, 4.46 mmol) & ethyl bromodifluoroacetate (1.5 eq., 452.52 mg, 0.29 mL, 2.23 mmol) were added dropwise successively. The reaction mixture was warmed to rt and stirred for 1 h. The reaction mixture was quenched with 0.2 M aq HCl (50 mL) and extracted with EtOAc (100 mL). The aqueous layer was washed with 0.2 M aq HCl (2 x 50 mL) and sat brine (50 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by normal phase flash chromatography (irregular SiOH, 20 g Agela, liquid injection (DCM), mobile phase gradient: DCM / MeOH 100:0 to 90:10 over 15 CV. Pure fractions were combined and concentrated in vacuo to give Int-157 (379 mg, 1.31 mmol, 87.9%) as a white solid.1.2.33. General method M3: 2-hydroxythiophenol alkylationR2Cs2CO3DMF

[0069] To a mixture of 2-hydroxythiophenol derivative (1 eq), Cs2CO3(5 eq) in DMF is added 1,3-dibromopropane derivative (1 eq.) dropwise. The reaction mixture was stirred at rt for 2 h. The reaction mixture was quenched with water and extracted with EtOAc (3 x). The combined organic layers werewashed with brine (3 x), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by normal phase flash chromatography using Heptane / EtOAc as mobile phase and give after evaporation of pure fraction the desired benzoxathiepine.1.2.33.1. Illustrative synthesis of Int-212Br BrCs2CO3, DMFrt, 2 hInt-213 Int-212

[0070] To a mixture of Int-213 (1 eq., 1.58 g, 6.005 mmol), Cs2CO3(5 eq., 9.78 g, 30.025 mmol) in DMF (60 mL) was added 1,3 -dibromopropane (1 eq., 1.21 g, 0.61 mL, 6.005 mmol) dropwise. The reaction mixture was stirred at rt for 2 h. The reaction mixture was quenched with water and extracted with EtOAc (3 x). The combined organic layers were washed with brine (3 x), dried over sodium sulfate, fdtered and concentrated in vacuo. The residue was purified by normal phase flash chromatography (regular SiOH, 80 g Agela, liquid injection (DCM), mobile phase gradient: Heptane / EtOAc 100:0 to 75:25 over 15 CV). Pure fractions were combined and concentrated in vacuo to give Int-212 (1.2 g, 3.96 mmol, 65.9%) as a colorless oil.1.2.34. General method Nl: Ester hydrolysis in acidic medium,9HCI / 9Ri- \ ► R-i- \O-R2OH

[0071] To a stirred solution of ester (1 eq) in a mixture of water and dioxane is added in one fraction HCI 4M in dioxane (6 eq to 9 eq) at rt then the solution was heated to 90 °C until the completion of reaction (16 to 72 h). The mixture was diluted with DCM then an aq. solution of 10% KHSO4 was added. The aqueous layer was extracted with DCM then the combined organic layers were dried over Na2SO4, filtered and evaporated to give carboxylic acid.1.2.34.1. Illustrative synthesis ofInt-202Int-203 Int-202

[0072] To a stirred solution of Int-203 (1 eq., 94 mg, 0.33 mmol) in water (1.84 mL) and dioxane (3.68 mL) was added in one fraction HCI 4M in dioxane (6 eq., 0.5 mL, 1.98 mmol) at rt and the solution was heated to 90 °C for 21 hours. An extra amount of HCI 4M in 1,4-dioxane (3 eq., 0.25 mL, 0.99 mmol) was added to the reaction mixture was stirred at 90 °C for 24 h. The mixture was diluted with DCM then an aq. solution of 10% KHSO4 was added. The aqueous layer was extracted with DCM then the combined organiclayers were dried over Na2SO4, filtered and evaporated to give Int-202 (81 mg, 0.3 mmol, 90.6%) as a yellow solid.1.2.35. General method N2: Ester hydrolysis in basic medium / ?LiOH / ?Ri — \ - ► Ri — \O-R2OH

[0073] To a stirred solution of ester (1 eq.) in a mixture of THF, water with or without addition of MeOH is added LiOH H2O (1.25 to 2 eq.) at 0 °C or rt then the solution is warmed to rt and stirred for 2 to 5 h. The mixture is diluted with water, acidified with aq 3 M HC1 and extracted with DCM. The combined organic layers were dried over Na2SO4, filtered and evaporated to dryness to give the desired carboxylic acid. Or the reaction mixture is evaporated to dryness to give the desired lithium carboxylate.1.2.35.1. Illustrative synthesis of Int-122LiOH H2O, THF, MeOH, H2O, 0 °C to rt, 18 hInt-122

[0074] Int-123 (1 eq., 100 mg, 0.39 mmol) was dissolved in amixture of THF (1.97 mL), water (0.98 mL) & MeOH (0.98 mL). The reaction mixture was cooled to 0 °C and Lithium hydroxide monohydrate (1.25 eq., 20.3 mg, 0.48 mmol) was added. The resulting mixture was stirred at rt for 5 h. The reaction mixture was diluted with water and the aqueous layer was acidified with few drops of 3 M aq HC1 and extracted with DCM (3x). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to give Int-122 (63 mg, 0.26 mmol, 66.6%) as a light yellow oil.1.2.36. General method N3: t-Butyl ester hydrolysis in acidic mediumO

[0075] tButyl ester (leq) is treated with TFA (50 eq) in DCM at rt for 18 h. The reaction mixture is evaporated to dryness to give the expected compound. Alternatively, when an alcohol function is present on the molecule, after the evaporation, the residue is treated with TEA (20eq.) in MeOH and stirred for 16 h. An aqueous work-up with 10%aqKHSO4 and DCM is performed. The combined organic layers were dried over Na2SO4, filtered and evaporated to dryness to give the expected compound.1.2.36.1. Illustrative synthesis of Int-394Int-355 Int-394

[0076] To a solution of Int-355 (1 eq., 234 mg, 0.68 mmol) in DCM (7.35 mL) was added TFA (50 eq., 3851.57 mg, 2.509 mL, 33.78 mmol). The reaction mixture was stirred at rt overnight. The reaction mixture was evaporated under vacuum. The residue was taken into MeOH (4.65 mL) and TEA (20 eq., 1367.28 mg, 1.88 mL, 13.51 mmol) was added. The reaction mixture was stirred at rt for 3 h. The reaction mixture was evaporated to dryness to give a brown oil. The latter was partitioned between 10% aq. KHSO4 and EtOAc. The aqueous layer was extracted twice with EtOAc. The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo to give Int-394 (196 mg, 0.68 mmol, 100%) as a cream solid.1.2.37. General method Ol: Bromination with l,3-dibromo-5,5-dimethylhydantoin

[0077] At 0 °C, to a solution of imidazole (1.0 eq.) in DCM is added 1, 3 -dibromo-5, 5 -dimethylhydantoin (CAS# 77-48-5; 0.5 eq.) then the reaction mixture is stirred at 0 °C for 1.5 h. The reaction mixture is evaporated to dryness. The crude residue is purified by column chromatography on silica gel to afford the desired bromo derivative.1.2.37.1. Illustrative synthesis ofInt-109Int-109

[0078] At 0 °C, to a solution of 1-(cyclopropylmethyl)-1H-imidazole (CAS# 717908-74-2; 240 mg, 1.96 mmol, 1.0 eq.) in DCM (19.7 mL) was added l,3-dibromo-5,5-dimethylhydantoin (CAS# 77-48-5; 280.8 mg, 0.98 mmol, 0.5 eq.) then the reaction mixture was stirred at 0 °C for 1.5 h. The reaction mixture was evaporated to dryness. The residue was purified by column chromatography on silica gel (eluting with DCM / (DCM / MeOH 80:20) from 100 / 0 to 75 / 25) to afford Int-109.1.2.38. General method 02: Bromination with Pyridinium perbromideR3R3At 0 °C, to a solution of substituted imidazole (1 eq.) in dichloromethane (20 mL) was added pyridin-1-ium; tribroman-2-uide (2 eq.) and the reaction mixture was stirred at 0 °C for 2 h. The mixture was evaporated to dryness to give a crude and the crude was used without further purification for the next step.1.2.38.1. Illustrative synthesis of Int-270BrInt-270At 0 °C, to a solution of (l,4-dimethyl-lH-imidazol-2-yl)methanol [59608-81-0] (1 eq., 660 mg, 5.23 mmol) in dichloromethane (20 mL) was added pyridin-l-ium; tribroman-2-uide (2 eq., 3346.29 mg, 10.46 mmol) and the reaction mixture was stirred at 0 °C for 2 h. The mixture was evaporated to dryness to give a crude which was used without further purification for the next step, (purity of Int-270 (-51% w / w))1.2.39. General method 03: Iodination with NISRi,R1_-NI >1" X2At rt, to a solution of azole (1.0 eq.) in MeCN or DCM is added NIS (CAS# 516-12-1; 1.2 eq.) then the reaction mixture is stirred at 80 °C for 1 h or 0 °C for 45 min. An aqueous work-up can be performed with aq K2CO3 10% or water or 10% aqNa2S2O3 and DCM or the mixture can be evaporated to dryness. The crude can be purified from liquid chromatography if necessary to give the iodo derivative.1.2.39.1. Illustrative synthesis of Int-297Int-298 Int-297At rt, to a solution of Int-298 (1 eq., 23 mg, 0.17 mmol) in MeCN (1.15 mL) was added NIS ((CAS# 516-12-1; 1.2 eq., 44.9 mg, 0.2 mmol) and the reaction mixture was stirred at 80 °C for 1 h. The mixture was allowed to cool down to rt, then diluted with water. The mixture was extracted 3 times with DCM. The organic layers were combined, washed with a solution of K2CO3 10%, dried over Na2SO4filtered and concentrated under reduced pressure to give crude Int-297 (24 mg, 0.091 mmol, 55%) as a brown solid.1.2.40. General method Pl: fluoro-ester reduction via NaBH4NaBH4ROH

[0079] To a mixture of fluoroester (1 eq) in EtOH or zPrOH was added NaBH4(2 eq) at 0 °C. The resulting mixture was stirred at 0 °C for 1 h to 2 h. Water or IN aqHCl and EtOAc were added. The layers were separated and the aqueous layer was extracted once again with EtOAc. The combined organic layers weredried over MgSO4or Na2SO4, filtered and the solvent was removed in vacuo. The residue was purified in case of need by liquid chromatography to give expected fluoroalcohol.1.2.40.1. Illustrative synthesis ofInt-182

[0080] To a mixture of Int-181 (1 eq., 492 mg, 1.44 mmol) in EtOH (28.11 mL) was added NaBH4(2 eq., 109.109 mg, 2.88 mmol) at 0 °C. The resulting mixture was stirred at 0 °C for 1 h. Water and EtOAc were added. The layers were separated and the aqueous layer was extracted once again with EtOAc. The combined organic layers were dried over MgSO4, filtered and the solvent was removed in vacuo. The residue was purified by preparative LC (irregular SiOH, 40-60 pm, 40 g Agela, liquid loading (DCM), mobile phase gradient: from heptane / EtOAc 100 / 0 to 40 / 60). The fractions containing product were combined and evaporated to dryness to give Int-182 (303 mg, 1.013 mmol, 70.2%) as sticky off-white solid.1.2.41. General method P2: carbonyl reduction via NaBH4OHNaBH4(1 to 1.1 eq) is added to a mixture of carbonyl compound (1 eq) in MeOH. The resulting mixture was stirred at rt for 1 h. An aqueous work-up is performed using DCM and IN aqHCl. The mixture was filtered over chromabond and the filtrate was evaporated to dryness to give the expected alcohol. Alternatively a classical work-up using DCM and IN aqHCl can be performed. The layers were separated, washed with brine, dried over Na2SO4, filtered and evaporated to dryness to give the expected alcohol.1.2.41.1. Illustrative synthesis of Int-355Int-339 Int-355To a mixture of Int-339 (1 eq., 200 mg, 0.58 mmol) in MeOH (4 mL) was added NaBH4 (1 eq., 22 mg, 0.58 mmol) at rt. The resulting mixture was stirred at rt for 1 h. IN aq HC1 and DCM were added. The mixture was filtered over chromabond PTS. The aqueous layer was extracted once again with DCM and filtered over chromabond PTS. The filtrate was evaporated to dryness. The aqueous layer was extractedtwice again with DCM. The combined organic layers were dried over Na2SO4, filtered and combined with the residue. The solvent was removed under reduced pressure to give Int-355 (190 mg, 0.55 mmol, 94%).1.2.42. General method QI: acetylation of alcoholOR^OH - *To a stirred solution of alcohol (1 eq.), DMAP (0.2 eq.) and DiPEA (3 eq.) in DCM at rt under N2 is added dropwise acetyl chloride (2.5 eq.) and the solution was allowed to stir at rt 1 h. The mixture is evaporated to dryness or diluted with DCM & washed with H2O. Organic layers are combined and washed with brine, dried over Na2SO4 and concentrated under reduced pressure. If necessary the crude residue was purified by normal phase preparative LC (eluent DCM / MeOH or heptane / EtOAc depending the polarity of expected molecule) The fractions containing compound were combined and evaporated under vacuum to give the expected compound.1.2.42.1. Illustrative synthesis of Int-236To a stirred solution of (5-bromo-l,2-dimethyl-lH-imidazol-4-yl)methanol [(1 eq., 674 mg, 3.29 mmol), DMAP (0.2 eq., 80.31 mg, 0.66 mmol) and DiPEA (3 eq., 1274.47 mg, 1.72 mL, 9.86 mmol) in DCM (15 mL) at rt under N2 was added dropwise acetyl chloride (2.5 eq., 645.059 mg, 0.59 mL, 8.22 mmol) and the solution was allowed to stir at rt 1 h. The mixture was evaporated to dryness then purified by normal phase preparative LC (Stationary phase: irregular SiOH, 40-60 pm, Agela, 40 g, liquid loading (DCM) Mobile phase Gradient from DCM / MeOH 100:00 to 90: 10 over 15 CV, then isocratic over 5 CV) The fractions containing compound were combined and evaporated under vacuum to give Int-236 (770 mg, 3.12 mmol, 95%) as a brown solid.1.2.43. General method Rl: Deacetylation of alcoholO- * R^OHTo a stirred solution of acetate (1 eq.) in MeOH is added LiOH H2O (5 eq.) at rt then the solution is stirred for 1 h. The mixture is diluted with water, acidified with aq 3 M HC1 and extracted with DCM. The reaction was quenched with water and extracted twice with 1:3 / PrOH / CHCE. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to give the desired alcohol.Ill1.2.43.1. Illustrative synthesis oflnt-304Int-305lnt-304Lithium hydroxide monohydrate (5 eq., 44.7 mg, 1.066 mmol) was added to a solution of Int-305 (1 eq., 92 mg, 0.21 mmol) in water (0.32 mL) and MeOH (0.96 mL) and the reaction mixture was stirred at rt for 1 h. The reaction was quenched with water and extracted twice with 1:3 iPrOH / CHCl3. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to give crude lnt-304 (60 mg, 0.16 mmol, 75%) as a yellow oil.1.2.44. General method SI: Sonogashira libraryTo a mixture of Int-334 (1 eq.), heteroaryl halide (3 eq.), EtsN (6 eq.) and CsF (1.5 eq.) in DMF is added XPhos Pd G3 (0.2 eq.) The reaction mixture is degassed with nitrogen for 5 minutes then heated at 120 °C for 45 min. The reaction mixture is quenched with sat aq NaHCO3. DCM was added and the biphasic mixture was fdtered through Chromabond or the reaction mixture was fdtered over a pad of celite and the cake was washed with EtOAc. The fdtrate was concentrated in genevac. The crude residue was purified by RPLC (Column YMC -Actus Triart Prep C18-S 150*30mm 5 pm Flow rate 5 Oml / min -Focused gradient MeCN / aq. NH4HCO3 0.2% pH=7.9) and freeze-dried to give the desired alkyne product.Illustrative synthesis of Cpd-343

[0081] A mixture of Int-334 (1 eq., 51.74 mg, 0.077 mmol), DMF (0.79 mL), 2-bromo- 5H,6H,7H,8H-imidazo[l,2-a]pyrazin-8-one (CAS# 1936039-76-7; 3 eq., 49.7 mg, 0.23 mmol), EtsN (6 eq., 0.064 mL, 0.46 mmol), CsF (1.5 eq., 17.5 mg, 0.12 mmol) and XPhos Pd G3 (0.2 eq., 123.0 mg, 0.015 mmol) was degassed with nitrogen then heated at 120 °C for 45 min. The reaction mixturewas quenched with sat aq NaHCO3. DCM was added and the biphasic mixture was filtered through Chromabond. The filtrate was concentrated in genevac. The crude residue was purified by RPLC (Column YMC -Actus Triart Prep C18-S 150*30mm 5 pm Flow rate 50ml / min-Focused gradient MeCN / aq. NH4HCO3 0.2% pH=7.9 Focused gradient 25-65) and freeze-dried to give Cpd-343 (1 mg, 0.0015 mmol, 2%) as a white fluffy solid.1.2.45. General method S2: Sonogashira libraryA mixture of lnt-225 (1 eq.), alkyne (2 eq.), TMG (2 eq.), xantphos (0.1 eq.,), PdC12(PPh3)2 (0.1 eq.) in THF is flushed with N2 and stirred at 90 °C for 18 h. The mixture was filtered on celite, the pad was washed. The filtrate was concentrated under vacuum. The crude residue was purified by reverse phase LC (Column YMC -Actus Triart Prep C18-S 150*30mm 5pm Flow rate 5 Oml / min -Focused gradient MeCN / aq. NH4HCO3 0.2% pH=7.9). The fractions containing the product were combined and concentrated under vacuum, freeze-dried to give the desired alkyne.1.2.45.1. Illustrative synthesis of Cpd-348lnt-225 Cpd-348A mixture of lnt-225 (1 eq., 50 mg, 0.088 mmol), prop-2-yn-l-ol (CAS# 107-19-7; 2 eq., 10.4 pL, 0.18 mmol), TMG (2 eq., 22.2 pL, 0.18 mmol), xantphos (0.1 eq., 5.1 mg, 0.0088 mmol), PdC12(PPh3)2 (0.1 eq., 6.16 mg, 0.0088 mmol) in THF (2.1 mL) was flushed with N2 and stirred at 90 °C for 18 h. The mixture was filtered on celite, the pad was washed. The filtrate was concentrated under vacuum. The crude residue was purified by reverse phase LC (Column YMC -Actus Triart Prep C18-S 150*30mm 5pm Flow rate 50ml / min-Focused gradient MeCN / aq. NH4HCO3 0.2% pH=7.9 Focused gradient from 35 / 65 to 65 / 35). The fractions containing the product were combined and concentrated under vacuum, freeze-dried to give Cpd-348 (7 mg, 0.012 mmol, 14%) as a white foam.1.2.46. General method Tl: N-alkylation_ x-XR2 R3 R2r, -NH - R1 R1 R3To a mixture of amine (1 eq.) and Cs2CO3(3 eq.) in MeCN is added alkyl halide (1.5 eq.). The reaction mixture is heated to 80 °C for 20 h. Water and EtOAc are added to the mixture. The layers are separated then the aqueous layer is extracted once with EtOAc. The combined organic layers are washed with brine,dried over Na2SO4, filtered and evaporated. The crude residue is purified by column chromatography on silica gel to afford the desired alkylated product.Illustrative synthesis of Int-346Int-346To a suspension of 4-bromo-lH-pyrrolo[2,3-b]pyridine (1 eq., 300 mg, 1.52 mmol) and Cs2CO3(3 eq., 1488 mg, 4.57 mmol) in MeCN (7.62 mL) was added 2-bromoethan-l-ol (1.5 eq., 0.16 mL, 2.28 mmol). The reaction mixture was heated to 80 °C for 20 h. Water and EtOAc were added to the mixture. The layers were separated then the aqueous layer was extracted once with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and evaporated. The crude residue was purified by normal phase preparative LC (irregular SiOH 40-60 pm, 20 g Agela, liquid loading (DCM), mobile phase gradient: Heptane / EtOAc: 70:30 to 0:100 over 12 CV then 100% over 3 CV). Fractions containing product were collected and evaporated to give Int-346 (137 mg, 0.57 mmol, 37%) as pale-yellow residue.1.2.47. General method T2: O-alkylationR-OH - * R-OR'To a mixture of alcohol (leq) and NaH (60% in mineral oil) (1.5eq) in THF is added Me2SO4 (3eq) at rt. The resulting mixture is stirred at rt for 18 h then an aqueous work-up is performed using EtOAc and water. The organic layer is dried over MgSO4 or Na2SO4, filtered ad the solvent is removed in vacuo. The crude was purified by liquid chromatography over normal phase silica.1.2.47.1. Illustrative synthesis ofInt-354Int-355 lnt-354To a suspension of Int-355 (1 eq., 39 mg, 0.11 mmol) & NaH (60% in mineral oil) (1.5 eq., 5.404 mg, 0.14 mmol) in THF (2 mL) at rt was slowly added dimethyl sulfate (3 eq., 21.303 mg, 0.016 mb, 0.17 mmol), The mixture was stirred at rt for 18 h. The reaction mixture was diluted with EtOAc and water was added. The mixture was extracted with EtOAc (3x). The organics layers were combined, washed with brine, dried over MgSO4, filtered and the solvent was evaporated under vacuo. The crude residue was purified by normal phase flash chromatography (irregular silice 40 - 60 pm, 4 g Agela, liquid injection (DCM), mobile phase gradient: heptane / EtOAc 100:0 to 50:50 over 10 CV, to give lnt-354 (20 mg, 0.055 mmol, 49%).1.2.48. General method Ul: oxidative cleavageTo a vinyl derivative in THF and water is added potassium osmate (VI) dihydrate (0.01 eq). The resulting mixture was stirred at rt for 10 min then NalCh (2.5 eq) was added. The reaction mixture was stired at rt for 2 h. An aqueous work-up was performed using water and EtOAc. The combined organic layers is washed with brine, dried over Na2SO4, filtered and the solvent was removed in vacuo to give the aldehyde derivative.1.2.48.1. Illustrative synthesis ofInt-339Int-340 Int-339Potassium osmate (VI) dihydrate (0.01 eq., 9.33 mg, 0.012 mmol) was added to a solution of Int-340 (1 eq., 397 mg, 1.16 mmol) in THF (17.87 mL) and H2O (5.96 mL) at room temperature. The resulting mixture was stirred 10 min then sodium periodate (2.5 eq., 620.03 mg, 2.9 mmol) was added at rt and the reaction mixture was stirred at rt for 2 h. The reaction mixture was diluted with H2O. The aqueous layer was extracted twice with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to dryness to afford Int-339 (360 mg, 1.045 mmol, 90%) as a lightly brown solid.

[0082]

[0083] Example 2. Preparation of the compounds of the invention2.1. Int-23Int-23

[0084] A mixture of 4-bromo-2-iodophenol (CAS # 207115-22-8; 100 mg, 0.33 mmol, 1.0 eq.), K2CO3 (69.36 mg, 0.502 mmol, 1.5 eq.) and tert-butyl(2-iodoethoxy)dimethylsilane (CAS# 101166-65-8; 0.074 mL, 0.33 mmol, 1.0 eq.) in DMF (1.00 mL) was stirred at RT for 18 h. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine (3x), dried over MgSO4, filtered and evaporated to dryness to afford Int-23.2.2. Int-512.2.1. Int-50D DInt-50

[0085] NaOMe (23.67 mg, 0.44 mmol, 0.5 eq.) was added to a solution of methyl 3-methanesulfonyl-4-methylbenzoate (CAS# 906816-32-8, 200 mg, 0.88 mmol, 1.0 eq.) in CD3OD (5 mL, 122.6 mmol, 139.8 eq.) at RT. The reaction mixture was stirred at 100 °C for 22 h. An extra amount of CD3OD (3.0 mL, 73.53 mmol, 83.9 eq.) and NaOMe (25 mg, 0.46 mmol, 0.53 eq.) was added and the mixture was stirred at 100 °C for 16 h. The mixture was evaporated to dryness, then taken -up with DCM and washed with HC1 (I M) aqueous solution then the organic layer was purified by column chromatography on silica gel (eluting with Heptane / EtOAc from 100 / 0 to 50 / 50) to afford a residue (114 mg). The residue (50 mg, 0.21 mmol, 1.0 eq.,) and MeONa (5.76 mg, 0.107 mmol, 0.5 eq.) in CD3OD (1.0 mL, 24.51 mmol, 114.9 eq.) was stirred at 70 °C for 16 h. D2SO4 (5%) in D2O (0.50 mL) was added. DCM and water were added. The layers were separated, and the aqueous layer was extracted once again with DCM. The combined organic layers were dried over MgSO4, filtered and the solvent was evaporated to dryness to afford Int-50.2.2.2. Int-51D DInt-50 Int-51

[0086] NaOD (40%) in D2O (0.023 mL, 0.32 mmol, 2.0 eq.) was added to a mixture of Int-50 (38 mg, 0.16 mmol, 1.0 eq.) in THF (1.0 mL) and D2O (0.2 mL). The resulting mixture was stirred at RT for 16 h.D2SO4 (5%) in D2O was added (0.5 mL), then H2O then EtOAc were added. The layers were separated, and the aqueous layer was extracted once again with EtOAc. The combined organic layers were dried over MgSO4, filtered and the filtrate was evaporated to dryness to afford Int-51.2.3. Int-711. MnO22. Et3SiHInt-71

[0087] To a solution of [5-bromo-3-fluoro-2-(hydroxymethyl)phenyl]methanol (CAS# 2923731-77-3; 1.27 g, 5.403 mmol, 1.0 eq.) in DCM (13.8 mL) at RT was added MnO2(CAS# 1313-13-9; 2.25 g, 25.93mmol, 4.8 eq.). The reaction mixture was stirred at RT for 20 h under nitrogen. The mixture was filtered over a pad of Celite®, washed with DCM, and the fdtrate was taken. Triethylsilane (CAS# 617-86-7; 1.88 g, 2.62 mL, 16.209 mmol, 3.0 eq.) and TFA (2.96 g, 1.93 mL, 25.93 mmol, 4.8 eq.) were added and the reaction mixture was stirred at RT for 4 h under nitrogen. The reaction mixture was evaporated to dryness, H2O (30.0 mL) was added, and the mixture was extracted with EtOAc (3x30.0 mL). The organic layer was dried over MgSO. fdtered and the solvent was evaporated to dryness to afford Int-712.4. Int-77Int-77

[0088] To a solution of Int-76 (35 mg, 0.12 mmol, 1.0 eq.) in THF (0.96 mL) and H2O (0.24 mL) was added LiOH monohydrate (31.22 mg, 0.74 mmol, 6.0 eq.) and the reaction was stirred at RT for 18 h. The solvent was evaporated to dryness to afford Int-77.2.5. Int-79lnt-78 Int-79

[0089] In a sealed vial, to a stirred solution of lnt-78 (400 mg, 1.57 mmol, 1.0 eq.), cyclopropylboronic acid (270.34 mg, 3.15 mmol, 2 eq.) and K3PO4 (668.02 mg, 3.15 mmol, 2.0 eq.) in toluene (3.50 mL) and water (0.90 mL) were added Pd(OAc)2(CAS# 3375-31-3; 17.66 mg, 0.079 mmol, 0.05 eq.) and P(Cy)3 (44.13 mg, 0.16 mmol, 0.1 eq.). The reaction mixture was backfilled (3x) with nitrogen and stirred at 100 °C for 2 h then was cooled down to RT. The reaction mixture was diluted with EtOAc and H2O. The mixture was filtered over a pad of Celite®. The fdtrate was extracted with EtOAc (3x). The organics layers were combined, washed with brine, dried over MgSO4, fdtered and the solvent was evaporated to dryness. The residue was purified by column chromatography (eluting with Heptane / EtOAc from 100 / 0 to 70 / 30) to afford Int-79.2.6. Int-80Int-80

[0090] To a mixture of 7-bromo-3,4-dihydro-2H-l,4-benzothiazine (CAS# 193414-60-7; 267 mg, 1.16 mmol, 1.0 eq.,) in DMF (3.00 mL) was added NaH (60%) dispersion in mineral oil (116.017 mg, 2.901 mmol, 2.5 eq.) at RT. The suspension was stirred for 15 min at RT. Mel (CAS# 74-88-4; 181.16 mg, 0.079 mL, 1.28 mmol, 1.1 eq.) was added and the reaction mixture was stirred at RT for 18 h. The reaction mixture was quenched with water and EtOAc. The layers were separated and the aqueous layer was extracted with EtOAc (2x). The combined organic layers were washed with brine, dried over MgSO4, fdtered and the solvent was evaporated to dryness. The residue was purified by column chromatography on silica gel (eluting with Heptane / EtOAc from 100 / 0 to 85 / 15) to afford Int-80.2.7. Int-84HN-N

[0091] A mixture of 4-ethynyl-lH-pyrazole (CAS# 57121-49-0; 200 mg, 2.17 mmol, 1.0 eq.) in ACN (10.9 mL), K2CO3 (1.80 g, 13.03 mmol, 6.0 eq.), KI (72.1 mg, 0.43 mmol, 0.2 eq.) and l-(2-chloroethyl)-4-methylpiperazine dihydrochloride (CAS# 5753-26-4; 1023.14 mg, 4.34 mmol, 2.0 eq.) was stirred at 85 °C for 20 h. The reaction mixture was quenched with H2O (30.0 mL) and extracted with DCM (3x 30.0 mL). The combined organic layers were dried over Na2SO4, filtered and evaporated to dryness. The residue was purified by column chromatography on silica gel (eluting with DCM / (80: 18:2 DCM / MeOH / NH4OH 30% aq.) from 100 / 0 to 0 / 100 to afford Int-84.2.8. Int-87OHlInt-87

[0092] To a mixture of 2-bromo-4-iodophenol (CAS# 133430-98-5; 300 mg, 1.004 mmol, 1.0 eq.) in THF anhydrous (10.0 mL) was added NaH (60%) in mineral oil (44.16 mg, 1.104 mmol, 1.1 eq.) and suspension was stirred at RT for 15 min then iodo(2H3)methane (CAS# 865-50-9; 174.59 mg, 0.075 mb, 1.204 mmol, 1.2 eq.) was added and the reaction mixture was stirred at RT for 17 h then at 65 °C for 24 h. iodo(2H3)methane (CAS# 865-50-9; 174.59 mg, 0.075 mb, 1.204 mmol, 1.2 eq.) was added. The reaction mixture was stirred at 65 °C for 24 h more then was cooled down to RT and water was added. The precipitate was fdtered over frit to afford Int-87.2.9. Int-93CAS# 1595650-07-9 Int-93

[0093] NaH (60%) in oil (113.036 mg, 2.83 mmol, 3.0 eq.) was added portionwise to a solution of 8-bromo-2,3,4,5-tetrahydro-l,5-benzothiazepine (CAS# 1595650-07-9; 230 mg, 0.94 mmol, 1.0 eq.) in THF (9.26 mL) at RT under nitrogen. The mixture was stirred for 20 min and lodomethane (CAS# 74-88-4; 0.23 mL, 3.77 mmol, 4.0 eq.) was added and the mixture was stirred at 60 °C for 84 h. An amount of lodomethane (CAS# 74-88-4; 0.12 mL, 1.88 mmol, 2.0 eq.) was added and the mixture was stirred at 60 °C for 32 h. Water was added to the mixture. The layers were separated and the aqueous one was extracted with EtOAc (2x). The combined organic extracts were washed with H2O, brine, dried over MgSO4, filtered and the filtrate was evaporated to dryness to afford Int-93.2.10. Int-96int-96

[0094] A mixture of 4-iodopyridin-3-ol (CAS# 188057-20-7; 100 mg, 0.45 mmol, 1.0 eq.), ACN (2.25 mL), K2CO3 (187.6 mg, 1.36 mmol, 3.0 eq.) then 1-bromo-2-methylpropane (CAS# 78-77-3; 124.0 mg, 0.098 mL, 0.905 mmol, 2.0 eq.) was stirred at 80 °C for 16 h. The reaction mixture was quenched with H2O (10 mL) and extracted with EtOAc (3x10 mL). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and the solvent was evaporated to dryness. The residue was purified by column chromatography on silica gel (eluting with Heptane / EtOAc from 100 / 0 to 75 / 25) to afford Int-96.2.11. Int-98Int-98

[0095] To a mixture of To a mixture of 4-ethynyl-lH-pyrazole (CAS# 57121-49-0; 200 mg, 2.17 mmol, 1.0 eq.) in THF (20.0 mL) was added NaH (60%) in mineral oil (95.54 mg, 2.39 mmol, 1.1 eq.) and the resulting mixture was stirred at RT for 10 min then iodo(2H3)methane (CAS# 865-50-9; 377.74 mg, 0.16 mL, 2.61 mmol, 1.2 eq.) was added and the resulting mixture was stirred at RT for 20 h. H2O and EtOAc were added. The layers were separated and the aqueous layer was extracted once again with EtOAc. The combined organic layers were dried over MgSO4, filtered and the solvent was evaporated to dryness to afford Int-98.2.12. Int-99ClInt-99

[0096] A mixture of 4-ethynyl-lH-pyrazole (CAS# 57121-49-0; 100 mg, 1.086 mmol, 1.0 eq.), ACN (5.4 mL), K2CO3 (900.4 mg, 6.51 mmol, 6.0 eq.), KI (36.048 mg, 0.024 mL, 0.22 mmol, 0.2 eq.) & 4-(2-chloroethyl)morpholine hydrochloride (CAS# 3647-69-6; 404.1 mg, 2.17 mmol, 2.0 eq.). The reaction mixture was heated at 85 °C for 18 h. The reaction mixture was quenched with H2O (30.0 mL) and extracted with DCM (3x30.0 mL). The combined organic layers were dried over Na2SO4, filtered and evaporated to dryness. The residue was purified by column chromatography on silica gel (eluting with Heptane / EtOAc from 100 / 0 to 50 / 50) to afford Int-99.2.13. Int-101lnt-100 lnt-101

[0097] Under Nitrogen, To a stirred solution of a mixture 4-bromo-2-iodo-l -methoxybenzene (CAS# 98273-59-7; 424 mg, 0.68 mmol, 1.0 eq.), Int-100 (166.93 mg, 0.81 mmol, 1.2 eq.) and CsF (205.82 mg, 1.35 mmol, 2.0 eq.) in TEA (1.30 mL, 9.38 mmol, 13.8 eq.) and DMF (1.3 mL) were added Cui (12.902 mg, 0.068 mmol, 0.1 eq.) and PdCh(PPh3)2 (23.78 mg, 0.034 mmol, 0.05 eq.) at RT. The reaction mixture was degassed with nitrogen for 5 min then stirred at 50 °C for 16 h. The reaction mixture was filtered over celite® and the fdtrate was evaporated to dryness. The residue was purified by column chromatography on silica gel (eluting with Heptane / EtOAc from 100 / 0 to 80 / 20) to afford Int-101.2.14. Int-107Int-107

[0098] To a solution of 1,2,4-trimethyl-lH-imidazole (CAS# 1842-63-3; 200 mg, 1.82 mmol, 1.0 eq.) in ACN (17.7 mL) was added NBS (CAS# 128-08-5; 355.5 mg, 2 mmol, 1.1 eq.) and the reaction mixture was added at RT for 1.5 h. Water and EtOAc were added. The aqueous layer was extracted with EtOActhen the combined organic layers were dried over Na2SO4, filtered and the solvent was evaporated to afford Int-107.2.15. Cpd-5

[0099] To a stirred solution of tributyl(l-propynyl)tin (CAS# 64099-82-7; 35.82 mg, 0.11 mmol, 1.0 eq.) in toluene (2.0 mL) was added Int-4 (50 mg, 0.109 mmol, 1.0 eq.) at RT. The reaction mixture was degassed with nitrogen for 5 min. Pd(PPh3)4(10.06 mg, 8.7 pmol, 0.08 eq.) was added and the reaction mixture was stirred at 90 °C for 1.5 h. The reaction mixture was evaporated to dryness. The residue was purified by column chromatography on a Biotage® Sfar HC chromatography cartridge (eluting with DCM / MeOH from 100 / 0 to 50 / 50) to afford Cpd-5.2.16. Cpd-8Int-1 Int-32.16.1. Int-3

[0100] To a stirred solution of Int-1 (1.0 g, 2.609 mmol, 1.0 eq.) and bis(pinacolato)diboron (CAS# 73183-34-3; 0.99 g, 3.91 mmol, 1.5 eq.) in 1,4-Dioxane (6.0 mL) was added AcOK (0.51 g, 5.22 mmol, 2.0 eq.) at RT. The reaction mixture was degassed with nitrogen for 5 min. Pd(dppf)C12'DCM (0.107 g, 0.13 mmol, 0.05 eq.) was added and the reaction mixture was stirred at 70 °C for 1 h 30, then 90 °C for 3 h. The reaction mixture was filtrated over a pad of Celite® and evaporated to dryness. The residue was purified by preparative HPLC to afford Int-3.2.16.2. Cpd-8

[0101] Cpd-8 is synthetized from Int-3 and 2-(2-(3-bromophenyl)ethynyl)pyridine (CAS# 1417162-68-5) following general method Cl.2.16.3. Int-3

[0102] To a stirred solution of Int-1 (1.0 g, 2.609 mmol, 1.0 eq.) and bis(pinacolato)diboron (CAS# 73183-34-3; 0.99 g, 3.91 mmol, 1.5 eq.) in 1,4-Dioxane (6.0 mL) was added AcOK (0.51 g, 5.22 mmol, 2.0 eq.) at RT. The reaction mixture was degassed with nitrogen for 5 min. Pd(dppf)C12'DCM (0.107 g, 0.13 mmol, 0.05 eq.) was added and the reaction mixture was stirred at 70 °C for 1 h 30, then 90 °C for 3 h. The reaction mixture was filtrated over a pad of Celite® and evaporated to dryness. The residue was purified by preparative HPLC to afford Int-3.2.17. Cpd-11\

[0103] To a solution of Int-33 (14 mg, 0.033 mmol, 1.0 eq.) in DCM (2.0 mL) was added HC1 (4 N) in 1,4-Dioxane (0.19 mL, 0.76 mmol, 22.7 eq.). The mixture was stirred at RT for 1 h. The reaction mixture was evaporated to dryness, then it was diluted in DCM (2.0 mL). 4-Methyl-3-(methylsulfonyl)benzoic acid (CAS# 51522-22-6; 8 mg, 0.037 mmol, 1.12 eq.) HATU (16.54 mg, 0.043 mmol, 1.3 eq.) then DIPEA (21.62 mg, 0.029 mL, 0.17 mmol, 5.0 eq.). The mixture was stirred at RT for 2 h. The reaction was poured into water and extracted with DCM. The combined organic layers were washed with water then dried over MgSO4and evaporated to dryness. The crude was purified by preparative HPLC to afford Cpd-11.2.18. Cpd-20

[0104] Step i: To a solution of 2,3-dihydro-5H-benzo[e][l,4]oxathiepine-8-carboxylic acid 1,1-dioxide (CAS# 2771132-16-0, synthesis ref.: WO2022 / 103899A1 page 177; 619 mg, 2.56 mmol, 1.0 eq.) in DCM (10.0 mL) and DMF (0.55 mL) at room temperature was added SOCI2 (0.28 mL, 3.83 mmol, 1.5 eq.). The reaction mixture was stirred at RT for 30 min. The reaction mixture is evaporated to dryness to afford a crude.

[0105] Step ii: A solution of the crude (1.0 eq.) in DCM (10 mL) was added dropwise to a solution of Int-34 (1000 mg, 2.56 mmol, 1.0 eq.) and TEA (1.42 mL, 10.22 mmol, 4.0 eq.) in DCM (10.0 mL) at 0 °C. The reaction is stirred at RT for 2 h. The reaction mixture was poured into NH4C1 saturated aqueous solution (100 mL) then washed with water. The organic layer was dried over MgSO4and evaporated to dryness. The crude was purified by column chromatography on silica gel (eluting with DCM / MeOH from 100 / 0 to 95 / 5) then by preparative HPLC to afford Cpd-20 as a formic acid salt (1.0 eq.).2.19. Cpd-34

[0106] To a solution of Int-25 (63.0 mg, 0.092 mmol, 1.0 eq.) in DCM (0.99 mL) was added HC1 (4 N) in 1,4-Dioxane (0.32 mL, 1.28 mmol, 14.0 eq.). The mixture was stirred at RT for 1 h. The reaction mixturewas quenched with NaHCO3saturated aqueous solution and DCM. The organic layer was filtered through hydrophobic frit then was evaporated to dryness. The residue was purified by preparative HPLC to afford Cpd-34.2.20. Cpd-722.20.1. Int-1Int-1

[0107] To a solution of 3-methanesulfonyl-4-methylbenzoic acid (CAS# 51522-22-6; 1.0 g, 4.67 mmol, 1 eq.) and l-(4-bromopyridin-2-yl)methanamine (CAS# 865156-50-9; 0.96 g, 5.13 mmol, 1.1 eq.) in DMF (10.0 mL) were added HATU (2.31 g, 6.07 mmol, 1.3 eq.) and DIPEA (2.4 mL, 11.67 mmol, 2.5 eq.). The reaction was stirred at RT for 18 h. The reaction mixture was evaporated to dryness and the residue was purified by column chromatography on silica gel (eluting with DCM / MeOH from 100 / 0 to 99 / 1) to afford Int-1.2.20.2. Int-2Int-1 Int-2

[0108] Under nitrogen atmosphere, to a stirred solution of 4,4,5,5-tetraethyl-2-(4,4,5,5-tetraethyl-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane (CAS# 2247367-07-1; 5.25 g, 14.35 mmol, 1.1 eq.) and Int-1 (5 g, 13.046 mmol, 1.0 eq.) in 1,4-Dioxane anhydrous (150 mL) was added AcOK (3.84 g, 39.14 mmol, 3.0 eq.) at RT. The reaction mixture was degassed with argon for 5 min. Pd(dppf)C12 • DCM (0.53 g, 0.65 mmol, 0.05 eq.) was added and the reaction mixture was stirred at 90°C overnight. The solvent was evaporated to dryness. The crude was purified by column chromatography on silica gel (eluting with DCM / MeOH from 100 / 0 to 97 / 3) to afford Int-2.2.20.3. Int-49Int-49

[0109] To a stirred solution of Int-2 (2 g, 4.11 mmol, 1.0 eq.) and 2-bromo-4-iodo-l -methoxybenzene (CAS# 182056-39-9; 1.42 g, 4.52 mmol, 1.1 eq.) in 1,4-Dioxane (36.0 mL) water (4.0 mL) was added Cs2CO3(2.68 g, 8.22 mmol, 2.0 eq.) in water (4.0 mb) at RT. The reaction mixture was degassed withnitrogen for 5 min. Pd(dppf)C12 • DCM (0.17 g, 0.206 mmol, 0.05 eq.) was added and the reaction mixture was stirred at 90°C Ih. Solvent was evaporated and the crude was purified by column chromatography on silica gel (eluting with DCM / MeOH from 100 / 0 to 97 / 3) to afford Int-49.2.20.4. Cpd-72int-49

[0110] A microwave vial equipped with a magnetic stirring bar was charged with Int-49 (70 mg, 0.14 mmol, 1.0 eq.), 4-ethynyl-l,5-dimethyl-lH-pyrazole (CAS# 61514-54-3; 85.93 mg, 0.72 mmol, 5.0 eq.), Xphos PdG3 (24.19 mg, 0.029 mmol, 0.2 eq.), DMF (1.48 mL) and TEA (0.12 mL, 0.86 mmol, 6.0 eq.). The reaction mixture was degassed with nitrogen for 5 min then heated at 100 °C using one single mode microwave (Biotage Initiator EXP 60) with a power output ranging from 0 to 400 W for 30 min. The reaction mixture was diluted with EtOAc (2.0 mL) and SiliaMetS thiol silica (Silicycle, 40-63 um) (60 mg) was added. After stirring for 30 min at rt, the reaction mixture was filtered over a pad of celite. The pad was eluted with EtOAc. The filtrate was washed with water twice and then with sat brine, dried over sodium sulfate, filtered and evaporated to dryness. The residue was purified by column chromatography on silica gel (eluting with DCM / (80:20 DCM / MeOH) from 100 / 0 to 50 / 50). Then the residue was purified by preparative HPLC (column YMC 25 pm 12 g, liquid deposit (ACN / H2O), mobile phase 0.2% aq. NH4HCO3(pH=7.9) / ACN gradient from 80 / 20 to 40 / 60). The solvent was evaporated and the product was freeze-dried to afford Cpd-72.2.21. Cpd-752.21.1. Int-38

[0111] Under nitrogen, to a stirred solution of 4-bromo-2-iodo-l -methoxybenzene (CAS# 98273-59-7; 2.00 g, 6.39 mmol, 1.0 eq.) and 4-ethynyl-l -methyl- IH-pyrazole (CAS# 39806-89-8; 678.28 mg, 6.39 mmol, 1.0 eq.) in TEA (14.5 mL, 104.304 mmol, 16.3 eq.) were added Cui (73.032 mg, 0.38 mmol, 0.06 eq.) and PdCl2(PPh3)2(224.3 mg, 0.32 mmol, 0.05 eq.) at RT. The reaction mixture was degassed with nitrogen for 5 min then stirred at RT for 1 h. The reaction mixture was diluted with EtOAc, filtered over Celite®, Celite® was washed with EtOAc and the filtrate was evaporated to dryness. The residue was purified by column chromatography on silica gel (eluting with Heptane / EtOAc from 100 / 0 to 50 / 50) to afford Int-38.Int-32

[0112] In a Schlenk®, a mixture of tert-butyl N-[(4-bromopyridin-2-yl)methyl]carbamate (CAS# 1060813-12-8; 2 g, 6.96 mmol, 1.0 eq.), 4,4,5,5-tetraethyl-2-(4,4,5,5-tetraethyl-l,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (CAS# 2247367-07-1; 3.57 g, 9.75 mmol, 1.4 eq.), AcOK (2.051 g, 20.89 mmol, 3.0 eq.) and Pd(dppf)C12 • DCM (0.57 g, 0.7 mmol, 0.1 eq.) in 1,4-Dioxane (71.6 mL) was purged with nitrogen for 5 min then stirred at 90 °C for 24 h. After cooling down to RT, the reaction mixture was fdtered over Celite®, Celite® was washed with EtOAc and the filtrate was evaporated to dryness. The residue was purified by column chromatography on silica gel (eluting with Heptane / EtOAc from 90 / 10 to 20 / 80). The product was coevaporated with heptane to afford Int-32.Int-33

[0113] In a sealed tube, to Int-32 (1.47 g, 3.78 mmol, 1.0 eq.), Int-38 (1.1 g, 3.78 mmol, 1.0 eq.), Cs2CO3(2.46 g, 7.56 mmol, 2.0 eq.) and Pd(dppf)C12'DCM (0.15 g, 0.19 mmol, 0.05 eq.) were added 1,4-Dioxane (30.8 mL) and water (3.1 mL). The resulting mixture was stirred at 90 °C for 18 h. SiliaMetS thiol silica (Silicycle, 40-63 um) (0.5 g) was added. The resulting suspension was stirred at RT for 1 h and the mixture was fdtered over Celite® and then the solvent was evaporated to dryness. The residue was purified by column chromatography on silica gel (eluting with DCM / MeOH from 100 / 0 to 96 / 4) to afford Int-33.

[0114] To a solution of Int-33 (1.44 g, 1.96 mmol, 1.0 eq.) in DCM (21.2 mL) was added HC1 (4 M) in 1,4-Dioxane (6.86 mL, 27.46 mmol, 14.0 eq.). The mixture was stirred at RT for 16 h. The reaction mixture was evaporated to dryness to afford Int-34 as a hydrochloride salt.2.21.5. Cpd-75Int-34 Cpd-75

[0115] T3P (50%) in EtOAc (94.2 mg, 88.1 pL. 0.15 mmol, 1.3 eq.) was added dropwise to a solution of 3-(2-hydroxyethanesulfonyl)-4-methylbenzoic acid (CAS# 1094404-86-0; 53.5 mg, 0.11 mmol, 1.0 eq.), Int-34 (70.0 mg, 0.13 mmol, 1.1 eq.) and DIPEA (99.15 pL, 0.57 mmol, 5.0 eq.) in DCM (0.545 mL) then the reaction mixture was stirred at RT for 3 h. Water and DCM were added, the organic layer was separated via hydrophobic frit and evaporated to dryness. The residue was purified by column chromatography on silica gel (eluting with DCM / MeOH from 100 / 0 to 96 / 4) then the product was purified via preparative HPLC (Column YMC 40 g, Focused gradient ACN / aq. NH4HCO3 0.2% Focused gradient from 0 / 100 to 45 / 55). The fractions containing product were evaporated then taken-up with ACN (3.0 mL), extended with water (10.0 mL) and freeze-dried to afford Cpd-75.2.22. Cpd-90 & Cpd-892.22.1. Int-89 & Int-111

[0116] In a 10-20 mL microwave vial, 3-methanesulfonyl-4-methylbenzoic acid (CAS# 51522-22-6; 100 mg, 0.47 mmol, 1.0 eq.), sodium persulfate (55.57 mg, 0.23 mmol, 0.5 eq.) and 1 -chloromethyl -4-fluoro-l,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (CAS# 140681-55-6; 496.07 mg, 1.4 mmol, 3.0 eq.) in a nitrogen atm. were added acetonitrile (0.5 mL) and water (0.5 mL) then silver nitrate (7.93 mg, 0.047 mmol, 0.1 eq.) was added. The reaction mixture was degassed three times by Freeze-Pump-Thaw cycles and then was stirred for 18 h at 80 °C. l-chloromethyl-4-fluoro-l,4-diazoniabicyclo[2.2.2]octane bis(tetrafhioroborate) (CAS# 140681-55-6; 826.78 mg, 2.33 mmol, 5 eq.), sodium persulfate (111.13 mg, 0.47 mmol, 1.0 eq.) and silver nitrate (7.93 mg, 0.047 mmol, 0.1 eq.) were added to the reaction mixture. The reaction mixture was degassed three times by Freeze-Pump-Thaw cycles and stirred at 80 °C for 6 h. After cooling to RT, the mixture was filtered through a pad of celite®, eluting with ethyl acetate. The filtrate was washed with NaHCO3saturated aqueous solution (2×25.0 mL). The aqueous phase was acidified slowly by HC1 (1 M) aqueous solution and extracted with EtOAc (3x25.0 mL). The organic layer was washed with NaCl saturated aqueous solution, dried over MgSO4. The filtrate was evaporated to dryness to afford a mixture of Int-89 & Int-111.2.22.2. Cpd-90 & Cpd-89

[0117] A mixture of Int-111 and Int-89 (72.0 mg, 0.29 mmol, 1.0 eq.), Int-34 (193.0 mg, 0.35 mmol, 1.2 eq.), T3P (50%) in EtOAc (219.73 mg, 205.5 pL, 0.35 mmol, 1.2 eq.) and DIPEA (200.5 pL, 1.15 mmol, 4.0 eq.) in DCM (1.84 mL) was stirred at RT for 1 h. NH4C1 (10%) aqueous solution and DCM were added, the organic layer was separated by hydrophobic frit and evaporated to dryness. The residue was purified by preparative HPLC (Column YMC -Actus Triart Prep C18-S 150*30mm 5pm Flow rate 50ml / min -Focused gradient ACN / aq. NH4HCO30.2% pH=7.9 Focused gradient from 35 / 65 to 45 / 55). The solvent was evaporated and the product was freeze-dried to afford Cpd-89 and Cpd-90.2.23. Cpd-91

[0118] To a mixture of Int-77 (34 mg, 0.13 mmol, 1.0 eq.) and Int-33 (59.65 mg, 0.14 mmol, 1.1 eq.) in DCM (1.4 mL) was added successively DIPEA (0.11 mL, 0.63 mmol, 5.0 eq.) then T3P (50%) in EtOAc (104.87 mg, 0.098 mL, 0.16 mmol, 1.3 eq.) at RT. The resulting mixture was stirred at RT for 21 h. T3P (50%) in EtOAc (104.87 mg, 0.098 mL, 0.16 mmol, 1.3 eq.) and DIPEA (0.11 mL, 0.63 mmol, 5.0 eq.) were added again and the reaction mixture was stirred at RT for 24 h. Then the reaction mixture was stirred at 40 °C for 4 h. DMF (1.00 mL) was added and the reaction mixture was stirred at 80 °C for 18 h. H2O and DCM were added. The layers were separated and the aqueous layer was extracted once again with DCM. The combined organic layers were washed with water, dried over Na2SO4, fdtered and the solvent was evaporated to dryness. The residue was purified by column chromatography on silica gel (eluting with DCM / (DCM / MeOH 80 / 20) from 100 / 0 to 75 / 25) to afford Cpd-91.2.24. Cpd-100 & Cpd-101Stereochemistry arbitrary assigned2.24.1. Step i: Cpd-41

[0119] In a sealed tube, to a mixture of Int-27 (636.9 mg, 0.69 mmol, 1.0 eq.), Int-38 (200 mg, 0.69 mmol, 1.0 eq.), Cs2CO3(447.6 mg, 1.37 mmol, 2.0 eq.) and Pd(dppf)C12'DCM (56.1 mg, 0.069 mmol, 0.1 eq.) were added 1,4-Dioxane (5.6 mL) and water (0.56 mL). The resulting mixture was stirred at 90 °C for 18 h. XPhos Pd G3 (79.4 mg, 0.069 mmol, 0.1 eq.) was added and the mixture was purged with nitrogen and then the resulting mixture was stirred at 120 °C using one single mode microwave (Anton Paar) with a power output ranging from 0 to 850 W for 30 min. SiliaMetS Imidazole (Silicycle, 40-63 um) (50 mg,) was added. The resulting suspension was stirred at RT for 1 h and the mixture was filtered over a pad of Celite® and then was evaporated to dryness. The residue was purified by column chromatography on silica gel (eluting with DCM / MeOH from 100 / 0 to 96 / 4) to afford Cpd-41.2.24.2. Step ii: Cpd-100 & Cpd-101

[0120] Cpd-100 & Cpd-101 are separated by SFC purification (Stationary phase: Chiralpak IH 20x250 mm, Mobile phase: CO2 / (iPrOH + 0,3%iPrNH2) 60 / 40) from racemate Cpd-41.Cpd-100Enantiomeric excess purity (RT: 2.87, 4.03, Aera %: 100.00, 0.00, Mw: 556.2, BPM1: 557.2, Method: Chiralpak IH-3 4.6x100 mm, Mobile phase: CO2 / (iPrOH + 0,3%iPrNH2) 55 / 45)[a]D20°c: +55,1520(589 nm, c 0,16 w / v %, DMF, 20° C.)Cpd-101Enantiomeric excess purity (RT: 2.87, 4.03, Aera %: 5.50, 94.50, Mw: 556.2, BPM1: 557.2, Method: Chiralpak IH-3 4.6x100 mm, Mobile phase: CO2 / (iPrOH + 0,3%iPrNH2) 55 / 45)[a]D20°c: -61,3640(589 nm, c 0,13 w / v %, DMF, 20° C.)2.25. Cpd-1202.25.1. Int-34Int-34 was already described for synthesis of Cpd-75.Cpd-120

[0121] A mixture of Int-34 (70 mg, 0.16 mmol, 1.0 eq.), 3-difhioromethanesulfonyl-4-methylbenzoic acid (CAS# 1823838-22-7; 45.043 mg, 0.18 mmol, 1.1 eq.), T3P (50%) in EtOAc (124.97 mg, 116.9 pL, 0.2 mmol, 1.2 eq.) and TEA (113.7 pL, 0.82 mmol, 5.0 eq.) in DCM (1.05 mL) was stirred at RT overnight. Water and DCM were added, the organic layer was separated via hydrophobic frit and evaporated to dryness. The residue was purified by column chromatography on silica gel (eluting with DCM / MeOH / NH4OH from 100 / 0 / 0 to 95 / 4 / 1) then the product was purified by preparative HPLC (Column YMC -Actus Triart Prep C18-S 150*30mm 5 pm Flow rate 50ml / min-Focused gradient ACN / aq. NH4HCO3 0.2% pH=7.9 Focused gradient from 40 / 60 to 70 / 30). The product was freeze dried to afford Cpd-120.2.26. Cpd 122Cpd-122

[0122] To a solution of Int-104 (32 mg, 0.108 mmol, 1.0 eq.), Int-34 (55.6 mg, 0.13 mmol, 1.2 eq.) and TEA (0.075 mL, 0.54 mmol, 5.0 eq.) in 1,4-Dioxane (0.96 mL) was added Pd(OAc)2 (2.43 mg, 0.0108 mmol, 0.1 eq.) and XantPhos (6.27 mg, 0.0108 mmol, 0.1 eq.) then the reaction mixture was carbonylated under CO (10 bars) for 18 h at 100 °C. The mixture was cooled down to RT then filtered over a pad of celite®, celite® was washed with DCM and the filtrate was evaporated. The residue was purified by preparative HPLC (Column YMC -Actus Triart Prep C18-S 150*30mm 5pm Flow rate 5 Oml / min -Focused gradient ACN / aq. NH4HCO3 0.2% pH=7.9 Focused-gradient from 35 / 65 to 65 / 35) then the product was freeze-dried to afford Cpd-122.2.27. Cpd-126lnt-103 Cpd-126Int-103 contains deprotected silane compound (N-{[4-(3-ethynyl-4-methoxyphenyl)pyridin-2-yl]methyl}-l,l-dioxo-3,5-dihydro-2H-4,1λ6-benzoxathiepine-8-carboxamide) as a minor product.In a microwave vial equipped with a magnetic stirring bar was charged with Int-103 (50 mg, 0.094 mmol, 1.0 eq.), 3-cyclopropoxy-4-iodopyridine (68.57 mg, 0.23 mmol, 2.5 eq.), CsF (28.409 mg, 0.19 mmol, 2.0 eq.), Xphos Pd G3 (15.81 mg, 0.019 mmol, 0.2 eq.), DMF (0.97 mL) and TEA (0.078 mL, 0.56 mmol, 6.0 eq.). The reaction mixture was degassed with nitrogen for 5 min then heated at 120 °C using one single mode microwave (Anton Paar) with a power output ranging from 0 to 850 W for 30 min. The reaction mixture were diluted with DCM and filtered over a pad of Celite® and the filtrate was evaporated to dryness. The residue was purified by column chromatography on silica gel (eluting with DCM / (DCM / MeOH / 30% aq. NH4OH 80:18:2) from 100 / 0 to 50 / 50) then was purified by preparative HPLC and freeze-dried to afford Cpd-126.2.28. Cpd-130 & Cpd-1292.28.1. Int-34Int-34 was already described for synthesis of Cpd-75.2.28.2. Int-103 & Int-106CAS# 2771132-64-8 lnt-105 Int-106Stereochemistry arbitrary assigned

[0123] Int-105 and Int-106 were separated from racemate intermediate 2-methyl-2,3-dihydro-5H-benzo[e][1,4]oxathiepine-8-carboxylic acid 1,1-dioxide (CAS# 2771132-64-8) by preparative chiral SFC (Stationary phase: Chiralpak IG 30x250 mm, Mobile phase: CO2 / (iPrOH + 0,3%iPrNH2) 75 / 25). Each intermediate was taken up at 0 °C into formic acid until pH = 6 then extracted with DCM, dried over MgSO4, filtered and the solvent was evaporated to afford Int-105 and Int-106.

[0124] Int-105

[0125] Enantiomeric excess purity (RT: 1.94, 2.43, Aera %: 100.00, 0.00, Mw:256, Method: Chiralpak IG-3 4.6x100 mm, Mobile phase: CO2 / (iPrOH + 0,3%iPrNH2) 75 / 25).

[0126] [a]D20°c: -0.0400(365 nm, c 0.15w / v %, DMF, 20° C.)

[0127] Int-106

[0128] Enantiomeric excess purity (RT: 1.94, 2.43, Aera %: 0.00, 100.00, Mw:256, Method: Chiralpak IG-3 4.6x100 mm, Mobile phase: CO2 / (iPrOH + 0,3%iPrNH2) 75 / 25).

[0129] [a]D20°c: 20.979° (365 nm, c 0.17 w / v %, DMF, 20° C.)2.28.3. Cpd-129Int-34 Int-106 Cpd-129Stereochemistry arbitrary assigned

[0130] A mixture of Int-34 (80.0 mg, 0.19 mmol, 1.0 eq.), Int-106 (47.9 mg, 0.19 mmol, 1.0 eq.), T3P (50%) in EtOAc (142.82 mg, 133.60 qL, 0.22 mmol, 1.2 eq.) and DIPEA (130.3 qL, 0.75 mmol, 4.0 eq.) in DCM (1.20 mL) was stirred at RT overnight. Water and DCM were added. The mixture was fdtered through hydrophobic frit and the fdtrate was evaporated to dryness. The residue was purified by column chromatography on silica gel (eluting with DCM / MeOH from 100 / 0 to 96 / 4). The product was solubilized with DCM and washed with a 10% aqueous solution of K2CO3. The mixture was filtered through hydrophobic frit and the filtrate was evaporated in vacuo. The residue was freeze-dried to afford Cpd-129.

[0131] Enantiomeric excess purity (RT: 1.91, 2.22, Aera %: 100.00, 0.00, Mw:556, BPM1:557, Method IH 3 pm 100X4.6mm, ISO 40% EtOH+BASE, 3.5ml / min).

[0132] [a]D20°c: -14.31° (365 nm, c 0.11 w / v %, DMF, 20° C.)2.28.4. Cpd-130\Int-34 Int-105 Cpd-130Stereochemistry arbitrary assignedInt-105 & Int-106CAS# 2771132-64-8 lnt-105 Int-106Stereochemistry arbitrary assigned

[0133] Int-105 and Int-106 were separated from racemate intermediate 2-methyl-2,3-dihydro-5H-benzo[e][1,4]oxathiepine-8-carboxylic acid 1,1-dioxide (CAS# 2771132-64-8) by preparative chiral SFC (Stationary phase: Chiralpak IG 30x250 mm, Mobile phase: CO2 / (iPrOH + 0,3%iPrNH2) 75 / 25). Each intermediate was taken up at 0 °C into formic acid until pH = 6 then extracted with DCM, dried over MgSO4, filtered and the solvent was evaporated to afford Int-105 and Int-106.

[0134] lnt-105

[0135] Enantiomeric excess purity (RT: 1.94, 2.43, Aera %: 100.00, 0.00, Mw:256, Method: Chiralpak IG-3 4.6x100 mm, Mobile phase: CO2 / (iPrOH + 0,3%iPrNH2) 75 / 25).

[0136] [a]D20°c: -0.0400(365 nm, c 0.15w / v %, DMF, 20° C.)

[0137] Int-106

[0138] Enantiomeric excess purity (RT: 1.94, 2.43, Aera %: 0.00, 100.00, Mw:256, Method: Chiralpak IG-3 4.6x100 mm, Mobile phase: CO2 / (iPrOH + 0,3%iPrNH2) 75 / 25).

[0139] [a]D20°c: 20.979° (365 nm, c 0.17 w / v %, DMF, 20° C.)

[0140]

[0141] A mixture of Int-34 (70 mg, 0.16 mmol, 1.0 eq.), Int-105 (41.94 mg, 0.16 mmol, 1.0 eq.), T3P (50%) in EtOAc (124.97 mg, 116.901 pL, 0.2 mmol, 1.2 eq.) and DIPEA (114.0 pL, 0.65 mmol, 4.0 eq.) in DCM (1.50 mL) was stirred at RT overnight. Water and DCM were added. The mixture was fdtered through hydrophobic frit and the fdtrate was evaporated to dryness. The residue was purified by column chromatography on silica gel (eluting with DCM / MeOH from 100 / 0 to 96 / 4). The product was solubilized with DCM and washed with K2CO3 (10%) aqueous solution. The organic layer was decanted via hydrophobic frit and the solvent was evaporated to dryness. The product was freeze-dried to afford Cpd-130.Enantiomeric excess purity (RT: 1.91, 2.22, Aera %: 0.60, 99.40, Mw:556, BPM1:557, Method:Chiralpak IH 3pm 100X4.6mm, ISO 40% EtOH+BASE, 3.5ml / min).

[0142] [a]D20°c: +7.575° (365 nm, c 0.18 w / v %, DMF, 20° C.)2.29. Cpd-135 and Cpd-136

[0143] A mixture of Int-34 (1 eq., 283.59 mg, 0.66 mmol), 2-methyl- 1,1 -dioxo-2, 3 -dihydro- IX6-benzothiophene-6-carboxylic acid [1860918-46-3] (1 eq., 150 mg, 0.66 mmol), T3P 50% in EtOAc (1.2 eq., 506.28 mg, 473.6 microL, 0.8 mmol) and DIPEA (4 eq., 342.75 mg, 461.93 microL, 2.65 mmol) in DCM (5 mL) was stirred at rt overnight. Water and DCM were added, the organic layer was separated (hydrophobic frit) and evaporated till dryness. The crude was purified by normal phase flash chromatography (irregular SiOH 15 pm, 12 g, Interchim, liquid loading (DCM), mobile phase: DCM / MeOH / aqNH3 100 / 0 / 0 to 95 / 4 / 1 for 15 CV). The pure fractions were combined and evaporated in vacuum till dryness. The residue was purified by reverse phase (Column YMC -Actus Triart Prep C18-S 150*30mm 5 pm Flow rate 50ml / min-Focused gradient MeCN / aq. NH4HCO3 0.2% pH=7.9 Focused gradient from 35 / 65 to 65 / 35). The fractions containing compound were combined and freeze dried overnight to give 110 mg of racemate. This one was purified by SFC (Stationary phase: Chiralpak OJ-H 20x250 mm, Mobile phase: CO2 / (EtOH + 0,3%zPrNH2) 65 / 35). The fractions containing compound were combined and freeze dried overnight to give Cpd-135 (40 mg, 0.076 mmol, 11.46%) as white powder and Cpd-136 (40 mg, 0.076 mmol, 11.46%) as white powder.Cpd-135Enantiomeric excess purity (RT: 1.89, 2.56, Aera %: 100.00, 0.00, Method: Chiralpak OJ 3pm 100X4.6mm, mobile phase CO2 / (EtOH+0.3%iPrNH2) 60 / 40, 3.5ml / min).[a]D20°c: +12,626 ° (589 nm, c 0,19 w / v %, DMF, 20°C)Cpd-136Enantiomeric excess purity (RT: 1.89, 2.56, Aera %: 1.04, 98.96, Method: Chiralpak OJ 3pm 100X4.6mm, mobile phase CO2 / (EtOH+0.3%iPrNH2) 60 / 40, 3.5ml / min).[a]D20°c: -10,264 ° (589 nm, c 0,2 w / v %, DMF, 20°C)2.30. Cpd-138

[0144] HOBt (1.1 eq., 10.017 mg, 0.074 mmol) followed by Int N (1 eq., 19.86 mg, 0.067 mmol) were added to a solution of Int-135 (1 eq., 80 mg, 0.067 mmol), EDCI. HC1 (1.1 eq., 14.21 mg, 0.074 mmol) and DIPEA (7 eq., 60.97 mg, 0.082 mL, 0.47 mmol) in DCM (0.33 mL) at rt. The reaction mixture was stirred at rt for 18 h. Water and DCM were added, the layers were separated, the aqueous layer was extracted twice with DCM. The combined organic layer were washed with brine, dried over MgSO4, fdtered, concentrated under vacuum then purified by normal phase flash chromatography (irregular SiOH 15 pm, 4 g, Interchim, liquid loading (DCM), mobile phase: DCM / MeOH 100 / 0 to 90 / 10 for 15 CV). The pure fractions were combined, evaporated in vacuum to give impure Cpd-138 (24 mg) which was puridied via Reverse phase (Column YMC -Actus Triart Prep C18-S 150*30mm 5 pm Flow rate 50ml / min-Focused gradient MeCN / aq. NH4HCO3 0.2% pH=7.9 Focused gradient from 50 / 50 to 70 / 30). The fraction containing compound were combined and evaporated under vacuum to give a residue. The residue was taken-up with MeCN (2 mL), extended with water (4 mL) then freeze-dried to give 14 mg of Cpd-138 (14 mg, 0.022 mmol, 33.3%) as a white fluffy solid.2.31. Cpd-146 and Cpd-148

[0145] Cpd-147 was synthetized according to general method A2 from Int-34 and Int-K. Cpd-147 (64 mg) was purified by chiral SFC (Chiralpak IC 20x250 mm, Mobile phase: CO2 / EtOH 75 / 25) to give, after freeze-drying, Cpd-146 (28 mg) as a white fluffy solid and Cpd-148 (30 mg) as a white fluffy solid.Cpd-146Enantiomeric excess purity (RT: 1.43, 2.17, Aera %: 100.00, 0.00, Method: Chiralpak IH3 3pm 100X4.6mm, Mobile phase: CO2 / EtOH 55 / 45, 3.5ml / min).[a]D20°c: +17,316 ° (589 nm, c 0,13 w / v %, DMF, 20°CCpd-148Enantiomeric excess purity (RT: 1.43, 2.17, Aera %: 100.00, 0.00, Method: Chiralpak IH3 3pm 100X4.6mm, Mobile phase: CO2 / EtOH 55 / 45, 3.5ml / min).[a]D20°c: -30,303 ° (589 nm, c 0,14 w / v %, DMF, 20°C2.32. Int-120Int-120

[0146] To a solution of 8-bromo-3,5-dihydro-2H-4,l-benzoxathiepine (CAS# 2940960-31-4; 1 eq., 200 mg, 0.82 mmol) in MeCN (8 mL) at 0 °C was added selectfluor (1.5 eq., 433.6 mg, 1.22 mmol) and DAST (0.2 eq., 26.3 mg, 0.02 mL, 0.16 mmol) successively. After 1 h at 0 °C, DIPEA (1.5 eq., 158.2 mg, 0.21 mL, 1.22 mmol) was added. The reaction mixture was warmed to rt and stirred at rt for 16 h. The reaction mixture was carefully added dropwise to cold sat aq NaHCO3 (25 mL). The aqueous layer was extracted with DCM (3 x 25 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The crude residue was purified by normal phase flash chromatography (Heptane / EtOAc from 100:0 to 0:100). Pure fractions were combined and concentrated in vacuo to give Int-120 (72 mg, 0.27 mmol, 33.5%) as a light yellow solid.2.33. Cpd-153 and Cpd-1552.33.1. Int-114BocHN

[0147] To a solution of Int-33 (1 eq., 150 mg, 0.36 mmol) in dichloromethane (5.6 mL) was added hydrogen chloride (4N in dioxane, 9.4 eq., 0.84 mL, 3.37 mmol). The mixture was stirred at rt for 2 h. At 0 °C, a 10% aqueous solution of K2CO3 and DCM were added. The mixture was filtered through Chromabond® and the filtrate was evaporated in vacuo to give Int-114 (87 mg, 0.27 mmol, 76.2%) as a pale brown oil2.33.2.SelectFluor, TEA, ACN, rt, 1 hInt-123To a solution of methyl 3,4-dihydro-2H-l,5-benzoxathiepine-7-carboxylate (CAS# 2771132-32-0; 1 eq., 545 mg, 2.43 mmol) in MeCN (24.3 mL) was added selectfluor (1.5 eq., 1291 mg, 3.65 mmol). After 30 min at rt, TEA (1.5 eq., 368.9 mg, 0.507 mL, 3.65 mmol) was added dropwise. The reaction mixture was stirred at rt for 30 min. The reaction mixture was quenched with sat aq NaHCO3 (20 mL) and extracted with DCM (3 x 20 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The crude residue was purified by normal phase flash chromatography (Heptane / EtOAc from 100:0 to 0:100). Pure fractions were combined and concentrated in vacuo to give Int-123 (90 mg, 0.35 mmol, 14.34%) as a white solid.2.33.3. Cpd 153 and 155

[0148] Cpd-154 was synthetized according to general method A2 from Int-114 and Int-123Cpd-154 (118 mg) was purified by chiral SFC (Chiralpak IH 20x250 mm, Mobile phase: CO2 / MeOH 50 / 50) to give, after freeze-drying, Cpd-153 (26 mg) as an off-white fluffy solid & Cpd-155 (34 mg) as an off-white fluffy solid.Cpd-153Enantiomeric excess purity (RT: 1.31, 2.04, Aera %: 100.00, 0.00, Method: Chiralpak IH3 3pm 100X4.6mm, Mobile phase: CCE / EtOH 55 / 45, 3.5ml / min).[a]D20°c: -33.3300(589 nm, c 0,16 w / v %, DMF, 20°C)Cpd-155Enantiomeric excess purity (RT: 1.31, 2.04, Aera %: 0.00, 100.00, Method: Chiralpak IH3 3pm 100X4.6mm, Mobile phase: CCE / EtOH 55 / 45, 3.5ml / min).[a]D20°c: +19,3930(589 nm, c 0,16 w / v %, DMF, 20°C)2.34. Int-142 (used for synthesis of cpd-163)

[0149] To a stirred solution of Int-144 (4.16 eq., 330 mg, 1.16 mmol) in THF (1.5 mL) at rt was added HC1 3M in water (16.11 eq., 1.5 mL, 4.5 mmol) and the solution was heated to 60 °C. The solution was allowed to stir at this temperature for 2 hours. The solution was diluted in EtOAc and distilled water. The organic layer was dried over MgSO4, fdtered and evaporated to dryness to afford Int-143 (323 mg, 1.26 mmol, quant.) as a light orange solid.Int-143 Int-142

[0150] To a stirred solution of Int-143 (1 eq., 323 mg, 1.26 mmol) in DCM (16.2 mL) at 0 °C under N2 was added dropwise DAST (3 eq., 609.5 mg, 0.46 mL, 3.78 mmol) and the solution was allowed to stir for 3 h. The solution was diluted in DCM and an aqueous solution of saturated NaHCO3. The organic layer was dried over MgSO4, filtered and evaporated to dryness to afford Int-142 (100 mg, 0.36 mmol, 28.5%) as a yellow solid.2.35. Int-146 (used for synthesis of cpd-164)Int-146

[0151] Under nitrogen atmosphere, to a mixture 8-bromo- 1 -imino-3,5-dihydro-2H-4, lX6-benzoxathiepin-1-one (CAS# 2771133-80-1; 1 eq., 204 mg, 0.74 mmol) and methylboronic acid (CAS# 13061-96-6; 2 eq., 88.4 mg, 1.48 mmol) in Dioxane (4.45 mL), Copper acetate (1.5 eq., 135.8 mg, 1.108 mmol) and pyridine (3 eq., 175.3 mg, 0.18 mL, 2.22 mmol) were added to the reaction and the mixture was stirred at 100 °C for 2 h. 1 M aqueous HC1 was added until to pH = 4. Then the aqueous layer was extracted 5 times with DCM. The combined organic layer were washed with brine, dried over MgSO4, filtered, concentrated under vacuum then purified by normal phase flash chromatography (eluting with Heptane / EtOAc from 75 / 25 to 25 / 75). The pure fractions were combined, evaporated in vacuum to give Int-146 (74 mg, 0.26 mmol, 34.5%) as a yellow oil.2.36. Int-148 and Int-152 (used in synthesis of cpd- Cpd-165 and Cpd-166)Int-149 Int-152 Int-148 Stereochemistry arbitrarily assigned

[0152] Int-149 (1 eq., 578 mg, 2.14 mmol) was separated by chiral SFC (Stationary phase: Chiralpak IG, 150 x 21mm, 5pm with Guard of 50 x 21mm, 5pm, Mobile phase: CO2 / EtOH 80 / 20). The fractions containing the products were evaporated to Int-152 (248.6 mg, 0.92 mmol, 33.9%) and Int-148 (224.8 mg, 0.83 mmol, 30.63%) both as sticky colorless oils.Int-152Enantiomeric excess purity (RT: 3.37, 4.58 min, Aera %: 100.00, 0.00, Method: Chiralpak IG, 150 x 4.6mm, 5pm, Mobile phase: CO2 / EtOH 80 / 20[a]D20°c: +38,9610(589 nm, c 0,13 w / v %, DMF, 20°C)Int-148Enantiomeric excess purity (RT: 3.37, 4.58 min, Aera %: 0.00, 100.00, Method: Chiralpak IG, 150 x 4.6mm, 5pm, Mobile phase: CO2 / EtOH 80 / 20[a]D20°c: -36,5730(589 nm, c 0,19 w / v %, DMF, 20°C)2.37. Cpd-167XPhos Pd G3, TEA, DMF |JW, 120 °C, 1 hCpd-167

[0153] In a microwave vial equipped with a magnetic stirring bar was charged with Int-48 (1 eq., 60 mg, 0.11 mmol), 3,3-dimethyl-l-butyne (5 eq., 46.68 mg, 0.0707 mL, 0.57 mmol), Xphos Pd G3 (0.2 eq., 19.22 mg, 0.023 mmol), DMF (1.18 mL) and TEA (6.014 eq., 69.16 mg, 0.095 mL, 0.68 mmol). The reaction mixture was degassed with nitrogen for 5 minutes then heated at 120 °C using one single mode microwave (Anton Paar) with a power output ranging from 0 to 850 W for 30 min. The reaction mixture was recharged with 3,3-dimethyl-1-butyne (5 eq., 46.68 mg, 0.0707 mL, 0.57 mmol), TEA (6.014 eq., 69.16 mg, 0.095 mL, 0.68 mmol) and Xphos Pd G3 (0.2 eq., 19.22 mg, 0.023 mmol). The reaction mixture was degassed with nitrogen for 5 minutes then heated at 120 °C using one single mode microwave (Anton Paar) with a power output ranging from 0 to 850 W for 30 min. EtOAc was added and the reaction mixture was filtered over celite® and the fdtrate was evaporated under vacuo. Water was added to the mixture and washed 3 times with EtOAc. (15 mL x 3). Organic layers were washed by brine and Na2SO4 was added. The mixture was fdtered out and evaporated under vacuo. The residue was purified by normal phase preparative LC (Stationary phase: irregular SiOH, 40-60 pm, Agela, 12 g, liquid loading, mobile phase: first isocratic 100% DCM for 2 CV then gradient from 100% DCM to 95% DCM, 5% MeOH for 20 CV). The fractionscontaining the corresponding product were collected, evaporated and charged on reverse phase preparative LC (Column YMC -Actus Triart Prep C18-S 150*30mm 5 pm Flow rate 20ml / min-Focused gradient MeCN / aq. NH4HCO3 0.2% pH=7.9 Firstly, isocratic flow was made with 5 / 95 for 2 CV, then a gradient from 5 / 95 to 100% for 20 CV, and lastly isocratic 100% MeCN for 3 CV). The fractions containing compound were combined and solvents were evaporated in vacuo. The residue was taken -up with MeCN, extended with water and freeze-dried to give Cpd-167 (31.1 mg, 0.06 mmol, 52.76%) as a white powder.2.38. Int-132 (used in cpd-170 synthesis)FInt-132

[0154] To a solution of 2 -methylimidazole (CAS# 693-98-1; 1 eq., 91.7 mg, 1.12 mmol) in DMF (4.3 mL) were added 1-(bromomethyl)-3-fluorobicyclo[l.l.l]pentane (CAS# 2168405-39-6; 1 eq., 200 mg, 1.12 mmol) and K2CO3 (2 eq., 308.8 mg, 2.23 mmol) and the reaction mixture was stirred at 80 °C for 24 h. Water and DCM were added, the layers were separated, the aqueous layer was extracted twice with DCM. The combined organic layer were washed 3 times with brine, dried over MgSO4, filtered, concentrated under vacuum to give Int-132 (115 mg, 0.64 mmol, 57.1%) as a pale yellow oil.2.39. Int-133 (used for cpd-171 synthesis)MsCl, Et3N, DCM, 0 °C to rt, 16 hInt-133

[0155] To a solution of (2R)-2-ethynylpyrrolidine hydrochloride (CAS# 2199141-10-9; 1 eq., 100 mg, 0.76 mmol), DCM (7.6 mL) & TEA (4 eq., 307.6 mg, 0.42 mL, 3.04 mmol) at 0 °C was added MsCl (2 eq., 174.1 mg, 0.12 mL, 1.52 mmol) dropwise. The reaction mixture was warmed to rt and stirred for 16 h. The reaction mixture was quenched with sat aq NaHCO3(10 mL) and extracted with DCM (3 x 10 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to give crude Int-133 (131.6 mg, 0.76 mmol, quant.) as an orange oil.2.40. Int-134 (used in cpd-172 synthesis)MsCl, Et3N, DCM, 0 °C to rt, 16 hInt-134

[0156] To a solution of (2S)-2-ethynylpyrrolidine hydrochloride (CAS# 190602-33-6; 1 eq., 25 mg, 0.19 mmol), DCM (1.9 mL) & TEA (4 eq., 76.9 mg, 0.106 mL, 0.76 mmol) at 0 °C was added MsCl (2 eq., 43.5mg, 0.029 mL, 0.38 mmol) dropwise. The reaction mixture was warmed to rt and stirred for 16 h. The reaction mixture was quenched with sat aq NaHCO3(10 mL) and extracted with DCM (3 x 10 mL). The combined organic layer were dried over sodium sulfate, filtered and concentrated in vacuo to give crude Int-134 (32.9 mg, 0.19 mmol, quant.) as a yellow oil.2.41. Cpd-175K2CO3MeOH, rt, 1 h

[0157] To a stirred solution of Cpd-174 (1 eq., 30 mg, 0.056 mmol) in MeOH (0.5 mL) and DCM (0.5 mL) at room temperature was added portionwise K2CO3 (2 eq., 15.45 mg, 0.11 mmol). The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was fdtered and directly purified by reverse phase preparative LC (Column YMC 40 g 25pm, focused gradient MeCN / aq. NH4HCO30.2% pH=7.9 Focused gradient from 05 / 95 to 60 / 40 15CV). Fractions containing product were evaporated to dryness then the residue was taken-up in MeCN, extended with water and freeze-dried to give Cpd-175 (11.4 mg, 0.025 mmol, 43.904%) as a white solid.2.42. Int-170 (used in Cpd-184 synthesis)F NCS, LiHMDS, THF, -78 °C to rt, 18 hInt-171 Int-170

[0158] A stirred solution of Int-171 (1 eq., 90 mg, 0.32 mmol) and NCS (2 eq., 84.305 mg, 0.63 mmol) in THF (5.17 mL) under N2 was cooled down to -78 °C. Then LiHMDS IM in THF (1.1 eq., 0.35 mL, 0.35 mmol) was added dropwise to the solution over 5 min and the solution was allowed to slowly warm up to rt and to stir for 16 h. The solution was cooled down to -78 °C again, and LiHMDS IM in THF (3.17 eq., 1 mL, 1 mmol) was added dropwise over 10 min and the solution was allowed to stir at this temperature for 2 h. The solution was quenched by adding an aq solution of NH4CI and EtOAc, the organic layer was dried over MgSO4, filtered and evaporated to dryness to afford crude Int-170 (120 mg, 0.38 mmol, quant.) as a dark solid.2.43. Int-113 (used for Cpd-186 and Cpd-187 synthesis)Int-104 Int-113

[0159] At 0 °C, NaH 60% dispersion in mineral oil (1.2 eq., 58.94 mg, 1.47 mmol) was added to a solution of Int-104 (1 eq., 400 mg, 1.23 mmol) in DMF (4.5 mL). The reaction mixture was stirred at 0 °C for 30 min. Then, Mel (1 eq., 174.3 mg, 0.076 mL, 1.23 mmol) was added slowly at 0 °C and the reaction mixture was stirred at rt for 4 h. An aq solution of NH4C1 and EtOAc were added. The mixture was extracted with EtOAc. The organic layers were combined and washed with water and brine, dried over Na2SO4, filtered and the solvent was evaporated in vacuo. The crude residue was purified by reverse phase flash chromatography (eluting with 0.2% aq NH4HCO3 (pH=7.9) / MeCN from 85:15 to 0:100). The fractions containing Int-113 were combined and the solvent was evaporated in vacuo to give Int-113 (72 mg, 0.23 mmol, 19%) as an off-white residue.2.44. Cpd-186 and Cpd-187

[0160] To a mixture Int-112 (1 eq., 46.5 mg, 0.17 mmol) and Int-34 (1.1 eq., 79.78 mg, 0.19 mmol) in DCM (1.87 mL) was added successively DIPEA (5 eq., 109.57 mg, 0.15 mL, 0.85 mmol) then T3P 50% in EtOAc (1.3 eq., 140.26 mg, 0.13 mL, 0.22 mmol) at rt. The resulting mixture was stirred at rt for 3 h. Water and DCM were added. The layers were separated and the aqueous layer was extracted once again with DCM. The combined organic layers were washed with water, dried over Na2SO4, filtered and the solvent was removed in vacuo. The residue was purified by normal phase preparative LC (irregular SiOH, 40-60 pm, 12 g Agela, liquid loading (DCM), mobile phase gradient: from DCM / (DCM / MeOH 80 / 20) 100:0 to 75:25 over 20 CV). The fractions containing product were combined and evaporated to dryness. The residue was purified by SFC chiral (Stationary phase: Chiralpak IH 20x250 mm, Mobile phase: CO2 / (zPrOH + 0,3%zPrNH2) 60 / 40). Pure fractions were collected and evaporated to give first enantiomer (15 mg) and second enantiomer (11 mg). First enantiomer (15 mg) was purified by normal phase preparative LC (irregular SiOH, 40-60 pm, 4 g Agela, liquid loading (DCM), mobile phase gradient: from 100% heptane over 3 CV then heptane / DCM 100:0 to 0:100 over 5 CV then (DCM / DCM / MeOH 80:20) 100:0 to 75:25 over 10 CV). The fractions containing product were combined, evaporated and freeze-dried to give Cpd-186 (9 mg, 0.016 mmol, 9.24%) as a white fluffy solid. Second enantiomer was purified by normal phase preparative LC (irregular SiOH, 40-60 pm, 4 g Agela, liquid loading (DCM), mobile phase gradient: from 100% heptane over 3 CV then heptane / DCM 100:0 to 0: 100 over 5 CV then (DCM / DCM / MeOH 80:20) 100:0 to 75:25 over 10 CV). The fractions containing product were combined, evaporated and freeze-dried to give Cpd-187 (9 mg, 0.016 mmol, 9.24%) as a white fluffy solid.Cpd-186Enantiomeric excess purity (RT: 2.74, 3.82, Aera %: 100.00, 0.00, Method: Chiralpak IH3 3pm 100X4.6mm, Mobile phase: CO2 / (iPrOH+0.3% iPrNH2) 60 / 40, 3.5ml / min).[a]D20°c: -2.164 ° (589 nm, c 0,14 w / v %, DMF, 20°C)Cpd-187Enantiomeric excess purity (RT: 2.74, 3.82, Aera %: 0.00, 100.00, Method: Chiralpak IH3 3pm 100X4.6mm, Mobile phase: CO2 / / (i'PrOH+0.3% iPrNH2) 60 / 40, 3.5ml / min).[a]D20°c: +2.635 ° (589 nm, c 0,15 w / v %, DMF, 20°C)2.45. Cpd-188 and Cpd-189

[0161] Cpd-178 was synthetized according to general method Al from Int-188 and Int-16225 mg of Cpd-178 were purified by SFC Stationary phase: Chiralpak IH 20x250 mm, Mobile phase: CO2 / EtOH 75 / 25) The fractions contains pure enantiomers were combined and evaporated to dryness to give Cpd-188 (10.9 mg) and Cpd-189 (11 mg).Cpd-188: Enantiomeric excess purity (RT: 3.61, 4.25, Aera %: 100.00, 0.00, Method: Chiralpak IH-3 4.6x100 mm, Mobile phase: CO2 / MeOH 75 / 25).Enantiomeric excess purity (RT: 3.61, 4.25, Aera %: 0.00, 100.00, Method: Chiralpak IH-3 4.6x100 mm, Mobile phase: CO2 / MeOH 75 / 25).2.46. Int-140 (used in Cpd -207 synthesis)Int-140

[0162] To a solution of 8-chloro-lH,2H,3H-pyrido[2,3-b][l,4]oxazine (CAS# 1198154-60-7; 1 eq., 200 mg, 1.17 mmol) in DMF (10 mL) was added carefully at 0 °C NaH (60% w / w in mineral oil, 1.2 eq., 56.3 mg, 1.407 mmol). The reaction mixture was stirred at rt for 30 min then Mel (2 eq., 332.8 mg, 0.15 mb, 2.34 mmol) was added. The reaction mixture was stirred at rt overnight. NaH (1.2 eq., 56.27 mg, 1.407 mmol) and Mel (2 eq., 332.8 mg, 0.15 mb, 2.34 mmol) were added at 0 °C and the mixture was stirred at rt overnight. The reaction mixture was stirred at 50 °C overnight. The reaction mixture was poured into water and extracted with EtOAc (3 x). The combined organic layers were dried over Na2SO4, filtered andevaporated under vacuum. The crude residue was purified by normal phase flash chromatography (eluting with heptane / EtOAc from 100 / 0 to 50 / 50) to give Int-140 (90 mg, 0.49 mmol, 41.6%) as off-white oil. 2.47. Int-211Selectfluor, DASTDiPEA, MeCN, rt, 18 hBrInt-212 Int-211

[0163] To a mixture of Int-212 (1 eq., 100 mg, 0.33 mmol) in MeCN (3.3 mL) were added at 0 °C selectfluor (1.25 eq., 146.065 mg, 0.41 mmol) and DAST (5 eq., 265.84 mg, 0.202 mL, 1.65 mmol). The reaction mixture was stirred at rt for 1 h. DIPEA (1.5 eq., 63.95 mg, 0.086 mL, 0.49 mmol) was added at 0 °C and the reaction mixture was stirred at rt for 16 h. The reaction mixture was quenched with cold sat aq NaHCO3(20 mL) and extracted with DCM (3 x 20 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by normal phase flash chromatography (irregular SiOH, 20 g Agela, liquid injection (DCM), mobile phase gradient: Heptane / EtOAc 100:0 to 0:100 for 30 CV). Pure fractions were combined and concentrated in vacuo to give methyl Int-211 (60 mg, 0.19 mmol, 56.6%) as a colorless oil.2.48. Int215CMBP, toluene100 °C, 3 h

[0164] A solution ofmethyl 3,5-dibromo-4-hydroxybenzoate (CAS# 41727-47-3; 1 eq., 5 g, 16.13 mmol), 4-methoxybenzyl alcohol (1.5 eq., 3.34 g, 3.005 mL, 24.2 mmol) and CMBP (3 eq., 11.68 g, 12.7 mL, 48.4 mmol) in toluene (150 mL) mixture was stirred at 100 °C for 3 h. The reaction mixture was quenched with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by normal phase flash chromatography (irregular SiOH 15-40 pm, 330 g Agela, liquid injection (DCM), mobile phase gradient: Heptane / EtOAc 100:0 to 70:30 over 15 CV). Pure fractions were combined and concentrated in vacuo to give Int-215 (5.17 g, 12.021 mmol, 74.5%) as a white powder.2.49. Int-214

[0165] A mixture of Int-215 (1 eq., 5.1 g, 11.86 mmol), 4-methoxybenzylmercaptan (1 eq., 1.83 g, 1.65 mL, 11.86 mmol), DIPEA (2 eq., 3.065 g, 4.13 mL, 23.72 mmol), Pd2(dba)3 (0.1 eq., 1.086 g, 1.19 mmol) and Xantphos (0.1 eq., 0.69 g, 1.19 mmol) in dioxane (102 mL) was degased with 3 cycles vacuum / N2 then heated at 90 °C for 18 h. The reaction mixture was filtered through a pad of celite and the filtrate was evaporated to dryness. The residue was purified by normal phase flash chromatography (irregular SiOH 40-60 pm, 330 g Agela, liquid injection (DCM), mobile phase gradient: Heptane / EtOAc 100:0 to 70:30 over 15 CV). Pure fractions were combined and concentrated in vacuo to give Int-214 (4 g, 7.95 mmol, 67.0%) as colorless oil.2.50. Int-213TFA, TES70 °C, 2 hInt-213

[0166] To a solution Int-214 (1 eq., 4 g, 6.36 mmol) in triethylsilane (1 eq., 0.74 g, 1.027 mL, 6.36 mmol) was added dropwise TFA (42.36 eq., 30.7 g, 20 mL, 269.24 mmol). The reaction mixture was stirred at 70 °C for 2 h. The reaction mixture was evaporated under vacuum. The residue was taken up in EtOAc and washed with IM NaOH (2 x). The combined aqueous phases were acidified with HC1 1 M until pH < 2 and extracted with EtOAc (3 x). The combined organic layers were dried over Na2SO4, filtered and evaporated under vacuum to give Int-213 (1.58 g, 6.005 mmol, 94.5%) as yellow powder.2.51. Int-186TEA, EtOHInt-186

[0167] To a stirred solution of 5-bromo-2-methylbenzene-l-thiol (CAS# 69321-55-7; 1 eq., 1.31 g, 0.88 mb, 6.47 mmol) and TEA (2 eq., 1.309 g, 1.8 m, 12.94 mmol) in ethanol (20 ml) was added propylene oxide (CAS# 75-56-9; 1.5 eq., 0.56 g, 0.68 m, 9.705 mmol) at rt, then, the solution was stirred overnight. The reaction mixture was concentrated under reduced pressure to give Int-186 (1690 mg, 6.47 mmol, 100%) as a colorless oil.2.52. Int-153 and Int-154

[0168] Int-188 (1 eq., 1184 mg, 4.58 mmol) was separated by STC (Stationary phase: Chiralpak AD-H 30x250 mm, Mobile phase: CO2 / (PrOH + 0,3%PrNH2) 70 / 30). The fraction containing product was combined and evaporated to dryness. Both residue were separately dissolved in water, acidified with aq. HCl 3N, extracted with EtOAc (2x) the organic layers were dried over MgSO4, and concentrated in reduced pressure to give Int-153 (336 mg, 1.301 mmol, 28.4%) as a white residue and Int-154 (354 mg, 1.37 mmol, 29.9%) as a white solid.Int-153Enantiomeric excess purity (RT: 1.24, 2.13, Aera %: 100.00, 0.00, Method: Chiralpak AD3 3pm 100X4.6mm, Mobile phase: CO2 / (z'PrOH+0.3% zPrNFE) 75 / 25, 3.5ml / min).[a]D20°c: -15,1510(589 nm, c 0,23 w / v %, DMF, 20°C)Int-154Enantiomeric excess purity (RT: 1.24, 2.13, Aera %: 0.00, 100.00, Method: Chiralpak AD3 3pm 100X4.6mm, Mobile phase: CO2 / (z'PrOH+0.3% zPrNFE) 75 / 25, 3.5ml / min).[a]D20°c: +5,050(589 nm, c 0,21 w / v %, DMF, 20°C)2.53. Int-183

[0169] A mixture of Int-182 (1 eq., 282 mg, 0.94 mmol) and CMBP (1 eq., 227.54 mg, 0.25 mb, 0.94 mmol) in toluene (13.43 mL) was stirred at rt for 4 h then at 80 °C for 20 h. An extra amount of CMBP (1 eq., 227.54 mg, 0.25 mL, 0.94 mmol) was added and the heating was carried on for 5 h. The reaction mixture was directly purified by normal phase preparative LC (regular SiOH, 30 pm, 20 g agela, liquid loading (toluene), mobile phase gradient: from heptane / EtOAc 100 / 0 to 60 / 40). The fractions containing product were combined and evaporated to dryness to give Int-183 (99 mg, 0.35 mmol, 37.4%)2.54. Int-195LiAlD4HSx^^BrTHFOInt-195

[0170] Under N2, at 0 °C, LiAlD4 (CAS# 14128-54-2; 2 eq., 218.81 mg, 5.21 mmol) was added carefully to a mixture of methyl 4-bromo-2-sulfanylbenzoate (CAS# 881900-17-0; 1 eq., 818 mg, 3.309 mmol) in THF (28 m ). The resulting mixture was stirred at rt for 2 h. IN aqHCl was added and EtOAc. The layers were separated and the aqueous layer was extracted twiceagain with EtOAc. The combined organic layers were dried over MgSO4, fdtered and the solvent was removed in vacuo and purified by normal phase preparative LC (irregular SiOH, 40-60 pm, 24 g agela, dry loading (celite), mobile phase gradient: from heptane / EtOAc 100 / 00 to 20 / 80). The fractions containing product were combined and evaporated to dryness to give Int-195 (720 mg, 3.26 mmol, 98.5%) as a white solid.2.55. Int-196D DBr— | — |— BrD DK2CO3, DMFInt-195

[0171] A mixture of Int-195 (1 eq., 250 mg, 1.13 mmol), dibromo(2H4)ethane (4 eq., 867.83 mg, 0.4 mb, 4.52 mmol) and K2CO3 (4 eq., 625.051 mg, 4.52 mmol) in DMF (7.5 mb) was stirred at 70 °C for 16 h. Water and EtOAc were added. The layers were separated and the aqueous layer was extracted once again with EtOAc. The combined organic layers were dried over MgSO4, filtered, concentrated under vacuum and purified by normal phase preparative LC (regular SiOH 50 pm, 12 g Interchim, liquid loading (DCM), mobile phase gradient: from Heptane / EtOAc 90 / 10 to 60 / 40, 10 CV). The fractions containing product were combined and evaporated to give Int-196 (134 mg, 0.54 mmol, 47.4%) as a colorless oil.2.56. Int-197OxoneMeOH, H2O

[0172] Int 197 was prepared according to general method II from Int-1962.57. lnt-198NaH 60%lnt-198

[0173] At 0 °C, under inert atmosphere, NaH 60% in mineral oil (2.014 eq., 41.27 mg, 1.032 mmol) was added in one portion to a mixture of Int-197 (0.99 eq., 143 mg, 0.507 mmol) in THF (3.71 mL). And the mixture was stirred at 0 °C for 1 h. A sat aqueous sol. of NH4C1 was added drowpise at 0°C to the reaction mixture, then EtOAc. The layers were separated. The aqueous layer was extracted twice again with EtOAc. The combined organic layer were washed with brine, dried over MgSO4, filtered and concentrated under vacuum to give lnt-198 (134 mg, 0.47 mmol, 93.37%) as a colorless oil.lnt-199

[0174] In a pressure vessel reactor were added lnt-198 (1 eq., 134 mg, 0.47 mmol), 1,3-Bis(dicyclohexylphosphino)propane bis(tetrafluoroborate) (0.2 eq., 57.76 mg, 0.095 mmol) and K2CO3 (1.5 eq., 98.049 mg, 0.709 mmol) in DMSO (1.34 mL) and D2O (0.14 mL) then Palladium acetate (0.1002 eq., 7.84 mg, 0.047 mmol). The reactor was filled with CO 5 bars. The mixture was heated at 100 °C for 4 h. The mixture was diluted was diluted with D2O and EtOAc. The layers were separated. The organic layer was discarded. The aqueous layer was acidified until pH ~3 with IM DC1 in D2O, then extracted 3 times with EtOAc, dried over MgSO4, filtered and concentrated under vacuum to give lnt-199 (108 mg, 0.43 mmol, 91.9%) as a colorless oil.2.59. Int-191Int-194PPh3tolueneInt-194

[0175] A mixture of 3-(chlorosulfonyl)-4-hydroxy-5-methylbenzoic acid (CAS# 2090711-42-3; 1 eq., 1000 mg, 3.99 mmol), toluene (18.88 mL) & PPhs (3.5 eq., 3662.57 mg, 13.96 mmol) was heated at 90 °C for 2 h. The reaction mixture was quenched with 10% aq NaOH (20 mL) and extracted with Et20 (3 x 20mL). The aqueous layer was acidified to pH = 2 with 3 M aq HC1 and extracted with EtOAc (3 x 20 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to give Int-194 (600 mg, 3.26 mmol, 81.6%) as an off-white solid.2.60. Int-193OH2SO4MeOHI nt- 194 Int-193

[0176] To a mixture of Int-194 ...

Claims

CLAIMS1. A compound according to Formula I:R5wherein,A is 6-10 membered monocyclic or bicyclic aryl, or 5-10 membered monocyclic or bicyclic heteroaryl comprising one, two or three heteroatoms independently selected from N, O, and S;Ryo..0 N OY is independently selected from' ', ' * andRyand Rzare each independently hydrogen or C1.3 alkyl;X is N or CH;R1is C1-6alkyl, C1-3alkoxy(C1-3)alkyl, -N(C1-3alkyl)2or hydroxy(C1-4)alkyl, wherein said alkyl and alkoxy groups are optionally substituted with one or more halogen;n is 0, 1, or 2;each R2is independently selected from halogen and C1-6 alkyl, which alkyl is optionally substituted with halo or C1-4 alkoxyor R1and one R2together with the atoms onto which they are attached form a fused 5-8 membered monocyclic cycloalkyl, or a fused 5-8 membered monocyclic heterocycloalkyl comprising Y in formula I and zero, one, or two additional heteroatoms independently selected from N, O, and S, wherein the cycloalkyl or heterocycloalkyl is optionally substituted with one or more independently selected halogens (preferably fluoro) or C1-4 alkyl;R3is hydrogen or C1-6 alkyl;R4aand R4bare each independently hydrogen or C1-6 alkyl optionally substituted with one or more independently selected halo or C1-4 alkoxy;or R4aand R4b, together with the carbon to which they are attached, form a C3-6 cycloalkyl or 4-6 membered heterocycloalkyl comprising one or two heteroatoms independently selected from N, O, and S, which cycloalkyl or heterocycloalkyl is optionally substituted with one or more halo or C1.4 alkoxy;Li is a bond, Ce-io aryl, or 5-6 membered monocyclic heteroaryl comprising one, two or three heteroatoms independently selected from N, O, and S, which aryl or heteroaryl is optionally substituted with one or more independently selected halo, C1-4 alkyl, C1-4 haloalkyl, -NH2, -NH(CI-4 alkyl), or -N(CI-4 alkyl)2, morpholine, -CH=CHCO2R9a, C1-4 alkoxy, C1-4 haloalkoxy or oxetane;B is Ce-io aryl, 5-10 membered monocyclic or bicyclic heteroaryl comprising one, two, three or four heteroatoms independently selected from N, O, and S, or a 5-10 membered monocyclic or bicyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S, each of which is optionally substituted with one or more independently selected R7;L2 is a bond or C1-6 alkyl, which alkyl is optionally substituted with one or more halo, -OH, -CN, or C1-4 alkoxy;R5is independently selected from- hydrogen,- oxo,- -OH,- -CN,- -P(O)(C1-4alkyl)2,- halo,- -S(=O)2-Ci.4 alkyl,- -NR8aR8b,- -CH=CHCO2R9a,- -S(=O)2NHC(O)C1-2alkyl,- -S(=O)2NH2,- -C(O)NHS(=O)2C1-2alkyl,- -CONR9aR9b,- -CO2R9a,- C1-4 alkyl optionally substituted with one or more independently selected halo, -OH, -CN, -CO2R9aor Ci -4 alkoxy,- C1-4 alkoxy optionally substituted with one or more independently selected halo, -OH, -CN, -CO2R9a, Ci -4 alkoxy, or C3-6 cycloalkyl,- C3-6 cycloalkyl, which cycloalkyl is optionally substituted with one or more independently selected oxo, halo, -OH, -CN, C1-4 alkyl, or C1-4 alkoxy,- 4-8 membered monocyclic or spirocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is optionally substituted with one or more independently selected oxo, halo, -OH, -CN, C1-4 alkyl, C1-4 alkoxy, -S(=O)2Ci-4 alkyl, - C(=O)Ci.4 alkyl, or -CO2R9a,- -Si(Ci-4alkyl)3, and- Q1;R6is hydrogen, halo, or C1-6 alkyl;each R7is independently selected from- oxo,- -OH,- -CN,- -P(O)(C1-4alkyl)2,- halo,- -S(=O)2-Ci.4 alkyl,- -NR8aR8b,- -CH=CHCO2R9a,- -S(=O)2NHC(O)CI-2alkyl,- -S(=O)2NH2,- -C(O)NHS(=O)2C1-2alkyl,- -CONR9aR9b,- -CO2R9a,- Ci-4 alkyl optionally substituted with one or more independently selected halo, -OH, -CN, -CO2R9aor Ci -4 alkoxy,- Ci-4 alkoxy optionally substituted with one or more independently selected halo, -OH, -CN, or C1-4 alkoxy,- C3-6 cycloalkyl, which cycloalkyl is optionally substituted with one or more independently selected oxo, halo, -OH, -CN, C1-4 alkyl, or C1-4 alkoxy, and- 4-8 membered monocyclic or spirocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is optionally substituted with one or more independently selected oxo, halo, -OH, -CN, C1-4 alkyl, or C1-4 alkoxy, and- Q2;Q1is selected from phenyl and 5-10 membered monocyclic or bicyclic heteroaryl comprising one, two, or three heteroatoms independently selected from N, O, and S, which phenyl and heteroaryl is optionally substituted with one or more R10a;Q2is selected from phenyl and 5-10 membered monocyclic or bicyclic heteroaryl comprising one, two, or three heteroatoms independently selected from N, O, and S, which phenyl and heteroaryl is optionally substituted with one or more R10b;each R8ais independently hydrogen or C1-4 alkyl;each R8bis independently hydrogen, C1-4 alkyl or -C(O)C1-2alkyl;each R9ais independently selected from hydrogen and C1-4 alkyl;R9bis hydrogen, C1-4 alkyl or C1-4 alkoxy, or R9aand R9btogether with the atoms onto which they are attached form a 4-7 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is optionally substituted with one or more independently selected oxo, halo, -OH, -CN, C1-4 alkyl;R10aand R10bare each independently selected from halo, -OH, -NR11aR11b, -CN, C1-4 alkyl, C1-4 haloalkyl, C1.4 alkoxy, C1.4 alkoxy(Ci.4)alkyl, C1.4 hydroxyalkyl, -CONR12aR12b, -CO2R12a, and -L3-Q3;-L3- is a bond, -O-, or C1-4 alkylene;Q3is selected from C3-6 cycloalkyl, 4-8 membered monocyclic heterocycloalkyl comprising one, two, or three heteroatoms independently selected from N, O, and S, 6-10 membered bicyclic fused, bridged, or spiro heterocycloalkyl comprising one, two, or three heteroatoms independently selected from N, O, and S, which cycloalkyl or heterocycloalkyl is optionally substituted with one or more independently selected oxo, halo, -OH, -CN, C1-4 alkyl, or C1-4 alkoxy;each R11ais independently hydrogen or C1-4 alkyl;each Rllbis independently hydrogen, C1.4 alkyl or -C(O)Ci-2 alkyl;each R12ais independently selected from hydrogen and C1.4 alkyl; andR12bis hydrogen, C1.4 alkyl or C 1.4 alkoxy, or R12aand R12btogether with the atoms onto which they are attached form a 4-7 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is optionally substituted with one or more independently selected oxo, halo, -OH, -CN, C1-4 alkyl;or a pharmaceutically acceptable salt and / or solvate thereof.

2. The compound, or a pharmaceutically acceptable salt and / or solvate thereof, according to claim 1, wherein R3is H.

3. The compound according to claim 1 or claim 2, wherein the compound is according to Formula III:or a pharmaceutically acceptable salt and / or solvate thereof, wherein R6 is hydrogen.

4. The compound, or a pharmaceutically acceptable salt and / or solvate thereof, according to any one of claims 1-3, wherein B is phenyl, which is optionally substituted with one or more independently selected R7.

5. The compound, or a pharmaceutically acceptable salt and / or solvate thereof, according to any one of claims 1-3, wherein B is 5-6 membered monocyclic heteroaryl comprising one, two, or three heteroatoms independently selected from N, O, and S, which heteroaryl is optionally substituted with one or more independently selected R76. The compound, or a pharmaceutically acceptable salt and / or solvate thereof, according to any one ofclaims 1-5, wherein Yis7. The compound, or a pharmaceutically acceptable salt and / or solvate thereof, according to any one ofsubstituted with 1 R2a, wherein R2ais selected from halogen (preferably fluoro) and Ci-4 alkyl.

8. The compound, or a pharmaceutically acceptable salt and / or solvate thereof, according to any one of9. The compound, or a pharmaceutically acceptable salt and / or solvate thereof, according to any one of10. The compound, or a pharmaceutically acceptable salt and / or solvate thereof, according to any one of11. The compound, or a pharmaceutically acceptable salt and / or solvate thereof, according to any one of claims 1 to 5, wherein Yis12. The compound, or a pharmaceutically acceptable salt and / or solvate thereof, according to any one ofclaims 1 to 5 or 11, wherein13. The compound according to any one of claims 1-12, wherein the compound is according to Formula14. The compound according to any one of claims 1 to 13, wherein the compound of Formula I is a compound according to Formula XII, XIV or XlVb:(XIV)(XlVb)or a pharmaceutically acceptable salt and / or solvate thereof,whereinn is 0, 1, or 2;nl is 0 or 1;n2 is 0 or 1;R1is selected from CHF2 or CHFCH2OH;each R2is independently selected from halogen, preferably chloro or fluoro, and CHF2;each R2ais independently selected from halogen, preferably fluoro, and Ci -4 alkyl.

15. The compound, or a pharmaceutically acceptable salt and / or solvate thereof, according to any one of claims 1 to 14, wherein R7is selected from:- -CN,halo,C1-4 alkoxy optionally substituted with one or more independently selected halo, -OH, -CN, or C1.4 alkoxy, and4-8 membered monocyclic or spirocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is optionally substituted with one or more independently selected oxo, halo, -OH, -CN, C1-4 alkyl, or C1-4 alkoxy.optionally wherein R7is C1-2 alkoxy optionally substituted with one or more independently selected - OH or C 1-2 alkoxy.

16. A compound according to Formula I:wherein,A is 6-10 membered monocyclic or bicyclic aryl, or 5-10 membered monocyclic or bicyclic heteroaryl comprising one, two or three heteroatoms independently selected from N, O, and S;Ry0.0 N 0* / / \\ / / V'S'VY is independently selected from' ', ' ' andRyand Rzare each independently hydrogen or C1-3 alkyl;X is N or CH;R1is C1-6alkyl, C1-3alkoxy(C1-3)alkyl, -N(C1-3alkyl)2or hydroxy(C1-4)alkyl, wherein said alkyl and alkoxy groups are optionally substituted with one or more halogen;n is 0, 1, or 2;each R2is independently selected from halogen and C1-6 alkyl, which alkyl is optionally substituted with halo, OH, or C1-4 alkoxy;or R1and one R2together with the atoms onto which they are attached form a fused 5-8 membered monocyclic cycloalkyl, or a fused 5-8 membered monocyclic heterocycloalkyl comprising Y in formula I and zero, one, or two additional heteroatoms independently selected from N, O, and S, wherein the cycloalkyl or heterocycloalkyl is optionally substituted with one or more independently selected halogens (preferably fluoro) or C1-4 alkyl;R3is hydrogen or C1-6alkyl;R4aand R4bare each independently hydrogen or Ci-e alkyl optionally substituted with one or more independently selected halo or C1.4 alkoxy;or R4aand R4b, together with the carbon to which they are attached, form a C3-6 cycloalkyl or 4-6 membered heterocycloalkyl comprising one or two heteroatoms independently selected from N, O, and S, which cycloalkyl or heterocycloalkyl is optionally substituted with one or more halo or C1-4 alkoxy;Li is a bond, Ce-io aryl, or 5-6 membered monocyclic heteroaryl comprising one, two or three heteroatoms independently selected from N, O, and S, which aryl or heteroaryl is optionally substituted with one or more independently selected halo, C1-4 alkyl, C1-4 haloalkyl, -NH2, -NH(CI-4 alkyl), or -N(CI-4 alkyl)2, morpholine, -CH=CHCO2R9a, C1-4 alkoxy, C1-4 haloalkoxy or oxetane;B is Ce-io aryl, 5-10 membered monocyclic or bicyclic heteroaryl comprising one, two, three or four heteroatoms independently selected from N, O, and S, or a 5-10 membered monocyclic or bicyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S, each of which is optionally substituted with one or more independently selected R7;L2 is a bond, Ci-e alkyl or C3-6 cycloalkyl, which alkyl or cycloalkyl is optionally substituted with one or more halo, -OH, -CN, or C1-4 alkoxy;R5is independently selected from- hydrogen,- oxo,- -OH,- -CN,- -P(O)(C1-4alkyl)2,- halo,- -S(=O)2-Ci.4 alkyl,- -NR8aR8b,- -CH=CHCO2R9a,- -S(=O)2NHC(O)C1-2alkyl,- -S(=O)2NH2,- -C(O)NHS(=O)2C1-2alkyl,- -CONR9aR9b,- -CO2R9a,- Ci-4 alkyl optionally substituted with one or more independently selected halo, -OH, -CN, -CO2R9a, Ci -4 alkyl, or C1-4 alkoxy,- C1-4 alkoxy optionally substituted with one or more independently selected halo, -OH, -CN, -CO2R9a, Ci -4 alkoxy, or C3-6 cycloalkyl,- C3-6 cycloalkyl, which cycloalkyl is optionally substituted with one or more independently selected oxo, halo, -OH, -CN, C1-4 alkyl, or C1-4 alkoxy,- 4-8 membered monocyclic or spirocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is optionally substituted with one or more independently selected oxo, halo, -OH, -CN, C1-4 alkyl, C1-4 alkoxy, -S(=O)2Ci-4 alkyl, - C(=O)Ci-4alkyl, or -CO2R9a,- -Si(Ci-4alkyl)3, and- Q1;R6is hydrogen, halo, or C1-6 alkyl;each R7is independently selected from- oxo,- -OH,- -CN,- -P(O)(C1-4alkyl)2,- halo,- -S(=O)2-Ci-4alkyl,- -NR8aR8b,- -CH=CHCO2R9a,- -S(=O)2NHC(O)C1-2alkyl,- -S(=O)2NH2,- -C(O)NHS(=O)2C1-2alkyl,- -CONR9aR9b,- -CO2R9a,- Ci-4 alkyl optionally substituted with one or more independently selected halo, -OH, -CN, -CO2R9aor Ci -4 alkoxy,- Ci-4 alkoxy optionally substituted with one or more independently selected halo, -OH, -CN, or C1-4 alkoxy,- C3-6 cycloalkyl, which cycloalkyl is optionally substituted with one or more independently selected oxo, halo, -OH, -CN, C1-4 alkyl, C1-4 alkoxy, or C1-4 alkyl, optionally substituted with OH;- 4-8 membered monocyclic or spirocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is optionally substituted with one or more independently selected oxo, halo, -OH, -CN, C1-4 alkyl, C1-4 alkoxy, or C1-4 alkyl, optionally substituted with OH; and- Q2;Q1is selected from phenyl and 5-12 membered monocyclic or bicyclic heteroaryl comprising one, two, or three heteroatoms independently selected from N, O, and S, which phenyl and heteroaryl is optionally substituted with one or more R10a;Q2is selected from phenyl and 5-10 membered monocyclic or bicyclic heteroaryl comprising one, two, or three heteroatoms independently selected from N, O, and S, which phenyl and heteroaryl is optionally substituted with one or more R10b;each R8ais independently hydrogen or C1-4 alkyl;each R8bis independently hydrogen, C1-4 alkyl or -C(O)Ci-2 alkyl;each R9ais independently selected from hydrogen and C1.4 alkyl;R9bis hydrogen, C1.4 alkyl or C1.4 alkoxy, or R9aand R9btogether with the atoms onto which they are attached form a 4-7 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is optionally substituted with one or more independently selected oxo, halo, -OH, -CN, C1.4 alkyl;R10aand R10bare each independently selected from halo, -OH, -NR11aR11b, -CN, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 alkoxy (Ci-4)alkyl, C1-4 hydroxyalkyl, -CONR12aR12b, -CO2R12a, -L3-Q3, and C1-4 alkoxy, optionally substituted by OH;-L3- is a bond, -O-, or C1-4 alkylene;Q3is selected from C3-6 cycloalkyl, 4-8 membered monocyclic heterocycloalkyl comprising one, two, or three heteroatoms independently selected from N, O, and S, 6-10 membered bicyclic fused, bridged, or spiro heterocycloalkyl comprising one, two, or three heteroatoms independently selected from N, O, and S, which cycloalkyl or heterocycloalkyl is optionally substituted with one or more independently selected oxo, halo, -OH, -CN, C1-4 alkyl, or C1-4 alkoxy;each R11ais independently hydrogen or C1-4 alkyl;each R11bis independently hydrogen, C1-4 alkyl or -C(O)C1-2 alkyl;each R12ais independently selected from hydrogen and C1.4 alkyl; andR12bis hydrogen, C1-4 alkyl or C 1-4 alkoxy, or R12aand R12btogether with the atoms onto which they are attached form a 4-7 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is optionally substituted with one or more independently selected oxo, halo, -OH, -CN, C1-4 alkyl;or a pharmaceutically acceptable salt and / or solvate thereof.

17. The compound, or a pharmaceutically acceptable salt and / or solvate thereof, according to claim 16,18. The compound according to claim 1 or 17, wherein said compound is selected from Table III of the description, or a pharmaceutically acceptable salt and / or solvate thereof.

19. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound, a pharmaceutically acceptable salt, a solvate, or a solvate of a pharmaceutically acceptable salt thereof according to any one of claims 1-18.

20. A compound, a pharmaceutically acceptable salt, a solvate, or a solvate of a pharmaceutically acceptable salt thereof, according to any one of claims 1-18, or a pharmaceutical composition according to claim 19 for use in medicine.

21. A compound, a pharmaceutically acceptable salt, a solvate, or a solvate of a pharmaceutically acceptable salt thereof, according to any one of claims 1 - 18 or a pharmaceutical composition according to claim 19 for use in the prophylaxis and / or treatment of proliferative diseases.

22. A compound, or a pharmaceutically acceptable salt and / or solvate thereof, according to any one of claims 1-18, or a pharmaceutical composition according to claim 19, for use in the prophylaxis and / or treatment of a disease, disorder or condition that is selected from metastatic tumours (such as but not limited to, melanoma, lymphoma, leukaemia, fibrosarcoma, rhabdomyosarcoma, and mastocytoma) and types of tissue carcinoma (such as but not limited to, colorectal cancer, prostate cancer, small cell lung cancer and non-small cell lung cancer, breast cancer, pancreatic cancer, bladder cancer, renal cancer, gastric cancer, glioblastoma, primary liver cancer, ovarian cancer, prostate cancer and uterine leiomyosarcoma), acute lymphoblastic leukemia, acute myeloidleukemia, adrenocortical carcinoma, anal cancer, appendix cancer, astrocytomas, atypical teratoid / rhabdoid tumor, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer (osteosarcoma and malignant fibrous histiocytoma), brain stem glioma, brain tumors, brain and spinal cord tumors, breast cancer, bronchial tumors, Burkittlymphoma, cervical cancer, chronic lymphocytic leukemia, chronic myelogenous leukemia, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T -Cell lymphoma, embryonal tumors, endometrial cancer, ependymoblastoma, ependymoma, esophageal cancer, ewing sarcoma family of tumors, eye cancer, retinoblastoma, gallbladder cancer, gastric (stomach) cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST), gastrointestinal stromal cell tumor, germ cell tumor, glioma, hairy cell leukemia, head and neck cancer, hepatocellular (liver) cancer, hodgkin lymphoma, hypopharyngeal cancer, intraocular melanoma, islet cell tumors (endocrine pancreas), Kaposi sarcoma, kidney cancer, Langerhans cell histiocytosis, laryngeal cancer, leukemia, acute lymphoblastic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, hairy cell leukemia, liver cancer, non-small cell lung cancer, small cell lung cancer, Burkitt lymphoma, cutaneous T-cell lymphoma, Hodgkin lymphoma, non -Hodgkin lymphoma, lymphoma, Waldenstrom macroglobulinemia, medulloblastoma, medulloepithelioma, melanoma, mesothelioma, mouth cancer, chronic myelogenous leukemia, myeloid leukemia, multiple myeloma, asopharyngeal cancer, neuroblastoma, non-Hodgkin lymphoma, non-small cell lung cancer, oral cancer, oropharyngeal cancer, osteosarcoma, malignant fibrous histiocytoma of bone, ovarian cancer, ovarian epithelial cancer, ovarian germ cell tumor, ovarian low malignant potential tumor, pancreatic cancer, papillomatosis, parathyroid cancer, penile cancer, pharyngeal cancer, pineal parenchymal tumors of intermediate differentiation, pineoblastoma and supratentorial primitive neuroectodermal tumors, pituitary tumor, plasma cell neoplasm / multiple myeloma, pleuropulmonary blastoma, primary central nervous system lymphoma, prostate cancer, rectal cancer, renal cell (kidney) cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcoma, Ewing sarcoma family of tumors, sarcoma, kaposi, Sezary syndrome, skin cancer, small cell Lung cancer, small intestine cancer, soft tissue sarcoma, squamous cell carcinoma, stomach (gastric) cancer, supratentorial primitive neuroectodermal tumors, T -cell lymphoma, testicular cancer, throat cancer, thymoma and thymic carcinoma, thyroid cancer, urethral cancer, uterine cancer, uterine sarcoma, vaginal cancer, vulvar cancer, Waldenstrom macroglobulinemia, Wilms tumor, a neoplastic disease of the blood and blood forming organs, including but not limited to: acute myeloid leukaemia (AML), and acute lymphoblastic leukemia (ALL) and chronic lymphoblastic leukaemia (CLL), breast cancer (e.g. invasive ductal cancer, invasive lobular cancer), lung cancer (e.g. non-small-cell lung cancer, lung adenocarcinoma, squamous cell lung cancer and small-cell lung cancer), urothelial cancer, bladder cancer (e.g. urothelial bladder cancer, nonmuscle invasive bladder cancer, muscle invasive bladder cancer), upper tract cancer (e.g. urothelial upper tract cancer), urethral cancer, gastric cancer, pancreatic cancer, prostate cancer, colorectal cancer, multiple myeloma, liver cancer, melanoma (e.g. cutaneous melanoma), head and neck cancer (e.g. oral cancer), thyroid cancer, renal cancer (e.g. renal pelvis cancer), glioblastoma, endometrial cancer, cervical cancer, ovarian cancer, and testicular cancer.

Images