Fused azines for the treatment of cancer

Abstract

The present invention discloses compounds according to Formula I: [Formula I] I wherein A, B, X1, X2, X3, Y, L1, R1, R2, R3, R4, R5, R6, n, p, and q 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

FUSED AZINES FOR THE TREATMENT OF CANCERFIELD 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 fortranscription 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: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;o.ZO N O RZY is independently selected from' ', ' ' and ' *;Ryand Rzare each independently hydrogen or C1-3 alkyl;R1is C1-6 alkyl, C1-3 alkoxy(Ci-3)alkyl, -N(CI-3 alkyl)2 or 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 C1-6 alkyl, which alkyl is optionally substituted with halo 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;B is 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;each R4is independently selected from halo or C1.4 alkoxy;Xi, X2, and X3are each independently selected from N and CH;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^ alkyl)2, morpholine, -CH=CHCO2R9a, C1-4alkoxy, C1-4haloalkoxy or oxetane;R5is halo, -OR10, C 6-10 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, which aryl, heteroaryl, and heterocycloalkyl groups are optionally substituted with one or more independently selected R7;q is 0, 1, 2, 3, or 4;each R6is independently selected from halo, or C1-6 alkyl;each R7is independently selected fromoxo,- -OH,- -CN,- -P(O)(Ci.4alkyl)2,halo,- -S(=O)2-CI-4alkyl,- -NR8aR8b,- -CH=CHCO2R9a,- -S(=O)2NHC(O)C1-2alkyl,- -S(=O)2NH2,- -C(O)NHS(=O)2CI.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, -CO2R9a, Ci -4 alkoxy, or C3-6 cycloalkyl,C2-4 alkynyl optionally substituted with one or more independently selected halo, -OH, -CN, -CO2R9a, C1-4 alkoxy, and Q1,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 - Q2;Q1and Q2are each independently 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; 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; andR10is hydrogen or C1-6 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):(la)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;o. > O N O RZ\\ / / \ / RVS'VY is independently selected from' ', ' ' and ' *;Ryand Rzare each independently hydrogen or C1-3 alkyl;R1is C1-6 alkyl, C1-3 alkoxy(C1-3)alkyl, C1-3 alkyl(C1-3)alkoxy, -N(CI-3 alkyl)2 or 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 C1-6 alkyl, which alkyl is optionally substituted with halo, OH, C1.4 alkoxy, O-cyclopropyl, CN, C1-4 haloalkoxy;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;B is 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;each R4is independently selected from halo or C1-4 alkoxy;Xi, X2, and X3 are each independently selected from N and CH;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=CHCC>2R9a, C1-4 alkoxy, C1-4 haloalkoxy or oxetane;R5is halo, -OR10, C 6-10 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, which aryl, heteroaryl, and heterocycloalkyl groups are optionally substituted with one or more independently selected R7;q is 0, 1, 2, 3, or 4;each R6is independently selected from halo, or C1-6 alkyl;each R7is independently selected fromoxo,-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)2CI.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, -CO2R9a, Ci-4 alkoxy, or C3-6 cycloalkyl,C2-4 alkynyl optionally substituted with one or more independently selected halo, -OH, -CN, -CO2R9a, C1.4 alkoxy, and Q1,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 Q2;Q1and Q2are each independently 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; 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; andR10is hydrogen or C1-6 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 suitablefor 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 asset 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 exampleindicates 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), w-propyl (-CH2-CH2-CH3), isopropyl (-CH(CH3)2), w-butyl (-CH2-CH2-CH2-CH3), tert-butyl (-C(CH3)3), sec-butyl (-CH(CH3)-CH2CH3), isobutyl (-CH2-CH(CH3)2), w-pcntyl (-CH2-CH2-CH2-CH2-CH3), w-hcxyl (-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] ‘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.

[0030] ‘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.

[0031] ‘ Amino’ refers to the radical -NH2.

[0032] ‘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.

[0033] “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:

[0034] ‘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.

[0035] ‘Cyano’ refers to the radical -CN.

[0036] ‘Halo’ or ‘halogen’ refers to fluoro (F), chloro (Cl), bromo (Br) and iodo (I). Particular halo groups are either fluoro or chloro.

[0037] 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.

[0038] ‘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.

[0039] ‘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, forexample, 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.

[0040] 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.

[0041] “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, 1,2,3,4-tetrahydro- 1,8-naphthyridinyl, l.2.3.4-tctrahydropyrido|2.3- / >|pyrazinyl and 3.4-dihydro-2 / / -pyrido|3.2- / ?|| l,4]oxazinyl.

[0042] 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.

[0043] Examples of six membered monocyclic heteroaryl groups include but are not limited to pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl and triazinyl.

[0044] 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.

[0045] 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.

[0046] 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 fromthiophenyl, pyrrolyl, benzothiophenyl, benzofuranyl, indolyl, pyridinyl, quinolinyl, imidazolyl, oxazolyl and pyrazinyl.

[0047] Examples of representative heteroaryls include the following:wherein each Y is selected from > C=O, NH, O and S.

[0048] ‘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.

[0049] 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-.

[0050] 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-.

[0051] 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.

[0052] Particular examples of spirocyclic rings are shown in the following illustrative examples:wherein each Y is selected from -CH2-, -NH-, -O- and -S-.

[0053] ‘Hydroxyl’ refers to the radical -OH.

[0054] ‘Oxo’ refers to the radical =0.

[0055] ‘ Substituted’ refers to a group in which one or more hydrogen atoms are each independently replaced with the same or different substituent(s).

[0056] 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.

[0057] 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.

[0058] ‘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.

[0059] ‘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 pharmaceutically acceptable 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.

[0060] ‘Pharmaceutically acceptable vehicle’ refers to a diluent, adjuvant, excipient or carrier with which a compound of the invention is administered.

[0061] ‘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.

[0062] ‘ 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.

[0063] ‘Subject’ includes humans. The terms ‘human’, ‘patient’ and ‘subject’ are used interchangeably herein.

[0064] ‘ 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.

[0065] ‘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.

[0066] 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.

[0067] ‘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.

[0068] 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.

[0069] 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.

[0070] 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.

[0071] 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, Waldenstrommacroglobulinemia, 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, Sézary 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.

[0072] 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).

[0073] ‘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.

[0074] When ranges are referred to herein, for example but without limitation, Ci-s alkyl, the citation of a range should be considered a representation of each member of said range.

[0075] 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 particularly useful 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 Ci-s alkyl, C2-8 alkenyl, Ce-io optionally substituted aryl, and (Ce-io aryl)-(Ci-4 alkyl) esters of the compounds of the invention.

[0076] 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 numberdifferent 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.

[0077] 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.

[0078] 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.

[0079] 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 of formulae 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, R6, R7, R8a, R8b, R9a, R9b, or R10is methyl, the invention also encompasses -CDs, -CHD2 and -CH2D. Similarly Ry, Rz, R3, R8a, R8b, R9a, R9b, or R10may be D.

[0080] 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’.

[0081] 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’.

[0082] ‘ 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 7i 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.

[0083] Tautomeric forms may be relevant to the attainment of the optimal chemical reactivity and biological activity of a compound of interest.

[0084] 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.

[0085] An optical isomer with unknown absolute configuration may be depicted with an asterix (*) at thechiral center, e.g., " Jb and / or Jb and / or ' J, '''and / 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*.

[0086] 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.

[0087] It will be appreciated that compounds of the invention may be metabolized to yield biologically active metabolites.THE INVENTION

[0088] 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.

[0089] 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.

[0090] Accordingly, in a first aspect of the invention, the compounds of the invention are provided having a 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;o. -O N O RZ'V' 'z \ / RV'S's / v wY is independently selected from' ', ' ' and ' *;Ryand Rzare each independently hydrogen or C1-3 alkyl;R1is C1-6 alkyl, C1-3 alkoxy(Ci-3)alkyl, -N(CI-3 alkyl)2 or 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 C1-6 alkyl, which alkyl is optionally substituted with halo 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;B is 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;each R4is independently selected from halo or Ci-4 alkoxy;Xi, X2, and X3 are each independently selected from N and CH;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 ormore independently selected halo, C1.4 alkyl, C1.4 haloalkyl, -NH2, -NH(CI-4 alkyl), or -N(Ci^ alkyl)2, morpholine, -CH=CHCO2R9a, C1.4 alkoxy, C1.4 haloalkoxy or oxetane;R5is halo, -OR10, 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, which aryl, heteroaryl, and heterocycloalkyl groups are optionally substituted with one or more independently selected R7;q is 0, 1, 2, 3, or 4;each R6is independently selected from halo, or C1-6 alkyl;each R7is independently selected fromoxo,- -OH,- -CN,- -P(O)(Ci.4alkyl)2,halo,- -S(=O)2-CI.4alkyl,- -NR8aR8b,- -CH=CHCO2R9a,- -S(=O)2NHC(O)CI.2alkyl,- -S(=O)2NH2,- -C(O)NHS(=O)2CI.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, -CO2R9a, C1.4 alkoxy, or C3-6 cycloalkyl,C2-4 alkynyl optionally substituted with one or more independently selected halo, -OH, -CN, -CO2R9a, C1.4 alkoxy, and Q1,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 - Q2;Q1and Q2are each independently 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; 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; andR10is hydrogen or C1-6 alkyl;or a pharmaceutically acceptable salt and / or solvate thereof.

[0091] In certain embodiments, the compound of the formula (I) is a compound of the formula (II):wherein A, R1, R2, R3, R4, R5, R6, Li, Xi, X2, X3, Y, n, p, and q are as defined for formula (I).

[0092] In certain embodiments, the compound of the formula (I) is a compound of the formula (III):wherein A, B, R1, R2, R3, R4, R5, R6, Li, Y, n, p, and q are as defined for formula (I).

[0093] In certain embodiments, the compound of the formula (I) is a compound of the formula (IV):(IV)wherein A, R1, R2, R3, R4, R5, R6, Li, Y, n, p, and q are as defined for formula (I).

[0094] In certain embodiments, the compound of the formula (I) is a compound of the formula (V):(V)wherein A, B, R1, R2, R3, R4, R5, R6, L1, X1, X2, X3, n, p, and q are as defined for formula (I).

[0095] In certain embodiments, the compound of the formula (I) is a compound of the formula (VI):wherein B, R1, R2, R3, R4, R5, R6, L1, X1, X2, X3, n, p, and q are as defined for formula (I).

[0096] In certain embodiments, the compound of the formula (I) is a compound of the formula (VII):wherein R1, R2, R3, R4, R5, R6, L1, n, p, and q are as defined for formula (I).

[0097] In certain embodiments, the compound of the formula (I) is a compound of the formula (VIII):whereinnl is 0 or 1;n2 is 0, 1, 2, 3, or 4;R2ais selected from halogen (preferably fluoro) and Ci-4 alkyl; andB, R2, R3, R4, R5, R6, L1, X1, X2, X3, n, p, and q are as defined for formula (I).

[0098] In certain embodiments, the compound of the formula (I) is a compound of the formula (IX):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, R4, R5, R6, L1, n, p, and q are as defined for formula (I).

[0099] In certain embodiments, the compound of the formula (I) is a compound of the formula (X):(X)wherein A, B, R1, R2, R3, R4, R5, R6, Rz, L1, X1, X2, X3, n, p, and q are as defined for formula (I).

[0100] 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 Ci-4 alkyl; andB, R2, R3, R4, R5, R6, Rz, L1, X1, X2, X3, n, p, and q are as defined for formula (I).

[0101] In certain embodiments, the compound of the formula (I) is a compound of the formula (XII):(XII)whereinris 0, 1, or 2; andA, B, R1, R2, R3, R4, R6, R7, X1, X2, X3, Y, n, p, and q are as defined for formula (I).

[0102] In certain embodiments, the compound of the formula (I) is a compound of the formula (XIII):whereinR7ais selected from 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; and C2-4 alkynyl optionally substituted with one or more independently selected halo, -OH, -CN, -CO2R9a, C1-4 alkoxy, and Q1; andA, B, R1, R2, R3, R4, R6, R9a, Q1, X1, X2, X3, Y, n, p, and q are as defined for formula (I).

[0103] In certain embodiments, the compound of the formula (I) is a compound of the formula (XIV):(XIV)whereinris 0, 1, or 2; andA, R1, R2, R3, R4, R6, R7, Y, n, p, and q are as defined for formula (I).

[0104] In certain embodiments, the compound of the formula (I) is a compound of the formula (XV):(XV)whereinR7ais selected from 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; and C2-4 alkynyl optionally substituted with one or more independently selected halo, -OH, -CN, -CO2R9a, C1-4 alkoxy, and Q1; andA, R1, R2, R3, R4, R6, R9a, Q1, Y, n, p, and q are as defined for formula (I).

[0105] In certain embodiments, the compound of the formula (I) is a compound of the formula (XVI):(XVI)whereinR7ais selected from 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; and C2-4 alkynyl optionally substituted with one or more independently selected halo, -OH, -CN, -CO2R9a, C1.4 alkoxy, and Q1; andA, R1, R2, R3, R4, R6, R9a, Q1, n, p, and q are as defined for formula (I).

[0106] In certain embodiments, the compound of the formula (I) is a compound of the formula (XVII):(XVII)whereinR7bis selected from C1-4 alkyl, C3-6 cycloalkyl, and C2-4 alkynyl substituted with Q1; andR1, R2, R3, R4, R6, Q1, n, p, and q are as defined for formula (I).

[0107] In certain embodiments, the compound of the formula (I) is a compound of the formula (XVIII):whereinR7bis selected from C1.4 alkyl, C3-6 cycloalkyl, and C2-4 alkynyl substituted with Q1; andR1, R2, R3, R4, R6, Q1, n, p, and q are as defined for formula (I).

[0108] In certain embodiments, the compound of Formula (I) is a compound according to Formula (XIX) or (XX):(XX)wherein Q1is a 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.

[0109] In certain embodiments, the compound of Formula (I) is a compound according to Formula (XIX) or (XX):wherein Qi is

[0110] The following embodiments apply to compounds of any of Formulae I-XVIII. 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.

[0111] In some embodiments, the compound is according to any one of Formulae I-XVIII, wherein R3is H.

[0112] In some embodiments, the compound is according to any one of Formulae I, II, V, VI, VIII, X, XI, XII, and XIII, wherein X1is N, X2, is CH, and X3is CH.

[0113] 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:

[0116] 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.

[0117] 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.and

[0120] In some embodiments, Y is independently selected from

[0121] In some embodiments,Y is*. In some embodiments, Ryis hydrogen. In some embodiments, Ryis methyl. In some embodiments, Ryis ethyl.

[0123] In some embodiments, Y isIn some embodiments, Rzis hydrogen. In some embodiments, Rzis methyl. In some embodiments, Rzis ethyl.

[0124] In some embodiments, R1is C1-3 alkyl, C1-3 alkoxy(Ci-3)alkyl, -N(CI-3 alkyl)2 or hydroxy(Ci-3)alkyl, wherein said alkyl and alkoxy groups are optionally substituted with one or more halogen.

[0125] In some embodiments, R1is C1-3 alkyl, C1-3 alkoxy(Ci-3)alkyl, or hydroxy(Ci-3)alkyl, wherein said alkyl and alkoxy groups are optionally substituted with one or more halogen.

[0126] In some embodiments, R1is C1-3 alkyl or C1-3 alkoxy (Ci-3)alkyl, wherein said alkyl and alkoxy groups are optionally substituted with one or more halogen.

[0127] 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.

[0128] In some embodiments, R1is methyl.

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

[0130] In some embodiments, R1is -N(C1-3alkyl)2.

[0131] In some embodiments, R1is hydroxy(Ci-3)alkyl.

[0132] In some embodiments,is selected from:

[0133] In some embodiments,

[0134] In some embodiments,

[0135] In some embodiments,

[0136] In some embodiments,

[0138] In some embodiments,

[0139] In some embodiments,

[0140] In some embodiments,

[0141] In some embodiments,

[0142] In some embodiments,

[0143] In some embodiments,R1

[0144] In some embodiments,

[0145] In some embodiments, andR1

[0146] In some embodiments,

[0147] In some embodiments,R1

[0149] In some embodiments,R1

[0150] In some embodiments,R1

[0151] In some embodiments,R1

[0152] In some embodiments,R1

[0153] In some embodiments,R1

[0154] In some embodiments,R1

[0155] In some embodiments,

[0156] R1

[0157] In some embodiments,R1

[0158] In some embodiments,R1

[0159] In some embodiments,R1

[0160] In some embodiments,R1

[0161] In some embodiments,R1

[0162] In some embodiments,R1

[0163] In some embodiments,R1CHF2

[0164] In some embodiments,

[0167] In some embodiments,

[0168] In some embodiments,

[0169] In some embodiments,

[0171] In some embodiments,

[0172] In some embodiments,

[0173] In some embodiments,

[0174] In some embodiments,

[0175] In some embodiments,

[0176] In some embodiments,

[0177] In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2.

[0178] In some embodiments, R2is independently selected from halogen and C1-3 alkyl, which alkyl is optionally substituted with halo or C1-4 alkoxy.

[0179] In some embodiments, R2is halogen. In some embodiments, R2is fluoro. In some embodiments, R2is chloro.

[0180] In some embodiments, R2is C1-3 alkyl, which alkyl is optionally substituted with halo or C1-4 alkoxy.

[0181] 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.

[0182] In some embodiments, R2is methyl, which methyl is optionally substituted with halo. In some embodiments, R2is methyl, which alkyl is optionally substituted with fluoro.

[0183] In some embodiments, R2is methyl.

[0184] 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 C1-4 alkyl.

[0185] 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 C1-4 alkyl.

[0186] 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 C1-4 alkyl.is 0 or 1, n4 isis 0 or 1, n4 is 0, 1, 2, 3, or 4 and R2ais selected from halogen (preferably fluoro) and C1-4 alkyl.R1

[0189] 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.is 0, 1, 2, 3, or 4 and R2ais selected from halogen (preferably fluoro) and C1.4 alkyl.R1

[0192] In some embodiments,is 0, 1, 2, 3, or 4 and R2ais selected from halogen (preferably fluoro) and C1.4 alkyl.

[0193] 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 the heterocycloalkyl is optionally substituted with one or more independently selected halogens (preferably fluoro) or C 1.4 alkyl.

[0194] 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 the S atom of Y 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.

[0195] In some embodiments,; wherein nl is 0 or 1, n2 is 0, 1, 2, 3, or 4 and R2ais selected from halogen (preferably fluoro) and C1-4 alkyl.oR1

[0196] In some embodiments,; wherein nl is 0 or 1, n2 is 0, 1, 2, 3, or 4 and R2ais selected from halogen (preferably fluoro) and C1-4 alkyl.

[0197] In some embodiments,1, 2, 3, or 4 and R2ais selected from halogen (preferably fluoro) and C1-4 alkyl.O SNH[R2|

[0198] In some embodiments,1 Jn1; wherein nl is 0 or 1, n5 is 0, 1, 2, 3, or 4 and R2ais selected from halogen (preferably fluoro) and C1-4 alkyl.9..0R1

[0199] In some embodiments,; wherein nl is 0 or 1, n6 is 0, 1, 2, 3, or 4 and R2ais selected from halogen (preferably fluoro) and C1-4 alkyl.

[0200] In some embodiments,; wherein nl is 0 or 1, n6 is 0, 1, 2, 3, or 4 and R2ais selected from halogen (preferably fluoro) and C1.4 alkyl.O JIs

[0201] In some embodiments,; wherein nl is 0 or 1, n7 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 Ci-4 alkyl.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.

[0205] In some embodiments nl is 0. In some embodiments nl is 1

[0206] In some embodiments n2 is 0. In some embodiments n2 is 1

[0207] In some embodiments n3 is 0. In some embodiments n3 is 1

[0208] In some embodiments n4 is 0. In some embodiments n4 is 1

[0209] In some embodiments n5 is 0. In some embodiments n5 is 1

[0210] In some embodiments n6 is 0. In some embodiments n6 is 1

[0211] In some embodiments n7 is 0. In some embodiments n7 is 1

[0212] In some embodiments n8 is 0. In some embodiments n8 is 1

[0213] In some embodiments, R2ais fluoro.

[0214] In some embodiments, R2ais methyl. In such embodiments, R2amay be a substituent on nitrogenwithin the ring, e.g., where, the -N(H)- may be -N(R2a)-.

[0219] In some embodiments, R3is hydrogen.

[0220] In some embodiments, R3is Ci-6 alkyl. In some embodiments, R3is methyl. In some embodiments, R3is ethyl.

[0221] In some embodiments, B is C3-6 cycloalkyl. In some embodiments, B is cyclopropyl. In some embodiments, B is cyclobutyl. In some embodiments, B is cyclopentyl.

[0222] In some embodiments, B is 4-6 membered heterocycloalkyl comprising one or two heteroatoms independently selected from N, O, and S. In some embodiments, B is 4-membered heterocycloalkyl comprising one heteroatom independently selected from N, O, and S. In some embodiments, B is 5-membered heterocycloalkyl comprising one or two heteroatoms independently selected from N, O, and S.

[0223] In some embodiments, B is selected from:

[0224] In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 0.

[0225] In some embodiments, R4is halo. In some embodiments, R4is fluoro.

[0226] In some embodiments, R4is Ci-4 alkoxy. In some embodiments, R4is -O-methyl. In some embodiments, R4is -O-ethyl.

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

[0229] In some embodiments, X1is N. In some embodiments, X1is CH.

[0230] In some embodiments, X2is N. In some embodiments, X2is CH.

[0231] In some embodiments, X3is N. In some embodiments, X3is CH.

[0232] In some embodiments, the group

[0234] In embodiments where X1, X2, and / or X3are CH, the hydrogen may be substituted by R6. Accordingly, in some embodiments, X1, X2, or X3are CR6.

[0235] In some embodiments, q is 0. In some embodiments, q is 1. In some embodiments, q is 2.

[0236] In some embodiments, R6is halo. In some embodiments, R6is fluoro.

[0237] In some embodiments, R6is C1-6alkyl. In some embodiments, R6is C1-3alkyl. In some embodiments, R6is methyl.

[0238] In some embodiments, Li is a bond.

[0239] 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, C1-4alkoxy, C1-4haloalkoxy or oxetane.

[0240] 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, C1-4alkoxy, C1-4haloalkoxy or oxetane.

[0241] In some embodiments, R5is halo. In some embodiments, R5is fluoro. In some embodiments, R5is chloro.

[0242] In some embodiments, Li is a bond and R5is halo. In some embodiments, Li is a bond and R5is chloro.

[0243] In some embodiments, R5is -OR10. In some embodiments, Li is a bond and R5is -OR10.

[0244] In some embodiments, R10is hydrogen. Thus, it may be that -Li-R5is -OH.

[0245] In some embodiments, R10is C1.3 alkyl. Thus, it may be that -L1-R5is -O-C1.3 alkyl.

[0246] In some embodiments, R5is Ce-io aryl, which aryl is optionally substituted with one or more independently selected R7. In some embodiments, Li is a bond and R5is Ce-io aryl, which aryl is optionally substituted with one or more independently selected R7.

[0247] In some embodiments, R5is phenyl, which is optionally substituted with one or more independently selected R7.

[0248] In some embodiments, R5is 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 R5is 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.

[0249] In some embodiments, R5is 5-10 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.

[0250] In some embodiments, R5is pyridyl, optionally substituted with one or more R7.

[0251] In some embodiments, R5is selected from:

[0252] In some embodiments, R5is 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.

[0253] In some embodiments, R5is 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.

[0254] In some embodiments, R5is 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.

[0255] In some embodiments, where R5is 9-10 membered bicyclic heteroaryl, R5is selected from:wherein r is 0, 1, 2, 3, or 4. In such embodiments, where R5comprises an -N(H)- group, the hydrogen may be substituted by R7Accordingly, such R5groups may comprise an -N(R7)- group. Similarly, such R5groups may be attached to the remainder of the compound via the nitrogen atom of a -N(H)- group, i.e., the group

[0257] In some embodiments, r is 0.

[0258] In some embodiments, r is 2.

[0259] In some embodiments, r is 3.

[0260] In some embodiments, r is 4.

[0261] In some embodiments, r is 1.

[0262] In some embodiments,R5is

[0263] In some embodiments, R5is 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 R5is a 5-10 membered monocyclic or bicyclic heterocycloalkyl comprising one, two or three heteroatomsindependently selected from N, O, and S, which heterocycloalkyl is optionally substituted with one or more independently selected R7.

[0264] In some embodiments, R7is selected from:- -CN,halo,- -S(=O)2-Ci.4 alkyl,- -NR8aR8b,- -S(=O)2NH2,- -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, -CO2R9a, Ci-4 alkoxy, or C3-6 cycloalkyl,C2-4 alkynyl optionally substituted with one or more independently selected halo, -OH, -CN, -CO2R9a, Ci -4 alkoxy, and Q1,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 - Q2

[0265] In some embodiments, R7is selected from:- -CN,- -CONR9aR9b,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,C2-4 alkynyl optionally substituted with one or more independently selected halo, -OH, -CN, -CO2R9a, C1.4 alkoxy, and Q1,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- Q2

[0266] In some embodiments, R7is -CN.

[0267] In some embodiments, R7is -CONR9aR9b. In some embodiments, R9aand R9bare each independently selected from hydrogen and C1.4 alkyl. Thus, in some embodiments, R7is -CONH2. Thus, in some embodiments, R7is -CON(H)C1-4alkyl. Thus, in some embodiments, R7is -CON(C1-4alkyl)2.

[0268] In some embodiments, R7is C1.4 alkyl optionally substituted with one or more independently selected halo, -OH, -CN, -CO2R9aor C1.4 alkoxy. In some embodiments, R7is C1-2alkyl optionally substituted with one or more independently selected halo, -OH, -CN, -CO2R9aor C1-4 alkoxy. In some embodiments, R7is C1-2 alkyl optionally substituted with one or more independently selected halo.

[0269] In some embodiments, R7is C1.4 alkyl. In some embodiments, R7is methyl. In some embodiments, R7is ethyl.

[0270] In some embodiments, R7is C1-4 alkoxy optionally substituted with one or more independently selected halo, -OH, -CN, -CO2R9a, C1.4 alkoxy, or C3-6 cycloalkyl. In some embodiments, R7is C1.4 alkoxy optionally substituted with C3-6 cycloalkyl. In some embodiments, R7is C1.4 alkoxy. In some embodiments, R7is C1-2alkoxy.

[0271] In some embodiments, R7is 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.

[0272] In some embodiments, R7is C3 cycloalkyl, which cycloalkyl is optionally substituted with one or more independently selected oxo, halo, -OH, -CN, C1-4 alkyl, or C1-4 alkoxy. In some embodiments, R7is C4 cycloalkyl, which cycloalkyl is optionally substituted with one or more independently selected oxo, halo, -OH, -CN, C1.4 alkyl, or C1.4 alkoxy. In some embodiments, R7is C5 cycloalkyl, which cycloalkyl 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 C2.4 alkynyl, optionally substituted with one or more independently selected halo, -OH, -CN, -CO2R9a, C1.4 alkoxy, and Q1. In some embodiments, R7is C2.4 alkynyl, optionally substituted with one or more independently selected -CN and Q1.

[0274] In some embodiments, R7is C2.4 alkynyl, optionally substituted with -CN.

[0275] In some embodiments, R7is C2.4 alkynyl, optionally substituted with Q1. In some embodiments, R7is C2alkynyl, optionally substituted with Q1. In some embodiments, R7is C2alkynyl substituted with Q1.

[0276] 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.

[0277] In some embodiments, Q1is 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 independently selected halo, -OH, -CN, C1.4 alkyl, or C1.4 alkoxy.

[0278] 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 halo, -OH, -CN, C1-4 alkyl, or C1-4 alkoxy.

[0279] 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 C1.4 alkyl.

[0280] In some embodiments, Q1isH, optionally substituted with one or more C1.4 alkyl.

[0281] In some embodiments, Q1is H 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.

[0282] In some embodiments, Q1is I

[0283] In some embodiments, R7is Q2.

[0284] 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 independently selected halo, -OH, -CN, C1.4 alkyl, or C1.4 alkoxy.

[0285] In some embodiments, Q2is 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 independently selected halo, -OH, -CN, C1.4 alkyl, or C1.4 alkoxy.

[0286] 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 independently selected halo, -OH, -CN, C1-4 alkyl, or C1-4 alkoxy.

[0287] 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.

[0288] In some embodiments, Q2is selected from:Hand, wherein Q2is optionally substituted with one or more independently selected halo, -OH, -CN, C1-4 alkyl, or C1-4 alkoxy.

[0289] In some embodiments, Q2isH, optionally substituted with one or more independently selected halo, -OH, -CN, C1-4 alkyl, or C1-4 alkoxy.

[0290] In some embodiments, Q2is selected from:and H, wherein Q2is optionally substituted with one or more independently selected halo, -OH, -CN, C1-4 alkyl, or C1-4 alkoxy.

[0291] In some embodiments, Q2isOI2NN, and

[0293] In some embodiments, R7is selected from:

[0294] In some embodiments, R8ais hydrogen. In some embodiments, R8ais C1-4 alkyl. In some embodiments, R8ais methyl. In some embodiments, R8ais ethyl.

[0295] 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.

[0296] 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.

[0297] In some embodiments, R1and one R2together with the atoms onto which they are attached form

[0298] In one embodiment, R5is 5-10 membered monocyclic or bicyclic heteroaryl comprising one, two or three heteroatoms independently selected from N, O, and S. In another embodiment, R5is 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, R5is 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,

[0299] In one embodiment, R5is 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, R5is 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, 1,2, 3, 4-tetrahydro- 1,5 -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, R5is 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, R5is 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.

[0300] In one embodiment, R5is 5-6 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S. In another embodiment, R5is pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, dioxanyl, or piperazinyl. In another embodiment, R5is piperidinyl or | NH I— / morpholinyl. In another embodiment, R5is’ ' - / or ‘ \.

[0301] In one embodiment, R5is 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, R5is 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, R5is 5-6 membered monocyclic 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 R7. In another embodiment, R5is 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, R5is piperidinyl, piperazinyl, or morpholinyl, each of which is substituted with one, two, or three independently selected R7. In another embodiment, R5is

[0302] In one embodiment, R5is 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.

[0303] In one embodiment, R5is 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 C1.4 alkyl. In another embodiment, R8aand R8bare both H. In another embodiment, one of R8aand R8bis H, and the other is C1.4 alkyl. 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.

[0304] In one embodiment, R5is 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.

[0305] In one embodiment, R5is 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 R7isCi-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 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 -CH3or -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.

[0306] In one embodiment, R5is 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.

[0307] In one embodiment, R5is 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-CH3or -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.

[0308] In one embodiment, R5is 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.

[0309] In one embodiment, R5is 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. In another embodiment,

[0310] In one embodiment, a compound of the invention is provided in a natural isotopic form.

[0311] 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 form which 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.

[0312] 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.

[0313] 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.

[0314] In one aspect a compound of the invention according to any one of the embodiments herein described is present as the free base.

[0315] 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.

[0316] In one aspect a compound of the invention according to any one of the embodiments herein described is a solvate of the compound.

[0317] 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.

[0318] 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.

[0319] 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 presentinvention is intended to include all combinations of variables from any of the disclosed embodiments within its scope.

[0320] 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.

[0321] 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.

[0322] 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, or delayed 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.

[0323] A further aspect of the invention concerns 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;R*N\O..0 N o RZV'S'VY is independently selected from' *, ' * and ' •;Ryand Rzare each independently hydrogen or C1-3 alkyl;R1is C1-6 alkyl, C1-3 alkoxy(C1-3)alkyl, C1-3 alkyl(C1-3)alkoxy, -N(CI-3 alkyl)2 or 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 C1-6 alkyl, which alkyl is optionally substituted with halo, OH, Ci-4 alkoxy, O-cyclopropyl, CN, C1.4 haloalkoxy;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;B is 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;each R4is independently selected from halo or C1-4 alkoxy;Xi, X2, and X3 are each independently selected from N and CH;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=CHCC>2R9a, C1-4 alkoxy, C1-4 haloalkoxy or oxetane;R5is halo, -OR10, C 6-10 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, which aryl, heteroaryl, and heterocycloalkyl groups are optionally substituted with one or more independently selected R7;q is 0, 1, 2, 3, or 4;each R6is independently selected from halo, or C1-6 alkyl;each R7is independently selected fromoxo,-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)2CI.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, -CO2R9a, Ci-4 alkoxy, or C3-6 cycloalkyl,C2-4 alkynyl optionally substituted with one or more independently selected halo, -OH, -CN, -CO2R9a, C1.4 alkoxy, and Q1,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 Q2;Q1and Q2are each independently 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; 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; andR10is hydrogen or C1-6 alkyl;or a pharmaceutically acceptable salt and / or solvate thereof.

[0324] In some embodiments, R1is C1-3 alkyl, C1-3 alkoxy(C1-3)alkyl, C1-3 alkyl(C1-3)alkoxy, -N(C1-3alkyl)2or hydroxy(Ci-3)alkyl, wherein said alkyl and alkoxy groups are optionally substituted with one or more halogen.

[0325] In some embodiments, R1is C1-3 alkyl, C1-3 alkoxy(C1-3)alkyl, C1-3 alkyl(C1-3)alkoxy, or hydroxy(Ci-3)alkyl, wherein said alkyl and alkoxy groups are optionally substituted with one or more halogen.

[0326] In some embodiments, R1is C1-3 alkyl, C1-3 alkoxy(Ci-3)alkyl, or C1-3 alkyl(Ci-3)alkoxy, wherein said alkyl and alkoxy groups are optionally substituted with one or more halogen.

[0327] In some embodiments, R1is C1.3 alkoxy(Ci.3)alkyl or C1.3 alkyl(Ci.3)alkoxy, wherein said alkyl and alkoxy groups are optionally substituted with one or more halogen. In some embodiments, R1is C1.3 alkoxy(Ci.3)alkyl or C1.3 alkyl(Ci.3)alkoxy, wherein said alkyl and alkoxy groups are optionally substituted with one or more fluoro.

[0329] In some embodiments,

[0330] In some embodiments,

[0331] In some embodiments,

[0332] In some embodiments,D

[0333] In some embodiments,r%2

[0334] In some embodiments,

[0335] In some embodiments, ^2R1

[0338] In some embodiments,R1

[0339] In some embodiments,R1

[0340] In some embodiments,R1

[0341] In some embodiments,R1

[0342] In some embodiments,R1

[0343] In some embodiments,R1

[0344] In some embodiments,R1

[0345] In some embodiments,R1

[0346] In some embodiments,

[0347] In some embodiments,R1

[0348] In some embodiments,R1

[0349] In some embodiments,R1

[0350] In some embodiments.R1

[0351] In some embodiments,R1

[0352] In some embodiments,CHF2R1

[0353] In some embodiments,R1

[0361] In some embodiments,R1

[0362] In some embodiments,F2HC R1

[0363] In some embodiments,F2HC R1

[0364] In some embodiments,CR1

[0365] In some embodiments,R1

[0366] In some embodiments,F2HC R1

[0367] In some embodiments,

[0368] In some embodiments,

[0369] In some embodiments,

[0370] In some embodiments,

[0371] In certain embodiments, the compound of Formula (I) is a compound according to Formula (X) or (XX):Q1(XIX)(XX)wherein Q1is a 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

[0372] 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

[0373] 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.

[0374] In one embodiment, the present invention provides pharmaceutical compositions comprising a compound of the invention and another therapeutic agent.

[0375] 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.

[0376] 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, Sézary 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

[0377] 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).

[0378] 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.

[0379] 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 pharmaceutical excipient, 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.

[0380] 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 corn 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.

[0381] 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.

[0382] 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.

[0383] 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.

[0384] 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.

[0385] 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).

[0386] 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

[0387] 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

[0388] 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 filled into 250 mg capsules (125 mg of active compound of the invention according to Formula I per capsule).Formulation 3 - Liquid

[0389] 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 sodiumcarboxymethyl 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

[0390] 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

[0391] 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

[0392] 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

[0393] In one embodiment, the present invention provides compounds of the invention, or pharmaceutical compositions comprising a compound of the invention, for use in medicine.

[0394] 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.

[0395] 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.

[0396] 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 proliferativediseases refers to cancer, myeloproliferative disorders, leukemia, multiple myeloma, psoriasis, restenosis, scleroderma or fibrosis. More particularly, the term refers to cancer, leukemia, and multiple myeloma.

[0397] 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, 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, Sézary 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.

[0398] 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 medicamentfor 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, 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, Sézary 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.

[0399] 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, prostatecancer, 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, Sézary 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.

[0400] 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).

[0401] 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 theblood and blood forming organs. More particularly, the term refers to acute myeloid leukemia (AML), and acute lymphoblastic leukemia (ALL) and chronic lymphoblastic leukemia (CLL).

[0402] 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).

[0403] 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.

[0404] 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.

[0405] 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.

[0406] Transdermal doses are generally selected to provide similar or lower blood levels than are achieved using injection doses.

[0407] 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.

[0408] 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.

[0409] 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.

[0410] 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.

[0411] 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

[0412] 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.

[0413] 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).

[0414] 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.

[0415] 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 chromatographyis 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% NH₄OH 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 EtOH ethanol AcOH acetic acid h hour AcOK potassium acetate 1- [bis(dimethylamino)meth Boc tert-butyloxy-carbonylylene]-lH-l,2,3- di-tert-butyloxy-carbonateBOC2O HATE triazolo [4,5 -b]pyridinium (CAS# 24424-99-5)3-oxid n-ButyllithiumwBuLi hexafluorophosphate (CAS# 109-72-8)(CAS# 148893-10-1) Potassium tert-butoxide / BuOK high-performance liquid (CAS# 865-47-4) HPLCchromatography Benzyl JV-SuccinimidylCbz-OSu Int intermediate CarbonatePotassium cyanide Cpd compound KCN(CAS# 151-50-8) d doubletliquid chromatographyLCMS DCM dichloromethane mass spectrometry dd doublet of doublets m multiplet N, N- MeOH methanol DIPEA diisopropylethylaminemin minute (CAS# 7087-68-5)mmol millimole DMA N, A'-di m ethy lacetam i deMtd method DMF N, A'-dimcthylfonn amideMW molecular weight DMSO dimethylsulfoxidemolecular weight Diphenyl phosphoryl MW (calcd)dppa calculated azidemolecular weight 1,1'- MW (obsd)observed bis(diphenylphosphino)dppf Pd / C palladium on carbon ferrocene(CAS# 12150-46-8) [1,1'- bis(diphenylphosphino) dt doublet of tripletsPd(dppf)Cl2ferrocene] dichloropalladi eq- equivalentum(II) (CAS# 72287-26- EtOAc ethyl acetate4)Et2O diethyl etherAbbreviation Definition Abbreviation Definition[1,1'- 2.4.6-tripropyl- bis(diphenylphosphino) 1, 3, 5, 2,4,6- ferrocene] dichloropalladi T3P trioxatriphosphorinane- Pd(dppf)Cl2DCum(II) complex with 2.4.6-trioxyde Mdichloro (CAS# 68957-94-8) methane 4,5- (CAS# 95464-05-4) Bis(diphenylphosphino)- Xantphos Tris(dibenzylideneacetone 9,9-dimethylxanthene Pd2(dba)3)dipalladium(0) (CAS# 161265-03-8)(CAS# 51364-51-3) (2- bis(tri-o- Dicyclohexylphosphino- Pd(P(oTol)3)2tolylphosphine)palladium 2',4',6'-triisopropyl-l,l'- (CAS# 69861-71-8) biphenyl)[2-(2'-amino- XPhos Pd G3q quartet 1,1'- biphenyl)]palladium(II) RT room temperaturemethanesulfonate s singlet(CAS# 1445085-55-1) sat. saturated (SP-4-3)- t triplet [Dicyclohexyl[2',4',6'- td triplet of doublets tris( 1 -methylethyl) [1,1'- biphenyl]-2- TEA triethylamineyl]phosphine](methanesul TFA trifluoroacetic acid XPhos Pd G4fonato-K(9)[2'- THF tetrahydrofuran (methylamino-KN) [ 1, 1 '-biphenyl] -2 -yl- KC]palladium (CAS# 1599466-81-5)SYNTHETIC PREPARATION OF THE COMPOUNDS OF THE INVENTIONExample 1. General synthetic methods1.1. Synthetic methods overviewGeneral method A: Curtius RearrangementGeneral method B: Suzuki couplingGeneral method D: iodination of pyridineGeneral method E: Heck reactionGeneral method F: Cyclization to 2-oxo-lH-l,6-naphthyridineGeneral method G: One pot Chlorination / BuchwaldGeneral method Hl: N-Boc deprotection with HC1General method H2: N-Boc deprotection with TFAGeneral method II: Peptide coupling with HATUGeneral method 12: Peptide coupling with T3PGeneral method J: Sonogashira cross couplingGeneral method K: Buchwald coupling from Cl-naphthyridineGeneral method L: Nucleophilic substitutionGeneral method M: Reduction with TriethylsilaneGeneral method N: OxidationGeneral method O: CarbonylationGeneral method P: Oxidation of sulfide to sulfoneGeneral method Q: Tert-butyl ester hydrolysis1.2. General methods1.2.1. General method A: Curtius RearrangementHO2C-R ——————► BocHN-R

[0416] TEA or DIPEA (1.5 to 2.5 eq.) is added to a solution of acid (1.0 eq.) and DPPA (1.2 to 1.5 eq.) in DCM and the reaction mixture is stirred at RT for 2 h. Then, the reaction mixture is evaporated to dryness. After dilution of the residue with toluene, the mixture is washed with water, brine, dried over Na2SO4, filtered and the solution is used as it or evaporated till dryness. The corresponding solution is stirred at 120 °C for 2 h, then / BuOH is added or the previous crude is dissolved in / BuOH and the reaction mixture is stirred at 90 to 120 °C for 5 to 72 h. The reaction mixture is cooled to RT, water is added, and the aqueouslayer is extracted with EtOAc (3x). The combined organic layers are washed with NaHCO3 saturated aqueous solution, NH4CI saturated aqueous solution, brine, dried over MgSO4, filtered and evaporated to dryness. The residue is purified by column chromatography on silica gel to afford the desired compound.1.2.1.1. Illustrative synthesis of Int-22Int-21 Int-22

[0417] DIPEA (336 pL, 1.93 mmol, 2.5 eq.) was added to a solution of Int-21 (290 mg, 0.77 mmol, 1.0 eq.) and DPPA (199 pL, 0.92 mmol, 1.2 eq.) in DCM (7.7 mL) and the reaction mixture was stirred for 2 h at RT. The volatiles were evaporated to dryness. The residue was dissolved in ‘BuOH (7.3 mL, 100.0 eq.) and the reaction mixture was stirred at 90 °C for 72 h. The reaction mixture was cooled to RT, H2O was added and the aqueous layer was extracted with EtOAc (3x). The combined organic layers were 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 50 / 50) to afford Int-22.1.2.2. General method B: Suzuki Coupling

[0418] To a stirred solution of chloro or bromo derivated (1.0 eq.) and boronic acid or ester derivative (1.3 eq.) in 1,4-dioxane is added K3PO4 (2.0 eq.) and water. The mixture is degassed either with argon or nitrogen for 5 min. PdCl2(dppf). DCM (0.1 eq.) is added and the reaction is stirred at 90 °C for 2 to 4 h. The reaction mixture is either filtered over a pad of celite® or diluted into DCM / H2O and filtered via hydrophobic frit. The solvent is evaporated, and the residue was purified by column chromatography on silica gel then if necessary, by preparative HPLC.Alternatively, after the end of reaction, SiliaMetS thiol silica (Silicycle, 40-63 pm) is added and stirred 1 to 18 h at RT then is filtered over a pad of celite® and evaporated to dryness. The residue is purified by column chromatography on silica gel then if necessary, by preparative HPLC.1.2.2.1. Illustrative synthesis of cpd-19Cpd 16 Cpd-19

[0419] A mixture of Cpd-16 (50.0 mg, 0.11 mmol, 1.0 eq.), 1H-indole,1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) (CAS# 898289-06-0; 75.3 mg, 0.15 mmol, 1.3 eq.), K3PO4 (47.8 mg, 0.23 mmol, 2.0 eq.) and PdC12(dppf). DCM (9.22 mg, 0.011 mmol, 0.1 eq.) was purged under nitrogen. Then 1,4-Dioxane (0.96 mL) and H2O (91.3 pL) were added. The reaction mixture was degassed by bubbling nitrogen for 5 min then the reaction mixture was stirred at 90 °C for 2 h. 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 celite® and then the solvent was evaporated to dryness. The residue was purified by column chromatography on silica gel (eluting with Heptane / EtOAc from 100 / 0 to 0 / 100) then by preparative HPLC. The residue was taken-up with Heptane (3.0 mL), filtered and dried to afford Cpd-19.1.2.2.2. Illustrative synthesis ofInt-46

[0420] A mixture of tert-butyl 6-bromo-2H,3H,4H-pyrido[3,2-b][l,4]oxazine-4-carboxylate (CAS# 959992-64-4; 400 mg, 1.27 mmol, 1.0 eq.), 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (CAS# 1020174-04-2; 343.3 mg, 1.65 mmol, 1.3 eq.), K3PO4 (538.8 mg, 2.54 mmol, 2.0 eq.) and PdC12(dppf). DCM (103.9 mg, 0.13 mmol, 0.1 eq.) was purged under nitrogen. 1,4-dioxane (10.8 mL) and H2O (1.0 mL) were added and the reaction mixture was degassed by bubbling nitrogen for 5 min then was stirred at 90 °C for 2 h. After cooling to RT, water and DCM were added to the reaction mixture. The organic layer was separated via hydrophobic frit and evaporated to dryness. The residue was purified by column chromatography on silica gel (eluting with Heptane / EtOAc from 80 / 20 to 0 / 100) to afford Int-46.1.2.3. General method C: Iodination of pyridine

[0421] NIS (1.1 eq.) is added to a solution of 4-amino-pyridine (1.0 eq.) in anhydrous ACN and the reaction mixture is stirred at RT for 3 to 72 h, then water or sodium thiosulfate saturated aqueous solution is added and the aqueous layer is extracted with EtOAc (3x). The combined organic layers are combined, washed with water, brine and dried over MgSCL, filtered and evaporated to dryness to afford the desired compound.1.2.3.1 Illustrative synthesis of Int-32oInt-32

[0422] NIS (920 mg, 4.01 mmol, 1.2 eq.) was added to a stirred suspension of Int-31 (1.0 g, 3.34 mmol, 1.0 eq.) in ACN (17.0 mL) and the reaction mixture was stirred at RT for 72 h. The solvent was evaporated, the residue was dissolved in sodium thiosulfate saturated aqueous solution and extracted with EtOAc. The organic layer was washed with water and brine, dried over MgSCE then was fdtered. The solvent was evaporated to dryness to afford Int-32.1.2.4. General method D: Heck reaction with Ethyl prop-2-enoate

[0423] Ethyl prop-2 -enoate (CAS# 140-88-5; 2.0 eq.), Pd(P(oTol)3)2 (0.05 eq.) and TEA (1.5 eq.) are added to a solution of iodo-pyridine (1.0 eq.) in anhydrous DMF and the reaction mixture is stirred at 90 to 100 °C for 1 to 3 h, then the mixture is cooled to RT, diluted with H2O (50.0 mL) and extracted with EtOAc. The organic layers are combined, dried and evaporated to dryness to afford the desired compound directly used in the next step.1.2.4.1. Illustrative synthesis ofInt-33Int-32

[0424] Ethyl prop-2-enoate (1.0 mL, 9.4 mmol, 2.0 eq.), Pd(P(oTol)3)2 (170 mg, 0.24 mmol, 0.05 eq.) and EtsN (0.98 ml, 7.1 mmol, 1.5 eq.) were added to a solution of Int-32 (2.0 g, 4.7 mmol, 1.0 eq.) in DMF (14.0 mL) and the reaction mixture was stirred at 90 °C for 1 h. The reaction mixture was cooled to RT, water added, the precipitate was fdtered off, washed with water and dissolved in EtOAc. The organic layer was dried over Na2SO4 and was fdtered then the solvent was evaporated to dryness to afford Int-33.1.2.5. General method E: Peptidic coupling with acyl chlorideR25AC| + R1 R1H2N' - - R2NH

[0425] A solution of acyl chloride (1.2 eq.) in anhydrous DCM is added to a solution of amine and TEA (5.0 to 10.0 eq.) in anhydrous DCM (5.0 mL) and the reaction mixture is stirred at RT for 5 to 30 min.Water is added and the aqueous layer was extracted with EtOAc. The Organic layer is washed with NaHCOs, brine, dried over Na2SO4 then filtered and the solvent is evaporated to dryness. The residue is purified by preparative HPLC to afford the desired compound.1.2.5.1. Illustrative synthesis of Cpd-5CONH2Cpd-5

[0426] A solution of 4-methyl-3-methylsulfonyl-benzoyl chloride (CAS# 1146702-14-8; 0.023 g, 0.10 mmol, 1.2 eq.) in anhydrous DCM (5.0 mL) was added to a solution of Int-17 (0.038 g, 0.085 mmol, 1.0 eq.) and TEA (0.059 mL, 0.428 mmol, 5.0 eq.) in anhydrous DCM (5.0 mL) and the reaction mixture was stirred at RT for 5 min. Water was added and the aqueous layer was extracted with EtOAc (3x). Organic layers were combined and washed with NaHCOs (2x), brine (lx), dried over Na2SO4 and evaporated to dryness. The residue was purified by preparative HPLC then the residue was triturated in ACN and filtered to afford Cpd-5.1.2.6. General method F: Cyclization to 2-oxo-lH-l,6-naphthyridine

[0427] NaSMe (2.5 eq.) is added to a solution of prop-2-enoate pyridine (1.0 eq.) in EtOH and the reaction mixture is stirred at 60 °C for 1 to 2 h, then the reaction mixture is cooled to RT and evaporated to dryness. The residue is purified by column chromatography on silica gel to afford the desired compound.1.2.6.1. Illustrative synthesis ofInt-34

[0428] NaSMe (845 mg, 11.4 mmol, 2.5 eq.) was added to a solution of Int-33 (1.82 g, 4.58 mmol, 1.0 eq.) in EtOH (23.0 mL) and the reaction mixture was stirred at 60 °C for 1 h. Celite® was added 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 90 / 10) to afford Int-34.1.2.7. General method G: One pot Chlorination / BuchwaldR2'N'R3H

[0429] CI3CCN (1.5 eq.) is added to a suspension of OH-naphtyridine (1.0 eq.) and PPI13 (3.0 eq.) in anhydrous toluene and the reaction mixture is stirred at 110 °C for 1 to 5 h, then XPhos Pd G4 (0.2 eq.) or Pd(OAc)2 (0.2 eq.) and XPhos (0.4 eq.), CS2CO3 (5.0 eq.) and the amine (2.0 eq.) are added and the reaction mixture is stirred at 110 °C for 48 h. The reaction mixture is cooled to RT, water is added, and the aqueous layer is extracted with EtOAc. The combined organic layers are washed with brine, dried over Na2SO4, filtered and evaporated to dryness. The residue is purified by column chromatography on silica gel to afford the desired compound.1.2.7.1. Illustrative synthesis oflnt-16Int-6

[0430] Cl₃CCN (0.039 mL, 0.39 mmol, 1.5 eq.) was added to a suspension of Int-6 (80.0 mg, 0.265 mmol, 1.0 eq.) and PPh₃ (0.20 g, 0.79 mmol, 3 eq.) in anhydrous toluene (2.0 mL) was stirred at 110 °C for 1 h. Pd(OAc)2 (11.0 mg, 0.053 mmol, 0.2 eq.), XPhos (51 mg, 0.10 mmol, 0.4 eq.), CS2CO3 (0.43 g, 1.32 mmol, 5.0 eq.) and 3,4-dihydro-2H-pyrido[3,2-b][l,4]oxazine-6-carbonitrile (CAS# 928118-39-2; 85 mg, 0.53 mmol, 2.0 eq.) were added and the reaction mixture was stirred at 110 °C for 48 h. H2O was added and the aqueous layer was extracted with EtOAc (3x). The combined organic layers were washed with brine, dried under 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 0 / 100) to afford Int-16.1.2.8. General method H: N-Boc deprotection with HClRXRBocHN' H2N. HCl

[0431] HCl (4 N) in 1,4-dioxane (10.0 to 40.0 eq.) is added to / V-Boc intermediate (1.0 eq.) neat or in solution in DCM and the reaction mixture is stirred at RT for 1 to 24 h, then the reaction mixture is evaporated to dryness to afford the desired compound. Alternatively, the free base can be obtained by dissolving the crude hydrochloride salt in EtOAc and treating it with NaHCO3 saturated aqueous solution. The organic layer is separated and evaporated in vacuum to afford the free amine.1.2.8.1. Illustrative synthesis ofInt-43Int-42 Int-43

[0432] HCl (4 N) in 1,4-dioxane (14.4 mL, 57.7 mmol, 40.0 eq.) was added Int-42 (381 mg, 1.44 mmol, 1.0 eq.) in DCM (5.5 mL) and the reaction mixture was stirred at RT for 24 h. The mixture was evaporated to dryness, the crude solid was dissolved in EtOAc and treated with NaHCO3 saturated aqueous solution. The organic layer was separated and evaporated to dryness to afford Int-43.1.2.9. General method H2: N-Boc deprotection with TFANHBoc „NH2R - ► R2

[0433] TFA (10.0 to 30.0 eq.) is added to A-Boc-aminc (1.0 eq.) in DCM and the reaction mixture is stirred at RT for 1 to 18 h. The reaction mixture is evaporated to dryness to afford the desired compound as trifluoroacetic acid salt. Alternatively, the free base can be obtained by adjusting the pH of the reaction mixture to 9 to 10, using Na2CO3powder or NaOH (5 N) aqueous solution. After extraction with DCM, the combined organic layers are washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude can be used as it or purified by column chromatography on silica gel to afford the desired compound.1.2.9.1. Illustrative synthesis ofInt-561.2.9.2. TFA (2.15 mL, 28.98 mmol, 30.0 eq.) was added to Int-55 (265 mg, 0.97 mmol, 1.0 eq.) in DCM (6.19 mL) and the reaction mixture was stirred at RT for 2 h. The solvent was evaporated to dryness to afford Int-56.Illustrative synthesis of lnt-64N-NInt-64

[0434] TFA (1.18 mL, 15.87 mmol, 30.0 eq.) was added to Int-63 (277 mg, 0.53 mmol, 1.0 eq.) in DCM (3.4 mL) and the reaction mixture was stirred at RT for 1 h. The solvent was evaporated to dryness then coevaporated with Heptane to afford Int-64 as tris(trifluoroacetic) salt. Illustrative synthesis of Int-31Int-30 Int-31

[0435] TFA (19.4 mL, 257 mmol, 30.0 eq.) was slowly added to Int-30 (3.42 g, 8.56 mmol, 1.0 eq.) in DCM (171.0 mL) at RT and the reaction mixture was stirred at 30 °C for 16 h. The reaction mixture was adjusted to pH = 10 at 0 °C, using NaOH (5.0 eq.) After extraction with DCM, the combined organic layers were washed with brine, dried over Na2SC>4, filtered and the solvent was evaporated to dryness to afford Int-31.1.2.9.4. Illustrative synthesis ofInt-64N-Nlnt-64

[0436] TFA (1.18 mL, 15.87 mmol, 30.0 eq.) was added to Int-63 (277 mg, 0.53 mmol, 1.0 eq.) in DCM (3.4 mL) and the reaction mixture was stirred at RT for 1 h. The solvent was evaporated to dryness then coevaporated with Heptane to afford lnt-64 as tris(trifluoroacetic) salt.1.2.9.5. Illustrative synthesis of Int-31Int-30 Int-31

[0437] TFA (19.4 mL, 257 mmol, 30.0 eq.) was slowly added to Int-30 (3.42 g, 8.56 mmol, 1.0 eq.) in DCM (171.0 mL) at RT and the reaction mixture was stirred at 30 °C for 16 h. The reaction mixture was adjusted to pH = 10 at 0 °C, using NaOH (5.0 eq.) After extraction with DCM, the combined organic layers were washed with brine, dried over Na2SO4, filtered and the solvent was evaporated to dryness to afford Int-31.

[0438] 1.2.10. General method II: Peptide coupling with HATUO OR1 jf JL R1H2N' + R2- * R2^N'RH

[0439] A mixture of amine (1.0 to 1.1 eq), acid (1.0 to 1.1 eq.), HATU (1.2 eq.) and DIPEA (5.0 eq.) in DCM is stirred at RT for 25 min to 1 h. NH4C1 (10 %) aqueous solution or water, DCM are added, the organic layer is separated, washed with water, HC1 (I N) aqueous solution and brine, dried, and evaporated to dryness. The residue is purified by column chromatography on silica gel or preparative HPLC to afford the desired compound.1.2.11. General method 12: Peptidic coupling with T3P0 flR^OH + H2N'R2- ► R^N'RH

[0440] To a solution of carboxylic acid (1.0 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 to 2 h. Water and DCM were added, the organic layer was separated with hydrophobic frit and evaporated to dryness. The crude is purified either by column chromatography on silica gel and / or if needed, by preparative HPLC to give the desired amide.1.2.11.1. Illustrative synthesis of lnt-52Int-10 Int-51 Int-52

[0441] A mixture of Int-10 (72 mg, 0.28 mmol, 1.1 eq.), Int-51 (93.03 mg, 0.26 mmol, 1.0 eq.), T3P (50%) in EtOAc (195.15 mg, 182.6 pL, 0.307 mmol, 1.2 eq.) and DIPEA (178.1 pL, 1.022 mmol, 4.0 eq.) in DCM (1.64 mL) was stirred at RT for 1 h. NH4C1 (10%) aqueous solution and DCM were added, the organic layer was separated via hydrophobic frit 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 93 / 7) to afford Int-52.1.2.11.2. Illustrative synthesis of Cpd-33N-N\

[0442] A mixture ofInt-64 (70 mg, 0.091 mmol, 1.1 eq.), 3-methanesulfonyl-4-methylbenzoic acid (CAS# 51522-22-6; 17.81 mg, 0.083 mmol, 1.0 eq.), T3P (50%) in EtOAc (63.48 mg, 59.38 pL, 0.1 mmol, 1.2 eq.) and DIPEA (72.4 pL, 0.42 mmol, 5.0 eq.) in DCM (532.8 pL) was stirred at RT for 1 h. NH4C1 (10%) aqueous solution 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 93 / 7). The residue was taken up with ACN (3.0 mL). The solid was filtered, washed with ACN (3.0 mL) and dried to afford Cpd-33.1.2.12. General method 13: Peptidic coupling with T4Po nR1\)H + H2N'R2- >• A'RH

[0443] To a solution of carboxylic acid (1.0 eq.), amine salt or free base (1.0 to 1.2 eq.) and DIEA (1 to 2 eq. ) in DMF is added T4P 1,3,5,2,4,6-Trioxatriphosphorinane, 2,4,6-tributyl-, 2,4,6-trioxide (50% in DMF) (3 eq.). The reaction mixture is stirred at RT for 16h. The crude is purified either by column chromatography on silica gel and / or if needed, by preparative HPLC to give the desired amide.1.2.12.1. Illustrative synthesis of Cpd-93Int-144 Int-97 Cpd-93To a solution of Int-144 (60 mg, 0.219 mmol) in DMF (5 mL) were added Int-97 (93 mg, 0.219 mmol), DIEA (283 mg, 2.190 mmol) and 1,3,5,2,4,6-Trioxatriphosphorinane, 2,4,6-tributyl-, 2,4,6-trioxide (50% in DMF) (473 mg, 0.657 mmol, 50% wt). The resulting mixture was stirred at rt for 16 h. The reaction mixture was purified by reverse phase column chromatography [column, 120 g Cis silica gel; mobile phase, 0~100% Acetonitrile in Water (10 mM NH4HCO3) in 60 min; flowrate, 40 mL / min; detector, UV 200 nm], then repurified by prep-HPLC [Column: Xselect CSH Prep C18 OBD Column, 30*150 mm, 5pm; Mobile Phase A: Water(0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient (B%): 32% B to 62% B in 10 min; Wave Length: 254nm / 220nm; RT(min): 6.42] to afford Cpd-93 (22.8 mg, 15.3%).1.2.13. General method 14: Peptidic coupling with EDCI

[0444] To a solution of carboxylic acid (1.0 eq.), amine salt or free base (1.0 to 1.2 eq.) and DMAP (3 to 4 eq) in DCM is added EDCI (2 eq.). The reaction mixture is stirred at RT for 1 to 16 h. After completion of reaction, the reaction mixture was quenched by addition of water. The aqueous layer was extracted with and organic solvent (DCM or EtOAc). The combined organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure The crude is purified either by column chromatography on silica gel and / or if needed, by preparative HPLC to give the desired amide.1.2.13.1. Illustrative synthesis of Cpd-94A mixture of (4R)-9-(cyclopropoxymethyl)-4-fhioro-5,5-dioxo-3,4-dihydro-2H-l,51ambda6-benzoxathiepine-7-carboxylic acid Int-145 (30 mg, 0.091 mmol) l-(2-{6-[2-(l-methylpyrazol-4-yl)ethynyl]-2H,3H-pyrido[3,2-b][l,4]oxazin-4-yl}-l,6-naphthyridin-7-yl)cyclopropan-l-amine (42 mg, 0.100 mmol) and DMAP (35 mg, 0.273 mmol) in DCM (1 mL) was stirred at 25°C,then added EDCI (28 mg, 0.182 mmol) at 0°C. After completion of reaction, the reaction mixture was quenched by addition of water. The aqueous layer was extracted with ethyl acetate. The combined organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give crude product which was further purified by column chromatography using 0% to 100% PE in ethyl acetate gradient to afford desired compound. The crude product (68 mg) was purified by prep-HPLC with the following conditions [Column: XBridge Prep OBD Cl 8 Column, 30*150 mm, 5pm; Mobile Phase A: Water ( 10 mmol / L NH4HCO3 ), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient (B%): 41% B to 71% B in 8 min; Wave Length: 254nm / 220nm nm; RTl(min): 7.1] to afford (4R)-9-(cyclopropoxymethyl)-4-fluoro-N-[l-(2-{6-[2-(l-methylpyrazol-4-yl)ethynyl]-2H,3H-pyrido[3,2-b][l,4]oxazin-4-yl}-l,6-naphthyridin-7-yl)cyclopropyl]-5,5-dioxo-3,4-dihydro-2H-l,51ambda6-benzoxathiepine-7-carboxamide Cpd-34 (22.4 mg, 33% yield, 99.9% purity).1.2.14. General method J: Sonogashira cross coupling(Het)Ar- (Het)Ar-BrHetAr HetAr

[0445] To a stirred solution of bromo derivated (1.0 eq.), alkyne (2.5 eq.) and TEA (3.0 eq.) in DMF (11.8 mL) was added Xphos Pd G3 (0.1 eq.) at RT. The reaction mixture was degassed with nitrogen for 5 minthen heated at 120 °C using a single mode microwave (Anton Paar) with a power output ranging from 0 to 850 W for 20 min. After cooling to RT, H2O and DCM were added to the reaction mixture. The organic layer was separated via hydrophobic frit and evaporated to dryness. The crude was purified by column chromatography on silica gel.1.2.14.1. Illustrative synthesis ofInt-62

[0446] To a mixture of 6-bromo-3,4-dihydro-2H-l,4-benzoxazine-4-carboxylate (CAS# 719310-31-3; 522 mg, 1.66 mmol, 1.0 eq.) 4-ethynyl-l -methyl- IH-pyrazole (CAS# 39806-89-8;440.82 mg, 4.15 mmol, 2.5 eq.) and TEA (504.39 mg, 0.69 mL, 4.98 mmol, 3.0 eq.) in DMF (7.7 mL) was added Xphos Pd G3 (140.47 mg, 0.17 mmol, 0.1 eq.) at RT. The reaction mixture was degassed with nitrogen for 5 min then stirred at 120 °C using one single mode microwave (Anton Paar) with a power output ranging from 0 to 850 W for 20 min. After cooling to RT, water and DCM were added to the reaction mixture. The organic layer was separated via hydrophobic frit and the solvent was evaporated to dryness. The residue was purified column chromatography on silica gel (eluting with Heptane / EtOAc from 100 / 0 to 0 / 100) to afford Int-62.

[0447] 1.2.15. General method J: N-Boc deprotection with TFAD„NHBOC _ NHK *" R2

[0448] TFA (10.0 to 30.0 eq.) is added to N-Boc-amine (1.0 eq.) in DCM and the reaction mixture is stirred at RT for 1 to 18 h. The reaction mixture is evaporated to dryness to afford the desired compound as trifluoroacetic acid salt. Alternatively, the free base can be obtained by adjusting the pH of the reaction mixture to 9 to 10, using Na2CO3powder or NaOH (5 N) aqueous solution. After extraction with DCM, the combined organic layers are washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude can be used as it or purified by column chromatography on silica gel to afford the desired compound.1.2.15.1. Illustrative synthesis of Int-56lnt-55 int-56

[0449] TFA (2.15 mL, 28.98 mmol, 30.0 eq.) was added to Int-55 (265 mg, 0.97 mmol, 1.0 eq.) in DCM (6.19 mL) and the reaction mixture was stirred at RT for 2 h. The solvent was evaporated to dryness to afford Int-56.1.2.16. General method K: Buchwald from Cl-naphtyridine

[0450] A vial is charged with Cl-naphtyridine (1.0 eq.), amine free base or salt (1.1 eq.), CS2CO3 (3.0 to 5.0 eq.) and XPhos Pd G4 (0.1 eq.) or Xantphos (0.2 eq.) and Pd₂(dba)₃ (0.1 eq.) or XPhos (0.4 eq.) and Pd(OAc)2 (0.2 eq.). The vial is capped then evacuated and backfilled with nitrogen (3x). 1,4-dioxane is added. The resulting mixture is degassed by bubbling nitrogen for 5 min and stirred at 80 to 90 °C for 1 h to 18 h. The reaction mixture is either directly filtered on a pad of celite® or SiliaMetS thiol silica (Silicycle, 40-63 pm) is added and this mixture is stirred for 1 to 16 h at RT then filtered on celite®. The filtrate is either evaporated to dryness or water and EtOAc are added to the reaction mixture and the layers are separated. The aqueous layer is extracted with EtOAc. The combined organic layers are washed with brine, dried over MgSO4, filtered and the solvent was 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. 1.2.16.1. Illustrative synthesis of Int-63

[0451] A vial was charged with Int-9 (240 mg, 0.75 mmol, 1.0 eq.), Int-13 (483.3 mg, 0.83 mmol, 1.1 eq.), CS2C03 (1.22 g, 3.75 mmol, 5.0 eq.) and XPhos Pd G4 (64.58 mg, 0.075 mmol, 0.1 eq.). The vial was capped then evacuated and backfilled with nitrogen (3x). 1,4-dioxane (6.40 mL) was added to the vial through the septum. The resulting mixture was degassed by bubbling nitrogen for 5 min and heated at 90 °C for 2 hours. SiliaMetS thiol silica (Silicycle, 40-63 pm) (500 mg) was added. The resulting suspension was stirred at RT for 2 h and the mixture was filtered over Celite® and the filtrate was evaporated to dryness. The residue was purified by column chromatography on silica gel (eluting with DCM / MeOH from 100 / 0 to 93 / 7) to afford Int-63.1.2.17. General method L: Nucleophilic substitutionc.x■'R1g-Na”R2R1R2^

[0452] To a mixture of aryl fluoride (1.0 eq.) in ACN or DMF is added sodium methylsulfanide (2.0 eq.) or sodium ethylsulfanide (1.5 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.1.2.17.1. Illustrative synthesis Int-48CAS# 1242157-14-7 Int-48

[0453] 5-bromo-7-fhioro-2,3-dihydro-lH-inden-l-one (CAS# 1242157-14-7; 1.0 g, 4.37 mmol, 1.0 eq.) was dissolved in DMF (15.0 mL) and MeSNa (0.61 g, 8.73 mmol, 2.0 eq.) was added, and the reaction mixture was stirred at RT for 24 h. The reaction system was diluted with H2O, extracted with EtOAc (2x) and the organic layers were combined, washed with brine (lx), 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 50 / 50) to afford Int-48.1.2.17.2. Illustrative synthesis Int-57

[0454] 5 -bromo-7-fluoro-2,3-dihydro-lH-inden-l-one (2.0 g, 8.73 mmol, 1.0 eq.) was dissolved in DMF (30.0 mL) and sodium ethylsulfanide (1.102 g, 13.098 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 with EtOAc (2x25 mL) and the organic phases were combined, washed with brine (lx), 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-57.1.2.18. General method M: Reduction with Triethylsilane

[0455] To a solution ofketone (1.0 eq.) in TFA was added triethylsilane (5.0 eq.). The reaction was stirred at RT for 18 h then the reaction was concentrated. The residue was taken up into EtOAc and H2O. Theorganic layer was washed with NaHCO3then brine and was dried over MgSO4and filtered. The solvent was evaporated to dryness and the residue was purified by column chromatography on silica gel to afford desired compound.1.2.18.1. Illustrative synthesis of Int-49Int-48 Int-49

[0456] Int-48 (280 mg, 1.089 mmol, 1.0 eq.) was dissolved in TFA (7.68 mL) then triethylsilane (CAS# 617-86-7; 633.06 mg, 0.88 mL, 5.44 mmol, 5.0 eq.) was added. The reaction mixture was stirred at RT for 18 h then the solvent was evaporated to dryness. EtOAc (30 mL) and water (30 mL) were added. The organic layer was decanted, washed once with NaHCOs sat. aqueous solution then brine, 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 70 / 30) to afford Int-49.1.2.18.2. Illustrative synthesis of Int-58Int-57 Int-58

[0457] Int-57 (1.43 g, 5.27 mmol, 1.0 eq.) was dissolved in TFA (37.2 mL) and triethylsilane (3.07 g, 4.26 mL, 26.37 mmol, 5.0 eq.) was added. The reaction mixture was stirred at RT for 18 h. The reaction mixture was concentrated. EtOAc (50 mL) and H2O (30 mL) were added. The organic layer was washed with NaHCO3 saturated aqueous solution (1x10 mL) then brine, dried over MgSO4, filtered, and was evaporated to dryness. The residue was purified by column chromatography (eluting with Heptane / EtOAc from 100 / 0 to 70 / 30) to afford Int-58.1.2.19. General method N: OxydationRO’ KCR2+O=S=O

[0458] To a mixture of aryl alkylsulfanyl (1.0 eq.) in ACN and water is added oxone® monopersulfate (CAS# 70693-62-8; 3.0 eq.). The reaction mixture is stirred at RT or 60 °C for 1 h to 18 h, then is concentrated, diluted into H2O and EtOAc. The aqueous layer is extracted with EtOAc and the organic layers are combined, washed once with H2O, brine (lx) and the solvent is evaporated to dryness to afford a desired compound.1.2.19.1. Illustrative synthesis of lnt-50O’o=s=o>K+Int-49 Int-50

[0459] Int-49 (401 mg, 1.105 mmol, 1.0 eq.) dissolved in ACN (10.8 mL) and water (10.75 mL), and oxone® monopersulfate (CAS# 70693-62-8; 2.018 g, 3.31 mmol, 3.0 eq.) was added. The reaction system was stirred at RT for 18 h. After the reaction was completed, it was concentrated, diluted with EtOAc and water and the aqueous layer was extracted once with EtOAc. The organic layers were combined, washed once with water and once with brine, dried over MgSO4, filtered, and the solvent was evaporated to dryness to afford Int-50.1.2.19.2. Illustrative synthesis of Int-59int-58

[0460] Int-58 (1.9 g, 5.25 mmol, 1.0 eq.) was dissolved in ACN (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, and solid precipitated. The reaction system was stirred at RT for 18 h. The reaction mixture was concentrated, diluted with EtOAc (30 mL) and H2O (30 mL). The aqueous layer was extracted with EtOAc (1x30 mL). The organic layers were combined, washed with H2O (lx), brine (lx), dried over MgSO4 and filtered then the solvent was evaporated to dryness to afford Int-59.1.2.20. General method O: CarbonylationR1-Br - ► R1-COOH

[0461] 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)Cl2.DCM (0.1 eq.). The sealed bomb is filled with CO (5 bar). The mixture is heated at 120 °C for 18 h. HC1 (1 M) aqueous solution is added and the mixture was extracted with EtOAc (3x). The combined organic layers are washed with brine, dried over MgSO4, filtered and the solvent is evaporated to dryness to afford the desired carboxylic acid.1.2.20.1. Illustrative synthesis oflnt-51lnt-50 lnt-51

[0462] Nitrogen was bubbled through a suspension of Int-50 (326 mg, 1.102 mmol, 1.0 eq.) and K2CO3 (456.84 mg, 3.305 mmol, 3.0 eq.) in DMSO (10.95 mL) and H2O (0.4 mL) for 10 min then Pd(OAc)2 (24.74 mg, 0.11 mmol, 0.1 eq.), l,3-bis(diphenylphosphino)propane (CAS# 6737-42-4; 45.5 mg, 0.11 mmol, 0.1 eq.) were added. The autoclave was purged with nitrogen then with CO (3x). The autoclave was pressurized with CO (5 bars) and heated at 110 °C overnight. The reaction mixture was cooled down to RT. The reaction mixture was filtered on celite®, washed with H2O twice. The filtrate was extracted once with EtOAc. The aqueous layer was adjusted to pH = 3 with HCl (1 M) aqueous solution, extracted three times with DCM / MeOH (10 / 1), the organic layers were combined, and the solvent was evaporated to dryness to afford Int-511.2.20.2. Illustrative synthesis of Int-60Int-59 Int-60

[0463] Nitrogen was bubbled through a suspension of Int-59 (1.5 g, 4.15 mmol, 1.0 eq.) and K2CO3 (1.72 g, 12.45 mmol, 3.0 eq.) in DMSO (35.4 mL) and H2O (1.5 mL) for 10 min then Pd(OAc)2 (0.093 g, 0.41 mmol, 0.1 eq.) and l,3-bis(diphenylphosphino)propane (CAS# 6737-42-4; 0.17 g, 0.41 mmol, 0.1 eq.) were added, the autoclave was purged with nitrogen then with CO (x3). The autoclave was pressurized with CO (5 bars) and heated at 110 °C for 18 h. The reaction mixture was cooled down to RT. The reaction mixture was filtered over Celite® and Celite® was washed with H2O (2x). The filtrate was extracted with EtOAc (lx). The aqueous layer was adjusted to pH = 2 with HC1 (3 M) aqueous solution, extracted three times with a mixture of DCM / MeOH (90 / 10). The organic layers were combined, washed with brine (3x), dried over MgSO4, filtered and the solvent was evaporated to dryness to afford Int-60.1.2.21. General method P: Oxidation of sulfide to sulfoneR"S'R' RR.

[0464] At 0 °C, ruthenium trichloride (CAS# 10049-08-8; 0.05 eq.) was added to a solution of sulfide (1 eq.), sodium periodate (CAS# 7790-28-5; 3.3 eq.) in DCE, CH3CN and water. The reaction mixture was stirred at rt for 2 h. The reaction was diluted with DCM. The salts were filtered over a pad of celite and the filtrate was washed with water three times. The organics layers were combined, dried over Na2SO4, filtered and the solvent was evaporated under vacuo to give sulfone.1.2.21.1. Illustrative synthesis of Int-114NalO4ClCAS# 7790-28-5 Int-114

[0465] At 0 °C, ruthenium trichloride (CAS# 10049-08-8; 0.05 eq., 6.93 mg, 33 pmol) was added to a solution of Int-113 (1 eq., 225 mg, 0.67 mmol), sodium periodate (CAS# 7790-28-5; 3.3 eq., 471.42 mg, 2.20 mmol) in DCE (1.23 mL), CH3CN (0.98 mL) and water (0.79 mL). The reaction mixture was stirred at rt for 2 h. The reaction was diluted with DCM. The salts were filtered over a pad of celite and the fdtrate was washed with water three times. The organics layers were combined, dried over Na2SO4, filtered and the solvent was evaporated under vacuo to give Int-114 (153 mg, 80%).1.2.22. General method Q: Tert-butyl ester hydrolysis with TFAOHCAS# 76-05-1

[0466] To a solution of tertbutylic ester (1 eq.) in DCM was added TFA (50 eq.). The reaction mixture was stirred at rt overnight. The reaction mixture was evaporated under vacuum to give the desired compound.1.2.22.1. Illustrative synthesis of Int-120Int-119 CAS# 76-05-1 Int-120

[0467] To a solution of Int-119 (1 eq., 100 mg, 0.28 mmol) in DCM (5.72 mL) was added TFA (50 eq., 1.03 mL, 13.87 mmol). The reaction mixture was stirred at rt overnight. The reaction mixture was evaporated under vacuum to give Int-120 (87 mg, 100%).

[0468] Example 2. Preparation of the compounds of the invention2.1. Cpd-22.1.1. Int-11OHCbzHNInt-11

[0469] HC1 (4 N) in 1,4-dioxane (2.65 mL, 10.6 mmol, 40.0 eq.) was added to Int-6 (80 mg, 0.265 mmol, 1.0 eq.) and the reaction mixture was stirred at RT for 2 h, then the reaction mixture was evaporated to dryness. The residue was suspended in THF (2.0 mL) and H2O (1.0 mL) then CbzOSu (CAS# 13139-17-8; 79 mg, 0.318 mmol, 1.2 eq.) and TEA (0.074 mL, 0.53 mmol, 2.0 eq.) were added and the reaction mixture was stirred at RT for 2 h. The reaction mixture was washed with NaHCCL saturated aqueous solution and extracted with EtOAc (2x). The organic layers were combined, dried over Na2SO4 and evaporated to dryness. The residue was purified by column chromatography on silica gel (eluting with DCM / MeOH from 100 / 0 to 90 / 10) to afford Int-11.2.1.2. Cpd-2Cpd-2

[0470] Int-11 (20.0 mg, 0.0596 mmol, 1.0 eq.) in POCI3 (0.27 mL, 2.98 mmol, 50.0 eq.) was stirred at 80 °C for 2 h then 1 drop of water was added to the reaction mixture. Thus, the reaction mixture was evaporated to dryness and dissolved in DCM (3.0 mL) and TEA (0.016 mL, 0.119 mmol, 2.0 eq.). 4-methyl-3-methylsulfonyl-benzoyl chloride (CAS# 1146702-14-8; 0.016 mL, 0.0715 mmol, 1.2 eq.) in DCM (1.00 mL) was added to the previous solution and the reaction mixture was stirred at RT for 10 min. H2O was added and the mixture was extracted with EtOAc (2x). The organic layers were combined, dried over MgSO4, evaporated to dryness and purified by preparative HPLC using acidic gradient to afford Cpd-2.2.2. Cpd-82.2.1. Int-7BocHNInt-6 Int-6 was already described for synthesis of Cpd-21

[0471] Cl3CCN (20.0 µL, 0.20 mmol, 1.5 eq.) was added to a suspension of Int-6 (40 mg, 0.13 mmol, 1.0 eq.) and PPh3(CAS# 603-35-0; 105 mg, 0.39 mmol, 3.0 eq.) in anhydrous toluene (2.5 mL) and the reaction mixture was stirred at 110 °C for 5 h, then XPhos Pd G4 (23.0 mg, 0.027 mmol, 0.2 eq.), CS2CO3 (216 mg, 0.66 mmol, 5.0 eq.) and 6-ethyl-3,4-dihydro-2H-pyrido[3,2-b][l,4]oxazine (CAS# 1018638-76- 0; 46.0 mg, 0.27 mmol, 2.0 eq.) were added and the reaction mixture was stirred at 110 °C for 48 h. The reaction mixture was cooled to RT, water was added, and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, 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 0 / 100) to afford Int-7.2.2.2. Int-8BocHN

[0472] HCl (4 N) in 1,4-dioxane (110 µL, 0.45 mmol, 10.0 eq.) was added to Int-7 (20.0 mg, 0.045 mmol, 1.0 eq.) and the reaction mixture was stirred at RT for 2 h, then the reaction mixture was evaporated to dryness to afford Int-8 as hydrochloride salt.2.2.3. Cpd-8Cpd-8

[0473] A solution of Int-8 (15.0 mg, 0.044 mmol, 1.0 eq.) and DIPEA (19.0 µL, 0.11 mmol, 5.0 eq.) in DCM (2.0 mL) was added to a stirred mixture of 4-methyl-3-(methylsulfonyl)benzoic acid (CAS# 51522- 22-6; 11.0 mg, 0.048 mmol, 1.1 eq.) and HATU (20.0 mg, 0.053 mmol, 1.2 eq.) in DCM (2.0 mL) at RT, then the reaction mixture was stirred for 45 min at RT. The mixture was diluted with DCM, washed with H2O, HC1 (1 N) aqueous solution and brine, dried over Na2SO4and evaporated to dryness. The residue was purified by preparative HPLC to afford Cpd-8.2.3. Cpd-15Cpd-16 Cpd-16 was already described as intermediate for synthesis of Cpd-21.

[0474] A mixture of Cpd-16 (50.0 mg, 0.11 mmol, 1.0 eq.), 6-ethyl-3,4-dihydro-2H-1,4-benzoxazine (CAS# 1018638-76-0; 20.2 mg, 0.12 mmol, 1.1 eq.), CS2CO3 (110 mg, 0.34 mmol, 3.0 eq.), Xantphos (13.0 mg, 0.023 mmol, 0.2 eq.) and Pd2(dba)3(10.3 mg, 0.011 mmol, 0.1 eq.) was purged with nitrogen (3x).1,4-Dioxane (1.4 mL) was added. The resulting mixture was degassed by bubbling nitrogen for 5 min and was stirred at 80 °C for 6 h. H2O then EtOAc were added and the layers were separated. The aqueous layer was extracted with EtOAc (2x). The combined organic layers were washed with brine, dried over MgSO4, filtered and the solvent was evaporated. The residue was purified by column chromatography on silica gel (eluting with Heptane / EtOAc from 50 / 50 to 0 / 100) to afford Cpd-15.2.4. Cpd-212.4.1. Int-1Int-1

[0475] TEA (0.086 mL, 0.61 mmol, 1.5 eq.) was added to a solution of 1 -(4-bromo-2-pyridyl)cyclopropanecarboxylic acid (100 mg, 0.41 mmol, 1.0 eq.) and dppa (CAS# 26386-88-9; 0.13 mL, 0.61 mmol, 1.5 eq.) in anhydrous DCM (5.0 mL) and the reaction mixture was stirred at RT for 2 h. Then, the reaction mixture was evaporated to dryness. After dilution of the residue with toluene, the mixture was washed with water, brine, dried over Na2SO4and filtered. The corresponding solution was stirred at 120 °C for 2 h, then, / BuOH (0.47 mL, 4.95 mmol, 12.0 eq.) was added and the reaction mixture was stirred at 120 °C for 16 h. The reaction mixture was cooled to RT, water was added, and the aqueous layer was extracted with EtOAc (3x). The combined organic layers were washed with NaHCO3 saturated aqueous solution, NH4CI saturated aqueous solution, brine, dried over MgSO4, 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-1.2.4.2. Int-2

[0476] Cs2CO3(5.87 g, 18 mmol, 4.0 eq.) was added to a solution of Int-1 (1.41 g, 4.50 mmol, 1.0 eq.), benzophenone imine (CAS# 1013-88-3; 1.13 mL, 6.75 mmol, 1.5 eq.), Pd2dba3(0.41 g, 0.45 mmol, 0.1 eq.) and BINAP (CAS# 98327-87-8; 0.561 g, 0.90 mmol, 0.2 eq.) in DME (45.0 mL) and the reaction mixture was stirred at 100 °C for 16 h. The reaction mixture was cooled down to RT, filtered, evaporated to dryness and purified by column chromatography on silica gel (eluting with Heptane / EtOAc from 100 / 0 to 0 / 100) to afford Int-2.2.4.3. Int-3

[0477] HC1 (1 N) aqueous solution (9.0 mL, 9.0 mmol, 2.0 eq.) was added to a solution of Int-2 (1.86 g, 4.50 mmol, 1.0 eq.) in THF (22.0 mL) and the reaction mixture was stirred at RT for 30 min. H2O (20 mL) and HC1 (I N) aqueous solution (5.0 mL) were added and the aqueous layer was extracted with Et2O (3 x). The aqueous layer was basified with NaOH (I N) aqueous solution to reach a pH = 12 and extracted with EtOAc (3x). The combined organic layers were dried with MgSO4, filtered and the solvent was evaporated to afford Int-3.2.4.4. Int-4NHBocHN2Int-3

[0478] NIS (0.91 g, 3.97 mmol, 1.1 eq.) was added to a solution of Int-3 (900 mg, 3.61 mmol, 1.0 eq.) in anhydrous ACN (15.0 mL) and the reaction mixture was stirred at RT for 3 h, then water was added and the aqueous layer was extracted with EtOAc (3x). The combined organic layers were combined, washed with H2O (2x), brine and dried over MgSO4, filtered and evaporated to dryness to afford Int-4 directly used in the next step.2.4.5. Int-5Int-4

[0479] Ethyl prop-2-enoate (CAS# 140-88-5; 0.78 mL, 7.20 mmol, 2.0 eq.), Pd(P(oTol)3)2(0.13 g, 0.18 mmol, 0.05 eq.) and TEA (0.5 mL, 5.40 mmol, 1.5 eq.) were added to a solution of Int-4 (1.35 g, 3.60 mmol, 1.0 eq.) in anhydrous DMF (25.0 mL) and the reaction mixture was stirred at 100 °C for 3 h, then the mixture was cooled to RT, diluted with water (50 mL) and extracted with EtOAc (2x). The organic layers were combined, dried over Na2SO4 and evaporated to dryness to afford Int-5 directly used in the next step.2.4.6. Int-6Olnt-5 lnt-6

[0480] NaSMe (0.664 g, 9.00 mmol, 2.5 eq.) was added to a solution of Int-5 (1.25 g, 3.60 mmol, 1.0 eq.) in EtOH (36.0 mL) and the reaction mixture was stirred at 60 °C for 2 h, then the reaction mixture was cooled to RT and evaporated to dryness. The residue was purified by column chromatography on silica gel (eluting with DCM / MeOH from 100 / 0 to 100 / 10) to afford Int-6.2.4.7. Int-9

[0481] Cl₃CCN (499 µL, 4.98 mmol, 1.5 eq.) was added to a suspension of Int-6 (1.0 g, 3.32 mmol, 1.0 eq.) and PPh₃ (2.61 g, 9.96 mmol, 3.0 eq.) in toluene (25.0 mL) and the reaction mixture was stirred at 110 °C for 4 h. The reaction mixture was cooled down to RT, filtered over celite®, washed with EtOAc and the filtrate was concentrated under vacuum. The residue was purified by column chromatography on silica gel (eluting with Heptane / EtOAc from 80 / 20 to 0 / 100) to afford Int-9.2.4.8. Int-10Int-9 Int-10

[0482] HC1 (4 N) in 1,4-dioxane (13.4 mL, 53.8 mmol, 40.0 eq.) was added to a solution of Int-9 (430 mg, 1.34 mmol, 1.0 eq.) in DCM (5.17 mL) and the reaction mixture was stirred at RT for 18 h, then the reaction mixture was evaporated to dryness to afford Int-10 as hydrochloride salt.2.4.9. Int-12CAS# 959992-64-4 CAS# 39806-89-8

[0483] To a stirred solution of tert-butyl 6-bromo-2H,3H,4H-pyrido[3,2-b][l,4]oxazine-4-carboxylate (CAS# 959992-64-4; 400 mg, 1.27 mmol, 1.0 eq.), 4-ethynyl-l -methyl- IH-pyrazole (CAS# 39806-89-8;337 mg, 3.17 mmol, 2.5 eq.) and TEA (0.53 mL, 3.81 mmol, 3.0 eq.) in DMF (11.8 mL) was added Xphos Pd G3 (107 mg, 0.13 mmol, 0.1 eq.) at RT. The reaction mixture was degassed with nitrogen for 5 min then heated at 120 °C using a single mode microwave (Anton Paar) with a power output ranging from 0 to 850 W for 20 min. After cooling to RT, H2O and DCM were added to the reaction mixture. The organic layer was separated via hydrophobic frit and evaporated to dryness. The crude was purified by column chromatography on silica gel (eluting with Heptane / EtOAc from 100 / 0 to 0 / 100) to afford Int-12.2.4.10. Int-15Int-15

[0484] Step i: HC1 (4 N in dioxane) (12.74 mL, 50.95 mmol, 40.0 eq.) was added to Int-12 (255 mg, 0.75 mmol, 0.59 eq.) in DCM (4.9 mL) and the reaction mixture was stirred at RT for 18 h. The mixture was evaporated to dryness to afford the crude as hydrochloric acid salt. The crude solid was dissolved in EtOAc and washed with aq. sat. NaHCOs then the organic layer was evaporated to dryness.

[0485] Step ii: On 200 mg of this residue in THF (4.15 mL) was added Potassium tertbutanolate (162.20 mg, 1.45 mmol, 2.0 eq.). The reaction mixture was stirred at RT for 18 hours. H2O and DCM were added to the mixture. The organic layer was separated via hydrophobic frit and evaporated to dryness. The residue was purified by normal column chromatography (eluting with DCM / MeOH from 100 / 0 to 95 / 5) to afford Int-15.2.4.11. Cpd-16lnt-10 Cpd-16

[0486] A mixture of In t- 10 (134 mg, 0.52 mmol, 1.1 eq.), 2,3-dihydro-5H-benzo[e][l,4]oxathiepine-8-carboxylic acid 1,1-dioxide (CAS# 2771132-16-0; 115 mg, 0.48 mmol, 1.0 eq.), HATU (217 mg, 0.57 mmol, 1.2 eq.) and DIPEA (414 pL, 2.38 mmol, 5.0 eq.) in DCM (3.7 mL) was stirred at RT for 1 h. NH4CI (10 %) aqueous solution 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 Heptane / EtOAc from 50 / 50 to 0 / 100) to afford Cpd-162.4.12. Cpd-21N-N \ Cpd-16 lnt-15

[0487] A mixture of Cpd-16 (50 mg, 0.11 mmol, 1.0 eq.), Int-15 (29.8 mg, 0.12 mmol, 1.1 eq.), Cs2CO3 (110 mg, 0.34 mmol, 3.0 eq.) and XPhos Pd G4 (9.69 mg, 0.011 mmol, 0.1 eq.) was purged with nitrogen (3 x). 1,4-Dioxane (0.96 mL) was added. The resulting mixture was degassed by bubbling nitrogen for 5 min and was stirred at 90 °C for 18 h. The reaction mixture was filtered on a short pad of celite® and evaporated to dryness. The residue was purified by column chromatography on silica gel (eluting with DCM / MeOH from 100 / 0 to 93 / 7) then by preparative HPLC to afford Cpd-21.2.5. Int-17

[0488] HC1 (4 N) in 1,4-dioxane (1.0 mL, 4.04 mmol, 40.0 eq.) was added to Int-16 (45.0 mg, 0.101 mmol, 1.0 eq.) and the reaction mixture was stirred at RT for 1 h. The reaction mixture was evaporated to dryness to afford Int-17 as hydrochloride salt.2.6. Int-212.6.1. Int-18CAS# 1578484-42-0 CAS# 20348-23-6

[0489] NaH (60 %) in mineral oil (57.0 mg, 2.26 mmol, 1.1 eq.) was added to a stirred solution of 3,4- dihydro-2H-pyrido[3,2-b][l,4]oxazine (CAS# 20348-23-6; 308 mg, 2.26 mmol, 1.1 eq.) in THF (15.0 mL) at 0 °C. The reaction mixture was warmed to RT and stirred for 15 min. Then, 7-bromo-2-chloro-l,6-naphthyridine (CAS# 1578484-42-0; 500 mg, 2.05 mmol, 1.0 eq.) was added and the reaction mixture was stirred for 4 h at RT, then the mixture was diluted with EtOAc, washed with water and brine and evaporated to dryness to afford Int-18.2.6.2. Int-19lnt-18 CAS#928664-98-6 Int-19

[0490] A solution of KF (609 mg, 10.5 mmol, 3.0 eq.) in water (6.3 mL) was added to a solution of Int-18 (1.2 g, 3.49 mmol, 1.0 eq.) and 4-isoxazoleboronic acid pinacol ester (CAS# 928664-98-6; 835 mg, 4.19 mmol, 1.2 eq.) in DMF (27.0 mL). The reaction mixture was sonicated and flushed with nitrogen for 5 min. Pd(dppf)C12 (269 mg, 0.35 mmol, 0.1 eq.) was added and the mixture was flushed with nitrogen. The reaction mixture was divided in two vials and each vial was stirred at 75 °C using one single mode microwave (biotage® initiator) with a power from 0 to 400 W for 45 min then heated at 130 °C for 10 h (without microwave). The reaction mixture was fdtered over celite®, diluted with brine and extracted with EtOAc (2x100 mL) and DCM (2x150 mL). The combined organic phases were dried over MgSCL and concentrated. The residue was purified by column chromatography on silica gel (eluting with Heptane / EtOAc from 100 / 0 to 50 / 50) to afford Int-19.2.6.3. Int-20Int-19 Int-20

[0491] A suspension of NaH (60%) in mineral oil (55.0 mg, 1.39 mmol, 2.1 eq.) in DMF (10.0 mL) was added to a solution Int-19 (200 mg, 0.66 mmol, 1.0 eq.) and 1,4-diiodobutane (CAS# 628-21-7; 87.0 pL, 0.66 mmol, 1.0 eq.) in DMF (10.0 mL) over 20 min at - 40 °C. Then, the reaction mixture was warmed to RT and stirred for 10 min. H2O and EtOAc were added, the layers were separated, and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4 and evaporated to dryness. The residue was purified by column chromatography on silica gel (eluting with Heptane / EtOAc from 100 / 0 to 65 / 35) to afford Int-20.2.6.4. Int-21

[0492] A solution of KOH (1.45 g, 25.9 mmol, 30.0 eq.) in water (8.0 mL) was added to a solution of Int-20 (463 mg, 1.30 mmol, 1.0 eq.) in EtOH (8.0 mL) at RT. The reaction mixture was stirred at 120 °C using one single mode microwave (biotage® initiator) with a power from 0 to 400 W and stirred for 3.5 h. Waterand EtOAc were added, and the layers were separated. The aqueous layer was acidified to pH = 4 and extracted with EtOAc / iPrOH (80 / 20) then DCM. The combined organic layers were washed with brine, dried over Na2SO4and evaporated to dryness to afford Int-21.2.7. Int-252.7.1. Int-24lnt-19

[0493] NaOH (17.0 g, 210 mmol, 52.0 eq.) was added to a solution lnt-19 (1.2 g, 4.0 mmol, 1.0 eq.), benzyl triethylammonium chloride (CAS# 56-37-1; 0.91 g, 4.0 mmol, 1.0 eq.), and 1,3 -dibromopropane (CAS# 109-64-8; 0.88 g, 0.44 mmol, 1.1 eq.) in THF (16.0 mL) and the reaction mixture was stirred at 50 °C for 1.5 h. H2O was added, the layers were separated, and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, 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 70 / 30) to afford Int-24.2.7.2. Int-25Int-25

[0494] A solution of KOH (2.55 g, 45.4 mmol, 30.0 eq.) in H2O (5.0 mL) was added to a solution of Int-24 (0.52 g, 1.51 mmol, 1.0 eq.) in EtOH (5.0 mL) and the reaction mixture was stirred at 90 °C for 16 h. The reaction mixture was acidified with HC1 (4 N) in 1,4-dioxane (12.0 mL, 50.0 mmol, 33.0 eq.) and evaporated to dryness. The residue was purified by preparative HPLC to afford Int-25.2.8. Int-302.8.1. Int-28CAS#2421135-16-0

[0495] MsCl (825 pl, 10.7 mmol, 1.1 eq.) was added to a solution of tert-butyl N- [2-(3 -hydroxy oxetan-3-yl)-4-pyridyl]carbamate (CAS# 2421135-16-0; 2.58 g, 9.69 mmol, 1.0 eq.) and TEA (2.70 ml, 19.4 mmol,2.0 eq.) in anhydrous DCM (97.0 mL) at 0 °C and the reaction mixture was stirred for 1 h at RT. NaHCO3 saturated aqueous solution was added, the layers were separated, the organic layer was evaporated to dryness and dissolved in EtOAc then was washed with NaHCO3 saturated aqueous solution and citric acid (20 %) aqueous solution, water and brine. The organic layers were dried over Na2SO4, filtered and evaporated to dryness to afford lnt-28.2.8.2. Int-29 / o \ _ Boc / \DBocMsO |T^N3 \ |]^lnt-28 Int-29

[0496] NaNs (CAS# 26628-22-8; 3.41 g, 52.5 mmol, 6.0 eq.) was added to a solution of lnt-28 (3.35 g, 8.75 mmol, 1.0 eq.) in anhydrous DMSO (35.0 mL) and the reaction mixture was stirred at 70 °C for 16 h. NaHCO3 saturated aqueous solution was added and the aqueous layer extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and evaporated to dryness to afford Int- 29.2.8.3. Int-30 / O \ Boc / A \ BocCbz.. NHNHInt-29 Int-30

[0497] PPh3(CAS# 603-35-0; 4.59 g, 17.5 mmol, 2.0 eq.) was added to a solution of Int-29 (3.19 g, 8.75 mmol, 1.0 eq.) in THF (40.0 mL) and the reaction mixture was stirred at RT for 1.5 h. Water (20.0 mL) was added and the reaction mixture was heated to 95 °C for 4 h, then the mixture was cooled to 50 °C and A-(benzyloxycarbonyloxy)succinimide (CAS# 13139-17-8, 4.36 g, 17.5 mmol, 2.0 eq.) and TEA (6.10 ml, 43.8 mmol, 5.0 eq.) were added and the reaction mixture was stirred at RT for 2 h. NaHCO3 saturated aqueous solution was added and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, fdtered 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- 30.2.9. Int-372.9.1. Int-35lnt-34 lnt-35

[0498] TEA (251 mg, 2.48 mmol, 1.4 eq.) was added to a solution of Int-34 (622 mg, 1.77 mmol, 1.0 eq.) in anhydrous DCM (5.9 ml). Then, TsCl (383 mg, 1.95 mmol, 1.1 eq.) and DMAP (21.0 mg, 0.18 mmol, 0.1 eq.) were added and the resulting mixture was stirred at RT for 18 h. The reaction mixture was diluted with EtOAc and the organic layer was washed with brine, dried over Na2SO4, fdtered and evaporated to dryness. The residue was purified by column chromatography on silica gel (eluting with Heptane / EtOAc from 100 / 0 to 40 / 60) to afford Int-35.2.9.2.CAS#20348-23-6 lnt-36

[0499] XPhos Pd G3 (197 mg, 0.24 mmol, 0.2 eq.) and CS2CO3 (1.97 g, 6.06 mmol, 5.0 eq.) were added to a solution of Int-35 (613 mg, 1.21 mmol, 1.0 eq.) and 3,4-dihydro-2H-pyrido[3,2-b][l,4]oxazine (CAS# 20348-23-6; 330 mg, 2.43 mmol, 2.0 eq.) in anhydrous 1,4-dioxane (12.0 mL) and the reaction mixture was stirred at 90 °C for 1 h. Water was added and the mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SC>4, filtered and evaporated to dryness. The residue was purified by preparative HPLC to afford Int-36.2.9.3. Int-37lnt-36 Int-37

[0500] Pd / C 10% (87.0 mg, 0.08 mmol, 0.2 eq.) was added to a solution of Int-36 (193 mg, 0.41 mmol, 1.0 eq.) in EtOAc (20.0 mL) under nitrogen. The reaction mixture was purged with hydrogen, then hydrogen was bubbled through the vigorously stirred solution for 24 h at RT. The reaction mixture was purged with nitrogen, celite® was added and the reaction mixture was filtered. The filtrate was evaporated to dryness to afford Int-37.2.10. Int-38Int-38

[0501] To a solution of tert-butyl 6-bromo-2H-pyrido[3,2-b][l,4]oxazine-4(3H)-carboxylate (CAS# 959992-64-4; 18 g, 57.1 mmol, 1.0 eq.) in DMA (180 mL) was added Zn (9.58 g, 146 mmol, 2.57 eq), 4-tert-butyl -2,6-pyridinedicarboximidamide hydrochloride (CAS# 3003061-14-8; 1.25 g, 5.71 mmol, 0.1 eq.) and dichloronickel; 1,2 -dimethoxy ethane (CAS# 29046-78-4; 1.25 g, 5.71 mmol, 0.1 eq.) then thereaction mixture was evacuated and backfilled with nitrogen (3x) and stirred at 25 C for 5 mm. Bromocyclobutane (CAS# 4399-47-7; 13.4 mL, 143 mmol, 2.5 eq.) was added dropwise and the reaction mixture was heated to 63 °C for 16 h. The reaction mixture was cooled to RT and additional amounts of dichloronickel; 1,2 -dimethoxy ethane (CAS# 29046-78-4; 1.25 g, 5.71 mmol, 0.1 eq.), 4-tert-butyl-2,6-pyridinedicarboximidamide hydrochloride (CAS# 3003061-14-8; 1.25 g, 5.71 mmol, 0.1 eq.) andZn (9.39 g, 143 mmol, 2.51 eq.) were added at 25 °C. The reaction mixture was evacuated and backfilled with nitrogen (3x), stirred at 25 °C for 5 min, then bromocyclobutane (CAS# 4399-47-7; 13.4 mL, 143 mmol, 2.5 eq.) was added dropwise at 25 °C and the reaction mixture was heated to 63 °C for 16 h. After cooling to RT, the reaction mixture was diluted with EtOAc (1000 mL) and filtered through celite®. Water (500 mL) was added to the filtrate and the mixture was extracted with EtOAc (300 mLx3). The organic layers were combined, dried over MgSO4, filtered and concentrated in vacuum. The residue was purified by column chromatography on silica gel (eluting with Petroleum ether / THF from 100 / 0 to 87 / 13) to afford Int-38.2.11. Int-42\0l\L Jx N r.0N

[0502] In a vial, tert-Butyl 6-bromo-2H-pyrido[3,2-b][l,4]oxazine-4(3H)-carboxylate (CAS# 959992-64-4; 500 mg, 1.59 mmol, 1.0 eq.), triethylborane (1 M) in THF (3.17 mL, 3.17 mmol, 2.0 eq.), CS2CO3 (1.03 g, 3.17 mmol, 2.0 eq.) and Pd(dppf)C12. DCM (130 mg, 0.16 mmol, 0.1 eq.). The vial was capped then evacuated and backfilled with nitrogen (3x). THF (3.25 mL) was added, the reaction mixture was degassed by bubbling nitrogen for 5 min then was stirred at 60 °C for 3 h. The reaction mixture was cooled down to RT, diluted with water and extracted with DCM. The combined organic layers were washed with water, brine, 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 85 / 15) to afford Int-42.2.12. Int-55N NInt-55

[0503] In a vial, tert-butyl 6-bromo-2H,3H,4H-pyrido[3,2-b][l,4]oxazine-4-carboxylate (CAS# 959992-64-4; 300 mg, 0.95 mmol, 1.0 eq.), l,8-diazabicyclo[5.4.0]undec-7-ene (CAS# 6674-22-2; 434.74 mg, 0.43 mb, 2.86 mmol, 3.0 eq.) and 2-butynoic acid (CAS# 590-93-2; 96.03 mg, 1.14 mmol, 1.2 eq.) weredissolved in DMSO (12.6 mL). The solution was degazed with nitrogen for 10 min, and then Pd(PPh₃)₂Cl₂ (66.8 mg, 0.095 mmol, 0.1 eq.) and l,4-di(diphenylphosphino)-butane (CAS# 7688-25-7; 162.38 mg, 0.38 mmol, 0.4 eq.) were added. The reaction was degazed with nitrogen bubbling for 10 min. The reaction mixture was stirred at 90 °C for 2 h. After cooling to RT, H2O and DCM were added. The organic layer was separated via hydrophobic frit 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 0 / 100) to afford Int-55.2.13. Int-62To a mixture of 6-bromo-3,4-dihydro-2H-l,4-benzoxazine-4-carboxylate (CAS# 719310-31-3; 522 mg, 1.66 mmol, 1.0 eq.) 4-ethynyl-l -methyl- IH-pyrazole (CAS# 39806-89-8; 440.82 mg, 4.15 mmol, 2.5 eq.) and TEA (504.39 mg, 0.69 mL, 4.98 mmol, 3.0 eq.) in DMF (7.7 mL) was added Xphos Pd G3 (140.47 mg, 0.17 mmol, 0.1 eq.) at RT. The reaction mixture was degassed with nitrogen for 5 min then stirred at 120 °C using one single mode microwave (Anton Paar) with a power output ranging from 0 to 850 W for 20 min. After cooling to RT, water and DCM were added to the reaction mixture. The organic layer was separated via hydrophobic frit and the solvent was evaporated to dryness. The residue was purified column chromatography on silica gel (eluting with Heptane / EtOAc from 100 / 0 to 0 / 100) to afford Int-62.Int-66CAS# 626-05-1 CAS# 73183-34-3 CAS# 886372-53-8 Int-66

[0504] To a solution of 4-bromo-6-methylpyridine-2-carbonitrile (CAS# 886372-53-8; 1 g, 5.08 mmol, 1 eq.) in Dioxane (25.95 mL) at room temperature were charged bis(pinacolato)diboron (CAS# 73183-34-3; 1.42 g, 5.58 mmol, 1.1 eq.), KOAc (1.49 g, 15.23 mmol, 3 eq.) and Pd(dppf)C12 (0.37 g, 0.51 mmol, 0.1 eq.). The vial was capped then set under inert atmosphere via 3 iterations of a cycle vaccum / N2. The resulting mixture was degassed by bubbling N2 for 5 min and heated at 90 °C for 2 hours. The reaction mixture was cooled down to rt then 2,6-dibromopyridine (CAS# 626-05-1; 2.04 g, 8.63 mmol, 1.7 eq.), K2CO3 (2.10 g, 15.23 mmol, 3 eq.) and tetrakis(triphenylphosphine)palladium (0.59 g, 0.51 mmol, 0.1 eq.)Illwere added to the reaction mixture. The vial was capped then set under inert atmosphere via 3 iterations of a cycle vaccum / N2. The resulting mixture was degassed by bubbling N2 for 5 min and heated at 90 °C for 2 hours. The reaction mixture was cooled down to room temperature, diluted with EtOAc and filtered through celite. The filtrate was concentrated under vacuum. The residue was purified by column chromatography on silica gel (eluting with Heptane / EtOAc from 100 / 0 to 65 / 35) to afford Int-66.2.14. Int-67CAS# 1260665-77-7 CAS# 76513-69-4 Int-67

[0505] To a solution of 5-chloro-lH,2H,3H-pyrido[3,4-b][l,4]oxazine (CAS# 1260665-77-7; 600 mg, 3.52 mmol, 1 eq.) in DMF (18 mL) was added cesium carbonate (3.44 g, 10.55 mmol, 3 eq.) and SEM-C1, (CAS # 76513-69-4; 1.56 mL, 8.79 mmol, 2.5 eq.) were and the reaction mixture was stirred at 60 °C for 2 h under nitrogen atmosphere. After full conversion, monitored by UPLC / MS, water was added and the aqueous layer was extracted with DCM (10 mL). The organic layer was separated via hydrophobic frit 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-67.2.15. Int-68

[0506] To a solution of Int-67 (386 mg, 1.28 mmol, 1 eq.) in Ethanol (11.22 mL) was added NaOEt (CAS# 141-52-6; 919.04 mg, 12.83 mmol, 10 eq.). The resulting mixture was degassed by bubbling N2 for 5 min and heated at 180 °C using one single mode microwave (Anton Paar) with a power output ranging from 0 to 850 W for 45 minutes. The reaction mixture was heated at 200 °C using one single mode microwave(Anton Paar) with a power output ranging from 0 to 850 W for 10 minutes. After complete reaction, the reaction mixture was concentrated under vacuum to give Int-68.2.16. Int-69

[0507] To a solution of Int-68 (1.4 g, 1.308 mmol, 1 eq.) in DCM (13.41 mL) was added TFA (12.63 mL, 170.00 mmol, 130 eq.). The reaction mixture was stirred at rt for 1 day. TFA (4.86 mL, 65.38 mmol, 50 eq.) was added to the reaction mixture and stirred at rt for 3 days. The mixture was evaporated to dryness then co-evaporated with Heptane. The residue was taken up with DCM and NH4OH (30%) aqueous solution and the resulting mixture was stirred at rt for 30 min. The organic layer was separated via hydrophobic frit and the solvent was evaporated to dryness to give Int-69.2.17. Int-77BocHN

[0508] To a solution of Int-76 (130 mg, 0.27 mmol, 1 eq.) in DCM (2.59 mL) was added Magnesium bromide (248 mg, 1.35 mmol, 5 eq.) was added. The reaction mixture was stirred at rt for 2 h. The mixture was filtered over celite and washed with DCM. Then K2CO3 (10%) aqueous solution was added to the organic layer. The layers were separated. The aqueous layer was extracted once with DCM. The combined organic layers were dried over MgSO4, filtered and concentrated under vacuum to give Int-77.2.18. Int-102BocHN

[0509] To a solution of Int-101 (49 mg, 0.09 mmol, 1 eq.) in MeOH (1 mL) was added oxalyl chloride (0.16 mL, 1.88 mmol, 20 eq.). The reaction mixture was stirred at rt for 2 h. The reaction mixture was concentrated in vacuo to give Int-102.2.19. Int-103OBnCAS# 959992-64-4 CAS# 1807941-88-3 Int-103

[0510] Zinc (124.47 mg, 1.904 mmol, 2 eq.), pyridine-2,6-bis(carboximidamide) (CAS# 150223-49-7; 15.53 mg, 0.095 mmol, 0.1 eq.) and NiCl2 (18.50mg, 0.14 mmol, 0.15 eq.) were added to a solution of tert-butyl 6-bromo-2H-pyrido[3,2-b][1,4]oxazine-4(3H)-carboxylate (CAS# 959992-64-4; 300 mg, 0.95 mmol, 1 eq.) in DMA (2.1 mL) at rt. The mixture was de-gassed with nitrogen for 5 min and stirred for 5 min at rt. {[(lr,3r)-3-bromocyclobutoxy]methyl}benzene (CAS# 1807941-88-3; 574 mg, 2.38 mmol, 2.5 eq.) was added at rt and the mixture heated to 65 °C for 30 min. Nal (142.68 mg, 0.95 mmol, 1 eq.) was added and the resulting mixture was stirred at 65 °C for 18 h. Water was added, layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO4 and 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-103.2.20. lnt-104OBn OHlnt-103 lnt-104

[0511] To a solution of lnt-103 (237 mg, 0.6 mmol, 1 eq.) in MeOH (12.63 mL) was added Pd / C (63.61 mg, 0.06 mmol, 0.1 eq.). The resulting mixture was stirred at rt for 3 days under hydrogen atmosphere. The reaction mixture was filtered over celite, washed with water. Then DCM was added, and the mixture was basified with K2CO3 (10%) aqueous solution, and the organic layer was separated via hydrophobic frit and the solvent was evaporated to dryness to give lnt-104.2.21. Int-105 & Int- 106lnt-104

[0512] A mixture of Int-9 (135 mg, 0.42 mmol, 1 eq.), lnt-104 (95.68 mg, 0.46 mmol, 1.1 eq.), CS2CO3 (412 mg, 1.27 mmol, 3 eq.) and XPhos Pd G4 (36.29 mg, 0.042 mmol, 0.1 eq.) was set under inert atmosphere via 3 iterations of a cycle vacuum / N2. Dioxane (3.59 mL) was added to the reaction mixture. The resulting mixture was degassed by bubbling N2 for 5 min and heated at 80 °C for 2 hours. SiliaMetS thiol silica (Silicycle, 40-63 pm) (50 mg) was added. The resulting suspension was stirred at rt for 18 h and the mixture was filtered over celite and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluting with DCM / MeOH 100 / 0 to 95 / 5), then by SFC (Stationary phase: Chiralpak IH 20x250 mm, Mobile phase: CO2 / zPrOH 70 / 30). The fractions containing product were evaporated to give Int-105 (first eluted) and Int-106 (second eluted).2.22. Int-109CAS# 1824151-57-6 CAS# 109-64-8 Int-109

[0513] To a solution of (4-bromo-2- sulfanylphenyl)methanol (CAS# 1824151-57-6; 600 mg, 2.33 mmol, 1 eq.), K2CO3 (965 mg, 6.98 mmol, 3 eq.), DMF (21.44 mL) was added dropwise 1,3-dibromopropane (1.18 mL, 11.64 mmol, 5 eq.) dropwise. The reaction mixture was stirred at rt for 24 h. The reaction mixture was filtered over Celite. The filtrate was concentrated under vacuum. The residue was purified by column chromatography on silica gel (eluting with Heptane / EtOAc from 90 / 10 to 60 / 40) to afford Int-109.2.23. Int-110Int-110

[0514] A mixture of Int-109 (235 mg, 0.69 mmol, 1 eq.), NaOH 1 M in water (3.46 mL, 3.46 mmol, 5 eq.) and TBAB (CAS# 1643 -19-2; 22.28 mg, 0.069 mmol, 0.1 eq.) in toluene (11.75 mL) was stirred at 80 °C for 18 h. Water and DCM were added. The layers were separated. The aqueous layer was extracted twice. The combined organic layer was washed with brine, dried over MgSO4, filtrated, concentrated under vacuum. The residue was purified by column chromatography on silica gel (eluting with Heptane / EtOAc from 95 / 5 to 50 / 50) to afford Int-110.2.24. Int-111Int-111Int-110

[0515] Int-110 (89 mg, 0.34 mmol, 1 eq.) was dissolved in MeOH (1.25 mL) and water (0.83 mL), and Oxone (631.63 mg, 1.027 mmol, 2.99 eq.) was added, and solid precipitated. The reaction system was stirred at room temperature for 18 hours. The reaction mixture was concentrated, diluted with EtOAc and water and the aqueous phase was extracted once with EtOAc. The organic phases were combined, washed once with water and once with a saturated sodium chloride solution, dried over MgSO4, filtered, and concentrated under vacuum to give Int-111.2.25. Cpd- 73, Cpd- 74 & Cpd- 75Cl CAS# 2361949-79-1

[0516] A mixture of 3-chloro-5-[(difluoromethyl)(imino)oxo-X6- sulfanyl]benzoic acid (CAS# 2361949-79-1; 109.77 mg, 0.41 mmol, 1 eq.) was purged with N2 then DCM (2.61 mL) was added followed by DIPEA (0.21 mL, 1.22 mmol, 3 eq.), T3P (50% in EtOAc) (0.29 mL, 0.49 mmol, 1.2 eq.) slowly added at 0 °C. The resulting mixture was stirred at 0 °C for 15 min then Int-97 (188 mg, 0.407 mmol, 1 eq.) was added and the reaction mixture was allowed to slowly warm-up to rt and stirred for 1 h. Water and DCM were added to the reaction mixture, the organic layer was separated via hydrophobic frit and evaporated till dryness. The crude was purified by column chromatography on silica gel (eluting with DCM / MeOH 100 / 0 to 96 / 4). The fractions containing the product were combined and concentrated under vacuum, then taken up with Diethyl Ether (5.0 mL). The solid formed was filtered, washed with Diethyl Ether (4.0 mL) and dried under high vacuum to give Cpd-73. Cpd-73 was separated by SFC (Stationary phase: Chiralpak IA 20x250 mm, Mobile phase: CO2 / (iPrOH + 0,3%zPrNH2) 55 / 45). The fractions containing product were evaporated to give Cpd-74 (first eluted, R*) and Cpd-75 (second eluted, S*)2.26. Int-113Cl Cl CAS# 1565036-94-3 CAS# 1493-03-4 Int-113

[0517] To a mixture of 3 -chloro-4-methyl-5 -sulfanylbenzoic acid (CAS# 1565036-94-3; 1 eq., 203 mg, 0.91 mmol) and NaH 60% in mineral oil (2.5 eq., 91.15 mg, 2.28 mmol) in THF (4.94 mL) was added difluoro(iodo)methane 10% in THF (CAS# 1493-03-4; 1.2 eq., 1.27 mL, 1.094 mmol) at rt. The resulting mixture was stirred at rt for 1.5 h. HC1 (IM aqueous solution) and DCM were added, the aqueous layer was extracted 3 times with DCM. The combined organic layers were washed with brine solution, dried over Na2SO4, filtered and the solvent was removed in vacuo to give Int-113 (170 mg, 74%).2.27. Int-115ClCAS# 3008582-64-4 CAS# 24424-99-5 Int-115

[0518] To a solution of (4R)-9-chloro-4-fluoro-5.5-dioxo-3.4-dihydro-2H-l.5Zfi-bcnzoxathicpinc-7-carboxylic acid (CAS# 3008582-64-4; 1 eq., 1000 mg, 3.39 mmol) in NMP (8.59 mL) was added DMAP (0.24 eq., 100 mg, 0.82 mmol) and BOC2O (CAS# 24424-99-5; 2 eq., 1.45 mL, 6.79 mmol), followed by the dropwise addition of EtsN (1.2 eq., 0.57 mL, 4.07 mmol). The resulting mixture was stirred at rt °C for 3 h. The reaction mixture was concentrated under reduced pressure in Genevac, then directly purified by column chromatography on silica gel (eluting with heptane / EtOAc 100:0 to 50:50) to give Int-115 (965.5 mg, 81%).2.28. Int-116Int-115 CAS# 75927-49-0 Int-116

[0519] In a schlenk flask under N2, Int-115 (1 eq., 965 mg, 2.75 mmol), 2-ethenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (CAS# 75927-49-0; 3 eq., 1.4 mL, 8.25 mmol), K3PO4 (3 eq., 1.75 g, 8.25 mmol), Pd 118 (0.1 eq., 179.29 mg, 0.28 mmol) are dissolved in dioxane (27 mL) and H2O (3 mL). The reaction mixture was stirred for 18 hours at 100 °C. 2-ethenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (CAS# 75927-49-0; 2 eq., 847.4 mg, 0.93 mL, 5.50 mmol) and Pd 118 (0.05 eq., 89.65 mg, 0.14 mmol) were added to the mixture. The schlenk was fded with N2 gas, then stirred at 100 °C for 6 h. The reaction mixture was stopped, cooled at rt, then filtered over a pad of celite and concentrated under reduced pressure, then the residual was directly purified by column chromatography on silica gel (eluting with heptane / EtOAc 100:0 to 50:50) to give Int-116 (761 mg, 73%).2.29. Int-117NalO4Int-116 CAS# 7790-28-5 Int-117

[0520] Potassium osmate (VI) dihydrate (CAS# 10022-66-9; 0.01 eq., 5.04 mg, 6.3 pmol) was added to a solution of Int-116 (1 eq., 238 mg, 0.63 mmol) in THF (5.95 mL) and H2O (1.79 mL) at room temperature. The resulting mixture was stirred 10 minutes then sodium periodate (CAS# 7790-28-5; 2.5 eq., 334.54 mg, 1.56 mmol) was added at rt and the reaction mixture was stirred at rt for 18 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. The crude obtained was directly purified by column chromatography on silica gel (eluting with heptane / EtOAc 100:0 to 0:100) to afford Int-117 (143.2 mg, 66%).2.30. Int-118NaBH4Int-117 CAS# 16940-66-2 Int-118

[0521] To a mixture of Int-117 (1 eq., 143.2 mg, 0.42 mmol) in MeOH (5 mL) was added NaBH4(CAS# 16940-66-2; 1.27 eq., 20 mg, 0.53 mmol) at rt. The resulting mixture was stirred at rt for 1 h. HC1 1 M aqueous solution and DCM were added, the mixture was extracted with DCM (x3), the combined organic layers were washed with brine and dried over Na2SO4, filtered. Then the solvent was removed under reduced pressure to give Int-118 (141.4 mg, 96 %).2.31. Int-119Int-118 CAS# 77-78-1 Int-119

[0522] To a suspension of Int-118 (1 eq., 144.14 mg, 0.408 mmol) and NaH (60% in mineral oil) (1.5 eq., 24.49 mg, 0.61 mmol) in THF (10 mL) at rt, was slowly added dimethyl sulfate (CAS# 77-78-1; 3 eq., 154.47 mg, 0.12 mL, 1.22 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 three times. The organics layers were combined, washed with brine, dried over Na2SO4, filtered and concentrated under vacuo. The crude was purified by column chromatography on silica gel (eluting with heptane / EtOAc 100:0 to 50:50) to give Int-119 (100 mg, 68%)2.32. Int-121Int-117 CAS# 38078-09-0 Int-121

[0523] Diethyl(trifluoro-X4-sulfanyl)amine (CAS# 38078-09-0; 3 eq., 0.15 mL, 1.24 mmol) was added dropwise at 0 °C to a solution of Int-117 (1 eq., 150 mg, 0.41 mmol) in DCM (3.8 mL). The reaction mixture was stirred at rt for 3 h. The reaction mixture was quenched with cold NaHCO3 saturated aqueous solution and extracted with DCM three times. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to give Int-121.2.33. Int-124OH OTBS lnt-123 CAS# 18162-48-6 Int-124

[0524] TBDMSC1 (CAS# 18162-48-6; 1.5 eq., 0.25 mL, 1.45 mmol) in DMF (5 mL) was added slowly at -5 °C to a solution of Int-123 (1 eq., 200 mg, 0.97 mmol) and IH-imidazole (2 eq., 131.41 mg, 1.93 mmol) in DMF (5 mL). The reaction mixture was stirred at -5 °C for 1 hour. DCM was added to the reaction mixture and the mixture was basified with K2CO3 10% aqueous solution then the organic layer was separated (hydrophobic frit) and evaporated till dryness. The crude was purified by column chromatography on silica gel (eluting with DCM / MeOH from 100 / 0 to 97 / 3) to give Int-124 (235 mg, 69%).2.34. Int-127CAS# 69321-55-7 Int-127

[0525] A reaction vial equipped with a magnetic stirring bar was charged with 5-bromo-2-methylbenzene-1 -thiol (CAS# 69321-55-7; 1 eq., 1.49 g, 7.33 mmol) and DMF (49.33 mL). The reaction mixture was degassed with N2 for 10 minutes, then cooled to 0 °C, under inert atmosphere. EtsN (3 eq., 3.06 mL, 22 mmol) and rac -ethyl (2R)-2-bromo-2- fluoroacetate (CAS# 401-55-8; 1.5 eq., 2.035 g, 11 mmol) were added dropwise successively. The reaction mixture was warmed to rt and stirred for 2 h. EtOAc and water were added. The aqueous layer was extracted with EtOAc then the combined organic layers were washed with water, dried over MgSO4, fdtered and evaporated to give Int-127 (2.14 g, 95%).2.35. Int-129

[0526] A reaction vial was charged with Int-128 (1 eq., 2.43 g, 7.16 mmol) & isopropanol (93.68 mL). The reaction mixture was cooled to 0 °C and NaBH4 (CAS# 16940-66-2; 2 eq., 0.54 g, 14.32 mmol) was added. The reaction mixture was warmed to rt and stirred for 2 h. HC1 IM aqueous solution and AcOEt were added to the mixture then the layers were separated. The aqueous layer was extracted with AcOEt then the combined organic layers were washed with brine, dried over MgSO4, fdtered and evaporated to give Int-129 (1.93 g, 91%).2.36. Int-130 & Int-131

[0527] In a pressure vessel reactor were added Int-129 (1 eq., 0.97 g, 3.26 mmol) and K2CO3 (1.5 eq., 0.68 g, 4.89 mmol) in DMSO (46.37 mL) and H2O (4.51 mL) then Palladium acetate (0.1 eq., 0.054 g, 0.33mmol) and 1,3-Bis(dicyclohexylphosphino)propane bis(tetrafluoroborate) (0.2 eq., 0.4 g, 0.65 mmol) were added. The reaction mixture was stirred under 5 bars of CO at 100 °C for 18 h. The mixture was diluted with H₂O and brine and filtered over a pad of celite. AcOEt was added to the filtrate and the layers were separated. The aqueous layer was extracted once with AcOEt and the organic layer was discarded. The aqueous layer was acidified until pH ~3 with KHSO4 10% aqueous solution then extracted 3 times with AcOEt. The combined organic layers were washed three more times with brine, then dried over MgSO4, filtered and concentrated under vacuum. The crude was purified by preparative chiral SFC (Stationary phase: Chiralpak IG 30x250 mm, Mobile phase: CO2 / MeOH 65 / 35). The fractions containing compound were combined and evaporated in vacuo to give Int-130 (316 mg, 36%, R*, first eluted) and Int-131 (329 mg, 38%, S*, second eluted).2.37. Int-132CAS# 3069004-35-6 CAS# 1512-30-7 Int-132

[0528] Under N2, difluoromethanesulfonyl chloride (CAS# 1512-30-7; 2.5 eq., 0.47 mL, 5.29 mmol) was added dropwise to a suspension of methyl 4-fluoro-2,3-dihydro-lH-indole-6-carboxylate (CAS# 3069004-35-6; 1 eq., 413 mg, 2.12 mmol) and K2CO3 (3 eq., 877.27 mg, 6.35 mmol) in dry THF (18.55 mL) at rt. The reaction mixture was stirred at rt for 16 h. The mixture was filtered over a pad of celite® and the filtrate was evaporated under vacuo. The crude was purified by column chromatography on silica gel (eluting with Heptane / AcOEt 95 / 5 to 70 / 30) to give Int-132 (270 mg, 41%).2.38. Int-133FF-— / FInt-133

[0529] Lithiumol hydrate (6 eq., 219.8 mg, 5.24 mmol) was added to a solution of Int-132 (1 eq., 270 mg, 0.87 mmol) in THF (59.06 mL) and water (14.64 mL) at rt. The reaction mixture was stirred at rt for 16 h; The pH was brought to 3 by addition of KHSO4 1 M aqueous solution. DCM was added and the mixture was filtered through Chromabond® and the filtrate was evaporated in vacuo to give Int-133 (225 mg, 87%).2.39. Int-134Int-118 I nt- 134

[0530] To a solution of Int-118 (1 eq., 234 mg, 0.68 mmol) in DCM (7.4 mL) was added TFA (50 eq., 2.51 mL, 33.78 mmol). The reaction mixture was stirred at rt overnight. The reaction mixture evaporated under vacuum. The residue was taken into MeOH (4.65 mL) and TEA (20 eq., 1.88 mL, 13.51 mmol) was added. The reaction mixture was stirred at rt for 3 h. The reaction mixture evaporated to dryness to give 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-135 (196 mg, 100%).2.40. Int-135lnt-136 Int-135

[0531] To a stirred solution of lnt-136 (1 eq., 314 mg, 0.96 mmol) in water (5.3 mL) and dioxane (10.6 mL) was added in one fraction hydrogen chloride 4 M in dioxane (6 eq., 1.43 mL, 5.73 mmol) at rt and the solution was heated to 90 °C for 18 h. Hydrogen chloride 4 M in dioxane (3 eq., 0.72 mL, 2.87 mmol) was added and the reaction mixture was stirred at 90 °C for 24 h. The reaction mixture was stirred at 90 °C for 18 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 Int-135 (285 mg, 99%).2.41. Int-137OH Cllnt-138 lnt-137

[0532] To a mixture of Int-138 (1 eq., 950 mg, 3.13 mmol) in DCM (28.5 mL) was added mCPBA (3 eq., 2315 mg, 9.39 mmol) at rt. The resulting mixture was stirred at rt for 16 h. mCPBA (1 eq., 540 mg, 3.13 mmol) was added and the reaction mixture was stirred at rt for 6 h. The reaction was diluted with DCM.10% aq. Na₂S₂O₅ and 10% aq. NaHCO₃ were added. The layers were separated over chromabond PTS and the organic layer was evaporated. The obtained residue was diluted with DCM then 10% aq. Na₂S₂O₅ and 10% aq. NaHCO₃ were added. The layers were separated, and the aqueous layer was extracted once again with DCM. The combined organic layers were dried over Na2SO4, filtered and evaporated to dryness to give Int-137 (949 mg, 90%) as a white residue.2.42. Int-138OH Cl OH ClCAS# 2384513-34-0 CAS# 1493-03-4 Int-138

[0533] To a mixture of (4-bromo-2-chloro-6-sulfanylphenyl)methanol (CAS# 2384513-34-0; 1 eq., 2 g, 7.89 mmol) and NaH 60% in mineral oil (1.1 eq., 0.35 g, 8.68 mmol) in THF (42.74 mL) was added difluoro(iodo)methane 10% in THF (CAS# 1493-03-4; 1.44 eq., 20.24 g, 23 mL, 11.38 mmol) at rt. The resulting mixture was stirred at rt 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 washed with water, dried over Na2SO4, filtered and the solvent was removed in vacuo. The crude residue was purified by preparative LC (irregular SiOH, 40-60 pm, 120 g Acela, liquid loading (DCM), mobile phase gradient: from Heptane / EtOAc 100 / 0 to 50 / 50). The fractions containing product were combined and evaporated to dryness to give Int-138 (950 mg, 40%).2.43. Int-140O OF FCAS# 1566568-09-9 CAS# 1493-03-4 Int-140

[0534] To a mixture of 3 -fluoro-4-methyl-5 -sulfanylbenzoic acid (CAS# 1566568-09-9; 1 eq., 422 mg, 2.27 mmol) in THF (12.3 mL) were added NaH 60% in mineral oil (2.5 eq., 226.62 mg, 5.67 mmol) and difluoro(iodo)methane 10% in THF (CAS# 1493-03-4; 1.2 eq., 5.44 mL, 2.72 mmol) then the mixture was stirred at rt for 1 h. Aq. HC1 1 M 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 brine, dried over Na2SO4, filtered and the solvent was removed in vacuo to give Int-140 (480 mg, 90%) as an orange oil.2.44. Int-141OHlnt-142

[0535] To a solution of lnt-142 (1 eq., 334 mg, 0.93 mmol) in DCM (10.1 mL) was added TFA (50 eq., 3.44 mL, 46.34 mmol). The reaction mixture was stirred at rt for 16 h. The reaction mixture was evaporated under vacuum. The residue was taken into MeOH (6.37 mL) and TEA (20 eq., 2.58 mL, 18.53 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 a brown solid. The latter was suspended in toluene and evaporated to dryness to give Int-141 (282 mg, 100%).2.45. lnt-142OHlnt-143 lnt-142

[0536] To a solution of lnt-143 (1 eq., 530 mg, 1.15 mmol) in MeOH (13.9 mL) was added NaBH₄ (1.1 eq., 48.002 mg, 1.27 mmol) at rt. The resulting mixture was stirred at rt for 1 h. IN aq HC1 and DCM were added, the mixture was extracted with DCM (x3), the combined organic layers were washed with brine and dried over Na2SC>4, filtered. Then the solvent was removed under reduced pressure the crude obtained was purified by normal phase flash chromatography (irregular SiOH, 12 g Agela, liquid injection (DCM), mobile phase gradient: heptane / EtOAc 100:0 to 40:60 over 10 CV the isocratic for 5 CV, to give lnt-142 (344 mg, 83%).2.46. Int-143Int-116

[0537] p-benzoquinone (1.15 eq., 363.077 mg, 3.36 mmol) and PdCl₂(CH₃CN)₂ (0.025 eq., 18.94 mg, 0.073 mmol) were added into tert-butanol (20 mL) at 85 °C, followed by Int-116 (1 eq., 1000 mg, 2.92 mmol) and water (1 eq., 52.57 mg, 0.053 mL, 2.92 mmol). The resulting solution was stirred at 85 °C for 0.5 h. The reaction mixture was stopped, concentrated to dryness, the residue was purified by normal phase flash chromatography (regular silice 50 pm, 80 g interchim, liquid injection (DCM), mobile phase gradient: heptane / EtOAc 100:0 to 50:50 over 10 CV, to give Int-143 (530 mg, 1.15 mmol, 40%).2.47. Int-144Cl3008582-64-4To a suspension of (4R)-9-chloro-4-fluoro-5,5-dioxo-3,4-dihydro-2H-l,51ambda6-benzoxathiepine-7-carboxylic acid (200 mg, 0.679 mmol) in dioxane (10 mL) were added trimethyl-1,3,5,2,4,6-trioxatriborinane (341 mg, 1.358 mmol, 50% wt), K3PO4 (432 mg, 2.037 mmol) and Pd(dtbpf)Cl₂ (45 mg, 0.068 mmol). The resulting mixture was degassed and refilled with nitrogen for three times, then stirred at 100 °C for 16 h. The reaction mixture was cooled to rt, then filtered. The filtrate was concentrated under reduced pressure. The residue was dissolved in DMSO (2 mL), purified by reverse phase column chromatography [column, 220 g Cis silica gel; mobile phase, ACN in H2O (with 10 mM NH4HCO3 + 0.1% cone. NH3. H2O), 0% to 100% gradient in 40 min; detector, UV 254&220 nm] to afford (4R)-4-fluoro-9-methyl-5,5-dioxo-3,4-dihydro-2H-l,51ambda6-benzoxathiepine-7-carboxylic acid Int-144 (155 mg, 75% yield, 90% purity).2.48. Int-145Int-145 was prepared using a procedure analogous to that employed for CAS#3080313-29-4 starting from CAS#3008582-64-4.2.49. Int-146Int-115 lnt-146a Int-146Step 1:A mixture of Int-115 (35 mg, 0.100 mmol), Zn(CN)2 (3 mg, 0.291 mmol), Pd₂(dba)₃ (44 mg, 0.049 mmol), dppf (27 mg, 0.049 mmol) and Zinc dust (3 mg, 0.058 mmol) in DMAc (5 mL) was degassed and refilled with nitrogen for three times, then heated at 120 °C for 16 h. The reaction mixture was cooled, partitioned between Ethyl acetate EA (100 mL) and brine (200 mL). The aqueous phase was back extracted with EA (2 x 100 mL). The combined organic layers were dried overNa2SC>4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with 0 -75% EA in PE) to Int-146a (95 mg, 57.43% yield, 85% purity).Step 2:A solution of Int-146a (90 mg, 0.264 mmol) in DCM (3 mL) and TFA (3 mL) was stirred at room temperature for 1 h. Then the reaction mixture was concentrated under reduced pressure to afford Int-146 (90 mg crude, TFA salt form) which was used in the next step directly without any further purification.2.50. Int-148 and 149Int-147 was prepared using a procedure analogous to that employed for Int-130 / 131 starting from CAS#1565036-94-3SFClnt-148 lnt-1493-chloro-5-((l-fluoro-2-hydroxyethyl)sulfonyl)-4-methylbenzoic acid (200 mg) was purified by SFC (Stationary phase: Chiralpak AD-H 20x250 mm, Mobile phase: CO2 / MeOH 70 / 30). The fractionscontaining compounds were combined and evaporated under vacuum to give Int-148 (68 mg, 0.23 mmol, 32%) as white powder and Int-149 (79 mg, 0.27 mmol, 38%) as white powder.2.51. Int-151 and 152Int-150 was prepared using a procedure analogous to that employed for Int-130 / 131 starting from CAS#1566273-16-2.lnt-150rac-3-chloro-5-[(lR)-l-fhioro-2-hydroxyethanesulfonyl]benzoic acid (803 mg) was purified by chiral SFC (Stationary phase: Chiralpak IG 20x250 mm, Mobile phase: CO2 / (iPrOH + 0,3%iPrNH2) 75 / 25) The fractions containing the product was combined and evaporated to dryness to give first enantiomer (313 mg) and second enantiomers (325 mg). First enantiomer (313 mg) was diluted with DCM then aq. HC1 IM was added. The layers were separated then the aqueous layer was extracted with DCM. The aqueous layer was extracted again with EtOAc. The combined organic layers were dried over Na2SO4, filtered and evaporated to give Int-151 (264 mg, 0.93 mmol, 35%). Second enantiomer (325 mg) was diluted with DCM then aq. HC1 IM was added. The layers were separated then the aqueous layer was extracted with DCM. The aqueous layer was extracted again with EtOAc. The combined organic layers were dried overNa2SO4, filtered and evaporated to give Int-152 (311 mg, 1.1 mmol, 41%).2.52. Int-153Int-153 was prepared using a procedure analogous to that employed for Int-120 starting from CAS# 2592405-50-8.2.53. Int-154Int-117 Int-154a lnt-154Under N2 atmospher, at 0°C, to a solution Int-117 (1 eq., 400 mg, 1.16 mmol) in THF (9.52 mL) was added dropwise bromo(methyl)magnesium (2 eq., 0.77 mL, 2.32 mmol). Then the reaction was stirred at rt for 2 h. The reaction was quenched with an aqueous solution of NH4C1 (10%) at 0°C, Then extracted with EtOAc (x2), dried over Na2SO4, filtered and concentrated under reduced pressure to give. The residue was purified by normal phase flash chromatography (irregular SiOH, 20 g Age la, liquid injection (DCM), mobile phase gradient: heptane / EtOAc 100:0 to 50:50 over 10 CV the isocratic for 10 CV, to give Int-154a (200.95 mg, 0.56 mmol, 48%).To a solution of Int-154a (0.96 eq., 191 mg, 0.53 mmol) in DCM (6 mL) was added TFA (50 eq., 3143.804 mg, 2.048 mL, 27.57 mmol). The reaction mixture was stirred at rt overnight. The reaction mixture was evaporated under vacuum. The residue was taken into MeOH (3.79 mL) and TEA (20 eq., 1116.024 mg, 1.53 mL, 11.029 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. The aqueous layer was extracted twice with EtOAc. The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo to give Int-154 (161.26 mg, 0.53 mmol, 100%).2.54. Cpd-98 and Cpd-99Cpd-98 and Cpd-99 were obtained after SFC separation of the racemic (Stationary phase: Cyano 20x250 mm, Mobile phase: CO2 / (MeOH + 0,3%iPrNH2) 85 / 15) and freeze-dried to give Cpd-98 (53 mg, 28% and Cpd-99 44 mg 24%).2.55. Int-156 and Int-157Step 1: To chlorosulfonic acid (86 g, 740 mmol) was added compound 3-bromo-4-hydroxybenzoic acid (20 g, 92.158 mmol) in portions carefully at 0 °C. The resulting mixture was stirred at 80 °C for 16 hrs. The reaction mixture was cooled to 0 °C, then poured into ice and filtered to obtain the filter cake. The filter cake was washed with ice-water (300 mL) and dried under vacuum to afford 3-bromo-5-(chlorosulfonyl)-4-hydroxybenzoic acid Int-155a (15.9 g, 55% yield).Step 2: To a solution of 3-bromo-5-(chlorosulfonyl)-4-hydroxybenzoic acid (15.9 g, 50.393 mmol) in toluene (160 mL) was added PPh3(46 g, 176.375 mmol) at rt. The resulting mixture was stirred at 85 °C for 12 hrs. The reaction mixture was cooled to 0 °C, then adjusted to pH =11-12 with 2 M NaOH solution (300 mL) and extracted with 2-Me THF (200 mL * 3) to remove PPh3and POPh3. The aqueous phase was acidified to pH = 1 with 12 M HC1 (100 mL) and extracted with 2-Me THF (200 mL * 2). The combined organic phases were washed with brine (200 mL), dried over Na3SO4 and filtered. The filtrate was concentrated to afford 3-bromo-4-hydroxy-5 -sulfanylbenzoic acid Int-155b (14 g, 89% yield, 80% purity).Step 3: To a solution of 3-bromo-6-chloropyrazin-2-amine (14 g, 67.166 mmol) in MeOH (140 mL) was added H2SO4 (5.5 g, 56.207 mmol) dropwise at 0 °C. The resulting mixture was stirred at 70 °C for 16 hrs. The reaction mixture was cooled, concentrated under vacuum. The residue was diluted with EA (1000 mL), poured into ice-water (100 mL) and separated. The aqueous layer was extracted with EA (500 mL). The combined organic layers were washed with brine (100 mL), dried over Na3SO4 and concentrated under vacuum to afford 6-chloro-2H,4H-pyrazino[2,3-b][l,4]oxazin-3-one Int-155c (14 g, crude).Step 4: To a mixture of methyl 3 -bromo-4-hydroxy-5 -sulfanylbenzoate (14 g, 53.210 mmol) and Cs3CO3(44 g, 133.025 mmol) in DMF (140 mL) was added 1,3 -dibromopropane (11 g, 53.210 mmol) at rt. The resulting mixture was stirred at rt for 2 hrs. The reaction mixture was diluted with water (300 mL), extracted with EtOAc (150 mL * 3). The combined organic phases were washed with brine (200 mL * 2), dried over Na3SO4 andfiltered. The filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography (eluting with 0-20% EA in PE) to afford methyl 9-bromo-3,4-dihydro-2H-l,5-benzoxathiepine-7-carboxylate Int-155d (6 g, 37.19% yield).Step 5: To a solution of methyl 9-bromo-3,4-dihydro-2H-l,5-benzoxathiepine-7-carboxylate (3.6 g, 11.875 mmol) in MeCN (40 mL) were added 4-(chloromethyl)-l-fluoro-l,4-diazabicyclo[2.2.2]octane-l,4-diium; bis(tetrafluoroboranuide) (5.3 g, 14.844 mmol) in portions and DAST (5.7 g, 35.625 mmol) by dropwise at 0 °C under N2 atmosphere. The resulting mixture was stirred at 35 °C for 2 hrs. The reaction mixture was diluted with DCM (200 mL), then poured into a solution of NaHCOs (10% w, 300 mL) at 0 °C. The resulting mixture was extracted with DCM (2 x 200 mL). The organic layer was washed with brine (2 x 50 mL), dried over anhydrous Na2SC>4 and filtered. The filtrate was concentrated in vacuo. The residue was purified by reverse phase column chromatography [column, 330 g Cis silica gel; mobile phase, 0~100% acetonitrile in water (10 mM NH4HCO3) in 40 min; flowrate, 50 mL / min; detector, UV 254 nm] to afford methyl 9-bromo-4-fluoro-3,4-dihydro-2H-l,5-benzoxathiepine-7-carboxylate Int-155e (2.2 g, 58% yield).Step 6: To a solution of methyl 9-bromo-4-fluoro-3,4-dihydro-2H-l,5-benzoxathiepine-7-carboxylate (2 g, 6.227 mmol) in DCM (60 mL) was added m-CPBA (2.9 g, 14.322 mmol, 85% purity) batchwise at rt. The resulting mixture stirred at rt for 18 hrs. The reaction mixture was diluted with DCM (500 mL), washed with Na₂S₂O₅ (5 x 100 mL). The organic layer was dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated (Note: For safety reasons, be sure to test for any significant peroxide residues with starch-iodide test paper before concentrating the filtrate.). The residue was purified by reverse phase column chromatography [column, 330 g Cis silica gel; mobile phase, 0—100% acetonitrile in water (10 mM NH4HCO3) in 40 min; flowrate, 50 mL / min; detector, UV 254 nm] to afford Int-155f (1.64 g, 75% yield).Step 7: To a solution of methyl 9-bromo-4-fluoro-5,5-dioxo-3,4-dihydro-2H-l,51ambda6-benzoxathiepine-7-carboxylate (1.67 g, 4.729 mmol) in THF (10 mL) and MeOH (5 mL) was added a solution of LiOH (0.34 g, 14.187 mmol) in H2O (5 mL, 166.528 mmol). The resulting mixture was stirred at rt for 2 hr. The reaction mixture was diluted with H2O (30 mL), then adjusted to pH = 1 with 12 M aq. HCl at 0 °C, extracted with EtOAc (200 mL * 3). The combined organic phases were dried over Na2SO4and filtered. The filtrate was concentrated under vacuum. The residue was purified by reverse phase column chromatography [column, 220 g Cis silica gel; mobile phase, 0—50% acetonitrile in water (0.05% TFA) in 50 min; flowrate, 50 mL / min; detector, UV 254 nm], then re-purified by prep-achiral SFC [Column: Torus Diol OBD, 5 pm, 250 mm x 30 mm; Mobile Phase A: CO2, Mobile Phase B: IPA (with 0.3% NH3 (7 M in MeOH)); Flow rate: 80 mL / min; Gradient (B%)50% B; Column Temperature(°C): 35; Back Pressure(bar): 100; Wave Length: 220 nm; RT(min): 7.09; Pressure(Bar): 60; Sample Solvent: MeOH+DCM; Injection Volume: 2 mL] to afford Int-155 (650 mg, 40.53% yield).Step 8: The product was separated by prep-chiral SFC [Column: (S, S)-WHELK-O1, 5 pm, 250 mm x 30 mm; Mobile Phase A: CO2, Mobile Phase B: MeOH (with 0.3% NH3 (7 M in MeOH)); Flow rate: 100 mL / min; Gradient (B%)20% B; Column Temperature(°C): 35; Back Pressure(bar): 100; Wave Length: 220 nm; RTl(min):6.63; RT2(min): 8.03; Pressure(Bar): 40; Sample Solvent: MeOH; Injection Volume: 0.5 mL] to afford two pr oducts:1steluting peak: Int-157, OR = +67.216° (c=0.208 g / 100 mL, 589 nm, DMF, 20 °C), (252 mg, 39% yield). 2ndeluting peak Int-156, OR = -79.515° (c=0.204 g / 100 mL, 589 nm, DMF, 20 °C), (220 mg, 34% yield).Step 1:A mixture of methyl 3-chloro-5-difluoromethanesulfonylbenzoate (100 mg, 0.351 mmol), 2-ethenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (162 mg, 1.053 mmol), K3PO4 (224 mg, 1.053 mmol) and Pd(dtbpf)C12 (23 mg, 0.035 mmol) in dioxane (3.6 mL) and H2O (0.4 mL) was stirred at 100 °C for 3 hrs underN2atmosphere. The reaction mixture was cooled, quenched by addition of water, extracted with ethyl acetate. The combined organic phase was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with 0% to 20% PE in ethyl acetate) to afford methyl 3-difluoromethanesulfonyl-5-ethenylbenzoate (60 mg, 52.55% yield, 85% purity).Step 2:A mixture of Int-158a (397 mg, 1.437 mmol) and potassium osmate (VI) dihydrate (6 mg, 0.014 mmol) in THF (20 mL) and H2O (6 mL) was stirred at rt for 10 min under N2 atmosphere. Then NaIO4 (768 mg, 3.593 mmol) was added. The resulting mixture stirred for 2 h. The reaction mixture was quenched by addition of water, extracted with ethyl acetate. The combined organic phase was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with 0% to 30% PE in ethyl acetate) to afford Int-158b (300 mg, 64% yield, 85% purity).Step 3:To a solution Int-158b (500 mg, 1.797 mmol) in DCM (25.00 mL) was added DAST (869 mg, 5.391 mmol) dropwise at 0 °C. The resulting mixture was stirred for 3 h at rt. The reaction mixture was basified to pH = 8 with saturated aq. NaHCO3. The resulting mixture was extracted with DCM. The combined organic phase was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with 5% to 30% PE in ethyl acetate) to afford Int-158c (470 mg, 74% yield, 85% purity).Step 4:A mixture of Int-158c (500 mg, 1.665 mmol) and LiOH (120 mg, 4.995 mmol) in THF (5.00 mL) and H2O (5.00 mL) was stirred at rt for 2 hrs. The reaction mixture was acidified to pH 2 with IM aq. HCl, extracted with ethyl acetate. The combined organic phase was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to afford Int-158 (412 mg, 73% yield, 85% purity).Table II. Intermediates used towards the compounds of the invention.SM = Starting Material, Mtd = Method, MS Mes’d = Measured mass, NA = not measuredMSInt# Structure Name SM Mtd MW Mes’d tert-butyl N-[l-(4- Int- bromo-2- CAS# Ex. 313.1 BocH N 313.2 1Brpy ridyl)cy clopropy 1] carb 2091004-88-3 2.4.1 315.1 amatetert-butyl N-[l-[4- (benzhydrylideneamino)- Int- Ex.2- In 413.2 414.1 2 BocH NN<YPht-12.4.2Ph py ridyl] cyclopropyl] carbamatetert-butyl N-[l-(4-amino- Int- 2- Ex.BocH N3N H2Int-2 249.3 250.1 pyridyl)cy clopropy 1] carb 2.4.3amatetert-butyl N-[l-(4-amino- Int- 5-iodo-2- Ex. No Int-3 375.24 pyridyl)cy clopropy 1] carb 2.4.4 LCMS N. A,amate(E)-3-[4-amino-6-[l- (tert- Int- BocH N N Ex. No butoxycarbonylamino)cy Int-4 347.45 2.4.5 LCMS clopropy 1] -3- Opyridyl]prop-2-enoatetert-butyl N-[l-(2-oxo- Int- 1H- 1,6-naphthyridin-7- Ex.BocHN^^Y^n Int-5 301.3 302.2 6 yl)cy clopropy 1] carbamat 2.4.6eMS Int# Structure Name SM Mtd MW Mes’d tert-butyl 7V-[l-[2-(6- ethyl-2,3- Int-6dihydropyrido [3,2- Int- + Ex.b][l,4]oxazin-4-yl)-l,6- 446.5 447.3 7 CAS#1018638- 2.2.1naphthyridin-7- 76-0yl]cyclopropyl]carbamate1-[2-(6-ethyl-2,3- dihydropyrido [3,2- V7 l^° 346.4Int- b][l,4]oxazin-4-yl)-l,6- Ex.HzNInt-7 Free 347.2 8. XHCI M naphthyridin-7- 2.2.2base yl]cyclopropanamine,hydrochloride salttert-butyl (l-(2-chloro- Int- JDI 1, 6 -naphthy ridin-7 - Ex.BocHN |j Y Int-6 319.8 320.1 9 yl)cyclopropyl)carbamat 2.4.7e1 -(2 -chloro- 1, 6- 219.7 naphthyridin-7- Ex. Int- H2N^^NYClInt-9 Free 220.1 10 y l)cy clopropan- 1 -amine, 2.4.8. X zIHCI base o o hydrochloride saltcnbenzyl (l-(2-hydroxy- Int-6Int- 1, 6 -naphthy ridin-7 - + Ex.CbzHN^f^Y 335.4 336.2 11 ™ yl)cyclopropyl)carbamat CAS# 13139- 2.1.1e 17-8tert-butyl 6-((l-methyl- f / X'CCAS#Boc lH-pyrazol-4- 959992-64-4Int- ) yl)ethynyl)-2,3 -dihydro- Ex.+ 340.4 285.1 12 1 4H-pyrido[3,2- 2.4.9CAS#b][l,4]oxazine-4- 39806-89-8N- N\ carboxylate3 6-((l -methyl- 1H- pyrazol-4-yl)eXTFAHNV thynyl)- 240.1Int- b 3,4-dihydro-2H- Int-12 J Free 241.2 13 pyrido[3,2- 1base b][l,4]oxazine,N -N Trifluoroacetic saltMS Int# Structure Name SM Mtd MW Mes’d 6-((l -methyl- 1H- pyrazol-4-yl)ethynyl)- Ex.Int- X)3,4-dihydro-2H- Int-12 2.4.1 240.1 241.2 15 I Ipyrido[3,2- 0b][l,4]oxazineN-N^tert-butyl (l-(2-(6-cyano- 2,3-dihydro-4H- Int-6V7 C° pyrido[3,2- Ex.Int- X -N. Js. +BocHN || || b][l,4]oxazin-4-yl)-l,6- 1.2.7. 444.5 445.3 16 CAS#naphthyridin-7- 1CN 928118-39-2 yl)cyclopropyl)carbamate4-(7-(l- aminocyclopropyl)-l,6- V7 Y naphthyridin-2-yl)-3,4- 362.4 n Q°I t- / ^° Ex.H2Nif^NYNPp c z ' — X dihydro-2H-pyrido[3,2- Int-16 Free17 2.5 - p.xzhp’ b][l,4]oxazine-6- base7 Z CONH2carboxamide,_ _ \Z= hydrochloride salt\z=LCAS#o'-''z CD 4-(7-bromo-l,6- 1578484-42-0Int- naphthyridin-2-yl)-3,4- Ex.+ 343.2 --344.8 18 dihydro-2H-pyrido[3,2- 2.6.1CAS#b][ 1,4] oxazine20348-23-62-(2-(2,3-dihydro-4H- Int-18pyrido[3,2- Int- + Ex.b][l,4]oxazin-4-yl)-l,6- 303.3 304.0 19NCY Y |1 CAS# 2.6.2naphthyridin-7- 928664-98-6yl)acetonitrilel-(2-(2,3-dihydro-4H- pyrido[3,2- Int-19Int- b][l,4]oxazin-4-yl)-l,6- + Ex.357.4 358.2 20 naphthyridin-7- CAS# 2.6.3yl)cyclopentane- 1 - 628-21-7carbonitrileMS Int# Structure Name SM Mtd MW Mes’d l-(2-(2,3-dihydro-4H- pyrido[3,2- Int- b][l,4]oxazin-4-yl)-l,6- Ex.Int-20 376.4 377.2 21 naphthyridin-7- 2.6.4yl)cyclopentane- 1 - carboxylic acidtert-butyl (l-(2-(2,3- dihydro-4H-pyrido[3,2- Ex.Int- b][l,4]oxazin-4-yl)-l,6- Int-21 1.2.1. 447.5 448.3 22 BocH hNnaphthyridin-7- 1 yl)cyclopentyl)carbamatel-(2-(2,3-dihydro-4H- pyrido[3,2- 347.4Int- Z~A b][l,4]oxazin-4-yl)-l,6- Int-22 H Free 348.2 23 naphthyridiX H2N^Cl WNYN''A n-7- base y l)cyclopentan- 1 -amine,P chydrochloride saltl-(2-(2,3-dihydro-4H- pyrido[3,2- Int-19Int- / \ r\ / ^Zr^° b][l,4]oxazin-4-yl)-l,6- + Ex.o 343.4 344.2 24NoCM C T V T Y |i naphthyridin-7- CAS# 2.7.1Iyl)cyclobutane-l- 109-64-8carbonitrilel-(2-(2,3-dihydro-4H- pyrido[3,2- Int- / \ r^° b][l,4]oxazin-4-yl)-l,6- Ex.Int-24 362.4 363.3 25 HOOC''YYYNyNnaphthyridin-7- 2.7.2NX^Ayl)cyclobutane-l- carboxylic acidtert-butyl (l-(2-(2,3- dihydro-4H-pyrido[3,2- Int- Z\ Y°Bocx,,>< / -x. N. b][l,4]oxazin-4-yl)-l,6- Int-25 A 433.5 434.3 26 N Y xf ■’>< 7]HiUU M naphthyridin-7- yl)cyclobutyl)carbamateMS Int# Structure Name SM Mtd MWI o Mes’d NJ CT z N / l-(2-(2,3-dihydro-4H- IZ / vz= pyrido[3,2- Int- )°\7 b][l,4]oxazin-4-yl)-l,6- Int-26 H 333.4 334.3 27 lVz—. / / naphthyridin-7- y l)cy clobutan- 1 -amineZI3-(4-((tert- Int- Z A \ Boc Obutoxycarbonyl)amino)p CAS# Ex.344.4 345.2 28 MsO yridin-2-yl)oxetan-3 -yl 2421135-16-0 2.8.1methanesulfonatetert-butyl (2-(3- AInt- Z \ Boc azidooxetan-3- Ex.Int-28 291.3 292.1 29N3 r ii yl)pyridin-4- 2.8.2yl)carbamatetert-butyl (2-(3- Int-29A (((benzyloxy)carbonyl)aInt- Z \ Boc + Ex.Cbz.,><f mino)oxetan-3- 399.4 400.2 30 CAS# 2.8.3yl)pyridin-4-HM 13139-17-8yl)carbamate0 benzyl (3-(4- Ex.Int-CbzN H2aminopyridin-2- Int-30 1.2.1 299.3 300.1 31 N ily l)oxetan-3 -y l)carbamate 1.3HM0 benzyl (3-(4-amino-5- Ex.Int- No Cbz. NH2iodopyridin-2-yl)oxetan- Int-31 1.2.3. 425.232 LCMSHNJL 3-yl)carbamate 1ethyl (E)-3-(4-amino-6- 0(3- Ex.Int-Cbz'|\f \Z'yNH2(((benzyloxy)carbonyl)a Int-32 1.2.4. 397.4 398.2 33HN^X^ -OEt mino)oxetan-3- 10 y l)py ridin-3 -yl)acry latebenzyl (3-(2-oxo-l,2- Ex.Int- dihydro-1,6- Int-33 1.2.6. 351.4 352.1 34 naphthyridin-7- 1y l)oxetan-3 -y l)carbamateMS Int# Structure Name SM Mtd MWo o Mes’d CT N N / / XZ x ~T~Z.. 7-(3- Z X Int-34D (((benzyloxy)carbonyl)aInt-O+ Ex.mino)oxetan-3 -y 1) - 1,6- 505.5 506.2 35 > Z z / / A CAS# 2.9.1o naphthyridin-2-yl 4- 98-59-9w methylbenzenesulfonate& o benzyl (3-(2-(2,3-1sdihydro-4H-pyrido[3,2- Int- Ex.b][l,4]oxazin-4-yl)-l,6- Int-35 469.5 470.3 36 2.9.2naphthyridin-7- y l)oxetan-3 -y l)carbamate3-(2-(2,3-dihydro-4H- pyrido[3,2- Int- Ex.b][l,4]oxazin-4-yl)-l,6- Int-36 335.4 336.2 37 2.9.3naphthyridin-7- y l)oxetan-3 -aminetert-butyl 6-cyclobutyl- CAS#z\,o z ' —x} HZ 2,3-dihydro-4H- 959992-64-4Int- Ex.zH pyrido[3,2- + 290.4 291.1 38 NT 2.10 / / i b][l,4]oxazine-4- CAS#Boccarboxylate 4399-47-7\ / \ z °o z Xo 04v6-cyclobutyl-3,4- Int- co Xdihydro-2H-pyrido[3,2- Int-38 J 190.2 191.2 39b][ 1,4] oxazinetert-butyl (l-(2-(6- cyclobutyl-2,3 -dihydro- 4H-pyrido[3,2- Int-39Int- b][l,4]oxazin-4-yl)-l,6- + G 473.6 474.3 40naphthyridin-7- Int-6yl)cyclopropyl)carbamate1 -(2-(6-cyclobuty 1-2,3 - V7 dihydro-4H-pyrido[3,2- 373.5Int- ^VYVYS b][l,4]oxazin-4-yl)-l,6-1Int-40 H Free 374.3 41 xHCI Ny naphthyridin-7- base y l)cy clopropan- 1 -amine,hydrochloride saltMS Int# Structure Name SM Mtd MWMes’d / D TZ tert-butyl 6-ethyl-2,3- Int- z dihydro-4H-pyrido[3,2- CAS# Ex.z — s. z y 264.3 209.1 42 b][l,4]oxazine-4- 959992-64-4 2.11~ < ° —— / \ / carboxylatert' z6-ethyl-3,4-dihydro-2H- Ex.Int- pyrido[3,2- Int-42 1.2.8. 164.2 165.1 43b][ 1,4] oxazine 1Mt MS Int# Structure Name SM MWd Mes’d tert-butyl (l-(2-(6-ethyl- 2,3-dihydro-4H- V7 1^ z° 1 pyrido[3,2- Int-6Int-44 BOCHN^ Y^TNYN^S1 b] [ 1,4]oxazin-4-yl)- 1,6- + G 447.5 448.3 naphthyridin-7- Int-43\ ) cz z—z ' — yl)cyclopropyl)carbamatMzozo o Z—u ' eCD / l-(2-(6-ethyl-2,3- y Z£ X \ dihydro-4H-pyrido [3,2- b] [ 1,4]oxazin-4-yl)- 1,6- 347.4Int-45 Int-44 H 348.3 naphthyridin-7- Free base yl)cyclopropan- 1 -amine,hydrochoride salttert-butyl 6-(l-methyl- CAS#lH-pyrazol-3-yl)-2,3- 959992-64-4 Ex.Int-46 dihydro-4H-pyrido [3,2- + 1.2. 316.4 317.3 b][l,4]oxazine-4- CAS# 2.2carboxylate 1020174-04-26-( 1 -methyl-lH-pyrazol- 3 -y 1) -3,4-dihydro-2H- Int-47 Int-46 H 216.2 217.2 pyrido[3,2- b][ 1,4] oxazine5-bromo-7-(methylthio)- CAS# Ex. 254.1 Int-48 jf J 2, 3 -dihydro - IH-inden-l- 257.21242157-14-7 1.2. 256.1 one13.1Mt MS Int# Structure Name SM MWd Mes’d u°x°< / = 1\ (6-bromo-2,3-dihydro- No Ex.Int-49 ( O ) j — j lH-inden-4- Int-48 243.2 ionizatioo / =A / \ / / ii()>' ' z c IZ 1.2.n — / — / / \ / x II > _ yl)(methyl)sulfane n O — \ 14.1 o ° / O 6-bromo-4- No I Ex.Int-50 ccy (methy Isulfony 1) -2,3 - Int-49 275.2o ionizatio 1.2.o=s=o dihydro-lH-indene n 1 15.17-(methylsulfonyl)-2,3- Ex.239.0 Int-51 dihydro-lH-indene-5- Int-50 1.2. 240.3[M-H] carboxylic acid 16.1N-( 1 -(2 -chloro- 1,6- Int-101 naphthyridin-7- + Ex.yl)cyclopropyl)-7- Int-52 Int-51 1.2. 441.9 442.0(methy Isulfony 1) -2,3 - CAS# 10.1dihydro-lH-indene-5- 3038250-89-1p Q carboxamideO CAS#tert-butyl 6-(l-methyl- 959992-64-4 261.1 lH-pyrazol-4-yl)-2,3- Int- [M- dihydro-4H-pyrido [3,2- + B 316.453 Tbu+2H] b][l,4]oxazine-4- CAS# + carboxylate761446-44-06-(l-methyl-lH-pyrazol- 4-yl)-3,4-dihydro-2H- Int-54 1 J Int-53 H 216.3 217.2H pyrido[3,2- b][l,4]oxazinetert-butyl 6-(prop-l-yn- CAS#1 -y 1) -2, 3 -dihydro-4H- 959992-64-4 219.2 pyrido[3,2- Ex. [M- Int-55 + 274.3cr^c ) b][l,4]oxazine-4- 2.12 tBu+2H] carboxylate CAS# + CAS# 2438610-42-3590-93-2Mt MS Int# Structure Name SM MWd Mes’d6-(prop-l-yn-l-yl)-3,4- Ex.174.2Int-56 N N dihydro-2H-pyrido [3,2- Int-55 I.2. 175.1H Free base b][l,4]oxazine II.1XTFA CAS# 2527879-90-75-bromo-7-(ethylthio)- Ex. No CAS#Int-57 Y J 2, 3 -dihydro - 1 H-inden- 1 - 1.2. 271.2 ionizatio 1242157-14-7one 13.2 n (6-bromo-2,3-dihydro- Ex. No Int-58 J J lH-inden-4- Int-57 1.2. 257.2 ionizatio yl)(ethyl)sulfane 14.2 n 6-bromo-4- Ex. No Int-59 (ethylsulfony 1) -2, 3 - Int-58 1.2. 289.2 ionizatio o=s=o dihydro-lH-indene 15.2 n <z''z\J., P OH 7-(ethylsulfonyl)-2,3- Ex. No Int-60 J dihydro-lH-indene-5- Int-59 1.2. 254.3 ionizatiosYT>0carboxylic acid 16.2 n _\ O zi N-( 1 -(2 -chloro- 1,6- naphthyridin-7- Ozp O „ Int-10 / Cl yl)cyclopropyl)-7- Int-61 H NT N ifInt-10 + I2 456.0 456.2NUU (ethylsulfony 1) -2, 3 - Int-60dihydro-lH-indene-5- carboxamide6-((l -methyl- 1H- CAS#pyrazol-4-yl)ethynyl)- 719310-31-3 Ex. No Int-62 3,4-dihydro-2H- 339.4+ 2.13 LCMS benzo [b] [ 1,4] oxazineCAS#CAS# 2645928-74-939806-89-8Mt MS Int# Structure Name SM MWd Mes’d tert-butyl (l-(2-(6-((l- methyl- 1H-pyrazol-4- yl)ethynyl)-2,3-dihydro- ) Int-13 Ex.4H-pyrido[3,2- Int-63 + 1.2. 523.6 524.4 b] [ 1,4]oxazin-4-yl)- 1,6- Int-9 12.1naphthyridin-7-N\ yl)cyclopropyl)carbamatel-(2-(6-((l -methyl- 1H- pyrazol-4-yl)ethynyl)- 2,3-dihydro-4H- Ex.pyrido[3,2- 423.5Int-64 Int-63 I.2. 424.4 b] [ 1,4]oxazin-4-yl)- 1,6- Free base II.2naphthyridin-7- Z yl)cyclopropan- 1 -amine, / / ° Az ^ trifluoroacetic saltz — ' / =Zl-(2-(6-ethyl-2,3- V7 l^° dihydro-4H- Int- « / YV 346.4A / y benzo [b] [ 1,4] oxazin-4- Int-7 H2 347.3 65 0xTFA \ZZFree baseI y 1) - 1,6-naphthyridin-7- < zLLI CXco H I y l)cy clopropan- 1 -amineX CAS# 626-05- 6-bromo-6'-methyl-[2,4'- 1 + CAS#Int- Ex. 274.0 bipyridine]-2'- 73183-34-3 + 274.166 2.13 276.0 carbonitrile CAS#886372-53-8Cl5-chloro-l-((2-r°> A CAS#1 L h (trimethylsilyl)ethoxy)mInt- 1260665-77-7 Ex. 301.3 ethyl)-2,3-dihydro-lH- 300.967 + CAS# 2.14 303.3 pyrido[3,4- 76513-69-4b][l,4]oxazine / SiCMt MS Int# Structure Name SM MWd Mes’d z M zo 5-ethoxy-l-((2- Q < (trimethylsilyl)ethoxy)m Int-67 +Int- Ex. 331.3 ethyl)-2,3-dihydro-lH- CAS# 141-52- 310.568 2.15 333.3 p C pyrido[3,4- 6o b][l,4]oxazine5-ethoxy-2,3-dihydro- Int- Ex.lH-pyrido[3,4- Int-68 180.2 181.3 69 2.16b][l,4]oxazineNTHtert-butyl (l-(2-(5- ethoxy-2,3 -dihydro- 1H- pyrido[3,4- Int- ( Vz —z \\O —Z=- — b] [ 1,4]oxazin- 1 -y 1) - 1,6- Int-9 + Int-69 K 463.5 464.3 70naphthyridin-7- > zH\ 7 \Oyl)cyclopropyl)carbamatCO C / ' — e\z l-(2-(5-ethoxy-2,3- cixI dihydro- IH-pyrido [3,4- Int- b] [ 1,4]oxazin- 1 -y 1) - 1,6- Int-70 H2 363.4 364.2 71naphthyridin-7- y l)cy clopropan- 1 -aminetert-butyl (l-(2-(6-((l- 3V7 methyl- 1H-pyrazol-4- BocH NNyl)ethynyl)-2,3-dihydro- Int- *34H-benzo [b] [ 1,4] oxazin- Int-9 + Int-62 K 522.6 523.4 72 1 14-yl)- 1,6-naphthyridin-7- yl)cyclopropyl)carbamatN- -Ne) l-(2-(6-((l -methyl- 1H- pyrazol-4-yl)ethynyl)- Int- ) 2,3-dihydro-4H- Int-72 H2 422.5 423.4 73 benzo [b] [ 1,4] oxazin-4- y 1) - 1,6-naphthyridin-7- yl)cy clopropan- 1 -amineN\Mt MS Int# Structure Name SM MWd Mes’d IX tert-butyl (l-(2-(6- - F (difluoromethyl)-2- Int- ethoxypyridin-3 -y 1) - 1,6- Int-9 + CAS#v Cv HiFB 456.5 457.3 74 BocH N naphthyridin-7- 3008582-87-10^2MZ — L yl)cyclopropyl)carbamate1 -(2-(6-(difluoromethyl)- F2-ethoxypyridin-3 -y 1)- Int- v HrF356.41,6-naphthy ridin-7- Int-74 Hl 357.2 75 Free base xHCI yl)cyclopropan- 1 -amine,hydrochloride salttert-butyl (l-(2-(2- F (cyclopropylmethoxy)-6- Int-9 +Int- vf(difluoromethyl)pyridin- BOCHN'^H;:^N';Y ^NCAS# B 482.5 483.3 76 3 -y 1)- 1,6-naphthy ridin-7 - 3008582-92-8 yl)cyclopropyl)carbamatAel-(2-(2- wz(cyclopropylmethoxy)-6- Int- Q Ex.(difluoromethyl)pyridin- Int-76 382.4 383.3 77 2.17CM zI 3 -y 1)- 1,6-naphthy ridin-7 - y l)cy clopropan- 1 -aminetert-butyl (l-(2-(6- 3 (pyridin-4-ylethynyl)- V7 r^(BocH N ^ 7JJ? XYN< SrNY* 2,3-dihydro-4H- Int- pyrido[3,2- Int-9 + CAS#K 520.6 521.3 78 1 1 b] [ 1,4]oxazin-4-yl)- 1,6- 2611142-40-4naphthyridin-7- c ) yl)cyclopropyl)carbamate) l-(2-(6-(pyridin-4- ylethynyl)-2,3-dihydro- ) 4H-pyrido[3,2- Int- b] [ 1,4]oxazin-4-yl)- 1,6- Int-78 Hl 420.5 421.4 79naphthyridin-7- yl)cyclopropan- 1 -amine,) hydrochloride saltMt MS Int# Structure Name SM MWd Mes’d tert-butyl (l-(2-(6-((l- methyl- lH-imidazol-5 - yl)ethynyl)-2,3-dihydro- Int- 4H-pyrido[3,2- Int-9 + CAS#523.6 524.3 80 b] [ 1,4]oxazin-4-yl)- 1,6- 2646848-11-3naphthyridin-7- yl)cyclopropyl)carbamatel-(2-(6-((l -methyl- 1H- imidazol-5-yl)ethynyl)- 2,3-dihydro-4H- Int- pyrido[3,2- 423.5Int-80 Hl 424.4 81 b] [ 1,4]oxazin-4-yl)- 1,6- Free base naphthyridin-7- yl)cyclopropan- 1 -amine,hydrochloride salttert-butyl (l-(2-(6-((l,5- dimethyl- 1H-pyrazol-4- yl)ethynyl)-2,3-dihydro- Int- 4H-pyrido[3,2- Int-9 + CAS#K 537.6 538.3 82 b] [ 1,4]oxazin-4-yl)- 1,6- 2436208-40-9naphthyridin-7- yl)cyclopropyl)carbamatl-(2-(6-((l,5-dimethyl- 1H-pyrazol-4- yl)ethynyl)-2,3-dihydro- Int- 4H-pyrido[3,2- Int-82 Hl 437.5 438.4 83b] [ 1,4]oxazin-4-yl)- 1,6- naphthyridin-7- y l)cy clopropan- 1 -amineMt MS Int# Structure Name SM MWd Mes’d tert-butyl (l-(2-(6-((l,3- dimethyl- 1H-pyrazol-4- V7 3BOCHN'^ YJ;^N^N^ yl)ethynyl)-2,3-dihydro- JInt- 4H-pyrido[3,2- Int-9 + CAS#K 537.6 538.4 84 b] [ 1,4]oxazin-4-yl)- 1,6- 2606666-96-8naphthyridin-7- / AN- -N / yl)cyclopropyl)carbamate1 -(2-(6-(( 1, 3 -dimethy 1- ) lH-pyrazol-4- H2N^ Y^fNyNY^ yl)ethynyl)-2,3-dihydro- Int- 4H-pyrido[3,2- Int-84 Hl 437.5 438.4 85 b] [ 1,4]oxazin-4-yl)- 1,6- xHCI naphthyridin-7- / T" / IM- N yl)cyclopropan- 1 -amine, / V / —hydrochloride saltz ' —l^°6-((l-methyl-lH-l,2,3- CAS#Int- 0 X) triazol-5-yl)ethynyl)-3,4- 959992-62-2 +z J 241.3 242.3 86 o I dihydro-2H-pyrido [3,2- CAS#ffi ob][l,4]oxazine 1602775-02-9N=Ntert-butyl (l-(2-(6-((l- 3 methy 1- 1H- 1,2, 3 -triazol- 5-yl)ethynyl)-2,3- Int- J dihydro-4H-pyrido [3,2- Int-9 +K 524.6 525.4 87 b] [ 1,4]oxazin-4-yl)- 1,6- Int-861naphthyridin-7- =N yl)cyclopropyl)carbamateMt MS Int# Structure Name SM MWd Mes’d 1 -(2-(6-((l -methyl- 1H- l,2,3-triazol-5- yl)ethynyl)-2,3-dihydro- Int- 4H-pyrido[3,2- 424.5Int-87 Hl 425.4 88 b] [ 1,4]oxazin-4-yl)- 1,6- Free base naphthyridin-7- yl)cyclopropan- 1 -amine,hydrochloride salttert-butyl 5-fluoro-6-((l- CAS#methyl- 1H-pyrazol-4- 1352318-72-9Int- yl)ethynyl)-2,3-dihydro- + J 357.3 358.3 89 4H- CAS# 39806- benzo[b] [l,4]oxazine-4- 89-8carboxylateN-N^5 -fluoro-6-(( 1 -methyl- No Int- lH-pyrazol-4- Int-89 H2 257.3 ionizatio 90 yl)ethynyl)-3,4-dihydro- n 2H-benzo [b] [ 1,4] oxazineN-N\tert-butyl (l-(2-(5-fluoro- 6-((l -methyl- 1H- pyrazol-4-yl)ethynyl)- Int- 2,3-dihydro-4H- Int-9 +K 540.6 541.3 91 benzo [b] [ 1,4] oxazin-4- Int-90yl)- 1,6-naphthyridin-7- yl)cyclopropyl)carbamatl-(2-(5-fluoro-6-((l- methyl- 1H-pyrazol-4- Int- yl)ethynyl)-2,3-dihydro- Int-91 H2 440.5 441.4 92 4H-benzo [b] [ 1,4] oxazin- 4-yl)- 1,6-naphthyridin-7- y l)cy clopropan- 1 -amineMt MS Int# Structure Name SM MWd Mes’d tert-butyl (l-(2-(6-((l- ethyl- lH-pyrazol-4- yl)ethynyl)-2,3-dihydro- Int- 4H-pyrido[3,2- Int-9 + CAS#537.6 538.3 93 b] [ 1,4]oxazin-4-yl)- 1,6- 2497547-17-6naphthyridin-7- yl)cyclopropyl)carbamatel-(2-(6-((l -ethyl- 1H- pyrazol-4-yl)ethynyl)- 2,3-dihydro-4H- Int- pyrido[3,2- Int-93 H2 437.5 438.4 94b] [ 1,4]oxazin-4-yl)- 1,6- naphthyridin-7- yl)cy clopropan- 1 -aminetert-butyl (l-(2-(6-((l- methyl- lH-pyrazol-3 - yl)ethynyl)-2,3-dihydro- Int- 4H-pyrido[3,2- Int-9 + CAS#K 523.6 524.2 95 b] [ 1,4]oxazin-4-yl)- 1,6- 2626911-33-7naphthyridin-7- yl)cyclopropyl)carbamatl-(2-(6-((l -methyl- 1H- pyrazol-3 -yl)ethynyl)- 2,3-dihydro-4H- Int- pyrido[3,2- Int-95 Hl 423.5 424.5 96b] [ 1,4]oxazin-4-yl)- 1,6- naphthyridin-7- y l)cy clopropan- 1 -aminel-(2-(6-((l -methyl- 1H- pyrazol-4-yl)ethynyl)- 2,3-dihydro-4H- Int- pyrido[3,2- Int-63 H2 423.5 424.2 97b] [ 1,4]oxazin-4-yl)- 1,6- naphthyridin-7- yl)cy clopropan- 1 -amineMt MS Int# Structure Name SM MWd Mes’d6-((l-methyl-lH-l,2,3- CAS#Int- triazol-4-yl)ethynyl)-3,4- 959992-62-2 +241.3 242.2 98 dihydro-2H-pyrido [3,2- CAS#b][l,4]oxazine 1809889-77-7NN-Ntert-butyl (l-(2-(6-((l- methy 1- 1H- 1,2, 3 -triazol- 4-yl)ethynyl)-2,3- Int- dihydro-4H-pyrido [3,2- Int-9 +524.6 525.4 99 b] [ 1,4]oxazin-4-yl)- 1,6- Int-98naphthyridin-7- yl)cyclopropyl)carbamate1 -(2-(6-((l -methyl- 1H- l,2,3-triazol-4- yl)ethynyl)-2,3-dihydro- Int- 4H-pyrido[3,2- Int-99 424.5 425.4 100xHCI b] [ 1,4]oxazin-4-yl)- 1,6- naphthyridin-7- y l)cy clopropan- 1 -aminetert-butyl (l-(2-(6- (pyridin-3 -ylethynyl)- 2,3-dihydro-4H- Int- pyrido[3,2- Int-9 + CAS#K 520.6 521.4 101 b] [ 1,4]oxazin-4-yl)- 1,6- 2614970-75-9naphthyridin-7- yl)cyclopropyl)carbamatl-(2-(6-(pyridin-3- ylethynyl)-2,3-dihydro- Int- 4H-pyrido[3,2- Ex.Int-101 420.5 421.4 102 b] [ 1,4]oxazin-4-yl)- 1,6- 2.18naphthyridin-7- yl)cy clopropan- 1 -amineMt MS Int# Structure Name SM MWd Mes’d 00 o ooZEBoc ZN — < ^ l tert-butyl 6-(3- CAS#\ / z— (benzyloxy)cyclobutyl)- 959992-64-4 +Int- X & O o v— ——\ / Z \ I) 2,3-dihydro-4H- Ex._ CAS# 396.5 397.2 103 z — < pyrido[3,2- 2.191807941-88-3~f\ < o o— y——\Z \ / X _ b][l,4]oxazine-4- carboxylateOBn3 -(3,4-dihy dro-2H- Int- pyrido[3,2- Ex.Int-103 206.2 207.2 104 b][l,4]oxazin-6- 2.20yl)cy clobutan- 1 -oltert-butyl (l-(2-(6- ((ls,3s)-3- z hydroxycyclobutyl)-2,3 - c o O XInt- o dihydro-4H-pyrido [3,2- Int-9 + Ex.489.6 490.4 105 b] [ 1,4]oxazin-4-yl)- 1,6- Int-104 2.21naphthyridin-7- yl)cyclopropyl)carbamatetert-butyl (l-(2-(6- ((lr,3r)-3- hydroxycyclobutyl)-2,3 - Int- dihydro-4H-pyrido [3,2- Int-9 + Ex.489.6 490.4 106 b] [ 1,4]oxazin-4-yl)- 1,6- Int-104 2.21naphthyridin-7- yl)cyclopropyl)carbamateMt MS Int# Structure Name SM MWd Mes’d (ls,3s)-3-(4-(7-(l- \zoIO OT- aminocyclopropyl)- 1,6- \bY= naphthyridin-2-yl)-3,4- Int- 389.5xHCI dihydro-2H-pyrido [3,2- Int-105 Hl 390.4 107 Free base° 2= b][l,4]oxazin-6- o i y l)cy clobutan- 1 -ol,OHhydrochloride salt(lr,3r)-3-(4-(7-(l- v r^° aminocyclopropyl)- 1,6- " / AVZ naphthyridin-2-yl)-3,4- Int- 389.5dihydro-2H-pyrido [3,2- Int-106 Hl 390.4 108 xHCI T Free base b][l,4]oxazin-6- yl)cy clobutan- 1 -ol,OHhydrochloride saltCAS#(4-bromo-2-((3- Int- CQ 1824151-57-6 Ex. No bromopropyl)thio)phenyl 340.1109 HO^l^ + CAS# 109- 2.22 LCMS)methanolw A 64-8°= 9-bromo-3,4-dihydro- Int- Ex. No \ z° 2H,6H- Int-109 259.2 110 I XX 2.23 LCMS benzo [c] [ 1, 5] oxathiocine9-bromo-3,4-dihydro- Int- 2H,6H- Ex. No Int-110 291.2111 benzo [c] [ 1,5]oxathiocine 2.24 LCMS 1,1 -dioxide3,4-dihydro-2H,6H- Int- benzo [c] [ 1, 5] oxathiocine No Int-111 O 256.3112 -9-carboxylic acid 1,1- LCMS dioxideCAS#3-chloro-5- Int-FTF 01565036-94-3 Ex. No ((difluoromethyl)thio)-4- 252.7113 + CAS# 1493- 2.26 LCMS V °" methylbenzoic acid03-4Cl1 0 ° 3-chloro-5- Int- No ((difluoromethyl)sulfony Int-113 P 284.7114 LCMSF°5X °ClHl)-4-methylbenzoic acidMt MS Int# Structure Name SM MWd Mes’d A tert-butyl (R)-9-chloro-4- CAS#o 0 fluoro-3,4-dihydro-2H- Int-uW oS xw< / Oo A 3008582-64-4 Ex. No 'O o benzo [b] [ 1,4]oxathiepine 350.8115 + CAS# 2.27 LCMS -7 -carboxy late 5,5- 24424-99-5° ° ° / / / dioxide° / o o o o I tert-butyl (R)-4-fluoro-9- vinyl-3,4-dihydro-2H- Int-115 +Int- Ex. No benzo [b] [ 1,4]oxathiepine CAS# 75927- 342.4116 2.28 LCMS -7 -carboxy late 5,5- 49-0dioxidetert-butyl (R)-4-fluoro-9- formyl-3,4-dihydro-2H- Int- Ex. No benzo [b] [ 1,4]oxathiepine Int-116 344.4117 2.29 LCMS -7 -carboxy late 5,5- dioxideA Ao o tert-butyl (R)-4-fluoro-9- o / o / == (hydroxymethyl)-3,4- Int- dihydro-2H- Ex. No Int-117 346.4 118 3> Q< / O= benzo [b] [ 1,4]oxathiepine 2.30 LCMS -7 -carboxy late 5,5- k> ° °"° dioxidetert-butyl (R)-4-fluoro-9- (methoxymethyl)-3,4- Int- dihydro-2H- Int-118 + Ex. No 360.4119 benzo [b] [ 1,4]oxathiepine CAS# 76-05-1 2.31 LCMS -7 -carboxy late 5,5- dioxide(R)-4-fluoro-9- (methoxymethyl)-3,4- Int- dihydro-2H- No Int-119 Q 304.3120 benzo [b] [ 1,4]oxathiepine LCMS -7 -carboxylic acid 5,5- dioxideMt MS Int# Structure Name SM MWd Mes’d tert-butyl (R)-9- (difluoromethyl)-4- o Int-117 +Int- \Z O m= fluoro-3,4-dihydro-2H- Ex. 365.0CAS# 38078- 366.4121 benzo [b] [ 1,4]oxathiepine 2.32 [M-H]- 09-0O= / -7 -carboxy late 5,5-O= / OOI dioxide(R)-9-(difluoromethyl)- 4-fluoro-3,4-dihydro-2H- Int- 308.8 benzo [b] [ 1,4]oxathiepine Int-121 Q 310.2122 [M-H]- -7 -carboxylic acid 5,5- dioxide^0HN J. 1 -(3,4-dihy dro-2H- Int- pyrido[3,2- CAS#u H2 207.2 208.3 123 b][l,4]oxazin-6- 3080313-30-7yl)azetidin-3-olOH|^^06-(3-((tert- HN^ lbutyldimethylsilyl)oxy)a Int-123 +Int- Ex.M zetidin-l-yl)-3,4- CAS# 18162- 321.5 322.3 124 2.33dihy dro-2H-pyrido [3,2- 48-6b][l,4]oxazineOTBStert-butyl (l-(2-(6-(3- ((tert- butyldimethylsilyl)oxy)aV7 r^°BocH N zetidin-l-yl)-2,3- Int-NInt-9 +dihydro-4H-pyrido [3,2- K 604.8 605.4 125 Int-124b] [ 1,4]oxazin-4-yl)- 1,6- OTBS naphthyridin-7- yl)cyclopropyl)carbamateMt MS Int# Structure Name SM MWd Mes’d X7 z o I l-(4-(7-(l- J " O ■n.m aminocyclopropyl)- 1,6- Int- ) \ O / Os _W \. naphthyridin-2-yl)-3,4- Cl / Int-125 H2 390.4 391.4 126 dihydro-2H-pyrido [3,2- b][l,4]oxazin-6- ° z —. / O 00\ yl)azetidin-3-ol" 4 O Z ov———\ / xz X _ethyl 2-((5-bromo-2- CAS# 69321- Int- Ex. No methylphenyl)thio)-2- 55-7 + CAS# 307.2127 2.34 LCMS fluoroacetate 401-55-8°^sxxBr0. X ethyl 2-((5-bromo-2- 336.8 Int- methylphenyl)sulfonyl)- Int-127 P 339.2 338.8 128 X 'PF S. xx / Br 2-fluoroacetate [M-H]- °'XX2-((5-bromo-2- Int- Ex. No methylphenyl)sulfonyl)- Int-128 297.1129 2.35 LCMS 2-fluoroethan- 1 -olHO.(R*)-3-((l-fluoro-2- Int- X° u Ex. No hydroxyethyl)sulfonyl)- Int-129 262.3130 2.36 LCMS 4-methylbenzoic acid° X^0HRelative stereochemistryHO.(S*)-3-((l-fluoro-2- Int- X° u Ex. No hydroxyethyl)sulfonyl)- Int-129 262.3131 2.36 LCMS ° X^0H4-methylbenzoic acidRelative stereochemistrymethyl 1- CAS# 1512- No Int- ((difluoromethyl)sulfony Ex.30-7 + CAS# 309.3 lonizatio 132 l)-4-fluoroindoline-6- 2.373069004-35-6 n carboxylateMt MS Int# Structure Name SM MWd Mes’d FF-~~ / 1- „V oo oInt- O ' U ((difluoromethyl)sulfony Ex. 294.1\ / xo Int-132 295.2133 l)-4-fluoroindoline-6- 2.38 [M-H]- D ( carboxylic acidF1° / oI (R)-4-fluoro-9- (hydroxymethyl)-3,4- Int- dihydro-2H- Ex. 289.1Int-118 290.3134 benzo [b] [ 1,4]oxathiepine 2.39 [M-H]- -7 -carboxylic acid 5,5- dioxideF 3-chloro-5- f? ((difluoromethyl)sulfony [M-H]- Int- F S. A Ex.l)-4- Int-136 300.7 298.8- 135 6ZnOx^ YAsJITJ0H2.40(hydroxymethyl)benzoic 300.8 Cl o4 ' acidethyl 3-chloro-5- ((difluoromethyl)sulfony [M-H]- Int- \k C / )kZ C l)-4- Int-137 O 328.7 326.8- 136AO U-° ' (hydroxymethyl)benzoat 328.8 k1eF(4-bromo-2-chloro-6- Int- F S. Rr Ex. Non ((difluoromethyl)sulfony Int-138 335.5137 °' Y |f 2.41 ionizable l)phenyl)methanolCl(4-bromo-2-chloro-6- Int- CAS# Ex. Non ((difluoromethyl)thio)ph 303.6138 2384513-34-0 2.42 ionizable ■ A enyl)methanolOH Cl3- 1 O 0Int- ((difluoromethyl)sulfony [M-H]- Int-140 P 268.2139F°'XYOHl)-5-fluoro-4- 266.9 methylbenzoic acidF03 -((difluoromethyl)thio)- Int- CAS#1566568 Ex. [M-H]- 5-fluoro-4- 236.2140 -09-9 2.43 234.9 methylbenzoic acidFMt MS Int# Structure Name SM MWd Mes’d (R)-4-fluoro-9-(2- B 9v / P fthydroxyethyl)-3,4- / (R)Int- OH dihydro-2H- Ex [M-H]- Int-142 304.3141 benzo [b] [ 1,4]oxathiepine 2.44 303.1-7 -carboxylic acid 5,5- OH dioxidetert-butyl (R)-4-fluoro-9- E %O 0 |7-SC JI J<f (2-hydroxyethyl)-3,4- Int- / (R) p " ||0dihydro-2H- Ex. [M-H]- Int-143 360.4142 ^~~o^y benzo [b] [ 1,4]oxathiepine 2.45 359.2-7-carboxylatc 5,5- OH dioxidetert-butyl (R)-4-fluoro-9- BZ%°? 1 / VsC JL (2-oxoethyl)-3,4- Int- / (R) p ' ||0dihydro-2H- Ex [M-H]- Int-116 358.4143 ^o^y benzo [b] [ 1,4]oxathiepine 2.46 357.1-7-carboxylatc 5,5- 110 dioxide(R)-4-fluoro-9-methyl- F, ° <0 9 3,4-dihydro-2H- Int- 7— s / JI 273.05[ benzo [b] [ 1,4]oxathiepine 3008582-64-4 Ex 274.26144 \ r II0HM-H]-.x--o'zy^ -7 -carboxylic acid 5,5- dioxide(R)-9- F,_? (cyclopropoxymethyl)-4- >-S' AInt- / abs || OH fluoro-3,4-dihydro-2H- 3008582-64-4 Ex 330.33 - 145 benzo [b] [ 1,4]oxathiepine%-7 -carboxylic acid 5,5- Adioxide(R)-9-cyano-4-fluoro- B?vP fl 3,4-dihydro-2H- Int- 284 [M- < h °Hbenzo [b] [ 1,4]oxathiepine Int- 146a Ex 285.25146 H]- i Nll -7 -carboxylic acid 5,5- dioxideMt MS Int# Structure Name SM MWd Mes’d tert-butyl (R)-9-cyano-4- )'n_oc<Q o & fluoro-3,4-dihydro-2H- Int- No MS benzo [b] [ 1,4]oxathiepine Int-115 Ex 341.35 146a Y%<c response -7 -carboxy late 5,5- Ndioxide° 2=o (RS)-3-chloro-5-((l- I [M-H]- Int- HO^LP? fluoro-2- 1565036-94-3 Ex 296.99 295.0- 147 hydroxyethyl)sulfonyl)- Cl 297.04-methylbenzoic acid(R*)-3 -chloro-5-(( 1 - [M-H]- Int- fluoro-2- Int-147 Ex 296.99 295.0- 148 O'XJ0Hhydroxyethyl)sulfonyl)- Cl 297.04-methylbenzoic acidRelative stereochemistry(S*)-3-chloro-5-((l- [M-H]- Int- fluoro-2- Int-147 Ex 296.99 295.0- 149 0^ hydroxyethyl)sulfonyl)- Cl 297.0 Relative stereochemistry 4-methylbenzoic acidmethyl 3-chloro-5-((l- [M+AcO Int- fluoro-2- ]- CAS#1566273 ex 296.7150 hydroxyethyl)sulfonyl)be 354.9- -16-2nzoate 356.9 Cl(R)-3-chloro-5-((l- U [M-H]- Int- fluoro-2- o' YjOHInt-150 ex 282.7 280.9- 151 hydroxyethyl)sulfonyl)be282.9 Cl nzoic acidRelative stereochemistry(S)-3-chloro-5-((l- HO^Y 'P? [M-H]- Int- ^ (S) s. X fluoro-2- o' YjOHInt-150 ex 282.7 280.9- 152 hydroxyethyl)sulfonyl)be282.9 Cl nzoic acidRelative stereochemistry3- ((difluoromethyl)sulfonyInt- CAS#2592405 [M-H]-:l)-5- ex 280.24153 -50-8 279.1,(methoxymethyl)benzoicacidMt MS Int# Structure Name SM MWd Mes’d tert-butyl (4R)-4-fluoro- QO 9-(l-hydroxyethyl)-3,4- Int- y( ° \= dihydro-2H- Int-117 ex 360.40 - 154a benzo [b] [ 1,4]oxathiepineY1° -7 -carboxy late 5,5- odioxide(4R)-4-fluoro-9-(l- hydroxyethyl)-3,4- Int- dihydro-2H- [M-H]- Int- 154a ex 304.29154 benzo [b] [ 1,4]oxathiepine 303.1-7 -carboxylic acid 5,5- dioxideo 2 3-bromo-5- Int-C|--s A 314.8(chlorosulfonyl)-4- 14348-41-5 ex 315.52155ao<" YY °H[M+H]+X hydroxybenzoic acidBr oO o / =Int- A< ° 3-bromo-4-hydroxy-5- 248.9 vII J H Int-155a ex 249.08155b mercaptobenzoic acid [M+H]£\s2 c»=+BrOmethyl 3-bromo-4- Int-HSyk°Me262.9 hydroxy-5- Int-155b ex 263.11155c [M+H]+Hcr 'y mercaptobenzoateBrO methyl 9-bromo-3,4- Int- ^S. A dihydro-2H- 302.9< Il ApOMeInt-155c ex 303.17 155d benzo [b] [ 1,4]oxathiepine [M+H]+X~~-o / y^Br -7 -carboxy latemethyl 9-bromo-4- R?Int- V-Sx A / Nf AK OMe fluoro-3,4-dihydro-2H- 320.9Int-155d ex 321.16155e benzo [b] [ 1,4]oxathiepine [M+H]+Br -7 -carboxy latemethyl 9-bromo-4- r F-. 0 0fluoro-3,4-dihydro-2H- 352.9 [M Int- ASKx^xC°2Mebenzo [b] [ 1,4]oxathiepine Int-155e ex 353.16 +H]+155f-7 -carboxy late 5,5- o?Br dioxideMt MS Int# Structure Name SM MWd Mes’d (RS)-9-bromo-4-fluoro- r- O rj3,4-dihydro-2H- Int- )'n-ex cx / CO2H 338.9[M 'O / m_ benzo [b] [ 1,4]oxathiepine Int-155d ex 339.13155 +H]+0 7 -7 -carboxylic acid 5,5- Br °= / dioxideo\ rel-(R)-9-bromo-4- FzzOr1° / P fluoro-3,4-dihydro-2H- Int- X-S, C°2H 338.9[M \ ]i jT benzo [b] [ 1,4]oxathiepine Int-155 ex 339.13 156 +H]+- -7 -carboxylic acid 5,5- Br dioxiderel-(S)-9-bromo-4- F<or1°< P fluoro-3,4-dihydro-2H- Int- V-Sx / ^, CO2Hns) y y 338.9[M benzo [b] [ 1,4]oxathiepine Int-155 ex 339.13157 +H]+- -7 -carboxylic acid 5,5- Br dioxideXo \o methyl 3- Int- JL? 1( o o / ==((difluoromethyl)sulfony 3068483-66-6 Ex 276.25 - 158aFl)-5-vinylbenzoatexX e C / / “■ 'methyl 3- Int- ((difluoromethyl)sulfony Int- 158a Ex 278.23 - 158bl)-5-formylbenzoatemethyl 3- Int- (difluoromethyl)-5- Int-158b Ex 300.22 - 158c ((difluoromethyl)sulfonyl)benzoate3 -(difluoromethy 1) -5 - Int- 285.1((difluoromethyl)sulfony Int-158c Ex 286.20158 [M-H]- l)benzoic acidEx: synthetic preparation is has been exemplified.Table III. Illustrative compounds of the invention.SM = Starting Material, Mtd = Method, MS Mes’d = Measured massc: MS Cpd# Structure Name SM Mtd MW Mes’d N-(l-(2-(2,3-dihydro-4H- Cpd- pyrido[3,2-b] [ 1,4]oxazin- 164-yl)- 1,6-naphthyridin-7 - +yl)cyclopropyl) -2,3 - CASCpd-1 K 543.6 544.3 dihydro-5H- #benzo[e] [ 1,4]oxathiepine- 20348 -carboxamide 1,1- 8-23- dioxide 6N-( 1 -(2 -hydroxy- 1,6- Int- P c naphthyridin-7- 11yl)cyclopropyl)-4-methyl- +3- CAS ExCpd-2 397.5 398.1JU NJU (methylsulfonyl)benzamid # 2.1.2e 1146702- 14-8N-(l-(2-(2,3-dihydro-4H- Int- pyrido[3,2-b] [ 1,4]oxazin- 154-yl)- 1,6-naphthyridin-7 - +yl)cyclopropyl)-4-methyl- CASCpd-3 K 515.6 516.23- # (methylsulfonyl)benzamid 2034e 8-23- 6MS Cpd# Structure Name SM Mtd MW Mes’d N-( 1 -(2-(6-cyano-2,3- Int- dihydro-4H-pyrido [3,2- 15b] [ 1,4]oxazin-4-yl)- 1,6- +9vp ov1^0naphthyridin-7- CASCpd-4 K 540.6 541.2 yl)cyclopropyl)-4-methyl- #N3- 9281 (methylsulfonyl)benzamid 18- e 39-24-(7-(l-(4-methyl-3- Int- (methylsulfonyl)benzamid 17o)cyclopropyl)-l,6- +q wp 0 v-7II \ / 1 1 naphthyridin-2-yl)-3,4- CAS Ex.l.Cpd-5 Ju " uQ u 558.6 559.3H2NU) dihydro-2H-pyrido [3,2- # 2.5.1b][l,4]oxazine-6- 1146carboxamide 702- 14-8N-(l-(2-(2,3-dihydro-4H- Int- pyrido[3,2-b] [ 1,4]oxazin- 234-yl)- 1,6-naphthyridin-7 - +yl)cyclopentyl)-4-methyl- CASCpd-6 I 543.6 544.03- # (methylsulfonyl)benzamid 5152e 2-22- 6N-( 1 -(2-(6-cyclobutyl- Int- 2,3-dihydro-4H- 41pyrido[3,2-b] [ 1,4]oxazin- +0 'X,*00Il V \- / 7 1 I4-yl)- 1,6-naphthyridin-7 - CASCpd-7 JJ OCU u E 569.7 570.2 yl)cyclopropyl)-4-methyl- #3- 1146 (methylsulfonyl)benzamid 702- e 14-8MS Cpd# Structure Name SM Mtd MW Mes’d N-(l-(2-(6-ethyl-2,3- Int-8dihydro-4H- +benzo [b] [ 1,4] oxazin-4- CASyl)- 1,6-naphthyridin-7 - Ex.Cpd-8 # 542.6 543.3 yl)cyclopropyl)-4-methyl- 2.2.251523- 2-22- (methylsulfonyl)benzamid6eN-(l-(2-(2,3-dihydro-4H- Int- pyrido[3,2-b] [ 1,4]oxazin- 274-yl)- 1,6-naphthyridin-7 - +yl)cyclobutyl)-4-methyl- CASCpd-9 I 529.6 530.23- #P c (methylsulfonyl)benzamid 5152e 2-22- 6ZIN-(3-(2-(2,3-dihydro-4H- Int-OS“ s ' pyrido[3,2-b] [ 1,4]oxazin- 374-yl)- 1,6-naphthyridin-7 - +yl)oxetan-3-yl)-2,3- CASCpd-10 I 559.6 560.2 dihydro-5H- #benzo[e] [ 1,4]oxathiepine- 27718 -carboxamide 1,1- 132- dioxide 16-0N-(3-(2-(2,3-dihydro-4H- CASpyrido[3,2-b] [ 1,4]oxazin- #4-yl)- 1,6-naphthyridin-7 - 5152yl)oxetan-3-yl)-4-methyl- 2-22- Cpd-11 I 531.6 532.23- 6 (methylsulfonyl)benzamid +e Int- 37MS Cpd# Structure Name SM Mtd MW Mes’d N-(l-(2-(6-ethyl-2,3- Int- dihydro-4H-pyrido [3,2- 45b] [ 1,4]oxazin-4-yl)- 1,6- +naphthyridin-7- CASCpd-12 yl)cyclopropyl) -2,3- I 571.6 572.2#dihydro-5H- 2771benzo[e] [ 1,4]oxathiepine- 132- 8 -carboxamide 1,1- 16-0dioxideN-( 1 -(2-(6-cyclobutyl- 2,3-dihydro-4H- pyrido[3,2-b] [ 1,4]oxazin- Cpd- 4-yl)- 1,6-naphthyridin-7 - 16Cpd-13 yl)cyclopropyl) -2,3 - + K 597.7 598.3 dihydro-5H- Int- benzo[e] [ 1,4]oxathiepine- 398 -carboxamide 1,1- dioxideN-( 1 -(2-(6-cyano-2,3- Cpd- dihydro-4H- 16benzo [b] [ 1,4] oxazin-4- +yl)- 1,6-naphthyridin-7 - CASCpd-14 yl)cyclopropyl) -2,3 - K 567.6 568.3#dihydro-5H- 9281benzo[e] [ 1,4]oxathiepine- 18- 8 -carboxamide 1,1- 07-4dioxideMS Cpd# Structure Name SM Mtd MW Mes’d N-(l-(2-(6-ethyl-2,3- Cpd- dihydro-4H- 16benzo [b] [ 1,4] oxazin-4- op ° v-7 +yl)- 1,6-naphthyridin-7 - CAS Ex.Cpd-15 Ou «Xu u yl)cyclopropyl) -2,3 - 570.7 571.3# 2.3dihydro-5H- 1018benzo[e] [ 1,4]oxathiepine- 638- 8 -carboxamide 1,1- 76-0dioxideN-( 1 -(2 -chloro- 1,6- Int- naphthyridin-7- 10yl)cyclopropyl) -2,3 - +Ex.dihydro-5H- CASCpd-16 o 2.4.1 443.9 444.1 benzo[e] [ 1,4]oxathiepine- #18 -carboxamide 1,1- 2771dioxide 132- 16-00 N-( 1 -(2 -chloro- 1,6- Int- naphthyridin-7- 10yl)cyclopropyl)-4-methyl- +3- CASd -' °SPV^O %CpKA V-17 ^N CI I 415.9 416.3Ju " uJ (methylsulfonyl)benzamid #e 51522-22- 6MS Cpd# Structure Name SM Mtd MW Mes’d N-(l-(2-(6-(l -methyl- 1H- fe pyrazol-4-yl)-2,3- dihydro-4H-pyrido [3,2- Cpd- b] [ 1,4]oxazin-4-yl)- 1,6- 16naphthyridin-7- Cpd-18 P c + K 623.7 624.3 yl)cyclopropyl) -2,3- Int- dihydro-5H- 54benzo[e] [ 1,4]oxathiepine- 8 -carboxamide 1,1- dioxideN-(l-(2-(l -methyl- 1H- Cpd- indol-4-yl)-l,6- 16naphthyridin-7- +yl)cyclopropyl) -2,3 - CASCpd-19 B 538.6 539.3 dihydro-5H- #benzo[e] [ 1,4]oxathiepine- 89828 -carboxamide 1,1- 89- dioxide 06-0N-(l-(2-(4-methyl-3,4- Cpd- dihydroquinoxalin- 1 (2H)- 16yl)- 1,6-naphthyridin-7 - +yl)cyclopropyl) -2,3 - CASCpd-20 K 555.6 556.3 dihydro-5H- #benzo[e] [ 1,4]oxathiepine- 36438 -carboxamide 1,1- 8-97- dioxide 8MS Cpd# Structure Name SM Mtd MW Mes’d Q N-( 1 -(2-(6-(( 1 -methyl - H lH-pyrazol-4-yl)ethynyl)- 2,3-dihydro-4H- Cpd- pyrido[3,2-b] [ 1,4]oxazin- 16 Ex.4-yl)- 1,6-naphthyridin-7 - Cpd-21 p ~ + 2.4.1 647.7 648.3 yl)cyclopropyl) -2,3- A Int- 2dihydro-5H- 15benzo[e] [ 1,4]oxathiepine- 8 -carboxamide 1,1- dioxideN-( 1 -(2-(6-cyano-2,3- Cpd- dihydro-4H-pyrido [3,2- 16b] [ 1,4]oxazin-4-yl)- 1,6- +naphthyridin-7- CASCpd-22 yl)cyclopropyl) -2,3 - K 568.6 569.3#dihydro-5H- 9281benzo[e] [ 1,4]oxathiepine- 18- 8 -carboxamide 1,1- 39-2dioxideCpd- N-( 1 -(2 -phenyl- 1,6- 16naphthyridin-7- +yl)cyclopropyl) -2,3 - Cpd-23 dihydro-5H- B 485.6 486.2JV W CASbenzo[e] [ 1,4]oxathiepine- #8 -carboxamide 1,1- 98- dioxide80-6N-( 1 -(2-(pyridin-3 -yl)- Cpd- 1,6-naphthyridin-7- 16yl)cyclopropyl) -2,3 - +Cpd-24 dihydro-5H- CAS B 486.6 487.2OCrrcO^benzo[e] [ 1,4]oxathiepine- #8 -carboxamide 1,1- 1692dioxide -25-7MS Cpd# Structure Name SM Mtd MW Mes’d N-(l-(2-(l -methyl- 1H- Cpd- H pyrazol-3-yl)-l,6- 16naphthyridin-7- +yl)cyclopropyl) -2,3- CASCpd-25 B 489.6 490.34 dihydro-5H- #1benzo[e] [ 1,4]oxathiepine- 10208 -carboxamide 1,1- 174- dioxide 04-2N-(l-(2-(l -methyl- 1H- Cpd- pyrazol-4-yl)-l,6- 16naphthyridin-7- +yl)cyclopropyl) -2,3 - CASCpd-26 B 489.6 490.3 dihydro-5H- #benzo[e] [ 1,4]oxathiepine- 76148 -carboxamide 1,1- 46-44-0N-(l-(2-(l -methyl- 1H- Cpd- b pyrazol-5-yl)-l,6- 16naphthyridin-7- +yl)cyclopropyl) -2,3 - CASCpd-27 B 489.6 490.3 dihydro-5H- #benzo[e] [ 1,4]oxathiepine- 84788 -carboxamide 1,1- 18- dioxide 74-0N-(l-(2-(6-(l -methyl- 1H- pyrazol-3-yl)-2,3- dihydro-4H-pyrido [3,2- Cpd- b] [ 1,4]oxazin-4-yl)- 1,6- 16naphthyridin-7- Cpd-28 + K 623.7 624.3 yl)cyclopropyl) -2,3 - Int- dihydro-5H- 47benzo[e] [ 1,4]oxathiepine- 8 -carboxamide 1,1- dioxideMS Cpd# Structure Name SM Mtd MW Mes’d N-( 1 -(2-(pyridin-4-yl)- Cpd- 1,6-naphthyridin-7- 16yl)cyclopropyl) -2,3- +Cpd-29 dihydro-5H- B 486.6 487.2<oJUHw CASbenzo[e] [ 1,4]oxathiepine- #8 -carboxamide 1, 16921- dioxide -15-5N-( 1 -(2-(6-cyclobutyl- 2,3-dihydro-4H- Int- 52 o wp o pyrido[3,2-b] [ 1,4]oxazin- ii \ / i iv 4-yl)- 1,6-naphthyr +AVx?-1tl N H'^NYNYS idin-7 - AJ Cpd-30 K 595.7 596.5 yl)cyclopropyl)-7 - Int- (methylsulfonyl)-2, 3 - 39dihydro- lH-indene-5 - carboxamide7 -(ethylsulfonyl)-N-( 1 -(2- (6-(prop- 1 -yn- 1 -yl)-2,3 - Int- dihydro-4H-pyrido [3,2- 56 \ 4'PU V b] [ 1,4]oxazin-4-yl)- 1,6- ^ CCr"^ i + Cpd-31 K 593.7 594.3 naphthyridin-7- Int- yl)cyclopropyl) -2,3 - 61dihydro- lH-indene-5 - carboxamideCpd-32 N-( 1 -(2-(6-(( 1 -methyl - lH-pyrazol-4-yl)ethynyl)- 2,3-dihydro-4H- Cpd- benzo [b] [ 1,4] oxazin-4- 16 dJ’VCr'X j yl)- 1,6-naphthyridin-7 - + K 646.7 647.5 yl)cyclopropyl) -2,3 - Int- dihydro-5H- 62benzo[e] [ 1,4]oxathiepine- 8 -carboxamide 1,1- dioxideMS Cpd# Structure Name SM Mtd MW Mes’d Cpd-33 4-methyl-N-( 1 -(2-(6-(( 1 - Int- methyl- 1H-pyrazol-4- 64yl)ethynyl)-2,3-dihydro- +4H-pyrido[3,2- CAS Ex.b] [ 1,4]oxazin-4-yl)- 1,6- # 1.2.1 619.2 620.3 naphthyridin-7- 5152 0.2 yl)cyclopropyl)-3 - 2-22- (methylsulfonyl)benzamid 6eCpd-34 4-chloro-N-(l-(2-(6-((l- Int- methyl- 1H-pyrazol-4- 64yl)ethynyl)-2,3-dihydro- +4H-pyrido[3,2- CASJb] [ 1,4]oxazin-4-yl)- 1,6- # I2 640.1 640.2 naphthyridin-7- 5152yl)cyclopropyl)-3 - 2-07- (methylsulfonyl)benzamid 7eInt- 4-chloro-N-( 1 -(2-(6-ethyl- 65 +2,3-dihydro-4H- CASbenzo [b] [ 1,4] oxazin-4- #Cpd-35 yl)- 1,6-naphthyridin-7 - I3 563.1 563.35152yl)cyclopropyl)-3 - J 2-07- (methylsulfonyl)benzamid7eMS Cpd# Structure Name SM Mtd MWMes’d j 6-fluoro-N-( 1 -(2-(6-(( 1 - methyl- 1H-pyrazol-4- A yl)ethynyl)-2,3-dihydro- Int- 4H-pyrido[3,2- 64 +Ob] [ 1,4]oxazin-4-yl)- 1,6- CASCpd-36 naphthyridin-7- # I2 665.7 666.5A yl)cyclopropyl) -2,3- 2771dihydro-5H- 132- benzo[e] [ 1,4]oxathiepine- 60-48 -carboxamide 1,1- dioxideCpd- N-(l-(2-(2'-cyano-6'- 16 +w methyl-[2,4'-bipyridin]-6- CASyl)- 1,6-naphthyridin-7 - #yl)cyclopropyl) -2,3 - Cpd-37 w 7318 P 602.7 603.4Q dihydro-5H- 3-34- benzo[e] [ 1,4]oxathiepine- 3 +8 -carboxamide 1,1- Int- dioxide66N-(l-(2-(6-ethyl-2,3- Int- dihydro-4H- 65 +benzo [b] [ 1,4] oxazin-4- CASCpd-38 yl)- 1,6-naphthyridin-7 - # I1 572.7 573.4 yl)cyclopropyl)-3 - 1490((methoxymethyl) sulfonyl 760- )-4-methylbenzamide 54-7MS Cpd# Structure Name SM Mtd MW Mes’d N-(l-(2-(5-ethoxy-2,3- dihydro- IH-pyrido [3,4- zzb] [ 1,4]oxazin- 1 -yl)- 1,6- Cpd- naphthyridin-7- 8 16 +yl)cyclopropyl) -2,3- Cpd-39 Int- K 587.7 588.4 fi • o dihydro-5H- 69benzo[e] [ 1,4]oxathiepine- 8 -carboxamide 1,1- dioxide3- CAS((methoxymethyl) sulfonyl#o o v-7 po )-4-methyl-N-( 1 -(2-(6- 1490(( 1 -methyl- 1H-pyrazol-4- 760- Cpd-40 yl)ethynyl)-2,3-dihydro- I1 649.7 650.554-78? 4H-pyrido[3,2- ZI ^ 7N-N +\ b] [ 1,4]oxazin-4-yl)- 1,6- Int-6naphthyridin-7-.sMh ' " oyl)cyclopropyl)benzamideCASN-( 1 -(2-(6-cyclobutyl- #2,3-dihydro-4H- 1823pyrido[3,2-b] [ 1,4]oxazin- 838- Cpd-41 4-yl)- 1,6-naphthyridin-7 - I2 605.7 606.222-7yl)cyclopropyl)-3 - + ((difluoromethyl)sulfonyl)Int- -4-methylbenzamide41MS Cpd# Structure Name SM Mtd MW Mes’d c)O (R)-4,9-difluoro-N-(l-(2- (6-(( 1 -methyl- 1H- A ■ CASIZ pyrazol-4-yl)ethynyl)-2,3- #3 dihydro-4H-pyrido [3,2- 3008J b] [ 1,4]oxazin-4-yl)- 1,6- 582- Cpd-42 naphthyridin-7- 12 683.7 684.41 H _ 1 33-7yl)cyclopropyl)-3,4- -N +\ dihydro-2H- Int- benzo [b] [ 1,4] oxathiepine - 977-carboxamide 5,5- dioxide(R)-9-chloro-4-fluoro-N- ( 1 -(2-(6-(( 1 -methyl- 1H- CASpyrazol-4-yl)ethynyl)-2,3- #FD dihydro-4H-pyrido [3,2-, °><-° fl v M 3008JHb] [ 1,4]oxazin-4-yl)- 1,6- v ^-o JU Y 1 582- 700.4 Cpd-43 c!1 naphthyridin-7- 12 700.164-4 702.4 yl)cyclopropyl)-3,4- N- -N +\ dihydro-2H- Int- benzo [b] [ 1,4] oxathiepine - 977-carboxamide 5,5- dioxideN-(l-(2-(5-ethoxy-2,3- CASdihydro- IH-pyrido [3,4- #b] [ 1,4]oxazin- 1 -yl)- 1,6- 2771naphthyridin-7- 132- Cpd-44 yl)cyclopropyl)-6-fluoro- 12 605.6 606.360-4F 2,3-dihydro-5H- +benzo[e] [ 1,4] oxathiepine - Int- 8 -carboxamide 1,1- 71dioxideMS Cpd# Structure Name SM Mtd MW Mes’d 3- CAS((difluoromethyl)sulfonyl)#-4-methyl-N-( 1 -(2-(6-(( 1 - 1823methyl- 1H-pyrazol-4- ) 838- Cpd-45 yl)ethynyl)-2,3-dihydro- 12 655.7 656.322-74H-pyrido[3,2- +b] [ 1,4]oxazin-4-yl)- 1,6- Int- naphthyridin-7- 97 yl)cyclopropyl)benzamide3-((2- CAShydroxyethyl)sulfonyl)-4- #methyl-N-( 1 -(2-(6-(( 1 - 1094methyl- 1H-pyrazol-4- b 404- Cpd-46 yl)ethynyl)-2,3-dihydro- 12 649.7 650.486-04H-pyrido[3,2- +b] [ 1,4]oxazin-4-yl)- 1,6- Int- naphthyridin-7- 97 yl)cyclopropyl)benzamide(R)-9-chloro-4-fluoro-N- ( 1 -(2-(6-(( 1 -methyl- 1H- CASpyrazol-4-yl)ethynyl)-2,3- #dihydro-4H- B, °<-° ^ 3008benzo [b] [ 1,4] oxazin-4- 582- 699.2 Cpd-47 yl)- 1,6-naphthyridin-7 - 12 699.264-4 701.3 yl)cyclopropyl)-3,4- +dihydro-2H- Int- benzo [b] [ 1,4] oxathiepine - 737-carboxamide 5,5- dioxideMS Cpd# Structure Name SM Mtd MWMes’d ^'°? o> (R)-N-( 1 -(2-(5 -ethoxy - CASc • 2,3-dihydro-lH- TZ #pyrido[3,4-b] [ 1,4]oxazin- 3008BO>zo o 1^0 1 -yl)- 1,6-naphthyridin-7 - 8, N. X ThCpd-48 / (R) Y ^< N T5^ T D 582- VHN^ yl)cyclopropyl)-4,9- 12 623.6 624.2 ^-o Y JUF GN 46-2p < difluoro-3,4-dihydro-2H- o +{ benzo [b] [ 1,4] oxathiepine - Int- 7-carboxamide 5,5- 71dioxide(R)-9-chloro-N-(l-(2-(5- CASethoxy-2, 3 -dihydro - 1 H- #pyrido[3,4-b] [ 1,4]oxazin- 30081 -yl)- 1,6-naphthyridin-7 - 582- 12 640.2 Cpd-49 yl)cyclopropyl)-4-fluoro- 640.164-4 642.2 3,4-dihydro-2H- +benzo [b] [ 1,4] oxathiepine - Int- 7-carboxamide 5,5- 71dioxide3- CAS ((difluoromethyl)sulfonyl) #T o o ^7 -4-methyl-N-( 1 -(2-(6-(( 1 - 1823F^OA«%T'6 methyl- 1H-pyrazol-4- 838- Cpd-50 12 654.7 655.3I I yl)ethynyl)-2,3-dihydro- 22-7V?N-N 4H-benzo [b] [ 1,4] oxazin- +\4-yl)- 1,6-naphthyridin-7 - Int- yl)cyclopropyl)benzamide 73MS Cpd# Structure Name SM Mtd MW Mes’d (R)-4,9-difluoro-N-(l-(2- (6-(( 1 -methyl- 1H- CASpyrazol-4-yl)ethynyl)-2,3- #dihydro-4H- 3008benzo [b] [ 1,4] oxazin-4- 582- Cpd-51FI I yl)- 1,6-naphthyridin-7 - 12 682.7 683.346-2^ 7 yl)cyclopropyl)-3,4- N-N +\ dihydro-2H- Int- benzo [b] [ 1,4] oxathiepine - 737-carboxamide 5,5- dioxide(R)-9-chloro-N-(l-(2-(6- CAS(difluoromethyl)-2- #ethoxypyridin-3 -yl)- 1,6- F 3008naphthyridin-7- T- °'< P n V f^irF582- 633.2 Cpd-52 yl)cyclopropyl)-4-fluoro- 12 633.0QV " LU X 64-4 635.1 Cl 1 3,4-dihydro-2H- +benzo [b] [ 1,4] oxathiepine - Int- 7-carboxamide 5,5- 75dioxide(R)-N-(l-(2-(6- CAS(difluoromethyl)-2- #ethoxypyridin-3 -yl)- 1,6- F 3008naphthyridin-7- F, %o 0 „F582- Cpd-53 XrAVrW yl)cyclopropyl)-4,9- 12 616.6 617.2Uy " LU 46-2difluoro-3,4-dihydro-2H- +benzo [b] [ 1,4] oxathiepine - Int- 7-carboxamide 5,5- 75dioxideMS Cpd# Structure Name SM Mtd MW Mes’d (R)-9-chloro-N-(l-(2-(2- CAS(cyclopropylmethoxy)-6- #(difluoromethyl)pyridin- 30083 -yl)- 1,6-naphthyridin-7 - 582- 659.2 Cpd-54 / S;SYVN>Y\ oNY YNyl)cyclopropyl)-4-fluoro- 12 659.1U7 Lu i 64-4 661.13,4-dihydro-2H- +benzo [b] [ 1,4] oxathiepine - Int- 7-carboxamide 5,5- 77dioxide(R)-N-(l-(2-(2- CAS(cyclopropylmethoxy)-6- #(difluoromethyl)pyridin- 30083 -yl)- 1,6-naphthyridin-7 - 582- Cpd-55 yl)cyclopropyl)-4,9- 12 642.6 643.346-2difluoro-3,4-dihydro-2H- +benzo [b] [ 1,4] oxathiepine - Int- 7-carboxamide 5,5- 77dioxideN-(l-(2-(6-(pyridin-4- ylethynyl)-2,3-dihydro- CAS4H-pyrido[3,2- #b] [ 1,4]oxazin-4-yl)- 1,6- 2771naphthyridin-7- 132- Cpd-56 12 644.7 645.4 yl)cyclopropyl) -2,3 - 16-0tJ dihydro-5H- +benzo[e] [ 1,4] oxathiepine - Int- 8 -carboxamide 1,1- 79dioxideMS Cpd# Structure Name SM Mtd MW Mes’d N-( 1 -(2-(6-(( 1 -methyl - 1H-imidazol-5- CASyl)ethynyl)-2,3-dihydro- #□ 4H-pyrido[3,2- 2771b] [ 1,4]oxazin-4-yl)- 1,6- (W W: 132- Cpd-57 naphthyridin-7- 12 647.7 648.41 16-0yl)cyclopropyl) -2,3- +=N dihydro-5H- Int- benzo[e] [ 1,4]oxathiepine- 818 -carboxamide 1,1- dioxideN-(l-(2-(6-((l,5- dimethyl- 1H-pyrazol-4- CASyl)ethynyl)-2,3-dihydro- #0 4H-pyrido[3,2- 2771b] [ 1,4]oxazin-4-yl)- 1,6- 5 132- Cpd-58 naphthyridin-7- 12 661.7 662.416-0yl)cyclopropyl) -2,3 - N -N + / dihydro-5H- Int- benzo[e] [ 1,4]oxathiepine- 838 -carboxamide 1,1- dioxideN-(l-(2-(6-((l,3- dimethyl- 1H-pyrazol-4- CASyl)ethynyl)-2,3-dihydro- #4H-pyrido[3,2- 2771b] [ 1,4]oxazin-4-yl)- 1,6- 132- Cpd-59 naphthyridin-7- 12 661.7 662.416-0\ yl)cyclopropyl) -2,3 - N-h + / dihydro-5H- Int- benzo[e] [ 1,4]oxathiepine- 858 -carboxamide 1,1- dioxideMS Cpd# Structure Name SM Mtd MW Mes’d N-( 1 -(2-(6-(( 1 -methyl - lH-l,2,3-triazol-5- CASyl)ethynyl)-2,3-dihydro- #o o0V7 f'''"04H-pyrido[3,2- 2771b] [ 1,4]oxazin-4-yl)- 1,6- ) 132- Cpd-60 naphthyridin-7- 12 648.7 649.416-0yl)cyclopropyl) -2,3- M"" +N=r J dihydro-5H- Int- benzo[e] [ 1,4] oxathiepine - 888 -carboxamide 1,1- dioxide(R)-4,9-difluoro-N-(l-(2- (5 -fluoro-6-(( 1 -methyl - CASlH-pyrazol-4-yl)ethynyl)- #3 2,3-dihydro-4H- 3008benzo [b] [ 1,4] oxazin-4- 582- Cpd-61F1 yl)- 1,6-naphthyridin-7 - 12 700.7 701.446-2yl)cyclopropyl)-3,4- N -N +\ dihydro-2H- Int- benzo [b] [ 1,4] oxathiepine - 927-carboxamide 5,5- dioxideN-(l-(2-(6-((l -ethyl- 1H- pyrazol-4-yl)ethynyl)-2,3- CASdihydro-4H-pyrido [3,2- #0b] [ 1,4]oxazin-4-yl)- 1,6- 27715 naphthyridin-7- 132- Cpd-62 12 661.7 662.5 yl)cyclopropyl) -2,3 - 16-0 / I_ — N dihydro-5H- +benzo[e] [ 1,4] oxathiepine - Int- 8 -carboxamide 1,1- 94dioxideMS Cpd# Structure Name SM Mtd MW Mes’d N-( 1 -(2-(6-(( 1 -methyl - 1H-pyrazol-3-yl)ethynyl)- CAS2,3-dihydro-4H- #pyrido[3,2-b] [ 1,4]oxazin- 27714-yl)- 1,6-naphthyridin-7 - 132- Cpd-63 12 647.7 648.4 yl)cyclopropyl) -2,3- 16-0c -N \ dihydro-5H- +benzo[e] [ 1,4]oxathiepine- Int- 8 -carboxamide 1,1- 96dioxideN-( 1 -(2-(6-(( 1 -methyl - CASJUO O „ lH-pyrazol-4-yl)ethynyl)- #2,3-dihydro-4H- 3056s pyrido[3,2-b] [ 1,4]oxazin- 392- Cpd-64 12 645.7 646.34-yl)- 1,6-naphthyridin-7 - 71-0N- -N \ yl)cyclopropyl)-3 - + (methylsulfonyl)benzofur Int- an-5 -carboxamide 97N-( 1 -(2-(6-(( 1 -methyl - 1H- 1,2,3-triazol-4- CASyl)ethynyl)-2,3-dihydro- 2 #4H-pyrido[3,2- 2771 cW ^oyx b] [ 1,4]oxazin-4-yl)- 1,6- 132- Cpd-65 naphthyridin-7- 12 648.7 649.416-0yl)cyclopropyl) -2,3 - / N- -N, N +dihydro-5H- Int- benzo[e] [ 1,4]oxathiepine- 1008 -carboxamide 1,1- dioxideMS Cpd# Structure Name SM Mtd MW Mes’d N-( 1 -(2-(6-(pyridin-3 - ylethynyl)-2,3-dihydro- CAS4H-pyrido[3,2- #b] [ 1,4]oxazin-4-yl)- 1,6- 2771naphthyridin-7- 132- Cpd-66 12 644.7 645.41 yl)cyclopropyl) -2,3- 16-0JN<t dihydro-5H- +benzo[e] [ 1,4] oxathiepine - Int- 8 -carboxamide 1,1- 102dioxide(R)-9-chloro-4-fluoro-N- (l-(2-(6-((ls,3s)-3- CAShydroxy cyclobutyl) -2,3- #dihydro-4H-pyrido [3,2- 3008b] [ 1,4]oxazin-4-yl)- 1,6- 582- 666.4 Cpd-67 naphthyridin-7- 12 666.164-4 668.4 yl)cyclopropyl)-3,4- +dihydro-2H- S^ 0"°“sInt- benzo [b] [ 1,4] oxathiepine - 1057-carboxamide 5,5- dioxide(R)-2,6-difluoro-N-(l-(2- (6-(( 1 -methyl- 1H- CASpyrazol-4-yl)ethynyl)-2,3- #F„ H V l^Cdihydro-4H- 3008) benzo [b] [ 1,4] oxazin-4- F | 582- Cpd-68 yl)- 1,6-naphthyridin-7 - 12 682.7 683.433-7V N- -N yl)cyclopropyl) -2,3 - \ +Relative stereochemistry dihydro-5H- Int- benzo[e] [ 1,4] oxathiepine - 738 -carboxamide 1,1- dioxideMS Cpd# Structure Name SM Mtd MW Mes’d (R)-2,6-difluoro-N-(l-(2- (6-(( 1 -methyl- 1H- CASpyrazol-4-yl)ethynyl)-2,3- F, 9,0 ft W 3 #dihydro-4H-pyrido [3,2-H) 3008L b] [ 1,4]oxazin-4-yl)- 1,6- F | 582- Cpd-69 naphthyridin-7- 12 683.7 684.433-7V N- -N yl)cyclopropyl) -2,3- \ +Relative stereochemistry dihydro-5H- Int- benzo[e] [ 1,4]oxathiepine- 978 -carboxamide 1,1- dioxideN-( 1 -(2-(6-(( 1 -methyl - 1H-pyrazol-4-yl)ethynyl)- 2,3-dihydro-4H- Int- pyrido[3,2-b] [ 1,4]oxazin- 112s 4-yl)- 1,6-naphthyridin-7 - Cpd-70 + 12 661.7 662.4 yl)cyclopropyl)-3,4- Int- N- -N dihydro-2H,6H- \ 97benzo [c] [ 1,5 ] oxathiocine - 9-carboxamide 1,1- dioxide(R)-9-chloro-4-fluoro-N- (l-(2-(6-((lr,3r)-3- CAShydroxy cyclobutyl) -2,3- #dihydro-4H-pyrido [3,2- E., 9< P Ov^0 3008b] [ 1,4]oxazin-4-yl)- 1,6- 582- 666.4 Cpd-71 naphthyridin-7- 12 666.164-4 668.401❖ yl)cyclopropyl)-3,4- OH +dihydro-2H- Int- benzo [b] [ 1,4] oxathiepine - 1067-carboxamide 5,5- dioxideMS Cpd# Structure Name SM Mtd MW Mes’d 3-chloro-5- CAS ((difluoromethyl)sulfonyl) #J o0V7 -N-( 1 -(2-(6-(( 1 -methyl - 2592FlH-pyrazol-4-yl)ethynyl)- 405- 676.3 Cpd-72 12 676.1Cl1 2,3-dihydro-4H- 50-8 678.3+N- -N pyrido[3,2-b] [ 1,4]oxazin- \4-yl)- 1,6-naphthyridin-7 - Int- yl)cyclopropyl)benzamide 973-chloro-5-(S- CAS(difluoromethyl)sulfonimi#doyl)-N-(l-(2-(6-((l- <xz,NHfl V 2361J methyl- 1H-pyrazol-4- 949- Ex. 675.3 Cpd-73 Cl I yl)ethynyl)-2,3-dihydro- 675.179-1 2.25 677.3 4H-pyrido[3,2- N- -N +\ b] [ 1,4]oxazin-4-yl)- 1,6- Int- naphthyridin-7- 97 yl)cyclopropyl)benzamide(R* )-3 -chloro-5 -(S- CAS(difluoromethyl)sulfonimi#O.,NHfl V 3doyl)-N-(l-(2-(6-((l- 2361methyl- 1H-pyrazol-4- Cl I 949- Ex. 675.3 Cpd-74 yl)ethynyl)-2,3-dihydro- 675.179-1 2.25 677.4 N- -N 4H-pyrido[3,2- \ +Relative stereochemistry b] [ 1,4]oxazin-4-yl)- 1,6- Int- naphthyridin-7- 97yl)cyclopropyl)benzamideMS Cpd# Structure Name SM Mtd MW Mes’d Q° O W / <° o (S*)-3-chloro-5-(S- CAS(difluoromethyl)sulfonimiO.zNH ) 9o=I V ) #Z doyl)-N-(l-(2-(6-((l-F H1 2361A XXX L methyl- 1H-pyrazol-4- Cl I 949- Ex. 675.3 Cpd-75 yl)ethynyl)-2,3-dihydro- 675.1< 79-1 2.26 677.3N- -N 4H-pyrido[3,2- \ +Relative stereochemistry b] [ 1,4]oxazin-4-yl)- 1,6- Int- naphthyridin-7- 97 yl)cyclopropyl)benzamide3-chloro-5- ((difluoromethyl)sulfonyl)-4-methyl-N-( 1 -(2-(6-(( 1 - Int- methyl- 1H-pyrazol-4- 114 XXXiX s 690.3 Cpd-76 C! yl)ethynyl)-2,3-dihydro- + 12 690.11 692.34H-pyrido[3,2- Int- N- -N\ b] [ 1,4]oxazin-4-yl)- 1,6- 97naphthyridin-7- yl)cyclopropyl)benzamide(R)-4-fluoro-9- (methoxymethyl)-N-( 1 - (2-(6-(( 1 -methyl- 1H- pyrazol-4-yl)ethynyl)-2,3- J Int- dihydro-4H-pyrido [3,2- ) 120b] [ 1,4]oxazin-4-yl)- 1,6- Cpd-77 + 12 709.8 710.5 naphthyridin-7- Int- -N yl)cyclopropyl)-3,4- \ 97dihydro-2H- benzo [b] [ 1,4] oxathiepine - 7-carboxamide 5,5- dioxideMS Cpd# Structure Name SM Mtd MW Mes’d (R)-9-(difluoromethyl)-4- fluoro-N-( 1 -(2-(6-(( 1 - Y methyl- 1H-pyrazol-4- yl)ethynyl)-2,3-dihydro- F, v 9 v r'""? Int- 4H-pyrido[3,2-H12N Ju 2NU1 b] [ 1,4]oxazin-4-yl)- 1,6- Cpd-78 1 + 12 715.7 716.4 naphthyridin-7- Int- N-N yl)cyclopropyl)-3,4- \ 97dihydro-2H- benzo [b] [ 1,4] oxathiepine - 7-carboxamide 5,5- dioxide(R)-4,9-difluoro-N-(l-(2- (6-(3 -hydroxyazetidin- 1 - CASyl)-2,3-dihydro-4H- #pyrido[3,2-b] [ 1,4]oxazin- 30084-yl)- 1,6-naphthyridin-7 - 582- Cpd-79 Co-VH-UU 12 650.7 651.4F N yl)cyclopropyl)-3,4- 46-2OH dihydro-2H- +benzo [b] [ 1,4] oxathiepine - Int- 7-carboxamide 5,5- 126dioxide(R)-9-chloro-4-fluoro-N- (l-(2-(6-(3- CAShydroxyazetidin- 1 -yl)- #2,3-dihydro-4H- 3008pyrido[3,2-b] [ 1,4]oxazin- 582- 667.4 Cpd-80 4-yl)- 1,6-naphthyridin-7 - 12 667.164-4 669.4 yl)cyclopropyl)-3,4- +dihydro-2H- Int- benzo [b] [ 1,4] oxathiepine - 1267-carboxamide 5,5- dioxideMS Cpd# Structure Name SM Mtd MW Mes’d (R* )-3 -(( 1 -fluoro-2- hydroxyethyl)sulfonyl)-4- HO.j o0V7 methyl-N-( 1 -(2-(6-(( 1 - Int-Fj) methyl- 1H-pyrazol-4- 130Cpd-81 yl)ethynyl)-2,3-dihydro- + II 667.7 668.5VN- -N 4H-pyrido[3,2- Int- \b] [ 1,4]oxazin-4-yl)- 1,6- 97Relative stereochemistrynaphthyridin-7- yl)cyclopropyl)benzamide(S)-3-((l-fluoro-2- hydroxyethyl)sulfonyl)-4- HO.1 o ° V7 methyl-N-( 1 -(2-(6-(( 1 - Int- methyl- 1H-pyrazol-4- 131Cpd-82 1 1 yl)ethynyl)-2,3-dihydro- + II 667.7 668.5N- -N 4H-pyrido[3,2- Int- b] [ 1,4]oxazin-4-yl)- 1,6- 97Relative stereochemistrynaphthyridin-7- yl)cyclopropyl)benzamide3-chloro-5- CAS ((difluoromethyl)sulfonyl) #j o 9 V7-N-(l-(2-(6-(3- 2592yrnuCx XJ hydroxyazetidin- 1 -yl)- 405- 643.4 Cpd-83 II 643.12,3-dihydro-4H- 50-8 645.4 OHpyrido[3,2-b] [ 1,4]oxazin- +Relative stereochemistry4-yl)- 1,6-naphthyridin-7 - Int- yl)cyclopropyl)benzamide 126MS Cpd# Structure Name SM Mtd MW Mes’d T °Z T! \ W\ / O _ (R* )-3 -chloro-5 -(( 1 - ■" W“ fluoro-2- HO.)O=1 o o IZ ^7 2 hydroxyethyl)sulfonyl)- Int-FA / aVjy x J N-( 1 -(2-(6-(( 1 -methyl - 130Cl 1 688.2 Cpd-84 lH-pyrazol-4-yl)ethynyl)- + II 688.1tf 690.2V N- -N 2,3-dihydro-4H- Int- \pyrido[3,2-b] [ 1,4]oxazin- 97Relative stereochemistry4-yl)- 1,6-naphthyridin-7 - yl)cyclopropyl)benzamide(S*)-3-chloro-5-((l- fluoro-2- HO.1 o ° V7 r^(hydroxyethyl)sulfonyl)- Int- J) N-( 1 -(2-(6-(( 1 -methyl- 131688.3 Cpd-85Cl1 1 lH-pyrazol-4-yl)ethynyl)- + II 688.1690.3 VN- -N 2,3-dihydro-4H- Int- \pyrido[3,2-b] [ 1,4]oxazin- 97Relative stereochemistry4-yl)- 1,6-naphthyridin-7 - yl)cyclopropyl)benzamide1- ((difluoromethyl)sulfonyl)-4-fluoro-N-( 1 -(2-(6-(( 1 - Int- methyl- 1H-pyrazol-4- 133yl)ethynyl)-2,3-dihydro- Cpd-86 + 12 700.7 701.51 4H-pyrido[3,2- Int- b] [ 1,4]oxazin-4-yl)- 1,6- -N\ 97naphthyridin-7- yl)cyclopropyl)indoline- 6-carboxamideMS Cpd# Structure Name SM Mtd MW Mes’d (R)-4-fluoro-9- (hydroxymethyl)-N-( 1 -(2- (6-(( 1 -methyl- 1H- pyrazol-4-yl)ethynyl)-2,3- J Int- dihydro-4H-pyrido [3,2- J 134b] [ 1,4]oxazin-4-yl)- 1,6- Cpd-87 ^OH | +1 II 695.7 696.4 naphthyridin-7- Int- N- -N yl)cyclopropyl)-3,4- / 97dihydro-2H- benzo [b] [ 1,4] oxathiepine - 7-carboxamide 5,5- dioxide3-chloro-5- ((difluoromethyl)sulfonyl)-4-(hydroxymethyl)-N-( 1 - Int- (2-(6-(( 1 -methyl- 1H- 135706.3 Cpd-88 a | pyrazol-4-yl)ethynyl)-2,3- + II 706.11 708.3 dihydro-4H-pyrido [3,2- Int- N- -N / b] [ 1,4]oxazin-4-yl)- 1,6- 97naphthyridin-7- yl)cyclopropyl)benzamide3- ((difluoromethyl)sulfonyl)-5 -fluoro-4-methyl-N-( 1 - Int- (2-(6-(( 1 -methyl- 1H- 139Cpd-89 pyrazol-4-yl)ethynyl)-2,3- + 12 673.7 674.3F1 1dihydro-4H-pyrido [3,2- Int- N- -N / b] [ 1,4]oxazin-4-yl)- 1,6- 97naphthyridin-7- yl)cyclopropyl)benzamideMS Cpd# Structure Name SM Mtd MWMes’d (R)-4-fluoro-9-(2- hydroxyethyl)-N-( 1 -(2-(6- (( 1 -methyl- 1H-pyrazol-4- yl)ethynyl)-2,3-dihydro- F, 9,_P OwInt- 4H-pyrido[3,2- II 141v JUHJJU U^-o y b] [ 1,4]oxazin-4-yl)- 1,6- Cpd-90 + II 709.8 710.5S i iOH naphthyridin-7- Int- N-r yl)cyclopropyl)-3,4- / 97dihydro-2H- benzo [b] [ 1,4] oxathiepine - 7-carboxamide 5,5- dioxide3- ((difluoromethyl)sulfonyl)3 -5 -(methoxymethyl) -N - Int- ( 1 -(2-(6-(( 1 -methyl- 1H- 97 + [M+H]+:Cpd-91 ^0 pyrazol-4-yl)ethynyl)-2,3- 12 685.711 Int- 686.5 dihydro-4H-pyrido [3,2- ffN -N 153 / b] [ 1,4]oxazin-4-yl)- 1,6- naphthyridin-7- yl)cyclopropyl)benzamide3 -(cyclopropoxymethyl) - 5- Int- 3 ((difluoromethyl)sulfonyl) 97+[M+H]+: -N-( 1 -(2-(6-(( 1 -methyl - CAS712.6, Cpd-92 ^0 lH-pyrazol-4-yl)ethynyl)- # 14 711.74[M-H]-:A?2,3-dihydro-4H- 3080' / )N -N 313- 710.3, / pyrido[3,2-b] [ 1,4]oxazin- 29-44-yl)- 1,6-naphthyridin-7 - yl)cyclopropyl)benzamideMS Cpd# Structure Name SM Mtd MWMes’d o\ ( 'o — (R)-4-fluoro-9-methyl-N- ZA _( 1 -(2-(6-(( 1 -methyl- 1H-o= / TZ pyrazol-4-yl)ethynyl)-2,3- Z z= dihydro-4H-pyrido [3,2- o Int- b] [ 1,4]oxazin-4-yl)- 1,6- 97 + 680.2 Cpd-93 naphthyridin-7- 13 679.73Int- [M+H]+. yl)cyclopropyl)-3,4- -N 144dihydro-2H- benzo [b] [ 1,4] oxathiepine - 7-carboxamide 5,5- dioxide(R)-9- (cyclopropoxymethyl)-4- fluoro-N-( 1 -(2-(6-(( 1 - methyl- 1H-pyrazol-4- F,_ ° / 0 0r< yl)ethynyl)-2,3-dihydro- Int- 4H-pyrido[3,2- OX b n 97 + 736.25 Cpd-94 b] [ 1,4]oxazin-4-yl)- 1,6- 14 735.79Int- [M+H]+. A } naphthyridin-7- N- -N 145 / yl)cyclopropyl)-3,4- dihydro-2H- benzo [b] [ 1,4] oxathiepine - 7-carboxamide 5,5- dioxideMS Cpd# Structure Name SM Mtd MWMes’d (R)-9-cyano-4-fluoro-N- ( 1 -(2-(6-(( 1 -methyl- 1H- pyrazol-4-yl)ethynyl)-2,3- F, 9,0 0VC? dihydro-4H-pyrido [3,2- Int- b] [ 1,4]oxazin-4-yl)- 1,6- 97 + 691.3 Cpd-95CNnaphthyridin-7- 14 690.71II Int [M+H]+.yl)cyclopropyl)-3,4- \ i] / N-N 146dihydro-2H- benzo [b] [ 1,4] oxathiepine - 7-carboxamide 5,5- dioxiderel-(R)-3 -(( 1 -fluoro-2- HO^ 9. v hydroxyethyl)sulfonyl)-4- V1°! PYNVN\AFmethyl-N-( 1 -(2-(6-(( 1 - Int- "' / H N'AX Omethyl- 1H-pyrazol-4- 73 + 667.3 [M+ Cpd-96 II 666.73yl)ethynyl)-2,3-dihydro- Int- H]+.ZN-N4H-benzo [b] [ 1,4] oxazin - 131Relative stereochemistry 4-yl)- 1,6-naphthyridin-7 - yl)cyclopropyl)benzamiderel-(R)-3 -chloro-5 -(( 1 - fluoro-2- HO^ 9 V hydroxyethyl)sulfonyl)-4-F.,s^ H rjQr rp methyl-N-( 1 -(2-(6-(( 1 - Int- methyl- 1H-pyrazol-4- 97+ [M+H]+ Cpd-97 II 702.16yl)ethynyl)-2,3-dihydro- Int- = 702.3 ° IZN-N 4H-pyrido[3,2- 149Relative stereochemistry b] [ 1,4]oxazin-4-yl)- 1,6- naphthyridin-7- yl)cyclopropyl)benzamideMS Cpd# Structure Name SM Mtd MWMes’d (R)-4-fluoro-9-((R* )- 1 - hydroxyethyl)-N-( 1 -(2-(6- (( 1 -methyl- 1H-pyrazol-4- yl)ethynyl)-2,3-dihydro- 4H-pyrido[3,2- Int- [M+H]+ l°r1*^OH | b] [ 1,4]oxazin-4-yl)- 1,6- 97+ 710.5, Cpd-98 II 709.21naphthyridin-7- Int- [M-H]- / N- -N yl)cyclopropyl)-3,4- 154 708.4 Relative stereochemistry dihydro-2H- benzo [b] [ 1,4] oxathiepine - 7-carboxamide 5,5- dioxide(R)-4-fluoro-9-((S*)-l- hydroxyethyl)-N-( 1 -(2-(6- (( 1 -methyl- 1H-pyrazol-4- E. °'<-° Il V yl)ethynyl)-2,3-dihydro- 4H-pyrido[3,2- [M+H]+ [or1'"“XOH | b] [ 1,4]oxazin-4-yl)- 1,6- Int- 710.5, Cpd-99 II 709.21naphthyridin-7- 97 [M-H]- / N- -N yl)cyclopropyl)-3,4- 708.4 Relative stereochemistry dihydro-2H- benzo [b] [ 1,4] oxathiepine - 7-carboxamide 5,5- dioxide3-chloro-5- ((difluoromethyl)sulfonyl)N V -4-methyl-N-( 1 -(2-(6-(( 1 - Int- Cpd-F! HC'S# « methyl- 1H-pyrazol-4- 73 + 689.25 [MCl14 689.13100 I yl)ethynyl)-2,3-dihydro- Int- +H]+.4H-benzo [b] [ 1,4] oxazin- 114 / N- -N4-yl)- 1,6-naphthyridin-7 - yl)cyclopropyl)benzamideMS Cpd# Structure Name SM Mtd MWMes’d (R)-9-(difluoromethyl)-4- fluoro-N-( 1 -(2-(6-(( 1 - methyl- 1H-pyrazol-4- yl)ethynyl)-2,3-dihydro- Int- 4H-benzo [b] [ 1,4] oxazin - Cpd- 73 + 715.2[M+CHF2| 4-yl)- 1,6-naphthyridin-7 - 14 714.72101 Int- H]+yl)cyclopropyl)-3,4- 122 / N- -N dihydro-2H- benzo [b] [ 1,4] oxathiepine - 7-carboxamide 5,5- dioxide(R)-9- (cyclopropoxymethyl)-4- fluoro-N-( 1 -(2-(6-(( 1 - methyl- 1H-pyrazol-4- E. °< P 9 V7 |^Cyl)ethynyl)-2,3-dihydro- Int- Cpd- 4H-benzo [b] [ 1,4] oxazin - 73+ 735.2[M+14 734.80102 4-yl)- 1,6-naphthyridin-7 - Int- H]+A }N- -N yl)cyclopropyl)-3,4- 145 / dihydro-2H- benzo [b] [ 1,4] oxathiepine - 7-carboxamide 5,5- dioxiderel-(R)-3 -chloro-5 -(( 1 - fluoro-2- hydroxyethyl)sulfonyl)-fInt- 6 T)Ho N-( 1 -(2-(6-(( 1 -methyl- Cpd- 73+1 687.2ci| lH-pyrazol-4-yl)ethynyl)- 14 687.14103 ntl5 [M+H]+.Z\ i)N-N 2,3-dihydro-4H- 1benzo [b] [ 1,4] oxazin-4- Relative stereochemistryyl)- 1,6-naphthyridin-7 - yl)cyclopropyl)benzamideMS Cpd# Structure Name SM Mtd MWMes’d rel-(R)-3 -(( 1 -fluoro-2- hydroxyethyl)sulfonyl)-4- F 6?~0 " " XJ Q methyl-N-( 1 -(2-(6-(( 1 - Int- Cpd- methyl- 1H-pyrazol-4- 73+1 667.2[M+I 14 666.73104 yl)ethynyl)-2,3-dihydro- ntl3 H]+ZN-N 4H-benzo [b] [ 1,4] oxazin - 1Relative stereochemistry 4-yl)- 1,6-naphthyridin-7 - yl)cyclopropyl)benzamiderel-(S)-3-chloro-5-((l- fluoro-2- HO^, 9 Vhydroxyethyl)sulfonyl)- Int-f" J'QH“Xj Q N-( 1 -(2-(6-(( 1 -methyl - Cpd-Cl73 + 687.2I lH-pyrazol-4-yl)ethynyl)- 14 687.14105 Int- [M+H]+ZV V 2,3-dihydro-4H- N-N 152benzo [b] [ 1,4] oxazin-4- Relative stereochemistryyl)- 1,6-naphthyridin-7 - yl)cyclopropyl)benzamide3- ((difluoromethoxy)methylInt- )-5- 73 + o o ° V7 C°((difluoromethyl)sulfonyl)CASFib^% yrjCpd- -N-( 1 -(2-(6-(( 1 -methyl- 721.45[M F2HC< J # 14 720.70106 lH-pyrazol-4-yl)ethynyl)- +H]+30802,3-dihydro-4H- 313- N-N / 09-0 benzo [b] [ 1,4] oxazin-4- yl)- 1,6-naphthyridin-7 - yl)cyclopropyl)benzamideMS Cpd# Structure Name SM Mtd MWMes’d 3- ((difluoromethoxy)methyl)-5- Int- 3F2HC' °S'VPS: XA NNXV^<N ((difluoromethyl)sulfonyl) 97 +Cpd- y H UJ X -N-( 1 -(2-(6-(( 1 -methyl - CAS 722.30F2HCO'ZJI 14 721.69107 lH-pyrazol-4-yl)ethynyl)- #308 [M+H]+N- “N 2,3-dihydro-4H- 0313 / pyrido[3,2-b] [ 1,4]oxazin- -09-04-yl)- 1,6-naphthyridin-7 - yl)cyclopropyl)benzamide3 -(cyclopropoxymethyl) - 5- Int- o ° ° v 3 ((difluoromethyl)sulfonyl) 73+F-HC-N-( 1 -(2-(6-(( 1 -methyl - CASCpd- 711.15[M 1 lH-pyrazol-4-yl)ethynyl)- # 14 710.76108 +H]+2,3-dihydro-4H- 3080N- -N / benzo [b] [ 1,4] oxazin-4- 313- yl)- 1,6-naphthyridin-7 - 29-4 yl)cyclopropyl)benzamide3- ((difluoromethyl)sulfonyl) Int- V N V 3F2HC'S^ A y ^ N -5 -fluoro-N-( 1 -(2-(6-(( 1 - 97 +UHN^U k methyl- 1H-pyrazol-4- CASCpd- 660.30F1 yl)ethynyl)-2,3-dihydro- # 14 659.64109 [M+H]+N- -N 4H-pyrido[3,2- 3068 / b] [ 1,4]oxazin-4-yl)- 1,6- 483- Relative stereochemistrynaphthyridin-7- 17-7yl)cyclopropyl)benzamideMS Cpd# Structure Name SM Mtd MWMes’d (R)-9-bromo-4-fluoro-N- ( 1 -(2-(6-(( 1 -methyl- 1H- pyrazol-4-yl)ethynyl)-2,3- F, O yydihydro-4H-pyrido [3,2- Int- b] [ 1,4]oxazin-4-yl)- 1,6- Cpd- 97 +Br744.1[M+1 naphthyridin-7- 14 744.60110 Int- H]+N yl)cyclopropyl)-3,4- / - -N 156dihydro-2H- Relative stereochemistrybenzo [b] [ 1,4] oxathiepine ...

Claims

CLAIMS1. 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;n nRyNXO N O RZ^ / / \\ / / \ / RY is independently selected from' *, ' * and ' ';Ryand Rzare each independently hydrogen or C 1.3 alkyl;R1is Ci-6 alkyl, C1.3 alkoxy(Ci.3)alkyl, -N(C1-3alkyl)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 C1-6 alkyl, which alkyl is optionally substituted with halo 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;B is 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;each R4is independently selected from halo or C1-4 alkoxy;Xi, X2, and X3are each independently selected from N and CH;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, C1-4alkoxy, C1-4haloalkoxy or oxetane;R5is halo, -OR10, C 6-10 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, which aryl, heteroaryl, and heterocycloalkyl groups are optionally substituted with one or more independently selected R7;q is 0, 1, 2, 3, or 4;each R6is independently selected from halo, or Ci-6 alkyl;each R7is independently selected fromoxo,- -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,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, - CO2R9a, Ci-4 alkoxy, or C3-6 cycloalkyl,C2-4 alkynyl optionally substituted with one or more independently selected halo, -OH, -CN, - CO2R9a, C1-4 alkoxy, and Q1,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- Q2;Q1and Q2are each independently selected from 5-10 membered monocyclic or bicyclic heteroaryl comprising one, two, or three heteroatoms independently selected from N, O, and S, which heteroarylis optionally substituted with one or more independently selected halo, -OH, -CN, C1-4 alkyl, or C1-4 alkoxy;each R8ais independently hydrogen or Ci-4 alkyl;each R8bis independently hydrogen, Ci-4 alkyl or -C(O)Ci-2 alkyl;each R9ais independently selected from hydrogen and Ci-4 alkyl;R9bis hydrogen, Ci-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; andR10is hydrogen or C1-6 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.

4. The compound, or a pharmaceutically acceptable salt and / or solvate thereof, according to any one of claims 1-3, wherein B is selected from:' ', ' *, ' ', and & ' '; optionally wherein B is substituted with 1 or 2 R4.

5. The compound, or a pharmaceutically acceptable salt and / or solvate thereof, according to any one ofclaims 1-4, wherein Bis6. 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 oforoptionally substituted with 1 R2a, wherein R2ais selected from halogen (preferably fluoro) and Ci-4 alkyl.

8. The compound, or 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 ofand11. The compound, or a pharmaceutically acceptable salt and / or solvate thereof, according to any one of claims 1-10, wherein Li is a bond.

12. The compound, or a pharmaceutically acceptable salt and / or solvate thereof, according to any one of claims 1-11, wherein R5is 5-10 membered monocyclic or bicyclic heteroaryl comprising one, two, three or four heteroatoms independently selected from N, O, and S, optionally substituted with one or more independently selected R7.

13. The compound, or a pharmaceutically acceptable salt and / or solvate thereof, according to any one of claims 1 to 12, wherein R5is selected from:

14. The compound, or a pharmaceutically acceptable salt and / or solvate thereof, according to any one of claims 1 to 12, wherein R7is selected from:- -CN,- -CONR9aR9b,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, -CO2R9a, Ci-4 alkoxy, or C3-6 cycloalkyl,C2-4 alkynyl optionally substituted with one or more independently selected halo, -OH, -CN, -CO2R9a, Ci -4 alkoxy, and Q1,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- Q215. The compound according to any one of claims 1 to 12, wherein the compound of Formula I is a compound according to Formula XVII or XVIII:(XVIII)or a pharmaceutically acceptable salt and / or solvate thereof,wherein R7bis selected from C1-4 alkyl, C3-6 cycloalkyl, and C2-4 alkynyl substituted with Q1.

16. The compound, or a pharmaceutically acceptable salt and / or solvate thereof, according to any one of claims 1 to 12, wherein the compound of Formula I is a compound according to Formula XIX or XX:Q1(XIX)(XX)wherein Q1is a 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.

17. The compound, or a pharmaceutically acceptable salt and / or solvate thereof, according to claim 16, wherein the compound of Formula I is a compound according to Formula XIX or XX:

18. 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;O.yO N o RZY is independently selected from' ', ' ' and ' ';Ryand Rzare each independently hydrogen or C 1-3 alkyl;R1is C1-6 alkyl, C1-3 alkoxy(C1-3)alkyl, C1-3 alkyl(C1-3)alkoxy, -N(C1-3alkyl)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 C1-6 alkyl, which alkyl is optionally substituted with halo, OH, C1.4 alkoxy, O-cyclopropyl, CN, C1.4 haloalkoxy;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;B is 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;each R4is independently selected from halo or C1-4 alkoxy;Xi, X2, and X3 are each independently selected from N and CH;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(C1-4 alkyl), or -N(C1-4 alkyl)2, morpholine, -CH=CHCO2R9a, C1.4 alkoxy, C1.4 haloalkoxy or oxetane;R5is halo, -OR10, C 6-10 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, which aryl, heteroaryl, and heterocycloalkyl groups are optionally substituted with one or more independently selected R7;q is 0, 1, 2, 3, or 4;each R6is independently selected from halo, or C1-6 alkyl;each R7is independently selected fromoxo,- -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, - CO2R9aor Ci.4 alkoxy,Ci.4 alkoxy optionally substituted with one or more independently selected halo, -OH, -CN, - CO2R9a, Ci-4 alkoxy, or C3-6 cycloalkyl,C2-4 alkynyl optionally substituted with one or more independently selected halo, -OH, -CN, - CO2R9a, C1-4 alkoxy, and Q1,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- Q2;Q1and Q2are each independently 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;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; andR10is hydrogen or C1-6 alkyl;or a pharmaceutically acceptable salt and / or solvate thereof.

19. The compound, or pharmaceutically acceptable salt and / or solvate thereof, according to claim 18,20. The compound, or a pharmaceutically acceptable salt and / or solvate thereof, according to claim 18,21. The compound, or a pharmaceutically acceptable salt and / or solvate thereof, according to any one of claims 18 to 20, wherein the compound of Formula I is a compound according to Formula XIX or XX:(XX)wherein Q1is a 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.

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

23. 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 1-22.

24. A compound, a pharmaceutically acceptable salt, a solvate, or a solvate of a pharmaceutically acceptable salt thereof, according to any one of claims 1-22, or a pharmaceutical composition according to claim 23 for use in medicine.

25. A compound, a pharmaceutically acceptable salt, a solvate, or a solvate of a pharmaceutically acceptable salt thereof, according to any one of claims 1-22, or a pharmaceutical composition according to claim 23 for use in the prophylaxis and / or treatment of proliferative diseases.

26. A compound, or a pharmaceutically acceptable salt and / or solvate thereof, according to any one of claims 1-22, or a pharmaceutical composition according to claim 23, 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, 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, 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, Sézary 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.

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