Aromatic carboxamide compounds and methods of using thereof

Abstract

The present disclosure relates to compound of Formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof, wherein the variable are as defined herein. The invention further provides modulators or inhibitors of STAT6 activity, processes for their preparation, pharmaceutical compositions, and medicaments containing them, and their use in diseases and disorders mediated by IL-4 and / or IL-13.

Description

[0001] PAT065083-PCT-SEC01 AROMATIC CARBOXAMIDE COMPOUNDS AND METHODS OF USING THEREOF FIELD OF THE INVENTION

[0002] The present disclosure relates to aromatic carboxamide compounds. The present disclosure also relates to processes for the preparation of said compounds, pharmaceutical compositions comprising said compounds, and use of said compounds in the treatment of conditions, diseases and disorders mediated by IL-4 and / or IL- 13.

[0003] BACKGROUND OF THE INVENTION

[0004] Cytokines are proteins made in response to pathogens and other antigens that regulate and mediate inflammatory and immune responses. Exemplary cytokines are Interleukin 4 (IL-4) and Interleukin 13 (IL-13). IL-4 and IL-13 cytokines are key drivers of so-called type 2 immune responses which are found to be dysregulated in a number of skin, respiratory and gastrointestinal inflammatory conditions and disorders. The signal from either cytokine is intracellularly integrated via the Janus kinase (JAK)-mediated phosphorylation of the signal transducer and activator of transcription (STAT) protein family member 6 (STAT6), which, in turn, regulates a signal-specific gene expression program. Biologic (antibody-based) antagonists acting either directly on IL-13 or on the IL-4 receptor alpha subunit shared by both cytokines [Review: Carla Tubau et al. Immunotherapy 2021 13:327:344] as well as small molecule inhibitors of Janus kinases [Review: Donal P McLornan et. al. Lancet 2021 398:803-16] have been described.

[0005] There is a need to provide new and / or alternative treatments for IL-4 and / or IL- 13 mediated diseases and / or conditions such as atopic dermatitis (AD).

[0006] SUMMARY OF THE DISCLOSURE

[0007] In the context of the present disclosure, modulation or inhibition of STAT6 activity is considered as a meaningful therapeutic strategy for treating type 2 driven inflammatory diseases. This applies to diseases and / or conditions mediated by IL-4 and / or IL-13 such as atopic dermatitis (AD). Additional indications include but are not limited to asthma, chronic rhinosinusitis with nasal polyposis (CRSwNS), eosinophilic esophagitis (EoE), prurigo nodularis (PN), chronic prurigo (CPG), chronic spontaneous urticaria (CSU), chronic pruritus, bullous pemphigoid (BP), chronic obstructive pulmonary disease (COPD), ulcerative colitis (UC), eosinophilic gastroenteritis and food allergy. Both systemic as well as organ-restricted inhibition or modulation of STAT6 activity is considered to be of high therapeutic value.

[0008] The present disclosure provides compounds of Formula (I), or a pharmaceutically acceptable salt thereof, as defined herein below. The compounds of Formula (I) modulate type 2 immune responses which are found to be dysregulated in a number of skin, respiratory and gastrointestinal inflammatory conditions and disorders. The present disclosure relates to compounds of Formula (I), and pharmaceutically acceptable salts thereof, as herein defined, which are STAT6 modulators or STAT6 inhibitors. Accordingly, compounds of the presentPAT065083-PCT-SEC01 disclosure may therefore be useful in the treatment of atopic dermatitis and other diseases and / or disorders that are susceptible to modulation or inhibition of STAT6 activity.

[0009] In a first aspect of the disclosure, the compounds of Formula (I) are described:

[0010]

[0011] or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof, wherein:

[0012] X is N or CR13, wherein R13is selected from the group consisting of hydrogen, halo, CN, NO2, Ci-Csalkyl, Ci-Csalkoxy, -S(O)o-2(Ci-C3)alkyl and NR14R15, and wherein R14and R15are each independently selected from the group consisting of hydrogen, Ci-Csalkyl and

[0013] Cs-Cscycloalkyl;

[0014] ring B is 1,3-phenylene, or ring B is a monocyclic 5-membered heteroarylene;

[0015] R1is C1-C3alkylcarbonyl or C1-C3alkoxycarbonyl and R2and R3are hydrogen; alternatively, R1is Ci-Csalkylcarbonyl, Ci-Csalkoxycarbonyl, Ci-Csalkyl-NH-carbonyl, Ci-C3alkyl-N(Ci-C3alkyl)-carbonyl or -S(O)2(Ci-C3)alkyl, and R2and R3, together with the nitrogen and carbon atoms that they each are attached to and the neighboring carbon atom, form a 6-membered heterocycloalkyl, which optionally comprises one further heteroatomic ring member selected from the group consisting of O, NH and N(Ci-C3alkyl), and is optionally substituted with R12, wherein R12is selected from the group consisting of Ci-Csalkyl,

[0016] Ci-CsalkoxyCi-Csalkyl and Ci-Cshydroxyalkyl;

[0017] alternatively, R3is hydrogen, and R1and R2, together with the nitrogen they are attached to, form an unsubstituted, monocyclic 5-membered heteroaryl, or a monocyclic 5-membered heterocycloalkyl (i) that is substituted with one or two oxo and is optionally substituted with phenyl or with up to three C1-C3alkyl, and (ii) that optionally fuses with a second ring to form a fused bicyclic 9-membered ring;

[0018] R4is hydrogen, C1-C3alkyl, C1-C3alkoxy or halo, wherein each of said C1-C3alkyl and C1-C3alkoxy is unsubstituted or is substituted with one or more substituents each independently selected from the group consisting of halo, hydroxy and C1-C3alkoxy;

[0019] R4bis hydrogen, unsubstituted C1-C3alkyl or halo;

[0020] R5is -CHR8CH2R7or -CHR8CH(OH)R7and R6is hydrogen, wherein R7is hydroxy, hydroxyphenyl or bicyclic C5-C7cycloalkyl optionally substituted with hydroxy, and R8is C1-C3alkyl or C1-C3alkyl-NH-carbonyl;PAT065083-PCT-SEC01 alternatively, R5and R6, together with the nitrogen they are attached to, form a monocyclic C4-C6heterocycloalkyl comprising one or two nitrogen heteroatoms and being substituted with oxo and being optionally substituted with up to three further substituents being R9, R10and R11, wherein each of R9, R10and R11is independently selected from the group consisting of C1-C3alkyl, C1-C3hydroxyalkyl, C1-C3fluoroalkyl, C1-C3alkoxyC1-C3alkyl, C1-C3alkoxy, benzyl substituted with hydroxy, and bicyclic C5-C7cycloalkyl(C0-1alkyl) substituted with hydroxy.

[0021] In another aspect, the invention provides a compound of Formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof for use as a medicament.

[0022] In another aspect, the disclosure provides a composition, in particular, a pharmaceutical composition, which comprises (e.g. a therapeutically effective amount of) a compound of Formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.

[0023] In another aspect, the disclosure provides a combination, in particular a pharmaceutical combination, which comprises (e.g. a therapeutically effective amount of) a compound of Formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof, and one or more therapeutic agents.

[0024] In another aspect, the disclosure provides compounds of Formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof, for use in methods of treating, preventing, or ameliorating a condition, disease, or disorder treatable by modulating (e.g. inhibiting) STAT6.

[0025] In another aspect, the invention provides a use of a compound of Formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating, preventing, or ameliorating a condition, disease, or disorder treatable by modulating (e.g. inhibiting) STAT6.

[0026] In another aspect, the disclosure provides a compound of Formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof, for use in the treatment, or prevention of a STAT6-dependent disease or disorder such as atopic dermatitis or a related condition.

[0027] DETAILED DESCRIPTION OF THE INVENTION

[0028] The present disclosure relates to compounds of Formula (I) or a stereoisomer or pharmaceutically acceptable salt thereof, and to their use in the treatment of conditions, diseases and disorders mediated by IL-4 and / or IL- 13. Such conditions, diseases and disorders are susceptible to STAT6 modulation or inhibition. Hence the present disclosure relates to compounds which are modulators or inhibitors of STAT6 activity.

[0029] In a first aspect of the disclosure, the compounds of Formula (I) are described:PAT065083-PCT-SEC01

[0030]

[0031] R2R3(I) or pharmaceutically acceptable salts, hydrates, solvates, stereoisomers, and tautomers thereof, wherein X, ring B and R1through R6are as described herein.

[0032] The details of the disclosure are set forth in the accompanying description below. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, illustrative methods and materials are now described. Other features, objects, and advantages of the disclosure will be apparent from the description and from the claims. In the specification and the appended claims, the singular forms also include the plural unless the context clearly dictates otherwise. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. All patents and publications cited in this specification are incorporated herein by reference in their entireties. Definition of Terms and Conventions Used

[0033] Terms not specifically defined herein should be given the meanings that would be given to them by one of skill in the art in light of the disclosure and the context. As used in the specification and appended claims, however, unless specified to the contrary, the following terms have the meaning indicated and the following conventions are adhered to.

[0034] A. Chemical Nomenclature, Terms, and Conventions

[0035] In the groups, radicals, or moieties defined below, the number of carbon atoms is often specified preceding the group, for example, Ci-C10alkyl means an alkyl group or radical having 1 to 10 carbon atoms. In general, for groups comprising two or more subgroups, the last-named group is the radical attachment point, for example, “alkylaryl” means a monovalent radical of the formula alkyl-aryl-, while “arylalkyl” means a monovalent radical of the formula aryl-alkyl-.

[0036] Furthermore, the use of a term designating a monovalent radical where a divalent radical is appropriate shall be construed to designate the respective divalent radical and vice versa. Unless otherwise specified, conventional definitions of terms control and conventional stable atom valences are presumed and achieved in all formulas and groups. The articles “a” and “an” refer to one or more than one (e.g., to at least one) of the grammatical object of the article. By way of example, “an element” means one element or more than one element.

[0037] The term “and / or” means either “and” or “or” unless indicated otherwise.PAT065083-PCT-SEC01 The term “optionally substituted” means that a given chemical moiety (e.g., an alkyl group) can (but is not required to) be bonded to other substituents (e.g., heteroatoms). For instance, an alkyl group that is optionally substituted can be a fully saturated alkyl chain (e.g., a pure hydrocarbon). Alternatively, the same optionally substituted alkyl group can have substituents different from hydrogen. For instance, it can, at any point along the chain be bonded to a halogen atom, a hydroxyl group, or any other substituent described herein. Thus, the term “optionally substituted” means that a given chemical moiety has the potential to contain other functional groups, but does not necessarily have any further functional groups. Suitable substituents used in the optional substitution of the described groups include, without limitation, halo, oxo, hydroxy, Ci-Csalkyl, Ci-Cshydroxyalkyl, Ci-Csfluoroalkyl, Ci-CsalkoxyCi-Csalkyl, benzyl and phenyl. The substituents can themselves be optionally substituted. “Optionally substituted” as used herein also refers to substituted or unsubstituted whose meaning is described below.

[0038] The term “substituted” means that the specified group or moiety bears one or more suitable substituents wherein the substituents may connect to the specified group or moiety at one or more positions. For example, an aryl substituted with a cycloalkyl may indicate that the cycloalkyl connects to one atom of the aryl with a bond or by fusing with the aryl and sharing two or more common atoms.

[0039] The term “unsubstituted” means that the specified group bears no substituents.

[0040] Unless otherwise specifically defined, “aryl” means a cyclic, aromatic hydrocarbon group having 1 to 3 aromatic rings, including monocyclic or bicyclic groups such as phenyl, biphenyl, or naphthyl. When containing two aromatic rings (bicyclic, etc.), the aromatic rings of the aryl group are optionally joined at a single point (e.g., biphenyl), or fused (e.g., naphthyl). The aryl group is optionally substituted by one or more substituents, e.g., 1 to 5 substituents, at any point of attachment. Exemplary substituents include, but are not limited to, -H, -halogen, -CN, -O-(Ci-Ce)alkyl, (Ci-Ce)alkyl, -O-(C2-Ce)alkenyl, -0-(C2-Ce)alkynyl, (C2-Ce)alkenyl, (C2-Ce)alkynyl, -OH, -OP(O)(OH)2, -OC(O)(Ci-C6)alkyl, -C(O)(Ci-C6)alkyl, -OC(O)O(Ci-C6) alkyl, NH2, NH((Ci-C6)alkyl), N((Ci-C6)alkyl)2, -S(O)2-(Ci-C6)alkyl, -S(O)NH(Ci-C6)alkyl, and -S(O)N((Ci-C6)alkyl)2. The substituents are themselves optionally substituted. Furthermore, when containing two fused rings, the aryl groups optionally have an unsaturated or partially saturated ring fused with a fully saturated ring. Exemplary ring systems of these aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl, anthracenyl, phenalenyl, phenanthrenyl, indanyl, indenyl, tetrahydronaphthalenyl, tetrahydrobenzoannulenyl, and the like.

[0041] An “arylene” is a divalent aryl such as phenylene. Phenylene is an example of 6-membered monocyclic arylene. The phenylene group has three structural isomers: paraphenylene, metaphenylene (i.e. 1,3-phenylene), and ortho-phenylene.

[0042] Unless otherwise specifically defined, “heteroaryl” means a monocyclic aromatic radical of 5 to 24 ring atoms or a polycyclic aromatic radical, each containing one or more ring heteroatomsPAT065083-PCT-SEC01 selected from N, O, or S, the remaining ring atoms being C. Heteroaryl as herein defined also means a bicyclic heteroaromatic group wherein the heteroatom is selected from N, O, or S. The aromatic radical is optionally substituted independently with one or more substituents described herein. Examples include, but are not limited to, furyl, thienyl, pyrrolyl, pyridyl, pyrazolyl, pyrimidinyl, imidazolyl, isoxazolyl, oxazolyl, oxadiazolyl, pyrazinyl, indolyl, thiophen-2-yl, quinolyl, benzopyranyl, isothiazolyl, thiazolyl, thiadiazole, indazole, benzimidazolyl, thieno[3,2-b]thiophene, triazolyl, triazinyl, imidazo[1,2-b]pyrazolyl, furo[2,3-c]pyridinyl, imidazo[1,2-a]pyridinyl, indazolyl, pyrrolo[2,3-c]pyridinyl, pyrrolo[3,2-c]pyridinyl, pyrazolo[3,4-c]pyridinyl, thieno[3,2-c]pyridinyl, thieno[2,3-c]pyridinyl, thieno[2,3-b]pyridinyl, benzothiazolyl, indolyl, indolinyl, indolinonyl, dihydrobenzothiophenyl, dihydrobenzofuranyl, benzofuran, chromanyl, thiochromanyl, tetrahydroquinolinyl, dihydrobenzothiazine, dihydrobenzoxanyl, quinolinyl, isoquinolinyl, 1,6-naphthyridinyl, benzo[de]isoquinolinyl, pyrido[4,3-b][1,6]naphthyridinyl, thieno[2,3-b]pyrazinyl, quinazolinyl, tetrazolo[1, 5-a]pyridinyl, [1,2,4]triazolo[4, 3-a]pyridinyl, isoindolyl, pyrrolo[2,3-b]pyridinyl, pyrrolo[3,4-b]pyridinyl, pyrrolo[3,2-b]pyridinyl, imidazo[5,4-b]pyridinyl, pyrrolo[1,2-a]pyrim idinyl, tetrahydropyrrolo[1,2-a]pyrimidinyl, 3,4-dihydro-2H-1Δ2-pyrrolo[2,1-b]pyrimidine, dibenzo[b,d]thiophene, pyridin-2-one, furo[3,2-c]pyridinyl, furo[2,3-c]pyridinyl, 1 H-pyrido[3,4-b][1,4]thiazinyl, benzooxazolyl, benzoisoxazolyl, furo[2,3-b]pyridinyl, benzothiophenyl, 1,5-naphthyridinyl, furo[3,2-b]pyridine, [1,2,4]triazolo[1,5-a]pyridinyl, benzo[1,2, 3]triazolyl, imidazo[1,2-a]pyrim idinyl, [1,2,4]triazolo[4, 3-b]pyridazinyl,

[0043] benzo[c][1,2, 5]thiadiazolyl, benzo[c][1,2,5]oxadiazole, 1,3-dihydro-2H-benzo[d]imidazol-2-one, 3,4-dihydro-2H-pyrazolo[1, 5- b] [ 1,2]oxazinyl, 4,5,6,7-tetrahydropyrazolo[1, 5-a] pyridi ny I, thiazolo[5,4 d]thiazolyl, imidazo[2, 1-b][1,3,4]thiadiazolyl, thieno[2,3-b]pyrrolyl, 3H-indolyl, and derivatives thereof. Furthermore, when containing two fused rings the heteroaryl groups herein defined may have an unsaturated or partially saturated ring fused with a fully saturated ring. Exemplary ring systems of these heteroaryl groups include indolinyl, indolinonyl, dihydrobenzothiophenyl, dihydrobenzofuranyl, chromanyl, thiochromanyl, tetrahydroquinolinyl, dihydrobenzothiazine, 3, 4-dihydro-IH-isoquinolinyl, 2,3-dihydrobenzofuran, indolinyl, indolyl, and dihydrobenzoxanyl.

[0044] “Monocyclic 5-membered heteroaryl” means a monocyclic heteroaryl of 5 ring atoms, containing one or more ring heteroatoms selected from N, O, or S, the remaining ring atoms being C. Examples include, but are not limited to thiophenyl, pyrazolyl, thiazolyl and imidazolyl.

[0045] A “heteroarylene” is a divalent heteroaryl as herein defined. A heteroaryl may be monocyclic or polycyclic. “Monocyclic 5-membered heteroarylene” is a divalent monocyclic aromatic radical of 5 ring atoms, containing one or more ring heteroatoms selected from N, O, or S, the remaining ring atoms being C. Divalent thiophenyl, pyrazolyl, thiazolyl and imidazolyl are exemplary monocyclic 5-membered heteroarylenes. Thiophene-2, 4-diyl is an exemplary divalent thiophenyl. Thiazol-2, 4-diyl is an exemplary divalent thiazolyl.PAT065083-PCT-SEC01 A fused bicyclic ring means a monovalent or divalent radical comprising two rings, wherein the two rings share one edge. The fused bicyclic ring is optionally substituted by one or more substituents, e.g., 1 to 5 substituents, at any point of attachment. A fused bicyclic ring may be a fused bicyclic aryl, arylene, heteroaryl or heteroarylene. A “fused bicyclic 9-membered ring” has 9 ring atoms that may or may not contain one or more ring heteroatoms selected from N, O, or S, the remaining ring atoms being C. A fused bicyclic 9-membered ring may contain a heteroaromatic ring that fuses with a second ring. Furthermore, a fused bicyclic 9-membered ring may be a monovalent or divalent radical. Thereby, conventional stable valences are presumed and achieved in all formulas and groups. By way of example, if a fused bicyclic 9-membered ring comprises a monocyclic 5-membered heteroarylene that fuses with a second ring, such fused bicyclic 9-membered ring is a divalent radical containing one or more ring heteroatoms selected from N, O, or S, the remaining ring atoms being C. Examples of fused bicyclic 9-membered rings include, but are not limited to divalent pyrrolo[1,2-a]pyrimidine and monovalent 2,3-dihydrothieno[3,4-b][1,4]dioxine.

[0046] Halogen or “halo” mean fluorine, chlorine, bromine, or iodine.

[0047] “Alkyl” means a straight or branched chain saturated hydrocarbon containing 1-12 carbon atoms. Examples of a Ci-Cealkyl group include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, neopentyl, and isohexyl. Terms such as " Ci-Csalkyl" are to be construed accordingly.

[0048] “Alkoxy” means a straight or branched chain saturated hydrocarbon containing 1-12 carbon atoms containing a terminal “O” in the chain, e.g., -O(alkyl). Examples of alkoxy groups include, without limitation, methoxy, ethoxy, propoxy, butoxy, t-butoxy, or pentoxy groups. Terms such as " Ci-Csalkoxy" are to be construed accordingly. Examples of a Ci-Csalkoxy group include, but are not limited to, methoxy, ethoxy and propoxy.

[0049] “Cycloalkyl” means a monocyclic or polycyclic saturated carbon ring containing 3-18 carbon atoms. Examples of cycloalkyl groups include, without limitations, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptanyl, cyclooctanyl, norboranyl, norborenyl, bicyclo[2.2.2]octanyl, or bicyclo[2.2.2]octenyl and derivatives thereof. A Cs-Cscycloalkyl is a cycloalkyl group containing from 3 to 8 carbon atoms. A cycloalkyl group can be fused (e.g., decalin) or bridged (e.g., norbomane). Terms such as "bicyclic Cs-Cycycloalkyl" are to be construed accordingly. Examples of a bicyclic Cs-Cycycloalkyl group include, but are not limited to, bridged bicyclic Cs-Cycycloalkyl such as bicyclo[1.1.1]pentan-1-yl. As used herein, the term “bicyclic Cs-Cycycloalky Co-i alkyl)” refers to a bicyclic Cs-Cycycloalkyl, and which is attached to the rest of the molecule by a single bond or by Ci alkyl such as -CH2- (i.e. methylene).

[0050] “Heterocycloalkyl” means a saturated or unsaturated nonaromatic, mono- or polycyclic ring containing carbon and at least one heteroatom selected from oxygen, nitrogen, or sulfur (O, N, or S) and wherein there is no delocalized n electrons (aromaticity) shared among the ring carbon or heteroatoms. The heterocycloalkyl ring structure may be substituted by one or morePAT065083-PCT-SEC01 substituents. The substituents can themselves be optionally substituted. Examples of heterocycloalkyl rings include, but are not limited to, oxetanyl, azetadinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, oxazolinyl, oxazolidinyl, thiazolinyl, thiazolidinyl, pyranyl, thiopyranyl, tetrahydropyranyl, dioxalinyl, piperidinyl, morpholinyl, thiomorpholinyl, thiomorpholinyl S-oxide, thiomorpholinyl S-dioxide, piperazinyl, azepinyl, oxepinyl, diazepinyl, tropanyl, oxazolidinonyl, 1,4-dioxanyl, di hydrofuranyl, 1,3-dioxolanyl, imidazolidinyl, imidazolinyl, dithiolanyl, and homotropanyl. Terms such as "monocyclic C4-C6heterocycloalkyl" are to be construed accordingly. Examples of a monocyclic C4-C6heterocycloalkyl include, but are not limited to, piperazine.

[0051] “Hydroxyalkyl” means an alkyl group substituted with one or more -OH groups. Examples of hydroxyalkyl groups include -CH2-OH, -CH2CH2-OH, and -CH(OH)-CH3. Terms such as " C1-C3 hydroxyalkyl" are to be construed accordingly.

[0052] “Haloalkyl” means an alkyl group substituted with one or more halogens. Examples of haloalkyl groups include, but are not limited to, trifluoromethyl, difluoromethyl, pentafluoroethyl, trichloromethyl, etc. Terms such as " Ci-Csfluoroalkyl" are to be construed accordingly.

[0053] Examples of a Ci-Csfluoroalkyl include, but are not limited to, trifluoromethyl and trifluoroethyl.

[0054] “AlkoxyCi-Csalkyl” means a Ci-Csalkyl group substituted with one or more alkoxy group. Terms such as “Ci-Csalkoxy Ci-Csalkyl” are to be construed accordingly.

[0055] “Haloalkoxy” means an alkoxy group substituted with one or more halogens. Examples of haloalkyl groups include, but are not limited to, trifluoromethoxy, difluoromethoxy, pentafluoroethoxy, trichloromethoxy, etc.

[0056] “Ci-Csalkylcarbonyl” refers to -C(O)( Ci-C3)alkyl.

[0057] “Ci-Csalkoxycarbonyl” refers to -C(O)O(Ci-C3)alkyl.

[0058] “Ci-Csalkyl-NH-carbonyl” means -C(O)NH(Ci-C3)alkyl. Terms such as Ci-C3alkyl-N(Ci-C3alkyl)-carbonyl are to be construed accordingly.

[0059] “Cyano” means a substituent having a carbon atom joined to a nitrogen atom by a triple bond, e.g., C = N.

[0060] “-S(0)o-2(Ci-C3)alkyl” means a substituent selected from the group consisting of -S-( C1-C3)alkyl, -S(O)( Ci-C3)alkyl and -S(O)2(Ci-C3)alkyl.

[0061] B. Salt, Derivative and Solvate Terms and Conventions

[0062] The terms “salt” or “salts” refers to an acid addition or base addition salt of a compound of the present disclosure. “Salts” include in particular “pharmaceutical acceptable salts”. The term “pharmaceutically acceptable salts” refers to salts that retain the biological effectiveness and properties of the compounds of this disclosure and, which typically are not biologically or otherwise undesirable. In many cases, the compounds of the present disclosure are capable of forming acid and / or base salts by virtue of the presence of amino and / or carboxyl groups or groups similar thereto. When both a basic group and an acid group are present in the same molecule, the compounds of the present disclosure may also form internal salts, e.g.,PAT065083-PCT-SEC01 zwitterionic molecules.

[0063] Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids.

[0064] Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.

[0065] Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, sulfosalicylic acid, and the like.

[0066] Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.

[0067] Inorganic bases from which salts can be derived include, for example, ammonium salts and metals from columns I to XII of the periodic table. In certain embodiments, the salts are derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper; particularly suitable salts include ammonium, potassium, sodium, calcium and magnesium salts.

[0068] Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like. Certain organic amines include isopropylamine, benzathine, cholinate, diethanolamine, diethylamine, lysine, meglumine, piperazine and tromethamine.

[0069] In another aspect, the present disclosure provides compounds of the present disclosure in acetate, ascorbate, adipate, aspartate, benzoate, besylate, bromide / hydrobromide, bicarbonate / carbonate, bisulfate / sulfate, camphorsulfonate, caprate, chloride / hydrochloride, chlortheophyllonate, citrate, ethandisulfonate, fumarate, gluceptate, gluconate, glucuronate, glutamate, glutarate, glycolate, hippurate, hydroiodide / iodide, isethionate, lactate, lactobionate, laurylsulfate, malate, maleate, malonate, mandelate, mesylate, methylsulphate, mucate, naphthoate, napsylate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate / hydrogen phosphate / dihydrogen phosphate, polygalacturonate, propionate, sebacate, stearate, succinate, sulfosalicylate, sulfate, tartrate, tosylate trifenatate, trifluoroacetate or xinafoate salt form.

[0070] “Solvate” means a complex of variable stoichiometry formed by a solute, for example, a compound of Formula (I) and solvent, for example, water, ethanol, or acetic acid. This physical association may involve varying degrees of ionic and covalent bonding, including hydrogen bonding. 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. In general, such solvents selected for the purpose of the disclosure do not interfere with the biological activity of the solute. Solvates encompasses both solution-phase and isolatable solvates.

[0071] Representative solvates include hydrates, ethanolates, methanolates, and the like.PAT065083-PCT-SEC01 “Hydrate” means a solvate wherein the solvent molecule(s) is / are water.

[0072] The compounds of the present disclosure as discussed below include the free base or acid thereof, their salts, solvates, and may include oxidized sulfur atoms or quaternized nitrogen atoms in their structure, although not explicitly stated or shown, particularly the pharmaceutically acceptable forms thereof. Such forms, particularly the pharmaceutically acceptable forms, are intended to be embraced by the appended claims.

[0073] C. Isomer Terms and Conventions

[0074] “Isomers” means compounds having the same number and kind of atoms, and hence the same molecular weight, but differing with respect to the arrangement or configuration of the atoms in space. The term includes stereoisomers and geometric isomers.

[0075] “Stereoisomer” or “optical isomer” means a stable isomer that has at least one chiral atom or restricted rotation giving rise to perpendicular dissymmetric planes (e.g., certain biphenyls, allenes, and spiro compounds) and can rotate plane-polarized light. Because asymmetric centers and other chemical structures exist in the compounds of the disclosure which may give rise to stereoisomerism, the disclosure contemplates stereoisomers and mixtures thereof. The compounds of the disclosure and their salts include asymmetric carbon atoms and may therefore exist as single stereoisomers, racemates, and as mixtures of enantiomers and diastereomers. Typically, such compounds will be prepared as a racemic mixture. If desired, however, such compounds can be prepared or isolated as pure stereoisomers, i.e., as individual enantiomers or diastereomers, or as stereoisomer-enriched mixtures. As discussed in more detail below, individual stereoisomers of compounds are prepared by synthesis from optically active starting materials containing the desired chiral centers or by preparation of mixtures of enantiomeric products followed by separation or resolution, such as conversion to a mixture of diastereomers followed by separation or recrystallization, chromatographic techniques, use of chiral resolving agents, or direct separation of the enantiomers on chiral chromatographic columns. Starting compounds of particular stereochemistry are either commercially available or are made by the methods described below and resolved by techniques well-known in the art.

[0076] “Enantiomers” means a pair of stereoisomers that are non-superimposable mirror images of each other.

[0077] “Diastereoisomers” or “diastereomers” mean optical isomers which are not mirror images of each other.

[0078] “Racemic mixture” or “racemate” mean a mixture containing equal parts of individual enantiomers.

[0079] “Non-racemic mixture” means a mixture containing unequal parts of individual enantiomers. “Geometrical isomer” means a stable isomer which results from restricted freedom of rotation about double bonds (e.g., cis-2-butene and trans-2-butene) or in a cyclic structure (e.g., cis-1,3-dichlorocyclobutane and trans-1,3-dichlorocyclobutane). Because carbon-carbon double (olefinic) bonds, C=N double bonds, cyclic structures, and the like may be present in thePAT065083-PCT-SEC01 compounds of the disclosure, the disclosure contemplates each of the various stable geometric isomers and mixtures thereof resulting from the arrangement of substituents around these double bonds and in these cyclic structures. The substituents and the isomers are designated using the cis / trans convention or using the E or Z system, wherein the term “E” means higher order substituents on opposite sides of the double bond, and the term “Z” means higher order substituents on the same side of the double bond. A thorough discussion of E and Z isomerism is provided in J. March, Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 4th ed., John Wiley & Sons, 1992, which is hereby incorporated by reference in its entirety. Several of the following examples represent single E isomers, single Z isomers, and mixtures of E / Z isomers. Determination of the E and Z isomers can be done by analytical methods such as x-ray crystallography,1H NMR, and13C NMR.

[0080] Some of the compounds of the disclosure can exist in more than one tautomeric form. As mentioned above, the compounds of the disclosure include all such tautomers.

[0081] It is well-known in the art that the biological and pharmacological activity of a compound is sensitive to the stereochemistry of the compound. Thus, for example, enantiomers often exhibit strikingly different biological activity including differences in pharmacokinetic properties, including metabolism, protein binding, and the like, and pharmacological properties, including the type of activity displayed, the degree of activity, toxicity, and the like.

[0082] Thus, although the racemic form of drug may be used, it is often less effective than administering an equal amount of enantiomerically pure drug; indeed, in some cases, one enantiomer may be pharmacologically inactive and would merely serve as a simple diluent. Furthermore, the pharmacological activities of enantiomers may have distinct biological activity. Indeed, some purified enantiomers have advantages over their racemates, as it has been reported that purified individual isomers have faster transdermal penetration rates compared to the racemic mixture.

[0083] Thus, if one enantiomer is pharmacologically more active, less toxic, or has a preferred disposition in the body than the other enantiomer, it would be therapeutically more beneficial to administer that enantiomer preferentially. In this way, the patient undergoing treatment would be exposed to a lower total dose of the drug and to a lower dose of an enantiomer that is possibly toxic or an inhibitor of the other enantiomer.

[0084] Preparation of pure enantiomers or mixtures of desired enantiomeric excess (ee) or enantiomeric purity are accomplished by one or more of the many methods of (a) separation or resolution of enantiomers, or (b) enantioselective synthesis known to those of skill in the art, or a combination thereof. These resolution methods generally rely on chiral recognition and include, for example, chromatography using chiral stationary phases, enantioselective hostguest complexation, resolution or synthesis using chiral auxiliaries, enantioselective synthesis, enzymatic and nonenzymatic kinetic resolution, or spontaneous enantioselective crystallization. Such methods are disclosed generally in Chiral Separation Techniques: A Practical ApproachPAT065083-PCT-SEC01 (2nd Ed.), G. Subramanian (ed.), Wiley-VCH, 2000; T. E. Beesley and R. P. W. Scott, Chiral Chromatography, John Wiley & Sons, 1999; and Satinder Ahuja, Chiral Separations by Chromatography, Am. Chem. Soc., 2000. Furthermore, there are equally well-known methods for the quantitation of enantiomeric excess or purity, for example, GC, HPLC, CE, or NMR, and assignment of absolute configuration and conformation, for example, CD ORD, X-ray crystallography, or NMR.

[0085] In general, all tautomeric forms and isomeric forms and mixtures, whether individual geometric isomers or stereoisomers or racemic or non-racemic mixtures, of a chemical structure or compound is intended, unless the specific stereochemistry or isomeric form is specifically indicated in the compound name or structure.

[0086] D. Pharmaceutical Administration and Treatment Terms and Conventions

[0087] A “patient” or “subject” is a mammal, e.g., a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, or nonhuman primate, such as a monkey, chimpanzee, baboon or, rhesus. In certain embodiments, the subject is a primate. In yet other embodiments, the subject is a human.

[0088] An “effective amount” or “therapeutically effective amount” when used in connection with a compound means an amount of a compound of the present disclosure that (i) treats or prevents the particular disease, condition, or disorder, (ii) attenuates, ameliorates, or eliminates one or more symptoms of the particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of the particular disease, condition, or disorder described herein.

[0089] The terms “pharmaceutically effective amount” or “therapeutically effective amount” means an amount of a compound according to the disclosure which, when administered to a patient in need thereof, is sufficient to effect treatment for disease-states, conditions, or disorders for which the compounds have utility. Such an amount would be sufficient to elicit the biological or medical response of a tissue, system, or patient that is sought by a researcher or clinician. The amount of a compound of according to the disclosure which constitutes a therapeutically effective amount will vary depending on such factors as the compound and its biological activity, the composition used for administration, the time of administration, the route of administration, the rate of excretion of the compound, the duration of treatment, the type of disease-state or disorder being treated and its severity, drugs used in combination with or coincidentally with the compounds of the disclosure, and the age, body weight, general health, sex, and diet of the patient. Such a therapeutically effective amount can be determined routinely by one of ordinary skill in the art having regard to their own knowledge, the prior art, and this disclosure.

[0090] As used herein, the term “pharmaceutical composition” refers to a compound of the disclosure, or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof, together with at least one pharmaceutically acceptable carrier, in a form suitable for oral or parenteral administration.PAT065083-PCT-SEC01 “Carrier” encompasses carriers, excipients, and diluents and means a material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting a pharmaceutical agent from one organ, or portion of the body, to another organ, or portion of the body of a subject.

[0091] A subject is “in need of” a treatment if such subject would benefit biologically, medically, or in quality of life from such treatment (preferably, a human).

[0092] As used herein, the term “inhibit”, “inhibition”, or “inhibiting” refers to the reduction or suppression of a given condition, symptom, or disorder, or disease, or a significant decrease in the baseline activity of a biological activity or process.

[0093] As used herein, the term “treat”, “treating”, or “treatment” of any disease or disorder refers to alleviating or ameliorating the disease or disorder (i.e., slowing or arresting the development of the disease or at least one of the clinical symptoms thereof); or alleviating or ameliorating at least one physical parameter or biomarker associated with the disease or disorder, including those which may not be discernible to the patient.

[0094] As used herein, the term “prevent”, “preventing", or “prevention” of any disease or disorder refers to the prophylactic treatment of the disease or disorder; or delaying the onset or progression of the disease or disorder.

[0095] “Pharmaceutically acceptable” means that the substance or composition must be compatible chemically and / or toxicologically, with the other ingredients comprising a formulation, and / or the mammal being treated therewith.

[0096] “Disorder” means, and is used interchangeably with, the terms disease, condition, or illness, unless otherwise indicated.

[0097] “Administer”, “administering”, or “administration” means either directly administering a disclosed compound or pharmaceutically acceptable salt of the disclosed compound or a composition to a subject, or administering a pharmaceutically acceptable salt of the compound or composition to the subject, which can form an equivalent amount of active compound within the subject’s body.

[0098] A ’’compound of the present disclosure”, “compounds of the disclosure”, “compound of the invention”, and equivalent expressions (unless specifically identified otherwise), refer to compounds of Formula (I) and subformulae thereof as described herein, including, the salts particularly the pharmaceutically acceptable salts, and the solvates and hydrates thereof, where the context so permits, as well as all stereoisomers (including diastereoisomers and enantiomers), rotamers, tautomers, and isotopically labelled compounds (including deuterium substitutions) thereof, as well as polymorphs thereof. For example, the term “compound of the invention” refers to a compound having Formula (I) or any sub-formula thereof, such as Formula (la), (II), (Ila’) (Ila), (lib), (He), (lid), (III), (Illa), (lllb), (lllc), (Hid), (Hie), (HI’), (IV), (IVa), (IVb), (IVc), (IVd), (IVe), (V), (Va), (Vb), (Vc), (Vd), (Ve), (VI), (Via), (Vlb), (Vic), (Vid), (Vie), (VII), (Villa), (Vlllb), (Ville), (Vllld), (IXa), (IXb), (IXc), (IXd), (IXe), (IXf) and (IXg). In general, thePAT065083-PCT-SEC01 compounds of the disclosure are understood to include the stable compounds thereof and exclude unstable compounds, even if an unstable compound might be considered to be literally embraced by the compound formula. Similarly, reference to intermediates, whether or not they themselves are claimed, is meant to embrace their salts and solvates, where the context so permits.

[0099] “Stable compound” or “stable structure” means a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic or diagnostic agent. For example, a compound which would have a “dangling valency” or is a carbanion is not a compound contemplated by the disclosure.

[0100] In a specific embodiment, the term “about” or “approximately” means within 20%, preferably within 10%, and more preferably within 5% of a given value or range.

[0101] The yield of each of the reactions described herein is expressed as a percentage of the theoretical yield.

[0102] “STAT6” refers to the Signal Transducer and Activator of Transcription 6 protein, which is encoded by the gene of the same name. STAT6 is a member of the STAT family of transcription factors, which, in response to cytokine or growth factor signaling, are phosphorylated by kinase(s) associated with the respective cytokine’s or growth factor’s receptor, receptors or receptor complex. Upon phosphorylation, STAT proteins form dimers which translocate to the cell’s nucleus and act as transcriptional activators of specific target genes. In the context of the present invention and unless indicated differently, the term “STAT6” refers to any kind of STAT6, including phosphorylated STAT6 (pSTAT6) and dimers thereof.

[0103] “STAT6-dependent disease or disorder” means any disease or disorder which is directly or indirectly affected by the modulation (e.g. inhibition) of STAT6 activity such as modulation of STAT6 phosphorylation, and / or the modulation of STAT6 capability to dimerize, translocate to the nucleus and / or to activate transcription. Thereby, the term STAT6 is to be understood broadly and includes phosphorylated STAT6 (pSTAT6) and dimers thereof. Indeed, in at least some STAT6-dependent diseases or disorders, pSTAT6 or dimers thereof are upregulated. An exemplary STAT6-dependent disease or disorder that is susceptible to STAT6 modulation is atopic dermatitis (AD).

[0104] In a number of skin, respiratory and gastrointestinal inflammatory conditions and disorders, IL-4 and / or IL-13 cytokines are key drivers. The term “IL-4 and / or IL-13 mediated disease or condition” means any disease or disorder which is directly or indirectly affected by the modulation of IL-4 and / or IL- 13 activity. This includes diseases and disorders which are affected by the modulation of the cytokines themselves or by the modulation of their respective receptors (or receptor complexes), including the IL-4 receptor alpha subunit utilized / engaged by both cytokines, or by modulation of the receptor-associated (Janus) kinases (JAKs). IL-4 and / or IL-13 mediated diseases or conditions are susceptible to STAT6 modulation. Therefore, the terms “IL-PAT065083-PCT-SEC01 4 and / or IL-13 mediated disease or condition” and “STAT6-dependent disease or disorder” overlap at least partially.

[0105] In the context of the present invention, inhibition or modulation of STAT6 activity downstream of and in response to IL-4 and / or IL-13 signaling is considered to be of high therapeutic value.

[0106] E. Specific Embodiments and Methods for Testing Compounds of Formula (I)

[0107] The present disclosure relates to compounds or pharmaceutically acceptable salts, hydrates, solvates, stereoisomers, or tautomers thereof, capable of modulating or inhibiting STAT6 activity, which is useful for the treatment of diseases and disorders that are susceptible to STAT6 modulation or STAT6 inhibition. The disclosure further relates to compounds, or pharmaceutically acceptable salts, hydrates, solvates, stereoisomers, or tautomers thereof, which are useful for modulating or inhibiting STAT6 activity.

[0108] In one aspect, the disclosure provides a compound of Formula (I):

[0109]

[0110] or a stereoisomer or pharmaceutically acceptable salt thereof, wherein:

[0111] X is N or CR13, wherein R13is selected from the group consisting of hydrogen, halo, CN, NO2, Ci-Csalkyl, Ci-Csalkoxy, -S(O)o-2(Ci-C3)alkyl and NR14R15, and wherein R14and R15are each independently selected from the group consisting of hydrogen, Ci-Csalkyl and

[0112] Cs-Cscycloalkyl;

[0113] ring B is 1,3-phenylene, or ring B is a monocyclic 5-membered heteroarylene;

[0114] R1is C1-C3alkylcarbonyl or C1-C3alkoxycarbonyl and R2and R3are hydrogen; alternatively, R1is Ci-Csalkylcarbonyl, Ci-Csalkoxycarbonyl, Ci-Csalkyl-NH-carbonyl, Ci-C3alkyl-N(Ci-C3alkyl)-carbonyl or -S(O)2(Ci-C3)alkyl, and R2and R3, together with the nitrogen and carbon atoms that they each are attached to and the neighboring carbon atom, form a 6-membered heterocycloalkyl, which optionally comprises one further heteroatomic ring member selected from the group consisting of O, NH and N(Ci-C3alkyl), and is optionally substituted with R12, wherein R12is selected from the group consisting of Ci-Csalkyl,

[0115] Ci-CsalkoxyCi-Csalkyl and Ci-Cshydroxyalkyl;

[0116] alternatively, R3is hydrogen, and R1and R2, together with the nitrogen they are attached to, form an unsubstituted, monocyclic 5-membered heteroaryl, or a monocyclic 5-memberedPAT065083-PCT-SEC01 heterocycloalkyl (i) that is substituted with one or two oxo and is optionally substituted with phenyl or with up to three C1-C3alkyl, and (ii) that optionally fuses with a second ring to form a fused bicyclic 9-membered ring;

[0117] R4is hydrogen, C1-C3alkyl, C1-C3alkoxy or halo, wherein each of said C1-C3alkyl and C1-C3alkoxy is unsubstituted or is substituted with one or more substituents each independently selected from the group consisting of halo, hydroxy and C1-C3alkoxy;

[0118] R4bis hydrogen, unsubstituted C1-C3alkyl or halo;

[0119] R5is -CHR8CH2R7or -CHR8CH(OH)R7and R6is hydrogen, wherein R7is hydroxy, hydroxyphenyl or bicyclic C5-C7cycloalkyl optionally substituted with hydroxy, and R8is C1-C3alkyl or C1-C3alkyl-NH-carbonyl;

[0120] alternatively, R5and R6, together with the nitrogen they are attached to, form a monocyclic C4-C6heterocycloalkyl comprising one or two nitrogen heteroatoms and being substituted with oxo and being optionally substituted with up to three further substituents being R9, R10and R11, wherein each of R9, R10and R11is independently selected from the group consisting of

[0121] C1-C3alkyl, C1-C3hydroxyalkyl, C1-C3fluoroalkyl, C1-C3alkoxyC1-C3alkyl, C1-C3alkoxy, benzyl substituted with hydroxy, and bicyclic C5-C7cycloalkyl(C0-1alkyl) substituted with hydroxy.

[0122] One embodiment relates to a compound of Formula (la):

[0123]

[0124] R2R3(ia)

[0125] or a stereoisomer or pharmaceutically acceptable salt thereof, wherein:

[0126] X, ring B, R1, R2, R3, R4, R5and R6are as defined in Formula (I).

[0127] In another embodiment, the disclosure provides a compound of Formula (II)

[0128]

[0129] R2 R3(II) or a stereoisomer or pharmaceutically acceptable salt thereof, wherein:PAT065083-PCT-SEC01 ring B, R1, R2, R3, R4, R5and R6are as defined in Formula (I); and

[0130] R4bis hydrogen, unsubstituted C1-C3alkyl or halo.

[0131] One embodiment relates to a compound of Formula (Ila’):

[0132] (Ha')

[0133]

[0134] or a stereoisomer or pharmaceutically acceptable salt thereof, wherein ring B, R1, R2, R3, R4, R5and R6are as defined in Formula (I).

[0135] In another embodiment, the disclosure provides a compound of Formula (I), (la), (II) or (Ila’), wherein ring B is a monocyclic 5-membered heteroarylene (i) comprising one sulfur and optionally one nitrogen heteroatom, or (ii) comprising one or two nitrogen heteroatoms. In some embodiment, ring B is a monocyclic 5-membered heteroarylene selected from the group consisting of divalent thiophenyl, thiazolyl, pyrazolyl and imidazolyl.

[0136] Examples include but are not limited to a compound having Formula (Ila), (lib), (He) or (lid):

[0137]

[0138] (Hd) or a stereoisomer or pharmaceutically acceptable salt thereof, wherein R1, R2, R3, R4, R5and R6are as defined in Formula (I).

[0139] One embodiment relates to a compound of Formula (III)PAT065083-PCT-SEC01

[0140] O

[0141]

[0142] or a stereoisomer or pharmaceutically acceptable salt thereof, wherein each Q is independently nitrogen or CH; and wherein ring B, R4, R4b, R5and R6are as defined in Formula (I).

[0143] Examples include but are not limited to a compound of Formula (Illa), Formula (I I lb), (I lie), (Hid) or (Hie):

[0144]

[0145] or a stereoisomer or pharmaceutically acceptable salt thereof, wherein each Q is independently nitrogen or CH; and R3is hydrogen; and

[0146] R3, R4, R5and R6are as defined in Formula (I).

[0147] In yet another embodiment, the disclosure provides a compound of Formula (I), (la), (II) or (Ila’), or a compound of Formula (Ila), (lib), (He) or (I Id), wherein R1and R2,

[0148] together with the nitrogen they are attached to, form an unsubstituted, monocyclic 5-membered heteroaryl (i) that is substituted with one or two oxo and is optionally substituted with phenyl or with up to three C1-C3alkyl, and (ii) that optionally fuses with a second ring to form a fused bicyclic 9-membered ring.

[0149] In yet another embodiment, the disclosure invention provides a compound of Formula (I), (la), (II) or (Ila’), or a compound of Formula (Ha), (I I b), (He) or (lid), wherein R1and R2, together with the nitrogen they are attached to, form a monocyclic 5-membered heterocycloalkyl (i) that is substituted with one or two oxo and is optionally substituted with phenyl or with up to threePAT065083-PCT-SEC01 Ci-C3alkyl, and (ii) that optionally fuses with a second ring to form a fused bicyclic 9-membered ring.

[0150] One embodiment relates to a compound of Formula (III’)

[0151]

[0152] or a stereoisomer or pharmaceutically acceptable salt thereof, wherein:

[0153] W is CH2, CH(Ci-C3alkyl), O or NH;

[0154] each Z is independently hydrogen, phenyl or Ci-C3alkyl; and

[0155] ring B, R3, R4, R5and R6are as defined in Formula (I).

[0156] One embodiment relates to a compound of Formula (IV):

[0157] O

[0158]

[0159] or a stereoisomer or pharmaceutically acceptable salt thereof, wherein W is CH2, O or NH; each Q is independently nitrogen or CH; and the fused bicyclic 9-membered ring accommodating W comprises at the most three nitrogen atoms; and

[0160] ring B, R4, R5and R6are as defined in Formula (I).

[0161] Examples include but are not limited to a compound of Formula (IVa), (IVb), (IVc), (IVd) and (IVe):

[0162]

[0163] PAT065083-PCT-SEC01

[0164]

[0165] or a stereoisomer or pharmaceutically acceptable salt thereof, wherein W is CH2, O or NH; each Q is independently nitrogen or CH; and the fused bicyclic 9-membered ring accommodating W comprises at the most three nitrogen atoms; and

[0166] R3, R4, R5and R6are as defined in Formula (I).

[0167] In yet another embodiment, the disclosure provides a compound of Formula (I), (la), (II) or (Ila’), or a compound of Formula (Ila), (lib), (He) or (lid), wherein R1is Ci-Csalkylcarbonyl, C1-Csalkoxycarbonyl, Ci-Csalkyl-NH-carbonyl, Ci-C3alkyl-N(Ci-C3alkyl)-carbonyl or-S(O)2(Ci-C3)alkyl; and R2and R3, together with the nitrogen and carbon atoms that they each are attached to and the neighboring carbon atom, form a 6-membered heterocycloalkyl, which optionally comprises one further heteroatomic ring member selected from the group consisting of O, NH and N(Ci-C3alkyl), and is optionally substituted with R12, wherein R12is selected from the group consisting of Ci-Csalkyl, Ci-CsalkoxyCi-Csalkyl and Ci-Cshydroxyalkyl.

[0168] One embodiment relates to a compound of Formula (V):

[0169]

[0170] or a stereoisomer or pharmaceutically acceptable salt thereof, wherein:

[0171] R1is Ci-Csalkylcarbonyl, Ci-Csalkoxycarbonyl, Ci-Csalkyl-NH-carbonyl, Ci-C3alkyl-N(Ci-C3alkyl)-carbonyl or -S(O)2(Ci-C3)alkyl;

[0172] R12is hydrogen or R12is selected from the group consisting of Ci-Csalkyl,

[0173] Ci-CsalkoxyCi-Csalkyl and Ci-Cshydroxyalkyl; and

[0174] Y is O, NH, NCH3, N(CH2CH3), N(CH2CH2CH3) or CH2; and

[0175] ring B, R4, R5and R6are as defined in Formula (I).PAT065083-PCT-SEC01 Examples include but are not limited to a compound of Formula (Va), (Vb), (Vc), (Vd) and (Ve):

[0176]

[0177] R1is Ci-C3alkylcarbonyl, Ci-C3alkoxycarbony, Ci-C3alkyl-NH-carbonyl, Ci-C3alkyl-N(Ci- C3alkyl)-carbonyl or -S(O)2(Ci-C3)alkyl;

[0178] R12is hydrogen or R12is selected from the group consisting of Ci-C3alkyl,

[0179] Ci-C3alkoxyCi-C3alkyl and Ci-C3hydroxyalkyl;

[0180] Y is O, NH, NCH3, N(CH2CH3), N(CH2CH2CH3) or CH2; and

[0181] R4, R5and R6are as defined in Formula (I).

[0182] In yet another embodiment, the disclosure provides a compound of Formula (I), (la), (II) or (Ila’), or a compound of Formula (Ila), (lib), (He) or (lid), wherein R1is Ci-C3alkylcarbonyl or Ci-C3alkoxycarbonyl; and R2and R3are hydrogen.

[0183] One embodiment relates to a compound having Formula (VI):

[0184]

[0185] or a stereoisomer or pharmaceutically acceptable salt thereof, wherein:

[0186] R1is Ci-C3alkylcarbonyl or Ci-C3alkoxycarbonyl; and

[0187] ring B, R4, R5and R6are as defined in Formula (la).PAT065083-PCT-SEC01 Examples include but are not limited to a compound having Formula (Via), (Vlb), (Vic), (Vid) and (Vie):

[0188] R1

[0189]

[0190] R1is Ci-Csalkylcarbonyl or Ci-Csalkoxycarbonyl; and

[0191] ring B, R4, R5and R6are as defined in Formula (I).

[0192] In yet one embodiment, the disclosure provides a compound of Formula (I), (la), (II) or (Ila’), wherein ring B is 1,3-phenylene.

[0193] One embodiment relates to a compound having Formula (VII):

[0194]

[0195] (VII)

[0196] or a stereoisomer or pharmaceutically acceptable salt thereof, wherein R1, R2, R3, R4, R5and R6are as defined in Formula (I).

[0197] In another embodiment, the disclosure provides a compound of Formula (I), (la), (II), (Ila’) (Ila), (lib), (He), (lid), (III), (Illa), (lllb), (lllc), (Hid), (Hie), (HI’), (IV), (IVa), (IVb), (IVc), (IVd), (IVe), (V), (Va), (Vb), (Vc), (Vd), (Ve), (VI), (Via), (Vlb), (Vic), (Vid), (Vle)and (VII), wherein

[0198] 0

[0199] 1 R5

[0200] ls

[0201] is selected from the group consisting of:PAT065083-PCT-SEC01

[0202]

[0203] wherein R7is hydroxy, hydroxyphenyl or bicyclic Cs-Cycyloalkyl optionally substituted with hydroxy; R8is Ci-Csalkyl or Ci-Csalkyl-NH-carbonyl; and

[0204] R9, R10and R11are each independently selected from the group consisting of hydrogen, C1-C3alkyl, C1-C3hydroxyalkyl, C1-C3fluoroalkyl, C1-C3alkoxyC1-C3alkyl, C1-C3alkoxy, benzyl substituted with hydroxy, and bicyclic C5-C7cycloalkyl(C0-1alkyl) substituted with hydroxy.

[0205] Examples include but are not limited to a compound of Formula (Villa), (VI I lb), (VI lie) or (Vllld):

[0206] R7

[0207] R8

[0208]

[0209] or a stereoisomer or pharmaceutically acceptable salt thereof, wherein:

[0210] R7is hydroxy, hydroxyphenyl or bicyclic Cs-Cycyloalkyl optionally substituted with hydroxy; R8is Ci-Csalkyl or Ci-Csalkyl-NH-carbonyl; and

[0211] R9, R10and R11are each independently selected from the group consisting of hydrogen, Ci-Csalkyl, Ci-Cshydroxyalkyl, Ci-Csfluoroalkyl, Ci-CsalkoxyCi-Csalkyl, Ci-Csalkoxy, benzyl substituted with hydroxy, and bicyclic Cs-CycycloalkyKCo-i alkyl) substituted with hydroxy; andPAT065083-PCT-SEC01 ring B, R1, R2, R3and R4are as defined in Formula (I).

[0212] Other embodiments relate to a compound selected from the group consisting of a compound

[0213]

[0214] PAT065083-PCT-SEC01 or a stereoisomer or pharmaceutically acceptable salt thereof, wherein

[0215] ring B, R1, R2, R3and R4are as defined in Formula (I).

[0216] In another aspect, the disclosure provides a pharmaceutical composition comprising a compound, or a stereoisomer or pharmaceutically acceptable salt thereof, according to a compound of Formula (I) or any sub-formula thereof as defined above, and a pharmaceutically acceptable carrier.

[0217] In yet another aspect, the disclosure provides a combination comprising a compound of the invention, or a stereoisomer or pharmaceutically acceptable salt thereof, and one or more therapeutically active agents.

[0218] In yet another aspect, the disclosure provides a compound of the invention, or a stereoisomer or pharmaceutically acceptable salt thereof, for use in the treatment, or prevention of a disease or disorder that is mediated by IL-4 and / or IL- 13; or for use in the treatment, or prevention of a STAT6-dependent disease or disorder.

[0219] In one embodiment, the disclosure provides a compound of the invention, or a stereoisomer or pharmaceutically acceptable salt thereof, for use in the treatment, or prevention of a disease selected from the group consisting of atopic dermatitis, asthma, chronic rhinosinusitis with nasal polyposis, eosinophilic esophagitis, prurigo nodularis, chronic prurigo, chronic spontaneous urticaria, chronic pruritus, bullous pemphigoid, chronic obstructive pulmonary disease, ulcerative colitis, eosinophilic gastroenteritis and food allergy.

[0220] The present disclosure also relates to the following embodiments:

[0221] Embodiment 1. A compound of Formula (I):

[0222]

[0223] or a stereoisomer or pharmaceutically acceptable salt thereof, wherein:

[0224] X is N or CR13, wherein R13is selected from the group consisting of hydrogen, halo, CN, NO2, Ci-Csalkyl, Ci-Csalkoxy, -S(O)o-2(Ci-C3)alkyl and NR14R15, and wherein R14and R15are each independently selected from the group consisting of hydrogen, Ci-Csalkyl and

[0225] Cs-Cscycloalkyl;

[0226] ring B is 1,3-phenylene, or ring B is a monocyclic 5-membered heteroarylene;

[0227] R1is Ci-Csalkylcarbonyl or Ci-Csalkoxycarbonyl; and R2and R3are hydrogen;PAT065083-PCT-SEC01 alternatively, R1is Ci-Csalkylcarbonyl, Ci-Csalkoxycarbonyl, Ci-Csalkyl-NH-carbonyl, Ci-C3alkyl-N(Ci-C3alkyl)-carbonyl or -S(O)2(Ci-C3)alkyl, and R2and R3, together with the nitrogen and carbon atoms that they each are attached to and the neighboring carbon atom, form a 6-membered heterocycloalkyl, which optionally comprises one further heteroatomic ring member selected from the group consisting of O, NH and N(Ci-C3alkyl), and is optionally substituted with R12, wherein R12is selected from the group consisting of Ci-Csalkyl,

[0228] Ci-CsalkoxyCi-Csalkyl and Ci-Cshydroxyalkyl;

[0229] alternatively, R3is hydrogen, and R1and R2, together with the nitrogen they are attached to, form an unsubstituted, monocyclic 5-membered heteroaryl, or a monocyclic 5-membered heterocycloalkyl (i) that is substituted with one or two oxo and is optionally substituted with phenyl or with up to three C1-C3alkyl, and (ii) that optionally fuses with a second ring to form a fused bicyclic 9-membered ring;

[0230] R4is hydrogen, C1-C3alkyl, C1-C3alkoxy or halo, wherein each of said C1-C3alkyl and C1-C3alkoxy is unsubstituted or is substituted with one or more substituents each independently selected from the group consisting of halo, hydroxy and C1-C3alkoxy;

[0231] R4bis hydrogen, unsubstituted C1-C3alkyl or halo;

[0232] R5is -CHR8CH2R7or -CHR8CH(OH)R7and R6is hydrogen, wherein R7is hydroxy, hydroxyphenyl or bicyclic C5-C7cycloalkyl optionally substituted with hydroxy, and R8is C1-C3alkyl or C1-C3alkyl-NH-carbonyl;

[0233] alternatively, R5and R6, together with the nitrogen they are attached to, form a monocyclic C4-C6heterocycloalkyl comprising one or two nitrogen heteroatoms and being substituted with oxo and being optionally substituted with up to three further substituents being R9, R10and R11, wherein each of R9, R10and R11is independently selected from the group consisting of

[0234] C1-C3alkyl, C1-C3hydroxyalkyl, C1-C3fluoroalkyl, C1-C3alkoxyC1-C3alkyl, C1-C3alkoxy, benzyl substituted with hydroxy, and bicyclic C5-C7cycloalkyl(C0-1alkyl) substituted with hydroxy.

[0235] Embodiment 2. A compound of Formula (la):

[0236] R2R3(|

[0237]

[0238] a)

[0239] or a stereoisomer or pharmaceutically acceptable salt thereof, wherein:

[0240] X is N or CR13, wherein R13is selected from the group consisting of hydrogen, halo, CN, NO2, Ci-Csalkyl, Ci-Csalkoxy, -S(O)o-2(Ci-C3)alkyl and NR14R15, and wherein R14and R15arePAT065083-PCT-SEC01 each independently selected from the group consisting of hydrogen, Ci-Csalkyl and

[0241] Cs-Cscycloalkyl;

[0242] ring B is a monocyclic 5-membered heteroarylene (i) comprising one sulfur and optionally one nitrogen heteroatom, or (ii) comprising one or two nitrogen heteroatoms;

[0243] R1is C1-C3alkylcarbonyl or C1-C3alkoxycarbonyl and R2and R3are hydrogen; alternatively, R1is Ci-Csalkylcarbonyl, Ci-Csalkoxycarbonyl, Ci-Csalkyl-NH-carbonyl, Ci-C3alkyl-N(Ci-C3alkyl)-carbonyl or -S(O)2(Ci-C3)alkyl, and R2and R3, together with the nitrogen and carbon atoms that they each are attached to and the neighboring carbon atom, form a 6-membered heterocycloalkyl, which optionally comprises one further heteroatomic ring member selected from the group consisting of O, NH and N(Ci-C3alkyl), and is optionally substituted with R12, wherein R12is selected from the group consisting of Ci-Csalkyl,

[0244] Ci-CsalkoxyCi-Csalkyl and Ci-Cshydroxyalkyl;

[0245] alternatively, R3is hydrogen, and R1and R2, together with the nitrogen they are attached to, form an unsubstituted, monocyclic 5-membered heteroaryl, or a monocyclic 5-membered heterocycloalkyl (i) that is substituted with one or two oxo and is optionally substituted with phenyl or with up to three C1-C3alkyl, and (ii) that optionally fuses with a second ring to form a fused bicyclic 9-membered ring;

[0246] R4is hydrogen, C1-C3alkyl, C1-C3alkoxy or halo, wherein each of said C1-C3alkyl and C1-C3alkoxy is unsubstituted or is substituted with one or more substituents each independently selected from the group consisting of halo, hydroxy and C1-C3alkoxy;

[0247] R5is -CHR8CH2R7or -CHR8CH(OH)R7and R6is hydrogen, wherein R7is hydroxy, hydroxyphenyl or bicyclic C5-C7cycloalkyl optionally substituted with hydroxy, and R8is C1-C3alkyl or C1-C3alkyl-NH-carbonyl;

[0248] alternatively, R5and R6, together with the nitrogen they are attached to, form a monocyclic C4-C6heterocycloalkyl comprising one or two nitrogen heteroatoms and being substituted with oxo and being optionally substituted with up to three further substituents being R9, R10and R11, wherein each of R9, R10and R11is independently selected from the group consisting of

[0249] C1-C3alkyl, C1-C3hydroxyalkyl, C1-C3fluoroalkyl, C1-C3alkoxyC1-C3alkyl, C1-C3alkoxy, benzyl substituted with hydroxy, and bicyclic C5-C7cycloalkyl(C0-1alkyl) substituted with hydroxy.

[0250] Embodiment 3. The compound according to embodiment 1 or 2, wherein ring B is a monocyclic 5-membered heteroarylene selected from the group consisting of divalent thiophenyl, thiazolyl, pyrazolyl and imidazolyl.

[0251] Embodiment 4. The compound according to any one of embodiments 1 to 3, having Formula (Ila), (lib), (He) or (lid):

[0252] R1R1

[0253]

[0254] PAT065083-PCT-SEC01

[0255] (Hb)

[0256]

[0257] or a stereoisomer or pharmaceutically acceptable salt thereof.

[0258] Embodiment 5. The compound according any one of embodiments 1 to 4, selected from the group consisting of

[0259]

[0260] or a stereoisomer or pharmaceutically acceptable salt thereof, wherein:

[0261] each Q is independently nitrogen or CH; and

[0262] R3is hydrogen.

[0263] Embodiment 6. The compound according to any one of embodiments 1 to 4 selected from

[0264]

[0265] or a stereoisomer or pharmaceutically acceptable salt thereof, wherein:

[0266] Wis O or NH;

[0267] R3is hydrogen;

[0268] each Q is independently nitrogen or CH; and

[0269] the fused bicyclic 9-membered ring accommodating W comprises at the most three nitrogen atoms.PAT065083-PCT-SEC01 Embodiment 7. The compound according to any one of embodiments 1 to 4 selected from the group consisting of:

[0270]

[0271] or a stereoisomer or pharmaceutically acceptable salt thereof, wherein:

[0272] R1is Ci-C3alkylcarbonyl, Ci-C3alkoxycarbonyl, Ci-C3alkyl-NH-carbonyl, Ci-C3alkyl-N(Ci-C3alkyl)-carbonyl or -S(O)2(Ci-C3)alkyl;

[0273] R12is hydrogen or R12is selected from the group consisting of Ci-C3alkyl,

[0274] Ci-C3alkoxyCi-C3alkyl and Ci-C3hydroxyalkyl; and

[0275] Y is O, NH, NCH3, N(CH2CH3), N(CH2CH2CH3) or CH2.

[0276] Embodiment 8. The compound according to any one of embodiments 1 to 4 selected from the group consisting of:

[0277]

[0278] R1is Ci-C3alkylcarbonyl or Ci-C3alkoxycarbonyl.

[0279] Embodiment 9. A compound of Formula (I):

[0280]

[0281] PAT065083-PCT-SEC01 or a stereoisomer or pharmaceutically acceptable salt thereof, wherein:

[0282] X is N or CR13, wherein R13is selected from the group consisting of hydrogen, halo, CN, NO2, Ci-Csalkyl, Ci-Csalkoxy, -S(O)o-2(Ci-C3)alkyl and NR14R15, and wherein R14and R15are each independently selected from the group consisting of hydrogen, Ci-Csalkyl and

[0283] Cs-Cscycloalkyl;

[0284] ring B is 1,3-phenylene;

[0285] R1is C1-C3alkylcarbonyl or C1-C3alkoxycarbonyl and R2and R3are hydrogen; alternatively, R1is Ci-Csalkylcarbonyl, Ci-Csalkoxycarbonyl, Ci-Csalkyl-NH-carbonyl, Ci-C3alkyl-N(Ci-C3alkyl)-carbonyl or -S(O)2(Ci-C3)alkyl, and R2and R3, together with the nitrogen and carbon atoms that they each are attached to and the neighboring carbon atom, form a 6-membered heterocycloalkyl, which optionally comprises one further heteroatomic ring member selected from the group consisting of O, NH and N(Ci-C3alkyl), and is optionally substituted with R12, wherein R12is selected from the group consisting of Ci-Csalkyl,

[0286] Ci-CsalkoxyCi-Csalkyl and Ci-Cshydroxyalkyl;

[0287] alternatively, R3is hydrogen, and R1and R2, together with the nitrogen they are attached to, form an unsubstituted, monocyclic 5-membered heteroaryl, or a monocyclic 5-membered heterocycloalkyl (i) that is substituted with one or two oxo and is optionally substituted with phenyl or with up to three C1-C3alkyl, and (ii) that optionally fuses with a second ring to form a fused bicyclic 9-membered ring;

[0288] R4is hydrogen, C1-C3alkyl, C1-C3alkoxy or halo, wherein each of said C1-C3alkyl and C1-C3alkoxy is unsubstituted or is substituted with one or more substituents each independently selected from the group consisting of halo, hydroxy and C1-C3alkoxy;

[0289] R4bis hydrogen, unsubstituted C1-C3alkyl or halo;

[0290] R5is -CHR8CH2R7or -CHR8CH(OH)R7and R6is hydrogen, wherein R7is hydroxy, hydroxyphenyl or bicyclic C5-C7cycloalkyl optionally substituted with hydroxy, and R8is C1-C3alkyl or C1-C3alkyl-NH-carbonyl;

[0291] alternatively, R5and R6, together with the nitrogen they are attached to, form a monocyclic C4-C6heterocycloalkyl comprising one or two nitrogen heteroatoms and being substituted with oxo and being optionally substituted with up to three further substituents being R9, R10and R11, wherein each of R9, R10and R11is independently selected from the group consisting of

[0292] C1-C3alkyl, C1-C3hydroxyalkyl, C1-C3fluoroalkyl, C1-C3alkoxyC1-C3alkyl, C1-C3alkoxy, benzyl substituted with hydroxy, and bicyclic C5-C7cycloalkyl(C0-1alkyl) substituted with hydroxy.

[0293] Embodiment 10. The compound according to embodiment 9, having Formula (VII):

[0294] R3i\r

[0295]

[0296] (VII)PAT065083-PCT-SEC01 or a stereoisomer or pharmaceutically acceptable salt thereof.

[0297] Embodiment 11. The compound according to any one of embodiments 9 to 10, having Formula (Illa):

[0298]

[0299] or a stereoisomer or pharmaceutically acceptable salt thereof, wherein:

[0300] each Q is independently nitrogen or CH; and

[0301] R3is hydrogen.

[0302] Embodiment 12. The compound according to any one of embodiments 9 to 10 having Formula (IVa):

[0303]

[0304] or a stereoisomer or pharmaceutically acceptable salt thereof, wherein:

[0305] Wis O or NH;

[0306] R3is hydrogen;

[0307] each Q is independently nitrogen or CH; and

[0308] the fused bicyclic 9-membered ring accommodating W comprises at the most three nitrogen atoms.

[0309] Embodiment 13. The compound according to any one of embodiments 9 to 10, having Formula (Va)

[0310] R1

[0311]

[0312] r4(Va)

[0313] or a stereoisomer or pharmaceutically acceptable salt thereof, wherein:

[0314] R1is Ci-Csalkylcarbonyl, Ci-Csalkoxycarbony, Ci-Csalkyl-NH-carbonyl, Ci-Csalkyl-N(Ci-CsalkyQ-carbonyl I or -S(O)2(Ci-C3)alkyl;

[0315] R12is hydrogen or R12is selected from the group consisting of Ci-Csalkyl,

[0316] Ci-CsalkoxyCi-Csalkyl and Ci-Cshydroxyalkyl; andPAT065083-PCT-SEC01 Y is O, NH, NCH3, N(CH2CH3), N(CH2CH2CH3) or CH2.

[0317] Embodiment 14. The compound according to any one of embodiments 9 to 10, having

[0318]

[0319] or a stereoisomer or pharmaceutically acceptable salt thereof, wherein:

[0320] R1is Ci-C3alkylcarbonyl or Ci-C3alkoxycarbonyl.

[0321] Embodiment 15. The compound according to any one of the preceding embodiments,

[0322]

[0323] or a stereoisomer or pharmaceutically acceptable salt thereof, and wherein:

[0324] R7is hydroxy, hydroxyphenyl or bicyclic Cs-Cycyloalkyl optionally substituted with hydroxy; R8is Ci-C3alkyl or Ci-C3alkyl-NH-carbonyl; and

[0325] R9, R10and R11are each independently selected from the group consisting of hydrogen, Ci-C3alkyl, Ci-C3hydroxyalkyl, Ci-C3fluoroalkyl, Ci-C3alkoxyCi-C3alkyl, Ci-C3alkoxy, benzyl substituted with hydroxy, and bicyclic Cs-Cycycloalky Co-i alkyl) substituted with hydroxy.

[0326] Embodiment 16. The compound according to claim 1 or 3, having Formula (II):PAT065083-PCT-SEC01

[0327]

[0328] or a stereoisomer or pharmaceutically acceptable salt thereof, wherein:

[0329] ring B is a monocyclic 5-membered heteroarylene;

[0330] R1is C1-C3alkylcarbonyl, C1-C3alkoxycarbonyl, C1-C3alkyl-NH-carbonyl, C1-C3alkyl-N(C1-C3alkyl)-carbonyl or -S(O)2(C1-C3)alkyl, and R2and R3, together with the nitrogen and carbon atoms that they each are attached to and the neighboring carbon atom, form a 6-membered heterocycloalkyl, which optionally comprises one further heteroatomic ring member selected from the group consisting of O, NH and N(C1-C3alkyl), and is optionally substituted with R12, wherein R12is selected from the group consisting of C1-C3alkyl, C1-C3alkoxyC1-C3alkyl and C1-C3hydroxyalkyl;

[0331] R4is hydrogen, C1-C3alkyl, C1-C3alkoxy or halo, wherein each of said C1-C3alkyl and C1-C3alkoxy is unsubstituted or is substituted with one or more substituents each independently selected from the group consisting of halo, hydroxy and C1-C3alkoxy;

[0332] R4bis hydrogen, unsubstituted C1-C3alkyl or halo; and

[0333] R5and R6, together with the nitrogen they are attached to, form a monocyclic C4-C6heterocycloalkyl comprising one or two nitrogen heteroatoms and being substituted with oxo and being optionally substituted with up to three further substituents being R9, R10and R11, wherein each of R9, R10and R11is independently selected from the group consisting of C1-C3alkyl, C1-C3hydroxyalkyl, C1-C3fluoroalkyl, C1-C3alkoxyC1-C3alkyl, C1-C3alkoxy, benzyl substituted with hydroxy, and bicyclic C5-C7cycloalkyl(C0-1alkyl) substituted with hydroxy.

[0334] Embodiment 17. The compound according to any one of embodiments 1, 2, 3, 9 and 16, having Formula (III):

[0335]

[0336] or a stereoisomer or pharmaceutically acceptable salt thereof, wherein:

[0337] each Q is independently nitrogen or CH.PAT065083-PCT-SEC01 Embodiment 18. The compound according to any one of embodiments 1, 2, 3, 9 and 16, having Formula (IV):

[0338]

[0339] or a stereoisomer or pharmaceutically acceptable salt thereof, wherein:

[0340] Wis CH2, O or NH;

[0341] each Q is independently nitrogen or CH; and

[0342] the fused bicyclic 9-membered ring accommodating W comprises at the most three nitrogen atoms.

[0343] Embodiment 19. The compound according to any one of embodiments 1, 2, 3, 9 and 16, having Formula (V):

[0344] R5

[0345]

[0346] (V)

[0347] or a stereoisomer or pharmaceutically acceptable salt thereof, wherein:

[0348] R1is Ci-C3alkylcarbonyl, Ci-C3alkoxycarbonyl, Ci-C3alkyl-NH-carbonyl, Ci-C3alkyl-N(Ci-C3alkyl)-carbonyl or -S(O)2(Ci-C3)alkyl;

[0349] R12is hydrogen or R12is selected from the group consisting of Ci-C3alkyl,

[0350] Ci-C3alkoxyCi-C3alkyl and Ci-C3hydroxyalkyl; and

[0351] Y is O, NH, NCH3, N(CH2CH3), N(CH2CH2CH3) or CH2.

[0352] Embodiment 20. The compound according to any one of embodiments 1, 2, 3, 9 and 16, having Formula (VI):

[0353] R5

[0354] R1

[0355]

[0356] (VI)PAT065083-PCT-SEC01 or a stereoisomer or pharmaceutically acceptable salt thereof, wherein:

[0357] R1is Ci-C3alkylcarbonyl or Ci-C3alkoxycarbonyl.

[0358] Embodiment 21. The compound according to any one of embodiments 1, 2, 3, 9 and 16, having Formula (III’):

[0359]

[0360] or a stereoisomer or pharmaceutically acceptable salt thereof, wherein:

[0361] W is CH2, CH(C1-C3alkyl), O or NH; and

[0362] each Z is independently hydrogen, phenyl or C1-C3alkyl.

[0363] Embodiment 22. The compound according to any one of embodiments 1, 2, 3, 9 and 16-21, having Formula (VIIIa), (VIIIb), (VIIIc) or (VIIId):

[0364]

[0365] (VIIIc) (VIIId) or a stereoisomer or pharmaceutically acceptable salt thereof, wherein:

[0366] R7is hydroxy, hydroxyphenyl or bicyclic Cs-Cycyloalkyl optionally substituted with hydroxy; R8is Ci-C3alkyl or Ci-C3alkyl-NH-carbonyl; andPAT065083-PCT-SEC01 R9, R10and R11are each independently selected from the group consisting of hydrogen, C1-C3alkyl, C1-C3hydroxyalkyl, C1-C3fluoroalkyl, C1-C3alkoxyC1-C3alkyl, C1-C3alkoxy, benzyl substituted with hydroxy, and bicyclic C5-C7cycloalkyl(C0-1alkyl) substituted with hydroxy.

[0367] Embodiment 23. The compound according to any one of embodiments 1, 2, 3, 9 and 16-21, selected from the group consisting of:

[0368]

[0369] PAT065083-PCT-SEC01

[0370] R2R3

[0371] (IXd)

[0372]

[0373] (IXf) or a stereoisomer or pharmaceutically acceptable salt thereof.

[0374] Embodiment 24. The compound according to any one of the preceding embodiments, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein halo is chloro or fluoro. Embodiment 25. The compound according to any one of the preceding embodiments, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein C1-C3fluoroalkyl is trifluoromethyl or trifluoroethyl.

[0375] Embodiment 26. The compound according to according to any one of the preceding embodiments, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein R4is methyl, ethyl, chloro, fluoro, methoxy or-OCH2CH3.

[0376] Embodiment 27. The compound according to according to any one of the preceding embodiments, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein R4bis hydrogen, methyl, chloro or fluoro.

[0377] Embodiment 28. The compound according to any one of embodiments 1, 2, 3 and 9, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein X is N.

[0378] Embodiment 29. The compound according to any one of embodiments 1, 2, 3 and 9, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein X is CR13, and wherein R13is selected from the group consisting of hydrogen, halo, CN, NO2, Ci-Csalkyl, Ci-Csalkoxy, -S(0)o-2(Ci-Cs)alkyl and NR14R15, and wherein R14and R15are each independently selected from the group consisting of hydrogen, Ci-Csalkyl and Cs-Cscycloalkyl.PAT065083-PCT-SEC01 Embodiment 30. The compound according to any one of embodiments 1, 2, 3 and 9, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein X is CR13, and wherein R13is hydrogen or halo.

[0379] Embodiment 31. The compound according to any one of the preceding embodiments, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein said compound is selected from:

[0380] 5-(4-acetamidophenyl)-4-chloro-N-(3-(4-hydroxyphenyl)-1-(methylamino)-1-oxopropan-2- yl)thiophene-2-carboxamide;

[0381] (S)-5-(4-acetamidophenyl)-4-chloro-N-(3-(4-hydroxyphenyl)-1-(methylamino)-1-oxopropan-2- yl)thiophene-2-carboxamide;

[0382] 4-chloro-N-(3-(4-hydroxyphenyl)-1-(methylamino)-1-oxopropan-2-yl)-5-(4-(2-oxopyrrolidin-1- yl)phenyl)thiophene-2-carboxamide;

[0383] (S)-4-chloro-N-(3-(4-hydroxyphenyl)-1-(methylamino)-1-oxopropan-2-yl)-5-(4-(2-oxopyrrolidin-1- yl)phenyl)thiophene-2-carboxamide;

[0384] 5-(4-acetamidophenyl)-N-(3-(4-hydroxyphenyl)-1-(methylamino)-1-oxopropan-2-yl)-4- methoxythiophene-2-carboxamide;

[0385] (S)-5-(4-acetamidophenyl)-N-(3-(4-hydroxyphenyl)-1-(methylamino)-1-oxopropan-2-yl)-4- methoxythiophene-2-carboxamide;

[0386] 5-(4-acetamidophenyl)-N-(1-(4-hydroxyphenyl)propan-2-yl)-4-methylthiophene-2-carboxamide; (R)-5-(4-acetamidophenyl)-N-(1-(4-hydroxyphenyl)propan-2-yl)-4-methylthiophene-2- carboxamide;

[0387] (S)-5-(4-acetamidophenyl)-N-(1-(4-hydroxyphenyl)propan-2-yl)-4-methylthiophene-2- carboxamide;

[0388] 5-(1-acetyl-1,2,3,4-tetrahydroquinolin-6-yl)-N-(3-(3-hydroxybicyclo- [1.1.1 ]pentan-1-yl)-1- (methylamino)-1-oxopropan-2-yl)-4-methylthiophene-2-carboxamide;

[0389] (S)-5-(1-acetyl-1,2,3,4-tetrahydroquinolin-6-yl)-N-(3-(3-hydroxybicyclo- [1.1.1 ]pentan-1-yl)-1- (methylamino)-1-oxopropan-2-yl)-4-methylthiophene-2-carboxamide;

[0390] 5-(4-acetamidophenyl)-N-(3-(4-hydroxyphenyl)-1-(methylamino)-1-oxopropan-2-yl)-4- methylthiophene-2-carboxamide;

[0391] (S)-5-(4-acetamidophenyl)-N-(3-(4-hydroxyphenyl)-1-(methylamino)-1-oxopropan-2-yl)-4- methylthiophene-2-carboxamide;

[0392] N-(3-(4-hydroxyphenyl)-1-(methylamino)-1-oxopropan-2-yl)-4-methyl-5-(4-(2-oxopyrrolidin-1- yl)phenyl)thiophene-2-carboxamide;

[0393] (S)-N-(3-(4-hydroxyphenyl)-1-(methylamino)-1-oxopropan-2-yl)-4-methyl-5-(4-(2-oxopyrrolidin-1- yl)phenyl)thiophene-2-carboxamide;

[0394] 5-(4-(1H-pyrazol-1-yl)phenyl)-N-(3-(4-hydroxyphenyl)-1-(methylamino)-1-oxopropan-2-yl)-4- methylthiophene-2-carboxamide;PAT065083-PCT-SEC01 (S)-5-(4-(1H-pyrazol-1-yl)phenyl)-N-(3-(4-hydroxyphenyl)-1-(methylamino)-1-oxopropan-2-yl)-4- methylthiophene-2-carboxamide;

[0395] 5-(1-acetyl-1,2,3,4-tetrahydroquinolin-6-yl)-N-(3-(4-hydroxyphenyl)-1-(methylamino)-1- oxopropan-2-yl)-4-methylthiophene-2-carboxamide;

[0396] (S)-5-(1-acetyl-1,2,3,4-tetrahydroquinolin-6-yl)-N-(3-(4-hydroxyphenyl)-1-(methylamino)-1- oxopropan-2-yl)-4-methylthiophene-2-carboxamide;

[0397] 4-(5-(1-acetyl-3-methyl-1,2,3,4-tetrahydroquinolin-6-yl)-4-methylthiophene-2-carbonyl)-3-ethyl-1- methylpiperazin-2-one;

[0398] (R)-4-(5-((R)-1-acetyl-3-methyl-1,2,3,4-tetrahydroquinolin-6-yl)-4-methylthiophene-2-carbonyl)- 3-ethyl-1-methylpiperazin-2-one;

[0399] (R)-4-(5-((S)-1-acetyl-3-methyl-1,2,3,4-tetrahydroquinolin-6-yl)-4-methylthiophene-2-carbonyl)- 3-ethyl-1-methylpiperazin-2-one;

[0400] (S)-4-(5-((R)-1-acetyl-3-methyl-1,2,3,4-tetrahydroquinolin-6-yl)-4-methylthiophene-2-carbonyl)- 3-ethyl-1-methylpiperazin-2-one;

[0401] (S)-4-(5-((S)-1-acetyl-3-methyl-1,2,3,4-tetrahydroquinolin-6-yl)-4-methylthiophene-2-carbonyl)-3- ethyl- 1-methylpiperazin-2-one;

[0402] 4-(5-(4-acetyl-2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-4-methylthiophene-2- carbonyl)-3-ethyl-1-methylpiperazin-2-one;

[0403] (S)-4-(5-((R)-4-acetyl-2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-4-methylthiophene-2- carbonyl)-3-ethyl-1-methylpiperazin-2-one;

[0404] 4-(5-(4-acetyl-3,4-dihydro-2H-benzo[b][1,4] oxazin-7-yl)-4-methylthiophene-2-carbonyl)-3- (methoxymethyl)-1-methylpiperazin-2-one;

[0405] (S)-4-(5-(4-acetyl-3,4-dihydro-2H-benzo[b][1,4] oxazin-7-yl)-4-methylthiophene-2-carbonyl)-3- (methoxymethyl)-1-methylpiperazin-2-one;

[0406] / V-(4-(5-(2-((3-hydroxybicyclo[1.1.1]pentan-1-yl)methyl)-4-methyl-3-oxopiperazine-1-carbonyl)-3- methylthiophen-2-yl)phenyl)acetamide;

[0407] (S)- / V-(4-(5-(2-((3-hydroxybicyclo[1.1.1]pentan-1-yl)methyl)-4-methyl-3-oxopiperazine-1- carbonyl)-3-methylthiophen-2-yl)phenyl)acetamide;

[0408] 5-(4-acetamidophenyl)-N-(3-(4-hydroxyphenyl)-1-(methylamino)-1-oxopropan-2-yl)-4- methylthiazole-2-carboxamide;

[0409] (S)-5-(4-acetamidophenyl)-N-(3-(4-hydroxyphenyl)-1-(methylamino)-1-oxopropan-2-yl)-4- methylthiazole-2-carboxamide;

[0410] Methyl-7-(2-(2-ethyl-3-oxopiperazine-1-carbonyl)-4-methylthiazol-5-yl)-2-methyl-2,3-dihydro-4H- benzo[b][1,4]oxazine-4-carboxylate;

[0411] Methyl (R)-7-(2-((R)-2-ethyl-3-oxopiperazine-1-carbonyl)-4-methylthiazol-5-yl)-2-methyl-2,3- dihydro-4H-benzo[b][1,4]oxazine-4-carboxylate;

[0412] Methyl (R)-7-(2-((S)-2-ethyl-3-oxopiperazine-1-carbonyl)-4-methylthiazol-5-yl)-2-methyl-2,3- dihydro-4H-benzo[b][1,4]oxazine-4-carboxylate;PAT065083-PCT-SEC01 4-(5-(4-acetyl-2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-4-methyl-thiazole-2-carbonyl)- 3-(2,2,2-trifluoroethyl)piperazin-2-one;

[0413] (R)-4-(5-((R)-4-acetyl-2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-4-methyl-thiazole-2- carbonyl)-3-(2,2,2-trifluoroethyl)piperazin-2-one;

[0414] (S)-4-(5-((R)-4-acetyl-2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-4-methyl-thiazole-2- carbonyl)-3-(2,2,2-trifluoroethyl)piperazin-2-one;

[0415] 3-ethyl-1-methyl-4-(4-methyl-5-(4-(2-oxopyrrolidin-1-yl)phenyl)thiazole-2-carbonyl)piperazin-2- one;

[0416] (S)-3-ethyl-1-methyl-4-(4-methyl-5-(4-(2-oxopyrrolidin-1-yl)phenyl)thiazole-2-carbonyl)piperazin- 2-one;

[0417] 1-(4-(2-(2-ethyl-4-methyl-3-oxopiperazine-1-carbonyl)-4-methylthiazol-5-yl)phenyl)-5- methylimidazolidine-2, 4-dione, trifluoroacetate;

[0418] 1-(4-(2-((S)-2-ethyl-4-methyl-3-oxopiperazine-1-carbonyl)-4-methylthiazol-5-yl)phenyl)-5- methylimidazolidine-2, 4-dione, trifluoroacetate;

[0419] 4-(5-(1-acetyl-1,2,3,4-tetrahydroquinolin-6-yl)-4-methylthiazole-2-carbonyl)-3-ethyl-1- methylpiperazin-2-one;

[0420] (R)-4-(5-(1-acetyl-1,2,3,4-tetrahydroquinolin-6-yl)-4-methylthiazole-2-carbonyl)-3-ethyl-1- methylpiperazin-2-one;

[0421] (S)-4-(5-(1-acetyl-1,2,3,4-tetrahydroquinolin-6-yl)-4-methylthiazole-2-carbonyl)-3-ethyl-1- methylpiperazin-2-one;

[0422] 4-(5-(4-acetyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-4-methylthiazole-2-carbonyl)-3-ethyl-1- methylpiperazin-2-one;

[0423] (R)-4-(5-(4-acetyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-4-methylthiazole-2-carbonyl)-3-ethyl-1-methylpiperazin-2-one;

[0424] (S)-4-(5-(4-acetyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-4-methylthiazole-2-carbonyl)-3-ethyl- 1 -methylpiperazin-2-one;

[0425] 4-(5-(4-acetyl-2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-4-methylthiazole-2-carbonyl)-3- (methoxymethyl)- 1-methylpiperazin-2-one;

[0426] (S)-4-(5-((R)-4-acetyl-2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-4-methylthiazole-2- carbonyl)-3-(methoxymethyl)-1-methylpiperazin-2-one;

[0427] 3-ethyl-1-methyl-4-(1-methyl-5-(4-(2-oxo-4-phenylpyrrolidin-1-yl)phenyl)-1H-pyrazole-3- carbonyl)piperazin-2-one;

[0428] (S)-3-ethyl-1-methyl-4-(1-methyl-5-(4-((S)-2-oxo-4-phenylpyrrolidin-1-yl)phenyl)-1H-pyrazole-3- carbonyl)piperazin-2-one;

[0429] (S)-3-ethyl-1-methyl-4-(1-methyl-5-(4-((R)-2-oxo-4-phenylpyrrolidin-1-yl)phenyl)-1H-pyrazole-3- carbonyl)piperazin-2-one;

[0430] 4-(5-(4-acetyl-3,4-dihydro-2H-benzo[b][1, 4]oxazin-7-yl)-1 -methyl- 1 H-pyrazole-3-carbonyl)-3- ethyl-1-methylpiperazin-2-one;PAT065083-PCT-SEC01 (R)-4-(5-(4-acetyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-1-methyl-1H-pyrazole-3-carbonyl)-3- ethyl-1-methylpiperazin-2-one;

[0431] (S)-4-(5-(4-acetyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-1-methyl-1H-pyrazole-3-carbonyl)-3- ethyl-1-methylpiperazin-2-one;

[0432] 3-(4-(3-(2-ethyl-4-methyl-3-oxopiperazine-1-carbonyl)-1-methyl-1H-pyrazol-5-yl)phenyl)-1,3- dihydro-2H-imidazo[4,5-b]pyridin-2-one;

[0433] (S)-3-(4-(3-(2-ethyl-4-methyl-3-oxopiperazine-1-carbonyl)-1-methyl-1H-pyrazol-5-yl)phenyl)-1,3- dihydro-2H-imidazo[4,5-b]pyridin-2-one;

[0434] Methyl 2-methyl-7-(1-methyl-3-(3-oxo-2-(2,2,2-trifluoroethyl)piperazine-1-carbonyl)-1H-pyrazol- 5-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazine-4-carboxylate;

[0435] Methyl (R)-2-methyl-7-(1-methyl-3-((S)-3-oxo-2-(2,2,2-trifluoroethyl)piperazine-1-carbonyl)-1H- pyrazol-5-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazine-4-carboxylate;

[0436] Methyl (R)-2-methyl-7-(1-methyl-3-((R)-3-oxo-2-(2,2,2-trifluoroethyl)piperazine-1-carbonyl)-1H- pyrazol-5-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazine-4-carboxylate;

[0437] N-(4-(4-(2-ethyl-4-methyl-3-oxopiperazine-1-carbonyl)-2-methyl-1H-imidazol-1- yl)phenyl)acetamide;

[0438] (S)-N-(4-(4-(2-ethyl-4-methyl-3-oxopiperazine-1-carbonyl)-2-methyl-1H-imidazol-1- yl)phenyl)acetamide;

[0439] 4'-acetamido-N-(3-(4-hydroxyphenyl)-1-(methylamino)-1-oxopropan-2-yl)-[1,1'-biphenyl]-3- carboxamide;

[0440] (S)-4'-acetamido-N-(3-(4-hydroxyphenyl)-1-(methylamino)-1-oxopropan-2-yl)-[1,1'-biphenyl]-3- carboxamide;

[0441] 5-(4-(1H-pyrazol-1-yl)phenyl)-4-chloro-N-(3-(4-hydroxyphenyl)-1-(methylamino)-1-oxopropan-2- yl)thiophene-2-carboxamide;

[0442] (S)-5-(4-(1H-pyrazol-1-yl)phenyl)-4-chloro-N-(3-(4-hydroxyphenyl)-1-(methylamino)-1- oxopropan-2-yl)thiophene-2-carboxamide;

[0443] 5-(4-(1H-1,2,4-triazol-1-yl)phenyl)-4-chloro-N-(3-(4-hydroxyphenyl)-1-(methylamino)-1- oxopropan-2-yl)thiophene-2-carboxamide;

[0444] (S)-5-(4-(1H-1,2,4-triazol-1-yl)phenyl)-4-chloro-N-(3-(4-hydroxyphenyl)-1-(methylamino)-1- oxopropan-2-yl)thiophene-2-carboxamide;

[0445] 5-(4-acetyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-N-(3-(4-hydroxyphenyl)-1-(methylamino)-1- oxopropan-2-yl)-4-methylthiophene-2-carboxamide;

[0446] (S)-5-(4-acetyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-N-(3-(4-hydroxyphenyl)-1- (methylamino)-1-oxopropan-2-yl)-4-methylthiophene-2-carboxamide;

[0447] 3-ethyl-1-methyl-4-(4-methyl-5-((R)-2-methyl-4-(methylsulfonyl)-3,4-dihydro-2H- benzo[b][1,4]oxazin-7-yl)thiophene-2-carbonyl)piperazin-2-one;

[0448] (S)-3-ethyl-1-methyl-4-(4-methyl-5-((R)-2-methyl-4-(methylsulfonyl)-3,4-dihydro-2H- benzo[b][1,4]oxazin-7-yl)thiophene-2-carbonyl)piperazin-2-one;PAT065083-PCT-SEC01 4-(5-(1-acetyl-5-fluoro-1,2,3,4-tetrahydroquinolin-6-yl)-4-methylthiophene-2-carbonyl)-3-ethyl-1- methylpiperazin-2-one;

[0449] (S)-4-(5-(1-acetyl-5-fluoro-1,2,3,4-tetrahydroquinolin-6-yl)-4-methylthiophene-2-carbonyl)-3- ethyl-1-methylpiperazin-2-one;

[0450] 4-(5-(5-acetyl-5,6,7,8-tetrahydro-1,5-naphthyridin-2-yl)-4-methylthiophene-2-carbonyl)-3-ethyl-1- methylpiperazin-2-one;

[0451] (S)-4-(5-(5-acetyl-5,6,7,8-tetrahydro-1,5-naphthyridin-2-yl)-4-methylthiophene-2-carbonyl)-3- ethyl-1-methylpiperazin-2-one;

[0452] 4-(5-(4-acetyl-2-ethyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-4-methylthiophene-2-carbonyl)- 3-ethyl-1-methylpiperazin-2-one;

[0453] (S)-4-(5-((R)-4-acetyl-2-ethyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-4-methylthiophene-2- carbonyl)-3-ethyl-1-methylpiperazin-2-one;

[0454] (S)-4-(5-((S)-4-acetyl-2-ethyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-4-methylthiophene-2- carbonyl)-3-ethyl-1-methylpiperazin-2-one;

[0455] 4-(5-(1-acetyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)-4-methylthiophene-2-carbonyl)-3- ethyl-1-methylpiperazin-2-one;

[0456] (S)-4-(5-(1-acetyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)-4-methylthiophene-2-carbonyl)- 3-ethyl-1-methylpiperazin-2-one;

[0457] N-(1-hydroxypropan-2-yl)-4-methyl-5-(4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1- yl)phenyl)thiazole-2-carboxamide;

[0458] (R)-N-(1-hydroxypropan-2-yl)-4-methyl-5-(4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1- yl)phenyl)thiazole-2-carboxamide;

[0459] 4-(5-(4-acetyl-2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-4-methylthiazole-2-carbonyl)-3- ethyl-6-methylpiperazin-2-one;

[0460] (3S,6S)-4-(5-((R)-4-acetyl-2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-4-methylthiazole- 2-carbonyl)-3-ethyl-6-methylpiperazin-2-one;

[0461] (3S,6R)-4-(5-((R)-4-acetyl-2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-4-methylthiazole- 2-carbonyl)-3-ethyl-6-methylpiperazin-2-one;

[0462] Methyl 7-(2-(2-ethyl-5-methyl-3-oxopiperazine-1-carbonyl)-4-methylthiazol-5-yl)-2-methyl-2,3- dihydro-4H-benzo[b][1,4]oxazine-4-carboxylate;

[0463] Methyl (R)-7-(2-((2S,5S)-2-ethyl-5-methyl-3-oxopiperazine-1-carbonyl)-4-methylthiazol-5-yl)-2- methyl-2,3-dihydro-4H-benzo[b][1,4]oxazine-4-carboxylate;

[0464] Methyl (R)-7-(2-((2S,5R)-2-ethyl-5-methyl-3-oxopiperazine-1-carbonyl)-4-methylthiazol-5-yl)-2- methyl-2,3-dihydro-4H-benzo[b][1,4]oxazine-4-carboxylate;

[0465] Methyl 7-(3-(2-ethyl-4-methyl-3-oxopiperazine- 1 -carbonyl)- 1 -methyl- 1H-pyrazol-5-yl)-2-methyl- 2,3-dihydro-4H-benzo[b][1,4]oxazine-4-carboxylate;

[0466] Methyl (R)-7-(3-((S)-2-ethyl-4-methyl-3-oxopiperazine-1 -carbonyl)- 1 -methyl- 1 H-pyrazol-5-yl)-2- methyl-2,3-dihydro-4H-benzo[b][1,4]oxazine-4-carboxylate;PAT065083-PCT-SEC01 3-ethyl-1-methyl-4-(1-methyl-5-(2-methyl-4-(methylsulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin- 7-yl)-1H-pyrazole-3-carbonyl)piperazin-2-one;

[0467] (S)-3-ethyl-1-methyl-4-(1-methyl-5-((R)-2-methyl-4-(methylsulfonyl)-3,4-dihydro-2H- benzo[b][1,4]oxazin-7-yl)-1H-pyrazole-3-carbonyl)piperazin-2-one;

[0468] 1-(4-(3-(2-ethyl-4-methyl-3-oxopiperazine-1-carbonyl)-1-methyl-1H-pyrazol-5-yl)phenyl)-1,3- dihydro-2H-imidazo[4,5-b]pyridin-2-one;

[0469] (S)-1-(4-(3-(2-ethyl-4-methyl-3-oxopiperazine-1-carbonyl)-1-methyl-1H-pyrazol-5-yl)phenyl)-1,3- dihydro-2H-imidazo[4,5-b]pyridin-2-one;

[0470] Methyl 7-(3-(2-ethyl-5-methyl-3-oxopiperazine-1-carbonyl)-1-methyl-1H-pyrazol-5-yl)-2-methyl- 2,3-dihydro-4H-benzo[b][1,4]oxazine-4-carboxylate;

[0471] Methyl (R)-7-(3-((2S,5S)-2-ethyl-5-methyl-3-oxopiperazine-1-carbonyl)-1-methyl-1H-pyrazol-5- yl)-2-methyl-2,3-dihydro-4H-benzo[b][1,4]oxazine-4-carboxylate;

[0472] Methyl (R)-7-(3-((2S,5R)-2-ethyl-5-methyl-3-oxopiperazine-1-carbonyl)-1-methyl-1H-pyrazol-5- yl)-2-methyl-2,3-dihydro-4H-benzo[b][1,4]oxazine-4-carboxylate;

[0473] 4-(5-((R)-4-acetyl-2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-1-methyl-1H-pyrazole-3- carbonyl)-1-methyl-3-(2,2,2-trifluoroethyl)piperazin-2-one;

[0474] (R)-4-(5-((R)-4-acetyl-2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-1-methyl-1H-pyrazole- 3-carbonyl)-1-methyl-3-(2,2,2-trifluoroethyl)piperazin-2-one;

[0475] (S)-4-(5-((R)-4-acetyl-2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-1-methyl-1H-pyrazole- 3-carbonyl)-1-methyl-3-(2,2,2-trifluoroethyl)piperazin-2-one;

[0476] 4-(5-((R)-4-acetyl-2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-1-ethyl-1H-pyrazole-3- carbonyl)-3-ethyl-1-methylpiperazin-2-one;

[0477] (S)-4-(5-((R)-4-acetyl-2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-1-ethyl-1H-pyrazole-3- carbonyl)-3-ethyl-1-methylpiperazin-2-one;

[0478] Methyl 7-(1-ethyl-3-((S)-2-ethyl-4-methyl-3-oxopiperazine-1-carbonyl)-1H-pyrazol-5-yl)-2- methyl-2,3-dihydro-4H-benzo[b][1,4]oxazine-4-carboxylate;

[0479] Methyl (R)-7-(1-ethyl-3-((S)-2-ethyl-4-methyl-3-oxopiperazine-1-carbonyl)-1H-pyrazol-5-yl)-2- methyl-2,3-dihydro-4H-benzo[b][1,4]oxazine-4-carboxylate;

[0480] Methyl 7-(1-ethyl-3-(2-ethyl-5-methyl-3-oxopiperazine-1-carbonyl)-1H-pyrazol-5-yl)-2-methyl- 2,3-dihydro-4H-benzo[b][1,4]oxazine-4-carboxylate;

[0481] Methyl (R)-7-(1-ethyl-3-((2S,5S)-2-ethyl-5-methyl-3-oxopiperazine-1-carbonyl)-1H-pyrazol-5-yl)- 2-methyl-2,3-dihydro-4H-benzo[b][1,4]oxazine-4-carboxylate;

[0482] Methyl (R)-7-(1-ethyl-3-((2S,5R)-2-ethyl-5-methyl-3-oxopiperazine-1-carbonyl)-1H-pyrazol-5-yl)- 2-methyl-2,3-dihydro-4H-benzo[b][1,4]oxazine-4-carboxylate;

[0483] 4-(3-((R)-4-acetyl-2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-2-fluorobenzoyl)-3-ethyl-1- methylpiperazin-2-one;

[0484] (S)-4-(3-((R)-4-acetyl-2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-2-fluorobenzoyl)-3- ethyl-1-methylpiperazin-2-one;PAT065083-PCT-SEC01 4-(5-((R)-1-acetyl-3-(hydroxymethyl)-1,2,3,4-tetrahydroquinolin-6-yl)-4-methylthiophene-2- carbonyl)-3-ethyl-1-methylpiperazin-2-one;

[0485] (S)-4-(5-((R)-1-acetyl-3-(hydroxymethyl)-1,2,3,4-tetrahydroquinolin-6-yl)-4-methylthiophene-2- carbonyl)-3-ethyl-1-methylpiperazin-2-one;

[0486] (S)-4-(5-((S)-1-acetyl-3-(hydroxymethyl)-1,2,3,4-tetrahydroquinolin-6-yl)-4-methylthio-phene-2- carbonyl)-3-ethyl-1-methylpiperazin-2-one;

[0487] 4-(5-(1-acetyl-1,2,3,4-tetrahydroquinoxalin-6-yl)-4-methylthiophene-2-carbonyl)-3-ethyl-1- methylpiperazin-2-one;

[0488] 4-(5-(1-acetyl-4-methyl-1,2,3,4-tetrahydroquinoxalin-6-yl)-4-methylthiophene-2-carbonyl)-3- ethyl-1-methylpiperazin-2-one;

[0489] 3-(4-hydroxybenzyl)-1-methyl-4-(4-methyl-5-(4-(2-oxopyrrolidin-1-yl)phenyl)thiophene-2- carbonyl)piperazin-2-one;

[0490] (S)-3-(4-hydroxybenzyl)-1-methyl-4-(4-methyl-5-(4-(2-oxopyrrolidin-1-yl)phenyl)thiophene-2- carbonyl)piperazin-2-one;

[0491] 7-(2-((S)-2-ethyl-4-methyl-3-oxopiperazine-1-carbonyl)-4-methylthiazol-5-yl)-N,2-dimethyl-2,3- dihydro-4H-benzo[b][1,4]oxazine-4-carboxamide;

[0492] (R)-7-(2-((S)-2-ethyl-4-methyl-3-oxopiperazine-1-carbonyl)-4-methylthiazol-5-yl)-N,2-dimethyl- 2,3-dihydro-4H-benzo[b][1,4]oxazine-4-carboxamide;

[0493] 4-(5-(4-(3,5-dimethyl-2-oxopyrrolidin-1-yl)phenyl)-4-methylthiazole-2-carbonyl)-1,3- dimethylpiperazin-2-one;

[0494] (S)-4-(5-(4-((3R,5R)-3,5-dimethyl-2-oxopyrrolidin-1-yl)phenyl)-4-methylthiazole-2-carbonyl)-1,3- dimethylpiperazin-2-one;

[0495] (S)-4-(5-(4-((3R,5S)-3,5-dimethyl-2-oxopyrrolidin-1-yl)phenyl)-4-methylthiazole-2-carbonyl)-1,3- dimethylpiperazin-2-one;

[0496] (S)-4-(5-(4-((3S,5S)-3,5-dimethyl-2-oxopyrrolidin-1-yl)phenyl)-4-methylthiazole-2-carbonyl)-1,3- dimethylpiperazin-2-one;

[0497] (S)-4-(5-(4-((3S,5R)-3,5-dimethyl-2-oxopyrrolidin-1-yl)phenyl)-4-methylthiazole-2-carbonyl)-1,3- dimethylpiperazin-2-one;

[0498] (R)-3-(4-(3-((S)-2-Ethyl-4-methyl-3-oxopiperazine-1-carbonyl)-1-methyl-1H-pyrazol-5-yl)phenyl)- 5-methyloxazolidin-2-one;;

[0499] 3-(4-(3-((S)-2-Ethyl-4-methyl-3-oxopiperazine-1-carbonyl)-1-methyl-1H-pyrazol-5-yl)phenyl)-5- methyloxazolidin-2-one; and

[0500] 2-((1E,3E)-5-((E)-1-((S)-1-(5-(4-acetamidophenyl)-4-chlorothiophen-2-yl)-3-(4-hydroxybenzyl)- 1,4,18-trioxo-8,11,14-trioxa-2,5,17-triazatricosan-23-yl)-3,3-dimethyl-5-sulfoindolin-2- ylidene)penta-1,3-dien-1-yl)-1-ethyl-3,3-dimethyl-3H-indol-1-ium-5-sulfonate.

[0501] Embodiment 32. A pharmaceutical composition comprising a compound, or a stereoisomer or pharmaceutically acceptable salt thereof, according to any one of embodiments 1 to 31, and a pharmaceutically acceptable carrier.PAT065083-PCT-SEC01 Embodiment 33. A combination comprising a compound, or a stereoisomer or pharmaceutically acceptable salt thereof, according to any one of embodiments 1 to 31, and one or more therapeutically active agents.

[0502] Embodiment 34. A combination according to embodiment 33, wherein the therapeutically active agent is selected from the group consisting of an MRGPRX2 inhibitor, a histamine antagonist, a PKC theta inhibitor, a PDE4 inhibitor and an bIRAK4 inhibitor and a Btk inhibitor such as Remibrutinib.

[0503] Embodiment 35. A compound, or a stereoisomer or pharmaceutically acceptable salt thereof, according to any one of embodiments 1 to 31, for use as a medicament.

[0504] Embodiment 36. A compound, or a stereoisomer or pharmaceutically acceptable salt thereof, according to any one of embodiments 1 to 31 for use in the treatment, or prevention of a disease or disorder that is mediated by IL-4 and / or IL-13.

[0505] Embodiment 37. A compound, or a stereoisomer or pharmaceutically acceptable salt thereof, according to any one of embodiments 1 to 31 for use in the treatment, or prevention of a STAT6-dependent disease or disorder.

[0506] Embodiment 38. A compound, or a stereoisomer or pharmaceutically acceptable salt thereof, according to any one of embodiments 1 to 31, for use in the treatment, or prevention of a disease selected from the group consisting of atopic dermatitis, asthma, chronic rhinosinusitis with nasal polyposis, eosinophilic esophagitis, prurigo nodularis, chronic prurigo, chronic spontaneous urticaria, chronic pruritus, bullous pemphigoid, chronic obstructive pulmonary disease, ulcerative colitis, eosinophilic gastroenteritis and food allergy.

[0507] Embodiment 39. A compound, or a stereoisomer or pharmaceutically acceptable salt thereof, according to any one of embodiments 1 to 31, for use in the treatment of atopic dermatitis.

[0508] Embodiment 40. A method of treating atopic dermatitis, wherein the method comprises administering to the subject a therapeutically effective amount of the compound, or a stereoisomer or pharmaceutically acceptable salt thereof, according to any one of embodiments 1 to 31.

[0509] Embodiment 41. Use a compound, or a stereoisomer or pharmaceutically acceptable salt thereof, according to any one of embodiments 1 to 31, in the manufacture of a medicament for treating, preventing, or ameliorating a STAT6-dependent disease or disorder.

[0510] Embodiment 42. Use of an intermediate for preparing the compound, or a stereoisomer or pharmaceutically acceptable salt thereof, according to any one of embodiments 1 to 31, wherein the intermediate is selected from the group consisting of Intermediates 1-1 to 1-15, 2-1 to 2-10, and 3-1 to 3-24.

[0511] Embodiment 43. Use of any one of intermediates 1-1 to 1-15 in a chemical cross coupling reaction such as use in a Suzuki coupling or any other Pd-assisted cross coupling reaction.PAT065083-PCT-SEC01 Embodiment 44. Use of any one of intermediates 2-1 to 2-10 and 3-1 to 3-24 in a chemical coupling reaction such as in an amide coupling reaction.

[0512] The non-limiting illustrative compounds of the disclosure include the compounds in Table 1 below. As discussed below, each of the exemplified compounds is illustrated by one tautomeric form about the structural features where tautomerization is possible. Prototropy is the most common form of tautomerism and refers to the relocation of a hydrogen atom. Unless otherwise specified, the IC50 is reported for the potential mixture in solution of the co-existing tautomers and / or racemates without regard to the specific tautomeric form.

[0513] Table 1

[0514] LC-MS Ex.1H-NMR

[0515] No. Structure and Name tR [min] (400 MHz, DMSO-d₆)

[0516] d [ppm] (Method) m / z 10.15 (s, 1H), 9.15 (s, 1 H),

[0517] £ T 8.74 (d, 1H), 8.02 (q, 1H),

[0518] 0 7.95 (s, 1 H), 7.74 - 7.65

[0519] (m, 2H), 7.64 - 7.55 (m, 0.75 (A) 1HH£ 2H), 7.14 - 7.02 (m, 2H),

[0520] cr 6.69 - 6.54 (m, 2H), 4.56 - 472.1 / 474.1 (S)-5-(4-acetamidophenyl)-4-chloro-N-(3-(4- 4.42 (m, 1H), 2.97 (dd, [M+H]+hydroxyphenyl)-1 -(methylamino)-l -oxopropan-2- 1H), 2.79 (dd, 1H), 2.60 (d,

[0521] yl)thiophene-2-carboxamide 3H), 2.07 (s, 3H)

[0522] 9.18 (s, 1 H), 8.77 (d, 1H),

[0523] 0 0 8.04 (m, 1H), 7.96 (s, 1H),

[0524] 7.79 (d, 2H), 7.66 (d, 2H), 0.86 (A) 2 7.08 (d, 2H), 6.63 (d, 2H),

[0525] cr 4.50 (m, 1H), 3.86 (m, 2H), 498.1 / 500.1 (S)-4-chloro-N-(3-(4-hydroxyphenyl)-1- 2.97 (m, 1H), 2.79 (m, 1H), [M+H]+ (methylamino)-1-oxopropan-2-yl)-5-(4-(2- 2.60 (d, 3H), 2.53 (m, 2H), oxopyrrolidin-1-yl)phenyl)thiophene-2-carboxamide 2.11 - 2.03 (m, 2H)

[0526] 10.05 (s, 1H), 9.17 (s, 1 H),

[0527] 0° rV 8.60 (d, 1H), 8.02 (m, 1H),

[0528] 7.95 (s, 1 H), 7.62 (m, 4H), 0.62 (A) 3 \== / yjH6 7.07 (d, 2H), 6.66-6.60

[0529] MeO (m, 2H), 4.52 (td, H), 3.91 468.3 (S)-5-(4-acetamidophenyl)-N-(3-(4-hydroxyphenyl)- (s, 3H), 2.95 (m, 1H), 2.80 [M+H]+.

[0530] 1 -(methylamino)-l -oxopropan-2-yl)-4- (m, 1H), 2.59 (d, 3H), 2.04 methoxythiophene-2-carboxamide (s, 3H)

[0531] ^. OH

[0532] O 0 AJ 10.09 (s, 1H), 9.17 (s, 1 H),

[0533] 8.19 (d, 1H), 7.66 (d, 2H),

[0534] 7.59 (s, 1H), 7.41 (d, 2H), 0.82 (A) 5 \=_ / M7.00 (d, 2H), 6.65 (d, 2H),

[0535] 4.06 (p, 1H), 2.74 (dd, 1H), 409.1 2.58 (dd, 1 H), 2.25 (s, 3H), [M+H]+ (R)-5-(4-acetamidophenyl)-N-(1-(4- 2.06 (s, 3H), 1.10 (d, 3H) hydroxyphenyl)propan-2-yl)-4-

[0536]

[0537] methylthiophene-2-carboxamide; orPAT065083-PCT-SEC01

[0538] 1H LC-MS Ex. -NMR

[0539] No. Structure and Name tR [min] (400 MHz, DMSO-d₆)

[0540] d [ppm] (Method) m / z.. OH

[0541] 0 0 JU

[0542] v= / '\ J / M

[0543] (S)-5-(4-acetamidophenyl)-N-(1-(4- hydroxyphenyl)propan-2-yl)-4- methylthiophene-2-carboxamide

[0544] 8.39 (s, 1 H), 7.85 - 7.96

[0545] (m, 1H), 7.73 (s, 1H), 7.43

[0546] - 7.70 (m, 1H), 7.31 (brd,

[0547] 2H), 5.95 (s, 1H), 4.25 - 4.37 (m, 1H), 3.71 (t, 2H),

[0548] \i / =\ s _ J HC. A f _" X 2.76 (s, 1 H), 2.73 - 2.81 0.72 (A) 6 (m, 2H), 2.55 - 2.59 (m,

[0549] 3H), 2.27 - 2.32 (m, 3H), 482.2 (S)-5-(1 -acetyl-1,2,3,4-tetrahydroquinolin-6-yl)-N- 2.18 - 2.24 (m, 3H), 2.04 [M+H] (3-(3-hydroxybicyclo- [1.1.1]pentan-1-yl)-1-+(s, 1H), 1.99 - 2.07 (m, (methylamino)-1-oxopropan-2-yl)-4- 1H), 1.91 (s, 1H), 1.91 (s, methylthiophene-2-carboxamide 1H), 1.85 - 1.96 (m, 3H),

[0550] 1.56 - 1.69 (m, 6H), 1.61

[0551] (s, 1H)

[0552] .^. OH 10.10 (s, 1H), 9.16 (s, 1 H),

[0553] 8.50 (d, 1H), 7.98 (q, 1H),

[0554] o 0 XX 7.71 (s, 1 H), 7.66 (d, 2H),

[0555] 7.41 (d, 2H), 7.08 (d, 2H), 0.67 (A) 7 \= / yjH8 6.63 (d, 2H), 4.53 - 4.45

[0556] (m, 1H), 2.94 (dd, 1H), 452.2 2.82 (dd, 1H), 2.59 (d, 3H), [M+H] (S)-5-(4-acetamidophenyl)-N-(3-(4-hydroxyphenyl)-+

[0557] 2.27 (s, 3H), 2.06 (s, 3H);

[0558] 1 -(methylamino)-l -oxopropan-2-yl)-4- MS (ESI): m / z = 452.2 methylthiophene-2-carboxamide [M+H]+

[0559] .. OH 9.16 (s, 1 H), 8.51 (d, 1H),

[0560] 7.98 (d, 1H), 7.75 (d, 2H),

[0561] j H 7.73 (s, 1 H), 7.48 (d, 2H),

[0562] 7.08 (d, 2H), 6.62 (d, 2H), 0.75 (A) 8 4.49 (m, 1H), 3.86 (t, 2H),

[0563] 2.94 (dd, 1H), 2.81 (dd, 478 [M+H]+(S)-N-(3-(4-hydroxyphenyl)-1 -(methylamino)-l - 1H), 2.59 (d, 3H), 2.53 (d, oxopropan-2-yl)-4-methyl-5-(4-(2-oxopyrrolidin-1- 2H), 2.28 (s, 3H), 2.07 (m, yl)phenyl)thiophene-2-carboxamide 2H)

[0564] OH

[0565] 9.17 (s, 1 H), 8.59 - 8.53

[0566] XT (m, 2H), 8.00 (q, 1H), 7.94

[0567] (d, 2H), 7.81 - 7.74 (m, 0.93 (A) 9 2H), 7.61 (d, 2H), 7.09 (d,

[0568] 2H), 6.63 (d, 2H), 6.58 (t, 461.3 (S)-5-(4-(1 H-pyrazol-1 -yl)phenyl)-N-(3-(4- 1H), 4.50 (ddd, 1 H), 2.95 [M+H]+hydroxyphenyl)-1 -(methylamino)-l -oxopropan-2- (dd, 1H), 2.82 (dd, 1H),

[0569] 2.60 (d, 3H), 2.32 (s, 3H)

[0570]

[0571] yl)-4-methylthiophene-2-carboxamidePAT065083-PCT-SEC01

[0572] 1LC-MS Ex. H-NMR

[0573] No. Structure and Name tR [min]

[0574] (400 MHz, DMSO-d₆)

[0575] d [ppm] (Method) m / z OH 9.17 (s, 1 H), 8.51 (d, 1H),

[0576] 7.98 (s, 1 H), 7.72 (s, 1H),

[0577] 7.66 (s, 1 H), 7.27 (m, 2H),

[0578] 7.08 (d, 2H), 6.62 (d, 2H), 0.81 (A) 10 4.48 (m, 1H), 3.70 (t, 2H), 492.4 (S)-5-(1 -acetyl-1,2,3,4-tetrahydroquinolin-6-yl)-N- 2.94 (dd, 1H), 2.81 (dd, [M+H]+(3-(4-hydroxyphenyl)-1 -(methylamino)-l - 1H), 2.76 (t, 2H), 2.59 (d, oxopropan-2-yl)-4-methylthiophene-2-carboxamide 3H), 2.29 (s, 3H), 2.20 (s,

[0579] 3H), 1.92 - 1.87 (m, 2H)

[0580] O O

[0581] / J

[0582] (R)-4-(5-((R)-1-acetyl-3-methyl-1, 2,3,4- tetrahydroquinolin-6-yl)-4-methylthiophene-2- carbonyl)-3-ethyl-1-methylpiperazin-2-one;

[0583] O O X

[0584] ( \s)_ / >= / I N 7.82 - 7.52 (m, 1H), 7.38

[0585] (s, 1H), 7.29 (d, 2H), 4.82

[0586] (R)-4-(5-((S)-1 -acetyl-3-methyl-1,2,3,4- - 4.60 (m, 1H), 4.40 - 4.24 tetrahydroquinolin-6-yl)-4-methylthiophene-2- (m, 1H), 4.00 - 3.85 (m,

[0587] 0.90 (A) carbonyl)-3-ethyl-1-methylpiperazin-2-one; 1H), 3.77 - 3.55 (m, 1H), 11 3.50 (td, 1H), 3.28 - 3.15

[0588] O o S' (m, 2H), 2.92 (dd, 1H), 454.3

[0589] 2.87 (s, 3H), 2.43 (dd, 1H), [M+H]+2.30 (s, 3H), 2.23 (s, 3H),

[0590] 2.08 - 1.79 (m, 3H), 1.03

[0591] (d, 3H), 0.91 (t, 3H)

[0592] (S)-4-(5-((R)-1 -acetyl-3-methyl-1,2,3,4- tetrahydroquinolin-6-yl)-4-methylthiophene-2- carbonyl)-3-ethyl-1 -methylpiperazin-2-one; or

[0593] O o S'

[0594] \ >= / I N

[0595] (S)-4-(5-((S)-1 -acetyl-3-methyl-1,2,3,4- tetrahydroquinolin-6-yl)-4-methylthiophene-2- carbonyl)-3-ethyl-1-methylpiperazin-2-one

[0596] 7.37 (s, 1 H), 7.01 (dd, 1H),

[0597] ? ( 6.98 (d, 1H), 4.77 - 4.63

[0598] (m, 1H), 4.38 (dtd, 1H),

[0599] 4.34 - 4.27 (m, 1H), 4.25 - 0.83 (A) 12 4.04 (m, 1H), 3.73 - 3.55

[0600] (m, 1H), 3.50 (td, 1 H), 3.25 456.2 (S)-4-(5-((R)-4-acetyl-2-methyl-3,4-dihydro-2H- (ddd, 1 H), 2.86 (s, 3H), [M+H]+benzo[b][1,4]oxazin-7-yl)-4-methylthiophene-2- 2.29 (d, 6H), 2.00 - 1.78 carbonyl)-3-ethyl-1-methylpiperazin-2-one (m, 2H), 1.32 (d, 3H), 0.91

[0601] (t, 3H)

[0602]

[0603] PAT065083-PCT-SEC01

[0604] Ex.1H-NMR LC-MS Structure and Name tR [min] No. (400 MHz, DMSO-d₆)

[0605] d [ppm] (Method) m / z 7.89 (s, 1 H), 7.38 (s, 1H),

[0606] O Q, OMe 7.15 - 6.92 (m, 2H), 4.84 - 4.76 (m, 1H), 4.41 - 4.33

[0607] (m, 1H), 4.30 (t, 2H), 3.97 0.73 (A) 13 (dd, 1H), 3.89 (t, 2H), 3.85

[0608] - 3.71 (m, 1H), 3.68 (dd, 458.3 (S)-4-(5-(4-acetyl-3,4-dihydro-2H-benzo[b][1,4] 1H), 3.59 - 3.49 (m, 1H), [M+H]+oxazin-7-yl)-4-methylthiophene-2-carbonyl)-3- 3.30 - 3.27 (m, 1H), 3.26 (methoxymethyl)-1-methylpiperazin-2-one (s, 3H), 2.89 (s, 3H), 2.29

[0609] (s, 3H), 2.27 (s, 3H)

[0610] 10.02 - 10.22 (m, 1H),

[0611] 7.62 - 7.75 (m, 2H), 7.38 - 7.50 (m, 2H), 7.26 - 7.38

[0612] 00 (m, 1H), 5.90 - 6.08 (m,

[0613] 1H), 4.78 - 5.00 (m, 1H),

[0614] 4.22 - 4.37 (m, 1 H), 3.67 - 0.72 (A) 14 3.82 (m, 1H), 3.38 - 3.47

[0615] (m, 1H), 3.16 - 3.23 (m, 468.3 1H) [M+H]+(S)- / V-(4-(5-(2-((3-hydroxybicyclo[1.1.1]pentan-1-, 2.80 - 2.88 (m, 3H), yl)methyl)-4-methyl-3-oxopiperazine-1-carbonyl)-3- 2.27 - 2.31 (m, 3H), 2.12 - methylthiophen-2-yl)phenyl)acetamide 2.21 (m, 1H), 2.03 - 2.12

[0616] (m, 4H), 1.57 - 1.65 (m,

[0617] 3H), 1.65 - 1.76 (m, 3H)

[0618] 10.15 (s, 1H), 9.19 (s, 1 H),

[0619] ° ° rV 8.37 (d, 1H), 8.05 (q, 1H),

[0620] 7.70 (d, 2H), 7.47 (d 0.66 (A) " Y^ N " YrTN, 2H),

[0621] 15 w yH8 7.00 (d, 2H), 6.62 (d, 2H),

[0622] 4.57 (td, 1H), 2.97 (qd, 453.2 (S)-5-(4-acetamid 2H), 2.60 (d, 3H), 2.48 (s, [M+H]+ophenyl)-N-(3-(4-hydroxyphenyl)- 1 -(methylamino)-l -oxopropan-2-yl)-4- 3H), 2.07 (s, 3H)

[0623] methylthiazole-2-carboxamide

[0624] O n Y

[0625] MeO- Z' 77 =

[0626] N_>rA / sy^N-;^Y'0

[0627] YNH8.06-8.10 (m, 1H), 8.05 (br

[0628] s, 1H), 7.93 (brd, 1H),

[0629] 7.52 - 7.66 (m, 2H), 7.03 - Methyl (R)-7-(2-((R)-2-ethyl-3-oxopiperazine-1 - 7.10 (m, 3H), 5.89 (brt, carbonyl)-4-methylthiazol-5-yl)-2-methyl-2,3- 1H), 5.49 (brd, 1H), 4.73 0.97 (A) dihydro-4H-benzo[b][1,4]oxazine-4-carboxylate; or

[0630] 16 (dd, 1H), 4.26-4.44 (m,

[0631] O n Y 2H), 4.19 (dd, 1H), 3.77 (s, 459.2 MeO-Y 77 f 4H), 3.50-3.66 (m, 2H), [M+H]+

[0632] 3.19-3.31 (m, 5H), 1.81- 2.01 (m, 3H), 1.32 (d, 4H), YNH1.17-1.28 (m, 1 H), 1.03

[0633] (d, 1H), 0.83-0.98 (m, 4H) Methyl (R)-7-(2-((S)-2-ethyl-3-oxopiperazine-1 - carbonyl)-4-methylthiazol-5-yl)-2-methyl-2,3-

[0634]

[0635] dihydro-4H-benzo[b][1,4]oxazine-4-carboxylatePAT065083-PCT-SEC01

[0636] Ex.1H-NMR LC-MS Structure and Na tR [min] No. me (400 MHz, DMSO-d₆)

[0637] d [ppm] (Method) m / z o o ycl=3

[0638] ^NH8.32-8.42 (m, 2H), 8.02 (br

[0639] s, 1H), 7.95 (brs, 1H),

[0640] (R)-4-(5-((R)-4-acetyl-2-methyl-3,4-dihydro-2H- 7.05 (br s, 3H), 6.61 (br d, benzo[b][1,4]oxazin-7-yl)-4-methyl-thiazole-2- 1H), 5.62 (brd, 1H), 5.17

[0641] 0.88 (A) carbonyl)-3-(2,2,2-trifluoroethyl)piperazin-2-one; or (br d, 1H), 4.49 (brd, 1H),

[0642] 17 4.34-4.41 (m, 1H), 4.18 (br

[0643] o o fCI=3d, 2H), 3.62-3.74 (m, 1H), 497.2

[0644] 3.24-3.28 (m, 2H), 3.17 (br [M+H]+d, 1H), 2.98-3.15 (m, 1H),

[0645] 2.72-2.89 (m, 2H), 2.29 (s,

[0646] 5H), 1.33 (brd, 5H)

[0647] (S)-4-(5-((R)-4-acetyl-2-methyl-3,4-dihydro-2H- benzo[b][1,4]oxazin-7-yl)-4-methyl-thiazole-2- carbonyl)-3-(2,2,2-trifluoroethyl)piperazin-2-one

[0648] 7.77-7.81 (m, 2 H), 7.54- 7.59 (m, 2 H), 5.74 (brd,

[0649] 1H), 4.94-5.04 (m, 1H),

[0650] 4.57 (br s, 1H), 3.99 (t,

[0651] 2H), 3.58-3.81 (m, 2H), 0.81 (A) 18 3.34-3.51 (m, 3H), 3.01 (s,

[0652] 3H), 2.62-2.67 (m, 3H), 427.3 (S)-3-ethyl-1-methyl-4-(4-methyl-5-(4-(2- 2.55 (s, 3H), 2.09-2.26 (m, [M+H]+oxopyrrolidin-1-yl)phenyl)thiazole-2- 3 H), 1.95-2.07 (m, 1H), carbonyl)piperazin-2-one 1.23-1.40 (m, 1H), 1.00- 1.08 (m, 3H), 0.88-0.94

[0653] (m, 1 H)

[0654] J 0 < 11.29 (s, 1H), 7.66 (d, 2H),

[0655] 7.59 (d, 2H), 6.03-5.51 Tk v yw 0.7 \= / y_Ki (m, 1H), 4.94 (q, 1H), 4.80 2 19 - 4.43 (m, 1H), 3.76-3.34

[0656] (m, 2H), 2.87 (s, 3H), 2.51 456.0 1 -(4-(2-((S)-2-ethyl-4-methyl-3-oxopiperazine-1 - (s, 3H), 2.03-1.83 (m, 2H), [M+H]+carbonyl)-4-methylthiazol-5-yl)phenyl)-5- 1.35 (d, 3H), 0.92 (q, 3H) methylimidazolidine-2, 4-dione, trifluoroacetate

[0657] O O

[0658] ( / = / / V-N \

[0659] (R)-4-(5-(1 -acetyl-1,2,3,4-tetrahydroquinolin-6-yl)- 7.65 (s, 1 H), 7.34 (d, 2H),

[0660] 4-methylthiazole-2-carbonyl)-3-ethyl-1- 6.23-4.38 (m, 2H), 3.94- 0.88 methylpiperazin-2-one; or

[0661] 20 3.43 (m, 5H), 2.86 (s, 3H),

[0662] O o / 2.77 (t, 2H), 2.21 (s, 3H), 441.4

[0663] 2.13-1.77 (m, 4H), 0.91 [M+H]+(q, 3H)

[0664] ( / V-N \

[0665] (S)-4-(5-(1 -acetyl-1, 2,3, 4-tetrahydroquinolin-6-yl)- 4-methylthiazole-2-carbonyl)-3-ethyl-1-

[0666]

[0667] methylpiperazin-2-onePAT065083-PCT-SEC01

[0668] 1LC-MS H-NMR

[0669] Ex. tR [min]

[0670] Structure and Name

[0671] No. (400 MHz, DMSO-d₆) (Method) d [ppm]

[0672] m / z O O

[0673] \== / y_Ki 8.01 (br s, 1H), 7.17 - 6.97

[0674] (m, 2H), 5.97 (t, 0.36H),

[0675] (R)-4-(5-(4-acetyl-3,4-dihydro-2H- 5.54 (d, 0.53H), 4.77 (dd, benzo[b][1,4]oxazin-7-yl)-4-methylthiazole-2- 0.54H), 4.55-4.38 (m, 0.82 carbonyl)-3-ethyl-1 -methylpiperazin-2-one; or 0.4H), 4.31 (t, 2H), 3.90 (t, 21

[0676] O o / 2H), 3.74-3.61 (m, 0.59H), 443.3

[0677] 3.60-3.43 (m, 1.18H), 3.29 [M+H]+(s, 1H), 2.86 (s, 3H), 2.51

[0678] (s, 3H), 2.28 (s, 3H), 2.07- \ r-N \ 1.78 (m, 2H), 0.91 (dt, 3H)

[0679] (S)-4-(5-(4-acetyl-3,4-dihydro-2H- benzo[b][1,4]oxazin-7-yl)-4-methylthiazole-2- carbonyl)-3-ethyl-1-methylpiperazin-2-one

[0680] 8.12 (d, 1H), 7.06 (d, 2H),

[0681] 0 x0Me6.02 (s, 0.5H), 5.61 (d,

[0682] 0.5H), 4.86 (s, 0.5H), 4.52 Y / V YW (d, 0.5H), 4.39 (t, 1 H), 4.18

[0683] 0.82 (s, 1H), 4.01 (h, 1H), 3.86

[0684] 22 (t, 1H), 3.79-3.62 (m, 1H),

[0685] 473.2 3.53 (dd, 1.5H), 3.32 (d,

[0686] (S)-4-(5-((R)-4-acetyl-2-methyl-3,4-dihydro-2H- [M+H]

[0687] 1H), 3.25 (s, 2.5H), 3.18+benzo[b][1,4]oxazin-7-yl)-4-methylthiazole-2- (s, 1.5H), 2.90 (s, 3H), carbonyl)-3-(methoxymethyl)-1-methylpiperazin-2- 2.49 (s, 3H), 2.29 (s, 3H),

[0688] one 1.33 (d, 3H)

[0689] 7.84 (d, 2H), 7.60 (d, 2H),

[0690] 7.44-7.40 (m, 2H), 7.37 (t,

[0691] / 2H), 7.31-7.24 (m, 1H),

[0692] 6.76 (s, 1 H), 5.49-5.42 (m,

[0693] (S)-3-ethyl-1 -methyl-4-(1 -methyl-5-(4-((S)-2-oxo-4- 0.5H), 4.95 (d, 1H), 4.86- ph e ny Ipy rro lid in- 1 -y I) ph eny I)- 1 H-pyrazole-3- 0.92

[0694] 4.79 (m, 1H), 4.51 (d, carbonyl)piperazin-2-one; or

[0695] 23 0.5H), 4.27 (dd, 1H), 3.95- 486.4

[0696] 3.87 (m, 4H), 3.75 (p, 1H),

[0697] [M+H] 3.64-3.54 (m, 1H), 3.48+(td, 1H), 3.31-3.19 (m,

[0698] 2H), 2.94 (dd, 1H), 2.86 (s, 3H), 2.76 (dd, 1H), 2.00- 'kX / 1.77 (m, 2H), 0.90 (t, 3H)

[0699] (S)-3-ethyl-1 -methyl-4-(1 -methyl-5-(4-((R)-2-oxo-4- ph e ny Ipy rro lid in- 1 -y I) ph eny I)- 1 H-pyrazole-3- carbonyl)piperazin-2-one

[0700] Oo / 7.12-7.04 (m, 2H), 6.73 (s,

[0701] 1H), 5.47-5.35 (m, 0.5H),

[0702] 4.92 (d, 1H), 4.86-4.76

[0703] 0.60 (A) (m, 1H), 4.49 (d, 0.5H),

[0704] 24 < y= / \_N 4.31 (t, 2H), 3.95-3.83 (m,

[0705] x-~c’ / 426.3

[0706] 5H), 3.64-3.53 (m, 1H),

[0707] (R)-4-(5-(4-acetyl-3,4-dihydro-2H- [M+H]

[0708] 3.34-3.18 (m, 2H), 2.85 (s,+benzo[b][1,4]oxazin-7-yl)-1 -methyl- 1 H-pyrazole-3- 3H), 2.28 (s, 3H), 2.02- carbonyl)-3-ethyl-1 -methylpiperazin-2-one; or 1.74 (m, 2H), 0.89 (t, 3H)

[0709]

[0710] PAT065083-PCT-SEC01

[0711] LC-MS Ex.1H-NMR

[0712] No. Structure and Name tR [min] (400 MHz, DMSO-d₆)

[0713] d [ppm] (Method) m / z O o s'

[0714] \ N-N

[0715] (S)-4-(5-(4-acetyl-3,4-dihydro-2H- benzo[b][1,4]oxazin-7-yl)-1 -methyl- 1 H-pyrazole-3- carbonyl)-3-ethyl-1-methylpiperazin-2-one

[0716] 11.47 (s, 1H), 7.97 (dd,

[0717] o 1H), 7.89-7.85 (m, 2H),

[0718] 7.78-7.73 (m, 2H), 7.43

[0719] (dd, 1H), 7.13 (dd, 1H), 0.60 25 6.85 (s, 1 H), 5.53-4.44 (m,

[0720] 2H), 3.98 (s, 3H), 3.62 (t, 460.4 (S)-3-(4-(3-(2-ethyl-4-methyl-3-oxopiperazine-1- 1H), 3.54-3.37 (m, 1H), [M+H]+carbonyl)-1 -methyl- 1 H-pyrazol-5-yl)phenyl)-1,3- 3.26 (d, 1H), 2.87 (s, 3H),

[0721] dihydro-2H-imidazo[4,5-b]pyridin-2-one 2.02-1.80 (m, 2H), 0.91 (t,

[0722] 3H)

[0723] MeO O

[0724] N^^

[0725] GRJ Ji JL / ? -CF3

[0726] 8.21-8.37 (m, 1H), 7.94 (br

[0727] d, 1H), 7.02-7.15 (m, 2H),

[0728] 6.74 (s, 1 H), 6.07 (br s,

[0729] Methyl (R)-2-methyl-7-(1 -methyl-3-((R)-3-oxo-2- 0.2H), 5.21 (dd, 0.8H),

[0730] (2,2,2-trifluoroethyl)piperazine-1 -carbonyl)-1 H- 5.05 (br d, 0.8H), 4.52 (br

[0731] pyrazol-5-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazine- 0.86 (A) d, 0.2H), 4.35 (cm, 1H),

[0732] 26 4-carboxylate; or 4.19 (dd, 1H), 3.90 (s, 3H), [496.3

[0733] MeO O 3.77 (s, 3H), 3.59 (cm, M+H]+0.8H), 3.15-3.40 (m, 3.2H),

[0734] N 3.07 (cm, 1H), 2.76 (cm,

[0735] GR; T 1 9 ^CF31H), 1.32 (d, 3H)

[0736] c'' r

[0737] \__NH

[0738] methyl (R)-2-methyl-7-(1 -methyl-3-((S)-3-oxo-2- (2,2,2-trifluoroethyl)piperazine-1 -carbonyl)-1 H- pyrazol-5-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazine- 4-carboxylate

[0739] 10.18 (s, 1H), 7.75 (s, 1 H),

[0740] oo / 7.74-7.71 (m, 2H), 7.44- \ / r~^ JL JL 7.39 (m, 2H), 6.08 (s, HIM—# 0.33H), 5.54 (d, 0.67H),

[0741] \= / 0.45 (A 27 4.83 (s, 0.67H), 4.50 (s, ) 0.33H), 3.63-3.38 (m, 2H), 384.3[M+H]+(S)-N-(4-(4-(2-ethyl-4-methyl-3-oxopiperazine-1- 3.31-3.07 (m, 1H), 2.85 (s, carbonyl)-2-methyl-1 H-imidazol-1 - 3H), 2.28 (s, 3H), 2.08 (s, yl)phenyl)acetamide 3H), 1.98-1.73 (m, 2H),

[0742] 0.89 (m, 3H)

[0743]

[0744] PAT065083-PCT-SEC01

[0745] Ex1H-NMR LC-MS. Structure and Name tR [min] No. (400 MHz, DMSO-d₆)

[0746] d [ppm] (Method) m / z 10.06 (s, 1H), 9.12 (s, 1 H),

[0747] 8.63 (d, 1H), 8.05 (s, 1H),

[0748] HN JL J 7.92-8.01 (m, 1H), 7.77 (d,

[0749] 1H), 7.66-7.74 (m, 5 H), 0.61 (A) N k JL JI 1 ^.o

[0750] 7.49 (t, 1H), 7.11 (m, 2 H), 28H6.61 (m, 2H), 4.54 - 4.61 432.4 (m, 1H), 3.00 (dd, 1H), [M+H]+(S)-4'-acetamido-N-(3-(4-hydroxyphenyl)-1- 2.86 (dd, 1H), 2.60 (d, 3H), (methylamino)-1-oxopropan-2-yl)-[1,1'-biphenyl]-3- 2.07 (s, 3H), 1.19-1.29 (m, carboxamide 1H)

[0751] 9.17 (s, 1H), 8.79 (d, 1H),

[0752] 8.58 (d, 1H), 8.04 (q, 1H), O

[0753] 7.96-8.01 (m, 3H), 7.77- 0.99 (A) 7.81 (m, 3H), 7.08 (cm, 2< NH 36 H), 6.63 (cm, 2H), 6.58 481.3 / 483.2 cr (dd, 1H), 4.51 (ddd, 1H), [M+H]+(S)-5-(4-(1 H-pyrazol-1 -yl)phenyl)-4-chloro-N-(3-(4- 2.98 (dd, 1 H), 2.80 (dd, hydroxyphenyl)-1 -(methylamino)-l -oxopropan-2- 1H), 2.60 (d, 3H)

[0754] yl)thiophene-2-carboxamide

[0755] _ OH

[0756] 9.39 (s, 1 H), 9.19 (s, 1H), JL JJ O 8.84 (d, 1H), 8.29 (s, 1H), N^\ z — > c 11 I n 0.81 (A) 8.07 (q, 1H), 8.04 - 7.97

[0757] < N H37 (m, 3H), 7.85 (d, 2H), 7.09 482.2 / 484.2 cr (d, 2H), 6.63 (d, 2H), 4.51

[0758] [M+H]+(cm, 1H), 2.98 (dd, 1H), (S)-5-(4-(1 H-1, 2,4-triazol- 1 -yl)phenyl)-4-chloro-N- 2.80 (dd, 1H), 2.60 (d, 3H) (3-(4-hydroxyphenyl)-1 -(methylamino)-l - oxopropan-2-yl)thiophene-2-carboxamide

[0759] ^. OH 9.12 (s, 1 H), 8.50 (d, 1H),

[0760] 7.96 (d, 1H), 7.71 (s, 1H),

[0761] 7.10 - 7.03 (m, 2H), 7.02 - -?°? I " 0.74 (A) 6.94 (m, 2H), 6.66 - 6.59

[0762] 38 (m, 2H), 4.54 - 4.43 (m, 494.4 1H), 4.29 (t, 2H), 3.88 (t, [M+H]+2H), 2.95 (dd, 1H), 2.88 - (S)-5-(4-acetyl-3,4-dihydro-2H-benzo[b][1,4]oxazin- 2.76 (m, 1H), 2.59 (d, 3H), 7-yl)-N-(3-(4-hydroxyphenyl)-1 -(methylamino)-l - 2.27 (d, 6H) oxopropan-2-yl)-4-methylthiophene-2-carboxamide

[0763] 7.68 (d, 1H), 7.38 (s, 1H), __^O0f 7.07 (dd, 1H), 7.03 (d, 1H),

[0764] 4.69 (s, 1 H), 4.38 - 4.26

[0765] (m, 2H), 4.13 (dd, 1H), 0.87 (A) ( \= / VJ I N

[0766] 3.77 - 3.56 (m, 1H), 3.50 39 (td, 1H), 3.28 - 3.21 (m, 492.3 2H), 3.19 (s, 3H), 2.86 (s, [M+H]+(S)-3-ethyl-1-methyl-4-(4-methyl-5-((R)-2-methyl-4- 3H), 2.30 (s, 3H), 1.99 - (methylsulfonyl)-3,4-dihydro-2H- 1.80 (m, 2H), 1.36 (d, 3H), benzo[b][1,4]oxazin-7-yl)thiophene-2- 0.91 (t, 3H) carbonyl)piperazin-2-one

[0767] 7.63 - 7.46 (m, 1H), 7.45 - 7.34 (m, 1H), 7.26 (t, 1H),

[0768] 0.86 (A) 4.80 - 4.60 (m, 1H), 4.40 - 4.22 (m, 1H), 3.79 - 3.71 40 458.1 (m, 2H), 3.71 - 3.56 (m,

[0769] \ / V \ [M+H]+1H), 3.56 (s, 1H), 3.29 - 3.23 (m, 1H), 2.87 (s, 3H),

[0770] 2.83 - 2.74 (m, 2H), 2.24

[0771]

[0772] PAT065083-PCT-SEC01

[0773] E1H-NMR LC-MS x.

[0774] N Structure and Name tR [min] o. (400 MHz, DMSO-d₆)

[0775] d [ppm] (Method) m / z (S)-4-(5-(1 -acetyl-5-fluoro-1,2,3,4- (s, 3H), 2.16 (d, 3H), 2.02 tetrahydroquinolin-6-yl)-4-methylthiophene-2- - 1.77 (m, 4H), 0.91 (t, 3H) carbonyl)-3-ethyl-1-methylpiperazin-2-one

[0776] 7.40 (d, 1H), 7.26 (s, 1H),

[0777] 7.17 (s, 1 H), 5.43 - 5.23

[0778] (m, OH), 5.03 (d, 1H), 4.61

[0779] (d, 1H), 3.81 (s, 2H), 3.72 071 (A) 41 - 3.36 (m, 2H), 3.20 (d,

[0780] 1H), 3.00 (d, 5H), 2.47 (s, 441.1 (S)-4-(5-(5-acety I-5,6, 7, 8-tetrahyd ro- 1, 5- 3H), 2.31 (s, 3H), 2.11 (dp, [M+H]+naphthyridin-2-yl)-4-methylthiophene-2-carbonyl)- 3H), 1.92 (dq, 1H), 1.04 (t,

[0781] 3-ethy I- 1 -methylpiperazin-2-one 3H)

[0782] o o s'

[0783] 8.09 (br s, 1H), 7.38 (s,

[0784] 1H), 7.04 - 6.98 (m, 2H),

[0785] (S)-4-(5-((R)-4-acetyl-2-ethyl-3,4-dihydro-2H- 4.70 (br s, 1H), 4.32 (d, benzo[b][1,4]oxazin-7-yl)-4-methylthiophene-2- 1H), 4.20 - 4.14 (m, 1H), 0.95 (A) carbonyl)-3-ethyl-1 -methylpiperazin-2-one; or 3.64 (br s, 1H), 3.50 (td,

[0786] 42 1H), 3.45 - 3.30 (m, 1H),

[0787] O o X 3.28 - 3.23 (m, 1H), 2.86 470.3 (s, 3H), 2.30 (s, 3H), 2.28 [M+H]+(s, 3H), 1.94 (ddd, 1H),

[0788] 1.86 (dt, 1H), 1.65 (m, 2H), / J 1.01 (t, 3H), 0.91 (t, 3H)

[0789] (S)-4-(5-((S)-4-acetyl-2-ethyl-3,4-dihydro-2H- benzo[b][1,4]oxazin-7-yl)-4-methylthiophene-2- carbonyl)-3-ethyl-1-methylpiperazin-2-one

[0790] 9.01 - 7.90 (m, 1H), 7.41 - 7.27 (m, 2H), 4.74 - 4.60

[0791] (m, 1H), 4.42 (dd, 2H),

[0792] 4.33 - 4.21 (m, 1H), 3.92 0.58 (A) 43 (dd, 2H), 3.71 - 3.55 (m,

[0793] 1H), 3.49 (td, 1H), 3.29 - 443.3 (S)-4-(5-(1-acetyl-2,3-dihydro-1H-pyrido[2,3- 3.19 (m, 1H), 2.86 (s, 3H), [M+H]+b][1,4]oxazin-6-yl)-4-methylthiophene-2-carbonyl)- 2.46 (s, 3H), 2.28 (s, 3H),

[0794] 3-ethy I- 1 -methylpiperazin-2-one 2.01 - 1.76 (m, 2H), 0.90

[0795] (t, 3H)

[0796] O <3H

[0797] 11.91 (brs, 1H), 8.39 (d,

[0798] HNA / =\ S A X 1H), 8.02 (dd, 1H), 7.73 0.70 (A)N|f W y_KlH(cm, 4H), 7.46 (dd, 1H), 44 7.05 (dd, 1H), 4.83 (t, 1H),

[0799] (R)-N-(1-hydroxypropan-2-yl)-4-methyl-5-(4-(2-oxo- 4.01 (cm, 1H), 3.59-3.37 410.1

[0800] [M+H]+2,3-dihydro-1 H-imidazo[4,5-b]pyridin-1 - (m, 2H), 2.56 (s, 3H), 1.16 yl)phenyl)thiazole-2-carboxamide (d, 3H)

[0801] 8.07 (br d, 1H), 7.03-7.08

[0802] O o X (m, 3H), 5.90-5.94 (m,

[0803] 1H), 5.53-5.57 (m, 1H), 0.90 (A) 45 4.72 (dd, 1 H), 4.49 (brdd,

[0804] 1H), 4.30 - 4.43 (m, 1H), 457.3 yNH4.10-4.27 (brs, 1H), 3.38- [M+H]+

[0805] 3.64 (m, 1H), 3.06-3.15

[0806]

[0807] (m, 1H), 2.77-2.86 (m,PAT065083-PCT-SEC01

[0808] 1H-NMR LC-MS Ex.

[0809] N Structure and Name tR [min] o. (400 MHz, DMSO-d₆)

[0810] d [ppm] (Method) m / z (3S,6S)-4-(5-((R)-4-acetyl-2-methyl-3,4-dihydro- 1H), 2.29 (s, 3H), 1.79- 2H-benzo[b][1,4]oxazin-7-yl)-4-methylthiazole-2- 2.03 (m, 2H), 1.33 (d, 3H), carbonyl)-3-ethyl-6-methylpiperazin-2-one; or 1.05-1.15 (m, 3H), 0.85- O o s' 0.97 (m, 3H)

[0811] (3S,6R)-4-(5-((R)-4-acetyl-2-methyl-3,4-dihydro- 2H-benzo[b][1,4]oxazin-7-yl)-4-methylthiazole-2- carbonyl)-3-ethyl-6-methylpiperazin-2-one

[0812] O o S'

[0813] MeO- / ' 77 f

[0814] 8.08 (br d, 1 H), 7.94 (br d,

[0815] 1H), 7.08 (dd, 1H), 7.04 (d,

[0816] 1H), 5.90-5.96 (m, 0.5H), Methyl (R)-7-(2-((2S,5S)-2-ethyl-5-methyl-3- 5.52-5.60 (m, 0.5H), 4.73 oxopiperazine-1-carbonyl)-4-methylthiazol-5-yl)-2- (dd, 0.5H), 4.50 (br dd,

[0817] methyl-2,3-dihydro-4H-benzo[b][1,4]oxazine-4- 0.5H), 4.30-4.39 (m, 1H), 1.06 (A) 46 carboxylate; or 4.20 (dd, 1H), 3.78 (s, 3H),

[0818] O n / 3.46-3.66 (m, 1H), 3.26- 473.4 MeO— Z' 77 ( 3.32 (m, 1H), 3.06-3.17 [M+H]+

[0819] (m, 0.5H), 2.78-2.90 (m,

[0820] 0.5H), 2.49-2.52 (m, 3H), WH1.80-2.06 (m, 1H), 1.33 (d,

[0821] 3H), 1.01-1.27 (m, 3H),

[0822] Methyl (R)-7-(2-((2S,5R)-2-ethyl-5-methyl-3- 0.87-0.96 (m, 3H)

[0823] oxopiperazine-1-carbonyl)-4-methylthiazol-5-yl)-2- methyl-2,3-dihydro-4H-benzo[b][1,4]oxazine-4- carboxylate

[0824] 7.94 (d, 1H), 7.15-6.99

[0825] o o s' (m, 2H), 6.72 (s, 1H),

[0826] MeOA A A / O 5.53-5.33 (m, 0.5H), 4.93

[0827] (d, 1H), 4.85-4.77 (m, 1H),

[0828] 4.50 (d, 0.5H), 4.34 (ddt, 0.82 (A) 47 1H), 4.19 (dd, 1H), 3.90 (s, 456.3 Methyl (R)-7-(3-((S)-2-ethyl-4-methyl-3- 3H), 3.77 (s, 3H), 3.65- [M+H]+oxopiperazine-1 -carbonyl)-1 -methyl- 1 H-pyrazol-5- 3.38 (m, 2H), 3.29 (dd,

[0829] yl)-2-methyl-2,3-dihydro-4H-benzo[b][1,4]oxazine- 2H), 2.85 (s, 3H), 2.03- 4-carboxylate 1.71 (m, 2H), 1.32 (d, 3H),

[0830] 0.90 (t, 3H)

[0831] 7.71 (d, 1H), 7.18-7.06

[0832] (m, 2H), 6.73 (s, 1H), 5.41

[0833] (s, 0.5H), 4.93 (d, 1H),

[0834] 4.81 (s, 1 H), 4.50 (d, 0.70 (A) 48 0.5H), 4.41-4.29 (m, 1H),

[0835] 4.15 (dd, 1H), 3.91 (s, 3H), 476.2 (S)-3-ethyl-1 -methyl-4-(1 -methyl-5-((R)-2-methyl-4- 3.54 (dt, 2H), 3.28-3.21 [M+H]+(methylsulfonyl)-3,4-dihydro-2H- (m, 2H), 3.20 (s, 3H), 2.86 benzo[b][1,4]oxazin-7-yl)-1 H-pyrazole-3- (s, 3H), 2.02-1.77 (m, 2H), carbonyl)piperazin-2-one 1.36 (d, 3H), 0.90 (t, 3H)

[0836]

[0837] PAT065083-PCT-SEC01

[0838] Ex.1H-NMR LC-MS N Structure and Name tR [min] o. (400 MHz, DMSO-d₆)

[0839] d [ppm] (Method) m / z o 11.92 (s, 1H), 8.02 (dd,

[0840] 1H), 7.82-7.70 (m, 4H),

[0841] 7.44 (dd, 1H), 7.06 (dd, 0.61 (A) 49 1H), 6.85 (s, 1H), 5.47- 4.46 (m, 2H), 3.98 (s, 3H), 460.1 (S)-1 -(4-(3-(2-ethyl-4-methyl-3-oxopiperazine-1 - 3.71-3.18 (m, 3H), 2.87 (s, [M+H]+carbonyl)-1 -methyl- 1 H-pyrazol-5-yl)phenyl)-1,3- 3H), 2.03-1.77 (m, 2H),

[0842] dihydro-2H-imidazo[4,5-b]pyridin-2-one 0.92 (t, 3H)

[0843] O o S'

[0844] MeO- / ' |j |

[0845] 8.00 (s, 1 H), 7.91 - 7.99 Vo=z WH (m, 1H), 7.10 (d, 1H), 7.08

[0846] / ' T (s, 1H), 6.72 (s, 1H), 5.33- Methyl (R)-7-(3-((2S,5S)-2-ethyb Cl-5-methyl-3- 5.36 (m, 0.5H), 4.89-4.94 oxopiperazine-1 -carbonyl)-1 -methyl- 1 H-p / oyrazol-5- (m, 0.5H), 4.75-4.78 (m,

[0847] yl)-2-methyl-2,3-dihydro-4H-benzo[b][1,4]oxazine- 0.5H), 4.51-4.55 (m, 0.85 (A)

[0848] 4-carboxylate; or 0.5H), 4.30-4.38 (m, 1H),

[0849] 50 4.19 (dd, 1H), 3.90 (s, 3H),

[0850] O o / 456. MeO-^ || f 3.77 (s, 3H), 3.43-3.65 (m, 2

[0851] 1H), 3.26-3.37 (m, 0.5H), [M+H]+z V- _N3.00-3.07 (m, 0.5H), 2.67- 2.73 (m, 0.5H), 1.75-1.99

[0852] / o / z (m, 1.5H), 1.32 (d, 3H),

[0853] 1.01-1.12 (m, 3H), 0.90 (t, Methyl (R)-7-(3-((2S,5R)-2-ethyl-5-methyl-3- 3H)

[0854] oxopiperazine-1 -carbonyl)-1 -methyl- 1 H-pyrazol-5- yl)-2-methyl-2,3-dihydro-4H-benzo[b][1,4]oxazine- 4-carboxylate

[0855] o o / CFs

[0856] 'N-'N

[0857] / o /

[0858] 8.53-7.50 (m, 2H), 7.08

[0859] (R)-4-(5-((R)-4-acetyl-2-methyl-3,4-dihydro-2H- (d, 2H), 6.75 (s, 1H), 5.27 benzo[b][1,4]oxazin-7-yl)-1 -methyl- 1 H-pyrazole-3- (d, 1H), 5.11 (d, 1H), 4.40 carbonyl)-1-methyl-3-(2,2,2-trifluoroethyl)piperazin- (ddt, 1H), 4.19 (s, 1H), 0.73 (A)

[0860] 2-one; or

[0861] 51 3.90 (d, 3H), 3.78-3.67

[0862] o o GF3(m, 1H), 3.51 (td, 1 H), 494.1

[0863] 3.32-3.22 (m, 1H), 3.09 [M+H]+(dt, 1H), 2.89 (s, 3H), 2.75

[0864] (t, 1H), 2.29 (s, 3H), 1.33

[0865] (d, 3H), 1.23 (s, 1H)

[0866] / O /

[0867] (S)-4-(5-((R)-4-acetyl-2-methyl-3,4-dihydro-2H- benzo[b][1,4]oxazin-7-yl)-1 -methyl- 1 H-pyrazole-3- carbonyl)-1-methyl-3-(2,2,2-trifluoroethyl)piperazin- 2-one

[0868] 7.01 (d, 2H), 6.68 (s, 1H),

[0869] 5.45 (s, 0.5H), 4.91 (d, 0.75 (A) 1H), 4.87-4.74 (m, 1 H),

[0870] 52 4.50 (d, 0.5H), 4.45-4.33 454.2 (m, 1H), 4.18 (q, 3H), [M+H] 3.64-3.49 (m, 2H), 3.30-+

[0871]

[0872] 3.18 (m, 2H), 2.86 (s, 3H),PAT065083-PCT-SEC01

[0873] LC-MS Ex.1H-NMR

[0874] S tR [min] No. tructure and Name (400 MHz, DMSO-d₆)

[0875] d [ppm] (Method) m / z (S)-4-(5-((R)-4-acetyl-2-methyl-3,4-dihydro-2H- 2.29 (s, 3H), 2.03-1.75 (m, benzo[b][1,4]oxazin-7-yl)-1 -ethyl- 1 H-pyrazole-3- 2H), 1.34 (t, 6H), 0.91 (t, carbonyl)-3-ethyl-1-methylpiperazin-2-one 3H)

[0876] 7.95 (s, 1 H), 7.09-6.94 (m, o o s' 2H), 6.67 (s, 1H), 5.45 (s,Meo^( U f o 0.5H), 4.92 (d, 1H), 4.85- 4.75 (m, 1H), 4.50 (d, ^So>= / jN-h0.5H), 4.39-4.29 (m, 1H), 0.90 (A) 53 4.19 (t, 3H), 3.77 (s, 3H), 470.2 Methyl (R)-7-(1 -ethyl-3-((S)-2-ethyl-4-methyl-3- 3.63-3.39 (m, 2H), 3.32- [M+H]+oxopiperazine-1 -carbonyl)-1 H-pyrazol-5-yl)-2- 3.20 (m, 3H), 2.85 (s, 3H), methyl-2,3-dihydro-4H-benzo[b][1,4]oxazine-4- 2.01-1.75 (m, 2H), 1.39- carboxylate 1.27 (m, 6H), 0.96-0.85

[0877] (m, 3H)

[0878] O o

[0879] MeO- / ' 77 f

[0880] 8.01 (s, 1 H), 7.92-7.99 (m, ^NH1H), 7.03 (brd, 1H), 7.00

[0881] (s, 1H), 6.67 (s, 1 H),

[0882] 5.35-5.39 (m, 0.5H), 4.87- Methyl (R)-7-(1 -ethyl-3-((2S,%S)-2-ethyl-5-methyl- 4.92 (m, 0.5H), 4.73-4.77

[0883] 3-oxopiperazine-1 -carbonyl)-1 H-pyrazol-5-yl)-2- (m, 0.5H), 4.51- 4.56 (m, methyl-2,3-dihydro-4H-benzo[b][1,4]oxazine-4- 0.5H), 4.28-4.38 (m, 1H), carboxylate; or

[0884] 54 4.14-4.22 (m, 3H), 3.77 (s, 0.93 (A)

[0885] O n / 3 H), 3.54-3.64 (m, 0.5H), MeO— || f 3.45-3.50 (m, 0.5H), 3.33 [M+H]+

[0886] (s, 2H), 3.27 - 3.32 (m,

[0887] 2H), 3.00 - 3.06 (m, 0.5H), )== / \i--N L^NH 2.67-2.73 (m, 0.5H), 1.75- 1.99 (m, 2H), 1.30-1.36

[0888] (m, 6H), 1.02-1.19 (m,

[0889] Methyl (R)-7-(1 -ethyl-3-((2S,5R)-2-ethyl-5-methyl- 3H), 0.91 (brt, 3H)

[0890] 3-oxopiperazine-1 -carbonyl)-1 H-pyrazol-5-yl)-2- methyl-2,3-dihydro-4H-benzo[b][1,4]oxazine-4- carboxylate

[0891] 8.61-7.65 (m, 1H), 7.63

[0892] (td, 1H), 7.52-7.32 (m,

[0893] 2H), 7.16-6.98 (m, 2H),

[0894] . r1^ X. k 1 i A? 1 r,0 4.88-4.77 (m, 1H), 4.56 0.76 (A) 55 (dd, 1H), 4.39 (ddt, 1H),

[0895] 3.76-3.07 (m, 5H), 2.86 454.1 (d, 3H), 2.29 (s, 3H), 2.04- [M+H]+(S)-4-(3-((R)-4-acetyl-2-methyl-3,4-dihydro-2H- benzo[b][1,4]oxazin-7-yl)-2-fluorobenzoyl)-3-ethyl- 1.68 (m, 2H), 1.33 (d, 3H),

[0896] 1 -methylpiperazin-2-one 0.84 (dt, 3H)

[0897] 7.62 (brs, 1H), 7.38 (s,

[0898] n r 1H), 7.33 - 7.27 (m, 2H),

[0899] N— $ ~~ V__ / S N4.79 (t, 1H), 4.70 (br s,

[0900] 1H), 4.32 (d, 1H), 3.93 - 0.73 (A) 67 3.88 (m, 1H), 3.64 (br s,

[0901] HO-VZ1H), 3.50 (td, 1H), 3.43 (dt, 470.3

[0902] 1H), 3.36 (dd, 1H), 3.26 [M+H]+(S)-4-(5-((R)-1 -acetyl-3-(hydroxymethyl)-1,2,3,4- (dt, 1H), 2.89 (d, 1H), 2.86 tetrahydroquinolin-6-yl)-4-methylthiophene-2- (s, 4H), 2.48 (d, 1H), 2.30 carbonyl)-3-ethyl-1 -methylpiperazin-2-one; or

[0903]

[0904] (s, 3H), 2.22 (s, 3H), 1.99PAT065083-PCT-SEC01

[0905] Ex.1H-NMR LC-MS Structure and Name tR [min] No. (400 MHz, DMSO-d₆)

[0906] d [ppm] (Method) m / z - 1.89 (m, 1H), 1.86 (dp, _J> n r 1H), 0.91 (t, 4H)

[0907] HO—-'7

[0908] (S)-4-(5-((S)-1 -acetyl-3-(hydroxymethyl)-1,2,3,4- tetrahydroquinolin-6-yl)-4-methylthio-phene-2- carbonyl)-3-ethyl-1-methylpiperazin-2-one

[0909] 7.63 (br s, 1H), 7.35 (s,

[0910] 1H), 7.20 (brs, 1H), 6.75

[0911] (s, 1H), 6.63 - 6.59 (m,

[0912] 1H), 6.44 (brs, 1H), 4.70 0.72 (A) ( / = / V-J I N (broad s, 1H), 4.32 (d, 1H),

[0913] 68 NH / 3.68 (t, 2H), 3.64 (br s,

[0914] 1H), 3.50 (td, 1H), 3.28 - 441.4 4-(5-(1 -acetyl-1,2,3,4-tetrahydroquinoxalin-6-yl)-4- 3.22 (m, 1H), 2.86 (s, 3H), [M+H]+methylthiophene-2-carbonyl)-3-ethyl-1- 2.29 (s, 3H), 2.19 (s, 3H), methylpiperazin-2-one 1.93 (tq, 1H), 1.86 (dq,

[0915] 1H), 0.91 (t, 3H)

[0916] 7.31 - 7.45 (m, 1 H), 6.63 - 6.80 (m, 2 H), 4.57 - 4.85

[0917] (m, 1 H), 4.23 - 4.41 (m, 1

[0918] H), 3.74 - 3.87 (m, 2 H),

[0919] ( >= / A J I A 3.55 - 3.74 (m, 1 H), 3.45 - 0.72 (A) 69 N / 3.55 (m, 1 H), 3.35 - 3.41

[0920] \ (m, 3 H), 2.89 - 2.98 (m, 3 455.2 H), 2.86 (s, 3 H), 2.31 (s, 1

[0921] 4-(5-(1-acetyl-4-methyl-1,2,3,4- [M+H]+

[0922] H), 2.24 - 2.38 (m, 3 H), tetrahydroquinoxalin-6-yl)-4-methylthiophene-2- 2.13 - 2.23 (m, 3 H), 1.76 - carbonyl)-3-ethyl-1-methylpiperazin-2-one 2.02 (m, 2 H), 0.85 - 0.98

[0923] (m, 3 H); MS (ESI)

[0924] 9.27 (s, 1 H), 7.78 - 7.73

[0925] (m, 2H), 7.47 (d, 2H), 7.08

[0926] ° o zXX (brs, 1H), 6.98 - 6.93 (m,

[0927] 2H), 6.67 (d, 2H), 4.83 (br 0.75 (A) 70 s, 1H), 4.21 (brs, 1H),

[0928] V= / yj / 3.86 (t, 2H), 3.42 (d, 1H), 504.4

[0929] 3.29 (br s, 1H), 3.15 (m, [M+H]+(S)-3-(4-hydroxybenzyl)-1-methyl-4-(4-methyl-5-(4- 2H), 3.03 (dd, 1H), 2.87 (s,

[0930] (2-oxopyrrolidin-1-yl)phenyl)thiophene-2- 3H), 2.52 (t, 2H), 2.22 (s, carbonyl)piperazin-2-one 3H), 2.12 - 2.04 (m, 2H)

[0931] Hn 7.73 (d, 1H), 6.98-7.05 (m, / N'V'° 3H) 5.55 (br d, 1H) 4.77

[0932] N^\ o (br dd, 1H) 4.20-4.28 (m,

[0933] 1H) 3.99 (dd, 1H) 3.62- 0.87 (A) 72 3.73 (m, 1H) 3.41-3.59 (m,

[0934] 1H) 3.31 (br s, 8H) 3.19 472.2 / X^-N (dd, 1 H) 2.86 (s, 3H) 2.65- [M+H]

[0935] \ (R)-7-(2-+

[0936] 2.69 (m, 3H) 1.82-2.04 (m,

[0937] ((S)-2-ethyl-4-methyl-3-oxopiperazine-1-carbonyl)- 2H) 1.30 (d, 4H) 0.84-0.96

[0938] 4-methylthiazol-5-yl)-N,2-dimethyl-2,3-dihydro-4H- (m, 4H)

[0939]

[0940] benzo[b][1,4]oxazine-4-carboxamidePAT065083-PCT-SEC01

[0941] Ex1H-NMR LC-MS. Structure and Name tR [min] No. (400 MHz, DMSO-d₆)

[0942] d [ppm] (Method) m / z

[0943] =< R>H l ° i

[0944] (S)-4-(5-(4-((3R,5R)-3,5-dimethyl-2-oxopyrrolidin-1- yl)phenyl)-4-methylthiazole-2-carbonyl)-1,3- dimethylpiperazin-2-one;

[0945] rs>H l ° i

[0946] ' A y -N4;r°

[0947] y-N

[0948] (S)-4-(5-(4-((3R,5S)-3,5-dimethyl-2-oxopyrrolidin-1- yl)phenyl)-4-methylthiazole-2-carbonyl)-1,3- 0.88 (A) dimethylpiperazin-2-one;

[0949] 74 441.2

[0950] [M+H]+ Xy^ ^.

[0951] rs>H l ° i

[0952] y-N

[0953] (S)-4-(5-(4-((3S,5S)-3,5-dimethyl-2-oxopyrrolidin-1- yl)phenyl)-4-methylthiazole-2-carbonyl)-1,3- dimethylpiperazin-2-one; or

[0954] ysi jP

[0955] =< R>H l ° i

[0956] y-N

[0957] (S)-4-(5-(4-((3S,5R)-3,5-dimethyl-2-oxopyrrolidin-1- yl)phenyl)-4-methylthiazole-2-carbonyl)-1,3- dimethylpiperazin-2-one

[0958] 7.69 (m, 2H), 7.61 (m, 2H),

[0959] 6.75 (s, 1 H), 4.95 (br d,

[0960] 1H) 4.81-4.87 (m, 2H),

[0961] 4.22 (t, 1H), 3.91 (s, 3H), 0.58 (A) 3.72 (dd, 1H), 3.56-3.63 75 (m, 1H), 3.45-3.52 (m, 426.4 1H), 3.23-3.31 (m, 1H), [M+H]+(S)-3-(4-(3-((S)-2-Ethyl-4-methyl-3-oxopiperazine- 2.86 (s, 3H), 1.92-1.98 (m,

[0962] 1 -carbonyl)-1 -methyl- 1 H-pyrazol-5-yl)phenyl)-5- 1H), 1.79-1.90 (m, 1H),

[0963] methyloxazolidin-2-one; or 1.44 (d, 3H), 0.90 (t, 3H)

[0964]

[0965] PAT065083-PCT-SEC01

[0966] LC-MS Ex.1H-NMR

[0967] S tR [min] No. tructure and Name (400 MHz, DMSO-d₆)

[0968] d [ppm] (Method) m / z

[0969] (R)-3-(4-(3-((S)-2-Ethyl-4-methyl-3-oxopiperazine- 1 -carbonyl)-1 -methyl- 1 H-pyrazol-5-yl)phenyl)-5- methyloxazolidin-2-one

[0970] 10.16 (s, 1H), 9.16 (bs,

[0971] 1H), 8.72 (d, 1H), 8.35 (t,

[0972] 2H), 8.19-8.09 (m, 1 H),

[0973] 7.95 (s, 1H), 7.82 (s, 3H),

[0974] 7.68 (d, 2H), 7.66-7.62

[0975] (m, 2H), 7.58 (d, 2H),

[0976] 7.34-7.28 (m, 2H), 7.09

[0977] (d, 2H), 6.62 (d, 2H), 6.57 0.65 (A) 76 so3(t, 1H), 6.29 (dd, 2H), 4.55

[0978] 2-((1 E,3E)-5-((E)-1 -((S)-1 -(5-(4-acetamidophenyl)- (td, 1H), 4.18-4.01 (m, 1272.6 4-chlorothiophen-2-yl)-3-(4-hydroxybenzyl)-1,4,18- 4H), 3.52-3.45 (m, 8H), [M+H]+trioxo-8,11,14-trioxa-2,5,17-triazatricosan-23-yl)- 3.36-3.30 (m, 6H), 3.24- 3,3-dimethyl-5-sulfoindolin-2-ylidene)penta-1,3- 3.18 (m, 2H), 3.15 (q, 2H),

[0979] dien-1 -yl)-1 -ethyl-3,3-dimethyl-3H-indol-1 -ium-5- 2.95 (dd, 1 H), 2.79 (dd,

[0980] sulfonate 1H), 2.12-1.99 (m, 5H),

[0981] 1.68 (s, 14H), 1.52 (p, 2H),

[0982] 1.31 (p, 2H), 1.25 (t, 3H)

[0983]

[0984] In another embodiment of the disclosure, the compounds of the present disclosure are enantiomers. In some embodiments the compounds are the (S)-enantiomer. In other embodiments the compounds are the (R)-enantiomer. In yet other embodiments, the compounds of the present disclosure may be (+) or (-) enantiomers.

[0985] It should be understood that all isomeric forms are included within the present disclosure, including mixtures thereof. If the compound contains a double bond, the substituent may be in the E or Z configuration. If the compound contains a disubstituted cycloalkyl, the cycloalkyl substituent may have a cis- or trans configuration. All tautomeric forms are also intended to be included.

[0986] Compounds of the disclosure, and pharmaceutically acceptable salts, hydrates, solvates, and stereoisomers thereof may exist in their tautomeric form (for example, as an amide or imino ether). All such tautomeric forms are contemplated herein as part of the present disclosure.

[0987] The compounds of the disclosure may contain asymmetric or chiral centers and, therefore, exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the compounds of the disclosure as well as mixtures thereof, including racemic mixtures, form part of the present disclosure. In addition, the present disclosure embraces all geometric and positional isomers. For example, if a compound of the disclosure incorporates a double bond or a fused ring, both the cis- and trans-forms, as well as mixtures, are embraced within the scopePAT065083-PCT-SEC01 of the disclosure. Each compound herein disclosed includes all the enantiomers that conform to the general structure of the compound. The compounds may be in a racemic or enantiomerically pure form, or any other form in terms of stereochemistry. The assay results may reflect the data collected for the racemic form, the enantiomerically pure form, or any other form in terms of stereochemistry.

[0988] Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods well known to those skilled in the art, such as, for example, by chromatography and / or fractional crystallization. Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Mosher’s acid chloride), separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure enantiomers. Also, some of the compounds of the disclosure may be atropisomers (e.g., substituted biaryls) and are considered as part of this disclosure. Enantiomers can also be separated by use of a chiral HPLC column.

[0989] It is also possible that the compounds of the disclosure may exist in different tautomeric forms, and all such forms are embraced within the scope of the disclosure and chemical structures and names. Also, for example, all keto-enol and imine-enamine forms of the compounds are included in the disclosure.

[0990] All stereoisomers (for example, geometric isomers, optical isomers, and the like) of the present compounds (including those of the salts, solvates, and esters of the compounds), such as those which may exist due to asymmetric carbons on various substituents, including enantiomeric forms (which may exist even in the absence of asymmetric carbons), rotameric forms, atropisomers, and diastereomeric forms, are contemplated within the scope of this disclosure, as are positional isomers (such as, for example, 4-pyridyl and 3-pyridyl). Individual stereoisomers of the compounds of the disclosure may, for example, be substantially free of other isomers, or is admixed, for example, as racemates or with all other, or other selected, stereoisomers.

[0991] The chiral centers of the compounds of the disclosure can have the S or R configuration as defined by the IUPAC 1974 Recommendations. In certain embodiments, each asymmetric atom has at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess in the (R)- or (S)-configuration. Substituents at atoms with unsaturated double bonds may, if possible, be present in cis-(Z)- or trans-(E)- form.

[0992] The use of the terms “salt”, “solvate”, “ester,” and the like, is intended to equally apply to the salt, solvate, and ester of enantiomers, stereoisomers, rotamers, tautomers, positional isomers, or racemates of the inventive compounds.PAT065083-PCT-SEC01 The compounds of the disclosure may form salts which are also within the scope of this disclosure. Reference to a compound of any of the Formulae disclosed herein is generally understood to include reference to salts thereof, unless otherwise indicated.

[0993] The compounds and intermediates may be isolated and used as the compound per se. Any formula given herein is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds. Isotopically labeled compounds have structures depicted by the formulae given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into compounds of the disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, and, such as2H,3H,11C,13C,14C,15N,18F,31P,32P, respectively. The disclosure includes various isotopically labeled compounds as defined herein, for example those into which radioactive isotopes, such as3H,13C, and14C, are present. Such isotopically labelled compounds are useful in metabolic studies (with14C), reaction kinetic studies (with, for example2H or3H), detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays, or in radioactive treatment of patients. In particular, an18F,11C or labeled compound may be particularly desirable for PET or SPECT studies.

[0994] Further, substitution with heavier isotopes, particularly deuterium (i.e.,2H or D) may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life, reduced dosage requirements, reduced CYP450 inhibition (competitive or time dependent) or an improvement in therapeutic index. For example, substitution with deuterium may modulate undesirable side effects of the undeuterated compound, such as competitive CYP450 inhibition, time dependent CYP450 inactivation, etc. It is understood that deuterium in this context is regarded as a substituent in compounds of the present disclosure. The concentration of such a heavier isotope, specifically deuterium, may be defined by the isotopic enrichment factor. The term “isotopic enrichment factor” as used herein means the ratio between the isotopic abundance and the natural abundance of a specified isotope. If a substituent in a compound of this disclosure is denoted deuterium, such compound has an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation).

[0995] Isotopically-labeled compounds of the present disclosure can generally be prepared by conventional techniques known to those skilled in the art or by carrying out the proceduresPAT065083-PCT-SEC01 disclosed in the schemes or in the examples and preparations described below using an appropriate isotopically-labeled reagent in place of the non-isotopically labeled reagent.

[0996] Pharmaceutically acceptable solvates in accordance with the disclosure include those wherein the solvent of crystallization may be isotopically substituted, e.g., D2O, d6-acetone, d6-DMSO.

[0997] The present disclosure relates to compounds which are modulators of STAT6 activity. In one embodiment, the compounds of the present disclosure decrease STAT6 activity. In yet one embodiment, the compounds of the present disclosure reduce STAT6 activity. In another embodiment, the compounds of the present disclosure are inhibitors of STAT6 activity.

[0998] In some embodiments, the compounds of the disclosure are selective over other proteins. As used herein “selective modulator”, “selective inhibitor”, or “selective compound” means, for example, a compound of the disclosure, that effectively modulates, decreases, or reduces the levels of a specific protein activity to a greater extent than any other protein. A “selective modulator”, “selective inhibitor”, or “selective compound” can be identified, for example, by comparing the ability of a compound to modulate, decrease, or reduce the levels of or to inhibit a specific protein to its ability to modulate, decrease, or reduce the levels of its activity. In some embodiments, the selectivity can be identified by measuring the EC50or IC50of the compounds.

[0999] In some embodiments, the compounds of the present application are selective STAT6 modulators. As used herein “selective STAT6 modulator”, “selective STAT6 inhibitor”, or “selective STAT6 compound” refers to a compound of the application, for example, that effectively modulates, decrease, or reduces the levels of STAT6 activity to a greater extent than any other protein.

[1000] Potency of can be determined by IC50 value. A compound with a lower IC50 value, as determined under substantially similar conditions, is a more potent inhibitor relative to a compound with a higher IC50 value. In some embodiments, the substantially similar conditions comprise determining inhibition of protein levels in cells expressing the specific protein, or a fragment of any thereof.

[1001] The disclosure is directed to compounds as described herein and pharmaceutically acceptable salts, hydrates, solvates, stereoisomers, or tautomers thereof, and pharmaceutical compositions comprising one or more compounds as described herein, or pharmaceutically acceptable salts, hydrates, solvates, stereoisomers, or tautomers thereof.

[1002] METHOD OF SYNTHESIZING THE COMPOUNDS OF THE DISCLOSURE

[1003] All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g. "such as”) provided herein is intended merely to better illustrate the disclosure and does not pose a limitation on the scope of the disclosure otherwise claimed.

[1004] The compounds of the present application can be prepared by those skilled in the art of organic synthesis using commercially available starting materials, compounds known in thePAT065083-PCT-SEC01 literature, or from readily prepared intermediates, by employing standard synthetic methods and procedures either known to those skilled in the art, or which will be apparent to the skilled chemist in light of the teachings herein.

[1005] The compounds of Formula (I) may be prepared by methods as set forth in the following synthetic reaction schemes. In the schemes described below, it is well understood that protecting groups for sensitive or reactive groups are employed where necessary in accordance with general principles of chemistry. Protecting groups are manipulated according to standard methods of organic synthesis as described for example in Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons: New York, 1999 or Protecting Groups, 3rd edition, Thieme, Stuttgart, 2004. Protective groups are removed at a convenient stage of the compound synthesis using methods that are readily apparent to those skilled in the art.

[1006] Those skilled in the art will recognize if a stereocenter exists in the compounds disclosed herein. Resolution of the final product, an intermediate, or a starting material may be affected by any suitable method known in the art. See, for example, " Stereochemistry of Organic Compounds" by E. L. Eliel, S. H. Wilen, and L. N. Mander (Wiley-lnterscience, 1994).

[1007] Compounds of the present disclosure can be synthesized by following the steps outlined in Schemes. Starting materials are either commercially available or made by known procedures in the reported literature or as illustrated.

[1008] In the following general methods, X, ring B and R1to R6are as previously defined in the above embodiments, or limited to designations in the Schemes. PG is a suitable protecting group. Unless otherwise stated, starting materials are either commercially available or are prepared by known methods.

[1009]

[1010] Intermediates 4

[1011] Scheme 1

[1012] Carboxamide containing compounds of Formula (I) can be prepared according to general routes A or B outlined in Scheme 1.PAT065083-PCT-SEC01 Route A: In a palladium assisted cross coupling reaction a suited boronic acid, boronic acid ester or tributylstannane (Intermediates 1) is reacted with a bromoaryl I bromoheteroaryl carboxylic acid or carboxylic acid ester to afford Intermediates 3. In a second step the target compounds of Formula (I) are obtained by coupling with a suitable amine (Intermediates 2).

[1013] Route B: Reverse order synthesis, in the first step a suited bromoaryl I bromoheteroaryl carboxylic acid is reacted with an amine to afford halo-functionalized carboxamides (Intermediates 4) which are then cross-coupled with a suitable intermediate 1 to obtain the target compounds of Formula (I).

[1014] R4 R4bO 1. Deprotection 2. HNR5R6(intermediate 2) Cu-assisted Ullmann-type Hal = Br, I coupling from intermediate 1

[1015]

[1016] syntheses Scheme 2

[1017] N-linked derivatives outlined in Scheme 2 can be prepared in a similar way as via Route A shown in Scheme 1: In a first step a suited aryl / heteroaryl halide (as used in the preparation of corresponding Intermediate 1) is coupled to an azole carboxylic ester via an Ullmann-type coupling. Final compounds can then be prepared by hydrolysis of the N-arylated ester formed followed by coupling with a suitable amine (Intermediates 2).

[1018] 1. Deprotection 2. 4-NPC Pd-assisted cross coupling

[1019] Intermediate 1

[1020]

[1021] Scheme 3

[1022] Urea-type compounds can be prepared as outlined in Scheme 3: First, a suited boronic acid, boronic acid ester or tributylstannane (Intermediates 1) is coupled with an appropriately

[1023] N-protected bromoazole. The obtained product is then deprotected and activated with 4-NPC. Reaction with a suitable amine (Intermediates 2) results in the formation of the desired urea compounds. The disclosure further includes any variant of the present processes, in which anPAT065083-PCT-SEC01 intermediate product obtainable at any stage thereof is used as starting material and the remaining steps are carried out, or in which the starting materials are formed in situ under the reaction conditions, or in which the reaction components are used in the form of their salts or optically pure material. Compounds of the disclosure and intermediates can also be converted into each other according to methods generally known to those skilled in the art.

[1024] In another aspect, the present disclosure provides a pharmaceutical composition comprising a compound of the present disclosure, i.e. a compound according to any one of embodiments 1 to 39, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[1025] In a further embodiment, the composition comprises at least two pharmaceutically acceptable carriers, such as those described herein. The pharmaceutical composition can be formulated for particular routes of administration such as oral administration, parenteral administration (e.g. by injection such as intratendinous, intraligamentous, peritendinous or periligamentous administration, infusion, transdermal or topical administration), and rectal administration. Topical administration may also pertain to inhalation or intranasal application. For topical administration the pharmaceutical compositions of the present disclosure can be made up, for example, as creams, ointments or gels. The pharmaceutical compositions of the present disclosure can be made up in a solid form (including, without limitation, capsules, tablets, pills, granules, powders or suppositories), or in a liquid form (including, without limitation, solutions, suspensions or emulsions). Certain injectable compositions are aqueous isotonic solutions or suspensions. Said compositions may be sterilized and / or contain adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure and / or buffers. In addition, they may also contain other therapeutically valuable substances. Said compositions are prepared according to conventional mixing, granulating or coating methods, respectively, and contain about 0.1-75%, or contain about 1-50%, of the active ingredient. Tablets may be either film coated or enteric coated according to methods known in the art. Typically, the pharmaceutical compositions are tablets or gelatin capsules comprising the active ingredient together with one or more of:

[1026] a) diluents, e.g., lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine; b) lubricants, e.g., silica, talcum, stearic acid, its magnesium or calcium salt and / or polyethyleneglycol; for tablets also

[1027] c) binders, e.g., magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone; if desired

[1028] d) disintegrants, e.g., starches, agar, alginic acid or its sodium salt, or effervescent mixtures; and

[1029] e) absorbents, colorants, flavors and sweeteners.

[1030] Crystalline forms may be prepared by a variety of methods, including for example, crystallization or recrystallization from a suitable solvent, sublimation, growth from a melt, solid state transformation from another phase, crystallization from a supercritical fluid, and jetPAT065083-PCT-SEC01 spraying. Techniques for crystallization or recrystallization of crystalline forms from a solvent mixture include, for example, evaporation of the solvent, decreasing the temperature of the solvent mixture, crystal seeding a supersaturated solvent mixture of the molecule and / or salt, freeze drying the solvent mixture, and addition of antisolvents (countersolvents) to the solvent mixture. High throughput crystallization techniques may be employed to prepare crystalline forms including polymorphs.

[1031] EXAMPLES

[1032] The disclosure is further illustrated by the following examples and synthetic methods, which are not to be construed as limiting this disclosure in scope or spirit to the specific procedures herein described. It is to be understood that the examples are provided to illustrate certain embodiments and that no limitation to the scope of the disclosure is intended thereby. It is to be further understood that resort may be had to various other embodiments, modifications, and equivalents thereof which may suggest themselves to those skilled in the art without departing from the spirit of the present disclosure and / or scope of the appended claims.

[1033] The compounds of the present disclosure can be produced by organic synthesis methods known to one of ordinary skill in the art as shown in the following examples. All starting materials, building blocks, reagents, acids, bases, dehydrating agents, solvents, and catalysts utilized to synthesize the compounds of the present disclosure are either commercially available or can be produced by organic synthesis methods known to one of ordinary skill in the art. In all of the methods it is understood that protecting groups for sensitive or reactive groups may be employed where necessary in accordance with general principles of chemistry. Protecting groups are manipulated according to standard methods of organic synthesis (T. W. Green and P. G. M. Wuts (2014) Protective Groups in Organic Synthesis, 5th edition, John Wiley & Sons). These groups are removed at a convenient stage of the compound synthesis using methods that are readily apparent to those skilled in the art. Unless otherwise noted, reagents and solvents were used as received from commercial suppliers.

[1034] The chemical names were generated using ChemDraw Professional v17.1.0.105 from PerkinElmer.

[1035] Temperatures are given in degrees Celsius. As used herein, unless specified otherwise, the term “room temperature” or “ambient temperature” means a temperature of from 15°C to 30°C, such as from 20°C to 30°C, such as of from 20°C to 25°C. If not mentioned otherwise, all evaporations are performed under reduced pressure, typically between about 15 mm Hg and 100 mm Hg (= 20 - 133 mbar). The structure of final products, intermediates and starting materials is confirmed by standard analytical methods, e.g., microanalysis and spectroscopic characteristics, e.g., MS, IR, NMR. Abbreviations used are those conventional in the art.

[1036] ABBREVIATIONS

[1037] Abbreviations used are those conventional in the art unless defined as the following:PAT065083-PCT-SEC01 ABPR automated back-pressure regulator

[1038] Ac acetyl

[1039] ACN acetonitrile

[1040] aq. aqueous

[1041] Boc tert-butyloxycarbonyl

[1042] B2pin2 bis(pinacolato)diborane

[1043] calc’d calculated

[1044] °C degree Celsius

[1045] DCM dichloromethane

[1046] DEA diethylamine

[1047] DIBAL diisobutylaluminum hydride

[1048] DIPEA N, N-diisopropylethylamine

[1049] DME 1,2’dimethoxyethane

[1050] DMEDA N, N’-dimethylethylenediamine

[1051] DMF N, N-dimethylformamide

[1052] DMSO dimethylsulfoxide

[1053] dppf 1, 1 ’-bis(diphenylphosphino)ferrocene

[1054] dtbpf 1, 1 ’-bis(di-t-butylphosphino)ferrocene

[1055] ESI electro spray ionization

[1056] eq. equivalent

[1057] Et ethyl

[1058] Et20 diethyl ether

[1059] Et3N triethylamine

[1060] EtOAc ethyl acetate

[1061] EtOH ethanol

[1062] FA formic acid

[1063] g gram

[1064] h hour(s)

[1065] HATU 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid-hexafluorophosphate

[1066] HCI hydrochloric acid

[1067] HPLC high performance liquid chromatography

[1068] HV high vacuum

[1069] Im imidazole

[1070] K3PO4 potassium phosphate tribasic

[1071] L liter

[1072] LC liquid chromatography

[1073] LCMS liquid chromatography and mass spectrometryPAT065083-PCT-SEC01

[1074] LiOH lithium hydroxide

[1075] M molar

[1076] Me methyl

[1077] MeOH methanol

[1078] mg milligram

[1079] mmol millimole

[1080] MS mass spectrometry

[1081] min minutes

[1082] mL milliliter(s)

[1083] m / z mass to charge ratio

[1084] nm nanometer

[1085] nM nanomolar

[1086] N normal

[1087] Na2SO4sodium sulfate

[1088] NaH sodium hydride

[1089] NaHCO3sodium bicarbonate

[1090] NaHMDS sodium bis(trimethylsilyl)amide

[1091] NaOH sodium hydroxide

[1092] NH4CI ammonium chloride

[1093] NMM N-methylmorpholine

[1094] 4-NPC 4-Nitrophenyl chloroformate

[1095] Pd(dppf)CI2[1, T-bis(diphenylphosphino)ferrocene]palladium(ll) dichloride Pd(dtbpf)CI2[1,1 ’-bis(di-t-butylphosphino)ferrocene]palladium(l I) dichloride PE petroleum ether

[1096] POCl3phosphorous oxychloride

[1097] RT, rt or r.t. room temperature

[1098] sat. saturated

[1099] SEM 2-(T rimethylsilyl)ethoxymethyl

[1100] SFC supercritical fluid chromatography

[1101] T3P propylphosphonic anhydride solution

[1102] TBAB tetrabutylammonium bromide

[1103] TBAF tetrabutylammonium fluoride

[1104] TBDMS tert-butyldimethylsilyl

[1105] TEA triethyl amine

[1106] TEMED N, N, N’, N’-T etramethylethylenediamine

[1107] TFA trifluoroacetic acid

[1108] THF tetrahydrofuran

[1109] Ts tosylPAT065083-PCT-SEC01 uPLC ultra performance liquid chromatography

[1110] GENERAL CONDITIONS:

[1111] NMR Spectroscopy: NMR spectra were obtained using Bruker Ultrashield™ spectrometers. All1H-NMR spectra are reported in 5 units (ppm) and were recorded in e.g. CDCh, DMSO-de or CD3OD and referenced to the solvent peaks. Spectra splitting patterns are designated as singlet (s), doublet (d), doublet of doublets (dd), doublet of triplets (dt), doublet of quartets (dq), triplet (t), triplet of doublets (td), quartet (q), quartet of doublets (qd), quintet (quint), septet (sep), multiplet, unresolved or overlapping signals (m), broad signal (br).

[1112] Analytical liquid chromatography: Waters Acquity uPLC / MS systems (Waters, Milford, MA) equipped with a binary solvent manager, a sample manager, a column manager, a photodiode array detector (PDA) and a Waters ZQ2000 MS detector. UV absorption was monitored at A = 210-450 nM. The MS detector was operated in continuously positive / negative ESI alternating mode with full scan from 120-1200 Da in 0.3 seconds. Mass spectra were acquired and stored in centroid mode. MS based confirmation of molecular weight was based on the formation of the pseudo-molecular ions [M+H]+in positive mode. In case of chlorine and bromine containing compounds the m / z values for the two naturally occurring isotope are reported.

[1113] Analytical HPLC, Method A: Column: CORTECS™ C18+ 2.7 μm, column dimension: 2.1x50 mm, column temperature: 80 °C; gradient: from 5 to 50% B in 1.4 min; 50 to 98% B in 0.3 min, flow: 1.0 mL / min; Eluent A: water + 0.05% formic acid + 3.75 mM ammonium acetate; Eluent B: isopropanol + 0.05% formic acid.

[1114] Analytical HPLC, Method B: Column: XBridge™ BEH C18 2.5 μm, column dimension:

[1115] 2.1x50 mm, column temperature: 80 °C; gradient: from 2 to 98% B in 1.4 min, 98% B 0.4 min, flow: 1.0 mL / min; Eluent A: water + 5 mM NH3, eluent B: acetonitrile + 5 mM NH3.

[1116] PREPARATION OF INTERMEDIATES:

[1117] Intermediate 1-1: 1-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-quinolin-1(2H)-yl)ethan-1-one

[1118]

[1119] Step 1: 1-(6-bromo-3,4-dihydroquinolin-1(2H)-yl)ethan-1-one

[1120] To a solution of 6-bromo-1,2,3,4-tetrahydroquinoline (75 g, 0.36 mol) and DIPEA (115 g, 0.89 mol) in DCM (750 mL) at 0 °C, was added AcCI (31 g, 0.39 mol) in dropwise way. The reaction mixture was stirred at room temperature for 1.5 h. The reaction mixture was quenchedPAT065083-PCT-SEC01 with water (3.25 L). The aq. layer was extracted with DCM (7.5 L); the combined organic layer was washed with brine (3.25 L), dried over Na2SO4and concentrated in vacuo to give the title compound as a light red oil:1H-NMR (300 MHz, CDCl3) 57.14-7.10 (m, 3H), 3.61-3.57 (m, 2H), 2.56-2.52 (m, 2H), 2.05 (s, 3H), 1.83-1.74 (m, 2H); MS (ESI): m / z = 254.0, 256.0 [M+H]+.

[1121] Step 2: 1-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-quinolin-1 (2H)-yl)ethan-1-one

[1122] CW <

[1123] A solution of 1-(6-bromo-3,4-dihydroquinolin-1(2H)-yl)ethan-1-one (75 g, 0.3 mol), bis(pinacolato) diboro 0n (113 g, 0.44 mol), KOAc (93 g, 0.95 mol) and Pd(dppf)Cl2’CH2Cl2 (24 g, 0.03 mol) in dioxane (0.75 L) w oo O-a \ 1s heated to 90 °C for 1.5 h. After the mixture reached rt, it was 7 o —

[1124] filtered, concentrated, and purified by flash chromatography (0%-90% EtOAc / PE). The crude product was triturated with n-heptane to afford the title compound as a colorless solid:1H NMR (300 MHz, DMSO-d6) 57.48-7.46 (m, 3H), 3.67-3.65 (m, 2H), 2.72-2.69 (m, 2H), 2.17 (s, 3H), 1.87-1.84 (m, 2H), 1.28 (s, 12H); MS (ESI): m / z = 302.2 [M+H]+.

[1125] The following intermediates 1 can be prepared by the same procedure using the appropriate starting materials:

[1126] LC tR[min] MS (ESI)

[1127] Structu co Or —e

[1128] (Method) m / z [M+H]+

[1129] A ° \ / 1.02

[1130] 1-2 304.2

[1131] (A)

[1132] 1.09

[1133] 1-3 320.2

[1134] OC^B.o (A)

[1135] 1.23

[1136] 1-4 332.2

[1137] (A)

[1138] 6^

[1139] 1.23 425.2

[1140] 1-5

[1141] (A) [M+Na]+

[1142]

[1143] PAT065083-PCT-SEC01 Intermediate 1-6: 1-(3-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroquinolin-1(2H)-yl)ethan-1-one

[1144]

[1145] Step 1: 6-bromo-3-methyl-1,2,3,4-tetrahydroquinoline

[1146] To a solution of 3-methyl-1,2,3,4-tetrahydroquinoline (Enamine EN300-69783 CAS 20668-20-6, 418 mg, 92 wt%, 2.61 mmol, 1 eq) in DCM (10 mL) was added portion wise NBS (456 mg, 2.56 mmol, 0.98 eq) at 0°C and stirring was continued for 10 min at 0°C. Then, saturated aqueous NaHCO3(25 mL) and heptane (25 mL) was added. The organic phase was washed three times with water, once with brine, dried over Na2SO4, and evaporated to dryness. The crude product was purified by flash chromatography on silica gel (80 g cartridge, DCM I heptane gradient) to afford the desired product as colorless oil: uPLC retention time: 1.30 min (method A); MS (ESI): m / z = 226.1 / 228.1 [M+H]+.

[1147] Step 2: 1-(6-bromo-3-methyl-3,4-dihydroquinolin-1(2 / 7)-yl)ethan-1-one

[1148] To a solution of 6-bromo-3-methyl-1,2,3,4-tetrahydroquinoline (440 mg, 1.95 mmol, 1 eq) in DCM (15 mL) was added triethylamine (0.81 mL, 0.59 g,, 5.84 mmol, 3 eq) and acetyl chloride (0.18 mL, 0.2 g, 2.53 mmol, 1.3 eq). The reaction mixture was stirred for 5 min at RT and then quenched by adding saturated aqueous NaHCO3(25 mL). The aqueous layer was extracted once with DCM. The combined organic layers were dried over Na2SO4and evaporated to dryness. The crude product was purified by flash chromatography on silica gel (40 g cartridge, MeOH I DCM gradient) to afford the title compound as colorless oil: uPLC retention time: 1.11 min (method A); MS (ESI): m / z = 268.0 / 270.0 [M+H]+.

[1149] Step 3: 1-(3-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroquinolin-1(2 / 7)-yl)ethan-1-one

[1150] To an argon flushed solution of 1-(6-bromo-3-methyl-3,4-dihydroquinolin-1(2H)-yl)ethan-1-one (448 mg, 1.67 mmol, 1 eq) in 1,4-dioxane (10 mL) was added bis(pinacolato)diboron (509 mg, 2.00 mmol, 1.2 eq), PdCl2(dppf)OCH2Cl2 adduct (96 mg, 0.12 mmol, 7 mol%) and potassium acetate (492 mg, 5.01 mmol, 3 eq). The reaction mixture was stirred at 90°C for 12h under argon in a sealed vial. The reaction mixture was evaporated to dryness and taken up in EtOAc (50 mL). The solution was washed with saturated aqueous NaHCO3 and brine. The organic layer was dried over Na2SO4and evaporated to dryness. Flash chromatography of the crude on silica gel (80 g cartridge, EtOAc / heptane gradient) afforded the title compound as colorless oil: uPLC retention time: 1.23 min (method A); MS (ESI): m / z = 277.0 / 278.0 [M+H]+. Intermediate 1-7: (R)-1-(2-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-onePAT065083-PCT-SEC01

[1151]

[1152] The title compound was prepared according to the procedure for intermediate 1-6 starting from (R)-7-bromo-2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine (G. Zhou et al., ACS Med. Chem. Lett. 2014, 5, 544-549, CAS 1245708-21-7).

[1153] Colorless solid: uPLC retention time 1.13 min (Method A);1H-NMR (400 MHz, DMSO-d₆) 5 7.78 (brs, 1H), 7.15 (dd, 1H), 7.09 (d, 1H), 4.32 (cm, 1H), 4.03-4.22 (br m, 1H), 3.22-3.45 (br m, 1H), 2.25 (s, 3H), 1.27 (s, 12H); m / z = 318.3 [M+H]+.

[1154] Intermediate 1-8: methyl (R)-2-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazine-4-carboxylate

[1155]

[1156] The title compound was prepared according to the procedure for intermediate 1-6 starting from (R)-7-bromo-2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine (G. Zhou et al., ACS Med. Chem. Lett. 2014, 5, 544-549, CAS 1245708-21-7) and substituting acetyl chloride by methyl chloro-formate in step2.

[1157] Yellowish oil: uPLC retention time 1.24 min (method A);1H-NMR (400 MHz, DMSO-d₆) 5 7.86 (d, 1H), 7.17 (dd, 1H), 7.08 (d, 1H), 4.27 (ddd, 1H), 4.12 (dd, 1H), 3.74 (s, 3H), 3.27 (dd, 1H), 1.27 (s, 12H), 1.08 (d, 3H); m / z = 334.2 [M+H]+.

[1158] Intermediate 1-9: (R)-2-methyl-4-(methylsulfonyl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine

[1159]

[1160] The title compound was prepared according to the procedure for intermediate 1-6 starting from (R)-7-bromo-2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine (G. Zhou et al., ACS Med. Chem. Lett. 2014, 5, 544-549, CAS 1245708-21-7) and substituting acetyl chloride by methanesulfonylchloride in step 2.PAT065083-PCT-SEC01 Beige solid: uPLC retention time 1.11 min (Method A);1H-NMR (400 MHz, DMSO-d₆) 57.62 (d, 1H), 7.19 (dd, 1H), 7.06 (d, 1H), 4.28 (cm, 1H), 4.09 (dd, 1H), 3.21 (dd, 1H), 3.14 (s, 3H), 1.27 (s, 12H); m / z = 371.2 [M+NH4]+.

[1161] Intermediate 1-10: 1-(3-(((tert-butyldimethylsilyl)oxy)methyl)-6-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-3,4-dihydroquinolin-1(2H)-yl)ethan-1-one

[1162]

[1163] Step 1: 6-bromo-1,2,3,4-tetrahydroquinolin-3-yl)methanol

[1164] To a mixture of 2M LiAlH4in THF (1.22 mL, 2.44 mmol, 2.5 eq) and dry THF (3 mL) was slowly added a solution of 6-bromo-1,2,3,4-tetrahydroquinoline-3-carboxylic acid (J& W PharmLab JWPH3249EA71, CAS: 885278-13-7, 250 mg, 0.98 mmol, 1 eq) in dry THF (3 mL) at 0 °C under argon. The reaction mixture was then stirred at RT for 3h. The reaction was quenched by careful addition of water at 0°C. The obtained mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous NaHCO3and the aqueous layer back extracted twice with ethyl acetate. The combined organic phases were dried over Na2SO4and evaporated under reduced pressure. The high vacuum dried material was sufficiently pure to be used in the next step: uPLC retention time: 0.75 min (method A); MS (ESI): m / z = 242.1 / 244.1 [M+H]+.

[1165] Step 2: 6-bromo-3-(((tert-butyldimethylsilyl)oxy)methyl)-1,2,3,4-tetrahydroquinoline

[1166] A mixture of (6-bromo-1,2,3,4-tetrahydroquinolin-3-yl)methanol (80 mg, 0.31 mmol, 1 eq), TBDMS-CI (99 mg, 0.66 mmol, 2.1 eq) and imidazole (75 mg, 1.10 mmol, 3.5 eq) in anhydrous DMF (1 mL) was stirred at RT for 4.5h. Then, the reaction mixture was poured into saturated aqueous NaHCO3and extracted twice with ethyl acetate. The organic extracts were dried over Na2SO4and evaporated under reduced pressure. The crude material was purified by flash chromatography on silica gel (12 g cartridge, EtOAc I cyclohexane gradient) to afford the title compound: uPLC retention time 1.72 min (method A); MS (ESI): m / z = 356.2 I 358.2 [M+H]+. Step 3: 1-(6-bromo-3-(((tert-butyldimethylsilyl)oxy)methyl)-3,4-dihydroquinolin-1(2H)-yl)ethan-1- one

[1167] To a solution of 6-bromo-3-(((tert-butyldimethylsilyl)oxy)methyl)-1,2,3,4-tetrahydroquinoline (90 mg, 0.25 mmol, 1 eq) in DCM (3 mL) and THF (1 mL) was added acetic acid (1 mL) followed by acetic anhydride (0.12 mL, 1.26 mmol). After stirring for 2h at RT the reaction mixture wasPAT065083-PCT-SEC01 poured into saturated aqueous NaHCO3and extracted twice with ethyl acetate. The organic layer was dried over Na2SO4and evaporated to dryness under reduced pressure. Purification by flash chromatography on silica gel (12 g cartridge, EtOAc / cyclohexane gradient) afforded the title compound: uPLC retention time: 1.65 min (method A); MS (ESI): m / z = 398.21400.2 [M+H]+.

[1168] Step 4: 1-(3-(((tert-butyldimethylsilyl)oxy)methyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroquinolin-1(2H)-yl)ethan-1-one

[1169] To a solution of 1-(6-bromo-3-(((tert-butyldimethylsilyl)oxy)methyl)-3,4-dihydroquinolin-1(2H)-yl)ethan-1-one (99 mg, 0.25 mmol, 1 eq) in 1,4-dioxane (4 mL) was added 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (63 mg, 0.25 mmol, 1 eq) potassium acetate (73 mg, 0.75 mmol, 3 eq) and Pd(dppf)Cl2 (18 mg, 25 pmol, 0.1 eq). After purging with argon the reaction mixture was stirred at 100 °C for 3h. After reaching RT the reaction mixture was diluted with ethyl acetate and then washed with water. The organic layer was dried with Na2SC>4 and evaporated under vacuum. The crude product was purified by flash chromatography on silica gel (12 g cartridge, EtOAc I cyclohexane gradient) to afford the title compound: uPLC retention time: 1.68 min (method A); MS (ESI): m / z = 446.3 [M+H]+.

[1170] Intermediate 1-11: 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1, 3-d i hydro-2 H-imidazo[4,5-b]pyridin-2-one

[1171] Step 1 step 2 Step 3

[1172]

[1173] Step 1: N-(4-bromophenyl)-2-nitropyridin-3-amine

[1174] In a vial were introduced under argon 3-Fluoro-2-nitropyridine (Apollo PC3369, CAS 54231-35-5, 200 mg, 1.41 mmol, 1 eq), 4-bromoaniline (485 mg, 2.82 mmol, 2 eq) and anhydrous DMSO (1mL). The mixture is then stirred at 80°C for 24h. The reaction mixture was taken up in a water (60 mL) I brine (10 mL) mixture and well sonicated. The resulting suspension was filtered and the cake was washed with some water, before being dissolved in EtOAc (70 mL). The organic layer was washed with brine (20 mL), dried over Na2SO4, filtered and evaporated to dryness to obtain the product as orange solid which was used in the next step without further purification: uPLC retention time: 0.99 min (method A); MS (ESI): m / z = 293.9 / 295.9 [M+H]+, Step 2: N3-(4-bromophenyl)pyridine-2,3-diaminePAT065083-PCT-SEC01 In a two-necked flask were introduced under nitrogen N-(4-bromophenyl)-2-nitropyridin-3-amine (420 mg, 1.41mmol, 1 eq), MeOH (15 mL), THF (15 mL), and Raney-Ni (500 mg, 8.52 mmol, 6 eq). The reaction mixture was then flushed with hydrogen and stirred under this atmosphere (~1.1bar) for 20 min at RT. The reaction mixture was filtered over Celite and the catalyst was rinsed with some MeOH. The filtrate was evaporated and the residue was dried under vacuum to afford the product which was used in the next step without further purification: uPLC retention time: 0.48 min (method A); MS (ESI): m / z = 263.9 / 265.9 [M+H]+.

[1175] Step 3: 1-(4-bromophenyl)-1,3-dihydro-2 / 7-imidazo[4,5-b]pyridin-2-one

[1176] To a solution of N3-(4-bromophenyl)pyridine-2,3-diamine (374 mg, 1.41 mmol, 1 eq) in acetonitrile (5 mL) and DMF (3 mL) was added GDI (345 mg, 2.13 mmol, 1.5 eq). The mixture was stirred at RT for 15.75h. The obtained suspension was diluted with water (40 mL) and well sonicated. The precipitated solid was filtered off, washed with water, redissolved in EtOAc / THF 1:1, washed with brine (20 mL), dried over Na2SO4, filtered and evaporated to dryness. The residue was used in the next step without further purification: uPLC retention time: 0.85 min (method A); MS (ESI): m / z = 288.0 / 290.0 [M+H]+.

[1177] Step 4: 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1,3-dihydro-2 / 7-imidazo[4,5-b]pyridin-2-one

[1178] In a vial was added under Ar 1-(4-bromophenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (120 mg, 0.41 mmol, 1 eq), bis(pinacolato)diboron (135 mg, 0.53 mmol, 1.3 eq), and potassium acetate (125 mg, 1.27 mmol, 3.1 eq) to dioxane (5mL). The reaction mixture was flushed with Ar and Pd(dppf)Ch (22 mg, 0.030 mmol, 7 mol%) was added. The vial was sealed and the reaction mixture was stirred for 17.5h at 90°C. Partial conversion was shown by LC / MS. Therefore, DMF (2mL) was added, followed by bis(pinacolato)diboron (85 mg, 0.34 mmol, 0.8 eq) and Pd(dppf)Ch (22 mg, 0.030 mmol, 7 mol%). Stirring was continued under argon at 90°C for 23h. Then, the reaction mixture was taken up in EtOAc (80 mL), washed with brine (20ml), dried over Na2SO4, and evaporated to dryness. The residue was purified by flash chromatography on silica gel (4 g cartridge, DCM I EtOAc gradient to obtain the desired product as a beige solid: uPLC retention time: 1.04 min; MS (ESI): m / z = 338.0 [M+H]+.

[1179] Intermediate 1-12: 5-methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-((2-(trimethylsilyl)ethoxy)methyl)imidazolidine-2, 4-dione

[1180]

[1181] Step 1: 1-(4-bromophenyl)-3-((2-(trimethylsilyl)ethoxy)methyl)imidazolidine-2, 4-dione

[1182] To a solution of 1-(4-bromophenyl)imidazolidine-2, 4-dione (BLD Pharmatech BD00988673, CAS: 32549-34-1, 100 mg, 0.37 mmol, 1 eq) and DIPEA (100. L, 74 mg, 0.57 mmol, 1.5 eq) inPAT065083-PCT-SEC01 DCM I DMF 1:1 (3 mL) was added SEM-CI (70 mg, 0.41 mmol, 1.1 eq) within 5 min at 0°C under argon. Stirring was continued at 0°C for 30min. Then, additional DI PEA (35. L, 26 mg, 0.20 mmol, 0.54 eq) and SEM-CI (25 mg, 0.15 mmol, 0.4 eq) was added. After stirring at 0°C for 2.5h, the reaction mixture was poured into saturated aqueous NaHCO3(30 mL) and extracted with EtOAc 2x 40 mL). The combined organic layers were washed with brine (2x 30mL), dried over Na2SO4, and evaporated to dryness. The crude product was purified by flash chromatography on silica gel (12 g cartridge, EtOAc I cyclohexane gradient) to afford an off-white solid: uPLC retention time: 1.39 min (method A); MS (ESI): m / z = 406.9 / 408.8 [M+Na]+. Step 2: 1-(4-bromophenyl)-5-methyl-3-((2-(trimethylsilyl)ethoxy)methyl)imidazolidine-2, 4-dione To a solution of 1-(4-bromophenyl)-3-((2-(trimethylsilyl)ethoxy)methyl)imidazolidine-2,4-dione (139 mg, 0.36 mmol, 1 eq) in anhydrous DMF (3 mL) was added NaH (60% in oil, 15 mg, 0.38 mmol, 1.05 eq) at 0°C under argon and stirred at 0°C for 15 min. Then, iodomethane (23 |j. L, 52 mg, 0.37 mmol, 1.03 eq) and stirring was continued at RT for 1.25h. The reaction mixture was diluted with saturated aqueous NaHCO3(20 mL) and extracted with EtOAc (2x 40mL). The combined organic layers were washed with brine (2x 20mL), dried over Na2SO4, and evaporated to dryness. The residue was purified by preparative RP-HPLC (column: Waters XSelect CSH C18OBD, 5μm, 30x100mm; flow: 30mL / min; gradient: A H2O[+0.1% TFA], B MeCN 50:50 to 0:100 in 15min.) to afford a brown syrup (still containing 45% starting material): uPLC retention time: 1.44 min (method A); MS (ESI): m / z = 420.9 / 422.8 [M+Na]+.

[1183] Step 3: 5-methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-((2-(trimethylsilyl)-ethoxy)methyl)imidazolidine-2, 4-dione

[1184] To a solution of 1-(4-bromophenyl)-5-methyl-3-((2-(trimethylsilyl)ethoxy)methyl)imidazolidine-2, 4-dione (110 mg, 0.28 mmol, 1 eq) and bis(pinacolato)diboron (91 mg, 0.36 mmol, 1.3 eq) in dioxane (2.5 mL) was added potassium acetate (81 mg, 0.83 mmol, 3 eq). The reaction mixture was flushed with Ar and Pd(dppf)Cl2 (16mg, 0.022 mmol, 8 mol%) was added. The vial was sealed and the reaction mixture was stirred at 90°C for 17h. at 90°C. The reaction mixture was taken up in EtOAc (70 mL), washed with brine (20 mL), dried over Na2SO4, and evaporated to dryness. The residue was purified by flash chromatography on silica gel (4 g cartridge, EtOAc I cyclohexane gradient) afforded a colorless syrup: uPLC retention time: 1.53 min (method A); MS (ESI): m / z = 915.2 [M2Na]+(Purity 55%, product contains 42% 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-((2-(trimethylsilyl)ethoxy)methyl)imidazolidine-2, 4-dione: uPLC retention time: 1.49 min; MS (ESI): m / z = 455.0 [M+H]+, 887.1 [M2Na]+).

[1185] Intermediate 1-13: 4-phenyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrrolidin-2-onePAT065083-PCT-SEC01

[1186]

[1187] Step 1: 1-(4-bromophenyl)-4-phenylpyrrolidin-2-one

[1188] To a solution of 1,4-dibromobenzene (1 g, 4.24 mmol, 1 eq) dioxane (10 mL) was added 4-phenylpyrrolidin-2-one (Synthonix P32385, CAS: 1198-47-6, 1.37 g, 8.48 mmol, 2 eq) and K2CO3 (1.17 g, 8.48 mmol, 2 eq). The reaction mixture was degassed and purged with argon for 10min. Then, TEMED (0.38 mL, 295 mg, 2.54 mmol, 0.6eq) and Cui (242 mg, 1.27 mmol, 0.3 eq) was added and the reaction mixture was stirred at 100°C for 6.5h. Then, DCM (50 mL) was added and washed with water (50 mL). The organic phase was dried (phase separator) and evaporated to dryness. The residue was purified by flash chromatography on silica gel (40 g cartridge, EtOAc / cyclohexane gradient) to afford a colorless solid: uPLC retention time: 1.25 min (method A); MS (ESI): m / z = 316.1 / 318.1 [M+H]+, 631.2 / 633.2 / 635.2 [M2+H]+.

[1189] Step 2: 4-phenyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrrolidin-2-one Under argon, to a solution of 1-(4-bromophenyl)-4-phenylpyrrolidin-2-one (624 mg, 81% wt, 1.60 mmol, 1 eq) in dioxane (5 mL) was added 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (812 mg, 3.20 mmol, 2eq), potassium acetate (471 mg, 4.80 mmol, 3 eq), and Pd(dppf)CI2(117 mg, 0.16 mmol, 0.1 eq). The reaction mixture is stirred at 100 °C for20h. Then, DCM (50 mL) was added and washed with water (50 mL). The organic phase was dried (phase separator) and evaporated to dryness. The residue was purified by flash chromatography on silica gel (40 g cartridge, EtOAc I cyclohexane gradient) to afford intermediate 1-12 as a colorless solid: uPLC retention time: 1.36 min (method A); MS (ESI): m / z = 364.3 [M+H]+.

[1190] Intermediate 1-14: 1-(6-(tributylstannyl)-3,4-dihydro-1,5-naphthyridin-1(2H)-yl)ethan-1-one

[1191] AcCI, DMAP (Bu3Sn)2. Pd(dtbpf)CI2DME DMF

[1192]

[1193] Step 1 Step 2

[1194] Step 1: 1-(6-bromo-3,4-dihydro-1,5-naphthyridin-1(2H)-yl)ethan-1-one

[1195] To a solution of 6-bromo-1,2,3,4-tetrahydro-1,5-naphthyridine (Enamine EN300-235213, CAS: 1219022-46-4, 300 mg, 1.41 mmol, 1 eq) in DME (10 mL) was added acetyl chloride (0.3 mL, 332 mg, 4.22 mmol, 3 eq), and DMAP (9 mg, 70 pmol, 5 mol%). The reaction mixture was stirred at RT for 1h.min. Then, diethyl ether (10 mL) was added and precipitate filtered off. The filtrate was evaporated to dryness leaving a pale yellow oil which was used without furtherPAT065083-PCT-SEC01 purification in the next step: uPLC retention time: 0.55 min (method A); MS (ESI): m / z = 255.1 / 257.1 [M+H]+.

[1196] Step 2: 1-(6-(tributylstannyl)-3,4-dihydro-1,5-naphthyridin-1(2H)-yl)ethan-1-one

[1197] To a solution of 1-(6-bromo-3,4-dihydro-1,5-naphthyridin-1(2 / 7)-yl)ethan-1-one (80 mg, 0.31 mmol 1 eq) in DMF (4 mL) was added 1,1,1,2,2,2-hexabutyldistannane (174 pL, 200 mg, 0.34, mmol, 1.1 eq) and Pd(dtbpf)Cl2 (39 mg, 60 pmol, 0.19 eq). The reaction mixture was purged with argon and stirred at 95°C for 12h. Then, saturated aqueous NaHCO3(20 mL) was added and extracted with heptane (30 mL). The organic phase was washed with brine (30 mL), dried over Na2SO4and evaporated to dryness. The crude product was purified by flash chromatography on silica gel (24 g cartridge, EtOAc I heptane gradient) to afford intermediate 1-13 as yellow oil: uPLC retention time: 1.51 min (method A); MS (ESI): m / z = 463.2 / 465.2 / 467.2 / 468.2 [M+H]+.

[1198] Intermediate 1-15: 1-(6-(tributylstannyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)ethan-1-one

[1199]

[1200] The target compound can be prepared by the same procedure as for 1-14 using 6-bromo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine as starting material.

[1201] Yellow oil: uPLC retention time: 1.67 min (method A); MS (ESI): m / z = 465.2 / 467.2 / 469.2 / 470.2 [M+H]+.

[1202] Intermediate 2-1: (S)-2-amino-3-(4-hydroxyphenyl)-N-methylpropanamide (HCI-salt)

[1203] Step 1: tert-butyl (S)-(3-(4-(benzyloxy)phenyl)-1-(methylamino)-1-oxopropan-2-yl)carbamate

[1204] 1 BocHN'tsT DIPEA, DMF BOCHN'T (SFN'f# '

[1205] HN

[1206] Stepl Step2

[1207] H2, Pd / C (10%), MeOH, rt, 18 h

[1208]

[1209] Step3

[1210] DIPEA (20.2 mL, 116 mmol) was added to a solution of (S)-3-(4-(benzyloxy)phenyl)-2-((tert-butoxycarbonyl)amino)propanoic acid (21.5 g, 57.9 mmol) and HATU (24.2 g, 63.7 mmol) in DMF (100 mL) at rt under Ar and this solution was stirred for 25 min. Then, 2M methyl amine inPAT065083-PCT-SEC01 THF (43.4 mL, 86.8 mmol) was added dropwise and the mixture was stirred a rt overnight. The reaction mixture was diluted with ethyl acetate and extracted with 10% NaHCO3. The organic layer was dried over Na2SO4and evaporated. A suspension formed which was filtered off. The solid was washed with ethyl acetate and dried under high vacuum to provide the title compound as a colorless solid. White solid: uPLC retention time 1.18 min (Method A); MS (ESI): m / z = 383.3 [M-H]-.

[1211] Step 2: (S)-2-amino-3-(4-(benzyloxy)phenyl)-N-methylpropanamide

[1212] To a solution of tert-butyl (S)-(3-(4-(benzyloxy)phenyl)-1-(methylamino)-1-oxopropan-2-yl)carbamate (6.2 g, 6.1 mmol) in DCM (20 mL) was added TFA (18.4 g, 12.4 mL, 161 mmol). The reaction mixture was stirred at room temperature for 180 minutes. The reaction mixture was slowly diluted with sat. NaHCO3and a strong gas evolution occurred. The mixture was extracted with DCM (3x). The combined DCM phases were filtered through a phase separator to obtain the crude product. The crude product was triturated in diethyl ether. The suspension was filtered to obtain the title compound as a colorless solid: uPLC retention time 0.61 min (Method A); MS (ESI): m / z = 285.1 [M+H]+.

[1213] Step 3: (S)-2-amino-3-(4-hydroxyphenyl)-N-methylpropanamide (HCI-salt)

[1214] To a solution of (S)-2-amino-3-(4-(benzyloxy)phenyl)-N-methylpropanamide (3.99 g, 14.0 mmol) in MeOH (50 mL) as added palladium on charcoal (400 mg, 10 wt%) under argon. The reaction mixture was stirred at room temperature overnight under a H2-balloon. The reaction mixture was filtered through Celite and the filtrate was concentrated. The crude product was taken up in 4M HCI in dioxane (17.5 mL, 70.1 mmol) and evaporated. The residue was dissolved in a small amount of EtOH and diethyl ether was added until a white suspension was obtained. The suspension was filtered and was washed once with diethyl ether and then dried under high vacuum to obtain the title compound as a light-yellow solid: uPLC retention time 0.12 min (Method A); MS (ESI): m / z = 195.2 [M+H]+.

[1215] Intermediate 2-2: (S)-2-amino-3-(3-hydroxybicyclo[1.1.1]pentan-1-yl)-N-methylpropanamide

[1216] MeNH2, HATU, HOBt Me2NH 1 FmocHN (s^ DIPEA, DCM / DMF FmocHN' A / (sS^N?

[1217]

[1218] OH HN Step 1 Step 2

[1219] Step 1: (9H-fluoren-9-yl)methyl (S)-(3-(3-hydroxybicyclo[1.1.1]pentan-1-yl)-1-(methylamino)-1-oxopropan-2-yl)carbamate: To a solution of (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(3-hydroxybicyclo[1.1.1]pentan-1-yl)propanoic acid (50 mg, 0.13 mmol, 1 eq - Y. P. Auberson et al., ChemMedChem 2017, 72, 590) in DCM (3 mL) were added HATU (53 mg, 0.14 mmol, 1.1 eq), HOBt (21.4 mg, 0.14 mmol, 1.1 eq), and DIPEA (66 pL, 0.38 mmol, 3 eq). After stirring for 5 mins DMF (1 mL) was added to the suspension to obtain a clearPAT065083-PCT-SEC01 solution. Then 2M methylamine in THF (76 pL, 0.15 mmol, 1.2 eq) was added and stirring was continued at RT. After 0.5 h additional 2M methylamine in THF (15. L, 0.03 mmol, 0.25 eq) was added. After 1.5 the reaction was complete and the reaction mixture was evaporated to almost dryness. The residue was taken up in DMSO and purified by RP-HPLC (column: 100x30 mm, Cis, flow 50 mL / min, eluents: A 0.2% formic acid in H₂O, B acetonitrile; gradient: 5%B to 100%B within 17.5 min, 1.5 min 100%B). Lyophilization of the product containing fractions afforded the title compound as colorless fluffy powder: uPLC (method A): tR= 0.90 min; MS (ESI): m / z = 407.3 [M+H]+, 429.2 [M+Na]+.

[1220] Step 2: (S)-2-amino-3-(3-hydroxybicyclo[1.1.1]pentan-1-yl)-N-methylpropanamide: To a solution of (9H-fluoren-9-yl)methyl (S)-(3-(3-hydroxybicyclo[1.1.1]pentan-1-yl)-1-(methylamino)-1-oxopropan-2-yl)carbamate (40 mg, 0.1 mmol, 1 eq) in acetonitrile (3 mL) was added 2M Me2NH in THF (0.25 mL, 0.5 mmol, 5 eq). To obtain a clear solution acetonitrile (3 mL) was added. Two further portions of 2M Me2NH in THF (0.25 mL, 0.5 mmol, 5 eq) were added after 30 and 90 minutes. Then the reaction mixture was evaporated several times with acetonitrile and the obtained residue was triturated with cold Et2O to leave an oil. Lyophilization from acetonitrile / H₂O afforded the title compound which was used without further purification (material contains residual dibenzofulvene): uPLC (method A): not detected, MS: no ionization. Preparation of 3-substituted piperazin-2-one-lntermediates

[1221] Intermediate 2-3: (S)-3-ethyl-1-methylpiperazin-2-one

[1222] n OMe N OMe O HBTU, DIEPA 1.o 70% TFA (aq.) N fspK OMe DMF, rt, 30 minHlil OMe 0°C -> RT, 18h Z-ABU-OH Step 1 90% 81%

[1223] Step 2

[1224] Et3SiH, TFA H2, Pd / C DCE, refl., 36h MeOH, RT, 24 h I N

[1225]

[1226] 49% 69% (99.9% ee) Step 3 Step 4

[1227] To a solution of benzyl (S)-2-ethyl-4-methyl-3-oxopiperazine-1 -carboxylate (135 g, 459 mmol, 1.0 eq) in MeOH (635 mL) was added Pd / C (25 g, 20wt%) in one portion at 25 °C. The mixture was degassed by N2-sparge for 5 mins, and the headspace of the flask was flushed with H2 three times. The resulting mixture was stirred under a H2 balloon for 24 h. The resulting mixture was filtered and concentrated at 50 °C in vacuo. The resulting residue was purified by silica gel column chromatography (n-heptane: ethyl acetate 2:1) to afford the title compound as a yellow oil: HPLC retention time 13.49 min (Method B); chiral LC (Chiralpak IG, 4.6 x 250 mm, eluent: 30% EtOH+O.1% Et2NH in hexanes, flow: 0.8 mL / min): peak 1 tR=16.3 min (0.04%);PAT065083-PCT-SEC01 peak 2 tR=17.5 (99.96%); => 99.9% ee;1H-NMR (400 MHz, CDCl3) δ 3.42 (ddd, 1H), 3.32 (dd, 1H), 3.25-3.08 (m, 2H), 3.09-2.88 (m, 4H), 2.01 (ddd, 1H), 1.77 (s, 1H), 1.71-1.58 (m, 1H), 0.97 (t, 3H); MS (ESI): m / z = 143.1 [M+H]+.

[1228] The starting material benzyl (S)-2-ethyl-4-methyl-3-oxopiperazine-1 -carboxylate can be prepared by the procedure outlined below:

[1229] Step 1: Benzyl (1-((2,2-dimethoxyethyl)(methyl)amino)-1-oxobutan-2-yl)carbamate

[1230] To a solution of Cbz-Abu-OH (440 g, 1.85 mol, 1.0 eq) and methylaminoacetaldehydedimethylacetal (221 g, 1.85 mol, 1.0 eq) in DMF (4.4 L) was added HBTU (844 g, 2.23 mol, 1.2 eq) and DIPEA (719.0 g, 5.56 mol, 3.0 eq) while maintaining the internal temperature below 25 °C. The resulting reaction mixture was stirred at room temperature for 0.5 h. Then, water (13.2 L) and ethyl acetate (4.4 L) were added. The mixture was stirred for 5 min and the layers were separated. The aqueous phase was extracted with ethyl acetate (4.4 L x 3), and the combined organic layers were washed with water (4.4 L x 4), 5wt% brine (4.4 L), dried over Na2SO4, filtered, and concentrated in vacuo at 50 °C to afford the title compound as a pink oil:1H-NMR (400 MHz, DMSO-d6) δ 7.60-7.21 (m, 6H), 5.02 (s, 2H), 4.38 (ddd, 2H), 3.59 (ddd, 1H), 3.30-3.17 (m, 5H), 3.07 (s, 2H), 2.84 (d, 1H), 2.69 (s, 1H), 1.56 (dtd, 2H), 0.85 (dt, 3H); MS (ESI): m / z = 307.15, 308.15 [M-32]+.

[1231] Step 2: Benzyl (S)-2-ethyl-4-methyl-3-oxo-3,4-dihydropyrazine-1(2H)-carboxylate

[1232] To a solution of 70% TFA in water (3.3 L) was added Benzyl (1-((2,2-dimethoxy-ethyl)(methyl)amino)-1-oxobutan-2-yl)carbamate (666 g, 1.67 mol, 1.0 eq) at 0 °C, and the mixture was warmed to 25 °C and stirred for 4 h. The mixture was concentrated in vacuo at 50 °C. Water (660 mL) and MTBE (1.32 L) were added, and the pH of the mixture was adjusted to 8.0 by sat’d. NaHCO3(aq., 2.66 L) while maintaining the internal temperature below 25 °C. The layers were separated, and the aqueous phase was extracted with MTBE (1 L x 2). The combined organic layers were washed with 20wt% brine (1.32 L), dried over Na2SO4, and concentrated in vacuo at 50 °C. The resulting residue was triturated with MTBE (660 mL) and dried at 50 °C in vacuo to give the title compound as an off-white solid:1H NMR (400 MHz, DMSO-ds) δ 7.47-7.28 (m, 5H), 6.28 (d, 1H), 5.91 (dd, 1H), 5.19 (s, 2H), 4.48 (t, 1H), 3.00 (s, 3H), 1.73-1.48 (m, 2H), 0.83 (t, J= 7.3 Hz, 3H). LC / MS: 275.1[M+H]+.

[1233] Step 3: Benzyl (S)-2-ethyl-4-methyl-3-oxopiperazine-1 -carboxylate

[1234] To a solution of benzyl (S)-2-ethyl-4-methyl-3-oxo-3,4-dihydropyrazine-1(2H)-carboxylate (300 g, 1.07 mol, 1.0 eq) in TFA (978 g, 8.57 mol, 8.0 eq) was added Et3SiH (311.5 g, 2.68 mol, 2.5 eq) under Ar, and the mixture was stirred for 2 h at 70 °C. The mixture was concentrated in vacuo at 50 °C. Water (600 mL) and DCM (600 mL) were added, and the pH of the mixture was adjusted to 8.0 by sat’d. NaHCO3(aq., 1.05 L) while maintaining the internal temperature below 25 °C. The layers were separated, and the aqueous phase was extracted with DCM (500 mL x 2). The combined organic layers were washed with 20wt% brine (600 mL), dried over Na2SO4,PAT065083-PCT-SEC01 and concentrated in vacuo at 50 °C to give a residue, which was purified with silica gel column chromatography (n-heptane:ethyl acetate 2:1) to afford the desired compound as a yellow oil:1H NMR (400 MHz, DMSO-d6) δ 7.45-7.27 (m, 5H), 5.13 (d, 2H), 4.26 (dd, 1H), 4.02 (t, 1H), 3.41 (td, 1H), 3.29-3.15 (m, 2H), 2.83 (s, 3H), 1.78 (ddq, 2H), 0.84 (t, 3H); MS: 277.2 ([M+H]+). By the same procedure using the appropriate Cbz- or Fmoc- protected amino acids and aminoacetaldehydedimethylacetal building blocks the following piperazin-3-one intermediates can be prepared:

[1235] LC MS

[1236] Intermediate Structure Configuration

[1237] tR[min] m / z [MH+]

[1238] HN^ I

[1239] 2-4 ^ 0.14 (A) 143.1 Mixture of

[1240] L^NH diastereomers

[1241] 2 HN^ I

[1242] -5 ^ 0.13 (A) 157.2 Mixture of

[1243] L^NH diastereomers

[1244] OMe

[1245] 2-6 HN^c^00.13 (A) 159.2 S

[1246] / ^.°H

[1247] 2-7a> 0.13 (A) 211.1 S

[1248] ^^ OMe

[1249] 2-8 0.20 (A) 235.3 S

[1250] N

[1251] \>

[1252] (R) \0H

[1253] 0.17 (B)

[1254] O

[1255] 2-9 + 159.2 Mixture of

[1256] k^NH diastereomers

[1257] 0.20 (B)

[1258]

[1259] a)Fmoc-AA SM prepared according to Y. P. Auberson et al., ChemMedChem 2017, 12, 590. Intermediate 2-10: (3S,6S)-3-ethyl-6-methylpiperazin-2-onePAT065083-PCT-SEC01

[1260] CO2Me

[1261]

[1262] Step 1: Benzyl (S)-(1-oxopropan-2-yl)carbamate

[1263] 1M DI BAL in hexane (15 mL, 15 mmol, 2.2 eq) was added dropwise to a solution of methyl ((benzyloxy)carbonyl)-L-alaninate (2.0 g, 81 wt%, 6.83 mmol, 1 eq) in DCM (40 mL) at -78 °C under argon and stirring. After 1h stirring at -78 °C 1M KHSO4 in water (17 mL, 17 mmol, 2.5 eq) was added to the reaction mixture at -78 °C and allowed to reach rt. The reaction mixture was diluted with DCM and water. The organic layer was separated, dried over Na2SO4and evaporated to dryness to obtain the product as colorless oil which can be used without further purification in the next step: uPLC retention time: 0.67 min (method B), MS (ESI): m / z = 208.1 [M+H]+.

[1264] Step 2: Methyl (S)-2-(((S)-2-(((benzyloxy)carbonyl)amino)propyl)amino)butanoate

[1265] To a solution of methyl (S)-2-aminobutanoate (1.03 g, 8.78 mmol, 1.3 eq) and benzyl (S)-(1-oxopropan-2-yl)carbamate (1.40 g, 6.76 mmol 1 eq) in DCM (45 ml, 6.756 mmol) was added 4 molecular sieve (20 g, HV-activated at 150 °C for 18 h) and stirred at rt for 2h. Then, sodium triacetoxyborohydrate (2.15 g, 10.1 mmol, 1.5 eq) and AcOH (0.58 mL, 0.61 g, 10.1 mmol, 1.5 mmol) were added with stirring. After stirring at rt for 2h, the molecular sieve was filtered off. The filtrate was diluted with DCM and extracted with 10% NaHCO3(aq). The organic layer was dried over Na2SO4and evaporated to dryness. Flash chromatography of the crude (0% to 10% MeOH / DCM) afforded the product as a light yellow oil: uPLC retention time: 0.94 min (method B), MS (ESI): m / z = 309.3 [M+H]+.

[1266] Step 3: (3S,6S)-3-ethyl-6-methylpiperazin-2-one (intermediate 2-10)

[1267] To a solution of methyl (S)-2-(((S)-2-(((benzyloxy)carbonyl)amino)propyl)amino)butanoate (1.40 g, 85 wt%, 3.86 mmol, 1 eq) in MeOH (45 mL) was added 10% Pd / C (0.41 g, 0.39 mmol, 0.1 eq) under Ar and stirring. This black suspension was then the hydrogenated under atmospheric pressure (balloon) at rt for 1.5h. Then, catalyst was filtered off over Hyflow and the filter cake was rinsed with additional MeOH. Evaporation to dryness afforded the product as colorless waxy solid which can be used without further purification: uPLC retention time: 0.13 min (method A), MS (ESI): m / z = 143.1 [M+H]+.

[1268] Intermediate 3-1: 5-(4-Acetamidophenyl)-4-chlorothiophene-2-carboxylic acidPAT065083-PCT-SEC01

[1269]

[1270] Step 1: Methyl 5-(4-actamidophenyl)-4-chlorothiophene-2-carboxylate

[1271] To a solution of methyl 5-bromo-4-chlorothiophene-2-carboxylate (5.000 g, 17.4 mmol) in dioxane:H₂O 5:1) (50 mL) were added (4-acetamidophenyl)boronic acid (3.43 g, 19.2 mmol), K3PO4 (11.1 g, 52.3 mmol) and tetrakis(triphenylphosphine)palladium (805 mg, 0.70 mmol) under argon. The reaction mixture was stirred at 100°C for 1h. After cooling to room temperature, H₂O was added and extracted with DCM. The DCM phase was separated, dried over Na2SO4and evaporated. The residue was purified by flash chromatography (6%-100% EtOAc / cyclohexane) to afford the product as a tan colored solid: uPLC retention time 1.02 min (Method A); MS (ESI): m / z = 310.1, 312.1 [M+H]+.

[1272] Step 2: 5-(4-acetamidophenyl)-4-chlorothiophene-2-carboxylic acid

[1273] To a solution of methyl 5-(4-acetamidophenyl)-4-chlorothiophene-2-carboxylate (8.3 g, 26.8 mmol) in THF:H₂O 5:1 (50 mL) was added lithium hydroxide monohydrate (5.62 g, 134 mmol) at room temperature. The reaction mixture was stirred at room temperature overnight. Then, H₂O was added and extracted with DCM (2x 25 mL). The aqueous phase was acidified with 4N HCI (pH=1). The precipitate formed was filtered off, washed three times with H₂O. After drying the final product was obtained a colorless solid: uPLC retention time 0.73 min (Method A);1H NMR (400 MHz, DMSO-d6) δ; 13.54 (br s, 1H), 10.22 (s, 1H), 7.69-7.74 (m, 3H), 7.61-7.66 (m, 2H), 3.37 - 3.39 (m, 1H), 2.08 (s, 3H); MS (ESI): m / z = 296.1, 298.1 [M+H]+.

[1274] The following intermediates can be prepared by the same procedure using the appropriate starting materials:

[1275] LC tR[min] MS (ESI)

[1276] Structure

[1277] (Method) m / z [M+H]+

[1278] 3-2 0.90(A) 322.2, 324.1

[1279] cr

[1280] 0

[1281] AcHN-_y==A / Sy^OH

[1282] 3-3 0.61(A) 291.0

[1283] MeO

[1284]

[1285] PAT065083-PCT-SEC01

[1286] LC tR[min] MS (ESI) Structure

[1287] (Method) m / z [M+H]+O

[1288] -5AcHN~^r=\_ / s^r 'OH 0.69 (A) 276.2 VZ yJ /

[1289] 0o

[1290] '''' [s

[1291] -6 0.88 (A) 316.2 0 IM *

[1292] Xco

[1293] -7 ) 2°O== 0.98 (A) 330.2 o O

[1294] I I

[1295] -8 0.83 (A) 302.1 o

[1296] -9 o^H vT=#y-- / vs" J / / ^oH0.97(A) 285.10o

[1297] -10 0.80(A) 318.0 CX y

[1298] -11 0.89 (A) 332.2

[1299] O

[1300] -12ACHN-- / ==\ / SY^OH

[1301] V / ~yK 0.39 (A) 277.2

[1302] -13 0.50 (A) 303.1

[1303]

[1304] PAT065083-PCT-SEC01

[1305] LC tR[min] MS (ESI) Structure

[1306] (Method) m / z [M+H]+00

[1307] 3-14 0.57 (A) 317.2

[1308] 3-15 0.49 319.1

[1309] sS ~ ~ °

[1310] 3-16O==

[1311] o o I I 0.55 (A) 333.2

[1312] ° n

[1313] MeO-<qI

[1314] 3-17 0.77 (A) 349.1

[1315] 3-18 0.82 (A) 362.3 -A^O <r,'°n

[1316] /

[1317] 3-19 0.42 (A) 302.1 K > Or0H

[1318] '~“c' /

[1319] O n

[1320] MeO- / ' ||

[1321] 3-20 0.71 (A) 332.2 / °1

[1322] AcHN

[1323] Yjl A

[1324] 3-21 0.68 (A) 256.1

[1325]

[1326] Intermediate 3-22: 4-methyl-5-(4-(5-methyl-2,4-dioxo-3-((2-(trimethylsilyl)ethoxy)-methyl)imidazolidin-1-yl)phenyl)thiazole-2-carboxylic acidPAT065083-PCT-SEC01

[1327]

[1328] Step 1: Methyl 4-methyl-5-(4-(5-methyl-2,4-dioxo-3-((2-(trimethylsilyl)ethoxy)methyl)imidazolidin-1-yl)phenyl)thiazole-2-carboxylate

[1329] A solution of methyl 5-bromo-4-methylthiazole-2-carboxylate (Enamine EN300-2941270, CAS: 79247-79-3, 60mg, 0.25mmol, 1 eq) and 5-methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-((2-(tri-methylsilyl)-ethoxy)methyl)imidazolidine-2, 4-dione (intermediate 1-12, 123 mg, 0.28 mmol, 1.08 eq) in THF (2.2 mL) was flushed with argon before adding Pd(dtbpf)Ch (25mg, 0.038mmol, 0.15 eq) and 2.4M aqueous Cs2CO3(0.27 mL, 0.64mmol, 2.5 eq). The reaction mixture was then stirred in a sealed vial under Ar at 60°C for 3.5h. Then, EtOAc (60 mL) was added and washed with brine (20 mL), dried over Na2SO4, and evaporated to dryness. The residue was purified by preparative RP-HPLC (column: Waters XBridge C18, 5μm, 50x100mm; flow: 90ml / min; gradient: H₂O[+0.1% TFA] / MeCN 65:35 to 0:100 in 17min) to afford a brown sticky oil: uPLC retention time: 1.29 min; MS (ESI): m / z = 476.1 [M+H]+.

[1330] Step 2: 4-methyl-5-(4-(5-methyl-2,4-dioxo-3-((2-(trimethylsilyl)ethoxy)methyl)imidazolidin-1-yl)phenyl)thiazole-2-carboxylic acid

[1331] To a solution of Methyl 4-methyl-5-(4-(5-methyl-2,4-dioxo-3-((2-(trimethylsilyl)ethoxy)ethyl)-imidazolidin-1-yl)phenyl)thiazole-2-carboxylate (52 mg, 0.11 mmol, 1 eq) in dioxane (2 mL) was added 1M aqueous LiOH (0.4 mL, 0.4 mmol, 3.6 eq). The solution is then stirred at 40°C for 2h. Then, water (30 mL) was added and basified with extra 1M aqueous LiOH before washed with DCM (2x 30 mL). The aqueous layer is adjusted to pH 2 with 1M aqueous HCI and extracted with EtOAc (2x 40ml). The combined EtOAc layers are washed with brine (20 mL) brine, dried over Na2SO4, and evaporated to dryness at RT to afford intermediate 3-19 as a beige solid: uPLC retention time: 0.39 min (method A); MS (ESI): m / z = 332.1 [M+H]+, 330.0 [M-H]-; 286.1 [M-H, -CO2]-.

[1332] Intermediate 3-23: 1-methyl-5-(4-(2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)phenyl)-1 H-pyrazole-3-carboxylic acidPAT065083-PCT-SEC01

[1333]

[1334] Step 1: N-(4-Bromophenyl)-3-nitropyridin-2-amine

[1335] To a solution of 3-chloro-2-nitropyridine (TCI C1765, CAS 54231-32-2, 500 mg, 3.15 mmol, 1 eq) and 4-bromoaniline (1.65 g, 9.59 mmol, 3 eq) in DMF (2.5 mL) was added KF (27 mg, 0.47 mmol, 0.15 eq) and K2CO3 (1.1 g, 7.96 mmol, 2.5 eq). The mixture was then stirred at 80°C for 5 days under argon. Then, water (20 mL) was added and extracted with EtOAc (2x 40 mL). The combined organic layers are washed with brine (3 x 20 mL), dried over Na2SO4, filtered and evaporated to dryness. The crude material was purified by flash chromatography on silica gel (40 g cartridge, EtOAc / cyclohexane gradient to afford a red sticky solid. Instead of the expected N-(4-bromophenyl)-2-nitropyridin-3-amine its regioisomer N-(4-bromophenyl)-3-nitropyridin-2-amine was formed (see analytical data for 3-(4-Bromophenyl)-1,3-dihydro-2 / 7-imidazo[4,5-b]pyridin-2-one, step 3): uPLC retention time: 1.32 min (method A); MS (ESI): m / z = 294.0 / 296.0 [M+H]+.

[1336] Step 2: N2-(4-Bromophenyl)pyridine-2,3-diamine

[1337] To a solution of N-(4-Bromophenyl)-3-nitropyridin-2-amine (112 mg, 0.38 mmol, 1 eq) in EtOH / H₂O 1:7 (4 mL) were added under argon NH4CI (102mg, 1.91 mmol, 5 eq) and iron powder (107 mg, 1.92mmol, 5 eq). The reaction mixture was stirred at 85°C for 30min. After reaching RT the reaction mixture was diluted with MeOH and filtered through a plug of Celite. The filtrate is evaporated to dryness and purified by preparative RP HPLC (column: Waters XSelect CSH C18OBD, 5μm, 30x100mm; flow:30ml / min; eluents: A: H₂O [+0.1% TFA], B: CH₃CN 95:5 to 50:50 in 15min.) to afford a beige solid: uPLC retention time: 0.42 min (method A); MS (ESI): m / z = 263.9 / 265.9 [M+H]+.

[1338] Step 3: 3-(4-Bromophenyl)-1,3-dihydro-2 / 7-imidazo[4,5-b]pyridin-2-one

[1339] To a solution of N2-(4-Bromophenyl)pyridine-2,3-diamine (67 mg, 0.25 mmol, 1 eq) and DIPEA (86 μL, 64 mg, 0.49 mmol, 2 eq) in acetonitrile (0.5 mL) was added CDI (62 mg, 0.37 mmol, 1.5 eq) at 0°C. Then, the ice-bath was removed and stirring was continued at RT for 1.5h. The reaction mixture is cooled in the freezer (-20°C) overnight and the suspension in then filtered. The cake is washed with some ice-cold acetonitrile and HV-dried to afford an off-whitePAT065083-PCT-SEC01 solid which was used in the next step without further purification: uPLC retention time: 0.82 min (method A); MS (ESI): m / z = 289.9 / 291.9;1H-NMR (400 MHz, DMSO-d6) 6 11.44 (s, 1H, NH-1), 7.95 (dd, 1H, H-6), 7.77-7.66 (m, 4H), 7.41 (dd, 1H, H8), 7.11 (dd, 1H, H-7);1H-ROESY:

[1340] Structure unequivocally confirmed by ROE between NH-1 and H-8.

[1341] Step 4: Methyl 1-methyl-5-(4-(2-oxo-1,2-dihydro-3 / 7-imidazo[4,5-b]pyridin-3-yl)phenyl)-1H-pyrazole-3-carboxylate

[1342] To a solution of 3-(4-Bromophenyl)-1,3-dihydro-2 / 7-imidazo[4,5-b]pyridin-2-one (20 mg, 0.068 mmol, 1 eq) in THF (0.7 mL) was added methyl 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxa-borolan-2-yl)-1H-pyrazole-3-carboxylate (PharmaBlock PBXAA892, CAS: 1616930-45-0, 24 mg, 0.090 mmol, 1.3 eq) and Pd(dtbpf)Cl2 (7 mg, 0.011 mmol, 0.16 eq). After the solution was sparged with argon, 2.4M aqueous Cs2CO3(75 μL, 0.18 mmol, 2.6 eq) was added. The reaction mixture was stirred under argon in sealed vial at 50°C for 2.75h. Then, he reaction mixture was taken up in EtOAc (70 mL), washed with brine (20ml), dried over Na2SO4, and evaporated to dryness. The residue was purified by flash chromatography on silica gel (4 g cartridge, DCM I EtOAc gradient) to afford an off-white solid: uPLC retention time: 0.64 min (method A); MS (ESI): m / z = 350.1 [M+H]+.

[1343] Step 5: 1-methyl-5-(4-(2-oxo-1,2-dihydro-3 / 7-imidazo[4,5-b]pyridin-3-yl)phenyl)-1 H-pyrazole-3-carboxylic acid

[1344] To a solution of methyl 1-methyl-5-(4-(2-oxo-1,2-dihydro-3 / 7-imidazo[4,5-b]pyridin-3-yl)phenyl)-1H-pyrazole-3-carboxylate (14mg, 0.039 mmol, 1 eq) in dioxane (1 mL) was added 1M aqueous LiOH (0.2 mL, 0.2 mmol, 5.1 eq). The reaction mixture was then stirred at 40°C for 3.25h. The reaction mixture was neutralized with 4M aqueous HCI (50 uL, 0.2 mmol, 5.1 eq) and blown-off with nitrogen. The residue was high vacuum dried to afford intermediate 3-20 which could be used without further purification: uPLC retention time: 0.46 min (method A); MS (ESI): m / z = 336.3 [M+H]+, 671.4 [2M+H]+,

[1345] Intermediate 3-24: 1-(4-acetamidophenyl)-2-methyl-1H-imidazole-4-carboxylic acid

[1346] Step 1 Step 2

[1347] AcCI, DIPEA LiOH. H2O

[1348]

[1349] DCM DCM Step 3 Step 4

[1350] Step 1: Methyl 2-methyl-1-(4-nitrophenyl)-1 / 7-imidazole-4-carboxylatePAT065083-PCT-SEC01 To a solution of methyl 2-methyl-1 / 7-imidazole-4-carboxylate (Enamine EN300-85495, CAS: 97602-72-7 (50 mg, 0.36 mmol, 1 eq) in DMF (2 mL) was added K2CO3 (148 mg, 1.08 mmol, 3 eq), 1-fluoro-4-nitrobenzene (76 mg, 0.54 mmOI, 1.5 eq). The reaction mixture was stirred at 60°C for 4.5h. To remove unreacted 1-fluoro-4-nitrobenzene, imidazole (70 mg, 1.03 mmol, 2.9 eq) was added and the reaction mixture was heated a second time at 60°C for 3.5h. Then, the reaction mixture was taken up in EtOAc (30 mL), washed with saturated aqueous NaHCO3 (10 mL) and NH4Cl (10 mL). The organic layer was dried (phase separator) and evaporated to dryness. The crude product was flash chromatographed (24 g cartridge, MeOH I DCM gradient) to afford a colorless solid: uPLC retention time: 0.49 min (method A); MS (ESI): m / z = 262.1 [M+H]+, 545.2 [M2+Na]+.

[1351] Step 2: Methyl 1-(4-aminophenyl)-2-methyl-1 / 7-imidazole-4-carboxylate

[1352] To a solution of methyl 2-methyl-1-(4-nitrophenyl)-1 / 7-imidazole-4-carboxylate (130 mg, 0.50 mmol, 1 eq) in MeOH (3 mL) and DCM (3 mL) was added 10% Pd / C (26 mg). The reaction mixture is stirred under hydrogen atmosphere at RT for 18h. The reaction mixture was filtered over Celite and evaporated to afford a colorless solid which was used without further purification in the next step: uPLC retention time: 0.33 min (method A); MS (ESI): m / z = 232.2 [M+H]+. Step 3: Methyl 1-(4-acetamidophenyl)-2-methyl-1 / 7-imidazole-4-carboxylate

[1353] To an ice cooled solution of methyl 1-(4-aminophenyl)-2-methyl-1 / 7-imidazole-4-carboxylate (120 mg, 0.52 mmol, 1 eq) DCM (2 mL) was added Te (0.23 mL, 168 mg, 1.30 mmol, 2.5 eq), and dropwise acetyl chloride (55 pL, 61 mg, 0.78 mmol, 1.5 Eq). The reaction mixture was stirred at RT for 1h. Then, DCM (10 mL) was added, and washed with saturated aqueous NaHCO3 (5 mL) and saturated aqueous NH4Cl (5 mL). The organic phase is dried (phase separator) and evaporated to dryness to afford a yellowish solid which was used without any further purification in the next step: uPLC retention time: 0.40 min; MS (ESI): m / z = 274.2 [M+H]+, 547 [M2+H]+.

[1354] Step 4: 1-(4-acetamidophenyl)-2-methyl-1H-imidazole-4-carboxylic acid

[1355] To a solution of Methyl 1-(4-acetamidophenyl)-2-methyl-1 / 7-imidazole-4-carboxylate (140.0 mg, 0.51 mmol 1 eq) in THF (2 mL) and water (0.4 mL) was added lithium hydroxide monohydrate (65 mg, 1.54 mmol, 3 eq). The reaction mixture was stirred at RT 18h. The obtained solution is acidified with 1M HCI and directly lyophilized to afford intermediate 3-21 as a yellowish solid mixture with LiCI: uPLC retention time: 0.19 min (method A); MS (ESI): m / z = 260.2 [M+H]+.

[1356] PREPARATION OF EXAMPLES

[1357] Examples 1-28 prepared via Route A

[1358] Example 1: (S)-5-(4-acetamidophenyl)-4-chloro-N-(3-(4-hydroxyphenyl)-1-(methylamino)-1-oxopropan-2-yl)thiophene-2-carboxamidePAT065083-PCT-SEC01

[1359] HATU, DIPEA, DMF

[1360]

[1361] Intermediate 2-1

[1362] To a solution of 5-(4-acetamidophenyl)-4-chlorothiophene-2-carboxylic acid (intermediate 3-1, 256 mg, 0.87 mmol) in DMF (5 mL) was added HATU (396 mg, 1.04 mmol) and DIPEA (0.3 mL, 1.73 mmol). The reaction mixture was stirred at room temperature for 15 min then a solution of (S)-2-amino-3-(4-hydroxyphenyl)-N-methylpropanamide hydrochloride (intermediate 2-1, 200 mg, 0,87 mmol) and DPIEA (0.3 mL, 1.73 mmol) in DMF (5 mL) was added and the reaction mixture was stirred at room temperature for additional 15 min. The reaction mixture is diluted with EtOAc (50 mL) and then washed with saturated aqueous NaHCO3 (30 mL) and NH4Cl (30 mL) solution. The organic phase was dried (phase separator) and concentrated under vacuum. The residue was purified by flash chromatography (0-15% MeOH / DCM) to give the title compound as a colorless solid: uPLC retention time 0.75 min (Method A);1H NMR (400 MHz, DMSO-d6) 5 10.15 (s, 1H), 9.15 (s, 1H), 8.74 (d, 1H), 8.02 (q, 1H), 7.95 (s, 1H), 7.74 -7.65 (m, 2H), 7.64 - 7.55 (m, 2H), 7.14 - 7.02 (m, 2H), 6.69 - 6.54 (m, 2H), 4.56 - 4.42 (m, 1H), 2.97 (dd, 1H), 2.79 (dd, 1H), 2.60 (d, 3H), 2.07 (s, 3H); MS (ESI): m / z = 472.1 [M+H]+.

[1363] The following examples can be prepared by the same procedure used for the synthesis of example 1 and the appropriate building blocks:

[1364] Example 2: (S)-4-chloro-N-(3-(4-hydroxyphenyl)-1-(methylamino)-1-oxopropan-2-yl)-5-(4-(2-oxopyrrolidin-1-yl)phenyl)thiophene-2-carboxamide

[1365]

[1366] Prepared using intermediate 3-2 and intermediate 2-1

[1367] Yellow powder; uPLC retention time 0.86 min (Method A);1H NMR (500 MHz, DMSO-de) 5 9.18 (s, 1H), 8.77 (d, 1H), 8.04 (m, 1H), 7.96 (s, 1H), 7.79 (d, 2H), 7.66 (d, 2H), 7.08 (d, 2H), 6.63 (d, 2H), 4.50 (m, 1H), 3.86 (m, 2H), 2.97 (m, 1H), 2.79 (m, 1H), 2.60 (d, 3H), 2.53 (m, 2H), 2.11 -2.03 (m, 2H); MS (ESI): m / z = 498.1 / 500.1 [M+H]+.

[1368] Example 3: (S)-5-(4-acetamidophenyl)-N-(3-(4-hydroxyphenyl)-1-(methylamino)-1-oxopropan-2-yl)-4-methoxythiophene-2-carboxamidePAT065083-PCT-SEC01

[1369]

[1370] Prepared using intermediate 3-3 and intermediate 2-1

[1371] Yellow powder: uPLC retention time 0.62 min (Method A);1H NMR (500 MHz, DMSO-de) 5 10.05 (s, 1H), 9.17 (s, 1H), 8.60 (d, 1H), 8.02 (m, 1H), 7.95 (s, 1H), 7.62 (m, 4H), 7.07 (d, 2H), 6.66-6.60 (m, 2H), 4.52 (td, H), 3.91 (s, 3H), 2.95 (m, 1H), 2.80 (m, 1H), 2.59 (d, 3H), 2.04 (s, 3H); MS (ESI): m / z = 468.3 / 469.2 [M+H]+.

[1372] Example 5: (R)-5-(4-acetamidophenyl)-N-(1-(4-hydroxyphenyl)propan-2-yl)-4-methylthiophene- 2-carboxamide or (S)-5-(4-acetamidophenyl)-N-(1-(4-hydroxyphenyl)propan-2-yl)-4-methylthiophene-2-carboxamide (eutomer, peak 2)

[1373]

[1374] Prepared using intermediate 3-5 and 4-(2-aminopropyl)phenol (CAS: 103-86-6)

[1375] The desired product was obtained as racemate which was separated into its enantiomers by chiral SFC. The eutomer eluted last (peak 2); column: Chiralpak AD 5pm 100x4.6mm, Eluent: 35% i-PrOH+0.05%NH3, flow: 3mL / min, ABPR 1800psi, 40°C; Peak 1: tR= 1.88 min, 99% ee; Peak 2: tR= 2.36min, 99% ee.

[1376] Colorless solid: uPLC retention time 0.82 min (Method A);1H NMR (400 MHz, DMSO-d₆) 5 10.09 (s, 1H), 9.17 (s, 1H), 8.19 (d, 1H), 7.66 (d, 2H), 7.59 (s, 1H), 7.41 (d, 2H), 7.00 (d, 2H), 6.65 (d, 2H), 4.06 (p, 1H), 2.74 (dd, 1H), 2.58 (dd, 1H), 2.25 (s, 3H), 2.06 (s, 3H), 1.10 (d, 3H); MS (ESI): m / z = 409.1 [M+H]+.

[1377] Example 6: (S)-5-(1 -acetyl- 1,2,3,4-tetrahydroquinolin-6-yl)-N-(3-(3-hydroxybicyclo-[1.1.1]pentan-1-yl)-1-(methylamino)-1-oxopropan-2-yl)-4-methylthiophene-2-carboxamide

[1378]

[1379] Prepared using intermediate 3-6 and intermediate 2-2PAT065083-PCT-SEC01 Colorless powder: uPLC retention time 0.72 min (Method A);1H NMR (600 MHz, DMSO-de) 5 ppm 8.39 (s, 1 H), 7.85 - 7.96 (m, 1 H), 7.73 (s, 1 H), 7.43 - 7.70 (m, 1 H), 7.31 (br d, 2H), 5.95 (s, 1H), 4.25 - 4.37 (m, 1H), 3.71 (t, 2H), 2.76 (s, 1H), 2.73 - 2.81 (m, 2H), 2.55 - 2.59 (m, 3H), 2.27 - 2.32 (m, 3H), 2.18 - 2.24 (m, 3H), 2.04 (s, 1H), 1.99 - 2.07 (m, 1H), 1.91 (s, 1H), 1.91 (s, 1 H), 1.85 - 1.96 (m, 3H), 1.56 - 1.69 (m, 6H), 1.61 (s, 1 H); MS (ESI): m / z = 482.2 [M + H]+.

[1380] Example 7: (S)-5-(4-acetamidophenyl)-N-(3-(4-hydroxyphenyl)-1-(methylamino)-1-oxopropan-2-yl)-4-methylthiophene-2-carboxamide

[1381]

[1382] Prepared using intermediate 3-5 and intermediate 2-1

[1383] Colorless solid: uPLC retention time 0.67 min (Method A);1H NMR (600 MHz, DMSO-de) 5 10.10 (s, 1H), 9.16 (s, 1H), 8.50 (d, 1H), 7.98 (q, 1H), 7.71 (s, 1H), 7.66 (d, 2H), 7.41 (d, 2H), 7.08 (d, 2H), 6.63 (d, 2H), 4.53 - 4.45 (m, 1 H), 2.94 (dd, 1 H), 2.82 (dd, 1 H), 2.59 (d, 3H), 2.27 (s, 3H), 2.06 (s, 3H); MS (ESI): m / z = 452.2 [M+H]+.

[1384] Example 8: (S)-N-(3-(4-hydroxyphenyl)-1-(methylamino)-1-oxopropan-2-yl)-4-methyl-5-(4-(2-oxopyrrolidin-1-yl)phenyl)thiophene-2-carboxamide

[1385]

[1386] Prepared using intermediate 3-8 and intermediate 2-1

[1387] Colorless powder: uPLC retention time 0.75 min (Method A);1H NMR (500 MHz, DMSO-de) 5 9.16 (s, 1H), 8.51 (d, 1H), 7.98 (d, 1H), 7.75 (d, 2H), 7.73 (s, 1H), 7.48 (d, 2H), 7.08 (d, 2H), 6.62 (d, 2H), 4.49 (m, 1H), 3.86 (t, 2H), 2.94 (dd, 1H), 2.81 (dd, 1H), 2.59 (d, 3H), 2.53 (d, 2H), 2.28 (s, 3H), 2.07 (m, 2H); MS (ESI): m / z = 478 [M+H]+.

[1388] Example 9: (S)-5-(4-(1H-pyrazol-1-yl)phenyl)-N-(3-(4-hydroxyphenyl)-1-(methylamino)-1-oxopropan-2-yl)-4-methylthiophene-2-carboxamide

[1389]

[1390] PAT065083-PCT-SEC01 Prepared using intermediate 3-9 and intermediate 2-1

[1391] Off white solid: uPLC retention time 0.93 min (Method A);1H NMR (600 MHz, DMSO-de) 5 9.17 (s, 1H), 8.59 - 8.53 (m, 2H), 8.00 (q, 1H), 7.94 (d, 2H), 7.81 - 7.74 (m, 2H), 7.61 (d, 2H), 7.09 (d, 2H), 6.63 (d, 2H), 6.58 (t, 1H), 4.50 (ddd, 1H), 2.95 (dd, 1H), 2.82 (dd, 1H), 2.60 (d, 3H), 2.32 (s, 3H); MS(ESI): m / z = 461.3 [M+H]+.

[1392] Example 10: (S)-5-(1-acetyl-1,2,3,4-tetrahydroquinolin-6-yl)-N-(3-(4-hydroxyphenyl)-1-(methylamino)-1-oxopropan-2-yl)-4-methylthiophene-2-carboxamide

[1393]

[1394] Prepared using intermediate 3-6 and intermediate 2-1

[1395] Colorless powder: uPLC retention time 0.81 min (Method A);1H-NMR (600 MHz, DMSO-de) 5 9.17 (s, 1H), 8.51 (d, 1H), 7.98 (s, 1H), 7.72 (s, 1H), 7.66 (s, 1H), 7.27 (m, 2H), 7.08 (d, 2H), 6.62 (d, 2H), 4.48 (m, 1H), 3.70 (t, 2H), 2.94 (dd, 1H), 2.81 (dd, 1H), 2.76 (t, 2H), 2.59 (d, 3H), 2.29 (s, 3H), 2.20 (s, 3H), 1.92 - 1.87 (m, 2H); MS (ESI): m / z = 492.4 [M+H]+

[1396] Example 11: (R)-4-(5-((R)-1-acetyl-3-methyl-1,2,3,4-tetrahydroquinolin-6-yl)-4-methylthiophene-2-carbonyl)-3-ethyl-1-methylpiperazin-2-one; (R)-4-(5-((S)-1-acetyl-3-methyl-1, 2,3,4-tetrahydroquinolin-6-yl)-4-methylthiophene-2-carbonyl)-3-ethyl-1-methylpiperazin-2-one; (S)-4-(5-((R)-1-acetyl-3-methyl-1,2,3,4-tetrahydroquinolin-6-yl)-4-methylthiophene-2-carbonyl)-3-ethyl- 1-methylpiperazin-2-one; or (S)-4-(5-((S)-1-acetyl-3-methyl-1,2,3,4-tetrahydroquinolin-6-yl)-4-methylthiophene-2-carbonyl)-3-ethyl-1-methylpiperazin-2-one (single diastereomer, peak4)

[1397]

[1398] Prepared using intermediate 3-7 1-methyl-3-ethyl-piperazin-2-one (CAS: 1214796-54-9) The desired product was obtained as a mixture of 4 diastereomers which were separated by chiral SFC. The most potent diastereomer eluted last (peak 4): SFC, column: Chiralpak IH 5pmPAT065083-PCT-SEC01 100x4.6mm, modifier: 30% MeOH+0.05%NH3, flow: 3mL / min ABPR 1800psi, 40°C; Peak 1: tp= 1.72min, >99% ee; Peak 2: tp= 1.91 min, >97% ee: Peak 3: tp= 3.47 min, >99% ee; Peak 4: tR= 4.14 min, >99% ee.

[1399] Colorless solid: uPLC retention time 0.90 min (Method A);1H-NMR (400 MHz, DMSO-d₆) 5 7.82 - 7.52 (m, 1 H), 7.38 (s, 1 H), 7.29 (d, 2H), 4.82 - 4.60 (m, 1 H), 4.40 - 4.24 (m, 1 H), 4.00 -3.85 (m, 1H), 3.77 - 3.55 (m, 1H), 3.50 (td, 1H), 3.28 - 3.15 (m, 2H), 2.92 (dd, 1H), 2.87 (s, 3H), 2.43 (dd, 1H), 2.30 (s, 3H), 2.23 (s, 3H), 2.08 - 1.79 (m, 3H), 1.03 (d, 3H), 0.91 (t, 3H); MS (ESI): m / z = 454.3 [M+H]+.

[1400] Example 12: (S)-4-(5-((R)-4-acetyl-2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-4-methylthiophene-2-carbonyl)-3-ethyl-1-methylpiperazin-2-one

[1401]

[1402] Prepared using Intermediate 3-11 and intermediate 2-3

[1403] Colorless solid: uPLC retention time 0.83 min (Method A);1H-NMR (600 MHz, DMSO-de) 5 7.37 (s, 1H), 7.01 (dd, 1H), 6.98 (d, 1H), 4.77 -4.63 (m, 1H), 4.38 (dtd, 1H), 4.34 -4.27 (m, 1 H), 4.25 - 4.04 (m, 1 H), 3.73 - 3.55 (m, 1 H), 3.50 (td, 1 H), 3.25 (ddd, 1 H), 2.86 (s, 3H), 2.29 (d, 6H), 2.00 - 1.78 (m, 2H), 1.32 (d, 3H), 0.91 (t, 3H); MS (ESI): m / z = 456.2 [M+H]+.

[1404] Example 13: (S)-4-(5-(4-acetyl-3,4-dihydro-2H-benzo[b][1,4] oxazin-7-yl)-4-methylthiophene-2-carbonyl)-3-(methoxymethyl)-1-methylpiperazin-2-one

[1405]

[1406] Prepared using intermediate 3-10 and intermediate 2-6

[1407] Yellowish solid: uPLC retention time 0.73 min (Method A);1H-NMR (400 MHz, DMSO) 5 7.89 (s, 1H), 7.38 (s, 1H), 7.15 -6.92 (m, 2H), 4.84 -4.76 (m, 1H), 4.41 -4.33 (m, 1H), 4.30 (t, 2H), 3.97 (dd, 1 H), 3.89 (t, 2H), 3.85 - 3.71 (m, 1 H), 3.68 (dd, 1 H), 3.59 - 3.49 (m, 1 H), 3.30 -3.27 (m, 1H), 3.26 (s, 3H), 2.89 (s, 3H), 2.29 (s, 3H), 2.27 (s, 3H). MS (ESI): m / z = 458.3 [M+H]+.

[1408] Example 14: (S)- / V-(4-(5-(2-((3-hydroxybicyclo[1.1.1 ]pentan- 1 -yl)methyl)-4-methyl-3-oxopiperazine-1-carbonyl)-3-methylthiophen-2-yl)phenyl)acetamidePAT065083-PCT-SEC01

[1409]

[1410] Prepared using intermediate 3-5 and intermediate 2-7

[1411] Colorless powder: uPLC retention time 0.72 min (Method A),1H NMR (600 MHz, DMSO-de) 5 10.02 - 10.22 (m, 1H), 7.62 - 7.75 (m, 2H), 7.38 - 7.50 (m, 2H), 7.26 - 7.38 (m, 1H), 5.90 -6.08 (m, 1 H), 4.78 - 5.00 (m, 1 H), 4.22 - 4.37 (m, 1 H), 3.67 - 3.82 (m, 1 H), 3.38 - 3.47 (m, 1 H), 3.16 - 3.23 (m, 1H), 2.80 - 2.88 (m, 3H), 2.27 - 2.31 (m, 3H), 2.12 - 2.21 (m, 1H), 2.03 - 2.12 (m, 4H), 1.57 - 1.65 (m, 3H), 1.65 - 1.76 (m, 3H); MS (ESI): m / z = 468.3 [M+H]+.

[1412] Example 15: (S)-5-(4-acetamidophenyl)-N-(3-(4-hydroxyphenyl)-1-(methylamino)-1-oxopropan-2-yl)-4-methylthiazole-2-carboxamide

[1413]

[1414] Prepared using intermediate 3-12 and intermediate 2-1

[1415] Beige solid: uPLC retention time 0.66 min (Method A);1H-NMR (600 MHz, DMSO-de) 5 10.15 (s, 1H), 9.19 (s, 1H), 8.37 (d, 1H), 8.05 (q, 1H), 7.70 (d, 2H), 7.47 (d, 2H), 7.00 (d, 2H), 6.62 (d, 2H), 4.57 (td, 1H), 2.97 (qd, 2H), 2.60 (d, 3H), 2.48 (s, 3H), 2.07 (s, 3H); MS (ESI): m / z = 453.2 [M+H]+.

[1416] Example 16: Methyl (R)-7-(2-((R)-2-ethyl-3-oxopiperazine-1-carbonyl)-4-methylthiazol-5-yl)-2-methyl-2,3-dihydro-4H-benzo[b][1,4]oxazine-4-carboxylate or Methyl (R)-7-(2-((S)-2-ethyl-3-oxopiperazine-1-carbonyl)-4-methylthiazol-5-yl)-2-methyl-2,3-dihydro-4H-benzo[b][1,4]oxazine-4-carboxylate (single diastereomer, peak 1)

[1417]

[1418] Prepared using intermediate 3-17 and 3-ethyl-piperazin-2-one (CAS: 90485-52-2)

[1419] The desired product was obtained as a mixture of 2 diastereomers which were separated by chiral SFC. The more potent diastereomer eluted first (peak 1): column: Chiralpak AD 5pm 100x4.6mm, modifier: 35% i-PrOH+0.05%NH3, flow: 3mL / min ABPR 1800psi, 40°C; peak 1: tp= 1.22 min, >99% ee; peak 2: tp= 1.74 min, >99% ee.PAT065083-PCT-SEC01 Colorless solid: uPLC retention time 0.97 min (Method A);1H-NMR (400 MHz, DMSO-d₆) 5 8.06-8.10 (m, 1H), 8.05 (br s, 1H), 7.93 (br d, 1H), 7.52 - 7.66 (m, 2H), 7.03 - 7.10 (m, 3H), 5.89 (brt, 1H), 5.49 (br d, 1H), 4.73 (dd, 1H), 4.26-4.44 (m, 2H), 4.19 (dd, 1H), 3.77 (s, 4H), 3.50-3.66 (m, 2H), 3.19-3.31 (m, 5H), 1.81-2.01 (m, 3H), 1.32 (d, 4H), 1.17-1.28 (m, 1 H), 1.03 (d, 1H), 0.83-0.98 (m, 4H); MS (ESI): m / z = 459.2 [M+H]+.

[1420] Example 17: (R)-4-(5-((R)-4-acetyl-2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-4-methyl-thiazole-2-carbonyl)-3-(2,2,2-trifluoroethyl)piperazin-2-one or (S)-4-(5-((R)-4-acetyl-2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-4-methyl-thiazole-2-carbonyl)-3-(2,2,2-trifluoroethyl)piperazin-2-one (single diastereomer, peak 2)

[1421]

[1422] Prepared using intermediate 3-16 and 3-(2,2,2-trifluoroethyl)piperazin-2-one (CAS: 1246548-79-7)

[1423] The desired product was obtained as a mixture of 2 diastereomers which were separated by chiral SFC. The more potent diastereomer eluted last:: SFC, column: Chiralpak IB 5pm 100x4.6mm, modifier: 35% MeOH+0.05%NH3, flow: 3mL / min, ABPR 1800psi, 40°C; peak 1: tp= 1.78 min, >99% ee; peak 2: tp= 2.7 min, 95% ee.

[1424] Beige solid: uPLC retention time 0.88 min (Method A);1H NMR (400 MHz, DMSO-d₆) 5 8.32-8.42 (m, 2H), 8.02 (br s, 1 H), 7.95 (br s, 1 H), 7.05 (br s, 3H), 6.61 (br d, 1 H), 5.62 (br d, 1H), 5.17 (br d, 1H), 4.49 (br d, 1H), 4.34-4.41 (m, 1H), 4.18 (br d, 2H), 3.62-3.74 (m, 1H), 3.24-3.28 (m, 2H), 3.17 (br d, 1H), 2.98-3.15 (m, 1H), 2.72-2.89 (m, 2H), 2.29 (s, 5H), 1.33 (br d, 5H); MS (ESI): m / z = 497.2 [M+H]+.

[1425] Example 18: (S)-3-ethyl-1-methyl-4-(4-methyl-5-(4-(2-oxopyrrolidin-1-yl)phenyl)thiazole-2-carbonyl)piperazin-2-one

[1426]

[1427] Prepared using intermediate 3-13 and intermediate 2-3

[1428] Colorless solid: uPLC retention time 0.81 min (Method A);1H-NMR (400 MHz, CD3OD ) 5 7.77-7.81 (m, 2 H), 7.54-7.59 (m, 2 H), 5.74 (br d, 1 H), 4.94-5.04 (m, 1 H), 4.57 (br s, 1 H), 3.99 (t, 2H), 3.58-3.81 (m, 2H), 3.34-3.51 (m, 3H), 3.01 (s, 3H), 2.62-2.67 (m, 3H), 2.55 (s, 3H), 2.09-PAT065083-PCT-SEC01 2.26 (m, 3 H), 1.95-2.07 (m, 1H), 1.23-1.40 (m, 1H), 1.00-1.08 (m, 3H), 0.88-0.94 (m, 1H); MS (ESI): m / z = 427.3 [M+H]+.

[1429] Example 19: 1-(4-(2-((S)-2-ethyl-4-methyl-3-oxopiperazine-1-carbonyl)-4-methylthiazol-5-yl)phenyl)-5-methylimidazolidine-2, 4-dione, trifluoroacetate (mixture of diastereomers)

[1430]

[1431] Prepared using intermediate 3-22 and intermediate 2-3

[1432] Slightly yellow powder: uPLC retention time 0.72 min (Method A);1H-NMR (400 MHz, DMSO-d6): 5 ppm 11.29 (s, 1H), 7.66 (d, 2H), 7.59 (d, 2H), 6.03-5.51 (m, 1H), 4.94 (q, 1H), 4.80 - 4.43 (m, 1 H), 3.76-3.34 (m, 2H), 2.87 (s, 3H), 2.51 (s, 3H), 2.03-1.83 (m, 2H), 1.35 (d, 3H), 0.92 (q, 3H); MS (ESI): m / z = 456.0 [M+H]+.

[1433] Example 20: (R)-4-(5-(1-acetyl-1,2,3,4-tetrahydroquinolin-6-yl)-4-methylthiazole-2-carbonyl)-3-ethyl-1-methylpiperazin-2-one or (S)-4-(5-(1 -acetyl- 1,2,3,4-tetrahydroquinolin-6-yl)-4-methylthiazole-2-carbonyl)-3-ethyl-1-methylpiperazin-2-one (single enantiomer, peak 2)

[1434]

[1435] Prepared using intermediate 3-14 and 1-methyl-3-ethyl-piperazin-2-one (CAS: 1214796-54-9) The desired product was obtained as racemate which was separated into its enantiomers by chiral SFC. The eutomer eluted last (peak 2): SFC, column: Chiralpak IB 5pm 100x4.6mm, modifier: 40% MeOH+0.05%NH3, flow: 3mL / min, ABPR 1800psi, 40°C; Peak 1: tR= 1.37 min, >99% ee; Peak 2: tR= 1.84 min, >99% ee.

[1436] Colorless solid: uPLC retention time 0.88 min (Method C);1H-NMR (400 MHz, DMSO-d₆) 5 7.65 (s, 1H), 7.34 (d, 2H), 6.23-4.38 (m, 2H), 3.94-3.43 (m, 5H), 2.86 (s, 3H), 2.77 (t, 2H), 2.21 (s, 3H), 2.13-1.77 (m, 4H), 0.91 (q, 3H); MS (ESI): m / z = 441.4 [M+H]+.

[1437] Example 21: (R)-4-(5-(4-acetyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-4-methylthiazole-2-carbonyl)-3-ethyl-1-methylpiperazin-2-one or (S)-4-(5-(4-acetyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-4-methylthiazole-2-carbonyl)-3-ethyl-1-methylpiperazin-2-one (single enantiomer, peak 2)

[1438]

[1439] PAT065083-PCT-SEC01 Prepared using intermediate 3-15 and 1-methyl-3-ethyl-piperazin-2-one (CAS: 1214796-54-9) The desired product was obtained as racemate which was separated into its enantiomers by chiral SFC. The eutomer eluted last: column: Chiralpak IB 5pm 100x4.6mm, modifier: 40% MeOH, flow: 3mL / Min ABPR 1800psi 40°C; peak 1: tp= 1.45min, >99% ee; peak 2: tp= 1.89 min, >99% ee.

[1440] Colorless solid: uPLC retention time 0.82 min (Method A);1H-NMR (400 MHz, DMSO) 5 8.01 (br s, 1H), 7.17- 6.97 (m, 2H), 5.97 (t, 0.36H), 5.54 (d, 0.53H), 4.77 (dd, 0.54H), 4.55-4.38 (m, 0.4H), 4.31 (t, 2H), 3.90 (t, 2H), 3.74-3.61 (m, 0.59H), 3.60-3.43 (m, 1.18H), 3.29 (s, 1H), 2.86 (s, 3H), 2.51 (s, 3H), 2.28 (s, 3H), 2.07-1.78 (m, 2H), 0.91 (dt, 3H); MS (ESI): m / z = 443.3 [M+H]+.

[1441] Example 22: (S)-4-(5-((R)-4-acetyl-2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-4-methylthiazole-2-carbonyl)-3-(methoxymethyl)-1-methylpiperazin-2-one

[1442]

[1443] Prepared using intermediate 3-16 and intermediate 2-6

[1444] Colorless powder: uPLC retention time 0.82 min (Method A);1H-NMR (400 MHz, DMSO-d₆) 5 8.12 (d, 1H), 7.06 (d, 2H), 6.02 (s, 0.5H), 5.61 (d, 0.5H), 4.86 (s, 0.5H), 4.52 (d, 0.5H), 4.39 (t, 1H), 4.18 (s, 1H), 4.01 (h, 1H), 3.86 (t, 1H), 3.79-3.62 (m, 1H), 3.53 (dd, 1.5H), 3.32 (d, 1H), 3.25 (s, 2.5H), 3.18 (s, 1.5H), 2.90 (s, 3H), 2.49 (s, 3H), 2.29 (s, 3H), 1.33 (d, 3H); MS / ESI: m / z = 473.2 [M+H]+.

[1445] Example 23: (S)-3-ethyl-1-methyl-4-(1-methyl-5-(4-((S)-2-oxo-4-phenylpyrrolidin-1-yl)phenyl)-1H-pyrazole-3-carbonyl)piperazin-2-one or (S)-3-ethyl-1-methyl-4-(1-methyl-5-(4-((R)-2-oxo-4-phenylpyrrolidin- 1 -yl)phenyl)- 1 H-pyrazole-3-carbonyl)piperazin-2-one (single diastereomer, peak 1)

[1446]

[1447] Prepared using intermediate 3-18 and intermediate 2-3

[1448] The desired product was obtained as a mixture of 2 diastereomers which were separated by chiral SFC. The most potent diastereomer eluted first (peak 1): column: Chiralpak IH 5pm 100x4.6mm, eluent: 25% MeOH+0.05%NH3, flow: 3mL / min, ABPR 1800psi, 40°C; peak 1: tp= 1.85 min, >99% ee; Peak 2: tp= 2.29 min, >99% ee.PAT065083-PCT-SEC01 Colorless solid: uPLC retention time 0.92 min (Method A);1H NMR (600 MHz, DMSO-d6) δ 7.84 (d, 2H), 7.60 (d, 2H), 7.44-7.40 (m, 2H), 7.37 (t, 2H), 7.31-7.24 (m, 1H), 6.76 (s, 1H), 5.49-5.42 (m, 0.5H), 4.95 (d, 1H), 4.86-4.79 (m, 1H), 4.51 (d, 0.5H), 4.27 (dd, 1H), 3.95-3.87 (m, 4H), 3.75 (p, 1H), 3.64-3.54 (m, 1H), 3.48 (td, 1H), 3.31-3.19 (m, 2H), 2.94 (dd, 1H), 2.86 (s, 3H), 2.76 (dd, 1H), 2.00-1.77 (m, 2H), 0.90 (t, 3H); MS (ESI): m / z = 486.4 [M+H]+.

[1449] Example 24: (R)-4-(5-(4-acetyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-1-methyl-1 H-pyrazole-3-carbonyl)-3-ethyl-1-methylpiperazin-2-one or (S)-4-(5-(4-acetyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-1-methyl-1H-pyrazole-3-carbonyl)-3-ethyl-1-methylpiperazin-2-one (single enantiomer, peak 2)

[1450]

[1451] Prepared using intermediate 3-19 and rac-3-ethyl-1-methyl-piperazin-2-one [CAS 1214796-54-9]

[1452] The desired product was obtained as racemate which was separated into its enantiomers by chiral SFC. The eutomer eluted last (peak 2): column: Chiralpak IB 5pm 100x4.6mm, modifier: 35% MeOH+0.05%NH3, flow: 3mL / min, ABPR 1800psi, 40°C; peak 1: tR= 1.43 min, 99% ee; peak 2: tR= 1.85 min, 99% ee.

[1453] Colorless solid (23 mg, 41%), uPLC retention time 0.60 min (Method A);1H-NMR (400 MHz, DMSO-d6) δ 7.12-7.04 (m, 2H), 6.73 (s, 1H), 5.47-5.35 (m, 0.5H), 4.92 (d, 1H), 4.86-4.76 (m, 1H), 4.49 (d, 0.5H), 4.31 (t, 2H), 3.95-3.83 (m, 5H), 3.64-3.53 (m, 1H), 3.34-3.18 (m, 2H), 2.85 (s, 3H), 2.28 (s, 3H), 2.02-1.74 (m, 2H), 0.89 (t, 3H); MS (ESI): m / z = 426.3 [M+H]+.

[1454] Example 25: (S)-3-(4-(3-(2-ethyl-4-methyl-3-oxopiperazine-1-carbonyl)-1-methyl-1 H-pyrazol-5-yl)phenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

[1455] o

[1456]

[1457] Prepared using intermediate 3-23 and intermediate 2-3

[1458] Off-white solid: uPLC retention time 0.60 min (Method A);1H NMR (400 MHz, DMSO-d₆): 5 ppm 11.47 (s, 1H), 7.97 (dd, 1H), 7.89-7.85 (m, 2H), 7.78-7.73 (m, 2H), 7.43 (dd, 1H), 7.13 (dd, 1H), 6.85 (s, 1H), 5.53-4.44 (m, 2H), 3.98 (s, 3H), 3.62 (t, 1H), 3.54-3.37 (m, 1H), 3.26 (d, 1H), 2.87 (s, 3H), 2.02-1.80 (m, 2H), 0.91 (t, 3H); MS / ESI: m / z = 460.4 [M+H]+.

[1459] Example 26: Methyl (R)-2-methyl-7-(1-methyl-3-((S)-3-oxo-2-(2,2,2-trifluoroethyl)piperazine-1-carbonyl)-1H-pyrazol-5-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazine-4-carboxylate or Methyl (R)-2-PAT065083-PCT-SEC01 methyl-7-(1-methyl-3-((R)-3-oxo-2-(2,2,2-trifluoroethyl)piperazine-1-carbonyl)-1H-pyrazol-5-yl)- 2,3-dihydro-4H-benzo[b][1,4]oxazine-4-carboxylate (single diastereomer, peak 1)

[1460] MeO O [Pd(dppf)Cl2] B2pin2

[1461] DIPEA KOAc

[1462] DCM Dioxane

[1463]

[1464] Step 1 Step 2

[1465] [Pd(PPh3)4], K2CO3 Dioxane I H2O 5:1

[1466] 2. Chiral Separation Step 3 Step 4

[1467]

[1468] Diastereomer A (peak 1) and Diastereomer B (peak 2) Step 1: Methyl (R)-7-bromo-2-methyl-2,3-dihydro-4 / 7-benzo[b][1,4]oxazine-4-carboxylate

[1469] To a stirred solution of (R)-7-bromo-2-methyl-3,4-dihydro-2 / 7-benzo[b][1,4]oxazine (1.0 g, 4.38 mmol, 1.0 eq) (G. Zhou et al., ACS Med. Chem. Lett. 2014, 5, 544-549, CAS 1245708-21- 7). in DCM (40.00 mL) at 0°C was added DIPEA (1.42 g, 1.91 mL, 10.96 mmol, 2.5 eq) and methyl chloroformate (829 mg, 0.68 mL, 8.77 mmol, 2.0 eq). After 5 min at 0°C, the ice bath was removed and stirring was continued at RT for 1.5h. The reaction mixture was quenched with saturated aqueous solution of NaHCO3(50 mL) and extracted twice with EtOAc (50 mL).

[1470] The combined organic layers were washed with brine, dried over Na2SO4, and evaporated to dryness. The crude product was purified by flash column chromatography on silica gel (40g cartridge, EtOAc / cyclohexane gradient) to afford the title compound as a yellow oil: uPLC retention time: 1.23 min: MS (ESI): m / z = 286.0 / 288.0 [M+H]+.

[1471] Step 2: Methyl (R)-2-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-4 / 7- benzo[b][1,4]oxazine-4-carboxylate (intermediate 1-8)

[1472] To a solution of methyl (R)-7-bromo-2-methyl-2,3-dihydro-4H-benzo[b][1,4]oxazine-4-carboxylate (0.5 g, 1.75 mmol, 1.0 eq) in 1,4-dioxane (10mL) was added 4, 4, 4', 4', 5, 5,5', 5'- octamethyl-2,2'-bi(1,3,2-dioxaborolane) (888 mg, 3.50 mmol, 2.0 eq), potassium acetate (515 mg, 5.24 mmol, 3.0 eq), and Pd(dppf)Cl2 (128 mg, 0.17 mmol, 0.1 eq). After purging with argon, the reaction mixture was stirred at 100°C for 3h. Then, DCM (50 mL) was added and washedPAT065083-PCT-SEC01 with water (20ml). The organic phase was dried (phase separator) and evaporated. Flash chromatography of the crude material on silica gel (50 g cartridge, EtOAc I cyclohexane gradient) afforded the desired material as a yellow oil: uPLC retention time: 1.26 min; MS (ESI): m / z = 334.2 [M+H]+, 351.2 [M+NH4]+, 356.2 [M+Na]+.

[1473] Step 3: (R)-5-(4-(methoxycarbonyl)-2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-1-methyl-1H-pyrazole-3-carboxylic acid (intermediate 3-20)

[1474] Under Ar, to a solution of 5-bromo-1-methyl-1H-pyrazole-3-carboxylic acid (100 mg, 0.49 mmol, 1 eq) in dioxane / water 5:1 (24 mL) was added methyl (R)-2-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazine-4-carboxylate (intermediate 1-8, 179 mg, 0.54 mmol, 1.1 eq), K2CO3 (202 mg, 1.46 mmol, 3.0 eq) and Pd(PPh3)4(8.5 mg, 7.32 μmol, 1.5 mol%). The reaction mixture was stirred at 100 °C for 1 hour. Additional 5-bromo-1-methyl-1H-pyrazole-3-carboxylic acid (100 mg, 0.49 mmol, 1 eq, 488 μmol) was added and the stirring at 100 °C was continued for 1h. Then, the reaction mixture was diluted with water (10 mL) and EtOAc (30 mL). As the phases did not separate the mixture was acidified to pH 1 with 6M HCI followed by extraction with DCM (2x 50 mL). The combined organic phases were dried (phase separator) and evaporated under vacuum. The crude product was purified by flash chromatography on silica gel (25 g cartridge, MeOH I DCM gradient) followed by preparative HPLC (column: XBridge C18OBD, 5μm, 30x100 mm; eluents A: H2O+ 0.2%FA, B: ACN, gradient: 5% to 50% B in 10min, flow: 50 mL / min). Freeze drying of the product containing fractions afforded a colorless solid: uPLC retention time: 0.71 min; MS (ESI): m / z = 332.2 [M+H]+.

[1475] Step 4: Methyl (R)-2-methyl-7-(1-methyl-3-((S)-3-oxo-2-(2,2,2-trifluoroethyl)piperazine-1-carbonyl)-1H-pyrazol-5-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazine-4-carboxylate or Methyl (R)-2-methyl-7-(1-methyl-3-((R)-3-oxo-2-(2,2,2-trifluoroethyl)piperazine-1-carbonyl)-1H-pyrazol-5-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazine-4-carboxylate (single diastereomer, peak 1)

[1476] To a solution of (R)-5-(4-(methoxycarbonyl)-2-methyl-3,4-dihydro-2H-benzo[b][1,4]-oxazin-7-yl)-1-methyl-1H-pyrazole-3-carboxylic acid (40 mg, 0.12 mmol, 1 eq) in DMF (1 mL) was added 3-(2,2,2-trifluoroethyl)piperazin-2-one (Enamine EN300-6436106, CAS# 1246548-79-7, 26.4 mg, 0.14 mmol, 1.2 eq), HATU (55 mg, 0.14 mmol, 1.2 eq), and 4-methylmorpholin (24.4 mg, 27 pL, 0.24 mmol, 2.0 eq). The reaction mixture was stirred at RT for 1 hour. Additional 3-(2,2,2-trifluoroethyl)piperazin-2-one (26.4 mg, 0.14 mmol, 1.2 eq) was added and stirring was continued at RT for 2h. Then, the reaction mixture was diluted with EtOAc (30 mL) and washed with saturated aqueous NaHCO3(10 mL) and saturated aqueous NH4CI (10 mL) solution. The organic phase was dried (phase separator) and concentrated under vacuum. The residue was purified by flash chromatography on silica gel (MeOH I DCM gradient) to afford a colorless oil (45 mg, 86 μmol, 71%); uPLC retention time: 0.86 min (method A); MS (ESI): m / z = 496.2

[1477] [M+H]+.PAT065083-PCT-SEC01 The diastereomeric mixture obtained was separated by chiral SFC: column: Chiralpak AD 5 pm 30x250 mm, modifier 35% IPA + 0.05% NH3, flow: 90 mL / min, BPR pressure: 100 bar. Diastereomer A (peak 1, eutomer): colorless solid; uPLC retention time 0.86 min (Method A); chiral analytical SFC: column: Chiralpak AD 5pm 100x4.6mm, modifier: 35% i-PrOH+0.05%NH3, flow: 3mL / min, ABPR 1800psi, 40°C; tR= 1.25 min, >99% ee.1H-NMR (400 MHz, DMSO-d6) δ 8.21-8.37 (m, 1H), 7.94 (br d, 1H), 7.02-7.15 (m, 2H), 6.74 (s, 1H), 6.07 (br s, 0.2H), 5.21 (dd, 0.8H), 5.05 (br d, 0.8H), 4.52 (br d, 0.2H), 4.35 (cm, 1H), 4.19 (dd, 1H), 3.90 (s, 3H), 3.77 (s, 3H), 3.59 (cm, 0.8H), 3.15-3.40 (m, 3.2H), 3.07 (cm, 1H), 2.76 (cm, 1H), 1.32 (d, 3H); MS (ESI): m / z = 496.3 [M+H]+.

[1478] Diastereomer B (peak 2, distomer): colorless solid; uPLC retention time 0.87 min (Method A); chiral analytical SFC: column: Chiralpak AD 5pm 100x4.6mm, modifier: 35% i-PrOH+0.05%NH3, flow: 3mL / min, ABPR 1800psi, 40°C; tR= 2.21 min, >99% ee.1H NMR (400 MHz, DMSO-d6) δ 8.23-8.37 (m, 1H), 7.94 (br d, 1H), 7.04-7.14 (m, 2H), 6.73 (s, 1H), 6.06 (br d, 0.2H), 5.21 (dd, 0.8H), 5.06 (br d, 0.8H), 4.52 (br d, 0.2H), 4.34 (cm, 1H), 4.19 (dd, 1H), 3.89 (s, 3H), 3.76 (s, 3H), 3.58 (cm, 0.8H), 3.15-3.42 (m, 3.2H), 3.07 (cm, 1H), 2.76 (cm, 1H), 1.32 (d, 3H); MS (ESI): m / z = 496 [M+H],

[1479] Example 27: (S)-N-(4-(4-(2-ethyl-4-methyl-3-oxopiperazine-1-carbonyl)-2-methyl-1 H-imidazol-1-yl)phenyl)acetamide

[1480]

[1481] Prepared using intermediate 3-24 and intermediate 2-3

[1482] Colorless solid: uPLC retention time 0.45 min (Method A);1H-NMR (600 MHz, DMSO-d6) δ 10.18 (s, 1H), 7.75 (s, 1H), 7.74-7.71 (m, 2H), 7.44-7.39 (m, 2H), 6.08 (s, 0.33H), 5.54 (d, 0.67H), 4.83 (s, 0.67H), 4.50 (s, 0.33H), 3.63-3.38 (m, 2H), 3.31-3.07 (m, 1H), 2.85 (s, 3H), 2.28 (s, 3H), 2.08 (s, 3H), 1.98-1.73 (m, 2H), 0.89 (m, 3H); MS (ESI): m / z = 384.3 [M+H]+.

[1483] Example 28: (S)-4'-acetamido-N-(3-(4-hydroxyphenyl)-1-(methylamino)-1-oxopropan-2-yl)-[1, T-biphenyl]-3-carboxamide

[1484]

[1485] Prepared using intermediate 3-21 and intermediate 2-1

[1486] Colorless solid: uPLC retention time 0.61 min (Method A);1H-NMR (400 MHz, DMSO-d₆) 5 10.06 (s, 1H), 9.12 (s, 1H), 8.63 (d, 1H), 8.05 (s, 1H), 7.92-8.01 (m, 1H), 7.77 (d, 1H), 7.66-7.74PAT065083-PCT-SEC01 (m, 5 H), 7.49 (t, 1H), 7.11 (m, 2 H), 6.61 (m, 2H), 4.54 - 4.61 (m, 1H), 3.00 (dd, 1H), 2.86 (dd, 1H), 2.60 (d, 3H), 2.07 (s, 3H), 1.19-1.29 (m, 1H); MS / ESI: m / z = 432.4 [M + H]+.

[1487] Examples 36 - 55 prepared via Route B

[1488] Example 36: (S)-5-(4-(1H-pyrazol-1-yl)phenyl)-4-chloro-N-(3-(4-hydroxyphenyl)-1- (methylamino)-1-oxopropan-2-yl)thiophene-2-carboxamide

[1489] K3PO4, dioxane: H2O 4:1

[1490]

[1491] Step 2

[1492] Step 1: (S)-5-bromo-4-chloro-N-(3-(4-hydroxyphenyl)-1-(methylamino)-1-oxopropan-2-yl)thiophene-2-carboxamide

[1493] To a solution of (S)-2-amino-3-(4-hydroxyphenyl)-N-methylpropanamide (intermediate 1-1, 50 mg, 0.26 mmol) in DMF (6 mL) were added 5-bromo-4-chlorothiophene-2-carboxylic acid (62.2 mg, 0.26 mmol), DIPEA (0.14 mL, 0.77 mmol), and HATU (147 mg, 0.39 mmol) at room temperature. The resulting yellow solution was stirred at room temperature for 15 min. H2O was added and extracted with DCM. The DCM phase was separated, dried over Na2SO4and evaporated. The residue was purified by flash chromatography (6%-100% EtOAc / cyclohexane) to afford the product as a yellow solid: uPLC retention time 0.94 min (Method A); MS (ESI): m / z = 417.0 / 419.0 [M+H]+.

[1494] Step 2: (S)-5-(4-(1H-pyrazol-1-yl)phenyl)-4-chloro-N-(3-(4-hydroxyphenyl)-1-(methylamino)-1-oxopropan-2-yl)thiophene-2-carboxamide

[1495] To a solution of (S)-5-bromo-4-chloro-N-(3-(4-hydroxyphenyl)-1-(methylamino)-1-oxopropan-2-yl)thiophene-2-carboxamide (35 mg, 84 μmol) in dioxane: H2O 4:1) (2 mL) were added (4-(1H-pyrazol-1-yl)phenyl)boronic acid (18.9 mg, 0.1 mmol), K3PO4 (71.1 mg, 0.34 mmol) and tetrakis(triphenylphosphine)palladium (9.7 mg, 8.4 μmol) under argon. The reaction mixture was stirred at room temperature for 1h. H2O was added and extracted with DCM. The DCM phase was separated, dried over Na2SO4and evaporated. The residue was purified by flash chromatography (2%-15% MeOH / DCM) to afford the product as a colorless solid: uPLC retention time 0.99 min (Method A);1H NMR (400 MHz, DMSO-d6) δ 9.17 (s, 1H), 8.79 (d, 1H), 8.58 (d, 1H), 8.04 (q, 1H), 7.96-8.01 (m, 3H), 7.77-7.81 (m, 3H), 7.08 (cm, 2 H), 6.63 (cm, 2H), 6.58 (dd, 1H), 4.51 (ddd, 1H), 2.98 (dd, 1H), 2.80 (dd, 1H), 2.60 (d, 3H); MS (ESI): m / z = 481.3 / 483.2 [M+H]+.

[1496] The following examples can be prepared by the procedure used for example 36 using the appropriate building blocks:PAT065083-PCT-SEC01 Example 37: (S)-5-(4-(1H-1,2,4-triazol-1-yl)phenyl)-4-chloro-N-(3-(4-hydroxyphenyl)-1- (methylamino)-1-oxopropan-2-yl)thiophene-2-carboxamide

[1497]

[1498] Prepared using 1-[4-(tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1H-1,2,4-triazole (CAS:

[1499] 1384951-86-3), 5-bromo-4-chlorothiophene-2-carboxylic acid (CAS: 123418-69-9), and intermediate 2-1

[1500] Colorless solid: uPLC retention time 0.81 min (Method A);1H NMR (600 MHz, DMSO-d6) δ 9.39 (s, 1H), 9.19 (s, 1H), 8.84 (d, 1H), 8.29 (s, 1H), 8.07 (q, 1H), 8.04 - 7.97 (m, 3H), 7.85 (d, 2H), 7.09 (d, 2H), 6.63 (d, 2H), 4.51 (cm, 1H), 2.98 (dd, 1H), 2.80 (dd, 1H), 2.60 (d, 3H); MS (ESI): m / z = 482.2 / 484.2 [M+H]+.

[1501] Example 38: (S)-5-(4-acetyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-N-(3-(4-hydroxyphenyl)-1-(methylamino)-1-oxopropan-2-yl)-4-methylthiophene-2-carboxamide

[1502]

[1503] Prepared using intermediate 1-2, 5-bromo-4-methylthiophene-2-carboxylic acid (CAS: 54796-53-1), and intermediate 2-1

[1504] Colorless powder: uPLC retention time 0.74 min (Method A);1H-NMR (400 MHz, DMSO-d₆) 6 9.12 (s, 1H), 8.50 (d, 1H), 7.96 (d, 1H), 7.71 (s, 1H), 7.10 - 7.03 (m, 2H), 7.02 - 6.94 (m, 2H), 6.66 - 6.59 (m, 2H), 4.54 - 4.43 (m, 1 H), 4.29 (t, 2H), 3.88 (t, 2H), 2.95 (dd, 1 H), 2.88 - 2.76 (m, 1H), 2.59 (d, 3H), 2.27 (d, 6H), one aromatic proton not visible (very broad signal); MS (ESI): m / z = 494.4 [M+H]+.

[1505] Example 39: (S)-3-ethyl-1-methyl-4-(4-methyl-5-((R)-2-methyl-4-(methylsulfonyl)-3,4-dihydro- 2H-benzo[b][1,4]oxazin-7-yl)thiophene-2-carbonyl)piperazin-2-one

[1506]

[1507] Prepared using intermediate 1-9, 5-bromo-4-methylthiophene-2-carboxylic acid (CAS: 54796-53-1), and intermediate 2-3PAT065083-PCT-SEC01 Colorless solid: uPLC retention time 0.87 min (Method A);1H-NMR (600 MHz, DMSO-d6) δ 7.68 (d, 1H), 7.38 (s, 1H), 7.07 (dd, 1H), 7.03 (d, 1H), 4.69 (s, 1H), 4.38 -4.26 (m, 2H), 4.13 (dd, 1H), 3.77 - 3.56 (m, 1H), 3.50 (td, 1H), 3.28 - 3.21 (m, 2H), 3.19 (s, 3H), 2.86 (s, 3H), 2.30 (s, 3H), 1.99 - 1.80 (m, 2H), 1.36 (d, 3H), 0.91 (t, 3H); MS (ESI): m / z = 492.3 [M+H]+.

[1508] Example 40: (S)-4-(5-(1-acetyl-5-fluoro-1,2,3,4-tetrahydroquinolin-6-yl)-4-methylthiophene-2-carbonyl)-3-ethyl-1-methylpiperazin-2-one

[1509] O JI

[1510]

[1511] Prepared using intermediate 1-3, 5-bromo-4-methylthiophene-2-carboxylic acid (CAS: 54796-53-1), and intermediate 2-3

[1512] Off white oil: uPLC retention time 0.86 min (Method A);1H-NMR (400 MHz, DMSO) 57.63 -7.46 (m, 1 H), 7.45 - 7.34 (m, 1 H), 7.26 (t, 1 H), 4.80 - 4.60 (m, 1 H), 4.40 - 4.22 (m, 1 H), 3.79 -3.71 (m, 2H), 3.71 - 3.56 (m, 1H), 3.56 (s, 1H), 3.29 - 3.23 (m, 1H), 2.87 (s, 3H), 2.83 - 2.74 (m, 2H), 2.24 (s, 3H), 2.16 (d, 3H), 2.02 - 1.77 (m, 4H), 0.91 (t, 3H); MS (ESI): m / z = 458.1 [M+H]+.

[1513] Example 41: (S)-4-(5-(5-acetyl-5,6,7,8-tetrahydro-1,5-naphthyridin-2-yl)-4-methylthiophene-2-carbonyl)-3-ethyl-1-methylpiperazin-2-one

[1514]

[1515] Prepared using intermediate 1-14, 5-bromo-4-methylthiophene-2-carboxylic acid (CAS: 54796-53-1), and intermediate 2-3

[1516] Colorless solid: uPLC retention time 0.71 min (Method A);1H-NMR (600 MHz, CDCl3) 5 7.40 (d, 1H), 7.26 (s, 1H), 7.17 (s, 1H), 5.43 - 5.23 (m, OH), 5.03 (d, 1H), 4.61 (d, 1H), 3.81 (s, 2H), 3.72 - 3.36 (m, 2H), 3.20 (d, 1H), 3.00 (d, 5H), 2.47 (s, 3H), 2.31 (s, 3H), 2.11 (dp, 3H), 1.92 (dq, 1H), 1.04 (t, 3H); MS (ESI): m / z = 441.1 [M+H]+.

[1517] Example 42: (S)-4-(5-((R)-4-acetyl-2-ethyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-4-methylthiophene-2-carbonyl)-3-ethyl-1-methylpiperazin-2-one or (S)-4-(5-((S)-4-acetyl-2-ethyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-4-methylthiophene-2-carbonyl)-3-ethyl-1-methylpiperazin-2-one (single diastereomer, Peak 1)PAT065083-PCT-SEC01

[1518]

[1519] Prepared using intermediate 1-4, 5-bromo-4-methylthiophene-2-carboxylic acid (CAS: 54796-53-1), and intermediate 2-3

[1520] The desired product was obtained as a mixture of 2 diastereomers which were separated by chiral SFC. The most potent diastereomer eluted first (peak 1): column: Chiralpak IH 5pm 100x4.6mm, modifier: 40% MeOH+0.05%NH3, flow 3mL / min, ABPR 1800psi, 40°C; Peak 1: tp= 1.5 min, 99.5% ee, Peak 2: tp= 2.4 min, 99.5% ee.

[1521] Colorless powder (12.00 mg, 16.0 %). UPLC retention time 0.95 min (Method A);1H-NMR (600 MHz, DMSO) δ 8.09 (br s, 1H), 7.38 (s, 1H), 7.04 -6.98 (m, 2H), 4.70 (br s, 1H), 4.32 (d, 1H), 4.20 -4.14 (m, 1H), 3.64 (br s, 1H), 3.50 (td, 1H), 3.45 - 3.30 (m, 1H), 3.28 - 3.23 (m, 1H), 2.86 (s, 3H), 2.30 (s, 3H), 2.28 (s, 3H), 1.94 (ddd, 1H), 1.86 (dt, 1H), 1.65 (m, 2H), 1.01 (t, 3H), 0.91 (t, 3H); MS (ESI): m / z = 470.3 [M+H]+.

[1522] Example 43: (S)-4-(5-(1-acetyl-2,3-dihydro-1 H-pyrido[2,3-b][1,4]oxazin-6-yl)-4-methylthiophene-2-carbonyl)-3-ethyl-1-methylpiperazin-2-one

[1523]

[1524] Prepared using intermediate 1-15, 5-bromo-4-methylthiophene-2-carboxylic acid (CAS: 54796-53-1), and intermediate 2-3

[1525] Colorless solid: uPLC retention time 0.58 min (Method A); 1H-NMR (400 MHz, DMSO) δ 9.01 – 7.90 (m, 1 H), 7.41 - 7.27 (m, 2H), 4.74 - 4.60 (m, 1 H), 4.42 (dd, 2H), 4.33 - 4.21 (m, 1H), 3.92 (dd, 2H), 3.71 - 3.55 (m, 1H), 3.49 (td, 1H), 3.29 - 3.19 (m, 1H), 2.86 (s, 3H), 2.46 (s, 3H), 2.28 (s, 3H), 2.01 - 1.76 (m, 2H), 0.90 (t, 3H); MS (ESI): m / z = 443.3 [M+H]+.

[1526] Example 44: (R)-N-(1-hydroxypropan-2-yl)-4-methyl-5-(4-(2-oxo-2,3-dihydro-1 H-imidazo[4,5-b]pyridin-1-yl)phenyl)thiazole-2-carboxamide

[1527]

[1528] Prepared using intermediate 1-11, methyl 5-bromo-4-methyl-1,3-thiazole-2-carboxylate (CAS: 79247-79-3), and D-alaninol (CAS: 35320-23-1)PAT065083-PCT-SEC01 Colorless solid: uPLC retention time 0.70 min (Method A);1H-NMR (400 MHz, DMSO-d₆) 5 11.91 (br s, 1 H), 8.39 (d, 1 H), 8.02 (dd, 1 H), 7.73 (cm, 4H), 7.46 (dd, 1 H), 7.05 (dd, 1 H), 4.83 (t, 1H), 4.01 (cm, 1H), 3.59-3.37 (m, 2H), 2.56 (s, 3H), 1.16 (d, 3H); MS (ESI): m / z = 410.1 [M+H]+. Example 45: (3S,6S)-4-(5-((R)-4-acetyl-2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-4-methylthiazole-2-carbonyl)-3-ethyl-6-methylpiperazin-2-one or (3S,6R)-4-(5-((R)-4-acetyl-2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-4-methylthiazole-2-carbonyl)-3-ethyl-6-methylpiperazin-2-one (single diastereomer, Peak 2)

[1529]

[1530] Prepared using intermediate 1-7, methyl 5-bromo-4-methyl-1,3-thiazole-2-carboxylate (CAS: 79247-79-3), and intermediate 2-4

[1531] The desired product was obtained as a mixture of 2 diastereomers which were separated by chiral SFC. The more potent diastereomer eluted second (Peak 2): column: Chiralpak IB 5pm 100x4.6mm, modifier: 45% iPrOH+0.05%NH3, flow: 3mL / min ABPR 1800psi, 40°C; peak 1: tR= 1.28 min, >99% ee; peak 2: tR= 1.98 min, >99% ee.

[1532] Colorless solid: uPLC retention time 0.90 min (Method A);1H-NMR (DMSO-d6): δ 8.07 (br d, 1 H), 7.03-7.08 (m, 3H), 5.90-5.94 (m, 1 H), 5.53-5.57 (m, 1 H), 4.72 (dd, 1 H), 4.49 (br dd, 1 H), 4.30 - 4.43 (m, 1H), 4.10-4.27 (br s, 1H), 3.38-3.64 (m, 1H), 3.06-3.15 (m, 1H), 2.77-2.86 (m, 1H), 2.29 (s, 3H), 1.79-2.03 (m, 2H), 1.33 (d, 3H), 1.05-1.15 (m, 3H), 0.85-0.97 (m, 3H); MS (ESI): m / z = 457.3 [M+H]+.

[1533] Example 46: Methyl (R)-7-(2-((2S,5S)-2-ethyl-5-methyl-3-oxopiperazine-1-carbonyl)-4-methylthiazol-5-yl)-2-methyl-2,3-dihydro-4H-benzo[b][1,4]oxazine-4-carboxylate or Methyl (R)-7-(2-((2S,5R)-2-ethyl-5-methyl-3-oxopiperazine-1-carbonyl)-4-methylthiazol-5-yl)-2-methyl-2,3-dihydro-4H-benzo[b][1,4]oxazine-4-carboxylate (single diastereomer, Peak 2)

[1534]

[1535] Prepared using intermediate 1-8, methyl 5-bromo-4-methyl-1,3-thiazole-2-carboxylate (CAS: 79247-79-3), and intermediate 2-4

[1536] The desired product was obtained as a mixture of 2 diastereomers which were separated by chiral SFC. The more potent diastereomer eluted second (Peak 2): column: Chiralpak IB 5pm 100x4.6mm, modifier: 35% iPrOH+0.05%NH3, flow: 3mL / min ABPR 1800psi, 40°C; Peak 1: tR= 1.54 min, >99% ee; Peak 2: tR= 2.46 min, >99% ee.PAT065083-PCT-SEC01 Colorless solid: uPLC retention time 1.06 min (Method A);1H-NMR (DMSO-d6): δ 8.08 (br d, 1H), 7.94 (br d, 1H), 7.08 (dd, 1H), 7.04 (d, 1H), 5.90-5.96 (m, 0.5H), 5.52-5.60 (m, 0.5H), 4.73 (dd, 0.5H), 4.50 (br dd, 0.5H), 4.30-4.39 (m, 1H), 4.20 (dd, 1H), 3.78 (s, 3H), 3.46-3.66 (m, 1H), 3.26-3.32 (m, 1H), 3.06-3.17 (m, 0.5H), 2.78-2.90 (m, 0.5H), 2.49-2.52 (m, 3H), 1.80-2.06 (m, 1H), 1.33 (d, 3H), 1.01-1.27 (m, 3H), 0.87-0.96 (m, 3H); MS (ESI): m / z = 473.4 [M+H]+.

[1537] Example 47: Methyl (R)-7-(3-((S)-2-ethyl-4-methyl-3-oxopiperazine-1-carbonyl)-1-methyl-1H-pyrazol-5-yl)-2-methyl-2,3-dihydro-4H-benzo[b][1,4]oxazine-4-carboxylate

[1538]

[1539] Prepared using intermediate 1-8, 5-bromo-1-methyl-1H-pyrazole-3-carboxylic acid (CAS:

[1540] 1222174-93-7), and intermediate 2-3

[1541] Colorless solid: uPLC retention time 0.82 min (Method A);1H-NMR (400 MHz, DMSO-d₆) 5 7.94 (d, 1H), 7.15–6.99 (m, 2H), 6.72 (s, 1H), 5.53-5.33 (m, 0.5H), 4.93 (d, 1H), 4.85-4.77 (m, 1H), 4.50 (d, 0.5H), 4.34 (ddt, 1H), 4.19 (dd, 1H), 3.90 (s, 3H), 3.77 (s, 3H), 3.65-3.38 (m, 2H), 3.29 (dd, 2H), 2.85 (s, 3H), 2.03-1.71 (m, 2H), 1.32 (d, 3H), 0.90 (t, 3H); MS (ESI): m / z = 456.3 [M+H]+.

[1542] Example 48: (S)-3-ethyl-1-methyl-4-(1-methyl-5-((R)-2-methyl-4-(methylsulfonyl)-3,4-dihydro- 2H-benzo[b][1,4]oxazin-7-yl)-1H-pyrazole-3-carbonyl)piperazin-2-one

[1543]

[1544] Prepared using intermediate 1-9, 5-bromo-1-methyl-1H-pyrazole-3-carboxylic acid (CAS:

[1545] 1222174-93-7), and intermediate 2-3

[1546] Colorless solid: uPLC retention time 0.70 min (Method A);1H-NMR (400 MHz, DMSO-d₆) 5 7.71 (d, 1H), 7.18-7.06 (m, 2H), 6.73 (s, 1H), 5.41 (s, 0.5H), 4.93 (d, 1H), 4.81 (s, 1H), 4.50 (d, 0.5H), 4.41-4.29 (m, 1H), 4.15 (dd, 1H), 3.91 (s, 3H), 3.54 (dt, 2H), 3.28-3.21 (m, 2H), 3.20 (s, 3H), 2.86 (s, 3H), 2.02-1.77 (m, 2H), 1.36 (d, 3H), 0.90 (t, 3H); MS (ESI): m / z = 476.2 [M+H]+. Example 49: (S)-1-(4-(3-(2-ethyl-4-methyl-3-oxopiperazine-1-carbonyl)-1-methyl-1 H-pyrazol-5-yl)phenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one, trifluoroacetate

[1547] o

[1548]

[1549] PAT065083-PCT-SEC01 Prepared using intermediate 1-11, 5-bromo-1-methyl-1H-pyrazole-3-carboxylic acid (CAS: 1222174-93-7), and intermediate 2-3

[1550] Off-white powder: uPLC retention time 0.61 min (Method A);1H-NMR (400 MHz, DMSO-d₆): 5 ppm 11.92 (s, 1H), 8.02 (dd, 1H), 7.82-7.70 (m, 4H), 7.44 (dd, 1H), 7.06 (dd, 1H), 6.85 (s, 1H), 5.47-4.46 (m, 2H), 3.98 (s, 3H), 3.71-3.18 (m, 3H), 2.87 (s, 3H), 2.03-1.77 (m, 2H), 0.92 (t, 3H); MS / ESI: m / z = 460.1 [M+H]+.

[1551] Example 50: Methyl (R)-7-(3-((2S,5S)-2-ethyl-5-methyl-3-oxopiperazine-1-carbonyl)-1-methyl-1H-pyrazol-5-yl)-2-methyl-2,3-dihydro-4H-benzo[b][1,4]oxazine-4-carboxylate or Methyl (R)-7-(3-((2S,5R)-2-ethyl-5-methyl-3-oxopiperazine-1-carbonyl)-1-methyl-1H-pyrazol-5-yl)-2-methyl-2,3-dihydro-4H-benzo[b][1,4]oxazine-4-carboxylate (single diastereomer, peak 1)

[1552]

[1553] Prepared using intermediate 1-8, 5-bromo-1-methyl-1H-pyrazole-3-carboxylic acid (CAS:

[1554] 1222174-93-7), and intermediate 2-4

[1555] Chiral separation: SFC, column: Chiralpak AD 5pm 100x4.6mm, modifier: 40% iPrOH+0.05%NH3, flow: 3mL / min, ABPR 1800psi, 40°C; Peak 1: tR= 1.31 min, >99% ee; Peak 2: tR= 1.95 min, >99% ee.

[1556] Colorless solid: uPLC retention time 0.85 min (Method A);1H NMR (DMSO-d₆): δ 8.00 (s, 1H), 7.91 - 7.99 (m, 1H), 7.10 (d, 1H), 7.08 (s, 1H), 6.72 (s, 1H), 5.33-5.36 (m, 0.5H), 4.89-4.94 (m, 0.5H), 4.75-4.78 (m, 0.5H), 4.51-4.55 (m, 0.5H), 4.30-4.38 (m, 1H), 4.19 (dd, 1H), 3.90 (s, 3H), 3.77 (s, 3H), 3.43-3.65 (m, 1H), 3.26-3.37 (m, 0.5H), 3.00-3.07 (m, 0.5H), 2.67-2.73 (m, 0.5H), 1.75-1.99 (m, 1.5H), 1.32 (d, 3H), 1.01-1.12 (m, 3H), 0.90 (t, 3H); MS / ESI: m / z = 456.2 [M + H]+.

[1557] Example 51: (R)-4-(5-((R)-4-acetyl-2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-1 -methyl-1 H-pyrazole-3-carbonyl)-1-methyl-3-(2,2,2-trifluoroethyl)piperazin-2-one or (S)-4-(5-((R)-4-acetyl-2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-1-methyl-1H-pyrazole-3-carbonyl)-1-methyl-3-(2,2,2-trifluoroethyl)piperazin-2-one (single diastereomer, peak 2)

[1558]

[1559] Prepared using intermediate 1-7, 5-bromo-1-methyl-1H-pyrazole-3-carboxylic acid (CAS:

[1560] 1222174-93-7), and 1-methyl-3-(2,2,2-trifluoroethyl)piperazin-2-one (CAS: 2352083-67-9)PAT065083-PCT-SEC01 The desired product was obtained as a mixture of 2 diastereomers which were separated by chiral SFC. The more potent diastereomer eluted second (Peak 2): column: Chiralpak IB 5pm 100x4.6mm, modifier: 30% i-PrOH+0.05%NH3, flow: 3mL / min, ABPR 1800psi, 40°C; Peak 1: tR= 2.32 min, >99% ee; Peak 2: tp= 2.84 min, >99% ee.

[1561] Colorless solid (9 mg, 36%), uPLC retention time 0.73 min (Method A);1H NMR (400 MHz, DMSO-d6) δ 8.53-7.50 (m, 2H), 7.08 (d, 2H), 6.75 (s, 1H), 5.27 (d, 1H), 5.11 (d, 1H), 4.40 (ddt, 1H), 4.19 (s, 1H), 3.90 (d, 3H), 3.78-3.67 (m, 1H), 3.51 (td, 1H), 3.32-3.22 (m, 1H), 3.09 (dt, 1H), 2.89 (s, 3H), 2.75 (t, 1H), 2.29 (s, 3H), 1.33 (d, 3H), 1.23 (s, 1H); MS (ESI): m / z = 494.1 [M+H]+.

[1562] Example 52: (S)-4-(5-((R)-4-acetyl-2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-1-ethyl-1H-pyrazole-3-carbonyl)-3-ethyl-1-methylpiperazin-2-one

[1563]

[1564] Prepared using intermediate 1-7, 5-bromo-1-ethyl-1H-pyrazole-3-carboxylic acid (CAS:

[1565] 2385950-17-2), and intermediate 2-3

[1566] Colorless solid: uPLC retention time 0.75 min (Method A);1H-NMR (400 MHz, DMSO-d₆) 5 7.01 (d, 2H), 6.68 (s, 1H), 5.45 (s, 0.5H), 4.91 (d, 1H), 4.87-4.74 (m, 1H), 4.50 (d, 0.5H), 4.45-4.33 (m, 1H), 4.18 (q, 3H), 3.64-3.49 (m, 2H), 3.30-3.18 (m, 2H), 2.86 (s, 3H), 2.29 (s, 3H), 2.03-1.75 (m, 2H), 1.34 (t, 6H), 0.91 (t, 3H); MS (ESI) m / z = 454.2 [M+H]+.

[1567] Example 53: Methyl (R)-7-(1-ethyl-3-((S)-2-ethyl-4-methyl-3-oxopiperazine-1-carbonyl)-1H-pyrazol-5-yl)-2-methyl-2,3-dihydro-4H-benzo[b][1,4]oxazine-4-carboxylate

[1568]

[1569] Prepared using intermediate 1-8, 5-bromo-1-ethyl-1H-pyrazole-3-carboxylic acid (CAS:

[1570] 2385950-17-2), and intermediate 2-3

[1571] Colorless solid: uPLC retention time 0.90 min (Method A);1H NMR (600 MHz, DMSO-d₆) δ 7.95 (s, 1H), 7.09-6.94 (m, 2H), 6.67 (s, 1H), 5.45 (s, 0.5H), 4.92 (d, 1H), 4.85-4.75 (m, 1H), 4.50 (d, 0.5H), 4.39-4.29 (m, 1H), 4.19 (t, 3H), 3.77 (s, 3H), 3.63-3.39 (m, 2H), 3.32-3.20 (m, 3H), 2.85 (s, 3H), 2.01-1.75 (m, 2H), 1.39-1.27 (m, 6H), 0.96-0.85 (m, 3H), MS (ESI): m / z = 470.2 [M+H]+.PAT065083-PCT-SEC01 Example 54: Methyl (R)-7-(1-ethyl-3-((2S,5S)-2-ethyl-5-methyl-3-oxopiperazine-1-carbonyl)-1H-pyrazol-5-yl)-2-methyl-2,3-dihydro-4H-benzo[b][1,4]oxazine-4-carboxylate or Methyl (R)-7-(1-ethyl-3-((2S,5R)-2-ethyl-5-methyl-3-oxopiperazine-1-carbonyl)-1H-pyrazol-5-yl)-2-methyl-2,3-dihydro-4H-benzo[b][1,4]oxazine-4-carboxylate (single diastereomer, peak 1)

[1572]

[1573] Prepared using intermediate 1-8, 5-bromo-1-ethyl-1H-pyrazole-3-carboxylic acid (CAS:

[1574] 2385950-17-2), and intermediate 2-4

[1575] The desired product was obtained as a mixture of 2 diastereomers which were separated by chiral SFC. The more potent diastereomer eluted first (Peak 1): column: Chiralpak AD 5pm 100x4.6mm, modifier: 40% iPrOH+0.05%NH3, flow: 3mL / min, ABPR 1800psi, 40°C; peak 1: tR= 1.16 min, >99% ee; peak 2: tR= 1.64 min, >99%.

[1576] Colorless solid: uPLC retention time 0.93 min (Method A);1H-NMR (DMSO-d₆): δ 8.01 (s, 1 H), 7.92-7.99 (m, 1 H), 7.03 (br d, 1 H), 7.00 (s, 1 H), 6.67 (s, 1 H), 5.35-5.39 (m, 0.5H), 4.87-4.92 (m, 0.5H), 4.73-4.77 (m, 0.5H), 4.51-4.56 (m, 0.5H), 4.28-4.38 (m, 1H), 4.14-4.22 (m, 3H), 3.77 (s, 3 H), 3.54-3.64 (m, 0.5H), 3.45-3.50 (m, 0.5H), 3.33 (s, 2H), 3.27 - 3.32 (m, 2H), 3.00 - 3.06 (m, 0.5H), 2.67-2.73 (m, 0.5H), 1.75-1.99 (m, 2H), 1.30-1.36 (m, 6H), 1.02-1.19 (m, 3H), 0.91 (brt, 3H); MS / ESI: m / z = 470.1 [M+H]+.

[1577] Example 55: (S)-4-(3-((R)-4-acetyl-2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-2-fluorobenzoyl)-3-ethyl-1-methylpiperazin-2-one

[1578]

[1579] Prepared using intermediate 1-7, 3-bromo-2-fluoro-benzoic acid (CAS: 161957-56-8), and intermediate 2-3

[1580] Off-white powder (contains residual TFA, 80%): uPLC retention time 0.76 min (Method A);1H-NMR (DMSO-d6): δ 8.61-7.65 (m, 1H), 7.63 (td, 1H), 7.52-7.32 (m, 2H), 7.16-6.98 (m, 2H), 4.88-4.77 (m, 1H), 4.56 (dd, 1H), 4.39 (ddt, 1H), 3.76-3.07 (m, 5H), 2.86 (d, 3H), 2.29 (s, 3H), 2.04-1.68 (m, 2H), 1.33 (d, 3H), 0.84 (dt, 3H); MS / ESI: m / z = 454.1 [M+H]+.

[1581] Example 67: (S)-4-(5-((R)-1-acetyl-3-(hydroxymethyl)-1,2,3,4-tetrahydroquinolin-6-yl)-4-methylthiophene-2-carbonyl)-3-ethyl-1-methylpiperazin-2-one or (S)-4-(5-((S)-1-acetyl-3-(hydroxymethyl)-1,2,3,4-tetrahydroquinolin-6-yl)-4-methylthio-phene-2-carbonyl)-3-ethyl-1-methylpiperazin-2-one (single diastereomer, peak 1)PAT065083-PCT-SEC01

[1582] 1M TBAF in THF Chiral Separation THF

[1583] Step 2

[1584]

[1585] Step 1: (3S)-4-(5-(1-acetyl-3-(((tert-butyldimethylsilyl)oxy)methyl)-1,2,3,4-tetrahydroquinolin-6-yl)-4-methylthiophene-2-carbonyl)-3-ethyl-1-methylpiperazin-2-one

[1586] A solution of 1-(3-(((tert-butyldimethylsilyl)oxy)methyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroquinolin-1(2H)-yl)ethan-1-one (intermediate 1-10, 85 mg, 0.17 mmol), (S)-4-(5-bromo-4-methylthiophene-2-carbonyl)-3-ethyl-1-methylpiperazin-2-one (85 mg, 0.23 mmol), and Pd(dtbpf)Cl2 (16 mg, 24 pmol) in THF (2 mL) was purged with argon. Then, 2.4M Cs2CO3in H2O (0.16 mL, 0.39 mmol) was added and the reaction mixture was stirred at 50°C for 3h. After cooling the reaction mixture was taken up in EtOAc (60 mL), washed once with brine (20 mL), dried over Na2SO4, and evaporated to dryness. Purification by flash chromatography (0-100% EtOAc / cyclohexane) afforded the title compound: uPLC retention time 1.37 min (Method A); (ESI): m / z = 584.5 [M+H]+.

[1587] Step 2: (3S)-4-(5-(1-acetyl-3-(hydroxymethyl)-1,2,3,4-tetrahydroquinolin-6-yl)-4-methylthiophene-2-carbonyl)-3-ethyl-1-methylpiperazin-2-one

[1588] To a solution of (3S)-4-(5-(1-acetyl-3-(((tert-butyldimethylsilyl)oxy)methyl)-1, 2,3,4-tetrahydroquinolin-6-yl)-4-methylthiophene-2-carbonyl)-3-ethyl-1-methylpiperazin-2-one (79 mg, 0.14 mmol) in dry THF (2 mL) was added 1M TBAF (1.08 mL, 1.08 mmol) and the obtained solution was stirred at rt for 1h. The reaction was quenched by adding sat. NaHCO3(aq.) and extracted twice with EtOAc. The combined organic layers were dried over Na2SO4and evaporated to dryness. Direct purification on RP-phase (5.5 g ISCO Redisep Gold C -column; eluent A: 0.1%NH3in H2O, B: ACN, gradient: 10% to 100% B in 20 min, flow 18 mL / min) afforded the title compound as a mixture of two diastereomers which were separated by chiral SFC. The more potent diastereomer eluted first (peak 1): column: Chiralpak IG 5pmPAT065083-PCT-SEC01 100x4.6mm, modifier: 60% MeOH+0.05%NH3, flow 3mL / min, ABPR 1800psi, 40°C; peak 1: tR= 3.3 min, 99% ee, peak 2: tR= 4.2 min, 99% ee.

[1589] Colorless powder: uPLC retention time 0.73 min (Method A);1H-NMR (600 MHz, DMSO) δ 7.62 (br s, 1 H), 7.38 (s, 1 H), 7.33 - 7.27 (m, 2H), 4.79 (t, 1 H), 4.70 (br s, 1 H), 4.32 (d, 1 H), 3.93 - 3.88 (m, 1 H), 3.64 (br s, 1 H), 3.50 (td, 1 H), 3.43 (dt, 1 H), 3.36 (dd, 1 H), 3.26 (dt, 1 H), 2.89 (d, 1 H), 2.86 (s, 4H), 2.48 (d, 1 H), 2.30 (s, 3H), 2.22 (s, 3H), 1.99 - 1.89 (m, 1 H), 1.86 (dp, 1 H), 0.91 (t, 4H); MS (ESI): m / z = 470.3 [M+H]+.

[1590] Example 68: 4-(5-(1-acetyl-1,2,3,4-tetrahydroquinoxalin-6-yl)-4-methylthiophene-2-carbonyl)-3-ethyl-1-methylpiperazin-2-one (racemate)

[1591] 4M in dioxane dioxane Step 2

[1592]

[1593] Intermediate 1-5 Step 1: tert-butyl 4-acetyl-7-(5-(2-ethyl-4-methyl-3-oxopiperazine-1-carbonyl)-3-methylthiophen-2-yl)-3,4-dihydroquinoxaline-1(2H)-carboxylate

[1594] The target compound can be prepared by the same procedure as in example 63 using tertbutyl 4-acetyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroquinoxaline-1 (2H)-carboxylate (intermediate 1-5) and 4-(5-bromo-4-methylthiophene-2-carbonyl)-3-ethyl-1-methylpiperazin-2-one as starting materials: uPLC retention time 0.95 min (Method A); MS (ESI): m / z = 541.4 [M+H]+.

[1595] Step 2: 4-(5-(1-acetyl-1,2,3,4-tetrahydroquinoxalin-6-yl)-4-methylthiophene-2-carbonyl)-3-ethyl-1-methylpiperazin-2-one

[1596] Tert-butyl 4-acetyl-7-(5-(2-ethyl-4-methyl-3-oxopiperazine-1-carbonyl)-3-methylthiophen-2-yl)-3,4-dihydroquinoxaline-1(2H)-carboxylate (110 mg, 0.17 mmol) was dissolved in 4M HCI in dioxane (2 mL) and stirred at rt for 1h. The reaction mixture was absorbed on ISOLURE® and the volatiles were removed in vacuo. After RP-chromatography (50 g ISCO Redisep Gold C -column; eluent A: 0.1%formic acid in H2O, B: ACN, gradient: 0% to 50% B in 17 min, flow 40 mL / min) the title compound was obtained as colorless powder: uPLC retention time 0.72 min (Method A);1H-NMR (600 MHz, DMSO) δ 7.63 (br s, 1H), 7.35 (s, 1H), 7.20 (br s, 1H), 6.75 (s, 1 H), 6.63 - 6.59 (m, 1 H), 6.44 (br s, 1 H), 4.70 (broad s, 1 H), 4.32 (d, 1 H), 3.68 (t, 2H), 3.64 (br s, 1H), 3.50 (td, 1H), 3.28 - 3.22 (m, 1H), 2.86 (s, 3H), 2.29 (s, 3H), 2.19 (s, 3H), 1.93 (tq, 1H), 1.86 (dq, 1H), 0.91 (t, 3H); MS (ESI): m / z = 441.4 [M+H]+.

[1597] Example 69: 4-(5-(1-acetyl-4-methyl-1,2,3,4-tetrahydroquinoxalin-6-yl)-4-methylthiophene-2-carbonyl)-3-ethyl-1-methylpiperazin-2-one (eutomer, peak2)PAT065083-PCT-SEC01

[1598] CH2O, NaBH3CN Chiral Separation MeOH

[1599]

[1600] 4-(5-(1-acetyl-1,2,3,4-tetrahydroquinoxalin-6-yl)-4-methylthiophene-2-carbonyl)-3-ethyl-1-methylpiperazin-2-one (example 64, 45 mg, 0.1 mmol) was dissolved in MeOH (2 mL). After formaldehyde was added (76 pL, 1.02 mmol, 37% solution in H2O), the solution was stirred at rt for 1h. Then, NaBH3CN was added (19 mg, 0.31 mmol) and stirring was continued at rtfor 1h. The reaction mixture was concentrated and directly subjected to RP-HPLC (C -column 30x100 mm; eluent A: 0.1%TFA in H2O, B: ACN, gradient: 2% to 48% B in 16 min, flow 50 mL / min). The lyophilizate obtained was directly subjected to chiral separation: SFC, column Chiralpak IB 5pm 100x4.6mm, modifier: eluent: 40% MeOH+0.05%NH3, flow: 3mL / min ABPR 1300psi, 40°C; peak 1: tR=1.6 min, >99% ee, peak 2: tR= 2.3 min, >99% ee.

[1601] Colorless powder: uPLC retention time 0.72 min (Method A);1H-NMR (600 MHz, DMSO-d₆) δ 7.31 - 7.45 (m, 1 H), 6.63 - 6.80 (m, 2 H), 4.57 - 4.85 (m, 1 H), 4.23 - 4.41 (m, 1 H), 3.74 - 3.87 (m, 2 H), 3.55 - 3.74 (m, 1 H), 3.45 - 3.55 (m, 1 H), 3.35 - 3.41 (m, 3 H), 2.89 - 2.98 (m, 3 H), 2.86 (s, 3 H), 2.31 (s, 1 H), 2.24 - 2.38 (m, 3 H), 2.13 - 2.23 (m, 3 H), 1.76 - 2.02 (m, 2 H), 0.85 -0.98 (m, 3 H); MS (ESI): m / z = 455.2 [M+ H]+.

[1602] Example 70: (S)-3-(4-hydroxybenzyl)-1-methyl-4-(4-methyl-5-(4-(2-oxopyrrolidin-1-yl)phenyl)thiophene-2-carbonyl)piperazin-2-one

[1603] DCM

[1604]

[1605] Step 3 Step 1: (S)-4-(5-bromo-4-methylthiophene-2-carbonyl)-3-(4-methoxybenzyl)-1-methylpiperazin-2-one

[1606] To a solution of (S)-3-(4-methoxybenzyl)-1-methylpiperazin-2-one (intermediate 2-8, 127 mg, 0.54 mmol) and 5-bromo-4-methylthiophene-2-carboxylic acid (200 mg, 0.90 mmol) in dry DMF (5 mL) was added TEA (1 mL, 7.2 mmol), and HATU (351 mg, 0.92 mmol). The reactionPAT065083-PCT-SEC01 mixture was stirred at rt for 45 min. Then, the solvent was evaporated in high vacuum and the residue was purified by flash chromatography (0%-5% MeOH / DCM) to afford the title compound: uPLC retention time 1.02 min (Method A); MS (ESI): m / z = 437.1, 439.1 [M+H]+. Step 2: (S)-3-(4-methoxybenzyl)-1-methyl-4-(4-methyl-5-(4-(2-oxopyrrolidin-1-yl)phenyl)thiophene-2-carbonyl)piperazin-2-one

[1607] To a solution of (S)-4-(5-bromo-4-methylthiophene-2-carbonyl)-3-(4-methoxybenzyl)-1-methylpiperazin-2-one (61 mg, 0.14 mmol) and 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrrolidin-2-one (CAS: 1003309-09-8, 88 mg, 0.31 mmol) in a mixture of dioxane (3 mL) and H2O (0.6 mL) was added K2CO3 (161 mg, 1.16 mmol). The suspension was flushed with argon followed by the addition of Pd(PPh3)4(10.2 mg, 8.8 pmol). The reaction mixture was heated in sealed vial at 115 °C for 1h. After reaching rt, saturated aqueous NaHCO3 was added and the mixture twice extracted with EtOAc. The combined organic phase were dried over Na2SO4and evaporated to dryness. Flash chromatography (0%-100% EtOAc / heptane, 0%-5% MeOH / DCM) afforded the desired product: uPLC retention time 0.87 min (Method A); MS (ESI): m / z = 518.3 [M+H]+.

[1608] Step 3: (S)-3-(4-hydroxybenzyl)-1-methyl-4-(4-methyl-5-(4-(2-oxopyrrolidin-1-yl)phenyl)thiophene-2-carbonyl)piperazin-2-one

[1609] To a colorless solution of (S)-3-(4-methoxybenzyl)-1-methyl-4-(4-methyl-5-(4-(2-oxopyrrolidin-1-yl)phenyl)thiophene-2-carbonyl)piperazin-2-one (55 mg, 0.64 mmol) in dry DCM (3 mL) cooled down to 0-5°C under Ar was slowly injected 1M BBrs in DCM (0.64 mL, 0.64 mmol) through the septum. The resulting solution was stirred at 0-5°C for 3.5hr. Then the reaction was quenched by adding MeOH (2 mL). A small amount of H2O was added and the mixture was evaporated in vacuo. RP-chromatography (15.5 g ISCO Redisep Gold Cis-column; eluent A: 0.1%NH3in H2O, B: ACN, gradient: 0% to 50% B in 15 min, 50% to 100% B in 6 min, flow 30 mL / min) afforded the final product as colorless powder: uPLC retention time 0.75 min (Method A);1H NMR (600 MHz, DMSO-d6) δ 9.27 (s, 1H), 7.78 - 7.73 (m, 2H), 7.47 (d, 2H), 7.08 (br s, 1 H), 6.98 - 6.93 (m, 2H), 6.67 (d, 2H), 4.83 (br s, 1 H), 4.21 (br s, 1 H), 3.86 (t, 2H), 3.42 (d, 1H), 3.29 (br s, 1H), 3.15 (m, 2H), 3.03 (dd, 1H), 2.87 (s, 3H), 2.52 (t, 2H), 2.22 (s, 3H), 2.12 -2.04 (m, 2H); MS / ESI: m / z = 504.3 [M+H]+.

[1610] Example 72: (R)-7-(2-((S)-2-ethyl-4-methyl-3-oxopiperazine-1-carbonyl)-4-methylthiazol-5-yl)-N,2-dimethyl-2,3-dihydro-4H-benzo[b][1,4]oxazine-4-carboxamide

[1611]

[1612] PAT065083-PCT-SEC01 Prepared using (R)-N,2-dimethyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazine-4-carboxamide (synthesis analogous to intermediate 1-7), methyl 5-bromo-4-methyl-1,3-thiazole-2-carboxylate (CAS: 79247-79-3), and intermediate 2-3.

[1613] Beige solid: uPLC retention time 0.87 min (Method A);1H NMR (400 MHz, DMSO-d6) δ 7.73 (d, 1 H), 6.98-7.05 (m, 3H) 5.55 (br d, 1 H) 4.77 (br dd, 1 H) 4.20-4.28 (m, 1 H) 3.99 (dd, 1 H) 3.62-3.73 (m, 1H) 3.41-3.59 (m, 1H) 3.31 (br s, 8H) 3.19 (dd, 1H) 2.86 (s, 3H) 2.65-2.69 (m, 3H) 1.82-2.04 (m, 2H) 1.30 (d, 4H) 0.84-0.96 (m, 4H); MS (ESI): m / z = 472.2 [MH+], 943.3 [M2H+], Example 74:

[1614] (S)-4-(5-(4-((3R,5R)-3,5-dimethyl-2-oxopyrrolidin-1-yl)phenyl)-4-methylthiazole-2-carbonyl)-1,3-dimethylpiperazin-2-one; (S)-4-(5-(4-((3R,5S)-3,5-dimethyl-2-oxopyrrolidin-1-yl)phenyl)-4-methylthiazole-2-carbonyl)-1,3-dimethylpiperazin-2-one; (S)-4-(5-(4-((3S,5S)-3,5-dimethyl-2-oxopyrrolidin-1-yl)phenyl)-4-methylthiazole-2-carbonyl)-1,3-dimethylpiperazin-2-one; or (S)-4-(5-(4-((3S,5R)-3,5-dimethyl-2-oxopyrrolidin-1-yl)phenyl)-4-methylthiazole-2-carbonyl)-1,3-dimethylpiperazin-2-one (single diastereomer, peak 4)

[1615] or

[1616]

[1617] Prepared using 3,5-dimethyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrrolidin-2-one (obtained from 3,5-dimethylpyrrolidin-2-one and (4-chlorophenyl)boronic acid), 5-bromo-4-methyl-1,3-thiazole-2-carboxylate (CAS: 79247-79-3), and (S)-1,3-dimethylpiperazin-2-one (CAS: 1240300-34-8). The desired product was obtained as a mixture of 4 diastereomers which were separated by chiral SFC. The most potent diastereomer eluted last (peak 4): column: Chiralpak IH 5pm 100x4.6mm, eluent: 40% IPA+0.05%NH3, Flow: 3mL / min, ABPR 1800psi, 40°C; peak 1: tR= 1.48 min, 99.5% de; peak 2: tR= 1.89 min, 99.5% de; peak 3: tR = 2.07 min, 96.4% de; peak 4: tR = 4.72 min, 99.5% de.

[1618] uPLC retention time: 0.88 min (Method A);1H NMR (600 MHz, DMSO-d6) δ 7.58 (cm, 2H), 7.50 (cm, 2H), 5.81, 5.53 (2x d, 1 H), 4.77, 4.46 (2x d, 1 H), 4.26-4.37 (m, 1 H), 3.70, 3.59 (2x br t,PAT065083-PCT-SEC01 1 H), 3.48, 3.38 (2x br t, 1 H), 2.88 (br d, 3H), 2.53-2.63 (m, 2H), 2.52 (s, 3H), 1.54, 1.42 (2x d, 3H), 1.26-1.35 (m, 1 H), 1.18 (d, 3H), 1.15 (d, 3H); MS (ESI): m / z = 441.2 [MH+], 903.3 [M2Na+], Example 75: (S)-3-(4-(3-((S)-2-Ethyl-4-methyl-3-oxopiperazine-1-carbonyl)-1-methyl-1H-pyrazol-5-yl)phenyl)-5-methyloxazolidin-2-one or (R)-3-(4-(3-((S)-2-Ethyl-4-methyl-3-oxopiperazine-1-carbonyl)-1-methyl-1H-pyrazol-5-yl)phenyl)-5-methyloxazolidin-2-one (single diastereomer, peak 2)

[1619]

[1620] Prepared using 5-methyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)oxazolidin-2-one (obtained 5-methyloxazolidin-2-one from and 1,4-dibromobenzene), 5-bromo-1-methyl-1H-pyrazole-3-carboxylic acid (CAS: 1222174-93-7), and intermediate 2-3.

[1621] The desired product was obtained as a mixture of 2 diastereomers which were separated by chiral SFC. The more potent diastereomer eluded last (peak 2): Chiralpak IB 5pm 100x4.6mm, eluent: 35% MeOH+0.05%NH3, Flow: 3mL / min, ABPR 1800psi, 40°C; peak 1: tR= 1.97 min, 95.2% ee; peak 2: tR= 2.18 min, 95.8% ee.

[1622] uPLC retention time 0.58 min (Method A);1H NMR (600 MHz, DMSO-d6) δ 7.69 (m, 2H), 7.61 (m, 2H), 6.75 (s, 1H), 4.95 (br d, 1H) 4.81-4.87 (m, 2H), 4.22 (t, 1H), 3.91 (s, 3H), 3.72 (dd, 1H), 3.56-3.63 (m, 1H), 3.45-3.52 (m, 1H), 3.23-3.31 (m, 1H), 2.86 (s, 3H), 1.92-1.98 (m, 1H), 1.79-1.90 (m, 1H), 1.44 (d, 3H), 0.90 (t, 3H); MS (ESI): m / z = 426.4 [MH+], 851.6 [M2H+], 873.6 [M2Na+],

[1623] Example 76: 2-((1 E,3E)-5-((E)-1-((S)-1-(5-(4-acetamidophenyl)-4-chlorothiophen-2-yl)-3-(4-hydroxy benzyl)- 1,4,18-trioxo-8, 11,14-trioxa-2,5, 17-triazatricosan-23-yl)-3,3-dimethyl-5-sulfoindolin-2-ylidene)penta-1,3-dien-1-yl)-1-ethyl-3,3-dimethyl-3H-indol-1-ium-5-sulfonate Fluorescence labeled STAT6 binder for TR-FRET biochemical assayPAT065083-PCT-SEC01

[1624] Step 4

[1625] Cy5-SE, NEt3 DMF

[1626] Step 5

[1627]

[1628] Step 1: Methyl (S)-2-(5-(4-acetamidophenyl)-4-chlorothiophene-2-carboxamido)-3-(4-(tert-butoxy)phenyl)propanoate

[1629] To a solution of 5-(4-acetamidophenyl)-4-chlorothiophene-2-carboxylic acid (intermediate 3-1, 150 mg, 0.51 mmol) in DMF (3 mL) was added methyl (S)-2-amino-3-(4-(tert-butoxy)phenyl)-propanoate hydrochloride (161 mg, 0.56 mmol), HATU (231 mg, 0.61 mmol) and DIPEA (0.27 mL, 1.52 mmol) and then the reaction mixture was stirred at room temperature for 18 hours.

[1630] The reaction mixture is diluted with EtOAc (30 mL) and then washed with saturated aqueous NaHCO3(10 mL) and NH4CI solution (10 mL). The organic phase was dried (phase separator) and concentrated under vacuum. The residue was purified by flash chromatography (0-100%-EtOAc / cyclohexane) to give the title compound as a colorless oil: uPLC retention time 1.16 min (Method A); MS / ESI: m / z = 529.1 / 531.1 [M+H]+.

[1631] Step 2: (S)-2-(5-(4-Acetamidophenyl)-4-chlorothiophene-2-carboxamido)-3-(4-(tert-butoxy)phenyl)propanoic acid

[1632] To a solution of methyl (S)-2-(5-(4-acetamidophenyl)-4-chlorothiophene-2-carboxamido)-3-(4-(tert-butoxy)phenyl)propanoate (250 mg, 0.47 mmol) in THF (2 mL) and water (0.4 mL) was added lithium hydroxide monohydrate (60 mg, 1.42 mmol). The reaction mixture was stirred at room temperature for 60 h. Volatiles were evaporated, and the residue was taken up in water.

[1633] The water phase was acidified to pH=1 with 6M HCI solution, then the reaction mixture was extracted with EtOAc (2x 10 mL). The combined organic phases were dried (phase separator)PAT065083-PCT-SEC01 and concentrated under vacuum to obtain the title compound as a yellow oil: uPLC retention time 1.06 min (Method A); MS / ESI: m / z = 515.3 / 517.3 [M+H]+. The crude material was used without further purification in the next step.

[1634] Step 3: tert-Butyl (S)-(1-(5-(4-acetamidophenyl)-4-chlorothiophen-2-yl)-3-(4-(tert-butoxy) benzyl)- 1,4-dioxo-8, 11,14-trioxa-2, 5-diazahexadecan- 16-yl)carbamate

[1635] To a solution of (S)-2-(5-(4-acetamidophenyl)-4-chlorothiophene-2-carboxamido)-3-(4-(tert-butoxy)phenyl)propanoic acid (250 mg, 0.49 mmol) in DMF (2.5 mL) is added tert-butyl (2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethyl)carbamate (156 mg, 0.53 mmol), HATU (221 mg, 0.58 mmol) and DIPEA (0.17 mL, 0.97 mmol). The reaction mixture is stirred at room temperature for 45 min. Then, the reaction mixture is diluted with EtOAc (30 mL) and then washed with saturated aqueous NaHCO3(10 mL) and NH4CI (10 mL) solution. The organic phase is dried (phase separator) and concentrated under vacuum. The residue was purified by flash chromatography (0%-9% MeOH / DCM) followed by RP-HPLC (XBridge C18OBD 30x100 mm, 5 μm; eluent A: 0.2% TFA in H2O, B: ACN, gradient: 5% to 75% B in 15 min, flow 50 mL / min) to give the title compound as a colorless solid: uPLC retention time 1.23 min (Method A); MS / ESI: m / z = 789.4 [M+H]+.

[1636] Step 4: (S)-5-(4-acetamidophenyl)-N-(1-amino-15-(4-hydroxyphenyl)-13-oxo-3,6,9-trioxa-12-azapentadecan-14-yl)-4-chlorothiophene-2-carboxamide

[1637] To a solution of tert-Butyl (S)-(1-(5-(4-acetamidophenyl)-4-chlorothiophen-2-yl)-3-(4-(tert-butoxy)benzyl)-1,4-dioxo-8,11,14-trioxa-2,5-diazahexadecan-16-yl)carbamate (230 mg, 0.29 mmol) in DCM (2 mL) was added TFA (0.34 mL, 4.4 mmol). The reaction mixture was stirred at room temperature for 18 h. A Pora Pack cartridge was first washed with MeOH. After loading the reaction mixture, TFA was eluted with MeOH MeOH. Then, the compound was eluted with 7M NH3 in MeOH. Evaporation of the solvent afforded the as a yellow oil: uPLC retention time 0.57 min (Method A); MS / ESI: m / z = 633.2 [M+H]+.

[1638] Step 5: 2-((1E,3E)-5-((E)-1-((S)-1-(5-(4-acetamidophenyl)-4-chlorothiophen-2-yl)-3-(4-hydroxybenzyl)- 1,4,18-trioxo-8, 11,14-trioxa-2,5, 17-triazatricosan-23-yl)-3,3-dimethyl-5-sulfoindolin-2-ylidene)penta-1,3-dien-1-yl)-1-ethyl-3,3-dimethyl-3H-indol-1-ium-5-sulfonate To a solution of Cy5-SE (Angene AGN-PC-0PYLM6, CAS: 146368-14-1) (101 mg, 0.13 mmol) in DMF (1.5 mL) was added (S)-5-(4-acetamidophenyl)-N-(1-amino-15-(4-hydroxyphenyl)-13-oxo-3,6,9-trioxa-12-azapentadecan-14-yl)-4-chlorothiophene-2-carboxamide (85 mg, 134 mmol) and TEA (56 pL, 0.4 mmol). The reaction mixture is stirred at room temperature for 2 h. More Cy5-SE (10 mg) was added and stirring at room temperature was continued for 18 h. The reaction mixture was absorbed on ISOLUTE® and purified in two runs by RP-chromatography (26 g ISCO Redisep C18-column; eluent A: 0.1%FA in H2O, B: ACN, gradient: 5% to 50% B in 12 min, flow 35 mL / min). The fractions containing the desired product were combined and concentrated under reduced pressure, followed by freeze-drying overnightPAT065083-PCT-SEC01 to obtain the title compound as a blue colored solid: uPLC retention time 0.65 min (Method A);1H NMR (600 MHz, DMSO-d6) δ 10.16 (s, 1H), 9.16 (bs, 1H), 8.72 (d, 1H), 8.35 (t, 2H), 8.19-8.09 (m, 1H), 7.95 (s, 1H), 7.82 (s, 3H), 7.68 (d, 2H), 7.66-7.62 (m, 2H), 7.58 (d, 2H), 7.34-7.28 (m, 2H), 7.09 (d, 2H), 6.62 (d, 2H), 6.57 (t, 1H), 6.29 (dd, 2H), 4.55 (td, 1H), 4.18–4.01 (m, 4H), 3.52-3.45 (m, 8H), 3.36-3.30 (m, 6H), 3.24-3.18 (m, 2H), 3.15 (q, 2H), 2.95 (dd, 1H), 2.79 (dd, 1H), 2.12-1.99 (m, 5H), 1.68 (s, 14H), 1.52 (p, 2H), 1.31 (p, 2H), 1.25 (t, 3H); MS / ESI: m / z = 1272.6 [M+H]+.

[1639] BIOLOGICAL ASSAYS AND DATA

[1640] hSTAT6 TR-FRET biochemical assay

[1641] To assess binding of test compounds to human STAT6 (hSTAT6) protein, an in vitro competitive binding assay was utilized. To this end, recombinant hSTAT6 (amino acids 2-640)-Avi_Biotin tagged protein was prepared at WuXi App Tec (Suzhou) Co. LTd. (Lot: 122274; recombinant protein stored at -80 °C in buffer containing 50 mM HEPES / NaOH, 150 mM NaCI, 5% Glycerol, and 1mM TCEP at pH8.3). Test compound interactions that interfere with the binding of a Cy5-conjugated small molecule STAT6 binder (probe, Example 68) to C-terminally biotinylated STAT6(2-640) (flSTAT6-BTN) bound by Eu-SA (Europium-labeled streptavidin) were detected and quantified using a sensitive TR-FRET (time-resolved fluorescence energy transfer)-based competitive binding assay format. Test compound binding events that result in spatial separation of Eu as the TR-FRET donor and Cy5 (probe) as the corresponding acceptor translate into a ceasing of energy transfer.

[1642] To determine the IC50 (half maximal inhibitory concentration, IC50) value for a given test compound’s ability to displace the Cy5-conjugated probe, i.e., inhibit the binding of the probe to hSTAT6, 45 nL per well of serially diluted (dose-response curve starting at 100 pM) test compound, dissolved in 90% (v / v) DMSO / water, were transferred from a master plate (384 well LabCyte LP-0200) to an assay microtiter plate (384 well Corning 4512, white round bottom polystyrene) using an ECHO 555 Liquid Handler (LabCyte, Sunnyvale, CA, USA). For the assay, 1.5 pl of flSTAT6-BTN (37.5 nM; 3X working solution) and 1.5 pl of Eu-SA (6.0 nM; 3X working solution; Lance EuW1024, AD0063, Revvity, 8.3 pM stock solution) were added to the assay plate with a CERTUS FLEX dispenser (Fritz Gyger AG, Gwatt, Switzerland) and preincubated for 30 min. The preincubation and subsequent measurements were conducted in "assay buffer," which was comprised of 50 mM HEPES / NaOH at pH 7.5, 150 mM NaCI, 1 mM EDTA, 2 mM TCEP, 0.005% (w / v) Tween-20, and 0.05% (w / w) BSA. All solutions were handled at a room temperature of 22 °C. Then, using the CERTUS FLEX dispenser, 1.5 pL of the probe (300 nM; 3X working solution) in assay buffer were added per well to the assay plate already containing pre-spotted test compound and the preincubated flSTAT6-BTN: Eu-SA (1:1), resulting in final assay concentrations of: 12.5 nM flSTAT6-BTN, 100 nM probe (example 68), 2 nM Eu-SA, and 0.9% (v / v) DMSO. After 60 minutes of incubation, the plate measurement was conducted with a PHERAstar FSX plate reader (BMG Labtech, Offenburg, Germany) equippedPAT065083-PCT-SEC01 with dual wavelength detection (Eu excitation at 337 nm, Eu emission at 620 nm = donor, Cy5 emission at 665 nm = acceptor).

[1643] The IC50 value was calculated in three steps as follows:

[1644] 1. Transformation of ratio of raw values: f * x1 / x2= 1000 * acceptor value / donor value.

[1645] 2. Control-based normalization: xn= -100 (x - NC) / (AC - NC), where AC and NC are the median of active control (AC) and neutral control (NC), respectively, and x is the transformed ratio above for a given test compound and dose.

[1646] 3. Auto fitting of the dose response curve using a parametric logistic function and Hillslope model: y = Ainf+ (A0- Ainf) / (1 + 10n*(log10 x - log10 IC50)), where x is the test compound concentration, n is the Hill coefficient (Hill slope) and IC50 is the test compound concentration at which the half maximal effect between Ao and Amf is reached, with Ao being the asymptotic value (plateau) at very low concentrations and Amf being the asymptotic value (plateau) at very large concentrations.

[1647] HaCaT STAT6 GFP reporter assay

[1648] To assess the effect of test compounds on hSTAT6 function as a transcription factor, a cellular reporter gene assay (RGA) was utilized by placing the expression of a GFP (green fluorescent protein) transgene under the control of a STAT6 response element. Specifically, HaCaT cells (from Addexbio Technologies, catalog number T0020001), a keratinocyte cell line from adult human skin (Boukamp et al., J. Cell. Biol. 1988), were maintained and cultured at 37°C and 5% CO2 in RPMI1640 media (Life Technologies #72400), supplemented with 10% heat inactivated FCS (fetal calf serum, Bioconcept #2-01 F26-I) and 1% Penicillin-Streptomycin (Life Technologies #15140). To generate the HaCaT_STAT6_GFP reporter cell line, HaCaT cells were infected 24 hours post-seeding with a lentivirus that included a 4x C / EBP-STAT6 DNA binding site response element upstream of a GFP (green fluorescent protein) reporter gene (Vectalys, Flash Therapeutics) at MOI (multiplicity of infection) of 5, 10 & 20. Infection media consisted of above cell culture media supplemented with polybrene at a final concentration of 4 pg / mL. After 24 hours, infection media was replaced with fresh cell culture media. After 3 more days in culture, cells were analyzed by stimulating the cells with IL-4 (interleukin-4, 10 ng / mL) and IFNp (interferon p, 10 ng / mL) for 24 hours and measuring GFP fluorescence. Subsequently, clonal selection of cells based on positive GFP signal was performed by FACS (fluorescence-activated cell sorting) using an FACSAria cell sorter (Beckton Dickinson). For the cellular assay, clonally selected and expanded HaCaT cells were seeded into an assay plate (1536 well, Greiner 792091-191, black clear-bottom, custom-made) at 600 cells / 5 pL per well using a Multidrop dispenser (Thermo Fisher Scientific) and cultured for 24 hours at 37°C and 5% CO2in above media.

[1649] To determine IC50 (half maximal inhibitory concentration, IC50) values for a given test compound’s ability to inhibit IL-4 stimulation induced and STAT6 dependent expression of the GFP reporter gene, 45 nL per well of serially diluted (dose-response curve starting at 90 pM)PAT065083-PCT-SEC01 test compound, dissolved in 90% (v / v) DMSO / water, were transferred from a master plate (384 well LabCyte LP-0200) to cultured cells in assay plate using an ECHO 555 Liquid Handler (LabCyte, Sunnyvale, CA, USA) and incubated for 6 hours, followed by stimulation of the cells with IL-4 (10 ng / mL) and additional incubation for 24 hours. Cell nuclei were stained with Hoechst 33342 (trihydrochloride trihydrate, Invitrogen H3570) and live GFP fluorescence was measured at 488 nM while the Hoechst 33342 signal was collected at 405 nM using a high content imaging and screening system (CV7000, Yokogawa). The Hoechst 33342-based nuclei count per well served as a proxy for cell number while the GFP fluorescence signal was converted into an IC50 value as follows:

[1650] 1. Control-based normalization: xn= -100 (x - NC) / (AC - NC), where AC and NC are the median of active control (AC) and neutral control (NC), respectively, and x is the GFP fluorescence intensity value (at 488 nm) for a given compound and dose.

[1651] 2. Auto fitting of the dose response curve using a parametric logistic function and Hillslope model: y = Ainf+ (A0- Ainf) / (1 + 10n*(log10 x - log10 IC50)), where x is the test compound concentration, n is the Hill coefficient (Hill slope) and IC50 is the test compound concentration at which the half maximal effect between Ao and Amf is reached, with Ao being the asymptotic value (plateau) at very low concentrations and Amf being the asymptotic value (plateau) at very large concentrations.

[1652] The IC50 values as a measure of the inhibitory effect exerted by selective test compounds in the hSTAT6 competitive binding assay (TR-FRET) or on hSTAT6 activity in the cellular GFP reporter gene assay (RGA), as described above respectively, are summarized Table 2.

[1653] Table 2

[1654] hSTAT6 HaCaT hSTAT6 HaCaT Example TR-FRET hSTAT-GFP Example TR-FRET hSTAT-GFP IC50[μM] RGA IC50[μM] IC50[μM] RGA IC50[μM]

[1655] 38 0.024 0.089 1 0.054 0.81 39 0.084 2.60 2 0.088 2.06 40 0.044 1.50 3 0.222 2.41 41 0.098 1.62 5 0.053 0.50 42 0.029 0.27 6 0.034 15.1 43 0.610 20.6 7 0.084 1.40 44 0.837 35.7 8 0.016 2.24 45 0.074 0.48 9 0.177 1.56 46 0.094 0.45 10 0.070 n.d. 47 0.138 1.10 11 0.102 0.19 48 0.342 16.4 12 0.055 0.39 49 0.030 6.40

[1656]

[1657]

[1658] PAT065083-PCT-SEC01 hSTAT6 HaCaT hSTAT6 HaCaT Example TR-FRET hSTAT-GFP Example TR-FRET hSTAT-GFP IC50[μM] RGA IC50[μM] IC50[μM] RGA IC50[μM] 13 0.733 16.5 50 0.210 0.57 14 0.196 8.54 51 0.567 24.7 15 0.364 1.93 52 0.197 1.35 16 0.084 0.64 53 0.167 1.71 17 0.497 5.75 54 0.238 0.49 18 0.145 18.2 55 1.066 2.45 19 0.047 6.78 67 0.180 0.252 20 0.189 2.09 68 0.506 2.76 21 0.272 3.45 69 0.342 1.26 22 0.239 2.68 70 0.068 >90 23 0.247 4.21 72 2.44 7.58 24 0.856 11.4 74 0.292 2.79 25 0.555 7.17 75 5.00 >90

[1659]

[1660] 26 0.506 1.92

[1661] 27 0.949 10.7

[1662] 28 1.152 n.d.

[1663] 36 0.240 0.90

[1664] 37 0.219 3.37

[1665]

Claims

1. PAT065083-PCT-SEC01CLAIMS1. A compound of formula (I):oR4bR4_ I H(B)R1J.R2R3or a stereoisomer or pharmaceutically acceptable salt thereof, wherein:X is N or CR13, wherein R13is selected from the group consisting of hydrogen, halo, CN, NO2, Ci-Csalkyl, Ci-Csalkoxy, -S(O)o-2(Ci-C3)alkyl and NR14R15, and wherein R14and R15are each independently selected from the group consisting of hydrogen, Ci-Csalkyl and Cs-Cscycloalkyl; ring B is 1,3-phenylene, or ring B is a monocyclic 5-membered heteroarylene;R1is C1-C3alkylcarbonyl or C1-C3alkoxycarbonyl and R2and R3are hydrogen; alternatively, R1is Ci-Csalkylcarbonyl, Ci-Csalkoxycarbonyl, Ci-Csalkyl-NH-carbonyl, Ci-C3alkyl-N(Ci-C3alkyl)-carbonyl or -S(O)2(Ci-C3)alkyl, and R2and R3, together with the nitrogen and carbon atoms that they each are attached to and the neighboring carbon atom, form a 6-membered heterocycloalkyl, which optionally comprises one further heteroatomic ring member selected from the group consisting of O, NH and N(Ci-C3alkyl), and is optionally substituted with R12, wherein R12is selected from the group consisting of Ci-Csalkyl,Ci-CsalkoxyCi-Csalkyl and Ci-Cshydroxyalkyl;alternatively, R3is hydrogen, and R1and R2, together with the nitrogen they are attached to, form an unsubstituted, monocyclic 5-membered heteroaryl, or a monocyclic 5-membered heterocycloalkyl (i) that is substituted with one or two oxo and is optionally substituted with phenyl or with up to three C1-C3alkyl, and (ii) that optionally fuses with a second ring to form a fused bicyclic 9-membered ring;R4is hydrogen, C1-C3alkyl, C1-C3alkoxy or halo, wherein each of said C1-C3alkyl and C1-C3alkoxy is unsubstituted or is substituted with one or more substituents each independently selected from the group consisting of halo, hydroxy and C1-C3alkoxy;R4bis hydrogen, unsubstituted C1-C3alkyl or halo;R5is -CHR8CH2R7or -CHR8CH(OH)R7and R6is hydrogen, wherein R7is hydroxy, hydroxyphenyl or bicyclic C5-C7cycloalkyl optionally substituted with hydroxy, and R8is C1-C3alkyl or C1-C3alkyl-NH-carbonyl;alternatively, R5and R6, together with the nitrogen they are attached to, form a monocyclic C4-C6heterocycloalkyl comprising one or two nitrogen heteroatoms and being substituted withPAT065083-PCT-SEC01 oxo and being optionally substituted with up to three further substituents being R9, R10and R11, wherein each of R9, R10and R11is independently selected from the group consisting of C1-C3alkyl, C1-C3hydroxyalkyl, C1-C3fluoroalkyl, C1-C3alkoxyC1-C3alkyl, C1-C3alkoxy, benzyl substituted with hydroxy, and bicyclic C5-C7cycloalkyl(C0-1alkyl) substituted with hydroxy.

2. The compound according to claim 1, wherein ring B is a monocyclic 5-membered heteroarylene (i) comprising one sulfur and optionally one nitrogen heteroatom, or (ii) comprising one or two nitrogen heteroatoms.

3. The compound according to claim 1 or 2, wherein ring B is a monocyclic 5-membered heteroarylene selected from the group consisting of divalent thiophenyl, thiazolyl, pyrazolyl and imidazolyl.

4. The compound according to any one of claims 1 to 3, having Formula (Ila), (lib), (lie) or (Hd):or a stereoisomer or pharmaceutically acceptable salt thereof.

5. The compound according to claim 1, having Formula (VII):(VII)or a stereoisomer or pharmaceutically acceptable salt thereof.

6. The compound according to any one of claims 1-5 having Formula (III):PAT065083-PCT-SEC01 oor a stereoisomer or pharmaceutically acceptable salt thereof, wherein:each Q is independently nitrogen or CH.

7. The compound according to claim 1 or 6, selected from:or a stereoisomer or pharmaceutically acceptable salt thereof, wherein:each Q is independently nitrogen or CH; andR3is hydrogen.

8. The compound according to any one of claims 1-5, having Formula (IV):Oor a stereoisomer or pharmaceutically acceptable salt thereof, wherein:Wis CH2, O, or NH;each Q is independently nitrogen or CH; andthe fused bicyclic 9-membered ring accommodating W comprises at the most three nitrogen atoms.PAT065083-PCT-SEC01 9. The compound according to any one of claims 1 or 8, selected from:or a stereoisomer or pharmaceutically acceptable salt thereof, wherein:Wis O or NH;R3is hydrogen;each Q is independently nitrogen or CH; andthe fused bicyclic 9-membered ring accommodating W comprises at the most three nitrogen atoms.

10. The compound according to any one of claims 1-5, having Formula (V):or a stereoisomer or pharmaceutically acceptable salt thereof, wherein:R1is C1-C3alkylcarbonyl, C1-C3alkoxycarbonyl, C1-C3alkyl-NH-carbonyl, C1-C3alkyl-N(C1-C3alkyl)-carbonyl or -S(O)2(C1-C3)alkyl;PAT065083-PCT-SEC01 R12is hydrogen or R12is selected from the group consisting of Ci-C3alkyl,Ci-C3alkoxyCi-C3alkyl and Ci-C3hydroxyalkyl; andY is O, NH, NCH3, N(CH2CH3), N(CH2CH2CH3) or CH2.

11. The compound according to any one of claims 1 or 10, selected from:R1andK(Va) or a stereoisomer or pharmaceutically acceptable salt thereof, wherein:R1is Ci-C3alkylcarbonyl, Ci-C3alkoxycarbonyl, Ci-C3alkyl-NH-carbonyl, Ci-C3alkyl-N(Ci-C3alkyl)-carbonyl or -S(O)2(Ci-C3)alkyl;R12is hydrogen or R12is selected from the group consisting of Ci-C3alkyl,Ci-C3alkoxyCi-C3alkyl and Ci-C3hydroxyalkyl; andY is O, NH, NCH3, N(CH2CH3), N(CH2CH2CH3) or CH2.

12. The compound according to any one of claims 1-5, having Formula (VI):or a stereoisomer or pharmaceutically acceptable salt thereof, wherein:R1is Ci-C3alkylcarbonyl or Ci-C3alkoxycarbonyl.

13. The compound according to any one of claims 1-5, having Formula (III’):PAT065083-PCT-SEC01or a stereoisomer or pharmaceutically acceptable salt thereof, wherein:W is CH2, CH(C1-C3alkyl), O or NH; andeach Z is independently hydrogen, phenyl or C1-C3alkyl.

14. The compound according to any one of the preceding claims, or a stereoisomer or pharmaceutically acceptable salt thereof,OAwherein5is selected from the group consisting of:R6R7is hydroxy, hydroxyphenyl or bicyclic C5-C7cyloalkyl optionally substituted with hydroxy;R8is C1-C3alkyl or C1-C3alkyl-NH-carbonyl; andR9, R10and R11are independently selected from the group consisting of hydrogen, C1-C3alkyl, C1-C3hydroxyalkyl, C1-C3fluoroalkyl, C1-C3alkoxyC1-C3alkyl, C1-C3alkoxy, benzyl substituted with hydroxy, and bicyclic C5-C7cycloalkyl(C0-1alkyl) substituted with hydroxy.

15. The compound according to any one of claims 1-3, 6, 8, 10 and 12-13, having Formula (VIIIa), (VIIIb), (VIIIc) or (VIIId):PAT065083-PCT-SEC01or a stereoisomer or pharmaceutically acceptable salt thereof, wherein:R7is hydroxy, hydroxyphenyl or bicyclic Cs-Cycyloalkyl optionally substituted with hydroxy; R8is Ci-Csalkyl or Ci-Csalkyl-NH-carbonyl; andR9, R10and R11are independently selected from the group consisting of hydrogen, C1-C3alkyl, C1-C3hydroxyalkyl, C1-C3fluoroalkyl, C1-C3alkoxyC1-C3alkyl, C1-C3alkoxy, benzyl substituted with hydroxy, and bicyclic C5-C7cycloalkyl(C0-1alkyl) substituted with hydroxy.

16. The compound according to any one of claims 1-3, 6, 8, 10 and 12-13, selected from:PAT065083-PCT-SEC01(IXd)(ixg)(IXf) or a stereoisomer or pharmaceutically acceptable salt thereof.

17. The compound according to any one of the preceding claims or a pharmaceutically acceptable salt thereof, wherein halo is chloro or fluoro.

18. The compound according to any one of the preceding claims or a pharmaceutically acceptable salt thereof, wherein C1-C3fluoroalkyl is trifluoromethyl or trifluoroethyl.

19. The compound according to any one of the preceding claims or a pharmaceutically acceptable salt thereof, wherein R4is methyl, ethyl, chloro, fluoro, methoxy or-OCH2CH3.

20. The compound according to any one of claims 1 to 3, having Formula (II)or a stereoisomer or pharmaceutically acceptable salt thereof, wherein:ring B is a monocyclic 5-membered heteroarylene;PAT065083-PCT-SEC01 R1is C1-C3alkylcarbonyl, C1-C3alkoxycarbonyl, C1-C3alkyl-NH-carbonyl, C1-C3alkyl-N(C1-C3alkyl)-carbonyl or -S(O)2(C1-C3)alkyl, and R2and R3, together with the nitrogen and carbon atoms that they each are attached to and the neighboring carbon atom, form a 6-membered heterocycloalkyl, which optionally comprises one further heteroatomic ring member selected from the group consisting of O, NH and N(C1-C3alkyl), and is optionally substituted with R12, wherein R12is selected from the group consisting of C1-C3alkyl, C1-C3alkoxyC1-C3alkyl and C1-C3hydroxyalkyl;R4is hydrogen, C1-C3alkyl, C1-C3alkoxy or halo, wherein each of said C1-C3alkyl and C1-C3alkoxy is unsubstituted or is substituted with one or more substituents each independently selected from the group consisting of halo, hydroxy and C1-C3alkoxy;R4bis hydrogen, unsubstituted C1-C3alkyl or halo; andR5and R6, together with the nitrogen they are attached to, form a monocyclic C4-Ceheterocycloalkyl comprising one or two nitrogen heteroatoms and being substituted with oxo and being optionally substituted with up to three further substituents being R9, R10and R11, wherein each of R9, R10and R11is independently selected from the group consisting ofC1-C3alkyl, C1-C3hydroxyalkyl, C1-C3fluoroalkyl, C1-C3alkoxyC1-C3alkyl, C1-C3alkoxy, benzyl substituted with hydroxy, and bicyclic C5-C7cycloalkyl(C0-1alkyl) substituted with hydroxy.

21. The compound according to any one of the preceding claims, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein R4bis hydrogen, methyl, chloro or fluoro.

22. The compound according to any one of the preceding claims, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein said compound is selected from Table 1, or a stereoisomer or pharmaceutically acceptable salt thereof.

23. A pharmaceutical composition comprising a compound, or a stereoisomer or pharmaceutically acceptable salt thereof, according to any one of claims 1 to 22, and a pharmaceutically acceptable carrier.

24. A combination comprising a compound, or a stereoisomer or pharmaceutically acceptable salt thereof, according to any one of claims 1 to 22, and one or more therapeutically active agents.

25. A combination according to claim 24, wherein the therapeutically active agent is selected from the group consisting of an MRGPRX2 inhibitor, a histamine antagonist, a PKC theta inhibitor, a PDE4 inhibitor and an bIRAK4 inhibitor and a Btk inhibitor such as Remibrutinib.

26. A compound, or a stereoisomer or pharmaceutically acceptable salt thereof, according to any one of claims 1 to 22, for use as a medicament.

27. A compound, or a stereoisomer or pharmaceutically acceptable salt thereof, according to any one of claims 1 to 22 for use in the treatment, or prevention of a disease or disorder that is mediated by IL-4 and / or IL-13.PAT065083-PCT-SEC01 28. A compound, or a stereoisomer or pharmaceutically acceptable salt thereof, according to any one of claims 1 to 22 for use in the treatment, or prevention of a STAT6-dependent disease or disorder.

29. A compound, or a stereoisomer or pharmaceutically acceptable salt thereof, according to any one of claims 1 to 22, for use in the treatment, or prevention of a disease selected from the group consisting of atopic dermatitis asthma, chronic rhinosinusitis with nasal polyposis, eosinophilic esophagitis, prurigo nodularis, chronic prurigo, chronic spontaneous urticaria, chronic pruritus, bullous pemphigoid, chronic obstructive pulmonary disease, ulcerative colitis, eosinophilic gastroenteritis and food allergy.

30. A compound, or a stereoisomer or pharmaceutically acceptable salt thereof, according to any one of claims 1 to 22, for use in the treatment of atopic dermatitis.

31. A method of treating atopic dermatitis, wherein the method comprises administering to the subject a therapeutically effective amount of the compound, or a stereoisomer or pharmaceutically acceptable salt thereof, according to any one of claims 1 to 22.

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