Thiomethyl carbonyl compounds and use thereof as HDAC6 inhibitors

Abstract

The present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof, wherein Y1 is a 9- or 10-membered bicyclic heteroaryl, X and W are carbon or nitrogen, L1 and L2 are simple bonds or linkers, and Z1 and R1 are hydrogen or various groups. The present invention further relates to a compound of formula (I) as HDAC6 inhibitor, typically for use in the treatment and / or the prevention of an HDAC6-associated disease, such as cancers, neurodegenerative diseases, neuropathies or cardiovascular diseases.

Description

[0001] AUG-P3833PCT 1 THIOMETHYL CARBONYL COMPOUNDS AND USE THEREOF AS HDAC6 INHIBITORSFIELD OF INVENTION[1] The present invention relates to amide-amine compounds useful as Histone Deacetylase subtype 6(HDAC6) inhibitors. In particular, the present invention relates to compounds for use in the treatment5 and / or the prevention of proliferative diseases such as cancers, neurodegenerative diseases, neuropathies orcardiovascular diseases. BACKGROUND OF INVENTION[2] Inhibition of the enzymes of the HDAC class, especially HDAC6 enzyme, plays a critical role ingene expression in humans. Thus, the development of potent HDAC inhibitors is of upmost clinical10 importance in severe medical conditions, including both major and rare diseases (Seidel C et al.: “Histone deacetylase 6 in health and disease.” Epigenomics. 2015, Vol.7, No.1, pp. 103-18). HDAC6 inhibitors areexpected to be useful for example in oncology, neurology, neuropsychiatry, neurodegeneration, inflammation (e.g., neuroinflammation), nephropathy, neuropathy and pain. Significant examples ofHDAC6 inhibitors with potential medical applications in the treatment of proliferative diseases are drugs15 of the hydroxamate class (hydroxamic acid and salts thereof), which include vorinostat (or “SAHA”, trade name Zolinza®), Trichostatin A (TSA), belinostat (trade name Beleodaq®), panobinostat (Farydak®) orromidepsin (Istodax®). [3] However, many HDAC6 inhibitors identified so far are not highly selective, so that they may causesignificant side-effects. Poor pharmacokinetics and low bioavailability also limit the potency of some20 HDAC6 inhibitors. Thus, most of the HDAC6 inhibitors have a poor developability profile, even for life- threatening applications in oncology. For example, high doses of non-selective HDAC inhibitors areresponsible for fatigue and nausea (Subramanian, S. et al.: Clinical toxicities of histone deacetylaseinhibitors. Pharmaceuticals 2010, 3, 2751–2767). Side-effects may be in particular be caused by theinhibition of class I HDACs. In addition, mutagenicity issues related to the hydroxamate function in25 approved HDAC inhibitors has been reported (Shen S. and Kozikowski A. P.: ChemMedChem 2016, No.11, 15-21). Other HDAC inhibitors, notably from the fluoromethyl oxadiazole class, have been reported tobe mechanism-based inhibitors forming a quasi-irreversible binding intermediate (Cellupica E. et al.: “Difluoromethyl-1,3,4-oxadiazoles are slow-binding substrate analog inhibitors of histone deacetylase 6 with unprecedented isotype selectivity”, J. Biol. Chem. 2023, 299, 102800; König, B. et al.:30 “Difluoromethyl-1,3,4-oxadiazoles Are Selective, Mechanism-Based, and Essentially Irreversible Inhibitors of Histone Deacetylase 6.” J. Med. Chem.2023, 66, 13821–13837; Ripa, L. et al.: “Selective andBioavailable HDAC6 2-(Difluoromethyl)-1,3,4-oxadiazole Substrate Inhibitors and Modeling of Their Bioactivation Mechanism.” J. Med. Chem. 2023, 66, 14188–14207). AUG-P3833PCT 2 [4] Therefore, there is an urgent need to develop highly selective HDAC6 inhibitors overcoming thelimitations of some of the state-of-the-art HDAC6 inhibitors, such as hydroxamic acid-based HDAC6 inhibitors. Isoform-selective inhibitors over pan-HDAC are potentially advantageous both in terms of therapeutic efficacy and toxicity. In particular, selective inhibition of cytoplasmic HDAC6 may avoid5 toxicity resulting from inhibition of other HDACs. [5] The Applicant surprisingly found out that thiomethyl carbonyl compounds of formula (I) asdescribed herein are potent HDAC6 inhibitors, and in at least some embodiments are highly selectiveHDAC6 inhibitors. The use of these thiomethyl carbonyl compounds may, in at least some embodiments,also represent significant improvements in terms of bioavailability, genotoxicity, side effects,10 pharmacokinetics, cell permeability and / or water solubility over prior art drugs such as hydroxamates.SUMMARY [6] This invention relates to a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof;15 wherein Y1, L1, W, X, L2, R1 and Z1 are as described in the claims or the detailed description.[7] According to one embodiment, the compound is selected from the compounds listed in Table 1,Table 2 and Table 3 herein, and pharmaceutically acceptable salts and / or solvates of any one thereof.[8] This invention also relates to a pharmaceutical composition comprising a compound according tothe invention and at least one pharmaceutically acceptable carrier.20 [9] This invention also relates to a compound according to the invention or a pharmaceuticalcomposition according to the invention for use as a medicament. This invention also relates to a compound according to the invention or a pharmaceutical composition according to the invention for use in the treatment and / or the prevention of an HDAC6-associated disease, including in particular diseases that may be prevented and / or treated by means of HDAC inhibition. According to one embodiment, the HDAC6-25 associated disease is selected from inflammatory diseases, autoimmune diseases, proliferative diseases (such as cancers), neurodegenerative diseases (including neuromuscular diseases), pains, neuropathies,psychiatric diseases, neurodevelopmental disorders, sleep disorders, cardiovascular diseases, kidneydiseases, and metabolic or hormonal disorders. AUG-P3833PCT 3

[10] This invention also relates to a process for manufacturing a compound according to the invention,wherein the process comprises a step of reacting: (i) a carboxylic acid with an amine; or (ii) a halo-ketone with a thiol. DEFINITIONS 5

[0011] In the present invention, the following terms have the following meanings, unless indicatedotherwise. Chemical definitions

[12] When referring to combinations of groups, such as, for example, “alkylene-heteroaryl”, the pointof attachment to the main structure is on the group cited on the left. Thus, the term “alkylene-cyclyl” and10 variants thereof (e.g., “alkylene-heteroaryl”, “alkylene-heterocycle”, “alkylene-cycloalkyl”, “alkylene- aryl”, “alkylene-heteroaryl”, “alkylene-heterocycle” and “alkylene-cycloalkyl”) refers to a cyclyl group that is attached via an alkylene moiety to the main structure. In other words, the point of attachment is thealkylene group, and not the cyclyl group.

[13] When groups, such as, for example, “-(C1-C6) alkyl” or “-(C1-C6) alkylene”, are said to be15 optionally substituted, such reference refers to optional substitution on all such instances of saidsubstituents. Thus, optional substitution of said groups refers to optional substitution on said groups per seas well as to optional substitution on said groups when said groups are a component of another substituent,such as, for example, optional substitution on the “-(C1-C6) alkyl” fragment in, for example, “-O-(C1-C6)alkyl”, “-NH-(C1-C6) alkyl”, or “-N-((C1-C6) alkyl)2”. Only substitutions wherein the resulting molecule is20 chemically stable are encompassed by this definition. When such groups are said to be optionally substituted: in one embodiment they are not substituted and in another embodiment they are substituted.

[14] “Alkene” or “alkenyl” refers to a linear or branched hydrocarbon chain comprising at least onedouble bond and typically from 2 to 12 carbon atoms, suitably 3 to 6 carbon atoms. Non-limiting examplesof alkenyl groups include ethynyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl and its isomers, 2-hexenyl25 and its isomers and 2,4-pentadienyl.

[15] “Alkyl” refers to a saturated linear or branched hydrocarbon chain, typically comprising from 1to 12 carbon atoms, suitably from 1 to 6 carbon atoms, more suitably from 1 to 3 carbon atoms. In thepresent invention, alkyl groups may be monovalent or polyvalent (i.e., “alkylene” groups as defined hereinare encompassed in “alkyl” definition) but alkyl groups are typically monovalent. Non-limiting examples30 of alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl and t-butyl, pentyl and its isomers (e.g., n-pentyl, iso-pentyl), and hexyl and its isomers (e.g., n-hexyl, iso-hexyl). Preferred alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl and t-butyl. AUG-P3833PCT 4

[16] “Alkylene” refers to a divalent alkyl group. Non-limiting examples of alkylene groups includemethylene, ethylene, n-propylene, i-propylene, divalent butyl, divalent pentyl and divalent hexyl. Preferredalkylene groups include methylene, ethylene, n-propylene, and n-butylene.

[17] “Alkyne” or “alkynyl” refers to a linear or branched hydrocarbon chain comprising at least one5 triple bond and typically from 2 to 12 carbon atoms, suitably 3 to 6 carbon atoms. Non-limiting examplesof alkynyl groups include ethynyl, 2-propynyl, 2-butynyl, 3-butynyl, 2-pentynyl and its isomers, and 2- hexynyl and its isomers.

[18] “Amine” refers to derivatives of ammonia (NH3), wherein one or more hydrogen atoms have beenreplaced by a substituent such as, for example, alkyl or aryl.10

[0019] “Amino” refers to the -NH2 group.

[0020] “Aryl” refers to a cyclic, polyunsaturated, aromatic hydrocarbyl group comprising at least onearomatic ring. Aryl groups may have a single ring (i.e., phenyl) or multiple aromatic rings fused together(e.g., naphthyl) or linked covalently. Typically, aryl groups have from 5 to 12 carbon atoms, suitably from6 to 10 carbon atoms. The aromatic ring may optionally include one to two additional rings (either 15 cycloalkyl, heterocycloalkyl or heteroaryl) fused thereto. Aryl is also intended to include the partially hydrogenated derivatives of the carbocyclic systems enumerated herein, as long as at least one ring is aromatic. Non-limiting examples of aryl groups include phenyl, biphenyl, biphenylenyl, 5- or 6-tetralinyl,naphthalen-1- or -2-yl, 4-, 5-, 6 or 7-indenyl, 1- 2-, 3-, 4- or 5-acenaphthylenyl, 3-, 4- or 5-acenaphthenyl,1- or 2-pentalenyl, 4- or 5-indanyl, 5-, 6-, 7- or 8-tetrahydronaphthyl, 1,2,3,4-tetrahydronaphthyl,20 1,4-dihydronaphthyl, 1-, 2-, 3-, 4- or 5-pyrenyl. A preferred aryl group is phenyl.

[0021] “Bicyclic”, when referring to a cyclic group, means that the cyclic group consists of exactly twofused rings. In monovalent bicyclic groups, the notation “[x, y]” wherein x and y are integers is used hereinto indicated that one cycle is x--membered and the other cycle is y--membered and that the point of attachment to the main structure is located on the x--membered cycle. “Tricyclic” and the like should be25 construed accordingly.

[22] “Cyano” refers to the -CN group.

[0023] “Cyclyl” collectively refers to “cycloalkyl”, “heterocycloalkyl”, “aryl” and “heteroaryl” groupsas defined herein.

[24] “Cycloalkyl” refers to a cyclic monovalent alkyl, typically comprising from 3 to 11 carbon atoms,30 suitably from 3 to 9 carbon atoms, suitably from 4 to 9 carbon atoms, more suitably from 5 to 7 carbonatoms, most suitably from 3 to 6 carbon atoms. This definition encompasses polycyclic cycloalkyls (e.g.,bicycles) and bridged cycloalkyl structures, including cycles bound together through one atom (“spiro”) orthrough two atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, AUG-P3833PCT 5 cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. Preferred cycloalkyl groups include cyclopropyl andcyclobutyl.

[25] “(Cx-Cy)” preceding the name of a group means that the group comprises from x to y carbon atoms,in accordance with common terminology in the chemistry field.5

[0026] “Difluoromethyl” refers to the -CHF2 group.

[0027] “Halide”, “halo” or “halogen” refers to a fluorine, chlorine, bromine or iodine atom, typically afluorine, chlorine or bromine atom, more typically a fluorine or chlorine atom.

[28] “Heteroaryl” refers to aromatic rings or aromatic ring systems comprising from 5 to 12 carbonatoms, suitably from 6 to 10 carbon atoms, having one or two rings which are fused together or linked10 covalently, wherein at least one ring is aromatic, and wherein one or more carbon atoms in one or more of these rings is replaced by oxygen, nitrogen and / or sulfur atoms. Suitably, one, two, three or four carbon atoms are replaced by oxygen, nitrogen and / or sulfur atoms, especially oxygen and / or nitrogen atoms. Moresuitably one, two or three carbon atoms are replaced by oxygen, nitrogen and / or sulfur atoms, especiallyoxygen and / or nitrogen atoms. Suitably, for a monocyclic heteroaryl, one or two carbon atoms are replaced15 by oxygen, nitrogen and / or sulfur atoms, especially oxygen and / or nitrogen atoms. Suitably, for a bicyclic heteroaryl, one, two or three carbon atoms are replaced by oxygen, nitrogen and / or sulfur, especially oxygenand / or nitrogen atoms. “Heteroaryl” may also be viewed as an “aryl” group as defined herein, wherein atleast one carbon atom in the aryl group is replaced with a heteroatom and wherein the resulting molecule is chemically stable. The nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen 20 heteroatoms may optionally be quaternized. The aromatic ring may optionally include one to two additional rings (either cycloalkyl, heterocycloalkyl or aryl) fused thereto. Heteroaryl is also intended to include the partially hydrogenated derivatives of the carbocyclic systems enumerated herein, as long as at least one ring is aromatic. Non-limiting examples of heteroaryl groups include furanyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, 25 oxatriazolyl, thiatriazolyl, pyridinyl, pyrimidyl, pyrazinyl, pyridazinyl, oxazinyl, dioxinyl, thiazinyl, triazinyl, imidazo[2,1-b][1,3] thiazolyl, thieno[3,2-b]furanyl, thieno[3,2-b]thiophenyl, thieno[2,3- d][1,3]thiazolyl, thieno[2,3-d]imidazolyl, tetrazolo[1,5-a]pyridinyl, indolyl, indolizinyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzothiophenyl, isobenzothiophenyl, indazolyl, benzimidazolyl, 1,3- benzoxazolyl, 1,2-benzisoxazolyl, 2,1-benzisoxazolyl, 1,3-benzothiazolyl, 1,2-benzoisothiazolyl, 2,1- 30 benzoisothiazolyl, benzotriazolyl, 1,2,3-benzoxadiazolyl, 2,1,3-benzoxadiazolyl, 1,2,3-benzothiadiazolyl, 2,1,3benzothiadiazolyl, thienopyridinyl, purinyl, pyrazolo[3,4-d]pyrimidinyl, imidazo[1,2-a]pyrimidinyl,imidazo[1,2-a]pyridinyl, 6-oxo-pyridazin-1-(6H)-yl, 2-oxopyridin-1-(2H)-yl, 6-oxo-pyridazin-1-(6H)-yl, 2-oxopyridin-1-(2H)-yl, 1,3-benzodioxolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, and 6,7-dihydro-5H-pyrrolo[1,2-a]imidazolyl. Non-limiting examples of35 heteroaryl also include pyrazolo[1,5-a]pyrimidinyl, 1,6-naphthyridinyl, pyrido[4,3-d]pyrimidinyl and AUG-P3833PCT 6 pyrido[3,2-d]pyrimidinyl. Non-limiting examples of heteroaryl also include pyrazolo[4,3-d]pyrimidinyl,furo[3,2-d]pyrimidinyl, pyrazolo[3,4-c]pyridinyl, pyrazolo[3,4-b]pyridinyl, pyrazolo[4,3-c]pyridinyl, pyrazolo[4,3-b]pyridinyl, pyrazolo[4,3-b]pyridinyl, imidazo[1,5-a]pyrazinyl, imidazo[4,5-c]pyridinyl,imidazo[4,5-c]pyridinyl, oxazolo[5,4-c]pyridinyl and imidazo[1,5-c]pyrimidinyl. 5

[0029] “Heterocycloalkyl” refers to a cyclic monovalent heteroalkyl, typically comprising from 2 to 9carbon atoms, suitably from 2 to 7 carbon atoms, suitably from 3 to 6 carbon atoms, more suitably from 4to 6 carbon atoms. The definition encompasses heterocycloalkyl groups typically containing one or moreheteroatoms in the cyclic ring, suitably one, two or three heteroatoms, most suitably one or two heteroatoms.Suitable heteroatoms are oxygen, nitrogen and / or sulfur atoms, especially oxygen and nitrogen. This10 definition encompasses polycyclic heterocycloalkyls (e.g., bicycles) and bridged heterocycloalkyl structures, including cycles bound together through one atom (“spiro”) or through two atoms. In oneembodiment, the heterocycloalkyl is bound to another group or molecule through a carbon atom, i.e., the binding atom is not selected among the heteroatoms included therein. In one embodiment, the heterocycloalkyl is bound to another group or molecule through one of the heteroatoms included therein.15 When substituted by one or more other group(s), a heterocycloalkyl may be substituted either through acarbon atom or through a heteroatom (e.g., nitrogen), unless otherwise specified. Non-limiting examples of heterocycloalkyl include aziridine, pyrrolidine, piperidine, piperazine (also known as“hexahydropyrazine”), morpholine, thiomorpholine, azepane, azocane, octahydro-1H-isoindole, decahydroisoquinoline, tetrahydrofuran, tetrahydropyran, tetrahydroisoquinoline (e.g., 1,2,3,4-20 tetrahydroisoquinoline), hexahydropyridazine, hexahydropyrimidine, decahydroquinoline,octahydropyrrolo[3,4-c]pyrrole, isoindoline, 1,2,3,4-tetrahydroquinoline and oxetane. Non-limitingexamples of heterocycloalkyl also include azetidine, oxetane, tetrahydrofuran, tetrahydropyran, 3-oxabicyclo[3.1.0]hexane, 1-azabicyclo[3.2.1]octane, 2-oxa-5-azabicyclo[2.2.1]heptane, 3-oxa-8-azabicyclo[3.2.1]octane, 3-azabicyclo[3.1.0]hexane, 4-oxa-7-azaspiro[2.5]octane, morpholin-3-one,25 quinuclidine, 8-oxabicyclo[3.2.1]octane, 3-oxa-9-azabicyclo[3.3.1]nonane, 9-azabicyclo[3.3.1]nonane, 3-azabicyclo[3.1.1]heptane, 8-azabicyclo[3.2.1]octane, 5-oxa-2-azaspiro[3.4]octane, 3-oxa-7-azabicyclo[3.3.1]nonane, 2-azabicyclo[2.2.1]heptane, octahydropyrido[2,1-c][1,4]oxazine, hexahydro- 1H-pyrrolo[2,1-c][1,4]oxazine and pyrrolidinone.

[0030] “Hydroxy” refers to the -OH group.30

[0031] “Ketone” refers to a functional group with the connectivity C-(C=O)-C.

[0032] “Oxo” refers to the =O group, i.e., one oxygen atom which is double-bonded, typically to a carbonatom.

[33] “Trifluoromethyl” refers to the -CF3 group.General definitions AUG-P3833PCT 7

[34] “About” is used herein to mean approximately, roughly, around, or in the region of. The term“about” preceding a figure means more or less 10 % of the value of the figure. When the term “about” isused in conjunction with a numerical range, it modifies that range by extending the boundaries above and below the numerical values set forth by 10%.5

[0035] “Administration", or a variant thereof (e.g., “administering”), means providing a therapeuticagent (e.g., a compound of the invention) alone or as part of a pharmaceutically acceptable composition, to the patient in whom / which the condition, symptom, or disease is to be treated and / or prevented.

[36] “Binding site” or “binding pocket” refers to a specific arrangement of amino acids located on aprotein (e.g., on HDAC6) to which a compound (e.g., the compounds of the present invention) bind. 10 Binding sites often consist of a chemically-active surface grouping of amino acids, and have specific 3-D structural characteristics as well as specific charge characteristics. Similarly to epitopes, binding sites can be linear or conformational, i.e., they can involve sequences of amino acids which are not necessarily contiguous in the primary structure of the protein.

[37] “Comprise” or a variant thereof (e.g., “comprises”, “comprising”) is used herein according to15 common patent application drafting terminology. Hence, “comprise” preceded by an object and followed by a constituent means that the presence of a constituent in the object is required (typically as a component of a composition), but without excluding the presence of any further constituent(s) in the object. Moreover, any occurrence herein of “comprise” or a variant thereof also encompasses narrower expression “substantially consist of” or “consists essentially of”, further narrower expression “consist of” and any20 variants thereof (e.g., “consists of”, “consisting of”).

[0038] “HDAC” or “Histone Deacetylase” refers to a class of enzymes that are able to remove acetylgroups (O=C-CH3) from an ε-N-acetyl lysine amino acid on a histone, allowing the histones to wrap the DNA more tightly and condensate the chromatin. Gene expression is regulated by histone acetylation and de-acetylation, and thus by HDAC activity. In the invention, HDAC is typically “HDAC6” as defined25 herein.

[39] “HDAC-associated disease” or a variant thereof (e.g., “HDAC6-associated disease”) refers to adisease that is caused by, or characterized by, or responsive to the dysregulation and in particular the increased activity of HDAC6 enzyme in a subject, resulting in an abnormal acetylation profile of HDAC substrates (e.g., histones, tubulin, Hsp90, cortactin, peroxiredoxin). Alternatively, “HDAC-associated 30 disease” or a variant thereof (e.g., “HDAC6-associated disease”) refers to a disease which can be treated by the effects of hyperacetylation through inhibition of HDAC6 enzyme. Typically, HDAC-associated diseases are associated with, inter alia, altered epigenetic regulation of gene expression and / or cell motility. This definition encompasses diseases wherein reducing (inhibiting) normal HDAC6 activity can treat and / or prevent the diseases. Thus, typically, an HDAC-associated disease may be prevented and / or treated AUG-P3833PCT 8 by means of HDAC6 inhibition. Non-limitative examples of HDAC-associated diseases include neuropathies, neurodegenerative diseases, proliferative diseases (e.g., cancer), metabolic disorders, immune disorders and inflammatory diseases.

[40] “HDAC6”, “HDAC6 enzyme” or “Histone Deacetylase subtype 6” refers to an HDAC enzyme5 that is encoded by the HDAC6 gene in humans.

[41] “HDAC6 gene” refers to the gene coding for HDAC6 in humans. HDAC6 gene is alsointerchangeably referred to as KIAA0901 or JM21.

[42] “Human” refers to a male or female subject at any stage of development, including neonate,infant, juvenile, adolescent and adult.10

[0043] “Patient” refers to an animal, typically a warm-blooded animal, suitably a mammal (e.g., mouse,rat, cat, guinea-pig, dog, monkey or human), more suitably a human, who / which is awaiting the receipt of,or is receiving medical care, or is / will be the object of a medical procedure. A patient may also be the subject of preventive care or procedure.

[44] “Pharmaceutically acceptable” means that the ingredients of a composition are compatible with15 each other and not deleterious to the patient to which / whom it is administered.

[45] “Pharmaceutically acceptable carrier” refers to an excipient that does not produce an adverse,allergic or other untoward reaction when administered to an animal, suitably a human. It includes any andall solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like. For human administration, preparations should meet sterility, pyrogenicity,20 general safety and purity standards as required by regulatory offices, such as, e.g., FDA Office or EMA.

[46] “Prevent”, “preventing” and “prevention” refer to delaying or precluding the onset of acondition and / or disease and / or any one of its attendant symptoms, barring a patient from acquiring a condition or disease, or reducing the risk for a patient of acquiring a condition and / or disease and / or any one of its attendant symptoms. The effect resulting from “preventing” a condition and / or disease is called25 “prophylactic”.

[47] “Prodrug” refers to a pharmacologically acceptable derivative of a therapeutic agent (e.g., acompound of the invention) whose in vivo biotransformation product is the therapeutic agent (active drug).Prodrugs are typically characterized by increased bioavailability and are readily metabolized in vivo intothe active compounds. Non-limiting examples of prodrugs include amide prodrugs and carboxylic acid ester 30 prodrugs, in particular alkyl esters, cycloalkyl esters and aryl esters.

[48] “Selected from” is used herein according to common patent application drafting terminology, tointroduce a list of elements among which an item is selected. Moreover, any occurrence herein of “selected AUG-P3833PCT 9 from” also encompasses the expression “selected from the group comprising or consisting of” and anyvariants thereof (e.g., “consists of”).

[49] “Solvate” refers to molecular complex comprising a compound along with stoichiometric or sub-stoichiometric amounts of one or more molecules of one or more solvents, typically the solvent is a 5 pharmaceutically acceptable solvent such as, for example, ethanol. The term “hydrate” refers to a solvate when the solvent is water (H2O).

[50] “Therapeutic agent”, “active pharmaceutical ingredient” and “active ingredient” refer to acompound for therapeutic use and relating to health. Especially, a therapeutic agent (e.g., a compound of the invention) may be indicated for treating and / or preventing a disease, suitably an infectious disease. An10 active ingredient may also be indicated for improving the therapeutic activity of another therapeutic agent.

[51] “Therapeutically effective amount” (in short “effective amount”) refers to the amount of atherapeutic agent (e.g., a compound of the invention) that is sufficient to achieve the desired therapeutic or prophylactic effect in the patient to which / whom it is administered.

[52] “Treat”, “treating” and “treatment” refer to alleviating, attenuating or abrogating a condition15 and / or disease and / or any one of its attendant symptoms, e.g., an infectious disease.

[0002] AUG-P3833PCT 10 DETAILED DESCRIPTION Compounds General formula

[53] This invention relates to a compound of formula (I)5 wherein Y1, L1, X, W, L2, R1 and Z1 are as defined hereinafter in the detailed description.

[0054] In the compounds of formula (I) as described hereinafter in the detailed description, unlessotherwise indicated, any alkyl group (which encompass alkylene group) may be “optionally substituted”,i.e., each hydrogen atom bound to a carbon atom in the alkyl moiety can optionally be replaced by at least10 one low-molecular weight substituent such as, for example, a substituent selected from halogen, cyano,hydroxy, oxo, amino, -O-(C1-C6) alkyl, -NH-(C1-C6) alkyl and -N-((C1-C6) alkyl)2. Only substitutionswherein the resulting molecule is chemically stable are encompassed by this definition. Typically, the -(C1-C6) alkyl group(s) present in the substituents are not themselves further substituted. Groups as describedhereinafter such as, for example, -(C1-C2) hydroxyalkyl, -(C1-C2) haloalkyl and -(C1-C2) aminoalkyl 15 encompass an alkyl group substituted by hydroxy, halogen and amino, respectively. Preferred substituted alkyls include alkyls substituted by one or more fluorine atom(s) and / or hydroxy such as, alkyls substituted by one or more fluorine atom(s), for example, trifluoromethyl. Preferred substituted alkyls also includealkyls substituted by one hydroxy or amino groups, such as, alkyls substituted by one hydroxy group, for example, hydroxymethyl.20

[0055] In the compounds of formula (I) as described hereinafter in the detailed description, unlessotherwise indicated, any cyclyl group (i.e., cycloalkyl, heterocycloalkyl, aryl or heteroaryl group) may be“optionally substituted”, i.e., each hydrogen atom bound to a carbon atom in the cyclyl moiety canoptionally be replaced by at least one low-molecular weight substituent such as, for example, a groupselected from halogen, cyano, hydroxy, oxo, amino, -(C1-C6) alkyl, -CH2-O-(C1-C6) alkyl, -CH2-NH-(C1-25 C6) alkyl, -CH2-N-((C1-C6) alkyl)2, -O-(C1-C6) alkyl, -NH-(C1-C6) alkyl and -N-((C1-C6) alkyl)2. Onlysubstitutions wherein the resulting molecule is chemically stable are encompassed by this definition. Typically, the -(C1-C6) alkyl group(s) present in the substituents are not themselves further substituted.Preferred substituted cyclyl groups include cyclyl substituted by one or more fluorine atom(s) such as, for AUG-P3833PCT 11 example, difluorocyclopropyl. Preferred substituted cyclyls also include cyclyls substituted by one hydroxyor amino groups, such as, for example hydroxycyclopropyl.

[0056] In the formulae represented herein, the dotted line --- represents the point of attachment of thedepicted moiety to the main molecular structure. 5 Y1definitions

[57] In formula (I) above, Y1 is selected from the following group of formulae (Y1-I) (also referred as“Scaffolds 1-19” or “Sc1-Sc19”) 10 AUG-P3833PCT 12 wherein A1, A2, A3, A4, A5, A6and A7are each independently selected from C-R7and N; A8, A9, A10and A11are each independently selected from C-R7and N, provided that at least one of 5 A8, A9, A10or A11is N; G1is selected from C-R3and N; G2is selected from O and N-R4; and Bis selected from O, S and N-R5, provided that when:i) A5, A6and B are present, and A5and A6are C-R7;10ii) A5, A7and B are present, and A5and A7are C-R7; or iii) A6, A7and B are present, and A6and A7are C-R7, then B is not S.

[0058] In an embodiment, Y1 is selected from the following group of formulae (Y1-II) (also referred as“Scaffolds 1-18” or “Sc1-18”)15 AUG-P3833PCT 13 wherein 5 A1, A2, A3, A4, A5, A6and A7are each independently selected from C-R7and N; A8, A9, A10 and A11 are each independently selected from C-R7 and N, provided that at least one ofA8, A9, A10or A11is N; G1 is selected from C-R3 and N; G2 is selected from O and N-R4; andB is selected from O, S and N-R5, provided that when A5, A6 and A7 are C-R7, then B is not S.10

[0059] According to one preferred embodiment, Y1 is selected from the following formulae (Sc1), (Sc2),(Sc3), (Sc4), (Sc5), (Sc6), (Sc9), (Sc10), (Sc12), (Sc13) and (Sc19)

[0003] AUG-P3833PCT 14 wherein A1-A7, B, G1, R2and R6are independently as defined hereinabove. 5

[0060] According to one preferred embodiment, Y1 is selected from the following formulae (Sc1), (Sc2),(Sc3), (Sc5), (Sc6), (Sc13) and (Sc19) wherein A1-A7, B, G1, R2and R6are independently as defined hereinabove.10

[0061] According to one preferred embodiment, Y1 is selected from the following formulae (Sc1), (Sc2),(Sc5), and (Sc6) AUG-P3833PCT 15 wherein A1-A4, B, A6, A7, G1, R2 and R6 are independently as defined hereinabove.

[0062] According to one preferred embodiment, Y1 is selected from the following formulae (Sc1), (Sc2)5 and (Sc3) wherein A1-A7, B, G1 and R2 are independently as defined hereinabove.

[0063] According to one preferred embodiment, Y1 is a 10-membered bicyclic heteroaryl of formula (Sc1) 10 wherein A1-A4, G1 and R2 are independently as defined hereinabove. AUG-P3833PCT 16

[64] In one embodiment, Y1 is a 10-membered bicyclic [6,6] heteroaryl selected from the followinggroup of formulae (Y1-1) 5 wherein R2, R3, R6and R7are independently as defined hereinabove.

[65] In one embodiment, Y1 is a 10-membered bicyclic [6,6] heteroaryl selected from the followinggroup of formulae (Y1-1a) 10 AUG-P3833PCT 17 wherein R2, R3, and R7are independently as defined hereinabove.

[66] In one embodiment, Y1 is a 10-membered bicyclic [6,6] heteroaryl selected from the followinggroup of formulae (Y1-1b) 5 wherein R2and R7are independently as defined hereinabove.

[67] In one preferred embodiment, Y1 is a 10-membered bicyclic [6,6] heteroaryl selected from thefollowing group of formulae (Y1-1c) wherein R2 and R7 are independently as defined hereinabove.10

[0068] In one embodiment, Y1 is a 10-membered bicyclic [6,6] heteroaryl selected from the followinggroup of formulae (Y1-1d) AUG-P3833PCT 18 wherein R2, R3, R6and R7are independently as defined hereinabove.

[69] In one preferred embodiment, when Y1 is a 10-membered bicyclic [6,6] heteroaryl as definedhereinabove, each R7group is hydrogen. 5

[0070] In another preferred embodiment, when Y1 is a 10-membered bicyclic [6,6] heteroaryl as definedhereinabove, one or more R7 groups, hereinafter referred to as R7a, are independently selected from halogen,amino, -NH-(C1-C6) alkyl, -N-((C1-C6) alkyl)2, hydroxy, cyano, -(C1-C6) alkyl, -O-(C1-C6) alkyl, -(C3-C9) cycloalkyl, -(C1-C6) alkylene-(C3-C9) cycloalkyl, -(C1-C6) alkylene-(C2-C9) heterocycloalkyl, -(C2-C9) heterocycloalkyl, aryl, and heteroaryl, and all remaining R7groups are hydrogen.10

[0071] In another preferred embodiment, Y1 is a 10-membered bicyclic [6,6] heteroaryl as definedhereinabove which contains one R7a group, and all remaining R7 groups are hydrogen.

[0072] In one preferred embodiment, Y1 is a 10-membered bicyclic [6,6] heteroaryl as definedhereinabove which contains one R7agroup and is selected from the following group of formulae (Y1-1e) 15 AUG-P3833PCT wherein R2, R3, R6, and R7aare independently as defined hereinabove. 5

[0073] In one embodiment, Y1 is a 10-membered bicyclic [6,6] heteroaryl which contains one R7a groupand is selected from the following group of formulae (Y1-1f) wherein R2, R3, R6, and R7aare independently as defined hereinabove.

[74] In another preferred embodiment, Y1 is a 10-membered bicyclic [6,6] heteroaryl as defined10 hereinabove, which contains two R7a groups, and all remaining R7 groups are hydrogen. AUG-P3833PCT

[75] In one embodiment, Y1 is a 10-membered bicyclic [6,6] heteroaryl which contains two R7a groupsand is selected from the following group of formulae (Y1-1g) 5 AUG-P3833PCT 5 wherein R2, R3, R6, and R7aare independently as defined hereinabove.

[76] In one preferred embodiment, Y1 is a 10-membered bicyclic [6,6] heteroaryl selected from thefollowing group of formulae (Y1-1h) AUG-P3833PCT wherein R2, R3, R6, and R7aare independently as defined hereinabove.

[77] In one preferred embodiment, Y1 is a 10-membered bicyclic [6,6] heteroaryl selected from thefollowing group of formulae (Y1-1i) 5 AUG-P3833PCT wherein R2, R3, R6, and R7aare independently as defined hereinabove.

[78] In one preferred embodiment, Y1 is a 10-membered bicyclic [6,6] heteroaryl selected from thefollowing group of formulae (Y1-1j) 5 wherein R2and R7aare as defined hereinabove.

[79] In one preferred embodiment, Y1 is a 10-membered bicyclic [6,6] heteroaryl selected from thefollowing group of formulae (Y1-1k) 10 wherein R2and R7aare as defined hereinabove.

[80] In one embodiment, Y1 is a 9-membered bicyclic [6,5] heteroaryl selected from the followinggroup of formulae (Y1-2) AUG-P3833PCT 5 AUG-P3833PCT 27 t 5 and the following group of formulae (Y1-6) AUG-P3833PCT wherein R2, R3, R5, R6and R7are independently as defined hereinabove.

[81] In one embodiment, Y1 is a 9-membered bicyclic [5,6] heteroaryl selected from5 the following group of formulae (Y1-7) and the following group of formulae (Y1-8) wherein A1A3 A3 ,, ,A4, R2, R4and R7are independently as defined hereinabove. AUG-P3833PCT

[82] In one preferred embodiment, Y1 is a 9-membered bicyclic [6,5] heteroaryl selected from thefollowing formulae wherein R2, R5 and R7 are independently as defined hereinabove.5

[0083] In one preferred embodiment, Y1 is a 9-membered bicyclic [6,5] heteroaryl of the followingformula wherein R2, R6 and R7 are independently as defined hereinabove.

[0084] In Y1 as defined herein, R2 is selected from hydrogen, halogen, cyano, amino, hydroxy, -(C1-10 C6) alkyl, -(C3-C9) cycloalkyl, -(C2-C9) heterocycloalkyl, aryl, heteroaryl, -(C1-C6) alkylene-(C3-C9) cycloalkyl, -(C1-C6) alkylene-(C 152-C9) heterocycloalkyl, -OR , -(C1-C6) alkylene-OR15, -O-(C2- C6) alkylene-OR15, -NR16(C 15 17 182-C6) alkylene-OR , -NR R , -(C1-C6) alkylene-NR17R18, -O-(C2- C6) alkylene-NR17R18, and -NR16-(C2-C6) alkylene-NR17R18.

[85] In an embodiment, R2 is selected from hydrogen, halogen, cyano, amino, hydroxy, -(C1-C6) alkyl,15 -(C3-C7) cycloalkyl, -(C3-C7) heterocycloalkyl, aryl, heteroaryl, -(C1-C6) alkylene-(C3-C7) cycloalkyl, -(C1-C ) alkylene-(C -C ) heterocycloalkyl, -OR15, 1515 63 7 -(C1-C6) alkylene-OR , -O-(C2-C6) alkylene-OR, - NR16(C -C ) alkylene-OR15, -NR17R18, 17 18 17 182 6 -(C1-C6) alkylene-NR R , -O-(C2-C6) alkylene-NR R , and -NR16-(C2-C6) alkylene-NR17R18.

[86] In Y1 as defined herein, R3 is selected from hydrogen, halogen, cyano, amino, hydroxy, -(C1-20 C6) alkyl, -(C3-C9) cycloalkyl, -(C2-C9) heterocycloalkyl, aryl, heteroaryl, -(C1-C6) alkylene-(C3-C 159) cycloalkyl, -(C1-C6) alkylene-(C2-C9) heterocycloalkyl, -OR , -(C1-C6) alkylene-OR15, -O-(C2- AUG-P3833PCT C6) alkylene-OR15, -NR16(C2-C6) alkylene-OR15, -NR17R18, -(C1-C6) alkylene-NR17R18, -O-(C2- C6) alkylene-NR17R18, and -NR16-(C2-C6) alkylene-NR17R18.

[87] In an embodiment, R3 is selected from hydrogen, halogen, cyano, amino, hydroxy, -(C1-C6) alkyl,-(C3-C7) cycloalkyl, -(C3-C7) heterocycloalkyl, aryl, heteroaryl, -(C1-C6) alkylene-(C3-C7) cycloalkyl, -(C1-5C6) alkylene-(C3-C7) heterocycloalkyl,-OR15, -(C 151-C6) alkylene-OR , -O-(C2-C6) alkylene-OR15, - NR16(C 15 17 18 12-C6) alkylene-OR , -NR R , -(C1-C6) alkylene-NR 7R18, -O-(C2-C6) alkylene-NR17R18, and -NR16-(C2-C6) alkylene-NR17R18.

[88] In Y1 as defined herein, R4 is selected from hydrogen, -(C1-C6) alkyl, and -(C3-C9) cycloalkyl, and-(C2-C9) heterocycloalkyl.10

[0089] In an embodiment, R4 is selected from hydrogen, -(C1-C6) alkyl, and -(C3-C7) cycloalkyl, and -(C3-C7) heterocycloalkyl.

[0090] In Y1 as defined herein, R5 is selected from hydrogen, -(C1-C6) alkyl, -(C3-C9) cycloalkyl, and -(C2-C9) heterocycloalkyl.

[0091] In an embodiment, R5 is selected from hydrogen, -(C1-C6) alkyl, -(C3-C7) cycloalkyl, and -(C3-15 C7) heterocycloalkyl.

[0092] In Y1 as defined herein, R6 is selected from hydrogen, halogen, cyano, and -(C1-C6) alkyl.

[0093] In Y1 as defined herein, R7 is independently selected from hydrogen, halogen, amino, -NH-(C1-C6) alkyl, -N-((C1-C6) alkyl)2, hydroxy, cyano, -(C1-C6) alkyl, -O-(C1-C6) alkyl, -(C3-C9) cycloalkyl, -O-(C3-C9) cycloalkyl, -(C1-C6) alkylene-(C3-C9) cycloalkyl, -(C1-C6) alkylene-(C2-C9) heterocycloalkyl, -(C2-20 C9) heterocycloalkyl, aryl, and heteroaryl.

[0094] In an embodiment, R7 is independently selected from hydrogen, halogen, amino, -NH-(C1-C6) alkyl, -N-((C1-C6) alkyl)2, hydroxy, cyano, -(C1-C6) alkyl, -O-(C1-C6) alkyl, -(C3-C9) cycloalkyl, -(C1-C6) alkylene-(C3-C9) cycloalkyl, -(C1-C6) alkylene-(C2-C9) heterocycloalkyl, -(C2-C9) heterocycloalkyl,aryl, and heteroaryl.25

[0095] In an embodiment, R7 is independently selected from hydrogen, halogen, amino, hydroxy, cyano,-(C1-C6) alkyl, -(C3-C7) cycloalkyl, -(C1-C6) alkylene-(C3-C7) cycloalkyl, -(C1-C6) alkylene-(C3-C7) heteroalkyl, -(C3-C7) heterocycloalkyl, aryl, and heteroaryl.

[0096] Moreover, in Y1 as defined herein, in an embodiment each of the -(C1-C6) alkyl, or -(C1-C6) alkylene in R2, R3, R4, R5, R6 or R7 is not substituted further; and each of said -(C3-C9) cycloalkyl, -30(C2-C9) heterocycloalkyl, aryl or heteroaryl in R2, R3, R4, R5, R6or R7is not substituted further.

[97] Moreover, in Y1 as defined herein, in an embodiment each of the -(C1-C6) alkyl, or -(C1-C6) alkylene in R2, R3, R4, R5, R6or R7is substituted with up to three groups e.g. three groups, or two AUG-P3833PCT groups, or one group; and each of said -(C3-C9) cycloalkyl, -(C2-C9) heterocycloalkyl, aryl or heteroaryl inR2, R3, R4, R5, R6 or R7 is substituted with up to three groups e.g. three groups, or two groups, or one group.

[0098] Moreover, in Y1 as defined herein, in an embodiment each of the -(C1-C6) alkyl or -(C1-C6) alkylene in R2, R3, R4, R5, R6or R7is optionally substituted with up to three groups e.g. three groups, 5or two groups, or one group selected from halogen, cyano, hydroxy, and amino; and each of the -(C3-C7) cycloalkyl, -(C3-C7) heterocycloalkyl, aryl or heteroaryl in R2, R3, R4, R5, R6or R7is optionally substituted with up to three groups e.g. three groups, or two groups, or one group selected from halogen,cyano, hydroxy, and amino.

[99] Moreover, in Y1 as defined herein, in an embodiment each of the -(C1-C6) alkyl or -(C1-10C6) alkylene in R2, R3, R4, R5, R6or R7is optionally substituted with up to three halogen groups, suitably two or three halogen groups, most suitably three halogen groups.

[100] In Y1 as defined herein, in an embodiment R15, R16, R17 and R18 are each independently selectedfrom hydrogen, -(C1-C6) haloalkyl, -(C1-C6) alkyl, -(C3-C9) cycloalkyl, -(C1-C6) alkylene-(C3-C9) cycloalkyl, -(C2-C9) heterocycloalkyl, aryl, heteroaryl, -(C1-C6) alkylene-(C2-C9) heterocycloalkyl,15 -(C1-C6) alkylene-heteroaryl, and-(C1-C6) alkylene-aryl; and / or two groups selected from R15, R16, R17and R18form together a cycle selected from -(C3-C9) cycloalkyl, -(C2-C9) heterocycloalkyl, aryl, and heteroaryl.

[0101] In an embodiment, R15, R16, R17 and R18 are each independently selected from hydrogen, -(C1-C6) haloalkyl, -(C1-C6) alkyl, -(C3-C7) cycloalkyl, -(C1-C6) alkylene-(C3-C7) cycloalkyl, -(C3-20 C7) heterocycloalkyl, aryl, heteroaryl, -(C1-C6) alkylene-(C3-C7) heterocycloalkyl, -(C1-C6) alkylene-heteroaryl, and -(C1-C6) alkylene-aryl; and / or two groups selected from R15, R16, R17and R18form together acycle selected from -(C3-C7) cycloalkyl, -(C3-C7) heterocycloalkyl, aryl, and heteroaryl.

[0102] Moreover, in Y1 as defined herein, in an embodiment each of said -(C1-C6) alkyl or -(C1-C6) alkylene in R15, R16, R17 or R18 is not substituted further; and each of the -(C3-C9) cycloalkyl, -(C2-25 C ) heterocycloalkyl, ar 15 16 17 189 yl or heteroaryl in R , R , R or R is not substituted further.

[0103] Moreover, in Y1 as defined herein, in an embodiment each of said -(C1-C6) alkyl or -(C1-C6) alkylene in R15, R16, R17or R18is substituted with up to three groups e.g. three groups, or two groups, or one group, selected from halogen, cyano, hydroxy, and amino; and each of the -(C3-C9) cycloalkyl, -(C2-C9) up to three groups e.g. three groups, or two groups, or one group, selected from halogen, cyano,30 hydroxy, and amino.

[0104] Moreover, in Y1 as defined herein, in an embodiment each of said -(C1-C6) alkyl or -(C1-C6) alkylene in R15, R16, R17or R18is substituted with up to three groups e.g. three groups, or two groups, or one group, selected from halogen and hydroxy; and each of the -(C3-C9) cycloalkyl, -(C2- AUG-P3833PCT C9) heterocycloalkyl, aryl or heteroaryl in R15, R16, R17 or R18 is substituted with up to three groups e.g.three groups, or two groups, or one group, selected from halogen and hydroxy.

[0105] Moreover, in Y1 as defined herein, in an embodiment each of the -(C1-C6) alkyl or -(C1-C6) alkylene in R15, R16, R17or R18is optionally substituted with at least one group selected from halogen, 5cyano, hydroxy, oxo, amino, -O-(C1-C6) alkyl, -NH-(C1-C6) alkyl, and -N-((C1-C6) alkyl)2; and each of the-(C3-C7) cycloalkyl, -(C3-C7) heterocycloalkyl, aryl or heteroaryl in R15, R16, R17or R18is optionally substituted with at least one group selected from halogen, cyano, hydroxy, oxo, amino, -(C1-C6) alkyl, -CH2-O-(C1-C6) alkyl, -CH2-NH-(C1-C6) alkyl, -CH2-N-((C1-C6) alkyl)2, -O-(C1-C6) alkyl, -NH-(C1-C6) alkyl, and -N-((C1-C6) alkyl)2.10

[0106] According to one embodiment, in Y1 as defined herein:R2 is selected from hydrogen, halogen, cyano, amino, hydroxy, -(C1-C6) alkyl,-(C3-C9) cycloalkyl, -(C2-C9) heterocycloalkyl, -(C1-C6) alkylene-(C3-C9) cycloalkyl, and -(C1-C ) alkylene-(C -C ) heterocycloalkyl; Suitably, 26 2 9 R is selected from hydrogen, -(C1-C6) alkyl, -(C3-C9) cycloalkyl, -NR17R18and -OR15; More suitably, R2is hydrogen or -(C1-C6) alkyl; Most suitably, R2is15 -(C1-C6) alkyl, e.g. methyl. R3 is selected from hydrogen, halogen, cyano, amino, hydroxy, -(C1-C6) alkyl,-(C3-C9) cycloalkyl, -(C2-C9) heterocycloalkyl, -(C1-C6) alkylene-(C3-C9) cycloalkyl, and -(C1-C6) alkylene-(C2-C9) heterocycloalkyl; Suitably, R3is selected from the group consisting of hydrogen, cyano and -(C1-C6) alkyl; Most suitably, R3is hydrogen.20 R4 is selected from hydrogen, -(C1-C6) alkyl -(C3-C9) cycloalkyl, and-(C2-C9) heterocycloalkyl; Suitably, R4 is hydrogen or -(C1-C6) alkyl; Most suitably R4is hydrogen. R5 is selected from hydrogen, -(C1-C6) alkyl -(C3-C9) cycloalkyl, and-(C2-C9) heterocycloalkyl; Suitably, R5 is hydrogen or -(C1-C6) alkyl; Most suitably R5is hydrogen. R6 is selected from hydrogen, halogen, cyano, and -(C1-C6) alkyl; Suitably, R6is hydrogen or -(C1-25C6) alkyl; Most suitably R6is hydrogen. R7 is independently selected from hydrogen, halogen, -NH-(C1-C6) alkyl, -N-((C1-C6) alkyl)2, cyano, -(C1-C6) alkyl, -O-(C1-C6) alkyl, -O-(C3-C9) cycloalkyl and -(C2-C9) heterocycloalkyl; Suitably, R7is independently selected from hydrogen, halogen, -(C1-C6) alkyl and -O-(C1-C6) alkyl; More suitably, R7is independently selected from hydrogen, halogen and -O-(C1-C6) alkyl; Most suitably, R7is -O-(C1-C6) alkyl,30 preferably methoxy. AUG-P3833PCT wherein each of the -(C1-C6) alkyl in R2, R3, R4, R5, R6or R7is optionally substituted with at least one halogen, suitably one, two or three halogen atoms, most suitably three halogen atoms; and R15, R16, R17 and R18 are independently hydrogen or -(C1-C6 alkyl), and -(C1-C6 alkyl) is not5 substituted further.

[107] According to one embodiment, in Y1 as defined herein:R2 is selected from hydrogen, halogen, cyano, amino, hydroxy, -(C1-C6) alkyl,-(C3-C9) cycloalkyl, -(C2-C9) heterocycloalkyl, -(C1-C6) alkylene-(C3-C9) cycloalkyl, and -(C1-C ) alkylene-(C -C ) hetero 26 2 9 cycloalkyl; Suitably, R is selected from hydrogen, -(C1-C6) alkyl, -(C3-10C9) cycloalkyl, -NR17R18 and -OR15; More suitably, R2 is hydrogen or -(C1-C6) alkyl; Most suitably, R2is -(C1-C6) alkyl, e.g. methyl. R3 is selected from hydrogen, halogen, cyano, amino, hydroxy, -(C1-C6) alkyl,-(C3-C9) cycloalkyl, -(C2-C9) heterocycloalkyl, -(C1-C6) alkylene-(C3-C9) cycloalkyl, and -(C1-C6) alkylene-(C2-C9) heterocycloalkyl; Suitably, R3is selected from the group consisting of hydrogen,15cyano and -(C1-C6) alkyl; Most suitably, R3is hydrogen. R4 is selected from hydrogen, -(C1-C6) alkyl -(C3-C9) cycloalkyl, and-(C2-C9) heterocycloalkyl; Suitably, R4 is hydrogen or -(C1-C6) alkyl; Most suitably R4is hydrogen. R5 is selected from hydrogen, -(C1-C6) alkyl -(C3-C9) cycloalkyl, and-(C2-C9) heterocycloalkyl; Suitably, R5 is hydrogen or -(C1-C6) alkyl; Most suitably R5is hydrogen.20R6 is selected from hydrogen, halogen, cyano, and -(C1-C6) alkyl; Suitably, R6is hydrogen or -(C1- C6) alkyl; Most suitably R6is hydrogen. R7 is independently selected from hydrogen, halogen, -N-((C1-C6) alkyl)2, cyano, -(C1-C6) alkyl, -O-(C1-C6) alkyl, and -(C2-C9) heterocycloalkyl; Suitably, R7is independently selected from hydrogen, halogen, - (C1-C6) alkyl and -O-(C1-C6) alkyl; More suitably, R7is independently selected from hydrogen, halogen25and -O-(C1-C6) alkyl; Most suitably, R7is -O-(C1-C6) alkyl, preferably methoxy. wherein each of the -(C1-C6) alkyl in R2, R3, R4, R5, R6or R7is optionally substituted with at least one halogen, suitably one, two or three halogen atoms, most suitably three halogen atoms; andR15, R16, R17 and R18 are independently hydrogen or -(C1-C6 alkyl), and -(C1-C6 alkyl) is not30 substituted further. AUG-P3833PCT

[108] According to one embodiment, in Y1 as defined herein:R2 is selected from hydrogen, halogen, cyano, amino, hydroxy, -(C1-C6) alkyl,-(C3-C7) cycloalkyl, -(C3-C7) heterocycloalkyl, -(C1-C6) alkylene-(C3-C7) cycloalkyl, and -(C1-C6) alkylene-(C3-C7) heterocycloalkyl;5 R3 is selected from hydrogen, halogen, cyano, amino, hydroxy, -(C1-C6) alkyl,-(C3-C7) cycloalkyl, -(C3-C7) heterocycloalkyl, -(C1-C6) alkylene-(C3-C7) cycloalkyl, and -(C1-C6) alkylene-(C3-C7) heterocycloalkyl;R4 is selected from hydrogen, -(C1-C6) alkyl -(C3-C7) cycloalkyl, and-(C3-C7) heterocycloalkyl;10 R5 is selected from hydrogen, -(C1-C6) alkyl -(C3-C7) cycloalkyl, and-(C3-C7) heterocycloalkyl;R6 is selected from hydrogen, halogen, cyano, and -(C1-C6) alkyl;R7 is independently selected from hydrogen, halogen, cyano, -(C1-C6) alkyl,-(C3-C7) cycloalkyl, and -(C3-C7) heterocycloalkyl;15 wherein each of the -(C1-C6) alkyl, -(C1-C6) alkylene, -(C3-C7) cycloalkyl,-(C3-C7) heterocycloalkyl, aryl or heteroaryl in R2, R3, R4, R5, R6or R7is optionally substituted as defined hereinabove; and R15, R16, R17 and R18 are independently as defined hereinabove.20

[0109] In one further preferred embodiment, Y1 is selected from 1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl, 6-methoxy-2-methylquinazolin-4-yl, 3-methoxy-7-methyl-1,6-naphthyridin-5-yl, 7- methylimidazo[1,2-a]pyrimidin-5-yl, 7-methoxyquinolin-4-yl, 7-methyl-3-(trifluoromethyl)-1,6-naphthyridin-5-yl, 6-chloro-7-fluoro-2-methylquinazolin-4-yl, 2-methyl-6-(trifluoromethyl)-1,8-naphthyridin-4-yl, 7-methoxy-2-25 methylquinazolin-4-yl, 2-methyl-6-(trifluoromethyl)quinolin-4-yl, 2-methylquinazolin-4-yl, 6-chloro-2-methylquinazolin-4-yl, 4-cyanoisoquinolin-1-yl, 6-cyano-2-methylquinazolin-4-yl, 6-cyano-2-methylquinolin-4-yl, 7-methyl-2- (trifluoromethyl)imidazo[1,2-a]pyrimidin-5-yl, 6-fluoro-2-methylquinazolin-4-yl, 2-methyl-6-(trifluoromethyl)-2H-pyrazolo[3,4-d]pyrimidin-4-yl, 5-fluoro-6-methoxy-2-methylquinazolin-30 4-yl, 5-methoxy-2-methylquinazolin-4-yl, 1,6-dimethyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl, 1-methyl-6- (trifluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl, 6-(difluoromethoxy)-2-methylquinazolin-4-yl, 6- methoxy-2,5-dimethylquinazolin-4-yl, 5-chloro-6-methoxy-2-methylquinazolin-4-yl, AUG-P3833PCT 6-(difluoromethoxy)-2-methylquinazolin-4-yl, 6-methoxy-2-methyl-1,5-naphthyridin-4-yl, 6-methoxy-2- methylpyrido[3,2-d]pyrimidin-4-yl, and 5-(difluoromethoxy)-2-methylquinazolin-4-yl.

[0110] In one further preferred embodiment, Y1 is selected from 6-cyclopropyl-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl, 2-methyl-5-(trifluoromethyl)quinazolin-4-yl, 3-cyano-7-methyl-1,6- 5 naphthyridin-5-yl, 6-cyano-5-methoxy-2-methylquinazolin-4-yl, 5-chloro-2-methylquinazolin-4-yl, 5-(2- ((5-methylpyrazolo[1,5-a]pyrimidin-7-yl, 5-(2-((2-methyl-5-(trifluoromethoxy)quinazolin-4-yl, 8-cyano- 5-methoxy-2-methylquinazolin-4-yl, 5-methoxy-2-methylpyrido[4,3-d]pyrimidin-4-yl, 2- (dimethylamino)-6-methylpyrido[3,2-d]pyrimidin-4-yl, 6-(dimethylamino)-2-methylpyrido[3,2- d]pyrimidin-4-yl, 2-methyl-6-(2-oxopyrrolidin-1-yl)pyrido[3,2-d]pyrimidin-4-yl, 2,6-dimethylpyrido[3,2-10 d]pyrimidin-4-yl, 2-methoxy-6-methylpyrido[3,2-d]pyrimidin-4-yl, and 6-methoxy-2-(trifluoromethyl)pyrido[3,2-d]pyrimidine.

[111] In one further preferred embodiment, Y1 is selected from 6-methyl-2-(methylamino)pyrido[3,2-d]pyrimidin-4-yl, 8-methoxy-2-methylpyrido[3,2-d]pyrimidin-4-yl, 6-cyclopropoxy-2-methylpyrido[3,2- d]pyrimidin-4-yl, 2-methyl-6-(3-oxomorpholino)pyrido[3,2-d]pyrimidin-4-yl, 2-methyl-6-15 (methylamino)pyrido[3,2-d]pyrimidin-4-yl, 3,3-dimethylazetidin-1-yl)-2-methylpyrido[3,2-d]pyrimidin- 4-yl, 1,5-dimethyl-1H-pyrazolo[4,3-d]pyrimidin-7-yl, 2-methyl-6-(trifluoromethyl)furo[3,2-d]pyrimidin- 4-yl)thio, 2-methoxy-6-methyl-pyrido[3,2-d]pyrimidin-4-yl, 1,5-dimethyl-1H-pyrazolo[3,4-c]pyridin-7- yl, 1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl, 1-methyl-1H-pyrazolo[4,3-c]pyridin-4-yl, 1,5-dimethyl- 1H-pyrazolo[4,3-b]pyridin-7-yl, 2,5-dimethyl-2H-pyrazolo[4,3-b]pyridin-7-yl, 1-methyl-1H-20 pyrazolo[3,4-c]pyridin-7-yl, 3-methylimidazo[1,5-a]pyrazin-8-yl, 1H-imidazo[4,5-c]pyridin-2-yl, 1- methylimidazo[4,5-c]pyridin-2-yl, 3-methyl-3H-imidazo[4,5-c]pyridin-2-yl, oxazolo[5,4-c]pyridin-2-yl, 3-methylimidazo[1,5-c]pyrimidin-5-yl, and 3,7-dimethylimidazo[1,5-c]pyrimidin-5-yl.

[112] In one further preferred embodiment, Y1 is a 10-membered bicyclic [6,6] heteroaryl selected from6-methoxy-2-methylquinazolin-4-yl, 3-methoxy-7-methyl-1,6-naphthyridin-5-yl, 7-methoxyquinolin-4-yl,25 7-methyl-3-(trifluoromethyl)-1,6-naphthyridin-5-yl, 6-chloro-7-fluoro-2-methylquinazolin-4-yl, 2-methyl- 6-(trifluoromethyl)-1,8-naphthyridin-4-yl, 7-methoxy-2-methylquinazolin-4-yl, 2-methyl-6- (trifluoromethyl)quinolin-4-yl, 2-methylquinazolin-4-yl, 6-chloro-2-methylquinazolin-4-yl, 4- cyanoisoquinolin-1-yl, 6-cyano-2-methylquinazolin-4-yl, 6-cyano-2-methylquinolin-4-yl, 6-fluoro-2- methylquinazolin-4-yl, 5-fluoro-6-methoxy-2-methylquinazolin-4-yl, 5-methoxy-2-methylquinazolin-4-30 yl, 6-(difluoromethoxy)-2-methylquinazolin-4-yl, 6-methoxy-2,5-dimethylquinazolin-4-yl, 5-chloro-6- methoxy-2-methylquinazolin-4-yl, 6-(difluoromethoxy)-2-methylquinazolin-4-yl, 6-methoxy-2-methyl- 1,5-naphthyridin-4-yl, 6-methoxy-2-methylpyrido[3,2-d]pyrimidin-4-yl, 5-(difluoromethoxy)-2- methylquinazolin-4-yl, 3-cyano-7-methyl-1,6-naphthyridin-5-yl, 6-cyano-5-methoxy-2-methylquinazolin- 4-yl, 5-chloro-2-methylquinazolin-4-yl, 5-(2-((2-methyl-5-(trifluoromethoxy)quinazolin-4-yl, 8-cyano-5- AUG-P3833PCT methoxy-2-methylquinazolin-4-yl, 5-methoxy-2-methylpyrido[4,3-d]pyrimidin-4-yl, 2-(dimethylamino)- 6-methylpyrido[3,2-d]pyrimidin-4-yl, 6-(dimethylamino)-2-methylpyrido[3,2-d]pyrimidin-4-yl, 2-methyl- 6-(2-oxopyrrolidin-1-yl)pyrido[3,2-d]pyrimidin-4-yl, 2,6-dimethylpyrido[3,2-d]pyrimidin-4-yl, 2- methoxy-6-methylpyrido[3,2-d]pyrimidin-4-yl, 6-methyl-2-(methylamino)pyrido[3,2-d]pyrimidin-4-yl, 8- 5 methoxy-2-methylpyrido[3,2-d]pyrimidin-4-yl, 6-cyclopropoxy-2-methylpyrido[3,2-d]pyrimidin-4-yl, 2- methyl-6-(3-oxomorpholino)pyrido[3,2-d]pyrimidin-4-yl, 2-methyl-6-(methylamino)pyrido[3,2- d]pyrimidin-4-yl, 3,3-dimethylazetidin-1-yl)-2-methylpyrido[3,2-d]pyrimidin-4-yl, and 2-methoxy-6- methyl-pyrido[3,2-d]pyrimidin-4-yl.

[113] In one further preferred embodiment, Y1 is a 10-membered bicyclic [6,6] heteroaryl selected from10 6-methoxy-2-methylquinazolin-4-yl, 3-methoxy-7-methyl-1,6-naphthyridin-5-yl, 7-methoxyquinolin-4-yl, 7-methyl-3-(trifluoromethyl)-1,6-naphthyridin-5-yl, 6-chloro-7-fluoro-2-methylquinazolin-4-yl, 2-methyl- 6-(trifluoromethyl)-1,8-naphthyridin-4-yl, 7-methoxy-2-methylquinazolin-4-yl, 2-methyl-6- (trifluoromethyl)quinolin-4-yl, 2-methylquinazolin-4-yl, 6-chloro-2-methylquinazolin-4-yl, 4- cyanoisoquinolin-1-yl, 6-cyano-2-methylquinazolin-4-yl, 6-cyano-2-methylquinolin-4-yl, 6-fluoro-2-15 methylquinazolin-4-yl, 5-fluoro-6-methoxy-2-methylquinazolin-4-yl, 5-methoxy-2-methylquinazolin-4- yl, 6-(difluoromethoxy)-2-methylquinazolin-4-yl, 6-methoxy-2,5-dimethylquinazolin-4-yl, 5-chloro-6- methoxy-2-methylquinazolin-4-yl, 6-(difluoromethoxy)-2-methylquinazolin-4-yl, 6-methoxy-2-methyl- 1,5-naphthyridin-4-yl, 6-methoxy-2-methylpyrido[3,2-d]pyrimidin-4-yl, 5-(difluoromethoxy)-2- methylquinazolin-4-yl, 3-cyano-7-methyl-1,6-naphthyridin-5-yl, 6-cyano-5-methoxy-2-methylquinazolin-20 4-yl, 5-chloro-2-methylquinazolin-4-yl, 5-(2-((2-methyl-5-(trifluoromethoxy)quinazolin-4-yl, 8-cyano-5- methoxy-2-methylquinazolin-4-yl, 5-methoxy-2-methylpyrido[4,3-d]pyrimidin-4-yl, 2-(dimethylamino)- 6-methylpyrido[3,2-d]pyrimidin-4-yl, 6-(dimethylamino)-2-methylpyrido[3,2-d]pyrimidin-4-yl, 2-methyl- 6-(2-oxopyrrolidin-1-yl)pyrido[3,2-d]pyrimidin-4-yl, 2,6-dimethylpyrido[3,2-d]pyrimidin-4-yl, and 2- methoxy-6-methylpyrido[3,2-d]pyrimidin-4-yl.25

[0114] In one further preferred embodiment, Y1 is a 10-membered bicyclic [6,6] heteroaryl selected from6-methoxy-2-methylquinazolin-4-yl, 3-methoxy-7-methyl-1,6-naphthyridin-5-yl, 7-methyl-3- (trifluoromethyl)-1,6-naphthyridin-5-yl, 6-chloro-7-fluoro-2-methylquinazolin-4-yl, 2-methylquinazolin- 4-yl, 5-fluoro-6-methoxy-2-methylquinazolin-4-yl, 5-methoxy-2-methylquinazolin-4-yl, 6- (difluoromethoxy)-2-methylquinazolin-4-yl, 6-methoxy-2,5-dimethylquinazolin-4-yl, 5-chloro-6-30 methoxy-2-methylquinazolin-4-yl, 6-(difluoromethoxy)-2-methylquinazolin-4-yl, 6-methoxy-2- methylpyrido[3,2-d]pyrimidin-4-yl, 2-methyl-5-(trifluoromethyl)quinazolin-4-yl, 5-chloro-2- methylquinazolin-4-yl, and 2-(dimethylamino)-6-methylpyrido[3,2-d]pyrimidin-4-yl. AUG-P3833PCT

[115] In one further preferred embodiment, Y1 is selected from 6-methoxy-2-methylquinazolin-4-yl, 6-methoxy-2-methylpyrido[3,2-d]pyrimidin-4-yl, 2-(dimethylamino)-6-methylpyrido[3,2-d]pyrimidine-4-yl and 2-methoxy-6-methylpyrido[3,2-d]pyrimidin-4-yl.

[116] In one further preferred embodiment, Y1 is selected from 6-methoxy-2-methylquinazolin-4-yl, 6-5 methoxy-2-methylpyrido[3,2-d]pyrimidin-4-yl, and 2-(dimethylamino)-6-methylpyrido[3,2-d]pyrimidine- 4-yl.

[117] In one embodiment, Y1 is not thieno[2,3-d]pyrimidin-4-yl.L1definitions

[118] In formula (I) above, L1 is -(NH) -, wherein m is an integer selected f1 mrom 0 and 1, i.e., L10 represents a simple bond or -NH-.

[119] In one preferred embodiment, m is 0, i.e., L1 represents a simple bond. In one embodiment, m is1, i.e., L1represents -NH-. W and X definitions

[120] In formula (I) above, W is N or C-R12; wherein R12 is selected from hydrogen, halogen and -15 (C1-C3) alkyl.

[0121] In one embodiment, W is N or C-R12; wherein R12 is selected from hydrogen and halogen.

[0122] In one embodiment, R12 is selected from hydrogen and -(C1-C3) alkyl. In one preferredembodiment, R12is hydrogen.

[123] In formula (I) above, X is N or C-R13; wherein R13 is selected from hydrogen, halogen and -20 (C1-C3) alkyl.

[0124] In one embodiment, X is N or C-R13, wherein R13 is selected from hydrogen and halogen.

[0125] In one embodiment, R13 is selected from hydrogen and (C1-C3) alkyl. In one preferredembodiment, R13is hydrogen.

[126] According to one preferred embodiment, W is C-R12 and / or X is C-R13. In one preferred25 embodiment, W is C-R12 and X is C-R13. In one preferred embodiment, W is C-R12 and X is N.L2definitions

[127] In formula (I) above, L2 is -(CR10R11)n whereinn is an integer selected from 0, 1, 2 and 3; AUG-P3833PCT R10 is selected from hydrogen, halogen, hydroxy, amino, -(C1-C3) alkyl, -(C1-C2) haloalkyl, -(C1-C2) hydroxyalkyl, -(C1-C2) aminoalkyl, -O-(C1-C4) alkyl, -NH-(C1-C3) alkyl, -N-((C1-C3) alkyl)2, -(C3-C9) cycloalkyl, -(C2-C9) heterocycloalkyl, aryl, and heteroaryl;wherein each of the -(C3-C9) cycloalkyl, -(C2-C9) heterocycloalkyl, aryl, heteroaryl is5 optionally substituted with at least one group selected from halogen, cyano, hydroxy, amino, -(C1-C6) alkyl, -(C1-C6) haloalkyl and -O-(C1-C6) alkyl; R11 is selected from hydrogen, halogen, hydroxy, amino, -(C1-C3) alkyl, -(C1-C2) haloalkyl, -(C1-C2) hydroxyalkyl, -(C1-C2) aminoalkyl, -O-(C1-C4) alkyl, -NH-(C1-C3) alkyl, -N-((C1-C3) alkyl)2;10 or R10and R11when bound to the same carbon atom together with the carbon atom to which they are bound form a (C3-C9) cycloalkyl or (C2-C9) heterocycloalkyl;or when n is 2 or 3, any two groups selected from R10and / or R11when bound to different carbon atoms together with the carbon atom to which they are bound and any intervening atompresent form a (C3-C9) cycloalkyl or (C2-C9) heterocycloalkyl.15

[0128] In one further embodiment, L2 is -(CR10R11)n whereinn is an integer selected from 0, 1, 2 and 3;R10 is selected from hydrogen, halogen, hydroxy, amino, -(C1-C3) alkyl, -(C1-C2) haloalkyl, -(C1-C2) hydroxyalkyl, -(C1-C2) aminoalkyl, -O-(C1-C4) alkyl, -NH-(C1-C3) alkyl, -N-((C1-C3) alkyl)2, -(C3-C9) cycloalkyl, -(C2-C9) heterocycloalkyl, aryl, and heteroaryl;20 wherein each of the -(C3-C9) cycloalkyl, -(C2-C9) heterocycloalkyl, aryl, heteroaryl isoptionally substituted with at least one group selected from halogen, cyano, hydroxy, amino, -(C1-C6) alkyl, -(C1-C6) haloalkyl and -O-(C1-C6) alkyl; R11 is selected from hydrogen, halogen, hydroxy, amino, -(C1-C3) alkyl, -(C1-C2) haloalkyl, -(C1-C2) hydroxyalkyl, -(C1-C2) aminoalkyl, -O-(C1-C4) alkyl, -NH-(C1-C3) alkyl, -N-((C1-25 C3) alkyl)2;or R10and R11form together with the carbon atom to which they are bound a (C3-C9) cycloalkyl or (C2-C9) heterocycloalkyl.

[0129] In one further embodiment, - L2 is -(CR10R11)n whereinn is an integer selected from 0, 1, 2 and 3; AUG-P3833PCT R10and R11are independently selected from hydrogen, halogen, hydroxy, amino, - (C1-C3) alkyl, -(C1-C2) haloalkyl, -(C1-C2) hydroxyalkyl,-(C1-C2) aminoalkyl, -O-(C1-C4) alkyl, -NH-(C1-C3) alkyl, and-N-((C1-C3) alkyl)2;5 or R10 and R11 form together with the carbon atom to which they are bound a (C3-C6) cycloalkyl or(C4-C9) heterocycloalkyl.

[0130] According to one embodiment, n is 1, 2 or 3. In another embodiment, n is 0, 1 or 2. In oneparticular embodiment, n is 0 or 1. In one preferred embodiment, n is 1. In another preferred embodimentn is 0, i.e., L2 represents a simple bond.10

[0131] According to one embodiment, R10 is selected from hydrogen, halogen, hydroxy, -(C1-C3) alkyl, -(C1-C2) haloalkyl, -(C1-C2) hydroxyalkyl, -O-(C1-C4) alkyl-(C3-C9) cycloalkyl, and aryl; and R11is selected from hydrogen, hydroxy, -(C1-C3) alkyl and -(C1-C2) haloalkyl. In one preferred embodiment, R10and R11are independently selected from hydrogen, hydroxy and -(C -C ) alkyl. In one pr10 13 eferred embodiment, Ris hydroxy and R11 is -(C -C ) alkyl e.g. methyl. In one pref 101 3 erred embodiment, R is -(C1-C3) alkyl e.g.15 methyl and R11is hydroxy.

[132] In one preferred embodiment, R10 is selected from -(C3-C9) cycloalkyl and aryl; and R11is selected from hydrogen, halogen, hydroxy, amino, -(C1-C3) alkyl, -(C1-C2) haloalkyl, -(C1-C2) hydroxyalkyl, -(C1-C2) aminoalkyl, -O-(C1-C4) alkyl, -NH-(C1-C3) alkyl, and -N-((C1-C3) alkyl)2. In one preferredembodiment, R10 is selected from -(C3-C9) cycloalkyl and aryl and R11is selected from hydrogen, halogen,20 hydroxy, and -(C1-C3) alkyl. In another preferred embodiment, R10 is selected from -(C3-C9) cycloalkyl andaryl, and R11is hydrogen.

[133] According to one embodiment, R10 and R11 are independently selected from hydrogen, halogen,hydroxy, -(C1-C3) alkyl, -(C1-C2) haloalkyl, -(C1-C2) hydroxyalkyl, and -O-(C1-C4) alkyl. In one particularembodiment, R10 and R11 are independently selected from hydrogen, hydroxy, -(C1-C3) alkyl and -(C1-25 C2) haloalkyl. In one particular embodiment, R10 and R11 are independently selected from hydrogen,hydroxy and -(C1-C3) alkyl. In one preferred embodiment, R10and R11are independently selected from hydrogen, hydroxy and methyl. In a further preferred embodiment, each of R10 and R11 is hydrogen. Inanother further preferred embodiment, R10 is hydrogen and R11 is methyl. In another further preferredembodiment, R10 is methyl and R11 is hydroxy.30

[0134] According to one embodiment, R10 and R11 form together with the carbon atom to which they arebound a cyclopropyl, for example wherein --- represents the point of attachment of the depicted AUG-P3833PCT moiety to the main molecular structure, or a tetrahyd rofuranyl, for example or wherein --- represents the point of attachment of the depicted moiety to the main molecular structure.

[0135] According to one embodiment, when n is 2 or 3, any two R10 and / or R11 form together atetrahydrofuranyl, for example wherein --- represents the point of attachment of5 the depicted moiety to the main molecular structure, or a tetrahydropyranyl, for example or wherein --- represents the point of attachment of the depicted moiety to the mainmolecular structure.

[136] In one preferred embodiment, L2 is selected from -CH10 2-, -CH(CH3)-, cycloprop-1,1-yl (i.e., Rand R11 form together with the carbon atom to which they are bound a cyclopropyl), -C(CH3)(OH)-,10 tetrahydrofuranyl and tetrahydropyranyl. In one preferred embodiment, L2 is selected from -CH2-, -CH(CH3)-, cycloprop-1,1-yl (i.e., R10and R11form together with the carbon atom to which they are bound acyclopropyl), and -C(CH3)(OH)-. In one further preferred embodiment, L2is -CH2-. In another further preferred embodiment, L2is -C(CH3)(OH)-.

[137] According to one embodiment, when n is 1, R10 and R11 are arranged as follows within a15 compound of formula (I): AUG-P3833PCT Z1definitions

[138] In formula (I) above, Z1 is selected from hydrogen, -(C1-C6) alkyl,-(C3-C9) cycloalkyl, -(C2-C9) heterocycloalkyl, aryl, heteroaryl, -(C1-C6) alkylene-(C3-C9) cycloalkyl, -(C1-C6) alkylene-(C2-C9) heterocycloalkyl, -(C1-C6) alkylene-aryl and -(C1-C6) alkylene-heteroaryl;5 wherein each of the -(C1-C6) alkyl, -(C3-C9) cycloalkyl, -(C2-C9) heterocycloalkyl, aryl or heteroarylin Z1is optionally substituted with at least one group selected from halogen, -NR23R24, methyl, hydroxy, -(C -C ) haloalkyl, and -(C -C ) hydro 23 241 2 1 2 xyalkyl; wherein R and R are each independentlyselected from hydrogen and methyl.

[139] In one embodiment, Z1 is selected from hydrogen, -(C1-C6) alkyl,10 -(C3-C6) cycloalkyl, -(C3-C9) heterocycloalkyl, aryl, heteroaryl, -(C1-C6) alkylene-(C3-C9) cycloalkyl, -(C1-C6) alkylene-(C3-C9) heterocycloalkyl, and -(C1-C6) alkylene-heteroaryl;wherein each of the -(C1-C6) alkyl, -(C3-C7) cycloalkyl, -(C3-C7) heterocycloalkyl, aryl or heteroarylin Z1is optionally substituted with at least one group selected from halogen, -NR23R24, methyl, and hydroxy; wherein R23 and R24 are each independently selected from hydrogen and methyl.15

[0140] According to one embodiment, Z1 is selected from hydrogen, -(C1-C6) alkyl,-(C3-C9) cycloalkyl, -(C2-C9) heterocycloalkyl, aryl, heteroaryl, -(C1-C6) alkylene-(C3-C9) cycloalkyl, -(C1-C6) alkylene-(C2-C9) heterocycloalkyl, -(C1-C6) alkylene-aryl and -(C1-C6) alkylene-heteroaryl. In apreferred embodiment, Z1 is -(C3-C9) cycloalkyl or -(C2-C9) heterocycloalkyl.

[0141] According to one embodiment, the -(C1-C6) alkyl, -(C3-C9) cycloalkyl,20-(C2-C9) heterocycloalkyl, aryl or heteroaryl in Z1is unsubstituted.

[142] According to one embodiment, the -(C1-C6) alkyl or -(C1-C6) alkylene in Z1is unsubstituted.

[143] According to one embodiment, the -(C1-C6) alkyl, -(C3-C9) cycloalkyl,-(C2-C9) heterocycloalkyl, aryl or heteroaryl in Z1is substituted with up to three groups e.g. three groups, or two groups, or one group.25

[0144] According to one embodiment, the -(C1-C6) alkyl, -(C3-C9) cycloalkyl,-(C2-C9) heterocycloalkyl, aryl or heteroaryl in Z1substituted with up to three groups e.g. three groups, or two groups, or one group selected from halogen, amino (i.e., R23 and R24 are each hydrogen), methyl, andhydroxy.

[145] According to one embodiment, the -(C1-C6) alkyl, -(C3-C9) cycloalkyl,30-(C2-C9) heterocycloalkyl, aryl or heteroaryl in Z1substituted with up to three groups e.g. three groups, or two groups, or one group selected from halogen, methyl, and hydroxy. AUG-P3833PCT

[146] According to one embodiment, the -(C3-C7) cycloalkyl in Z1is substituted with at least one group selected from halogen, amino (i.e., R23 and R24 are each hydrogen), methyl, and hydroxy.

[0147] According to one embodiment, Z1 is hydrogen. In one preferred embodiment, Z1 is hydrogen andR1 is hydrogen.5

[0148] In one preferred embodiment, Z1 is selected from hydrogen, methyl, 2-propyl, ethyl, cyclopropyl,tert-butyl, 1-methylcyclopropyl, oxetan-3-yl, tetrahydro-2H-pyran-4-yl, 2-hydroxypropyl, 1- methylazetidin-3-yl, (1-methylazetidin-3-yl)methyl, (1R,3R)-3-hydroxycyclobutyl, (1S,3S)-3-hydroxycyclobutyl, 1-methylpyrrolidin-3-yl, piperidin-3-yl, piperidin-4-yl, 1-cyclopropylpiperidin-4-yl,quinuclidin-3-yl, 1-methylpiperidin-3-yl, 1-ethylpiperidin-4-yl, 3,3-difluorocyclobutyl, (1S,3S)-3-10 fluorocyclobutyl, pyridin-3-ylmethyl, pyridin-2-ylmethyl, 1-fluorocyclopropyl)methyl, oxetan-3-ylmethyl,1-methyl-1H-pyrazol-5-yl, 1-methylpiperidin-4-yl, (1-methylpiperidin-4-yl)methyl, pyridin-4-ylmethyl, 8-oxabicyclo[3.2.1]octan-3-yl, octahydropyrido[2,1-c][1,4]oxazin-8-yl, 8-azabicyclo[3.2.1]octan-3-yl, 9-methyl-9-azabicyclo[3.3.1]nonan-3-yl, 8-methyl-8-azabicyclo[3.2.1]octan-3-yl, 3-hydroxy-1-methylpiperidin-4-yl, 3-methyl-3-azabicyclo[3.1.0]hexan-6-yl, 3-methyl-3-azabicyclo[3.1.1]heptan-6-yl,15 9-methyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl, 4-(hydroxymethyl)-1-methylpiperidin-4-yl, 2-methyl-2-azabicyclo[2.2.1]heptan-5-yl, 1,3-dimethylpiperidin-4-yl, 1,4-dimethylpiperidin-4-yl, 3-methoxy-1- methylpiperidin-4-yl, 7-methyl-3-oxa-7-azabicyclo[3.3.1]nonan-9-yl, 3-fluoro-1-methylpiperidin-4-yl, 1-methylazepan-4-yl, 2-methyl-5-oxa-2-azaspiro[3.4]octan-7-yl, 3-oxabicyclo[3.1.0]hexan-6-yl, and 4-(fluoromethyl)-1-methylpiperidin-4-yl.20

[0149] In one preferred embodiment, Z1 is selected from 3-methoxycyclobutyl, tetrahydrofuran-3-yl orhexahydro-1H-pyrrolo[2,1-c][1,4]oxazin-7-yl.

[150] In another preferred embodiment, Z1 is selected from methyl, cyclopropyl or octahydropyrido[2,1-c][1,4]oxazin-8-yl. R1definitions25

[0151] In formula (I) above, either:R1 is selected from hydrogen, -(C1-C6) alkyl, -(C3-C9) cycloalkyl, -(C1-C6) alkylene-(C3-C9) cycloalkyl,and (C2-C9) heterocycloalkyl;wherein the -(C1-C6) alkyl or -(C1-C6) alkylene in R1is optionally substituted with at least one group selected from halogen, cyano, hydroxy, amino, -(C1-C6) alkyl,30 -CH2-O-(C1-C6) alkyl, and -O-(C1-C6) alkyl; AUG-P3833PCT wherein the -(C3-C9) cycloalkyl or -(C2-C9) heterocycloalkyl in R1is optionally substituted with at least one group selected from halogen, cyano, hydroxy, amino, -(C1-C6) alkyl, -CH2-O-(C1-C6) alkyl, and -O-(C1-C6) alkyl;or R1 and one of R10 or R11 from together a -(C2-C9) heterocycloalkyl comprising at least one nitrogen atom;5wherein the (C2-C9) heterocycloalkyl in R1and R10or R11is optionally substituted with at least one group selected from halogen, cyano, hydroxy, amino, -(C1-C6) alkyl, -CH2-O-(C1-C6) alkyl, and -O-(C1-C6) alkyl.or R1 and Z1 form together with the nitrogen atom to which they are bound a -(C2-C9) heterocycloalkyl;wherein the -(C2-C9) heterocycloalkyl in R1and Z1is optionally substituted with at least one group selected10 from halogen, cyano, hydroxy, amino, -(C1-C6) alkyl,-CH2-O-(C1-C6) alkyl, -O-(C1-C6) alkyl, -(C1-C2) haloalkyl, and -(C1-C2) hydroxyalkyl.

[0152] In one embodiment, either:R1 is selected from hydrogen, -(C1-C6) alkyl, -(C3-C7) cycloalkyl, -(C1-C6) alkylene-(C3-C7) cycloalkyl,and -(C3-C7) heterocycloalkyl;15wherein the -(C1-C6) alkyl or -(C1-C6) alkylene in R1is optionally substituted with at least one group selected from halogen, cyano, hydroxy, amino, -(C1-C6) alkyl,-CH2-O-(C1-C6) alkyl, and -O-(C1-C6) alkyl;wherein the -(C3-C7) cycloalkyl or -(C3-C7) heterocycloalkyl in R1is optionally substituted with at least one group selected from halogen, cyano, hydroxy, amino, -(C1-C6) alkyl, -CH2-O-(C1-C6) alkyl, and -O-(C1-20 C6) alkyl;or R1 and one of R10 or R11 from together a -(C3-C7) heterocycloalkyl comprising at least one nitrogen atom;wherein the -(C3-C7) heterocycloalkyl in R1and R10or R11is optionally substituted with at least one group selected from halogen, cyano, hydroxy, amino, -(C1-C6) alkyl, -CH2-O-(C1-C6) alkyl, and -O-(C1-C6) alkyl.25 or R1 and Z1 form together with the nitrogen atom to which they are bound a -(C3-C9) heterocycloalkyl;wherein the -(C3-C9) heterocycloalkyl in R1and Z1is optionally substituted with at least one group selected from halogen, cyano, hydroxy, amino, -(C1-C6) alkyl,-CH2-O-(C1-C6) alkyl, and -O-(C1-C6) alkyl.

[0153] According to one embodiment, R1 is selected from hydrogen, -(C1-C3) alkyl, and aryl. In one30 preferred embodiment, R1is hydrogen. AUG-P3833PCT

[154] According to one embodiment, R1 and one of R10 or R11 form together a -(C2-C9) heterocycloalkylcomprising at least one nitrogen atom. In one embodiment, R1and one of R10or R11form together a -(C2- C9) heterocycloalkyl comprising exactly one nitrogen atom and, optionally, at least one oxygen atom.

[0155] According to one embodiment, R1 and one of R10 or R11 form together a -(C3-C7) heterocycloalkyl5 comprising at least one nitrogen atom. In one embodiment, R1and one of R10or R11from together a -(C3- C7) heterocycloalkyl comprising exactly one nitrogen atom and, optionally, at least one oxygen atom. Inanother preferred embodiment, the ring formed by R1and one of R10or R11together is selected from pyrrolidinyl, piperidinyl, and morpholinyl.

[156] In another preferred embodiment, the ring formed by R1 and R10 or R11 together is selected from10 pyrrolidin-2-one and morpholin-3-one.

[0157] According to one embodiment, R1 and Z1 form together a -(C2-C9) heterocycloalkyl comprisingat least one nitrogen atom. In one embodiment, R1 and Z1 form together a -(C2-C9) heterocycloalkylcomprising two nitrogen atoms or one nitrogen atom and optionally, at least one oxygen atom.

[158] In another embodiment, said -(C2-C9) heterocycloalkyl in R1and Z1is optionally substituted with 15 at least one group selected from halogen, hydroxy, -(C1-C6) alkyl, -CH2-O-(C1-C6) alkyl, -O-(C1-C6) alkyl, -(C1-C2) haloalkyl, and -(C1-C2) hydroxyalkyl.

[0159] In another preferred embodiment, the ring formed by R1 and Z1 together is selected frommorpholinyl, piperazin-1-yl, 4-methylpiperazin-1-yl, 2-oxa-5-azabicyclo[2.2.1]heptan-5-yl, 3-oxa-8- azabicyclo[3.2.1]octan-8-yl, 3-(2-hydroxypropan-2-yl)azetidin-1-yl, 3-azabicyclo[3.1.0]hexan-3-yl, 6,6-20 difluoro-3-azabicyclo[3.1.0]hexan-3-yl, 1-(3-(trifluoromethyl)azetidin-1-yl, 3-hydroxy-3-methylazetidin- 1-yl, 4-hydroxy-4-methylpiperidin-1-yl, 3-hydroxy-3-methylpyrrolidin-1-yl, 2,5-dimethylmorpholino, 2- (hydroxymethyl)piperidin-1-yl, and 3-hydroxy-3-methylpyrrolidin-1-yl, 4-oxa-7-azaspiro[2.5]octan-7-yl.Further general formulae

[160] According to one embodiment, the compound of formula (I) is a compound of formula (I-a) or25 formula (I-b) AUG-P3833PCT or a pharmaceutically acceptable salt and / or solvate thereof; wherein Y1, X, W, R10, Z1, and R1 are as defined hereinabove under formula (I).

[0161] In one preferred embodiment, R10 is methyl.5

[0162] In one preferred embodiment, Z1 is selected from hydrogen, -(C1-C3) alkyl (e.g., methyl), and -(C3-C5) cycloalkyl (e.g., cyclopropyl).

[0163] In one preferred embodiment, R1 is hydrogen.

[0164] According to one embodiment, the compound of formula (I) is a compound of formula (I-c) 10 or a pharmaceutically acceptable salt and / or solvate thereof; wherein Y1, X, W, Z1, and R1 are as defined hereinabove under formula (I).

[0165] In one preferred embodiment, Z1 is a -(C2-C9) heterocycloalkyl comprising exactly one nitrogenatom (e.g., piperidin-4-yl, 8-azabicyclo[3.2.1]octan-3-yl, and octahydropyrido[2,1-c][1,4]oxazin-8-yl), wherein the -(C2-C9) heterocycloalkyl in Z1is optionally substituted as defined hereinabove under formula15 (I).

[166] In one preferred embodiment, Z1 is a -(C3-C7) heterocycloalkyl comprising exactly one nitrogenatom (e.g., piperidin-4-yl, 8-azabicyclo[3.2.1]octan-3-yl, and octahydropyrido[2,1-c][1,4]oxazin-8-yl), wherein the -(C3-C7) heterocycloalkyl in Z1is optionally substituted as defined hereinabove under formula (I).20

[0167] In one preferred embodiment, R1 is hydrogen.

[0168] According to one embodiment, the compound of formula (I) is a compound of formula (I-d) AUG-P3833PCT or a pharmaceutically acceptable salt and / or solvate thereof; wherein Y1, X, Z1, and R1 are as defined hereinabove under formula (I).

[0169] In one preferred embodiment, Z1 is selected from octahydropyrido[2,1-c][1,4]oxazin-8-yl, 1-5 methylpiperidin-4-yl, 8-methyl-8-azabicyclo[3.2.1]octan-3-yl, and 3-methoxy-1-methylpiperidin-4-yl.

[170] In one preferred embodiment, R1 is hydrogen.

[0171] According to one embodiment, the compound of formula (I) is a compound of formula (I-e) or a pharmaceutically acceptable salt and / or solvate thereof;10 wherein Y1, L2, Z1, and R1 are as defined hereinabove under formula (I).

[0172] In one preferred embodiment, Z1 is selected from octahydropyrido[2,1-c][1,4]oxazin-8-yl, 1-methylpiperidin-4-yl, 8-methyl-8-azabicyclo[3.2.1]octan-3-yl, and 3-methoxy-1-methylpiperidin-4-yl.

[173] In one preferred embodiment, R1 is hydrogen.

[0174] According to one embodiment, the compound of formula (I) is a compound of formula (I-f)15 or a pharmaceutically acceptable salt and / or solvate thereof; wherein R2, G1, A1-A4, L2, Z1, and R1 are as defined hereinabove under formula (I).

[0175] According to one embodiment, the compound of formula (I) is a compound of formula (I-g) AUG-P3833PCT or a pharmaceutically acceptable salt and / or solvate thereof; wherein R2, A1-A4, L2, Z1, and R1 are as defined hereinabove under formula (I).

[0176] According to one embodiment, the compound of formula (I) is a compound of formula (I-h)5 or a pharmaceutically acceptable salt and / or solvate thereof; wherein R2, A1-A4, R10, R11, Z1, and R1 are as defined hereinabove under formula (I).

[0177] According to one embodiment, the compound of formula (I) is a compound of formula (I-ha) orformula (I-hb) 10 AUG-P3833PCT or a pharmaceutically acceptable salt and / or solvate thereof; wherein R2, A1-A4, R10, R11, Z1, and R1 are as defined hereinabove under formula (I).

[0178] According to one preferred embodiment, the compound of formula (I) is a compound of5 formula (I-ha) or (I-hb) wherein R10 is hydroxy and R11 is methyl. More preferably the compound offormula (I) is a compound of formula (I-hb) wherein R10 is hydroxy and R11 is methyl or a compound offormula (I-ha) wherein R10 is methyl and R11 is hydroxy.

[0179] According to one embodiment, the compound of formula (I) is a compound of formula (I-j) 10 or a pharmaceutically acceptable salt and / or solvate thereof; wherein R2, A1-A4, Z1, and R1 are as defined hereinabove under formula (I).

[0180] According to one embodiment, the compound of formula (I) is a compound of formula (I-k) or a pharmaceutically acceptable salt and / or solvate thereof; 15 wherein R2, A1-A4, R10, R11and Z1are as defined hereinabove under formula (I). AUG-P3833PCT

[181] According to one embodiment, the compound of formula (I) is a compound of formula (I-ka) orformula (I-kb) 5 or a pharmaceutically acceptable salt and / or solvate thereof; wherein R2, A1-A4, R10, R11and Z1are as defined hereinabove under formula (I).

[182] In one preferred embodiment, R2 is methyl or 1-methylpiperidin-4-yl.

[0183] In one preferred embodiment, A4 is N, A1-A2 are each CH, and A3 is C-R7.

[0184] In one preferred embodiment, Z1 is cyclopropyl or octahydropyrido[2,1-c][1,4]oxazin-8-yl.10

[0185] In one preferred embodiment, one of R10 and R11 is methyl and the other is hydroxy.

[0186] In one preferred embodiment, the compound of formula (I) is a compound of formula (I-ka) or (I-kb) wherein R10is hydroxy and R11is methyl. More preferably the compound of formula (I) is a compound of formula (I-kb) wherein R10 is hydroxy and R11 is methyl or a compound of formula (I-ka) wherein R10is methyl and R11is hydroxy.15

[0187] According to one embodiment, the compound of formula (I) is a compound of formula (I-m) or a pharmaceutically acceptable salt and / or solvate thereof; AUG-P3833PCT wherein Y1 and Z1 are as defined hereinabove under formula (I).

[0188] According to one embodiment, the compound of formula (I) is a compound of formula (I-ma) orformula (I-mb) 5 or a pharmaceutically acceptable salt and / or solvate thereof; wherein Y1 and Z1 are as defined hereinabove under formula (I).

[0189] In one preferred embodiment, Z1 is hydrogen.Further compound definitions10

[0190] According to one preferred embodiment, the compound of formula (I) is not 1-morpholino-2-(5-(2-(thieno[2,3-d]pyrimidin-4-ylthio)acetyl)thiophen-2-yl)ethan-1-one of the following formula or a pharmaceutically acceptable salt and / or solvate thereof. Specific compounds15

[0191] According to one embodiment, the compound of formula (I) is selected from the compounds ofTable 1 below. AUG-P3833PCT AUG-P3833PCT AUG-P3833PCT 53 AUG-P3833PCT AUG-P3833PCT AUG-P3833PCT AUG-P3833PCT 57 AUG-P3833PCT 58 AUG-P3833PCT AUG-P3833PCT AUG-P3833PCT AUG-P3833PCT 62 AUG-P3833PCT 63 AUG-P3833PCT 64 AUG-P3833PCT 65 AUG-P3833PCT 66 AUG-P3833PCT 67 AUG-P3833PCT 68 AUG-P3833PCT AUG-P3833PCT 70 AUG-P3833PCT 71 AUG-P3833PCT 72 AUG-P3833PCT 73 AUG-P3833PCT 74 AUG-P3833PCT 75 AUG-P3833PCT AUG-P3833PCT 77 AUG-P3833PCT AUG-P3833PCT 79 AUG-P3833PCT 80 AUG-P3833PCT AUG-P3833PCT 82 AUG-P3833PCT 83 AUG-P3833PCT Table 1

[192] According to one embodiment, the compound of formula (I) is selected from the compounds ofTable 2 below.5 AUG-P3833PCT 85 AUG-P3833PCT AUG-P3833PCT 87 AUG-P3833PCT 88 AUG-P3833PCT AUG-P3833PCT AUG-P3833PCT AUG-P3833PCT AUG-P3833PCT AUG-P3833PCT 94 Table 2 AUG-P3833PCT 95

[0193] According to one embodiment, the compound of formula (I) is selected from the compounds ofTable 3 below. AUG-P3833PCT 96 AUG-P3833PCT AUG-P3833PCT AUG-P3833PCT 99 Table 3

[194] The compounds of Table 1, Table 2 and Table 3 were named using ChemDraw®Professional 22.0 (PerkinElmer / Revvity).

[0195] According to one embodiment, the compound of formula (I) is selected from the compounds of5 Table 1 herein and pharmaceutically acceptable salts and / or solvates of any one thereof.

[0196] According to one embodiment, the compound of formula (I) is selected from the compounds ofTable 1 and Table 2 herein and pharmaceutically acceptable salts and / or solvates of any one thereof. AUG-P3833PCT

[197] According to one embodiment, the compound of formula (I) is selected from the compounds ofTable 1, Table 2 and Table 3 herein and pharmaceutically acceptable salts and / or solvates of any one thereof. Alternative forms of the compounds 5

[0198] All references herein to a compound of the invention (e.g., a “compound of formula (I)”) includereferences to salts – suitably pharmaceutically acceptable salts, solvates, multi-component complexes andliquid crystals thereof. All references herein to a compound of the invention include references to polymorphs and crystal habits thereof. All references to a compound of the invention include references to pharmaceutically acceptable prodrugs thereof. All references to a compound of the invention include10 references to isotopically labelled compounds, including deuterated compounds.

[0199] A compound of the invention (e.g., a “compound of formula (I)”) and subformulae thereof maycontain at least one asymmetric center(s) and thus may exist as different stereoisomeric forms. Accordingly, all references to a compound of the invention include references to all possible stereoisomers and includes not only the racemic compounds but the individual enantiomers and their non-racemic mixtures as well. 15 When a compound is desired as a single enantiomer, such single enantiomer may be obtained by stereospecific synthesis, by resolution of the final product or any convenient intermediate, or by chiral chromatographic methods as each are known in the art. Resolution of the final product, an intermediate, ora starting material may be carried out by any suitable method known in the art.

[200] The compounds of the invention (e.g., a “compound of formula (I)”) may be in the form of20 pharmaceutically acceptable salts. Pharmaceutically acceptable salts include the acid addition and base salts thereof. Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include the acetate, adipate, aspartate, benzoate, besylate, bicarbonate / carbonate, bisulphate / sulphate, borate, camsylate, citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, 25 isethionate, lactate, malate, maleate, malonate, mesylate, methylsulphate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate / hydrogen phosphate / dihydrogen phosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate and xinafoate salts. Suitable base salts are formed from bases which form non-toxic salts. Examples include the aluminium, arginine, benzathine, calcium, choline, diethylamine, 2-(diethylamino)ethanol, diolamine,30 ethanolamine, glycine, 4-(2-hydroxyethyl)-morpholine, lysine, magnesium, meglumine, morpholine, olamine, potassium, sodium, tromethamine and zinc salts. Hemisalts of acids and bases may also be formed, for example, hemisulfate and hemicalcium salts. When a compound contains an acidic group as well as a basic group the compound may also form internal salts, and such compounds are within the scope of the invention. When a compound contains a hydrogen-donating heteroatom (e.g., NH), the invention also AUG-P3833PCT covers salts and / or isomers formed by transfer of said hydrogen atom to a basic group or atom within the molecule. Pharmaceutically acceptable salts of compounds of the invention may be prepared by one ormore of these methods: (i) by reacting the compound with the desired acid; (ii) by reacting the compound with the desired base; (iii) by removing an acid- or base-labile protecting group from a suitable precursor5 of the compound or by ring-opening a suitable cyclic precursor, e.g., a lactone or lactam, using the desired acid; and / or (iv) by converting one salt of the compound to another by reaction with an appropriate acid or by means of a suitable ion exchange column. All these reactions are typically carried out in solution. The salt may precipitate from solution and be collected by filtration or may be recovered by evaporation of thesolvent. The degree of ionization in the salt may vary from completely ionized to almost non-ionized.10 Manufacturing process

[201] This invention also relates to a process for manufacturing a compound of the invention asdescribed herein.

[202] According to one embodiment, the process comprises a step of reacting: (i) a carboxylic acid withan amine; or (ii) a halo-ketone with a thiol. In one embodiment, the process comprises a step of reacting a15 carboxylic acid with an amine. In one embodiment, the process comprises a step of reacting a halo-ketone with a thiol. Pharmaceutical compositions

[203] This invention also relates to a pharmaceutical composition comprising a compound of theinvention as described herein and at least one pharmaceutically acceptable carrier.20

[0204] According to one embodiment, the pharmaceutical composition does not comprise any therapeuticagent other than the compound of the invention. According to another embodiment, the pharmaceuticalcomposition further comprises at least another therapeutic agent. In one embodiment, the at least anothertherapeutic agent is selected from therapeutic agent known in the art for treating inflammatory diseases, autoimmune diseases, proliferative diseases (such as cancers), neurodegenerative diseases (including25 neuromuscular diseases), pains, neuropathies, psychiatric diseases, neurodevelopmental disorders, sleep disorders, cardiovascular diseases, kidney diseases, and metabolic or hormonal disorders.

[0205] The compound of the invention may be formulated, alone or together, in suitable dosage unitformulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles appropriate for each route of administration.30 Medical uses and methods of treatment

[0206] This invention also relates to a compound of the invention as described herein, or a pharmaceuticalcomposition of the invention as described herein, for use as a medicament. AUG-P3833PCT

[207] According to one particular embodiment, the compound or pharmaceutical composition of theinvention is for use in the treatment and / or prevention of an HDAC6-associated disease as defined herein.

[208] This invention also relates to a method of inhibiting an HDAC6 enzyme. According to oneembodiment, the inhibition of an HDAC6 enzyme treats and / or prevents an HDAC6-associated disease. 5 According to one embodiment, the method comprises a step of administering to a subject in need thereof a therapeutically effective amount of a compound of the invention as described herein, or of a pharmaceutical composition of the invention as described herein.

[209] This invention also relates to a method for treating and / or preventing a HDAC6-associated diseasecomprising a step of administering to a subject in need thereof a therapeutically effective amount of a 10 compound of the invention as described herein, or of a pharmaceutical composition of the invention as described herein. This invention also relates to the use of a compound of the invention as described herein, or a pharmaceutical composition of the invention as described herein, in the manufacture of a medicament for the treatment and / or prevention of an HDAC6-associated disease. This invention also relates to the useof a compound of the invention as described herein, or a pharmaceutical composition of the invention as15 described herein, in the treatment and / or prevention of an HDAC6-associated disease.

[210] Advantageously, the compound of the invention shows a superior inhibitory activity against anHDAC enzyme (e.g., class II HDAC enzyme, suitably HDAC6 enzyme) compared to state-of-the artcompounds for treating and / or preventing an HDAC-associated disease.

[0211] Advantageously, the compound of the invention shows a low toxicity (e.g., acute toxicity, chronic20 toxicity, genetic toxicity, hematotoxicity, reproductive toxicity, cardiotoxicity, carcinogenicity) against an HDAC enzyme (e.g., class II HDAC enzyme, suitably HDAC6 enzyme) compared to state-of-the artcompounds for treating and / or preventing an HDAC-associated disease. In particular, the compound of theinvention shows a low or no genetic toxicity, suitably the compound of the invention does not show genetictoxicity in relevant assays known in the art such as, for example, the Ames fluctuation test.25

[0212] Advantageously, the compound of the invention is selective over at least one HDAC other thanHDAC6, suitably over at least one class II HDAC other than HDAC6, more suitably over any class IIHDAC other than HDAC6. Particularly advantageously, the compound of the invention is selective over HDAC10. Furthermore, the compound of the invention is suitably selective over class I HDACs.Particularly advantageously, the compound of the invention is selective over HDAC1 and HDAC3. 30 Selectivity is strongly associated with the avoidance of side-effects of HDAC inhibitors.

[213] According to one embodiment, the HDAC6-associated disease is selected from inflammatorydiseases, autoimmune diseases, proliferative diseases (such as cancers), neurodegenerative diseases(including neuromuscular diseases), pains, neuropathies, psychiatric diseases, neurodevelopmental AUG-P3833PCT disorders, sleep disorders, cardiovascular diseases, addiction-related disorders, gastrointestinal diseases, pulmonary diseases, metabolic or hormonal disorders, immune disorders, age-related diseases, and idiopathic diseases. According to one embodiment, the HDAC6-associated disease is selected frominflammatory diseases, autoimmune diseases, proliferative diseases (such as cancers), neurodegenerative 5diseases (including neuromuscular diseases), pains, neuropathies, psychiatric diseases,neurodevelopmental disorders, sleep disorders, cardiovascular diseases, kidney diseases, and metabolic or hormonal disorders. According to one embodiment, the HDAC6-associated disease is selected from inflammatory diseases, autoimmune diseases, proliferative diseases (such as cancers), neurodegenerative diseases (including neuromuscular diseases), pains, neuropathies, psychiatric diseases, neurodevelopmental10 disorders, sleep disorders and cardiovascular diseases. According to one embodiment, the HDAC6- associated disease is selected from inflammatory diseases, autoimmune diseases, proliferative diseases (such as cancers), neurodegenerative diseases, pains, neuropathies, psychiatric diseases, neurodevelopmental disorders, sleep disorders and cardiovascular diseases. According to one embodiment,the HDAC6-associated disease is selected from proliferative diseases (such as cancers), neurodegenerative15 diseases (including neuromuscular diseases), neuropathies, and cardiovascular diseases. According to oneembodiment, the HDAC6-associated disease is selected from proliferative diseases (such as cancers), neurodegenerative diseases, neuropathies, and cardiovascular diseases.

[0214] A selection of references evidencing that inhibition of HDAC6 has the effect of treating and / orpreventing a given class of diseases are listed as follows. AUG-P3833PCT AUG-P3833PCT

[0215] According to one embodiment, the HDAC6-associated disease is an inflammatory disease. In oneembodiment, the inflammatory disease is selected from acute pancreatitis, chronic pancreatitis, asthma, AUG-P3833PCT adult respiratory distress syndrome, chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis, inflammatory bone disease, inflammatory pulmonary disease, inflammatory bowel disease, celiac disease, hepatitis, systemic inflammatory response syndrome (SIRS), postoperative or posttraumatic inflammation, pneumonia, nephritis, meningitis, cystitis, pharyngolaryngitis, gastric mucosal injury, 5 spondylitis, arthritis, dermatitis, chronic pneumonia, bronchitis, pulmonary infarction, silicosis, pulmonary sarcoidosis, diabetic nephropathy, uveitis, suppurative hidradenitis, cerebrospinal meningitis, inflammatory bowel disease, ulcerative colitis, and Crohn's disease.

[0216] According to one embodiment, the HDAC6-associated disease is an autoimmune disease. In oneembodiment, the autoimmune disease is selected from arthritis, rheumatoid arthritis, psoriasis,10 inflammatory bowel disease (e.g., Crohn's disease or ulcerative colitis), Sjogren's syndrome, multiplesclerosis, systemic lupus erythematosus, lupus nephritis, discoid lupus erythematosus, Castleman's disease, ankylopoietic spondylarthritis, polymyositis, dermatomyositis (DM), polyarteritis nodosa (PN), mixed connective tissue disease (MCTD), scleroderma, lupus erythematosus profundus, chronic thyroiditis, Graves' disease, autoimmune gastritis, type I diabetes, autoimmune hemolytic anemia, autoimmune15 neutropenia, thrombocytopenia, atopic dermatitis, pemphigus, chronic active hepatitis, myasthenia gravis, graft versus host disease, dermatitis, radiodermatitis, and primary biliary cirrhosis.

[0217] According to one embodiment, the HDAC6-associated disease is a proliferative disease, such as,for example, cancer. In one embodiment, the proliferative disease (e.g., cancer) is selected from malignanttumor, angiogenesis glaucoma, infantile hemangioma, multiple myeloma, chronic sarcoma, metastasis 20 melanoma, Kaposi's sarcoma, vascular proliferation, cachexia, metastasis of the breast cancer, colorectal cancer (e.g., familial colorectal cancer, hereditary nonpolyposis colorectal cancer or gastrointestinal stromal tumor), lung cancer (e.g., non-small cell lung cancer, small cell lung cancer or malignant mesothelioma), mesothelioma, pancreatic cancer (e.g., pancreatic duct cancer), gastric cancer (e.g., papillaryadenocarcinoma, mucinous adenocarcinoma or adenosquamous carcinoma), breast cancer (e.g., invasive25 ductal carcinoma, ductal carcinoma in situ or inflammatory breast cancer), ovarian cancer (e.g., ovarianepithelial carcinoma, extragonadal germ cell tumor, ovarian germ cell tumor or ovarian low malignantpotential tumor), prostate cancer (e.g., hormone-dependent- prostate cancer or non-hormone dependentprostate cancer), liver cancer (e.g., primary liver cancer or extrahepatic bile duct cancer), thyroid cancer (e.g., medullary thyroid carcinoma), kidney cancer (e.g., renal cell carcinoma, transitional cell carcinoma30 in kidney or transitional cell carcinoma in urinary duct), uterine cancer, brain tumor (e.g., pinealastrocytoma, pilocytic astrocytoma, diffuse astrocytoma or anaplastic astrocytoma), melanoma, sarcoma, urinary bladder cancer, hematologic cancer and the like including multiple myeloma, hypophyseal adenoma, glioma, acoustic neurinoma, retinoblastoma, pharyngeal cancer, laryngeal cancer, cancer of the tongue, thymoma, esophagus cancer, duodenal cancer, colorectal cancer, rectal cancer, hepatoma, AUG-P3833PCT pancreatic endocrine tumor, bile duct cancer, gallbladder cancer, penile cancer, urinary duct cancer, testis tumor, vulvar cancer, cervix cancer, endometrial cancer, uterus sarcoma, chorionic disease, vaginal cancer, skin cancer, fungoid mycosis, basal cell tumor, soft tissue sarcoma, malignant lymphoma, Hodgkin's disease, myelodysplastic syndrome, adult T cell leukemia, chronic bone marrow proliferative disease, 5pancreatic endocrine, tumor fibrous histiocytoma, leiomyosarcoma, rhabdomyosarcoma, cancer ofunknown primary, leukemia (such as acute leukemia (e.g., acute lymphatic leukemia or acute myelocyticleukemia), chronic leukemia (e.g., chronic lymphatic leukemia or chronic myelocytic leukemia)),myelodysplastic syndrome, uterine sarcoma (e.g., mixed mesodermal tumor, uterine leiomyosarcoma or endometrial stromal tumor), and myelofibrosis. In one particular embodiment, the proliferative disease is10 cancer. In one particular embodiment, the cancer is selected from malignant melanoma, multiple myeloma,leukemia, lymphoma, breast cancer, and Hodgkin's disease.

[0218] According to one embodiment, the HDAC6-associated disease is a neurodegenerative disease. Inone embodiment, the neurodegenerative disease is selected from Alzheimer's disease, dementia ofAlzheimer type, Alzheimer-type senile dementia, Parkinson's disease, muscular dystrophy, Parkinson's 15 disease associated with dementia, senile dementia, age-related cognition memory disorders, Huntington's disease, multi-infarct dementia, frontotemporal lobar degeneration, frontotemporal dementia, Pick's disease, Parkinson's type dementia, Niemann-Pick syndrome, Down's disease, vascular dementia, postencephalitic parkinsonism, Lewy body dementia, Rubinstein-Taybi syndrome, HIV dementia, amyotrophic lateral sclerosis (ALS), motor neurogenesis disease (MND), and Creutzfeldt. Further20 examples of neurodegenerative diseases include Duchenne’s muscular dystrophy (DMD) and spinal muscular atrophy (SMA). In one particular embodiment, the neurodegenerative disease is selected from Alzheimer's disease, Parkinson's disease, Huntington's disease, frontotemporal dementia, Pick's disease, Niemann-Pick syndrome, Down's disease, Lewy body dementia, HIV dementia, amyotrophic lateral sclerosis (ALS), multiple sclerosis, Duchenne’s muscular dystrophy (DMD) and spinal muscular atrophy25 (SMA). In one particular embodiment, the neurodegenerative disease is selected from Alzheimer's disease,Parkinson's disease, Huntington's disease, frontotemporal dementia, Pick's disease, Niemann-Pick syndrome, Down's disease, Lewy body dementia, HIV dementia, amyotrophic lateral sclerosis (ALS), and multiple sclerosis.

[219] According to one embodiment, the HDAC6-associated disease is a pain (including central or30 peripheral pain). In one embodiment, the pain is selected from pain, cancer pain, acute pain caused byinflammation, pain associated with chronic inflammation, postoperative pain (e.g., incision pain, deep pain, visceral pain or chronic pain after operation), muscular pain (e.g., muscular pain associated with chronic pain disease or stiff shoulder), arthralgia, toothache, temporomandibular joint pain, headache (e.g., migraine, catatonic headache, headache associated with fever or headache associated with hypertension), AUG-P3833PCT visceral pain (e.g., cardiac pain, angina pain, abdominal pain, renal pain, urinary tract pain or bladder pain), obstetric and gynecologic pain (e.g., mittelschmerz, dysmenorrhea, or labor pain), neuropathic pain (e.g., hernia of intervertebral disk, nerve root pain, neuralgia after herpes zoster, trigeminal neuralgia or lumbago), migraine, stress headache, catatonic headache, muscular spasm, and irritable bowel syndrome.5

[0220] According to one embodiment, the HDAC6-associated disease is a neuropathy (including centralor peripheral neuropathy), such as. In one embodiment, the neuropathy is selected from demyelinatingdiseases and neuropathy (e.g., multiple sclerosis, Guillain-Barre syndrome, Fisher syndrome, chronicinflammatory demyelinating polyneuropathy (CIDP), multifocal motor neuropathy (MMN), Charcot- Marie-Tooth disease, hereditary sensory and autonomic neuropathy or familial amyloidotic 10 polyneuropathy), peripheral neuropathy (CIPN) derived from anticancer drugs and neurological symptoms associated therewith (e.g., chemotherapy-induced neuropathic pain (CINP)), diabetic neuropathy, autonomic ataxia, and injury-related neuropathy (e.g., traumatic brain injury or cerebral apoplexy).Anticancer drugs susceptible to cause neuropathy include taxanes (e.g., paclitaxel (Taxol)), vinca alkaloids(e.g., vincristine), platinum-based agents (e.g., cisplatin, carboplatin or oxaliplatin), or other molecularly15 targeted drugs (e.g., bortezomib). In one particular embodiment, the neuropathy is selected from Guillain-Barre syndrome, chronic inflammatory demyelinating polyneuropathy (CIDP), multifocal motor neuropathy (MMN), Charcot-Marie-Tooth disease, hereditary sensory and autonomic neuropathy, familial amyloidotic polyneuropathy, chemotherapy-induced peripheral neuropathy (CIPN) using chemotherapeutic anticancer agents, diabetic peripheral neuropathy (DPN), neuralgia, pain, and20 neuropathic pain.

[221] According to one embodiment, the HDAC6-associated disease is a psychiatric disease. In oneembodiment, the psychiatric disease is selected from depression, major depression, bipolar depression,psychotic major depression, refractory major depression, treatment-resistant depression, depression symptom, postpartum depression, bipolar disorder, schizophrenia (e.g., positive symptom, negative25 symptom or cognitive symptom), cognitive dysfunction associated with schizophrenia, stress disorder, mania, anxiety, generalized anxiety disorder, anxiety syndrome, panic disorder, social anxiety disorder, obsessive disorder, post-traumatic stress syndrome, post-traumatic stress disorder, dysthymic disorder, emotional disorder (e.g., seasonal affective disorder), phobia, social phobia, neurosis, chronic fatigue syndrome, epilepsy, cyclothymia, addiction, neurotic anorexia, eating disorder, anorexia nervosa,30 hyperorexia or other eating disorder, pharmacophilia, pharmacophobia, and pharmacomania.

[222] According to one embodiment, the HDAC6-associated disease is a neurodevelopmental disorder.In one embodiment, the neurodevelopmental disorder is selected from Tourette syndrome, autism, autisticspectrum syndrome, fragile X syndrome, Rett syndrome, and attention deficit hyperactivity disorder (ADHD). AUG-P3833PCT

[223] According to one embodiment, the HDAC6-associated disease is a sleep disorder. In oneembodiment, the sleep disorder is selected from intrinsic sleep disorders (e.g., psychophysiologicalinsomnia), extrinsic sleep disorder, circadian rhythm disorders (e.g., time zone change syndrome (jet lag), shift work sleep disorder, irregular sleep-wake pattern, delayed sleep phase syndrome, advanced sleep 5 phase syndrome or non-24-hour sleep-wake), parasomnia, sleep disorders associated with internal medical or psychiatric disorder (e.g., chronic obstructive pulmonary diseases, Alzheimer's disease, Parkinson's disease, cerebrovascular dementia, schizophrenia, depression or anxiety neurosis), stress, insomnia, insomnia, insomniac neurosis, and sleep apnea syndrome.

[0224] According to one embodiment, the HDAC6-associated disease is a cardiovascular disease. In one10 embodiment, the cardiovascular disease is selected from chronic heart failure or acute heart failure, heartfailure with preserved ejection fraction, acute decompensated heart failure, ischemic heart disease, arrythmia, tachycardia, atrial fibrillation, cardiomyopathy, myocarditis, valvular disease, hypertension, cardiac disease, and congestive cardiac failure. In one particular embodiment, the heart-related disease isselected from heart failure, cardiomyopathy, and myocarditis.15

[0225] According to one embodiment, the HDAC6-associated disease is an addiction-related disorder. Inone embodiment, the addiction related disorder is selected from alcohol dependence, alcohol abuse,alcoholic amnesia, alcohol paranoia, alcohol preference, alcohol withdrawal, alcoholic insanity, alcohol poisoning, alcoholic jealousy, alcoholic mania, alcohol-dependent psychiatric disorder, alcoholic insanity, and drug withdrawal.20

[0226] According to one embodiment, the HDAC6-associated disease is a gastrointestinal disease. In oneembodiment, the gastrointestinal disease is selected from peptic ulcer, stress gastrointestinal disorder, stressvomiting, peptic ulcer, diarrhea, constipation ileus, and postoperative ileus.

[0227] According to one embodiment, the HDAC6-associated disease is a pulmonary disease. In oneembodiment, the pulmonary disease is selected from hyperventilation, bronchial asthma, and apnea.25

[0228] According to one embodiment, the HDAC6-associated disease is a metabolic or hormonaldisorder. In one embodiment, the metabolic or hormonal disorder is selected from obesity, diabetes,acromegaly, infertility, and metabolic syndrome.

[0229] According to one embodiment, the HDAC6-associated disease is an immune disorder. In oneembodiment, the immune disorder is selected from allergic disease, immunodeficiency syndrome caused30 by HIV infection, and immunodeficiency syndrome caused by stress. In one embodiment, the immunedisorder is selected from immunodeficiency syndrome caused by HIV infection and immunodeficiencysyndrome caused by stress. AUG-P3833PCT

[230] According to one embodiment, the HDAC6-associated disease is an age-related disease. In oneembodiment, the age-related disease is selected from alopecia, glaucoma, impotence, climacteric disorder,incontinence, and osteoporosis.

[0231] According to one embodiment, the HDAC6-associated disease is a kidney disease. In one5 embodiment, the age-related disease is selected from chronic kidney disease, diabetic nephropathy, andautosomal dominant polycystic kidney disease.

[232] According to one embodiment, the HDAC6 associated disease is an idiopathic disease. In oneembodiment, the idiopathic disease is selected from Meniere's disease and sudden infant death syndrome.

[233] The compound or pharmaceutical composition of the invention may be administered by oral,10 parenteral (e.g., intramuscular, intraperitoneal, intravenous, intracerebroventricular (ICV), intracisternalinjection or infusion, subcutaneous injection, or implant), by inhalation spray, nasal, vaginal, rectal, sublingual, or topical routes of administration. In the treatment and / or prevention of an infectious disease an appropriate dosage level may be from about 0.01 to 500 mg per kg patient body weight per day (mg / kg / day), which can be administered in single or multiple doses. Typically, the dosage level will be15 from about 0.1 to about 250 mg / kg / day, suitably from about 0.5 to about 100 mg / kg / day, more suitablyfrom about 2.5 to about 20 mg / kg / day. The compounds may be administered on a regimen of 1 to 4 timesper day, suitably once or twice per day. It will be understood, however, that the specific dose level andfrequency of dosage for any particular patient may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of 20 that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular diseases and the host undergoing therapy. Kit

[234] This invention also relates to a kit comprising a compound of the invention as described herein,or a pharmaceutical composition of the invention as described herein, and means to administer said25 compound or pharmaceutical composition.

[235] Means for administering a compound or a pharmaceutical composition are well-known in the artand may be identified by a person skilled in the art depending of the desired administration route.

[236] Aspects of the invention may be defined by the following clauses:30 Clause 1. A compound of formula (I)wherein said compound is a compound of formula (I) AUG-P3833PCT 111 or a pharmaceutically acceptable salt and / or solvate thereof; wherein -Y1 is a 9 or 10-membered bicyclic heteroaryl selected from the following formulae5 10 wherein AUG-P3833PCT A1, A2, A3, A4, A5, A6and A7are each independently selected from C-R7and N; A8, A9, A10 and A11 are each independently selected from C-R7 and N, provided that at least one ofA8, A9, A10or A11is N; G1is selected from C-R3and N; 5 G2is selected from O and N-R4; Bis selected from O, S and N-R5, provided that when:i) A5, A6and B are present, and A5and A6are C-R7; or ii) A5, A7and B are present, and A5and A7are C-R7; or iii) A6, A7and B are present, and A6and A7are C-R7,10 then B is not S; andR2 is selected from hydrogen, halogen, cyano, amino, hydroxy, -(C1-C6) alkyl,-(C3-C9) cycloalkyl, -(C2-C9) heterocycloalkyl, aryl, heteroaryl, -(C1-C6) alkylene-(C3-C9) cycloalkyl, -(C1-C6) alkylene-(C2-C9) heterocycloalkyl, -OR15, -(C1-C6) alkylene-OR15, -O-(C2- C6) alkylene-OR15, -NR16-(C2-C 15 17 186) alkylene-OR , -NR R , -(C1-C6) alkylene-NR17R18, -O-(C2-15C 17 186) alkylene-NR R , and -NR16-(C2-C6) alkylene-NR17R18; R3 is selected from hydrogen, halogen, cyano, amino, hydroxy, -(C1-C6) alkyl,-(C3-C9) cycloalkyl, -(C2-C9) heterocycloalkyl, aryl, heteroaryl, -(C1-C6) alkylene-(C3-C9) cycloalkyl, -(C 151-C6) alkylene-(C2-C9) heterocycloalkyl, -OR , -(C1-C6) alkylene-OR15, -O-(C2- C6) alkylene-OR15, -NR16-(C 15 17 182-C6) alkylene-OR , -NR R , -(C1-C6) alkylene-NR17R18, -O-(C2-20C6) alkylene-NR17R18, and -NR16-(C2-C6) alkylene-NR17R18; R4 is selected from hydrogen, -(C1-C6) alkyl, -(C3-C9) cycloalkyl, and -(C2-C9) heterocycloalkyl;R5 is selected from hydrogen, -(C1-C6) alkyl, -(C3-C9) cycloalkyl, and -(C2-C9) heterocycloalkyl;R6 is selected from hydrogen, halogen, cyano, and -(C1-C6) alkyl;R7 is independently selected from hydrogen, halogen, amino, -NH-(C1-C6) alkyl, -N-((C1-C6) alkyl)225 hydroxy, cyano, -(C1-C6) alkyl, -O-(C1-C6) alkyl, -(C3-C9) cycloalkyl, -O-(C3-C9) cycloalkyl, -(C1-C6) alkylene-(C3-C9) cycloalkyl, -(C1-C6) alkylene-(C2-C9) heterocycloalkyl, -(C2-C9) heterocycloalkyl, aryl, and heteroaryl; AUG-P3833PCT wherein each of said -(C1-C6) alkyl or -(C1-C6) alkylene in R2, R3, R4, R5, R6or R7is optionally substituted with at least one group selected from halogen, cyano, hydroxy, oxo, amino, -O-(C1-C6) alkyl, -NH-(C1-C6) alkyl, and -N-((C1-C6) alkyl)2;5each of said -(C3-C9) cycloalkyl, -(C2-C9) heterocycloalkyl, aryl or heteroaryl in R2, R3, R4, R5, R6or R7is optionally substituted with at least one group selected from halogen, cyano, hydroxy, oxo, amino, -(C1-C6) alkyl, -CH2-O-(C1-C6) alkyl, -CH2-NH-(C1-C6) alkyl, -CH2-N-((C1-C6) alkyl)2, -O-(C1-C6) alkyl,-NH-(C1-C6) alkyl, and -N-((C1-C6) alkyl)2;10 R15, R16, R17 and R18 are each independently selected from hydrogen,-(C1-C6) haloalkyl, -(C1-C6) alkyl, -(C3-C9) cycloalkyl, -(C1-C6) alkylene-(C3-C9) cycloalkyl, -(C2-C9) heterocycloalkyl, aryl, heteroaryl, -(C1-C6) alkylene-(C2-C9) heterocycloalkyl, -(C1-C6) alkylene-heteroaryl, and -(C1-C6) alkylene-aryl; and / or two groups selected from R15, R16, R17and R18 form together a cycle selected from -(C3-C9) cycloalkyl, -(C2-C9) heterocycloalkyl, aryl,15 and heteroaryl; wherein each of said -(C1-C6) alkyl or -(C1-C6) alkylene in R15, R16, R17or R18is optionally substituted with at least one group selected from halogen, cyano, hydroxy, oxo, amino, -O-(C1-C6) alkyl,-NH-(C1-C6) alkyl, and -N-((C1-C6) alkyl)2;20each of said -(C3-C9) cycloalkyl, -(C2-C9) heterocycloalkyl, aryl or heteroaryl in R15, R16, R17or R18is optionally substituted with at least one group selected from halogen, cyano, hydroxy, oxo, amino, -(C1-C6) alkyl, -CH2-O-(C1-C6) alkyl, -CH2-NH-(C1-C6) alkyl, -CH2-N-((C1-C6) alkyl)2, -O-(C1-C6) alkyl, -NH-(C1-C6) alkyl, and -N-((C1-C6) alkyl)2;- L1 is -(NH)m-, wherein m is an integer selected from 0 and 1;25 - W is N or C-R12;- X is N or C-R13;wherein R12and R13are each independently selected from hydrogen, halogen, and -(C1- C3) alkyl;- L2 is -(CR10R11)n;30 wherein nis an integer selected from 0, 1, 2 and 3; AUG-P3833PCT R10 is selected from hydrogen, halogen, hydroxy, amino, -(C1-C3) alkyl, -(C1-C2) haloalkyl, -(C1-C2) hydroxyalkyl, -(C1-C2) aminoalkyl, -O-(C1-C4) alkyl, -NH-(C1-C3) alkyl, and -N-((C1-C3) alkyl)2, -(C3-C9) cycloalkyl, -(C2-C9) heterocycloalkyl, aryl, and heteroaryl;wherein each of the -(C3-C9) cycloalkyl, -(C2-C9) heterocycloalkyl, aryl, heteroaryl is5 optionally substituted with at least one group selected from halogen, cyano, hydroxy, amino, -(C1-C6) alkyl, -(C1-C6) haloalkyl and -O-(C1-C6) alkyl; R11 is selected from hydrogen, halogen, hydroxy, amino, -(C1-C3) alkyl, -(C1-C2) haloalkyl, -(C1-C2) hydroxyalkyl, -(C1-C2) aminoalkyl, -O-(C1-C4) alkyl, -NH-(C1-C3) alkyl, -N-((C1-C3) alkyl)2;or R10 and R11 when bound to the same carbon atom together with the carbon atom to which they10 are bound form a (C3-C9) cycloalkyl or (C2-C9) heterocycloalkyl;or when n is 2 or 3, any two groups selected from R10 and R11 when bound to different carbonatoms together with the carbon atom to which they are bound and any intervening atom presentform a (C3-C9) cycloalkyl or (C2-C9) heterocycloalkyl;- Z1 is selected from hydrogen, -(C1-C6) alkyl, -(C3-C9) cycloalkyl,15 -(C2-C9) heterocycloalkyl, aryl, heteroaryl, -(C1-C6) alkylene-(C3-C9) cycloalkyl,-(C1-C6) alkylene-(C2-C9) heterocycloalkyl, -(C1-C6) alkylene-aryl and -(C1-C6) alkylene-heteroaryl;wherein each of the -(C1-C6) alkyl, -(C3-C9) cycloalkyl, -(C2-C9) heterocycloalkyl, aryl orheteroaryl in Z1is optionally substituted with at least one group selected from halogen, - NR23R24, methyl, hydroxy, -(C1-C2) haloalkyl, and -(C1-C2) hydroxyalkyl; wherein R23and 20 R24are each independently selected from hydrogen and methyl; -R1 is selected from hydrogen, -(C1-C6) alkyl, -(C3-C9) cycloalkyl,-(C1-C6) alkylene-(C3-C9) cycloalkyl, and -(C2-C9) heterocycloalkyl;wherein the -(C1-C6) alkyl or -(C1-C6) alkylene in R1is optionally substituted with at least one group selected from halogen, cyano, hydroxy, amino,25 -(C1-C6) alkyl, -CH2-O-(C1-C6) alkyl, and -O-(C1-C6) alkyl;wherein the -(C3-C9) cycloalkyl or -(C2-C9) heterocycloalkyl in R1is optionally substituted with at least one group selected from halogen, cyano, hydroxy, amino, -(C1-C6) alkyl, -CH2-O-(C1-C6) alkyl, and -O-(C1-C6) alkyl;or R1 and one of R10 or R11 form together a -(C2-C9) heterocycloalkyl comprising at least one nitrogen30 atom; AUG-P3833PCT wherein said -(C2-C9) heterocycloalkyl in R1and R10or R11is optionally substituted with at least one group selected from halogen, cyano, hydroxy, amino, -(C1-C6) alkyl, -CH2-O-(C1-C6) alkyl, and -O-(C1-C6) alkyl; andor R1and Z1form together with the nitrogen atom to which they are bound a - 5(C2-C9) heterocycloalkyl;wherein said -(C2-C9) heterocycloalkyl in R1and Z1is optionally substituted with at least one group selected from halogen, cyano, hydroxy, amino, -(C1-C6) alkyl, -CH2-O-(C1-C6) alkyl, -O-(C1-C6) alkyl, -(C1-C2) haloalkyl, and -(C1-C2) hydroxyalkyl;10 provided that the compound is not 1-morpholino-2-(5-(2-(thieno[2,3-d]pyrimidin-4-ylthio)acetyl)thiophen-2-yl)ethan-1-one or a pharmaceutically acceptable salt and / or solvate thereof. Clause 2. The compound or a pharmaceutically acceptable salt and / or solvate thereof of formula (I)according to clause 1, wherein said compound is a compound of formula (I) 15 or a pharmaceutically acceptable salt and / or solvate thereof; wherein -Y1 is a 9 or 10-membered bicyclic heteroaryl selected from the following formulae AUG-P3833PCT 5 wherein A1, A2, A3, A4, A5, A6and A7are each independently selected from C-R7and N; A8, A9, A10 and A11 are each independently selected from C-R7 and N, provided that at least one ofA8, A9, A10or A11is N; G1is selected from C-R3and N; 10 G2is selected from O and N-R4; Bis selected from O, S and N-R5, provided that when:i) A5, A6and B are present, and A5and A6are C-R7; or ii) A5, A7and B are present, and A5and A7are C-R7; or iii) A6, A7and B are present, and A6and A7are C-R7,15 then B is not S; and AUG-P3833PCT R2 is selected from hydrogen, halogen, cyano, amino, hydroxy, -(C1-C6) alkyl,-(C3-C9) cycloalkyl, -(C2-C9) heterocycloalkyl, aryl, heteroaryl, -(C1-C6) alkylene-(C3-C9) cycloalkyl, -(C1-C6) alkylene-(C2-C9) heterocycloalkyl, -OR15, -(C1-C6) alkylene-OR15, -O-(C2- C6) alkylene-OR15, -NR16-(C 15 17 182-C6) alkylene-OR , -NR R , -(C1-C6) alkylene-NR17R18, -O-(C2- 5C 17 18 166) alkylene-NR R , and -NR -(C2-C6) alkylene-NR17R18; R3 is selected from hydrogen, halogen, cyano, amino, hydroxy, -(C1-C6) alkyl,-(C3-C9) cycloalkyl, -(C2-C9) heterocycloalkyl, aryl, heteroaryl, -(C1-C6) alkylene-(C3-C9) cycloalkyl, -(C 151-C6) alkylene-(C2-C9) heterocycloalkyl, -OR , -(C1-C6) alkylene-OR15, -O-(C2- C6) alkylene-OR15, -NR16-(C2-C6) alkylene-OR15, -NR17R18, -(C1-C6) alkylene-NR17R18, -O-(C2-10C6) alkylene-NR17R18, and -NR16-(C2-C6) alkylene-NR17R18; R4 is selected from hydrogen, -(C1-C6) alkyl, -(C3-C9) cycloalkyl, and -(C2-C9) heterocycloalkyl;R5 is selected from hydrogen, -(C1-C6) alkyl, -(C3-C9) cycloalkyl, and -(C2-C9) heterocycloalkyl;R6 is selected from hydrogen, halogen, cyano, and -(C1-C6) alkyl;R7 is independently selected from hydrogen, halogen, amino, -NH-(C1-C6) alkyl, -N-((C1-C6) alkyl)215 hydroxy, cyano, -(C1-C6) alkyl, -O-(C1-C6) alkyl, -(C3-C9) cycloalkyl, -(C1-C6) alkylene-(C3-C9) cycloalkyl, -(C1-C6) alkylene-(C2-C9) heterocycloalkyl, -(C2-C9) heterocycloalkyl, aryl, andheteroaryl; wherein each of said -(C1-C6) alkyl or -(C1-C6) alkylene in R2, R3, R4, R5, R6or R7is optionally substituted20 with at least one group selected from halogen, cyano, hydroxy, oxo, amino, -O-(C1-C6) alkyl, -NH-(C1-C6) alkyl, and -N-((C1-C6) alkyl)2;each of said -(C3-C9) cycloalkyl, -(C2-C9) heterocycloalkyl, aryl or heteroaryl in R2, R3, R4, R5, R6or R7is optionally substituted with at least one group selected from halogen, cyano, hydroxy, oxo, amino, -(C1-C6) alkyl, -CH2-O-(C1-C6) alkyl, -CH2-NH-(C1-C6) alkyl, -CH2-N-((C1-25 C6) alkyl)2, -O-(C1-C6) alkyl,-NH-(C1-C6) alkyl, and -N-((C1-C6) alkyl)2;R15, R16, R17 and R18 are each independently selected from hydrogen,-(C1-C6) haloalkyl, -(C1-C6) alkyl, -(C3-C9) cycloalkyl, -(C1-C6) alkylene-(C3-C9) cycloalkyl, -(C2-C9) heterocycloalkyl, aryl, heteroaryl, -(C1-C6) alkylene-(C2-C9) heterocycloalkyl, -(C1-30C6) alkylene-heteroaryl, and -(C1-C6) alkylene-aryl; and / or two groups selected from R15, R16, R17and R18 form together a cycle selected from -(C3-C9) cycloalkyl, -(C2-C9) heterocycloalkyl, aryl,and heteroaryl; AUG-P3833PCT wherein each of said -(C1-C6) alkyl or -(C1-C6) alkylene in R15, R16, R17or R18is optionally substituted with at least one group selected from halogen, cyano, hydroxy, oxo, amino, -O-(C1-C6) alkyl,-NH-(C1-C6) alkyl, and -N-((C1-C6) alkyl)2;5each of said -(C3-C9) cycloalkyl, -(C2-C9) heterocycloalkyl, aryl or heteroaryl in R15, R16, R17or R18is optionally substituted with at least one group selected from halogen, cyano, hydroxy, oxo, amino, -(C1-C6) alkyl, -CH2-O-(C1-C6) alkyl, -CH2-NH-(C1-C6) alkyl, -CH2-N-((C1-C6) alkyl)2, -O-(C1-C6) alkyl, -NH-(C1-C6) alkyl, and -N-((C1-C6) alkyl)2;- L1 is -(NH)m-, wherein m is an integer selected from 0 and 1;10 - W is N or C-R12;- X is N or C-R13;wherein R12and R13are each independently selected from hydrogen, halogen, and -(C1- C3) alkyl;- L2 is -(CR10R11)n;15 wherein nis an integer selected from 0, 1, 2 and 3;R10 is selected from hydrogen, halogen, hydroxy, amino, -(C1-C3) alkyl, -(C1-C2) haloalkyl, -(C1-C2) hydroxyalkyl, -(C1-C2) aminoalkyl, -O-(C1-C4) alkyl, -NH-(C1-C3) alkyl, and -N-((C1-C3) alkyl)2, -(C3-C9) cycloalkyl, -(C2-C9) heterocycloalkyl, aryl, and heteroaryl;20 wherein each of the -(C3-C9) cycloalkyl, -(C2-C9) heterocycloalkyl, aryl, heteroaryl isoptionally substituted with at least one group selected from halogen, cyano, hydroxy, amino, -(C1-C6) alkyl, -(C1-C6) haloalkyl and -O-(C1-C6) alkyl; R11 is selected from hydrogen, halogen, hydroxy, amino, -(C1-C3) alkyl, -(C1-C2) haloalkyl, -(C1-C2) hydroxyalkyl, -(C1-C2) aminoalkyl, -O-(C1-C4) alkyl, -NH-(C1-C3) alkyl, -N-((C1-C3) alkyl)2;25 or R10 and R11 form together with the carbon atom to which they are bound a (C3-C9) cycloalkyl or(C2-C9) heterocycloalkyl; AUG-P3833PCT -Z1 is selected from hydrogen, -(C1-C6) alkyl, -(C3-C9) cycloalkyl,-(C2-C9) heterocycloalkyl, aryl, heteroaryl, -(C1-C6) alkylene-(C3-C9) cycloalkyl,-(C1-C6) alkylene-(C2-C9) heterocycloalkyl, -(C1-C6) alkylene-aryl and -(C1-C6) alkylene-heteroaryl;wherein each of the -(C1-C6) alkyl, -(C3-C9) cycloalkyl, -(C2-C9) heterocycloalkyl, aryl or5 heteroaryl in Z1is optionally substituted with at least one group selected from halogen, - NR23R24, methyl, hydroxy, -(C1-C2) haloalkyl, and -(C1-C2) hydroxyalkyl; wherein R23and R24are each independently selected from hydrogen and methyl; -R1 is selected from hydrogen, -(C1-C6) alkyl, -(C3-C9) cycloalkyl,-(C1-C6) alkylene-(C3-C9) cycloalkyl, and -(C2-C9) heterocycloalkyl;10wherein the -(C1-C6) alkyl or -(C1-C6) alkylene in R1is optionally substituted with at least one group selected from halogen, cyano, hydroxy, amino, -(C1-C6) alkyl, -CH2-O-(C1-C6) alkyl, and -O-(C1-C6) alkyl;wherein the -(C3-C9) cycloalkyl or -(C2-C9) heterocycloalkyl in R1is optionally substituted with at least one group selected from halogen, cyano, hydroxy, amino, -(C1-C6) alkyl, -CH2-15 O-(C1-C6) alkyl, and -O-(C1-C6) alkyl;or R1 and one of R10 or R11 form together a -(C2-C9) heterocycloalkyl comprising at least one nitrogenatom; wherein said -(C2-C9) heterocycloalkyl in R1and R10or R11is optionally substituted with at least one group selected from halogen, cyano, hydroxy, amino, -(C1-C6) alkyl, -CH2-O-(C1-20 C6) alkyl, and -O-(C1-C6) alkyl; andor R1and Z1form together with the nitrogen atom to which they are bound a - (C2-C9) heterocycloalkyl;wherein said -(C2-C9) heterocycloalkyl in R1and Z1is optionally substituted with at least one group selected from halogen, cyano, hydroxy, amino,25 -(C1-C6) alkyl, -CH2-O-(C1-C6) alkyl, -O-(C1-C6) alkyl, -(C1-C2) haloalkyl, and -(C1-C2) hydroxyalkyl;provided that the compound is not 1-morpholino-2-(5-(2-(thieno[2,3-d]pyrimidin-4-ylthio)acetyl)thiophen-2-yl)ethan-1-one or a pharmaceutically acceptable salt and / or solvate thereof. AUG-P3833PCT Clause 3. The compound or a pharmaceutically acceptable salt and / or solvate thereof of formula (I) according to clause 1 or 2,wherein said compound is a compound of formula (I) 5 or a pharmaceutically acceptable salt and / or solvate thereof; wherein -Y1 is a 9 or 10-membered bicyclic heteroaryl selected from the following formulae10 AUG-P3833PCT wherein A1, A2, A3, A4, A5, A6and A7are each independently selected from C-R7and N; A8, A9, A10 and A11 are each independently selected from C-R7 and N, provided that at least one of5 A8, A9, A10or A11is N; G1is selected from C-R3and N; G2is selected from O and N-R4; Bis selected from O, S and N-R5, provided that when A5, A6 and A7 are C-R7, then B is not S; andR2 is selected from hydrogen, halogen, cyano, amino, hydroxy, -(C1-C6) alkyl,10 -(C3-C7) cycloalkyl, -(C3-C7) heterocycloalkyl, aryl, heteroaryl, -(C1-C6) alkylene-(C3-C7) cycloalkyl, -(C1-C6) alkylene-(C3-C7) heterocycloalkyl, -OR15, -(C1-C6) alkylene-OR15, -O-(C2-C6) alkylene-OR15, -NR16-(C2-C6) alkylene-OR15, -NR17R18, -(C -C ) alkylene-NR17R18, -O-(C -C ) alkylene-NR17R18, and -NR161 6 2 6 -(C2-C6) alkylene-NR17R18;15 R3 is selected from hydrogen, halogen, cyano, amino, hydroxy, -(C1-C6) alkyl,-(C3-C7) cycloalkyl, -(C3-C7) heterocycloalkyl, aryl, heteroaryl, -(C1-C6) alkylene-(C3-C7) cycloalkyl, -(C1-C6) alkylene-(C3-C7) heterocycloalkyl, -OR15, -(C1-C6) alkylene-OR15, -O-(C2-C6) alkylene-OR15, -NR16-(C2-C6) alkylene-OR15, -NR17R18, -(C -C ) alkylene-NR17R18, -O-(C -C ) alkylene-NR17R18, and 161 6 2 6 -NR -(C2-C6) alkylene-20NR17R18; R4 is selected from hydrogen, -(C1-C6) alkyl, -(C3-C7) cycloalkyl, and-(C3-C7) heterocycloalkyl;R5 is selected from hydrogen, -(C1-C6) alkyl, -(C3-C7) cycloalkyl, and-(C3-C7) heterocycloalkyl;25 R6 is selected from hydrogen, halogen, cyano, and -(C1-C6) alkyl;R7 is selected from hydrogen, halogen, amino, hydroxy, cyano, -(C1-C6) alkyl,-(C3-C7) cycloalkyl, -(C1-C6) alkylene-(C3-C7) cycloalkyl, -(C1-C6) alkylene-(C3-C7) heterocycloalkyl, -(C3-C7) heterocycloalkyl, aryl, and heteroaryl; AUG-P3833PCT wherein each of said -(C1-C6) alkyl or -(C1-C6) alkylene in R2, R3, R4, R5, R6or R7is optionally substituted with at least one group selected from halogen, cyano, hydroxy, oxo, amino, -O-(C1-C6) alkyl, -NH-(C1-C6) alkyl, and5 -N-((C1-C6) alkyl)2;each of said -(C3-C7) cycloalkyl, -(C3-C7) heterocycloalkyl, aryl or heteroaryl in R2, R3, R4, R5, R6or R7is optionally substituted with at least one group selected from halogen, cyano, hydroxy, oxo, amino, -(C1-C6) alkyl, -CH2-O-(C1-C6) alkyl, -CH2-NH-(C1-C6) alkyl, -CH2-N-((C1-C6) alkyl)2, -O-(C1-C6) alkyl,10 -NH-(C1-C6) alkyl, and -N-((C1-C6) alkyl)2;R15, R16, R17 and R18 are each independently selected from hydrogen,-(C1-C6) haloalkyl, -(C1-C6) alkyl, -(C3-C7) cycloalkyl, -(C1-C6) alkylene-(C3-C7) cycloalkyl, -(C3-C7) heterocycloalkyl, aryl, heteroaryl,-(C1-C6) alkylene-(C3-C7) heterocycloalkyl, -(C1-C6) alkylene-heteroaryl, and15-(C1-C6) alkylene-aryl; and / or two groups selected from R15, R16, R17and R18form together a cycle selected from -(C3-C7) cycloalkyl,-(C3-C7) heterocycloalkyl, aryl, and heteroaryl;wherein each of said -(C1-C6) alkyl or -(C1-C6) alkylene in R15, R16, R17or R18is optionally substituted20 with at least one group selected from halogen, cyano, hydroxy, oxo, amino, -O-(C1-C6) alkyl,-NH-(C1-C6) alkyl, and-N-((C1-C6) alkyl)2;each of said -(C3-C7) cycloalkyl, -(C3-C7) heterocycloalkyl, aryl or heteroaryl in R15, R16, R17or R18is optionally substituted with at least one group selected from halogen, cyano, hydroxy,25 oxo, amino, -(C1-C6) alkyl, -CH2-O-(C1-C6) alkyl, -CH2-NH-(C1-C6) alkyl, -CH2-N-((C1-C6) alkyl)2,-O-(C1-C6) alkyl, -NH-(C1-C6) alkyl, and -N-((C1-C6) alkyl)2;- L1 is -(NH)m-, wherein m is an integer selected from 0 and 1;- W is N or C-R12;30 - X is N or C-R13;wherein R12and R13are each independently selected from hydrogen and halogen; AUG-P3833PCT -L2 is -(CR10R11)n;wherein nis an integer selected from 0, 1, 2 and 3;R10 and R11 are independently selected from hydrogen, halogen, hydroxy, amino, -(C1-C3) alkyl,5 -(C1-C2) haloalkyl, -(C1-C2) hydroxyalkyl,-(C1-C2) aminoalkyl, -O-(C1-C4) alkyl, -NH-(C1-C3) alkyl, and-N-((C1-C3) alkyl)2;or R10 and R11 form together with the carbon atom to which they are bound a (C3-C6) cycloalkylor (C4-C9) heterocycloalkyl;10 - Z1 is selected from hydrogen, -(C1-C6) alkyl, -(C3-C6) cycloalkyl,-(C3-C9) heterocycloalkyl, aryl, heteroaryl, -(C1-C6) alkylene-(C3-C9) cycloalkyl,-(C1-C6) alkylene-(C3-C9) heterocycloalkyl, and -(C1-C6) alkylene-heteroaryl;wherein each of the -(C1-C6) alkyl, -(C3-C7) cycloalkyl,-(C3-C7) heterocycloalkyl, aryl or heteroaryl in Z1is optionally substituted with at least one group15 selected from halogen, -NR23R24, methyl, and hydroxy; wherein R23 and R24 are eachindependently selected from hydrogen and methyl; -R1 is selected from hydrogen, -(C1-C6) alkyl, -(C3-C7) cycloalkyl,-(C1-C6) alkylene-(C3-C7) cycloalkyl, and (C3-C7) heterocycloalkyl;wherein the -(C1-C6) alkyl or -(C1-C6) alkylene in R1is optionally substituted with at least one 20 group selected from halogen, cyano, hydroxy, amino, -(C1-C6) alkyl, -CH2-O-(C1-C6) alkyl, and -O-(C1-C6) alkyl;wherein the -(C3-C7) cycloalkyl or (C3-C7) heterocycloalkyl in R1is optionally substituted with at least one group selected from halogen, cyano, hydroxy, amino, -(C1-C6) alkyl, -CH2-O-(C1-C6) alkyl, and -O-(C1-C6) alkyl;25 or R1 and one of R10 or R11 form together a (C3-C7) heterocycloalkyl comprising at least one nitrogenatom; wherein said (C3-C7) heterocycloalkyl in R1and R10or R11is optionally substituted with at least one group selected from halogen, cyano, hydroxy, amino, -(C1-C6) alkyl, -CH2-O-(C1-C6) alkyl, and -O-(C1-C6) alkyl; and AUG-P3833PCT or R1and Z1form together with the nitrogen atom to which they are bound a (C3-C9) heterocycloalkyl;wherein said (C3-C7) heterocycloalkyl in R1and Z1is optionally substituted with at least one group selected from halogen, cyano, hydroxy, amino, 5-(C1-C6) alkyl, -CH2-O-(C1-C6) alkyl, and -O-(C1-C6) alkyl;provided that the compound is not selected from 1-morpholino-2-(5-(2-(thieno[2,3-d]pyrimidin-4-ylthio)acetyl)thiophen-2-yl)ethan-1-one; or a pharmaceutically acceptable salt and / or solvate thereof. Clause 4. The compound or a pharmaceutically acceptable salt and / or solvate thereof according to10 clause 1 or 2, wherein Y1 is a 9- or 10-membered bicyclic heteroaryl selected from:the following formulae wherein A1-A7, B, G1, R2 and R6 are independently as defined in clause 1 or 2.15 Clause 5. The compound or a pharmaceutically acceptable salt and / or solvate thereof according to any one of clauses 1 to 3, wherein Y1 is a 9- or 10-membered bicyclic heteroaryl selected from:the following formulae AUG-P3833PCT wherein A1-A4, B, A6, A7, G1, R2 and R6 are independently as defined in any one of clauses 1 to3. Clause 6. The compound or a pharmaceutically acceptable salt and / or solvate thereof according to clause 5, wherein Y1 is a 10-membered bicyclic heteroaryl of the following formula5 wherein A1-A4, G1, and R2 are independently as defined in clause 5.Clause 7. The compound or a pharmaceutically acceptable salt and / or solvate thereof according toany one of clauses 1 to 3, wherein Y1 is selected from(i) a 10-membered bicyclic [6,6] heteroaryl selected from the following formulae 10 wherein R2, R3, R6 and R7 are independently as defined in any one of clauses 1 to 3; AUG-P3833PCT (ii) a 9-membered bicyclic [6,5] heteroaryl selected fromthe following formulae 5 AUG-P3833PCT 5 AUG-P3833PCT and the following formulae 5 wherein R2, R3, R5, R6 and R7 are independently as defined in any one of clauses 1 to 3; or(iii) a 9-membered bicyclic [5,6] heteroaryl selected from: the following formulae AUG-P3833PCT and the following formulae wherein A13 34, A , A , A, R2, R4 and R7 are independently as defined in any one of clauses 1 to 3.5 Clause 8. The compound or a pharmaceutically acceptable salt and / or solvate thereof according toclause 7, wherein Y1 is selected from:(i) a 10-membered bicyclic [6,6] heteroaryl selected from the following formulae (ii) a 9-membered bicyclic [6,5] heteroaryl selected from the following formulae 10 wherein R2, R3, R5, R6 and R7 are independently as defined in clause 7.Clause 9. The compound or a pharmaceutically acceptable salt and / or solvate thereof according toclause 8, wherein Y1 is selected from: AUG-P3833PCT wherein R2 and R7 are independently as defined in clause 8.Clause 10. The compound or a pharmaceutically acceptable salt and / or solvate thereof according toclause 9, wherein Y1 is selected from:5 wherein R2 and R7 are independently as defined in clause 9.Clause 11. The compound or a pharmaceutically acceptable salt and / or solvate thereof according toany one of clauses 1 to 10, wherein R2 is selected from the group consisting of hydrogen, -(C1-C ) alkyl, -(C -C ) c 17 18 156 3 9 ycloalkyl, -NR R and -OR , wherein -(C1-C6) alkyl is optionally substituted10 with at least one halogen. Clause 12. The compound or a pharmaceutically acceptable salt and / or solvate thereof according to clause 11, wherein each of R15, R17 and R18 are -(C1-C6) alkyl, preferably methyl.Clause 13. The compound or a pharmaceutically acceptable salt and / or solvate thereof according toclause 11, wherein R2 is hydrogen or -(C1-C6) alkyl, preferably methyl.15 Clause 14. The compound or a pharmaceutically acceptable salt and / or solvate thereof according toany one of clauses 1 to 13, wherein R3 is selected from the group consisting of hydrogen, cyano and-(C1-C6) alkyl, preferably hydrogen.Clause 15. The compound or a pharmaceutically acceptable salt and / or solvate thereof according toany one of clauses 1 to 14, wherein R4 is hydrogen or -(C1-C6) alkyl, preferably hydrogen.20 Clause 16. The compound or a pharmaceutically acceptable salt and / or solvate thereof according toany one of clauses 1 to 15, wherein R5 is hydrogen or -(C1-C6) alkyl, preferably hydrogen. AUG-P3833PCT Clause 17. The compound or a pharmaceutically acceptable salt and / or solvate thereof according toany one of clauses 1 to 16, wherein R6 is hydrogen or -(C1-C6) alkyl, preferably hydrogen.Clause 18. The compound or a pharmaceutically acceptable salt and / or solvate thereof according toany one of clauses 1 to 17, wherein R7 is independently selected from the group consisting of5 hydrogen, halogen, -N-((C1-C6) alkyl)2, cyano, -(C1-C6) alkyl, -O-(C1-C6) alkyl, and -(C2-C9) heterocycloalkyl, wherein each -(C1-C6) alkyl and -O-(C1-C6) alkyl are optionally substitutedwith at least one halogen group and each -(C2-C9) heterocycloalkyl is optionally substituted with atleast one oxo. Clause 19. The compound or a pharmaceutically acceptable salt and / or solvate thereof according to10 clause 18, wherein R7 is independently selected from the group consisting of hydrogen, halogen, -(C1-C6) alkyl and -O-(C1-C6) alkyl, wherein each -(C1-C6) alkyl and -O-(C1-C6) alkyl are optionallysubstituted with at least one halogen group. Clause 20. The compound or a pharmaceutically acceptable salt and / or solvate thereof according toclause 19, wherein R7 is independently selected from hydrogen, halogen and -O-(C1-C6) alkyl,15 preferably methoxy. Clause 21. The compound or a pharmaceutically acceptable salt and / or solvate thereof according toany one of clauses 1 to 20, wherein X is C-R12 and / or W is C-R13, preferably X is C-R12 and W is C-R13. Clause 22. The compound or a pharmaceutically acceptable salt and / or solvate thereof according to20 clause 21, wherein R12 and / or R13 is hydrogen.Clause 23. The compound or a pharmaceutically acceptable salt and / or solvate thereof according toany one of clauses 1 to 22, wherein m is 0.Clause 24. The compound or a pharmaceutically acceptable salt and / or solvate thereof according toany one of clauses 1 to 23, wherein n is 0.25 Clause 25. The compound or a pharmaceutically acceptable salt and / or solvate thereof according toany one of clauses 1 to 23, wherein n is selected from 1 and 2, preferably 1.Clause 26. The compound or a pharmaceutically acceptable salt and / or solvate thereof according toany one of clauses 1 to 23 or clause 25, wherein R10 and R11 are independently selected fromhydrogen, hydroxy, and -(C1-C3) alkyl.30 Clause 27. The compound according to any one of clauses 1 to 23 or clause 25, wherein L2 is selectedfrom -CH2-, -CH(CH3)-, cycloprop-1,1-yl, and-C(CH3)(OH)-. AUG-P3833PCT Clause 28. The compound according to clause 27, wherein L2 is -C(CH3)(OH)-.Clause 29. The compound according to any one of clauses 1 to 28, wherein R1 is selected fromhydrogen, -(C1-C3) alkyl, and aryl.Clause 30. The compound according to clause 29, wherein R1 is hydrogen.5 Clause 31. The compound according to any one of clauses 1 to 30, wherein Z1 is selected fromhydrogen, -(C1-C6) alkyl, -(C3-C9) cycloalkyl, -(C2-C9) heterocycloalkyl, aryl, heteroaryl, -(C1-C6) alkylene-(C3-C9) cycloalkyl, -(C1-C6) alkylene-(C2-C9) heterocycloalkyl, -(C1-C6) alkylene-aryland -(C1-C6) alkylene-heteroaryl.Clause 32. The compound according to clause 31, wherein Z1 is -(C3-C9) cycloalkyl or -(C2-10 C9) heterocycloalkyl, preferably cyclopropyl or octahydropyrido[2,1-c][1,4]oxazin-8-yl.Clause 33. The compound according to any one of clauses 1 to 30, wherein Z1 is selected fromhydrogen, methyl, 2-propyl, ethyl, cyclopropyl, tert-butyl, 1-methylcyclopropyl, oxetan-3-yl, tetrahydro-2H-pyan-4-yl, 2-hydroxypropyl, 1-methylazetidin-3-yl, (1R,3R)-3-hydroxycyclobutyl, (1S,3S)-3-hydroxycyclobutyl, 1-methylpyrrolidin-3-yl, piperidin-3-yl, piperidin-4-yl, 1-15 cyclopropylpiperidin-4-yl, quinuclidin-3-yl, 1-methylpiperidin-3-yl, 1-ethylpiperidin-4-yl, 3,3- difluorocyclobutyl, (1S,3S)-3-fluorocyclobutyl, pyridin-3-ylmethyl, pyridin-2-ylmethyl, 1- fluorocyclopropyl)methyl, oxetan-3-ylmethyl, 1-methyl-1H-pyrazol-5-yl, 1-ethylpiperidin-4-yl, 1- methylpiperidin-3-yl, 1-methylpiperidin-4-ylmethyl, pyridine-4-ylmethyl, 1-methylcyclopropyl, 8- oxabicyclo[3.2.1]octan-3-yl, octahydropyrido[2,1-c][1,4]oxazin-8-yl, 8-azabicyclo[3.2.1]octan-3- 20 yl, 9-methyl-9-azabicyclo[3.3.1]nonan-3-yl, 8-methyl-8-azabicyclo[3.2.1]octan-3-yl, 3-hydroxy-1-methylpiperidin-4-yl, 3-methyl-3-azabicyclo[3.1.0]hexan-6-yl, 3-methyl-3-azabicyclo[3.1.1]heptan-6-yl, 9-methyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl, 4-(hydroxymethyl)-1-methylpiperidin-4-yl, 2-methyl-2-azabicyclo[2.2.1]heptan-5-yl,1, 3-dimethylpiperidin-4-yl, 1,4-dimethylpiperidin-4-yl, 3-methoxy-1-methylpiperidin-4-yl, 7-methyl-3-oxa-7-25 azabicyclo[3.3.1]nonan-9-yl, 3-fluoro-1-methylpiperidin-4-yl, 1-methylazepan-4-yl, 2-methyl-5- oxa-2-azaspiro[3.4]octan-7-yl, 3-oxabicyclo[3.1.0]hexan-6-yl, 3-methoxycyclobutyl, tetrahydrofuran-3-yl, and hexahydro-1H-pyrrolo[2,1-c][1,4]oxazin-7-yl. Clause 34. The compound according to any one of clauses 1 to 28, wherein R1 and one of R10 or R11form together a -(C3-C7) heterocycloalkyl comprising exactly one nitrogen atom.30 Clause 35. The compound according to clause 34, wherein the ring formed by R1and one of R10or R11together is selected from pyrrolidinyl, piperidinyl, and morpholinyl, preferably pyrrolidinyl. AUG-P3833PCT Clause 36. The compound or a pharmaceutically acceptable salt and / or solvate thereof of formula (I) according to any one of clauses 1 to 24 and 29 to 33,wherein said compound is a compound of formula (I-c) 5 or a pharmaceutically acceptable salt and / or solvate thereof; wherein Y1, X, W, Z1, and R1 are as defined in any one of clauses 1 to 24 and 29 to 33.Clause 37. The compound or a pharmaceutically acceptable salt and / or solvate thereof of formula (I) according to any one of clauses 1 to 22, 24 and 29 to 33,wherein said compound is a compound of formula (I-d) 10 or a pharmaceutically acceptable salt and / or solvate thereof; wherein Y1, X, Z1, and R1 are as defined in any one of clauses 1 to 22, 24 and 29 to 33.Clause 38. The compound or a pharmaceutically acceptable salt and / or solvate thereof of formula (I) according to any one of clauses 1 to 23 and 25 to 33,15 wherein said compound is a compound of formula (I-e) or a pharmaceutically acceptable salt and / or solvate thereof; AUG-P3833PCT wherein Y1, L2, Z1, and R1 are as defined in any one of clauses 1 to 23 and 25 to 33.Clause 39. The compound or a pharmaceutically acceptable salt and / or solvate thereof according to clause 38, wherein said compound is a compound of formula (I-f) 5 or a pharmaceutically acceptable salt and / or solvate thereof; wherein L2, Z1, and R1 are as defined in clauses 38 and R2, G1 and A1-A4 are as defined in any oneof clauses 1 to 6.Clause 40. The compound or a pharmaceutically acceptable salt and / or solvate thereof according to10 clauses 39,wherein said compound is a compound of formula (I-g) or a pharmaceutically acceptable salt and / or solvate thereof; wherein R2, A1-A4, L2, Z1, and R1 are as defined in clause 39. AUG-P3833PCT Clause 41. The compound or a pharmaceutically acceptable salt and / or solvate thereof according to clause 40,wherein said compound is a compound of formula (I-h) 5 or a pharmaceutically acceptable salt and / or solvate thereof; wherein R2, A1-A4, Z1, and R1 are as defined in clause 40, and R10 and R11 are as defined in any oneof clauses 1 to 3 and 26 to 29.Clause 42. The compound or a pharmaceutically acceptable salt and / or solvate thereof according to clause 41,10 wherein said compound is a compound of formula (I-ha) or a pharmaceutically acceptable salt and / or solvate thereof; wherein R2, A1-A4, R10, R11, Z1, and R1 are as defined in clause 41.Clause 43. The compound or a pharmaceutically acceptable salt and / or solvate thereof according to15 clause 41,wherein said compound is a compound of formula (I-hb) AUG-P3833PCT or a pharmaceutically acceptable salt and / or solvate thereof; wherein R2, A1-A4, R10, R11, Z1, and R1 are as defined in clause 41.Clause 44. The compound or a pharmaceutically acceptable salt and / or solvate thereof according to 5clause 42 or clause 43, wherein R10 is methyl and R11 is hydroxy.Clause 45. The compound or a pharmaceutically acceptable salt and / or solvate thereof according to clause 36,wherein said compound is a compound of formula (I-j) 10 or a pharmaceutically acceptable salt and / or solvate thereof; wherein Z1 and R1 are as defined in clause 36, and R2 and A1-A4 are as defined in any one of clauses1 to 6.Clause 46. The compound or a pharmaceutically acceptable salt and / or solvate thereof of formula (I) according to any one of clauses 1 to 23, 25 to 26 and 29 to 33,15 wherein said compound is a compound of formula (I-a) AUG-P3833PCT or a pharmaceutically acceptable salt and / or solvate thereof; wherein Y1, X, W, R10, Z1, and R1 are as defined in any one of clauses 1 to 23, 25 to 26 and 29 to33. 5 Clause 47. The compound or a pharmaceutically acceptable salt and / or solvate thereof of formula (I) according to any one of clauses 1 to 23, 25 to 26 and 29 to 33,wherein said compound is a compound of formula (I-b) or a pharmaceutically acceptable salt and / or solvate thereof;10 wherein Y1, X, W, R10, Z1, and R1 are as defined in any one of clauses 1 to 23, 25 to 26 and 29 to33. Clause 48. The compound or a pharmaceutically acceptable salt and / or solvate thereof according to clauses 46 or clause 47, wherein R10 is methyl.Clause 49. The compound or a pharmaceutically acceptable salt and / or solvate thereof of formula (I)15 according to any one of clauses 1 to 23, 25 and 34 to 35,wherein said compound is a compound of formula (I-m) AUG-P3833PCT or a pharmaceutically acceptable salt and / or solvate thereof; wherein Y1 and Z1 are as defined in any one of clauses 1 to 23, 25 and 34 to 35.Clause 50. The compound or a pharmaceutically acceptable salt and / or solvate thereof of formula (I) according to any clause 49, 5 wherein said compound is a compound of formula (I-ma) or a pharmaceutically acceptable salt and / or solvate thereof; wherein Y1 and Z1 are as defined in clause 49.Clause 51. The compound or a pharmaceutically acceptable salt and / or solvate thereof of formula (I)10 according to clause 49, wherein said compound is a compound of formula (I-mb) or a pharmaceutically acceptable salt and / or solvate thereof; wherein Y1 and Z1 are as defined in clause 49.15 Clause 52. The compound or a pharmaceutically acceptable salt and / or solvate thereof according to any one of clauses 49 to 51, wherein Z1 is hydrogen.Clause 53. The compound according to clause 1, wherein said compound is selected from the groupconsisting of: AUG-P3833PCT AUG-P3833PCT AUG-P3833PCT AUG-P3833PCT AUG-P3833PCT AUG-P3833PCT AUG-P3833PCT AUG-P3833PCT or a pharmaceutically acceptable salt and / or solvate of any one thereof. AUG-P3833PCTClause 54. The compound according to clause 1, wherein said compound is selected from the groupconsisting of: AUG-P3833PCT AUG-P3833PCT or a pharmaceutically acceptable salt and / or solvate of any one thereof. Clause 55. The compound according to clause 1, wherein said compound is selected from the group consisting of: AUG-P3833PCT AUG-P3833PCT or a pharmaceutically acceptable salt and / or solvate of any one thereof. Clause 56. A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt and / or solvate thereof according to any one of clauses 1 to 55 and at least one pharmaceuticallyacceptable carrier. 5Clause 57. A compound or a pharmaceutically acceptable salt and / or solvate thereof according to anyone of clauses 1 to 55 or a pharmaceutical composition according to clause 56 for use as amedicament. Clause 58. The compound or a pharmaceutically acceptable salt and / or solvate thereof according toany one of clauses 1 to 55 or the pharmaceutical composition according to clause 56 for use in the10 treatment and / or the prevention of an HDAC6-associated disease, wherein said HDAC6-associated disease is selected from inflammatory diseases, autoimmune diseases, proliferative diseases (such as cancers), neurodegenerative diseases (including neuromuscular diseases), pains, neuropathies,psychiatric diseases, neurodevelopmental disorders, sleep disorders, cardiovascular diseases, kidney diseases, and metabolic or hormonal disorders.15 Clause 59. Use of a compound or a pharmaceutically acceptable salt and / or solvate thereof accordingto any one of clauses 1 to 55 or a pharmaceutical composition according to clause 56 in themanufacture of a medicament. Clause 60. Use of the compound or a pharmaceutically acceptable salt and / or solvate thereof or thepharmaceutical composition according to clause 59 for the treatment and / or the prevention of an20 HDAC6-associated disease, wherein said HDAC6-associated disease is selected from inflammatory diseases, autoimmune diseases, proliferative diseases (such as cancers), neurodegenerative diseases (including neuromuscular diseases), pains, neuropathies, psychiatric diseases,neurodevelopmental disorders, sleep disorders, cardiovascular diseases, kidney diseases, and metabolic or hormonal disorders. AUG-P3833PCT Clause 61. A method for treating and / or preventing a HDAC6-associated disease comprising a step ofadministering to a subject in need thereof a therapeutically effective amount of a compound or a pharmaceutically acceptable salt and / or solvate thereof according to any one of clauses 1 to 55, or ofa pharmaceutical composition pharmaceutical composition according to clause 56. 5Clause 62. The method according to clause 61 for treating and / or preventing a HDAC6-associateddisease, wherein said HDAC6-associated disease is selected from inflammatory diseases, autoimmune diseases, proliferative diseases (such as cancers), neurodegenerative diseases (includingneuromuscular diseases), pains, neuropathies, psychiatric diseases, neurodevelopmental disorders, sleep disorders, cardiovascular diseases, kidney diseases, and metabolic or hormonal disorders.10 Clause 63. A process for manufacturing a compound or a pharmaceutically acceptable salt and / orsolvate thereof according to any one of clauses 1 to 55, wherein said process comprises a step ofreacting: (i) a carboxylic acid with an amine; or (ii) a halo-ketone with a thiol.15 Clause 64. A compound of formula T-4 wherein R10 is as defined in any one of clauses 1 to 3, Y2 represents the 5-membered sulfur-containing heteroaryl comprising the W and X groups, as defined any one of clauses 1 to 3, X1 ishalo and PG is a suitable acid protective group; or a salt thereof.20 Clause 65. A compound of formula T-6 Wherein Y1 and R10 are as defined in any one of clauses 1 to 3 and Y2 represents the 5-memberedsulfur-containing heteroaryl comprising the W and X groups, as defined any one of clauses 1 to 3;or a salt thereof.25 Clause 66. A compound of formula T-10 AUG-P3833PCT wherein R10, R1 and Z1 are as defined in any one of clauses 1 to 3, Y2 represents the 5-memberedsulfur-containing heteroaryl comprising the W and X groups, as defined any one of clauses 1 to 3and X1 is halo; or a salt thereof.5 Clause 67. A compound of formula T-4-a wherein R10 is as defined in any one of clauses 1 to 3, Y2 represents the 5-membered sulfur-containing heteroaryl comprising the W and X groups, as defined any one of clauses 1 to 3, X1 ishalo and PG is a suitable acid protective group; or a salt thereof.10 Clause 68. A compound of formula T-6-a wherein Y1 and R10 are as defined in any one of clauses 1 to 3 and Y2 represents the 5-memberedsulfur-containing heteroaryl comprising the W and X groups, as defined any one of clauses 1 to 3;or a salt thereof.15 Clause 69. A compound of formula T-10-a wherein R10, R1 and Z1 are as defined in any one of clauses 1 to 3, Y2 represents the 5-memberedsulfur-containing heteroaryl comprising the W and X groups, as defined any one of clauses 1 to 3and X1 is halo; or a salt thereof.20 Clause 70. A compound of formula T-15 AUG-P3833PCT wherein L2 is as defined in any one of clauses 1 to 3, Y2 represents the 5-membered sulfur-containing heteroaryl comprising the W and X groups, as defined any one of clauses 1 to 3, X1 ishalo and PG is a suitable acid protective group; or a salt thereof.5 Clause 71. A compound of formula T-17 wherein Y1 and L2 are as defined in any one of clauses 1 to 3 and Y2 represents the 5-memberedsulfur-containing heteroaryl comprising the W and X groups, as defined any one of clauses 1 to 3;or a salt thereof.10 Clause 72. A compound of formula T-27 wherein L2 is as defined in any one of clauses 1 to 3, Y2 represents the 5-membered sulfur-containing heteroaryl comprising the W and X groups, as defined any one of clauses 1 to 3, X1 ishalo and PG is a suitable acid protective group; or a salt thereof.15 EXAMPLES

[237] The present invention is further illustrated by the following examples.Example 1: Synthesis of the compounds

[238] The compounds of formula (I) (1)-(121) and (123)-(190) represented in Table 1 and / or (191)-(245) represented in Table 2 and / or (246)-(274) represented in Table 3 hereinabove were prepared as20 described hereinafter. General synthetic methods

[239] The compounds according to the invention, in particular the compounds according to the formula(I), may be prepared by methods known to the person skilled in the art of organic synthesis or by using the AUG-P3833PCT following synthesis schemes. In all of the schemes described below it is understood that protecting groups for sensitive or reactive groups are employed where necessary in accordance with the general principles of organic chemistry. Protecting groups are manipulated according to standard methods (T.W. Green and P.G.M. Wuts, Protecting Groups in Organic Synthesis, 1991, John Wiley & Sons, Inc.). These groups are 5 then removed at a convenient stage of the synthesis using methods that are readily apparent to those skilled in the art. Many of the heterocyclic compounds of formula (I) where Y1 is a heteroaryl may be preparedusing synthetic routes well known in the art (A.R. Katrizky and C. W. Rees, 1984, Comprehensive Heterocyclic Chemistry, Pergamon Press).

[240] The HDAC6 inhibitors disclosed in the present invention have been prepared using the following10 synthetic schemes. Specific conditions for carrying out these reactions are provided in the detailed examples. The synthetic schemes described below show exemplified approaches to compounds of the present invention, but these routes should not be taken as the only possible synthetic routes to compounds of the present invention.

[241] Certain compounds of formula (I), in particular formula (I-a) and formula (I-b), in which Y215 represents the 5-membered sulfur-containing heteroaryl comprising the W and X groups, as defined above,and Y1, R1, Z1, and R10 are as defined above, may be obtained also according to Scheme 1 (Method 1)below: Scheme 1 / Method 1 AUG-P3833PCT

[242] Alpha-keto esters T-1 in which PG is a suitable acid protective group such as, for example, methyl,and Y2 is a 5-membered sulfur-containing heteroaryl such as, for example, thiophene, are commerciallyavailable or may be synthesized by a person skilled in the art of organic chemistry using multiple ways described in the literature. Intermediates T-2 may be prepared by reacting T-1 with an organometallic5 nucleophile such as, for example, methylmagnesium bromide, in a solvent (e.g., THF) at a suitabletemperature such as, for example -40 °C (Step 1). Intermediates T-2 may also be prepared by reacting T-1with other ketone-reactive nucleophiles such as, for example, trifluoromethyltrimethylsilane in presence of a suitable anionic initiator such as, for example, tetrabutylammonium fluoride, in a suitable solvent such as, for example, DCM, at a suitable temperature such as, for example, 0 °C to room temperature.10 Intermediate T-3 can be prepared by reacting intermediate T-2 with a suitable halogenating reagent suchas, for example, NBS, in a suitable solvent such as, for example, DMF, at a suitable temperature such as, for example, 25 °C (Step 2). Intermediate T-3 can be converted to haloketone T-4, in which X1 is a suitablehalogen such as, for example, bromide, via a suitable haloacetylation method such as, for example, metal-catalyzed cross coupling sequence using tributyl(1-ethoxyvinyl)tin, in the presence of a catalyst / ligand15 system (e.g., Pd(PPh3)4), a base (e.g., t-BuOK), in a solvent (e.g., dioxane), at the appropriate temperatureto provide the enol ether intermediate, which can in turn be transformed into haloketone T-4 using a suitablehalogenating reagent such as, for example, NBS, in a suitable solvent such as, for example, THF / water, ata suitable temperature such as, for example, room temperature (Step 3). Intermediate T-4 can be reactedwith heteroaryl thiol derivatives of formula Y1-SH in the presence of a base (e.g., MeONa or K2CO3) in a20 solvent (e.g., DMF or ACN) at the appropriate temperature to provide intermediate T-5 (Step 4). HeteroarylY1-SH are commercially available or may be prepared by methods known to the person skilled in the art, for example from the corresponding heteroaryl Y1-OH derivatives using Lawesson’s reagent or P2S5 reagentin a solvent (e.g., toluene) at the appropriate temperature (e.g., 110 °C). Heteroaryl Y1-OH are commerciallyavailable or may be prepared by methods known to the person skilled in the art. Alternatively, Y1-SH can 25 be prepared by reacting a halo-substituted heteroaryl with a suitable thiol nucleophile such as, for example, (4-methoxyphenyl)methanethiol, in presence of a suitable base such as, for example, Cs2CO3, in a suitable solvent such as, for example, 1,4-dioxane, at a suitable temperature such as, for example, 50 °C, and subsequent removal of the 4-methoxybenzyl group with a deprotecting reagent such as, for example, TFA in presence of m-cresol, at a suitable temperature such as, for example, 80 °C. Intermediate acids T-6 can30 be obtained by reacting esters T-5 with a suitable hydrolyzing reagent such as, for example, LiOH.H2O, ina suitable solvent such as, for example, THF / EtOH, at a suitable temperature such as, for example, 25 °C (Step 5). Compounds of formula (I), wherein L2 is -(C(OH)R10), can be obtained by reacting acid T-6 withan amine such as, for example, cyclopropylamine, using a suitable amide coupling reagent such as, for example, EDCI / HOBt, in presence of a suitable base such as, for example, TEA, in a suitable solvent such AUG-P3833PCT as, for example, DMF, at a suitable temperature such as, for example, 25 °C (Step 6). Compounds of formula(I-a) and (I-b) can be obtained by a chiral separation method such as, for example, chiral SFC (Step 7).

[0243] Certain compounds of formula (I), in particular formula (I-a) and formula (I-b), in which Y2represents the 5-membered sulfur-containing heteroaryl comprising the W and X groups, as defined above,5 and Y1, R1, Z1, and R10 are as defined above may also be obtained according to Scheme 2 (Method 2)below: Scheme 2 / Method 2

[244] Amides T-7 in which Y2 is a 5-membered sulfur-containing heteroaryl such as, for example,10 thiophene, can be made using art known conditions or obtained commercially. Intermediates T-8 may beprepared by reacting T-7 with an organometallic nucleophile such as, for example, thienyl magnesiumbromide, in a solvent (e.g., THF) at a suitable temperature such as, for example -40 °C (Step 1). Intermediates T-9 can be prepared by reacting intermediates T-8 with a suitable brominating reagent suchas, for example, NBS, in a suitable solvent such as, for example, DMF, at a suitable temperature such as,15 for example 25 °C. Alternatively, intermediates T-9 may be prepared in one step from intermediate T-7’by reacting intermediate T-7’ with an organometallic nucleophile such as, for example, (5-bromothiophen-2-yl)magnesium bromide, in a solvent (e.g., THF) at a suitable temperature such as, for example -40 °C(Step 3). Intermediate T-9 can be converted to T-10, in which X1 is a suitable halogen such as, for example,bromide, via a suitable acetylation method such as, for example, metal-catalyzed cross coupling sequence20 using tributyl(1-ethoxyvinyl)tin, in the presence of a catalyst / ligand system (e.g., Pd(PPh3)4), a base (e.g., t-BuOK), in a solvent (e.g., dioxane), at the appropriate temperature to provide the enol ether intermediate, AUG-P3833PCT which can in turn be transformed into haloketone T-10 using a suitable halogenating reagent such as, forexample, NBS, in a suitable solvent such as, for example, THF / water, at a suitable temperature such as, for example, room temperature (Step 4). Intermediate T-10 can react with heteroaryl thiol derivatives ofFormula Y1-SH in the presence of a base (e.g., MeONa or K2CO3) in a solvent (e.g., DMF or ACN) at the5 appropriate temperature to provide compounds of formula (I) , wherein L2 is -(C(OH)R10) (Step 5).Intermediate thiols Y1-SH can be prepared as described hereinbefore. Compounds of formula (I-a) and (I-b) can be obtained by a chiral separation method such as, for example, chiral SFC (Step 6).

[0245] Certain compounds of formula (I-a) in which Y2 represents the 5-membered sulfur-containingheteroaryl comprising the W and X groups, as defined above, and Y1, R1, Z1, and R10 are as defined above10 may also be obtained according to Scheme 3 (Method 3) below, wherein the -a and -b are nomenclaturefor enantiomers: Scheme 3 / Method 3

[246] Homochiral intermediates T-3-a and T-3-b in which PG is a suitable protective group such as, for15 example, ethyl, and Y2 is a 5-membered sulfur-containing heteroaryl such as, for example, thiophene, canbe obtained from racemic T-2 by a chiral separation method such as, for example, chiral SFC (Step 1). Theabsolute configuration of T-3-a and T-3-b can be determined by art known conditions such as, for example,x-ray crystallography on a monocrystal. Intermediate T-3-a can be converted to haloketoneT-4-a, in which X1 is a suitable halogen such as, for example, bromide, via a suitable acetylation method20 such as, for example, metal-catalyzed cross coupling sequence using tributyl(1-ethoxyvinyl)tin, in the presence of a catalyst / ligand system (e.g., Pd(PPh3)4), a base (e.g., t-BuOK), in a solvent (e.g., dioxane), atthe appropriate temperature to provide the enol ether intermediate, which can in turn be transformed into haloketone T-4-a using a suitable halogenating reagent such as, for example, NBS, in a suitable solventsuch as, for example, THF / water, at a suitable temperature such as, for example, room temperature (Step25 2). Intermediate T-4-a can be reacted with heteroaryl thiol derivatives of Formula Y1-SH in the presenceof a base (e.g., MeONa or K2CO3) in a solvent (e.g., DMF or ACN) at the appropriate temperature to provide AUG-P3833PCT intermediates T-5-a (Step 3). Intermediate thiols Y1-SH can be prepared as described hereinbefore.Intermediate acids T-6-a can be obtained by reacting esters T-5-a with a suitable hydrolyzing reagent suchas, for example, LiOH.H2O, in a suitable solvent such as, for example, THF / EtOH, at a suitable temperature such as, for example, 25 °C (Step 4). Compounds of formula (I-a) can be obtained by reacting acid T-6-a 5 with an amine such as, for example, cyclopropylamine, using a suitable amide coupling reagent such as, for example, EDCI / HOBt, in presence of a suitable base such as, for example, TEA, in a suitable solvent such as, for example, DMF, at a suitable temperature such as, for example, 25 °C (Step 5). A skilled personwill understand that the corresponding enantiomer compound of formula I-b can be prepared analogouslyfrom enantiomeric intermediate T-3-b shown between parentheses in Scheme 3, which can also be obtained10 by chiral SFC separation of intermediate T-2.

[247] Certain compounds of formula (I-a) in which Y2 represents the 5-membered sulfur-containingheteroaryl comprising the W and X groups, as defined above, and Y1, R1, Z1, and R10 are as defined abovemay also be obtained according to Scheme 4 (Method 4) below: 15 Scheme 4 / Method 4

[248] Intermediate T-11 can be obtained by hydrolysis of T-3 with a suitable base such as, for example,KOH, in a suitable solvent such as, for example, EtOH / water, at a suitable temperature such as, for example 25 °C (Step 1). Homochiral intermediateT-12-a can be obtained by chiral resolution of racemic T-11 via salt formation with an appropriate chiral20 base such as, for example, (R)-2-amino-2-phenylethan-1-ol, in a suitable solvent such as, for example 2- propanol / 2-propyl acetate, at a suitable temperature such as, for example, 80 °C to 25 °C (Step 2). Amide AUG-P3833PCT intermediate T-8-a can be prepared by reacting intermediate T-12-a with a suitable amine such as, forexample, cyclopropylamine, using a suitable amide coupling reagent such as, for example, DIC / oxyma, in a suitable solvent such as, for example, THF, at a suitable temperature such as, for example, 0-25 °C (Step 3). Bromo intermediate T-9-a can be obtained by reacting intermediate T-8-a with a suitable brominating5 reagent such as, for example, NBS, in a suitable solvent such as, for example, DMF, at a suitable temperature such as, for example, 25 °C (Step 4). Intermediate T-9-a can be converted to haloketone T-10-a via a suitable acetylation method such as, for example, metal-catalyzed cross coupling sequence usingtributyl(1-ethoxyvinyl)tin, in the presence of a catalyst / ligand system (e.g., Pd(PPh3)4), a base (e.g., t-BuOK), in a solvent (e.g., dioxane), at the appropriate temperature to provide the enol ether intermediate,10 which can in turn be transformed into halo-ketone T-10-a using a suitable halogenating reagent such as,for example, NBS, in a suitable solvent such as, for example, THF / water, at a suitable temperature such as, for example, room temperature (Step 5). Intermediate T-10-a can be reacted with heteroaryl thiolderivatives of Formula Y1-SH in the presence of a base (e.g., MeONa or K2CO3) in a solvent (e.g., DMF or ACN) at the appropriate temperature to provide compounds of formula (I-a) (Step 6). Intermediate thiols15 Y1-SH can be prepared as described hereinbefore. A skilled person will understand that the corresponding enantiomer compound of formula (I-b) can be prepared analogously when isolating the enantiomer ofintermediate T-12-a via chiral resolution and progressing it similarly.

[0249] Certain compounds of formula (I-c), in which Y2 represents the 5-membered sulfur-containingheteroaryl comprising the W and X groups, as defined above, L2 is a direct bond between Y2 and the ester20 group, Y1, R1, and Z1 are defined as hereinbefore, may be obtained according to Scheme 5 (Method 5)below: Scheme 5 / Method 5

[0250] Esters T-13 in which Y2 is a 5-membered sulfur-containing heteroaryl such as, for example,25 thiophene, and PG is a suitable acid protective group such as, for example, methyl, can be made using art known conditions or obtained commercially. Intermediate T-14 can be obtained by the reaction of ester T- AUG-P3833PCT 13 with a suitable brominating reagent such as, for example, NBS, in a suitable solvent such as, for example,DCM, at a suitable temperature such as, for example, 25°C (Step 1). Intermediate T-14 can be converted toT-15, in which X1 is a suitable halogen such as, for example, bromide, via a suitable acetylation methodsuch as, for example, a metal-catalyzed cross coupling sequence using tributyl(1-ethoxyvinyl)tin, in the 5presence of a catalyst / ligand system (e.g., Pd(PPh3)4), a base (e.g., t-BuOK), in a solvent (e.g., dioxane), atthe appropriate temperature to provide the enol ether intermediate, which can in turn be transformed into halo-ketone T-15 using a suitable halogenating reagent such as, for example, NBS, in a suitable solventsuch as, for example, THF / water, at a suitable temperature such as, for example, room temperature (Step2). Intermediate T-15 can be reacted with heteroaryl thiol derivatives of Formula Y1-SH in the presence of10 a base (e.g., MeONa or K2CO3) in a solvent (e.g., DMF or ACN) at the appropriate temperature to provide intermediate T-16 (Step 3). Intermediate thiols Y1-SH can be prepared as described hereinbefore.Intermediate acids T-17 can be obtained by reacting esters T-16 with a suitable hydrolyzing reagent suchas, for example, LiOH.H2O, in a suitable solvent such as, for example, THF / EtOH, at a suitable temperature such as, for example, 25 °C (Step 4). Compounds of formula (I) can be obtained by reacting acid T-17 with15 an amine such as, for example, 1-methylpiperidin-4-amine, using a suitable amide coupling reagent such as, for example, EDCI / HOBt, in presence of a suitable base such as, for example, TEA, in a suitable solvent such as, for example, DMF, at a suitable temperature such as, for example, 25 °C (Step 5). A skilled personwill understand that the last two steps in Scheme 5, which comprise an ester hydrolysis and ensuing amideformation, can also be performed at an earlier stage of the synthesis, after which the resulting amide can be20 similarly progressed to compounds of formula (I). A skilled person will also understand that othercompounds of formula (I), including, for example, compounds of formula (I-e), (I-f), (I-g), (I-h), (I-j) and (I-k), can be obtained using the procedure described in Scheme 5 when L2 is -(CR10R11)n- with n=1, 2 or3. A skilled person will also understand that compounds of formula (I-ha) and (I-hb) and formulae (I-ka)and (I-kb) can be obtained by a chiral separation method such as, for example, chiral SFC, as outlined25 hereinbefore.

[251] Certain compounds of formula (I-d) in which Y2 represents the 5-membered sulfur-containingheteroaryl comprising the W and X groups, as defined above, and Y1, R1, and Z1 are defined as hereinbefore,may be obtained also according to Scheme 6 (Method 6) below: AUG-P3833PCT Scheme 6 / Method 6

[0252] Esters T-18 in which Y2 is a 5-membered sulfur-containing heteroaryl such as, for example,thiazole, and PG is a suitable acid protective group such as, for example, ethyl, can be made using art known 5 conditions or obtained commercially. Intermediates T-19, in which X1is a suitable halogen such as, for example, bromide, can be prepared by acylation of T-18 with a suitable acid halide such as, for example,bromoacetyl bromide, in a suitable solvent such as, for example, DCM, at a suitable temperature such as, for example, 0 °C (Step 1). Intermediate T-19 can be reacted with heteroaryl thiol derivatives of FormulaY1-SH in the presence of a base (e.g., MeONa or K2CO3) in a solvent (e.g., DMF or ACN) at the appropriate10 temperature to provide intermediate T-20 (Step 2). Intermediate thiols Y1-SH can be prepared as describedhereinbefore. Intermediate acids T-21 can be obtained by reacting esters T-20 with a suitable hydrolyzingreagent such as, for example, KOH, in a suitable solvent such as, for example, EtOH / water, at a suitable temperature such as, for example, 25 °C (Step 3). Compounds of formula (I-d) can be obtained by reacting acid T-21 with an amine such as, for example, 1-methylpiperidin-4-amine, using a suitable amide coupling15 reagent such as, for example, DIC / oxyma, in a suitable solvent such as, for example, THF, at a suitable temperature such as, for example, 0-25 °C (Step 4).

[253] Certain compounds of formula (I) (compounds of formula (I’)) in which Y2 represents the 5-membered sulfur containing heteroaryl comprising the W and X groups, as defined above, and Y1, R10, andZ1 are defined as hereinbefore, may be obtained also according to Scheme 7 (Method 7) below: AUG-P3833PCT Scheme 7 / Method 7

[254] Intermediates T-9-a in which R1 is a halo-alkyl group such as, for example, 2-chloroethyl, can bereacted intramolecularly to intermediates T-22-a using a suitable base such as, for example, tBuOK, in a5 suitable solvent such as, for example DMF, at a suitable temperature such as, for example 0-80 °C (Step 1).Intermediate T-22-a can be converted to haloketone T-23-a, in which X1 is a suitable halogen such as, forexample, bromide, via a suitable acetylation method such as, for example, metal-catalyzed cross couplingsequence using tributyl(1-ethoxyvinyl)tin, in the presence of a catalyst / ligand system (e.g., Pd(PPh3)4), a base (e.g., t-BuOK), in a solvent (e.g., dioxane), at the appropriate temperature to provide the enol ether10 intermediate, which can in turn be transformed into haloketone T-23-a using a suitable halogenating reagentsuch as, for example, NBS, in a suitable solvent such as, for example, THF / water, at a suitable temperature such as, for example, room temperature (Step 2). Intermediate T-23-a can be reacted with heteroaryl thiolderivatives of Formula Y1-SH in the presence of a base (e.g., MeONa or K2CO3) in a solvent (e.g., DMF orACN) at the appropriate temperature to provide compounds of formula (I’) (Step 3). Intermediate thiols Y1-15 SH can be prepared as described hereinbefore. A skilled person will understand that the correspondingenantiomer of formula (I’) can be prepared analogously when isolating the enantiomer of intermediate T-9-a via chiral resolution and progressing it similarly. A skilled person will also understand that Z1 can be aprotective group, which can be removed to provide compounds of formula (I) in which Z1is hydrogen.

[255] Certain compounds of formula (I) (compounds of formula (I’’)) in which Y2 represents 5-20 membered sulfur-containing heteroaryl comprising the W and X groups, as defined above, and Y1 and Z1are defined as hereinbefore, may be obtained according to Scheme 8 (Method 8) below: AUG-P3833PCT Scheme 8 / Method 8

[256] Intermediates T-24 can be obtained commercially or prepared using art known conditions.Intermediates T-25 can be prepared by reacting intermediate T-24 with a suitable organometal such as, for5 example, thiophen-2-ylmagnesium bromide, in a suitable solvent such as, for example, THF, at a suitable temperature such as, for example, -78 to 25 °C (Step 1). Intermediate T-26 can be prepared by reactingintermediate T-25 with a suitable halogenating reagent such as, for example, NBS, in a suitable solventsuch as, for example, DMF, at a suitable temperature such as, for example, 25 °C (Step 2). Alternatively, intermediate T-26 can be prepared from intermediate T-24 by reaction with a suitable halogen-bearing10 organometal such as, for example, (5-bromothiophen-2-yl)lithium, in a suitable solvent such as, for example, toluene, at a suitable temperature such as, for example -70 °C to room temperature (Step 3).Intermediate T-26 can be converted to haloketone T-27, in which X1 is a suitable halogen such as, forexample, bromide, via a suitable haloacetylation method such as, for example, metal-catalyzed crosscoupling sequence using tributyl(1-ethoxyvinyl)tin, in the presence of a catalyst / ligand system (e.g.,15 Pd(PPh3)4), a base (e.g., t-BuOK), in a solvent (e.g., dioxane), at the appropriate temperature to provide theenol ether intermediate, which can in turn be transformed into haloketone T-27 using a suitablehalogenating reagent such as, for example, NBS, in a suitable solvent such as, for example, THF / water, at asuitable temperature such as, for example, room temperature (Step 4). Intermediate T-27 can react withheteroaryl thiol derivatives of formula Y1-SH in the presence of a base (e.g., MeONa or K2CO3) in a solvent20 (e.g., DMF or ACN) at the appropriate temperature to provide compounds of formula (I’’) (Step 5).Intermediate thiols Y1-SH can be prepared as described hereinbefore. Compounds of formula (I’’-a) and(I’’-b) can be obtained by a chiral separation method such as, for example, chiral SFC (Step 6). A skilled AUG-P3833PCT person will understand that Z1 can be a protective group, which can be removed to provide compounds offormula (I’’-a) and (I’’-b) in which Z1 is hydrogen. A skilled person will also understand that analogousbeta-keto lactams to intermediate T-24 having different ring sizes such as, for example, piperidine-2,3-dione carrying a Z1 group on the nitrogen atom, can similarly provide compounds of formula (I’’-a) and5 (I’’-b) with a lactam of different ring size, such as, for example, a 6-membered ring. Synthesis of the compounds – Experimental results

[0257] Several methods for preparing the compounds of this invention are illustrated in the followingExamples. Unless otherwise noted, all starting materials were obtained from commercial suppliers and used without further purification. Specifically, the following abbreviations may be used in the examples and10 throughout the specification. Abbreviations

[258] Abbreviations are used as follows. AUG-P3833PCT AUG-P3833PCT Materials and analytical methods

[259] LCMS (Method 1): LC-MS were recorded on an Agilent 1200-G6140 apparatus. The HighPerformance Liquid Chromatography (HPLC) measurement was performed using an LC pump, a diode-array or a UV detector. Flow from the column was brought to the Mass Spectrometer (MS) which was 5 configured with an atmospheric pressure ion source. It is within the knowledge of the skilled person to set the tune parameters in order to obtain ions allowing the identification of the compound's nominal monoisotopic molecular weight (MW) and / or exact mass monoisotopic molecular weight. Data acquisition was performed with appropriate software. An ES MS detector was used, acquiring in positive or negative ionization modes. Compounds can be described by their molecular ion corresponding to the [M+H+]10 (protonated molecule) or [M-H+] (deprotonated molecule). For molecules with multiple isotopic patterns (Br, Cl), the reported value is the one obtained for the lowest isotope mass. All results were obtained with experimental uncertainties that are commonly associated with the method used. The gradient conditions used are described below: AUG-P3833PCT

[260] LCMS (Method 2): LC-MS were recorded on an Agilent 1200-G6140 apparatus. The HighPerformance Liquid Chromatography (HPLC) measurement was performed using an LC pump, a diode-array or a UV detector. Flow from the column was brought to the Mass Spectrometer (MS) which was configured with an atmospheric pressure ion source. It is within the knowledge of the skilled person to set 5 the tune parameters in order to obtain ions allowing the identification of the compound's nominal monoisotopic molecular weight (MW) and / or exact mass monoisotopic molecular weight. Data acquisition was performed with appropriate software. An ES MS detector was used, acquiring in positive or negative ionization modes. Compounds can be described by their molecular ion corresponding to the [M+H+](protonated molecule) or [M-H+] (deprotonated molecule). For molecules with multiple isotopic patterns 10 (Br, Cl), the reported value is the one obtained for the lowest isotope mass. All results were obtained with experimental uncertainties that are commonly associated with the method used. The gradient conditions used are described below:

[261] LCMS (Method 3): LC-MS were recorded on an Agilent 1200 apparatus. The High PerformanceLiquid Chromatography (HPLC) measurement was performed using an LC pump, a diode-array or a UV15 detector. Mobile Phase: 1.5 mL / 4 L TFA in water (solvent A) and 0.75 mL / 4 L TFA in acetonitrile (solventB), using the elution gradient 1%-100% (solvent B) over 3.85 minutes at a flow rate of 0.8 mL / min; Column: Waters, Xbridge C1850 x 2.1 mm, 5 μm; Wavelength: UV 220 nm; Column temperature: 40 oC;MS ionization: ESI. AUG-P3833PCT

[262] LCMS (Method 4): LC-MS spectra were recorded on a Waters Acquity I class UPLC system. Thegradient conditions used are described below:

[263] LCMS (Method 5): LC-MS spectra were recorded on a Waters Acquity I class UPLC system. Thegradient conditions used are described below: 5

[264] LCMS (Method 6): LC-MS were recorded on Shimadzu LC-20AB &MS 2010. TheHigh-Performance Liquid Chromatography (HPLC) measurement was performed using an LC pump, adiode-array or a UV detector. Flow from the column was brought to the Mass Spectrometer (MS) which AUG-P3833PCT was configured with an atmospheric pressure ion source. It is within the knowledge of the skilled person to set the tune parameters in order to obtain ions allowing the identification of the compound's nominal monoisotopic molecular weight (MW) and / or exact mass monoisotopic molecular weight. Data acquisition was performed with appropriate software. An ES MS detector was used, acquiring in positive or negative 5ionization modes. Compounds can be described by their molecular ion corresponding to the [M+H+](protonated molecule) or [M-H+] (deprotonated molecule). For molecules with multiple isotopic patterns (Br, Cl), the reported value is the one obtained for the lowest isotope mass. All results were obtained with experimental uncertainties that are commonly associated with the method used. The gradient conditions used are described below: 10

[0265] 1H NMR spectra were recorded on Varian 400 MHz (Example 1) or Buker AVANCE III HD400MHz (other Examples) spectrometers and are reported in ppm with the solvent resonance employed as the internal standard [CDCl3 at 7.26 ppm, DMSO-d6 at 2.50 ppm]. Peaks are reported as (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet or unresolved, br s = broad signal, coupling constant(s) in Hz, integration). 15 Preparation of synthetic intermediates

[266] Preparation of intermediate compounds I:

[0267] Synthesis of methyl 5-(2-bromoacetyl)thiophene-2-carboxylate (I-1): AUG-P3833PCT

[268] Synthesis of methyl 5-(1-ethoxyvinyl)thiophene-2-carboxylate (I-1-2) To a solution of methyl5-bromothiophene-2-carboxylate (5.00 g, 22.6 mmol) in dioxane (50 mL) was added tributyl(1- ethoxyvinyl)stannane (12.5 g, 34.7 mmol), TEA (4.58 g, 45.2 mmol) and Pd(PPh3)2Cl2 (794 mg, 1.13 mmol) under N2. The mixture was stirred at 80 °C for 16 h. The reaction mixture was quenched with 5saturated KF solution (50 mL) and was extracted with EtOAc (50 mL × 3). The combined organic layersare dried over Na2SO4, filtered and concentrated to give intermediate I-1-2 (15.0 g, 14.1 mmol, 62.5 %yield, 20 % purity) as a black oil.

[269] Synthesis of methyl 5-(2-bromoacetyl)thiophene-2-carboxylate (I-1) To a solution of I-1-2(15.0 g, 14.1 mmol) in THF (110 mL) and H2O (40 mL) was added NBS (2.52 g, 14.1 mmol). The mixture 10 was stirred at 25 °C for 2 h. The reaction mixture was quenched with H2O (100 mL) and was extracted with EtOAc (150 mL). The combined organic layers are dried over Na2SO4, filtered and concentrated to give aresidue. The residue was purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash® Silica Flash Column, Eluent: 0~18 % EtOAc / PE gradient @ 80 mL / min) to give compound I-1 (2.80 g, 9.05 mmol,64.0 % yield, 85 % purity) as a yellow solid.15

[0270] Synthesis of ethyl 2-(5-(2-bromoacetyl)thiophen-2-yl)-2-hydroxypropanoate (I-2):

[271] Synthesis of ethyl 2-hydroxy-2-(thiophen-2-yl)propanoate (I-2-1) To a solution of ethyl 2-oxo-2-(2-thienyl)acetate (23 g, 125 mmol) in THF (300 mL) was added MeMgBr (3 M, 49.9 mL) at -78 °C under N2 atmosphere. The mixture was stirred at -78 °C for 3 h. The reaction mixture was quenched by20 addition saturated ammonium chloride solution (200 mL) at 0 °C, and then diluted with H2O (100 mL) andextracted with EtOAc (200 mL × 3), dried over MgSO4, filtered and concentrated under reduced pressure to give intermediate I-2-1 (28 g, crude) was obtained as a yellow oil.

[0272] Synthesis of ethyl 2-(5-bromothiophen-2-yl)-2-hydroxypropanoate (I-2-2) To a solution of I-2-1 (29 g, 145 mmol) in DMF (260 mL) was added NBS (33.5 g, 188 mmol). The mixture was stirred at25 25 °C for 6 h. The reaction mixture was partitioned between EtOAc (600 mL) and H2O (600 mL). Theorganic phase was separated, washed with brine (400 mL × 2), dried over MgSO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography(ISCO®; 120 g SepaFlash® Silica Flash Column, Eluent: 0~4% EtOAc / PE gradient @ 80 mL / min).Intermediate I-2-2 (28 g, 69.3% yield) was obtained as a red oil. AUG-P3833PCT

[273] Synthesis of ethyl 2-(5-(1-ethoxyvinyl)thiophen-2-yl)-2-hydroxypropanoate (I-2-3) A mixtureof I-2-2 (20 g, 71.7 mmol), tributyl(1-ethoxyvinyl)stannane (51.8 g, 143 mmol), TEA (21.8 g, 215 mmol)and Pd(PPh3)2Cl2 (2.51 g, 3.58 mmol) in dioxane (200 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 90 °C for 16 h under N2 atmosphere. The reaction mixture was5 partitioned between EtOAc (800 mL) and H2O (600 mL). The organic phase was separated, washed withbrine (300 mL × 2), dried over MgSO4, filtered and concentrated under reduced pressure to give intermediate I-2-3 (50 g, crude) as a black oil.

[0274] Synthesis of ethyl 2-(5-(2-bromoacetyl)thiophen-2-yl)-2-hydroxypropanoate (I-2) To asolution of I-2-3 (20 g, 74 mmol) in THF (200 mL) and H2O (100 mL) was added NBS (13.8 g, 74 mmol).10 The mixture was stirred at 0 °C for 2 h. The reaction mixture was partitioned between EtOAc (800 mL)and H2O (600 mL). The organic phase was separated, washed with brine (300 mL × 2), dried over MgSO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silicagel chromatography (ISCO®; 220 g SepaFlash® Silica Flash Column, Eluent: 0~12% EtOAc / PE gradient@ 80 mL / min). Compound I-2 (13 g, 29.8% yield, 54.5% purity) was obtained as a colorless oil.15

[0275] Synthesis of ethyl (S)-2-(5-(2-bromoacetyl)thiophen-2-yl)-2-hydroxypropanoate (I-3):

[276] Synthesis of ethyl (S)-2-(5-bromothiophen-2-yl)-2-hydroxypropanoate (I-3-1) I-2-2 (30 g, 107mmol) was further separated by SFC (Column: DAICEL CHIRALPAK AD (250 mm × 30 mm, 10 μm),Mobile phase: Solvent A: (Supercritical CO2), Solvent B: i-PrOH (0.1%NH3H2O), A / B=60 / 40 isocratic20 elution) to give elution peak 1 as intermediate I-3-1 (12 g, 40% yield).

[0277] Synthesis of ethyl (S)-2-(5-(1-ethoxyvinyl)thiophen-2-yl)-2-hydroxypropanoate (I-3-2) Amixture of I-3-1 (9.5 g, 34.0 mmol), tributyl(1-ethoxyvinyl)stannane (24.6 g, 68.1 mmol), TEA (10.3 g,102 mmol) and Pd(PPh3)2Cl2 (1.19 g, 1.70 mmol, 0.05 eq) in dioxane (100 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 90 °C for 16 h under N2 atmosphere. The reaction25 mixture was partitioned between EtOAc (600 mL) and H2O (600 mL). The organic phase was separated,washed with brine (300 mL × 2), dried over MgSO4, filtered and concentrated under reduced pressure to give intermediate I-3-2 (15 g, crude) as a black oil.

[0278] Synthesis of ethyl (S)-2-(5-(2-bromoacetyl)thiophen-2-yl)-2-hydroxypropanoate (I-3) To asolution of I-3-2 (9.2 g, 34.0 mmol) in THF (100 mL) and H2O (50 mL) was added NBS (12.1 g, 68.130 mmol). The mixture was stirred at 0 °C for 1 h. The reaction mixture was partitioned between EtOAc (300 AUG-P3833PCT mL) and H2O (300 mL). The organic phase was separated, washed with brine (100 mL × 2), dried overMgSO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 120 g SepaFlash® Silica Flash Column, Eluent: 0~35%EtOAc / PE gradient @ 70 mL / min). Compound I-3 (6.1 g, 52.5% yield, 94% purity) was obtained as a5 brown oil.

[279] Synthesis of 3-(5-(2-bromoacetyl) thiophen-2-yl)-1-cyclopropyl-3-hydroxypyrrolidin-2-one(I-4):

[280] Synthesis of methyl 3-(cyclopropylamino) propanoate (I-4-1) To a solution of10 cyclopropanamine (20.0 g, 350 mmol, 24.3 mL, 1.00 eq) in EtOH (200 mL) was added methyl prop-2- enoate (32.2 g, 374 mmol, 33.7 mL, 1.07 eq) slowly dropwise. The mixture was stirred at 25 °C for 16 h.TLC (PE / THF = 0 / 1) showed one new spot was formed. The reaction mixture was added water (300 mL) and extracted with EtOAc (300 mL × 3). The combined organic layers were dried over Na2SO4, filtered andconcentrated to give intermediate I-4-1 (50.1 g, 350 mmol, 99.9% yield) as a yellow oil.15

[0281] Synthesis of ethyl 1-cyclopropyl-4,5-dioxopyrrolidine-3-carboxylate (I-4-2) To a solution ofcompound I-4-1 (43.4 g, 303 mmol, 1.00 eq) in THF (400 mL) was added diethyl oxalate (53.1 g, 363mmol, 49.6 mL, 1.20 eq) and EtONa (206 g, 606 mmol, 20.0% purity, 2.00 eq). The mixture was stirred at 50 °C for 16 h. The reaction mixture was concentrated to give a residue. To the residue was added water (500 mL), the pH was adjusted to pH = 1 with 1 N HCl and the mixture was filtered to give intermediate I-20 4-2 (29.2 g, 133 mmol, 43.8% yield, 96.0% purity) as a brown solid.

[0282] Synthesis of tert-butyl 1-cyclopropylpyrrolidine-2,3-dione (I-4-3) A solution of compound I-4-2 (25.0 g, 114 mmol, 1.00 eq) in HCl (1.00 M, 500 mL, 4.40 eq) was stirred at 100 °C for 16 h. Thereaction mixture was extracted with DCM (800 mL × 3). The combined organic layers were dried overNa2SO4, filtered and concentrated in vacuum to give intermediate I-4-3 (9.70 g, crude) as a brown oil.25

[0283] Synthesis of 3-(5-bromothiophen-2-yl)-1-cyclopropyl-3-hydroxypyrrolidin-2-one (I-4-4) Toa solution of 2,5-dibromothiophene (5.00 g, 20.7 mmol, 2.33 mL, 1.00eq) in Toluene (50.0 mL) was addedn-BuLi (2.50 M, 9.92 mL, 1.20 eq) at -70 °C under N2. The mixture was stirred at -70 °C for 1 h under N2.A solution of compound I-4-3 (4.31 g, 31.0 mmol, 1.50 eq) in toluene (50.0 mL) was added into abovereaction mixture at -70 °C and stirred at -70 °C for 1 h under N2. The mixture was stirred at 25 °C for 16 h.30 The reaction mixture quenched with saturated aqueous NH4Cl solution (100 mL) and extracted with EtOAc (150 mL × 2). The combined organic phase was dried over Na2SO4, filtered and concentrated in vacuum to AUG-P3833PCT give a residue. The residue was purified by column chromatography (SiO2, PE / THF = 100 / 1 to 3 / 1) to giveintermediate I-4-4 (3.33 g, 7.05 mmol, 34.1% yield, 64.5% purity) as a yellow solid.

[0284] Synthesis of 1-cyclopropyl-3-(5-(1-ethoxyvinyl) thiophen-2-yl)-3-hydroxypyrrolidin-2-one(I-4-5) To a solution of compound I-4-4 (3.13 g, 10.4 mmol, 1.00 eq) in dioxane (32.0 mL) was added5 tributyl(1-ethoxyvinyl)stannane (6.26 g, 17.3 mmol, 5.86 mL, 1.67 eq), TEA (2.10 g, 20.7 mmol, 2.88 mL, 2.00 eq) and Pd(PPh3)2Cl2 (727 mg, 1.04 mmol, 0.100 eq) under N2. The mixture was stirred at 90 °C for 16 h under N2. The reaction mixture was quenched by saturated aqueous KF solution (60 mL) and extractedwith EtOAc (100 mL × 2). The combined organic layers were dried over MgSO4, filtered and concentratedin vacuum to give intermediate I-4-5 (9.80 g, crude) as a brown oil.10

[0285] Synthesis of 3-(5-(2-bromoacetyl) thiophen-2-yl)-1-cyclopropyl-3-hydroxypyrrolidin-2-one(I-4) To a solution of compound I-4-5 (2.50 g, 8.52 mmol, 1.00 eq) in THF (25.0 mL) and H2O (12.5 mL)was added NBS (607 mg, 3.41 mmol, 0.400 eq) at 0 °C. The mixture was stirred at 0 °C for 1 h. The reactionmixture was poured into water (20 mL) and extracted with EtOAc (30 mL × 2). The combined organic layers were dried with Na2SO4, filtered and concentrated in vacuum to give a compound I-4 (2.62 g, crude)15 as a brown oil.

[286] Synthesis of 3-(5-(2-bromoacetyl)thiophen-2-yl)-3-hydroxy-1-methylpyrrolidin-2-one (I-5):

[287] Synthesis of 3-(5-bromothiophen-2-yl)-3-hydroxy-1-methylpyrrolidin-2-one (I-5-1) To asolution of 2,5-dibromothiophene (6.68 g, 27.6 mmol) in THF (100 mL) was added dropwise n-BuLi (2.520 M, 11.6 mL) at -78°C under N2. The mixture was stirred at -78 °C for 0.5 h, then the mixture was added 1-methylpyrrolidine-2,3-dione (2.50 g, 22.1 mmol) in THF (100 mL) and was stirred at -78°C for 16 h. The reaction mixture was quenched by addition H2O (100 mL) at 0 °C, and extracted with EtOAc (50 mL × 3).The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash®25 Silica Flash Column, Eluent: 0~30% THF / PE gradient @ 60 mL / min) to give intermediate I-5-1 (1.90 g,6.88 mmol, 24.9 % yield) as a yellow solid.

[288] Synthesis of 3-(5-(1-ethoxyvinyl)thiophen-2-yl)-3-hydroxy-1-methylpyrrolidin-2-one (I-5-2)To a solution of compound I-5-1 (1.00 g, 3.62 mmol) in dioxane (10 mL) was added tributyl(1-ethoxyvinyl)stannane (2.10 g, 5.81 mmol) , TEA (733 mg, 7.24 mmol) and Pd(PPh3)2Cl2 (254 mg, 362 30 μmol) under N2. The mixture was stirred at 80 °C for 16 h. The reaction mixture was quenched with saturated KF (10 mL) and was extracted with EtOAc (10 mL × 3). The combined organic layers are dried AUG-P3833PCT over Na2SO4, filtered and concentrated to give intermediate I-5-2 (2.50 g, 2.81 mmol, 77.5 % yield, 30 %purity) was obtained as a black oil.

[289] Synthesis of 3-(5-(2-bromoacetyl)thiophen-2-yl)-3-hydroxy-1-methylpyrrolidin-2-one (I-5)To a solution of I-5-2 (2.50 g, 2.81 mmol) in H2O (10 mL) and THF (20 mL) was added NBS (549 mg,5 3.09 mmol). The mixture was stirred at 0 °C for 1 h. The reaction mixture was quenched with H2O (30 mL)and was extracted with EtOAc (100 mL). The combined organic layers are dried over Na2SO4, filtered and concentrated to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 20 gSepaFlash® Silica Flash Column, Eluent: 0~60 % THF / PE gradient @ 60 mL / min) to give compound I-5(650 mg, 1.63 mmol, 58.2 % yield, 80 % purity) was obtained as a yellow solid.10

[0290] Synthesis of methyl 2-(5-(2-bromoacetyl)thiophen-2-yl)acetate (I-6):

[291] Synthesis of methyl 2-(5-bromothiophen-2-yl)acetate (I-6-2) To a solution of methyl 2-(thiophen-2-yl)acetate (20 g, 128 mmol) in CH2Cl2(50 mL) and AcOH (50 mL) was added NBS (23.2 g, 130.6 mmol). The mixture was stirred at 25 °C for 12 h. The reaction mixture was partitioned between15 CH2Cl2 (600 mL) and H2O (600 mL). The organic phase was separated, washed with brine 800 mL (400mL × 2), dried over MgSO4, filtered and concentrated under reduced pressure to give a residue. The residuewas purified by flash silica gel chromatography (ISCO®; 120 g SepaFlash® Silica Flash Column, Eluent: 0~40% EtOAc / PE gradient @ 80 mL / min). Intermediate I-6-2 (20.1 g, 66.4% yield) was obtained as ayellow oil.20

[0292] Synthesis of methyl 2-(5-(1-ethoxyvinyl)thiophen-2-yl)acetate (I-6-3) To a solution of I-6-2(10.0 g, 42.5 mmol) in dioxane (100 mL) was added tributyl(1-ethoxyvinyl)stannane (30.7 g, 85.1 mmol), TEA (12.9 g, 127.6 mmol) and Pd(PPh3)2Cl2 (1.5 g, 2.1 mmol) under N2. The mixture was stirred at 80 °C for 16 h. The reaction mixture was quenched with saturated KF solution (50 mL) and was extracted with EtOAc (50 mL × 3). The combined organic layers are dried over Na2SO4, filtered and concentrated to give25 intermediate I-6-3 (26.0 g, 11.5 mmol, 58.6 % yield, 30 % purity) as a black oil.

[0293] Synthesis of methyl 2-(5-(2-bromoacetyl)thiophen-2-yl)acetate (I-6) To a solution of I-6-3(10.0 g, 44.2 mmol) in THF (110 mL) and H2O (40 mL) was added NBS (7.8 g, 44.2 mmol). The mixture was stirred at 0 °C for 2 h. The reaction mixture was quenched with H2O (100 mL) and was extracted with EtOAc (150 mL). The combined organic layers are dried over Na2SO4, filtered and concentrated to give a30 residue. The residue was purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash® Silica Flash AUG-P3833PCT Column, Eluent: 0~40 % EtOAc / PE gradient @ 80 mL / min) to give compound I-6 (6.1 g, 22.8 mmol, 62.0% yield, 85 % purity) as a yellow solid.

[0294] Synthesis of 2-(5-(2-bromoacetyl)thiophen-2-yl)-N- cyclopropyl-propanamide (I-7): 5

[0295] Synthesis of methyl 2-(5-bromothiophen-2-yl)propanoate (I-7-1) To a solution of methyl 2-(thiophen-2-yl)propanoate (1.0 g, 5.87 mmol) in CH2Cl2(30 mL) and AcOH (30 mL) was added NBS (1.3 g, 7.1 mmol) at 25 °C under N2 atmosphere. The mixture was stirred at 25 °C for 6 h. The reaction mixturewas quenched by addition of saturated ammonium chloride solution (20 mL) at 0 °C, and then diluted withH2O (10 mL) and extracted with CH2Cl2 (20 mL × 3), dried over MgSO4, filtered and concentrated under10 reduced pressure to give I-7-1 (1.1 g, crude) which was obtained as a yellow oil.

[0296] Synthesis of 2-(5-bromothiophen-2-yl)propanoic acid (I-7-2) To a solution of I-7-1 (8.9 g,35.73 mmol) in THF (15 mL) and EtOH (15 mL) was added LiOH.H2O (284 mg, 6.76 mmol) in H2O (5 mL) at 0 °C. The mixture was stirred at 25 °C for 2 h. The reaction mixture was added HCl (1 N, 2 mL)and concentrated. The solid was filtered and concentrated to give intermediate I-7-2 (5.0 g, 20.1 mmol,15 65.2 % yield, 88 % purity) as a yellow solid.

[297] Synthesis of 2-(5-bromothiophen-2-yl)-N-cyclopropylpropanamide (I-7-3) A mixture of I-7-2(200 mg, 850 μmol) in DMF (2 mL) was added cyclopropanamine (54.9 mg, 961 μmol), TEA (146 mg, 1.44 mmol), EDCI (138 mg, 721 μmol) and HOBt (97.4 mg, 721 μmol). The mixture was stirred at 25 °Cfor 2 h. The mixture was filtered and concentrated under reduced pressure to give a residue. The residue20 was purified by flash silica gel chromatography (ISCO®; 220 g SepaFlash® Silica Flash Column, Eluent: 0~12% EtOAc / PE gradient @ 80 mL / min). Intermediate I-7-3 (170 mg, 75.8% yield, 90.5% purity) wasobtained as a colorless oil.

[0298] Synthesis of N-cyclopropyl-2-(5-(1-ethoxyvinyl)thiophen-2-yl)propanamide (I-7-4) To asolution of I-7-3 (10.5 g, 29.2 mmol) in dioxane (100 mL) was added tributyl(1-ethoxyvinyl)stannane (30.725 g, 85.1 mmol), TEA (12.9 g, 127.6 mmol) and Pd(PPh3)2Cl2 (1.5 g, 2.1 mmol) under N2. The mixture was stirred at 80 °C for 16 h. The reaction mixture was quenched with saturated KF solution (50 mL) and was extracted with EtOAc (50 mL × 3). The combined organic layers are dried over Na2SO4, filtered andconcentrated to give intermediate I-7-4 (26.0 g, crude) as a black oil.

[0299] Synthesis 2-(5-(2-bromoacetyl)thiophen-2-yl)-N-cyclopropylpropanamide (I-7) To a solution30 of I-7-4 (3.87 g, 14.6 mmol) in THF (110 mL) and H2O (40 mL) was added NBS (7.8 g, 44.2 mmol). The AUG-P3833PCT mixture was stirred at 0 °C for 2 h. The reaction mixture was quenched with H2O (100 mL) and was extracted with EtOAc (150 mL). The combined organic layers are dried over Na2SO4, filtered and concentrated to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash® Silica Flash Column, Eluent: 0~40 % EtOAc / PE gradient @ 80 mL / min) to give compound I-5 7 (6.1 g, crude) as a yellow oil.

[0300] Synthesis of 2-(5-(2-bromoacetyl)thiophen-2-yl)propanamide (I-8):

[301] Synthesis of 2-(5-bromothiophen-2-yl)propanamide (I-8-1) A mixture of I-7-2 (200 mg, 850μmol) in DMF (2 mL) was added NH4Cl (455 mg, 8.51 μmol), TEA (146 mg, 1.44 mmol), EDCI (138 mg,10 721 μmol) and HOBt (97.4 mg, 721 μmol). The mixture was stirred at 25 °C for 2 h. The mixture wasfiltered and concentrated under reduced pressure to give a residue. The residue was purified by flash silicagel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent: 0~40% EtOAc / PE gradient@ 80 mL / min). Intermediate I-8-1 (140 mg, 63% yield, 90% purity) was obtained as a colorless oil.

[0302] Synthesis of 2-(5-(1-ethoxyvinyl)thiophen-2-yl)propanamide (I-8-2) To a solution of I-8-115 (10.5 g, 4.5 mmol) in dioxane (100 mL) was added tributyl(1-ethoxyvinyl)stannane (31.7 g, 84.1 mmol), TEA (12.8 g, 127.6 mmol) and Pd(PPh3)2Cl2 (1.5 g, 2.1 mmol) under N2. The mixture was stirred at 80 °C for 16 h. The reaction mixture was quenched with saturated KF solution (50 mL) and was extracted with EtOAc (50 mL × 3). The combined organic layers were dried over Na2SO4, filtered and concentrated togive intermediate I-8-2 (22.0 g, crude) as a black oil.20

[0303] Synthesis of 2-(5-(2-bromoacetyl)thiophen-2-yl)propanamide (I-8) To a solution of I-8-2 (3.29g, 14.59 mmol) in THF (110 mL) and H2O (40 mL) was added NBS (2.6 g, 14.6 mmol). The mixture was stirred at 0 °C for 2 h. The reaction mixture was quenched with H2O (100 mL), extracted with EtOAc (150mL). The combined organic layers were dried over Na2SO4, filtered and concentrated to give a residue. Theresidue was purified by flash silica gel chromatography (ISCO®; 40 SepaFlash® Silica Flash Column,25 Eluent: 0~40 % EtOAc / PE gradient @ 80 mL / min) to give compound I-8 (5.3 g, crude) as a yellow oil.

[0304] Synthesis of methyl 2-(5-(2-bromoacetyl)thiophen-2-yl)acetate (I-9): AUG-P3833PCT

[305] Synthesis of 2-(5-bromothiophen-2-yl)-N-(2-chloroethyl)-2-hydroxypropanamide (I-9-1) Toa solution of 2-(5-bromothiophen-2-yl)-2-hydroxypropanoic acid (0.5 g, 1.99 mmol) in DMF (50 mL) was added 2-chloroethan-1-amine (346 mg, 2.99 mmol). HATU (1.14 g, 2.99 mmol), DIEA (772.1 mg, 5.97 mmol). The mixture was stirred at 25 °C for 12 h. The reaction mixture was partitioned between EtOAc5 (60 mL) and H2O (60 mL). The organic phase was separated, washed with brine 80 mL (40 mL × 2), driedover MgSO4, filtered and concentrated under reduced pressure to give a residue. The residue was purifiedby flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent: 0~40%EtOAc / PE gradient @ 80 mL / min). Intermediate I-9-1 (460 mg, 73.9% yield) was obtained as a white oil.

[0306] Synthesis of 2-(5-bromothiophen-2-yl)-2-methylmorpholin-3-one (I-9-2) To a solution of I-9-10 1 (81.3 mg, 0.26 mmol) in DMF (10 mL) was added t-BuOK (29.2 mg, 0.26 mmol) under N2. The mixturewas stirred at 25 °C for 1 h. The reaction mixture was extracted with EtOAc (5 mL × 3). The combinedorganic layers were dried over Na2SO4, filtered and concentrated to give intermediate I-9-2 (32 mg, 0.16mmol, 44.5 % yield) as a yellow oil.

[307] Synthesis of 2-(5-(1-ethoxyvinyl)thiophen-2-yl)-2-methylmorpholin-3-one (I-9-3) To a15 solution of I-9-2 (2 g, 7.24 mmol) in dioxane (100 mL) was added tributyl(1-ethoxyvinyl)stannane (5.23 g,14.48 mmol, 4.89 mL), TEA (2.20 g, 21.73 mmol, 3.02 mL) and Pd(PPh3)2Cl2(508.34 mg, 724.24 μmol) under N2. The mixture was stirred at 80 °C for 16 h. The reaction mixture was quenched with saturated KFsolution (50 mL), extracted with EtOAc (50 mL × 3). The combined organic layers are dried over Na2SO4,filtered and concentrated to give intermediate I-9-3 (6.0 g, crude) as a black oil.20

[0308] Synthesis of 2-(5-(2-bromoacetyl)thiophen-2-yl)-2-methylmorpholin-3-one (I-9) To a solutionof I-9-3 (1 g, 3.95 mmol) in THF (10 mL) and H2O (4 mL) was added NBS (702.61 mg, 3.95 mmol). Themixture was stirred at 0 °C for 2 h. The reaction mixture was quenched with H2O (10 mL), extracted withEtOAc (15 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated to give aresidue. The residue was purified by flash silica gel chromatography (ISCO®; 40 SepaFlash® Silica Flash25 Column, Eluent: 0~40 % EtOAc / PE gradient @ 80 mL / min) to give compound I-9 (1.4 g, crude) as a yellowoil.

[309] 2-(5-(2-bromoacetyl)thiophen-2-yl)-2,4-dimethylmorpholin-3-one (I-10):

[310] Synthesis of 2-(5-bromothiophen-2-yl)-N-(2-chloroethyl)-2-hydroxy-N-methylpropanamide30 (I-10-1) To a solution of 2-(5-bromothiophen-2-yl)-2-hydroxypropanoic acid (2.5 g, 9.96 mmol) in DMF AUG-P3833PCT (50 mL) was added 2-chloro-N-methylethan-1-amine (1.94 g, 14.93 mmol). HATU (5.68 g, 14.93 mmol), DIEA (3.86 g, 29.87 mmol, 5.20 mL). The mixture was stirred at 25 °C for 12 h. LC-MS showed the startingmaterial was consumed completely and one main peak was detected. The reaction mixture was partitioned between EtOAc (60 mL) and H2O (60 mL). The organic phase was separated, washed with brine 80 mL5 (40 mL × 2), dried over MgSO4, filtered and concentrated under reduced pressure to give a residue. Theresidue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent: 0~40% EtOAc / PE gradient @ 80 mL / min). Intermediate I-10-1 (1.5 g, 4.59 mmol, 46.12% yield)was obtained as a yellow oil.

[311] Synthesis of 2-(5-bromothiophen-2-yl)-2,4-dimethylmorpholin-3-one (I-10-2) To a solution of10 I-10-1 (0.1 g, 306.15 μmol) in DMF (10 mL) was added t-BuOK (68.71 mg, 612.30 μmol). The mixturewas stirred at 25 °C for 1 h. The reaction mixture was extracted with EtOAc (5 mL × 3). The combinedorganic layers are dried over Na2SO4, filtered and concentrated to give intermediate I-10-2 (36 mg, 0.21mmol, 46.5 % yield) as a yellow oil.

[312] Synthesis of 2-(5-(1-ethoxyvinyl)thiophen-2-yl)-2,4-dimethylmorpholin-3-one (I-10-3) To a15 solution of I-10-2 (400 mg, 1.38 mmol) in dioxane (10 mL) was added tributyl(1-ethoxyvinyl)stannane(995.67 mg, 2.76 mmol, 931.40 μL), TEA (418.46 mg, 4.14 mmol) and Pd(PPh3)2Cl2(96.75 mg, 137.85 μmol,) under N2. The mixture was stirred at 80 °C for 16 h. The reaction mixture was quenched withsaturated KF solution (50 mL), extracted with EtOAc (50 mL × 3). The combined organic layers were driedover Na2SO4, filtered and concentrated to give intermediate I-10-3 (2.3 g, crude) as a black oil.20

[0313] Synthesis of 2-(5-(2-bromoacetyl)thiophen-2-yl)-2,4-dimethylmorpholin-3-one (I-10) To asolution of I-10-3 (1.00 g, 3.55 mmol) in THF (10 mL) and H2O (4 mL) was added NBS (632.55 mg, 3.55mmol). The mixture was stirred at 0 °C for 2 h. The reaction mixture was quenched with H2O (10 mL),extracted with EtOAc (15 mL). The combined organic layers were dried over Na2SO4, filtered andconcentrated to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 4025 SepaFlash® Silica Flash Column, Eluent: 0~40 % EtOAc / PE gradient @ 80 mL / min) to give compound I-10 (1.6 g, crude) as a yellow oil.

[0314] 2-(5-(2-bromoacetyl)thiophen-2-yl)-4-cyclopropyl-2-methylmorpholin-3-one (I-11):

[315] Synthesis of 2-(5-bromothiophen-2-yl)-N-(2-chloroethyl)-N-cyclopropyl-2-30 hydroxypropanamide (I-11-1) To a solution of 2-(5-bromothiophen-2-yl)-2-hydroxypropanoic acid (3 g, AUG-P3833PCT 11.95 mmol) in DMF (50 mL) was added N-(2-chloroethyl)cyclopropanamine (1.71 g, 14.34 mmol),HATU (6.81 g, 17.92 mmol), DIEA (4.63 g, 35.84 mmol, 6.24 mL). The mixture was stirred at 25 °C for12 h. The reaction mixture was partitioned between EtOAc (60 mL) and H2O (60 mL). The organic phasewas separated, washed with brine 80 mL (40 mL × 2), dried over MgSO4, filtered and concentrated under 5reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®;12 g SepaFlash® Silica Flash Column, Eluent: 0~40% EtOAc / PE gradient @ 80 mL / min). Intermediate I-11-1 (0.5 g, 1.42 mmol, 11.87% yield) was obtained as a yellow oil.

[0316] Synthesis of 2-(5-bromothiophen-2-yl)-4-cyclopropyl-2-methylmorpholin-3-one (I-11-2) Toa solution of I-11-1 (0.45 g, 1.28 mmol) in DMF (10 mL) was added t-BuOK (286.36 mg, 2.55 mmol)10 under N2. The mixture was stirred at 25 °C for 1 h. The reaction mixture was extracted with EtOAc (5 mL× 3). The combined organic layers are dried over Na2SO4, filtered and concentrated to give compound I-11-2 (0.2 g, 632.48 μmol, 49.57% yield) as a yellow oil.

[0317] Synthesis of 4-cyclopropyl-2-(5-(1-ethoxyvinyl)thiophen-2-yl)-2-methylmorpholin-3-one (I-11-3) To a solution of I-11-2 (0.2 g, 632.48 μmol) in dioxane (10 mL) was added tributyl(1-15 ethoxyvinyl)stannane (456.84 mg, 1.26 mmol, 427.35 μL), TEA (192.00 mg, 1.90 mmol) and Pd(PPh3)2Cl2(44.39 mg, 63.25 μmol) under N2. The mixture was stirred at 80 °C for 16 h. The reaction mixture wasquenched with a saturated KF solution (50 mL), extracted with EtOAc (50 mL × 3). The combined organiclayers are dried over Na2SO4, filtered and concentrated to give intermediate I-11-3 (1.1 g, crude) as a blackoil.20

[0318] Synthesis of 2-(5-(2-bromoacetyl)thiophen-2-yl)-4-cyclopropyl-2-methylmorpholin-3-one (I-11) To a solution of I-11-3 (1.21 g, 3.95 mmol) in THF (10 mL) and H2O (4 mL) was added NBS (702.60mg, 3.95 mmol). The mixture was stirred at 0 °C for 2 h. The reaction mixture was quenched with H2O(100 mL), extracted with EtOAc (150 mL). The combined organic layers are dried over Na2SO4, filteredand concentrated to give a residue. The residue was purified by flash silica gel chromatography (ISCO®;25 40 SepaFlash® Silica Flash Column, Eluent: 0~40 % EtOAc / PE gradient @ 80 mL / min) to give compoundI-11 (1.6 g, crude) as a yellow oil.

[0319] Synthesis of ethyl 2-[5-(2-bromoacetyl)-2-thienyl]-2-cyclopropyl-2-hydroxy-acetate (I-12):

[320] Synthesis of ethyl 2-cyclopropyl-2-hydroxy-2-(2-thienyl) acetate (I-12-1) A mixture of ethyl30 2-oxo-2-(2-thienyl)acetate (5.00 g, 27.1 mmol, 1.00 eq) in THF (50 mL) was degassed and purged with N2 AUG-P3833PCT for 3 times and cooled to -60 °C, and then bromo(cyclopropyl)magnesium (0.5 M, 59.7 mL, 1.10 eq) was added, the mixture was stirred at -60 °C for 3 h under N2 atmosphere. The reaction mixture was quenchedwith a saturated ammonium chloride solution (100 mL) at 0 °C, and then diluted with H2O (100 mL) andextracted with EtOAc (300 mL), dried over MgSO4, filtered and concentrated under reduced pressure to 5give crude product I-12-1 (6.50 g, crude) as black oil was used into the next step without furtherpurification.

[321] Synthesis of ethyl 2-(5-bromo-2-thienyl)-2-cyclopropyl-2-hydroxy-acetate (I-12-2) To asolution of I-12-1 (5.50 g, 24.3 mmol, 1 eq) in DMF (30 mL) was added NBS (6.49 g, 36.5 mmol, 1.5 eq)at 0 °C and then mixture was stirred at 0 °C for 1 h. The mixture was clear. The mixture was diluted with10 H2O (100 mL), and then extracted with EtOAc (300 mL). The organic phase was combined andconcentrated in vacuum to give the residue. The residue was purified by flash silica gel chromatography(ISCO®; 80 g SepaFlash® Silica Flash Column, Eluent: 0~50% EtOAc / PE gradient) to give product I-12-2 (3.50 g, 11.47 mmol, 47.19% yield) as brown oil.

[0322] Synthesis of ethyl 2-cyclopropyl-2-[5-(1-ethoxyvinyl)-2-thienyl]-2-hydroxy-acetate (I-12-3)15 A mixture of tributyl(1-ethoxyvinyl)stannane (8.28 g, 22.9 mmol, 7.75 mL, 2 eq), I-12-2 (3.50 g, 11.5mmol, 1 eq), TEA (3.48 g, 34.4 mmol, 4.79 mL, 3 eq) and Pd(PPh3)2Cl2(805 mg, 1.15 mmol, 0.1 eq) in dioxane (40 mL) was degassed and purged with N2for 3 times, and then the mixture was stirred at 80 °C for 3 h under N2 atmosphere. The reaction mixture was quenched by adding a saturated aq. CsF solution(50 mL), and extracted with EtOAc (200 mL). The organic layer was washed with brine (100 mL), dried20 over Na2SO4, filtered and concentrated under reduced pressure to give the crude product I-12-3 (5 g, crude) as black oil was used into the next step without further purification.

[323] Synthesis of ethyl 2-[5-(2-bromoacetyl)-2-thienyl]-2-cyclopropyl-2-hydroxy-acetate (I-12) Toa solution of I-12-3 (2.50 g, 8.44 mmol, 1 eq) in THF (30 mL) and H2O (15 mL) was added NBS (1.50 g,8.44 mmol, 1 eq) at 0 °C. The mixture was stirred at 25 °C for 1 h. The mixture was diluted with H2O (10025 mL), extracted with EtOAc (300 mL). The organic phase was concentrated in vacuum to give the residue.The residue was purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash® Silica Flash Column, Eluent: 0~50%EtOAc / PE gradient) to give the I-12 (0.5 g, 1.44 mmol, 17.07% yield) as a brownoil.

[324] Synthesis of ethyl 2-[5-(2-bromoacetyl)-2-thienyl]-2-(4-fluorophenyl)-2-hydroxy-acetate (I-30 13): AUG-P3833PCT

[325] Synthesis of ethyl 2-(4-fluorophenyl)-2-hydroxy-2-(thiophen-2-yl)acetate (I-13-1): A mixtureof ethyl 2-oxo-2-(2-thienyl)acetate (5 g, 27.1 mmol, 1 eq) in THF (50 mL) was degassed and purged with N2for 3 times and cooled to -65 °C, and then bromo-(4-fluorophenyl)magnesium (2 M, 14.9 mL, 1.1 eq) 5was added and the mixture was stirred at -60 °C for 2 h under N2 atmosphere. The mixture was quenchedwith NH4Cl aq. (100 mL), then extracted with EtOAc (300 mL). The organic phases were combined andconcentrated in vacuum to give the crude product I-13-1 (6 g, crude) as orange oil and used into the nextstep without further purification.

[326] Synthesis of ethyl 2-(5-bromo-2-thienyl)-2-(4-fluorophenyl)-2-hydroxy-acetate (I-13-2): To a10 solution of I-13-1 (1 g, 3.57 mmol, 1 eq) in DMF (10 mL) was added NBS (952 mg, 5.35 mmol, 1.5 eq) at0 °C and stirred at 25 °C for 3 h. The mixture was diluted with H2O (20 mL), and then extracted with EtOAc(150 mL), the organic phase was combined and concentrated in vacuum to give the residue. The residuewas purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent: 0~50% EtOAc / PE gradient) to give the intermediate I-13-2 (1 g, 2.78 mmol, 78.0% yield) as a yellow oil.15

[0327] Synthesis of ethyl 2-[5-(1-ethoxyvinyl)-2-thienyl]-2-(4-fluorophenyl)-2-hydroxy-acetate (I-13-3): A mixture of tributyl(1-ethoxyvinyl)stannane (2.01 g, 5.57 mmol, 1.88 mL, 2 eq), I-13-2 (1 g, 2.78mmol, 1 eq), TEA (845 mg, 8.35 mmol, 1.16 mL, 3 eq) and Pd(PPh3)2Cl2 (195 mg, 278 μmol, 0.1 eq) in dioxane (15 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 85 °C for 3 h under N2 atmosphere. The reaction mixture was quenched by CsF saturated aq. solution addition 5020 mL and extracted with EtOAc (150 mL). The combined organic layers were washed with brine 80 mL,dried over Na2SO4, filtered and concentrated under reduced pressure to give the crude product I-13-3 (3 g,crude) as black oil and used into the next step without further purification.

[0328] Synthesis of ethyl 2-[5-(2-bromoacetyl)-2-thienyl]-2-(4-fluorophenyl)-2-hydroxy-acetate (I-13): To a solution of I-13-3 (2.5 g, 7.13 mmol, 1 eq) in THF (6 mL) and H2O (3 mL) was added NBS (1.2725 g, 7.13 mmol, 1 eq). The mixture was stirred at 0 °C for 3 h. The mixture was suspension. The mixture wasdiluted with H2O (20 mL), and then extracted with EtOAc (150 mL), the organic phase was combined and concentrated in vacuum to give the residue. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent: 0~70% EtOAc / PE gradient) give the compoundI-13 (0.48 g, 1.20 mmol, 16.8% yield) was obtained as a yellow oil. AUG-P3833PCT

[329] Synthesis of (S)-2-(5-(2-bromoacetyl)thiophen-2-yl)-N-cyclopropyl-2-hydroxypropanamide(I-14):

[330] Synthesis of ethyl 2-hydroxy-2-(thiophen-2-yl)propanoate (I-14-1) To a solution of ethyl 2-5 oxo-2-(2-thienyl)acetate (50 g, 271 mmol) in THF (500 mL) was added MeMgBr (3 M, 109 mL) at -78 °C under N2 atmosphere. The mixture was stirred at -78 °C for 3 h. The reaction mixture was quenched byaddition of saturated aq. ammonium chloride solution (1000 mL) at 0 °C, and then diluted with H2O (1000mL) and extracted with EtOAc (1500 mL × 3), dried over MgSO4, filtered and concentrated under reducedpressure to give I-14-1 (60 g, crude) which was obtained as a yellow oil.10

[0331] Synthesis of ethyl 2-(5-bromothiophen-2-yl)-2-hydroxypropanoate (I-14-2) To a solution of I-14-1 (54.4 g, 271 mmol) in DMF (500 mL) was added NBS (72.5 g, 407 mmol). The mixture was stirredat 25 °C for 6 h. The reaction mixture was partitioned between EtOAc (800 mL) and H2O (600 mL). Theorganic phase was separated, washed with brine (400 mL × 2), dried over MgSO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography15 (ISCO®; 330 g SepaFlash® Silica Flash Column, Eluent: 0~4% EtOAc / PE gradient @ 80 mL / min).Intermediate I-14-2 (67 g, 88.4% yield) was obtained as a red oil.

[0332] Synthesis of 2-(5-bromothiophen-2-yl)-2-hydroxypropanoic acid (I-14-3) To a solution of I-14-2 (40 g, 143 mmol) in THF (200 mL) and EtOH (200 mL) at 0 °C. and then KOH (16.1 g, 287 mmol)in H2O (200 mL) was added dropwise at 0 °C. The resulting mixture was stirred at 0 °C for 1 h. The reaction20 mixture was concentrated under reduced pressure to remove the organic solvent. The combined water layers were washed with DCM (300 mL), The reaction mixture was poured into 1 N HCl solution (pH <7), Thereaction mixture was partitioned between DCM (600 mL) and H2O (500 mL). The organic phase wasseparated, washed with brine (300 mL × 2), dried over MgSO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 220 g25 SepaFlash® Silica Flash Column, Eluent: 0~50% THF / PE gradient @ 90 mL / min) to give intermediate I-14-3 (35 g, 97.3% yield) as a brown solid.

[0333] Synthesis of (S)-2-(5-bromothiophen-2-yl)-2-hydroxypropanoic acid (I-14-4) To a solution ofI-14-3 (21 g, 83.6 mmol) and (2R)-2-amino-2-phenyl-ethanol (9.18 g, 66.9 mmol) in IPA (105 mL) andisopropyl acetate (210 mL). The mixture was stirred at 80 °C for 1 h. then the mixture was cooled to 25 °C30 stirred for 15 h. The reaction liquid was filtered directly and the solids were collected. the solid was AUG-P3833PCT partitioned between DCM (500 mL) and 1 M HCl (100 mL). The organic phase was separated, dried overMgSO4, filtered and concentrated under reduced pressure to give intermediate I-14-4 (4.7 g, 22.4% yield)as a white solid.

[334] Absolute configuration determination of (S)-2-(5-bromothiophen-2-yl)-2-hydroxypropanoic5 acid (I-14-4): Intermediate I-14-4 (20 mg) was dissolved in 0.8 mL acetone using gentle heating. Themixture was then left to stand at room temperature until crystals formed, which were filtered and dried. One colorless crystal with dimensions 0.30 × 0.10 × 0.10 mm3 was used to determine the absolute configurationvia X-ray diffraction. The absolute configuration was determined to be (S). Description of Equipment and Data Collection 10 Summary of X-ray Crystallographic Data AUG-P3833PCT Determined configuration:

[335] Synthesis of (S)-2-(5-bromothiophen-2-yl)-N-cyclopropyl-2-hydroxypropanamide (I-14-5)To a solution of I-14-4 (4.7 g, 18.7 mmol) in THF (50 mL) was added dropwise ethyl (2E)-2-cyano-2-5 hydroxyimino-acetate (3.99 g, 28.1 mmol) and DIC (3.54 g, 28.1 mmol) at 0 °C. After addition, the mixture was stirred at this temperature for 0.5 h, and then cyclopropanamine (2.14 g, 37.4 mmol) was added dropwise at 0 °C. The resulting mixture was stirred at 0 °C for 0.5 h. The reaction mixture was partitionedbetween EtOAc (100 mL) and saturated NaHCO3 (100 mL). The organic phase was separated, washed with AUG-P3833PCT brine (150 mL × 2), dried over MgSO4, filtered and concentrated under reduced pressure to give compound I-14-5 (5 g, 92.1% yield) as a white solid.

[0336] Synthesis of (S)-N-cyclopropyl-2-(5-(1-ethoxyvinyl)thiophen-2-yl)-2-hydroxypropanamide(I-14-6) A mixture of I-14-5 (5 g, 17.2 mmol), tributyl(1-ethoxyvinyl)stannane (15.6 g, 43.1 mmol), TEA5 (5.23 g, 51.7 mmol) and Pd(PPh3)2Cl2 (605 mg, 862 μmol) in dioxane (50 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 90 °C for 6 h under N2 atmosphere. The reactionmixture was quenched by addition saturated KF aqueous solution (100 mL) at 25 °C, and then diluted withH2O (300 mL) and extracted with EtOAc (100 mL × 2). dried over MgSO4, filtered and concentrated underreduced pressure to give Compound I-14-6 (10 g, crude) as a black oil.10

[0337] Synthesis of (S)-2-(5-(2-bromoacetyl)thiophen-2-yl)-N-cyclopropyl-2-hydroxypropanamide(I-14) To a solution of I-14-6 (7.7 g, 27.4 mmol) in THF (70 mL) and H2O (40 mL) was added NBS (9.74g, 54.7 mmol). The mixture was stirred at 0 °C for 1 h. The reaction mixture was partitioned between EtOAc(100 mL) and H2O (100 mL). The organic phase was separated, washed with brine (100 mL × 2), driedover MgSO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified15 by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent: 0~40% THF / PEgradient @ 60 mL / min) to give compound I-14 (5.4 g, 59.4% yield) as a yellow oil.

[0338] Synthesis of ethyl 2-[5-(2-bromoacetyl)-2-thienyl]-3,3,3-trifluoro-2-hydroxy-propanoate (I-15): 20

[0339] Synthesis of ethyl 2-(5-bromo-2-thienyl)-3,3,3-trifluoro-2-trimethylsilyloxy-propanoate (I-15-1) To a solution of ethyl 3,3,3-trifluoro-2-(2-thienyl)-2-trimethylsilyloxy-propanoate (3 g, 9.19 mmol, 1eq) in DMF (30 mL) was added NBS (3.60 g, 20.2 mmol, 2.2 eq). The mixture was stirred at 80 °C for 3h. The mixture was suspension. The mixture was diluted with H2O (50 mL), and then extracted with EtOAc(100 mL), the organic phase was combined and concentrated in vacuum to give the residue. The residue25 was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent: 0~20% EtOAc / PE gradient) to give the I-15-1 (2 g, 4.93 mmol, 53.7% yield) as a colorless oil.

[0340] Synthesis of ethyl 2-[5-(1-ethoxyvinyl)-2-thienyl]-3,3,3-trifluoro-2-hydroxy-propanoate (I-15-2) A mixture of tributyl(1-ethoxyvinyl)stannane (4.34 g, 12.0 mmol, 4.06 mL, 2 eq), I-15-1 (2 g, 6.00mmol, 1 eq), TEA (1.82 g, 18.0 mmol, 2.51 mL, 3 eq) and PdCl2(PPh3)2 (421 mg, 601 μmol, 0.1 eq) in30dioxane (20 mL) was degassed and purged with N2for 3 times, and then the mixture was stirred at 80 °C AUG-P3833PCT for 16 h under N2 atmosphere. The reaction mixture was quenched by CsF saturated aq. solution addition(100 mL) and extracted with EtOAc (150 mL). The combined organic layers were washed with brine (80mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give the crude product I-15-2 (5.9 g, crude) as black oil and used into the next step without further purification.5

[0341] Synthesis of ethyl 2-[5-(2-bromoacetyl)-2-thienyl]-3,3,3-trifluoro-2-hydroxy-propanoate (I-15) To a solution of I-15-2 (5.90 g, 18.2 mmol, 1 eq) in THF (30 mL) and H2O (15 mL) was added NBS(3.89 g, 21.8 mmol, 1.2 eq). The mixture was stirred at 0 °C for 3 h and diluted with H2O (50 mL), and thenextracted with (100 mL) EtOAc. The organic phases were combined and concentrated in vacuum to give aresidue. The residue was purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash® Silica Flash10 Column, Eluent: 0~30% EtOAc / PE gradient) give the compound I-15 (0.9 g, 2.40 mmol, 13.19% yield) asa yellow solid.

[342] Synthesis of 1-[5-(2-bromoacetyl)-2-thienyl]-N-methyl-cyclopropanecarboxamide (I-16):

[343] Synthesis of N-methyl-1-(2-thienyl)cyclopropanecarboxamide (I-16-1) To a solution of15 methanamine (361 mg, 5.35 mmol, 3 eq, HCl) and 1-(2-thienyl)cyclopropanecarboxylic acid (0.3 g, 1.78 mmol, 1 eq) in THF (10 mL) was added HATU (1.70 g, 4.46 mmol, 2.5 eq) and TEA (722 mg, 7.13 mmol, 993 μL, 4 eq). The mixture was stirred at 25 °C for 1 h. The mixture was diluted with H2O (30 mL),extracted with EtOAc (50 mL). The organic phase was combined and concentrated in vacuum to give theresidue. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash20 Column, Eluent: 0~50% EtOAc / PE gradient) give intermediate I-16-1 (0.33 g, 1.73 mmol, 97.0% yield,95% purity) was obtained as a white solid.

[344] Synthesis of 1-(5-bromo-2-thienyl)-N-methyl-cyclopropanecarboxamide (I-16-2) To asolution of I-16-1 (0.32 g, 1.77 mmol, 1 eq) in DMF (5 mL) was added NBS (471 mg, 2.65 mmol, 1.5 eq)at 0 °C. The mixture was stirred at 0 °C for 1 h. The mixture was clear. The mixture was diluted with H2O25 (30 mL), and then extracted with EtOAc (50 mL), the organic phase was combined and concentrated in vacuum to give the residue. The residue was purified by flash silica gel chromatography (ISCO®; 20 gSepaFlash® Silica Flash Column, Eluent: 0~50% EtOAc / PE gradient) to give intermediate I-16-2 (0.4 g,1.54 mmol, 87.1% yield) was obtained as a white solid.

[345] Synthesis of 1-[5-(1-ethoxyvinyl)-2-thienyl]-N-methyl-cyclopropanecarboxamide (I-16-3): A30 mixture of I-16-2 (0.4 g, 1.54 mmol, 1 eq), tributyl(1-ethoxyvinyl)stannane (1.11 g, 3.08 mmol, 1.04 mL, AUG-P3833PCT 2 eq), TEA (467 mg, 4.61 mmol, 642 μL, 3 eq) and PdCl2(PPh3)2 (108 mg, 154 μmol, 0.1 eq) in dioxane (10 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 80 °C for 16 h under N2 atmosphere. The reaction mixture was quenched by CsF saturated aq. solution addition (50 mL)and extracted with EtOAc (50 mL). The combined organic layers were washed with brine (30 mL), dried5 over Na2SO4, filtered and concentrated under reduced pressure to give a residue to give the crude product I-16-3 (1.7 g, crude) as black oil and used into the next step without further purification.

[0346] Synthesis of 1-[5-(2-bromoacetyl)-2-thienyl]-N-methyl-cyclopropane-carboxamide (I-16) Toa solution of I-16-3 (1.7 g, 6.76 mmol, 1 eq) in THF (10 mL) and H2O (5 mL) was added NBS (1.44 g, 8.12mmol, 1.2 eq) at 0 °C. The mixture was stirred at 0 °C for 2 h. The mixture was diluted with H2O (30 mL),10 and then extracted with EtOAc (30 mL), the organic phase was combined and concentrated in vacuum to give the residue. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash®Silica Flash Column, Eluent: 0~70% EtOAc / PE gradient) to give compound I-16 (0.24 g, 794 μmol, 11.7%yield) as an orange solid.

[347] Synthesis of 2-(5-(2-bromoacetyl)thiophen-2-yl)-N-(tert-butyl)acetamide (I-17):15

[348] Synthesis of N-(tert-butyl)-2-(thiophen-2-yl)acetamide (I-17-1) To a solution of 2-(thiophen-2-yl)acetic acid (4.0 g, 28.1 mmol) in DMF (30 mL) was added DIPEA (8.0 g, 61.8 mmol) followed by EDCI.HCl (8.0 g, 42.2 mmol) and HOBt (5.7 g, 42.2 mmol) at 0 °C. Tert-butyl amine (3.0 g, 42.2 mmol) was added to the reaction mixture at 0 °C and the reaction mixture was stirred at rt for 16 h. The reaction20 mixture was concentrated to get crude compound. The crude residue was purified by column chromatography using a silica gel (60:120 mesh) to afford I-17-1 (2.5 g, 47.2% yield) as a yellow gummyliquid.

[349] Synthesis of 2-(5-bromothiophen-2-yl)-N-(tert-butyl)acetamide (I-17-2) To a solution of I-17-1 (2.0 g, 10.137 mmol) in acetonitrile (20 mL) was added NBS (1.8 g, 10.137 mmol) at 0 °C and the mixture25 was stirred for 2 h at rt. The reaction mixture was concentrated, diluted with water (50 mL) and extracted with EtOAc (2 x 100 mL). The organic layer was separated, dried over Na2SO4, concentrated under reducedpressure. The residue was purified by Combi flash reverse phase to afford I-17-2 (1.3 g, 48% yield) as ayellow gummy liquid.

[350] Synthesis of 2-(5-acetylthiophen-2-yl)-N-(tert-butyl)acetamide (I-17-3) To a stirred solution of30 I-17-2 (1.0 g, 3.64 mmol) in toluene (10 mL) purged with N2 and tributyl(1-ethoxyvinyl)stannane (1.58 g, AUG-P3833PCT 4.30 mmol) was added followed by Pd(PPh3)4 (0.4 g, 0.361 mmol). The mixture was stirred at 110 °C for 16 h. Saturated KF solution was added to the reaction mixture and the mixture was stirred for 30 min atRT. The organic layer was separated and concentrated under reduced pressure. THF was added to the crude compound followed by conc. HCl and stirred for 30 min. Solid Na2CO3 was added to the mixture until pH 5~7. The reaction mixture diluted with water (50 mL) extracted with DCM (2 × 50 mL). The organic layerwas separated, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified bycolumn chromatography using a silica gel (60:120 mesh) to afford I-17-3 (0.6 g, 69 % yield) as a whitesolid.

[351] Synthesis of 2-(5-(2-bromoacetyl)thiophen-2-yl)-N-(tert-butyl)acetamide (I-17) To a solution10 of I-17-3 (0.6 g, 2.510 mmol) in dry THF (10 mL) was added tetrabutylammonium tribromide (1.2 g, 2.510mmol) and the mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated toget crude compound. The crude was purified by Combi flash reverse phase to afford I-17 (0.15 g, 20%yield) as a white solid.

[352] The compounds I-25 and I-43 have been prepared using the experimental conditions described for15 I-14. Table 4 Table 5

[353] Synthesis of rac-(2R,3R)-2-(5-(2-bromoacetyl)thiophen-2-yl)-N-methyltetrahydrofuran-3-20 carboxamide (I-23): AUG-P3833PCT

[354] Synthesis of rac-tert-butyl (2R,3R)-2-(thiophen-2-yl)tetrahydrofuran-3-carboxylate (I-23-1)To a solution of tert-butyl 4-bromobutanoate (30 g, 134 mmol), thiophene-2-carbaldehyde (22.6 g, 201 mmol, 18.8 mL) in THF (540 mL) was cooled to -78°C under N2. A solution of t-BuOK (1 M, 268.93 mL) was added slowly with stirring at 0°C for 3 hrs. The mixture was quenched with saturated NH4Cl (1500 5 mL), extracted with EtOAc (500 mL*3). The combined organic layer was washed with brine (300 mL), dried over MgSO4, filtered, and concentrated to give crude product. The residue was purified by flash silica gel chromatography (ISCO®; 120 g SepaFlash® Silica Flash Column, Eluent of 0~30% Ethyl acetate / Commercial hexanes gradient @ 100 mL / min). Compound I-23-1 (0.65 g, 2.33 mmol, 1.73% yield,91% purity) was obtained as a colorless oil.10

[0355] Synthesis of rac-(2R,3R)-2-(thiophen-2-yl)tetrahydrofuran-3-carboxylic acid (I-23-2)To a solution of compound I-23-1 (0.65 g, 2.56 mmol) in DCM (2 mL) was added TFA (2.27 g, 19.88mmol, 1.48 mL), and the mixture was stirred at 25°C for 16 hrs. The mixture was concentrated to give crude product. Compound I-23-2 (1.19 g, crude) was obtained as a red oil which was used for next stepdirectly.15

[0356] Synthesis of rac-(2R,3R)-N-methyl-2-(thiophen-2-yl)tetrahydrofuran-3-carboxamide (I-23-3) To a solution of compound I-23-2 (690 mg, 3.48 mmol), HATU (2.65 g, 6.96 mmol) in THF (7 mL) wasadded methanamine (2 M in THF) and DIEA (2.70 g, 20.8 mmol, 3.64 mL) under N2at 0°C, and the mixture was stirred at 25°C for 16 hrs. The mixture was added H2O (5 mL), and the mixture was extracted with 20 EtOAc (5 mL*3). The combined organic layer was washed with brine (5 mL), dried over MgSO4, filtered, and concentrated to give crude product. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0~41% Ethyl acetate / Commercial hexanes gradient @ 100 mL / min). Compound I-23-3 (0.4 g, 1.67 mmol, 47.8% yield, 88% purity) was obtained asa yellow solid.25

[0357] Synthesis of rac-(2R,3R)-2-(5-bromothiophen-2-yl)-N-methyltetrahydrofuran-3-carboxamide (I-23-4)To a solution of compound I-23-3 (2 g, 9.47 mmol) in DMF (30 mL) was added NBS (2.53 g, 14.2 mmol)under 0°C, and the mixture was stirred at 25°C for 2 hrs. The reaction mixture was quenched by addition NaHCO3 aq.200 mL at 25 °C, and then diluted with water 20 mL and extracted with EtOAc 300 mL (150 30 mL * 2). The combined organic layer was dried over MgSO4, filtered and concentrated to give crude product. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0~35% THF / Commercial hexanes gradient @ 100 mL / min). Compound I-23-4 (5 g, crude) was obtained as a yellow oil. AUG-P3833PCT

[358] Synthesis of rac-(2R,3R)-2-(5-(1-ethoxyvinyl)thiophen-2-yl)-N-methyltetrahydrofuran-3-carboxamide (I-23-5)To a solution of compound I-23-4 (5 g, 9.48 mmol) and tributyl(1-ethoxyvinyl)stannane (6.85 g, 18.9mmol, 6.40 mL) in dioxane (50 mL) was added Pd(PPh3)2Cl2 (332 mg, 473 μmol) and TEA (2.88 g, 28.4 5 mmol, 3.96 mL) under N2. The reaction was stirred at 80 °C for 4 hrs. The reaction was quenched with KF solution (100 mL) and diluted with water 200 mL and extracted with EtOAc 500 mL (250 mL * 2). The combined organic layers were washed with brine 100 mL, dried over Na2SO4, filtered and concentrated under reduced pressure to give a crude product. Compound I-23-5 (12.4 g, crude) wasobtained as a yellow oil.10

[0359] Synthesis of rac-(2R,3R)-2-(5-(1-ethoxyvinyl)thiophen-2-yl)-N-methyltetrahydrofuran-3-carboxamide (I-23)To a solution of compound I-23-5 (12.4 g, 11.0 mmol) in THF (80 mL) and H2O (40 mL) was added NBS(3.92 g, 22.0 mmol) at 0 °C and stirred at 25 °C for 2 hrs. The reaction was diluted with water 200 mL and extracted with EtOAc 200 mL (100 mL * 2). The combined organic layers were washed with brine 10015 mL, dried over Na2SO4, filtered, and concentrated under reduced pressure to give a crude product. Theresidue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0~40% THF / Commercial hexanes gradient @ 100 mL / min), then the crude product was triturated with Commercial hexanes / EtOAc=3 / 1 (80 mL) at 25 oC for 3 hrs. Compound I-23 (1 g, 2.77 mmol, 25.1%yield, 92% purity) was obtained as a yellow solid. 20

[360] Synthesis of rac-(2R,4S)-2-(5-(2-bromoacetyl)thiophen-2-yl)-N-methyltetrahydro-2H-pyran-4-carboxamide (I-24):

[361] Synthesis of rac-(2R,4R)-2-(thiophen-2-yl)tetrahydro-2H-pyran-4-ol (I-24-1)25 To a solution of thiophene-2-carbaldehyde (100 g, 892 mmol, 83.3 mL) and H2SO4 (87.5 g, 892 mmol, 47.5 mL) in DCM (1000 mL) was added but-3-en-1-ol (64.3 g, 892 mmol, 76.7 mL) at -78 °C. After addition, the mixture was stirred at 25 °C for 16 hrs. The mixture was a purple suspension. The reaction mixture was quenched by addition ice water 500 mL at 0 °C, the mixture was then basified with NaHCO3 solutionto pH=8 and then extracted with DCM 900 mL (300 mL * 3). The combined organic layers were washed AUG-P3833PCT with brine 500 mL, dried over MgSO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 330 g SepaFlash® Silica Flash Column, Eluent of 0~14% THF / Commercial hexanes gradient @ 100 mL / min). Compound I-24-1 (30 g,163 mmol, 18.3% yield) was obtained as a brown oil. 5

[0362] Synthesis of rac-(2R,4R)-2-(thiophen-2-yl)tetrahydro-2H-pyran-4-yl methanesulfonate (I-24-2) To a solution of I-24-1 (30 g, 163 mmol) in DCM (330 mL) was added TEA (32.9 g, 326 mmol, 45.3 mL)and MsCl (24.8 g, 217 mmol, 16.8 mL) at 0 °C under N2. After addition, the mixture was stirred at 25 °C for 3 hrs. The reaction mixture was quenched by addition water 300 mL, and then extracted with DCM 10 900 mL (300 mL * 3). The combined organic layers were washed with brine 300 mL, dried over MgSO4, filtered and concentrated under reduced pressure to give a residue. The residue was used into the next step without further purification. Compound I-24-2 (42.7 g, 163 mmol, 99.97% yield) was obtained as a yellowoil.

[363] rac-(2R,4S)-2-(thiophen-2-yl)tetrahydro-2H-pyran-4-carbonitrile (I-24-3)15 To a solution of I-24-2 (42.7 g, 163 mmol) in DMSO (500 mL) was added NaCN (46.1 g, 941 mmol) at 25°C. After addition, the mixture was stirred at 80 °C for 16 hrs. The reaction mixture was quenched by addition water 300 mL, and then extracted with EtOAc 900 mL (300 mL * 3). The combined organic layers were washed with brine 500 mL, dried over MgSO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®;330 g SepaFlash®20 Silica Flash Column, Eluent of 0~12% THF / Commercial hexanes gradient @ 100 mL / min). Compound I- 24-3 (10 g, 51.7 mmol, 31.79% yield) was obtained as a light yellow solid.

[0364] Synthesis of rac-(2R,4S)-2-(thiophen-2-yl)tetrahydro-2H-pyran-4-carboxylic acid (I-24-4)To a solution of I-24-3 (10 g, 51.7 mmol) in MeOH (71 mL) and H2O (29 mL) was added NaOH (10.3 g,259 mmol) at 25 °C. After addition, the mixture was stirred at 80 °C for 16 hrs. The reaction mixture was 25 acidified to pH=1 with 4 N HCl and then filtered and concentrated under reduced pressure to give a residue. The residue was used into the next step without further purification. Compound I-24-4 (10.9 g, 51.3 mmol,99.2% yield) was obtained as a brown solid.

[365] Synthesis of rac-(2R,4S)-N-methyl-2-(thiophen-2-yl)tetrahydro-2H-pyran-4-carboxamide(I-24-5)30 To a solution of I-24-4 (10.9 g, 51.3 mmol) in THF (110 mL) was added DIEA (33.2 g, 257 mmol, 44.7mL) and MeNH2 (2 M, 695.18 mL), T4P (74.0 g, 103 mmol, 50% purity) at 25 °C. After addition, the mixture was stirred at 25 °C for 16 hrs. The reaction mixture was quenched by addition water 100 mL, and AUG-P3833PCT then extracted with EtOAc 300 mL (100 mL * 3). The combined organic layers were washed with NaHCO3 solution 300 mL (100 mL*3) and brine 100 mL, dried over MgSO4, filtered and concentrated under reduced pressure to give a residue. The residue was used into the next step without further purification. Compound I-24-5 (10 g, 44.4 mmol, 86.43% yield) was obtained as a brown solid.5

[0366] Synthesis of rac-(2R,4S)-2-(5-bromothiophen-2-yl)-N-methyltetrahydro-2H-pyran-4-carboxamide (I-24-6) To a solution of I-24-5 (3 g, 11.3 mmol) in AcOH (30 mL) was added Br2 (2.71 g, 16.9 mmol, 875 μL)) at0 °C. After addition, the mixture was stirred at 25 °C for 3 hrs. The reaction mixture was quenched by addition NaHCO3100 mL, and then extracted with EtOAc 300 mL (100 mL * 3). The combined organic 10 layers were washed with brine 100 mL, dried over MgSO4, filtered and concentrated under reduced pressure to give a residue. The residue was used into the next step without further purification. Compound I-24-6 (2.6 g, 8.55 mmol, 75.5% yield) was obtained as a brown solid.

[367] Synthesis of rac-(2R,4S)-2-(5-(1-ethoxyvinyl)thiophen-2-yl)-N-methyltetrahydro-2H-pyran-4-carboxamide (I-24-7)15 To a solution of I-24-6 (600 mg, 1.97 mmol), tributyl(1-ethoxyvinyl)stannane (1.32 g, 3.65 mmol, 1.23mL), TEA (598.75 mg, 5.92 mmol, 823.58 μL) and Pd(PPh3)2Cl2(69.22 mg, 98.62 μmol) in dioxane (6 mL) was degassed and purged with N2for 3 times. And then the mixture was stirred at 80 °C for 2 hrs under N2atmosphere. The reaction mixture was quenched by addition water 10 mL at 25 °C, and then diluted with EtOAc 10 mL and extracted with EtOAc 30 mL (10 mL * 3). The combined organic layers were dried20 over Na2SO4, filtered and concentrated under reduced pressure to give compound I-24-7 (582 mg, 1.97mmol, 99.89% yield) as a brown oil.

[368] Synthesis of rac-(2R,4S)-2-(5-(2-bromoacetyl)thiophen-2-yl)-N-methyltetrahydro-2H-pyran-4-carboxamide (I-24) To a solution of I-24-7 (522.00 mg, 1.77 mmol) in THF (5 mL) in H2O (2.5 mL) was added NBS (377.4225 mg, 2.12 mmol) at 0 °C. The mixture was stirred at 0 °C for 0.5 hr. The reaction mixture was diluted with water 10 mL and extracted with EtOAc 30 mL (10 mL * 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~42% THF / Commercial hexanes gradient @ 40 mL / min) to give compound I-24 (433 mg, 1.25 mmol, 70.77%30 yield) as a white solid.

[369] Synthesis of ethyl 2-(5-(2-bromoacetyl)thiazol-2-yl)-2-hydroxypropanoate (I-44): AUG-P3833PCT

[370] Synthesis of ethyl 2-oxo-2-(thiazol-2-yl)acetate (I-44-1) To a solution of trimethyl(thiazol-2-yl)silane (5.00 g, 31.8 mmol, 5.05 mL, 1.00 eq) in DCM (50.0 mL) was added ethyl 2-chloro-2-oxo-acetate (8.68 g, 63.6 mmol, 7.10 mL, 2.00 eq). The mixture was stirred at 25 °C for 1 h. The reaction was diluted5 with water (50 mL), extracted with EtOAc (40 mL × 3). The combined organic layers were washed withbrine (30 mL × 2), dried with MgSO4, filtered and concentrated in vacuum to give a residue. The residuewas purified by column chromatography (SiO2, PE / EtOAc = 100 / 1 to 9 / 1) to give I-44-1 (1.10 g, 5.94mmol, 18.7% yield) as a yellow oil.

[371] Synthesis of ethyl 2-hydroxy-2-(thiazol-2-yl)propanoate (I-44-2) To a solution of I-44-1 (1.1010 g, 5.94 mmol, 1.00 eq) in THF (15.0 mL) was added MeMgBr (3.00 M, 1.98 mL, 1.00 eq) at -40 °C under N2. The mixture was stirred at -40 °C for 0.1 h. The reaction was quenched by aq. NH4Cl (20 mL) at 0 °C and extracted with EtOAc (20 mL × 3). The combined organic layers were dried over anhydrous Na2SO4,filtered and concentrated in vacuum to give compound I-44-2 (1.10 g, 5.47 mmol, 92.0% yield) as a yellowoil.15

[0372] Synthesis of ethyl 2-(5-bromothiazol-2-yl)-2-hydroxypropanoate (I-44-3) To a solution ofcompound I-44-2 (1.10 g, 5.47 mmol, 1.00 eq) in DMF (15.0 mL) was added NBS (1.17 g, 6.56 mmol,1.20 eq). The mixture was stirred at 25 °C for 6 h. The reaction was diluted with water (30 mL), extractedwith EtOAc (30 mL× 3). The combined organic layers were washed with brine (30 mL x 2), dried withMgSO4, filtered and concentrated in vacuo to provide residue. The residue was purified by column20 chromatography (SiO2, PE / EtOAc = 100 / 1 to 4 / 1) to give compound I-44-3 (820 mg, 2.93 mmol, 53.6%yield) as a yellow oil.

[373] Synthesis of ethyl 2-(5-(1-ethoxyvinyl)thiazol-2-yl)-2-hydroxypropanoate (I-44-4) To asolution of compound I-44-3 (820 mg, 2.93 mmol, 1.00 eq) and tributyl(1-ethoxyvinyl)stannane (1.60 g,4.40 mmol, 1.49 mL, 1.50 eq) in dioxane (9.00 mL) was added TEA (888 mg, 8.79 mmol, 1.21 mL, 3.0025 eq) and Pd(PPh3)2Cl2 (206 mg, 293 μmol, 0.100 eq) under N2. The mixture was stirred at 90 °C for 16 h. The reaction was quenched with aq. KF (20 mL) and extracted with EtOAc (30 mL × 2). The combinedorganic layers were dried over Na2SO4, filtered and concentrated to give compound I-44-4 (2.12 g, crude)as a yellow oil.

[374] Synthesis of ethyl 2-(5-(2-bromoacetyl)thiazol-2-yl)-2-hydroxypropanoate (I-44) To a30 solution of compound I-44-4 (2.12 g, 7.81 mmol, 1.00 eq) in THF (21.0 mL) and H2O (10.0 mL) was addedNBS (1.39 g, 7.81 mmol, 1.00 eq) at 0 °C. The mixture was stirred at 0 °C for 1 h. The reaction mixturewas quenched by H2O (20 mL) and was extracted with EtOAc (30 mL × 2). The combined organic layers AUG-P3833PCT were dried over Na2SO4, filtered and concentrated in vacuum to give a residue. The residue was purifiedby column chromatography (SiO2, PE / THF = 50 / 1 to 3 / 1) to give compound I-44 (367 mg, 1.14 mmol) asa yellow oil.

[375] Synthesis of 3-(5-(2-bromoacetyl)thiophen-2-yl)-3-hydroxy-1-(4-methoxybenzyl)pyrrolidin-5 2-one (I-18):

[376] Synthesis of methyl 3-((4-methoxybenzyl)amino)propanoate (I-18-1) To (4-methoxyphenyl)methanamine (25.0 g, 182 mmol, 23.7 mL) in EtOH (250 mL) was added methyl prop-2- enoate (18.1 g, 210 mmol, 18.9 mL) slowly dropwise. The mixture was stirred at 25 °C for 16 h. The10 mixture was quenched with water (300 mL) and extracted with EtOAc (300 mL × 3). The combined organiclayers were dried over Na2SO4, filtered and concentrated to give compound I-18-1 (36.0 g, 161 mmol,88.5% yield) as a yellow solid.

[377] Synthesis of ethyl 1-(4-methoxybenzyl)-4,5-dioxopyrrolidine-3-carboxylate (I-18-2) To asolution of compound I-18-1 (30.6 g, 137 mmol) in THF (300 mL) and EtOH (150 mL) was added diethyl15 oxalate (24.0 g, 164 mmol, 22.4 mL) and EtONa (18.6 g, 274 mmol). The mixture was stirred at 50 °C for16 h. The reaction mixture was concentrated in vacuum to give a residue. To the residue was added water(700 mL), then the pH was adjusted to pH = 1 with 1 N HCl. A solid precipitated which was collected byfiltration and dried under reduced pressure. Compound I-18-2 (31.6 g, 106 mmol, 77.1% yield, 97.4%purity) was obtained as a yellow solid.20

[0378] Synthesis of 1-(4-methoxybenzyl)pyrrolidine-2,3-dione (I-18-3) To a solution of compound I-18-2 (15.0 g, 49.4 mmol) in H2O (300 mL) was added HCl (12.0 M, 30 mL). The mixture was stirred at140 °C for 16 h. The reaction mixture was concentrated in vacuum to give compound I-18-3 (5.41 g, 24.7mmol, 49.9% yield) as a yellow oil.

[379] Synthesis of 3-(5-bromothiophen-2-yl)-3-hydroxy-1-(4-methoxybenzyl)pyrrolidin-2-one (I-25 18-4) To a solution of 2,5-dibromothiophene (4.50 g, 18.6 mmol, 2.10 mL) in THF (45.0 mL) was added n-BuLi (2.50 M, 8.93 mL) at -70 °C under N2. The mixture was stirred at -70 °C for 1 h under N2. Asolution of compound I-18-3 (4.49 g, 20.5 mmol) in THF (50 mL) was added into above mixture at -70 °Cand stirred at -70 °C for 1 h under N2. The mixture was stirred at 25 °C for 16 h. The reaction was quenchedwith aq. NH4Cl (50 mL) at 0 °C and extracted with EtOAc (100 mL × 2). The combined organic layers30 were dried over anhydrous Na2SO4, filtered and concentrated in vacuum to give a residue. The residue was AUG-P3833PCT purified by column chromatography (SiO2, PE / THF = 100 / 1 to 3 / 2) to give compound I-18-4 (470 mg, 771μmol, 4.14% yield, 62.7% purity) as a yellow oil

[380] Synthesis of 3-(5-(1-ethoxyvinyl)thiophen-2-yl)-3-hydroxy-1-(4-methoxybenzyl)pyrrolidin-2-one (I-18-5) To a solution of compound I-18-4 (450 mg, 791 μmol) in dioxane (5 mL) was added5 tributyl(1-ethoxyvinyl)stannane (990 mg, 2.74 mmol, 926 μL), TEA (160 mg, 1.58 mmol, 220 μL) and Pd(PPh3)2Cl2 (55.5 mg, 79.1 μmol) under N2. The mixture was stirred at 90 °C for 16 h under N2. Thereaction was quenched with aq. KF (8 mL) at 0 °C and extracted with EtOAc (10 mL × 2). The combinedorganic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuum to give compoundI-18-5 (1.30 g, crude) as a brown oil.10

[0381] Synthesis of 3-(5-(2-bromoacetyl)thiophen-2-yl)-3-hydroxy-1-(4-methoxybenzyl)pyrrolidin-2-one (I-18) To a solution of compound I-18-5 (1.30 g, 3.48 mmol) in THF (14 mL) and H2O (7 mL) wasadded NBS (372 mg, 2.09 mmol) at 0 °C. The mixture was stirred at 0 °C for 1 h. The reaction wasextracted with EtOAc (20 mL × 2). The combined organic layers were dried over anhydrous Na2SO4,filtered and concentrated in vacuum to give compound I-18 (1.58 g, crude) as a brown oil.15

[0382] Synthesis of ethyl 2-(2-bromoacetamido)thiazole-5-carboxylate (I-19):

[383] Synthesis of ethyl 2-(2-bromoacetamido)thiazole-5-carboxylate (I-19) To a solution of ethyl2-aminothiazole-5-carboxylate (10.0 g, 58.1 mmol) in DCM (100 mL) was added TEA (9.99 g, 98.7 mmol) and 2-bromoacetyl bromide (14.1 g, 69.7 mmol). The mixture was stirred at 0 °C for 1 h. The reaction20 mixture was partitioned between DCM (100 mL) and H2O (200 mL). The organic phase was separated,washed with brine (60 mL × 2), dried over MgSO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 120 g SepaFlash®Silica Flash Column, Eluent: 0~20% EtOAc / PE gradient @ 70 mL / min). Compound I-19 (3.5 g, 11.9mmol, 20.6% yield) was obtained as a white solid.25

[0384] Synthesis of ethyl 2-[2-[(2-chloroacetyl)amino]thiazol-5-yl]-2-hydroxy-propanoate (I-20):

[385] Synthesis of ethyl 2-[2-(tert-butoxycarbonylamino)thiazol-5-yl]acetate (I-20-1) To a solutionof ethyl 2-(2-aminothiazol-5-yl)acetate (10.0 g, 53.7 mmol) in THF (100 mL) was added DIEA (10.4 g, AUG-P3833PCT 80.6 mmol, 14.0 mL) and DMAP (656 mg, 5.37 mmol). Then Boc2O (14.1 g, 64.4 mmol, 14.8 mL) wasadded at 0°C. The mixture was stirred at 25 °C for 2 h. The reaction mixture was concentrated under reducedpressure to give a residue. The residue was purified by flash silica gel chromatography (SiO2, Eluent:0~50% EtOAc / PE gradient). Compound I-20-1 (9.60 g, 33.5 mmol, 62.4 % yield) was obtained as a yellow5 solid.

[386] Synthesis of ethyl 2-[2-(tert-butoxycarbonylamino)thiazol-5-yl]-2-oxo-acetate (I-20-2) To asolution of compound I-20-1 (9.2 g, 32.13 mmol) in dioxane (150 mL) was added SeO2 (3.56 g, 32.1 mmol,3.50 mL). The mixture was stirred at 105 °C for 16 h. The reaction mixture was concentrated under reducedpressure to give a residue. The residue was purified by flash silica gel chromatography (SiO2, Eluent:10 0~50% EtOAc / PE gradient). Compound I-20-2 (6.50 g, 21.6 mmol, 67.4 % yield) was obtained as a yellowsolid.

[387] Synthesis of ethyl 2-[2-(tert-butoxycarbonylamino)thiazol-5-yl]-2-hydroxy-propanoate (I-20-3) A solution of compound I-20-2 (6.50 g, 21.6 mmol) in THF (200 mL) was purged with N2 for 3times. Then MeMgBr (3.00 M, 18.0 mL) was added at -78°C. The mixture was stirred at -78 °C for 1 h15 under N2 atmosphere. The reaction mixture was quenched by addition saturated NH4Cl (100 mL) at 0°Cunder N2 atmosphere. The reaction mixture was extracted with EtOAc (100 mL × 3). The combinedorganic layers were washed with brine (500 mL). The combined organic layers were dried over Na2SO4,filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silicagel chromatography (SiO2, Eluent: 0~50% EtOAc / PE gradient). Compound I-20-3 (4.30 g, 13.6 mmol,20 62.8 % yield) was obtained as a yellow solid.

[388] Synthesis of ethyl 2-(2-aminothiazol-5-yl)-2-hydroxy-propanoate (I-20-4) To a solution ofcompound I-20-3 (1.50 g, 4.74 mmol) in dioxane (10 mL) was added HCl / dioxane (2 M, 10 mL). Themixture was stirred at 25 °C for 6 h. The reaction mixture was under reduced pressure to give aresidue. The product was used for next step without purification. Compound I-20-4 (1.00 g, crude) was25 obtained as a white solid.

[389] Synthesis of ethyl 2-[2-[(2-chloroacetyl)amino]thiazol-5-yl]-2-hydroxy-propanoate (I-20) Toa solution of compound I-20-4 (1.00 g, 4.62 mmol), TEA (468 mg, 4.62 mmol, 644 μL) in DCM (15 mL)was added and 2-chloroacetyl chloride (522 mg, 4.62 mmol, 368 μL) at 0 °C. The mixture was stirred at 0°C for 1 h. The reaction mixture was added H2O (10 mL), extracted with DCM (10 mL × 3). The combined30 organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (SiO2, Eluent: 0~45% EtOAc / PEgradient). Compound I-20 (0.90 g, 3.07 mmol, 66.5% yield) was obtained as a yellow oil.

[0390] Synthesis of methyl 5-(2-bromoacetyl)thiazole-2-carboxylate (I-21): AUG-P3833PCT

[391] Synthesis of methyl 5-(1-ethoxyvinyl)thiazole-2-carboxylate (I-21-1) To a solution of methyl5-bromothiazole-2-carboxylate (10.0 g, 45.0 mmol) and tributyl(1-ethoxyvinyl)stannane (24.6 g, 68.2 mmol, 23.0 mL) in dioxane (100 mL) was added Pd(PPh3)2Cl2 (1.58 g, 2.25 mmol) and TEA (13.7 g, 135 5 mmol, 18.8 mL) under N2. The reaction was stirred at 80°C for 16 h. LCMS indicated the material was consumed and main peak with desired MS was detected. The reaction was filtered and concentrated under reduced pressure to give a residue to give I-21-1 (30.0 g, crude) as a yellow liquid.

[0392] Synthesis of methyl 5-(2-bromoacetyl)thiazole-2-carboxylate (I-21) To a solution of I-21-1(27.0 g, 38.0 mmol) in THF (200 mL) and H2O (100 mL) was added NBS (10.1 g, 57.0 mmol) at 0°C. The 10 reaction was stirred at 25°C for 1 h. The reaction was diluted with water 500 mL and extracted with EtOAc 1000 mL (500 mL * 2). The combined organic layers were washed with brine 200 mL, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash® Silica Flash Column, Eluent of 0~50% THF / Petroleum ether gradient @ 50 mL / min) to give I-21 (5.50 g, 19.8 mmol, 52.1% yield, 95% purity) as a light green15 solid.

[393] Synthesis of 3-(5-(2-bromoacetyl)thiophen-2-yl)-N-cyclopropyltetrahydrofuran-3-carboxamide (I-22):

[394] Synthesis of methyl 3-(thiophen-2-yl)tetrahydrofuran-3-carboxylate (I-22-1) To the mixture20 of methyl 2-(2-thienyl)acetate (30 g, 192 mmol) in DMF (1500 mL) was added NaH (19.2 g, 480 mmol, 60% purity) in portions at 0°C. The mixture was stirred at 0°C for 20 min under N2. 1-chloro-2- (chloromethoxy) ethane (29.7 g, 230 mmol) was added drop-wise at 0°C. The mixture was stirred for 10 minutes at 0°C, then warmed to 25°C and stirred for 16 hrs under N2. The mixture was poured into sat. NH4Cl (100 mL) aqueous solution under N2. Then extracted with EtOAc (200 mL * 3). The combined 25 organic layers were washed with brine (600 mL), dried over anhydrous Na2SO4, filtered and concentrated to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 330 g SepaFlash® Silica Flash Column, Eluent of 0~10% Ethyl acetate / Petroleum ether gradient @ 80 mL / min) to give compound I-22-1 (21 g, 98.9 mmol, 51.5% yield) as a yellow oil. AUG-P3833PCT

[395] Synthesis of methyl 3-(5-bromothiophen-2-yl)tetrahydrofuran-3-carboxylate (I-22-2) To asolution of I-22-1 (21 g, 98.9 mmol) in DMF (300 mL) was added NBS (21.1 g, 119 mmol). The mixturewas stirred at 25°C for 6 hrs. The reaction mixture was partitioned between EtOAc 600 mL and H2O 600 mL. The organic phase was separated, washed with brine 600 mL (300 mL * 2), dried over MgSO4, filtered 5 and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 120 g SepaFlash® Silica Flash Column, Eluent of 0~10% Ethyl acetate / Petroleum ether gradient @ 80 mL / min) to give compound I-22-2 (26 g, 89.3 mmol, 90.3% yield)as a yellow oil.

[396] Synthesis of 3-(5-bromothiophen-2-yl)tetrahydrofuran-3-carboxylic acid (I-22-3) To a10 solution of I-22-2 (8 g, 27.5 mmol) in EtOH (80 mL) was added KOH (2 M, 27.48 mL). The mixture wasstirred at 25°C for 1 hr. The reaction mixture was concentrated under reduced pressure to remove THF (30 mL). The residue was adjusted the pH to 6 with HCl (1M), the yellow solid was precipitated out. The solid was collected by filtration and dried. Compound I-22-3 (6 g, 21.7 mmol, 78.8% yield) was obtained as ayellow solid.15

[0397] Synthesis of 3-(5-bromothiophen-2-yl)-N-cyclopropyltetrahydrofuran-3-carboxamide (I-22-4) To a solution of I-22-3 (6 g, 21.7 mmol) in THF (50 mL) was added dropwise DIC (4.10 g, 32.5 mmol)and ethyl (2E)-2-cyano-2-hydroxyimino-acetate (4.62 g, 32.5 mmol) at 25°C. After addition, the mixture was stirred at this temperature for 0.5 hrs, and then cyclopropanamine (1.85 g, 32.5 mmol) was addeddropwise at 0°C. The resulting mixture was stirred at 0°C for 0.5 hrs. The reaction mixture was partitioned 20 between EtOAc 100 mL and saturated NaHCO3100 mL. The organic phase was separated, washed with brine 300 mL (150 mL * 2), dried over MgSO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash® Silica Flash Column, Eluent of 0~30% Ethyl acetate / Petroleum ether gradient @ 70 mL / min) to give compound I-22-4 (5.3 g, 16.8 mmol, 77.4% yield) as a yellow oil.25

[0398] Synthesis of N-cyclopropyl-3-(5-(1-ethoxyvinyl)thiophen-2-yl)tetrahydrofuran-3-carboxamide (I-22-5) A mixture of I-22-4 (5.2 g, 16.4 mmol), tributyl(1-ethoxyvinyl)stannane (11.5 g,31.7 mmol), Pd(PPh3)2Cl2 (1.15 g, 1.64 mmol) and TEA (4.99 g, 49.3 mmol) in dioxane (50 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 90°C for 16 hrs under N2 atmosphere. The reaction mixture was quenched by addition KF (4 M, 20 mL) at 30°C and the reaction 30 mixture was stirred at 30°C for 2 hrs. Then the reaction mixture was filtered and then extracted with EtOAc mL (100 mL * 3). The combined organic layers were concentrated to give compound I-22-5 (8 g, crude) asa black oil.

[399] Synthesis of 3-(5-(2-bromoacetyl)thiophen-2-yl)-N-cyclopropyltetrahydrofuran-3-carboxamide (I-22) To a solution of I-22-5 (5 g, 16.3 mmol) in THF (60 mL) and H2O (30 mL) was added AUG-P3833PCT NBS (5.79 g, 32.5 mmol). The mixture was stirred at 0°C for 1 hr. The reaction mixture was partitioned between EtOAc 200 mL and H2O 60 mL. The organic phase was separated, washed with brine 120 mL (60 mL * 2), dried over MgSO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash® Silica Flash Column, Eluent of 50~50% Ethyl acetate / Petroleum ether gradient @ 70 mL / min) to give compound I-22 (2.99 g, 8.35 mmol,51.3% yield) as a yellow oil.

[400] Preparation of intermediate compounds M:

[0401] Synthesis of 6-methoxy-2-methylquinazoline-4-thiol (M-11): -11)10

[0402] Synthesis of 6-methoxy-2-methylquinazolin-4-ol (M-11-1) To EtOH (500 mL) was added NaH(42.1 g, 1.05 mol, 60% purity) in portions at 0 °C and then 2-amino-5-methoxybenzamide (25.0 g, 150mmol) was added followed by EtOAc (53.0 g, 601 mmol, 58.91 mL). The resulting mixture was stirred at 90 °C for 12 h. The reaction mixture was quenched by 1 M HCl (500 mL) and filtered. The filter cake was collected. The collected filter cake was dissolved in EtOAc / MeOH (V / V = 1 / 1, 200 mL) and filtered. The15 filtrate was concentrated in vacuum to give compound M-11-1 (34.0 g, crude) as an off-white solid. 1HNMR: (400 MHz, DMSO-d6) δ 12.2 (s, 1H), 7.51 (d, J = 9.2 Hz, 1H), 7.45 (d, J = 2.8 Hz), 7.36 (dd, J =8.8 Hz, 1H), 3.84 (s, 1H), 2.32 (s, 3H).

[403] Synthesis of 6-methoxy-2-methylquinazoline-4-thiol (M-11) To a solution of compound M-11-1 (20.0 g, 105 mmol) in toluene (140 mL) was added Lawesson’s reagent (46.8 g, 115 mmol) and the20 mixture was stirred at 120 °C for 12 h under N2 atmosphere. Two additional runs were done of this reaction on 18.0 g scale and 7.20 g scale of M-11-1, and the crude mixtures of all three runs were combined for work-up. The reaction mixture was concentrated in vacuum to remove solvent. The residue was triturated with EtOAc / MeOH (V / V = 10 / 1, 10 V, 3 times) at 25 °C for 6 h to give compound M-11 (25.5 g, 72%yield, 85.3% purity) as a yellow solid after filtration and drying.1H NMR: (400 MHz, DMSO-d6) δ 13.9 (s,25 1H), 7.91 (d, J = 2.4 Hz, 1H), 7.65 (d, J = 8.8 Hz, 1H), 7.51 (dd, J = 8.8 Hz, 1H), 3.87 (s, 3H), 2.48 (s, 3H).

[0404] Synthesis of 7-methylimidazo[1,2-a]pyrimidine-5-thiol (M-12): AUG-P3833PCT

[405] To a solution of 7-methylimidazo[1,2-a]pyrimidin-5-ol (0.45 g, 3.02 mmol) and P2S5 (670.62 mg,3.02 mmol, 320.87 μL) in anisole (4 mL) was added trimethyl(trimethylsilyloxy)silane (2.45 g, 15.09 mmol, 3.21 mL). The mixture was stirred at 120 °C for 3 h. TLC (PE / EtOAc = 1 / 1, compound M-12 Rf = 0.42)showed the compound starting material was consumed and one new spot was formed. The mixture was 5filtered, and the solid was dried in vacuum to give compound M-12 (0.4 g, 2.42 mmol, 80.25% yield) as agray solid.

[406] Synthesis of 6-chloro-7-fluoro-2-methylquinazoline-4-thiol (M-13):

[407] Synthesis of 2-amino-5-chloro-4-fluorobenzoic acid (M-13-1) To a solution of 2-amino-4-10 fluoro-benzoic acid (50.0 g, 322 mmol, 1.00 eq) in DMF (700 mL) was added NCS (41.0 g, 307 mmol, 0.953 eq). The reaction mixture was stirred at 50 °C for 5 h. The mixture was poured into water (2000 mL) and filtered. The filter cake was washed with water and dried to give intermediate M-13-1 (56.7 g, 254mmol, 78.7% yield, 84.8% purity) as a brown solid.

[408] Synthesis of 6-chloro-7-fluoro-2-methylquinazolin-4(3H)-one (M-13-2) To a solution of15 compound M-13-1 (55.7 g, 249 mmol, 1.00 eq) in 2-methoxyethanol (557 mL) was added acetamidinehydrochloride (58.9 g, 623 mmol, 2.50 eq) and NaOAc (51.1 g, 623 mmol, 2.50 eq). The mixture was stirred at 130 °C for 16 h. The mixture was poured into water (2000 mL) and filtered. The filter cake was washed with water and dried to give intermediate M-13-2 (34.9 g, 154 mmol, 61.7% yield, 93.7% purity)as a brown solid.20

[0409] Synthesis of 6-chloro-7-fluoro-2-methylquinazoline-4-thiol (M-13) To a solution of compoundM-13-2 (20.0 g, 94.1 mmol, 1.00 eq) in toluene (400 mL) was added Lawesson’s reagent (47.6 g, 118mmol, 1.25 eq). The mixture was stirred at 120 °C for 2 h. The mixture was poured into water (500 mL) and filtered. The filter cake was washed with water and dried to give a residue. The residue was purified by re-crystallization from H2O (1000 mL) and EtOAc (300 mL) at 25 °C for 1 h to give compound M-1325 (13.5 g, 57.8 mmol, 61.4% yield, 97.6% purity) as a yellow solid.

[410] Synthesis of 3-methoxy-7-methyl-1,6-naphthyridine-5-thiol (M-14):

[411] Synthesis of 5,7-dichloro-3-iodo-1,6-naphthyridine (M-14-1) To a solution of 5,7-dichloro-1,6-naphthyridine (4.00 g, 20.1 mmol, 1.00 eq) in AcOH (60.0 mL) was added NIS (9.04 g, 40.2 mmol, 2.00 AUG-P3833PCT eq) under N2. The mixture was stirred at 100 °C for 16 h. The mixture was concentrated to give a residue.The residue was purified by column chromatography (SiO2, PE / EtOAc = 100 / 1 to 20 / 1) to give intermediateM-14-1 (3.14 g, 8.79 mmol, 43.8% yield, 91.2% purity) as a yellow solid.

[0412] Synthesis of (5,7-dichloro-1,6-naphthyridin-3-yl)boronic acid (M-14-2) To a solution of5 compound M-14-1 (5.08 g, 15.6 mmol, 1.00 eq) and B2Pin2 (4.37 g, 17.2 mmol, 1.10 eq) in dioxane (51.0mL) was added KOAc (3.07 g, 31.3 mmol, 2.00 eq) and Pd(dppf)Cl2 (1.14 g, 1.56 mmol, 0.100 eq) under N2. The mixture was stirred at 90 °C for 16 h. The mixture was quenched by water (100 mL) and wasextracted with EtOAc (200 mL × 3). The combined organic layers were dried over Na2SO4, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO2, PE / EtOAc =10 100 / 1 to 25 / 2) to give intermediate M-14-2 (2.90 g, 11.1 mmol, 71.0% yield, 93.0% purity) was obtainedas a yellow solid.

[413] Synthesis of 5,7-dichloro-1,6-naphthyridin-3-ol (M-14-3) To a solution of compound M-14-2(2.90 g, 11.9 mmol, 1.00 eq) in DCM (15.0 mL) was added H2O2(7.30 g, 64.4 mmol, 6.19 mL, 30.0% purity, 5.39 eq) at 0 °C. The mixture was stirred at 25 °C for 16 h. The reaction mixture was filtered, and15 the filter cake was concentrated to give intermediate M-14-3 (2.45 g, 11.3 mmol, 94.5% yield, 99.0%purity) as a white solid.

[414] Synthesis of 5,7-dichloro-3-methoxy-1,6-naphthyridine (M-14-4) To a solution of compoundM-14-3 (2.45 g, 11.4 mmol, 1.00 eq) in DMF (25.0 mL) was added K2CO3 (4.72 g, 34.2 mmol, 3.00 eq)and MeI (3.23 g, 22.8 mmol, 1.42 mL, 2.00 eq). The mixture was stirred at 25 °C for 2 h. The reaction20 mixture was added water (70 mL) and extracted with EtOAc (100 mL × 2). The combined organic layers were washed with brine (400 mL × 2), dried over Na2SO4, filtered and concentrated in vacuum to give intermediate M-14-4 (2.24 g, 9.73 mmol, 85.4% yield, 99.5% purity) as a yellow solid.

[0415] Synthesis of 7-chloro-3-methoxy-5-((4-methoxybenzyl)thio)-1,6-naphthyridine (M-14-5) Toa solution of compound M-14-4 (2.24 g, 9.73 mmol, 1.00 eq) in dioxane (23.0 mL) was added (4-25 methoxyphenyl)methanethiol (2.25 g, 14.6 mmol, 2.03 mL, 1.50 eq) and Cs2CO3 (6.34 g, 19.5 mmol, 2.00 eq). The mixture was stirred at 50 °C for 2 h. The reaction mixture was added water (50 mL) and extractedwith EtOAc (100 mL × 2). The combined organic layers were dried over Na2SO4, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO2, PE / EtOAc = 100 / 1 to 20 / 1)to give intermediate M-14-5 (2.01 g, 5.59 mmol, 57.5% yield, 96.5% purity) as a yellow solid.30

[0416] Synthesis of 3-methoxy-5-((4-methoxybenzyl)thio)-7-methyl-1,6-naphthyridine (M-14-6) Toa solution of compound M-14-5 (1.90 g, 5.29 mmol, 1.00 eq) and methylboronic acid (633 mg, 10.6 mmol,2.00 eq) in DMF (19.0 mL) was added K3PO4 (3.37 g, 15.9 mmol, 3.00 eq) and Pd(PPh3)4 (611 mg, 529 μmol, 0.100 eq) under N2. The mixture was stirred at 110 °C for 2 h. The reaction mixture was added water AUG-P3833PCT (50 mL) and extracted with EtOAc (100 mL × 2). The combined organic layers were dried over Na2SO4, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO2, PE / EtOAc = 100 / 1 to 20 / 1) to give intermediate M-14-6 (1.43 g, 3.96 mmol, 74.8% yield, 90.3% purity)as a yellow solid. 5

[0417] Synthesis of 3-methoxy-7-methyl-1,6-naphthyridine-5-thiol (M-14) To a solution of compoundM-14-6 (500 mg, 1.53 mmol, 1.00 eq) in TFA (5.00 mL) was added m-cresol (166 mg, 1.53 mmol, 160 μL,1.00 eq). The mixture was stirred at 80 °C for 2 h. The reaction mixture was quenched by addition H2O (10 mL) and extracted with EtOAc (15 mL × 3). The combined organic layers were washed with brine (30 mL ×3), dried over Na2SO4, filtered and concentrated to give compound M-14 (735 mg, crude) as a red solid.10

[0418] Synthesis of 5-fluoro-6-methoxy-2-methylquinazoline-4-thiol (M-16):

[419] Synthesis of 6-bromo-2-fluoro-3-methoxybenzoic acid (M-16-1) To a solution of 2-fluoro-3-methoxybenzoic acid (100 g, 588 mmol) in AcOH (500 mL) and H2O (500 mL) was added dropwise Br2 (188 g, 1.18 mol) at 0 °C. The resulting mixture was stirred at 25 °C for 16 h. The reaction mixture was15 quenched by addition H2O (2.5 L) at 25 °C, the precipitate was filtered, and the filter cake was washed withwater. Intermediate M-16-1 (127 g, 86.8% yield, 100% purity) was obtained as a white solid.

[0420] Synthesis of ethyl 6-bromo-2-fluoro-3-methoxybenzoate (M-16-2) To a solution of M-16-1(127 g, 510 mmol) in ACN (1000 mL) was added Cs2CO3 (199 g, 612 mmol) and iodoethane (119 g, 765 mmol). The mixture was stirred at 25 °C for 72 h. The mixture was filtered through celite, washed with 20 MeCN (500 mL) and concentrated in vacuo. The residue was purified by flash silica gel chromatography (ISCO®; 330 g SepaFlash® Silica Flash Column, eluent: 0~10% EtOAc / PE gradient @ 80 mL / min).Intermediate M-16-2 (137 g, 96.5% yield, 99.5% purity) was obtained as a yellow oil.

[0421] Synthesis of ethyl 6-((tert-butoxycarbonyl)amino)-2-fluoro-3-methoxybenzoate (M-16-3) M-16-2 (100 g, 361 mmol) was dissolved in dioxane (1000 mL). tert-butyl carbamate (50.7 g, 433 mmol),25 Xantphos (20.9 g, 36.1 mmol), Pd(OAc)2 (8.10 g, 36.1 mmol) and Cs2CO3 (235 g, 722 mmol) were added, and the mixture was stirred for 16 h at 100 °C. The mixture was cooled, diluted with EtOAc (1000 mL) and filtered through Celite washing with EtOAc (1000 mL). The filtrate was concentrated in vacuo. The residue was purified by flash silica gel chromatography (ISCO®; 330 g SepaFlash® Silica Flash Column, Eluent: 0~10% EtOAc / PE gradient @ 80 mL / min). Intermediate M-16-3 (97 g, 82.9% yield, 96.6% purity) was30 obtained as a yellow solid. AUG-P3833PCT

[422] Synthesis of ethyl 6-amino-2-fluoro-3-methoxybenzoate (M-16-4) To a solution of M-16-3 (97g, 310 mmol) in dioxane (200 mL) was added HCl / dioxane (2 M, 619 mL). The mixture was stirred at 25 °C for 16 h. The reaction liquid was filtered directly, and the solids were collected. Intermediate M-16-4(74 g, 95.7% yield, 100% purity, HCl) was obtained as a white solid. 5

[0423] Synthesis of 5-fluoro-6-methoxy-2-methylquinazolin-4-ol (M-16-5) To a solution of M-16-4(55 g, 258 mmol, 1 eq) in ACN (500 mL) was added HCl (12 M, 215 mL). The mixture was stirred at 100 °C for 16 h. The reaction mixture was quenched by addition NH3H2O (220 mL) at 20 °C (pH >7). Thereaction liquid was filtered directly, and the solids were collected. Intermediate M-16-5 (42 g, 78.2% yield)was obtained as a white solid.10

[0424] Synthesis of 5-fluoro-6-methoxy-2-methylquinazoline-4-thiol (M-16) To a solution of M-16-5(5 g, 24.0 mmol) in anisole (50 mL) was added P2S5(2.67 g, 12.0 mmol) and trimethyl(trimethylsilyloxy)silane (19.5 g, 120 mmol). The mixture was stirred at 110 °C for 16 h. The mixture was cooled to 0 °C and quenched by addition of K2CO3aqueous solution (5.3 M, 300 mL) at 0 °C, then acetone (200 mL) was added. The mixture was stirred at 0 °C for 1 h. The crude product was triturated 15 with MeCN (200 mL) at 25 °C for 12 h. The mixture was filtered, and the filter cake was washed with MeCN (100 mL × 3) and collected. Intermediate M-16 (5 g, 86.3% yield, 93% purity) was obtained as ayellow solid.

[425] Synthesis of 7-methyl-3-(trifluoromethyl)-1,6-naphthyridine-5-thiol(M-18): 20

[426] Synthesis of 5,7-dichloro-3-iodo-1,6-naphthyridine (M-18-1) To a solution of 5,7-dichloro-1,6-naphthyridine (5.00 g, 25.1 mmol, 1.00 eq) in AcOH (75.0 mL) was added NIS (11.3 g, 50.2 mmol, 2.00 eq) under N2. The mixture was stirred at 100 °C for 16 h. The reaction mixture was concentrated in vacuumto give a residue. The residue was purified by column chromatography (SiO2, PE / EtOAc = 100 / 1 to 19 / 1)25 to give intermediate M-18-1 (5.12 g, 15.3 mmol, 61.0% yield, 97.3% purity) as a brown solid.

[0427] Synthesis of 5,7-dichloro-3-(trifluoromethyl)-1,6-naphthyridine (M-18-2) To a solution ofcompound M-18-1 (2.00 g, 5.99 mmol, 1.00 eq) in DMF (20.0 mL) was added CuI (2.85 g, 15.0 mmol,2.50 eq) and HMPA (5.37 g, 29.9 mmol, 5.24 mL, 5.00 eq) under N2. The mixture was heated to 90 °C. Methyl 2,2-difluoro-2-fluorosulfonyl-acetate (2.30 g, 12.0 mmol, 1.52 mL, 2.00 eq) was added into the30 above reaction mixture at 90 °C and stirred at 90 °C for 2 h under N2. To the reaction mixture was addedwater (20 mL) and the mixture was extracted with EtOAc (30 mL × 3). The combined organic layers were AUG-P3833PCT dried over Na2SO4, filtered and concentrated in vacuum to give a residue. The residue was purified by column chromatography (SiO2, PE / EtOAc = 100 / 1 to 19 / 1) to give intermediate M-18-2 (820 mg, 2.93mmol, 48.9% yield, 95.4% purity) as a yellow solid.

[428] Synthesis of 7-chloro-5-((4-methoxybenzyl)thio)-3-(trifluoromethyl)-1,6-naphthyridine (M-5 18-3) To a solution of compound M-18-2 (800 mg, 2.70 mmol, 1.00 eq) and PMBSH (457 mg, 2.97 mmol,413 μL, 1.10 eq) in dioxane (16.0 mL) was added Cs2CO3 (879 mg, 2.70 mmol, 1.00 eq). The mixture was stirred at 25 °C for 2 h. To the reaction mixture was added water (10 mL) and then it was extracted with EtOAc (20 mL × 2). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuum to give a residue. The residue was purified by column chromatography (SiO2, PE / EtOAc = 100 / 110 to 19 / 1) to give intermediate M-18-3 (736 mg, 1.71 mmol, 63.6% yield, 89.6% purity) as a white solid.

[0429] Synthesis of 5-((4-methoxybenzyl)thio)-7-methyl-3-(trifluoromethyl)-1,6-naphthyridine (M-18-4) To a solution of compound M-18-3 (716 mg, 1.80 mmol, 1.00 eq) and methylboronic acid (215 mg,3.59 mmol, 2.00 eq) in DMF (8.00 mL) was added K3PO4(1.14 g, 5.39 mmol, 3.00 eq) and Pd(PPh3)4(207 mg, 180 μmol, 0.100 eq) under N2. The mixture was stirred at 110 °C for 2 h. The reaction mixture was 15 added water (15 mL) and extracted with EtOAc (20 mL × 2). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuum to give a residue. The residue was purified by column chromatography (SiO2, PE / EtOAc = 100 / 1 to 19 / 1) to give intermediate M-18-4 (182 mg, 471 μmol, 26.2%yield, 94.3% purity) as a yellow solid.

[430] Synthesis of 7-methyl-3-(trifluoromethyl)-1,6-naphthyridine-5-thiol (M-18) To a solution of20 compound M-18-4 (182 mg, 471 μmol, 1.00 eq) in TFA (2.00 mL) was added m-cresol (50.9 mg, 471μmol, 49.3 μL, 1.00 eq). The mixture was stirred at 80 °C for 2 h. The reaction mixture was added water (5 mL) and extracted with EtOAc (5 mL × 3). The combined organic layers were washed with brine (10 mL ×3), dried over Na2SO4, filtered and concentrated in vacuum to give compound M-18 (202 mg, crude) asa red solid.25

[0431] Synthesis of 2-methyl-6-(trifluoromethyl)quinoline-4-thiol (M-19)

[432] Synthesis of 2-methyl-6-(trifluoromethyl)quinoline-4-thiol (M-19) To a solution of 4-chloro-2-methyl-6-(trifluoromethyl)quinoline (400 mg, 1.63 mmol) in DMF (10 mL) was added NaSH (273.89mg, 4.89 mmol). The mixture was stirred at 80 °C for 3 h. TLC (PE / EtOAc = 1 / 1, compound M-19 Rf =30 0.42) showed the compound starting material was consumed and one new spot was formed. The mixture AUG-P3833PCT was filtered, and the solid was dried in vacuum to give compound M-19 (300 mg, 1.23 mmol, 75.73% yield) as a yellow solid.

[433] Synthesis of 6-chloro-2-methylquinazoline-4-thiol (M-20) 5

[0434] Synthesis of 6-chloro-2-methylquinazoline-4-thiol (M-20). To a solution of 6-chloro-2-methyl-1H-quinazolin-4-one (2.50 g, 12.9 mmol, 1.00 eq) in toluene (30.0 mL) was added Lawesson's reagent (6.23 g, 15.41 mmol, 1.20 eq). The mixture was stirred at 110 °C for 12 h under N2atmosphere. The mixture was cooled to 0 °C. The reaction mixture was quenched by addition of K2CO3aqueous solution (5.30 M, 50.0 mL) at 0 °C. The mixture was stirred at 0 °C for 1 h and then diluted with H2O (20.0 mL). The mixture10 was filtered, and the filter cake was washed with H2O (20.0 mL × 3) to give the crude product. The crudeproduct was triturated with MTBE (20.0 mL) at 25 °C for 12 h. The mixture was filtered, and the filter cakewas washed with MTBE (20.0 mL × 3) to give compound M-20 (1.35 g, 6.41 mmol, 49.9% yield) as a graysolid.

[435] Synthesis of 1-mercaptoisoquinoline-4-carbonitrile (M-23)15

[436] To a solution of 1-chloroisoquinoline-4-carbonitrile (600 mg, 3.18 mmol, 1.00 eq) in DMF (5.0mL) was added sodium hydrogensulfide (214 mg, 3.82 mmol, 1.20 eq). The mixture was stirred at 80 °Cfor 2 h. The reaction mixture was added water (80 mL) and extracted with EtOAc (80 mL × 2). The combined organic layers were dried over Na2SO4, filtered and concentrated to give a residue. The residue20 was purified by column chromatography (SiO2, PE / EtOAc = 100 / 1 to 1 / 1) to give compound M-23 (400mg, 2.15 mmol, 67.5% yield, 90.5% purity) as a yellow solid.

[437] Synthesis of 4-mercapto-2-methylquinazoline-6-carbonitrile (M-24)

[438] Synthesis of 4-hydroxy-2-methyl-quinazoline-6-carbonitrile (M-24-1) A mixture of 2-amino-25 5-cyano-benzoic acid (1 g, 6.17 mmol, 1 eq), acetamidine hydrochloride (1.46 g, 15.4 mmol, 2.5 eq) and NaOAc (1.26 g, 15.4 mmol, 2.5 eq) in 2-methoxyethanol (10 mL) was degassed and purged with N2 for 3 AUG-P3833PCT times, and then the mixture was stirred at 130 °C for 16 h under N2 atmosphere. The mixture was suspension. The reaction was cooled and then filtered, the solid was dried in vacuum to give intermediate M-24-1 (1 g, 5.40 mmol, 87.6% yield) was obtained as grey solid.

[0439] Synthesis of 4-mercapto-2-methylquinazoline-6-carbonitrile (M-24) The mixture of M-24-15 (0.5 g, 2.70 mmol, 1 eq) and Lawesson's reagent (1.31 g, 3.24 mmol, 1.2 eq) in THF (15 mL) was stirred at 80 °C for 3 h. The mixture was clear. The mixture was concentrated in vacuum to give the residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent: 0~50% EtOAc / PE gradient) to give M-24 (0.25 g, 1.24 mmol, 46.0% yield) was obtained as anorange solid.10

[0440] Synthesis of 4-mercapto-2-methylquinoline-6-carbonitrile (M-25)

[441] Synthesis of 4-chloro-2-methyl-quinoline-6-carbonitrile (M-25-1) To a solution of 2-amino-5-cyano-benzoic acid (1.01 g, 6.23 mmol, 1 eq) in POCl3 (10 mL) was added acetone (1.45 g, 24.9 mmol, 1.83 mL, 4 eq) at 0 °C. The mixture was stirred at 80 °C for 3 h. The mixture was clear. The mixture was15 concentrated in vacuum to remove the POCl3, and then adjusted to pH 8~9 with NaOH aq., then filtered.The solid was dried in vacuum to give the crude product M-25-1 (1 g, 4.04 mmol, 64.8% yield, 81.8%purity) as a gray solid which was used for next step without further purification.

[0442] Synthesis of 4-mercapto-2-methylquinoline-6-carbonitrile (M-25) To a solution of M-25-1(0.8 g, 3.95 mmol, 1 eq) in EtOH (10 mL) was added sodium hydrogensulfide (885 mg, 15.79 mmol, 4 eq).20 The mixture was stirred at 80 °C for 3 h. The mixture was clear. The mixture was filtered, and then concentrated in vacuum to give the residue. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, eluent: 0~50% EtOAc / PE gradient) to give compound M-25 (0.5 g, 2.50 mmol, 63.2% yield) as a yellow solid.

[0443] Synthesis of 1,6-dimethylpyrazolo[3,4-d]pyrimidine-4-thiol (M-26)25

[444] Synthesis of 1,6-dimethylpyrazolo[3,4-d]pyrimidine-4-thiol (M-26) The solution of 4-chloro-1,6-dimethyl-pyrazolo[3,4-d]pyrimidine (0.1 g, 548 μmol, 1 eq) and NaHS (123 mg, 2.19 mmol, 4 eq) in DMF (2 mL) was stirred at 25 °C for 3 h. The mixture was clear. The mixture was concentrated in vacuum AUG-P3833PCT to give the residue. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent: 0~50% EtOAc / PE gradient) give compound M-26 (0.05 g, 277 μmol, 50.7%yield) as a white solid.

[445] 2-methyl-6-(trifluoromethyl)-2H-pyrazolo[3,4-d]pyrimidine-4-thiol5 (M-30)

[446] Synthesis of 3-amino-1-methyl-1H-pyrazole-4-carbonitrile (M-30-1) To a solution of 5-amino-1H-pyrazole-4-carbonitrile (10.00 g, 92.51 mmol) and CH3I (15.76 g, 111.01 mmol, 6.91 mL), K2CO3(15.76 g, 111.01 mmol, 6.91 mL) in DMF (100 mL) The mixture was stirred at 100 °C for 12 h. The mixture10 was filtered, and the solid was dried in vacuum to give intermediate M-30-1 (2.5 g, 20.47 mmol) as a whitesolid.

[447] Synthesis of 3-amino-1-methyl-1H-pyrazole-4-carboxamide (M-30-2) To a solution of M-30-1 (2 g, 16.38 mmol) in H2SO4(20 mL) was stirred at 0 °C for 2 h. The reaction mixture was quenched with H2O (100 mL), extracted with EtOAc (150 mL). The combined organic layers are dried over Na2SO4, 15 filtered and concentrated to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 40 SepaFlash® Silica Flash Column, Eluent: 0~40 % EtOAc / PE gradient @ 80 mL / min) to giveintermediate M-30-2 (1.5 g, 10.70 mmol, 65.36% yield) as a yellow solid.

[0448] Synthesis of 2-methyl-6-(trifluoromethyl)-2H-pyrazolo[3,4-d]pyrimidin-4-ol (M-30-3) To asolution of M-30-2 ((1.5 g, 10.70 mmol) and ethyl 2,2,2-trifluoroacetate (6.08 g, 42.81 mmol, 5.88 mL), 20 NaH (3.00 g, 74.92 mmol, 60% purity) in EtOH (50 mL) was stirred at 90 °C for 3 h. The reaction mixture was quenched with H2O (100 mL), extracted with EtOAc (150 mL). The combined organic layers are dried over Na2SO4, filtered and concentrated to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 40 SepaFlash® Silica Flash Column, Eluent: 0~40 % EtOAc / PE gradient @ 80mL / min) to give intermediate M-30-3 (1.5 g, 6.88 mmol, 64.25% yield) as a yellow solid.25

[0449] Synthesis of 2-methyl-6-(trifluoromethyl)-2H-pyrazolo[3,4-d]pyrimidine-4-thiol (M-30) To asolution of M-30-3 (1 g, 4.58 mmol) in toluene (50 mL) was added P2S5 (1.02 g, 4.58 mmol). The mixturewas stirred at 120 °C for 3 h. The reaction mixture was quenched with H2O (100 mL) and was extracted with EtOAc (150 mL). The combined organic layers are dried over Na2SO4, filtered and concentrated to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 40 SepaFlash® Silica30 Flash Column, Eluent: 0~40 % EtOAc / PE gradient @ 80 mL / min) to give compound M-30 (980 mg, 4.18mmol, 91.28% yield) as a yellow solid. AUG-P3833PCT

[450] Synthesis of 1-methyl-1H-pyrazolo[3,4-d]pyrimidine-4-thiol (M-32):

[451] Synthesis of 1-methyl-1,7-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one(M-32-1) To a solution mixture of ethyl 5-amino-1-methyl-1H-pyrazole-4-carboxylate (10 g, 59.1 mmol)5 in formamide (40 mL) was stirred at 180oC for 4 h. The reaction mixture was cooled to rt, and the resulting precipitate was filtered under vacuo. The solid was washed with hexane and dried under vacuo to afford M-32-1 (7.2 g, Yield: 79.1%) as an off white solid.

[0452] Synthesis of 1-methyl-1H-pyrazolo[3,4-d]pyrimidine-4-thiol (M-32) To a solution of M-32-1(3.4 g, 22.6 mmol) in toluene (50.0 mL) was added Lawesson’s reagent (5.4 g, 13.5 mmol) at 0oC. The 10 reaction mixture was stirred for 2 h at 120oC, after which it was concentrated under vacuo. The residue was purified by column chromatography over silica gel (60:120 mesh). The compound was eluted using 10% EtOAc in hexane to afford compound M-32 (3.0 g, Yield: 81%) as pale-yellow solid.

[453] Synthesis of 5-(difluoromethoxy)-2-methylquinazolin-4-ol (M-56-6) 15

[0454] Synthesis of methyl 2-methoxy-6-nitrobenzoate (M-56-1) To a solution of 2-methoxy-6-nitro-benzoic acid (24.5 g, 124 mmol, 1.00 eq) in DMF (250 mL) was added MeI (35.3 g, 249 mmol, 15.5 mL, 2.00 eq) and K2CO3 (51.5 g, 373 mmol, 3.00 eq). The mixture was stirred at 25 °C for 2 h. The reactionmixture was quenched by water (500 mL) and extracted with EtOAc (500 mL × 2). The combined organiclayers were washed with brine (400 mL × 2), dried over Na2SO4, filtered and concentrated in vacuum to20 give a residue. The residue was purified by column chromatography (SiO2, PE / EtOAc = 100 / 1 to 2 / 1) togive compound M-56-1 (22.2 g, 105 mmol, 84.6% yield) as a yellow solid.

[0455] Synthesis of methyl 2-hydroxy-6-nitrobenzoate (M-56-2) To a solution of compound M-56-1(21.4 g, 101 mmol, 1.00 eq) in DCM (400 mL) was added BBr3(2.00 M, 203 mL, 4.00 eq) dropwise at 0 °C under N2. The mixture was stirred at 25 °C for 1 h. The resulting mixture was poured into ice (600 g)25 and extracted with EtOAc (500 mL × 2). The combined organic phases were dried over MgSO4, filteredand concentrated under reduced pressure to give a residue. The residue was purified by columnchromatography (SiO2, PE / THF = 100 / 1 to 5 / 1) to give compound M-56-2 (6.90 g, 35.0 mmol, 34.5%yield) as a yellow solid. AUG-P3833PCT

[456] Synthesis of 2-(difluoromethoxy)-6-nitrobenzoic acid (M-56-3) To a solution of compound M-56-2 (6.90 g, 35.0 mmol, 1.00 eq) in ACN (34.0 mL) and H2O (34.0 mL) was added KOH (39.3 g, 700mmol, 20.0 eq) at 0 °C. The mixture was stirred at 0 °C for 1 h. Diethyl (bromodifluoromethyl)phosphonate(18.7 g, 70.0 mmol, 2.00 eq) was added into above reaction mixture at 0 °C. The mixture was stirred at 255 °C for 16 h. The resulting mixture was adjusted to pH = 4 with 1 N HCl, extracted with EtOAc (50 mL ×3). The combined organic phases were dried over MgSO4, filtered and concentrated under reduced pressureto give compound M-56-3 (4.16 g, crude) as a brown oil.

[0457] Synthesis of methyl 2-(difluoromethoxy)-6-nitrobenzoate (M-56-4) To a solution of compoundM-56-3 (4.16 g, 17.8 mmol, 1.00 eq) in DMF (42.0 mL) was added MeI (5.07 g, 35.7 mmol, 2.22 mL, 2.0010 eq) and K2CO3 (7.40 g, 53.5 mmol, 3.00 eq). The mixture was stirred at 25 °C for 1 h. The reaction mixturewas quenched by water (50 mL) and extracted with EtOAc (50 mL × 2). The combined organic layers werewashed with brine (40 mL × 2), dried over Na2SO4, filtered and concentrated in vacuum to give a residue.The residue was purified by column chromatography (SiO2, PE / EtOAc = 100 / 1 to 5 / 1) to give compoundM-56-4 (1.19 g, 4.65 mmol, 26.1% yield, 96.6% purity) as a yellow oil.15

[0458] Synthesis of methyl 2-amino-6-(difluoromethoxy)benzoate (M-56-5) To a solution ofcompound M-56-4 (1.16 g, 4.69 mmol, 1.00 eq) and NH4Cl (1.26 g, 23.5 mmol, 5.00 eq) in MeOH (12.0mL) and H2O (12.0 mL) was added Fe (2.62 g, 46.9 mmol, 10.0 eq) at 80 °C in batches. The mixture was stirred at 80 °C for 16 h. The reaction mixture was quenched by water (30 mL) and extracted with DCM (50 mL × 3). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuum to20 give compound M-56-5 (523 mg, 2.41 mmol, 51.3% yield) as a brown oil.

[0459] Synthesis of 5-(difluoromethoxy)-2-methylquinazolin-4-ol (M-56-6) To a solution ofcompound M-56-5 (363 mg, 1.67 mmol, 1.00 eq) in ACN (5.00 mL) was added HCl (12.0 M, 1.39 mL,10.0 eq). The mixture was stirred at 100 °C for 16 h. To the mixture was added ACN (8 mL) and it wasfiltered. To the filter cake was added water (8 mL), and the pH was adjusted to pH = 8 with aq. NaHCO3,25 after which the mixture was extracted with DCM (10 mL × 3). The combined organic phases were driedover Na2SO4, filtrated and concentrated under reduced pressure to give compound M-56-6 (205 mg, 906μmol, 54.2% yield) as a yellow solid.

[460] Synthesis of 5-(difluoromethoxy)-2-methylquinazoline-4-thiol (M-56) To a solution ofcompound M-56-6 (190 mg, 840 μmol, 1.00 eq) in toluene (3.50 mL) was added Lawesson’s reagent (51030 mg, 1.26 mmol, 1.50 eq). The mixture was stirred at 100 °C for 4 h. To the mixture was added water (30mL), after which it was filtered. The organic layer of the filtrate was separated, dried over Na2SO4, and concentrated under reduced pressure to give compound M-56 (205 mg, 751 μmol, 89.4% yield, 88.7%purity) as a yellow solid. AUG-P3833PCT

[461] Synthesis of 6-methoxy-2-methylpyrido[3,2-d]pyrimidine-4-thiol (M-57)

[462] Synthesis of 6-methoxy-2-methylpyrido[3,2-d]pyrimidin-4-ol (M-57-1) To a solution of 3-5 amino-6-methoxypicolinic acid (93.0 g, 553 mmol) in 2-methoxyethanol (930 mL) was added AcONa (136 g, 1659 mmol) and acetamidine; hydrochloride (189 g, 2.77 mol). The mixture was stirred at 130°C for 16 hrs. The reaction mixture was diluted with H2O 300 mL and filtered to give the insoluble. The product was used to next step without purification. The solid was dried down in Vacuum Dryer. Compound M-57-1 (75.0 g, 392 mmol, 71.0% yield, 99% purity) was obtained as a white solid. 10

[463] Synthesis of 4-chloro-6-methoxy-2-methylpyrido[3,2-d]pyrimidine (M-57-2) To a solution ofM-57-1 (75.0 g, 392 mmol) in toluene (750 mL) was added dropwise POCl3 (90.2 g, 588 mmol) and DIEA(76.1 g, 588 mmol) at 0°C over 10 min. After addition, the mixture was stirred at 80°C for 5 min, and then POCl3 (180 g, 1.18 mol) was added dropwise at 80°C. The resulting mixture was stirred at 110°C for 0.5 15 hr. The reaction mixture was concentrated under reduced pressure to remove solvent. The mixture cooled to 25°C, then the mixture was poured into 500 mL ice water in portions slowly at 0°C with stirring. Then extracted with EtOAc (500 mL*3), the combined organic layers were washed with brine (1500 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give the crude compound. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=10 / 1). Compound M-57-220 (75.9 g, 362 mmol, 91.2% yield, 100% purity) was obtained as a white solid.

[464] Synthesis of 6-methoxy-2-methylpyrido[3,2-d]pyrimidine-4-thiol (M-57) To a solution ofcompound M-57-2 (75.9 g, 362 mmol) in EtOH (760 mL) was added thiourea (83.0 g, 1.09 mol).Themixture was stirred at 25°C for 2 hrs. After 2 h, KOH (1 M, 724 mL) was added dropwise at 0°C. The resulting mixture was stirred at 0°C for 1 hr. The reaction was adjusted the pH to 4 with 4N HCl, and25 filtered to give the insoluble. Compound M-57 (70.0 g, 338 mmol, 100% purity, 93.4% yield) was obtained as a yellow solid.

[465] Synthesis of 6-methoxy-2-methylpyrido[3,2-d]pyrimidine-4-thiol (M-57) (M-57) AUG-P3833PCT

[466] Synthesis of 6-methoxy-2-methyl-pyrido[3,2-d]pyrimidin-4-ol (M-57-1) To a solution of 3-amino-6-methoxy-pyridine-2-carboxylic acid (2.00 g, 11.89 mmol) in 2-methoxyethanol (20 mL) wasadded NaOAc (2.44 g, 29.7 mmol) and acetamidine hydrochloride (2.81 g, 29.7 mmol). The mixture wasstirred at 130 °C for 4 h, after which the reaction was quenched by addition H2O (20 mL). A brown solid5 precipitated out, which was collected by filtration and dried under reduced pressure. Then the solid was triturated with MeCN (20 mL) at 25 °C for 30 min to give M-57-1 (1.94 g, 10.1 mmol, 85.3 % yield) as abrown solid.

[467] Synthesis of 6-methoxy-2,5-dimethylquinazoline-4-thiol (M-33): (M-33)10

[0468] Synthesis of 3-fluoro-2-methyl-6-nitrobenzoic acid (M-33-1) To a solution of 3-fluoro-2-methyl-benzoic acid (43.0 g, 279 mmol) in H2SO4(215 mL) was added HNO3(27.7 g, 440 mmol, 19.8 mL) dropwise at 0°C. The mixture was stirred at 0 °C for 5 h. The reaction solution was added into water (700mL) dropwise at 0°C. White solid was precipitated. The solid was collected by filtration and dried underreduced pressure to give compound M-33-1 (55.9 g, crude) as a white solid.15

[0469] Synthesis of 3-methoxy-2-methyl-6-nitrobenzoic acid (M-33-2) To a solution of compound M-33-1 (53.9 g, 271 mmol) in MeOH (500 mL) and THF (500 mL) was added potassium methoxide (57.0 g,812 mmol). The mixture was stirred at 100 °C for 4 h. The reaction mixture was quenched with 1 N HClsolution (660 mL) at 25 °C and extracted with EtOAc (500 mL × 2). The combined organic layerswerewashed with brine (700 mL), dried over Na2SO4, filtered and concentrated in vacuum to give20 compound M-33-2 (55.4 g, 262 mmol, 96.8% yield) as a yellow solid.

[0470] Synthesis of ethyl 3-methoxy-2-methyl-6-nitrobenzoate (M-33-3) To a solution of compoundM-33-2 (55.4 g, 262 mmol) in DMF (550 mL) was added EtI (81.8 g, 524 mmol, 41.9 mL) and K2CO3 (109g, 787 mmol). The mixture was stirred at 25 °C for 2 h. The reaction mixture was added water (700 mL)and extracted with EtOAc (800 mL × 2). The combined organic layers were washed with brine (700 mL ×25 2), dried over Na2SO4, filtered and concentrated in vacuum to give a residue. The residue was purified bycolumn chromatography (SiO2, PE / EtOAc = 100 / 1 to 2 / 1) to give compound M-33-3 (45.1 g, 178 mmol,67.8% yield, 94.3% purity) as a yellow solid.

[0471] Synthesis of ethyl 6-amino-3-methoxy-2-methylbenzoate (M-33-4) To a solution of compoundM-33-3 (40.9 g, 171 mmol) and NH4Cl (45.7 g, 855 mmol) in MeOH (410 mL) and H2O (410 mL) was30 added Fe (95.5 g, 1.71 mol) at 80 °C in batches. The mixture was stirred at 80 °C for 2 h. The reaction AUG-P3833PCT mixture was filtered. The filtrate was added DCM (1000 mL), washed with water (800 mL × 2), dried overNa2SO4, filtered and concentrated in vacuum to give compound M-33-4 (48.3 g, crude) as a brown solid.

[0472] Synthesis of 6-methoxy-2,5-dimethylquinazolin-4-ol (M-33-5) To a solution of compound M-33-4 (42.0 g, 200 mmol) in 2-methoxyethanol (420 mL) was added acetamidine hydrochloride (47.4 g, 5015 mmol) and NaOAc (41.1 g, 501 mmol). The mixture was stirred at 130 °C for 20 h. The mixture wasadded water (800 mL) and filtered. The solid was washed with water and dried to give compound M-33-5(18.9 g, 91.4 mmol, 45.6% yield, 98.8% purity) as a brown solid.

[473] Synthesis of 6-methoxy-2,5-dimethylquinazoline-4-thiol (M-33) To a solution of compound M-33-5 (10.0 g, 49.0 mmol) in pyridine (100 mL) was added Lawesson’s reagent (33.8 g, 83.6 mmol). The10 mixture was stirred at 145 °C for 16 h. The reaction was diluted with H2O (300 mL) and extracted withEtOAc (300 mL × 3). The combined organic layers were washed with brine (200 mL), dried over Na2SO4,filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silicagel chromatography (SiO2; 120 g SepaFlash® Silica Flash Column, Eluent: 0~70% THF / PE gradient @ 60mL / min) to give compound M-33 (9.93 g, 41.8 mmol, 85.3% yield, 92.7% purity) as a yellow solid.15

[0474] Synthesis of 5-chloro-6-methoxy-2-methylquinazoline-4-thiol (M-34): (M-34)

[475] Synthesis of 6-bromo-2-chloro-3-methoxybenzoic acid (M-34-1) To a solution of 2-chloro-3-methoxy-benzoic acid (60.0 g, 322 mmol) in AcOH (300 mL) and H2O (300 mL) was added Br2(103 g, 643 mmol). The reaction was stirred at 60 °C for 16 h. The reaction mixture was quenched by H2O (150020 mL) at 25 °C, extracted with EtOAc (1000 mL × 2). The combined organic layers were washed with brine(500 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give compound M-34-1 (78.0 g, 264 mmol, 82.2% yield) as a yellow solid.

[476] Synthesis of ethyl 6-bromo-2-chloro-3-methoxybenzoate (M-34-2) To a solution of compoundM-34-1 (77.0 g, 290 mmol) in ACN (770 mL) was added EtI (67.8 g, 435 mmol) and Cs2CO3 (113 g, 34825 mmol). The reaction was stirred at 25 °C for 16 h. The reaction was filtered, and the filtrate wasconcentrated under reduced pressure to give a residue. The residue was purified by flash silica gelchromatography (SiO2; 220 g SepaFlash® Silica Flash Column, Eluent: 0~10% EtOAc / PE gradient @ 100mL / min) to give compound M-34-2 (83.0 g, 268 mmol, 92.6% yield) as a yellow oil.

[0477] Synthesis of ethyl 6-((tert-butoxycarbonyl)amino)-2-chloro-3-methoxybenzoate (M-34-3) To30 a solution of compound M-34-2 (82.0 g, 279 mmol) and tert-butyl carbamate (36.0 g, 307 mmol) in dioxane (800 mL) was added Xantphos (16.2 g, 27.9 mmol) , Cs2CO3 (182 g, 559 mmol) and Pd(OAc)2 (3.14 g, AUG-P3833PCT 14.0 mmol) under N2. The reaction was stirred at 100 °C for 16 h. The reaction was filtered andconcentrated under reduced pressure to give a residue. The residue was purified by flash silica gelchromatography (SiO2; 220 g SepaFlash® Silica Flash Column, Eluent: 0~10% EtOAc / PE gradient @ 100mL / min) to give compound M-34-3 (76.0 g, 207 mmol, 74.3% yield) as a yellow oil.5

[0478] Synthesis of ethyl 6-amino-2-chloro-3-methoxybenzoate (M-34-4) To a solution of compoundM-34-3 (76.0g, 230 mmol) in EtOAc (300 mL) was added HCl / EtOAc (500 mL) at 0 °C and stirred at 25°C for 12 h. The reaction was filtered, and the solid was concentrated under reduced pressure to givecompound M-34-4 (59.0 g, 211 mmol, 91.4% yield, HCl) as a white solid.

[0479] Synthesis of 5-chloro-6-methoxy-2-methylquinazolin-4-ol (M-34-5) To a solution of compound10 M-34-4 (57.0 g, 248 mmol) in CH3CN (500 mL) was added HCl (12.0 M, 207 mL) and stirred at 110 °Cfor 16 h. The reaction was concentrated to give a residue. The residue was diluted water (800 mL). ThepH was adjusted to 8 with NH3.H2O (400 mL). The solid precipitated out, was collected by filtration anddried under reduced pressure. The solid was triturated with MTBE (500 mL) at 25 oC for 60 min to givecompound M-34-5 (40.0 g, 160 mmol, 64.6% yield) as an off-white solid.15

[0480] Synthesis of 5-chloro-6-methoxy-2-methylquinazoline-4-thiol (M-34). To a solution ofcompound M-34-5 (10.0 g, 44.5 mmol) in toluene (150 mL) was added Lawesson's reagent (21.6 g, 53.4mmol) and stirred at 120 °C for 12 h. The reaction was diluted with K2CO3 aq. (300 mL) and extracted withEtOAc (300 mL × 3). The combined organic layers were washed with brine (200 mL), dried over Na2SO4,filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica20 gel chromatography (SiO2; 120 g SepaFlash® Silica Flash Column, Eluent: 0~70% THF / PE gradient @ 60mL / min) to give compound M-34 (4.50 g, 16.8 mmol, 37.8% yield) as a brown solid.

[0481] Synthesis of 2-methyl-5-(trifluoromethyl)quinazoline-4-thiol (M-35) 25

[0482] Synthesis of 2-methyl-5-(trifluoromethyl)quinazolin-4-ol (M-35-1) To a solution of 2-amino-6-(trifluoromethyl)benzoic acid (2 g, 9.75 mmol) in Ac2O (20 mL) The mixture was stirred at 140°C for 4 hrs. Then AcONH4 (1.67 g, 21.63 mmol) was added into the mixture and was stirred at 140°C for 2 hrs.White solid was precipitated out and the solid was collected by filtration and dried in vacuum to give compound M-35-1 (0.6 g, 2.63 mmol) as a white solid. AUG-P3833PCT

[483] Synthesis of 4-chloro-2-methyl-5-(trifluoromethyl)quinazoline (M-35-2) To a solution of M-35-1(50 mg, 219.13 μmol) in toluene (4 mL) was added POCl3 (67.20 mg, 438.27 μmol, 40.85 μL) and DIEA (56.64 mg, 438.27 μmol), then the mixture was stirred at 110oC for 3 h. The reaction mixture was quenched with ice water (10 mL) and was extracted with EtOAc 15 mL. The combined organic layers are dried over 5Na2SO4, filtered and concentrated to give compound M-35-2 (150 mg, crude) as a yellow solid.

[0484] Synthesis of 2-methyl-5-(trifluoromethyl)quinazoline-4-thiol (M-35) To a solution of M-35-2(500 mg, 2.03 mmol), NaHS (113.66 mg, 2.03 mmol) in DMF (10 mL) was stirred at 0°C for 1 hrs. The reaction mixture was quenched with H2O (100 mL) and was extracted with EtOAc 150 mL. The combined organic layers are dried over Na2SO4, filtered and concentrated to give a residue. The residue was purified 10 by flash silica gel chromatography (ISCO®; 20 SepaFlash® Silica Flash Column, Eluent of 0~40 % EtOAc / Petroleum ether gradient @ 80 mL / min) to give compound M-35 (320 mg, 1.31 mmol) as a yellow solid

[485] Synthesis of 6-cyclopropyl-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-4-thiol (M-36): 15

[0486] Synthesis of 6-chloro-4-((4-methoxybenzyl)thio)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine (M-36-1) To a solution of 4,6-dichloro-1-methyl-pyrazolo[3,4-d]pyrimidine (6.00 g, 29.6 mmol) and PMBSH(5.93 g, 38.4 mmol, 5.35 mL) in dioxane (60.0 mL) was added Cs2CO3(9.63 g, 29.6 mmol). The mixture was stirred at 25°C for 2 hrs. LCMS showed the desired product was formed and the starting material wasconsumed completely. The reaction was added water (100 mL) and extracted with EtOAc (200 mL* 3). 20 The combined organic layer was dried over Na2SO4, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / Ethyl acetate = 100 / 1 to 15 / 1) to give compound M-36-1 (6.02 g, 18.8 mmol, 63.5% yield) as a yellow solid.

[0487] Synthesis of 6-cyclopropyl-4-((4-methoxybenzyl)thio)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine (M-36-2) To a solution of compound M-36-1 (6.00 g, 18.7 mmol) and cyclopropylboronic25 acid (4.82 g, 56.1 mmol) in H2O (9.00 mL) and dioxane (45.0 mL) was added Cs2CO3(12.2 g, 37.4 mmol) and Pd(dppf)Cl2(1.37 g, 1.87 mmol) under N2. The mixture was stirred at 110°C for 4 hrs. LCMS showed the desired product was formed and the starting material was consumed completely. The mixture was added water (60 mL) and was extracted with EtOAc (60 mL * 2). The combined organic layer was dried over Na2SO4, filtered and concentrated to give a residue. The residue was purified by column30 chromatography (SiO2, petroleum ether / Ethyl acetate = 100 / 1 to 9 / 1) to give compound M-36-2 (2.96 g,9.07 mmol, 48.5% yield) was obtained as a yellow solid. AUG-P3833PCT

[488] Synthesis of 6-cyclopropyl-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-4-thiol (M-36) To asolution of compound M-36-2 (2.19 g, 6.71 mmol,) in TFA (22.0 mL) was added m-cresol (726 mg, 6.71mmol, 702 μL). The mixture was stirred at 80°C for 1 hr. LCMS showed the desired product was formedand the starting material was consumed completely. The reaction mixture was concentrated to give a 5 residue. The residue was purified by column chromatography (SiO2, petroleum ether / Ethyl acetate = 100 / 1 to 2 / 1) to give compound M-36 (1.03 g, 4.99 mmol, 74.4% yield) as a yellow solid.

[0489] Synthesis of 5-mercapto-7-methyl-1,6-naphthyridine-3-carbonitrile (M-37):

[490] Synthesis of 5,7-dichloro-3-iodo-1,6-naphthyridine (M-37-1) To a solution of 5,7-dichloro-1,6-10 naphthyridine (20.0 g, 100 mmol) in AcOH (350 mL) was added NIS (45.2 g, 201 mmol) under N2. The mixture was stirred at 100°C for 16 hrs. LCMS showed the desired product was formed and the starting material was consumed completely. The reaction mixture was concentrated in vacuum to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / Ethyl acetate = 100 / 1 to 19 / 1) to give compound M-37-1 (23.0 g, 70.8 mmol, 70.4% yield) as a yellow solid.15

[0491] Synthesis of 5,7-dichloro-1,6-naphthyridine-3-carbonitrile (M-37-2) To a solution ofcompound M-37-1 (7.73 g, 23.8 mmol) in DMF (78.0 mL) was added CuCN (2.56 g, 28.6 mmol). Themixture was stirred at 100°C for 16 hrs. LCMS showed the desired product was formed and the startingmaterial was consumed completely. The reaction was added water (80 mL) and extracted with EtOAc (80 mL* 2). The combined organic layer was washed with brine (100 mL * 3), dried over Na2SO4, filtered and20 concentrated in vacuum to give compound M-37-2 (5.33 g, 23.8 mmol, 100% yield) as a yellow solid.

[0492] Synthesis of 7-chloro-5-((4-methoxybenzyl)thio)-1,6-naphthyridine-3-carbonitrile (M-37-3)To a solution of compound M-37-2 (5.33 g, 23.8 mmol) in dioxane (55.0 mL) was added PMBSH (5.50 g,35.7 mmol, 4.97 mL) and Cs2CO3(11.6 g, 35.7 mmol). The mixture was stirred at 25°C for 2 hrs. LCMS showed the desired product was formed and the starting material was consumed completely. The reaction25 was added water (60 mL) and extracted with EtOAc (60 mL * 2). The combined organic layer was dried over Na2SO4, filtered and concentrated in vacuum to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / Ethyl acetate = 100 / 1 to 9 / 1) to give compound M-37-3 (7.60 g,22.2 mmol, 93.5% yield) as a yellow solid.

[493] Synthesis of 5-((4-methoxybenzyl)thio)-7-methyl-1,6-naphthyridine-3-carbonitrile (M-37-4)30 To a solution of compound M-37-3 (6.60 g, 19.3 mmol) and methylboronic acid (3.47 g, 57.9 mmol,) indioxane (66.0 mL) and H2O (13.0 mL) was added Cs2CO3 (12.6 g, 38.6 mmol) and Pd(dppf)Cl2 (1.41 g, AUG-P3833PCT 1.93 mmol) under N2. The mixture was stirred at 110°C for 4 hrs. LCMS showed the desired product wasformed and the starting material was consumed completely. The reaction mixture was quenched by water (70 mL) and extracted with EtOAc (80 mL * 2). The combined organic layer was dried over Na2SO4, filtered and concentrated in vacuum to give a residue. The residue was purified by column chromatography 5(SiO2, petroleum ether / Ethyl acetate = 100 / 1 to 9 / 1) to give compound M-37-4 (2.95 g, 9.18 mmol, 47.5%yield) as a yellow solid.

[494] Synthesis of 5-mercapto-7-methyl-1,6-naphthyridine-3-carbonitrile (M-37) To a solution ofCF3SO3H (467 mg, 3.11 mmol, 275 μL) and anisole (336 mg, 3.11 mmol, 338 μL) in TFA (1.77 g, 15.6 mmol, 1.16 mL) was added compound M-37-4 (500 mg, 1.56 mmol, 1.00 eq) at 0°C. The mixture was10 stirred at 0°C for 0.5 hr. LCMS showed the desired product was formed and the starting material wasconsumed completely. The mixture was added into ice-water (10 mL), adjusted to pH=8 with aq. NaHCO3, extracted with EtOAc (60 mL * 2). The combined organic layer was dried over Na2SO4, filtered and concentrated in vacuum to give compound M-37 (342 mg, crude) as a yellow solid.

[0495] Synthesis of 4-mercapto-5-methoxy-2-methylquinazoline-6-carbonitrile (M-38)15

[496] Synthesis of 6-bromo-5-methoxy-2H-benzo[d][1,3]oxazine-2,4(1H)-dione (M-38-1) To asolution of M-11-1 (40.0 g, 207 mmol) in DMF (150 mL) CH2Cl2 (300 mL) was added NBS (38.7 g, 217mmol) over 40 min at 0°C. The mixture was stirred at 0°C for 2hr. The reaction mixture was filtered. The 20 filter was added saturated NaHCO3solution (50 mL) and Na2S2O3solution (50 mL). Then extracted with EtOAc (100 mL*3), the combined organic layers were washed with brine (500 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give compound M-38-1 (32.0 g, 117 mmol, 56.80%yield) was obtained as a white solid.

[497] Synthesis of methyl 6-amino-3-bromo-2-methoxybenzoate (M-38-2) To a solution of M-38-125 (26.0 g, 95.5 mmol) in MeOH (260 mL) was added K2CO3(13.2 g, 95.5 mmol). The mixture was stirred at 80°C for 6hr. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~4% THF / PE@ 60mL / min) to give a compound M-38-2 (8.60 g, 33.0 mmol, 34.60% yield) wasobtained as a colorless oil. AUG-P3833PCT

[498] Synthesis of methyl 6-amino-3-cyano-2-methoxybenzoate (M-38-3) A mixture of M-38-2 (15.0g, 57.6 mmol), Zn(CN)2 (19.9 g, 169 mmol, 10.8 mL), Zn (960 mg, 14.7 mmol), Pd(PPh3)4 (6.66 g, 5.77 mmol) in DMF (200 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 135°C for 16hr under N2 atmosphere. The reaction mixture was cooled to 25°C, and 500 mL of a 10:2:88 5 (NaCl, K2CO3, H2O, wt%) solution was added followed by EtOAc (500 mL). The organic layers were separated, and the aqueous layer was extracted with EtOAc (500 mL). The combined organics were washed with H2O (200 mL) and dried Na2SO4. The residue was purified by flash silica gel chromatography (ISCO®; 220 g SepaFlash® Silica Flash Column, Eluent of 0~5% THF / PE@ 100 mL / min) to give a compound M-38-3 (6.20 g, 30.0 mmol, 52.14% yield) was obtained as a white solid.10

[0499] Synthesis of 6-amino-3-cyano-2-methoxybenzoic acid (M-38-4) To a solution of M-38-3 (4.50g, 21.8 mmol) in THF (50 mL) was added KOH (4 M, 16.3 mL). The mixture was stirred at 60°C for 16hr. The reaction mixture was concentrated under reduced pressure to remove THF (50 mL). The residue was adjusted the pH to 6 with HCl (1M), the white solid was precipitated out. The solid was collected by filtration and dried. Compound M-38-4 (2.80 g, 14.5 mmol, 66.76% yield) was obtained as a white solid.15

[0500] Synthesis of 5-methoxy-2-methyl-4-oxo-4,4a-dihydro-2H-benzo[d][1,3]oxazine-6-carbonitrile (M-38-5) A solution of M-38-4 (3.00 g, 15.6 mmol) in Ac2O (30 mL) was stirred at 140°Cfor 4 hr under N2 atmosphere. The reaction mixture was concentrated under reduced pressure to give acompound M-38-5 (5 g, crude) was obtained as a yellow oil.

[501] Synthesis of 4-hydroxy-5-methoxy-2-methylquinazoline-6-carbonitrile (M-38-6) A mixture of20 M-38-5 (5.00 g, 22.9 mmol, 1.00 eq), AcONH4 (17.6 g, 229 mmol) was stirred at 140°C for 2hr. Thereaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 120 g SepaFlash® Silica Flash Column, Eluent of 0~50% MeOH / DCM @ 100 mL / min) to give a compound M-38-6 (5.00 g, crude) was obtained as a white solid.

[0502] Synthesis of 4-mercapto-5-methoxy-2-methylquinazoline-6-carbonitrile (M-38) To a solution25 of M-38-6 (840 mg, 3.90 mmol) in Tol. (5 mL) was added Lawesson's Reagent (1.89 g, 4.68 mmol). Themixture was stirred at 110°C for 0.5hr. The reaction mixture concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0~100% THF / PE @ 70 mL / min) to give a compound M-38 (920 mg, crude) wasobtained as a yellow solid.30

[0503] Synthesis of 5-chloro-2-methylquinazoline-4-thiol (M-39) AUG-P3833PCT

[504] Synthesis of 5-chloro-2-methyl-2,4a-dihydro-4H-benzo[d][1,3]oxazin-4-one(M-39-1) To asolution of 2-amino-6-chloro-benzoic acid (11.0 g, 64.1 mmol) in Ac2O (120 mL) The reaction mixture was stirred at 140°C for 4 hrs. The reaction was concentrated under reduced pressure to give compound M- 39-1 (12.0 g, 60.7 mmol, 94.7% yield, crude) as a light yellow solid.5

[0505] Synthesis of 5-chloro-2-methylquinazolin-4-ol (M-39-2) To a mixture of compound M-39-1(12.0 g, 60.7 mmol) and NH4OAc (23.4 g, 304 mmol). The mixture was stirred at 140°C for 2 hrs. Themixture was poured into water (50 mL), White solid was precipitated out and the solid was collected by filtration and dried in vacuum to give compound M-39-2 (6.90 g, 35.5 mmol, 58.4% yield, 100% purity)as a brown solid.10

[0506] Synthesis of 5-chloro-2-methylquinazoline-4-thiol (M-39) To a solution of compound M-39-2(3.00 g, 15.4 mmol) in Tol. (110 mL) was added Lawesson's Reagent (7.48 g, 18.5 mmol). The reactionmixture was concentrated in vacuum to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 100 / 30) to give compound M-39 (1.90 g, 9.02 mmol, 58.5%yield, 98.2% purity) as a yellow solid.15

[0507] Synthesis of 5-methylpyrazolo[1,5-a]pyrimidine-7-thiol (M-40)

[508] Synthesis of 2,6-dimethylpyridine-4-thiol (M-40) To a solution of 7-chloro-5-methyl-pyrazolo[1,5-a]pyrimidine (150 mg, 895 μmol) in EtOH (3.00 mL) was added thiourea (136 mg, 1.79mmol). The...

Claims

1. AUG-P3833PCT 348 CLAIMS 1. A compound of formula (I)wherein said compound is a compound of formula (I) 5 or a pharmaceutically acceptable salt and / or solvate thereof; wherein -Y1 is a 9 or 10-membered bicyclic heteroaryl selected from the following formulae10 AUG-P3833PCT wherein A1, A2, A3, A4, A5, A6and A7are each independently selected from C-R7and N; A8, A9, A10 and A11 are each independently selected from C-R7 and N, provided that at least one of5 A8, A9, A10or A11is N; G1is selected from C-R3and N; G2is selected from O and N-R4; Bis selected from O, S and N-R5, provided that when:i) A5, A6and B are present, and A5and A6are C-R7; or 10 ii) A5, A7and B are present, and A5and A7are C-R7; or iii) A6, A7and B are present, and A6and A7are C-R7, then B is not S; andR2 is selected from hydrogen, halogen, cyano, amino, hydroxy, -(C1-C6) alkyl,-(C3-C9) cycloalkyl, -(C2-C9) heterocycloalkyl, aryl, heteroaryl, -(C1-C6) alkylene-(C3-15C9) cycloalkyl, -(C1-C6) alkylene-(C2-C9) heterocycloalkyl, -OR15, -(C1-C6) alkylene-OR15, -O-(C2- C6) alkylene-OR15, -NR16-(C2-C6) alkylene-OR15, -NR17R18, -(C1-C6) alkylene-NR17R18, -O-(C2- C6) alkylene-NR17R18, and -NR16-(C2-C6) alkylene-NR17R18; R3 is selected from hydrogen, halogen, cyano, amino, hydroxy, -(C1-C6) alkyl,-(C3-C9) cycloalkyl, -(C2-C9) heterocycloalkyl, aryl, heteroaryl, -(C1-C6) alkylene-(C3-20C9) cycloalkyl, -(C 151-C6) alkylene-(C2-C9) heterocycloalkyl, -OR , -(C1-C6) alkylene-OR15, -O-(C2- C6) alkylene-OR15, -NR16-(C 15 17 182-C6) alkylene-OR , -NR R , -(C1-C6) alkylene-NR17R18, -O-(C2- C6) alkylene-NR17R18, and -NR16-(C2-C6) alkylene-NR17R18; R4 is selected from hydrogen, -(C1-C6) alkyl, -(C3-C9) cycloalkyl, and -(C2-C9) heterocycloalkyl;R5 is selected from hydrogen, -(C1-C6) alkyl, -(C3-C9) cycloalkyl, and -(C2-C9) heterocycloalkyl;25 R6 is selected from hydrogen, halogen, cyano, and -(C1-C6) alkyl; AUG-P3833PCT R7 is independently selected from hydrogen, halogen, amino, -NH-(C1-C6) alkyl, -N-((C1-C6) alkyl)2hydroxy, cyano, -(C1-C6) alkyl, -O-(C1-C6) alkyl, -(C3-C9) cycloalkyl, -O-(C3-C9) cycloalkyl, -(C1-C6) alkylene-(C3-C9) cycloalkyl, -(C1-C6) alkylene-(C2-C9) heterocycloalkyl, -(C2-C9) heterocycloalkyl, aryl, and heteroaryl;5 wherein each of said -(C1-C6) alkyl or -(C1-C6) alkylene in R2, R3, R4, R5, R6or R7is optionally substituted with at least one group selected from halogen, cyano, hydroxy, oxo, amino, -O-(C1-C6) alkyl, -NH-(C1-C6) alkyl, and -N-((C1-C6) alkyl)2;each of said -(C3-C9) cycloalkyl, -(C2-C9) heterocycloalkyl, aryl or heteroaryl in R2, R3, R4, R5, 10 R6or R7is optionally substituted with at least one group selected from halogen, cyano, hydroxy, oxo, amino, -(C1-C6) alkyl, -CH2-O-(C1-C6) alkyl, -CH2-NH-(C1-C6) alkyl, -CH2-N-((C1-C6) alkyl)2, -O-(C1-C6) alkyl,-NH-(C1-C6) alkyl, and -N-((C1-C6) alkyl)2;R15, R16, R17 and R18 are each independently selected from hydrogen,15 -(C1-C6) haloalkyl, -(C1-C6) alkyl, -(C3-C9) cycloalkyl, -(C1-C6) alkylene-(C3-C9) cycloalkyl, -(C2-C9) heterocycloalkyl, aryl, heteroaryl, -(C1-C6) alkylene-(C2-C9) heterocycloalkyl, -(C1-C6) alkylene-heteroaryl, and -(C1-C6) alkylene-aryl; and / or two groups selected from R15, R16, R17and R18 form together a cycle selected from -(C3-C9) cycloalkyl, -(C2-C9) heterocycloalkyl, aryl,and heteroaryl; 20 wherein each of said -(C1-C6) alkyl or -(C1-C6) alkylene in R15, R16, R17or R18is optionally substituted with at least one group selected from halogen, cyano, hydroxy, oxo, amino, -O-(C1-C6) alkyl,-NH-(C1-C6) alkyl, and -N-((C1-C6) alkyl)2;each of said -(C3-C9) cycloalkyl, -(C2-C9) heterocycloalkyl, aryl or heteroaryl in R15, R16, R1725 or R18is optionally substituted with at least one group selected from halogen, cyano, hydroxy, oxo, amino, -(C1-C6) alkyl, -CH2-O-(C1-C6) alkyl, -CH2-NH-(C1-C6) alkyl, -CH2-N-((C1-C6) alkyl)2, -O-(C1-C6) alkyl, -NH-(C1-C6) alkyl, and -N-((C1-C6) alkyl)2;- L1 is -(NH)m-, wherein m is an integer selected from 0 and 1;- W is N or C-R12;30 - X is N or C-R13;wherein R12and R13are each independently selected from hydrogen, halogen, and -(C1- C3) alkyl; AUG-P3833PCT -L2 is -(CR10R11)n;wherein nis an integer selected from 0, 1, 2 and 3;R10 is selected from hydrogen, halogen, hydroxy, amino, -(C1-C3) alkyl, -(C1-C2) haloalkyl, -(C1-5 C2) hydroxyalkyl, -(C1-C2) aminoalkyl, -O-(C1-C4) alkyl, -NH-(C1-C3) alkyl, and -N-((C1-C3) alkyl)2, -(C3-C9) cycloalkyl, -(C2-C9) heterocycloalkyl, aryl, and heteroaryl;wherein each of the -(C3-C9) cycloalkyl, -(C2-C9) heterocycloalkyl, aryl, heteroaryl isoptionally substituted with at least one group selected from halogen, cyano, hydroxy, amino, -(C1-C6) alkyl, -(C1-C6) haloalkyl and -O-(C1-C6) alkyl;10 R11 is selected from hydrogen, halogen, hydroxy, amino, -(C1-C3) alkyl, -(C1-C2) haloalkyl, -(C1-C2) hydroxyalkyl, -(C1-C2) aminoalkyl, -O-(C1-C4) alkyl, -NH-(C1-C3) alkyl, -N-((C1-C3) alkyl)2;or R10and R11when bound to the same carbon atom together with the carbon atom to which they are bound form a (C3-C9) cycloalkyl or (C2-C9) heterocycloalkyl;or when n is 2 or 3, any two groups selected from R10 and R11 when bound to different carbon15 atoms together with the carbon atom to which they are bound and any intervening atom present form a (C3-C9) cycloalkyl or (C2-C9) heterocycloalkyl;- Z1 is selected from hydrogen, -(C1-C6) alkyl, -(C3-C9) cycloalkyl,-(C2-C9) heterocycloalkyl, aryl, heteroaryl, -(C1-C6) alkylene-(C3-C9) cycloalkyl,-(C1-C6) alkylene-(C2-C9) heterocycloalkyl, -(C1-C6) alkylene-aryl and -(C1-C6) alkylene-heteroaryl;20 wherein each of the -(C1-C6) alkyl, -(C3-C9) cycloalkyl, -(C2-C9) heterocycloalkyl, aryl orheteroaryl in Z1is optionally substituted with at least one group selected from halogen, - NR23R24, methyl, hydroxy, -(C1-C2) haloalkyl, and -(C1-C2) hydroxyalkyl; wherein R23and R24are each independently selected from hydrogen and methyl; -R1 is selected from hydrogen, -(C1-C6) alkyl, -(C3-C9) cycloalkyl,25 -(C1-C6) alkylene-(C3-C9) cycloalkyl, and -(C2-C9) heterocycloalkyl;wherein the -(C1-C6) alkyl or -(C1-C6) alkylene in R1is optionally substituted with at least one group selected from halogen, cyano, hydroxy, amino, -(C1-C6) alkyl, -CH2-O-(C1-C6) alkyl, and -O-(C1-C6) alkyl;wherein the -(C3-C9) cycloalkyl or -(C2-C9) heterocycloalkyl in R1is optionally substituted30 with at least one group selected from halogen, cyano, hydroxy, amino, -(C1-C6) alkyl, -CH2-O-(C1-C6) alkyl, and -O-(C1-C6) alkyl; AUG-P3833PCT or R1 and one of R10 or R11 form together a -(C2-C9) heterocycloalkyl comprising at least one nitrogenatom; wherein said -(C2-C9) heterocycloalkyl in R1and R10or R11is optionally substituted with at least one group selected from halogen, cyano, hydroxy, amino, -(C1-C6) alkyl, -CH2-O-(C1-5 C6) alkyl, and -O-(C1-C6) alkyl; andor R1and Z1form together with the nitrogen atom to which they are bound a - (C2-C9) heterocycloalkyl;wherein said -(C2-C9) heterocycloalkyl in R1and Z1is optionally substituted with at least one group selected from halogen, cyano, hydroxy, amino,10 -(C1-C6) alkyl, -CH2-O-(C1-C6) alkyl, -O-(C1-C6) alkyl, -(C1-C2) haloalkyl, and -(C1-C2) hydroxyalkyl;provided that the compound is not 1-morpholino-2-(5-(2-(thieno[2,3-d]pyrimidin-4-ylthio)acetyl)thiophen-2-yl)ethan-1-one or a pharmaceutically acceptable salt and / or solvate thereof. 15 2. The compound or a pharmaceutically acceptable salt and / or solvate thereof of formula (I) according to claim 1, wherein said compound is a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof; 20 wherein -Y1 is a 9 or 10-membered bicyclic heteroaryl selected from the following formulae AUG-P3833PCT 5 wherein A1, A2, A3, A4, A5, A6and A7are each independently selected from C-R7and N; A8, A9, A10 and A11 are each independently selected from C-R7 and N, provided that at least one ofA8, A9, A10or A11is N; G1is selected from C-R3and N; 10 G2is selected from O and N-R4; Bis selected from O, S and N-R5, provided that when:i) A5, A6 and B are present, and A5 and A6 are C-R7; orii) A5, A7and B are present, and A5and A7are C-R7; or iii) A6, A7and B are present, and A6and A7are C-R7,15 then B is not S; and AUG-P3833PCT R2 is selected from hydrogen, halogen, cyano, amino, hydroxy, -(C1-C6) alkyl,-(C3-C9) cycloalkyl, -(C2-C9) heterocycloalkyl, aryl, heteroaryl, -(C1-C6) alkylene-(C3-C ) cycloalkyl, -(C -C ) alkylene-(C -C ) heterocyc 15 159 1 6 2 9 loalkyl, -OR , -(C1-C6) alkylene-OR , -O-(C2-C6) alkylene-OR15, -NR16-(C 15 17 182-C6) alkylene-OR , -NR R , -(C1-C6) alkylene-NR17R18, -O-(C2- 5C 17 18 166) alkylene-NR R , and -NR -(C2-C6) alkylene-NR17R18; R3 is selected from hydrogen, halogen, cyano, amino, hydroxy, -(C1-C6) alkyl,-(C3-C9) cycloalkyl, -(C2-C9) heterocycloalkyl, aryl, heteroaryl, -(C1-C6) alkylene-(C3-C ) cycloalk 15 159 yl, -(C1-C6) alkylene-(C2-C9) heterocycloalkyl, -OR , -(C1-C6) alkylene-OR , -O-(C2-C6) alkylene-OR15, -NR16-(C2-C6) alkylene-OR15, -NR17R18, -(C1-C6) alkylene-NR17R18, -O-(C2-10C6) alkylene-NR17R18, and -NR16-(C2-C6) alkylene-NR17R18; R4 is selected from hydrogen, -(C1-C6) alkyl, -(C3-C9) cycloalkyl, and -(C2-C9) heterocycloalkyl;R5 is selected from hydrogen, -(C1-C6) alkyl, -(C3-C9) cycloalkyl, and -(C2-C9) heterocycloalkyl;R6 is selected from hydrogen, halogen, cyano, and -(C1-C6) alkyl;R7 is independently selected from hydrogen, halogen, amino, -NH-(C1-C6) alkyl, -N-((C1-C6) alkyl)215 hydroxy, cyano, -(C1-C6) alkyl, -O-(C1-C6) alkyl, -(C3-C9) cycloalkyl, -(C1-C6) alkylene-(C3-C9) cycloalkyl, -(C1-C6) alkylene-(C2-C9) heterocycloalkyl, -(C2-C9) heterocycloalkyl, aryl, andheteroaryl; wherein each of said -(C1-C6) alkyl or -(C1-C6) alkylene in R2, R3, R4, R5, R6or R7is optionally substituted20 with at least one group selected from halogen, cyano, hydroxy, oxo, amino, -O-(C1-C6) alkyl, -NH-(C1-C6) alkyl, and -N-((C1-C6) alkyl)2;each of said -(C3-C9) cycloalkyl, -(C2-C9) heterocycloalkyl, aryl or heteroaryl in R2, R3, R4, R5, R6or R7is optionally substituted with at least one group selected from halogen, cyano, hydroxy, oxo, amino, -(C1-C6) alkyl, -CH2-O-(C1-C6) alkyl, -CH2-NH-(C1-C6) alkyl, -CH2-N-((C1-25 C6) alkyl)2, -O-(C1-C6) alkyl,-NH-(C1-C6) alkyl, and -N-((C1-C6) alkyl)2;R15, R16, R17 and R18 are each independently selected from hydrogen,-(C1-C6) haloalkyl, -(C1-C6) alkyl, -(C3-C9) cycloalkyl, -(C1-C6) alkylene-(C3-C9) cycloalkyl, -(C2-C9) heterocycloalkyl, aryl, heteroaryl, -(C1-C6) alkylene-(C2-C9) heterocycloalkyl, -(C1-30C6) alkylene-heteroaryl, and -(C1-C6) alkylene-aryl; and / or two groups selected from R15, R16, R17and R18 form together a cycle selected from -(C3-C9) cycloalkyl, -(C2-C9) heterocycloalkyl, aryl,and heteroaryl; AUG-P3833PCT wherein each of said -(C1-C6) alkyl or -(C1-C6) alkylene in R15, R16, R17or R18is optionally substituted with at least one group selected from halogen, cyano, hydroxy, oxo, amino, -O-(C1-C6) alkyl,-NH-(C1-C6) alkyl, and -N-((C1-C6) alkyl)2;5each of said -(C3-C9) cycloalkyl, -(C2-C9) heterocycloalkyl, aryl or heteroaryl in R15, R16, R17or R18is optionally substituted with at least one group selected from halogen, cyano, hydroxy, oxo, amino, -(C1-C6) alkyl, -CH2-O-(C1-C6) alkyl, -CH2-NH-(C1-C6) alkyl, -CH2-N-((C1-C6) alkyl)2, -O-(C1-C6) alkyl, -NH-(C1-C6) alkyl, and -N-((C1-C6) alkyl)2;- L1 is -(NH)m-, wherein m is an integer selected from 0 and 1;10 - W is N or C-R12;- X is N or C-R13;wherein R12 and R13 are each independently selected from hydrogen, halogen, and -(C1-C3) alkyl;- L2 is -(CR10R11)n;15 wherein nis an integer selected from 0, 1, 2 and 3;R10 is selected from hydrogen, halogen, hydroxy, amino, -(C1-C3) alkyl, -(C1-C2) haloalkyl, -(C1-C2) hydroxyalkyl, -(C1-C2) aminoalkyl, -O-(C1-C4) alkyl, -NH-(C1-C3) alkyl, and -N-((C1-C3) alkyl)2, -(C3-C9) cycloalkyl, -(C2-C9) heterocycloalkyl, aryl, and heteroaryl;20 wherein each of the -(C3-C9) cycloalkyl, -(C2-C9) heterocycloalkyl, aryl, heteroaryl isoptionally substituted with at least one group selected from halogen, cyano, hydroxy, amino, -(C1-C6) alkyl, -(C1-C6) haloalkyl and -O-(C1-C6) alkyl; R11 is selected from hydrogen, halogen, hydroxy, amino, -(C1-C3) alkyl, -(C1-C2) haloalkyl, -(C1-C2) hydroxyalkyl, -(C1-C2) aminoalkyl, -O-(C1-C4) alkyl, -NH-(C1-C3) alkyl, -N-((C1-C3) alkyl)2;25 or R10 and R11 form together with the carbon atom to which they are bound a (C3-C9) cycloalkyl or(C2-C9) heterocycloalkyl; AUG-P3833PCT -Z1 is selected from hydrogen, -(C1-C6) alkyl, -(C3-C9) cycloalkyl,-(C2-C9) heterocycloalkyl, aryl, heteroaryl, -(C1-C6) alkylene-(C3-C9) cycloalkyl,-(C1-C6) alkylene-(C2-C9) heterocycloalkyl, -(C1-C6) alkylene-aryl and -(C1-C6) alkylene-heteroaryl;wherein each of the -(C1-C6) alkyl, -(C3-C9) cycloalkyl, -(C2-C9) heterocycloalkyl, aryl or5 heteroaryl in Z1is optionally substituted with at least one group selected from halogen, - NR23R24, methyl, hydroxy, -(C1-C2) haloalkyl, and -(C1-C2) hydroxyalkyl; wherein R23and R24are each independently selected from hydrogen and methyl; -R1 is selected from hydrogen, -(C1-C6) alkyl, -(C3-C9) cycloalkyl,-(C1-C6) alkylene-(C3-C9) cycloalkyl, and -(C2-C9) heterocycloalkyl;10wherein the -(C1-C6) alkyl or -(C1-C6) alkylene in R1is optionally substituted with at least one group selected from halogen, cyano, hydroxy, amino, -(C1-C6) alkyl, -CH2-O-(C1-C6) alkyl, and -O-(C1-C6) alkyl;wherein the -(C3-C9) cycloalkyl or -(C2-C9) heterocycloalkyl in R1is optionally substituted with at least one group selected from halogen, cyano, hydroxy, amino, -(C1-C6) alkyl, -CH2-15 O-(C1-C6) alkyl, and -O-(C1-C6) alkyl;or R1 and one of R10 or R11 form together a -(C2-C9) heterocycloalkyl comprising at least one nitrogenatom; wherein said -(C2-C9) heterocycloalkyl in R1and R10or R11is optionally substituted with at least one group selected from halogen, cyano, hydroxy, amino, -(C1-C6) alkyl, -CH2-O-(C1-20 C6) alkyl, and -O-(C1-C6) alkyl; andor R1and Z1form together with the nitrogen atom to which they are bound a - (C2-C9) heterocycloalkyl;wherein said -(C2-C9) heterocycloalkyl in R1and Z1is optionally substituted with at least one group selected from halogen, cyano, hydroxy, amino,25 -(C1-C6) alkyl, -CH2-O-(C1-C6) alkyl, -O-(C1-C6) alkyl, -(C1-C2) haloalkyl, and -(C1-C2) hydroxyalkyl;provided that the compound is not 1-morpholino-2-(5-(2-(thieno[2,3-d]pyrimidin-4-ylthio)acetyl)thiophen-2-yl)ethan-1-one or a pharmaceutically acceptable salt and / or solvate thereof. AUG-P3833PCT 3. The compound or a pharmaceutically acceptable salt and / or solvate thereof of formula (I) accordingto claim 1 or claim 2,wherein said compound is a compound of formula (I) 5 or a pharmaceutically acceptable salt and / or solvate thereof; wherein -Y1 is a 9 or 10-membered bicyclic heteroaryl selected from the following formulae10 AUG-P3833PCT wherein A1, A2, A3, A4, A5, A6and A7are each independently selected from C-R7and N; A8, A9, A10 and A11 are each independently selected from C-R7 and N, provided that at least one of5 A8, A9, A10or A11is N; G1is selected from C-R3and N; G2is selected from O and N-R4; Bis selected from O, S and N-R5, provided that when A5, A6 and A7 are C-R7, then B is not S; andR2 is selected from hydrogen, halogen, cyano, amino, hydroxy, -(C1-C6) alkyl,10 -(C3-C7) cycloalkyl, -(C3-C7) heterocycloalkyl, aryl, heteroaryl, -(C1-C6) alkylene-(C3-C7) cycloalkyl, -(C1-C6) alkylene-(C3-C7) heterocycloalkyl, -OR15, -(C1-C6) alkylene-OR15, -O-(C2-C6) alkylene-OR15, -NR16-(C2-C6) alkylene-OR15, -NR17R18, -(C -C ) alkylene-NR17R18, -O-(C -C ) alkylene-NR17R18, and -NR161 6 2 6 -(C2-C6) alkylene-NR17R18;15 R3 is selected from hydrogen, halogen, cyano, amino, hydroxy, -(C1-C6) alkyl,-(C3-C7) cycloalkyl, -(C3-C7) heterocycloalkyl, aryl, heteroaryl, -(C1-C6) alkylene-(C3-C7) cycloalkyl, -(C1-C6) alkylene-(C3-C7) heterocycloalkyl, -OR15, -(C1-C6) alkylene-OR15, -O-(C2-C6) alkylene-OR15, -NR16-(C2-C6) alkylene-OR15, -NR17R18, -(C -C ) alkylene-NR17R18, -O-(C -C ) alkylene-NR17R18, and 161 6 2 6 -NR -(C2-C6) alkylene-20NR17R18; R4 is selected from hydrogen, -(C1-C6) alkyl, -(C3-C7) cycloalkyl, and-(C3-C7) heterocycloalkyl;R5 is selected from hydrogen, -(C1-C6) alkyl, -(C3-C7) cycloalkyl, and-(C3-C7) heterocycloalkyl;25 R6 is selected from hydrogen, halogen, cyano, and -(C1-C6) alkyl;R7 is selected from hydrogen, halogen, amino, hydroxy, cyano, -(C1-C6) alkyl,-(C3-C7) cycloalkyl, -(C1-C6) alkylene-(C3-C7) cycloalkyl, -(C1-C6) alkylene-(C3-C7) heterocycloalkyl, -(C3-C7) heterocycloalkyl, aryl, and heteroaryl; AUG-P3833PCT wherein each of said -(C1-C6) alkyl or -(C1-C6) alkylene in R2, R3, R4, R5, R6or R7is optionally substituted with at least one group selected from halogen, cyano, hydroxy, oxo, amino, -O-(C1-C6) alkyl, -NH-(C1-C6) alkyl, and5 -N-((C1-C6) alkyl)2;each of said -(C3-C7) cycloalkyl, -(C3-C7) heterocycloalkyl, aryl or heteroaryl in R2, R3, R4, R5, R6or R7is optionally substituted with at least one group selected from halogen, cyano, hydroxy, oxo, amino, -(C1-C6) alkyl, -CH2-O-(C1-C6) alkyl, -CH2-NH-(C1-C6) alkyl, -CH2-N-((C1-C6) alkyl)2, -O-(C1-C6) alkyl,10 -NH-(C1-C6) alkyl, and -N-((C1-C6) alkyl)2;R15, R16, R17 and R18 are each independently selected from hydrogen,-(C1-C6) haloalkyl, -(C1-C6) alkyl, -(C3-C7) cycloalkyl, -(C1-C6) alkylene-(C3-C7) cycloalkyl, -(C3-C7) heterocycloalkyl, aryl, heteroaryl,-(C1-C6) alkylene-(C3-C7) heterocycloalkyl, -(C1-C6) alkylene-heteroaryl, and15-(C1-C6) alkylene-aryl; and / or two groups selected from R15, R16, R17and R18form together a cycle selected from -(C3-C7) cycloalkyl,-(C3-C7) heterocycloalkyl, aryl, and heteroaryl;wherein each of said -(C1-C6) alkyl or -(C1-C6) alkylene in R15, R16, R17or R18is optionally substituted20 with at least one group selected from halogen, cyano, hydroxy, oxo, amino, -O-(C1-C6) alkyl,-NH-(C1-C6) alkyl, and-N-((C1-C6) alkyl)2;each of said -(C3-C7) cycloalkyl, -(C3-C7) heterocycloalkyl, aryl or heteroaryl in R15, R16, R17or R18is optionally substituted with at least one group selected from halogen, cyano, hydroxy,25 oxo, amino, -(C1-C6) alkyl, -CH2-O-(C1-C6) alkyl, -CH2-NH-(C1-C6) alkyl, -CH2-N-((C1-C6) alkyl)2,-O-(C1-C6) alkyl, -NH-(C1-C6) alkyl, and -N-((C1-C6) alkyl)2;- L1 is -(NH)m-, wherein m is an integer selected from 0 and 1;- W is N or C-R12;30 - X is N or C-R13;wherein R12and R13are each independently selected from hydrogen and halogen; AUG-P3833PCT -L2 is -(CR10R11)n;wherein nis an integer selected from 0, 1, 2 and 3;R10 and R11 are independently selected from hydrogen, halogen, hydroxy, amino, -(C1-C3) alkyl,5 -(C1-C2) haloalkyl, -(C1-C2) hydroxyalkyl,-(C1-C2) aminoalkyl, -O-(C1-C4) alkyl, -NH-(C1-C3) alkyl, and-N-((C1-C3) alkyl)2;or R10 and R11 form together with the carbon atom to which they are bound a (C3-C6) cycloalkylor (C4-C9) heterocycloalkyl;10 - Z1 is selected from hydrogen, -(C1-C6) alkyl, -(C3-C6) cycloalkyl,-(C3-C9) heterocycloalkyl, aryl, heteroaryl, -(C1-C6) alkylene-(C3-C9) cycloalkyl,-(C1-C6) alkylene-(C3-C9) heterocycloalkyl, and -(C1-C6) alkylene-heteroaryl;wherein each of the -(C1-C6) alkyl, -(C3-C7) cycloalkyl,-(C3-C7) heterocycloalkyl, aryl or heteroaryl in Z1is optionally substituted with at least one group15 selected from halogen, -NR23R24, methyl, and hydroxy; wherein R23 and R24 are eachindependently selected from hydrogen and methyl; -R1 is selected from hydrogen, -(C1-C6) alkyl, -(C3-C7) cycloalkyl,-(C1-C6) alkylene-(C3-C7) cycloalkyl, and (C3-C7) heterocycloalkyl;wherein the -(C1-C6) alkyl or -(C1-C6) alkylene in R1is optionally substituted with at least one 20 group selected from halogen, cyano, hydroxy, amino, -(C1-C6) alkyl, -CH2-O-(C1-C6) alkyl, and -O-(C1-C6) alkyl;wherein the -(C3-C7) cycloalkyl or (C3-C7) heterocycloalkyl in R1is optionally substituted with at least one group selected from halogen, cyano, hydroxy, amino, -(C1-C6) alkyl, -CH2-O-(C1-C6) alkyl, and -O-(C1-C6) alkyl;25 or R1 and one of R10 or R11 form together a (C3-C7) heterocycloalkyl comprising at least one nitrogenatom; wherein said (C3-C7) heterocycloalkyl in R1and R10or R11is optionally substituted with at least one group selected from halogen, cyano, hydroxy, amino, -(C1-C6) alkyl, -CH2-O-(C1-C6) alkyl, and -O-(C1-C6) alkyl; and AUG-P3833PCT or R1and Z1form together with the nitrogen atom to which they are bound a (C3-C9) heterocycloalkyl;wherein said (C3-C7) heterocycloalkyl in R1and Z1is optionally substituted with at least one group selected from halogen, cyano, hydroxy, amino, 5-(C1-C6) alkyl, -CH2-O-(C1-C6) alkyl, and -O-(C1-C6) alkyl;provided that the compound is not selected from 1-morpholino-2-(5-(2-(thieno[2,3-d]pyrimidin-4-ylthio)acetyl)thiophen-2-yl)ethan-1-one; or a pharmaceutically acceptable salt and / or solvate thereof.

4. The compound or a pharmaceutically acceptable salt and / or solvate thereof according to any one of10 claims 1 to 3, wherein Y1 is a 9- or 10-membered bicyclic heteroaryl selected from:the following formulae wherein A1-A4, B, A6, A7, G1, R2 and R6 are independently as defined in any one of claims 1 to3. 15 5. The compound or a pharmaceutically acceptable salt and / or solvate thereof according to claim 4, wherein Y1is a 10-membered bicyclic heteroaryl of the following formula wherein A1-A4, G1, and R2are independently as defined in claim 4.

6. The compound or a pharmaceutically acceptable salt and / or solvate thereof according to claim 5,20 wherein Y1is selected from: AUG-P3833PCT ,preferably selected from: wherein R2 and R7 are independently as defined in any one of claims 1 to 3.5 7. The compound or a pharmaceutically acceptable salt and / or solvate thereof according to any one ofclaims 1 to 6, wherein R2 is selected from the group consisting of hydrogen, -(C1-C6) alkyl, -(C3-C9) cycloalkyl, -NR17R18 and -OR15, wherein -(C1-C6) alkyl is optionally substituted with at least onehalogen, wherein each of R15, R17 and R18 are -(C1-C6) alkyl, preferably methyl.

8. The compound or a pharmaceutically acceptable salt and / or solvate thereof according to claim 7,10 wherein R2 is hydrogen or -(C1-C6) alkyl, preferably methyl.

9. The compound or a pharmaceutically acceptable salt and / or solvate thereof according to any one ofclaims 1 to 8, wherein R3 is selected from the group consisting of hydrogen, cyano and -(C1-C6) alkyl,preferably hydrogen.

10. The compound or a pharmaceutically acceptable salt and / or solvate thereof according to any one of15 claims 1 to 9, whereinR4 is hydrogen or -(C1-C6) alkyl, preferably hydrogen; and / orR5 is hydrogen or -(C1-C6) alkyl, preferably hydrogen; and / orR6 is hydrogen or -(C1-C6) alkyl, preferably hydrogen. AUG-P3833PCT 11. The compound or a pharmaceutically acceptable salt and / or solvate thereof according to any one ofclaims 1 to 10, wherein R7 is independently selected from the group consisting of hydrogen, halogen,-N-((C1-C6) alkyl)2, cyano, -(C1-C6) alkyl, -O-(C1-C6) alkyl, -O-(C3-C9) cycloalkyl and -(C2-C9) heterocycloalkyl, wherein each -(C1-C6) alkyl and -O-(C1-C6) alkyl are optionally substituted5 with at least one halogen group and each -(C2-C9) heterocycloalkyl is optionally substituted with atleast one oxo.

12. The compound or a pharmaceutically acceptable salt and / or solvate thereof according to claim 11,wherein R7 is independently selected from the group consisting of hydrogen, halogen, -(C1-C6) alkyland -O-(C1-C6) alkyl, wherein each -(C1-C6) alkyl and -O-(C1-C6) alkyl are optionally substituted10 with at least one halogen group.

13. The compound or a pharmaceutically acceptable salt and / or solvate thereof according to claim 12,wherein R7is independently selected from hydrogen, halogen and -O-(C1-C6) alkyl, preferably methoxy.

14. The compound or a pharmaceutically acceptable salt and / or solvate thereof according to any one of15 claims 1 to 13, whereinX is C-R12 and / or W is C-R13, preferably X is C-R12 and W is C-R13; and / orR12and / or R13is hydrogen; and / or mis 0.

15. The compound or a pharmaceutically acceptable salt and / or solvate thereof according to any one of20 claims 1 to 14, wherein n is selected from 1 and 2, preferably n is 1.

16. The compound or a pharmaceutically acceptable salt and / or solvate thereof according to any one ofclaims 1 to 15, wherein R10 and R11 are independently selected from hydrogen, hydroxy, and -(C1-C3) alkyl.

17. The compound according to any one of claims 1 to 15, wherein L2 is selected from -CH2-, -CH(CH3)-25 , cycloprop-1,1-yl, and -C(CH3)(OH)-, preferably -C(CH3)(OH)-.

18. The compound according to any one of claims 1 to 17, wherein R1 is selected from hydrogen, -(C1-C3) alkyl, and aryl, preferably hydrogen.

19. The compound according to any one of claims 1 to 17, wherein R1 and one of R10 or R11 form togethera -(C2-C9) heterocycloalkyl comprising exactly one nitrogen atom, preferably selected from30 pyrrolidinyl, piperidinyl, and morpholinyl, more preferably pyrrolidinyl.

20. The compound according to any one of claims 1 to 19, wherein Z1 is selected from hydrogen, -(C1-C6) alkyl, -(C3-C9) cycloalkyl, -(C2-C9) heterocycloalkyl, aryl, heteroaryl, -(C1-C6) alkylene-(C3- AUG-P3833PCT C9) cycloalkyl, -(C1-C6) alkylene-(C2-C9) heterocycloalkyl, -(C1-C6) alkylene-aryl and -(C1-C6) alkylene-heteroaryl, preferably -(C3-C9) cycloalkyl or -(C2-C9) heterocycloalkyl, morepreferably cyclopropyl or octahydropyrido[2,1-c][1,4]oxazin-8-yl.

21. The compound according to any one of claims 1 to 20, wherein Z1 is selected from hydrogen, methyl,5 2-propyl, ethyl, cyclopropyl, tert-butyl, 1-methylcyclopropyl, oxetan-3-yl, tetrahydro-2H-pyan-4-yl, 2-hydroxypropyl, 1-methylazetidin-3-yl, (1R,3R)-3-hydroxycyclobutyl, (1S,3S)-3- hydroxycyclobutyl, 1-methylpyrrolidin-3-yl, piperidin-3-yl, piperidin-4-yl, 1-cyclopropylpiperidin- 4-yl, quinuclidin-3-yl, 1-methylpiperidin-3-yl, 1-ethylpiperidin-4-yl, 3,3-difluorocyclobutyl, (1S,3S)-3-fluorocyclobutyl, pyridin-3-ylmethyl, pyridin-2-ylmethyl, 1-fluorocyclopropyl)methyl,10 oxetan-3-ylmethyl, 1-methyl-1H-pyrazol-5-yl, 1-ethylpiperidin-4-yl, 1-methylpiperidin-3-yl, 1- methylpiperidin-4-ylmethyl, pyridine-4-ylmethyl, 1-methylcyclopropyl, 8-oxabicyclo[3.2.1]octan- 3-yl, octahydropyrido[2,1-c][1,4]oxazin-8-yl, 8-azabicyclo[3.2.1]octan-3-yl, 9-methyl-9- azabicyclo[3.3.1]nonan-3-yl, 8-methyl-8-azabicyclo[3.2.1]octan-3-yl, 3-hydroxy-1-methylpiperidin-4-yl,3-methyl-3-azabicyclo[3.1.0]hexan-6-yl, 3-methyl-3-azabicyclo[3.1.1]heptan-15 6-yl, 9-methyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl, 4-(hydroxymethyl)-1-methylpiperidin-4-yl,2-methyl-2-azabicyclo[2.2.1]heptan-5-yl, 1,3-dimethylpiperidin-4-yl, 1,4-dimethylpiperidin-4-yl, 3-methoxy-1-methylpiperidin-4-yl, 7-methyl-3-oxa-7-azabicyclo[3.3.1]nonan-9-yl, 3-fluoro-1- methylpiperidin-4-yl, 1-methylazepan-4-yl, 2-methyl-5-oxa-2-azaspiro[3.4]octan-7-yl, 3- oxabicyclo[3.1.0]hexan-6-yl, 3-methoxycyclobutyl, tetrahydrofuran-3-yl, and hexahydro-1H-20 pyrrolo[2,1-c][1,4]oxazin-7-yl.

22. The compound or a pharmaceutically acceptable salt and / or solvate thereof of formula (I) according to any one of claims 1 to 21,wherein said compound is a compound of formula (I-e) 25 or a pharmaceutically acceptable salt and / or solvate thereof; wherein Y1, L2, Z1, and R1 are as defined in any one of claims 1 to 21,preferably wherein said compound is a compound of formula (I-f) AUG-P3833PCT or a pharmaceutically acceptable salt and / or solvate thereof; wherein L2, Z1, and R1 are as defined in any one of claims 1 to 21 and R2, G1 and A1-A4 are asdefined in any one of claims 1 to 5.5 23. The compound according to claim 1, wherein said compound is selected from the group consistingof: AUG-P3833PCT AUG-P3833PCT AUG-P3833PCT AUG-P3833PCT AUG-P3833PCT AUG-P3833PCT AUG-P3833PCT AUG-P3833PCT AUG-P3833PCT AUG-P3833PCT AUG-P3833PCT AUG-P3833PCT or a pharmaceutically acceptable salt and / or solvate of any one thereof.

24. A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt and / or solvate thereof according to any one of claims 1 to 23 and at least one pharmaceuticallyacceptable carrier.

525. The compound or a pharmaceutically acceptable salt and / or solvate thereof according to any one ofclaims 1 to 23 or the pharmaceutical composition according to claim 24 for use as a medicament.

26. The compound or a pharmaceutically acceptable salt and / or solvate thereof according to any one ofclaims 1 to 23 or the pharmaceutical composition according to claim 24 for use in the treatmentand / or the prevention of an HDAC6-associated disease, wherein said HDAC6-associated disease is 10 selected from inflammatory diseases, autoimmune diseases, proliferative diseases (such as cancers), neurodegenerative diseases (including neuromuscular diseases), pains, neuropathies, psychiatricdiseases, neurodevelopmental disorders, sleep disorders, cardiovascular diseases, kidney diseases,and metabolic or hormonal disorders.

27. A process for manufacturing a compound or a pharmaceutically acceptable salt and / or solvate15 thereof according to any one of claims 1 to 23, wherein said process comprises a step of reacting:(i) a carboxylic acid with an amine; or AUG-P3833PCT (ii) a halo-ketone with a thiol.

28. A compound of formula T-10 wherein R10, R1 and Z1 are as defined in any one of claims 1 to 3, Y2 represents the 5-membered5 sulfur-containing heteroaryl comprising the W and X groups, as defined any one of claims 1 to 3and X1 is halo; or a salt thereof.

29. A compound of formula T-17 wherein Y1 and L2 are as defined in any one of claims 1 to 3 and Y2 represents the 5-membered10 sulfur-containing heteroaryl comprising the W and X groups, as defined any one of claims 1 to 3;or a salt thereof.15

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