NEW COMPOUNDS ____________________________________________________________ ________ FIELD OF THE INVENTION The present invention relates to novel triazinones that are useful as inhibitors of NOD-like receptor protein 3 (NLRP3) inflammasome pathway. The present invention also relates to processes for the preparation of said compounds, pharmaceutical compositions comprising said compounds, methods of using said compounds in the treatment of various diseases and disorders, and medicaments containing them, and their use in diseases and disorders mediated by NLRP3. BACKGROUND OF THE INVENTION Inflammasomes, considered as central signalling hubs of the innate immune system, are multi-protein complexes that are assembled upon activation of a specific set of intracellular pattern recognition receptors (PRRs) by a wide variety of pathogen- or danger- associated molecular patterns (PAMPs or DAMPs). To date, it was shown that inflammasomes can be formed by nucleotide-binding oligomerization domain (NOD)- like receptors (NLRs) and Pyrin- and HIN200-domain-containing proteins (Van Opdenbosch N and Lamkanfi M. Immunity, 2019 Jun 18;50(6):1352-1364). The NLRP3 inflammasome is assembled upon detection of environmental crystals, pollutants, host-derived DAMPs and protein aggregates (Tartey S and Kanneganti TD. Immunology, 2019 Apr;156(4):329-338). Clinically relevant DAMPs that engage NLRP3 include uric acid and cholesterol crystals that cause gout and atherosclerosis, amyloid-β fibrils that are neurotoxic in Alzheimer’s disease and asbestos particles that cause mesothelioma (Kelley et al., Int J Mol Sci, 2019 Jul 6;20(13)). Additionally, NLRP3 is activated by infectious agents such as Vibrio cholerae; fungal pathogens such as Aspergillus fumigatus and Candida albicans; adenoviruses, influenza A virus and SARS-CoV-2 (Tartey and Kanneganti, 2019 (see above); Fung et al. Emerg Microbes Infect, 2020 Mar 14;9(1):558-570). Although the precise NLRP3 activation mechanism remains unclear, for human monocytes, it has been suggested that a one-step activation is sufficient while in mice a two-step mechanism is in place. Given the multitude in triggers, the NLRP3 inflammasome requires add-on regulation at both transcriptional and post- transcriptional level (Yang Y et al., Cell Death Dis, 2019 Feb 12;10(2):128). The NLRP3 protein consists of an N-terminal pyrin domain, followed by a nucleotide-binding site domain (NBD) and a leucine-rich repeat (LRR) motif on C- terminal end (Sharif et al., Nature, 2019 Jun; 570(7761):338-343). Upon recognition of PAMP or DAMP, NLRP3 aggregates with the adaptor protein, apoptosis-associated speck-like protein (ASC), and with the protease caspase-1 to form a functional inflammasome. Upon activation, procaspase-1 undergoes autoproteolysis and consequently cleaves gasdermin D (Gsdmd) to produce the N-terminal Gsdmd molecule that will ultimately lead to pore-formation in the plasma membrane and a lytic form of cell death called pyroptosis. Alternatively, caspase-1 cleaves the pro- inflammatory cytokines pro-IL-Ib and pro-IL-18 to allow release of its biological active form by pyroptosis (Kelley et ak, 2019 - see above).

Dysregulation of the NLRP3 inflammasome or its downstream mediators are associated with numerous pathologies ranging from immune/inflammatory diseases, auto-immune/auto-inflammatory diseases (Cryopyrin-associated Periodic Syndrome (Miyamae T. Paediatr Drugs, 2012 Apr 1;14(2):109-17); sickle cell disease; systemic lupus erythematosus (SLE)) to hepatic disorders (eg. non-alcoholic steatohepatitis (NASH), chronic liver disease, viral hepatitis, alcoholic steatohepatitis, and alcoholic liver disease) (Szabo G and Petrasek J. Nat Rev Gastroenterol Hepatol, 2015 Jul;12(7):387-400) and inflammatory bowel diseases (eg. Crohn’s disease, ulcerative colitis) (Zhen Y and Zhang H. Front Immunol, 2019 Feb 28;10:276). Also, inflammatory joint disorders (eg. gout, pseudogout (chondrocalcinosis), arthropathy, osteoarthritis, and rheumatoid arthritis (Vande Walle L et ah, Nature, 2014 Aug 7;512(7512):69-73) were linked to NLRP3. Additionally, kidney related diseases (hyperoxaluria (Knauf et ah, Kidney Int, 2013 Nov;84(5):895-901), lupus nephritis, hypertensive nephropathy (Krishnan et ah, Br J Pharmacol, 2016 Feb;173(4):752-65), hemodialysis related inflammation and diabetic nephropathy which is a kidney -related complication of diabetes (Type 1, Type 2 and mellitus diabetes), also called diabetic kidney disease (Shahzad et ah, Kidney Int, 2015 Jan;87(l):74-84) are associated to NLRP3 inflammasome activation. Reports link onset and progression of neuroinflammation-related disorders (eg. brain infection, acute injury, multiple sclerosis, Alzheimer's disease) and neurodegenerative diseases (Parkinsons disease) to NLRP3 inflammasome activation (Sarkar et ah, NPJ Parkinsons Dis, 2017 Oct 17;3:30). In addition, cardiovascular or metabolic disorders (eg. cardiovascular risk reduction (CvRR), atherosclerosis, type I and type II diabetes and related complications (e.g. nephropathy, retinopathy), peripheral artery disease (PAD), acute heart failure and hypertension (Ridker et ah, CANTOS Trial Group. N Engl J Med, 2017 Sep 21;377(12): 1119-1131; and Toldo S and Abbate A. Nat Rev Cardiol,

2018 Apr;15(4):203-214) have recently been associated to NLRP3. Also, skin associated diseases were described (eg. wound healing and scar formation; inflammatory skin diseases, eg. acne, hidradenitis suppurativa (Kelly et ah, BrJ Dermatol, 2015 Dec;173(6)). In addition, respiratory conditions have been associated with NLRP3 inflammasome activity (eg. asthma, sarcoidosis, Severe Acute Respiratory Syndrome (SARS) (Nieto-Torres et al., Virology, 2015 Nov;485:330-9)) but also age- related macular degeneration (Doyle et al., Nat Med, 2012 May;18(5):791-8). Several cancer related diseases/disorders were described linked to NLRP3 (eg. myeloproliferative neoplasms, leukemias, myelodysplastic syndromes (MOS), myelofibrosis, lung cancer, colon cancer (Ridker et al., Lancet, 2017 Oct 21;390(10105):1833-1842; Derangere et al., Cell Death Differ.2014 Dec;21(12):1914- 24; Basiorka et al., Lancet Haematol, 2018 Sep;5(9): e393-e402, Zhang et al., Hum Immunol, 2018 Jan;79(1):57-62). Several patent applications describe NLRP3 inhibitors, with recent ones including for instance international patent application WO 2020/018975, WO 2020/037116, WO 2020/021447, WO 2020/010143, WO 2019/079119, WO 2019/0166621 and WO 2019/121691, which disclose a range of specific compounds. There is a need for inhibitors of the NLRP3 inflammasome pathway to provide new and/or alternative treatments for the diseases/disorders mentioned herein. SUMMARY OF THE INVENTION The invention provides compounds which inhibit the NLRP3 inflammasome pathway. Thus, in an aspect of the invention, there is now provided a compound of formula (I), R ¹ represents: (i) C _3-6 cycloalkyl optionally substituted with one or more substituents independently selected from -OH and -C _1-3 alkyl; (ii) aryl or heteroaryl, each of which is optionally substituted with 1 to 3 substituents independently selected from halo, -OH, -O-C _1-3 alkyl, -C _1-3 alkyl, haloC _1-3 alkyl, hydroxyC _1-3 alkyl, C _1-3 alkoxy, haloC _1-3 alkoxy; or (iii) heterocyclyl, optionally substituted with 1 to 3 substituents independently selected from C _1-3 alkyl and C _3-6 cycloalkyl;

R ² represents:

(i) C _1-3 alkyl optionally substituted with one or more substituents independently selected from halo, -OH and -OC _1-3 alkyl;

(ii) C _3-6 cycloalkyl;

(iii) C _2-4 alkenyl optionally substituted with -OC _1-3 alkyl; or

(iv)-N(R ^2a )R ^2b ;

R ^2a and R ^2b each represent hydrogen or C _1-4 alkyl, or R ^2a and R ^2b may be linked together to form a 3- to 4-membered ring optionally substituted by one or more fluoro atoms;

R ³ represents:

(i) hydrogen;

(ii) halo;

(iii) C _1-4 alkyl optionally substituted with one or more substituents independently selected from halo, -OH and -OC _1-3 alkyl;

(iv) C _2-4 alkenyl optionally substituted with -OC _1-3 alkyl;

(v) C _3-6 cycloalkyl; or

(vi) -OC _1-3 alkyl, which compounds may be referred to herein as “compounds of the invention”.

In an embodiment, compounds of the invention that may be mentioned include those in which:

(i) when R ³ represents hydrogen, R ² represents methyl, then R ¹ does not represent 4-methylphenyl;

(ii) when R ³ represents hydrogen, R ² represents cyclohexyl, then R ¹ does not represent 2-indanyl (2,3-dihydro-lH-indene linked at the 2-position), which may be referred to herein as “the provisos”.

For instance, there is provided a compound of formula (I) as hereinbefore defined, or a pharmaceutically acceptable salt thereof, for use as an NLRP3 inhibitor (e.g. in the treatment of a disease or disorder that is associated with NLRP3 inflammasome activity), provided that it is not a compound of the provisos. There is also provided a compound of formula (I) as hereinbefore defined, or a pharmaceutically JAB7061WOPCT1 - 5 - acceptable salt thereof, for use as an NLRP3 inhibitor in the treatment of a cancer, provided that it is not compound (i) of the provisos. There is also provided a compound of formula (I) as hereinbefore defined, or a pharmaceutically acceptable salt thereof, for use as an NLRP3 inhibitor in the treatment of Alzeheimer’s disease,5 provided that it is not compound (ii) of the provisos In an aspect of the invention, there is provided a compound of formula (I) as hereinbefore defined, or a pharmaceutically acceptable salt thereof, wherein: 1 R represents: 10 (i) C3-6 cycloalkyl optionally substituted with one or more substituents independently selected from halo, -OH, -C1-3 alkyl (itself optionally substituted by one or more substituents selected from fluoro and -OH) and -OC1-3alkyl; (ii) aryl or heteroaryl, each of which is optionally substituted with 1 to 315 substituents independently selected from halo, -CN, -OH, -O-C1-3 alkyl, -C1- 6 alkyl (e.g. -C _1-3 alkyl), haloC _1-3 alkyl, hydroxyC _1-3 alkyl, C _1-3 alkoxyC _{1- 3} alkyl, haloC _1-3 alkoxy, aminoC _1-3 alkyl (e.g. H ₂ N-C _1-3 alkyl or (CH ₃ ) ₂ N-C _1-3 alkyl), C _3-6 cycloalkyl or aryl/heteroaryl (wherein such latter groups are themselves optionally substituted by one or more substituents selected from20 halo, C _1-3 alkyl and -OC _1-3 alkyl); or (iii) heterocyclyl, optionally substituted with 1 to 3 substituents independently selected from halo, =O, -OH, -C1-4 alkyl (itself optionally substituted by one or more substituents selected from fluoro, =O and -OH), -OC1-3alkyl, C3-6 cycloalkyl and a 3-6 membered heterocyclyl ring; 25 R2 represents: (i) C _1-6 alkyl (e.g C _1-4 alkyl or C _1-3 alkyl) optionally substituted with one or more substituents independently selected from halo, =O, -OH and -OC1-3 alkyl; (ii) C3-6 cycloalkyl optionally substituted by one or more substituents selected from halo (e.g. fluoro), C1-3 alkyl and -OC1-3 alkyl; 30 (iii) C2-4 alkenyl optionally substituted with -OC1-3 alkyl; or 2a 2b (iv) -N(R )R ; R2a and R2b each represent hydrogen or C 2a 2b 1 _-4 alkyl, or R and R may be linked together to form a 3- to 4-membered ring optionally substituted by one or more fluoro atoms; 3 35 R represents: (i) hydrogen; (ii) halo or -CN;

JAB7061WOPCT1 - 6 - (iii) C1-6 alkyl (e.g. C1-4 alkyl) optionally substituted with one or more substituents independently selected from halo, -OH and -OC1-3 alkyl; (iv) C2-4 alkenyl optionally substituted with -OC1-3 alkyl; (v) C _3-6 cycloalkyl optionally substituted by one or more fluoro atoms;5 (vi) -NH ₂ , -N(H)(C _1-3 alkyl) or N(C _1-3 alkyl) ₂ ; or (vii) -OC _1-3 alkyl optionally substituted by one or more fluoro atoms; 3 and wherein the R containing benzene ring may also be optionally substituted (at the three relevant positions) with one substituent selected from halo (e.g. fluoro), -OH and -CN, 10 which compounds may also be referred to herein as “compounds of the invention”. In an embodiment, there is provided a compound of formula (I), as hereinbefore 3 defined, or a pharmaceutically acceptable salt thereof, wherein R does not represent hydrogen. 15 In another aspect, there is provided compounds of the inventon for use as a medicament. In another aspect, there is provided a pharmaceutical composition comprising a therapeutically effective amount of a compound of the invention. In a further aspect, there is provided compounds of the invention (and/or pharmaceutical compositions comprising such compounds) for use: in the treatment of 20 a disease or disorder associated with NLRP3 activity (including inflammasome activity); in the treatment of a disease or disorder in which the NLRP3 signalling contributes to the pathology, and/or symptoms, and/or progression, of said disease/disorder; in inhibiting NLRP3 inflammasome activity (including in a subject in need thereof); and/or as an NLRP3 inhibitor. Specific diseases or disorders may be25 mentioned herein, and may for instance be selected from inflammasome-related diseases or disorders, immune diseases, inflammatory diseases, auto-immune diseases, or auto-inflmmatory diseases. In another aspect, there is provided a use of compounds of the invention (and/or pharmaceutical compositions comprising such compounds): in the treatment of a30 disease or disorder associated with NLRP3 activity (including inflammasome activity); in the treatment of a disease or disorder in which the NLRP3 signalling contributes to the pathology, and/or symptoms, and/or progression, of said disease/disorder; in inhibiting NLRP3 inflammasome activity (including in a subject in need thereof); and/or as an NLRP3 inhibitor. 35 In another aspect, there is provided use of compounds of the invention (and/or pharmaceutical compositions comprising such compounds) in the manufacture of a medicament for: the treatment of a disease or disorder associated with NLRP3 activity (including inflammasome activity); the treatment of a disease or disorder in which the JAB7061WOPCT1 - 7 - NLRP3 signalling contributes to the pathology, and/or symptoms, and/or progression, of said disease/disorder; and/or inhibiting NLRP3 inflammasome activity (including in a subject in need thereof). In another aspect, there is provided a method of treating a disease or disorder in 5 which the NLRP3 signalling contributes to the pathology, and/or symptoms, and/or progression, of said disease/disorder, comprising administering a therapeutically effective amount of a compound of the invention, for instance to a subject (in need thereof). In a further aspect there is provided a method of inhibiting the NLRP3 inflammasome activity in a subject (in need thereof), the method comprising 10 administering to the subject in need thereof a therapeutically effective amount of a compound of the invention. In further aspect, there is a provided a compound of the invention in combination (including a pharmaceutical combination) with one or more therapeutic agents (for instance as described herein). Such combination may also be provided for 15 use as described herein in respect of compounds of the invention, or, a use of such combination as described herein in respect of compounds of the invention. There may also be provided methods as described herein in repsect of compounds of the invention, but wherein the method comprises administering a therapeutically effective amount of such combination. 20 DETAILED DESCRIPTION OF THE INVENTION The invention provides a compound of formula (I), (I) or a pharmaceutically acceptable salt thereof, wherein: 25 1 R represents: (i) C _3-6 cycloalkyl optionally substituted independently selected from -OH a (ii) aryl or heteroaryl, each of which is opt 30 substituents independently selected alkyl, haloC _1-3 alkyl, hydroxyC _1-3 alkyl, C _1-3 alkoxy, haloC _1-3 alkoxy; or (iii) heterocyclyl, optionally substituted with 1 to 3 substituents independently selected from C _1-3 alkyl and C _3-6 cycloalkyl; JAB7061WOPCT1 - 8 - R2 represents: (i) C1-3 alkyl optionally substituted with one or more substituents independently selected from halo, -OH and -OC1-3 alkyl; (ii) C _3-6 cycloalkyl; 5 (iii) C _2-4 alkenyl optionally substituted with -OC _1-3 alkyl; or 2a 2b (iv) -N(R )R ; 2a 2b 2a 2b R and R each represent hydrogen or C _1-4 alkyl, or R and R may be linked together to form a 3- to 4-membered ring optionally substituted by one or more fluoro10 atoms; 3 R represents: (i) hydrogen; (ii) halo; 15 (iii) C1-4 alkyl optionally substituted with one or more substituents independently selected from halo, -OH and -OC _1-3 alkyl; (iv) C _2-4 alkenyl optionally substituted with -OC _1-3 alkyl; (v) C _3-6 cycloalkyl; or (vi) -OC1-3 alkyl. 20 As indicated above, such compounds may be referred to herein as “compounds of the invention”. Pharmaceutically-acceptable salts include acid addition salts and base addition salts. Such salts may be formed by conventional means, for example by reaction of a 25 free acid or a free base form of a compound of the invention with one or more equivalents of an appropriate acid or base, optionally in a solvent, or in a medium in which the salt is insoluble, followed by removal of said solvent, or said medium, using standard techniques (e.g. in vacuo, by freeze-drying or by filtration). Salts may also be prepared by exchanging a counter-ion of a compound of the invention in the form of a30 salt with another counter-ion, for example using a suitable ion exchange resin. Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid,35 and the like. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, JAB7061WOPCT1 - 9 - methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, sulfosalicylic acid, and the like. Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases. 5 Inorganic bases from which salts can be derived include, for example, ammonium salts and metals from columns I to XII of the periodic table. In certain embodiments, the salts are derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper; particularly suitable salts include ammonium, potassium, sodium, calcium and magnesium salts. 10 Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like. Certain organic amines include isopropylamine, benzathine, cholinate, diethanolamine, diethylamine, lysine, meglumine, piperazine, and tromethamine 15 For the purposes of this invention solvates, prodrugs, N-oxides and stereoisomers of compounds of the invention are also included within the scope of the invention. The term “prodrug” of a relevant compound of the invention includes any compound that, following oral or parenteral administration, is metabolised in vivo to 20 form that compound in an experimentally-detectable amount, and within a predetermined time (e.g. within a dosing interval of between 6 and 24 hours (i.e. once to four times daily)). For the avoidance of doubt, the term “parenteral” administration includes all forms of administration other than oral administration. Prodrugs of compounds of the invention may be prepared by modifying 25 functional groups present on the compound in such a way that the modifications are cleaved, in vivo when such prodrug is administered to a mammalian subject. The modifications typically are achieved by synthesising the parent compound with a prodrug substituent. Prodrugs include compounds of the invention wherein a hydroxyl, amino, sulfhydryl, carboxy or carbonyl group in a compound of the invention is bonded 30 to any group that may be cleaved in vivo to regenerate the free hydroxyl, amino, sulfhydryl, carboxy or carbonyl group, respectively. Examples of prodrugs include, but are not limited to, esters and carbamates of hydroxy functional groups, esters groups of carboxyl functional groups, N-acyl derivatives and N-Mannich bases. General information on prodrugs may be found e.g. 35 in Bundegaard, H. “Design of Prodrugs” p. l-92, Elesevier, New York-Oxford (1985). Compounds of the invention may contain double bonds and may thus exist as E (entgegen) and Z (zusammen) geometric isomers about each individual double bond. Positional isomers may also be embraced by the compounds of the invention. All such JAB7061WOPCT1 - 10 - isomers (e.g. if a compound of the invention incorporates a double bond or a fused ring, the cis- and trans- forms, are embraced) and mixtures thereof are included within the scope of the invention (e.g. single positional isomers and mixtures of positional isomers may be included within the scope of the invention). 5 Compounds of the invention may also exhibit tautomerism. All tautomeric forms (or tautomers) and mixtures thereof are included within the scope of the invention. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies which are interconvertible via a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) include interconversions via 10 migration of a proton, such as keto-enol and imine-enamine isomerisations. Valence tautomers include interconversions by reorganisation of some of the bonding electrons. Compounds of the invention may also contain one or more asymmetric carbon atoms and may therefore exhibit optical and/or diastereoisomerism. Diastereoisomers may be separated using conventional techniques, e.g. chromatography or fractional15 crystallisation. The various stereoisomers may be isolated by separation of a racemic or other mixture of the compounds using conventional, e.g. fractional crystallisation or HPLC, techniques. Alternatively the desired optical isomers may be made by reaction of the appropriate optically active starting materials under conditions which will not cause racemisation or epimerisation (i.e. a ‘chiral pool’ method), by reaction of the 20 appropriate starting material with a ‘chiral auxiliary’ which can subsequently be removed at a suitable stage, by derivatisation (i.e. a resolution, including a dynamic resolution), for example with a homochiral acid followed by separation of the diastereomeric derivatives by conventional means such as chromatography, or by reaction with an appropriate chiral reagent or chiral catalyst all under conditions known 25 to the skilled person. All stereoisomers (including but not limited to diastereoisomers, enantiomers and atropisomers) and mixtures thereof (e.g. racemic mixtures) are included within the scope of the invention. In the structures shown herein, where the stereochemistry of any particular 30 chiral atom is not specified, then all stereoisomers are contemplated and included as the compounds of the invention. Where stereochemistry is specified by a solid wedge or dashed line representing a particular configuration, then that stereoisomer is so specified and defined. When an absolute configuration is specified, it is according to the Cahn-Ingold- 35 Prelog system. The configuration at an asymmetric atom is specified by either R or S. Resolved compounds whose absolute configuration is not known can be designated by (+) or (-) depending on the direction in which they rotate plane polarized light.

JAB7061WOPCT1 - 11 - When a specific stereoisomer is identified, this means that said stereoisomer is substantially free, i.e. associated with less than 50%, preferably less than 20%, more preferably less than 10%, even more preferably less than 5%, in particular less than 2% and most preferably less than 1%, of the other isomers. Thus, when a compound of 5 formula (I) is for instance specified as (R), this means that the compound is substantially free of the (S) isomer. The compounds of the present invention may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and it is intended that the invention embrace both solvated and unsolvated10 forms. The present invention also embraces isotopically-labeled compounds of the present invention which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature (or the most abundant 15 one found in nature). All isotopes of any particular atom or element as specified herein are contemplated within the scope of the compounds of the invention. Exemplary isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine and iodine, 2 3 11 13 14 13 15 17 18 32 33 35 18 36 123 125 such as H, H, C, C, C , N, O, O, O, P, P, S, F, Cl, I, and I. 20 Certain isotopically-labeled compounds of the present invention (e.g., those labeled with 3H and 14C) are useful in compound and for substrate tissue distribution assays. 3 14 Tritiated (H) and carbon-l4 ( C) isotopes are useful for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e., 2H may afford certain therapeutic advantages resulting from greater metabolic stability 25 (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be 15 13 11 preferred in some circumstances. Positron emitting isotopes such as O, N, C and 18 F are useful for positron emission tomography (PET) studies to examine substrate receptor occupancy. Isotopically labeled compounds of the present invention can generally be prepared by following procedures analogous to those disclosed in the 30 description/Examples hereinbelow, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent. Unless otherwise specified, C1-q alkyl groups (where q is the upper limit of the range) defined herein may be straight-chain or, when there is a sufficient number (i.e. a minimum of two or three, as appropriate) of carbon atoms, be branched-chain. Such a35 group is attached to the rest of the molecule by a single bond. C2-q alkenyl when used herein (again where q is the upper limit of the range) refers to an alkyl group that contains unsaturation, i.e. at least one double bond.

JAB7061WOPCT1 - 12 - C3-q cycloalkyl (where q is the upper limit of the range) refers to an alkyl group that is cyclic, for instance cycloalkyl groups may be monocyclic or, if there are sufficient atoms, bicyclic. In an embodiment, such cycloalkyl groups are monocyclic. Such cycloalkyl groups are unsaturated. Substituents may be attached at any point on5 the cycloalkyl group. The term “halo”, when used herein, preferably includes fluoro, chloro, bromo and iodo. C _1-q alkoxy groups (where q is the upper limit of the range) refers to the radical a a of formula -OR, where R is a C1-q alkyl group as defined herein. 10 HaloC1-q alkyl (where q is the upper limit of the range) goups refer to C1-q alkyl groups, as defined herein, where such group is substituted by one or more halo. HydroxyC1-q alkyl (where q is the upper limit of the range) refers to C1-q alkyl groups, as defined herein, where such group is substituted by one or more (e.g. one) hydroxy (-OH) groups (or one or more, e.g. one, of the hydrogen atoms15 is replaced with -OH). Similarly, haloC1-q alkoxy and hydroxyC1-q alkoxy represent corresponding -OC _1-q alkyl groups that are substituted by one or more halo, or, substituted by one or more (e.g. one) hydroxy, respectively. Heterocyclyl groups that may be mentioned include non-aromatic monocyclic and bicyclic heterocyclyl groups in which at least one (e.g. one to four) of the atoms in 20 the ring system is other than carbon (i.e. a heteroatom), and in which the total number of atoms in the ring system is between 3 and 20 (e.g. between three and ten, e.g between 3 and 8, such as 5- to 8-). Such heterocyclyl groups may also be bridged. Such heterocyclyl groups are saturated. C2-q heterocyclyl groups that may be mentioned include 7-azabicyclo[2.2.1]heptanyl, 6-azabicyclo[3.1.1]heptanyl, 25 6-azabicyclo[3.2.1]-octanyl, 8-azabicyclo-[3.2.1]octanyl, aziridinyl, azetidinyl, dihydropyranyl, dihydropyridyl, dihydropyrrolyl (including 2,5-dihydropyrrolyl), dioxolanyl (including 1,3-dioxolanyl), dioxanyl (including 1,3-dioxanyl and 1,4-dioxanyl), dithianyl (including 1,4-dithianyl), dithiolanyl (including 1,3-dithiolanyl), imidazolidinyl, imidazolinyl, morpholinyl, 7-oxabicyclo[2.2.1]-30 heptanyl, 6-oxabicyclo-[3.2.1]octanyl, oxetanyl, oxiranyl, piperazinyl, piperidinyl, non- aromatic pyranyl, pyrazolidinyl, pyrrolidinonyl, pyrrolidinyl, pyrrolinyl, quinuclidinyl, sulfolanyl, 3-sulfolenyl, tetrahydropyranyl, tetrahydrofuranyl, tetrahydropyridyl (such as 1,2,3,4-tetrahydropyridyl and 1,2,3,6-tetrahydropyridyl), thietanyl, thiiranyl, thiolanyl, thiomorpholinyl, trithianyl (including 1,3,5-trithianyl), tropanyl and the like. 35 Substituents on heterocyclyl groups may, where appropriate, be located on any atom in the ring system including a heteroatom. The point of attachment of heterocyclyl groups may be via any atom in the ring system including (where appropriate) a heteroatom (such as a nitrogen atom), or an atom on any fused carbocyclic ring that may be present JAB7061WOPCT1 - 13 - as part of the ring system. Heterocyclyl groups may also be in the N- or S- oxidised form. In an embodiment, heterocyclyl groups mentioned herein are monocyclic. Aryl groups that may be mentioned include C6-20, such as C6-12 (e.g. C6-10) aryl groups. Such groups may be monocyclic, bicyclic or tricyclic and have between 6 and 5 12 (e.g.6 and 10) ring carbon atoms, in which at least one ring is aromatic. C _6-10 aryl groups include phenyl, naphthyl and the like, such as 1,2,3,4-tetrahydronaphthyl. The point of attachment of aryl groups may be via any atom of the ring system. For example, when the aryl group is polycyclic the point of attachment may be via atom including an atom of a non-aromatic ring. However, when aryl groups are polycyclic 10 (e.g. bicyclic or tricyclic), they are preferably linked to the rest of the molecule via an aromatic ring. When aryl groups are polycyclic, in an embodiment, each ring is aromatic. In an embodiment, aryl groups mentioned herein are monocyclic or bicyclic. In a further embodiment, aryl groups mentioned herein are monocyclic. “Heteroaryl” when used herein refers to an aromatic group containing one or 15 more heteroatom(s) (e.g. one to four heteroatoms) preferably selected from N, O and S. Heteroaryl groups include those which have between 5 and 20 members (e.g. between 5 and 10) and may be monocyclic, bicyclic or tricyclic, provided that at least one of the rings is aromatic (so forming, for example, a mono-, bi-, or tricyclic heteroaromatic group). When the heteroaryl group is polycyclic the point of attachment may be via 20 any atom including an atom of a non-aromatic ring. However, when heteroaryl groups are polycyclic (e.g. bicyclic or tricyclic), they are preferably linked to the rest of the molecule via an aromatic ring. In an embodiment, when heteroaryl groups are polycyclic, then each ring is aromatic. Heteroaryl groups that may be mentioned include 3,4-dihydro-1H-isoquinolinyl, 1,3-dihydroisoindolyl, 1,3-dihydroisoindolyl25 (e.g.3,4-dihydro-1H-isoquinolin-2-yl, 1,3-dihydroisoindol-2-yl, 1,3-dihydroisoindol-2- yl; i.e. heteroaryl groups that are linked via a non-aromatic ring), or, preferably, acridinyl, benzimidazolyl, benzodioxanyl, benzodioxepinyl, benzodioxolyl (including 1,3-benzodioxolyl), benzofuranyl, benzofurazanyl, benzothiadiazolyl (including 2,1,3-benzothiadiazolyl), benzothiazolyl, benzoxadiazolyl (including 30 2,1,3-benzoxadiazolyl), benzoxazinyl (including 3,4-dihydro-2H-1,4-benzoxazinyl), benzoxazolyl, benzomorpholinyl, benzoselenadiazolyl (including 2,1,3-benzoselena- diazolyl), benzothienyl, carbazolyl, chromanyl, cinnolinyl, furanyl, imidazolyl, imidazo[1,2-a]pyridyl, indazolyl, indolinyl, indolyl, isobenzofuranyl, isochromanyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiaziolyl, isothiochromanyl, isoxazolyl, 35 naphthyridinyl (including 1,6-naphthyridinyl or, preferably, 1,5-naphthyridinyl and 1,8-naphthyridinyl), oxadiazolyl (including 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl and 1,3,4-oxadiazolyl), oxazolyl, phenazinyl, phenothiazinyl, phthalazinyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, JAB7061WOPCT1 - 14 - quinazolinyl, quinolinyl, quinolizinyl, quinoxalinyl, tetrahydroisoquinolinyl (including 1,2,3,4-tetrahydroisoquinolinyl and 5,6,7,8-tetrahydroisoquinolinyl), tetrahydro- quinolinyl (including 1,2,3,4-tetrahydroquinolinyl and 5,6,7,8-tetrahydroquinolinyl), tetrazolyl, thiadiazolyl (including 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl and 5 1,3,4-thiadiazolyl), thiazolyl, thiochromanyl, thiophenetyl, thienyl, triazolyl (including 1,2,3-triazolyl, 1,2,4-triazolyl and 1,3,4-triazolyl) and the like. Substituents on heteroaryl groups may, where appropriate, be located on any atom in the ring system including a heteroatom. The point of attachment of heteroaryl groups may be via any atom in the ring system including (where appropriate) a heteroatom (such as a nitrogen 10 atom), or an atom on any fused carbocyclic ring that may be present as part of the ring system. Heteroaryl groups may also be in the N- or S- oxidised form. When heteroaryl groups are polycyclic in which there is a non-aromatic ring present, then that non- aromatic ring may be substituted by one or more =O group. In an embodiment, heteroaryl groups mentioned herein may be monocyclic or bicyclic. In a further15 embodiment, heteroaryl groups mentioned herein are monocyclic. Heteroatoms that may be mentioned include phosphorus, silicon, boron and, preferably, oxygen, nitrogen and sulfur. For the avoidance of doubt, where it is stated herein that a group may be substituted by one or more substituents (e.g. selected from C _1-6 alkyl), then those 20 substituents (e.g. alkyl groups) are independent of one another. That is, such groups may be substituted with the same substituent (e.g. same alkyl substituent) or different (e.g. alkyl) substituents. All individual features (e.g. preferred features) mentioned herein may be taken in isolation or in combination with any other feature (including preferred feature) 25 mentioned herein (hence, preferred features may be taken in conjunction with other preferred features, or independently of them). The skilled person will appreciate that compounds of the invention that are the subject of this invention include those that are stable. That is, compounds of the invention include those that are sufficiently robust to survive isolation from e.g. a 30 reaction mixture to a useful degree of purity. Various embodiments of the invention will now be described, including embodiments of the compounds of the invention. In an embodiment, there is provided a compound of formula (I), as hereinbefore defined, or a pharmaceutically acceptable salt thereof, wherein R3 does not represent35 hydrogen. In an embodiment, there is provided a compound of formula (I), as hereinbefore 3 defined, or a pharmaceutically acceptable salt thereof, wherein R represents: (i) halo; JAB7061WOPCT1 - 15 - (ii) C1-4 alkyl optionally substituted with one or more substituents independently selected from halo, -OH and -OC1-3 alkyl; (iii) C2-4 alkenyl optionally substituted with -OC1-3 alkyl; (iv) C _3-6 cycloalkyl; or 5 (v) -OC1-3 alkyl. In an embodiment, compounds of the invention include those in which R1 represents: (i) C3-6 cycloalkyl; (ii) aryl or heteroaryl; or (iii) or heterocyclyl, all of which are optionally substituted as herein defined. In a particular embodiment, R1 represents: (i) C3-6 cycloalkyl; or (ii) aryl or heteroaryl, all of which are optionally 10 substituted as herein defined. 1 In an embodiment when R represents optionally substituted C _3-6 cycloalkyl, then it represents C _3-6 cycloalkyl (or, in an embodiment, C _3-4 cycloalkyl) optionally substituted by one or two substituents selected from C1-3 alkyl (e.g. methyl) and -OH. 1 In a further embodiment, R represents cyclopropyl (e.g. unsubstituted) or cyclobutyl. 15 In a further embodiment, R1 represents cyclohexyl. In yet a further embodiment, R1 represents unsubstituted cyclopropyl or cyclobutyl substituted by -OH and methyl (e.g. at the same carbon atom). In yet a further embodiment, R1 represents cyclohexyl, for 1 instance substituted by -OH (e.g. by one -OH group). In an embodiment therefore, R represents: 20 1a where each R represents one or two optional substituents selected from -OH and C _1-3 1 alkyl (e.g. methyl). In a particular embodiment of this aspect, R represents C _3-6 cyclolkyl, such as op25 or unsubstituted (or where each R1ab represents one or two optional substituents selected from those defined by R1a, and in an embodiment, represents one optional substituent selected from -OH; JAB7061WOPCT1 - 16 - 1aa where each R represents one or two optional substituents selected from those defined 1a by R , and in an embodiment represents two substituents, methyl and -OH; or 1a 5 where R is as defined above, but where, in a particular embodiment, it is not present. In an embodiment where R1 represents aryl or heteroaryl, optionally substituted as defined herein, cyclic heteroaryl which are optiona 10 embodiment, the aorementoned ary and eteroary groups are optona y substtuted with one or two (e.g. one) substituent(s) selected from halo (e.g. fluoro), -OH, C1-3 alkyl and -OC a 1 1-3 lkyl. In one embodiment, R represents phenyl or a mono-cyclic 6- membered heteroaryl group and in another embodiment it may represent a 9- or 10- membered (e.g.9-membered) bicyclic heteroaryl group. Hence, in an embodiment, R1 15 may represent: O 1b wherein R represents one or two optional substituents selected from halo, -CH3, -OH and -OCH3 (and in a further embodiment, such optional substituents are selected from fluoro and methoxy), and at least one of R _b R R _d R and R _f reresents a nitroen 20 heteroatom (and the R _c , R _d , R _e and R _f rep nitrogen and, option (i) R _b and R _d represe 1 nitrogen. Hence, R may represent 3-pyridyl or 4-pyrimidinyl, both of which are 25 optionally substituted as herein defined; however, in an embodiment, such groups are unsubstituted.

JAB7061WOPCT1 - 17 - 1 In another embodiment, R may represent: O wherein R1b is 5 but in an aspect, is pref an unsubstituted 5-mem represents a heteroatom the others are independ enty seecte rom , , an (prov e t at t e rues o valency are adhered to); for instance, in an embodiment, one of R _k and R _n represents N, 10 the other represents N, O, S or CH, and Rl and Rm each represent CH, and, in a further a a particular embodiment, X represents N, O, S or CH, for instance X represents O, so forming a 2-oxazolyl group. As such, in a particular embodiment, R1 represents unsubstituted 2-oxazolyl. In another particular embodiment, R1 represents a 3-pyrazolyl 1b group (for instance in which Rk and Rl represents N, Rn and Rm represent CH, and R 15 represents a C1-4 alkyl (e.g. isopropyl) that is on the 1-(N) atom). 1 In another embodiment, R may represent: O _O O _O wherein R1b is as defined above (i.e. represents one or two optional substituents as defined above), each ring of the bicyclic system is aromatic, Rg represents a N or C 20 atom and any one or t f R R d R f i t t f R d R represents N and the understand, the rules the (hetero)aromatic

JAB7061WOPCT1 - 18 - 1 In an embodiment R represents: O 1b in which Rb and Rd represent a nitrogen atom, and, in an embodiment, there is no R substituent present. 5 In another emb O O in which one of R _i and R _j represents N and the other represents C, or, both R _i and R _j 1b represent N, and, in an embodiment, there is no R substituent present. In a further em10 group (containing betw substituted as defined ring containing one to group is optionally substituted as herein defined. 1 In a further embodiment, R represents: 15 O N O in which R ⁱ , R ^j and R ^1b are as hereinbefore defined. 1 In an embodiment where R represents heterocyclyl, optionally substituted as defined herein, such goup is in a further aspect a 5- or 6-membered heterocyclyl group 20 for instance containing particular embodiment containing heterocycly C1-3 alkyl and C3-6 cyc heterocyclyl group may be piperidinyl (e.g.3-piperidinyl) optionally substituted by C3-4

JAB7061WOPCT1 - 19 - cycloalkyl (e.g. cyclobutyl) or the 6-membered heterocyclyl group may be tetrahydropyran, e.g.4-tetrahydropyranyl (which is preferably unsubstituted). In an embodiment R2 represents: (i) C1-3 alkyl optionally substituted with one or more substituents independently selected from halo (e.g. fluoro), -OH and -OC _1-2 alkyl;5 (ii) C _3-6 cycloalkyl; or (iii) C _2-4 alkenyl optionally substituted by -OC _1-2 alkyl. In a 2 further embodiment, R represents C _1-3 alkyl optionally substituted with one or more substituents independently selected from halo, -OH and -OC _1-2 alkyl. In yet a further 2 embodiment, R represents unsubstituted C _1-3 alkyl. 2 In a particular embodiment R represents unsubstituted isopropyl or10 unsubstituted ethyl. 3 In an embodiment, R represents (i) hydrogen; (ii) halo (e.g. bromo); (iii) C1-4 alkyl optionally substituted with one or more substituents independently selected from halo, -OH and -OC _1-2 alkyl; (iv) C _3-6 cycloalkyl (e.g. cyclopropyl); or (v) 3 -OC _1-3 alkyl. In an embodiment when R represents optionally substituted C _1-4 alkyl,15 then it represents C _1-3 alkyl optionally substituted by one or more fluoro atoms. In an embodiment when R3 represents C3-6 cycloalkyl, then it represents cyclopropyl. In an 3 embodiment when R represents -OC1-3 alkyl, then it represents -OC1-2 alkyl (e.g. -OCH ₃ ). 3 In a particular embodiment, R represents hydrogen, bromo, methyl, ethyl,20 isopropyl -CF3, -CHF2, cyclopropyl or methoxy. The names of the compounds of the present invention were generated according to the nomenclature rules agreed upon by the Chemical Abstracts Service (CAS) using Advanced Chemical Development, Inc., software (ACD/Name product version 10.01; Build 15494, 1 Dec 2006) or according to the nomenclature rules agreed upon by the25 International Union of Pure and Applied Chemistry (IUPAC) using Advanced Chemical Development, Inc., software (ACD/Name product version 10.01.0.14105, October 2006). In case of tautomeric forms, the name of the depicted tautomeric form of the structure was generated. The other non-depicted tautomeric form is also included within the scope of the present invention. 30 Preparation of the compounds In an aspect of the invention, there is provided a process for the preparation of compounds of the invention, where reference here is made to compounds of formula (I) as defined herein.

JAB7061WOPCT1 - 20 - Compounds of formula (I) may be prepared by: (i) reaction of a compound of formula (II), (II) 2 3 or a derivative thereof (e.g. a salt), wherein R and R are as hereinbefore 5 defined, with a compound of formula (III), 1 H ₂ N-R or a derivative thereof, wherein R1 is as forming reaction conditions (also referred to as a , of a suitable coupling reagent (e.g. propylphosphonic anhydride, 1-[bis(dimethyl-10 amino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (O-(7-azabenzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate), 1,1’-carbonyldiimidazole, N,N’-dicyclohexylcarbodiimide, 1-(3-dimethylaminopropyl)- 3-ethylcarbodiimide (or hydrochloride thereof), N,N’-disuccinimidyl carbonate, benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluoro-phosphate, 15 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexa-fluorophosphate (i.e. O-(1H-benzotriazol-1-yl)-N,N,N´,N´-tetramethyluronium hexafluorophosphate), benzotriazol-1-yloxytris-pyrrolidinophosphonium hexa-fluorophosphate, bromo-tris- pyrrolidinophosponium hexafluorophosphate, 2-(1H-benzotriazol-1-yl)-1,1,3,3- tetramethyluronium tetra-fluorocarbonate, 1-cyclohexylcarbodiimide-3-propyloxy- 20 methyl polystyrene, O-benzotriazol-1-yl-N,N,N’,N’-tetramethyluronium tetrafluoroborate), optionally in the presence of a suitable base (e.g. sodium hydride, sodium bicarbonate, potassium carbonate, pyridine, triethylamine, dimethylaminopyridine, diisopropylamine, sodium hydroxide, potassium tert-butoxide and/or lithium diisopropylamide (or variants thereof) and an appropriate solvent (e.g. 25 tetrahydrofuran, pyridine, toluene, dichloromethane, chloroform, acetonitrile, dimethylformamide, trifluoromethylbenzene, dioxane or triethylamine). Such reactions may be performed in the presence of a further additive such as 1-hydroxybenzotriazole hydrate. Alternatively, a carboxylic acid group may be converted under standard conditions to the corresponding acyl chloride (e.g. in the presence of SOCl ₂ or oxalyl 30 chloride), which acyl chloride is then reacted with a compound of formula (II), for example under similar conditions to those mentioned above;

JAB7061WOPCT1 - 21 - (ii) reaction of a compound of formula (IV), (IV) wherein R ² and R ³ are as hereinbefore defined, with a compound of formula (V) LGa-CH 1 2-C(O)-N(H)R (V)5 wherein LGa represents a suitable leaving group (e.g. halo, such as chloro) and defined herein, under suitable reaction conditions, e.g. in the presence of an ap base, e.g. Cs2CO3, K2CO3 or LiHMDS, or the like, or alternative alkylation rea con conditions; 10 (iii) by transformation (such transformation steps may also take place on intermediates) of a certain compound of formula (I) into another, for example: - for compounds of formula (I) in which R2 represents -N(R2a)R2b, 2 reaction of a corresponding compound of formula (I) in which R 2a 2b 2a represents halo, with an appropriate amine HN(R)R (wherein R 15 and R2b are as herein defined), in an amination reaction under appropriate conditions, e.g. using under standard coupling conditions, in the presence of a catalyst, e.g. CuI, a ligand, e.g. D/L-proline and a base, e.g. K2CO3; similar transformations may be performed on compounds in which another group represents halo, 20 and an amine is desired at another position; - for compounds of formula (I) containing an alkene, reduction to a corresponding compound of formula (I) containing an alkane, under reduction conditions, e.g. with hydrogen in the presence of a suitable catalyst such as, for example, palladium on carbon, in a suitable 25 reaction-inert solvent, such as, for example, ethanol or methanol; - coupling to convert a halo or triflate group to e.g. an alkyl, alkenyl or cycloalkyl group, for example in the presence of a suitable coupling reagent, e.g. where the reagent comprises the appropriate alkyl, alkenyl or aryl/heteroaryl group attached to a suitable group wx wx 30 such as -B(OH)2, -B(OR )2, zincates (e.g. including -Zn(R )2, wx wx wx -ZnBrR ) or -Sn(R )3, in which each R independently represents JAB7061WOPCT1 - 22 - a C alkyl group, or, in the case of -B(ORwx), the wx 1-6 2 respective R groups may be linked together to form a 4- to 6-membered cyclic group (such as a 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl group), thereby forming e.g. a pinacolato boronate ester group. The reaction 5 may be performed in the presence of a suitable catalyst system, e.g. a metal (or a salt or complex thereof) such as Pd, CuI, Pd/C, PdCl ₂ , Pd(OAc) ₂ , Pd(Ph ₃ P) ₂ Cl ₂ , Pd(Ph ₃ P) ₄ (i.e. palladium tetrakistriphenyl- phosphine), Pd ₂ (dba) ₃ and/or NiCl ₂ (preferred cataysts include RuPhos Pd G3, XPhos Pd and bis(tri-tert-butylphosphine)- 10 palladium(0)) and optionally a ligand such as PdCl2(dppf).DCM, t-Bu3P, (C6H11)3P, Ph3P, AsPh3, P(o-Tol)3, 1,2-bis(diphenyl- phosphino)ethane, 2,2'-bis(di-tert-butylphosphino)-1,1'-biphenyl, 2,2'-bis(diphenylphosphino)-1,1'-bi-naphthyl, 1,1’-bis(diphenyl- phosphino-ferrocene), 1,3-bis(diphenylphosphino)propane,15 xantphos, or a mixture thereof, together with a suitable base, such as Na ₂ CO ₃ , K ₃ PO ₄ , Cs ₂ CO ₃ , NaOH, KOH, K ₂ CO ₃ , CsF, Et ₃ N, (i-Pr) ₂ NEt, t-BuONa or t-BuOK (or mixtures thereof; preferred bases include Na ₂ CO ₃ and K ₂ CO ₃ ) in a suitable solvent such as dioxane, toluene, ethanol, dimethylformamide, dimethoxyethane, ethylene 20 glycol dimethyl ether, water, dimethylsulfoxide, acetonitrile, dimethylacetamide, N-methylpyrrolidinone, tetrahydrofuran or mixtures thereof (preferred solvents include dimethylformamide and dimethoxyethane); - reduction of a ketone to an alcohol, in the presence of suitable25 reducing conditions, e.g. NaBH4 or the like; - conversion of a -C(O)alkyl moiety to a -C(OH)(alkyl)(alkyl) moiety by reaction of an appropriate Grignard reagent, e.g. alkylMgBr; - transformation of a alkene =CH2 moiety to a carbonyl =O moiety, for instance, in the presence of AD-mix-Alpha and methane-30 sulfonamide, for instance a -CH=CH ₂ moiety may be converted to a -C(O)H moiety (e.g. by reaction with osmium tetraoxide), which in turn may be converted to a -CHF ₂ group by reaction with DAST; - transformation of a ketone to an alcohol -OH moiety; - alkylation of a -OH moiety (to -O-alkyl), under appropriate reaction35 conditions.

JAB7061WOPCT1 - 23 - The compound of formula (II) may be prepared by hydrolysis of the corresponding carboxylic acid ester (for example under standard hydrolysis conditions, e.g. base hydrolysis in the presence of an alkali metal hydroxide (such as lithium hydroxide)), which in turn is prepared by reaction of a compound of formula (IV), (IV) 5 2 3 wherein R and R are as hereinbefore defined, with a compound of formula (VI), aa LG-CH2-C(O)O-R (VI) aa wherein R represents C1-6 alkyl (e.g ethyl) and LG represents a suitable10 leaving group, such as halo (e.g. chloro), for instance under reaction conditions and using reagent such as those described herein. In general the compounds of the invention can therefore be made with reference to the procedures above. However, in the interests of versatility, further schemes are provided below in order to provide intermediate and final compounds of the invention. 15 Further details are provided in the schemes below (as well as in the specific details of the experimental described hereinafter). In this respect, Scheme 1 outlines a typical synthesis: Scheme 1

JAB7061WOPCT1 - 24 - (M5) (M1) Alkylation + (M6) Li (M2) (M3) (M4) Hydrolysis Amidation (I) (M7) (M8) Compounds of the invention, as described herein, can be prepared by a reaction sequence shown in Scheme 1 (above), whereby an appropriate acyl chloride (M1),5 wherein R3 is as defined herein, is reacted with 2-amino-2-methyl-1-propanol to obtain the corresponding oxazolyl compound (M2), which is reacted with an organometal (e.g. organolithum) to provide a corresponding compound with an ortho-metal substituent (e.g. ortho-lithiated intermediate), which is quenched with an appropriate compound such as an appropriate aldehyde to provide the compound (M3). (M3) is in turn10 oxidized, e.g. with Dess-Martin reagent, to provide the corresponding ketone (M4). The oxazolyl moiety of (M4) may be hydrolysed to the corresponding ester (M5), e.g. in the presence of a corresponding acid (such as H2SO4), however either (M4) or (M5) may be reacted with hydrazine (e.g. in the form of a hydrate) under appropriate conditions to provide compound (M6) (also referred to herein as the compound of 15 formula (IV)). That compound is then alkylated with an appropriate alkyl haloacetate, wherein R is C1-4 alkyl, in the presence of a base, e.g. K2CO3, a nucleophilic catalyst, e.g. KI and a crown ether, e.g.18-crown-6, to provide ester (M7) which is typically cleaved e. g. under basic conditions, e.g. aqueous LiOH in THF or NaOH in MeOH to yield the acid intermediate (M8) (also referred to herein as compound of formula (II)), 1 1 20 followed by amidation with R-NH2 (wherein if R has a functional group such as OH, NH2, CO2H, such group is optionally protected) using standard coupling conditions, e.g.1-propanephosphonic anhydride and a base, e.g. triethylamine, optionally followed by an additional deprotection step to provide a compound of Formula (I), or a pharmaceutically acceptable salt thereof. JAB7061WOPCT1 - 25 - Further the following transformations, depicted in Schemes 2 and 3 below, 2 show versatility in allowing introduction of other substituents at the R position of such intermediates too (as well as for final compounds). 5 Scheme 2 Alkylation Ph-NH2 Grignard R ² MgBr (M11) (M6) (M9) (M10) St10 Gr on th Thereafter transformation may take place for instance in accordance with the procedures outlined by Scheme 1. 15

JAB7061WOPCT1 - 26 - Scheme 3 1. NBS, AIBN, CCl ₄ 2. H2O or aq NaOH bromination ( ^M12) (M13) _(M6A) (M6B) Buchwald 1. (alkyl) ₃ Sn-C(=CH ₂ )-OC2H5 (with amine) 5 al co fo 2 R Buchwald coupling may provide further compounds such as those of formula (IV) in 10 which R2 represents an amino (e.g. -N(R2a)(R2b) group, or an another amine group which may be converted to such a group), for instance by reaction in the presence of an 2a 2b amine (e.g. HN(R )R ) and an appropriate catalyst (e.g. Pd-based catalyst or another as described herein), optionally with a suitable base and ligand (for example one as described herein, in respect of preparations of compounds of formula (I)). 15 Alternatively, the compound (M6B) may be converted to (M6D), for example in the presence of an appropriate tin-based reagent. That compound (M6D) may then be further converted to either (M6E) or (M6F) by reduction or Grignard reaction, 2 providing alternative R groups, e.g. optionally substituted alkyl groups (as depicted). Certain intermediate compounds may be commercially available, may be 20 known in the literature, or may be obtained either by analogy with the processes described herein, or by conventional synthetic procedures, in accordance with standard

JAB7061WOPCT1 - 27 - techniques, from available starting materials using appropriate reagents and reaction conditions. Certain substituents on/in final compounds of the invention or relevant intermediates may be modified one or more times, after or during the processes 5 described above by way of methods that are well known to those skilled in the art. Examples of such methods include substitutions, reductions, oxidations, alkylations, acylations, hydrolyses, esterifications, etherifications, halogenations, nitrations or couplings. Compounds of the invention may be isolated from their reaction mixtures using 10 conventional techniques (e.g. recrystallisations, where possible under standard conditions). It will be appreciated by those skilled in the art that, in the processes described above and hereinafter, the functional groups of intermediate compounds may need to be protected by protecting groups. 15 The need for such protection will vary depending on the nature of the remote functionality and the conditions of the preparation methods (and the need can be readily determined by one skilled in the art). Suitable amino-protecting groups include acetyl, trifluoroacetyl, t-butoxycarbonyl (BOC), benzyloxycarbonyl (CBz), 9-fluorenyl- methyleneoxycarbonyl (Fmoc) and 2,4,4-trimethylpentan-2-yl (which may be 20 deprotected by reaction in the presence of an acid, e.g. HCl in water/alcohol (e.g. MeOH)) or the like. The need for such protection is readily determined by one skilled in the art. For example the a -C(O)O-tert-butyl ester moiety may serve as a protecting group for a -C(O)OH moiety, and hence the former may be converted to the latter for instance by reaction in the presence of a mild acid (e.g. TFA, or the like). 25 The protection and deprotection of functional groups may take place before or after a reaction in the above-mentioned schemes. Protecting groups may be removed in accordance with techniques that are well known to those skilled in the art and as described hereinafter. For example, protected compounds/intermediates described herein may be converted chemically to unprotected 30 compounds using standard deprotection techniques. The type of chemistry involved will dictate the need, and type, of protecting groups as well as the sequence for accomplishing the synthesis. The use of protecting groups is fully described in “Protective Groups in Organic Synthesis”, 3rd edition, T.W. Greene & P.G.M. Wutz, Wiley-Interscience35 (1999). The compounds of the invention as prepared in the hereinabove described processes may be synthesized in the form of racemic mixtures of enantiomers which can be separated from one another following art-known resolution procedures. Those JAB7061WOPCT1 - 28 - compounds of the invention that are obtained in racemic form may be converted into the corresponding diastereomeric salt forms by reaction with a suitable chiral acid. Said diastereomeric salt forms are subsequently separated, for example, by selective or fractional crystallization and the enantiomers are liberated therefrom by alkali. An5 alternative manner of separating the enantiomeric forms of the compounds of the invention involves liquid chromatography using a chiral stationary phase. Said pure stereochemically isomeric forms may also be derived from the corresponding pure stereochemically isomeric forms of the appropriate starting materials, provided that the reaction occurs stereospecifically. Preferably if a specific stereoisomer is desired, said 10 compound will be synthesized by stereospecific methods of preparation. These methods will advantageously employ enantiomerically pure starting materials. PHARMACOLOGY There is evidence for a role of NLRP3-induced IL-1 and IL-18 in the15 inflammatory responses occurring in connection with, or as a result of, a multitude of different disorders (Menu et al., Clinical and Experimental Immunology, 2011, 166, 1- 15; Strowig et al., Nature, 2012, 481, 278-286). NLRP3 mutations have been found to be responsible for a set of rare autoinflammatory diseases known as CAPS (Ozaki et al., J. Inflammation Research, 2015, 8,15-27; Schroder et al., Cell, 2010, 140: 821-20 832; Menu et al., Clinical and Experimental Immunology, 2011, 166, 1-15). CAPS are heritable diseases characterized by recurrent fever and inflammation and are comprised of three autoinflammatory disorders that form a clinical continuum. These diseases, in order of increasing severity, are familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), and chronic infantile25 cutaneous neurological articular syndrome (CINCA; also called neonatal- onset multisystem inflammatory disease, NOMID), and all have been shown to result from gain-of- function mutations in the NLRP3 gene, which leads to increased secretion of IL-1 beta. NLRP3 has also been implicated in a number of autoinflammatory diseases, including pyogenic arthritis, pyoderma gangrenosum and acne (PAPA),30 Sweet's syndrome, chronic nonbacterial osteomyelitis (CNO), and acne vulgaris (Cook et al., Eur. J. lmmunol., 2010, 40, 595-653). A number of autoimmune diseases have been shown to involve NLRP3 including, in particular, multiple sclerosis, type-1 diabetes (T1D), psoriasis, rheumatoid arthritis (RA), Behcet's disease, Schnitzler syndrome, macrophage35 activation syndrome (Braddock et al., Nat. Rev. Drug Disc.2004, 3, 1-10; Inoue et a/., Immunology, 2013, 139, 11-18; Coll et a/., Nat. Med.2015, 21(3), 248-55; Scott et al., Clin. Exp. Rheumatol.2016, 34(1), 88-93), systemic lupus erythematosus and

JAB7061WOPCT1 - 29 - its complications such as lupus nephritis (Lu et al., J. lmmunol. , 2017, 198(3), 1119-29), and systemic sclerosis (Artlett et al., Arthritis Rheum.2011, 63(11), 3563-74). NLRP3 has also been shown to play a role in a number of lung diseases including chronic obstructive pulmonary disorder (COPD), asthma (including steroid-5 resistant asthma), asbestosis, and silicosis (De Nardo et al., Am. J. Pathol., 2014, 184: 42-54; Kim et al., Am. J. Respir. Crit. Care Med, 2017, 196(3), 283-97). NLRP3 has also been suggested to have a role in a number of central nervous system conditions, including Multiple Sclerosis (MS), Parkinson's disease (PD), Alzheimer's disease (AD), dementia, Huntington's disease, cerebral malaria, brain injury from10 pneumococcal meningitis (Walsh et al., Nature Reviews, 2014, 15, 84-97; and Dempsey et al., Brain. Behav. lmmun.2017, 61, 306-16), intracranial aneurysms (Zhang et al., J. Stroke and Cerebrovascular Dis., 2015, 24, 5, 972-9), and traumatic brain injury (Ismael et al., J. Neurotrauma., 2018, 35(11), 1294-1303). NLRP3 activity has also been shown to be involved in various metabolic diseases including15 type 2 diabetes (T2D) and its organ-specific complications, atherosclerosis, obesity, gout, pseudo-gout, metabolic syndrome (Wen et al., Nature Immunology, 2012, 13, 352-357; Duewell et al., Nature, 2010, 464, 1357-1361; Strowig et al., Nature, 2014, 481, 278- 286), and non-alcoholic steatohepatitis (Mridha et al., J. Hepatol.2017, 66(5), 1037-46). A role for NLRP3 via IL-1 beta has also been suggested in20 atherosclerosis, myocardial infarction (van Hout et al., Eur. Heart J.2017, 38(11), 828-36), heart failure (Sano et al., J. Am. Coll. Cardiol.2018, 71(8), 875-66), aortic aneurysm and dissection (Wu et al., Arteriosc/er. Thromb. Vase. Biol., 2017,37(4), 694-706), and other cardiovascular events (Ridker et al., N. Engl. J. Med., 2017, 377(12), 1119-31). 25 Other diseases in which NLRP3 has been shown to be involved include: ocular diseases such as both wet and dry age-related macular degeneration (Doyle et al., Nature Medicine, 2012, 18, 791-798; Tarallo et al., Cell 2012, 149(4), 847-59), diabetic retinopathy (Loukovaara et al., Acta Ophthalmol., 2017, 95(8), 803-8), non- infectious uveitis and optic nerve damage (Puyang et al., Sci. Rep.2016, 6, 20998);30 liver diseases including non-alcoholic steatohepatitis (NASH) and acute alcoholic hepatitis (Henao-Meija et al., Nature, 2012, 482, 179-185); inflammatory reactions in the lung and skin (Primiano et al., J. lmmunol.2016, 197(6), 2421-33) including contact hypersensitivity (such as bullous pemphigoid (Fang et al., J Dermatol Sci. 2016, 83(2), 116-23)), atopic dermatitis (Niebuhr et al., Allergy, 2014, 69(8), 1058-35 67), Hidradenitis suppurativa (Alikhan et al., J. Am. Acad. Dermatol. , 2009 ,60(4), 539-61), and sarcoidosis (Jager et al., Am. J. Respir. Crit. Care Med., 2015, 191, A5816); inflammatory reactions in the joints (Braddock et al., Nat. Rev. Drug Disc, 2004, 3, 1-10); amyotrophic lateral sclerosis (Gugliandolo et al., Int. J. Mo/. Sci., JAB7061WOPCT1 - 30 - 2018, 19(7), E1992); cystic fibrosis (lannitti et al., Nat. Commun., 2016, 7, 10791); stroke (Walsh et al., Nature Reviews, 2014, 15, 84-97); chronic kidney disease (Granata et al., PLoS One 2015, 10(3), eoi22272); and inflammatory bowel diseases including ulcerative colitis and Crohn's disease (Braddock et al., Nat. Rev. Drug Disc,5 2004, 3, 1-10; Neudecker et a/., J. Exp. Med.2017, 214(6), 1737-52; Lazaridis et al., Dig. Dis. Sci.2017, 62(9), 2348-56). The NLRP3 inflammasome has been found to be activated in response to oxidative stress. NLRP3 has also been shown to be involved in inflammatory hyperalgesia (Dolunay et al., Inflammation, 2017, 40, 366- 86). 10 Activation of the NLRP3 inflammasome has been shown to potentiate some pathogenic infections such as influenza and Leishmaniasis (Tate et al., Sci Rep., 2016, 10(6), 27912-20; Novias et al., PLOS Pathogens 2017, 13(2), e1006196). NLRP3 has also been implicated in the pathogenesis of many cancers (Menu et al., Clinical and Experimental Immunology, 2011, 166, 1-15). For example,15 several previous studies have suggested a role for IL-1 beta in cancer invasiveness, growth and metastasis, and inhibition of IL-1 beta with canakinumab has been shown to reduce the incidence of lung cancer and total cancer mortality in a randomised, double-blind, placebo-controlled trial (Ridker et al., Lancet. , 2017, 390(10105), 1833-42). Inhibition of the NLRP3 inflammasome or IL-1 beta has also been shown20 to inhibit the proliferation and migration of lung cancer cells in vitro (Wang et al., Onco/ Rep., 2016, 35(4), 2053-64). A role for the NLRP3 inflammasome has been suggested in myelodysplastic syndromes, myelofibrosis and other myeloproliferative neoplasms, and acute myeloid leukemia (AML) (Basiorka et al., Blood, 2016, 128(25), 2960-75.) and also in the carcinogenesis of various other cancers including25 glioma (Li et al., Am. J. Cancer Res.2015, 5(1), 442-9), inflammation- induced tumors (Allen et al., J. Exp. Med.2010, 207(5), 1045-56; Hu et al., PNAS., 2010, 107(50), 21635-40), multiple myeloma (Li et al., Hematology, 201621(3), 144-51), and squamous cell carcinoma of the head and neck (Huang et al., J. Exp. Clin. Cancer Res., 2017, 36(1), 116). Activation of the NLRP3 inflammasome has also30 been shown to mediate chemoresistance of tumor cells to 5-Fluorouracil (Feng et al., J. Exp. Clin. Cancer Res., 2017, 36(1), 81), and activation of NLRP3 inflammasome in peripheral nerve contributes to chemotherapy-induced neuropathic pain (Jia et al., Mol. Pain., 2017, 13, 1-11). NLRP3 has also been shown to be required for the efficient control of viruses, bacteria, and fungi. 35 The activation of NLRP3 leads to cell pyroptosis and this feature plays an important part in the manifestation of clinical disease (Yan-gang et al., Cell Death and Disease, 2017, 8(2), 2579; Alexander et al., Hepatology, 2014, 59(3), 898-910; JAB7061WOPCT1 - 31 - Baldwin et al., J. Med. Chem., 2016, 59(5), 1691- 1710; Ozaki et a/., J. Inflammation Research, 2015, 8, 15-27; Zhen et a/., Neuroimmunology Neuroinflammation, 2014, 1(2), 60-65; Mattia et a/., J. Med. Chem., 2014, 57(24), 10366-82; Satoh et al., Cell Death and Disease, 2013, 4, 644). Therefore, it is anticipated that inhibitors of5 NLRP3 will block pyroptosis, as well as the release of pro-inflammatory cytokines (e.g. IL-1 beta) from the cell. Hence, the compounds of the invention, as described herein (e.g. in any of the embodiments described herein, including by the examples, and/or in any of the forms described herein, e.g. in a salt form or free form, etc) exhibit valuable pharmacological10 properties, e.g. NLRP3 inhibiting properties on the NLRP3 inflammasome pathway e.g. as indicated in vitro tests as provided herein, and are therefore indicated for therapy or for use as research chemicals, e.g. as tool compounds. Compounds of the invention may be useful in the treatment of an indication selected from: inflammasome-related diseases/disorders, immune diseases, inflammatory diseases,15 auto-immune diseases, or auto-inflammatory diseases, for example, of diseases, disorders or conditions in which NLRP3 signaling contributes to the pathology, and/or symptoms, and/or progression, and which may be responsive to NLRP3 inhibition and which may be treated or prevented, according to any of the methods/uses described herein, e.g. by use or administration of a compound of the invention, and,20 hence, in an embodiment, such indications may include: I. Inflammation, including inflammation occurring as a result of an inflammatory disorder, e.g. an autoinflammatory disease, inflammation occurring as a symptom of a non- inflammatory disorder, inflammation occurring as a result of infection, or inflammation secondary to trauma,25 injury or autoimmunity. Examples of inflammation that may be treated or prevented include inflammatory responses occurring in connection with, or as a result of: a. a skin condition such as contact hypersensitivity, bullous pemphigoid, sunburn, psoriasis, atopical dermatitis, contact dermatitis,30 allergic contact dermatitis, seborrhoetic dermatitis, lichen planus, scleroderma, pemphigus, epidermolysis bullosa, urticaria, erythemas, or alopecia; b. a joint condition such as osteoarthritis, systemic juvenile idiopathic arthritis, adult-onset Still's disease, relapsing polychondritis, 35 rheumatoid arthritis, juvenile chronic arthritis, crystal induced arthropathy (e.g. pseudo-gout, gout), or a seronegative

JAB7061WOPCT1 - 32 - spondyloarthropathy (e.g. ankylosing spondylitis, psoriatic arthritis or Reiter's disease); c. a muscular condition such as polymyositis or myasthenia gravis; d. a gastrointestinal tract condition such as inflammatory bowel disease5 (including Crohn's disease and ulcerative colitis), gastric ulcer, coeliac disease, proctitis, pancreatitis, eosinopilic gastro- enteritis, mastocytosis, antiphospholipid syndrome, or a food-related allergy which may have effects remote from the gut (e.g., migraine, rhinitis or eczema); 10 e. a respiratory system condition such as chronic obstructive pulmonary disease (COPD), asthma (including bronchial, allergic, intrinsic, extrinsic or dust asthma, and particularly chronic or inveterate asthma, such as late asthma and airways hyper- responsiveness), bronchitis, rhinitis (including acute rhinitis, allergic rhinitis, atrophic rhinitis,15 chronic rhinitis, rhinitis caseosa, hypertrophic rhinitis, rhinitis pumlenta, rhinitis sicca, rhinitis medicamentosa, membranous rhinitis, seasonal rhinitis e.g. hay fever, and vasomotor rhinitis), sinusitis, idiopathic pulmonary fibrosis (IPF), sarcoidosis, farmer's lung, silicosis, asbestosis, adult respiratory distress syndrome,20 hypersensitivity pneumonitis, or idiopathic interstitial pneumonia; f. a vascular condition such as atherosclerosis, Behcet's disease, vasculitides, or Wegener's granulomatosis; g. an immune condition, e.g. autoimmune condition, such as systemic lupus erythematosus (SLE), Sjogren's syndrome, systemic sclerosis,25 Hashimoto's thyroiditis, type I diabetes, idiopathic thrombocytopenia purpura, or Graves disease; h. an ocular condition such as uveitis, allergic conjunctivitis, or vernal conjunctivitis; i. a nervous condition such as multiple sclerosis or encephalomyelitis;30 j. an infection or infection-related condition, such as Acquired Immunodeficiency Syndrome (AIDS), acute or chronic bacterial infection, acute or chronic parasitic infection, acute or chronic viral infection, acute or chronic fungal infection, meningitis, hepatitis (A, B or C, or other viral hepatitis), peritonitis, pneumonia, epiglottitis,35 malaria, dengue hemorrhagic fever, leishmaniasis, streptococcal

JAB7061WOPCT1 - 33 - myositis, mycobacterium tuberculosis, mycobacterium avium intracellulare, Pneumocystis carinii pneumonia, orchitis/epidydimitis, legionella, Lyme disease, influenza A, epstein-barr virus, viral encephalitis/aseptic meningitis, or pelvic inflammatory disease; 5 k. a renal condition such as mesangial proliferative glomerulonephritis, nephrotic syndrome, nephritis, glomerular nephritis, acute renal failure, uremia, or nephritic syndrome; l. a lymphatic condition such as Castleman's disease; m. a condition of, or involving, the immune system, such as hyper lgE10 syndrome, lepromatous leprosy, familial hemophagocytic lymphohistiocytosis, or graft versus host disease; n. a hepatic condition such as chronic active hepatitis, non-alcoholic steatohepatitis (NASH), alcohol-induced hepatitis, non-alcoholic fatty liver disease (NAFLD), alcoholic fatty liver disease (AFLD), alcoholic15 steatohepatitis (ASH) or primary biliary cirrhosis; o. a cancer, including those cancers listed herein below; p. a burn, wound, trauma, haemorrhage or stroke; q. radiation exposure; r. obesity; and/or 20 s. pain such as inflammatory hyperalgesia; II. Inflammatory disease, including inflammation occurring as a result of an inflammatory disorder, e.g. an autoinflammatory disease, such as cryopyrin-associated periodic syndromes (CAPS), Muckle-Wells syndrome (MWS), familial cold autoinflammatory syndrome (FCAS),25 familial Mediterranean fever (FMF), neonatal onset multisystem inflammatory disease (NOMID), Majeed syndrome, pyogenic arthritis, pyoderma gangrenosum and acne syndrome (PAPA), adult-onset Still's disease (AOSD), haploinsufficiency of A20 (HA20), pediatric granulomatous arthritis (PGA), PLCG2-associated antibody deficiency and30 immune dysregulation (PLAID), PLCG2- associated autoinflammatory, antibody deficiency and immune dysregulation (APLAID), or sideroblastic anaemia with B-cell immunodeficiency, periodic fevers and developmental delay (SIFD);

JAB7061WOPCT1 - 34 - III. Immune diseases, e.g. auto-immune diseases, such as acute disseminated encephalitis, Addison's disease, ankylosing spondylitis, antiphospholipid antibody syndrome (APS), anti-synthetase syndrome, aplastic anemia, autoimmune adrenalitis, autoimmune hepatitis, autoimmune oophoritis,5 autoimmune polyglandular failure, autoimmune thyroiditis, Coeliac disease, Crohn's disease, type 1 diabetes (T1D), Goodpasture's syndrome, Graves' disease, Guillain-Barre syndrome (GBS), Hashimoto's disease, idiopathic thrombocytopenic purpura, Kawasaki's disease, lupus erythematosus including systemic lupus erythematosus (SLE), multiple10 sclerosis (MS) including primary progressive multiple sclerosis (PPMS), secondary progressive multiple sclerosis (SPMS) and relapsing remitting multiple sclerosis (RRMS), myasthenia gravis, opsoclonus myoclonus syndrome (OMS), optic neuritis, Ord's thyroiditis, pemphigus, pernicious anaemia, polyarthritis, primary biliary cirrhosis, rheumatoid arthritis (RA),15 psoriatic arthritis, juvenile idiopathic arthritis or Still's disease, refractory gouty arthritis, Reiter's syndrome, Sjogren's syndrome, systemic sclerosis a systemic connective tissue disorder, Takayasu's arteritis, temporal arteritis, warm autoimmune hemolytic anemia, Wegener's granulomatosis, alopecia universalis, Beliefs disease, Chagas' disease, dysautonomia,20 endometriosis, hidradenitis suppurativa (HS), interstitial cystitis, neuromyotonia, psoriasis, sarcoidosis, scleroderma, ulcerative colitis, Schnitzler syndrome, macrophage activation syndrome, Blau syndrome, giant cell arteritis, vitiligo or vulvodynia; IV. Cancer including lung cancer, renal cell carcinoma, non-small cell lung25 carcinoma (NSCLC), Langerhans cell histiocytosis (LCH), myeloproliferative neoplams (MPN), pancreatic cancer, gastric cancer, myelodysplastic syndrome (MOS), leukaemia including acute lymphocytic leukaemia (ALL) and acute myeloid leukaemia (AML), promyelocytic leukemia (APML, or APL), adrenal cancer, anal cancer, basal and30 squamous cell skin cancer, bile duct cancer, bladder cancer, bone cancer, brain and spinal cord tumours, breast cancer, cervical cancer, chronic lymphocytic leukaemia (CLL), chronic myeloid leukaemia (CML), chronic myelomonocytic leukaemia (CMML), colorectal cancer, endometrial cancer, oesophagus cancer, Ewing family of tumours, eye35 cancer, gallbladder cancer, gastrointestinal carcinoid tumours, gastrointestinal stromal tumour (GIST), gestational trophoblastic disease, glioma, Hodgkin lymphoma, Kaposi sarcoma, kidney cancer, laryngeal and hypopharyngeal cancer, liver cancer, lung carcinoid tumour, JAB7061WOPCT1 - 35 - lymphoma including cutaneous T cell lymphoma, malignant mesothelioma, melanoma skin cancer, Merkel cell skin cancer, multiple myeloma, nasal cavity and paranasal sinuses cancer, nasopharyngeal cancer, neuroblastoma, non-Hodgkin lymphoma, non-small cell lung cancer, oral5 cavity and oropharyngeal cancer, osteosarcoma, ovarian cancer, penile cancer, pituitary tumours, prostate cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, skin cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, stomach cancer, testicular cancer, thymus cancer, thyroid cancer including anaplastic thyroid10 cancer, uterine sarcoma, vaginal cancer, vulvar cancer, Waldenstrom macroglobulinemia, and Wilms tumour; V. Infections including viral infections (e.g. from influenza virus, human immunodeficiency virus (HIV), alphavirus (such as Chikungunya and Ross River virus), flaviviruses (such as Dengue virus and Zika virus), herpes15 viruses (such as Epstein Barr Virus, cytomegalovirus, Varicella-zoster virus, and KSHV), poxviruses (such as vaccinia virus (Modified vaccinia virus Ankara) and Myxoma virus), adenoviruses (such as Adenovirus 5), papillomavirus, or SARS-CoV-2) bacterial infections (e.g. from Staphylococcus aureus, Helicobacter pylori, Bacillus anthracis, Bordatella20 pertussis, Burkholderia pseudomallei, Corynebacterium diptheriae, Clostridium tetani, Clostridium botulinum, Streptococcus pneumoniae, Streptococcus pyogenes, Listeria monocytogenes, Hemophilus influenzae, Pasteurella multicida, Shigella dysenteriae, Mycobacterium tuberculosis, Mycobacterium leprae, Mycoplasma pneumoniae, Mycoplasma hominis,25 Neisseria meningitidis, Neisseria gonorrhoeae, Rickettsia rickettsii, Legionella pneumophila, Klebsiella pneumoniae, Pseudomonas aeruginosa, Propionibacterium acnes, Treponema pallidum, Chlamydia trachomatis, Vibrio cholerae, Salmonella typhimurium, Salmonella typhi, Borrelia burgdorferi or Yersinia pestis), fungal infections (e.g. from Candida or30 Aspergillus species), protozoan infections (e.g. from Plasmodium, Babesia, Giardia, Entamoeba, Leishmania or Trypanosomes), helminth infections (e.g. from schistosoma, roundworms, tapeworms or flukes), and prion infections; VI. Central nervous system diseases such as Parkinson's disease, Alzheimer's35 disease, dementia, motor neuron disease, Huntington's disease, cerebral malaria, brain injury from pneumococcal meningitis, intracranial

JAB7061WOPCT1 - 36 - aneurysms, traumatic brain injury, multiple sclerosis, and amyotrophic lateral sclerosis; VII. Metabolic diseases such as type 2 diabetes (T2D), atherosclerosis, obesity, gout, and pseudo-gout; 5 VIII.Cardiovascular diseases such as hypertension, ischaemia, reperfusion injury including post-Ml ischemic reperfusion injury, stroke including ischemic stroke, transient ischemic attack, myocardial infarction including recurrent myocardial infarction, heart failure including congestive heart failure and heart failure with preserved ejection fraction, embolism, aneurysms10 including abdominal aortic aneurysm, cardiovascular risk reduction (CvRR), and pericarditis including Dressler's syndrome; IX. Respiratory diseases including chronic obstructive pulmonary disorder (COPD), asthma such as allergic asthma and steroid-resistant asthma, asbestosis, silicosis, nanoparticle induced inflammation, cystic fibrosis, and15 idiopathic pulmonary fibrosis; X. Liver diseases including non-alcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) including advanced fibrosis stages F3 and F4, alcoholic fatty liver disease (AFLD), and alcoholic steatohepatitis (ASH); 20 XI. Renal diseases including acute kidney disease, hyperoxaluria, chronic kidney disease, oxalate nephropathy, nephrocalcinosis, glomerulonephritis, and diabetic nephropathy; XII. Ocular diseases including those of the ocular epithelium, age-related macular degeneration (AMO) (dry and wet), uveitis, corneal25 infection, diabetic retinopathy, optic nerve damage, dry eye, and glaucoma; XIII.Skin diseases including dermatitis such as contact dermatitis and atopic dermatitis, contact hypersensitivity, sunburn, skin lesions, hidradenitis suppurativa (HS), other cyst-causing skin diseases, and acne30 conglobata; XIV.Lymphatic conditions such as lymphangitis, and Castleman's disease; XV. Psychological disorders such as depression, and psychological stress; XVI. Graft versus host disease; XVII. Bone diseases including osteoporosis, osteopetrosis;

JAB7061WOPCT1 - 37 - XVIII. Blood disease including sickle cell disease; XIX. Allodynia including mechanical allodynia; and XX. Any disease where an individual has been determined to carry a germline or somatic non-silent mutation in NLRP3. 5 More specifically the compounds of the invention may be useful in the treatment of an indication selected from: inflammasome-related diseases/disorders, immune diseases, inflammatory diseases, auto-immune diseases, or auto-inflammatory diseases, for example, autoinflammatory fever syndromes (e.g., cryopyrin-associated periodic syndrome), sickle cell disease,10 systemic lupus erythematosus (SLE), liver related diseases/disorders (e.g. chronic liver disease, viral hepatitis, non-alcoholic steatohepatitis (NASH), alcoholic steatohepatitis, and alcoholic liver disease), inflammatory arthritis related disorders (e.g. gout, pseudogout (chondrocalcinosis), osteoarthritis, rheumatoid arthritis, arthropathy e.g acute, chronic), kidney related diseases (e.g. 15 hyperoxaluria, lupus nephritis, Type I/Type II diabetes and related complications (e.g. nephropathy, retinopathy), hypertensive nephropathy, hemodialysis related inflammation), neuroinflammation-related diseases (e.g. multiple sclerosis, brain infection, acute injury, neurodegenerative diseases, Alzheimer's disease), cardiovascular/metabolic diseases/disorders (e.g. 20 cardiovascular risk reduction (CvRR), hypertension, atherosclerosis, Type I and Type II diabetes and related complications, peripheral artery disease (PAD), acute heart failure), inflammatory skin diseases (e.g. hidradenitis suppurativa, acne), wound healing and scar formation, asthma, sarcoidosis, age-related macular degeneration, and cancer related diseases/disorders (e.g. colon cancer, lung25 cancer, myeloproliferative neoplasms, leukemias, myelodysplastic syndromes (MOS), myelofibrosis). In particular, autoinflammatory fever syndromes (e.g. CAPS), sickle cell disease, Type I/Type II diabetes and related complications (e.g. nephropathy, retinopathy), hyperoxaluria, gout, pseudogout (chondrocalcinosis), chronic liver disease, NASH, neuroinflammation-related30 disorders (e.g. multiple sclerosis, brain infection, acute injury, neurodegenerative diseases, Alzheimer's disease), atherosclerosis and cardiovascular risk (e.g. cardiovascular risk reduction (CvRR), hypertension), hidradenitis suppurativa, wound healing and scar formation, and cancer (e.g. colon cancer, lung cancer, myeloproliferative neoplasms, leukemias, myelodysplastic syndromes (MOS),35 myelofibrosis). In particular, compounds of the invention, may be useful in the treatment of a disease or disorder selected from autoinflammatory fever syndromes (e.g. CAPS), JAB7061WOPCT1 - 38 - sickle cell disease, Type I/ Type II diabetes and related complications (e.g. nephropathy, retinopathy), hyperoxaluria, gout, pseudogout (chondrocalcinosis), chronic liver disease, NASH, neuroinflammation-related disorders (e.g. multiple sclerosis, brain infection, acute injury, neurodegenerative diseases, Alzheimer's5 disease), atherosclerosis and cardiovascular risk (e.g. cardiovascular risk reduction (CvRR), hypertension), hidradenitis suppurativa, wound healing and scar formation, and cancer (e.g. colon cancer, lung cancer, myeloproliferative neoplasms, leukemias, myelodysplastic syndromes (MOS), myelofibrosis). Thus, as a further aspect, the present invention provides the use of a compound of the invention (hence, including a 10 compound as defined by any of the embodiments/forms/examples herein) in therapy. In a further embodiment, the therapy is selected from a disease, which may be treated by inhibition of NLRP3 inflammasome. In another embodiment, the disease is as defined in any of the lists herein. Hence, there is provided any one of the compounds of the invention described herein (including any of the embodiments/forms/examples) 15 for use in the treatment of any of the diseases or disorders described herein (e.g. as described in the aforementioned lists). PHARMACEUTICAL COMPOSITIONS AND COMBINATIONS In an embodiment, the invention also relates to a composition comprising a 20 pharmaceutically acceptable carrier and, as active ingredient, a therapeutically effective amount of a compound of the invention. The compounds of the invention may be formulated into various pharmaceutical forms for administration purposes. As appropriate compositions there may be cited all compositions usually employed for systemically administering drugs. To prepare the pharmaceutical compositions of this25 invention, an effective amount of the particular compound, optionally in salt form, as the active ingredient is combined in intimate admixture with a pharmaceutically acceptable carrier, which carrier may take a wide variety of forms depending on the form of preparation desired for administration. These pharmaceutical compositions are desirable in unitary dosage form suitable, in particular, for administration orally or by 30 parenteral injection. For example, in preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be employed such as, for example, water, glycols, oils, alcohols and the like in the case of oral liquid preparations such as suspensions, syrups, elixirs, emulsions and solutions; or solid carriers such as starches, sugars, kaolin, diluents, lubricants, binders, disintegrating agents and the like in the 35 case of powders, pills, capsules and tablets. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit forms in which case solid pharmaceutical carriers are obviously employed. For parenteral compositions, the carrier will usually comprise sterile water, at least in large part, JAB7061WOPCT1 - 39 - though other ingredients, for example, to aid solubility, may be included. Injectable solutions, for example, may be prepared in which the carrier comprises saline solution, glucose solution or a mixture of saline and glucose solution. Injectable suspensions may also be prepared in which case appropriate liquid carriers, suspending agents and 5 the like may be employed. Also included are solid form preparations which are intended to be converted, shortly before use, to liquid form preparations. In an embodiment, and depending on the mode of administration, the pharmaceutical composition will preferably comprise from 0.05 to 99 % by weight, more preferably from 0.1 to 70 % by weight, even more preferably from 0.1 to 50 % by 10 weight of the active ingredient(s), and, from 1 to 99.95 % by weight, more preferably from 30 to 99.9 % by weight, even more preferably from 50 to 99.9 % by weight of a pharmaceutically acceptable carrier, all percentages being based on the total weight of the composition. The pharmaceutical composition may additionally contain various other 15 ingredients known in the art, for example, a lubricant, stabilising agent, buffering agent, emulsifying agent, viscosity-regulating agent, surfactant, preservative, flavouring or colorant. It is especially advantageous to formulate the aforementioned pharmaceutical compositions in unit dosage form for ease of administration and uniformity of dosage. 20 Unit dosage form as used herein refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. Examples of such unit dosage forms are tablets (including scored or coated tablets), capsules, pills, powder packets, wafers, suppositories,25 injectable solutions or suspensions and the like, and segregated multiples thereof. The daily dosage of the compound according to the invention will, of course, vary with the compound employed, the mode of administration, the treatment desired and the mycobacterial disease indicated. However, in general, satisfactory results will be obtained when the compound according to the invention is administered at a daily30 dosage not exceeding 1 gram, e.g. in the range from 10 to 50 mg/kg body weight. In an embodiment, there is provided a combination comprising a therapeutically effective amount of a compound of the invention, according to any one of the embodiments described herein, and another therapeutic agent (including one or more therapeutic agents). In a further embodiment, there is provided such a combination35 wherein the other therapeutic agent is selected from (and where there is more than one therapeutic agent, each is independently selected from): farnesoid X receptor (FXR) agonists; anti-steatotics; anti-fibrotics; JAK inhibitors; checkpoint inhibitors including anti-PD1 inhibitors, anti-LAG-3 inhibitors, anti-TIM-3 inhibitors, or anti- JAB7061WOPCT1 - 40 - POL 1 inhibitors; chemotherapy, radiation therapy and surgical procedures; urate- lowering therapies; anabolics and cartilage regenerative therapy; blockade of IL-17; complement inhibitors; Bruton's tyrosine Kinase inhibitors (BTK inhibitors); Toll Like receptor inhibitors (TLR7/8 inhibitors); CAR-T therapy; anti-hypertensive agents;5 cholesterol lowering agents; leukotriene A4 hydrolase (LTAH4) inhibitors; SGLT2 inhibitors; 132-agonists; anti-inflammatory agents; nonsteroidal anti-inflammatory drugs ("NSAIDs"); acetylsalicylic acid drugs (ASA) including aspirin; paracetamol; regenerative therapy treatments; cystic fibrosis treatments; or atherosclerotic treatment. In a further embodiment, there is also provided such (a) combination(s) for use as 10 described herein in respect of compounds of the invention, e.g. for use in the treatment of a disease or disorder in which the NLRP3 signalling contributes to the pathology, and/or symptoms, and/or progression, of said disease/disorder, or, a disease or disorder associated with NLRP3 activity (including NLRP3 inflammasome activity), including inhibiting NLRP3 inflammasome activity, and in this respect the specific15 disease/disorder mentioned herein apply equally here. There may also be provided methods as described herein in repsect of compounds of the invention, but wherein the method comprises administering a therapeutically effective amount of such combination (and, in an embodiment, such method may be to treat a disease or disorder mentioned herein in the context of inhibiting NLRP3 inflammasome activity). The 20 combinations mentioned herein may be in a single preparation or they may be formulated in separate preparations so that they can be administered simultaneously, separately or sequentially. Thus, in an embodiment, the present invention also relates to a combination product containing (a) a compound according to the invention, according to any one of the embodiments described herein, and (b) one or more other 25 therapeutic agents (where such therapeutic agents are as described herein), as a combined preparation for simultaneous, separate or sequential use in the treatment of a disease or disorder associated with inhibiting NLRP3 inflammasome activity (and where the disease or disorder may be any one of those described herein), for instance, in an embodiment, the combination may be a kit of parts. Such combinations may be 30 referred to as “pharmaceutical combinations”. The route of administration for a compound of the invention as a component of a combination may be the same or different to the one or more other therapeutic agent(s) with which it is combined. The other therapeutic agent is, for example, a chemical compound, peptide, antibody, antibody fragment or nucleic acid, which is therapeutically active or enhances the35 therapeutic activity when administered to a patient in combination with a compound of the invention. The weight ratio of (a) the compound according to the invention and (b) the other therapeutic agent(s) when given as a combination may be determined by the JAB7061WOPCT1 - 41 - person skilled in the art. Said ratio and the exact dosage and frequency of administration depends on the particular compound according to the invention and the other antibacterial agent(s) used, the particular condition being treated, the severity of the condition being treated, the age, weight, gender, diet, time of administration and 5 general physical condition of the particular patient, the mode of administration as well as other medication the individual may be taking, as is well known to those skilled in the art. Furthermore, it is evident that the effective daily amount may be lowered or increased depending on the response of the treated subject and/or depending on the evaluation of the physician prescribing the compounds of the instant invention. A 10 particular weight ratio for the present compound of the invention and another antibacterial agent may range from 1/10 to 10/1, more in particular from 1/5 to 5/1, even more in particular from 1/3 to 3/1. The pharmaceutical composition or combination of the present invention can be in unit dosage of about 1-1000 mg of active ingredient(s) for a subject of15 about 50 - 70 kg, or about 1 - 500 mg, or about 1 - 250 mg, or about 1 - 150 mg, or about 1 - 100 mg, or about 1 - 50 mg of active ingredients. The therapeutically effective dosage of a compound, the pharmaceutical composition, or the combinations thereof, is dependent on the species of the subject, the body weight, age and individual condition, the disorder or disease or the severity thereof being treated. A20 physician, clinician or veterinarian of ordinary skill can readily determine the effective amount of each of the active ingredients necessary to prevent, treat or inhibit the progress of the disorder or disease. The above-cited dosage properties are demonstrable in vitro and in vivo tests using advantageously mammals, e.g., mice, rats, dogs, monkeys or isolated organs,25 tissues and preparations thereof. The compounds of the present invention can be applied in vitro in the form of solutions, e.g., aqueous solutions, and in vivo either enterally, parenterally, advantageously intravenously, e.g., as a suspension or in aqueous solution. The dosage in vitro may range between about 10- ³ molar and 10- ⁹ molar concentrations. A therapeutically effective amount in vivo may range30 depending on the route of administration, between about 0.1 - 500 mg/kg, or between about 1 - 100 mg/kg. As used herein, term "pharmaceutical composition" refers to a compound of the invention, or a pharmaceutically acceptable salt thereof, together with at least one pharmaceutically acceptable carrier, in a form suitable35 for oral or parenteral administration. As used herein, the term "pharmaceutically acceptable carrier" refers to a substance useful in the preparation or use of a pharmaceutical composition and JAB7061WOPCT1 - 42 - includes, for example, suitable diluents, solvents, dispersion media, surfactants, antioxidants, preservatives, isotonic agents, buffering agents, emulsifiers, absorption delaying agents, salts, drug stabilizers, binders, excipients, disintegration agents, lubricants, wetting agents, sweetening agents, flavoring5 agents, dyes, and combinations thereof, as would be known to those skilled in the art (see, for example, Remington The Science and Practice of Pharmacy, 22nd Ed. Pharmaceutical Press, 2013, pp.1049-1070). The term "subject" as used herein, refers to an animal, preferably a mammal, most preferably a human, for example who is or has been the object of treatment,10 observation or experiment. The term "therapeutically effective amount" as used herein, means that amount of compound of the invention (including, where applicable, form, composition, combination comprising such compound of the invention) elicits the biological or medicinal response of a subject, for example, reduction or inhibition of an enzyme15 or a protein activity, or ameliorate symptoms, alleviate conditions, slow or delay disease progression, or prevent a disease, etc. In one non-limiting embodiment, the term "a therapeutically effective amount" refers to the amount of the compound of the present invention that, when administered to a subject, is effective to (1) at least partially alleviate, inhibit, prevent and/or ameliorate a condition, or a disorder or a20 disease (i) mediated by NLRP3, or (ii) associated with NLRP3 activity, or (iii) characterised by activity (normal or abnormal) of NLRP3; or (2) reduce or inhibit the activity of NLRP3; or (3) reduce or inhibit the expression of NLRP3. In another non-limiting embodiment, the term "a therapeutically effective amount" refers to the amount of the compound of the present invention that, when administered to a cell,25 or a tissue, or a non-cellular biological material, or a medium, is effective to at least partially reduce or inhibit the activity of NLRP3; or at least partially reduce or inhibit the expression of NLRP3. As used herein, the term "inhibit", "inhibition" or "inhibiting" refers to the reduction or suppression of a given condition, symptom, or disorder, or disease, or a30 significant decrease in the baseline activity of a biological activity or process. Specifically, inhibiting NLRP3 or inhibiting NLRP3 inflammasome pathway comprises reducing the ability of NLRP3 or NLRP3 inflammasome pathway to induce the production of IL-1 and/or IL-18. This can be achieved by mechanisms including, but not limited to, inactivating, destabilizing, and/or altering distribution of35 NLRP3. As used herein, the term "NLRP3" is meant to include, without limitation, nucleic acids, polynucleotides, oligonucleotides, sense and anti-sense polynucleotide JAB7061WOPCT1 - 43 - strands, complementary sequences, peptides, polypeptides, proteins, homologous and/or orthologous NLRP molecules, isoforms, precursors, mutants, variants, derivatives, splice variants, alleles, different species, and active fragments thereof. As used herein, the term "treat", "treating" or "treatment" of any disease or5 disorder refers to alleviating or ameliorating the disease or disorder (i.e., slowing or arresting the development of the disease or at least one of the clinical symptoms thereof); or alleviating or ameliorating at least one physical parameter or biomarker associated with the disease or disorder, including those which may not be discernible to the patient. 10 As used herein, the term "prevent", "preventing" or "prevention" of any disease or disorder refers to the prophylactic treatment of the disease or disorder; or delaying the onset or progression of the disease or disorder. As used herein, a subject is "in need of” a treatment if such subject would benefit biologically, medically or in quality of life from such treatment. 15 "Combination" refers to either a fixed combination in one dosage unit form, or a combined administration where a compound of the present invention and a combination partner (e.g. another drug as explained below, also referred to as "therapeutic agent" or "co-agent") may be administered independently at the same time or separately within time intervals. The single components may be packaged in a kit20 or separately. One or both of the components (e.g. powders or liquids) may be reconstituted or diluted to a desired dose prior to administration. The terms "co- administration" or "combined administration" or the like as utilized herein are meant to encompass administration of the selected combination partner to a single subject in need thereof (e.g. a patient), and are intended to include treatment regimens in which25 the agents are not necessarily administered by the same route of administration or at the same time. The term "pharmaceutical combination" as used herein means a product that results from the mixing or combining of more than one therapeutic agent and includes both fixed and non-fixed combinations of the therapeutic agents. The term30 "pharmaceutical combination" as used herein refers to either a fixed combination in one dosage unit form, or non-fixed combination or a kit of parts for the combined administration where two or more therapeutic agents may be administered independently at the same time or separately within time intervals. The term "fixed combination" means that the therapeutic agents, e.g. a compound of the present35 invention and a combination partner, are both administered to a patient simultaneously in the form of a single entity or dosage. The term "non-fixed combination" means that the therapeutic agents, e.g. a compound of the present invention and a

JAB7061WOPCT1 - 44 - combination partner, are both administered to a patient as separate entities either simultaneously, concurrently or sequentially with no specific time limits, wherein such administration provides therapeutically effective levels of the two compounds in the body of the patient. The latter also applies to cocktail5 therapy, e.g. the administration of three or more therapeutic agents. The term "combination therapy" refers to the administration of two or more therapeutic agents to treat a therapeutic condition or disorder described in the present disclosure. Such administration encompasses co-administration of these therapeutic agents in a substantially simultaneous manner, such as in a10 single capsule having a fixed ratio of active ingredients. Alternatively, such administration encompasses co-administration in multiple, or in separate containers (e.g. tablets, capsules, powders, and liquids) for each active ingredient. Powders and/or liquids may be reconstituted or diluted to a desired dose prior to administration. In addition, such administration also encompasses use of each15 type of therapeutic agent in a sequential manner, either at approximately the same time or at different times. In either case, the treatment regimen will provide beneficial effects of the drug combination in treating the conditions or disorders described herein. 20 Summary of pharmacology, uses, compositions and combinations In an embodiment, there is provided a pharmaceutical composition comprising a therapeutically effective amount of a compound of the invention, according to any one of the embodiments described herein, and a pharmaceutically acceptable carrier (including one or more pharmaceutically acceptale carriers). 25 In an embodiment, there is provided a compound of the invention, according to any one of the embodiments described herein, for use as a medicament. In an embodiment, there is provided a compound of the invention, according to any one of the embodiments described herein (and/or pharmaceutical compositions comprising such compound of the invention, according to any one of the embodiment 30 described herein) for use: in the treatment of a disease or disorder associated with NLRP3 activity (including inflammasome activity); in the treatment of a disease or disorder in which the NLRP3 signalling contributes to the pathology, and/or symptoms, and/or progression, of said disease/disorder; in inhibiting NLRP3 inflammasome activity (including in a subject in need thereof); and/or as an NLRP3 inhibitor. 35 In an embodiment, there is provided a use of compounds of the invention, according to any one of the embodiments described herein (and/or pharmaceutical compositions comprising such compound of the invention, according to any one of the embodiment described herein): in the treatment of a disease or disorder associated with JAB7061WOPCT1 - 45 - NLRP3 activity (including inflammasome activity); in the treatment of a disease or disorder in which the NLRP3 signalling contributes to the pathology, and/or symptoms, and/or progression, of said disease/disorder; in inhibiting NLRP3 inflammasome activity (including in a subject in need thereof); and/or as an NLRP3 inhibitor. 5 In an embodiment, there is provided use of compounds of the invention, according to any one of the embodiments described herein (and/or pharmaceutical compositions comprising such compound of the invention, according to any one of the embodiment described herein), in the manufacture of a medicament for: the treatment of a disease or disorder associated with NLRP3 activity (including inflammasome 10 activity); the treatment of a disease or disorder in which the NLRP3 signalling contributes to the pathology, and/or symptoms, and/or progression, of said disease/disorder; and/or inhibiting NLRP3 inflammasome activity (including in a subject in need thereof). In an embodiment, there is provided a method of treating a disease or disorder15 in which the NLRP3 signalling contributes to the pathology, and/or symptoms, and/or progression, of said disease/disorder, comprising administering a therapeutically effective amount of a compound of the invention, according to any one of the embodiments described herein (and/or pharmaceutical compositions comprising such compound of the invention, according to any one of the embodiment described herein),20 for instance to a subject (in need thereof). In a further embodiment, there is provided a method of inhibiting the NLRP3 inflammasome activity in a subject (in need thereof), the method comprising administering to the subject in need thereof a therapeutically effective amount of a compound of the invention, according to any one of the embodiments described herein (and/or pharmaceutical compositions comprising such25 compound of the invention, according to any one of the embodiment described herein). In all relevant embodiment of the invention, where a disease or disorder is mentioned (e.g. hereinabove), for instance a disease or disorder in which the NLRP3 signalling contributes to the pathology, and/or symptoms, and/or progression, of said disease/disorder, or, a disease or disorder associated with NLRP3 activity (including 30 NLRP3 inflammasome activity), including inhibiting NLRP3 inflammasome activity, then such disease may include inflammasome-related diseases or disorders, immune diseases, inflammatory diseases, auto-immune diseases, or auto-inflammatory diseases. In a further embodiment, such disease or disorder may include autoinflammatory fever syndromes (e.g cryopyrin-associated periodic syndrome), liver related35 diseases/disorders (e.g. chronic liver disease, viral hepatitis, non-alcoholic steatohepatitis (NASH), alcoholic steatohepatitis, and alcoholic liver disease), inflammatory arthritis related disorders (e.g. gout, pseudogout (chondrocalcinosis), osteoarthritis, rheumatoid arthritis, arthropathy e.g acute, chronic), kidney related JAB7061WOPCT1 - 46 - diseases (e.g. hyperoxaluria, lupus nephritis, Type I/Type II diabetes and related complications (e.g. nephropathy, retinopathy), hypertensive nephropathy, hemodialysis related inflammation), neuroinflammation-related diseases (e.g. multiple sclerosis, brain infection, acute injury, neurodegenerative diseases, Alzheimer's5 disease), cardiovascular/metabolic diseases/ disorders (e.g. cardiovascular risk reduction (CvRR), hypertension, atherosclerosis, Type I and Type II diabetes and related complications, peripheral artery disease (PAD), acute heart failure), inflammatory skin diseases (e.g. hidradenitis suppurativa, acne), wound healing and scar formation, asthma, sarcoidosis, age-related macular degeneration, and cancer10 related diseases/disorders (e.g. colon cancer, lung cancer, myeloproliferative neoplasms, leukaemia, myelodysplastic syndromes (MOS), myelofibrosis). In a particular aspect, such disease or disorder is selected from autoinflammatory fever syndromes (e.g. CAPS), sickle cell disease, Type I/Type II diabetes and related complications (e.g. nephropathy, retinopathy), hyperoxaluria, gout, pseudogout15 (chondrocalcinosis), chronic liver disease, NASH, neuroinflammation-related disorders (e.g. multiple sclerosis, brain infection, acute injury, neurodegenerative diseases, Alzheimer's disease), atherosclerosis and cardiovascular risk (e.g. cardiovascular risk reduction (CvRR), hypertension), hidradenitis suppurativa, wound healing and scar formation, and cancer (e.g. colon cancer, lung cancer,20 myeloproliferative neoplasms, leukemias, myelodysplastic syndromes (MOS), myelofibrosis). In a particular embodiment, the disease or disorder associated with inhibition of NLRP3 inflammasome activity is selected from inflammasome related diseases and disorders, immune diseases, inflammatory diseases, auto-immune diseases, auto-inflammatory fever syndromes, cryopyrin-associated periodic syndrome, 25 chronic liver disease, viral hepatitis, non-alcoholic steatohepatitis, alcoholic steatohepatitis, alcoholic liver disease, inflammatory arthritis related disorders, gout, chondrocalcinosis, osteoarthritis, rheumatoid arthritis, chronic arthropathy, acute arthropathy, kidney related disease, hyperoxaluria, lupus nephritis, Type I and Type II diabetes, nephropathy, retinopathy, hypertensive nephropathy, hemodialysis related 30 inflammation, neuroinflammation-related diseases, multiple sclerosis, brain infection, acute injury, neurodegenerative diseases, Alzheimer’s disease, cardiovascular diseases, metabolic diseases, cardiovascular risk reduction, hypertension, atherosclerosis, peripheral artery disease, acute heart failure, inflammatory skin diseases, acne, wound healing and scar formation, asthma, sarcoidosis, age-related macular degeneration, 35 colon cancer, lung cancer, myeloproliferative neoplasms, leukemias, myelodysplastic syndromes and myelofibrosis. In an embodiment, there is provided a combination comprising a therapeutically effective amount of a compound of the invention, according to any one of the JAB7061WOPCT1 - 47 - embodiments described herein, and another therapeutic agent (including one or more therapeutic agents). In a further embodiment, there is provided such a combination wherein the other therapeutic agent is selected from (and where there is more than one therapeutic agent, each is independently selected from): farnesoid X receptor (FXR)5 agonists; anti-steatotics; anti-fibrotics; JAK inhibitors; checkpoint inhibitors including anti-PD1 inhibitors, anti-LAG-3 inhibitors, anti-TIM-3 inhibitors, or anti- POL 1 inhibitors; chemotherapy, radiation therapy and surgical procedures; urate- lowering therapies; anabolics and cartilage regenerative therapy; blockade of IL-17; complement inhibitors; Bruton's tyrosine Kinase inhibitors (BTK inhibitors); Toll Like10 receptor inhibitors (TLR7/8 inhibitors); CAR-T therapy; anti-hypertensive agents; cholesterol lowering agents; leukotriene A4 hydrolase (LTAH4) inhibitors; SGLT2 inhibitors; 132-agonists; anti-inflammatory agents; nonsteroidal anti-inflammatory drugs ("NSAIDs"); acetylsalicylic acid drugs (ASA) including aspirin; paracetamol; regenerative therapy treatments; cystic fibrosis treatments; or atherosclerotic treatment. 15 In a further embodiment, there is also provided such (a) combination(s) for use as described herein in respect of compounds of the invention, e.g. for use in the treatment of a disease or disorder in which the NLRP3 signalling contributes to the pathology, and/or symptoms, and/or progression, of said disease/disorder, or, a disease or disorder associated with NLRP3 activity (including NLRP3 inflammasome activity), including20 inhibiting NLRP3 inflammasome activity, and in this respect the specific disease/disorder mentioned herein apply equally here. There may also be provided methods as described herein in repsect of compounds of the invention, but wherein the method comprises administering a therapeutically effective amount of such combination (and, in an embodiment, such method may be to treat a disease or disorder 25 mentioned herein in the context of inhibiting NLRP3 inflammasome activity). The combinations mentioned herein may be in a single preparation or they may be formulated in separate preparations so that they can be administered simultaneously, separately or sequentially. Thus, in an embodiment, the present invention also relates to a combination product containing (a) a compound according to the invention, 30 according to any one of the embodiments described herein, and (b) one or more other therapeutic agents (where such therapeutic agents are as described herein), as a combined preparation for simultaneous, separate or sequential use in the treatment of a disease or disorder associated with inhibiting NLRP3 inflammasome activity (and where the disease or disorder may be any one of those described herein). 35 Compounds of the invention (including forms and compositions/combinations comprising compounds of the invention) may have the advantage that they may be more efficacious than, be less toxic than, be longer acting than, be more potent than, produce fewer side effects than, be more easily absorbed than, and/or have a better JAB7061WOPCT1 - 48 - pharmacokinetic profile (e.g. higher oral bioavailability and/or lower clearance) than, and/or have other useful pharmacological, physical, or chemical properties over, compounds known in the prior art, whether for use in the above-stated indications or otherwise. 5 For instance, compounds of the invention may have the advantage that they have a good or an improved thermodynamic solubility (e.g. compared to compounds known in the prior art; and for instance as determined by a known method and/or a method described herein). Compounds of the invention may have the advantage that they will block pyroptosis, as well as the release of pro-inflammatory cytokines (e.g. 10 IL-1 ^) from the cell. Compounds of the invention may also have the advantage that they avoid side-effects, for instance as compared to compounds of the prior art, which may be due to selectivity of NLRP3 inhibition. Compounds of the invention may also have the advantage that they have good or improved in vivo pharmacokinetics and oral bioavailabilty. They may also have the advantage that they have good or improved in15 vivo efficacy. Specifically, compounds of the invention may also have advantages over prior art compounds when compared in the tests outlined hereinafter (e.g. in Examples C and D). GENERAL PREPARATION AND ANALYTICAL PROCESSES 20 The compounds according to the invention can generally be prepared by a succession of steps, each of which may be known to the skilled person or described herein. It is evident that in the foregoing and in the following reactions, the reaction products may be isolated from the reaction medium and, if necessary, further purified 25 according to methodologies generally known in the art, such as extraction, crystallization and chromatography. It is further evident that reaction products that exist in more than one enantiomeric form, may be isolated from their mixture by known techniques, in particular preparative chromatography, such as preparative HPLC, chiral chromatography. Individual diastereoisomers or individual enantiomers can also be 30 obtained by Supercritical Fluid Chromatography (SFC). The starting materials and the intermediates are compounds that are either commercially available or may be prepared according to conventional reaction procedures generally known in the art.

JAB7061WOPCT1 - 49 - Analytical Part LC-MS (LIQUID CHROMATOGRAPHY/MASS SPECTROMETRY) General procedure The High Performance Liquid Chromatography (HPLC) measurement was performed using a LC pump, a diode-array (DAD) or a UV detector and a column as specified in the respective methods. If necessary, additional detectors were included (see table of methods below). 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 the tune parameters (e.g. scanning range, dwell time…) in order to obtain ions allowing the identification of the compound’s nominal monoisotopic molecular weight (MW). Data acquisition was performed with appropriate software. Compounds are described by their experimental retention times (Rt) and ions. If not specified differently in the table of data, the reported molecular ion corresponds to the + - [M+H] (protonated molecule) and/or [M-H] (deprotonated molecule). In case the + compound was not directly ionizable the type of adduct is specified (i.e. [M+NH4], - [M+HCOO], etc…). 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. Hereinafter, “SQD” means Single Quadrupole Detector, “MSD” Mass Selective Detector, “RT” room temperature, “BEH” bridged ethylsiloxane/silica hybrid, “DAD” Diode Array Detector, ”HSS” High Strength silica. Table: LCMS Method codes (Flow expressed in mL/min; column temperature (T) in °C; Run time in minutes). Flow Method Run Instrument column mobile phase gradient ------ code time Col T From 95% A to Agilent YMC-pack 5% A in 1100 A: 0.1% ODS-AQ 4.8 min, 2.6 HPLC HCOOH in Method 1 C18 (50 x held for ---- 6.2 DAD H2O 4.6 mm, 3 1.0 min, 35 LC/MS B: CH3CN μm) to 95% A JAB7061WOPCT1 - 50 - From 100% A Waters: A: 10mM ® Waters to Acquity NH4HCO3 0.6 ® :BEH 5% A in Method 2 UPLC - in 95% H2O ---- 3.5 (1.8µm, 2.10min, DAD and + 5% CH ₃ CN 55 2.1*100mm) to 0% A SQD2 B: MeOH in 1.4 min Method Method Method Method Method JAB7061WOPCT1 - 51 - Waters: Waters: A: 95% From Acquity® BEH C18 CH ₃ COONH ₄ 95% A to IClass (1.7µm, 6.5mM + 5% 40 % A ® UPLC - 2.1x50mm) CH ₃ CN, B: in 1 DAD and CH3CN 1.2min, Method 8 ---- 2 Xevo G2-S to 5% A 50 QTOF in 0.6min, NMR For Avance III 5 operating a on a Bruke 600 spectro chloroform, CDCl3), DMSO-d6 (deuterated DMSO, dimethyl-d6 sulfoxide), METHANOL-d4 (deuterated methanol), BENZENE-d6 (deuterated benzene, C6D6) or 10 ACETONE-d6 (deuterated acetone, (CD3)2CO) as solvents. Chemical shifts (^) are reported in parts per million (ppm) relative to tetramethylsilane (TMS), which was used as internal standard. Melting Points 15 Values are either peak values or melt ranges, and are obtained with experimental uncertainties that are commonly associated with this analytical method. Method A: For a number of compounds, melting points were determined in open capillary tubes on a Mettler Toledo MP50. Melting points were measured with a temperature gradient of 10 ºC/minute. Maximum temperature was 300 ºC. The melting20 point data was read from a digital display and checked from a video recording system Method B: For a number of compounds, melting points were determined with a DSC823e (Mettler Toledo) apparatus. Melting points were measured with a temperature gradient of 10 ºC/minute. Standard maximum temperature was 300 ºC. 25 EXPERIMENTAL PART Hereinafter, the term “m.p.” means melting point, “aq.” means aqueous, “r.m.” means reaction mixture, “rt” means room temperature, ‘DIPEA’ means N,N-diiso- propylethylamine, “DIPE” means diisopropylether, ‘THF’ means tetrahydrofuran, ‘DMF’ means dimethylformamide, ‘DCM’ means dichloromethane, “EtOH” means 30 ethanol ‘EtOAc’ means ethyl acetate, “AcOH” means acetic acid, “iPrOH” means

JAB7061WOPCT1 - 52 - isopropanol, “iPrNH2” means isopropylamine, “MeCN” or “ACN” means acetonitrile, “MeOH” means methanol, “Pd(OAc)2” means palladium(II)diacetate, “rac” means racemic, ‘sat.’ means saturated, ‘SFC’ means supercritical fluid chromatography, ‘SFC- MS’ means supercritical fluid chromatography/mass spectrometry, “LC-MS” means 5 liquid chromatography/mass spectrometry, “GCMS” means gas chromatography/mass spectrometry, “HPLC” means high-performance liquid chromatography, “RP” means ” reversed phase, “UPLC” means ultra-performance liquid chromatography, “R _t (or +” “RT”) means retention time (in minutes), “[M+H] means the protonated mass of the free base of the compound, “DAST” means diethylaminosulfur trifluoride, “DMTMM” 10 means 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride, “HATU” means O-(7-azabenzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyr idinium 3-oxide hexafluorophosphate), “Xantphos” means (9,9-dimethyl-9H-xanthene-4,5- diyl)bis[diphenylphosphine], “TBAT” means tetrabutyl ammonium 15 triphenyldifluorosilicate, “TFA” means trifuoroacetic acid, “Et2O” means diethylether, “DMSO” means dimethylsulfoxide, “SiO ₂ ” means silica, “XPhos Pd G3” means (2- dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-bip henyl)[2-(2′-amino-1,1′- biphenyl)]palladium(II) ethanesulfonate, “CDCl ₃ ” means deuterated chloroform, “MW” means microwave or molecular weight, “min” means minutes, “h” means hours, 20 “rt” means room temperature, “quant” means quantitative, “n.t.” means not tested, “Cpd” means compound, “POCl ₃ ” means phosphorus(V) oxychloride. For key intermediates, as well as some final compounds, the absolute configuration of chiral centers (indicated as R and/or S) were established via comparison with samples of known configuration, or the use of analytical techniques 25 suitable for the determination of absolute configuration, such as VCD (vibrational cicular dichroism) or X-ray crystallography. When the absolute configuration at a chiral center is unknown, it is arbitrarily designated R*. Examples – Example A 30 PREPARATION OF INTERMEDIATES Synthesis of 6-chloro-1-methyl-1H-pyrazolo[3,4-b]pyridine I-133 To a solution of 6-chloro-1H-pyrazolo[3,4-b]pyridine [63725-51-9] (1 g, 6.51 mmol) in acetonitrile (10 mL) was added Cs2CO3 [534-17-8] (4.24 g, 13 mmol) and the mixture 35 was stirred for 30 min at rt. The reaction mixture was then cooled to 0 °C and JAB7061WOPCT1 - 53 - iodomethane [74-88-4] (1.63 mL, 2.28 g/mL, 26.15 mmol) was added dropwise. After addition, the reaction mixture was stirred at rt for 1 hour and then heated in the MW at 150 °C for 10 minutes and then left stirring at rt for two days. The reaction was quenched with ice water and extracted with EtOAc. The combined organic extracts 5 were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The crude residue was purified by FCC (Hept/EtOAc 0 to 30%) to give I-133 (500 mg, 46%) as a yellow solid. Synthesis of N-(1-methyl-1H-pyrazolo[3,4-b]pyridin-6-yl)acetamide I-132 10 A solution of 6-chloro-1-methyl-1H-pyrazolo[3,4-b]pyridine I-133 (500 mg, 2.98 mmol) in 1,4-dioxane (5 mL) was sparged with nitrogen for 15 min. Acetamide [60-35- 5] (212 mg, 3.59 mmol), Pd(OAc)2 [3375-31-3] (67 mg, 0.3 mmol), xanthphos [161265-03-8] (86.5 mg 0.15 mmol) and cesium carbonate [534-17-8] (1.95 g 5.97 15 mmol) were add was concentrate filtered. The filtrate was concentrated under vaccum and the obtained solid was purified by FCC (Hept/EtOAc 0 to 20%) to obtain I-132 (458 mg, 81%) as a solid. 20 Synthesis of 1-methyl-1H-pyrazolo[3,4-b]pyridin-6-amine I-131 A 37% aqueous solution of HCl [7647-01-0] (23 mL, 1.18 g/mL, 274.8 mmol) was added to a suspension of N-(1-methyl-1H-pyrazolo[3,4-b]pyridin-6-yl)acetamide I-132 (458 mg, 2.41 mmol) in water (25 mL). The resulting solution was heated at reflux for 25 3 hours. The volatiles were evporated under vacuum to crude I-131 (444 mg, 100%) as a yellow solid tht d ith t f th ifi ti

JAB7061WOPCT1 - 54 - Synthesis of 5-chloro-3-methyl-3H-imidazo[4,5-b]pyridine I-135 and 5-chloro-1- methyl-1H-imidazo[4,5-b]pyridine I-134 5 NaH [7646-69-7] (60% dispersion in mineral oil, 1.5 g, 37.5 mmol) was added portionwise to a stirred mixture of 5-chloro-3H-imidazo[4,5-b]pyridine [52090-89-8] (5 g, 32.56 mmol to warm to rt 2.28 g/mL, 36 , 10 quenched with water. EtOAc and more water were added. The organic layer was separated, washed with brine (x5), dried (MgSO ₄ ), filtered and evaporated under reduced pressure. The crude mixture was purified by FCC (DCM/MeOH 1 to 3%) to afford I-135 (3.7 g, 68%) as a pale orange solid and I-134 (880 mg, 16%) as a white solid. 15 Synthesis of 1-ethyl-5-nitroindoline I-148 5-nitroindoline [32692-19-6] (3 g, 18.27 mmol) was dissolved in dry DMF (60 mL) while stirring under a nitrogen atmosphere. NaH [7646-69-7] (60% suspension in 20 mineral oil, 1.46 g, 36.55 mmol) was added portionwise at rt over a 10 min period. The reaction mixture 29.88 mmol) in mixture was heat cool to rt, quenched by addition of water and extracted with EtOAc. The organic 25 extracts were combined and washed with brine, dried over MgSO4 and evaporated. The residue was purified by FCC (Hept/DCM 0 to 80% yielding I-148 (2.24 g, 64%) as a orange solid.

JAB7061WOPCT1 - 55 - Structural analogues were synthesized according to the above procedure. Alkylating agent Intermediate [75-30-9] I-147 [513-38-2] Synthesis o 5 A mixture , , , 0.094 mmol) in MeOH (25 mL) was placed under hydrogen atmosphere at rt and stirred until uptake of 3 eqquivalents of hydrogen was observed. The catalyst was filtered and the filtrate con FCC (DCM/M Substrate I-147 I-144 I-149 10 JAB7061WOPCT1 - 56 - Synthesis of 1-(difluoromethyl)-6-nitro-1H-indazole I-157 NaH [7646-69-7] (60% dispersion in mineral oil, 0.1 g, 2.54 mmol) was added to a solution of 6-nitro-2H-indazole [65750-02-9] (500 mg, 3.06 mmol) and sodium 5 chlorodifluoroac 1895392 078 509 l i N hl lidi 85 ml). Thereafter, 100 °C for 30 m water and brine. The combined organic extracts were dried over MgSO ₄ , filtered and the solvent was evaporated under vacuum. The residue was purified by FCC 10 (Hept/EtOAc 0 to 20%) to obtain I-157 (130 mg, 20%) as a solid. Synthesis of 1-(difluoromethyl)-1H-indazol-6-amine I-156 Pd/C (10%wt. Pd, 68.09 mg, 0.064 mmol) was added to a solution of I-157 (120 mg, 15 0.56 mmol) in ethyl acetate (5 mL) in a 100-mL hydrogenation flask. The reaction was purged three times (hydrogen/vacuum) and placed under hydrogen atmosphere. The reaction was stir with EtOAc and (103 mg, 100%) 20 Synthesis of 1-(difluoromethyl)-1H-indazol-5-amine I-158 Iron powder [7439-89-6] (513.4 mg, 9.19 mmol) was added to a mixture of 2-methyl-5- nitro-2H-indazole [5228-48-8] (228.5 mg, 1.29 mmol), ammonium chloride [12125-02- 25 9] (209.5 mg, 3.92 mmol) in a mixture of EtOH (11 mL) and DI water (11 mL) in a MW vial. The vial was sealed and the reaction mixture was stirred vigorously and heated at 100 °C for 1 hour. The crude mixture was filtered over Celite and the cake was washed with JAB7061WOPCT1 - 57 - and the cake was washed with EtOAc (~20 mL). The filtrate was washed with water (~10 mL), dried over MgSO ₄ and concentrated under reduced pressure at 50 °C to afford I-158 (193 mg, 97%) as a brown oil which was used in the next step without further purification. 5 Synthesis of 3-bromo-2-hydrazineyl-5-nitropyridine I-161 3-Bromo-2-chloro-5-nitropyridine [5470-17-7] (1.5 g, 6.32 mmol) was dissolved in 1,4-dioxane (81 mL), the solution cooled to 0 °C and hydrazine hydrate [7803-57-8] 10 (9.2 mL, 1.03 g/mL, 0.19 mol) was added quickly (<15 seconds) at 0 °C. After addition, the mix to r.t. and stirr evaporator to abo . (150 mL) was added. A solid precipitated and was filtered off on a sinter funnel, 15 washing the flask and solid with ca.5 + 5 mL of DI water. After drying in the oven at 50 °C under vacuum for 16 hours, I-161 (1.21 g, 82%, ca.96-97% purity) was isolated as a greyish solid. Synthesis of 8-bromo-6-nitro-[1,2,4]triazolo[4,3-a]pyridine I-160 20 3-Bromo-2-hydrazinyl-5-nitropyridine I-161 (4 g, 17.2 mmol) was suspended in trimethyl orthoformate [149-73-5] (28.2 mL, 0.97 g/mL, 0.26 mol) in an EasyMax pressure tube. The tube was sealed with a screw-cap and the mixture heated at 100 °C for 2.5 hours. The reaction was allowed to cool to rt, then cooled to 0 °C for ca.30 min 25 and the suspensi 1:1 mixture of H pale brown solid.

JAB7061WOPCT1 - 58 - Synthesis of 8-bromo-[1,2,4]triazolo[1,5-a]pyridin-6-amine I-159 8-bromo-6-nitro-[1,2,4]triazolo[4,3-a]pyridine pyridine I-160 (500 mg, 2.06 mmol), NH ₄ Cl [12125-02-9] (880.4 mg, 16.5 mmol) and iron powder [7439-89-6] (804.3 mg, 5 14.4 mmol) were placed in a screw-cap vial equipped with a magnetic stir bar and suspended in EtOH (8 mL). The sus y and heated at 85 °C for 64 hours. The suspension was fil e filtrate concentrated in vacuo, retaken in MeCN (ca.20 mL) and concentrated again to give a tan solid (423 mg, containes large amount of salts/iron).147 mg of this material was partitioned 10 between a saturated aqueous solution of NaHCO ₃ aq. (50 mL) and DCM/MeOH 95:5 (25 mL). The organic layer was collected and the aqueous layer re-extracted with DCM/MeOH 95:5 (15 + 10 mL). The combined organic layers were concentrated under reduced pressure to give I-159 (78 mg, 18%) as a greenish solid. 15 Synthesis of 8-bromo-[1,2,4]triazolo[4,3-a]pyridin-6-amine I-162 8-Bromo-6-nitro-[1,2,4]triazolo[4,3-a]pyridine I-160 (1 g, 4.11 mmol, 1 equiv) and iron powder [7439-89-6] (1.38 g, 24.7 mmol) were placed in a screw-cap tube and AcOH [64-19-7] (18.8 mL) was added. The mixture was stirred vigorously at rt for 3 20 hours. The green thick susension was diluted with DI water (30-40 mL) This thus obtained dark m The residue was aqueous NaHCO ₃ and K ₂ CO ₃ (effervescence ceased after addition of ca.10-15 mL, then a solid formed that redissolved upon addition of more basic solution). The mixture 25 was then extracted with DCM/MeOH 95:5 (5 x 150 mL). The combined organic extracts were dried over Na ₂ SO ₄ , filtered and the filtrate concentrated in vacuo to afford I-162 (450 mg, 51%) as a pale tan solid.

JAB7061WOPCT1 - 59 - Synthesis of tert-butyl (5-hydroxy-1-methylpiperidin-3-yl)carbamate I-164 A mixture of benzyl 3-((tert-butoxycarbonyl)amino)-5-hydroxypiperidine-1- carboxylate [1785642-46-7] (1 g, 2.85 mmol) and Pd/C (10%wt. Pd, 3.04 g, 2.85 5 mmol) in MeO hydrogen until fu without purificat mmol) and paraformaldehyde [30525-89-4] (0.5 g, 16.67 mmol) and the mixture was placed under hydrogen until full conversion was observed. The catalyst was filtered and 10 the filtrate was concentrated in vacuo. The obtained residue was purified by FCC (DCM/MeOH:NH ₃ (7N) 0 to 7% yielding I-164 (537 mg, 82%) as a white solid. Synthesis of tert-butyl (R)-(1-ethylpiperidin-3-yl)carbamate I-1001 15 Sodium triacetoxyborohydride [56553-60-7] (19.84 g, 93.62 mmol) was added portionwise to a mixture of (R)-3-(BOC-amino)piperidine [309956-78-3] (12.5 g, 62.41 mmol) and acetaldehyde, 5 M in THF [75-07-0] (14.98 mL, 5 M, 74.89 mmol). The mixture was sti 20 mixture was ex MgSO4, filtered chromatography (silica; MeOH-NH3 in DCM, 0 to 4 %). The desired fractions were collected and concentrated in vacuo to yield tert-butyl (R)-(1-ethylpiperidin-3- yl)carbamate I-1001 as a white solid. 25

JAB7061WOPCT1 - 60 - Synthesis of 3-amino-5-hydroxy-1-methylpiperidine hydrochloride I-163 A 4M solution HCl in 1,4-dioxane (6.89 mL, 27.6 mmol) was added to a solution of (5- hydroxy-1-methylpiperidin-3-yl)carbamate I-164 (520 mg, 2.26 mmol) in 1,4-dioxane 5 (6.9 mL). The concentrated to without furthe Structural analogues were synthesized according to the above procedure. Substrate Intermediate I-165 I-166 (RS)-cis/tra [1609546-1 I-201 JAB7061WOPCT1 - 61 - Synthesis of tert-butyl (1-acetyl-5-hydroxypiperidin-3-yl)carbamate I-166 Ac2O [108-24-7] (229 µL, 2.43 mmol) was added dropwise to a solution of tert-butyl N-(5-hydroxypiperidin-3-yl)carbamate [1502766-14-4] (0.5 g, 2.31 mmol) and 5 triethylamine [12 was stirred at rt o NaHCO ₃ , dried o foam. 10 Synthesis of tert-butyl (R)-(1-cyclopropylpiperidin-3-yl)carbamate I-201 Sodium cyanoborohydride [25895-60-7] (667 mg, 10.61 mmol) was addded to a suspension of (R)-3-Boc-aminopiperidine [309956-78-3] (1 g, 4.99 mmol), (1- ethoxycyclopropoxy)trimethylsilane [27374-25-0] (1 mL 499 mmol) and acetic acid 15 (3 mL, 52.4 mm mixture was stirr HPLC (Stationa phase: 0.25% NH4HCO3 solution in water, MeOH) to afford I-201 (600 mg, 50%) as a white solid. 20 Synthesis of 3-chloro-1-(difluoromethyl)-5-nitropyridin-2(1H)-one I-168 A solution of 3-chloro-2-hydroxy-5-nitropyridine [22353-38-4] (2 g, 11.46 mmol) in DMSO (20 mL) was placed in an EasyMax pressure tube under an inert atmosphere of 25 nitrogen at room temperature. NaH [7646-69-7] (60% dispersion in mineral oil, 0.5 g, JAB7061WOPCT1 - 62 - 12.5 mmol) was added to this mixture which was allowed to react for 15 min at rt. Sodium chlorodifluoroacetate [1895-39-2] (2 g, 13.12 mmol) was added to the mixture and the resulting solution was stirred overnight at 60 °C. The reaction mixture was allowed to cool to rt and quenched by addition of DI water. The resulting solution was 5 extracted three times with EtOA.c The combined organic extracts were dried over MgSO ₄ , filtered and concentrated under vacuum. The residue was purified by FCC (Hept/EtOAc 0 to 40%) to obtain I-168 (390 mg, 15%) as a white solid. Synthesis of 5-amino-3-chloro-1-(difluoromethyl)pyridin-2(1H)-one I-167 10 A mixture of 3-chloro-1-(difluoromethyl)-5-nitropyridin-2(1H)-one I-168 (100 mg, 0.45 mmol), iron powder [7439-89-6] (73.8 mg, 1.32 mmol) and a saturated aqueous solution of ammonium chloride [12125-02-9] (0.42 mL, ca.7.2 M, ca.3.01 mmol) in EtOH (1.7 mL) i15 reaction mixture washing through suspended in DCM and filtered again. The filtrate was concentrated and purifed by FCC (DCM/MeOH 0 to 5%) to obtain I-167 (37 mg, 43%) as a dark film. 20 Synthesis of 6-chloroimidazo[1,2-b]pyridazine-2-carbaldehyde I-172 Methyl 6-chloroimidazo[1,2-b]pyridazine-2-carboxylate [572910-59-9] (2 g, 9.45 mmol) was placed in a 100-mL RB flask equipped with a magnetic stir bar. The flask was placed under nitrogen (3 vacuum/nitrogen cycles). Anhydrous DCM (26 mL) was 25 added and the mixture stirred vigorously and cooled to - 78 °C. Then, a 1M solution of DIBAL in cyclohexane [1191-15-7] (15.6 mL, 15.6 mmol) was added dropwise over 10 minutes. The by addition of , mL) and the mixture was extracted with DCM (5 x 60 mL). The combined organic 30 extracts were dried over Na2SO4, filtered and concentrated in vacuo. The crude solid JAB7061WOPCT1 - 63 - was purified by FCC (Hept/EtOAc 4:1 to 1:4) to give I-172 (795 mg, 46%) as a colorless solid. Synthesis of 6-chloro-2-(difluoromethyl)imidazo[1,2-b]pyridazine I-171 5 6-Chloroimidazo[1,2-b]pyridazine-2-carbaldehyde I-172 (795 mg, 4.38 mmol) was suspended in anhydrous DCM (15 mL), the suspension cooled to 0 °C and DAST [38078-09-0] (1.74 mL, 13.1 mmol) was added dropwise at 0 °C. The resulting mixture was stirred at 0 ° f i h ll i f h h 10 portion of DAS resulting suspension stirred at rt for 16 hours. The crude mixture was cooled to 0 C and quenched by slow addition of a saturated aqueous solution of NaHCO ₃ (50 mL) The biphasic mixture was stirred at rt until effervescence had ceased and the product was extracted with DCM (3 x 20 mL). The combined organic extracts were dried over 15 Na2SO4, filtered and concentrated in vacuo. The obtained residue was purified by FCC (Hept/EtOAc 9:1 to 1:1) to afford I-171 (790 mg, 89%) as a colorless crystalline solid. Synthesis of N-(2-(difluoromethyl)imidazo[1,2-b]pyridazin-6-yl)-1,1- diphenylmethanimine I-170 20 6-Chloro-2-(difluoromethyl)imidazo[1,2-b]pyridazine I-171 (250 mg, 1.23 mmol), Pd2dba3 [51364-51-3] (112.5 mg, 0.12 mmol), BINAP [98327-87-8] (152.9 mg, 0.25 t mmol), and NaOBu [865-48-5] (188.8 mg, 1.96 mmol) were placed in a 20-mL MW vial. The vial was sealed and placed under nitrogen (3 vacuum/nitrogen cycles). Then, 25 benzophenonimin [1013883] (309 L 108 / L 184 l) ddd solution in dega vigorously and h eae a or ours. e mxure was concenrae n vacuo an the residue purified by FCC (Hept/EtOAc 3:1 to 3:7) to afford I-170 (300 mg, ca.95% purity, 67%) as an orange solid that was used without further purification. 30 Structural analogues were synthesized according to the above procedure.

JAB7061WOPCT1 - 64 - Substrate Intermediate I-175 I-174 I-183 [55286-05- Synthesis o 5 N-(2-(Diflu (300 mg, ca.95% purity, 67%) was dissolved in THF (5 mL) and a 1M aqueous solution of HCl [7647-01-0] (7.5 mL, 7.5 mmol) was added. The mixture was stirred vigorously at rtfor 2 hours. The mixture was concentrated in vacuo at 50 °C and retaken in acetonitrile ( 10 triturated with M pale yellow solid that was used without further purification. Structural analogues were synthesized according to the above procedure. Substrate Intermediate I-174 I-173 JAB7061WOPCT1 - 65 - I-182 I-181 I-198 Synthesis o methylben 5 4-Methylbenzenesulfonylhydrazide [1576-35-8] (1.0 g, 5.38 mmol) was added to a solution of 5-bromopyridine-2-carbaldehyde [31181-90-5] (1.0 g, 5.376 mmol) in DCM (10 mL) and MeOH (10 mL). The reaction was stirred at rt for 1 hour. Volatiles were removed quantitative) w 10 Synthesis of 6-bromo-[1,2,3]triazolo[1,5-a]pyridine I-175 A mixture of crude EZ)-N'-((5-bromopyridin-2-yl)methylene)-4- methylbenzenesulfonohydrazide I-176 (1.90 g, 5.36 mmol) and morpholine [110-91-8] 15 (10 mL, 115.9 mmol) were stirred at 90 °C for 1 hour. The reaction was cooled to rt and then cooled discarded and was purified by solid. 20

JAB7061WOPCT1 - 66 - Synthesis of 6-aminoimidazo[1,2-a]pyridine-2-carboxamide I-180 A mixture of ethyl 6-aminoimidazo[1,2-a]pyridine-2-carboxylate [158980-21-3] (1 g, 4.87 mmol) in aqueous ammonia [7664-41-7] (28% in H2O, 20 mL) was stirred and 5 heated in a pressure tube at 90 °C for 3 hours. Volatiles were evaporated under vacuum and the crude the next step. Synthesis of N-(2-cyanoimidazo[1,2-a]pyridin-6-yl)-2,2,2-trifluoroacetami de I-179 10 TFAA [407-25-0] (0.28 mL, 1.51 g/mL, 1.99 mmol) was added to a solution of 6- aminoimidazo[1,2-a]pyridine-2-carboxamide I-180 (100 mg, 0.57 mmol) and triethylamine [121-44-8] (0.39 mL, 0.73 g/mL, 2.84 mmol) in dry THF (3 mL) under nitrogen at 0 °C. Th ti ti d t 0 °C f th h d th t t f 2 15 hours. The react DCM. The comb vacuo. The obtained solid I-179 (140 mg ,quantitative) was used without further purification in the next step. 20 Synthesis of 6-aminoimidazo[1,2-a]pyridine-2-carbonitrile I-178 A solution of N-(2-cyanoimidazo[1,2-a]pyridin-6-yl)-2,2,2-trifluoroacetami de I-179 (150 mg, 0.59 mmol) and K2CO3 [584-08-7] (163.1 mg, 1.18 mmol) in DI water (3.11 mL) and MeOH (3.11 mL) was stirred at rt overnight. The reaction mixture was diluted 25 with water (20 mL) and it was extracted with 2-MeTHF, washed with brine, dried on MgSO4, filtered and concentrated under vacuum to yield I-178 (93 mg quantitative) as a brown/green

JAB7061WOPCT1 - 67 - Synthesis of ethyl 6-iodoimidazo[1,5-a]pyridine-1-carboxylate I-186 Anhydrous DMF (50 mL) was added to a vial charged with NaH [7646-69-7] (60% dispersion in mineral oil, 2,24 g, 56.06 mmol) under nitrogen. The mixture was cooled 5 to 0 °C and ethyl isocyanoacetate [2999-46-4] (6.13 mL, 56.06 mmol) was added dropwise. After 30 min at 0 °C, 2-fluoro-5-iodo-pyridine [171197-80-1] (10.0 g, 44.85 mmol) was added in three portions. The reaction was allowed to warm to rt and then heated at 60 °C for 16 hour. The reaction was cooled to rt and diluted with EtOAc (500 mL) and water (300 mL). The organic layer was separated and washed with brine (2 x 10 100 mL). The combined aqueous layers were extracted with EtOAc (200 mL). The combined organic layers were dried over MgSO4, filtered and concentrated in vacuo. The crude product was purified by FCC (Hept/EtOAc 0 to 70%) to obtain I-186 (2.94 g, 21%) as an off-white solid. 15 Synthesis of 6-iodoimidazo[1,5-a]pyridine-1-carboxylic acid I-185 A 1M aqueous solution of NaOH [1310-73-2] (36 mL, 36 mmol) was added to a solution of ethyl 6-iodoimidazo[1,5-a]pyridine-1-carboxylate I-186 (3.75 g, 11.86 mmol) in THF (35 mL). The reaction mixture was stirred at 60 °C for 2 hours. Volatiles 20 were concentrated under reduced pressure and the aqueous leftovers were treated with 1M aqueous H washed with w as an off-white solid. 25 Synthesis of 6-iodoimidazo[1,5-a]pyridine-1-carboxamide I-184 JAB7061WOPCT1 - 68 - SOCl2 [7719-09-7] (4.1 mL, 56.5 mmol) was added dropwise to a suspension of 6- iodoimidazo[1,5-a]pyridine-1-carboxylic acid I-185 (3.25 g, 11.28 mmol) in dry acetonitrile (30 mL). The reaction was stirred at 60 °C for 1 hour. Volatiles were removed under reduced pressure. The crude product was dissolved in dry DCM (50 5 mL), the solution cooled to 0 °C and an aqueous solution of NH3 [7664-41-7] (28% in water, 50 mL, 740 mmol) was added portionwise and the mixture was allowed to warm to rt and stirred at this temperature for 1 hour. The reaction mixture was filtered and the solid cake was washed with water and dried to obtain I-184 (2.29 g, 71%) as a brownish solid. 10 Synthesis of 6-iodoimidazo[1,5-a]pyridine-1-carbonitrile I-183 POCl ₃ [10025-87-3] (0.82 mL, 8.78 mmol) was added dropwise to a solution of 6- iodoimidazo[1,5-a]pyridine-1-carboxamide I-184 (2.29 g, 7.98 mmol) in anhydrous 15 DMF (23 mL) stirring at 0 °C. The reaction was allowed to warm to rt and stirred for 30 min. The reac mL) and water ( extracted with E MgSO ₄ , filtered and concentrated under reduced pressure to yield desired I-183 (2.15 g, 20 97%) as a brown solid. Synthesis of 6-chloro-2-(2-methoxyethyl)pyridazin-3(2H)-one I-189 6-Chloropyridazin-3-ol [19064-67-6] (1 g, 7.66 mmol), K2CO3 [584-08-7] (1.27 g, 9.18 25 mmol) and tetrabutylammonium bromide [1643-19-2] (0.049 g, 0.15 mmol) were placed in a 50-mL pressure tube and acetonitrile (12.5 mL) and 2-bromoethyl methyl ether [6482-24-2 medium was stir JAB7061WOPCT1 - 69 - onto DI water (50 mL) and extracted with DCM (2x). The combined organic sextracts were dried over MgSO ₄ , filtered and concentrated under vacuum. The obtained crude material was purified by FCC (Hept/EtOAc 0 to 60%) to obtain I-189 (1.13 g, 78%) as a white solid. 5 Synthesis of tert-butyl (1-(2-methoxyethyl)-6-oxo-1,6-dihydropyridazin-3- yl)carbamate I-188 Two identical reactions were run in parallel wherein 10 bis(dibenzylideneacetone)palladium [32005-36-0] (86.12 mg, 0.15 mmol) was added to a stirred suspen mg, 3 mmol), bis(diphenylphos and cesium carbo 15 under nitrogen. The mixture was stirred in a sealed tube at 95 ºC for two days. The two reaction mixtures were combined and concentrated under vacuum. The crude material was partitioned between DCM and water, the organic layer was separated and the aqueous layer back-extracted with DCM. The combined organic layers were dried over MgSO4, filtered and evaporated under vacuum. The obtained crude solid was 20 suspended in DCM (20 mL), filtered and the filtrate was concentrated under vacuum and the obtained residue purified by FCC (Hept/EtOAc 100:0 to 0:100) to obtain I-188 (842 mg, 52%) as a yellow solid. Structural analogues were synthesized according to the above procedure. Substrate Intermediate I-192 I-191 JAB7061WOPCT1 - 70 - I-195 I-194 Synthesis o A 4M HCl solution in 1,4-dioxane [7647-01-0] (14.25 mL, 57 mmol) was added to a 5 soluton of tert-b l12 h hl 1 ih i i l I-188 (842 mg, 3 one day The mix oil that was used Structural analog Substrate Intermediate I-191 I-190 I-194 10 Synthesis o JAB7061WOPCT1 - 71 - 4-Bromo-6-chloro-2-methylpyridazin-3(2H)-one [1178884-53-1] (1.024 g, 4.58 mmol), Cs ₂ CO ₃ [534-17-8] (2.481 g, 7.62 mmol) and 1,1'-bis(diphenylphosphino)ferrocene- palladium(II)dichloroide dichloromethane complex [95464-05-4] (88 mg, 0.108 mmol) were placed in a VLT tube and left under nitrogen (3 vacuum/nitrogen cycles). 5 Trimethylboroxine [823-96-1] (0.5 mL, 3.58 mmol), 1,4-dioxane (17 mL) and DI water (1 mL) were then added. The reaction mixture was stirred at 110 °C for 2.5 hours. The reaction mixture was allowed to cool to rt, diluted with DI water (~50 mL) and the crude material was extracted with DCM (3 x 20 mL). The combined organic layers were dried over MgSO ₄ , filtered and concentrated under reduced pressure. A 10 purification by FCC (Hept/EtOAc 0 to 50 %) afforded the I-192 (532 mg, 73%) as a white powder. Synthesis of 6-chloro-2-(2-(dimethylamino)ethyl)pyridazin-3(2H)-one I-195 15 6-Chloropyridazin-3-ol [19064-67-6] (500 mg, 3.83 mmol) was added to a stirring solution of DMEA [108-01-0] (0.46 mL, 0.89 g/mL, 4.6 mmol) in dry toluene (10 mL) under nitrogen. T added and the re mixture was allo 20 purified by FCC as a dark brown oil. Synthesis of 9-methyl-9H-purin-2-amine I-196 25 A mixture of 6-chloro-9-methyl-9H-purin-2-amine [3035-73-2] (500 mg, 2.72 mmol), Pd/C (10%wt. Pd, 289.8 mg, 0.27 mmol) in MeOH (30 mL) and THF (50 mL) was hydrogenated at rt overnight. The catalyst was filtered and the filtrate was concentrated to obtain I-196 (780 mg, 85%) as a red solid that was used without further purification. JAB7061WOPCT1 - 72 - Synthesis of 9-methyl-9H-purin-2-amine I-199 Aqueous ammonia [7664-41-7] (28% in water, 10.53 mL, 0.9 g/mL, 155.76 mmol) was 5 added to a mixture of 3,6-dichloro-[1,2,4]triazolo[4,3-b]pyridazine [33050-38-3] (2 g, 10.58 mmol) in 1,4-dioxane (10.5 mL) was stirred and heated in a pressure tube at 90 °C for 4 hours. T washed with wat solid. 10 Synthesis of 3-oxocyclobutane-1-carboxylate I-1003 15 To a mixture of 3-oxocyclobutane-1-carboxylic acid [23761-23-1] (10 g, 87.64 mmol) in DCM (400 ml) Et3N [121-44-8] (18.3 mL 0.728 g/mL 131.46 mmol) and DMAP [1122-58-3] (1.0 and benzyl chlo dropwise. The m 20 extracted with DCM, the organic layer was separated . The combined organic layers were dried (Na2SO4), filtered and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (MeOH in DCM 0/100 to 3/97). The desired fractions were collected, the solvent evaporated in vacuo to yield 3- oxocyclobutane-1-carboxylate I-1003 (9 g, yield 50%).

JAB7061WOPCT1 - 73 - Synthesis of benzyl 3-ethyl-3-hydroxycyclobutane-1-carboxylate I-1004 5 To a mixture of in THF (20 mL), at -60ºC. The mi 10 was added and t layers were dried and evaporated in vacuo to afford P1. The crude was purified by flash chromatography (silica AcOEt in Hept 0/100 to 20/80), the correspoinding layers were evaporated in vacuo to yield benzyl 3-ethyl-3-hydroxycyclobutane-1-carboxylate I- 1004 (750 mg, yield 44%) as oil. 15 1H NMR (400 MHz, CHLOROFORM-d) d 7.31-7.40 (m, 1H), 5.14 (s, 1H), 2.73 (quin, J=8.38 Hz, 1H), 2.20-2.45 (m, 5H), 1.62 (q, J=7.40 Hz, 2H), 1.28 (br s, 1H), 0.95 (t, J=7.40 Hz, 3H) 20 Synthesis of benzyl 3-((tert-butyldimethylsilyl)oxy)-3-ethylcyclobutane-1-carbox ylate I-1005 JAB7061WOPCT1 - 74 - To a mixture of benzyl 3-ethyl-3-hydroxycyclobutane-1-carboxylate I-1004 (750 mg, 3.2011 mmol) in DCM (25 ml), tert-butyldimethylsilyl trifluoromethanesulphonate [69739-34-0] (1015 mg, 3.84 mmol), DIPEA [7087-68-5], (0.82 mL, 0.75 g/mL, 4.8 mmol) and 4-dimethylaminopyridine [1122-58-3 ] (40 mg, 0.32 mmol) were added. 5 The mixture was stirred for 24 h at rt. Water was added at rt, and the crude was extracted with DCM (2 x 10 mL), the combined organic layers were dried and evaporated in vacuo. The crude was purified by flash chromatography (silica AcOEt in Hept 0/100 to 10/90), the correspoinding layers were evaporated in vacuo to yield 3- ((tert-butyldimethylsilyl)oxy)-3-ethylcyclobutane-1-carboxyl ate I-1005 (750 mg, yield 10 67%) as oil. Synthesis of benzyl ((1r,3s)-3-((tert-butyldimethylsilyl)oxy)-3- ethylcyclobutyl)carbamate I-1006 15 To a mixture of (1r,3s)-3-((tert-butyldimethylsilyl)oxy)-3-ethylcyclobutane- 1- carboxylic ac20 triethylamine [26386-88-9] reaction mixtu re was en cooe o room emperaure an enzy acoo - - (251 mg, 2.3 mmol) was added. The resulting solution was heated to reflux 10h. The crude was cooled and evapoarated in vacuo and treated with a saturated solution of 25 NaHCO3 and extracted with AcOEt (2 x 5 ml), the combined organic layers were evaporated to afford an oil. The crude was purified by columm chromatograpy (silica, AcOEt in heptane 0/100 to 20/80), the correspoinding fractions were evaporated in vacuo to yield ((1r,3s)-3-((tert-butyldimethylsilyl)oxy)-3-ethylcyclobutyl) carbamate I- 1006 (400 mg, yield 57%) as oil wich solidified upon standing. 30

JAB7061WOPCT1 - 75 - 1H NMR (400 MHz, CHLOROFORM-d) d ppm 0.06 (s, 6 H) 0.88 (s, 9 H) 0.88 - 0.93 (m, 3 H) 1.48 - 1.61 (m, 2 H) 1.81 - 1.95 (m, 2 H) 2.42 - 2.61 (m, 2 H) 3.65 - 3.80 (m, 1 H) 4.83 (br d, J=5.1 Hz, 1 H) 5.08 (s, 2 H) 7.28 - 7.43 (m, 5 H) 5 Synthesis of (1r,3s)-3-((tert-butyldimethylsilyl)oxy)-3-ethylcyclobutan-1 -amine I-1008 10 To a mi ethylcyclobutyl) (120mg, 0.112 with baloon at r The crude product was purified by flash column chromatography (silica, MeOH in 15 DCM 0/100 to 10/90), the correspoinding fractions were evaporated in vacuo to yield (1r,3s)-3-((tert-butyldimethylsilyl)oxy)-3-ethylcyclobutan-1 -amine I-1008 (200 mg, yield 79%) as transparent oil. 1H NMR (400 MHz, CHLOROFORM-d) d 2.86-2.99 (m, 1H), 2.39-2.51 (m, 2H), 20 1.69-1.82 (m, 2H), 1.50 (q, J=7.24 Hz, 4H), 0.81-0.93 (m, 12H), 0.05-0.12 (m, 6H) Structure analogs were synthesized using the same procedure. Starting material Intermediate I-1007 I-1005 JAB7061WOPCT1 - 76 - Synthesis of 2-(benzyloxy)acetyl chloride I-1009 5 Thionyl chloride [7719-09-7] (588 µL, 7.82 mmol) was added to a stirred solution of benzyloxyacetic acid [30379-55-6] (1 g, 6.02 mmol) in DCM anhydrous (20 mL) at 0ºC. The mixture was stirred from 45ºC to rt for 3h The solvent was evaorated in vacuo to yield solid. 10 Synthesis of 1-fluorocyclopropane-1-carbonyl chloride I-111 15 Oxalyl chloride [79-37-8] (3.08 mL, 1.48 g/mL, 35.9 mmol) was added dropwise to a solution of 1-fluorocyclopropanecarboxylic acid [137081-41-5] (4.14 g, 39.8 mmol) and DMF (100 µL, 0.94 g/mL, 1.29 mmol) in dry DCM (150 mL). The reaction mixture was stir ° mbars) and the o 20 The crude was used without further purification in the next step. Synthesis of (tributylstannyl)methanol I-117 25 A 2.5M solution of n-BuLi in hexanes [109-72-8] (5.4 mL, 13.5 mmol) was added dropwise to a stirred solution of diisipropylamine [108-18-9] (2 mL, 0.72 g/mL, 14.26 mmol) in dry THF (45 mL) at -20 ºC. The reaction mixture was stirred at -20 ºC for 30 min. Then was cooled to -78 ºC and tributyltin hydride [688-73-3] (3.53 mL, 1.08 g/mL, 12.73 mmol) was added dropwise. The mixture was allowed to warm to 0 ºC for 30 30 min. Then was cooled to -78 ºC and paraformaldehyde [30525-89-4] (463 mg, 5.09 JAB7061WOPCT1 - 77 - mmol) was added portionwise. After addition, the reaction was allowed to warm slowly from -78 ºC to rt over 30 min and stirred at rt for further 30 min. The mixture was diluted with water and extracted with Et2O. The organic layer was separated, dried (MgSO ₄ ), filtered and the volatiles evaporated in vacuo. The crude product was 5 purified by FCC (Hept/EtOAc 0 to 10%) to yield I-117 (2.8 g, 68%) as a colorless oil. Synthesis of methyl 4-(1-fluorocyclopropyl)benzoate I-1010 10 A mixture of MeOH (10 mL) and THF, dry (30 mL) was degassed with nitrogen. Triethylamine [121-44-8] (6.48 mL 46.5 mmol) 45-bis(diphenylphosphino)-99- dimethylxanth fluorocyclopro 15 [3375-31-3] (8 under 20 bar carbon monoxide in an autoclave for 24 h. The solvent was evaporated, taken up in sat NaHCO3 solution, extracted with DCM, dried on MgSO4 and evaporated. The residue was purified on a column with silicagel, eluent : EtOAc in Heptane, from 0 to 10 %. The pure fractions were evaporated, yielding methyl 4-(1- 20 fluorocyclopropyl)benzoate I-1010 (2.92 g, yield 81%) as colorless oil which solidified to a white solid upon cooling to rt. Synthesis of 3-fluoro-4-(trifluoromethyl)benzoic acid I-93 25 To a mixture of 3-fluoro-4-(trifluoromethyl)benzonitrile [231953-38-1] (1 g, 5.29 mmol) in EtOH (20 ml) was added a 2M aqueous solution NaOH [1310-73-2] (4 mL, 8 mmol). The mixture was heated for at 80 ºC for 16 hours. The mixture was cooled at rt and aqueous HCl JAB7061WOPCT1 - 78 - (2 x 5 ml), the combined organic layers were dried over MgSO4 and evaporated in vacuo to afford I-93 (0.9 g, 82%) as a white solid. Synthesis of 2-fluoro-6-iodo-4-(trifluoromethyl)benzoic acid I-97 5 Iodine [7553-56-2] (2.68 g, 10.6 mmol) was added to a stirred solution of 2-fluoro-4- (trifluoromethyl)benzoic acid [115029-24-8] (2 g 9.61 mmol) ) PIDA [3240-34-4] (3.4 g, 10.6 mmo 10 under nitrogen. T HCl were added, t e organc ayer was separated, dred over MgSO4, tered and t e volatiles were removed in vacuo to yield crude I-97 as a brown sticky solid that was used without further purification. The crude was used in the next reaction step without further purification. 15 Synthesis of tert-butyl 3-fluoro-4-(trifluoromethyl)benzoate I-94 2-Methyl-2-propanol [75-65-0] (4.6 g, 62.5 mmol), N,N'-dicyclohexylcarbodiimide 20 [538-75-0] (13.9 g, 67.3 mmol) and 4-(dimethylamino)pyridine [1122-58-3] (0.587 g, 4.8 mmol) were added to a mixture of 3-fluoro-4-(trifluoromethyl)benzoic acid I-93 (10 g, 48 mmol) in mixture was fi filtrated was evaporated in vacuo. The residue was purified by FCC (DCM) to afford I-25 94 (9 g, 71%).

JAB7061WOPCT1 - 79 - Synthesis of methyl 4-bromo-2-iodobenzoate I-1011 5 Cesium carbonate [534-17-8] (5.98 g, 18.35 mmol) and methyl iodide [74-88-4] (1.14 mL, 2.28 g/mL 1 l ddd i d l i f 4b 2 iodobenzoic ac reaction mixtu organic layer was concentrated in vacuo. The crude was purified by flash column 10 chromatography (silica; EtOAc in Heptane from 0/100 to 20/80). The desired fractions were collected and concentrated in vacuo to yield methyl 4-bromo-2-iodobenzoate I- 1011 (4.27 g, 80%) as a colorless oil. Structural analogues were synthesized according to the above procedure. Reagent Intermediate I-1014 [13421-13-1] I-97 15 Synthesis o A 2M solu was added , JAB7061WOPCT1 - 80 - 18.9 mmol) in dry THF (125 ml) at -78ºC. The mixture was stirred at -78 ºC for 45 min, then isobutyryl chloride [79-30-1] (2.1 mL, 1.017 g/mL, 20.8 mmol) was added dropwise at -78 ºC. The reaction was stirred at -78 ºC for 2 hours. The reaction was quenched by addition of a saturated aqueous solution of NH ₄ Cl was added at -78 ºC. 5 The crude mixture was allowed to warm to rt and extracted with EtOAc (2 x 25 ml), the organic layer was separated dried and evaporated in vacuo. The residue was purified by FCC (DCM) yielding I-95 (5.2g, 82%) as an oil. Synthesis of methyl 2-(2-(benzyloxy)acetyl)-4-bromobenzoate I-1012 10 Isopropylmagnes was added drop15 1.47 mmol) in T at 0ºC for 30 mi 8] (367 mg, 1.61 min. 2-(Benzyloxy)acetyl chloride I-1009 (325 mg, 1.76 mmol) and tetrakis(triphenylphosphine)palladium (0) [14221-01-3] (86 mg, 0.073 mmol) were 20 added and the resulting mixture was stirred at 60ºC for 2h under nitrogen atmosphere. The reaction mixture was diluted with sat. aqueous NH4Cl and extracted with EtOAc. The organic layer was separated, dried (MgSO4), filtered and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica; DCM in heptane 0/100 to 100/0). The desired fractions were collected and concentrated 25 in vacuo to yield methyl 2-(2-(benzyloxy)acetyl)-4-bromobenzoate I-1012 (468 mg, 82%) as a yellow sticky solid. Structural analogues were synthesized according to the above procedure.

JAB7061WOPCT1 - 81 - Reagent Intermediate product Cl O [ _4023-34-1] ^I-1011 I-1013 Cl O [ _4023-34-1 [79-30-1] I-111 Synthesis o 5 4-(Trifluoromethoxy)benzoic acid [330-12-1] (2000 mg, 9.7 mmol) and dibromomethane (37 mL) were added to potassium phosphate dibasic [7758-11-4] (5070 mg, 29. 10 tube under nit JAB7061WOPCT1 - 82 - was filtered through a short pad of celite, and the solvent was removed in vacuo. The crude product was purified by flash column chromatography (silica; EtOAc in heptane 0/100 to 20/80). The desired fractions were collected and concentrated in vacuo toyield 5-(trifluoromethoxy)isobenzofuran-1(3H)-one I-1016 (771 mg, 36%) as a yellowish 5 solid. Structural analogs were synthesized using the same procedure. Intermediate Product [455-24-3] I-89 [98-73-7] [383-13-1] Synthesis o 10 N-Bromosuccinimide [128-08-5] (10 g, 56.33 mmol) and azobisisobutyronitrile (AIBN) [78-67-1] (231 mg, 1.41 mmol) were added to a stirred solution of 5- JAB7061WOPCT1 - 83 - bromophthalide [64169-34-2] (10 g, 46.94 mmol) in DCE (200 mL). The mixture was stirred at 80 ºC for 18h. The reaction mixture was cooled at rt and the solvent was concentrated. The crude was purified by flash column chromatography (silica; EtOAc in heptane 0/100 to 20/80). The desired fractions were collected and concentrated in 5 vacuo to yield 3,5-dibromoisobenzofuran-1(3H)-one I-1021 (10.9 g, 73%) as a white solid. Structural analogs were synthesized using the same procedure. Intermediate Product I-1016 I-1022 I-89 10 JAB7061WOPCT1 - 84 - Synthesis of 5-bromo-3-hydroxyisobenzofuran-1(3H)-one I-1026 5 3,5-Dibromoisobenzofuran-1(3H)-one I-1021 (7.34 g, 25.14 mmol) was suspended in water (300 mL) with DCM:MeO MgSO4 anh., fil hydroxyisobenzofuran-1(3H)-one I-1026 (5.9 g, 99%) as a white solid. 10 Structural analogs were synthesized using the same procedure. Intermediate Product I-1022 I-1027 I-90 JAB7061WOPCT1 - 85 - I-1025 I-1030 Synthesis of 2-(4-methoxyphenyl)-4,4-dimethyl-5H-oxazole (I-1) A solution of 2-amino-2-methyl-1-propanol [124-68-5] (53.03 g, 0.59 mol) in 5 anhydrous DCM (200 mL) was dropwise added in 30 min to a stirred solution of ethyl 4-methoxybenzoyl chloride [100-07-2] (51.18 g, 0.3 mol) in anhydrou under nitrogen keeping the temperature at about 18ºC using an ice/wa under stirring the precipitate was filtered through celite and washed organic phase was stirred under nitrogen at 2ºC and dropwise added to thionyl chloride 10 [7719-09-7] (65.29 ml, 0.9 mol), keeping the temperature below 10ºC. At the end of the dropping the reaction mixture was stirred at room temperature for 18 h, then concentrated under vacuo. The residue was purified by column chromatography (silica, MeOH in DCM 0/100 to 1/99). The desired fractions were collected and the solvents evaporated in vacuo to yield 2-(4-methoxyphenyl)-4,4-dimethyl-5H-oxazole (I-1) (42 15 g, 68%) as yellow oil. Synthesis of [2-(4,4-dimethyl-5H-oxazol-2-yl)-5-methoxy-phenyl]-2-methyl- propan-1- ol (I-2) 20 A 1M solution of 2,2,6,6-Tetramethylpiperidinylmagnesium chloride lithium chloride complex in THF/toluene [898838-07-8] (60 ml, 60 mmol) was added dropwise to a stirred solution of 2-(4-methoxyphenyl)-4,4-dimethyl-5H-oxazole (I-1) (5.29 g, 25.78 mmol) in anhydrous THF (100 mL) at room temperature. Aft JAB7061WOPCT1 - 86 - mixture was cooled to 0ºC and a solution of isobutyraldehyde [78-84-2] (7 mL, 76.69 mmol) in anhydrous THF (10 mL) was added dropwise. The resulting reaction mixture was stirred at room temperature for 2 h. The solvent was partially removed in vacuo and the residue was diluted with saturated aqueous solution of NH ₄ Cl and extracted 5 with EtOAc. The combined organic layers were separated, dried (MgSO4), filtered and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica, EtOAc in heptane 0/100 to 50/50). The desired fractions were collected and concentrated in vacuo to yield [2-(4,4-dimethyl-5H-oxazol-2-yl)-5- methoxy-phenyl]-2-methyl-propan-1-ol (I-2) (6.3 g, 89%) as yellow oil. 10 Structural analogs were synthesized using the same procedure. Reagent Starting material Intermediate [123-38-6] ( _I-1) ^(I-3) Synthesis of 1-[2-(4,4-dimethyl-5H-oxaz 1-one (I-4) 15 Dess-Martin periodinane [87413-09-0] (4.07 g, 9.59 mmol) was added to a stirred solution of [2-(4,4-dimethyl-5H-oxazol-2-yl)-5-methoxy-phenyl]-2-methyl- propan-1-ol (I-2) (1.98 g, 7.14 mmol) in anhydrous DCM (120 mL) at room temperature. After 2.5 h stirring, additional Dess-Martin periodinane [87413-09-0] (1.35 g, 3.1 20 added and the resulting mixture was stirred for 1 h more. The mixture wa to the filtrate was added 20% aqueous solution of Na2S2O3. The product with DCM and the organic layer was further washed with saturated aqueou s souton o NaHCO3 and brine. The organic layer was dried (MgSO4), filtered and the solvents evaporated in vacuo to yield 1-[2-(4,4-dimethyl-5H-oxazol-2-yl)-5-methoxy-phenyl]-2-

JAB7061WOPCT1 - 87 - methyl-propan-1-one (I-4) (0.50 g, 48% purity) as yellow solid, that was used in next step without further purification. Structural analogs were synthesized using the same procedure. Starting material Intermediate ( _I-3) ^(I-5) (I-1031) (I-1032 5 Synthesis of ethyl 4-methoxy-2-propanoyl-benzoate (I-6) H2SO4 [7664-93-9] (2.5 mL, 46.9 mmol) was added dropwise to a stirred solution of 1- [2-(4,4-dimethyl-5H-oxazol-2-yl)-5-methoxy-phenyl]propan-1-o ne (I-5) (2 g, 7.65 10 mmol) in a mixture of water (3 mL) and EtOH (57 mL). The mixture was stirred at 90 ºC for 20 h. The solvent was concentrated in vacuo and the residue w water and extracted with Et2O. The organic layer was separated, d filtered and the solvents evaporated in vacuo to yield ethyl 4-metho benzoate (I-6) (1.52 g, 84%), that was used in next step without further purification. 15 Synthesis of 5-methyl-2-phenyl-isoindoline-1,3-dione (I-7) JAB7061WOPCT1 - 88 - Aniline [62-53-3] (1.24 mL, 13.57 mmol) was added dropwise to a stirred solution of 5-methylisobenzofuran-1,3-dione [19438-61-0] (2 g, 12.33 mmol) in AcOH [64-19-7] (12.3 mL). The mixture was stirred at 140ºC for 2 h. To the cooled mixture was added water and the resulting reaction mixture was stirred at room temperature for 2 h. The 5 solid formed was filtered and washed with additional water to yield 5-methyl-2-phenyl- isoindoline-1,3-dione (I-7) (2.77 g, 95%) as a white solid, that was used in next step without further purification. Structural analogs were synthesized using the same procedure. Starting material Intermediate [ _26238-14-2] ^(I-8) [86-9-8] (I-17) [118-45-6] (I-1033) 10 Synthesis of 5-bromo-3-ethyl-3-hydroxy-2-phenyl-isoindolin-1-one (I A 3M solution of ethylmagnesium bromide [925-90-6] (1.65 mL, added dropwise to a stirred solution of 5-bromo-2-phenyl-isoindoline-1,3-dione 15 [82104-66-3] (1 g, 3.31 mmol) in THF (20 mL) at 0ºC and under nitrogen. After 5 min JAB7061WOPCT1 - 89 - stirring, the mixture was quenched by the addition of water. The solvents were evaporated in vacuo to yield 5-bromo-3-ethyl-3-hydroxy-2-phenyl-isoindolin-1-one (I- 9) (1.1 g, quant.) as yellowish oil, that was used in next step without further purification. 5 Structural analogs were synthesized using the same procedure. Reagent Starting material Intermediate [925-90-6] (I-7) (I-10) [1068-55- [925-90-6 [1068-55- [1068-55- Synthesis o JAB7061WOPCT1 - 90 - Hydrazine hydrate [7803-57-8] (0.15 mL, 3.09 mmol) was added to a stirred solution of 1-[2-(4,4-dimethyl-5H-oxazol-2-yl)-5-methoxy-phenyl]-2-methy l-propan-1-one (I-4) (0.50 g, 48% purity) in AcOH [64-19-7] (3 mL). The mixture was stirred at 80ºC for 18 5 h. The mixture was diluted with water and extracted with DCM. The aqueous phase was basified with aqueous saturated solution of NaHCO3 and extracted with DCM. The combined organic layers were dried (MgSO4), filtered and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica, EtOAc in heptane 0/100 to 50/50). The desired fractions were collected and the solvents 10 concentrated in vacuo to yield 4-isopropyl-6-methoxy-2H-phthalazin-1-one (I-12) (103 mg, 54%). Structural analogs were synthesized using the same procedure. Starting material Intermediate (I-13) (I-5) 15 Synthesis of 6-bromo-4-ethyl-2H-phthalazin-1-one (I-14) Hydrazine hydrate [7803-57-8] (0.52 mL, 16.56 mmol) was added to of 5-bromo-3-ethyl-3-hydroxy-2-phenyl-isoindolin-1-one (I-9) (1.1 g, 3.31 mmol) in EtOH (12 mL) in a sealed tube. The mixture was stirred at 80 ºC for 16 h. Additional 20 hydrazine hydrate [7803-57-8] (0.52 mL, 16.56 mmol) was added stirred at 80 ºC for 5 h. Additional hydrazine hydrate [7803-57 JAB7061WOPCT1 - 91 - mmol) was added and the mixture was stirred at 80 ºC for 3 days. After cooling the mixture, the solid formed was filtered and dried under vacuo to yield 6-bromo-4-ethyl- 2H-phthalazin-1-one (I-14) (500 mg, 60%). 5 Structural analogs were synthesized using the same procedure. Starting material Intermediate (I-10) (I-16) JAB7061WOPCT1 - 92 - I-1012 (I-1036) I-95 JAB7061WOPCT1 - 93 - I-99 I-100 Synthesis carbonitril 5 KCN [151-50-8] (130.6 mg, 2.01 mmol) was added to a solution of 5-fluoro-4- isopropyl-6-(trifluoromethyl)phthalazin-1(2H)-one (I-86) (500 mg, 1.82 mmol) in DMSO (20 ml) at rt. The mixture was heated under MW irradiation at 150 ºC for 40 min. The crude i ll l il ih JAB7061WOPCT1 - 94 - with EtOAc (3x 5 mL). The organic layer was evaporated in vacuo and purified by FCC (DCM/MeOH 0 to 5%) to afford (I-85) (420 mg, yield 82%) as a solid. Synthesis of 4,6-dibromophthalazin-1(2H)-one I-1044 5 K2CO3 [584-08-7] (3.07 g, 22.22 mmol) was added to a mixture of 6-bromophthalazin- 1(2H)-one I-103 10 rt for 10 min. Th mmol) was adde solution was add p . . g layer was separated and dried over MgSO4 anh, filtered and solvent was concentrated in vacuo. The product was co-distillated with toluene (x5) to yield 4,6- 15 dibromophthalazin-1(2H)-one I-1044 (685 mg, 19%) as a beige solid. The aq. layer was extracted with DCM:MeOH (9:1). The organic layer was separated and dried over MgSO4 anh, filtered and solvent was concentrated in vacuo. The product was co- distillated with toluene to yield 4,6-dibromophthalazin-1(2H)-one I-1044 (2.32 g, 67%) as a beige solid. 20 Structural analogs were synthesized using the same procedure. Intermediate Product (I-1040) I-1045 JAB7061WOPCT1 - 95 - O NH N F ₃ C (I-83) (I-82) Synthesis carbonitril 5 A solution of 4-bromo-6-(trifluoromethyl)phthalazin-1(2H)-one I-82 (4 g, 13.65 mmol) in 1,4-dioxane (89.7 mL) and DI water (29.9 mL) was placed in an Easymax pressure tube and degassed with nitrogen during 15 min. Then, 4,4,5,5-tetramethyl-2-(prop-1- en-2-yl)-1,3,2- 10 K3PO4 [7778- 0.71 mmol) w reaction was q EtOAc (3 x 200 mL). The combined organic extracts were dried over MgSO4, filtered

JAB7061WOPCT1 - 96 - and concentrated under reduced pressure at 40 °C. The crude compound was purified by FCC (Het/EtOAc 0 to 30%) to afford I-105 (3 g, 86%) as a white solid. Structural analogs were synthesized using the same procedure. 5 Intermediate Product I-1049 I-1050 Synthesis carbonitril 10 A 1M solution of diethylzinc in hexanes [557-20-0] (22.6 mL, 22.6 mmol) was added in a flask containing dry DCM (20 mL) under nitrogen atmosphere and it was stirred at 0 ºC. TFA [76 15 min via syrin diiodomethane syringe pump. (prop-1-en-2-yl)-6-(trifluoromethyl)phthalazin-1(2H)-one I-105 (500 mg, 1.97 mmol) in DCM (10 mL) was added over 20 min via syringe pump. After addition, the reaction 20 mixture was allowed to warm to rt and stirred for additional 2 hours. The reaction was quenched by addition of a saturated aqueous solution of NH ₄ Cl and the solids were filtered. The organic layer was separated, dried on MgSO4 and concentrated. A purification was performed via preparative HPLC (Stationary phase: RP XBridge Prep C18 OBD-10µm, 50x250mm, Mobile phase: 0.25% NH ₄ HCO ₃ solution in water, 25 CH3CN) yielding I-104 (302 mg, 57%) as a white solid.

JAB7061WOPCT1 - 97 - Synthesis of 4-(1-ethoxyvinyl)-6-(trifluoromethyl)phthalazin-1(2H)-one I-116 5 Bis(triphenylphosphine)palladium(II) dichloride [13965-03-2] (244.4 mg, 0.34 mmol) and tributyl(1-ethoxvinl)tin [97674-02-7] (143 mL 107 /mL 41 mmol) were added to a stirr g, 3.41 mmol) stirred at 100 10 solution of NaH CO3 and extracted wt EtOAc. Te organc ayer was separated, dred (MgSO4), filtered and the volatiles concentrated under vacuum. The crude product was purified by FCC (Hept/EtOAc0 to 30%) to yield I-116 (948 mg, 95% purity, 93%) as a pale yellow solid. 15 Synthesis of 4-acetyl-6-(trifluoromethyl)phthalazin-1(2H)-one I-115 6M aqueous HCl [7647-01-0] (2.77 mL, 16.6 mmol) was added dropwise to a stirred solution of 4-(1-ethoxyvinyl)-6-(trifluoromethyl)phthalazin-1(2H)-one I-116 (945 mg, 20 3.32 mmol) in 1,4-dioxane at 0 ºC. The mixture was stirred at rt for 1 hour. It was then diluted with a sa organic layer wa vacuo to yield I-1

JAB7061WOPCT1 - 98 - Synthesis of 4-(2-hydroxypropan-2-yl)-6-(trifluoromethyl)phthalazin-1(2H) -one I-114 A 1.4M solution of methylmagnesium bromide in THF [75-16-1] (7 mL, 9.83 mmol) 5 was added dro i t ti d l ti f 4 t l6 tifl thl hthl i 1(2H)-one I-11 The mixture wa solution of NaH (MgSO4), filtered and the volatiles evaporated in vacuo. The crude product was10 purified by FCC (Hept/EtOAc 0 to 30%) to yield I-114 (576 mg, 97-98% purity, 64%) as an off-white solid. Intermediate Product I-1051 I-1052 Synthesis o 15 A mixture of 4-(1-fluorocyclopropyl)-6-(trifluoromethyl)phthalazin-1(2H)- one I-109 (300 mg, 1.1 mmol) and 0.5M NaOMe in MeOH [124-41-4] (22 mL, 11 mmol) was JAB7061WOPCT1 - 99 - stirred under a nitrogen atmosphere and heated in a pressure tube at 120 °C for 12 hours. The solvent was evaporated and the residue taken in DI water. NH ₄ Cl [12125- 02-9] (1 g) was added and the mixture extracted with EtOAc. The combined organic extracts were washed with brine, dried on MgSO ₄ and evaporated. The residue was 5 purified by FCC (DCM/MeOH 0 to 5 %) yielding I-126 (200 mg, 64%) as a white solid. Synthesis of ethyl 2-(4-isopropyl-6-methoxy-1-oxo-phthalazin-2-yl)acetate (I-21) 10 Ethyl chloroacetate [105-39-5] (80 µL, 0.85 mmol) was added to a stirred mixture of 4- isopropyl-6-methoxy-2H-phthalazin-1-one (I-12) (148 mg, 0.68 mmol), 18-crown-6 [17455-13-9] (11 mg, 0.042 mmol), potassium K2CO3 [584-08-7] (118 mg, 0.85 mmol) in anh 15 in a sealed tube. The mixture was stirred at 90º water and brine and then extracted with DCM. e organc ayer was separae, re (MgSO4), filtered and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica, EtOAc in heptane 0/100 to 30/70). The desired fractions were collected and concentrated in vacuo to yield ethyl 2-(4- 20 isopropyl-6-methoxy-1-oxo-phthalazin-2-yl)acetate (I-21) (163 mg, 79%) as a white solid. Structural analogs were synthesized using the same procedure. Reagent Starting material Intermediate [105-39-5] (I-13) (I-22) JAB7061WOPCT1 - 100 - [105-39-5] [54145-30-1] (I-23) [105-39- [105-39- [105-36- Cs2CO [534-17- [105-36- [105-36- Cs2CO [534-17- JAB7061WOPCT1 - 101 - [105-36-2] (I-1038) I-1058 [105-36- [105-36- Cs2CO [534-17- [105-36- [105-36- [105-36- [105-36- JAB7061WOPCT1 - 102 - I-100 I-101 [105-39- [105-39- [105-36- [105-36- [105-36- JAB7061WOPCT1 - 103 - [105-36-2] Cs2CO3 I-1066 I-1065 [534-17-8] [105-39- [105-36- Cs2CO [534-17- [105-36- Cs2CO [534-17- [105-36- [105-36- Cs2CO [534-17- JAB7061WOPCT1 - 104 - [105-39-5] I-1048 I-1049 Synthesis of hl b hl hhl i l Ethyl bromoacetate [105-36-2] (0.82 mL, 7.4 mmol) was added to a stirred suspension 5 of 7-bromo-4-ethyl-2H-phthalazin-1-one (I-14) (2.6 g, 6.16 mmol, 60% purity) and NaH [7646-69-7] (60% dispersion in mineral oil, 0.2 DMF (24.6 mL) at 0ºC. The mixture was stirred at mixture was diluted with water and extracted with separated, dried (MgSO4), filtered and the solvents evaporated n vacuo. Te crude 10 product was purified by flash column chromatography (silica, EtOAc in heptane 0/100 to 20/80). The desired fractions were collected and concentrated in vacuo to yield ethyl 2-(7-bromo-4-ethyl-1-oxo-phthalazin-2-yl)acetate (I-28) (1.15 g, 55%) as pale yellow oil. Structural analogs were synthesized using the same procedure. Starting material Intermediate (I-15) (I-31) (I-16) (I-30) 15 JAB7061WOPCT1 - 105 - Synthesis of ethyl 2-(6-bromo-4-(hydroxymethyl)-1-oxophthalazin-2(1H)-yl)acetat e I- 1031 5 Chlorotrimethyls [7681-82-5] (1.6 ((benzyloxy)met mmol) in acetoni 10 was stirred at 80 or . e mxture was ute wt sat. aqueous a ( mL) and 10% aqueous Na2S2O3 (32 mL) and extracted with AcOEt. The organic layer was separated, dried (MgSO4), filtered and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica; AcOEt in heptane 0/100 to 35/65). The desired fractions were collected and concentrated in vacuo to yield ethyl 15 2-(6-bromo-4-(hydroxymethyl)-1-oxophthalazin-2(1H)-yl)acetat e I-1031 (523 mg, 33%) as a white solid. Synthesis of ethyl 2-(6-bromo-4-(1-ethoxyvinyl)-1-oxophthalazin-2(1H)-yl)acetat e I- 1074 20 Bis(triphenylphosphine)palladium(II) dichloride [13965-03-2] (92 mg, 0.13 mmol) and tributyl (1-eth25 to a stirred so JAB7061WOPCT1 - 106 - (500 mg, 1.28 mmol) in toluene (10 mL) under nitrogen atmosphere in a sealed tube. The mixture was stirred at 80ºC for 4h. The mixture was diluted with sat. aqueous NaHCO3 and extracted with AcOEt. The organic layer was separated, dried (MgSO4), filtered and the solvents evaporated in vacuo. The crude product was purified by flash5 column chromatography (silica, AcOEt in heptane 0/100 to 20/80). The desired fractions were collected and concentrated in vacuo to yield ethyl 2-(6-bromo-4-(1- ethoxyvinyl)-1-oxophthalazin-2(1H)-yl)acetate I-1074 (252 mg, 41%) as a yellow solid. Structural analogues were synthesized using the same procedure. 10 Reagent Starting material Intermediate [97674-02-7] [ ^97674-02- [ _81177-90- JAB7061WOPCT1 - 107 - [81177-90-4] I-81 I-121 [ _97674-02- Synthesis I-1077 5 Tris(triphenylp added to a stir 10 2(1H)-yl)aceta atmosphere. T mixture was st . p . p was purified by flash column chromatography (silica 12g; AcOEt in heptane 0/100 to 20/80). The desired fractions were collected and concentrated in vacuo to yield ethyl 2- 15 (6-(1-ethoxyethyl)-4-isopropyl-1-oxophthalazin-2(1H)-yl)acet ate I-1077 (107 mg, 90%) as a colorless sticky solid.

JAB7061WOPCT1 - 108 - Intermediate Product I-1063 I-1078 I ^{-121 I-129} Synthesis o 5 Chlorotrimethylsilane [75-77-4] (250 µL, 1.95 mmol) and sodium iodide [7681-82-5] (2.96 mg, 1.95 mmol) were added to a stirred solution of ethyl 2-(4-isopropyl-6- methoxy-1-oxo10 rt under nit Chlorotrimethy (2.96 mg, 1.95 . mixture was diluted with sat. aqueous NaHCO3 (18 mL) and 10% aqueous Na2S2O3 (18 mL) and extracted with AcOEt. The organic layer was separated, dried (MgSO4),

JAB7061WOPCT1 - 109 - filtered and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica 25g; AcOEt in heptane 0/100 to 100/0). The desired fractions were collected and concentrated in vacuo to yield ethyl 2-(6-hydroxy-4- isopropyl-1-oxophthalazin-2(1H)-yl)acetate I-1079 (55 mg, 21%) as a beige solid. 5 Synthesis of ethyl 2-(4-isopropyl-1-oxo-6-(2,2,2-trifluoroethoxy)phthalazin-2(1 H)- yl)acetate I-1080 10 2,2,2-Trifluoroethl erfluorobut lsulfonate [79963-95-4] (47 L 168 /mL 021 mmol) was ad oxophthalazin-2( 178] (93 mg, 0.2 15 mixture was dilu layer was separated, dried (MgSO4), filtered and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica 25g; AcOEt in heptane 0/100 to 15/85). The desired fractions were collected and concentrated in vacuo to yield ethyl 2-(4-isopropyl-1-oxo-6-(2,2,2-trifluoroethoxy)phthalazin-2(1 H)-20 yl)acetate I-1080 (36 mg, 51%) as a yellow solid Synthesis of ethyl 2-(4-bromo-6-(dimethylamino)-1-oxophthalazin-2(1H)-yl)acetat e I- 1081 25 JAB7061WOPCT1 - 110 - Dimethylamine solution 2M in THF [124-40-3] (1.92 mL, 3.85 mmol) was added to a stirred solution of ethyl 2-(4,6-dibromo-1-oxophthalazin-2(1H)-yl)acetate I-1055 (500 mg, 1.28 mmol) and N,N-diisopropylethylamine [7087-68-5] (1.35 mL, 0.74 g/mL, 7.69 mmol) in DMSO in a sealed tube. The mixture was stirred at 125ºC for 16h. The 5 mixture was diluted with water and extracted with AcOEt. The organic layer was washed with water (x3), separated, dried (MgSO4), filtered and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica; AcOEt in heptane 0/100 to 50/50). The desired fractions were collected and concentrated in vacuo to ethyl 2-(4-bromo-6-(dimethylamino)-1-oxophthalazin-2(1H)-10 yl)acetate I-1081 (142 mg, 31%) as a white solid. Structural analogs were synthesized using the same procedure. Starting material Intermediate ( ^I-81) _(I-155) Synthesis of ethyl 2-(6-cyclopropyl-4- 15 [1,1'-Bis(diphenylphosphino)ferrocene ]dc oropa adum(II), compex wt dichloromethane [95464-05-4] (109 mg, 0.13 mmol) was added to a stirred suspension of ethyl 2-(6-bromo-4-ethyl-1-oxo-phthalazin-2-yl)acetate (I-28) (300 mg, 0.88 mmol), cyclopropyl boronic acid [4 20 [534-17-8] (0.63 g, 1.95 mm under nitrogen. The mixtur diluted with water and extra . , (MgSO ₄ ), filtered and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica; EtOAc in heptane 0/100 to 50/50). The 25 desired fractions were collected and the solvents evaporated in vacuo to yield ethyl 2-

JAB7061WOPCT1 - 111 - (6-cyclopropyl-4-ethyl-1-oxo-phthalazin-2-yl)acetate (I-32) (129 mg, 48%) as yellow oil. Synthesis of ethyl 2-(4-ethyl-6-isopropenyl-1-oxo-phthalazin-2-yl)acetate (I-33) 5 [1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane [95464-05-4] (0.15 g, 0.18 mmol) was added to a stirred suspension of ethyl 2-(6-bromo-4-ethyl potassium isopropenyltrifluo 10 carbonate [534-17-8] (0.84 g (2 mL) under nitrogen. The . was diluted with water and extracted with EtOAc. The organic layer was separated, washed with brine, dried (MgSO ₄ ), filtered and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica; EtOAc in heptane 15 0/100 to 50/50). The desired fractions were collected and the solvents evaporated in vacuo to yield ethyl 2-(4-ethyl-6-isopropenyl-1-oxo-phthalazin-2-yl)acetate (I-33) (148 mg, 87%) as yellow oil. Structural analogs were synthesized using the same procedure. Reagent Starting material Intermediate [13682-77-4] (I- (I-34) 28) [ _126726-6 JAB7061WOPCT1 - 112 - O O N N O _{[411235-57-9]} ^(I-31) (I-56) I-1081 [13682-77 [395083-1 ^{[395083-1 [395083-1} [13682-77 Synthesis yl)phthalaz JAB7061WOPCT1 - 113 - Pd(PPh3)4 [14221-01-3] (76.2 mg, 0.066 mmol) was added to a stirred solution of ethyl 2-(4-bromo-1-oxo-6-(trifluoromethyl)phthalazin-2(1H)-yl)acet ate I-81, 1- (trifluoromethyl)vinylboronic acid hexylene glycol ester [1011460-68-6] (307.4 mg, 1.38 mmol) and Na ₂ CO ₃ [497-19-8] (559.1 mg, 5.28 mmol) in DME / DI water (7.6 5 mL / 3.8 mL) at rt under nitrogen. The resulting mixture was stirred at 95 ºC for 3.5 hours. The reaction was allowed to cool to rt, diluted with water and extracted with EtOAc. The organic extracts were washed with brine, dried over MgSO4, filtered and concentrated under vacuum. The crude product was purified by FCC (Hept/EtOAc 0 to 10%) to yield I-129 (287 mg, 52%) as a colorless oil. 10 Synthesis of ethyl 2-(4-ethyl-6-isopropyl-1-oxo-phthalazin-2-yl)acetate (I-35) Palladium on active carbon (10%) [7440-05-3] (31 mg) was added to a solution of ethyl 2-(4-ethyl-6-isopropenyl-1-oxo-phthalazin-2-yl)acetate (I-33) (309 mg, 1.03 mmol) in 15 EtOH (13 mL) at 0ºC and under nitrogen. The resulting mixture was stirred under an atmosphere of hydrogen for 16 washed with MeOH and the solv ethyl-6-isopropyl-1-oxo-phthalazi that was used in next step without further purification. 20 Structural analogs were synthesized using the same procedure. Starting material Intermediate (I-34) (I-36) JAB7061WOPCT1 - 114 - I-1087 I-1086 Synthesis o 5 Osmium te ethyl 2-(4-ethyl-1-oxo-6-vinyl-phthalazin-2-yl)acetate (I-34) (0.74 g, 2.57 mmol) and JAB7061WOPCT1 - 115 - sodium periodate [7790-28-5] (1.1 mL, 5.13 mmol) in a mixture of THF (10 mL) and water (10 mL). The mixture was stirred at room temperature for 16 h. The mixture was diluted with water and extracted with EtOAc. The organic layer was separated, dried (MgSO ₄ ), filtered and the solvents evaporated in vacuo. The crude product was purified 5 by flash column chromatography (silica; EtOAc in heptane 0/100 to 15/85). The desired fractions were collected and the solvents evaporated in vacuo to yield (I-37) (0.5 g, 68%) as a white solid. Synthesis of ethyl 2-(4-formyl-1-oxo-6-(trifluoromethyl)phthalazin-2(1H)-yl)ace tate (I-10 119) Dess-Martin periodinane [87413-09-0] (1.1 g, 2.51 mmol) was added portionwise to a stirred solution of ethyl 2-(4-(hydroxymethyl)-1-oxo-6-(trifluoromethyl)phthalazin- 2(1H)-yl)acetate I-118 15 mixture was stirred at solution of NaHCO ₃ ( DCM. The organic l , , concentrated in vacuo. The crude product was purified by FCC (Hept/EtOAc 0 to 42%) to yield I-119 (381 mg, 92% purity, 55%) as a white solid. 20 Synthesis of ethyl 2-[6-(difluoromethyl)-4-ethyl-1-oxo-phthalazin-2-yl]acetate (I-38) DAST [38078-09-0] (0.7 mL, 5.27 mmol) was added dropwise to a stirred solution of ethyl 2-(4-ethyl-6-formyl-1-oxo-phthalazin-2-yl)acetate (I-37) (0.5 g, 1.76 mmol) in 25 anhydrous DCM (10 mL) at -10ºC and under nitrogen. The mixture was stirred at room temperature for 16 h. The mixture was diluted with aqueous saturated solution of NaHCO3 and extracted with DC filtered and the solvents evaporat column chromatography (silica; JAB7061WOPCT1 - 116 - fractions were collected and the solvents evaporated in vacuo to yield (I-38) (0.39 g, 71%) as a white solid. Structural analogues were synthesized using the same procedure. 5 Starting material Intermediate I-1032 I-1091 I-119 Synthesis (trifluorom 10 A 1M solution of TBAF in THF [429-41-4] (152 μL, 015 mmol) was added dropwise to a stirred solution of ethyl 2-(4-formyl-1-oxo-6-(trifluoromethyl)phthalazin-2(1H)- yl)acetate I-119 (250 mg, 0.76 mmol) and 2-trifluoromethyltrimethylsilane [81290-20- 2] (230 μL, 1.52 mmo stirred at 0 ºC for 15 m 15 1M solution of TBA mixture was stirred at rt for 20 min. The mixture was diluted with a saturated aqueous solution of NaHCO3 and extracted with EtOAc. The organic layer was separated, dried (MgSO ₄ ), filtered and the volatiles evaporated in vacuo. The crude product was

JAB7061WOPCT1 - 117 - purified by FCC (Hept/EtOAcO0 to 30%) to yield I-125 (235 mg, 75%) as a white foamy solid. Synthesis of ethyl 2-(6-bromo-4-(1-methoxyethyl)-1-oxophthalazin-2(1H)-yl)aceta te I-5 1092 Trimethyloxonium tetrafluoroborate [420-37-1] (161 mg, 1.09 mmol) and 2,6-di-tert- 10 butyl-4-methy sealed and left 2-(6-bromo-4- mmol) in dry at r.t for 1.5 hours. Then, the reaction was quenched by addition of aq. sat. NaHCO3 15 and extracted with DCM (x3). The organic layer was separated, dried (MgSO4), filtered and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica, AcOEt in Heptane 0/100 to 50/50). The desired fractions were collected and concentrated in vacuo to yield ethyl 2-(6-bromo-4-(1- methoxyethyl)-1-oxophthalazin-2(1H)-yl)acetate I-1092 (61 mg, 43%) as a yellow oil. 20 Structural analogs were synthesized using the same procedure. Starting material Intermediate I-124 I-123 JAB7061WOPCT1 - 118 - I-1094 I-1064 Synthesis I-1095 5 Dimethylamine solution 2M in THF [124-40-3] (0.64 mL 1.23 mmol) and cesium carbonate [53 10 (6-bromo-4-is 1,4-dioxane (1 RuPhos Pd G4 [1599466-85-9] (145 mg, 0.17 mmol) was added to the mixture and the reaction was stirred at 70ºC for 16h. Then, dimethylamine solution 2M in THF [124- 40-3] (0.64 mL, 1.23 mmol), cesium carbonate [534-17-8] (277 mg, 0.85 mmol) and 15 RuPhos Pd G4 [1599466-85-9] (145 mg, 0.17 mmol) were added and the mixture was stirred at 75ºC for 16. The mixture was diluted with brine and extracted with EtOAc. The organic layer was washed with brine, dried (MgSO4), filtered and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica; EtOAc in heptane 0/100 to 50/50). The desired fractions were collected and 20 concentrated in vacuo to yield ethyl 2-(6-(dimethylamino)-4-isopropyl-1- oxophthalazin-2(1H)-yl)acetate I-1095 (208 mg, 73%) as a brown oil.

JAB7061WOPCT1 - 119 - Synthesis of ethyl 2-(4-(sec-butyl)-1-oxo-6-(trifluoromethyl)phthalazin-2(1H)- yl)acetate I-102 A 0.5M solution of sec-butylzinc bromide [171860-66-5] (12.7 mL, 6.33 mmol) was 5 added dropwise to a stirred solution of ethyl 2-(4-bromo-1-oxo-6- (trifluoromethy butylphosphin mL). The resu quenched by a 10 removed under vacuum and the aquous phase was extracted with EtOAc. The organic extracts were washed with brine and dried over MgSO4. The crude compound was purified by FCC (Hept/EtOAc 0/100 to 25/75) to yield a white solid which was further purified by preparative SFC (Stationary phase: Chiralpak Daicel IC 20 x 250 mm, Mobile phase: CO2, EtOH + 0.4 iPrNH2) yielding I-102 (65 mg, 9%) as a white solid. 15 Structural analogs were synthesized using the same procedure. Reagent Starting material Intermediate [1174507-16-4] (I-81) (I-106) [126403-67-6] JAB7061WOPCT1 - 120 - [126403-68-7] (I-81) (I-130) Synthesis of ethyl 2-(8 yl)acetate I-84 5 Ethyl 2-(4-isopropyl-1-oxo-6-(trifluoromethyl)phthalazin-2(1H)-yl) acetate (I-29) (600 mg, 1.74 mmol) [Cp*Rh(MeCN)3](SbF6)2 [59738-27-1] (144.5 mg 0.17 mmol) NIS [516-12-1] (7810 placed in a 20 and suspension with DCM (30 mL) and quenched by addition of a saturated aqueous solution of Na2S2O3 (50 mL). After stirring the biphasic mixture vigorously at rt for 5 min, the 2 layers were separated and the aqueous layer back-extracted with DCM (2 x 20 mL). the 15 combined organic extracts were dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The obtained residue was purified by FCC (Hept/EtOAc 93:7 to 7:3) to afford I-84 (360 mg, 44%) as a pale pink solid. Synthesis of ethyl 2-(8-hydroxy-4-isopropyl-1-oxo-6-(trifluoromethyl)phthalazin -20 2(1H)-yl)acetate I-74 JAB7061WOPCT1 - 121 - Ethyl 2-(8-iodo-4-isopropyl-1-oxo-6-(trifluoromethyl)phthalazin-2( 1H)-yl)acetate (I- 74) (200 mg, 0.43 mmol), PdCl ₂ (dppf) [72287-26-4] (31.3 mg, 0.043 mmol), KOAc [127-08-2] (125.8 mg, 1.28 mmol) and bis(pinacolato)diboron [73183-34-3] (217 mg, 0.85 mmol) were placed in a 20-mL MW vial. The vial was sealed and placed under 5 nitrogen (3 vacuum/nitrogen cycles) and dry DMSO (4 mL) was added. The suspension was then heated at 80 °C for 16 hours. The crude mixture was diluted with brine (30 mL) and extracted with DCM (4 x 25 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The obtained dark brown residue (crude ethyl 2-(4-isopropyl-1-oxo-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborol an-2-yl)-6- 10 (trifluoromethyl)phthalazin-2(1H)-yl)acetate) and sodium perborate tetrahydrate (265 mg, 1.72 mmol) were placed in a screw-cap tube and a 1:1 mixture of THF/DI water (2 mL) was added and the mixture stirred vigorously at rt for 2 hours. A further portion of sodium perborate tetrahydrate (265 mg, 1.72 mmol, 4 equiv) was added and the mixture stirred for further 14 hours at rt. 15 The mixture was diluted with DI water (5 mL), the pH acidified to pH <3 and the mixture extracted with DCM (3 x 15 mL). The combined organic extracts were dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The resulting brown residue was purified by FCC (Hept/EtOAc 95:5 to 4:1) to afford I-74 (85.5 mg, 55%) as a colorless crystalline solid. 20 Synthesis of ethyl 2-(4-(2-fluoropropan-2-yl)-1-oxo-6-(trifluoromethyl)phthalaz in- 2(1H)-yl)acetate I-112 25 DAST [38078-09-0] (394 μL, 2.84 mmol) was added dropwise to a stirred solution of ethyl 2-(4-(2-hydroxypropan-2-yl)-1-oxo-6-(trifluoromethyl)phthala zin-2(1H)- yl)acetate I-11 nitrogen. The30 stirred at rt for JAB7061WOPCT1 - 122 - NaHCO3 and extracted with EtOAc. The organic layer was separated, dried (MgSO4), filtered and the solvent evaporated in vacuo. The crude product was purified by FCC (Hept/EtOAc 0 to 16%). The desired fractions were collected and concentrated in vacuo to yield I-112 (458 mg, 89%) as a white solid. 5 Structural analogs were synthesized using the same procedure. Intermediate Product I-1064 I-1096 Synthesis 10 1097 Ethyl 2-(6-bromo-4-isopropyl-1-oxophthalazin-2(1H)-yl)acetate (I-31) (894 mg, 2.531 15 mmol) and potassium cyclobutyltrifluoroborate [395083-14-4] (451 mg, 2.784 mmol) were added to cataCXium A (2.47 g, 7.593 resulting mixture was heated at 100 ºC for 16h. The reaction mixture was diluted with 20 H2O and the organic layer was extracted with DCM, dried with MgSO4 anh., filtered and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica 25g; EtOAc in heptane 0/100 to 15/85). The desired fractions were collected and concentrated in vacuo to yield ethyl 2-(6-cyclobutyl-4-isopropyl-1- oxophthalazin-2(1H)-yl)acetate I-1097 (176 mg, 21%) as a yellow oil. 25

JAB7061WOPCT1 - 123 - Synthesis of 4-isopropyl-1-oxo-1,2-dihydrophthalazine-6-carbonitrile I-1069 5 tBuXPhos [564483-19-8] and Pd2(dba)3 [51364-51-3] were added to DMA while the solvent was deg nitrogen at 45ºC under nitrogen a under nitrogen at 45C. The mixture was stirred in a sealed tube at 120C for 16h. The 10 mixture was cooled down to rt, then was diluted with sat NaHCO3 and extracted with AcOEt. The organic layer was separated, washed with water, dried (MgSO4), filtered and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica 25g; AcOEt in heptane 0/100 to 70/30). The desired fractions were collected and concentrated in vacuo to yield 4-isopropyl-1-oxo-1,2-15 dihydrophthalazine-6-carbonitrile I-1069 (100 mg, 31%) as a white solid. Synthesis of ethyl 2-(6-(1,1-difluoroethyl)-4-isopropyl-1-oxophthalazin-2(1H)- yl)acetate I-1098 20 To a mixture of ethyl 2-(6-acetyl-4-isopropyl-1-oxophthalazin-2(1H)-yl)acetate I-1071 (0.3 g, 0.94 mmol) i DCM (8 l) di thl i lf tifl id 38078090 (1 L 25 1.22 g/mL, 7.5 0.989 g/mL, 2.8 days. The crude (dropwise). The crude was extracted with CH2Cl2 (2 x 5 ml), the organic layers were

JAB7061WOPCT1 - 124 - dried and evaporated in vacuo to afford an oil which was purified by column chromatography (SiO2, CH2Cl2). The desired fractions were concentrated to yield ethyl 2-(6-(1,1-difluoroethyl)-4-isopropyl-1-oxophthalazin-2(1H)-y l)acetate I-1098 (189 mg, yield 59%) as oil. 5 Synthesis of ethyl 2-(6-(2,2-difluorocyclopropyl)-4-isopropyl-1-oxophthalazin-2 (1H)- yl)acetate I-1099 10 Methyl fluorosulfonyldifluoroacetate [680-15-9] (099 mL 152 g/mL 784 mmol) was added to a st yl)acetate I-10 15 mmol) in prop 120h. After cooling to rt, the mixture was quenched water and extracted with heptane (3x). The organic layers were separated, combined, wash with saturated aq NaHCO3 and brine, dried (MgSO4), filtered and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica 25 g; EtOAc in heptane 20 0/100 to 40/60). The desired fractions were collected and concentrated in vacuo to yield ethyl 2-(6-(2,2-difluorocyclopropyl)-4-isopropyl-1-oxophthalazin-2 (1H)-yl)acetate I- 1099 (200 mg, 29%) as yellow oil. Synthesis of 2-(6-ethyl-4-isopropyl-1-oxophthalazin-2(1H)-yl)acetic acid I-1100 25 JAB7061WOPCT1 - 125 - To a mixture of 2-(6-bromo-4-isopropyl-1-oxophthalazin-2(1H)-yl)acetic acid (I-53) (250 mg, 0.7688 mmol) in THF (7 ml), triethylborane [97-94-9] (2.3 mL, 1 M, 2.306 mmol), Cs2CO3 [534-17-8] (751.5 mg, 2.31 mmol) and [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II) [72287-26-4] (56.65 mg, 0.077 5 mmol) were added, the mixture was bubbled with N2 for 10 min. The reaction was stirred at 95ºC for 16h. The crude was treated with water and acidified with HCl (2N to PH= 2-3), the organic layer was extracted with AcOEt (2 x 5 ml), the organic layers were dried and evaporated in vacuo to afford 2-(6-ethyl-4-isopropyl-1-oxophthalazin- 2(1H)-yl)acetic acid I-1100 (130 mg, yield 62%) as solid. 10 Synthesis of 2-(4-isopropyl-6-methoxy-1-oxo-phthalazin-2-yl)acetic acid (I-39) Lithium hydroxide [1310-65-2] (45 mg, 1.88 mmol) was added to a stirred solution of 15 ethyl 2-(4-isopropyl-6-methoxy-1-oxo-phthalazin-2-yl)acetate (I-21) (163 mg, 0.54 mmol) in THF (2 mL) and water (05 mL) Th mixt r tirrd t r m temperature for 2 h. The solvent was diluted with water and acidified with formed was filtered and dried under 20 methoxy-1-oxo-phthalazin-2-yl)acetic acid (I-39) (116 mg, 78%) as white solid, that was used in next step without further purification. Structural analogs were synthesized using the same procedure. Starting material Intermediate (I-22) (I-40) JAB7061WOPCT1 - 126 - (I-23) (I-41) I-1095 JAB7061WOPCT1 - 127 - I-1061 I-1107 JAB7061WOPCT1 - 128 - I-1110 I-1070 Synthesis o A 1N aque 5 solution of ey --romo--ey--oxo-p aazn--yaceae - mg, 0.59 mmol) in MeOH (3 mL). The mixture was stirred at 70ºC for 1.5 h. The mixture was acidified with 1N aqueous solutio f Hl ilH=1 dh d ih DCM. The organic layer was separa evaporated in vacuo to yield 2-(4-ethy 10 44) (150 mg, 82%) as white solid, purification. Note: this reaction can most of the time be performed at rt for 2 hours.

JAB7061WOPCT1 - 129 - Structural analogues were synthesized using the same procedure. Starting Material Intermediate (I-30) (I-46) JAB7061WOPCT1 - 130 - (I-29) (I-52) JAB7061WOPCT1 - 131 - (I-102) (I-57) JAB7061WOPCT1 - 132 - ^I-1080 _I-1116 JAB7061WOPCT1 - 133 - ( _I-127) ^(I-72) JAB7061WOPCT1 - 134 - I-1121 I-1097 Synthesis o 5 A 1M aqueous solution of NaOH [1310-73-2] (43 mL 43 mmol) was added dro wise to a stirred solut 2(1H)-yl)acetate stirred at rt for 10 [7647-01-0] to p over MgSO4, filtered and concentrated in vacuo. The crude solid was dissolved in 1,4- dioxane (20 mL) and a 6M aqueous solution of HCl [7647-01-0] (1.79 mL, 10.8 mmol) was added dropwise at 10 °C. After addition, the mixture was stirred at rt for 1 hour. It was extracted with EtOAc and the organic extracts dried over MgSO4, filtered and 15 concentrated in vacuo to give I-61 (652 mg, 96%) as a brown solid. Intermediate Product I ^-1075 _I-1051 JAB7061WOPCT1 - 135 - Synthesis of N-(2,3-dihydro-1H-inden-4-yl)pivalamide I-1122 5 Pivaloyl chlorid to a stirred sol in DCM (25 m 0ºC. Then the was extracted with DCM (x3). The organic layer was separated, dried over MgSO4 10 anh., filtered and concentrated in vacuo. The product was purified by flash column chromatography (silica; EtOAc in heptane 0/100 to 80/0) to yield N-(2,3-dihydro-1H- inden-4-yl)pivalamide I-1122 (3 g, 91%) as a white solid. Synthesis of N-(5-bromo-2,3-dihydro-1H-inden-4-yl)pivalamide I-1123 15 4-Methylbenzenesulfonic acid [104-15-4] (1.19 g, 6.9 mmol), palladium(II) acetate [3375-31-3] (155 m 069 mm l) nd NBS 128-08-5 (221 1242 mm l) r 20 added to a stirr 13.81 mmol) in added and the m dried over anh. g , tere an concentrate n vacuo. e pro uct was pur e by flash column chromatography (silica; EtOAc in heptane 0/100 to 80/0). The desired 25 fractions were collected and concentrated in vacuo to yield N-(5-bromo-2,3-dihydro- 1H-inden-4-yl)pivalamide I-1123 (4.7 g, 98%) as a white solid.

JAB7061WOPCT1 - 136 - Synthesis of 5-bromo-2,3-dihydro-1H-inden-4-amine I-1124 5 N-(5-bromo-2,3- dissolved in eth mL, 390.81 mm the reaction mix was cooled to rt and then basified with 2M aq. NaOH. The crude mixture was extracted 10 with dichloromethane and then the organic layer was dried over anh. MgSO4, filtered and concentrated in vacuo to yield 5-bromo-2,3-dihydro-1H-inden-4-amine I-1124 (1895 mg, 94%) as a brown oil. Synthesis of 5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-amine I-1125 15 5-bromo-2,3-dihydro-1H-inden-4-amine I-1124 (1895 mg, 7.15 mmol) was dissolved in dioxane (29 mL) nd thn t i m rbnt [584-08-7] (217 1573 mm l) in 20 water (5.7 mL mmol) were a Pd(dppf)Cl2·C mixture was he ate to or ours. e mxture was cooe to room temperature and it was extracted with AcOEt and water. The organic phase was separated, dried 25 over anh. MgSO4, filtered and concentrated in vacuo. The crude product was purified by flash column chromatography (silica; EtOAc in heptane 0/100 to 80/20) to yield 5-

JAB7061WOPCT1 - 137 - (2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-amine I-1125 (1650 mg, 95%) as a beige solid. Synthesis of 1-isopropyl-3-nitro-1H-pyrazole I-1086 5 Potassium Carbonate [584-08-7] (59.9 g, 433.34 mmol) and 2-iodopropane [75-30-9] (28 mL, 1.7 g/ mL, 279.46 mmol) were added to a solution of 3-nitro-1H-pyrazole [26621-44-3] ( 10 45ºC for 24h. acetonitrile (3 stirred for 30 m . and MTBE (2:8). The solvent was removed in vacuo at 45ºC and co-distilled with MTBE at 45ºC. The crude product was allowed to stand for 12h to yield solid crystals. 15 The crystals were dissolved with heptane (124 mL) and stirred for 1.5 h at RT and the mixture was filtered and washed with heptane, and dried 4.5 h to yield 1-isopropyl-3- nitro-1H-pyrazole I-1086 (20.2 g, 73%) as a white solid. Synthesis of 2-(4-(1-ethoxyvinyl)-1-oxo-6-(trifluoromethyl)phthalazin-2(1 H)-yl)-N-20 (pyrimidin-4-yl)acetamide I-79 A 1M aqueous solution of NaOH [1310-73-2] (2.33 mL, 2.33 mmol) was added to a solution of ethyl 2-(4-(1-ethoxyvinyl)-1-oxo-6-(trifluoromethyl)phthalazin-2(1 H)-25 yl)acetate (I-80) in MeOH (7.7 mL) and the reaction mixture was stirred at rt for 16 hours. The vol JAB7061WOPCT1 - 138 - ethoxyvinyl)-1-oxo-6-(trifluoromethyl)phthalazin-2(1H)-yl)ac etate (I-79) as a bronish solid that was used without further purification. Synthesis of 2-(4-(1-ethoxyvinyl)-1-oxo-6-(trifluoromethyl)phthalazin-2(1 H)-yl)-N-5 (pyrimidin-4-yl)acetamide I-78 Triethylamine [121-44-8] (486 μL, 3.47 mmol) was added to a stirred solution of 10 sodium 2-(4-(1- 79) (474 mg, 1.1 dry DMF (12.6 m solution of T3P the mixture was stirred at rt for 18h. It was diluted with a saturated aqueous solution of 15 NaHCO ₃ and extracted with EtOAc. The organic layer was separated, dried (MgSO ₄ ), filtered and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (DCM/MeOH 0 to 1%) to I-78 (56 mg, 11%) as a yellow solid. 20 Synthesis of 2-(4-acetyl-1-oxo-6-(trifluoromethyl)phthalazin-2(1H)-yl)-N- (pyrimidin- 4-yl)acetamide I-76 25 6M aqueous HCl [7647-01-0] (107 μL, 0.64 mmol) was added dropwise to a stirred solution of 2-(4-(1-ethoxyvinyl)-1-oxo-6-(trifluoromethyl)phthalazin-2(1 H)-yl)-N- (pyrimidin-4-yl i l i i º The mixture JAB7061WOPCT1 - 139 - NaHCO3 solution and extracted with EtOAc. The organic layer was separated, dried (MgSO ₄ ), filtered and the solvents evaporated in vacuo to yield I-76 (42 mg, 82%) as a white solid that was used without further purification. Intermediate Product I-1053 I-1076 5 Synthesis 77 10 A T3P solution [68957-94-8] (3.61 mL, 50%wt. in EtOAc, 6.05 mmol) was added to a stirred mixture of 2-(4-isopropyl-1-oxo-6-(trifluoromethyl)phthalazin-2(1H)-yl) acetic JAB7061WOPCT1 - 140 - acid (I-29) (950 mg, 3.02 mmol), 0.5M solution of NH3 in 1,4-dioxane [7664-41-7] (12 mL, 6.05 mmol) and triethylamine [121-44-8] (1.68 mL, 0.728 g/mL, 12.09 mmol) in 12 mL of anhydrous 1,4-dioxane. After 24 hour at rt, water and ethyl acetate were added. The organic layer was separated, washed with brine, dried (MgSO4), filtered 5 and evaporated under reduced pressure to afford I-77 (948 mg, 87%) as a white solid that was used without further purification. In general intermediates are labelled with the prefix “I-“ and final compounds are indicated as such and may have the prefix “X-”. 10 PREPARATION OF FINAL COMPOUNDS Example A1 Synthesis of 2-(6-bromo-4-ethyl-1-oxo-phthalazin-2-yl)-N-pyrimidin-4-yl-a cetamide (Final compound 2) 15 A 2M solution of isopropyl magnesium chloride in THF [1068-55-9] (0.325 mL, 0.65 mmol) was added to a stirred solution of ethyl 2-(6-bromo-4-ethyl-1-oxo-phthalazin-2- yl)acetate (I-28) (0.1 g, 0.29 mmol) and 4-aminopyrimidine [591-54-8] (31 mg 0.34 mmol) in anhydrous THF (4 mL 20 room temperature for 3 h. The mix EtOAc. The organic layer was s evaporated in vacuo. The crude product was purified by flash column chromatography (silica, MeOH in DCM 0/100 to 10/90). The desired fractions were collected and concentrated in vacuo to yield 2-(6-bromo-4-ethyl-1-oxo-phthalazin-2-yl)-N-pyrimidin-25 4-yl-acetamide (Final compound 2) (18 mg, 15%) as a white solid. Additional analogs were accessed using similar reaction conditions, using the appropriate reagent.

JAB7061WOPCT1 - 141 - Reagent Intermediate Final compound Number 4 [591-54- 8] (I-30) Example A Synthesis (trifluorom 5 [1,2,4]Triazolo[4,3-b]pyridazin-6-amine [19195-46-1] (42.6 mg, 0.32 mmol) was placed in a dry MW vial equipped with a magnetic stir bar and the setup placed under nitrogen (3 vacuum/nitrogen cycles). Anhydrous DMF (0.9 mL) was added and the solution cooled to 0 °C. After 10 minutes 10 THF, 0.56 mL, 0.56 mmol) was added drop °C for 15 minutes. Then, a solut (trifluoromethyl)phthalazin-2(1H)-yl)acetate (I-29) (80 mg, 0.23 mmol) in anhydrous THF (0.76 mL) was added dropwise at 0 °C. The resulting mixture was allowed to warm from 0 °C to rt over 1 hour while stirring vigorously and stirred at rt for 15 additional 3 hours. The mixture was concentrated in vacuo (down to 60 mbars, at 50 °C). The obtained glassy residue was purified by preparative HPLC (Stationary phase: RP XBridge Prep C18 OBD-10µm, 50x250mm, Mobile phase: 0.25% NH4HCO3 solution in water, CH3CN) to give X2 as a colorless solid (51 mg, 51%). Note: THF and toluene were used as solvent instead of DMF for the synthesis of some 20 examples, however, DMF is the solvent that generally gives better result with poorly soluble amines. Additional analogs were accessed using similar reaction conditions, using the appropriate reagent.

JAB7061WOPCT1 - 142 - Reagent Intermediate Final compound Number 5 [591-54-8] (I-32) [591-54 [591-54 [591-54 [19195- 1] [19195- 1 ^] JAB7061WOPCT1 - 143 - X3 [19195-46- 1 ^] _(I-88) [19195- 1 _] [6653-9 19195-4 [822-69 [1052 9 ^9-1 [19195- 1 ^] JAB7061WOPCT1 - 144 - X63 (I-199) (I-29) O N [700-00 (I-1 [19195- 1 ^] [30 7 ^3-2 (I-1 19195-4 JAB7061WOPCT1 - 145 - O H N N N N N [ N O N X-1003 F F 19195-46-1] I-1098 19195-4 [6653-9 19195-4 19195-4 19195-4 JAB7061WOPCT1 - 146 - [ X-1010 19195-46-1] I-1096 [ _6653-9 19195-4 Exampl Synthesi acetami 5 4-Aminopyrimidine [591-54-8] (28 mg, 0.29 mmol) was added to a stirred solution of 2-(4-isopropyl-6-methoxy-1-oxo-phthalazin-2-yl)acetic acid (I-39) (56 mg, 0.2 mmol), 1-propanephosphonic anhydride [68957-94-8] (0.3 mL, 0.47 mmol) and triethylamine [121-44-8] (0.1 mL, 0.72 mmol) in a 10 room temperature for 4 h. The mixtu Na2CO3 and extracted with DCM. filtered and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica, EtOAc in heptane 0/100 to 100/0). The desired fractions were collected and concentrated in vacuo to yield 2-(4-isopropyl-6-methoxy-

JAB7061WOPCT1 - 147 - 1-oxo-phthalazin-2-yl)-N-pyrimidin-4-yl-acetamide (Final compound 10) (45 mg, 63%) as white solid. Note: DCM and DMF can be used indiscriminately as solvent in this reaction. Additional analogs were accessed using similar reaction conditions, using the5 appropriate reagent. Reagent Intermediate Final compound Number 11 [591-54-8] (I-40) [591-54-8 [462-08-8 [765-30-0 [591-54-8 JAB7061WOPCT1 - 148 - O H N N OH F N O 17 [1363381- F ^58-1] _(I-50) [1363381 ^58-1] [1363381 ^58-1] [1363381 58-1] [1363381 58-1] [1363381 ^58-1] JAB7061WOPCT1 - 149 - 1 [1087448- (I-44) 58-5] I-1125 [1087448 ^58-5] [1087448 58-5] [591-54-8 [591-54-8 JAB7061WOPCT1 - 150 - 25 [1363381- 58-1] (I-52) [1087448 ^58-5] [1363381 58-1] [1087448 ^58-5] [1363381 58-1] [591-54-8 JAB7061WOPCT1 - 151 - 36 [1087448- 58-5] (I-53) [1363381 58-1] [591-54-8 I-1087 [591-54-8 JAB7061WOPCT1 - 152 - I-1129 [1523606- 23-6] I1101 [1087448 58-5] [20744-39 [591-54-8 [1087448 58-5] [1523606 23-6] JAB7061WOPCT1 - 153 - [1087448- X-1019 58-5] I-1114 [1523606 23-6] [13506-28 [1523606 23-6] [54732-89 [1087448 5 ^8-5] JAB7061WOPCT1 - 154 - (R) X9 [1020396- 26-2] (I-52) (R) (I-200) [1087448 58-5] [69825-84 [1523606 23-6] [1508379 00-7] JAB7061WOPCT1 - 155 - X-1022 [1523606- 2 ^3-6] _I-1103 [1082448- 58-5] [13506-28- [1087448 58-5] [1087448 58-5] [26530-93 JAB7061WOPCT1 - 156 - X26 [1087448- 5 ^8-5] _(I-58) [860258-0 5 ^] [20744-39 [235106-5 3] [1087448 5 ^8-5] [13506-28 JAB7061WOPCT1 - 157 - [1251924- X35 07-8] (I-52) Mixture of diastereom s [1523606 23-6] [31052-94 [1284220 4 ^9-0] (I-193) (RS) [1251923 84-8] JAB7061WOPCT1 - 158 - X43 [1087448- (RS) 58-5] (I-57) [27489-62 [177906-4 6] [26861-23 [591-54-8 (I-190) JAB7061WOPCT1 - 159 - X52 (I-162) (I-52) [154704-3 5] [421595-8 5] (RS) _. ^2HCl [2260932 3 ^6-1] ( ^RS _)- ^trans [1609406 69-0] [7169-94- JAB7061WOPCT1 - 160 - X58 [1087448- 58-5] (I-61) [1087448 58-5] _{. 2HCl} [MFCD28 2924] [1087448 58-5] (I-187) [1036260 4 ^3-1] JAB7061WOPCT1 - 161 - (RS) (RS) X68 [1251923- 84-8] (I-52) [1087448 58-5] [944900-1 0 ^] [573764-9 6] [1087448 58-5] . HCl cis/trans mixture [1803601 06-0] JAB7061WOPCT1 - 162 - X78 [177908-37- 1] (I-52) . HBr [1803596 49-7] [1523606 23-6] [1523606 23-6] _. ^{HCl ( (} _R ⁾ [68327-11 I-181 JAB7061WOPCT1 - 163 - (RS) .2HCl (RS) X89 [2260932- 3 ^6-1] _(I-52) [1396312 30-3] ( ^RS _)- ^trans [1609406 69-0] . HCl [1803591 03-8] [13506-28 . HCl [1205037 95-1] JAB7061WOPCT1 - 164 - . HCl (RS)-cis X95 (RS)-cis [2070860- (I-52) 49-8] (I-178) . HCl (R) (S) [2070860 49-8] Cis/tran mixture [1609546 13-5] (RS)- cis/trans mixture I-177 (I-173) JAB7061WOPCT1 - 165 - X102 [1087448- (RS) (RS) 58-5] (I-66) (RS) .2HCl [2260932 36-1] [1523606 23-6] Cis/tran mixture [1609546 13-5] (RS)- cis/trans mixture I-177 [591-54- JAB7061WOPCT1 - 166 - X113 [27799-83-3] (I-52) [74728-65 . HCl (RS)-cis [2070860 49-8] (I-169) [1251924 07-8] Mixture o diastereom s JAB7061WOPCT1 - 167 - X120 (I-167) (I-52) . HCl [1403766 64-2] Mixture o diastereom s . HCl Cis/tran mixture (I-163) [50593-30 . HCl ( ^RS _)- ^cis [2070860 49-8] JAB7061WOPCT1 - 168 - X125 [1087448- (RS) 58-5] (I-67) . HCl [1408076 03-8] [462651-8 5] (RS) [1785762 88-0] _. HCl (RS) [2126160 3 ^7-8] . HCl Cis/tran mixture (I-163) JAB7061WOPCT1 - 169 - (I-159) X132 (I-52) . HCl Cis/tran mixture (I-163) [1523606 23-6] [1087448 58-5] [1087448 58-5] (I-158) JAB7061WOPCT1 - 170 - . HCl X138 Cis/trans mixture (I-52) (I-165) [10394-38 [1087448 58-5] [1087448 58-5] [1523606 23-6] I-156 JAB7061WOPCT1 - 171 - . HCl Cis/trans X148 mixture [2102408- (I-52) 50-2] (RS)-trans [1609406 69-0] . HCl Cis/tran mixture (I-165) [13506-27 . HCl (RS) [2126160 37-8] JAB7061WOPCT1 - 172 - X155 [20744-39-2] (I-70) [637031-9 7] . HCl Cis/tran mixture [2102408 50-2] [1087448 58-5] . HCl Cis/tran mixture (I-165) (RS) [1251923 84-8] JAB7061WOPCT1 - 173 - . HCl X164 Cis/trans mixture (I-52) (I-165) [1214900 87-4] . HCl (RS) [2126160 37-8] [1215984 92-1] (I-146) [89852-83 JAB7061WOPCT1 - 174 - X170 [1087448- 58-5] (I-73) (I-145) (I-144) [50593-24 [591-54- [591-54-8 JAB7061WOPCT1 - 175 - X-1026 I-1087 [1523606- _23-6] [591-54-8] [1082448- 58-5] [1508379- 00-7] [54732-89- JAB7061WOPCT1 - 176 - I-1002 X-1032 I-1131 [74728-65- I-156 I-200 [13506-28- [1523606 23-6] JAB7061WOPCT1 - 177 - [591-54-8] X-1038 I-1107 [1523606- _23-6] [1082448- 58-5] [1523606- 23-6] [1523606- ^23-6] [1523606- 23-6] JAB7061WOPCT1 - 178 - [591-54-8] X-1044 I-1052 [1082448- 58-5] [1082448- 58-5] [1523606- 23-6] [1082448- 58-5] [1523606- 23-6] JAB7061WOPCT1 - 179 - [591-54-8] X-1050 I-1108 [1082448- 58-5] [20744-39- [1082448- 58-5] [1523606- 23-6] JAB7061WOPCT1 - 180 - [591-54-8] X-1056 I-1118 [1082448- 58-5] [1523606- 23-6] [591-54-8] [1523606- 23-6] [591-54-8] JAB7061WOPCT1 - 181 - I-1111 X-1062 [1523606- 23-6] [1082448- 58-5] [20744-39- [13506-28- [33630-96 [235106-5 3] JAB7061WOPCT1 - 182 - X-1068 [1523606- I-1112 23-6] [1082448- 58-5] [1523606- _23-6] [1082448- 58-5] ^[13506-28- [1082448- 58-5] JAB7061WOPCT1 - 183 - I-1120 [1082448- X-1074 58-5] [15931-21- [1082448- 58-5] [235106-53 3] [1820579 78-9] (R) (S) [1638759 8 ^3-7] JAB7061WOPCT1 - 184 - (I-150) [1392473- 3 ^2-3] _(I-52) (RS)-tran [1638772 2 _7-6] [87120-72 (RS)- cis/trans mixture [203503-3 4] [1082448 58-5] JAB7061WOPCT1 - 185 - Note: X12 & X43 were isolated by chiral SFC separation of X24; X41 was isolated by chiral SFC separation of X68;X55 and X106 were isolated by chiral SFC separation of X89; X56 and X149 were isolated by chiral SFC separation of X91; X124 and X115 were isolated by chiral SFC separation of X95; X122 and X130 were isolated by chiral 5 SFC separation of X133; X163 was isolated by chiral SFC separation of X68; X166 was isolated by chiral SFC separation of X152 Example A4 Synthesis of trans- 2-(6-methyl-4-ethyl-1-oxo-phthalazin-2-yl)-N-(4-10 hydroxycyclohexyl)acetamide (Final compound 26) 1-Hydroxybenzotriazole [123333-53-9] (84.9 mg, 0.72 mmol) was added to a stirred solution of 2-(6-bromo-4-ethyl-1- hhl i l i id 15 mmol) and trans-4-aminocyclo anhydrous DCM (5 mL). The m Then, 1-(3-dimethylaminopropyl (120 mg, 0.62 mmol) was added and the mixture was stirred at room temperature for 5 h. The mixture was diluted with water and extracted with DCM. The organic layer was 20 separated, dried (MgSO4), filtered and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica, MeOH in DCM 0/100 to 10/90). The desired fractions were collected and concentrated in vacuo to yield trans-2- (6-bromo-4-ethyl-1-oxo-phthalazin-2-yl)-N-(4-hydroxycyclohex yl)acetamide (Final compound 23) (29.2 mg, 15%) as a white solid. 25 Additional analogs were accessed using similar reaction conditions, using the appropriate reagent.

JAB7061WOPCT1 - 186 - Reagent Intermediate XX Final compound Number 26 [ ^27489-62-9] _(I-46) [ ^{27489-62-9 [27489-62-9 [27489-62-9 [27489-62-9} Example A5 Synthesis 5 isopropyl-1 JAB7061WOPCT1 - 187 - Sodium borohydride [16940-66-2] (4 mg, 0.1 mmol) was added to a stirred solution of 2-(4-acetyl-6-bromo-1-oxophthalazin-2(1H)-yl)-N-(1-isopropyl -1H-pyrazol-3- yl)acetamide X-1014 (45 mg, 0.1 mmol) in THF (3 mL) and water (1 mL) at 0ºC. The resulting mixture was stirred at rt for 30 min. NaHCO3 sat. aq. and EtOAc were added 5 and the organic layer was separated, dried over MgSO4 anh, filtered and the solvent was concentrated in vacuo. The crude was purified by flash column chromatography (silica, DCM/MeOH (9:1)/ DCM from 0/100 to 100/0). The desired fractions were collected and concentrated in vacuo. The product was triturated with DIPE to yield 2- (6-bromo-4-(1-hydroxyethyl)-1-oxophthalazin-2(1H)-yl)-N-(1-i sopropyl-1H-pyrazol-3-10 yl)acetamide X-1079 (34 mg, 74%) as a white solid. Structural analogues were synthesized using the same procedure. Intermediate Final compound Number X-1080 I-1129 I-1127 I-1130 I-1126 JAB7061WOPCT1 - 188 - X66 (RS) X58 O O H H X75 F ₃ C O I-75 I-76 Example A Synthesis 5 purin-2-yl) Pd/C (10%wt Pd, 14.8 mg, 0.014 mmol) was added to a stirred solution of N-(6-chloro- 9H-purin-2-yl)-2-(4-isopropyl-1-oxo-6-(trifluoromethyl)phtha lazin-2(1H)-yl)acetamide 10 X11 (57 mg, 012 mml) nd trithl min (20 L 015 mml) in THF (10 mL) t rt The reaction mixture stirred filtered over D in vacuo. The crude colorless solid obtained was further purified by preparative HPLC 15 (Stationary phase: RP XBridge Prep C18 OBD-10µm, 50x250mm, Mobile phase: 0.25% NH4HCO3 solution in water, CH3CN) followed by preparative SFC (Stationary phase: Chiralpak Daicel IG 20 x 250 mm, Mobile phase: CO ₂ , EtOH + 0.4 iPrNH ₂ ) to afford X1 as a colorless solid (5 mg, 9%). JAB7061WOPCT1 - 189 - Example A7 Synthesis of N-((3S,4R)-4-hydroxypiperidin-3-yl)-2-(4-isopropyl-1-oxo-6- (trifluoromethyl)phthalazin-2(1H)-yl)acetamide hydrochloride (I-136) 5 A 4M solution of HCl in 1,4-dioxane [7647-01-0] (7 mL, 28 mmol) was added to a suspension of tert-butyl (3S,4R)-4-hydroxy-3-(2-(4-isopropyl-1-oxo-6- (trifluoromethyl)phthalazin-2(1H)-yl)acetamido)piperidine-1- carboxylate (I-143) (936 mg, 1.826 mm10 was stirred at hydroxypiperid yl)acetamide (I-136) (880 mg, 98%) as a white powder that was used without further purification. Additional analogs were accessed using similar reaction conditions, using the 15 appropriate substrate. Substrate Product ( _I-142) ^(I-137) I-1132 JAB7061WOPCT1 - 190 - (I-150) (I-138) (RS)-trans mixture (I-152) (I-153) Synthesis of N-(4-hydroxypiperidin-3-yl) (trifluoromethyl)phthalazin-2(1H)-yl)ace 5 Pd/C (10%wt. Pd, 75 mg, 0.07 mmol) was added to a solution of I-151 (450 mg, 0.82 mmol) in EtOH (30 mL) under nitrogen. The reaction vessel was placed under hydrogen atmo over Celite und 10 40 °C. The cru and the filtate was concentrated under reduced pressure at 40 °C to afford I-139 (347 mg, 98%) as a white solid that was used without further purification.

JAB7061WOPCT1 - 191 - Synthesis of N-((3S,4R)-1-ethyl-4-hydroxypiperidin-3-yl)-2-(4-isopropyl-1 -oxo-6- (trifluoromethyl)phthalazin-2(1H)-yl)acetamide (Final compound X6) 5 Iodoethane [75-03-6] (0.1 mL, 1.244 mmol) was added to a suspension of N-((3S,4R)- 4-hydroxypipe yl)acetamide h 10 8] (0.6 mL, 4. was stirred ov purified by preparative HPLC. (Stationary phase: RP XBridge Prep C18 OBD-10µm, 50x250mm, Mobile phase: 0.25% NH4HCO3 solution in water, MeOH) to afford X6 (149 mg, 82%) as a white powder. 15 Additional analogs were accessed using similar reaction conditions, using the appropriate substrate. Substrate Final compound Cpd N° ( _S ⁾ X19 ( _R ⁾ (I-137) (RS)-tran (I-1 JAB7061WOPCT1 - 192 - (R) X117 (I-138) (RS)-cis/tra (I-1 (RS)-cis/tra (I-1 (I-1 (RS)-cis/tra (I-1 JAB7061WOPCT1 - 193 - X153 (RS)-trans mixture (I-1 (RS)-cis/tra (I-1 (I-1 I-11 JAB7061WOPCT1 - 194 - Example A8 Synthesis of N-((3S,4R)-1-cyclopropyl-4-hydroxypiperidin-3-yl)-2-(4-isopr opyl-1-oxo- 6-(trifluoromethyl)phthalazin-2(1H)-yl)acetamide (Final compound X15) 5 Sodium cyanoborohydride [25895-60-7] (30 mg 0.477 mmol) was addded to a suspension of [27374-25-0] ( 10 (1.5 mL) in a M °C. The crude mixture was purified by preparative HPLC (Stationary phase: RP XBridge Prep C18 OBD-10µm, 50x250mm, Mobile phase: 0.25% NH4HCO3 solution in water, MeOH) to afford X15 (68 mg, 71%) as a white powder. 15 Additional analogs were accessed using similar reaction conditions, using the appropriate substrate. Substrate Final compound Cpd N° (R) X45 (S) (I-137) I-11 JAB7061WOPCT1 - 195 - Example A9 Synthesis of N-((3S,4R)-1-cyclopropyl-4-hydroxy-1-((R*)-3-hydroxybutyl)pi peridin-3- yl)-2-(4-isopropyl-1-oxo-6-(trifluoromethyl)phthalazin-2(1H) -yl)acetamide, N- ((3S,4R)-4-hydroxy-1-((S*)-3-hydroxybutyl)piperidinhydroxypi peridin-3-yl)-2-(4- 5 isopropyl-1-oxo-6-(trifluoromethyl)phthalazin-2(1H)-yl)aceta mide (Final compounds X70, X81 and X83 ) 10 Sodium cyanob suspension of (I 99-0] (50 mg, 0 reaction mixture preparative HPL , , 15 Mobile phase: 0.25% NH4HCO3 solution in water, MeOH) to afford X70 (8 mg, 9%) as an off-white solid, X81 (11 mg, 12%) as an off-white solid and X83 (46 mg, 48%) as a colorless solid. Additional analogs were accessed using similar reaction conditions, using the appropriate reagent. Reagent Intermediate XX Final compound Number (R) (S ) (R) (S) X104 [6704-31-0] (I-136) 20 JAB7061WOPCT1 - 196 - Example A10 Synthesis of N-([1,2,4]triazolo[4,3-a]pyrazin-6-yl)-2-(4-isopropyl-1-oxo- 6- (trifluoromethyl)phthalazin-2(1H)-yl)acetamide (X14) 5 TCFH [207915-99-9] (268 mg, 0.95 mmol) was added to a solution of (I-52) (150 mg, 0.48 mmol), [1,2,4]triazolo[4,3-a]pyrazin-6-amine [2111465-25-7] (97 mg, 0.72 mmol) and 1-methylimidazole [616-47-7] (019 mL 103 g/mL 239 mmol) in dry MeCN (37 mL). The rea purified by pr10 50x250mm, M (101 mg, 49%) as a pale tan solid. Additional analogs were accessed using similar reaction conditions, using the appropriate reagent. Reagent Intermediate XX Final compound Number . HCl X42 [56239-26-0] (I-29) [1122-47-0 [187973-60 0] JAB7061WOPCT1 - 197 - X161 [935777-24- 5 ^] _(I-29) [1706450- 11-4] [1159814- 07-9] [2111465- 25-7] [2111465- 25-7] [2111465- ^25-7] JAB7061WOPCT1 - 198 - Example A11 Synthesis of 2-(4-isopropyl-1-oxo-6-(trifluoromethyl)phthalazin-2(1H)-yl) -N-(2- (trifluoromethyl)imidazo[1,2-a]pyridin-6-yl)acetamide (X64 ) 5 1-chloro-N,N,2-trimethyl-1-propenylamine [26189-59-3] (104 µL, 0.78 mmol) was added to a mixture of carboxylic acid (I-29) (80 mg, 0.25 mmol) in dioxane (2 mL) in a dry vial under nitrogen The mixture was stirred at rt for 1 hour 2- (Trifluoromet was then adde10 mmol). The product was extracted with EtOAc (3 x 5 ml) the combined organic layers were dried, filtered and evaporated in vacuo. A purification was performed via preparative HPLC (Stationary phase: RP XBridge Prep C18 OBD-10µm, 50x250mm, Mobile phase: 0.25% NH ₄ HCO ₃ solution in water, CH ₃ CN).to amide X64 (46 mg, 36%) as a dark 15 green solid. Additional analogs were accessed using similar reaction conditions, using the appropriate reagent. Amine Substrate Final compound Number X87 [889943-49- 1 ^] _(I-29) [672-41-3] JAB7061WOPCT1 - 199 - Example A12 Synthesis of 2-(4-isopropyl-1-oxo-6-(trifluoromethyl)phthalazin-2(1H)-yl) -N-(8- methyl-[1,2,4]triazolo[4,3-a]pyridin-6-yl)acetamide (X28) 5 N-(8-Bromo-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-2-(4-isopropy l-1-oxo-6- (trifluoromethyl)phthalazin-2(1H)-yl)acetamide X52 (50 mg, 0.1 mmol, 1 equiv) and bis(tri-tert-butylphosphine)palladium(0) [53199-31-8] (20 mg 0039 mmol 40 mol%) were placed in a vacuum/nitrogen 10 was added, the MeZnCl [5158-46-3] (2 M in THF, 147 µL, 0.29 mmol, 3 equiv) was added dropwise over 2 min. The resulting solution was stirred vigorously at rt for 18 hours. The crude mixture was quenched by addition of 0.2M aqueous HCl (ca.5 mL) and extracted with EtOAc (4 x 5 mL). The combined organic layers were dried over Na ₂ SO ₄ , filtered and 15 concentrated in vacuo. The obtained residue was purified by preparative HPLC (Stationary phase: RP XBridge Prep C18 OBD-10µm, 50x250mm, Mobile phase: 0.25% NH4HCO3 solution in water, CH3CN) to give X28 (20 mg, 46%) as a colorless solid. Example A13 20 Synthesis of N-(8-cyano-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-2-(4-isopropy l-1-oxo-6- (trifluoromethyl)phthalazin-2(1H)-yl)acetamide (X72) tBuXPhos Pd G3 [1447963-75-8] (15.2 mg, 19 µmol), Zn(CN)2 [557-21-1] (27 mg, 0.23 mmol) and N-(8-bromo-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-2-(4-isopropy l-1-oxo- 25 6-(trifluoromethyl)phthalazin-2(1H)-yl)acetamide X52 (65 mg, 0.13 mmol) were placed in a dry MW vial. The vial was sealed and placed under nitrogen (3 vacuum/nitroge added. The vi JAB7061WOPCT1 - 200 - sonicated until a fine suspension was observed and it was heated at 60 °C for further 24 hours. The mixture was partitioned between DI water (10 mL) and DCM (10 mL). The organic layer was collected and the aqueous re-extracted with DCM (2 x 10 mL) then 5 DCM/MeOH 95:5 (4 x 10 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The obtained residue was further purified by preparative HPLC (Stationary phase: RP XBridge Prep C18 OBD- 5µm, 50x250mm, Mobile phase: 0.25% NH4HCO3 solution in water, CH3CN) followed by preparative SFC (Stationary phase: Chiralpak Daicel ID 20 x 250 mm, Mobile phase: CO ₂ , EtOH 10 + 0.4 iPrNH2) to give X72 (9 mg, 15%) as a pale tan solid. Additional analogs were accessed using similar reaction conditions, using the appropriate reagent. Intermediate XX Final compound Number X162 X132 Example A14 15 Synthesis of 2-(4-isopropyl-1-oxo-6-(tri 3-methoxy-3-methylcyclobutyl)acetamid N-((1s,3s)-3-Hydroxy-3-methylcyclobutyl)-2-(4-isopropyl-1-ox o-6- (trifluoromethyl)phthalazin-2(1H)-yl)acetamide X25 (108 mg, 0.27 mmol, 1 equiv) was 20 placed in a 20-mL vial and dissolved in anhydrous DCM (10.4 mL). The solution was cooled to 0 °C in an ice-bath and placed under nitrogen. After 10 min at 0 °C, 2,6-di- tert-butyl-4-me trimethyloxoni added sequent JAB7061WOPCT1 - 201 - stirred at 0 °C for 5 min then allowed to warm to rt and stirred for 2 hours. The mixture was then quenched by addition of a saturated aqueous solution of NaHCO3 (ca.5 mL) and extracted with DCM (2 x 8 mL). The combined organic extracts were concentrated and purified by FCC (Hept/EtOAc 4:1 to 0:1) to afford the title amide X29 (74 mg,5 66%)as a colorless solid. Additional analogs were accessed using similar reaction conditions, using the appropriate reagent. Intermediate XX Final compound Number X105 X94 X67 X42 X44 JAB7061WOPCT1 - 202 - Example A15 Synthesis of 2-(4-isopropyl-1-oxo-6-(trifluoromethyl)phthalazin-2(1H)-yl) -N-(3- methyl-3H-imidazo[4,5-b]pyridin-5-yl)acetamide (X47 ) 5 2-(4-Isopropyl-1-oxo-6-(trifluoromethyl)phthalazin-2(1H)-yl) acetamide (I-77) (20 mg, 0.119 mmol), 5-chloro-3-methyl-3H-imidazo[4,5-b]pyridine (I-135) (50 mg, 0.16 mmol), K2CO3 (36 mg 026 mmol) CuI (12 mg 00063 mmol) and trans-NN'- dimethylcyclohe 2 mL of anhyd 10 degassed 5 min 18 h. The mixture was filtered over PTFE filter and washed with MeOHand purified by preparative HPLC (Stationary phase: RP XBridge Prep C18 OBD-10µm, 50x250mm, Mobile phase: 0.25% NH4HCO3 solution in water, MeOH) to afford X47 (9 mg, 17%) as white solid. 15 Additional analogs were accessed using similar reaction conditions, using the appropriate reagent. Halide Amide substrate Final compound Number X48 [1379355- 1 ^9-7] _I-77 (I-134) JAB7061WOPCT1 - 203 - Example A16 Synthesis of 2-(4-isopropyl-1-oxo-6-(trifluoromethyl)phthalazin-2(1H)-yl) -N-(2- (trifluoromethyl)imidazo[1,2-a]pyridin-6-yl)acetamide (X109 ) 5 A mixture of carboxylic acid (I-29) (100 mg, 0.32 mmol) and 1-methyl-1H- pyrazolo[3,4-b]pyridin-6-amine (I-131) (88.1 mg, 0.48 mmol) in dry pyridine [110-86- 1] (8 ml) under nitrogenwas sonicated for 10 min and then stirred for 40 min at rt A 1M solution of added dropwise 10 ºC for 30 hour with 1M aqueous HCl until pH <7. The crude product was extracted with AcOEt and the combined organic layers were dried over MgSO ₄ , filtered and evaporated in vacuo. This crude compound was recristallized from 15 mL of hot acetonitrile to yield X109 (90 mg, 64%) as a colorless solid. 15 Example A17 Synthesis of tert-butyl (3S,4R)-3-(2-(6-bromo-4-isopropyl-1-oxophthalazin-2(1H)- yl)acetamido)-4-hydroxypiperidine-1-carboxylate I-1132 20 HATU [148893- bromo-4-isoprop in DMF (3.5 m hydroxypiperidin 25 [7087-68-5] (2.6 h. Water is adde JAB7061WOPCT1 - 204 - solid is filtered and washed with water. The solid is dried in the oven at 50°C overnight to obtain tert-butyl (3S,4R)-3-(2-(6-bromo-4-isopropyl-1-oxophthalazin-2(1H)- yl)acetamido)-4-hydroxypiperidine-1-carboxylate I-1132 (570 mg, yield 67%) as a white solid. 5 Reagent Intermediate Final cpd Number X-1089 Synthesis hydroxycy 10 To a mixture butyldimethyl15 in DCM (5 m rt. The mixtur sat. Na2CO3 , extracted with DCM, the organic layer was separated, and the aqueous phase was further extracted with additional DCM (2x). The combined organic layers were dried 20 (Na2SO4), filtered and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (Silica MeOH in DCM 0/100 to 3/97). The desired fractions were collected, the solvent evaporated in vacuo to yield 2-(6-bromo-4-

JAB7061WOPCT1 - 205 - isopropyl-1-oxophthalazin-2(1H)-yl)-N-((1r,3s)-3-ethyl-3- hydroxycyclobutyl)acetamide X-1090 (57 mg, yield 60%) as white solid. Characterising Data – LC-MS and melting point + 5 LCMS: [M+H] means the protonated mass of the free base of the compound, Rt means retention time (in minutes), method refers to the method used for LCMS. LCMS F ^{inal Cpd} _{M.p. ºC (Method) [M+H]} + R _t Method 2 _{265.1 (A) 388 2.90 1} 4 _{246.6 (A) 324 2.64 1} 5 _{193.2 (A) 350 2.96 1} 6 179.7 (A) 352 3.18 1 7 ₁ 9 ₂ 1 ⁰ ₁ 1 ^{1 12} ₂ 1 ^{3 14} ₂ 1 ⁶ ₂ 1 ⁷ ₂ 1 ⁸ ₂ 1 ⁹ ₂ 2 ⁰ ₁ 2 ¹ ₁ 2 ² ₁ 2 ⁴ ₂ 2 ⁶ ₂ 2 ⁷ ₂ 2 ⁸ ₁ 2 ⁹ ₁ 3 ⁰ 2 X1 X ² 246. 258.2 JAB7061WOPCT1 - 206 - X3 NA 450 1.86 3 X4 236.7 (A) 396 2.84 1 X5 276.97 (B) 460 1.81 3 X6 1 X8 X9 X10 1 X11 X12 X13 X14 X15 2 ^X16 _238. 251.1 X17 X18 X19 X20 X21 X22 JAB7061WOPCT1 - 207 - X23 294.49 429 1.67 4 X24 247.79 (B) 445 2.02 4 X25 228.24 (B) 444 1.85 4 X26 X27 2 X28 2 X29 1 X30 2 X31 2 X32 X33 2 X34 2 X35 2 X36 2 X37 X38 2 X39 X40 2 X41 JAB7061WOPCT1 - 208 - X42 N.D. 412 1.78 4 X43 - 445 1.81 3 X44 235.29 (B) 412 1.80 4 X45 2 X46 1 X47 X48 X49 2 X50 2 X51 2 X52 X53 2 X54 188.06 X55 2 X56 2 X57 2 X58 X59 JAB7061WOPCT1 - 209 - X60 - 437 1.94 4 X61 >300 (A) 487 2.74 1 X62 241.74 & 36278 (B) 466 183 3 X63 2 X64 X66 X67 X68 2 X69 2 X70 X71 2 X72 X73 2 X74 X75 2 X76 3 JAB7061WOPCT1 - 210 - X77 163.33 (B) 436 2.09 4 X78 178.70 (B) 426 0.96 8 X79 - 444 197 4 X80 X81 X82 2 X83 X84 1 X85 1 X86 1 X87 2 X88 2 X89 X90 X91 X92 JAB7061WOPCT1 - 211 - X93 247.78 (B) 420 1.70 4 X-1027 193.2 (A) 364 2.80 1 X-1028 2 X-1029 X-1088 X-1031 X-1080 2 X-1081 2 X-1046 2 X-1048 1 X-1049 1 JAB7061WOPCT1 - 212 - X-1050 158.1 (A) 380 3.73 1 X-1082 >300 (A) 443 2.08 1 X-1054 1 X-1090 X-1018 1 X-1017 2 X-1016 2 X-1062 1 X-1063 2 X-1051 2 X-1030 2 JAB7061WOPCT1 - 213 - X-1032 169.86 (B) 435 1.93 4 X-1033 177.71 & 233.44 (B) 454 2.00 3 X-1022 2 X-1023 X-1070 2 X-1002 2 X-1003 2 X-1064 1 X-1071 X-1004 X-1019 JAB7061WOPCT1 - 214 - X-1001 285.2 (A) 440 2.82 1 X-1000 >300 (A) 452 2.81 1 X-1035 185.61 X-1020 2 X-1024 2 X-1036 237.49 X-1083 141.19 X-1021 2 X-1084 2 X-1065 2 X-1073 JAB7061WOPCT1 - 215 - X-1006 237.41 (B) 427 1.81 4 X-1007 - 422 1.70 4 X-1075 X-1074 X-1066 1 X-1008 2 X-1067 2 X-1009 2 X-1085 145.85 X-1086 2 X-1012 2 JAB7061WOPCT1 - 216 - X-1010 235.83 (B) 424 1.74 4 X-1011 239.24 (B) 423 1.85 4 X-1076 1 X-1077 1 X-1087 2 Characterising Data – 5 This is depicted in the fo Compound NMR 1 H NM Final Cpd 1 J=7.4 Hz, 2 H) 5.04 (s, 2 H) 6.97 (dd, J=9.8, 1.9 Hz, 1 H) 7.71 (br d, J=9.9 Hz, 1 H) 7.94 (dd, J=8.5, 1.8 Hz, 1 H) 8.01 (t, J=1.9 Hz, 1 H) 8.37 (dd, J=8.4, 1.9 Hz, 1 H) 8.75 (br s, 1 H) 9.15 (br s, 1 H) 9.20 (s, 1 H) 1 H NMR (400 MHz, CDCl3) δ ppm 1.38 (t, J=7.4 Hz, 3 H) 2.99 (q, Final Cpd 2 J=7.4 Hz, 2 H) 5.05 (s, 2 H) 7.91 (dd, J=8.5, 1.8 Hz, 1 H) 7.99 (d, J=17 H 1 H 814 dd J=5710 H 1 H 837d J=85 H 1 H Final Cpd JAB7061WOPCT1 - 217 - 1 H NMR (400 MHz, CDCl ₃ ) δ ppm 1.38 (t, J=7.4 Hz, 3 H) 2.58 (s, 3 Final Cpd 4 H) 3.01 (q, J=7.4 Hz, 2 H) 5.06 (s, 2 H) 7.56 - 7.67 (m, 2 H) 8.15 (dd, J=5.7, 1.2 Hz, 1 H) 8.40 (d, J=8.7 Hz, 1 H) 8.61 (d, J=5.8 Hz, 1 H) 8.84 (d, J=1.0 Hz, 1 H) 9.04 (br s, 1 H) 1H NMR (300 MHz, CDCl3) δ ppm 0.80 - 0.93 (m, 2 H) 1.10 - 1.22 (m, 2 H) 1.38 (t, J=7.4 Hz, 3 H) 2.06 - 2.18 (m, 1 H) 3.00 (q, J=7.4 Final Cpd 5 Hz, 2 H) 5.05 (s, 2 H) 7.42 (br d, J=8.4 Hz, 1 H) 7.51 (s, 1 H) 8.15 Final Cpd Final Cpd Final Cpd Final Cpd Final Cpd Final Cpd Final Cpd JAB7061WOPCT1 - 218 - 1 H NMR (400 MHz, CDCl ₃ ) δ ppm 1.38 (t, J=7.4 Hz, 3 H) 3.03 (q, J=7.4 Hz, 2 H) 5.07 (s, 2 H) 7.19 (dd, J=8.3, 4.8 Hz, 1 H) 7.77 - Final Cpd 13 7.84 (m, 1 H) 7.84 - 7.90 (m, 2 H) 8.07 - 8.12 (m, 1 H) 8.29 (dd, J=4.8, 1.4 Hz, 1 H) 8.51 (dt, J=7.8, 1.0 Hz, 1 H) 8.57 (d, J=2.2 Hz, 1 H) 9.11 (br s, 1 H) 1 H NMR (400 MHz, DMSO-d6) δ ppm 0.36 - 0.49 (m, 2 H) 0.55 - 0.68 (m, 2 H) 1.25 (t, J=7.5 Hz, 3 H) 2.64 (tq, J=7.4, 3.9 Hz, 1 H) Final Cpd 14 Final Cpd Final Cpd Final Cpd Final Cpd Final Cpd Final Cpd Final Cpd JAB7061WOPCT1 - 219 - 1 H NMR (400 MHz, CDCl ₃ ) δ ppm 1.38 – 1.31 (m, 9 H) 2.05 – 1.99 Final Cpd 22 (m, 2 H) 2.54 – 2.45 (m, 2 H) 2.91 – 2.80 (m, 2 H) 3.05 – 2.95 (m, 2 H) 3.99 (dd, J=15.8, 7.9 Hz, 1 H) 4.84 (s, 2 H) 6.51 (d, J=5.7 Hz, 1 H) 7.63 (d, J=10.3 Hz, 2 H) 8.38 (d, J=8.1 Hz, 1 H) 1H NMR (400 MHz, DMSO-d6) δ ppm 0.87 - 0.95 (m, 2 H) 1.08 - Final Cpd 23 1.18 (m, 2 H) 1.26 (d, J=6.6 Hz, 6 H) 2.16 - 2.28 (m, 1 H) 3.64 (spt, J=6.8 Hz, 1 H) 5.00 (s, 2 H) 7.52 (dd, J=8.4, 1.8 Hz, 1 H) 7.76 (d, Final Cpd Final Cpd Final Cpd Final Cpd Final Cpd Final Cpd JAB7061WOPCT1 - 220 - 1 H NMR (400 MHz, CDCl ₃ ) δ ppm 1.14 - 1.28 (m, 2 H) 1.32 - 1.45 (m, 2 H) 1.38 (t, J=7.4 Hz, 3 H) 1.90 - 2.07 (m, 4 H) 3.04 (q, J=7.4 Final Cpd 30 Hz, 2 H) 3.53 - 3.65 (m, 1 H) 3.78 (tdt, J=11.4, 11.4, 7.6, 4.0, 4.0 Hz, 1 H) 4.84 (s, 2 H) 5.97 (br d, J=6.6 Hz, 1 H) 7.99 (dd, J=8.3, 1.3 Hz, 1 H) 8.08 (br s, 1 H) 8.60 (d, J=8.4 Hz, 1 H); 1H exchanged 1 H NMR (400 MHz, DMSO-d6) δ ppm 0.86 - 0.98 (m, 2 H) 1.08 - 1.19 (m, 2 H) 1.27 (d, J=6.8 Hz, 6 H) 2.18 - 2.28 (m, 1 H) 3.65 (spt, Final Cpd Final Cpd Final Cpd Final Cpd Final Cpd Final Cpd Final Cpd JAB7061WOPCT1 - 221 - 1 H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.25 (d, J=6.7 Hz, 6 H) 3.64 Final Cpd 38 (spt, J=6.7 Hz, 1 H) 4.97 - 5.14 (m, 2 H) 7.98 (dd, J=5.9, 1.3 Hz, 1 H) 8.06 (dd, J=8.5, 1.8 Hz, 1 H) 8.21 (d, J=8.5 Hz, 1 H) 8.32 (d, J=1.9 Hz, 1 H) 8.66 (d, J=5.7 Hz, 1 H) 8.91 - 8.93 (m, 1 H) 11.32 (s, 1 H) 1 H NMR (400 MHz, DMSO-d6) δ ppm 1.29 (d, J=6.7 Hz, 6 H) 3.77 Final Cpd X2 (spt, J=6.7 Hz, 1 H) 5.10 (s, 2 H) 7.92 (br d, J=10.0 Hz, 1 H) 8.22 Final Cpd Final Cpd Final Cpd Final Cpd Final Cpd Final Cpd JAB7061WOPCT1 - 222 - 1 H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.21 - 0.27 (m, 2 H) 0.37 (br d, J=6.4 Hz, 2 H) 1.22 (br s, 1 H) 1.26 (d, J=6.6 Hz, 6 H) 1.32 - 1.47 Final Cpd X10 (m, 1 H) 1.56 - 1.60 (m, 1 H) 1.60 - 1.65 (m, 1 H) 1.65 - 1.73 (m, 1 H) 2.04 (br t, J=9.8 Hz, 1 H) 2.17 (br t, J=9.5 Hz, 1 H) 2.69 (br d, J=10.6 Hz, 1 H) 2.79 - 2.93 (m, 1 H) 3.58 - 3.69 (m, 1 H) 3.69 - 3.76 (m, 1 H) 4.72 (s, 2 H) 7.90 (br d, J=7.7 Hz, 1 H) 8.19 (d, J=8.4 Hz, 1 H) 8.38 (s, 1 H) 8.50 (d, J=8.4 Hz, 1 H) Final Cpd Final Cpd Final Cpd Final Cpd Final Cpd Final Cpd Final Cpd Final Cpd JAB7061WOPCT1 - 223 - 1 H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.27 - 1.32 (m, 6 H) 3.77 (dt, Final Cpd X20 J=13.4, 6.7 Hz, 1 H) 5.00 (s, 2 H) 6.74 (dd, J=9.7, 1.7 Hz, 1 H) 7.31 (s, 1 H) 7.55 (d, J=9.6 Hz, 1 H) 8.21 (dd, J=8.4, 1.6 Hz, 1 H) 8.34 (s, 1 H) 8.42 (s, 1 H) 8.52 (d, J=8.1 Hz, 1 H) 8.98 (s, 1 H) 10.29 - 10.35 (m, 1 H) 1 H NMR (400 MHz, DMSO-d6) ppm 1.28 (d, J=6.6 Hz, 6 H) 3.77 Final Cpd X21 (spt, J=6.6 Hz, 1 H) 5.13 (s, 2 H) 8.22 (dd, J=8.4, 1.1 Hz, 1 H) 8.42 Final Cpd Final Cpd Final Cpd Final Cpd Final Cpd Final Cpd Final Cpd JAB7061WOPCT1 - 224 - 1H NMR (400 MHz, CDCl3) δ ppm 1.29 (s, 3 H) 1.38 (d, J=6.8 Hz, 6 H) 1.87 - 1.94 (m, 2 H) 2.35 - 2.43 (m, 2 H) 3.12 (s, 3 H) 3.52 Final Cpd X29 (spt, J=6.8 Hz, 1 H) 4.14 (sxt, J=8.0 Hz, 1 H) 4.86 (s, 2 H) 6.28 (br d, J=7.0 Hz, 1 H) 7.99 (dd, J=8.4, 1.1 Hz, 1 H) 8.14 (s, 1 H) 8.63 (d, J=8.4 Hz, 1 H) 19 F NMR (377 MHz, CDCl ₃ ) δ ppm -63.00 (s, 3 F) 1 H NMR (400 MHz, CDCl3) δ ppm 1.41 (t, J=7.4 Hz, 3H) 3.08 (q, Final Cpd X30 J=74 H 2H 511 2H 804 dd J=9661 H 2H 813 1H Final Cpd Final Cpd Final Cpd Final Cpd Final Cpd Final Cpd Final Cpd JAB7061WOPCT1 - 225 - 1 H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.26 - 1.33 (m, 6 H) 3.71 - Final Cpd X38 3.84 (m, 1 H) 5.01 - 5.09 (m, 2 H) 7.64 (dd, J=9.5, 2.0 Hz, 1 H) 7.87 (dd, J=9.6, 0.8 Hz, 1 H) 8.22 (d, J=8.5 Hz, 1 H) 8.41 - 8.49 (m, 2 H) 8.53 (dt, J=8.4, 0.9 Hz, 1 H) 9.36 - 9.41 (m, 1 H) 10.68 - 10.78 (m, 1 H) 1 H NMR (400 MHz, CDCl3) δ ppm 1.36 - 1.43 (m, 6 H) 3.55 (quin, Final Cpd X39 J=6.8 Hz, 1 H) 5.04 - 5.15 (m, 2 H) 6.21 (s, 1 H) 6.62 (t, J=54.9 Hz, Final Cpd Final Cpd Final Cpd Final Cpd Final Cpd Final Cpd Final Cpd JAB7061WOPCT1 - 226 - 1 H NMR (400 MHz, CDCl ₃ ) δ ppm 1.42 (d, J=6.8 Hz, 6 H) 2.53 (br Final Cpd X48 s, 3 H) 3.56 (dt, J=13.6, 6.7 Hz, 1 H) 5.09 (s, 2 H) 6.59 (br d, J=6.4 Hz, 1 H) 7.01 - 7.24 (m, 1 H) 7.43 (br d, J=7.3 Hz, 1 H) 7.76 (br s, 1 H) 8.01 (d, J=8.1 Hz, 1 H) 8.16 (s, 1 H) 8.65 (br d, J=8.1 Hz, 1 H) 9.11 (br s, 1 H) 1 H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.29 (d, J=6.6 Hz, 6 H) 3.77 Final Cpd X49 (dt, J=13.4, 6.6 Hz, 1 H) 4.20 (s, 3 H) 5.04 (s, 2 H) 7.30 - 7.41 (m, 1 Final Cpd Final Cpd Final Cpd Final Cpd Final Cpd Final Cpd Final Cpd JAB7061WOPCT1 - 227 - 1H NMR (400 MHz, DMSO-d6) δ ppm 1.25 - 1.33 (m, 6 H), 2.41 - Final Cpd X57 2.47 (m, 3 H), 3.77 (quin, J=6.7 Hz, 1 H), 4.99 - 5.05 (m, 2 H), 7.57 (dd, J=9.5, 2.0 Hz, 1 H), 7.72 (dd, J=9.5, 0.9 Hz, 1 H), 8.22 (dd, J=8.4, 1.6 Hz, 1 H), 8.41 - 8.43 (m, 1 H), 8.52 (d, J=8.3 Hz, 1 H), 9.26 (dd, J=2.1, 0.9 Hz, 1 H), 10.63 - 10.67 (m, 1 H) 1H NMR (400 MHz, DMSO-d6) δ ppm 2.63 (s, 3 H) 5.18 (s, 2 H) Final Cpd X58 7.33 (dd, J=9.8, 1.8 Hz, 1 H) 7.81 (d, J=9.8 Hz, 1 H) 8.26 (dd, J=8513 H 1 H 852 d J=84 H 1 H 915 1 H 920 1 Final Cpd Final Cpd Final Cpd Final Cpd Final Cpd Final Cpd Final Cpd JAB7061WOPCT1 - 228 - 1H NMR (400 MHz, DMSO-d6) δ ppm 1.26 (d, J=6.5 Hz, 6 H) 1.70 Final Cpd X67 - 1.80 (m, 2 H) 2.44 - 2.49 (m, 2 H) 3.64 - 3.82 (m, 3 H) 4.68 (s, 2 H) 5.07 (d, J=5.3 Hz, 1 H) 8.19 (dd, J=8.4, 1.4 Hz, 1 H) 8.24 (d, J=7.3 Hz, 1 H) 8.38 (s, 1 H) 8.49 (d, J=8.2 Hz, 1 H) 19 F NMR (377 MHz, DMSO-d ₆ ) δ ppm -61.30 (s, 3 F) 1H NMR (400 MHz, CDCl ₃ ) δ ppm 1.38 (d, J=6.6 Hz, 6 H) 1.92 (dtd, J=13.6, 8.1, 2.8 Hz, 1 H) 2.14 - 2.24 (m, 1 H) 2.30 (s, 3 H) Final Cpd X68 298 (dd J=7957 Hz 2 H) 350 (spt J=68 Hz 1 H) 381 (dd Final Cpd Final Cpd Final Cpd Final Cpd Final Cpd Final Cpd JAB7061WOPCT1 - 229 - 1 H NMR (400 MHz, CDCl ₃ ) δ ppm 1.36 (s, 3 H) 1.67 (d, J=6.5 Hz, Final Cpd X75 3 H) 1.99 (s, 1 H) 2.04 (dd, J=8.5, 3.0 Hz, 2 H) 2.49 - 2.56 (m, 2 H) 2.90 (d, J=6.9 Hz, 1 H) 4.01 (h, J=7.9 Hz, 1 H) 4.85 (s, 2 H) 5.30 (p, J=6.6 Hz, 1 H) 6.33 (d, J=6.6 Hz, 1 H) 8.01 (d, J=8.4 Hz, 1 H) 8.33 (s, 1 H) 8.61 (d, J=8.4 Hz, 1 H) 1 H NMR (400 MHz, DMSO-d ₆ ) δ ppm 2.70 - 2.83 (m, 2 H), 3.32 - Final Cpd X76 3.42 (m, 2 H), 5.04 (s, 2 H), 7.32 (dd, J=9.8, 1.9 Hz, 1 H), 7.80 (d, Final Cpd Final Cpd Final Cpd Final Cpd Final Cpd Final Cpd JAB7061WOPCT1 - 230 - 1 H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.21 (s, 3 H) 1.90 - 1.99 (m, Final Cpd X84 2 H) 2.18 - 2.27 (m, 2 H) 3.70 - 3.84 (m, 1 H) 4.69 (d, J=15.9 Hz, 1 H) 4.77 (d, J=15.9 Hz, 1 H) 4.98 (br s, 1 H) 5.61 (q, J=7.4 Hz, 1 H) 7.65 (br s, 1 H) 8.23 (dd, J=8.4, 1.0 Hz, 1 H) 8.35 (br d, J=7.2 Hz, 1 H) 8.50 (d, J=8.4 Hz, 1 H) 8.70 (s, 1 H) 1 H NMR (400 MHz, DMSO-d6) δ ppm 1.21 (s, 3 H) 1.49 (d, J=6.9 Final Cpd X85 Hz, 3 H) 1.94 (t, J=9.7 Hz, 2 H) 2.17 - 2.26 (m, 2 H) 3.69 - 3.83 (m, Final Cpd Final Cpd Final Cpd Final Cpd Final Cpd Final Cpd Final Cpd JAB7061WOPCT1 - 231 - 1H NMR (400 MHz, DMSO-d6) δ ppm 0.83 - 0.97 (m, 2 H), 0.97 - Final Cpd X93 1.06 (m, 2 H), 2.54 - 2.67 (m, 1 H), 3.59 (s, 3 H), 4.92 (s, 2 H), 6.97 (d, J=9.9 Hz, 1 H), 7.91 (br d, J=9.9 Hz, 1 H), 8.22 (d, J=8.5 Hz, 1 H), 8.48 (d, J=8.3 Hz, 1 H), 8.61 (s, 1 H), 10.83 - 10.98 (m, 1 H) 1H NMR (400 MHz, CDCl3) d 1.36 (s, 3H), 1.35 (d, J = 6.8 Hz, 6H), 2.04 – 1.96 (m, 2H), 2.54 – 2.46 (m, 2H), 2.10 (s, 1H), 3.42 X-1027 (hept, J = 6.7 Hz, 1H), 4.00 (h, J = 7.9 Hz, 1H), 4.83 (s, 2H), 6.46 X-1028 X-1029 X-1088 X-1031 X-1080 X-1081 X-1046 JAB7061WOPCT1 - 232 - 1H NMR (400 MHz, DMSO) d 1.29 (d, J = 6.7 Hz, 6H), 1.41 (s, 9H), 3.64 – 3.75 (m, J = 13.6, 6.9 Hz, 1H), 4.97 (s, 2H), 7.32 (d, J = X-1048 9.4 Hz, 1H), 7.79 (d, J = 9.7 Hz, 1H), 7.97 (d, J = 10.3 Hz, 2H), 8.24 (d, J = 8.2 Hz, 1H), 9.20 (s, 1H), 9.24 (s, 1H), 10.54 (s, 1H). 1H NMR (400 MHz, DMSO) d 1.21 (s, 3H), 1.27 (d, J = 6.7 Hz, 6H), 1.39 (s, 9H), 1.94 (t, J = 9.9 Hz, 2H), 2.17 – 2.26 (m, 2H), 3.69 X-1049 – 3.59 (m, 1H), 3.72 – 3.83 (m, 1H), 4.64 (s, 2H), 4.95 (s, 1H), 7.90 X-1050 X-1082 X-1054 X-1090 X-1018 X-1017 X-1016 JAB7061WOPCT1 - 233 - 1H NMR (400 MHz, CDCl3) d 1.36 (s, 3H), 1.37 (d, J = 6.8 Hz, 6H), 1.94 – 2.05 (m, 5H), 2.06 (s, 1H), 2.47 – 2.54 (m, 2H), 3.53 X-1062 (hept, J = 6.8 Hz, 1H), 4.01 (h, J = 7.9 Hz, 1H), 4.86 (s, 2H), 6.45 (d, J = 7.1 Hz, 1H), 7.87 (dd, J = 8.4, 1.3 Hz, 1H), 8.01 (s, 1H), 8.54 (d, J = 8.3 Hz, 1H). 1H NMR (400 MHz, DMSO) d 1.29 (d, J = 6.7 Hz, 6H), 2.11 (t, J = 19.1 Hz, 3H), 3.72 (hept, J = 6.7 Hz, 1H), 5.01 (s, 2H), 7.32 (dd, J = X-1063 X-1051 X-1030 X-1032 X-1033 X-1022 X-1023 JAB7061WOPCT1 - 234 - 1H NMR (400 MHz, CDCl3) d 1.07 (d, J = 6.7 Hz, 4H), 1.38 (s, 3H), 2.02 (dd, J = 13.7, 4.3 Hz, 2H), 2.15 – 2.26 (m, 1H), 2.46 – X-1070 2.56 (m, 2H), 4.01 (h, J = 7.9 Hz, 1H), 4.79 (s, 2H), 6.41 (d, J = 6.9 Hz, 1H), 7.76 (dd, J = 8.5, 1.9 Hz, 1H), 8.12 (d, J = 1.9 Hz, 1H), 8.41 (d, J = 8.5 Hz, 1H). 1H NMR (400 MHz, CDCl3) d 1.10 (d, J = 6.6 Hz, 4H), 2.18 – 2.28 (m, 1H), 5.04 (s, 2H), 7.79 (dd, J = 8.5, 1.9 Hz, 1H), 8.10 (d, J = X-1002 X-1003 X-1064 X-1071 X-1004 X-1019 X-1001 X-1000 JAB7061WOPCT1 - 235 - 1H NMR (400 MHz, DMSO-d6) δ ppm 0.18 - 0.30 (m, 2 H), 0.34 - 0.41 (m, 2 H), 1.19 - 1.43 (m, 8 H), 1.55 - 1.71 (m, 3 H), 2.00 - 2.22 X-1035 (m, 2 H), 2.69 (br d, J=11.4 Hz, 1 H), 2.84 (br d, J=9.9 Hz, 1 H), 3.57 - 3.69 (m, 2 H), 4.67 (s, 2 H), 7.87 (br d, J=7.9 Hz, 1 H), 8.04 (dd, J=8.5, 1.8 Hz, 1 H), 8.20 (d, J=8.6 Hz, 1 H), 8.28 (d, J=1.8 Hz, 1 H) 1H NMR (400 MHz, DMSO) d 1.21 (s, 3H), 1.90 – 1.98 (m, 2H), 220 – 227 (m 2H) 371 – 381 (m 1H) 474 (s 2H) 499 (s 1H) X-1020 X-1024 X-1036 X-1083 X-1021 X-1084 X-1065 X-1073 JAB7061WOPCT1 - 236 - 1H NMR (400 MHz, DMSO-d6) ppm 1.29 (d, J=6.6 Hz, 6 H), 2.11 (t, J=19.0 Hz, 3 H), 3.72 (spt, J=6.8 Hz, 1 H), 5.06 (s, 2 H), 7.73 (d, J=1.3 Hz, 1 H), 7.83 (br d, J=9.7 Hz, 1 H), 8.06 (dd, J=8.4, 1.3 Hz, 1 X-1006 H), 8.11 (d, J=9.9 Hz, 1 H), 8.16 (s, 1 H), 8.18 (s, 1 H), 8.42 (d, J=8.4 Hz, 1 H), 11.23 (br s, 1 H). 19F NMR (377 MHz, DMSO-d6) ppm -85.51 (q, J=19.1 Hz, 2 F). 1H NMR (400 MHz, DMSO-d6) d ppm 1.28 (d, J=6.8 Hz, 6 H) 1.40 X-1007 X-1075 X-1074 X-1066 X-1008 X-1067 JAB7061WOPCT1 - 237 - 1H NMR (400 MHz, DMSO-d6) d ppm 1.29 (d, J=6.8 Hz, 6 H), 1.31 (d, J=7.0 Hz, 6 H), 3.18 (spt, J=6.9 Hz, 1 H), 3.66 (spt, J=6.8 X-1009 Hz, 1 H), 5.05 (s, 2 H), 7.80 (dd, J=8.4, 1.3 Hz, 1 H), 7.90 (s, 1 H), 7.92 (br d, J=10.1 Hz, 1 H), 8.24 (d, J=8.1 Hz, 1 H), 8.34 (d, J=9.9 Hz, 1 H), 9.52 (s, 1 H), 11.44 (br s, 1 H). 1H NMR (400 MHz, DMSO-d6) d ppm 1.29 (d, J=6.8 Hz, 6 H), 2.11 (t, J=19.1 Hz, 3 H), 3.72 (spt, J=6.8 Hz, 1 H), 5.07 (s, 2 H), X-1085 X-1086 X-1012 X-1010 X-1011 X-1076 X-1077 X-1087 JAB7061WOPCT1 - 238 - Example B – Pharmaceutical Compositions A compound of the invention (for instance, a compound of the examples) is brought into association with a pharmaceutically acceptable carrier, thereby providing a5 pharmaceutical composition comprising such active compound. A therapeutically effective amount of a compound of the invention (e.g. a compound of the examples) is intimately mixed with a pharmaceutically acceptable carrier, in a process for preparing a pharmaceutical composition. 10 Example C - Biological Examples The activity of a compound according to the present invention can be assessed by in vitro methods. A compound the invention exhibits valuable pharmacological properties, e.g. properties susceptible to inhibit NLRP3 activity, for instance as indicated the following test, and are therefore indicated for therapy related15 to NLRP3 inflammasome activity.

JAB7061WOPCT1 - 239 - PBMC assay Peripheral venous blood was collected from healthy individuals and human peripheral blood mononuclear cells (PBMCs) were isolated from blood by Ficoll- Histopaque (Sigma-Aldrich, A0561) density gradient centrifugation. After isolation, 5 PBMCs were stored in liquid nitrogen for later use. Upon thawing, PBMC cell viability was determined in growth medium (RPMI media supplemented with 10% fetal bovine serum, 1% Pen-Strep and 1% L-glutamine). Compounds were spotted in a 1:3 serial dilution in DMSO and diluted to the final concentration in 30 µl medium in 96 well 4 plates (Falcon, 353072). PBMCs were added at a density of 7.5 × 10 cells per well and 10 incubated for 30 min in a 5% CO2 incubator at 37 °C. LPS stimulation was performed by addition of 100 ng/ml LPS (final concentration, Invivogen, tlrl-smlps) for 6 hrs followed by collection of cellular supernatant and the analysis of IL-1β (µM) and TNF cytokines levels (µM) via MSD technology according to manufacturers’ guidelines (MSD, K151A0H). 15 The IC50 values (for IL-1β) and EC50 values (TNF) were obtained on compounds of the invention/examples, and are depicted in the following table: Number Compound _{IL1 ^} TNF IC ₅₀ EC50 (µM) (µM) Final Cpd 2 0.19 >10 Fin Fin Fin JAB7061WOPCT1 - 240 - 1.70 Final Cpd 7 (384 >10 well plate) Finl d Fina Fina Fina Fina Fina Fina JAB7061WOPCT1 - 241 - Final Cpd 17 0.54 >10 Final Cpd 18 0.03 >10 Fina Fina Fina Fina Fina Fina Fina JAB7061WOPCT1 - 242 - Final Cpd 28 0.97 >10 Final Cpd 29 3.59 >10 Fina Fin Fin Fin Fina Fina Fina JAB7061WOPCT1 - 243 - Final Cpd 31 0.103 13.61 Fina Fina Fina Fina Fina Fina JAB7061WOPCT1 - 244 - Final Cpd 38 <0.02 >10 5 Final d X1 Fina Fina Fina Fina Fina Fina Fina JAB7061WOPCT1 - 245 - Final Cpd X10 0.092 >20 Final Cpd X11 0.105 >20 Final Final Final Final Final Final Final JAB7061WOPCT1 - 246 - (S) Final Cpd X19 0.161 >20 (R) Final Cpd X20 Final Final Final Final Final Final JAB7061WOPCT1 - 247 - Final Cpd X27 0.189 >20 Final Cpd X28 0.193 >20 Final Final Final Final Final Final JAB7061WOPCT1 - 248 - Final Cpd X35 0.303 >20 O OH H N Final Cpd X36 N Final Final Final Final Final Final JAB7061WOPCT1 - 249 - Final Cpd X43 0.374 >20 Final Cpd X44 Final Final Final Final Final Final Final JAB7061WOPCT1 - 250 - Final Cpd X52 0.442 >20 Final Cpd X53 0.444 >20 Final Final Final Final Final Final Final JAB7061WOPCT1 - 251 - Final Cpd X61 0.588 >20 (RS) Final Final Final Final Final Final Final JAB7061WOPCT1 - 252 - O N H N N Final Cpd X69 N N O N N 0.735 >20 F ₃ C (S) Final Cpd X70 0.74 >20 R Final Final Final Final Final Final JAB7061WOPCT1 - 253 - Final Cpd X77 0.83 >20 Final Final Final Final Final Final Final JAB7061WOPCT1 - 254 - Final Cpd X85 0.915 >20 (RS) ( ^S ₎ Final Final Final Final Final Final Final JAB7061WOPCT1 - 255 - Final Cpd X93 1.007 >20 Final Cpd X94 Final Final Final Final Final Final Final JAB7061WOPCT1 - 256 - Final Cpd X102 1.297 >20 (RS) Final d X1 Final Final Final Final Final Final JAB7061WOPCT1 - 257 - Final Cpd X110 1.635 >20 ( ^RS _)- ^trans Final d X111 Final Final Final Final Final Final JAB7061WOPCT1 - 258 - Final Cpd X118 2.126 >20 Final Cpd X119 2.128 >20 Final Final Final Final Final Final JAB7061WOPCT1 - 259 - Final Cpd X126 2.938 >20 Final Final Final Final Final JAB7061WOPCT1 - 260 - Final Cpd X132 3.255 >20 Final Final Final Final Final Final JAB7061WOPCT1 - 261 - Final Cpd X139 4.276 >20 Final Final Final Final JAB7061WOPCT1 - 262 - Final Cpd X144 4.945 >20 Final Final Final Final Final Final JAB7061WOPCT1 - 263 - Final Cpd X151 7.449 >20 Final Final Final Final Final Final JAB7061WOPCT1 - 264 - Final Cpd X158 9.988 >20 Final Final Final Final Final Final JAB7061WOPCT1 - 265 - Final Cpd X165 16.13 >20 2 Final Final Final Final Final Final JAB7061WOPCT1 - 266 - Final Cpd X172 >20 >20 Final Final Final Final Final JAB7061WOPCT1 - 267 - Final Cpd X178 >20 >20 Final Final Final X X X JAB7061WOPCT1 - 268 - X-1014 >20 >20 X-1079 9.786 >20 X X X X X JAB7061WOPCT1 - 269 - X-1019 0.183 >20 X-1000 0.122 >20 X X X X X JAB7061WOPCT1 - 270 - X-1024 0.497 >20 X-1088 0.196 >20 X X X X X X JAB7061WOPCT1 - 271 - X-1035 0.032 >20 X-1036 0.141 >20 X X X X X X JAB7061WOPCT1 - 272 - X-1006 0.128 4.47 X-1085 0.143 >20 X X X X X X JAB7061WOPCT1 - 273 - X-1060 1.741 >20 X-1061 >20 >20 X X X X X X JAB7061WOPCT1 - 274 - X-1002 0.453 >20 X-1072 1.4 >20 X X X X X X JAB7061WOPCT1 - 275 - X-1025 2.515 >20 X X X X X X X JAB7061WOPCT1 - 276 - X-1042 12.20 >20 4 X-1007 0.015 2.133 X X X X X X JAB7061WOPCT1 - 277 - X-1073 0.22 >20 X-1010 0.017 3.113 X X X X X JAB7061WOPCT1 - 278 - X-1077 0.144 16.527 X X X X X X X JAB7061WOPCT1 - 279 - X-1078 1.309 >20 Exam 5 exam prop solub y. Permeability test 10 The in vitro passive permeability and the ability to be a transported substrate of P-glycoprotein (P-gp) is tested using MDCKcells stably transduced with MDR1 (this may be performed at a commercial organisaiton offering ADME, PK services, e.g. Cyprotex). Permeability experiments are conducted in duplicate at a single concentration (5 µM) in a transwell system with an incubation of 120 min. The apical 15 to basolateral (AtoB) transport in the presence and absence of the P-gp inhibitor GF120918 and the basolateral to apical (BtoA) transport in the absence of the P-gp inhibitor is measured and permeation rates (Apparent Permeability) of the test compounds (P -6 app x10 cm/sec) are calculated. 20 Metabolic stability test in liver microsomes The metabolic stability of a test compound is tested (this may be performed at a commercial organisaiton offering ADME, PK services, e.g. Cyprotex) by using liver microsomes (0.5 mg/ml protein) from human and preclinical species incubated up to o 60 minutes at 37C with 1 µM test compound. 25 The in vitro metabolic half-life (t _1/2 ) is calculated using the slope of the log- linear regression from the percentage parent compound remaining versus time relationship ( ^), t _1/2 = - ln(2)/ ^. 30 The in vitro intrinsic clearance (Clint) (ml/min/mg microsomal protein) is calculated using the following formula:

JAB7061WOPCT1 - 280 - Where: Vinc = incubation volume, Wmic prot,inc = weight of microsomal protein in the incubation. 5 Metabolic stability test in liver hepatocytes The metabolic stability of a test compound is tested using liver hepatocytes (1 o milj cells) from human and preclinical species incubated up to 120 minutes at 37C with 1 µM test compound. The in vitro metabolic half-life (t1/2) is calculated using the slope of the log-linear 10 regression from the percentage parent compound remaining versus time relationship ( ^), t1/2 = - ln(2)/ ^. The in vitro intrinsic clearance (Cl _int ) (µl/min/million cells) is calculated using the following formula: 15 Where: Vinc = incubation volume, # cellsinc = number of cells (x106) in the incubation 20 Solubility test The test/as i rn in tri li t nd i mi- t mtd in th T n Fl nt f r all liquid hand - 20µl of 10mM stock solution is dispensed in a 500µl 96 well plate - DMSO is evaporated (Genevac) 25 - a stir bar and 400µl of buffer/biorelevant media is added - the solution is stirred for 72h (pH2 and pH7) or 24h (FaSSIF and FeSSIF) - the solution is filtered - the filtrate is quantified by UPLC/UV using a three-points calibration curve 30 The LC conditions are: - Waters Acquity UPLC - Mobile phase A: 0.1% formic acid in H2O, B: 0.1% formic acid in CH3CN - Column: Waters HSS T31.8µm 2.1x50mm - Column temp.: 55°C 35 - Inj.vol.: 2µl - Flow: 0.6ml/min

JAB7061WOPCT1 - 281 - - Wavelength UV: 250_350nm - Gradient : 0min: 0%B, 0.3min: 5%B, 1.8min: 95%B, 2.6min: 95%B Blood Stability assay 5 The compound of the invention/examples is spiked at a certain concentration in plasma or blood from the agreed preclinical species; then after incubating to predetermined times and conditions (37°C, 0°C (ice) or room temperature) the concentration of the test compound in the blood or plasma matrix with LCMS/MS can then be determined. 10