Novel compounds and pharmaceutical compositions thereof for the treatment of infectious diseases

Abstract

The present invention discloses compounds according to Formula (I), wherein G and Cy are as defined herein. Herein are disclosed compounds, methods for their production, pharmaceutical compositions comprising the same, and methods of treatment using the same, for the prophylaxis and / or treatment of diseases involving tuberculosis (TB) and / or non-tuberculous mycobacteria (NTM).

Description

GAL-363-WO-PCT 1NOVEL COMPOUNDS AND PHARMACEUTICAL COMPOSITIONS THEREOF FOR THETREATMENT OF INFECTIOUS DISEASES.FIELD

[0001] Herein are provided inter alia, compounds that may be useful in the prophylaxis and / or treatmentof tuberculosis (TB) and / or non-tuberculous mycobacteria (NTM). Herein is also provided methods for theproduction of the compound of the invention, pharmaceutical compositions comprising the compound ofthe invention, methods for the prophylaxis and / or treatment of NTM by administering the compound of theinvention. BACKGROUND

[0002] Tuberculosis (TB) is a contagious and deadly disease caused by Mycobacterium tuberculosis(MTB), that has reached pandemic proportions: 8 - 10 million new cases of tuberculosis (TB) are diagnosedeach year, leading to death in adults (2-3 million / year) according to the World Health Organization (WHO).

[0003] In addition to TB, recent epidemiological studies have shown the emergence of non-tuberculousmycobacteria (NTM) species in causing lung diseases in humans. Non-tuberculous mycobacteria (NTM)are referred to as atypical mycobacteria and are defined as mycobacteria other than Mycobacterium (M).leprae and M. tuberculosis (MTB) with its close relatives, M. africanum, M. bovis, M. canetti and caprae.

[0004] Although more than 170 NTM species (Gopalaswamy et al. 2020) are present in variousenvironmental niches, only a handful, primarily M avium complex and M abscessus, have been implicatedin pulmonary disease causing opportunistic infections in humans with pre-existing conditions, particularly in individuals with suppressed immune systems or underlying structural lung damage such as bronchiectasis, cystic fibrosis (CF), Chronic Obstructive Pulmonary Disease (COPD), or asthma, and patients with other diseases such as HIV and diabetes are at high risk of contracting pulmonary NTM disease. NTM disease is mostly disseminated through aerosols originated from the environment (Gopalaswamy et al.2020).

[0005] The incidence and number of deaths from NTM disease have steadily increased globally, especiallyin developed countries (Prevots and Marras 2015). However, early patient diagnosis is challenging due tonon-specific symptoms in patients, which may result in underestimation of the overall incidence.

[0006] Although the pathophysiology of TB and NTM diseases share several fundamental cellular andmolecular events, the host-susceptibility to MTB and NTM infections are different.

[0007] In general, drug-sensitive TB is treated with a standard multi-drug regimen containing well-definedfirst- and second-line antibiotics (Gopalaswamy et al.2020).

[0008] In contrast, the NTM species display significant heterogeneity in their susceptibility to standardanti-TB drugs. Thus, the treatment for NTM diseases usually involves inter alia, the use of macrolides and injectable aminoglycosides. Although well-established international guidelines are available, treatment of NTM disease is mostly empirical and not entirely successful. In general, the treatment duration is muchlonger for NTM diseases (18-24 months), compared to TB, and resection surgery of affected organ(s) isGAL-363-WO-PCT 2part of treatment for patients with NTM diseases that do not respond to the antibiotic treatment.(Daley et al.2020; Gopalaswamy et al.2020).

[0009] In fighting TB and / or NTM, the rifamycins (RIFs) are the most commonly used drugs despiteserious drawbacks including: Cyp450 induction, which is particularly problematic for HIV-MTB co- infection, and the existence of resistant mutations that yield RIF-resistant (RIFR) MTB strains. In addition, certain detoxification pathways are present in some NTM species which render rifamycins inactive.

[0010] Semisynthetic rifamycin derivatives including rifampin, rifalazil (RLZ), rifapentine (RFP), andrifabutin (RFB) appear to show improved antimycobacterial activities. However, all RIFs are ineffective against the most prevalent RIFR MTB mutant (rpoB S450L) (Tuberculosis (2008) 88(2) 148-150), and a major downside to using rifamycins to treat TB is their many drug-drug interactions due to extremely potent activation of the human pregnane X receptor (hPXR) leading to a dramatic induction of CYP2C9, CYP3A4 and other hepatic metabolizing enzymes and transporters.

[0011] The long and toxic treatment, the raise of resistance, the worldwide increasing prevalence and thehigh hospital costs makes TB and / or NTM infections a high unmet medical need for which new drugs aredesperately needed. SUMMARY

[0012] There is a need for new compounds which are not associated with the disadvantages of priorcompounds, to provide new treatments and methods of prophylaxis, and / or treatment of TB and / or NTM.

[0013] As such, herein are provided inter alia, compounds that may be useful in the prophylaxis and / ortreatment of TB and / or NTM. In particular, the compounds provided herein may show improved potencyagainst TB and / or NTM, reduced toxicity, and / or improved PK / PD profile.

[0014] In some aspects, herein are also provided methods for the production of the compounds of theinvention, pharmaceutical compositions comprising the compounds of the invention, methods for theprophylaxis and / or treatment of TB and / or NTM by administering the compounds of the invention.

[0015] Accordingly, in a first aspect of the invention, the compounds of the invention are provided havinga Formula (I):IGAL-363-WO-PCT 3wherein G is -R1,- -L-R1,- -N(R4a)-R1, or- -N(R4b)-L-R1;L is C1-4 alkylenyl, or C1-4 alkenylenyl; R1is -phenyl optionally substituted with one or more independently selected R5a,- 5-6 membered monocyclic heteroaryl comprising one or more independently selected N, O, or Sheteroatoms, unsubstituted or substituted with one or more independently selected R5b, -8-10 membered fused bicyclic heteroaryl comprising one or more independently selected N, O, orS heteroatoms, unsubstituted or substituted with one or more independently selected R5c, -4-7 membered monocyclic heterocycloalkyl, comprising one or more independently selected N, Oor S heteroatoms, unsubstituted or substituted with one or more groups independently selected from =O and R5d, -4-7 membered monocyclic heterocycloalkyl fused to a phenyl, or pyridinyl, which heterocycloalkylcomprising one or more independently selected N, O or S heteroatoms, unsubstituted or substituted with one or more groups independently selected from =O and R5e, or -5-10 membered bicyclic fused, bridged or spiro heterocycloalkyl, comprising one or moreindependently selected N, O or S heteroatoms, unsubstituted or substituted with one or more groups independently selected from =O and R5f; Cy is -4-7 membered monocyclic heterocycloalkyl comprising one or more independently selected N, Oor S heteroatoms, which heterocycloalkyl is substituted with one or more independently selected R2agroups, -5-10 membered bridged, fused, or spiro bicyclic heterocycloalkyl comprising one or moreindependently selected N, O or S heteroatoms, which heterocycloalkyl substituted with one or more independently selected R2bgroup, -C3-7 cycloalkyl monocyclic unsubstituted or substituted with one or more independently selectedR2c, or -C5-10 cycloalkyl bridged, fused, or spiro bicyclic unsubstituted or substituted with one or moreindependently selected R2d; Each R2a, R2b, R2cand R2dis selected from: -R3a,- C alkyl unsubstituted o 3b1-6 r substituted with one or more independently selected R , and- C c 3c3-7 ycloalkyl unsubstituted or substituted with one or more independently selected R ;Each R3a, R3band R3cis independently selected from:GAL-363-WO-PCT 4- halo,- -OH,- =O,- -CN,- -C(=O)R6a,- -C(=O)OH,- -C(=O)OR6b,- -C(=O)NH2,- -C(=O)NHR6c,- -C(=O)NR6cR6d,- -S(=O)R6e,- -S(=O) 6f2OR ,- -S(=O)2NH2,- -S(=O)2NHR6g, --S(=O) 6g 6h2NR R ,- -NHC(=O)R6i,- -P(=O)R6jR6k,- -NHR6l,- -NR6lR6m,- C3-7 cycloalkyl unsubstituted or substituted unsubstituted or substituted with one or moreindependently selected R8a groups, and- 4-7 membered monocyclic heterocycloalkyl, comprising one or more independently selected N, Oor S heteroatoms, unsubstituted or substituted with one or more independently selected R8bgroups; Each R4aand R4bis selected from H and C1-4 alkyl; Each R5a, R5b, R5c, R5d, R5e, and R5fis independently selected from: -halo,- -OH,- CN,- C1-4 alkyl optionally substituted with one or more independently selected halo,- C1-4 alkoxy optionally substituted with one or more independently selected halo,- C3-7 cycloalkyl unsubstituted or substituted unsubstituted or substituted with one or moreindependently selected halo, -4-7 membered monocyclic heterocycloalkyl, comprising one or more independently selected N, Oor S heteroatoms, unsubstituted or substituted with one or more independently selected halo, --C(=O)R7a,- -C(=O)OH,- -C(=O)OR7b,- -C(=O)NH2,GAL-363-WO-PCT 5- -C(=O)NHR7c,- -C(=O)NR7cR7d,- -S(=O)R7e,- -S(=O)2R7f, --S(=O)2NH2,- -S(=O)2NHR7g, --S(=O)2NR7hR7g, --NHC(=O)R7i,- -P(=O)R7jR7k,- -NHR7l, and- -NR7lR7m;Each R6a, R6b, R6c, R6d, R6e, R6f, R6e, R6g, R6h, R6i, R6j, R6k, R6l, R6m, R7a, R7b, R7c, R7d, R7e, R7f, R7g, R7h, R7i, R7j, R7kR7l, and R7mis independently selected from: -C1-4 alkyl unsubstituted or substituted with one or more independently selected halo, phenyl orpyridinyl, -C1-4 alkoxy unsubstituted or substituted with one or more independently selected halo, phenyl orpyridinyl, -C3-7 cycloalkyl unsubstituted or substituted with one or more independently selected halo,- 4-7 membered monocyclic heterocycloalkyl, comprising one or more independently selected N, Oor S heteroatoms, unsubstituted or substituted with one or more independently selected halo, -phenyl, and- 5-6 membered heteroaryl comprising one or more independently selected N, O, or S heteroatoms;Each R8aand R8bis independently selected from -halo,- -OH,- =O,- -CN,- C1-4 alkyl unsubstituted or substituted with one or more independently selected halo, and- C1-4 unsubstituted or substituted with one or more selected.GAL-363-WO-PCT 6

[0016] In a particular aspect, the compounds of the invention are provided for use in the prophylaxis and / or treatment of TB and / or NTM.

[0017] Furthermore, it has also been unexpectedly demonstrated that the compounds of the inventionexhibit improved DDI profile.

[0018] In a further aspect, herein are also provided pharmaceutical compositions comprising a compoundof the invention, and a pharmaceutical carrier, excipient, or diluent. In a particular aspect, thepharmaceutical composition may additionally comprise further therapeutically active ingredients suitable for use in combination with the compounds of the invention. In a more particular aspect, the further therapeutically active ingredient is an agent for the treatment of TB and / or NTM.

[0019] Moreover, the compounds of the invention, useful in the pharmaceutical compositions andtreatment methods disclosed herein, are pharmaceutically acceptable as prepared and used.

[0020] In a further aspect, this invention provides a method of treating a mammal, in particular humans,afflicted with a condition selected from among those listed herein, and particularly TB and / or NTM, which method comprises administering an effective amount of the pharmaceutical composition or compounds of the invention as described herein.

[0021] The present invention also provides pharmaceutical compositions comprising a compound of theinvention, and a suitable pharmaceutical carrier, excipient or diluent for use in medicine. In a particular aspect, the pharmaceutical composition is for use in the prophylaxis and / or treatment of TB and / or NTM.

[0022] In additional aspects, this invention provides methods for synthesizing the compounds of theinvention, with representative synthetic protocols and pathways disclosed later on herein.

[0023] Other objects and advantages will become apparent to those skilled in the art from a considerationof the ensuing detailed description. DETAILED DESCRIPTIONDefinitions

[0024] The following terms are intended to have the meanings presented therewith below and are usefulin understanding the description and intended scope of the present invention.

[0025] When describing the invention, which may include compounds, pharmaceutical compositionscontaining such compounds and methods of using such compounds and compositions, the following terms, if present, have the following meanings unless otherwise indicated. It should also be understood that when described herein any of the moieties defined forth below may be substituted with a variety of substituents, and that the respective definitions are intended to include such substituted moieties within their scope as set out below. Unless otherwise stated, the term “substituted” is to be defined as set out below. It should be further understood that the terms “groups” and “radicals” can be considered interchangeable when used herein.

[0026] The articles ‘a’ and ‘an’ may be used herein to refer to one or to more than one (i.e. at least one) ofthe grammatical objects of the article. By way of example ‘an analogue’ means one analogue or more than one analogue.GAL-363-WO-PCT 7

[0027] ‘Alkyl’ means straight or branched aliphatic hydrocarbon having the specified number of carbonatoms. Particular alkyl groups have 1 to 6 carbon atoms or 1 to 4 carbon atoms. Branched means that one or more alkyl groups such as methyl, ethyl or propyl is attached to a linear alkyl chain. Particular alkyl groups are methyl (-CH3), ethyl (-CH2-CH3), n-propyl (-CH2-CH2-CH3), isopropyl (-CH(CH3)2), n-butyl (- CH2-CH2-CH2-CH3), tert-butyl (-C(CH3)3), iso-butyl (-CH2-CH(CH3)2), n-pentyl (-CH2-CH2-CH2-CH2- CH3), n-hexyl (-CH2-CH2-CH2-CH2-CH2-CH3), and 1,2-dimethylbutyl (-CHCH3)-C(CH3)H2-CH2-CH3). Particular alkyl groups have between 1 and 4 carbon atoms.

[0028] ‘Alkenyl’ refers to monovalent olefinically (unsaturated) hydrocarbon groups with the number ofcarbon atoms specified. Particular alkenyl has 2 to 8 carbon atoms, and more particularly, from 2 to 6 carbon atoms, which can be straight-chained or branched and having at least 1 and particularly from 1 to 2 sites of olefinic unsaturation. Particular alkenyl groups include ethenyl (-CH=CH2), n-propenyl (-CH2CH=CH2), isopropenyl (-C(CH3)=CH2) and the like.

[0029] ‘Alkylenyl’ refers to divalent alkene radical groups having the number of carbon atoms specified,in particular having 1 to 6 carbon atoms and more particularly 1 to 4 carbon atoms which can be straight-chained or branched. This term is exemplified by groups such as methylene (-CH2-), ethylene(-CH2-CH2-), or -CH(CH3)- and the like.

[0030] ‘Alkenylenyl’ refers to divalent alkyne radical groups having the number of carbon atoms and thenumber of triple bonds specified, in particular 2 to 6 carbon atoms and more particularly 2 to 4 carbon atoms which can be straight-chained or branched. This term is exemplified by groups such as -C=C-, -CH2- C=C-, and -C(CH3)H-C=CH-.

[0031] ‘Alkoxy’ refers to the group O-alkyl, where the alkyl group has the number of carbon atomsspecified. In particular the term refers to the group -O-C1-6alkyl. Particular alkoxy groups are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy. Particular alkoxy groups are lower alkoxy, i.e. with between 1 and 6 carbon atoms. Further particular alkoxy groups have between 1 and 4 carbon atoms.

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

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

[0034] ‘Cycloalkyl’ refers to a non-aromatic hydrocarbyl ring structure, monocyclic, fused polycyclic,bridged polycyclic, or spirocyclic, with the number of ring atoms specified. A cycloalkyl may have from 3to 12 carbon atoms, in particular from 3 to 10, and more particularly from 3 to 7 carbon atoms. Suchcycloalkyl groups include, by way of example, single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

[0035] ‘Cyano’ refers to the radical -CN.GAL-363-WO-PCT 8

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

[0037] ‘Hetero’ when used to describe a compound or a group present on a compound means that one ormore carbon atoms in the compound or group have been replaced by a nitrogen, oxygen, or sulfur heteroatom. Hetero may be applied to any of the hydrocarbyl groups described above such as alkyl, e.g.heteroalkyl, cycloalkyl, e.g. heterocycloalkyl, aryl, e.g. heteroaryl, and the like having from 1 to 4, andparticularly from 1 to 3 heteroatoms, more typically 1 or 2 heteroatoms, for example a single heteroatom.

[0038] ‘Heteroaryl’ means an aromatic ring structure, monocyclic or fused polycyclic, that includes oneor more heteroatoms independently selected from O, N and S and the number of ring atoms specified. In particular, the aromatic ring structure may have from 5 to 9 ring members. The heteroaryl group can be, for example, a five membered or six membered monocyclic ring or a fused bicyclic structure formed from fused five and six membered rings or two fused six membered rings or, by way of a further example, two fused five membered rings. Each ring may contain up to four heteroatoms typically selected from nitrogen,sulfur and oxygen. Typically the heteroaryl ring will contain up to 4 heteroatoms, more typically up to 3heteroatoms, more usually up to 2, for example a single heteroatom. In one embodiment, the heteroaryl ring contains at least one ring nitrogen atom. The nitrogen atoms in the heteroaryl rings can be basic, as in the case of an imidazole or pyridine, or essentially non-basic as in the case of an indole or pyrrole nitrogen. In general the number of basic nitrogen atoms present in the heteroaryl group, including any amino group substituents of the ring, will be less than five.

[0039] Examples of five membered monocyclic heteroaryl groups include but are not limited to pyrrolyl,furanyl, thiophenyl, imidazolyl, furazanyl, oxazolyl, oxadiazolyl, oxatriazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl and tetrazolyl groups.

[0040] Examples of six membered monocyclic heteroaryl groups include but are not limited to pyridinyl,pyrazinyl, pyridazinyl, pyrimidinyl and triazinyl.

[0041] Particular examples of bicyclic heteroaryl groups containing a five membered ring fused to anotherfive-membered ring include but are not limited to imidazothiazolyl and imidazoimidazolyl.

[0042] Particular examples of bicyclic heteroaryl groups containing a six membered ring fused to a fivemembered ring include but are not limited to benzofuranyl, benzothiophenyl, benzoimidazolyl, benzoxazolyl, isobenzoxazolyl, benzisoxazolyl, benzothiazolyl, benzoisothiazolyl, isobenzofuranyl,indolyl, isoindolyl, indolizinyl, purinyl (e.g. adenine, guanine), indazolyl, pyrazolopyrimidinyl,triazolopyrimidinyl, and pyrazolopyridinyl groups.

[0043] Particular examples of bicyclic heteroaryl groups containing two fused six membered rings includebut are not limited to quinolinyl, isoquinolinyl, pyridopyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, naphthyridinyl, and pteridinyl groups. Particular heteroaryl groups are those derived from thiophenyl, pyrrolyl, benzothiophenyl, benzofuranyl, indolyl, pyridinyl, quinolinyl, imidazolyl, oxazolyl and pyrazinyl.

[0044] Examples of representative heteroaryls include the following:GAL-363-WO-PCT 9wherein

[0045] ‘Heterocycloalkyl’ means a non-aromatic fully saturated ring structure, monocyclic, fusedpolycyclic, spirocyclic, or bridged polycyclic, that includes one or more heteroatoms independently selected from O, N and S and the number of ring atoms specified. The heterocycloalkyl ring structure may have from 4 to 12 ring members, in particular from 4 to 10 ring members and more particularly from 4 to 7 ring members. Each ring may contain up to four heteroatoms typically selected from nitrogen, sulphurand oxygen. Typically the heterocycloalkyl ring will contain up to 4 heteroatoms, more typically up to 3heteroatoms, more usually up to 2, for example a single heteroatom. Examples of heterocyclic rings include,but are not limited to azetidinyl, oxetanyl, thietanyl, pyrrolidinyl (e.g. 1-pyrrolidinyl, 2-pyrrolidinyl and 3-pyrrolidinyl), tetrahydrofuranyl (e.g. 1-tetrahydrofuranyl, 2-tetrahydrofuranyl and 3-tetrahydrofuranyl),tetrahydrothiophenyl (e.g. 1-tetrahydrothiophenyl, 2-tetrahydrothiophenyl and 3-tetrahydrothiophenyl),piperidinyl (e.g. 1-piperidinyl, 2-piperidinyl, 3-piperidinyl and 4-piperidinyl), tetrahydropyranyl (e.g. 4-tetrahydropyranyl), tetrahydrothiopyranyl (e.g. 4-tetrahydrothiopyranyl), morpholinyl, thiomorpholinyl,dioxanyl, or piperazinyl.

[0046] As used herein, the term ‘heterocycloalkenyl’ means a ‘heterocycloalkyl’, which comprises at leastone double bond. Particular examples of heterocycloalkenyl groups are shown in the following illustrative examples:wherein each W is selected from CH2, NH, O and S; each Y is selected from NH, O, C(=O), SO2, and S; and each Z is selected from N or CH.

[0047] Particular of are shown in the illustrativewherein each W and Y is independently selected from -CH2-, -NH-, -O- and –S-.

[0048] Particular examples:wherein each W and Y is independently selected from -CH2-, -NH-, -O- and –S-.

[0049] Particular examples of bridged bicyclic rings are shown in the following illustrative examples:GAL-363-WO-PCT 10wherein each W and Y isand –S- and each Z is selectedfrom N or CH.

[0050] Particular examples of spirocyclic rings are shown in the following illustrative examples:wherein each Y is selected-, - , - .

[0051] ‘Hydroxyl’ refers to the radical -OH.

[0052] ‘Oxo’ refers to the radical =O.

[0053] ‘Substituted’ refers to a group in which one or more hydrogen atoms are each independentlyreplaced with the same or different substituent(s).

[0054] ‘Sulfo’ or ‘sulfonic acid’ refers to a radical such as –SO3H.

[0055] ‘Thiol’ refers to the group -SH.

[0056] As used herein, term ‘substituted with one or more’ refers to one to four substituents. In oneembodiment it refers to one to three substituents. In further embodiments it refers to one or two substituents. In a yet further embodiment it refers to one substituent.

[0057] ‘Thioalkoxy’ refers to the group –S-alkyl where the alkyl group has the number of carbon atomsspecified. In particular the term refers to the group -S-C1-6 alkyl. Particular thioalkoxy groups are thiomethoxy, thioethoxy, n-thiopropoxy, isothiopropoxy, n-thiobutoxy, tert-thiobutoxy, sec-thiobutoxy, n- thiopentoxy, n-thiohexoxy, and 1,2-dimethylthiobutoxy. Particular thioalkoxy groups are lower thioalkoxy,i.e. with between 1 and 6 carbon atoms. Further particular alkoxy groups have between 1 and 4 carbonatoms.

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

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

[0060] ‘Pharmaceutically acceptable salt’ refers to a salt of a compound of the invention that ispharmaceutically acceptable and that retains the biological activity of the given compound, and which are is not biologically or otherwise undesirable. In particular, such salts may be inorganic or organic acid addition salts and base addition salts. For example, pharmaceutically acceptable salts are described inGAL-363-WO-PCT 11Handbook of Pharmaceutical Salts: Properties, Selection, and Use (Stahl and Wermuth 2011). The salts canbe prepared in situ during the final isolation and purification of the compounds described herein orseparately, e.g., by reacting the free base group with a suitable inorganic or organic acid. The compounds of the invention may have ionizable groups so as to be capable of preparation as pharmaceutically acceptable salts. These salts may be acid addition salts involving inorganic or organic acids or the saltsmay, in the case of acidic forms of the compounds of the invention be prepared from inorganic or organicbases. Frequently, the compounds are prepared or used as pharmaceutically acceptable salts prepared as addition products of pharmaceutically acceptable acids or bases. Suitable pharmaceutically acceptable acids and bases are well known in the art, such as, e.g., hydrochloric acid for forming acid addition salts, andsuch as, e.g., sodium hydroxide for forming basic salts. The term ‘pharmaceutically acceptable cation’refers to an acceptable cationic counter-ion of an acidic functional group. Such cations are exemplified by sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium cations, and the like.

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

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

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

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

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

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

[0067] The term ‘prophylaxis’ is related to ‘prevention’, and refers to a measure or procedure the purposeof which is to prevent, rather than to treat or cure a disease. Non-limiting examples of prophylactic measures may include the administration of vaccines; the administration of low molecular weight heparin to hospitalGAL-363-WO-PCT 12patients at risk for thrombosis due, for example, to immobilization; and the administration of an anti- malarial agent such as chloroquine, in advance of a visit to a geographical region where malaria is endemic or the risk of contracting malaria is high.

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

[0069] As used herein the term tuberculosis (TB) diseases refers to the group of conditions caused by themycobacterium tuberculosis (MTB), affecting primarily the lungs, but also inter alia, the bones, lymphnodes, bone marrow (miliary TB), liver, heart, genitourinary and gastrointestinal tract, meninges (meningeal tuberculosis) and / or the skin.

[0070] As used herein the term non-tuberculous mycobacteria (NTM) disease, also known asenvironmental mycobacteria, atypical mycobacteria and mycobacteria other than MTB (MOTT), diseasesrefers to the group of conditions are mycobacteria which do not cause tuberculosis or leprosy (also knownas Hansen's disease). NTM do cause pulmonary diseases that resemble tuberculosis. The most commonclinical manifestation of NTM disease is lung disease, but lymphatic, skin / soft tissue, and disseminateddiseases, which can affect nearly all organs are also important.

[0071] ‘Compound(s) of the invention’, and equivalent expressions, are meant to embrace compounds ofthe Formula(e) as herein described, which expression includes the pharmaceutically acceptable salts, andthe solvates, e.g. hydrates, and the solvates of the pharmaceutically acceptable salts where the context sopermits. Similarly, reference to intermediates, whether or not they themselves are claimed, is meant to embrace their salts, and solvates, where the context so permits.

[0072] When ranges are referred to herein, for example but without limitation, C1-8 alkyl, the citation of arange should be considered a representation of each member of said range.

[0073] Other derivatives of the compounds of this invention have activity in both their acid and acidderivative forms, but in the acid sensitive form often offers advantages of solubility, tissue compatibility,or delayed release in the mammalian organism (Bundgard, H, 1985). Prodrugs include acid derivatives wellknow to practitioners of the art, such as, for example, esters prepared by reaction of the parent acid with a suitable alcohol, or amides prepared by reaction of the parent acid compound with a substituted or unsubstituted amine, or acid anhydrides, or mixed anhydrides. Simple aliphatic or aromatic esters, amides and anhydrides derived from acidic groups pendant on the compounds of this invention are particularly useful prodrugs. In some cases it is desirable to prepare double ester type prodrugs such as (acyloxy)alkyl esters or ((alkoxycarbonyl)oxy)alkylesters. Particular such prodrugs are the C1-8alkyl, C2-8alkenyl, C6-10optionally substituted aryl, and (C6-10aryl)-(C1-4alkyl) esters of the compounds of the invention.GAL-363-WO-PCT 13

[0074] The present disclosure includes all isotopic forms of the compounds of the invention providedherein, whether in a form (i) wherein all atoms of a given atomic number have a mass number (or mixtureof mass numbers) which predominates in nature (referred to herein as the “natural isotopic form”) or (ii)wherein one or more atoms are replaced by atoms having the same atomic number, but a mass number different from the mass number of atoms which predominates in nature ( referred to herein as an “unnaturalvariant isotopic form”). It is understood that an atom may naturally exists as a mixture of mass numbers.The term “unnatural variant isotopic form” also includes embodiments in which the proportion of an atom of given atomic number having a mass number found less commonly in nature (referred to herein as an “uncommon isotope”) has been increased relative to that which is naturally occurring e.g. to the level of >20%, >50%, >75%, >90%, >95% or> 99% by number of the atoms of that atomic number (the latterembodiment referred to as an "isotopically enriched variant form"). The term “unnatural variant isotopicform” also includes embodiments in which the proportion of an uncommon isotope has been reducedrelative to that which is naturally occurring. Isotopic forms may include radioactive forms (i.e. theyincorporate radioisotopes) and non-radioactive forms. Radioactive forms will typically be isotopicallyenriched variant forms.

[0075] An unnatural variant isotopic form of a compound may thus contain one or more artificial oruncommon isotopes such as deuterium (2H or D), carbon-11 (11C), carbon-13 (13C), carbon-14 (14C), nitrogen-13 (13N), nitrogen-15 (15N), oxygen-15 (15O), oxygen-17 (17O), oxygen-18 (18O), phosphorus-32 (32P), sulphur-35 (35S), chlorine-36 (36Cl), chlorine-37 (37Cl), fluorine-18 (18F) iodine-123 (123I), iodine-125 (125I) in one or more atoms or may contain an increased proportion of said isotopes as compared with the proportion that predominates in nature in one or more atoms.

[0076] Unnatural variant isotopic forms comprising radioisotopes may, for example, be used for drugand / or substrate tissue distribution studies. The radioactive isotopes tritium, i.e. 3H, and carbon-14, i.e. 14C,are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.Unnatural variant isotopic forms which incorporate deuterium i.e 2H or D may afford certain therapeuticadvantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduceddosage requirements, and hence may be preferred in some circumstances. Further, unnatural variant isotopicforms may be prepared which incorporate positron emitting isotopes, such as 11C, 18F, 150 and 13N, andwould be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy.

[0077] It is also to be understood that compounds that have the same molecular formula but differ in thenature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed ‘isomers’. Isomers that differ in the arrangement of their atoms in space are termed ‘stereoisomers’.

[0078] Stereoisomers that are not mirror images of one another are termed ‘diastereomers’ and those thatare non-superimposable mirror images of each other are termed ‘enantiomers’. When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible. An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described bythe R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the planeGAL-363-WO-PCT 14of polarized light and designated as dextrorotatory or levorotatory (i.e. as (+) or (-)-isomers respectively). A chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a ‘racemic mixture’.

[0079] ‘Tautomers’ refer to compounds that are interchangeable forms of a particular compound structure,and that vary in the displacement of hydrogen atoms and electrons. Thus, two structures may be in equilibrium through the movement of π electrons and an atom (usually H). For example, enols and ketones are tautomers because they are rapidly interconverted by treatment with either acid or base. Anotherexample of tautomerism is the aci- and nitro- forms of phenylnitromethane, that are likewise formed bytreatment with acid or base.

[0080] Tautomeric forms may be relevant to the attainment of the optimal chemical reactivity andbiological activity of a compound of interest.

[0081] The compounds of the invention may possess one or more asymmetric centers; such compoundscan therefore be produced as individual (R)- or (S)- stereoisomers or as mixtures thereof.

[0082] Unless indicated otherwise, the description or naming of a particular compound in the specificationand claims is intended to include both individual enantiomers and mixtures, racemic or otherwise, thereof. The methods for the determination of stereochemistry and the separation of stereoisomers are well-known in the art.

[0083] It will be appreciated that compounds of the invention may be metabolized to yield biologicallyactive metabolites. EMBODIMENTS

[0084] Herein are provided inter alia, compounds that may be useful in the prophylaxis and / or treatmentof NTM. In some aspects, herein are also provided methods for the production of the compounds of the invention, pharmaceutical compositions comprising the compounds of the invention, methods for theprophylaxis and / or treatment of NTM by administering the compounds of the invention.

[0085] Accordingly, in a first embodiment, the compounds of the invention are provided having a Formula(I):IGAL-363-WO-PCT 15wherein G is -R1,- -L-R1,- -N(R4a)-R1, or- -N(R4b)-L-R1;L is C1-4 alkylenyl, or C1-4 alkenylenyl; R1is -phenyl optionally substituted with one or more independently selected R5a,- 5-6 membered monocyclic heteroaryl comprising one or more independently selected N, O, or Sheteroatoms, unsubstituted or substituted with one or more independently selected R5b, -8-10 membered fused bicyclic heteroaryl comprising one or more independently selected N, O, orS heteroatoms, unsubstituted or substituted with one or more independently selected R5c, -4-7 membered monocyclic heterocycloalkyl, comprising one or more independently selected N, Oor S heteroatoms, unsubstituted or substituted with one or more groups independently selected from =O and R5d, -4-7 membered monocyclic heterocycloalkyl fused to a phenyl, or pyridinyl, which heterocycloalkylcomprising one or more independently selected N, O or S heteroatoms, unsubstituted or substituted with one or more groups independently selected from =O and R5e, or -5-10 membered bicyclic fused, bridged or spiro heterocycloalkyl, comprising one or moreindependently selected N, O or S heteroatoms, unsubstituted or substituted with one or more groups independently selected from =O and R5f; Cy is -4-7 membered monocyclic heterocycloalkyl comprising one or more independently selected N, Oor S heteroatoms, which heterocycloalkyl is substituted with one or more independently selected R2agroups, -5-10 membered bridged, fused, or spiro bicyclic heterocycloalkyl comprising one or moreindependently selected N, O or S heteroatoms, which heterocycloalkyl substituted with one or more independently selected R2bgroup, -C3-7 cycloalkyl monocyclic unsubstituted or substituted with one or more independently selectedR2c, or -C5-10 cycloalkyl bridged, fused, or spiro bicyclic unsubstituted or substituted with one or moreindependently selected R2d; Each R2a, R2b, R2cand R2dis selected from: -R3a,- C alkyl unsubstituted o 3b1-6 r substituted with one or more independently selected R , and- C c 3c3-7 ycloalkyl unsubstituted or substituted with one or more independently selected R ;Each R3a, R3band R3cis independently selected from:GAL-363-WO-PCT 16- halo,- -OH,- =O,- -CN,- -C(=O)R6a,- -C(=O)OH,- -C(=O)OR6b,- -C(=O)NH2,- -C(=O)NHR6c,- -C(=O)NR6cR6d,- -S(=O)R6e,- -S(=O) 6f2OR ,- -S(=O)2NH2,- -S(=O)2NHR6g, --S(=O) 6g 6h2NR R ,- -NHC(=O)R6i,- -P(=O)R6jR6k,- -NHR6l,- -NR6lR6m,- C3-7 cycloalkyl unsubstituted or substituted unsubstituted or substituted with one or moreindependently selected R8a groups, and- 4-7 membered monocyclic heterocycloalkyl, comprising one or more independently selected N, Oor S heteroatoms, unsubstituted or substituted with one or more independently selected R8bgroups; Each R4aand R4bis selected from H and C1-4 alkyl; Each R5a, R5b, R5c, R5d, R5e, and R5fis independently selected from: -halo,- -OH,- -CN,- C1-4 alkyl optionally substituted with one or more independently selected halo,- C1-4 alkoxy optionally substituted with one or more independently selected halo,- C3-7 cycloalkyl unsubstituted or substituted unsubstituted or substituted with one or moreindependently selected halo, -4-7 membered monocyclic heterocycloalkyl, comprising one or more independently selected N, Oor S heteroatoms, unsubstituted or substituted with one or more independently selected halo, --C(=O)R7a,- -C(=O)OH,- -C(=O)OR7b,- -C(=O)NH2,GAL-363-WO-PCT 17- -C(=O)NHR7c,- -C(=O)NR7cR7d,- -S(=O)R7e,- -S(=O)2R7f, --S(=O)2NH2,- -S(=O)2NHR7g, --S(=O)2NR7gR7h, --NHC(=O)R7i,- -P(=O)R7jR7k,- -NHR7l, and- -NR7lR7m;Each R6a, R6b, R6c, R6d, R6e, R6f, R6g, R6h, R6i, R6j, R6k, R6l, R6m, R7a, R7b, R7c, R7d, R7e, R7f, R7g, R7h, R7i, R7j, R7kR7l, and R7mis independently selected from: -C1-4 alkyl unsubstituted or substituted with one or more independently selected halo, phenyl orpyridinyl, -C1-4 alkoxy unsubstituted or substituted with one or more independently selected halo, phenyl orpyridinyl, -C3-7 cycloalkyl unsubstituted or substituted with one or more independently selected halo,- 4-7 membered monocyclic heterocycloalkyl, comprising one or more independently selected N, Oor S heteroatoms, unsubstituted or substituted with one or more independently selected halo, -phenyl, and- 5-6 membered heteroaryl comprising one or more independently selected N, O, or S heteroatoms;Each R8aand R8bis independently selected from -halo,- -OH,- =O,- -CN,- C1-4 alkyl unsubstituted or substituted with one or more independently selected halo, and- C1-4 unsubstituted or substituted with one or more selected.GAL-363-WO-PCT 18

[0086] In one embodiment, the compound of the invention is according to Formula I, wherein Cy is 4-7membered monocyclic heterocycloalkyl comprising one or more independently selected N, O or S heteroatoms, which heterocycloalkyl is substituted with one or more independently selected R2agroup. In a particular embodiment, Cy is 4-7 membered monocyclic heterocycloalkyl comprising one or more independently selected N, O or S heteroatoms, which heterocycloalkyl is substituted with one, two or threeindependently selected R2a group. In a more particular embodiment, Cy is pyrrolidinyl, or piperidinyl, eachof which is substituted with one, two or three independently selected R2agroup. In a more particular embodiment, Cy is pyrrolidinyl, or piperidinyl, each of which is substituted with one R2agroup.

[0087] In one embodiment, the compound of the invention is according to Formula I, wherein Cy is C3-7cycloalkyl monocyclic unsubstituted or substituted with one or more independently selected R2cgroups. In a particular embodiment, Cy is C3-7 cycloalkyl monocyclic unsubstituted or substituted with one, two or three independently selected R2cgroup. In a more particular embodiment, Cy is cyclopentyl or cyclohexyl, each of which is substituted with one, two or three independently selected R2cgroup. In a more particular embodiment, Cy is cyclopentyl or cyclohexyl, each of which is substituted with one R2cgroup.

[0088] In one embodiment, the compound of the invention is according to Formula II:Wherein G and R2aas described above.

[0089] In one embodiment, the compound of the invention is according to Formula I or II, wherein R2a isR3a, and R3ais -C(=O)R6a. In a particular embodiment, R6ais C3-7cycloalkyl. In a more particular embodiment, R6ais cyclopropyl, cyclobutyl or cyclopentyl.

[0090] In one embodiment, the compound of the invention is according to Formula I or II, wherein R2a isC1-6alkyl.

[0091] In one embodiment, the compound of the invention is according to Formula I or II, wherein R2a isC1-6 alkyl substituted with one, two or three independently selected R3b. In a particular embodiment, eachR3b is independently selected from -C(=O)R7a, -C(=O)NH 7c 7b 7d2,-C(=O)NHR , -C(=O)NR R . In a moreparticular embodiment, R2ais C1-6alkyl substituted with one, two or three independently selected R3band each R3bis independently selected from -C(=O)-cyclopropyl, -C(=O)-morpholinyl, -C(=O)NH2, - C(=O)N(CH3)2, -C(=O)NH-cyclopropyl. In a most particular embodiment, R2ais -CH3, or -CH2CH3substituted with one R3band each R3bis independently selected from -C(=O)-cyclopropyl, -C(=O)- morpholinyl, -C(=O)NH2, -C(=O)N(CH3)2, -C(=O)NH-cyclopropyl.GAL-363-WO-PCT 19

[0092] In one embodiment, the compound of the invention is according to Formula I, wherein Cy isselected from: , ,wherein * represents the points of attachment.

[0093] In one embodiment, the compound of the invention is according to Formula I, or II, wherein G isR1. In a particular embodiment, R1is 4-7 membered monocyclic heterocycloalkyl, comprising one or more independently selected N, O or S heteroatoms. In a more particular embodiment, R1is pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, 2-oxa-5- azabicyclo[2.2.1]heptanyl, or oxazepanyl.

[0094] In one embodiment, the compound of the invention is according to Formula I, or II, wherein G isR1. In a particular embodiment, R1is 4-7 membered monocyclic heterocycloalkyl, comprising one or more independently selected N, O or S heteroatoms, which heterocycloalkyl is substituted with one or more groups independently selected from =O and R5d. In a more particular embodiment, R1is pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, 2-oxa-5- azabicyclo[2.2.1]heptanyl, or oxazepanyl, each of which is substituted with one or more groupsindependently selected from =O and R5d. In a further more particular embodiment, R1 is pyrrolidinyl,tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, 2-oxa-5- azabicyclo[2.2.1]heptanyl, or oxazepanyl, each of which is substituted with one or more groups independently selected from =O, halo, -CN, -C(=O)OR7b, C1-4alkyl, C3-7cycloalkyl, -NHCH2phenyl, -C(=O)R7a, -C(=O)NHR7c, -S(=O) R7f, and -P(=O)R7jR7k 12 . In a most particular embodiment, R ispyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, or oxazepanyl, each of which is substituted with one or more groups independently selected from =O, F, Cl, -CN, -C(=O)OH, -CH3, cyclopropyl, -NHCH2phenyl, -C(=O)-cyclopropyl, -C(=O)-pyridinyl, -C(=O)NH-cyclopropyl, -S(=O)2CH3, -S(=O)2-cyclopropyl, and - P(=O)(CH3)2.

[0095] In one embodiment, the compound of the invention is according to Formula I, or II, wherein G isGAL-363-WO-PCT 20, F ,wherein * represents the points of attachment.

[0096] In one embodiment, the compound of the invention is according to Formula I or II, wherein G isR1, wherein R1is phenyl optionally substituted with one or more independently selected R5a. In a particular embodiment, R1is phenyl optionally substituted with one, two or three independently selected R5a. In a further particular embodiment, each R5ais independently selected from halo, -OH, -C(=O)NH2, or C1-4 alkyl,

[0097] In one embodiment, the compound of the invention is according to Formula I or II, wherein G isR1, wherein R1is 5-6 membered monocyclic heteroaryl comprising one or more independently selected N, O, or S heteroatoms, unsubstituted or substituted with one or more independently selected R5b. In a particular embodiment, R1is 5-6 membered monocyclic heteroaryl comprising one or more independently selected N, O, or S heteroatoms, unsubstituted or substituted with one, two or three independently selected R5b. In a further particular embodiment, R1is oxazolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, each of which is unsubstituted or substituted with one, two or three independently selected R5b. In a more particular embodiment, each R5bis independently selected from halo, -OH, -C(=O)NH2, or C1-4alkyl.

[0098] In one embodiment, the compound of the invention is according to Formula I or II, wherein G isR1, wherein R1is 8-10 membered fused bicyclic heteroaryl comprising one or more independently selected N, O, or S heteroatoms, unsubstituted or substituted with one or more independently selected R5c. In a particular embodiment, R1is 8-10 membered fused bicyclic heteroaryl comprising one or more independently selected N, O, or S heteroatoms, unsubstituted or substituted with one, two or three independently selected R5c. In a further particular embodiment, R1is indolyl or indazolyl, each of which isGAL-363-WO-PCT 21unsubstituted or substituted with one, two or three independently selected R5c. In a more particular embodiment, each R5cis independently selected from halo, -OH, -C(=O)NH2, or C1-4 alkyl.

[0099] In one embodiment, the compound of the invention is according to Formula I or II, wherein G isN ,wherein * represents the points of attachment.

[0100] In one embodiment, the compound of the invention is according to Formula I or II, wherein G is -L-R1, wherein L is C1-4 alkylenyl, and R1is 5-6 membered monocyclic heteroaryl comprising one or more independently selected N, O, or S heteroatoms, unsubstituted or substituted with one or more independently selected R5b. In a particular embodiment, G is -CH2-R1, wherein R1is 5-6 membered monocyclic heteroaryl comprising one or more independently selected N, O, or S heteroatoms, unsubstituted or substituted with one or more independently selected R5b. In a more particular embodiment, G is -CH2-R1, wherein R1is 5-6 membered monocyclic heteroaryl comprising one or more independently selected N, O, or S heteroatoms. In a more particular embodiment, G is -CH2-R1, wherein R1is pyridinyl.

[0101] In one embodiment, the compound of the invention is according to Formula I or II, wherein G is -L-R1, wherein L is C1-4alkenylenyl, and R1phenyl optionally substituted with one or more independently selected R5a. In a particular embodiment, G is -CH=CH-R1, wherein R1is phenyl, unsubstituted or substituted with one or more independently selected R5b. In a more particular embodiment, G is -CH=CH- R1, wherein R1is phenyl.

[0102] In one embodiment, the compound of the invention is according to Formula I or II, wherein G is --N(R4b)-L-R1, wherein R4bis H, L is C1-4alkylenyl, and R1is 5-6 membered monocyclic heteroaryl comprising one or more independently selected N, O, or S heteroatoms, unsubstituted or substituted with one or more independently selected R5b. In a particular embodiment, G is -NH-CH2-R1, wherein R1is 5-6 membered monocyclic heteroaryl comprising one or more independently selected N, O, or S heteroatoms, unsubstituted or substituted with one or more independently selected R5b. In a more particular embodiment, G is -NH-CH2-R1, wherein R1is 5-6 membered monocyclic heteroaryl comprising one or more independently selected N, O, or S heteroatoms. In a more particular embodiment, G is -NH-CH2-R1, wherein R1is pyridinyl.

[0103] In one embodiment, I or II, wherein G is, , or wherein * represents the points of attachment.GAL-363-WO-PCT 22

[0104] In one embodiment, the compound of the invention is according to Formula I or II, wherein G is -N(R4a)-R1, wherein R4ais H, and R1is 5-6 membered monocyclic heteroaryl comprising one or more independently selected N, O, or S heteroatoms. In a particular embodiment, G is -NH-R1, wherein R1is pyrazolyl or pyridinyl.

[0105] In one embodiment, the compound of the invention is according to Formula I or II, wherein G is -N(R4a)-R1, wherein R4ais H, and R1is 5-6 membered monocyclic heteroaryl comprising one or more independently selected N, O, or S heteroatoms, substituted with one or more independently selected R5b. In a particular embodiment, G is -NH-R1, wherein R1is 5-6 membered monocyclic heteroaryl comprising one or more independently selected N, O, or S heteroatoms, substituted with one two or three independently R5bgroups selected from C1-4 alkyl. In a more particular embodiment, G is -NH-R1, wherein R1is pyrazolyl or pyridinyl, each of which is substituted with one two or three independently R5bgroups selected from C1- 4 alkyl.

[0106] In one embodiment, the compound of the invention is according to Formula I or II, wherein G iswherein * represents the points of attachment.

[0107] In one embodiment, the compound of the invention is selected from the compounds of Table IIherein

[0108] In one embodiment, a compound of the invention are provided in a natural isotopic form.

[0109] In one embodiment, a compound of the invention are provided in an unnatural variant isotopicform. In a specific embodiment, the unnatural variant isotopic form is a form in which deuterium (i.e.2H or D) is incorporated where hydrogen is specified in the chemical structure in one or more atoms of a compound of the invention. In one embodiment, the atoms of the compounds of the invention are in anisotopic form which is not radioactive. In one embodiment, one or more atoms of the compounds of theinvention are in an isotopic form which is radioactive. Suitably radioactive isotopes are stable isotopes.Suitably the unnatural variant isotopic form is a pharmaceutically acceptable form.

[0110] In one embodiment, a compound of the invention is provided whereby a single atom of thecompound exists in an unnatural variant isotopic form. In another embodiment, a compound of the invention is provided whereby two or more atoms exist in an unnatural variant isotopic form.

[0111] Unnatural isotopic variant forms can generally be prepared by conventional techniques known tothose skilled in the art or by processes described herein e.g. processes analogous to those described in theaccompanying Examples for preparing natural isotopic forms. Thus, unnatural isotopic variant forms couldbe prepared by using appropriate isotopically variant (or labelled) reagents in place of the normal reagentsemployed in the illustrative example as examples.

[0112] In one aspect a compound of the invention according to any one of the embodiments hereindescribed is present as the free base.GAL-363-WO-PCT 23

[0113] In one aspect a compound of the invention according to any one of the embodiments hereindescribed is a pharmaceutically acceptable salt.

[0114] In one aspect a compound of the invention according to any one of the embodiments hereindescribed is a solvate of the compound.

[0115] In one aspect a compound of the invention according to any one of the embodiments hereindescribed is a solvate of a pharmaceutically acceptable salt of a compound.

[0116] While specified groups for each embodiment have generally been listed above separately, acompound of the invention includes one in which several or each embodiment in the above Formula, aswell as other formulae presented herein, is selected from one or more of particular members or groups designated respectively, for each variable. Therefore, this invention is intended to include all combinations of such embodiments within its scope.

[0117] While specified groups for each embodiment have generally been listed above separately, acompound of the invention may be one for which one or more variables (for example, R groups) is selected from one or more embodiments according to any of the Formula(e) listed above. Therefore, the present invention is intended to include all combinations of variables from any of the disclosed embodiments within its scope.

[0118] Alternatively, the exclusion of one or more of the specified variables from a group or anembodiment, or combinations thereof is also contemplated by the present invention.

[0119] In certain aspects, the present invention provides prodrugs and derivatives of the compoundsaccording to the formulae above. Prodrugs are derivatives of the compounds of the invention, which have metabolically cleavable groups and become by solvolysis or under physiological conditions the compounds of the invention, which are pharmaceutically active, in vivo. Such examples include, but are not limited to, choline ester derivatives and the like, N-alkylmorpholine esters and the like.

[0120] Other derivatives of the compounds of this invention have activity in both their acid and acidderivative forms, but the acid sensitive form often offers advantages of solubility, tissue compatibility, ordelayed release in the mammalian organism (Bundgard, H, 1985). Prodrugs include acid derivatives wellknown to practitioners of the art, such as, for example, esters prepared by reaction of the parent acid with asuitable alcohol, or amides prepared by reaction of the parent acid compound with a substituted or unsubstituted amine, or acid anhydrides, or mixed anhydrides. Simple aliphatic or aromatic esters, amides and anhydrides derived from acidic groups pendant on the compounds of this invention are preferred prodrugs. In some cases it is desirable to prepare double ester type prodrugs such as (acyloxy)alkyl esters or ((alkoxycarbonyl)oxy)alkylesters. Particularly useful are the C1to C8alkyl, C2-C8alkenyl, aryl, C7-C12substituted aryl, and C7-C12arylalkyl esters of the compounds of the invention. PHARMACEUTICAL COMPOSITIONS

[0121] When employed as a pharmaceutical, a compound of the invention is typically administered in theform of a pharmaceutical composition. Such compositions can be prepared in a manner well known in the pharmaceutical art and comprise at least one active compound of the invention according to Formula I.GAL-363-WO-PCT 24Generally, a compound of the invention is administered in a pharmaceutically effective amount. The amount of compound of the invention actually administered will typically be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound of the invention administered, the age, weight, and response of the individual patient, the severity of the patient’s symptoms, and the like.

[0122] The pharmaceutical compositions of this invention can be administered by a variety of routesincluding oral, rectal, transdermal, subcutaneous, intra-articular, intravenous, intramuscular, and intranasal. Depending on the intended route of delivery, a compound of the invention is preferably formulated as either injectable or oral compositions or as salves, as lotions or as patches all for transdermal administration.

[0123] The compositions for oral administration can take the form of bulk liquid solutions or suspensions,or bulk powders. More commonly, however, the compositions are presented in unit dosage forms to facilitate accurate dosing. The term ‘unit dosage forms’ refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient, vehicle or carrier. Typical unit dosage forms include prefilled, premeasured ampules or syringes of the liquid compositions or pills, tablets, capsules or the like in the case of solid compositions. In such compositions, the compound of the invention according to Formula I is usually a minor component (from about 0.1 to about 50% by weight or preferably from about 1 to about 40% by weight) with the remainder being various vehicles or carriers and processing aids helpful for forming the desired dosing form.

[0124] Liquid forms suitable for oral administration may include a suitable aqueous or non-aqueousvehicle with buffers, suspending and dispensing agents, colorants, flavors and the like. Solid forms may include, for example, any of the following ingredients, or compound of the inventions of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint or orange flavoring.

[0125] Injectable compositions are typically based upon injectable sterile saline or phosphate-bufferedsaline or other injectable carriers known in the art. As before, the active compound of the invention according to Formula I in such compositions is typically a minor component, often being from about 0.05 to 10% by weight with the remainder being the injectable carrier and the like.

[0126] Transdermal compositions are typically formulated as a topical ointment or cream containing theactive ingredient(s), generally in an amount ranging from about 0.01 to about 20% by weight, preferably from about 0.1 to about 20% by weight, preferably from about 0.1 to about 10% by weight, and more preferably from about 0.5 to about 15% by weight. When formulated as an ointment, the active ingredients will typically be combined with either a paraffinic or a water-miscible ointment base. Alternatively, the active ingredients may be formulated in a cream with, for example an oil-in-water cream base. Such transdermal formulations are well-known in the art and generally include additional ingredients to enhanceGAL-363-WO-PCT 25the dermal penetration of stability of the active ingredients or the formulation. All such known transdermal formulations and ingredients are included within the scope of this invention.

[0127] A compound of the invention can also be administered by a transdermal device. Accordingly,transdermal administration can be accomplished using a patch either of the reservoir or porous membrane type, or of a solid matrix variety.

[0128] The above-described components for orally administrable, injectable or topically administrablecompositions are merely representative. Other materials as well as processing techniques and the like are set forth in Part 8 of Remington’s Pharmaceutical Sciences, 17thedition, 1985, Mack Publishing Company, Easton, Pennsylvania, which is incorporated herein by reference.

[0129] A compound of the invention can also be administered in sustained release forms or from sustainedrelease drug delivery systems. A description of representative sustained release materials can be found in Remington’s Pharmaceutical Sciences.

[0130] The following formulation examples illustrate representative pharmaceutical compositions thatmay be prepared in accordance with this invention. The present invention, however, is not limited to the following pharmaceutical compositions. Formulation 1 - Tablets

[0131] A compound of the invention according to Formula I may be admixed as a dry powder with a drygelatin binder in an approximate 1:2 weight ratio. A minor amount of magnesium stearate may be added as a lubricant. The mixture may be formed into 240-270 mg tablets (80-90 mg of active compound of the invention according to Formula I per tablet) in a tablet press. Formulation 2 - Capsules

[0132] A compound of the invention according to Formula I may be admixed as a dry powder with a starchdiluent in an approximate 1:1 weight ratio. The mixture may be filled into 250 mg capsules (125 mg of active compound of the invention according to Formula I per capsule). Formulation 3 - Liquid

[0133] A compound of the invention according to Formula I (125 mg), may be admixed with sucrose (1.75g) and xanthan gum (4 mg) and the resultant mixture may be blended, passed through a No.10 mesh U.S. sieve, and then mixed with a previously made solution of microcrystalline cellulose and sodium carboxymethyl cellulose (11:89, 50 mg) in water. Sodium benzoate (10 mg), flavor, and color may be diluted with water and added with stirring. Sufficient water may then be added with stirring. Further sufficient water may be then added to produce a total volume of 5 mL. Formulation 4 - Tablets

[0134] A compound of the invention according to Formula I may be admixed as a dry powder with a drygelatin binder in an approximate 1:2 weight ratio. A minor amount of magnesium stearate may be added as a lubricant. The mixture may be formed into 450-900 mg tablets (150-300 mg of active compound of the invention according to Formula I) in a tablet press.GAL-363-WO-PCT 26Formulation 5 - Injection

[0135] A compound of the invention according to Formula I may be dissolved or suspended in a bufferedsterile saline injectable aqueous medium to a concentration of approximately 5 mg / mL. Formulation 6 - Topical

[0136] Stearyl alcohol (250 g) and a white petrolatum (250 g) may be melted at about 75ºC and then amixture of A compound of the invention according to Formula I (50 g) methylparaben (0.25 g), propylparaben (0.15 g), sodium lauryl sulfate (10 g), and propylene glycol (120 g) dissolved in water (about 370 g) may be added and the resulting mixture may be stirred until it congeals. METHODS OF TREATMENT

[0137] In one embodiment, the present invention provides compounds of the invention, or pharmaceuticalcompositions comprising a compound of the invention, for use in medicine. In a particular embodiment, the present invention provides compounds of the invention or pharmaceutical compositions comprising a compound of the invention, for use in the prophylaxis and / or treatment of tuberculosis (TB) and / or non-tuberculous mycobacteria (NTM).

[0138] In another embodiment, the present invention provides compounds of the invention, orpharmaceutical compositions comprising a compound of the invention for use in the manufacture of a medicament for use in the prophylaxis and / or treatment of tuberculosis (TB) and / or non-tuberculousmycobacteria (NTM).

[0139] In additional method of treatment aspects, this invention provides methods of prophylaxis and / ortreatment of a mammal afflicted with tuberculosis (TB) and / or non-tuberculous mycobacteria (NTM),which methods comprise the administration of an effective amount of a compound of the invention or one or more of the pharmaceutical compositions herein described for the treatment or prophylaxis of said condition.

[0140] In one embodiment, the present invention provides pharmaceutical compositions comprising acompound of the invention, and another therapeutic agent. In a particular embodiment, the other therapeuticagent is a tuberculosis (TB) and / or non-tuberculous mycobacteria (NTM)treatment agent.

[0141] Injection dose levels range from about 0.1 mg / kg / h to at least 10 mg / kg / h, all for from about 1 toabout 120 h and especially 24 to 96 h. A preloading bolus of from about 0.1 mg / kg to about 10 mg / kg or more may also be administered to achieve adequate steady state levels. The maximum total dose is not expected to exceed about 1 g / day for a 40 to 80 kg human patient.

[0142] For the prophylaxis and / or treatment of long-term conditions, such as degenerative conditions, theregimen for treatment usually stretches over many months or years so oral dosing is preferred for patient convenience and tolerance. With oral dosing, one to four (1-4) regular doses daily, especially one to three (1-3) regular doses daily, typically one to two (1-2) regular doses daily, and most typically one (1) regulardose daily are representative regimens. Alternatively for long lasting effect drugs, with oral dosing, onceevery other week, once weekly, and once a day are representative regimens. In particular, dosage regimenGAL-363-WO-PCT 27can be every 1-14 days, more particularly 1-10 days, even more particularly 1-7 days, and most particularly 1-3 days.

[0143] Using these dosing patterns, each dose provides from about 1 to about 1000 mg of a compound ofthe invention, with particular doses each providing from about 10 to about 500 mg and especially about 30 to about 250 mg.

[0144] Transdermal doses are generally selected to provide similar or lower blood levels than are achievedusing injection doses.

[0145] When used to prevent the onset of a condition, a compound of the invention will be administeredto a patient at risk for developing the condition, typically on the advice and under the supervision of a physician, at the dosage levels described above. Patients at risk for developing a particular condition generally include those that have a family history of the condition, or those who have been identified by genetic testing or screening to be particularly susceptible to developing the condition.

[0146] A compound of the invention can be administered as the sole active agent or it can be administeredin combination with other therapeutic agents, including other compound of the inventions that demonstratethe same or a similar therapeutic activity and that are determined to be safe and efficacious for suchcombined administration. In a specific embodiment, co-administration of two (or more) agents allows for significantly lower doses of each to be used, thereby reducing the side effects seen.

[0147] In one embodiment, a compound of the invention or a pharmaceutical composition comprising acompound of the invention is administered as a medicament. In a specific embodiment, said pharmaceutical composition additionally comprises a further active ingredient.

[0148] In one embodiment, a compound of the invention is co-administered with the standard of care forMycobacterium avium complex (MAC) infections, namely azithromycin or clarithromycin, along withethambutol and rifampin. In a specific embodiment, a compound of the invention could be in the place of rifampin along with azithromycin or clarithromycin, and ethambutol.

[0149] In one embodiment, a compound of the invention is co-administered with the standards of care forMycobacterium tuberculosis including isoniazid (CAS#54-85-3), pyrazinamide (CAS#98-96-4), and ethambutol (CAS#74-55-5).

[0150] In one embodiment, a compound of the invention is co-administered with one or more compoundfrom one or more compounds from the following classes of compounds;- Macrolide antibiotic such as but not limited to azithromycin (CAS#83905-01-5) or clarithromycin(CAS#81103-11-9),- aminoglycoside antibiotic such as but not limited to gentamicin (CAS#1403-66-3), tobramycin(CAS#32986-56-4), amikacin (CAS#37517-28-5), plazomicin (CAS#1154757-24-0), streptomycin (CAS#57-92-1), neomycin (CAS#1404-04-2) and paromomycin (CAS#1263-89-4),- carbapenem antibiotics such as but not limited to imipenem (CAS#64221-86-9), meropenem(CAS#119478-56-7),GAL-363-WO-PCT 28- Fluoroquinolones such as but not limited to levofloxacin (CAS#100986-85-4), ciprofloxacin(CAS#85721-33-1), moxifloxacin (CAS#151096-09-2), ofloxacin (CAS#82419-36-1), gemifloxacin (CAS#175463-14-6) and delafloxacin (CAS#189279-58-1)- Oxazolidinones such as but not limited to linezolid (CAS#165800-03-3), posizolid (CAS#252260-02-9), tedizolid (CAS#856866-72-3) and radezolid (CAS#869884-78-6)- Tetracyclines such as but not limited to tetracycline (CAS#60-54-8), doxycycline (CAS#564-25-0),minocycline (CAS#10118-90-8), tigecycline (CAS#220620-09-7)- Cephalosporins such as but not limited to cefazolin (CAS#25953-19-9), cephalexin (CAS#25953-19-9), cefuroxime (CAS#55268-75-2), cefoxitin (CAS#35607-66-0), ceftriaxone (CAS#73384-59-5), ceftazidime (CAS#72558-82-8), cefepime (CAS#88040-23-7), ceftaroline (CAS#229016‐73‐3)- Riminophenazine antimycobacterials such as but not limited to clofazimine (CAS#2030-63-9), and- bedaquiline (CAS#843663-66-1)

[0151] In a further embodiment a compound of the invention is used in combination with one or moreinhibitor(s) of the mycobacterial enzymes InhA, Dpre1, coenzyme A, adenosine triphosphate (ATP) synthase,.

[0152] In one embodiment, a compound of the invention may be co-administered with a therapeuticallyeffective amount of one or more additional therapeutic agents to treat a CFTR mediated disease, where examples of the therapeutic agents include, but are not limited to antibiotics (for example, aminoglycosides, colistin, aztreonam, ciprofloxacin, and azithromycin), expectorants (for example, hypertonic saline, acetylcysteine, dornase alfa, and denufosol), pancreatic enzyme supplements (for example, pancreatin, and pancrelipase), epithelial sodium channel blocker (ENaC) inhibitors, CFTR modulators (for example, CFTR potentiators, CFTR correctors), and CFTR amplifiers. In one embodiment, the CFTR mediated disease is cystic fibrosis, chronic obstructive pulmonary disease (COPD), dry eye disease, pancreatic insufficiency, or Sjogren's syndrome. In one embodiment, the CFTR mediated disease is cystic fibrosis. In oneembodiment, a compound of the invention may be co-administered with one or two CFTR modulators andone CFTR amplifier. In one embodiment, a compound of the invention may be co-administered with onepotentiator, one or more correctors, and one CFTR amplifier. In one embodiment, a compound of theinvention may be co-administered with one or more CFTR modulators. In one embodiment, a compoundof the invention may be co-administered with one, two or three CFTR modulators. In one embodiment, thecompounds of the invention may be co-administered with one potentiator and one or more correctors. In one embodiment, the compounds of the invention may be co-administered with one potentiator. In one embodiment, the compounds of the invention may be co-administered with one or more correctors.

[0153] Examples of CFTR potentiators include, but are not limited to, Ivacaftor (VX-770), CTP-656,NVS-QBW251, FD1860293, GLPG2451, GLPG1837, N-(3-carbamoyl-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-2-yl)-1H-pyrazole-5-carboxamide and 3-amino-N-[(2S)-2-hydroxypropyl]-5-{[4-(trifluoromethoxy)phenyl]sulfonyl}pyridine-2-carboxamide. Examples of potentiators are also disclosed in publications: WO2005120497, WO2008147952, WO2009076593, WO2010048573, WO2006002421,GAL-363-WO-PCT 29WO2011072241, WO2011113894, WO2013038373, WO2013038378, WO2013038381, WO2013038386, WO2013038390, WO2014180562, WO2015018823.

[0154] Non-limiting examples of correctors include Lumacaftor (VX-809), 1-(2,2-difluoro-1,3-benzodioxol-5-yl)-N-{1-[(2R)-2,3-dihydroxypropyl]-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl}cyclopropanecarboxamide (VX-661), VX-983, GLPG2222, GLPG2665, GLPG2851, VX-152,VX-440, FDL169, FDL304, FD2052160, and FD2035659. Examples of correctors are also disclosed in US Applications 14 / 925,649, 14 / 926,727, 62 / 193,391, 62 / 299,633, and 62 / 239475.

[0155] In one embodiment, the additional therapeutic agent is a CFTR amplifier. CFTR amplifiersenhance the effect of known CFTR modulators, such as potentiators and correctors. Examples of CFTR amplifiers are PTI130 and PTI-428. Examples of amplifiers are also disclosed in publications: WO2015138909 and WO2015138934.

[0156] In one embodiment, the additional therapeutic agent is a corrected CFTR stabilizer. CorrectedCFTR stabilizers enhance the stability of CFTR that has been treated with a corrector. An examples of acorrected CFTR stabilizer is cavosonstat (CAS# 1371587-51-7). Examples of stabilizers are also disclosedin publication: WO2012048181.

[0157] In one embodiment, the additional therapeutic agent is an agent that reduces the activity of theepithelial sodium channel blocker (ENaC) either directly by blocking the channel or indirectly by modulation of proteases that lead to an increase in ENaC activity (e.g., serine proteases, channel-activating proteases). Exemplary of such agents include camostat (a trypsin-like protease inhibitor), QAU145, 552- 02, GS-9411, INO-4995, Aerolytic, amiloride, and VX-371. Additional agents that reduce the activity of the epithelial sodium channel blocker (ENaC) can be found, for example, in PCT Publication No. WO2009074575 and WO2013043720; and US Patent No. US8999976.

[0158] In one embodiment, a compound of the invention is co-administered with another therapeutic agentfor the treatment and / or prophylaxis of a disease involving inflammation, particular agents include, but arenot limited to, immunoregulatory agents e.g. azathioprine, corticosteroids (e.g. prednisolone ordexamethasone), cyclophosphamide, cyclosporin A, tacrolimus, mycophenolate, mofetil, muromonab-CD3(OKT3, e.g. Orthocolone®), ATG, aspirin, acetaminophen, ibuprofen, naproxen, and piroxicam.

[0159] In one embodiment, a compound of the invention is co-administered with another therapeutic agentfor the treatment and / or prophylaxis of arthritis (e.g. rheumatoid arthritis), particular agents include but arenot limited to analgesics, non-steroidal anti-inflammatory drugs (NSAIDS), steroids, synthetic DMARDS (for example but without limitation methotrexate, leflunomide, sulfasalazine, auranofin, sodium aurothiomalate, penicillamine, chloroquine, hydroxychloroquine, azathioprine, tofacitinib, baricitinib, fostamatinib, and cyclosporin), and biological DMARDS (for example but without limitation infliximab, etanercept, adalimumab, rituximab, and abatacept).

[0160] In one embodiment, a compound of the invention is co-administered with another therapeutic agentfor the treatment and / or prophylaxis of proliferative disorders, particular agents include but are not limited to: methotrexate, leukovorin, adriamycin, prednisone, bleomycin, cyclophosphamide, 5-fluorouracil, paclitaxel, docetaxel, vincristine, vinblastine, vinorelbine, doxorubicin, tamoxifen, toremifene, megestrolGAL-363-WO-PCT 30acetate, anastrozole, goserelin, anti-HER2 monoclonal antibody (e.g. HerceptinTM), capecitabine,raloxifene hydrochloride, EGFR inhibitors (e.g. lressa®, Tarceva™, Erbitux™), VEGF inhibitors (e.g.Avastin™), proteasome inhibitors (e.g. Velcade™), Glivec® and hsp90 inhibitors (e.g. 17-AAG).Additionally, the compound of the invention according to Formula I may be administered in combination with other therapies including, but not limited to, radiotherapy or surgery. In a specific embodiment theproliferative disorder is selected from cancer, myeloproliferative disease or leukaemia.

[0161] In one embodiment, a compound of the invention is co-administered with another therapeutic agentfor the treatment and / or prophylaxis of autoimmune diseases, particular agents include but are not limitedto: glucocorticoids, cytostatic agents (e.g. purine analogs), alkylating agents, (e.g nitrogen mustards(cyclophosphamide), nitrosoureas, platinum compound of the inventions, and others), antimetabolites (e.g.methotrexate, azathioprine and mercaptopurine), cytotoxic antibiotics (e.g. dactinomycin anthracyclines,mitomycin C, bleomycin, and mithramycin), antibodies (e.g. anti-CD20, anti-CD25 or anti-CD3 (OTK3)monoclonal antibodies, Atgam® and Thymoglobuline®), cyclosporin, tacrolimus, rapamycin (sirolimus),interferons (e.g. IFN-β), TNF binding proteins (e.g. infliximab, etanercept, or adalimumab),mycophenolate, fingolimod and myriocin..

[0162] In one embodiment, a compound of the invention is co-administered with another therapeutic agentfor the treatment and / or prophylaxis of transplant rejection, particular agents include but are not limited to:calcineurin inhibitors (e.g. cyclosporin or tacrolimus (FK506)), mTOR inhibitors (e.g. sirolimus,everolimus), anti-proliferatives (e.g. azathioprine, mycophenolic acid), corticosteroids (e.g. prednisolone,hydrocortisone), antibodies (e.g. monoclonal anti-IL-2Rα receptor antibodies, basiliximab, daclizumab),polyclonal anti-T-cell antibodies (e.g. anti-thymocyte globulin (ATG), anti-lymphocyte globulin (ALG)).

[0163] In one embodiment, a compound of the invention is co-administered with another therapeutic agentfor the treatment and / or prophylaxis of asthma and / or rhinitis and / or COPD, particular agents include butare not limited to: beta2-adrenoceptor agonists (e.g. salbutamol, levalbuterol, terbutaline and bitolterol),epinephrine (inhaled or tablets), anticholinergics (e.g. ipratropium bromide), glucocorticoids (oral orinhaled). Long-acting β2-agonists (e.g. salmeterol, formoterol, bambuterol, and sustained-release oralalbuterol), Long-acting muscarinic antagonists (e.g. tiotropium, aclidinium, umeclidinium, andglycopyrrolate), Leukotriene modifiers (e.g montelukast, zafirlukast and zileuton), combinations of inhaledsteroids and long-acting bronchodilators (e.g. fluticasone / salmeterol, budesonide / formoterol), leukotrieneantagonists and synthesis inhibitors (e.g. montelukast, zafirlukast and zileuton), inhibitors of mediatorrelease (e.g. cromoglycate and ketotifen), biological regulators of IgE response (e.g. omalizumab),antihistamines (e.g. ceterizine, cinnarizine, fexofenadine) and vasoconstrictors (e.g. oxymethazoline,xylomethazoline, nafazoline and tramazoline).

[0164] Additionally, a compound of the invention may be administered in combination with emergencytherapies for asthma and / or COPD, such therapies include oxygen or heliox administration, nebulizedsalbutamol or terbutaline (optionally combined with an anticholinergic (e.g. ipratropium), systemic steroids(oral or intravenous, e.g. prednisone, prednisolone, methylprednisolone, dexamethasone, orhydrocortisone), intravenous salbutamol, non-specific beta-agonists, injected or inhaled (e.g. epinephrine,GAL-363-WO-PCT 31isoetharine, isoproterenol, metaproterenol), anticholinergics (IV or nebulized, e.g. glycopyrrolate, atropine,ipratropium), methylxanthines (theophylline, aminophylline, bamiphylline), inhalation anesthetics thathave a bronchodilatory effect (e.g. isoflurane, halothane, enflurane), ketamine and intravenous magnesiumsulfate.

[0165] In one embodiment, a compound of the invention is co-administered with another therapeutic agentfor the treatment of bronchiectasis, including but not limited to mucolytic agents (e.g. carbocysteine, N- acetylcysteine, mannitol, human DNAse, sodium hyaluronate).

[0166] In one embodiment, a compound of the invention is co-administered with another therapeutic agentfor the treatment and / or prophylaxis of allergic reaction, particular agents include but are not limited to:antihistamines (e.g. cetirizine, diphenhydramine, fexofenadine, levocetirizine), glucocorticoids (e.g.prednisone, betamethasone, beclomethasone, dexamethasone), epinephrine, theophylline or anti-leukotrienes (e.g. montelukast or zafirlukast), anti-cholinergics and decongestants.

[0167] By co-administration is included any means of delivering two or more therapeutic agents to thepatient as part of the same treatment regime, as will be apparent to the skilled person. Whilst the two ormore agents may be administered simultaneously in a single formulation, i.e. as a single pharmaceuticalcomposition, this is not essential. The agents may be administered in different formulations and at different times. CHEMICAL SYNTHETIC PROCEDURES General

[0168] The compound of the invention can be prepared from readily available starting materials using thefollowing general methods and procedures. It will be appreciated that where typical or preferred processconditions (i.e. reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given,other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures.

[0169] Additionally, as will be apparent to those skilled in the art, conventional protecting groups may benecessary to prevent certain functional groups from undergoing undesired reactions. The choice of a suitable protecting group for a particular functional group as well as suitable conditions for protection anddeprotection are well known in the art (Greene, T W; Wuts, P G M;, 1991).

[0170] The following methods are presented with details as to the preparation of a compound of theinvention as defined hereinabove and the comparative examples. A compound of the invention may be prepared from known or commercially available starting materials and reagents by one skilled in the art of organic synthesis.

[0171] All reagents are of commercial grade and are used as received without further purification, unlessotherwise stated. Commercially available anhydrous solvents are used for reactions conducted under inert atmosphere. Reagent grade solvents are used in all other cases, unless otherwise specified.GAL-363-WO-PCT 32

[0172] Column chromatography was performed using Isolute SPE 20g Flash Si II Column; weak solvent:DCM, strong solvent: 5% methanol in DCM, 30-100% strong solvent over 15 column volumes.

[0173] Silica gel flash column chromatography was performed on:

[0174] Buchi Pure C-810 Flash using Interchim PF-15SIHC-JP / 12G and Interchim PF-15SIHC-JP / 40Gcolumns; weak solvent: DCM, strong solvent: 5% methanol in DCM, 0-100% strong solvent over 25 column volumes, flow 12-25mL / min.

[0175] Interchim puriFlash XS 420 using Interchim PF-15SIHC-JP / 4G column; weak solvent: DCM,strong solvent: 5% methanol in DCM, 0-100% strong solvent over 25 column volumes, flow 12-25mL / min and Interchim PF-15SIHC-JP / 80G column weak solvent: cyclohexane, strong solvent: ethyl acetate, 0- 100% strong solvent over 30 column volumes, flow 24mL / min.

[0176] Silica gel Prep Flash Column Chromatography was performed on Buchi Pure C-850 FlashPrepusing XBridge BEH C18 OBD Prep Column, 130Å, 5 µm, 30 mm X 150 mm column, strong solvent:acetonitrile, weak solvent: ammonium bicarbonate water solution buffer pH=9.2, 3%-97%-3% strongsolvent over 25 column volumes, flow 17mL / min. LC-MS Methods (analytical):

[0177] Method 1 (LC-MS) 2min_low_3_97_BEH

[0178] LC / MS System: Acquity UPLC coupled with SQD mass spectrometer; Column: Acquity UPLCBEH C18 (50mm x 2.1mm i.d., 1.7μm packing diameter); mobile phase A: 0.1% formic acid in water, mobile phase B: 0.1% formic acid in acetonitrile; gradient: 0.0 min 97 % A, 3 % B, flow rate 0.9 mL / min; 1.5 min 3 % A, 97 % B, flow rate 0.9 mL / min; 1.9 min 3 % A, 97 % B, flow rate 0.9 mL / min; 2.0 min 97 % A, 3 % B, flow rate 0.05 mL / min; column temperature: 40 °C; UV detection: from 210 nm to 350 nm; MS conditions: Ionisation Mode: alternate-scan Positive and Negative Electrospray (ES+ / ES-); Scan Range: 100 to 1000 AMU. Method 2 (LC-MS): 2min_high_3_97_BEH

[0179] LC / MS System: Acquity UPLC coupled with SQD mass spectrometer; Column: Acquity UPLCBEH C18 (50mm x 2.1mm i.d., 1.7μm packing diameter); mobile phase A: 10 mM aqueous solution of ammonium bicarbonate (adjusted to pH 10 with ammonia), mobile phase B: acetonitrile; gradient: 0.0 min 97 % A, 3 % B, flow rate 0.9 mL / min; 1.5 min 3 % A, 97 % B, flow rate 0.9 mL / min; 1.9 min 3 % A, 97 % B, flow rate 0.9 mL / min; 2.0 min 97 % A, 3 % B, flow rate 0.05 mL / min; column temperature: 40 °C; UV detection: from 210 nm to 350 nm; MS conditions: Ionisation Mode: alternate-scan Positive and Negative Electrospray (ES+ / ES-); Scan Range: 100 to 1500 AMU. Method 3 (LC-MS): 4min_low_3_97_BEH

[0180] LC / MS System: Acquity UPLC coupled with SQD mass spectrometer; Column: Acquity UPLCBEH C18 (50mm x 2.1mm i.d., 1.7μm packing diameter); mobile phase A: 0.1% formic acid in water, mobile phase B: 0.1% formic acid in acetonitrile; gradient: 0.0 min 97 % A, 3 % B, flow rate 0.9 mL / min; 3.2 min 97 % A, 3 % B, flow rate 0.9 mL / min; 3.9 min 3 % A, 97 % B, flow rate 0.9 mL / min; 4.0 min 97GAL-363-WO-PCT 33% A, 3 % B, flow rate 0.05 mL / min; column temperature: 40 °C; UV detection: from 210 nm to 350 nm; MS conditions: Ionisation Mode: alternate-scan Positive and Negative Electrospray (ES+ / ES-); Scan Range: 100 to 1500 AMU. Method 4 (LC-MS): 4min_high_3_97_BEH

[0181] LC / MS System: Acquity UPLC coupled with SQD mass spectrometer; Column: Acquity UPLCBEH C18 (50mm x 2.1mm i.d., 1.7μm packing diameter); mobile phase A: 10 mM aqueous solution ofammonium bicarbonate (adjusted to pH 10 with ammonia), mobile phase acetonitrile; gradient: 0.0 min 95 % A, 5 % B, flow rate 0.5 mL / min; 3.0 min 95 % A, 5 % B, flow rate 0.5 mL / min; 17.50 min 5 % A, 95 % B, flow rate 0.5 mL / min; 19.00 min 5 % A, 95 % B, flow rate 0.5 mL / min; 19.50 min 95 % A, 5 % B, flow rate 0.5 mL / min; 20.00 min 95 % A, 5 % B, flow rate 0.5 mL / min; column temperature: 40 °C; UV detection: from 210 nm to 350 nm; MS conditions: Ionisation Mode: alternate-scan Positive and Negative Electrospray (ES+ / ES-); Scan Range: 100 to 1500 AMU. Method 5 (LC-MS): 12min_low_3_97_BEH

[0182] LC / MS System: Acquity UPLC coupled with SQD mass spectrometer; Column: Acquity UPLCBEH C18 (50mm x 2.1mm i.d., 1.7μm packing diameter); mobile phase A: 0.1% formic acid in water, mobile phase B: 0.1% formic acid in acetonitrile; gradient: 0.0 min 97 % A, 3 % B, flow rate 0.9 mL / min; 1.5 min 97 % A, 3 % B, flow rate 0.9 mL / min; 11.5 min 3 % A, 97 % B, flow rate 0.9 mL / min; 12.0 min 97 % A, 3 % B, flow rate 0.05 mL / min; column temperature: 40 °C; UV detection: from 210 nm to 350 nm; MS conditions: Ionisation Mode: alternate-scan Positive and Negative Electrospray (ES+ / ES-); Scan Range: 100 to 1500 AMU. Method 6 (LC-MS): 12min_high_3_97_BEH

[0183] LC / MS System: Acquity UPLC coupled with SQD mass spectrometer; Column: Acquity UPLCBEH C18 (50mm x 2.1mm i.d., 1.7μm packing diameter); mobile phase A: 10 mM aqueous solution of ammonium bicarbonate (adjusted to pH 10 with ammonia), mobile phase B: acetonitrile; gradient: 0.0 min 97 % A, 3 % B, flow rate 0.9 mL / min; 1.5 min 97 % A, 3 % B, flow rate 0.9 mL / min; 11.5 min 3 % A, 97 % B, flow rate 0.9 mL / min; 12.0 min 97 % A, 3 % B, flow rate 0.05 mL / min; column temperature: 40 °C;UV detection: from 210 nm to 350 nm; MS conditions: Ionisation Mode: alternate-scan Positive andNegative Electrospray (ES+ / ES-); Scan Range: 100 to 1500 AMU. Method 7 (LC-MS): (8_min_low_pH_3_97_BEH)

[0184] LC / MS System: Acquity UPLC coupled with SQD mass spectrometer; Column: Acquity UPLCBEH C18 (100mm x 2.1mm i.d., 1.7μm packing diameter); mobile phase A: Water + 0.1% of Formic Acid, mobile phase B: Acetonitrile + 0.1% of Formic Acid; gradient: 0.0 min 97 % A, 3 % B, flow rate 0.6 mL / min; 0.5 min 97 % A, 3 % B, flow rate 0.6 mL / min; 7.0 min 3 % A, 97 % B, flow rate 0.6 mL / min; 7.5 min 3 % A, 97 % B, flow rate 0.6 mL / min; 7.6 min 97 % A, 3 % B, flow rate 0.6 mL / min; 8.0 min 97 % A, 3 % B, flow rate 0.6 mL / min; column temperature: 40 °C; UV detection: from 210 nm to 400 nm; MS conditions: Ionisation Mode: Electrospray Positive and Negative (ES+ / ES-); Scan Range: 100 to 1500 AMU.GAL-363-WO-PCT 34Method 8 (LC-MS): (8_min_high_pH_3_97_BEH)

[0185] LC / MS System: Acquity UPLC coupled with SQD mass spectrometer; Column: Acquity UPLCBEH C18 (100mm x 2.1mm i.d., 1.7μm packing diameter); mobile phase A: Water + 0.05% of Ammonia,mobile phase B: Acetonitrile + 0.05% of Ammonia; gradient: 0.0 min 97 % A, 3 % B, flow rate 0.6 mL / min;0.5 min 97 % A, 3 % B, flow rate 0.6 mL / min; 7.0 min 3 % A, 97 % B, flow rate 0.6 mL / min; 7.5 min 3 % A, 97 % B, flow rate 0.6 mL / min; 7.6 min 97 % A, 3 % B, flow rate 0.6 mL / min; 8.0 min 97 % A, 3 % B, flow rate 0.6 mL / min; column temperature: 40 °C; UV detection: from 210 nm to 400 nm; MS conditions: Ionisation Mode: Electrospray Positive and Negative (ES+ / ES-); Scan Range: 100 to 1500 AMU. Method 9 (Q-TOF) 12 min_high_3-97_BEH

[0186] LC / MS System: Agilent 1260 LC System coupled with SFC and G6540B UHD Accurate-Mass Q-TOF mass spectrometer; Column: Acquity UPLC BEH C18 (2.1 mm x 100 mm, 1.7 μm); mobile phase A: 10 mM aqueous solution of ammonium bicarbonate (adjusted to pH 10 with ammonia), mobile phase B: acetonitrile; gradient: 0.0 min 97 % A, 3 % B, flow rate 0.5 mL / min; 0.5 min 97 % A, 3 % B, flow rate 0.5 mL / min; 8.0 min 0 % A, 100 % B, flow rate 0.5 mL / min; 9.5 min 0 % A, 100 % B, flow rate 0.5 mL / min; 10 min 97 % A, 3 % B, flow rate 0.5 mL / min; 12.0 min 97 % A, 3 % B, flow rate 0.5 mL / min;

[0187] column temperature: 40 °C; UV detection: from 190 nm to 400 nm; makeup composition 0.1%formic acid in acetonitrile; makeup flow 2.5 mL / min; MS conditions: Ion source: dual AJS ESI; Scan Range: 100 to 1000 AMU. Method 10 (Q-TOF) 12 min_low_3-97_BEH

[0188] LC / MS System: Agilent 1260 LC System coupled with SFC and G6540B UHD Accurate-Mass Q-TOF mass spectrometer; Column: Acquity UPLC BEH C18 (2.1 mm x 100 mm, 1.7 μm); mobile phase A:water + 0.1% of formic acid, mobile phase B: acetonitrile; gradient: 0.0 min 97 % A, 3 % B, flow rate 0.5mL / min; 0.0 min 97 % A, 3 % B, flow rate 0.5 mL / min; 8.0 min 0 % A, 100 % B, flow rate 0.5 mL / min; 9.5 min 0 % A, 100 % B, flow rate 0.5 mL / min; 10 min 97 % A, 3 % B, flow rate 0.5 mL / min; 12.0 min 97% A, 3 % B, flow rate 0.5 mL / min; column temperature: 40 °C; UV detection: from 190 nm to 400 nm;makeup composition 0.1% formic acid in acetonitrile; makeup flow 2.5 mL / min; MS conditions: Ion source: dual AJS ESI; Scan Range: 100 to 1000 AMU. LC-MS Methods (preparative): Method 11 (prep-HPLC): C_high

[0189] LC / MS System: Waters Mass Directed Auto Purification System with QDa mass

[0190] spectrometer; Column: XBridge C18 OBD (30 x 150mm, 5μm) with XBridge C18 OBD GuardCartridge (30 x 10mm, 5 μm); mobile phase A: 10 mM aqueous solution of ammonium bicarbonate(adjusted to pH 10 with ammonia), mobile phase B: acetonitrile; gradient: 0.0 min 97 % A, 3 % B, flowrate 50 mL / min; 1.0 min 70 % A, 30 % B, flow rate 50 mL / min; 10.0 min 20 % A, 80 % B, flow rate 50 mL / min; 10.5 min 0 % A, 100 % B, flow rate 50 mL / min; 15.0 min 0 % A, 100 % B, flow rate 50 mL / min; column temperature: 40 °C; UV detection: from 210 nm to 350 nm; MS conditions: Ionisation Mode: alternate-scan Positive and Negative Electrospray (ES+ / ES-); Scan Range: 50 to 1200 AMU.GAL-363-WO-PCT 35Method 12 (prep-HPLC): C_low

[0191] LC / MS System: Waters Mass Directed Auto Purification System with QDa mass

[0192] spectrometer; Column: XBridge C18 OBD (30 x 150mm, 5μm) with XBridge C18 OBD GuardCartridge (30 x 10mm, 5 μm); mobile phase A: 0.1% formic acid in water, mobile phase B: 0.1% formic acid in acetonitrile; gradient: 0.0 min 97 % A, 3 % B, flow rate 50 mL / min; 1.0 min 70 % A, 30 % B, flow rate 50 mL / min; 10.0 min 20 % A, 80 % B, flow rate 50 mL / min; 10.5 min 0 % A, 100 % B, flow rate 50 mL / min; 15.0 min 0 % A, 100 % B, flow rate 50 mL / min; column temperature: 40 °C; UV detection: from 210 nm to 350 nm; MS conditions: Ionisation Mode: alternate-scan Positive and Negative Electrospray (ES+ / ES-); Scan Range: 50 to 1200 AMU.Table I. List of abbreviations used in the experimental sectionAbbreviation Definition Abbreviation DefinitionACN acetonitrile eq. equivalentAcOH acetic acid Et2O diethyl ether2,2′-azobis(2-methylpro AIBNEtOAc ethyl acetatepionitrile) (CAS# 78-67-1) EtOH ethanolaq. aqueoush hourATP adenosine 5´-triphosphate1-[bis(dimethylamino) b.i.d. bis in die (twice a day)methylene]-1H-1,2,3- Boc tert-butyloxy-carbonylHATU triazolo[4,5-b]pyridinium 3- br s broad singletoxid hexafluorophosphate (CAS# 148893-10-1) calcd calculatedhigh-performance liquid chemical abstracts service HPLC CAS# chromatography registry number i-PrOH isopropanold doubletliquid chromatography-mass DCE dichloroethaneLCMS spectrometry DCM dichloromethanelithium LiHMDS dd doublet of doubletshexamethyldisilazane DIPEA N,N-diisopropylethylamine m multipletDMF N,N-dimethylformamide MeOH methanolDMSO dimethylsulfoxide min minute1,1′-bis(diphenylphosphino)MS mass spectrometrydppf ferroceneMTBE methyl tert-butyl ether(CAS# 12150-46-8)MW molecular weightGAL-363-WO-PCT 36Abbreviation Definition Abbreviation DefinitionMW (calc) molecular weight calculated q.d. quaque die (once daily)MW (obs) molecular weight observed RT room temperatureNA not available s singletNaBH3(CN) sodium cyanoborohydride sat. saturatedsodium NaBH(OAc)t triplet3 triacetoxyborohydridetd triplet of doubletsobsd observedTEA triethylaminePBS phosphate-buffered salineTFA trifluoroacetic acidp.o. per os (orally)TFAA trifluoroacetic anhydrideppm part-per-millionTHF tetrahydrofuranq quadruplettt triplet of tripletsSYNTHETIC PREPARATION OF THE COMPOUNDS OF THE INVENTIONExample 1. General synthetic routes

[0193] The compounds presented herein may be prepared inter alia, via the general methods presentedbelow. 1.1. Reaction scheme 1

[0194] The free hydroxyl groups (at C21 and C23) are protected, typically as an acetonide. Ester hydrolysisof the acetate at C25, is followed by protection of the nucleophilic atoms (typically with bis-AllocGAL-363-WO-PCT 37protection). The new ester bond at position C25 is then installed via conventional methods (typically coupling with acid anhydride or with acid via activating agent). The synthetic pathway is concluded by removal of the protecting groups. 1.2. Reaction scheme 2

[0195] The free hydroxyl groups (at C21 and C23) are protected, typically as an acetonide. Ester hydrolysisof the acetate at C25, is followed by formation of an activated species (carbamate or carbonate) which can then react with a selected amine derivative (primary or secondary) to form the carbamate. The syntheticpathway is concluded by removal of the protecting group(s).GAL-363-WO-PCT 381.3. Reaction scheme 3

[0196] The free hydroxyl groups (at C21 and C23) are protected, typically as an acetonide. Ester hydrolysisof the acetate at position C25, is followed by protection of the phenolic hydroxyl group (typically with a MOM protecting group). After installing the ester at C25, the protecting groups are removed. A primary amine is introduced at C3, followed by transformation of the ketone at C4 into an imine. The synthetic pathway is finalized by cyclization with a ketone (commercially available or synthesized) to put the spirocycle in place.GAL-363-WO-PCT 391.4. Reaction scheme 4

[0197] A primary amine is introduced at C3, followed by transformation of the ketone at C4 into an imine.Cyclization with a ketone (commercially available or synthesized) puts the spirocycle in place. The free hydroxyl groups (at C21 and C23) are protected, typically as an acetonide. Ester hydrolysis of the acetate at C25, is followed by formation of an activated species (carbamate or carbonate) which can then react with a selected amine derivative (primary or secondary) to form the carbamate. The synthetic pathway is concluded by removal of the protecting group(s). 1.5. Representative intermediates preparation

[0198] To a solution of Rifabutin (CAS#72559-06-93, g, 3.54 mmol, 1.0 eq.) in anhydrous N,N-dimethylformamide (10 mL) were added 2,2-dimethoxypropane (8.71 mL, 70.8 mmol, 20 eq.) andGAL-363-WO-PCT 40[(1R,4S)-7,7-dimethyl-2-oxo-norbornan-1-yl]methanesulfonic acid (864 mg, 3.72 mmol, 1.05 eq.), and the reaction mixture was stirred at room temperature for 18h. After complete conversion, NaHCO3 (1.07 g, 12.8 mmol, 3.6 eq.) was added to the reaction mixture and this was further stirred at room temperature for 30 min. Then, the reaction mixture was diluted with EtOAc, and washed subsequently with water (3x) andbrine. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. Thecrude residue was purified by column chromatography (silica gel; DCM to 5%MeOH in DCM) to affordInt 1 (2.8 g, 89% yield).

[0199] LCMS: MW (calcd): 886.5; m / z MW (obsd): 887.6 (M+H)1.5.2. Int 2O

[0200] To a solution of Int 1 (1g, 1.13 mmol, 1.0 eq.) in methanol (70 mL), were added sodium hydroxide(902 mg, 22.5 mmol, 20 eq.) and dichlorozinc (384 mg, 2.82 mmol, 2.5 eq.) dissolved in water (30 mL),and the reaction mixture was heated at 50 °C overnight. The reaction mixture was cooled to roomtemperature, and water was added. After extraction with EtOAc (3x), the organic layers were combined,dried over Na2SO4, filtered and concentrated under reduced pressure to afford crude Int 2 (894 mg, 57%yield).

[0201] LCMS: MW (calcd): 844.5; m / z MW (obsd): 845.6 (M+H)

[0202] To a solution of Int 2 (5.00 g, 0.00592 mol, 1.0 eq.) and DIPEA (12.2 g, 0.0947 mol, 16 eq.) inDCM (50 mL) at 0 °C was added dropwise allyl chloroformate (5.03 mL, 0.0473 mol, 8 eq.), and the reaction mixture was stirred at room temperature for 18 h. After addition of a saturated aqueous NaHCO3 solution, and extraction with DCM, the combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography (silicagel; 0-100% EtOAc in cyclohexane) to afford Int 3 (5.08 g, 67 % yield).

[0203] LCMS: MW (calcd): 1012.5; m / z MW (obsd): 1013.5 (M+H)GAL-363-WO-PCT 411.5.4. Int 4

[0204] To,added CDT (1,1′-carbonyl-di-(1, 2, 4-triazole)) (1.553 g, 9.465 mmol, 10.25 eq.), and the reaction mixture was stirred overnight at 40 °C. The reaction mixture was cooled to room temperature, diluted with water and extracted with DCM. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography (silicagel; DCM to 5%MeOH in DCM) to afford Int 4 (500 mg, 52% yield).

[0205] LCMS: MW (calcd): 939.5; m / z MW (obsd): 941.3 (M+H)1.5.5. Int 5

[0206] To solution of compound Int 4 (1.41 g, 1.50 mmol, 1.0 eq.) in DCE (15 mL) were added 4-nitrophenol (835 mg, 6.00 mmol, 4 eq.) and TEA (0.843 mL, 6.00 mmol, 4 eq.), and the reaction mixture was heated at 60 °C overnight. After cooling to room temperature, the mixture was diluted with DCM, and water was added. After extraction, the combined organic layers were washed with saturated NH4Cl solution (2x), and brine, dried over Na2SO4, and concentrated under reduced pressure. The crude residue waspurified by column chromatography (silica gel; DCM to 50% EtOAc in DCM) to afford Int 5 (707 mg,47% yield).

[0207] LCMS: MW (calcd): 1009.5; m / z MW (obsd): 1010.4 (M+H)GAL-363-WO-PCT 421.5.6. Int 6

[0208] To a(20 mL) were added 2,2-dimethoxypropane (37.11 mL, 301.8 mmol, 21 eq.) and [(1R,4S)-7,7-dimethyl-2- oxo-norbornan-1-yl]methanesulfonic acid (4.007 g, 17.25 mmol, 1.2 eq.), and the reaction mixture was stirred at room temperature for 2h. Then, NaHCO3 (4.347 g, 51.74 mmol, 3.6 eq.) was added and the mixture was further stirred for 30 min at room temperature. The reaction mixture was diluted with EtOAc and water was added. After extraction, the combined organic layers were washed with water (3x) and brine, driedover Na2SO4, filtered, and concentrated under reduced pressure to afford Int 6 (10.43 g, 95% yield).

[0209] LCMS: MW (calcd): 735.3; m / z MW (obsd): 736.4 (M+H)1.5.7. Int 7

[0210] Int 6 (10.52 g, 14.3 mmol, 1.0 eq.) was added to a solution of KOH (40.11 g, 714.9 mmol, 50 eq.)in anhydrous ethanol (150 mL) cooled to -10 °C, and the reaction mixture was stirred at -10 °C for 5h, and then at 4 °C overnight. The pH of the reaction mixture was then adjusted to ~ 6 with citric acid (10% aqueous solution) while maintaining the temperature below 3 °C. The precipitate formed was filtered, washed with water, and triturated with cold acetonitrile. The obtained solid was filtered, washed with coldacetonitrile and dried in vacuo to afford Int 7 (6.01 g, 58% yield).

[0211] LCMS: MW (calcd): 693.3; m / z MW (obsd): 692.4 (M-H)GAL-363-WO-PCT 431.5.8. Int 8

[0212] To a solution(12 mL), were addednicotinic anhydride (645 mg, 2.83 mmol, 2.1 eq.) and N,N-dimethylpyridin-4-amine (259 mg, 2.12 mmol, 1.6 eq.), and the reaction mixture was stirred at room temperature overnight. The reaction mixture wasdiluted with DCM, and water was added. After extraction, the combined organic layers were washed withsaturated aqueous NaHCO3solution, saturated NH4Cl solution and brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography (silicagel; DCM to EtOAc:CH3CN (1:1)) to afford Int 8 (100 mg, 8% yield).

[0213] LCMS: MW (calcd): 798.3; m / z MW (obsd): 799.5 (M+H)

[0214] 1H NMR (CDCl3-d, 600 MHz) δ = 12.46 (1H, s), 9.12 (1H, br d), 8.70 (1H, br d), 8.23 (1H, br d),8.11 (1H, s), 7.82 (1H, s), 7.31 - 7.42 (1H, m), 6.08 - 6.19 (2H, m), 6.05 (1H, dd), 5.86 (1H, d), 5.14 (1H,dd), 5.10 (1H, dd), 3.54 (1H, dd), 3.40 - 3.45 (1H, m), 3.01 - 3.07 (1H, m), 2.81 (3H, s), 2.25 (3H, s), 2.16- 2.22 (1H, m), 2.00 (3H, s), 1.88 - 1.96 (1H, m), 1.69 (3H, s), 1.59 - 1.64 (1H, m), 1.57 (1H, br s), 1.15(3H, s), 0.83 (3H, d), 0.78 (3H, s), 0.78 (3H, br d), 0.74 - 0.77 (3H, m), 0.49 (3H, d); 13C NMR (151 MHz,CDCl3-d): δ = 7.6, 8.9, 11.3, 11.5, 15.3, 20.1, 22.0, 23.5, 31.0, 33.1, 34.1 , 37.6, 38.0, 56.7, 71.7, 75.0, 77.4, 80.5, 108.2, 110.7, 115.8, 116.3, 117.9, 123.3, 125.3, 130.7, 131.0, 136.3, 137.4, 138.9, 144.5, 151.3, 153.8, 166.9, 169.8 , 172.5, 184.9, 191.8 ppm

[0215] To a solution of Int 8 (1.23 g, 1.51 mmol, 1.0 eq.) in absolute ethanol (35 mL) was added camfor-10-sulphonic acid (876 mg, 3.77 mmol, 2.5 eq.), and the resulting solution was stirred at room temperature for 6 h. NaHCO3 (456 mg, 5.43 mmol, 3.6 eq.) was added and the mixture was further stirred for 30 min at room temperature, diluted with water, and extracted with DCM (3x). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude residueGAL-363-WO-PCT 44was triturated with acetonitrile, the precipitate was filtered, washed with acetonitrile and dried in vacuo toafford Int 9 (300 mg, 26.% yield).

[0216] LCMS: MW (calcd): 758.3; m / z MW (obsd): 759.3 (M+H)1.5.10. Int 9 – Procedure B

[0217] To a solution of Int 14 (5.6 g, 6.643 mmol, 1.0 eq.) in a mixture of ACN (100 mL) and water (100mL) was added TFA (10 mL, 134.631 mmol, 20.27 eq.), and the resulting solution was stirred at room temperature for 2h. The mixture was extracted with EtOAc (3 x 100 mL), and the combined organic layers were washed with saturated NaHCO3 solution (100 mL) and water (3 x 100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude residue was purified by reversed-phase flash chromatography (C18 column; ACN in Water (0.1% FA), 10% to 60% gradient in 30min) to afford Int 9 (4 g, 79% yield).

[0218] LCMS: MW (calcd): 758.3; m / z MW (obsd): 759.3 (M+H)1.5.11.

[0219] To a solution of Int 9 (735 mg, 0.9492 mmol, 1.0 eq.) in N-methylformamide (2 mL) was addedsodium azide (123.4 mg, 1.898 mmol, 2 eq.), and the reaction mixture was stirred at 35 °C overnight. The resulting solution was partitioned between ethyl acetate and brine. After extraction, the combined organic layers were washed with brine, dried over a hydrophobic frit, and concentrated under reduced pressure. The crude residue was purified by column chromatography (silica gel; DCM to DCM:ACN:EtOAc=1:2:2) toafford Int 10 (121 mg, 16% yield).

[0220] LCMS: MW (calcd): 773.3; m / z MW (obsd): 774.7 (M+H)GAL-363-WO-PCT 451.5.12. Int 11

[0221] Through amL) was bubbledammonia gas (generated by dropwise addition of ~25% aqueous ammonia solution to sodium hydroxide pellets) at room temperature. After 2h, the reaction mixture was left to stand at 4 °C overnight. Bubbling of ammonia gas was continued for another 7h, the reaction mixture was stored at 4 °C overnight, and ammonia gas was bubbled for an additional 5h. The reaction mixture was concentrated under reduced pressure and dissolved in a minimal amount of DCM. Pentane was added and the heterogeneous mixtureformed was concentrated under reduced pressure to afford Int 11 (100 mg, 95 % yield).

[0222] LCMS: MW (calcd): 772.3; m / z MW (obsd): 773.4 (M+H)

[0223] 1H NMR (CDCl3-d, 600 MHz) δ = 14.33 (1H, s), 14.58 (1H, br s), 9.18 (1H, s), 8.76 - 8.79 (1H,m), 8.26 (1H, br d), 8.07 (1H, br s), 7.34 - 7.42 (1H, m), 6.93 - 7.07 (2H, m), 6.42 (1H, dd), 6.26 (1H, d),6.15 (1H, br d), 6.10 (1H, br dd), 5.18 - 5.29 (2H, m), 3.76 (1H, br d), 3.67 (1H, br ), 3.42 (1H, br d), 3.25(1H, br s), 3.07 - 3.13 (1H, m), 2.92 (3H, s), 2.36 - 2.44 (1H, m), 2.33 (3H, s), 2.09 (3H, s), 1.86 - 1.93 (1H,m), 1.80 - 1.84 (1H, m), 1.79 (3H, s), 1.68 - 1.74 (1H, m), 1.03 (3H, br d), 0.88 (3H, br d), 0.79 (3H, br d),0.08 (3H, br d);13C NMR (151 MHz, CDCl3-d): δ = 7.7, 9.2, 10.9, 11.2, 17.6, 20.4, 21.9, 33.6, 38.3, 38.5, 38.7, 57.1, 73.7, 74.9, 77.3, 80.0, 107.9, 114.5, 117.7, 123.5, 124.7, 126.2, 129.8, 132.8, 132.8, 137.4, 141.2, 143.4, 145.0, 151.1, 153.6, 153.8, 166.1, 169.2, 169.4, 172.4, 196.7 ppm 1.5.13. Int 12

[0224] To a solution of piperidin-4-one hydrochloride (250 mg, 1.844 mmol, 1.0 eq.) in acetonitrile (10mL) was added 2-chloro-1-morpholino-ethanone (301.6 mg, 1.844 mmol, 1.0 eq.) and potassium carbonate(637.0 mg, 4.609 mmol, 2.5 eq.), and the reaction mixture was stirred at ambient temperature for 21 h. Thereaction mixture was partitioned between ethyl acetate and brine. After extraction, the combined organic layers were dried over a hydrophobic frit and concentrated under reduced pressure. The crude residue waspurified by flash column chromatography (silica gel; DCM to DCM / methanol=9 / 1) to afford Int 12 (215mg; 49% yield).GAL-363-WO-PCT 46

[0225] 1H NMR (500 MHz, CDCl3-d) δ = 3.62 - 3.72 (m, 8 H) 3.33 (s, 2 H) 2.85 (m, 4 H) 2.49 (m, 4 H)ppm. 1.5.14. Int 13ag, was added K2CO3(2.48 g, 17.945 mmol, 2.49 eq.), and the reaction mixture was stirred at 0 °C for 15 min. Then, bromomethoxymethane (2.70 g, 21.621 mmol, 3 eq.) was added dropwise at 0 °C, and the resulting solution was stirred at 0 °C for 3h. The reaction was diluted with DCM (500 mL).and filtered. The filtrate wasconcentrated under reduced pressure to afford Int 13 (5 g, crude).

[0227] LCMS: MW (calcd): 737.3; m / z MW (obsd): 738.3 (M+H)1.5.15. Int 14

[0228] To a solution of Int 13 (5 g, 6.777 mmol, 1.0 eq.) in DCE (100 mL) at 0 °C was added pyridine-3-carbonyl pyridine-3-carboxylate (3.09 g, 13.554 mmol, 2 eq.). Then, DMAP (1.24 g, 10.165 mmol, 1.5 eq.) was added portion wise at 0 °C, and the resulting solution was stirred for at 0 °C for 3h. The reaction was quenched by adding water (100 mL), and the mixture was extracted with DCM (3 x 100 mL). The combined organic layers were washed with water (3 x 100 mL), dried over anhydrous sodium sulfate,filtered and concentrated under reduced pressure to afford Int 14 (5.6 g, crude).

[0229] LCMS: MW (calcd): 842.4; m / z MW (obsd): 841.4 (M+H)GAL-363-WO-PCT 471.6. Illustrative compounds1.6.1. Cpd 1

[0230] A solution of 6-methylpyridine-3-carboxylic acid (135 mg, 0.987 mmol, 5 eq.), 2-methyl-6-nitrobenzoic anhydride (340 mg, 0.987 mmol, 5 eq.), triethylamine (138 µL, 0.987 mmol, 5 eq.) and N,N-dimethylpyridin-4-amine (96.5 mg, 0.790 mmol, 4 eq.) in dry DCM (5 mL) was stirred at room temperaturefor 30 minutes. Int 3 (200 mg, 0.197 mmol, 1.0 eq.) was added and the reaction mixture was stirred at roomtemperature for 36 hours, during which additional portions of pre-activated acid were added. After completeconversion, the reaction mixture was partitioned between DCM and a saturated aqueous NaHCO3 solution.The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The cruderesidue was purified by flash column chromatography (silica gel; 5% MeOH / DCM) to afford Int A1. (155mg, 67% yield).

[0231] LCMS: MW (calcd): 1047.5; m / z MW (obsd): 1048.4 (M+H)GAL-363-WO-PCT 481.6.1.2. Step ii: Int B1

[0232] To a solution of Int A1 (155 mg, 0.133 mmol, 1.0 eq.) in dry tetrahydrofuran (3 mL), were addedPd(PPh3)4(15.4 mg, 0.013 mmol, 0.1 eq.) and 1,3-dimethylhexahydropyrimidine-2,4,6-trione (93.5 mg, 0.599 mmol, 4.5 eq.) were added, and the reaction mixture was stirred at room temperature for 30 minutes.After complete conversion, the reaction mixture was partitioned between DCM and a saturated aqueousNaHCO3solution. The organic layer was dried over Na2SO4, filtered, and concentrated under reducedpressure. The crude residue was purified by flash column chromatography (silica gel; 5% MeOH / DCM) toafford Int B1. (42 mg, 33% yield).

[0233] LCMS: MW (calcd): 963.5; m / z MW (obsd): 964.5 (M+H)1.6.1.3. Step iii: Cpd 1

[0234] To a solution of Int B1 (42 mg, 0.0437 mmol, 1.0 eq.) in methanol (1 mL), was added camfor-10-sulphonic acid (20.3 mg, 0.087 mmol, 2 eq.), and the reaction mixture was stirred at room temperature for 3 hours. After complete conversion, NaHCO3 (8.80 mg, 0.105 mmol, 2.4 eq.) was added and the reaction mixture was allowed to stir at room temperature for 30 minutes. The resulting solution was partitionedbetween DCM and a saturated aqueous NaHCO3 solution. The organic layer was dried over Na2SO4,filtered, and concentrated under reduced pressure. The crude residue was purified by flash columnchromatography (silica gel; 5% MeOH / DCM) to afford Cpd 1 (40 mg, 100% yield).GAL-363-WO-PCT 49

[0235] LCMS: MW (calcd): 923.5; m / z MW (obsd): 924.5 (M+H)

[0236] 1H NMR (CDCl3, 600 MHz) δ = 0.02 - 0.01 (m, 3 H), 0.68 - 0.73 (m, 3 H), 0.82 - 0.87 (m, 3 H),0.93 - 0.96 (m, 6 H), 0.98 - 1.01 (m, 3 H), 1.52 - 1.57 (m, 1 H), 1.74 - 1.76 (m, 3 H), 1.77 - 1.77 (m, 1 H),1.85 (td, 1 H), 1.90 - 1.93 (m, 1 H), 1.93 - 1.98 (m, 1 H), 1.98 - 2.05 (m, 2 H), 2.05 (br s, 3 H), 2.14 (br s,1 H), 2.28 - 2.33 (m, 2 H), 2.34 - 2.40 (m, 3 H), 2.37 - 2.42 (m, 1 H), 2.59 - 2.62 (m, 3 H), 2.66 (br s, 2 H),2.84 - 2.94 (m, 3 H), 2.96 - 3.02 (m, 2 H), 3.05 (br d, 1 H), 3.32 - 3.35 (m, 1 H), 3.44 (br s, 1 H), 3.70 (brd, 1 H), 3.79 (br s, 1 H), 5.03 (br d, 1 H), 5.16 - 5.21 (m, 1 H), 5.93 - 6.06 (m, 1 H), 6.15 - 6.18 (m, 1 H),6.26 (br d, J = 10.1 Hz, 1 H), 6.35 - 6.40 (m, 1 H), 7.21 - 7.24 (m, 1 H), 8.11 - 8.13 (m, 1 H), 8.25 (s, 1 H),9.02 - 9.03 (m, 1 H), 9.18 (br s, 1 H), 14.73 (s, 1 H) ppm; 13C NMR (CDCl3, 151 MHz) δ = 7.8, 9.1, 11.4,17.6, 20.4, 21.0, 22.1, 24.9, 26.0, 33.2, 35.5, 36.4, 38.0, 38.2, 38.4, 51.6, 51.7, 56.7, 66.5, 72.7, 74.2, 77.0, 81.0, 94.9, 104.7, 107.5, 109.1, 111.9, 114.5, 116.1, 123.1, 123.4, 124.2, 125.3, 131.6, 133.2, 137.8, 141.0, 142.2, 144.6, 150.9, 155.3, 163.4, 166.3, 168.3, 168.6, 171.7, 181.2, 192.6 ppm.

[0237] Int A2 was synthesized in analogy to Int A1, using 5-fluoropyridine-3-carboxylic acid instead of6-methylpyridine-3-carboxylic acid.

[0238] LCMS: MW (calcd): 1051.5; m / z MW (obsd): 1052.5 (M+H)GAL-363-WO-PCT 501.6.2.2. Step ii: Int B2

[0239] Int B2 was synthesized in

[0240] LCMS: MW (calcd): 967.5; m / z MW (obsd): 968.4 (M+H)1.6.2.3. Step iii: Cpd 2

[0241] Cpd 2 was synthesized in analogy to Cpd 1.

[0242] LCMS: MW (calcd): 927.4; m / z MW (obsd): 928.5 (M+H)

[0243] 1H NMR (600 MHz, CDCl3-d): δ = 0.02 - 0.02 (m, 3H), 0.75 (br d, 3 H), 0.83 - 0.90 (m, 3 H), 0.95- 0.99 (m, 6 H), 1.02 - 1.07 (m, 3 H), 1.48 (br s, 1 H), 1.77 (br s, 3 H), 1.78 - 1.81 (m, 1 H), 1.83 - 1.89 (m,1 H), 1.91 - 2.04 (m, 2 H), 2.00 - 2.06 (m, 1 H), 2.08 (br s, 3 H), 2.10 - 2.14 (m, 2 H), 2.33 (br d, 2 H), 2.41- 2.43 (m, 3 H), 2.43 - 2.45 (m, 1 H), 2.63 - 2.76 (m, 2 H), 2.85 - 2.89 (m, 3 H), 2.96 - 3.04 (m, 2 H), 3.05- 3.11 (m, 1 H), 3.22 (s, 1 H), 3.26 - 3.31 (m, 1 H), 3.58 (s, 1 H), 3.73 (br d, 1 H), 5.05 (br d, 1 H), 5.30 -5.35 (m, 1 H), 5.98 (br dq, 1 H), 6.22 - 6.26 (m, 1 H), 6.28 - 6.32 (m, 1 H), 6.32 - 6.38 (m, 1 H), 7.95 - 7.98(m, 1 H), 8.26 (s, 1 H), 8.61 - 8.64 (m, 1 H), 8.98 (br s, 1 H), 9.44 (br s, 1 H), 14.64 (s, 1 H) ppmGAL-363-WO-PCT 511.6.3. Cpd 3

[0244] To a solution of Int 17 (180 mg, 0.194 mmol, 1.0 eq.) in DCM (10 mL), were added N,N-dimethylpyridin-4-amine (0.0947 g, 0.775 mmol, 4 eq.), triethylamine (0.0980 g, 0.969 mmol, 5 eq.) andInt 16 (153 mg, 0.969 mmol, 5 eq.), and the reaction mixture was stirred at room temperature for 18 hours.After addition of a saturated aqueous NaHCO3solution, and extraction with DCM, the combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue waspurified by column chromatography (silica gel; 5% MeOH / DCM) to afford compound Int A3 (72 mg, 24%yield).

[0245] LCMS: MW (calcd): 1049.5; m / z MW (obsd): 1050.4 (M+H)1.6.3.2. Step ii: Int B3

[0246] To a solution of Int A3 (72 mg, 0.0686 mmol, 1.0 eq.) in dry DCM (5 mL), were added Pd(PPh3)4(0.00792 g, 0.0686 mmol, 1 eq.) and 1,3-dimethylhexahydropyrimidine-2,4,6-trione (0.0482 g, 0.309 mmol, 4.5 eq.), and the reaction mixture was stirred at room temperature for 18 hours. After addition of aGAL-363-WO-PCT 52saturated aqueous NaHCO3 solution, and extraction with DCM, the combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by columnchromatography (silica gel; 5% MeOH / DCM) to afford Int B3 (56 mg, 86% yield).

[0247] LCMS: MW (calcd): 965.5; m / z MW (obsd): 966.4 (M+H)1.6.3.3. Step iii: Cpd 3

[0248] To a solution of Int B3 (55 mg, 0.0438 mmol, 1.0 eq.) in methanol (0.5 mL), was added camfor-10-sulphonic acid (0.0204 g, 0.0877 mmol, 2 eq.), and the reaction mixture was stirred at room temperature for 2 hours. After addition of a saturated aqueous NaHCO3solution, and extraction with DCM, thecombined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. Thecrude residue was purified by column chromatography (silica gel; 5% MeOH / DCM) to afford Cpd 3 (27mg, 64% yield).

[0249] LCMS: MW (calcd): 925.5; m / z MW (obsd): 926.2 (M+H)

[0250] 1H NMR (CDCl3, 600 MHz) δ = 14.53 (1H, s), 9.49 (1H, br s), 8.66 (1H, t), 8.24 - 8.27 (2H, m),7.81 (1H, dt), 7.30 (1H, dd), 6.23 - 6.34 (2H, m), 6.20 (1H, d), 5.88 - 5.96 (1H, m), 5.34 (1H, dd), 5.00 (1H,dd), 3.68 (1H, br d), 3.43 (1H, d), 3.19 (1H, dd), 3.06 (1H, s), 2.98 - 3.04 (1H, m), 2.89 - 2.98 (2H, m), 2.82(3H, s), 2.58 - 2.69 (2H, m, H), 2.39 - 2.44 (1H, m), 2.38 (3H, s), 2.28 (2H, d), 2.03 - 2.15 (3H, m), 2.03(3H, s), 1.92 - 2.02 (2H, m), 1.79 - 1.84 (1H, m), 1.72 - 1.77 (1H, m), 1.71 (3H, s), 1.30 - 1.42 (1H, m),1.00 (3H, d), 0.92 (6H, d), 0.81 (3H, d), 0.68 (3H, d), -0.07 (3H, d) ppm; 13C NMR (CDCl3, 151 MHz) δ =7.9, 9.2, 11.2, 12.4, 17.5, 20.4, 21.1, 22.6, 26.1, 33.1, 35.5, 37.6, 38.7, 39.3, 51.8, 56.4, 66.6, 72.1, 74.8, 76.7, 83.1, 95.1, 104.5, 107.9, 109.6, 111.7, 115.2, 116.2, 123.7, 125.1, 125.8, 127.3, 131.0, 132.7, 133.0, 140.7, 140.8, 142.1, 142.3, 146.2, 155.2, 163.0, 168.2, 168.6, 171.7, 180.9, 192.6 ppm.GAL-363-WO-PCT 531.6.4. Cpd 4

[0251] To a solution of 1-methylpyrazole-4-carboxylic acid (72.8 mg, 0.000577 mol, 2.5 eq.) in DCM (10mL), were added (2-methyl-6-nitro-benzoyl) 2-methyl-6-nitro-benzoate (MNBA) (0.199 g, 0.000577 mol, 2.5 eq.), triethylamine (0.0584 g, 0.000577 mol, 2.5 eq.) and DMAP (0.0564 g, 0.000462 mol, 2 eq.), andthe reaction mixture was stirred at room temperature for 20 min. Int 3 (234 mg, 0.000231 mol, 1.0 eq.) wasadded, and the reaction mixture was stirred at room temperature for 18 h. Then, a pre-mixed (20 min) solution of 1-methylpyrazole-4-carboxylic acid (146 mg, 0.00115 mol, 5 eq.), (2-methyl-6-nitro-benzoyl) 2-methyl-6-nitro-benzoate (MNBA) (0.398 g, 0.00115 mol, 5 eq.), triethylamine (0.117 g, 0.00115 mol, 5 eq.) and DMAP (0.113 g, 0.000924 mol, 4 eq.) was added. The addition of this pre-mixed solution (same quantities) was repeated three more times with 24h intervals. After stirring for a total of 7 days, the mixture was partitioned between DCM and a saturated aqueous bicarbonate solution. The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to afford crude Int A4.

[0252] LCMS: MW (calcd): 1144.6; m / z MW (obsd): 1145.5 (M+H)GAL-363-WO-PCT 541.6.4.2. Step ii: Int B4

[0253] To a solution of Int A4 mg, THF (5 mL), was added sodiumhydroxide (0.0953 g, 0.00238 mol, 2 eq.), and the reaction mixture was stirred at room temperature for 6 hours. The mixture was partitioned between DCM and a saturated aqueous bicarbonate solution, and the combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure The crude residue was purified by column chromatography (silica gel; DCM to 5%DCM / MEOH) to afford Int B4.

[0254] LCMS: MW (calcd): 1036.5; m / z MW (obsd): 1037.5 (M+H)

[0255] Int C4 was synthesized in analogy to Int B1.

[0256] LCMS: MW (calcd): 952.5; m / z MW (obsd): 953.6 (M+H)GAL-363-WO-PCT 551.6.4.4. Step iv: Cpd 4

[0257] Cpd 4 was synthesized in analogy to Cpd 1.

[0258] LCMS: MW (calcd): 912.5; m / z MW (obsd): 913.5 (M+H)

[0259] 1H NMR (600 MHz, CDCl3-d): δ = 0.01 (d, 3 H), 0.69 (d, 3 H), 0.88 (d, 3 H), 0.99 (dd, 6 H), 1.04(d, 3 H), 1.60 - 1.71 (m, 1 H), 1.73 - 1.80 (m, 2 H), 1.81 (s, 3 H), 1.88 (t, 1 H,), 1.98 - 2.08 (m, 2 H), 2.11(d, 3 H), 2.18 (br s, 2 H), 2.34 (dd, 2 H), 2.36 (s, 3 H), 2.38 - 2.44 (m, 1 H), 2.62 - 2.76 (m, 2 H), 3.01 (s, 3H), 3.02 - 3.06 (m, 2 H), 3.10 (br d, 1 H), 3.47 (ddd, 1 H), 3.73 - 3.81 (m, 2 H), 3.96 (s, 3H), 4.16 (br d, 1H), 5.02 (dd, 1 H), 5.11 (dd, 1 H), 6.09 - 6.13 (m, 1 H), 6.15 (dd, 1 H), 6.29 (d, 1 H), 6.45 (dd, 1 H), 7.88(d, 1 H), 7.89 (q, 1 H), 8.42 (s, 1 H), 8.91 (br s, 1 H), 14.90 (s, 1 H) ppmGAL-363-WO-PCT 56

[0260] To a solution of Int 4 (50 mg, 0.05319 mmol, 1.0 eq.) in DCE (1 mL), were added morpholine(18.53 mg, 0.2127 mmol, 4 eq.) and TEA (21.53 mg, 0.2127 mmol, 4 eq.), and the reaction mixture was stirred at room temperature for 18h. After extraction, and washing subsequently with water and brine, the organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residuewas purified by column chromatography (silica gel; 5% MeOH / DCM) to afford Int A9 (45 mg, 83% yield).

[0261] LCMS: MW (calcd): 957.5; m / z MW (obsd): 959.4 (M+H)1.6.5.2. Step ii: Cpd 9

[0262] To a solution of Int A9 (45 mg, 0.04415 mmol, 1.0 eq.) in MeOH (0.3 mL), (±)-Camphor-10-sulfonic acid (20.51 mg, 0.08830 mmol) was added, and the reaction mixture was stirred at room temperature for 5 h. The solution was partitioned between DCM and water, and the organic layer waswashed with brine, dried over sodium sulfate and concentrated under reduced pressure. The crude residuewas purified by column chromatography (silica gel; 5% MeOH / DCM) to afford Cpd 9 (35 mg, 85% yield).

[0263] LCMS: MW (calcd): 917.5; m / z MW (obsd): 918.5 (M+H)

[0264] 1H NMR (600 MHz, CDCl3) δ 14.86 (1H, s), 8.97 (1H, br s), 8.30 (1H, s), 6.41 (1H, dd), 6.26 (1H,d), 6.18 (1H, d), 6.03 (1H, dd), 5.04 (1H, dd), 4.57 (1H, s), 4.57 (1H, d), 3.80 (1H, s), 3.66 (2H, br d), 3.54- 3.71 (4H, m), 3.44 (4H, br s), 3.35 (1H, br dd), 3.09 (3H, s), 3.01 - 3.05 (1H, m), 2.94 - 3.00 (2H, m), 2.57- 2.71 (2H, m), 2.34 - 2.41 (1H, m), 2.32 (3H, s), 2.30 (2H, br d), 2.13 (1H, br s), 2.06 (3H, s), 1.96 (2H, brs), 1.82 - 1.90 (1H, m), 1.77 (3H, s), 1.71 - 1.76 (2H, m), 1.47 - 1.53 (1H, m), 1.05 (3H, d), 0.95 (6H, d),0.84 (3H, d), 0.59 (3H, d), -0.01 (3H, d).

[0265] 13C NMR (CDCl3, 151 MHz) δ = 192.5, 181.3, 171.5, 168.4, 168.3, 156.1, 155.3, 144.0, 142.1,141.0, 133.1, 130.8, 125.2, 124.3, 115.5, 114.1, 111.9, 108.6, 107.2, 80.4, 77.8, 74.8, 72.9, 66.5, 66.3, 56.9, 51.4, 44.1, 38.2, 37.8, 37.6, 35.4, 33.1, 25.8, 21.8, 20.8, 20.3, 17.4, 11.5, 11.0, 8.8, 7.6.GAL-363-WO-PCT 571.6.6. Cpd 12

[0266] To Int 4 (250 mg, 0.2659 mmol, 1.0 eq.) in DCM (5 mL), were added piperazine (91.62 mg, 1.064mmol, 4 eq.) and TEA (107.6 mg, 1.064 mmol, 4 eq.), and the reaction mixture was stirred at room temperature for 18h. After extraction with water and brine, the organic layer was dried over Na2SO4, filtered, and the solvent was removed under reduced pressure. The crude residue was purified by columnchromatography (silica gel; 5% MeOH / DCM) to afford Int A12 (195 mg, 77% yield).

[0267] LCMS: MW (calcd): 956.5; m / z MW (obsd): 957.5 (M+H)1.6.6.2. Step ii: Int B12

[0268] To a solution of Int A12 (120 mg, 0.1254 mmol, 1.0 eq.) in DCM (3 mL), were added TEA (31.72mg, 0.3134 mmol, 2.5 eq.) and pyridine-3-carbonyl pyridine-3-carboxylate (34.33 mg, 0.1504 mmol, 1.2 eq.), and the reaction mixture was stirred at room temperature for 2h. The resultant solution was then partitioned between DCM and a saturated aqueous NaHCO3 solution. The organic layer was separated, washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to affordInt B12 (130 mg, 96% yield).

[0269] LCMS: MW (calcd): 1061.6; m / z MW (obsd): 1062.52 (M+H)GAL-363-WO-PCT 581.6.6.3. Step iii: Cpd 12

[0270] To a solution of compoundeq.) in MeOH (1 mL), was added(±)-camphor-10-sulfonic acid (0.0569 g, 0.245 mmol, 2 eq.), and the reaction mixture was stirred at room temperature for 1h. The resultant solution was partitioned between DCM and sat. aq. solution NaHCO3. The resultant solution was then partitioned between DCM and a saturated aqueous NaHCO3 solution. The organic layer was separated, washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by column chromatography (silica gel; 5% MeOH / DCM)to afford Cpd 12 (90 mg, 71% yield).

[0271] LCMS: MW (calcd): 1021.5; m / z MW (obsd): 1022.6 (M+H)

[0272] 1H NMR (600 MHz, CDCl3) δ 14.79 (1H, s), 9.08 (1H, br s), 8.66 (1H, dd), 8.63 (1H, d,), 8.24 (1H,s), 7.73 (1H, dt), 7.36 (1H, dd), 6.36 (1H, dd), 6.16 - 6.26 (2H, m), 5.94 (1H, dd), 5.03 (1H, dd), 4.46 (1H,br d), 4.31 (1H, d), 3.64 (1H, s), 3.60 (1H, br d), 3.34 - 3.67 (8H, m), 3.26 (1H, br d), 3.04 (3H, s), 2.90 -2.99 (3H, m), 2.61 (2H, br s), 2.30 - 2.38 (1H, m), 2.28 (3H, s), 2.24 - 2.27 (2H, m), 2.08 (1H, br s), 2.02(3H, s), 1.94 (2H, br s), 1.77 - 1.88 (4H, m), 1.72 (3H, s), 1.36 - 1.47 (1H, m), 1.01 (3H, d), 0.91 (6H, d),0.80 (3H, d), 0.57 (3H, d), -0.02 (3H, d);13C NMR (CDCl3, 151 MHz) δ. = 191.9, 180.7, 171.0, 168.0, 167.9, 167.7, 155.5, 154.9, 150.8, 147.6, 144.7, 141.5, 140.5, 134.8, 132.7, 130.7, 124.7, 123.9, 123.3,114.8, 114.0, 111.5, 108.3, 107.1, 104.3, 94.2, 81.3, 76.9, 74.7, 72.2, 65.9, 56.4, 51.1, 51.1, 43.0, 37.8, 37.6,37.5, 35.9, 35.1, 32.8, 25.5, 21.7, 20.5, 19.9, 17.0, 11.4, 11.3, 8.5, 7.3 ppm. 1.6.7. 13

[0273] To a solution of Int 11 (50 mg, 0.05758 mmol, 1.0 eq.) in tetrahydrofuran (0.5 mL) were added Int12 (32.29 mg, 0.1439 mmol, 2.5 eq.), ammonium acetate (11.10 mg, 0.1439 mmol, 2.5 eq.) and zinc (9.416GAL-363-WO-PCT 59mg, 0.1439 mmol, 2.5 eq.), and the reaction mixture was stirred at ambient temperature for 3h. The reactionmixture was concentrated under reduced pressure, dissolved in DCM and washed with a saturated NH4Clsolution (3x). The organic layer was dried over a hydrophobic frit and concentrated under reduced pressure.The crude residue was purified by flash column chromatography (silica gel; DCM to DCM / methanol=9 / 1).The obtained product was redissolved in a minimal amount of DCM. Adding pentane resulted in aheterogeneous mixture which was concentrated under reduced pressure to afford Cpd 13 (11.92 mg; 21%yield).

[0274] LCMS: MW (calcd): 980.5; m / z MW (obsd): 981.8 (M+H)

[0275] 1H NMR (600 MHz, CDCl3-d): δ = -0.01 (d, 3 H), 0.70 (d, 3 H), 0.83 (d, 3 H), 1.00 (d, 3 H), 1.47- 1.53 (m, 1 H), 1.73 (s, 3 H), 1.74 - 1.77 (m, 1 H), 1.82 - 1.92 (m, 1 H), 2.00 (ddd, 1 H), 1.97 - 2.03 (m, 1H), 2.05 (s, 3 H), 2.07 (br s, 2 H), 2.37 - 2.39 (m, 1 H), 2.38 (s, 3 H), 2.78 - 2.85 (m, 2 H), 2.87 (s, 3 H),3.01 - 3.06 (m, 1 H), 3.06 - 3.13 (m, 2 H), 3.30 (dd, 1 H), 3.32 (s, 1 H), 3.41 (s, 2 H), 3.61 - 3.73 (m, 10 H),5.01 (d, 1 H), 5.20 (dd, 1 H), 5.98 (dd, 1 H), 6.18 (d, 1 H), 6.27 (br d, 1 H), 6.36 (dd, 1 H), 7.36 (ddd, 1 H),8.21 (s, 1 H), 8.24 (dt, 1 H), 8.74 (dd, 1 H), 9.10 - 9.18 (m, 2 H), 14.62 (s, 1 H) ppm; 13C NMR (151 MHz,CDCl3-d): δ = 7.7, 8.9, 11.1, 11.4, 17.3, 20.2, 22.0, 32.9, 35.2, 36.2, 37.6, 38.0, 38.4, 42.2, 46.1, 51.0, 51.4, 56.4, 61.1, 67.0, 72.1, 74.1, 76.8, 81.6, 93.0, 107.0, 114.7, 115.7, 123.2, 123.8, 125.9, 131.4, 133.5, 137.4, 140.8, 141.7, 144.9, 151.1, 153.4, 165.3, 168.0, 168.4, 171.5, 181.0, 192.5 ppm. 1.6.8. Cpd 22GAL-363-WO-PCT 60

[0276] To a mixture of Int 4 (100 mg, 0.106 mmol, 1.0 eq.) and TEA (60 µL, 0.425 mmol, 4 eq.) in dry1,2-dichloroethane (2 mL), was added 1-(cyclopropylcarbonyl)piperazine (57 µL, 0.425 mmol, 4 eq.),and the reaction mixture was stirred at room temperature for 3 days. The solvent was removed underreduced pressure and the crude residue was purified by column chromatography (silica gel; DCM to 5%MeOH in DCM) to afford Int A22 (80 mg, 69% yield).

[0277] LCMS: MW (calcd): 1024.6; m / z MW (obsd): 1025.3 (M+H)1.6.8.2. Step ii: Cpd 22

[0278] Cpd 22 was synthesized using a process analogous to that for Cpd 1.

[0279] LCMS: MW (calcd): 984.5; m / z MW (obsd): 985.6 (M+H)

[0280] 1H NMR (600 MHz, CDCl3-d): δ = -0.01 (br s, 3 H), 0.58 (br d), 0.77 (br s, 2 H), 0.82 (br s, 3 H),0.92 (br d, 6 H), 0.97 (br s, 2 H), 1.01 (br d, 3 H), 1.41 - 1.47 (m, 1 H), 1.67 - 1.71 (m, 1 H), 1.73 (br d, 4H), 1.78 - 1.85 (m, 3 H), 1.95 (br s, 2 H), 2.03 (br d, 3 H), 2.06 - 2.15 (m, 1 H), 2.25 - 2.31 (m, 5 H), 2.34(br s, 1 H), 2.52 - 2.71 (m, 2 H), 2.89 - 3.01 (m, 3 H), 3.05 (br d, 3 H), 3.26 - 3.73 (m, 8 H), 3.29 (br s, 1H), 3.61 (br s, 1 H), 3.69 (br d, 1 H), 4.42 (br s, 1 H), 4.50 (br s, 1 H), 4.99 - 5.06 (m, 1 H), 5.91 - 6.03 (m,1 H), 6.13 - 6.20 (m, 1 H), 6.21 - 6.27 (m, 1 H), 6.33 - 6.42 (m, 1 H), 8.21 (br d, 1 H), 9.04 (s, 1 H), 14.80(s, 1 H) ppm.GAL-363-WO-PCT 611.6.9.1. Step i: Int A24

[0281] To a mixture of Int 4 mg, (47.8 µL, 0.340 mmol, 4 eq.) indry 1,2-dichloroethane (2 mL) was added N-cyclopropylpiperidine-4-carboxamide (57.3 mg, 0.340 mmol,4 eq.), and the reaction mixture was stirred at room temperature overnight. The solvent was removedunder reduced pressure and the crude residue was purified by column chromatography (silica gel; DCMto 5% MeOH in DCM) to afford Int A24 (108 mg, 97% yield).

[0282] LCMS: MW (calcd): 1038.6; m / z MW (obsd): 1039.5 (M+H)1.6.9.2. Step ii: Cpd 24

[0283] Cpd 24 was synthesized using a process analogous to that for Cpd 1.

[0284] LCMS: MW (calcd): 998.5; m / z MW (obsd): 999.4 (M+H)

[0285] 1H NMR (600 MHz, CDCl3-d): δ = 14.90 (1H, br s), 8.94 (1H, br s), 8.26 (1H, s), 6.40 - 6.50 (1H,m), 6.28 (1H, br d), 6.16 (1H, d), 6.09 (1H, br dd), 5.74 (1H, br d), 4.98 - 5.12 (1H, m), 4.74 (1H, br s),4.63 (1H, br d), 4.05 - 4.24 (2H, m), 3.86 (1H, br d), 3.70 (1H, br d), 3.41 (1H, br d), 2.97 - 3.17 (6H, m),2.76 - 2.85 (2H, m), 2.70 - 2.75 (1H, m), 2.59 - 2.70 (2H, m), 2.36 - 2.43 (1H, m), 2.34 (3H, s), 2.30 - 2.33(2H, m), 2.16 - 2.25 (2H, m), 2.09 (3H, s), 1.93 - 2.06 (2H, m), 1.83 - 1.92 (2H, m), 1.80 (3H, s), 1.75 -1.82 (3H, m), 1.67 - 1.74 (1H, m), 1.58 - 1.66 (2H, m), 1.51 - 1.57 (1H, m), 1.03 - 1.10 (3H, m), 0.97 (6H,d, J = 6.4 Hz), 0.88 (3H, br d), 0.77 - 0.84 (2H, m), 0.61 (3H, d), 0.52 - 0.48 (2H, m), -0.01 (3H, br d).GAL-363-WO-PCT 621.6.10. Cpd 27

[0286] To a mixture of Int 4 (100 mg, 0.0989 mmol, 1.0 eq.) and TEA (55.6 µL, 0.396 mmol, 4 eq.) indry 1,2-dichloroethane (2 mL), was added 2-oxa-6-azaspiro[3.3]heptane (35.0 µL, 0.396 mmol, 4 eq.),and the reaction mixture was stirred at room temperature overnight. The solvent was removed underreduced pressure and the crude residue was purified by column chromatography (silica gel; DCM to 5%MeOH in DCM) to afford Int A27 (39 mg, 41% yield).

[0287] LCMS: MW (calcd): 969.5; m / z MW (obsd): 970.4 (M+H)1.6.10.2. Step ii: Cpd 27

[0288] Cpd 27 was synthesized using a process analogous to that for Cpd 1.

[0289] LCMS: MW (calcd): 929.5; m / z MW (obsd): 930.4 (M+H)

[0290] 1H NMR (600 MHz, CDCl3-d): δ = 14.86 (1H, s), 9.00 (1H, br s), 8.24 (1H, s), 6.44 (1H, dd), 6.29(1H, dd), 6.19 (1H, dd), 6.09 (1H, dd), 5.11 (1H, dd), 4.81 (4H, br s), 4.61 (1H, dd), 4.38 (1H, d), 4.15 -4.19 (2H, m), 4.09 - 4.15 (2H, m), 3.73 (1H, s), 3.70 (1H, d), 3.41 (1H, ddd), 3.12 (3H, s), 3.08 (1H, ddd),2.98 - 3.06 (2H, m), 2.60 - 2.76 (2H, m), 2.38 - 2.44 (1H, m), 2.35 (3H, s), 2.32 - 2.35 (2H, m), 2.12 - 2.27(2H, m), 2.10 (3H, d), 1.95 - 2.09 (2H, m), 1.84 - 1.93 (1H, m), 1.81 (3H, s), 1.77 - 1.81 (1H, m), 1.69 -1.76 (1H, m), 1.49 - 1.56 (1H, m), 1.08 (3H, d), 0.99 (6H, d), 0.89 (3H, d), 0.62 (3H, d), -0.01 (3H, d).GAL-363-WO-PCT 631.6.11. Cpd 28

[0291] To a mixture of Int 5 (40 mg, 0.0396 mmol, 1.0 eq.) and TEA (22.3 μL, 0.158 mmol, 4 eq.) in dry1,2-dichloroethane (2 mL) was added 1,4-thiazinane 1,1-dioxide (21.4 mg, 0.158 mmol, 4 eq.), and thereaction mixture was stirred at 60 °C overnight. The reaction mixture was partitioned between DCM andsaturated NaHCO3 solution. After extraction, the combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography (silicagel; DCM; to 5% MeOH in DCM) to afford Int A28 (33.7 mg, 73% yield).

[0292] LCMS: MW (calcd): 1005.5; m / z MW (obsd): 1006.4 (M+H)1.6.11.2. Step ii: Cpd 28

[0293] Cpd 28 was synthesized using a process analogous to that for Cpd 1.

[0294] LCMS: MW (calcd): 965.5; m / z MW (obsd): 966.5 (M+H)

[0295] 1H NMR (600 MHz, CDCl3-d): δ = 14.64 (1H, s), 9.45 (1H, br s), 8.26 (1H, s), 6.33 (1H, dd), 6.29(1H, br d), 6.27 - 6.29 (1H, m), 5.92 (1H, dd), 5.31 (1H, dd), 4.51 (1H, dd), 4.17 - 4.24 (1H, m), 3.96 - 4.04(1H, m), 3.73 (1H, d), 3.68 - 3.76 (2H, m), 3.63 (1H, d), 3.27 (1H, s), 3.20 (1H, dd), 3.09 (3H, s), 3.06 -3.12 (1H, m), 2.94 - 3.04 (5H, m), 2.85 -2.92 (1H, m), 2.58 - 2.75 (2H, m), 2.36 - 2.45 (1H, m), 2.35 (3H,s), 2.30 - 2.34 (2H, m), 2.05 - 2.15 (2H, m), 2.06 (3H, s), 1.99 - 2.04 (2H, m), 1.87 - 1.98 (1H, m), 1.83 -GAL-363-WO-PCT 641.88 (1H, m), 1.75 (3H, s), 1.73 -1.79 (1H, m), 1.28 - 1.36 (1H, m), 1.07 (3H, d), 0.96 (6H, d), 0.84 (3H,d), 0.62 (3H, d), 0.01 (3H, d). 1.6.12. Cpd 301.6.12.1. Step i: Int A30

[0296] To a solution of Int 5 (300 mg, 0.297 mmol, 1.0 eq.) in DCE (3 mL) were added pyrimidin-3-amine (112 mg, 1.19 mmol, 4 eq.) and TEA (167 μL, 1.19 mmol, 4 eq.), and the reaction mixture wasstirred at 60 °C for 4 days. Additional amounts of pyridin-3-amine (112 mg, 1.19 mmol, 4 eq.) and TEA(167μL, 1.19 mmol, 4 eq.) were added, and the reaction was stirred at 60 °C overnight, and at roomtemperature for another 2 days. The reaction mixture was concentrated under reduced pressure, and thecrude residue was purified by flash chromatography (silica gel; DCM to 50%DCM:EtOH:NH4OH=90:9:1 in DCM) to afford 47 mg of crude Int A30.

[0297] LCMS: MW (calcd): 964.5; m / z MW (obsd): 965.5 (M+H)1.6.12.2. Step ii: Cpd 30

[0298] Cpd 30 was synthesized using a process analogous to that for Cpd 1.

[0299] LCMS: MW (calcd): 924.5; m / z MW (obsd): 925.4 (M+H)

[0300] 1H NMR (CDCl3-d, 600 MHz) δ = 14.79 (1H, s), 9.12 (1H, br s), 8.44 (1H, d), 8.32 (1H, dd), 8.26(1H, s), 7.97 - 8.06 (1H, m), 7.27 (2H, dd), 6.99 (1H, s), 6.39 (1H, dd), 6.24 - 6.27 (1H, m), 6.20 (1H, dd),6.00 (1H, dd), 5.15 (1H, dd), 4.70 (1H, br d), 3.98 (1H, br d), 3.67 (1H, d), 3.54 (1H, s), 3.42 (1H, br d),3.14 - 3.21 (1H, m), 3.07 (3H, s), 2.93 - 3.02 (2H, m), 2.58 - 2.71 (2H, m), 2.36 - 2.42 (1H, m), 2.35 (3H,s), 2.27 - 2.32 (2H, m), 2.10 - 2.18 (1H, m), 2.06 (3H, s), 1.89 - 2.02 (2H, m), 1.81 - 1.86 (2H, m), 1.77 -1.80 (1H, m), 1.75 (3H, s), 1.46 -1.52 (1H, m), 1.04 (3H, d), 0.95 (6H, d), 0.85 (3H, d), 0.64 (3H, d), 0.01 (3H, d).GAL-363-WO-PCT 65Table II. Illustrative compoundsCpd Cpd Structure Structure # # N O O HOOOHOH O O 4 1 NH OONH N O N 5 2 6 3 7GAL-363-WO-PCT 66Cpd CpdGAL-363-WO-PCT 67Cpd Cpd Structure Structure # # 24 28 30 27 31 BIOLOGICAL EXAMPLESExample 2. In vitro assays2.1. Nuclear Receptor Activation (PXR)

[0301] Cytochrome P450 induction is one of the factors that can affect the pharmacokinetics of a drugmolecule upon multiple dosing, and it can result in pharmacokinetic drug-drug interactions with coadministered drugs causing potential therapeutic failures (Chu et al.2009).

[0302] The primary mechanism of cytochrome P450 induction is via increased gene transcription whichtypically occurs through nuclear receptor activation. The most common nuclear receptors involved in theGAL-363-WO-PCT 68induction of drug metabolising enzymes include inter alia the pregnane X receptor (PXR), which is knownto regulate CYP3A4, CYP1A2 and CYP2B6, respectively.

[0303] This assay use nuclear receptor transactivation to assess the potential of a test compounds to causeenzyme induction, and was performed at Cyprotex Discovery Limited, 24 Mereside, Alderley Park, Macclesfield, Cheshire SK104TG, United Kingdom, reference Human Pregnane X Receptor (PXR, NR 112) Activation). 2.1.1. Protocol Summary

[0304] A test compound is incubated with the Human Pregnane X Receptor (PXR) reporter cells (from theIndigo PXR kit) for 24 h. At the end of the incubation period, cell viability and transcriptional activationare measured and reported as fold increase in transcriptional activation of PXR above vehicle control foreach test compound concentration measured along with derived EC50 value.

[0305] Each test compound is provided in DMSO (100 µL of 20 mM solutions).

[0306] The assay utilizes the Human PXR Reporter Assay Kit (Indigo Biosciences, Inc, 3006 ResearchDrive, Suite A1, State College, PA 16801, USA) with engineered human cells expressing constitutive and functional Human PXR. Upon ligand activation, PXR will bind to the GAL4 DNA binding sequence linkedto a luciferase reporter gene. Therefore, the change in PXR activity is quantified by luminescence detectionon a plate reader.

[0307] The PXR reporter cells are seeded in 384-well plates and recovered at 37 °C in 5 % CO2 for 4-6 hprior to dosing. The cells are dosed with increasing concentrations of test article (final DMSO concentration0.4 %; final test compound concentrations of 0.15, 0.48, 1.5, 4.9, 15.6, and 50 µM for a six-point doseresponse curve; n = 2 replicates per concentration), positive control or vehicle control and incubated at 37°c for 22-24 h. Rifampicin is used as a positive control (final control compound concentrations of 0.032, 0.1,0.32, 1.0, 3.2 and 10 µM).

[0308] At the end of the incubation period, the culture media is discarded and cell viability is assessedfluorimetrically using the Live Cell Multiplex Assay Kit (Indigo Biosciences, Inc, 3006 Research Drive, Suite A1, State College, PA 16801, USA), and luciferase activity is measured using the Luciferase Detection Reagent provided in the PXR Assay Kit. 2.1.2. Data Analysis

[0309] Transcriptional activation is monitored by luminescence. Data are expressed as fold activationrelative to the vehicle control, following normalization of luciferase activity against cell viability. The use of 5 or more doses of test article and positive control allows for the derivation of EC50and Emaxvalues from nonlinear regression analysis of the log dose-response curves.

[0310] The average observed fold activation is calculated as a percentage of rifampicin (10 µM) to allowfor inter-day comparison and ranking of test articles, using the equation below: (fold ac )% ^^^^^^^^^^^^ (10 µ^) = tivation of test compound(fold activation of rifampycin (10µM)) ∗ 100GAL-363-WO-PCT 692.1.3. Results

[0311] The fold increase in transcriptional activation of PXR above vehicle control at each test compoundconcentration is returned, in addition to derived EC50 value where appropriate. The observed fold activation as a percentage of rifampicin (10 µM) is also provided to allow for inter-day comparison and ranking of test compounds.

[0312] A low PXR activation (%max or Emax) is indicative of a lack of / low Cytochrome P450 induction,and therefore lack of / low DDI.

[0313] Where low PXR is observed, it may not be possible to calculate an EC50Table III. PXR values of illustrative compounds% max stimulation Emax Fold increase Fold increase at Cpd#vs 10 µM rifampicinEC50 (µM) vs vehicle 4 µM vs vehicle 17.7 0.9 NC 0.892 8.3 1 NC 0.963 9.6 1.1 NC 1.34 10 0.95 NC NA5 7.9 0.9 NC 0.756 9.7 1.1 NC 1.17 9.4 1.1 NC 1.18 8.7 1.1 NC 0.749 11 1.1 NC 0.8410 5 0.85 NC 0.8511 6.9 0.7 NC 0.7312 11 1.1 NC 0.8318 9.9 1.1 NC 1.022 10 1.2 NC 1.223 10 1.2 NC 1.324 9.0 0.9 NC 1.127 34.1 3.4 14.6 0.8128 12.5 1.0 NC 1.030 9.1 0.7 NC 0.8431 34 3.9 12.1 1.6Rifabutin 62;13;116 10.4;4.31;24.6 1.78;2.33;9.85 9; 12; 4NC: cannot be calculatedGAL-363-WO-PCT 702.2. Cytochrome P450 Induction in HepaRG Cells (mRNA Assessment; CYP3A4 only)2.2.1. Objective

[0314] This assay evaluates the potential of a test compound to induce the cytochrome P450 isoformCYP3A4.

[0315] Cytochrome P450 (CYP) 3A4 induction is an important cause of drug–drug interactions, that canresult in undesired therapeutic responses and adverse drug reactions. (Hendriks et al.2020) 2.2.2. Protocol Summary

[0316] Cryopreserved, differentiated HepaRG cells (Catalog #: HPR116080, Biopredic, Parc d'affaires dela Brétèche Bât. A435760 Saint-Grégoire, France) are cultured on collagen coated 96-well plates prior to addition of test compound. Test compounds are added at six concentrations in triplicate and incubated for48 h; the dosing solutions are replaced every 24 h throughout the dosing period.

[0317] After the dosing period, changes in CYP3A4 mRNA expression in the HepaRG cells are quantifiedby qRT-PCR. 2.2.3. Experimental procedure

[0318] Cryopreserved, differentiated HepaRG cells are obtained from Biopredic International and usedaccording to the supplier's instructions. The HepaRG cells are thawed, plated at a cell density of 0.72xl06cells / mL into 96-well plates and incubated in recovery medium (Williams' E medium with thawing / platingsupplement ADD670C; Biopredic International). The recovery medium is renewed (100 µL / well) 4-6 hoursafter plating and left for 72 h. Cells are used from day 3 onwards. Cells will be examined microscopically to ensure cells are suitable for use and photographs will be taken at this time.

[0319] Each test compound is dosed at six concentrations (typical final DMSO concentration 0.1 %) intriplicate, in serum free Williams E medium supplemented with 0.1 µM hydrocortisone, 10 µg / mL insulin,2 mM glutamine, 100 IU / mL penicillin, and 100 µg / mL streptomycin. The cells are exposed to the solutionsfor 48 h with fresh solution added every 24 h. Positive control inducer rifampicin (CYP3A4; top concentration 20 µM) is incubated alongside the test compounds. Negative control wells are included wherethe test compound is replaced by vehicle solvent (typically 0.l % DMSO in assay medium). Each testcompound is dosed in triplicate at each concentration. The cells are exposed to the solutions for 48 h with fresh solution added every 24 h.

[0320] Cells will also be examined microscopically and photographs are taken at this time. At the end ofthe incubation period all media is removed from each of the wells and the cells are washed twice withphosphate buffered saline or culture media. The cells are lysed by adding 100 µL of lysis solution to eachwell. Total RNA is then isolated from the cell lysates. Reverse transcription is performed and quantitative PCR analysis is performed on the resulting cDNA, using a gene-specific primer probe set for CYP3A4 target cDNA and endogenous control. Samples are analysed using an Applied Biosystems QuantStudio™ 7 Real Time PCR system.GAL-363-WO-PCT 712.2.4. Data Analysis

[0321] For mRNA assessment, relative fold mRNA expression is determined based on the threshold cycle(CT) data of target gene relative to endogenous control for each reaction, and normalised to vehicle control using the 2∆∆Ctmethod (Livak and Schmittgen 2001). To determine the statistical significance of any fold change of mRNA expression, a one way ANOVA with two tailed Dunnett's post-test is performed usingthe ∆Ct values. Differences with a p value less than 0.05 are taken to be significant.

[0322] Where appropriate, EC50 and Emax values will be determined from nonlinear regression analysis(using a four-parameter sigmoidal model) of the log dose-response curve. 2.2.5. Results

[0323] Results are presented in an Excel spreadsheet containing mRNA ∆Ct recorded in each well. Thefold change and the probability that a statistically significant difference exists between the wells exposed to test compound and the vehicle control wells is also reported. Where determined, EC50 and calculated Emax values will also be reported.

[0324] A low induction in this assay may be indicative of a low DDITable IV. CYP induction HepaRG CYP3A4 values of illustrative compoundsCYP induction % max Emax fold CYP induction HepaRG HepaRG CYP3A4 Cpd# stimulation vs induction (Max fold induction vsCYP3A4 - Fold inductionrifampicin (fitted top) vs vehicle (tested conc.) vehicle) 19.7 78 NA 27 (4 µM)2 5.9 48 NA 13 (4 µM)3 0.050 NA 1.4 1.4 (4 µM)4 2.7 16.8 NA 2.7 (4 µM)6 0.52 5.1 NA 3.2 (4 µM)8 0.77 NA 7.1 2.0 (4µM)9 0.86 6 NA 3.6 (4 µM)10 24.3 106 15.3 3.0 (5 µM)12 0.6 NA 4.5 1.9 (4 µM)18 2.8 24 NA 2.7 (4 µM)22 21 109 NA 2.5 (4 µM)23 33.7 124 NA 35 (4 µM)24 0.49 5 NA 3.1 (4 µM)27 36 187 NA 3.2 (4 µM)28 0.78 6.95 NA 2.8 (4 µM)30 6.8 80 NA 18 (4 µM)Rifabutin 88;143 381;1100 NA;1080 922 (4 µM); 167 (5 µM)NA not availableGAL-363-WO-PCT 72Example 3. Cellular assays3.1. Susceptibility testing in dose response

[0325] The Minimum Inhibitory Concentration (MIC) against MAB (M. abscessus subsp. abscessusATCC 19977, M. abscessus subsp. abscessus ATCC700868, M. abscessus subsp. massiliense CIP108297Tand M. abscessus subsp. bolletii CIP108541T) and MAC (M. avium ATCC700898, M. intracellulareATCC13950) was determined following the broth dilution method (CLSI M24: SUSCEPTIBILITY TESTING 2018). MICs were performed in Middlebrook 7H9 broth (Merck cat n° M0178) supplementedwith 10% Middlebrook ADC growth supplement (Merck cat n° M0553), 0.44% glycerol (Sigma cat n°49781) and 0.05% Tween80 (Sigma cat n° 59924). The inoculum was prepared by picking at least 3 – 5well-isolated colonies from an agar culture plate and transferred in Dulbecco’s Phosphate Buffered Saline(DPBS) (Gibco cat n° 14190-144). Next, the turbidity was adjusted to an optical density (OD) at 600nm of~0.1 and further diluted 1:200 in bacterial culture medium to achieve a final bacterial density of ~5 x 105Colony Forming Units (CFU / mL). Inocula were plated on Middlebrook 7H11 agar (Merck cat n° M0428) to confirm that the bacterial load (CFU / mL).

[0326] Starting from DMSO stock, 2-fold serial dilutions of compounds were made in 100 µL of bacterialculture medium and transferred to 96-well plates to obtain a final concentration range of 32 µg / mL to 0.06µg / mL. Plates were inoculated with an additional volume of 100µL of the correspondent inoculum. Each96-well plated contained a growth control (only bacteria, no compound), and a negative control (no bacteria, no compound).

[0327] Plates were incubated at 37°C and MIC determined after 4 and 7 days for MAB and MACrespectively. After incubation, plates were visually inspected for bacterial growth. The lowest concentration that did not show growth was marked as the MIC.Table V. MIC values of illustrative compoundsCp MIC_Mabscess MIC_Mabscess MIC_Mabscess MIC_Mmassilie MIC_Mbolletii_ d us_Mab1_7H9 us_Mab2_7H9 us_Mab3_7H9 nse_Mma1_7H9 Mbo1_7H9 # (MIC (µg / mL)) (MIC (µg / mL)) (MIC (µg / mL)) (MIC (µg / mL)) (MIC (µg / mL)) 1<=0.060 <=0.060 <=0.060 <=0.060 <=0.0602 <=0.060 <=0.060 <=0.060 <=0.060 <=0.0600.060 0.12 0.12 0.12 0.060 3 0.12 0.12 0.060 0.12 0.060 4<=0.060 <=0.060 <=0.060 <=0.060 0.125 1 1 1 0.03 16 0.06 0.12 0.06 0.06 0.12GAL-363-WO-PCT 73Cp MIC_Mabscess MIC_Mabscess MIC_Mabscess MIC_Mmassilie MIC_Mbolletii_ d us_Mab1_7H9 us_Mab2_7H9 us_Mab3_7H9 nse_Mma1_7H9 Mbo1_7H9 # (MIC (µg / mL)) (MIC (µg / mL)) (MIC (µg / mL)) (MIC (µg / mL)) (MIC (µg / mL)) 7<=0.060 <=0.060 <=0.060 <=0.060 <=0.0608 <=0.060 <=0.060 <=0.060 <=0.060 <=0.0609 <=0.060 0.12 <=0.060 <=0.060 0.250.03, <=0.060, <=0.060, <=0.060, <=0.060, 0. <=0.060, 0 <=0.060, < 12, 1 =0.060, <=0.060, <=0.060, <=0.060, <=0.060, <=0.060, <=0.060, <=0.06 <=0.060, <=0.060 <=0.060 <=0.060 0 <=0.060 0.12, 0.12, 0.12, 0.25 0.12 <=0.060 0.25 11 0.12, 0.12, 0.12, 0.12 0.12 <=0.060 0.25 0.25, 0.12, 0.25 2 1 <=0.060 0.12 12 0.12 <=0.060 <=0.060 <=0.060 <=0.06018 <=0.060 <=0.060 0.12 <=0.060 <=0.0600.060 0.060 0.060 <=0.015 0.060 22 <=0.060 <=0.060 <=0.060 <=0.060 <=0.060 23 0.12 0.12 <=0.060 <=0.060 0.120.12 0.12 0.060 0.12 0.12 24 0.25 0.12 0.25 <=0.060 <=0.060 27 0.12 0.12 <=0.060 <=0.060 <=0.06028 0.25 0.25 0.25 0.03 0.250.060 0.060 0.030 0.030 0.060 30 <=0.015 <=0.015 <=0.015 <=0.015 <=0.015 <=0.060 0.12 <=0.060 <=0.060 <=0.060 31 <=0.060 0.12 <=0.060 <=0.060 <=0.060Example 4. In vivo assays4.1. Murine in vivo efficacy model for M. avium

[0328] Female Balb / c mice (6-8 weeks) are intranasally infected with 5x10^6 CFU of M. avium ATCC700898 in 50 µL of sterile PBS. Mice are treated for 8 consecutive weeks (7 days / week) starting from 1day post-infection. Control mice are treated with clarithromycin at 200mg / kg in 0.5% methocel suspension.Mice are sacrificed after 1 day, 4 weeks and 8 weeks. Lungs and spleen are collected, examined for grosslesions and homogenized in sterile PBS. For bacterial load determination (CFU / mL), serial dilutions are plated on selective Middlebrook 7H11 agar (Merck cat n° M0428) plates and incubated for 4-8 weeks at 37°C.GAL-363-WO-PCT 744.1.1. Murine in vivo efficacy model for M. abscessus

[0329] Two murine models are used for in vivo efficacy testing against M. abscessus, the subacute andmore established chronic M. abscessus infection model.

[0330] In both models, mice lacking the GM-CSF gene (GM-CSF KO mice) are infected with 1x10^6CFU of M. abscessus ATCC19977 in 50 µL sterile saline through the intrapulmonary aerosol route, usinga microsprayer device (MicroSprayer, model IA-C; PennCentury), attached to an FMJ-250 high-pressuresyringe (PennCentury) as described previously (Pearce et al. 2020). Briefly, mice are temporarilyanaesthetized using a mixture of isoflurane and oxygen, the MicroSprayer tip is placed in the laryngealvestibule and the bacterial suspension is sprayed. Body weight and clinical signs are monitored on a dailybasis. To evaluate in vivo efficacy in the subacute model, mice are treated for 10 consecutive days (7days / week), starting at 1 day post-infection. For the chronic model, infected animals are dosed for 4consecutive weeks (7 days / week), starting the treatment 10 days post-infection. Control mice are treatedwith azithromycin dihydrate in 0.3% acetic acid at a dose of 100 mg / kg. To determine the bacterial load,mice are sacrificed 1, 5, 10 and 28 days (chronic model) post-infection, lungs and spleen are harvested andhomogenized. Upon chronic infection, the right lower lung lobe is fixed in 4% paraformaldehyde forhistopathological evaluation. Serial dilutions of homogenized organs are cultured on nutrient Middlebrook7H11 agar (Merck cat n° M0428). Plates are incubated for 3–4 days at 37°C, after which CFUs per plateare enumerated.FINAL REMARKS

[0331] It will be appreciated by those skilled in the art that the foregoing descriptions are exemplary andexplanatory in nature, and intended to illustrate the invention and its preferred embodiments. Through routine experimentation, an artisan will recognize apparent modifications and variations that may be made without departing from the spirit of the invention. All such modifications coming within the scope of the appended claims are intended to be included therein. Thus, the invention is intended to be defined not by the above description, but by the following claims and their equivalents.

[0332] All publications, including but not limited to patents and patent applications, cited in thisspecification are herein incorporated by reference as if each individual publication are specifically and individually indicated to be incorporated by reference herein as though fully set forth.

[0333] It should be understood that factors such as the differential cell penetration capacity of the variouscompounds can contribute to discrepancies between the activity of the compounds in the in vitro biochemical and cellular assays.

[0334] At least some of the chemical names of compound of the invention as given and set forth in thisapplication, may have been generated on an automated basis by use of a commercially available chemical naming software program, and have not been independently verified. Representative programs performing this function include the Lexichem naming tool sold by Open Eye Software, Inc. and the Autonom Software tool sold by MDL, Inc. In the instance where the indicated chemical name and the depicted structure differ, the depicted structure will control.GAL-363-WO-PCT 75REFERENCES Chu, Valeria, Heidi J. Einolf, Raymond Evers, Gondi Kumar, David Moore, Sharon Ripp, Jose Silva, Vikram Sinha, Michael Sinz, and Andrej Skerjanec. 2009. “In Vitro and in Vivo Induction of Cytochrome P450: A Survey of the Current Practices and Recommendations: A Pharmaceutical Research and Manufacturers of America Perspective.” Drug Metabolism and Disposition 37 (7):1339–54. https: / / doi.org / 10.1124 / dmd.109.027029. CLSI M24: SUSCEPTIBILITY TESTING. 2018. CLSI M24: Susceptibility Testing of Mycobacteria, Nocardia Spp., and Other Aerobic Actinomycetes. GOBI US LIBRARY SOLUTIONS. Daley, Charles L, Jonathan M Iaccarino, Christoph Lange, Emmanuelle Cambau, Richard J Wallace, Claire Andrejak, Erik C Böttger, et al. 2020. “Treatment of Nontuberculous Mycobacterial Pulmonary Disease: An Official ATS / ERS / ESCMID / IDSA Clinical Practice Guideline.” Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America 71 (4): e1–36.https: / / doi.org / 10.1093 / cid / ciaa241. Gopalaswamy, Radha, Sivakumar Shanmugam, Rajesh Mondal, and Selvakumar Subbian. 2020. “Of Tuberculosis and Non-Tuberculous Mycobacterial Infections – a Comparative Analysis ofEpidemiology, Diagnosis and Treatment.” Journal of Biomedical Science 27 (1): 74.https: / / doi.org / 10.1186 / s12929-020-00667-6. Hendriks, Delilah F. G., Sabine U. Vorrink, Tomas Smutny, Sarah C. Sim, Åsa Nordling, Shahid Ullah, Masaki Kumondai, et al.2020. “Clinically Relevant Cytochrome P4503A4 Induction Mechanisms and Drug Screening in Three‐Dimensional Spheroid Cultures of Primary Human Hepatocytes.” Clinical Pharmacology & Therapeutics 108 (4). https: / / doi.org / 10.1002 / cpt.1860.Livak, Kenneth J., and Thomas D. Schmittgen. 2001. “Analysis of Relative Gene Expression Data Using Real-Time Quantitative PCR and the 2−ΔΔCT Method.” Methods 25 (4): 402–8.https: / / doi.org / 10.1006 / meth.2001.1262. Prevots, D. Rebecca, and Theodore K Marras.2015. “Epidemiology of Human Pulmonary Infection with Non-Tuberculous Mycobacteria: A Review.” Clinics in Chest Medicine 36 (1): 13–34.https: / / doi.org / 10.1016 / j.ccm.2014.10.002. Stahl, P. Heinrich, and Camille G. Wermuth.2011. Pharmaceutical Salts: Properties, Selection, and Use, 2nd Revised Edition | Wiley. https: / / www.wiley.com / en- us / Pharmaceutical+Salts%3A+Properties%2C+Selection%2C+and+Use%2C+2nd+Revised+Edit ion-p-9783906390512.

Claims

GAL-363-WO-PCT 76CLAIMS1. A compound according to Formula I:I or a pharmaceutically acceptable salt, solvate, or the salt of a solvate thereof, G is -R1,- -L-R1,--L is C1-4alkylenyl, or C1-4alkenylenyl; R1is -phenyl optionally substituted with one or more independently selected R5a,- 5-6 membered monocyclic heteroaryl comprising one or more independently selected N, O, or Sheteroatoms, unsubstituted or substituted with one or more independently selected R5b, -8-10 membered fused bicyclic heteroaryl comprising one or more independently selected N, O, orS heteroatoms, unsubstituted or substituted with one or more independently selected R5c, -4-7 membered monocyclic heterocycloalkyl, comprising one or more independently selected N, Oor S heteroatoms, unsubstituted or substituted with one or more groups independently selected from =O and R5d, -4-7 membered monocyclic heterocycloalkyl fused to a phenyl, or pyridinyl, which heterocycloalkylcomprising one or more independently selected N, O or S heteroatoms, unsubstituted or substituted with one or more groups independently selected from =O and R5e, or -5-10 membered bicyclic fused, bridged or spiro heterocycloalkyl, comprising one or moreindependently selected N, O or S heteroatoms, unsubstituted or substituted with one or more groups independently selected from =O and R5f; Cy is -4-7 membered monocyclic heterocycloalkyl comprising one or more independently selected N, Oor S heteroatoms, which heterocycloalkyl is substituted with one or more independently selected R2agroups,GAL-363-WO-PCT 77- 5-10 membered bridged, fused, or spiro bicyclic heterocycloalkyl comprising one or moreindependently selected N, O or S heteroatoms, which heterocycloalkyl substituted with one or more independently selected R2bgroup, -C3-7 cycloalkyl monocyclic unsubstituted or substituted with one or more independently selectedR2c, or -C5-10 cycloalkyl bridged, fused, or spiro bicyclic unsubstituted or substituted with one or moreindependently selected R2d; Each R2a, R2b, R2cand R2dis selected from: -R3a,- C alkyl unsubst 3b1-6 ituted or substituted with one or more independently selected R , and- C3-7 cycloalkyl unsubstituted or substituted with one or more independently selected R3c; Each R3a, R3band R3cis independently selected from: -halo,- -OH,- =O,- -CN,- -C(=O)R6a,- -C(=O)OH,- -C(=O)OR6b,- -C(=O)NH2,- -C(=O)NHR6c,- -C(=O)NR6cR6d,- -S(=O)R6e,- -S(=O) OR6f2 ,- -S(=O)2NH2,- -S(=O) 6g2NHR ,- -S(=O) 6g 6h2NR R ,- -NHC(=O)R6i,- -P(=O)R6jR6k,- -NHR6l,- -NR6lR6m,- C3-7 cycloalkyl unsubstituted or substituted unsubstituted or substituted with one or moreindependently selected R8a groups, and- 4-7 membered monocyclic heterocycloalkyl, comprising one or more independently selected N, Oor S heteroatoms, unsubstituted or substituted with one or more independently selected R8bgroups; Each R4aand R4bis selected from H and C1-4alkyl; Each R5a, R5b, R5c, R5d, R5e, and R5fis independently selected from: -halo,GAL-363-WO-PCT 78- -OH,- -CN,- C1-4 alkyl optionally substituted with one or more independently selected halo,- C1-4 alkoxy optionally substituted with one or more independently selected halo,- C3-7 cycloalkyl unsubstituted or substituted unsubstituted or substituted with one or moreindependently selected halo, -4-7 membered monocyclic heterocycloalkyl, comprising one or more independently selected N, Oor S heteroatoms, unsubstituted or substituted with one or more independently selected halo, --C(=O)R7a,- -C(=O)OH,- -C(=O)OR7b,- -------S(=O)2NH2,- -S(=O)2NHR7g,- -S(=O)2NR7hR7g, --NHC(=O)R7i,- -P(=O)R7jR7k,- -NHR7l, and- -NR7lR7m;Each R6a, R6b, R6c, R6d, R6e, R6f, R6e, R6g, R6h, R6i, R6j, R6k, R6l, R6m, R7a, R7b, R7c, R7d, R7e, R7f, R7g, R7h, R7i, R7j, R7kR7l, and R7mis independently selected from: -C1-4 alkyl unsubstituted or substituted with one or more independently selected halo, phenyl orpyridinyl, -C1-4 alkoxy unsubstituted or substituted with one or more independently selected halo, phenyl orpyridinyl, -C3-7 cycloalkyl unsubstituted or substituted with one or more independently selected halo,- 4-7 membered monocyclic heterocycloalkyl, comprising one or more independently selected N, Oor S heteroatoms, unsubstituted or substituted with one or more independently selected halo, -phenyl, and- 5-6 membered heteroaryl comprising one or more independently selected N, O, or S heteroatoms;Each R8aand R8bis independently selected from -halo,- -OH,- =O,GAL-363-WO-PCT 79- -CN,- C1-4 alkyl unsubstituted or substituted with one or more independently selected halo, and- C1-4 alkoxy unsubstituted or substituted with one or more independently selected halo;.

2. A compound or a pharmaceutically acceptable salt thereof, according to claim 1, wherein Cy is 4-7 membered monocyclic heterocycloalkyl comprising one or more independently selected N, O or S heteroatoms, which heterocycloalkyl is substituted with one, two or three independently selected R2agroup.

3. A compound or a pharmaceutically acceptable salt thereof, according to claim 1 or 2, wherein R2ais C1-6 alkyl.

4. A compound or a pharmaceutically acceptable salt thereof, according to claim 1 or 2, wherein R2ais C1-6 alkyl substituted with one, two or three independently selected R3band each R3bis independently selected from -C(=O)-cyclopropyl, -C(=O)-morpholinyl, -C(=O)NH2, -C(=O)N(CH3)2, -C(=O)NH-cyclopropyl.

5. A compound or a pharmaceutically acceptable salt thereof, according to claim 1, wherein Cy isselected from:, , , , and wherein * represents the points of attachment.

6. A compound or a pharmaceutically acceptable salt thereof, according to any one of claims 1-5,wherein G is:GAL-363-WO-PCT 80, , F7. A compound or a pharmaceutically acceptable salt thereof, according to any one of claims 1-5,wherein G is: O * ,wherein * represents the points of attachment.

8. A compound or a pharmaceutically acceptable salt thereof, according to any one of claims 1-5,wherein G is: , orwherein * represents the points of attachment.

9. A compound or a pharmaceutically acceptable salt thereof, according to any one of claims 1-5,wherein G is:, , or wherein * represents the points of attachment.GAL-363-WO-PCT 8110. A pharmaceutical composition comprising a compound or a pharmaceutically acceptable saltthereof, according to any one of claims 1-9 and pharmaceutically acceptable excipients.

11. A pharmaceutical composition according to claim 10, comprising a further therapeutical agent.

12. A compound or a pharmaceutically acceptable salt thereof, according to any one of claims 1-9, ora pharmaceutical composition according to claim 10 or 11 for use in medicine.

13. A compound or a pharmaceutically acceptable salt thereof, according to any one of claims 1-9, ora pharmaceutical composition according to claim 10 or 11 for use in the prevention and or treatmentof tuberculosis, and / or non-tuberculous mycobacteria diseases.

14. A pharmaceutical composition according to claim 11, wherein the further therapeutical agent is anagent for the prevention and or treatment of tuberculosis, and / or non-tuberculous mycobacteria diseases.

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