WO2022214519A1 - Antibacterial compounds - Google Patents
Antibacterial compounds Download PDFInfo
- Publication number
- WO2022214519A1 WO2022214519A1 PCT/EP2022/059062 EP2022059062W WO2022214519A1 WO 2022214519 A1 WO2022214519 A1 WO 2022214519A1 EP 2022059062 W EP2022059062 W EP 2022059062W WO 2022214519 A1 WO2022214519 A1 WO 2022214519A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- compound
- ring
- mmol
- alkyl
- inhibitor
- Prior art date
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 264
- 230000000844 anti-bacterial effect Effects 0.000 title description 7
- 201000008827 tuberculosis Diseases 0.000 claims abstract description 50
- 239000003814 drug Substances 0.000 claims abstract description 36
- 238000011282 treatment Methods 0.000 claims abstract description 29
- 238000002360 preparation method Methods 0.000 claims description 73
- 239000003112 inhibitor Substances 0.000 claims description 70
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 68
- 229910052757 nitrogen Inorganic materials 0.000 claims description 44
- 125000003118 aryl group Chemical group 0.000 claims description 43
- 239000001257 hydrogen Chemical group 0.000 claims description 41
- 229910052739 hydrogen Inorganic materials 0.000 claims description 41
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical group [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 40
- 102000018832 Cytochromes Human genes 0.000 claims description 38
- 108010052832 Cytochromes Proteins 0.000 claims description 38
- 125000001424 substituent group Chemical group 0.000 claims description 37
- 238000000034 method Methods 0.000 claims description 35
- 125000005842 heteroatom Chemical group 0.000 claims description 32
- 230000027721 electron transport chain Effects 0.000 claims description 23
- 125000001153 fluoro group Chemical group F* 0.000 claims description 22
- 238000006243 chemical reaction Methods 0.000 claims description 17
- 125000000217 alkyl group Chemical group 0.000 claims description 16
- 230000000694 effects Effects 0.000 claims description 16
- 208000035143 Bacterial infection Diseases 0.000 claims description 15
- 208000022362 bacterial infectious disease Diseases 0.000 claims description 14
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 14
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 13
- 230000015572 biosynthetic process Effects 0.000 claims description 13
- 150000003839 salts Chemical class 0.000 claims description 13
- 229910052717 sulfur Inorganic materials 0.000 claims description 13
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 12
- 238000003786 synthesis reaction Methods 0.000 claims description 12
- 125000006574 non-aromatic ring group Chemical group 0.000 claims description 11
- 239000008194 pharmaceutical composition Substances 0.000 claims description 11
- 125000005843 halogen group Chemical group 0.000 claims description 10
- 229910052760 oxygen Inorganic materials 0.000 claims description 9
- 239000011593 sulfur Substances 0.000 claims description 9
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 8
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 8
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- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 7
- HYPYXGZDOYTYDR-HAJWAVTHSA-N 2-methyl-3-[(2e,6e,10e,14e)-3,7,11,15,19-pentamethylicosa-2,6,10,14,18-pentaenyl]naphthalene-1,4-dione Chemical compound C1=CC=C2C(=O)C(C/C=C(C)/CC/C=C(C)/CC/C=C(C)/CC/C=C(C)/CCC=C(C)C)=C(C)C(=O)C2=C1 HYPYXGZDOYTYDR-HAJWAVTHSA-N 0.000 claims description 6
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- 101100348119 Yarrowia lipolytica (strain CLIB 122 / E 150) NDH2 gene Proteins 0.000 claims description 6
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- LISFMEBWQUVKPJ-UHFFFAOYSA-N quinolin-2-ol Chemical compound C1=CC=C2NC(=O)C=CC2=C1 LISFMEBWQUVKPJ-UHFFFAOYSA-N 0.000 claims description 5
- YMMHAIJRFWRDMG-UHFFFAOYSA-N 3,4,4a,5-tetrahydro-1h-quinolin-2-one Chemical compound C1C=CC=C2NC(=O)CCC21 YMMHAIJRFWRDMG-UHFFFAOYSA-N 0.000 claims description 4
- 125000005647 linker group Chemical group 0.000 claims description 4
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- 125000001246 bromo group Chemical group Br* 0.000 claims description 3
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- 125000006163 5-membered heteroaryl group Chemical group 0.000 claims description 2
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- HUOFUOCSQCYFPW-UHFFFAOYSA-N [4-(trifluoromethoxy)phenyl]boronic acid Chemical compound OB(O)C1=CC=C(OC(F)(F)F)C=C1 HUOFUOCSQCYFPW-UHFFFAOYSA-N 0.000 description 9
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- MYPYJXKWCTUITO-LYRMYLQWSA-O vancomycin(1+) Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1=C2C=C3C=C1OC1=CC=C(C=C1Cl)[C@@H](O)[C@H](C(N[C@@H](CC(N)=O)C(=O)N[C@H]3C(=O)N[C@H]1C(=O)N[C@H](C(N[C@@H](C3=CC(O)=CC(O)=C3C=3C(O)=CC=C1C=3)C([O-])=O)=O)[C@H](O)C1=CC=C(C(=C1)Cl)O2)=O)NC(=O)[C@@H](CC(C)C)[NH2+]C)[C@H]1C[C@](C)([NH3+])[C@H](O)[C@H](C)O1 MYPYJXKWCTUITO-LYRMYLQWSA-O 0.000 description 1
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
- A61P31/06—Antibacterial agents for tuberculosis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Definitions
- the present invention relates to novel compounds.
- the invention also relates to such compounds for use as a pharmaceutical and further for the use in the treatment of bacterial diseases, including diseases caused by pathogenic mycobacteria such as Mycobacterium tuberculosis.
- Such compounds may work by targeting the respiratory chain, and thereby blocking all energy production of mycobacteria.
- There are several ways of targeting the electron transport chain of mycobacteria for instance by interfering with ATP synthase in M. tuberculosis.
- This particular invention focuses on the cytochrome bd target of the respiratory chain, which may be the primary mode of action.
- such compounds are antitubercular agents, and in particular may act as such when combined with another tuberculosis drug (e.g. another inhibitor of a different target of the electron transport chain).
- Mycobacterium tuberculosis is the causative agent of tuberculosis (TB), a serious and potentially fatal infection with a world-wide distribution.
- TB tuberculosis
- Estimates from the World Health Organization indicate that more than 8 million people contract TB each year, and 2 million people die from tuberculosis yearly. In the last decade, TB cases have grown 20% worldwide with the highest burden in the most impoverished communities. If these trends continue, TB incidence will increase by 41% in the next twenty years. Fifty years since the introduction of an effective chemotherapy, TB remains after AIDS, the leading infectious cause of adult mortality in the world. Complicating the TB epidemic is the rising tide of multi-drug-resistant strains, and the deadly symbiosis with HIV. People who are HIV-positive and infected with TB are 30 times more likely to develop active TB than people who are HIV-negative and TB is responsible for the death of one out of every three people with HIV/AIDS worldwide.
- MDR-TB multi-drug-resistant strains
- MDR-TB multi-drug-resistant strains
- MDR-TB multi-drug-resistant strains
- isoniazid and rifampin the most effective drugs of the four-drug standard, isoniazid and rifampin.
- MDR-TB is lethal when untreated and cannot be adequately treated through the standard therapy, so treatment requires up to 2 years of "second-line" drags. These drugs are often toxic, expensive and marginally effective.
- infectious MDR-TB patients continue to spread the disease, producing new infections with MDR-TB strains.
- There is a high medical need for a new drag with a new mechanism of action which is likely to demonstrate activity against drag resistant, in particular MDR strains.
- a drag resistant Mycobacterium is a Mycobacterium which is no longer susceptible to at least one previously effective drag; which has developed the ability to withstand antibiotic attack by at least one previously effective drug.
- a drug resistant strain may relay that ability to withstand to its progeny. Said resistance may be due to random genetic mutations in the bacterial cell that alters its sensitivity to a single drug or to different drugs.
- MDR tuberculosis is a specific form of drug resistant tuberculosis due to a bacterium resistant to at least isoniazid and rifampicin (with or without resistance to other drugs), which are at present the two most powerful anti-TB drugs.
- drag resistant includes multi drug resistant.
- Another factor in the control of the TB epidemic is the problem of latent TB.
- tuberculosis (TB) control programs about 2 billion people are infected by M. tuberculosis, though asymptomatically. About 10% of these individuals are at risk of developing active TB during their lifespan.
- the global epidemic of TB is fuelled by infection of HIV patients with TB and rise of multi-drug resistant TB strains (MDR-TB).
- MDR-TB multi-drug resistant TB strains
- the reactivation of latent TB is a high risk factor for disease development and accounts for 32% deaths in HIV infected individuals.
- To control TB epidemic the need is to discover new drugs that can kill dormant or latent bacilli.
- the dormant TB can get reactivated to cause disease by several factors like suppression of host immunity by use of immunosuppressive agents like antibodies against tumor necrosis factor a or interferon-g.
- immunosuppressive agents like antibodies against tumor necrosis factor a or interferon-g.
- the only prophylactic treatment available for latent TB is two- three months regimens of rifampicin, pyrazinamide.
- the tubercle bacilli enter healthy individuals by inhalation; they are phagocytosed by the alveolar macrophages of the lungs. This leads to potent immune response and formation of granulomas, which consist of macrophages infected with M. tuberculosis surrounded by T cells. After a period of 6-8 weeks the host immune response cause death of infected cells by necrosis and accumulation of caseous material with certain extracellular bacilli, surrounded by macrophages, epitheloid cells and layers of lymphoid tissue at the periphery.
- Self-medication with antimicrobials is another major factor contributing to resistance.
- Self-medicated antimicrobials may be unnecessary, are often inadequately dosed, or may not contain adequate amounts of active drug.
- Patient compliance with recommended treatment is another major problem. Patients forget to take medication, interrupt their treatment when they begin to feel better, or may be unable to afford a full course, thereby creating an ideal environment for microbes to adapt rather than be killed.
- M. tuberculosis is dependent on respiration to synthesise adequate amounts of ATP.
- targeting the electron transport chain of the mycobacteria and thereby blocking energy production of mycobacteria is thought to be a potentially effective way of providing an efficient regimen against mycobacteria.
- ATP synthase inhibitors as example of which is bedaquiline (marketed as Sirturo®)
- cytochrome be inhibitors examples of which include the compound Q203 described in Journal article Nature Medicine, 19, 1157-1160 (2013) by Pethe et al “Discovery of Q203, a potent clinical candidate for the treatment of tuberculosis”, as well as patent applications such as internataional patent applcations WO 2017/001660, WO 2017/001661, WO 2017/216281 and WO 2017/216283.
- journal article Antimicrob. Agents Chemother, 2014, 6962-6965 by Arora et al describes compounds that target the respiratory bci complex in M. tuberculosis, and where deletion of the cytochrome bd oxidase generated a hypersusceptible mutant.
- Journal article PANS (Early Edition), 2017, “Exploiting the synthetic lethality between terminal respiratory oxidases to kill Mycobacterium tuberculosis and clear host infection” by Kalia et al discloses various data around various tuberculosis compounds that target the respiratory chain.
- Cytochrome bd itself is not essential for aerobic growth, but is upregulated and protects against a variety of stresses in various bacterial strains, for example as described in journal article Biochimica et Biophysica Acta 1837 (2014)
- the compound CK-2-63 is described as a cytochrome bd inhibitor showing various inhibitor activity data, and combination data is also disclosed including combination of CK-2-63 with a mycobacterium cytochrome bcc inhibitor (e.g. AWE-402, where it is indicated therein that it is structurally related to the cytochrome bcc inhibitor Q203). It is indicated that such dual combination led to in increase in mycobacteria kill. It also described a combination of bedaquiline (a known ATP synthase inhibitor) with CK-2-63, and it is indicated that CK-2-63 showed an enhancement of bedaquiline activity at low concentrations. Data around a triple combination of bedaquiline, AWE-402 (a be inhibitor; see above) and CK-2-63 is also shown.
- a mycobacterium cytochrome bcc inhibitor e.g. AWE-402
- This particular invention focuses on novel compounds of the cytochrome bd target of the respiratory chain. New alternative/improved compounds are required, which may be tested/employed for use in combination.
- R 1 represents C 1 - 6 alkyl, -Br, hydrogen or -C(0)N(R ql )R q2 ;
- R ql and R q2 independently represent hydrogen or C 1 - 6 alkyl, or may be linked together to form a 3-6 membered carbocylic ring optionally substituted by one or more C1-3 alkyl substituents;
- Sub represents one or more optional substituents selected from halo (e.g. fluoro), -CN, C 1 - 6 alkyl and -O-Ci alkyl (wherein the latter two alkyl moieties are optionally substituted by one or more fluoro atoms);
- the “A” ring represents a 6-membered ring which may be aromatic or non-aromatic, or it represents a 5-membered aromatic ring containing one heteroatom (e.g. a sulfur heteroatom);
- the “B” ring represents a 5-membered heteroaryl ring, which contains between one and four heteroatoms (e.g. selected from nitrogen, oxygen and sulfur), and which “B” ring is optionally substituted by one or more substituents selected from halo and C 1 - 6 alkyl (itself optionally substituted by one or more fluoro atoms);
- L 1 represents an optional linker group, and hence may be a direct bond, -O- or -C(R xl )(R x2 )-;
- R xl and R x2 independently represent hydrogen or C1-3 alkyl
- Z 1 represents any one of the following moieties: (i) ring C represents a 5-membered aromatic ring containing at least one heteroatom (preferably containing at least one nitrogen atom), and which ring is optionally substituted by one or more substituents independently selected from R f ; ring D represents a 6-membered aromatic ring containing at least one heteroatom (preferably containing at least one nitrogen atom), and which ring is optionally substituted by one or more substituents independently selected from R g ; Y b represents -[(CH 2 ) I -4 ]- (so forming a 3- to 6-membered N-containing ring), and R h represents one or more optional substituents on such ring;
- R a , R b , R c , R d and R e independently represent hydrogen or a substituent selected from B 1 ; each R f , each R g and each R h (which are optional substituents), when present, independently represent a substituent selected from B 1 ; each B 1 independently represents a substituent selected from:
- R el , R e2 , R e3 , R e4 and R e5 each independently represent hydrogen or C 1 - 6 alkyl optionally substituted by one or more fluoro atoms; or a pharmaceutic ally-acceptable salt thereof, which compounds may be referred to herein as “compounds of the invention”.
- Pharmaceutically-aceeptable salts include acid addition salts and base addition salts.
- Such salts may be formed by conventional means, for example by reaction of a free acid or a free base form of a compound of formula I with one or more equivalents of an appropriate acid or base, optionally in a solvent, or in a medium in which the salt is insoluble, followed by removal of said solvent, or said medium, using standard techniques (e.g. in vacuo, by freeze-drying or by filtration). Salts may also be prepared by exchanging a counter-ion of a compound of the invention in the form of a salt with another counter-ion, for example using a suitable ion exchange resin.
- the pharmaceutically acceptable acid addition salts as mentioned hereinabove are meant to comprise the therapeutically active non-toxic acid addition salt forms that the compounds of formula (I) are able to form.
- These pharmaceutically acceptable acid addition salts can conveniently be obtained by treating the base form with such appropriate acid.
- Appropriate acids comprise, for example, inorganic acids such as hydrohalic acids, e.g. hydrochloric or hydrobromic acid, sulfuric, nitric, phosphoric and the like acids; or organic acids such as, for example, acetic, propanoic, hydroxy acetic, lactic, pyruvic, oxalic (i.e. ethanedioic), malonic, succinic (i.e.
- butanedioic acid maleic, fumaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic, p-aminosalicylic, pamoic and the like acids.
- prodrug of a relevant compound of the invention includes any compound that, following oral or parenteral administration, is metabolised in vivo to form that compound in an experimentally-detectable amount, and within a predetermined time (e.g. within a dosing interval of between 6 and 24 hours (i.e. once to four times daily)).
- parenteral administration includes all forms of administration other than oral administration.
- Prodrugs of compounds of the invention may be prepared by modifying functional groups present on the compound in such a way that the modifications are cleaved, in vivo when such prodrag is administered to a mammalian subject. The modifications typically are achieved by synthesising the parent compound with a prodrug substituent.
- Prodrugs include compounds of the invention wherein a hydroxyl, amino, sulfhydryl, carboxy or carbonyl group in a compound of the invention is bonded to any group that may be cleaved in vivo to regenerate the free hydroxyl, amino, sulfhydryl, carboxy or carbonyl group, respectively.
- prodrugs include, but are not limited to, esters and carbamates of hydroxy functional groups, esters groups of carboxyl functional groups, N-acyl derivatives and N-Mannich bases.
- General information on prodrugs may be found e.g. in Bundegaard, H. “Design of Prodrugs” p. 1-92, Elesevier, New York-Oxford (1985).
- Compounds of the invention may contain double bonds and may thus exist as E (ent ought) and Z ( Milton ) geometric isomers about each individual double bond. Positional isomers may also be embraced by the compounds of the invention. All such isomers (e.g.
- a compound of the invention incorporates a double bond or a fused ring, the cis- and trans- forms, are embraced) and mixtures thereof are included within the scope of the invention (e.g. single positional isomers and mixtures of positional isomers may be included within the scope of the invention).
- Compounds of the invention may also exhibit tautomerism. All tautomeric forms (or tautomers) and mixtures thereof are included within the scope of the invention.
- the term "tautomer” or "tautomeric form” refers to structural isomers of different energies which are interconvertible via a low energy barrier.
- proton tautomers also known as prototropic tautomers
- proton tautomers include interconversions via migration of a proton, such as keto-enol and imine-enamine isomerisations.
- Valence tautomers include interconversions by reorganisation of some of the bonding electrons.
- Compounds of the invention may also contain one or more asymmetric carbon atoms and may therefore exhibit optical and/or diastereoisomerism.
- Diastereoisomers may be separated using conventional techniques, e.g. chromatography or fractional crystallisation. The various stereoisomers may be isolated by separation of a racemic or other mixture of the compounds using conventional, e.g. fractional crystallisation or HPLC, techniques.
- the desired optical isomers may be made by reaction of the appropriate optically active starting materials under conditions which will not cause racemisation or epimerisation (i.e. a ‘chiral pool’ method), by reaction of the appropriate starting material with a ‘chiral auxiliary’ which can subsequently be removed at a suitable stage, by derivatisation (i.e.
- a resolution for example with a homochiral acid followed by separation of the diastereomeric derivatives by conventional means such as chromatography, or by reaction with an appropriate chiral reagent or chiral catalyst all under conditions known to the skilled person.
- stereoisomers including but not limited to diastereoisomers, enantiomers and atropisomers
- mixtures thereof e.g. racemic mixtures
- stereochemistry of any particular chiral atom is not specified, then all stereoisomers are contemplated and included as the compounds of the invention. Where stereochemistry is specified by a solid wedge or dashed line representing a particular configuration, then that stereoisomer is so specified and defined.
- the compounds of the present invention may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and it is intended that the invention embrace both solvated and unsolvated forms.
- the present invention also embraces isotopically-labeled compounds of the present invention which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature (or the most abundant one found in nature). All isotopes of any particular atom or element as specified herein are contemplated within the scope of the compounds of the invention.
- Exemplary isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine and iodine, such as 2 H, ⁇ , n C, 13 C, 14 C , 13 N, 15 0, 17 0, 18 0, 32 P, 33 P, 35 S, 1S F, 36 C1, l23 I, and 125 I.
- Certain isotopically-labeled compounds of the present invention e.g., those labeled with 3 H and 14 C
- Tritiated (3 ⁇ 4) and carbon-14 ( 14 C) isotopes are useful for their ease of preparation and detectability.
- isotopically labeled compounds of the present invention can generally be prepared by following procedures analogous to those disclosed in the description/Examples hereinbelow, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.
- Ci- q alkyl groups (where q is the upper limit of the range) defined herein may be straight-chain or, when there is a sufficient number (i.e. a minimum of two or three, as appropriate) of carbon atoms, be branched-chain, and/or cyclic (so forming a C3- q -cycloalkyl group).
- Such cycloalkyl groups may be monocyclic or bicyclic and may further be bridged. Further, when there is a sufficient number (i.e. a minimum of four) of carbon atoms, such groups may also be part cyclic.
- Such alkyl groups may also be saturated or, when there is a sufficient number (i.e. a minimum of two) of carbon atoms, be unsaturated (forming, for example, a Ci- q alkenyl or a C2- q alkynyl group).
- C_3- q cycloalkyl groups may be monocyclic or bicyclic alkyl groups, which cycloalkyl groups may further be bridged (so forming, for example, fused ring systems such as three fused cycloalkyl groups).
- Such cycloalkyl groups may be saturated or unsaturated containing one or more double bonds (forming for example a cycloalkenyl group).
- Substituents may be attached at any point on the cycloalkyl group. Further, where there is a sufficient number (i.e. a minimum of four) such cycloalkyl groups may also be part cyclic.
- halo when used herein, preferably includes fluoro, chloro, bromo and iodo.
- Heterocyclic groups when referred to herein may include aromatic or non-aromatic heterocyclic groups, and hence encompass heterocycloalkyl and hetereoaryl.
- aromatic or non-aromatic 5- or 6-membered rings may be heterocyclic groups (as well as carbocyclic groups) that have 5- or 6-members in the ring.
- Heterocycloalkyl groups that may be mentioned include non-aromatic monocyclic and bicyclic heterocycloalkyl groups in which at least one (e.g. one to four) of the atoms in the ring system is other than carbon (i.e. a heteroatom), and in which the total number of atoms in the ring system is between 3 and 20 (e.g. between three and ten, e.g between 3 and 8, such as 5- to 8-). Such heterocycloalkyl groups may also be bridged. Further, such heterocycloalkyl groups may be saturated or unsaturated containing one or more double and/or triple bonds, forming for example a Ci- q heterocycloalkenyl (where q is the upper limit of the range) group.
- a Ci- q heterocycloalkenyl where q is the upper limit of the range
- Ci- q heterocycloalkyl groups that may be mentioned include 7-azabicyclo[2.2. ljheptanyl, 6-azabicyclo[3.1.1]heptanyl, 6- azabicyclo[3.2.1]-octanyl, 8-azabicyclo-[3.2.
- heterocycloalkyl groups may, where appropriate, be located on any atom in the ring system including a heteroatom.
- the point of attachment of heterocycloalkyl groups may be via any atom in the ring system including (where appropriate) a heteroatom (such as a nitrogen atom), or an atom on any fused carbocyclic ring that may be present as part of the ring system.
- Heterocycloalkyl groups may also be in the N- or S- oxidised form.
- Heterocycloalkyl mentioned herein may be stated to be specifically monocyclic or bicyclic.
- Aromatic groups may be aryl or heteroaryl.
- Aryl groups that may be mentioned include C6 ⁇ 20, such as Ce-ii (e.g. C6-10) aryl groups. Such groups may be monocyclic, bicyclic or tricyclic and have between 6 and 12 (e.g. 6 and 10) ring carbon atoms, in which at least one ring is aromatic.
- C6-10 aryl groups include phenyl, naphthyl and the like, such as 1,2,3,4-tetrahydronaphthyl.
- the point of attachment of aryl groups may be via any atom of the ring system. For example, when the aryl group is polycyclic the point of attachment may be via atom including an atom of a non-aromatic ring.
- aryl groups are polycyclic (e.g. bicyclic or tricyclic), they are preferably linked to the rest of the molecule via an aromatic ring. Most preferred aryl groups that may be mentioned herein are “phenyl”. Unless otherwise specified, the term “heteroaryl” when used herein refers to an aromatic group containing one or more heteroatom(s) (e.g. one to four heteroatoms) preferably selected from N, O and S. Heteroaryl groups include those which have between 5 and 20 members (e.g.
- heteroaryl group may be monocyclic, bicyclic or tricyclic, provided that at least one of the rings is aromatic (so forming, for example, a mono-, bi-, or tricyclic heteroaromatic group).
- the heteroaryl group is polycyclic the point of attachment may be via any atom including an atom of a non-aromatic ring.
- heteroaryl groups are polycyclic (e.g. bicyclic or tricyclic), they are preferably linked to the rest of the molecule via an aromatic ring.
- Heteroaryl groups that may be mentioned include 3,4-dihydro- 1/f-isoquinolinyl, 1 ,3-dihydroisoindolyl, 1 ,3-dihydroisoindolyl (e.g. 3,4-dihydro-l//-isoquinolin-2-yl, l,3-dihydroisoindol-2-yl,
- oxadiazolyl including 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl and 1,3,4-oxadiazolyl
- oxazolyl phenazinyl, phenothiazinyl, phthalazinyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinolizinyl, quinoxalinyl, tetrahydroisoquinolinyl (including 1 ,2,3,4-tetrahydroisoquinolinyl and 5,6,7,8-tetra- hydroisoquinolinyl), tetrahydroquinolinyl
- heteroaryl groups may, where appropriate, be located on any atom in the ring system including a heteroatom.
- the point of attachment of heteroaryl groups may be via any atom in the ring system including (where appropriate) a heteroatom (such as a nitrogen atom), or an atom on any fused carbocyclic ring that may be present as part of the ring system.
- Heteroaryl groups may also be in the N- or S- oxidised form.
- Most preferred heteroaryl groups that may be mentioned herein are 5- or 6- membered aromatic groups containing 1 , 2 or 3 heteroatoms (e.g. preferably selected from nitrogen, oxygen and sulfur).
- the heteroaryl group is monocyclic or bicyclic.
- the heteroaryl may consist of a five-, six- or seven-membered monocyclic ring (e.g. a monocyclic heteroaryl ring) fused with another five-, six- or seven-membered ring (e.g. a monocyclic aryl or heteroaryl ring).
- Heteroatoms that may be mentioned include phosphorus, silicon, boron and, preferably, oxygen, nitrogen and sulfur.
- aromatic groups When “aromatic” groups are referred to herein, they may be aryl or heteroaryl.
- aromatic linker groups When “aromatic linker groups” are referred to herein, they may be aryl or heteroaryl, as defined herein, are preferably monocyclic (but may be polycyclic) and attached to the remainder of the molecule via any possible atoms of that linker group. However, when, specifically carbocyclic aromatic linker groups are referred to, then such aromatic groups may not contain a heteroatom, i.e. they may be aryl (but not heteroaryl). For the avoidance of doubt, where it is stated herein that a group may be substituted by one or more substituents (e.g.
- substituents are independent of one another. That is, such groups may be substituted with the same substituent (e.g. same alkyl substituent) or different (e.g. alkyl) substituents.
- compounds of the invention that are the subject of this invention include those that are stable. That is, compounds of the invention include those that are sufficiently robust to survive isolation from e.g. a reaction mixture to a useful degree of purity.
- R 1 represents hydrogen or C 1.3 alkyl.
- Preferred compounds of the invention include those in which R 1 represents C1-3 alkyl such as methyl or ethyl.
- R 1 represents methyl.
- Sub is either not present or represents a halo (e.g. fluoro) atom.
- Compounds of the invention may have a non-aromatic 6-membered A ring such as in formula la:
- compounds of the invention may have an aromatic 6-membered A ring such as in formula lb:
- Compounds of the invention may have an aromatic 5-membered ring in which X x represents a heteroatom such as nitrogen, oxygen or sulfur (and in an embodiment represents sulfur), such as in formula Ic.
- the “A” ring is unsubstituted or substituted with one fluoro atom. In an embodiment, the “A” ring is a 6-membered aromatic or non-aromatic ring.
- Preferred compounds of the invention include those in which the “B” ring contain at least one nitrogen atom (in an embodiment, at the ring junction); and/or contains one, two, three or four heteroatoms in total.
- compounds of the invention are those in which the “B” ring and adjacent 6 membered non-aromatic ring are represented by a sub-formula (II) as defined hereinbelow (where it will be appreciated that the rules of valency will be adhered to, e.g. where C is mentioned then it may need to have a H attached to it), in which: one of X 1 and X 2 represents N (i.e. there is an essential nitrogen at the ring junction) and the other represents C; the other integers X 3 , X 4 and X 5 may represent C (or CH) or a heteroatom (such as N,
- any one or two of X 3 , X 4 and X 3 represents a heteroatom (e.g. N, O and/or S; and, in an embodiment, N) and the other(s) represents C (or CH).
- preferred compounds of the invention include those in which: one of X 1 and X 2 represents N; and none, one or two of X 3 , X 4 and X 5 represents N.
- the “B” ring and adjacent 6 membered non-aromatic ring in compounds of the invention may be depicted as follows in sub formula (II) (in which the left hand side would be further bound to the requisite quinolinone, or tetrahydro-quinolinone, of formula (I) and the right hand side would be further bound to the L 1 group of formula wherein: one of X 1 and X 2 represents N (i.e. there is an essential nitrogen at the ring junction) and the other represents C; the other integers X 3 , X 4 and X 3 may represent C (or CH) or a heteroatom (such as N,
- any one or two of X 3 , X 4 and X 5 represents a heteroatom (e.g. N, O and/or S) and the other represents C (or CH), and in which in all of the cases above, it will be understood that the rules of valency will need to be adhered to.
- preferred compounds of the invention include those in which in the sub-formula (II) depicted above:
- X 1 , X 3 and X 5 represent a heteroatom (e.g. nitrogen) and X 2 and X 4 represent C (or CH).
- preferred compounds of the invention include those in which in the sub-formula (II) depicted above:
- X 2 , X 3 and X 5 represent a heteroatom (e.g. nitrogen) and X 1 and X 4 represent C (or CH).
- sub-formula (II) represents:
- the “B” ring and adjacent 6 membered non-aromatic ring in compounds of the invention may be depicted as follows, (in which the left hand side would be further bound to the requisite quinolinone, or tetrahydro-quinolinone, of formula (I) and the right hand side would be further bound to the L 1 group of formula (I)):
- preferred compounds of the invention include those in which in the sub-formula (II) depicted above: X 2 and X 3 represent a heteroatom (e.g. nitrogen) and X 1 , X 4 and X 5 represent C (or CH).
- X 2 and X 3 represent a heteroatom (e.g. nitrogen) and X 1 , X 4 and X 5 represent C (or CH).
- the “B” ring and adjacent 6 membered non-aromatic ring in compounds of the invention may be depicted as follows, (in which the left hand side would be further bound to the requisite quinolinone, or tetrahydro-quinolinone, of formula (I) and the right hand side would be further bound to the L 1 group of formula
- L 1 represents a direct bond or -C(R xl )(R x2 )-;
- R xl and R x2 independently represent hydrogen for example:
- L 1 may specifically represent a direct bond, -O- or -CH2- (or, in a more specific embodiment, a direct bond or -CH 2 -; especially a direct bond).
- L 1 represents a direct bond
- Z 1 represents:
- Z 1 represents (i), (ii), (iii) or (iv) (e.g. Z 1 represents (i) or (ii)).
- Z 1 represents an aromatic ring (i.e. (i), (ii), (iii) or (iv) above), for instance (i) or (ii).
- Z 1 represents (iv), i.e. a cyclic amino group, then L 1 represenst a direct bond or -CH 2 - (but cannot represent -O-).
- Z 1 in a specific embodiment represents a 5- or 6-membered ring (pyrrolinyl or piperidinyl; i.e. Y b represents — [(CH 2 )3-4]-), which is optionally substituted by one or more (e.g. one) R h substituent (and R h represents a B 1 susbtituent, and is, in an embodiment, C1-3 alkyl optionally substituted by one or more fluoro atoms).
- compounds of the invention include those in which when ring C is present, it represents a 5-membered aromatic ring, it contains one, two or three heteroatoms preferably selected from nitrogen, oxygen and sulfur; in a further embodiment, such ring is optionally substituted by one or two substituents independently selected from R f ; when ring D is present, it represents a 6-membered aromatic ring containing one nitrogen atom; and, in a further embodiment, such ring is optionally substituted by one or two substituents independently selected from R g ;
- R a , R b , R c , R d and R e independently represent hydrogen or a substituent selected from B 1 ;
- R f and R g each independently represent a substituent selected from B 1 .
- such aromatic 5-membered (optionally substituted) ring may: (i) contain one sulfur atom (so forming a thienyl); (ii) contain one nitrogen and one sulfur atom (so forming e.g. thiazolyl); (iii) contain two nitrogen atoms (so forming e.g. a pyrazolyl); (iv) contains two nitrogen atoms and one sulfur atom; (v) contains two nitrogen atoms and one oxygen atom; (vi) contains three nitrogen atoms.
- Ring D is present (i.e. Z 1 represents (iii)
- such aromatic 6-membered ring may contain one nitrogen atom, so forming a pyridyl group (e.g. a 3- pyridyl group).
- further preferred compounds of the inventions include those in which: none, but preferably, one or two (e.g. one) of R a , R b , R c , R d and R e represents B 1 and the others represent hydrogen; and/or one or two (e.g. one) of R b .
- R c and R d (preferably R c ) represents B 1 and the others represent hydrogen.
- preferred compounds of the inventions include those in which: R b and one of R c or R d represent B 1 and the others represent hydrogen.
- preferred compounds of the inventions include those in which: R b and R e represent B 1 and the others represent hydrogen.
- preferred compounds of the inventions include those in which: R b and R d represent B 1 and the others represent hydrogen.
- preferred compounds of the inventions include those in which: R b represent B 1 and the others represent hydrogen.
- preferred compounds of the inventions include those in which: R c represent B 1 and the others represent hydrogen.
- R e2 and R e4 independently represent hydrogen
- R el , R e3 and R c:! each independently represent C 1.3 alkyl (e.g. methyl) substituted by one or more fluoro atoms.
- yet further preferred compounds of the inventions include those in which:
- B 1 represents a substituent selected from:
- Ci -6 alkyl preferably C 1-3 alkyl, substituted by one or more fluoro atom; (iii) -OR el .
- B 1 represents a substituent selected from halo (e.g. fluoro), C 1-3 alkyl (optionally substituted by one or more fluoro atom) and -OR el (in which R ei represents C 1-3 alkyl optionally substituted by one or more fluoro atom, so forming e.g. -OCH 3 or-OCFs).
- B 1 is selected from fluoro, -CH 3, -0CH 3 , -CF 3 , -CHF2, -CH 2 CF3, -CH 2 CHF2, -CH 2 CH 2 CF 3 and -OCF3.
- B 1 is selected from fluoro, -CH 3 , -CF 3 , -OCH 3 and -OCF3.
- Z 1 represents:
- ring C represents a 5-membered aromatic ring containing at least two heteroatoms, wherein at least one of said heteroatom is a nitrogen atom, and which ring is substituted by one or more substituents independently selected from R f ; one or two (e.g. one) of R b R c and R d (preferably R c ) represents B 1 and the others represent hydrogen;
- R 1 and R h independently represent hydrogen or a substituent selected from B 1 ; each B 1 independently represents a substituent selected from:
- R dl represents C 1 - 6 alkyl, preferably C 1-3 alkyl, optionally substituted by one or more fluoro atoms; and/or R el represent hydrogen or C 1 - 6 alkyl optionally substituted by one or more fluoro atoms.
- the compounds according to the invention have surprisingly been shown to be suitable for the treatment of a bacterial infection including a mycobacterial infection, particularly those diseases caused by pathogenic mycobacteria such as Mycobacterium tuberculosis (including the latent and drug resistant form thereof).
- the present invention thus also relates to compounds of the invention as defined hereinabove, for use as a medicine, in particular for use as a medicine for the treatment of a bacterial infection including a mycobacterial infection.
- Such compounds of the invention may act by interfering with ATP synthase in M. tuberculosis, with the inhibition of cytochrome bd activity being the primary mode of action.
- cytochrome bd inhibition may have an effect in killing mycobacteria (and hence having an anti-tuberculosis effect directly).
- cytochrome bd is not necessarily essential for aerobic growth, it may have the most pronounced effect in combination with another inhibitor of a target of the electron transport chain of mycobacteria.
- Such compounds may be tested for cytochrome bd activity by testing in an enzymatic assay, and may also be tested for activity in the treatment of a bacterial infection (e.g.
- mycobacterial infection by testing the kill kinetics, for example of such compounds alone or in combination (as mentioned herein, e.g. with one or more other inhibitor(s) of a (different) target of the electron transport chain of mycobacteria; such other different targets may be more implicated in aerobic growth).
- Cytochrome bd is a component of the electron transport chain, and therefore may be implicated with ATP synthesis, for instance alone or especially with one or more other inhibitor(s) of a target of the electron transport chain of mycobacteria.
- the present invention also relates to the use of a compound of the invention, as well as any of the pharmaceutical compositions thereof as described hereinafter for the manufacture of a medicament for the treatment of a bacterial infection including a mycobacterial infection (for instance when such compound of the invention is used in combination with another inhibitor of a target of the electron transport chain of mycobacteria).
- the invention provides a method of treating a patient suffering from, or at risk of, a bacterial infection, including a mycobacterial infection, which comprises administering to the patient a therapeutically effective amount of a compound or pharmaceutical composition according to the invention (for instance a therapeutically effective amount of a compound or pharmaceutical composition of the invention, in combination with one or more other inhibitor(s) of a target of the electron transport chain of mycobacteria).
- the compounds of the present invention also show activity against resistant bacterial strains (for instance alone or in combination with another inhibitor of a target of the electron transport chain of mycobacteria).
- the compounds can treat a bacterial infection (alone or in combination) it is meant that the compounds can treat an infection with one or more bacterial strains.
- the invention also relates to a composition
- a composition comprising a pharmaceutically acceptable carrier and, as active ingredient, a therapeutically effective amount of a compound according to the invention.
- the compounds according to the invention may be formulated into various pharmaceutical forms for administration purposes. As appropriate compositions there may be cited all compositions usually employed for systemically administering drugs.
- an effective amount of the particular compound, optionally in addition salt form, as the active ingredient is combined in intimate admixture with a pharmaceutically acceptable carrier, which carrier may take a wide variety of forms depending on the form of preparation desired for administration.
- a pharmaceutically acceptable carrier which carrier may take a wide variety of forms depending on the form of preparation desired for administration.
- These pharmaceutical compositions are desirable in unitary dosage form suitable, in particular, for administration orally or by parenteral injection.
- any of the usual pharmaceutical media may be employed such as, for example, water, glycols, oils, alcohols and the like in the case of oral liquid preparations such as suspensions, syrups, elixirs, emulsions and solutions; or solid carriers such as starches, sugars, kaolin, diluents, lubricants, binders, disintegrating agents and the like in the case of powders, pills, capsules and tablets. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit forms in which case solid pharmaceutical carriers are obviously employed.
- the carrier will usually comprise sterile water, at least in large part, though other ingredients, for example, to aid solubility, may be included.
- injectable solutions for example, may be prepared in which the carrier comprises saline solution, glucose solution or a mixture of saline and glucose solution.
- injectable suspensions may also be prepared in which case appropriate liquid carriers, suspending agents and the like may be employed.
- solid form preparations which are intended to be converted, shortly before use, to liquid form preparations.
- the pharmaceutical composition will preferably comprise from 0.05 to 99 % by weight, more preferably from 0.1 to 70 % by weight, even more preferably from 0.1 to 50 % by weight of the active ingredient(s), and, from 1 to 99.95 % by weight, more preferably from 30 to 99.9 % by weight, even more preferably from 50 to 99.9 % by weight of a pharmaceutically acceptable carrier, all percentages being based on the total weight of the composition.
- the pharmaceutical composition may additionally contain various other ingredients known in the art, for example, a lubricant, stabilising agent, buffering agent, emulsifying agent, viscosity-regulating agent, surfactant, preservative, flavouring or colorant.
- a lubricant for example, a lubricant, stabilising agent, buffering agent, emulsifying agent, viscosity-regulating agent, surfactant, preservative, flavouring or colorant.
- Unit dosage form refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.
- unit dosage forms are tablets (including scored or coated tablets), capsules, pills, powder packets, wafers, suppositories, injectable solutions or suspensions and the like, and segregated multiples thereof.
- the daily dosage of the compound according to the invention will, of course, vary with the compound employed, the mode of administration, the treatment desired and the mycobacterial disease indicated. However, in general, satisfactory results will be obtained when the compound according to the invention is administered at a daily dosage not exceeding 1 gram, e.g. in the range from 10 to 50 mg/kg body weight.
- the present compounds may be combined with other antibacterial agents in order to effectively combat bacterial infections.
- compounds may be useful against bacterial infections, we mean that those compounds may have activity as such or those compounds may be effective in combination (as described herein, e.g. with one or more other inhibitors of the electron transport chain of mycobacteria) by enhancing activity or providing synergistic combinations, for example as may be described in the experimental hereinafter.
- the present invention also relates to a combination of (a) a compound according to the invention, and (b) one or more other antibacterial agents (e.g. one or more other inhibitors of the electron transport chain of mycobacteria, for instance a cytochrome be inhibitor, an ATP synthase inhibitor, a NDH2 inhibitor and/or an inhibitor of the menaquinone synthesis pathway, such as a MenCi inhibitor).
- one or more other antibacterial agents e.g. one or more other inhibitors of the electron transport chain of mycobacteria, for instance a cytochrome be inhibitor, an ATP synthase inhibitor, a NDH2 inhibitor and/or an inhibitor of the menaquinone synthesis pathway, such as a MenCi inhibitor.
- the present invention also relates to such a compound or combination, for use as a medicine.
- the present invention also relates to the use of a combination or pharmaceutical composition as defined directly above for the treatment of a bacterial infection.
- a pharmaceutical composition comprising a pharmaceutically acceptable carrier and, as active ingredient, a therapeutically effective amount of (a) a compound according to the invention, and (b) one or more other antibacterial agents (e.g. one or more other inhibitors of the electron transport chain of mycobacteria, for instance a cytochrome be inhibitor, an ATP synthase inhibitor, a NDH2 inhibitor and/or an inhibitor of the menaquinone synthesis pathway, such as a MenG inhibitor), is also comprised by the present invention.
- one or more other antibacterial agents e.g. one or more other inhibitors of the electron transport chain of mycobacteria, for instance a cytochrome be inhibitor, an ATP synthase inhibitor, a NDH2 inhibitor and/or an inhibitor of the menaquinone synthesis pathway, such as a MenG inhibitor
- the weight ratio of (a) the compound according to the invention and (b) the other antibacterial agent(s) when given as a combination may be determined by the person skilled in the art. Said ratio and the exact dosage and frequency of administration depends on the particular compound according to the invention and the other antibacterial agent(s) used, the particular condition being treated, the severity of the condition being treated, the age, weight, gender, diet, time of administration and general physical condition of the particular patient, the mode of administration as well as other medication the individual may be taking, as is well known to those skilled in the art. Furthermore, it is evident that the effective daily amount may be lowered or increased depending on the response of the treated subject and/or depending on the evaluation of the physician prescribing the compounds of the instant invention.
- a particular weight ratio for the present compound of the invention and another antibacterial agent may range from 1/10 to 10/1, more in particular from 1/5 to 5/1, even more in particular from 1/3 to 3/1.
- the compounds according to the invention and the one or more other antibacterial agents may be combined in a single preparation or they may be formulated in separate preparations so that they can be administered simultaneously, separately or sequentially.
- the present invention also relates to a product containing (a) a compound according to the invention, and (b) one or more other antibacterial agents (e.g.
- one or more other inhibitors of the electron transport chain of mycobacteria for instance a cytochrome be inhibitor, an ATP synthase inhibitor, a NDH2 inhibitor and/or an inhibitor of the menaquinone synthesis pathway, such as a MenG inhibitor), as a combined preparation for simultaneous, separate or sequential use in the treatment of a bacterial infection.
- a cytochrome be inhibitor for instance a cytochrome be inhibitor, an ATP synthase inhibitor, a NDH2 inhibitor and/or an inhibitor of the menaquinone synthesis pathway, such as a MenG inhibitor
- antibacterial agents which may be combined with the compounds of the invention are for example antibacterial agents known in the art.
- the compounds of the invention may be combined with antibacterial agents known to interfere with the respiratory chain of Mycobacterium tuberculosis, including for example direct inhibitors of the ATP synthase (e.g. bedaquiline, bedaquiline fumarate or any other compounds that may have be disclosed in the prior art, e.g. compounds disclosed in W02004/011436), inhibitors of ndh2 (e.g. clofazimine) and inhibitors of cytochrome bd.
- direct inhibitors of the ATP synthase e.g. bedaquiline, bedaquiline fumarate or any other compounds that may have be disclosed in the prior art, e.g. compounds disclosed in W02004/011436
- inhibitors of ndh2 e.g. clofazimine
- inhibitors of cytochrome bd e.g. cytochrome bd.
- compounds of the invention may be combined with one or more other inhibitors of the electron transport chain of mycobacteria, for instance a cytochrome be inhibitor, an ATP synthase inhibitor, a NDH2 inhibitor and/or an inhibitor of the menaquinone synthesis pathway, such as a MenG inhibitor.
- a cytochrome be inhibitor for instance a cytochrome be inhibitor, an ATP synthase inhibitor, a NDH2 inhibitor and/or an inhibitor of the menaquinone synthesis pathway, such as a MenG inhibitor.
- the compounds of the invention might act as cytochrome bd inhibitors, and hence target the electron transport chain of the mycobacteria (thereby blocking energy production of mycobacteria), the compounds of the invention (cytochrome bd inhibitors), combinations with one or more other inhibitors of the electron transport chain is thought to be a potentially effective way of providing an efficient regimen against mycobacteria. Even if the compounds of the invention (cytochrome bd inhibitors) alone might not be effective against mycobacteria, combining with one or more other such inhibitors may provide an effective regimen where the activity of one or more components of the combination is/are enhanced and/or such combinations act more effectively (e.g. synergistically).
- the compounds according to the invention can generally be prepared by a succession of steps, each of which may be known to the skilled person or described herein.
- reaction products may be isolated from the reaction medium and, if necessary, further purified according to methodologies generally known in the art, such as extraction, crystallization and chromatography. It is further evident that reaction products that exist in more than one enantiomeric form, may be isolated from their mixture by known techniques, in particular preparative chromatography, such as preparative HPLC, chiral chromatography. Individual diastereoisomers or individual enantiomers can also be obtained by Supercritical Fluid Chromatography (SCF).
- SCF Supercritical Fluid Chromatography
- the starting materials and the intermediates are compounds that are either commercially available or may be prepared according to conventional reaction procedures generally known in the art.
- reaction products may be isolated from the reaction medium and, if necessary, further purified according to methodologies generally known in the art, such as extraction, crystallization and chromatography. It is further evident that reaction products that exist in more than one enantiomeric form, may be isolated from their mixture by known techniques, in particular preparative chromatography, such as preparative HPLC, chiral chromatography. Individual diastereoisomers or individual enantiomers can also be obtained by Supercritical Fluid Chromatography (SCF).
- SCF Supercritical Fluid Chromatography
- the starting materials and the intermediates are compounds that are either commercially available or may be prepared according to conventional reaction procedures generally known in the art.
- compound AB-2 was prepared in the same way as compound AB-1 starting from AA-3 (0.452 mmol) and 4-Trifluoromethoxyphenylboronic acid (CAS [139301-27-2], 0.542 mmol), to give 0.106 g (54%) as a white solid.
- compound AB-3 was prepared in the same way as compound AB-1 starting from AA-3 (0.845 mmol) and 3,4-difluorophenylboronic acid (CAS [168267- 41-2], 1.35 mmol) to give a beige solid, 0.093 g (28%).
- compound AB-4 was prepared in the same way as compound AB-1 starting from AA-3 (1.41 mmol) and 4-methoxybenzeneboronic acid (CAS [5720-07- 0], 2.11 mmol) to give a pale beige powder, 0.528 g (98%).
- compound AB-5 was prepared in the same way as compound AB-1 starting from AA-3 (1.41 mmol) and 3-fluoro-5-methylphenylboronic acid (CAS [850593-06-5], 2.11 mmol) to give a pale beige powder, 0.528 g (98%).
- compound AB-6 was prepared in the same way as compound AB-1 starting from AA-3 (1.18 mmol) and 3-Fluoro-4-methylbenzeneboronic acid (CAS [168267-99-0], 1.77 mmol) to give a pale beige powder, 0.292 g (64%).
- compound AB-7 was prepared in the same way as compound AB-1 starting from AA-3 (1.18 mmol) and 3-Fluoro-5-methoxyphenylboronic acid (CAS [609807-25-2], 1.77 mmol) to give a pale beige powder, 0.34 g (72%).
- CAS [609807-25-2] 1.77 mmol
- compound AB-8 was prepared in the same way as compound AB- 1 starting from AA-3 (1.18 mmol) and 3,5-dimethoxybenzeneboronic acid (CAS [192182-54-0], 2.11 mmol) to give a pale beige powder, 0.5 g (86%).
- compound AB-9 was prepared in the same way as compound AB-1 starting from AA-3 (1.18 mmol) and 3-Fluoro-5-(trifluoromethyl)benzene boronic acid (CAS [159020-59-4], 1.77 mmol) to give a pale beige powder, 0.32 g (62%).
- compound AB-10 was prepared in the same way as compound AB-1 starting from AA-3 (0.84 mmol) and 3-(Trifluoromethoxy)-benzeneboronic acid (CAS [179113-90-7], 1.27 mmol) to give a pale beige powder, 0.325 g (88%).
- compound AB-11 was prepared in the same way as compound AB-1 starting from AA-3 (1.35 mmol) and [3-(2,2,2)-trifluoroethyl)phenyl]boronic acid (CAS [1620056-82-7], 2.03 mmol) to give a pale beige powder, 0.538 g (91%).
- compound AB-12 was prepared in the same way as compound AB-1 starting from AA-3 (1.35 mmol) and 4-Fluoro-3-methoxybenzeneboronie acid (CAS [854778-31-7], 2.03 mmol) to give a pale beige powder, 0.16 g (29%).
- FT was solubilized with Acetonitrile (2 mL) and extended with water (8 mL), the solution was freeze-dried overnight giving compound 57 as white foam, 0.022 g (5%).
- reaction mixture was cooled to room temperature, diluted with water (25 mL), filtered through a glass frit to collect after rinsing with water (3 x 5 mL) a black solid. This was purified by flash chromatography on silica gel (25 g), DCM/Methanol 100/0 to 98/2 over 50 min) to afford an off-white solid. The solid was triturated with methanol (3 x 2 mL) and dried under high vacuum at 50°C (for 18 h) to afford AC-3 as a white solid, 0.107 g (50%).
- Compound 7 was purified via chiral SFC (Stationary phase: CHIRALPAK AD-H 5 ⁇ m 250*30mm, Mobile phase: 60% CO2, 40% MeOH) affording 185 mg of compound 16 5 as white powder (41%) and 163 mg of compound 17 as white powder (36%).
- the precipitate was filtered on a glass frit, washed with water and purified by flash chromatography over silica gel (cyclohexane/EtOAc from 100:0 to 0: 100) to afford AH-4 as a white solid (60 mg, 34%).
- intermediate AE-3 (464 mg, 1.31 mmol), THF (4.5 mL) and water (4.5 mL) was added LiOH.H2O (110 mg, 2.62 mmol). The resulting mixture was stirred at room temperature for 6 h and then acidified with 1 M HC1 aqueous solution until pH- 1-2. The resulting precipitate was collected by filtration on a glass frit and washed with water, then dissolved in a CH2C12/MeOH mixture (9: 1), dried over Na 2 SO 4 , filtered and concentrated to dryness to afford intermediate AE-4 as a white solid (394 mg, 92%).
- Trifluoromethoxyphenylboronic acid (CAS [139301-27-2], 1.81 g, 8,79 mmol) and 5 Potassium phosphatetribasic monohydrate (5.06 g, 22.0 mmol) in 1,4-dioxane (29.6 mL) and water (7.4 mL) was purged with nitrogen, 1,1'-
- reaction mixture was cooled to room temperature and filtered on celite® and washed with a DCM/EtOH mixture (9: 1, 200 mL) to afford a yellow oil, 0.29 g. It was purified by flash chromatography over silica gel (DCM/MeOH from 100/0 to 95/5 over 40 min.). The desired fractions were concentrated under reduced pressure and the resulting solids were vacuum-dried at 60 °C for 20 h to afford compound 32 (0.084 g, 33%) as a yellow solid and compound 34 (0.044 g, 17%) as a yellowish solid.
- HPLC High Performance Liquid Chromatography
- MS Mass Spectrometer
- SQL Single Quadrupole Detector
- RT room temperature
- BEH bridged ethylsiloxane/silica hybrid
- HSS High Strength Silica
- DAD Diode Array Detector
- Melting points were determined by DSC on a Mettler-Toledo DSC1 instrument (using aluminum standard 40 pL pans with air as purge gas and a thermal gradient between - 10 °C and 350 °C) or on a melting point apparatus Buchi M-560, both applying indicated heating rates.
- individual compounds of the invention/examples (or combinations containing such compounds, for instance cytochrome bd inhibitors of the invention/examples in combination with one or more other inhibitor(s) of a (different) target of the electron transport chain of mycobacteria, as described herein) may be tested.
- combinations may be tested (e.g. combinations of test cytochrome bd compounds with known cytochrome be inhibitors, such as Q203 and Compound X).
- CK- 2-63 is employed.
- the compound Q203 (cytochrome bcl inhibitor) may be prepared in accordance with the procedures in J. Medicinal Chemistry, 2014, 57 (12), pp 5293-5305, as well as, in WO 2011/113606 (see Compound 289 “6-chloro-2-ethyl-/V-(4-(4-(4- (trifluoromethoxy)phenyl)piperidin-l-yl)benzyl)imidazo[l,2-a]pyridine-3- carboxamide”).
- Compound X is 6-chloro-2-ethyl-/V-( ⁇ 4-[2-(trifluoromethanesulfonyl)-2- azaspiro[3.3]heptan-6-yl]phenyl ⁇ methyl)imidazo[ 1 ,2-a]pyridine-3-carboxamide, which is described as Compound 154 of WO 2017/001660 and may be prepared according to the procedures described therein.
- CK-2-63 may be prepared in accordance with the procedures disclosed in WO 2017/103615 (see experimental and the disclosures therein, referring to WO 2012/2069856, where an experimental procedure is provided for “3-methyl-2-(4-(4- (trifluoromethoxy)phenoxy)phenyl)quinolin-4(lH)-one”).
- Test compounds and reference compounds were dissolved in DMSO and 1 m ⁇ of solution was spotted per well in 96 well plates at 200x the final concentration. Column 1 and column 12 were left compound-free, and from column 2 to 11 compound concentration was diluted 3-fold. Frozen stocks of Mycobacterium tuberculosis strain EH4.0 expressing green-fluorescent protein (GFP) were previously prepared and titrated. To prepare the inoculum, 1 vial of frozen bacterial stock was thawed to room temperature and diluted to 5x10 exp5 colony forming units per ml in 7H9 broth. 200 m ⁇ of inoculum, which corresponds to 1x10 exp5 colony forming units, were transferred per well to the whole plate, except column 12.
- GFP green-fluorescent protein
- fluorescence was measured on a Gemini EM Microplate Reader with 543 excitation and 590 nm emission wavelengths and MIC50 and/or pICso values (or the like, e.g. IC50, IC90, rK3 ⁇ 4o, etc) were (or may be) calculated.
- Time kill kinetics assays test 3 Bactericidal or bacteriostatic activity of the compounds can be determined in a time kill kinetic assay using the broth dilution method.
- the starting inoculum of M. tuberculosis (strain H37Rv and H37Ra) is 10 6 CFU / ml in Middlebrook (lx) 7H9 broth.
- the test compounds (cyt bd inhibitors) are tested in combination with a cyt be inhibitor (for example Q203 or Compound X) at the concentration ranging from 10- 30mM to 0.9-0.3mM respectively. Tubes receiving no antibacterial agent constitute the culture growth control.
- the tubes containing the microorganism and the test compounds are incubated at 37 °C. After 0, 1, 4, 7, 14 and 21 days of incubation samples are removed for determination of viable counts by serial dilution (10° to 10 ⁇ 6 ) in Middlebrook 7H9 medium and plating (100 m ⁇ ) on Middlebrook 7H11 agar. The plates are incubated at 37 °C for 21 days and the number of colonies are determined. Killing curves can be constructed by plotting the logioCFU per ml versus time.
- a bactericidal effect of a cytochrome be and cytochrome bd inhibitor is commonly defined as 2-log 10 decrease (decrease in CFU per ml) compared to Day 0.
- the potential carryover effect of the drugs is limited by using 0.4% charcoal in the agar plates, and by serial dilutions and counting the colonies at highest dilution possible used for plating.
- Phenotypic assay to determine the O2 consumption rate of Mycobacterium tuberculosis test 4 The aim of this assay is to evaluate the O2 consumption rate of Mycobacterium tuberculosis (Mtb) bacilli after inhibition of cyt be 1 and cyt bd, using extracellular flux technology. Inhibition of cyt bcl (e.g. using known inhibitors such as Q203 or Compound X) forces the bacillus to use the less energetically efficient terminal oxidase cyt bd. The inhibition of cyt bd will cause a significant decrease O2 consumption. A sustained decrease of O2 consumption under membrane potential disrupting conditions, via the addition of the uncoupler CCCP, will show to the efficacy of the cyt bd inhibitor.
- Mtb Mycobacterium tuberculosis
- OCR oxygen consumption rate
- the Compound X (final concentration of 0.9 mM, Compound X), is used to inhibit cyt bcl and the cyt bd inhibitor, CK-2-63 (final concentration of 10 mM), is used as a positive control.
- the uncoupler CCCP is used at a final concentration of 1 mM.
- Phenotypic assay using a cytochrome be knock-out TB strain and MIC determination against M. tuberculosis ⁇ , test 5
- Biological Data - Example A Compounds of the invention/examples (or combinations, e.g. compounds of the invention/examples in combination with one or more other inhibitors of a target of the electron transport chain), for example when tested in any of Tests 1 to 3, may display activity.
- Biological Data - Example B Compounds of the invention/examples (or combinations, e.g. compounds of the invention/examples in combination with one or more other inhibitors of a target of the electron transport chain), for example when tested in any of Tests 1 to 3, may display activity.
- Biological Data - Example B Compounds of the invention/examples (or combinations, e.g. compounds of the invention/examples in combination with one or more other inhibitors of a target of the electron transport chain), for example when tested in any of Tests 1 to 3, may display activity.
- Biological Data - Example B Compounds of the invention/examples (or combinations, e.g. compounds of the invention/example
- the compounds of the invention/examples may have advantages associated with in vitro potency, kill kinetics (i.e. bactericidal effect) in vitro, PK properties, food effect, safety/toxicity (including liver toxicity, coagulation, 5-LO oxygenase), metabolic stability, Ames II negativity, MNT negativity, aqueous based solubility (and ability to formulate) and/or cardiovascular effect e.g. on animals (e.g. anesthetized guinea pig).
- the data below that was generated/calculated may be obtained using standard methods/assays, for instance that are available in the literature or which may be performed by a supplier (e.g. Microsomal Stability Assay - Cyprotex, Mitochondrial toxicity (Glu/Gal) assay - Cyprotex, as well as literature CYP cocktail inhibition assays).
- compounds of the invention/examples may be found to be advantageous as no mitotoxicity alerts were observed (e.g. in the Glu/Gal assay).
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Abstract
The present invention relates to the following compounds (I) wherein the integers are as defined in the description, and where the compounds may be useful as medicaments, for instance for use in the treatment of tuberculosis (e.g. in combination).
Description
ANTIBACTERIAL COMPOUNDS
The present invention relates to novel compounds. The invention also relates to such compounds for use as a pharmaceutical and further for the use in the treatment of bacterial diseases, including diseases caused by pathogenic mycobacteria such as Mycobacterium tuberculosis. Such compounds may work by targeting the respiratory chain, and thereby blocking all energy production of mycobacteria. There are several ways of targeting the electron transport chain of mycobacteria, for instance by interfering with ATP synthase in M. tuberculosis. This particular invention focuses on the cytochrome bd target of the respiratory chain, which may be the primary mode of action. Hence, primarily, such compounds are antitubercular agents, and in particular may act as such when combined with another tuberculosis drug (e.g. another inhibitor of a different target of the electron transport chain).
BACKGROUND OF THE INVENTION
Mycobacterium tuberculosis is the causative agent of tuberculosis (TB), a serious and potentially fatal infection with a world-wide distribution. Estimates from the World Health Organization indicate that more than 8 million people contract TB each year, and 2 million people die from tuberculosis yearly. In the last decade, TB cases have grown 20% worldwide with the highest burden in the most impoverished communities. If these trends continue, TB incidence will increase by 41% in the next twenty years. Fifty years since the introduction of an effective chemotherapy, TB remains after AIDS, the leading infectious cause of adult mortality in the world. Complicating the TB epidemic is the rising tide of multi-drug-resistant strains, and the deadly symbiosis with HIV. People who are HIV-positive and infected with TB are 30 times more likely to develop active TB than people who are HIV-negative and TB is responsible for the death of one out of every three people with HIV/AIDS worldwide.
Existing approaches to treatment of tuberculosis all involve the combination of multiple agents. For example, the regimen recommended by the U.S. Public Health Service is a combination of isoniazid, rifampicin and pyrazinamide for two months, followed by isoniazid and rifampicin alone for a further four months. These drugs are continued for a further seven months in patients infected with HIV. For patients infected with multi drug resistant strains of M. tuberculosis, agents such as ethambutol, streptomycin, kanamycin, amikacin, capreomycin, ethionamide, cycloserine, ciprofoxacin and ofloxacin are added to the combination therapies. There exists no single agent that is
effective in the clinical treatment of tuberculosis, nor any combination of agents that offers the possibility of therapy of less than six months’ duration.
There is a high medical need for new drags that improve current treatment by enabling regimens that facilitate patient and provider compliance. Shorter regimens and those that require less supervision are the best way to achieve this. Most of the benefit from treatment comes in the first 2 months, during the intensive, or bactericidal, phase when four drugs are given together; the bacterial burden is greatly reduced, and patients become noninfectious. The 4- to 6-month continuation, or sterilizing, phase is required to eliminate persisting bacilli and to minimize the risk of relapse. A potent sterilizing drag that shortens treatment to 2 months or less would be extremely beneficial. Drugs that facilitate compliance by requiring less intensive supervision also are needed. Obviously, a compound that reduces both the total length of treatment and the frequency of drug administration would provide the greatest benefit.
Complicating the TB epidemic is the increasing incidence of multi-drug-resistant strains or MDR-TB. Up to four percent of all cases worldwide are considered MDR-TB - those resistant to the most effective drugs of the four-drug standard, isoniazid and rifampin. MDR-TB is lethal when untreated and cannot be adequately treated through the standard therapy, so treatment requires up to 2 years of "second-line" drags. These drugs are often toxic, expensive and marginally effective. In the absence of an effective therapy, infectious MDR-TB patients continue to spread the disease, producing new infections with MDR-TB strains. There is a high medical need for a new drag with a new mechanism of action, which is likely to demonstrate activity against drag resistant, in particular MDR strains.
The term “drug resistant” as used hereinbefore or hereinafter is a term well understood by the person skilled in microbiology. A drag resistant Mycobacterium is a Mycobacterium which is no longer susceptible to at least one previously effective drag; which has developed the ability to withstand antibiotic attack by at least one previously effective drug. A drug resistant strain may relay that ability to withstand to its progeny. Said resistance may be due to random genetic mutations in the bacterial cell that alters its sensitivity to a single drug or to different drugs.
MDR tuberculosis is a specific form of drug resistant tuberculosis due to a bacterium resistant to at least isoniazid and rifampicin (with or without resistance to other drugs), which are at present the two most powerful anti-TB drugs. Thus, whenever used hereinbefore or hereinafter “drag resistant” includes multi drug resistant.
Another factor in the control of the TB epidemic is the problem of latent TB. In spite of decades of tuberculosis (TB) control programs, about 2 billion people are infected by M. tuberculosis, though asymptomatically. About 10% of these individuals are at risk of developing active TB during their lifespan. The global epidemic of TB is fuelled by infection of HIV patients with TB and rise of multi-drug resistant TB strains (MDR-TB). The reactivation of latent TB is a high risk factor for disease development and accounts for 32% deaths in HIV infected individuals. To control TB epidemic, the need is to discover new drugs that can kill dormant or latent bacilli. The dormant TB can get reactivated to cause disease by several factors like suppression of host immunity by use of immunosuppressive agents like antibodies against tumor necrosis factor a or interferon-g. In case of HIV positive patients the only prophylactic treatment available for latent TB is two- three months regimens of rifampicin, pyrazinamide. The efficacy of the treatment regime is still not clear and furthermore the length of the treatments is an important constrain in resource-limited environments. Hence there is a drastic need to identify new drugs, which can act as chemoprophylatic agents for individuals harboring latent TB bacilli.
The tubercle bacilli enter healthy individuals by inhalation; they are phagocytosed by the alveolar macrophages of the lungs. This leads to potent immune response and formation of granulomas, which consist of macrophages infected with M. tuberculosis surrounded by T cells. After a period of 6-8 weeks the host immune response cause death of infected cells by necrosis and accumulation of caseous material with certain extracellular bacilli, surrounded by macrophages, epitheloid cells and layers of lymphoid tissue at the periphery. In case of healthy individuals, most of the mycobacteria are killed in these environments but a small proportion of bacilli still survive and are thought to exist in a non-replicating, hypometabolic state and are tolerant to killing by anti-TB drugs like isoniazid. These bacilli can remain in the altered physiological environments even for individual’s lifetime without showing any clinical symptoms of disease. However, in 10% of the cases these latent bacilli may reactivate to cause disease. One of the hypothesis about development of these persistent bacteria is patho-physiological environment in human lesions namely, reduced oxygen tension, nutrient limitation, and acidic pH. These factors have been postulated to render these bacteria phenotypieally tolerant to major anti-mycobacterial drugs.
In addition to the management of the TB epidemic, there is the emerging problem of
resistance to first-line antibiotic agents. Some important examples include penicillin- resistant Streptococcus pneumoniae, vancomycin-resistant enterococci, methicillin- resistant Staphylococcus aureus, multi-resistant salmonellae.
The consequences of resistance to antibiotic agents are severe. Infections caused by resistant microbes fail to respond to treatment, resulting in prolonged illness and greater risk of death. Treatment failures also lead to longer periods of infectivity, which increase the numbers of infected people moving in the community and thus exposing the general population to the risk of contracting a resistant strain infection.
Hospitals are a critical component of the antimicrobial resistance problem worldwide. The combination of highly susceptible patients, intensive and prolonged antimicrobial use, and cross-infection has resulted in infections with highly resistant bacterial pathogens.
Self-medication with antimicrobials is another major factor contributing to resistance. Self-medicated antimicrobials may be unnecessary, are often inadequately dosed, or may not contain adequate amounts of active drug.
Patient compliance with recommended treatment is another major problem. Patients forget to take medication, interrupt their treatment when they begin to feel better, or may be unable to afford a full course, thereby creating an ideal environment for microbes to adapt rather than be killed.
Because of the emerging resistance to multiple antibiotics, physicians are confronted with infections for which there is no effective therapy. The morbidity, mortality, and financial costs of such infections impose an increasing burden for health care systems worldwide.
Therefore, there is a high need for new compounds to treat bacterial infections, especially mycobacterial infections including drug resistant and latent mycobacterial infections, and also other bacterial infections especially those caused by resistant bacterial strains.
There are several ways of targeting the electron transport chain of mycobacteria, for instance by interfering with ATP synthase in M. tuberculosis. Unlike many bacteria,
M. tuberculosis is dependent on respiration to synthesise adequate amounts of ATP. Hence targeting the electron transport chain of the mycobacteria and thereby blocking energy production of mycobacteria is thought to be a potentially effective way of providing an efficient regimen against mycobacteria. Targets already known are ATP synthase inhibitors, as example of which is bedaquiline (marketed as Sirturo®),
cytochrome be inhibitors, examples of which include the compound Q203 described in Journal article Nature Medicine, 19, 1157-1160 (2013) by Pethe et al “Discovery of Q203, a potent clinical candidate for the treatment of tuberculosis”, as well as patent applications such as internataional patent applcations WO 2017/001660, WO 2017/001661, WO 2017/216281 and WO 2017/216283.
Additionally, journal article Antimicrob. Agents Chemother, 2014, 6962-6965 by Arora et al describes compounds that target the respiratory bci complex in M. tuberculosis, and where deletion of the cytochrome bd oxidase generated a hypersusceptible mutant. Journal article PANS (Early Edition), 2017, “Exploiting the synthetic lethality between terminal respiratory oxidases to kill Mycobacterium tuberculosis and clear host infection” by Kalia et al discloses various data around various tuberculosis compounds that target the respiratory chain. For instance, it is shown that the compound Q203 (a known be inhibitor; see above) could inhibit mycobacteria completely and become bactericidal, after genetic deletion of the cytochrome bd oxidase-encoding genes CydAB. Similarly, journal article MBio, 2014 Jul 15;5(4) by Berney et al “A Mycobacterium tuberculosis cytochrome bd oxidase mutant is hypersensitive to bedaquiline” shows that the activity of bedaquiline is enhanced when bd is inactiviated.
One known cytochrome bd inhibitor is Aurachin D, which is a quinolone with a realtively long side -chain. Cytochrome bd itself is not essential for aerobic growth, but is upregulated and protects against a variety of stresses in various bacterial strains, for example as described in journal article Biochimica et Biophysica Acta 1837 (2014)
1178-1187 by Giuffre et al. Hence, monotherapy with a cytochrome bd inhibitor would not necessarily be expected to inhibit mycobacteria growth, but a combination with another inihibitor of a target of the electron transport chain of mycobacteria could be. Various compounds are described in international patent applications WO 2012/069856 and WO 2017/103615, with the latter application describing such compounds as cytochrome bd inhibitors and indicates that thereapeutic combination products comprising one or more respiratory electron transport chain inhibitor and a cytochrome bd inhibitor is disclosed. Specifically, the compound CK-2-63 is described as a cytochrome bd inhibitor showing various inhibitor activity data, and combination data is also disclosed including combination of CK-2-63 with a mycobacterium cytochrome bcc inhibitor (e.g. AWE-402, where it is indicated therein that it is structurally related to the cytochrome bcc inhibitor Q203). It is indicated that such dual combination led to in increase in mycobacteria kill. It also described a combination of bedaquiline (a known ATP synthase inhibitor) with CK-2-63, and it is indicated that CK-2-63 showed an enhancement of bedaquiline activity at low concentrations. Data around a triple
combination of bedaquiline, AWE-402 (a be inhibitor; see above) and CK-2-63 is also shown.
This particular invention focuses on novel compounds of the cytochrome bd target of the respiratory chain. New alternative/improved compounds are required, which may be tested/employed for use in combination.
R1 represents C1-6 alkyl, -Br, hydrogen or -C(0)N(Rql)Rq2;
Rql and Rq2 independently represent hydrogen or C1-6 alkyl, or may be linked together to form a 3-6 membered carbocylic ring optionally substituted by one or more C1-3 alkyl substituents;
Sub represents one or more optional substituents selected from halo (e.g. fluoro), -CN, C1-6 alkyl and -O-Ci alkyl (wherein the latter two alkyl moieties are optionally substituted by one or more fluoro atoms); the “A” ring represents a 6-membered ring which may be aromatic or non-aromatic, or it represents a 5-membered aromatic ring containing one heteroatom (e.g. a sulfur heteroatom); the “B” ring represents a 5-membered heteroaryl ring, which contains between one and four heteroatoms (e.g. selected from nitrogen, oxygen and sulfur), and which “B” ring
is optionally substituted by one or more substituents selected from halo and C1-6 alkyl (itself optionally substituted by one or more fluoro atoms);
L1 represents an optional linker group, and hence may be a direct bond, -O- or -C(Rxl)(Rx2)-;
Rxl and Rx2 independently represent hydrogen or C1-3 alkyl;
Z1 represents any one of the following moieties: (i)
ring C represents a 5-membered aromatic ring containing at least one heteroatom (preferably containing at least one nitrogen atom), and which ring is optionally substituted by one or more substituents independently selected from Rf;
ring D represents a 6-membered aromatic ring containing at least one heteroatom (preferably containing at least one nitrogen atom), and which ring is optionally substituted by one or more substituents independently selected from Rg; Yb represents -[(CH2)I -4]- (so forming a 3- to 6-membered N-containing ring), and Rh represents one or more optional substituents on such ring;
Ra, Rb, Rc, Rd and Re independently represent hydrogen or a substituent selected from B1; each Rf, each Rg and each Rh (which are optional substituents), when present, independently represent a substituent selected from B 1 ; each B 1 independently represents a substituent selected from:
Rd1 represents C1-6 alkyl, preferably C1-3 alkyl, optionally substituted by one or more halo (e.g. fluoro) atoms; Rel , Re2, Re3, Re4 and Re5 each independently represent hydrogen or C1-6 alkyl optionally substituted by one or more fluoro atoms; or a pharmaceutic ally-acceptable salt thereof, which compounds may be referred to herein as “compounds of the invention”.
Pharmaceutically-aceeptable salts include acid addition salts and base addition salts. Such salts may be formed by conventional means, for example by reaction of a free acid or a free base form of a compound of formula I with one or more equivalents of an appropriate acid or base, optionally in a solvent, or in a medium in which the salt is insoluble, followed by removal of said solvent, or said medium, using standard techniques (e.g. in vacuo, by freeze-drying or by filtration). Salts may also be prepared
by exchanging a counter-ion of a compound of the invention in the form of a salt with another counter-ion, for example using a suitable ion exchange resin.
The pharmaceutically acceptable acid addition salts as mentioned hereinabove are meant to comprise the therapeutically active non-toxic acid addition salt forms that the compounds of formula (I) are able to form. These pharmaceutically acceptable acid addition salts can conveniently be obtained by treating the base form with such appropriate acid. Appropriate acids comprise, for example, inorganic acids such as hydrohalic acids, e.g. hydrochloric or hydrobromic acid, sulfuric, nitric, phosphoric and the like acids; or organic acids such as, for example, acetic, propanoic, hydroxy acetic, lactic, pyruvic, oxalic (i.e. ethanedioic), malonic, succinic (i.e. butanedioic acid), maleic, fumaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic, p-aminosalicylic, pamoic and the like acids.
For the purposes of this invention solvates, prodrugs, N-oxides and stereoisomers of compounds of the invention are also included within the scope of the invention.
The term “prodrug” of a relevant compound of the invention includes any compound that, following oral or parenteral administration, is metabolised in vivo to form that compound in an experimentally-detectable amount, and within a predetermined time (e.g. within a dosing interval of between 6 and 24 hours (i.e. once to four times daily)). For the avoidance of doubt, the term “parenteral” administration includes all forms of administration other than oral administration.
Prodrugs of compounds of the invention may be prepared by modifying functional groups present on the compound in such a way that the modifications are cleaved, in vivo when such prodrag is administered to a mammalian subject. The modifications typically are achieved by synthesising the parent compound with a prodrug substituent. Prodrugs include compounds of the invention wherein a hydroxyl, amino, sulfhydryl, carboxy or carbonyl group in a compound of the invention is bonded to any group that may be cleaved in vivo to regenerate the free hydroxyl, amino, sulfhydryl, carboxy or carbonyl group, respectively.
Examples of prodrugs include, but are not limited to, esters and carbamates of hydroxy functional groups, esters groups of carboxyl functional groups, N-acyl derivatives and N-Mannich bases. General information on prodrugs may be found e.g. in Bundegaard, H. “Design of Prodrugs” p. 1-92, Elesevier, New York-Oxford (1985).
Compounds of the invention may contain double bonds and may thus exist as E (entgegen) and Z ( zusammen ) geometric isomers about each individual double bond. Positional isomers may also be embraced by the compounds of the invention. All such isomers (e.g. if a compound of the invention incorporates a double bond or a fused ring, the cis- and trans- forms, are embraced) and mixtures thereof are included within the scope of the invention (e.g. single positional isomers and mixtures of positional isomers may be included within the scope of the invention). Compounds of the invention may also exhibit tautomerism. All tautomeric forms (or tautomers) and mixtures thereof are included within the scope of the invention. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies which are interconvertible via a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) include interconversions via migration of a proton, such as keto-enol and imine-enamine isomerisations. Valence tautomers include interconversions by reorganisation of some of the bonding electrons.
Compounds of the invention may also contain one or more asymmetric carbon atoms and may therefore exhibit optical and/or diastereoisomerism. Diastereoisomers may be separated using conventional techniques, e.g. chromatography or fractional crystallisation. The various stereoisomers may be isolated by separation of a racemic or other mixture of the compounds using conventional, e.g. fractional crystallisation or HPLC, techniques. Alternatively the desired optical isomers may be made by reaction of the appropriate optically active starting materials under conditions which will not cause racemisation or epimerisation (i.e. a ‘chiral pool’ method), by reaction of the appropriate starting material with a ‘chiral auxiliary’ which can subsequently be removed at a suitable stage, by derivatisation (i.e. a resolution, including a dynamic resolution), for example with a homochiral acid followed by separation of the diastereomeric derivatives by conventional means such as chromatography, or by reaction with an appropriate chiral reagent or chiral catalyst all under conditions known to the skilled person.
All stereoisomers (including but not limited to diastereoisomers, enantiomers and atropisomers) and mixtures thereof (e.g. racemic mixtures) are included within the scope of the invention.
In the structures shown herein, where the stereochemistry of any particular chiral atom is not specified, then all stereoisomers are contemplated and included as the compounds
of the invention. Where stereochemistry is specified by a solid wedge or dashed line representing a particular configuration, then that stereoisomer is so specified and defined.
The compounds of the present invention may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and it is intended that the invention embrace both solvated and unsolvated forms.
The present invention also embraces isotopically-labeled compounds of the present invention which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature (or the most abundant one found in nature). All isotopes of any particular atom or element as specified herein are contemplated within the scope of the compounds of the invention. Exemplary isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine and iodine, such as 2H, Ή, nC, 13C, 14C , 13N, 150, 170, 180, 32P, 33P, 35S, 1SF, 36C1, l23I, and 125I. Certain isotopically-labeled compounds of the present invention (e.g., those labeled with 3H and 14C) are useful in compound and for substrate tissue distribution assays. Tritiated (¾) and carbon-14 (14C) isotopes are useful for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e., 2H may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances. Positron emitting isotopes such as 150, 13N, 1 'C and 18F are useful for positron emission tomography (PET) studies to examine substrate receptor occupancy. Isotopically labeled compounds of the present invention can generally be prepared by following procedures analogous to those disclosed in the description/Examples hereinbelow, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.
Unless otherwise specified, Ci-q alkyl groups (where q is the upper limit of the range) defined herein may be straight-chain or, when there is a sufficient number (i.e. a minimum of two or three, as appropriate) of carbon atoms, be branched-chain, and/or cyclic (so forming a C3-q-cycloalkyl group). Such cycloalkyl groups may be monocyclic or bicyclic and may further be bridged. Further, when there is a sufficient number (i.e. a minimum of four) of carbon atoms, such groups may also be part cyclic. Such alkyl groups may also be saturated or, when there is a sufficient number (i.e. a
minimum of two) of carbon atoms, be unsaturated (forming, for example, a Ci-q alkenyl or a C2-q alkynyl group).
C_3-q cycloalkyl groups (where q is the upper limit of the range) that may be specifically mentioned may be monocyclic or bicyclic alkyl groups, which cycloalkyl groups may further be bridged (so forming, for example, fused ring systems such as three fused cycloalkyl groups). Such cycloalkyl groups may be saturated or unsaturated containing one or more double bonds (forming for example a cycloalkenyl group). Substituents may be attached at any point on the cycloalkyl group. Further, where there is a sufficient number (i.e. a minimum of four) such cycloalkyl groups may also be part cyclic.
The term “halo”, when used herein, preferably includes fluoro, chloro, bromo and iodo.
Heterocyclic groups when referred to herein may include aromatic or non-aromatic heterocyclic groups, and hence encompass heterocycloalkyl and hetereoaryl. Equally, “aromatic or non-aromatic 5- or 6-membered rings” may be heterocyclic groups (as well as carbocyclic groups) that have 5- or 6-members in the ring.
Heterocycloalkyl groups that may be mentioned include non-aromatic monocyclic and bicyclic heterocycloalkyl groups in which at least one (e.g. one to four) of the atoms in the ring system is other than carbon (i.e. a heteroatom), and in which the total number of atoms in the ring system is between 3 and 20 (e.g. between three and ten, e.g between 3 and 8, such as 5- to 8-). Such heterocycloalkyl groups may also be bridged. Further, such heterocycloalkyl groups may be saturated or unsaturated containing one or more double and/or triple bonds, forming for example a Ci-q heterocycloalkenyl (where q is the upper limit of the range) group. Ci-q heterocycloalkyl groups that may be mentioned include 7-azabicyclo[2.2. ljheptanyl, 6-azabicyclo[3.1.1]heptanyl, 6- azabicyclo[3.2.1]-octanyl, 8-azabicyclo-[3.2. l]octanyl, aziridinyl, azetidinyl, dihydropyranyl, dihydropyridyl, dihydropyrrolyl (including 2,5-dihydropyrrolyl), dioxolanyl (including 1,3-dioxolanyl), dioxanyl (including 1,3-dioxanyl and 1,4- dioxanyl), dithianyl (including 1,4-dithianyl), dithiolanyl (including 1 ,3-dithiolanyl), imidazolidinyl, imidazolinyl, morpholinyl, 7-oxabicyclo[2.2.1]heptanyl, 6-oxabicyclo- [3.2.1]oetanyl, oxetanyl, oxiranyl, piperazinyl, piperidinyl, non-aromatic pyranyl, pyrazolidinyl, pyrrolidinonyl, pyrrolidinyl, pyrrolinyl, quinuclidinyl, sulfolanyl, 3- sulfolenyl, tetrahydropyranyl, tetrahydrofuranyl, tetrahydropyridyl (such as 1, 2,3,4- tetrahydropyridyl and 1,2,3,6-tetrahydropyridyl), thietanyl, thiiranyl, thiolanyl, thiomorpholinyl, trithianyl (including 1,3,5-trithianyl), tropanyl and the like.
Substituents on heterocycloalkyl groups may, where appropriate, be located on any atom in the ring system including a heteroatom. The point of attachment of heterocycloalkyl groups may be via any atom in the ring system including (where appropriate) a heteroatom (such as a nitrogen atom), or an atom on any fused carbocyclic ring that may be present as part of the ring system. Heterocycloalkyl groups may also be in the N- or S- oxidised form. Heterocycloalkyl mentioned herein may be stated to be specifically monocyclic or bicyclic.
Aromatic groups may be aryl or heteroaryl. Aryl groups that may be mentioned include C6~20, such as Ce-ii (e.g. C6-10) aryl groups. Such groups may be monocyclic, bicyclic or tricyclic and have between 6 and 12 (e.g. 6 and 10) ring carbon atoms, in which at least one ring is aromatic. C6-10 aryl groups include phenyl, naphthyl and the like, such as 1,2,3,4-tetrahydronaphthyl. The point of attachment of aryl groups may be via any atom of the ring system. For example, when the aryl group is polycyclic the point of attachment may be via atom including an atom of a non-aromatic ring. However, when aryl groups are polycyclic (e.g. bicyclic or tricyclic), they are preferably linked to the rest of the molecule via an aromatic ring. Most preferred aryl groups that may be mentioned herein are “phenyl”. Unless otherwise specified, the term “heteroaryl” when used herein refers to an aromatic group containing one or more heteroatom(s) (e.g. one to four heteroatoms) preferably selected from N, O and S. Heteroaryl groups include those which have between 5 and 20 members (e.g. between 5 and 10) and may be monocyclic, bicyclic or tricyclic, provided that at least one of the rings is aromatic (so forming, for example, a mono-, bi-, or tricyclic heteroaromatic group). When the heteroaryl group is polycyclic the point of attachment may be via any atom including an atom of a non-aromatic ring. However, when heteroaryl groups are polycyclic (e.g. bicyclic or tricyclic), they are preferably linked to the rest of the molecule via an aromatic ring. Heteroaryl groups that may be mentioned include 3,4-dihydro- 1/f-isoquinolinyl, 1 ,3-dihydroisoindolyl, 1 ,3-dihydroisoindolyl (e.g. 3,4-dihydro-l//-isoquinolin-2-yl, l,3-dihydroisoindol-2-yl,
1.3-dihydroisoindol-2-yl; i.e. heteroaryl groups that are linked via a non-aromatic ring), or, preferably, acridinyl, benzimidazolyl, benzodioxanyl, benzodioxepinyl, benzo- dioxolyl (including 1,3-benzodioxolyl), benzofuranyl, benzofurazanyl, benzothiadiazolyl (including 2,1,3-benzothiadiazolyl), benzothiazolyl, benzoxadiazolyl (including 2,1,3-benzoxadiazolyl), benzoxazinyl (including 3,4-dihydro-2/?-l,4- benzoxazinyl), benzoxazolyl, benzomorpholinyl, benzoselenadiazolyl (including
2.1.3-benzoselenadiazolyl), benzothienyl, carbazolyl, chromanyl, cinnolinyl, furanyl, imidazolyl, imidazo[l,2-n]pyridyl, indazolyl, indolinyl, indolyl, isobenzofuranyl,
isochromanyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiaziolyl, isothiochromanyl, isoxazolyl, naphthyridinyl (including 1 ,6-naphthyridinyl or, preferably,
1 ,5-naphthyridinyl and 1,8-naphthyridinyl), oxadiazolyl (including 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl and 1,3,4-oxadiazolyl), oxazolyl, phenazinyl, phenothiazinyl, phthalazinyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinolizinyl, quinoxalinyl, tetrahydroisoquinolinyl (including 1 ,2,3,4-tetrahydroisoquinolinyl and 5,6,7,8-tetra- hydroisoquinolinyl), tetrahydroquinolinyl (including 1,2,3,4-tetrahydroquinolinyl and 5,6,7,8-tetrahydroquinolinyl), tetrazolyl, thiadiazolyl (including 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl and 1,3,4-thiadiazolyl), thiazolyl, thiochromanyl, thiophenetyl, thienyl, triazolyl (including 1,2,3-triazolyl, 1,2,4-triazolyl and 1,3,4-triazolyl) and the like. Substituents on heteroaryl groups may, where appropriate, be located on any atom in the ring system including a heteroatom. The point of attachment of heteroaryl groups may be via any atom in the ring system including (where appropriate) a heteroatom (such as a nitrogen atom), or an atom on any fused carbocyclic ring that may be present as part of the ring system. Heteroaryl groups may also be in the N- or S- oxidised form. Heteroaryl groups mentioned herein may be stated to be specifically monocyclic or bicyclic. When heteroaryl groups are polycyclic in which there is a nonaromatic ring present, then that non-aromatic ring may be substituted by one or more =0 group. Most preferred heteroaryl groups that may be mentioned herein are 5- or 6- membered aromatic groups containing 1 , 2 or 3 heteroatoms (e.g. preferably selected from nitrogen, oxygen and sulfur).
It may be specifically stated that the heteroaryl group is monocyclic or bicyclic. In the case where it is specified that the heteroaryl is bicyclic, then it may consist of a five-, six- or seven-membered monocyclic ring (e.g. a monocyclic heteroaryl ring) fused with another five-, six- or seven-membered ring (e.g. a monocyclic aryl or heteroaryl ring).
Heteroatoms that may be mentioned include phosphorus, silicon, boron and, preferably, oxygen, nitrogen and sulfur.
When “aromatic” groups are referred to herein, they may be aryl or heteroaryl. When “aromatic linker groups” are referred to herein, they may be aryl or heteroaryl, as defined herein, are preferably monocyclic (but may be polycyclic) and attached to the remainder of the molecule via any possible atoms of that linker group. However, when, specifically carbocyclic aromatic linker groups are referred to, then such aromatic groups may not contain a heteroatom, i.e. they may be aryl (but not heteroaryl).
For the avoidance of doubt, where it is stated herein that a group may be substituted by one or more substituents (e.g. selected from C1-6 alkyl), then those substituents (e.g. alkyl groups) are independent of one another. That is, such groups may be substituted with the same substituent (e.g. same alkyl substituent) or different (e.g. alkyl) substituents.
All individual features (e.g. preferred features) mentioned herein may be taken in isolation or in combination with any other feature (including preferred feature) mentioned herein (hence, preferred features may be taken in conjunction with other preferred features, or independently of them).
The skilled person will appreciate that compounds of the invention that are the subject of this invention include those that are stable. That is, compounds of the invention include those that are sufficiently robust to survive isolation from e.g. a reaction mixture to a useful degree of purity.
In an embodiment, R1 represents hydrogen or C 1.3 alkyl. Preferred compounds of the invention include those in which R1 represents C1-3 alkyl such as methyl or ethyl. In another embodiment, R1 represents methyl. In an embodiment, Sub is either not present or represents a halo (e.g. fluoro) atom.
Alternatively, compounds of the invention may have an aromatic 6-membered A ring such as in formula lb:
Compounds of the invention may have an aromatic 5-membered ring in which Xx represents a heteroatom such as nitrogen, oxygen or sulfur (and in an embodiment represents sulfur), such as in formula Ic.
In an embodiment the “A” ring is unsubstituted or substituted with one fluoro atom. In an embodiment, the “A” ring is a 6-membered aromatic or non-aromatic ring.
Preferred compounds of the invention include those in which the “B” ring contain at least one nitrogen atom (in an embodiment, at the ring junction); and/or contains one, two, three or four heteroatoms in total.
In an embodiment of the invention, compounds of the invention are those in which the “B” ring and adjacent 6 membered non-aromatic ring are represented by a sub-formula (II) as defined hereinbelow (where it will be appreciated that the rules of valency will be adhered to, e.g. where C is mentioned then it may need to have a H attached to it), in which: one of X1 and X2 represents N (i.e. there is an essential nitrogen at the ring junction) and the other represents C; the other integers X3, X4 and X5 may represent C (or CH) or a heteroatom (such as N,
O and/or S; and, in an embodiment, represent N); and/or
none, any one or two of X3, X4 and X3 represents a heteroatom (e.g. N, O and/or S; and, in an embodiment, N) and the other(s) represents C (or CH).
Hence, in view of the foregoing, preferred compounds of the invention include those in which: one of X1 and X2 represents N; and none, one or two of X3, X4 and X5 represents N.
The “B” ring and adjacent 6 membered non-aromatic ring in compounds of the invention may be depicted as follows in sub formula (II) (in which the left hand side would be further bound to the requisite quinolinone, or tetrahydro-quinolinone, of formula (I) and the right hand side would be further bound to the L1 group of formula
wherein: one of X1 and X2 represents N (i.e. there is an essential nitrogen at the ring junction) and the other represents C; the other integers X3, X4 and X3 may represent C (or CH) or a heteroatom (such as N,
O and/or S); and/or none, any one or two of X3, X4 and X5 represents a heteroatom (e.g. N, O and/or S) and the other represents C (or CH), and in which in all of the cases above, it will be understood that the rules of valency will need to be adhered to.
In a further embodiment, preferred compounds of the invention include those in which in the sub-formula (II) depicted above:
X1, X3 and X5 represent a heteroatom (e.g. nitrogen) and X2 and X4 represent C (or CH).
In an alternate further embodiment, preferred compounds of the invention include those in which in the sub-formula (II) depicted above:
X2, X3 and X5 represent a heteroatom (e.g. nitrogen) and X1 and X4 represent C (or CH).
In a preferred embodiment the “B” ring and adjacent 6 membered non-aromatic ring in compounds of the invention may be depicted as follows, (in which the left hand side would be further bound to the requisite quinolinone, or tetrahydro-quinolinone, of formula (I) and the right hand side would be further bound to the L1 group of formula (I)):
In yet a further embodiment, preferred compounds of the invention include those in which in the sub-formula (II) depicted above: X2 and X3 represent a heteroatom (e.g. nitrogen) and X1, X4 and X5 represent C (or CH).
In a preferred embodiment the “B” ring and adjacent 6 membered non-aromatic ring in compounds of the invention may be depicted as follows, (in which the left hand side would be further bound to the requisite quinolinone, or tetrahydro-quinolinone, of
formula (I) and the right hand side would be further bound to the L1 group of formula
Other preferred compounds of the invention include those in which:
L1 represents a direct bond or -C(Rxl)(Rx2)-;
Rxl and Rx2 independently represent hydrogen for example:
L1 may specifically represent a direct bond, -O- or -CH2- (or, in a more specific embodiment, a direct bond or -CH2-; especially a direct bond).
In a particular embodiment, L1 represents a direct bond.
In embodiments of the invention, Z1 represents:
(iii)
(iv)
and hence there are four embodiments of the invention, and in an aspect, Z1 represents (i), (ii), (iii) or (iv) (e.g. Z1 represents (i) or (ii)). Hence, in an embodiment, Z1 represents an aromatic ring (i.e. (i), (ii), (iii) or (iv) above), for instance (i) or (ii).
When Z1 represents (iv), i.e. a cyclic amino group, then L1 represenst a direct bond or -CH2- (but cannot represent -O-). In such an embodiment, Z1 in a specific embodiment represents a 5- or 6-membered ring (pyrrolinyl or piperidinyl; i.e. Yb represents — [(CH2)3-4]-), which is optionally substituted by one or more (e.g. one) Rh substituent (and Rh represents a B1 susbtituent, and is, in an embodiment, C1-3 alkyl optionally substituted by one or more fluoro atoms).
In a further embodiment, compounds of the invention include those in which when ring C is present, it represents a 5-membered aromatic ring, it contains one, two or three heteroatoms preferably selected from nitrogen, oxygen and sulfur; in a further embodiment, such ring is optionally substituted by one or two substituents independently selected from Rf; when ring D is present, it represents a 6-membered aromatic ring containing one nitrogen atom; and, in a further embodiment, such ring is optionally substituted by one or two substituents independently selected from Rg;
Ra, Rb, Rc, Rd and Re independently represent hydrogen or a substituent selected from B1;
Rf and Rg each independently represent a substituent selected from B1.
In an embodiment, when Ring C is present (i.e. Z1 represents (ii)), then such aromatic 5-membered (optionally substituted) ring may: (i) contain one sulfur atom (so forming a thienyl); (ii) contain one nitrogen and one sulfur atom (so forming e.g. thiazolyl); (iii) contain two nitrogen atoms (so forming e.g. a pyrazolyl); (iv) contains two nitrogen atoms and one sulfur atom; (v) contains two nitrogen atoms and one oxygen atom; (vi) contains three nitrogen atoms.
In an embodiment, when Ring D is present (i.e. Z1 represents (iii)), then such aromatic 6-membered ring may contain one nitrogen atom, so forming a pyridyl group (e.g. a 3- pyridyl group).
In an embodiment, further preferred compounds of the inventions include those in which: none, but preferably, one or two (e.g. one) of Ra, Rb, Rc, Rd and Re represents B1 and the others represent hydrogen; and/or one or two (e.g. one) of Rb. Rc and Rd (preferably Rc) represents B1 and the others represent hydrogen.
In a further embodiment, preferred compounds of the inventions include those in which: Rb and one of Rc or Rd represent B 1 and the others represent hydrogen.
In a further embodiment, preferred compounds of the inventions include those in which: Rb and Re represent B1 and the others represent hydrogen.
In a further embodiment, preferred compounds of the inventions include those in which: Rb and Rd represent B1 and the others represent hydrogen.
In a further embodiment, preferred compounds of the inventions include those in which: Rb represent B1 and the others represent hydrogen.
In a further embodiment, preferred compounds of the inventions include those in which: Rc represent B1 and the others represent hydrogen.
In an embodiment of the invention:
Re2 and Re4 independently represent hydrogen;
Rel, Re3 and Rc:! each independently represent C1.3 alkyl (e.g. methyl) substituted by one or more fluoro atoms.
In a further embodiment, yet further preferred compounds of the inventions include those in which:
B 1 represents a substituent selected from:
(i) fluoro;
(ii) Ci -6 alkyl, preferably C1-3 alkyl, substituted by one or more fluoro atom;
(iii) -ORel.
In a further embodiment of the invention, B 1 represents a substituent selected from halo (e.g. fluoro), C1-3 alkyl (optionally substituted by one or more fluoro atom) and -ORel (in which Rei represents C1-3 alkyl optionally substituted by one or more fluoro atom, so forming e.g. -OCH3 or-OCFs). In a specific embodiment, B1 is selected from fluoro, -CH3, -0CH3, -CF3, -CHF2, -CH2CF3, -CH2CHF2, -CH2CH2CF3 and -OCF3.
In a further specific embodiment, B1 is selected from fluoro, -CH3, -CF3, -OCH3 and -OCF3.
In embodiments of the invention, Z1 represents:
(i)
ring C represents a 5-membered aromatic ring containing at least two heteroatoms, wherein at least one of said heteroatom is a nitrogen atom, and which ring is substituted by one or more substituents independently selected from Rf; one or two (e.g. one) of Rb Rc and Rd (preferably Rc) represents B1 and the others represent hydrogen;
R1 and Rh independently represent hydrogen or a substituent selected from B1; each B 1 independently represents a substituent selected from:
(i) fluoro; (ii) -ORel;
(iii) -Rdl;
Rdl represents C1-6 alkyl, preferably C1-3 alkyl, optionally substituted by one or more fluoro atoms; and/or
Rel represent hydrogen or C1-6 alkyl optionally substituted by one or more fluoro atoms.
PHARMACOLOGY The compounds according to the invention have surprisingly been shown to be suitable for the treatment of a bacterial infection including a mycobacterial infection, particularly those diseases caused by pathogenic mycobacteria such as Mycobacterium tuberculosis (including the latent and drug resistant form thereof). The present invention thus also relates to compounds of the invention as defined hereinabove, for use as a medicine, in particular for use as a medicine for the treatment of a bacterial infection including a mycobacterial infection.
Such compounds of the invention may act by interfering with ATP synthase in M. tuberculosis, with the inhibition of cytochrome bd activity being the primary mode of action. Such bd inhibition may have an effect in killing mycobacteria (and hence having an anti-tuberculosis effect directly). However, as cytochrome bd is not necessarily essential for aerobic growth, it may have the most pronounced effect in combination with another inhibitor of a target of the electron transport chain of mycobacteria. Such compounds may be tested for cytochrome bd activity by testing in an enzymatic assay, and may also be tested for activity in the treatment of a bacterial infection (e.g. mycobacterial infection) by testing the kill kinetics, for example of such compounds alone or in combination (as mentioned herein, e.g. with one or more other inhibitor(s) of a (different) target of the electron transport chain of mycobacteria; such other different targets may be more implicated in aerobic growth).
Cytochrome bd is a component of the electron transport chain, and therefore may be implicated with ATP synthesis, for instance alone or especially with one or more other inhibitor(s) of a target of the electron transport chain of mycobacteria. Further, the present invention also relates to the use of a compound of the invention, as well as any of the pharmaceutical compositions thereof as described hereinafter for the manufacture of a medicament for the treatment of a bacterial infection including a mycobacterial infection (for instance when such compound of the invention is used in combination with another inhibitor of a target of the electron transport chain of mycobacteria).
Accordingly, in another aspect, the invention provides a method of treating a patient suffering from, or at risk of, a bacterial infection, including a mycobacterial infection, which comprises administering to the patient a therapeutically effective amount of a compound or pharmaceutical composition according to the invention (for instance a therapeutically effective amount of a compound or pharmaceutical composition of the invention, in combination with one or more other inhibitor(s) of a target of the electron transport chain of mycobacteria).
The compounds of the present invention also show activity against resistant bacterial strains (for instance alone or in combination with another inhibitor of a target of the electron transport chain of mycobacteria).
Whenever used hereinbefore or hereinafter, that the compounds can treat a bacterial infection (alone or in combination) it is meant that the compounds can treat an infection with one or more bacterial strains.
The invention also relates to a composition comprising a pharmaceutically acceptable carrier and, as active ingredient, a therapeutically effective amount of a compound according to the invention. The compounds according to the invention may be formulated into various pharmaceutical forms for administration purposes. As appropriate compositions there may be cited all compositions usually employed for systemically administering drugs. To prepare the pharmaceutical compositions of this invention, an effective amount of the particular compound, optionally in addition salt form, as the active ingredient is combined in intimate admixture with a pharmaceutically acceptable carrier, which carrier may take a wide variety of forms depending on the form of preparation desired for administration. These pharmaceutical compositions are desirable in unitary dosage form suitable, in particular, for administration orally or by parenteral injection. For example, in preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be employed such as, for example, water, glycols, oils, alcohols and the like in the case of oral liquid preparations such as suspensions, syrups, elixirs, emulsions and solutions; or solid carriers such as starches, sugars, kaolin, diluents, lubricants, binders, disintegrating agents and the like in the case of powders, pills, capsules and tablets. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit forms in which case solid pharmaceutical carriers are obviously employed. For parenteral compositions, the carrier will usually comprise sterile water, at least in large part, though other ingredients, for example, to aid solubility, may be included. Injectable solutions, for example, may be prepared in
which the carrier comprises saline solution, glucose solution or a mixture of saline and glucose solution. Injectable suspensions may also be prepared in which case appropriate liquid carriers, suspending agents and the like may be employed. Also included are solid form preparations which are intended to be converted, shortly before use, to liquid form preparations.
Depending on the mode of administration, the pharmaceutical composition will preferably comprise from 0.05 to 99 % by weight, more preferably from 0.1 to 70 % by weight, even more preferably from 0.1 to 50 % by weight of the active ingredient(s), and, from 1 to 99.95 % by weight, more preferably from 30 to 99.9 % by weight, even more preferably from 50 to 99.9 % by weight of a pharmaceutically acceptable carrier, all percentages being based on the total weight of the composition.
The pharmaceutical composition may additionally contain various other ingredients known in the art, for example, a lubricant, stabilising agent, buffering agent, emulsifying agent, viscosity-regulating agent, surfactant, preservative, flavouring or colorant.
It is especially advantageous to formulate the aforementioned pharmaceutical compositions in unit dosage form for ease of administration and uniformity of dosage. Unit dosage form as used herein refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. Examples of such unit dosage forms are tablets (including scored or coated tablets), capsules, pills, powder packets, wafers, suppositories, injectable solutions or suspensions and the like, and segregated multiples thereof.
The daily dosage of the compound according to the invention will, of course, vary with the compound employed, the mode of administration, the treatment desired and the mycobacterial disease indicated. However, in general, satisfactory results will be obtained when the compound according to the invention is administered at a daily dosage not exceeding 1 gram, e.g. in the range from 10 to 50 mg/kg body weight.
Given the fact that the compounds of the invention are useful against bacterial infections, the present compounds may be combined with other antibacterial agents in order to effectively combat bacterial infections. Where it is indicated that compounds may be useful against bacterial infections, we mean that those compounds may have activity as such or those compounds may be effective in combination (as described herein, e.g. with one or more other inhibitors of the electron transport chain of
mycobacteria) by enhancing activity or providing synergistic combinations, for example as may be described in the experimental hereinafter.
Therefore, the present invention also relates to a combination of (a) a compound according to the invention, and (b) one or more other antibacterial agents (e.g. one or more other inhibitors of the electron transport chain of mycobacteria, for instance a cytochrome be inhibitor, an ATP synthase inhibitor, a NDH2 inhibitor and/or an inhibitor of the menaquinone synthesis pathway, such as a MenCi inhibitor). The present invention also relates to such a compound or combination, for use as a medicine.
The present invention also relates to the use of a combination or pharmaceutical composition as defined directly above for the treatment of a bacterial infection.
A pharmaceutical composition comprising a pharmaceutically acceptable carrier and, as active ingredient, a therapeutically effective amount of (a) a compound according to the invention, and (b) one or more other antibacterial agents (e.g. one or more other inhibitors of the electron transport chain of mycobacteria, for instance a cytochrome be inhibitor, an ATP synthase inhibitor, a NDH2 inhibitor and/or an inhibitor of the menaquinone synthesis pathway, such as a MenG inhibitor), is also comprised by the present invention.
The weight ratio of (a) the compound according to the invention and (b) the other antibacterial agent(s) when given as a combination may be determined by the person skilled in the art. Said ratio and the exact dosage and frequency of administration depends on the particular compound according to the invention and the other antibacterial agent(s) used, the particular condition being treated, the severity of the condition being treated, the age, weight, gender, diet, time of administration and general physical condition of the particular patient, the mode of administration as well as other medication the individual may be taking, as is well known to those skilled in the art. Furthermore, it is evident that the effective daily amount may be lowered or increased depending on the response of the treated subject and/or depending on the evaluation of the physician prescribing the compounds of the instant invention. A particular weight ratio for the present compound of the invention and another antibacterial agent may range from 1/10 to 10/1, more in particular from 1/5 to 5/1, even more in particular from 1/3 to 3/1.
The compounds according to the invention and the one or more other antibacterial agents may be combined in a single preparation or they may be formulated in separate preparations so that they can be administered simultaneously, separately or sequentially. Thus, the present invention also relates to a product containing (a) a compound according to the invention, and (b) one or more other antibacterial agents (e.g. one or more other inhibitors of the electron transport chain of mycobacteria, for instance a cytochrome be inhibitor, an ATP synthase inhibitor, a NDH2 inhibitor and/or an inhibitor of the menaquinone synthesis pathway, such as a MenG inhibitor), as a combined preparation for simultaneous, separate or sequential use in the treatment of a bacterial infection.
The other antibacterial agents which may be combined with the compounds of the invention are for example antibacterial agents known in the art. For example, the compounds of the invention may be combined with antibacterial agents known to interfere with the respiratory chain of Mycobacterium tuberculosis, including for example direct inhibitors of the ATP synthase (e.g. bedaquiline, bedaquiline fumarate or any other compounds that may have be disclosed in the prior art, e.g. compounds disclosed in W02004/011436), inhibitors of ndh2 (e.g. clofazimine) and inhibitors of cytochrome bd. Additional mycobacterial agents which may be combined with the compounds of the invention are for example rifampicin (=rifampin); isoniazid; pyrazinamide; amikacin; ethionamide; ethambutol; streptomycin; para-aminosalicylic acid; cycloserine; capreomycin; kanamycin; thioacetazone; PA-824; delamanid; quinolones/fluoroquinolones such as for example moxifloxacin, gatifloxacin, ofloxacin, ciprofloxacin, sparfloxacin; macrolides such as for example clarithromycin, amoxycillin with clavulanic acid; rifamycins; rifabutin; rifapentin; as well as others, which are currently being developed (but may not yet be on the market; see e.g. http://www.newtbdrugs.org/pipeline.php). In particular, and as mentioned herein, compounds of the invention may be combined with one or more other inhibitors of the electron transport chain of mycobacteria, for instance a cytochrome be inhibitor, an ATP synthase inhibitor, a NDH2 inhibitor and/or an inhibitor of the menaquinone synthesis pathway, such as a MenG inhibitor. Given that the compounds of the invention might act as cytochrome bd inhibitors, and hence target the electron transport chain of the mycobacteria (thereby blocking energy production of mycobacteria), the compounds of the invention (cytochrome bd inhibitors), combinations with one or more other inhibitors of the electron transport chain is thought to be a potentially effective way of providing an efficient regimen against mycobacteria. Even if the compounds of the invention (cytochrome bd inhibitors) alone might not be effective against mycobacteria, combining with one or more other such inhibitors may provide an
effective regimen where the activity of one or more components of the combination is/are enhanced and/or such combinations act more effectively (e.g. synergistically).
GENERAL PREPARATION The compounds according to the invention can generally be prepared by a succession of steps, each of which may be known to the skilled person or described herein.
EXPERIMENTAL PART
Compounds of formula I may be prepared in accordance with the techniques employed in the examples hereinafter (and those methods know by those skilled in the art), for example by using the following techniques.
Compounds of formula (I) may be prepared by:
(i) conversion of a compound of formula (II),
in which the integers are hereinbefore defined, by reaction with an appropriate reagent such as BBb or NaSCIL (for example, as described in the examples);
(ii) reaction of a compound of formula (III),
wherein the integers are as defined in Claim 1, with a compound of formula (IV),
wherein the integers are hereinbefore defined, for example, in the presence of a reagent such as ZrCU, P I SA or the like, optionally in the presence of a solvent, such as an alcohol (e.g. butanol), under sutiable reaction conditions (which may be further described in the examples);
(iii) hydrogenation of a compound of formula (V),
in which the integers are hereinbefore defined, by reaction with an appropriate reagent such as H2 and a palladium on carbon catalyst (for example, as described in the examples).
It is evident that in the foregoing and in the following reactions, the reaction products may be isolated from the reaction medium and, if necessary, further purified according to methodologies generally known in the art, such as extraction, crystallization and chromatography. It is further evident that reaction products that exist in more than one enantiomeric form, may be isolated from their mixture by known techniques, in particular preparative chromatography, such as preparative HPLC, chiral chromatography. Individual diastereoisomers or individual enantiomers can also be obtained by Supercritical Fluid Chromatography (SCF).
The starting materials and the intermediates are compounds that are either commercially available or may be prepared according to conventional reaction procedures generally known in the art.
Experimental
Compounds of formula I may be prepared in accordance with the techniques employed in the examples hereinafter (and those methods know by those skilled in the art), for example by using the following techniques. It is evident that in the foregoing and in the following reactions, the reaction products may be isolated from the reaction medium and, if necessary, further purified according to methodologies generally known in the art, such as extraction, crystallization and chromatography. It is further evident that reaction products that exist in more than one enantiomeric form, may be isolated from their mixture by known techniques, in particular preparative chromatography, such as preparative HPLC, chiral chromatography. Individual diastereoisomers or individual enantiomers can also be obtained by Supercritical Fluid Chromatography (SCF).
The starting materials and the intermediates are compounds that are either commercially available or may be prepared according to conventional reaction procedures generally known in the art.
Abbreviations
AcOH Acetic acid
ACN / CH3CN Acetonitrile
(Bpin)2 Bis(pinacolato)diboron
CO Carbon monoxide gaz
C02 Carbon dioxide gaz
(COCl)2 Oxalyl chloride
DCM or CH2CI2 Dichloromethane
DCE Dichloroethane
DIPEA N,N-Diisopropylethylamine
DIPE Diisopropylethyl ether
DMF Dimethylformamide
Et3N or TEA Triethylamine Et30 or DIPE Diisopropyl ether
EtOAc Ethyl acetate
EtOH Ethanol
EtMgBr Ethylmagnesium bromide h hour
HATU Hexafluorophosphate Azabenzotriazole Tetramethyl Uronium
H2 Dihydrogen gas
H2O Water
HC1 Hydrochloric acid i-PrOH Isopropyl alcohol i-PrNH2 Isopropylamine
LiOH. H20 Lithium hydroxide hydrate
K3PO4.H2O Potassium phosphate tribasic monohydrate
KOAc Potassium Acetate
MeOH Methanol
MeNH2 Methyl amine
MeTHF Methyltetrahydrofurane
MgS04 Magnesium sulfate
MSH O-Mesitylenesulfonylhydroxylamine min Minute
N2 Nitrogen
NaHCOa Sodium Bicarbonate
NaOH Sodium hydroxide
Na2S04 Sodium sulfate
NBS N-Bromosuccinimide
NH4CI Ammonium, chloride
NMR Nuclear Magnetic Resonance
Pd/C Palladium on carbon
PddppfCh [1, 1 '-Bis(diphenylphosphino)ferrocene]dichloropalladium (II)
Pd(PPh3)4 T etrakis(triphenylphosphine)palladium (0)
PPA Polyphosphoric Acid
SFC Supercritical fluid chromatography rt / RT Room temperature
THF Tetrahydrofuran
TMSOTf T rimethylsily 1 trifluoromethanesulfonate
Experimental Part
To a solution of ethyl 6-bromo-[l,2,4]triazolo[l,5-a]pyridine-2-carboxylate (CAS [1427376-40-6], 0. 100 g, 0.370 mmol) in THF (2 mL) were added LiOH.H20 (46.6 mg, 1.11 mmol) and water (2 mL) and the resulting mixture was stirred at room temperature for 4.5 h under nitrogen atmosphere. The reaction mixture was acidified with aqueous 1 M HC1 solution to pH~l and extracted with CH2CI2. The combined organic layers were washed with brine, dried over Na2S04. filtered and concentrated to dryness under reduced pressure to afford intermediate AA-1 as a white solid (88.2 mg, 98%).
Preparation of intermediate AA-2
To an nitrogen-purged solution of intermediate A ,4-1 (88.2 mg, 0.364 mmol) and l-(2- Amino-phenyl)-propanone (CAS [1196-28-7], 54.4 mg, 0.364 mmol) in DMF (0.7 mL) were added HATU (0.166 g, 0.437 mmol) and DIPEA (0.127 mL, 0.729 mmol) and the resulting mixture was stirred at room temperature for 17 h. The reaction mixture was added dropwise into water (10 mL) and the resulting precipitate was filtered on a glass frit, dissolved in CH2CI2 and washed with aqueous 1 M HC1 solution and brine, dried over NaiSCL, filtered and concentrated to dryness under reduced pressure to afford intermediate AA-2 as a beige solid (94.6 mg, 70%). Preparation of intermediate AA3
An nitrogen-purged mixture of AA-2 (72.0 mg, 0. 193 mmol) and NaOH (23.1 mg, 0.579 mmol) in 1,4-dioxane (2 mL) was stirred at 110 °C for 17 h, then cooled to room temperature, diluted with aqueous saturated NH4CI solution and water and extracted with CH2C12/MeOH (9: 1 mixture). The combined organic layers were washed with brine, dried over \a28O4. filtered and concentrated under reduced pressure to afford intermediate AA-3 as a yellow solid (59.3 mg, 87%).
A mixture of intermediate AA-3 (300 mg, 0.845 mmol), 4- (trifluoromethyl)phenylboronic acid (CAS [128796-39-4], 193 mg, 1.01 mmol) and potassium phosphate monohydrate (584 mg, 2.53 mmol) in 1,4-dioxane (3.2 mL) and water (0.8 mL) was purged with nitrogen. [l,l'-bis(diphenylphosphino)ferrocene] dichloropalladium (61.8 mg, 84.5 μmol) was then added and the resulting mixture was purged again with nitrogen and stirred at 100°C for 19 h. Water (50 mL) was added and the aqueous layers was filtered through a glass-frit to collect a black solid, 0.36 g. This was purified by column chromatography over silica gel (100/0 to 98/2 DCM/MeOH) to give a yellow solid, 0.235 g. This one was triturated with MeOH (2 x 2.5 mL) and dried under high vacuum at 50°C (20 h) to afford Compound AB- 1 as a pale-yellow solid, 0.21 g (59%).
Preparation of Compound AB-2
Accordingly, compound AB-2 was prepared in the same way as compound AB-1 starting from AA-3 (0.452 mmol) and 4-Trifluoromethoxyphenylboronic acid (CAS [139301-27-2], 0.542 mmol), to give 0.106 g (54%) as a white solid.
Accordingly, compound AB-3 was prepared in the same way as compound AB-1 starting from AA-3 (0.845 mmol) and 3,4-difluorophenylboronic acid (CAS [168267- 41-2], 1.35 mmol) to give a beige solid, 0.093 g (28%).
Accordingly, compound AB-4 was prepared in the same way as compound AB-1 starting from AA-3 (1.41 mmol) and 4-methoxybenzeneboronic acid (CAS [5720-07- 0], 2.11 mmol) to give a pale beige powder, 0.528 g (98%).
Accordingly, compound AB-5 was prepared in the same way as compound AB-1 starting from AA-3 (1.41 mmol) and 3-fluoro-5-methylphenylboronic acid (CAS [850593-06-5], 2.11 mmol) to give a pale beige powder, 0.528 g (98%).
Accordingly, compound AB-6 was prepared in the same way as compound AB-1 starting from AA-3 (1.18 mmol) and 3-Fluoro-4-methylbenzeneboronic acid (CAS [168267-99-0], 1.77 mmol) to give a pale beige powder, 0.292 g (64%).
Accordingly, compound AB-7 was prepared in the same way as compound AB-1 starting from AA-3 (1.18 mmol) and 3-Fluoro-5-methoxyphenylboronic acid (CAS [609807-25-2], 1.77 mmol) to give a pale beige powder, 0.34 g (72%).
Preparation of Compound AB-8
Accordingly, compound AB-8 was prepared in the same way as compound AB- 1 starting from AA-3 (1.18 mmol) and 3,5-dimethoxybenzeneboronic acid (CAS [192182-54-0], 2.11 mmol) to give a pale beige powder, 0.5 g (86%).
Accordingly, compound AB-9 was prepared in the same way as compound AB-1 starting from AA-3 (1.18 mmol) and 3-Fluoro-5-(trifluoromethyl)benzene boronic acid (CAS [159020-59-4], 1.77 mmol) to give a pale beige powder, 0.32 g (62%).
Accordingly, compound AB-10 was prepared in the same way as compound AB-1 starting from AA-3 (0.84 mmol) and 3-(Trifluoromethoxy)-benzeneboronic acid (CAS [179113-90-7], 1.27 mmol) to give a pale beige powder, 0.325 g (88%).
Preparation of Compound AB- 11
Accordingly, compound AB-11 was prepared in the same way as compound AB-1 starting from AA-3 (1.35 mmol) and [3-(2,2,2)-trifluoroethyl)phenyl]boronic acid (CAS [1620056-82-7], 2.03 mmol) to give a pale beige powder, 0.538 g (91%).
Accordingly, compound AB-12 was prepared in the same way as compound AB-1 starting from AA-3 (1.35 mmol) and 4-Fluoro-3-methoxybenzeneboronie acid (CAS [854778-31-7], 2.03 mmol) to give a pale beige powder, 0.16 g (29%).
Preparation of compound 1, compound 2, compound 3, compound 4, compound 5
& compound 6
5 A mixture of compound AB-2 (200 mg, 0.458 mmol), EtOH (10 mL) and THF (10 mL) was stirred in a 100 mL Parr reactor vessel in the presence of 10 wt% palladium on carbon (97.6 mg, 91.7 μmol) under hydrogen atmosphere (30 bar) at 60 °C for 5 h. The reaction mixture was diluted at room temperature with CH2CI2 and filtered through a pad of Celite®. The filter cake was rinsed with CH2CI2 and the filtrate was 0 concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (Cl bCb/MeOII from 100:0 to 95:5) to afford after coevaporation with MeOH, trituration with Et20 and vacuum-drying (60 °C, 3 days) compound 2 as a white solid (121 mg, 60 %).
I ll NMR (400 MHz. DMSCM5) 0 ppm 11.62 (s, 1H), 8.10 (dd, J = 8.2 Hz, 1.2 Hz, 5 1H), 7.93 (d, / = 8.2 Hz, 1H), 7.64-7.55 (m, 3H), 7.40 (d, J= 8.1 Hz, 2H), 7.31-7.26
(m, 1H), 4.57 (dd. ./ = 12.4 Hz, 5.4 Hz, 1H), 4.35 (t, / = 11.7 Hz, 1H), 3.62-3.51 (m, 1H), 3.19-3.03 (m, 2H), 2.36 (s, 3H), 2.34-2.17 (m, 2H).
A mixture of compound AB-2 (500 mg, 1.15 mmol), EtOH (25 mL) and THF (25 mL) was stirred in a 100 mL Parr reactor vessel in the presence of 10 wt% palladium on 0 carbon (610 mg, 0.573 mmol) under hydrogen atmosphere (50 bar) at 60 °C for 18 h. The reaction mixture was diluted at room temperature with CH2CI2 and filtered through a pad of Celite®. The filter cake was rinsed with a CftCb/MeOH mixture (95:5) and the filtrate was concentrated under reduced pressure. The residue was filtered again with CH2CI2 through a pad of Celite®, concentrated under reduced pressure and then
filtered with MeOH through a PTFE filter. Concentration of the filtrate under reduced pressure, trituration of the residue with Et20 and vacuum-drying (60 °C, 16 h) afforded compound 1 as a white solid (364 mg, 71%).
1H NMR (400 MHz, DMSOd6) δ ppm 10.82 (s, 1H), 7.60-7.52 (m, 2H), 7.39 (d , J = 8.1 Hz, 2H), 4.51 (dd../ = 12.5 Hz, 5.3 Hz, 1H), 4.28 (t, J= 11.7 Hz, 1H), 3.57-3.47
(m, 1H), 3.13-2.97 (m, 2H), 2.67-2.61 (m, 2H), 2.36-2.14 (m, 7H including s, 3H at 2.17), 1.73-1.60 (m, 4H).
Preparation of compound 3 and compound 4
A purification of compound 1 was performed via chiral SFC (Stationary phase:
CHIRALPAK AD-H 5um 250*21.2mm, Mobile phase: 67% C02, 33% MeOH (0.3% iPrNH:)). Pure fractions were collected and evaporated affording FI, 0.114 g and F2, 0.105 g.
FI was triturated with DIPE and a few heptane, the precipitate was filtered off, dried under vacuum at 60°C affording compound 3 as white powder, 0.091 (39%).
1H NMR (500 MHz, DMSO-d6) δ ppm 10.83 (br s, 1H), 7.56 (br d, J=8,2 Hz, 2H), 7.39 (br d, J=8.2 Hz, 2H), 4.51 (br dd, .1=12.5, 4.9 Hz, 1H), 4.29 (br t, J=11.7 Hz, 1H),
3.38 - 3.59 (m, 1H), 2.97 - 3.14 (m, 2H), 2.57 - 2.71 (m, 2H), 2.19 - 2.44 (m, 4H), 2.17 (s, 3H), 1.59 - 1.74 (m, 4H) F2 was triturated with DIPE and a few heptane, the precipitate was filtered off, dried under vacuum at 60°C affording compound 4 white powder, 0.080 g (34%).
1H NMR (500 MHz, DMSO-d6) δ ppm 10.82 (br s, 1H), 7.56 (br d, J=8.5 Hz, 2H),
7.39 (br d, J=7.9 Hz, 2H), 4.51 (br dd, J=12.5, 5.2 Hz, 1H), 4.29 (br t, J=11.8 Hz, 1H), 3.36 - 3.57 (m, 1H), 2.98 - 3.13 (m, 2H), 2.55 - 2.71 (m, 2H), 2.31 - 2.45 (m, 3H), 2.21 - 2.31 (m, 1H), 2.17 (s, 3H), 1.60 - 1.73 (m, 4H)
Preparation of compound 5 and compound 6
A purification of compound 2 was performed via chiral SFC (Stationary phase: CHIRALPAK AD-H 5μm 250*21.2mm, Mobile phase: 63% C02, 37% EtOH (0.3% iPrNHi)). Pure fractions were collected and evaporated affording FI, 0.163 g and F2, 0.164 g.
FI was triturated with DIPE and a few heptane, the precipitate was filtered off, dried under vacuum at 60°C affording compound 3 as white powder, 0.128 g (39%).
1H NMR (500 MHz, DMSO-d6) δ ppm 11.63 (br s, lH), 8.11 (dd, J=8.0, 1.1 Hz, 1H), 7.93 (d, J=8,5 Hz, 1H), 7.56 - 7.64 (m, 3H), 7.40 (d, J=8.2 Hz, 2H), 7.29 (t, J=7.6 Hz,
1H), 4.57 (dd, J=12.6, 5.4 Hz, 1H), 4.35 (t, J=11.8 Hz, lH), 3.51 - 3.61 (m, 1H), 3.05 -
3.17 (m, 2H), 2.36 (s, 3H), 2.15 - 2.34 (m, 2H)
F2 was triturated with DIPE and a few heptane, the precipitate was filtered off, dried under vacuum at 60°C affording compound 4 white powder, 0.134 g (41%). 1H NMR (500 MHz, DMSO-d6) δ ppm 11.63 (br s, 1H), 8.10 (dd, J=8.2, 1.3 Hz, 1H), 7.93 (d, J=8.2 Hz, 1H), 7.56 - 7.63 (m, 3H), 7.40 (d, J=7.9 Hz, 2H), 7.29 (t, J=7.5 Hz, 1H), 4.57 (dd, J=12.3, 5.4 Hz, 1H), 4.35 (t, J=11.7 Hz, 1H), 3.53 - 3.61 (m, I I I). 3.05 -
3.18 (m, 2H), 2.36 (s, 3H), 2.15 - 2.34 (m, 2H) Preparation of compound 9, compound 10, compound 28, compound 29, compound
30 & compound 31
A solution of compound AB-KΌ.877 g, 2.09 mmol) in EtOH (15 mL) and THF (15 mL) was stirred in a 100 mL Parr reactor vessel in the presence of 10 wt% palladium
on carbon (0.444 g, 0.417 mmol) under hydrogen atmosphere (30 bar) at 60 °C for 4 h, then cooled to room temperature and filtered through a pad of Celite®. The filter cake was rinsed with Cl hCk/MeOH (9: 1 mixture) and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (ClhCk/MeOH from 100:0 to 90: 10) to afford after vacuum-drying (60 C. 3 days) compound 9 as a white solid (0.579 g, 65%) and compound 10 as a white solid (0.178 g, 20%).
Compound 9
1H NMR (400 MHz, DMSO -d6) δ ppm 11.63 (s, 1H), 8.10 (d, 7 = 7.9 Hz, 1H), 7.93 (d, j = 8.1 Hz, 1H), 111 (d, J = 7.5 Hz, 2H), 7.68 (d, J = 7.5 Hz, 2H), 7.62 (t, J = 7.4 Hz,
1H), 7.29 (t, j = 7.2 Hz, 111). 4.59 (del, 7 = 12.1 Hz, 4.5 Hz, lH), 4.39 (t, 7 = 11.4 Hz, 1H), 3.69-3.57 (m, lH), 3.20-3.04 (m, 2H), 2.40-2.18 (m, 5H including s, 3H at 2.36).
Compound 10
1H NMR (400 MHz, DMSO-d6) δ ppm 10.82 (s, 1H), 7.76 (d, 7 = 7.5 Hz, 2H), 7.66 (d, 7 = 7.5 Hz, 2H), 4.53 idd, 7 = 12.3 Hz, 4.9 Hz, 1H), 4.32 (t, 7 = 11.6 Hz, lH), 3.65-3.52
(m, 1H), 3.14-2.98 (m, 2H), 2.71-2.59 (m, 2H), 2.38-2.13 (m, 7H including s, 3H at 2.18), 1.74-1.59 (m, 4H).
Preparation of compound 28 and compound 29
compound 9 compound 28 compound 29 A purification of compound 9 was performed via chiral SFC (Stationary phase: CHIRALPAK AD-H 5mih 250*30mm, Mobile phase: 55% C02, 45% mixture of EtOH/iPrOH 50/50 v/v(+0.3%iPrNH2)). Pure fractions were collected and evaporated affording FI 0.259 g and F20.244 g.
FI was triturated with DIPE and a few heptane, the precipitate was filtered off, dried under vacuum at 60°C affording compound 28 as white powder, 0.233 g (41%).
1H NMR (500 MHz, DMSO-d6) δ ppm 11.63 (br s, 1H), 8.11 (dd, J=8.2, 1.1 Hz, 1H), 7.93 (d, J=8.4 Hz, 1H), 7.77 (d, J=8.2 Hz, 2H), 7.68 (d, J=8.1 Hz, 2H), 7.62 (td, J=7.7, 1.4 Hz, 1H), 7.29 (t, .1=7.2 Hz, 1H), 4.59 (dd, J=12.4, 5.3 Hz, 1H), 4.39 (t, J=11.7 Hz, 1H), 3.60 - 3.67 (m, 1H), 3.07 - 3.18 (m, 2H), 2.20 - 2.38 (m, 5H)
F2 was triturated with DIPE and a few heptane, the precipitate was filtered off, dried under vacuum at 60°C affording compound 29 as white powder, 0.223 g (39%).
1H NMR (500 MHz, DMSO-d6) δ ppm 11.62 (br s, 1H), 8.10 (d, J=7.3 Hz, 1H), 7.93 (d, J=8.2 Hz, 1H), 7.77 (d, J=8.2 Hz, 2H), ), 7.68 (d, J=8.1 Hz, 2H), 7.62 (td, J=7.7, 1.4 Hz, 1H), 7.29 (t, J=7.5 Hz, 1H), 4.59 (dd, 1=12.6, 5.1 Hz, 1H), 4.39 (t, J=11.6 Hz, 1H), 3.63 (br s, 1H), 3.06 - 3.18 (m, 2H), 2.20 - 2.38 (m, 5H)
Preparation of compound 30 and compound 31
A purification of compound 10 was performed via chiral SFC (Stationary phase: CHIRALPAK AD-H 5mih 250*30mm, Mobile phase: 50% C02, 50% mixture of MeOH/ACN 90/10 v/v(+0.3%iPrNH2)). Pure fractions were collected and evaporated affording FI, 0.080 g and F2, 0.079 g.
FI was triturated with DIPE and a few heptane, the precipitate was filtered off, dried under vacuum at 60°C affording compound 30 as white powder, 0.071 g (41%).
1H NMR (500 MHz, DMSO-d6) δ ppm 10.82 (br s, 1H), 7.76 (d, J=8.1 Hz, 2H), 7.66 (d, J=8.2 Hz, 2H), 4.53 (dd, 1=12.6, 5.4 Hz, 1H), 4.32 (t, J=11.7 Hz, 1H), 3.55 - 3.63 (m, lH), 3.00 - 3.12 (m, 2H), 2.54 - 2.67 (m, 2H), 2.20 - 2.37 (m, 4H), 2.18 (s, 3H), 1.59 - 1.74 (m, 4 H) F2 was triturated with DIPE and a few heptane, the precipitate was filtered off, dried under vacuum at 60°C affording compound 31 as white powder, 0.068 g (39%).
1H NMR (500 MHz, DMSO-d6) δ ppm 10.82 (br s, 1H), 7.76 (d, J=8.2 Hz, 2H), 7.66 (d, .1=8.1 Hz, 2H), 4.53 (dd, J=12.4, 5.3 Hz, 1H), 4.32 (t, J=11.7 Hz, 1H), 3.55 - 3.63 (m, 1H), 3.00 - 3.12 (m, 2H), 2.55 - 2.68 (m, 2H), 2.20 - 2.37 (m, 4H), 2.18 (s, 3H), 1.59 - 1.74 (m, 4H)
Preparation of compound 11
A mixture of compound AB-3 (200 mg, 0.515 mmol), EtOH (10 mL) and THF (10 mL) was stirred in a 100 mL Parr reactor vessel in the presence of 10 wt% palladium on carbon ( 110 mg, 0.103 mmol) under hydrogen atmosphere (30 bar) at 60 °C for 24 h. Additional 10 wt% palladium on carbon (110 mg, 0.103 mmol) was added and stirring was continued under hydrogen atmosphere (30 bar) at 60 °C for another 24 h. The reaction mixture was diluted at room temperature with CH2CI2 and filtered through a pad of Celite®. The filter cake was rinsed with a CFbCb/MeOH mixture (9:1) and the filtrate was concentrated under reduced pressure. The residue was purified twice by flash chromatography over silica gel (CFLCb/MeOH from 100:0 to 90:10) affording after vacuum-drying (60 °C, 63 h) compound 11 as a white solid (66 mg, 32%).
1H NMR (400 MHz, DMSO-d6) δ ppm 10.81 (s, 1H), 7.55 (ddd, J = 12.1 Hz, 7.9 Hz, 2.1 Hz, 1H), 7.45 (dt, J = 10.8 Hz, 8.6 Hz, 1H), 7.30-7.24 (m, 1H), 4.49 (dd, I = 12.5 Hz, 5.4 Hz, 1H), 4.26 (t, J = 11.7 Hz, 1H), 3.54-3.43 (m, 1H), 3.13-2.95 (m, 2H), 2.67- 2.60 (m, 2H), 2.37-2.12 (m, 7H including s, 3H at 2.17), 1.73-1.59 (m, 4H).
Preparation of compound 49, compound 50 & compound 51
In a steel bomb, a solution of compound AB-4 (0.47 g, 1.23 mmol) in THF (16 mL) and EtOH (8.6 mL) was stirred at room temperature and purged with a N2 flow. 10 wt% palladium on carbon (52.3 mg, 0.25 mmol) was added then the mixture was purged with H2. The resulting solution was stirred and heated at 60°C for 5 hours under Hi atm (30 bar). The solution was cooled down to room temperature. The mixture was filtered off over celite®, washed with THF/EtOH (1/1). The filtrate was evaporated. THF (16 mL) and EtOH (8.6 mL) were added to the residue and the solution was placed in a steel bomb and purged with a Ni flow. 10 wt% palladium on carbon (52.3 mg, 0.25 mmol) was added then the mixture was purged with Hi. The resulting solution was stirred and heated at 60°C for 4 hours under Hi atm (30 bar). The solution was cooled down to room temperature. The mixture was filtered off over celite®, washed with THF/EtOH (1/1). The filtrate was evaporated to give a crude, 0.45 g. A purification was performed via chiral SFC (Stationary phase: CHIRALPAK AD-H 5mpi 250*30mm, Mobile phase: 55% C02, 45% mixture of iPrOH/ACN 80/20 v/v(+0.3%iPrNHi)). Pure fractions were collected and evaporated giving FI , 0.108 g,
F2, 0.1 18 g and F3, 0.083 g.
FI was triturated with D1PE and a few Heptane, the precipitate was filtered off and dried under vacuum at 60°C affording compound 49 as white powder, 0.087 g.
1H NMR (500 MHz, DMSO-d6) δ ppm 10.80 (br s, 1H), 7.32 (d, J=8.5 Hz, 2H), 6.94 (d, .1=8.5 Hz, 2H), 4.44 (dd, .1=12.5. 5.2 Hz, 1H), 4.21 (t, .1=1 1.7 Hz, lH), 3.75 (s, 3H),
3.35 - 3.44 (m, 1H), 2.95 - 3.09 (m, 2H), 2.64 (br t, J=5.6 Hz, 2H), 2.30 - 2.38 (m, 2H), 2.11 - 2.25 (m, 5H), 1.66 (dt, J=11.0, 5.3 Hz, 4H)
F2 was triturated with DIPE and a few Heptane, the precipitate was filtered off and dried under vacuum at 60°C affording compound 50 as white powder, 0.092 g. 1H NMR (500 MHz, DMSO-d6) δ ppm 11.59 (br s, 1H), 8.10 (dd, J=8.0, 1.0 Hz, 1H), 7.93 (d, J=8.4 Hz, 1H), 7.61 (t, J=7.7 Hz, 1H), 7.26 - 7.39 (m, 3H), 6.95 (d, J=8.5 Hz, 2H), 4.50 (dd, J=12.4, 5.3 Hz, 1H), 4.28 (t, J=1 1.7 Hz, 1H), 3.76 (s, 3H), 3.37 - 3.47 (m, lH), 3.02 - 3.16 (m, 2H), 2.36 (s, 3H), 2.14 - 2.30 (m, 2H)
F3 was triturated with DIPE and a few Heptane, the precipitate was filtered off and dried under vacuum at 60°C affording compound 51 as white powder, 0.067 g.
1H NMR (500 MHz, DMSO-d6) δ ppm 11.61 (br s, 1H), 8.10 (d, J=7.3 Hz, 1H), 7.93 (d, J=8.4 Hz, 1H), 7.61 (t, J=7.6 Hz, 1H), 7.27 - 7.38 (m, 3H), 6.95 (d, 1=8.5 Hz, 2H), 4.50 (dd, J=12.5, 5.2 Hz, 1H), 4.28 (t, J=1 1.7 Hz, 1H), 3.76 (s, 3H), 3.38 - 3.47 (m,
In a steel bomb, a solution of compound AB-5 (0.418 g, 1.09 mmol) in THF (14.2 mL) and EtOH (7.6 mL) was stirred at room temperature and purged with a N2 flow. 10 wt% palladium on carbon (46.3 mg, 0.22 mmol) was added then the mixture was purged with ¾. The resulting solution was stirred and heated at 60°C for 5 hours under H2 atm (30 bar). The solution was cooled down to room temperature. The mixture was filtered off over celite®, washed with THF/EtOH (1/1). The filtrate was evaporated. THF (14.2 mL) and EtOH (7.2 mL) were added to the residue and the solution was placed in a steel bomb and purged with a N2 flow. 10 wt% palladium on carbon (46.3 mg, 0.22 mmol) was added then the mixture was purged with ¾. The resulting solution was stirred and heated at 60°C for 4 hours under ¾ atm (30 bar). The solution was cooled down to room temperature. The mixture was filtered off over celite®, washed with THF/EtOH (1/1). The filtrate was evaporated to give 0.21 g. Purification was carried out by flash chromatography over silica gel (12 g, irregular SiOH 25-40mM, DCM/MeOH from 100/0 to 97/3). Pure fractions were collected and evaporated affording a white powder, 0.2 g. This was triturated with DIPE and a few Heptane, the precipitate was filtered off and dried under vacuum at 60°C affording compound 52 as white powder, 0.156 g (36%). 1H NMR (500 MHz, DMSO-d6) δ ppm 10.83 (br s, 1H), 7.05 - 7.12 (m, 2H), 6.96 (br d, .1=9.5 Hz, 1H), 4.48 (br dd, .1= 12.4. 5.0 Hz, 1H), 4.27 (br t, .1=1 1.7 Hz, 1H), 3.39 - 3.56 (m, IH), 2.97 - 3.12 (m, 2H), 2.56 - 2.71 (m, 2H), 2.33 (s, 5H), 2.14 - 2.26 (m,
Accordingly, the procedure was the same as preparation of compound 52 starting from compound AB-8 (1.21 mmol). A purification was performed via achiral SFC (Stationary phase: AMINO 6mpi 150x21.2mm, Mobile phase: 80% CO2, 20% MeOH (0.3% iPrNFb)). Pure fractions were collected and evaporated affording FI, 0.279 g and F2, 0.055 g.
FI was triturated with DIPE and a few Heptane, the precipitate was filtered off and dried under vacuum at 60°C affording compound 53 as white powder, 0.243 g (48%).
1H NMR (500 MHz, DMSO-d6) δ ppm 10.81 (br s, 1H), 6.58 (d, J=2.0 Hz, 2H), 6.43 (t, J=2. 1 Hz, 1H), 4.46 (dd, .1=12.4, 5.3 Hz, 1H), 4.28 (t, J=11.7 Hz, 1H), 3.75 (s, 6H), 3.23 - 3.34 (m, 2H), 2.96 - 3.11 (m, 2H), 2.55 - 2.72 (m, 2H), 2.30 - 2.37 (m, 2H), 2.14 - 2.27 (m, 5H), 1.61 - 1.72 (m, 4H)
A purification of F2 was performed via chiral SFC (Stationary phase: Chiralpak IC 5mih 250*21.2mm, Mobile phase: 55% CO2, 45% EtOH (0.3% iPrN¾)). Pure fractions were collected and evaporated affording FT and F2’
FT was solubilized with Acetonitrile (2 mL) and extended with water (8 mL), the solution was freeze-dried overnight giving compound 57 as white foam, 0.022 g (5%).
1H NMR (500 MHz, DMSO-d6) δ ppm 11.60 (br s, 1H), 8.10 (dd, 1=8.1, 1.1 Hz, 1H), 7.92 (d, J=8.4 Hz, 1H), 7.61 (t, 1=1.1 Hz, 1H), 7.28 (t, J=7.6 Hz, 1H), 6.60 (d, J=2.1 Hz, 2H), 6.44 (t, .1=2.1 Hz, 1H), 4.52 (dd, .1=12.5. 5.2 Hz, 1H), 4.34 (t, .1= 1 1.7 Hz, 1H), 3.75 (s, 6H), 3.37 - 3.49 (m, 1H), 3.02 - 3.16 (m, 2H), 2.33 - 2.37 (m, 3H), 2.16 - 2.31 (m, 2H)
F2’ was solubilized with Acetonitrile (2 mL) and extended with water (8 mL), the solution was freeze-dried overnight giving compound 58 as white foam, 0.021 g (5%).
1H NMR (500 MHz, DMSO-d6) δ ppm 11.60 (br s, 1H), 8.10 (dd, J=8.1, 1.1 Hz, 1H), 7.92 (d, J=8.4 Hz, 1H), 7.61 (t, J=7.7 Hz, 1H), 7.28 (t, J=7.6 Hz, 1H), 6.60 (d, J=2.1 Hz, 2H), 6.44 (t, J=2. 1 Hz, 111). 4.52 (dd, J=12.5, 5.2 Hz, 1H), 4.34 (t, J=11.7 Hz, 1H), 3.75 (s, 6H), 3.37 - 3.49 (m, 1H), 3.02 - 3.16 (m, 2H), 2.33 - 2.37 (m, 3H), 2.16 - 2.31 (m, 2H)
In a steel bomb, a solution of compound AB-6 (0.23 g, 0.6 mmol) in THF (7.8 mL) and EtOH (4.2 mL) was stirred at room temperature and purged with a N? flow. 10 wt% palladium on carbon (0.025 g, 0.12 mmol) was added then the mixture was purged with H2. The resulting solution was stirred and heated at 60°C for 5 hours under I f atm (30 bar). The solution was cooled down to room temperature. The mixture was filtered off over celite®, washed with THF/EtOH (1/1). The filtrate was evaporated to give 0.2 g. Purification was carried out by flash chromatography over silica gel (12 g, irregular SiOH 25-40mM, DCM/MeOH from 100/0 to 97/3). Pure fractions were collected and evaporated affording 0.19 g. A purification was performed via achiral SFC (Stationary phase: AMINO 5mhi 150*30 mm, Mobile phase: 80% C02, 20% MeOH (0.3% iPrNHi)). Pure fractions were collected and evaporated affording FI, 0.105 g and F2, 0.042 g.
FI was triturated with DIPE and a few Heptane, the precipitate was filtered off and dried under vacuum at 60°C affording compound 54 as white powder, 0.093 g (40%).
1H NMR (500 MHz, DMSO-d6) 5 ppm 10.82 (br s, 1H), 7.18 - 7.32 (m, 2H), 7.14 (br d, J=7.6 Hz, 1H), 4.47 (br dd, J= 12.2. 4.9 Hz, 1H), 4.25 (br t, J=11.7 Hz, 1H), 3.39 - 3.57 (m, 1H), 2.97 - 3.12 (m, 2H), 2.56 - 2.72 (m, 2H), 2.29 - 2.45 (m, 2H), 2.22 (br s,
4H), 2.17 (s, 4H), 1.59 - 1.74 (m, 4H)
A purification of F2 was performed via chiral SFC (Stationary phase: CHIRACEL OJ- H 5mih 250*20nun, Mobile phase: 90% C02, 10% MeOH (0.3% iPrNH2)). Pure fractions were collected and evaporated affording FT, 0.015 g and F2\ 0.02 g.
FT was solubilized with Acetonitrile (2 mL) and extended with water (8 mL), the solution was freeze-dried overnight giving compound 62 as white foam, 0.014 g (6%).
1 H NMR (500 MHz, DMSO-d6) δ ppm 1 1.62 (br s, 1 H), 8.10 (dd, J=8.1 , 1.2 Hz, 1 H), 7.92 (d, J=8.2 Hz, 1H), 7.61 (ddd, J=8.4, 6.9, 1.4 Hz, 1H), 7.22 - 7.32 (m, 3H), 7.16 (dd, J=7.8, 1.4 Hz, 1H), 4.53 (dd, J= 12.5. 5.2 Hz, 1 H). 4.31 (t, .1=1 1.7 Hz, 1H), 3.35 - 3.56 (m, 1H), 3.03 - 3.17 (m, 2H), 2.35 (s, 3H), 2.16 - 2.31 (m, 5H) F2’ was solubilized with Acetonitrile (2 mL) and extended with water (8 mL), the solution was freeze-dried overnight giving compound 63 as white foam, 0.019 g (8%).
1H NMR (500 MHz, DMSO-d6) δ ppm 11.61 (br s, 1H), 8.10 (dd, 1=8.1, 1.2 Hz, 1H), 7.92 (d, J=8.2 Hz, 1H), 7.61 (t, J=7.6 Hz, 1H), 7.22 - 7.32 (m, 3H), 7.16 (dd, J=7.8, 1.4 Hz, 1H), 4.53 (dd, J=12.5, 5.2 Hz, 1H), 4.26 - 4.34 (m, 1H), 3.45 - 3.52 (m, 1H), 3.04 - 3.17 (m, 2H), 2.35 (s, 3H), 2.17 - 2.31 (m, 5H)
In a steel bomb, a solution of compound AB-7 (0.275 g, 0.69 mmol) in THF (9 mL) and EtOH (4.8 mL) was stirred at room temperature and purged with a N2 flow. 10 wt% palladium on carbon (0.029 g, 0.14 mmol) was added then the mixture was purged with H2. The resulting solution was stirred and heated at 60°C for 5 hours under H2 atm (30 bar). The solution was cooled down to room temperature. The mixture was filtered off over celite®, washed with THF/EtOH (1/1). The filtrate was evaporated. THF (9 mL) and EtOH (4.8 mL) were added and the solution was placed in a steel bomb and purged with a N2 flow. 10 wt% palladium on carbon (0.029 g, 0.14 mmol) was added then the mixture was purged with H2. The resulting solution was stirred and heated at 60°C for 2.5 hours under H2 atm (30 bar). The solution was cooled down to room temperature. The mixture was filtered off over celite®, washed with THF/EtOH (1/1). The filtrate was evaporated to give 0.263 g. Purification was carried out by flash
chromatography over silica gel (12 g, irregular SiOH 25-40mM, DCM/MeOH from 100/0 to 97/3). Pure fractions were collected and evaporated affording a white powder,
0.16 g.
A purification was performed via achiral SFC (Stationary phase: AMINO 6μm 150x21.2mm, Mobile phase: 80% C02, 20% MeOH (0.3% iPrXIl·)!. Pure fractions were collected and evaporated affording FI, 0.096 g and F2, 0.026 g.
FI was triturated with DIPE and a few Heptane, the precipitate was filtered off and dried under vacuum at 60°C affording compound 55 as white powder, 0.077 g (27%).
1H NMR (500 MHz, DMSO-d6) δ ppm 10.82 (br s, 1H), 6.82 - 6.90 (m, 2H), 6.76 (br d, J= 11.0 Hz, 1H), 4.48 (br dd, J= 12.4, 5.1 Hz, 1H), 4.28 (br t, J=11.7 Hz, 1H), 3.78 (s, 3H), 3.44 (br s, 1H), 2.96 - 3.13 (m, 2H), 2.56 - 2.72 (m, 2H), 2.31 - 2.46 (m, 2H), 2.14 - 2.28 (m, 5H), 1.60 - 1.74 (m, 4H)
F2 was solubilized with Acetonitrile (2 mL) and extended with water (8 mL), the solution was freeze-dried overnight giving compound 59 as white foam, 0.029 g (10%). 1H NMR (500 MHz, DMSO-d6) 5 ppm 8.10 (br d, J=7.9 Hz, 1H), 7.92 (br d, J=8.4 Hz, 1H), 7.61 (br t, J=7.6 Hz, 1H), 7.29 (t, J=7.5 Hz, 1H), 6.84 - 6.92 (m, 2H), 6.77 (br d, J=11.0 Hz, 1H), 4.55 (br dd, J=12.4, 5.0 Hz, 1H), 4.35 (br t, J=11.7 Hz, 1H), 3.79 (s, 3H), 3.49 (br s, 1H), 3.03 - 3.22 (m, 2H), 2.18 - 2.38 (m, 5H) Preparation of compound 56
In a steel bomb, a solution of compound AB-9 (0.317 g, 0.72 mmol) in THF (9.4 mL) and EtOH (5 mL) was stirred at room temperature and purged with a N? flow. 10 wt% palladium on carbon (0.031 g, 0.14 mmol) was added then the mixture was purged with ¾. The resulting solution was stirred and heated at 60°C for 5 hours under Hz atm (30 bar). The solution was cooled down to room temperature. The mixture was filtered off over celite®, washed with THF/EtOH (1/1). The filtrate was evaporated. Purification was carried out by flash chromatography over silica gel (12 g, irregular SiOH 25- 40mM, DCM/MeOH from 100/0 to 97/3). Pure fractions were collected and evaporated
affording a white powder, 0.215 g. This was triturated with DIPE and a few Heptane, the precipitate was filtered off and dried under vacuum at 60°C affording compound 56 as white powder, 0.192 g (59%).
‘H NMR (500 MHz, DMSO-d6) δ ppm 10.83 (s, 1 H), 7.58 - 7.75 (m, 3 H), 4.50 - 4.63 (m, 1 H), 4.36 (br t, 7=11.6 Hz, 1 H), 3.63 (s, 1 H), 3.32 (s, 3 H), 2.99 - 3.20 (m, 2 H),
2.59 - 2.71 (m, 2 H), 2.09 - 2.41 (m, 8 H), 1.59 - 1.74 (m, 4 H)
Preparation of compound 60 & compound 61
In a steel bomb, a solution of compound AB-10 (0.325 g, 0.74 mmol) in THF (9.7 mL) and EtOH (5.2 mL) was stirred at room temperature and purged with a N2 flow. 10 wt% palladium on carbon (0.032 g, 0. 15 mmol) was added then the mixture was purged with ¾. The resulting solution was stirred and heated at 60°C for 4 hours under ¾ atm (20 bar). The solution was cooled down to room temperature. The mixture was filtered off over celite®, washed with THF/EtOH ( 1/1). The filtrate was evaporated giving 0.335 g. Purification was carried out by flash chromatography over silica gel (24 g, irregular SiOH 25-40mM, solid deposit on celite®, DCM/MeOH from 100/0 to 97/3). Pure fractions were collected and evaporated affording FI as beige powder, 0.043 g and F2, as white powder, 0.208 g. F 1 was triturated with DIPE and a few Heptane, the precipitate was filtered off and dried under vacuum at 60°C affording compound 60 as white powder, 0.032 g (10%).
1H NMR (500 MHz, DMSOd6) δ ppm 1 1.63 (br s, 1H), 8.10 (dd, .1=8.2, 1.2 Hz, 1H), 7.93 (d, J=8.2 Hz, 1H), 7.62 (ddd, J=8.5, 6.9, 1.5 Hz, 1H), 7.46 - 7.56 (m, 3H), 7.27 - 7.34 (m, 2H), 4.59 (dd, J=12.5, 5.2 Hz, 1H), 4.37 (t, .1=1 1.7 Hz, 1H), 3.55 - 3.62 (m, 1H), 3.05 - 3.18 (m, 2H), 2.22 - 2.38 (m, 5H)
F2 was triturated with DIPE and a few Heptane, the precipitate was filtered off and dried under vacuum at 60°C affording compound 61 as white powder, 0.185 g (56%).
1H NMR (500 MHz, DMSO-d6) 5 ppm 10.82 (s, lH), 7.44 - 7.55 (m, 3H), 7.31 (d, J=8.0 Hz, 1H), 4.52 (dd, J=12.4, 5.3 Hz, 1H), 4.31 (t, J=11.7 Hz, 1H), 3.51 - 3.58 (m,
1H), 2.99 - 3.11 (m, 2H), 2.64 (br t, J=6.0 Hz, 2H), 2.16 - 2.37 (m, 7H), 1.61 - 1.72 (m, 4H)
Accordingly, compounds 66 and 67 were prepared in the same way as compounds 60 and 61, starting from compound AB-11 (0.96 mmol). Those affording 0.081 g as a white powder (19%) of compound 66 and 0.22 g as a white powder (55%) of compound 67. Compound 66
1H NMR (500 MHz, DMSO-d6) δ ppm 11.62 (br s, 1H), 8.10 (d, J=7.2 Hz, 1H), 7.93 (d, J=8,4 Hz, 1H), 7.62 (t, J=7.7 Hz, 1H), 7.38 - 7.47 (m, 3H), 7.26 - 7.34 (m, 2H), 4.56 (dd, .1=12.4. 5.3 Hz, 1H), 4.34 (t, J=11.7 Hz, 1H), 3.66 (q, J=11.5 Hz, 2H), 3.34 - 3.55 (m, 1H), 3.05 - 3.17 (m, 2H), 2.21 - 2.38 (m, 5H) Compound 67
1H NMR (500 MHz, DMSO-d6) δ ppm 11.62 (br s, 1H), 8.10 (d, J=7.2 Hz, 1H), 7.93 (d, J=8.4 Hz, 1H), 7.62 (t, J=7.7 Hz, 1H), 7.38 - 7.47 (m, 3H), 7.26 - 7.34 (m, 2H), 4.56 (dd, .1=12.4. 5.3 Hz, 1H), 4.34 (t, J=11.7 Hz, 1H), 3.66 (q, J=11.5 Hz, 2H), 3.34 - 3.55 (m, 1H), 3.05 - 3.17 (m, 2H), 2.21 - 2.38 (m, 5H)
Preparation of intermediate AC- 1
To a mixture of diethyl oxalpropionate (CAS [759-65-9], 2.00 g, 9.89 mmol) and polyphosphoric acid (4.00 g) was added 4-fluoroaniline (CAS [371-40-4], 0.949 mL, 0.989 mmol) at room temperature. The resulting mixture was stirred at 130°C for 2 h. The reaction mixture was poured onto ice water (50 mL). The aqueous layer was extracted with DCM (3 x 50 mL). The combined organic layers were washed with water (50 mL), a saturated aqueous NaHCOi solution (50 mL), dried over sodium sulfate, filtered and concentrated to dryness to afford a brownish sticky solid. It was triturated with diethyl ether (3 x 5 mL) and dried under reduced pressure to afford intermediate AC-1 as a pale- yellow solid, 0.565 g (23%).
Preparation of intermediate AC-2
To a solution of 5-bromo-l,2-diaminopyridinium 2,4,6-trimethylbenzenesulfonate (CAS [1202704-57-1], 862 mg, 2.22 mmol) and triethylamine (0.928 mL, 6.66 mmol) in n-butanol (11.1 mL) was added intermediate AC-1 (553 mg, 2.22 mmol) at 0°C. The resulting mixture was stirred at 100°C for 18 h. The reaction mixture was concentrated to dryness and the residue was triturated with methanol (20 mL) collected on a glass frit and rinsed with methanol (3 x 10 mL) to afford intermediate AC-2 as a beige solid, 0.18 g (22%).
Preparation of AC-3
A mixture of intermediate AC-2 (175 mg, 0.469 mmol), 4-
(trifluoromethoxy)phenylboronic acid (CAS [139301-27-2], 116 mg, 0.563 mmol) and Potassium phosphate monohydrate (324 mg, 1.41 mmol) in 1,4-dioxane (1.8 mL) and water (0.45 mL) was purged with nitrogen (vacuum/nitrogen: 3 times). [1,1 - Bis(diphenylphosphino)ferrocene] dichloropalladium (II) (34.3 mg, 46.9 μmol) was added and the reaction mixture was purged with nitrogen (vacuum/nitrogen: 3 times). The resulting mixture was stirred at 100°C for 18 h. The reaction mixture was cooled to room temperature, diluted with water (25 mL), filtered through a glass frit to collect after rinsing with water (3 x 5 mL) a black solid. This was purified by flash chromatography on silica gel (25 g), DCM/Methanol 100/0 to 98/2 over 50 min) to afford an off-white solid. The solid was triturated with methanol (3 x 2 mL) and dried under high vacuum at 50°C (for 18 h) to afford AC-3 as a white solid, 0.107 g (50%).
Preparation of compound 7
A mixture of compound AC-3 (600 mg, 1.32 mmol) in EtOH (30 mL) and THF (30 mL) was stirred in a 100 mL Parr reactor vessel in the presence of 10 wt% palladium on carbon (281 mg, 0.264 mmol) under hydrogen atmosphere (30 bar) at 60 °C for 4 h. The reaction mixture was diluted at room temperature with CH2CI2 and filtered through a pad of Celite®. The filter cake was rinsed with a CHiCb/MeOH mixture (9: 1) and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (PF-15SIHP, CFLCb/MeOH from 100:0 to 95:5), then triturated with EtiO, co-evaporated with methanol and vacuum-dried (60 °C, 16 h) to afford compound 7 as a white solid (456 mg, 75%).
1H NMR (400 MHz, DMSO-d6) δ ppm 11.83 (s, 1H), 8.03 (dd, J = 9.2 Hz, 4.7 Hz, 1H), 7.73 (dd, J = 9.4 Hz, 3.0 Hz, 1H), 7.60-7.53 (m, 3H), 7.40 (d, J = 8.2 Hz, 2H),
4.57 (dd, J = 12.4 Hz, 5.4 Hz, Hi). 4.35 (t, J = 11.7 Hz, 1H), 3.62-3.51 (m, 1H), 3.19- 3.03 (m, 2H), 2.37 (s, 3H), 2.32-2.16 (m, 2H).
Compound 7 was purified via chiral SFC (Stationary phase: CHIRALPAK AD-H 5μm 250*30mm, Mobile phase: 60% CO2, 40% MeOH) affording 185 mg of compound 16 5 as white powder (41%) and 163 mg of compound 17 as white powder (36%).
Compound 16
Ή NMR (500 MHz, DMF-77) δ ppm 8.23 (dd, 7=9.2, 4.6 Hz, 1 H), 7.86 (dd, 7=9.5, 3.1 Hz, 1 H), 7.60 - 7.71 (m, 3 H), 7.47 (d, 7=7.9 Hz, 2 H), 4.66 (dd, 7=12.6, 5.3 Hz, 1 H), 4.42 (t, 7=11.7 Hz, 1 H), 3.55 - 3.72 (m, 1 H), 3.12 - 3.25 (m, 2 H), 2.33 - 2.53 (m, 5 H) 10 (NH not visible)
Compound 17
Ή NMR (500 MHz, DMF-d7) δ ppm 8.23 (dd, 7=9.2, 4.6 Hz, 1 H), 7.86 (dd, 7=9.5, 3.1 Hz, 1 H), 7.60 - 7.71 (m, 3 H), 7.47 (d, 7=7.9 Hz, 2 H), 4.66 (dd, 7=12.6, 5.3 Hz, 1 H), 4.42 (t, 7=11.7 Hz, 1 H), 3.55 - 3.72 (m, 1 H), 3.12 - 3.25 (m, 2 H), 2.33 - 2.53 (m, 5 H) 15 (NH not visible)
Synthesis of compound 41 & compound 42, compound 45, compound 46, compound
To a solution of Ethyl 3-methyl-4-oxo-l,4-dihydroquinoline-2-carboxylate (CAS [402491-57-0], 26.6 g, 68.5 mmol) in «-butanol (340 mL) were successively added triethylamine (28.6 mL, 206 mmol) and l,2-diamino-4-bromo-pyridinium-2,4,6- trimethyl-benzenesulfonate (CAS[1202704-61-7], 15.8 g, 68.5 mmol). The reaction mixture was stirred at 120°C for 1.5 days. The reaction mixture was concentrated to dryness to afford a brown solid. The crude solid was purified by flash chromatography over silica gel (DCM/Acetone 95/5 to 85/15 over 30 min then 85/15 to 80/20 over 30 min and 80/20 for 40 min) to give a yellow solid. It was dried under high vacuum at 50 °C (20 h) to afford intermediate AD-1 as a yellow solid, 2.1 g (9%).
Preparation of AD-2
A mixture of intermediate AD-1 (175 mg, 0.469 mmol), 4-
(trifluoromethoxy)phenylboronic acid (CAS [139301-27-2], 116 mg, 0.563 mmol) and Potassium phosphate monohydrate (324 mg, 1.41 mmol) in 1,4-dioxane (1.8 mL) and water (0.45 mL) was purged with nitrogen (vacuum/nitrogen: 3 times). [1,1'-
Bis(diphenylphosphino)ferrocene] dichloropalladium (II) (34.3 mg, 46.9 μmol) was added and the reaction mixture was purged with nitrogen (vacuum/nitrogen: 3 times). The resulting mixture was stirred at 100°C for 18 h. The reaction mixture was cooled to room temperature, diluted with water (25 mL), filtered through a glass frit to collect after rinsing with water (3 x 5 mL) a black solid. This was purified by flash chromatography on silica gel (25 g, DCM/Methanol 100/0 to 98/2 over 50 min) to afford an off-white solid. The solid was triturated with methanol (3 x 2 mL) and dried under high vacuum at 50°C (for 18 h) to afford intermediate AD-2 as a white solid, 0.107 g (50%). Preparation of compound 41 and compound 42
An nitrogen-purged mixture of compound AD-2 (600 mg, 1.37 mmol) in EtOH (15 mL) and THF (15 mL) was stirred in a 100 mL Parr reactor vessel in the presence of 10 wt% palladium on carbon (293 mg, 0.275 mmol) under hydrogen atmosphere (30 bar) at 60 °C for 5 h. The mixture was diluted at room temperature with CH2CI2 and filtered through a pad of Celite®. The filter cake was rinsed with a CFLCli/MeOH mixture
(9:1) and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography over silica gel (PF-15SIHP, CFbCb/MeOH from 100:0 to 94:6) to afford after vacuum-drying (60 °C, 15 h) compound 41 as a beige solid (165 mg, 27%) and compound 42 was obtained as a white solid (185 mg, 31%).
Compound 41
1H NMR (400 MHz, DMSO-d6) δ ppm 10.83 (s, lH), 7.57-7.50 (m, 2H), 7.38 (d, J = 8.2 Hz, 2H), 4.42-4.34 (m, 1H), 4.34-4.24 (m, lH), 3.41 (tdd, J = 11.5 Hz, 4.7 Hz, 2.9 Hz, 1H), 3.25 (ddd, J = 16.8 Hz, 5.0 Hz, 1.0 Hz, 1H), 3.08 (dd, J = 16.7 Hz, 11.3 Hz, lH), 2.68-2.60 (m, 2H), 2.43-2.22 (m, 4H), 2.18 (s, 3H), 1.74-1.59 (m, 4H).
Compound 42
1H NMR (400 MHz, DMSO-d6) δ ppm 11.64 (s, 1H), 8.10 (dd, J = 8.1 Hz, 0.9 Hz,
1H), 7.93 (d, J = 8.4 Hz, 1H), 7.61 (ddd, J = 8.4 Hz, 7.0 Hz, 1.4 Hz, 1H), 7.58-7.52 (m, 2H), 7.39 (d, J = 8.3 Hz, 2H), 7.29 (t, J = 7.6 Hz, 1H), 4.48-4.40 (m, 1H), 4.40-4.30 (m, 1H), 3.51-3.40 (m, 1H), -3.33-3.27 (m, 1H, overlapped with solvent water peak), 3.14
(dd, J = 16.8 Hz, 11.2 Hz, 1H), 2.46-2.37 (m, 1H), 2.36 (s, 3H), 2.34-2.25 (m, 1H).
A purification of compound 42 was performed via chiral SFC (Stationary phase: CHIRALPAK AD-H 5um 250*21 ,2mm, Mobile phase: 70% C02, 30% iPrOH (0.3% iPrNH2)). Pure fractions were collected and evaporated affording FI, 0.072 g and F2, 0.076 g.
FI was triturated with DIPE and a few Heptane, the precipitate was filtered off and dried under vacuum at 60°C affording compound 45 as white powder, 0.06 g (36%). 1H NMR (500 MHz, DMSO-d6) δ ppm 1 1.65 (br s, 1H), 8.10 (dd, J=8.1, 1.1 Hz, 1H), 7.93 (d, J=8.4 Hz, 1H), 7.54 - 7.63 (m, 3H), 7.39 (d, J=8.1 Hz, 2H), 7.29 (t, J=7.5 Hz, 1H), 4.40 - 4.47 (m, lH), 4.32 - 4.40 (m, 1H), 3.40 - 3.55 (m, 1H), 3.26 - 3.31 (m, 1H), 3.10 - 3.19 (m, 1H), 2.35 - 2.45 (m, 4H), 2.26 - 2.33 (m, 1H)
F2 was triturated with DIPE and a few Heptane, the precipitate was filtered off and dried under vacuum at 60°C affording compound 46 as white powder, 0.069 g (41%).
1H NMR (500 MHz, DMSO-d6) δ ppm 11.65 (br s, 1H), 8.10 (dd, J=8.2, 1.1 Hz, 1H), 7.93 (d, J=8.4 Hz, 1H), 7.54 - 7.63 (m, 3H), 7.39 (d, J=8.1 Hz, 2H), 7.29 (t, J=7.5 Hz,
1H), 4.40 - 4.47 (m, 1H), 4.32 - 4.39 (m, 1H), 3.39 - 3.55 (m, 1H), 3.27 - 3.31 (m, 1H), 3.11 - 3.18 (m, 1H), 2.35 - 2.45 (m, 4H), 2.26 - 2.33 (m, 1H)
A purification of compound 41 was performed via chiral SFC (Stationary phase: CHIRALPAK AD-H 5mhi 250*21.2mm, Mobile phase: 70% C02, 30% EtOH (0.3% iPrNH2)). Pure fractions were collected and evaporated affording FI, 0.062 g and F2,
0.061 g.
FI was triturated with DIPE and a few Heptane, the precipitate was filtered off and dried under vacuum at 60°C affording compound 47 as white powder, 0.056 g (40%).
1H NMR (500 MHz, DMSO-d6) δ ppm 10.84 (s, 1H), 7.54 (d, J=8,7 Hz, 2H), 7.38 (d, 1=8.1 Hz, 2H), 4.34 - 4.41 (m, 1H), 4.25 - 4.34 (m, 1H), 3.35 - 3.53 (m, 2H), 3.22 - 3.31 (m, 1H), 3.04 - 3.13 (m, 1H), 2.58 - 2.70 (m, 1H), 2.31 - 2.41 (m, 3H), 2.23 - 2.30 (m, 1H), 2.18 (s, 3H), 1.61 - 1.72 (m, 4H) F2 was triturated with DIPE and a few Heptane, the precipitate was filtered off and dried under vacuum at 60°C affording compound 48 as white powder, 0.056 g (40%).
1H NMR (500 MHz, DMSO-d6) δ ppm 10.84 (s, 1H), 7.54 (d, J=7.7 Hz, 2H), 7.38 (d, J=8.1 Hz, 2H), 4.34 - 4.41 (m, 1H), 4.26 - 4.33 (m, 1H), 3.35 - 3.54 (m, 2H), 3.23 - 3.31 (m, 1H), 3.04 - 3.11 (m, 1H), 2.58 - 2.71 (m, 1H), 2.32 - 2.41 (m, 3H), 2.23 - 2.30 (m, 1 H), 2.18 (s, 3H), 1.62 - 1.71 (m, 4H)
Preparation of intermediate AH- 1
A nitrogen mixture of ethyl 6-bromo-[ 1 ,2,4]triazolo[l,5-a]pyridine-2-carboxylate (CAS
5 [1427376-40-6], 1.00 g, 3.70 mmol), bis(pinacolato)diboron (1.13 g, 4.44 mmol), KOAc (0.908 g, 9.26 mmol) and Pd(dppf)Cl2 (0.271 g, 0.370 mmol) in 1,4-dioxane (18 mL) was stirred at 100 °C for 2.5 h, allowed to cool back to room temperature and concentrated to dryness under reduced pressure affording crude as a brown gum (4.84 g). A nitrogen purged mixture of this crude, 2-bromo-4-(trifluoromethyl)thiazole (CAS
10 [41731-39-9], 0.860 g, 3.71 mmol), K3P04.H20 (2.56 g, 11.1 mmol), Pd(dppf)Cl2 (271 mg, 0.371 mmol) in 1,4-dioxane (58.7 mL) and water (11.7 mL) was stirred at 100 °C for 18 h, then cooled to room temperature and filtered through Celite®. The filter cake was washed with CH2Cl2/MeOH (9: 1 mixture) and the filtrate was concentrated under reduced pressure and purified by flash chromatography on silica gel
15 (cyclohexane/EtOAc 100:0 to 50:50) and subsequent trituration with Et20 to afford AH-1 as a beige solid (428 mg, 34%).
Preparation of intermediate AH-2
A mixture of intermediate AH-1 (272 mg, 0.795 mmol) in EtOH (20 ml) and THF (20 mL) was stirred in a 100 ml Parr reactor vessel in the presence of 10 wt% palladium on
20 carbon (338 mg, 0.318 mmol) under hydrogen atmosphere (30 bar) at 60 °C for 16 h. Additional 10 wt% palladium on carbon (338 mg, 0.318 mmol) was added and hydrogenation (30 bar) was continued at 60 °C for 23 h. The reaction mixture was cooled to room temperature and filtered through a pad of Celite®. The filter cake was rinsed with a CH2Cl2/MeOH mixture (9: 1) and the filtrate was concentrated under
reduced pressure. The residue was purified by flash chromatography (cyclohexane/EtOAc from 90: 10 to 50:50) to afford AH-2 as a yellow oil (184 mg, 67%).
Preparation of intermediate AH-3 To a mixture of intermediate AH-2 (194 mg, 0.531 mmol) in THF ( 1.6 mL) and water (1.6 mL) was added LiOH.HaO (66.9 mg, 1.59 mmol) at room temperature. The resulting mixture was stirred under nitrogen atmosphere at room temperature for 2 h, then concentrated under reduced pressure and acidified with a 1 M aqueous HC1 solution (~5 ml, resulting in pH~l). The resulting solid was collected, washed with water and dried under vacuum to afford AH-3 as a white solid (126 mg, 75%).
Preparation of intermediate AH-4
To an nitrogen-purged mixture of intermediate AH-3 (126 mg, 0.396 mmol) in DMF (1.4 mL) was added HATU (181 mg, 0.475 mmol). The mixture was stirred for 5 minutes at room temperature before the addition of CAS [1196-28-7J (59.1 mg, 0.396 mmol) and DIPEA (138 pL, 0.792 mmol). The resulting mixture was stirred at room temperature for 16 h. Additional HATU (150 mg, 0.396 mmol) and DIPEA (138 pL, 0.792 mmol) were added and the mixture was stirred at 50 °C for 23 h, then poured at room temperature into water (15 ml). The precipitate was filtered on a glass frit, washed with water and purified by flash chromatography over silica gel (cyclohexane/EtOAc from 100:0 to 0: 100) to afford AH-4 as a white solid (60 mg, 34%).
Preparation of compound 20
An nitrogen-purged mixture of intermediate AH-4 (60.0 mg, 0.133 mmol) and NaOH (16.0 mg, 0.400 mmol) in 1,4-dioxane (2.5 mL) was stirred at 110 °C for 16 h, then cooled to room temperature, quenched with aqueous saturated NH4CI solution and water and extracted with CH2CI2. The combined organic layers were washed with brine, dried over ISfeSCL, filtered and concentrated under reduced pressure. The crude residue was combined with the one of a second analogous experiment (starting from 25.2 mg A3-IT-5) and purified by flash chromatography over silica gel (CHaCb/MeOH from 100:0 to 90: 10) to afford after vacuum-drying (60 °C, 48 h) to afford compound 20 as an off-white solid (50.0 mg, 61%).
1H NMR (400 MHz, DMSO-d6) δ ppm 11.60 (s, 1H), 8.53 (s, 1H), 8.10 (dd, dd, J = 8.1 Hz, 1.1 Hz, 1H), 7.92 (d, J = 8.3 Hz, 1H), 7.64-7.58 (m, 1H), 7.32-7.25 (m, 1H), 4.79 (dd, J = 12.6 Hz, 5.3 Hz, 1H), 4.57 (dd, J = 12.6 Hz, 8.9 Hz, 1H), 4.18-4.10 (m,
1H), 3.21-3.03 (m, 2H), ~2.5-2.29 (m, 5H including s, 3H at 2.35, overlapped with DMSO solvent peak).
Preparation of intermediate AI- 1
A mixture of intermediate AA-3 (5.00 g, 14.1 mmol), Et3N (3.91 ml, 28.2 mmol) and Pd(dppf)Cl2 (1.03 g, 1.41 mmol) in EtOH (200 ml) was stirred under CO (atmospheric pressure) at 80 °C for 18 h, then concentrated under reduced pressure. The residue was purified by flash chromatography over silica gel (CH2Cl2/MeOH from 100:0 to 90: 10), then triturated in acetone to afford after vacuum-drying AI- 1 as a pale brown solid (3.81 g, 78%).
Preparation of intermediate AI-2
A mixture of intermediate AI-1 (1.00 g, 2.87 mmol), EtOH (25 ml) and THF (25 ml) was stirred in a 100 ml Parr reactor vessel in the presence of 10 wt% palladium on carbon (611 mg, 0.574 mmol) under hydrogen atmosphere (30 bar) at 60 °C for 10 h. The reaction mixture was diluted at room temperature with CH2CI2/Me011 (9: 1 mixture) and filtered through a pad of Celite® and washed with (Ί ECb/MeOH (9:1 mixture) and the filtrate was concentrated under reduced pressure. Purification by flash chromatography on silica gel (CH2Cl2/MeOH from 100:0 to 90: 10) afforded AI-2 (638 mg, 63%) as white solid.
Preparation of compound 12
A mixture of intermediate AI-2 (100 mg, 0.284 mmol) and 33 wt% MeNH2 in EtOH (5 ml) was stirred at 80 °C for 6.5 h under nitrogen atmosphere, then concentrated under reduced pressure. The residue was triturated with hot MeOH (3 times, supernatant
removed each time after cooling back to room temperature) affording compound 12 after vacuum-drying (60 °C, 18 h) as a white solid (75 mg, 78%).
1H NMR (400 MHz, DMSO-d6) δ ppm 11.55 (s, 1H), 8.15-8.05 (m, 2H), 7.91 (d, J = 8.4 Hz, 1H), 7.64-7.57 (m, 1H), 7.31-7.25 (m, 1H), 4.41 (dd, J = 12.8 Hz, 5.6 Hz, 1H), 4.32 (dd, J = 12.8 Hz, 8.1 Hz, 1H), 3.11-2.90 (m, 3H), 2.64 (d, J = 4.5 Hz, 3H), 2.34 (s,
3H), 2.26-2.16 (m, lH), 2.15-2.04 (m, 1H).
In accordance with the procedures described herein, including the procedures to prepare reference Compound 12, the following compound was prepared:
Synthesis of compound AE-5, compound 36, compound 43 and compound 44
Preparation of intermediate AE- 1
To a solution of 3-amino-2-cyano-thiophene (CAS [56489-05-5], 500 mg, 4.03 mmol) in THF (20 mL) was added a 1 M solution of ethylmagnesium bromide in THF (12.1 mL, 12.1 mmol) dropwise at 0 °C. The resulting mixture was stirred at 0 °C for 0.5 h, then allowed to warm to room temperature and stirred at 60 °C for 14 h. The reaction mixture was cooled to room temperature, quenched slowly with a 3 M HC1 aqueous solution (to pJT~l) and diluted with water. The resulting mixture was extracted with CH2CI2 and the combined organic layers were washed with brine, dried over Na2SO4. filtered and concentrated under reduced pressure. The residue was purified by flash chromatography over silica gel (PF-15SIHP, cyclohexane/EtOAc from 100:0 to 84: 16) and re-purified by flash chromatography over silica gel (1R-50S1, cyclohexane/EtOAc from 100:0 to 84:16) to afford intermediate AE-1 as an orange solid (155 mg, 25%).
Preparation of intermediate AE-2
A mixture of ethyl 6-bromo-[l,2,4]triazolo[l,5-a]pyridine-2-carboxylate (CAS [1427376-40-6], 500 mg, 1.85 mmol), 4-(trifluoromethoxy)phenylboronic acid (CAS
[139301-27-2], 572 mg, 2.78 mmol) and NaHCCE (467 mg, 5.55 mmol) in a mixture of 1,4-dioxane (10 mL) and water (2.5 mL) was purged with nitrogen. Pd(dppf)Ck (136 mg, 0.185 mmol) was added and the resulting mixture was purged again with nitrogen and stirred at 80 °C for 1.5 h. The reaction mixture was diluted at room temperature with CH2CI2 and filtered through Celite®. The filter cake was rinsed with a
Cl LCf/EtOAc mixture (1: 1) and the filtrate was concentrated to dryness. The residue was purified by flash chromatography over silica gel (IR-50SI, cyclohexane/EtOAc from 100:0 to 30:70) and re-purified by flash chromatography over silica gel (1R-50SI. cyclohexane/EtOAc from 90: 10 to 20:80) affording intermediate AE-2 as a white solid (532 mg, 82%).
Preparation of intermediate AE-3
A mixture of AE-2 (382 mg, 1.09 mmol), EtOH (12 mL) and THF (12 mL) was stirred in a 100 mL Parr reactor vessel in the presence of 10 wt% palladium on carbon (231 mg, 0.217 mmol) under hydrogen atmosphere (30 bar) at 60 °C for 4 h. The reaction mixture was diluted at room temperature with EtOAc and filtered through a pad of Celite®. The filter cake was rinsed with EtOAc and the filtrate was concentrated to dryness to afford intermediate AE-3 as a beige solid (386 mg, quantitative) which was used as such.
Preparation of intermediate AE-4
To a mixture of intermediate AE-3 (464 mg, 1.31 mmol), THF (4.5 mL) and water (4.5 mL) was added LiOH.H2O (110 mg, 2.62 mmol). The resulting mixture was stirred at room temperature for 6 h and then acidified with 1 M HC1 aqueous solution until pH- 1-2. The resulting precipitate was collected by filtration on a glass frit and washed with water, then dissolved in a CH2C12/MeOH mixture (9: 1), dried over Na2SO4 , filtered and concentrated to dryness to afford intermediate AE-4 as a white solid (394 mg, 92%).
Preparation of intermediate AE-5 To a suspension of AE-4 (360 mg, 1.10 mmol) in CH2CI2 (10 mL) were added DMF (3 drops) and oxalyl chloride (0.186 mL, 2.20 mmol) at 0 °C under nitrogen atmosphere. The reaction mixture was stirred at 0 °C for 0.5 h, then allowed to warm to room temperature and stirred for 2 h and concentrated to dryness. To a solution of the resulting residue (crude acyl chloride intermediate) in 1,4-dioxane (5 mL) was added dropwise a solution of AE-1 (195 mg, 1.26 mmol) in 1,4-dioxane (5 mL) at room temperature under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 16 h and concentrated to dryness. The resulting residue was partitioned between CH2CI2 and water and the layers were separated. The aqueous layer was extracted with CH2CI2 and the combined organic layers were washed with brine, dried over Na2SC>4, filtered and concentrated to dryness. Purification by flash chromatography over silica gel (IR-50SI, cyclohexane/EtOAc from 95:5 to 0: 100) afforded intermediate AE-5 as a beige solid (444 mg, 87%).
Preparation of compound 36
To a solution of AE-5 (165 mg, 0.355 mmol) in 1,2-dichloroethane (7 mL) were added successively Et3,N (0.208 mL, 1.49 mmol) and TMSOTf (0.450 mL, 2.49 mmol) at room temperature under nitrogen atmosphere. The resulting solution was stirred at 95 °C for 22 h and then cooled to room temperature. Additional Et3N (59.4 pL, 0.426 mmol) and TMSOTf (0.129 mL, 0.711 mmol) were introduced and the resulting mixture was stirred at 95 °C for 8 h. The mixture was quenched by slow addition of MeOH at room temperature and then concentrated to dryness. The resulting residue was taken in EtOAc and washed successively with a saturated NaHCOi aqueous solution and brine. The organic layer was dried over Na2SOi, filtered and concentrated to dryness. The residue was purified by flash chromatography over silica gel (IR-50SI, CtbCb/MeOH from 100:0 to 95:5) to afford after trituration with Et:0. co-evaporation with MeOH, and vacuum-drying (60 °C, 20 h) compound 36 as a beige solid (110 mg, 69 %).
1H NMR (400 MHz, DMS04) d ppm 12.32 (s, 1H), 7.92 (d, J = 5.4 Hz, 1H), 7.60- 7.54 (m, 2H), 7.43-7.37 (m, 3H), 4.55 (dd, J= 12.5 Hz, 5.3 Hz, 1H), 4.33 (t../ = 1 1.7 Hz, 1H), 3.61-3.50 (m, 1H), 3.17-3.02 (m, 2H), 2.37 (s, 3H), 2.31-2.16 (m, 2H).
A purification of compound 36 was performed via chiral SFC (Stationary phase: CHIRACEL OJ-H 5μm 250*20mm, Mobile phase: 90% C02, 10% MeOH (0.3% iPrNH2)). Pure fractions were collected and evaporated affording FI, 0.04 g and F2, 0.042g. Acetonitrile (2 mL) was added to FI, then extended with water (8 mL), the solution was freeze-dried overnight affording compound 43 as white powder, 0.036 g (37%).
1H NMR (500 MHz, CHLOROFORM-d) 5 ppm 9.92 (br s, 1H), 7.58 (d, J=5.3 Hz,
1H), 7.23 - 7.29 (m, 2H), 7. 18 - 7.21 (m, 2H, partially obscured by solvent peak), 7.03 (d, J=5.3 Hz, 1H), 4.50 (dd, J=13.0, 5.3 Hz, 1H), 4.12 - 4.19 (m, 1H), 3.37 (tdd, J=11.0, 11.0, 5.4, 2.7 Hz, 1H), 3.08 - 3.15 (m, 1H), 2.98 (ddd, J=17.4, 11.1, 6.0 Hz, 1H), 2.54
(s, 3H), 2.28 - 2.35 (m, 1H), 2.09 - 2.22 (m, lH)
Acetonitrile (2 mL) was added to F2, then extended with water (8 mL), the solution was freeze-dried overnight affording compound 44 as white powder, 0.04 g (41%).
1H NMR (500 MHz, CHLOROFORM-d) δ ppm 9.92 (br s, 1H), 7.58 (d, J=5.3 Hz, 1H), 7.23 - 7.28 (m, 2H), 7.18 - 7.21 (m, 2H, partially obscured by solvent peak), 7.03
(d, 1=5.5 Hz, 1H), 4.51 (dd, J= 13.0. 5.3 Hz, 1H), 4.12 - 4.20 (m, 1H), 3.37 (tdd. J= 1 1.0, 11.0, 5.4, 2.7 Hz, 1H), 3.08 - 3.15 (m, 1H), 2.98 (ddd, J=17.4, 11.1, 6.0 Hz, 1H), 2.55 (s, 3H), 2.28 - 2.35 (m, 1H), 2.09 - 2.24 (m, 1H)
Synthesis of compound 71 & compound 72
Preparation of intermediate AF-1
To a solution of 2-aminopropiophenone (CAS [1196-28-7], 124 mg, 0.830 mmol) and 6-Bromopyrazolo[l,5-a]pyridine-2-carboxylic acid (CAS [876379-74-7], 200 mg,
0.830 mmol) in DMF (1.6 mL) were added HATU (379 mg, 0.996 mmol) and DIPEA (0.289 mL, 1.66 mmol). The resulting mixture was stirred at room temperature for 18 h under nitrogen atmosphere. Additional DMF (1 mL) was added and the suspension was further stirred for 2 h at room temperature before addition of THF (1 mL) at 50 °C. The resulting mixture was stirred at 50 °C for 30 h, then added dropwise into water (20 mL). The precipitate was filtered on a glass frit, washed with water and vacuum dried (50 °C, 3 h) affording AF-1 as a brown solid (250 mg, 81%).
Preparation of intermediate AF-2
To nitrogen-purged mixture of AF-1 (240 mg, 0.645 mmol) and 1,4-dioxane (12 mL) was added NaOH (77.4 mg, 1.93 mmol). The resulting mixture was stirred at 110 °C for 5 h, then cooled to room temperature and diluted with saturated aqueous NaHCCL solution. The resulting solid was filtered on a glass frit, washed with water and dried under vacuum (40 °C, 2 h) affording AF-2 as a white solid (191 mg, 84%).
Preparation of compound AF-3
To an nitrogen-purged mixture of AF-2 (191 mg, 0.539 mmol), 4- trifluoromethoxyphenylboronic acid (CAS [139301-27-2], 133 mg, 0.647 mmol) and K3PO4.H2O (373 mg, 1.62 mmol) in 1,4-dioxane (2.4 niL) and water (0.6 mL) was added Pd(dppf)Cl2 (39.5 mg, 0.054 mmol). The resulting mixture was stirred at 100 °C for 16 h, then allowed to cool back to room temperature. Water was added and the precipitate was filtered on a glass frit, then purified by flash chromatography on silica gel (IR-50SI, CH2Cl2/MeOH from 100:0 to 95:5) affording AF-3 as a beige solid (190 mg, 81%). Preparation of compound 71 & compound 72
A mixture of AF-3 (180 mg, 0.413 mmol) in EtOH (10 mL) and THF (10 mL) was stirred in a 100 mL Parr reactor vessel in the presence of 10 wt% palladium on carbon (88.0 mg, 0.083 mmol) under hydrogen atmosphere (30 bar) at 60 °C for 3 h, then cooled to room temperature, diluted with CH2CI2 and filtered through a pad of Celite®. The filter cake was rinsed with CH2Q2 and the filtrate was concentrated to dryness affording a yellow solid. A mixture of this solid in EtOH (10 mL) and THF (10 mL) was further stirred in a 100 mL Parr reactor vessel in the presence of fresh 10 wt% palladium on carbon (88.0 mg, 0.083 mmol ) under hydrogen atmosphere (30 bar) at 60 °C for additional 16 h, then cooled to room temperature, diluted with CH2CI2 and filtered through a pad of Celite®. The filter cake was rinsed with CH2CI2 and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography over silica gel (PF-15SIHP CHiCb/MeOH from 100:0 to 95:5) to afford after trituration with Et20 and vacuum-drying (60 °C, 65 h) compound 72 as a white solid (68 mg, 37%). Vacuum-drying (60 °C, 65 h) of the other desired fraction afforded compound 71 as a white solid (59 mg, 32%).
Compound 72
1H NMR (400 MHz, DMSO-d6) δ ppm 11.37 (s, 1H), 8.09 (dd, J = 8.1 Hz, 1.2 Hz,
1H), 7.79 (d, 1 = 8.1 Hz, 1H), 7.62-7.54 (m, 3H), 7.39 (d, J = 7.9 Hz, 2H), 7.30-7.23 (m, 1H), 6.60 (s, 1H), 4.51 (dd, J = 12.5 Hz, 5.1 Hz, 1H), 4.24 (t, J = 11.8 Hz, 1H), 3.53-3.42 (m, 1H), 3.10-2.90 (m, 2H), 2.21-2.08 (m, 5H including s, 3H at 2.17).
Compound 71
1H NMR (400 MHz, DMSO-d6) δ ppm 10.61 (s, 1H), 7.58-7.51 (m, 2H), 7.37 (d, J = 8.0 Hz, 2H), 6.42 (s, HI). 4.44 (dd, J = 12.5 Hz, 5.1 Hz, 1H), 4.16 (t, J = 11.8 Hz, 1H), 3.48-3.38 (m, 1H), 3.06-2.85 (m, 2H), 2.62-2.56 (m, 2H), 2.35-2.28 (m, 2H), 2.16-2.04 (m, 2H), 1.99 (s, 3H), 1.72-1.58 (m, 4H).
Svnthesis of compound 32 & compound 33
The reaction was performed in anhydrous conditions, under N2-atmosphere. To a 5 solution of 5-bromo- 1 ,2-diaminopyridinium 2,4,6-trimethylbenzenesulfonate (CAS [1202704-57-1], 8.94 g, 23.0 mmol) in «-butanol (90 mL) were successively added triethylamine (9.63 mL, 69.1 mmol) and Ethyl4-hydroxyquinoline-2-carboxylate (CAS [24782-43-2], 5,00 g, 23.0 mmol). The resulting mixture was stirred at 100 °C for 20 h. The reaction mixture was concentrated under reduced pressure then the crude solid was0 triturated with methanol (3 x 15 mL). The resulting precipitate was dried in vacuo for 4 h at 50 °C to afford AG-1 as a beige solid, 6.3 g (80%).
Preparation of intermediate AG-2
A mixture of intermediate AG-1 (2.50 g, 7.33 mmol), 4-
Trifluoromethoxyphenylboronic acid (CAS [139301-27-2], 1.81 g, 8,79 mmol) and 5 Potassium phosphatetribasic monohydrate (5.06 g, 22.0 mmol) in 1,4-dioxane (29.6 mL) and water (7.4 mL) was purged with nitrogen, 1,1'-
Bis(diphenylphosphino)ferrocene dichloropalladium (II) (536 mg, 0.733 mmol) was added and the resulting mixture was purged again with nitrogen and stirred at 100 °C for 20 h. The reaction mixture was concentrated to dryness then, water (50 mL) was 0 added, the suspension was sonicated, and the precipitate was collected by filtration on a glass frit and washed with water (2 x 15 mL). The precipitate was triturated with
MeOH (2 x 20 mL) and collected by filtration on a glass frit then dried in vacuo for 15 h at 50 °C to afford AG-2 as a beige solid, 2.32 g (75%).
Preparation of intermediate AG-3
To a suspension of intermediate AG-2 (2.30 g, 5.45 mmol) in DMF (62 mL) was added N-Bromosuccinimide (0.969 g, 5.45 mmol) at room temperature, under Na-atmosphere. The resulting mixture was stirred for 20 h at room temperature, then water (20 mL) was added. The resulting precipitate was filtered on a glass frit and washed with water (2 x 30 mL), then dried in vacuo for 20 h at 60°C, to afford AG-3 as a yellow solid, 2.5 g (92%).
Preparation of intermediate AG-4
A solution of intermediate AG-3 (500 mg, 0.997 mmol) and Tetrakis (triphenylphosphine)palladium (0) (115 mg, 0.100 mmol) in DMF (10 mL) was purged with nitrogen. Tributyl(vinyl)tin (0.350 mL, 1.20 mmol) was added and the resulting mixture was purged again with nitrogen and stirred at 80 °C for 6 h. The mixture was concentrated under reduced pressure and followed by addition of water (15 mL). The suspension was sonicated, the supernatant was removed, and the resulting precipitate was extracted with DCM (2 x 20 mL). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to give 0.4 g as crude. This was purified by flash chromatography over silica gel (IR-50SI/F0040, DCM / EtOAc from 100/0 to 90/10) to give 0.205 g as a yellow solid. This solid was triturated with diethyl ether (2 x 10 mL), the resulting solid was collected on a glass frit to give after vacuum drying at 60°C for 16h giving AG-4 as a yellow solid, 0.19 g (43%).
Preparation of compound 32 & compound 33
An nitrogen-purged mixture of intermediate AG-4 (252 mg, 0.562 mmol) in Ethanol ( 10 mL) and THF (10 mL) was hydrogenated (with ¾) in the presence of 10 wt% palladium on carbon (120 mg, 0.1 12 mmol, 0.2 eq.) in a 100 mL PAAR vessel at 30 bar and 60 °C under stirring for 4 h. The reaction mixture was cooled to room temperature and purged with nitrogen before the addition of 10 wt% palladium on carbon (120 mg, 0.112 mmol, 0.2 eq.). The reaction mixture was hydrogenated (with C) at 30 bar and 60 °C under stirring for 4.5 h. The reaction mixture was cooled to room temperature and filtered on celite® and washed with a DCM/EtOH mixture (9: 1, 200 mL) to afford a yellow oil, 0.29 g. It was purified by flash chromatography over silica gel (DCM/MeOH from 100/0 to 95/5 over 40 min.). The desired fractions were concentrated under reduced pressure and the resulting solids were vacuum-dried at 60
°C for 20 h to afford compound 32 (0.084 g, 33%) as a yellow solid and compound 34 (0.044 g, 17%) as a yellowish solid.
Compound 32
1H NMR (400 MHz, DMSO-d6) δ ppm 11.56 (s, 1H), 8.10 (dd, J = 8.2 Hz, 0.9 Hz, 1H), 7.90 (d, J = 8.4 Hz, 1H), 7.64-7.55 (m, 3H), 7.40 (d, J = 8.1 Hz, 2H), 7.31-7.25
(m, 1H), 4.56 (dd, J = 12.5 Hz, 5.2 Hz, 1H), 4.35 (t, J = 11.7 Hz, 1H), 3.62-3.51 (m, 1H), 3.19-3.03 (m, 2H), 2.94 (q, J = 7.2 Hz, 2H), 2.35-2.17 (m, 2H), 1.07 (t, J = 7.2 Hz, 3H).
Compound 33 1H NMR (400 MHz, DMSO-d6) δ ppm 10.75 (s, 1H), 7.59-7.53 (m, 2H), 7.38 (d, J = 8.2 Hz, 2H), 4.50 (dd, J = 12.5 Hz, 5.4 Hz, 1H), 4.28 (t, J = 11.7 Hz, 1H), 3.57-3.47 (m, 1H), 3.13-2.97 (m, 2H), 2.75 (q, J = 7.2 Hz, 2H), 2.65-2.59 (m, 2H), 2.36-2.13 (m, 4H), 1.72-1.59 (m, 4H), 0.98 (t, J = 7.2 Hz, 3H).
The following compounds are/were also prepared in accordance with the methods described herein:
5
Experimental - Further characterising Data
Table: LCMS methods used for final products (Flow expressed in mL/min; column temperature (T) in °C; Run time in minutes).
The High Performance Liquid Chromatography (HPLC) measurement was performed using a LC pump, a diode-array (DAD) or a UV detector and a column as specified in the respective methods. If necessary, additional detectors were included (see table of methods below).
Flow from the column was brought to the Mass Spectrometer (MS) which was configured with an atmospheric pressure ion source. It is within the knowledge of the skilled person to set the tune parameters (e.g. scanning range, dwell time...) in order to obtain ions allowing the identification of the compound’s nominal monoisotopic molecular weight (MW). Data acquisition was performed with appropriate software.
Compounds are described by their experimental retention times (Rt) and ions. If not specified differently in the table of data, the reported molecular ion corresponds to the [M+H]+ (protonated molecule) and/or [M-H] (deprotonated molecule). In case the compound was not directly ionizable the type of adduct is specified (i.e. IM+NIHG- [M+HCOOr, etc...). For molecules with multiple isotopic patterns (Br, Cl..), the
reported value is the one obtained for the lowest isotope mass. All results were obtained with experimental uncertainties that are commonly associated with the method used.
Hereinafter, “SQD” means Single Quadrupole Detector, “RT” room temperature, “BEH” bridged ethylsiloxane/silica hybrid, “HSS” High Strength Silica, “DAD” Diode Array Detector.
Reactions were in general carried out in anhydrous solvents under argon atmosphere if no other gas atmosphere was required.
NMR was carried out on a Bruker 400 MHz spectrometer or 500 MHz spectrometer.
Melting points were determined by DSC on a Mettler-Toledo DSC1 instrument (using aluminum standard 40 pL pans with air as purge gas and a thermal gradient between - 10 °C and 350 °C) or on a melting point apparatus Buchi M-560, both applying indicated heating rates.
For flash chromatography, in general the following stationary phases were used: Interchim Silica gel IR-50SI (irregular, 50 μm), Interchim silica gel PF-15S1HP (spherical, 15 μm), Interchim C 18-reversed silica gel IR-50C18 (irregular, 50 μm) or Buchi FlashPure silica gel (irregular, 50 μm).
Characterising Data
Pharmacological Examples
In the tests described below, individual compounds of the invention/examples (or combinations containing such compounds, for instance cytochrome bd inhibitors of the invention/examples in combination with one or more other inhibitor(s) of a (different) target of the electron transport chain of mycobacteria, as described herein) may be
tested. For instance, in Tests 1 to 4, combinations may be tested (e.g. combinations of test cytochrome bd compounds with known cytochrome be inhibitors, such as Q203 and Compound X). Where a control cytochrome bd compound is employed, then CK- 2-63 is employed.
The compound Q203 (cytochrome bcl inhibitor) may be prepared in accordance with the procedures in J. Medicinal Chemistry, 2014, 57 (12), pp 5293-5305, as well as, in WO 2011/113606 (see Compound 289 “6-chloro-2-ethyl-/V-(4-(4-(4- (trifluoromethoxy)phenyl)piperidin-l-yl)benzyl)imidazo[l,2-a]pyridine-3- carboxamide”).
Compound X is 6-chloro-2-ethyl-/V-({4-[2-(trifluoromethanesulfonyl)-2- azaspiro[3.3]heptan-6-yl]phenyl}methyl)imidazo[ 1 ,2-a]pyridine-3-carboxamide, which is described as Compound 154 of WO 2017/001660 and may be prepared according to the procedures described therein.
CK-2-63 may be prepared in accordance with the procedures disclosed in WO 2017/103615 (see experimental and the disclosures therein, referring to WO 2012/2069856, where an experimental procedure is provided for “3-methyl-2-(4-(4- (trifluoromethoxy)phenoxy)phenyl)quinolin-4(lH)-one”).
MIC determination against M. tuberculosis·, test 1
Test compounds and reference compounds were dissolved in DMSO and 1 mΐ of solution was spotted per well in 96 well plates at 200x the final concentration. Column 1 and column 12 were left compound-free, and from column 2 to 11 compound concentration was diluted 3-fold. Frozen stocks of Mycobacterium tuberculosis strain EH4.0 expressing green-fluorescent protein (GFP) were previously prepared and titrated. To prepare the inoculum, 1 vial of frozen bacterial stock was thawed to room temperature and diluted to 5x10 exp5 colony forming units per ml in 7H9 broth. 200 mΐ of inoculum, which corresponds to 1x10 exp5 colony forming units, were transferred per well to the whole plate, except column 12. 200m17H9 broth were transferred to wells of column 12. Plates were incubated at 37°C in plastic bags to prevent evaporation. After 7 days, fluorescence was measured on a Gemini EM Microplate Reader with 485 excitation and 538 nm emission wavelengths and IC50 and/or pICso values (or the like, e.g. IC50, IC90, rK¾o, etc) were (or may be) calculated.
MIC determination against M. tuberculosis : test 2
Appropriate solutions of experimental and reference compounds were made in 96 well plates with 7H9 medium. Samples of Mycobacterium tuberculosis strain H37Rv were taken from cultures in logarithmic growth phase. These were first diluted to obtain an optical density of 0.3 at 600 nm wavelength and then diluted 1/100, resulting in an inoculum of approximately 5x10 exp5 colony forming units per ml. IOOmI of inoculum, which corresponds to 5x10 exp4 colony forming units, wer transferred per well to the whole plate, except column 12. Plates were incubated at 37°C in plastic bags to prevent evaporation. After 7 days, resazurin was added to all wells. Two days later, fluorescence was measured on a Gemini EM Microplate Reader with 543 excitation and 590 nm emission wavelengths and MIC50 and/or pICso values (or the like, e.g. IC50, IC90, rK¾o, etc) were (or may be) calculated.
Time kill kinetics assays: test 3 Bactericidal or bacteriostatic activity of the compounds can be determined in a time kill kinetic assay using the broth dilution method. In this assay, the starting inoculum of M. tuberculosis (strain H37Rv and H37Ra) is 106 CFU / ml in Middlebrook (lx) 7H9 broth. The test compounds (cyt bd inhibitors) are tested in combination with a cyt be inhibitor (for example Q203 or Compound X) at the concentration ranging from 10- 30mM to 0.9-0.3mM respectively. Tubes receiving no antibacterial agent constitute the culture growth control. The tubes containing the microorganism and the test compounds are incubated at 37 °C. After 0, 1, 4, 7, 14 and 21 days of incubation samples are removed for determination of viable counts by serial dilution (10° to 10~6) in Middlebrook 7H9 medium and plating (100 mΐ) on Middlebrook 7H11 agar. The plates are incubated at 37 °C for 21 days and the number of colonies are determined. Killing curves can be constructed by plotting the logioCFU per ml versus time. A bactericidal effect of a cytochrome be and cytochrome bd inhibitor (either alone or in combinaton) is commonly defined as 2-log 10 decrease (decrease in CFU per ml) compared to Day 0. The potential carryover effect of the drugs is limited by using 0.4% charcoal in the agar plates, and by serial dilutions and counting the colonies at highest dilution possible used for plating.
Phenotypic assay to determine the O2 consumption rate of Mycobacterium tuberculosis : test 4 The aim of this assay is to evaluate the O2 consumption rate of Mycobacterium tuberculosis (Mtb) bacilli after inhibition of cyt be 1 and cyt bd, using extracellular flux technology. Inhibition of cyt bcl (e.g. using known inhibitors such as Q203 or Compound X) forces the bacillus to use the less energetically efficient terminal oxidase
cyt bd. The inhibition of cyt bd will cause a significant decrease O2 consumption. A sustained decrease of O2 consumption under membrane potential disrupting conditions, via the addition of the uncoupler CCCP, will show to the efficacy of the cyt bd inhibitor.
The oxygen consumption rate (OCR) of Mtb (stain H37Ra) bacilli adhered to the bottom of a Cell-Tak (BD Biosciences) coated XF cell culture microplate (Agilent), at 5x 106 bacilli per well, was measured using the Agilent Seahorse XFe96. Prior to the assay Mtb bacilli are cultured for two days to an OD600 -0.7-0.9 in liquid medium, using 7H9 supplemented with 10% and 0,02% Tyloxapol. The assay media used is unbuffered 7H9 only supplemented with 0.2% glucose. For this assay the Compound X (final concentration of 0.9 mM, Compound X), is used to inhibit cyt bcl and the cyt bd inhibitor, CK-2-63 (final concentration of 10 mM), is used as a positive control. The uncoupler CCCP is used at a final concentration of 1 mM.
In general, four basal OCR measurements are taken before the automatic addition of Compound X, through drug port A of the sensor cartridge, after which seven more OCR measurements are taken to allow enough time for the inhibition of cyt bcl. Next the cyt bd test compounds (final concentration of 10 mM), as well as the positive and negative controls (assay media with a final DMSO concentration of 0.4%), are added (drug port B) followed by seven OCR measurements. Finally, CCCP is added followed by three OCR measurements, this is done twice (drug ports C and D). For the control’s measurements are performed in eight replicate wells and for the assay compounds six replicate wells per condition. Compounds are scored for their sustained inhibition of cyt bd in relation to the positive and negative controls.
Further Phenotypic assay: using a cytochrome be knock-out TB strain and MIC determination against M. tuberculosis·, test 5
Appropriate solutions of experimental and reference compounds were made in 384 well plates with 7H9 medium. Samples of Mycobacterium tuberculosis strain H37Rv ActaE- AqcrCAB (Nat Common 10, 4970. 2019. https://doi.org/10.1038/s41467-Q19-12956-2) were taken from cultures in logarithmic growth phase. These were first diluted to obtain an optical density of 0.4 at 600 nm wavelength and then diluted 1/150, resulting in an inoculum of approximately 5x10 exp5 colony forming units per ml. 30m1 of inoculum, which corresponds to 5x10 exp5 colony forming units, were transferred per well to the whole plate, except columns 23-24. Plates were incubated at 37°C, in an extra humidified incubator, in plastic bags to prevent evaporation. After 10 days, optical density at 620 nm wavelength was measured on an EnVision 2105 Multimode Plate Reader with a Photometric 620/8 excitation filter, and MIC50 and/or pICso values (or the like, e.g. IC50, IC90, PIC90, etc) were (or may be) calculated.
Further Phenotypic assay: using a cytochrome be knock-out TB strain and MIC determination against M. tuberculosis,· test 6
Appropriate solutions of experimental and reference compounds were made in 384 well plates with 7H9 medium. Samples of Mycobacterium tuberculosis strain H37Rv ActaE- AqcrCAB ( Nat Commun 10. 4970. 2019. https://doi.org/10.1038/s41467-019- 12956-2) were taken from frozen stock (titer of 8.83c10L6). The stock is diluted to get an inoculum of 5c10L5 colony forming units per ml. 30m1 of inoculum, which corresponds to 5x 10 exp5 colony forming units, were transferred per well to the whole plate, except the first 2 and the last 2 columns and the first 2 and the last 2 rows. These wells are filled with media to avoid evaporation. Plates were incubated at 37°C, in an extra humidified incubator, in plastic bags to prevent evaporation. After 10 days, optical density at 620 nm wavelength was measured on an EnVision 2105 Multimode Plate Reader with a Photometric 620/8 excitation filter, and MIC50 and/or pICso values (or the like, e.g. IC50, IC90, pICgo, etc) were (or may be) calculated.
Pharmacological Results
Biological Data - Example A Compounds of the invention/examples (or combinations, e.g. compounds of the invention/examples in combination with one or more other inhibitors of a target of the electron transport chain), for example when tested in any of Tests 1 to 3, may display activity. Biological Data - Example B
Compounds of the examples were tested in Test 4 described above (in section “Pharmacological Examples”; O2 consumption rate testing), together with Compound X - a known cytochrome be inhibitor - as described above, and the following results were obtained:
Biological Data - Example C
Compounds of the examples are tested in Test 3 (the kill kinetics) described above, obtaining results expressed as a log reduction in CFUs per ml as compared to Day 0.
Biological Data - Example D
Compounds of the examples are/were re-tested in Test 5 and/or Test 6 described above. The following results were obtained in Test 5
The following result was obtained in Test 6: compound 6 had a rK¼o of 6.116
Further Data
The compounds of the invention/examples may have advantages associated with in vitro potency, kill kinetics (i.e. bactericidal effect) in vitro, PK properties, food effect, safety/toxicity (including liver toxicity, coagulation, 5-LO oxygenase), metabolic stability, Ames II negativity, MNT negativity, aqueous based solubility (and ability to formulate) and/or cardiovascular effect e.g. on animals (e.g. anesthetized guinea pig). The data below that was generated/calculated may be obtained using standard methods/assays, for instance that are available in the literature or which may be performed by a supplier (e.g. Microsomal Stability Assay - Cyprotex, Mitochondrial toxicity (Glu/Gal) assay - Cyprotex, as well as literature CYP cocktail inhibition assays).
In the table above, “negative” means that in the test, it was found to have low mitotoxicity (and hence no mitotoxicity alerts), “positive” means that there were some mitotoxicity alerts and “inconclusive” means that no accurate conclusion could be drawn, e.g. due to issues with the compound being tested in the assay, e.g. solubility or precipitation issues (e.g. compound may not be soluble enough or may precipitate).
In view of the data above, compounds of the invention/examples may be found to be advantageous as no mitotoxicity alerts were observed (e.g. in the Glu/Gal assay).
Claims
R1 represents C1-6 alkyl, -Br, hydrogen or -C(0)N(Rq,)Rq2;
Rql and Rq2 independently represent hydrogen or Ci-6 alkyl, or may be linked together to form a 3-6 membered carboeylic ring optionally substituted by one or more C1-3 alkyl substituents;
Sub represents one or more optional substituents selected from halo (e.g. fluoro), -CN, Ci -6 alkyl and -O-Ci-6 alkyl (wherein the latter two alkyl moieties are optionally substituted by one or more fluoro atoms); the “A” ring represents a 6-membered ring which may be aromatic or non-aromatic, or it represents a 5 -membered aromatic ring containing one heteroatom; the “B” ring represents a 5-membered heteroaryl ring, which contains between one and four heteroatoms (e.g. selected from nitrogen, oxygen and sulfur), and which “B” ring is optionally substituted by one or more substituents selected from halo and Ci-6 alkyl (itself optionally substituted by one or more fluoro atoms); L1 represents an optional linker group, and hence may be a direct bond, -O- or -C(Rxl)(Rx2)-;
Rxl and Rx2 independently represent hydrogen or C 1-3 alkyl; Z1 represents any one of the following moieties:
(i)
ring C represents a 5-membered aromatic ring containing at least one heteroatom (preferably containing at least one nitrogen atom), and which ring is optionally substituted by one or more substituents independently selected from Rf; ring D represents a 6-membered aromatic ring containing at least one heteroatom (preferably containing at least one nitrogen atom), and which ring is optionally substituted by one or more substituents independently selected from Rg;
Yh represents —[(CH2) i ; ]- (so forming a 3- to 6-membered N-containing ring), and Rh represents one or more optional substituents on such ring;
Ra, Rb, Re, Rd and Re independently represent hydrogen or a substituent selected from B1; each Rf, each Rg and each Rh (which are optional substituents), when present, independently represent a substituent selected from B1; each B1 independently represents a substituent selected from:
(i) halo;
(ii) -Rdl;
(iii) -ORel;
(iv) -C(0)N(Re2)Re3
(v) -SFs;
(vi) -N(Re4)S(0)2Re5; Rdl represents C1-6 alkyl, preferably C1-3 alkyl, optionally substituted by one or more halo (e.g. fluoro) atoms;
Rcl, Rc2, Re3, Re4 and Re5each independently represent hydrogen or C1-6 alkyl optionally substituted by one or more fluoro atoms; or a pharmaceutically-acceptable salt thereof.
2. A compound as claimed in Claim 1, wherein R1 represents C1-3 alkyl such as methyl.
3. A compound as claimed in Claim 1 which is represented as follows:
4. A compound as claimed in any of the preceding claims, wherein the “B” ring and adjacent 6 membered non-aromatic ring in compounds of the invention may be depicted as follows in sub formula (II) (in which the left hand side would be further bound to the requisite quinolinone, or tetrahydro-quinolinone, of formula (I) and the right hand side would be further bound to the L1 group of formula (I)):
wherein: one of X1 and X2 represents N (i.e. there is an essential nitrogen at the ring junction) and the other represents C; the other integers X3, X4 and X5 may represent C (or CH) or a heteroatom (such as N,
O and/or S); and/or none, any one or two of X3, X4 and X5 represents a heteroatom (e.g. N, O and/or S) and the other represents C (or CH).
5. A compound as claimed in any of the preceding claims wherein:
L1 represents a direct bond or -C(RX | )(Rx2)-;
Rxl and Rx2 independently represent hydrogen.
6. A compound as claimed in any one of the preceding claims, wherein: none, but preferably, one or two (e.g. one) of Ra, Rb, Rc, Rd and Rc represents B1 and the others represent hydrogen; and/or one of Rb Rc and Rd (preferably Rc) represents B 1 and the others represent hydrogen.
7. A compound as claimed in any one of the preceding claims, wherein B1 represents a substituent selected from:
(i) fluoro;
(ii) C1-6 alkyl, preferably C1-3 alkyl, substituted by one or more fluoro atom;
(iii) -ORel;
(iv) -C(0)N(Re2)Re3;
(v) -SF5.
(vi) -N(Re4)S(0)2Re5·
8. A compound as claimed in any one of the preceding claims, wherein: Re2 and Re4 independently represent hydrogen;
Rel, Re3 and Re5 each independently represent C1-3 alkyl (e.g. methyl) substituted by one or more fluoro atoms.
9. A compound as claimed in any one of claims 1 to 8, for use as a pharmaceutical.
10. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and, as active ingredient, a therapeutically effective amount of a compound as defined in any one of claims 1-8.
11. Compound according to any one of claims 1-8 for use in the treatment of tuberculosis.
12. Use of a compound according to any one of claims 1 to 8 for the manufacture of a medicament for the treatment of tuberculosis.
13. A method of treatment of tuberculosis, which method comprises administration of a therapeutically effective/useful amount of a compound according to any one of Claim 1 to 8.
14. A combination of (a) a compound according to any one of claims 1 to 8, and (b) one or more other anti-tuberculosis agent (e.g. one or more other inhibitors of the electron transport chain of mycobacteria, for instance a cytochrome be inhibitor, an ATP synthase inhibitor, a NDH2 inhibitor and/or an inhibitor of the menaquinone synthesis pathway, such as a MenG inhibitor).
15. A product containing (a) a compound according to any one of claims 1 to 8, and (b) one or more other anti-tuberculosis agent (e.g. one or more other inhibitors of the electron transport chain of mycobacteria, for instance a cytochrome be inhibitor, an ATP synthase inhibitor, a NDH2 inhibitor and/or an inhibitor of the menaquinone synthesis pathway, such as a MenG inhibitor), as a combined preparation for simultaneous, separate or sequential use in the treatment of a bacterial infection.
16. A combination or product according to Claim 14 or Claim 15 for use in the treatment of tuberculosis.
17. Use of a combination or product according to Claim 14 or Claim 15 for the manufacture of a medicament for the treatment of tuberculosis.
18. A method of treatment of tuberculosis, which method comprises administration of a therapeutically effective amount of a combination or product according to Claim 14 or Claim 15.
19. Compound according to any one of claims 1-8 for use in enhancement of activity of another anti-tuberculosis agent (as defined in Claim 14 or Claim 15) when employed in combination.
20. A process for the preparation of a compound of formula (I) as claimed in Claim 1, which process comprises:
(ii) reaction of a compound of formula (III),
wherein the integers are as defined in Claim 1, with a compound of formula (IV),
wherein the integers are defined in Claim 1 ;
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