WO2020021252A1 - Compounds for treating infections caused by rifampicin-resistant bacteria - Google Patents
Compounds for treating infections caused by rifampicin-resistant bacteria Download PDFInfo
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- WO2020021252A1 WO2020021252A1 PCT/GB2019/052061 GB2019052061W WO2020021252A1 WO 2020021252 A1 WO2020021252 A1 WO 2020021252A1 GB 2019052061 W GB2019052061 W GB 2019052061W WO 2020021252 A1 WO2020021252 A1 WO 2020021252A1
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- WIPO (PCT)
- Prior art keywords
- alkyl
- numbered
- compound
- numbered paragraphs
- heterocyclyl
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 364
- 241000894006 Bacteria Species 0.000 title claims abstract description 35
- 208000015181 infectious disease Diseases 0.000 title claims abstract description 20
- 229960001225 rifampicin Drugs 0.000 title claims description 95
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- 238000011282 treatment Methods 0.000 claims abstract description 22
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- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 125000000018 nitroso group Chemical group N(=O)* 0.000 description 1
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- 239000002674 ointment Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 125000003566 oxetanyl group Chemical group 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 150000002923 oximes Chemical class 0.000 description 1
- 125000000466 oxiranyl group Chemical group 0.000 description 1
- 125000005476 oxopyrrolidinyl group Chemical group 0.000 description 1
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- 230000037361 pathway Effects 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- 125000004817 pentamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 description 1
- 150000004965 peroxy acids Chemical class 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
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- 125000001791 phenazinyl group Chemical group C1(=CC=CC2=NC3=CC=CC=C3N=C12)* 0.000 description 1
- 150000003014 phosphoric acid esters Chemical class 0.000 description 1
- 238000003322 phosphorimaging Methods 0.000 description 1
- 125000004592 phthalazinyl group Chemical group C1(=NN=CC2=CC=CC=C12)* 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 230000004260 plant-type cell wall biogenesis Effects 0.000 description 1
- 229920002401 polyacrylamide Polymers 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 230000002062 proliferating effect Effects 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- QQONPFPTGQHPMA-UHFFFAOYSA-N propylene Natural products CC=C QQONPFPTGQHPMA-UHFFFAOYSA-N 0.000 description 1
- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 230000005180 public health Effects 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 125000004151 quinonyl group Chemical group 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 238000004366 reverse phase liquid chromatography Methods 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- ATEBXHFBFRCZMA-VXTBVIBXSA-N rifabutin Chemical group O([C@](C1=O)(C)O/C=C/[C@@H]([C@H]([C@@H](OC(C)=O)[C@H](C)[C@H](O)[C@H](C)[C@@H](O)[C@@H](C)\C=C\C=C(C)/C(=O)NC(=C2N3)C(=O)C=4C(O)=C5C)C)OC)C5=C1C=4C2=NC13CCN(CC(C)C)CC1 ATEBXHFBFRCZMA-VXTBVIBXSA-N 0.000 description 1
- SGHWBDUXKUSFOP-KYALZUAASA-N rifalazil Chemical compound O([C@](C1=O)(C)O/C=C/[C@@H]([C@H]([C@@H](OC(C)=O)[C@H](C)[C@H](O)[C@H](C)[C@@H](O)[C@@H](C)\C=C\C=C(C)/C(=O)N=C2C(=O)C=3C(O)=C4C)C)OC)C4=C1C=3C(NC1=C(O)C=3)=C2OC1=CC=3N1CCN(CC(C)C)CC1 SGHWBDUXKUSFOP-KYALZUAASA-N 0.000 description 1
- 229950005007 rifalazil Drugs 0.000 description 1
- SQTCRTQCPJICLD-KTQDUKAHSA-N rifamycin B Chemical compound OC1=C(C(O)=C2C)C3=C(OCC(O)=O)C=C1NC(=O)\C(C)=C/C=C/[C@H](C)[C@H](O)[C@@H](C)[C@@H](O)[C@@H](C)[C@H](OC(C)=O)[C@H](C)[C@@H](OC)\C=C\O[C@@]1(C)OC2=C3C1=O SQTCRTQCPJICLD-KTQDUKAHSA-N 0.000 description 1
- WDZCUPBHRAEYDL-GZAUEHORSA-N rifapentine Chemical compound O([C@](C1=O)(C)O/C=C/[C@@H]([C@H]([C@@H](OC(C)=O)[C@H](C)[C@H](O)[C@H](C)[C@@H](O)[C@@H](C)\C=C\C=C(C)/C(=O)NC=2C(O)=C3C(O)=C4C)C)OC)C4=C1C3=C(O)C=2\C=N\N(CC1)CCN1C1CCCC1 WDZCUPBHRAEYDL-GZAUEHORSA-N 0.000 description 1
- 229960002599 rifapentine Drugs 0.000 description 1
- NZCRJKRKKOLAOJ-XRCRFVBUSA-N rifaximin Chemical compound OC1=C(C(O)=C2C)C3=C4N=C5C=C(C)C=CN5C4=C1NC(=O)\C(C)=C/C=C/[C@H](C)[C@H](O)[C@@H](C)[C@@H](O)[C@@H](C)[C@H](OC(C)=O)[C@H](C)[C@@H](OC)\C=C\O[C@@]1(C)OC2=C3C1=O NZCRJKRKKOLAOJ-XRCRFVBUSA-N 0.000 description 1
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- 238000002741 site-directed mutagenesis Methods 0.000 description 1
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- 150000003512 tertiary amines Chemical class 0.000 description 1
- 125000003039 tetrahydroisoquinolinyl group Chemical group C1(NCCC2=CC=CC=C12)* 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000000147 tetrahydroquinolinyl group Chemical group N1(CCCC2=CC=CC=C12)* 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/08—Bridged systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/4025—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil not condensed and containing further heterocyclic rings, e.g. cromakalim
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/453—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with oxygen as a ring hetero atom
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
-
- 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
-
- 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
Definitions
- the present invention relates to certain compounds that are active against rifampicin- resistant RNA polymerases and rifampicin-resistant bacteria, as well as to pharmaceutical compositions comprising them, and to their use in the treatment of infections caused by rifampicin-resistant bacteria.
- RNA polymerase is an essential enzyme accomplishing transcription in all living organisms.
- sequence divergence between bacterial and human RNAPs makes bacterial RNAP an excellent target for antibiotic development (Ho et al., 2009).
- rifamycins a family of mainly semisynthetic ansamycins derived from the natural product rifamycin S, of which rifampicin (RIF) is the most widely used (Aristoff et al., 2010).
- RIF rifampicin
- the collision of RNA and RIF happens when RNA reaches the length of 3-4 nucleotides, after which the RNA is released from the promoter complex as an abortive transcript.
- the rifamycins are used, as part of the current combination therapy, for the first line treatment of tuberculosis (TB), the leading cause of death by infectious disease worldwide (WHO Global Tuberculosis report, 2017), as well as treatment for non-tuberculous mycobacterial infections (Ryu et al., 2016).
- One of the major problems with known rifamycins is the rapid selection for mutations in the RIF-binding pocket that lead to resistance.
- Multi-drug-resistant strains of Mycobacterium tuberculosis presents a major clinical problem, as these strains are resistant to RIF, as well as several other first line drugs (such as isoniazid).
- a pharmaceutical composition comprising a compound of formula (I), (II) or (III) defined herein, or a pharmaceutically acceptable salt or solvate thereof, and one or more pharmaceutically acceptable excipients or carriers.
- a method of inhibiting RIF-resistant RNA polymerase comprising contacting a cell with an effective amount of a compound of formula (I), (II) or (III) or a pharmaceutically acceptable salt, hydrate or solvate thereof as defined herein.
- a method of inhibiting bacterial cell proliferation comprising contacting a bacterial cell with an effective amount of a compound of formula (I), (II) or (III) or a pharmaceutically acceptable salt, hydrate or solvate thereof as defined herein, or a pharmaceutical composition as defined herein.
- a method of treating an infection caused by RIF-resistant bacteria in a patient in need of such treatment comprising administering to said patient a therapeutically effective amount of a compound of formula (I), (II) or (III) or a pharmaceutically acceptable salt, hydrate or solvate thereof as defined herein, or a pharmaceutical composition as defined herein.
- the infection caused by RIF-resistant bacteria is RIF-resistant tuberculosis.
- references to“treating” or“treatment” include prophylaxis as well as the alleviation of established symptoms of a condition.“Treating” or“treatment” of a state, disorder or condition therefore includes: (1) preventing or delaying the appearance of clinical symptoms of the state, disorder or condition developing in a human that may be afflicted with or predisposed to the state, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the state, disorder or condition, (2) inhibiting the state, disorder or condition, i.e., arresting, reducing or delaying the development of the disease or a relapse thereof (in case of maintenance treatment) or at least one clinical or subclinical symptom thereof, or (3) relieving or attenuating the disease, i.e., causing regression of the state, disorder or condition or at least one of its clinical or subclinical symptoms.
- a “therapeutically effective amount” means the amount of a compound that, when administered to a mammal for treating a disease, is sufficient to effect such treatment for the disease.
- the “therapeutically effective amount” will vary depending on the compound, the disease and its severity and the age, weight, etc., of the mammal to be treated.
- alkyl includes both straight and branched chain alkyl groups. References to individual alkyl groups such as“propyl” are specific for the straight chain version only and references to individual branched chain alkyl groups such as“isopropyl” are specific for the branched chain version only.
- “(1 -6C)alkyl” includes (1-4C)alkyl, (1- 3C)alkyl, propyl, isopropyl and f-butyl.
- (m-nC) or "(m-nC) group” used alone or as a prefix, refers to any group having m to n carbon atoms.
- An“alkylene” group is an alkyl group that is positioned between and serves to connect two other chemical groups.
- “(1-6C)alkylene” means a linear saturated divalent hydrocarbon radical of one to six carbon atoms or a branched saturated divalent hydrocarbon radical of three to six carbon atoms, for example, methylene (-CH2-), ethylene (-CH2CH2-), propylene (- CH2CH2CH2-), 2-methylpropylene (-CH 2 CH(CH 3 )CH 2 -), pentylene (-CH2CH2CH2CH2CH2-), and the like.
- (3-10C)cycloalkyl means a hydrocarbon ring containing from 3 to 10 carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and bicyclo[2.2.1]heptyl.
- “(3-10C)cycloalkenyl” means a hydrocarbon ring containing from 3 to 10 carbon atoms and at least one double bond, for example, cyclobutenyl, cyclopentenyl, cyclohexenyl or cycloheptenyl, such as 3-cyclohexen-1-yl, or cyclooctenyl.
- halo or“halogeno” refers to fluoro, chloro, bromo and iodo, suitably fluoro, chloro and bromo, more suitably, fluoro and chloro.
- heterocyclyl means a non-aromatic saturated or partially saturated monocyclic, fused, bridged, or spiro bicyclic heterocyclic ring system(s).
- Monocyclic heterocyclic rings contain from about 3 to 12 (suitably from 3 to 7) ring atoms, with from 1 to 5 (suitably 1 , 2 or 3) heteroatoms selected from nitrogen, oxygen or sulfur in the ring.
- Bicyclic heterocycles contain from 7 to 17 member atoms, suitably 7 to 12 member atoms, in the ring.
- Bicyclic heterocyclic(s) rings may be fused, spiro, or bridged ring systems.
- heterocyclic groups include cyclic ethers such as oxiranyl, oxetanyl, tetrahydrofuranyl, dioxanyl, and substituted cyclic ethers.
- Heterocycles containing nitrogen include, for example, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, tetrahydrotriazinyl, tetrahydropyrazolyl, and the like.
- Typical sulfur containing heterocycles include tetrahydrothienyl, dihydro-1 , 3-dithiol, tetrahydro-2/-/- thiopyran, and hexahydrothiepine.
- heterocycles include dihydro-oxathiolyl, tetrahydro-oxazolyl, tetrahydro-oxadiazolyl, tetrahydrodioxazolyl, tetrahydro-oxathiazolyl, hexahydrotriazinyl, tetrahydro-oxazinyl, morpholinyl, thiomorpholinyl, tetrahydropyrimidinyl, dioxolinyl, octahydrobenzofuranyl, octahydrobenzimidazolyl, and octahydrobenzothiazolyl.
- the oxidized sulfur heterocycles containing SO or SO2 groups are also included.
- examples include the sulfoxide and sulfone forms of tetrahydrothienyl and thiomorpholinyl such as tetrahydrothiene 1 , 1 -dioxide and thiomorpholinyl 1 , 1 -dioxide.
- heterocyclyl groups are saturated monocyclic 3 to 7 membered heterocyclyls containing 1 , 2 or 3 heteroatoms selected from nitrogen, oxygen or sulfur, for example azetidinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, morpholinyl, tetrahydrothienyl, tetrahydrothienyl 1 , 1 -dioxide, thiomorpholinyl, thiomorpholinyl 1 , 1-dioxide, piperidinyl, homopiperidinyl, piperazinyl or homopiperazinyl.
- any heterocycle may be linked to another group via any suitable atom, such as via a carbon or nitrogen atom.
- heterocycles are suitably linked to another group via a nitrogen atom.
- spiro bi-cyclic heterocyclic ring systems we mean that the two ring systems share one common spiro carbon atom, i.e. the heterocyclic ring is linked to a further cycloalkyl, cycloalkenyl or heterocyclic ring through a single common spiro carbon atom.
- spiro ring systems examples include 6-azaspiro[3.4]octane, 2-oxa-6-azaspiro[3.4]octane, 2- azaspiro[3.3]heptanes, 2-oxa-6-azaspiro[3.3]heptanes, 7-oxa-2-azaspiro[3.5]nonane, 6-oxa-2- azaspiro[3.4]octane, 2-oxa-7-azaspiro[3.5]nonane and 2-oxa-6-azaspiro[3.5]nonane.
- heteroaryl or“heteroaromatic” means an aromatic mono-, bi-, or polycyclic ring incorporating one or more (for example 1-4, particularly 1 , 2 or 3) heteroatoms selected from nitrogen, oxygen or sulfur.
- heteroaryl includes both monovalent species and divalent species. Examples of heteroaryl groups are monocyclic and bicyclic groups containing from five to twelve ring members, and more usually from five to ten ring members.
- the heteroaryl group can be, for example, a 5- or 6-membered monocyclic ring or a 9- or 10-membered bicyclic ring, for example a bicyclic structure formed from fused five and six membered rings or two fused six membered rings.
- Each ring may contain up to about four heteroatoms typically selected from nitrogen, sulfur and oxygen.
- the heteroaryl ring will contain up to 3 heteroatoms, more usually up to 2, for example a single heteroatom.
- the heteroaryl ring contains at least one ring nitrogen atom.
- the nitrogen atoms in the heteroaryl rings can be basic, as in the case of an imidazole or pyridine, or essentially non-basic as in the case of an indole or pyrrole nitrogen. In general the number of basic nitrogen atoms present in the heteroaryl group, including any amino group substituents of the ring, will be less than five.
- heteroaryl examples include furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1 ,3,5-triazenyl, benzofuranyl, indolyl, isoindolyl, benzothienyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, benzothiazolyl, indazolyl, purinyl, benzofurazanyl, quinolyl, isoquinolyl, quinazolinyl, quinoxalinyl, cinnolinyl, pteridinyl, naphthy
- Heteroaryl also covers partially aromatic bi- or polycyclic ring systems wherein at least one ring is an aromatic ring and one or more of the other ring(s) is a non-aromatic, saturated or partially saturated ring, provided at least one ring contains one or more heteroatoms selected from nitrogen, oxygen or sulfur.
- partially aromatic heteroaryl groups include for example, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 2-oxo-1 ,2,3,4-tetrahydroquinolinyl, dihydrobenzthienyl, dihydrobenzfuranyl, 2,3-dihydro-benzo[1 ,4]dioxinyl, benzo[1 ,3]dioxolyl, 2,2- dioxo-1 ,3-dihydro-2-benzothienyl, 4,5,6,7-tetrahydrobenzofuranyl, indolinyl,
- Examples of five membered heteroaryl groups include but are not limited to pyrrolyl, furanyl, thienyl, imidazolyl, furazanyl, oxazolyl, oxadiazolyl, oxatriazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl and tetrazolyl groups.
- Examples of six membered heteroaryl groups include but are not limited to pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl and triazinyl.
- a bicyclic heteroaryl group may be, for example, a group selected from:
- thiazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms
- thiophene ring fused to a 5- or 6-membered ring containing 1 , 2 or 3 ring heteroatoms
- bicyclic heteroaryl groups containing a six membered ring fused to a five membered ring include but are not limited to benzfuranyl, benzthiophenyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzthiazolyl, benzisothiazolyl, isobenzofuranyl, indolyl, isoindolyl, indolizinyl, indolinyl, isoindolinyl, purinyl (e.g., adeninyl, guaninyl), indazolyl, benzodioxolyl and pyrazolopyridinyl groups.
- bicyclic heteroaryl groups containing two fused six membered rings include but are not limited to quinolinyl, isoquinolinyl, chromanyl, thiochromanyl, chromenyl, isochromenyl, chromanyl, isochromanyl, benzodioxanyl, quinolizinyl, benzoxazinyl, benzodiazinyl, pyridopyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, naphthyridinyl and pteridinyl groups.
- aryl means a cyclic or polycyclic aromatic ring having from 5 to 12 carbon atoms.
- aryl includes both monovalent species and divalent species. Examples of aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl and the like. In a particular embodiment, an aryl is phenyl.
- the present invention provides a compound of formula (I), (II) or (III) shown below, or a pharmaceutically acceptable salt, hydrate or solvate thereof, for use in the treatment of infection caused by rifampicin-resistant bacteria:
- Ri is selected from hydrogen, halo, cyano, isocyano, nitro, hydroxy, (1-6C)alkyl, (1-6C)haloalkyl, (2-4C)alkenyl, (2-4C)alkynyl, (1-8C)heteroalkyl, aryl, aryl(1-2C)alkyl, heteroaryl, heteroaryl(1-2C)alkyl, (3-8C)heterocyclyl, (3-8C)heterocyclyl(1-2C)alkyl, (3- 8C)cycloalkyl, (3-8C)cycloalkyl(1-2C)alkyl, NR a R b , OR c , 0C(0)R a , N(R b )OR a , N(R b )C(0)ORa, N(R b )C(0)Ra, S(0) P R a (where p is 0, 1 or 2), S0 2 N(R b )R a , and
- R 1 and R 2 are each independently optionally substituted by one or more substituent groups selected from fluoro, chloro, trifluoromethyl, trifluoromethoxy, cyano, nitro, hydroxy, amino, carboxy, carbamoyl, sulphamoyl, (1-4C)alkyl, (1-4C)alkoxy, S(0) q CH 3 (where q is 0, 1 or 2), methylamino or dimethylamino, aryl, aryl(1-2C)alkyl, heteroaryl, heteroaryl(1-2C)alkyl, (3-8C)heterocyclyl, (3- 8C)heterocyclyl(1-2C)alkyl, (3-8C)cycloalkyl, or (3-8C)cycloalkyl(1- 2C)alkyl;
- Xi is selected from O and NR g ;
- X 2 is hydroxy or a group of formula (A) shown below:
- n 0, 1 , 2, 3 or 4;
- R 3 is independently optionally substituted by one or more substituent groups selected from fluoro, chloro, trifluoromethyl, trifluoromethoxy, cyano, nitro, hydroxy, amino, carboxy, carbamoyl, sulphamoyl, (1- 4C)alkyl, (1-4C)alkoxy, S(0) q CH 3 (where q is 0, 1 or 2), methylamino or dimethylamino, aryl, aryl(1-2C)alkyl, heteroaryl, heteroaryl(1-2C)alkyl, (3-8C)heterocyclyl, (3- 8C)heterocyclyl
- R 2 and X1 or R 2 and X 2 are linked, such that when they are taken in combination with the carbon atoms to which they are attached, they collectively form a 5-12 membered heteroaryl or heterocycle that is optionally substituted with one or more R 4 substituents;
- each R 4 is independently selected from halo, cyano, isocyano, nitro, hydroxy, (1-6C)alkyl, (1-6C)haloalkyl, (2-4C)alkenyl, (2- 4C)alkynyl, (1-8C)heteroalkyl, aryl, aryl(1-2C)alkyl, heteroaryl, heteroaryl(1-2C)alkyl, (3-8C)heterocyclyl, (3-8C)heterocyclyl(1-2C)alkyl, (3-8C)cycloalkyl, (3-8C)cycloalkyl(1-2C)alkyl, NR m R n , OR 0 , C(0)R m , C(0)0R m , 0C(0)R m , N(R m )OR n , N(R m )C(0)0R n , C(0)N(R m )R n ,
- each R 4 is independently optionally substituted with one or more groups selected from fluoro, chloro, trifluoromethyl, trifluoromethoxy, cyano, nitro, hydroxy, amino, carboxy, carbamoyl, sulphamoyl, (1-4C)alkyl, (2-4C)alkenyl, (2-4C)alkynyl, (1-4C)alkoxy, S(0) q CH 3 (where q is 0, 1 or 2), methylamino or dimethylamino, aryl, aryl(1-2C)alkyl, heteroaryl, heteroaryl(1-2C)alkyl, (3-8C)heterocyclyl, (3- 8C)heterocyclyl(1-2C)alkyl, (3-8C)cycloalkyl, and (3-8C)cycloalkyl(1- 2C)alkyl;
- X3 and X 4 are independently selected from hydroxy, OR p , NR q R r and a group of formula (A) shown above;
- X3 and X 4 are linked, such that when they are taken in combination with the carbon atom to which they are attached, they collectively form a 4-6 membered heterocycle that is optionally substituted with one or more R 5 substituents;
- each R 5 is independently selected from fluoro, chloro, trifluoromethyl, trifluoromethoxy, cyano, nitro, hydroxy, oxo, amino, carboxy, carbamoyl, sulphamoyl, (1-6C)alkyl, (2-6C)alkenyl, (2- 6C)alkynyl, (1-4C)alkoxy, S(0) q CH 3 (where q is 0, 1 or 2), methylamino or dimethylamino, aryl, aryl(1-2C)alkyl, heteroaryl, heteroaryl(1-2C)alkyl, (3- 8C)heterocyclyl, (3-8C)heterocyclyl(1-2C)alkyl, (3-8C)cycloalkyl, and (3- 8C)cycloalkyl(1-2C)alkyl;
- each R a to R r is independently selected from hydrogen, fluoro, chloro, trifluoromethyl, trifluoromethoxy, cyano, nitro, hydroxy, amino, carboxy, carbamoyl, sulphamoyl, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (1-4C)alkoxy, S(0) q CH 3 (where q is 0, 1 or 2), methylamino or dimethylamino, aryl, aryl(1-2C)alkyl, heteroaryl,
- heteroaryl(1-2C)alkyl (3-8C)heterocyclyl, (3-8C)heterocyclyl(1-2C)alkyl, (3- 8C)cycloalkyl, and (3-8C)cycloalkyl(1-2C)alkyl;
- each R a to R r is independently optionally substituted with one or more groups selected from fluoro, chloro, trifluoromethyl, trifluoromethoxy, cyano, nitro, hydroxy, amino, carboxy, carbamoyl, sulphamoyl, (1-4C)alkyl, (2-4C)alkenyl, (2-4C)alkynyl, (1-4C)alkoxy, S(0) q CH 3 (where q is 0, 1 or 2), methylamino or dimethylamino, aryl, aryl(1-2C)alkyl, heteroaryl, heteroaryl(1-2C)alkyl, (3-8C)heterocyclyl, (3- 8C)heterocyclyl(1-2C)alkyl, (3-8C)cycloalkyl, and (3-8C)cycloalkyl(1- 2C)alkyl.
- the compound of formula (I), (II) or (III) has a structure according to formula (G), (IG) or (IN’) shown below:
- R1 is selected from hydrogen, halo, hydroxy, (1-6C)alkyl, (1-6C)haloalkyl, (2-4C)alkenyl, (2-4C)alkynyl, (1-8C)heteroalkyl, aryl, aryl(1-2C)alkyl, heteroaryl, heteroaryl(1-2C)alkyl, (3-8C)heterocyclyl, (3-8C)heterocyclyl(1-2C)alkyl, (3-8C)cycloalkyl, (3-8C)cycloalkyl(1- 2C)alkyl, NR a R b , 0R C , 0C(0)R a , N(R b )OR a , N(R b )C(0)0R a and N(R b )C(0)R a , wherein Ri is optionally substituted by one or more substituent groups selected from (1-4C)alkyl and (1-3C)alkoxy.
- Ri is selected from hydrogen, halo, hydroxy, (1-6C)alkyl, (1-6C)haloalkyl, (2-4C)alkenyl, (2-4C)alkynyl, (1-8C)heteroalkyl, aryl, aryl(1-2C)alkyl, heteroaryl, heteroaryl(1-2C)alkyl, (3-8C)heterocyclyl, (3-8C)heterocyclyl(1-2C)alkyl, (3-8C)cycloalkyl, (3-8C)cycloalkyl(1- 2C)alkyl, NR a R b and OR c , wherein Ri is optionally substituted by one or more substituent groups selected from (1-4C)alkyl and (1-3C)alkoxy.
- Ri is selected from hydrogen, halo, hydroxy, (1-6C)alkyl, aryl, aryl(1-2C)alkyl, heteroaryl, heteroaryl(1-2C)alkyl, (3-8C)heterocyclyl, (3-8C)heterocyclyl(1-2C)alkyl, (3- 8C)cycloalkyl, (3-8C)cycloalkyl(1-2C)alkyl, NR a R b and OR c , wherein Ri is optionally substituted by one or more substituent groups selected from (1-2C)alkyl and (1- 2C)alkoxy.
- Ri is selected from hydroxy, (1-6C)alkyl, aryl, heteroaryl, (3-8C)heterocyclyl, (3- 8C)cycloalkyl, NR a R b and OR c , wherein Ri is optionally substituted by one or more substituent groups selected from (1-2C)alkyl and (1-2C)alkoxy.
- Ri is selected from hydroxy, (1-4C)alkyl, N-linked (3-8C)heterocyclyl, NR a R b and OR c , wherein Ri is optionally substituted by one or more (1-2C)alkyl.
- Ri is selected from hydroxy, N-linked (3-6C)heterocyclyl, NR a R b and OR c , wherein the N- linked (3-6C)heterocyclyl contains 1 or 2 heteroatoms, wherein Ri is optionally substituted by one or more (1-2C)alkyl.
- Ri is selected from hydroxy, NR a R b , OR c or any one of the following:
- Ri is selected from hydroxy and OR c (e.g. methoxy or ethoxy).
- Each R a and R b are independently selected from hydrogen, (1-6C)alkyl, (1-4C)alkoxy, aryl and (3-8C)heterocyclyl.
- Each R a and R b are independently selected from hydrogen, (1-6C)alkyl, aryl and N- linked (3-8C)heterocyclyl.
- R a and R b are independently selected from hydrogen, (1-6C)alkyl, phenyl and 5-6 membered N-linked heterocyclyl.
- R a and R b are independently selected from hydrogen, (1-6C)alkyl, phenyl or any one of the following:
- Each R a and R b are independently selected from hydrogen, (1-6C)alkyl, amino, aryl, aryl(1-2C)alkyl, (3-8C)cycloalkyl or any one of the following wherein each R a and R b is optionally substituted with one or more substituent groups selected from halo, hydroxy, (1-3C)alkyl and (1-3C)haloalkyl.
- R a is hydrogen or (1-6C)alkyl and R b is selected from (1-6C)alkyl, amino, aryl, aryl(1- 2C)alkyl, (3-8C)cycloalkyl or any one of the following wherein each R b is optionally substituted with one or more substituent groups selected from halo, hydroxy, (1-3C)alkyl and (1-3C)haloalkyl.
- Each R a and R b are independently selected from hydrogen, (1-3C)alkyl, amino, aryl, aryl(1-2C)alkyl, (3-6C)cycloalkyl or any one of the following wherein each of the said amino, aryl and aryl(1-2C)alkyl groups is optionally substituted with one or more substituent groups selected from halo, hydroxy, (1-3C)alkyl and (1- 3C)haloalkyl.
- R a is hydrogen or (1-3C)alkyl and R b is selected from (1-3C)alkyl, amino, aryl, aryl(1- 2C)alkyl, (3-6C)cycloalkyl or any one of the following wherein each of the said amino, aryl and aryl(1-2C)alkyl groups is optionally substituted with one or more substituent groups selected from halo, hydroxy, (1-3C)alkyl and (1- 3C)haloalkyl.
- Each R a and R b are independently selected from hydrogen, (1-3C)alkyl, amino, phenyl, benzyl, (3-6C)cycloalkyl or any one of the following wherein each of the said phenyl and benzyl groups is optionally substituted with one or more substituent groups selected from fluoro, chloro hydroxy, (1-3C)alkyl and (1- 3C)haloalkyl, and each of the said amino groups is optionally substituted with one or more substituent groups selected from (1-3C)alkyl.
- R a is hydrogen or (1-3C)alkyl and R b is selected from (1-3C)alkyl, amino, phenyl, benzyl, (3-6C)cycloalkyl or any one of the following wherein each of the said phenyl and benzyl groups is optionally substituted with one or more substituent groups selected from fluoro, chloro hydroxy, (1-3C)alkyl and (1- 3C)haloalkyl, and each of the said amino groups is optionally substituted with one or more substituent groups selected from (1-3C)alkyl.
- Each R a and R b are independently selected from hydrogen, (1-2C)alkyl, NH2, N(Me)2, N(H)(Me), phenyl, benzyl, cyclopropyl or any one of the following wherein each of the said phenyl and benzyl groups is optionally substituted with one or two substituent groups selected from fluoro, chloro, hydroxy and trifluoromethyl.
- R a is hydrogen or (1-2C)alkyl and R b is selected from (1-2C)alkyl, NH2, N(Me)2, N(H)(Me), phenyl, benzyl, cyclopropyl or any one of the following wherein each of the said phenyl and benzyl groups is optionally substituted with one or two substituent groups selected from fluoro, chloro, hydroxy and trifluoromethyl.
- R a and R b are independently selected from hydrogen, (1-2C)alkyl, N(Me)2, benzyl, cyclopropyl or any one of the following wherein each of the said benzyl groups is optionally substituted with one substituent group selected from fluoro, chloro, hydroxy and trifluoromethyl.
- R a is hydrogen or (1-2C)alkyl and R b is selected from (1-2C)alkyl, N(Me)2, benzyl, cyclopropyl or any one of the following wherein each of the said benzyl groups is optionally substituted with one substituent group selected from fluoro, chloro, hydroxy and trifluoromethyl.
- Each R c is independently (1-6C)alkyl.
- Each R c is independently (1-3C)alkyl.
- Each R c is independently methyl or ethyl.
- Each R d is independently selected from hydrogen and (1-6C)alkyl.
- Each R d is hydrogen.
- Each R e is independently selected from hydrogen, (1-6C)alkyl and (3-8C)heterocyclyl, any of which is optionally substituted with one or more substituent groups selected from (1-6C)alkyl and (3-8C)cycloalkyl.
- Each R e is independently selected from hydrogen, (1-4C)alkyl and (3-6C)heterocyclyl containing 1 or 2 heteroatoms selected from O and N, any of which is optionally substituted with one or more substituent groups selected from (1-4C)alkyl and (4- 6C)cycloalkyl.
- Each R e is independently selected from hydrogen, (1-4C)alkyl and N-piperazinyl, any of which is optionally substituted with cyclopentyl.
- Each R e is N-piperazinyl, any of which is optionally substituted with cyclopentyl.
- X 2 is a group of formula (A).
- n 1 or 2.
- R 3 is selected from hydrogen, halo, hydroxy, (1-6C)alkyl, (1-6C)haloalkyl, (2-4C)alkenyl, (2-4C)alkynyl, (1-8C)heteroalkyl, aryl, aryl(1-2C)alkyl, heteroaryl, heteroaryl(1-2C)alkyl, (3-8C)heterocyclyl, (3-8C)heterocyclyl(1-2C)alkyl, (3-8C)cycloalkyl, (3-8C)cycloalkyl(1- 2C)alkyl, NR j R k and ORi, wherein R 3 is independently optionally substituted by one or more substituent groups selected from fluoro, chloro, trifluoromethyl, trifluoromethoxy, amino, (1-4C)alkyl and (1-4C)alkoxy.
- R 3 is selected from hydroxy, (1-6C)alkyl, aryl, aryl(1-2C)alkyl, heteroaryl, heteroaryl(1- 2C)alkyl, (3-8C)heterocyclyl, (3-8C)heterocyclyl(1-2C)alkyl, (3-8C)cycloalkyl, (3- 8C)cycloalkyl(1-2C)alkyl, NR j R k and ORi, wherein R 3 is independently optionally substituted by one or more substituent groups selected from fluoro, chloro, trifluoromethyl, trifluoromethoxy, amino, (1-4C)alkyl and (1-4C)alkoxy.
- R is selected from hydroxy, (1-6C)alkyl, (3-8C)heterocyclyl, (3-8C)heterocyclyl(1- 2C)alkyl, NR j R k and ORi, wherein R 3 is optionally substituted by one or more substituent groups selected from (1-4C)alkyl and (1-3C)alkoxy.
- R 3 is selected from hydroxy, (1-3C)alkyl, (3-8C)heterocyclyl, NR j R k and ORi, wherein R 3 is optionally substituted by one or more substituent groups selected from (1-2C)alkyl and (1-2C)alkoxy.
- R 3 is selected from hydroxy, N-linked (3-8C)heterocyclyl, NR j R k and ORi, wherein R 3 is optionally substituted by one or more (1-2C)alkyl.
- R 3 is selected from hydroxy, NR j R k , ORi or any one of the following:
- R is selected from hydroxy or ORi (e.g. methoxy).
- Each R h and R are independently selected from hydrogen and (1-6C)alkyl.
- Each R h and R are independently selected from hydrogen and (1-2C)alkyl.
- Each R, and R k are independently selected from hydrogen, (1-6C)alkyl, (1-4C)alkoxy, aryl and (3-8C)heterocyclyl.
- Each R, and R k are independently selected from hydrogen, (1-6C)alkyl, aryl and N-linked (3-8C)heterocyclyl.
- Each R, and R k are independently selected from hydrogen, (1-6C)alkyl, phenyl and 5-6 membered N-linked heterocyclyl.
- R, and R k are independently selected from hydrogen, (1-6C)alkyl, phenyl or any one of the following:
- Each Ri is independently (1-6C)alkyl.
- Each Ri is independently (1-3C)alkyl.
- Each Ri is independently methyl or ethyl.
- R and X or R and X are linked, such that when they are taken in combination with the carbon atoms to which they are attached, they collectively form a 5-12 membered heterocycle that is optionally substituted with one or more R substituents.
- R 2 and Xi or R 2 and X 2 are linked, such that when they are taken in combination with the carbon atoms to which they are attached, they collectively form a 8-12 membered fused heterobicycle or spiro bi-cyclic heterocyclic ring system that is optionally substituted with one or more R 4 substituents.
- R 2 and Xi or R 2 and X 2 are linked, such that when they are taken in combination with the carbon atoms to which they are attached, they collectively form a 8-12 membered fused heterobicycle or spiro bi-cyclic heterocyclic ring system containing 1 , 2 or 3 heteroatoms selected from O and N, wherein said 8-12 membered fused or spiro heterobicycle is optionally substituted with one or more R 4 substituents.
- R 2 and Xi or R 2 and X 2 are linked, such that when they are taken in combination with the carbon atoms to which they are attached, they collectively form a 9-11 membered fused heterobicycle or spiro bi-cyclic heterocyclic ring system containing 1 , 2 or 3 heteroatoms selected from O and N, wherein said 9-11 membered fused or spiro heterobicycle is optionally substituted with one or more R 4 substituents.
- R 2 and Xi or R 2 and X 2 are linked, such that when they are taken in combination with the carbon atoms to which they are attached, they collectively form a 10 membered fused heterobicycle or spiro bi-cyclic heterocyclic ring system containing 1 , 2 or 3 heteroatoms selected from O and N, wherein said 10 membered fused or spiro heterobicycle is optionally substituted with one or more R 4 substituents.
- R 2 and Xi or R 2 and X 2 are linked, such that when they are taken in combination with the carbon atoms to which they are attached, they collectively form either of the following groups:
- v is a number 0, 1 or 2.
- R 2 and Xi or R 2 and X 2 are linked, such that when they are taken in combination with the carbon atoms to which they are attached, they collectively form either of the following groups:
- each R 4 is independently selected from halo, hydroxy, (1-6C)alkyl, (1-6C)haloalkyl, (2-
- each R 4 is independently optionally substituted with one or more groups selected from fluoro, chloro, (1-4C)alkyl, (2-4C)alkenyl, (2-4C)alkynyl, (1-4C)alkoxy, aryl, aryl(1-2C)alkyl, heteroaryl, heteroaryl(1-2C)alkyl, (3-8C)heterocyclyl, (3-8C)heterocyclyl(1-2C)alkyl, (3-
- each R 4 is independently selected from halo, hydroxy, (1-6C)alkyl, aryl, aryl(1-2C)alkyl, heteroaryl, heteroaryl(1-2C)alkyl, (3-8C)heterocyclyl, (3-8C)heterocyclyl(1-2C)alkyl, (3- 8C)cycloalkyl, (3-8C)cycloalkyl(1-2C)alkyl, NR m R n , OR 0 , wherein each R 4 is independently optionally substituted with one or more groups selected from fluoro, chloro, (1-4C)alkyl and (1-4C)alkoxy.
- each R 4 is independently selected from halo, hydroxy, (1-6C)alkyl, (3-8C)heterocyclyl, (3-8C)heterocyclyl(1-2C)alkyl, NR m R n , OR 0 , wherein each R 4 is independently optionally substituted with one or more groups selected from fluoro, chloro, (1-4C)alkyl and (1- 4C)alkoxy.
- each R 4 is independently selected from hydroxy, (1-6C)alkyl and (3-8C)heterocyclyl, wherein each R 4 is independently optionally substituted with one or more groups, (1- 4C)alkyl.
- each R 4 is independently selected from hydroxy, (1-4C)alkyl or a group:
- X 3 and X 4 are independently selected from hydroxy, OR p and NR q R r .
- X3 and X 4 are linked, such that when they are taken in combination with the carbon atom to which they are attached, they collectively form a 4-6 membered heterocycle containing 1 or 2 heteroatoms selected from O and N, wherein the 4-6 membered heterocycle is optionally substituted with one or more R 5 substituents.
- X 3 and X 4 are linked, such that when they are taken in combination with the carbon atom to which they are attached, they collectively form a group having a structure according to formula (B) shown below:
- X 5 is selected from O or NR m ;
- n is a number selected from 1 and 2;
- o is a number selected from 1 and 2.
- X5 is selected from O or NR m ;
- n is a number selected from 1 and 2;
- o is a number selected from 1 and 2.
- Each R 5 is independently selected from fluoro, chloro, trifluoromethyl, trifluoromethoxy, hydroxy, oxo, amino, carboxy, (1-6C)alkyl, (1-4C)alkoxy, methylamino or dimethylamino, aryl, aryl(1-2C)alkyl, heteroaryl, heteroaryl(1-2C)alkyl, (3-8C)heterocyclyl, heterocyclyl(1- 2C)alkyl, (3-8C)cycloalkyl, and (3-8C)cycloalkyl(1-2C)alkyl.
- Each R 5 is independently selected from fluoro, chloro, trifluoromethyl, trifluoromethoxy, hydroxy, oxo, amino, carboxy, (1-6C)alkyl, (1-4C)alkoxy, methylamino and dimethylamino.
- Each R 5 is independently selected from fluoro, chloro, hydroxy, oxo, amino, (1-3C)alkyl and (1-3C)alkoxy.
- Each R 5 is independently selected from hydroxy, oxo and (1-4C)alkoxy.
- R 5 is oxo.
- R f , R g , R m , R n , R o , R P , R q , R r are each independently selected from hydrogen and (1- 6C)alkyl.
- R f , R g , R m , R n , R o , R P , Rq, R r are each independently selected from hydrogen and (1- 3C)alkyl.
- R f , Rg, R m , Rn, Ro, R , Rq, R r are each hydrogen.
- the compound has a structure according to formula (I).
- the compound has a structure according to formula (II).
- the compound has a structure according to formula (III).
- the compound has a structure according to formula (I) or (II).
- the compound has a structure according to formula (I) or (III).
- the compound has a structure according to formula (II) or (III).
- (3-8)heterocycles are linked to the group to which they are attached via a nitrogen atom present within the heterocyclic ring (i.e. “N-linked”). More suitably, (3- 8) heterocycles are 5-6 membered, containing 1-2 ring heteroatoms selected from N and O. Most suitably, (3-8)heterocycles are selected from the following:
- an aryl group is phenyl
- R 1 is as described in any of numbered paragraphs (3) to (8), wherein R a and R b are suitably as described in any of numbered paragraphs (10) to (12) and R c is suitably as described in any of numbered paragraphs (23) to (25). More suitably, Ri is as described in any of numbered paragraphs (5) to (8), wherein R a and R b are suitably as described in any of numbered paragraphs (11) to (12) and R c is suitably as described in any of numbered paragraphs (24) to (25).
- Ri is as described in any of numbered paragraphs (7) to (8), wherein R a and R b are suitably as described in any of numbered paragraphs (11) to (12) and R c is suitably as described in any of numbered paragraphs (24) to (25). Most suitably, Ri is as described in numbered paragraph (8), wherein R c is suitably as described in numbered paragraph (25).
- Ri is as described in any of numbered paragraphs (3) to (8), wherein R a and R b are suitably as described in any of numbered paragraphs (13) to (22) and R c is suitably as described in any of numbered paragraphs (23) to (25). More suitably, Ri is as described in any of numbered paragraphs (5) to (8), wherein R a and R b are suitably as described in any of numbered paragraphs (17) to (22) and R c is suitably as described in any of numbered paragraphs (24) to (25).
- Ri is as described in any of numbered paragraphs (7) to (8), wherein R a and R b are suitably as described in any of numbered paragraphs (19) to (22) and R c is suitably as described in any of numbered paragraphs (24) to (25). Most suitably, Ri is as described in any of numbered paragraphs (7) to (8), wherein R a and R b are suitably as described in any of numbered paragraphs (21) to (22) and R c is suitably as described in numbered paragraph (25)..
- R 2 is as described in any of numbered paragraphs (28) to (32), wherein R d is suitably as described in any of numbered paragraphs (33) to (34) and R e is suitably as described in any of numbered paragraphs (36) to (38). More suitably, R 2 is as described in any of numbered paragraphs (30) to (32), wherein R d is suitably as described in numbered paragraph (34) and R e is suitably as described in any of numbered paragraphs (37) to (38). Most suitably, R 2 is as described in numbered paragraph (32), wherein R d is suitably as described in numbered paragraph (34) and R e is suitably as described in numbered paragraph (38)
- X 2 is as described in numbered paragraph (41), wherein n is suitably as described in numbered paragraph (42) or (43), R 3 is suitably as described in any of numbered paragraphs (46) to (50), R h and R, are suitably as described in any of numbered paragraphs (52) to (53), R j and R k are suitably as described in any of numbered paragraphs (55) to (57) and Ri is suitably as described in any of numbered paragraphs (59) to (60).
- X 2 is as described in numbered paragraph (41), wherein n is suitably as described in numbered paragraph (42) or (43), R 3 is suitably as described in any of numbered paragraphs (48) to (50), R h and R, are suitably as described in numbered paragraph (53), R j and R k are suitably as described in any of numbered paragraphs (56) to (57) and Ri is suitably as described in any of numbered paragraphs (59) to (60).
- X 2 is as described in numbered paragraph (41), wherein n is suitably as described in numbered paragraph (43), R 3 is suitably as described in any of numbered paragraphs (49) to (50), R h and R, are suitably as described in numbered paragraph (53), R j and R k are suitably as described in numbered paragraph (57) and Ri is suitably as described in numbered paragraph (60).
- R 2 and X 1 or R 2 and X 2 are as described in any of numbered paragraphs (64) to (67), wherein R 4 is suitably as described in any of numbered paragraphs (69) to (72). More suitably, R 2 and X 1 or R 2 and X 2 are as described in any of numbered paragraphs (65) to (67), wherein R 4 is suitably as described in any of numbered paragraphs (70) to (72). Most suitably, R 2 and Xi or R 2 and X 2 are as described in any of numbered paragraphs (66) to (67), wherein R 4 is suitably as described in paragraph (72).
- X3 and X 4 are as described in any of numbered paragraphs (75) to (76), wherein m is as described in numbered paragraph (78) and R 5 is as described in any of numbered paragraphs (81) to (84). More suitably, X3 and X 4 are as described in any of numbered paragraphs (75) to (76), wherein m is as described in numbered paragraph (78), o is as described in numbered paragraph (79) and Rs is as described in any of numbered paragraphs (81) to (84).
- X3 and X 4 are as described in any of numbered paragraphs (75) to (76), wherein X5 is as described in numbered paragraph (77), m is as described in numbered paragraph (78), o is as described in numbered paragraph (79) and Rs is as described in any of numbered paragraphs (82) to (84). Yet more suitably, X3 and X 4 are as described in any of numbered paragraphs (75) to (76), wherein X5 is as described in numbered paragraph (77), m is as described in numbered paragraph (78), o is as described in numbered paragraph (79) and R 5 is as described in any of numbered paragraphs (83) to (84).
- X3 and X 4 are as described in numbered paragraph (76), wherein X5 is as described in numbered paragraph (77), m is as described in numbered paragraph (78), o is as described in numbered paragraph (79) and Rs is as described in any of numbered paragraphs (83) to (84).
- R f , R g , R m , R n , R o , R P , R q , R r are as described in numbered paragraph (86) or (87). Most suitably, R f , R g , R m , R n , R o , R P , Rq, R r are as described in numbered paragraph (87).
- R 2 is hydrogen, such that the compounds have a structure according to formula (la), (lla) or (Ilia) shown below:
- R 1 is as described in any of numbered paragraphs (3) to (8);
- R a and R b are as described in any of numbered paragraphs (10) to (12);
- R c is as described in any of numbered paragraphs (23) to (25);
- R 1 is as described in any of numbered paragraphs (5) to (8);
- R a and R b are as described in any of numbered paragraphs (11) to (12);
- R c is as described in any of numbered paragraphs (24) to (25);
- R 1 is as described in any of numbered paragraphs (5) to (8);
- R a and R b are as described in any of numbered paragraphs (11) to (12);
- R c is as described in any of numbered paragraphs (24) to (25); Xi is as described in numbered paragraph (39); and
- R1 is as described in any of numbered paragraphs (5) to (8);
- R a and R b are as described in any of numbered paragraphs (11) to (12);
- R c is as described in any of numbered paragraphs (24) to (25);
- Xi is as described in numbered paragraph (39);
- X2 is as described in numbered paragraph (40) or (41);
- n is as described in numbered paragraph (42) or (43);
- R3 is as described in any of numbered paragraphs (46) to (50);
- R h and R are as described in any of numbered paragraphs (52) to (53);
- R j and R k are as described in any of numbered paragraphs (55) to (57);
- Ri is as described in any of numbered paragraphs (59) to (60);
- R1 is as described in any of numbered paragraphs (5) to (8);
- R a and R b are as described in any of numbered paragraphs (11) to (12);
- R c is as described in any of numbered paragraphs (24) to (25);
- Xi is as described in numbered paragraph (39);
- X2 is as described in numbered paragraph (40) or (41);
- n is as described in numbered paragraph (42) or (43);
- R3 is as described in any of numbered paragraphs (46) to (50);
- R h and R are as described in any of numbered paragraphs (52) to (53);
- R j and R k are as described in any of numbered paragraphs (55) to (57);
- Ri is as described in any of numbered paragraphs (59) to (60);
- X3 and X4 are as described in any of numbered paragraphs (75) to (76); m is as described in numbered paragraph (78);
- R1 is as described in any of numbered paragraphs (6) to (8);
- R a and R b are as described in any of numbered paragraphs (11) to (12);
- R c is as described in any of numbered paragraphs (24) to (25);
- Xi is as described in numbered paragraph (39);
- X2 is as described in numbered paragraph (40) or (41); n is as described in numbered paragraph (43);
- R3 is as described in any of numbered paragraphs (48) to (50);
- R h and R are as described in numbered paragraph (53);
- R j and R k are as described in any of numbered paragraphs (56) to (57); Ri is as described in any of numbered paragraphs (59) to (60);
- X3 and X 4 are as described in any of numbered paragraphs (75) to (76); m is as described in numbered paragraph (78);
- R5 IS as described in any of numbered paragraphs (83) to (84).
- R1 is as described in any of numbered paragraphs (7) to (8);
- R a and R b are as described in numbered paragraph (12);
- R c is as described in numbered paragraph (25);
- Xi is as described in numbered paragraph (39);
- X2 is as described in numbered paragraph (40) or (41); n is as described in numbered paragraph (43);
- R3 is as described in any of numbered paragraphs (48) to (50);
- R h and R are as described in numbered paragraph (53);
- R j and R k are as described in any of numbered paragraphs (56) to (57); Ri is as described in any of numbered paragraphs (59) to (60);
- X 3 and X 4 are as described in any of numbered paragraphs (75) to (76);
- R 5 IS as described in any of numbered paragraphs (83) to (84).
- R 1 is as described in numbered paragraphs (8);
- R c is as described in numbered paragraph (25);
- Xi is as described in numbered paragraph (39);
- X 2 is as described in numbered paragraph (40) or (41);
- n is as described in numbered paragraph (43);
- R 3 is as described in any of numbered paragraphs (48) to (50);
- R h and R are as described in numbered paragraph (53);
- R j and R k are as described in any of numbered paragraphs (56) to (57);
- Ri is as described in any of numbered paragraphs (59) to (60);
- X3 and X 4 are as described in any of numbered paragraphs (75) to (76);
- R 5 IS as described in any of numbered paragraphs (83) to (84).
- Ri is as described in any of numbered paragraphs (3) to (8);
- R a and R b are as described in any of numbered paragraphs (13) to (22);
- R c is as described in any of numbered paragraphs (23) to (25);
- Ri is as described in any of numbered paragraphs (5) to (8);
- R a and R b are as described in any of numbered paragraphs (15) to (22); R c is as described in any of numbered paragraphs (24) to (25); and
- R1 is as described in any of numbered paragraphs (5) to (8);
- R a and R b are as described in any of numbered paragraphs (15) to (22);
- R c is as described in any of numbered paragraphs (24) to (25);
- Xi is as described in numbered paragraph (39).
- R1 is as described in any of numbered paragraphs (5) to (8);
- R a and R b are as described in any of numbered paragraphs (17) to (22);
- R c is as described in any of numbered paragraphs (24) to (25);
- Xi is as described in numbered paragraph (39);
- X2 is as described in numbered paragraph (40) or (41);
- n is as described in numbered paragraph (42) or (43);
- R3 is as described in any of numbered paragraphs (46) to (50);
- R h and R are as described in any of numbered paragraphs (52) to (53);
- R j and R k are as described in any of numbered paragraphs (55) to (57);
- Ri is as described in any of numbered paragraphs (59) to (60);
- R1 is as described in any of numbered paragraphs (5) to (8);
- R a and R b are as described in any of numbered paragraphs (19) to (22);
- R c is as described in any of numbered paragraphs (24) to (25);
- Xi is as described in numbered paragraph (39);
- X2 is as described in numbered paragraph (40) or (41); n is as described in numbered paragraph (42) or (43);
- R 3 is as described in any of numbered paragraphs (46) to (50);
- R h and R are as described in any of numbered paragraphs (52) to (53);
- R j and R k are as described in any of numbered paragraphs (55) to (57);
- Ri is as described in any of numbered paragraphs (59) to (60);
- X3 and X 4 are as described in any of numbered paragraphs (75) to (76); m is as described in numbered paragraph (78);
- R 5 IS as described in any of numbered paragraphs (82) to (84).
- R 1 is as described in any of numbered paragraphs (6) to (8);
- R a and R b are as described in any of numbered paragraphs (19) to (22); R c is as described in any of numbered paragraphs (24) to (25);
- Xi is as described in numbered paragraph (39);
- X 2 is as described in numbered paragraph (40) or (41); n is as described in numbered paragraph (43);
- R 3 is as described in any of numbered paragraphs (48) to (50);
- R h and R are as described in numbered paragraph (53);
- R j and R k are as described in any of numbered paragraphs (56) to (57); Ri is as described in any of numbered paragraphs (59) to (60);
- X3 and X 4 are as described in any of numbered paragraphs (75) to (76); m is as described in numbered paragraph (78);
- R 5 IS as described in any of numbered paragraphs (83) to (84).
- Ri is as described in any of numbered paragraphs (7) to (8);
- R a and R b are as described in numbered paragraph (21) or (22);
- R c is as described in numbered paragraph (25); Xi is as described in numbered paragraph (39);
- X 2 is as described in numbered paragraph (40) or (41);
- n is as described in numbered paragraph (43);
- R3 is as described in any of numbered paragraphs (48) to (50);
- R h and R are as described in numbered paragraph (53);
- R j and R k are as described in any of numbered paragraphs (56) to (57);
- Ri is as described in any of numbered paragraphs (59) to (60);
- X3 and X 4 are as described in any of numbered paragraphs (75) to (76);
- R5 IS as described in any of numbered paragraphs (83) to (84).
- Xi is as described in numbered paragraph (39);
- X2 is as described in numbered paragraph (40) or (41);
- n is as described in numbered paragraph (42) or (43);
- R3 is as described in any of numbered paragraphs (46) to (50);
- R h and R are as described in any of numbered paragraphs (52) to (53);
- R j and R k are as described in any of numbered paragraphs (55) to (57);
- Ri is as described in any of numbered paragraphs (59) to (60);
- Xi is as described in numbered paragraph (39);
- X2 is as described in numbered paragraph (40) or (41);
- n is as described in numbered paragraph (42) or (43);
- R3 is as described in any of numbered paragraphs (46) to (50);
- R h and R are as described in any of numbered paragraphs (52) to (53);
- R j and R k are as described in any of numbered paragraphs (55) to (57);
- Ri is as described in any of numbered paragraphs (59) to (60);
- X3 and X 4 are as described in any of numbered paragraphs (75) to (76);
- R5 IS as described in any of numbered paragraphs (81) to (84).
- Xi is as described in numbered paragraph (39);
- X2 is as described in numbered paragraph (40) or (41);
- n is as described in numbered paragraph (43);
- R3 is as described in any of numbered paragraphs (48) to (50);
- R h and R are as described in numbered paragraph (53);
- R j and R k are as described in any of numbered paragraphs (56) to (57);
- Ri is as described in any of numbered paragraphs (59) to (60);
- X3 and X 4 are as described in any of numbered paragraphs (75) to (76);
- R5 IS as described in any of numbered paragraphs (83) to (84).
- Ri is hydroxy, such that the compounds have a structure according to formula (lb), (lib) or (lllb) shown below: wherein R 2 , Xi , X 2 , X3 and X 4 , and any of their associated substituents, have any of the definitions appearing hereinbefore.
- R 2 is as described in any of numbered paragraphs (28) to (32);
- R d is as described in any of numbered paragraphs (33) to (34);
- R e is as described in any of numbered paragraphs (36) to (38);
- Xi is as described in numbered paragraph (39).
- R 2 is as described in any of numbered paragraphs (30) to (32);
- R d is as described in any of numbered paragraphs (33) to (34);
- R e is as described in any of numbered paragraphs (37) to (38);
- Xi is as described in numbered paragraph (39);
- X 2 is as described in numbered paragraph (40) or (41);
- n is as described in numbered paragraph (42) or (43);
- R3 is as described in any of numbered paragraphs (46) to (50);
- R h and R are as described in any of numbered paragraphs (52) to (53); R j and R k are as described in any of numbered paragraphs (55) to (57);
- Ri is as described in any of numbered paragraphs (59) to (60);
- R2 is as described in numbered paragraph (32);
- R d is as described in any of numbered paragraphs (33) to (34);
- R e is as described in any of numbered paragraphs (37) to (38);
- Xi is as described in numbered paragraph (39);
- X2 is as described in numbered paragraph (40) or (41);
- n is as described in numbered paragraph (42) or (43);
- R3 is as described in any of numbered paragraphs (46) to (50);
- R h and R are as described in any of numbered paragraphs (52) to (53);
- R j and R k are as described in any of numbered paragraphs (55) to (57);
- Ri is as described in any of numbered paragraphs (59) to (60);
- X3 and X 4 are as described in any of numbered paragraphs (75) to (76);
- X5 is as described in numbered paragraph (77);
- R5 IS as described in any of numbered paragraphs (81) to (84).
- R2 is as described in numbered paragraph (32);
- R d is as described in numbered paragraph (34);
- R e is as described in numbered paragraph (38);
- Xi is as described in numbered paragraph (39);
- X2 is as described in numbered paragraph (40) or (41);
- n is as described in numbered paragraph (43);
- R3 is as described in any of numbered paragraphs (48) to (50);
- R h and R, are as described in numbered paragraph (53);
- R j and R k are as described in any of numbered paragraphs (56) to (57); Ri is as described in any of numbered paragraphs (59) to (60);
- X3 and X 4 are as described in any of numbered paragraphs (75) to (76);
- X5 is as described in numbered paragraph (77);
- R5 IS as described in any of numbered paragraphs (83) to (84).
- R2 is as described in numbered paragraph (32);
- R d is as described in numbered paragraph (34);
- R e is as described in numbered paragraph (38);
- Xi is as described in numbered paragraph (39);
- X2 is as described in numbered paragraph (40) or (41); n is as described in numbered paragraph (43);
- R3 is as described in any of numbered paragraphs (48) to (50);
- R h and R are as described in numbered paragraph (53);
- R j and R k are as described in any of numbered paragraphs (56) to (57); Ri is as described in any of numbered paragraphs (59) to (60);
- X3 and X 4 are as described in any of numbered paragraphs (75) to (76);
- X5 is as described in numbered paragraph (77);
- R5 IS as described in any of numbered paragraphs (83) to (84).
- R2 is as described in any of numbered paragraphs (30) to (32);
- R d is as described in any of numbered paragraphs (33) to (34);
- R e is as described in any of numbered paragraphs (37) to (38);
- Xi is as described in numbered paragraph (39);
- X 2 is as described in numbered paragraph (40) or (41);
- n is as described in numbered paragraph (42) or (43);
- R3 is as described in any of numbered paragraphs (46) to (50);
- R h and R are as described in any of numbered paragraphs (52) to (53);
- R j and R k are as described in any of numbered paragraphs (55) to (57);
- Ri is as described in any of numbered paragraphs (59) to (60);
- R 2 and X1 or R2 and X2 are as described in any of numbered paragraphs (65) to (67), wherein R 4 is as described in any of numbered paragraphs (70) to (72); and
- R2 is as described in numbered paragraph (32);
- R d is as described in any of numbered paragraphs (33) to (34);
- R e is as described in any of numbered paragraphs (37) to (38);
- Xi is as described in numbered paragraph (39);
- X2 is as described in numbered paragraph (40) or (41);
- n is as described in numbered paragraph (42) or (43);
- R3 is as described in any of numbered paragraphs (46) to (50);
- R h and R are as described in any of numbered paragraphs (52) to (53);
- R j and R k are as described in any of numbered paragraphs (55) to (57);
- Ri is as described in any of numbered paragraphs (59) to (60);
- R2 and Xi or R2 and X2 are as described in any of numbered paragraphs (65) to (57), wherein R 4 is as described in any of numbered paragraphs (70) to (72);
- X3 and X 4 are as described in any of numbered paragraphs (75) to (76);
- X5 is as described in numbered paragraph (77);
- o is as described in numbered paragraph (79); and R5 IS as described in any of numbered paragraphs (81) to (84).
- R2 is as described in numbered paragraph (32);
- R d is as described in numbered paragraph (34);
- R e is as described in numbered paragraph (38);
- Xi is as described in numbered paragraph (39);
- X2 is as described in numbered paragraph (40) or (41);
- n is as described in numbered paragraph (43);
- R3 is as described in any of numbered paragraphs (48) to (50);
- R h and R are as described in numbered paragraph (53);
- R j and R k are as described in any of numbered paragraphs (56) to (57);
- Ri is as described in any of numbered paragraphs (59) to (60);
- R2 and X1 or R2 and X2 are as described in any of numbered paragraphs (66) to (57), wherein R 4 is as described in any of numbered paragraphs (71) to (72);
- X3 and X 4 are as described in any of numbered paragraphs (75) to (76);
- X5 is as described in numbered paragraph (77);
- R5 IS as described in any of numbered paragraphs (83) to (84).
- R2 is as described in numbered paragraph (32);
- R d is as described in numbered paragraph (34);
- R e is as described in numbered paragraph (38);
- Xi is as described in numbered paragraph (39);
- X2 is as described in numbered paragraph (40) or (41);
- n is as described in numbered paragraph (43);
- R3 is as described in any of numbered paragraphs (48) to (50);
- R h and R are as described in numbered paragraph (53);
- R j and R k are as described in any of numbered paragraphs (56) to (57);
- Ri is as described in any of numbered paragraphs (59) to (60);
- R 2 and X 1 or R 2 and X 2 are as described in any of numbered paragraphs (66) to (67), wherein R 4 is as described in any of numbered paragraphs (71) to (72);
- X3 and X 4 are as described in any of numbered paragraphs (75) to (76);
- X5 is as described in numbered paragraph (77);
- R 5 IS as described in any of numbered paragraphs (83) to (84).
- R2 is as described in any of numbered paragraphs (30) to (32);
- R d is as described in any of numbered paragraphs (33) to (34);
- R e is as described in any of numbered paragraphs (37) to (38);
- X 2 is as described in numbered paragraph (40) or (41);
- n is as described in numbered paragraph (42) or (43);
- R3 is as described in any of numbered paragraphs (46) to (50);
- R h and R are as described in any of numbered paragraphs (52) to (53);
- R j and R k are as described in any of numbered paragraphs (55) to (57);
- Ri is as described in any of numbered paragraphs (59) to (60);
- X5 is as described in numbered paragraph (77);
- R5 IS as described in any of numbered paragraphs (81) to (84).
- R2 is as described in any of numbered paragraphs (31) to (32);
- R d is as described in any of numbered paragraphs (33) to (34);
- R e is as described in any of numbered paragraphs (37) to (38);
- X2 is as described in numbered paragraph (40) or (41);
- n is as described in numbered paragraph (42) or (43);
- R3 is as described in any of numbered paragraphs (48) to (50);
- R h and R are as described in any of numbered paragraphs (52) to (53);
- R j and R k are as described in any of numbered paragraphs (55) to (57);
- Ri is as described in any of numbered paragraphs (59) to (60);
- X5 is as described in numbered paragraph (77);
- R5 IS as described in any of numbered paragraphs (83) to (84). [0091] In an embodiment of the compounds of formula (lc), (lie) or (I lie):
- Ri is as described in any of numbered paragraphs (5) to (8);
- R a and R b are as described in any of numbered paragraphs (11) to (12);
- R c is as described in any of numbered paragraphs (24) to (25);
- R 2 is as described in any of numbered paragraphs (31) to (32);
- R d is as described in any of numbered paragraphs (33) to (34);
- R e is as described in any of numbered paragraphs (37) to (38);
- X 2 is as described in numbered paragraph (40) or (41); n is as described in numbered paragraph (42) or (43);
- R 3 is as described in any of numbered paragraphs (48) to (50);
- R h and R are as described in any of numbered paragraphs (52) to (53);
- R j and R k are as described in any of numbered paragraphs (55) to (57);
- Ri is as described in any of numbered paragraphs (59) to (60);
- X5 is as described in numbered paragraph (77);
- R 5 IS as described in any of numbered paragraphs (83) to (84).
- Ri is as described in any of numbered paragraphs (6) to (8);
- R a and R b are as described in any of numbered paragraphs (11) to (12);
- R c is as described in any of numbered paragraphs (24) to (25);
- R 2 is hydrogen
- X 2 is as described in numbered paragraph (40) or (41); n is as described in numbered paragraph (42) or (43);
- R 3 is as described in any of numbered paragraphs (48) to (50);
- R h and R are as described in any of numbered paragraphs (52) to (53); R j and R k are as described in any of numbered paragraphs (55) to (57); Ri is as described in any of numbered paragraphs (59) to (60); X5 is as described in numbered paragraph (77);
- R5 IS as described in any of numbered paragraphs (83) to (84).
- R1 is as described in numbered paragraph (8);
- R c is as described in any of numbered paragraphs (24) to (25);
- R2 is hydrogen
- X2 is as described in numbered paragraph (40) or (41); n is as described in numbered paragraph (42) or (43);
- R3 is as described in any of numbered paragraphs (49) to (50);
- R h and R are as described in numbered paragraphs (53);
- R j and R k are as described in any of numbered paragraphs (56) to (57); Ri is as described in any of numbered paragraphs (59) to (60);
- X5 is as described in numbered paragraph (77);
- R5 IS as described in any of numbered paragraphs (83) to (84).
- R1 is as described in any of numbered paragraphs (5) to (8);
- R a and R b are as described in any of numbered paragraphs (13) to (22);
- R c is as described in any of numbered paragraphs (24) to (25);
- R2 is as described in any of numbered paragraphs (31) to (32);
- R d is as described in any of numbered paragraphs (33) to (34);
- R e is as described in any of numbered paragraphs (37) to (38);
- X2 is as described in numbered paragraph (40) or (41); n is as described in numbered paragraph (42) or (43);
- R3 is as described in any of numbered paragraphs (48) to (50);
- R h and R are as described in any of numbered paragraphs (52) to (53);
- R j and R k are as described in any of numbered paragraphs (55) to (57);
- Ri is as described in any of numbered paragraphs (59) to (60);
- X 5 is as described in numbered paragraph (77);
- R 5 IS as described in any of numbered paragraphs (83) to (84).
- R 1 is as described in any of numbered paragraphs (6) to (8);
- R a and R b are as described in any of numbered paragraphs (17) to (22);
- R c is as described in any of numbered paragraphs (24) to (25);
- R 2 is hydrogen
- X 2 is as described in numbered paragraph (40) or (41); n is as described in numbered paragraph (42) or (43);
- R 3 is as described in any of numbered paragraphs (48) to (50);
- R h and R are as described in any of numbered paragraphs (52) to (53);
- R j and R k are as described in any of numbered paragraphs (55) to (57);
- Ri is as described in any of numbered paragraphs (59) to (60);
- X5 is as described in numbered paragraph (77);
- R 5 IS as described in any of numbered paragraphs (83) to (84).
- Ri is as described in any of numbered paragraphs (6) to (8);
- R a and R b are as described in any of numbered paragraphs (21) to (22);
- R c is as described in any of numbered paragraphs (24) to (25);
- R 2 is hydrogen
- X 2 is as described in numbered paragraph (40) or (41); n is as described in numbered paragraph (42) or (43);
- R is as described in any of numbered paragraphs (48) to (50);
- R h and R are as described in any of numbered paragraphs (52) to (53);
- R j and R k are as described in any of numbered paragraphs (55) to (57);
- Ri is as described in any of numbered paragraphs (59) to (60);
- X5 is as described in numbered paragraph (77);
- R 2 is as described in any of numbered paragraphs (30) to (32);
- R d is as described in any of numbered paragraphs (33) to (34);
- R e is as described in any of numbered paragraphs (37) to (38);
- R 3 is as described in any of numbered paragraphs (46) to (50);
- R h and R are as described in any of numbered paragraphs (52) to (53);
- R j and R k are as described in any of numbered paragraphs (55) to (57);
- Ri is as described in any of numbered paragraphs (59) to (60);
- X5 is as described in numbered paragraph (77);
- R 5 IS as described in any of numbered paragraphs (81) to (84).
- R 2 is as described in any of numbered paragraphs (31) to (32);
- R d is as described in any of numbered paragraphs (33) to (34);
- R e is as described in any of numbered paragraphs (37) to (38);
- R 3 is as described in any of numbered paragraphs (48) to (50);
- R h and R are as described in any of numbered paragraphs (52) to (53);
- R j and R k are as described in any of numbered paragraphs (55) to (57);
- Ri is as described in any of numbered paragraphs (59) to (60);
- X5 is as described in numbered paragraph (77);
- R 5 IS as described in any of numbered paragraphs (83) to (84).
- Ri is as described in any of numbered paragraphs (5) to (8);
- R a and R b are as described in any of numbered paragraphs (11) to (12);
- R c is as described in any of numbered paragraphs (24) to (25);
- R 2 is as described in any of numbered paragraphs (31) to (32);
- R d is as described in any of numbered paragraphs (33) to (34);
- R e is as described in any of numbered paragraphs (37) to (38);
- R 3 is as described in any of numbered paragraphs (48) to (50);
- R h and R are as described in any of numbered paragraphs (52) to (53);
- R j and R k are as described in any of numbered paragraphs (55) to (57);
- Ri is as described in any of numbered paragraphs (59) to (60);
- X5 is as described in numbered paragraph (77);
- R 5 IS as described in any of numbered paragraphs (83) to (84).
- R 1 is as described in any of numbered paragraphs (6) to (8);
- R a and R b are as described in any of numbered paragraphs (11) to (12);
- R c is as described in any of numbered paragraphs (24) to (25);
- R 2 is hydrogen
- R 3 is as described in any of numbered paragraphs (48) to (50);
- R h and R are as described in any of numbered paragraphs (52) to (53);
- R j and R k are as described in any of numbered paragraphs (55) to (57);
- Ri is as described in any of numbered paragraphs (59) to (60);
- X5 is as described in numbered paragraph (77);
- R 5 IS as described in any of numbered paragraphs (83) to (84).
- Ri is as described in numbered paragraph (8);
- R c is as described in any of numbered paragraphs (24) to (25);
- R 2 is hydrogen
- R 3 is as described in any of numbered paragraphs (49) to (50);
- R h and R, are as described in numbered paragraphs (53);
- R j and R k are as described in any of numbered paragraphs (56) to (57); Ri is as described in any of numbered paragraphs (59) to (60);
- X 5 is as described in numbered paragraph (77);
- R 5 IS as described in any of numbered paragraphs (83) to (84).
- R 1 is as described in any of numbered paragraphs (5) to (8);
- R a and R b are as described in any of numbered paragraphs (13) to (22);
- R c is as described in any of numbered paragraphs (24) to (25);
- R 2 is as described in any of numbered paragraphs (31) to (32);
- R d is as described in any of numbered paragraphs (33) to (34);
- R e is as described in any of numbered paragraphs (37) to (38);
- R 3 is as described in any of numbered paragraphs (48) to (50);
- R h and R are as described in any of numbered paragraphs (52) to (53);
- R j and R k are as described in any of numbered paragraphs (55) to (57);
- Ri is as described in any of numbered paragraphs (59) to (60);
- X5 is as described in numbered paragraph (77);
- R 5 IS as described in any of numbered paragraphs (83) to (84).
- Ri is as described in any of numbered paragraphs (6) to (8);
- R a and R b are as described in any of numbered paragraphs (17) to (22);
- R c is as described in any of numbered paragraphs (24) to (25);
- R 2 is hydrogen
- R 3 is as described in any of numbered paragraphs (48) to (50);
- R h and R are as described in any of numbered paragraphs (52) to (53);
- R j and R k are as described in any of numbered paragraphs (55) to (57);
- Ri is as described in any of numbered paragraphs (59) to (60);
- X 5 is as described in numbered paragraph (77);
- R 5 IS as described in any of numbered paragraphs (83) to (84).
- R 1 is as described in numbered paragraph (7) or (8);
- R a and R b are as described in any of numbered paragraphs (21) to (22);
- R c is as described in any of numbered paragraphs (24) to (25);
- R 2 is hydrogen
- R 3 is as described in any of numbered paragraphs (49) to (50);
- R h and R are as described in numbered paragraphs (53);
- R j and R k are as described in any of numbered paragraphs (56) to (57);
- Ri is as described in any of numbered paragraphs (59) to (60);
- X5 is as described in numbered paragraph (77);
- R 5 IS as described in any of numbered paragraphs (83) to (84).
- Ri is hydroxy
- X1 is O
- X2 is as defined in numbered paragraph (41)
- n is 1
- X3 and X 4 are as defined in numbered paragraph (76), such that the compounds have a structure according to formula (le), (lie) or (I lie) shown below:
- R is as described in any of numbered paragraphs (30) to (32);
- R d is as described in any of numbered paragraphs (33) to (34);
- R e is as described in any of numbered paragraphs (37) to (38);
- R is as described in any of numbered paragraphs (46) to (50);
- R h and R are as described in any of numbered paragraphs (52) to (53);
- R j and R k are as described in any of numbered paragraphs (55) to (57);
- Ri is as described in any of numbered paragraphs (59) to (60);
- X 5 is as described in numbered paragraph (77);
- R is as described in any of numbered paragraphs (31) to (32);
- R d is as described in any of numbered paragraphs (33) to (34);
- R e is as described in any of numbered paragraphs (37) to (38); R is as described in any of numbered paragraphs (48) to (50);
- R h and R are as described in any of numbered paragraphs (52) to (53);
- R j and R k are as described in any of numbered paragraphs (55) to (57);
- Ri is as described in any of numbered paragraphs (59) to (60);
- X5 is as described in numbered paragraph (77);
- R is as described in any of numbered paragraphs (31) to (32);
- R d is as described in any of numbered paragraphs (33) to (34);
- R e is as described in any of numbered paragraphs (37) to (38);
- R is as described in any of numbered paragraphs (48) to (50);
- R h and R are as described in any of numbered paragraphs (52) to (53);
- R j and R k are as described in any of numbered paragraphs (55) to (57);
- Ri is as described in any of numbered paragraphs (59) to (60);
- X5 is as described in numbered paragraph (77);
- R is hydrogen
- R is as described in any of numbered paragraphs (48) to (50);
- R h and R are as described in any of numbered paragraphs (52) to (53);
- R j and R k are as described in any of numbered paragraphs (55) to (57);
- Ri is as described in any of numbered paragraphs (59) to (60);
- X5 is as described in numbered paragraph (77);
- R2 is hydrogen
- R3 is as described in any of numbered paragraphs (49) to (50);
- R h and R are as described in numbered paragraphs (53);
- R j and R k are as described in any of numbered paragraphs (56) to (57);
- Ri is as described in any of numbered paragraphs (59) to (60);
- X 5 is as described in numbered paragraph (77);
- R5 IS as described in any of numbered paragraphs (83) to (84).
- R 2 is as described in any of numbered paragraphs (30) to (32);
- Rd is as described in any of numbered paragraphs (33) to (34);
- R e is as described in any of numbered paragraphs (37) to (38);
- R 5 IS as described in any of numbered paragraphs (81) to (84).
- R 1 and any of its associated substituents, has any of the definitions appearing hereinbefore;
- R 2 is as described in any of numbered paragraphs (31) to (32);
- Rd is as described in any of numbered paragraphs (33) to (34);
- R e is as described in any of numbered paragraphs (37) to (38); and R 5 IS as described in any of numbered paragraphs (83) to (84).
- R 1 is as described in any of numbered paragraphs (5) to (8);
- R a and R b are as described in any of numbered paragraphs (11) to (12);
- R c is as described in any of numbered paragraphs (24) to (25);
- R 2 is as described in any of numbered paragraphs (31) to (32);
- Rd is as described in any of numbered paragraphs (33) to (34);
- R e is as described in any of numbered paragraphs (37) to (38); and R 5 IS as described in any of numbered paragraphs (83) to (84).
- R 1 is as described in any of numbered paragraphs (6) to (8);
- R a and R b are as described in any of numbered paragraphs (11) to (12);
- R c is as described in any of numbered paragraphs (24) to (25);
- R 2 is hydrogen
- R 5 IS as described in any of numbered paragraphs (83) to (84).
- Ri is as described in numbered paragraph (8);
- R c is as described in any of numbered paragraphs (24) to (25);
- R 2 is hydrogen
- R 1 is as described in any of numbered paragraphs (5) to (8);
- R a and R b are as described in any of numbered paragraphs (13) to (22);
- R c is as described in any of numbered paragraphs (24) to (25);
- R 2 is as described in any of numbered paragraphs (31) to (32);
- R d is as described in any of numbered paragraphs (33) to (34);
- R e is as described in any of numbered paragraphs (37) to (38);
- R 5 IS as described in any of numbered paragraphs (83) to (84).
- R 1 is as described in any of numbered paragraphs (6) to (8);
- R a and R b are as described in any of numbered paragraphs (17) to (22);
- R c is as described in any of numbered paragraphs (24) to (25);
- R 2 is hydrogen
- R 5 IS as described in any of numbered paragraphs (83) to (84).
- R 1 is as described in numbered paragraph (7) or (8);
- R a and R b are as described in any of numbered paragraphs (19) to (22); R c is as described in any of numbered paragraphs (24) to (25);
- R 2 is hydrogen
- R 5 IS as described in any of numbered paragraphs (83) to (84).
- R 1 is as described in numbered paragraph (7) or (8);
- R a and R b are as described in any of numbered paragraphs (21) to (22); R c is as described in any of numbered paragraphs (24) to (25); R 2 is hydrogen; and
- the compound having a structure according to formula (I), (II) or (III) has any of the following structures:
- the compound having a structure according to formula (I), (II) or (III) has any of the following structures:
- the compound having a structure according to formula (I), (II) or (III) has any of the following structures:
- the compound having a structure according to formula (I), (II) or (III) has any of the following structures:
- the compound having a structure according to formula (I), (II) or (III) has the following structure:
- the compound having a structure according to formula (I), (II) or (III) has the following structure:
- the present invention also provides a method of inhibiting RIF-resistant RNA polymerase, in vitro or in vivo, said method comprising contacting a cell with an effective amount of a compound of formula (I), (II) or (III), or a pharmaceutically acceptable salt, hydrate or solvate thereof as defined herein.
- the present invention also provides a method of inhibiting bacterial cell proliferation, in vitro or in vivo, said method comprising contacting a bacterial cell with an effective amount of a compound of formula (I), (II) or (III), or a pharmaceutically acceptable salt, hydrate or solvate thereof as defined herein, or a pharmaceutical composition as defined herein.
- the present invention also provides a method of treating an infection caused by RIF- resistant bacteria in a patient in need of such treatment, said method comprising administering to said patient a therapeutically effective amount of a compound of formula (I), (II) or (III), or a pharmaceutically acceptable salt, hydrate or solvate thereof as defined herein, or a pharmaceutical composition as defined herein.
- the present invention also provides a use of a compound of formula (I), (II) or (III), or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein in the manufacture of a medicament for the inhibition of RIF-resistant RNA polymerase.
- the present invention also provides a use of a compound of formula (I), (II) or (III), or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein in the manufacture of a medicament for the treatment of an infection caused by RIF-resistant bacteria.
- the RIF-resistant bacteria is one or more RIF-resistant Gram positive bacteria.
- the RIF-resistant bacteria is RIF-resistant S. aureus.
- the RIF-resistant bacteria is RIF-resistant M. tuberculosis
- the infection caused by RIF-resistant bacteria is RIF-resistant tuberculosis.
- the compound of formula (I), (II) or (III) may be used (e.g. administered) in combination with one or more other active ingredients.
- the one or more other active ingredients is rifampicin or a derivative thereof.
- a suitable pharmaceutically acceptable salt of a compound of formula (I), (II) or (III) is, for example, an acid-addition salt of a compound of formula (I), (II) or (III) which is sufficiently basic, for example, an acid-addition salt with, for example, an inorganic or organic acid, for example hydrochloric, hydrobromic, sulfuric, phosphoric, trifluoroacetic, formic, citric methane sulfonate or maleic acid.
- a suitable pharmaceutically acceptable salt of a compound of formula (I), (II) or (III) which is sufficiently acidic is an alkali metal salt, for example a sodium or potassium salt, an alkaline earth metal salt, for example a calcium or magnesium salt, an ammonium salt or a salt with an organic base which affords a pharmaceutically acceptable cation, for example a salt with methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine.
- An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or (-)-isomers respectively).
- a chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a“racemic mixture”.
- the compounds of formula (I), (II) or (III) may possess one or more asymmetric centers; such compounds can therefore be produced as individual (R)- or (S)-stereoisomers or as mixtures thereof.
- the description or naming of a particular compound in the specification and claims is intended to include both individual enantiomers and mixtures, racemic or otherwise, thereof.
- the methods for the determination of stereochemistry and the separation of stereoisomers are well-known in the art (see discussion in Chapter 4 of“Advanced Organic Chemistry”, 4th edition J. March, John Wiley and Sons, New York, 2001), for example by synthesis from optically active starting materials or by resolution of a racemic form.
- Some of the compounds of formula (I), (II) or (III) may have geometric isomeric centres (E- and Z- isomers). It is to be understood that the present invention encompasses all optical, diastereoisomers and geometric isomers and mixtures thereof that possess antiproliferative activity.
- the present invention also encompasses compounds of formula (I), (II) or (III) as defined herein which comprise one or more isotopic substitutions.
- H may be in any isotopic form, including 1 H, 2H(D), and 3H (T);
- C may be in any isotopic form, including 12C, 13C, and 14C; and
- O may be in any isotopic form, including 160 and180; and the like.
- tautomeric forms include keto-, enol-, and enolate-forms, as in, for example, the following tautomeric pairs: keto/enol (illustrated below), imine/enamine, amide/imino alcohol, amidine/amidine, nitroso/oxime, thioketone/enethiol, and nitro/aci-nitro.
- N- oxides Compounds of formula (I), (II) or (III) containing an amine function may also form N- oxides.
- a reference herein to a compound of formula (I), (II) or (III) that contains an amine function also includes the N-oxide.
- one or more than one nitrogen atom may be oxidised to form an N-oxide.
- Particular examples of N- oxides are the N-oxides of a tertiary amine or a nitrogen atom of a nitrogen-containing heterocycle.
- N-Oxides can be formed by treatment of the corresponding amine with an oxidizing agent such as hydrogen peroxide or a per-acid (e.g.
- the compounds of formula (I), (II) or (III) may be administered in the form of a pro-drug which is broken down in the human or animal body to release a compound of formula (I), (II) or (III).
- a pro-drug may be used to alter the physical properties and/or the pharmacokinetic properties of a compound of formula (I), (II) or (III).
- a pro-drug can be formed when the compound formula (I), (II) or (III) contains a suitable group or substituent to which a property-modifying group can be attached.
- pro-drugs examples include in vivo cleavable ester derivatives that may be formed at a carboxy group or a hydroxy group in a compound of formula (I), (II) or (III), and in- vivo cleavable amide derivatives that may be formed at a carboxy group or an amino group in a compound of formula (I), (II) or (III).
- the present invention includes those compounds of formula (I), (II) or (III) as defined hereinbefore, when made available by organic synthesis and when made available within the human or animal body by way of cleavage of a pro-drug thereof. Accordingly, the present invention includes those compounds of formula (I), (II) or (III) that are produced by organic synthetic means and also such compounds that are produced in the human or animal body by way of metabolism of a precursor compound, that is a compound of formula (I), (II) or (III) may be a synthetically-produced compound or a metabolically-produced compound.
- a suitable pharmaceutically acceptable pro-drug of a compound of formula (I), (II) or (III) is one that is based on reasonable medical judgement as being suitable for administration to the human or animal body without undesirable pharmacological activities and without undue toxicity.
- a suitable pharmaceutically acceptable pro-drug of a compound of formula (I), (II) or (III) that possesses a carboxy group is, for example, an in vivo cleavable ester thereof.
- An in vivo cleavable ester of a compound of formula (I), (II) or (III) containing a carboxy group is, for example, a pharmaceutically acceptable ester which is cleaved in the human or animal body to produce the parent acid.
- Suitable pharmaceutically acceptable esters for carboxy include C1-6alkyl esters such as methyl, ethyl and tert- butyl, C1-6alkoxymethyl esters such as methoxymethyl esters, C1-6alkanoyloxymethyl esters such as pivaloyloxymethyl esters, 3-phthalidyl esters, C3-8cycloalkylcarbonyloxy- C1-6alkyl esters such as cyclopentylcarbonyloxymethyl and 1-cyclohexylcarbonyloxyethyl esters,
- 2-oxo-1 ,3-dioxolenylmethyl esters such as 5-methyl-2-oxo-1 ,3-dioxolen-4-ylmethyl esters and C1-6alkoxycarbonyloxy- C1-6alkyl esters such as methoxycarbonyloxymethyl and 1- methoxycarbonyloxyethyl esters.
- a suitable pharmaceutically acceptable pro-drug of a compound of formula (I), (II) or (III) that possesses a hydroxy group is, for example, an in vivo cleavable ester or ether thereof.
- An in vivo cleavable ester or ether of a compound of formula (I), (II) or (III) containing a hydroxy group is, for example, a pharmaceutically acceptable ester or ether which is cleaved in the human or animal body to produce the parent hydroxy compound.
- Suitable pharmaceutically acceptable ester forming groups for a hydroxy group include inorganic esters such as phosphate esters (including phosphoramidic cyclic esters).
- ester forming groups for a hydroxy group include C1-10alkanoyl groups such as acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups, C1-10alkoxycarbonyl groups such as ethoxycarbonyl, N,N -(C1-6)2carbamoyl, 2-dialkylaminoacetyl and 2-carboxyacetyl groups.
- Suitable pharmaceutically acceptable ether forming groups for a hydroxy group include a-acyloxyalkyl groups such as acetoxymethyl and pivaloyloxymethyl groups.
- a suitable pharmaceutically acceptable pro-drug of a compound of formula (I), (II) or (III) that possesses a carboxy group is, for example, an in vivo cleavable amide thereof, for example an amide formed with an amine such as ammonia, a C1-4alkylamine such as methylamine, a (C1-4alkyl)2amine such as dimethylamine, N-ethyl-N-methylamine or diethylamine, a C1- 4alkoxy- C2-4alkylamine such as 2-methoxyethylamine, a phenyl-C1-4alkylamine such as benzylamine and amino acids such as glycine or an ester thereof.
- an amine such as ammonia
- a C1-4alkylamine such as methylamine
- a (C1-4alkyl)2amine such as dimethylamine, N-ethyl-N-methylamine or diethylamine
- a suitable pharmaceutically acceptable pro-drug of a compound of formula (I), (II) or (III) that possesses an amino group is, for example, an in vivo cleavable amide derivative thereof.
- Suitable pharmaceutically acceptable amides from an amino group include, for example an amide formed with C1-10alkanoyl groups such as an acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups.
- Examples of ring substituents on the phenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl, piperazin-1-ylmethyl and
- the in vivo effects of a compound of formula (I), (II) or (III) may be exerted in part by one or more metabolites that are formed within the human or animal body after administration of a compound of formula (I), (II) or (III).
- the in vivo effects of a compound of formula (I), (II) or (III) may also be exerted by way of metabolism of a precursor compound (a pro-drug).
- the present invention may relate to any compound or particular group of compounds defined herein by way of optional, preferred or suitable features or otherwise in terms of particular embodiments, the present invention may also relate to any compound or particular group of compounds that specifically excludes said optional, preferred or suitable features or particular embodiments.
- the present invention excludes any individual compounds not possessing the biological activity defined herein.
- the compounds formula (I), (II) or (III) or pharmaceutical compositions comprising these compounds may be administered to a subject by any convenient route of administration, whether systemically, peripherally or topically (i.e., at the site of desired action).
- Routes of administration include, but are not limited to, oral (e.g, by ingestion); buccal; sublingual; transdermal (including, e.g., by a patch, plaster, etc.); transmucosal (including, e.g., by a patch, plaster, etc.); intranasal (e.g., by nasal spray); ocular (e.g., by eye drops); pulmonary (e.g., by inhalation or insufflation therapy using, e.g., via an aerosol, e.g., through the mouth or nose); rectal (e.g., by suppository or enema); vaginal (e.g., by pessary); parenteral, for example, by injection, including subcutaneous, intradermal, intramuscular, intravenous, intra-arterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcut
- the compound has any of those definitions appearing hereinbefore in relation to formula (I), (II) or (III), with the proviso that, in formula (I), Ri is not hydroxy.
- the compound has any of those definitions appearing hereinbefore in relation to formula (I’), (II’) or (III’), with the proviso that, in formula (I’), Ri is not hydroxy.
- the compound has any of those definitions appearing hereinbefore in relation to formula (la), (I la) or (Ilia), with the proviso that, in formula (la), Ri is not hydroxy.
- the compound has any of those definitions appearing hereinbefore in relation to formula (lc), (lie) or (lllc), with the proviso that, in formula (lc), Ri is not hydroxy.
- the compound has any of those definitions appearing hereinbefore in relation to formula (Id), (lid) or (Hid), with the proviso that, in formula (Id), Ri is not hydroxy.
- the compound has any of those definitions appearing hereinbefore in relation to formula (If), (Ilf) or (I Ilf), with the proviso that, in formula (If), Ri is not hydroxy.
- the compound has any of those definitions appearing hereinbefore in relation to formula (I), (II) or (III), with the proviso that, in formula (I), R 2 is not hydrogen.
- the compound has any of those definitions appearing hereinbefore in relation to formula (I’), (II’) or (III’), with the proviso that, in formula (I’), R 2 is not hydrogen.
- the compound has any of those definitions appearing hereinbefore in relation to formula (lb), (lib) or (Nib), with the proviso that, in formula (lb), R 2 is not hydrogen.
- the compound has any of those definitions appearing hereinbefore in relation to formula (lc), (lie) or (lllc), with the proviso that, in formula (lc), R 2 is not hydrogen.
- the compound has any of those definitions appearing hereinbefore in relation to formula (Id), (lid) or (I lid), with the proviso that, in formula (Id), R 2 is not hydrogen.
- the compound has any of those definitions appearing hereinbefore in relation to formula (le), (lie) or (I lie), with the proviso that, in formula (le), R 2 is not hydrogen.
- the compound has any of those definitions appearing hereinbefore in relation to formula (If), (Ilf) or (I Ilf), with the proviso that, in formula (If), R 2 is not hydrogen.
- the compound has any of the following structures:
- the compound has any of the following structures:
- the compound has any of the following structures:
- the compound has any of the following structures:
- the compound has the following structure:
- the present invention also provides a compound of the invention, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein for use in therapy.
- the present invention also provides a compound of the invention, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein for use as a medicament.
- the present invention also provides a method of treating a bacterial infection in a patient in need of such treatment, said method comprising administering to said patient a therapeutically effective amount of a compound of the invention.
- the infection may be caused by RIF-resistant bacteria (e.g. RIF-resistant tuberculosis) or RIF-susceptible bacteria.
- RIF-resistant bacteria e.g. RIF-resistant tuberculosis
- RIF-susceptible bacteria e.g. RIF-resistant tuberculosis
- the method of treatment may prevent the bacteria from becoming RIF-resistant.
- the compound of the invention may be used (e.g. administered) in combination with one or more other active ingredients.
- the one or more other active ingredients is rifampicin or a derivative thereof.
- a pharmaceutical composition which comprises a compound of the invention as defined hereinbefore, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in association with a pharmaceutically acceptable diluent or carrier.
- compositions of the invention may be in a form suitable for oral use (for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for topical use (for example as creams, ointments, gels, or aqueous or oily solutions or suspensions), for administration by inhalation (for example as a finely divided powder or a liquid aerosol), for administration by insufflation (for example as a finely divided powder) or for parenteral administration (for example as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular, intraperitoneal or intramuscular dosing or as a suppository for rectal dosing).
- oral use for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or
- compositions of the invention may be obtained by conventional procedures using conventional pharmaceutical excipients, well known in the art.
- compositions intended for oral use may contain, for example, one or more colouring, sweetening, flavouring and/or preservative agents.
- An effective amount of a compound of the present invention for use in therapy is an amount sufficient to treat or prevent a proliferative condition referred to herein, slow its progression and/or reduce the symptoms associated with the condition.
- the amount of active ingredient that is combined with one or more excipients to produce a single dosage form will necessarily vary depending upon the individual treated and the particular route of administration.
- a formulation intended for oral administration to humans will generally contain, for example, from 0.5 mg to 0.5 g of active agent (more suitably from 0.5 to 100 mg, for example from 1 to 30 mg) compounded with an appropriate and convenient amount of excipients which may vary from about 5 to about 98 percent by weight of the total composition.
- the size of the dose for therapeutic or prophylactic purposes of a compound of the formula I will naturally vary according to the nature and severity of the conditions, the age and sex of the animal or patient and the route of administration, according to well-known principles of medicine.
- a daily dose in the range for example, 0.1 mg/kg to 75 mg/kg body weight is received, given if required in divided doses.
- a parenteral route is employed.
- a dose in the range for example, 0.1 mg/kg to 30 mg/kg body weight will generally be used.
- a dose in the range for example, 0.05 mg/kg to 25 mg/kg body weight will be used.
- Oral administration may also be suitable, particularly in tablet form.
- unit dosage forms will contain about 0.5 mg to 0.5 g of a compound of this invention.
- Ri is selected from hydrogen, halo, cyano, isocyano, nitro, hydroxy, (1-6C)alkyl, (1-6C)haloalkyl, (2-4C)alkenyl, (2-4C)alkynyl, (1-8C)heteroalkyl, aryl, aryl(1-2C)alkyl, heteroaryl, heteroaryl(1-2C)alkyl, (3-8C)heterocyclyl, (3-8C)heterocyclyl(1-2C)alkyl, (3- 8C)cycloalkyl, (3-8C)cycloalkyl(1-2C)alkyl, NR a R b , OR c , 0C(0)R a , N(R b )OR a , N(R b )C(0)ORa, N(R b )C(0)Ra, S(0) P R a (where p is 0, 1 or 2), S0 2 N(R b )R a , and
- R 1 and R 2 are each independently optionally substituted by one or more substituent groups selected from fluoro, chloro, trifluoromethyl, trifluoromethoxy, cyano, nitro, hydroxy, amino, carboxy, carbamoyl, sulphamoyl, (1-4C)alkyl, (1-4C)alkoxy, S(0) q CH 3 (where q is 0, 1 or 2), methylamino or dimethylamino, aryl, aryl(1-2C)alkyl, heteroaryl, heteroaryl(1-2C)alkyl, (3-8C)heterocyclyl, (3- 8C)heterocyclyl(1-2C)alkyl, (3-8C)cycloalkyl, or (3-8C)cycloalkyl(1- 2C)alkyl;
- Xi is selected from O and NR g ;
- X 2 is hydroxy or a group of formula (A) shown below:
- n 0, 1 , 2, 3 or 4;
- R 3 is independently optionally substituted by one or more substituent groups selected from fluoro, chloro, trifluoromethyl, trifluoromethoxy, cyano, nitro, hydroxy, amino, carboxy, carbamoyl, sulphamoyl, (1- 4C)alkyl, (1-4C)alkoxy, S(0) q CH 3 (where q is 0, 1 or 2), methylamino or dimethylamino, aryl, aryl(1-2C)alkyl, heteroaryl, heteroaryl(1-2C)alkyl, (3-8C)heterocyclyl, (3- 8C)heterocyclyl, (3- 8C)heterocycly
- R 2 and X1 or R 2 and X 2 are linked, such that when they are taken in combination with the carbon atoms to which they are attached, they collectively form a 5-12 membered heteroaryl or heterocycle that is optionally substituted with one or more R 4 substituents;
- each R 4 is independently selected from halo, cyano, isocyano, nitro, hydroxy, (1-6C)alkyl, (1-6C)haloalkyl, (2-4C)alkenyl, (2- 4C)alkynyl, (1-8C)heteroalkyl, aryl, aryl(1-2C)alkyl, heteroaryl, heteroaryl(1-2C)alkyl, (3-8C)heterocyclyl, (3-8C)heterocyclyl(1-2C)alkyl, (3-8C)cycloalkyl, (3-8C)cycloalkyl(1-2C)alkyl, NR m R n , OR 0 , C(0)R m , C(0)OR m , OC(0)R m , N(R m )OR n , N(R m )C(0)OR n , C(0)N(R m )R n ,
- each R 4 is independently optionally substituted with one or more groups selected from fluoro, chloro, trifluoromethyl, trifluoromethoxy, cyano, nitro, hydroxy, amino, carboxy, carbamoyl, sulphamoyl, (1-4C)alkyl, (2-4C)alkenyl, (2-4C)alkynyl, (1-4C)alkoxy, S(0) q CH 3 (where q is 0, 1 or 2), methylamino or dimethylamino, aryl, aryl(1-2C)alkyl, heteroaryl, heteroaryl(1-2C)alkyl, (3-8C)heterocyclyl, (3- 8C)heterocyclyl(1-2C)alkyl, (3-8C)cycloalkyl, and (3-8C)cycloalkyl(1- 2C)alkyl;
- X3 and X 4 are independently selected from hydroxy, OR p , NR q R r and a group of formula (A) shown above;
- X3 and X 4 are linked, such that when they are taken in combination with the carbon atom to which they are attached, they collectively form a 4-6 membered heterocycle that is optionally substituted with one or more R 5 substituents;
- each R 5 is independently selected from fluoro, chloro, trifluoromethyl, trifluoromethoxy, cyano, nitro, hydroxy, oxo, amino, carboxy, carbamoyl, sulphamoyl, (1-6C)alkyl, (2-6C)alkenyl, (2- 6C)alkynyl, (1-4C)alkoxy, S(0) q CH 3 (where q is 0, 1 or 2), methylamino or dimethylamino, aryl, aryl(1-2C)alkyl, heteroaryl, heteroaryl(1-2C)alkyl, (3- 8C)heterocyclyl, (3-8C)heterocyclyl(1-2C)alkyl, (3-8C)cycloalkyl, and (3- 8C)cycloalkyl(1-2C)alkyl;
- each R a to R r is independently selected from hydrogen, fluoro, chloro, trifluoromethyl, trifluoromethoxy, cyano, nitro, hydroxy, amino, carboxy, carbamoyl, sulphamoyl, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (1-4C)alkoxy, S(0) q CH 3 (where q is 0, 1 or 2), methylamino or dimethylamino, aryl, aryl(1-2C)alkyl, heteroaryl,
- heteroaryl(1-2C)alkyl (3-8C)heterocyclyl, (3-8C)heterocyclyl(1-2C)alkyl, (3- 8C)cycloalkyl, and (3-8C)cycloalkyl(1-2C)alkyl;
- each R a to R r is independently optionally substituted with one or more groups selected from fluoro, chloro, trifluoromethyl, trifluoromethoxy, cyano, nitro, hydroxy, amino, carboxy, carbamoyl, sulphamoyl, (1-4C)alkyl, (2-4C)alkenyl, (2-4C)alkynyl, (1-4C)alkoxy, S(0) q CH 3 (where q is 0, 1 or 2), methylamino or dimethylamino, aryl, aryl(1-2C)alkyl, heteroaryl, heteroaryl(1-2C)alkyl, (3-8C)heterocyclyl, (3- 8C)heterocyclyl(1-2C)alkyl, (3-8C)cycloalkyl, and (3-8C)cycloalkyl(1- 2C)alkyl.
- the compound for use according to statement 1 wherein the compound has a structure according to formula (G), (IG) or (IG)
- Ri is selected from hydrogen, halo, hydroxy, (1-6C)alkyl, (1-6C)haloalkyl, (2-4C)alkenyl, (2-4C)alkynyl, (1- 8C)heteroalkyl, aryl, aryl(1-2C)alkyl, heteroaryl, heteroaryl(1-2C)alkyl, (3- 8C)heterocyclyl, (3-8C)heterocyclyl(1-2C)alkyl, (3-8C)cycloalkyl, (3-8C)cycloalkyl(1- 2C)alkyl, NR a R b , OR c , 0C(0)R a , N(R b )OR a , N(R b )C(0)0R a and N(R b )C(0)R a ,
- Ri is optionally substituted by one or more substituent groups selected from (1-4C)alkyl and (1-3C)alkoxy.
- Ri is optionally substituted by one or more substituent groups selected from (1-4C)alkyl and (1-3C)alkoxy.
- Ri is selected from hydrogen, halo, hydroxy, (1-6C)alkyl, aryl, aryl(1-2C)alkyl, heteroaryl, heteroaryl(1- 2C)alkyl, (3-8C)heterocyclyl, (3-8C)heterocyclyl(1-2C)alkyl, (3-8C)cycloalkyl, (3- 8C)cycloalkyl(1-2C)alkyl, NR a R b and OR c ,
- Ri is optionally substituted by one or more substituent groups selected from (1-2C)alkyl and (1-2C)alkoxy.
- Ri is selected from hydroxy, (1-6C)alkyl, aryl, heteroaryl, (3-8C)heterocyclyl, (3-8C)cycloalkyl, NR a R b and ORc,
- Ri is optionally substituted by one or more substituent groups selected from (1-2C)alkyl and (1-2C)alkoxy.
- Ri is selected from hydroxy, (1-4C)alkyl, N-linked (3-8C)heterocyclyl, NR a R b and OR c ,
- Ri is optionally substituted by one or more (1-2C)alkyl.
- Ri is selected from hydroxy, (1-3C)alkyl, N-linked (3-6C)heterocyclyl, NR a R b and OR c , wherein the N- linked (3-6C)heterocyclyl contains 1 or 2 heteroatoms,
- Ri is optionally substituted by one or more (1-2C)alkyl.
- Ri is selected from hydroxy, NR a R b , OR c or any one of the following:
- R a and R b are independently selected from hydrogen, (1-6C)alkyl, (1-4C)alkoxy, aryl and (3- 8C)heterocyclyl.
- R a and R b are independently selected from hydrogen, (1-6C)alkyl, aryl and N-linked (3- 8C)heterocyclyl.
- R a and R b are independently selected from hydrogen, (1-6C)alkyl, phenyl and 5-6 membered N-linked heterocyclyl.
- R a and R b are independently selected from hydrogen, (1-6C)alkyl, phenyl or any one of the following:
- R a and R b are independently selected from hydrogen, (1-6C)alkyl and phenyl.
- each R a and R b are independently selected from hydrogen, (1-6C)alkyl, amino, aryl, aryl(1-2C)alkyl, (3-8C)cycloalkyl or any one of the following: wherein each R a and R b is optionally substituted with one or more substituent groups selected from halo, hydroxy, (1-3C)alkyl and (1-3C)haloalkyl.
- R a is hydrogen or (1-6C)alkyl and R b is selected from (1-6C)alkyl, amino, aryl, aryl(1-2C)alkyl, (3-8C)cycloalkyl or any one of the following: wherein each R b is optionally substituted with one or more substituent groups selected from halo, hydroxy, (1-3C)alkyl and (1-3C)haloalkyl.
- each R a and R b are independently selected from hydrogen, (1-3C)alkyl, amino, phenyl, benzyl, (3- 6C)cycloalkyl or any one of the following: wherein each of the said phenyl and benzyl groups is optionally substituted with one or more substituent groups selected from fluoro, chloro hydroxy, (1-3C)alkyl and (1- 3C)haloalkyl, and each of the said amino groups is optionally substituted with one or more substituent groups selected from (1-3C)alkyl.
- R a is hydrogen or (1-3C)alkyl and R b is selected from (1-3C)alkyl, amino, phenyl, benzyl, (3- 6C)cycloalkyl or any one of the following: wherein each of the said phenyl and benzyl groups is optionally substituted with one or more substituent groups selected from fluoro, chloro hydroxy, (1-3C)alkyl and (1- 3C)haloalkyl, and each of the said amino groups is optionally substituted with one or more substituent groups selected from (1-3C)alkyl.
- each R a and R b are independently selected from hydrogen, (1-2C)alkyl, N(Me)2, benzyl, cyclopropyl or any one of the following: wherein each of the said benzyl groups is optionally substituted with one substituent group selected from fluoro, chloro, hydroxy and trifluoromethyl.
- R a is hydrogen or (1-2C)alkyl and R b is selected from (1-2C)alkyl, N(Me)2, benzyl, cyclopropyl or any one of the following: wherein each of the said benzyl groups is optionally substituted with one substituent group selected from fluoro, chloro, hydroxy and trifluoromethyl.
- R c is (1-6C)alkyl.
- R c is (1-3C)alkyl.
- R2 selected from hydrogen, halo, hydroxy, (1-6C)alkyl, (1-6C)haloalkyl, (2-4C)alkenyl, (2-4C)alkynyl,
- R d is independently selected from hydrogen and (1-6C)alkyl.
- R e is independently selected from hydrogen, (1-6C)alkyl and (3-8C)heterocyclyl, any of which is optionally substituted with one or more substituent groups selected from (1-6C)alkyl and (3-8C)cycloalkyl.
- each R e is independently selected from hydrogen, (1-4C)alkyl and (3-6C)heterocyclyl containing 1 or 2 heteroatoms selected from O and N, any of which is optionally substituted with one or more substituent groups selected from (1-4C)alkyl and (4-6C)cycloalkyl.
- each R e is independently selected from hydrogen, (1-4C)alkyl and N-piperazinyl, any of which is optionally substituted with cyclopentyl.
- each R e is N- piperazinyl, which is optionally substituted with cyclopentyl.
- Xi is O.
- X 2 is hydroxy or a group of formula (A), wherein
- n 1 or 2;
- R 3 is selected from hydrogen, halo, hydroxy, (1-6C)alkyl, (1-6C)haloalkyl, (2-4C)alkenyl, (2-4C)alkynyl, (1-8C)heteroalkyl, aryl, aryl(1-2C)alkyl, heteroaryl, heteroaryl(1-2C)alkyl, (3-8C)heterocyclyl, (3-8C)heterocyclyl(1-2C)alkyl, (3-8C)cycloalkyl, (3-8C)cycloalkyl(1- 2C)alkyl, NR j R k and ORi,
- R 3 is independently optionally substituted by one or more substituent groups selected from fluoro, chloro, trifluoromethyl, trifluoromethoxy, amino, (1- 4C)alkyl and (1-4C)alkoxy.
- substituent groups selected from fluoro, chloro, trifluoromethyl, trifluoromethoxy, amino, (1- 4C)alkyl and (1-4C)alkoxy.
- n 1 or 2;
- R 3 is selected from hydroxy, (1-6C)alkyl, aryl, aryl(1-2C)alkyl, heteroaryl, heteroaryl(1- 2C)alkyl, (3-8C)heterocyclyl, (3-8C)heterocyclyl(1-2C)alkyl, (3-8C)cycloalkyl, (3- 8C)cycloalkyl(1-2C)alkyl, NR j R k and ORi,
- R 3 is independently optionally substituted by one or more substituent groups selected from fluoro, chloro, trifluoromethyl, trifluoromethoxy, amino, (1- 4C)alkyl and (1-4C)alkoxy.
- substituent groups selected from fluoro, chloro, trifluoromethyl, trifluoromethoxy, amino, (1- 4C)alkyl and (1-4C)alkoxy.
- n 1 ;
- R 3 is selected from hydroxy, (1-6C)alkyl, (3-8C)heterocyclyl, (3-8C)heterocyclyl(1- 2C)alkyl, NR j R k and ORi,
- R 3 is optionally substituted by one or more substituent groups selected from (1-4C)alkyl and (1-3C)alkoxy.
- X 2 is hydroxy or a group of formula (A), wherein n is 1 ;
- R 3 is selected from hydroxy, (1-3C)alkyl, (3-8C)heterocyclyl, NR,R k and ORi,
- R 3 is optionally substituted by one or more substituent groups selected from (1-2C)alkyl and (1-2C)alkoxy.
- X 2 is a group of formula (A), wherein
- n 1 ;
- R 3 is selected from hydroxy, N-linked (3-8C)heterocyclyl, NR j R k and ORi,
- R 3 is optionally substituted by one or more (1-2C)alkyl.
- X 2 is a group of formula (A), wherein
- n 1 ;
- R 3 is selected from hydroxy, NR j R k , ORi (e.g. methoxy or ethoxy) or any one of the following:
- the compound for use according to any preceding statement, wherein R h and R, are independently selected from hydrogen and (1-6C)alkyl.
- the compound for use according to any preceding statement, wherein R h and R, are independently selected from hydrogen and (1-2C)alkyl.
- the compound for use according to any preceding statement, wherein R h and R, are hydrogen.
- R j and R k are independently selected from hydrogen, (1-6C)alkyl, (1-4C)alkoxy, aryl and (3- 8C)heterocyclyl.
- R j and R k are independently selected from hydrogen, (1-6C)alkyl, aryl and N-linked (3- 8C)heterocyclyl.
- R j and R k are independently selected from hydrogen, (1-6C)alkyl, phenyl and 5-6 membered N-linked heterocyclyl.
- R j and R k are independently selected from hydrogen, (1-6C)alkyl, phenyl or any one of the following:
- R j and R k are independently selected from hydrogen, (1-6C)alkyl and phenyl.
- Ri is (1-6C)alkyl.
- Ri is (1-3C)alkyl.
- X 2 is hydroxy.
- R 2 and Xi or R 2 and X 2 are linked, such that when they are taken in combination with the carbon atoms to which they are attached, they collectively form a 5-12 membered heterocycle that is optionally substituted with one or more R 4 substituents.
- R 2 and Xi or R 2 and X 2 are linked, such that when they are taken in combination with the carbon atoms to which they are attached, they collectively form a 8-12 membered fused heterobicycle or spiro bi-cyclic heterocyclic ring system that is optionally substituted with one or more R 4 substituents.
- R 2 and Xi or R 2 and X 2 are linked, such that when they are taken in combination with the carbon atoms to which they are attached, they collectively form a 8-12 membered fused heterobicycle or spiro bi-cyclic heterocyclic ring system containing 1 , 2 or 3 heteroatoms selected from O and N, wherein said 8-12 membered fused or spiro heterobicycle is optionally substituted with one or more R 4 substituents.
- R 2 and Xi or R 2 and X 2 are linked, such that when they are taken in combination with the carbon atoms to which they are attached, they collectively form a 9-11 membered fused heterobicycle or spiro bi-cyclic heterocyclic ring system containing 1 , 2 or 3 heteroatoms selected from O and N, wherein said 9-11 membered fused or spiro heterobicycle is optionally substituted with one or more R 4 substituents.
- R 2 and Xi or R 2 and X 2 are linked, such that when they are taken in combination with the carbon atoms to which they are attached, they collectively form a 10 membered fused heterobicycle or spiro bi-cyclic heterocyclic ring system containing 1 , 2 or 3 heteroatoms selected from O and N, wherein said 10 membered fused or spiro heterobicycle is optionally substituted with one or more R 4 substituents.
- R 2 and Xi or R 2 and X 2 are linked, such that when they are taken in combination with the carbon atoms to which they are attached, they collectively form either of the following groups:
- each R 4 is independently selected from halo, hydroxy, (1-6C)alkyl, (1-6C)haloalkyl, (2-4C)alkenyl, (2-4C)alkynyl, (1-8C)heteroalkyl, aryl, aryl(1-2C)alkyl, heteroaryl, heteroaryl(1-2C)alkyl, (3-8C)heterocyclyl, (3-8C)heterocyclyl(1-2C)alkyl, (3-8C)cycloalkyl, (3-8C)cycloalkyl(1- 2C)alkyl, NR m Rn, OR 0 ,
- each R 4 is independently optionally substituted with one or more groups selected from fluoro, chloro, (1-4C)alkyl, (2-4C)alkenyl, (2-4C)alkynyl, (1- 4C)alkoxy, aryl, aryl(1-2C)alkyl, heteroaryl, heteroaryl(1-2C)alkyl, (3- 8C)heterocyclyl, (3-8C)heterocyclyl(1-2C)alkyl, (3-8C)cycloalkyl, and (3- 8C)cycloalkyl(1-2C)alkyl.
- each R 4 is independently selected from halo, hydroxy, (1-6C)alkyl, aryl, aryl(1-2C)alkyl, heteroaryl, heteroaryl(1-2C)alkyl, (3-8C)heterocyclyl, (3-8C)heterocyclyl(1-2C)alkyl, (3- 8C)cycloalkyl, (3-8C)cycloalkyl(1-2C)alkyl, NR m R n , OR 0 ,
- each R 4 is independently optionally substituted with one or more groups selected from fluoro, chloro, (1-4C)alkyl and (1-4C)alkoxy.
- each R 4 is independently selected from halo, hydroxy, (1-6C)alkyl, (3-8C)heterocyclyl, (3- 8C)heterocyclyl(1-2C)alkyl, NR m R n , OR 0 ,
- each R 4 is independently optionally substituted with one or more groups selected from fluoro, chloro, (1-4C)alkyl and (1-4C)alkoxy.
- each R 4 is independently selected from hydroxy, (1-6C)alkyl and (3-8C)heterocyclyl,
- each R 4 is independently optionally substituted with one or more groups, (1-4C)alkyl.
- X 3 and X 4 are independently selected from hydroxy, OR p and NR q R r .
- X 3 and X 4 are linked, such that when they are taken in combination with the carbon atom to which they are attached, they collectively form a group having a structure according to formula (B) shown below:
- X 5 is selected from O or NR m ;
- n is a number selected from 1 and 2;
- o is a number selected from 1 and 2.
- X5 is selected from O or NR m ;
- n is a number selected from 1 and 2;
- o is a number selected from 1 and 2.
- each Rs is independently selected from fluoro, chloro, trifluoromethyl, trifluoromethoxy, hydroxy, oxo, amino, carboxy, (1-6C)alkyl, (1-4C)alkoxy, methylamino or dimethylamino, aryl, aryl(1-2C)alkyl, heteroaryl, heteroaryl(1-2C)alkyl, (3-8C)heterocyclyl, (3- 8C)heterocyclyl(1-2C)alkyl, (3-8C)cycloalkyl, and (3-8C)cycloalkyl(1-2C)alkyl.
- each Rs is independently selected from fluoro, chloro, trifluoromethyl, trifluoromethoxy, hydroxy, oxo, amino, carboxy, (1-6C)alkyl, (1-4C)alkoxy, methylamino and dimethylamino.
- each Rs is independently selected from fluoro, chloro, hydroxy, oxo, amino, (1-3C)alkyl and (1- 3C)alkoxy.
- each Rs is independently selected from hydroxy, oxo and (1-4C)alkoxy.
- Rs is oxo.
- Ri is as described in any of numbered paragraphs (5) to (8);
- R a and R b are as described in any of numbered paragraphs (11) to (12);
- R c is as described in any of numbered paragraphs (24) to (25);
- Xi is as described in numbered paragraph (39);
- X 2 is as described in numbered paragraph (40) or (41);
- n is as described in numbered paragraph (42) or (43);
- R 3 is as described in any of numbered paragraphs (46) to (50);
- R h and R are as described in any of numbered paragraphs (52) to (53);
- R j and R k are as described in any of numbered paragraphs (55) to (57);
- Ri is as described in any of numbered paragraphs (59) to (60);
- X3 and X 4 are as described in any of numbered paragraphs (75) to (76); m is as described in numbered paragraph (78); o is as described in numbered paragraph (79); and
- R1 is as described in any of numbered paragraphs (5) to (8);
- R a and R b are as described in any of numbered paragraphs (15) to (22);
- R c is as described in any of numbered paragraphs (24) to (25);
- Xi is as described in numbered paragraph (39);
- X2 is as described in numbered paragraph (40) or (41);
- n is as described in numbered paragraph (42) or (43);
- R3 is as described in any of numbered paragraphs (46) to (50);
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Abstract
Novel compounds of formulae (l)-(lll) are provided, as well as pharmaceutical compositions comprising the novel compounds. Also described are therapeutic uses of the novel compounds, in particular in relation to the treatment of infections caused by rifampicin- resistant bacteria, e.g. rifampicin-resistant tuberculosis.
Description
COMPOUNDS FOR TREATING INFECTIONS CAUSED BY
RIFAMPICIN-RESISTANT BACTERIA
INTRODUCTION
[0001] The present invention relates to certain compounds that are active against rifampicin- resistant RNA polymerases and rifampicin-resistant bacteria, as well as to pharmaceutical compositions comprising them, and to their use in the treatment of infections caused by rifampicin-resistant bacteria.
BACKGROUND OF THE INVENTION
[0002] Antibiotic resistance is on the increase, exacerbated by the fact that, in recent years, only a few new compounds have reached the clinic. RNA polymerase (RNAP) is an essential enzyme accomplishing transcription in all living organisms. At the same time, the sequence divergence between bacterial and human RNAPs, makes bacterial RNAP an excellent target for antibiotic development (Ho et al., 2009). In the last few years, details of the mode of action of a number of inhibitors of RNAP have been described (Bae et al., 2015; Degen et al., 2014; Maffioli et al., 2017; Molodtsov et al., 2015; Mukhopadhyay et al., 2008; Zhang et al., 2014a). However, most of these molecules have limited clinical utility, mainly due to their poor penetration of the bacterial cell envelope or strong binding to human plasma protein. Nevertheless, the search for new molecules that target RNAP and the analysis of their mode of action is a promising approach for the development of new antibiotics, as exemplified by the now clinically used fidaxomicin (trade name Dificid) for Clostridium difficile-associated diarrhea (Tupin et al., 2010).
[0003] The most studied class of antibiotics known to inhibit bacterial RNA transcription are the rifamycins, a family of mainly semisynthetic ansamycins derived from the natural product rifamycin S, of which rifampicin (RIF) is the most widely used (Aristoff et al., 2010). RIF (and the other rifamycins) binds in a pocket (the RIF-pocket) on the b subunit of RNAP in the vicinity of the catalytic site, and sterically blocks propagation of the growing RNA chain through the main channel of RNAP (Campbell et al., 2001 ; McClure and Cech, 1978). The collision of RNA and RIF happens when RNA reaches the length of 3-4 nucleotides, after which the RNA is released from the promoter complex as an abortive transcript.
[0004] The rifamycins are used, as part of the current combination therapy, for the first line treatment of tuberculosis (TB), the leading cause of death by infectious disease worldwide (WHO Global Tuberculosis report, 2017), as well as treatment for non-tuberculous mycobacterial infections (Ryu et al., 2016). One of the major problems with known rifamycins is the rapid selection for mutations in the RIF-binding pocket that lead to resistance. Multi-drug-resistant
strains of Mycobacterium tuberculosis (MDR-/W. tuberculosis) presents a major clinical problem, as these strains are resistant to RIF, as well as several other first line drugs (such as isoniazid). In 2016, there were 600,000 new cases with resistance to rifampicin, of which 490,000 had MDR- TB. With a treatment success rate of only 54%, this highlights the requirement for improved treatment options. There are -100 different amino acid substitutions in the RIF-pocket that have been found in RIF-resistant clinical isolates of M. tuberculosis (Sandgren et al., 2009), with mutations at three positions of the RIF-pocket that account for -70% of the total substitutions (D516 - 7.4%, H526 - 20%, and S531 - 42%; E. coli numbering).
[0005] Previous efforts to probe the structure-activity relationships of the rifamycins, and to maximize their binding affinity for RNA polymerase, showed that even minor modifications of the ansa-chain resulted in decreased binding, due to changes in the spatial arrangement of the four hydroxyl groups (at C1 , C8, C21 and C23) which form critical hydrogen bonds with the RIF pocket (Bacchi et al., 2008). Hence the production of clinically used semisynthetic rifamycins (rifampicin, rifabutin, rifapentine, rifalazil and rifaximin) has focused on the introduction of functionality at the C3 position to stabilize the oxidation state of the naphthoquinone core and to improve bioavailability (Floss and Yu, 2005; Perlman, 1977).
[0006] In spite of the advances to date, there remains a need for new compounds having potency against RIF-resistant RNAPs and RIF-resistant bacteria.
[0007] The present invention was devised with the foregoing in mind.
SUMMARY OF THE INVENTION
[0008] According to a first aspect of the present invention there is provided a compound of formula (I), (II) or (III) defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, for use in the treatment of infection caused by rifampicin-resistant bacteria.
[0009] According to a further aspect of the present invention there is provided a compound of formula (I), (II) or (III) as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof,
with the proviso that, in formula (I), when Ri is hydroxy and R2 is hydrogen, Xi is not O.
[0010] According to a further aspect of the present invention there is provided a pharmaceutical composition comprising a compound of formula (I), (II) or (III) defined herein, or a pharmaceutically acceptable salt or solvate thereof, and one or more pharmaceutically acceptable excipients or carriers.
[0011] According to a further aspect of the present invention, there is provided a compound of
formula (I), (II) or (III), or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein for use in therapy.
[0012] According to a further aspect of the present invention, there is provided a compound of formula (I), (II) or (III), or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein for use as a medicament.
[0013] According to a further aspect of the present invention there is provided a method of inhibiting RIF-resistant RNA polymerase, in vitro or in vivo, said method comprising contacting a cell with an effective amount of a compound of formula (I), (II) or (III) or a pharmaceutically acceptable salt, hydrate or solvate thereof as defined herein.
[0014] According to a further aspect of the present invention, there is provided a method of inhibiting bacterial cell proliferation, in vitro or in vivo, said method comprising contacting a bacterial cell with an effective amount of a compound of formula (I), (II) or (III) or a pharmaceutically acceptable salt, hydrate or solvate thereof as defined herein, or a pharmaceutical composition as defined herein.
[0015] According to a further aspect of the present invention, there is provided a method of treating an infection caused by RIF-resistant bacteria in a patient in need of such treatment, said method comprising administering to said patient a therapeutically effective amount of a compound of formula (I), (II) or (III) or a pharmaceutically acceptable salt, hydrate or solvate thereof as defined herein, or a pharmaceutical composition as defined herein.
[0016] According to a further aspect of the present invention, there is provided a use of a compound of formula (I), (II) or (III), or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein in the manufacture of a medicament for the inhibition of RIF-resistant RNA polymerase.
[0017] According to a further aspect of the present invention, there is provided a use of a compound of formula (I), (II) or (III), or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein in the manufacture of a medicament for the treatment of an infection caused by RIF-resistant bacteria.
[0018] Suitably, the infection caused by RIF-resistant bacteria is RIF-resistant tuberculosis.
[0019] Features, including optional, suitable, and preferred features in relation to one aspect of the invention may also be features, including optional, suitable and preferred features in relation to any other aspect of the invention.
DETAILED DESCRIPTION OF THE INVENTION
Definitions
[0020] Unless otherwise stated, the following terms used in the specification and claims have the following meanings set out below.
[0021] It is to be appreciated that references to“treating” or“treatment” include prophylaxis as well as the alleviation of established symptoms of a condition.“Treating” or“treatment” of a state, disorder or condition therefore includes: (1) preventing or delaying the appearance of clinical symptoms of the state, disorder or condition developing in a human that may be afflicted with or predisposed to the state, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the state, disorder or condition, (2) inhibiting the state, disorder or condition, i.e., arresting, reducing or delaying the development of the disease or a relapse thereof (in case of maintenance treatment) or at least one clinical or subclinical symptom thereof, or (3) relieving or attenuating the disease, i.e., causing regression of the state, disorder or condition or at least one of its clinical or subclinical symptoms.
[0022] A “therapeutically effective amount” means the amount of a compound that, when administered to a mammal for treating a disease, is sufficient to effect such treatment for the disease. The "therapeutically effective amount" will vary depending on the compound, the disease and its severity and the age, weight, etc., of the mammal to be treated.
[0023] In this specification the term “alkyl” includes both straight and branched chain alkyl groups. References to individual alkyl groups such as“propyl” are specific for the straight chain version only and references to individual branched chain alkyl groups such as“isopropyl” are specific for the branched chain version only. For example,“(1 -6C)alkyl” includes (1-4C)alkyl, (1- 3C)alkyl, propyl, isopropyl and f-butyl.
[0024] The term "(m-nC)" or "(m-nC) group" used alone or as a prefix, refers to any group having m to n carbon atoms.
[0025] An“alkylene” group is an alkyl group that is positioned between and serves to connect two other chemical groups. Thus,“(1-6C)alkylene” means a linear saturated divalent hydrocarbon radical of one to six carbon atoms or a branched saturated divalent hydrocarbon radical of three to six carbon atoms, for example, methylene (-CH2-), ethylene (-CH2CH2-), propylene (- CH2CH2CH2-), 2-methylpropylene (-CH2CH(CH3)CH2-), pentylene (-CH2CH2CH2CH2CH2-), and the like.
[0026] “(3-10C)cycloalkyl” means a hydrocarbon ring containing from 3 to 10 carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and bicyclo[2.2.1]heptyl.
[0027]“(3-10C)cycloalkenyl” means a hydrocarbon ring containing from 3 to 10 carbon atoms and at least one double bond, for example, cyclobutenyl, cyclopentenyl, cyclohexenyl or cycloheptenyl, such as 3-cyclohexen-1-yl, or cyclooctenyl.
[0028] The term“halo” or“halogeno” refers to fluoro, chloro, bromo and iodo, suitably fluoro, chloro and bromo, more suitably, fluoro and chloro.
[0029] The term“heterocyclyl”,“heterocyclic” or“heterocycle” means a non-aromatic saturated or partially saturated monocyclic, fused, bridged, or spiro bicyclic heterocyclic ring system(s). Monocyclic heterocyclic rings contain from about 3 to 12 (suitably from 3 to 7) ring atoms, with from 1 to 5 (suitably 1 , 2 or 3) heteroatoms selected from nitrogen, oxygen or sulfur in the ring. Bicyclic heterocycles contain from 7 to 17 member atoms, suitably 7 to 12 member atoms, in the ring. Bicyclic heterocyclic(s) rings may be fused, spiro, or bridged ring systems. Examples of heterocyclic groups include cyclic ethers such as oxiranyl, oxetanyl, tetrahydrofuranyl, dioxanyl, and substituted cyclic ethers. Heterocycles containing nitrogen include, for example, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, tetrahydrotriazinyl, tetrahydropyrazolyl, and the like. Typical sulfur containing heterocycles include tetrahydrothienyl, dihydro-1 , 3-dithiol, tetrahydro-2/-/- thiopyran, and hexahydrothiepine. Other heterocycles include dihydro-oxathiolyl, tetrahydro-oxazolyl, tetrahydro-oxadiazolyl, tetrahydrodioxazolyl, tetrahydro-oxathiazolyl, hexahydrotriazinyl, tetrahydro-oxazinyl, morpholinyl, thiomorpholinyl, tetrahydropyrimidinyl, dioxolinyl, octahydrobenzofuranyl, octahydrobenzimidazolyl, and octahydrobenzothiazolyl. For heterocycles containing sulfur, the oxidized sulfur heterocycles containing SO or SO2 groups are also included. Examples include the sulfoxide and sulfone forms of tetrahydrothienyl and thiomorpholinyl such as tetrahydrothiene 1 , 1 -dioxide and thiomorpholinyl 1 , 1 -dioxide. A suitable value for a heterocyclyl group which bears 1 or 2 oxo (=0) or thioxo (=S) substituents is, for example, 2-oxopyrrolidinyl, 2-thioxopyrrolidinyl, 2-oxoimidazolidinyl, 2-thioxoimidazolidinyl, 2-oxopiperidinyl, 2,5-dioxopyrrolidinyl, 2,5-dioxoimidazolidinyl or 2,6-dioxopiperidinyl. Particular heterocyclyl groups are saturated monocyclic 3 to 7 membered heterocyclyls containing 1 , 2 or 3 heteroatoms selected from nitrogen, oxygen or sulfur, for example azetidinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, morpholinyl, tetrahydrothienyl, tetrahydrothienyl 1 , 1 -dioxide, thiomorpholinyl, thiomorpholinyl 1 , 1-dioxide, piperidinyl, homopiperidinyl, piperazinyl or homopiperazinyl. As the skilled person would appreciate, any heterocycle may be linked to another group via any suitable atom, such as via a carbon or nitrogen atom. In this specification, heterocycles are suitably linked to another group via a nitrogen atom.
[0030] By“spiro bi-cyclic heterocyclic ring systems” we mean that the two ring systems share one common spiro carbon atom, i.e. the heterocyclic ring is linked to a further cycloalkyl, cycloalkenyl or heterocyclic ring through a single common spiro carbon atom. Examples of spiro ring systems include 6-azaspiro[3.4]octane, 2-oxa-6-azaspiro[3.4]octane, 2-
azaspiro[3.3]heptanes, 2-oxa-6-azaspiro[3.3]heptanes, 7-oxa-2-azaspiro[3.5]nonane, 6-oxa-2- azaspiro[3.4]octane, 2-oxa-7-azaspiro[3.5]nonane and 2-oxa-6-azaspiro[3.5]nonane.
[0031] The term“heteroaryl” or“heteroaromatic” means an aromatic mono-, bi-, or polycyclic ring incorporating one or more (for example 1-4, particularly 1 , 2 or 3) heteroatoms selected from nitrogen, oxygen or sulfur. The term heteroaryl includes both monovalent species and divalent species. Examples of heteroaryl groups are monocyclic and bicyclic groups containing from five to twelve ring members, and more usually from five to ten ring members. The heteroaryl group can be, for example, a 5- or 6-membered monocyclic ring or a 9- or 10-membered bicyclic ring, for example a bicyclic structure formed from fused five and six membered rings or two fused six membered rings. Each ring may contain up to about four heteroatoms typically selected from nitrogen, sulfur and oxygen. Typically the heteroaryl ring will contain up to 3 heteroatoms, more usually up to 2, for example a single heteroatom. In one embodiment, the heteroaryl ring contains at least one ring nitrogen atom. The nitrogen atoms in the heteroaryl rings can be basic, as in the case of an imidazole or pyridine, or essentially non-basic as in the case of an indole or pyrrole nitrogen. In general the number of basic nitrogen atoms present in the heteroaryl group, including any amino group substituents of the ring, will be less than five.
[0032] Examples of heteroaryl include furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1 ,3,5-triazenyl, benzofuranyl, indolyl, isoindolyl, benzothienyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, benzothiazolyl, indazolyl, purinyl, benzofurazanyl, quinolyl, isoquinolyl, quinazolinyl, quinoxalinyl, cinnolinyl, pteridinyl, naphthyridinyl, carbazolyl, phenazinyl, benzisoquinolinyl, pyridopyrazinyl, thieno[2,3-b]furanyl, 2H-furo[3,2-b]-pyranyl, 5H-pyrido[2,3-d]-o-oxazinyl, 1 H-pyrazolo[4,3-d]-oxazolyl, 4H-imidazo[4,5-d]thiazolyl, pyrazino[2,3-d]pyridazinyl, imidazo[2, 1 -b]thiazolyl, imidazo[1 ,2-b][1 ,2,4]triazinyl. “Heteroaryl” also covers partially aromatic bi- or polycyclic ring systems wherein at least one ring is an aromatic ring and one or more of the other ring(s) is a non-aromatic, saturated or partially saturated ring, provided at least one ring contains one or more heteroatoms selected from nitrogen, oxygen or sulfur. Examples of partially aromatic heteroaryl groups include for example, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 2-oxo-1 ,2,3,4-tetrahydroquinolinyl, dihydrobenzthienyl, dihydrobenzfuranyl, 2,3-dihydro-benzo[1 ,4]dioxinyl, benzo[1 ,3]dioxolyl, 2,2- dioxo-1 ,3-dihydro-2-benzothienyl, 4,5,6,7-tetrahydrobenzofuranyl, indolinyl,
1.2.3.4-tetrahydro-1 ,8-naphthyridinyl, 1 ,2,3,4-tetrahydropyrido[2,3-b]pyrazinyl and
3.4-dihydro-2/-/-pyrido[3,2-b][1 ,4]oxazinyl.
[0033] Examples of five membered heteroaryl groups include but are not limited to pyrrolyl, furanyl, thienyl, imidazolyl, furazanyl, oxazolyl, oxadiazolyl, oxatriazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl and tetrazolyl groups.
[0034] Examples of six membered heteroaryl groups include but are not limited to pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl and triazinyl.
[0035] A bicyclic heteroaryl group may be, for example, a group selected from:
a benzene ring fused to a 5- or 6-membered ring containing 1 , 2 or 3 ring heteroatoms;
a pyridine ring fused to a 5- or 6-membered ring containing 1 , 2 or 3 ring heteroatoms;
a pyrimidine ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms;
a pyrrole ring fused to a 5- or 6-membered ring containing 1 , 2 or 3 ring heteroatoms;
a pyrazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms;
a pyrazine ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms;
an imidazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms;
an oxazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms;
an isoxazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms;
a thiazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms;
an isothiazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms;
a thiophene ring fused to a 5- or 6-membered ring containing 1 , 2 or 3 ring heteroatoms;
a furan ring fused to a 5- or 6-membered ring containing 1 , 2 or 3 ring heteroatoms;
a cyclohexyl ring fused to a 5- or 6-membered heteroaromatic ring containing 1 , 2 or 3 ring heteroatoms; and
a cyclopentyl ring fused to a 5- or 6-membered heteroaromatic ring containing 1 , 2 or 3 ring heteroatoms.
[0036] Particular examples of bicyclic heteroaryl groups containing a six membered ring fused to a five membered ring include but are not limited to benzfuranyl, benzthiophenyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzthiazolyl, benzisothiazolyl, isobenzofuranyl, indolyl, isoindolyl, indolizinyl, indolinyl, isoindolinyl, purinyl (e.g., adeninyl, guaninyl), indazolyl, benzodioxolyl and pyrazolopyridinyl groups.
[0037] Particular examples of bicyclic heteroaryl groups containing two fused six membered rings include but are not limited to quinolinyl, isoquinolinyl, chromanyl, thiochromanyl, chromenyl, isochromenyl, chromanyl, isochromanyl, benzodioxanyl, quinolizinyl, benzoxazinyl, benzodiazinyl, pyridopyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, naphthyridinyl and pteridinyl groups.
[0038] The term“aryl” means a cyclic or polycyclic aromatic ring having from 5 to 12 carbon atoms. The term aryl includes both monovalent species and divalent species. Examples of aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl and the like. In a particular embodiment, an aryl is phenyl.
[0039] The term "optionally substituted" refers to either groups, structures, or molecules that are substituted and those that are not substituted.
[0040] Where optional substituents are chosen from“one or more” groups it is to be understood that this definition includes all substituents being chosen from one of the specified groups or the substituents being chosen from two or more of the specified groups.
Therapeutic Uses and Applications
[0041] In one aspect, the present invention provides a compound of formula (I), (II) or (III) shown below, or a pharmaceutically acceptable salt, hydrate or solvate thereof, for use in the treatment of infection caused by rifampicin-resistant bacteria:
wherein,
Ri is selected from hydrogen, halo, cyano, isocyano, nitro, hydroxy, (1-6C)alkyl, (1-6C)haloalkyl, (2-4C)alkenyl, (2-4C)alkynyl, (1-8C)heteroalkyl, aryl, aryl(1-2C)alkyl, heteroaryl, heteroaryl(1-2C)alkyl, (3-8C)heterocyclyl, (3-8C)heterocyclyl(1-2C)alkyl, (3- 8C)cycloalkyl, (3-8C)cycloalkyl(1-2C)alkyl, NRaRb, ORc, 0C(0)Ra, N(Rb)ORa,
N(Rb)C(0)ORa, N(Rb)C(0)Ra, S(0)PRa (where p is 0, 1 or 2), S02N(Rb)Ra, and
N(Rb)S02Ra;
R2 is selected from hydrogen, halo, cyano, isocyano, nitro, hydroxy, (1-6C)alkyl, (1-6C)haloalkyl, (2-4C)alkenyl, (2-4C)alkynyl, (1-8C)heteroalkyl, aryl, aryl(1-2C)alkyl, heteroaryl, heteroaryl(1-2C)alkyl, (3-8C)heterocyclyl, (3-8C)heterocyclyl(1-2C)alkyl, (3- 8C)cycloalkyl, (3-8C)cycloalkyl(1-2C)alkyl, NRdRe, ORf, C(0)Rd, C(0)ORd, OC(0)Rd, C(Rd)=N(Re), N(Rd)ORe, N(Rd)C(0)ORe, C(0)N(Rd)Re, N(Rd)C(0)Re, S(0)PRd (where p is 0, 1 or 2), S02N(Rd)Re, and N(Rd)S02Re;
and wherein R1 and R2 are each independently optionally substituted by one or more substituent groups selected from fluoro, chloro, trifluoromethyl, trifluoromethoxy, cyano, nitro, hydroxy, amino, carboxy, carbamoyl, sulphamoyl, (1-4C)alkyl, (1-4C)alkoxy, S(0)qCH3 (where q is 0, 1 or 2), methylamino or dimethylamino, aryl, aryl(1-2C)alkyl, heteroaryl, heteroaryl(1-2C)alkyl, (3-8C)heterocyclyl, (3- 8C)heterocyclyl(1-2C)alkyl, (3-8C)cycloalkyl, or (3-8C)cycloalkyl(1- 2C)alkyl;
Xi is selected from O and NRg;
X2 is hydroxy or a group of formula (A) shown below:
n is 0, 1 , 2, 3 or 4; and
R3 is selected from hydrogen, halo, cyano, isocyano, nitro, hydroxy, (1-6C)alkyl, (1-6C)haloalkyl, (2-4C)alkenyl, (2- 4C)alkynyl, (1-8C)heteroalkyl, aryl, aryl(1-2C)alkyl, heteroaryl, heteroaryl(1-2C)alkyl, (3-8C)heterocyclyl, (3-8C)heterocyclyl(1- 2C)alkyl, (3-8C)cycloalkyl, (3-8C)cycloalkyl(1-2C)alkyl, NRjRk, OR,, C(0)Rj, C(0)ORj, OC(0)Rj, C(Rj)=N(Rk), N(Rj)ORk,
N(Rj)C(0)ORk, C(0)N(Rj)Rk, N(Rj)C(0)Rk, S(0)PRj (where p is 0, 1 or 2), S02N(Rj)Rk, and N(Rj)S02Rk;
and wherein R3 is independently optionally substituted by one or more substituent groups selected from fluoro, chloro, trifluoromethyl, trifluoromethoxy, cyano, nitro, hydroxy, amino, carboxy, carbamoyl, sulphamoyl, (1- 4C)alkyl, (1-4C)alkoxy, S(0)qCH3 (where q is 0, 1 or 2), methylamino or dimethylamino, aryl, aryl(1-2C)alkyl, heteroaryl, heteroaryl(1-2C)alkyl, (3-8C)heterocyclyl, (3- 8C)heterocyclyl(1-2C)alkyl, (3-8C)cycloalkyl, or (3- 8C)cycloalkyl(1-2C)alkyl;
or R2 and X1 or R2 and X2 are linked, such that when they are taken in combination with the carbon atoms to which they are attached, they collectively form a 5-12 membered heteroaryl or heterocycle that is optionally substituted with one or more R4 substituents;
and wherein each R4 is independently selected from halo, cyano, isocyano, nitro, hydroxy, (1-6C)alkyl, (1-6C)haloalkyl, (2-4C)alkenyl, (2- 4C)alkynyl, (1-8C)heteroalkyl, aryl, aryl(1-2C)alkyl, heteroaryl, heteroaryl(1-2C)alkyl, (3-8C)heterocyclyl, (3-8C)heterocyclyl(1-2C)alkyl, (3-8C)cycloalkyl, (3-8C)cycloalkyl(1-2C)alkyl, NRmRn, OR0, C(0)Rm, C(0)0Rm, 0C(0)Rm, N(Rm)ORn, N(Rm)C(0)0Rn, C(0)N(Rm)Rn,
C(Rm)=N(Rn), N(Rm)C(0)Rn, S(0)PRm (where p is 0, 1 or 2), S02N(Rm)Rn, and N(Rm)S02Rn;
and wherein each R4 is independently optionally substituted with one or more groups selected from fluoro, chloro, trifluoromethyl, trifluoromethoxy, cyano, nitro, hydroxy, amino, carboxy, carbamoyl, sulphamoyl, (1-4C)alkyl, (2-4C)alkenyl, (2-4C)alkynyl, (1-4C)alkoxy, S(0)qCH3 (where q is 0, 1 or 2), methylamino or dimethylamino, aryl, aryl(1-2C)alkyl, heteroaryl, heteroaryl(1-2C)alkyl, (3-8C)heterocyclyl, (3- 8C)heterocyclyl(1-2C)alkyl, (3-8C)cycloalkyl, and (3-8C)cycloalkyl(1- 2C)alkyl;
X3 and X4 are independently selected from hydroxy, ORp, NRqRr and a group of formula (A) shown above;
or X3 and X4 are linked, such that when they are taken in combination with the carbon atom to which they are attached, they collectively form a 4-6 membered heterocycle that is optionally substituted with one or more R5 substituents;
and wherein each R5 is independently selected from fluoro, chloro, trifluoromethyl, trifluoromethoxy, cyano, nitro, hydroxy, oxo, amino, carboxy, carbamoyl, sulphamoyl, (1-6C)alkyl, (2-6C)alkenyl, (2-
6C)alkynyl, (1-4C)alkoxy, S(0)qCH3 (where q is 0, 1 or 2), methylamino or dimethylamino, aryl, aryl(1-2C)alkyl, heteroaryl, heteroaryl(1-2C)alkyl, (3- 8C)heterocyclyl, (3-8C)heterocyclyl(1-2C)alkyl, (3-8C)cycloalkyl, and (3- 8C)cycloalkyl(1-2C)alkyl;
each Ra to Rr is independently selected from hydrogen, fluoro, chloro, trifluoromethyl, trifluoromethoxy, cyano, nitro, hydroxy, amino, carboxy, carbamoyl, sulphamoyl, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (1-4C)alkoxy, S(0)qCH3 (where q is 0, 1 or 2), methylamino or dimethylamino, aryl, aryl(1-2C)alkyl, heteroaryl,
heteroaryl(1-2C)alkyl, (3-8C)heterocyclyl, (3-8C)heterocyclyl(1-2C)alkyl, (3- 8C)cycloalkyl, and (3-8C)cycloalkyl(1-2C)alkyl;
and wherein each Ra to Rr is independently optionally substituted with one or more groups selected from fluoro, chloro, trifluoromethyl, trifluoromethoxy, cyano, nitro, hydroxy, amino, carboxy, carbamoyl, sulphamoyl, (1-4C)alkyl, (2-4C)alkenyl, (2-4C)alkynyl, (1-4C)alkoxy, S(0)qCH3 (where q is 0, 1 or 2), methylamino or dimethylamino, aryl, aryl(1-2C)alkyl, heteroaryl, heteroaryl(1-2C)alkyl, (3-8C)heterocyclyl, (3- 8C)heterocyclyl(1-2C)alkyl, (3-8C)cycloalkyl, and (3-8C)cycloalkyl(1- 2C)alkyl.
[0042] In an embodiment, the compound of formula (I), (II) or (III) has a structure according to formula (G), (IG) or (IN’) shown below:
[0043] In particular compounds of formula (I), (II) or (III), or pharmaceutically acceptable salts, hydrates and/or solvates thereof, unless otherwise stated, each of Ri, R2, Xi, X2, X3 and X4, and any of their associated substituents, has any of the meanings defined hereinbefore or in any of numbered paragraphs (1) to (87) hereinafter:
(1) R1 is selected from hydrogen, halo, hydroxy, (1-6C)alkyl, (1-6C)haloalkyl, (2-4C)alkenyl, (2-4C)alkynyl, (1-8C)heteroalkyl, aryl, aryl(1-2C)alkyl, heteroaryl, heteroaryl(1-2C)alkyl,
(3-8C)heterocyclyl, (3-8C)heterocyclyl(1-2C)alkyl, (3-8C)cycloalkyl, (3-8C)cycloalkyl(1- 2C)alkyl, NRaRb, 0RC, 0C(0)Ra, N(Rb)ORa, N(Rb)C(0)0Ra and N(Rb)C(0)Ra, wherein Ri is optionally substituted by one or more substituent groups selected from (1-4C)alkyl and (1-3C)alkoxy.
(2) Ri is selected from hydrogen, halo, hydroxy, (1-6C)alkyl, (1-6C)haloalkyl, (2-4C)alkenyl, (2-4C)alkynyl, (1-8C)heteroalkyl, aryl, aryl(1-2C)alkyl, heteroaryl, heteroaryl(1-2C)alkyl, (3-8C)heterocyclyl, (3-8C)heterocyclyl(1-2C)alkyl, (3-8C)cycloalkyl, (3-8C)cycloalkyl(1- 2C)alkyl, NRaRb and ORc, wherein Ri is optionally substituted by one or more substituent groups selected from (1-4C)alkyl and (1-3C)alkoxy.
(3) Ri is selected from hydrogen, halo, hydroxy, (1-6C)alkyl, aryl, aryl(1-2C)alkyl, heteroaryl, heteroaryl(1-2C)alkyl, (3-8C)heterocyclyl, (3-8C)heterocyclyl(1-2C)alkyl, (3- 8C)cycloalkyl, (3-8C)cycloalkyl(1-2C)alkyl, NRaRb and ORc, wherein Ri is optionally substituted by one or more substituent groups selected from (1-2C)alkyl and (1- 2C)alkoxy.
(4) Ri is selected from hydroxy, (1-6C)alkyl, aryl, heteroaryl, (3-8C)heterocyclyl, (3- 8C)cycloalkyl, NRaRb and ORc, wherein Ri is optionally substituted by one or more substituent groups selected from (1-2C)alkyl and (1-2C)alkoxy.
(5) Ri is selected from hydroxy, (1-4C)alkyl, N-linked (3-8C)heterocyclyl, NRaRb and ORc, wherein Ri is optionally substituted by one or more (1-2C)alkyl.
(6) Ri is selected from hydroxy, N-linked (3-6C)heterocyclyl, NRaRb and ORc, wherein the N- linked (3-6C)heterocyclyl contains 1 or 2 heteroatoms, wherein Ri is optionally substituted by one or more (1-2C)alkyl.
(7) Ri is selected from hydroxy, NRaRb, ORc or any one of the following:
(8) Ri is selected from hydroxy and ORc (e.g. methoxy or ethoxy).
(9) Each Ra and Rb are independently selected from hydrogen, (1-6C)alkyl, (1-4C)alkoxy, aryl and (3-8C)heterocyclyl.
(10) Each Ra and Rb are independently selected from hydrogen, (1-6C)alkyl, aryl and N- linked (3-8C)heterocyclyl.
(1 1) Each Ra and Rb are independently selected from hydrogen, (1-6C)alkyl, phenyl and 5-6 membered N-linked heterocyclyl.
(12) Each Ra and Rb are independently selected from hydrogen, (1-6C)alkyl, phenyl or any one of the following:
(13) Each Ra and Rb are independently selected from hydrogen, (1-6C)alkyl, amino, aryl, aryl(1-2C)alkyl, (3-8C)cycloalkyl or any one of the following
wherein each Ra and Rb is optionally substituted with one or more substituent groups selected from halo, hydroxy, (1-3C)alkyl and (1-3C)haloalkyl.
(14) Ra is hydrogen or (1-6C)alkyl and Rb is selected from (1-6C)alkyl, amino, aryl, aryl(1- 2C)alkyl, (3-8C)cycloalkyl or any one of the following
wherein each Rb is optionally substituted with one or more substituent groups selected from halo, hydroxy, (1-3C)alkyl and (1-3C)haloalkyl.
(15) Each Ra and Rb are independently selected from hydrogen, (1-3C)alkyl, amino, aryl, aryl(1-2C)alkyl, (3-6C)cycloalkyl or any one of the following
wherein each of the said amino, aryl and aryl(1-2C)alkyl groups is optionally substituted with one or more substituent groups selected from halo, hydroxy, (1-3C)alkyl and (1- 3C)haloalkyl.
(16) Ra is hydrogen or (1-3C)alkyl and Rb is selected from (1-3C)alkyl, amino, aryl, aryl(1- 2C)alkyl, (3-6C)cycloalkyl or any one of the following
wherein each of the said amino, aryl and aryl(1-2C)alkyl groups is optionally substituted with one or more substituent groups selected from halo, hydroxy, (1-3C)alkyl and (1- 3C)haloalkyl.
(17) Each Ra and Rb are independently selected from hydrogen, (1-3C)alkyl, amino, phenyl, benzyl, (3-6C)cycloalkyl or any one of the following
wherein each of the said phenyl and benzyl groups is optionally substituted with one or more substituent groups selected from fluoro, chloro hydroxy, (1-3C)alkyl and (1- 3C)haloalkyl, and each of the said amino groups is optionally substituted with one or more substituent groups selected from (1-3C)alkyl.
(18) Ra is hydrogen or (1-3C)alkyl and Rb is selected from (1-3C)alkyl, amino, phenyl, benzyl, (3-6C)cycloalkyl or any one of the following
wherein each of the said phenyl and benzyl groups is optionally substituted with one or more substituent groups selected from fluoro, chloro hydroxy, (1-3C)alkyl and (1- 3C)haloalkyl, and each of the said amino groups is optionally substituted with one or more substituent groups selected from (1-3C)alkyl.
(19) Each Ra and Rb are independently selected from hydrogen, (1-2C)alkyl, NH2, N(Me)2, N(H)(Me), phenyl, benzyl, cyclopropyl or any one of the following
wherein each of the said phenyl and benzyl groups is optionally substituted with one or two substituent groups selected from fluoro, chloro, hydroxy and trifluoromethyl.
(20) Ra is hydrogen or (1-2C)alkyl and Rb is selected from (1-2C)alkyl, NH2, N(Me)2, N(H)(Me), phenyl, benzyl, cyclopropyl or any one of the following
wherein each of the said phenyl and benzyl groups is optionally substituted with one or two substituent groups selected from fluoro, chloro, hydroxy and trifluoromethyl.
(21) Each Ra and Rb are independently selected from hydrogen, (1-2C)alkyl, N(Me)2, benzyl, cyclopropyl or any one of the following
wherein each of the said benzyl groups is optionally substituted with one substituent group selected from fluoro, chloro, hydroxy and trifluoromethyl.
(22) Ra is hydrogen or (1-2C)alkyl and Rb is selected from (1-2C)alkyl, N(Me)2, benzyl, cyclopropyl or any one of the following
wherein each of the said benzyl groups is optionally substituted with one substituent group selected from fluoro, chloro, hydroxy and trifluoromethyl.
(23) Each Rc is independently (1-6C)alkyl.
(24) Each Rc is independently (1-3C)alkyl.
(25) Each Rc is independently methyl or ethyl.
(26) R2 IS selected from hydrogen, halo, hydroxy, (1-6C)alkyl, (1-6C)haloalkyl, (2-4C)alkenyl, (2-4C)alkynyl, (1-8C)heteroalkyl, aryl, aryl(1-2C)alkyl, heteroaryl, heteroaryl(1-2C)alkyl, (3-8C)heterocyclyl, (3-8C)heterocyclyl(1-2C)alkyl, (3-8C)cycloalkyl, (3-8C)cycloalkyl(1- 2C)alkyl, NRdRe, ORf, C(0)Rd, C(0)0Rd, 0C(0)Rd, C(Rd)=N(Re), N(Rd)ORe, N(Rd)C(0)0Re, C(0)N(Rd)Re and N(Rd)C(0)Re.
(27) R2 IS selected from hydrogen, halo, hydroxy, (1-6C)alkyl, (1-6C)haloalkyl, (2-4C)alkenyl, (2-4C)alkynyl, (1-8C)heteroalkyl, aryl, aryl(1-2C)alkyl, heteroaryl, heteroaryl(1-2C)alkyl, (3-8C)heterocyclyl, (3-8C)heterocyclyl(1-2C)alkyl, (3-8C)cycloalkyl, (3-8C)cycloalkyl(1- 2C)alkyl, NRdRe, ORf, C(0)Rd, C(0)0Rd, 0C(0)Rd and C(Rd)=N(Re).
(28) R2IS selected from hydrogen, halo, hydroxy, (1-6C)alkyl, aryl, aryl(1-2C)alkyl, heteroaryl, heteroaryl(1-2C)alkyl, (3-8C)heterocyclyl, (3-8C)heterocyclyl(1-2C)alkyl, (3- 8C)cycloalkyl, (3-8C)cycloalkyl(1-2C)alkyl, NRdRe, ORf, and C(Rd)=N(Re).
(29) R2 is selected from hydrogen, (1-6C)alkyl, aryl, aryl(1-2C)alkyl, heteroaryl, heteroaryl(1- 2C)alkyl, (3-8C)heterocyclyl, (3-8C)heterocyclyl(1-2C)alkyl, (3-8C)cycloalkyl, (3- 8C)cycloalkyl(1-2C)alkyl and C(Rd)=N(Re).
(30) R2 is selected from hydrogen, (1-6C)alkyl, (3-8C)heterocyclyl, (3-8C)heterocyclyl(1- 2C)alkyl, (3-8C)cycloalkyl, (3-8C)cycloalkyl(1-2C)alkyl and C(Rd)=N(Re).
(31) R2 IS selected from hydrogen, (3-8C)heterocyclyl(1-2C)alkyl and C(Rd)=N(Re).
(32) R2 IS selected from hydrogen, N-pyrrolidinyl(1-2C)alkyl and C(Rd)=N(Re).
(33) Each Rd is independently selected from hydrogen and (1-6C)alkyl.
(34) Each Rd is hydrogen.
(35) Each Re is independently selected from hydrogen, (1-6C)alkyl and (3-8C)heterocyclyl, any of which is optionally substituted with one or more substituent groups selected from (1-6C)alkyl and (3-8C)cycloalkyl.
(36) Each Re is independently selected from hydrogen, (1-4C)alkyl and (3-6C)heterocyclyl containing 1 or 2 heteroatoms selected from O and N, any of which is optionally substituted with one or more substituent groups selected from (1-4C)alkyl and (4- 6C)cycloalkyl.
(37) Each Re is independently selected from hydrogen, (1-4C)alkyl and N-piperazinyl, any of which is optionally substituted with cyclopentyl.
(38) Each Re is N-piperazinyl, any of which is optionally substituted with cyclopentyl.
(39) Xi is O.
(40) X2 is hydroxy.
(41) X2 is a group of formula (A).
(42) n is 1 or 2.
(43) n is
(44) R3 is selected from hydrogen, halo, hydroxy, (1-6C)alkyl, (1-6C)haloalkyl, (2-4C)alkenyl, (2-4C)alkynyl, (1-8C)heteroalkyl, aryl, aryl(1-2C)alkyl, heteroaryl, heteroaryl(1-2C)alkyl, (3-8C)heterocyclyl, (3-8C)heterocyclyl(1-2C)alkyl, (3-8C)cycloalkyl, (3-8C)cycloalkyl(1- 2C)alkyl, NRjRk and ORi, wherein R3 is independently optionally substituted by one or more substituent groups selected from fluoro, chloro, trifluoromethyl, trifluoromethoxy, amino, (1-4C)alkyl and (1-4C)alkoxy.
(45) R3 is selected from hydroxy, (1-6C)alkyl, aryl, aryl(1-2C)alkyl, heteroaryl, heteroaryl(1- 2C)alkyl, (3-8C)heterocyclyl, (3-8C)heterocyclyl(1-2C)alkyl, (3-8C)cycloalkyl, (3- 8C)cycloalkyl(1-2C)alkyl, NRjRk and ORi, wherein R3 is independently optionally substituted by one or more substituent groups selected from fluoro, chloro, trifluoromethyl, trifluoromethoxy, amino, (1-4C)alkyl and (1-4C)alkoxy.
(46) R is selected from hydroxy, (1-6C)alkyl, (3-8C)heterocyclyl, (3-8C)heterocyclyl(1- 2C)alkyl, NRjRk and ORi, wherein R3 is optionally substituted by one or more substituent groups selected from (1-4C)alkyl and (1-3C)alkoxy.
(47) R3 is selected from hydroxy, (1-3C)alkyl, (3-8C)heterocyclyl, NRjRk and ORi, wherein R3 is optionally substituted by one or more substituent groups selected from (1-2C)alkyl and (1-2C)alkoxy.
(48) R3 is selected from hydroxy, N-linked (3-8C)heterocyclyl, NRjRk and ORi, wherein R3 is optionally substituted by one or more (1-2C)alkyl.
(49) R3 is selected from hydroxy, NRjRk, ORi or any one of the following:
(50) R is selected from hydroxy or ORi (e.g. methoxy).
(51) Each Rh and R, are independently selected from hydrogen and (1-6C)alkyl.
(52) Each Rh and R, are independently selected from hydrogen and (1-2C)alkyl.
(53) Each Rh and R, are hydrogen.
(54) Each R, and Rk are independently selected from hydrogen, (1-6C)alkyl, (1-4C)alkoxy, aryl and (3-8C)heterocyclyl.
(55) Each R, and Rk are independently selected from hydrogen, (1-6C)alkyl, aryl and N-linked (3-8C)heterocyclyl.
(56) Each R, and Rk are independently selected from hydrogen, (1-6C)alkyl, phenyl and 5-6 membered N-linked heterocyclyl.
(57) Each R, and Rk are independently selected from hydrogen, (1-6C)alkyl, phenyl or any one of the following:
(58) Each Ri is independently (1-6C)alkyl.
(59) Each Ri is independently (1-3C)alkyl.
(60) Each Ri is independently methyl or ethyl.
(61) R and X or R and X are linked, such that when they are taken in combination with the carbon atoms to which they are attached, they collectively form a 5-12 membered heterocycle that is optionally substituted with one or more R substituents.
(62) R2 and Xi or R2 and X2 are linked, such that when they are taken in combination with the carbon atoms to which they are attached, they collectively form a 8-12 membered fused heterobicycle or spiro bi-cyclic heterocyclic ring system that is optionally substituted with one or more R4 substituents.
(63) R2 and Xi or R2 and X2 are linked, such that when they are taken in combination with the carbon atoms to which they are attached, they collectively form a 8-12 membered fused heterobicycle or spiro bi-cyclic heterocyclic ring system containing 1 , 2 or 3 heteroatoms selected from O and N, wherein said 8-12 membered fused or spiro heterobicycle is optionally substituted with one or more R4 substituents.
(64) R2 and Xi or R2 and X2 are linked, such that when they are taken in combination with the carbon atoms to which they are attached, they collectively form a 9-11 membered fused heterobicycle or spiro bi-cyclic heterocyclic ring system containing 1 , 2 or 3 heteroatoms selected from O and N, wherein said 9-11 membered fused or spiro heterobicycle is optionally substituted with one or more R4 substituents.
(65) R2 and Xi or R2 and X2 are linked, such that when they are taken in combination with the carbon atoms to which they are attached, they collectively form a 10 membered fused heterobicycle or spiro bi-cyclic heterocyclic ring system containing 1 , 2 or 3 heteroatoms selected from O and N, wherein said 10 membered fused or spiro heterobicycle is optionally substituted with one or more R4 substituents.
(66) R2 and Xi or R2 and X2 are linked, such that when they are taken in combination with the carbon atoms to which they are attached, they collectively form either of the following groups:
(67) R2 and Xi or R2 and X2 are linked, such that when they are taken in combination with the carbon atoms to which they are attached, they collectively form either of the following groups:
(68) each R4 is independently selected from halo, hydroxy, (1-6C)alkyl, (1-6C)haloalkyl, (2-
4C)alkenyl, (2-4C)alkynyl, (1-8C)heteroalkyl, aryl, aryl(1-2C)alkyl, heteroaryl, heteroaryl(1-2C)alkyl, (3-8C)heterocyclyl, (3-8C)heterocyclyl(1-2C)alkyl, (3-
8C)cycloalkyl, (3-8C)cycloalkyl(1-2C)alkyl, NRmRn, OR0, wherein each R4 is independently optionally substituted with one or more groups selected from fluoro, chloro, (1-4C)alkyl, (2-4C)alkenyl, (2-4C)alkynyl, (1-4C)alkoxy, aryl, aryl(1-2C)alkyl, heteroaryl, heteroaryl(1-2C)alkyl, (3-8C)heterocyclyl, (3-8C)heterocyclyl(1-2C)alkyl, (3-
8C)cycloalkyl, and (3-8C)cycloalkyl(1-2C)alkyl.
(69) each R4 is independently selected from halo, hydroxy, (1-6C)alkyl, aryl, aryl(1-2C)alkyl, heteroaryl, heteroaryl(1-2C)alkyl, (3-8C)heterocyclyl, (3-8C)heterocyclyl(1-2C)alkyl, (3- 8C)cycloalkyl, (3-8C)cycloalkyl(1-2C)alkyl, NRmRn, OR0, wherein each R4 is independently optionally substituted with one or more groups selected from fluoro, chloro, (1-4C)alkyl and (1-4C)alkoxy.
(70) each R4 is independently selected from halo, hydroxy, (1-6C)alkyl, (3-8C)heterocyclyl, (3-8C)heterocyclyl(1-2C)alkyl, NRmRn, OR0, wherein each R4 is independently optionally substituted with one or more groups selected from fluoro, chloro, (1-4C)alkyl and (1- 4C)alkoxy.
(71) each R4 is independently selected from hydroxy, (1-6C)alkyl and (3-8C)heterocyclyl, wherein each R4 is independently optionally substituted with one or more groups, (1- 4C)alkyl.
(72) each R4 is independently selected from hydroxy, (1-4C)alkyl or a group:
(73) X3 and X4 are independently selected from hydroxy, ORp and NRqRr.
(74) X3 and X4 are linked, such that when they are taken in combination with the carbon atom to which they are attached, they collectively form a 4-6 membered heterocycle containing
1 or 2 heteroatoms selected from O and N, wherein the 4-6 membered heterocycle is optionally substituted with one or more R5 substituents.
(75) X3 and X4 are linked, such that when they are taken in combination with the carbon atom to which they are attached, they collectively form a group having a structure according to formula (B) shown below:
X5 is selected from O or NRm;
m is a number selected from 1 and 2; and
o is a number selected from 1 and 2.
(76) X3 and X4 are linked, such that when they are taken in combination with the carbon atom to which they are attached, they collectively form a group having a structure according to formula (B’) shown below:
X5 is selected from O or NRm;
m is a number selected from 1 and 2; and
o is a number selected from 1 and 2.
(77) X5 is O.
(78) m is 1.
(79) o is 1.
(80) Each R5 is independently selected from fluoro, chloro, trifluoromethyl, trifluoromethoxy, hydroxy, oxo, amino, carboxy, (1-6C)alkyl, (1-4C)alkoxy, methylamino or dimethylamino,
aryl, aryl(1-2C)alkyl, heteroaryl, heteroaryl(1-2C)alkyl, (3-8C)heterocyclyl, heterocyclyl(1- 2C)alkyl, (3-8C)cycloalkyl, and (3-8C)cycloalkyl(1-2C)alkyl.
(81) Each R5 is independently selected from fluoro, chloro, trifluoromethyl, trifluoromethoxy, hydroxy, oxo, amino, carboxy, (1-6C)alkyl, (1-4C)alkoxy, methylamino and dimethylamino.
(82) Each R5 is independently selected from fluoro, chloro, hydroxy, oxo, amino, (1-3C)alkyl and (1-3C)alkoxy.
(83) Each R5 is independently selected from hydroxy, oxo and (1-4C)alkoxy.
(84) R5 is oxo.
(85) Rf, Rg, Rm, Rn, Ro, RP, Rq, Rr are each independently selected from hydrogen and (1- 6C)alkyl.
(86) Rf, Rg, Rm, Rn, Ro, RP, Rq, Rr are each independently selected from hydrogen and (1- 3C)alkyl.
(87) Rf, Rg, Rm, Rn, Ro, R , Rq, Rr are each hydrogen.
[0044] Suitably, the compound has a structure according to formula (I).
[0045] Suitably, the compound has a structure according to formula (II).
[0046] Suitably, the compound has a structure according to formula (III).
[0047] Suitably, the compound has a structure according to formula (I) or (II).
[0048] Suitably, the compound has a structure according to formula (I) or (III).
[0049] Suitably, the compound has a structure according to formula (II) or (III).
[0050] Suitably, (3-8)heterocycles are linked to the group to which they are attached via a nitrogen atom present within the heterocyclic ring (i.e. “N-linked”). More suitably, (3- 8) heterocycles are 5-6 membered, containing 1-2 ring heteroatoms selected from N and O. Most suitably, (3-8)heterocycles are selected from the following:
[0051] Suitably an aryl group is phenyl.
[0052] Suitably, R1 is as described in any of numbered paragraphs (3) to (8), wherein Ra and Rb are suitably as described in any of numbered paragraphs (10) to (12) and Rc is suitably as
described in any of numbered paragraphs (23) to (25). More suitably, Ri is as described in any of numbered paragraphs (5) to (8), wherein Ra and Rb are suitably as described in any of numbered paragraphs (11) to (12) and Rc is suitably as described in any of numbered paragraphs (24) to (25). Yet more suitably, Ri is as described in any of numbered paragraphs (7) to (8), wherein Ra and Rb are suitably as described in any of numbered paragraphs (11) to (12) and Rc is suitably as described in any of numbered paragraphs (24) to (25). Most suitably, Ri is as described in numbered paragraph (8), wherein Rc is suitably as described in numbered paragraph (25).
[0053] Suitably, Ri is as described in any of numbered paragraphs (3) to (8), wherein Ra and Rb are suitably as described in any of numbered paragraphs (13) to (22) and Rc is suitably as described in any of numbered paragraphs (23) to (25). More suitably, Ri is as described in any of numbered paragraphs (5) to (8), wherein Ra and Rb are suitably as described in any of numbered paragraphs (17) to (22) and Rc is suitably as described in any of numbered paragraphs (24) to (25). Yet more suitably, Ri is as described in any of numbered paragraphs (7) to (8), wherein Ra and Rb are suitably as described in any of numbered paragraphs (19) to (22) and Rc is suitably as described in any of numbered paragraphs (24) to (25). Most suitably, Ri is as described in any of numbered paragraphs (7) to (8), wherein Ra and Rb are suitably as described in any of numbered paragraphs (21) to (22) and Rc is suitably as described in numbered paragraph (25)..
[0054] Suitably, R2 is as described in any of numbered paragraphs (28) to (32), wherein Rd is suitably as described in any of numbered paragraphs (33) to (34) and Re is suitably as described in any of numbered paragraphs (36) to (38). More suitably, R2 is as described in any of numbered paragraphs (30) to (32), wherein Rd is suitably as described in numbered paragraph (34) and Re is suitably as described in any of numbered paragraphs (37) to (38). Most suitably, R2 is as described in numbered paragraph (32), wherein Rd is suitably as described in numbered paragraph (34) and Re is suitably as described in numbered paragraph (38)
[0055] Suitably, X2 is as described in numbered paragraph (41), wherein n is suitably as described in numbered paragraph (42) or (43), R3 is suitably as described in any of numbered paragraphs (46) to (50), Rh and R, are suitably as described in any of numbered paragraphs (52) to (53), Rj and Rk are suitably as described in any of numbered paragraphs (55) to (57) and Ri is suitably as described in any of numbered paragraphs (59) to (60). More suitably, X2 is as described in numbered paragraph (41), wherein n is suitably as described in numbered paragraph (42) or (43), R3 is suitably as described in any of numbered paragraphs (48) to (50), Rh and R, are suitably as described in numbered paragraph (53), Rj and Rk are suitably as described in any of numbered paragraphs (56) to (57) and Ri is suitably as described in any of numbered paragraphs (59) to (60). Most suitably, X2 is as described in numbered paragraph (41),
wherein n is suitably as described in numbered paragraph (43), R3 is suitably as described in any of numbered paragraphs (49) to (50), Rh and R, are suitably as described in numbered paragraph (53), Rj and Rk are suitably as described in numbered paragraph (57) and Ri is suitably as described in numbered paragraph (60).
[0056] Suitably, R2 and X1 or R2 and X2 are as described in any of numbered paragraphs (64) to (67), wherein R4 is suitably as described in any of numbered paragraphs (69) to (72). More suitably, R2 and X1 or R2 and X2 are as described in any of numbered paragraphs (65) to (67), wherein R4 is suitably as described in any of numbered paragraphs (70) to (72). Most suitably, R2 and Xi or R2 and X2 are as described in any of numbered paragraphs (66) to (67), wherein R4 is suitably as described in paragraph (72).
[0057] Suitably, X3 and X4 are as described in any of numbered paragraphs (75) to (76), wherein m is as described in numbered paragraph (78) and R5 is as described in any of numbered paragraphs (81) to (84). More suitably, X3 and X4 are as described in any of numbered paragraphs (75) to (76), wherein m is as described in numbered paragraph (78), o is as described in numbered paragraph (79) and Rs is as described in any of numbered paragraphs (81) to (84). Even more suitably, X3 and X4 are as described in any of numbered paragraphs (75) to (76), wherein X5 is as described in numbered paragraph (77), m is as described in numbered paragraph (78), o is as described in numbered paragraph (79) and Rs is as described in any of numbered paragraphs (82) to (84). Yet more suitably, X3 and X4 are as described in any of numbered paragraphs (75) to (76), wherein X5 is as described in numbered paragraph (77), m is as described in numbered paragraph (78), o is as described in numbered paragraph (79) and R5 is as described in any of numbered paragraphs (83) to (84). Most suitably, X3 and X4 are as described in numbered paragraph (76), wherein X5 is as described in numbered paragraph (77), m is as described in numbered paragraph (78), o is as described in numbered paragraph (79) and Rs is as described in any of numbered paragraphs (83) to (84).
[0058] Suitably, Rf, Rg, Rm, Rn, Ro, RP, Rq, Rr are as described in numbered paragraph (86) or (87). Most suitably, Rf, Rg, Rm, Rn, Ro, RP, Rq, Rr are as described in numbered paragraph (87).
[0059] In a particular group of compounds having a structure according to formula (I), (II) or (III), R2 is hydrogen, such that the compounds have a structure according to formula (la), (lla) or (Ilia) shown below:
(I la)
[0060] In an embodiment of the compounds of formula (la), (I la) or (Ilia):
R1 is as described in any of numbered paragraphs (3) to (8);
Ra and Rb are as described in any of numbered paragraphs (10) to (12);
Rc is as described in any of numbered paragraphs (23) to (25); and
Xi, X2, X3 and X4, and any of their associated substituents, have any of the definitions appearing hereinbefore.
[0061] In an embodiment of the compounds of formula (la), (I la) or (Ilia):
R1 is as described in any of numbered paragraphs (5) to (8);
Ra and Rb are as described in any of numbered paragraphs (11) to (12);
Rc is as described in any of numbered paragraphs (24) to (25); and
Xi, X2, X3 and X4, and any of their associated substituents, have any of the definitions appearing hereinbefore.
[0062] In an embodiment of the compounds of formula (la), (I la) or (Ilia):
R1 is as described in any of numbered paragraphs (5) to (8);
Ra and Rb are as described in any of numbered paragraphs (11) to (12);
Rc is as described in any of numbered paragraphs (24) to (25);
Xi is as described in numbered paragraph (39); and
X2, X3 and X4, and any of their associated substituents, have any of the definitions appearing hereinbefore.
[0063] In an embodiment of the compounds of formula (la), (I la) or (Ilia):
R1 is as described in any of numbered paragraphs (5) to (8);
Ra and Rb are as described in any of numbered paragraphs (11) to (12);
Rc is as described in any of numbered paragraphs (24) to (25);
Xi is as described in numbered paragraph (39);
X2 is as described in numbered paragraph (40) or (41);
n is as described in numbered paragraph (42) or (43);
R3 is as described in any of numbered paragraphs (46) to (50);
Rh and R, are as described in any of numbered paragraphs (52) to (53);
Rj and Rk are as described in any of numbered paragraphs (55) to (57);
Ri is as described in any of numbered paragraphs (59) to (60); and
X3 and X4, and any of their associated substituents, have any of the definitions appearing hereinbefore.
[0064] In an embodiment of the compounds of formula (la), (I la) or (Ilia):
R1 is as described in any of numbered paragraphs (5) to (8);
Ra and Rb are as described in any of numbered paragraphs (11) to (12);
Rc is as described in any of numbered paragraphs (24) to (25);
Xi is as described in numbered paragraph (39);
X2 is as described in numbered paragraph (40) or (41);
n is as described in numbered paragraph (42) or (43);
R3 is as described in any of numbered paragraphs (46) to (50);
Rh and R, are as described in any of numbered paragraphs (52) to (53);
Rj and Rk are as described in any of numbered paragraphs (55) to (57);
Ri is as described in any of numbered paragraphs (59) to (60);
X3 and X4 are as described in any of numbered paragraphs (75) to (76);
m is as described in numbered paragraph (78);
o is as described in numbered paragraph (79); and
Rs is as described in any of numbered paragraphs (81) to (84).
[0065] In an embodiment of the compounds of formula (la), (I la) or (Ilia):
R1 is as described in any of numbered paragraphs (6) to (8);
Ra and Rb are as described in any of numbered paragraphs (11) to (12); Rc is as described in any of numbered paragraphs (24) to (25);
Xi is as described in numbered paragraph (39);
X2 is as described in numbered paragraph (40) or (41); n is as described in numbered paragraph (43);
R3 is as described in any of numbered paragraphs (48) to (50);
Rh and R, are as described in numbered paragraph (53);
Rj and Rk are as described in any of numbered paragraphs (56) to (57); Ri is as described in any of numbered paragraphs (59) to (60);
X3 and X4 are as described in any of numbered paragraphs (75) to (76); m is as described in numbered paragraph (78);
o is as described in numbered paragraph (79); and
R5 IS as described in any of numbered paragraphs (83) to (84).
[0066] In an embodiment of the compounds of formula (la), (I la) or (Ilia):
R1 is as described in any of numbered paragraphs (7) to (8);
Ra and Rb are as described in numbered paragraph (12);
Rc is as described in numbered paragraph (25);
Xi is as described in numbered paragraph (39);
X2 is as described in numbered paragraph (40) or (41); n is as described in numbered paragraph (43);
R3 is as described in any of numbered paragraphs (48) to (50);
Rh and R, are as described in numbered paragraph (53);
Rj and Rk are as described in any of numbered paragraphs (56) to (57);
Ri is as described in any of numbered paragraphs (59) to (60);
X3 and X4 are as described in any of numbered paragraphs (75) to (76);
m is as described in numbered paragraph (78);
o is as described in numbered paragraph (79); and
R5 IS as described in any of numbered paragraphs (83) to (84).
[0067] In an embodiment of the compounds of formula (la), (I la) or (Ilia):
R1 is as described in numbered paragraphs (8);
Rc is as described in numbered paragraph (25);
Xi is as described in numbered paragraph (39);
X2 is as described in numbered paragraph (40) or (41);
n is as described in numbered paragraph (43);
R3 is as described in any of numbered paragraphs (48) to (50);
Rh and R, are as described in numbered paragraph (53);
Rj and Rk are as described in any of numbered paragraphs (56) to (57);
Ri is as described in any of numbered paragraphs (59) to (60);
X3 and X4 are as described in any of numbered paragraphs (75) to (76);
m is as described in numbered paragraph (78);
o is as described in numbered paragraph (79); and
R5 IS as described in any of numbered paragraphs (83) to (84).
[0068] In an embodiment of the compounds of formula (la), (I la) or (Ilia):
Ri is as described in any of numbered paragraphs (3) to (8);
Ra and Rb are as described in any of numbered paragraphs (13) to (22);
Rc is as described in any of numbered paragraphs (23) to (25); and
Xi, X2, X3 and X4, and any of their associated substituents, have any of the definitions appearing hereinbefore.
[0069] In an embodiment of the compounds of formula (la), (lla) or (Ilia):
Ri is as described in any of numbered paragraphs (5) to (8);
Ra and Rb are as described in any of numbered paragraphs (15) to (22);
Rc is as described in any of numbered paragraphs (24) to (25); and
Xi, X2, X3 and X4, and any of their associated substituents, have any of the definitions appearing hereinbefore.
[0070] In an embodiment of the compounds of formula (la), (I la) or (Ilia):
R1 is as described in any of numbered paragraphs (5) to (8);
Ra and Rb are as described in any of numbered paragraphs (15) to (22);
Rc is as described in any of numbered paragraphs (24) to (25);
Xi is as described in numbered paragraph (39); and
X2, X3 and X4, and any of their associated substituents, have any of the definitions appearing hereinbefore.
[0071] In an embodiment of the compounds of formula (la), (I la) or (Ilia):
R1 is as described in any of numbered paragraphs (5) to (8);
Ra and Rb are as described in any of numbered paragraphs (17) to (22);
Rc is as described in any of numbered paragraphs (24) to (25);
Xi is as described in numbered paragraph (39);
X2 is as described in numbered paragraph (40) or (41);
n is as described in numbered paragraph (42) or (43);
R3 is as described in any of numbered paragraphs (46) to (50);
Rh and R, are as described in any of numbered paragraphs (52) to (53);
Rj and Rk are as described in any of numbered paragraphs (55) to (57);
Ri is as described in any of numbered paragraphs (59) to (60); and
X3 and X4, and any of their associated substituents, have any of the definitions appearing hereinbefore.
[0072] In an embodiment of the compounds of formula (la), (I la) or (Ilia):
R1 is as described in any of numbered paragraphs (5) to (8);
Ra and Rb are as described in any of numbered paragraphs (19) to (22);
Rc is as described in any of numbered paragraphs (24) to (25);
Xi is as described in numbered paragraph (39);
X2 is as described in numbered paragraph (40) or (41);
n is as described in numbered paragraph (42) or (43);
R3 is as described in any of numbered paragraphs (46) to (50);
Rh and R, are as described in any of numbered paragraphs (52) to (53); Rj and Rk are as described in any of numbered paragraphs (55) to (57); Ri is as described in any of numbered paragraphs (59) to (60);
X3 and X4 are as described in any of numbered paragraphs (75) to (76); m is as described in numbered paragraph (78);
o is as described in numbered paragraph (79); and
R5 IS as described in any of numbered paragraphs (82) to (84).
[0073] In an embodiment of the compounds of formula (la), (I la) or (Ilia):
R1 is as described in any of numbered paragraphs (6) to (8);
Ra and Rb are as described in any of numbered paragraphs (19) to (22); Rc is as described in any of numbered paragraphs (24) to (25);
Xi is as described in numbered paragraph (39);
X2 is as described in numbered paragraph (40) or (41); n is as described in numbered paragraph (43);
R3 is as described in any of numbered paragraphs (48) to (50);
Rh and R, are as described in numbered paragraph (53);
Rj and Rk are as described in any of numbered paragraphs (56) to (57); Ri is as described in any of numbered paragraphs (59) to (60);
X3 and X4 are as described in any of numbered paragraphs (75) to (76); m is as described in numbered paragraph (78);
o is as described in numbered paragraph (79); and
R5 IS as described in any of numbered paragraphs (83) to (84).
[0074] In an embodiment of the compounds of formula (la), (I la) or (Ilia):
Ri is as described in any of numbered paragraphs (7) to (8);
Ra and Rb are as described in numbered paragraph (21) or (22);
Rc is as described in numbered paragraph (25);
Xi is as described in numbered paragraph (39);
X2 is as described in numbered paragraph (40) or (41);
n is as described in numbered paragraph (43);
R3 is as described in any of numbered paragraphs (48) to (50);
Rh and R, are as described in numbered paragraph (53);
Rj and Rk are as described in any of numbered paragraphs (56) to (57);
Ri is as described in any of numbered paragraphs (59) to (60);
X3 and X4 are as described in any of numbered paragraphs (75) to (76);
m is as described in numbered paragraph (78);
o is as described in numbered paragraph (79); and
R5 IS as described in any of numbered paragraphs (83) to (84).
[0075] In an embodiment of the compounds of formula (la), (I la) or (Ilia):
Ri, and any of its associated substituents, has any of the definitions appearing hereinbefore;
Xi is as described in numbered paragraph (39);
X2 is as described in numbered paragraph (40) or (41);
n is as described in numbered paragraph (42) or (43);
R3 is as described in any of numbered paragraphs (46) to (50);
Rh and R, are as described in any of numbered paragraphs (52) to (53);
Rj and Rk are as described in any of numbered paragraphs (55) to (57);
Ri is as described in any of numbered paragraphs (59) to (60); and
X3 and X4, and any of their associated substituents, have any of the definitions appearing hereinbefore.
[0076] In an embodiment of the compounds of formula (la), (I la) or (Ilia):
Ri, and any of its associated substituents, has any of the definitions appearing hereinbefore;
Xi is as described in numbered paragraph (39);
X2 is as described in numbered paragraph (40) or (41);
n is as described in numbered paragraph (42) or (43);
R3 is as described in any of numbered paragraphs (46) to (50);
Rh and R, are as described in any of numbered paragraphs (52) to (53);
Rj and Rk are as described in any of numbered paragraphs (55) to (57);
Ri is as described in any of numbered paragraphs (59) to (60);
X3 and X4 are as described in any of numbered paragraphs (75) to (76);
m is as described in numbered paragraph (78);
o is as described in numbered paragraph (79); and
R5 IS as described in any of numbered paragraphs (81) to (84).
[0077] In an embodiment of the compounds of formula (la), (I la) or (Ilia):
Ri, and any of its associated substituents, has any of the definitions appearing hereinbefore;
Xi is as described in numbered paragraph (39);
X2 is as described in numbered paragraph (40) or (41);
n is as described in numbered paragraph (43);
R3 is as described in any of numbered paragraphs (48) to (50);
Rh and R, are as described in numbered paragraph (53);
Rj and Rk are as described in any of numbered paragraphs (56) to (57);
Ri is as described in any of numbered paragraphs (59) to (60);
X3 and X4 are as described in any of numbered paragraphs (75) to (76);
m is as described in numbered paragraph (78);
o is as described in numbered paragraph (79); and
R5 IS as described in any of numbered paragraphs (83) to (84).
[0078] In a particular group of compounds having a structure according to formula (I), (II) or (III), Ri is hydroxy, such that the compounds have a structure according to formula (lb), (lib) or (lllb) shown below:
wherein R2, Xi , X2, X3 and X4, and any of their associated substituents, have any of the definitions appearing hereinbefore.
[0079] In an embodiment of the compounds of formula (lb), (lib) or (I I lb):
R2 is as described in any of numbered paragraphs (28) to (32);
Rd is as described in any of numbered paragraphs (33) to (34);
Re is as described in any of numbered paragraphs (36) to (38);
Xi is as described in numbered paragraph (39); and
X2, X3 and X4, and any of their associated substituents, have any of the definitions appearing hereinbefore.
[0080] In an embodiment of the compounds of formula (lb), (lib) or (I I lb):
R2 is as described in any of numbered paragraphs (30) to (32);
Rd is as described in any of numbered paragraphs (33) to (34);
Re is as described in any of numbered paragraphs (37) to (38);
Xi is as described in numbered paragraph (39);
X2 is as described in numbered paragraph (40) or (41);
n is as described in numbered paragraph (42) or (43);
R3 is as described in any of numbered paragraphs (46) to (50);
Rh and R, are as described in any of numbered paragraphs (52) to (53);
Rj and Rk are as described in any of numbered paragraphs (55) to (57);
Ri is as described in any of numbered paragraphs (59) to (60); and
X3 and X4, and any of their associated substituents, have any of the definitions appearing hereinbefore.
[0081] In an embodiment of the compounds of formula (lb), (lib) or (lllb):
R2 is as described in numbered paragraph (32);
Rd is as described in any of numbered paragraphs (33) to (34);
Re is as described in any of numbered paragraphs (37) to (38);
Xi is as described in numbered paragraph (39);
X2 is as described in numbered paragraph (40) or (41);
n is as described in numbered paragraph (42) or (43);
R3 is as described in any of numbered paragraphs (46) to (50);
Rh and R, are as described in any of numbered paragraphs (52) to (53);
Rj and Rk are as described in any of numbered paragraphs (55) to (57);
Ri is as described in any of numbered paragraphs (59) to (60);
X3 and X4 are as described in any of numbered paragraphs (75) to (76);
X5 is as described in numbered paragraph (77);
m is as described in numbered paragraph (78);
o is as described in numbered paragraph (79); and
R5 IS as described in any of numbered paragraphs (81) to (84).
[0082] In an embodiment of the compounds of formula (lb), (lib) or (lllb):
R2 is as described in numbered paragraph (32);
Rd is as described in numbered paragraph (34);
Re is as described in numbered paragraph (38);
Xi is as described in numbered paragraph (39);
X2 is as described in numbered paragraph (40) or (41);
n is as described in numbered paragraph (43);
R3 is as described in any of numbered paragraphs (48) to (50);
Rh and R, are as described in numbered paragraph (53);
Rj and Rk are as described in any of numbered paragraphs (56) to (57); Ri is as described in any of numbered paragraphs (59) to (60);
X3 and X4 are as described in any of numbered paragraphs (75) to (76);
X5 is as described in numbered paragraph (77);
m is as described in numbered paragraph (78);
o is as described in numbered paragraph (79); and
R5 IS as described in any of numbered paragraphs (83) to (84).
[0083] In an embodiment of the compounds of formula (lb), (lib) or (lllb):
R2 is as described in numbered paragraph (32);
Rd is as described in numbered paragraph (34);
Re is as described in numbered paragraph (38);
Xi is as described in numbered paragraph (39);
X2 is as described in numbered paragraph (40) or (41); n is as described in numbered paragraph (43);
R3 is as described in any of numbered paragraphs (48) to (50);
Rh and R, are as described in numbered paragraph (53);
Rj and Rk are as described in any of numbered paragraphs (56) to (57); Ri is as described in any of numbered paragraphs (59) to (60);
X3 and X4 are as described in any of numbered paragraphs (75) to (76);
X5 is as described in numbered paragraph (77);
m is as described in numbered paragraph (78);
o is as described in numbered paragraph (79); and
R5 IS as described in any of numbered paragraphs (83) to (84).
[0084] In an embodiment of the compounds of formula (lb), (lib) or (lllb):
R2 is as described in any of numbered paragraphs (30) to (32);
Rd is as described in any of numbered paragraphs (33) to (34);
Re is as described in any of numbered paragraphs (37) to (38);
Xi is as described in numbered paragraph (39);
X2 is as described in numbered paragraph (40) or (41);
n is as described in numbered paragraph (42) or (43);
R3 is as described in any of numbered paragraphs (46) to (50);
Rh and R, are as described in any of numbered paragraphs (52) to (53);
Rj and Rk are as described in any of numbered paragraphs (55) to (57);
Ri is as described in any of numbered paragraphs (59) to (60);
or R2 and X1 or R2 and X2 are as described in any of numbered paragraphs (65) to (67), wherein R4 is as described in any of numbered paragraphs (70) to (72); and
X3 and X4, and any of their associated substituents, have any of the definitions appearing hereinbefore.
[0085] In an embodiment of the compounds of formula (lb), (lib) or (lllb):
R2 is as described in numbered paragraph (32);
Rd is as described in any of numbered paragraphs (33) to (34);
Re is as described in any of numbered paragraphs (37) to (38);
Xi is as described in numbered paragraph (39);
X2 is as described in numbered paragraph (40) or (41);
n is as described in numbered paragraph (42) or (43);
R3 is as described in any of numbered paragraphs (46) to (50);
Rh and R, are as described in any of numbered paragraphs (52) to (53);
Rj and Rk are as described in any of numbered paragraphs (55) to (57);
Ri is as described in any of numbered paragraphs (59) to (60);
or R2 and Xi or R2 and X2 are as described in any of numbered paragraphs (65) to (57), wherein R4 is as described in any of numbered paragraphs (70) to (72);
X3 and X4 are as described in any of numbered paragraphs (75) to (76);
X5 is as described in numbered paragraph (77);
m is as described in numbered paragraph (78);
o is as described in numbered paragraph (79); and
R5 IS as described in any of numbered paragraphs (81) to (84).
[0086] In an embodiment of the compounds of formula (lb), (lib) or (lllb):
R2 is as described in numbered paragraph (32);
Rd is as described in numbered paragraph (34);
Re is as described in numbered paragraph (38);
Xi is as described in numbered paragraph (39);
X2 is as described in numbered paragraph (40) or (41);
n is as described in numbered paragraph (43);
R3 is as described in any of numbered paragraphs (48) to (50);
Rh and R, are as described in numbered paragraph (53);
Rj and Rk are as described in any of numbered paragraphs (56) to (57);
Ri is as described in any of numbered paragraphs (59) to (60);
or R2 and X1 or R2 and X2 are as described in any of numbered paragraphs (66) to (57), wherein R4 is as described in any of numbered paragraphs (71) to (72);
X3 and X4 are as described in any of numbered paragraphs (75) to (76);
X5 is as described in numbered paragraph (77);
m is as described in numbered paragraph (78);
o is as described in numbered paragraph (79); and
R5 IS as described in any of numbered paragraphs (83) to (84).
[0087] In an embodiment of the compounds of formula (lb), (lib) or (lllb):
R2 is as described in numbered paragraph (32);
Rd is as described in numbered paragraph (34);
Re is as described in numbered paragraph (38);
Xi is as described in numbered paragraph (39);
X2 is as described in numbered paragraph (40) or (41);
n is as described in numbered paragraph (43);
R3 is as described in any of numbered paragraphs (48) to (50);
Rh and R, are as described in numbered paragraph (53);
Rj and Rk are as described in any of numbered paragraphs (56) to (57);
Ri is as described in any of numbered paragraphs (59) to (60);
or R2 and X1 or R2 and X2 are as described in any of numbered paragraphs (66) to (67), wherein R4 is as described in any of numbered paragraphs (71) to (72);
X3 and X4 are as described in any of numbered paragraphs (75) to (76);
X5 is as described in numbered paragraph (77);
m is as described in numbered paragraph (78);
o is as described in numbered paragraph (79); and
R5 IS as described in any of numbered paragraphs (83) to (84).
[0088] In a particular group of compounds having a structure according to formula (I), (II) or (III), Xi is O and X3 and X4 are as defined in numbered paragraph (75), such that the compounds have a structure according to formula (lc), (lie) or (I lie) shown below:
(I He) wherein Ri, R2, R5, X2, X5, m and o, and any of their associated substituents, have any of the definitions appearing hereinbefore.
[0089] In an embodiment of the compounds of formula (lc), (lie) or (I lie):
Ri, and any of its associated substituents, has any of the definitions appearing hereinbefore;
R2 is as described in any of numbered paragraphs (30) to (32);
Rd is as described in any of numbered paragraphs (33) to (34);
Re is as described in any of numbered paragraphs (37) to (38);
X2 is as described in numbered paragraph (40) or (41);
n is as described in numbered paragraph (42) or (43);
R3 is as described in any of numbered paragraphs (46) to (50);
Rh and R, are as described in any of numbered paragraphs (52) to (53);
Rj and Rk are as described in any of numbered paragraphs (55) to (57);
Ri is as described in any of numbered paragraphs (59) to (60);
X5 is as described in numbered paragraph (77);
m is as described in numbered paragraph (78);
o is as described in numbered paragraph (79); and
R5 IS as described in any of numbered paragraphs (81) to (84).
[0090] In an embodiment of the compounds of formula (lc), (lie) or (I lie):
Ri, and any of their associated substituents, has any of the definitions appearing hereinbefore;
R2 is as described in any of numbered paragraphs (31) to (32);
Rd is as described in any of numbered paragraphs (33) to (34);
Re is as described in any of numbered paragraphs (37) to (38);
X2 is as described in numbered paragraph (40) or (41);
n is as described in numbered paragraph (42) or (43);
R3 is as described in any of numbered paragraphs (48) to (50);
Rh and R, are as described in any of numbered paragraphs (52) to (53);
Rj and Rk are as described in any of numbered paragraphs (55) to (57);
Ri is as described in any of numbered paragraphs (59) to (60);
X5 is as described in numbered paragraph (77);
m is as described in numbered paragraph (78);
o is as described in numbered paragraph (79); and
R5 IS as described in any of numbered paragraphs (83) to (84).
[0091] In an embodiment of the compounds of formula (lc), (lie) or (I lie):
Ri is as described in any of numbered paragraphs (5) to (8);
Ra and Rb are as described in any of numbered paragraphs (11) to (12); Rc is as described in any of numbered paragraphs (24) to (25);
R2 is as described in any of numbered paragraphs (31) to (32);
Rd is as described in any of numbered paragraphs (33) to (34);
Re is as described in any of numbered paragraphs (37) to (38);
X2 is as described in numbered paragraph (40) or (41); n is as described in numbered paragraph (42) or (43);
R3 is as described in any of numbered paragraphs (48) to (50);
Rh and R, are as described in any of numbered paragraphs (52) to (53); Rj and Rk are as described in any of numbered paragraphs (55) to (57); Ri is as described in any of numbered paragraphs (59) to (60);
X5 is as described in numbered paragraph (77);
m is as described in numbered paragraph (78);
o is as described in numbered paragraph (79); and
R5 IS as described in any of numbered paragraphs (83) to (84).
[0092] In an embodiment of the compounds of formula (lc), (lie) or (I lie):
Ri is as described in any of numbered paragraphs (6) to (8);
Ra and Rb are as described in any of numbered paragraphs (11) to (12); Rc is as described in any of numbered paragraphs (24) to (25);
R2 is hydrogen;
X2 is as described in numbered paragraph (40) or (41); n is as described in numbered paragraph (42) or (43);
R3 is as described in any of numbered paragraphs (48) to (50);
Rh and R, are as described in any of numbered paragraphs (52) to (53); Rj and Rk are as described in any of numbered paragraphs (55) to (57); Ri is as described in any of numbered paragraphs (59) to (60);
X5 is as described in numbered paragraph (77);
m is as described in numbered paragraph (78);
o is as described in numbered paragraph (79); and
R5 IS as described in any of numbered paragraphs (83) to (84).
[0093] In an embodiment of the compounds of formula (lc), (lie) or (I lie):
R1 is as described in numbered paragraph (8);
Rc is as described in any of numbered paragraphs (24) to (25);
R2 is hydrogen;
X2 is as described in numbered paragraph (40) or (41); n is as described in numbered paragraph (42) or (43);
R3 is as described in any of numbered paragraphs (49) to (50);
Rh and R, are as described in numbered paragraphs (53);
Rj and Rk are as described in any of numbered paragraphs (56) to (57); Ri is as described in any of numbered paragraphs (59) to (60);
X5 is as described in numbered paragraph (77);
m is as described in numbered paragraph (78);
o is as described in numbered paragraph (79); and
R5 IS as described in any of numbered paragraphs (83) to (84).
[0094] In an embodiment of the compounds of formula (lc), (lie) or (I lie):
R1 is as described in any of numbered paragraphs (5) to (8);
Ra and Rb are as described in any of numbered paragraphs (13) to (22); Rc is as described in any of numbered paragraphs (24) to (25);
R2 is as described in any of numbered paragraphs (31) to (32);
Rd is as described in any of numbered paragraphs (33) to (34);
Re is as described in any of numbered paragraphs (37) to (38);
X2 is as described in numbered paragraph (40) or (41); n is as described in numbered paragraph (42) or (43);
R3 is as described in any of numbered paragraphs (48) to (50);
Rh and R, are as described in any of numbered paragraphs (52) to (53); Rj and Rk are as described in any of numbered paragraphs (55) to (57); Ri is as described in any of numbered paragraphs (59) to (60);
X5 is as described in numbered paragraph (77);
m is as described in numbered paragraph (78);
o is as described in numbered paragraph (79); and
R5 IS as described in any of numbered paragraphs (83) to (84).
[0095] In an embodiment of the compounds of formula (lc), (lie) or (I lie):
R1 is as described in any of numbered paragraphs (6) to (8);
Ra and Rb are as described in any of numbered paragraphs (17) to (22); Rc is as described in any of numbered paragraphs (24) to (25);
R2 is hydrogen;
X2 is as described in numbered paragraph (40) or (41); n is as described in numbered paragraph (42) or (43);
R3 is as described in any of numbered paragraphs (48) to (50);
Rh and R, are as described in any of numbered paragraphs (52) to (53); Rj and Rk are as described in any of numbered paragraphs (55) to (57); Ri is as described in any of numbered paragraphs (59) to (60);
X5 is as described in numbered paragraph (77);
m is as described in numbered paragraph (78);
o is as described in numbered paragraph (79); and
R5 IS as described in any of numbered paragraphs (83) to (84).
[0096] In an embodiment of the compounds of formula (lc), (lie) or (I lie):
Ri is as described in any of numbered paragraphs (6) to (8);
Ra and Rb are as described in any of numbered paragraphs (21) to (22); Rc is as described in any of numbered paragraphs (24) to (25);
R2 is hydrogen;
X2 is as described in numbered paragraph (40) or (41);
n is as described in numbered paragraph (42) or (43);
R is as described in any of numbered paragraphs (48) to (50);
Rh and R, are as described in any of numbered paragraphs (52) to (53);
Rj and Rk are as described in any of numbered paragraphs (55) to (57);
Ri is as described in any of numbered paragraphs (59) to (60);
X5 is as described in numbered paragraph (77);
m is as described in numbered paragraph (78);
o is as described in numbered paragraph (79); and
R IS as described in any of numbered paragraphs (83) to (84).
[0097] In a particular group of compounds having a structure according to formula (I), (II) or (III), Xi is O, X is as defined in numbered paragraph (41), n is 1 , and X3 and X are as defined in numbered paragraph (76), such that the compounds have a structure according to formula (Id), (lid) or (Mid) shown below:
[0098] In an embodiment of the compounds of formula (Id), (lid) or (I lid):
Ri, and any of its associated substituents, has any of the definitions appearing hereinbefore;
R2 is as described in any of numbered paragraphs (30) to (32);
Rd is as described in any of numbered paragraphs (33) to (34);
Re is as described in any of numbered paragraphs (37) to (38);
R3 is as described in any of numbered paragraphs (46) to (50);
Rh and R, are as described in any of numbered paragraphs (52) to (53);
Rj and Rk are as described in any of numbered paragraphs (55) to (57);
Ri is as described in any of numbered paragraphs (59) to (60);
X5 is as described in numbered paragraph (77);
m is as described in numbered paragraph (78); and
R5 IS as described in any of numbered paragraphs (81) to (84).
[0099] In an embodiment of the compounds of formula (Id), (lid) or (I lid):
Ri, and any of its associated substituents, has any of the definitions appearing hereinbefore;
R2 is as described in any of numbered paragraphs (31) to (32);
Rd is as described in any of numbered paragraphs (33) to (34);
Re is as described in any of numbered paragraphs (37) to (38);
R3 is as described in any of numbered paragraphs (48) to (50);
Rh and R, are as described in any of numbered paragraphs (52) to (53);
Rj and Rk are as described in any of numbered paragraphs (55) to (57);
Ri is as described in any of numbered paragraphs (59) to (60);
X5 is as described in numbered paragraph (77);
m is as described in numbered paragraph (78); and
R5 IS as described in any of numbered paragraphs (83) to (84).
[00100] In an embodiment of the compounds of formula (Id), (lid) or (I lid):
Ri is as described in any of numbered paragraphs (5) to (8);
Ra and Rb are as described in any of numbered paragraphs (11) to (12);
Rc is as described in any of numbered paragraphs (24) to (25);
R2 is as described in any of numbered paragraphs (31) to (32);
Rd is as described in any of numbered paragraphs (33) to (34);
Re is as described in any of numbered paragraphs (37) to (38);
R3 is as described in any of numbered paragraphs (48) to (50);
Rh and R, are as described in any of numbered paragraphs (52) to (53); Rj and Rk are as described in any of numbered paragraphs (55) to (57); Ri is as described in any of numbered paragraphs (59) to (60);
X5 is as described in numbered paragraph (77);
m is as described in numbered paragraph (78); and
R5 IS as described in any of numbered paragraphs (83) to (84).
[00101] In an embodiment of the compounds of formula (Id), (lid) or (I lid):
R1 is as described in any of numbered paragraphs (6) to (8);
Ra and Rb are as described in any of numbered paragraphs (11) to (12); Rc is as described in any of numbered paragraphs (24) to (25);
R2 is hydrogen;
R3 is as described in any of numbered paragraphs (48) to (50);
Rh and R, are as described in any of numbered paragraphs (52) to (53); Rj and Rk are as described in any of numbered paragraphs (55) to (57); Ri is as described in any of numbered paragraphs (59) to (60);
X5 is as described in numbered paragraph (77);
m is as described in numbered paragraph (78); and
R5 IS as described in any of numbered paragraphs (83) to (84).
[00102] In an embodiment of the compounds of formula (Id), (lid) or (Mid):
Ri is as described in numbered paragraph (8);
Rc is as described in any of numbered paragraphs (24) to (25);
R2 is hydrogen;
R3 is as described in any of numbered paragraphs (49) to (50);
Rh and R, are as described in numbered paragraphs (53);
Rj and Rk are as described in any of numbered paragraphs (56) to (57); Ri is as described in any of numbered paragraphs (59) to (60);
X5 is as described in numbered paragraph (77);
m is as described in numbered paragraph (78); and
R5 IS as described in any of numbered paragraphs (83) to (84).
[00103] In an embodiment of the compounds of formula (Id), (lid) or (I lid):
R1 is as described in any of numbered paragraphs (5) to (8);
Ra and Rb are as described in any of numbered paragraphs (13) to (22); Rc is as described in any of numbered paragraphs (24) to (25);
R2 is as described in any of numbered paragraphs (31) to (32);
Rd is as described in any of numbered paragraphs (33) to (34);
Re is as described in any of numbered paragraphs (37) to (38);
R3 is as described in any of numbered paragraphs (48) to (50);
Rh and R, are as described in any of numbered paragraphs (52) to (53); Rj and Rk are as described in any of numbered paragraphs (55) to (57); Ri is as described in any of numbered paragraphs (59) to (60);
X5 is as described in numbered paragraph (77);
m is as described in numbered paragraph (78); and
R5 IS as described in any of numbered paragraphs (83) to (84).
[00104] In an embodiment of the compounds of formula (Id), (lid) or (I lid):
Ri is as described in any of numbered paragraphs (6) to (8);
Ra and Rb are as described in any of numbered paragraphs (17) to (22); Rc is as described in any of numbered paragraphs (24) to (25);
R2 is hydrogen;
R3 is as described in any of numbered paragraphs (48) to (50);
Rh and R, are as described in any of numbered paragraphs (52) to (53); Rj and Rk are as described in any of numbered paragraphs (55) to (57);
Ri is as described in any of numbered paragraphs (59) to (60);
X5 is as described in numbered paragraph (77);
m is as described in numbered paragraph (78); and
R5 IS as described in any of numbered paragraphs (83) to (84).
[00105] In an embodiment of the compounds of formula (Id), (lid) or (I lid):
R1 is as described in numbered paragraph (7) or (8);
Ra and Rb are as described in any of numbered paragraphs (21) to (22);
Rc is as described in any of numbered paragraphs (24) to (25);
R2 is hydrogen;
R3 is as described in any of numbered paragraphs (49) to (50);
Rh and R, are as described in numbered paragraphs (53);
Rj and Rk are as described in any of numbered paragraphs (56) to (57);
Ri is as described in any of numbered paragraphs (59) to (60);
X5 is as described in numbered paragraph (77);
m is as described in numbered paragraph (78); and
R5 IS as described in any of numbered paragraphs (83) to (84).
[00106] In a particular group of compounds having a structure according to formula (I), (II) or (III), Ri is hydroxy, X1 is O, X2 is as defined in numbered paragraph (41), n is 1 , and X3 and X4 are as defined in numbered paragraph (76), such that the compounds have a structure according to formula (le), (lie) or (I lie) shown below:
[00107] In an embodiment of the compounds of formula (le), (lie) or (I lie):
R is as described in any of numbered paragraphs (30) to (32);
Rd is as described in any of numbered paragraphs (33) to (34);
Re is as described in any of numbered paragraphs (37) to (38);
R is as described in any of numbered paragraphs (46) to (50);
Rh and R, are as described in any of numbered paragraphs (52) to (53);
Rj and Rk are as described in any of numbered paragraphs (55) to (57);
Ri is as described in any of numbered paragraphs (59) to (60);
X5 is as described in numbered paragraph (77);
m is as described in numbered paragraph (78); and
R IS as described in any of numbered paragraphs (81) to (84).
[00108] In an embodiment of the compounds of formula (le), (lie) or (I lie):
R is as described in any of numbered paragraphs (31) to (32);
Rd is as described in any of numbered paragraphs (33) to (34);
Re is as described in any of numbered paragraphs (37) to (38);
R is as described in any of numbered paragraphs (48) to (50);
Rh and R, are as described in any of numbered paragraphs (52) to (53); Rj and Rk are as described in any of numbered paragraphs (55) to (57); Ri is as described in any of numbered paragraphs (59) to (60);
X5 is as described in numbered paragraph (77);
m is as described in numbered paragraph (78); and
R IS as described in any of numbered paragraphs (83) to (84).
[00109] In an embodiment of the compounds of formula (le), (lie) or ( 111 e) :
R is as described in any of numbered paragraphs (31) to (32);
Rd is as described in any of numbered paragraphs (33) to (34);
Re is as described in any of numbered paragraphs (37) to (38);
R is as described in any of numbered paragraphs (48) to (50);
Rh and R, are as described in any of numbered paragraphs (52) to (53); Rj and Rk are as described in any of numbered paragraphs (55) to (57); Ri is as described in any of numbered paragraphs (59) to (60);
X5 is as described in numbered paragraph (77);
m is as described in numbered paragraph (78); and
R IS as described in any of numbered paragraphs (83) to (84).
[00110] In an embodiment of the compounds of formula (le), (lie) or (I lie):
R is hydrogen;
R is as described in any of numbered paragraphs (48) to (50);
Rh and R, are as described in any of numbered paragraphs (52) to (53); Rj and Rk are as described in any of numbered paragraphs (55) to (57); Ri is as described in any of numbered paragraphs (59) to (60);
X5 is as described in numbered paragraph (77);
m is as described in numbered paragraph (78); and
R IS as described in any of numbered paragraphs (83) to (84).
[00111] In an embodiment of the compounds of formula (le), (lie) or (I lie):
R2 is hydrogen;
R3 is as described in any of numbered paragraphs (49) to (50);
Rh and R, are as described in numbered paragraphs (53);
Rj and Rk are as described in any of numbered paragraphs (56) to (57);
Ri is as described in any of numbered paragraphs (59) to (60);
X5 is as described in numbered paragraph (77);
m is as described in numbered paragraph (78); and
R5 IS as described in any of numbered paragraphs (83) to (84).
[00112] In a particular group of compounds having a structure according to formula (I), (II) or (III), Xi is O, X2 is as defined in numbered paragraph (41), n is 1 , Rh and R, are hydrogen, R3 is hydroxy, X3 and X4 are as defined in numbered paragraph (76), X5 is O, and m is 1 , such that the compounds have a structure according to formula (If), (Ilf) or (I I If) shown below:
[00113] In an embodiment of the compounds of formula (If), (Ilf) or (lllf):
Ri, and any of its associated substituents, has any of the definitions appearing hereinbefore;
R2 is as described in any of numbered paragraphs (30) to (32);
Rd is as described in any of numbered paragraphs (33) to (34);
Re is as described in any of numbered paragraphs (37) to (38); and
R5 IS as described in any of numbered paragraphs (81) to (84).
[00114] In an embodiment of the compounds of formula (If), (Ilf) or (lllf):
R1, and any of its associated substituents, has any of the definitions appearing hereinbefore;
R2 is as described in any of numbered paragraphs (31) to (32);
Rd is as described in any of numbered paragraphs (33) to (34);
Re is as described in any of numbered paragraphs (37) to (38); and R5 IS as described in any of numbered paragraphs (83) to (84).
[00115] In an embodiment of the compounds of formula (If), (Ilf) or (lllf):
R1 is as described in any of numbered paragraphs (5) to (8);
Ra and Rb are as described in any of numbered paragraphs (11) to (12);
Rc is as described in any of numbered paragraphs (24) to (25);
R2 is as described in any of numbered paragraphs (31) to (32);
Rd is as described in any of numbered paragraphs (33) to (34);
Re is as described in any of numbered paragraphs (37) to (38); and R5 IS as described in any of numbered paragraphs (83) to (84).
[00116] In an embodiment of the compounds of formula (If), (Ilf) or (lllf):
R1 is as described in any of numbered paragraphs (6) to (8);
Ra and Rb are as described in any of numbered paragraphs (11) to (12);
Rc is as described in any of numbered paragraphs (24) to (25);
R2 is hydrogen; and
R5 IS as described in any of numbered paragraphs (83) to (84).
[00117] In an embodiment of the compounds of formula (If), (Ilf) or (lllf):
Ri is as described in numbered paragraph (8);
Rc is as described in any of numbered paragraphs (24) to (25);
R2 is hydrogen; and
Rs is as described in any of numbered paragraphs (83) to (84).
[00118] In an embodiment of the compounds of formula (If), (Ilf) or (lllf):
R1 is as described in any of numbered paragraphs (5) to (8);
Ra and Rb are as described in any of numbered paragraphs (13) to (22); Rc is as described in any of numbered paragraphs (24) to (25);
R2 is as described in any of numbered paragraphs (31) to (32);
Rd is as described in any of numbered paragraphs (33) to (34);
Re is as described in any of numbered paragraphs (37) to (38); and
R5 IS as described in any of numbered paragraphs (83) to (84).
[00119] In an embodiment of the compounds of formula (If), (Ilf) or (lllf):
R1 is as described in any of numbered paragraphs (6) to (8);
Ra and Rb are as described in any of numbered paragraphs (17) to (22); Rc is as described in any of numbered paragraphs (24) to (25);
R2 is hydrogen; and
R5 IS as described in any of numbered paragraphs (83) to (84).
[00120] In an embodiment of the compounds of formula (If), (Ilf) or (lllf):
R1 is as described in numbered paragraph (7) or (8);
Ra and Rb are as described in any of numbered paragraphs (19) to (22); Rc is as described in any of numbered paragraphs (24) to (25);
R2 is hydrogen; and
R5 IS as described in any of numbered paragraphs (83) to (84).
[00121] In an embodiment of the compounds of formula (If), (Ilf) or (lllf):
R1 is as described in numbered paragraph (7) or (8);
Ra and Rb are as described in any of numbered paragraphs (21) to (22); Rc is as described in any of numbered paragraphs (24) to (25);
R2 is hydrogen; and
Rs is as described in any of numbered paragraphs (83) to (84).
[00122] In a particular embodiment, the compound having a structure according to formula (I), (II) or (III) has any of the following structures:
[00123] In a particular embodiment, the compound having a structure according to formula (I), (II) or (III) has any of the following structures:
[00125] In a particular embodiment, the compound having a structure according to formula (I), (II) or (III) has any of the following structures:
[00126] In a particular embodiment, the compound having a structure according to formula (I), (II) or (III) has the following structure:
[00127] In a particular embodiment, the compound having a structure according to formula (I), (II) or (III) has the following structure:
[00128] The present invention also provides a method of inhibiting RIF-resistant RNA polymerase, in vitro or in vivo, said method comprising contacting a cell with an effective amount of a compound of formula (I), (II) or (III), or a pharmaceutically acceptable salt, hydrate or solvate thereof as defined herein.
[00129] The present invention also provides a method of inhibiting bacterial cell proliferation, in vitro or in vivo, said method comprising contacting a bacterial cell with an effective amount of a compound of formula (I), (II) or (III), or a pharmaceutically acceptable salt, hydrate or solvate thereof as defined herein, or a pharmaceutical composition as defined herein.
[00130] The present invention also provides a method of treating an infection caused by RIF- resistant bacteria in a patient in need of such treatment, said method comprising administering to said patient a therapeutically effective amount of a compound of formula (I), (II) or (III), or a pharmaceutically acceptable salt, hydrate or solvate thereof as defined herein, or a pharmaceutical composition as defined herein.
[00131] The present invention also provides a use of a compound of formula (I), (II) or (III), or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein in the manufacture of a medicament for the inhibition of RIF-resistant RNA polymerase.
[00132] The present invention also provides a use of a compound of formula (I), (II) or (III), or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein in the manufacture of a medicament for the treatment of an infection caused by RIF-resistant bacteria.
[00133] Suitably, the RIF-resistant bacteria is one or more RIF-resistant Gram positive bacteria.
[00134] Suitably, the RIF-resistant bacteria is RIF-resistant S. aureus.
[00135] Suitably, the RIF-resistant bacteria is RIF-resistant M. tuberculosis
[00136] Suitably, the infection caused by RIF-resistant bacteria is RIF-resistant tuberculosis.
[00137] For those aspects of the invention concerning therapy (e.g. medical uses, methods of treatment, etc), it will be appreciated that the compound of formula (I), (II) or (III) may be used (e.g. administered) in combination with one or more other active ingredients. Suitably, the one or more other active ingredients is rifampicin or a derivative thereof.
[00138] A suitable pharmaceutically acceptable salt of a compound of formula (I), (II) or (III) is, for example, an acid-addition salt of a compound of formula (I), (II) or (III) which is sufficiently basic, for example, an acid-addition salt with, for example, an inorganic or organic acid, for example hydrochloric, hydrobromic, sulfuric, phosphoric, trifluoroacetic, formic, citric methane sulfonate or maleic acid. In addition, a suitable pharmaceutically acceptable salt of a compound of formula (I), (II) or (III) which is sufficiently acidic is an alkali metal salt, for example a sodium or potassium salt, an alkaline earth metal salt, for example a calcium or magnesium salt, an ammonium salt or a salt with an organic base which affords a pharmaceutically acceptable cation, for example a salt with methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine.
[00139] Compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed“isomers”. Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers”. Stereoisomers that are not mirror images of one another are termed“diastereomers” and those that are non-superimposable mirror images of each other are termed“enantiomers”. When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible. An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or (-)-isomers respectively). A chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a“racemic mixture”.
[00140] The compounds of formula (I), (II) or (III) may possess one or more asymmetric centers; such compounds can therefore be produced as individual (R)- or (S)-stereoisomers or as mixtures thereof. Unless indicated otherwise, the description or naming of a particular compound in the specification and claims is intended to include both individual enantiomers and mixtures, racemic or otherwise, thereof. The methods for the determination of stereochemistry and the separation of stereoisomers are well-known in the art (see discussion in Chapter 4 of“Advanced Organic Chemistry”, 4th edition J. March, John Wiley and Sons, New York, 2001), for example by synthesis from optically active starting materials or by resolution of a racemic form. Some of the compounds of formula (I), (II) or (III) may have geometric isomeric centres (E- and Z- isomers). It is to be understood that the present invention encompasses all optical,
diastereoisomers and geometric isomers and mixtures thereof that possess antiproliferative activity.
[00141] The present invention also encompasses compounds of formula (I), (II) or (III) as defined herein which comprise one or more isotopic substitutions. For example, H may be in any isotopic form, including 1 H, 2H(D), and 3H (T); C may be in any isotopic form, including 12C, 13C, and 14C; and O may be in any isotopic form, including 160 and180; and the like.
[00142] It is also to be understood that certain compounds of formula (I), (II) or (III) may exist in solvated as well as unsolvated forms such as, for example, hydrated forms. It is to be understood that the invention encompasses all such solvated forms that possess activity towards RIF- resistant bacteria.
[00143] It is also to be understood that certain compounds of formula (I), (II) or (III) may exhibit polymorphism, and that the invention encompasses all such forms that possess activity towards RIF-resistant bacteria.
[00144] Compounds of formula (I), (II) or (III) may exist in a number of different tautomeric forms and references to compounds of formula (I), (II) or (III) include all such forms. For the avoidance of doubt, where a compound can exist in one of several tautomeric forms, and only one is specifically described or shown, all others are nevertheless embraced by formula (I), (II) or (III). Examples of tautomeric forms include keto-, enol-, and enolate-forms, as in, for example, the following tautomeric pairs: keto/enol (illustrated below), imine/enamine, amide/imino alcohol, amidine/amidine, nitroso/oxime, thioketone/enethiol, and nitro/aci-nitro.
keto enol enolate
[00145] Compounds of formula (I), (II) or (III) containing an amine function may also form N- oxides. A reference herein to a compound of formula (I), (II) or (III) that contains an amine function also includes the N-oxide. Where a compound contains several amine functions, one or more than one nitrogen atom may be oxidised to form an N-oxide. Particular examples of N- oxides are the N-oxides of a tertiary amine or a nitrogen atom of a nitrogen-containing heterocycle. N-Oxides can be formed by treatment of the corresponding amine with an oxidizing agent such as hydrogen peroxide or a per-acid (e.g. a peroxycarboxylic acid), see for example Advanced Organic Chemistry, by Jerry March, 4th Edition, Wiley Interscience, pages. More particularly, N-oxides can be made by the procedure of L. W. Deady (Syn. Comm. 1977, 7, 509- 514) in which the amine compound is reacted with m-chloroperoxybenzoic acid (mCPBA), for example, in an inert solvent such as dichloromethane.
[00146] It will be understood that compound of formula (I), (II) or (III) containing a quinone moiety may readily convert into the corresponding hydroquinone form (see below), and vice versa. Both forms are encompassed by the present invention.
Quinone Hydroquinone
[00147] The compounds of formula (I), (II) or (III) may be administered in the form of a pro-drug which is broken down in the human or animal body to release a compound of formula (I), (II) or (III). A pro-drug may be used to alter the physical properties and/or the pharmacokinetic properties of a compound of formula (I), (II) or (III). A pro-drug can be formed when the compound formula (I), (II) or (III) contains a suitable group or substituent to which a property-modifying group can be attached. Examples of pro-drugs include in vivo cleavable ester derivatives that may be formed at a carboxy group or a hydroxy group in a compound of formula (I), (II) or (III), and in- vivo cleavable amide derivatives that may be formed at a carboxy group or an amino group in a compound of formula (I), (II) or (III).
[00148] Accordingly, the present invention includes those compounds of formula (I), (II) or (III) as defined hereinbefore, when made available by organic synthesis and when made available within the human or animal body by way of cleavage of a pro-drug thereof. Accordingly, the present invention includes those compounds of formula (I), (II) or (III) that are produced by organic synthetic means and also such compounds that are produced in the human or animal body by way of metabolism of a precursor compound, that is a compound of formula (I), (II) or (III) may be a synthetically-produced compound or a metabolically-produced compound.
[00149] A suitable pharmaceutically acceptable pro-drug of a compound of formula (I), (II) or (III) is one that is based on reasonable medical judgement as being suitable for administration to the human or animal body without undesirable pharmacological activities and without undue toxicity.
[00150] Various forms of pro-drug have been described, for example in the following documents
a) Methods in Enzymology, Vol. 42, p. 309-396, edited by K. Widder, et al. (Academic Press, 1985);
b) Design of Pro-drugs, edited by H. Bundgaard, (Elsevier, 1985);
c) A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H. Bundgaard, Chapter 5“Design and Application of Pro-drugs”, by H. Bundgaard p. 113-191 (1991);
d) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992);
e) H. Bundgaard, et al. , Journal of Pharmaceutical Sciences, 77, 285 (1988);
f) N. Kakeya, et al., Chem. Pharm. Bull., 32, 692 (1984);
g) T. Higuchi and V. Stella,“Pro-Drugs as Novel Delivery Systems”, A.C.S. Symposium Series, Volume 14; and
h) E. Roche (editor),“Bioreversible Carriers in Drug Design”, Pergamon Press, 1987.
[00151] A suitable pharmaceutically acceptable pro-drug of a compound of formula (I), (II) or (III) that possesses a carboxy group is, for example, an in vivo cleavable ester thereof. An in vivo cleavable ester of a compound of formula (I), (II) or (III) containing a carboxy group is, for example, a pharmaceutically acceptable ester which is cleaved in the human or animal body to produce the parent acid. Suitable pharmaceutically acceptable esters for carboxy include C1-6alkyl esters such as methyl, ethyl and tert- butyl, C1-6alkoxymethyl esters such as methoxymethyl esters, C1-6alkanoyloxymethyl esters such as pivaloyloxymethyl esters, 3-phthalidyl esters, C3-8cycloalkylcarbonyloxy- C1-6alkyl esters such as cyclopentylcarbonyloxymethyl and 1-cyclohexylcarbonyloxyethyl esters,
2-oxo-1 ,3-dioxolenylmethyl esters such as 5-methyl-2-oxo-1 ,3-dioxolen-4-ylmethyl esters and C1-6alkoxycarbonyloxy- C1-6alkyl esters such as methoxycarbonyloxymethyl and 1- methoxycarbonyloxyethyl esters.
[00152] A suitable pharmaceutically acceptable pro-drug of a compound of formula (I), (II) or (III) that possesses a hydroxy group is, for example, an in vivo cleavable ester or ether thereof. An in vivo cleavable ester or ether of a compound of formula (I), (II) or (III) containing a hydroxy group is, for example, a pharmaceutically acceptable ester or ether which is cleaved in the human or animal body to produce the parent hydroxy compound. Suitable pharmaceutically acceptable ester forming groups for a hydroxy group include inorganic esters such as phosphate esters (including phosphoramidic cyclic esters). Further suitable pharmaceutically acceptable ester forming groups for a hydroxy group include C1-10alkanoyl groups such as acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups, C1-10alkoxycarbonyl groups such as ethoxycarbonyl, N,N -(C1-6)2carbamoyl, 2-dialkylaminoacetyl and 2-carboxyacetyl groups. Examples of ring substituents on the phenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl, piperazin-1- ylmethyl and 4-(C1-4alkyl)piperazin-1-ylmethyl. Suitable pharmaceutically acceptable ether
forming groups for a hydroxy group include a-acyloxyalkyl groups such as acetoxymethyl and pivaloyloxymethyl groups.
[00153] A suitable pharmaceutically acceptable pro-drug of a compound of formula (I), (II) or (III) that possesses a carboxy group is, for example, an in vivo cleavable amide thereof, for example an amide formed with an amine such as ammonia, a C1-4alkylamine such as methylamine, a (C1-4alkyl)2amine such as dimethylamine, N-ethyl-N-methylamine or diethylamine, a C1- 4alkoxy- C2-4alkylamine such as 2-methoxyethylamine, a phenyl-C1-4alkylamine such as benzylamine and amino acids such as glycine or an ester thereof.
[00154] A suitable pharmaceutically acceptable pro-drug of a compound of formula (I), (II) or (III) that possesses an amino group is, for example, an in vivo cleavable amide derivative thereof. Suitable pharmaceutically acceptable amides from an amino group include, for example an amide formed with C1-10alkanoyl groups such as an acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups. Examples of ring substituents on the phenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl, piperazin-1-ylmethyl and
4-(C1-4alkyl)piperazin-1-ylmethyl.
[00155] The in vivo effects of a compound of formula (I), (II) or (III) may be exerted in part by one or more metabolites that are formed within the human or animal body after administration of a compound of formula (I), (II) or (III). As stated hereinbefore, the in vivo effects of a compound of formula (I), (II) or (III), may also be exerted by way of metabolism of a precursor compound (a pro-drug).
[00156] Though the present invention may relate to any compound or particular group of compounds defined herein by way of optional, preferred or suitable features or otherwise in terms of particular embodiments, the present invention may also relate to any compound or particular group of compounds that specifically excludes said optional, preferred or suitable features or particular embodiments.
[00157] Suitably, the present invention excludes any individual compounds not possessing the biological activity defined herein.
Routes of Administration
[00158] The compounds formula (I), (II) or (III) or pharmaceutical compositions comprising these compounds may be administered to a subject by any convenient route of administration, whether systemically, peripherally or topically (i.e., at the site of desired action).
[00159] Routes of administration include, but are not limited to, oral (e.g, by ingestion); buccal;
sublingual; transdermal (including, e.g., by a patch, plaster, etc.); transmucosal (including, e.g., by a patch, plaster, etc.); intranasal (e.g., by nasal spray); ocular (e.g., by eye drops); pulmonary (e.g., by inhalation or insufflation therapy using, e.g., via an aerosol, e.g., through the mouth or nose); rectal (e.g., by suppository or enema); vaginal (e.g., by pessary); parenteral, for example, by injection, including subcutaneous, intradermal, intramuscular, intravenous, intra-arterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intraarticular, subarachnoid, and intrasternal; by implant of a depot or reservoir, for example, subcutaneously or intramuscularly.
Compounds of the invention
[00160] In one aspect of the present invention there is provided a compound of formula (I), (II) or (III) as hereinbefore, or a pharmaceutically acceptable salt, hydrate or solvate thereof,
with the proviso that, in formula (I), when Ri is hydroxy and R2 is hydrogen, Xi is not O. [00161] The following compound is not a compound of the invention:
[00162] It will be understood that the compounds of the invention may have any of those definitions described hereinbefore in respect of formula (I), (II) or (III) - including all sub-formulae - subject to the aforementioned proviso.
[00163] In an embodiment, the compound has any of those definitions appearing hereinbefore in relation to formula (I), (II) or (III), with the proviso that, in formula (I), Ri is not hydroxy.
[00164] In an embodiment, the compound has any of those definitions appearing hereinbefore in relation to formula (I’), (II’) or (III’), with the proviso that, in formula (I’), Ri is not hydroxy.
[00165] In an embodiment, the compound has any of those definitions appearing hereinbefore in relation to formula (la), (I la) or (Ilia), with the proviso that, in formula (la), Ri is not hydroxy.
[00166] In an embodiment, the compound has any of those definitions appearing hereinbefore in relation to formula (lc), (lie) or (lllc), with the proviso that, in formula (lc), Ri is not hydroxy.
[00167] In an embodiment, the compound has any of those definitions appearing hereinbefore in relation to formula (Id), (lid) or (Hid), with the proviso that, in formula (Id), Ri is not hydroxy.
[00168] In an embodiment, the compound has any of those definitions appearing hereinbefore in relation to formula (If), (Ilf) or (I Ilf), with the proviso that, in formula (If), Ri is not hydroxy.
[00169] In an embodiment, the compound has any of those definitions appearing hereinbefore in relation to formula (I), (II) or (III), with the proviso that, in formula (I), R2 is not hydrogen.
[00170] In an embodiment, the compound has any of those definitions appearing hereinbefore in relation to formula (I’), (II’) or (III’), with the proviso that, in formula (I’), R2 is not hydrogen.
[00171] In an embodiment, the compound has any of those definitions appearing hereinbefore in relation to formula (lb), (lib) or (Nib), with the proviso that, in formula (lb), R2 is not hydrogen.
[00172] In an embodiment, the compound has any of those definitions appearing hereinbefore in relation to formula (lc), (lie) or (lllc), with the proviso that, in formula (lc), R2 is not hydrogen.
[00173] In an embodiment, the compound has any of those definitions appearing hereinbefore in relation to formula (Id), (lid) or (I lid), with the proviso that, in formula (Id), R2 is not hydrogen.
[00174] In an embodiment, the compound has any of those definitions appearing hereinbefore in relation to formula (le), (lie) or (I lie), with the proviso that, in formula (le), R2 is not hydrogen.
[00175] In an embodiment, the compound has any of those definitions appearing hereinbefore in relation to formula (If), (Ilf) or (I Ilf), with the proviso that, in formula (If), R2 is not hydrogen.
[00176] In a particular embodiment, the compound has any of the following structures:
[00177] In a particular embodiment, the compound has any of the following structures:
[00178] In a particular embodiment, the compound has any of the following structures:
[00179] In a particular embodiment, the compound has any of the following structures:
[00180] In a particular embodiment, the compound has the following structure:
[00181] The present invention also provides a compound of the invention, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein for use in therapy.
[00182] The present invention also provides a compound of the invention, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein for use as a medicament.
[00183] The present invention also provides a method of treating a bacterial infection in a patient in need of such treatment, said method comprising administering to said patient a therapeutically effective amount of a compound of the invention. The infection may be caused by RIF-resistant bacteria (e.g. RIF-resistant tuberculosis) or RIF-susceptible bacteria. When the infection is
caused by RIF-susceptible bacteria, the method of treatment may prevent the bacteria from becoming RIF-resistant.
[00184] For those aspects of the invention concerning therapy (e.g. medical uses, methods of treatment, etc), it will be appreciated that the compound of the invention may be used (e.g. administered) in combination with one or more other active ingredients. Suitably, the one or more other active ingredients is rifampicin or a derivative thereof.
Pharmaceutical Compositions
[00185] In one aspect of the present invention there is provided a pharmaceutical composition which comprises a compound of the invention as defined hereinbefore, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in association with a pharmaceutically acceptable diluent or carrier.
[00186] The compositions of the invention may be in a form suitable for oral use (for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for topical use (for example as creams, ointments, gels, or aqueous or oily solutions or suspensions), for administration by inhalation (for example as a finely divided powder or a liquid aerosol), for administration by insufflation (for example as a finely divided powder) or for parenteral administration (for example as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular, intraperitoneal or intramuscular dosing or as a suppository for rectal dosing).
[00187] The compositions of the invention may be obtained by conventional procedures using conventional pharmaceutical excipients, well known in the art. Thus, compositions intended for oral use may contain, for example, one or more colouring, sweetening, flavouring and/or preservative agents.
[00188] An effective amount of a compound of the present invention for use in therapy is an amount sufficient to treat or prevent a proliferative condition referred to herein, slow its progression and/or reduce the symptoms associated with the condition.
[00189] The amount of active ingredient that is combined with one or more excipients to produce a single dosage form will necessarily vary depending upon the individual treated and the particular route of administration. For example, a formulation intended for oral administration to humans will generally contain, for example, from 0.5 mg to 0.5 g of active agent (more suitably from 0.5 to 100 mg, for example from 1 to 30 mg) compounded with an appropriate and convenient amount of excipients which may vary from about 5 to about 98 percent by weight of the total composition.
[00190] The size of the dose for therapeutic or prophylactic purposes of a compound of the formula I will naturally vary according to the nature and severity of the conditions, the age and sex of the animal or patient and the route of administration, according to well-known principles of medicine.
[00191] In using a compound of the invention for therapeutic or prophylactic purposes it will generally be administered so that a daily dose in the range, for example, 0.1 mg/kg to 75 mg/kg body weight is received, given if required in divided doses. In general lower doses will be administered when a parenteral route is employed. Thus, for example, for intravenous or intraperitoneal administration, a dose in the range, for example, 0.1 mg/kg to 30 mg/kg body weight will generally be used. Similarly, for administration by inhalation, a dose in the range, for example, 0.05 mg/kg to 25 mg/kg body weight will be used. Oral administration may also be suitable, particularly in tablet form. Typically, unit dosage forms will contain about 0.5 mg to 0.5 g of a compound of this invention.
[00192] The following numbered statements 1 - 93 are not claims, but instead describe particular aspects and embodiments of the invention:
1. A compound of formula (I), (II) or (III) shown below, or a pharmaceutically acceptable salt, hydrate or solvate thereof, for use in the treatment of infection caused by rifampicin-resistant bacteria:
wherein,
Ri is selected from hydrogen, halo, cyano, isocyano, nitro, hydroxy, (1-6C)alkyl, (1-6C)haloalkyl, (2-4C)alkenyl, (2-4C)alkynyl, (1-8C)heteroalkyl, aryl, aryl(1-2C)alkyl, heteroaryl, heteroaryl(1-2C)alkyl, (3-8C)heterocyclyl, (3-8C)heterocyclyl(1-2C)alkyl, (3- 8C)cycloalkyl, (3-8C)cycloalkyl(1-2C)alkyl, NRaRb, ORc, 0C(0)Ra, N(Rb)ORa,
N(Rb)C(0)ORa, N(Rb)C(0)Ra, S(0)PRa (where p is 0, 1 or 2), S02N(Rb)Ra, and
N(Rb)S02Ra;
R2 is selected from hydrogen, halo, cyano, isocyano, nitro, hydroxy, (1-6C)alkyl, (1-6C)haloalkyl, (2-4C)alkenyl, (2-4C)alkynyl, (1-8C)heteroalkyl, aryl, aryl(1-2C)alkyl, heteroaryl, heteroaryl(1-2C)alkyl, (3-8C)heterocyclyl, (3-8C)heterocyclyl(1-2C)alkyl, (3- 8C)cycloalkyl, (3-8C)cycloalkyl(1-2C)alkyl, NRdRe, ORf, C(0)Rd, C(0)ORd, OC(0)Rd, C(Rd)=N(Re), N(Rd)ORe, N(Rd)C(0)ORe, C(0)N(Rd)Re, N(Rd)C(0)Re, S(0)PRd (where p is 0, 1 or 2), S02N(Rd)Re, and N(Rd)S02Re;
and wherein R1 and R2 are each independently optionally substituted by one or more substituent groups selected from fluoro, chloro, trifluoromethyl, trifluoromethoxy, cyano, nitro, hydroxy, amino, carboxy, carbamoyl, sulphamoyl, (1-4C)alkyl, (1-4C)alkoxy, S(0)qCH3 (where q is 0, 1 or 2), methylamino or dimethylamino, aryl, aryl(1-2C)alkyl, heteroaryl, heteroaryl(1-2C)alkyl, (3-8C)heterocyclyl, (3- 8C)heterocyclyl(1-2C)alkyl, (3-8C)cycloalkyl, or (3-8C)cycloalkyl(1- 2C)alkyl;
Xi is selected from O and NRg;
X2 is hydroxy or a group of formula (A) shown below:
n is 0, 1 , 2, 3 or 4; and
R3 is selected from hydrogen, halo, cyano, isocyano, nitro, hydroxy, (1-6C)alkyl, (1-6C)haloalkyl, (2-4C)alkenyl, (2- 4C)alkynyl, (1-8C)heteroalkyl, aryl, aryl(1-2C)alkyl, heteroaryl, heteroaryl(1-2C)alkyl, (3-8C)heterocyclyl, (3-8C)heterocyclyl(1- 2C)alkyl, (3-8C)cycloalkyl, (3-8C)cycloalkyl(1-2C)alkyl, NRjRk, OR,, C(0)Rj, C(0)0Rj, 0C(0)Rj, C(Rj)=N(Rk), N(Rj)ORk,
N(Rj)C(0)0Rk, C(0)N(Rj)Rk, N(Rj)C(0)Rk, S(0)PRj (where p is 0, 1 or 2), S02N(Rj)Rk, and N(Rj)S02Rk;
and wherein R3 is independently optionally substituted by one or more substituent groups selected from fluoro, chloro, trifluoromethyl, trifluoromethoxy, cyano, nitro, hydroxy, amino, carboxy, carbamoyl, sulphamoyl, (1- 4C)alkyl, (1-4C)alkoxy, S(0)qCH3 (where q is 0, 1 or 2), methylamino or dimethylamino, aryl, aryl(1-2C)alkyl, heteroaryl, heteroaryl(1-2C)alkyl, (3-8C)heterocyclyl, (3- 8C)heterocyclyl(1-2C)alkyl, (3-8C)cycloalkyl, or (3- 8C)cycloalkyl(1-2C)alkyl;
or R2 and X1 or R2 and X2 are linked, such that when they are taken in combination with the carbon atoms to which they are attached, they collectively form a 5-12 membered heteroaryl or heterocycle that is optionally substituted with one or more R4 substituents;
and wherein each R4 is independently selected from halo, cyano, isocyano, nitro, hydroxy, (1-6C)alkyl, (1-6C)haloalkyl, (2-4C)alkenyl, (2- 4C)alkynyl, (1-8C)heteroalkyl, aryl, aryl(1-2C)alkyl, heteroaryl, heteroaryl(1-2C)alkyl, (3-8C)heterocyclyl, (3-8C)heterocyclyl(1-2C)alkyl, (3-8C)cycloalkyl, (3-8C)cycloalkyl(1-2C)alkyl, NRmRn, OR0, C(0)Rm, C(0)ORm, OC(0)Rm, N(Rm)ORn, N(Rm)C(0)ORn, C(0)N(Rm)Rn,
C(Rm)=N(Rn), N(Rm)C(0)Rn, S(0)PRm (where p is 0, 1 or 2), S02N(Rm)Rn, and N(Rm)S02Rn;
and wherein each R4 is independently optionally substituted with one or more groups selected from fluoro, chloro, trifluoromethyl, trifluoromethoxy, cyano, nitro, hydroxy, amino, carboxy, carbamoyl, sulphamoyl, (1-4C)alkyl, (2-4C)alkenyl, (2-4C)alkynyl, (1-4C)alkoxy, S(0)qCH3 (where q is 0, 1 or 2), methylamino or dimethylamino, aryl, aryl(1-2C)alkyl, heteroaryl, heteroaryl(1-2C)alkyl, (3-8C)heterocyclyl, (3- 8C)heterocyclyl(1-2C)alkyl, (3-8C)cycloalkyl, and (3-8C)cycloalkyl(1- 2C)alkyl;
X3 and X4 are independently selected from hydroxy, ORp, NRqRr and a group of formula (A) shown above;
or X3 and X4 are linked, such that when they are taken in combination with the carbon atom to which they are attached, they collectively form a 4-6 membered heterocycle that is optionally substituted with one or more R5 substituents;
and wherein each R5 is independently selected from fluoro, chloro, trifluoromethyl, trifluoromethoxy, cyano, nitro, hydroxy, oxo, amino, carboxy, carbamoyl, sulphamoyl, (1-6C)alkyl, (2-6C)alkenyl, (2-
6C)alkynyl, (1-4C)alkoxy, S(0)qCH3 (where q is 0, 1 or 2), methylamino or dimethylamino, aryl, aryl(1-2C)alkyl, heteroaryl, heteroaryl(1-2C)alkyl, (3- 8C)heterocyclyl, (3-8C)heterocyclyl(1-2C)alkyl, (3-8C)cycloalkyl, and (3- 8C)cycloalkyl(1-2C)alkyl;
each Ra to Rr is independently selected from hydrogen, fluoro, chloro, trifluoromethyl, trifluoromethoxy, cyano, nitro, hydroxy, amino, carboxy, carbamoyl, sulphamoyl, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (1-4C)alkoxy, S(0)qCH3 (where q is 0, 1 or 2), methylamino or dimethylamino, aryl, aryl(1-2C)alkyl, heteroaryl,
heteroaryl(1-2C)alkyl, (3-8C)heterocyclyl, (3-8C)heterocyclyl(1-2C)alkyl, (3- 8C)cycloalkyl, and (3-8C)cycloalkyl(1-2C)alkyl;
and wherein each Ra to Rr is independently optionally substituted with one or more groups selected from fluoro, chloro, trifluoromethyl, trifluoromethoxy, cyano, nitro, hydroxy, amino, carboxy, carbamoyl, sulphamoyl, (1-4C)alkyl, (2-4C)alkenyl, (2-4C)alkynyl, (1-4C)alkoxy, S(0)qCH3 (where q is 0, 1 or 2), methylamino or dimethylamino, aryl, aryl(1-2C)alkyl, heteroaryl, heteroaryl(1-2C)alkyl, (3-8C)heterocyclyl, (3- 8C)heterocyclyl(1-2C)alkyl, (3-8C)cycloalkyl, and (3-8C)cycloalkyl(1- 2C)alkyl. The compound for use according to statement 1 , wherein the compound has a structure according to formula (G), (IG) or (IN’) shown below:
wherein Ri is optionally substituted by one or more substituent groups selected from (1-4C)alkyl and (1-3C)alkoxy.
The compound for use according to statement 1 , 2 or 3, wherein Ri is selected from hydrogen, halo, hydroxy, (1-6C)alkyl, (1-6C)haloalkyl, (2-4C)alkenyl, (2-4C)alkynyl, (1- 8C)heteroalkyl, aryl, aryl(1-2C)alkyl, heteroaryl, heteroaryl(1-2C)alkyl, (3- 8C)heterocyclyl, (3-8C)heterocyclyl(1-2C)alkyl, (3-8C)cycloalkyl, (3-8C)cycloalkyl(1- 2C)alkyl, NRaRb and ORc,
wherein Ri is optionally substituted by one or more substituent groups selected from (1-4C)alkyl and (1-3C)alkoxy.
The compound for use according to any preceding statement, wherein Ri is selected from hydrogen, halo, hydroxy, (1-6C)alkyl, aryl, aryl(1-2C)alkyl, heteroaryl, heteroaryl(1- 2C)alkyl, (3-8C)heterocyclyl, (3-8C)heterocyclyl(1-2C)alkyl, (3-8C)cycloalkyl, (3- 8C)cycloalkyl(1-2C)alkyl, NRaRb and ORc,
wherein Ri is optionally substituted by one or more substituent groups selected from (1-2C)alkyl and (1-2C)alkoxy.
The compound for use according to any preceding statement, wherein Ri is selected from hydroxy, (1-6C)alkyl, aryl, heteroaryl, (3-8C)heterocyclyl, (3-8C)cycloalkyl, NRaRb and ORc,
wherein Ri is optionally substituted by one or more substituent groups selected from (1-2C)alkyl and (1-2C)alkoxy.
The compound for use according to any preceding statement, wherein Ri is selected from hydroxy, (1-4C)alkyl, N-linked (3-8C)heterocyclyl, NRaRb and ORc,
wherein Ri is optionally substituted by one or more (1-2C)alkyl.
The compound for use according to any preceding statement, wherein Ri is selected from hydroxy, (1-3C)alkyl, N-linked (3-6C)heterocyclyl, NRaRb and ORc, wherein the N- linked (3-6C)heterocyclyl contains 1 or 2 heteroatoms,
wherein Ri is optionally substituted by one or more (1-2C)alkyl.
The compound for use according to any preceding statement, wherein Ri is selected from hydroxy, NRaRb, ORc or any one of the following:
The compound for use according to any preceding statement, wherein Ri is selected from hydroxy and ORc (e.g. methoxy or ethoxy). The compound for use according to any preceding statement, wherein Ra and Rb are independently selected from hydrogen, (1-6C)alkyl, (1-4C)alkoxy, aryl and (3- 8C)heterocyclyl. The compound for use according to any preceding statement, wherein Ra and Rb are independently selected from hydrogen, (1-6C)alkyl, aryl and N-linked (3- 8C)heterocyclyl. The compound for use according to any preceding statement, wherein Ra and Rb are independently selected from hydrogen, (1-6C)alkyl, phenyl and 5-6 membered N-linked heterocyclyl. The compound for use according to any preceding statement, wherein Ra and Rb are independently selected from hydrogen, (1-6C)alkyl, phenyl or any one of the following:
The compound for use according to any preceding statement, wherein Ra and Rb are independently selected from hydrogen, (1-6C)alkyl and phenyl. The compound for use according to any one of statements 1 to 9, wherein each Ra and Rb are independently selected from hydrogen, (1-6C)alkyl, amino, aryl, aryl(1-2C)alkyl, (3-8C)cycloalkyl or any one of the following:
wherein each Ra and Rb is optionally substituted with one or more substituent groups selected from halo, hydroxy, (1-3C)alkyl and (1-3C)haloalkyl.
The compound for use according to any one of statements 1 to 9, wherein Ra is hydrogen or (1-6C)alkyl and Rb is selected from (1-6C)alkyl, amino, aryl, aryl(1-2C)alkyl, (3-8C)cycloalkyl or any one of the following:
wherein each Rb is optionally substituted with one or more substituent groups selected from halo, hydroxy, (1-3C)alkyl and (1-3C)haloalkyl. The compound for use according to any one of statements 1 to 9, wherein each Ra and Rb are independently selected from hydrogen, (1-3C)alkyl, amino, phenyl, benzyl, (3- 6C)cycloalkyl or any one of the following:
wherein each of the said phenyl and benzyl groups is optionally substituted with one or more substituent groups selected from fluoro, chloro hydroxy, (1-3C)alkyl and (1- 3C)haloalkyl, and each of the said amino groups is optionally substituted with one or more substituent groups selected from (1-3C)alkyl. The compound for use according to any one of statements 1 to 9, wherein Ra is hydrogen or (1-3C)alkyl and Rb is selected from (1-3C)alkyl, amino, phenyl, benzyl, (3- 6C)cycloalkyl or any one of the following:
wherein each of the said phenyl and benzyl groups is optionally substituted with one or more substituent groups selected from fluoro, chloro hydroxy, (1-3C)alkyl and (1- 3C)haloalkyl, and each of the said amino groups is optionally substituted with one or more substituent groups selected from (1-3C)alkyl.
The compound for use according to any one of statements 1 to 9, wherein each Ra and Rb are independently selected from hydrogen, (1-2C)alkyl, N(Me)2, benzyl, cyclopropyl or any one of the following:
wherein each of the said benzyl groups is optionally substituted with one substituent group selected from fluoro, chloro, hydroxy and trifluoromethyl. The compound for use according to any one of statements 1 to 9, wherein Ra is hydrogen or (1-2C)alkyl and Rb is selected from (1-2C)alkyl, N(Me)2, benzyl, cyclopropyl or any one of the following:
wherein each of the said benzyl groups is optionally substituted with one substituent group selected from fluoro, chloro, hydroxy and trifluoromethyl. The compound for use according to any preceding statement, wherein Rc is (1-6C)alkyl. The compound for use according to any preceding statement, wherein Rc is (1-3C)alkyl. The compound for use according to any preceding statement, wherein R2 IS selected from hydrogen, halo, hydroxy, (1-6C)alkyl, (1-6C)haloalkyl, (2-4C)alkenyl, (2-4C)alkynyl,
(1-8C)heteroalkyl, aryl, aryl(1-2C)alkyl, heteroaryl, heteroaryl(1-2C)alkyl, (3- 8C)heterocyclyl, (3-8C)heterocyclyl(1-2C)alkyl, (3-8C)cycloalkyl, (3-8C)cycloalkyl(1- 2C)alkyl, NRdRe, ORf, C(0)Rd, C(0)ORd, OC(0)Rd, C(Rd)=N(Re), N(Rd)ORe,
N(Rd)C(0)ORe, C(0)N(Rd)Re and N(Rd)C(0)Re. The compound for use according to any preceding statement, wherein R2 IS selected from hydrogen, halo, hydroxy, (1-6C)alkyl, (1-6C)haloalkyl, (2-4C)alkenyl, (2-4C)alkynyl, (1-8C)heteroalkyl, aryl, aryl(1-2C)alkyl, heteroaryl, heteroaryl(1-2C)alkyl, (3- 8C)heterocyclyl, (3-8C)heterocyclyl(1-2C)alkyl, (3-8C)cycloalkyl, (3-8C)cycloalkyl(1- 2C)alkyl, NRdRe, ORf, C(0)Rd, C(0)ORd, OC(0)Rd and C(Rd)=N(Re).
The compound for use according to any preceding statement, wherein R2 is selected from hydrogen, halo, hydroxy, (1-6C)alkyl, aryl, aryl(1-2C)alkyl, heteroaryl, heteroaryl(1- 2C)alkyl, (3-8C)heterocyclyl, (3-8C)heterocyclyl(1-2C)alkyl, (3-8C)cycloalkyl, (3- 8C)cycloalkyl(1-2C)alkyl, NRdRe, ORf, and C(Rd)=N(Re). The compound for use according to any preceding statement, wherein R2 is selected from hydrogen, (1-6C)alkyl, aryl, aryl(1-2C)alkyl, heteroaryl, heteroaryl(1-2C)alkyl, (3- 8C)heterocyclyl, (3-8C)heterocyclyl(1-2C)alkyl, (3-8C)cycloalkyl, (3-8C)cycloalkyl(1- 2C)alkyl and C(Rd)=N(Re). The compound for use according to any preceding statement, wherein R2 is selected from hydrogen, (1-6C)alkyl, (3-8C)heterocyclyl, (3-8C)heterocyclyl(1-2C)alkyl, (3- 8C)cycloalkyl, (3-8C)cycloalkyl(1-2C)alkyl and C(Rd)=N(Re). The compound for use according to any preceding statement, wherein R2 is selected from hydrogen, (3-8C)heterocyclyl(1-2C)alkyl and C(Rd)=N(Re). The compound for use according to any preceding statement, wherein R2 is selected from hydrogen, N-pyrrolidinyl(1-2C)alkyl and C(Rd)=N(Re). The compound for use according to any preceding statement, wherein each Rd is independently selected from hydrogen and (1-6C)alkyl. The compound for use according to any preceding statement, wherein each Re is independently selected from hydrogen, (1-6C)alkyl and (3-8C)heterocyclyl, any of which is optionally substituted with one or more substituent groups selected from (1-6C)alkyl and (3-8C)cycloalkyl. The compound for use according to any preceding statement, wherein each Re is independently selected from hydrogen, (1-4C)alkyl and (3-6C)heterocyclyl containing 1 or 2 heteroatoms selected from O and N, any of which is optionally substituted with one or more substituent groups selected from (1-4C)alkyl and (4-6C)cycloalkyl. The compound for use according to any preceding statement, wherein each Re is independently selected from hydrogen, (1-4C)alkyl and N-piperazinyl, any of which is optionally substituted with cyclopentyl.
The compound for use according to any preceding statement, wherein each Re is N- piperazinyl, which is optionally substituted with cyclopentyl. The compound for use according to any preceding statement, wherein Xi is O. The compound for use according to any preceding statement, wherein X2 is hydroxy or a group of formula (A), wherein
n is 1 or 2;
R3 is selected from hydrogen, halo, hydroxy, (1-6C)alkyl, (1-6C)haloalkyl, (2-4C)alkenyl, (2-4C)alkynyl, (1-8C)heteroalkyl, aryl, aryl(1-2C)alkyl, heteroaryl, heteroaryl(1-2C)alkyl, (3-8C)heterocyclyl, (3-8C)heterocyclyl(1-2C)alkyl, (3-8C)cycloalkyl, (3-8C)cycloalkyl(1- 2C)alkyl, NRjRk and ORi,
wherein R3 is independently optionally substituted by one or more substituent groups selected from fluoro, chloro, trifluoromethyl, trifluoromethoxy, amino, (1- 4C)alkyl and (1-4C)alkoxy. The compound for use according to any preceding statement, wherein X2 is hydroxy or a group of formula (A), wherein
n is 1 or 2;
R3 is selected from hydroxy, (1-6C)alkyl, aryl, aryl(1-2C)alkyl, heteroaryl, heteroaryl(1- 2C)alkyl, (3-8C)heterocyclyl, (3-8C)heterocyclyl(1-2C)alkyl, (3-8C)cycloalkyl, (3- 8C)cycloalkyl(1-2C)alkyl, NRjRk and ORi,
wherein R3 is independently optionally substituted by one or more substituent groups selected from fluoro, chloro, trifluoromethyl, trifluoromethoxy, amino, (1- 4C)alkyl and (1-4C)alkoxy. The compound for use according to any preceding statement, wherein X2 is hydroxy or a group of formula (A), wherein
n is 1 ;
R3 is selected from hydroxy, (1-6C)alkyl, (3-8C)heterocyclyl, (3-8C)heterocyclyl(1- 2C)alkyl, NRjRk and ORi,
wherein R3 is optionally substituted by one or more substituent groups selected from (1-4C)alkyl and (1-3C)alkoxy. The compound for use according to any preceding statement, wherein X2 is hydroxy or a group of formula (A), wherein
n is 1 ;
R3 is selected from hydroxy, (1-3C)alkyl, (3-8C)heterocyclyl, NR,Rk and ORi,
wherein R3 is optionally substituted by one or more substituent groups selected from (1-2C)alkyl and (1-2C)alkoxy. The compound for use according to any preceding statement, wherein X2 is a group of formula (A), wherein
n is 1 ; and
R3 is selected from hydroxy, N-linked (3-8C)heterocyclyl, NRjRk and ORi,
wherein R3 is optionally substituted by one or more (1-2C)alkyl. The compound for use according to any preceding statement, wherein X2 is a group of formula (A), wherein
n is 1 ; and
R3 is selected from hydroxy, NRjRk, ORi (e.g. methoxy or ethoxy) or any one of the following:
The compound for use according to any preceding statement, wherein Rh and R, are independently selected from hydrogen and (1-6C)alkyl. The compound for use according to any preceding statement, wherein Rh and R, are independently selected from hydrogen and (1-2C)alkyl. The compound for use according to any preceding statement, wherein Rh and R, are hydrogen. The compound for use according to any preceding statement, wherein Rj and Rk are independently selected from hydrogen, (1-6C)alkyl, (1-4C)alkoxy, aryl and (3- 8C)heterocyclyl. The compound for use according to any preceding statement, wherein Rj and Rk are independently selected from hydrogen, (1-6C)alkyl, aryl and N-linked (3- 8C)heterocyclyl.
The compound for use according to any preceding statement, wherein Rj and Rk are independently selected from hydrogen, (1-6C)alkyl, phenyl and 5-6 membered N-linked heterocyclyl. The compound for use according to any preceding statement, wherein Rj and Rk are independently selected from hydrogen, (1-6C)alkyl, phenyl or any one of the following:
The compound for use according to any preceding statement, wherein Rj and Rk are independently selected from hydrogen, (1-6C)alkyl and phenyl. The compound for use according to any preceding statement, wherein Ri is (1-6C)alkyl. The compound for use according to any preceding statement, wherein Ri is (1-3C)alkyl. The compound for use according to any preceding statement, wherein X2 is hydroxy. The compound for use according to any preceding statement, wherein R2 and Xi or R2 and X2 are linked, such that when they are taken in combination with the carbon atoms to which they are attached, they collectively form a 5-12 membered heterocycle that is optionally substituted with one or more R4 substituents. The compound for use according to any preceding statement, wherein R2 and Xi or R2 and X2 are linked, such that when they are taken in combination with the carbon atoms to which they are attached, they collectively form a 8-12 membered fused heterobicycle or spiro bi-cyclic heterocyclic ring system that is optionally substituted with one or more R4 substituents. The compound for use according to any preceding statement, wherein R2 and Xi or R2 and X2 are linked, such that when they are taken in combination with the carbon atoms to which they are attached, they collectively form a 8-12 membered fused heterobicycle or spiro bi-cyclic heterocyclic ring system containing 1 , 2 or 3 heteroatoms selected
from O and N, wherein said 8-12 membered fused or spiro heterobicycle is optionally substituted with one or more R4 substituents. The compound for use according to any preceding statement, wherein R2 and Xi or R2 and X2 are linked, such that when they are taken in combination with the carbon atoms to which they are attached, they collectively form a 9-11 membered fused heterobicycle or spiro bi-cyclic heterocyclic ring system containing 1 , 2 or 3 heteroatoms selected from O and N, wherein said 9-11 membered fused or spiro heterobicycle is optionally substituted with one or more R4 substituents. The compound for use according to any preceding statement, wherein R2 and Xi or R2 and X2 are linked, such that when they are taken in combination with the carbon atoms to which they are attached, they collectively form a 10 membered fused heterobicycle or spiro bi-cyclic heterocyclic ring system containing 1 , 2 or 3 heteroatoms selected from O and N, wherein said 10 membered fused or spiro heterobicycle is optionally substituted with one or more R4 substituents. The compound for use according to any preceding statement, wherein R2 and Xi or R2 and X2 are linked, such that when they are taken in combination with the carbon atoms to which they are attached, they collectively form either of the following groups:
wherein each R4 is independently optionally substituted with one or more groups selected from fluoro, chloro, (1-4C)alkyl, (2-4C)alkenyl, (2-4C)alkynyl, (1- 4C)alkoxy, aryl, aryl(1-2C)alkyl, heteroaryl, heteroaryl(1-2C)alkyl, (3-
8C)heterocyclyl, (3-8C)heterocyclyl(1-2C)alkyl, (3-8C)cycloalkyl, and (3- 8C)cycloalkyl(1-2C)alkyl. The compound for use according to any preceding statement, wherein each R4 is independently selected from halo, hydroxy, (1-6C)alkyl, aryl, aryl(1-2C)alkyl, heteroaryl, heteroaryl(1-2C)alkyl, (3-8C)heterocyclyl, (3-8C)heterocyclyl(1-2C)alkyl, (3- 8C)cycloalkyl, (3-8C)cycloalkyl(1-2C)alkyl, NRmRn, OR0,
wherein each R4 is independently optionally substituted with one or more groups selected from fluoro, chloro, (1-4C)alkyl and (1-4C)alkoxy. The compound for use according to any preceding statement, wherein each R4 is independently selected from halo, hydroxy, (1-6C)alkyl, (3-8C)heterocyclyl, (3- 8C)heterocyclyl(1-2C)alkyl, NRmRn, OR0,
wherein each R4 is independently optionally substituted with one or more groups selected from fluoro, chloro, (1-4C)alkyl and (1-4C)alkoxy. The compound for use according to any preceding statement, wherein each R4 is independently selected from hydroxy, (1-6C)alkyl and (3-8C)heterocyclyl,
wherein each R4 is independently optionally substituted with one or more groups, (1-4C)alkyl. The compound for use according to any preceding statement, wherein each R4 is independently selected from hydroxy, (1-4C)alkyl or a group:
Wherein,
X5 is selected from O or NRm;
m is a number selected from 1 and 2; and
o is a number selected from 1 and 2. The compound for use according to any preceding statement, wherein X3 and X4 are linked, such that when they are taken in combination with the carbon atom to which they are attached, they collectively form a group having a structure according to formula (B’) shown below:
X5 is selected from O or NRm;
m is a number selected from 1 and 2; and
o is a number selected from 1 and 2. The compound for use according to statement 61 or 62, wherein X5 is O.
The compound for use according to statement 61 , 62 or 63, wherein m is 1. The compound for use according to any one of statement 61 to 64, wherein o is 1. The compound for use according to any preceding statement, wherein each Rs is independently selected from fluoro, chloro, trifluoromethyl, trifluoromethoxy, hydroxy, oxo, amino, carboxy, (1-6C)alkyl, (1-4C)alkoxy, methylamino or dimethylamino, aryl, aryl(1-2C)alkyl, heteroaryl, heteroaryl(1-2C)alkyl, (3-8C)heterocyclyl, (3- 8C)heterocyclyl(1-2C)alkyl, (3-8C)cycloalkyl, and (3-8C)cycloalkyl(1-2C)alkyl. The compound for use according to any preceding statement, wherein each Rs is independently selected from fluoro, chloro, trifluoromethyl, trifluoromethoxy, hydroxy, oxo, amino, carboxy, (1-6C)alkyl, (1-4C)alkoxy, methylamino and dimethylamino. The compound for use according to any preceding statement, wherein each Rs is independently selected from fluoro, chloro, hydroxy, oxo, amino, (1-3C)alkyl and (1- 3C)alkoxy. The compound for use according to any preceding statement, wherein each Rs is independently selected from hydroxy, oxo and (1-4C)alkoxy. The compound for use according to any preceding statement, wherein Rs is oxo. The compound for use according to any preceding statement, wherein the compound has a structure according to formula (la), (lla) or (Ilia) shown herein, wherein
Ri is as described in any of numbered paragraphs (5) to (8);
Ra and Rb are as described in any of numbered paragraphs (11) to (12);
Rc is as described in any of numbered paragraphs (24) to (25);
Xi is as described in numbered paragraph (39);
X2 is as described in numbered paragraph (40) or (41);
n is as described in numbered paragraph (42) or (43);
R3 is as described in any of numbered paragraphs (46) to (50);
Rh and R, are as described in any of numbered paragraphs (52) to (53);
Rj and Rk are as described in any of numbered paragraphs (55) to (57);
Ri is as described in any of numbered paragraphs (59) to (60);
X3 and X4 are as described in any of numbered paragraphs (75) to (76); m is as described in numbered paragraph (78);
o is as described in numbered paragraph (79); and
Rs is as described in any of numbered paragraphs (81) to (84) The compound for use according to any preceding statement, wherein the compound has a structure according to formula (la), (I la) or (Ilia) shown herein, wherein
R1 is as described in any of numbered paragraphs (5) to (8);
Ra and Rb are as described in any of numbered paragraphs (15) to (22);
Rc is as described in any of numbered paragraphs (24) to (25);
Xi is as described in numbered paragraph (39);
X2 is as described in numbered paragraph (40) or (41);
n is as described in numbered paragraph (42) or (43);
R3 is as described in any of numbered paragraphs (46) to (50);
Rh and R, are as described in any of numbered paragraphs (52) to (53);
Rj and Rk are as described in any of numbered paragraphs (55) to (57);
Ri is as described in any of numbered paragraphs (59) to (60);
X3 and X4 are as described in any of numbered paragraphs (75) to (76); m is as described in numbered paragraph (78);
o is as described in numbered paragraph (79); and
R5 IS as described in any of numbered paragraphs (81) to (84) The compound for use according to any preceding statement, wherein the compound has a structure according to formula (la), (I la) or (Ilia) shown herein, wherein
R1 is as described in any of numbered paragraphs (7) to (8);
Ra and Rb are as described in numbered paragraph (12);
Rc is as described in numbered paragraph (25);
Xi is as described in numbered paragraph (39);
X2 is as described in numbered paragraph (40) or (41);
n is as described in numbered paragraph (43);
R3 is as described in any of numbered paragraphs (48) to (50);
Rh and R, are as described in numbered paragraph (53);
Rj and Rk are as described in any of numbered paragraphs (56) to (57);
Ri is as described in any of numbered paragraphs (59) to (60);
X3 and X4 are as described in any of numbered paragraphs (75) to (76); m is as described in numbered paragraph (78);
o is as described in numbered paragraph (79); and
R5 IS as described in any of numbered paragraphs (83) to (84).
The compound for use according to any preceding statement, wherein the compound has a structure according to formula (la), (I la) or (Ilia) shown herein, wherein
Ri is as described in any of numbered paragraphs (7) to (8);
Ra and Rb are as described in any one of numbered paragraphs (19) to (22); Rc is as described in numbered paragraph (25);
Xi is as described in numbered paragraph (39);
X2 is as described in numbered paragraph (40) or (41);
n is as described in numbered paragraph (43);
R3 is as described in any of numbered paragraphs (48) to (50);
Rh and R, are as described in numbered paragraph (53);
Rj and Rk are as described in any of numbered paragraphs (56) to (57);
Ri is as described in any of numbered paragraphs (59) to (60);
X3 and X4 are as described in any of numbered paragraphs (75) to (76); m is as described in numbered paragraph (78);
o is as described in numbered paragraph (79); and
R5 IS as described in any of numbered paragraphs (83) to (84). The compound for use according to any preceding statement, wherein the compound has a structure according to formula (lb), (lib) or (lllb) shown herein, wherein
R2 is as described in numbered paragraph (32);
Rd is as described in any of numbered paragraphs (33) to (34);
Re is as described in any of numbered paragraphs (37) to (38);
Xi is as described in numbered paragraph (39);
X2 is as described in numbered paragraph (40) or (41);
n is as described in numbered paragraph (42) or (43);
R3 is as described in any of numbered paragraphs (46) to (50);
Rh and R, are as described in any of numbered paragraphs (52) to (53);
Rj and Rk are as described in any of numbered paragraphs (55) to (57);
Ri is as described in any of numbered paragraphs (59) to (60);
X3 and X4 are as described in any of numbered paragraphs (75) to (76);
X5 is as described in numbered paragraph (77);
m is as described in numbered paragraph (78);
o is as described in numbered paragraph (79); and
R5 IS as described in any of numbered paragraphs (81) to (84). The compound for use according to any preceding statement, wherein the compound has a structure according to formula (lb), (lib) or (lllb) shown herein, wherein
R2 is as described in numbered paragraph (32);
Rd is as described in any of numbered paragraphs (33) to (34);
Re is as described in any of numbered paragraphs (37) to (38);
Xi is as described in numbered paragraph (39);
X2 is as described in numbered paragraph (40) or (41);
n is as described in numbered paragraph (42) or (43);
R3 is as described in any of numbered paragraphs (46) to (50);
Rh and R, are as described in any of numbered paragraphs (52) to (53);
Rj and Rk are as described in any of numbered paragraphs (55) to (57);
Ri is as described in any of numbered paragraphs (59) to (60);
or R2 and X1 or R2 and X2 are as described in any of numbered paragraphs (65) to (67), wherein R4 is as described in any of numbered paragraphs (70) to (72); X3 and X4 are as described in any of numbered paragraphs (75) to (76);
X5 is as described in numbered paragraph (77);
m is as described in numbered paragraph (78);
o is as described in numbered paragraph (79); and
R5 IS as described in any of numbered paragraphs (81) to (84). The compound for use according to any preceding statement, wherein the compound has a structure according to formula (lc), (lie) or ( 111 c) shown herein, wherein
R1 is as described in any of numbered paragraphs (5) to (8);
Ra and Rb are as described in any of numbered paragraphs (11) to (12);
Rc is as described in any of numbered paragraphs (24) to (25);
R2 is as described in any of numbered paragraphs (31) to (32);
Rd is as described in any of numbered paragraphs (33) to (34);
Re is as described in any of numbered paragraphs (37) to (38);
X2 is as described in numbered paragraph (40) or (41);
n is as described in numbered paragraph (42) or (43);
R3 is as described in any of numbered paragraphs (48) to (50);
Rh and R, are as described in any of numbered paragraphs (52) to (53);
Rj and Rk are as described in any of numbered paragraphs (55) to (57);
Ri is as described in any of numbered paragraphs (59) to (60);
X5 is as described in numbered paragraph (77);
m is as described in numbered paragraph (78);
o is as described in numbered paragraph (79); and
R5 IS as described in any of numbered paragraphs (83) to (84).
The compound for use according to any preceding statement, wherein the compound has a structure according to formula (lc), (lie) or ( 111 c) shown herein, wherein
Ri is as described in any of numbered paragraphs (5) to (8);
Ra and Rb are as described in any of numbered paragraphs (15) to (22);
Rc is as described in any of numbered paragraphs (24) to (25);
R2 is as described in any of numbered paragraphs (31) to (32);
Rd is as described in any of numbered paragraphs (33) to (34);
Re is as described in any of numbered paragraphs (37) to (38);
X2 is as described in numbered paragraph (40) or (41);
n is as described in numbered paragraph (42) or (43);
R3 is as described in any of numbered paragraphs (48) to (50);
Rh and R, are as described in any of numbered paragraphs (52) to (53);
Rj and Rk are as described in any of numbered paragraphs (55) to (57);
Ri is as described in any of numbered paragraphs (59) to (60);
X5 is as described in numbered paragraph (77);
m is as described in numbered paragraph (78);
o is as described in numbered paragraph (79); and
R5 IS as described in any of numbered paragraphs (83) to (84). The compound for use according to any preceding statement, wherein the compound has a structure according to formula (lc), (lie) or ( 111 c) shown herein, wherein
Ri is as described in numbered paragraph (8);
Rc is as described in any of numbered paragraphs (24) to (25);
R2 is as described in numbered paragraph (32);
Rd is as described in numbered paragraph (34);
Re is as described in numbered paragraph (38);
X2 is as described in numbered paragraph (40) or (41);
n is as described in numbered paragraph (42) or (43);
R3 is as described in any of numbered paragraphs (49) to (50);
Rh and R, are as described in numbered paragraphs (53);
Rj and Rk are as described in any of numbered paragraphs (56) to (47);
Ri is as described in any of numbered paragraphs (59) to (60);
X5 is as described in numbered paragraph (77);
m is as described in numbered paragraph (78);
o is as described in numbered paragraph (79); and
R5 IS as described in any of numbered paragraphs (83) to (84).
The compound for use according to any preceding statement, wherein the compound has a structure according to formula (lc), (lie) or ( 111 c) shown herein, wherein
Ri is as described in numbered paragraph (7) or (8);
Ra and Rb are as described in any of numbered paragraphs (21) to (22);
Rc is as described in any of numbered paragraphs (24) to (25);
R2 is as described in numbered paragraph (32);
Rd is as described in numbered paragraph (34);
Re is as described in numbered paragraph (38);
X2 is as described in numbered paragraph (40) or (41);
n is as described in numbered paragraph (42) or (43);
R3 is as described in any of numbered paragraphs (49) to (50);
Rh and R, are as described in numbered paragraphs (53);
Rj and Rk are as described in any of numbered paragraphs (56) to (57);
Ri is as described in any of numbered paragraphs (59) to (60);
X5 is as described in numbered paragraph (77);
m is as described in numbered paragraph (78);
o is as described in numbered paragraph (79); and
R5 IS as described in any of numbered paragraphs (83) to (84). The compound for use according to any preceding statement, wherein the compound has a structure according to formula (Id), (lid) or (I lid) shown herein, wherein
Ri is as described in any of numbered paragraphs (5) to (8);
Ra and Rb are as described in any of numbered paragraphs (11) to (12);
Rc is as described in any of numbered paragraphs (24) to (25);
R2 is as described in any of numbered paragraphs (31) to (32);
Rd is as described in any of numbered paragraphs (33) to (34);
Re is as described in any of numbered paragraphs (37) to (38);
R3 is as described in any of numbered paragraphs (48) to (50);
Rh and R, are as described in any of numbered paragraphs (52) to (53);
Rj and Rk are as described in any of numbered paragraphs (55) to (57);
Ri is as described in any of numbered paragraphs (59) to (60);
X5 is as described in numbered paragraph (77);
m is as described in numbered paragraph (78); and
R5 IS as described in any of numbered paragraphs (83) to (84). The compound for use according to any preceding statement, wherein the compound has a structure according to formula (Id), (lid) or (I lid) shown herein, wherein
Ri is as described in any of numbered paragraphs (5) to (8);
Ra and Rb are as described in any of numbered paragraphs (19) to (22); Rc is as described in any of numbered paragraphs (24) to (25);
R2 is as described in any of numbered paragraphs (31) to (32);
Rd is as described in any of numbered paragraphs (33) to (34);
Re is as described in any of numbered paragraphs (37) to (38);
R3 is as described in any of numbered paragraphs (48) to (50);
Rh and R, are as described in any of numbered paragraphs (52) to (53); Rj and Rk are as described in any of numbered paragraphs (55) to (57); Ri is as described in any of numbered paragraphs (59) to (60);
X5 is as described in numbered paragraph (77);
m is as described in numbered paragraph (78); and
R5 IS as described in any of numbered paragraphs (83) to (84).
The compound for use according to any preceding statement, wherein the compound has a structure according to formula (Id), (lid) or (I lid) shown herein, wherein
Ri is as described in numbered paragraph (8);
Rc is as described in any of numbered paragraphs (24) to (25);
R2 is as described in numbered paragraph (32);
Rd is as described in numbered paragraph (34);
Re is as described in numbered paragraph (38);
R3 is as described in any of numbered paragraphs (49) to (50);
Rh and R, are as described in numbered paragraphs (53);
Rj and Rk are as described in any of numbered paragraphs (56) to (57);
Ri is as described in any of numbered paragraphs (59) to (60);
X5 is as described in numbered paragraph (77);
m is as described in numbered paragraph (78); and
R5 IS as described in any of numbered paragraphs (83) to (84). The compound for use according to any preceding statement, wherein the compound has a structure according to formula (Id), (lid) or (I lid) shown herein, wherein
Ri is as described in numbered paragraph (7) or (8);
Ra and Rb are as described in any of numbered paragraphs (21) to (22);
Rc is as described in any of numbered paragraphs (24) to (25);
R2 is as described in numbered paragraph (32);
Rd is as described in numbered paragraph (34);
Re is as described in numbered paragraph (38);
R is as described in any of numbered paragraphs (49) to (50);
Rh and R, are as described in numbered paragraphs (53);
Rj and Rk are as described in any of numbered paragraphs (56) to (57);
Ri is as described in any of numbered paragraphs (59) to (60);
X5 is as described in numbered paragraph (77);
m is as described in numbered paragraph (78); and
R IS as described in any of numbered paragraphs (83) to (84). The compound for use according to any preceding statement, wherein the compound has a structure according to formula (le), (lie) or (I lie) shown herein, wherein
R is as described in any of numbered paragraphs (31) to (32);
Rd is as described in any of numbered paragraphs (33) to (34);
Re is as described in any of numbered paragraphs (37) to (38);
R is as described in any of numbered paragraphs (48) to (50);
Rh and R, are as described in any of numbered paragraphs (52) to (53);
Rj and Rk are as described in any of numbered paragraphs (55) to (57);
Ri is as described in any of numbered paragraphs (59) to (60);
X5 is as described in numbered paragraph (77);
m is as described in numbered paragraph (78); and
R IS as described in any of numbered paragraphs (83) to (84). The compound for use according to any preceding statement, wherein the compound has a structure according to formula (le), (lie) or (I lie) shown herein, wherein
R is as described in numbered paragraph (32);
Rd is as described in numbered paragraph (34);
Re is as described in numbered paragraph (38);
R is as described in any of numbered paragraphs (49) to (50);
Rh and R, are as described in numbered paragraphs (53);
Rj and Rk are as described in any of numbered paragraphs (56) to (57);
Ri is as described in any of numbered paragraphs (59) to (60);
X5 is as described in numbered paragraph (77);
m is as described in numbered paragraph (78); and
R IS as described in any of numbered paragraphs (83) to (84). The compound for use according to any preceding statement, wherein the compound has a structure according to formula (If), (Ilf) or (lllf) shown herein, wherein
Ri is as described in any of numbered paragraphs (5) to (8);
Ra and Rb are as described in any of numbered paragraphs (11) to (12);
Rc is as described in any of numbered paragraphs (24) to (25);
R2 is as described in any of numbered paragraphs (31) to (32);
Rd is as described in any of numbered paragraphs (33) to (34);
Re is as described in any of numbered paragraphs (37) to (38); and
Rs is as described in any of numbered paragraphs (83) to (84). The compound for use according to any preceding statement, wherein the compound has a structure according to formula (If), (Ilf) or (lllf) shown herein, wherein
R1 is as described in any of numbered paragraphs (5) to (8);
Ra and Rb are as described in any of numbered paragraphs (15) to (22);
Rc is as described in any of numbered paragraphs (24) to (25);
R2 is as described in any of numbered paragraphs (31) to (32);
Rd is as described in any of numbered paragraphs (33) to (34);
Re is as described in any of numbered paragraphs (37) to (38); and
R5 IS as described in any of numbered paragraphs (83) to (84). The compound for use according to any preceding statement, wherein the compound has a structure according to formula (If), (Ilf) or (lllf) shown herein, wherein
R1 is as described in numbered paragraph (8);
Rc is as described in any of numbered paragraphs (24) to (25);
R2 is as described in numbered paragraph (32);
Rd is as described in numbered paragraph (34);
Re is as described in numbered paragraph (38); and
R5 IS as described in any of numbered paragraphs (83) to (84). The compound for use according to any preceding statement, wherein the compound has a structure according to formula (If), (Ilf) or (lllf) shown herein, wherein
R1 is as described in numbered paragraph (7) or (8);
Ra and Rb are as described in any of numbered paragraphs (21) to (22);
Rc is as described in any of numbered paragraphs (24) to (25);
R2 is as described in numbered paragraph (32);
Rd is as described in numbered paragraph (34);
Re is as described in numbered paragraph (38); and
R5 IS as described in any of numbered paragraphs (83) to (84).
The compound for use according to any preceding statement, wherein the compound has any one of the following structures:
98. The compound for use according to any preceding statement, wherein the compound has any one of the following structures:
with the proviso that, in formula (I), when Ri is hydroxy and R2 is hydrogen, Xi is not O. . The compound of statement 103, wherein, in formula (I), Ri is not hydroxy.
105. The compound of statement 103 or 104, wherein, in formula (I), R2 is not hydrogen.
106. A compound of any one of statements 103, 104 or 105 for use in therapy.
107. A compound of any one of statements 103, 104 or 105 for use as a medicament.
108. A pharmaceutical composition comprising a compound as defined in any one of statements 103, 104 or 105, or a pharmaceutically acceptable salt or solvate thereof, and one or more pharmaceutically acceptable excipients or carriers.
EXAMPLES
[00193] One or more examples of the invention will now be described, for the purpose of illustration only, with reference to the accompanying figures, in which:
Fig. 1 shows identification and mode of action of KglA. A. Disk diffusion assay with rifampicin (RIF), carbenicillin (Cb) and Kanglemycin A (KglA). The paper disks soaked with antibiotics were placed on the lawns of wild-type B. subtilis carrying lacZ gene under PheiD promoter, inducible during partial inhibition of transcription (left plate), and RIF-resistant B. subtilis (right plate). Note the blue halo around growth inhibition zones in the case of transcription inhibitors. B. Chemical structure of KglA in comparison with RIF. The ansa-chain modifications in KglA are highlighted. The semi-synthetic group of RIF is shown in purple. C. Transcription in vitro by E. coli RNAP on linear template containing T7A1 promoter. Run off, termination, and abortive tri- and tetra- nucleotides are marked. Note that tetra-nucleotide migrates faster than tri-nucleotide in these electrophoretic conditions. D and E. Inhibition of wild-type and RIF-resistant E. coli RNAPs by RIF and KglA. Error bars are ±SD. The brackets in the table contain ±SD, and Hill slope. F. Different ratio of the di- (pppApU) and the tri-nucleotide long (pppApUpC) abortive products in the presence of RIF and KglA. Transcription in the presence of nucleotides depicted (in the absence of CpA primer). Note that in 33% gel, run off and termination products remain in the well.
Fig. 2 shows A. Mass spectrum of KglA showing peaks at 1004.3866, 1020.3632 and 1985.7900 Da, assigned as [M+Na]+ [Ma+K]+ and [2M+Na]+ respectively. B. Crystallographically determined structure of KglA (from synchrotron data). Non-H atoms are labelled. C. 500 MHz 1H NMR spectra of KglA in CDCh. D. 125 MHz 13C{1H} NMR spectra of KglA in CDCh.
Fig. 3 shows the mass spectrum of DEMB1 showing peaks at 1042.42 and 1064.4074, assigned as [M+H]+ and [M+Na]+ respectively, which is the expected mass according to the DEMB1 structure.
Fig. 4 shows the mass spectrum of DEMB3 showing peaks at 1056.44 and 1078.42, assigned as [M+H]+ and [M+Na]+ respectively. Some contamination with DEMB1 was observed as [M+H]+=1042.42.
Fig. 5 shows the mass spectrum of DEMB1 C shown as [M+H]+ =10062.3932.
Fig. 6 shows the inhibition of RIF-resistant E. coli b8531 L RNAP by DEMB1 shows very low IC50 (for comparison IC50[Rif] = 675 pM=675pg/mL).
Fig. 7 shows the inhibition of RIF-resistant E. coli bd531 L RNAP by DEMB3 shows very low IC50 (for comparison IC50[Rif] = 675 pM=675pg/mL).
Fig. 8 shows the inhibition of RIF-resistant E. coli bd531 E RNAP by DEMB1 C shows relatively low IC50 (for comparison IC50[Rif] = 675 pM=675pg/mL).
Analytical methods and assays
NMR analysis of Kanglemycin A (KglA)
[00194] All NMR spectra were recorded in CDCh at 10°C. 1 H and 13C{1 H} NMR spectra were recorded directly with a Jeol Lambda 500 MHz spectrometer, whilst 1 H COSY; 45, 90 and 135 DEPT; HMQC and HMBC were recorded with a Jeol ECS 400 MHz spectrometer (not shown). Proton and carbon assignment was performed de novo from both 1 D and 2D NMR experiments and was in close agreement with the literature (Wang et al., 1988).
Disk diffusion assay
[00195] Standard disc diffusion assay (Kirby-Bauer) was performed with the B. subtilis 168 amyEv.P etDJacZ cat reporter strain or RIF-resistant B. subtilis 168 rpoBH482R strain as described (Bauer et al. , 1966). Briefly, disks were loaded with to 10 pg of each drug, air-dried and placed on nutrient agar plates with embedded lawn of bacteria and x-gal (100 pg/mL). Plates were incubated overnight at 37°C and scanned.
Purification of E. coli RNAP core and o70 for transcription assays
[00196] RIF-resistant mutations were introduced in pETLRpoB plasmid (6xHis-tag on N- terminus of b subunit of E. coli RNAP) (Smith and Savery, 2005) by site-directed mutagenesis
using QuikChange II kit (Stratagene). Wild-type or mutant plasmids were transformed along with pRSFD2-rpoZ (encoding for w subunit) in T7 Express strain (New England Biolabs). Expression and purification of core RNAP was performed as described (Kashlev et al., 1996) (with heparin chromatography used instead of gel filtration as suggested). N-terminal 6xHis-tagged E. coli o70 subunit was purified as described (Zenkin et al., 2007).
In vitro transcription
[00197] One pmol of wild-type or mutant RNAP core and 3 pmols of o70 and 0.1 pmols of linear template containing T7A1 promoter (Julius and Yuzenkova, 2017; Roghanian et al. , 2015) were mixed in 7 pi of transcription buffer (20 mM Tris HCI pH 7.9, 40 mM KCI, 10 mM MgCh). 1 pL of DMSO containing or not containing antibiotics (concentrations specified in Figures) was added to the reaction. Transcription was initiated by the addition of 2 pl_ of the mixture of nucleotides in transcription buffer, containing (final concentrations): 25 mM CpA (or none in Fig. 1 E), 100 mM ATP, CTP and GTP and 10 mM a-[32P]UTP (20 Ci/mmol) (Hartmann Analytic). Reactions were stopped after 10-min incubation at 37°C by the addition of formamide-containing loading buffer. Products were separated on 20% or 33% denaturing (8M urea) polyacrylamide gels, revealed by Phosphorimaging (GE Healthcare), and analyzed using ImageQuant software (GE Healthcare). Activities (a sum of run off and termination products) were normalized to the activity without antibiotic, which was taken as 100%. The average activity of at least three replicates for each concentration of antibiotic was plotted (with their standard deviations as error bars) against concentration and fitted in four parameter logistic equation by nonlinear regression using SigmaPlot. The averages and standard deviations of the three individual IC50S are reported in Fig 1 E.
Determination of minimum inhibitory concentrations for bacteria
[00198] MICs were determined using the agar dilution method specified by the British Society for Antimicrobial Chemotherapy against a collection of 56 isolates (Andrews, 2001). Briefly, KglA was initially dissolved in a minimal volume of dimethyl sulfoxide and diluted in water before incorporation into IsoSensitest agar (Oxoid) at a final concentration range of 128 - 0.031 pg/mL. A final inoculum of 10 000 CFU/spot was used for inoculation of plates. Cultures were incubated for 22 hours at 37 ± 0.5 °C. The MIC was recorded as the lowest concentration of KglA that achieved complete inhibition of visible growth. Inhibitor-free controls were also tested, including those containing equivalent solvent concentrations. All tests were performed at least twice on separate occasions to demonstrate reproducibility.
[00199] The collection included 16 isolates acquired from the National Collection of Type Cultures (NCTC; Colindale, UK), 3 isolates from the American Type Culture Collection (ATCC; Manassas, USA), and one from the National Collection of Pathogenic Fungi (NCPF; Colindale, UK). Also included were 36 strains of methicillin-resistant Staphylococcus aureus (MRSA) kindly supplied by Public Health England (Colindale, UK). These 36 strains were isolated from clinical samples in five European countries and included representatives of the major clones responsible for outbreaks of infection.
Example 1 - Kanglemycin A (“KglA”)
Isolation of KglA
[00200] Actinomycete bacteria have historically been an excellent source of bioactive compounds, particularly antibiotics. To identify new antibiotics targeting transcription, a subset of strains from the Demuris collection of actinomycetes were screened for their ability to inhibit cell growth and to inhibit cellular transcription. As a reporter strain, previously described B. subtilis strain was used, which has a lacZ gene fused to the promoter of the bacterial helicase helD. This promoter is upregulated by the stress induced by partial inhibition of transcription resulting in a colorimetric response on an X-gal infused agar plate, thus indicating the presence of sub- inhibitory concentrations of an antibiotic targeting transcription (Fig. 1A left Petri dish; compare halos produced by RIF and carbenicillin, an inhibitor of cell wall synthesis) (Urban et al. , 2007). The isolate Amycolatopsis DEM30355 was of particular interest as it produced a compound (identified as KglA, see below), which gave a blue halo at the edge of the zone of bacteria growth inhibition indicative of transcription inhibition (Fig. 1A, left Petri dish). Importantly, in contrast to RIF, this new compound inhibited RIF-resistant B. subtilis strain ^H482R; bH526R in E. coli numbering) (Fig. 1A, right Petri dish).
[00201] Amycolatopsis DEM30355 was cultivated as follows:
The fermentation of the Amycolatopsis sp. DEM303555 was conducted as previously described (Kepplinger et al., 2018). One kilogram of Amberlite XAD-16 resin was washed with deionized water and then applied to 50 L of filtered culture supernatant in batch absorption. The material was eluted with 32 L of 100% methanol and concentrated under reduced pressure (2.5 L). The concentrate was adjusted to pH 6.5 and extracted eight times with an equal amount of ethyl acetate. The organic extracts were combined and evaporated to dryness to yield 22.5 g of crude extract. A sample of the crude extract (3.91 g) was subjected to silica gel chromatography (eluent = 100% ethyl acetate, Biotage SNAP 100g cartridge). KglA-containing fractions were combined and the solvent was removed under reduced pressure to give 1.24 g of a dark coloured solid. This material was subjected to a second silica gel chromatography step (eluent = linear gradient
from diethyl ether to ethyl acetate. Evaporation of the KglA containing fractions yielded 806.2 g as an orange solid.
[00202] The resulting orange crystalline compound retained the observed biological activity against both the reporter and RIF-resistant strains (Fig. 1A). ESI-MS revealed the mass [M+Na]+ = 1004.3866 m/z (Fig. 2A), which corresponded to the mass of previously described kanglemycin A (KglA). 1 H and 13C NMR, extensive 2-D NMR analysis, and, finally, single-crystal X-ray analysis (Fig. 2B, C, D) unambiguously confirmed the structure of the isolated compound to be KglA (Fig. 1 B):
Mode of action and specificity of KglA
[00203] KglA is an antibiotic originally isolated from the fermentation broth of Nocardia mediterranei var. kanglensis 1741-64 (Wang et al., 1988), for which no mode of action has been previously proposed and only limited information on its biological activity has been reported. It is an ansamycin antibiotic which shares similarities with rifamycins, albeit with a number of unusual structural features. Most notably KglA differs from known rifamycins and their semisynthetic derivatives in that it contains two large ansa-bridge substituents, a pendant 2,2-dimethyl succinic acid side chain at C20 and a unique sugar moiety ^-0-3,4-0,0’-methylene digitoxose) at C27 (Fig. 1 B). Furthermore, these modifications are unusual for bioactive natural and semi-synthetic rifamycins whose modifications are typically concentrated at the naphthoquinone core.
[00204] Activation of the helD promoter and its structural similarity to the rifamycins suggested that KglA targets bacterial RNAP. Therefore, the effects of KglA on in vitro transcription by wild- type E. coli RNAP were analyzed. KglA efficiently inhibited transcription on a linear DNA template containing the strong T7A1 promoter (Fig. 1 C). Inhibition of full-sized RNA products (run off or terminated) coincided with increased accumulation of short abortive tri- and tetra- nucleotide products (Fig. 1C; the reactions were started with the dinucleotide primer CpA). Such a mode of
action is characteristic of the rifamycins (Campbell et al., 2005; McClure and Cech, 1978), as can be seen from the pattern of inhibition of transcription by RIF (Fig. 1C). In this mode of action, the antibiotic binds in the pathway of the nascent RNA, physically blocking its extension and inducing the release of short RNAs as abortive products.
[00205] The ICso’s of KglA and RIF were similar against wild-type RNAP (Fig 1 D, E). However, despite having a similar mode of action to RIF, it was observed that KglA killed RIF-resistant bacteria (compare inhibition zones in Fig. 1A, right plate). To investigate this phenomenon, E. coli RNAPs carrying a series of rifampicin-resistant mutations were prepared, including bd531 I_, bϋ516n, bϋ516U, bH526U, bH526R, bH526R, and bI572R. These mutations correspond to the RIF-resistance mutations in M. tuberculosis most frequently observed in clinical isolates, with bd531 I_, bϋdΐqn and bH526U accounting for 73% of all clinical RIF-resistant M. tuberculosis isolates (Gill and Garcia, 2011). Compared to RIF, KglA was much more potent against six out of seven RIF-resistant RNAPs (Fig. 1 D, E); in particular the KglA was 10 times more active than RIF against bd531 I_ and bϋ516n mutants. Note that while mutations at bH526 made RNAP insensitive to RIF (no inhibition at 2.5 mg/ml_), KglA was still able to inhibit RNAPs with these mutations.
[00206] It was noted that the ratio of tri- (CpApU) and tetra-nucleotide (CpApUpC) products made, when transcription started with the dinucleotide primer CpA, was different for RIF and KglA (Fig. 1C; note the odd migration of abortive products in the gel described earlier (Borukhov et al., 1993)). Tetra-nucleotide production in the presence of KglA was inhibited as compared to RIF, suggesting that binding of KglA results in stronger steric hindrance towards RNA progression. To investigate this further, transcription starting with ATP (in the absence of CpA primer) was analyzed. As can be seen from Fig. 1 F, KglA completely blocked the formation of triphosphorylated trinucleotide, pppApUpC, while RIF allowed some of its production (compare lanes 2 and, 5 and 6). Furthermore, KglA strongly diminished (70-fold inhibition) the formation of the first dinucleotide pppApU, while RIF had only moderate effect (3 fold inhibition). This further suggests that extra groups and/or the mode of binding of KglA sterically precludes translocation of the triphosphorylated 5’ end of dinucleotide RNA and even interferes with the first phosphodiester bond formation, which both, conversely, are allowed in the case of RIF binding.
[00207] These results and in vivo data (Fig. 1A) suggest that KglA binds to RNAP in the RIF- binding pocket of b subunit, but in a manner different from known rifamycins, resulting in an increased resilience to the rifampicin-resistant amino acid substitutions in the RIF-binding pocket of RNAP. Furthermore, mode of action of KglA deviates from that of RIF, as KglA inhibits formation of the first phosphodiester bond, when transcription is started with nucleotide triphosphate.
KglA potency against Gram-positive pathogens
[00208] The results discussed above suggest that KglA may be effective against RIF-resistant bacteria. Thus, KglA was tested against 20 clinically relevant pathogenic species, 8 Gram positive, 10 Gram-negative and 2 eukaryotes (Table 1). Amongst the eight Gram-positive pathogens tested, KglA was highly active against six species, and had somewhat lower activity against the remaining two. Out of 10 Gram-negative pathogens, KglA was active against only Providencia rettgeri. No activity was observed towards the two strains of eukaryotic microorganisms (yeast): Candida albicans and Candida glabrata. The antibacterial potential of KglA was further tested against 38 MRSA strains. 35 of these strains showed low MICs (0.025- 2 pg/mL). Only three MRSA strains had relatively high MICs of KglA (32-128 pg/mL), however these were still significantly lower than the comparable MICs for RIF (>128 pg/ml). The results suggest that KglA has potential as a Gram-positive-specific antimicrobial, and, importantly, against RIF-resistant species.
Table 1. Minimum inhibitory concentrations (MICs) of KglA against bacterial and eukaryotic pathogens (‘Andrews, J.M. (2001). Determination of minimum inhibitory concentrations. The
Journal of antimicrobial chemotherapy 48 Suppl 1, 5-16.).
Example 2 - DEMB1
Isolation of B1 , B3 and B1 C
[00209] B1 was isolated from Amycolatopsis DEM30355 in a similar manner to KglA (Example 1). In the process of B1 purification, two new compounds with the accurate masses of 1055.44 Da and 1061.39Da were identified, presumed to be the methyl ester and cyclized/oxidised derivatives of B1 correspondingly. The new compounds were named B3 (methyl ester) and B1C
(cyclized/oxidised). To further investigate the hypothesis, 10 mg of B1 was dissolved in 0.5 ml_ of methanol, stored at -20 °C and analysed by LC-MS every 24 hour. The time kinetic experiment confirmed the conversion of B1 to B3 where about half of B1 was converted to B3 after 7 days. The time kinetic experiment did not show any changes in the proportion of B1 C after storage in methanol. However, it was observed that conversion to B1C is increased in aqueous solutions of B1
[00210] The mixture containing B1 , B3 and B1 C was then evaporated to dryness and dissolved in 20% Acetonitrile: H20. To purify the two derivatives of B1 , the reaction mixture was subjected to the C18 column and separated by reversed-phase chromatography (eluent=linear gradient 20% Acetonitrile in H2O to 100% acetonitrile). Fractions containing the B1 , B3 and B1C were collected and analysed separately by LC-MS (Figs 3, 4 and 5).
B3
Potency against RIF-resistant RNAPs
[00211] To investigate the efficacy of B1 , B3 and B1C against rifampicin-resistant RNA polymerase (RNAP), they were tested against the E.coli RNAP carrying bd531 I_ (the most frequently observed RIF-resistant mutation in clinical isolates). The IC50 of B3 against bd531 I_ RNAP (2 pg/mL) was similar to that of B1 (3 pg/mL) suggesting that methylation of carboxylic group does not affect the RNAP binding. (Figs 6 and 7) The inhibition of bd531 L RNAP by B1 C was weaker than the other two compounds (30 pg/mL). Compared to Rif, all three derivatives are very potent inhibitors of Rif-resistant bd531 I_ RNAP (IC50[Rif] = 675pg/ml_).
[00212] The potency of B1 against other E. coli RNAPs carrying rifampicin-resistant mutations, including bd531 I_, bϋ516n, bϋ516U, bH526U, bH526R, bH526R, and bI572R, was analysed. Table 2 below compares the potency of B1 against various RIF-resistant RNAPs with that of RIF and rifamycin B (“rifB”):
Table 2 - IC50 of inhibition of RIF-resistant RNAPs by B1 , RIF and rifB (pg/ml)
Example 3 - c17b-001 to c17b-018
Preparation of compounds
[00213] Compounds c17b-001 to c17b-018 were prepared by reaction of KglA (Example 1) with a series of different amines (see Table 3) according to the reaction scheme below:
[00214] To a round bottom flask, under an atmosphere of nitrogen, was added KglA (1 eq.), 4- dimethylaminopyridine (6 eq.), hexafluorophosphate azabenzotriazole tetramethyl uronium (3 eq.), amine (10 eq.) and DMF (55 mL/mmol of KglA). The reaction mixture was stirred at room temperature, until the reaction was complete (typically 2-8 hours). The reaction sample then underwent solid phase extraction using increasing amounts of methanol (20%, 50%, 75%, 100%). The fraction in 75% methanol was then ran on HPLC. Peaks produced by the sample were collected and analysed by LCMS. The fraction containing the desired product was made up to a concentration of 1 mg/ml_ and froze in 100% methanol.
Table 3 - Preparation of compounds c17b-001 to c17b-018 - reagents and reaction times
LCMS
[00215] Compounds c17b-001 to c17b-018, as purified by HPLC, were analysed by LCMS according to the following protocol:
Solvent: Water, MeCN, 0.1 % formic acid
Column flow rate: 0.2 pl_/ min
Gradient:
Time/ min Water / % MeCN / %
0 80 20
20 0 100
25 0 100
26 80 20
30 80 20
[00216] Tables 4 and 5 below show the theoretical and observed mass of compounds c17b-001 to c17b-018, as determined by LCMS.
Table 4 - Theoretical mass of compounds c17b-001 to c17b-018
Table 5 - Observed mass of compounds c17b-001 to c17b-018 as determined by LCMS
Minimum inhibitory concentration (MIC)
[00217] To test the MIC, the following dilution was performed. A sample of 1 :9 Staphylococcus aureus strain RN4220: LB (Luria broth growth media) was made up and incubated for 4 hours. An optical density of a 1 :9 sample was 0.120 at 600nm. The amount of 1 :9 Staphylococcus aureus: LB was calculated in the following way:
OD (600nm) X 10 = 0.120 x 10 = 1.20
Ci Vi = C2V2
0.05 (desired concentration) x 20ml_ (desired volume) = 1.20 x V2 V2 = 0.83ml_ = 833.88 mI_ of 1 :9 1 :9 Staphylococcus aureus: LB in 20mL of LB.
180 pl_ of the 20ml_ diluted Staphylococcus aureus: LB was added to each column to make the volume up to 200 pL. The plates were left overnight in a shaking incubator.
[00218] The MIC results are shown in Table 6:
Table 6 - MIC for compounds c17b-001 to c17b-018 against Staphylococcus aureus strain
RN4220
[00219] While specific embodiments of the invention have been described herein for the purpose of reference and illustration, various modifications will be apparent to a person skilled in the art without departing from the scope of the invention as defined by the appended claims.
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Claims
1. A compound of formula (I), (II) or (III) shown below, or a pharmaceutically acceptable salt, hydrate or solvate thereof, for use in the treatment of infection caused by rifampicin-resistant bacteria:
wherein,
Ri is selected from hydrogen, halo, cyano, isocyano, nitro, hydroxy, (1-6C)alkyl, (1-6C)haloalkyl, (2-4C)alkenyl, (2-4C)alkynyl, (1-8C)heteroalkyl, aryl, aryl(1-2C)alkyl, heteroaryl, heteroaryl(1-2C)alkyl, (3-8C)heterocyclyl, (3-8C)heterocyclyl(1-2C)alkyl, (3- 8C)cycloalkyl, (3-8C)cycloalkyl(1-2C)alkyl, NRaRb, ORc, 0C(0)Ra, N(Rb)ORa,
N(Rb)C(0)0Ra, N(Rb)C(0)Ra, S(0)PRa (where p is 0, 1 or 2), S02N(Rb)Ra, and
N(Rb)S02Ra;
R2 is selected from hydrogen, halo, cyano, isocyano, nitro, hydroxy, (1-6C)alkyl, (1-6C)haloalkyl, (2-4C)alkenyl, (2-4C)alkynyl, (1-8C)heteroalkyl, aryl, aryl(1-2C)alkyl, heteroaryl, heteroaryl(1-2C)alkyl, (3-8C)heterocyclyl, (3-8C)heterocyclyl(1-2C)alkyl, (3- 8C)cycloalkyl, (3-8C)cycloalkyl(1-2C)alkyl, NRdRe, ORf, C(0)Rd, C(0)0Rd, 0C(0)Rd, C(Rd)=N(Re), N(Rd)ORe, N(Rd)C(0)0Re, C(0)N(Rd)Re, N(Rd)C(0)Re, S(0)PRd (where p is 0, 1 or 2), S02N(Rd)Re, and N(Rd)S02Re;
and wherein Ri and R2 are each independently optionally substituted by one or more substituent groups selected from fluoro, chloro,
trifluoromethyl, trifluoromethoxy, cyano, nitro, hydroxy, amino, carboxy, carbamoyl, sulphamoyl, (1-4C)alkyl, (1-4C)alkoxy, S(0)qCH3 (where q is 0, 1 or 2), methylamino or dimethylamino, aryl, aryl(1-2C)alkyl, heteroaryl, heteroaryl(1-2C)alkyl, (3-8C)heterocyclyl, (3- 8C)heterocyclyl(1-2C)alkyl, (3-8C)cycloalkyl, or (3-8C)cycloalkyl(1- 2C)alkyl;
Xi is selected from O and NRg;
X2 is hydroxy or a group of formula (A) shown below:
n is 0, 1 , 2, 3 or 4; and
R3 is selected from hydrogen, halo, cyano, isocyano, nitro, hydroxy, (1-6C)alkyl, (1-6C)haloalkyl, (2-4C)alkenyl, (2- 4C)alkynyl, (1-8C)heteroalkyl, aryl, aryl(1-2C)alkyl, heteroaryl, heteroaryl(1-2C)alkyl, (3-8C)heterocyclyl, (3-8C)heterocyclyl(1- 2C)alkyl, (3-8C)cycloalkyl, (3-8C)cycloalkyl(1-2C)alkyl, NRjRk, OR,, C(0)Rj, C(0)ORj, OC(0)Rj, C(Rj)=N(Rk), N(Rj)ORk,
N(Rj)C(0)ORk, C(0)N(Rj)Rk, N(Rj)C(0)Rk, S(0)PRj (where p is 0, 1 or 2), S02N(Rj)Rk, and N(Rj)S02Rk;
and wherein R3 is independently optionally substituted by one or more substituent groups selected from fluoro, chloro, trifluoromethyl, trifluoromethoxy, cyano, nitro, hydroxy, amino, carboxy, carbamoyl, sulphamoyl, (1- 4C)alkyl, (1-4C)alkoxy, S(0)qCH3 (where q is 0, 1 or 2), methylamino or dimethylamino, aryl, aryl(1-2C)alkyl, heteroaryl, heteroaryl(1-2C)alkyl, (3-8C)heterocyclyl, (3- 8C)heterocyclyl(1-2C)alkyl, (3-8C)cycloalkyl, or (3- 8C)cycloalkyl(1-2C)alkyl;
or R2 and X1 or R2 and X2 are linked, such that when they are taken in combination with the carbon atoms to which they are attached, they collectively form a 5-12 membered heteroaryl or heterocycle that is optionally substituted with one or more R4 substituents;
and wherein each R4 is independently selected from halo, cyano, isocyano, nitro, hydroxy, (1-6C)alkyl, (1-6C)haloalkyl, (2-4C)alkenyl, (2- 4C)alkynyl, (1-8C)heteroalkyl, aryl, aryl(1-2C)alkyl, heteroaryl, heteroaryl(1-2C)alkyl, (3-8C)heterocyclyl, (3-8C)heterocyclyl(1-2C)alkyl,
(3-8C)cycloalkyl, (3-8C)cycloalkyl(1-2C)alkyl, NRmRn, OR0, C(0)Rm, C(0)0Rm, 0C(0)Rm, N(Rm)ORn, N(Rm)C(0)0Rn, C(0)N(Rm)Rn,
C(Rm)=N(Rn), N(Rm)C(0)Rn, S(0)PRm (where p is 0, 1 or 2), S02N(Rm)Rn, and N(Rm)S02Rn;
and wherein each R4 is independently optionally substituted with one or more groups selected from fluoro, chloro, trifluoromethyl, trifluoromethoxy, cyano, nitro, hydroxy, amino, carboxy, carbamoyl, sulphamoyl, (1-4C)alkyl, (2-4C)alkenyl, (2-4C)alkynyl, (1-4C)alkoxy, S(0)qCH3 (where q is 0, 1 or 2), methylamino or dimethylamino, aryl, aryl(1-2C)alkyl, heteroaryl, heteroaryl(1-2C)alkyl, (3-8C)heterocyclyl, (3- 8C)heterocyclyl(1-2C)alkyl, (3-8C)cycloalkyl, and (3-8C)cycloalkyl(1- 2C)alkyl;
X3 and X4 are independently selected from hydroxy, ORp, NRqRr and a group of formula (A) shown above;
or X3 and X4 are linked, such that when they are taken in combination with the carbon atom to which they are attached, they collectively form a 4-6 membered heterocycle that is optionally substituted with one or more R5 substituents;
and wherein each R5 is independently selected from fluoro, chloro, trifluoromethyl, trifluoromethoxy, cyano, nitro, hydroxy, oxo, amino, carboxy, carbamoyl, sulphamoyl, (1-6C)alkyl, (2-6C)alkenyl, (2- 6C)alkynyl, (1-4C)alkoxy, S(0)qCH3 (where q is 0, 1 or 2), methylamino or dimethylamino, aryl, aryl(1-2C)alkyl, heteroaryl, heteroaryl(1-2C)alkyl, (3- 8C)heterocyclyl, (3-8C)heterocyclyl(1-2C)alkyl, (3-8C)cycloalkyl, and (3- 8C)cycloalkyl(1-2C)alkyl;
each Ra to Rr is independently selected from hydrogen, fluoro, chloro, trifluoromethyl, trifluoromethoxy, cyano, nitro, hydroxy, amino, carboxy, carbamoyl, sulphamoyl, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (1-4C)alkoxy, S(0)qCH3 (where q is 0, 1 or 2), methylamino or dimethylamino, aryl, aryl(1-2C)alkyl, heteroaryl,
heteroaryl(1-2C)alkyl, (3-8C)heterocyclyl, (3-8C)heterocyclyl(1-2C)alkyl, (3- 8C)cycloalkyl, and (3-8C)cycloalkyl(1-2C)alkyl;
and wherein each Ra to Rr is independently optionally substituted with one or more groups selected from fluoro, chloro, trifluoromethyl, trifluoromethoxy, cyano, nitro, hydroxy, amino, carboxy, carbamoyl, sulphamoyl, (1-4C)alkyl, (2-4C)alkenyl, (2-4C)alkynyl, (1-4C)alkoxy, S(0)qCH3 (where q is 0, 1 or 2), methylamino or dimethylamino, aryl, aryl(1-2C)alkyl, heteroaryl, heteroaryl(1-2C)alkyl, (3-8C)heterocyclyl, (3-
8C)heterocyclyl(1-2C)alkyl, (3-8C)cycloalkyl, and (3-8C)cycloalkyl(1- 2C)alkyl.
2. The compound for use according to claim 1 , wherein the compound has a structure according to formula (G), (IG) or (IN’) shown below:
3. The compound for use according to claim 1 or 2, wherein Ri is selected from hydrogen, halo, hydroxy, (1-6C)alkyl, (1-6C)haloalkyl, (2-4C)alkenyl, (2-4C)alkynyl, (1- 8C)heteroalkyl, aryl, aryl(1-2C)alkyl, heteroaryl, heteroaryl(1-2C)alkyl, (3- 8C)heterocyclyl, (3-8C)heterocyclyl(1-2C)alkyl, (3-8C)cycloalkyl, (3-8C)cycloalkyl(1- 2C)alkyl, NRaRb and ORc,
wherein Ri is optionally substituted by one or more substituent groups selected from (1-4C)alkyl and (1-3C)alkoxy.
4. The compound for use according to claim 3, wherein Ri is selected from hydroxy,
NRaRb, ORc or any one of the following:
5. The compound for use according to any preceding claim, wherein Ra and Rb are
independently selected from hydrogen, (1-6C)alkyl, phenyl or any one of the following:
6. The compound for use according to any one of claims 1 to 4, wherein Ra is hydrogen or (1-2C)alkyl and Rb is selected from (1-2C)alkyl, N(Me)2, benzyl, cyclopropyl or any one of the following:
wherein each of the said benzyl groups is optionally substituted with one substituent group selected from fluoro, chloro, hydroxy and trifluoromethyl.
7. The compound for use according to any preceding claim, wherein Rc is (1-6C)alkyl.
8. The compound for use according to any preceding claim, wherein R2 is selected from hydrogen, (1-6C)alkyl, (3-8C)heterocyclyl, (3-8C)heterocyclyl(1-2C)alkyl, (3- 8C)cycloalkyl, (3-8C)cycloalkyl(1-2C)alkyl and C(Rd)=N(Re).
9. The compound for use according to any preceding claim, wherein each Rd is
independently selected from hydrogen and (1-6C)alkyl.
10. The compound for use according to any preceding claim, wherein each Re is
independently selected from hydrogen, (1-4C)alkyl and N-piperazinyl, any of which is optionally substituted with cyclopentyl.
11. The compound for use according to any preceding claim, wherein Xi is O.
12. The compound for use according to any preceding claim, wherein X2 is hydroxy or a group of formula (A), wherein
n is 1 ;
Rh and R, are independently selected from hydrogen and (1-2C)alkyl;
R3 is selected from hydroxy, (1-6C)alkyl, (3-8C)heterocyclyl, (3-8C)heterocyclyl(1- 2C)alkyl, NRjRk and ORi,
wherein R3 is optionally substituted by one or more substituent groups selected from (1-4C)alkyl and (1-3C)alkoxy.
13. The compound for use according to any preceding claim, wherein Rj and Rk are independently selected from hydrogen, (1-6C)alkyl, phenyl and 5-6 membered N-linked heterocyclyl.
14. The compound for use according to any preceding claim, wherein Ri is (1-6C)alkyl.
15. The compound for use according to any preceding claim, wherein R2 and Xi or R2 and X2 are linked, such that when they are taken in combination with the carbon atoms to which they are attached, they collectively form a 9-11 membered fused heterobicycle or spiro bi-cyclic heterocyclic ring system containing 1 , 2 or 3 heteroatoms selected from O and N, wherein said 9-11 membered fused or spiro heterobicycle is optionally substituted with one or more R4 substituents.
16. The compound for use according to any preceding claim, wherein each R4 is
independently selected from hydroxy, (1-6C)alkyl and (3-8C)heterocyclyl,
wherein each R4 is independently optionally substituted with one or more groups, (1-4C)alkyl.
17. The compound for use according to any preceding claim, wherein X3 and X4 are linked, such that when they are taken in combination with the carbon atom to which they are attached, they collectively form a 4-6 membered heterocycle containing 1 or 2 heteroatoms selected from O and N, wherein the 4-6 membered heterocycle is optionally substituted with one or more R5 substituents.
18. The compound for use according to any preceding claim, wherein each R5 is
independently selected from fluoro, chloro, hydroxy, oxo, amino, (1-3C)alkyl and (1- 3C)alkoxy.
19. The compound for use according to any preceding claim, wherein the compound has any one of the following structures:
20. The compound for use according to any preceding claim, wherein the infection caused by rifampicin-resistant bacteria is tuberculosis.
21. A compound of formula (I), (II) or (III) as defined in any preceding claim, or a
pharmaceutically acceptable salt, hydrate or solvate thereof,
with the proviso that, in formula (I), when Ri is hydroxy and R2 is hydrogen, Xi is not O.
22. A pharmaceutical composition comprising a compound as claimed in claim 21 , or a
pharmaceutically acceptable salt or solvate thereof, and one or more pharmaceutically acceptable excipients or carriers.
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| GBGB1812078.2A GB201812078D0 (en) | 2018-07-24 | 2018-07-24 | Novel compounds and their uses |
| GB1812078.2 | 2018-07-24 |
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| US11325920B2 (en) | 2018-01-24 | 2022-05-10 | The Rockefeller University | Antibacterial compounds, compositions thereof, and methods using same |
| US11339184B2 (en) * | 2019-07-23 | 2022-05-24 | The Rockefeller University | Antibacterial compounds, compositions thereof, and methods using same |
| EP4296674A1 (en) | 2022-06-20 | 2023-12-27 | Université Toulouse III - Paul Sabatier | Innovative molecules decreasing virulence of mycobacterium for the treatment of tuberculosis |
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| WO2019147753A1 (en) * | 2018-01-24 | 2019-08-01 | The Rockefeller University | Antibacterial compounds, compositions thereof, and methods using same |
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