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EP-4739390-A1 - 2-(1H-INDOL-4-YL)METHYL)2H-INDAZOLE DERIVATIVES AS FACTOR B INHIBITORS

EP4739390A1EP 4739390 A1EP4739390 A1EP 4739390A1EP-4739390-A1

Abstract

The present invention relates to compounds of formula (I) possessing an indole moiety linked to an indazole moiety, to compounds having similar core structures, and to associated salts, solvates, prodrugs and pharmaceutical compositions. The present invention further relates to methods of synthesising such compounds, and to the use of such compounds in the treatment and prevention of medical disorders and diseases, most especially by Factor B inhibition.

Inventors

  • CHRISTOPHER, JOHN ANDREW
  • SHANNON, Jonathan Martin
  • STRUTT, Ian Richard
  • HUSSAIN, Klara Abdul
  • BLUNT, CHRISTOPHER EDWARD
  • WYATT, PAUL GRAHAM
  • AITKEN, Lewis Scott
  • MATHIEU, Arnaud Cyrille
  • HORNSBY, Thomas William
  • COOPER, MARTIN EDWARD
  • WAUGH, Thomas Michael
  • Mills, Mark
  • AHER, Ravindra Dattatray

Assignees

  • Sitala Bio Ltd

Dates

Publication Date
20260513
Application Date
20240704

Claims (20)

  1. - 404 - Claims 1. A compound of Formula (I): or a pharmaceutically acceptable salt and/or solvate and/or prodrug thereof; wherein: R 1 is hydrogen; R 2 is selected from hydrogen or a halo group; R 3 is selected from hydrogen or a halo, -SO 2 NH 2 , or a C 1 -C 8 saturated or unsaturated hydrocarbyl group, wherein the hydrocarbyl group may be straight- chained or branched, or be or include one or more cyclic groups, wherein the hydrocarbyl group may optionally be substituted with one or more halo groups, wherein the hydrocarbyl group may optionally include one or more heteroatoms each independently selected from N, O and S in its carbon skeleton, and wherein any -S- moiety may optionally be substituted with one or two groups each independently selected from oxo (=O) and =NH to form a -SO-, -SO2-, -S(=NH)- or -SO(=NH)- moiety; R 4 is selected from hydrogen or a halo, -OH, -NH 2 , -SO 2 NH 2 , or a C 1 -C 8 saturated or unsaturated hydrocarbyl group, wherein the hydrocarbyl group may be straight-chained or branched, or be or include one or more cyclic groups, wherein the hydrocarbyl group may optionally be substituted with one or more halo groups, wherein the hydrocarbyl group may optionally include one or more heteroatoms each independently selected from N, O and S in its carbon skeleton, and wherein any -S- moiety may optionally be substituted with one or two groups each independently selected from oxo (=O) and =NH to form a -SO-, -SO 2 -, -S(=NH)- or -SO(=NH)- moiety; R 5 is selected from hydrogen or a halo group; R 6 is selected from hydrogen or a halo, -R 60 or -OR 60 group, wherein R 60 is selected from a C1-C4 alkyl, C3-C4 cycloalkyl, C1-C4 fluoroalkyl or C3-C4 fluorocycloalkyl group; R 7 and R 8 are each independently selected from hydrogen or a fluoro or a C 1 - C12 saturated or unsaturated hydrocarbyl group, wherein the hydrocarbyl group may be straight-chained or branched, or be or include one or more cyclic groups, wherein the hydrocarbyl group may optionally be substituted with one or more halo groups, wherein the hydrocarbyl group may optionally include one or more heteroatoms each independently selected from N, O and S in its carbon skeleton, and wherein any -S- moiety may optionally be substituted with one or two groups each independently selected from oxo (=O) and =NH to form a -SO-, -SO2-, -S(=NH)- or -SO(=NH)- moiety, provided that the atom of any hydrocarbyl group of R 7 or R 8 that is directly attached to the reminder of the molecule is a carbon atom; or R 7 and R 8 together with the carbon atom to which they are attached form a 3- to 10-membered cyclic group, such that each ring atom of the cyclic group that is directly attached to the carbon atom to which R 7 and R 8 are attached is a ring carbon atom, wherein the cyclic group may optionally be substituted with one or more substituents each independently selected from a halo, oxo (=O), -OH, -NH2 or a C1-C4 saturated or unsaturated hydrocarbyl group, wherein the hydrocarbyl group may be straight-chained or branched, or be or include a cyclic group, wherein the hydrocarbyl group may optionally be substituted with one or more halo groups, and wherein the hydrocarbyl group may optionally include one or two heteroatoms each independently selected from N and O in its carbon skeleton; or R 3 and R 7 , or R 4 and R 7 , together form a C 1 -C 6 saturated or unsaturated hydrocarbylene group, wherein the hydrocarbylene group may be straight-chained or branched, or be or include one or more cyclic groups, wherein the hydrocarbylene group may optionally be substituted with one or more halo groups, wherein the hydrocarbylene group may optionally include one or more heteroatoms each independently selected from N, O and S in its carbon skeleton, and wherein any -S- moiety may optionally be substituted with one or two groups each independently selected from oxo (=O) and =NH to form a -SO-, -SO 2 -, -S(=NH)- or -SO(=NH)- moiety, provided that the atom of the hydrocarbylene group that is directly attached to the carbon atom to which R 8 is attached is a carbon atom; X 9 is N or CR 9 ; R 9 is hydrogen or a halo, -OH, -SH, -NH 2 , -SO 2 NH 2 , or a C 1 -C 12 saturated or unsaturated hydrocarbyl group, wherein the hydrocarbyl group may be straight- chained or branched, or be or include one or more cyclic groups, wherein the hydrocarbyl group may optionally be substituted with one or more halo groups, wherein the hydrocarbyl group may optionally include one or more heteroatoms each independently selected from N, O and S in its carbon skeleton, and wherein any -S- moiety may optionally be substituted with one or two groups each independently selected from oxo (=O) and =NH to form a -SO-, -SO2-, -S(=NH)- or -SO(=NH)- moiety; X 10 is N or CR 10 ; X 11 is N or CR 11 ; X 12 is N or CR 12 ; X 13 is N or CR 13 ; no more than two of X 10 , X 11 , X 12 and X 13 are N; and each R 10 , R 11 , R 12 and R 13 is independently selected from hydrogen or a halo, -OH, -SH, -NH2, -SO2NH2, or a C1-C12 saturated or unsaturated hydrocarbyl group, wherein the hydrocarbyl group may be straight-chained or branched, or be or include one or more cyclic groups, wherein the hydrocarbyl group may optionally be substituted with one or more halo groups, wherein the hydrocarbyl group may optionally include one or more heteroatoms each independently selected from N, O and S in its carbon skeleton, and wherein any -S- moiety may optionally be substituted with one or two groups each independently selected from oxo (=O) and =NH to form a -SO-, -SO2-, -S(=NH)- or -SO(=NH)- moiety.
  2. 2. A compound as claimed in claim 1, or a pharmaceutically acceptable salt and/or solvate and/or prodrug thereof, wherein R 2 is selected from hydrogen or a fluoro, chloro or bromo group.
  3. 3. A compound as claimed in claim 1 or claim 2, or a pharmaceutically acceptable salt and/or solvate and/or prodrug thereof, wherein R 3 is selected from hydrogen or a fluoro, chloro, bromo, -R 30 , -CN, -CHO, -COR 30 , -CO2H or -CO2R 30 group, wherein R 30 is selected from a C 1 -C 6 alkyl, C 1 -C 6 fluoroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 fluoroalkenyl or -R 31 group, wherein R 31 is a 3- to 6-membered monocyclic group, wherein the 3- to 6- membered monocyclic group may optionally be substituted with one or more fluoro, chloro and/or bromo groups, and/or with one or two groups R 32 , wherein each R 32 is independently selected from a methyl or a fluoromethyl group, provided that the group R 3 , including any optional substituents, contains no more than 8 carbon atoms.
  4. 4. A compound of Formula (II): Formula (II) or a pharmaceutically acceptable salt and/or solvate and/or prodrug thereof; wherein: R 1 is hydrogen; R 4 is selected from hydrogen or a halo, -OH, -NH 2 , -SO 2 NH 2 , or a C 1 -C 8 saturated or unsaturated hydrocarbyl group, wherein the hydrocarbyl group may be straight-chained or branched, or be or include one or more cyclic groups, wherein the hydrocarbyl group may optionally be substituted with one or more halo groups, wherein the hydrocarbyl group may optionally include one or more heteroatoms each independently selected from N, O and S in its carbon skeleton, and wherein any -S- moiety may optionally be substituted with one or two groups each independently selected from oxo (=O) and =NH to form a -SO-, -SO2-, -S(=NH)- or -SO(=NH)- moiety; R 5 is selected from hydrogen or a halo group; R 6 is selected from hydrogen or a halo, -R 60 or -OR 60 group, wherein R 60 is selected from a C1-C4 alkyl, C3-C4 cycloalkyl, C1-C4 fluoroalkyl or C3-C4 fluorocycloalkyl group; R 7 and R 8 are each independently selected from hydrogen or a fluoro or a C 1 - C12 saturated or unsaturated hydrocarbyl group, wherein the hydrocarbyl group may be straight-chained or branched, or be or include one or more cyclic groups, wherein the hydrocarbyl group may optionally be substituted with one or more halo groups, wherein the hydrocarbyl group may optionally include one or more heteroatoms each independently selected from N, O and S in its carbon skeleton, and wherein any -S- moiety may optionally be substituted with one or two groups each independently selected from oxo (=O) and =NH to form a -SO-, -SO2-, -S(=NH)- or -SO(=NH)- moiety, provided that the atom of any hydrocarbyl group of R 7 or R 8 that is directly attached to the reminder of the molecule is a carbon atom; or R 7 and R 8 together with the carbon atom to which they are attached form a 3- to 10-membered cyclic group, such that each ring atom of the cyclic group that is directly attached to the carbon atom to which R 7 and R 8 are attached is a ring carbon atom, wherein the cyclic group may optionally be substituted with one or more substituents each independently selected from a halo, oxo (=O), -OH, -NH2 or a C1-C4 saturated or unsaturated hydrocarbyl group, wherein the hydrocarbyl group may be straight-chained or branched, or be or include a cyclic group, wherein the hydrocarbyl group may optionally be substituted with one or more halo groups, and wherein the hydrocarbyl group may optionally include one or two heteroatoms each independently selected from N and O in its carbon skeleton; X 9 is N or CR 9 ; R 9 is hydrogen or a halo, -OH, -SH, -NH 2 , -SO 2 NH 2 , or a C 1 -C 12 saturated or unsaturated hydrocarbyl group, wherein the hydrocarbyl group may be straight- chained or branched, or be or include one or more cyclic groups, wherein the hydrocarbyl group may optionally be substituted with one or more halo groups, wherein the hydrocarbyl group may optionally include one or more heteroatoms each independently selected from N, O and S in its carbon skeleton, and wherein any -S- moiety may optionally be substituted with one or two groups each independently selected from oxo (=O) and =NH to form a -SO-, -SO 2 -, -S(=NH)- or -SO(=NH)- moiety; X 10 is N or CR 10 ; X 11 is N or CR 11 ; X 12 is N or CR 12 ; X 13 is N or CR 13 ; no more than two of X 10 , X 11 , X 12 and X 13 are N; each R 10 , R 11 , R 12 and R 13 is independently selected from hydrogen or a halo, -OH, -SH, -NH 2 , -SO 2 NH 2 , or a C 1 -C 12 saturated or unsaturated hydrocarbyl group, wherein the hydrocarbyl group may be straight-chained or branched, or be or include one or more cyclic groups, wherein the hydrocarbyl group may optionally be substituted with one or more halo groups, wherein the hydrocarbyl group may optionally include one or more heteroatoms each independently selected from N, O and S in its carbon skeleton, and wherein any -S- moiety may optionally be substituted with one or two groups each independently selected from oxo (=O) and =NH to form a -SO-, -SO2-, -S(=NH)- or -SO(=NH)- moiety; each R 14 and R 15 is independently selected from hydrogen or a C1-C4 alkyl, C3- C 4 cycloalkyl, C 1 -C 4 fluoroalkyl or C 3 -C 4 fluorocycloalkyl group, or R 14 and R 15 together with the carbon atom to which they are attached form a 3- to 6-membered cyclic group, wherein the cyclic group may optionally be substituted with one or more substituents each independently selected from a fluoro, -OH, oxo (=O), methyl or ethyl group, wherein any methyl or ethyl group may optionally be fluoro substituted; R 16 is selected from hydrogen or a fluoro, -SO2NH2, or a C1-C8 saturated or unsaturated hydrocarbyl group, wherein the hydrocarbyl group may be straight- chained or branched, or be or include one or more cyclic groups, wherein the hydrocarbyl group may optionally be substituted with one or more halo groups, wherein the hydrocarbyl group may optionally include one or more heteroatoms each independently selected from N, O and S in its carbon skeleton, and wherein any -S- moiety may optionally be substituted with one or two groups each independently selected from oxo (=O) and =NH to form a -SO-, -SO 2 -, -S(=NH)- or -SO(=NH)- moiety; R 17 is selected from hydrogen or a fluoro, C1-C4 alkyl, C3-C4 cycloalkyl, C1-C4 fluoroalkyl or C 3 -C 4 fluorocycloalkyl group; or R 16 and R 17 together with the carbon atom to which they are attached form a 3- to 6-membered cyclic group, wherein the cyclic group may optionally be substituted with one or more substituents each independently selected from a fluoro, -OH, oxo (=O), methyl or ethyl group, wherein any methyl or ethyl group may optionally be fluoro substituted; or R 17 and R 7 , or R 4 and R 7 , together form a C1-C6 saturated or unsaturated hydrocarbylene group, wherein the hydrocarbylene group may be straight-chained or branched, or be or include one or more cyclic groups, wherein the hydrocarbylene group may optionally be substituted with one or more halo groups, wherein the hydrocarbylene group may optionally include one or more heteroatoms each independently selected from N, O and S in its carbon skeleton, and wherein any -S- moiety may optionally be substituted with one or two groups each independently selected from oxo (=O) and =NH to form a -SO-, -SO 2 -, -S(=NH)- or -SO(=NH)- moiety, provided that the atom of the hydrocarbylene group that is directly attached to the carbon atom to which R 8 is attached is a carbon atom.
  5. 5. A compound as claimed in claim 4, or a pharmaceutically acceptable salt and/or solvate and/or prodrug thereof, wherein each R 14 and R 15 is independently selected from hydrogen or a C1-C3 alkyl, cyclopropyl, C1-C3 fluoroalkyl or fluorocyclopropyl group, or R 14 and R 15 together with the carbon atom to which they are attached form a cyclopropyl or a cyclobutyl group, wherein the cyclopropyl or cyclobutyl group may optionally be substituted with one or more fluoro groups.
  6. 6. A compound as claimed in claim 4 or claim 5, or a pharmaceutically acceptable salt and/or solvate and/or prodrug thereof, wherein: R 16 is selected from hydrogen or a fluoro, -R 160 , -CN, -CHO, -COR 160 , -CO2H or -CO2R 160 group, provided that R 16 , including any optional substituents, contains no more than 8 carbon atoms; R 160 is selected from a C 1 -C 6 alkyl, C 1 -C 6 fluoroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 fluoroalkenyl or -R 161 group; R 161 is a 3- to 6-membered monocyclic group, wherein the 3- to 6-membered monocyclic group may optionally be substituted with one or more fluoro, chloro and/or bromo groups, and/or with one or two groups R 162 ; each R 162 is independently selected from a methyl or a fluoromethyl group; and R 17 is selected from hydrogen or a fluoro, C1-C3 alkyl, cyclopropyl, C1-C3 fluoroalkyl or fluorocyclopropyl group; or R 16 and R 17 together with the carbon atom to which they are attached form a 3- to 5-membered saturated monocyclic group, wherein the saturated monocyclic group may optionally be substituted with one or more fluoro groups and/or one or two substituents each independently selected from oxo (=O) or a methyl or fluoromethyl group.
  7. 7. A compound as claimed in any one of claims 1 to 6, or a pharmaceutically acceptable salt and/or solvate and/or prodrug thereof, wherein: R 4 is selected from a fluoro, chloro, bromo, -OH, -OR 41 , -N(R 42 )2, -SO2-R 41 , -SO2-N(R 42 )2, -L 4 -OH, -L 4 -OR 41 , -L 4 -N(R 42 )2, -L 4 -SO2-R 41 , -L 4 -SO2-N(R 42 )2, -O-L 4 -OH, -O-L 4 -OR 41 , -O-L 4 -N(R 42 ) 2 , -O-L 4 -SO 2 -R 41 , -O-L 4 -SO 2 -N(R 42 ) 2 , -NR 43 -L 4 -OH, -NR 43 -L 4 -OR 41 , -NR 43 -L 4 -N(R 42 ) 2 , -NR 43 -L 4 -SO 2 -R 41 , -NR 43 -L 4 -SO 2 -N(R 42 ) 2 , -SO2-L 4 -OH, -SO2-L 4 -OR 41 , -SO2-L 4 -N(R 42 )2, -R 44 , -R 45 or -L 4 -R 45 group; R 41 is selected from a -R 44 or -R 45 group; each R 42 is independently selected from hydrogen or a -R 44 or -R 45 group, or any two R 42 may, together with the nitrogen atom to which they are attached, form a 3- to 6-membered saturated monocyclic heterocyclic group, wherein the 3- to 6- membered saturated monocyclic heterocyclic group may optionally be substituted with one or two oxo (=O) groups and/or with one or more fluoro, methyl and/or fluoromethyl groups; L 4 is a straight-chained alkylene group, wherein the straight-chained alkylene group optionally includes one or two heteroatoms each independently selected from O and N in its carbon skeleton, wherein L 4 has a chain length of from 1 to 4 atoms, and wherein L 4 may optionally be substituted with one or two oxo (=O) groups and/or with one or more groups R L4 ; each R L4 is independently selected from a fluoro, methyl or fluoromethyl group; or any R L4 and R 41 , or any R L4 and any R 42 , may together with the atoms to which they are attached, form a 3- to 6-membered saturated monocyclic heterocyclic group, wherein the 3- to 6-membered saturated monocyclic heterocyclic group may optionally be substituted with one or two oxo (=O) groups and/or with one or more fluoro, methyl and/or fluoromethyl groups; R 43 is selected from hydrogen or a -R 44 group; each R 44 is independently selected from a C1-C4 alkyl or C3-C6 cycloalkyl group, wherein the C1-C4 alkyl or C3-C6 cycloalkyl group may optionally be substituted with one or more fluoro groups and/or one or two oxo (=O) groups; and each R 45 is independently selected from a phenyl or a 5- or 6-membered heteroaryl group, wherein the phenyl or the 5- or 6-membered heteroaryl group may optionally be substituted with one or more groups each independently selected from fluoro, chloro and bromo, and/or with one or two groups each independently selected from methyl (Me), -CN, -OH, -OMe, -NH 2 , -NHMe, and -NMe 2 , wherein any methyl group of R 45 may optionally be fluoro substituted; provided that R 4 , including any optional substituents, contains no more than 8 carbon atoms.
  8. 8. A compound as claimed in any one of claims 1 to 7, or a pharmaceutically acceptable salt and/or solvate and/or prodrug thereof, wherein R 5 is selected from hydrogen or a fluoro, chloro or bromo group.
  9. 9. A compound as claimed in any one of claims 1 to 8, or a pharmaceutically acceptable salt and/or solvate and/or prodrug thereof, wherein: R 6 is selected from a chloro, bromo, -R 60 or -OR 60 group; and R 60 is selected from a C 1 -C 3 alkyl, cyclopropyl, C 1 -C 3 fluoroalkyl or fluorocyclopropyl group.
  10. 10. A compound as claimed in any one of claims 1 to 9, or a pharmaceutically acceptable salt and/or solvate and/or prodrug thereof, wherein: R 7 is selected from hydrogen or a fluoro, -CN, -COOH, -COOR 71 , -CO-N(R 72 )2, -L 7 -COOH, -L 7 -COOR 71 , -L 7 -CO-N(R 72 ) 2 , -L 7 -OH, -L 7 -OR 71 , -L 7 -N(R 72 ) 2 , -R 73 , -R 74 or -L 7 -R 74 group, provided that R 7 , including any optional substituents, contains no more than 12 carbon atoms, and that the atom of R 7 that is directly attached to the reminder of the molecule is a carbon, hydrogen or fluorine atom; R 71 is selected from a -R 73 or -R 74 group; each R 72 is independently selected from hydrogen or a -R 73 or -R 74 group, or any two R 72 may, together with the nitrogen atom to which they are attached, form a 3- to 6-membered saturated monocyclic heterocyclic group, wherein the 3- to 6- membered saturated monocyclic heterocyclic group may optionally be substituted with one or two oxo (=O) groups and/or with one or more fluoro, methyl and/or fluoromethyl groups; L 7 is a straight-chained alkylene or alkenylene group, wherein the straight- chained alkylene or alkenylene group optionally includes one or two heteroatoms each independently selected from O and N in its carbon skeleton, wherein L 7 has a chain length of from 1 to 4 atoms, and wherein L 7 may optionally be substituted with one or two oxo (=O) groups and/or with one or more groups R L7 ; each R L7 is independently selected from a fluoro, methyl or fluoromethyl group; or any two R L7 may together with the atom or atoms to which they are attached form a 3- to 6-membered monocyclic group, wherein the 3- to 6-membered monocyclic group is saturated or monounsaturated, and wherein the 3- to 6-membered monocyclic group may optionally be substituted with one or two oxo (=O) groups and/or with one or more fluoro, methyl and/or fluoromethyl groups; or any R L7 and R 71 , or any R L7 and any R 72 , may together with the atoms of the -L 7 -COOR 71 , -L 7 -CO-N(R 72 ) 2 , -L 7 -OR 71 or -L 7 -N(R 72 ) 2 group to which they are attached, form a 3- to 6-membered monocyclic heterocyclic group, wherein the 3- to 6- membered monocyclic heterocyclic group is saturated or monounsaturated, and wherein the 3- to 6-membered monocyclic heterocyclic group may optionally be substituted with one or two oxo (=O) groups and/or with one or more fluoro, methyl and/or fluoromethyl groups; each R 73 is independently selected from a C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 3 -C 6 cycloalkyl or C5-C6 cycloalkenyl group, wherein the C1-C4 alkyl, C2-C4 alkenyl, C3-C6 cycloalkyl or C5-C6 cycloalkenyl group may optionally be substituted with one or more fluoro groups and/or one or two oxo (=O) groups; each R 74 is independently selected from a phenyl or a 5- or 6-membered heteroaryl group, wherein the phenyl or the 5- or 6-membered heteroaryl group may optionally be substituted with one or more groups each independently selected from fluoro, chloro and bromo, and/or with one or two groups each independently selected from methyl (Me), -CN, -OH, -OMe, -NH 2 , -NHMe, and -NMe 2 , wherein any methyl group of R 74 may optionally be fluoro substituted; and R 8 is selected from a hydrogen or a fluoro, methyl or fluoromethyl group; or R 7 and R 8 together form a group -L 78 -, wherein -L 78 - is selected from a -CH 2 -CH 2 -, -CH 2 -CH 2 -CH 2 -, -CH 2 -NH-CH 2 -, -CH 2 -O-CH 2 -, -CH 2 -CH 2 -CH 2 -CH 2 -, -CH2-CH2-NH-CH2-, -CH2-CH2-O-CH2-, -CH2-NH-CH2-CH2- or -CH2-O-CH2-CH2- group, wherein -L 78 - may optionally be substituted with one or more fluoro groups and/or one or two substituents each independently selected from an oxo (=O), -CN, methyl (Me), -OH, -OMe, -NH 2 , -NHMe or -NMe 2 group, and wherein any methyl group of a -L 78 - substituent may optionally be fluoro substituted.
  11. 11. A compound as claimed in any one of claims 1 to 10, or a pharmaceutically acceptable salt and/or solvate and/or prodrug thereof, wherein X 9 is CR 9 .
  12. 12. A compound as claimed in any one of claims 1 to 11, or a pharmaceutically acceptable salt and/or solvate and/or prodrug thereof, wherein R 9 is selected from hydrogen or a fluoro, chloro, bromo, -OH, -NH 2 or a C 1 -C 6 saturated or unsaturated hydrocarbyl group, wherein the hydrocarbyl group may be straight-chained or branched, or be or include a cyclic group, wherein the hydrocarbyl group may optionally be substituted with one or more fluoro, chloro and/or bromo groups, and wherein the hydrocarbyl group may optionally include one or two heteroatoms each independently selected from N and O in its carbon skeleton.
  13. 13. A compound as claimed in any one of claims 1 to 12, or a pharmaceutically acceptable salt and/or solvate and/or prodrug thereof, wherein: X 10 is N or CR 10 ; X 11 is CR 11 and X 12 is CR 12 , or X 11 is CR 11 and X 12 is N, or X 11 is N and X 12 is CR 12 ; X 13 is N or CR 13 ; and no more than one of X 10 , X 11 , X 12 and X 13 is N.
  14. 14. A compound as claimed in any one of claims 1 to 13, or a pharmaceutically acceptable salt and/or solvate and/or prodrug thereof, wherein: one of R 11 and R 12 is present and selected from a fluoro, chloro, bromo, fluoromethyl, methoxy, fluoromethoxy, -CH2OH, -CN, -COOH, -CONH2 or -C(=NH)NH 2 group; one remaining R 10 , R 11 , R 12 or R 13 is independently selected from hydrogen or a fluoro, chloro, bromo, -OH, -SH, -NH2, -SO2NH2, or a C1-C10 saturated or unsaturated hydrocarbyl group, wherein the hydrocarbyl group may be straight-chained or branched, or be or include one or two cyclic groups, wherein the hydrocarbyl group may optionally be substituted with one or more fluoro, chloro and/or bromo groups, wherein the hydrocarbyl group may optionally include one, two, three, four, five or six heteroatoms each independently selected from N, O and S in its carbon skeleton, and wherein one -S- moiety may optionally be substituted with one or two groups each independently selected from oxo (=O) and =NH to form a -SO-, -SO 2 -, -S(=NH)- or -SO(=NH)- moiety; and if present each further remaining R 10 , R 11 , R 12 or R 13 is independently selected from hydrogen or a fluoro, chloro or bromo group.
  15. 15. A compound as claimed in claim 1, or a pharmaceutically acceptable salt and/or solvate and/or prodrug thereof, wherein the compound is a compound of Formula (Ia): wherein: R 1 is hydrogen; R 2 is hydrogen; R 3 is selected from hydrogen or a fluoro, chloro, bromo, -R 30 , -R 31 , -CN, -CHO, -COR 30 , -CO2H or -CO2R 30 group; R 30 is selected from a methyl or fluoromethyl group; R 31 is a 5-membered heteroaryl group, wherein the 5-membered heteroaryl group may optionally be substituted with one or more fluoro, chloro and/or bromo groups, and/or with one or two groups R 32 ; each R 32 is independently selected from a methyl or fluoromethyl group; R 4 is selected from a fluoro, chloro, bromo, -OR 44 , -CON(R 42 ) 2 , -SO 2 -R 44 , -SO2-N(R 42 )2, -O-CH2-CH2-OR 44 , -O-CH2-CH2-N(R 42 )2, or -R 44 group, each R 42 is independently selected from hydrogen or a -R 44 group; each R 44 is independently selected from a C1-C3 alkyl, cyclopropyl, C1-C3 fluoroalkyl or fluorocyclopropyl group; R 5 is hydrogen or a fluoro, chloro or bromo group; R 6 is a chloro, bromo, methyl or a fluoromethyl group; R 7 is selected from hydrogen or a fluoro, -COOH, -COOR 75 , -CONH2, -CONHR 75 , -CON(R 75 ) 2 , -L 71 -COOH, -L 71 -COOR 75 , -L 71 -CONH 2 , -L 71 -CONHR 75 , -L 71 -CON(R 75 )2, -L 71 -OH, -L 71 -OR 75 or -R 75 group; each -L 71 - is independently selected from a -CH2-, -CHMe-, -CMe2-, , -CH 2 -CH 2 -, -CH 2 -CHMe-, -CH 2 -CMe 2 -, -CHMe-CH 2 -, -CHMe-CHMe-, -CHMe-CMe 2 -, -CMe 2 -CH 2 -, -CMe 2 -CHMe-, -CMe 2 -CMe 2 -, , , , -CH2-CH2-CH2-, -CHMe-CH2-CH2-, -CH2-CHMe-CH2-, -CH2-CH2-CHMe-, -CMe2-CH2-CH2-, -CHMe-CHMe-CH2-, -CHMe-CH2-CHMe-, -CH2-CMe2-CH2-, -CH 2 -CHMe-CHMe-, -CH 2 -CH 2 -CMe 2 -, -CMe 2 -CHMe-CH 2 -, -CMe 2 -CH 2 -CHMe-, -CHMe-CHMe 2 -CH 2 -, -CHMe-CHMe-CHMe-, -CHMe-CH 2 -CMe 2 -, -CH 2 -CMe 2 -CHMe-, -CH2-CHMe-CMe2-, -CMe2-CMe2-CH2-, -CMe2-CHMe-CHMe-, -CMe2-CH2-CMe2-, -CHMe-CMe 2 -CHMe-, -CHMe-CHMe-CMe 2 -, -CH 2 -CMe 2 -CMe 2 -, , , , or group, wherein any -L 71 - moiety may optionally be fluoro substituted; and each R 75 is independently selected from a C1-C4 alkyl, C2-C4 alkenyl, cyclopropyl, cyclobutyl, C1-C4 fluoroalkyl, C2-C4 fluoroalkenyl, fluorocyclopropyl or fluorocyclobutyl group, or any two R 75 attached to the same nitrogen atom may together with the nitrogen atom to which they are attached form a 4- to 6-membered saturated monocyclic heterocyclic group, wherein the 4- to 6-membered saturated monocyclic heterocyclic group may optionally be substituted with one or more fluoro groups and/or with one or two methyl groups, wherein said methyl groups may optionally be fluoro-substituted; or R 7 is: wherein: m is 0, 1, 2, 3, 4 or 5; n is 0, 1, 2, 3, 4 or 5; 2 ≤ m + n ≤ 5; and R 76 is selected from hydrogen or a C1-C3 alkyl, cyclopropyl, C1-C3 fluoroalkyl or fluorocyclopropyl group; R 7 contains no more than 10 carbon atoms; R 8 is selected from a hydrogen or a fluoro, methyl or fluoromethyl group; X 10 is N or CR 10 ; X 13 is N or CR 13 ; no more than one of X 10 and X 13 is N; R 10 if present is selected from hydrogen or a fluoro, chloro, bromo, -R 131 , -OR 131 , -N(R 132 )2, -L 13 -OH, -L 13 -SH, -L 13 -OR 131 , -L 13 -SR 131 , -L 13 -N(R 132 )2, -L 13 -SO2-R 131 , -L 13 -SO 2 -N(R 132 ) 2 , -O-L 13 -OH, -O-L 13 -SH, -O-L 13 -OR 131 , -O-L 13 -SR 131 , -O-L 13 -N(R 132 ) 2 , -O-L 13 -SO 2 -R 131 , -O-L 13 -SO 2 -N(R 132 ) 2 , -NR 133 -L 13 -OH, -NR 133 -L 13 -SH, -NR 133 -L 13 -OR 131 , -NR 133 -L 13 -SR 131 , -NR 133 -L 13 -N(R 132 )2, -NR 133 -L 13 -SO2-R 131 or -NR 133 -L 13 -SO2-N(R 132 )2 group, provided that R 10 , including any optional substituents, contains no more than 10 carbon atoms, wherein: each R 131 is independently selected from a C1-C4 alkyl or C3-C6 cycloalkyl group, wherein the C1-C4 alkyl or C3-C6 cycloalkyl group may optionally be substituted with one or more fluoro groups and/or one or two oxo (=O) groups; each R 132 is independently selected from hydrogen or a -R 131 group; R 133 is selected from hydrogen or a -R 131 group; L 13 is a straight-chained alkylene or alkenylene group, wherein the straight- chained alkylene or alkenylene group optionally includes one, two or three heteroatoms each independently selected from O and N in its carbon skeleton, wherein L 13 has a chain length of from 1 to 8 atoms, and wherein L 13 may optionally be substituted with one or two groups each independently selected from oxo (=O) and -OH, and/or with one or more groups R L13 ; each R L13 is independently selected from a fluoro, C1-C3 alkyl, cyclopropyl, C1- C3 fluoroalkyl, fluorocyclopropyl, -CH2OH, -CH2OMe or -CH2O-fluoromethyl group; or any two R L13 , or any R L13 and any R 131 , or any two R 131 , may, together with the atom or atoms to which they are attached, form a 3- to 7-membered monocyclic group, wherein the 3- to 7-membered monocyclic group may optionally be substituted with one or two groups each independently selected from oxo (=O) and -OH, and/or with one or more fluoro, methyl and/or fluoromethyl groups; or any two R L13 and any R 131 , or any three R L13 and any R 131 , or any two R L13 and any two R 131 , may, together with the atoms to which they are attached, form a 6- to 10- membered bicyclic heterocyclic group, wherein the 6- to 10-membered bicyclic heterocyclic group may optionally be substituted with one or two groups each independently selected from oxo (=O) and -OH, and/or with one or more fluoro, methyl and/or fluoromethyl groups; R 12 is selected from hydrogen or a fluoro, chloro or bromo group; and R 13 if present is selected from hydrogen or a fluoro, chloro or bromo group.
  16. 16. A compound as claimed in claim 1, or a pharmaceutically acceptable salt and/or solvate and/or prodrug thereof, wherein the compound is a compound of Formula (Ib): Formula (Ib) wherein: R 1 is hydrogen; R 2 is hydrogen; R 3 is selected from hydrogen or a fluoro, chloro, bromo, -R 30 , -R 31 , -CN, -CHO, -COR 30 , -CO2H or -CO2R 30 group; R 30 is selected from a methyl or fluoromethyl group; R 31 is a 5-membered heteroaryl group, wherein the 5-membered heteroaryl group may optionally be substituted with one or more fluoro, chloro and/or bromo groups, and/or with one or two groups R 32 ; each R 32 is independently selected from a methyl or fluoromethyl group; R 4 is selected from a fluoro, chloro, bromo, -OR 44 , -CON(R 42 )2, -SO2-R 44 , -SO 2 -N(R 42 ) 2 , -O-CH 2 -CH 2 -OR 44 , -O-CH 2 -CH 2 -N(R 42 ) 2 , or -R 44 group, each R 42 is independently selected from hydrogen or a -R 44 group; each R 44 is independently selected from a C1-C3 alkyl, cyclopropyl, C1-C3 fluoroalkyl or fluorocyclopropyl group; R 5 is hydrogen or a fluoro, chloro or bromo group; R 6 is a chloro, bromo, methyl or a fluoromethyl group; R 7 is selected from hydrogen or a fluoro, -COOH, -COOR 75 , -CONH2, -CONHR 75 , -CON(R 75 ) 2 , -L 71 -COOH, -L 71 -COOR 75 , -L 71 -CONH 2 , -L 71 -CONHR 75 , -L 71 -CON(R 75 ) 2 , -L 71 -OH, -L 71 -OR 75 or -R 75 group; each -L 71 - is independently selected from a -CH2-, -CHMe-, -CMe2-, , -CH2-CH2-, -CH2-CHMe-, -CH2-CMe2-, -CHMe-CH2-, -CHMe-CHMe-, -CHMe-CMe2-, -CMe 2 -CH 2 -, -CMe 2 -CHMe-, -CMe 2 -CMe 2 -, , , , -CH 2 -CH 2 -CH 2 -, -CHMe-CH 2 -CH 2 -, -CH 2 -CHMe-CH 2 -, -CH 2 -CH 2 -CHMe-, -CMe2-CH2-CH2-, -CHMe-CHMe-CH2-, -CHMe-CH2-CHMe-, -CH2-CMe2-CH2-, -CH2-CHMe-CHMe-, -CH2-CH2-CMe2-, -CMe2-CHMe-CH2-, -CMe2-CH2-CHMe-, -CHMe-CHMe 2 -CH 2 -, -CHMe-CHMe-CHMe-, -CHMe-CH 2 -CMe 2 -, -CH 2 -CMe 2 -CHMe-, -CH 2 -CHMe-CMe 2 -, -CMe 2 -CMe 2 -CH 2 -, -CMe 2 -CHMe-CHMe-, -CMe 2 -CH 2 -CMe 2 -, -CHMe-CMe2-CHMe-, -CHMe-CHMe-CMe2-, -CH2-CMe2-CMe2-, , group, wherein any -L 71 - moiety may optionally be fluoro substituted; and each R 75 is independently selected from a C 1 -C 4 alkyl, C 2 -C 4 alkenyl, cyclopropyl, cyclobutyl, C1-C4 fluoroalkyl, C2-C4 fluoroalkenyl, fluorocyclopropyl or fluorocyclobutyl group, or any two R 75 attached to the same nitrogen atom may together with the nitrogen atom to which they are attached form a 4- to 6-membered saturated monocyclic heterocyclic group, wherein the 4- to 6-membered saturated monocyclic heterocyclic group may optionally be substituted with one or more fluoro groups and/or with one or two methyl groups, wherein said methyl groups may optionally be fluoro-substituted; or R 7 is: wherein: m is 0, 1, 2, 3, 4 or 5; n is 0, 1, 2, 3, 4 or 5; 2 ≤ m + n ≤ 5; and R 76 is selected from hydrogen or a C1-C3 alkyl, cyclopropyl, C1-C3 fluoroalkyl or fluorocyclopropyl group; R 7 contains no more than 10 carbon atoms; R 8 is selected from a hydrogen or a fluoro, methyl or fluoromethyl group; R 9 is selected from hydrogen or a fluoro, chloro or bromo group; X 10 is N or CR 10 ; X 13 is N or CR 13 ; no more than one of X 10 and X 13 is N; R 10 if present is selected from hydrogen or a fluoro, chloro or bromo group; R 11 is selected from hydrogen or a fluoro, chloro or bromo group; R 12 is selected from a chloro, bromo, methoxy, fluoromethoxy, -CH 2 OH or -CN group; R 13 if present is selected from hydrogen or a fluoro, chloro, bromo, -R 131 , -OR 131 , -N(R 132 )2, -L 13 -OH, -L 13 -SH, -L 13 -OR 131 , -L 13 -SR 131 , -L 13 -N(R 132 )2, -L 13 -SO2-R 131 , -L 13 -SO 2 -N(R 132 ) 2 , -O-L 13 -OH, -O-L 13 -SH, -O-L 13 -OR 131 , -O-L 13 -SR 131 , -O-L 13 -N(R 132 ) 2 , -O-L 13 -SO 2 -R 131 , -0-L 13 -S02-N(R 132 ) 2 , -NR 133 -L 13 -OH, -NR 133 -L 13 -SH, -NR 133 -L 13 -OR 131 , -NR 133 -L 13 -SR 131 , -NR 133 -L 13 -N(R 132 ) 2 , -NR 133 -L 13 -SO 2 -R 131 or -NR 133 -L 13 -SO 2 -N(R 132 ) 2 group; each R 131 is independently selected from a C1-C4 alkyl or C 3 -C6 cycloalkyl group, wherein the C1-C4 alkyl or C 3 -C6 cycloalkyl group may optionally be substituted with one or more fluoro groups and/or one or two oxo (=0) groups; each R 132 is independently selected from hydrogen or a -R 131 group; R 133 is selected from hydrogen or a -R 131 group; L 13 is a straight-chained alkylene or alkenylene group, wherein the straight- chained alkylene or alkenylene group optionally includes one, two or three heteroatoms each independently selected from O and N in its carbon skeleton, wherein L 13 has a chain length of from 1 to 8 atoms, and wherein L 13 may optionally be substituted with a one or two groups each independently selected from oxo (=0) and -OH, and/or with one or more groups R L13 ; each R L13 is independently selected from a fluoro, Ci-C 3 alkyl, cyclopropyl, Ci- C 3 fluoroalkyl, fluorocyclopropyl, -CH 2 0H, -CH 2 0Me or -CH 2 O-fluoromethyl group; or any two R L13 , or any R L13 and any R 131 , or any two R 131 , may, together with the atom or atoms to which they are attached, form a 3- to 7-membered monocyclic group, wherein the 3- to 7-membered monocyclic group may optionally be substituted with one or two groups each independently selected from oxo (=0) and -OH, and/or with one or more fluoro, methyl and/or fluoromethyl groups; or any two R L13 and any R 131 , or any three R L13 and any R 131 , or any two R L13 and any two R 131 , may, together with the atoms to which they are attached, form a 6- to 10- membered bicyclic heterocyclic group, wherein the 6- to 10-membered bicyclic heterocyclic group may optionally be substituted with one or two groups each independently selected from oxo (=0) and -OH, and/or with one or more fluoro, methyl and/or fluoro methyl groups; provided that R 13 , including any optional substituents, contains no more than 10 carbon atoms.
  17. 17- A compound selected from the group consisting of:
  18. 18. A pharmaceutical composition comprising a compound, or a pharmaceutically acceptable salt and/or solvate and/or prodrug thereof, as claimed in any one of claims i to 17, and a pharmaceutically acceptable excipient.
  19. 19. A compound, or a pharmaceutically acceptable salt and/ or solvate and/ or prodrug thereof, as claimed in any one of claims 1 to 17, or a pharmaceutical composition as claimed in claim 18, for use in medicine.
  20. 20. A compound, or a pharmaceutically acceptable salt and/ or solvate and/ or prodrug thereof, as claimed in any one of claims 1 to 17, or a pharmaceutical composition as claimed in claim 18, for use in the treatment or prevention of a disease, disorder or condition, wherein the disease, disorder or condition is responsive to Factor B inhibition.

Description

Novel Compounds Field of the Invention The present invention relates to compounds possessing an indole moiety linked to an indazole moiety, to compounds having similar core structures, and to associated salts, solvates, prodrugs and pharmaceutical compositions. The present invention further relates to methods of synthesising such compounds, and to the use of such compounds in the treatment and prevention of medical disorders and diseases, most especially by Factor B inhibition. Background of the Invention The complement system is a critical part of the innate immune system and serves to help the body fight against infection from pathogens, ultimately leading to inflammation and phagocytic removal of pathogens or foreign particles. The complement system is comprised of multiple proteins, including zymogens which undergo proteolytic cleavage to become activated and facilitate the activation of further zymogens in the cascade. The proteins may be zymogens or proteins without potential for enzymatic activity that change conformation revealing binding sites for other components of the system. These successive enzymatic cleavages lead to a large, amplified response and many regulatory components exist in this system to prevent uncontrolled activation. The complement system can be activated via three pathways: classical, lectin, and alternative. The classical pathway is triggered by antigen: antibody complexes and connects the innate to the adaptive immune system. The lectin pathway is triggered directly by the pathogen when serum protein mannan-binding lectin, collectins or ficolins bind to bacterial or viral mannose-containing carbohydrates. The alternative pathway (also known as the alternate pathway) is initiated by activation of the central complement component, C3, either through spontaneous hydrolysis or enzymatic cleavage. The alternative pathway also serves as a critical amplification loop of all three pathways of complement activation. Ultimately, all of these pathways lead to the generation of C3 convertase which cleaves and activates further C3 molecules to promote: 1) opsonization of pathogens so they can be engulfed by phagocytes that recognise key receptors, 2) the recruitment of inflammatory cells by generating chemoattractants at the site of activation, and 3) formation of the C5 convertase resulting in production of Csa and Csb, the latter of which induces direct killing of pathogens by assembling terminal complement components to create membrane attack complex (MAC) pores in the membrane of bacteria or other target cells (Janeway, C. A. Jr. et al, (2001) The complement system and innate immunity, in Immunobiology: The Immune System in Health and Disease, Garland Science, New York). Factor B, a trypsin-like serine protease, is an element of the alternative pathway of the complement cascade. It exists in circulation in its zymogen form until the pathway becomes activated (Schubart, A. et al, Proc. Natl. Acad. Sci. U.S.A. 2019, 116, 7926- 7931)- Spontaneous steady-state hydrolysis of C3 leads to the formation of C3(H20). Factor B can bind to the active forms of C3: C3(H20) and C3b, generating the proenzyme CsbB (or C3(H2O)B), a target for activation by Factor D. Upon cleavage by Factor D, two fragments are generated: Ba and Bb (Schwaeble, W. J., Ali, Y. M., and Sim, R. B., (2020) Chapter 14 - The Roles and Contributions of the Complement System in the Pathophysiology of Autoimmune Diseases, in The Autoimmune Diseases (Sixth Edition) (Rose, N. R., and Mackay, I. R. eds.), Academic Press). Ba is released and Bb, containing a serine protease domain, remains bound to C3(H20) and C3b, forming the alternative pathway C3 convertases [C3(H2O)Bb and CsbBb]. These trigger the amplification loop by converting C3 to C3a and more C3b. With the addition of yet another C3b to the C3 convertase, the C5 convertase is generated (CsbBbCsb) (Laskowski, J., Thurman, J. M. (2018) Chapter 14 - Factor B, in The Complement FactsBook (Second Edition) (Barnum, S., and Schein, T. eds.), Academic Press). C5 convertase cleaves C5 to generate the anaphylatoxin Csa, and Csb which serves as a platform for the formation of the membrane attack complex. Dysregulation of the alternative complement pathway due to genetics or the presence of autoantibodies can lead to many different diseases. Inhibition of Factor B is therefore a key therapeutic target for modulation of the alternative pathway and hence the treatment of numerous diseases, disorders and conditions. Iptacopan (LNP023), disclosed in Mainolfi et al., J. Med. Chem., 2020, vol. 63, pp. 5697-5722, is a known Factor B inhibitor having the following structure: Iptacopan is highly selective for Factor B, showing no inhibition of Factor D or the classical or lectin complement pathways. Also, no significant effects have been observed in a broad assay panel of receptors, ion channels, kinases, and proteases (Schubart, A. et al, Proc. Natl. Acad. Sci. U.S.A. 2019, 116, 7926-7931).