Indole derivatives for use in medicine
Provided is a tryptophan-2,3-dioxygenase (TDO) and/or indoleamine-2,3-dioxygenase (IDO) inhibitor compound for use in medicine, which compound comprises the following formula: wherein X 1 , X 2 , X 3 , X 4 , and X 5 may be the same or different and each is independently selected from C, N and O; each atom having a dotted line may independently have a double bond or a single bond, provided that valencies at each atom are maintained; each R 1 , R 2 , R 3 , R 4 , R 5 , and R 7 may be present or absent and may be the same or different and is selected from H and a substituted or unsubstituted organic group, provided that the number of such R groups present is such that the valencies of X 1 , X 2 , X 3 , X 4 , and X 5 are maintained; one or two R 6 groups may be present and are selected from H and a substituted or unsubstituted organic group, provided that the number of R 6 groups present is such that the valency of the carbon atom to which they are attached is maintained, and provided that at least one R 6 is an organic group comprising an atom double-bonded to an oxygen atom (preferably a carbonyl group or a sulphonyl group) at an α-, β-, or γ-position to the carbon atom to which the R 6 is attached and in which the atom double-bonded to an oxygen atom is also bonded to a hetero-atom.
1. A compound of the following formula, or a pharmaceutically acceptable salt thereof:
wherein:
each of R 1 , R 2 , R 3 and R 4 is independently selected from H, halogen, —CN, C 1 -C 6 alkyl, C 1 -C 6 halogenated alkyl, —OH, C 1 -C 7 alkoxy, —O—CF 3 , —C(O)—NH 2 , —C(O)—NHMe, NH—SO 2 Me, NH—SO 2 Et, —NH—SO 2 Pr, and —NH—SO 2 iPr;
R 5 is H;
R 7 is selected from H and C 1 -C 6 alkyl;
R 61 is selected from H and C 1 -C 6 alkyl;
R 65 is a heterocyclic group selected from pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl, 1,2,3-triazol-4-yl, 1,2,3-triazol-5-yl, 1,2,4-triazol-1-yl, 1,2,4-triazol-3-yl, 1,2,4-triazol-5-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyrimidin-6-yl, piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, tetrazol-1-yl, tetrazol-2-yl, and tetrazol-5-yl; each of which is optionally substituted with one to three substituents independently selected from halogen, methyl, ethyl, propyl, —C(O)-methyl, —S(O) 2 -methyl and phenyl; and
R 63 and R 64 together form a 3-6 membered carbocyclic or heterocyclic ring selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxetanyl, tetrahydrofuranyl and tetrahydropyranyl.
2. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
each of R 1 , R 2 , R 3 and R 4 is independently selected from H, halogen, —CN, methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, —CF 3 , —CHF 2 , —OH, —O-methyl, —O— ethyl, —O-propyl, and —OCF 3 ;
R 5 is H;
R 7 is selected from H and methyl;
R 61 is selected from H, methyl, ethyl, propyl and iso-propyl;
R 65 is pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl, 1,2,3-triazol-1-yl, 1,2,3-triazol-4-yl, 1,2,3-triazol-5-yl, 1,2,4-triazol-1-yl, 1,2,4-triazol-3-yl, 1,2,4-triazol-5-yl, oxazol-2-yl, oxazol-4-yl, isoxazol-3-yl, tetrazol-1-yl, tetrazol-2-yl, and tetrazol-5-yl; each of which is optionally substituted with one to three substituents independently selected from halogen, methyl, ethyl, propyl and phenyl; and
R 63 and R 64 together form a 3-6 membered saturated carbocyclic or heterocyclic ring selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxetanyl, tetrahydrofuranyl and tetrahydropyranyl.
3. The compound according to claim 2 , or a pharmaceutically acceptable salt thereof, wherein:
each of R 1 , R 3 and R 4 is independently selected from H, halogen and methyl;
R 2 is selected from halogen, —CN, methyl, ethyl, propyl, iso-propyl, —CF 3 , —CHF 2 , —OH, —O— methyl, —O-ethyl, —O-propyl and —OCF 3 ; and
each of R 5 and R 7 is H.
4. The compound according to claim 3 , or a pharmaceutically acceptable salt thereof, wherein R 61 is H.
5. The compound according to claim 4 , or a pharmaceutically acceptable salt thereof, wherein:
R 65 is a heterocyclic group selected from pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl, 1,2,4-triazol-1-yl, 1,2,4-triazol-3-yl, 1,2,4-triazol-5-yl, oxazol-4-yl, isoxazol-3-yl, tetrazol-1-yl, tetrazol-2-yl, tetrazol-5-yl; each of which is optionally substituted with one to three substituents independently selected from halogen, methyl, ethyl, propyl, and phenyl; and
R 63 and R 64 together form a 3-6 membered carbocyclic or heterocyclic ring selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
6. The compound according to claim 2 , or a pharmaceutically acceptable salt thereof, wherein:
each of R 1 , R 3 , and R 4 is H;
R 2 is selected from halogen, —CN, methyl, ethyl, —CF 3 , —O-methyl and —OCF 3 ;
each of R 5 and R 61 is H;
R 7 is H;
R 65 is a heterocyclic group selected from pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl, oxazol-4-yl, isoxazol-3-yl, tetrazol-1-yl, tetrazol-2-yl, and tetrazol-5-yl; each of which is optionally substituted with one to three substituents independently selected from halogen, methyl, ethyl, propyl, and phenyl; and
R 63 and R 64 together form a 3-6 membered unsubstituted saturated carbocyclic ring selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
7. The compound according to claim 1 selected from the following, or a pharmaceutically acceptable salt thereof:
8. A compound according to claim 1 , or a pharmaceutically acceptable salt thereof, which compound comprises:
an isolated enantiomer,
a mixture of two or more enantiomers,
a mixture of two or more diastereomers, and/or epimers,
a racemic mixture, and/or
one or more tautomers of the compound.
9. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof.
10. The compound according to claim 1 selected from the following, or a pharmaceutically acceptable salt thereof:
11. The compound according to claim 1 selected from the following, or a pharmaceutically acceptable salt thereof:
12. The compound according to claim 1 selected from the following, or a pharmaceutically acceptable salt thereof:
13. The compound according to claim 2 of the following formula, or a pharmaceutically acceptable salt thereof:
14. The compound according to claim 2 of the following formula, or a pharmaceutically acceptable salt thereof:
15. The compound according to claim 2 of the following formula, or a pharmaceutically acceptable salt thereof:
16. The compound according to claim 2 of the following formula, or a pharmaceutically acceptable salt thereof:
17. The compound according to claim 2 of the following formula, or a pharmaceutically acceptable salt thereof:
18. The compound according to claim 2 , or a pharmaceutically acceptable salt thereof,
wherein:
each of R 1 , R 3 and R 4 is independently selected from H, methyl, ethyl and halogen;
R 2 is selected from H, methyl, ethyl, propyl, —O-methyl, —O-ethyl, —O-propyl, —O-isopropyl, —O—CF 3 , —CF 3 , —CHF 2 , —CN, F, Cl and Br;
each of R 5 and R 7 is H;
R 61 is selected from H, methyl and ethyl;
R 63 and R 64 together form a 3-6 membered saturated carbocyclic or heterocyclic ring selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxetanyl, tetrahydrofuranyl and tetrahydropyranyl; and
R 65 is selected from:
pyrazol-1-yl, optionally substituted with methyl, ethyl or propyl;
pyrazol-3-yl, optionally substituted with methyl, ethyl or propyl;
pyrazol-4-yl, optionally substituted with methyl, ethyl or propyl; and
pyrazol-5-yl, optionally substituted with methyl, ethyl or propyl.
19. The compound according to claim 18 , wherein:
each of R 1 , R 3 and R 4 is independently selected from H, methyl and halogen;
R 2 is selected from methyl, ethyl, —O-methyl, —O-ethyl, F, Cl, Br and —CN;
each of R 5 , R 7 and R 61 is H;
R 63 and R 64 together form a 3-6 membered saturated carbocyclic ring selected from cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; and
R 65 is selected from:
pyrazol-1-yl, optionally substituted with methyl, ethyl or propyl;
pyrazol-3-yl, optionally substituted with methyl, ethyl or propyl;
pyrazol-4-yl, optionally substituted with methyl, ethyl or propyl; and
pyrazol-5-yl, optionally substituted with methyl, ethyl or propyl.
20. The compound according to claim 18 , wherein:
each of R 1 , R 3 and R 4 is H;
R 2 is selected from methyl, ethyl, F, Cl, Br and —CN;
each of R 5 , R 7 and R 61 is H;
R 63 and R 64 together form cyclopropyl; and
R 65 is selected from:
pyrazol-1-yl, optionally substituted with methyl, ethyl or propyl;
pyrazol-3-yl, optionally substituted with methyl, ethyl or propyl; and
pyrazol-4-yl, optionally substituted with methyl, ethyl or propyl.
21. A compound of the following formula:
22. A compound of the following formula:
23. A compound of the following formula:
24. A compound of the following formula: