Pyrrole derivatives as therapeutic compounds
Novel pyrrole derivatives are disclosed as Aβ 42 -lowering agents for the treatment and prevention of neurodegenerative disorders characterized by the formation or accumulation of amyloid plaques comprising the Aβ 42 peptide.
1. A compound having a structure according to Formula I:
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is a hydrogen atom, halogen, hydroxyl, C 1-6 alkyl optionally substituted with 1, 2, or 3 halogens or hydroxyls, C 1-6 alkoxy or —(CH) q CO 2 R 10 , wherein R 10 is a hydrogen atom or C 1-6 alkyl, and q is the integer 0, 1, 2, 3, or 4;
R 2 is a hydrogen atom, halogen, hydroxyl, C 1-6 alkyl optionally substituted with 1, 2, or 3 halogens or hydroxyls, C 1-6 alkoxy optionally substituted with 1, 2, or 3 halogens, hydroxyls or amino groups, or phenyl, optionally substituted with 1, 2, 3, 4, or 5 of the same or different substituents chosen from halogen, C 1-6 alkyl optionally substituted with 1, 2, or 3 halogens or hydroxyls, or —(CH) q CO 2 R 10 wherein R 10 is a hydrogen atom or a C 1-6 alkyl and q is the integer 0, 1, 2, 3, or 4;
R 3 is a hydrogen atom, halogen, hydroxyl, C 1-6 alkyl optionally substituted with 1, 2, or 3 halogens or hydroxyls, C 1-6 alkoxy optionally substituted with 1, 2, or 3 halogens, hydroxyls or amino groups, when R 2 is an optionally substituted phenyl; or, when R 2 is not an optionally substituted phenyl, R 3 is —CH 2 CH 2 -phenyl, optionally substituted with 1, 2, 3, 4, or 5 of the same or different substituents chosen from halogen, C 1-6 alkyls optionally substituted with 1, 2, or 3 halogens or hydroxyls, or —(CH) q CO 2 R 10 , wherein R 10 is a hydrogen atom or a C 1-6 alkyl, and q is the integer 0, 1, 2, 3, or 4;
R 4 is a hydrogen atom, halogen, hydroxyl, C 1-6 alkyl optionally substituted with 1, 2, or 3 halogens or hydroxyls, or C 1-6 alkoxy optionally substituted with 1, 2, or 3 halogens, hydroxyls or amino groups;
R 5 is a hydrogen atom, halogen, hydroxyl, C 1-6 alkyl optionally substituted with 1, 2, or 3 halogens or hydroxyls, or C 1-6 alkoxy optionally substituted with 1, 2, or 3 halogens, hydroxyls or amino groups;
one of R 6 and R 7 is —(CH 2 ) n CO 2 R 11 or —O(CH 2 ) n CO 2 R 11 , wherein n is the integer 0, 1, 2, 3, 4, 5, or 6, and R 11 is a hydrogen atom, C 1-6 alkyl optionally substituted with 1, 2, or 3 halogens, or is —(CH 2 ) m O(CH 2 ) p CO 2 R 11 , wherein m is the integer 0, 1, 2, 3, or 4, and p is the integer from 0, 1, 2, 3, 4, 5, or 6, and R 11 is a hydrogen atom, C 1-6 alkyl optionally substituted with 1, 2, or 3 halogens; while the other of R 6 and R 7 is a hydrogen atom, halogen, hydroxyl, C 1-6 alkyl optionally substituted with 1, 2, or 3 halogens, C 1-6 alkoxy optionally substituted with 1, 2, or 3 halogens, hydroxyls, or amino groups;
R 8 is a hydrogen atom, halogen, hydroxyl, C 1-6 alkyl optionally substituted with 1, 2, or 3 halogens or hydroxyls, or C 1-6 alkoxy optionally substituted with 1, 2, or 3 halogens, hydroxyls or amino groups; and
R 9 is independently 0, 1, 2, 3, 4, or 5 substituents, which are independently selected from a hydrogen atom, halogen, hydroxyl, C 1-6 alkyl optionally substituted with 1, 2, or 3 halogens or hydroxyl groups, C 1-6 haloalkyl, aryl, heteroaryl, heterocycle, —OR, —C(═O)R, —C(═O)OR, —C(═O)NRR, —NRR, —NRC(═O)R, —NRC(═O)OR, —NRC(═O)NRR, —OC(═O)R, —OC(═O)OR, —OC(═O)NRR, —SH, —SR, —SOR, —SO 2 R, —SO 2 NR 2 , —NRSO 2 R, —NR 2 SO 2 R, —Si(R) 3 , or —OP(OR) 3 , wherein each occurrence of R is the same or different and independently a hydrogen atom, C 1-6 alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heterocycle, substituted heterocycle, heterocyclealkyl or substituted heterocyclealkyl, or wherein any two R groups attached to the same nitrogen atom, taken together with the nitrogen atom to which they are attached, form a heterocyclic ring or a substituted heterocyclic ring.
2. A compound of claim 1 , wherein R 1 , R 5 and R 8 are hydrogen atoms, and the compound has a structure according to Formula II:
or a pharmaceutically acceptable salt thereof, wherein:
R 2 is a hydrogen atom, halogen, hydroxyl, C 1-6 alkyl optionally substituted with 1, 2, or 3 halogens or hydroxyls, C 1-6 alkoxy optionally substituted with 1, 2, or 3 halogens, hydroxyls or amino groups, or phenyl, optionally substituted with 1, 2, 3, 4, or 5 of the same or different substituents chosen from halogen, C 1-6 alkyl optionally substituted with 1, 2, or 3 halogens or hydroxyls, or —(CH) q CO 2 R 10 wherein R 10 is a hydrogen atom or a C 1-6 alkyl and q is the integer 0, 1, 2, 3, or 4;
R 3 is a hydrogen atom, halogen, hydroxyl, C 1-6 alkyl optionally substituted with 1, 2, or 3 halogens or hydroxyls, C 1-6 alkoxy optionally substituted with 1, 2, or 3 halogens, hydroxyls or amino groups, when R 2 is an optionally substituted phenyl; or, when R 2 is not an optionally substituted phenyl, R 3 is —CH 2 CH 2 -phenyl, optionally substituted with 1, 2, 3, 4, or 5 of the same or different substituents chosen from halogen, C 1-6 alkyls optionally substituted with 1, 2, or 3 halogens or hydroxyls, or —(CH) q CO 2 R 10 , wherein R 10 is a hydrogen atom or a C 1-6 alkyl, and q is the integer 0, 1, 2, 3, or 4;
R 4 is a hydrogen atom, halogen, hydroxyl, C 1-6 alkyl optionally substituted with 1, 2, or 3 halogens or hydroxyls, or C 1-6 alkoxy optionally substituted with 1, 2, or 3 halogens, hydroxyls or amino groups;
one of R 6 and R 7 is —(CH 2 ) n CO 2 R 11 or —O(CH 2 ) n CO 2 R 11 , wherein n is the integer 0, 1, 2, 3, 4, 5, or 6, and R 11 is a hydrogen atom, C 1-6 alkyl optionally substituted with 1, 2, or 3 halogens, or is —(CH 2 ) m O(CH 2 ) p CO 2 R 11 , wherein m is the integer 0, 1, 2, 3, or 4, and p is the integer from 0, 1, 2, 3, 4, 5, or 6, and R 11 is a hydrogen atom, C 1-6 alkyl optionally substituted with 1, 2, or 3 halogens; while the other of R 6 and R 7 is a hydrogen atom, halogen, hydroxyl, C 1-6 alkyl optionally substituted with 1, 2, or 3 halogens, C 1-6 alkoxy optionally substituted with 1, 2, or 3 halogens, hydroxyls, or amino groups;
R 9 is independently 0, 1, 2, 3, 4, or 5 substituents, which are independently selected from a hydrogen atom, halogen, hydroxyl, C 1-6 alkyl optionally substituted with 1, 2, or 3 halogens or hydroxyl groups, C 1-6 haloalkyl, aryl, heteroaryl, heterocycle, —OR, —C(═O)R, —C(═O)OR, —C(═O)NRR, —NRR, —NRC(═O)R, —NRC(═O)OR, —NRC(═O)NRR, —OC(═O)R, —OC(═O)OR, —OC(═O)NRR, —SH, —SR, —SOR, —SO 2 R, —SO 2 NR 2 , —NRSO 2 R, —NR 2 SO 2 R, —Si(R) 3 , or —OP(OR) 3 , wherein each occurrence of R is the same or different and independently a hydrogen atom, C 1-6 alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heterocycle, substituted heterocycle, heterocyclealkyl or substituted heterocyclealkyl, or wherein any two R groups attached to the same nitrogen atom, taken together with the nitrogen atom to which they are attached, form a heterocyclic ring or a substituted heterocyclic ring.
3. A compound of claim 1 , having a structure according to Formula III:
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is a hydrogen atom, halogen, hydroxyl, C 1-6 alkyl optionally substituted with 1, 2, or 3 halogens or hydroxyls, C 1-6 alkoxy or —(CH) q CO 2 R 10 , wherein R 10 is a hydrogen atom or C 1-6 alkyl, and q is the integer 0, 1, 2, 3, or 4;
R 3 is a hydrogen atom, halogen, hydroxyl, C 1-6 alkyl optionally substituted with 1, 2, or 3 halogens or hydroxyls, C 1-6 alkoxy optionally substituted with 1, 2, or 3 halogens, hydroxyls or amino groups, when R 2 is an optionally substituted phenyl; or, when R 2 is not an optionally substituted phenyl, R 3 is —CH 2 CH 2 -phenyl, optionally substituted with 1, 2, 3, 4, or 5 of the same or different substituents chosen from halogen, C 1-6 alkyls optionally substituted with 1, 2, or 3 halogens or hydroxyls, or —(CH) q CO 2 R 10 , wherein R 10 is a hydrogen atom or a C 1-6 alkyl, and q is the integer 0, 1, 2, 3, or 4;
R 4 is a hydrogen atom, halogen, hydroxyl, C 1-6 alkyl optionally substituted with 1, 2, or 3 halogens or hydroxyls, or C 1-6 alkoxy optionally substituted with 1, 2, or 3 halogens, hydroxyls or amino groups;
R 5 is a hydrogen atom, halogen, hydroxyl, C 1-6 alkyl optionally substituted with 1, 2, or 3 halogens or hydroxyls, or C 1-6 alkoxy optionally substituted with 1, 2, or 3 halogens, hydroxyls or amino groups;
one of R 6 and R 7 is —(CH 2 ) n CO 2 R 11 or —O(CH 2 ) n CO 2 R 11 , wherein n is the integer 0, 1, 2, 3, 4, 5, or 6, and R 11 is a hydrogen atom, C 1-6 alkyl optionally substituted with 1, 2, or 3 halogens, or is —(CH 2 ) m O(CH 2 ) p CO 2 R 11 , wherein m is the integer 0, 1, 2, 3, or 4, and p is the integer from 0, 1, 2, 3, 4, 5, or 6, and R 11 is a hydrogen atom, C 1-6 alkyl optionally substituted with 1, 2, or 3 halogens; while the other of R 6 and R 7 is a hydrogen atom, halogen, hydroxyl, C 1-6 alkyl optionally substituted with 1, 2, or 3 halogens, C 1-6 alkoxy optionally substituted with 1, 2, or 3 halogens, hydroxyls, or amino groups;
R 8 is a hydrogen atom, halogen, hydroxyl, C 1-6 alkyl optionally substituted with 1, 2, or 3 halogens or hydroxyls, or C 1-6 alkoxy optionally substituted with 1, 2, or 3 halogens, hydroxyls or amino groups; and
R 9 and R 12 are independently 0, 1, 2, 3, 4, or 5 substituents, which are independently selected from a hydrogen atom, halogen, hydroxyl, C 1-6 alkyl optionally substituted with 1, 2, or 3 halogens or hydroxyl groups, C 1-6 haloalkyl, aryl, heteroaryl, heterocycle, —OR, —C(═O)R, —C(═O)OR, —C(═O)NRR, —NRR, —NRC(═O)R, —NRC(═O)OR, —NRC(═O)NRR, —OC(═O)R, —OC(═O)OR, —OC(═O)NRR, —SH, —SR, —SOR, —SO 2 R, —SO 2 NR 2 , —NRSO 2 R, —NR 2 SO 2 R, —Si(R) 3 , or —OP(OR) 3 , wherein each occurrence of R is the same or different and independently a hydrogen atom, C 1-6 alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heterocycle, substituted heterocycle, heterocyclealkyl or substituted heterocyclealkyl, or wherein any two R groups attached to the same nitrogen atom, taken together with the nitrogen atom to which they are attached, form a heterocyclic ring or a substituted heterocyclic ring.
4. A compound of claim 3 , wherein R 1 , R 5 and R 8 are hydrogen atoms, and the compound has a structure according to Formula IV:
or a pharmaceutically acceptable salt thereof, wherein:
R 3 is a hydrogen atom, halogen, hydroxyl, C 1-6 alkyl optionally substituted with 1, 2, or 3 halogens or hydroxyls, C 1-6 alkoxy optionally substituted with 1, 2, or 3 halogens, hydroxyls or amino groups, when R 2 is an optionally substituted phenyl; or, when R 2 is not an optionally substituted phenyl, R 3 is —CH 2 CH 2 -phenyl, optionally substituted with 1, 2, 3, 4, or 5 of the same or different substituents chosen from halogen, C 1-6 alkyls optionally substituted with 1, 2, or 3 halogens or hydroxyls, or —(CH) q CO 2 R 10 , wherein R 10 is a hydrogen atom or a C 1-6 alkyl, and q is the integer 0, 1, 2, 3, or 4;
R 4 is a hydrogen atom, halogen, hydroxyl, C 1-6 alkyl optionally substituted with 1, 2, or 3 halogens or hydroxyls, or C 1-6 alkoxy optionally substituted with 1, 2, or 3 halogens, hydroxyls or amino groups;
one of R 6 and R 7 is —(CH 2 ) n CO 2 R 11 or —O(CH 2 ) n CO 2 R 11 , wherein n is the integer 0, 1, 2, 3, 4, 5, or 6, and R 11 is a hydrogen atom, C 1-6 alkyl optionally substituted with 1, 2, or 3 halogens, or is —(CH 2 ) m O(CH 2 ) p CO 2 R 11 , wherein m is the integer 0, 1, 2, 3, or 4, and p is the integer from 0, 1, 2, 3, 4, 5, or 6, and R 11 is a hydrogen atom, C 1-6 alkyl optionally substituted with 1, 2, or 3 halogens; while the other of R 6 and R 7 is a hydrogen atom, halogen, hydroxyl, C 1-6 alkyl optionally substituted with 1, 2, or 3 halogens, C 1-6 alkoxy optionally substituted with 1, 2, or 3 halogens, hydroxyls, or amino groups;
R 9 and R 12 are independently 0, 1, 2, 3, 4, or 5 substituents, which are independently selected from a hydrogen atom, halogen, hydroxyl, C 1-6 alkyl optionally substituted with 1, 2, or 3 halogens or hydroxyl groups, C 1-6 haloalkyl, aryl, heteroaryl, heterocycle, —OR, —C(═O)R, —C(═O)OR, —C(═O)NRR, —NRR, —NRC(═O)R, —NRC(═O)OR, —NRC(═O)NRR, —OC(═O)R, —OC(═O)OR, —OC(═O)NRR, —SH, —SR, —SOR, —SO 2 R, —SO 2 NR 2 , —NRSO 2 R, —NR 2 SO 2 R, —Si(R) 3 , or —OP(OR) 3 , wherein each occurrence of R is the same or different and independently a hydrogen atom, C 1-6 alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heterocycle, substituted heterocycle, heterocyclealkyl or substituted heterocyclealkyl, or wherein any two R groups attached to the same nitrogen atom, taken together with the nitrogen atom to which they are attached, form a heterocyclic ring or a substituted heterocyclic ring.
5. A compound of claim 1 , having a structure according to Formula V:
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is a hydrogen atom, halogen, hydroxyl, C 1-6 alkyl optionally substituted with 1, 2, or 3 halogens or hydroxyls, C 1-6 alkoxy or —(CH) q CO 2 R 10 , wherein R 10 is a hydrogen atom or C 1-6 alkyl, and q is the integer 0, 1, 2, 3, or 4;
R 2 is a hydrogen atom, halogen, hydroxyl, C 1-6 alkyl optionally substituted with 1, 2, or 3 halogens or hydroxyls, C 1-6 alkoxy optionally substituted with 1, 2, or 3 halogens, hydroxyls or amino groups, or phenyl, optionally substituted with 1, 2, 3, 4, or 5 of the same or different substituents chosen from halogen, C 1-6 alkyl optionally substituted with 1, 2, or 3 halogens or hydroxyls, or —(CH) q CO 2 R 10 wherein R 10 is a hydrogen atom or a C 1-6 alkyl and q is the integer 0, 1, 2, 3, or 4;
R 4 is a hydrogen atom, halogen, hydroxyl, C 1-6 alkyl optionally substituted with 1, 2, or 3 halogens or hydroxyls, or C 1-6 alkoxy optionally substituted with 1, 2, or 3 halogens, hydroxyls or amino groups;
R 5 is a hydrogen atom, halogen, hydroxyl, C 1-6 alkyl optionally substituted with 1, 2, or 3 halogens or hydroxyls, or C 1-6 alkoxy optionally substituted with 1, 2, or 3 halogens, hydroxyls or amino groups;
one of R 6 and R 7 is —(CH 2 ) n CO 2 R 11 or —O(CH 2 ) n CO 2 R 11 , wherein n is the integer 0, 1, 2, 3, 4, 5, or 6, and R 11 is a hydrogen atom, C 1-6 alkyl optionally substituted with 1, 2, or 3 halogens, or is —(CH 2 ) m O(CH 2 ) p CO 2 R 11 , wherein m is the integer 0, 1, 2, 3, or 4, and p is the integer from 0, 1, 2, 3, 4, 5, or 6, and R 11 is a hydrogen atom, C 1-6 alkyl optionally substituted with 1, 2, or 3 halogens; while the other of R 6 and R 7 is a hydrogen atom, halogen, hydroxyl, C 1-6 alkyl optionally substituted with 1, 2, or 3 halogens, C 1-6 alkoxy optionally substituted with 1, 2, or 3 halogens, hydroxyls, or amino groups;
R 8 is a hydrogen atom, halogen, hydroxyl, C 1-6 alkyl optionally substituted with 1, 2, or 3 halogens or hydroxyls, or C 1-6 alkoxy optionally substituted with 1, 2, or 3 halogens, hydroxyls or amino groups; and
R 9 and R 12 are independently 0, 1, 2, 3, 4, or 5 substituents, which are independently selected from a hydrogen atom, halogen, hydroxyl, C 1-6 alkyl optionally substituted with 1, 2, or 3 halogens or hydroxyl groups, C 1-6 haloalkyl, aryl, heteroaryl, heterocycle, —OR, —C(═O)R, —C(═O)OR, —C(═O)NRR, —NRR, —NRC(═O)R, —NRC(═O)OR, —NRC(═O)NRR, —OC(═O)R, —OC(═O)OR, —OC(═O)NRR, —SH, —SR, —SOR, —SO 2 R, —SO 2 NR 2 , —NRSO 2 R, —NR 2 SO 2 R, —Si(R) 3 , or —OP(OR) 3 , wherein each occurrence of R is the same or different and independently a hydrogen atom, C 1-6 alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heterocycle, substituted heterocycle, heterocyclealkyl or substituted heterocyclealkyl, or wherein any two R groups attached to the same nitrogen atom, taken together with the nitrogen atom to which they are attached, form a heterocyclic ring or a substituted heterocyclic ring.
6. A compound of claim 5 , wherein R 1 , R 5 and R 8 are hydrogen atoms, and the compound has a structure according to Formula VI:
or a pharmaceutically acceptable salt thereof, wherein:
R 2 is a hydrogen atom, halogen, hydroxyl, C 1-6 alkyl optionally substituted with 1, 2, or 3 halogens or hydroxyls, C 1-6 alkoxy optionally substituted with 1, 2, or 3 halogens, hydroxyls or amino groups, or phenyl, optionally substituted with 1, 2, 3, 4, or 5 of the same or different substituents chosen from halogen, C 1-6 alkyl optionally substituted with 1, 2, or 3 halogens or hydroxyls, or —(CH) q CO 2 R 10 wherein R 10 is a hydrogen atom or a C 1-6 alkyl and q is the integer 0, 1, 2, 3, or 4;
R 4 is a hydrogen atom, halogen, hydroxyl, C 1-6 alkyl optionally substituted with 1, 2, or 3 halogens or hydroxyls, or C 1-6 alkoxy optionally substituted with 1, 2, or 3 halogens, hydroxyls or amino groups;
one of R 6 and R 7 is —(CH 2 ) n CO 2 R 11 or —O(CH 2 ) n CO 2 R 11 , wherein n is the integer 0, 1, 2, 3, 4, 5, or 6, and R 11 is a hydrogen atom, C 1-6 alkyl optionally substituted with 1, 2, or 3 halogens, or is —(CH 2 ) m O(CH 2 ) p CO 2 R 11 , wherein m is the integer 0, 1, 2, 3, or 4, and p is the integer from 0, 1, 2, 3, 4, 5, or 6, and R 11 is a hydrogen atom, C 1-6 alkyl optionally substituted with 1, 2, or 3 halogens; while the other of R 6 and R 7 is a hydrogen atom, halogen, hydroxyl, C 1-6 alkyl optionally substituted with 1, 2, or 3 halogens, C 1-6 alkoxy optionally substituted with 1, 2, or 3 halogens, hydroxyls, or amino groups;
R 9 and R 12 are independently 0, 1, 2, 3, 4, or 5 substituents, which are independently selected from a hydrogen atom, halogen, hydroxyl, C 1-6 alkyl optionally substituted with 1, 2, or 3 halogens or hydroxyl groups, C 1-6 haloalkyl, aryl, heteroaryl, heterocycle, —OR, —C(═O)R, —C(═O)OR, —C(═O)NRR, —NRR, —NRC(═O)R, —NRC(═O)OR, —NRC(═O)NRR, —OC(═O)R, —OC(═O)OR, —OC(═O)NRR, —SH, —SR, —SOR, —SO 2 R, —SO 2 NR 2 , —NRSO 2 R, —NR 2 SO 2 R, —Si(R) 3 , or —OP(OR) 3 , wherein each occurrence of R is the same or different and independently a hydrogen atom, C 1-6 alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heterocycle, substituted heterocycle, heterocyclealkyl or substituted heterocyclealkyl, or wherein any two R groups attached to the same nitrogen atom, taken together with the nitrogen atom to which they are attached, form a heterocyclic ring or a substituted heterocyclic ring.
7. A pharmaceutical composition comprising a compound according to claim 1 in combination with a pharmaceutically acceptable carrier or excipient.
8. A method of making a compound of Formula III, comprising providing a compound having a Formula (VII)
and a compound having a Formula (VIII)
and reacting the two compounds under conditions to form a compound of Formula (III)
wherein R 1 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , and R 12 are as defined above for the compounds of Formula III.
9. A method of making a compound of Formula V, comprising providing a compound having a Formula (IX),
and a compound having a Formula (VIII)
and reacting the two compounds under conditions to form a compound of Formula (V)
wherein R 1 , R 2 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , and R 12 are as defined above for the compounds of Formula V.