Templates for nucleation and propagation of peptide secondary structure
View Patent ↗Compounds having the Formula I and pharmaceutically acceptable salts thereof are provided in which the variables are described herein. Methods of making the compounds of Formula I are also disclosed.
1. A compound of formula I
and stereoisomers, tautomers and pharmaceutically acceptable salts thereof,
wherein
Z is —NR 5
X is —CR a R b —;
Y is —CR c R d —;
R a , R c , R b , and R d are independently —H or a substituted or unsubstituted alkyl or aralkyl group;
R 1 at each occurrence is independently —H or a substituted or unsubstituted alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroaralkyl group; or, R 1 together with the carbon to which it is attached and the adjacent nitrogen, forms a substituted or unsubstituted pyrrolidine, oxazolidine, thiazolidine, imidazolidine, or piperidine ring;
R 2 is —H or a substituted or unsubstituted alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroaralkyl group; or R 2 and R 3 together with the atoms to which they are attached form a substituted or unsubstituted pyrrolidine, oxazolidine, thiazolidine, imidazolidine, or piperidine ring;
R 3 is —H, PG 3 , or a substituted or unsubstituted alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroaralkyl group; wherein PG 3 is a protecting group; or R 2 and R 3 together with the atoms to which they are attached form a substituted or unsubstituted pyrrolidine, oxazolidine, thiazolidine, imidazolidine, or piperidine ring;
R 4 is —H, a substituted or unsubstituted alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroaralkyl group, or a CHR 1 —NH—R 6 group;
R 5 is a —H, a substituted or unsubstituted alkyl, aryl, aralkyl, heteroaryl or a heteroaralkyl group, or a —NH—CHR 1 —C(O)—R 7 group;
R 6 is —H, a substituted or unsubstituted alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroaralkyl group, C(O)R 10 , —C(O)OR 10 , —[C(O)—CHR 1 —NH] m —R 10 , —[C(O)—CHR 1 —NH] m —C(O)R 10 , or —[C(O)—CHR 1 —NH] m —C(O)R 10 ;
R 7 is a substituted or unsubstituted alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroaralkyl group, —OR 10 , NR 10 R 10 , or —[NH—CHR 10 —C(O)] m —;
R 10 at each occurrence is independently —H or a substituted or unsubstituted alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroaralkyl group;
m at each occurrence is independently an integer from 1 to 20; and
n is an integer from 1 to 20.
2. The compound of claim 1 wherein R a is a substituted or unsubstituted C 1-6 alkyl group, R c is a substituted or unsubstituted C 1-6 alkyl group, or both R a and R c are substituted or unsubstituted C 1-6 alkyl groups.
3. The compound of claim 1 wherein R b is —H, R d is —H, or both R b and R d are —H.
4. The compound of claim 1 wherein X is —CH 2 —, Y is —CH 2 —, or X and Y are —CH 2 —.
5. The compound of claim 1 wherein R 1 at each occurrence and R 2 are independently —H, benzyl optionally substituted with one or more OH or halogen, imidazolylmethyl, indolylmethyl, or a C 1-6 alkyl group optionally substituted with one or more substituents selected from —F, —Cl, —Br, —I, —OH, —O-PG 1 , —SH, —S-PG 2 , —NH 2 , —NH-PG 3 , —C(O)OH, —C(O)O-PG 4 , —C(O)NH 2 , or —NHC(NH)NH 2 ; and wherein
PG 1 is a hydroxyl protecting group;
PG 2 is a thiol protecting group;
PG 3 is an amino protecting group; and
PG 4 is a carboxyl protecting group.
6. The compound of claim 1 wherein R 1 at each occurrence and R 2 are independently selected from the group consisting of —H, methyl, isopropyl, isobutyl, sec-butyl, hydroxymethyl, 1-hydroxyethyl, thiomethyl, 4-aminobutyl, 3-guanidinopropyl, benzyl, 4-hydroxybenzyl, indolylmethyl, methylthioethyl, carboxymethyl, carboxyethyl, carboxamidomethyl, carboxamidoethyl, and imidazolylmethyl.
7. The compound of claim 1 wherein R 3 is —H or PG 3 .
8. The compound of claim 1 wherein R 2 and R 3 together form an unsubstituted pyrrolidine group.
9. The compound of claim 1 wherein R 4 is a —CHR 1 —NH—R 6 group.
10. The compound of claim 9 wherein R 6 is —H, —C(O)R 10 , —C(O)OR 10 , —[C(O)—CHR 1 —NH] m —R 10 , or —[C(O)—CHR 1 —NH] m —C(O)R 10 .
11. The compound of claim 1 wherein R 5 is a —CHR 1 —C(O)—R 7 group.
12. The compound of claim 11 wherein R 7 is —OR 10 , —NR 10 R 10 , or —[NH—CHR 1 —C(O)] m —.
13. The compound of claim 1 wherein n is 1, 2, or 3.
14. A method of preparing a compound of claim 1 comprising cyclizing a compound of Formula III,
to produce the compound of Formula I,
wherein
Z is NR 5 ;
X is —CR a R b —;
Y is —CR c R d —;
J is a leaving group or an oxo group, and the dashed line indicates a single or double bond to the leaving group or oxo group, respectively;
R a , R c , R b , and R d are independently —H or a substituted or unsubstituted alkyl or aralkyl group;
R 1 at each occurrence is independently —H or a substituted or unsubstituted alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroaralkyl group; or, R 1 together with the carbon to which it is attached and the adjacent nitrogen, forms a substituted or unsubstituted pyrrolidine, oxazolidine, thiazolidine, imidazolidine, or piperidine ring;
R 2 is —H or a substituted or unsubstituted alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroaralkyl group; or R 2 and R 3 together with the atoms to which they are attached form a substituted or unsubstituted pyrrolidine, oxazolidine, thiazolidine, imidazolidine, or piperidine ring;
R 3 is —H, PG 3 , or a substituted or unsubstituted alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroaralkyl group; wherein PG 3 is an amino protecting group; or R 2 and R 3 together with the atoms to which they are attached form a substituted or unsubstituted pyrrolidine, oxazolidine, thiazolidine, imidazolidine, or piperidine ring;
R 4 is a substituted or unsubstituted alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroaralkyl group, or a —CHR 1 —NH—R 6 group;
R 5 is a —H, a substituted or unsubstituted alkyl, aryl, aralkyl, heteroaryl or a heteroaralkyl group, or a —CHR 1 —C(O)—R 7 group;
R 6 is —H, a substituted or unsubstituted alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroaralkyl group, —C(O)R 10 , —C(O)OR 10 , —[C(O)—CHR 1 —NH] m —R 10 , —[C(O)—CHR 1 —NH] m —C(O)R 10 , or —[C(O)—CHR 1 —NH] m —C(O)—OR 10 ;
R 7 is a substituted or unsubstituted alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroaralkyl group, —OR 10 , —NR 10 R 10 , or —[NH—CHR 1 —C(O)] m —;
R 10 at each occurrence is independently —H or a substituted or unsubstituted alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroaralkyl group;
m is an integer from 1 to 20; and
n is an integer from 1 to 20.
15. The method of claim 14 wherein the compound of Formula III is selected from a compound of Formula IIIA, a compound of Formula IIIB, or a compound of Formula IIIC,
wherein G is a halogen and L is a leaving group.
16. The method of claim 15 further comprising coupling a compound of Formula IV
with a compound of Formula VA or VB,
and removing the amino-protecting group PG 3 to provide the compound of Formula IIIA.
17. A method of making a compound of claim 1 comprising cyclizing a compound of Formula IX,
to produce a compound of Formula I,
wherein
X is —CR a R b —;
Y is —CR c R d —;
R a , R c , R b , and R d are independently —H or a substituted or unsubstituted alkyl or aralkyl group;
R 1 at each occurrence is independently —H or a substituted or unsubstituted alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroaralkyl group; or, R 1 together with the carbon to which it is attached and the adjacent nitrogen, forms a substituted or unsubstituted pyrrolidine, oxazolidine, thiazolidine, imidazolidine, or piperidine ring;
R 2 is —H or a substituted or unsubstituted alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroaralkyl group; or R 2 and R 3 together with the atoms to which they are attached form a substituted or unsubstituted pyrrolidine, oxazolidine, thiazolidine, imidazolidine, or piperidine ring;
R 3 is —H, —PG 3 , or a substituted or unsubstituted alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroaralkyl group; wherein PG 3 is an amino protecting group; or R 2 and R 3 together with the atoms to which they are attached form a substituted or unsubstituted pyrrolidine, oxazolidine, thiazolidine, imidazolidine, or piperidine ring;
R 4 is a substituted or unsubstituted alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroaralkyl group, or a —CHR 1 —NH—R 6 group;
R 5 is a —H, a substituted or unsubstituted alkyl, aryl, aralkyl, heteroaryl or a heteroaralkyl group, or a —CHR 1 —C(O)—R 7 group;
R 6 is —H, a substituted or unsubstituted alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroaralkyl group, —C(O)R 10 , —C(O)OR 10 , —[C(O)—CHR 1 —NH] m —R 10 , —[C(O)—CHR 1 —NH] m —C(O)R 10 , or —[C(O)—CHR 1 —NH] m —C(O)—OR 10 ;
R 7 is a substituted or unsubstituted alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroaralkyl group, —OR 10 , —NR 10 R 10 , or [NH—CHR 1 —C(O)]— m —;
R 10 at each occurrence is independently —H or a substituted or unsubstituted alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroaralkyl group;
m is an integer from 1 to 20; and
n is an integer from 1 to 20.
18. A compound of formula I
and stereoisomers, tautomers and pharmaceutically acceptable salts thereof,
wherein
Z is O or —NR 5
X is —CR a R b —;
Y is —CR c R d ;
R a , R b , R c , and Rd are independently —H or a substituted or unsubstituted alkyl or aralkyl group;
R 1 at each occurrence is independently —H or a substituted or unsubstituted alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroaralkyl group; or, R 1 together with the carbon to which it is attached and the adjacent nitrogen, forms a substituted or unsubstituted pyrrolidine, oxazolidine, thiazolidine, imidazolidine, or piperidine ring;
R 2 is —H or a substituted or unsubstituted alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroaralkyl group; or R 2 and R 3 together with the atoms to which they are attached form a substituted or unsubstituted pyrrolidine, oxazolidine, thiazolidine, imidazolidine, or piperidine ring;
R 3 is —H, PG 3 , or a substituted or unsubstituted alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroaralkyl group; wherein PG 3 is a protecting group; or R 2 and R 3 together with the atoms to which they are attached form a substituted or unsubstituted pyrrolidine, oxazolidine, thiazolidine, imidazolidine, or piperidine ring;
R 4 is —H
R 5 is a —H, a substituted or unsubstituted alkyl, aryl, aralkyl, heteroaryl or a heteroaralkyl group, or a —NH—CHR 1 —C(O)—R 7 group;
R 6 is —H, a substituted or unsubstituted alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroaralkyl group, C(O)R 10 , —C(O)OR 10 , —[C(O)—CHR 1 —NH] m —R 10 , —[C(O)—CHR 1 —NH] m —C(O)R 10 , or —[C(O)—CHR 1 —NH] m —C(O)R 10 ;
R 7 is a substituted or unsubstituted alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroaralkyl group, —OR 10 , NR 10 R 10 , or —[NH—CHR 10 —C(O)] m —;
R 10 at each occurrence is independently —H or a substituted or unsubstituted alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroaralkyl group;
m at each occurrence is independently an integer from 1 to 20; and
n is an integer from 1 to 20.
19. The compound of claim 18 wherein Z is —NR 5 and R 5 is —H.
20. The composition of claim 18 wherein the compounds is
or stereoisomers, tautomers, or pharmaceutically acceptable salts thereof.