Thienopyrazine carboxamides as ubiquitin-specific protease inhibitors
The disclosure relates to inhibitors of USP28 and/or USP25 useful in the treatment of cancers, inflammation, autoimmune diseases, and infectious diseases, having the Formula: (I), where R 1 , R 2 , R 3 , R 4 , R 4′ , R 5 , R 6 , X, and n are described herein.
1. A compound of Formula (Ia):
or a pharmaceutically acceptable salt, stereoisomer, and tautomer thereof,
wherein:
R 1 is H, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, (C 1 -C 6 ) hydroxyalkyl, halogen, (C 3 -C 8 ) cycloalkyl, —CN, or —NR 8 R 9 ;
R 2 is H, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, (C 1 -C 6 ) hydroxyalkyl, halogen, (C 3 -C 8 ) cycloalkyl, or —NR 10 R 11 ;
or R 1 and R 2 together form a (C 4 -C 8 ) cycloalkyl optionally substituted with one or more R 12 ;
R 3 is H, (C 1 -C 6 ) alkyl, or (C 1 -C 6 ) haloalkyl;
R 4 is H, (C 1 -C 6 ) alkyl, halogen, or (C 1 -C 6 ) haloalkyl;
R 4′ is H, (C 1 -C 6 ) alkyl, halogen, or (C 1 -C 6 ) haloalkyl;
R 5 is —(C 0 -C 3 ) alkylene-C(O)OH, —(C 0 -C 3 ) alkylene-heterocyclyl, —O-heterocyclyl, —(C 0 -C 3 ) alkylene-aryl, —(C 0 -C 3 ) alkylene-heteroaryl or —N(R 7 )—(C 0 -C 3 ) alkylene-heterocyclyl, wherein the heterocyclyl, aryl and heteroaryl are optionally substituted with one or more R 13 ;
each R 6 is independently at each occurrence H, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, halogen, —OH, —CN, (C 3 -C 8 ) cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein the alkyl is optionally substituted with one or more (C 1 -C 6 ) alkoxy or —OH, and wherein the cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more R 14 ; or
R 5 and R 6 together when on adjacent atoms form a (C 4 -C 8 ) cycloalkyl ring optionally substituted with one or more R 15 ; or R 5 and R 6 together when on adjacent atoms form a heterocyclyl ring optionally substituted with one or more R 15 ; R 5 and R 6 together when on adjacent atoms form an aryl ring optionally substituted with one or more R 15 ; or R 5 and R 6 together when on adjacent atoms form a heteroaryl ring optionally substituted with one or more R 15 ; or
two R 6 together when on adjacent atoms form a (C 4 -C 8 ) cycloalkyl ring; or two R 6 together when on adjacent atoms form a heterocyclyl ring; two R 6 together when on adjacent atoms form an aryl ring; or two R 6 together when on adjacent atoms form a heteroaryl ring;
R 7 is H or (C 1 -C 6 ) alkyl;
each R 8 , R 9 , R 10 , and R 11 is independently H, (C 1 -C 6 ) alkyl, or —C(O)(C 1 -C 6 ) alkyl;
each R 12 is independently at each occurrence (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, halogen, or —OH;
each R 13 is independently at each occurrence (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, (C 1 -C 6 ) hydroxyalkyl, halogen, (C 3 -C 8 ) cycloalkyl, —C(O)NR 18 R 19 , —S(O) 2 (C 1 -C 6 ) alkyl, —OH, or —NR 16 R 17 , wherein the alkyl is optionally substituted with one or more substituents independently selected from (C 1 -C 6 ) alkoxy, OH, and heterocyclyl; or
two R 13 together when attached to the same carbon can form —C═O when R 5 is —(C 0 -C 3 ) alkylene-heterocyclyl, —O-heterocyclyl, or —N(R 7 )—(C 0 -C 3 ) alkylene-heterocyclyl; or two R 13 together when attached to the same atom form a (C 3 -C 8 ) spirocycloalkyl optionally substituted with one or more R 20 when R 5 is
—(C 0 -C 3 ) alkylene-heterocyclyl, —O-heterocyclyl, or —N(R 7 )—(C 0 -C 3 ) alkylene-heterocyclyl; or two R 13 together when attached to the same atom
form a (C 3 -C 8 ) spiroheterocyclyl optionally substituted with one or more R 20 when R 5 is
—(C 0 -C 3 ) alkylene-heterocyclyl, —O-heterocyclyl, or
—N(R 7 )—(C 0 -C 3 ) alkylene-heterocyclyl; or two R 13 together when on adjacent atoms form a heterocyclyl ring optionally substituted with one or more R 20 ; or two R 13 together when on adjacent atoms form a heteroaryl ring optionally substituted with one or more R 20 ; or two R 13 together with the atoms to which they are attached can form a bridged heterocyclyl ring optionally substituted with one or more R 20 when R 5 is —(C 0 -C 3 ) alkylene-heterocyclyl,
—O-heterocyclyl, or —N(R 7 )—(C 0 -C 3 ) alkylene-heterocyclyl;
each R 14 is independently at each occurrence (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, halogen, cycloalkyl, heterocyclyl, or —C(O)-heterocyclyl, wherein the alkyl is optionally substituted with one or more substituents independently selected from (C 1 -C 6 ) alkoxy and —OH;
each R 15 is independently at each occurrence (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, halogen, —OH, —CN, —C(O)OH, or —C(O)O(C 1 -C 6 ) alkyl;
each R 16 and R 17 is independently H, (C 1 -C 6 ) alkyl, (C 3 -C 8 ) cycloalkyl, —CH 2 C(O)NH 2 , —S(O) 2 (C 1 -C 6 ) alkyl, —S(O) 2 (C 6 -C 10 ) aryl or —C(O)(C 1 -C 6 ) alkyl;
each R 18 and R 19 is independently H or (C 1 -C 6 ) alkyl;
each R 20 is independently at each occurrence (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, or halogen; or
two R 20 together when attached to the same carbon form —C═(O);
n is 0, 1, 2, or 3;
wherein a heterocyclyl comprises a monocyclic or polycyclic ring containing from 1 to 3 heteroatoms selected from O, N, S and is fully or partially unsaturated; and
wherein a heteroaryl comprises a monocylclic or polycyclic aromatic radical of 5 to 24 ring atoms containing 1 to 4 heteroatoms selected from O, N and S.
2. The compound of claim 1 , wherein the compound is of Formula (Ib):
or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.
3. The compound of claim 1 , wherein the compound is of Formula (Ib):
or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.
4. The compound of claim 3 , wherein R 3 is H, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.
5. The compound of claim 3 , wherein R 1 is selected from H and (C 1 -C 6 ) alkyl, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.
6. The compound of claim 5 , wherein R 1 is methyl, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.
7. The compound of claim 6 , wherein R 2 is hydrogen, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.
8. The compound of claim 1 , wherein R 4 is H or (C 1 -C 6 ) alkyl, and R 4′ is H or (C 1 -C 6 ) alkyl, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.
9. The compound of claim 8 , wherein R 4 is H and R 4′ is methyl, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.
10. The compound of claim 1 , wherein n is 0, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.
11. The compound of claim 1 , wherein n is 1 or 2, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.
12. The compound of claim 11 , wherein each R 6 is independently at each occurrence halogen or —CN, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.
13. The compound of claim 1 , wherein R 5 is —(C 0 -C 3 )alkylene-heterocyclyl, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.
14. The compound of claim 13 , wherein R 5 is —(C 0 )alkylene-heterocyclyl, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.
15. The compound of claim 1 , wherein R 5 is piperazinyl, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.
16. The compound of claim 1 , wherein R 5 is 8- or 9-membered bicyclic heterocyclyl, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.
17. A compound of Formula (Id):
or a pharmaceutically acceptable salt, stereoisomer, and tautomer thereof,
wherein:
R 1 is H, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, (C 1 -C 6 ) hydroxyalkyl, halogen, (C 3 -C 8 ) cycloalkyl, —CN, or —NR 8 R 9 ;
R 2 is H, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, (C 1 -C 6 ) hydroxyalkyl, halogen, (C 3 -C 8 ) cycloalkyl, or —NR 10 R 11 ;
or R 1 and R 2 together form a (C 4 -C 8 ) cycloalkyl optionally substituted with one or more R 12 ;
R 3 is H, (C 1 -C 6 ) alkyl, or (C 1 -C 6 ) haloalkyl;
R 4 is H, (C 1 -C 6 ) alkyl, halogen, or (C 1 -C 6 ) haloalkyl;
R 4′ is H, (C 1 -C 6 ) alkyl, halogen, or (C 1 -C 6 ) haloalkyl;
R 5 is —(C 0 -C 3 ) alkylene-C(O)OH, —(C 0 -C 3 ) alkylene-heterocyclyl, —O-heterocyclyl, —(C 0 -C 3 ) alkylene-aryl, —(C 0 -C 3 ) alkylene-heteroaryl or —N(R 7 )—(C 0 -C 3 ) alkylene-heterocyclyl, wherein the heterocyclyl, aryl and heteroaryl are optionally substituted with one or more R 13 ;
each R 6 is independently at each occurrence H, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, halogen, —OH, —CN, (C 3 -C 8 ) cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein the alkyl is optionally substituted with one or more (C 1 -C 6 ) alkoxy or —OH, and wherein the cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more R 14 ; or
R 5 and R 6 together when on adjacent atoms form a (C 4 -C 8 ) cycloalkyl ring optionally substituted with one or more R 15 ; or R 5 and R 6 together when on adjacent atoms form a heterocyclyl ring optionally substituted with one or more R 15 ; R 5 and R 6 together when on adjacent atoms form an aryl ring optionally substituted with one or more R 15 ; or R 5 and R 6 together when on adjacent atoms form a heteroaryl ring optionally substituted with one or more R 15 ; or
two R 6 together when on adjacent atoms form a (C 4 -C 8 ) cycloalkyl ring; or two R 6 together when on adjacent atoms form a heterocyclyl ring; two R 6 together when on adjacent atoms form an aryl ring; or two R 6 together when on adjacent atoms form a heteroaryl ring;
R 7 is H or (C 1 -C 6 ) alkyl;
each R 8 , R 9 , R 10 , and R 11 is independently H, (C 1 -C 6 ) alkyl, or —C(O)(C 1 -C 6 ) alkyl;
each R 12 is independently at each occurrence (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, halogen, or —OH;
each R 13 is independently at each occurrence (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, (C 1 -C 6 ) hydroxyalkyl, halogen, (C 3 -C 8 ) cycloalkyl, —C(O)NR 18 R 19 , —S(O) 2 (C 1 -C 6 ) alkyl, —OH, or —NR 16 R 17 , wherein the alkyl is optionally substituted with one or more substituents independently selected from (C 1 -C 6 ) alkoxy, OH, and heterocyclyl; or
two R 13 together when attached to the same carbon can form —C═(O) when R 5 is —(C 0 -C 3 ) alkylene-heterocyclyl, —O-heterocyclyl, or —N(R 7 )—(C 0 -C 3 ) alkylene-heterocyclyl; or two R 13 together when attached to the same atom form a (C 3 -C 8 ) spirocycloalkyl optionally substituted with one or more R 20 when R 5 is
—(C 0 -C 3 ) alkylene-heterocyclyl, —O-heterocyclyl, or
—N(R 7 )—(C 0 -C 3 ) alkylene-heterocyclyl; or two R 13 together when attached to the same atom
form a (C 3 -C 8 ) spiroheterocyclyl optionally substituted with one or more R 20 when R 5 is
—(C 0 -C 3 ) alkylene-heterocyclyl, —O-heterocyclyl, or
—N(R 7 )—(C 0 -C 3 ) alkylene-heterocyclyl; or two R 13 together when on adjacent atoms form a heterocyclyl ring optionally substituted with one or more R 20 ; or two R 13 together when on adjacent atoms form a heteroaryl ring optionally substituted with one or more R 20 ; or two R 13 together with the atoms to which they are attached can form a bridged heterocyclyl ring optionally substituted with one or more R 20 when R 5 is —(C 0 -C 3 ) alkylene-heterocyclyl,
—O-heterocyclyl, or —N(R 7 )—(C 0 -C 3 ) alkylene-heterocyclyl;
each R 14 is independently at each occurrence (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, halogen, cycloalkyl, heterocyclyl, or —C(O)-heterocyclyl, wherein the alkyl is optionally substituted with one or more substituents independently selected from (C 1 -C 6 ) alkoxy and —OH;
each R 15 is independently at each occurrence (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, halogen, —OH, —CN, —C(O)OH, or —C(O)O(C 1 -C 6 ) alkyl;
each R 16 and R 17 is independently H, (C 1 -C 6 ) alkyl, (C 3 -C 8 ) cycloalkyl, —CH 2 C(O)NH 2 , —S(O) 2 (C 1 -C 6 ) alkyl, —S(O) 2 (C 6 -C 10 ) aryl or —C(O)(C 1 -C 6 ) alkyl;
each R 18 and R 19 is independently H or (C 1 -C 6 ) alkyl;
each R 20 is independently at each occurrence (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, or halogen; or
two R 20 together when attached to the same carbon form —C═(O);
n is 0, 1, 2, or 3;
wherein a heterocyclyl comprises a monocyclic or polycyclic ring containing from 1 to 3 heteroatoms selected from O, N, S and is fully or partially unsaturated; and
wherein a heteroaryl comprises a monocyclic or polycyclic aromatic radical of 5 to 24 ring atoms containing 1 to 4 heteroatoms selected from O, N and S.
18. A method of making a compound of Formula (I), comprising: reacting a compound of Formula 2a with a compound of Formula 2b in the presence of a coupling agent and a base:
wherein:
X is N or CR 6 ;
R 1 is H, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, (C 1 -C 6 ) hydroxyalkyl, halogen, (C 3 -C 8 ) cycloalkyl, —CN, or —NR 8 R 9 ;
R 2 is H, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, (C 1 -C 6 ) hydroxyalkyl, halogen, (C 3 -C 8 ) cycloalkyl, or —NR 10 R 11 ;
or R 1 and R 2 together form a (C 4 -C 8 ) cycloalkyl optionally substituted with one or more R 12 ;
R 3 is H, (C 1 -C 6 ) alkyl, or (C 1 -C 6 ) haloalkyl;
R 4 is H, (C 1 -C 6 ) alkyl, halogen, or (C 1 -C 6 ) haloalkyl;
R 4′ is H, (C 1 -C 6 ) alkyl, halogen, or (C 1 -C 6 ) haloalkyl;
R 5 is —(C 0 -C 3 ) alkylene-C(O)OH, —(C 0 -C 3 ) alkylene-heterocyclyl, —O-heterocyclyl, —(C 0 -C 3 ) alkylene-aryl, —(C 0 -C 3 ) alkylene-heteroaryl or —N(R 7 )—(C 0 -C 3 ) alkylene-heterocyclyl, wherein the heterocyclyl, aryl and heteroaryl are optionally substituted with one or more R 13 ;
each R 6 is independently at each occurrence H, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, halogen, —OH, —CN, (C 3 -C 8 ) cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein the alkyl is optionally substituted with one or more (C 1 -C 6 ) alkoxy or —OH, and wherein the cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more R 14 ; or
R 5 and R 6 together when on adjacent atoms form a (C 4 -C 8 ) cycloalkyl ring optionally substituted with one or more R 15 ; or R 5 and R 6 together when on adjacent atoms form a heterocyclyl ring optionally substituted with one or more R 15 ; R 5 and R 6 together when on adjacent atoms form an aryl ring optionally substituted with one or more R 15 ; or R 5 and R 6 together when on adjacent atoms form a heteroaryl ring optionally substituted with one or more R 15 ; or
two R 6 together when on adjacent atoms form a (C 4 -C 8 ) cycloalkyl ring; or two R 6 together when on adjacent atoms form a heterocyclyl ring; two R 6 together when on adjacent atoms form an aryl ring; or two R 6 together when on adjacent atoms form a heteroaryl ring;
R 7 is H or (C 1 -C 6 ) alkyl;
each R 8 , R 9 , R 10 , and R 11 is independently H, (C 1 -C 6 ) alkyl, or
—C(O)(C 1 -C 6 ) alkyl;
each R 12 is independently at each occurrence (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, halogen, or —OH;
each R 13 is independently at each occurrence (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, (C 1 -C 6 ) hydroxyalkyl, halogen, (C 3 -C 8 ) cycloalkyl, —C(O)NR 18 R 19 , —S(O) 2 (C 1 -C 6 ) alkyl, —OH, or —NR 16 R 17 , wherein the alkyl is optionally substituted with one or more substituents independently selected from (C 1 -C 6 ) alkoxy, OH, and heterocyclyl; or
two R 13 together when attached to the same carbon can form —C═(O) when R 5 is —(C 0 -C 3 ) alkylene-heterocyclyl, —O-heterocyclyl, or —N(R 7 )—(C 0 -C 3 ) alkylene-heterocyclyl; or two R 13 together when attached to the same atom form a (C 3 -C 8 ) spirocycloalkyl optionally substituted with one or more R 20 when R 5 is
—(C 0 -C 3 ) alkylene-heterocyclyl, —O-heterocyclyl, or
—N(R 7 )—(C 0 -C 3 ) alkylene-heterocyclyl; or two R 13 together when attached to the same atom
form a (C 3 -C 8 ) spiroheterocyclyl optionally substituted with one or more R 20 when R 5 is
—(C 0 -C 3 ) alkylene-heterocyclyl, —O-heterocyclyl, or
—N(R 7 )—(C 0 -C 3 ) alkylene-heterocyclyl; or two R 13 together when on adjacent atoms form a heterocyclyl ring optionally substituted with one or more R 20 ; or two R 13 together when on adjacent atoms form a heteroaryl ring optionally substituted with one or more R 20 ; or two R 13 together with the atoms to which they are attached can form a bridged heterocyclyl ring optionally substituted with one or more R 20 when R 5 is —(C 0 -C 3 ) alkylene-heterocyclyl,
—O-heterocyclyl, or —N(R 7 )—(C 0 -C 3 ) alkylene-heterocyclyl;
each R 14 is independently at each occurrence (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, halogen, cycloalkyl, heterocyclyl, or —C(O)-heterocyclyl, wherein the alkyl is optionally substituted with one or more substituents independently selected from (C 1 -C 6 ) alkoxy and —OH;
each R 15 is independently at each occurrence (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, halogen, —OH, —CN, —C(O)OH, or —C(O)O(C 1 -C 6 ) alkyl;
each R 16 and R 17 is independently H, (C 1 -C 6 ) alkyl, (C 3 -C 8 ) cycloalkyl, —CH 2 C(O)NH 2 , —S(O) 2 (C 1 -C 6 ) alkyl, —S(O) 2 (C 6 -C 10 ) aryl or —C(O)(C 1 -C 6 ) alkyl;
each R 18 and R 19 is independently H or (C 1 -C 6 ) alkyl;
each R 20 is independently at each occurrence (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, or halogen; or
two R 20 together when attached to the same carbon form —C═(O);
n is 0, 1, 2, or 3;
wherein a heterocyclyl comprises a monocyclic or polycyclic ring containing from 1 to 3 heteroatoms selected from O, N, S and is fully or partially unsaturated; and
wherein a heteroaryl comprises a monocyclic or polycyclic aromatic radical of 5 to 24 ring atoms containing 1 to 4 heteroatoms selected from O, N and S.
19. The method of claim 18 , wherein the coupling agent is selected from the group consisting of 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide with 1-hydroxybenzotriazole (EDCl/HOBt); (Benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP); O-benzotriazole-N,N,N,N′-tetramethyl-uronium-hexafluoro-phosphate (HBTU); and [bis (dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate (HATU).
20. The method of claim 18 , wherein the base is selected from triethylamine (TEA), N,N-diisopropylethylamine (DIEA), and 4-dimethylaminopyridine (DMAP).