Selective Grp94 inhibitors and uses thereof
The disclosure relates to novel selective Grp94 inhibitors, compositions comprising an effective amount of such compounds, and methods to treat or prevent a condition, such as cancer, comprising administering to an animal in need thereof an effective amount of such compounds.
1. A compound of the Formula (I):
or a pharmaceutically acceptable salt thereof, wherein:
(a) Y is —C(R Y ) 2 —, —S—, —NR—, —O—,
(b) each of Z 1 and Z 3 are independently —N—;
(c) Z 2 is —N—;
(d) each of Z 4 , Z 5 , Z 6 , Z 7 and Z 8 are independently —C—;
(e) X 1 is —H, -halo, —N(R) 2 , —OR, —CN, or unsubstituted or substituted —(C 1 -C 6 )aliphatic;
(f) each of X 2 and X 6 is independently —H, -halo, —SR, —N(R) 2 , —OR, —CN, —NO 2 , —CN, —C(O)R, —C(O) 2 R, —S(O)R, —S(O) 2 R, —C(O)N(R) 2 , —SO 2 N(R) 2 , —OC(O)R, —N(R)C(O)R, —N(R)SO 2 R, —OC(O)N(R) 2 , unsubstituted or substituted —(C 1 -C 6 )aliphatic, or an unsubstituted or substituted group selected from (5- or 6-membered)aryl, (5- or 6-membered)arylalkyl, and (5- or 6-membered)heterocyclic aromatic or heterocyclic non-aromatic group; each of X 3 , X 4 , and X 5 is independently —H, -halo, or unsubstituted —(C 1 -C 6 )aliphatic; with the proviso that at least one of X 2 , X 4 and X 5 is —H;
(g) R 1 is —(C 1 -C 6 )aliphatic-N + —(R 2 )(R 3 )(R 4 ), —(C 1 -C 6 )aliphatic-N—R 3 R 4 , —(C 1 -C 6 )aliphatic-C(═O)N—R 3 R 4 , —(C 1 -C 6 )aliphatic-N—CR 2 R 3 R 4 , —(C 1 -C 6 )aliphatic-C(halo) 3 , —(C 1 -C 6 )aliphatic-(C 3 -C 8 )cycloalkyl, —(C 1 C 6 aliphatic-(C 3 -C 8 )heterocyclo, —(C 1 -C 6 )aliphatic-(5 or 6-membered)heteroaryl, —(C 1 -C 6 )aliphatic-cyano, where the cycloalkyl, heterocyclo, or heteroaryl is unsubstituted or substituted, with the proviso that when all of R 2 -R 4 are present the compound further comprises a pharmaceutically acceptable counter ion;
(h) R 2 and R 3 are independently hydrogen, —N(R) 2 , —CH 2 CH(OH)R 4 , —CH(OH)CH 2 R 4 , —CH 2 SO 2 NHR 4 , —CH 2 NHSO 2 R 4 , or unsubstituted or substituted —(C 1 -C 6 )aliphatic, or R 3 and R 4 form an unsubstituted or substituted 3- to 7-membered heterocyclic ring when taken together with the nitrogen to which they are attached;
(i) R 4 is hydrogen, halogen, or unsubstituted or substituted —(C 1 -C 6 )aliphatic;
(j) each R Y is independently R, —OR, or halo; and
(k) each R is independently hydrogen, unsubstituted C 1-6 aliphatic, or C 1-6 aliphatic substituted with halo, —OH, —CN, or —NH 2 ;
wherein each substituted group is substituted with one or more groups selected from halo, —N(R) 2 , —OR, —CN, oxo, unsubstituted C 1-6 aliphatic, or C 1-6 aliphatic substituted with halo, —OH, —CN, or —NH 2 .
2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein:
(a) Y is —CH 2 —, —S—, —NH—, —O—,
(b) each of Z 1 and Z 3 are independently —N—;
(c) Z 2 is;
(d) each of Z 4 , Z 5 , Z 6 , Z 7 and Z 8 are independently —C—;
(e) X 1 is —H, -halo, —NH 2 , —CN, —(C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl, —CH 2 OH, —C(halo) 3 , —CH(halo) 2 , —CH 2 (halo), —OC(halo) 3 , —OCH(halo) 2 , or —OCH 2 (halo);
(f) X 2 is —H, -halo, —NH 2 , —CN, —(C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl, —CH 2 OH, —C(halo) 3 , —CH(halo) 2 , —CH 2 (halo), —OC(halo) 3 , —OCH(halo) 2 , —OCH 2 (halo), or an unsubstituted or substituted (5- or 6-membered)aryl, heterocyclic aromatic, or non-aromatic group selected from pyridyl, furyl, thiophenyl, pyrrolyl, oxazolyl, imidazolyl, phenyl, benzyl, thiazolidinyl, thiadiazolyl, thiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, triazinyl, morpholinyl, pyrrolidinonyl, pyrrolidinyl, piperidinyl, piperazinyl, 2,3-dihydrofuranyl, dihydropyridinyl, tetrahydropyridinyl, tetrahydropyrimidinyl, tetrahydrothiophenyl, or tetrahydrothiopyranyl, each of X 3 , X 4 , and X 5 is independently —H, -halo, or —(C 1 -C 6 )alkyl; with the provisos that at least one of X 2 , X 4 and X 5 is —H;
(g) X 6 is —H;
(h) R 1 is —(CH 2 ) m —N + —(R 2 )(R 3 )(R 4 ), —(CH 2 ) m —N—R 3 R 4 , —(CH 2 ) m —C(═O)N—R 3 R 4 , —(CH 2 ) m —C(halo) 3 , —(CH 2 ) m —(C 3 -C 8 )cycloalkly, —(CH 2 ) m —(C 3 -C 8 )heterocycloalkyl, (CH 2 ) m -(5 or 6-membered)heteroaryl, —(CH 2 ) m -cyano, where m is 1, 2, 3, 4 or 5 and where the cycloalkyl or heterocycle is unsubstituted or substituted with one or more X 1 groups, with the proviso that when all of R 2 -R 4 are present the compound further comprises a pharmaceutically acceptable counter ion;
(i) R 2 and R 3 are independently hydrogen, methyl, ethyl, ethenyl, ethynyl, propyl, butyl, pentyl, hexyl, isopropyl, t-butyl, isobutyl, —C(halo) 3 , —CH(halo) 2 , —CH 2 (halo), —CH 2 C(halo) 3 , —CHCH(halo) 2 , CHCH 2 (halo), —CH 2 OH, —CH 2 CH 2 OH, —CH 2 C(CH 3 ) 2 OH, —CH 2 CH(CH 3 )OH, —C(CH 3 ) 2 CH 2 OH, —CH(CH 3 )CH 2 OH, —CH(CH 3 )CH(OH)R 4 , —CH 2 CH(OH)R 4 , —CH 2 SO 2 NHR 4 , —CH 2 NHSO 2 R 4 or R 4 and R 3 form an unsubstituted or substituted aziridine, azetidine, pyrrolidine or piperidine ring when taken together with the nitrogen to which they are attached; and
(j) R 4 is hydrogen, methyl, ethyl, isopropyl, t-butyl, isobutyl, or —C(halo) 3 .
3. The compound of claim 1 , having the following formula:
or a pharmaceutically acceptable salt thereof.
4. The compound of claim 1 , having Formula(II):
or a pharmaceutically acceptable salt thereof, wherein:
(a) Y is —C(R Y ) 2 —, —S—, —NR—, —O—,
(b) each of Z 1 and Z 3 is independently —N—;
(c) Z 2 is —N—;
(d) X 1 is —H, -halo, —N(R) 2 , —OR, —CN, or unsubstituted or substituted —(C 1 -C 6 )aliphatic;
(e) each of X 2 and X 6 is independently —H, -halo, —SR, —N(R) 2 , —OR, —CN, —NO 2 , —CN, —C(O)R, —C(O) 2 R, —S(O)R, —S(O) 2 R, —C(O)N(R) 2 , —SO 2 N(R) 2 , —OC(O)R, —N(R)C(O)R, —N(R)SO 2 R, —OC(O)N(R) 2 , unsubstituted or substituted —(C 1 -C 6 )aliphatic, or an unsubstituted or substituted group selected from (5- or 6-membered)aryl, (5- or 6-membered)arylalkyl, and (5- or 6-membered)heterocyclic aromatic or heterocyclic non-aromatic group; X 4 is —H, -halo, or unsubstituted —(C 1 -C 6 )aliphatic;
(f) R 1 is —(C 1 -C 6 )aliphatic-N + —(R 2 )(R 3 )(R 4 ), —(C 1 -C 6 )aliphatic-N—R 3 R 4 , —(C 1 -C 6 )aliphatic-C(═O)N—R 3 R 4 , —(C 1 -C 6 )aliphatic-N—CR 2 R 3 R 4 , —(C 1 -C 6 )aliphatic-C(halo) 3 , —(C 1 -C 6 )aliphatic-(C 3 -C 8 )cycloalkyl, —(C 1 -C 6 )aliphatic-(C 3 -C 8 )heterocycloalkyl, —(C 1 -C 6 )aliphatic-(5 or 6-membered)heteroaryl, —(C 1 -C 6 )aliphatic-cyano, with the proviso that when all of R 2 -R 4 are present the compound further comprises a pharmaceutically acceptable counter ion;
(g) R 2 and R 3 are independently hydrogen, —N(R) 2 , —CH 2 CH(OH)R 4 , —CH(OH)CH 2 R 4 , —CH 2 SO 2 NHR 4 , —CH 2 NHSO 2 R 4 , or unsubstituted or substituted —(C 1 -C 6 )aliphatic, or R 3 and R 4 form an unsubstituted or substituted 3- to 7-membered heterocyclic ring when taken together with the nitrogen to which they are attached;
(h) each R Y is independently R, —OR, or halo;
(i) R 4 is hydrogen, halogen, or unsubstituted or substituted —(C 1 -C 6 )aliphatic; and
(j) each R is independently hydrogen, unsubstituted C 1-6 aliphatic, or C 1-6 aliphatic substituted with halo, —OH, —CN, or —NH 2 ;
wherein each substituted group is substituted with one or more groups selected from halo, —N(R) 2 , —OR, —CN, oxo, unsubstituted C 1-6 aliphatic, or C 1-6 aliphatic substituted with halo, —OH, —CN, or —NH 2 .
5. The compound of claim 4 , or a pharmaceutically acceptable salt thereof, wherein:
(a) Y is —CH 2 —, —S—, —NH—, —O—,
(b) each of Z 1 and Z 3 is independently —N—;
(c) Z 2 is —N—;
(d) X 1 is —H, -halo, —NH 2 , —CN, —(C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl, —CH 2 OH, —C(halo) 3 , —CH(halo) 2 , —CH 2 (halo), —OC (halo) 3 , —OCH(halo) 2 , or —OCH 2 (halo);
(e) each of X 2 and X 6 is independently —H, -halo, —NH 2 , —CN, —(C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl, —CH 2 OH, —C(halo) 3 , —CH(halo) 2 , —CH 2 (halo), —OC(halo) 3 , —OCH(halo) 2 , —OCH 2 (halo), or a (5- or 6-membered)aryl, heterocyclic aromatic, or non-aromatic group selected from pyridyl, furyl, thiophenyl, pyrrolyl, oxazolyl, imidazolyl, phenyl, benzyl, thiazolidinyl, thiadiazolyl, thiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, triazinyl, morpholinyl, pyrrolidinonyl, pyrrolidinyl, piperidinyl, piperazinyl, 2,3-dihydrofuranyl, dihydropyridinyl, tetrahydropyridinyl, tetrahydropyrimidinyl, tetrahydrothiophenyl, or tetrahydrothiopyranyl; X 4 is —H, -halo, or —(C 1 -C 6 )alkyl;
(f) R 1 is —(CH 2 ) m —N + —(R 2 )(R 3 )(R 4 ), —(CH 2 ) m —N—R 3 R 4 , —(CH 2 ) m —C(═O)N—R 3 R 4 , —(CH 2 ) m —C(halo) 3 , —(CH 2 ) m —(C 3 -C 8 )cycloalkyl, —(CH 2 ) m —(C 3 -C 8 )heterocycloalkyl, —(CH 2 ) m -(5 or 6-membered)heteroaryl, —(CH 2 ) m -cyano, where m is 1, 2, 3, 4 or 5 and where the cycloalkyl or heterocycle is unsubstituted or substituted with one or more X 1 groups, with the proviso that when all of R 2 -R 4 are present the compound further comprises a pharmaceutically acceptable counter ion;
(g) R 2 and R 3 are independently hydrogen, methyl, ethyl, ethenyl, ethynyl, propyl, butyl, pentyl, hexyl, isopropyl, t-butyl, isobutyl, —C(halo) 3 , —CH(halo) 2 , —CH 2 (halo), —CH 2 C(halo) 3 , —CHCH(halo) 2 , CHCH 2 (halo), —CH 2 OH, —CH 2 CH 2 OH, —CH 2 C(CH 3 ) 2 OH, —CH 2 CH(CH 3 )OH, —C(CH 3 ) 2 CH 2 OH, —CH(CH 3 )CH 2 OH, —CH(CH 3 )CH(OH)R 4 , —CH 2 CH(OH)R 4 , —CH 2 SO 2 NHR 4 , —CH 2 NHSO 2 R 4 , or R 4 and R 3 form an unsubstituted or substituted aziridine, azetidine, pyrrolidine or piperidine ring when taken together with the nitrogen to which they are attached; and
(h) R 4 is hydrogen, methyl, ethyl, isopropyl, t-butyl, isobutyl, or —C(halo) 3 .
6. The compound of claim 4 , having the following formula:
or a pharmaceutically acceptable salt thereof.
7. The compound of claim 1 , having the following formula:
or a pharmaceutically acceptable salt thereof.
8. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
9. A pharmaceutical composition comprising a compound of claim 4 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
10. A pharmaceutical composition comprising a compound of claim 3 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
11. A pharmaceutical composition comprising a compound of claim 7 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
12. The compound of claim 3 , having the following formula:
or a pharmaceutically acceptable salt thereof.
13. The compound of claim 3 , having the following formula:
or a pharmaceutically acceptable salt thereof.
14. The compound of claim 3 , having the following formula:
or a pharmaceutically acceptable salt thereof.
15. The compound of claim 6 , having the following formula:
or a pharmaceutically acceptable salt thereof.
16. The compound of claim 13 , wherein X 1 is —H or -halo.
17. The compound of claim 14 , wherein X 1 is —H or -halo.
18. The compound of claim 15 , wherein X 1 is —H or -halo.
19. The compound of claim 16 , wherein X 2 is -halo, unsubstituted or substituted —(C 1 -C 6 )aliphatic, or unsubstituted or substituted (5- or 6-membered)heterocyclic aromatic.
20. The compound of claim 17 , wherein each of X 3 and X 5 is independently -halo or unsubstituted or substituted —(C 1 -C 6 )aliphatic.
21. The compound of claim 18 , wherein each of X 2 and X 6 is independently —H, -halo, -unsubstituted or substituted —(C 1 -C 6 )aliphatic, or an unsubstituted or substituted (5- or 6-membered)heterocyclic aromatic.
22. The compound of claim 19 , wherein R 1 is selected from the group consisting of —(C 1 -C 6 )aliphatic-N—R 3 R 4 , —(C 1 -C 6 )aliphatic-C(halo) 3 , —(C 1 -C 6 )aliphatic-(C 3 -C 8 )cycloalkyl, —(C 1 -C 6 )aliphatic-(C 3 -C 8 )heterocyclo, and —(C 1 -C 6 )aliphatic-(5 or 6-membered)heteroaryl.
23. The compound of claim 20 , wherein R 1 is selected from the group consisting of —(C 1 -C 6 )aliphatic-N—R 3 R 4 , —(C 1 -C 6 )aliphatic-C(halo) 3 , —(C 1 -C 6 )aliphatic-(C 3 -C 8 )cycloalkyl, —(C 1 -C 6 )aliphatic-(C 3 -C 8 )heterocyclo, and —(C 1 -C 6 )aliphatic-(5 or 6-membered)heteroaryl.
24. The compound of claim 21 , wherein R 1 is selected from the group consisting of —(C 1 -C 6 )aliphatic-N—R 3 R 4 , —(C 1 -C 6 )aliphatic-C(halo) 3 , —(C 1 -C 6 )aliphatic-(C 3 -C 8 )cycloalkyl, —(C 1 -C 6 )aliphatic-(C 3 -C 8 )heterocyclo, and —(C 1 -C 6 )aliphatic-(5 or 6-membered)heteroaryl.
25. The compound of claim 22 , wherein R 1 is —(C 1 -C 6 )aliphatic-N—R 3 R 4 .
26. The compound of claim 22 , wherein —(C 1 -C 6 )aliphatic-(5 or 6-membered)heteroaryl.
27. The compound of claim 23 , wherein R 1 is —(C 1 -C 6 )aliphatic-N—R 3 R 4 .
28. The compound of claim 23 , wherein R 1 —(C 1 -C 6 )aliphatic-(5 or 6-membered)heteroaryl.
29. The compound of claim 23 , wherein R 1 —(C 1 -C 6 )aliphatic-C(halo) 3 .
30. The compound of claim 24 , wherein R 1 is —(C 1 -C 6 )aliphatic-N-R 3 R 4 .
31. The compound of claim 24 , wherein R 1 —(C 1 -C 6 )aliphatic-(5 or 6-membered)heteroaryl.
32. The compound of claim 7 , selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.