Indoline scaffold SHP-2 inhibitors and cancer treatment method
The subject invention concerns methods and compounds for inhibiting Shp2. In one embodiment, a compound of the invention has a chemical structure as shown in formula I or II: wherein X, Y, and Z are independently N or S; R 1 is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, any of which can be optionally substituted with one or more of halogen; alkyl; heteroalkyl; —COOH; —C(R 3 ) 3 , wherein R 3 can independently be any of —H or halogen; or —OR 4 , wherein R 4 can be any of H, alkyl, or heteroalkyl; R 2 is alkyl, alkylcarbonyl, heteroalkylcarbonyl, aryl, arylcarbonyl, heterocycloalkylcarbonyl, cycloalkylcarbonyl, or —C(O)NR 6 R 7 , any of which can be optionally substituted with one or more of halogen; alkyl; heteroalkyl; carbonyl; —OR 4 , wherein R 4 can be —H, alkyl, or heteroalkyl; —OH; —C(R 3 ) 3 , wherein R 3 can independently be any of —H or halogen; aryl, which can be substituted with one or more of halogen or —OR 4 ; heterocycloalkyl; or —C(O)OR 5 , wherein R 5 can be —H or alkyl; R 6 and R 7 are independently —H, alkyl, heteroalkyl, aryl, or heteroaryl; and R′ is H or alkyl; or a pharmaceutically acceptable salt or hydrate thereof.
1. A Shp2 inhibitor compound having the chemical structure shown in formula I:
or a pharmaceutically acceptable salt or hydrate thereof,
wherein:
X, Y, and Z are N;
R 1 is: phenyl substituted with one or more of Cl, Br, I, COOH, or C(R 3 ) 3 , where R 3 can independently be halogen or OR 4 , where R 4 can be H or alkyl; or methylphenyl optionally substituted with one or more of Cl, Br, or I;
R 2 is:
1) ethanoyl substituted with fluoro, chloro, bromo, iodo, OH, OR 4 , C(O)OH, or C(O)ONa, unsubstituted phenyl, or phenyl substituted with one or more of fluoro, chloro, bromo, iodo, methyl, ethyl, propyl, butyl, C 5 -C 20 alkyl, OH, OR 4 , or C(O)OR 5 , where R 4 is methyl, ethyl, propyl, butyl or C 5 -C 20 alkyl, and where R 5 is H, Na, methyl, ethyl, propyl, butyl or C 5 -C 20 alkyl;
propanoyl optionally unsaturated and substituted with fluoro, chloro, bromo, iodo, OH, OR 4 , C(O)OH, C(O)ONa, unsubstituted phenyl, or phenyl substituted with one or more of fluoro, chloro, bromo, iodo, methyl, ethyl, propyl, butyl, C 5 -C 20 alkyl, OH, OR 4 , or C(O)OR 5 , where R 4 is methyl, ethyl, propyl, butyl or C 5 -C 20 alkyl, and where R 5 is H, Na, methyl, ethyl, propyl, butyl or C 5 -C 20 alkyl;
butanoyl, optionally unsaturated and unsubstituted or substituted with fluoro, chloro, bromo, iodo, OH, OR 4 , C(O)OH, C(O)ONa, unsubstituted phenyl, or phenyl substituted with one or more of fluoro, chloro, bromo, iodo, methyl, ethyl, propyl, butyl, C 5 -C 20 alkyl, OH, OR 4 , or C(O)OR 5 , where R 4 is methyl, ethyl, propyl, butyl or C 5 -C 20 alkyl, and where R 5 is H, Na, methyl, ethyl, propyl, butyl or C 5 -C 20 alkyl; or
C 5 -C 21 alkanoyl, optionally unsaturated and unsubstituted or substituted with fluoro, chloro, bromo, iodo, OH, OR 4 , C(O)OH, C(O)ONa, unsubstituted phenyl, or phenyl substituted with one or more of fluoro, chloro, bromo, iodo, methyl, ethyl, propyl, butyl, C 5 -C 20 alkyl, OH, OR 4 , or C(O)OR 5 , where R 4 is methyl, ethyl, propyl, butyl, or C 5 -C 20 alkyl, and where R 5 is H, Na, methyl, ethyl, propyl, butyl or C 5 -C 20 alkyl;
2) phenylcarbonyl substituted with fluoro, chloro, bromo, iodo, OH, OR 4 , or C(O)OR 5 , where R 4 is methyl, ethyl, propyl, butyl, or C 5 -C 20 alkyl, and where R 5 can be H, Na, methyl, ethyl, propyl, butyl or C 5 -C 20 alkyl;
3) cyclobutylcarbonyl substituted with fluoro, chloro, bromo, iodo, OH, OR 4 , unsubstituted phenyl, or phenyl substituted with one or more of fluoro, chloro, bromo, iodo, methyl, ethyl, propyl, butyl, C 5 -C 20 alkyl, OH, OR 4 , or C(O)OR 5 where R 4 is methyl, ethyl, propyl, butyl or C 5 -C 20 alkyl and where R 5 is H, Na, methyl, ethyl, propyl, butyl or C 5 -C 20 alkyl;
cyclopentylcarbonyl optionally unsaturated and unsubstituted or substituted with fluoro, chloro, bromo, iodo, OH, OR 4 , unsubstituted phenyl, or phenyl substituted with one or more of fluoro, chloro, bromo, iodo, methyl, ethyl, propyl, butyl, C 5 -C 20 alkyl, OH, OR 4 , or C(O)OR 5 , where R 4 is methyl, ethyl, propyl, butyl, or C 5 -C 20 alkyl, and where R 5 is H, Na, methyl, ethyl, propyl, butyl or C 5 -C 20 alkyl; or
cyclohexylcarbonyl optionally unsaturated and unsubstituted or substituted with fluoro, chloro, bromo, iodo, OH, OR 4 , unsubstituted phenyl, or phenyl substituted with one or more of fluoro, chloro, bromo, iodo, methyl, ethyl, propyl, butyl, C 5 -C 20 alkyl, OH, OR 4 , or C(O)OR 5 , where R 4 is methyl, ethyl, propyl, butyl, or C 5 -C 20 alkyl, and where R 5 is H, Na, methyl, ethyl, propyl, butyl, or C 5 -C 20 alkyl; or
4) —C(O)NH 2 ;
—C(O)NR 6 R 7 where R 6 and R 7 are independently methyl, ethyl, propyl, butyl, C 5 -C 20 alkyl, or phenyl, wherein any of which can be optionally substituted with one or more of halogen, alkyl, OR 4 , OH, C(R 3 ) 3 , or phenyl is further substituted with C(O)OR 5 , where R 3 is independently fluoro, chloro, bromo, or iodo, where R 4 is methyl, ethyl, propyl, butyl, or C 5 -C 20 alkyl, and where R 5 is H, Na, methyl, ethyl, propyl, butyl or C 5 -C 20 alkyl; or
—C(O)NHR 6 where R 6 is methyl, ethyl, propyl, butyl, C 5 -C 20 alkyl, or phenyl, any of which can be optionally substituted with one or more of halogen, alkyl, OR 4 , OH, C(R 3 ) 3 , or phenyl is further substituted with C(O)OR 5 , where R 3 is independently fluoro, chloro, bromo, or iodo, where R 4 is methyl, ethyl, propyl, butyl, or C 5 -C 20 alkyl, and where R 5 is H, Na, methyl, ethyl, propyl, butyl or C 5 -C 20 alkyl; and
R′ is H, methyl, or C 2 -C 20 alkyl.
2. The compound of claim 1 , wherein R 1 is phenyl optionally substituted with one or more of —Cl, —COOH, —CF 3 , or —OCH 3 .
3. The compound of claim 1 , wherein —OR 4 is —OCH 3 or —OCH 2 CH 3 .
4. The compound of claim 1 , wherein R 1 has a structure selected from:
wherein
indicates the point of attachment.
5. The compound of claim 1 , wherein R 2 is propanoyl substituted with one or more of —OH, —COOH, phenyl, or —OR 4 , wherein R 4 is alkyl, or wherein R 2 is C 4 -C 20 alkanoyl optionally substituted with one or more of —OH, —COOH, phenyl, or OR 4 wherein R 4 is alkyl.
6. A composition comprising a compound having the chemical structure shown in formula I:
or a pharmaceutically acceptable salt or hydrate thereof,
wherein:
X, Y, and Z are N;
R 1 is: phenyl substituted with one or more of Cl, Br, I, COOH, or C(R 3 ) 3 , where R 3 can independently be halogen or OR 4 , where R 4 can be H or alkyl; or methylphenyl optionally substituted with one or more of Cl, Br, or I;
R 2 is:
1) ethanoyl substituted with fluoro, chloro, bromo, iodo, OH, OR 4 , C(O)OH, or C(O)ONa, unsubstituted phenyl, or phenyl substituted with one or more of fluoro, chloro, bromo, iodo, methyl, ethyl, propyl, butyl, C 5 -C 20 alkyl, OH, OR 4 , or C(O)OR 5 , where R 4 is methyl, ethyl, propyl, butyl or C 5 -C 20 alkyl, and where R 5 is H, Na, methyl, ethyl, propyl, butyl or C 5 -C 20 alkyl;
propanoyl optionally unsaturated and substituted with fluoro, chloro, bromo, iodo, OH, OR 4 , C(O)OH, C(O)ONa, unsubstituted phenyl, or phenyl substituted with one or more of fluoro, chloro, bromo, iodo, methyl, ethyl, propyl, butyl, C 5 -C 20 alkyl, OH, OR 4 , or C(O)OR 5 , where R 4 is methyl, ethyl, propyl, butyl or C 5 -C 20 alkyl, and where R 5 is H, Na, methyl, ethyl, propyl, butyl or C 5 -C 20 alkyl;
butanoyl, optionally unsaturated and unsubstituted or substituted with fluoro, chloro, bromo, iodo, OH, OR 4 , C(O)OH, C(O)ONa, unsubstituted phenyl, or phenyl substituted with one or more of fluoro, chloro, bromo, iodo, methyl, ethyl, propyl, butyl, C 5 -C 20 alkyl, OH, OR 4 , or C(O)OR 5 , where R 4 is methyl, ethyl, propyl, butyl or C 5 -C 20 alkyl, and where R 5 is H, Na, methyl, ethyl, propyl, butyl or C 5 -C 20 alkyl; or
C 5 -C 21 alkanoyl, optionally unsaturated and unsubstituted or substituted with fluoro, chloro, bromo, iodo, OH, OR 4 , C(O)OH, C(O)ONa, unsubstituted phenyl, or phenyl substituted with one or more of fluoro, chloro, bromo, iodo, methyl, ethyl, propyl, butyl, C 5 -C 20 alkyl, OH, OR 4 , or C(O)OR 5 , where R 4 is methyl, ethyl, propyl, butyl, or C 5 -C 20 alkyl, and where R 5 is H, Na, methyl, ethyl, propyl, butyl or C 5 -C 20 alkyl;
2) phenylcarbonyl substituted with fluoro, chloro, bromo, iodo, OH, OR 4 , or C(O)OR 5 , where R 4 is methyl, ethyl, propyl, butyl, or C 5 -C 20 alkyl, and where R 5 can be H, Na, methyl, ethyl, propyl, butyl or C 5 -C 20 alkyl;
3) cyclobutylcarbonyl substituted with fluoro, chloro, bromo, iodo, OH, OR 4 , unsubstituted phenyl, or phenyl substituted with one or more of fluoro, chloro, bromo, iodo, methyl, ethyl, propyl, butyl, C 5 -C 20 alkyl, OH, OR 4 , or C(O)OR 5 where R 4 is methyl, ethyl, propyl, butyl or C 5 -C 20 alkyl and where R 5 is H, Na, methyl, ethyl, propyl, butyl or C 5 -C 20 alkyl;
cyclopentylcarbonyl optionally unsaturated and unsubstituted or substituted with fluoro, chloro, bromo, iodo, OH, OR 4 , unsubstituted phenyl, or phenyl substituted with one or more of fluoro, chloro, bromo, iodo, methyl, ethyl, propyl, butyl, C 5 -C 20 alkyl, OH, OR 4 , or C(O)OR 5 , where R 4 is methyl, ethyl, propyl, butyl, or C 5 -C 20 alkyl, and where R 5 is H, Na, methyl, ethyl, propyl, butyl or C 5 -C 20 alkyl; or
cyclohexylcarbonyl optionally unsaturated and unsubstituted or substituted with fluoro, chloro, bromo, iodo, OH, OR 4 , unsubstituted phenyl, or phenyl substituted with one or more of fluoro, chloro, bromo, iodo, methyl, ethyl, propyl, butyl, C 5 -C 20 alkyl, OH, OR 4 , or C(O)OR 5 , where R 4 is methyl, ethyl, propyl, butyl, or C 5 -C 20 alkyl, and where R 5 is H, Na, methyl, ethyl, propyl, butyl, or C 5 -C 20 alkyl; or
4) —C(O)NH 2 ;
—C(O)NR 6 R 7 where R 6 and R 7 are independently methyl, ethyl, propyl, butyl, C 5 -C 20 alkyl, or phenyl, wherein any of which can be optionally substituted with one or more of halogen, alkyl, OR 4 , OH, C(R 3 ) 3 , or phenyl is further substituted with C(O)OR 5 , where R 3 is independently fluoro, chloro, bromo, or iodo, where R 4 is methyl, ethyl, propyl, butyl, or C 5 -C 20 alkyl, and where R 5 is IL Na, methyl, ethyl, propyl, butyl or C 5 -C 20 alkyl; or
—C(O)NHR 6 where R 6 is methyl, ethyl, propyl, butyl, C 5 -C 20 alkyl, or phenyl, any of which can be optionally substituted with one or more of halogen, alkyl, OR 4 , OH, C(R 3 ) 3 , or phenyl is further substituted with C(O)OR 5 , where R 3 is independently fluoro, chloro, bromo, or iodo, where R 4 is methyl, ethyl, propyl, butyl, or C 5 -C 20 alkyl, and where R 5 is H, Na, methyl, ethyl, propyl, butyl or C 5 -C 20 alkyl; and
R′ is H, methyl, or C 2 -C 24 alkyl.
7. A kit comprising in one or more containers a compound having the chemical structure shown in formula I:
or a pharmaceutically acceptable salt or hydrate thereof,
wherein:
X, Y, and Z are N;
R 1 is: phenyl substituted with one or more of Cl, Br, I, COOH, or C(R 3 ) 3 , where R 3 can independently be halogen or OR 4 , where R 4 can be H or alkyl; or methylphenyl optionally substituted with one or more of Cl, Br, or I;
R 2 is:
1) ethanoyl substituted with fluoro, chloro, bromo, iodo, OH, OR 4 , C(O)OH, or C(O)ONa, unsubstituted phenyl, or phenyl substituted with one or more of fluoro, chloro, bromo, iodo, methyl, ethyl, propyl, butyl, C 5 -C 20 alkyl, OH, OR 4 , or C(O)OR 5 where R 4 is methyl, ethyl, propyl, butyl or C 5 -C 20 alkyl and where R 5 is H, Na, methyl, ethyl, propyl, butyl or C 5 -C 20 alkyl;
propanoyl optionally unsaturated and substituted with fluoro, chloro, bromo, iodo, OH, OR 4 , C(O)OH, C(O)ONa, unsubstituted phenyl, or phenyl substituted with one or more of fluoro, chloro, bromo, iodo, methyl, ethyl, propyl, butyl, C 5 -C 20 alkyl, OH, OR 4 , or C(O)OR 5 , where R 4 is methyl, ethyl, propyl, butyl or C 5 -C 20 alkyl, and where R 5 is H, Na, methyl, ethyl, propyl, butyl or C 5 -C 20 alkyl;
butanoyl, optionally unsaturated and unsubstituted or substituted with fluoro, chloro, bromo, iodo, OH, OR 4 , C(O)OH, C(O)ONa, unsubstituted phenyl, or phenyl substituted with one or more of fluoro, chloro, bromo, iodo, methyl, ethyl, propyl, butyl, C 5 -C 20 alkyl, OH, OR 4 , or C(O)OR 5 , where R 4 is methyl, ethyl, propyl, butyl or C 5 -C 20 alkyl, and where R 5 is H, Na, methyl, ethyl, propyl, butyl or C 5 -C 20 alkyl; or
C 5 -C 21 alkanoyl, optionally unsaturated and unsubstituted or substituted with fluoro, chloro, bromo, iodo, OH, OR 4 , C(O)OH, C(O)ONa, unsubstituted phenyl, or phenyl substituted with one or more of fluoro, chloro, bromo, iodo, methyl, ethyl, propyl, butyl, C 5 -C 20 alkyl, OH, OR 4 , or C(O)OR 5 , where R 4 is methyl, ethyl, propyl, butyl, or C 5 -C 20 alkyl, and where R 5 is H, Na, methyl, ethyl, propyl, butyl or C 5 -C 20 alkyl;
2) phenylcarbonyl substituted with fluoro, chloro, bromo, iodo, OH, OR 4 , or C(O)OR 5 , where R 4 is methyl, ethyl, propyl, butyl, or C 5 -C 20 alkyl, and where R 5 can be H, Na, methyl, ethyl, propyl, butyl or C 5 -C 20 alkyl;
3) cyclobutylcarbonyl substituted with fluoro, chloro, bromo, iodo, OH, OR 4 , unsubstituted phenyl, or phenyl substituted with one or more of fluoro, chloro, bromo, iodo, methyl, ethyl, propyl, butyl, C 5 -C 20 alkyl, OH, OR 4 , or C(O)OR 5 where R 4 is methyl, ethyl, propyl, butyl or C 5 -C 20 alkyl and where R 5 is H, Na, methyl, ethyl, propyl, butyl or C 5 -C 20 alkyl;
cyclopentylcarbonyl optionally unsaturated and unsubstituted or substituted with fluoro, chloro, bromo, iodo, OH, OR 4 , unsubstituted phenyl, or phenyl substituted with one or more of fluoro, chloro, bromo, iodo, methyl, ethyl, propyl, butyl, C 5 -C 20 alkyl, OH, OR 4 , or C(O)OR 5 , where R 4 is methyl, ethyl, propyl, butyl, or C 5 -C 20 alkyl, and where R 5 is H, Na, methyl, ethyl, propyl, butyl or C 5 -C 20 alkyl; or
cyclohexylcarbonyl optionally unsaturated and unsubstituted or substituted with fluoro, chloro, bromo, iodo, OH, OR 4 , unsubstituted phenyl, or phenyl substituted with one or more of fluoro, chloro, bromo, iodo, methyl, ethyl, propyl, butyl, C 5 -C 20 alkyl, OH, OR 4 , or C(O)OR 5 , where R 4 is methyl, ethyl, propyl, butyl, or C 5 -C 20 alkyl, and where R 5 is H, Na, methyl, ethyl, propyl, butyl, or C 5 -C 20 alkyl; or
4) —C(O)NH 2 ;
—C(O)NR 6 R 7 where R 6 and R 7 are independently methyl, ethyl, propyl, butyl, C 5 -C 20 alkyl, or phenyl, wherein any of which can be optionally substituted with one or more of halogen, alkyl, OR 4 , OH, C(R 3 ) 3 , or phenyl is further substituted with C(O)OR 5 , where R 3 is independently fluoro, chloro, bromo, or iodo, where R 4 is methyl, ethyl, propyl, butyl, or C 5 -C 20 alkyl, and where R 5 is H, Na, methyl, ethyl, propyl, butyl or C 5 -C 20 alkyl; or
—C(O)NHR 6 where R 6 is methyl, ethyl, propyl, butyl, C 5 -C 20 alkyl, or phenyl, any of which can be optionally substituted with one or more of halogen, alkyl, OR 4 , OH, C(R 3 ) 3 , or phenyl is further substituted with C(O)OR 5 , where R 3 is independently fluoro, chloro, bromo, or iodo, where R 4 is methyl, ethyl, propyl, butyl, or C 5 -C 20 alkyl, and where R 5 is H, Na, methyl, ethyl, propyl, butyl or C 5 -C 20 alkyl; and
R′ is H, methyl, or C 2 -C 20 alkyl.
8. The compound of claim 1 , wherein the compound has the structure:
9. The composition of claim 6 , wherein the compound has the structure:
10. The kit of claim 7 , wherein the compound has the structure:
11. A Shp2 inhibitor compound having the chemical structure shown in formula I:
or a pharmaceutically acceptable salt or hydrate thereof,
wherein:
X, Y, and Z are N;
R 1 is: phenyl substituted with one or more of Cl, Br, I, COOH, or C(R 3 ) 3 , where R 3 can independently be halogen or OR 4 , where R 4 can be H or alkyl; or methylphenyl optionally substituted with one or more of Cl, Br, or I;
R 2 has a structure selected from:
wherein
indicates the point of attachment; and
R′ is H, methyl, or C 2 -C 20 alkyl.
12. A compound having the structure: