Indoline scaffold SHP-2 inhibitors and cancer treatment method

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;
• R1 is:
• phenyl substituted with one or more of Cl, Br, I, COOH, or C(R3)3, where R3 can independently be halogen or OR4, where R4 can be H or alkyl;
• or methylphenyl optionally substituted with one or more of Cl, Br, or I;
• R2 is:
• 1) ethanoyl substituted with fluoro, chloro, bromo, iodo, OH, OR4, 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, C5-C20 alkyl, OH, OR4, or C(O)OR5, where R4 is methyl, ethyl, propyl, butyl or C5-C20 alkyl, and where R5 is H, Na, methyl, ethyl, propyl, butyl or C5-C20 alkyl;
• propanoyl optionally unsaturated and substituted with fluoro, chloro, bromo, iodo, OH, OR4, C(O)OH, C(O)ONa, unsubstituted phenyl, or phenyl substituted with one or more of fluoro, chloro, bromo, iodo, methyl, ethyl, propyl, butyl, C5-C20 alkyl, OH, OR4, or C(O)OR5, where R4 is methyl, ethyl, propyl, butyl or C5-C20 alkyl, and where R5 is H, Na, methyl, ethyl, propyl, butyl or C5-C20 alkyl;
• butanoyl, optionally unsaturated and unsubstituted or substituted with fluoro, chloro, bromo, iodo, OH, OR4, C(O)OH, C(O)ONa, unsubstituted phenyl, or phenyl substituted with one or more of fluoro, chloro, bromo, iodo, methyl, ethyl, propyl, butyl, C5-C20 alkyl, OH, OR4, or C(O)OR5, where R4 is methyl, ethyl, propyl, butyl or C5-C20 alkyl, and where R5 is H, Na, methyl, ethyl, propyl, butyl or C5-C20 alkyl;
• or
• C5-C21 alkanoyl, optionally unsaturated and unsubstituted or substituted with fluoro, chloro, bromo, iodo, OH, OR4, C(O)OH, C(O)ONa, unsubstituted phenyl, or phenyl substituted with one or more of fluoro, chloro, bromo, iodo, methyl, ethyl, propyl, butyl, C5-C20 alkyl, OH, OR4, or C(O)OR5, where R4 is methyl, ethyl, propyl, butyl, or C5-C20 alkyl, and where R5 is H, Na, methyl, ethyl, propyl, butyl or C5-C20 alkyl;
• 2) phenylcarbonyl substituted with fluoro, chloro, bromo, iodo, OH, OR4, or C(O)OR5, where R4 is methyl, ethyl, propyl, butyl, or C5-C20 alkyl, and where R5 can be H, Na, methyl, ethyl, propyl, butyl or C5-C20 alkyl;
• 3) cyclobutylcarbonyl substituted with fluoro, chloro, bromo, iodo, OH, OR4, unsubstituted phenyl, or phenyl substituted with one or more of fluoro, chloro, bromo, iodo, methyl, ethyl, propyl, butyl, C5-C20 alkyl, OH, OR4, or C(O)OR5 where R4 is methyl, ethyl, propyl, butyl or C5-C20 alkyl and where R5 is H, Na, methyl, ethyl, propyl, butyl or C5-C20 alkyl;
• cyclopentylcarbonyl optionally unsaturated and unsubstituted or substituted with fluoro, chloro, bromo, iodo, OH, OR4, unsubstituted phenyl, or phenyl substituted with one or more of fluoro, chloro, bromo, iodo, methyl, ethyl, propyl, butyl, C5-C20 alkyl, OH, OR4, or C(O)OR5, where R4 is methyl, ethyl, propyl, butyl, or C5-C20 alkyl, and where R5 is H, Na, methyl, ethyl, propyl, butyl or C5-C20 alkyl;
• or
• cyclohexylcarbonyl optionally unsaturated and unsubstituted or substituted with fluoro, chloro, bromo, iodo, OH, OR4, unsubstituted phenyl, or phenyl substituted with one or more of fluoro, chloro, bromo, iodo, methyl, ethyl, propyl, butyl, C5-C20 alkyl, OH, OR4, or C(O)OR5, where R4 is methyl, ethyl, propyl, butyl, or C5-C20 alkyl, and where R5 is H, Na, methyl, ethyl, propyl, butyl, or C5-C20 alkyl;
• or
• 4) —C(O)NH2;
• —C(O)NR6R7 where R6 and R7 are independently methyl, ethyl, propyl, butyl, C5-C20 alkyl, or phenyl, wherein any of which can be optionally substituted with one or more of halogen, alkyl, OR4, OH, C(R3)3, or phenyl is further substituted with C(O)OR5, where R3 is independently fluoro, chloro, bromo, or iodo, where R4 is methyl, ethyl, propyl, butyl, or C5-C20 alkyl, and where R5 is IL Na, methyl, ethyl, propyl, butyl or C5-C20 alkyl;
• or
• —C(O)NHR6 where R6 is methyl, ethyl, propyl, butyl, C5-C20 alkyl, or phenyl, any of which can be optionally substituted with one or more of halogen, alkyl, OR4, OH, C(R3)3, or phenyl is further substituted with C(O)OR5, where R3 is independently fluoro, chloro, bromo, or iodo, where R4 is methyl, ethyl, propyl, butyl, or C5-C20 alkyl, and where R5 is H, Na, methyl, ethyl, propyl, butyl or C5-C20 alkyl;
• and
• R′ is H, methyl, or C2-C24 alkyl.

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;
• R1 is:
• phenyl substituted with one or more of Cl, Br, I, COOH, or C(R3)3, where R3 can independently be halogen or OR4, where R4 can be H or alkyl;
• or methylphenyl optionally substituted with one or more of Cl, Br, or I;
• R2 is:
• 1) ethanoyl substituted with fluoro, chloro, bromo, iodo, OH, OR4, 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, C5-C20 alkyl, OH, OR4, or C(O)OR5 where R4 is methyl, ethyl, propyl, butyl or C5-C20 alkyl and where R5 is H, Na, methyl, ethyl, propyl, butyl or C5-C20 alkyl;
• propanoyl optionally unsaturated and substituted with fluoro, chloro, bromo, iodo, OH, OR4, C(O)OH, C(O)ONa, unsubstituted phenyl, or phenyl substituted with one or more of fluoro, chloro, bromo, iodo, methyl, ethyl, propyl, butyl, C5-C20 alkyl, OH, OR4, or C(O)OR5, where R4 is methyl, ethyl, propyl, butyl or C5-C20 alkyl, and where R5 is H, Na, methyl, ethyl, propyl, butyl or C5-C20 alkyl;
• butanoyl, optionally unsaturated and unsubstituted or substituted with fluoro, chloro, bromo, iodo, OH, OR4, C(O)OH, C(O)ONa, unsubstituted phenyl, or phenyl substituted with one or more of fluoro, chloro, bromo, iodo, methyl, ethyl, propyl, butyl, C5-C20 alkyl, OH, OR4, or C(O)OR5, where R4 is methyl, ethyl, propyl, butyl or C5-C20 alkyl, and where R5 is H, Na, methyl, ethyl, propyl, butyl or C5-C20 alkyl;
• or
• C5-C21 alkanoyl, optionally unsaturated and unsubstituted or substituted with fluoro, chloro, bromo, iodo, OH, OR4, C(O)OH, C(O)ONa, unsubstituted phenyl, or phenyl substituted with one or more of fluoro, chloro, bromo, iodo, methyl, ethyl, propyl, butyl, C5-C20 alkyl, OH, OR4, or C(O)OR5, where R4 is methyl, ethyl, propyl, butyl, or C5-C20 alkyl, and where R5 is H, Na, methyl, ethyl, propyl, butyl or C5-C20 alkyl;
• 2) phenylcarbonyl substituted with fluoro, chloro, bromo, iodo, OH, OR4, or C(O)OR5, where R4 is methyl, ethyl, propyl, butyl, or C5-C20 alkyl, and where R5 can be H, Na, methyl, ethyl, propyl, butyl or C5-C20 alkyl;
• 3) cyclobutylcarbonyl substituted with fluoro, chloro, bromo, iodo, OH, OR4, unsubstituted phenyl, or phenyl substituted with one or more of fluoro, chloro, bromo, iodo, methyl, ethyl, propyl, butyl, C5-C20 alkyl, OH, OR4, or C(O)OR5 where R4 is methyl, ethyl, propyl, butyl or C5-C20 alkyl and where R5 is H, Na, methyl, ethyl, propyl, butyl or C5-C20 alkyl;
• cyclopentylcarbonyl optionally unsaturated and unsubstituted or substituted with fluoro, chloro, bromo, iodo, OH, OR4, unsubstituted phenyl, or phenyl substituted with one or more of fluoro, chloro, bromo, iodo, methyl, ethyl, propyl, butyl, C5-C20 alkyl, OH, OR4, or C(O)OR5, where R4 is methyl, ethyl, propyl, butyl, or C5-C20 alkyl, and where R5 is H, Na, methyl, ethyl, propyl, butyl or C5-C20 alkyl;
• or
• cyclohexylcarbonyl optionally unsaturated and unsubstituted or substituted with fluoro, chloro, bromo, iodo, OH, OR4, unsubstituted phenyl, or phenyl substituted with one or more of fluoro, chloro, bromo, iodo, methyl, ethyl, propyl, butyl, C5-C20 alkyl, OH, OR4, or C(O)OR5, where R4 is methyl, ethyl, propyl, butyl, or C5-C20 alkyl, and where R5 is H, Na, methyl, ethyl, propyl, butyl, or C5-C20 alkyl;
• or
• 4) —C(O)NH2;
• —C(O)NR6R7 where R6 and R7 are independently methyl, ethyl, propyl, butyl, C5-C20 alkyl, or phenyl, wherein any of which can be optionally substituted with one or more of halogen, alkyl, OR4, OH, C(R3)3, or phenyl is further substituted with C(O)OR5, where R3 is independently fluoro, chloro, bromo, or iodo, where R4 is methyl, ethyl, propyl, butyl, or C5-C20 alkyl, and where R5 is H, Na, methyl, ethyl, propyl, butyl or C5-C20 alkyl;
• or
• —C(O)NHR6 where R6 is methyl, ethyl, propyl, butyl, C5-C20 alkyl, or phenyl, any of which can be optionally substituted with one or more of halogen, alkyl, OR4, OH, C(R3)3, or phenyl is further substituted with C(O)OR5, where R3 is independently fluoro, chloro, bromo, or iodo, where R4 is methyl, ethyl, propyl, butyl, or C5-C20 alkyl, and where R5 is H, Na, methyl, ethyl, propyl, butyl or C5-C20 alkyl;
• and
• R′ is H, methyl, or C2-C20 alkyl.

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;
• R1 is:
• phenyl substituted with one or more of Cl, Br, I, COOH, or C(R3)3, where R3 can independently be halogen or OR4, where R4 can be H or alkyl;
• or methylphenyl optionally substituted with one or more of Cl, Br, or I;
• R2 has a structure selected from:
• wherein
• indicates the point of attachment;
• and
• R′ is H, methyl, or C2-C20 alkyl.