Compounds that enhance Atoh1 expression

A method of treating a gastrointestinal cancer in a subject, the method comprising selecting a subject in need of treatment, and administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising a compound of the following formula:

• or a pharmaceutically acceptable salt thereof, wherein:
• X is O or S;
• each of R143, R144, R145, and R146 is, independently selected from H, halo, OH, CN, NO2, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy;
• and —NHC(O)(C1-C3 alkyl);
• R147 is NReRf, wherein one of Re and Rf is hydrogen or C1-C3 alkyl;
• and the other of Re and Rf is:
• (i) —C(O)Rg;
• wherein Rg is C6-C10 aryl or heteroaryl including 5-10 atoms, each of which is optionally substituted with from 1-5 Rh;
• or
• (ii) C1-C3 alkyl;
• or
• R147 is C6-C10 aryl or heteroaryl including 5-10 atoms, each of which is optionally substituted with from 1-5 Rh;
• or
• R147 is —SCH2Ri, wherein Ri is:
• (i) C6-C10 aryl or heteroaryl including 5-10 atoms, each of which is optionally substituted with from 1-5 Rh;
• or
• (ii) —C(O)NReRf, wherein one of Re and Rf is hydrogen or C1-C3 alkyl;
• and the other of Re and Rf is —C(O)Rg;
• wherein Rg is C6-C10 aryl or heteroaryl including 5-10 atoms, each of which is optionally substituted with from 1-5 Rh;
• and
• Rh at each occurrence is, independently:
• (i) halo;
• NH2;
• NH(C1-C3 alkyl);
• N(C1-C3 alkyl)2;
• hydroxy;
• C1-C6 alkoxy or C1-C6 haloalkoxy;
• nitro;
• or cyano;
• or
• (ii) C1-C6 alkyl or C1-C6 haloalkyl;
• and a pharmaceutically acceptable carrier,
• wherein the pharmaceutical composition is administered locally to the proliferating cells.

A method of treating cerebellar granule neuron deficiencies, joint disease, or osteoarthritis in a subject, the method comprising selecting a subject in need of treatment, and administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising a compound of the following formula:

• or a pharmaceutically acceptable salt thereof, wherein:
• X is O or S;
• each of R143, R144, R145, and R146 is, independently selected from H, halo, OH, CN, NO2, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy;
• and —NHC(O)(C1-C3 alkyl);
• R147 is NReRf, wherein one of Re and Rf is hydrogen or C1-C3 alkyl;
• and the other of Re and Rf is:
• (i) —C(O)Rg;
• wherein Rg is C6-C10 aryl or heteroaryl including 5-10 atoms, each of which is optionally substituted with from 1-5 Rh;
• or
• (ii) C1-C3 alkyl;
• or
• R147 is C6-C10 aryl or heteroaryl including 5-10 atoms, each of which is optionally substituted with from 1-5 Rh;
• or
• R147 is —SCH2Ri, wherein Ri is:
• (i) C6-C10 aryl or heteroaryl including 5-10 atoms, each of which is optionally substituted with from 1-5 Rh;
• or
• (ii) —C(O)NReRf, wherein one of Re and Rf is hydrogen or C1-C3 alkyl;
• and the other of Re and Rf is —C(O)Rg;
• wherein Rg is C6-C10 aryl or heteroaryl including 5-10 atoms, each of which is optionally substituted with from 1-5 Rh;
• and
• Rh at each occurrence is, independently:
• (i) halo;
• NH2;
• NH(C1-C3 alkyl);
• N(C1-C3 alkyl)2;
• hydroxy;
• C1-C6 alkoxy or C1-C6 haloalkoxy;
• nitro;
• or cyano;
• or
• (ii) C1-C6 alkyl or C1-C6 haloalkyl;
• and a pharmaceutically acceptable carrier.

A method of treating a subject who has a hearing impairment or imbalance disorder associated with a loss of auditory hair cells, the method comprising:

• selecting a subject in need of treatment;
• obtaining a population of cells capable of differentiating into auditory hair cells;
• contacting the population of cells in vitro with an effective amount of at least one compound of the following formula:
• or a pharmaceutically acceptable salt thereof, wherein:
• X is O or S;
• each of R143, R144, R145, and R146 is, independently selected from H, halo, OH, CN, NO2, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, and —NHC(O)(C1-C3 alkyl);
• R147 is NReRf, wherein one of Re and Rf is hydrogen or C1-C3 alkyl, and the other of Re and Rf is:
• (i) —C(O)Rg;
• wherein Rg is C6-C10 aryl or heteroaryl including 5-10 atoms, each of which is optionally substituted with from 1-5 Rh, or
• (ii) C1-C3 alkyl;
• or
• R147 is C6-C10 aryl or heteroaryl including 5-10 atoms, each of which is optionally substituted with from 1-5 Rh;
• or
• R147 is —SCH2Ri, wherein Ri is:
• (i) C6-C10 aryl or heteroaryl including 5-10 atoms, each of which is optionally substituted with from 1-5 Rh, or
• (ii) —C(O)NReRf, wherein one of Re and Rf is hydrogen or C1-C3 alkyl, and the other of Re and Rf is —C(O)Rg;
• wherein Rg is C6-C10 aryl or heteroaryl including 5-10 atoms, each of which is optionally substituted with from 1-5 Rh, and
• Rh at each occurrence is, independently:
• (i) halo;
• NH2;
• NH(C1-C3 alkyl);
• N(C1-C3 alkyl)2;
• hydroxy;
• C1-C6 alkoxy or C1-C6 haloalkoxy;
• nitro;
• or cyan;
• or
• (ii) C1-C6 alkyl or C1-C6 haloalkyl,
• for a time sufficient to increase the number cells in the population that have characteristics of a differentiated auditory hair cell;
• and
• administering the population of cells, or a subset thereof, to the subject's ear, thereby treating the subject.

A method of increasing the number of cells with the characteristics of auditory hair cells in a population of cells in vitro, the method comprising obtaining a population of cells capable of differentiating into auditory hair cells, contacting the population of cells in vitro with an effective amount of at least one compound of the following formula:

• or a pharmaceutically acceptable salt thereof, wherein:
• X is O or S;
• each of R143, R144, R145, and R146 is, independently selected from H, halo, OH, CN, NO2, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy;
• and —NHC(O)(C1-C3 alkyl);
• R147 is NReRf, wherein one of Re and Rf is hydrogen or C1-C3 alkyl;
• and the other of Re and Rf is:
• (i) —C(O)Rg;
• wherein Rg is C6-C10 aryl or heteroaryl including 5-10 atoms, each of which is optionally substituted with from 1-5 Rh;
• or
• (ii) C1-C3 alkyl;
• or
• R147 is C6-C10 aryl or heteroaryl including 5-10 atoms, each of which is optionally substituted with from 1-5 Rh;
• or
• R147 is —SCH2Ri, wherein Ri is:
• (i) C6-C10 aryl or heteroaryl including 5-10 atoms, each of which is optionally substituted with from 1-5 Rh;
• or
• (ii) —C(O)NReRf, wherein one of Re and Rf is hydrogen or C1-C3 alkyl;
• and the other of Re and Rf is —C(O)Rg;
• wherein Rg is C6-C10 aryl or heteroaryl including 5-10 atoms, each of which is optionally substituted with from 1-5 Rh;
• and
• Rh at each occurrence is, independently:
• (i) halo;
• NH2;
• NH(C1-C3 alkyl);
• N(C1-C3 alkyl)2;
• hydroxy;
• C1-C6 alkoxy or C1-C6 haloalkoxy;
• nitro;
• or cyano;
• or
• (ii) C1-C6 alkyl or C1-C6 haloalkyl,
• for a time sufficient to increase the number of cells with the characteristics of auditory hair cells in the population of cells.