1h-pyrrole-2,5-dione compounds and methods of using them to induce self-renewal of stem/progenitor supporting cells

Abstract

The present invention relates to 1H-pyrrole-2,5-dione compounds and methods of using them to induce self-renewal of stem/progenitor supporting cells, including inducing the stem/progenitor cells to proliferate while maintaining, in the daughter cells, the capacity to differentiate into tissue cells.

What is claimed is: 
     
         1 . A compound of Formula (I): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or tautomer thereof, wherein: 
         Q 1  is CH or N; 
         Q 2  is C or N; 
         Q 3  is C or N;
 wherein at least one of Q 1 , Q 2 , and Q 3  is N; 
 
         R 1  is selected from the group consisting of hydrogen, halo, C 1 -C 4 alkyl, C 1 -C 4 alkenyl, C 1 -C 4 alkynyl, —CN, —OH, —O—C 1 -C 4 alkyl, —NH 2 , —NHC(O)R 1a , and —S(O) 2 NH 2 ; wherein the alkyl is optionally substituted with one to 3 substituents independently selected from the group consisting of halo and —OH; and wherein R 1a  is C 1 -C 4 alkyl; 
         R 2  is selected from the group consisting of halo, C 1 -C 4 alkyl, C 1 -C 4 alkenyl, C 1 -C 4 alkynyl, —CN, —OH, —O—C 1 -C 4 alkyl, —NH 2 , —NH(C 1 -C 4 alkyl), —N(C 1 -C 4 alkyl) 2 , —NHC(O)R 2a , and —S(O) 2 NH 2 ; wherein the alkyl is optionally substituted with one to 3 substituents independently selected from the group consisting of halo and —OH; and wherein R 2a  is C 1 -C 4 alkyl; 
         R 3  is selected from the group consisting of hydrogen, halo, C 1 -C 4 alkyl, C 1 -C 4 alkenyl, C 1 -C 4 alkynyl, —CN, —OH, —O—C 1 -C 4 alkyl, —NH 2 , —NHC(O)R 3a , and —S(O) 2 NH 2 ; wherein the alkyl is optionally substituted with one to 3 substituents independently selected from the group consisting of halo and —OH; and wherein R 3a  is C 1 -C 4 alkyl; 
         Ar is selected from the group consisting of 
       
       
         
           
           
               
               
           
         
         —Z—W—X—Y— is —C(R Z ) 2 —C(R W ) 2 —N(R X )—C(R Y ) 2 —, —C(R Z ) 2 —C(R W ) 2 —CH(R X )—C(R Y ) 2 —, or —C(R W ) 2 —CH(R X )—C(R Y ) 2 —; 
         each R Z  is independently selected from the group consisting of hydrogen, deuterium, halo, and C 1 -C 4 alkyl, or both R Z  groups together form C 3 -C 6 cycloalkyl or oxo; 
         each R W  is independently selected from the group consisting of hydrogen, deuterium, halo, and C 1 -C 4 alkyl, or both R W  groups together form C 3 -C 6 cycloalkyl or oxo; 
         or R Z  and R W  together with the carbons to which they are attached form a C 3 -C 6 cycloalkyl; 
         R X  is selected from the group consisting of —COR X1 , —SO 2 R X1 , heteroaryl, and —(C 1 -C 4 alkylene)-(C 3 -C 8 cycloalkyl), and wherein the —(C 1 -C 4 alkylene)-(C 3 -C 8 cycloalkyl) is optionally substituted with one to four halo on the C 1 -C 4 alkylene; 
         wherein R X1  is heterocyclyl, wherein the heterocyclyl is optionally substituted with one to twelve substituents independently selected from the group consisting of deuterium, halo, —[C(R X1a ) 2 ] p —CN, —CFs, C 1 -C 4 alkyl, —(CH 2 ) p —OH, —[C(R X1a ) 2 ] p —OH, —[C(R X1a ) 2 ] p —O—C 1 -C 4 alkyl, —NHCOC 1 -C 4 alkyl, —CONHC 1 -C 4 alkyl, —COH, —CO 2 H, —[C(R X1a ) 2 ] p —COO—C 1 -C 4 alkyl, —(CH 2 ) p —NH 2 , —[C(R X1a ) 2 ] p —NH 2 , —[C(R X1a ) 2 ] p —NH—C 1 -C 4 alkyl, —[C(R X1a ) 2 ] p —N—(C 1 -C 4 alkyl) 2 ; wherein p is 0, 1, 2, or 3; wherein each R X1a  is independently selected from the group consisting of hydrogen, deuterium, halo, —CF 3 , and C 1 -C 4 alkyl, or both R X1a  groups together form C 3 -C 6 cycloalkyl; 
         or R X1  is N(R X2 ) 2  wherein R X2  is independently selected from hydrogen, alkyl, substituted alkyl, wherein the alkyl substitution can be halo, heterocycles and substituted heterocycles; 
         each R Y  is independently selected from the group consisting of hydrogen, deuterium, halo, and C 1 -C 4 alkyl, or both R Y  groups together form C 3 -C 6 cycloalkyl or oxo; and 
         m is 0, 1, or 2; 
         provided that the compound is not 
       
       
         
           
           
               
               
           
         
       
     
     
         2 . The compound of  claim 1 , wherein R X  is —COR X1 . 
     
     
         3 . The compound of  claim 2 , wherein R X1  is piperidine, 2,8-diazaspiro[4,5]decane, 2,5-diazabicyclo[2,2,1]heptane, or 8-oxa-3-azabicyclo[3.2.1]octane, each of which is optionally substituted with one to twelve substituents independently selected from the group consisting of deuterium, halo, C 1 -C 4 alkyl, —[C(RX 1a ) 2 ] p —OH, —(CH 2 ) p —NMe 2 , —(CH 2 ) p —NHMe, —(CH 2 ) p —NH 2 ; wherein p is 0, 1, 2, or 3. 
     
     
         4 . The compound of  claim 3 , wherein R X1  is piperidine, optionally substituted with one to six halo substituents. 
     
     
         5 . The compound of  claim 4 , the piperidine is optionally substituted with —[C(R X1a ) 2 ] p —OH, —(CH 2 ) p —NMe 2 . 
     
     
         6 . The compound of  claim 1 , wherein R X  is heteroaryl. 
     
     
         7 . The compound of  claim 6 , wherein the heteroaryl is monocyclic or bicyclic. 
     
     
         8 . The compound of  claim 6 , wherein the heteroaryl contains one to three nitrogens. 
     
     
         9 . The compound of  claim 1 , wherein R X  is —(C 1 -C 4 alkylene)-(C 3 -C 8 cycloalkyl). 
     
     
         10 . The compound of  claim 9 , wherein the —(C 1 -C 4 alkylene)-(C 3 -C 8 cycloalkyl) is substituted with one or two halogens on the C 1 -C 4 alkylene. 
     
     
         11 . The compound of  claim 9 , wherein the C 3 -C 8 cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. 
     
     
         12 . A compound of Formula (Ia): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or tautomer thereof, wherein: 
         Q 1  is CH or N; 
         Q 2  is C or N; 
         Q 3  is C or N; 
         wherein at least one of Q 1 , Q 2 , and Q 3  is N; 
         R 1  is selected from the group consisting of hydrogen, halo, C 1 -C 4 alkyl, C 1 -C 4 alkenyl, C 1 -C 4 alkynyl, —CN, —OH, —O—C 1 -C 4 alkyl, —NH 2 , —NHC(O)R 3a , and —S(O) 2 NH 2 ; wherein the alkyl is optionally substituted with one to 3 substituents independently selected from the group consisting of halo and —OH; and wherein R 1a  is C 1 -C 4 alkyl; 
         R 2  is selected from the group consisting of hydrogen, halo, C 1 -C 4 alkyl, C 1 -C 4 alkenyl, C 1 -C 4 alkynyl, —CN, —OH, —O—C 1 -C 4 alkyl, —NH 2 , —NH(C 1 -C 4 alkyl), —N(C 1 -C 4 alkyl) 2 , —NHC(O)R 2a , and —S(O) 2 NH 2 ; wherein the alkyl is optionally substituted with one to 3 substituents independently selected from the group consisting of halo and —OH; and wherein R 2a  is C 1 -C 4 alkyl; 
         R 3  is selected from the group consisting of hydrogen, halo, C 1 -C 4 alkyl, C 1 -C 4 alkenyl, C 1 -C 4 alkynyl, —CN, —OH, —O—C 1 -C 4 alkyl, —NH 2 , —NHC(O)R 3a , and —S(O) 2 NH 2 ; wherein the alkyl is optionally substituted with one to 3 substituents independently selected from the group consisting of halo and —OH; and wherein R 3a  is C 1 -C 4 alkyl; 
         Ar is selected from the group consisting of 
       
       
         
           
           
               
               
           
         
       
       wherein Ar is optionally substituted with deuterium, halo, alkyl, alkoxy, and CN;
 Q 7  is selected from S, O, CH 2 , and NR Q7 ; wherein R Q7  is hydrogen or optionally substituted C 1 -C 4 alkyl; 
 —Z—W—X—Y— is —C(R Z ) 2 —C(R W ) 2 —N(R X )—C(R Y ) 2 —, —C(R Z ) 2 —C(R W ) 2 —CH(R X )—C(R Y ) 2 —, or —C(R W ) 2 —CH(R X )—C(R Y ) 2 —; 
 each R Z  is independently selected from the group consisting of hydrogen, deuterium, halo, and C 1 -C 4 alkyl, or both R Z  groups together form C 3 -C 6 cycloalkyl or oxo; 
 each R W  is independently selected from the group consisting of hydrogen, deuterium, halo, and C 1 -C 4 alkyl, or both R W  groups together form C 3 -C 6 cycloalkyl or oxo; 
 or R Z  and R W  together with the carbons to which they are attached form a C 3 -C 6 cycloalkyl; 
 R X  is selected from the group consisting of hydrogen, R X1 , —COR X1 , —SO 2 R X1 , —(C 1 -C 4 alkylene)-R X1 , and wherein the —(C 1 -C 4 alkylene)-R X1  is optionally substituted with one to four halo on the C 1 -C 4 alkylene; 
 wherein R X1  is C 3 -C 8 cycloalkyl, heteroaryl, or heterocyclyl, wherein the heterocyclyl is optionally substituted with one to twelve substituents independently selected from the group consisting of deuterium, halo, —[C(R X1a ) 2 ] p —CN, —CF 3 , C 1 -C 4 alkyl, —(CH 2 ) p —OH, —[C(R X1a ) 2 ] p —OH, —[C(R X1a ) 2 ] p —O—C 1 -C 4 alkyl, —NHCOC 1 -C 4 alkyl, CONHC 1 -C 4 alkyl, COH, —CO 2 H, —[C(R X1a ) 2 ] p —COO—C 1 -C 4 alkyl, —(CH 2 ) p —NH 2 , —[C(R X1a ) 2 ] p —NH 2 , —[C(R X1a ) 2 ] p —NH—C 1 - C 4 alkyl, —[C(R X1a ) 2 ] p —N—(C 1 -C 4 alkyl) 2 ; wherein p is 0, 1, 2, or 3; wherein each R X1a  is independently selected from the group consisting of hydrogen, deuterium, halo, —CF 3 , and C 1 -C 4 alkyl, or both R X1a  groups together form C 3 -C 6 cycloalkyl; 
 or R X1  is N(R X2 ) 2  wherein R X2  is independently selected from hydrogen, alkyl, substituted alkyl, wherein the alkyl substitution can be halo, heterocycles and substituted heterocycles; 
 each R Y  is independently selected from the group consisting of hydrogen, deuterium, halo, and C 1 -C 4 alkyl, or both R Y  groups together form C 3 -C 6 cycloalkyl or oxo; and 
 m is 0, 1, or 2. 
 
     
     
         13 . A compound of Formula (Ib): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or tautomer thereof, wherein: 
         Q 1  is CH or N; 
         Q 2  is C or N; 
         Q 3  is C or N;
 wherein at least one of Q 1 , Q 2 , and Q 3  is N; and provided that when Q 1  is CH and Q 3  is C, Q 2  is not N; 
 
         R 1  is selected from the group consisting of hydrogen, halo, C 1 -C 4 alkyl, C 1 -C 4 alkenyl, C 1 -C 4 alkynyl, —CN, —OH, —O—C 1 -C 4 alkyl, —NH 2 , —NHC(O)R 3a , and —S(O) 2 NH 2 ; wherein the alkyl is optionally substituted with one to 3 substituents independently selected from the group consisting of halo and —OH; and wherein R 1a  is C 1 -C 4 alkyl; 
         R 2  is selected from the group consisting of hydrogen, halo, C 1 -C 4 alkyl, C 1 -C 4 alkenyl, C 1 -C 4 alkynyl, —CN, —OH, —O—C 1 -C 4 alkyl, —NH 2 , —NH(C 1 -C 4 alkyl), —N(C 1 -C 4 alkyl) 2 , —NHC(O)R 2a , and —S(O) 2 NH 2 ; wherein the alkyl is optionally substituted with one to 3 substituents independently selected from the group consisting of halo and —OH; and wherein R 2a  is C 1 -C 4 alkyl; 
         R 3  is selected from the group consisting of hydrogen, halo, C 1 -C 4 alkyl, C 1 -C 4 alkenyl, C 1 -C 4 alkynyl, —CN, —OH, —O—C 1 -C 4 alkyl, —NH 2 , —NHC(O)R 3a , and —S(O) 2 NH 2 ; wherein the alkyl is optionally substituted with one to 3 substituents independently selected from the group consisting of halo and —OH; and wherein R 3a  is C 1 -C 4 alkyl; 
         Ar is selected from the group consisting of 
       
       
         
           
           
               
               
           
         
       
       wherein Ar is optionally substituted with deuterium, halo, alkyl, alkoxy, and CN;
 each Q 6  is independently selected from CR Q6  and N; wherein CR Q6  is hydrogen, halo, —CN, lower alkyl, or substituted alkyl; 
 Q 7  is selected from S, O, CH 2 , and NR Q7 ; wherein R Q7  is hydrogen or optionally substituted C 1 -C 4 alkyl; 
 —Z—W—X—Y— is —C(R Z ) 2 —C(R W ) 2 —N(R X )—C(R Y ) 2 —, —C(R Z ) 2 —C(R W ) 2 —CH(R X )—C(R Y ) 2 —, or —C(R W ) 2 —CH(R X )—C(R Y ) 2 —; 
 each R Z  is independently selected from the group consisting of hydrogen, deuterium, halo, and C 1 -C 4 alkyl, or both R Z  groups together form C 3 -C 6 cycloalkyl or oxo; 
 each R W  is independently selected from the group consisting of hydrogen, deuterium, halo, and C 1 -C 4 alkyl, or both R W  groups together form C 3 -C 6 cycloalkyl or oxo; 
 or R Z  and R W  together with the carbons to which they are attached form a C 3 -C 6 cycloalkyl; 
 R X  is selected from the group consisting of hydrogen, R X1 , —COR X1 , —SO 2 R X1 , —(C 1 -C 4 alkylene)-R X1 , and wherein the —(C 1 -C 4 alkylene)-R X1  is optionally substituted with one to four halo on the C 1 -C 4 alkylene; 
 wherein R X1  is C 3 -C 8 cycloalkyl, heteroaryl, or heterocyclyl, wherein the heterocyclyl is optionally substituted with one to twelve substituents independently selected from the group consisting of deuterium, halo, —[C(R X1a ) 2 ] p —CN, —CF 3 , C 1 -C 4 alkyl, —(CH 2 ) p —OH, —[C(R X1a ) 2 ] p —OH, —[C(R X1a ) 2 ] p —O—C 1 -C 4 alkyl, —NHCOC 1 -C 4 alkyl, CONHC 1 -C 4 alkyl, COH, —CO 2 H, —[C(R X1a ) 2 ] p —COO—C 1 -C 4 alkyl, —(CH 2 ) p —NH 2 , —[C(R X1a ) 2 ] p —NH 2 , —[C(R X1a ) 2 ] p —NH—C 1 - C 4 alkyl, —[C(R X1a ) 2 ] p —N—(C 1 -C 4 alkyl) 2 ; wherein p is 0, 1, 2, or 3; wherein each R X1a  is independently selected from the group consisting of hydrogen, deuterium, halo, —CF 3 , and C 1 -C 4 alkyl, or both R X1a  groups together form C 3 -C 6 cycloalkyl; 
 or R X1  is N(R X2 ) 2  wherein R X2  is independently selected from hydrogen, alkyl, substituted alkyl, wherein the alkyl substitution can be halo, heterocycles and substituted heterocycles; 
 each R Y  is independently selected from the group consisting of hydrogen, deuterium, halo, and C 1 -C 4 alkyl, or both R Y  groups together form C 3 -C 6 cycloalkyl or oxo; and 
 m is 0, 1, or 2. 
 
     
     
         14 . The compound of any one of  claims 1 - 12 , wherein Q 1  is CH; Q 2  is N; and Q 3  is C. 
     
     
         15 . The compound of any one of  claims 1 - 13 , wherein Q 1  is N; Q 2  is C; and Q 3  is N. 
     
     
         16 . The compound of any one of  claims 1 - 13 , wherein Q 1  is CH; Q 2  is C; and Q 3  is N. 
     
     
         17 . The compound of any one of  claims 1 - 13 , wherein Q 1  is N; Q 2  is N; and Q 3  is C. 
     
     
         18 . The compound of any one of  claims 1 - 17 , wherein R 1  is hydrogen or halo. 
     
     
         19 . The compound of any one of  claims 1 - 18 , wherein R 2  is halo. 
     
     
         20 . The compound of any one of  claims 1 - 18 , wherein R 2  is selected from the group consisting of halo, —CF 3 , —CN, —C≡CH, —NH 2 , and —NHC(O)CH 3 . 
     
     
         21 . The compound of any one of  claims 1 - 20 , wherein R 3  is hydrogen or halo. 
     
     
         22 . The compound of any one of  claims 1  and  13 - 21 , wherein Ar is N 
       
         
           
           
               
               
           
         
       
     
     
         23 . The compound of any one of  claims 1 - 22 , wherein —Z—W—X—Y— is —C(R Z ) 2 —C(R W ) 2 —N(R X )—C(R Y ) 2 —. 
     
     
         24 . The compound of any one of  claims 1 - 22 , wherein —Z—W—X—Y— is —C(R Z ) 2 —C(R W ) 2 —CH(R X )—C(R Y ) 2 —. 
     
     
         25 . The compound of any one of  claims 23 - 24 , wherein each R Z  is independently selected from the group consisting of hydrogen and halo. 
     
     
         26 . The compound of any one of  claims 23 - 24 , wherein both R Z  groups together form C 3 -C 6 cycloalkyl. 
     
     
         27 . The compound of any one of  claims 1 - 24 , wherein R Z  and R W  together with the carbons to which they are attached form a C 3 -C 6 cycloalkyl. 
     
     
         28 . The compound of any one of  claims 1 - 22 , wherein —Z—W—X—Y— is —C(R W ) 2 —CH(R X )—C(R Y ) 2 —. 
     
     
         29 . The compound of any one of  claims 1 - 28 , wherein each R W  is independently selected from the group consisting of hydrogen and halo. 
     
     
         30 . The compound of any one of  claims 1 - 28 , wherein both R W  groups together form C 3 -C 6 cycloalkyl. 
     
     
         31 . The compound of any one of  claims 1 - 30 , wherein each R Y  is independently selected from the group consisting of hydrogen and halo. 
     
     
         32 . The compound of any one of  claims 1 - 30 , wherein both R Y  groups together form C 3 -C 6 cycloalkyl. 
     
     
         33 . The compound of any one of  claims 12 - 32 , wherein R X  is R X1 , wherein R X1  is heteroaryl. 
     
     
         34 . The compound of any one of  claims 12 - 32 , wherein R X  is —COR X1 . 
     
     
         35 . The compound of any one of  claims 12 - 32 , wherein R X  is —SO 2 R X1 . 
     
     
         36 . The compound of any one of  claims 12 - 32 , wherein R X  is —(C 1 -C 4 alkylene)-R X1 . 
     
     
         37 . The compound of any one of  claims 34 - 36 , wherein R X1  is C 3 -C 8 cycloalkyl. 
     
     
         38 . The compound of any one of  claims 34 - 36 , wherein R X1  is heterocyclyl, wherein the heterocyclyl is optionally substituted with one to twelve substituents that is halo. 
     
     
         39 . A compound, or a pharmaceutically acceptable salt or tautomer thereof, selected from the group consisting of 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         40 . A pharmaceutical composition comprising a compound of any one of  claims 1 - 39 , or a pharmaceutically acceptable salt or tautomer thereof, and a pharmaceutically acceptable carrier. 
     
     
         41 . The pharmaceutical composition of  claim 40 , further comprising HDAC inhibitor. 
     
     
         42 . The pharmaceutical composition of  claim 40 , further comprising TGF beta inhibitor. 
     
     
         43 . The pharmaceutical composition of  claim 40 , further comprising BMP inhibitor. 
     
     
         44 . The pharmaceutical composition of any one of  claims 40 - 43 , further comprising poloxamer. 
     
     
         45 . A method of expanding a population of cochlear cells in a cochlear tissue comprising a parent population, the method comprising contacting the cochlear tissue with a compound of any one of  claims 1 - 39 , or a pharmaceutically acceptable salt or tautomer thereof or a pharmaceutical composition of any one of  claims 40 - 44 . 
     
     
         46 . The method of  claim 45 , wherein the cochlear tissue is in a subject. 
     
     
         47 . The method of  claim 46 , wherein the contacting the cochlear tissue with the composition is achieved by administering the composition trans-tympanically to the subject. 
     
     
         48 . The method of  claim 47 , wherein contacting the cochlear tissue with the composition results in improved auditory functioning of the subject. 
     
     
         49 . A method of facilitating the generation of tissue cells, the method comprising administering or causing to be administered to a stem cell population a compound of any one of  claims 1 - 39 , or a pharmaceutically acceptable salt or tautomer thereof or a pharmaceutical composition of any one of  claims 40 - 44 . 
     
     
         50 . The method of  claim 49 , wherein the tissue cells are cochlear cells. 
     
     
         51 . The method of  claim 50 , wherein the tissue cells are inner ear hair cells. 
     
     
         52 . A method of treating a subject who has, or is at risk of developing, a disease associated with absence or lack of certain tissue cells, comprising administering or causing to be administered to a stem cell population a compound of any one of  claims 1 - 39 , or a pharmaceutically acceptable salt or tautomer thereof or a pharmaceutical composition of any one of  claims 40 - 44 . 
     
     
         53 . The method of  claim 52 , wherein the tissue cells are cochlear cells. 
     
     
         54 . The method of  claim 52 , wherein the tissue cells are inner ear hair cells. 
     
     
         55 . A method of treating a subject who has, or is at risk of developing, hearing loss, the method comprising administering a compound of any one of  claims 1 - 39 , or a pharmaceutically acceptable salt or tautomer thereof or a pharmaceutical composition of any one of  claims 40 - 44 . 
     
     
         56 . The method of  claim 55 , wherein the compound is administered trans-tympanically to a cochlear tissue of the subject. 
     
     
         57 . A method of facilitating the generation of inner ear hair cells, the method comprising: administering a compound of any one of  claims 1 - 39  or a pharmaceutically acceptable salt thereof, alone or in combination with an HDAC inhibitor, to expand the stem cell population of cochlear tissue. 
     
     
         58 . The method of regenerating hearing in mammals, the method comprising administering a compound of any one of  claims 1 - 39 , or a pharmaceutically acceptable salt or tautomer thereof, alone or in combination with an HDAC inhibitor. 
     
     
         59 . The method of  claims 57  or  58 , wherein the administration is to a stem cell population is of an in vivo subject. 
     
     
         60 . A method of generating inner ear hair cells, the method comprising administering a compound of any one of  claims 1 - 39 , or a pharmaceutically acceptable salt or tautomer thereof, alone or in combination with an HDAC inhibitor, wherein the method proliferates LGR5+ cells in an initial population in vivo, resulting in an expanded population of LGR5+ cells, resulting in generation of inner ear hair cells. 
     
     
         61 . A method of facilitating generation of intestinal cells, the method comprising: administering a compound of any one of  claims 1 - 39  or a pharmaceutically acceptable salt thereof, alone or in combination with an HDAC inhibitor, to expand the stem cell population of intestinal epithelia. 
     
     
         62 . The method of  claim 61 , wherein the intestinal epithelia is regenerated. 
     
     
         63 . The method of  claim 61 , wherein the method is a treatment for promoting repair of damaged mucosa related to chemotherapy-induced gastrointestinal mucositis, Graph Versus Host Disease, gastric ulcer, Crohns, or ulcerative colitis. 
     
     
         64 . A method of expanding Lgr5+ cell population of intestinal epithelia, the method comprising: administering a compound of any one of  claims 1 - 39  or a pharmaceutically acceptable salt thereof, alone or in combination with an HDAC inhibitor. 
     
     
         65 . The method of use of a compound of any one of  claims 1 - 39 , or a pharmaceutically acceptable salt or tautomer thereof, alone or in combination with an HDAC inhibitor to regenerate Lgr5+ cell population intestinal cells in mammals. 
     
     
         66 . The method of  claim 65 , wherein the method is a treatment for promoting the repair of damaged mucosa related to chemotherapy-induced gastrointestinal mucositis, Graph Versus Host Disease, gastric ulcer, Crohns, or ulcerative colitis. 
     
     
         67 . A method of proliferating Lgr5+ epithelial cells in in vivo, the method comprising: administering a compound of any one of  claims 1 - 39  or a pharmaceutically acceptable salt thereof. 
     
     
         68 . A method for expanding a population of vestibular cells in a vestibular tissue comprising contacting the vestibular tissue with (i) a compound of any one of  claims 1 - 39  or a pharmaceutically acceptable salt thereof, and (ii) a TGF-β Inhibitor to form an expanded population of cells in the vestibular tissue. 
     
     
         69 . A system for treating a subject who has, or is at risk of developing, a disease associated with absence or lack of certain tissue cells, comprising administering:
 a compound of any one of  claims 1 - 39 , or a pharmaceutically acceptable salt or tautomer thereof; and a trans-tympanic administrative device.   
     
     
         70 . A compound of any one of  claims 1 - 39 , or a pharmaceutically acceptable salt or tautomer thereof, for use in treating a subject who has, or is at risk of developing, a disease associated with absence or lack of certain tissue cells. 
     
     
         71 . A compound of any one of  claims 1 - 39 , or a pharmaceutically acceptable salt or tautomer thereof, for use in treating a subject who has, or is at risk of developing, hearing loss. 
     
     
         72 . Use of a compound of any one of  claims 1 - 39 , or a pharmaceutically acceptable salt or tautomer thereof, in the manufacture of a medicament for treating a subject who has, or is at risk of developing, a disease associated with absence or lack of certain tissue cells. 
     
     
         73 . Use of a compound of any one of  claims 1 - 39 , or a pharmaceutically acceptable salt or tautomer thereof, in the manufacture of a medicament for treating a subject who has, or is at risk of developing, hearing loss.