Benzimidazole and azabenzimidazole compounds that inhibit anaplastic lymphoma kinase

Abstract

Compounds of Formula (I) are useful inhibitors of anaplastic lymphoma kinase. Compounds of Formula (I) have the following structure: where the definitions of the variables are provided herein.

1 - 35 . (canceled) 
     
     
         36 . A method of treating cancer, the method comprising: administering to a subject an effective amount of the compound or a pharmaceutical compositions comprising the compound of Formula I: 
       
         
           
           
               
               
           
         
         or the pharmaceutically acceptable salt thereof, tautomer thereof, the pharmaceutically acceptable salt of the tautomer, or the stereoisomer of any of the foregoing, wherein. 
         R 1  is —H; 
         R 2  is —H; 
         R 3  is —H; 
         X is selected from CR 4 ; 
         R 4  is —H; 
         Y is selected from a C 3 -C 12  cycloalkyl or a 3-10 membered heterocyclyl comprising 1, 2, or 3 heteroatoms selected from O, S, or N; wherein the C 3 -C 12  cycloalkyl and the 3-10 membered heterocyclyl may be monocyclic, bicyclic, or tricyclic, and further wherein the C 3 -C 12  cycloalkyl and the 3-10 membered heterocyclyl comprise a substituent selected from —C(═O)NH 2 , —C(═O)NH((C 1 -C 6 )alkyl), —C(═O)NH—(C 1 -C 4 )alkylene-CF 3 , —C(═O)NH—(C 1 -C 4 )alkylene-F, —C(═O)NH—(C 2 -C 4 )alkenyl, —C(═O)N((C 1 -C 6 )alkyl) 2 , —C(═O)NH—OH, —C(═O)NH—O—(C 1 -C 6 )alkyl, —C(═O)NH—Y″, —C(═O)—(C 1 -C 4 )alkylene-CF 3 , —C(═O)N—(C 1 -C 4 )alkylene-F, —C(═O)—(C 2 -C 4 )alkenyl, —C(═O)—(C 1 -C 4 )alkylene-NH 2 , —C(═O)—(C 1 -C 4 )alkylene-NH((C 1 -C 4 )alkyl), —C(═O)—(C 1 -C 4 )alkylene-N((C 1 -C 4 )alkyl) 2 , —C(═O)NH—(C 1 -C 4 )alkylene-OH, —C(═O)NH—(C 1 -C 4 )alkylene-O—(C 1 -C 6 )alkyl, —C(═O)NH—(C 1 -C 4 )alkylene-Y″, —C(═O)—(C 1 -C 6 )alkyl, —C(═O)—Y″, —CO 2 H, —C(═O)—O—(C 1 -C 6 )alkyl, —C(═O)NH—(C 1 -C 4 )alkylene-NH 2 , —C(═O)NH—(C 1 -C 4 )alkylene-NH((C 1 -C 6 )alkyl), and —C(═O)NH—(C 1 -C 4 )alkylene-N((C 1 -C 6 )alkyl) 2 , —(C 1 -C 4 )alkylene-NH—C(═O)—(C 1 -C 6 )alkyl; and 
         wherein Y optionally further comprises 1 or 2 substituents selected from Y′, —F, —Cl, —Br, —I, —C≡N, —NO 2 , —OH, —O—(C 1 -C 6 )alkyl, —SH, —S—(C 1 -C 6 )alkyl, —OCF 3 , —OCHF 2 , —CF 3 , —(C 1 -C 6 )alkyl, —(C 2 -C 6 )alkenyl, —(C 2 -C 6 )alkynyl, —NH 2 , —NH((C 1 -C 4 )alkyl), —N((C 1 -C 4 )alkyl) 2 , —NHSO 2 —(C 1 -C 6 )alkyl, —NHC(═O)—(C 1 -C 6 )alkyl, —C(═O)NH 2 , —C(═O)NH((C 1 -C 6 )alkyl), —C(═O)NH—(C 1 -C 4 )alkylene-CF 3 , —C(═O)NH—(C 1 -C 4 )alkylene-F, —C(═O)NH—(C 2 -C 4 )alkenyl, —C(═O)N((C 1 -C 6 )alkyl) 2 , —C(═O)NH—OH, —C(═O)NH—O—(C 1 -C 6 )alkyl, —C(═O)NH—Y″, —C(═O)—(C 1 -C 4 )alkylene-CF 3 , —C(═O)N—(C 1 -C 4 )alkylene-F, —C(═O)—(C 2 -C 4 )alkenyl, —C(═O)—(C 1 -C 4 )alkylene-NH 2 , —C(═O)—(C 1 -C 4 )alkylene-NH((C 1 -C 4 )alkyl), —C(═O)—(C 1 -C 4 )alkylene-N((C 1 -C 4 )alkyl) 2 , —C(═O)NH—(C 1 -C 4 )alkylene-OH, —C(═O)NH—(C 1 -C 4 )alkylene-O—(C 1 -C 6 )alkyl, —C(═O)NH—(C 1 -C 4 )alkylene-Y″, —C(═O)—(C 1 -C 6 )alkyl, —C(═O)—Y″, —CO 2 H, —C(═O)—O—(C 1 -C 6 )alkyl, —C(═O)NH—(C 1 -C 4 )alkylene-NH 2 , —C(═O)NH—(C 1 -C 4 )alkylene-NH((C 1 -C 6 )alkyl), and —C(═O)NH—(C 1 -C 4 )alkylene-N((C 1 -C 6 )alkyl) 2 , —SO 2 NH 2 , —SO 2 NH((C 1 -C 6 )alkyl), —SO 2 N((C 1 -C 6 )alkyl) 2 , —SO 2 NH((C 2 -C 4 )alkenyl), —SO 2 NH((C 2 -C 4 )alkynyl), —SO 2 NH—Y″, —SO 2 NH—(C 1 -C 4 )alkylene-OH, —SO 2 NH—(C 1 -C 4 )alkylene-O—(C 1 -C 4 )alkyl, —SO 2 —(C 1 -C 6 )alkyl, —SO 2 —Y″, —SO—(C 1 -C 6 )alkyl, —(C 1 -C 4 )alkylene-NH—C(═O)—(C 1 -C 6 )alkyl, —(C 1 -C 4 )alkylene-NH—(C 1 -C 6 )alkyl, —(C 1 -C 4 )alkylene-N((C 1 -C 6 )alkyl) 2 -(C 1 -C 4 )alkylene-OH, —(C 1 -C 4 )alkylene-O—(C 1 -C 6 )alkyl, —(C 1 -C 4 )alkylene-C(═O)—(C 1 -C 6 )alkyl, —(C 1 -C 4 )alkylene-C(═O)—O—(C 1 -C 6 )alkyl, or —(C 1 -C 4 )alkylene-C(═O)—OH, wherein two substituents on a carbon ring member of the Y cycloalkyl or heterocyclyl may join to form a 3-7 membered cycloalkyl group or a 3-7 membered heterocyclyl group that comprises 1 to 3 heteroatoms selected from N, O, or S; and further wherein 1 or 2 carbon atom ring members of the 3-7 membered cycloalkyl or the 3-7 membered heterocyclyl group formed from the two substituents on the carbon ring member of the Y cycloalkyl or heterocyclyl may be double bonded to an O atom; 
         Y′ may be absent or is a C 6 -C 10  aryl, a 5-10 membered heteroaryl comprising 1, 2, 3, or 4 heteroatoms independently selected from O, S, or N, or a 3-7 membered heterocyclyl comprising 1, 2, or 3 heteroatoms selected from O, S, or N, wherein the C 6 -C 10  aryl, the 5-10 membered heteroaryl, or the 3-7 membered heterocyclyl Y′ groups are unsubstituted or are optionally substituted with 1, 2, or 3 substituents independently selected from —F, —Cl, —Br, —I, —C≡N, —NO 2 , —(C 1 -C 6 )alkyl, —(C 2 -C 6 )alkenyl, —(C 2 -C 6 )alkynyl, —(C 1 -C 4 )alkylene-OH, —NH 2 , —NH((C 1 -C 4 )alkyl), —N((C 1 -C 4 )alkyl) 2 , —C(═O)NH 2 , —C(═O)NH((C 1 -C 4 )alkyl), —C(═O)N((C 1 -C 4 )alkyl) 2 , —SO 2 NH 2 , —SO 2 NH((C 1 -C 4 )alkyl), —SO 2 N((C 1 -C 4 )alkyl) 2 , —NHSO 2 —(C 1 -C 4 )alkyl, —NHC(═O)—(C 1 -C 4 )alkyl, —SO 2 —(C 1 -C 6 )alkyl, —SO—(C 1 -C 4 )alkyl, —(C 1 -C 4 )alkylene-NH—C(═O)—(C 1 -C 4 )alkyl, —CF 3 , —C(═O)—(C 1 -C 4 )alkyl, —CO 2 H, —C(═O)—O—(C 1 -C 4 )alkyl, —C(═O)NH—(C 1 -C 4 )alkylene-NH 2 , —C(═O)NH—(C 1 -C 4 )alkylene-NH((C 1 -C 4 )alkyl), —C(═O)NH—(C 1 -C 4 )alkylene-N((C 1 -C 4 )alkyl) 2 , —C(═O)NH—(C 1 -C 4 )alkylene-OH, —C(═O)NH—(C 1 -C 4 )alkylene-CF 3 , —C(═O)NH—(C 1 -C 4 )alkylene-O—(C 1 -C 4 )alkyl, —(C 1 -C 4 )alkylene-C(═O)—(C 1 -C 4 )alkyl, —(C 1 -C 4 )alkylene-C(═O)—O—(C 1 -C 4 )alkyl, —(C 1 -C 4 )alkylene-C(═O)—OH, —OH, —O—(C 1 -C 6 )alkyl, —SH, —S—(C 1 -C 6 )alkyl, —OCF 3 , or —OCHF 2 ; 
         Y″ may be absent or is selected from a C 3 -C 10  cycloalkyl; a 3-10 membered heterocyclyl comprising 1, 2, or 3 heteroatoms selected from N, O, and S; a C 6 -C 10  aryl; or a 5-10 membered heteroaryl comprising 1, 2, 3, or 4 heteroatoms independently selected from N, O, or S; wherein the C 3 -C 10  cycloalkyl and the 3-10 membered heterocyclyl may be monocyclic or bicyclic, and further wherein the C 3 -C 10  cycloalkyl, the 3-10 membered heterocyclyl, the C 6 -C 10  aryl, or the 5-10 membered heteroaryl Y″ groups are unsubstituted or are optionally substituted with 1, 2, or 3 substituents independently selected from —F, —Cl, —Br, —I, —C≡N, —NO 2 , —(C 1 -C 6 )alkyl, —(C 2 -C 6 )alkenyl, —(C 2 -C 6 )alkynyl, —(C 1 -C 4 )alkylene-OH, —NH 2 , —NH((C 1 -C 4 )alkyl), —N((C 1 -C 4 )alkyl) 2 , —C(═O)NH 2 , —C(═O)NH((C 1 -C 4 )alkyl), —C(═O)N((C 1 -C 4 )alkyl) 2 , —SO 2 NH 2 , —SO 2 NH((C 1 -C 4 )alkyl), —SO 2 N((C 1 -C 4 )alkyl) 2 , —NHSO 2 —(C 1 -C 4 )alkyl, —NHC(═O)—(C 1 -C 4 )alkyl, —SO 2 —(C 1 -C 6 )alkyl, —SO—(C 1 -C 4 )alkyl, —(C 1 -C 4 )alkylene-NH—C(═O)—(C 1 -C 4 )alkyl, —CF 3 , —C(═O)—(C 1 -C 4 )alkyl, —CO 2 H, —C(═O)—O—(C 1 -C 4 )alkyl, —C(═O)NH—(C 1 -C 4 )alkylene-NH 2 , —C(═O)NH—(C 1 -C 4 )alkylene-NH((C 1 -C 4 )alkyl), —C(═O)NH—(C 1 -C 4 )alkylene-N((C 1 -C 4 )alkyl) 2 , —C(═O)NH—(C 1 -C 4 )alkylene-OH, —C(═O)NH—(C 1 -C 4 )alkylene-CF 3 , —C(═O)NH—(C 1 -C 4 )alkylene-O—(C 1 -C 4 )alkyl, —(C 1 -C 4 )alkylene-C(═O)—(C 1 -C 4 )alkyl, —(C 1 -C 4 )alkylene-C(═O)—O—(C 1 -C 4 )alkyl, —(C 1 -C 4 )alkylene-C(═O)—OH, —OH, —O—(C 1 -C 6 )alkyl, —SH, —S—(C 1 -C 6 )alkyl, —OCF 3 , or —OCHF 2 ; 
         W is selected from —(CR a R a′ ) q —O—(C 1 -C 6 )alkyl, —(CR a R a′ ) q —O—W′, —O—(CR a R a′ ) q —W′, —O—(CR a R a′ ) q —OH, —O—(CR a R a′ ) q —O—(C 1 -C 6 )alkyl, —(CR a R a′ ) q —O—(CR a R a′ ) q —OH, —(CR a R a′ ) q —O—(CR a R a′ ) q —O—(C 1 -C 6 )alkyl, —(CR a R a′ ) q —SH, —(CR a R a′ ) q —S—(C 1 -C 6 )alkyl, —(CR a R a′ ) q —S—W′, —S—(CR a R a′ ) q —W′, —(CR a R a′ ) q —S(O) 2 —(C 1 -C 6 )alkyl, —(CR a R a′ ) q —S(O) 2 —W′, —S(O) 2 —(CR a R a′ ) q —W′, —(CR a R a′ ) q —NH 2 , —(CR a R a′ ) q —NH—(C 1 -C 6 )alkyl, —(CR a R a′ ) q —N—((C 1 -C 6 )alkyl,) 2 , —(CR a R a′ ) q —N + —((C 1 -C 6 )alkyl,) 3 , —(CR a R a′ ) q —NH—W′, —(CR a R a′ ) q —NH—(CR a R a′ ) q —OH, —NH—(CR a R a′ ) q —W′, or —(CR a R a′ ) q —W′; 
         W′ may be absent or is selected from a C 3 -C 10  cycloalkyl; a 3-10 membered heterocyclyl comprising 1, 2, or 3 heteroatoms selected from N, O, and S; a C 6 -C 10  aryl; or a 5-10 membered heteroaryl comprising 1, 2, 3, or 4 heteroatoms independently selected from N, O, or S; wherein the C 3 -C 10  cycloalkyl and the 3-10 membered heterocyclyl may be monocyclic or bicyclic, and further wherein the C 3 -C 10  cycloalkyl, the 3-10 membered heterocyclyl, the C 6 -C 10  aryl, or the 5-10 membered heteroaryl W′ groups are unsubstituted or are optionally substituted with 1, 2, 3, or 4 substituents independently selected from —F, —Cl, —Br, —I, —C≡N, —NO 2 , —(C 1 -C 6 )alkyl, —(C 2 -C 6 )alkenyl, —(C 2 -C 6 )alkynyl, —(C 1 -C 4 )alkylene-OH, —NH 2 , —NH((C 1 -C 4 )alkyl), —N((C 1 -C 4 )alkyl) 2 , —CH(CF 3 )(OH), —(C 1 -C 4 )alkylene-NH 2 , —(C 1 -C 4 )alkylene-NH((C 1 -C 4 )alkyl), —(C 1 -C 4 )alkylene-NH—(C 1 -C 4 )alkylene-CF 3 , —(C 1 -C 4 )alkylene-N((C 1 -C 4 )alkyl) 2 , —C(═O)NH 2 , —C(═O)NH((C 1 -C 4 )alkyl), —C(═O)N((C 1 -C 4 )alkyl) 2 , —SO 2 NH 2 , —SO 2 NH((C 1 -C 4 )alkyl), —SO 2 N((C 1 -C 4 )alkyl) 2 , —NHSO 2 —(C 1 -C 4 )alkyl, —NHC(═O)—(C 1 -C 4 )alkyl, —SO 2 —(C 1 -C 6 )alkyl, —SO—(C 1 -C 4 )alkyl, —(C 1 -C 4 )alkylene-NH—C(═O)—(C 1 -C 4 )alkyl, —CF 3 , —C(═O)—(C 1 -C 4 )alkyl, —CO 2 H, —C(═O)—O—(C 1 -C 4 )alkyl, —C(═O)NH—(C 1 -C 4 )alkylene-NH 2 , —C(═O)NH—(C 1 -C 4 )alkylene-NH((C 1 -C 4 )alkyl), —C(═O)NH—(C 1 -C 4 )alkylene-N((C 1 -C 4 )alkyl) 2 , —C(═O)NH—(C 1 -C 4 )alkylene-OH, —C(═O)NH—(C 1 -C 4 )alkylene-CF 3 , —C(═O)NH—(C 1 -C 4 )alkylene-O—(C 1 -C 4 )alkyl, —(C 1 -C 4 )alkylene-C(═O)—(C 1 -C 4 )alkyl, —(C 1 -C 4 )alkylene-C(═O)—O—(C 1 -C 4 )alkyl, —(C 1 -C 4 )alkylene-C(═O)—OH, —(C 1 -C 4 )alkylene-OH, —OH, —O—(C 1 -C 6 )alkyl, —SH, —S—(C 1 -C 6 )alkyl, —SO 3 H, —OCF 3 , —OCHF 2 , or —C(═O)—W″; and further wherein W′ may include 0, 1, or 2 ═O groups when W′ is a C 3 -C 10  cycloalkyl or a 3-10 membered heterocyclyl, and further wherein the ═O groups may be bonded to a ring carbon atom or a ring S atom; 
         W″ may be absent or is selected from a C 3 -C 10  cycloalkyl; a 3-10 membered heterocyclyl comprising 1, 2, or 3 heteroatoms selected from N, O, and S; a C 6 -C 10  aryl; or a 5-10 membered heteroaryl comprising 1, 2, 3, or 4 heteroatoms independently selected from N, O, or S; wherein the C 3 -C 10  cycloalkyl and the 3-10 membered heterocyclyl may be monocyclic or bicyclic, and further wherein the C 3 -C 10  cycloalkyl, the 3-10 membered heterocyclyl, the C 6 -C 10  aryl, or the 5-10 membered heteroaryl W″ groups are unsubstituted or are optionally substituted with 1, 2, 3, or 4 substituents independently selected from —F, —Cl, —Br, —I, —C≡N, —NO 2 , —(C 1 -C 6 )alkyl, —(C 2 -C 6 )alkenyl, —(C 2 -C 6 )alkynyl, —OH, —NH 2 , —NH((C 1 -C 4 )alkyl), —N((C 1 -C 4 )alkyl) 2 , —CF 3 , —CO 2 H, —C(═O)—O—(C 1 -C 4 )alkyl, —SH, —S—(C 1 -C 6 )alkyl, —OCF 3 , or —OCHF 2 ; and further wherein W″ may include 0, 1, or 2 ═O groups when W″ is a C 3 -C 10  cycloalkyl or a 3-10 membered heterocyclyl, and further wherein the ═O groups may be bonded to a ring carbon atom or a ring S atom; 
         the subscript q is, in each instance, independently selected from 0, 1, 2, 3, or 4; 
         R a  is, in each instance, independently selected from —H, —CH 3 , —CH 2 CH 3 , —F, —CF 3 , or —C≡N; 
         R a′  is, in each instance, independently selected from —H, —CH 3 , —CH 2 CH 3 , —F, —CF 3 , or —C≡N; or R a  and R a′  may join to form a cyclopropyl ring together with the carbon atom to which they are attached; 
         Z is selected from —OMe or —NH-cyclohexyl; or a phenyl, pyridyl, benzothiophenyl, thiazolyl, pyradizinyl, pyrimidinyl, indolyl, cyclohexyl, morpholinyl, pyrrolidinyl, piperazinyl, or piperidinyl group; wherein the —NH-cyclohexyl, phenyl, pyridyl, benzothiophenyl, thiazolyl, pyradizinyl, pyrimidinyl, indolyl, cyclohexyl, morpholinyl, pyrrolidinyl, piperazinyl, or piperidinyl group is unsubstituted or is optionally substituted with 1, 2, or 3 substituents independently selected from —F, —Cl, —Br, —I, —C≡N, —NO 2 , —CF 3 , —(C 1 -C 6 )alkyl, —(C 2 -C 6 )alkenyl, —(C 2 -C 6 )alkynyl, —(C 1 -C 4 )alkylene-OH, —NH 2 , —NH((C 1 -C 6 )alkyl), —N((C 1 -C 6 )alkyl) 2 , —C(═O)NH 2 , —C(═O)NH((C 1 -C 6 )alkyl), —C(═O)N((C 1 -C 6 )alkyl) 2 , —SO 2 NH 2 , —SO 2 NH((C 1 -C 6 )alkyl), —SO 2 N((C 1 -C 6 )alkyl) 2 , —SO 2 NH((C 2 -C 6 )alkenyl), —SO 2 NH((C 2 -C 6 )alkynyl), —SO 2 NH—(C 1 -C 4 )alkylene-OH, —SO 2 NH—(C 1 -C 4 )alkylene-O—(C 1 -C 6 )alkyl, —NHSO 2 —(C 1 -C 6 )alkyl, —NHC(═O)—(C 1 -C 6 )alkyl, —SO 2 —(C 1 -C 6 )alkyl, —SO—(C 1 -C 6 )alkyl, —(C 1 -C 4 )alkylene-NH—C(═O)—(C 1 -C 6 )alkyl, —C(═O)—(C 1 -C 6 )alkyl, —CO 2 H, —C(═O)—O—(C 1 -C 6 )alkyl, —C(═O)NH—(C 1 -C 4 )alkylene-NH 2 , —C(═O)NH—(C 1 -C 4 )alkylene-NH((C 1 -C 6 )alkyl), —C(═O)NH—(C 1 -C 4 )alkylene-N((C 1 -C 6 )alkyl) 2 , —(C 1 -C 4 )alkylene-C(═O)—(C 1 -C 6 )alkyl, —(C 1 -C 4 )alkylene-C(═O)—O—(C 1 -C 6 )alkyl, —(C 1 -C 4 )alkylene-C(═O)—OH, —OH, —O—(C 1 -C 6 )alkyl, —SH, —S—(C 1 -C 6 )alkyl, —OCF 3 , or —OCHF 2 . 
       
     
     
         37 . The method of  claim 36 , wherein Z is an unsubstituted or substituted phenyl, pyridyl, benzothiophenyl, thiazolyl, pyradizinyl, pyrimidinyl, indolyl, cyclohexyl, morpholinyl, pyrrolidinyl, piperazinyl, or piperidinyl group, or a pharmaceutically acceptable salt thereof, tautomer thereof, a pharmaceutically acceptable salt of the tautomer, or a stereoisomer of any of the foregoing. 
     
     
         38 . The method of  claim 36 , wherein Z is an unsubstituted or substituted phenyl or pyridyl, or a pharmaceutically acceptable salt thereof, tautomer thereof, a pharmaceutically acceptable salt of the tautomer, or a stereoisomer of any of the foregoing. 
     
     
         39 . The method of  claim 36 , wherein Z is selected from 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, tautomer thereof, a pharmaceutically acceptable salt of the tautomer, or a stereoisomer of any of the foregoing, wherein the symbol  , when drawn across a bond, indicates the point of attachment to the rest of the molecule. 
     
     
         40 . The method of  claim 36 , wherein Z is selected from 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, tautomer thereof, a pharmaceutically acceptable salt of the tautomer, or a stereoisomer of any of the foregoing, wherein the symbol  , when drawn across a bond, indicates the point of attachment to the rest of the molecule. 
     
     
         41 . The method of  claim 36 , wherein Y is substituted cycloheptyl, cyclohexyl, cyclopentyl, cyclobutyl, piperidinyl, pyrrolidinyl, azetidinyl, adamantyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, bicyclo[4.1.1]octyl, bicyclo[2.2.1]heptyl, bicyclo[3.1.1]heptyl, or bicyclo[2.1.1]hexyl, or a pharmaceutically acceptable salt thereof, tautomer thereof, a pharmaceutically acceptable salt of the tautomer, or a stereoisomer of any of the foregoing. 
     
     
         42 . The method of  claim 41 , wherein Y is substituted cyclohexyl, or a pharmaceutically acceptable salt thereof, tautomer thereof, a pharmaceutically acceptable salt of the tautomer, or a stereoisomer of any of the foregoing. 
     
     
         43 . The compound of  claim 36 , wherein Y is selected from 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, tautomer thereof, a pharmaceutically acceptable salt of the tautomer, or a stereoisomer of any of the foregoing, wherein the symbol  , when drawn across a bond, indicates the point of attachment to the rest of the molecule. 
     
     
         44 . The method of  claim 36 , wherein Y is selected from 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, tautomer thereof, a pharmaceutically acceptable salt of the tautomer, or a stereoisomer of any of the foregoing, wherein the symbol  , when drawn across a bond, indicates the point of attachment to the rest of the molecule. 
     
     
         45 . The method of  claim 36 , wherein Y is selected from 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, tautomer thereof, a pharmaceutically acceptable salt of the tautomer, or a stereoisomer of any of the foregoing, wherein the symbol  , when drawn across a bond, indicates the point of attachment to the rest of the molecule. 
     
     
         46 . The compound of  claim 45 , wherein Y is 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, tautomer thereof, a pharmaceutically acceptable salt of the tautomer, or a stereoisomer of any of the foregoing, wherein the symbol  , when drawn across a bond, indicates the point of attachment to the rest of the molecule. 
     
     
         47 . The compound of  claim 36 , wherein W is selected from —CH 2 OCH 3 , —CH 2 OCH 2 CH 2 OH, —CH 2 OCH 2 CH 2 OCH 3 , —OCH 2 CH 2 OH, —OCH 2 CH 2 OMe, —W′, —CH 2 W′, —OW′, —OCH 2 W′, —OCH 2 CH 2 W′, —OCH 2 CH 2 CH 2 W′, —NHW′, —NHCH 2 W′, —NHCH 2 CH 2 W′, —NHCH 2 CH 2 CH 2 W′, or —W′—C(═O)—W″; wherein W′, if present, is selected from a 3-10 membered heterocyclyl comprising 1 or 2 heteroatoms selected from N, O, and S; a C 6 -C 10  aryl; or a 5-10 membered heteroaryl comprising 1, 2, 3, or 4 heteroatoms independently selected from N, O, or S; wherein the 3-10 membered heterocyclyl W′ group may be monocyclic or bicyclic, and further wherein the 3-10 membered heterocyclyl, the C 6 -C 10  aryl, or the 5-10 membered heteroaryl W′ groups are unsubstituted or are substituted with 1, 2, 3, or 4 substituents independently selected from —F, —Cl, —Br, —(C 1 -C 6 )alkyl, —CH(CF 3 )(OH), —(C 1 -C 4 )alkylene-NH 2 , —(C 1 -C 4 )alkylene-NH—(C 1 -C 4 )alkylene-CF 3 , —C(═O)NH 2 , —SO 2 —(C 1 -C 6 )alkyl, —CF 3 , —CO 2 H, —(C 1 -C 4 )alkylene-C(═O)—(C 1 -C 4 )alkyl, —(C 1 -C 4 )alkylene-C(═O)—O—(C 1 -C 4 )alkyl, —(C 1 -C 4 )alkylene-C(═O)—OH, —(C 1 -C 4 )alkylene-OH, —OH, —O—(C 1 -C 6 )alkyl, or —SO 3 H; and further wherein W′ may include 0, 1, or 2 ═O groups when W′ is a 3-10 membered heterocyclyl, and further wherein the ═O groups may be bonded to a ring carbon atom or a ring S atom; and further wherein W″, if present, is a 3-10 membered heterocyclyl comprising 1, 2, or 3 heteroatoms selected from N, O, and S, wherein the 3-10 membered heterocyclyl W″ group may be monocyclic or bicyclic, and further wherein the 3-10 membered heterocyclyl W″ group is unsubstituted or is optionally substituted with 1, 2, 3, or 4 substituents independently selected from —F, —Cl, —Br, —I, —C≡N, —NO 2 , —(C 1 -C 6 )alkyl, —(C 2 -C 6 )alkenyl, —(C 2 -C 6 )alkynyl, —OH, —NH 2 , —NH((C 1 -C 4 )alkyl), —N((C 1 -C 4 )alkyl) 2 , —CF 3 , —CO 2 H, —C(═O)—O—(C 1 -C 4 )alkyl, —SH, —S—(C 1 -C 6 )alkyl, —OCF 3 , or —OCHF 2 , or a pharmaceutically acceptable salt thereof, tautomer thereof, a pharmaceutically acceptable salt of the tautomer, or a stereoisomer of any of the foregoing. 
     
     
         48 . The method of  claim 36 , wherein W is selected from —OMe, —SO 2 Me, —CH 2 OMe, —OCH 2 CH 2 OH, —OCH 2 CH 2 OMe, or a group selected from 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, tautomer thereof, a pharmaceutically acceptable salt of the tautomer, or a stereoisomer of any of the foregoing, wherein the symbol  , when drawn across a bond, indicates the point of attachment to the rest of the molecule. 
     
     
         49 . The method of  claim 36 , wherein W is selected from —SO 2 Me, —CH 2 OMe, —OCH 2 CH 2 OH, —OCH 2 CH 2 OMe, or a group selected from 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, tautomer thereof, a pharmaceutically acceptable salt of the tautomer, or a stereoisomer of any of the foregoing, wherein the symbol  , when drawn across a bond, indicates the point of attachment to the rest of the molecule. 
     
     
         50 . The method of  claim 36 , wherein W is selected from 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, tautomer thereof, a pharmaceutically acceptable salt of the tautomer, or a stereoisomer of any of the foregoing, wherein the symbol  , when drawn across a bond, indicates the point of attachment to the rest of the molecule. 
     
     
         51 . The method of  claim 36 , wherein the cancer is due to abnormal cell growth and is selected from the group consisting of small cell lung carcinoma, non-small cell lung carcinoma, liver cancer, lung cancer, sarcoma, stomach cancer, cholangiocarcinoma, mesothelioma, prostate cancer. lung cancer, bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, colon cancer, breast cancer, uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin's Disease, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, prostate cancer, chronic or acute leukemia, lymphocytic lymphomas, cancer of the bladder, cancer of the kidney or ureter, renal cell carcinoma, carcinoma of the renal pelvis, neoplasms of the central nervous system (CNS), primary CNS lymphoma, spinal axis tumors, brain stem glioma, and pituitary adenoma. 
     
     
         52 . The method of  claim 51 , wherein the cancer is selected from the group consisting of small cell lung carcinoma, non-small cell lung carcinoma, esophageal cancer, kidney cancer, pancreatic cancer, melanoma, bladder cancer, breast cancer, colon cancer, liver cancer, lung cancer, sarcoma, stomach cancer, cholangiocarcinoma, mesothelioma, or prostate cancer. 
     
     
         53 . The method of  claim 36 , wherein the subject has a cancer that expresses an ALK fusion protein. 
     
     
         54 . The method of  claim 53 , wherein the ALK fusion protein is EML4-ALK fusion protein or NPM-ALK fusion protein. 
     
     
         55 . The method of  claim 54 , wherein the subject is a human cancer patient, and the cancer is selected from adenocarcinoma, lung cancer, non-small cell lung carcinoma, breast cancer, colorectal cancer, lymphoma, neuroblastoma, ovarian cancer, mesothelioma, melanoma, glioblastoma, diffuse large B-cell lymphomas, systemic histiocytosis, or inflammatory myofibroblastic tumors. 
     
     
         56 . The method of  claim 55 , wherein the cancer is non-small cell lung carcinoma.