LERICHE GEOFFRAY (US)
WO2014140076A1 | 2014-09-18 |
US5262564A | 1993-11-16 |
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WHAT IS CLAIMED IS: 1. A compound of formula I: or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, wherein: m is an integer from 0 to 4; n is an integer from 0 to 4; Y is CH(R4), NR5, or O; each of X1 and X2 is independently CH(R4) or NR5; Q is H, -CH3, -CH2OH, -CH(CH3)N(R13)2, -CH2N(R13)2, -CH2N(R13)C(O)R1, or -CH2CH2N(R13)2; R1 is C1-C6 alkyl, C3-C10 cycloalkyl, aryl, heteroaryl, or heterocyclyl, wherein each C1-C6 alkyl, C3-C10 cycloalkyl, aryl, heteroaryl, or heterocyclyl is independently unsubstituted or substituted with one to five Z1a; each of R2 and R3 is independently selected from halo, -N(R13)2, -OR14, C1-C6 alkyl, aryl, cyano, C3-C10 cycloalkyl, heteroaryl, heterocyclyl, guanidino, and nitro, wherein each C1-C6 alkyl, aryl, C3-C10 cycloalkyl, heteroaryl, heterocyclyl, and guanidino is independently unsubstituted or substituted with one to five Z1a; each R4 is independently H, halo, cyano, hydroxy, -SH, -N(R13)2, -NO2, -SF5, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, aryl, heterocyclyl, or heteroaryl, wherein each of C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, aryl, heterocyclyl, or heteroaryl is independently unsubstituted or substituted with one to five Z1a; each R5 is independently H, -C(O)R13, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -C(O)OC1-C6 alkyl, aryl, heterocyclyl, or heteroaryl, wherein each C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -C(O)OC1-C6 alkyl, aryl, heterocyclyl, or heteroaryl is independently unsubstituted or substituted with one to five Z1a; each Z1a is independently halo, cyano, -NO2, -SF5, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C10 cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R13)2, -OR13, -C(O)R13, -C(O)OR13, -S(O)0-2R13, -NR13S(O)1-2-R13, -S(O)1-2N(R13)2, -NR13S(O)1-2N(R13)2, -NR13C(O)N(R13)2, -C(O)N(R13)2, -NR13C(O)R13, -OC(O)N(R13)2, or -NR13C(O)OR13; wherein each C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently unsubstituted or substituted with one to five Z1b; each R13 is independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C10 cycloalkyl, heterocyclyl, aryl, or heteroaryl of R13 is independently unsubstituted or substituted with one to five Z1b; each R14 is independently H, C1-C6 alkyl, C3-C10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each C1-C6 alkyl, C3-C10 cycloalkyl, heterocyclyl, aryl, or heteroaryl of R14 is independently unsubstituted or substituted with one to five Z1b; each Z1b is independently halo, cyano, hydroxy, -SH, -NH2, -NO2, -SF5, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, -L-C1-6 alkyl, -L-C2-6 alkenyl, -L-C2-6 alkynyl, -L-C1-6 haloalkyl, -L-C3-10 cycloalkyl, -L-heterocyclyl, -L-aryl, or -L-heteroaryl; each L is independently -O-, -NH-, -S-, -S(O)-, -S(O)2-, -N(C1-C6 alkyl)-, -N(C2-C6 alkenyl), -N(C2-C6 alkynyl)-, -N(C1-C6 haloalkyl)-, -N(C3-10 cycloalkyl)-, -N(heterocyclyl)-, -N(aryl)-, -N(heteroaryl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N(C1-C6 alkyl)-, -C(O)N(C2-C6 alkenyl)-, -C(O)N(C2-C6 alkynyl)-, -C(O)N(C1-6 haloalkyl)-, -C(O)N(C3-10 cycloalkyl)-, -C(O)N(heterocyclyl)-, -C(O)N(aryl)-, -C(O)N(heteroaryl)-, -NHC(O)-, -NHC(O)O-, -NHC(O)NH-, -NHS(O)-, or -S(O)2NH-; and wherein each C1-C6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-C6 haloalkyl, C3-C10 cycloalkyl, heterocyclyl, aryl, and heteroaryl of Z1b and L is further independently unsubstituted or substituted with one to five halo, cyano, hydroxy, -SH, -NH2, -NO2, -SF5, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C10 cycloalkyl, heterocyclyl, aryl, or heteroaryl. 2. A compound of formula I: or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, wherein: m is an integer from 0 to 4; n is an integer from 0 to 4; Y is CH(R4), NR5, or O; each of X1 and X2 is independently CH(R4) or NR5; Q is H, -CH3, -CH2OH, -CH(CH3)N(R13)2, -CH2N(R13)2, -CH2N(R13)C(O)R1, or -CH2CH2N(R13)2; R1 is C1-C6 alkyl, C3-C10 cycloalkyl, aryl, heteroaryl, or heterocyclyl, wherein each C1-C6 alkyl, C3-C10 cycloalkyl, aryl, heteroaryl, or heterocyclyl is independently unsubstituted or substituted with one to five Z1a; each of R2 and R3 is independently selected from halo, -N(R13)2, -OR14, C1-C6 alkyl, aryl, cyano, C3-C10 cycloalkyl, heteroaryl, heterocyclyl, guanidino, and nitro, wherein each C1-C6 alkyl, aryl, C3-C10 cycloalkyl, heteroaryl, heterocyclyl, and guanidino is independently unsubstituted or substituted with one to five Z1a; each R4 is independently H, halo, cyano, hydroxy, -SH, -N(R13)2, -NO2, -SF5, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, aryl, heterocyclyl, or heteroaryl, wherein each of C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, aryl, heterocyclyl, or heteroaryl is independently unsubstituted or substituted with one to five Z1a; each R5 is independently H, -C(O)R13, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -C(O)OC1-C6 alkyl, aryl, heterocyclyl, or heteroaryl, wherein each C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -C(O)OC1-C6 alkyl, aryl, heterocyclyl, or heteroaryl is independently unsubstituted or substituted with one to five Z1a; each Z1a is independently halo, cyano, -NO2, -SF5, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C10 cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R13)2, -OR13, -C(O)R13, -C(O)OR13, -S(O)0-2R13, -NR13S(O)1-2-R13, -S(O)1-2N(R13)2, -NR13S(O)1-2N(R13)2, -NR13C(O)N(R13)2, -C(O)N(R13)2, -NR13C(O)R13, -OC(O)N(R13)2, or -NR13C(O)OR13; wherein each C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently unsubstituted or substituted with one to five Z1b; each R13 is independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C10 cycloalkyl, heterocyclyl, aryl, or heteroaryl of R13 is independently unsubstituted or substituted with one to five Z1b; each R14 is independently H, C1-C6 alkyl, C3-C10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each C1-C6 alkyl, C3-C10 cycloalkyl, heterocyclyl, aryl, or heteroaryl of R14 is independently unsubstituted or substituted with one to five Z1b; each Z1b is independently halo, cyano, hydroxy, -SH, -NH2, -NO2, -SF5, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, -L-C1-6 alkyl, -L-C2-6 alkenyl, -L-C2-6 alkynyl, -L-C1-6 haloalkyl, -L-C3-10 cycloalkyl, -L-heterocyclyl, -L-aryl, or -L-heteroaryl; each L is independently -O-, -NH-, -S-, -S(O)-, -S(O)2-, -N(C1-C6 alkyl)-, -N(C2-C6 alkenyl), -N(C2-C6 alkynyl)-, -N(C1-C6 haloalkyl)-, -N(C3-10 cycloalkyl)-, -N(heterocyclyl)-, -N(aryl)-, -N(heteroaryl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N(C1-C6 alkyl)-, -C(O)N(C2-C6 alkenyl)-, -C(O)N(C2-C6 alkynyl)-, -C(O)N(C1-6 haloalkyl)-, -C(O)N(C3-10 cycloalkyl)-, -C(O)N(heterocyclyl)-, -C(O)N(aryl)-, -C(O)N(heteroaryl)-, -NHC(O)-, -NHC(O)O-, -NHC(O)NH-, -NHS(O)-, or -S(O)2NH-; and wherein each C1-C6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-C6 haloalkyl, C3-C10 cycloalkyl, heterocyclyl, aryl, and heteroaryl of Z1b and L is further independently unsubstituted or substituted with one to five halo, cyano, hydroxy, -SH, -NH2, -NO2, -SF5, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C10 cycloalkyl, heterocyclyl, aryl, or heteroaryl, provided that the compound at 1 µM concentration degrades BRD4 by 30% or more. 3. A compound of formula IA: or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, wherein: m is an integer from 0 to 4; n is an integer from 0 to 4; Y is CH(R4), NR5, or O; each of X1 and X2 is independently CH(R4) or NR5; each R2 is independently selected from halo, -N(R13)2, -OR14, C1-C6 alkyl, aryl, cyano, C3-C10 cycloalkyl, heteroaryl, heterocyclyl, guanidino, and nitro, wherein each C1-C6 alkyl, aryl, C3-C10 cycloalkyl, heteroaryl, heterocyclyl, and guanidino is independently unsubstituted or substituted with one to five Z1a, provided that R2 is not imidazolyl, isooxazolyl, pyrazol-4-yl, or pyrimidin-5-yl; each R3 is independently selected from halo, -N(R13)2, -OR14, C1-C6 alkyl, aryl, cyano, C3-C10 cycloalkyl, heteroaryl, heterocyclyl, guanidino, and nitro, wherein each C1-C6 alkyl, aryl, C3-C10 cycloalkyl, heteroaryl, heterocyclyl, and guanidino is independently unsubstituted or substituted with one to five Z1a; each R4 is independently H, halo, cyano, hydroxy, -SH, -NH2, -NO2, -SF5, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, aryl, heterocyclyl, or heteroaryl, wherein each of C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, aryl, heterocyclyl, or heteroaryl is independently unsubstituted or substituted with one to five Z1a; each R5 is independently H, -C(O)R13, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -C(O)OC1-C6 alkyl, aryl, heterocyclyl, or heteroaryl, wherein each C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -C(O)OC1-C6 alkyl, aryl, heterocyclyl, or heteroaryl is independently unsubstituted or substituted with one to five Z1a; each Z1a is independently halo, cyano, -NO2, -SF5, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C10 cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R13)2, -OR13, -C(O)R13, -C(O)OR13, -S(O)0-2R13, -NR13S(O)1-2-R13, -S(O)1-2N(R13)2, -NR13S(O)1-2N(R13)2, -NR13C(O)N(R13)2, -C(O)N(R13)2, -NR13C(O)R13, -OC(O)N(R13)2, or -NR13C(O)OR13; wherein each C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently unsubstituted or substituted with one to five Z1b; each R13 is independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C10 cycloalkyl, heterocyclyl, aryl, or heteroaryl of R13 is independently unsubstituted or substituted with one to five Z1b; each R14 is independently H, C1-C6 alkyl, C3-C10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each C1-C6 alkyl, C3-C10 cycloalkyl, heterocyclyl, aryl, or heteroaryl of R14 is independently unsubstituted or substituted with one to five Z1b; each Z1b is independently halo, cyano, hydroxy, -SH, -NH2, -NO2, -SF5, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, -L-C1-6 alkyl, -L-C2-6 alkenyl, -L-C2-6 alkynyl, -L-C1-6 haloalkyl, -L-C3-10 cycloalkyl, -L-heterocyclyl, -L-aryl, or -L-heteroaryl; each L is independently -O-, -NH-, -S-, -S(O)-, -S(O)2-, -N(C1-C6 alkyl)-, -N(C2-C6 alkenyl), -N(C2-C6 alkynyl)-, -N(C1-C6 haloalkyl)-, -N(C3-10 cycloalkyl)-, -N(heterocyclyl)-, -N(aryl)-, -N(heteroaryl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N(C1-C6 alkyl)-, -C(O)N(C2-C6 alkenyl)-, -C(O)N(C2-C6 alkynyl)-, -C(O)N(C1-6 haloalkyl)-, -C(O)N(C3-10 cycloalkyl)-, -C(O)N(heterocyclyl)-, -C(O)N(aryl)-, -C(O)N(heteroaryl)-, -NHC(O)-, -NHC(O)O-, -NHC(O)NH-, -NHS(O)-, or -S(O)2NH-; and wherein each C1-C6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-C6 haloalkyl, C3-C10 cycloalkyl, heterocyclyl, aryl, and heteroaryl of Z1b and L is further independently unsubstituted or substituted with one to five halo, cyano, hydroxy, -SH, -NH2, -NO2, -SF5, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C10 cycloalkyl, heterocyclyl, aryl, or heteroaryl, provided that the following compounds are excluded: , , , , , . 4. The compound of claim 3, wherein the compound is represented by formula IB: or a pharmaceutically accepta ble salt, solvate, stereoisomer, or tautomer thereof. 5. The compound of claim 4, wherein the compound is represented by formula IC: or a pharmaceutically accepta , , , eof. 6. The compound of claim 5, wherein the compound is represented by formula ID: or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof. 7. The compound of claim 6, wherein R4 is C1-C6 alkyl and n is 0. 8. The compound of claim 6, wherein the compound is represented by formula 1E: NH or a pharmaceutically acceptable s alt, solvate, stereoisomer, or tautomer thereof. 9. The compound of claim 8, wherein R2 is H, halo, C1-C6 alkyl, phenyl substituted with C1-C6 alkoxy, pyridyl, or 1-methylpyrazol-5-yl. 10. A compound of formula I-1: or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, wherein: m is an integer from 0 to 4; n is an integer from 0 to 4; each of X1 and X2 is independently CH(R4) or NR5; Q is H, -CH2OH, -CH2N(R13)2, -CH2CH2N(R13)2, -CH2N(R13)C(O)R1, or heterocyclyl; R1 is C1-C6 alkyl, C3-C10 cycloalkyl, aryl, heteroaryl, or heterocyclyl, wherein each C1-C6 alkyl, C3-C10 cycloalkyl, aryl, heteroaryl, or heterocyclyl is independently unsubstituted or substituted with one to five Z1a; each of R2 and R3 is independently selected from halo, -N(R13)2, -OR14, C1-C6 alkyl, aryl, cyano, C3-C10 cycloalkyl, heteroaryl, heterocyclyl, guanidino, and nitro, wherein each C1-C6 alkyl, aryl, C3-C10 cycloalkyl, heteroaryl, heterocyclyl, and guanidino is independently unsubstituted or substituted with one to five Z1a; each R4 is independently H, halo, cyano, hydroxy, -SH, -N(R13)2, -NO2, -SF5, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, aryl, heterocyclyl, or heteroaryl, wherein each of C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, aryl, heterocyclyl, or heteroaryl is independently unsubstituted or substituted with one to five Z1a; each R5 is independently H, -C(O)R13, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -C(O)OC1-C6 alkyl, aryl, heterocyclyl, or heteroaryl, wherein each C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -C(O)OC1-C6 alkyl, aryl, heterocyclyl, or heteroaryl is independently unsubstituted or substituted with one to five Z1a; each Z1a is independently halo, cyano, -NO2, -SF5, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C10 cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R13)2, -OR13, -C(O)R13, -C(O)OR13, -S(O)0-2R13, -NR13S(O)1-2-R13, -S(O)1-2N(R13)2, -NR13S(O)1-2N(R13)2, -NR13C(O)N(R13)2, -C(O)N(R13)2, -NR13C(O)R13, -OC(O)N(R13)2, or -NR13C(O)OR13; wherein each C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently unsubstituted or substituted with one to five Z1b; each R13 is independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C10 cycloalkyl, heterocyclyl, aryl, or heteroaryl of R13 is independently unsubstituted or substituted with one to five Z1b; each R14 is independently H, C1-C6 alkyl, C3-C10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each C1-C6 alkyl, C3-C10 cycloalkyl, heterocyclyl, aryl, or heteroaryl of R14 is independently unsubstituted or substituted with one to five Z1b; each Z1b is independently halo, cyano, hydroxy, -SH, -NH2, -NO2, -SF5, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, -L-C1-6 alkyl, -L-C2-6 alkenyl, -L-C2-6 alkynyl, -L-C1-6 haloalkyl, -L-C3-10 cycloalkyl, -L-heterocyclyl, -L-aryl, or -L-heteroaryl; each L is independently -O-, -NH-, -S-, -S(O)-, -S(O)2-, -N(C1-C6 alkyl)-, -N(C2-C6 alkenyl), -N(C2-C6 alkynyl)-, -N(C1-C6 haloalkyl)-, -N(C3-10 cycloalkyl)-, -N(heterocyclyl)-, -N(aryl)-, -N(heteroaryl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N(C1-C6 alkyl)-, -C(O)N(C2-C6 alkenyl)-, -C(O)N(C2-C6 alkynyl)-, -C(O)N(C1-6 haloalkyl)-, -C(O)N(C3-10 cycloalkyl)-, -C(O)N(heterocyclyl)-, -C(O)N(aryl)-, -C(O)N(heteroaryl)-, -NHC(O)-, -NHC(O)O-, -NHC(O)NH-, -NHS(O)-, or -S(O)2NH-; and wherein each C1-C6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-C6 haloalkyl, C3-C10 cycloalkyl, heterocyclyl, aryl, and heteroaryl of Z1b and L is further independently unsubstituted or substituted with one to five halo, cyano, hydroxy, -SH, -NH2, -NO2, -SF5, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C10 cycloalkyl, heterocyclyl, aryl, or heteroaryl. 11. A compound of formula I-1: I-1 or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, wherein: m is an integer from 0 to 4; n is an integer from 0 to 4; each of X1 and X2 is independently CH(R4) or NR5; Q is H, -CH2OH, -CH2N(R13)2, -CH2CH2N(R13)2, -CH2N(R13)C(O)R1, or heterocyclyl; R1 is C1-C6 alkyl, C3-C10 cycloalkyl, aryl, heteroaryl, or heterocyclyl, wherein each C1-C6 alkyl, C3-C10 cycloalkyl, aryl, heteroaryl, or heterocyclyl is independently unsubstituted or substituted with one to five Z1a; each of R2 and R3 is independently selected from halo, -N(R13)2, -OR14, C1-C6 alkyl, aryl, cyano, C3-C10 cycloalkyl, heteroaryl, heterocyclyl, guanidino, and nitro, wherein each C1-C6 alkyl, aryl, C3-C10 cycloalkyl, heteroaryl, heterocyclyl, and guanidino is independently unsubstituted or substituted with one to five Z1a; each R4 is independently H, halo, cyano, hydroxy, -SH, -N(R13)2, -NO2, -SF5, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, aryl, heterocyclyl, or heteroaryl, wherein each of C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, aryl, heterocyclyl, or heteroaryl is independently unsubstituted or substituted with one to five Z1a; each R5 is independently H, -C(O)R13, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -C(O)OC1-C6 alkyl, aryl, heterocyclyl, or heteroaryl, wherein each C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -C(O)OC1-C6 alkyl, aryl, heterocyclyl, or heteroaryl is independently unsubstituted or substituted with one to five Z1a; each Z1a is independently halo, cyano, -NO2, -SF5, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C10 cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R13)2, -OR13, -C(O)R13, -C(O)OR13, -S(O)0-2R13, -NR13S(O)1-2-R13, -S(O)1-2N(R13)2, -NR13S(O)1-2N(R13)2, -NR13C(O)N(R13)2, -C(O)N(R13)2, -NR13C(O)R13, -OC(O)N(R13)2, or -NR13C(O)OR13; wherein each C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently unsubstituted or substituted with one to five Z1b; each R13 is independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C10 cycloalkyl, heterocyclyl, aryl, or heteroaryl of R13 is independently unsubstituted or substituted with one to five Z1b; each R14 is independently H, C1-C6 alkyl, C3-C10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each C1-C6 alkyl, C3-C10 cycloalkyl, heterocyclyl, aryl, or heteroaryl of R14 is independently unsubstituted or substituted with one to five Z1b; each Z1b is independently halo, cyano, hydroxy, -SH, -NH2, -NO2, -SF5, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, -L-C1-6 alkyl, -L-C2-6 alkenyl, -L-C2-6 alkynyl, -L-C1-6 haloalkyl, -L-C3-10 cycloalkyl, -L-heterocyclyl, -L-aryl, or -L-heteroaryl; each L is independently -O-, -NH-, -S-, -S(O)-, -S(O)2-, -N(C1-C6 alkyl)-, -N(C2-C6 alkenyl), -N(C2-C6 alkynyl)-, -N(C1-C6 haloalkyl)-, -N(C3-10 cycloalkyl)-, -N(heterocyclyl)-, -N(aryl)-, -N(heteroaryl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N(C1-C6 alkyl)-, -C(O)N(C2-C6 alkenyl)-, -C(O)N(C2-C6 alkynyl)-, -C(O)N(C1-6 haloalkyl)-, -C(O)N(C3-10 cycloalkyl)-, -C(O)N(heterocyclyl)-, -C(O)N(aryl)-, -C(O)N(heteroaryl)-, -NHC(O)-, -NHC(O)O-, -NHC(O)NH-, -NHS(O)-, or -S(O)2NH-; and wherein each C1-C6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-C6 haloalkyl, C3-C10 cycloalkyl, heterocyclyl, aryl, and heteroaryl of Z1b and L is further independently unsubstituted or substituted with one to five halo, cyano, hydroxy, -SH, -NH2, -NO2, -SF5, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C10 cycloalkyl, heterocyclyl, aryl, or heteroaryl, provided that the compound at 1 µM concentration degrades BRD4 by 30% or more. 12. A compound of formula IA-1: or a pharmaceutically a cceptable salt, solvate, stereoisomer, or tautomer thereof, wherein: m is an integer from 0 to 4; n is an integer from 0 to 4; each of X1 and X2 is independently CH(R4) or NR5; each of R2 and R3 is independently selected from halo, -N(R13)2, -OR14, C1-C6 alkyl, aryl, cyano, C3-C10 cycloalkyl, heteroaryl, heterocyclyl, guanidino, and nitro, wherein each C1-C6 alkyl, aryl, C3-C10 cycloalkyl, heteroaryl, heterocyclyl, and guanidino is independently unsubstituted or substituted with one to five Z1a; each R4 is independently H, halo, cyano, hydroxy, -SH, -N(R13)2, -NO2, -SF5, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, aryl, heterocyclyl, or heteroaryl, wherein each of C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, aryl, heterocyclyl, or heteroaryl is independently unsubstituted or substituted with one to five Z1a; each R5 is independently H, -C(O)R13, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -C(O)OC1-C6 alkyl, aryl, heterocyclyl, or heteroaryl, wherein each C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -C(O)OC1-C6 alkyl, aryl, heterocyclyl, or heteroaryl is independently unsubstituted or substituted with one to five Z1a; each Z1a is independently halo, cyano, -NO2, -SF5, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C10 cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R13)2, -OR13, -C(O)R13, -C(O)OR13, -S(O)0-2R13, -NR13S(O)1-2-R13, -S(O)1-2N(R13)2, -NR13S(O)1-2N(R13)2, -NR13C(O)N(R13)2, -C(O)N(R13)2, -NR13C(O)R13, -OC(O)N(R13)2, or -NR13C(O)OR13; wherein each C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently unsubstituted or substituted with one to five Z1b; each R13 is independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C10 cycloalkyl, heterocyclyl, aryl, or heteroaryl of R13 is independently unsubstituted or substituted with one to five Z1b; each R14 is independently H, C1-C6 alkyl, C3-C10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each C1-C6 alkyl, C3-C10 cycloalkyl, heterocyclyl, aryl, or heteroaryl of R14 is independently unsubstituted or substituted with one to five Z1b; each Z1b is independently halo, cyano, hydroxy, -SH, -NH2, -NO2, -SF5, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, -L-C1-6 alkyl, -L-C2-6 alkenyl, -L-C2-6 alkynyl, -L-C1-6 haloalkyl, -L-C3-10 cycloalkyl, -L-heterocyclyl, -L-aryl, or -L-heteroaryl; each L is independently -O-, -NH-, -S-, -S(O)-, -S(O)2-, -N(C1-C6 alkyl)-, -N(C2-C6 alkenyl), -N(C2-C6 alkynyl)-, -N(C1-C6 haloalkyl)-, -N(C3-10 cycloalkyl)-, -N(heterocyclyl)-, -N(aryl)-, -N(heteroaryl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N(C1-C6 alkyl)-, -C(O)N(C2-C6 alkenyl)-, -C(O)N(C2-C6 alkynyl)-, -C(O)N(C1-6 haloalkyl)-, -C(O)N(C3-10 cycloalkyl)-, -C(O)N(heterocyclyl)-, -C(O)N(aryl)-, -C(O)N(heteroaryl)-, -NHC(O)-, -NHC(O)O-, -NHC(O)NH-, -NHS(O)-, or -S(O)2NH-; and wherein each C1-C6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-C6 haloalkyl, C3-C10 cycloalkyl, heterocyclyl, aryl, and heteroaryl of Z1b and L is further independently unsubstituted or substituted with one to five halo, cyano, hydroxy, -SH, -NH2, -NO2, -SF5, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C10 cycloalkyl, heterocyclyl, aryl, or heteroaryl, provided that the following compounds are excluded: , . 13. The compound of claim 11 or claim 12, wherein the compound is represented by formula IB-1: or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof. 14. The compound of claim 13, wherein each R4 independently is H or C1-C6 alkyl. 15. The compound of claim 14, wherein the compound is represented by formula IC-1: or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof. 16. The compound of claim 15, wherein each R4 independently is H or methyl. 17. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and an effective amount of a compound of claim 1. 18. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and an effective amount of a compound of claim 10. 19 A pharmaceutical composition comprising a pharmaceutically acceptable excipient and an effective amount of a compound of any one of claims 2-9. 20 A pharmaceutical composition comprising a pharmaceutically acceptable excipient and an effective amount of a compound of any one of claims 11-16. 21. A compound or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, selected from Table 1. 22. A compound or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, selected from Table 1A. 23. A compound or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, selected from Table 2. 24. A compound or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, selected from Table 2A. 25. A method for modulating or degrading BRD4 which method comprises contacting BRD4 with an effective amount of a compound according to claim 1. 26. A method for modulating or degrading BRD4 which method comprises contacting BRD4 with an effective amount of a compound according to claim 2 or claim 3 under conditions wherein BRD4 is modulated or degraded. 27. A method for modulating or degrading BRD4 in a subject, which method comprises administering to said subject an effective amount of a compound according to claim 2 or claim 3. 28. A method for modulating or degrading BRD4 which method comprises contacting BRD4 with an effective amount of a compound according to claim 10. 29. A method for modulating or degrading BRD4 which method comprises contacting BRD4 with an effective amount of a compound according to claim 11 or claim 12 under conditions wherein BRD4 is modulated or degraded. 30. A method for modulating or degrading BRD4 in a subject, which method comprises administering to said subject an effective amount of a compound according to claim 11 or claim 12. 31. A method for modulating or degrading BRD4 in a subject, which method comprises administering to said subject an effective amount of a pharmaceutical composition according to claim 19. 32. A method for modulating or degrading BRD4 in a subject, which method comprises administering to said subject an effective amount of a pharmaceutical composition according to claim 20. 33. A method for treating cancer in a subject in need thereof which method comprises administering to said subject an effective amount of a compound according to claim 2 or claim 3. 34. A method for treating cancer in a subject in need thereof which method comprises administering to said subject an effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable excipient and an effective amount of a compound according to claim 2 or claim 3. 35. A method for treating cancer in a subject in need thereof which method comprises administering to said subject an effective amount of a compound according to claim 11 or claim 12. 36. A method for treating cancer in a subject in need thereof which method comprises administering to said subject an effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable excipient and an effective amount of a compound according to claim 11 or claim 12. |
[0074] In some embodiments, the compound of formula I is represented by formula IB:
or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, wherein Y, R 2 , R 3 , R 4 , m, and n are as defined herein. [0075] In some embodiments, the compound of formula IB is represented by formula IC: or a pharmaceutically accep table salt, solvate, stereoisomer, or tautomer thereof, wherein R 2 , R 3 , R 4 , m, and n are as defined herein. [0076] In some embodiments, the compound of formula IC is represented by formula ID: or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, wherein R 2 , R 3 , R 4 , and n are as defined herein. [0077] In some embodiments, this disclosure provides a compound of formula I, IA, IB, IC, or ID, wherein each R 4 independently is C 1 -C 6 alkyl. In some embodiments, this disclosure provides a compound of formula ID, wherein R 4 is C1-C6 alkyl and n is 0. [0078] In some embodiments, the compound of formula ID is represented by formula IE: NH or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, wherein R 2 is as defined herein. [0079] In some embodiments, this disclosure provides a compound of formula I, IA, IB, or IC, wherein each R 2 independently is H, halo, C 1 -C 6 alkyl, phenyl substituted with C 1 -C 6 alkoxy, pyridyl, or 1-methylpyrazol-5-yl. In some embodiments, this disclosure provides a compound of formula ID or IE, wherein each R 2 independently is H, halo, C 1 -C 6 alkyl, phenyl substituted with C 1 -C 6 alkoxy, pyridyl, or 1-methylpyrazol-5-yl. [0080] In some embodiments, this disclosure provides a compound selected from Table 1 or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof.
Table 1.
[0081] In some embodiments, this disclosure provides a compound selected from Table 2, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof. Compounds of Table 2 degrade BRD4 by less than 30% at 1 µM concentration. Table 2 C d [0082] In one embodiment, this disclosure provides a compound of formula I-1: or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, wherein: m is an integer from 0 to 4; n is an integer from 0 to 4; each of X 1 and X 2 is independently CH(R 4 ) or NR 5 ; Q is H, -CH 2 OH, -CH 2 N(R 13 ) 2 , -CH 2 CH 2 N(R 13 ) 2 , -CH 2 N(R 13 )C(O)R 1 , or heterocyclyl; R 1 is C1-C6 alkyl, C3-C10 cycloalkyl, aryl, heteroaryl, or heterocyclyl, wherein each C1-C6 alkyl, C 3- C 10 cycloalkyl, aryl, heteroaryl, or heterocyclyl is independently unsubstituted or substituted with one to five Z 1a ; each of R 2 and R 3 is independently selected from halo, -N(R 13 ) 2 , -OR 14 , C 1 -C 6 alkyl, aryl, cyano, C 3- C 10 cycloalkyl, heteroaryl, heterocyclyl, guanidino, and nitro, wherein each C 1 -C 6 alkyl, aryl, C 3- C 10 cycloalkyl, heteroaryl, heterocyclyl, and guanidino is independently unsubstituted or substituted with one to five Z 1a ; each R 4 is independently H, halo, cyano, hydroxy, -SH, -N(R 13 ) 2 , -NO 2 , -SF 5 , C 1- C 6 alkyl, C 2- C 6 alkenyl, C 2- C 6 alkynyl, C 1- C 6 haloalkyl, C 1- C 6 alkoxy, C 1- C 6 haloalkoxy, aryl, heterocyclyl, or heteroaryl, wherein each of C 1- C 6 alkyl, C 2- C 6 alkenyl, C 2- C 6 alkynyl, C 1- C 6 haloalkyl, C 1- C 6 alkoxy, C 1- C 6 haloalkoxy, aryl, heterocyclyl, or heteroaryl is independently unsubstituted or substituted with one to five Z 1a ; each R 5 is independently H, -C(O)R 13 , C 1- C 6 alkyl, C 2- C 6 alkenyl, C 2- C 6 alkynyl, C 1- C 6 haloalkyl, C 1- C 6 alkoxy, C 1- C 6 haloalkoxy, -C(O)OC 1- C 6 alkyl, aryl, heterocyclyl, or heteroaryl, wherein each C 1- C 6 alkyl, C 2- C 6 alkenyl, C 2- C 6 alkynyl, C 1- C 6 haloalkyl, C 1- C 6 alkoxy, C1-C6 haloalkoxy, -C(O)OC1-C6 alkyl, aryl, heterocyclyl, or heteroaryl is independently unsubstituted or substituted with one to five Z 1a ; each Z 1a is independently halo, cyano, -NO2, -SF5, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C10 cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R 13 )2, -OR 13 , -C(O)R 13 , -C(O)OR 13 , -S(O) 0-2 R 13 , -NR 13 S(O) 1-2 -R 13 , -S(O) 1-2 N(R 13 ) 2 , -NR 13 S(O) 1-2 N(R 13 ) 2 , -NR 13 C(O)N(R 13 ) 2 , -C(O)N(R 13 ) 2 , -NR 13 C(O)R 13 , -OC(O)N(R 13 ) 2 , or -NR 13 C(O)OR 13 ; wherein each C 1- C 6 alkyl, C 2- C 6 alkenyl, C 2- C 6 alkynyl, C 1- C 6 haloalkyl, C 3- C 10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently unsubstituted or substituted with one to five Z 1b ; each R 13 is independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C 3- C 10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each C 1- C 6 alkyl, C 2- C 6 alkenyl, C 2- C 6 alkynyl, C 1- C 6 haloalkyl, C 3- C 10 cycloalkyl, heterocyclyl, aryl, or heteroaryl of R 13 is independently unsubstituted or substituted with one to five Z 1b ; each R 14 is independently H, C1-C6 alkyl, C3-C10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each C1-C6 alkyl, C3-C10 cycloalkyl, heterocyclyl, aryl, or heteroaryl of R 14 is independently unsubstituted or substituted with one to five Z 1b ; each Z 1b is independently halo, cyano, hydroxy, -SH, -NH2, -NO2, -SF5, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, -L-C1-6 alkyl, -L-C2-6 alkenyl, -L-C2-6 alkynyl, -L-C1-6 haloalkyl, -L-C3-10 cycloalkyl, -L-heterocyclyl, -L-aryl, or -L-heteroaryl; each L is independently -O-, -NH-, -S-, -S(O)-, -S(O)2-, -N(C1-C6 alkyl)-, -N(C2-C6 alkenyl), -N(C2-C6 alkynyl)-, -N(C1-C6 haloalkyl)-, -N(C3-10 cycloalkyl)-, -N(heterocyclyl)-, -N(aryl)-, -N(heteroaryl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N(C1-C6 alkyl)-, -C(O)N(C2-C6 alkenyl)-, -C(O)N(C2-C6 alkynyl)-, -C(O)N(C1-6 haloalkyl)-, -C(O)N(C3-10 cycloalkyl)-, -C(O)N(heterocyclyl)-, -C(O)N(aryl)-, -C(O)N(heteroaryl)-, -NHC(O)-, -NHC(O)O-, -NHC(O)NH-, -NHS(O)-, or -S(O)2NH-; and wherein each C1-C6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-C6 haloalkyl, C3-C10 cycloalkyl, heterocyclyl, aryl, and heteroaryl of Z 1b and L is further independently unsubstituted or substituted with one to five halo, cyano, hydroxy, -SH, -NH2, -NO2, -SF5, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C10 cycloalkyl, heterocyclyl, aryl, or heteroaryl. [0083] In some embodiments, this disclosure provides a compound of formula I-1 as described above, provided that the compound at 1 µM concentration degrades BRD4 by 30% or more. [0084] In some embodiments, this disclosure provides a compound of formula IA-1:
or a pharmaceutically acc eptable salt, solvate, stereoisomer, or tautomer thereof, wherein: m is an integer from 0 to 4; n is an integer from 0 to 4; each of X 1 and X 2 is independently CH(R 4 ) or NR 5 ; each of R 2 and R 3 is independently selected from halo, -N(R 13 )2, -OR 14 , C1-C6 alkyl, aryl, cyano, C3-C10 cycloalkyl, heteroaryl, heterocyclyl, guanidino, and nitro, wherein each C1-C6 alkyl, aryl, C3-C10 cycloalkyl, heteroaryl, heterocyclyl, and guanidino is independently unsubstituted or substituted with one to five Z 1a ; each R 4 is independently H, halo, cyano, hydroxy, -SH, -N(R 13 )2, -NO2, -SF5, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, aryl, heterocyclyl, or heteroaryl, wherein each of C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, aryl, heterocyclyl, or heteroaryl is independently unsubstituted or substituted with one to five Z 1a ; each R 5 is independently H, -C(O)R 13 , C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -C(O)OC1-C6 alkyl, aryl, heterocyclyl, or heteroaryl, wherein each C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C 1- C 6 haloalkoxy, -C(O)OC 1- C 6 alkyl, aryl, heterocyclyl, or heteroaryl is independently unsubstituted or substituted with one to five Z 1a ; each Z 1a is independently halo, cyano, -NO 2 , -SF 5 , C 1- C 6 alkyl, C 2- C 6 alkenyl, C 2- C 6 alkynyl, C 1- C 6 haloalkyl, C 3- C 10 cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R 13 ) 2 , -OR 13 , -C(O)R 13 , -C(O)OR 13 , -S(O) 0-2 R 13 , -NR 13 S(O) 1-2 -R 13 , -S(O) 1-2 N(R 13 ) 2 , -NR 13 S(O) 1-2 N(R 13 ) 2 , -NR 13 C(O)N(R 13 ) 2 , -C(O)N(R 13 ) 2 , -NR 13 C(O)R 13 , -OC(O)N(R 13 ) 2 , or -NR 13 C(O)OR 13 ; wherein each C 1- C 6 alkyl, C 2- C 6 alkenyl, C 2- C 6 alkynyl, C 1- C 6 haloalkyl, C 3- C 10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently unsubstituted or substituted with one to five Z 1b ; each R 13 is independently H, C 1- C 6 alkyl, C 2- C 6 alkenyl, C 2- C 6 alkynyl, C 1- C 6 haloalkyl, C 3- C 10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each C 1- C 6 alkyl, C 2- C 6 alkenyl, C 2- C 6 alkynyl, C 1- C 6 haloalkyl, C 3- C 10 cycloalkyl, heterocyclyl, aryl, or heteroaryl of R 13 is independently unsubstituted or substituted with one to five Z 1b ; each R 14 is independently H, C1-C6 alkyl, C3-C10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each C 1- C 6 alkyl, C 3- C 10 cycloalkyl, heterocyclyl, aryl, or heteroaryl of R 14 is independently unsubstituted or substituted with one to five Z 1b ; each Z 1b is independently halo, cyano, hydroxy, -SH, -NH2, -NO2, -SF5, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, -L-C1-6 alkyl, -L-C2-6 alkenyl, -L-C2-6 alkynyl, -L-C1-6 haloalkyl, -L-C3-10 cycloalkyl, -L-heterocyclyl, -L-aryl, or -L-heteroaryl; each L is independently -O-, -NH-, -S-, -S(O)-, -S(O)2-, -N(C1-C6 alkyl)-, -N(C2-C6 alkenyl), -N(C2-C6 alkynyl)-, -N(C1-C6 haloalkyl)-, -N(C3-10 cycloalkyl)-, -N(heterocyclyl)-, -N(aryl)-, -N(heteroaryl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N(C1-C6 alkyl)-, -C(O)N(C2-C6 alkenyl)-, -C(O)N(C2-C6 alkynyl)-, -C(O)N(C1-6 haloalkyl)-, -C(O)N(C3-10 cycloalkyl)-, -C(O)N(heterocyclyl)-, -C(O)N(aryl)-, -C(O)N(heteroaryl)-, -NHC(O)-, -NHC(O)O-, -NHC(O)NH-, -NHS(O)-, or -S(O)2NH-; and wherein each C1-C6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-C6 haloalkyl, C3-C10 cycloalkyl, heterocyclyl, aryl, and heteroaryl of Z 1b and L is further independently unsubstituted or substituted with one to five halo, cyano, hydroxy, -SH, -NH2, -NO2, -SF5, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C10 cycloalkyl, heterocyclyl, aryl, or heteroaryl, provided that the following compounds are excluded: ,
, . [0085] In some embodiments, the compound of formula I-1 is represented by formula IB-1: [0086] or a pharmaceutically ac ceptable salt, solvate, stereoisomer, or tautomer thereof, wherein R 2 , R 3 , R 4 , m, and n are as defined herein. [0087] In some embodiments, the compound of formula IB-1 is represented by formula IC-1:
or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, wherein R 4 is as defined herein. [0088] In some embodiments, this disclosure provides a compound of formula I-1, IA-1, IB-1, or IC-1, wherein each R 4 independently is C1-C6 alkyl. In some embodiments, this disclosure provides a compound of formula I-1, IA-1, IB-1, or IC-1, wherein each R 4 independently is methyl. In some embodiments, this disclosure provides a compound of formula I-1, IA-1, IB-1, or IC-1, wherein each R 4 independently is hydrogen. In some embodiments, this disclosure provides a compound of formula I-1, IA-1, IB-1, or IC-1, wherein one R 4 is methyl and the other R 4 is hydrogen. In some embodiments, this disclosure provides a compound of formula IB-1, wherein R 4 is C1-C6 alkyl and n is 0. [0089] In some embodiments, this disclosure provides a compound of formula I-1, IA-1, or IB-1, wherein each R 2 independently is H, halo, C1-C6 alkyl, phenyl substituted with C1-C6 alkoxy, pyridyl, or 1-methylpyrazol-5-yl. [0090] In some embodiments, this disclosure provides a compound selected from Table 1A or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof. Table 1A Compound # Structure Name
[0091] In some embodiments, this disclosure provides a compound selected from Table 2A, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof. Compounds of Table 2A degrade BRD4 by less than 30% at 1 µM concentration. Table 2A Compound # Structure Name
General Synthetic Methods [0092] The compounds described herein can be prepared from readily available starting materials using the following general methods and procedures. It will be appreciated that where typical process conditions (e.g., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures. [0093] Additionally, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions. Suitable protecting groups for various functional groups as well as suitable conditions for protecting and deprotecting particular functional groups are well known in the art. For example, numerous protecting groups are described in T. W. Greene and P. G. M. Wuts, Protecting Groups in Organic Synthesis, Third Edition, Wiley, New York, 1999, and references cited therein. [0094] The starting materials for the following reactions are generally known compounds or can be prepared by known procedures or obvious modifications thereof. For example, many of the starting materials are available from commercial suppliers such as Sigma Aldrich (St. Louis, Missouri, USA), Bachem (Torrance, California, USA), Emka-Chemce (St. Louis, Missouri, USA). Others may be prepared by procedures, or obvious modifications thereof, described in standard reference texts such as Fieser and Fieser’s Reagents for Organic Synthesis, Volumes 1-15 (John Wiley, and Sons, 2016), Rodd’s Chemistry of Carbon Compounds, Volumes 1-5, and Supplementals (Elsevier Science Publishers, 2001), Organic Reactions, Volumes 1-40 (John Wiley, and Sons, 2019), March’s Advanced Organic Chemistry, (John Wiley, and Sons, 8th Edition, 2019), and Larock’s Comprehensive Organic Transformations (VCH Publishers Inc., 1989). Synthesis of Representative Compounds [0095] The general synthesis of the compounds described herein is set forth in the reaction schemes below. Scheme 1 illustrates a general method for preparing compounds of formula I. In Scheme 1, substituents and variables X 1 , X 2 , R 1 , R 2 , R 3 , R 4 , Y, Q, m, and n are as defined throughout the specification. X is a suitable Suzuki cross-coupling partner for a boronic ester (including, but not limited to, Br, Cl, I, triflate, and the like).
[0096] As to the reaction in Scheme 1, the first step is an Ullmann N-Arylation reaction, wherein at least a stoichiometric equivalent of a suitable amine, compound 1, is combined with a suitably functionalized aryl halide, compound 2, in an inert diluent such as tetrahydrofuran, DMF, DMSO, and the like, typically in the presence of a copper(I) catalyst (e.g. CuI) and a suitable base such as cesium carbonate, potassium carbonate, and the like. The reaction is typically maintained at from 80° to 120°C until it is substantially complete. Conventional workup of the reaction solution can be followed by isolation / purification processes, such as crystallization, chromatography, high performance liquid chromatography (HPLC), and the like to provide for compound 3. [0097] In the next step, the ester, compound 3, may be converted to a primary amide (Journal of Medicinal Chemistry, 2005, vol.48, # 25, p.8045 - 8054), wherein at least a stoichiometric equivalent of ammonia or ammonium hydroxide is combined with compound 3, in an inert diluent, such as MeOH, EtOH, THF, and the like. The reaction is typically maintained at from 60° to 100°C until it is substantially complete. Conventional workup of the reaction solution can be followed by isolation / purification processes, such as crystallization, chromatography, high performance liquid chromatography (HPLC), and the like to provide for compound 4. [0098] In the next step, the free amino group of compound 4 is protected (Journal of general chemistry of the USSR, 1966, vol.36, # 8, p. 1448 – 1450), wherein at least a stoichiometric equivalent of isopropyl carbonochloridate is combined with compound 4, typically in the presence of a suitable base such as cesium carbonate, potassium carbonate, lithium tert-butoxide, and the like, in an inert diluent such as DMF, THF, dioxane, and the like. The reaction is typically maintained at from 20° to 60°C for a period of time sufficient for substantial completion of the reaction, as evidenced by e.g., thin layer chromatography. Upon reaction completion, conventional workup of the reaction solution can be followed by isolation / purification processes, such as crystallization, chromatography, high performance liquid chromatography (HPLC), and the like to provide for compound 5. The isopropylcarbonyl group is illustrative only and other conventional amino protecting groups, such as benzyl, t-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), p-nitrobenzyloxycarbonyl, and the like could be used. [0099] In the next step, compound 5 is cyclized under conventional reaction conditions (Journal of Medicinal Chemistry, 2014, vol.57, # 19, p.8111 – 8131) well known in the art, including the use of sodium tetrahydroborate, magnesium chloride, and lithium tert-butoxide. The reaction is typically conducted in an inert solvent such as ethanol, THF, toluene, N,N-dimethylformamide, and the like. The reaction is typically conducted at from about -10º to about 20º C for a period of time sufficient for substantial completion of the reaction, as evidenced by e.g., thin layer chromatography. Upon reaction completion, conventional workup of the reaction solution can be followed by isolation / purification processes, such as crystallization, chromatography, high performance liquid chromatography (HPLC), and the like to provide for compound 6. [0100] In the next step, at least a stoichiometric amount of a suitably substituted carboxylic acid or carboxylic halide compound is combined with compound 6 under conventional amidation reaction conditions well known in the art, including the use of N,N-dicyclohexylcarbodiimide (DCC) as an activation agent for the carboxyl group. Other activation agents are well known in the art. The reaction is typically conducted in an inert solvent, such as chloroform, methylene chloride, toluene, N,N- dimethylformamide, and the like. The reaction is typically conducted at from about 0º to about 30º C for a period of time sufficient for substantial completion of the reaction, as evidenced by e.g., thin layer chromatography. Upon reaction completion, conventional workup of the reaction solution can be followed by isolation / purification processes, such as crystallization, chromatography, high performance liquid chromatography (HPLC), and the like to provide for compound 7. [0101] In the next step, the isopropylcarbonyl protecting group is removed by conventional conditions, such as aluminum trichloride in dichloromethane, to provide for compound 8. The isopropylcarbonyl group is illustrative only and other conventional amino protecting groups, such as benzyl, t-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), p-nitrobenzyloxycarbonyl, and the like could be used. Upon reaction completion, conventional workup of the reaction solution can be followed by isolation / purification processes, such as crystallization, chromatography, high performance liquid chromatography (HPLC), and the like to provide for compound 8. [0102] In the next step, a Chan-Evans-Lam reaction (Tetrahedron Lett.39 (19): 2933–293), wherein at least a stoichiometric amount of a suitably substituted aryl boronic acid, compound 9, is combined with compound 8 in an inert diluent such as acetonitrile, dichloromethane, toluene, and the like, typically in the presence of a copper(II) catalyst (e.g. Cu(OAc)2) and a suitable base, such as pyridine, triethylamine, and the like. The reaction is typically maintained at from 20° to 80°C until it is substantially complete. Conventional workup of the reaction solution can be followed by isolation / purification processes, such as crystallization, chromatography, high performance liquid chromatography (HPLC), and the like to provide for compound 10. [0103] In the next step, a conventional Suzuki coupling reaction, wherein at least a stoichiometric equivalent of a suitable boronic acid is combined with compound 10, in an inert diluent, such as tetrahydrofuran, dioxane, toluene, dimethoxyethane, and the like, typically in the presence of a palladium catalyst (e.g, palladium diacetate) and a suitable base, such as diisopropylethylamine, triethylamine, pyridine, potassium carbonate, and the like. The reaction is typically maintained at from 10° to 65°C until it is substantially complete. Conventional workup of the reaction solution can be followed by isolation / purification processes, such as crystallization, chromatography, high performance liquid chromatography (HPLC), and the like to provide for compound 11. [0104] In the final step, at least a stoichiometric amount of compound 11 is combined with a terminal alkyne under conventional Sonogashira coupling conditions, in an inert diluent such as tetrahydrofuran, dioxane, DMSO, DMF, and the like, typically in the presence of a palladium catalyst (e.g. bis(triphenylphosphine)palladium (II) dichloride), a copper(I) co-catalyst (e.g. CuI), and a suitable base, such as diisopropylethylamine, triethylamine, pyridine, potassium carbonate, and the like. The reaction is typically conducted at from about 30º to about 120º C for a period of time sufficient for substantial completion of the reaction, as evidenced by e.g., thin layer chromatography. Upon reaction completion, conventional workup of the reaction solution can be followed by isolation / purification processes, such as crystallization, chromatography, high performance liquid chromatography (HPLC), and the like to provide for compounds of formula I. [0105] Other starting materials used herein are either well known in the art, commercially available, or can be prepared by conventional synthetic methods. [0106] Scheme 1A illustrates a general method for preparing compounds of formula I-1. In Scheme 1A, substituents and variables X 1 , X 2 , R 1 , R 2 , and m are as defined throughout the specification. X is a suitable Suzuki cross-coupling partner for a boronic ester (including, but not limited to, Br, Cl, I, triflate, and the like). [0107] As to the reaction in Scheme 1A, the first step is a conventional SNAR reaction wherein at least a stoichiometric equivalent of compound 1A, is combined with compound 2A, in an inert diluent such as tetrahydrofuran, dioxane, DMSO, DMF, and the like, typically in the presence of a suitable base such as diisopropylethylamine, triethylamine, pyridine, potassium carbonate, and the like. The reaction is typically maintained at from 25 °C to 100 °C until it is substantially complete. Conventional workup of the reaction solution can be followed by isolation / purification processes such as crystallization, chromatography, high performance liquid chromatography (HPLC), and the like to provide for compound 3A. [0108] In the next step, compound 3A, is reduced under conventional nitro reduction reaction conditions well known in the art including the use Fe in the presence of ammonium chloride. Other nitro reducing reagents are well known in the art. The reaction is typically conducted in an inert solvent such as EtOH, ethyl acetate, toluene, and the like. The reaction is typically conducted from about 20 ºC to about 60 ºC for a period of time sufficient for substantial completion of the reaction as evidenced by e.g., thin layer chromatography. Upon reaction completion, conventional workup of the reaction solution can be followed by isolation / purification processes such as crystallization, chromatography, high performance liquid chromatography (HPLC), and the like to provide for compound 4A. [0109] In the next step, the amine is activated as a tosyl sulfonamide. At least a stoichiometric amount of tosyl chloride is added to compound 4A, in an inert diluent such as THF, MeCN, toluene and the like in the presence of a suitable base such as triethylamine, diisopropylethylamine, pyridine and the like. The reaction is typically maintained at from 0 °C to 30 °C until it is substantially complete. Conventional workup of the reaction solution can be followed by isolation / purification processes such as crystallization, chromatography, high performance liquid chromatography (HPLC), and the like to provide for compound 5A. [0110] In the next step, a conventional Mitsunobu reaction, wherein at least a stoichiometric equivalent of 5A, under conventional reaction conditions [Hughes, D.L. (2004). The Mitsunobu Reaction, Organic Reactions, (Ed.).] well known in the art, including the use diethylazodicarboxylate and triphenylphosphine. The reaction is typically conducted in an inert solvent such as acetonitrile, THF, toluene, and the like. The reaction is typically maintained at from 0 °C to 30 °C until it is substantially complete. Conventional workup of the reaction solution can be followed by isolation / purification processes such as crystallization, chromatography, high performance liquid chromatography (HPLC), and the like to provide for compound 6A. [0111] In the next step, at least a stoichiometric amount of a suitably carboxylic acid compound, is combined with compound 6A under conventional amidation reaction conditions (Angewandte Chemie- International Edition, 2020, 59, 3028-3032) well known in the art, including the use of N,N- dicyclohexylcarbodiimide (DCC), as an activation agent for the carboxyl group. Other activation agents are well known in the art. The reaction is typically conducted in an inert solvent such as chloroform, methylene chloride, toluene, N,N-dimethylformamide, and the like. The reaction is typically conducted at from about 0 ºC to about 30 ºC for a period of time sufficient for substantial completion of the reaction as evidenced by e.g., thin layer chromatography. Upon reaction completion, conventional workup of the reaction solution can be followed by isolation / purification processes such as crystallization, chromatography, high performance liquid chromatography (HPLC), and the like to provide for compound 7A. [0112] In the next step, the tosyl (Ts) protecting group is removed by conventional conditions to provide for compound 8A. Upon reaction completion, conventional workup of the reaction solution can be followed by isolation / purification processes such as crystallization, chromatography, high performance liquid chromatography (HPLC), and the like. [0113] In the next step, the amine 8A is protected with t-butoxycarbonyl (BOC) group with. At least a stoichiometric amount of a BOC anhydride is combined with compound 8A in an inert diluent such as dichloromethane, dichloroethane, THF, and the like. The reaction is typically maintained at from about 20 °C to about 50 °C until it is substantially complete. Conventional workup of the reaction solution can be followed by isolation/purification processes such as crystallization, chromatography, high performance liquid chromatography (HPLC), and the like to provide for compound 9A. The BOC group is illustrative only and other conventional amino blocking groups such as benzyl, 9-fluorenylmethoxycarbonyl (Fmoc), benzyloxycarbonyl (Cbz), p-nitrobenzyloxycarbonyl and the like could be used. [0114] In the next step, a Miyuaura borylation reaction (J. Org. Chem., 1995, 60, 7508), at least a stoichiometric amount of compound 9A and bis(pinacolato)diboron are combined, in an inert diluent such as DMSO, 1,4-dioxane, and the like, in the presence of a suitable catalyst such as PdCl2(dppf)2, PdCl2(PPh3)2, and the like. The reaction is typically maintained at from 80 °C to 110 °C until it is substantially complete. Conventional workup of the reaction solution can be followed by isolation / purification processes such as crystallization, chromatography, high performance liquid chromatography (HPLC), and the like to provide for compound 10A. [0115] In the next step, a conventional Suzuki coupling reaction wherein at least a stoichiometric equivalent of compound 10A, is combined with a suitable aryl halide, in an inert diluent such as tetrahydrofuran, dioxane, toluene, dimethoxyethane, and the like, typically in the presence of a palladium catalyst (e.g, palladium diacetate) and a suitable base such as diisopropylethylamine, triethylamine, pyridine, potassium carbonate, and the like. The reaction is typically maintained at from 10 °C to 65 °C until it is substantially complete. Conventional workup of the reaction solution can be followed by isolation / purification processes such as crystallization, chromatography, high performance liquid chromatography (HPLC), and the like to provide for compound 11A. [0116] In the final step, the t-butoxycarbonyl (BOC) protecting group is removed by conventional conditions. The BOC group is illustrative only and other conventional amino blocking groups such as benzyl, 9-fluorenylmethoxycarbonyl (Fmoc), benzyloxycarbonyl (Cbz), p-nitrobenzyloxycarbonyl and the like. Upon reaction completion, conventional workup of the reaction solution can be followed by isolation / purification processes such as crystallization, chromatography, high performance liquid chromatography (HPLC), and the like to provide for compound 12A. [0117] Compound 12A can be used in scheme 2A. Scheme 2A [0118] As to the reaction in Scheme 2A, the first step is a conventional alkylation reaction wherein at least a stoichiometric equivalent of a suitable amine, compound 12A (R 2 = H, R 1 = CH3, X 1 and X 2 = CH2, CAS# 6639-92-5), is combined with a suitably functionalized benzylic halide, in an inert diluent such as tetrahydrofuran, dioxane, toluene, dimethoxyethane, and the like, typically in the presence of a suitable base such as diisopropylethylamine, triethylamine, pyridine, potassium carbonate, and the like. The reaction is typically maintained at from 80 °C to 120 °C until it is substantially complete. Conventional workup of the reaction solution can be followed by isolation / purification processes such as crystallization, chromatography, high performance liquid chromatography (HPLC), and the like to provide for compound 13A. [0119] In the final step, at least a stoichiometric amount of compound 13A is combined with a terminal alkyne under conventional Sonogashira coupling conditions, in an inert diluent such as tetrahydrofuran, dioxane, DMSO, DMF, and the like, typically in the presence of a palladium catalyst (e.g, Bis(triphenylphosphine)palladium(II) dichloride), a copper(I) co-catalyst (e.g. CuI), and a suitable base such as diisopropylethylamine, triethylamine, pyridine, potassium carbonate, and the like. The reaction is typically conducted at from about 30 ºC to about 120 ºC for a period of time sufficient for substantial completion of the reaction as evidenced by e.g., thin layer chromatography. Upon reaction completion, conventional workup of the reaction solution can be followed by isolation / purification processes such as crystallization, chromatography, high performance liquid chromatography (HPLC), and the like to provide for compound 14A. [0120] Other variants of compound 12A are commercially available or can be prepared by conventional reaction conditions well known in the art. [0121] Other starting materials used herein are either well known in the art, commercially available, or can be prepared by conventional synthetic methods. Methods [0122] In one embodiment, the compounds and compositions described herein are useful in methods for treating a BRD4 dependent disease or disorder or a disease or disorder that is mediated, at least in part by, BRD4. The methods comprise administering to a subject suffering from a BRD4 dependent disease or disorder an effective amount of a compound, or a pharmaceutically acceptable salt, solvate, stereoisomer, mixture of stereoisomers, or tautomer of each thereof or a pharmaceutical composition comprising said compound, or a pharmaceutically acceptable salt, solvate, stereoisomer, mixture of stereoisomers, or tautomer of each thereof as described herein. [0123] In one embodiment, there is provided a compound, or a pharmaceutically acceptable salt, solvate, stereoisomer, mixture of stereoisomers, or tautomer of each thereof or a pharmaceutical composition comprising said compound, or a pharmaceutically acceptable salt, solvate, stereoisomer, mixture of stereoisomers, or tautomer of each thereof as described herein for use in treating an BRD4 dependent disease or disorder. [0124] In one embodiment, the method relates a compound, or a pharmaceutically acceptable salt, solvate, stereoisomer, mixture of stereoisomers, or tautomer of each thereof or a pharmaceutical composition comprising said compound, or a pharmaceutically acceptable salt, solvate, stereoisomer, mixture of stereoisomers, or tautomer of each thereof as described herein for use in manufacture of a medicament for reducing BRD4 protein levels where reduction of such protein levels treats or ameliorates the diseases or disorder. [0125] In one embodiment, the method relates a compound, or a pharmaceutically acceptable salt, solvate, stereoisomer, mixture of stereoisomers, or tautomer of each thereof or a pharmaceutical composition comprising said compound, or a pharmaceutically acceptable salt, solvate, stereoisomer, mixture of stereoisomers, or tautomer of each thereof as described herein for use as described herein, wherein the BRD4 degradation at 1µM concentration of the compounds described herein is at least 50% or at least 70%. The BRD4 degradation is measured by the assay described in the biological example. [0126] The compounds and compositions described herein are useful in treating BRD4 dependent diseases or disorders such as liposarcoma, glioblastoma, bladder cancer, adrenocortical cancer, multiple myeloma, colorectal cancer, non-small cell lung cancer, Human Papilloma Virus-associated cervical, oropharyngeal, penis, anal, thyroid, or vaginal cancer or Epstein-Barr Virus-associated nasopharyngeal carcinoma, gastric cancer, rectal cancer, thyroid cancer, Hodgkin lymphoma or diffuse large B-cell lymphoma. The cancer may be selected from prostate cancer, breast carcinoma, lymphomas, leukemia, myeloma, bladder carcinoma, colon cancer, cutaneous melanoma, hepatocellular carcinoma, endometrial cancer, ovarian cancer, cervical cancer, lung cancer, renal cancer, glioblastoma multiform, glioma, thyroid cancer, parathyroid tumor, nasopharyngeal cancer, tongue cancer, pancreatic cancer, esophageal cancer, cholangiocarcinoma, gastric cancer, soft tissue sarcomas, rhabdomyosarcoma (RMS), synovial sarcoma, osteosarcoma, rhabdoid cancers, cancer for which the immune response is deficient, an immunogenic cancer, and Ewing’s sarcoma. In one embodiment, the BRD4-dependent disease or disorder is a disease or disorder is selected from non-small cell lung cancer (NSCLC), melanoma, triple-negative breast cancer (TNBC), nasopharyngeal cancer (NPC), microsatellite stable colorectal cancer (mssCRC), thymoma, carcinoid, and gastrointestinal stromal tumor (GIST). In another embodiment, the cancer is selected from non-small cell lung cancer (NSCLC), melanoma, triple-negative breast cancer (TNBC), nasopharyngeal cancer (NPC), microsatellite stable colorectal cancer (mssCRC), thymoma, carcinoid, acute myelogenous leukemia, and gastrointestinal stromal tumor (GIST). In another embodiment, the BRD4-dependent disease or disorder is a disease or disorder is selected from non-small cell lung cancer (NSCLC), melanoma, triple- negative breast cancer (TNBC), nasopharyngeal cancer (NPC), and microsatellite stable colorectal cancer (mssCRC). [0127] The compounds of the disclosure can be administered in effective amounts to treat or prevent a disorder and/or prevent the development thereof in subjects. [0128] In general, methods of using the compounds of the present application comprise administering to a subject in need thereof an effective amount of a compound as described herein. [0129] In certain embodiments, compounds as described herein are useful in the treatment of proliferative disorders (e.g., cancer, benign neoplasms, inflammatory disease, and autoimmune diseases). In certain embodiments, according to the methods of treatment of the present application, levels of cell proteins of interest, e.g., pathogenic and oncogenic proteins are modulated, or their expression is inhibited or the proteins are modulated or degraded by contacting said cells with a compound or composition, as described herein. In other embodiments, the compounds are useful in treating cancer. [0130] Thus, in another aspect of the application, methods for the treatment of cancer are provided comprising administering an effective amount of compound or composition, as described herein, to a subject in need thereof. In certain embodiments, a method for the treatment of cancer is provided comprising administering an effective amount of a compound, or a pharmaceutical composition comprising a compound as described herein to a subject in need thereof, in such amounts and for such time as is necessary to achieve the desired result. In some embodiments, the compounds of present application are administered orally. The compounds and compositions, according to the method of the present application, are administered orally to a subject using any amount and any route of administration effective for killing or inhibiting the growth of tumor cells. Thus, the expression “amount effective to kill or inhibit the growth of tumor cells,” as used herein, refers to a sufficient amount of agent to kill or inhibit the growth of tumor cells. The exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the disease, and the like. [0131] In certain embodiments, the method involves the administration of a therapeutically effective amount of the compound or a pharmaceutically acceptable salt thereof to a subject (including, but not limited to a human or other mammal in need of it. In certain embodiments, the compounds or compositions described herein are useful for the treatment of cancer (including, but not limited to, glioblastoma, retinoblastoma, breast cancer, cervical cancer, colon and rectal cancer, leukemia, lymphoma, lung cancer (including, but not limited to small cell lung cancer), melanoma and/or skin cancer, multiple myeloma, non-Hodgkin's lymphoma, ovarian cancer, pancreatic cancer, prostate cancer and gastric cancer, bladder cancer, uterine cancer, kidney cancer, testicular cancer, stomach cancer, brain cancer, liver cancer, or esophageal cancer). [0132] In certain embodiments, the compounds or compositions described herein are useful in the treatment of cancers and other proliferative disorders, including, but not limited to breast cancer, cervical cancer, colon and rectal cancer, leukemia, lung cancer, melanoma, multiple myeloma, non-Hodgkin's lymphoma, ovarian cancer, pancreatic cancer, prostate cancer, and gastric cancer. In certain embodiments, compounds or compositions described herein are active against solid tumors. [0133] Additionally, the present application provides pharmaceutically acceptable derivatives of the compounds, and methods of treating a subject using these compounds, pharmaceutical compositions thereof, or either of these in combination with one or more additional therapeutic agents. [0134] Another aspect of the application relates to a method of treating or lessening the severity of a disease or condition associated with a proliferation disorder in a patient, said method comprising a step of administering to said patient, a compound of Formula I or Formula I-1, or a composition comprising said compound. [0135] It will be appreciated that the compounds and compositions, according to the method of the present application, may be administered using any amount and any route of administration effective for the treatment of cancer and/or disorders associated with cell hyperproliferation. [0136] The present application provides methods for the treatment of a proliferative disorder in a subject in need thereof by administering to a subject in need of such treatment, a therapeutically effective amount of a compound of the present application, or a pharmaceutically acceptable salt, solvate, stereoisomer, mixture of stereoisomers, or tautomer of each thereof. The proliferative disorder can be cancer or a precancerous condition. The present application further provides the use of a compound of the present application, or a pharmaceutically acceptable salt, salt, solvate, stereoisomer, mixture of stereoisomers, or tautomer of each thereof, for the preparation of a medicament useful for the treatment of a proliferative disorder. [0137] The present application also provides methods of protecting against a proliferative disorder in a subject in need thereof by administering a therapeutically effective amount of compound of the present application, or a pharmaceutically acceptable salt, salt, solvate, stereoisomer, mixture of stereoisomers, or tautomer of each thereof, to a subject in need of such treatment. The proliferative disorder can be cancer or a precancerous condition. The present application also provides the use of compound of the present application, or a pharmaceutically acceptable salt, salt, solvate, stereoisomer, mixture of stereoisomers, or tautomer of each thereof, for the preparation of a medicament useful for the prevention of a proliferative disorder. [0138] As used herein, the term “proliferative disorder” refers to conditions in which unregulated or abnormal growth, or both, of cells can lead to the development of an unwanted condition or disease, which may or may not be cancerous. Exemplary proliferative disorders of the application encompass a variety of conditions wherein cell division is deregulated. Exemplary proliferative disorders include, but are not limited to, neoplasms, benign tumors, malignant tumors, uterine fibroids, pre-cancerous conditions, in situ tumors, encapsulated tumors, metastatic tumors, liquid tumors, solid tumors, immunological tumors, hematological tumors, cancers, carcinomas, leukemias, lymphomas, sarcomas, and rapidly dividing cells. The term “rapidly dividing cell” as used herein is defined as any cell that divides at a rate that exceeds or is greater than what is expected or observed among neighboring or juxtaposed cells within the same tissue. A proliferative disorder includes a precancer or a precancerous condition. A proliferative disorder includes cancer. In some embodiments, the methods provided herein are used to treat or alleviate a symptom of cancer. The term “cancer” includes solid tumors, as well as, hematologic tumors and/or malignancies. A “precancer cell” or “precancerous cell” is a cell manifesting a proliferative disorder that is a precancer or a precancerous condition. A “cancer cell” or “cancerous cell” is a cell manifesting a proliferative disorder that is a cancer. Any reproducible means of measurement may be used to identify cancer cells or precancerous cells. Cancer cells or precancerous cells can be identified by histological typing or grading of a tissue sample (e.g., a biopsy sample). Cancer cells or precancerous cells can be identified through the use of appropriate molecular markers. [0139] Exemplary non-cancerous conditions or disorders include, but are not limited to, rheumatoid arthritis; inflammation; autoimmune disease; lymphoproliferative conditions; acromegaly; rheumatoid spondylitis; osteoarthritis; gout, other arthritic conditions; sepsis; septic shock; endotoxic shock; gram- negative sepsis; toxic shock syndrome; asthma; adult respiratory distress syndrome; chronic obstructive pulmonary disease; chronic pulmonary inflammation; inflammatory bowel disease; Crohn's disease; psoriasis; eczema; ulcerative colitis; pancreatic fibrosis; hepatic fibrosis; acute and chronic renal disease; irritable bowel syndrome; pyresis; restenosis; cerebral malaria; stroke and ischemic injury; neural trauma; Alzheimer's disease; Huntington's disease; Parkinson's disease; acute and chronic pain; allergic rhinitis; allergic conjunctivitis; chronic heart failure; acute coronary syndrome; cachexia; malaria; leprosy; leishmaniasis; Lyme disease; Reiter's syndrome; acute synovitis; muscle degeneration, bursitis; tendonitis; tenosynovitis; herniated, ruptures, or prolapsed intervertebral disk syndrome; osteopetrosis; thrombosis; restenosis; silicosis; pulmonary sarcoidosis; bone resorption diseases, such as osteoporosis; graft-versus-host reaction; Multiple Sclerosis; lupus; fibromyalgia; AIDS and other viral diseases such as Herpes Zoster, Herpes Simplex I or II, influenza virus and cytomegalovirus; and diabetes mellitus. [0140] Exemplary cancers include, but are not limited to, adrenocortical carcinoma, AIDS-related cancers, AIDS-related lymphoma, anal cancer, anorectal cancer, cancer of the anal canal, appendix cancer, childhood cerebellar astrocytoma, childhood cerebral astrocytoma, basal cell carcinoma, skin cancer (non-melanoma), biliary cancer, extrahepatic bile duct cancer, intrahepatic bile duct cancer, bladder cancer, urinary bladder cancer, bone and joint cancer, osteosarcoma and malignant fibrous histiocytoma, brain cancer, brain tumor, brain stem glioma, cerebellar astrocytoma, cerebral astrocytoma/malignant glioma, ependymoma, medulloblastoma, supratentorial primitive neuroectodermal tumors, visual pathway and hypothalamic glioma, breast cancer, bronchial adenomas/carcinoids, carcinoid tumor, gastrointestinal, nervous system cancer, nervous system lymphoma, central nervous system cancer, central nervous system lymphoma, cervical cancer, childhood cancers, chronic lymphocytic leukemia, chronic myelogenous leukemia, chronic myeloproliferative disorders, colon cancer, colorectal cancer, cutaneous T-cell lymphoma, lymphoid neoplasm, mycosis fungoides, Sezary Syndrome, endometrial cancer, esophageal cancer, extracranial germ cell tumor, extragonadal germ cell tumor, extrahepatic bile duct cancer, eye cancer, intraocular melanoma, retinoblastoma, gallbladder cancer, gastric (stomach) cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST), germ cell tumor, ovarian germ cell tumor, gestational trophoblastic tumor glioma, head and neck cancer, hepatocellular (liver) cancer, Hodgkin lymphoma, hypopharyngeal cancer, intraocular melanoma, ocular cancer, islet cell tumors (endocrine pancreas), Kaposi Sarcoma, kidney cancer, renal cancer, kidney cancer, laryngeal cancer, acute lymphoblastic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, hairy cell leukemia, lip and oral cavity cancer, liver cancer, lung cancer, non-small cell lung cancer, small cell lung cancer, AIDS-related lymphoma, non-Hodgkin lymphoma, primary central nervous system lymphoma, Waldenstrom macroglobulinemia, medulloblastoma, melanoma, intraocular (eye) melanoma, merkel cell carcinoma, mesothelioma malignant, mesothelioma, metastatic squamous neck cancer, mouth cancer, cancer of the tongue, multiple endocrine neoplasia syndrome, mycosis fungoides, myelodysplastic syndromes, myelodysplastic/myeloproliferative diseases, chronic myelogenous leukemia, acute myeloid leukemia, multiple myeloma, chronic myeloproliferative disorders, nasopharyngeal cancer, neuroblastoma, oral cancer, oral cavity cancer, oropharyngeal cancer, ovarian cancer, ovarian epithelial cancer, ovarian low malignant potential tumor, pancreatic cancer, islet cell pancreatic cancer, paranasal sinus and nasal cavity cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pheochromocytoma, pineoblastoma and supratentorial primitive neuroectodermal tumors, pituitary tumor, plasma cell neoplasm/multiple myeloma, pleuropulmonary blastoma, prostate cancer, rectal cancer, renal pelvis and ureter, transitional cell cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, Ewing family of sarcoma tumors, Kaposi Sarcoma, soft tissue sarcoma, uterine cancer, uterine sarcoma, skin cancer (non-melanoma), skin cancer (melanoma), merkel cell skin carcinoma, small intestine cancer, soft tissue sarcoma, squamous cell carcinoma, stomach (gastric) cancer, supratentorial primitive neuroectodermal tumors, testicular cancer, throat cancer, thymoma, thymoma and thymic carcinoma, thyroid cancer, transitional cell cancer of the renal pelvis and ureter and other urinary organs, gestational trophoblastic tumor, urethral cancer, endometrial uterine cancer, uterine sarcoma, uterine corpus cancer, vaginal cancer, vulvar cancer, and Wilms’ Tumor. [0141] A “proliferative disorder of the hematologic system” is a proliferative disorder involving cells of the hematologic system. A proliferative disorder of the hematologic system can include lymphoma, leukemia, myeloid neoplasms, mast cell neoplasms, myelodysplasia, benign monoclonal gammopathy, lymphomatoid granulomatosis, lymphomatoid papulosis, polycythemia vera, chronic myelocytic leukemia, agnogenic myeloid metaplasia, and essential thrombocythemia. A proliferative disorder of the hematologic system can include hyperplasia, dysplasia, and metaplasia of cells of the hematologic system. In some embodiments, the compositions of the present application may be used to treat a cancer selected from the group consisting of a hematologic cancer of the present application or a hematologic proliferative disorder of the present application. A hematologic cancer of the present application can include multiple myeloma, lymphoma (including Hodgkin's lymphoma, non-Hodgkin's lymphoma, childhood lymphomas, and lymphomas of lymphocytic and cutaneous origin), leukemia (including childhood leukemia, hairy-cell leukemia, acute lymphocytic leukemia, acute myelocytic leukemia, chronic lymphocytic leukemia, chronic myelocytic leukemia, chronic myelogenous leukemia, and mast cell leukemia), myeloid neoplasms and mast cell neoplasms. [0142] A “proliferative disorder of the lung” is a proliferative disorder involving cells of the lung. Proliferative disorders of the lung can include all forms of proliferative disorders affecting lung cells. Proliferative disorders of the lung can include lung cancer, a precancer or precancerous condition of the lung, benign growths or lesions of the lung, and malignant growths or lesions of the lung, and metastatic lesions in tissue and organs in the body other than the lung. In some embodiments, the compositions of the present application may be used to treat lung cancer or proliferative disorders of the lung. Lung cancer can include all forms of cancer of the lung. Lung cancer can include malignant lung neoplasms, carcinoma in situ, typical carcinoid tumors, and atypical carcinoid tumors. Lung cancer can include small cell lung cancer (“SCLC”), non-small cell lung cancer (“NSCLC”), squamous cell carcinoma, adenocarcinoma, small cell carcinoma, large cell carcinoma, adenosquamous cell carcinoma, and mesothelioma. Lung cancer can include “scar carcinoma”, bronchioalveolar carcinoma, giant cell carcinoma, spindle cell carcinoma, and large cell neuroendocrine carcinoma. Lung cancer can include lung neoplasms having histologic and ultrastructual heterogeneity (e.g., mixed cell types). [0143] Proliferative disorders of the lung can include all forms of proliferative disorders affecting lung cells. Proliferative disorders of the lung can include lung cancer, precancerous conditions of the lung. Proliferative disorders of the lung can include hyperplasia, metaplasia, and dysplasia of the lung. Proliferative disorders of the lung can include asbestos-induced hyperplasia, squamous metaplasia, and benign reactive mesothelial metaplasia. Proliferative disorders of the lung can include replacement of columnar epithelium with stratified squamous epithelium, and mucosal dysplasia. Individuals exposed to inhaled injurious environmental agents such as cigarette smoke and asbestos may be at increased risk for developing proliferative disorders of the lung. Prior lung diseases that may predispose individuals to development of proliferative disorders of the lung can include chronic interstitial lung disease, necrotizing pulmonary disease, scleroderma, rheumatoid disease, sarcoidosis, interstitial pneumonitis, tuberculosis, repeated pneumonias, idiopathic pulmonary fibrosis, granulomata, asbestosis, fibrosing alveolitis, and Hodgkin's disease. [0144] A “proliferative disorder of the colon” is a proliferative disorder involving cells of the colon. In one embodiment, the proliferative disorder of the colon is colon cancer. In one embodiment, compositions of the present application may be used to treat colon cancer or proliferative disorders of the colon. Colon cancer can include all forms of cancer of the colon. Colon cancer can include sporadic and hereditary colon cancers. Colon cancer can include malignant colon neoplasms, carcinoma in situ, typical carcinoid tumors, and atypical carcinoid tumors. Colon cancer can include adenocarcinoma, squamous cell carcinoma, and adenosquamous cell carcinoma. Colon cancer can be associated with a hereditary syndrome selected from the group consisting of hereditary nonpolyposis colorectal cancer, familial adenomatous polyposis, Gardner's syndrome, Peutz-Jeghers syndrome, Turcot's syndrome and juvenile polyposis. Colon cancer can be caused by a hereditary syndrome selected from the group consisting of hereditary nonpolyposis colorectal cancer, familial adenomatous polyposis, Gardner's syndrome, Peutz- Jeghers syndrome, Turcot's syndrome and juvenile polyposis. [0145] Proliferative disorders of the colon can include all forms of proliferative disorders affecting colon cells. Proliferative disorders of the colon can include colon cancer, precancerous conditions of the colon, adenomatous polyps of the colon and metachronous lesions of the colon. A proliferative disorder of the colon can include adenoma. Proliferative disorders of the colon can be characterized by hyperplasia, metaplasia, and dysplasia of the colon. Prior colon diseases that may predispose individuals to development of proliferative disorders of the colon can include prior colon cancer. Current disease that may predispose individuals to development of proliferative disorders of the colon can include Crohn's disease and ulcerative colitis. A proliferative disorder of the colon can be associated with a mutation in a gene selected from the group consisting of p53, ras, FAP and DCC. An individual can have an elevated risk of developing a proliferative disorder of the colon due to the presence of a mutation in a gene selected from the group consisting of p53, ras, FAP and DCC. [0146] A “proliferative disorder of the pancreas” is a proliferative disorder involving cells of the pancreas. Proliferative disorders of the pancreas can include all forms of proliferative disorders affecting pancreatic cells. Proliferative disorders of the pancreas can include pancreas cancer, a precancer or precancerous condition of the pancreas, hyperplasia of the pancreas, and dysplasia of the pancreas, benign growths or lesions of the pancreas, and malignant growths or lesions of the pancreas, and metastatic lesions in tissue and organs in the body other than the pancreas. Pancreatic cancer includes all forms of cancer of the pancreas. Pancreatic cancer can include ductal adenocarcinoma, adenosquamous carcinoma, pleomorphic giant cell carcinoma, mucinous adenocarcinoma, osteoclast-like giant cell carcinoma, mucinous cystadenocarcinoma, acinar carcinoma, unclassified large cell carcinoma, small cell carcinoma, pancreatoblastoma, papillary neoplasm, mucinous cystadenoma, papillary cystic neoplasm, and serous cystadenoma. Pancreatic cancer can also include pancreatic neoplasms having histologic and ultrastructual heterogeneity (e.g., mixed cell types). [0147] A “proliferative disorder of the prostate” is a proliferative disorder involving cells of the prostate. Proliferative disorders of the prostate can include all forms of proliferative disorders affecting prostate cells. Proliferative disorders of the prostate can include prostate cancer, a precancer or precancerous condition of the prostate, benign growths or lesions of the prostate, and malignant growths or lesions of the prostate, and metastatic lesions in tissue and organs in the body other than the prostate. Proliferative disorders of the prostate can include hyperplasia, metaplasia, and dysplasia of the prostate. [0148] A “proliferative disorder of the skin” is a proliferative disorder involving cells of the skin. Proliferative disorders of the skin can include all forms of proliferative disorders affecting skin cells. Proliferative disorders of the skin can include a precancer or precancerous condition of the skin, benign growths or lesions of the skin, melanoma, malignant melanoma and other malignant growths or lesions of the skin, and metastatic lesions in tissue and organs in the body other than the skin. Proliferative disorders of the skin can include hyperplasia, metaplasia, and dysplasia of the skin. [0149] A “proliferative disorder of the ovary” is a proliferative disorder involving cells of the ovary. Proliferative disorders of the ovary can include all forms of proliferative disorders affecting cells of the ovary. Proliferative disorders of the ovary can include a precancer or precancerous condition of the ovary, benign growths or lesions of the ovary, ovarian cancer, malignant growths or lesions of the ovary, and metastatic lesions in tissue and organs in the body other than the ovary. Proliferative disorders of the skin can include hyperplasia, metaplasia, and dysplasia of cells of the ovary. [0150] A “proliferative disorder of the breast” is a proliferative disorder involving cells of the breast. Proliferative disorders of the breast can include all forms of proliferative disorders affecting breast cells. Proliferative disorders of the breast can include breast cancer, a precancer or precancerous condition of the breast, benign growths or lesions of the breast, and malignant growths or lesions of the breast, and metastatic lesions in tissue and organs in the body other than the breast. Proliferative disorders of the breast can include hyperplasia, metaplasia, and dysplasia of the breast. [0151] A cancer that is to be treated can be staged according to the American Joint Committee on Cancer (AJCC) TNM classification system, where the tumor (T) has been assigned a stage of TX, T1, T1mic, T1a, T1b, T1c, T2, T3, T4, T4a, T4b, T4c, or T4d; and where the regional lymph nodes (N) have been assigned a stage of NX, N0, N1, N2, N2a, N2b, N3, N3a, N3b, or N3c; and where distant metastasis (M) can be assigned a stage of MX, M0, or M1. A cancer that is to be treated can be staged according to an American Joint Committee on Cancer (AJCC) classification as Stage I, Stage IIA, Stage IIB, Stage IIIA, Stage IIIB, Stage IIIC, or Stage IV. A cancer that is to be treated can be assigned a grade according to an AJCC classification as Grade GX (e.g., grade cannot be assessed), Grade 1, Grade 2, Grade 3 or Grade 4. A cancer that is to be treated can be staged according to an AJCC pathologic classification (pN) of pNX, pN0, PN0 (I-), PN0 (I+), PN0 (mol-), PN0 (mol+), PN1, PN1(mi), PN1a, PN1b, PN1c, pN2, pN2a, pN2b, pN3, pN3a, pN3b, or pN3c. [0152] A cancer that is to be treated can include a tumor that has been determined to be less than or equal to about 2 centimeters in diameter. A cancer that is to be treated can include a tumor that has been determined to be from about 2 to about 5 centimeters in diameter. A cancer that is to be treated can include a tumor that has been determined to be greater than or equal to about 3 centimeters in diameter. A cancer that is to be treated can include a tumor that has been determined to be greater than 5 centimeters in diameter. A cancer that is to be treated can be classified by microscopic appearance as well differentiated, moderately differentiated, poorly differentiated, or undifferentiated. A cancer that is to be treated can be classified by microscopic appearance with respect to mitosis count (e.g., amount of cell division) or nuclear pleiomorphism (e.g., change in cells). A cancer that is to be treated can be classified by microscopic appearance as being associated with areas of necrosis (e.g., areas of dying or degenerating cells). A cancer that is to be treated can be classified as having an abnormal karyotype, having an abnormal number of chromosomes, or having one or more chromosomes that are abnormal in appearance. A cancer that is to be treated can be classified as being aneuploid, triploid, tetraploid, or as having an altered ploidy. A cancer that is to be treated can be classified as having a chromosomal translocation, or a deletion or duplication of an entire chromosome, or a region of deletion, duplication or amplification of a portion of a chromosome. [0153] A cancer that is to be treated can be evaluated by DNA cytometry, flow cytometry, or image cytometry. A cancer that is to be treated can be typed as having 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% of cells in the synthesis stage of cell division (e.g., in S phase of cell division). A cancer that is to be treated can be typed as having a low S-phase fraction or a high S-phase fraction. [0154] As used herein, a “normal cell” is a cell that cannot be classified as part of a “proliferative disorder”. A normal cell lacks unregulated or abnormal growth, or both, that can lead to the development of an unwanted condition or disease. In one embodiment, a normal cell possesses normally functioning cell cycle checkpoint control mechanisms. [0155] One skilled in the art may refer to general reference texts for detailed descriptions of known techniques discussed herein or equivalent techniques. These texts include Ausubel et al., Current Protocols in Molecular Biology, John Wiley and Sons, Inc. (2005); Sambrook et al., Molecular Cloning, A Laboratory Manual (3rd edition), Cold Spring Harbor Press, Cold Spring Harbor, N.Y. (2000); Coligan et al., Current Protocols in Immunology, John Wiley & Sons, N.Y.; Erma et al., Current Protocols in Pharmacology, John Wiley & Sons, N.Y.; Fingl et al., The Pharmacological Basis of Therapeutics (1975), Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa., 18th edition (1990). These texts can, of course, also be referred to in making or using an aspect of the application. [0156] In certain embodiments, compounds of the application are useful in the treatment of proliferative disorders (e.g., cancer, benign neoplasms, inflammatory disease, and autoimmune diseases). In certain embodiments, according to the methods of treatment of the present application, levels of cell proteins of interest, e.g., pathogenic and oncogenic proteins are modulated, or their growth is inhibited by contacting said cells with a compound or composition, as described herein. In other embodiments, the compounds are useful in treating cancer. [0157] In certain embodiments, the method involves the administration of a therapeutically effective amount of the compound or a pharmaceutically acceptable derivative thereof to a subject (including, but not limited to a human or animal) in need of it. In certain embodiments, the compounds are useful for the treatment of cancer (including, but not limited to, glioblastoma, retinoblastoma, breast cancer, cervical cancer, colon and rectal cancer, leukemia, lymphoma, lung cancer (including, but not limited to small cell lung cancer), melanoma and/or skin cancer, multiple myeloma, non-Hodgkin's lymphoma, ovarian cancer, pancreatic cancer, prostate cancer and gastric cancer, bladder cancer, uterine cancer, kidney cancer, testicular cancer, stomach cancer, brain cancer, liver cancer, or esophageal cancer). [0158] In certain embodiments, the anticancer agents are useful in the treatment of cancers and other proliferative disorders, including, but not limited to breast cancer, cervical cancer, colon and rectal cancer, leukemia, lung cancer, melanoma, multiple myeloma, non-Hodgkin's lymphoma, ovarian cancer, pancreatic cancer, prostate cancer, and gastric cancer. In certain embodiments, the anticancer agents are active against solid tumors. [0159] Additionally, the present application provides pharmaceutically acceptable derivatives of the compounds, and methods of treating a subject using these compounds, pharmaceutical compositions thereof, or either of these in combination with one or more additional therapeutic agents. [0160] For example, other therapies or anticancer agents that may be used in combination with the compounds disclosed herein including surgery, radiotherapy, endocrine therapy, biologic response modifiers (interferons, interleukins, and tumor necrosis factor (TNF), to name a few), hyperthermia and cryotherapy, agents to attenuate any adverse effects (e.g., antiemetics), and other approved chemotherapeutic drugs, including, but not limited to, alkylating drugs (mechlorethamine, chlorambucil, Cyclophosphamide, Melphalan, Ifosfamide), antimetabolites (Methotrexate), purine antagonists and pyrimidine antagonists (6-Mercaptopurine, 5-Fluorouracil, Cytarabile, Gemcitabine), spindle poisons (Vinblastine, Vincristine, Vinorelbine, Paclitaxel), podophyllotoxins (Etoposide, Irinotecan, Topotecan), antibiotics (Doxorubicin, Bleomycin, Mitomycin), nitrosoureas (Carmustine, Lomustine), inorganic ions (Cisplatin, Carboplatin), enzymes (Asparaginase), and hormones (Tamoxifen, Leuprolide, Flutamide, and Megestrol), to name a few. For a more comprehensive discussion of overview of cancer therapy see The Merck Manual, Twentieth Ed.2020, the entire contents of which are hereby incorporated by reference. See also the National Cancer Institute (NCI) website (www.nci.nih.gov) and the Food and Drug Administration (FDA) website for a list of the FDA approved oncology drugs (www.fda.gov/cder/cancer/druglistframe). [0161] In certain embodiments, the pharmaceutical compositions comprising the compounds disclosed herein further comprise one or more additional therapeutically active ingredients (e.g., chemotherapeutic and/or palliative). For purposes of the application, the term “palliative” refers to treatment that is focused on the relief of symptoms of a disease and/or side effects of a therapeutic regimen, but is not curative. For example, palliative treatment encompasses painkillers, antinausea medications and anti-sickness drugs. In addition, chemotherapy, radiotherapy and surgery can all be used palliatively (that is, to reduce symptoms without going for cure; e.g., for shrinking tumors and reducing pressure, bleeding, pain and other symptoms of cancer). Administration, Pharmaceutical Compositions [0162] Administration of the disclosed compounds and pharmaceutical compositions can be accomplished via any mode of administration for therapeutic agents. These modes include systemic or local administration such as oral, nasal, parenteral, transdermal, subcutaneous, vaginal, buccal, rectal or topical administration modes. [0163] Depending on the intended mode of administration, the disclosed compositions can be in solid, semi-solid or liquid dosage form, such as, for example, injectables, tablets, suppositories, pills, time- release capsules, elixirs, tinctures, emulsions, syrups, powders, liquids, suspensions, or the like, sometimes in unit dosages and consistent with conventional pharmaceutical practices. Likewise, they can also be administered in intravenous (both bolus and infusion), intraperitoneal, subcutaneous or intramuscular form, and all using forms well known to those skilled in the pharmaceutical arts. [0164] Illustrative pharmaceutical compositions are tablets and gelatin capsules comprising a compound of the disclosure and a pharmaceutically acceptable carrier, such as a) a diluent, e.g., purified water, triglyceride oils, such as hydrogenated or partially hydrogenated vegetable oil, or mixtures thereof, com oil, olive oil, sunflower oil, safflower oil, fish oils, such as EPA or DHA, or their esters or triglycerides or mixtures thereof, omega-3 fatty acids or derivatives thereof, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, sodium, saccharin, glucose and/or glycine; b) a lubricant, e.g., silica, talcum, stearic acid, its magnesium or calcium salt, sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and/or polyethylene glycol; for tablets also; c) a binder, e.g., magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, magnesium carbonate, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, waxes, and/or polyvinylpyrrolidone, if desired; d) a disintegrant, e.g., starches, agar, methyl cellulose, bentonite, xanthan gum, algic acid or its sodium salt, or effervescent mixtures; e) absorbent, colorant, flavorant and sweetener; f) an emulsifier or dispersing agent, such as Tween 80, Labrasol, HPMC, DOSS, caproyl 909, labrafac, labrafil, peceol, transcutol, capmul MCM, capmul PG-12, captex 355, gelucire, vitamin E TGPS or other acceptable emulsifier; and/or g) an agent that enhances absorption of the compound such as cyclodextrin, hydroxypropyl-cyclodextrin, PEG400, PEG200. [0165] Liquid, particularly injectable, compositions can, for example, be prepared by dissolution, dispersion, etc. For example, the disclosed compound is dissolved in or mixed with a pharmaceutically acceptable solvent such as, for example, water, saline, aqueous dextrose, glycerol, ethanol, and the like, to thereby form an injectable isotonic solution or suspension. Proteins such as albumin, chylomicron particles, or serum proteins can be used to solubilize the disclosed compounds. [0166] The disclosed compounds can be also formulated as a suppository that can be prepared from fatty emulsions or suspensions; using polyalkylene glycols such as propylene glycol, as the carrier. [0167] The disclosed compounds can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, containing cholesterol, stearylamine or phosphatidylcholines. [0168] In some embodiments, a film of lipid components is hydrated with an aqueous solution of drug to a form lipid layer encapsulating the drug, as described in U.S. Pat. No.5,262,564, which is hereby incorporated by reference in its entirety. [0169] Disclosed compounds can also be delivered by the use of monoclonal antibodies as individual carriers to which the disclosed compounds are coupled. The disclosed compounds can also be coupled with soluble polymers as targetable drug carriers. Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethylaspanamidephenol, or polyethyleneoxidepolylysine substituted with palmitoyl residues. Furthermore, the disclosed compounds can be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, and cross-linked or amphipathic block copolymers of hydrogels. In one embodiment, disclosed compounds are not covalently bound to a polymer, e.g., a polycarboxylic acid polymer, or a polyacrylate. [0170] Parental injectable administration is generally used for subcutaneous, intramuscular or intravenous injections and infusions. Injectables can be prepared in conventional forms, either as liquid solutions or suspensions or solid forms suitable for dissolving in liquid prior to injection. [0171] Another aspect of the disclosure is directed to pharmaceutical compositions comprising a compound of Formula I, I-1, IA, or IA-1 and a pharmaceutically acceptable carrier. Another aspect of the disclosure is directed to pharmaceutical compositions comprising a compound of Formula I, I-1, IA, or IA-1, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof and a pharmaceutically acceptable carrier. The pharmaceutically acceptable carrier may further include an excipient, diluent, or surfactant. [0172] Compositions can be prepared according to conventional mixing, granulating or coating methods, respectively, and the present pharmaceutical compositions can contain from about 0.1% to about 99%, from about 5% to about 90%, or from about 1% to about 20% of the disclosed compound by weight or volume. [0173] In one embodiment, the disclosure provides a kit comprising two or more separate pharmaceutical compositions, at least one of which contains a compound of the present disclosure. In one embodiment, the kit comprises means for separately retaining said compositions, such as a container, divided bottle, or divided foil packet. An example of such a kit is a blister pack, as typically used for the packaging of tablets, capsules and the like. [0174] The kit of the disclosure may be used for administering different dosage forms, for example, oral and parenteral, for administering the separate compositions at different dosage intervals, or for titrating the separate compositions against one another. To assist compliance, the kit of the disclosure typically comprises directions for administration. [0175] Pharmaceutical dosage forms of a compound of this disclosure may be manufactured by any of the methods well-known in the art, such as, for example, by conventional mixing, sieving, dissolving, melting, granulating, dragee-making, tableting, suspending, extruding, spray-drying, levigating, emulsifying, (nano-/micro-) encapsulating, entrapping, or lyophilization processes. As noted above, the compositions of this disclosure can include one or more physiologically acceptable inactive ingredients that facilitate processing of active molecules into preparations for pharmaceutical use. [0176] As noted above, the compositions are comprised of, in general, a compound of this disclosure in combination with at least one pharmaceutically acceptable excipient. Acceptable excipients are non- toxic, aid administration, and do not adversely affect the therapeutic benefit of the claimed compounds. Such excipient may be any solid, liquid, semi-solid or, in the case of an aerosol composition, gaseous excipient that is generally available to one of skill in the art. [0177] Solid pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, dried skim milk and the like. Liquid and semi-solid excipients may be selected from glycerol, propylene glycol, water, ethanol and various oils, including those of petroleum, animal, vegetable or synthetic origin, e.g., peanut oil, soybean oil, mineral oil, sesame oil, etc. In some embodiments, liquid carriers, particularly for injectable solutions, include water, saline, aqueous dextrose, and glycols. [0178] Compressed gases may be used to disperse a compound of this disclosure in an aerosol form. Inert gases suitable for this purpose are nitrogen, carbon dioxide, etc. Other suitable pharmaceutical excipients and their formulations are described in Remington’s Pharmaceutical Sciences, edited by E. W. Martin (Mack Publishing Company, 18th ed., 1990). [0179] The compositions of this disclosure may, if desired, be presented in a pack or dispenser device containing one or more unit dosage forms containing the active ingredient. Such a pack or device may, for example, comprise metal or plastic foil, such as a blister pack, or glass, and rubber stoppers such as in vials. The pack or dispenser device may be accompanied by instructions for administration. Compositions comprising a compound of this disclosure that can be formulated in a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition. [0180] The amount of the compound in a formulation can vary within the full range employed by those skilled in the art. Typically, the formulation will contain, on a weight percent (wt %) basis, from about 0.01-99.99 wt % of a compound of this disclosure based on the total formulation, with the balance being one or more suitable pharmaceutical excipients. In one embodiment, the compound is present at a level of about 1-80 wt %. Representative pharmaceutical formulations are described below. Formulation Examples [0181] The following are representative pharmaceutical formulations containing a compound of this disclosure. Formulation Example 1 -- Tablet formulation [0182] The following ingredients are mixed intimately and pressed into single scored tablets. Quantity per Formulation Example 2 -- Capsule formulation [0183] The following ingredients are mixed intimately and loaded into a hard-shell gelatin capsule Quantity per Formulation Example 3 -- Suspension formulation [0184] The following ingredients are mixed to form a suspension for oral administration. Formulation Example 4 -- Injectable formulation [0185] The following ingredients are mixed to form an injectable formulation. di Formulation Example 5 -- Suppository Formulation [0186] A suppository of total weight 2.5 g is prepared by mixing the compound of this disclosure with Witepsol® H-15 (triglycerides of saturated vegetable fatty acid; Riches-Nelson, Inc., New York), and has the following composition: Ingredient Amount Dosing [0187] The dosage regimen utilizing the disclosed compound is selected in accordance with a variety of factors including type, species, age, weight, sex, and medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal or hepatic function of the patient; and the particular disclosed compound employed. A physician or veterinarian of ordinary skill in the art can readily determine and prescribe the effective amount of the drug required to prevent, counter or arrest the progress of the condition. [0188] Effective dosage amounts of the disclosed compounds, when used for the indicated effects, range from about 0.5 mg to about 5000 mg of the disclosed compound as needed to treat the condition. Compositions for in vivo or in vitro use can contain about 0.5, 5, 20, 50, 75, 100, 150, 250, 500, 750, 1000, 1250, 2500, 3500, or 5000 mg of the disclosed compound, or, in a range of from one amount to another amount in the list of doses. In one embodiment, the compositions are in the form of a tablet that can be scored. EXAMPLES [0189] The following synthetic and biological examples are offered to illustrate this disclosure and are not to be construed in any way as limiting the scope of this disclosure. Unless otherwise stated, all temperatures are in degrees Celsius. [0190] This disclosure is further understood by reference to the following examples, which are intended to be purely exemplary of this disclosure. This disclosure is not limited in scope by the exemplified embodiments, which are intended as illustrations of single aspects of this disclosure only. Any methods that are functionally equivalent are within the scope of this disclosure. Various modifications of this disclosure in addition to those described herein will become apparent to those skilled in the art from the foregoing description and accompanying figures. Such modifications fall within the scope of the appended claims. [0191] In the specification and in the examples below, all temperatures are in degrees Celsius. In addition, the following abbreviations have the following meanings. If not defined, these abbreviations have their art recognized meaning. Abbreviation Meaning δ chemical shift (ppm) ACN or MeCN acetonitrile Boc tert -butoxycarbonyl BPD bis(pinacolato)diboron BRET bioluminescence resonance energy transfer Cbz benzyloxycarbonyl DAPI 4’,6-diamidino-2-phenylindole DC50 concentration that resulted in a 50% targeted protein degradation DCC N,N-dicyclohexylcarbodiimide DCM dichloromethane DMA dimethylacetamide DMF N,N-dimethylformamide DMP 2,6-dimethylpyridine DMSO dimethylsulfoxide CDCl3 deuterated chloroform d6-DMSO deuterated dimethylsulfoxide d4-MeOD deuterated methanol eq. equivalent(s) ESI electrospray ionization EtOAc ethyl acetate EtOH ethanol g grams 1 H NMR proton nuclear magnetic resonance spectroscopy h hour(s) HPLC high performance liquid chromatography L liter LC liquid chromatography LC-MS liquid chromatography – mass spectrometry M molar MeOH methanol mg milligram mL milliliter mmol millimole μL microliter umol or μmol micromole μM micromolar m/z mass-to-charge ratio min minute(s) N normal nm nanometer PBS phosphate-buffered saline Pd(Cy*Phine)2Cl2 bis[dicyclohexyl(2;,4;,6;-triisopropyl [1,1':3',1"-terphenyl]-2- yl)phosphane]palladium(II) dichloride Pd(dppf)Cl2 [1,1’-bis(diphenylphosphino)ferrocene]dichloropalladium(II ) pM picomolar Pyr pyridine q.s. amount which is sufficient rt room temperature Select-Fluor 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) t-Bu tert-butyl THF tetrahydrofuran TMSOTf trimethylsilyl trifluoromethanesulfonate UV ultraviolet v/v volume/volume ratio XPhos-Pd-G 2 chloro(2-dicyclohexylphosphino-2’,4’,6’-triisopropyl-1 ,1’- biphenyl)[2-(2’-amino-1,1’-biphenyl)]palladium(II) NMR abbreviations br = broad d = doublet dd = doublet of doublets ddt = doublet of doublet of triplets dtd = doublet of triplet of doublets m = multiplet qd = quartet of doublets quin = quintet s = singlet t = triplet LC-MS Methods (General Method) [0192] Experiments were performed using a Phenomenex Gemini-NX C1875×30mm×3µm LC Column, at a flow rate of 25 mL/min, and a mass spectrometer using ESI as ionization source. The solvent A was 0.075% v/v NH4HCO3 in water, and solvent B was acetonitrile. The gradient consisted of 10-100% solvent B over 20 minutes, LC column temperature was 40 °C. UV absorbance was collected at 220 nm and 254 nm. Starting Materials Compound A: 1-[(2S)-2-methyl-1,2,3,4-tetrahydroquinoxalin-1-yl]ethan-1-o ne [0193] Compound A, CAS # 1563614-79- 8 s co e ca y available from ASW MedChem, New Brunswick, New Jersey, USA. Example 1 Preparation of (R)-1-(4-((4-(3-aminoprop-1-yn-1-yl)phenyl)amino)-3,4-dihydr oquinolin-1(2H)- yl)ethan-1-one (Compound P-2): S [0194] To a solution of 2,3-dihydro-1H-quinolin-4-one (2.0 g, 13.6 mmol, 1.0 eq) in DCM (20 mL) was added pyridine (2.1 g, 27.2 mmol, 2.2 mL, 2.0 eq) at 25 °C. Acetyl chloride (1.2 g, 14.9 mmol, 1.1 mL, 1.1 eq) was added dropwise at 0 °C. The resulting mixture was stirred at 25 °C for 20 hr. The solvents were evaporated in vacuo, and the residue diluted with water (20 mL), then extracted with ethyl acetate (40 mL). The organic phase was separated, washed with brine (20 mL), dried over Na 2 SO 4 , filtered and the solvents were evaporated in vacuo to give 1-acetyl-2,3-dihydroquinolin-4(1H)-one, which was used in the next step without further purification. m/z (ESI + ) 231.1 (M+42) + . 1 H NMR (400 MHz, d 4 -DMSO) δ 7.86 (dd, J = 1.4, 8.0 Hz, 1 H), 7.70 (d, J = 8.0 Hz, 1H), 7.60 (dt, J = 1.6, 7.2 Hz, 1H), 7.29 (t, J = 8.0 Hz, 1H), 4.12 (t, J = 6.0 Hz, 2H), 2.78 (t, J = 6.4 Hz, 2H), 2.29 (s, 3H). Step 2: [0195] To a solution o -acety - , - y roqu no n- -one . g, . mmo , .0 eq) and (R)-2- methylpropane-2-sulfinamide (2.2 g, 18.3 mmol, 3.0 eq) in THF (15 mL), was added titanium(IV)tetraisopropoxide (10.4 g, 36.7 mmol, 10.8 mL, 6.0 eq) dropwise at 0 °C. The reaction was degassed, purged with N 2 , and stirred at 80 °C for 20 hrs. The mixture was cooled to -78 °C and NaBH 4 (1.4 g, 36.7 mmol, 6.0 eq) was added and stirred at -78 °C for 2 hrs. The reaction mixture was quenched by slow addition 0.5 N hydrochloric acid (20 mL) and diluted with H 2 O (50 mL), then extracted with ethyl acetate (50 mL). The combined organic layers were washed with brine (10 mL), dried over Na 2 SO 4 , filtered and the solvents were evaporated in vacuo. The residue was purified by column chromatography (SiO 2 , 0 to 50% ethyl acetate in petroleum ether) to give (R)-N-((R)-1-acetyl-1,2,3,4-tetrahydroquinolin- 4-yl)-2-methylpropane-2-sulfinamide. m/z (ESI + ) 295.1 (M+42) + . 1 H NMR (400 MHz, d 6 -DMSO) δ 7.58 (d, J = 7.2 Hz, 1H), 7.54 - 7.34 (m, 1H), 7.24 (t, J = 7.2 Hz, 1H), 7.19 - 7.11 (m, 1H), 5.78 (d, J = 7.2 Hz, 1H), 4.41 - 4.32 (m, 1H), 3.85 - 3.63 (m, 2H), 2.20 - 2.13 (m, 3H), 2.01 - 1.83 (m, 2H), 1.19 - 1.11 (m, 9H). Step 3: [0196] To a solution of (R)-N-((R)-1-acetyl-1,2,3,4-tetrahydroquinolin-4-yl)-2-methy lpropane-2- sulfinamide (1.2 g, 4.3 mmol, 1.0 eq) in dioxane (13 mL) was added HCl/dioxane (6.4 mL) dropwise at 0 °C. The mixture was stirred at 25 °C for 3 hr. The reaction mixture was quenched by addition of triethylamine (20 mL) in portions, and then diluted with H2O (50 mL) and extracted with ethyl acetate (50 mL). The combined organic layers were washed with brine (10 mL), dried over by Na2SO4, filtered, and the solvents were evaporated in vacuo. The residue was purified by prep-HPLC to give (R)-1-(4-amino- 3,4-dihydroquinolin-1(2H)-yl)ethan-1-one. m/z (ESI + ) 174.1 (M-16) + . Step 4: [0197] To a solution of (R)-1-(4-amino-3,4-dihydroquinolin-1(2H)-yl)ethan-1-one (50.0 mg, 262.8 µmol, 1.0 eq) and [4-[3-(1,3-dioxoisoindolin-2-yl)prop-1-ynyl]phenyl]boronic acid (96.2 mg, 315.3 µmol, 1.2 eq) in MeCN (4 mL), was added pyridine (62.3 mg, 788.4 µmol, 63.6 µL, 3.0 eq) and Cu(OAc) 2 (95.4 mg, 525.6 µmol, 2.0 eq). The mixture was stirred at 25 °C for 2 hr. Water (10 mL) was added at 0 °C, and then diluted with DCM (10 mL) and extracted with DCM (10 mL). The combined organic layers were washed with brine (10 mL), dried over Na 2 SO 4 , filtered, and the solvents were evaporated in vacuo. The residue was purified by column chromatography (SiO 2 , 0 to 50% ethyl acetate in petroleum ether) to give (R)-2-(3-(4-((1-acetyl-1,2,3,4-tetrahydroquinolin-4-yl)amino )phenyl)prop-2-yn-1-yl)isoindoline-1,3- dione. m/z (ESI + ) 450.2 (M+1) + . Step 5: [0198] To a solution of (R)-2-(3-(4-((1-acetyl-1,2,3,4-tetrahydroquinolin-4-yl)amino )phenyl)prop-2-yn- 1-yl)isoindoline-1,3-dione (50.0 mg, 111.2 µmol, 1.0 eq) in EtOH (0.3 mL) was added hydrazine hydrate (139.2 mg, 2.7 mmol, 135.1 µL, 25.0 eq). The mixture was stirred at 25 °C for 2 hr. The reaction mixture was partitioned between H 2 O (3 mL) and DCM (3 mL). The organic phase was separated, washed with brine (3 mL), dried over Na 2 SO 4 , filtered, and the solvents were evaporated in vacuo. The crude product was purified by prep-HPLC to give (R)-1-(4-((4-(3-aminoprop-1-yn-1-yl)phenyl)amino)- 3,4-dihydroquinolin-1(2H)-yl)ethan-1-one. 1 H NMR (400 MHz, d 4 -MeOD) δ 7.49 - 7.24 (m, 3H), 7.18 (d, J = 8.6 Hz, 3H), 6.62 (d, J = 8.6 Hz, 2H), 4.19 - 4.10 (m, 1H), 3.66 - 3.61 (m, 2H), 2.36 - 2.24 (m, 4H), 1.87 (d, J = 9.0 Hz, 1H), 1.30 (br s, 2H).
Example 2 Preparation of 1-((2S,4R)-4-((4-(3-aminoprop-1-yn-1-yl)phenyl)amino)-6-brom o-2-methyl-3,4- dihydroquinolin-1(2H)-yl)ethan-1-one (Compound P-3): Step 1: [0199] To a mixture of (S)-3-aminobutanoic acid (20 g, 193.95 mmol) in ethanol (100 mL) was added thionyl chloride (39.23 g, 329.71 mmol) dropwise at 0 ℃. The mixture was stirred at 25 °C for 12 hours. The mixture was concentrated under pressure to give ethyl (S)-3-aminobutanoate, which was used directly without purification. m/z (ESI + ) 132.2 (M+H) + . Step 2: [0200] To a mixture of ethyl (S)-3-aminobutanoate (32 g, 243.95 mmol) and 1-bromo-4-iodobenzene (57.51 g, 203.29 mmol) in DMF (500 mL), was added CuI (3.87 g, 20.33 mmol), 2-(2- methylpropanoyl)cyclohexanone (6.84 g, 40.66 mmol), and Cs 2 CO 3 (132.47 g, 406.59 mmol) at 20 ℃. The mixture was stirred at 100 °C for 12 h under N 2 . The mixture was poured into water (2 L) and extracted with ethyl acetate (3x500 mL). The combined organic phases were washed with brine (200 mL), dried over Na 2 SO 4 , filtered and concentrated. The residue was purified by column chromatography (SiO 2 , 20 to 50% ethyl acetate in petroleum ether) to give ethyl (S)-3-((4-bromophenyl)amino)butanoate. 1 H NMR (400 MHz, CDCl 3 ) δ 7.26 (d, J = 9.2 Hz, 2H), 6.49 (d, J = 7.2 Hz, 2H), 4.19 - 4.09 (m, 3H), 2.65 - 2.53 (m, 1H), 2.43 (dd, J = 6.4, 15.2 Hz, 1H), 1.29 - 1.25 (m, 6H). Step 3: [0201] To (S)-3-((4-bromophenyl)amino)butanoate (10 g, 34.94 mmol) was added 7 N NH 3 in MeOH (17.14 g, 349.45 mmol, 60 mL) at 20 °C. One additional vial was set up as above describe, and the two reactions were combined for work up. The mixture was concentrated in vacuo. The residue was purified by column chromatography (SiO2, 25 to 100% ethyl acetate in petroleum ether) to give (S)-3-((4- bromophenyl)amino)butanamide. 1 H NMR (400 MHz, d6-DMSO) δ 7.23 - 7.15 (m, 2H), 6.55 - 6.48 (m, 2H), 5.67 (d, J = 8.8 Hz, 1H), 3.78 - 3.63 (m, 1H), 2.39 - 2.29 (m, 1H), 2.08 - 1.98 (m, 1H), 1.11 (d, J = 6.4 Hz, 3H). Step 4: [0202] To a mixture of (S)-3-((4-bromophenyl)amino)butanamide (12 g, 46.67 mmol) in ethyl acetate (100 mL) was added isopropyl carbonochloridate (7.44 g, 60.67 mmol, 8.42 mL) at -10 °C. Lithium tert- butoxide (8.97 g, 112.01 mmol, 10.10 mL) in tetrahydrofuran (150 mL) was added dropwise at -10 ℃ to the mixture. The reaction was stirred 0 ℃ for 0.5 h. The mixture was partitioned between ethyl acetate (200 mL) and 2N HCl (300 mL). The organic phase was washed with brine (200 mL), dried over Na 2 SO 4, filtered, and the solvents evaporated in vacuo. The residue was purified by column chromatography (SiO 2 , 20 to 50% ethyl acetate in petroleum ether) to give isopropyl (S)-(3-((4- bromophenyl)amino)butanoyl)carbamate. 1 H NMR (400 MHz, CDCl 3 ) δ 7.24 - 7.18 (m, 2H), 6.52 - 6.44 (m, 2H), 4.95 (q, J = 6.4 Hz, 1H), 4.02 - 3.92 (m, 1H), 3.07 (dd, J = 5.6, 16.0 Hz, 1H), 2.88 (dd, J = 6.0, 16.0 Hz, 1H), 1.29 - 1.26 (m, 9H). Step 5: [0203] To a mixture of isopropyl (S)-(3-((4-bromophenyl)amino)butanoyl)carbamate (12 g, 34.96 mmol) in ethanol (120 mL) was added NaBH 4 (992.06 mg, 26.22 mmol) at -20 °C. MgCl 2 (3.66 g, 38.46 mmol) in water (12 mL) was added dropwise at -20 ℃. The mixture was stirred at 0 ℃ for 1 h. The reaction was poured into citric acid (40.30 g, 209.78 mmol) in 1N HCl (150 mL) and extracted with dichloromethane (3x100 mL). The combined organic phases were washed with brine (200 mL), dried over Na 2 SO 4, filtered, and the solvents evaporated in vacuo. The residue was purified by column chromatography (SiO 2 , 20 to 50% ethyl acetate in petroleum ether) to give isopropyl ((2S,4R)-6-bromo-2- methyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate. 1 H NMR (400 MHz, CDCl3) δ 7.47 (s, 1H), 7.31 - 7.27 (m, 1H), 6.95 (d, J = 8.0 Hz, 1H), 5.03 - 4.96 (m, 2H), 3.68 - 3.56 (m, 1H), 2.46 - 2.33 (m, 1H), 1.91 - 1.71 (m, 1H), 1.31 (dd, J = 6.0, 15.2 Hz, 6H), 1.27 - 1.23 (m, 3H). Step 6: [0204] To a solution of isopropyl ((2S,4R)-6-bromo-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl)ca rbamate (8.6 g, 26.28 mmol) and pyridine (8.32 g, 105.13 mmol, 8.49 mL) in dichloromethane (90 mL), was added acetyl chloride (6.19 g, 78.85 mmol, 5.63 mL) dropwise under nitrogen at 20 °C. The mixture was stirred for 1 h. The mixture was poured into saturated NaHCO3 solution (200 mL) and extracted with dichloromethane (3x100 mL). The organic phase was washed with brine (200 mL), dried over MgSO4, filtered, and the solvents evaporated in vacuo. The residue was purified by column chromatography (SiO2, 25 to 50% ethyl acetate in petroleum ether) to give isopropyl ((2S,4R)-1-acetyl-6-bromo-2-methyl- 1,2,3,4-tetrahydroquinolin-4-yl)carbamate. 1 H NMR (400 MHz, d4-methanol) δ 7.48 (dd, J = 2.0, 8.4 Hz, 1H), 7.35 (s, 1H), 7.22 (d, J = 8.8 Hz, 1H), 4.93 (td, J = 6.4, 12.8 Hz, 1H), 4.85 - 4.72 (m, 1H), 4.47 (dd, J = 4.0, 12.4 Hz, 1H), 2.53 (ddd, J = 4.4, 8.8, 12.8 Hz, 1H), 2.13 (s, 3H), 1.36 - 1.21 (m, 7H), 1.12 (d, J = 6.4 Hz, 3H). Step 7: [0205] A solution of aluminum trichloride (10.11 g, 75.83 mmol) in dichloromethane (60 mL) was added dropwise to isopropyl ((2S,4R)-1-acetyl-6-bromo-2-methyl-1,2,3,4-tetrahydroquinoli n-4-yl)carbamate (7 g, 18.96 mmol) in dichloromethane (20 mL) at 0 °C under nitrogen. The mixture was stirred at 0 °C for 0.5 h. Triethylamine (23.02 g, 227.49 mmol, 31.66 mL) in methanol (8 mL) was added at 0 ℃. Ethyl acetate (50 mL) was added and the mixture was stirred at 20 ℃ for 30 minutes, and then filtered. The filter cake was dissolved in dichloromethane (200 mL) and NaHCO 3 (300 mL). Sodium potassium tartrate (85 g) was added and the resulting mixture was stirred at 20 ℃ for 2 h. The organic phase was washed with brine (300 mL), dried over Na2SO4, filtered, and the solvents evaporated in vacuo. The residue was purified by prep-HPLC to give 1-((2S,4R)-4-amino-6-bromo-2-methyl-3,4-dihydroquinolin- 1(2H)-yl)ethan-1-one. 1 H NMR (400 MHz, CDCl3) δ 7.66 (s, 1H), 7.41 (dd, J = 2.0, 8.4 Hz, 1H), 7.04 - 6.93 (m, 1H), 4.90 - 4.73 (m, 1H), 3.73 (dd, J = 4.4, 12.4 Hz, 1H), 2.54 (ddd, J = 4.4, 8.4, 12.8 Hz, 1H), 2.10 (s, 3H), 1.12 (d, J = 6.4 Hz, 3H). Step 8: [0206] To a solution of 1-((2S,4R)-4-amino-6-bromo-2-methyl-3,4-dihydroquinolin-1(2H )-yl)ethan-1- one (1 g, 3.5 mmol, 1.0 eq) in ACN (10 mL), was added (4-(3-((tert-butoxycarbonyl)amino)prop-1-yn-1- yl)phenyl)boronic acid (1.9 g, 7.1 mmol, 2.0 eq), Cu(OAc)2 (641.4 mg, 3.5 mmol, 1.0 eq), and pyridine (558.7 mg, 7.1 mmol, 570.1 µL, 2.0 eq). The mixture was stirred at 25 °C for 10 hrs. The residue was diluted with H2O (20 mL) and extracted with ethyl acetate (3x15 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and the solvents evaporated in vacuo. The residue was purified by column chromatography (SiO2, 20 to 100% ethyl acetate in petroleum ether) to give tert-butyl (3-(4-(((2S,4R)-1-acetyl-6-bromo-2-methyl-1,2,3,4-tetrahydro quinolin-4-yl)amino)phenyl)prop-2-yn-1- yl)carbamate. 1 H NMR (400 MHz, d 6 -DMSO) δ 7.46 (dd, J = 2.4, 8.4 Hz, 1H), 7.34 - 7.25 (m, 2H), 7.19 - 7.13 (m, 3H), 6.65 (d, J = 8.6 Hz, 2H), 6.48 (d, J = 7.8 Hz, 1H), 4.74 - 4.61 (m, 1H), 4.28 -4.26 (m, 1H), 3.93 (d, J = 5.4 Hz, 2H), 2.62 - 2.60 (m, 1H), 2.10 (s, 3H), 1.40 (s, 9H), 1.28 - 1.20 (m, 1H), 1.06 (d, J = 6.4 Hz, 3H). Step 9: [0207] To a solution of tert-butyl (3-(4-(((2S,4R)-1-acetyl-6-bromo-2-methyl-1,2,3,4-tetrahydro quinolin- 4-yl)amino)phenyl)prop-2-yn-1-yl)carbamate (200 mg, 390.3 µmol, 1.0 eq) in DCM (3 mL), was added 2,6-dimethylpyridine (250.9 mg, 2.3 mmol, 272.7 µL, 6.0 eq) at 25 °C. The reaction was cooled to 0 °C, and trimethylsilyl trifluoromethanesulfonate (347.0 mg, 1.6 mmol, 282.10 µL, 4.0 eq) was added. The reaction was allowed to warm to room temperature, and then stirred for 2 hrs. The reaction was diluted with H2O (9 mL) and extracted into ethyl acetate (3x5 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and the solvents evaporated in vacuo. The residue was purified by prep-HPLC to give 1-((2S,4R)-4-((4-(3-aminoprop-1-yn-1-yl)phenyl)amino)-6-brom o-2-methyl-3,4- dihydroquinolin-1(2H)-yl)ethan-1-one. 1 H NMR (400 MHz, DMSO-d6) δ 7.46 (dd, J = 2.0, 8.4 Hz, 1H), 7.32 (d, J = 8.0 Hz, 1H), 7.19 - 7.12 (m, 3H), 6.64 (d, J = 8.8 Hz, 2H), 6.44 (d, J = 7.6 Hz, 1H), 4.67 – 4.65 (m, 1H), 4.31 - 4.23 (m, 1H), 3.45 (s, 2H), 2.62 - 2.56 (m, 1H), 2.10 (s, 3H), 1.97 - 1.68 (m, 2H), 1.29 - 1.12 (m, 1H), 1.10 - 1.01 (m, 3H). Example 3 Preparation of 1-((2S,4R)-4-((4-(3-aminoprop-1-yn-1-yl)phenyl)amino)-2,6-di methyl-3,4- dihydroquinolin-1(2H)-yl)ethan-1-one (Compound P-1): Step 1: [0208] A mixture tert-butyl (3-(4-(((2S,4R)-1-acetyl-6-bromo-2-methyl-1,2,3,4-tetrahydro quinolin-4- yl)amino)phenyl)prop-2-yn-1-yl)carbamate (180 mg, 351.26 µmol, 1 eq), 2,4,6-trimethyl-1,3,5,2,4,6- trioxatriborinane (431.90 mg, 1.72 mmol, 480.96 µL, 50% purity, 4.90 eq), Pd(dppf)Cl 2 (25.70 mg, 35.13 µmol, 0.1 eq), and Cs 2 CO 3 (228.90 mg, 702.52 µmol, 2 eq) in H 2 O (0.5 mL) and THF (2 mL) was degassed and purged with N 2 . The mixture was stirred at 80 °C for 2 hours. The reaction was filtered and the solvents evaporated in vacuo. The residue was purified by column chromatography (silica, 50% ethyl acetate in petroleum ether) to give tert-butyl (3-(4-(((2R,4S)-1-acetyl-2,6-dimethyl-1,2,3,4- tetrahydroquinolin-4-yl)amino)phenyl)prop-2-yn-1-yl)carbamat e. m/z (ESI + ): 447.25 (M+42) + . Step 2: [0209] To a solution of tert-butyl (3-(4-(((2R,4S)-1-acetyl-2,6-dimethyl-1,2,3,4-tetrahydroquin olin-4- yl)amino)phenyl)prop-2-yn-1-yl)carbamate (20 mg, 44.69 µmol, 1 eq) in CH2Cl2 (0.5 mL), was added TMSOTf (59.59 mg, 268.12 µmol, 48.45 µL, 6 eq) and 2,6-dimethylpyridine (19.15 mg, 178.74 µmol, 20.82 µL, 4 eq). The mixture was stirred at 25 °C for 2 hr. The reaction mixture was partitioned between H2O (20 mL) and ethyl acetate (20 mL). The organic phase was separated, washed with ethyl acetate (3x10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by prep-HPLC to give 1-((2S,4R)-4-((4-(3-aminoprop-1-yn-1-yl)phenyl)amino)-2,6-di methyl- 3,4-dihydroquinolin-1(2H)-yl)ethan-1-one. 1 H NMR (400 MHz, d4-methanol) δ 7.20 - 7.10 (m, 4H), 7.05 (s, 1H), 6.59 (d, J = 8.6 Hz, 2H), 4.66 - 4.52 (m, 1H), 4.18 (br dd, J = 4.0, 12.2 Hz, 1H), 3.59 (br s, 2H), 2.65 – 2.58 (m, 1H), 2.28 (s, 3H), 2.15 (s, 3H), 1.15 - 1.09 (m, 4H). Example 4 Preparation of 1-((2S,4R)-4-((4-(3-aminoprop-1-yn-1-yl)phenyl)amino)-6-fluo ro-2-methyl-3,4- dihydroquinolin-1(2H)-yl)ethan-1-one (Compound P-4): Step 1: [0210] A mixture of isopropyl ((2S,4R)-1-acetyl-6-bromo-2-methyl-1,2,3,4-tetrahydroquinoli n-4- yl)carbamate (0.5 g, 1.35 mmol, 1 eq), bis(pinacolato)diboron (0.5 g, 2.03 mmol, 1.5 eq), KOAc (266 mg, 2.71 mmol, 2 eq), and Pd(dppf)Cl2 (100 mg, 135 µmol, 0.1 eq) in dioxane (5 mL) was de-gassed and then heated to 80 °C for 1 h under N2. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (2x10 mL). The combined organic layers were washed with brine (3x10 mL), dried over Na2SO4, filtered, and the solvents evaporated in vacuo. The residue was purified by column chromatography (SiO 2 , 30 to 50% ethyl acetate in petroleum ether) to give the crude product, isopropyl ((2S,4R)-1-acetyl-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-diox aborolan-2-yl)-1,2,3,4-tetrahydroquinolin-4- yl)carbamate, which was used into the next step without further purification. m/z (ESI + ) 417.2 (M+H) + . Step 2: [0211] To a solu ton o a . mg, . mmo , . eq n e m at , was added isopropyl ((2S,4R)-1-acetyl-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-diox aborolan-2-yl)-1,2,3,4- tetrahydroquinolin-4-yl)carbamate (400 mg, 960.81 µmol, 1 eq). After stirring for 15 min at 20 °C, the reaction mixture was cooled to 0 °C and silver trifluoromethanesulfonate (740.60 mg, 2.88 mmol, 3 eq) was added. The reaction was stirred at 0 ºC for 30 min. The solvents were evaporated in vacuo at 0 ºC, and the residual MeOH was removed by co-evaporation with acetone (2x2 mL). The residue was diluted with acetone (8 mL), and Select-Fluor™ (357.39 mg, 1.01 mmol, 1.05 eq) was added. The mixture was stirred for 12 h at 20 °C. The mixture was filtered and the solvents were evaporated in vacuo. The residue was purified by prep-HPLC to give the product, isopropyl ((2S,4R)-1-acetyl-6-fluoro-2-methyl- 1,2,3,4-tetrahydroquinolin-4-yl)carbamate. 1 H NMR (400 MHz, CDCl 3 ) δ 7.14 - 7.05 (m, 1H), 7.03 - 6.95 (m, 2H), 4.99 (td, J = 5.6, 12.4 Hz, 1H), 4.93 - 4.82 (m, 1H), 4.68 - 4.56 (m, 1H), 2.60 (ddd, J = 4.4, 8.4, 12.4 Hz, 1H), 2.11 (s, 3H), 1.30 (br dd, J = 6.0, 12.0 Hz, 6H), 1.21 (br dd, J = 8.8, 12.4 Hz, 1H), 1.13 (d, J = 6.4 Hz, 3H). Step 3: [0212] To a mixture of AlCl3 (173 mg, 1.30 mmol, 63.80 µL, 4 eq) in DCM (1 mL) at 0 °C was added a solution of isopropyl ((2S,4R)-1-acetyl-6-fluoro-2-methyl-1,2,3,4-tetrahydroquinol in-4-yl)carbamate (100 mg, 324.31 µmol, 1 eq) in DCM (1 mL) at 0 °C. The mixture was stirred at 0 °C for 30 minutes. Triethylamine (2 mL) was slowly added to the reaction at 0 °C. The reaction mixture was diluted with water (5 mL) and extracted with DCM (2x10 mL). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the crude product, 1-((2S,4R)-4-amino-6-fluoro-2-methyl-3,4-dihydroquinolin-1(2 H)-yl)ethan-1-one, which was used in the next step without further purification. m/z (ESI + ): 206.0 (benzylic cation) + . Step 4: [0213] A solution of 1-((2S,4R)-4-amino-6-fluoro-2-methyl-3,4-dihydroquinolin-1(2 H)-yl)ethan-1-one (70 mg, 314.95 µmol, 1 eq), [4-[3-(tert-butoxycarbonylamino)prop-1-ynyl]phenyl]boronic acid (173.29 mg, 629.90 µmol, 2 eq), Cu(OAc) 2 (57.20 mg, 314.95 µmol, 1 eq), and pyridine (49.82 mg, 629.90 µmol, 50.84 µL, 2 eq) in ACN (1 mL) was stirred at 20 °C for 12 h. The reaction mixture was filtered and the solvents were evaporated in vacuo. The residue was purified by prep-HPLC to give the product, tert- butyl (3-(4-(((2S,4R)-1-acetyl-6-fluoro-2-methyl-1,2,3,4-tetrahydr oquinolin-4-yl)amino)phenyl)prop-2- yn-1-yl)carbamate. 1 H NMR (400 MHz, CDCl3) δ 7.23 - 7.07 (m, 2H), 7.06 - 6.94 (m, 3H), 6.54 (d, J = 8.4 Hz, 2H), 4.99 - 4.86 (m, 1H), 4.83 - 4.70 (m, 1H), 4.24 - 4.07 (m, 4H), 2.67 (dt, J = 4.4, 8.4 Hz, 1H), 2.18 (s, 3H), 1.47 (s, 9H), 1.32 - 1.29 (m, 1H), 1.15 (br d, J = 6.4 Hz, 3H). Step 5: [0214] To a solution of tert-butyl (3-(4-(((2S,4R)-1-acetyl-6-fluoro-2-methyl-1,2,3,4-tetrahydr oquinolin- 4-yl)amino)phenyl)prop-2-yn-1-yl)carbamate (30 mg, 66.44 µmol, 1 eq) and lutidine (28.48 mg, 265.76 µmol, 30.95 µL, 4 eq) in DCM (1 mL), was added trimethylsilyl trifluoromethanesulfonate (44.30 mg, 199.32 µmol, 36.02 µL, 3 eq) dropwise at 20 °C, and the mixture was stirred for 2 h. The solvents were evaporated in vacuo. The residue was purified by prep-HPLC to give 1-((2S,4R)-4-((4-(3-aminoprop-1- yn-1-yl)phenyl)amino)-6-fluoro-2-methyl-3,4-dihydroquinolin- 1(2H)-yl)ethan-1-one. 1 H NMR (400 MHz, CDCl3) δ 7.26 - 7.06 (m, 3H), 7.04 - 6.93 (m, 2H), 6.54 (d, J = 8.4 Hz, 2H), 5.02 - 4.84 (m, 1H), 4.23 - 4.13 (m, 1H), 3.92 (br d, J = 7.6 Hz, 1H), 3.64 (s, 2H), 2.66 (ddd, J = 4.0, 8.4, 12.4 Hz, 1H), 2.18 (s, 3H), 1.33 - 1.27 (m, 1H), 1.15 (d, J = 6.4 Hz, 3H).
Example 5 Preparation of 1-((2S,4R)-4-((4-(3-aminoprop-1-yn-1-yl)phenyl)amino)-2-meth yl-6-(1-methyl-1H- pyrazol-5-yl)-3,4-dihydroquinolin-1(2H)-yl)ethan-1-one (Compound P-7): S [0215] To a solution of 1-((2S,4R)-4-amino-6-bromo-2-methyl-3,4-dihydroquinolin-1(2H )-yl)ethan-1- one (300.0 mg, 1.1 mmol, 1.0 eq) in DCM (5 mL), was added (4-chlorophenyl)boronic acid (248.5 mg, 1.6 mmol, 1.5 eq), Cu(OAc) 2 (192.4 mg, 1.1 mmol, 1.0 eq), and Et 3 N (321.6 mg, 3.2 mmol, 442.4 µL, 3.0 eq). The reaction was stirred at 25 °C for 10 hrs. Water (15 mL) was added and the product extracted into ethyl acetate (3x5 mL). The combined organic layers were washed with brine, dried over Na 2 SO 4 , filtered, and the solvents were evaporated in vacuo. The residue was purified by column chromatography (SiO 2 , 20 to 50% ethyl acetate in petroleum ether) to give 1-((2S,4R)-6-bromo-4-((4- chlorophenyl)amino)-2-methyl-3,4-dihydroquinolin-1(2H)-yl)et han-1-one. 1 H NMR (400 MHz, d 6 - DMSO) δ ppm 7.50 - 7.39 (m, 2H), 7.29 (d, J = 8.2 Hz, 1H), 7.22 - 7.14 (m, 2H), 7.10 (d, J = 8.6 Hz, 2H), 6.66 (d, J = 8.6 Hz, 2H), 6.36 - 6.22 (m, 1H), 4.78 - 4.43 (m, 3H), 4.27 - 4.15 (m, 2H), 2.07 (br s, 3H), 2.03 - 1.91 (m, 1H), 1.25 - 1.10 (m, 3H), 1.03 (d, J = 6.0 Hz, 3H), 0.93 (t, J = 6.8 Hz, 7H). Step 2: [0216] To a solution of 1-((2S,4R)-6-bromo-4-((4-chlorophenyl)amino)-2-methyl-3,4-di hydroquinolin- 1(2H)-yl)ethan-1-one (50.0 mg, 127.0 µmol, 1.0 eq) in THF (0.8 mL) and H 2 O (0.2 mL), was added 1- methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-py razole (39.6 mg, 190.5 µmol, 1.5 eq), K 3 PO 4 (80.8 mg, 381.0 µmol, 3.0 eq), and XPhos-Pd-G 2 (10.0 mg, 12.7 µmol, 0.1 eq). The mixture was stirred at 90 °C for 12 hrs. Water (3 mL) was added to the reaction mixture, and the product was extracted into ethyl acetate (3x1 mL). The combined organic layers were washed with brine, dried over Na 2 SO 4 , filtered, and the solvents were evaporated in vacuo. The residue was purified by prep-HPLC to give 1-((2S,4R)-4-((4-chlorophenyl)amino)-2-methyl-6-(1-methyl-1H -pyrazol-5-yl)-3,4-dihydroquinolin- 1(2H)-yl)ethan-1-one. 1 H NMR (400 MHz, d 6 -DMSO) δ 7.49 - 7.40 (m, 3H), 7.18 (s, 1H), 7.16 - 7.07 (m, 2H), 6.72 (d, J = 8.8 Hz, 2H), 6.35 - 6.27 (m, 2H), 4.71 (d, J = 6.4 Hz, 1H), 4.31 (m, J = 4.0, 8.0, 11.7 Hz, 1H), 3.69 (s, 3H), 2.62 (m, J = 4.0, 8.4, 12.4 Hz, 1H), 2.15 (s, 3H), 1.31 - 1.19 (m, 1H), 1.11 (d, J = 6.4 Hz, 3H). Step 3: [02 7] .5 m otage m crowave reactor was c arge wt -[( S, )- -[( -c orop eny)am no]- - methyl-6-(1-methyl-1H-pyrazol-5-yl)-1,2,3,4-tetrahydroquinol in-1-yl]ethan-1-one (52.0 mg, 132 µmol), prop-2-yn-1-amine (25.3 µL, 3 eq., 395 µmol), cesium carbonate (257 mg, 6 eq., 790 µmol), degassed ACN (3 mL), and Pd(Cy*Phine) 2 Cl 2 (14.0 mg, 132 µmol). The microwave tube was then sealed under an argon atmosphere and heated at 90 °C under microwave irradiation for 2 hours. The solvents were evaporated in vacuo and the resulting residue was dissolved in a mixture of DCM and DMA (2 mL). The insoluble solid was filtered and the solvents were evaporated in vacuo. The resulting residue was purified by prep-HPLC to give 1-((2S,4R)-4-((4-(3-aminoprop-1-yn-1-yl)phenyl)amino)-2-meth yl-6-(1-methyl- 1H-pyrazol-5-yl)-3,4-dihydroquinolin-1(2H)-yl)ethan-1-one. 1 H NMR (499 MHz, d 6 -DMSO) δ 8.30 (s, 1H), 7.48 – 7.40 (m, 3H), 7.17 – 7.12 (m, 3H), 6.70 – 6.64 (m, 2H), 6.46 (d, J = 8.0 Hz, 1H), 6.28 (d, J = 1.9 Hz, 1H), 4.73 – 4.68 (m, 1H), 4.34 (ddd, J = 12.1, 8.0, 4.2 Hz, 1H), 3.66 (s, 3H), 3.53 (s, 2H), 2.62 (ddd, J = 12.5, 8.5, 4.1 Hz, 1H), 2.15 (s, 3H), 1.27 (td, J = 12.3, 9.3 Hz, 1H), 1.11 (d, J = 6.3 Hz, 3H). [0218] Each of the compounds set forth in Table 3 was prepared following one of the procedures set forth above. Table 3
Example 6 Preparation of 1-((2S)-4-(1-(4-(3-aminoprop-1-yn-1-yl)phenyl)ethyl)-2-methy l-3,4- dihydroquinoxalin-1(2H)-yl)ethan-1-one (Compound P-10A & P-3A): Step 1: [0219] To a soluti on of 1-[(2S)-2-methyl-3,4-dihydro-2H-quinoxalin-1-yl]ethanone (1 g, 5.26 mmol, 1 eq) and 1-bromo-4-(1-bromoethyl)benzene (1.65 g, 6.31 mmol, 1.2 eq) in DMF (15 mL) was added K2CO3 (1.45 g, 10.51 mmol, 2 eq). The mixture was stirred at 100 °C for 2 hr. The reaction mixture was partitioned between H2O (20 mL) and ethyl acetate (20 mL). The organic phase was separated, washed with ethyl acetate (3x10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC to give 1-((2S)-4-(1-(4-bromophenyl)ethyl)-2-methyl-3,4- dihydroquinoxalin-1(2H)-yl)ethan-1-one. Step 2: [0220] To a solution of 1-((2S)-4-(1-(4-bromophenyl)ethyl)-2-methyl-3,4-dihydroquino xalin-1(2H)- yl)ethan-1-one (50 mg, 139 µmol, 1 eq) and prop-2-yn-1-amine (15.33 mg, 278 µmol, 17.83 µL, 2 eq) in DMSO (2 mL) was added CuI (2.65 mg, 13.92 µmol, 0.1 eq), Pd(PPh3)2Cl2 (9.77 mg, 13.92 µmol, 0.1 eq) and Cs2CO3 (136.04 mg, 417.53 µmol, 3 eq). The mixture was stirred at 80 °C for 8 hr. The reaction mixture was partitioned between ethyl acetate (3 mL) and H2O (3 mL). The organic phase was separated, washed with ethyl acetate (3x3 mL), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC to give 1-((2S)-4-(1-(4-(3-aminoprop-1-yn-1-yl)phenyl)ethyl)-2- methyl-3,4-dihydroquinoxalin-1(2H)-yl)ethan-1-one as two separable isomers. [0221] Isomer 1: MS (ESI + ): m/z 348.1 (M+H) + . 1 H NMR (400 MHz, d 6 -DMSO) δ 7.67 - 7.54 (m, 1H), 7.41 - 7.35 (m, 2H), 7.33 - 7.27 (m, 2H), 6.98 (d, J = 6.4 Hz, 1H), 6.93 - 6.86 (m, 1H), 6.59 (t, J = 7.6 Hz, 1H), 5.31 - 5.21 (m, 1H), 3.50 (s, 2H), 3.20 - 3.10 (m, 1H), 3.02 - 2.89 (m, 1H), 2.12 (s, 3H), 1.49 (d, J = 7.2 Hz, 3H), 0.95 (d, J = 3.2 Hz, 3H). [0222] Isomer 2: MS (ESI + ): m/z 348.1 (M+H) + . 1 H NMR (400 MHz, d 6 -DMSO) δ 7.66 - 7.52 (m, 1H), 7.40 - 7.35 (m, 2H), 7.34 - 7.29 (m, 2H), 7.00 - 6.92 (m, 1H), 6.87 (d, J = 8.4 Hz, 1H), 6.57 (t, J = 7.6 Hz, 1H), 5.21 (q, J = 6.4 Hz, 1H), 3.52 (s, 2H), 3.26 (m, 1H), 2.98 (d, J = 11.6 Hz, 1H), 2.12 (s, 3H), 1.51 (d, J = 7.2 Hz, 3H), 0.85 (s, 3H). Example 7 (S)-1-(4-(4-(3-aminoprop-1-yn-1-yl)benzyl)-6-fluoro-2-methyl -3,4-dihydroquinoxalin-1(2H)- yl)ethan-1-one (Compound P-2A): Step 1: [0223] To a mixture of 4-bromo-1-fluoro-2-nitrobenzene (100 g, 454.55 mmol, 55.87 mL) and (2S)-2- aminopropan-1-ol (37.56 g, 500.01 mmol, 38.92 mL) in DMF (500 mL) was added K 2 CO 3 (69.10 g, 500.01 mmol). The mixture was stirred at 60°C for 12 h. Water (2 L) was added dropwise to the reaction mixture to give a precipitate. The precipitated solid was filtered. The solid was washed with water (1 L) and dried to give (S)-2-((4-bromo-2-nitrophenyl)amino)propan-1-ol. m/z (ESI + ): 275.0 (M+H) + . Step 2: [0224] A mixture o Fe (233.45 g, 4.18 mo ) an NH 4 C (2.24 g, 41.80 mmo) n EtOH (600 mL) and H 2 O (360 mL) was heated to 80 °C. (S)-2-((4-bromo-2-nitrophenyl)amino)propan-1-ol (115 g, 418.03 mmol) in EtOH (600 mL) was added dropwise. The mixture was stirred at 80°C for 4 h. The mixture was cooled to 20°C, filtered and concentrated to give (S)-2-((2-amino-4-bromophenyl)amino)propan-1-ol. 1 H NMR (400 MHz, d6-DMSO) δ = 6.67 (d, J = 2.4 Hz, 1H), 6.57 (dd, J = 2.4, 8.4 Hz, 1H), 6.37 (d, J = 8.8 Hz, 1H), 4.81 (s, 2H), 4.68 (t, J = 5.6 Hz, 1H), 4.20 (d, J = 6.4 Hz, 1H), 3.49 - 3.42 (m, 1H), 3.30 - 3.23 (m, 1H), 1.11 (d, J = 6.4 Hz, 3H). Step 3: [0225] A mixture of (S)-2-((2-amino-4-bromophenyl)amino)propan-1-ol (93 g, 379.41 mmol) in pyridine (1 L) was added 4-methylbenzene-1-sulfonyl chloride (72.33 g, 379.41 mmol) dropwise at 0 °C. The mixture was stirred at 0°C for 2 h. The mixture was poured into water (2 L) and extracted with ethyl acetate (3 × 1 L). The organic phase was washed with brine (1.5 L), dried over Na2SO4 and concentrated to give a residue. The residue was purified by column chromatography (SiO2, 25 to 50% ethyl acetate in petroleum ether) to give (S)-N-(5-bromo-2-((1-hydroxypropan-2-yl)amino)phenyl)-4- methylbenzenesulfonamide. 1 H NMR (400 MHz, d6-DMSO) δ 7.55 (d, J = 8.0 Hz, 2H), 7.35 (d, J = 8.0 Hz, 2H), 7.13 (dd, J = 2.4, 8.8 Hz, 1H), 6.81 (d, J = 2.4 Hz, 1H), 6.52 (d, J = 9.2 Hz, 1H), 4.69 (t, J = 5.2 Hz, 1H), 3.29 (dd, J = 4.0, 7.2 Hz, 2H), 3.16 - 3.04 (m, 1H), 2.36 (s, 3H), 0.94 (d, J = 6.0 Hz, 3H). Step 4: [0226] To a mixture of (S)-N-(5-bromo-2-((1-hydroxypropan-2-yl)amino)phenyl)-4- methylbenzenesulfonamide (140 g, 350.61 mmol) and PPh 3 (110.35 g, 420.73 mmol) in THF (2.5 L) was added DIAD (77.99 g, 385.67 mmol, 74.99 mL) dropwise at 0°C. The mixture was stirred at 0°C for 1.5 h. The mixture was concentrated under pressure to give a residue. The residue was purified by column chromatography (SiO 2 , 25 to 50% ethyl acetate in petroleum ether) to give (S)-7-bromo-3-methyl-1-tosyl- 1,2,3,4-tetrahydroquinoxaline. 1 H NMR (400 MHz, CDCl 3 ) δ 7.81 (d, J = 2.4 Hz, 1H), 7.48 (d, J = 8.4 Hz, 2H), 7.21 (d, J = 8.4 Hz, 2H), 7.03 (dd, J = 2.4, 8.8 Hz, 1H), 6.34 (d, J = 8.8 Hz, 1H), 4.24 - 4.13 (m, 1H), 3.77 (s, 1H), 2.84 - 2.74 (m, 2H), 2.38 (s, 3H), 1.03 (d, J = 5.6 Hz, 3H). Step 5: [0227] To a mixture of (S)-7-bromo-3-methyl-1-tosyl-1,2,3,4-tetrahydroquinoxaline (133 g, 348.82 mmol) and pyridine (41.39 g, 523.23 mmol, 42.23 mL) in DCM (3 L) at 0°C was added acetyl chloride (32.86 g, 418.58 mmol, 29.87 mL) dropwise. The mixture was stirred at 0°C for 1.5 h. The mixture was concentrated under pressure to give (S)-1-(6-bromo-2-methyl-4-tosyl-3,4-dihydroquinoxalin-1(2H)- yl)ethan-1-one. m/z (ESI + ): 423.0 (M+H) + . Step 6: [0228] To a mixture of (S)-1-(6-bromo-2-methyl-4-tosyl-3,4-dihydroquinoxalin-1(2H)- yl)ethan-1-one (130 g, 307.09 mmol) in DCM (650 mL) at 0°C was added H2SO4 (180.72 g, 1.84 mol, 98.22 mL) dropwise. The mixture was stirred at 0°C for 1.5 h. The reaction mixture was added to ice water (5 L) slowly to maintain the solution temperature below 10 ° C. The mixture was extracted with dichloromethane (3 × 1 L). The combined organic phases were washed with brine (1 L), dried over Na2SO4 and concentrated to give a residue. The residue was purified by column chromatography (SiO2, 50 to 70% ethyl acetate in petroleum ether) to give (S)-1-(6-bromo-2-methyl-3,4-dihydroquinoxalin- 1(2H)-yl)ethan-1-one. 1 H NMR (400 MHz, CDCl 3 ) δ 6.83 (br s, 1H), 6.78 - 6.65 (m, 2H), 5.20 (br s, 1H), 4.18 (br s, 1H), 3.42 (dd, J = 4.0, 11.6 Hz, 1H), 3.22 (d, J = 11.6 Hz, 1H), 2.23 (s, 3H), 1.06 (s, 3H). Step 7: [0229] To a solution o (S)- -(6- romo- -met y-3, - y roqu noxa n- ( )-y )ethan-1-one (2 g, 7.43 mmol, 1 eq) and DMAP (90.79 mg, 743.12 µmol, 0.1 eq) in DCE (30 mL) was added Boc 2 O (2.43 g, 11.15 mmol, 2.56 mL, 1.5 eq) dropwise. The mixture was stirred at 50°C for 1 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO 2 , 10 to 25% ethyl acetate in petroleum ether) to give tert-butyl (S)-4-acetyl-7- bromo-3-methyl-3,4-dihydroquinoxaline-1(2H)-carboxylate. 1 H NMR (400 MHz, CDCl 3 ) δ 8.12 (s, 1H), 7.19 (dd, J = 2.4, 8.4 Hz, 1H), 7.04 (s, 1H), 5.13 (s, 1H), 3.93 (dd, J = 6.4, 12.4 Hz, 1H), 3.56 - 3.42 (m, 1H), 2.19 (s, 3H), 1.54 (s, 9H), 1.04 (d, J = 6.8 Hz, 3H). Step 8: [0230] A mixture of tert-butyl (S)-4-acetyl-7-bromo-3-methyl-3,4-dihydroquinoxaline-1(2H)- carboxylate (1.5 g, 4.06 mmol, 1 eq), BPD (3.09 g, 12.19 mmol, 3 eq), Pd(dppf)Cl 2 (297.24 mg, 406.23 µmol, 0.1 eq) and KOAc (1.20 g, 12.19 mmol, 3 eq) in DMSO (15 mL) was heated at 80°C for 12 h under a N 2 atmosphere. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (2 × 50 mL). The combined organic layers were washed with brine (4 × 100 mL), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO 2 , 20 to 35% ethyl acetate in petroleum ether) to give tert-butyl (S)-4-acetyl-3- methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-d ihydroquinoxaline-1(2H)-carboxylate. 1 H NMR (400 MHz, CDCl 3 ) δ 8.20 (s, 1H), 7.51 (dd, J = 1.2, 8.0 Hz, 1H), 7.14 (d, J = 7.6 Hz, 1H), 5.21 - 5.06 (m, 1H), 4.08 (dd, J = 7.2, 12.8 Hz, 1H), 3.34 (dd, J = 4.4, 12.8 Hz, 1H), 2.21 (s, 3H), 1.55 (s, 9H), 1.35 (s, 12H), 1.05 (d, J = 6.8 Hz, 3H). Step 9: [0231] To a mixture of KOtBu (424.51 mg, 3.78 mmol, 1.05 eq) in MeOH (15 mL) was added tert-butyl (S)-4-acetyl-3-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaboro lan-2-yl)-3,4-dihydroquinoxaline-1(2H)- carboxylate (1.5 g, 3.60 mmol, 1 eq) at 20 ° C. After stirring for 15 min, the reaction mixture was cooled to 0 ° C and AgOTf (2.78 g, 10.81 mmol, 3 eq) was added. After stirring for 30 min at 0 °C, the solvent was removed under reduced pressure at 0°C and the residual MeOH was removed by co-evaporation with acetone (20 mL × 3) to give a residue. The residue was dissolved in acetone (20 mL) and 1- (chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane;dit etrafluoroborate (1.34 g, 3.78 mmol, 1.05 eq) was added. The mixture was stirred at 20°C for 0.5 h. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC to give tert-butyl (S)-4-acetyl-7-fluoro-3-methyl-3,4-dihydroquinoxaline-1(2H)- carboxylate. 1 H NMR (400 MHz, CDCl 3 ) δ 7.76 (d, J = 9.6 Hz, 1H), 7.09 (br s, 1H), 6.86 - 6.72 (m, 1H), 5.19 (br s, 1H), 3.94 (dd, J = 6.4, 12.4 Hz, 1H), 3.48 (d, J = 12.4 Hz, 1H), 2.18 (s, 3H), 1.55 (s, 9H), 1.03 (d, J = 6.8 Hz, 3H). Step 10: [0232] To a solution of tert-butyl (S)-4-acetyl-7-fluoro-3-methyl-3,4-dihydroquinoxaline-1(2H)- carboxylate (0.46 g, 1.49 mmol, 1 eq) in DCM (10 mL) was added TFA (1.70 g, 14.92 mmol, 1.10 mL, 10 eq) dropwise. The mixture was stirred for 12 h. The reaction mixture was concentrated under reduced pressure to give (S)-1-(6-fluoro-2-methyl-3,4-dihydroquinoxalin-1(2H)-yl)etha n-1-one as a TFA salt, which was used into the next step without purification. 1 H NMR (400 MHz, CDCl3) δ 6.93 (br s, 1H), 6.42 (dt, J = 2.4, 8.4 Hz, 1H), 6.36 (dd, J = 2.4, 9.6 Hz, 1H), 5.24 (br s, 1H), 3.49 (d, J = 8.8 Hz, 1H), 3.26 (d, J = 11.6 Hz, 1H), 2.34 (s, 3H), 1.08 (br s, 3H). Step 11: I [0233] A so lutio of (S) 1 (6 fluo o 2 ethyl 3,4 dihyd oqui o ali 1(2H) yl)etha 1 o e (400 mg, 1.24 mmol, 1 eq, TFA salt), KI (20.61 mg, 124.13 µmol, 0.1 eq), DIEA (802.12 mg, 6.21 mmol, 1.08 mL, 5 eq) and 1-(bromomethyl)-4-iodo-benzene (1.11 g, 3.72 mmol, 3 eq) in DMF (4 mL) was stirred at 50°C for 1 h. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO 2 , 10 to 25% ethyl acetate in petroleum ether to give (S)-1-(6-fluoro-4-(4-iodobenzyl)-2-methyl-3,4-dihydroquinoxa lin-1(2H)-yl)ethan-1-one. 1 H NMR (400 MHz, CDCl 3 ) δ 7.67 (d, J = 8.4 Hz, 2H), 6.97 (d, J = 8.4 Hz, 2H), 6.94 (d, J = 2.0 Hz, 1H), 6.38 (dt, J = 2.4, 8.4 Hz, 1H), 6.32 (dd, J = 2.4, 11.2 Hz, 1H), 5.36 - 5.17 (m, 1H), 4.43 (s, 2H), 3.55 (dd, J = 4.4, 11.2 Hz, 1H), 3.12 (d, J = 11.6 Hz, 1H), 2.22 (s, 3H), 1.08 (d, J = 4.4 Hz, 3H). Step 12: [0234] To a solution of (S)-1-(6-fluoro-4-(4-iodobenzyl)-2-methyl-3,4-dihydroquinoxa lin-1(2H)- yl)ethan-1-one (20 mg, 47.14 µmol, 1 eq) and prop-2-yn-1-amine (7.79 mg, 141.43 µmol, 9.06 µL, 3 eq) in ACN (1 mL) was added Pd(PPh3)2Cl2 (3.31 mg, 4.71 µmol, 0.1 eq), Cs2CO3 (46.08 mg, 141.43 µmol, 3 eq) and CuI (897.82 µg, 4.71 µmol, 0.1 eq) under a N2 atmosphere. The mixture was stirred at 30°C for 12 h. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (Prep-HPLC method: column: Phenomenex Luna C18 75×30mm×3µm;mobile phase: [water(FA)-ACN]; B%: 1%-40%, 8min) to give (S)-1-(4-(4-(3- aminoprop-1-yn-1-yl)benzyl)-6-fluoro-2-methyl-3,4-dihydroqui noxalin-1(2H)-yl)ethan-1-one. 1 H NMR (400 MHz, d4-MeOD) δ 8.62 - 8.43 (m, 1H), 7.44 (d, J = 8.0 Hz, 2H), 7.26 (d, J = 8.0 Hz, 2H), 7.15 - 7.03 (m, 1H), 6.46 - 6.31 (m, 2H), 5.26 - 5.08 (m, 1H), 4.67 - 4.46 (m, 2H), 3.86 (s, 2H), 3.60 - 3.50 (m, 1H), 3.26 - 3.19 (m, 1H), 2.20 (s, 3H), 1.06 (dd, J = 1.6, 3.6 Hz, 3H). [0235] Each of the compounds set forth in Table 3A was prepared following one of the procedures set forth above. Table 3A Compound Biological Examples Target engagement assay [0236] The ability of a compound to bind to BRD4 is assessed using HEK-293T cells and the NanoBRET Target Engagement Intracellular BET BRD Assay from Promega (Cat. No. N2131). Assays were run according to manufacturer’s specifications and luminescent readout was recorded using a CLARIOstar Plus instrument (BMG Labtech). Resulting BRET ratios were plotted and IC50s determined by non-linear regression analyses (GraphPad Prism). BRD4 degradation assay [0237] BRD4 degradation was monitored by immunofluorescence in HEK-293T cells. In brief, 96-well plates (black, clear-bottom) were seeded with HEK-293T cells at 10,000 cells/well and incubated overnight at 37 °C to allow cell attachment. After overnight incubation, test compounds were added in a 10-point dilution series (typically 30 µM to 100 pM) using a TECAN D300e Digital Dispenser, and plates were subsequently incubated for 24 hours at 37 °C. Media was carefully removed, and cells were fixed in PBS + 2.5% formalin (50 µL) for 20 minutes at 37 °C. Following formalin fixation, cells were washed once with PBS and methanol was added (30 µL). Plates were wrapped in parafilm and incubated at -20 °C for 1 hour to overnight. For immunostaining, plates were removed from -20 °C and cells were washed with PBS (3x).50 µL of blocking solution (PBS + 1X fish gelatin, 0.3% Triton X-100) were added to each well and plates were incubated at room temperature for 30 minutes to 1 hour. Blocking buffer was removed, and 40 µL primary BRD4 antibody (Sigma-Aldrich HPA061646; diluted 1:1000 in PBS + 1X fish gelatin, 0.1% Triton X-100) was added. Plates were incubated at 4 °C for 4 hours to overnight, after which cells were washed (3x) with PBS + 0.1% tween-20 at room temperature. DAPI (1 µM final) plus secondary antibody (Southern Biotech 4030-30 anti-Rabbit IgG Alexa Fluor 488; diluted 1:2000 in PBS + 1X fish gelatin, 0.1% Triton X-100) were added at 40 µL/well, and plates were incubated at room temperature for 2 hours, covered with foil. Cells were washed (3x) with PBS + 0.1% tween-20, followed by one wash with PBS, and the addition of 100 µL of PBS for imaging. Images were acquired using the ImageXpress Pico system (Molecular Devices). Cell Reporter Xpress software was utilized to segment cells and determine fluorescence intensities, which were used to construct dose- response curves and calculation of degradation DC 50 s (GraphPad Prism). Results for certain compounds are reported in Table 4 and 4A below. Table 4 Table 4A
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