BAILEY SIMON (US)
LERICHE GEOFFRAY (US)
KUMAR DANGE VIJAY (US)
BURNS AARON C (US)
FREEMAN-COOK KEVIN D (US)
BISHOP MICHAEL J (US)
WO2016138114A1 | 2016-09-01 | |||
WO2020251971A1 | 2020-12-17 | |||
WO2023018648A1 | 2023-02-16 |
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: X is hydroxy, halo, cyano, C1-4 alkoxy, or -N(R)2; Y is N, C, or CH; Y1 is N, C, or CH; X1 is either CH, CR6, or N; X2 is either CH, CR6, or N; wherein at least one of X1 or X2 is N; T is -N(R)2; Ring A is C4-8 cycloalkyl, C6-10 aryl, 4- to 11-membered heterocycloalkyl, or 5- to 10-membered heteroaryl, wherein each heterocycloalkyl or heteroaryl have from 1 to 3 heteroatoms selected from O, N, NR, and S, and wherein each cycloalkyl, aryl, heterocycloalkyl, or heteroaryl is independently unsubstituted or substituted with one to four R1; L is a bond, -CH2- or -O-; L1 is -RC=CR- or -C≡C-; L2 is selected from: a b c) ; wherein t is 0 or 1, p is 0, 1, 2, or 3, and wherein the dashed line ( ) denotes the point of attachment from L2 to L1, and the wavy line ( ) denotes the point of attachment from L2 to Z; Z is C1-10 alkyl, -N(R)2, -OH, C1-10 alkoxy, C3-8 cycloalkyl, 4- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl, wherein each heterocycloalkyl or heteroaryl have from 1 to 4 heteroatoms selected from NR, N, O, and S, and wherein each heterocycloalkyl or heteroaryl is independently unsubstituted or substituted with one to four R2, and wherein each alkyl, alkoxy, or cycloalkyl is independently unsubstituted or substituted with one to three R3; each R is independently hydrogen, C1-4 alkyl, or C3-6 cycloalkyl, wherein each alkyl or cycloalkyl is unsubstituted or substituted with one to three R4; or two R groups, when attached to the same nitrogen, form a 4- to 7-membered heterocycloalkyl, which is unsubstituted or substituted with one to four R4; each Rx and Ry is independently hydrogen, C1-4 alkyl, or C1-4 haloalkyl substituted with 1 to 3 halo; or Rx and Ry, together with the atoms to which they are attached, form a C3-6 cycloalkyl, which is unsubstituted or substituted with one to four R4; each R1 is independently cyano, halo, hydroxyl, nitro, oxo, -N(R)2, C1-4 alkyl, C1-4 haloalkyl substituted with 1 to 3 halo, C1-4 alkoxy unsubstituted or substituted with 1 to 3 halo, C5-6 heteroaryl having from 1 to 3 heteroatoms selected from O, N, NR, and/or S, 4- to 7-membered heterocycloalkyl having from 1 to 3 heteroatoms selected from oxygen, nitrogen, and/or sulfur, -C(O)OR, -OC(O)R, or -C(O)R; each R2 is independently oxo, hydroxy, cyano, halo, -N(R)2, -C(O)OR, -NRC(O)OR, C1-4 alkyl, C1-4 haloalkyl substituted with from 1 to 3 halo groups, C1-4 alkoxy, C1-4 alkoxy substituted with from 1 to 3 halo groups, C1-4 alkyl substituted with C1-2 alkoxy, C5-6 heteroaryl having from 1 to 3 heteroatoms selected from O, N, and NR, or C3-6 cycloalkyl; each R3 is independently oxo, cyano, hydroxy, halogen, C1-4 alkyl, C1-4 alkoxy, C1-4 alkoxy substituted with from 1 to 3 halo groups, C1-4 haloalkyl substituted with from 1 to 3 halo groups, C1-6 aryl, C1-4 alkyl substituted with 1 to 3 phenyl, or C3-6 cycloalkyl; each R4 is independently -N(R)2, cyano, halo, or hydroxyl; each R5 is D, halo, C1-3 haloalkyl, or C1-4 alkoxy; each R6 is N(R)2, SR, halo, cyano, C1-4 alkoxy unsubstituted or substituted with 1 to 3 halo, unsubstituted C1-4 alkyl, C1-4 alkyl substituted with C1-2 alkoxy, or C1-4 alkyl substituted with hydroxy; m is 0, 1, or 2; and n is 0, 1, 2, or 3; with the proviso that when the compound is the following moiety: and L2 is a -C(O)NH-, bond, -CH2-, or -(CH2)2-, then Z is not a heterocyclyl (wherein the heterocyclyl is unsubstituted or substituted), -C1-6 alkylene-NH2, or -C1-6 alkylene-OH, and the compound is not: 2-(6-amino-5-(8-(2-(3-((2- hydroxyethyl)(methyl)amino)prop-1-yn-1-yl)pyridin-4-yl)-3,8- diazabicyclo[3.2.1]octan-3-yl)pyridazin-3-yl)phenol, 2-(6-amino-5-(8-(2-(3-(2-hydroxyethoxyprop-1-yn-1-yl)pyridin-4-yl)-3,8-diazabicyclo[3.2.1]octan- 3-yl)pyridazin-3-yl)phenol, 2-(6-amino-5-(8-(2-(3-(diethylamino)prop-1-yn-1-yl)pyridin-4-yl)-3,8-diazabicyclo[3.2.1]octan-3- yl)pyridazin-3-yl)phenol, 2-(6-amino-5-(8-(2-(3-(piperidin-3-yloxy)prop-1-yn-1-yl)pyridin-4-yl)-3,8-diazabicyclo[3.2.1]octan- 3-yl)pyridazin-3-yl)phenol, 2-(6-amino-5-(8-(2-((l-methyl-lH-pyrazol-4-yl)ethynyl)pyridin-4-yl)-3,8-diazabicyclo[3.2.1]octan-3- yl)pyridazin-3-yl)phenol, N-[3-[4-[3-[3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2- pyridyl]prop-2-ynyl]piperidine-4-carboxamide, 2-[6-amino-5-[8-[2-[3-(azepan-1-yl)prop-1-ynyl]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octan-3- yl]pyridazin-3-yl]phenol, 2-[6-amino-5-[9-[2-[3-(azepan-l-yl)prop-l-ynyl]-4-pyridyl]-3,9-diazaspiro[5.5]undecan-3- yl]pyridazin-3-yl]phenol, 2-[6-amino-5-[2-[2-[3-(azepan-1-yl)prop-1-ynyl]-4-pyridyl]-2,8-diazaspiro[4.5]decan-8-yl]pyridazin- 3-yl]phenol, 2-[6-amino-5-[6-[2-[3-(azepan-1-yl)prop-1-ynyl]-4-pyridyl]-2,6-diazaspiro[3.3]heptan-2- yl]pyridazin-3-yl]phenol, 2-(6-amino-5-(8-(2-(((1r,4r)-4-aminocyclohexyl)ethynyl)pyridin-4-yl)-3,8-diazabicyclo[3.2.1]octan- 3-yl)pyridazin-3-yl)phenol, or 2-[6-amino-5-[8-[2-[(E)-3-(azepan-1-yl)prop1-enyl]-4-pyridyl]-3,8-diazabicyclo[3.2.1]octan-3- yl]pyridazin-3-yl]phenol. 2. A compound of formula IA: or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, wherein: X is hydroxy, halo, cyano, C1-4 alkoxy, or -N(R)2; Y is N, C, or CH; Y1 is N, C, or CH; T is -N(R)2; Ring A is C4-8 cycloalkyl, C6-10 aryl, 4- to 11-membered heterocycloalkyl, or 5- to 10-membered heteroaryl, wherein each heterocycloalkyl or heteroaryl have from 1 to 3 heteroatoms selected from O, N, NR, and S, and wherein each cycloalkyl, aryl, heterocycloalkyl, or heteroaryl is independently unsubstituted or substituted with one to four R1; L is a bond, -CH2-, or -O-; L1 is -RC=CR- or -C≡C-; L2 is selected from: a c wherein t is 0 or 1, p is 0, 1, 2, or 3, and wherein the dashed line ( ) denotes the point of attachment from L2 to L1, and the wavy line ( ) denotes the point of attachment from L2 to Z; Z is C1-10 alkyl, -N(R)2, -OH, C1-10 alkoxy, C3-8 cycloalkyl, 4- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl, wherein each heterocycloalkyl or heteroaryl have from 1 to 4 heteroatoms selected from NR, N, O, and S, and wherein each heterocycloalkyl or heteroaryl is independently unsubstituted or substituted with one to four R2, and wherein each alkyl, alkoxy, or cycloalkyl is independently unsubstituted or substituted with one to three R3; each R is independently hydrogen, C1-4 alkyl, or C3-6 cycloalkyl, wherein each alkyl or cycloalkyl is unsubstituted or substituted with one to three R4; or two R groups, when attached to the same nitrogen, form a 4- to 7-membered heterocycloalkyl, which is unsubstituted or substituted with one to four R4; each Rx and Ry is independently hydrogen, C1-4 alkyl, or C1-4 haloalkyl substituted with 1 to 3 halo; or Rx and Ry, together with the atoms to which they are attached, form a C3-6 cycloalkyl, which is unsubstituted or substituted with one to four R4; each R1 is independently cyano, halo, hydroxyl, nitro, oxo, -N(R)2, C1-4 alkyl, C1-4 haloalkyl substituted with 1 to 3 halo, C1-4 alkoxy unsubstituted or substituted with 1 to 3 halo, C5-6 heteroaryl having from 1 to 3 heteroatoms selected from O, N, NR, and/or S, 4- to 7-membered heterocycloalkyl having from 1 to 3 heteroatoms selected from oxygen, nitrogen, and/or sulfur, -C(O)OR, -OC(O)R, or -C(O)R; each R2 is independently oxo, hydroxy, cyano, halo, -N(R)2, -C(O)OR, -NRC(O)OR, C1-4 alkyl, C1-4 haloalkyl substituted with from 1 to 3 halo groups, C1-4 alkoxy, C1-4 alkoxy substituted with from 1 to 3 halo groups, C1-4 alkyl substituted with C1-2 alkoxy, C5-6 heteroaryl having from 1 to 3 heteroatoms selected from O, N, and NR, or C3-6 cycloalkyl; each R3 is independently oxo, cyano, hydroxy, halogen, C1-4 alkyl, C1-4 alkoxy, C1-4 alkoxy substituted with from 1 to 3 halo groups, C1-4 haloalkyl substituted with from 1 to 3 halo groups, C1-6 aryl, C1-4 alkyl substituted with 1 to 3 phenyl, or C3-6 cycloalkyl; each R4 is independently -N(R)2, cyano, halo, or hydroxyl; each R5 is D, halo, C1-3 haloalkyl, or C1-4 alkoxy; each R6 is N(R)2, SR, halo, cyano, C1-4 alkoxy unsubstituted or substituted with 1 to 3 halo, unsubstituted C1-4 alkyl, C1-4 alkyl substituted with C1-2 alkoxy, or C1-4 alkyl substituted with hydroxy; m is 0, 1, or 2; and n is 0, 1, 2, or 3; with the proviso that the compound is not 2-[6-amino-5-[8-[2-[3-(azepan-1-yl)prop-1- ynyl]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octan-3-yl]pyridazin-3-yl]phenol. 3. A compound of formula Iʹ: or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, wherein: X is hydroxy, halo, cyano, C1-4 alkoxy, or -N(R)2; Y is N, C, or CH; Y1 is N, C, or CH; T is -N(R)2; Ring A is C4-8 cycloalkyl, C6-10 aryl, 4- to 11-membered heterocycloalkyl, or 5- to 10-membered heteroaryl, wherein each heterocycloalkyl or heteroaryl have from 1 to 3 heteroatoms selected from O, N, NR, and S, and wherein each cycloalkyl, aryl, heterocycloalkyl, or heteroaryl is independently unsubstituted or substituted with one to four R1; L1 is -RC=CR- or -C≡C-; L2 is selected from: a c wherein t is 0 or 1, p is 0, 1, 2, or 3, and wherein the dashed line ( ) denotes the point of attachment from L2 to L1, and the wavy line ( ) denotes the point of attachment from L2 to Z; Z is C1-10 alkyl, -N(R)2, -OH, C1-10 alkoxy, C3-8 cycloalkyl, 4- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl, wherein each heterocycloalkyl or heteroaryl have from 1 to 4 heteroatoms selected from NR, N, O, and S, and wherein each heterocycloalkyl or heteroaryl is independently unsubstituted or substituted with one to four R2, and wherein each alkyl, alkoxy, or cycloalkyl is independently unsubstituted or substituted with one to three R3; each R is independently hydrogen, C1-4 alkyl, or C3-6 cycloalkyl, wherein each alkyl or cycloalkyl is unsubstituted or substituted with one to three R4; or two R groups, when attached to the same nitrogen, form a 4- to 7-membered heterocycloalkyl, which is unsubstituted or substituted with one to four R4; each Rx and Ry is independently hydrogen, C1-4 alkyl, or C1-4 haloalkyl substituted with 1 to 3 halo; or Rx and Ry, together with the atoms to which they are attached, form a C3-6 cycloalkyl, which is unsubstituted or substituted with one to four R4; each R1 is independently cyano, halo, hydroxyl, nitro, oxo, -N(R)2, C1-4 alkyl, C1-4 haloalkyl substituted with 1 to 3 halo, C1-4 alkoxy unsubstituted or substituted with 1 to 3 halo, C5-6 heteroaryl having from 1 to 3 heteroatoms selected from O, N, NR, and/or S, 4- to 7-membered heterocycloalkyl having from 1 to 3 heteroatoms selected from oxygen, nitrogen, and/or sulfur, -C(O)OR, -OC(O)R, or -C(O)R; each R2 is independently oxo, hydroxy, cyano, halo, -N(R)2, -C(O)OR, -NRC(O)OR, C1-4 alkyl, C1-4 haloalkyl substituted with from 1 to 3 halo groups, C1-4 alkoxy, C1-4 alkoxy substituted with from 1 to 3 halo groups, C1-4 alkyl substituted with C1-2 alkoxy, C5-6 heteroaryl having from 1 to 3 heteroatoms selected from O, N, and NR, or C3-6 cycloalkyl; each R3 is independently oxo, halogen, C1-4 alkyl, C1-4 alkoxy, C1-4 alkoxy substituted with from 1 to 3 halo groups, C1-4 haloalkyl substituted with from 1 to 3 halo groups, or C3-6 cycloalkyl; each R4 is independently -N(R)2, cyano, halo, or hydroxyl; each R5 is D, halo, C1-3 haloalkyl, or C1-4 alkoxy; each R6 is N(R)2, SR, cyano, C1-4 alkoxy unsubstituted or substituted with 1 to 3 halo, C1-4 alkyl substituted with C1-2 alkoxy, or C1-4 alkyl substituted with hydroxy; m is 0, 1, or 2; and n is 0, 1, 2, or 3; with the proviso that the compound is not 2-[6-amino-5-[8-[2-[3-(azepan-1-yl)prop-1- ynyl]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octan-3-yl]pyridazin-3-yl]phenol. 4. The compound of claim 3, wherein the compound of Formula Iʹ is represented by Formula IIʹ: or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof. 5. The compound of claim 4, wherein the compound of Formula IIʹ is represented by Formula IIaʹ: , or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof. 6. The compound of claim 5, wherein the compound of Formula IIaʹ is represented by Formula IIaʹ- 1: IIaʹ-1, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof. 7. The compound of claim 5, wherein the compound of Formula IIaʹ is represented by Formula IIaʹ- 2: IIaʹ-2, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof. 8. The compound of claim 4, wherein the compound of Formula IIʹ is represented by Formula IIbʹ: , or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof. 9. The compound of claim 4, wherein the compound of Formula IIʹ is represented by Formula IIcʹ: , or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof. 10. The compound of claim 4, wherein the compound of Formula IIʹ is represented by Formula IIdʹ: or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof. 11. The compound of claim 3, wherein the compound of Formula Iʹ is represented by Formula IIIʹ-E: IIIʹ-E, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof. 12. The compound of claim 11, wherein the compound of Formula IIIʹ-E is represented by Formula IIIaʹ-E: IIIaʹ-E, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof. 13. The compound of claim 11, wherein the compound of Formula IIIʹ-E is represented by Formula IIIbʹ-E: or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof. 14. The compound of claim 3, wherein the compound of Formula Iʹ is represented by Formula IIIʹ-Z: IIIʹ-Z, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof. 15. The compound of claim 14, wherein the compound of Formula IIIʹ-Z is represented by Formula IIIaʹ-Z: IIIaʹ-Z, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof. 16. The compound of claim 14, wherein the compound of Formula IIIʹ-Z is represented by Formula IIIbʹ-Z: IIIbʹ-Z, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof. 17. The compound of any one of claims 1-16, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, wherein , , wherein the dashed line ( ) denotes the point of attachment from Ring A to pyrimidine, and the wavy line ( ) denotes the point of attachment from Ring A to L or pyridazine, and wherein each Ring A is independently unsubstituted or substituted with one to four R1, wherein each R1 is independently halo or C1-4 alkyl. 18. The compound of any one of claims 1-16, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, wherein , , , , , , , wherein the dashed line ( ) denotes the point of attachment from Ring A to pyrimidine, and the wavy line ( ) denotes the point of attachment from Ring A to L or pyridazine, and wherein each Ring A is independently unsubstituted or substituted with one to four R1, wherein each R1 is independently halo or C1-4 alkyl. 19. The compound of any one of claims 1-16, or a pharmaceutically acceptable salt, solvate, s , , , , , wherein the dashed line ( ) denotes the point of attachment from Ring A to pyrimidine, and the wavy line ( ) denotes the point of attachment from Ring A to L or pyridazine, and wherein each Ring A is independently unsubstituted or substituted with one to four R1, wherein each R1 is independently halo or C1-4 alkyl. 20. The compound of any one of claims 1-16, or a pharmaceutically acceptable salt, solvate, s , , , , , wherein the dashed line ( ) denotes the point of attachment from Ring A to pyrimidine, and the wavy line ( ) denotes the point of attachment from Ring A to L or pyridazine, and wherein each Ring A is independently unsubstituted or substituted with one to four R1, wherein each R1 is independently halo or C1-4 alkyl. 21. The compound of any one of claims 1-20, or a pharmaceutically acceptable salt, solvate, s , wherein each Z is independently unsubstituted or substituted with one to four R2, wherein each R2 is independently oxo, halo, -C(O)OR, -NRC(O)OR, C1-4 alkyl, C1-4 haloalkyl substituted with from 1 to 3 halo groups, C5-6 heteroaryl having from 1 to 3 heteroatoms selected from O, N, and NR, or C3-6 cycloalkyl. 22. The compound of any one of claims 1-20, or a pharmaceutically acceptable salt, solvate, s , , , , , , wherein each Z is independently unsubstituted or substituted with one to four R2, wherein each R2 is independently oxo, halo, -C(O)OR, -NRC(O)OR, C1-4 alkyl, C1-4 haloalkyl substituted with from 1 to 3 halo groups, C5-6 heteroaryl having from 1 to 3 heteroatoms selected from O, N, and NR, or C3-6 cycloalkyl. 23. The compound of any one of claims 1-20, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, wherein Z is ; wherein Z is independently unsubstituted or substituted with one to four R2, wherein each R2 is independently oxo, halo, -C(O)OR, -NRC(O)OR, C1-4 alkyl, C1-4 haloalkyl substituted with from 1 to 3 halo groups, C5-6 heteroaryl having from 1 to 3 heteroatoms selected from O, N, and NR, or C3-6 cycloalkyl. 24. The compound of any one of claims 1-20, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, wherein Z is selected from , , , wherein Z is independently unsubstituted or substituted with one to four R2, wherein each R2 is independently oxo, halo, -C(O)OR, -NRC(O)OR, C1-4 alkyl, C1-4 haloalkyl substituted with from 1 to 3 halo groups, C5-6 heteroaryl having from 1 to 3 heteroatoms selected from O, N, and NR, or C3-6 cycloalkyl. 25. The compound of any one of claims 1-20, or a pharmaceutically acceptable salt, solvate, s , , , , , , , , wherein each Z is independently unsubstituted or substituted with one to four R2, wherein each R2 is independently oxo, halo, -C(O)OR, -NRC(O)OR, C1-4 alkyl, C1-4 haloalkyl substituted with from 1 to 3 halo groups, C5-6 heteroaryl having from 1 to 3 heteroatoms selected from O, N, and NR, or C3-6 cycloalkyl. 26. The compound of any one of claims 1-20, or a pharmaceutically acceptable salt, solvate, s , wherein each Z is independently unsubstituted or substituted with one to four R2, wherein each R2 is independently oxo, halo, -C(O)OR, -NRC(O)OR, C1-4 alkyl, C1-4 haloalkyl substituted with from 1 to 3 halo groups, C5-6 heteroaryl having from 1 to 3 heteroatoms selected from O, N, and NR, or C3-6 cycloalkyl. 27. The compound of any one of claims 1-20, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, wherein Z is selected from ; wherein each Z is independently unsubstituted or substituted with one to four R2, wherein each R2 is independently oxo, halo, -C(O)OR, -NRC(O)OR, C1-4 alkyl, C1-4 haloalkyl substituted with from 1 to 3 halo groups, C5-6 heteroaryl having from 1 to 3 heteroatoms selected from O, N, and NR, or C3-6 cycloalkyl. 28. The compound of any one of claims 1-20, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, wherein Z is selected from , , d wherein each Z is independently unsubstituted or substituted with one to four R2, wherein each R2 is independently oxo, halo, -C(O)OR, -NRC(O)OR, C1-4 alkyl, C1-4 haloalkyl substituted with from 1 to 3 halo groups, C5-6 heteroaryl having from 1 to 3 heteroatoms selected from O, N, and NR, or C3-6 cycloalkyl. 29. The compound of any one of claims 1-20, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, wherein Z is C1-10 alkyl. 30. The compound of any one of claims 1-20, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, wherein Z is -N(R)2. 31. The compound of any one of claims 1-20, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, wherein Z is C1-10 alkoxy. 32. The compound of any one of claims 1-20, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, wherein Z is -OH. 33. The compound of any preceding claim, wherein X is hydroxy. 34. The compound of any preceding claim, wherein T is -NH2. 35. The compound of any preceding claim, wherein both Y and Y1 are N. 36. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and an effective amount of a compound of any one of claims 1-3, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof. 37. A compound or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, selected from Table 1, Table 1A, or Table 2. 38. A method for modulating or degrading protein which is expressed from the SMARCA2 gene, which method comprises contacting the protein with an effective amount of a compound according to any one of claims 1-3. 39. A method for modulating or degrading protein which is expressed from the SMARCA4 gene, which method comprises contacting the protein with an effective amount of a compound according to any one of claims 1-3. 40. A method for modulating or degrading protein which is expressed from the SMARCA2 gene in a subject, which method comprises administering to said subject an effective amount of a compound according to any one of claims 1-3. 41. A method for modulating or degrading protein which is expressed from the SMARCA4 gene in a subject, which method comprises administering to said subject an effective amount of a compound according to any one of claims 1-3. 42. A method for modulating or degrading protein which is expressed from the SMARCA2 gene in a subject, which method comprises administering to said subject an effective amount of a pharmaceutical composition according to claim 36. 43. A method for modulating or degrading protein which is expressed from the SMARCA4 gene in a subject, which method comprises administering to said subject an effective amount of a pharmaceutical composition according to claim 36. 44. 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 any one of claims 1-3. 45. 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 according to claim 36. 46. A method for treating hyperplasias in a subject in need thereof, which method comprises administering to said subject an effective amount of a compound according to claim 1. 47. A method for treating hyperplasias in a subject in need thereof, which method comprises administering to said subject an effective amount of a pharmaceutical composition according to claim 36. |
and L 2 is a -C(O)NH-, bond, -CH 2 -, or -(CH 2 ) 2 -, then Z is not a heterocyclyl (wherein the heterocyclyl is unsubstituted or substituted), -C 1-6 alkylene-NH 2 , or -C 1-6 alkylene-OH, and the compound is not: 2-(6-amino-5-(8-(2-(3-((2- hydroxyethyl)(methyl)amino)prop-1-yn-1-yl)pyridin-4-yl)-3,8- diazabicyclo[3.2.1]octan-3-yl)pyridazin-3-yl)phenol, 2-(6-amino-5-(8-(2-(3-(2-hydroxyethoxyprop-1-yn-1-yl)pyridin -4-yl)-3,8- diazabicyclo[3.2.1]octan-3-yl)pyridazin-3-yl)phenol, 2-(6-amino-5-(8-(2-(3-(diethylamino)prop-1-yn-1-yl)pyridin-4 -yl)-3,8-diazabicyclo[3.2.1]octan- 3-yl)pyridazin-3-yl)phenol, 2-(6-amino-5-(8-(2-(3-(piperidin-3-yloxy)prop-1-yn-1-yl)pyri din-4-yl)-3,8- diazabicyclo[3.2.1]octan-3-yl)pyridazin-3-yl)phenol, 2-(6-amino-5-(8-(2-((l-methyl-lH-pyrazol-4-yl)ethynyl)pyridi n-4-yl)-3,8- diazabicyclo[3.2.1]octan-3-yl)pyridazin-3-yl)phenol, N-[3-[4-[3-[3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-d iazabicyclo[3.2.1]octan-8-yl]-2- pyridyl]prop-2-ynyl]piperidine-4-carboxamide, 2-[6-amino-5-[8-[2-[3-(azepan-1-yl)prop-1-ynyl]pyrimidin-4-y l]-3,8-diazabicyclo[3.2.1]octan-3- yl]pyridazin-3-yl]phenol, 2-[6-amino-5-[9-[2-[3-(azepan-l-yl)prop-l-ynyl]-4-pyridyl]-3 ,9-diazaspiro[5.5]undecan-3- yl]pyridazin-3-yl]phenol, 2-[6-amino-5-[2-[2-[3-(azepan-1-yl)prop-1-ynyl]-4-pyridyl]-2 ,8-diazaspiro[4.5]decan-8- yl]pyridazin-3-yl]phenol, 2-[6-amino-5-[6-[2-[3-(azepan-1-yl)prop-1-ynyl]-4-pyridyl]-2 ,6-diazaspiro[3.3]heptan-2- yl]pyridazin-3-yl]phenol, 2-(6-amino-5-(8-(2-(((1r,4r)-4-aminocyclohexyl)ethynyl)pyrid in-4-yl)-3,8- diazabicyclo[3.2.1]octan-3-yl)pyridazin-3-yl)phenol, or 2-[6-amino-5-[8-[2-[(E)-3-(azepan-1-yl)prop1-enyl]-4-pyridyl ]-3,8-diazabicyclo[3.2.1]octan-3- yl]pyridazin-3-yl]phenol. [0079] In one embodiment, this disclosure provides a compound of formula IA: IA or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, wherein: X is hydroxy, halo, cyano, C 1-4 alkoxy, or -N(R)2; Y is N, C, or CH; Y 1 is N, C, or CH; T is -N(R)2; Ring A is C 4-8 cycloalkyl, C 6-10 aryl, 4- to 11-membered heterocycloalkyl, or 5- to 10-membered heteroaryl, wherein each heterocycloalkyl or heteroaryl have from 1 to 3 heteroatoms selected from O, N, NR, and S, and wherein each cycloalkyl, aryl, heterocycloalkyl, or heteroaryl is independently unsubstituted or substituted with one to four R 1 ; L is a bond, -CH 2 -, or -O-; L 1 is -RC=CR- or -C≡C-; L 2 is selected from: a b c) ; wherein t is 0 or 1, p is 0, 1, 2, or 3, and wherein the dashed line ( ) denotes the point of attachment from L 2 to L 1 , and the wavy line ( ) denotes the point of attachment from L 2 to Z; Z is C 1-10 alkyl, -N(R) 2 , -OH, C 1-10 alkoxy, C 3-8 cycloalkyl, 4- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl, wherein each heterocycloalkyl or heteroaryl have from 1 to 4 heteroatoms selected from NR, N, O, and S, and wherein each heterocycloalkyl or heteroaryl is independently unsubstituted or substituted with one to four R 2 , and wherein each alkyl, alkoxy, or cycloalkyl is independently unsubstituted or substituted with one to three R 3 ; each R is independently hydrogen, C 1-4 alkyl, or C 3-6 cycloalkyl, wherein each alkyl or cycloalkyl is unsubstituted or substituted with one to three R 4 ; or two R groups, when attached to the same nitrogen, form a 4- to 7-membered heterocycloalkyl, which is unsubstituted or substituted with one to four R 4 ; each R x and R y is independently hydrogen, C 1-4 alkyl, or C 1-4 haloalkyl substituted with 1 to 3 halo; or R x and R y , together with the atoms to which they are attached, form a C 3-6 cycloalkyl, which is unsubstituted or substituted with one to four R 4 ; each R 1 is independently cyano, halo, hydroxyl, nitro, oxo, -N(R)2, C 1-4 alkyl, C 1-4 haloalkyl substituted with 1 to 3 halo, C 1-4 alkoxy unsubstituted or substituted with 1 to 3 halo, C 5-6 heteroaryl having from 1 to 3 heteroatoms selected from O, N, NR, and/or S, 4- to 7-membered heterocycloalkyl having from 1 to 3 heteroatoms selected from oxygen, nitrogen, and/or sulfur, -C(O)OR, -OC(O)R, or -C(O)R; each R 2 is independently oxo, hydroxy, cyano, halo, -N(R)2, -C(O)OR, -NRC(O)OR, C 1-4 alkyl, C 1-4 haloalkyl substituted with from 1 to 3 halo groups, C 1-4 alkoxy, C 1-4 alkoxy substituted with from 1 to 3 halo groups, C 1-4 alkyl substituted with C 1-2 alkoxy, C 5-6 heteroaryl having from 1 to 3 heteroatoms selected from O, N, and NR, or C 3-6 cycloalkyl; each R 3 is independently oxo, cyano, hydroxy, halogen, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkoxy substituted with from 1 to 3 halo groups, C 1-4 haloalkyl substituted with from 1 to 3 halo groups, C1-6 aryl, C 1-4 alkyl substituted with 1 to 3 phenyl, or C 3-6 cycloalkyl; each R 4 is independently -N(R)2, cyano, halo, or hydroxyl; each R 5 is D, halo, C 1-3 haloalkyl, or C 1-4 alkoxy; each R 6 is N(R)2, SR, halo, cyano, C 1-4 alkoxy unsubstituted or substituted with 1 to 3 halo, unsubstituted C 1-4 alkyl, C 1-4 alkyl substituted with C 1-2 alkoxy, or C 1-4 alkyl substituted with hydroxy; m is 0, 1, or 2; and n is 0, 1, 2, or 3; with the proviso that the compound is not 2-[6-amino-5-[8-[2-[3-(azepan-1-yl)prop-1- ynyl]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octan-3-yl]pyrid azin-3-yl]phenol. [0080] In one embodiment, this disclosure provides a compound of formula Iʹ:
or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, wherein: X is hydroxy, halo, cyano, C 1-4 alkoxy, or -N(R) 2 ; Y is N, C, or CH; Y 1 is N, C, or CH; T is -N(R) 2 ; Ring A is C 4-8 cycloalkyl, C 6-10 aryl, 4- to 11-membered heterocycloalkyl, or 5- to 10-membered heteroaryl, wherein each heterocycloalkyl or heteroaryl have from 1 to 3 heteroatoms selected from O, N, NR, and S, and wherein each cycloalkyl, aryl, heterocycloalkyl, or heteroaryl is independently unsubstituted or substituted with one to four R 1 ; L 1 is -RC=CR- or -C≡C-; L 2 is selected from: a c wherein t is 0 or 1, p is 0, 1, 2, or 3, and wherein the dashed line ( ) denotes the point of attachment from L 2 to L 1 , and the wavy line ( ) denotes the point of attachment from L 2 to Z; Z is C 1-10 alkyl, -N(R)2, -OH, C 1-10 alkoxy, C 3-8 cycloalkyl, 4- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl, wherein each heterocycloalkyl or heteroaryl have from 1 to 4 heteroatoms selected from NR, N, O, and S, and wherein each heterocycloalkyl or heteroaryl is independently unsubstituted or substituted with one to four R 2 , and wherein each alkyl, alkoxy, or cycloalkyl is independently unsubstituted or substituted with one to three R 3 ; each R is independently hydrogen, C 1-4 alkyl, or C 3-6 cycloalkyl, wherein each alkyl or cycloalkyl is unsubstituted or substituted with one to three R 4 ; or two R groups, when attached to the same nitrogen, form a 4- to 7-membered heterocycloalkyl, which is unsubstituted or substituted with one to four R 4 ; each R x and R y is independently hydrogen, C 1-4 alkyl, or C 1-4 haloalkyl substituted with 1 to 3 halo; or R x and R y , together with the atoms to which they are attached, form a C 3-6 cycloalkyl, which is unsubstituted or substituted with one to four R 4 ; each R 1 is independently cyano, halo, hydroxyl, nitro, oxo, -N(R) 2 , C 1-4 alkyl, C 1-4 haloalkyl substituted with 1 to 3 halo, C 1-4 alkoxy unsubstituted or substituted with 1 to 3 halo, C 5-6 heteroaryl having from 1 to 3 heteroatoms selected from O, N, NR, and/or S, 4- to 7-membered heterocycloalkyl having from 1 to 3 heteroatoms selected from oxygen, nitrogen, and/or sulfur, -C(O)OR, -OC(O)R, or -C(O)R; each R 2 is independently oxo, hydroxy, cyano, halo, -N(R)2, -C(O)OR, -NRC(O)OR, C 1-4 alkyl, C 1-4 haloalkyl substituted with from 1 to 3 halo groups, C 1-4 alkoxy, C 1-4 alkoxy substituted with from 1 to 3 halo groups, C 1-4 alkyl substituted with C 1-2 alkoxy, C 5-6 heteroaryl having from 1 to 3 heteroatoms selected from O, N, and NR, or C 3-6 cycloalkyl; each R 3 is independently oxo, halogen, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkoxy substituted with from 1 to 3 halo groups, C 1-4 haloalkyl substituted with from 1 to 3 halo groups, or C 3-6 cycloalkyl; each R 4 is independently -N(R)2, cyano, halo, or hydroxyl; each R 5 is D, halo, C 1-3 haloalkyl, or C 1-4 alkoxy; each R 6 is N(R)2, SR, cyano, C 1-4 alkoxy unsubstituted or substituted with 1 to 3 halo, C 1-4 alkyl substituted with C 1-2 alkoxy, or C 1-4 alkyl substituted with hydroxy; m is 0, 1, or 2; and n is 0, 1, 2, or 3; with the proviso that the compound is not 2-[6-amino-5-[8-[2-[3-(azepan-1-yl)prop-1- ynyl]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octan-3-yl]pyrid azin-3-yl]phenol. [0081] In one embodiment, this disclosure provides a compound of formula Iʹ: Iʹ or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, wherein: X is hydroxy, halo, cyano, C 1-4 alkoxy, or -N(R) 2 ; Y is N, C, or CH; Y 1 is N, C, or CH; T is -N(R) 2 ; Ring A is C 4-8 cycloalkyl, C 6-10 aryl, 4- to 11-membered heterocycloalkyl, or 5- to 10-membered heteroaryl, wherein each heterocycloalkyl or heteroaryl have from 1 to 3 heteroatoms selected from O, N, NR, and S, and wherein each cycloalkyl, aryl, heterocycloalkyl, or heteroaryl is independently unsubstituted or substituted with one to four R 1 ; L 1 is -RC=CR- or -C≡C-; L 2 is selected from: a c wherein t is 0 or 1, p is 0, 1, 2, or 3, and wherein the dashed line ( ) denotes the point of attachment from L 2 to L 1 , and the wavy line ( ) denotes the point of attachment from L 2 to Z; Z is C 1-10 alkyl, -N(R)2, -OH, C 1-10 alkoxy, C 3-8 cycloalkyl, 4- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl, wherein each heterocycloalkyl or heteroaryl have from 1 to 4 heteroatoms selected from NR, N, O, and S, and wherein each heterocycloalkyl or heteroaryl is independently unsubstituted or substituted with one to four R 2 , and wherein each alkyl, alkoxy, or cycloalkyl is independently unsubstituted or substituted with one to three R 3 ; each R is independently hydrogen, C 1-4 alkyl, or C 3-6 cycloalkyl, wherein each alkyl or cycloalkyl is unsubstituted or substituted with one to three R 4 ; or two R groups, when attached to the same nitrogen, form a 4- to 7-membered heterocycloalkyl, which is unsubstituted or substituted with one to four R 4 ; each R x and R y is independently hydrogen, C 1-4 alkyl, or C 1-4 haloalkyl substituted with 1 to 3 halo; or R x and R y , together with the atoms to which they are attached, form a C 3-6 cycloalkyl, which is unsubstituted or substituted with one to four R 4 ; each R 1 is independently cyano, halo, hydroxyl, nitro, oxo, -N(R) 2 , C 1-4 alkyl, C 1-4 haloalkyl substituted with 1 to 3 halo, C 1-4 alkoxy unsubstituted or substituted with 1 to 3 halo, C 5-6 heteroaryl having from 1 to 3 heteroatoms selected from O, N, NR, and/or S, 4- to 7-membered heterocycloalkyl having from 1 to 3 heteroatoms selected from oxygen, nitrogen, and/or sulfur, -C(O)OR, -OC(O)R, or -C(O)R; each R 2 is independently oxo, hydroxy, cyano, halo, -N(R) 2 , -C(O)OR, -NRC(O)OR, C 1-4 alkyl, C 1-4 haloalkyl substituted with from 1 to 3 halo groups, C 1-4 alkoxy, C 1-4 alkoxy substituted with from 1 to 3 halo groups, C 1-4 alkyl substituted with C 1-2 alkoxy, C 5-6 heteroaryl having from 1 to 3 heteroatoms selected from O, N, and NR, or C 3-6 cycloalkyl; each R 3 is independently oxo, halogen, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkoxy substituted with from 1 to 3 halo groups, C 1-4 haloalkyl substituted with from 1 to 3 halo groups, or C 3-6 cycloalkyl; each R 4 is independently -N(R)2, cyano, halo, or hydroxyl; each R 5 is D, halo, C 1-3 haloalkyl, or C 1-4 alkoxy; each R 6 is N(R)2, SR, cyano, C 1-4 alkoxy unsubstituted or substituted with 1 to 3 halo, C 1-4 alkyl substituted with C 1-2 alkoxy, or C 1-4 alkyl substituted with hydroxy; m is 0, 1, or 2; and n is 0, 1, 2, or 3. [0082] In some embodiments, provided is a compound of Formula I represented by Formula II: , or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, wherein L, L 2 , m, n, R 5 , R 6 , T, X, Y, Y 1 , X 1 , X 2 , Z, and Ring A are each independently as defined herein. [0083] In some embodiments, provided is a compound of Formula II represented by Formula II-1: II-1, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, wherein L, L 2 , m, n, R 5 , R 6 , T, X, Y, Y 1 , Z, and Ring A are each independently as defined herein. [0084] In some embodiments, provided is a compound of Formula II represented by Formula II-2: or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, wherein L, L 2 , m, n, R 5 , R 6 , T, X, Y, Y 1 , Z, and Ring A are each independently as defined herein. [0085] In some embodiments, provided is a compound of Formula II represented by Formula II-3: , or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, wherein L, L 2 , m, n, R 5 , R 6 , T, X, Y, Y 1 , Z, and Ring A are each independently as defined herein. [0086] In some embodiments, provided is a compound of Formula I represented by Formula IIa: , or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, wherein L, m, n, p, R, R x , R y , R 5 , R 6 , T, X, Y, Y 1 , X 1 , X 2 , Z, and Ring A are each independently as defined herein. [0087] In some embodiments, provided is a compound of Formula I represented by Formula IIb:
or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, wherein L, m, n, p, R, R x , R y , R 5 , R 6 , T, X, Y, Y 1 , X 1 , X 2 , Z, and Ring A are each independently as defined herein. [0088] In some embodiments, provided is a compound of Formula I represented by Formula IIc: , or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, wherein L, m, n, p, R x , R y , R 5 , R 6 , T, X, Y, Y 1 , X 1 , X 2 , Z, and Ring A are each independently as defined herein. [0089] In some embodiments, provided is a compound of Formula IIc represented by Formula IIc-1: , or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, wherein L, m, n, p, R x , R y , R 5 , R 6 , T, X, Y, Y 1 , Z, and Ring A are each independently as defined herein. [0090] In some embodiments, provided is a compound of Formula IIc represented by Formula IIc-2:
or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, wherein L, m, n, p, R x , R y , R 5 , R 6 , T, X, Y, Y 1 , Z, and Ring A are each independently as defined herein. [0091] In some embodiments, provided is a compound of Formula IIc represented by Formula IIc-3: , or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, wherein L, m, n, p, R x , R y , R 5 , R 6 , T, X, Y, Y 1 , Z, and Ring A are each independently as defined herein. [0092] In some embodiments, provided is a compound of Formula I represented by Formula III-E: , or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, wherein L, L 1 , m, n, R 5 , R 6 , T, X, Y, Y 1 , X 1 , X 2 , Z, and Ring A are each independently as defined herein. [0093] In some embodiments, provided is a compound of Formula I represented by Formula IIIb-E: IIIb-E, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, wherein L, m, n, p, R x , R y , R 5 , R 6 , T, X, Y, Y 1 , X 1 , X 2 , Z, and Ring A are each independently as defined herein. [0094] In some embodiments, provided is a compound of Formula Iʹ represented by Formula IIʹ: or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, wherein L 2 , m, n, R 5 , R 6 , T, X, Y, Y 1 , Z, and Ring A are each independently as defined herein. [0095] In some embodiments, the compound of Formula IIʹ is represented by Formula IIaʹ: , or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, wherein m, n, p, R, R 5 , R 6 , R x , R y , T, X, Y, Y 1 , Z, and Ring A are each independently as defined herein. [0096] In some embodiments, the compound of Formula IIaʹ is represented by Formula IIaʹ-1:
IIaʹ-1, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, wherein m, n, R, R 5 , R 6 , T, X, Y, Y 1 , Z, and Ring A are each independently as defined herein. [0097] In some embodiments, the compound of Formula IIaʹ is represented by Formula IIaʹ-2: IIaʹ-2, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, wherein m, n, R, R 5 , R 6 , T, X, Y, Y 1 , Z, and Ring A are each independently as defined herein. [0098] In some embodiments, the compound of Formula IIʹ is represented by Formula IIbʹ: , or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, wherein m, n, p, R, R 5 , R 6 , R x , R y , T, X, Y, Y 1 , Z, and Ring A are each independently as defined herein. [0099] In some embodiments, the compound of Formula IIʹ is represented by Formula IIcʹ:
IIcʹ, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, wherein m, n, p, R 5 , R 6 , R , R y , T, X, Y, Y 1 , Z, and Ring A are each independently as defined herein. [0100] In some embodiments, the compound of Formula IIʹ is represented by Formula IIdʹ: , or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, wherein m, n, p, R 5 , R 6 , R x , R y , T, X, Y, Y 1 , Z, and Ring A are each independently as defined herein. [0101] In some embodiments, provided is a compound of Formula Iʹ represented by Formula IIIʹ-E: , or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, wherein L 2 , m, n, R 5 , R 6 , T, X, Y, Y 1 , Z, and Ring A are each independently as defined herein. [0102] In some embodiments, the compound of Formula IIIʹ-E is represented by Formula IIIaʹ-E: IIIaʹ-E, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, wherein m, n, p, R, R 5 , R 6 , R x , R y , T, X, Y, Y 1 , Z, and Ring A are each independently as defined herein. [0103] In some embodiments, the compound of Formula IIIʹ-E is represented by Formula IIIbʹ-E: IIIbʹ-E, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, wherein m, n, p, R 5 , R 6 , R x , R y , T, X, Y, Y 1 , Z, and Ring A are each independently as defined herein. [0104] In some embodiments, provided is a compound of Formula Iʹ represented by Formula IIIʹ-Z: IIIʹ-Z, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, wherein L 2 , m, n, R 5 , R 6 , T, X, Y, Y 1 , Z, and Ring A are each independently as defined herein. [0105] In some embodiments, the compound of Formula IIIʹ-Z is represented by Formula IIIaʹ-Z: IIIaʹ-Z, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, wherein m, n, p, R, R 5 , R 6 , R x , R y , T, X, Y, Y 1 , Z, and Ring A are each independently as defined herein. [0106] In some embodiments, the compound of Formula IIIʹ-Z is represented by Formula IIIbʹ-Z: IIIbʹ-Z, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, wherein m, n, p, R 5 , R 6 , R x , R y , T, X, Y, Y 1 , Z, and Ring A are each independently as defined herein. [0107] In some embodiments of compounds of Formula I or Formula Iʹ, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, is a monocyclic nitrogen-containing 4- to 1 , , , wherein the dashed line ( ) denotes the point of attachment from Ring A to pyrimidine, and the wavy line ( ) denotes the point of attachment from Ring A to L or pyridazine, and wherein each Ring A is independently unsubstituted or substituted with one to four R 1 , wherein each R 1 is independently halo or C 1-4 alkyl. [0108] In some embodiments of compounds of Formula I, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, is a monocyclic nitrogen-containing 4- to 11-membered heterocycloalkyl. In some embodiments, is selected from and wherein the dashed line ( ) denotes the point of attachment from Ring A to pyrimidine, and the wavy line ( ) denotes the point of attachment from Ring A to pyridazine, and wherein each Ring A is independently unsubstituted or substituted with one to four R 1 , wherein each R 1 is independently halo or C 1-4 alkyl. [0109] In some embodiments of compounds of Formula I or Formula Iʹ, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, is a fused-bicyclic nitrogen-containing 4- t , , , , , wherein the dashed line ( ) denotes the point of attachment from Ring A to pyrimidine, and the wavy line ( ) denotes the point of attachment from Ring A to L or pyridazine, and wherein each Ring A is independently unsubstituted or substituted with one to four R 1 , wherein each R 1 is independently halo or C 1-4 alkyl. [0110] In some embodiments of compounds of Formula I, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, is a fused-bicyclic nitrogen-containing 4- to 11- membered heterocycloalkyl. In some embodiments, is selected from , , wherein the dashed line ( ) denotes the point of attachment from Ring A to pyrimidine, and the wavy line ( ) denotes the point of attachment from Ring A to pyridazine, and wherein each Ring A is independently unsubstituted or substituted with one to four R 1 , wherein each R 1 is independently halo or C 1-4 alkyl. [0111] In some embodiments of compounds of Formula I or Formula Iʹ, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, is a spirocyclic nitrogen-containing 4- to 1 , , , , , ; wherein the dashed line ( ) denotes the point of attachment from Ring A to pyrimidine, and the wavy line ( ) denotes the point of attachment from Ring A to L or pyridazine, and wherein each Ring A is independently unsubstituted or substituted with one to four R 1 , wherein each R 1 is independently halo or C 1-4 alkyl. [0112] In some embodiments of compounds of Formula I, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, is a spirocyclic nitrogen-containing 4- to 11-membered h , , , , , wherein the dashed line ( ) denotes the point of attachment from Ring A to pyrimidine, and the wavy line ( ) denotes the point of attachment from Ring A to pyridazine, and wherein each Ring A is independently unsubstituted or substituted with one to four R 1 , wherein each R 1 is independently halo or C 1-4 alkyl. [0113] In some embodiments of compounds of Formula I or Formula Iʹ, or a pharmaceutically acceptable s - , , , , , wherein the dashed line ( ) denotes the point of attachment from Ring A to pyrimidine, and the wavy line ( ) denotes the point of attachment from Ring A to L or pyridazine, and wherein each Ring A is independently unsubstituted or substituted with one to four R 1 , wherein each R 1 is independently halo or C 1-4 alkyl. [0114] In some embodiments of compounds of Formula I, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, is a bridged nitrogen-containing 4- to 11-membered h , wherein the dashed line ( ) denotes the point of attachment from Ring A to pyrimidine, and the wavy line ( ) denotes the point of attachment from Ring A to pyridazine, and wherein each Ring A is independently unsubstituted or substituted with one to four R 1 , wherein each R 1 is independently halo or C 1-4 alkyl. [0115] In some embodiments of compounds of Formula I or Formula Iʹ, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, Z is a nitrogen-containing 4- to 10-membered h , wherein each Z is independently unsubstituted or substituted with one to four R 2 , wherein each R 2 is independently oxo, hydroxy, cyano, halo, -C(O)OR, -NRC(O)OR, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl substituted with from 1 to 3 halo groups, C 5-6 heteroaryl having from 1 to 3 heteroatoms selected from O, N, and NR, or C 3-6 cycloalkyl. [0116] In some embodiments of compounds of Formula I, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, Z is a nitrogen-containing 4- to 10-membered heterocycloalkyl. In s , wherein each Z is independently unsubstituted or substituted with one to four R 2 , wherein each R 2 is independently oxo, halo, -C(O)OR, -NRC(O)OR, C 1-4 alkyl, C 1-4 haloalkyl substituted with from 1 to 3 halo groups, C 5-6 heteroaryl having from 1 to 3 heteroatoms selected from O, N, and NR, or C 3-6 cycloalkyl. [0117] In some embodiments of compounds of Formula I or Formula Iʹ, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, Z is an oxygen- and nitrogen-containing 4- to 10- , , , , , , wherein each Z is independently unsubstituted or substituted with one to four R 2 , wherein each R 2 is independently oxo, halo, -C(O)OR, -NRC(O)OR, C 1-4 alkyl, C 1-4 haloalkyl substituted with from 1 to 3 halo groups, C 5-6 heteroaryl having from 1 to 3 heteroatoms selected from O, N, and NR, or C 3-6 cycloalkyl. [0118] In some embodiments of compounds of Formula I, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, Z is an oxygen- and nitrogen-containing 4- to 10-membered heterocycloalkyl. In some embodiments, Z is selected from , , and wherein each Z is independently unsubstituted or substituted with one to four R 2 , wherein each R 2 is independently oxo, halo, -C(O)OR, -NRC(O)OR, C 1-4 alkyl, C 1-4 haloalkyl substituted with from 1 to 3 halo groups, C 5-6 heteroaryl having from 1 to 3 heteroatoms selected from O, N, and NR, or C 3-6 cycloalkyl. [0119] In some embodiments of compounds of Formula I, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, Z is a sulfur- and nitrogen-containing 4- to 10-membered heterocycloalkyl. In some embodiments, Z is ; wherein Z is independently unsubstituted or substituted with one to four R 2 , wherein each R 2 is independently oxo, halo, -C(O)OR, -NRC(O)OR, C 1-4 alkyl, C 1-4 haloalkyl substituted with from 1 to 3 halo groups, C 5-6 heteroaryl having from 1 to 3 heteroatoms selected from O, N, and NR, or C 3-6 cycloalkyl. [0120] In some embodiments of compounds of Formula I or Formula Iʹ, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, Z is an oxygen-containing 4- to 10-membered heterocycloalkyl. In some embodiments, Z is selected from , , , wherein Z is independently unsubstituted or substituted with one to four R 2 , wherein each R 2 is independently oxo, halo, -C(O)OR, -NRC(O)OR, C 1-4 alkyl, C 1-4 haloalkyl substituted with from 1 to 3 halo groups, C 5-6 heteroaryl having from 1 to 3 heteroatoms selected from O, N, and NR, or C 3-6 cycloalkyl. [0121] In some embodiments of compounds of Formula I, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, Z is an oxygen-containing 4- to 10-membered heterocycloalkyl. In some embodiments, wherein Z is independently unsubstituted or substituted with one to four R 2 , wherein each R 2 is independently oxo, halo, -C(O)OR, -NRC(O)OR, C 1-4 alkyl, C 1-4 haloalkyl substituted with from 1 to 3 halo groups, C 5-6 heteroaryl having from 1 to 3 heteroatoms selected from O, N, and NR, or C 3-6 cycloalkyl. [0122] In some embodiments of compounds of Formula I or Formula Iʹ, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, Z is a nitrogen-containing 5- to 10-membered heteroaryl. I , wherein each Z is independently unsubstituted or substituted with one to four R 2 , wherein each R 2 is independently oxo, halo, -C(O)OR, -NRC(O)OR, C 1-4 alkyl, C 1-4 haloalkyl substituted with from 1 to 3 halo groups, C 5-6 heteroaryl having from 1 to 3 heteroatoms selected from O, N, and NR, or C 3-6 cycloalkyl. [0123] In some embodiments of compounds of Formula I, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, Z is a nitrogen-containing 5- to 10-membered heteroaryl. In some embodiments, Z is selected from , , , , , , , , wherein each Z is independently unsubstituted or substituted with one to four R 2 , wherein each R 2 is independently oxo, halo, -C(O)OR, -NRC(O)OR, C 1-4 alkyl, C 1-4 haloalkyl substituted with from 1 to 3 halo groups, C 5-6 heteroaryl having from 1 to 3 heteroatoms selected from O, N, and NR, or C 3-6 cycloalkyl. [0124] In some embodiments of compounds of Formula I, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, Z is an oxygen- and nitrogen-containing 5- to 10-membered heteroaryl. I wherein each Z is independently unsubstituted or substituted with one to four R 2 , wherein each R 2 is independently oxo, halo, -C(O)OR, -NRC(O)OR, C 1-4 alkyl, C 1-4 haloalkyl substituted with from 1 to 3 halo groups, C 5-6 heteroaryl having from 1 to 3 heteroatoms selected from O, N, and NR, or C 3-6 cycloalkyl. [0125] In some embodiments of compounds of Formula I, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, Z is a sulfur- and nitrogen-containing 5- to 10-membered heteroaryl. In some embodiments, Z is selected from an ; wherein each Z is independently unsubstituted or substituted with one to four R 2 , wherein each R 2 is independently oxo, halo, -C(O)OR, -NRC(O)OR, C 1-4 alkyl, C 1-4 haloalkyl substituted with from 1 to 3 halo groups, C 5-6 heteroaryl having from 1 to 3 heteroatoms selected from O, N, and NR, or C 3-6 cycloalkyl. [0126] In some embodiments of compounds of Formula I, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, Z is an oxygen-containing 5- to 10-membered heteroaryl. In some embodiments, Z is selected from , , ; wherein each Z is independently unsubstituted or substituted with one to four R 2 , wherein each R 2 is independently oxo, halo, -C(O)OR, -NRC(O)OR, C 1-4 alkyl, C 1-4 haloalkyl substituted with from 1 to 3 halo groups, C 5-6 heteroaryl having from 1 to 3 heteroatoms selected from O, N, and NR, or C 3-6 cycloalkyl. [0127] In some embodiments of compounds of Formula I, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, Z is C 1-10 alkyl. In some embodiments of compounds of Formula I, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, Z is -N(R) 2 . In some embodiments of compounds of Formula I, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, Z is C 1-10 alkoxy. In some embodiments of compounds of Formula I, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, Z is -OH. [0128] In some embodiments, provided is a compound of Formula I, wherein X is hydroxy. [0129] In some embodiments, provided is a compound of Formula I, wherein T is -NH2. [0130] In some embodiments, provided is a compound of Formula I, wherein Y is N. In some embodiments, provided is a compound of Formula I, wherein Y 1 is N. In some embodiments, provided is a compound of Formula I, wherein both Y and Y 1 are N. [0131] In some embodiments, provided is a compound of Formula I, wherein L 2 is , wherein t is 0 or 1, p is 1, 2, or 3, and wherein the dashed line ( ) denotes the point of attachment from L 2 to L 1 , and the wavy line ( ) denotes the point of attachment from L 2 to Z. In some embodiments, provided is a compound of Formula I, wherein L 2 is , wherein the dashed line ( ) denotes the point of attachment from L 2 to L 1 , and the wavy line ( ) denotes the point of attachment from L 2 to Z. [0132] Representative and non-limiting examples of compounds within the scope of Formula I above are set forth in Table 1, where each of which include their pharmaceutically acceptable salts, solvates, hydrates, or tautomers thereof. Table 1
[0133] Also provided herein are the following compounds within the scope of Formula I, or their pharmaceutically acceptable salts, solvates, hydrates, or tautomers thereof. N-[3-(4-{4-[3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl]pipera zin-1-yl}pyrimidin-2- P-1 yl)prop-2-yn-1-yl]-5-methyl-1,2-oxazole-3-carboxamide N-[3-(4-{4-[3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl]pipera zin-1-yl}pyrimidin-2- P-2 yl)prop-2-yn-1-yl]-5-ethyl-1-methyl-1H-pyrazole-3-carboxamid e N-[3-(4-{4-[3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl]pipera zin-1-yl}pyrimidin-2- P-3 yl)prop-2-yn-1-yl]-5-methyl-1,2-oxazole-4-carboxamide N-[3-(4-{4-[3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl]pipera zin-1-yl}pyrimidin-2- P-4 yl)prop-2-yn-1-yl]pyridine-3-carboxamide N-[3-(4-{4-[3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl]pipera zin-1-yl}pyrimidin-2- P yl)prop-2-yn-1-yl]pyridazine-3-carboxamide N-[3-(4-{4-[3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl]pipera zin-1-yl}pyrimidin-2- P-6 yl)prop-2-yn-1-yl]-5-cyclopropyl-1-methyl-1H-pyrazole-3-carb oxamide N-[3-(4-{4-[3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl]pipera zin-1-yl}pyrimidin-2- P-7 yl)prop-2-yn-1-yl]-1-methyl-1H-pyrazole-3-carboxamide N-[3-(4-{4-[3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl]pipera zin-1-yl}pyrimidin-2- P-8 yl)prop-2-yn-1-yl]-1,4,5-trimethyl-1H-pyrazole-3-carboxamide N-[3-(4-{4-[3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl]pipera zin-1-yl}pyrimidin-2- P-9 yl)prop-2-yn-1-yl]-1-(2,2,2-trifluoroethyl)-1H-pyrazole-3-ca rboxamide N-[3-(4-{4-[3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl]pipera zin-1-yl}pyrimidin-2- P-10 yl)prop-2-yn-1-yl]-1-(difluoromethyl)-1H-pyrazole-3-carboxam ide N-[3-(4-{4-[3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl]pipera zin-1-yl}pyrimidin-2- P-11 yl)prop-2-yn-1-yl]-1-cyclopropyl-1H-pyrazole-3-carboxamide N-[3-(4-{4-[3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl]pipera zin-1-yl}pyrimidin-2- P-12 yl)prop-2-yn-1-yl]-1,5-dimethyl-1H-pyrazole-3-carboxamide (R)-N-(3-(4-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)-7 -methyl-1,4-diazepan-1- P-14 yl)pyrimidin-2-yl)prop-2-yn-1-yl)pyrazolo[1,5-a]pyrimidine-2 -carboxamide N-(3-(4-((3S,5S)-4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-y l)-3,5- P-16 dimethylpiperazin-1-yl)pyrimidin-2-yl)prop-2-yn-1-yl)pyrazol o[1,5-a]pyrimidine-2- carboxamide N-(3-(4-(6-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)-3,6-d iazabicyclo[3.2.1]octan- P-17 3-yl)pyrimidin-2-yl)prop-2-yn-1-yl)pyrazolo[1,5-a]pyrimidine -2-carboxamide N-(3-(4-(6-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)-2,6-d iazabicyclo[3.2.0]heptan- P-18 2-yl)pyrimidin-2-yl)prop-2-yn-1-yl)pyrazolo[1,5-a]pyrimidine -2-carboxamide N-(3-(4-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)-5-met hyl-1,4-diazepan-1- P-19 yl)pyrimidin-2-yl)prop-2-yn-1-yl)pyrazolo[1,5-a]pyrimidine-2 -carboxamide N-(3-(4-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)-2-met hyl-1,4-diazepan-1- P-20 yl)pyrimidin-2-yl)prop-2-yn-1-yl)pyrazolo[1,5-a]pyrimidine-2 -carboxamide N-(4-(4-(8-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)-3,8-d iazabicyclo[3.2.1]octan- P-22 3-yl)pyrimidin-2-yl)but-3-yn-1-yl)pyrazolo[1,5-a]pyrimidine- 2-carboxamide N-(4-(4-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)-1,4-d iazepan-1-yl)pyrimidin- P-23 2-yl)but-3-yn-1-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide N-(3-(4-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)-1,4-d iazepan-1-yl)pyrimidin- P-24 2-yl)prop-2-yn-1-yl)-N-methylpyrazolo[1,5-a]pyrimidine-2-car boxamide N-(3-(4-((1R,4R)-5-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-y l)-2,5- P-25 diazabicyclo[2.2.1]heptan-2-yl)pyrimidin-2-yl)prop-2-yn-1-yl )pyrazolo[1,5- a]pyrimidine-2-carboxamide N-(3-(4-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)-6-met hyl-1,4-diazepan-1- P-27 yl)pyrimidin-2-yl)prop-2-yn-1-yl)pyrazolo[1,5-a]pyrimidine-2 -carboxamide N-(3-(4-(5-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)-2,5-d iazabicyclo[4.1.0]heptan- P-28 2-yl)pyrimidin-2-yl)prop-2-yn-1-yl)pyrazolo[1,5-a]pyrimidine -2-carboxamide N-(3-(4-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)-3-met hyl-1,4-diazepan-1- P-29 yl)pyrimidin-2-yl)prop-2-yn-1-yl)pyrazolo[1,5-a]pyrimidine-2 -carboxamide N-(3-(4-((1S,4S)-5-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-y l)-2,5- P-30 diazabicyclo[2.2.1]heptan-2-yl)pyrimidin-2-yl)prop-2-yn-1-yl )pyrazolo[1,5- a]pyrimidine-2-carboxamide N-(3-(4-(2-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)-2,7-d iazaspiro[3.5]nonan-7- P-31 yl)pyrimidin-2-yl)prop-2-yn-1-yl)pyrazolo[1,5-a]pyrimidine-2 -carboxamide N-(3-(4-(8-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)-2,8-d iazaspiro[4.5]decan-2- P-32 yl)pyrimidin-2-yl)prop-2-yn-1-yl)pyrazolo[1,5-a]pyrimidine-2 -carboxamide N-(3-(4-(2-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)-2,9-d iazaspiro[5.5]undecan-9- P-33 yl)pyrimidin-2-yl)prop-2-yn-1-yl)pyrazolo[1,5-a]pyrimidine-2 -carboxamide N-(3-(4-(2-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)-2,8-d iazaspiro[4.5]decan-8- P-34 yl)pyrimidin-2-yl)prop-2-yn-1-yl)pyrazolo[1,5-a]pyrimidine-2 -carboxamide N-(3-(4-(9-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)-2,9-d iazaspiro[5.5]undecan-2- P-35 yl)pyrimidin-2-yl)prop-2-yn-1-yl)pyrazolo[1,5-a]pyrimidine-2 -carboxamide N-(3-(4-(5-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)hexahy dropyrrolo[3,4-b]pyrrol- P-36 1(2H)-yl)pyrimidin-2-yl)prop-2-yn-1-yl)pyrazolo[1,5-a]pyrimi dine-2-carboxamide N-(3-(4-(6-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)octahy dro-1H-pyrrolo[2,3- P-37 c]pyridin-1-yl)pyrimidin-2-yl)prop-2-yn-1-yl)pyrazolo[1,5-a] pyrimidine-2-carboxamide N-(3-(4-(1-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)octahy dro-4H-pyrrolo[3,2- P-38 b]pyridin-4-yl)pyrimidin-2-yl)prop-2-yn-1-yl)pyrazolo[1,5-a] pyrimidine-2-carboxamide N-(3-(4-(5-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)hexahy dropyrrolo[3,4-c]pyrrol- P-41 2(1H)-yl)pyrimidin-2-yl)prop-2-yn-1-yl)pyrazolo[1,5-a]pyrimi dine-2-carboxamide N-(3-(4-(9-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)-3,9-d iazaspiro[5.5]undecan-3- P-42 yl)pyrimidin-2-yl)prop-2-yn-1-yl)pyrazolo[1,5-a]pyrimidine-2 -carboxamide N-(3-(4-(3-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)-3,6-d iazabicyclo[3.2.0]heptan- P-43 6-yl)pyrimidin-2-yl)prop-2-yn-1-yl)pyrazolo[1,5-a]pyrimidine -2-carboxamide N-(3-(4-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)-6-flu oro-1,4-diazepan-1- P-44 yl)pyrimidin-2-yl)prop-2-yn-1-yl)pyrazolo[1,5-a]pyrimidine-2 -carboxamide N-(3-(4-(6-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)-3,6-d iazabicyclo[3.2.0]heptan- P-45 3-yl)pyrimidin-2-yl)prop-2-yn-1-yl)pyrazolo[1,5-a]pyrimidine -2-carboxamide N-(3-(4-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)-7-met hyl-1,4-diazepan-1- P-46 yl)pyrimidin-2-yl)prop-2-yn-1-yl)pyrazolo[1,5-a]pyrimidine-2 -carboxamide N-(3-(4-((1R,5R)-2-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-y l)-2,6- P-47 diazabicyclo[3.2.0]heptan-6-yl)pyrimidin-2-yl)prop-2-yn-1-yl )pyrazolo[1,5- a]pyrimidine-2-carboxamide (S)-N-(3-(4-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)-3 -methylpiperazin-1- P-48 yl)pyrimidin-2-yl)prop-2-yn-1-yl)pyrazolo[1,5-a]pyrimidine-2 -carboxamide (R)-N-(3-(4-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)-3 -methylpiperazin-1- P-49 yl)pyrimidin-2-yl)prop-2-yn-1-yl)pyrazolo[1,5-a]pyrimidine-2 -carboxamide (R)-N-(3-(4-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)-2 -methylpiperazin-1- P-50 yl)pyrimidin-2-yl)prop-2-yn-1-yl)pyrazolo[1,5-a]pyrimidine-2 -carboxamide N-(3-(4-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)-3-eth ylpiperazin-1- P-51 yl)pyrimidin-2-yl)prop-2-yn-1-yl)pyrazolo[1,5-a]pyrimidine-2 -carboxamide N-(3-(4-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)pipera zin-1-yl)pyrimidin-2- P-52 yl)prop-2-yn-1-yl)-6-fluorobenzofuran-2-carboxamide N-(3-(4-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)pipera zin-1-yl)pyrimidin-2- P-53 yl)prop-2-yn-1-yl)-6-fluorobenzofuran-2-carboxamide N-(3-(4-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)pipera zin-1-yl)pyrimidin-2- P-54 yl)prop-2-yn-1-yl)benzo[d]isoxazole-3-carboxamide N-(3-(4-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)pipera zin-1-yl)pyrimidin-2- P-55 yl)prop-2-yn-1-yl)benzofuran-3-carboxamide N-(3-(4-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)pipera zin-1-yl)pyrimidin-2- P-56 yl)prop-2-yn-1-yl)isonicotinamide N-(3-(4-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)pipera zin-1-yl)pyrimidin-2- P-60 yl)prop-2-yn-1-yl)imidazo[1,2-a]pyrazine-2-carboxamide N-(3-(4-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)pipera zin-1-yl)pyrimidin-2- P-62 yl)prop-2-yn-1-yl)-4-methylthiazole-5-carboxamide N-(3-(4-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)pipera zin-1-yl)pyrimidin-2- P-63 yl)prop-2-yn-1-yl)benzofuran-7-carboxamide N-(3-(4-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)pipera zin-1-yl)pyrimidin-2- P-64 yl)prop-2-yn-1-yl)quinoline-2-carboxamide N-(3-(4-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)pipera zin-1-yl)pyrimidin-2- P-65 yl)prop-2-yn-1-yl)pyrazolo[1,5-a]pyridine-3-carboxamide N-(3-(4-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)pipera zin-1-yl)pyrimidin-2- P-66 yl)prop-2-yn-1-yl)imidazo[1,2-a]pyridine-3-carboxamide N-(3-(4-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)pipera zin-1-yl)pyrimidin-2- P-67 yl)prop-2-yn-1-yl)-1-methyl-1H-imidazole-4-carboxamide N-(3-(4-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)pipera zin-1-yl)pyrimidin-2- P-68 yl)prop-2-yn-1-yl)acetamide N-(3-(4-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)pipera zin-1-yl)pyrimidin-2- P-70 yl)prop-2-yn-1-yl)-5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-c arboxamide N-(3-(4-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)pipera zin-1-yl)pyrimidin-2- P-71 yl)prop-2-yn-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide N-(3-(4-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)pipera zin-1-yl)pyrimidin-2- P-72 yl)prop-2-yn-1-yl)quinoxaline-2-carboxamide N-(3-(4-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)pipera zin-1-yl)pyrimidin-2- P-73 yl)prop-2-yn-1-yl)-1H-indole-2-carboxamide N-(3-(4-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)pipera zin-1-yl)pyrimidin-2- P-74 yl)prop-2-yn-1-yl)-3-methylbenzofuran-2-carboxamide N-(3-(4-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)pipera zin-1-yl)pyrimidin-2- P-75 yl)prop-2-yn-1-yl)benzofuran-2-carboxamide N-(3-(4-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)-1,4-d iazepan-1-yl)pyrimidin- P-76 2-yl)prop-2-yn-1-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide N-(3-(4-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)hexahy dropyrrolo[3,2-b]pyrrol- P-77 1(2H)-yl)pyrimidin-2-yl)prop-2-yn-1-yl)pyrazolo[1,5-a]pyrimi dine-2-carboxamide N-(3-(4-(8-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)-3,8-d iazabicyclo[3.2.1]octan- P-78 3-yl)pyrimidin-2-yl)prop-2-yn-1-yl)pyrazolo[1,5-a]pyrimidine -2-carboxamide N-(3-(4-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)octahy dro-1H-pyrrolo[3,2- P-79 b]pyridin-1-yl)pyrimidin-2-yl)prop-2-yn-1-yl)pyrazolo[1,5-a] pyrimidine-2-carboxamide N-(3-(4-(6-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)-3,6-d iazabicyclo[3.1.1]heptan- P-80 3-yl)pyrimidin-2-yl)prop-2-yn-1-yl)pyrazolo[1,5-a]pyrimidine -2-carboxamide (R)-N-(3-(4-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)-2 -methylpiperazin-1- P-81 yl)pyrimidin-2-yl)prop-2-yn-1-yl)pyrazolo[1,5-a]pyrimidine-2 -carboxamide N-(3-(4-((3R,5R)-4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-y l)-3,5- P-82 dimethylpiperazin-1-yl)pyrimidin-2-yl)prop-2-yn-1-yl)pyrazol o[1,5-a]pyrimidine-2- carboxamide N-(3-(4-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)-3,3-d imethylpiperazin-1- P-83 yl)pyrimidin-2-yl)prop-2-yn-1-yl)pyrazolo[1,5-a]pyrimidine-2 -carboxamide N-(5-(4-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)pipera zin-1-yl)pyrimidin-2- P-92 yl)pent-4-yn-1-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide N-(3-(4-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)pipera zin-1-yl)pyrimidin-2- P-93 yl)prop-2-yn-1-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide N-(4-(4-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)pipera zin-1-yl)pyrimidin-2- P-94 yl)but-3-yn-1-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide N-(4-(4-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)pipera zin-1-yl)pyrimidin-2- P-95 yl)but-3-yn-2-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide N-(4-(4-(3-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)-3,8-d iazabicyclo[3.2.1]octan- P-96 8-yl)pyrimidin-2-yl)but-3-yn-1-yl)pyrazolo[1,5-a]pyrimidine- 2-carboxamide N-(4-(4-(3-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)-3,8-d iazabicyclo[3.2.1]octan- P-97 8-yl)pyrimidin-2-yl)but-3-yn-2-yl)pyrazolo[1,5-a]pyrimidine- 2-carboxamide N-(1-((4-(3-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)-3,8- diazabicyclo[3.2.1]octan- P-98 8-yl)pyrimidin-2-yl)ethynyl)cyclopropyl)pyrazolo[1,5-a]pyrim idine-2-carboxamide N-(5-(4-(3-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)-3,8-d iazabicyclo[3.2.1]octan- P-99 8-yl)pyrimidin-2-yl)pent-4-yn-1-yl)pyrazolo[1,5-a]pyrimidine -2-carboxamide (S)-N-(3-(4-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)-7 -methyl-1,4-diazepan-1- P-101 yl)pyrimidin-2-yl)prop-2-yn-1-yl)quinoxaline-2-carboxamide (S)-N-(3-(4-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)-7 -methyl-1,4-diazepan-1- P-102 yl)pyrimidin-2-yl)prop-2-yn-1-yl)pyrazolo[1,5-a]pyrimidine-2 -carboxamide 2-(6-amino-5-(4-(2-(3-(3,5-diisopropyl-1H-pyrazol-1-yl)prop- 1-yn-1-yl)pyrimidin-4-yl)- P-104 1,4-diazepan-1-yl)pyridazin-3-yl)phenol 2-(6-amino-5-(8-(2-(3-(oxazol-2-ylamino)prop-1-yn-1-yl)pyrim idin-4-yl)-3,8- P-106 diazabicyclo[3.2.1]octan-3-yl)pyridazin-3-yl)phenol 2-(6-amino-5-(4-(2-(3-(benzo[d]oxazol-2-yl(methyl)amino)prop -1-yn-1-yl)pyrimidin-4- P-107 yl)-1,4-diazepan-1-yl)pyridazin-3-yl)phenol 2-(6-amino-5-(4-(2-(3-((1-methyl-1H-pyrazol-3-yl)oxy)prop-1- yn-1-yl)pyrimidin-4-yl)- P-108 1,4-diazepan-1-yl)pyridazin-3-yl)phenol (E)-N-(3-(4-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)-1 ,4-diazepan-1- P-110 yl)pyrimidin-2-yl)allyl)quinoxaline-2-carboxamide (E)-N-(3-(4-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)-1 ,4-diazepan-1- P-111 yl)pyrimidin-2-yl)allyl)-1,4,5-trimethyl-1H-pyrazole-3-carbo xamide (E)-N-(3-(4-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)-1 ,4-diazepan-1- P-112 yl)pyrimidin-2-yl)allyl)pyrazolo[1,5-a]pyrimidine-2-carboxam ide (E)-2-(6-amino-5-(4-(2-(3-aminoprop-1-en-1-yl)pyrimidin-4-yl )-1,4-diazepan-1- P-113 yl)pyridazin-3-yl)phenol tert-butyl (E)-(3-(4-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)-1,4 -diazepan-1- P-114 yl)pyrimidin-2-yl)allyl)carbamate 2-(5-(4-(2-(3-(1H-pyrazolo[3,4-c]pyridin-1-yl)prop-1-yn-1-yl )pyrimidin-4-yl)-1,4- P-116 diazepan-1-yl)-6-aminopyridazin-3-yl)phenol N-(3-(4-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)pipera zin-1-yl)pyrimidin-2- P-117 yl)prop-2-yn-1-yl)-4-fluoropyrazolo[1,5-a]pyridine-3-carboxa mide N-(3-(4-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)pipera zin-1-yl)pyrimidin-2- P-118 yl)prop-2-yn-1-yl)benzo[d]thiazole-2-carboxamide N-(3-(4-(3-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)-3,8-d iazabicyclo[3.2.1]octan- P-119 8-yl)pyrimidin-2-yl)prop-2-yn-1-yl)pyrazolo[1,5-a]pyrimidine -2-carboxamide tert-butyl (3-(4-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)-1,4-dia zepan-1- P-121 yl)pyrimidin-2-yl)prop-2-yn-1-yl)carbamate N-(3-(4-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)-1,4-d iazepan-1-yl)pyrimidin- P-122 2-yl)prop-2-yn-1-yl)acetamide N-(3-(4-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)-1,4-d iazepan-1-yl)-6- P-124 ethoxypyrimidin-2-yl)prop-2-yn-1-yl)pyrazolo[1,5-a]pyrimidin e-2-carboxamide N-(3-(4-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)-1,4-d iazepan-1-yl)-6- P-126 (methoxymethyl)pyrimidin-2-yl)prop-2-yn-1-yl)-1,4,5-trimethy l-1H-pyrazole-3- carboxamide N-(3-(4-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)-1,4-d iazepan-1-yl)-6- P-127 (methoxymethyl)pyrimidin-2-yl)prop-2-yn-1-yl)pyrazolo[1,5-a] pyrimidine-2- carboxamide 2-(6-amino-5-(4-(2-(3-(oxazol-2-yloxy)prop-1-yn-1-yl)pyrimid in-4-yl)-1,4-diazepan-1- P-128 yl)pyridazin-3-yl)phenol 2-(6-amino-5-(4-(2-(3-((1-methyl-1H-pyrazol-5-yl)oxy)prop-1- yn-1-yl)pyrimidin-4-yl)- P-131 1,4-diazepan-1-yl)pyridazin-3-yl)phenol 2-(5-(8-(2-(3-(1H-benzo[d][1,2,3]triazol-1-yl)prop-1-yn-1-yl )pyrimidin-4-yl)-3,8- P-132 diazabicyclo[3.2.1]octan-3-yl)-6-aminopyridazin-3-yl)phenol 2-(5-(8-(2-(3-(1H-pyrazol-1-yl)prop-1-yn-1-yl)pyrimidin-4-yl )-3,8- P-133 diazabicyclo[3.2.1]octan-3-yl)-6-aminopyridazin-3-yl)phenol 2-(6-amino-5-(4-(2-(3-(3-(pyridin-2-yl)-1H-pyrazol-1-yl)prop -1-yn-1-yl)pyrimidin-4-yl)- P-138 1,4-diazepan-1-yl)pyridazin-3-yl)phenol N-(3-(4-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)-1,4-d iazepan-1-yl)-6- P-139 (dimethylamino)pyrimidin-2-yl)prop-2-yn-1-yl)pyrazolo[1,5-a] pyrimidine-2- carboxamide N-(3-(4-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)-1,4-d iazepan-1-yl)-6- P-140 (dimethylamino)pyrimidin-2-yl)prop-2-yn-1-yl)-1,4,5-trimethy l-1H-pyrazole-3- carboxamide N-(3-(4-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)-1,4-d iazepan-1-yl)-6- P-141 (methylamino)pyrimidin-2-yl)prop-2-yn-1-yl)-1,4,5-trimethyl- 1H-pyrazole-3- carboxamide tert-butyl (1-(3-(4-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)-1,4- diazepan-1- P-142 yl)pyrimidin-2-yl)prop-2-yn-1-yl)piperidin-4-yl)carbamate tert-butyl 4-(3-(4-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)-1,4-d iazepan-1- P-143 yl)pyrimidin-2-yl)prop-2-yn-1-yl)piperazine-1-carboxylate 2-(5-(4-(2-(3-(1H-1,2,3-triazol-1-yl)prop-1-yn-1-yl)pyrimidi n-4-yl)-1,4-diazepan-1-yl)- P-144 6-aminopyridazin-3-yl)phenol 2-(5-(4-(2-(3-(1H-imidazol-1-yl)prop-1-yn-1-yl)pyrimidin-4-y l)-1,4-diazepan-1-yl)-6- P-145 aminopyridazin-3-yl)phenol 2-(5-(4-(2-(3-(1H-1,2,4-triazol-1-yl)prop-1-yn-1-yl)pyrimidi n-4-yl)-1,4-diazepan-1-yl)- P-148 6-aminopyridazin-3-yl)phenol 2-(5-(4-(2-(3-(1H-pyrazol-1-yl)prop-1-yn-1-yl)pyrimidin-4-yl )-1,4-diazepan-1-yl)-6- P-149 aminopyridazin-3-yl)phenol 2-(5-(4-(2-(3-(1H-benzo[d]imidazol-1-yl)prop-1-yn-1-yl)pyrim idin-4-yl)-1,4-diazepan- P-150 1-yl)-6-aminopyridazin-3-yl)phenol 2-(5-(4-(2-(3-(1H-indol-1-yl)prop-1-yn-1-yl)pyrimidin-4-yl)- 1,4-diazepan-1-yl)-6- P-151 aminopyridazin-3-yl)phenol [0134] Representative and non-limiting examples of compounds within the scope of Formula I or Formula Iʹ above are set forth in Table 1A, where each of which include their pharmaceutically acceptable salts, solvates, hydrates, or tautomers thereof. Table 1A
[0135] Representative and non-limiting examples of compounds within the scope of Formula I or Formula Iʹ above are set forth in Table 2, where each of which include their pharmaceutically acceptable salts, solvates, hydrates, or tautomers thereof. Table 2
HO H 2 N N N N N N N H 2 N HO H 2 N N N N N N N H 2 N
[0136] In some embodiments, this disclosure provides for a method for modulating or degrading protein which is expressed from the SMARCA2 gene, which method comprises contacting the protein with an effective amount of a compound of Formula I, IA, II, II-1, II-2, II-3, IIa, IIb, IIc, IIc-1, IIc-2, IIc-3, III-E, IIIb-E, Iʹ, IIʹ, IIaʹ, IIaʹ-1, IIaʹ-2, IIbʹ, IIcʹ, IIdʹ, IIIʹ-E, IIIaʹ-E, IIIbʹ-E, IIIʹ-Z, IIIaʹ-Z, or IIIbʹ-Z, under conditions wherein the protein which is expressed from the SMARCA2 gene is modulated or degraded. [0137] In some embodiments, this disclosure provides for a method for modulating or degrading protein which is expressed from the SMARCA4 gene, which method comprises contacting the protein with an effective amount of a compound of Formula I, IA, II, II-1, II-2, II-3, IIa, IIb, IIc, IIc-1, IIc-2, IIc-3, III-E, IIIb-E, Iʹ, IIʹ, IIaʹ, IIaʹ-1, IIaʹ-2, IIbʹ, IIcʹ, IIdʹ, IIIʹ-E, IIIaʹ-E, IIIbʹ-E, IIIʹ-Z, IIIaʹ-Z, or IIIbʹ-Z, under conditions wherein the protein which is expressed from the SMARCA4 gene is modulated or degraded. [0138] In some embodiments, there is provided a method to modulate or degrade protein which is expressed from the SMARCA2 gene in a subject, which method comprises administering to said subject an effective amount of a compound of formula I, IA, II, II-1, II-2, II-3, IIa, IIb, IIc, IIc-1, IIc-2, IIc-3, III- E, IIIb-E, Iʹ, IIʹ, IIaʹ, IIaʹ-1, IIaʹ-2, IIbʹ, IIcʹ, IIdʹ, IIIʹ-E, IIIaʹ-E, IIIbʹ-E, IIIʹ-Z, IIIaʹ-Z, or IIIbʹ-Z, or a pharmaceutical composition comprising a pharmaceutically acceptable excipient and an effective amount of a compound of formula I, IA, II, II-1, II-2, II-3, IIa, IIb, IIc, IIc-1, IIc-2, IIc-3, III-E, IIIb-E, Iʹ, IIʹ, IIaʹ, IIaʹ-1, IIaʹ-2, IIbʹ, IIcʹ, IIdʹ, IIIʹ-E, IIIaʹ-E, IIIbʹ-E, IIIʹ-Z, IIIaʹ-Z, or IIIbʹ-Z. [0139] In some embodiments, there is provided a method to modulate or degrade protein which is expressed from the SMARCA4 gene in a subject, which method comprises administering to said subject an effective amount of a compound of formula I, IA, II, II-1, II-2, II-3, IIa, IIb, IIc, IIc-1, IIc-2, IIc-3, III- E, IIIb-E, Iʹ, IIʹ, IIaʹ, IIaʹ-1, IIaʹ-2, IIbʹ, IIcʹ, IIdʹ, IIIʹ-E, IIIaʹ-E, IIIbʹ-E, IIIʹ-Z, IIIaʹ-Z, or IIIbʹ-Z, or a pharmaceutical composition comprising a pharmaceutically acceptable excipient and an effective amount of a compound of formula I, IA, II, II-1, II-2, II-3, IIa, IIb, IIc, IIc-1, IIc-2, IIc-3, III-E, IIIb-E, Iʹ, IIʹ, IIaʹ, IIaʹ-1, IIaʹ-2, IIbʹ, IIcʹ, IIdʹ, IIIʹ-E, IIIaʹ-E, IIIbʹ-E, IIIʹ-Z, IIIaʹ-Z, or IIIbʹ-Z. [0140] In some embodiments, there is provided a method for treating cancer in a subject in need thereof, which method comprises selecting a subject whose cancer is mediated at least in part by SMARCA2 and administering to said subject an effective amount of a compound of formula I, IA, II, II-1, II-2, II-3, IIa, IIb, IIc, IIc-1, IIc-2, IIc-3, III-E, IIIb-E, Iʹ, IIʹ, IIaʹ, IIaʹ-1, IIaʹ-2, IIbʹ, IIcʹ, IIdʹ, IIIʹ-E, IIIaʹ-E, IIIbʹ-E, IIIʹ-Z, IIIaʹ-Z, or IIIbʹ-Z, or an effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable excipient and an effective amount of a compound of formula I, IA, II, II-1, II-2, II-3, IIa, IIb, IIc, IIc-1, IIc-2, IIc-3, III-E, IIIb-E, Iʹ, IIʹ, IIaʹ, IIaʹ-1, IIaʹ-2, IIbʹ, IIcʹ, IIdʹ, IIIʹ-E, IIIaʹ-E, IIIbʹ-E, IIIʹ-Z, IIIaʹ-Z, or IIIbʹ-Z. [0141] In some embodiments, there is provided a method for treating cancer in a subject in need thereof, which method comprises selecting a subject whose cancer is mediated at least in part by SMARCA4 and administering to said subject an effective amount of a compound of formula I, IA, II, II-1, II-2, II-3, IIa, IIb, IIc, IIc-1, IIc-2, IIc-3, III-E, IIIb-E, Iʹ, IIʹ, IIaʹ, IIaʹ-1, IIaʹ-2, IIbʹ, IIcʹ, IIdʹ, IIIʹ-E, IIIaʹ-E, IIIbʹ-E, IIIʹ-Z, IIIaʹ-Z, or IIIbʹ-Z, or an effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable excipient and an effective amount of a compound of formula I, IA, II, II-1, II-2, II-3, IIa, IIb, IIc, IIc-1, IIc-2, IIc-3, III-E, IIIb-E, Iʹ, IIʹ, IIaʹ, IIaʹ-1, IIaʹ-2, IIbʹ, IIcʹ, IIdʹ, IIIʹ-E, IIIaʹ-E, IIIbʹ-E, IIIʹ-Z, IIIaʹ-Z, or IIIbʹ-Z. General Synthetic Methods [0142] 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 (i.e., 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. [0143] 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. [0144] 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, 8 th Edition, 2019), and Larock’s Comprehensive Organic Transformations (VCH Publishers Inc., 1989). Synthesis of Representative Compounds [0145] The general synthesis of the compounds described herein is set forth in the reaction schemes below. Schemes 1, 2, 3, 4, 5, and 6 illustrate general methods for preparing compounds of formula I and Iʹ. In Schemes 1, 2, 3, 4, 5, and 6, substituents L, L 1 , L 2 , m, n, R 5 , R 6 , T, X, Y, Y 1 , X 1 , X 2 , Z, and Ring A are as defined throughout the specification. PG is a protecting group (including, but not limited to, Boc and the like). LG is a suitable coupling partner (including, but not limited to, hydrogen when undertaking a Sonogashira coupling, boronic acid or ester when undertaking a Suzuki coupling, and the like). Scheme 1 [0146] In some embodiments, compounds of formula Iʹ and sub-formulae thereof are prepared as shown in Scheme 1. In Scheme 1, the first step is a conventional SN AR reaction, wherein at least a stoichiometric amount of a protected Ring A, compound 2, is combined with compound 1 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 3. [0147] In the next step, a conventional Suzuki coupling reaction is performed, wherein at least a stoichiometric amount of aryl boronic acid, compound 4, is combined with compound 3, 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 5. [0148] In the next step, the protecting group, such as t-butoxycarbonyl (t-BOC), is removed under conventional conditions, depending on the specific protecting group employed. The t-BOC group is illustrative only, and other conventional amino protecting groups, such as benzyl, 9- fluorenylmethoxycarbonyl (Fmoc), benzyloxycarbonyl (Cbz), p-nitrobenzyloxycarbonyl, and the like could be employed. 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. [0149] In the next step, a conventional SNAR reaction is performed, wherein at least a stoichiometric amount of the deprotected product from the previous step is combined 2,4-dibromopyrimidine, compound 6, 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 7. [0150] In the final step, a conventional coupling reaction, including, but not limited to, a Sonogashira coupling, a Suzuki coupling, and the like, is performed, wherein at least a stoichiometric amount of a suitable coupling partner, compound 8, is combined with compound 7 under conventional coupling reaction conditions well known in the art, including the use of a palladium catalyst (e.g., palladium(II) bis(triphenylphosphine) dichloride, palladium diacetate, and the like), a co-catalyst (e.g., copper (I) iodide and the like), and typically in the presence of a suitable base (e.g., diisopropylethylamine, triethylamine, pyridine, cesium carbonate, and the like). The coupling reaction is typically conducted in an inert solvent, such as toluene, N,N-dimethylformamide, tetrahydrofuran, dioxane, dimethoxyethane, and the like. The reaction is typically conducted at from about 10 C to about 110 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 Iʹ. Scheme 2 [0151] In some embodiments, compounds of formula Iʹ and sub-formulae thereof are prepared as shown in Scheme 2. In Scheme 2, the first step is a conventional Sonogashira coupling reaction employing at least a stoichiometric amount of protected propargyl amine, compound 9, combined with compound 7 under conventional reaction conditions well known in the art, including the use of palladium (II) bis(triphenylphosphine) dichloride and copper (I) iodide as catalysts, and typically in the presence of a suitable base, such as diisopropylethylamine, triethylamine, pyridine, cesium carbonate, and the like. The reaction is typically conducted in an inert solvent, such as toluene, N,N-dimethylformamide, and the like. The reaction is typically conducted at from about 25 ºC to about 110 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 10. [0152] In the next step, the protecting group, such as t-butoxycarbonyl (t-BOC), is removed under conventional conditions, depending on the specific protecting group employed. The t-BOC group is illustrative only, and other conventional amino protecting groups, such as benzyl, 9- fluorenylmethoxycarbonyl (Fmoc), benzyloxycarbonyl (Cbz), p-nitrobenzyloxycarbonyl, and the like could be employed. 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 11. [0153] In the final step, at least a stoichiometric amount of a suitable carboxylic acid, compound 12, is combined with compound 11, under conventional amide bond formation 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 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 compounds of Formula Iʹ.
Scheme 3 [0154] In some embodiments, compounds of formula Iʹ and sub-formulae thereof are prepared as shown in Scheme 3. In Scheme 3, the first step is a conventional Suzuki coupling reaction, wherein at least a stoichiometric amount of protected amino vinylboronic acid, compound 13, is combined with compound 7, 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 14. [0155] In the next step, the protecting group, such as t-butoxycarbonyl (t-BOC), is removed under conventional conditions, depending on the specific protecting group employed. The t-BOC group is illustrative only, and other conventional amino protecting groups, such as benzyl, 9- fluorenylmethoxycarbonyl (Fmoc), benzyloxycarbonyl (Cbz), p-nitrobenzyloxycarbonyl, and the like could be employed. 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 15. In the final step, at least a stoichiometric amount of a suitable carboxylic acid, compound 12, is combined with compound 15, under conventional amide bond formation 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 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 compounds of Formula Iʹ. Scheme 4 [0156] In some embodiments, compounds of formula I and sub-formulae thereof are prepared as shown in Scheme 4. In Scheme 4, the first step is a conventional SNAR reaction, wherein at least a stoichiometric amount of a protected Ring A, compound 2A, is combined with compound 1 in an inert diluent, such as tetrahydrofuran, dioxane, DMSO, DMF, and the like, typically in the presence of a suitable base, such as sodium hydride, potassium carbonate, cesium 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. [0157] In the next step, a conventional Suzuki coupling reaction is performed, wherein at least a stoichiometric amount of aryl boronic acid, compound 4, is combined with compound 3A, 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 5A. [0158] In the next step, the protecting group, such as t-butoxycarbonyl (t-BOC), is removed under conventional conditions, depending on the specific protecting group employed. The t-BOC group is illustrative only, and other conventional amino protecting groups, such as benzyl, 9- fluorenylmethoxycarbonyl (Fmoc), benzyloxycarbonyl (Cbz), p-nitrobenzyloxycarbonyl, and the like could be employed. 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. [0159] In the next step, a conventional SNAR reaction is performed, wherein at least a stoichiometric amount of the deprotected product from the previous step is combined 2,4-dibromopyrimidine, compound 6, 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 7A. [0160] In the final step, a conventional coupling reaction, including, but not limited to, a Sonogashira coupling, a Suzuki coupling, and the like, is performed, wherein at least a stoichiometric amount of a suitable coupling partner, compound 8, is combined with compound 7 under conventional coupling reaction conditions well known in the art, including the use of a palladium catalyst (e.g., palladium(II) bis(triphenylphosphine) dichloride, palladium diacetate, and the like), a co-catalyst (e.g., copper (I) iodide and the like), and typically in the presence of a suitable base (e.g., diisopropylethylamine, triethylamine, pyridine, cesium carbonate, and the like). The coupling reaction is typically conducted in an inert solvent, such as toluene, N,N-dimethylformamide, tetrahydrofuran, dioxane, dimethoxyethane, and the like. The reaction is typically conducted at from about 10 C to about 110 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. Scheme 5 [0161] In some embodiments, compounds of formula I and sub-formulae thereof are prepared as shown in Scheme 5. In Scheme 5, the first step is a conventional Sonogashira coupling reaction employing at least a stoichiometric amount of protected propargyl amine, compound 9, combined with compound 7A under conventional reaction conditions well known in the art, including the use of palladium (II) bis(triphenylphosphine) dichloride and copper (I) iodide as catalysts, and typically in the presence of a suitable base, such as diisopropylethylamine, triethylamine, pyridine, cesium carbonate, and the like. The reaction is typically conducted in an inert solvent, such as toluene, N,N-dimethylformamide, and the like. The reaction is typically conducted at from about 25 ºC to about 110 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 10A. [0162] In the next step, the protecting group, such as t-butoxycarbonyl (t-BOC), is removed under conventional conditions, depending on the specific protecting group employed. The t-BOC group is illustrative only, and other conventional amino protecting groups, such as benzyl, 9- fluorenylmethoxycarbonyl (Fmoc), benzyloxycarbonyl (Cbz), p-nitrobenzyloxycarbonyl, and the like could be employed. 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 11A. [0163] In the final step, at least a stoichiometric amount of a suitable carboxylic acid, compound 12, is combined with compound 11A, under conventional amide bond formation 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 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 compounds of Formula I.
Scheme 6 [0164] In some embodiments, compounds of formula I and sub-formulae thereof are prepared as shown in Scheme 3’. In Scheme 3’, the first step is a conventional Suzuki coupling reaction, wherein at least a stoichiometric amount of protected amino vinylboronic acid, compound 13, is combined with compound 7A, 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 14A. [0165] In the next step, the protecting group, such as t-butoxycarbonyl (t-BOC), is removed under conventional conditions, depending on the specific protecting group employed. The t-BOC group is illustrative only, and other conventional amino protecting groups, such as benzyl, 9- fluorenylmethoxycarbonyl (Fmoc), benzyloxycarbonyl (Cbz), p-nitrobenzyloxycarbonyl, and the like could be employed. 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 15A. [0166] In the final step, at least a stoichiometric amount of a suitable carboxylic acid, compound 12, is combined with compound 15A, under conventional amide bond formation 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 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 compounds of Formula I. [0167] Other starting materials used herein are either well known in the art, commercially available, or can be prepared by conventional synthetic methods. Methods [0168] In one embodiment, the compounds and compositions described herein are useful in methods for treating a SMARCA2 dependent disease or disorder or a disease or disorder that is mediated, at least in part by, SMARCA2. The methods comprise administering to a subject suffering from a SMARCA2 dependent disease or disorder an effective amount of a compound, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof or a pharmaceutical composition comprising said compound, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof as described herein. [0169] In one embodiment, there is provided a compound, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof or a pharmaceutical composition comprising said compound, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof as described herein for use in treating an SMARCA2 dependent disease or disorder. [0170] In one embodiment, the method relates a compound, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof or a pharmaceutical composition comprising said compound, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof as described herein for use in manufacture of a medicament for reducing levels of protein which is expressed from the SMARCA2 gene, where reduction of such protein levels treats or ameliorates the diseases or disorder. [0171] In one embodiment, the methods described herein comprise use of a prodrug of the compounds described herein. [0172] In one embodiment, the method relates a compound, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof or a pharmaceutical composition comprising said compound, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof as described herein for use as described herein, wherein the degradation of protein which is expressed from the SMARCA2 gene at 1 µM concentration of the compounds described herein is in the range of about 25%-99%. The degradation of the protein which is expressed from the SMARCA2 gene is measured by the assay described in the biological example. In some embodiments, the degradation of the protein which is expressed from the SMARCA2 gene is from about 25% to about 50%, from about 45% to about 70%, from about 65% to about 90% or from about 75% to about 99%. In some embodiments, the degradation of the protein which is expressed from the SMARCA2 gene is from about 25% to about 35%, from about 35% to about 45%, from about 45% to about 55%, from about 55% to about 65%, from about 65% to about 75%, from about 75% to about 85%, from about 85% to about 99%. In some embodiments, the degradation of the protein which is expressed from the SMARCA2 gene is more than 60%. In some embodiments, the degradation of the protein which is expressed from the SMARCA2 gene is more than 70%. In some embodiments, the degradation of the protein which is expressed from the SMARCA2 gene is more than 80%. In some embodiments, the degradation of the protein which is expressed from the SMARCA2 gene is more than 90%. [0173] The compounds and compositions described herein are useful in treating SMARCA2 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 SMARCA2-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 SMARCA2-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). [0174] 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. [0175] In general, methods of using the compounds of the present application comprise administering to a subject in need thereof a therapeutically effective amount of a compound as described herein. [0176] 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 growth is inhibited or the proteins are degraded by contacting said cells with an compound or composition, as described herein. In other embodiments, the compounds are useful in treating cancer. [0177] Thus, in another aspect of the application, methods for the treatment of cancer are provided comprising administering a therapeutically 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 a therapeutically 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 or intravenously. In certain embodiments of the present application a “therapeutically effective amount” of the compound or pharmaceutical composition is that amount effective for killing or inhibiting the growth of tumor cells. 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 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, the particular anticancer agent, its mode of administration, and the like. In certain embodiments of the present application a “therapeutically effective amount” of the compound or pharmaceutical composition described herein is that amount effective for reducing the levels of target proteins. In certain embodiments of the present application a “therapeutically effective amount” of the compound or pharmaceutical composition is that amount effective to kill or inhibit the growth of skin cells. [0178] 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 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). [0179] 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. [0180] 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. [0181] 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 a composition comprising said compound. [0182] 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. For example, when using the compounds for the treatment of cancer, the expression “effective amount” as used herein, refers to a sufficient amount of agent to inhibit proliferation, or refers to a sufficient amount to reduce the effects of cancer. 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 diseases, the particular anticancer agent, its mode of administration, and the like. [0183] 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, or tautomer 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, or tautomer thereof, for the preparation of a medicament useful for the treatment of a proliferative disorder. [0184] 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, or tautomer 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, or tautomer thereof, for the preparation of a medicament useful for the prevention of a proliferative disorder. [0185] 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 disorder include, but are not limited to, neoplasms, benign tumors, malignant tumors, 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. 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. [0186] 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; Reiters 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. [0187] 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, Waldenström 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. [0188] 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. 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. [0189] 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. 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 ultrastructural heterogeneity (e.g., mixed cell types). [0190] 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. [0191] 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. [0192] 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 Crohns 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. [0193] 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 ultrastructural heterogeneity (e.g., mixed cell types). [0194] 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. [0195] 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. [0196] 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. [0197] 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. [0198] 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. [0199] 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. [0200] 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. [0201] 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. [0202] 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. [0203] 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 an compound or composition, as described herein. In other embodiments, the compounds are useful in treating cancer. [0204] 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). [0205] 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-Hodgkins lymphoma, ovarian cancer, pancreatic cancer, prostate cancer, and gastric cancer. In certain embodiments, the anticancer agents are active against solid tumors. [0206] 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. [0207] 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, cytarabine, 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). [0208] 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 [0209] 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. [0210] 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. [0211] 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. [0212] 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. [0213] 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. [0214] 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. [0215] 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. [0216] 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. [0217] 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. [0218] Another aspect of the disclosure is directed to pharmaceutical compositions comprising a compound of Formula I, and a pharmaceutically acceptable carrier. The pharmaceutically acceptable carrier may further include an excipient, diluent, or surfactant. [0219] 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. [0220] 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. [0221] 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. [0222] 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. [0223] 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. [0224] 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. [0225] 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). [0226] 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. [0227] 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 [0228] The following are representative pharmaceutical formulations containing a compound of this disclosure. Formulation Example 1 -- Tablet formulation [0229] The following ingredients are mixed intimately and pressed into single scored tablets. Quantity per Ingredient tablet, mg compound of this disclosure 400 Cornstarch 50 croscarmellose sodium 25 Lactose 120 magnesium stearate 5 Formulation Example 2 -- Capsule formulation [0230] The following ingredients are mixed intimately and loaded into a hard-shell gelatin capsule. Quantity per Ingredient capsule, mg compound of this disclosure 200 lactose, spray-dried 148 magnesium stearate 2 Formulation Example 3 -- Suspension formulation [0231] The following ingredients are mixed to form a suspension for oral administration. Ingredient Amount compound of this disclosure 1.0 g fumaric acid 0.5 g sodium chloride 2.0 g methyl paraben 0.15 g propyl paraben 0.05 g granulated sugar 25.0 g sorbitol (70% solution) 13.00 g Veegum K (Vanderbilt Co.) 1.0 g Flavoring 0.035 mL Colorings 0.5 mg distilled water q.s. to 100 mL Formulation Example 4 -- Injectable formulation [0232] The following ingredients are mixed to form an injectable formulation. Ingredient Amount compound of this disclosure 0.2 mg-20 mg sodium acetate buffer solution, 0.4 M 2.0 mL HC1 (1N) or NaOH (1N) q.s. to suitable pH water (distilled, sterile) q.s. to 20 mL Formulation Example 5 -- Suppository Formulation [0233] 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 Compound of this disclosure 500 mg Witepsol® H-15 balance Dosing [0234] 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. [0235] 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 [0236] 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. [0237] 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) Å Angstrom ACN or MeCN acetonitrile Boc or t-Boc tert-butoxycarbonyl Cbz benzyloxycarbonyl CDCl3 deuterated chloroform DC50 concentration that resulted in a 50% targeted protein degradation DCC N,N-dicyclohexylcarbodiimide DCM dichloromethane DHA docosahexaenoic acid DIEA diisopropylethylamine DMAP 4-dimethylaminopyridine DMF N,N-dimethylformamide DMSO dimethylsulfoxide d6-DMSO deuterated dimethylsulfoxide d 4 -MeOD deuterated methanol EPA eicosapentaenoic acid eq. equivalent(s) ESI electrospray ionization EtOH ethanol Fmoc fluorenylmethyloxycarbonyl g grams 1 H NMR proton nuclear magnetic resonance spectroscopy h or hr hour(s) HATU 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyri dinium 3- oxide hexafluorophosphate HPLC high performance liquid chromatography HPMC hydroxypropyl methylcellulose L liter LC liquid chromatography LC-MS liquid chromatography – mass spectrometry LiHMDS lithium bis(trimethylsilyl)amide M molar mCPBA meta-Chloroperoxybenzoic acid mg milligrams m/z mass-to-charge ratio min minute(s) mmol millimole mL milliliter MTBE methyl tert-butyl ether µL microliter µmol or µmol micromole µM micromolar N normal Pd(dppf)Cl2 1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) Pd(OAc)2 palladium(II) acetate Pd(PPh3)2Cl2 bis(triphenylphosphine)palladium(II) dichloride PPh3 triphenylphosphine q.s. amount which is sufficient TEA triethylamine TFA trifluoroacetic acid THF tetrahydrofuran UV ultraviolet wt % weight percent NMR abbreviations br = broad d = doublet dd = doublet of doublets m = multiplet q = quartet s = singlet t = triplet LC-MS Methods (General Method) [0238] Method A: Experiments were performed using a Luna ® 5 µm C18(2) 100 Å, LC Column 250 × 21.2 mm, AXIA™ Packed (00G-4252-P0-AX), at a flow rate of 20 mL/min, and a mass spectrometer using ESI as ionization source. The solvent A was 4.0 mL of TFA in 4 L of water, and solvent B was 4.0 mL of TFA in 4 L of 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. Example 1 Preparation of N-(3-(4-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)pipera zin-1-yl)pyrimidin-2- yl)prop-2-yn-1-yl)-1,5-dimethyl-1H-pyrazole-3-carboxamide (Compound P-12) S [0239] To a solution of 4-bromo-6-chloropyridazin-3-amine (1 g, 4.80 mmol, 1 eq) in EtOH (10 mL) was added DIEA (1.86 g, 14.39 mmol, 2.51 mL, 3 eq) and tert-butyl piperazine-1-carboxylate (1.34 g, 7.20 mmol, 1.5 eq). The mixture was stirred at 80 °C for 12 hr. The reaction was concentrated under reduced pressure to give a residue. The residue was dissolved in ethyl acetate (20 mL) and washed with water, dried over magnesium sulfate, and the solvents evaporated in vacuo to give tert-butyl 4-(3-amino- 6-chloropyridazin-4-yl)piperazine-1-carboxylate. Step 2: [0240] A mixture of tert-butyl 4-(3-amino-6-chloropyridazin-4-yl)piperazine-1-carboxylate (1.3 g, 4.14 mmol, 1 eq), (2-hydroxyphenyl)boronic acid (857.16 mg, 6.21 mmol, 1.5 eq), Pd(dppf)2Cl2 (303.15 mg, 414.30 µmol, 0.1eq), and Cs2CO3 (8.10 g, 24.86 mmol, 6 eq) in dioxane (14 mL) and H2O (1.4 mL) was degassed and purged with N2. The mixture was stirred at 80 °C for 12 hours under N2 atmosphere. The reaction was extracted with ethyl acetate (5 mL), and the organic phase was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, 0 to 100% ethyl acetate in petroleum ether) to give tert-butyl 4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)piperazine- 1-carboxylate. 1 H NMR (400 MHz, d6-DMSO) δ 7.92 (dd, J=8.25, 1.25 Hz, 1 H) 7.55 (s, 1 H) 7.18 - 7.29 (m, 1 H) 6.82 - 6.95 (m, 2 H) 6.38 (s, 2 H) 3.55 (br s, 5 H) 2.99 - 3.08 (m, 4 H) 1.43 (s, 9 H). Step 3: [0241] To a solution of tert-butyl 4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)piperazine-1- carboxylate (1 g, 2.69 mmol, 1 eq) in DCM (8 mL), was added TFA (4 mL). The mixture was stirred at 25 °C for 12 hr. The reaction was concentrated under reduced pressure to give a residue, which was triturated with MTBE to give 2-(6-amino-5-(piperazin-1-yl)pyridazin-3-yl)phenol as a TFA salt. 1 H NMR (400 MHz, d6-DMSO) δ 9.34 - 9.61 (m, 2 H) 8.27 - 8.48 (m, 1 H) 7.79 (br d, J=7.50 Hz, 1 H) 7.61 (s, 1 H) 7.31 (br t, J=7.50 Hz, 1 H) 7.05 - 7.22 (m, 2 H) 6.99 (br d, J=8.13 Hz, 1 H) 6.93 (br t, J=7.44 Hz, 1 H) 3.37 (br s, 7 H). Step 4: [0242] To a solution of 4-bromo-2-(methylthio)pyrimidine (5 g, 24.38 mmol, 1 eq) in MeCN (20 mL), DCM (20 mL), and H 2 O (20 mL) at 0 °C, was added NaIO 4 (10.41 g, 48.76 mmol, 2 eq). RuCl 3 (0.1 g, 0.02 eq) was added and the reaction warmed to 25 °C and stirred for 12 hours. The reaction mixture was diluted with water (50 mL) and extracted with DCM (100 mL). The organic layer was separated and washed with saturated Na 2 S 2 O 3 (50 mL) and dried over sodium sulfate. The organic layer was concentrated to give a residue, which was purified by column chromatography to give 4-bromo-2- (methylsulfonyl)pyrimidine. Step 5: [0243] Di-tert-butyl prop-2-yn-1-yliminodicarbonate (2.16 g, 8.44 mmol, 1 eq) was added to a solution of LiHMDS (10 mL, 1.2 eq, 1N) in THF (30 mL) at -78 °C, and stirred for 1 h.4-Bromo-2- (methylsulfonyl)pyrimidine (2 g, 8.44 mmol, 1 eq) in DCM (10 mL) was added dropwise and stirred at -78 °C for 2 h. The reaction mixture was quenched with saturated NH4Cl (30 mL), diluted with water (50 mL), and extracted with MTBE (50 mL). The organic layer was separated, dried over sodium sulfate, and concentrated to give a residue. The residue was purified by column chromatography to give di-tert-butyl (3-(4-bromopyrimidin-2-yl)prop-2-yn-1-yl)iminodicarbonate. 1 H NMR (400 MHz, CDCl3) δ 8.44 (d, J=6.4 Hz, 1H), 7.45 (d, J=6.4 Hz, 1H), 4.66 (s, 2H), 1.54 (s, 18H). Step 6: [0244] A solution of 2-(6-amino-5-(piperazin-1-yl)pyridazin-3-yl)phenol (802 mg, 2.08 mmol, 1 eq), di- tert-butyl (3-(4-bromopyrimidin-2-yl)prop-2-yn-1-yl)iminodicarbonate (650 mg, 2.08 mmol, 1 eq), and DIEA (807 mg, 6.25 mmol, 3 eq) in DMF (5.0 mL) was stirred at room temperature overnight. 1M citric acid solution was added to the reaction mixture until pH =~4. The precipitate was filtered and washed with ethyl acetate and dried to give tert-butyl (3-(4-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4- yl)piperazin-1-yl)pyrimidin-2-yl)prop-2-yn-1-yl)(tert-butoxy carbonyl)carbamate. Step 7: [0245] To a solution of tert-butyl (3-(4-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)piperazi n-1- yl)pyrimidin-2-yl)prop-2-yn-1-yl)(tert-butoxycarbonyl)carbam ate (162 mg, 322 µmol) in dichloromethane (3 mL), was added trifluoroacetic acid (2 mL). The solution was stirred at room temperature for 1 hour. The solvents were evaporated in vacuo to give 2-(6-amino-5-(4-(2-(3-aminoprop- 1-yn-1-yl)pyrimidin-4-yl)piperazin-1-yl)pyridazin-3-yl)pheno l. Step 8: H [0246] A solution of 1,5-dimethyl-1H-pyrazole-3-carboxylic acid (3.3 mg, 23.8 µmol) and HATU (9.1 mg, 24 µmol) in DMF (0.3 mL) was stirred at room temperature for 2 minutes.2-(6-amino-5-(4-(2-(3- aminoprop-1-yn-1-yl)pyrimidin-4-yl)piperazin-1-yl)pyridazin- 3-yl)phenol (15 mg, 24 µmol) and DIEA (12.3mg, 95.2 µmol, 4 eq) in DMF (0.2 mL) was added. The solution was stirred at room temperature for 5 hours. The solution was purified by prep-HPLC (column: Phenomenex Luna C18100×40mm×5 mm; mobile phase: (0.1% formic acid in water-0.1% formic acid in ACN); B%: 5%-50%, 8 min). The fractions were combined and lyophilized to give N-(3-(4-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4- yl)piperazin-1-yl)pyrimidin-2-yl)prop-2-yn-1-yl)-1,5-dimethy l-1H-pyrazole-3-carboxamide. Example 2 Preparation of N-(3-(4-(3-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)-3,8- diazabicyclo[3.2.1]octan-8-yl)pyrimidin-2-yl)prop-2-yn-1-yl) pyrazolo[1,5-a]pyrimidine-2- carboxamide (Compound P-119) Step 1: [0247] To a solution of 4-bromo-6-chloropyridazin-3-amine (1 g, 4.80 mmol, 1 eq.) in EtOH (10 mL), was added DIEA (1.86 g, 14.39 mmol, 2.51 mL, 3 eq.) and tert-butyl 3,8-diazabicyclo[3.2.1]octane-8- carboxylate (1.53 g, 7.20 mmol, 1.5 eq). The mixture was stirred at 100 °C for 12 hr. The reaction was concentrated under reduced pressure to give a residue. The residue was triturated with MTBE to give tert- butyl 3-(3-amino-6-chloropyridazin-4-yl)-3,8-diazabicyclo[3.2.1]oc tane-8-carboxylate. m/z (ESI + ): 340.2 (M+H) + . Step 2: [0248] A mixture of tert-butyl 3-(3-amino-6-chloropyridazin-4-yl)-3,8-diazabicyclo[3.2.1]oc tane-8- carboxylate (2.4 g, 7.06 mmol, 1 eq), (2-hydroxyphenyl)boronic acid (1.46 g, 10.59 mmol, 1.5 eq), Pd(dppf)2Cl2 (516.78 mg, 706.26 µmol, 0.1 eq), and Cs2CO3 (13.81 g, 42.38 mmol, 6 eq) in dioxane (20 mL) and H 2 O (2 mL) was degassed and purged with N 2 . The mixture was stirred at 80 °C for 12 hr under N 2 atmosphere. The reaction was extracted with ethyl acetate (5 mL), and the organic phase was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO 2 , 0 to 100% ethyl acetate in petroleum ether) to give tert-butyl 3-(3-amino-6-(2- hydroxyphenyl)pyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octane- 8-carboxylate. m/z (ESI + ) 298.2.2 (M- 100+H) + . Step 3: [0249] To a solution tert-butyl 3-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (0.92 g, 2.31 mmol, 1 eq) in DCM (6 mL), was added TFA (3 mL). The mixture was stirred at 25 °C for 12 hr. The reaction was concentrated under reduced pressure to give a residue, which was triturated with MTBE to give 2-(6-amino-5-(3,8-diazabicyclo[3.2.1]octan-3- yl)pyridazin-3-yl)phenol as a TFA salt. 1 H NMR (400 MHz, d6-DMSO) δ 9.15 (br s, 2 H) 7.69 (br d, J=7.25 Hz, 1 H) 7.57 (s, 1 H) 7.36 (br t, J=7.63 Hz, 1 H) 6.76 - 7.09 (m, 4 H) 4.18 (br s, 2 H) 3.69 (br d, J=12.63 Hz, 2 H) 3.25 (br d, J=13.13 Hz, 2 H) 2.23 (br d, J=7.75 Hz, 2 H) 1.90 - 2.02 (m, 2 H). Step 4: [0250] To a solution of 2-(6-amino-5-(3,8-diazabicyclo[3.2.1]octan-3-yl)pyridazin-3- yl)phenol trifluoroacetic acid (250 mg, 608 µmol, 1.0 eq) in DMF (4 mL), was added DIEA (259 mg, 2.01 mmol, 3.3 eq) and 2,4-dibromopyrimidine (145 mg, 608 µmol, 1 eq). The reaction was stirred at room temperature for 16 hours. The solution was purified by prep-HPLC (column: Phenomenex Luna C 18 100 mm × 40 mm × 5 µm; mobile phase: (0.1% formic acid in water-0.1% formic acid in ACN); B%: 20%- 80%, 8 min). The fractions were combined and lyophilized to give 2-(6-amino-5-(8-(2-bromopyrimidin- 4-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridazin-3-yl)pheno l. 1 H NMR (400 MHz, d 6 -DMSO) δ 8.02 (d, J = 6.0 Hz, 1H), 7.93 (dd, J = 7.9, 1.6 Hz, 1H), 7.58 (s,1H), 7.23 (ddd, J = 8.5, 7.2, 1.6 Hz, 1H), 6.91 – 6.83 (m, 4H), 6.03 (s, 3H), 4.88 - 4.64 (m, 2H), 3.50 - 3.32 (m, 2H), 3.06 - 2.95 (m, 2H), 2.24 - 2.06 (m, 2H), 1.97 - 1.91 (m, 2H). Step 5: [0251] 2-(6-amino-5-(8-(2-bromopyrimidin-4-yl)-3,8-diazabicyclo[3.2 .1]octan-3-yl)pyridazin-3- yl)phenol (15 mg, 33 µmol, 1 eq), N-(but-3-yn-1-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (66 µmol, 2 eq), and DIEA (12.8 mg, 99 µmol, 3 eq) were dissolved in anhydrous DMF (0.7 mL), and the resulting solution was degassed under an argon stream for 5 minutes. Palladium(II)bis(triphenylphosphine) dichloride (16.4 mg, 0.0233 mmol, 0.1 eq.) and CuI (2.5 mg, 13.2 µmol, 0.4 eq) were added. The reaction was stirred at 90 °C for 6 hours, and then cooled to room temperature. The solution was purified by prep- HPLC (Method A) to give N-(3-(4-(3-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)-3,8- diazabicyclo[3.2.1]octan-8-yl)pyrimidin-2-yl)prop-2-yn-1-yl) pyrazolo[1,5-a]pyrimidine-2-carboxamide. Example 3 Preparation of (E)-N-(3-(4-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)-1 ,4-diazepan-1- yl)pyrimidin-2-yl)allyl)quinoxaline-2-carboxamide (Compound P-110) Step 1: [0252] A mixture of 4-bromo-6-chloropyridazin-3-amine (2.07 g, 10.0 mmol, 2 eq), DIEA (6.45 g, 49.93 mmol, 8.70 mL, 10 eq), and tert-butyl 1,4-diazepane-1-carboxylate (1 g, 4.99 mmol, 980.39 µL, 1 eq) in DMSO (10 mL) was degassed and purged with N2 three times. The mixture was stirred at 120 °C for 4 days under a N 2 atmosphere. The reaction mixture was concentrated under reduced pressure. The residue provided was diluted with water (20 mL) and extracted with ethyl acetate (2 × 10 mL). The combined organic layers were washed with brine (10 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 , 1 to 100% ethyl acetate in petroleum ether) to give tert-butyl 4-(3-amino-6-chloropyridazin-4-yl)-1,4-diazepane-1- carboxylate. 1 H NMR (400 MHz, CDCl 3 ) δ 6.76 (s, 1H), 5.07 (s, 1H), 4.79 (d, J = 2.0 Hz, 1H), 3.71 - 3.46 (m, 4H), 3.37 - 3.18 (m, 4H), 2.04 - 1.86 (m, 2H), 1.47 (s, 9H). Step 2: A mixture of tert-butyl 4-(3-amino-6-chloropyridazin-4-yl)-1,4-diazepane-1-carboxyla te (8 g, 24.40 mmol, 1 eq), (2-hydroxyphenyl)boronic acid (5.05 g, 36.61 mmol, 1.5 eq), Cs2CO3 (47.71 g, 146.43 mmol, 6 eq), and Pd(dppf)Cl2 (1.79 g, 2.44 mmol, 0.1 eq) in dioxane (100 mL) and water (20 mL) was degassed and purged with N2 three times. The mixture was stirred at 80 °C for 12 hours under a N2 atmosphere. The reaction mixture was quenched by addition of water (200 mL) and extracted with ethyl acetate (3 × 100 mL). The combined organic layers were washed with brine (2 × 50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, 1 to 100% ethyl acetate in petroleum ether) to give tert-butyl 4-(3-amino- 6-(2-hydroxyphenyl)pyridazin-4-yl)-1,4-diazepane-1-carboxyla te. 1 H NMR (400 MHz, CDCl3) δ 14.04 - 13.51 (m, 1H), 7.62 - 7.56 (m, 1H), 7.39 - 7.28 (m, 2H), 7.05 (d, J = 8.0 Hz, 1H), 6.91 (t, J = 7.6 Hz, 1H), 5.02 (s, 1H), 4.79 (s, 1H), 3.74 - 3.52 (m, 4H), 3.44 - 3.26 (m, 4H), 2.11 - 1.90 (m, 2H), 1.48 (s, 9H). Step 3: [0253] A mixture of tert-butyl 4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)-1,4-diazepane- 1- carboxylate (8 g, 20.75 mmol, 1 eq) and TFA (15.40 g, 135.06 mmol, 10 mL, 6.51 eq) in DCM (80 mL) was prepared. The mixture was stirred at 20 °C for 2 hours. The reaction mixture was concentrated in vacuo. The crude product was triturated with MTBE (20 mL) to give 2-(6-amino-5-(1,4-diazepan-1- yl)pyridazin-3-yl)phenol. 1 H NMR (400 MHz, d4-MeOD) δ 7.58 (, J = 1.6, 8.0 Hz, 1H), 7.49 (s, 1H), 7.47 - 7.41 (m, 1H), 7.08 - 7.01 (m, 2H), 4.04 - 3.96 (m, 2H), 3.82 - 3.74 (m, 2H), 3.58 - 3.50 (m, 2H), 3.47 - 3.39 (m, 2H), 2.29 (quin, J = 5.6 Hz, 2H). Step 4: [0254] A mixture of 2-(6-amino-5-(1,4-diazepan-1-yl)pyridazin-3-yl)phenol (3.57 g, 15.02 mmol, 1.5 eq), DIEA (6.47 g, 50.08 mmol, 8.72 mL, 5 eq), and DMAP (122.36 mg, 1.00 mmol, 0.1 eq) in DMF (40 mL) was degassed and purged with N2 three times. The mixture was stirred at 20 °C for 12 hours under a N2 atmosphere. The reaction mixture was filtered. The residue was purified by prep-HPLC (column: Welch Xtimate C18250×70mm×10µm; mobile phase: (water (NH4HCO3)-ACN); B%: 33%-63%, 20 min) to give 2-(6-amino-5-(4-(2-bromopyrimidin-4-yl)-1,4-diazepan-1-yl)py ridazin-3-yl)phenol. 1 H NMR (400 MHz, d4-MeOD) δ 7.90 (s, 1H), 7.69 (d, J = 8.0 Hz, 1H), 7.52 (s, 1H), 7.28 - 7.20 (m, 1H), 6.95 - 6.88 (m, 2H), 6.78 - 6.64 (m, 1H), 4.22 - 4.09 (m, 1H), 4.07 - 3.94 (m, 1H), 3.86 - 3.70 (m, 2H), 3.62 - 3.50 (m, 2H), 3.44 - 3.35 (m, 2H), 2.21 - 2.09 (m, 2H). Step 5: [0255] A solution of 2-(6-amino-5-(4-(2-bromopyrimidin-4-yl)-1,4-diazepan-1-yl)py ridazin-3-yl)phenol (50.0 mg, 113 µmol, 1 eq.), tert-butyl (E)-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)allyl)ca rbamate (38.4 mg, 136 µmol, 1.2 eq.), triphenylphosphine (5.93 mg, 22.6 µmol, 0.2 eq.), and cesium carbonate (110 mg, 339 µmol, 3 eq.) in ACN (2 mL) and water (0.5 mL) was degassed under an argon stream for 5 minutes. Palladium(II)acetate (1.27 mg, 5.65 µmol, 0.05 eq.) was added. The reaction was stirred at 100 °C for 4 hours. The reaction was cooled to room temperature. The solution was purified by prep-HPLC (column: Phenomenex Luna C18100×40mm×5 mm; mobile phase: (0.1% formic acid in water-0.1% formic acid in ACN); B%: 5%-75%, 8 min). The fractions were combined and lyophilized to give tert- butyl (E)-(3-(4-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)-1,4 -diazepan-1-yl)pyrimidin-2- yl)allyl)carbamate. m/z (ESI + ) 519 (M+H) + . Step 6: [0256] To a solution of tert-butyl (E)-(3-(4-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)-1,4 - diazepan-1-yl)pyrimidin-2-yl)allyl)carbamate (55.8 mg, 108 µmol, 1 eq) in DCM (2 mL), was added TFA (1 mL). The mixture was stirred at 20 °C for 1.5 hours. The reaction mixture was concentrated in vacuo. The crude product was triturated with diethyl ether (20 mL) to give (E)-2-(6-amino-5-(4-(2-(3- aminoprop-1-en-1-yl)pyrimidin-4-yl)-1,4-diazepan-1-yl)pyrida zin-3-yl)phenol, which was used directly in the next step. Step 7: [0257] To a solution of quinoxaline-2-carboxylic acid (6.44 mg, 371 µmol, 1 eq) in DMF (1.0 mL), was added (E)-2-(6-amino-5-(4-(2-(3-aminoprop-1-en-1-yl)pyrimidin-4-yl )-1,4-diazepan-1-yl)pyridazin-3- yl)phenol (23.9 mg, 37 µmol, 1 eq), HATU (14.1 mg, 37 µmol, 1 eq), and DIEA (19.1 mg, 25.8 µL, 148 µmol, 4 eq). The reaction was stirred at 25 °C for 16 hrs. The solution was purified by prep-HPLC (column: Phenomenex Luna C18100×40mm×5 mm; mobile phase: (0.1% formic acid in water-0.1% formic acid in ACN); B%: 10%-40%, 8 min). The fractions were combined and lyophilized to give (E)-N- (3-(4-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)-1,4-dia zepan-1-yl)pyrimidin-2- yl)allyl)quinoxaline-2-carboxamide. m/z (ESI + ) 575 (M+H) + . Example 4 Preparation of N-(3-(4-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)-1,4-d iazepan-1-yl)-6- ethoxypyrimidin-2-yl)prop-2-yn-1-yl)pyrazolo[1,5-a]pyrimidin e-2-carboxamide (Compound P-124) Step 1: [0258] To a mixture of 4,6-dichloro-2-(methylthio)pyrimidine (6 g, 30.76 mmol, 1 eq) in ethanol (60 mL), was added sodium ethoxide (10.47 g, 30.76 mmol, 20 % purity, 1 eq) in one portion at 20 °C under a N 2 atmosphere. The mixture was stirred at room temperature for 16 h. Saturated NH 4 Cl solution (100 mL) was added. The aqueous layer was extracted with ethyl acetate (2 × 50 mL). The combined organic layers were washed with brine (100 mL), dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure to give 4-chloro-6-ethoxy-2-(methylthio)pyrimidine, which was used into the next step without further purification. 1 H NMR (400 MHz, CDCl 3 ) δ 6.39 (s, 1 H) 4.43 (q, J=7.2 Hz, 2 H) 2.54 (s, 3 H) 1.39 (t, J=7.2 Hz, 3 H). Step 2: [0259] To a mixture of 4-chloro-6-ethoxy-2-(methylthio)pyrimidine (5.81 g, 28.39 mmol, 1 eq) in DCM (60 mL), was added mCPBA (48.98 g, 283.86 mmol, 10 eq) in one portion. The mixture was stirred at room temperature for 16 h. Saturated sodium thiosulfate solution (40 mL) was added. The organic layer was washed with brine (40 mL), dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure to give a 4-chloro-6-ethoxy-2-(methylsulfonyl)pyrimidine, which was used into the next step without further purification. m/z (ESI + ) 237.1 (M+H) + . Step 3: [0260] To a solution of 4-chloro-6-ethoxy-2-(methylsulfonyl)pyrimidine (1 g, 4.23 mmol, 1 eq) in THF (20 mL) at -78 °C, was added LiHMDS (1 M, 5.07 mL, 99.5 % purity, 1.2 eq) dropwise over 15 min. The mixture was stirred at -78 °C for 30 min. Tert-butyl N-tert-butoxycarbonyl-N-prop-2-ynyl-carbamate (1.08 g, 4.23 mmol, 1 eq) in THF (20 mL) was added dropwise. The resulting mixture was stirred at -78 °C for 2 h. Saturated NH4Cl solution (20 mL) was added. The aqueous layer was extracted with ethyl acetate (2 × 10 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by prep- HPLC (method A) to give di-tert-butyl (3-(4-chloro-6-ethoxypyrimidin-2-yl)prop-2-yn-1- yl)iminodicarbonate. 1 H NMR (400 MHz, CDCl3) δ 6.67 (s, 1 H) 4.63 (s, 2 H) 4.44 (q, J=7.2 Hz, 2 H) 1.63 (br s, 3 H) 1.55 (s, 18 H). Step 4: [0261] To a solution of di-tert-butyl (3-(4-chloro-6-ethoxypyrimidin-2-yl)prop-2-yn-1- yl)iminodicarbonate (150 mg, 364.18 µmol, 1 eq) in DMSO (5 mL), was added dropwise 2-[6-amino-5- (1,4-diazepan-1-yl)pyridazin-3-yl]phenol (103.92 mg, 364.18 µmol, 1 eq) at 50 °C over 15 min. After addition, the mixture was stirred at 50 °C for 30 min, and then DIEA (470.67 mg, 3.64 mmol, 634.33 µL, 10 eq) was added dropwise. The resulting mixture was stirred at 50 °C for 2 hours. Saturated NH 4 Cl solution (1 mL) was added. The aqueous layer was extracted with ethyl acetate (2 × 0.5 mL). The combined organic layers were washed with brine (1 mL), dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure to give tert-butyl (3-(4-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)-1,4- diazepan-1-yl)-6-ethoxypyrimidin-2-yl)prop-2-yn-1-yl)(tert-b utoxycarbonyl)carbamate. 1 H NMR (400 MHz, CDCl 3 ) δ 7.51 - 7.55 (m, 1 H) 7.32 - 7.34 (m, 1 H) 7.28 - 7.31 (m, 1 H) 7.04 - 7.07 (m, 1 H) 6.88 - 6.93 (m, 1 H) 4.33 - 4.39 (m, 2 H) 5.74 (s, 1 H) 4.13 (q, J=7.2 Hz, 2 H) 3.96 - 4.09 (m, 2 H) 3.67 - 3.79 (m, 2 H) 3.45 (br t, J=5.2 Hz, 2 H) 3.30 - 3.35 (m, 2 H) 2.09 - 2.13 (m, 2 H) 1.56 (s, 18 H) 1.41 (s, 3 H). Step 5: [0262] To a solution of tert-butyl (3-(4-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)-1,4-dia zepan-1- yl)-6-ethoxypyrimidin-2-yl)prop-2-yn-1-yl)(tert-butoxycarbon yl)carbamate (50 mg, 75.67 µmol, 1 eq) in DCM (1 mL), was added TFA (1 M, 378.35 µL, 5 eq). The mixture was stirred at room temperature for 1 h. The solvents were evaporated in vacuo to give 2-(6-amino-5-(4-(2-(3-aminoprop-1-yn-1-yl)-6- ethoxypyrimidin-4-yl)-1,4-diazepan-1-yl)pyridazin-3-yl)pheno l. m/z (ESI + ) 459.2 (M-1) + . Step 6: [0263] To a solution of pyrazolo[1,5-a]pyrimidine-2-carboxylic acid (7.08 mg, 43.43 µmol, 1 eq) in DMF (1 mL), was added 2-(6-amino-5-(4-(2-(3-aminoprop-1-yn-1-yl)-6-ethoxypyrimidin -4-yl)-1,4- diazepan-1-yl)pyridazin-3-yl)phenol (20 mg, 43.43 µmol, 1 eq), HATU (16.51 mg, 43.43 µmol, 1 eq), and DIEA (11.23 mg, 86.86 µmol, 15.13 µL, 2 eq). The mixture was stirred at 0 °C for 1 hour. Saturated NH 4 Cl solution (1 mL) was added. The aqueous layer was extracted with ethyl acetate (2 × 0.5 mL). The combined organic layers were washed with brine (1 mL), dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (method A) to give N- (3-(4-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)-1,4-dia zepan-1-yl)-6-ethoxypyrimidin-2-yl)prop- 2-yn-1-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide. 1 H NMR (400 MHz, d4-MeOD) δ 14.23 - 14.28 (m, 1 H) 9.16 - 9.21 (m, 1 H) 9.13 - 9.16 (m, 1 H) 8.66 (dd, J=4.0, 1.6 Hz, 1 H) 7.81 - 7.87 (m, 1 H) 7.49 (s, 1 H) 7.23 (s, 2 H) 6.82 - 6.88 (m, 2 H) 6.17 (s, 1 H) 5.96 (s, 1 H) 4.33 (d, J=6.0 Hz, 2 H) 4.22 (q, J=6.8 Hz, 2 H) 3.37 - 3.43 (m, 2 H) 3.31 (s, 2 H) 3.23 (br dd, J=5.2, 4.4 Hz, 2 H) 3.16 (d, J=5.2 Hz, 1 H) 2.02 (br s, 2 H) 1.24 (t, J=7.2 Hz, 3 H). Example 5 Preparation of 2-(5-(4-(2-(3-(1H-benzo[d]imidazol-1-yl)prop-1-yn-1-yl)pyrim idin-4-yl)-1,4- diazepan-1-yl)-6-aminopyridazin-3-yl)phenol (Compound P-150) S [0264] To a solution of 3-bromoprop-1-yne (80%, 3.78 g, 25.39 mmol, 2.74 mL, 3.0 eq) in DMF (10 mL), was added K2CO3 (2.34 g, 16.93 mmol, 2.0 eq) and 1H-benzo[d]imidazole (1.00 g, 8.46 mmol, 1 eq). The mixture was stirred at 25 °C for 12 hours. Water (30 mL) was added, and the resulting mixture was extracted with ethyl acetate (2 × 60 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated to give a residue. The residue was purified by prep-HPLC (method A) to give 1-(prop-2-yn-1-yl)-1H-benzo[d]imidazole. 1 H NMR (400 MHz, CDCl3) δ 8.01 (s, 1H), 7.84 - 7.79 (m, 1H), 7.50 - 7.45 (m, 1H), 7.37 - 7.28 (m, 2H), 4.91 (d, J = 2.8 Hz, 2H), 2.49 (t, J = 2.4 Hz, 1H). Step 2: [0265] A mixture of 2-(6-amino-5-(4-(2-bromopyrimidin-4-yl)-1,4-diazepan-1-yl)py ridazin-3-yl)phenol (35.31 mg, 226.08 µmol, 2.0 eq), 1-(prop-2-yn-1-yl)-1H-benzo[d]imidazole (50 mg, 113.04 µmol, 1 eq), Pd(PPh 3 ) 2 Cl 2 (7.93 mg, 11.30 µmol, 0.1 eq), CuI (6.46 mg, 33.91 µmol, 0.3 eq), and DIEA (51.13 mg, 395.65 µmol, 68.91 µL, 3.5 eq) in DMF (0.5 mL) was degassed and purged with nitrogen. The mixture was stirred at 70 °C for 1 hour under a N 2 atmosphere. The reaction mixture was filtered and the filtrate was purified by prep-HPLC (method A) to give 2-(5-(4-(2-(3-(1H-benzo[d]imidazol-1-yl)prop-1-yn-1- yl)pyrimidin-4-yl)-1,4-diazepan-1-yl)-6-aminopyridazin-3-yl) phenol. 1 H NMR (400 MHz, d4-CD3OD) δ 8.32 (d, J = 3.2 Hz, 1H), 7.99 (d, J = 0.8 Hz, 1H), 7.78 - 7.67 (m, 2H), 7.59 (d, J = 8.0 Hz, 1H), 7.41 (s, 1H), 7.38 - 7.28 (m, 2H), 7.19 (t, J = 7.6 Hz, 1H), 6.88 (d, J = 8.0 Hz, 1H), 6.85 - 6.80 (m, 1H), 6.68 - 6.60 (m, 1H), 5.40 (s, 2H), 4.16 - 3.87 (m, 2H), 3.83 - 3.61 (m, 2H), 3.58 - 3.41 (m, 2H), 3.33 (d, J = 3.6 Hz, 2H), 2.13 - 2.05 (m, 2H). Example 6 Preparation of o-{5-[(R)-4-{2-[(E)-3-(dimethylamino)-1-propenyl]-4-pyrimidi nyl}-5-methyl-1,4- diazepan-1-yl]-6-amino-3-pyridazinyl}phenol (Compound P-218) S [0266] To a solution of (R)-2-(6-amino-5-(4-(2-bromopyrimidin-4-yl)-5-methyl-1,4-dia zepan-1- yl)pyridazin-3-yl)phenol (350 mg, 766.98 μmol, 1 eq), N,N-dimethylprop-2-yn-1-amine (191.28 mg, 2.30 mmol, 243.98 μL, 3 eq), DIEA (346.94 mg, 2.68 mmol, 467.58 μL, 3.5 eq), CuI (43.82 mg, 230.09 μmol, 0.3 eq) in DMF (3 mL) was added Pd(PPh3)2Cl2 (53.83 mg, 76.70 μmol, 0.1 eq) at 25 °C under N2. The reaction mixture was degassed and purged with N2 three times. The reaction mixture was stirred at 70 °C for 1 hour under a N2 atmosphere. The reaction mixture was partitioned between ethyl acetate (5 mL) and H 2 O (5 mL). The organic phase was separated, washed with brine (3 mL), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give (R)-2-(6-amino-5-(4-(2-(3-(dimethylamino)prop-1-yn-1- yl)pyrimidin-4-yl)-5-methyl-1,4-diazepan-1-yl)pyridazin-3-yl )phenol which was used in the following step directly. 1 H NMR (400 MHz, CD 3 OD) δ 8.15 - 7.99 (m, 1 H), 7.83 - 7.68 (m, 1 H), 7.55 - 7.45 (m, 1 H), 7.28 - 7.15 (m, 1 H), 7.00 - 6.85 (m, 2 H), 6.74 (d, J = 6.0 Hz, 1 H), 4.77 - 4.54 (m, 1 H), 4.16 - 3.99 (m, 1 H), 3.92 - 3.75 (m, 1 H), 3.69 - 3.54 (m, 2 H), 3.53 (s, 2 H), 3.38 (s, 1 H), 3.31 (d, J = 3.2 Hz, 1 H), 3.22 - 3.00 (m, 1 H), 2.92 - 2.72 (m, 1 H), 2.40 (s, 6 H), 1.32 - 1.20 (m, 4 H). Step 2: [0267] To a solution of (R)-2-(6-amino-5-(4-(2-(3-(dimethylamino)prop-1-yn-1-yl)pyri midin-4-yl)-5- methyl-1,4-diazepan-1-yl)pyridazin-3-yl)phenol (10 mg, 21.81 μmol, 1 eq) in THF (0.5 mL) was added Pd/C (5 mg, 21.81 μmol, 60% wt. %, 1 eq) at 25 °C under an argonatmosphere. The reaction mixture was stirred 25 °C for 1 hour under a H2 atmosphere. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (Phenomenex Luna C1875 mm × 30 mm × 3µm; Mobile phase: [water (+ 1% formic acid)-ACN]; B%: 1%-30%, 8 min gradient) to give o-{5-[(R)-4-{2-[(E)-3-(dimethylamino)-1-propenyl]-4-pyrimidi nyl}-5- methyl-1,4-diazepan-1-yl]-6-amino-3-pyridazinyl}phenol. 1 H NMR (400 MHz, CD 3 OD) δ 8.50 - 8.45 (m, 1 H), 8.13 - 8.12 (m, 1 H), 7.80 - 7.72 (m, 1 H), 7.52 - 7.49 (m, 1 H), 7.30 - 7.26 (m, 1 H), 6.92 - 6.85 (m, 2 H), 6.80 - 6.61 (m, 1 H), 4.13 - 4.12 (m, 1 H), 3.87 - 3.84 (m, 2 H), 3.63 - 3.60 (m, 5 H), 3.25 - 3.19 (m, 3 H), 3.15 – 3.10 (m, 6 H), 2.40 - 2.19 (m, 4 H), 1.36 - 1.28 (m, 3 H). Example 7 Preparation of o-[6-amino-5-(3-{2-[3-(dimethylamino)-1-propynyl]-4-pyridylo xy}-1-azetidinyl)-3- pyridazinyl]phenol (Compound P-387) Step 1: [0268] A solution of 4-bromo-6-chloropyridazin-3-amine (5 g, 23.99 mmol, 1 eq), azetidin-3-ol (2.63 g, 23.99 mmol, 1 eq, HCl) and DIEA (31.00 g, 239.87 mmol, 41.78 mL, 10 eq) in DMF (50 mL) was degassed and purged with N 2 , and the mixture was stirred at 120 °C for 12 hours under a N 2 atmosphere. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, 0 to 10% methanol in ethyl acetate) to give 1-(3-amino-6- chloropyridazin-4-yl)azetidin-3-ol. 1 H NMR (400 MHz, d 6 -DMSO) δ 6.32 (s, 1H), 5.73 (s, 2H), 5.68 (d, J = 6.4 Hz, 1H), 4.52 - 4.46 (m, 1H), 4.35 - 4.28 (m, 2H), 3.73 (dd, J = 4.8, 9.2 Hz, 2H). Step 2: [0269] A mixture of 1-(3-amino-6-chloropyridazin-4-yl)azetidin-3-ol (4.4 g, 21.93 mmol, 1 eq), [2- (methoxymethoxy)phenyl]boronic acid (4.39 g, 24.12 mmol, 1.1 eq), Pd(dppf)Cl 2 (1.60 g, 2.19 mmol, 0.1 eq) and Cs2CO3 (42.87 g, 131.59 mmol, 6 eq) in dioxane (45 mL) and water (22.5 mL) was degassed and purged with N 2 three times. The mixture was stirred at 80 °C for 5 hours under a N 2 atmosphere. The residue was diluted with water (50 mL) and extracted with ethyl acetate (3 × 50 mL). The combined organic layers were washed with brine (2 × 50 mL), dried over Na 2 SO 4 , filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was triturated with ACN (20 mL) to give 1-(3-amino-6-(2-(methoxymethoxy)phenyl)pyridazin-4-yl)azetid in-3-ol. 1 H NMR (400 MHz, d 6 - DMSO) δ 7.59 (d, J = 7.6 Hz, 1H), 7.34 (t, J = 7.6 Hz, 1H), 7.17 (d, J = 8.0 Hz, 1H), 7.07 (t, J = 7.6 Hz, 1H), 6.65 (s, 1H), 5.68 (s, 1H), 5.61 (s, 2H), 5.20 (s, 2H), 4.50 (d, J = 6.0 Hz, 1H), 4.28 (t, J = 7.2 Hz, 2H), 3.63 (t, J = 6.4 Hz, 2H), 3.38 - 3.36 (m, 3H). Step 3: [0270] To a solution of 1-(3-amino-6-(2-(methoxymethoxy)phenyl)pyridazin-4-yl)azetid in-3-ol (1 g, 3.31 mmol, 1 eq) in DMF (10 mL) was added NaH (661.47 mg, 16.54 mmol, 60% purity, 5 eq) in portions at 0 °C under N2. After 10 mins, 2-bromo-4-fluoro-pyridine (582.10 mg, 3.31 mmol, 1 eq) in DMF (5 mL) was added dropwise to the solution at 0 °C. The mixture was stirred at 20 °C for 1 hour. Saturated NH 4 Cl solution (10 mL) was added and the reaction extracted with ethyl acetate (3 × 10 mL). The combined organic layers were washed with brine (2 × 10 mL), dried over Na 2 SO 4 , filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was triturated with ACN (5 mL) to give 4-(3-((2-bromopyridin-4-yl)oxy)azetidin-1-yl)-6-(2-(methoxym ethoxy)phenyl)pyridazin- 3-amine. 1 H NMR (400 MHz, d 6 - DMSO) δ 8.24 (d, J = 6.0 Hz, 1H), 7.59 (dd, J = 1.6, 7.6 Hz, 1H), 7.39 - 7.29 (m, 1H), 7.21 - 7.15 (m, 2H), 7.08 (dt, J = 1.2, 7.6 Hz, 1H), 7.01 (dd, J = 2.4, 5.6 Hz, 1H), 6.73 (s, 1H), 5.66 (s, 2H), 5.23 (td, J = 2.8, 6.4 Hz, 1H), 5.19 (s, 2H), 4.49 (dd, J = 6.4, 9.6 Hz, 2H), 4.08 - 4.01 (m, 2H), 3.33 (s, 3H). Step 4: [0271] A solution of 4-(3-((2-bromopyridin-4-yl)oxy)azetidin-1-yl)-6-(2- (methoxymethoxy)phenyl)pyridazin-3-amine (140 mg, 305.47 μmol, 1 eq) in HCOOH (1.4 mL) was stirred at 20 °C for 5 hours. Saturated NaHCO3 solution (5 mL) was added and the mixture was extracted with ethyl acetate (3 × 2 mL). The combined organic layers were washed with brine (2 × 2 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC to give 4-(3-((2-bromopyridin-4-yl)oxy)azetidin-1-yl)-6-(2- (methoxymethoxy)phenyl)pyridazin-3-amine. 1 H NMR (400 MHz, d6-DMSO) δ 14.62 (s, 1H), 8.25 (d, J = 5.6 Hz, 1H), 7.92 (dd, J = 1.6, 8.4 Hz, 1H), 7.25 - 7.18 (m, 2H), 7.06 - 7.01 (m, 2H), 6.88 - 6.83 (m, 2H), 5.97 (s, 2H), 5.27 (dt, J = 3.6, 6.4 Hz, 1H), 4.65 (dd, J = 6.4, 9.6 Hz, 2H), 4.22 (dd, J = 3.2, 9.6 Hz, 2H) Step 5: [0272] A mixture of 4-(3-((2-bromopyridin-4-yl)oxy)azetidin-1-yl)-6-(2- (methoxymethoxy)phenyl)pyridazin-3-amine (20 mg, 48.28 μmol, 1 eq), N,N-dimethylprop-2-yn-1-amine (12.04 mg, 144.84 μmol, 15.36 μL, 3 eq), CuI (2.76 mg, 14.48 μmol, 0.3 eq), DIEA (31.20 mg, 241.40 μmol, 42.05 μL, 5 eq) and Pd(PPh 3 ) 2 Cl 2 (6.78 mg, 9.66 μmol, 0.2 eq) in DMF (0.2 mL) was degassed and purged with N2 three times. The mixture was stirred at 40 °C for 2 hours under a N2 atmosphere. The reaction mixture was filtered and the filtrate was purified by prep-HPLC (Phenomenex Luna C 18 75 mm × 30 mm × 3µm; Mobile phase: [water (+ 1% formic acid)-ACN]; B%: 1%-30%, 8 min gradient) to give o- [6-amino-5-(3-{2-[3-(dimethylamino)-1-propynyl]-4-pyridyloxy }-1-azetidinyl)-3-pyridazinyl]phenol. 1 H NMR (400 MHz, d6-DMSO) δ 14.97 - 13.52 (m, 1H), 8.40 (s, 1H), 8.26 - 8.04 (m, 1H), 7.92 (d, J = 7.6 Hz, 1H), 7.22 (t, J = 7.6 Hz, 1H), 7.07 - 7.00 (m, 2H), 6.98 - 6.93 (m, 1H), 6.88 - 6.82 (m, 2H), 5.97 (s, 2H), 5.30 - 5.22 (m, 1H), 4.65 (dd, J = 6.4, 9.6 Hz, 2H), 4.21 (dd, J = 3.2, 9.6 Hz, 2H), 3.49 (s, 2H), 2.26 (s, 6H). [0273] Each of the compounds set forth in Table 3 were prepared following the procedures set forth above. Table 3
Biological Examples SMARCA2 and SMARCA4 Degradation Assay [0274] Degradation of protein which is expressed from the SMARCA2 and SMARCA4 genes was monitored using engineered HiBiT-fusion HeLa cell lines from Promega. In brief, 384-well white opaque plates (Greiner) were seeded with SMARCA2-HiBiT or SMARCA4-HiBiT HeLa cells at 8,000 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 10 µM to 300 pM) using a TECAN D300e Digital Dispenser, and plates were subsequently incubated for 24 hours at 37° C.24-hours post-treatment, protein levels were quantified with the addition of HiBiT lytic buffer, LgBiT protein, and HiBiT substrate, according to manufacturer’s specifications. Plates were incubated on an orbital plate shaker for 10 minutes at room temperature. Resulting luminescent values were read out using a ClarioStar plate reader and used to construct dose-response curves and calculation of degradation DC50s (GraphPad Prism). [0275] Table 4 provides data from the assays. Activity of the tested compounds is provided in Table 4 below as follows: A = DC50 < 0.050 µM; B = 0.05 µM < DC50 < 0.50 µM; C = < 0.5 µM < DC50 <5.0 µM; D = DC50 > 5.0 µM. For SMARCA2 and SMARCA4 degradation activity @ 1 µM, +++ = > 70%; ++ = 30-70%; + = < 30%. Table 4
[0276] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. [0277] The disclosure illustratively described herein may suitably be practiced in the absence of any element or elements, limitation or limitations, not specifically disclosed herein. Thus, for example, the terms “comprising,” “including,” “containing,” etc. shall be read expansively and without limitation. Additionally, the terms and expressions employed herein have been used as terms of description and not of limitation, and there is no intention in the use of such terms and expressions of excluding any equivalents of the features shown and described or portions thereof, but it is recognized that various modifications are possible within the scope of the claims. [0278] All publications, patent applications, patents, and other references mentioned herein are expressly incorporated by reference in their entirety, to the same extent as if each were incorporated by reference individually. In case of conflict, the present specification, including definitions, will control. It is to be understood that while the disclosure has been described in conjunction with the above embodiments, that the foregoing description and examples are intended to illustrate and not limit the scope of the disclosure. Other aspects, advantages and modifications within the scope of the disclosure will be apparent to those skilled in the art to which the disclosure pertains.