Pyridone-based epigenetic modifiers and uses thereof

文档序号：1116967 发布日期：2020-09-29 浏览：8次中文

阅读说明：本技术 基于吡啶酮的表观遗传修饰剂及其用途 (Pyridone-based epigenetic modifiers and uses thereof ) 是由 G·R·撒切尔熊瑞赵颎李洋峰于 2018-12-01 设计创作，主要内容包括：本文描述了基于吡啶酮的化合物、其衍生物以及其药物制剂。在一些方面中,基于吡啶酮的化合物、其衍生物和/或其药物制剂可以被施用至有相应需要的受试者。在一些方面中,基于吡啶酮的化合物、其衍生物和/或其药物制剂可以调节BRD蛋白和/或BET蛋白的活性和/或功能。(Described herein are pyridone-based compounds, derivatives thereof, and pharmaceutical formulations thereof. In some aspects, the pyridone-based compounds, derivatives thereof, and/or pharmaceutical formulations thereof can be administered to a subject in need thereof. In some aspects, the pyridone-based compounds, derivatives thereof, and/or pharmaceutical formulations thereof may modulate the activity and/or function of a BRD protein and/or a BET protein.)

1. A compound according to formula XXV

Wherein R is₁Is that

WhereinR₂Is that

Wherein R is₃Is H, CH₃Or CH₂CH₃And is and

wherein X₁、X₂And X₃Each independently selected from the group consisting of: c or N.

2. The compound of claim 1, wherein the compound is selected from the group consisting of: (70) (71), (72), (73), (74), (126), (130), (131) and (132).

3. A compound according to formula XXIV

Wherein R is₁And R₂Each independently selected from CH₃Or a combination of H and a nitrogen atom,

wherein R is₃Is CH₃Or CH₂CH₃And is and

wherein X is C or N.

4. The compound of claim 3, wherein the compound is selected from the group consisting of: (22) and (23), (30) and (31).

5. A compound according to formula XXVI

Wherein R is₁₂Is C₁-C₃Alkyl radical, C₁-C₃Haloalkyl, propenyl, -CH₂(CO)CH＝CH₂Oxiran-2-ylmethyl or-CH₂(CO)CH₂Cl，

Wherein R is₁₁Is a nitrogen-containing bicyclic ringOr a tricyclic heteroaryl, aryl, or biaryl, each of which is optionally substituted with 1,2, or 3 substituents each independently selected from the group consisting of: -N (R)^a)S(O)₂R^b、-S(O)₂NR^aR^b、-C(O)NR^aR^b、-N(R^a)C(O)R^b、-NR^aR^b、-(C₁-C₆Alkylene) R^c、-(C₁-C₃Cycloalkylene) R^cAryl, heteroaryl, and- (C)₁-C₆Alkylene) R^cR^c’-H, halogen, -CN, propenyl, C₁-C₃Alkyl radical, C₁-C₃Haloalkyl, -OR₇₀、-NR₇₀R₇₀、-C(O)OR₇₀、-C(O)NR₇₀R₇₀、-S(O)₂R₇₀、-S(O)₂NR₇₀R₇₀、-CH₂(CO)CH＝CH₂Oxiran-2-ylmethyl, and-CH₂(CO)CH₂Cl and R₇₀，

Wherein X is optionally present and, when present, is selected from-O-, -C (O) -, -N (R)₇₇) -and-CH (R)₇₀)-，

R₇₇Selected from the group consisting of: -H, halogen, -CN, C₁-C₃Haloalkyl, -OR₇₀、-NR₇₀R₇₀、-C(O)OR₇₀、-C(O)NR₇₀R₇₀、-S(O)₂R₇₀、-S(O)₂NR₇₀R₇₀And R₇₀，

Wherein R is₇₀Each occurrence is independently selected from the group consisting of: c₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, halogen, C₁-C₆Haloalkyl, -CN, -NO₂、-OR^e、-S(O)₂NR^eR^f、-C(O)R^e、-C(O)NR^eR^f、-NR^eR^f、-N(R^e)C(O)R^f、-(C₁-C₆Alkylene) -OR^e、-(C₁-C₆Alkylene) -C (O) NR^eR^f、-(C₁-C₆Alkylene) -NR^eR^fAnd- (C)₁-C₆Alkylene) -N (R)^e)C(O)R^f，

Wherein R is^aAnd R^bIndependently at each occurrence, selected from the group consisting of: H. c₁-C₆Alkenyl radical, C₁-C₆Alkynyl, C₁-C₆Haloalkyl, R^cAnd C₁-C₆Alkyl radical, wherein said C₁-C₆The alkyl group is optionally substituted with one substituent selected from the group consisting of: -OR^e、-NR^eR^f、-C(O)OR^e、-C(O)NR^eR^f、-S(O)₂R^e、-S(O)₂NR^eR^fAnd R^c，

Wherein R is^cAnd R^c’Each occurrence is independently selected from the group consisting of: aryl, heteroaryl, heterocycle, cycloalkyl, and cycloalkenyl, and wherein each R^cThe radical being optionally substituted by 1,2,3, 4 or 5R^dThe substitution of the group(s),

wherein R is^dEach occurrence is independently selected from the group consisting of: c₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, halogen, C₁-C₆Haloalkyl, -CN, -NO₂、-OR^e、-S(O)₂NR^eR^f、-C(O)R^e、-C(O)NR^eR^f、-NR^eR^f、-N(R^e)C(O)R^f、-(C₁-C₆Alkylene) -OR^e、-(C₁-C₆Alkylene) -C (O) NR^eR^f、-(C₁-C₆Alkylene) -NR^eR^fAnd- (C)₁-C₆Alkylene) -N (R)^e)C(O)R^f，

And wherein R^eAnd R^fEach occurrence is independently selected from the group consisting of: H. c₁-C₆Alkyl radical, C₁-C₆Cycloalkyl, aryl, heteroaryl and C₁-C₆A haloalkyl group.

6. The compound of claim 5, wherein the compound is according to formula I

Wherein R is₁₂Is C₁-C₃Alkyl radical, C₁-C₃Haloalkyl, propenyl, -CH₂(CO)CH＝CH₂Oxiran-2-ylmethyl or CH₂(CO)CH₂Cl，

Wherein R is₁₁Is a nitrogen-containing bicyclic or tricyclic heteroaryl, each of which is optionally substituted with 1,2, or 3 substituents each independently selected from the group consisting of: -N (R)^a)S(O)₂R^b、-S(O)₂NR^aR^b、-C(O)NR^aR^b、-N(R^a)C(O)R^b、-NR^aR^b、-(C₁-C₆Alkylene) R^c、-(C₁-C₃Cycloalkylene) R^cAryl, heteroaryl and- (C)₁-C₆Alkylene) R^cR^c’，

Wherein R is^aAnd R^bEach occurrence is independently selected from the group consisting of: H. c₁-C₆Alkenyl radical, C₁-C₆Alkynyl, C₁-C₆Haloalkyl, R^cAnd C₁-C₆An alkyl group, a carboxyl group,

wherein said C₁-C₆The alkyl group is optionally substituted with one substituent selected from the group consisting of: -OR^e、-NR^eR^f、-C(O)OR^e、-C(O)NR^eR^f、-S(O)₂R^e、-S(O)₂NR^eR^fAnd R^c，

And wherein R^eAnd R^fEach occurrence is independently selected from the group consisting of: H. c₁-C₆Alkyl radical, C₁-C₆Cycloalkyl, aryl, heteroaryl and C₁-C₆A haloalkyl group.

7. The compound of any one of claims 5 or 6, wherein the compound is according to formula II

Wherein R is²¹is-N (R)^a)S(O)₂R^b、-S(O)₂NR^aR^b、-S(O)₂R^a、-C(O)NR^aR^b、-N(R^a)C(O)R^b、-NR^aR^bOr- (C)₁-C₆Alkylene) R^c，

Wherein R is^aAnd R^bEach occurrence is independently selected from the group consisting of: H. c₁-C₆Alkyl radical, C₁-C₆Alkenyl radical, C₁-C₆Alkynyl, C₁-C₆Haloalkyl, R^cAnd C₁-C₆Alkyl radical, wherein said C₁-C₆The alkyl group is optionally substituted with one substituent selected from the group consisting of: -OR^y1、-NR^y3R^y4、-C(O)OR^y2、-C(O)NR^y3R^y4、-S(O)₂R^y1、-S(O)₂NR^y3R^y4And R^c，

Wherein R is^y1Each occurrence is independently selected from the group consisting of: H. c₁-C₆Alkyl radical, C₁-C₆Cycloalkyl, aryl, heteroaryl and C₁-C₆A halogenated alkyl group,

wherein R is^y2Each occurrence is independently selected from the group consisting of: H. c₁-C₆Alkyl radical, C₁-C₆Cycloalkyl, aryl, heteroaryl and C₁-C₆A halogenated alkyl group,

wherein R is^y3Each occurrence is independently selected from the group consisting of: H. c₁-C₆Alkyl radical, C₁-C₆Cycloalkyl, aryl, heteroaryl and C₁-C₆A halogenated alkyl group,

wherein R is^y4Each occurrence is independently selected from the group consisting of: H. c₁-C₆Alkyl radical, C₁-C₆Cycloalkyl, aryl, heteroaryl and C₁-C₆A halogenated alkyl group,

wherein R is²²Selected from the group consisting of: - (C)₁-C₆Alkylene) R^c、-(C₁-C₃Cycloalkylene) R^cAnd- (C)₁-C₆Alkylene) R^cR^c’，

Wherein R is^cAnd R^c’Each occurrence is independently selected from the group consisting of: aryl, heteroaryl, and heteroaryl,Heteroaryl, heterocycle, cycloalkyl and cycloalkenyl, and each R^cThe radical being optionally substituted by 1,2,3, 4 or 5R^dThe substitution of the group(s),

And wherein R^eAnd R^fEach occurrence is independently selected from the group consisting of: H. c₁-C₆Alkyl and C₁-C₆A haloalkyl group.

8. The compound of any one of claims 5 or 6, wherein the compound is according to formula III

Wherein R is₃₁Selected from the group consisting of: c₁-C₆Alkenyl radical, C₁-C₆Cycloalkyl and C₁-C₆A halogenated alkyl group,

wherein R is₃₂Selected from the group consisting of: c₁-C₆Alkenyl radical, C₁-C₈Cycloalkyl, -H, -D, C₁-C₈Substituted cycloalkylene, substituted aryl and substituted heteroaryl,

and wherein R₃₃、R₃₄、R₃₅、R₃₆And R₃₇Each independently selected from the group consisting of: -H, halogen, -CN and C₁-C₃A haloalkyl group.

9. The compound of any one of claims 5 or 6, wherein the compound is according to formula IV

Wherein R is₄₁Selected from the group consisting of: c₁-C₆Alkylene radical, C₁-C₆Cycloalkyl and C₁-C₆A halogenated alkyl group,

wherein R is₄₂Selected from the group consisting of: c₁-C₆Alkenyl radical, C₁-C₈Cycloalkyl, -H, -D, C₁-C₈Substituted cycloalkylene, substituted aryl, substituted heteroaryl,

and wherein R₄₃、R₄₄、R₄₅、R₄₆And R₄₇Each independently selected from the group consisting of: -H, halogen, -CN and C₁-C₃A haloalkyl group.

10. The compound of any one of claims 5 or 6, wherein the compound is according to formula V

Wherein R is₅₁Selected from the group consisting of: c₁-C₆Alkenyl radical, C₁-C₆Cycloalkyl and C₁-C₆A halogenated alkyl group,

wherein R is₅₂Selected from the group consisting of: c₁-C₆Alkenyl radical, C₁-C₈Cycloalkyl, -H, -D, C₁-C₈Substituted cycloalkylene, substituted aryl and substituted heteroaryl,

and wherein R₅₃、R₅₄、R₅₅、R₅₆And R₅₇Each independently selected from the group consisting of: -H, halogen, -CN and C₁-C₃A haloalkyl group.

11. The compound of any one of claims 5 or 6, wherein the compound is according to formula VI

Wherein X is C or N, or a salt thereof,

wherein R is₆₁Selected from the group consisting of: c₁-C₆Alkenyl radical, C₁-C₆Cycloalkyl and C₁-C₆A halogenated alkyl group,

wherein R is₆₂Selected from the group consisting of: c₁-C₆Alkenyl radical, C₁-C₈Cycloalkyl, -H, -D, C₁-C₈Substituted cycloalkylene, substituted aryl and substituted heteroaryl,

and wherein R₆₃、R₆₄、R₆₅、R₆₆And R₆₇Each independently selected from the group consisting of: -H, halogen, -CN and C₁-C₃A haloalkyl group.

12. The compound of any one of claims 5 or 6, wherein the compound is according to formula IX,

wherein X is C or N, or a salt thereof,

wherein R is₉₁Selected from the group consisting of: c₁-C₆Alkenyl radical, C₁-C₆Cycloalkyl and C₁-C₆A halogenated alkyl group,

wherein R is₉₂Selected from the group consisting of: c₁-C₆Alkenyl radical, C₁-C₈Cycloalkyl, -H, -D, C₁-C₈Substituted cycloalkylene, substituted aryl and substituted heteroaryl,

and wherein R₉₃、R₉₄、R₉₅、R₉₆And R₉₇Each independently selected from the group consisting of: -H, halogen, -CN and C₁-C₃A haloalkyl group.

13. The compound of any one of claims 5 or 6, wherein the compound is according to formula XVI

Wherein R is₁₃₃Selected from the group consisting of: c₁-C₆Alkenyl radical, C₁-C₆Cycloalkyl and C₁-C₆A halogenated alkyl group,

wherein R is₁₃₄Selected from the group consisting of: c₁-C₆Alkenyl radical, C₁-C₈Cycloalkyl, -H, -D, C₁-C₈Substituted cycloalkylene, substituted aryl and substituted heteroaryl,

wherein R is₁₃₅、R₁₃₆、R₁₃₇、R₁₃₈And R₁₃₉Each independently selected from the group consisting of: -H, halogen, -CN and C₁-C₃A haloalkyl group.

14. The compound of any one of claims 5 or 6, wherein the compound is according to formula XVII

Wherein R is₁₄₁Selected from the group consisting of: c₁-C₆Alkenyl radical, C₁-C₈Cycloalkyl, -H, -D, C₁-C₈Substituted sub-ringsAlkyl, substituted aryl and substituted heteroaryl,

and wherein R₁₄₂、R₁₄₃、R₁₄₄、R₁₄₅And R₁₄₆Each independently selected from the group consisting of: -H, halogen, -CN and C₁-C₃A halogenated alkyl group,

and wherein R₁₄₀Selected from the group consisting of: c₁-C₆Alkenyl radical, C₁-C₈Cycloalkyl, -H, -D, C₁-C₈Substituted cycloalkylene, substituted aryl, and substituted heteroaryl.

15. The compound of any one of claims 5 or 6, wherein the compound is according to formula XIX

Wherein R is₁₅₆Is that

Wherein R is₁₅₇Is Me or CH₂CH₃，

Wherein R is₁₅₈Is Me, CH₂CH₃Or

Wherein R is₁₅₉Is H, CH₂CH₃Or

Wherein R is₁₆₀Is that

Wherein R is₁₆₁Is H, Me or Cl, or a salt thereof,

wherein R is₁₆₂Is a compound of formula (I) or (II),

wherein R is₁₆₃Is a compound of formula (I) or (II),

and wherein R₁₆₄Is H or Me.

16. The compound of any one of claims 5 or 6, wherein the compound is according to formula XX

Wherein R is₁₆₅Is that

Wherein R is₁₆₆Is H, Me or Cl, or a salt thereof,

wherein R is₁₆₇Is a compound of formula (I) or (II),

wherein R is₁₆₈Is a compound of formula (I) or (II),

and wherein R₁₆₉Is H or Me.

17. The compound of any one of claims 5 or 6, wherein the compound is according to formula XXI

Wherein R is₃₁Is that

Wherein R is₁₅₇Is Me or CH₂CH₃、CH(CH₃)₂Wherein R is₁₅₈Can be Me, CH₂CH₃、CH(CH₃)₂Or

Wherein R is₃₁Selected from the group consisting of: c₁-C₆Alkyl radical, C₁-C₆Alkenyl radical, C₁-C₆Cycloalkyl and C₁-C₆A halogenated alkyl group,

wherein R is₃₂Selected from the group consisting of: c₁-C₆Alkyl radical, C₁-C₆Alkenyl radical, C₁-C₈Cycloalkyl, -H, -D, C₁-C₈Substituted cycloalkylene, substituted aryl and substituted heteroaryl,

and wherein R₃₃、R₃₄、R₃₅、R₃₆、R₃₇、R₃₃'、R₃₄'、R₃₅'、R₃₆' and R₃₇' each is independently selected from the group consisting of: -H, halogen, -CN, C₁-C₃Haloalkyl, C₁-C₆Cycloalkyl radical, C₁-C₆Alkylamine, C₁-C₆Cycloalkylamine, C₁-C₆Alkyl esters and C₁-C₆An alkylamide.

18. The compound of any one of claims 5 or 6, wherein the compound is according to formula XXII,

wherein R is₃₁Is that

Wherein R is₁₅₇Is Me, CH₂CH₃Or CH (CH)₃)₂，

Wherein R is₃₂Selected from the group consisting of: c₁-C₆Alkyl radical, C₁-C₆Alkenyl radical, C₁-C₈Cycloalkyl, -H, -D, C₁-C₈Substituted cycloalkylene, substituted aryl and substituted heteroaryl,

and wherein R₃₃、R₃₄、R₃₅、R₃₆、R₃₇、R₃₄’、R₃₅’、R₃₆’、R₃₇' each is independently selected from the group consisting of: -H, halogen, -CN, C₁-C₃Haloalkyl, C₁-C₆Cycloalkyl radical, C₁-C₆Alkylamine, C₁-C₆Cycloalkylamine, C₁-C₆Alkyl esters and C₁-C₆An alkylamide.

19. The compound of any one of claims 5 or 6, wherein the compound is according to formula XXIII,

wherein R is²¹is-N (R)^a)S(O)₂R^b、-S(O)₂NR^aR^b、-S(O)₂R^a、-C(O)NR^aR^b、-N(R^a)C(O)R^b、-NR^aR^bOr- (C)₁-C₆Alkylene) R^c，

Wherein R is^aAnd R^bEach occurrence is independently selected from the group consisting of: H. c₁-C₆Alkyl radical, C₁-C₆Alkenyl radical, C₁-C₆Alkynyl, C₁-C₆Haloalkyl, R^cAnd C₁-C₆Alkyl radical, wherein said C₁-C₆The alkyl group can be substituted with one substituent selected from the group consisting of: -OR^y1、-NR^y3R^y4、-C(O)OR^y2、-C(O)NR^y3R^y4、-S(O)₂R^y1、-S(O)₂NR^y3R^y4And R^c，

Wherein R is^y1Each occurrence is independently selected from the group consisting of: H. me or CH₂CH₃、CH(CH₃)₂，

Wherein R is^y2Each occurrence is independently selected from the group consisting of: H. me or CH₂CH₃、CH(CH₃)₂，

Wherein R is^y3Each occurrence is independently selected from the group consisting of: H. me or CH₂CH₃、CH(CH₃)₂，

Wherein R is^y4Each occurrence is independently selected from the group consisting of: H. me or CH₂CH₃、CH(CH₃)₂，

Wherein R is²²Selected from the group consisting of: - (C)₁-C₆Alkylene) R^c、-(C₁-C₃Cycloalkylene) R^cAnd- (C)₁-C₆Alkylene) R^cR^c’，

Wherein R is^cAnd R^c’Each occurrence is independently selected from the group consisting of: aryl, heteroaryl, heterocycle, cycloalkyl, and cycloalkenyl; and each R^cThe radical can optionally be substituted by 1,2,3, 4 or 5R^dThe substitution of the group(s),

And wherein R^eAnd R^fCan be independently selected at each occurrence from the group consisting of: H. c₁-C₆Alkyl and C₁-C₆A haloalkyl group.

20. The compound of claim 5, wherein the compound is according to formula VII

Wherein X is selected from the group consisting of: -O-, -C (O) -, -N (R)₇₇) -and-CH (R)₇₀)-，

Wherein R is₇₁Selected from the group consisting of: c₁-C₃Alkyl radical, C₁-C₃Haloalkyl, propenyl, -CH₂(CO)CH＝CH₂Oxiran-2-ylmethyl and CH₂(CO)CH₂Cl，

Wherein R is₇₂、R₇₃、R₇₄、R₇₅、R₇₆And R₇₇Each independently selected from the group consisting of: -H, halogen, -CN, C₁-C₃Haloalkyl, -OR₇₀、-NR₇₀R₇₀、-C(O)OR₇₀、-C(O)NR₇₀R₇₀、-S(O)₂R₇₀、-S(O)₂NR₇₀R₇₀And R₇₀，

Wherein R is₇₀Each occurrence is independently selected from the group consisting of: c₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, halogen, C₁-C₆Haloalkyl, -CN, -NO₂、-OR^e、-S(O)₂NR^eR^f、-C(O)R^e、-C(O)NR^eR^f、-NR^eR^f、-N(R^e)C(O)R^f、-(C₁-C₆Alkylene) -OR^e、-(C₁-C₆Alkylene) -C(O)NR^eR^f、-(C₁-C₆Alkylene) -NR^eR^fAnd- (C)₁-C₆Alkylene) -N (R)^e)C(O)R^f，

And wherein R^eAnd R^fEach occurrence is independently selected from the group consisting of: H. c₁-C₆Alkyl and C₁-C₆A haloalkyl group.

21. The compound of claim 5, wherein the compound is according to formula VIII

Wherein R is₈₁、R₈₂And R₈₃Each independently selected from the group consisting of: c₁-C₃Alkyl radical, C₁-C₃Haloalkyl, propenyl, -CH₂(CO)CH＝CH₂Oxiran-2-ylmethyl and CH₂(CO)CH₂Cl。

22. A compound according to formula X

Wherein each X is C or N at each occurrence,

wherein R is₉₈Is a group of H or Me, and,

wherein R is₉₉Selected from the group consisting of: me, Et and CH (CH)₂)₂，

Wherein R is₁₀₀Selected from the group consisting of:

wherein R is₁₀₁Selected from the group consisting of: cl, F, H, Me, cycloheteroalkyl and

wherein R is₁₀₂Selected from the group consisting of: H. cl, F, OH, CF₃And a CN group, wherein the CN group is a group,

wherein R is₁₀₃Selected from the group consisting of: cl, F, H,

wherein R is₁₀₄Is a compound of formula (I) or (II),

and wherein R₁₀₅Is H or

23. A compound according to formula XII

Wherein R is₁₀₉Is that

Wherein R is₁₁₀Is Me or CH₂CH₃，

Wherein R is₁₁₁Is F, H, Cl or CN, and the content is,

wherein R is₁₁₂Is H, Cl or F, and the ratio of,

and wherein R₁₁₃Is H, Me, Cl or F.

24. A compound according to formula XIII

Wherein R is₁₁₄Is Me or CH₂CH₃，

Wherein R is₁₁₅Is selected from the group consisting ofThe group consisting of:

wherein R is₁₁₆Is H, F or N (CH)₃)₂，

Wherein R is₁₁₇Is H, Cl, F, CF₃Or a group of groups Me,

wherein R is₁₁₈Is H, Me or CF₃，

Wherein R is₁₁₉Is H, F or N (CH)₃)₂，

Wherein R is₁₂₀Is H, Me or CF₃，

And wherein R₁₂₁Is H or Me.

25. A compound according to formula XIV

Wherein R is₁₂₂Is Me or CH₂CH₃，

Wherein R is₁₂₃Is that

Wherein R is₁₂₄Is that

Wherein R is₁₂₅Is a compound of formula (I) or (II),

wherein R is₁₂₆Is a group of H or Me, and,

and wherein R₁₂₇Is H or Me.

26. A compound according to formula XV

Wherein R is₁₂₈Is that

Wherein R is₁₂₉Is Me or CH₂CH₃，

Wherein R is₁₃₀Is a compound of formula (I) or (II),

wherein R is₁₃₁Is a group of H or Me, and,

wherein R is₁₃₂Is a group of H or Me, and,

and wherein X is C or N.

27. A compound according to formula XVIII

Wherein R is₁₄₇Is a group of H or Me, and,

wherein R is₁₄₈Is that

Wherein R is₁₄₉Is H, CH₂CH₃Or

Wherein R is₁₅₀Is that

Wherein R is₁₅₁Is Me, Et or CH (CH)₂)₂，

Wherein R is₁₅₂Is H, Me or Cl, wherein R₁₅₃Can be H or F, and can be,

wherein R is₁₅₄Is a compound of formula (I) or (II),

and wherein R₁₅₅Is H or Me.

28. A compound according to formula XI

Wherein R is₁₀₇Is a group of H or Me, and,

wherein R is₁₀₈Selected from the group consisting of: me, Et and CH (CH)₂)₂，

And wherein R₁₀₆Selected from the group consisting of:

29. a compound according to formula VII

Wherein X is selected from the group consisting of: -O-, -C (O) -, -N (R)₇₇) -and-CH (R)₇₀)-，

Wherein R is₇₁Selected from the group consisting of: c₁-C₃Alkyl radical, C₁-C₃Haloalkyl, propenyl, -CH₂(CO)CH＝CH₂Oxiran-2-ylmethyl and CH₂(CO)CH₂Cl，

And wherein R^eAnd R^fEach occurrence is independently selected from the group consisting of: H. c₁-C₆Alkyl and C₁-C₆A haloalkyl group.

30. A compound according to formula VIII

31. The compound of any one of claims 1-30, wherein the compound is any one of compounds (1) - (132).

32. The compound of any one of claims 1-30, wherein the compound is selected from the group consisting of: compound (2), compound (10), compound (22), compound (23), compound (30), compound (31), compound (70), compound (71), compound (72), compound (73), compound (74), compound (126), compound (130), compound (131), compound (132), and any combination thereof.

33. The compound of any one of claims 1-30, wherein the compound is selected from the group consisting of: (22) (23), (30), (31), and any combination thereof.

34. The compound of any one of claims 1-30, wherein the compound is selected from the group consisting of: (70) (71), (72), (73), (74), (126), (130), (131), (132) and any combination thereof.

35. The compound of any one of claims 1-30, wherein the compound is selected from the group consisting of: (70) (71), (72), and any combination thereof.

36. The compound of any one of claims 1-30, wherein the compound is selected from the group consisting of: (126) (130), (131), (132), and any combination thereof.

37. The compound of any one of claims 1-30, wherein the compound is selected from the group consisting of: (70) (71), (72), (73), (74) and any combination thereof.

38. The compound of any one of claims 1-37, wherein the compound has an IC for cells of less than 0.001 μ Μ, less than 0.01 μ Μ, less than 0.1 μ Μ, less than 1 μ Μ, less than 3 μ Μ and/or less than 5 μ Μ₅₀。

39. The compound of any one of claims 1-37, wherein the compound has an affinity for cells at from 0.0001 μIC in the range of M to 0.001. mu.M, from 0.001. mu.M to 0.01. mu.M, from 0.01. mu.M to 0.1. mu.M, 0.1. mu.M to 1. mu.M, 1. mu.M to 2. mu.M, 2. mu.M to 3. mu.M, 3. mu.M to 4. mu.M, or 4. mu.M to 5. mu.M₅₀。

40. The compound of any one of claims 38-39, wherein the cell is a cancer cell and/or a tolerogenic cancer cell.

41. The compound of any one of claims 1-40, wherein the compound is capable of specifically binding a bromodomain, a BRD protein, a BET protein, or any combination thereof.

42. The compound of any one of claims 1-40, wherein the compound is capable of modulating the activity or functionality of a BRD protein, a BET protein, or both.

43. The compound of any one of claims 1-40, wherein the compound is capable of reducing, inhibiting, or eliminating the activity or functionality of a BRD protein, a BET protein, or both a BRD protein and a BET protein.

44. A pharmaceutical formulation comprising:

the compound of any one of claims 1-43; and

a pharmaceutically acceptable carrier.

45. Use of a compound of any one of claims 1-43 in the manufacture of a medicament for the treatment or prevention of cancer or other disease for which histone modifications are modulated to treat and/or prevent a disease and/or symptoms thereof, wherein the other disease is arthritis, lupus, pulmonary hypertension, cardiac remodeling, neurodegenerative disease, or any combination thereof.

46. Use of a compound of any one of claims 1-43 or a pharmaceutical formulation of claim 44 for treating or preventing cancer or other disease whose histone modifications are modulated to treat and/or prevent a disease and/or symptoms thereof, wherein the other disease is arthritis, lupus, pulmonary hypertension, cardiac remodeling, neurodegenerative disease or any combination thereof.

47. A method, comprising:

administering to a subject a compound of any one of claims 1-43 or a pharmaceutical formulation of claim 44.

48. The method of claim 47, wherein the subject has or is suspected of having a cancer or other disease whose histone modifications are modulated to treat and/or prevent a disease and/or symptoms thereof, wherein the other disease is arthritis, lupus, pulmonary hypertension, cardiac remodeling, neurodegenerative disease, or any combination thereof.

49. A method of treating or preventing a disease or disorder in a subject in need thereof, the method comprising:

administering to the subject in need thereof the compound of any one of claims 1-43 or the pharmaceutical formulation of claim 44, and wherein the disease or disorder is cancer or other disease whose histone modifications are modulated to treat and/or prevent disease and/or symptoms thereof, wherein the other disease is arthritis, lupus, pulmonary hypertension, cardiac remodeling, neurodegenerative disease or any combination thereof.

50. A kit, comprising:

the compound of any one of claims 1-43 or the pharmaceutical formulation of claim 44; and

instructions for use immobilized in a tangible expression medium, wherein the instructions direct the administration of the compound or pharmaceutical formulation to a subject in need thereof, wherein the subject in need thereof has or is suspected of having a cancer or other disease whose histone modification is modulated to treat and/or prevent the disease and/or symptoms thereof, wherein the other disease is arthritis, lupus, pulmonary hypertension, cardiac remodeling, neurodegenerative disease or any combination thereof.

51. The kit of claim 50, wherein the kit further comprises an adjuvant.

52. The kit of claim 51, wherein the adjuvant is a chemotherapeutic agent.

53. A method, comprising:

contacting a cell with a compound of any one of claims 1-43 or a pharmaceutical formulation of claim 44.

54. The method of claim 53, wherein the cell is a cancer cell and/or a tolerogenic cancer cell.

55. The method of any one of claims 53-54, further comprising the step of specifically binding the compound to a bromodomain of a protein within the cell.

56. The method of any one of claims 53-55, further comprising the step of specifically binding the compound to a BRD protein, a BET protein, or both a BRD protein and a BET protein within the cell.

57. A method of modulating an activity or functionality of a BRD protein, a BET protein, or a BRD protein and a BET protein in a cell, the method comprising:

contacting the cell with a compound of any one of claims 1-43 or a pharmaceutical formulation of claim 44.

58. The method of claim 57, wherein the cell is a cancer cell and/or a tolerogenic cancer cell.

Brief Description of Drawings

Additional aspects of the present disclosure will be readily appreciated upon review of the following detailed description of the various aspects of the present disclosure, taken in conjunction with the accompanying drawings.

Figure 1 shows a graph demonstrating the growth inhibition of compound (23) in the MCF-7: CFR breast cancer cell model of fulvestrant tolerance.

Figure 2 shows a graph that can demonstrate growth inhibition of compound (20) in the fulvestrant-tolerant MCF-7: CFR breast cancer cell model.

Figure 3 shows a graph that can demonstrate growth inhibition of compound (21) in the fulvestrant-tolerant MCF-7: CFR breast cancer cell model.

Figure 4 shows a graph that can demonstrate growth inhibition of compound (22) in the fulvestrant-tolerant MCF-7: CFR breast cancer cell model.

Figure 5 shows a graph that can demonstrate growth inhibition of compound (2) in the fulvestrant-tolerant MCF-7: CFR breast cancer cell model.

Figure 6 shows a BromoScan of compound (70), which measures binding affinity in all bromodomain proteins, showing that compound (70) is selective for the BET family with sub-nanomolar potency.

Figure 7 shows a graph that can demonstrate growth inhibition of compound (70) in a fulvestrant-tolerant MCF-7: CFR breast cancer cell model.

Figure 8 shows a graph that can demonstrate growth inhibition of compound (71) in the fulvestrant-tolerant MCF-7: CFR breast cancer cell model.

Figure 9 shows a graph that can demonstrate growth inhibition of compound (72) in the fulvestrant-tolerant MCF-7: CFR breast cancer cell model.

Figure 10 shows a graph that can demonstrate growth inhibition of compound (70) in fulvestrant-tolerant MCF-7: CFR breast cancer cell models compared to other clinical baseline BET inhibitors, including BMS-98615, ABBV-075, AVR-771, AZD-5153, I-BET-762, and JQ1, showing the superior potency of compound (70).

Figure 11 shows a set of photographic images that may demonstrate the efficacy of compound (70) in the growth of 3D spheres of MCF-7: CFR that inhibit fulvestrant tolerance; in this assay, compound (70) was more potent than JQ1 and AZD-5153.

Detailed Description

Before the present disclosure is described in greater detail, it is to be understood that this disclosure is not limited to particular aspects described, but, of course, may vary per se. It is also to be understood that the terminology used herein is for the purpose of describing particular aspects only and is not intended to be limiting.

Unless defined otherwise, 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. Although any methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present disclosure, the preferred methods and materials are now described.

All publications and patents cited in this specification are herein incorporated by reference to disclose and describe the methods and/or materials in connection with which the publications are cited. All such publications and patents are herein incorporated by reference to the same extent as if each individual publication or patent was specifically and individually indicated to be incorporated by reference. Such incorporation by reference is expressly limited to the methods and/or materials described in the cited publications and patents and does not extend to any dictionary definitions derived from the cited publications and patents. Any dictionary definitions in the cited publications and patents that are not explicitly repeated in this application are not to be read as such, and should not be read as defining any terms appearing in the appended claims. The citation of any publication is for its disclosure prior to the filing date and should not be construed as an admission that the present disclosure is not entitled to antedate such publication by virtue of prior disclosure. Further, the dates of publication provided may be different from the actual publication dates which may need to be independently confirmed.

As will be apparent to those of skill in the art upon reading this disclosure, each of the individual aspects described and illustrated herein has discrete components and features which may be readily separated from or combined with the features of any of the other several aspects without departing from the scope or spirit of the present disclosure. Any recited method may be performed in the order of events recited, or in any other order that is logically possible.

Where a range is expressed, additional aspects include from the one particular value and/or to the other particular value. Where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise, between the upper and lower limit of that range and any other stated or intervening value in that stated range is encompassed within the disclosure. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges, and are also encompassed within the disclosure, subject to any specifically excluded limit in the stated range. Where stated ranges include one or both of the limits, ranges excluding either or both of those included limits are also included in the disclosure. For example, where a stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the disclosure, e.g., the phrase "x to y" includes ranges from 'x' to 'y' as well as ranges greater than 'x' and less than 'y'. Ranges can also be expressed as upper limits, e.g., 'about x, y, z, or less', and should be interpreted to include specific ranges of 'about x', 'about y', and 'about z', as well as ranges of 'less than x', 'less than y', and 'less than z'. Likewise, the phrase 'about x, y, z or greater' should be construed to include specific ranges of 'about x', 'about y' and 'about z' as well as ranges of 'greater than x', 'greater than y' and 'greater than z'. Further, the expression "about 'x' to 'y'" includes "about 'x' to about 'y'" in the case where 'x' and 'y' are numerical values.

It should be noted that ratios, concentrations, amounts, and other numerical data may be expressed herein in a range format. It will be further understood that the endpoints of each of the ranges are significant both in relation to the other endpoint, and independently of the other endpoint. It will also be understood that there are many values disclosed herein, and that each value is disclosed herein as "about" that particular value in addition to the value itself. For example, if the value "10" is disclosed, then "about 10" is also disclosed. Ranges may be expressed herein as from "about" one particular value, and/or to "about" another particular value. Similarly, when values are expressed as approximations, by use of the antecedent "about," it will be understood that the particular value forms another aspect. For example, if the value "about 10" is disclosed, then "10" is also disclosed.

It is to be understood that such a range format is used for convenience and brevity, and thus, should be interpreted in a flexible manner to include not only the numerical values explicitly recited as the limits of the range, but also to include all the individual numerical values or sub-ranges encompassed within that range as if each numerical value and sub-range is explicitly recited. For purposes of this specification, a numerical range of "about 0.1% to 5%" should be interpreted to include not only the explicitly recited values of about 0.1% to about 5%, but also include individual values (e.g., about 1%, about 2%, about 3%, and about 4%) and sub-ranges (e.g., about 0.5% to about 1.1%, about 0.5% to about 2.4%, about 0.5% to about 3.2%, and about 0.5% to about 4.4%, as well as other possible sub-ranges) within the indicated range.

As used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

As used herein, "about (about)", "about (approximately)", "substantially (substantally)", and the like, when used in conjunction with a numerical variable, can generally refer to the value of the variable as well as all values of the variable that are within experimental error (e.g., within a 95% confidence interval of the mean) or within +/-10% of the indicated value, subject to a wide range. As used herein, the terms "about," "approximately," "at or about," and "substantially" may mean that the amount or value in question may be an exact value or a value that provides an equivalent result or effect as recited in the claims or as taught herein. That is, it is to be understood that the amounts, dimensions, formulations, parameters and other amounts and characteristics are not and need not be exact, but may be approximate and/or larger or smaller, as desired, reflecting tolerances, conversion factors, rounding off, measurement error and the like, and other factors known to those of skill in the art such that an equivalent result or effect is obtained. In some cases, values that provide equivalent results or effects cannot be reasonably determined. Typically, an amount, size, formulation, parameter, or other amount or characteristic is "about", "approximately" or "at or about", whether or not explicitly stated as such. It is understood that where "about," "approximately," or "at or about" is used before a quantitative value, a parameter also includes the specific quantitative value itself, unless specifically stated otherwise.

Unless otherwise indicated, aspects of the present disclosure will employ techniques of molecular biology, microbiology, organic chemistry, biochemistry, physiology, cell biology, cancer biology, and the like, which are within the skill of the art. Such techniques are explained fully in the literature.

Before the aspects of the present disclosure are described in detail, it is to be understood that this disclosure is not limited to particular materials, reagents, reaction materials, manufacturing processes, etc., as such may, unless otherwise indicated, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular aspects only and is not intended to be limiting. It is also possible in the present disclosure that the steps may be performed in a different order than is logically possible, unless the context clearly dictates otherwise.

Definition of

As used herein, "active agent" or "active ingredient" refers to a substance, compound, or molecule that is biologically active or otherwise induces a biological or physiological effect on a subject to which it is administered. In other words, "active agent" or "active ingredient" refers to one or more components of a composition to which all or part of the effect of the composition is attributed. The active agent may be the primary active agent or, in other words, a component of the composition to which all or part of the effect of the composition is attributed. The active agent may be a minor agent or, in other words, a component of the composition to which additional portions of the composition are attributed and/or to which other effects of the composition are attributed.

As used herein, "administration" and similar phrases refer to the administration of: oral, topical, intravenous, subcutaneous, transdermal, intramuscular, intra-articular (intra-joint), parenteral, intraarterial, intradermal, intraventricular, intraosseous, intraocular, intracranial, intraperitoneal, intralesional, intranasal, intracardiac, intraarticular (intraarticular), intracavernosal, intrathecal, intravitreal, intracerebroventricular, intratympanic, intracochlear, rectal, vaginal, by inhalation, by catheter, stent, or via active or passive (e.g., by diffusion) administration of the composition to implanted reservoirs (reservoirs) or other devices of the perivascular space (perivasular) and adventitia (adventitia). For example, a medical device such as a stent may comprise a composition or formulation disposed on its surface, which may then be dissolved or otherwise distributed to surrounding tissues and cells. The term "parenteral" includes subcutaneous, intravenous, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques.

As used herein, "anti-infective" refers to a compound or molecule that can kill or inhibit the spread of an infectious agent. Anti-infective agents include, but are not limited to, antibiotics, antibacterial agents, antifungal agents, antiviral agents, and antiprotozoal agents.

The term "biocompatible" as used herein refers to a material, along with any metabolites or degradation products thereof, that is generally non-toxic to a recipient and does not cause any significant adverse effects to the recipient. Generally, biocompatible materials are materials that do not elicit a significant inflammatory or immune response when administered to a patient.

The term "biodegradable" as used herein generally refers to a material that will degrade or erode under physiological conditions into smaller units or chemicals that can be metabolized, eliminated, or excreted by a subject. Degradation time is a function of composition and morphology. The degradation time can be from a few hours to a few weeks.

As used herein, "cancer" may refer to one or more types of cancer, including, but not limited to, acute lymphocytic leukemia, acute myelogenous leukemia, adrenocortical carcinoma, kaposi's sarcoma, AIDS-related lymphoma, primary Central Nervous System (CNS) lymphoma, anal carcinoma, appendiceal carcinoma, astrocytoma, atypical teratoid/rhabdoid tumors, basal cell carcinoma of the skin, biliary tract carcinoma, bladder carcinoma, bone carcinoma (including, but not limited to ewing's sarcoma, osteosarcoma, and malignant fibrous histiocytoma), brain tumor, breast carcinoma, bronchial tumor, burkitt's lymphoma, carcinoid tumors, heart tumors, germ cell tumors, embryonic tumors, cervical carcinoma, cholangiocarcinoma, chordoma (chordoma), chronic lymphocytic leukemia, chronic myeloproliferative neoplasm, colorectal carcinoma, genital cell tumor, embryonic tumor, cervical carcinoma, biliary tract carcinoma, spinal cord tumor, and spinal cord tumor (chordoma), chronic lymphocytic leukemia, chronic myelogenous leukemia, chronic myeloproliferative, Craniopharyngioma, cutaneous T-cell lymphoma, ductal carcinoma in situ, endometrial carcinoma, ependymoma, esophageal carcinoma, olfactory neuroblastoma, extracranial germ cell tumor, extragonally germ cell tumor, ocular carcinoma (including but not limited to intraocular melanoma and retinoblastoma), carcinoma of fallopian tubes, carcinoma of gallbladder, renal carcinoma, gastric carcinoma, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor, central nervous system germ cell tumor, extracranial germ cell tumor, extragonally germ cell tumor, ovarian carcinoma, testicular carcinoma, trophoblastic disease, hairy cell leukemia, head and neck carcinoma, hepatocellular (liver) carcinoma, Langerhans's cell histiocytosis, Hodgkin's lymphoma, hypopharyngeal carcinoma, islet cell tumor, pancreatic neuroendocrine tumor, renal (renal cell) carcinoma, laryngeal carcinoma (aryngeal), leukemia, lip carcinoma, carcinoma of the head and neck carcinoma, gastrointestinal stromal carcinoma, carcinoma of the colon carcinoma, carcinoma of the head carcinoma, bladder, Oral cancer, lung cancer (non-small cell and small cell), lymphoma, melanoma, Merkel cell carcinoma (Merkel cell carcinoma), mesothelioma, metastatic squamous cell neck cancer, midline tract cancer (midline tract cancer) with and without NUT gene alterations, including NUT-midline cancer (NUT-midline cancer), multiple endocrine tumor syndrome, multiple myeloma, plasma cell neoplasm (plasmacytom), mycosis fungoides, myelodysplastic syndrome, myelodysplastic/myeloproliferative neoplasm, chronic myelogenous leukemia, nasal cancer, sinus cancer, non-hodgkin' S lymphoma, pancreatic cancer, paraganglioma, paranasal sinus cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pheochromocytoma, pituitary cancer, peritoneal cancer, prostate cancer, rectal cancer, rhabdomyosarcoma, salivary gland cancer, uterine sarcoma, S-zaza syndrome, Skin cancer, small intestine cancer, large intestine cancer (colon cancer), soft tissue sarcoma, T-cell lymphoma, laryngeal cancer (throat cancer), oropharyngeal cancer, nasopharyngeal cancer, hypopharyngeal cancer, thymoma (thymoma), thymus cancer (thymoma), thyroid cancer, transitional cell carcinoma of renal pelvis and ureter, cancer of urethra, cancer of uterus, vaginal cancer, cervical cancer, vascular tumors and carcinomas, cancer of the vulva, and Wilms Tumor (Wilms Tumor). The cancer may be breast cancer, endocrine-resistant breast cancer, CDK 4/6-resistant breast cancer, prostate cancer, castration-resistant prostate cancer (castrate-refractory cancer), myelofibrosis, acute myelogenous leukemia, diffuse large B-cell lymphoma. The cancer may be a cancer that is resistant to conventional or conventional therapies. The cancer may be resistant to endocrine therapy, kinase inhibitor therapy, cell cycle inhibitor therapy. The cancer may be a cancer that is resistant to CDK4/6 inhibitors, aromatase inhibitors, fulvestrant, tamoxifen (tamoxifen), or any combination thereof.

As used herein, "chemotherapeutic agent" or "chemotherapeutic agent" refers to a therapeutic agent used to prevent or treat cancer.

As used herein, "concentrated" refers to molecules or populations thereof, including but not limited to polynucleotides, peptides, polypeptides, proteins, antibodies or fragments thereof, that are distinguishable from their naturally occurring counterparts as a result of the concentration or number of molecules per volume being greater than the concentration or number of molecules per volume of their naturally occurring counterparts.

As used herein, "control" refers to an alternative subject or sample used in an experiment for comparative purposes, and included to minimize or distinguish the effects of variables other than independent variables.

The term "copolymer" as used herein generally refers to a single polymeric material that includes two or more different monomers. The copolymers may be in any form, such as random, block, graft, and the like. The copolymer may have any end group, including capped end groups or acidic end groups.

As used herein, "deoxyribonucleic acid (DNA)" and "ribonucleic acid (RNA)" may generally refer to any polyribonucleotide or polydeoxyribonucleotide, which may be unmodified RNA or DNA or modified RNA or DNA. The RNA may be in the form of non-coding RNA, such as tRNA (transfer RNA), snRNA (small nuclear RNA), rRNA (ribosomal RNA), antisense RNA, RNAi (RNA interference construct), siRNA (short interfering RNA), microrna (mirna), or ribozymes, aptamers, guide RNA (grna), or coding mRNA (messenger RNA).

As used herein, a "derivative" may refer to any compound having the same or similar core structure as the compound, but having at least one structural difference (including substitution, deletion, and/or addition of one or more atoms or functional groups). The term "derivative" does not mean that the derivative is synthesized from the parent compound as a starting material or intermediate, although this may be the case. The term "derivative" may include a prodrug or a metabolite of the parent compound. Derivatives include compounds wherein the free amino group in the parent compound has been derivatized to form an amine hydrochloride, p-toluenesulfonamide, benzyloxyformamide, tert-butoxyformamide, thiocarbamate-type derivative, trifluoroacetamide, chloroacetamide or formamide. Derivatives include compounds in which the carboxyl group in the parent compound has been derivatized to form methyl and ethyl esters or other types of esters or hydrazides. Derivatives include compounds in which the hydroxy group in the parent compound has been derivatised to form an O-acyl derivative or an O-alkyl derivative. Derivatives include compounds in which a hydrogen bond donating group in the parent compound is replaced by another hydrogen bond donating group such as OH, NH or SH. Derivatives include replacing a hydrogen bond accepting group in the parent compound with another hydrogen bond accepting group such as esters, ethers, ketones, carbonates, tertiary amines, imines, thiones, sulfones, tertiary amides, and sulfides. "derivatives" also include extensions in which the cyclopentane ring is replaced by saturated or unsaturated cyclohexane or other more complex, for example nitrogen-containing, rings, and extensions in which these rings are extended with various pendant groups. Derivatives may also include salt forms, such as pharmaceutically acceptable salt forms of the parent compound or a derivative thereof.

As used herein, "diluted" refers to an amount of a molecule, compound, or composition (including but not limited to a chemical compound, polynucleotide, peptide, polypeptide, protein, antibody, or fragment thereof) that indicates that a sample is distinguishable from its naturally-occurring counterpart by virtue of the concentration or number of molecules per volume being less than the concentration or number of molecules per volume of its naturally-occurring counterpart.

As used herein, "dose", "unit dose" or "dose" may refer to physically discrete units suitable for use in a subject, each unit comprising a predetermined amount of a pyridone-based compound described herein, a derivative thereof and/or a pharmaceutical formulation thereof calculated to produce a desired response or responses associated with its administration.

As used herein, "hydrate" refers to a compound formed by the addition of water. Typically, but not always, this will be a lattice structure incorporating water molecules. Hydrates include stoichiometric hydrates, as well as compositions containing variable amounts of water.

The term "hydrophilic" as used herein refers to a substance having strong polar groups that are readily soluble in water.

The term "hydrophobic" as used herein refers to a lack of affinity for water; materials that tend to repel water and do not absorb water nor dissolve in or mix with water.

As used herein, "immunomodulator" refers to an agent, such as a therapeutic agent, that is capable of modulating or modulating one or more immune functions or immune responses.

As used herein, "isolated" means separated from components (cellular and other components) in which polynucleotides, peptides, polypeptides, proteins, antibodies, or fragments thereof are normally associated in nature. A non-naturally occurring polynucleotide, peptide, polypeptide, protein, antibody, or fragment thereof does not need to be "isolated" to distinguish it from its naturally occurring counterpart.

The term "lipophilic" as used herein refers to compounds having affinity for lipids.

As used herein, "mammal" for therapeutic purposes may refer to any animal classified as a mammal, including humans, domestic and farm animals, non-human primates and zoo animals, sports animals, or pet animals, such as, but not limited to, dogs, horses, cats, and cattle.

As used herein, "modulate" refers to altering the behavior, characteristics, action, and/or activity of something, such as, but not limited to, a polynucleotide, a protein, an enzymatic process or other cellular process, a cellular function, a tissue function, an organ function, and/or a subject function or a disease-causing entity (e.g., a tumor, a bacterium, a virus, etc.).

The term "molecular weight" as used herein may generally refer to the mass or average mass of a material. In the case of polymers or oligomers, molecular weight may refer to the relative average chain length or relative chain mass of the bulk polymer. In practice, the molecular weight of polymers and oligomers can be assessed or characterized in a variety of ways, including Gel Permeation Chromatography (GPC) or capillary viscometry (capillary viscometry). GPC molecular weight is reported as weight average molecular weight (M)_w) Rather than number average molecular weight (M)_n). Capillary viscometry provides an estimate of molecular weight asInherent viscosity (capillary viscometry) determined from dilute polymer solutions using a specific set of concentration, temperature and solvent conditions.

As used herein, "negative control" refers to a "control" designed to produce no effect or result, provided that all reagents function properly and the experiment is performed properly. Other terms that are interchangeable with "negative control" include "pseudo", "placebo" and "mock".

As used herein, "neurodegenerative disease" refers to a disease that results in and/or is characterized by deterioration of one or more components of the brain and/or nervous system. Neurodegenerative diseases include, but are not limited to, Alzheimer's disease and related dementias, Parkinson's disease, and frontotemporal dementia.

As used herein, "pharmaceutical formulation" refers to the combination of an active agent, compound or ingredient with a pharmaceutically acceptable carrier or excipient, such that the composition is suitable for diagnostic, therapeutic or prophylactic use in vitro, in vivo or ex vivo.

As used herein, "pharmaceutically acceptable" can refer to compounds, materials, compositions, and/or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio, according to the guidelines of the agency, such as the Food and Drug Administration.

As used herein, "pharmaceutically acceptable carrier or excipient" refers to a carrier or excipient that is useful in preparing a pharmaceutical formulation, is generally safe, non-toxic, and neither biologically nor otherwise undesirable, and includes carriers or excipients that are acceptable for veterinary use as well as human pharmaceutical use. As used in the specification and claims, "pharmaceutically acceptable carrier or excipient" includes one and more than one such carrier or excipient.

As used herein, "pharmaceutically acceptable salt" refers to any acid addition salt or base addition salt whose counter ion is non-toxic to the subject to which they are administered in a pharmaceutical dosage of the salt.

As used herein, "positive control" refers to a "control" designed to produce the desired result, provided that all reagents function properly and the experiment is performed properly.

As used herein, "prophylactic" and "preventing" refer to preventing, slowing the progression of, or stopping a disease or condition before it occurs (even if not diagnosed) or while the disease or condition is still in a subclinical stage. "prophylactic" and "prevention" also refer to the partial or complete delay or elimination of recurrence of a disease, disorder, condition, or symptom thereof, or the re-acquisition of a disease, disorder, condition, or symptom thereof. "prophylactic" and "prevention" also refer to reducing the risk of a subject acquiring or regaining a disease, disorder, condition, or symptom thereof.

As used herein, "solvate" refers to a complex of variable stoichiometry formed by a solute (e.g., of formulas (I) - (XX) (a), (B), (C), (D), etc., or any other compound described herein or derivative thereof) and a solvent. Pharmaceutically acceptable solvates of the crystalline compounds may be formed, wherein solvent molecules are incorporated into the crystal lattice during crystallization. The incorporated solvent molecules may be water molecules or non-water containing molecules such as, but not limited to, ethanol, isopropanol, dimethyl sulfoxide, acetic acid, ethanolamine, and ethyl acetate molecules.

As used herein, the term "specific binding" may refer to a non-covalent physical association of a first moiety and a second moiety, wherein the association between the first moiety and the second moiety is at least 2-fold stronger, at least 5-fold stronger, at least 10-fold stronger, at least 50-fold stronger, at least 100-fold stronger, or stronger than the association of either moiety with most or all of the other moieties present in the environment in which the binding occurs. If the equilibrium dissociation constant Kd is under the conditions employed, for example inThe physiological condition such as a physiological condition inside a cell or a physiological condition consistent with cell survival is 10^-3M or less, 10^-4M or less, 10^-5M or less, 10^-6M or less, 10^-7M or less, 10^-8M or less, 10^-9M or less, 10^-10M or less, 10^-11M or less or 10^-12M or lower, the binding of two or more entities may be considered specific. In some embodiments, specific binding may be through a plurality of weaker interactions (e.g., a plurality of individual interactions, wherein each individual interaction is greater than 10^-3Kd of M is characteristic). In some embodiments, specific binding, which may be referred to as "molecular recognition," is a saturable binding interaction between two entities, depending on the complementary orientation of the functional groups on each entity. Examples of specific binding interactions include primer-polynucleotide interactions, aptamer-aptamer target interactions, antibody-antigen interactions, avidin-biotin interactions, ligand-receptor interactions, metal-chelate interactions, hybridization between complementary nucleic acids, molecule-protein interactions, and the like.

As used interchangeably herein, "subject," "individual," or "patient" may refer to a vertebrate organism, such as a mammal (e.g., a human). "subject" may also refer to a cell, population of cells, tissue, organ, or organism, preferably a human being and components thereof.

As used herein, "substantially pure" can mean that the substance of interest is the predominant substance present (i.e., it is more abundant than any other individual substance in the composition on a molar basis), and preferably, the substantially purified fraction is a composition in which the substance of interest constitutes about 50% of all substances present. Generally, a substantially pure composition will constitute more than about 80%, more preferably more than about 85%, 90%, 95%, and 99% of all materials present in the composition. Most preferably, the target substance is purified to substantial homogeneity (contaminant substances cannot be detected in the composition by conventional detection methods), wherein the composition consists essentially of a single substance.

As used interchangeably herein, the terms "sufficient" and "effective" may refer to an amount (e.g., mass, volume, dose, concentration, and/or time period) necessary to achieve one or more desired results. For example, a "therapeutically effective amount" refers to the amount needed to achieve one or more therapeutic effects. As another example, an "effective amount" refers to an amount necessary to achieve one or more desired effects. In some aspects, an "effective amount" can be a "therapeutically effective amount". The desired effect may include specific binding of a bromodomain, BRD protein and/or BET protein, modulation of the activity or function of a BRD protein and/or BET protein, inhibition of the activity or function of a BRD protein and/or BET protein, treatment and/or prevention of cancer or other diseases whose histone modification can be modulated to treat and/or prevent a disease and/or symptoms thereof, which other diseases may include, but are not limited to, arthritis, lupus, pulmonary hypertension, cardiac remodeling and/or neurodegenerative disease in a subject.

As used herein, "tangible medium of expression" may refer to a medium that is physically tangible and not merely abstract thinking or unrecorded spoken language. Tangible expression media include, but are not limited to, text on cellulose or plastic material or data stored on a suitable device such as flash memory or CD-ROM.

As used herein, "therapeutic" may refer to treating, curing and/or ameliorating a disease, disorder, condition or side effect, or to a reduction in the rate of progression of a disease, disorder, condition or side effect.

As used herein, the terms "treating" and "treatment" generally refer to obtaining a desired pharmacological and/or physiological effect. The effect may be, but need not be, prophylactic in the following respects: preventing or partially preventing a disease, condition, or condition thereof such as cancer or other disease whose histone modifications can be modulated to treat and/or prevent the disease and/or a condition thereof, which other disease may include, but is not limited to, arthritis, lupus, pulmonary hypertension, cardiac remodeling, and/or neurodegenerative disease. The effect can be therapeutic in terms of a partial or complete cure for a disease, condition, symptom, or adverse effect due to the disease, disorder, or condition. The term "treatment" as used herein encompasses any treatment of cancer or other disease whose histone modifications can be modulated to treat and/or prevent the disease and/or symptoms thereof, which other disease may include, but is not limited to, arthritis, lupus, pulmonary hypertension, cardiac remodeling and/or neurodegenerative disease in a subject, particularly a human, and may include any one or more of (a) preventing the disease from occurring in a subject who may be predisposed to the disease but has not yet been diagnosed as having the disease, (b) inhibiting the disease, i.e., arresting the development of the disease, and (c) relieving the disease, i.e., alleviating or ameliorating the disease and/or symptoms or conditions thereof To include subjects who already have the disorder, and/or subjects in which the disorder is to be prevented. As used herein, the term "treating" may include inhibiting a disease, disorder, or condition, e.g., arresting its progression; and alleviating the disease, disorder, or condition, e.g., causing regression of the disease, disorder, and/or condition. Treating a disease, disorder, or condition can include ameliorating at least one symptom of a particular disease, disorder, or condition, even if the underlying pathophysiology is not affected, such as treating pain in a subject by administering an analgesic agent, even if such agent does not treat the cause of the pain.

As used herein, "alkyl" and "alkylene" refer to a saturated hydrocarbon chain having a specified number of member atoms. The term "alkyl" may also refer to a radical (i.e., an alkane from which one hydrogen atom is removed) of a saturated aliphatic group, including straight-chain alkyl groups, branched-chain alkyl groups, cycloalkyl (alicyclic) groups, alkyl-substituted cycloalkyl groups, and cycloalkyl-substituted alkyl groups. "alkyl" also refers to a saturated hydrocarbon chain having a specified number of atoms.

The term "alkyl" (or "lower alkyl") as used herein may include both "unsubstituted alkyls" and "substituted alkyls," wherein the latter refers to alkyl moieties having one or more substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone. Such substituents include, but are not limited to, halogen, hydroxy, carbonyl (such as carboxy, alkoxycarbonyl, formyl, or acyl), thiocarbonyl (such as thioester, thioacetate, or thioformate), alkoxy, phosphoryl, phosphate, phosphonate, phosphinate, amino, amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, aralkyl, or an aromatic or heteroaromatic moiety.

As used herein, "lower alkyl" may refer to an alkyl group as defined above but having from one to ten carbons in its backbone structure, unless the number of carbons is otherwise specified. Likewise, "lower alkenyl" and "lower alkynyl" have similar chain lengths.

The skilled person will appreciate that the moiety substituted on the hydrocarbon chain may itself be substituted, if appropriate. For example, substituents of substituted alkyl groups may include halogen groups, hydroxyl groups, nitro groups, thiol groups, amino groups, azido groups, imino groups, amido groups, phosphoryl (including phosphonate and phosphinate) groups, sulfonyl (including sulfate, sulfonamido, sulfamoyl and sulfonate) groups, and silyl groups, as well as ethers, alkylthios, carbonyls (including ketones, aldehydes, carboxylates and esters), -CF groups₃CN and the like. Cycloalkyl groups may be substituted in the same manner.

As used herein, "C" is_1-6Alkyl "may refer to an alkyl group having any number of member atoms from 1 to 6, such as, for example, 1 to 4 atoms. Other alkyl groups may have any number of member atoms as indicated by the numbers given in the formula, like the previous onesAs an example, it can refer to an alkyl group having any number of member atoms within the specified range of member atoms. The alkyl group may be linear or branched. Representative branched alkyl groups have one, two, or three branches. Alkyl groups include methyl, ethyl, propyl (n-propyl and isopropyl), butyl (n-butyl, isobutyl and tert-butyl), pentyl (n-pentyl, isopentyl and neopentyl) and hexyl.

As used herein, "heterocyclic group" may refer to a non-aromatic ring, and having the indicated number of member atoms, being saturated or having one or more degrees of unsaturation, and, unless otherwise indicated, containing one or more heteroatoms.

As used herein, "heteroaryl" can refer to an aromatic ring having the indicated number of member atoms, and containing one or more heteroatoms, unless otherwise indicated. Bicyclic and other polycyclic systems with heteroaryl rings are described as fused systems.

The term "heteroalkyl," as used herein, may refer to a straight or branched chain or cyclic carbon-containing radical containing at least one heteroatom, or a combination thereof. Suitable heteroatoms include, but are not limited to, O, N, Si, P, Se, B, and S, wherein the phosphorus and sulfur atoms are optionally oxidized, and the nitrogen heteroatom is optionally quaternized. The heteroalkyl group may be substituted as defined above for the alkyl group.

As used herein, "alkoxy" or "alkoxy" as used herein may refer to an alkyl group as defined above having an oxygen group attached thereto. Representative alkoxy groups include methoxy, ethoxy, propoxy, t-butoxy, and the like. An "ether" is two hydrocarbons covalently linked by oxygen. Thus, a substituent of an alkyl group that renders the alkyl group an ether or the like an alkoxy group, for example, may be represented by one of-O-alkyl, -O-alkenyl, and-O-alkynyl. The terms "aryloxy" and "aryloxy" as used interchangeably herein may be represented by-O-aryl or-O-heteroaryl, wherein aryl and heteroaryl are defined as below. The alkoxy and aryloxy groups may be substituted as described above for alkyl.

As used herein, "amine" and "amino" (and protonated forms thereof) are art-recognized and refer to both unsubstituted amines and substituted amines, e.g., moieties that can be represented by the general formula:

wherein R, R 'and R' each independently represent hydrogen, alkyl, alkenyl, - (CH)₂)_m-R_COr R and R' together with the N atom to which they are attached form a heterocyclic ring having from 4 to 8 atoms in the ring structure; r_CRepresents aryl, cycloalkyl, cycloalkenyl, heterocycle or polycycle; and m is zero or an integer in the range of 1 to 8. In some embodiments, only one of R or R 'may be a carbonyl group, e.g., R, R' and the nitrogen together do not form an imide. In other embodiments, the term "amine" does not encompass amides, for example, where one of R and R' represents a carbonyl group. In a further embodiment, R and R' (and optionally R ") each independently represent hydrogen, alkyl or cycloalkyl, alkenyl or cycloalkenyl or alkynyl. Thus, the term "alkylamine" as used herein means an amine group as defined above having a substituted (as described above for alkyl) or unsubstituted alkyl group attached thereto, i.e. at least one of R and R' is an alkyl group.

As used herein, "amido" is art-recognized as a carbonyl substituted with an amino group and includes moieties that can be represented by the general formula:

wherein R and R' are as defined above.

As used herein, "aryl" may refer to C₅-C₁₀A meta-aromatic ring system, a heterocyclic ring system, a fused aromatic ring system, a fused heterocyclic ring system, a bi-aromatic ring system, or a bi-heterocyclic ring system. Broadly defined, "aryl" as used herein includes 5-, 6-, 7-, 8-, 9-and 10-membered monocyclic aromatic groups, which may include from zero to four heteroatoms, such as benzene, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine, pyrimidine and similar aromatic groups. Those aryl groups having heteroatoms in the ring structure may also be referred to as "aryl heterocycles" or "heteroaromatics". The aromatic ring may be substituted at one or more ring positions with one or more substituents including, but not limited to, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxy, alkoxy, amino (or quaternized amino), nitro, mercapto, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamido, ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaromatic moieties, -CF₃CN, -CN, and combinations thereof.

The term "aryl" can also include polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings (i.e., "fused rings"), wherein at least one of the rings is aromatic, e.g., the other cyclic ring or rings can be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, and/or heterocyclic. Examples of heterocycles include, but are not limited to, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolinyl, benzothiazolyl, benzotriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5, 2-dithiazinyl, dihydrofuro [2,3-b ] tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isanoyl, isobenzofuranyl, isochromanyl, isoindolyl, isoindolinyl, Isoindolinyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, methylenedioxyphenyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2, 3-oxadiazolyl, 1,2, 4-oxadiazolyl, 1,2, 5-oxadiazolyl, 1,3, 4-oxadiazolyl, oxazolidinyl, oxazolyl, oxindolyl (oxindolyl), pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, piperidinonyl (piperidonyl), 4-piperidonyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl (pyridinyl), pyridinyl (pyridinol), pyridinyl (pyridil), pyridoxal, pyridinyl, pyridini, Pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuryl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl, 6H-1,2, 5-thiadiazolyl, 1,2, 3-thiadiazolyl, 1,2, 4-thiadiazolyl, 1,2, 5-thiadiazolyl, 1,3, 4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thienyl, and xanthenyl. One or more of the rings may be substituted, as defined above for "aryl".

As used herein, "aralkyl" may refer to an alkyl group substituted with an aryl group (e.g., an aromatic or heteroaromatic group).

As used herein, "aralkoxy" may be represented by — O-aralkyl, wherein aralkyl is as defined above.

As used herein, "carbocycle" may refer to an aromatic or non-aromatic ring, wherein each atom of the ring is carbon.

As used herein, "heterocycle" or "heterocyclic" may refer to a monocyclic or bicyclic ring structure containing 3 to 10 ring atoms, and in some embodiments, from 5 to 6 ring atoms, wherein the ring atoms are carbon and one to four heteroatoms each selected from the group consisting of: non-peroxide oxygen, sulfur and N (Y), wherein Y is absent or is H, O, (C)₁-C₁₀) Alkyl, phenyl or benzyl, and optionally contains 1 to 3 double bonds and is optionally substituted with one or more substituents. Examples of heterocycles include, but are not limited to, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5, 2-dithiazinyl, dihydrofuro [2,3-b ] dihydrofuro]Tetrahydrofuran, furyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isatoiyl, isobenzofuryl, isochromanyl, isoindolyl, isoindolinyl, isoindolyl, isothiazolyl, isoxazolyl, methylenedioxyphenyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2, 3-oxadiazolyl, 1,2, 4-oxadiazolyl, 1,2, 5-oxadiazolyl, 1,3, 4-oxadiazolyl, oxazolidinyl, oxazolyl, oxepanyl (oxepanyl), oxetanyl (oxetanyl), oxindolyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxazinyl, oxaxazinyl, Phthalazinyl, piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl (pyridinyl)) Pyridyl (pyridil), pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydropyranyl, tetrahydroquinolinyl, tetrazolyl, 6H-1,2, 5-thiadiazinyl, 1,2, 3-thiadiazolyl, 1,2, 4-thiadiazolyl, 1,2, 5-thiadiazolyl, 1,3, 4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thienyl, and xanthenyl. The heterocyclic group may optionally be substituted at one or more positions with one or more substituents as defined above for alkyl and aryl, for example halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxy, amino, nitro, mercapto, imino, amido, phosphate, phosphonate, phosphinate, carbonyl, carboxy, silyl, ether, alkylthio, sulfonyl, ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaromatic moieties, -CF₃CN or the like.

The term "carbonyl" is art-recognized and includes such moieties as may be represented by the general formula:

wherein X is a bond or represents oxygen or sulphur and R' are as defined above. In the case where X is oxygen and R or R' is not hydrogen, the formula represents an "ester". Where X is oxygen and R is as defined above, the moiety is referred to herein as a carboxyl group, and in particular when R is hydrogen, the formula represents a "carboxylic acid". In the case where X is oxygen and R' is hydrogen, the formula represents a "formate". Typically, where the oxygen atom of the above formula is replaced by sulfur, the formula represents a "thiocarbonyl" group. In the case where X is sulfur and R or R' is not hydrogen, the formula represents a "thioester". Where X is sulfur and R is hydrogen, the formula represents a "thiocarboxylic acid". In the case where X is sulfur and R' is hydrogen, the formula represents a "thioformate". On the other hand, where X is a bond and R is other than hydrogen, the above formula represents a "ketone" group. Where X is a bond and R is hydrogen, the above formula represents an "aldehyde" group.

As used herein, "heteroatom" as used herein may refer to an atom of any element other than carbon or hydrogen. Exemplary heteroatoms include, but are not limited to, boron, nitrogen, oxygen, phosphorus, sulfur, silicon, arsenic, and selenium.

As used herein, "nitro" may refer to-NO₂(ii) a The term "halogen" denotes-F, -Cl, -Br or-I; the term "mercapto" refers to-SH; the term "hydroxy" refers to-OH; and the term "sulfonyl" refers to-SO₂-。

The term "substituted" as used herein may refer to all permissible substituents of compounds described herein. In the broadest sense, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds. Illustrative substituents include, but are not limited to, halogen, hydroxyl groups, or any other organic group containing any number of carbon atoms (e.g., 1 to 14 carbon atoms), and optionally include one or more heteroatoms such as oxygen, sulfur, or nitrogen groups in the form of linear, branched, or cyclic structures. Representative substituents include alkyl groups, substituted alkyl groups, alkenyl groups, substituted alkenyl groups, alkynyl groups, substituted alkynyl groups, phenyl groups, substituted phenyl groups, aryl groups, substituted aryl groups, heteroaryl groups, substituted heteroaryl groups, halogen groups, hydroxyl groups, alkoxy groups, substituted alkoxy groups, phenoxy groups, substituted phenoxy groups, aryloxy groups, substituted aryloxy groups, alkylthio groups, substituted alkylthio groups, phenylthio groups, substituted phenylthio groups, arylthio groups, substituted arylthio groups, cyano groups, isocyano groups, substituted isocyano groups, carbonyl groups, substituted carbonyl groups, carboxyl groups, substituted carboxyl groups, amino groups, substituted aryl groups, heteroaryl groups, halogen groups, hydroxyl groups, alkoxy groups, substituted alkoxy groups, phenoxy groups, substituted phenoxy groups, aryloxy groups, substituted aryloxy groups, alkylthio groups, substituted alkylthio groups, phenylthio groups, Amide compoundA radical group, a substituted acylamino group, a sulfonyl group, a substituted sulfonyl group, a sulfonic acid group, a phosphoryl group, a substituted phosphoryl group, a phosphonyl group, a substituted phosphonyl group, a polyaryl group, a substituted polyaryl group, C₃-C₂₀Cyclic group, substituted C₃-C₂₀Cyclic groups, heterocyclic groups, substituted heterocyclic groups, amino acid groups, peptide groups, and polypeptide groups.

Heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein that satisfy the valencies of the heteroatoms. It is understood that "substituted" or "substituted" includes the implicit proviso that such substitution is according to permitted valences of the atoms and substituents replaced, and that the substitution results in a stable compound, i.e., a compound that does not spontaneously undergo transformation, such as by rearrangement, cyclization, elimination, and the like.

As used herein, "suitable substituent" may refer to a chemically and pharmaceutically acceptable group, i.e., a moiety that does not significantly interfere with the preparation of, or eliminate the potency of, the compounds of the invention. Such suitable substituents may be routinely selected by those skilled in the art. Suitable substituents include, but are not limited to, the following: halogen, C₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₁-C₆Haloalkyl, C₁-C₆Alkoxy radical, C₁-C₆Haloalkoxy, C₂-C₆Alkynyl, C₃-C₈Cycloalkenyl group, (C)₃-C₈Cycloalkyl) C₁-C₆Alkyl, (C)₃-C₈Cycloalkyl) C₂-C₆Alkenyl, (C)₃-C₈Cycloalkyl) C₁-C₆Alkoxy radical, C₃-C₇Heterocycloalkyl group, (C)₃-C₇Heterocycloalkyl) C₁-C₆Alkyl, (C)₃-C₇Heterocycloalkyl) C₂-C₆Alkenyl, (C)₃-C₇Heterocycloalkyl) C₁-C₆Alkoxy radicalHydroxy, carboxy, oxo, sulfonyl, C₁-C₆Alkylsulfonyl, aryl, heteroaryl, aryloxy, heteroaryloxy, aralkyl, heteroaralkyl, arylalkoxy, heteroarylalkoxy, nitro, cyano, amino, C₁-C₆Alkylamino, di- (C)₁-C₆Alkyl) amino, carbamoyl, (C)₁-C₆Alkyl) carbonyl (C)₁-C₆Alkoxy) carbonyl (C)₁-C₆Alkyl) aminocarbonyl, di- (C)₁-C₆Alkyl) aminocarbonyl, arylcarbonyl, aryloxycarbonyl, (C)₁-C₆Alkyl) sulfonyl and arylsulfonyl. The groups listed above as suitable substituents are as defined below, except that suitable substituents may not be further optionally substituted.

As used herein, "optionally substituted" may indicate that the group may be unsubstituted or substituted with one or more substituents as defined herein.

It will be understood that, as used herein, the following structures are equivalent as tautomers.

Unless defined otherwise herein, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art.

Discussion of the related Art

Cancer and other diseases such as arthritis, lupus and neurodegenerative disorders are associated with, for example, a significant amount of mortality and/or morbidity and remain major health problems worldwide. Despite advances in understanding these diseases and disorders, there remains a need for additional and/or improved treatments.

Histone modifications are modifications to histones, such as acetylation or methylation, which can result in changes in gene expression. Gene expression can be altered by recombination of the genome as a result of histone modification. Recombination alters which regions of the genome are active (called euchromatins) in which DNA is readily transcribed; and which regions are inactive (called heterochromatin), where the DNA is more compact and less readily transcribed.

The main types of histones are H1 (which is the link histone and is responsible for stabilization), H2A, H2B, H3 and H4 (these are referred to as core histones). Histones package and order DNA into structures called nucleosomes. Each nucleosome comprises two subunits, each subunit being a core histone. Histones can be modified by methylation at lysine residues and/or arginine residues, acetylation, ubiquitination and/or phosphorylation at lysine residues. Histones may be acetylated on lysine. Histone acetylation is often associated with an open chromatin structure, which makes chromatin accessible to transcription factors and thus is associated with increased gene expression. Histone acetylation is usually in the promoter region of DNA.

Histone modification is a dynamic process and is regulated by a specific set of enzymes. These epigenetic regulators can be divided into writers (writers), readers (readers), and erasers (erasers). Epigenetic writers include enzymes such as Histone Acetyltransferase (HAT), histone methyltransferase (HMT/KMT), protein arginine methyltransferase (PRMT), and kinases, which add epigenetic marks to histones. Epigenetic erasers include enzymes such as Histone Deacetylases (HDACs), lysine demethylases (KDMs), and phosphatases, which catalyze the reversal of epigenetic marks. The epigenetic reader comprises an enzyme that recognizes and binds to an epigenetic signature formulated by an epigenetic writer, thereby determining its functional outcome, and comprises a protein comprising a bromodomain, a cromoman domain (chromomodel) and Tudor.

Bromodomains are protein domains of about 110 amino acids that recognize acetylated lysine residues. As discussed above, bromodomains are lysine acetylated epigenetic readers that transduce the signal carried by the acetylated lysine residues and convert it to a phenotype. Bromodomains have been implicated to have a role in a variety of diseases including, but not limited to, cancer and multiple sclerosis.

As described above, compounds and formulations thereof are described herein that can modulate the activity of bromodomains and additionally terminal (BET) bromodomain families and bromodomain proteins (e.g., BRD2, BRD3, MRD4, and BRDT). Also described herein are methods of treating and/or preventing diseases or disorders using the compounds described herein and formulations thereof. Other compositions, compounds, methods, features and advantages of the disclosure will be, or will become, apparent to one of ordinary skill in the art upon examination of the following figures, detailed description and examples. It is intended that all such additional compositions, compounds, methods, features and advantages be included within this description, be within the scope of the present disclosure.

Pyridone-based compounds

Described herein are pyridone-based compounds that, in some aspects, can modulate the activity of a bromodomain protein (BRD) and/or a Bromodomain and Extra Terminal (BET) bromodomain family. In some aspects, the pyridone-based compounds and/or derivatives thereof described herein can inhibit or reduce the activity of a BRD protein and/or a BET protein.

In some aspects, the compound may be according to formula I

Wherein R is₁₂May be C₁-C₃Alkyl radical, C₁-C₃Haloalkyl, propenyl, -CH₂(CO)CH＝CH₂Oxiran-2-ylmethyl or CH₂(CO)CH₂Cl，

Wherein R is₁₁May be a nitrogen-containing bicyclic or tricyclic heteroaryl group, each of which may be substituted with 1,2 or 3 substituents, which may each be independently selected from the group consisting of: -N (R)^a)S(O)₂R^b、-S(O)₂NR^aR^b、-C(O)NR^aR^b、-N(R^a)C(O)R^b、-NR^aR^b、-(C₁-C₆Alkylene) R^c、-(C₁-C₃Cycloalkylene) R^cAnd- (C)₁-C₆Alkylene) R^cR^c’，

Wherein R is^aAnd R^bEach occurrence may be independently selected from the group consisting of: H. c₁-C₆Alkenyl radical, C₁-C₆Alkynyl, C₁-C₆Haloalkyl, R^cOr C₁-C₆Alkyl radical, wherein C₁-C₆The alkyl group may be substituted with one substituent selected from the group consisting of: -OR^e、-NR^eR^f、-C(O)OR^e、-C(O)NR^eR^f、-S(O)₂R^e、-S(O)₂NR^eR^fAnd R^c，

Wherein R is^cAnd R^c’Each occurrence may be independently selected from the group consisting of: aryl, heteroaryl, heterocycle, cycloalkyl or cycloalkenyl, and wherein each R^cThe radical may be substituted by 1,2,3, 4 or 5R^dThe substitution of the group(s),

wherein R is^dMay be independently selected at each occurrence from the group consisting of: c₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, halogen, C₁-C₆Haloalkyl, -CN, -NO₂、-OR^e、-S(O)₂NR^eR^f、-C(O)R^e、-C(O)NR^eR^f、-NR^eR^f、-N(R^e)C(O)R^f、-(C₁-C₆Alkylene) -OR^e、-(C₁-C₆Alkylene) -C (O) NR^eR^f、-(C₁-C₆Alkylene) -NR^eR^fAnd- (C)₁-C₆Alkylene) -N (R)^e)C(O)R^fAnd wherein R is^eAnd R^fAt each timeMay each independently at the time of occurrence be selected from the group of: H. c₁-C₆Alkyl radical, C₁-C₆Cycloalkyl, aryl, heteroaryl and C₁-C₆A haloalkyl group.

In some aspects, the compound may be according to formula II:

wherein R is²¹May be-N (R)^a)S(O)₂R^b、-S(O)₂NR^aR^b、-S(O)₂R^a、-C(O)NR^aR^b、-N(R^a)C(O)R^b、-NR^aR^bOr- (C)₁-C₆Alkylene) R^c，

Wherein R is^aAnd R^bEach occurrence may be independently selected from the group consisting of: H. c₁-C₆Alkyl radical, C₁-C₆Alkenyl radical, C₁-C₆Alkynyl, C₁-C₆Haloalkyl, R^cAnd C₁-C₆Alkyl radical, wherein C₁-C₆The alkyl group may be substituted with one substituent selected from the group consisting of: -OR^y1、-NR^y3R^y4、-C(O)OR^y2、-C(O)NR^y3R^y4、-S(O)₂R^y1、-S(O)₂NR^y3R^y4And R^c，

Wherein R is^y1Each occurrence may be independently selected from the group consisting of: H. c₁-C₆Alkyl radical, C₁-C₆Cycloalkyl, aryl, heteroaryl and C₁-C₆A halogenated alkyl group,

wherein R is^y2Each occurrence may be independently selected from the group consisting of: H. c₁-C₆Alkyl radical, C₁-C₆Cycloalkyl, aryl, heteroaryl and C₁-C₆A halogenated alkyl group,

wherein R is^y3Each occurrence may be individually independentThe ground is selected from the group of: H. c₁-C₆Alkyl radical, C₁-C₆Cycloalkyl, aryl, heteroaryl and C₁-C₆A halogenated alkyl group,

wherein R is^y4Each occurrence may be independently selected from the group consisting of: H. c₁-C₆Alkyl radical, C₁-C₆Cycloalkyl, aryl, heteroaryl and C₁-C₆A halogenated alkyl group,

wherein R is²²May be selected from the group of: - (C)₁-C₆Alkylene) R^c、-(C₁-C₃Cycloalkylene) R^cAnd- (C)₁-C₆Alkylene) R^cR^c’，

Wherein R is^cAnd R^c’Each occurrence may be independently selected from the group consisting of: aryl, heteroaryl, heterocycle, cycloalkyl, and cycloalkenyl; and each R^cThe radical may be substituted by 1,2,3, 4 or 5R^dThe substitution of the group(s),

wherein R is^dEach occurrence may be independently selected from the group consisting of: c₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, halogen, C₁-C₆Haloalkyl, -CN, -NO₂、-OR^e、-S(O)₂NR^eR^f、-C(O)R^e、-C(O)NR^eR^f、-NR^eR^f、-N(R^e)C(O)R^f、-(C₁-C₆Alkylene) -OR^e、-(C₁-C₆Alkylene) -C (O) NR^eR^f、-(C₁-C₆Alkylene) -NR^eR^fAnd- (C)₁-C₆Alkylene) -N (R)^e)C(O)R^f，

And wherein R^eAnd R^fEach occurrence may be independently selected from the group consisting of: H. c₁-C₆Alkyl and C₁-C₆A haloalkyl group.

In some aspects, the compound may be according to formula III

Wherein R is₃₁May be selected from the group of: c₁-C₆Alkenyl radical, C₁-C₆Cycloalkyl and C₁-C₆A halogenated alkyl group,

wherein R is₃₂May be selected from the group of: c₁-C₆Alkenyl radical, C₁-C₈Cycloalkyl, -H, -D, C₁-C₈Substituted cycloalkylene, substituted aryl and substituted heteroaryl, which may include pure enantiomers if the molecule contains a chiral center,

and wherein R₃₃、R₃₄、R₃₅、R₃₆And R₃₇May each be independently selected from the group of: -H, halogen, -CN and C₁-C₃A haloalkyl group.

In some aspects, the compound may be according to formula IV

Wherein R is₄₁May be selected from the group of: c₁-C₆Alkylene radical, C₁-C₆Cycloalkyl and C₁-C₆A halogenated alkyl group,

wherein R is₄₂May be selected from the group of: c₁-C₆Alkenyl radical, C₁-C₈Cycloalkyl, -H, -D, C₁-C₈Substituted cycloalkylene, substituted aryl, substituted heteroaryl, which may include pure enantiomers if the molecule contains a chiral center,

and wherein R₄₃、R₄₄、R₄₅、R₄₆And R₄₇May each be independently selected from the group of: -H, halogen, -CN and C₁-C₃A haloalkyl group.

In some aspects, the compound may be according to formula V

Wherein R is₅₁May be selected from the group of: c₁-C₆Alkenyl radical, C₁-C₆Cycloalkyl and C₁-C₆A halogenated alkyl group,

wherein R is₅₂May be selected from the group of: c₁-C₆Alkenyl radical, C₁-C₈Cycloalkyl, -H, -D, C₁-C₈Substituted cycloalkylene, substituted aryl and substituted heteroaryl, which may include pure enantiomers if the molecule contains a chiral center,

and wherein R₅₃、R₅₄、R₅₅、R₅₆And R₅₇May each be independently selected from the group of: -H, halogen, -CN and C₁-C₃A haloalkyl group.

In some aspects, the compound may be according to formula VI

Wherein X may be selected from the group consisting of C or N,

wherein R is₆₁May be selected from the group of: c₁-C₆Alkenyl radical, C₁-C₆Cycloalkyl and C₁-C₆A halogenated alkyl group,

wherein R is₆₂May be selected from the group of: c₁-C₆Alkenyl radical, C₁-C₈Cycloalkyl, -H, -D, C₁-C₈Substituted cycloalkylene, substituted aryl and substituted heteroaryl, which may include pure enantiomers if the molecule contains a chiral center,

and wherein R₆₃、R₆₄、R₆₅、R₆₆And R₆₇May each be independently selected from the group of: -H, halogen, -CN and C₁-C₃A haloalkyl group.

In some aspects, the compound may be according to formula VII

Wherein X may be selected from the group of: -O-, -C (O) -, -N (R)₇₇) -and-CH (R)₇₀)-，

Wherein R is₇₁May be selected from the group of: c₁-C₃Alkyl radical, C₁-C₃Haloalkyl, propenyl, -CH₂(CO)CH＝CH₂Oxiran-2-ylmethyl and CH₂(CO)CH₂Cl，

Wherein R is₇₂、R₇₃、R₇₄、R₇₅、R₇₆And R₇₇May each be independently selected from the group of: -H, halogen, -CN, C₁-C₃Haloalkyl, -OR₇₀、-NR₇₀R₇₀、-C(O)OR₇₀、-C(O)NR₇₀R₇₀、-S(O)₂R₇₀、-S(O)₂NR₇₀R₇₀And R₇₀，

Wherein R is₇₀Each occurrence may be independently selected from the group consisting of: c₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, halogen, C₁-C₆Haloalkyl, -CN, -NO₂、-OR^e、-S(O)₂NR^eR^f、-C(O)R^e、-C(O)NR^eR^f、-NR^eR^f、-N(R^e)C(O)R^f、-(C₁-C₆Alkylene) -OR^e、-(C₁-C₆Alkylene) -C (O) NR^eR^f、-(C₁-C₆Alkylene) -NR^eR^fAnd- (C)₁-C₆Alkylene) -N (R)^e)C(O)R^fAnd wherein R is^eAnd R^fEach occurrence may be independently selected from the group consisting of: H. c₁-C₆Alkyl and C₁-C₆A haloalkyl group.

In some aspects, the compound may be according to formula VIII

Wherein R is₈₁、R₈₂、R₈₃May each be independently selected from the group of: c₁-C₃Alkyl radical, C₁-C₃Haloalkyl, propenyl, -CH₂(CO)CH＝CH₂Oxiran-2-ylmethyl and CH₂(CO)CH₂Cl。

In some aspects, the compound may be according to formula IX,

wherein R is₉₁May be selected from the group of: c₁-C₆Alkenyl radical, C₁-C₆Cycloalkyl and C₁-C₆A halogenated alkyl group,

wherein R is₉₂May be selected from the group of: c₁-C₆Alkenyl radical, C₁-C₈Cycloalkyl, -H, -D, C₁-C₈Substituted cycloalkylene, substituted aryl and substituted heteroaryl, which may include pure enantiomers if the molecule contains a chiral center,

and wherein R₉₃、R₉₄、R₉₅、R₉₆And R₉₇May each be independently selected from the group of: -H, halogen, -CN and C₁-C₃A haloalkyl group.

In some aspects, the compound may be according to formula X

Wherein each X may be independently selected from C or N,

wherein R is₉₈May be selected from the group: h or Me, and the salts thereof,

wherein R is₉₉May each be selected from the group of: me, Et and CH (CH)₂)₂，

Wherein R is₁₀₀May be selected from the group of:

wherein R is₁₀₁Can be Cl, F, H, Me, cycloheteroalkyl or

Wherein R is₁₀₂Can be H, Cl, F, OH, CF₃Or the CN group is selected from the group consisting of,

wherein R is₁₀₃May be Cl, F, H,

Or a group of groups Me,

and wherein R₁₀₄May be H or F, and wherein R₁₀₅May be H or

In some aspects, the compound can be according to formula XI

Wherein R is₁₀₇May be selected from the group of: h or Me, and the salts thereof,

wherein R is₁₀₈May each be selected from the group of: me, Et and CH (CH)₂)₂，

Wherein R is₁₀₆May be selected from the group of:

in some aspects, the compound may be according to formula XII

Wherein R is₁₀₉Can be

Wherein R is₁₁₀May be Me or CH₂CH₃，

Wherein R is₁₁₁May be F, H, Cl or CN, wherein R₁₁₂May be H, Cl or F, and wherein R₁₁₃Can be H, Me, Cl or F.

In some aspects, the compound can be according to formula XIII

Wherein R is₁₁₄May be Me or CH₂CH₃，

Wherein R is₁₁₅Can be

Wherein R is₁₁₆May be H, F or N (CH)₃)₂，

Wherein R is₁₁₇Can be H, Cl, F, CF₃Or a group of groups Me,

wherein R is₁₁₈May be H, Me or CF₃，

Wherein R is₁₁₉May be H, F or N (CH)₃)₂，

Wherein R is₁₂₀May be H, Me or CF₃，

And wherein R₁₂₁May be H or Me.

In some aspects, the compound may be according to formula XIV

Wherein R is₁₂₂May be Me or CH₂CH₃，

Wherein R is₁₂₃Can be

Wherein R is₁₂₄Can be

Wherein R is₁₂₅Can be H or F, R₁₂₆May be H or Me, and wherein R₁₂₇May be H or Me.

In some aspects, the compound may be according to formula XV

Wherein R is₁₂₈Can be

Wherein R is₁₂₉May be Me or CH₂CH₃Wherein R is₁₃₀Can be H or F, and can be H or F,

wherein R is₁₃₁Can be H or Me, wherein R₁₃₂Can be H or Me, and can be used,

and wherein X may be C or N.

In some aspects, the compound may be according to formula XVI

Wherein R is₁₃₃May be selected from the group of: c₁-C₆Alkenyl radical, C₁-C₆Cycloalkyl and C₁-C₆A halogenated alkyl group,

wherein R is₁₃₄May be selected from the group of: c₁-C₆Alkenyl radical, C₁-C₈Cycloalkyl, -H, -D, C₁-C₈Substituted cycloalkylene, substituted aryl and substituted heteroaryl, which may include pure enantiomers if the molecule contains a chiral center,

wherein R is₁₃₅、R₁₃₆、R₁₃₇、R₁₃₈And R₁₃₉Each independently selected from the group of: -H, halogen, -CN and C₁-C₃A halogenated alkyl group,

and wherein R₁₄₀May be selected from the group of: c₁-C₆Alkenyl radical, C₁-C₈Cycloalkyl, -H, -D, C₁-C₈Substituted cycloalkylene, substituted aryl, and substituted heteroaryl.

In some aspects, the compound can be according to formula XVII

Wherein R is₁₄₁May be selected from the group of: c₁-C₆Alkenyl radical, C₁-C₈Cycloalkyl, -H, -D, C₁-C₈Substituted cycloalkylene, substituted aryl and substituted heteroaryl, which may include pure enantiomers if the molecule contains a chiral center,

and wherein R₁₄₂、R₁₄₃、R₁₄₄、R₁₄₅And R₁₄₆Each independently selected from the group of: -H, halogen, -CN and C₁-C₃A haloalkyl group.

In some aspects, the compound may be according to formula XVIII

Wherein R is₁₄₇Can be H or Me, and can be used,

wherein R is₁₄₈Can be

Wherein R is₁₄₉May be H, CH₂CH₃Or

Wherein R is₁₅₀Can be

Wherein R is₁₅₁Can be Me, Et or CH (CH)₂)₂，

Wherein R is₁₅₂May be H, Me or Cl, wherein R₁₅₃Can be H or F, and can be H or F,

wherein R is₁₅₄Can be H or F, and can be H or F,

and wherein R₁₅₅May be H or Me.

In some aspects, the compound may be according to formula XIX

Wherein R is₁₅₆Can be

Wherein R is₁₅₇May be Me or CH₂CH₃，

Wherein R is₁₅₈Can be Me and CH₂CH₃Or

Wherein R is₁₅₉May be H, CH₂CH₃Or

Wherein R is₁₆₀Can be

Wherein R is₁₆₁May be H, Me or may be Cl,

wherein R is₁₆₂Can be H or F, and can be H or F,

wherein R is₁₆₃Can be H or F, and can be H or F,

and wherein R₁₆₄May be H or Me.

In some aspects, the compound may be according to formula XX

Wherein R is₁₆₅Can be

Wherein R is₁₆₆May be H, Me or may be Cl,

wherein R is₁₆₇Can be H or F, and can be H or F,

wherein R is₁₆₈Can be H or F, and can be H or F,

and wherein R₁₆₉May be H or Me.

In some aspects, the compound can be according to formula XXI

Wherein R is₃₁Can be

Wherein R is₁₅₇May be Me or CH₂CH₃、CH(CH₃)₂Wherein R is₁₅₈Can be Me and CH₂CH₃、CH(CH₃)₂Or

Wherein R is₃₁May be selected from the group of: c₁-C₆Alkyl radical, C₁-C₆Alkenyl radical, C₁-C₆Cycloalkyl and C₁-C₆A halogenated alkyl group,

wherein R is₃₂May be selected from the group of: c₁-C₆Alkyl radical, C₁-C₆Alkenyl radical, C₁-C₈Cycloalkyl, -H, -D, C₁-C₈Substituted cycloalkylene, substituted aryl and substituted heteroaryl, which may include pure enantiomers if the molecule contains a chiral center,

and wherein R₃₃、R₃₄、R₃₅、R₃₆、R₃₇、R₃₃'、R₃₄'、R₃₅'、R₃₆ ^’And R₃₇ ^’May each be independently selected from the group of: -H, halogen, -CN, C₁-C₃Haloalkyl, C₁-C₆Cycloalkyl radical, C₁-C₆Alkylamine, C₁-C₆Cycloalkylamine, C₁-C₆Alkyl esters and C₁-C₆An alkylamide.

In some aspects, the compound may be according to formula XXII,

wherein R is₃₁Can be

Wherein R is₁₅₇May be Me or CH₂CH₃、CH(CH₃)₂，

Wherein R is₃₂May be selected from the group of: c₁-C₆Alkyl radical, C₁-C₆Alkenyl radical, C₁-C₈Cycloalkyl, -H, -D, C₁-C₈Substituted cycloalkylene, substituted aryl and substituted heteroaryl, which may include pure enantiomers if the molecule contains a chiral center,

and wherein R₃₃、R₃₄、R₃₅、R₃₆、R₃₇、R₃₄’、R₃₅’、R₃₆’、R₃₇' may each be independently selected from the group of: -H, halogen, -CN, C₁-C₃Haloalkyl, C₁-C₆Cycloalkyl radical, C₁-C₆Alkylamine, C₁-C₆Cycloalkylamine, C₁-C₆Alkyl esters and C₁-C₆An alkylamide.

In some aspects, the compound may be according to formula XXIII,

wherein R is²¹May be-N (R)^a)S(O)₂R^b、-S(O)₂NR^aR^b、-S(O)₂R^a、-C(O)NR^aR^b、-N(R^a)C(O)R^b、-NR^aR^bOr- (C)₁-C₆Alkylene) R^c，

Wherein R is^y1Each occurrence may be independently selected from the group consisting of: H. me or CH₂CH₃、CH(CH₃)₂，

Wherein R is^y2Each occurrence may be independently selected from the group consisting of: H. me or CH₂CH₃、CH(CH₃)₂，

Wherein R is^y3Each occurrence may be independently selected from the group consisting of: H. me or CH₂CH₃、CH(CH₃)₂，

Wherein R is^y4Each occurrence may be independently selected from the group consisting of: H. me or CH₂CH₃、CH(CH₃)₂，

Wherein R is²²May be selected from the group of: - (C)₁-C₆Alkylene) R^c、-(C₁-C₃Cycloalkylene) R^cAnd- (C)₁-C₆Alkylene) R^cR^c’，

And wherein R^eAnd R^fEach occurrence may be independently selected from the group consisting of: H. c₁-C₆Alkyl and C₁-C₆A haloalkyl group.

In some aspects, the compound may be according to formula XXIV

Wherein R is₁And R₂May each be independently selected from CH₃Or a combination of H and a nitrogen atom,

wherein R is₃May be CH₃Or CH₂CH₃And is and

wherein X may be C or N.

In some aspects, the compound may be according to formula XXV

Wherein R is₁Can be

Wherein R is₂Can be

Wherein R is₃May be H, CH₃Or CH₂CH₃，

And wherein X₁、X₂And X₃May each be independently selected from the group of: c or N.

In aspects, described herein are compounds according to formula XXV

Wherein R is₁Can be

Wherein R is₂Can be

Wherein R is₃May be H, CH₃Or CH₂CH₃And is and

wherein X₁、X₂And X₃May each be independently selected from the group of: c or N.

In some aspects, the compound according to formula XXV may be selected from the group of: (70) (71), (72), (73), (74), (126), (130), (131) and (132).

In some aspects, the compound may be according to formula XXIV

Wherein R is₁And R₂May each be independently selected from CH₃Or a combination of H and a nitrogen atom,

wherein R is₃May be CH₃Or CH₂CH₃And is and

wherein X may be C or N.

In some aspects, the compound according to formula XXV may be selected from the group of: (22) and (23), (30) and (31).

In some aspects, the compound may be according to formula XXVI

Wherein R is₁₂May be C₁-C₃Alkyl radical, C₁-C₃Haloalkyl, propenyl, -CH₂(CO)CH＝CH₂Oxiran-2-ylmethyl or CH₂(CO)CH₂Cl，

Wherein R is₁₁Is a nitrogen-containing bicyclic or tricyclic heteroaryl, aryl or biaryl, each of which is optionally substituted with 1,2 or 3 substituents, which may each be independently selected from the group of: -N (R)^a)S(O)₂R^b、-S(O)₂NR^aR^b、-C(O)NR^aR^b、-N(R^a)C(O)R^b、-NR^aR^b、-(C₁-C₆Alkylene) R^c、-(C₁-C₃Cycloalkylene) R^cAryl, heteroaryl, and- (C)₁-C₆Alkylene) R^cR^c’-H, halogen, -CN, propenyl, C₁-C₃Alkyl radical, C₁-C₃Haloalkyl, -OR₇₀、-NR₇₀R₇₀、-C(O)OR₇₀、-C(O)NR₇₀R₇₀、-S(O)₂R₇₀、-S(O)₂NR₇₀R₇₀、-CH₂(CO)CH＝CH₂Oxiran-2-ylmethyl, and CH₂(CO)CH₂Cl and R₇₀，

Wherein X may optionally be present and, when present, may be selected from-O-, -C (O) -, -N (R)₇₇) -and-CH (R)₇₀)-，

R₇₇May be selected from the group of: -H, halogen, -CN, C₁-C₃Haloalkyl, -OR₇₀、-NR₇₀R₇₀、-C(O)OR₇₀、-C(O)NR₇₀R₇₀、-S(O)₂R₇₀、-S(O)₂NR₇₀R₇₀And R₇₀，

Wherein R is^aAnd R^bEach occurrence may be independently selected from the group consisting of: H. c₁-C₆Alkenyl radical, C₁-C₆Alkynyl, C₁-C₆Haloalkyl, R^cAnd C₁-C₆Alkyl radical, wherein C₁-C₆Alkyl is optionally substituted with one substituent selected from the group consisting of: -OR^e、-NR^eR^f、-C(O)OR^e、-C(O)NR^eR^f、-S(O)₂R^e、-S(O)₂NR^eR^fAnd R^c，

Wherein R is^cAnd R^c’Each occurrence may be independently selected from the group consisting of: aryl, heteroaryl, heterocycle, cycloalkyl, and cycloalkenyl, and wherein each R^cThe radical being optionally substituted by 1,2,3, 4 or 5R^dThe substitution of the group(s),

And wherein R^eAnd R^fEach occurrence may be independently selected from the group consisting of: H. c₁-C₆Alkyl radical, C₁-C₆Cycloalkyl, aryl, heteroaryl and C₁-C₆A haloalkyl group.

In some aspects, the compound can be any one of compounds (1) - (132) as shown in table 1. In some aspects, the compound can be any of compound (2), compound (10), compound (22), compound (23), compound (30), compound (31), compound (70), compound (71), compound (72), compound (73), compound (74), compound (126), compound (130), compound (131), or compound (132). In some aspects, the compound may be any of compound (2), compound (10), compound (22), compound (23), compound (30), or compound (31). In some aspects, the compound may be any of compound (3), compound (7), compound (12), compound (13), compound (14), compound (15), compound (16), compound (17), compound (18), compound (19), or compound (20). In some aspects, the compound can be any of compound 2 or compound 10. In some aspects, the compound may be any one of compound (1), compound (4), compound (5), compound (6), compound (8), compound (9), or compound (11). In some aspects, the compound can be any of compound (70), compound (71), or compound (72). In some aspects, the compound may be any one of compound (73) or compound (74). In some aspects, the compound can be any of compound (126), compound (130), compound (131), or compound (132). In some aspects, the compound may be (24), (25), (26), (32), (29), (34), or (35).

In some aspects, the free compound or pharmaceutical formulation thereof (discussed in more detail elsewhere herein) can have an IC of less than 0.001 μ Μ, less than 0.01 μ Μ, less than 0.1 μ Μ, less than 1 μ Μ, less than 3 μ Μ and/or less than 5 μ Μ₅₀. In some aspects, the free compound or pharmaceutical formulation thereof (further elsewhere herein)Discussed in detail) may have an IC in a range from 0.0001. mu.M to 0.001. mu.M, from 0.001. mu.M to 0.01. mu.M, from 0.01. mu.M to 0.1. mu.M, 0.1. mu.M to 1. mu.M, 1. mu.M to 2. mu.M, 2. mu.M to 3. mu.M, 3. mu.M to 4. mu.M, or 4. mu.M to 5. mu.M₅₀. In some aspects, the free compound or pharmaceutical formulation thereof (discussed in more detail elsewhere herein) can have an IC of less than 0.001 μ Μ, less than 0.01 μ Μ, less than 0.1 μ Μ, less than 1 μ Μ, less than 3 μ Μ and/or less than 5 μ Μ against cells, cancer cells and/or resistant cancer cells₅₀. In some aspects, the free compound or pharmaceutical formulation thereof (discussed in more detail elsewhere herein) can have an IC in the range of from 0.0001 μ Μ to 0.001 μ Μ, from 0.001 μ Μ to 0.01 μ Μ, from 0.01 μ Μ to 0.1 μ Μ, 0.1 μ Μ to 1 μ Μ,1 μ Μ to 2 μ Μ,2 μ Μ to 3 μ Μ,3 μ Μ to 4 μ Μ or 4 μ Μ to 5 μ Μ against cells, cancer cells and/or resistant cancer cells₅₀。

The compounds described herein can be prepared by using techniques and methods generally known in the art.

In some aspects, the pyridone-based compound and/or derivative thereof can specifically bind to a bromodomain. In some aspects, the pyridone-based compound and/or derivative thereof can specifically bind to a BRD protein or a BET protein. In some aspects, the pyridone-based compound and/or derivative thereof can specifically bind to a bromodomain of a BRD protein or a BET protein. In some aspects, the pyridone-based compounds and/or derivatives thereof can modulate the activity of a BRD protein and/or a BET protein. In some aspects, the pyridone-based compound and/or derivative thereof can reduce, inhibit, and/or eliminate the activity of a BRD protein or BET protein. In some aspects, the pyridone-based compound and/or derivative thereof can specifically bind to and can modulate the activity of a BRD protein and/or a BET protein. In some aspects, the pyridone-based compound and/or derivative thereof can specifically bind to and can reduce, inhibit, and/or eliminate the activity of a BRD protein and/or a BET protein. In some aspects, these functionalities of the pyridone-based compounds and/or derivatives thereof may be maintained when included in a pharmaceutical formulation as described elsewhere herein.

Pharmaceutical preparation

The pyridone-based compounds described herein (e.g., any compound having a structure according to any of formulas I-XX or any other compound or formula described herein) can be included as an ingredient, such as an active ingredient, in a pharmaceutical formulation that can include, but is not limited to, any pharmaceutical formulation and/or derivatives thereof (e.g., such as pharmaceutically acceptable salts and prodrugs thereof). Accordingly, pharmaceutical formulations comprising one or more of the compounds described herein and/or pharmaceutically acceptable salts and/or prodrugs thereof are also described. Suitable salts include, but are not limited to, sulfate, citrate, acetate, oxalate, chloride, hydrochloride, bromide, hydrobromide, iodide, nitrate, bisulfate, phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisate (gentisate), fumarate, gluconate, glucuronate (glucaronate), saccharate (saccharate), formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, camphorsulfonate, naphthalenesulfonate, propionate, malonate, mandelate, malate, phthalate, and pamoate. The pharmaceutical formulation may comprise a racemic mixture of one or more pyridone-based compounds. The pharmaceutical formulation may comprise the pyridone-based compound in an enantiomerically pure amount. The pharmaceutical formulations described herein can comprise an effective amount of any one or more of the pyridone-based compounds described herein.

The pharmaceutical formulations described herein can be administered to a subject in need thereof. In some aspects, a subject may have or is suspected of having cancer or other disease whose histone modifications can be modulated to treat and/or prevent the disease and/or symptoms thereof, which other disease may include, but is not limited to, arthritis, lupus, pulmonary hypertension, cardiac remodeling, and/or neurodegenerative disease.

Pharmaceutically acceptable carriers, auxiliary components and auxiliary agents

Pharmaceutical formulations containing an amount of a pyridone-based compound described herein (e.g., a compound having a structure according to any one of formulas 1-XX or any other formula described herein) and/or a derivative thereof may further comprise a pharmaceutically acceptable carrier. Suitable pharmaceutically acceptable carriers include, but are not limited to, water, salt solutions, alcohols, gum arabic, vegetable oils, benzyl alcohols, polyethylene glycols, gelatin, carbohydrates such as lactose, amylose or starch, magnesium stearate, talc, silicic acid, viscous paraffin, perfume oil (perfume oil), fatty acid esters, hydroxymethylcellulose, and polyvinylpyrrolidone, which do not deleteriously react with the active composition.

The pharmaceutical preparations described herein and their derivatives can be sterilized and, if desired, mixed with adjuvants, such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, colorants, flavoring and/or aromatic substances and the like, which do not deleteriously react with the active compound.

In addition to an amount, such as an effective amount, of a pyridone-based compound and/or derivative thereof described herein, a pharmaceutical formulation may also contain an effective amount of one or more auxiliary active agents, including, but not limited to, antisense or RNA interfering molecules, chemotherapeutic or antineoplastic agents, hormones, antibiotics, antiviral agents, immunomodulators, antinausea, pain modifying compounds (such as opioids), anti-inflammatory agents, antipyretics (antipyrotic), antibiotics and/or antibodies or fragments thereof.

In some aspects, the co-active agent is a conventional chemotherapeutic agent or a pharmaceutical formulation thereof. The chemotherapeutic agent may include busulfan, improsulfan, piposulfan, benzotepa, carboquone, meltupipa, uredepa, altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, trimethylolmelamine, chlorambucil (chlorenaphazine), cyclophosphamide, estramustine, ifosfamide, mechlorethamine hydrochloride (mechlorethamine oxide hydrochloride), melphalan, neoenrichine, benzene mustard cholesterol, prednimustine (prednimustine), trofosfamide, uracil mustard, carmustine, chlorourethramycin, fotemustine, lomustine, nimustine, ramustine, dacarbazine, mannomustine, dibromomannitol, dibromodulobroman, pipobroman, aclacinomycin, clarithromycin F (1), amikacin, gentamycin C, gentamycin, and/or, Carrubicin, carcinostatin, chromomycin, dactinomycin, daunorubicin, 6-diazo-5-oxo-1-norleucine, doxorubicin, epirubicin, mitomycin C, mycophenolic acid, nogomycin, olivomycin, pelomycin, plicamycin, posomycin, puromycin, streptonigrin, streptozotocin, tubercidin, ubenimex, secstatin, zorubicin, dimethylfolic acid, methotrexate, pteropterin, trimetrexate, fludarabine, 6-mercaptopurine, thioprimine, thioguanine, azacitidine, azauridine, carmofur, cytarabine, dideoxyuridine, floxuridine, enocitabine, floxuridine, fluorouracil, tegafur, L-asparaginase, alfa streptozyme (pulmozyme), Acetoglucuronide, aldphosphoramide glycoside, aminoacetylpropionic acid, amsacrine, betanidine (benzarbucil), bisantrene, carboplatin, cisplatin, cyclophosphamide, colchicine, siluroquinone, efluoromithine, etilinicum acetate, etogrel, etoposide, flutamide, gallium nitrate, hydroxyurea, interferon- α, interferon- β, interferon- γ, interleukin-2, lentinan, lonidamine, mitoguazone, mitoxantrone, mopidanol, diamminenitracridine (nitrarine), pentostatin, mechlorethamine (phenamant), pirarubicin, podophyllic acid, 2-ethyl hydrazide, procarbazine, raxazone (raxadone), sisolane (sizoiran), german (spirogyrine), paclitaxel, tamoxifene, teniposide, tenuicin (tenuic), tenuizid, 2,3, etc., german, spironolamine, paclitaxel, tamoxifen, tenuim, tebufenon, tebufenozide, tebufeno, 2' -trichlorotriethylamine, urethane, vinblastine, vincristine, vindesine, and combinations thereof.

Effective amount of pyridone-based compounds, derivatives thereof and/or auxiliary active agents

The amount of the pyridone-based compound included in the pharmaceutical formulation or derivative thereof may be an effective amount. Where a co-active agent is included, the amount included in the pharmaceutical formulation or derivative thereof may be an effective amount of the co-active agent. An effective amount of a pyridone-based compound (e.g., a compound having a structure according to any one of formulas I-XX or any other formula described herein) or derivative thereof included in a pharmaceutical formulation may range from about 0.001 micrograms to about 1000 grams. In some aspects, an effective amount of a compound and/or derivative thereof may range from about 0.001 micrograms to about 0.01 micrograms. In other aspects, an effective amount of a compound and/or derivative thereof can range from about 0.01 micrograms to about 0.1 micrograms. In further aspects, an effective amount of a compound and/or derivative thereof can range from about 0.1 micrograms to about 1.0 gram. In yet further aspects, an effective amount of a compound and/or derivative thereof can range from about 1.0 gram to about 10 grams. In other aspects, an effective amount of a compound and/or derivative thereof can range from about 10 grams to about 100 grams. In still other aspects, an effective amount of a compound and/or derivative thereof can range from about 100 grams to about 1000 grams. The amount administered can be calculated based on the free form or salt form of the pyridone-based compound or derivative thereof.

In aspects in which a co-active agent is included in the pharmaceutical formulation with the pyridone-based compound or derivative thereof, the effective amount of the co-active agent will vary depending on, for example, the amount of the co-active agent and/or the pyridone-based compound. In some aspects, an effective amount of the auxiliary active agent can range from 0.001 micrograms to about 1000 grams. In other aspects, an effective amount of the auxiliary active agent can range from about 0.01IU to about 1000 IU. In further aspects, an effective amount of the auxiliary active agent can range from 0.001mL to about 1000 mL. In still other aspects, an effective amount of a co-active agent can be from about 0% w/w to about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, of the total pharmaceutical formulation, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88% to about 90% or more w/w, v/v or w/v.

The co-active agent may be included in the same pharmaceutical formulation as the pyridone-based compound, or may be present as a separate compound or pharmaceutical formulation which may be administered to the subject simultaneously, contemporaneously (cotemporaneously) or sequentially with the pyridone-based compound, derivative thereof or pharmaceutical formulation thereof. In aspects in which the co-active agent is a separate compound or pharmaceutical formulation from the pyridone-based compound, the effective amount of the co-active agent may vary depending on the co-active agent used. In some of these aspects, the effective amount of the auxiliary active agent may range from 0.001 micrograms to about 1000 grams. In other aspects, an effective amount of the auxiliary active agent can range from about 0.01IU to about 1000 IU. In further aspects, an effective amount of the auxiliary active agent can range from 0.001mL to about 1000 mL. The amount administered can be calculated based on the free or salt form of the auxiliary active agent.

Dosage forms

In some aspects, a pharmaceutical formulation described herein or a derivative thereof can be in one dosage form. The dosage form can be administered to a subject in need thereof. In some aspects, a subject in need thereof has or is suspected of having a cancer or other disease whose histone modifications can be modulated to treat and/or prevent the disease and/or symptoms thereof, which other disease may include, but is not limited to, arthritis, lupus, pulmonary hypertension, cardiac remodeling, and/or neurodegenerative diseases.

The dosage form may be suitable for administration by any suitable route. Suitable routes include, but are not limited to, oral (including buccal or sublingual), rectal, intraocular, inhalation, intranasal, topical (including buccal, sublingual or transdermal), vaginal, parenteral, subcutaneous, intramuscular, intravenous, intranasal (intranasal) and intradermal. Such formulations may be prepared by any method known in the art.

Dosage forms suitable for oral administration may be discrete dosage units such as capsules, pills (pellets) or tablets, powders or granules, solutions or suspensions in aqueous or non-aqueous liquids; edible foam or whipped cream confection (whip), or oil-in-water liquid emulsions or water-in-oil liquid emulsions. In some aspects, a pharmaceutical formulation suitable for oral administration further comprises one or more agents that flavor, preserve, color, or aid in dispersion of the pharmaceutical formulation. Dosage forms prepared for oral administration may also be in the form of liquid solutions that may be delivered as foams, sprays, or liquid solutions. The oral dosage form can be administered to a subject in need thereof. In some aspects, a subject in need thereof may have or is suspected of having cancer or other disease whose histone modifications can be modulated to treat and/or prevent the disease and/or its symptoms, which other disease may include, but is not limited to, arthritis, lupus, pulmonary hypertension, cardiac remodeling, and/or neurodegenerative disease.

Where appropriate, the dosage forms described herein may be microencapsulated. The dosage form may also be formulated to prolong or sustain the release of any of the ingredients. In some aspects, the compound or derivative thereof is a component whose release is delayed. In other aspects, the release of the secondary ingredient is delayed. Suitable methods for delaying the release of the ingredient include, but are not limited to, coating or embedding the ingredient in a material such as a polymer, wax, gel, and the like. Delayed release dosage formulations may be prepared as described in standard references such as "Pharmaceutical dosage form tables," editors, Liberman et al (New York, Marcel Dekker, Inc.,1989), "Remington-The science and practice of medicine", 20 th edition, Lippincott Williams & Wilkins, Baltimore, MD,2000, and "Pharmaceutical dosage forms and drug delivery systems", 6 th edition, Ansel et al, (Media, PA: Williams and Wilkins, 1995). These references provide information on the excipients, materials, equipment and processes used to prepare the delayed release dosage forms of tablets and capsules, and tablets and pills, capsules and granules. The delayed release may be any time from about one hour to about 3 months or more.

Examples of suitable coating materials include, but are not limited to, cellulosic polymers such as cellulose acetate phthalate, hydroxypropyl cellulose, hydroxypropyl methylcellulose phthalate, and hydroxypropyl methylcellulose acetate succinate; polyvinyl acetate phthalate, acrylic polymers and copolymers, and also under the trade nameCommercially available (Roth Pharma, Westerstadt, Germany) methacrylic resins, zein, shellac and polysaccharides.

Coatings may be formed with different ratios of water soluble polymers, water insoluble polymers and/or pH dependent polymers, with or without water insoluble/water soluble non-polymeric excipients, to produce a desired release profile. Coating is performed on dosage forms (either matrix dosage forms or simple dosage forms) including, but not limited to, tablets (compressed tablets, with or without coated beads), capsules (with or without coated beads), beads, granular compositions, as "as is" ingredients formulated, but not limited to, in suspension form or as a spray dosage form.

Where appropriate, the dosage forms described herein may be liposomes. In these aspects, the compound, derivative thereof, co-active ingredient, and/or pharmaceutically acceptable salt thereof is incorporated into the liposome. In some aspects, the compound, derivative thereof, co-active ingredient, and/or pharmaceutically acceptable salt thereof is incorporated into the lipid membrane of the liposome. In other aspects, the compound, derivative thereof, co-active ingredient, and/or pharmaceutically acceptable salt thereof is contained in the aqueous phase of the liposome. In aspects wherein the dosage form is a liposome, the pharmaceutical formulation is therefore a liposomal formulation. The liposome formulation can be administered to a subject in need thereof. In some aspects, a subject in need thereof may have or is suspected of having cancer or other disease whose histone modifications can be modulated to treat and/or prevent the disease and/or its symptoms, which other disease may include, but is not limited to, arthritis, lupus, pulmonary hypertension, cardiac remodeling, and/or neurodegenerative disease.

Dosage forms suitable for topical administration may be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols or oils. In some aspects for treating the eye or other external tissues, such as the mouth or skin, the pharmaceutical formulation is applied as a topical ointment or cream. When formulated as an ointment, the compound, derivative thereof, co-active ingredient and/or pharmaceutically acceptable salt thereof may be formulated with a paraffinic ointment base or a water-miscible ointment base. In other aspects, the active ingredient may be formulated as a cream with an oil-in-water cream base or a water-in-oil base. Dosage forms suitable for topical administration in the mouth include lozenges (lozenge), dragees (pastille) and mouthwashes.

Dosage forms suitable for nasal or inhalation administration include aerosols, solutions, drops of suspensions (supensiondrop), gels or dry powders. In some aspects, the compound, derivative thereof, auxiliary active ingredient and/or pharmaceutically acceptable salt thereof in a dosage form suitable for inhalation is in a particle size reduced form obtained or obtainable by micronization. In some aspects, the particle size of the size-reduced (e.g., micronized) compound or salt or solvate thereof is determined by a D of about 0.5 microns to about 10 microns as measured by suitable methods known in the art₅₀And (4) value definition. Dosage forms suitable for administration by inhalation also include particulate dusts or mists. Suitable dosage forms in which the carrier or excipient is a liquid for administration as a nasal spray or nasal drops include aqueous or oily solutions/suspensions of the active ingredient, which may be produced by various types of metered dose pressurised nebulisers, nebulisers or insufflators. The nasal preparation/inhalant preparation canTo be administered to a subject in need thereof. In some aspects, a subject in need thereof may have or is suspected of having cancer or other disease whose histone modifications can be modulated to treat and/or prevent the disease and/or its symptoms, which other disease may include, but is not limited to, arthritis, lupus, pulmonary hypertension, cardiac remodeling, and/or neurodegenerative disease.

In some aspects, the dosage form is an aerosol formulation suitable for administration by inhalation. In some of these aspects, the aerosol formulation comprises a solution or fine suspension of the compound, its derivative, the co-active ingredient and/or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable aqueous or non-aqueous solvent. Aerosol formulations may be presented in sterile form in single or multiple dose amounts in a sealed container. For some of these aspects, the sealed container is a single-or multi-dose nasal dispenser or aerosol dispenser (e.g., a metered dose inhaler) equipped with a metering valve, which is intended to be disposed of after the contents of the container have been depleted.

Where the aerosol dosage form is contained in an aerosol dispenser, the dispenser contains a suitable propellant under pressure, such as compressed air, carbon dioxide or organic propellants including, but not limited to, hydrofluorocarbons. In other aspects, the aerosol formulation dosage form is contained in a pump nebulizer. Pressurized aerosol formulations may also comprise solutions or suspensions of the compounds, their derivatives, auxiliary active ingredients and/or their pharmaceutically acceptable salts. In further aspects, the aerosol formulation further comprises a co-solvent and/or modifier incorporated to improve, for example, the stability and/or taste and/or fine particle quality characteristics (amount and/or profile) of the formulation. Administration of the aerosol formulation may be once daily or several times daily, for example 2,3, 4 or 8 times daily, with 1,2 or 3 doses delivered per time. The aerosol formulation may be administered to a subject in need thereof. In some aspects, a subject in need thereof may have or is suspected of having cancer or other disease whose histone modifications can be modulated to treat and/or prevent the disease and/or its symptoms, which other disease may include, but is not limited to, arthritis, lupus, pulmonary hypertension, cardiac remodeling, and/or neurodegenerative disease.

For some dosage forms suitable and/or suitable for administration by inhalation, the pharmaceutical formulation is a dry powder inhalable formulation. Such dosage forms may contain, in addition to the compound, its derivatives, auxiliary active ingredients and/or pharmaceutically acceptable salts thereof, a powder base such as lactose, glucose, trehalose, mannitol and/or starch. In some of these aspects, the compound, derivative thereof, co-active ingredient, and/or pharmaceutically acceptable salt thereof is in a particle size reduced form. In further aspects, a performance modifier such as L-leucine or another amino acid, cellobiose octaacetate, and/or a metal salt of stearic acid such as magnesium stearate or calcium stearate.

In some aspects, the aerosol formulation is arranged such that each metered dose of the aerosol comprises a predetermined amount of an active ingredient, such as one or more of the pyridone-based compounds described herein.

Dosage forms suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations. Dosage forms suitable for rectal administration include suppositories or enemas. The vaginal formulation may be administered to a subject in need thereof. In some aspects, a subject in need thereof may have or is suspected of having cancer or other disease whose histone modifications can be modulated to treat and/or prevent the disease and/or its symptoms, which other disease may include, but is not limited to, arthritis, lupus, pulmonary hypertension, cardiac remodeling, and/or neurodegenerative disease.

Dosage forms suitable for parenteral administration and/or for injection may include aqueous and/or non-aqueous sterile injection solutions which may contain antioxidants, buffers, bacteriostats, solutes which render the composition isotonic with the blood of the subject; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. Dosage forms suitable for parenteral administration may be presented in single unit dose containers or in multiple unit dose containers, including but not limited to sealed ampoules or vials. The dose can be lyophilized and resuspended in a sterile vehicle prior to administration to reconstitute the dose. In some aspects, extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets. The parenteral formulation can be administered to a subject in need thereof. In some aspects, a subject in need thereof may have or is suspected of having cancer or other disease whose histone modifications can be modulated to treat and/or prevent the disease and/or its symptoms, which other disease may include, but is not limited to, arthritis, lupus, pulmonary hypertension, cardiac remodeling, and/or neurodegenerative disease.

For some aspects, the dosage form comprises a predetermined amount of the compound and/or derivative thereof per unit dose. In aspects, the predetermined amount of the compound or derivative thereof is an effective amount of the compound and/or derivative thereof for treating, preventing, or alleviating one or more symptoms of cancer or other diseases whose histone modifications can be modulated to treat and/or prevent the disease and/or symptoms thereof, which other diseases may include, but are not limited to, arthritis, lupus, pulmonary hypertension, cardiac remodeling, and/or neurodegenerative diseases. In other aspects, the predetermined amount of the compound and/or derivative thereof may be an appropriate fraction of the effective amount of the active ingredient. Thus, such unit doses may be administered once or more than once per day (e.g., 1,2,3, 4,5, 6, or more times per day). Such pharmaceutical formulations may be prepared by any method well known in the art.

Process for preparing compounds and derivatives thereof

Compounds (e.g., compounds having a structure according to any one of formulas I-XX or any other formula or compound provided herein) and derivatives thereof, such as salts, can be synthesized via a number of methods generally known to one of ordinary skill in the art and other methods as provided elsewhere herein. The present disclosure is not intended to be limited by the particular methods of synthesizing the compounds described herein. The skilled artisan will recognize additional methods of synthesizing the compounds described herein.

The compounds described herein, including the compounds of formula (I) and specific examples, may be prepared by the methods in the reaction schemes depicted in schemes 1-7.

Methods of using pyridone-based compounds and formulations thereof

Any amount of a pyridone-based compound described herein (e.g., a compound having a structure according to any of formulas I-XX or any other formula or compound provided herein) and derivatives thereof, as well as pharmaceutical formulations thereof, can be administered to a subject in need thereof once or more times daily, weekly, monthly, or yearly. In some aspects, the amount administered is an effective amount of a pyridone-based compound, a derivative thereof, and/or a pharmaceutical formulation thereof. For example, the pyridone-based compound, derivative thereof and/or pharmaceutical formulation thereof may be administered in a total daily dose. The total daily dose may be administered as a single dose per day. In other aspects, the total daily dose may be administered in multiple doses per day, where each dose may comprise a fraction (sub-dose) of the total daily dose to be administered. In some aspects, the amount of agent delivered per day can be 2,3, 4,5, 6, or more. In further aspects, the pyridone-based compound, derivative thereof, and/or pharmaceutical formulation thereof may be administered to the subject one or more times per week, such as 1,2,3, 4,5, or 6 times per week. In other aspects, the pyridone-based compound, derivative thereof, and/or pharmaceutical formulation thereof is administered to the subject one or more times per month, such as 1,2,3, 4 to 5 or more times per month. In still further aspects, the pyridone-based compound, derivative thereof, pharmaceutical formulation thereof may be administered to the subject one or more times per year, such as 1,2,3, 4,5, 6,7, 8, 9,10 to 11 or more times per year.

In some aspects, a pyridone-based compound, derivative thereof, and/or pharmaceutical formulation thereof may be administered to a subject in need thereof who may have or is suspected of having cancer or other disease whose histone modifications may be modulated to treat and/or prevent the disease and/or symptoms thereof, which may include, but are not limited to, arthritis, lupus, pulmonary hypertension, cardiac remodeling, and/or neurodegenerative diseases.

In some aspects, the pyridone-based compounds, derivatives thereof, and/or pharmaceutical formulations thereof may be used as a co-therapy or combination therapy with one or more other co-active agents or modes of treatment. In some aspects, the pyridone-based compound, derivative thereof, and/or pharmaceutical formulation thereof may be administered simultaneously, contemporaneously, and/or sequentially with conventional chemotherapeutic agents or pharmaceutical formulations thereof, radiation, and/or other cancer treatment modalities.

In aspects in which more than one of the pyridone-based compound, derivative thereof, pharmaceutical formulation thereof, additional therapeutic agent and/or co-active agent or pharmaceutical formulation thereof and/or other mode of treatment is administered sequentially to the subject, the sequential administration may be proximate in time or distant in time. For example, administration of the second compound, second formulation, or other therapeutic agent or therapeutic pattern may occur (be proximate in time) within seconds or minutes (up to about 1 hour) after administration of the first dose. In other aspects, administration of the second compound, second agent, other therapeutic agent, and/or other treatment pattern occurs at some other time that is more than one hour after administration of the administered first dose. In some aspects, the pyridone-based compounds, derivatives thereof, and/or pharmaceutical formulations thereof and/or other modes of treatment may be administered first prior to administration of the co-active or therapeutic agent. In some aspects, the pyridone-based compounds, derivatives thereof, and/or pharmaceutical formulations thereof and/or other modes of treatment may be administered after administration of the co-active agent.

The amount of the pyridone-based compounds, derivatives thereof, and/or pharmaceutical formulations thereof described herein can be administered in an amount ranging from about 0.001mg to about 1000mg per day, as calculated from the free or salt-free compound. In some aspects, the amount of a pyridone-based compound, derivative thereof, and/or pharmaceutical formulation thereof described herein can range from 0.001mg/kg body weight to 1000mg/kg body weight. In some aspects, the amount of a pyridone-based compound, derivative thereof, and/or pharmaceutical formulation thereof described herein can be about 0.1mg/kg body weight, 0.5mg/kg body weight, 1mg/kg body weight, 2mg/kg body weight, 3mg/kg body weight, 4mg/kg body weight, 5mg/kg body weight, 6mg/kg body weight, 7mg/kg body weight, 8mg/kg body weight, 9mg/kg body weight, 10mg/kg body weight, 11mg/kg body weight, 12mg/kg body weight, 13mg/kg body weight, 14mg/kg body weight, 15mg/kg body weight, 16mg/kg body weight, 17mg/kg body weight, 18mg/kg body weight, 19mg/kg body weight, 20mg/kg body weight, 25mg/kg body weight, 50mg/kg body weight to about 100mg/kg body weight. In some aspects, the amount administered is an effective amount when considered as a single dose or the sum of sub-doses.

The pyridone-based compounds, derivatives thereof, and/or pharmaceutical formulations thereof described herein can be administered in combination with or include one or more other adjuvants or therapeutic compounds as discussed elsewhere herein. Suitable adjuvants include, but are not limited to, antisense or RNA interfering molecules, chemotherapeutic agents, antineoplastic agents, hormones, antibiotics, antiviral agents, immunomodulators, anti-nausea agents, pain-ameliorating compounds (such as opioids), anti-inflammatory agents, antipyretics, antibiotics and/or antibodies or fragments thereof. The compounds and/or formulations and/or additional therapeutic agents may be administered simultaneously or sequentially in separate or combined pharmaceutical formulations by any convenient route. The additional therapeutic agent may be provided in its optically pure form or a pharmaceutically acceptable salt thereof.

The pyridone-based compounds described herein and/or derivatives thereof may be used in the manufacture of a medicament for the treatment and/or prevention of cancer or other diseases whose histone modifications may be modulated to treat and/or prevent the disease and/or symptoms thereof, which other diseases may include, but are not limited to, arthritis, lupus, pulmonary hypertension, cardiac remodeling, and/or neurodegenerative diseases. The pyridone-based compounds and/or derivatives thereof described herein may be used to treat and/or prevent cancer or other diseases whose histone modifications may be modulated to treat and/or prevent disease and/or symptoms thereof, which may include, but are not limited to, arthritis, lupus, pulmonary hypertension, cardiac remodeling, and/or neurodegenerative diseases.

Reagent kit

Pyridone-based compounds described herein (e.g., compounds having a structure according to any of formulas I-XX or any other compound or formula described herein), derivatives thereof, pharmaceutical formulations thereof can be presented as a combination kit. As used herein, the term "combination kit" or "kit of parts" refers to any of the compounds, derivatives or pharmaceutical formulations thereof described herein, as well as any additional means for packaging, marketing (marker), delivering and/or administering a combination of the elements contained therein or a single element, such as the primary active ingredient. Such additional components include, but are not limited to, packages, syringes, blister packs (bottles), bottles, and the like. When one or more components (e.g., active agents) contained in the kit are administered simultaneously, the combination kit may contain the active agents in a single pharmaceutical formulation (e.g., a tablet) or in separate pharmaceutical formulations.

When the agents are not administered simultaneously, the combination kit may comprise each agent in separate pharmaceutical preparations. The separate pharmaceutical preparations may be contained in a single package or separate packages within the kit.

In some aspects, the combination kit further comprises instructions for use printed on or otherwise contained in the tangible expression medium. The instructions may provide information regarding the amount of the compound or pharmaceutical agent contained therein, safety information regarding the amount of the compound or pharmaceutical agent contained therein, dosage amounts of the compound and/or pharmaceutical agent contained therein, indications of use, and/or recommended treatment regimens. In some aspects, the instructions provide directions for administering the compound, pharmaceutical formulation, or salt thereof to a subject in need thereof. A subject in need thereof may have or is suspected of having a cancer or other disease whose histone modifications can be modulated to treat and/or prevent the disease and/or symptoms thereof, which other disease may include, but is not limited to, arthritis, lupus, pulmonary hypertension, cardiac remodeling, and/or neurodegenerative disease.

In some aspects, the kit may include one or more auxiliary active agents in addition to the pyridone-based compound, derivative thereof, or pharmaceutical formulation thereof. In some aspects, the co-active agent is a conventional chemotherapeutic agent or a pharmaceutical formulation thereof. The chemotherapeutic agent may include busulfan, improsulfan, piposulfan, benzotepa, carboquone, meltupipa, uredepa, altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, trimethylolmelamine, chlorambucil, cyclophosphamide, estramustine, ifosfamide, nitrogen mustard, mechlorethamine hydrochloride, melphalan, neonebixine, benzene mustard cholesterol, prednimustine, trofosfamide, uracil mustard, carmustine, chlorourethricin, fotemustine, lomustine, nimustine, ramustine, dacarbazine, mannomustine, dibromomannitol, dibromodulcitol, pipobroman, aclacinomycin, dactinomycin, amicin, azamethicillin, bleomycin, dactinomycin, carcinostatin, chroman, chromomycin, Dactinomycin, daunorubicin, 6-diazo-5-oxo-1-norleucine, doxorubicin, epirubicin, mitomycin C, mycophenolic acid, nogomycin, olivomycin, pellomycin, plicamycin, posomycin, puromycin, streptonigrin, streptozotocin, tubercidin, ubenimex, setastin, zorubicin, dimethylfolic acid, methotrexate, pteropterin, trimetrexate, fludarabine, 6-mercaptopurine, thioprine, thioguanine, ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine, fluorouracil, tegafur, L-asparaginase, alfa streptodornase, acerolactone, aldehydic glycoside, aminoacetylpropionic acid, doxycycline, floxuridine, fluorouracil, tegafur, Amsacrine, betamethacin, bismuthyl, carboplatin, cisplatin, cyclophosphamide, colchicine, mitoquinone, eflornithine, etiloamine, etodol, etoposide, flutamide, gallium nitrate, hydroxyurea, interferon-alpha, interferon-beta, interferon-gamma, interleukin-2, lentinan, lonidamine, mitoguazone, mitoxantrone, mopidanol, diaminenitracridine, pentostatin, mechlorethamine, pirarubicin, podophyllic acid, 2-ethyl hydrazide, procarbazine, razol, sisofilan, germanospiramine, paclitaxel, tamoxifen, teniposide, tenuazonic acid, triimiquone, 2',2 "-trichlorotriethylamine, uratan, vinblastine, vincristine, vindesine, and combinations thereof.

Examples

Having now generally described aspects of the present disclosure, the following examples describe some additional aspects of the present disclosure. While aspects of the disclosure are described in connection with the following embodiments and the corresponding text and figures, there is no intent to limit aspects of the disclosure to that description. On the contrary, it is intended to cover all alternatives, modifications, and equivalents as may be included within the spirit and scope of aspects of the disclosure. The following examples are put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how to perform the methods disclosed and claimed herein and how to use the probes disclosed and claimed herein. Efforts have been made to ensure accuracy with respect to numbers (e.g., amounts, temperature, etc.) but some errors and deviations should be accounted for. Parts are parts by weight (parts by weight), temperature is in degrees celsius, and pressure is at or near atmospheric, unless otherwise indicated. The standard temperature and standard pressure are defined as 20 ℃ and 1 atmosphere.

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