Inhibitors of ENL / AF9 YEATS

Abstract

Acylated 6-aminoindoles, acylated 6-aminopyrrolopyridines, and acylated 3-aminopyrrolo[3,2-c]pyridazines of the formula: 9 It inhibits YEATS and is therefore useful in the treatment of leukemia. [Formula 1] TIFF2023527487000282.tif29135

Claims

1. A compound of formula Ia, 【Chemistry 1】 During the ceremony, X １ , X ２ , and X ３ N and CR ４ are independently selected from (1) X １ , X ２ , and X ３ At most two of are N, (2) X １ and / or X ２ is CR ４ If X ３ is not N, R １ is H, (C １－６ ) alkyl, aryl (C １－６ ) alkyl, (C ３－１２ ) Cycloalkyl(C １－６ ) alkyl, heterocyclyl, heterocyclyl (C １－６ ) alkyl, (C １－６ ) alkylamino (C １－６ ) alkyl, heterocyclylamino (C １－６ ) alkyl, heterocyclyl (C １－６ ) alkylamino (C １－６ ) alkyl, (C ３－１２ ) cycloalkylamino (C １－６ ) alkyl, (C ３－１２ ) Cycloalkyl(C １－６ ) alkylamino (C １－６ ) alkyl, arylamino (C １－６ ) alkyl, and aryl (C １－６ ) alkylamino (C １－６ ) alkyl; R ４ is H, CH ３ and Cl; R ５ is selected from a 5- or 6-membered carbocyclic or heterocyclic ring; a bicyclic 5:6 carbocyclic or heterocyclic ring and a bicyclic 6:6 carbocyclic or heterocyclic ring, which is not attached to a nitrogen of said heterocyclic ring, and said carbocyclic or heterocyclic ring is selected from (C １－８ ) hydrocarbyl, (C １－１０ ) oxaalkyl, halogen, (C １－６ ) haloalkyl, -SO ２ (C １－６ ) alkyl, -SO ２ NH (C ０－３ H １－７ ), -CONH(C ０－３ H １－７ ), -SO ２ NH (C １－６ ) Oxaalkyl, -CN, CH ２ C.N., C.H. ２ N.H. ２ , -NH ２ , N(R 14 ) 2 , -CH ２ OH, benzyloxy, -C(=NH)-NH ２ or -A-Het, where each instance of R 14 is independently selected from hydrogen, (C 1-6 )fluoroalkyl, and (C 1-3 )oxaalkyl; and further where R ５ When is a 5- or 6-membered heterocycle, a bicyclic 5:6 heterocycle, quinoline, isoquinoline, quinazoline, or benzo[b][1,4]oxazine, R 5 is optionally substituted with ═O, A is a direct bond, —(C １－６ ) alkyl-, -(C １－１０ ) oxaalkyl-, -CO(C １－６ ) Alkyl-, -SO ２ (C １－６ ) Alkyl-, -SO ２ NH (C １－６ ) alkyl-, and -CONH(C １－６ ) alkyl-, Het is selected from (C １－６ ) hydrocarbyl, (C １－１０ ) oxaalkyl, (C １－１０ ) oxaalkyl(C=O)-, heterocyclyl optionally substituted with hydroxy, =O or halogen; however, (1) X １ , X ２ , and X ３ are all carbon, and R ５ When is optionally substituted phenyl, R ５ teeth 【Chemistry 2】 and (2) R ５ is not a 1,3-disubstituted pyrazole or a 5-oxaalkylindazole, R ６ is selected from H, Me, F, and Cl; R ７ is hydrogen or halogen, R ８ (C １－１０ ) oxaalkyl, and heterocyclyl; R １１ , R １２ and R １３ is selected from the following three groups: (a) R １１ is H or CH ３ and R １２ is H, (C １ -C ６ ) hydrocarbyl, hydroxy (C １ -C ６ ) hydrocarbyl, and a 5- or 6-membered monocyclic heterocycle, wherein the heterocycle is selected from (C １ -C ６ ) hydrocarbyl, hydroxyl, or hydroxy (C １ -C ６ ) optionally substituted with hydrocarbyl; R １３ is hydrogen or methyl; or (b) R １１ and R １２ are taken together to form an optionally substituted nitrogen heterocycle linked through the nitrogen, said nitrogen heterocycle being selected from (a) a monocyclic aliphatic nitrogen heterocycle, (b) a 5:5 or 5:6 bicyclic aliphatic nitrogen heterocycle, (c) a spirocyclic aliphatic nitrogen heterocycle, and (d) 8-azabicyclo[3.2.1]octane, said optional substituents being selected from (C １－１０ ) hydrocarbyl, halo(C １－１０ ) hydrocarbyl, halo(C １－１０ ) hydrocarbyloxy, -(C １－１０ ) Oxaalkyl, COOH, -SO ２ (C １－６ ) alkyl, =O, =S, =NH, further R １１ and R １２ are taken together to form a spirocyclic aliphatic nitrogen heterocycle, are independently selected from halogen, R １３ is H, (C １－１０ ) hydrocarbyl, halo(C １－１０ ) hydrocarbyl, halo(C １－１０ ) hydrocarbyloxy, -(C １－１０ ) Oxaalkyl, —SO ２ (C １－６ ) selected from alkyl, =O, =S and =NH; or (c) R １１ is H, R １２ and R １３ taken together form a 3- to 7-membered aliphatic carbocyclic ring, said carbocyclic ring being １ -C ６ ) hydrocarbyl, hydroxyl or hydroxy (C １ -C ６ ) optionally substituted with hydrocarbyl; A compound of formula Ia.

2. Of formula Ib, 【Chemistry 3】 In the formula, R １１ and R １２ together form an optionally substituted nitrogen heterocycle Q selected from (a) a monocyclic aliphatic nitrogen heterocycle, (b) a 5:5 or 5:6 bicyclic aliphatic nitrogen heterocycle, (c) a spirocyclic aliphatic nitrogen heterocycle, and (d) 8-azabicyclo[3.2.1]octane, wherein said optional substituents are selected from (C １－１０ ) hydrocarbyl, halo(C １－１０ ) hydrocarbyl, halo(C １－１０ ) hydrocarbyloxy, -(C １－１０ ) Oxaalkyl, COOH, -SO ２ (C １－６ ) independently selected from alkyl, =O, =S, =NH; and R １１ and R １２ when taken together to form a spirocyclic aliphatic nitrogen heterocycle, said optional substituents are independently selected from: (C 1-10 )hydrocarbyl, halo(C 1-10 )hydrocarbyl, halo(C 1-10 )hydrocarbyloxy, -(C 1-10 )oxaalkyl, COOH, -SO 2 (C 1-6 )alkyl, ═O, ═S, ═NH, and halogen; R １ But, H, (C １－６ ) alkyl, aryl (C １－６ ) alkyl, (C ３－１２ ) Cycloalkyl(C １－６ ) alkyl, heterocyclyl, heterocyclyl (C １－６ ) alkyl, (C １－６ ) alkylamino (C １－６ ) alkyl, heterocyclylamino (C １－６ ) alkyl, heterocyclyl (C １－６ ) alkylamino (C １－６ ) alkyl, (C ３－１２ ) cycloalkylamino (C １－６ ) alkyl, (C ３－１２ ) Cycloalkyl(C １－６ ) alkylamino (C １－６ ) alkyl, arylamino (C １－６ ) alkyl, and aryl (C １－６ ) alkylamino (C １－６ ) alkyl; 2. The compound of claim 1 of formula Ib.

3. R １１ is H, R １２ and R １３ are taken together to form a 3- to 7-membered aliphatic carbocyclic ring, said carbocyclic ring being １ -C ６ ) hydrocarbyl, hydroxyl, or hydroxy (C １ -C ６ ) optionally substituted with hydrocarbyl; The compound of claim 1.

4. R １１ is H or CH ３ and R １２ But, H, (C １ -C ６ ) hydrocarbyl, hydroxy (C １ -C ６ ) hydrocarbyl, and a 5- or 6-membered monocyclic heterocycle, wherein the heterocycle is selected from (C １ -C ６ ) hydrocarbyl, hydroxyl, or hydroxy (C １ -C ６ ) optionally substituted with hydrocarbyl; R １３ is hydrogen or methyl; The compound of claim 1.

5. R ５ is selected from a bicyclic 5:6 carbocycle or heterocycle and a bicyclic 6:6 carbocycle or heterocycle, is not bonded at a nitrogen of said heterocycle, and said carbocycle or heterocycle is selected from １－６ ) alkyl, (C １－６ ) alkoxy, halogen, (C １－６ ) haloalkyl, CH ２ C.N., C.H. ２ N.H. ２ , -NH ２ , N(R 14 ) 2 , -CH ２ and optionally substituted with a group selected from -OH and -A-Het, where each occurrence of R 14 is independently selected from hydrogen, (C 1-6 )fluoroalkyl, and (C 1-3 )oxaalkyl; and ５ When is a 5- or 6-membered heterocycle, a bicyclic 5:6 heterocycle, quinoline, isoquinoline, quinazoline, or benzo[b][1,4]oxazine, R 5 is optionally substituted with ═O, A is a direct bond, —(C １－６ ) alkyl-, -(C １－１０ ) oxaalkyl-, -CO(C １－６ ) Alkyl-, -SO ２ (C １－６ ) Alkyl-, -SO ２ NH (C １－６ ) alkyl-, and -CONH(C １－６ ) alkyl-, Het is selected from (C １－６ ) hydrocarbyl, (C １－１０ ) oxaalkyl, (C １－１０ 2. The compound of claim 1, wherein the heterocyclyl is optionally substituted with oxaalkyl(C=O)-, hydroxy, =O or halogen.

6. R ５ is selected from a bicyclic 5:6 carbocycle or heterocycle and a bicyclic 6:6 carbocycle or heterocycle, said carbocycle or heterocycle being １－６ ) alkyl, (C １－６ ) alkoxy, halogen, and (C １－６ 2. The compound of claim 1, optionally substituted with a group selected from: haloalkyl.

7. Q is (C １－１０ ) hydrocarbyl, halo(C １－１０ ) hydrocarbyl, halo(C １－１０ ) hydrocarbyloxy, -(C １－１０ ) Oxaalkyl, COOH, -SO ２ (C １－６ 2. The compound of claim 1 , wherein the heterocyclic ring is a monocyclic aliphatic nitrogen heterocycle optionally substituted with one or more groups selected from alkyl, =O, =S, and =NH.

8. Q is (C １－１０ ) hydrocarbyl, halo(C １－１０ ) hydrocarbyl, halo(C １－１０ ) hydrocarbyloxy, -(C １－１０ ) Oxaalkyl, COOH, -SO ２ (C １－６ 2. The compound of claim 1 , wherein the heterocyclic ring is a 5:5 or 5:6 bicyclic aliphatic nitrogen heterocycle optionally substituted with one or more groups selected from alkyl, =O, =S, and =NH.

9. The compound of claim 2 , wherein Q is a spiro bicyclic aliphatic nitrogen heterocycle.

10. R ５ However, (C １－８ ) hydrocarbyl, (C １－１０ ) oxaalkyl, halogen, (C １－６ ) haloalkyl, -SO ２ (C １－６ ) alkyl, -SO ２ NH (C ０－３ H １－７ ), -CONH(C ０－３ H １－７ ), -SO ２ NH (C １－６ ) Oxaalkyl, -CN, -NH ２ , -CH ２ phenyl substituted with one or more groups selected from OH, benzyloxy, and -A-Het, where A is a direct bond, -(C １－６ ) alkyl-, -(C １－１０ ) oxaalkyl-, -CO(C １－６ ) Alkyl-, -SO ２ (C １－６ ) Alkyl-, -SO ２ NH (C １－６ ) alkyl-, and -CONH(C １－６ ) alkyl-, Het is selected from (C １－６ ) hydrocarbyl, (C １－１０ ) oxaalkyl, (C １－１０ 2. The compound of claim 1, wherein the heterocyclyl is optionally substituted with oxaalkyl(C=O)-, hydroxy, =O, or halogen.

11. R １１ is H, R １２ is selected from optionally substituted pyrazole, triazole, oxadiazole, and pyridine, wherein said optional substituents may be hydroxy or methyl; R １３ is hydrogen, The compound according to claim 4.

12. 8. The compound of claim 7, wherein Q is a monocyclic aliphatic nitrogen heterocycle optionally substituted with one or more groups selected from methyl and =O.

13. 10. The compound of claim 9, wherein Q is selected from the group consisting of azaspirohexane, heptane and octane, and oxazaspirohexane, heptane and octane.

14. Formula I, 【Chemistry 4】 During the ceremony, X １ , X ２ , and X ３ But N and CR ４ Independently selected from １ , X ２ , and X ３ At most two of are N, n is 1, 2 or 3; R １ But, H, (C １－６ ) alkyl, aryl (C １－６ ) alkyl, (C ３－１２ ) Cycloalkyl(C １－６ ) alkyl, heterocyclyl, heterocyclyl (C １－６ ) alkyl, (C １－６ ) alkylamino (C １－６ ) alkyl, heterocyclylamino (C １－６ ) alkyl, heterocyclyl (C １－６ ) alkylamino (C １－６ ) alkyl, (C ３－１２ ) cycloalkylamino (C １－６ ) alkyl, (C ３－１２ ) Cycloalkyl(C １－６ ) alkylamino (C １－６ ) alkyl, arylamino (C １－６ ) alkyl, and aryl (C １－６ ) alkylamino (C １－６ ) alkyl; R ２ａ and R ２ｂ H and (C １－６ ) alkyl, independently or together, R ２ａ and R ２ｂ forms a spiro 4-, 5-, or 6-membered carbocyclic or heterocyclic ring, R ３ But, CHCOOH, NR １０ , O, and C.R. １０ａ R １０ｂ is independently selected in each case from R １０ , R １０ａ and R １０ｂ H and (C １－６ ) alkyl, independently or together, R １０ａ and R １０ｂ forms a spiro 4-, 5- or 6-membered carbocyclic or heterocyclic ring; or Together, R ２ａ and R １０ａ form a fused 4-, 5- or 6-membered carbocyclic or heterocyclic ring, R ４ But, H, CH ３ , F and Cl; R ５ is selected from a 5- or 6-membered carbocyclic or heterocyclic ring; a bicyclic 5-6 carbocyclic or heterocyclic ring and a bicyclic 6-6 carbocyclic or heterocyclic ring, said carbocyclic or heterocyclic ring being selected from (C １－６ ) hydrocarbyl, (C １－６ ) alkoxy, halogen, (C １－６ ) haloalkyl, -SO ２ (C １－６ ) alkyl, -SO ２ NH (C ０－３ H １－７ ), -CONH(C ０－３ H １－７ ), -CN, -NH ２ , -CH ２ OH, benzyloxy, and (C １－６ ) hydrocarbyl, (C １－６ ) optionally substituted with one or more groups selected from alkoxy, hydroxy, =O, or heterocyclyl optionally substituted with halogen; However, X １ , X ２ , and X ３ are all carbon, and R ５ When is optionally substituted phenyl, R ５ but 【Chemistry 5】 and R ６ is selected from H, Me, F, and Cl; R ７ is hydrogen or halogen; R ８ is heterocyclyl; A compound according to claim 1 of formula I.

15. X １ , X ２ Or X ３ is N and the other two instances of X are C.

16. The pyrrolo[3,2-c]pyridine according to claim 6, wherein 【Chemistry 6】

17. The pyrrolo[3,2-b]pyridine according to claim 15, wherein 【Chemistry 7】

18. The pyrrolo[3,2-c]pyridazine according to claim 1, having the following formula: 【Chemistry 8】

19. 2. The indole of claim 1 of the formula: 【Chemistry 9】

20. R ５ is a carbocyclic or heterocyclic ring selected from phenyl, indazole, pyridine, imidazolopyridine, pyrazolopyrimidine, imidazolopyrazine, triazolopyridine, and benzoxazine, or a reduced form thereof, said carbocyclic or heterocyclic ring being optionally substituted.

21. Formula Vb: 【Chemistry 10】 During the ceremony, R ５ａ is selected from a 5- or 6-membered heterocyclic or aliphatic carbocyclic ring; a bicyclic 5:6 carbocyclic or heterocyclic ring and a bicyclic 6:6 carbocyclic or heterocyclic ring, said carbocyclic, heterocyclic or aliphatic carbocyclic ring being selected from (C １－６ ) alkyl, (C １－６ ) alkoxy, halogen, and (C １－６ ) haloalkyl, 12. An indole according to claim 11 of formula Vb.

22. Formula Vc: 【Chemistry 11】 During the ceremony, R ５ｂ but 【Chemistry 12】 and R ７ is hydrogen or halogen; R ８ is heterocyclyl; 12. The indole of claim 11 of formula Vc.

23. R ８ 23. The indole of claim 22, wherein is selected from pyrazine, pyrimidine, pyridazine, and pyridine.

24. R １ The compound according to any one of claims 1 to 19 or 21 to 23, wherein is hydrogen.

25. 15. The compound of claim 14, wherein n is 2.

26. R ２ａ , R ２ｂ , R １０ａ , and R １０ｂ 26. The compound of claim 25, wherein one of is selected from methyl and carboxy, and the remaining instances are hydrogen.

27. R ３ is CHCOOH, R ２ａ , R ２ｂ , R １０ａ , and R １０ｂ 26. The compound of claim 25, wherein is hydrogen.

28. R ２ａ is methyl, R ３ is CR １０ａ R １０ｂ and R ２ｂ , R １０ａ , and R １０ｂ is hydrogen, R ２ａ and R ２ｂ 27. The compound of claim 26, wherein the carbon to which is attached is in the (S) absolute configuration.

29. R ４ The compound according to any one of claims 1 to 19 or 21 to 23, wherein is hydrogen.

30. R ６ The compound according to any one of claims 1 to 19 or 21 to 23, wherein is hydrogen or methyl.

31. R ５ is selected from optionally substituted pyridine, indazole, pyrazine, pyrazole, thiazole, and pyrimidine, and is an optionally substituted heterocycle, —CN or —SO ２ N.H.C.H. ３ 20. The compound of any one of claims 1-4, 7-9, or 11-19, substituted with:

32. R ５ However, (C １－６ ) hydrocarbyl, (C １－６ ) alkoxy, halogen, (C １－６ ) haloalkyl, -SO ２ (C １－６ ) alkyl, -SO ２ NH (C ０－３ H １－７ ), -CN, -NH ２ , -CH ２ OH, benzyloxy, and (C １－６ ) hydrocarbyl, (C １－６ 20. The compound of claim 15 or 17, wherein said phenyl is substituted with one or more groups selected from alkoxy, hydroxy, =O, or heterocyclyl optionally substituted with halogen.

33. R ５ 33. The compound of claim 32, wherein is phenyl substituted with fluoro and an optionally substituted heterocycle.

34. R ５ 21. The compound of claim 20, wherein is a methyl substituted indazole.

35. 27. An in vitro method of inhibiting oncogene expression in a cell, comprising exposing said cell to a compound according to any one of claims 1-19 or 21-23.

36. A pharmaceutical composition for suppressing oncogene expression in a cell, comprising an effective dose of a compound according to any one of claims 1 to 19 or 21 to 23.

37. 27. A pharmaceutical composition for treating a patient with leukemia, comprising an effective dose of a compound according to any one of claims 1 to 19 or 21 to 23.

38. 38. The pharmaceutical composition of claim 37, further comprising a BET inhibitor.

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