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1. (WO2018098561) FUSED PYRIMIDINE COMPOUNDS AS BRD4 AND JAK2 DUAL INHIBITORS AND METHODS FOR USE THEREOF
Note: Text based on automatic Optical Character Recognition processes. Please use the PDF version for legal matters
WHAT IS CLAIMED IS:

1. A compound of formula (I):


or a pharmaceutically acceptable salt or solvate thereof;

wherein:

R1 is H, halogen, alkyl, haloalkyl, hydroxyl, alkylhydroxyl, alkoxy, haloalkoxy, or - NRaRb;

R2 and R3 are each independently H or alkyl;

R4 and R5 are each independently H, halogen, hydroxyl or alkyl;

R6 and R7 are each independently H, halogen, hydroxyl or alkyl; or

alternatively, R6 and R3 together or R7 and R3 together forms a saturated, unsaturated, or partially saturated, 5- or 6-membered ring;

ring A and ring B are each aromatic;

Z1 is C or N;

Z2 is C, CR8, or N;

Z3 and Z4 are each independently C, CR8, N, or S;

provided that at least one of Z1, Z2, Z3, and Z4 is N or S and at most two of Z1, Z2, Z3, and Z4 is N;

R8 is H, halogen, or alkyl;

L is a bond or -CH2-;

W is -S(O)mR9, -P(O)2R9, or -P(=S)2R9;

R9 is alkyl, cycloalkyl, or aryl, wherein cycloalkyl and aryl is optionally substituted with more of halogen or alkyl;

Y is selected from


in Y1 and Y2, R10 and R14 are each independently H, halogen, hydroxyl, alkyl, or alkoxy; in Y1, R1 1, R12 and R13 are each independently H, halogen, alkyl, alkoxy, heterocyclyl, -(CH2)n-C(O)NRaRc, -(CH2)n-NRaC(O)Rd, -(CH2)n-C(O)(CH2)n-, -NRaRb -NRa-alkylene-NRaRb or -(CH2)n-C(O)NRa-alkylene-NRaRb; or

in Y2, R1 1 is H, halogen, hydroxyl or alkyl;

in Y2, ring C is a monocyclic, bicyclic, or tricyclic 5- to 12-membered heterocycle containing at least one atom selected from N, O, or S, wherein ring C is optionally substituted with R15;

Ra and Rb are each independently, H or alkyl;

Rc is H, alkyl, -alkyl-NRaRb, or heterocyclyl;

Rd is alkyl, -alkyl-NRaRb, or heterocyclyl;

wherein hetercocycyl in R11, R12, R13, Rc, and Rd is each independently optionally substituted with R15;

R15 is halogen, hydroxyl, alkyl, alkylhydroxyl, oxo, -C(O)-alkyl, -C(O)ORa; -NRaC(O)-alkyl, -(CH2)n-C(O)NRaRb, -NRaRb; or -S(O)n-alkyl,

n is 0, 1 , or 2; and

m is 0, 1, or 2;

wherein the com ound is not

2. The compound of claim 1, wherein Z2 is N and Z1, Z3, and Z4 are each independently C or CR8.

3. The compound of claim 1, wherein Z1 is N and Z2, Z3, and Z4 are each independently C or CR8.

4. The compound of claim 1, wherein Z1 and Z3 are each N, and Z2 and Z4 are each independently C or CR8.

5. The compound of claim 1, wherein Z1 and Z4 are each N, and Z3 and Z4 are each independently C or CR8.

6. The compound of claim 1 having the formula (II)

or a pharmaceutically acceptable salt or solvate thereof.

7. The compound of any one of claims 1-6, wherein W is -S(O)2R9.

8. The compound of claim 7, wherein R9 is C1-C6 alkyl or C3-C6 alkyl, each optionally substituted.

9. The compound of any one of claims 1-7, wherein L is a bond.

10. The compound of claim 1 having the formula (III)

11. The compound of any one of claims 1-10, wherein R2 and R3 are each H or C1-C3 alkyl.

12. The compound of any one of claims 1-1 1 wherein R4 and R5 are each H.

13. The compound of any one of claims 1-12, wherein R6 and R7 are each independently H or halogen.

14 The compound of any one of claims 1-12, wherein R6 and R3 together forms a saturated, unsaturated, or partially saturated, 5- or 6-membered ring.

15. The compound of claim 14, wherein, R6 and R3 together forms a saturated 5- membered ring.

16. The compound of any one of claims 1 -15, wherein, R10 and R14 are each H.

17. The compound of any one of claims 1-16, wherein, at least one of R" and R13 is a halogen.

18. The compound of any one of claims 1-17, wherein Y is Y1.

19. The compound of claim 18, wherein one of R1 1 , R12 and R13 is an optionally substituted heterocyclyl.

20. The compound of claim 19, wherein the heterocyclyl is selected from piperidine, piperazine, hexahydropyrimidine, morpholine, tetrahydropyran, thiane, or thiomorpholine, each optionally substituted.

21. The compound of claim 19, wherein the heterocyclyl is a bicycle.

22. The compound of claim 19, wherein the heterocyclyl is selected from

each of which is optionally substituted with R15.


23. The compound of claim 18, wherein one of Rn, R12 and R13 is -(CH2)n-C(O)NRaRc, - (CH2)„-NRaC(O)Rd, -(CH2)„-C(O)(CH2)„-, -NRaRb, -NRa-alkylene-NRaRb, or -(CH2)„-C(O)NRa- alkylene-NRaRb;

24. The compound of claim 23, wherein one of R11, R12 and R13 is -NRa-alkylene -NRaRb or- (CH2)„-C(O)NRa-alkylene-NRaRb.

25. The compound of any one of claims 1-17, wherein Y is Y2.

26. The compound of claim 25, wherein Y2 is selected from:

each of which is optionally substituted with R15; and

R16 is H or C1-C3 alkyl.

27. The compound of claim 10, wherein R9 is C1-C6 alkyl or C3-C6 alkyl, each optionally substituted.

28. The compound of claim 1 having the formula (IV)


or a pharmaceutically acceptable salt or solvate thereof.

29. The compound of claim 28, wherein W is -S(O)2R9.

30. The compound of claim 29, wherein R9 is C1-C6 alkyl or C3-C6 alkyl, each optionally substituted.

31. The compound of any one of claims 29 or 30, wherein L is a bond.

32. The compound of claim 1 having the formula (V)

or a pharmaceutically acceptable salt or solvate thereof.

33. The compound of any one of claims 28-32, wherein R2 and R3 are each H or C1-C3 alkyl.

34. The compound of any one of claims 28-33 wherein R4 and R5 are each H.

35. The compound of any one of claims 31-37, wherein R6 and R7 are each independently H or halogen.

36. The compound of any one of claims 28-35, wherein, R10 and R14 are each H.

37. The compound of any one of claims 28-36, wherein, at least one of R11 and R13 is a halogen.

38. The compound of any one of claims 28-37, wherein Y is Y1.

39. The compound of claim 38, wherein one of R1 1, R12 and R13 is an optionally substituted heterocyclyl.

40. The compound of claim 39, wherein the heterocyclyl is selected from piperidine, piperazine, hexahydropyrimidine, morpholine, tetrahydropyran, thiane, or thiomorpholine, each optionally substituted.

41. The compound of claim 40, wherein the heterocyclyl is a bicycle

42. The compound of claim 41 , wherein the heterocyclyl is selected from


each of which is optionally substituted with R .

43. The compound of claim 38, wherein one of R11, R12 and R13 is -(CH2)n-C(O)NRaRc, - (CH2)n-NRaC(O)Rd, -(CH2)„-C(O)(CH2)n-, -NRaRb -NRa-alkylene-NRaRb, or -(CH2)n-C(O)NRa- alkylene-NRaRb;

44. The compound of claim 43, wherein one of R11, R12 and R13 is -NRa-alkylene -NRaRb or - (CH2)n-C(O)NRa-alkylene-NRaRb.

45. The compound of any one of claims 28-37, wherein Y is Y2.

46. The compound of claim 45, wherein Y2 is selected from:


each of which is optionally substituted with R15; and

R16 is H or C1-C3 alkyl.

47. The compound of any one of claims 1-47 having a BRD4-inhibiting activity

corresponding to an IC50 of 10 μΜ or less.

48. The compound of any one of claims 1-46 having JAK2 tyrosine kinase inhibiting activity corresponding to an IC50 of 0.1 μΜ or less.

49. The compound of claim 47 having JAK2 tyrosine kinase inhibiting activity

corresponding to an IC5o of .01 μΜ or less.

50. The pharmaceutical composition comprising a compound of any one of claims 1-49, further comprising one additional therapeutically active agent.

51. A method of treating a disease or condition responsive to the inhibition of a

bromodomain-containing protein comprising administering to the subject in need thereof, a therapeutically effective amount of a compound of any one of claims 1-50, or a pharmaceutically acceptable salt thereof.

52. The method of claim 51 , wherein the bromodomain-containing protein is BRD4.

53. The method of claim 51 or claim 52, wherein the subject is human.

54. The method of any one of claims 51-53, wherein the disease or condition is cancer.

55. The method of claim 54, wherein the cancer is selected from one or more of the group consisting of bladder cancer, brain cancer, breast cancer, colorectal cancer, leukemia, cervical cancer, gastrointestinal cancer, genitourinary cancer, head and neck cancer, lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, renal cancer, skin cancer, and testicular cancer.

56. The method of any one of claims 51-53, wherein the disease or condition is is leukemia.

57. A method of treating a disease or condition responsive to the inhibition of a JAK2 tyrosine kinase comprising administering to the subject in need thereof, a therapeutically effective amount of a compound of any one of claims 1-49, or a pharmaceutically acceptable salt thereof.

58. The method of claim 57, wherein the subject is human.

59. The method of claim 57 or claim 58, wherein the disease or condition is cancer.

60. The method of claim 59, wherein the cancer is selected from one or more of the group consisting of bladder cancer, brain cancer, breast cancer, colorectal cancer, leukemia, cervical cancer, gastrointestinal cancer, genitourinary cancer, head and neck cancer, lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, renal cancer, skin cancer, and testicular cancer.

61. The method of claim 57 or claim 58, wherein the disease or condition is leukemia.

62. A compound of formula (X):


or a pharmaceutically acceptable salt or solvate thereof;

wherein:

Z1, Z2 and Z3 are each S, N or CR8, provided that at least one of Z1, Z2 or Z3 is N or S and at most two of Z1, Z2 or Z3 is N or S ;

ring A and ring B are each aromatic;

V is


L is a bond or -CH2-;

W is -S(O)mR9, -P(O)2R9, or -P(=S)2R9;

R2, R2a and R3 are each independently H or alkyl;

R4 and R5 are each independently H, halogen, hydroxyl or alkyl;

R6 and R7 are each independently H, halogen, hydroxyl or alkyl; or

alternatively, R6 and R3 together or R7 and R3 together forms a saturated, unsaturated, or partially saturated, 5- or 6-membered ring;

R8 is H, halogen, or alkyl;

R9 is alkyl, cycloalkyl, or aryl, wherein cycloalkyl and aryl is optionally substituted with one or more of halogen or alkyl;

Y is selected from


in Y1 and Y2, R10 and R14 are each independently H, halogen, hydroxyl or alkyl;

in Y1, R1 1, R12 and R13 are each independently H, halogen, alkyl, alkoxy, heterocyclyl, -(CH2)n-C(O)NRaRc, -(CH2)n-NRaC(O)Rd, -(CH2)n-C(O)(CH2)n-, -NRaRb -NRa-alkylene-NRaRb or -(CH2)n-C(O)NRa-alkylene-NRaRb; or

in Y2, R1 1 is H, halogen, hydroxyl or alkyl;

in Y2, ring C is a monocyclic, bicyclic, or tricyclic 5- to 12-membered heterocycle containing at least one atom selected from N, O, or S, wherein ring C is optionally substituted with R15;

in Y3, R10, R11, R13 and R14 are each H, halogen, hydroxyl or alkyl;

in Y3, R16 is H or alkyl;

in Y4, R10, R13 and R14 are each H, halogen, hydroxyl or alkyl;

in Y4, Z4 is NRa or O;

in Y3 and Y4, M is a bond or -CH2-;

Ra and Rb are each independently, H or alkyl;

Rc is H, alkyl, -alkyl-NRaRb, or heterocyclyl;

Rd is alkyl, -alkyl-NRaRb, or heterocyclyl;

wherein hetercocycyl in Ru, R12, R13, Rc, and Rd is each independently optionally substituted with R15;

R15 is halogen, hydroxyl, alkyl, alkylhydroxyl, oxo, -C(O)-alkyl, -C(O)ORa; -NRaC(O)-alkyl, -(CH2)n-C(O)NRaRb, -NRaRb; or -S(O)n-alkyl,

n is 0, 1, or 2; and

m is 0, 1, or 2.

63. The compound of claim 62, wherein Z1, Z2 and Z3 are each S or CR8, wherein exactly one of Z', Z2 or Z3 is S.

64. The compound of claim 63, wherein Z1 is S.

65. The compound of claim 63, wherein Z3 is S.

66. The compound of claim 63, wherein V is V2.

67. The compound of claim 66, wherein R2a is H and R3 is alkyl.

68. The compound of claim 67, wherein R2a is H and R3 is C3-C6 cycloalkyl.

69. The compound of claim 63, wherein V is

70. The compound of claim 63, wherein V is V1.

71. The compound of claim 70, wherein W is -S(O)2R9.

72. The compound of claim 71, wherein R9 is C1-C6 alkyl or C3-C6 alkyl, each optionally substituted.

73. The compound of any one of claims 70-72, wherein L is a bond.

74. The compound of any one of claims 70-73, wherein R4 and R5 are each H.

75. The compound of any one of claims 70-74, wherein R6 and R7 are each independently H or halogen.

76. The compound of any one of claims 70-73, wherein R6 and R3 together forms a saturated, unsaturated, or partially saturated, 5- or 6-membered ring.

77. The compound of claim 76, wherein, R6 and R3 together forms a saturated 5- membered ring.

78. The compound of any one of claims 63-77, wherein Y is Y1.

79. The compound of claim 78, wherein one of R1 R12 and R13 is an optionally substituted heterocyclyl.

80. The compound of claim 79, wherein the heterocyclyl is selected from piperidine, piperazine, hexahydropyrimidine, morpholine, tetrahydropyran, thiane, or thiomorpholine, each optionally substituted.

81. The compound of claim 79, wherein the heterocyclyl is a bicycle.

82. The compound of claim79, wherein the heterocyclyl is selected from


each of which is optionally substituted with R .

83. The compound of claim 78, wherein one of R11, R12 and R13 is -(CH2)n-C(O)NRaRc, - (CH2)n-NRaC(O)Rd, -(CH2)n-C(O)(CH2)n-, -NRaRb -NRa-alkylene-NRaRb, or -(CH2)n-C(O)NRa- alkylene-NRaRb;

84. The compound of claim 83, wherein one of Rn, R12 and R13 is -NRa-alkylene -NRaRb or - (CH2)n-C(O)NRa-alkylene-NRaRb.

85. The compound of any one of claims 63-77, wherein Y is Y2.

86. The compound of claim 85, wherein Y2 is selected from:

each of which is optionally substituted with R15; and

R16 is H or C1-C3 alkyl.

87. The compound of any one of claims 63-77, wherein Y is Y3.

88. The compound of claim 87, wherein R10, R11, R13 and R14 are each H.

89. The compound of claim 87 or 88, wherein R16 is H or methyl.

90. The compound of any one of claims 87-89, wherein M is -CH2-.

91. The compound of any one of claims 63-77, wherein Y is Y4.

92. The compound of claim 91 , wherein R10, R13 and R14 are each H.

93. The compound of claim 91 or 92, wherein Z4 is NH or NCH3.

94. The compound of claim 62 selected from:

or a pharmaceutically acceptable salt or solvate thereof.

95. The compound of claim 62, wherein the compound is
or a pharmaceutically acceptable salt or solvate thereof.

96. The compound of any one of claims 62-95 having a BRD4-inhibiting activity

corresponding to an IC50 of 10 μΜ or less.

97. The compound of any one of claims 62-95 having JAK2 tyrosine kinase inhibiting activity corresponding to an IC50 of 0.1 μΜ or less.

98. The compound of claim 96 having JAK2 tyrosine kinase inhibiting activity

corresponding to an IC50 of 1.0 μΜ or less.

99. The pharmaceutical composition comprising a compound of any one of claims 62-98, further comprising one additional therapeutically active agent.

100. A method of treating a disease or condition responsive to the inhibition of a

bromodomain-containing protein comprising administering to the subject in need thereof, a therapeutically effective amount of a compound of any one of claims 62-98, or a

pharmaceutically acceptable salt thereof.

101. The method of claim 100, wherein the bromodomain-containing protein is BRD4.

102. The method of claim 100 or claim 101, wherein the subject is human.

103. The method of any one of claims 100-102, wherein the disease or condition is cancer.

104. The method of claim 103, wherein the cancer is selected from one or more of the group consisting of bladder cancer, brain cancer, breast cancer, leukemia, colorectal cancer, cervical cancer, gastrointestinal cancer, genitourinary cancer, head and neck cancer, lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, renal cancer, skin cancer, and testicular cancer.

105. The method of any one of claims 100-102, wherein the disease or condition is leukemia.

106. A method of treating a disease or condition responsive to the inhibition of a JAK2 tyrosine kinase comprising administering to the subject in need thereof, a therapeutically effective amount of a compound of any one of claims 62-95, or a pharmaceutically acceptable salt thereof.

107. The method of claim 106, wherein the subject is human.

108. The method of claim 106 or claim 107, wherein the disease or condition is cancer.

109. The method of claim 108, wherein the cancer is selected from one or more of the group consisting of bladder cancer, brain cancer, breast cancer, leukemia, colorectal cancer, cervical cancer, gastrointestinal cancer, genitourinary cancer, head and neck cancer, lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, renal cancer, skin cancer, and testicular cancer.