阅读说明：本技术 Hdac6抑制剂和显像剂 (HDAC6 inhibitors and imaging agents ) 是由 J·K·罗卡 J·胡克尔 王长宁 M·G·斯特里布-班蒂洛 于 2018-04-11 设计创作，主要内容包括：本文中提供对于结合至一种或多种组蛋白去乙酰化酶(HDAC)有用的化合物。本申请进一步提供作为用于HDAC的正电子发射断层扫描显像的放射性示踪剂有用的放射性标记的化合物。还提供了用于制备未标记的和标记的化合物的方法、诊断方法以及治疗与HDAC相关的疾病的方法。(Provided herein are compounds useful for binding to one or more Histone Deacetylases (HDACs). The present application further provides radiolabeled compounds useful as radiotracers for positron emission tomography imaging of HDACs. Also provided are methods for making unlabeled and labeled compounds, diagnostic methods, and methods of treating diseases associated with HDACs.)

1. A compound of formula I or a pharmaceutically acceptable salt thereof:

wherein:

X¹is-N (R)^N) -or-CH (R)^C)-；

X²Is CR²Or N;

X³is CR³Or N;

R^Nselected from the group consisting of H, C_1-6Alkyl and C_1-6Haloalkyl groups;

R^Cselected from the group consisting of H, C_1-6Alkyl and C_1-6Haloalkyl groupA group of (a);

L¹is a bond or is C_1-6An alkylene group;

L²is a bond or is C_1-6An alkylene group;

R¹selected from the group consisting of C_1-6Alkyl radical, C_1-6Alkoxy radical, C_3-10Cycloalkyl and C_6-10Aryl, wherein said C_3-10Cycloalkyl and said C_6-10Each aryl group is optionally selected from 1 or 2 independently selected from C_1-6Alkyl and halogen;

R²、R³、R⁴and R⁵Each independently selected from the group consisting of H, C_1-6Alkyl, halogen and C_1-6Haloalkyl groups.

2. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein X¹is-N (R)^N)-。

3. A compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R^NSelected from the group consisting of H and methyl.

4. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein X¹is-CH (R)^C)-。

5. A compound according to claim 1 or 4, or a pharmaceutically acceptable salt thereof, wherein R^CIs H.

6. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein L¹Is a bond.

7. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein L¹Is C_1-6An alkylene group.

8. According to the rightThe compound of any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein L¹Selected from the group consisting of methylene and propylene.

9. The compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein L²Is a bond.

10. The compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein L²Is methylene.

11. The compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein R¹Is optionally 1 or 2 independently selected C_1-3Alkyl substituted C_6-10A cycloalkyl group.

12. The compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein R¹Selected from the group consisting of cyclohexyl, adamantyl, norbornyl and 6, 6-dimethylbicyclo [3.1.1]Heptyl groups.

13. The compound according to any one of claims 1 to 12, wherein R¹Is adamantyl.

14. The compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, wherein X²Is N.

15. The compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, wherein X²Is CR²。

16. The compound according to any one of claims 1 to 13 and 15, or a pharmaceutically acceptable salt thereof, wherein R²Is H or F.

17. According to claimThe compound of any one of claims 1 to 13 and 15, or a pharmaceutically acceptable salt thereof, wherein R²Is F.

18. The compound according to any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, wherein X³Is N.

19. The compound according to any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, wherein X³Is CR³。

20. The compound according to any one of claims 1 to 17 and 19, or a pharmaceutically acceptable salt thereof, wherein R³Is H or F.

21. The compound according to any one of claims 1 to 17 and 19, or a pharmaceutically acceptable salt thereof, wherein R³Is H.

22. The compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, wherein X²And X³Each is N.

23. The compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, wherein X²Is CR²And X³Is CR³。

24. The compound according to any one of claims 1 to 13, 15 and 19, or a pharmaceutically acceptable salt thereof, wherein R²Is F and R³Is H.

25. The compound according to any one of claims 1 to 24, or a pharmaceutically acceptable salt thereof, wherein R⁴Is H or CF₃。

26. A compound according to any one of claims 1 to 24, or a pharmaceutically acceptable salt thereof, which isIn R⁴Is H.

27. The compound according to any one of claims 1 to 26, or a pharmaceutically acceptable salt thereof, wherein R⁵Is H or CF₃。

28. The compound according to any one of claims 1 to 26, or a pharmaceutically acceptable salt thereof, wherein R⁵Is H.

29. The compound according to any one of claims 1 to 13, 15, 19 and 23, or a pharmaceutically acceptable salt thereof, wherein R²Is F and R³、R⁴And R⁵Each is H.

30. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein:

X¹is-N (R)^N) -or-CH₂-；

X²Is CR²Or N;

X³is CR³Or N;

R^Nselected from the group consisting of H and methyl;

L¹is a bond or C_1-3An alkylene group;

L²is a bond or methylene;

R¹selected from the group consisting of C_6-10Cycloalkyl and phenyl, wherein said C_6-10Cycloalkyl and said phenyl are each optionally selected from 1 or 2 independently from C_1-3Alkyl and halogen;

R²selected from the group consisting of H and halogen;

R³、R⁴and R⁵Each is H.

31. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein:

X¹is-N (R)^N) -or-CH₂-；

X²Is CR²Or N;

X³is CR³Or N;

R^Nselected from the group consisting of H and methyl;

L¹is a bond or is selected from the group consisting of methylene and propylene,

L²is a bond or methylene;

R¹selected from the group consisting of C_6-10Cycloalkyl and phenyl, wherein said C_6-10Cycloalkyl and said phenyl are each optionally selected from 1 or 2 independently from C_1-3Alkyl and halogen;

R²selected from the group consisting of H and halogen;

R³、R⁴and R⁵Each is H.

32. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound of formula I is a compound of formula II:

33. the compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound of formula I is a compound of formula III:

34. the compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound of formula I is a compound of formula IV:

35. the compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound of formula I is a compound of formula V:

36. the compound of any one of claims 1 to 35, or a pharmaceutically acceptable salt thereof, wherein the compound or pharmaceutically acceptable salt comprises at least one radioisotope.

37. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 35, wherein the compound or pharmaceutically acceptable salt comprises at least one selected from the group consisting of¹¹C and¹⁸f, or a radioisotope of the group.

38. The compound of any one of claims 1 to 35, or a pharmaceutically acceptable salt thereof, wherein the compound or pharmaceutically acceptable salt comprises at least one¹⁸A radioactive isotope of F.

39. The compound of any one of claims 1 and 36 to 38, or a pharmaceutically acceptable salt thereof, wherein the compound of formula I is a compound of formula VI:

40. the compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound of formula I is a compound selected from the group consisting of:

41. the compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound of formula I is selected from the group consisting of:

42. the compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound of formula I is selected from the group consisting of:

43. a pharmaceutical composition comprising a compound according to any one of claims 1 to 42, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

44. A method of inhibiting the activity of a Histone Deacetylase (HDAC) enzyme, comprising contacting the HDAC enzyme with a compound according to any one of claims 1 to 42, or a pharmaceutically acceptable salt thereof.

45. The method of claim 44, wherein inhibiting the activity of a Histone Deacetylase (HDAC) enzyme comprises deregulating the Histone Deacetylase (HDAC) enzyme.

46. The method of claim 44 or 45, wherein the Histone Deacetylase (HDAC) enzyme is HDAC 6.

47. The method of any one of claims 44 to 46, wherein the compound selectively inhibits one or more of HDAC6, HDAC1, HDAC2, HDAC3, HDAC4, HDAC5, HDAC7, HDAC8, HDAC9, HDAC10, and HDAC 11.

48. The method of any one of claims 44 to 47, wherein the method is an in vitro method.

49. The method of any one of claims 44 to 47, wherein the method is an in vivo method.

50. A method of visualizing a subject, comprising:

i) administering to the subject a radiolabeled compound according to any one of claims 36 to 39 to 42, or a pharmaceutically acceptable salt thereof; and

ii) imaging the subject with an imaging technique.

51. A method of imaging Histone Deacetylation (HDAC) enzymes in a cell or tissue, comprising:

i) contacting the cell or tissue with a radiolabeled compound according to any one of claims 36 to 39 to 42, or a pharmaceutically acceptable salt thereof; and

ii) imaging said cell or tissue using an imaging technique.

52. A method of imaging Histone Deacetylation (HDAC) enzymes in a subject, comprising:

i) administering to the subject a radiolabeled compound according to any one of claims 36 to 39 to 42, or a pharmaceutically acceptable salt thereof; and

ii) imaging the subject with an imaging technique.

53. A method of imaging a disease associated with aberrant expression or aberrant activity of a Histone Deacetylase (HDAC) enzyme in a subject, the method comprising:

i) administering to the subject a radiolabeled compound according to any one of claims 36 to 39 to 42, or a pharmaceutically acceptable salt thereof; and

ii) imaging the subject with an imaging technique.

54. A method of monitoring treatment of a disease associated with aberrant expression or aberrant activity of a Histone Deacetylase (HDAC) enzyme in a subject, comprising:

i) imaging the subject with an imaging technique;

ii) administering to the subject a therapeutically effective amount of a compound according to any one of claims 1 to 42, or a pharmaceutically acceptable salt thereof;

iii) imaging the subject with an imaging technique; and

iv) comparing the image of step i) with the image of step iii).

55. The method of any one of claims 50 to 54, wherein the imaging technique is selected from the group consisting of single photon emission computed tomography, positron emission tomography, computed tomography, positron emission tomography with magnetic resonance imaging.

56. The method of any one of claims 50 to 54, wherein the imaging technique is positron emission tomography imaging.

57. The method according to any one of claims 51 to 56, wherein the Histone Deacetylase (HDAC) enzyme is HDAC 6.

58. A method of imaging the brain in a subject, comprising:

i) administering to the subject a radiolabeled compound according to any one of claims 36 to 39 to 42, or a pharmaceutically acceptable salt thereof; and

ii) imaging the subject with an imaging technique.

59. A method of treating a disease in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound according to any one of claims 1 to 42, or a pharmaceutically acceptable salt thereof, wherein the disease is selected from the group consisting of cancer, a disease of the central nervous system, and an inflammatory autoimmune disease.

60. The method of claim 59, wherein the disease is cancer.

61. The method of claim 59 or 60, wherein the cancer comprises a solid tumor.

62. The method of any one of claims 59 to 61, wherein the cancer is selected from the group consisting of glioma, glioblastoma and non-small cell lung cancer.

63. The method of claim 59 or 60, wherein the cancer is a hematological cancer.

64. The method of claim 63, wherein the hematologic cancer is selected from the group consisting of leukemia and lymphoma.

65. The method of any one of claims 59 to 64, wherein the cancer is associated with aberrant expression or aberrant activity of Histone Deacetylase (HDAC) enzymes.

66. The method of any one of claims 59 to 64, wherein the cancer is associated with aberrant expression or aberrant activity of HDAC 6.

67. The method of claim 59, wherein the disease is a disease of the central nervous system.

68. The method of claim 59 or 67, wherein the disease of the central nervous system comprises a neurodegenerative disease.

69. The method of claim 59 or 67, wherein the disorder of the central nervous system is depression.

70. The method according to claim 59 or 67, wherein the disease of the central nervous system is selected from the group consisting of schizophrenia, bipolar disorder, Alzheimer's disease and Huntington's disease.

71. The method according to any one of claims 59, 68 and 70, wherein the disease of the central nervous system further comprises depression.

72. The method according to any one of claims 59 and 67 to 71, wherein the disease of the central nervous system is associated with abnormal expression or abnormal activity of Histone Deacetylase (HDAC) enzymes.

73. The method of any one of claims 59 and 67 to 71, wherein the disease of the central nervous system is associated with aberrant expression or aberrant activity of HDAC 6.

74. The method of claim 59, wherein the disease is an inflammatory autoimmune disease.

75. The method of claim 74, wherein the inflammatory autoimmune disease is associated with aberrant expression or aberrant activity of a Histone Deacetylase (HDAC) enzyme.

76. The method of any one of claims 59, 74, and 75, wherein the inflammatory autoimmune disease is associated with aberrant expression or aberrant activity of HDAC 6.

77. The method of any one of claims 49-58, wherein about 0.1% to about 5% of the compound administered crosses the blood-brain barrier.

78. The method of any one of claims 49-58, wherein the compound administered has a brain to plasma ratio of at least about 1:1 to at least about 50: 1.

79. A method of treating cancer in a subject, comprising:

i) determining that the cancer is associated with aberrant activity or aberrant expression of Histone Deacetylase (HDAC) enzymes; and

ii) administering to the subject a therapeutically effective amount of a compound according to any one of claims 1 to 42, or a pharmaceutically acceptable salt thereof.

80. A method of treating a disease of the central nervous system in a subject, comprising:

i) determining that the disease of the central nervous system is associated with abnormal activity or abnormal expression of Histone Deacetylase (HDAC) enzymes; and

ii) administering to the subject a therapeutically effective amount of a compound according to any one of claims 1 to 42, or a pharmaceutically acceptable salt thereof.

81. A method of treating an inflammatory autoimmune disease in a subject, the method comprising:

i) determining that the inflammatory autoimmune disease is associated with aberrant activity or aberrant expression of Histone Deacetylase (HDAC) enzymes; and

ii) administering to the subject a therapeutically effective amount of a compound according to any one of claims 1 to 42, or a pharmaceutically acceptable salt thereof.

82. The method of any one of claims 79 to 81, wherein the Histone Deacetylase (HDAC) enzyme is HDAC 6.

Technical Field

The present application provides compounds useful for inhibiting Histone Deacetylase (HDAC) enzymes. The present application further provides compounds (e.g., labeled or unlabeled compounds) useful for treating diseases associated with aberrant expression levels and/or activity of Histone Deacetylase (HDAC) enzymes and methods of using radiolabeled compounds to image HDAC enzymes.

Background

Histone Deacetylases (HDACs) are a family of chromatin modifying enzymes (chromatins) that regulate DNA packaging, gene expression, and are associated with biological functions ranging from differentiation at the cellular level to higher brain functions via behavioral changes at the organism level. Evidence increasingly supports that targeting epigenetic mechanisms (epigenetic mechanism) and chromatin-mediated neuroplasticity (neuroplasticity) can improve treatment of neuropsychiatric diseases.

Disclosure of Invention

The present application provides, inter alia, compounds of formula I:

or a pharmaceutically acceptable salt thereof, wherein:

X¹is-N (R)^N) -or-CH (R)^C)-；

X²Is CR²Or N;

X³is CR³Or N;

R^Nselected from the group consisting of H, C_1-6Alkyl and C_1-6Haloalkyl groups;

R^Cselected from the group consisting of H, C_1-6Alkyl and C_1-6Haloalkyl groups;

L¹is a bond or is selected from the group consisting of C_1-6Alkylene radical, connecting to C_3-10Cycloalkyl and linking a 4-10 membered heterocycloalkyl group, wherein the 4-10 membered heterocycloalkyl group is optionally comprised of 1 or 2 independent C_1-6Alkyl substitution;

L²is a bond or is C_1-6An alkylene group;

R¹selected from the group consisting of C_1-6Alkyl radical, C_1-6Alkoxy radical, C_3-10Cycloalkyl and C_6-10Aryl radicals, in which C_3-10Cycloalkyl and C_6-10Each aryl group is optionally substituted with 1 or 2 independently selected halogen groups;

R²、R³、R⁴and R⁵Each independently selected from the group consisting of H, halogen and C_1-6Haloalkyl groups.

In some embodiments, X¹is-N (R)^N) -. In some embodiments, R^NSelected from the group consisting of H and methyl.

In some embodiments, X¹is-CH (R)^C) -. In some embodiments, R^CIs H.

In some embodiments, L is¹Is a bond. In some embodiments, L is¹Selected from the group consisting of C_1-6Alkylene radical, connecting to C_3-10Cycloalkyl and linking a 4-10 membered heterocycloalkyl group, wherein the 4-10 membered heterocycloalkyl group is optionally comprised of 1 or 2 independent C_1-6Alkyl substitution. In some embodiments, L is¹Selected from the group consisting of: methylene, and,

Wherein:

represents L¹And X¹A bond between; and is

- - - -represents L¹And R¹A bond between them.

In some embodiments, L is²Is a bond. In some embodiments, L is²Is methylene.

In some embodiments, R¹Selected from the group consisting of C_1-3Alkyl radical, C_1-3Alkoxy radical, C_6-10Cycloalkyl and phenyl, wherein phenyl is optionally substituted with 1 or 2 independently selected halogen groups. In some embodiments, R¹Selected from the group consisting of methyl, methoxy, cyclohexyl, adamantyl, norbornyl, phenyl and 3-fluorophenyl.

In some embodiments, X²Is N. In some embodiments, X²Is CR². In some embodiments, R²Is H or F. In some embodiments, R²Is F.

In some embodiments, X³Is N. In some embodiments, X³Is CR³. In some embodiments, R³Is H or F. In some embodiments, R³Is H.

In some embodiments, X²And X³Each is N. In some embodiments, X²Is CR²And X³Is CR³. In some embodiments, R²Is F and R³Is H.

In some embodiments, R⁴Is H or CF₃. In some embodiments, R⁴Is H.

In some embodiments, R⁵Is H or CF₃。

In some embodiments, R⁵Is H.

In some embodiments, R²Is F and R³、R⁴And R⁵Each is H.

In some embodiments:

X¹is-N (R)^N) -or-CH₂-；

X²Is CR²Or N;

X³is CR³Or N;

R^Nselected from the group consisting of H and methyl;

L¹is a bond or is selected from the group consisting of C_1-3Alkylene radical, connecting to C_6-10Cycloalkyl and linking a 4-10 membered heterocycloalkyl group, wherein the 4-10 membered heterocycloalkyl group is optionally comprised of 1 or 2 independent C_1-3Alkyl substitution;

L²is a bond or methylene;

R¹selected from the group consisting of C_1-3Alkyl radical, C_1-3Alkoxy radical, C_6-10Cycloalkyl and phenyl, wherein phenyl is optionally substituted with 1 or 2 independently selected halogen groups;

R²selected from the group consisting of H and halogen; and is

R³、R⁴And R⁵Each is H.

In some embodiments:

X¹is-N (R)^N) -or-CH₂-；

X²Is CR²Or N;

X³is CR³Or N;

R^Nselected from the group consisting of H and methyl;

L¹is a bond or is selected from the group consisting of: methylene, and,

Wherein:

represents L¹And X¹A bond between; and is

- - - -represents L¹And R¹A bond between;

L²is a bond or methylene;

R¹selected from the group consisting of C_1-3Alkyl radical, C_1-3Alkoxy radical, C_6-10Cycloalkyl and phenyl, wherein phenyl is optionally substituted with 1 or 2 independently selected halogen groups;

R²selected from the group consisting of H and halogen; and is

R³、R⁴And R⁵Each is H.

In some embodiments, the compound of formula I is a compound of formula II:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of formula I is a compound of formula III:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of formula I is a compound of formula IV:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of formula I is a compound of formula V:

or a pharmaceutically acceptable salt thereof.

In some embodiments, a compound or pharmaceutically acceptable salt provided herein comprises at least one radioisotope. In some embodiments, a compound or pharmaceutically acceptable salt provided herein comprises at least one compound selected from the group consisting of¹¹C and¹⁸f, or a radioisotope of the group. In some embodiments, a compound or pharmaceutically acceptable salt provided herein comprises at least one¹⁸A radioactive isotope of F.

In some embodiments, the compound of formula I is a compound of formula VI:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of formula I is a compound selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of formula I is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

The present application further provides a pharmaceutical composition comprising a compound provided herein, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

The present application further provides a method of inhibiting the activity of a Histone Deacetylase (HDAC) enzyme, comprising contacting the HDAC enzyme with a compound provided herein or a pharmaceutically acceptable salt thereof. In some embodiments, inhibiting the activity of a Histone Deacetylase (HDAC) enzyme comprises deregulating (deraegulate) the Histone Deacetylase (HDAC) enzyme. In some embodiments, the Histone Deacetylase (HDAC) enzyme is HDAC 6. In some embodiments, the compound selectively inhibits one or more of HDAC6, HDAC1, HDAC2, HDAC3, HDAC4, HDAC5, HDAC7, HDAC8, HDAC9, HDAC10, and HDAC 11.

In some embodiments, the method is an in vitro method. In some embodiments, the method is an in vivo method.

The present application further provides a method of imaging a subject comprising:

i) administering to a subject a radiolabeled compound provided herein, or a pharmaceutically acceptable salt thereof; and

ii) imaging the subject using imaging techniques.

The present application further provides a method of imaging Histone Deacetylation (HDAC) enzymes in a cell or tissue, comprising:

i) contacting a cell or tissue with a radiolabeled compound provided herein, or a pharmaceutically acceptable salt thereof; and

ii) imaging the cells or tissue using imaging techniques.

The present application further provides a method of imaging Histone Deacetylation (HDAC) enzymes in a subject, comprising:

i) administering to a subject a radiolabeled compound provided herein, or a pharmaceutically acceptable salt thereof; and

ii) imaging the subject using imaging techniques.

The present application further provides a method of imaging a disease associated with aberrant expression or aberrant activity of a Histone Deacetylase (HDAC) enzyme in a subject, the method comprising:

i) administering to a subject a radiolabeled compound provided herein, or a pharmaceutically acceptable salt thereof; and

ii) imaging the subject using imaging techniques.

The present application further provides a method of monitoring treatment of a disease associated with aberrant expression or aberrant activity of a Histone Deacetylase (HDAC) enzyme in a subject, comprising:

i) imaging the subject with an imaging technique;

ii) administering to the subject a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof;

iii) imaging the subject using imaging techniques; and

iv) comparing the image of step i) with the image of step iii).

In some embodiments, the imaging technique is selected from the group consisting of single-photon emission computed tomography (single-photon computed tomography), positron emission tomography (positron emission tomography), computed tomography, positron emission tomography with magnetic resonance imaging. In some embodiments, the imaging technique is positron emission tomography imaging. In some embodiments, the Histone Deacetylase (HDAC) enzyme is HDAC 6.

The present application further provides a method of imaging the brain in a subject comprising:

i) administering to a subject a radiolabeled compound provided herein, or a pharmaceutically acceptable salt thereof; and

ii) imaging the subject using imaging techniques.

The present application further provides a method of treating a disease in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof, wherein the disease is selected from the group consisting of cancer, a disease of the central nervous system, and an inflammatory autoimmune disease.

In some embodiments, the disease is cancer. In some embodiments, the cancer comprises a solid tumor. In some embodiments, the cancer is selected from the group consisting of glioma, glioblastoma, and non-small cell lung cancer. In some embodiments, the cancer is a hematologic cancer. In some embodiments, the hematologic cancer is selected from the group consisting of leukemia and lymphoma. In some embodiments, the cancer is associated with aberrant expression or aberrant activity of Histone Deacetylase (HDAC) enzymes. In some embodiments, the cancer is associated with aberrant expression or aberrant activity of HDAC 6.

In some embodiments, the disease is a disease of the central nervous system. In some embodiments, the disease of the central nervous system comprises a neurodegenerative disease. In some embodiments, the disorder of the central nervous system is depression. In some embodiments, the disease of the central nervous system is selected from the group consisting of schizophrenia, bipolar disorder, alzheimer's disease, and huntington's disease. In some embodiments, the disease of the central nervous system further comprises depression. In some embodiments, the disease of the central nervous system is associated with aberrant expression or aberrant activity of Histone Deacetylase (HDAC) enzymes. In some embodiments, the disease of the central nervous system is associated with aberrant expression or aberrant activity of HDAC 6.

In some embodiments, the disease is an inflammatory autoimmune disease. In some embodiments, the inflammatory autoimmune disease is associated with aberrant expression or aberrant activity of Histone Deacetylase (HDAC) enzymes. In some embodiments, the inflammatory autoimmune disease is associated with aberrant expression or aberrant activity of HDAC 6.

In some embodiments, about 0.1% to about 5% of the administered compound crosses the blood-brain barrier. In some embodiments, the compound administered has a brain to plasma ratio of at least about 1:1 to at least about 50: 1.

The present application further provides a method of treating cancer in a subject comprising:

i) determining that the cancer is associated with aberrant activity or aberrant expression of Histone Deacetylase (HDAC) enzymes; and

ii) administering to the subject a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof.

The present application further provides a method of treating a disease of the central nervous system in a subject comprising:

i) determining that a disease of the central nervous system is associated with abnormal activity or abnormal expression of Histone Deacetylase (HDAC) enzymes; and

ii) administering to the subject a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof.

The present application further provides a method of treating an inflammatory autoimmune disease in a subject, the method comprising:

i) determining that the inflammatory autoimmune disease is associated with abnormal activity or abnormal expression of Histone Deacetylase (HDAC) enzymes; and

ii) administering to the subject a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof.

In some embodiments, the Histone Deacetylase (HDAC) enzyme is HDAC 6.

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 invention belongs. Methods and materials for use in the present invention are described herein; in addition, suitable methods and materials known in the art can also be used. The materials, methods, and examples are illustrative only and not intended to be limiting. All publications, patent applications, patents, sequences, database entries, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control.

Drawings

Fig. 1 shows the results of histone and tubulin acetylation assays for human neural progenitor cells.

FIG. 2A shows injection of [ alpha ], [¹⁸F]Average (N ═ 3) time-activity curves for whole brain ROI of Sprague-Dawley rats radiolabeled 4- (((((3s) -adamantan-1-yl) methyl) (methyl) amino) methyl) -3-fluoro-N-hydroxybenzamide (example 2). In blocked animals, 1mg/kg of unlabeled 4- (((((3s) -adamantan-1-yl) methyl) (methyl) amino) methyl) -3-fluoro-N-hydroxybenzamide (example 1) was injected immediately prior to radiotracer administration and baseline animals were treated with vehicle.

FIG. 2B shows injection of [ alpha ], [¹⁸F]PET images of Sprague-Dawley rats of radiolabeled 4- (((((3s) -adamantan-1-yl) methyl) (methyl) amino) methyl) -3-fluoro-N-hydroxybenzamide (example 2). The image shows sagittal sections taken together from 30 to 90 minutes.

Figure 3 shows representative autoradiographic images of sagittal sections of Sprague-Dawley rat brain exposed to the radiolabeled compound of example 2 in the presence of the compound of example 1 or Tubastatin.

Figure 4 shows a comparison of SUV analysis, baseline and pretreatment distribution using a black baboon map (atlas) in 15 regions within baboon brain. Each region of interest (ROI) is shown as a distribution of SUV values (60-120 min average) for each voxel (voxel) within the ROI. ACC, amygdala, CB, cerebellum, DLPFC, dorsolateral prefrontal cortex, HC, hippocampus, M1, primary motor area, NAc, Nucleus accumbens, OFC, orbital cortex, PCC, posterior cingulate cortex, putamen core, SMA auxiliary motor area, Th, V1, primary white matter cortex, WM, primary white matter cortex, and tm.

FIG. 5 shows SUVs and V_TAnd (6) comparing. The region of interest data for example 2 was plotted as SUV value (average 60-120min) versus distribution volume (Vt) to show the linearity of these two measures (measures). This data supports the potential use of reference strategies for quantization of signals.

Fig. 6A-6B show the mean uptake image and time-activity curves for comparison between baseline (example 2) and pre-processed PET scans, where the target was pre-saturated by administration of the non-radiolabeled form of example 1.

Figures 7A-7B show in vitro autoradiographic data from competition experiments. Fig. 7B, top view: example 2, no competitor (competitor); middle diagram: example 2+ example 1; bottom view: example 2+ tubastatin A.

Fig. 8A-8B show the compound of example 2 docked into the CD2 hdac6 complex.

Detailed Description

Histone deacetylases have emerged as drug targets with a range of promising indications. Several pan HDAC inhibitors targeting multiple of the 11 isoforms of Zn-dependent HDAC (isofomm) are approved by the FDA or are currently undergoing clinical trials (see, e.g., Mottamal et al, Molecules (Basel, Switzerland),2015,20 (3): 3898-. However, these non-selective agents often lead to undesirable side effects (see, e.g., Estimu et al, Bioorganic & Medicinal Chemistry,2010,18 (11): 4103-.

The cytoplasmic location (cytosolic location) and structure of HDAC6 are unique among isoforms, and HDAC 6-selective therapeutic regimens have been shown to be promising in avoiding many of the side effects of first-generation pan-HDAC inhibitors (see, e.g., Santo et al, Blood,2012,119 (11): 2579-. Isotype selectivity is difficult to engineer and HDAC6 differs structurally from the other isoforms, providing a starting point for rational design of selective inhibitors.

Aberrant HDAC6 expression levels are implicated in the pathophysiology of the following diseases: glioblastoma multiforme (see, e.g., Li et al, Tumor Biology,2015,36 (12): 9661-; 9665; Wang et al, Cancer Letters,2016,379 (1): 134-; and Lucio-Eterovic et al, BMC Cancer,2008,8 (1): 243), Rett syndrome (see, e.g., Del é pine et al, Human Molecular Genetics,2015,25 (1): 146-; and Gold et al, Journal of Molecular Medicine,2015,93 (1): 63-72), Alzheimer's disease (see, e.g., Anderson et al, PLOS ONE,2015,10 (5): e 0126592; and Cuadado-Tejodor et al, neuropathology, 2017, 20142 (2011, 2011; Neurosche et al, 2011; Neurosche, 120; J.: 779; J.),7713, J, 2014,35(10): 2316-2328), but the understanding of these correlations in the living human brain is still limited. Furthermore, the design of brain-permeable HDAC6 selective agents has proven to be challenging and often requires high doses to achieve the functional effects of HDAC6 inhibition (see, e.g., Jochems et al, Neuropsychopharmacology,2014,39 (2): 389-400).

Positron Emission Tomography (PET) has the potential to improve the understanding of human neuroepigenetics (neuroepigenetics) and related processes, and the study of probes for HDAC6 has the potential to gain insight into the molecular basis of brain function and disease, as well as validation of therapeutic targets and therapeutic small molecules. Thus, the present application describes the development of brain-permeable, selective HDAC6 inhibitors and their use in PET imaging.

Compound (I)

The present application provides compounds of formula I:

or a pharmaceutically acceptable salt thereof, wherein:

X¹is-N (R)^N) -or-CH (R)^C)-；

X²Is CR²Or N;

X³is CR³Or N;

R^Nselected from the group consisting of H, C_1-6Alkyl and C_1-6Haloalkyl groups;

R^Cselected from the group consisting of H, C_1-6Alkyl and C_1-6Haloalkyl groups;

L¹is a bond or is selected from the group consisting of C_1-6Alkylene radical, connecting to C_3-10Cycloalkyl and linking a 4-10 membered heterocycloalkyl group, wherein the 4-10 membered heterocycloalkyl group is optionally comprised of 1 or 2 independent C_1-6Alkyl substitution;

L²is a bond or is C_1-6An alkylene group;

R¹selected from the group consisting of C_1-6Alkyl radical, C_1-6Alkoxy radical, C_3-10Cycloalkyl and C_6-10Aryl radicals, in which C_3-10Cycloalkyl and C_6-10Each aryl group is optionally selected from 1 or 2 independently selected from C_1-6Alkyl and halogen;

R²、R³、R⁴and R⁵Each independently selected from the group consisting of H, C_1-6Alkyl, halogen and C_1-6Haloalkyl groups.

In some embodiments, the compound of formula I is not a compound selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

In some embodiments:

X¹is-N (R)^N) -or-CH (R)^C)-；

X²Is CR²Or N;

X³is CR³Or N;

R^Nselected from the group consisting of H, C_1-6Alkyl and C_1-6Haloalkyl groups;

R^Cselected from the group consisting of H, C_1-6Alkyl and C_1-6Haloalkyl groups;

L¹is a bond or is C_1-6An alkylene group;

L²is a bond or is C_1-6An alkylene group;

R¹selected from the group consisting of C_1-6Alkyl radical, C_1-6Alkoxy radical, C_3-10Cycloalkyl and C_6-10Aryl radicals, in which C_3-10Cycloalkyl and C_6-10Each aryl group is optionally selected from 1 or 2 independently selected from C_1-6Alkyl and halogen;

R²、R³、R⁴and R⁵Each independently selected from the group consisting of H, C_1-6Alkyl, halogen and C_1-6Haloalkyl groupGroup (d) of (a).

In some embodiments:

X¹is-N (R)^N) -or-CH (R)^C)-；

X²Is CR²Or N;

X³is CR³Or N;

R^Nselected from the group consisting of H, C_1-6Alkyl and C_1-6Haloalkyl groups;

R^Cselected from the group consisting of H, C_1-6Alkyl and C_1-6Haloalkyl groups;

L¹is a bond or is selected from the group consisting of C_1-6Alkylene radical, connecting to C_3-10Cycloalkyl and linking a 4-10 membered heterocycloalkyl group, wherein the 4-10 membered heterocycloalkyl group is optionally comprised of 1 or 2 independent C_1-6Alkyl substitution;

L²is a bond or is C_1-6An alkylene group;

R¹selected from the group consisting of C_1-6Alkyl radical, C_1-6Alkoxy radical, C_3-10Cycloalkyl and C_6-10Aryl radicals, in which C_3-10Cycloalkyl and C_6-10Each aryl group is optionally substituted with 1 or 2 independently selected halogen groups;

R²、R³、R⁴and R⁵Each independently selected from the group consisting of H, halogen and C_1-6Haloalkyl groups.

In some embodiments, X¹is-N (R)^N) -. In some embodiments, R^NSelected from the group consisting of H, C_1-3Alkyl and C_1-3Haloalkyl groups. In some embodiments, R^NSelected from H and C_1-3Alkyl groups. In some embodiments, R^NSelected from the group consisting of H and methyl. In some embodiments, R^NIs C_1-6An alkyl group. In some embodiments, R^NSelected from the group consisting of methyl and pentyl (e.g., n-pentyl). In some embodiments, R^NSelected from the group consisting of H, methyl and pentyl.

In some embodiments, X¹is-CH (R)^C)-。

In some embodiments, R^CSelected from the group consisting of H, C_1-3Alkyl and C_1-3Haloalkyl groups. In some embodiments, R^CSelected from H and C_1-3Alkyl groups. In some embodiments, R^CIs H.

In some embodiments, L is¹Is a bond. In some embodiments, L is¹Selected from the group consisting of C_1-6Alkylene radical, connecting to C_3-10Cycloalkyl and linking a 4-10 membered heterocycloalkyl group, wherein the 4-10 membered heterocycloalkyl group is optionally comprised of 1 or 2 independent C_1-6Alkyl substitution. In some embodiments, L is¹Selected from the group consisting of C_1-3Alkylene radical, connecting to C_6-10Cycloalkyl and linking a 4-10 membered heterocycloalkyl group, wherein the 4-10 membered heterocycloalkyl group is optionally comprised of 1 or 2 independent C_1-3Alkyl substitution.

In some embodiments, L is¹Is C_1-6An alkylene group. In some embodiments, L is¹Is C_1-3An alkylene group. In some embodiments, L is¹Selected from the group consisting of methylene and propylene (e.g., -CH)₂CH(CH₃) -or-CH (CH)₂CH₃) -) of groups.

In some embodiments, L is¹Selected from the group consisting of: methylene, propylene, or a salt thereof,

Wherein:

represents L¹And X¹A bond between; and is

- - - -represents L¹And R¹A bond between them.

In some embodiments, L is¹Selected from the group consisting of: methylene, and,

Wherein:

represents L¹And X¹A bond between; and is

- - - -represents L¹And R¹A bond between them.

In some embodiments, L is²Is a bond. In some embodiments, L is²Is C_1-3An alkylene group. In some embodiments, L is²Is methylene.

In some embodiments, R¹Selected from the group consisting of C_1-3Alkyl radical, C_1-3Alkoxy radical, C_6-10Cycloalkyl and phenyl, wherein C_6-10Cycloalkyl and phenyl are optionally selected from 1 or 2 independently from C_1-3Alkyl and halogen. In some embodiments, R¹Selected from the group consisting of C_1-3Alkyl radical, C_1-3Alkoxy radical, C_6-10Cycloalkyl and phenyl, wherein C_6-10Cycloalkyl and phenyl are optionally substituted with 1 or 2 groups independently selected from methyl and fluoro. In some embodiments, R¹Selected from the group consisting of C_1-3Alkyl radical, C_1-3Alkoxy radical, C_6-10Cycloalkyl and phenyl, wherein phenyl is optionally substituted with 1 or 2 independently selected halogen groups. In some embodiments, R¹Selected from the group consisting of C_1-3Alkyl radical, C_1-3Alkoxy radical, C_6-10Cycloalkyl and phenyl, wherein phenyl is optionally substituted with 1 or 2 fluoro groups.

In some embodiments, R¹Selected from the group consisting of C_6-10Cycloalkyl and phenyl, wherein C_6-10Cycloalkyl and phenyl are each optionally selected from 1 or 2 independently from C_1-6Alkyl and halogen. In some embodiments, R¹Selected from the group consisting of C_6-10CycloalkanesA group consisting of a phenyl group, wherein C_6-10Cycloalkyl and phenyl are each optionally selected from 1 or 2 independently from C_1-3Alkyl and fluoro. In some embodiments, R¹Is C_6-10Cycloalkyl optionally substituted by 1 or 2 independently selected from C_1-6Alkyl groups. In some embodiments, R¹Is C_6-10Cycloalkyl optionally substituted by 1 or 2 independently selected from C_1-3Alkyl groups.

In some embodiments, R¹Selected from methyl, methoxy, cyclohexyl, adamantyl, norbornyl, phenyl, 6-dimethylbicyclo [3.1.1]Heptyl (e.g. 6, 6-dimethylbicyclo [ 3.1.1)]Hept-3-yl) and 3-fluorophenyl. In some embodiments, R¹Selected from the group consisting of methyl, methoxy, cyclohexyl, adamantyl, norbornyl, phenyl and 3-fluorophenyl. In some embodiments, R¹Is adamantyl or 6, 6-dimethylbicyclo [3.1.1]Heptyl (e.g. 6, 6-dimethylbicyclo [ 3.1.1)]Hept-3-yl). In some embodiments, R¹Is adamantyl. In some embodiments, R¹Is 6, 6-dimethylbicyclo [3.1.1]Heptyl (e.g. 6, 6-dimethylbicyclo [ 3.1.1)]Hept-3-yl).

In some embodiments, X²Is N.

In some embodiments, X²Is CR²。

In some embodiments, R²Is H or F. In some embodiments, R²Is F. In some embodiments, R²Is H. In some embodiments, R²Selected from the group consisting of H, C_1-6Alkyl and halogen. In some embodiments, R²Selected from the group consisting of H, methyl, F, Cl and Br. In some embodiments, R²Selected from the group consisting of H, methyl and F.

In some embodiments, X³Is N.

In some embodiments, X³Is CR³。

In some casesIn the embodiment, R³Is H or F. In some embodiments, R³Is H. In some embodiments, R³Selected from the group consisting of H, C_1-6Alkyl and halogen. In some embodiments, R³Selected from the group consisting of H, methyl, F, Cl and Br. In some embodiments, R³Selected from the group consisting of H, methyl and F.

In some embodiments, X²And X³Each is N.

In some embodiments, X²Is CR²And X³Is CR³。

In some embodiments, X²Is N and X³Is CR³。

In some embodiments, X²Is CR²And X³Is N.

In some embodiments, R²Is F and R³Is H. In some embodiments, R²And R³Each is H. In some embodiments, R²And R³Each is a halogen. In some embodiments, R²And R³Each is F.

In some embodiments, R⁴Selected from the group consisting of H, halogen and C_1-3Fluoroalkyl groups. In some embodiments, R⁴Selected from the group consisting of H, F and CF₃Group (d) of (a). In some embodiments, R⁴Is H.

In some embodiments, R⁵Selected from the group consisting of H, halogen and C_1-3Fluoroalkyl groups. In some embodiments, R⁵Selected from the group consisting of H, F and CF₃Group (d) of (a). In some embodiments, R⁵Is H.

In some embodiments, R²、R³、R⁴And R⁵At least one of them is C_1-6Alkyl, halogen or C_1-6A haloalkyl group. In some embodiments, R²、R³、R⁴And R⁵At least one of which is halogen or C_1-6A haloalkyl group. In some casesIn embodiments, R²、R³、R⁴And R⁵At least one of which is a halogen group. In some embodiments, R²、R³、R⁴And R⁵At least one of them is C_1-6An alkyl group. In some embodiments, R²、R³、R⁴And R⁵Is F. In some embodiments, R²、R³、R⁴And R⁵At least one of which is methyl. In some embodiments, R²、R³、R⁴And R⁵One of which is F and the other variables are each H. In some embodiments, R²、R³、R⁴And R⁵One of which is methyl and the other variables are each H. In some embodiments, R²、R³、R⁴And R⁵One of them is¹⁸F and the other variables are each H. In some embodiments, R²Is F and R³、R⁴And R⁵Each is H.

In some embodiments:

X¹is-N (R)^N) -or-CH₂-；

X²Is CR²Or N;

X³is CR³Or N;

R^Nselected from H and C_1-6Alkyl groups;

L¹is a bond or is selected from the group consisting of C_1-3Alkylene radical, connecting to C_6-10Cycloalkyl and linking a 4-10 membered heterocycloalkyl group, wherein the 4-10 membered heterocycloalkyl group is optionally comprised of 1 or 2 independent C_1-3Alkyl substitution;

L²is a bond or methylene;

R¹selected from the group consisting of C_1-3Alkyl radical, C_1-3Alkoxy radical, C_6-10Cycloalkyl and phenyl, wherein C_6-10Cycloalkyl and phenyl are optionally selected from 1 or 2 independently from C_1-3Alkyl and halogen;

R²selected from the group consisting of H, C_1-6Alkyl and halogen; and is

R³、R⁴And R⁵Each is H.

In some embodiments:

X¹is-N (R)^N) -or-CH₂-；

X²Is CR²Or N;

X³is CR³Or N;

R^Nselected from the group consisting of H and methyl;

L¹is a bond or is selected from the group consisting of C_1-3Alkylene radical, connecting to C_6-10Cycloalkyl and linking a 4-10 membered heterocycloalkyl group, wherein the 4-10 membered heterocycloalkyl group is optionally comprised of 1 or 2 independent C_1-3Alkyl substitution;

L²is a bond or methylene;

R¹selected from the group consisting of C_1-3Alkyl radical, C_1-3Alkoxy radical, C_6-10Cycloalkyl and phenyl, wherein phenyl is optionally substituted with 1 or 2 independently selected halogen groups;

R²selected from the group consisting of H and halogen; and is

R³、R⁴And R⁵Each is H.

In some embodiments:

X¹is-N (R)^N) -or-CH₂-；

X²Is CR²Or N;

X³is CR³Or N;

R^Nselected from H and C_1-6Alkyl groups;

L¹is a bond or is selected from the group consisting of: methylene, propylene, or a salt thereof,

Wherein:

represents L¹And X¹A bond between; and is

- - - -represents L¹And R¹A bond between;

L²is a bond or methylene;

R¹selected from the group consisting of C_1-3Alkyl radical, C_1-3Alkoxy radical, C_6-10Cycloalkyl and phenyl, wherein C_6-10Cycloalkyl and phenyl are optionally selected from 1 or 2 independently from C_1-6Alkyl and halogen;

R²selected from the group consisting of H, C_1-6Alkyl and halogen; and is

R³、R⁴And R⁵Each is H.

In some embodiments:

X¹is-N (R)^N) -or-CH₂-；

X²Is CR²Or N;

X³is CR³Or N;

R^Nselected from the group consisting of H and methyl;

L¹is a bond or is selected from the group consisting of: methylene, and,

Wherein:

represents L¹And X¹A bond between; and is

- - - -represents L¹And R¹A bond between;

L²is a bond or methylene;

R¹selected from the group consisting of C_1-3Alkyl radical, C_1-3Alkoxy radical, C_6-10Cycloalkyl and phenyl, wherein phenyl is optionally substituted with 1 or 2 independently selected halogen groups;

R²selected from the group consisting of H and halogen; and is

R³、R⁴And R⁵Each is H.

In some embodiments:

X¹is-N (R)^N) -or-CH₂-；

X²Is CR²Or N;

X³is CR³Or N;

R^Nselected from the group consisting of H and methyl;

L¹is a bond or is selected from the group consisting of: methylene, and,

Wherein:

represents L¹And X¹A bond between; and is

- - - -represents L¹And R¹A bond between;

L²is a bond or methylene;

R¹selected from the group consisting of methyl, methoxy, cyclohexyl, adamantyl, norbornyl, phenyl and 3-fluorophenyl;

R²selected from the group consisting of H and halogen; and is

R³、R⁴And R⁵Each is H.

In some embodiments:

X¹is-N (R)^N)-；

X²Is CR²；

X³Is CR³；

R^NIs C_1-3An alkyl group;

L¹and L²Each independently selected C_1-3An alkylene group;

R¹is C_6-10A cycloalkyl group;

R²and R³Each independently selected from the group consisting of H and halogen; and is

R⁴And R⁵Each is H.

In some embodiments:

X¹is-N (R)^N)-；

X²Is CR²；

X³Is CR³；

R^NIs C_1-3An alkyl group;

L¹and L²Each independently selected C_1-3An alkylene group;

R¹is adamantyl or 6, 6-dimethylbicyclo [3.1.1]Heptyl (e.g. 6, 6-dimethylbicyclo [ 3.1.1)]Hept-3-yl);

R²and R³Each independently selected from the group consisting of H and halogen; and is

R⁴And R⁵Each is H.

In some embodiments:

X¹is-N (R)^N) -or-CH₂-；

X²Is CR²Or N;

X³is CR³Or N;

R^Nselected from the group consisting of H and methyl;

L¹is a bond or C_1-3An alkylene group;

L²is a bond or methylene;

R¹selected from the group consisting of C_6-10Cycloalkyl and phenyl, wherein C_6-10Cycloalkyl and phenyl are each optionally selected from 1 or 2 independently from C_1-3Alkyl and halogen;

R²is selected fromThe group consisting of H and halogen;

R³、R⁴and R⁵Each is H.

In some embodiments:

X¹is-N (R)^N) -or-CH₂-；

X²Is CR²Or N;

X³is CR³Or N;

R^Nselected from the group consisting of H and methyl;

L¹is a bond or is selected from the group consisting of methylene and propylene,

L²is a bond or methylene;

R¹selected from the group consisting of C_6-10Cycloalkyl and phenyl, wherein C_6-10Cycloalkyl and phenyl are each optionally selected from 1 or 2 independently from C_1-3Alkyl and halogen;

R²selected from the group consisting of H and halogen;

R³、R⁴and R⁵Each is H.

In some embodiments, the compound of formula I is a compound of formula II:

or a pharmaceutically acceptable salt thereof, wherein the variable R¹、X¹、X²And X³Are defined according to the definitions provided herein for compounds of formula I.

In some embodiments, the compound of formula I is a compound of formula III:

or a pharmaceutically acceptable salt thereof, wherein the variable R¹、L¹、X¹、X²And X³According to the definition provided herein for the compounds of formula IIs defined by the definition.

In some embodiments, the compound of formula I is a compound of formula IV:

or a pharmaceutically acceptable salt thereof, wherein the variable R¹、R^N、X²And X³Are defined according to the definitions provided herein for compounds of formula I.

In some embodiments, the compound of formula I is a compound of formula V:

or a pharmaceutically acceptable salt thereof, wherein the variable R¹And R^NAre defined according to the definitions provided herein for compounds of formula I.

Unless specifically defined, the compounds and salts provided herein may also contain all isotopes of atoms occurring in the intermediates or final compounds. Isotopes include those atoms having the same atomic number but different mass numbers.

In some embodiments, a compound provided herein (e.g., a compound of any one of formulas I-V), or a pharmaceutically acceptable salt thereof, comprises at least one radioisotope. As used herein, the term "radioisotope" refers to an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature (i.e., naturally occurring). A "radiolabeled" compound is a compound provided herein, wherein one or more atoms are replaced or substituted by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature (i.e., naturally occurring). Examples of radioisotopes include, but are not limited to¹¹C、¹³N、¹⁵O、¹⁸F、^34mCl、³⁸K、⁴⁵Ti、⁵¹Mn、^52mMn、⁵²Fe、⁵⁵Co、⁶⁰Cu、⁶¹Cu、⁶²Cu、⁶⁴Cu、⁶⁶Ga、⁶⁷Ga、⁶⁸Ga、⁷¹As、⁷²As、⁷⁴As、⁷⁵Br、⁷⁶Br、⁸²Rb、⁸⁶Y、⁸⁹Zr、⁹⁰Nb、^94mTc、^99mTc、^110mIn、¹¹¹In、¹¹⁸Sb、¹²⁰I、¹²¹I、¹²²I、¹²³I、¹²⁴I、¹²⁴I、¹³¹I and²⁰¹Tl。

in some embodiments, the radioisotope is a positron emitter. As used herein, the term "positron emitter" refers to a radioisotope in which a proton is converted into a neutron, thereby releasing a positron and an electron neutron. In some embodiments, the positron emitter is¹¹C or¹⁸F。

In some embodiments, a compound or pharmaceutically acceptable salt provided herein comprises at least one compound selected from the group consisting of¹¹C and¹⁸f, or a radioisotope of the group. In some embodiments, the compound or pharmaceutically acceptable salt comprises at least one¹⁸A radioactive isotope of F. In some embodiments, at least one halogen group of a compound provided herein is a radioisotope. In some embodiments, at least one halogen group of a compound provided herein is¹⁸F. In some embodiments, at least one haloalkyl or fluoroalkyl group of a compound provided herein comprises at least one radioisotope. In some embodiments, at least one haloalkyl or fluoroalkyl group of a compound provided herein comprises at least one¹⁸A radioactive isotope of F.

In some embodiments, R^NComprising at least one radioisotope. In some embodiments, R^NComprising a radioisotope. In some embodiments, R^NComprises one¹⁸A radioactive isotope of F.

In some embodimentsIn, R^CComprising at least one radioisotope. In some embodiments, R^CComprising a radioisotope. In some embodiments, R^CComprises one¹⁸A radioactive isotope of F.

In some embodiments, R¹Comprising at least one radioisotope. In some embodiments, R¹Comprising a radioisotope. In some embodiments, R¹Comprises one¹⁸A radioactive isotope of F.

In some embodiments, R²Comprising at least one radioisotope. In some embodiments, R²Comprising a radioisotope. In some embodiments, R²Comprises one¹⁸A radioactive isotope of F.

In some embodiments, R³Comprising at least one radioisotope. In some embodiments, R³Comprising a radioisotope. In some embodiments, R³Comprises one¹⁸A radioactive isotope of F.

In some embodiments, R⁴Comprising at least one radioisotope. In some embodiments, R⁴Comprising a radioisotope. In some embodiments, R⁴Comprises one¹⁸A radioactive isotope of F.

In some embodiments, R⁵Comprising at least one radioisotope. In some embodiments, R⁵Comprising a radioisotope. In some embodiments, R⁵Comprises one¹⁸A radioactive isotope of F.

In some embodiments, the compound of formula I is a compound of formula VI:

or a pharmaceutically acceptable salt thereof, wherein the variable R¹And R^NAre defined according to the definitions provided herein for compounds of formula I.

Unless otherwise indicated, when an atom is designated as an isotope or radioisotope (e.g., deuterium, hydrogen, and the like),¹¹C、¹⁸F) An atom is understood to include an isotope or radioisotope in an amount at least greater than the natural abundance of the isotope or radioisotope. For example, when an atom is designated as "D" or "deuterium," that position is understood to have deuterium at an abundance that is at least 3000 times greater than the natural abundance of deuterium (which is 0.015%) (i.e., the incorporation rate (incorporation) of deuterium is at least 45%).

As used herein, the term "Ci" refers to "curie," a unit of radioactivity.

As used herein, the term "specific activity" refers to the activity of a given radioisotope per unit mass, e.g., Ci/g.

In some embodiments, the compound of formula I is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of formula I is a compound selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of formula I is a compound selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of formula I is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

Synthesis of

As will be appreciated, the compounds provided herein, including salts thereof, may be prepared using known organic synthesis techniques and may be synthesized according to any of a variety of possible synthetic routes.

The compounds provided herein can be prepared, for example, according to the representative procedures shown in scheme 1, preparation η, for example, using an air-stable ruthenium complex⁶-a coordinated phenol precursor and using it as eluent without further purification to elute from the anion exchange column [ 2 ]¹⁸F]A fluoride compound. Usually at high conversion (detected by TLC)>70%) was marked. Subsequent transacylation in the same pot yielded the final radiolabeled product (e.g., example 2).

Scheme 1.

Additional synthetic methods for introducing radioisotopes into organic compounds are well known in the art, and one of ordinary skill in the art will readily recognize other methods that may be used to prepare the radiolabeled compounds and salts provided herein.

One skilled in the art will appreciate that the methods described are not exclusive means by which the compounds provided herein may be synthesized, and that a wide collection of synthetic organic reactions may be obtained for potential use in synthesizing the compounds provided herein. The skilled person knows how to select and implement an appropriate synthetic route. Suitable synthetic methods for starting materials, intermediates and products can be determined by reference to documents including, for example, the following references: advances in heterocyclic chemistry, Vol.1-107 (Elsevier, 1963-; journal of heterocyclic chemistry, Vol.1-49 (journal of heterocyclic chemistry, 1964-; carreira et al (eds.), science of Synthesis, Vol.1-48 (2001-; 2011/1-4; 2012/1-2(Thieme, 2001-; katritzky et al (eds.), integrated organofunctional group transformations (PergamonPress, 1996); katritzky et al (eds); integration of organofunctional group transformations II (Elsevier, 2 nd edition, 2004); katritzky et al (eds.), general heterocyclic chemistry (Pergamon Press, 1984); katritzky et al, general heterocyclic chemistry II (Pergamon Press, 1996); smith et al, March's high organic chemistry: reactions, mechanisms and structures, 6 th edition (Wiley, 2007); trost et al (eds.), in combination with organic synthesis (Pergamon Press, 1991).

The preparation of the compounds described herein may involve the protection and deprotection of various chemical groups. The need for protection and deprotection and the choice of an appropriate protecting group can be readily determined by one skilled in the art. The chemistry of protecting groups can be found, for example, in t.w.greene and p.g.m.wuts, protecting groups in organic synthesis, 3 rd edition, Wiley & Sons, inc., New York (1999).

The reaction may be monitored according to any suitable method known in the art. For example, product formation can be monitored by: spectroscopic means, such as nuclear magnetic resonance spectroscopy (e.g.,¹h or¹³C) Infrared spectroscopy, spectrophotometry (e.g., UV-visible), mass spectrometry, or chromatographic methods such as High Performance Liquid Chromatography (HPLC), liquid chromatography-mass spectrometry (LCMS), or Thin Layer Chromatography (TLC). The compounds can be purified by a wide variety of methods including High Performance Liquid Chromatography (HPLC) and normal phase silica gel chromatography by those skilled in the art.

In various places in this specificationDivalent linking substituents are described. It is specifically intended that each divalent linking substituent includes both the forward and backward forms of the linking substituent. For example, -NR (CR' R ")_n-comprises-NR (CR 'R')_n-and- (CR 'R')_nNR-both. Where a linking group is explicitly required for a structure, the markush variables listed for that group are understood to be linking groups.

As used herein, the phrase "optionally substituted" means unsubstituted or substituted. As used herein, the term "substituted" means that a hydrogen atom is removed and replaced with a substituent. It is understood that substitution on a given atom is limited by valence.

Throughout all definitions, the term "C_n-m"denotes a range including endpoints, where n and m are integers and represent a carbon number. Examples include C_1-4And C_1-6And the like.

As used herein, the term "C_n-mAlkylene "refers to a divalent alkyl linking group having n to m carbons. Examples of alkylene groups include, but are not limited to, methylene, ethyl-1, 2-diyl, propyl-1, 3-diyl, propyl-1, 2-diyl, and the like. In some embodiments, the alkylene moiety comprises 1 to 6,1 to 3, or 1 to 2 carbon atoms.

As used herein, the term "C" used alone or in combination with other terms_n-mAlkyl "refers to a saturated hydrocarbon group having n to m carbons that may be straight or branched. Examples of alkyl moieties include, but are not limited to, chemical groups such as: methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl; higher homologues such as 2-methyl-1-butyl, n-pentyl, 3-pentyl, n-hexyl and 1,2, 2-trimethylpropyl and the like. In some embodiments, the alkyl group contains 1 to 6 carbon atoms, 1 to 4 carbon atoms, 1 to 3 carbon atoms, or 1 to 2 carbon atoms.

As used herein, the term "C" used alone or in combination with other terms_n-mAlkoxy "refers to a group of the formula-O-alkyl, wherein the alkyl group has n to m carbons. Examples of alkoxy groups include methoxy, ethoxy, propoxyRadicals (e.g., n-propoxy and isopropoxy), and tert-butoxy, and the like. In some embodiments, the alkyl group has 1 to 6,1 to 4, or 1 to 3 carbon atoms.

As used herein, "halogen" refers to F, Cl, Br, or I. In some embodiments, the halogen is F, Cl or Br. In some embodiments, halogen is F. In some embodiments, the halogen is¹⁸F。

As used herein, the term "C_n-mHaloalkyl "refers to an alkyl group having from 1 halogen atom to 2s +1 halogen atoms, which may be the same or different, wherein" s "is the number of carbon atoms in the alkyl group, wherein the alkyl group has from n to m carbon atoms. In some embodiments, the haloalkyl is fluorinated only (e.g., C)_1-6Fluoroalkyl groups). In some embodiments, the alkyl group has 1 to 6,1 to 4, or 1 to 3 carbon atoms. In some embodiments, the haloalkyl group comprises one or more¹⁸A radioactive isotope of F. In some embodiments, haloalkyl comprises one¹⁸A radioactive isotope of F.

As used herein, the term "aryl" refers to an aromatic hydrocarbon group that may be monocyclic or polycyclic (e.g., having 2,3, or 4 fused rings). The term "C_n-mAryl "refers to an aryl group having n to m ring carbon atoms. Aryl groups include, for example, phenyl, naphthyl, anthryl, phenanthryl, indanyl (indanyl), indenyl, and the like. In some embodiments, aryl groups have from 6 to about 20 carbon atoms, from 6 to about 15 carbon atoms, or from 6 to about 10 carbon atoms. In some embodiments, aryl is substituted or unsubstituted phenyl.

As used herein, "cycloalkyl" refers to a non-aromatic cyclic hydrocarbon that includes cyclized alkyl and/or alkenyl groups. Cycloalkyl groups can include monocyclic or polycyclic (e.g., having 2,3, or 4 fused rings) groups and spirocyclic rings. Cycloalkyl groups can have 3, 4,5, 6, 7, 8, 9, or 10 ring-forming carbons (i.e., C)_3-10Cycloalkyl groups). The ring-forming carbon atoms of the cycloalkyl group may be optionally substituted with an oxy group (oxo) or a thio group (sulfido) (e.g., C (═ O) or C (═ S)). Examples of cycloalkyl groups includeIncluding but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, adamantyl, and the like. In some embodiments, the cycloalkyl group is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, and adamantyl. In some embodiments, cycloalkyl has 6 to 10 ring-forming carbon atoms (i.e., C)_6-10Cycloalkyl groups). In some embodiments, cycloalkyl has 3-6 ring-forming carbon atoms (i.e., C)_3-6Cycloalkyl groups). In some embodiments, the cycloalkyl group is adamantyl.

As used herein, the term "linking cycloalkyl" refers to a divalent cycloalkyl linking group. The linking cycloalkyl groups can include monocyclic or polycyclic (e.g., having 2,3, or 4 fused rings) groups and spiro rings. Cycloalkyl groups can have 3, 4,5, 6, 7, 8, 9, or 10 ring-forming carbons (i.e., C)_3-10Cycloalkyl groups). Also included in the definition of cycloalkyl are moieties having one or more aromatic rings fused (i.e., having a common bond) to the cycloalkyl ring, e.g., benzo derivatives of cyclopentane and cyclohexane, and the like. Exemplary linking cycloalkyl groups include, but are not limited to, 1, 3-cyclobutyl, 1, 4-cyclohexylene, 1, 3-cyclohexylene, 1-cyclohexylene, and the like. Exemplary polycyclic connecting cycloalkyl groups include, but are not limited to:

and the like.

As used herein, "heterocycloalkyl" refers to a non-aromatic monocyclic or polycyclic heterocycle having one or more ring-forming heteroatoms selected from O, N or S. Included among the heterocycloalkyl groups are monocyclic 4-, 5-, 6-and 7-membered heterocycloalkyl groups. Heterocycloalkyl groups may also include spiro rings. Examples of heterocycloalkyl include pyrrolidin-2-one, 1, 3-isoxazolidin-2-one, pyranyl, tetrahydropyranyl, oxetanyl, azetidinyl, morpholino, thiomorpholino, piperazinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, pyrrolidinyl, isoxazolidinyl (isoxazolidinyl), isothiazolidinyl (isothiazolidinyl), pyrazolidinyl, oxazolidinyl, thiazolidinyl, imidazolidinyl, azanyl (azepanyl), and benzazepine (benzazapene), and the like. The ring-forming carbon atoms and heteroatoms of the heterocycloalkyl group may be optionally substituted with oxy (═ O). The heterocycloalkyl group may be attached through a ring-forming carbon atom or a ring-forming heteroatom. In some embodiments, the heterocycloalkyl group contains 0 to 3 double bonds. In some embodiments, the heterocycloalkyl group contains 0 to 2 double bonds. Also included in the definition of heterocycloalkyl are moieties having one or more aromatic rings fused (i.e., having a common bond) to a cycloalkyl ring, e.g., benzo or thienyl derivatives of piperidine, morpholine, azepine, and the like. The heterocycloalkyl group comprising a fused aromatic ring may be attached through any ring-forming atom including ring-forming atoms of the fused aromatic ring. In some embodiments, heterocycloalkyl has 4 to 10, 4 to 7, or 4 to 6 ring atoms with 1 or 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

As used herein, the term "linked heterocycloalkyl" refers to a divalent heterocyclic linking group. Exemplary divalent heterocycloalkyl groups include, but are not limited to, 1, 4-piperidylene, 4-piperidylene, 1, 3-azetidinylene, and benzo-fused heterocycloalkyl groups such as the following:

and the like. In some embodiments, the linking heterocycloalkyl group has 4 to 10, 4 to 7, or 4 to 6 ring atoms with 1 or 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

The term "compound" as used herein is intended to include all stereoisomers, geometric isomers, tautomers and isotopes of the depicted structures. Unless otherwise indicated, a compound identified herein by name or structure as one particular tautomeric form is intended to include the other tautomeric forms.

The compounds provided herein also include tautomeric forms. The tautomeric form results from the exchange of a single bond with an adjacent double bond and the concomitant migration of protons. Tautomeric forms include prototropic tautomers, which are isomeric protonated states having the same empirical formula and total charge. Examples of prototropic tautomers include keto-enol pairs, amide-imide pairs, lactam-lactam pairs, enamine-imide pairs, and cyclic forms in which the protons may occupy more than two positions of a heterocyclic ring system, for example, 1H-and 3H-imidazole, 1H-, 2H-and 4H-1,2, 4-triazole, 1H-and 2H-isoindole, and 1H-and 2H-pyrazole. Tautomeric forms can be in equilibrium or sterically locked into one form by appropriate substitution.

All compounds and pharmaceutically acceptable salts thereof may be found together with other substances such as water and solvents (e.g. hydrates and solvates) or may be isolated.

In some embodiments, preparation of the compounds may involve the addition of an acid or base to affect, for example, catalysis of a desired reaction or formation of salt forms such as acid addition salts.

Examples of acids may be inorganic or organic acids and include, but are not limited to, strong and weak acids. Some examples of acids include hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, p-toluenesulfonic acid, 4-nitrobenzoic acid, methanesulfonic acid, benzenesulfonic acid, trifluoroacetic acid, and nitric acid. Some weak acids include, but are not limited to, acetic acid, propionic acid, butyric acid, benzoic acid, tartaric acid, valeric acid, caproic acid, enanthic acid, caprylic acid, pelargonic acid, and capric acid.

Examples of the base include lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, and sodium hydrogencarbonate. Some examples of strong bases include, but are not limited to, hydroxides, alkoxides, metal amides, metal hydrides, metal dialkylamides, and arylamines, wherein alkoxides include lithium, sodium, and potassium salts of methyl, ethyl, and t-butyl oxides; metal amino compounds include sodium amide, potassium amide, and lithium amide; metal hydrides including sodium hydride, potassium hydride and lithium hydride; and metal dialkylamides include lithium, sodium and potassium salts of methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, trimethylsilyl and cyclohexyl substituted amides.

In some embodiments, the compounds and salts provided herein are substantially isolated. By "substantially separated" is meant that the compound is at least partially or substantially separated from the environment in which it is formed or detected. Partial isolation may include, for example, compositions enriched for the compounds provided herein. Substantially isolating may include compositions comprising at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 97%, or at least about 99% by weight of a compound provided herein, or a salt thereof. Methods for isolating compounds and their salts are conventional in the art.

The phrase "pharmaceutically acceptable" is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which 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.

The present application also includes pharmaceutically acceptable salts of the compounds described herein. As used herein, "pharmaceutically acceptable salts" refer to derivatives of the disclosed compounds wherein the parent compound is modified by conversion of an existing acid or base moiety to its salt form. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic residues such as amines; and alkali metal salts or organic salts of acidic residues such as carboxylic acids; and the like. Pharmaceutically acceptable salts herein include the conventional non-toxic salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. Pharmaceutically acceptable salts of the present application can be synthesized from the parent compound, which contains a basic or acidic moiety, by conventional chemical methods. In general, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media such as ether, ethyl acetate, alcohols (e.g., methanol, ethanol, isopropanol, or butanol), or acetonitrile (MeCN) are preferred. A list of suitable salts can be found in Remington's pharmaceutical sciences, 17 th edition, Mack Publishing Company, Easton, Pa.,1985, p.1418 and Journal of pharmaceutical Science,66,2 (1977). Conventional methods for preparing salt forms are described, for example, in handbooks for pharmaceutically acceptable salts: properties, selection and uses, Wiley-VCH, 2002.

Method of use

The present application further provides methods of inhibiting the activity of a Histone Deacetylase (HDAC) enzyme in a cell sample, a tissue sample, or a subject. In some embodiments, the method is an in vitro method. In some embodiments, the method is an in vivo method. In some embodiments, the method comprises contacting a cell or tissue (e.g., a cell sample or tissue sample) having an HDAC enzyme with a compound provided herein (e.g., a compound of any of formulas I-VI), or a pharmaceutically acceptable salt thereof. In some embodiments, the method comprises administering to the subject a compound provided herein, or a pharmaceutically acceptable salt thereof. In some embodiments, inhibiting the activity of a Histone Deacetylase (HDAC) enzyme comprises deregulating the Histone Deacetylase (HDAC) enzyme.

In some embodiments, the HDAC enzyme is a class IIb HDAC enzyme. In some embodiments, the Histone Deacetylase (HDAC) enzyme is HDAC 6.

As used herein, the term "subject" refers to any animal, including mammals. Examples of subjects include, but are not limited to, mice, rats, rabbits, dogs, cats, pigs, cattle, sheep, horses, primates, and humans. In some embodiments, the subject is a human. In some embodiments, the method comprises administering to the subject a therapeutically effective amount of a compound provided herein (e.g., a compound of any one of formulas I-VI), or a pharmaceutically acceptable salt thereof.

The compounds provided herein can be selective HDAC inhibitors. As used, the term "selective" means that a compound binds to or inhibits a particular enzyme with greater affinity or potency, respectively, than at least one other enzyme. In some embodiments, selectivity includes about 2-fold to about 1000-fold selectivity for a particular enzyme as compared to at least one other enzyme, e.g., about 2-fold to about 1000-fold, about 2-fold to about 500-fold, about 2-fold to about 100-fold, about 2-fold to about 50-fold, about 2-fold to about 20-fold, about 2-fold to about 10-fold, about 10-fold to about 1000-fold, about 10-fold to about 500-fold, about 10-fold to about 100-fold, about 10-fold to about 50-fold, about 10-fold to about 20-fold, about 20-fold to about 1000-fold, about 20-fold to about 500-fold, about 20-fold to about 50-fold, about 50-fold to about 1000-fold, about 50-fold to about 500-fold, about 50-fold to about 100-fold, about 100-fold to about 1000-fold, about 100-fold to about 500-fold, or about 500-fold to about 1000-fold.

In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, selectively inhibits HDAC6 over one or more of HDAC1, HDAC2, HDAC3, HDAC4, HDAC5, HDAC7, HDAC8, HDAC9, HDAC10, and HDAC 11.

The present application further provides a method of imaging a subject comprising:

i) administering to a subject a radiolabeled compound provided herein (e.g., a radiolabeled compound of any one of formulae I-VI), or a pharmaceutically acceptable salt thereof; and

ii) imaging the subject using imaging techniques.

The present application further provides a method of imaging Histone Deacetylation (HDAC) enzymes in a cell or tissue, comprising:

i) contacting a cell or tissue with a radiolabeled compound provided herein, or a pharmaceutically acceptable salt thereof; and

ii) imaging the cells or tissue using imaging techniques.

The present application further provides a method of imaging Histone Deacetylation (HDAC) enzymes in a subject, comprising:

i) administering to a subject a radiolabeled compound provided herein, or a pharmaceutically acceptable salt thereof; and

ii) imaging the subject using imaging techniques.

The present application further provides a method of imaging a disease (e.g., a tumor) in a subject, the method comprising:

i) administering to a subject a radiolabeled compound provided herein, or a pharmaceutically acceptable salt thereof; and

ii) imaging the subject using imaging techniques.

The present application further provides a method of monitoring treatment of a disease in a subject, comprising:

i) imaging the subject with an imaging technique;

ii) administering to the subject a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof;

iii) imaging the subject using imaging techniques; and

iv) comparing the image of step i) with the image of step iii).

In some embodiments, the method further comprises administering an imaging agent to the subject prior to the imaging of step i). In some embodiments, the method further comprises administering an imaging agent to the subject prior to the imaging of step iii). In some embodiments, the imaging agent is a radiolabeled compound provided herein (e.g., a radiolabeled compound of any one of formulas I-VI). In some embodiments, the compound administered in step ii) further comprises an imaging agent (e.g., a fluorescent moiety or radioisotope capable of being imaged using imaging techniques).

In some embodiments, the disease is associated with aberrant expression or aberrant activity of a Histone Deacetylase (HDAC) enzyme in the subject. In some embodiments, the disease to be imaged is associated with aberrant expression or aberrant activity of HDAC 6.

The present application further provides a method of imaging the brain in a subject comprising:

i) administering to a subject a radiolabeled compound provided herein, or a pharmaceutically acceptable salt thereof; and

ii) imaging the subject using imaging techniques.

In some embodiments, the imaging technique is a non-invasive imaging technique. In some embodiments, the imaging technique is a minimally invasive imaging technique. As used herein, the term "minimally invasive imaging technique" includes imaging techniques that employ the use of an internal probe or injection of a compound (e.g., a radiolabeled compound) via a syringe.

Examples of imaging techniques include, but are not limited to, Magnetic Resonance Imaging (MRI), ultrasound imaging, tomography (tomographic imaging), positron emission tomography, computed tomography, positron emission tomography with computed tomography imaging, and positron emission tomography with magnetic resonance imaging.

In some embodiments, the imaging technique is selected from the group consisting of single photon emission computed tomography, positron emission tomography, computed tomography, positron emission tomography with computed tomography imaging, positron emission tomography with magnetic resonance imaging. In some embodiments, the imaging technique is positron emission tomography imaging.

The present application further provides a method of treating a disease in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof. In some embodiments, the disease is associated with aberrant expression or aberrant activity of Histone Deacetylase (HDAC) enzymes. In some embodiments, the disease is selected from the group consisting of cancer, a disease of the central nervous system, and an inflammatory autoimmune disease.

In some embodiments, the disease is cancer. In some embodiments, the cancer is selected from the group consisting of breast cancer, prostate cancer, colon cancer, endometrial cancer, brain cancer (e.g., glioblastoma multiforme), bladder cancer, skin cancer, uterine cancer, ovarian cancer, lung cancer, pancreatic cancer, renal cancer, gastric cancer, and hematologic cancer. In some embodiments, the cancer comprises a solid tumor. In some embodiments, the cancer is selected from the group consisting of glioma, glioblastoma, non-small cell lung cancer, and hematologic cancer.

In some embodiments, the cancer is a hematologic cancer. In some embodiments, the hematologic cancer is selected from the group consisting of leukemia and lymphoma. In some embodiments, the hematologic cancer is selected from the group consisting of: acute myeloblastic leukemia, chronic myeloid leukemia, B-cell lymphoma, Chronic Lymphocytic Leukemia (CLL), non-hodgkin's lymphoma, hairy cell leukemia, mantle cell lymphoma, Burkitt's lymphoma, small lymphocytic lymphoma, follicular lymphoma, lymphoplasmacytic lymphoma, perinodal lymphoma (extra-nodal marginal zone lymphoma), activated B-cell-like (ABC) diffuse large B-cell lymphoma (activated B-cell like (ABC) diffuse large B-cell lymphoma), and germinocenter B-cell (GCB) diffuse large B-cell lymphoma. In some embodiments, the cancer is associated with aberrant expression or aberrant activity of HDAC 6.

In some embodiments, the present application provides a method of treating cancer in a subject comprising:

i) determining that the cancer is associated with aberrant activity or aberrant expression of a Histone Deacetylase (HDAC) enzyme (e.g., HDAC 6); and is

ii) administering to the subject a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof, if the cancer is determined to be associated with abnormal activity of Histone Deacetylase (HDAC) enzymes.

In some embodiments, the disease to be treated is a disease of the central nervous system. In some embodiments, the disease of the central nervous system is selected from the group consisting of: alzheimer's disease, attention deficit/hyperactivity disorder (ADHD), Bell's Palsy (Bell's Palsy), bipolar disorder, catalepsy, cerebral Palsy, epilepsy, encephalitis, huntington's chorea, atresia syndrome, meningitis, migraine, Multiple Sclerosis (MS), parkinson's disease, rett syndrome, schizophrenia, tropical spastic hemiplegia (tropical spastic paresis), and tourette's syndrome. In some embodiments, the disease of the central nervous system is selected from the group consisting of alzheimer's disease, bipolar disorder, depression, huntington's chorea and schizophrenia. In some embodiments, the disease of the central nervous system comprises a neurodegenerative disease (e.g., Amyotrophic Lateral Sclerosis (ALS), parkinson's disease, alzheimer's disease, huntington's disease, etc.). In some embodiments, the disease of the central nervous system is selected from the group consisting of schizophrenia, bipolar disorder, alzheimer's disease, and huntington's disease. In some embodiments, the disease of the central nervous system further comprises depression. In some embodiments, the disorder of the central nervous system is depression. In some embodiments, the disease of the central nervous system is associated with aberrant expression or aberrant activity of HDAC 6.

In some embodiments, the present application provides a method of treating a disease of the central nervous system in a subject, comprising:

i) determining that a disease of the central nervous system is associated with abnormal activity or abnormal expression of a Histone Deacetylase (HDAC) enzyme (e.g., HDAC 6); and is

ii) administering to the subject a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof, if the disease of the central nervous system is determined to be associated with aberrant activity or aberrant expression of Histone Deacetylase (HDAC) enzymes.

In some embodiments, the disease to be treated is an inflammatory autoimmune disease. In some embodiments, the inflammatory autoimmune disease is selected from the group consisting of: alopecia areata, autoimmune hemolytic anemia, autoimmune hepatitis, dermatomyositis, diabetes (type 1), juvenile idiopathic arthritis (juvenile idiopathetic arthritis), glomerulonephritis, graves ' disease, guillain-barre syndrome, idiopathic thrombocytopenic purpura, myasthenia gravis, myocarditis, pemphigus/pemphigoid, pernicious anemia, polyarteritis nodosa, polymyositis, primary biliary cirrhosis, psoriasis, rheumatoid arthritis, scleroderma/systemic sclerosis, sjogren's syndrome, systemic lupus erythematosus, thyroiditis, uveitis, vitiligo, and granulomatosis with polyangiitis (wegener's granulomatosis). In some embodiments, the inflammatory autoimmune disease is associated with aberrant expression or aberrant activity of HDAC 6.

In some embodiments, the present application provides a method of treating an inflammatory autoimmune disease in a subject, the method comprising:

i) determining that the inflammatory autoimmune disease is associated with aberrant activity or aberrant expression of a Histone Deacetylase (HDAC) enzyme (e.g., HDAC 6); and is

ii) administering to the subject a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof, if the inflammatory autoimmune disease is determined to be associated with aberrant activity or aberrant expression of Histone Deacetylase (HDAC) enzymes.

In some embodiments, about 0.1% to about 5% of the compound or salt administered to a subject crosses the blood-brain barrier, e.g., about 0.1% to about 4%, about 0.1% to about 3%, about 0.1% to about 2%, about 0.1% to about 1%, about 0.1% to about 0.75%, about 0.1% to about 0.5%, about 0.1% to about 0.25%, about 0.25% to about 5%, about 0.25% to about 4%, about 0.25% to about 3%, about 0.25% to about 2%, about 0.25% to about 1%, about 0.25% to about 0.75%, about 0.25% to about 0.5%, about 0.5% to about 5%, about 0.5% to about 4%, about 0.5% to about 3%, about 0.5% to about 2%, about 0.5% to about 1%, about 0.5% to about 0.75%, about 0.5% to about 1%, about 0.75%, about 1% to about 3%, about 0.75%, about 1% to about 1%, about 0.75%, about 0., About 1% to about 2%, about 2% to about 5%, about 2% to about 4%, about 2% to about 3%, about 3% to about 5%, about 3% to about 4%, or about 4% to about 5%.

In some embodiments, the brain to plasma ratio of the compound administered to the subject is about 1:1 to about 100:1, e.g., about 1:1 to about 2:1, about 1:1 to about 3:1, about 1:1 to about 4:1, about 1:1 to about 5:1, about 1:1 to about 10:1, about 1:1 to about 15:1, about 1:1 to about 20:1, about 1:1 to about 30:1, about 1:1 to about 1:40, about 1:1 to about 50:1, about 1:1 to about 60:1, about 1:1 to about 70:1, about 1:1 to about 80:1, about 1:1 to about 90:1, about 1:1 to about 100:1, about 1:1 to about 3:2, or about 1:1 to about 4: 3. In some embodiments, the brain to plasma ratio is about 1:100 to about 1:1, e.g., about 1:100 to about 1:1, about 1:100 to about 1:2, about 1:100 to about 1:3, about 1:100 to about 1:4, about 1:100 to about 1:5, about 1:100 to about 1:10, about 1:100 to about 1:15, about 1:100 to about 1:20, about 1:100 to about 1:30, about 1:100 to about 1:40, about 1:100 to about 1:50, about 1:100 to about 1:60, about 1:100 to about 1:70, about 1:100 to about 1:80, about 1:100 to about 1:90, at least about 1:100, about 1:100 to about 2:3, about 1:100 to about 2:5, about 1:100 to about 3:4, about 1:5 to about 1:4, or about 1: 5: 4. In some embodiments, the compound administered has a brain to plasma ratio of about 1:1 to about 50: 1.

As used herein, the phrase "therapeutically effective amount" refers to an amount of an active compound or pharmaceutical agent that elicits a biological or medicinal response (biological or medicinal response) that is being sought in a tissue, system, animal, subject, or human by a researcher, veterinarian, medical doctor (medical doctor) or other clinician.

As used herein, the term "treating" or "treatment" refers to one or more of the following: (1) inhibiting the disease; for example, inhibiting a disease, condition, or disorder (i.e., arresting further development of the pathology and/or disorder) in an individual who is experiencing or displaying the pathology or symptom of the disease, condition, or disorder; and (2) ameliorating the disease; for example, ameliorating a disease, condition, or disorder (i.e., reversing the pathology and/or symptoms) in an individual who is experiencing or displaying the pathology or symptoms of the disease, condition, or disorder, such as reducing the severity of the disease or alleviating or relieving one or more symptoms of the disease.

Combination therapy

One or more additional therapeutic agents, such as, for example, chemotherapeutic agents, anti-inflammatory agents, steroids, immunosuppressive agents, therapeutic antibodies, and/or anesthetic agents, may be used in combination with the compounds and salts provided herein for the treatment of a disease, disorder, or condition associated with HDAC.

Examples of chemotherapeutic agents include proteosome inhibitors (e.g., bortezomib), thalidomide, lenalidomide, and DNA-damaging agents (DNA-damaging agents) such as melphalan, doxorubicin, cyclophosphamide, vincristine, etoposide, and carmustine.

Examples of anti-inflammatory agents include, but are not limited to, aspirin, choline salicylates (cholines salicylates), celecoxib, diclofenac potassium, diclofenac sodium with misoprostol, diflunisal, etodolac, fenoprofen, flurbiprofen, ibuprofen, ketoprofen, meclofenamate sodium, mefenamic acid, nabumetone (nabumetone), naproxen sodium, oxaprozin (oxaprozin), piroxicam, rofecoxib, salicylsalicylic acid (salsalate), sodium salicylate, sulindac, tolmetin sodium, and valdecoxib.

Examples of steroids include, but are not limited to, corticosteroids, such as cortisone, dexamethasone, hydrocortisone, methylprednisolone, prednisolone, and prednisone.

Examples of immunosuppressive agents include, but are not limited to, azathioprine, chlorambucil, cyclophosphamide, cyclosporine, daclizumab, infliximab, methotrexate, and tacrolimus.

Examples of anesthetics include, but are not limited to, local anesthetics (e.g., lidocaine, procaine, ropivacaine) and general anesthetics (e.g., desflurane, enflurane, halothane, methoxyflurane, nitrous oxide, sevoflurane, amobarbital, methohexital, thiopental (thiamylal), thiopental, diazepam, lorazepam, midazolam, etomidate, ketamine, propofol, alfentanil, fentanyl, remifentanil, buprenorphine, butorphanol, hydromorphone (hydromorphone), levorphanol (levorphanol), pethidine, methadone, morphine, nalbuphine, oxymorphone, pentazocine).

In some embodiments, the additional therapeutic agent is administered concurrently with the compound or salt provided herein. In some embodiments, the additional therapeutic agent is administered after administration of the compound or salt provided herein. In some embodiments, the additional therapeutic agent is administered prior to the administration of the compound or salt provided herein. In some embodiments, a compound or salt provided herein is administered during a surgical procedure. In some embodiments, the compounds or salts provided herein are administered in combination with an additional therapeutic agent during a surgical procedure.

Pharmaceutical compositions and formulations

When used as a medicament, the compounds and salts provided herein may be administered in the form of a pharmaceutical composition. These compositions may be prepared as described herein or elsewhere, and may be administered by a variety of routes depending on whether local or systemic treatment is desired and on the area to be treated. Administration can be topical (including transdermal, subcutaneous, ocular, and to the mucosa including intranasal, vaginal, and rectal delivery), pulmonary (e.g., by inhalation or insufflation of powders or aerosols, including by nebulizer; intratracheal or intranasal), oral, or parenteral. Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular injection or infusion; or intracranial (e.g., intrathecal or intraventricular administration). Parenteral administration may be in the form of a single bolus dose, or may be, for example, by means of a continuous infusion pump. In some embodiments, the compounds, salts, and pharmaceutical compositions provided herein are suitable for parenteral administration. In some embodiments, the compounds, salts, and pharmaceutical compositions provided herein are suitable for intravenous administration.

Pharmaceutical compositions and formulations for topical administration may include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids and powders. Conventional pharmaceutical carriers, aqueous, powder or oily bases, and thickening agents and the like may be necessary or desirable.

Also provided are pharmaceutical compositions comprising a compound provided herein, or a pharmaceutically acceptable salt thereof, as an active ingredient in combination with one or more pharmaceutically acceptable carriers (e.g., excipients). In preparing the compositions provided herein, the active ingredient is typically mixed with an excipient, diluted by an excipient or enclosed within such a carrier in the form of, for example, a capsule, sachet (sachet), paper or other container. When the excipient serves as a diluent, it may be a solid, semi-solid, or liquid material that acts as a vehicle, carrier, or medium for the active ingredient. Thus, the composition may be in the form of: tablets, pills, powders, lozenges, sachets (sachets), cachets (cachets), elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.

Some examples of suitable excipients include, without limitation: lactose, glucose, sucrose, sorbitol, mannitol, starch, gum arabic, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose. The formulation may additionally include, without limitation: lubricants, such as talc, magnesium stearate and mineral oil; a wetting agent; emulsifying and suspending agents; preservatives, such as methyl and propyl hydroxybenzoate; a sweetener; a flavoring agent; or a combination thereof.

The active ingredient may be administered in an effective and generally pharmaceutically effective amount over a wide dosage range. However, it will be understood that the amount of the compound actually administered will generally be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, and response of the individual subject, and the severity of the subject's symptoms, etc.