COMPOSITIONS AND METHODS FOR TREATING CNS DISORDERS

Abstract

Described herein are neuroactive steroids of the Formula (II): or a pharmaceutically acceptable salt thereof; wherein A, R.sup.1, R.sup.2a, R.sup.2b, R.sup.3a, R.sup.3b, R.sup.4a, R.sup.4b, R.sup.5, R.sup.6 and are as defined herein. Such compounds are envisioned, in certain embodiments, to behave as GABA modulators. The present invention also provides pharmaceutical compositions comprising a compound of the present invention and methods of use and treatment, e.g., such for inducing sedation and/or anesthesia.

##STR00001##

Claims

1. A compound of the Formula (II): ##STR00188## or a pharmaceutically acceptable salt thereof; wherein: Ring A is substituted or unsubstituted aryl or heteroaryl; R.sup.1 is hydrogen, or substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl, substituted or unsubstituted C.sub.2-6 alkynyl, or substituted or unsubstituted C.sub.3-6 carbocyclyl; each of R.sup.2a and R.sup.2b is independently selected from hydrogen, halogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl, substituted or unsubstituted C.sub.2-6 alkynyl, substituted or unsubstituted C.sub.3-6 carbocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —N(R.sup.A)(R.sup.B), or —OR.sup.A2, wherein each of R.sup.A and R.sup.B is independently hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl, substituted or unsubstituted C.sub.2-6 alkynyl, substituted or unsubstituted C.sub.3-6 carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or R.sup.A and R.sup.B, together with the nitrogen atom to which they are attached form a ring or R.sup.2a and R.sup.2b, together with the carbon atom to which they are attached form a ring; R.sup.A2 is hydrogen or substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl, substituted or unsubstituted C.sub.2-6 alkynyl, substituted or unsubstituted C.sub.3-6 carbocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R.sup.3a is hydrogen, —N(R.sup.A)(R.sup.B), or —OR.sup.A3, wherein R.sup.A3 is hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl, substituted or unsubstituted C.sub.2-6 alkynyl, or substituted or unsubstituted C.sub.3-6 carbocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and R.sup.3b is hydrogen or —N(R.sup.A)C(O)R.sup.A3; or R.sup.3a and R.sup.3b are joined to form an oxo (═O) group; each of R.sup.4a and R.sup.4b is independently selected from hydrogen or halogen; R.sup.5 is hydrogen, unsubstituted C.sub.1-6 alkyl, or —CH.sub.2OR.sup.A5, wherein R.sup.A5 is hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl, substituted or unsubstituted C.sub.2-6 alkynyl, or substituted or unsubstituted C.sub.3-6 carbocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl; R.sup.6 is absent or hydrogen; and represents a single or double bond, wherein when one of is a double bond, the other is a single bond; and when one of the is a double bond, R.sup.6 is absent.

2. A compound of the Formula (I): ##STR00189## or a pharmaceutically acceptable salt thereof; wherein: Ring A is substituted or unsubstituted aryl or heteroaryl; R.sup.1 is hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl, or substituted or unsubstituted C.sub.3-6 carbocyclyl; R.sup.2 is hydrogen, halogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl, substituted or unsubstituted C.sub.2-6 alkynyl, substituted or unsubstituted C.sub.3-6 carbocyclyl, —N(R.sup.A)(R.sup.B), or —OR.sup.A2, wherein each of R.sup.A and R.sup.B is independently hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl, substituted or unsubstituted C.sub.2-6 alkynyl, substituted or unsubstituted C.sub.3-6 carbocyclyl, or substituted or unsubstituted heterocyclyl, or R.sup.A and R.sup.B, together with the nitrogen atom to which they are attached form a ring; R.sup.A2 is hydrogen or substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl, substituted or unsubstituted C.sub.2-6 alkynyl, or substituted or unsubstituted C.sub.3-6 carbocyclyl; R.sup.3a is hydrogen, —N(R.sup.A)(R.sup.B), or —OR.sup.A3, wherein R.sup.A3 is hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl, substituted or unsubstituted C.sub.2-6 alkynyl, or substituted or unsubstituted C.sub.3-6 carbocyclyl, and R.sup.3b is hydrogen or N(R.sup.A)C(O)R.sup.A3; or R.sup.3a and R.sup.3b are joined to form an oxo (═O) group; R.sup.4 is hydrogen or halogen; R.sup.5 is hydrogen, unsubstituted C.sub.1-6 alkyl, or —CH.sub.2OR.sup.A5, wherein R.sup.A5 is hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl, substituted or unsubstituted C.sub.2-6 alkynyl, or substituted or unsubstituted C.sub.3-6 carbocyclyl; R.sup.6 is absent or hydrogen; and represents a single or double bond, wherein when one of is a double bond, the other is a single bond; and when one of the is a double bond, R.sup.6 is absent.

3. The compound of claim 2, wherein the compound of Formula (I) is a compound of Formula (I-a): ##STR00190## wherein: n is 0, 1, 2, 3, 4, 5, or 6; and each R.sup.a is independently halogen, cyano, C.sub.1-6 alkyl, —N(R.sup.A)(R.sup.B), —N(R.sup.A)C(O)R.sup.AA, —N(R.sup.A)C(O)OR.sup.AA, —SR.sup.AA or —OR.sup.AA, wherein R.sup.AA is hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl, substituted or unsubstituted C.sub.2-6 alkynyl, substituted or unsubstituted C.sub.3-6 carbocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or two R.sup.a groups, together with the atoms with which they are attached form a ring.

4. The compound of claim 2, wherein the compound of Formula (I) is a compound of Formula (I-b): ##STR00191##

5. The compound of claim 2, wherein the compound of Formula (I) is a compound of Formula (I-b-i) or (I-b-ii): ##STR00192##

6. The compound of claim 2, wherein the compound of Formula (I) is a compound of Formula (I-c): ##STR00193##

7. The compound of claim 2, wherein the compound of Formula (I) is a compound of Formula (I-c-i) or (I-c-ii): ##STR00194##

8. The compound of claim 2, wherein the compound of Formula (I) is a compound of Formula (I-f): ##STR00195##

9. The compound of claim 2, wherein the compound of Formula (I) is a compound of Formula (I-d-i) or (I-d-ii): ##STR00196##

10. The compound of claim 2, wherein A is a 5-10-membered ring.

11. The compound of claim 10, wherein A is phenyl, naphthyl, furan, thiophene, thiazole, pyrrole, imidazole, pyrazole, or triazole.

12. The compound of claim 10, wherein A is a fused bicyclic ring.

13. The compound of claim 12, wherein A is benzofuran, benzoimidazole, indole, benzothiazole, or benzothiophene.

14. The compound of claim 10, wherein A is linked through a carbon atom.

15. The compound of claim 2, wherein R.sup.1 is hydrogen or substituted or unsubstituted C.sub.1-6 alkyl.

16. The compound of claim 15, wherein R.sup.1 is unsubstituted C.sub.1-6 alkyl.

17. The compound of claim 16, wherein R.sup.1 is —CH.sub.3.

18. The compound of claim 15, wherein R.sup.1 is hydrogen.

19. The compound of claim 2, wherein n is 0, 1, or 2.

20. The compound of claim 19, wherein n is 0 or 1.

21. The compound of claim 2, wherein n is 0, 1, or 2, and each R.sup.a is independently halogen, C.sub.1-6 alkyl, or —OR.sup.AA, wherein R.sup.AA is hydrogen, or substituted or unsubstituted C.sub.1-6 alkyl.

22. The compound of claim 19, wherein R.sup.a is —CH.sub.3.

23. The compound of claim 2, wherein R.sup.a is C.sub.1-6 alkyl.

24. The compound of claim 1, wherein the compound is: ##STR00197## ##STR00198## ##STR00199## ##STR00200## ##STR00201## ##STR00202## ##STR00203## ##STR00204## ##STR00205## ##STR00206## ##STR00207## ##STR00208## ##STR00209## ##STR00210## ##STR00211## ##STR00212## ##STR00213## ##STR00214## ##STR00215## ##STR00216## ##STR00217## ##STR00218## ##STR00219## ##STR00220## ##STR00221## ##STR00222## ##STR00223##

25. A pharmaceutical composition comprising a compound of any one of the preceding claims and a pharmaceutically acceptable excipient.

26. A method of inducing sedation and/or anesthesia in a subject, comprising administering to the subject an effective amount of a compound of the Formula (II): ##STR00224## or a pharmaceutically acceptable salt thereof; wherein: Ring A is substituted or unsubstituted aryl or heteroaryl; R.sup.1 is hydrogen, or substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl, substituted or unsubstituted C.sub.2-6 alkynyl, or substituted or unsubstituted C.sub.3-6 carbocyclyl; each of R.sup.2a and R.sup.2b is independently selected from hydrogen, halogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl, substituted or unsubstituted C.sub.2-6 alkynyl, substituted or unsubstituted C.sub.3-6 carbocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —N(R.sup.A)(R.sup.B), or —OR.sup.A2, wherein each of R.sup.A and R.sup.B is independently hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl, substituted or unsubstituted C.sub.2-6 alkynyl, substituted or unsubstituted C.sub.3-6 carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or R.sup.A and R.sup.B, together with the nitrogen atom to which they are attached form a ring, or R.sup.2a and R.sup.2b, together with the carbon atom to which they are attached form a ring; R.sup.A2 is hydrogen or substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl, substituted or unsubstituted C.sub.2-6 alkynyl, substituted or unsubstituted C.sub.3-6 carbocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R.sup.3a is hydrogen, —N(R.sup.A)(R.sup.B), or —OR.sup.A3, wherein R.sup.A3 is hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl, substituted or unsubstituted C.sub.2-6 alkynyl, or substituted or unsubstituted C.sub.3-6 carbocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and R.sup.3b is hydrogen or —N(R.sup.A)C(O)R.sup.A3; or R.sup.3a and R.sup.3b are joined to form an oxo (═O) group; each of R.sup.4a and R.sup.4b is independently selected from hydrogen or halogen; R.sup.5 is hydrogen, unsubstituted C.sub.1-6 alkyl, or —CH.sub.2OR.sup.A5, wherein R.sup.A5 is hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl, substituted or unsubstituted C.sub.2-6 alkynyl, or substituted or unsubstituted C.sub.3-6 carbocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl; R.sup.6 is absent or hydrogen; and represents a single or double bond, wherein when one of is a double bond, the other is a single bond; and when one of the is a double bond, R.sup.6 is absent.

27. A method of administering an effective amount of a compound, a pharmaceutically acceptable salt thereof, or pharmaceutical composition of a compound of claim 1, to a subject in need thereof, wherein the subject experiences sedation and/or anesthesia within two hours of administration.

28. The method of claim 27, wherein the subject experiences sedation and/or anesthesia within one hour of administration.

29. The method of claim 28, wherein the subject experiences sedation and/or anesthesia instantaneously.

30. The method of claim 28, wherein the compound is administered by intravenous administration.

31. The method of claim 28, wherein the compound is administered chronically.

32. The method of claim 28, wherein the subject is a mammal.

33. The method of claim 32, wherein the subject is a human.

34. The method of 27, wherein the compound is administered in combination with another therapeutic agent.

35. A method for treating seizure in a subject, comprising administering to the subject an effective amount of a compound of the Formula (II): ##STR00225## or a pharmaceutically acceptable salt thereof; wherein: Ring A is substituted or unsubstituted aryl or heteroaryl; R.sup.1 is hydrogen, or substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl, substituted or unsubstituted C.sub.2-6 alkynyl, or substituted or unsubstituted C.sub.3-6 carbocyclyl; each of R.sup.2a and R.sup.2b is independently selected from hydrogen, halogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl, substituted or unsubstituted C.sub.2-6 alkynyl, substituted or unsubstituted C.sub.3-6 carbocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —N(R.sup.A)(R.sup.B), or —OR.sup.A2, wherein each of R.sup.A and R.sup.B is independently hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl, substituted or unsubstituted C.sub.2-6 alkynyl, substituted or unsubstituted C.sub.3-6 carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or R.sup.A and R.sup.B, together with the nitrogen atom to which they are attached form a ring, or R.sup.2a and R.sup.2b, together with the carbon atom to which they are attached form a ring; R.sup.A2 is hydrogen or substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl, substituted or unsubstituted C.sub.2-6 alkynyl, substituted or unsubstituted C.sub.3-6 carbocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R.sup.3a is hydrogen, —N(R.sup.A)(R.sup.B), or —OR.sup.A3, wherein R.sup.A3 is hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl, substituted or unsubstituted C.sub.2-6 alkynyl, or substituted or unsubstituted C.sub.3-6 carbocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and R.sup.3b is hydrogen or —N(R.sup.A)C(O)R.sup.A3; or R.sup.3a and R.sup.3b are joined to form an oxo (═O) group; each of R.sup.4a and R.sup.4b is independently selected from hydrogen or halogen; R.sup.5 is hydrogen, unsubstituted C.sub.1-6 alkyl, or —CH.sub.2OR.sup.A5, wherein R.sup.A5 is hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl, substituted or unsubstituted C.sub.2-6 alkynyl, or substituted or unsubstituted C.sub.3-6 carbocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl; R.sup.6 is absent or hydrogen; and represents a single or double bond, wherein when one of is a double bond, the other is a single bond; and when one of the is a double bond, R.sup.6 is absent.

36. A method for treating epilepsy or status or status epilepticus in a subject, the method comprising administering to the subject an effective amount of a compound of the Formula (II): ##STR00226## or a pharmaceutically acceptable salt thereof; wherein: Ring A is substituted or unsubstituted aryl or heteroaryl; R.sup.1 is hydrogen, or substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl, substituted or unsubstituted C.sub.2-6 alkynyl, or substituted or unsubstituted C.sub.3-6 carbocyclyl; each of R.sup.2a and R.sup.2b is independently selected from hydrogen, halogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl, substituted or unsubstituted C.sub.2-6 alkynyl, substituted or unsubstituted C.sub.3-6 carbocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —N(R.sup.A)(R.sup.B), or —OR.sup.A2, wherein each of R.sup.A and R.sup.B is independently hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl, substituted or unsubstituted C.sub.2-6 alkynyl, substituted or unsubstituted C.sub.3-6 carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or R.sup.A and R.sup.B, together with the nitrogen atom to which they are attached form a ring, or R.sup.2a and R.sup.2b, together with the carbon atom to which they are attached form a ring; R.sup.A2 is hydrogen or substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl, substituted or unsubstituted C.sub.2-6 alkynyl, substituted or unsubstituted C.sub.3-6 carbocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R.sup.3a is hydrogen, —N(R.sup.A)(R.sup.B), or —OR.sup.A3, wherein R.sup.A3 is hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl, substituted or unsubstituted C.sub.2-6 alkynyl, or substituted or unsubstituted C.sub.3-6 carbocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and R.sup.3b is hydrogen or —N(R.sup.A)C(O)R.sup.A3; or R.sup.3a and R.sup.3b are joined to form an oxo (═O) group; each of R.sup.4a and R.sup.4b is independently selected from hydrogen or halogen; R.sup.5 is hydrogen, unsubstituted C.sub.1-6 alkyl, or —CH.sub.2OR.sup.A5, wherein R.sup.A5 is hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl, substituted or unsubstituted C.sub.2-6 alkynyl, or substituted or unsubstituted C.sub.3-6 carbocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl; R.sup.6 is absent or hydrogen; and represents a single or double bond, wherein when one of is a double bond, the other is a single bond; and when one of the is a double bond, R.sup.6 is absent.

37. A method for treating a subject having an injury resulting from exposure to a warfare agent, the method comprising administering to the subject a compound described herein.

38. A method of treating an injury in a subject who has been exposed to a chemical warfare agent, the method comprising administering to the subject a compound described herein.

39. A method of treating a subject, the method comprising: identifying a subject that has been exposed to a chemical warfare agent such as a nerve agent or toxin; and administering to the subject a compound described herein.

40. The method of claim 39, wherein the injury is a seizure.

41. The method of claim 40, wherein the injury is a myoclonic seizure.

42. The method of claim 39, wherein the injury is status epilepticus.

43. The method of claim 39, wherein the administration is within 1 week; 6, 5, 4, 3, 2, or 1 days; 24, 22, 20, 18, 16, 14, 12, 10, 8, 7, 6, 5, 4, 3, 2, or 1 hours; or 45, 30, 20, 10, or 5 minutes of exposure to the chemical warfare agent.

44. The method of one of claims 37-39, wherein the compound is administered parenterally.

45. The method of claim 37, wherein the compound is administered by intravenous administration.

46. The method of claim 37, wherein the subject is a human.

47. The method of claim 37, wherein the chemical warfare agent is a nerve agent or toxin.

48. The method of claim 47, wherein the chemical warfare agent is a nerve agent.

49. The method of claim 48, wherein the nerve agent is a phosphorus-containing organic chemical.

50. The method of claim 48, wherein the nerve agent is a G agent.

51. The method of claim 48, wherein the nerve agent is a V agent.

52. The method of claim 47, wherein the toxin is abrin, ricin, or saxitoxin.

53. A method for treating disorders related to GABA function in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound, a pharmaceutically acceptable salt thereof, or pharmaceutical composition of one of a compound of Formula (II): ##STR00227## or a pharmaceutically acceptable salt thereof; wherein: Ring A is substituted or unsubstituted aryl or heteroaryl; R.sup.1 is hydrogen, or substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl, substituted or unsubstituted C.sub.2-6 alkynyl, or substituted or unsubstituted C.sub.3-6 carbocyclyl; each of R.sup.2a and R.sup.2b is independently selected from hydrogen, halogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl, substituted or unsubstituted C.sub.2-6 alkynyl, substituted or unsubstituted C.sub.3-6 carbocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —N(R.sup.A)(R.sup.B), or —OR.sup.A2, wherein each of R.sup.A and R.sup.B is independently hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl, substituted or unsubstituted C.sub.2-6 alkynyl, substituted or unsubstituted C.sub.3-6 carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or R.sup.A and R.sup.B, together with the nitrogen atom to which they are attached form a ring, or R.sup.2a and R.sup.2b, together with the carbon atom to which they are attached form a ring; R.sup.A2 is hydrogen or substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl, substituted or unsubstituted C.sub.2-6 alkynyl, substituted or unsubstituted C.sub.3-6 carbocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R.sup.3a is hydrogen, —N(R.sup.A)(R.sup.B), or —OR.sup.A3, wherein R.sup.A3 is hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl, substituted or unsubstituted C.sub.2-6 alkynyl, or substituted or unsubstituted C.sub.3-6 carbocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and R.sup.3b is hydrogen or —N(R.sup.A)C(O)R.sup.A3; or R.sup.3a and R.sup.3b are joined to form an oxo (═O) group; each of R.sup.4a and R.sup.4b is independently selected from hydrogen or halogen; R.sup.5 is hydrogen, unsubstituted C.sub.1-6 alkyl, or —CH.sub.2OR.sup.A5, wherein R.sup.A5 is hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl, substituted or unsubstituted C.sub.2-6 alkynyl, or substituted or unsubstituted C.sub.3-6 carbocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl; R.sup.6 is absent or hydrogen; and represents a single or double bond, wherein when one of is a double bond, the other is a single bond; and when one of the is a double bond, R.sup.6 is absent.

54. A method for treating a CNS-related disorder in a subject in need thereof, comprising administering to the subject an effective amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof.

55. The method of claim 37, wherein the CNS-related disorder is a sleep disorder, a mood disorder, a schizophrenia spectrum disorder, a convulsive disorder, a disorder of memory and/or cognition, a movement disorder, a personality disorder, autism spectrum disorder, pain, traumatic brain injury, a vascular disease, a substance abuse disorder and/or withdrawal syndrome, or tinnitus.

56. The method of claim 37, wherein the CNS-related disorder is tremor.

57. The method of claim 37, wherein the CNS-related disorder is depression.

58. The method of claim 37, wherein the compound is administered orally.

59. The method of claim 37, wherein the compound is administered parenterally.

60. The method of claim 37, wherein the compound is administered intravaneously.

61. The method of claim 37, wherein the compound is administered intramuscularly.

62. The method of claim 37, wherein the subject is a subject with Rett syndrome, Fragile X syndrome, or Angelman syndrome.

63. A kit comprising a solid composition comprising a compound of Formula (II): ##STR00228## or a pharmaceutically acceptable salt thereof; wherein: Ring A is substituted or unsubstituted aryl or heteroaryl; R.sup.1 is hydrogen, or substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl, substituted or unsubstituted C.sub.2-6 alkynyl, or substituted or unsubstituted C.sub.3-6 carbocyclyl; each of R.sup.2a and R.sup.2b is independently selected from hydrogen, halogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl, substituted or unsubstituted C.sub.2-6 alkynyl, substituted or unsubstituted C.sub.3-6 carbocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —N(R.sup.A)(R.sup.B), or —OR.sup.A2, wherein each of R.sup.A and R.sup.B is independently hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl, substituted or unsubstituted C.sub.2-6 alkynyl, substituted or unsubstituted C.sub.3-6 carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or R.sup.A and R.sup.B, together with the nitrogen atom to which they are attached form a ring, or R.sup.2a and R.sup.2b, together with the carbon atom to which they are attached form a ring; R.sup.A2 is hydrogen or substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl, substituted or unsubstituted C.sub.2-6 alkynyl, substituted or unsubstituted C.sub.3-6 carbocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R.sup.3a is hydrogen, —N(R.sup.A)(R.sup.B), or —OR.sup.A3, wherein R.sup.A3 is hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl, substituted or unsubstituted C.sub.2-6 alkynyl, or substituted or unsubstituted C.sub.3-6 carbocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and R.sup.3b is hydrogen or N(R.sup.A)C(O)R.sup.A3; or R.sup.3a and R.sup.3b are joined to form an oxo (═O) group; each of R.sup.4a and R.sup.4b is independently selected from hydrogen or halogen; R.sup.5 is hydrogen, unsubstituted C.sub.1-6 alkyl, or —CH.sub.2OR.sup.A5, wherein R.sup.A5 is hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl, substituted or unsubstituted C.sub.2-6 alkynyl, or substituted or unsubstituted C.sub.3-6 carbocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl; R.sup.6 is absent or hydrogen; and represents a single or double bond, wherein when one of is a double bond, the other is a single bond; and when one of the is a double bond, R.sup.6 is absent.

Description

DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS OF THE INVENTION

[0093] As generally described herein, the present invention provides C21-substituted neuroactive steroids designed, for example, to act as GABA modulators. In certain embodiments, such compounds are envisioned to be useful as therapeutic agents for the inducement of anesthesia and/or sedation in a subject. In certain embodiments, such compounds are envisioned to be useful as therapeutic agents for treating a CNS-related disorder.

Compounds

[0094] In one aspect, provided is a compound of Formula (I):

##STR00007##

or a pharmaceutically acceptable salt thereof; wherein: Ring A is substituted or unsubstituted aryl or heteroaryl; R.sup.1 is hydrogen, or substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl, substituted or unsubstituted C.sub.2-6 alkynyl, or substituted or unsubstituted C.sub.3-6 carbocyclyl; each of R.sup.2a and R.sup.2b is independently selected from hydrogen, halogen, substituted or unsubstituted C.sub.1-6alkyl, substituted or unsubstituted C.sub.2-6 alkenyl, substituted or unsubstituted C.sub.1-6 alkynyl, substituted or unsubstituted C.sub.3-6 carbocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —N(R.sup.A)(R.sup.B), or —OR.sup.A2, wherein each of R.sup.A and R.sup.B is independently hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl, substituted or unsubstituted C.sub.2-6 alkynyl, substituted or unsubstituted C.sub.3-6 carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or R.sup.A and R.sup.B, together with the nitrogen atom to which they are attached form a ring (e.g., heteroaryl, heterocyclyl), or R.sup.2a and R.sup.2b, together with the carbon atom to which they are attached form a ring; R.sup.A2 is hydrogen or substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl, substituted or unsubstituted C.sub.2-6 alkynyl, substituted or unsubstituted C.sub.3-6 carbocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R.sup.3a is hydrogen, —N(R.sup.A)(R.sup.B), or —OR.sup.A3, wherein R.sup.A3 is hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl, substituted or unsubstituted C.sub.2-6 alkynyl, or substituted or unsubstituted C.sub.3-6 carbocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and R.sup.3b is hydrogen or —N(R.sup.A)C(O)R.sup.A3; or R.sup.3a and R.sup.3b are joined to form an oxo (═O) group; each of R.sup.4a and R.sup.4b is independently selected from hydrogen or halogen; R.sup.5 is hydrogen, unsubstituted C.sub.1-6 alkyl, or —CH.sub.2OR.sup.A5, wherein R.sup.A5 is hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl, substituted or unsubstituted C.sub.2-6 alkynyl, or substituted or unsubstituted C.sub.3-6 carbocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl; R.sup.6 is absent or hydrogen; and represents a single or double bond, wherein one of is a double bond, the other is a single bond; and when one of the is a double bond, R.sup.6 is absent.

[0095] In one aspect, provided is a compound of Formula (I):

##STR00008##

or a pharmaceutically acceptable salt thereof; wherein: Ring A is substituted or unsubstituted aryl or heteroaryl; R.sup.1 is hydrogen, or substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl, or substituted or unsubstituted C.sub.3-6 carbocyclyl. R.sup.2 is hydrogen, halogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl, substituted or unsubstituted C.sub.2-6 alkynyl, substituted or unsubstituted C.sub.3-6 carbocyclyl, —N(R.sup.A)(R.sup.B), or —OR.sup.A2, wherein each of R.sup.A and R.sup.B is independently hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl, substituted or unsubstituted C.sub.2-6 alkynyl, substituted or unsubstituted C.sub.3-6 carbocyclyl, or substituted or unsubstituted heterocyclyl, or R.sup.A and R.sup.B, together with the nitrogen atom to which they are attached form a ring (e.g., heteroaryl, heterocyclyl); R.sup.A2 is hydrogen or substituted or unsubstituted C.sub.1-6alkyl, substituted or unsubstituted C.sub.2-6 alkenyl, substituted or unsubstituted C.sub.2-6 alkynyl, or substituted or unsubstituted C.sub.3-6 carbocyclyl; R.sup.3a is hydrogen, —N(R.sup.A)(R.sup.B), or —OR.sup.A3, wherein R.sup.A3 is hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl, substituted or unsubstituted C.sub.2-6 alkynyl, or substituted or unsubstituted C.sub.3-6 carbocyclyl, and R.sup.3b is hydrogen or —N(R.sup.A)C(O)R.sup.A3; or R.sup.3a and R.sup.3b are joined to form an oxo (═O) group; R.sup.4 is hydrogen or halogen; R.sup.5 is hydrogen, unsubstituted C.sub.1-6alkyl, or —CH.sub.2OR.sup.A5, wherein R.sup.A5 is hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl, substituted or unsubstituted C.sub.2-6 alkynyl, or substituted or unsubstituted C.sub.3-6 carbocyclyl; R.sup.6 is absent or hydrogen; and represents a single or double bond, wherein when one of is a double bond, the other is a single bond; and when one of the is a double bond, R.sup.6 is absent.

[0096] In some embodiments, the compound of Formula (I) is a compound of Formula (I-a):

##STR00009##

wherein: n is 0, 1, 2, 3, 4, 5, or 6; and each R.sup.a is independently halogen, cyano, C.sub.1-6 alkyl, —N(R.sup.A)(R.sup.B), —N(R.sup.A)C(O)R.sup.AA, —N(R.sup.A)C(O)OR.sup.AA, —SR.sup.AA or —OR.sup.AA, wherein R.sup.AA is hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl, substituted or unsubstituted C.sub.2-6 alkynyl, substituted or unsubstituted C.sub.3-6 carbocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or two R.sup.a groups, together with the atoms with which they are attached form a ring.

[0097] In some embodiments, the compound of Formula (I) is a compound of Formula (I-b):

##STR00010##

[0098] In some embodiments, the compound of Formula (I) is a compound of Formula (I-b-i) or (I-b-ii):

##STR00011##

[0099] In some embodiments, the compound of Formula (I) is a compound of Formula (I-c):

##STR00012##

[0100] In some embodiments, the compound of Formula (I) is a compound of Formula (I-c-i) or (I-c-ii):

##STR00013##

[0101] In some embodiments, the compound of Formula (I) is a compound of Formula (I-f):

##STR00014##

[0102] In some embodiments, the compound of Formula (I) is a compound of Formula (I-d-i) or (I-d-ii):

##STR00015##

[0103] In some embodiments, A is a 5-10-membered ring. In some embodiments, A is phenyl, naphthyl, furan, thiophene, thiazole, pyrrole, imidazole, pyrazole, or triazole.

[0104] In some embodiments. A is a fused bicyclic ring. In some embodiments, A is benzofuran, benzoimidazole, indole, benzothiazole, or benzothiophene.

[0105] In some embodiments, A is linked through a carbon atom.

[0106] In some embodiments, R.sup.1 is hydrogen or substituted or unsubstituted C.sub.1-6 alkyl.

[0107] In some embodiments, R.sup.1 is unsubstituted C.sub.1-6 alkyl. In some embodiments, R.sup.1 is —CH.sub.3.

[0108] In some embodiments, R.sup.1 is hydrogen.

[0109] In some embodiments, R.sup.2 is hydrogen or halogen. In some embodiments, R.sup.2 is hydrogen.

[0110] In some embodiments, R.sup.3a is —N(R.sup.A)(R.sup.B). In some aspects of these embodiments, each of R.sup.A and R.sup.B is independently hydrogen or substituted or unsubstituted C.sub.1-6 alkyl. In some embodiments, R.sup.3a is —NH.sub.2. In some embodiments, R.sup.3a is —NHCH.sub.3 or —NHCH.sub.2CH.sub.3. In some embodiments, R.sup.3a is —N(CH.sub.3)(CH.sub.2CH.sub.3), —N(CH.sub.2CH.sub.3).sub.2 or —N(CH.sub.3).sub.2. In some aspects of these embodiments, R.sup.A and R.sup.B, together with the nitrogen atom to which they are attached form a ring (e.g., heteroaryl, heterocyclyl). In some embodiments, R.sup.A and R.sup.B, together with the nitrogen atom to which they are attached form a 3-7-membered ring (e.g., pyrrolidine, imidazolidine, piperidine, piperazine, morpholine, pyrrole, imidazole, triazole, tetrazole).

[0111] In some embodiments, R.sup.3b is hydrogen.

[0112] In some embodiments, R.sup.3b is —N(R.sup.A)C(O)R.sup.A3. In some aspects of these embodiments, R.sup.A is hydrogen or substituted or unsubstituted C.sub.1-6 alkyl. In some aspects of these embodiments, R.sup.A3 is hydrogen or substituted or unsubstituted C.sub.1-6 alkyl.

[0113] In some embodiments, R.sup.4 is hydrogen.

[0114] In some embodiments, R.sup.5 is hydrogen or unsubstituted C.sub.1-6 alkyl. In some embodiments, R.sup.5 is —CH.sub.2OR.sup.A5. In some aspects of these embodiments, R.sup.A5 is hydrogen or substituted or unsubstituted C.sub.1-6 alkyl.

[0115] In some embodiments, n is 0, 1, or 2. In some embodiments, n is 0 or 1.

[0116] In some embodiments, n is 0, 1, or 2, and each R.sup.a is independently halogen, C.sub.1-6 alkyl, or —OR.sup.AA. In some aspects of these embodiments, R.sup.AA is hydrogen, or substituted or unsubstituted C.sub.1-6 alkyl. In some embodiments, R.sup.a is —CH.sub.3.

[0117] In some embodiments, R.sup.a is C.sub.1-6 alkyl.

[0118] In some embodiments, R.sup.a is —N(R.sup.A)(R.sup.B). In some aspects of these embodiments, each of R.sup.A and R.sup.B is independently hydrogen or substituted or unsubstituted C.sub.1-6 alkyl. In some embodiments, R.sup.a is —NH.sub.2. In some embodiments, R.sup.a is —NHCH.sub.3 or —NHCH.sub.2CH.sub.3. In some embodiments, R.sup.a is —N(CH.sub.3)(CH.sub.2CH.sub.3), —N(CH.sub.2CH.sub.3).sub.2 or —N(CH.sub.3).sub.2. In some aspects of these embodiments, R.sup.A and R.sup.B, together with the nitrogen atom to which they are attached form a ring (e.g., heteroaryl, heterocyclyl). In some embodiments, R.sup.A and R.sup.B, together with the nitrogen atom to which they are attached form a 3-7-membered ring (e.g., pyrrolidine, imidazolidine, piperidine, piperazine, morpholine, pyrrole, imidazole, triazole, tetrazole).

[0119] In some embodiments, R is —N(R.sup.A)C(O)R.sup.AA. In some aspects of these embodiments, R.sup.A is hydrogen or substituted or unsubstituted C.sub.1-6 alkyl. In some aspects of these embodiments, R.sup.AA is hydrogen or substituted or unsubstituted C.sub.1-6 alkyl.

[0120] In some embodiments, R.sup.a is —N(R.sup.A)C(O)OR.sup.AA. In some aspects of these embodiments, R.sup.A is hydrogen or substituted or unsubstituted C.sub.1-6 alkyl. In some aspects of these embodiments, R.sup.AA is hydrogen or substituted or unsubstituted C.sub.1-6 alkyl.

[0121] In some embodiments, R.sup.a is —OR.sup.AA. In some embodiments, R.sup.a is —OCH.sub.3, —OCH.sub.2CH.sub.3.

[0122] In some embodiments, the compound is:

##STR00016## ##STR00017## ##STR00018## ##STR00019## ##STR00020## ##STR00021## ##STR00022## ##STR00023## ##STR00024## ##STR00025## ##STR00026## ##STR00027## ##STR00028## ##STR00029## ##STR00030## ##STR00031## ##STR00032## ##STR00033## ##STR00034## ##STR00035## ##STR00036## ##STR00037## ##STR00038## ##STR00039## ##STR00040## ##STR00041## ##STR00042##

[0123] In one aspect, provided is a pharmaceutical composition comprising a compound of Formula (I) and a pharmaceutically acceptable excipient.

[0124] In one aspect, provided is a method of inducing sedation and/or anesthesia in a subject, comprising administering to the subject an effective amount of a compound of the Formula (II):

##STR00043##

or a pharmaceutically acceptable salt thereof; wherein: Ring A is substituted or unsubstituted aryl or heteroaryl; R.sup.1 is hydrogen, or substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl, substituted or unsubstituted C.sub.2-6 alkynyl, or substituted or unsubstituted C.sub.3-6 carbocyclyl; each of R.sup.2a and R.sup.2b is independently selected from hydrogen, halogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl, substituted or unsubstituted C.sub.2-6 alkynyl, substituted or unsubstituted C.sub.3-6 carbocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —N(R.sup.A)(R.sup.B), or —OR.sup.A2, wherein each of R.sup.A and R.sup.B is independently hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl, substituted or unsubstituted C.sub.2-6 alkynyl, substituted or unsubstituted C.sub.3-6 carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or R.sup.A and R.sup.B, together with the nitrogen atom to which they are attached form a ring (e.g., heteroaryl, heterocyclyl), or R.sup.2a and R.sup.2b, together with the carbon atom to which they are attached form a ring; R.sup.A2 is hydrogen or substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl, substituted or unsubstituted C.sub.2-6 alkynyl, substituted or unsubstituted C.sub.3-6 carbocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R.sup.3a is hydrogen, —N(R.sup.A)R.sup.B), or —OR.sup.A3, wherein R.sup.A3 is hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl, substituted or unsubstituted C.sub.2-6 alkynyl, or substituted or unsubstituted C.sub.3-6 carbocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and R.sup.3b is hydrogen or —N(R.sup.A)C(O)R.sup.A; or R.sup.3a and R.sup.3b are joined to form an oxo (═O) group; each of R.sup.4a and R.sup.4b is independently selected from hydrogen or halogen; R.sup.5 is hydrogen, unsubstituted C.sub.1-6 alkyl, or —CH.sub.2OR.sup.A5, wherein R.sup.A5 is hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl, substituted or unsubstituted C.sub.2-6 alkynyl, or substituted or unsubstituted C.sub.3-6 carbocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl; R.sup.6 is absent or hydrogen; and represents a single or double bond, wherein when one of is a double bond, the other is a single bond; and when one of the is a double bond, R.sup.6 is absent.

[0125] In one aspect, provided is a method of administering an effective amount of a compound, a pharmaceutically acceptable salt thereof, or pharmaceutical composition of a compound of Formula (I), to a subject in need thereof, wherein the subject experiences sedation and/or anesthesia within two hours of administration.

[0126] In some embodiments, the subject experiences sedation and/or anesthesia within one hour of administration. In some embodiments, the subject experiences sedation and/or anesthesia instantaneously.

[0127] In some embodiments, compound is administered by intravenous administration.

[0128] In some embodiments, compound is administered chronically.

[0129] In some embodiments, the subject is a mammal. In some embodiments, the subject is a human.

[0130] In some embodiments, the compound is administered in combination with another therapeutic agent.

[0131] In one aspect, provided is a method for treating seizure in a subject, comprising administering to the subject an effective amount of a compound of the Formula (II):

##STR00044##

or a pharmaceutically acceptable salt thereof; wherein: Ring A is substituted or unsubstituted aryl or heteroaryl; R.sup.1 is hydrogen, or substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl, substituted or unsubstituted C.sub.2-6 alkynyl, or substituted or unsubstituted C.sub.3-6 carbocyclyl; each of R.sup.2a and R.sup.2b is independently selected from hydrogen, halogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl, substituted or unsubstituted C.sub.2-6 alkynyl, substituted or unsubstituted C.sub.3-6 carbocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —N(R.sup.A)(R.sup.B), or —OR.sup.A2, wherein each of R.sup.A and R.sup.B is independently hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl, substituted or unsubstituted C.sub.2-6 alkynyl, substituted or unsubstituted C.sub.3-6 carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or R.sup.A and R.sup.B, together with the nitrogen atom to which they are attached form a ring (e.g., heteroaryl, heterocyclyl), or R.sup.2a and R.sup.2b, together with the carbon atom to which they are attached form a ring; R.sup.A2 is hydrogen or substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl, substituted or unsubstituted C.sub.2-6 alkynyl, substituted or unsubstituted C.sub.3-6 carbocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R.sup.3a is hydrogen, —N(R.sup.A)(R.sup.B), or —OR.sup.A3, wherein R.sup.A3 is hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl, substituted or unsubstituted C.sub.2-6 alkynyl, or substituted or unsubstituted C.sub.3-6 carbocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and R.sup.3b is hydrogen or —N(R.sup.A)C(O)R.sup.A3; or R.sup.3a and R.sup.3b are joined to form an oxo (═O) group; each of R.sup.4a and R.sup.4b is independently selected from hydrogen or halogen; R.sup.5 is hydrogen, unsubstituted C.sub.1-6 alkyl, or —CH.sub.2OR.sup.A5, wherein R.sup.A5 is hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl, substituted or unsubstituted C.sub.2-6 alkynyl, or substituted or unsubstituted C.sub.3-6 carbocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl; R.sup.6 is absent or hydrogen; an represents a single or double bond, wherein when one of is a double bond, the other is a single bond; and when one of the is a double bond, R.sup.6 is absent.

[0132] In one aspect, provided is a method for treating epilepsy or status or status epilepticus in a subject, the method comprising administering to the subject an effective amount of a compound of the Formula (II):

##STR00045##

or a pharmaceutically acceptable salt thereof; wherein: Ring A is substituted or unsubstituted aryl or heteroaryl; R.sup.1 is hydrogen, or substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl, substituted or unsubstituted C.sub.2-6 alkynyl, or substituted or unsubstituted C.sub.3-6 carbocyclyl; each of R.sup.2a and R.sup.2b is independently selected from hydrogen, halogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl, substituted or unsubstituted C.sub.2-6 alkynyl, substituted or unsubstituted C.sub.3-6 carbocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —N(R.sup.A)(R.sup.B), or —OR.sup.A2, wherein each of R.sup.A and R.sup.B is independently hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl, substituted or unsubstituted C.sub.2-6 alkynyl, substituted or unsubstituted C.sub.3-6 carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or R.sup.A and R.sup.B, together with the nitrogen atom to which they are attached form a ring (e.g., heteroaryl, heterocyclyl), or R.sup.2a and R.sup.2b, together with the carbon atom to which they are attached form a ring; R.sup.A2 is hydrogen or substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl, substituted or unsubstituted C.sub.2-6 alkynyl, substituted or unsubstituted C.sub.3-6 carbocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R.sup.3a is hydrogen, —N(R.sup.A)(R.sup.B), or —OR.sup.A3, wherein R.sup.A3 is hydrogen, substituted or unsubstituted C.sub.1-6alkyl, substituted or unsubstituted C.sub.2-6 alkenyl, substituted or unsubstituted C.sub.2-6 alkynyl, or substituted or unsubstituted C.sub.3-6 carbocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and R.sup.3b is hydrogen or —N(R.sup.A)C(O)R.sup.A3; or R.sup.3a and R.sup.3b are joined to form an oxo (═O) group; each of R.sup.4a and R.sup.4b is independently selected from hydrogen or halogen; R.sup.5 is hydrogen, unsubstituted C.sub.1-6 alkyl, or —CH.sub.2OR.sup.A5, wherein R.sup.A5 is hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl, substituted or unsubstituted C.sub.2-6 alkynyl, or substituted or unsubstituted C.sub.3-6 carbocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl; R.sup.6 is absent or hydrogen; and represents a single or double bond, wherein when one of is a double bond, the other is a single bond; and when one of the is a double bond, R.sup.6 is absent.

[0133] In one aspect, provided is a method for treating disorders related to GABA function in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound, a pharmaceutically acceptable salt thereof, or pharmaceutical composition of one of a compound of Formula (II):

##STR00046##

or a pharmaceutically acceptable salt thereof; wherein: Ring A is substituted or unsubstituted aryl or heteroaryl; R.sup.1 is hydrogen, or substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl, substituted or unsubstituted C.sub.2-6 alkynyl, or substituted or unsubstituted C.sub.3-6 carbocyclyl; each of R.sup.2a and R.sup.2b is independently selected from hydrogen, halogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl, substituted or unsubstituted C.sub.2-6 alkynyl, substituted or unsubstituted C.sub.3-6 carbocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —N(R.sup.A)(R.sup.B), or —OR.sup.A2, wherein each of R.sup.A and R.sup.B is independently hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl, substituted or unsubstituted C.sub.2-6 alkynyl, substituted or unsubstituted C.sub.3-6 carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or R.sup.A and R.sup.B, together with the nitrogen atom to which they are attached form a ring (e.g., heteroaryl, heterocyclyl), or R.sup.2a and R.sup.2b, together with the carbon atom to which they are attached form a ring; R.sup.A2 is hydrogen or substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl, substituted or unsubstituted C.sub.2-6 alkynyl, substituted or unsubstituted C.sub.3-6 carbocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R.sup.3a is hydrogen, —N(R.sup.A)(R.sup.B), or —OR.sup.A3, wherein R.sup.A3 is hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl, substituted or unsubstituted C.sub.2-6 alkynyl, or substituted or unsubstituted C.sub.3-6 carbocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and R.sup.3b is hydrogen or —N(R.sup.A)C(O)R.sup.A3; or R.sup.3a and R.sup.3b are joined to form an oxo (═O) group; each of R.sup.4a and R.sup.4b is independently selected from hydrogen or halogen; R.sup.5 is hydrogen, unsubstituted C.sub.1-6 alkyl, or —CH.sub.2OR.sup.A5, wherein R.sup.A5 is hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl, substituted or unsubstituted C.sub.2-6 alkynyl, or substituted or unsubstituted C.sub.3-6 carbocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl; R.sup.6 is absent or hydrogen; and represents a single or double bond, wherein when one of is a double bond, the other is a single bond; and when one of the is a double bond, R.sup.6 is absent.

[0134] In one aspect, provided is a method for treating a CNS-related disorder in a subject in need thereof, comprising administering to the subject an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.

[0135] In some embodiments, the CNS-related disorder is a sleep disorder, a mood disorder, a schizophrenia spectrum disorder, a convulsive disorder, a disorder of memory and/or cognition, a movement disorder, a personality disorder, autism spectrum disorder, pain, traumatic brain injury, a vascular disease, a substance abuse disorder and/or withdrawal syndrome, or tinnitus.

[0136] In some embodiments, the disorder is tremor (e.g., essential tremor).

[0137] In some embodiments, the disorder is depression (e.g., postpartum depression).

[0138] In some embodiments, the compound is administered orally. In some embodiments, the compound is administered parenterally. In some embodiments, the compound is administered intravaneously. In some embodiments, the compound is administered intramuscularly.

[0139] In some embodiments, the subject is a subject with Rett syndrome, Fragile X syndrome, or Angelman syndrome.

[0140] In one aspect, provided is a method for treating a subject having an injury resulting from exposure to a warfare agent (e.g., a chemical warfare agent), the method comprising administering to the subject a compound described herein (e.g., a GABA modulator such as a compound (e.g., neuroactive steroid) described herein).

[0141] In one aspect, provided is a method of treating an injury in a subject who has been exposed to a chemical warfare agent, the method comprising administering to the subject a compound described herein (e.g., GABA modulator such as a compound (e.g., neuroactive steroid) described herein).

[0142] In one aspect, provided is a method of treating a subject, the method comprising: identifying a subject that has been exposed to a chemical warfare agent such as a nerve agent or toxin; and administering to the subject a compound described herein (e.g., GABA modulator such as a neuroactive steroid described herein).

[0143] In some embodiments, the injury is a seizure. In some embodiments, the injury is a myoclonic seizure (e.g., sporadic jerks).

[0144] In some embodiments, the injury is status epilepticus.

[0145] In some embodiments, the administration is within 1 week; 6, 5, 4, 3, 2, 1 day; 24, 22, 20, 18, 16, 14, 12, 10, 8, 7, 6, 5, 4, 3, 2, 1 hour, 45, 30, 20, 10, or 5 minutes of exposure to the chemical warfare agent.

[0146] In some embodiments, the compound is administered parenterally. In some embodiments, the compound is administered by intravenous administration.

[0147] In some embodiments, the subject is a human.

[0148] In some embodiments, the chemical warfare agent is a nerve agent or toxin. In some embodiments, the chemical warfare agent is a nerve agent. In some embodiments, the nerve agent is a phosphorus-containing organic chemical. In some embodiments, the nerve agent is a G agent (e.g., tabun (GA), sarin (GB), soman (GD), cyclosarin (GF), and GV). In some embodiments, the nerve agent is a V agent (e.g., VE, VG, VM, VX, and Novichok agents). In some embodiments, the toxin is abrin, ricin, or saxitoxin.

[0149] In one aspect, provided is a kit comprising a solid composition comprising a compound of Formula (II):

##STR00047##

or a pharmaceutically acceptable salt thereof; wherein: Ring A is substituted or unsubstituted aryl or heteroaryl; R.sup.1 is hydrogen, or substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl, substituted or unsubstituted C.sub.2-6 alkynyl, or substituted or unsubstituted C.sub.3-6 carbocyclyl; each of R.sup.2a and R.sup.2b is independently selected from hydrogen, halogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6alkenyl, substituted or unsubstituted C.sub.2-6 alkynyl, substituted or unsubstituted C.sub.3-6 carbocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —N(R.sup.A)(R.sup.B), or —OR.sup.A2, wherein each of R.sup.A and R.sup.B is independently hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl, substituted or unsubstituted C.sub.2-6 alkynyl, substituted or unsubstituted C.sub.3-6 carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or R.sup.A and R.sup.B, together with the nitrogen atom to which they are attached form a ring (e.g., heteroaryl, heterocyclyl), or R.sup.2a and R.sup.2b, together with the carbon atom to which they are attached form a ring; R.sup.A2 is hydrogen or substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl, substituted or unsubstituted C.sub.2-6 alkynyl, substituted or unsubstituted C.sub.3-6 carbocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R.sup.3a is hydrogen, —N(R.sup.A)(R.sup.B), or —OR.sup.A3, wherein R.sup.A3 is hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl, substituted or unsubstituted C.sub.2-6 alkynyl, or substituted or unsubstituted C.sub.3-6 carbocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and R.sup.3b is hydrogen or —N(R.sup.A)C(O)R.sup.A3; or R.sup.3a and R.sup.3b are joined to form an oxo (═O) group; each of R.sup.4a and R.sup.4b is independently selected from hydrogen or halogen; R.sup.5 is hydrogen, unsubstituted C.sub.1-6 alkyl, or —CH.sub.2OR.sup.A5, wherein R.sup.A5 is hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl, substituted or unsubstituted C.sub.2-6 alkynyl, or substituted or unsubstituted C.sub.3-6 carbocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl; R.sup.6 is absent or hydrogen; and represents a single or double bond, wherein when one of is a double bond, the other is a single bond; and when one of the is a double bond, R.sup.6 is absent.

Pharmaceutical Compositions

[0150] In one aspect, the invention provides a pharmaceutical composition comprising a compound of the present invention (also referred to as the “active ingredient”) and a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition comprises an effective amount of the active ingredient. In certain embodiments, the pharmaceutical composition comprises a therapeutically effective amount of the active ingredient. In certain embodiments, the pharmaceutical composition comprises a prophylactically effective amount of the active ingredient.

[0151] The pharmaceutical compositions provided herein can be administered by a variety of routes including, but not limited to, oral (enteral) administration, parenteral (by injection) administration, rectal administration, transdermal administration, intradermal administration, intrathecal administration, subcutaneous (SC) administration, intravenous (IV) administration, intramuscular (IM) administration, and intranasal administration.

[0152] Generally, the compounds provided herein are administered in an effective amount. The amount of the compound actually administered will typically 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 patient, the severity of the patient's symptoms, and the like.

[0153] When used to prevent the onset of a CNS-disorder, the compounds provided herein will be administered to a subject at risk for developing the condition, typically on the advice and under the supervision of a physician, at the dosage levels described above. Subjects at risk for developing a particular condition generally include those that have a family history of the condition, or those who have been identified by genetic testing or screening to be particularly susceptible to developing the condition.

[0154] The pharmaceutical compositions provided herein can also be administered chronically (“chronic administration”). Chronic administration refers to administration of a compound or pharmaceutical composition thereof over an extended period of time, e.g., for example, over 3 months, 6 months, 1 year, 2 years, 3 years, 5 years, etc, or may be continued indefinitely, for example, for the rest of the subject's life. In certain embodiments, the chronic administration is intended to provide a constant level of the compound in the blood, e.g., within the therapeutic window over the extended period of time.

[0155] The pharmaceutical compostions of the present invention may be further delivered using a variety of dosing methods. For example, in certain embodiments, the pharmaceutical composition may be given as a bolus, e.g., in order to raise the concentration of the compound in the blood to an effective level. The placement of the bolus dose depends on the systemic levels of the active ingredient desired throughout the body, e.g., an intramuscular or subcutaneous bolus dose allows a slow release of the active ingredient, while a bolus delivered directly to the veins (e.g., through an IV drip) allows a much faster delivery which quickly raises the concentration of the active ingredient in the blood to an effective level. In other embodiments, the pharmaceutical composition may be administered as a continuous infusion, e.g., by IV drip, to provide maintenance of a steady-state concentration of the active ingredient in the subject's body. Furthermore, in still yet other embodiments, the pharmaceutical composition may be administered as first as a bolus dose, followed by continuous infusion.

[0156] The compositions for oral administration can take the form of bulk liquid solutions or suspensions, or bulk powders. More commonly, however, the compositions are presented in unit dosage forms to facilitate accurate dosing. The term “unit dosage forms” refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient. Typical unit dosage forms include prefilled, premeasured ampules or syringes of the liquid compositions or pills, tablets, capsules or the like in the case of solid compositions. In such compositions, the compound is usually a minor component (from about 0.1 to about 50% by weight or preferably from about 1 to about 40% by weight) with the remainder being various vehicles or excipients and processing aids helpful for forming the desired dosing form.

[0157] With oral dosing, one to five and especially two to four and typically three oral doses per day are representative regimens. Using these dosing patterns, each dose provides from about 0.01 to about 20 mg/kg of the compound provided herein, with preferred doses each providing from about 0.1 to about 10 mg/kg, and especially about 1 to about 5 mg/kg.

[0158] Transdermal doses are generally selected to provide similar or lower blood levels than are achieved using injection doses, generally in an amount ranging from about 0.01 to about 20% by weight, preferably from about 0.1 to about 20% by weight, preferably from about 0.1 to about 10% by weight, and more preferably from about 0.5 to about 15% by weight.

[0159] Injection dose levels range from about 0.1 mg/kg/hour to at least 20 mg/kg/hour, all for from about 1 to about 120 hours and especially 24 to 96 hours. A preloading bolus of from about 0.1 mg/kg to about 10 mg/kg or more may also be administered to achieve adequate steady state levels. The maximum total dose is not expected to exceed about 5 g/day for a 40 to 80 kg human patient.

[0160] Liquid forms suitable for oral administration may include a suitable aqueous or nonaqueous vehicle with buffers, suspending and dispensing agents, colorants, flavors and the like. Solid forms may include, for example, any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.

[0161] Injectable compositions are typically based upon injectable sterile saline or phosphate-buffered saline or other injectable excipients known in the art. As before, the active compound in such compositions is typically a minor component, often being from about 0.05 to 10% by weight with the remainder being the injectable excipient and the like.

[0162] Transdermal compositions are typically formulated as a topical ointment or cream containing the active ingredient(s). When formulated as a ointment, the active ingredients will typically be combined with either a paraffinic or a water-miscible ointment base. Alternatively, the active ingredients may be formulated in a cream with, for example an oil-in-water cream base. Such transdermal formulations are well-known in the art and generally include additional ingredients to enhance the dermal penetration of stability of the active ingredients or Formulation. All such known transdermal formulations and ingredients are included within the scope provided herein.

[0163] The compounds provided herein can also be administered by a transdermal device. Accordingly, transdermal administration can be accomplished using a patch either of the reservoir or porous membrane type, or of a solid matrix variety.

[0164] The above-described components for orally administrable, injectable or topically administrable compositions are merely representative. Other materials as well as processing techniques and the like are set forth in Part 8 of Remington's Pharmaceutical Sciences, 17th edition, 1985, Mack Publishing Company, Easton, Pa., which is incorporated herein by reference.

[0165] The compounds of the present invention can also be administered in sustained release forms or from sustained release drug delivery systems. A description of representative sustained release materials can be found in Remington's Pharmaceutical Sciences.

[0166] The present invention also relates to the pharmaceutically acceptable acid addition salt of a compound of the present invention. The acid which may be used to prepare the pharmaceutically acceptable salt is that which forms a non-toxic acid addition salt, i.e., a salt containing pharmacologically acceptable anions such as the hydrochloride, hydroiodide, hydrobromide, nitrate, sulfate, bisulfate, phosphate, acetate, lactate, citrate, tartrate, succinate, maleate, fumarate, benzoate, para-toluenesulfonate, and the like.

[0167] In another aspect, the invention provides a pharmaceutical composition comprising a compound of the present invention and a pharmaceutically acceptable excipient, e.g., a composition suitable for injection, such as for intravenous (IV) administration.

[0168] Pharmaceutically acceptable excipients include any and all diluents or other liquid vehicles, dispersion or suspension aids, surface active agents, isotonic agents, preservatives, lubricants and the like, as suited to the particular dosage form desired, e.g., injection. General considerations in the formulation and/or manufacture of pharmaceutical compositions agents can be found, for example, in Remington's Pharmaceutical Sciences, Sixteenth Edition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1980), and Remington: The Science and Practice of Pharmacy, 21.sup.st Edition (Lippincott Williams & Wilkins, 2005).

[0169] For example, injectable preparations, such as sterile injectable aqueous suspensions, can be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. Exemplary excipients that can be employed include, but are not limited to, water, sterile saline or phosphate-buffered saline, or Ringer's solution.

[0170] In certain embodiments, the pharmaceutical composition further comprises a cyclodextrin derivative. The most common cyclodextrins are α-, β- and γ-cyclodextrins consisting of 6, 7 and 8 α-1,4-linked glucose units, respectively, optionally comprising one or more substituents on the linked sugar moieties, which include, but are not limited to, substituted or unsubstituted methylated, hydroxyalkylated, acylated, and sulfoalkylether substitution. In certain embodiments, the cyclodextrin is a sulfoalkyl ether β-cyclodextrin, e.g., for example, sulfobutyl ether β-cyclodextrin, also known as Captisol®. See, e.g., U.S. Pat. No. 5,376,645. In certain embodiments, the composition comprises hexapropyl-β-cyclodextrin. In a more particular embodiment, the composition comprises hexapropyl-β-cyclodextrin (10-50% in water).

[0171] The injectable composition can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

[0172] Generally, the compounds provided herein are administered in an effective amount. The amount of the compound actually administered will typically 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, response of the individual patient, the severity of the patient's symptoms, and the like.

[0173] The compositions are presented in unit dosage forms to facilitate accurate dosing. The term “unit dosage forms” refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient. Typical unit dosage forms include pre-filled, pre-measured ampules or syringes of the liquid compositions. In such compositions, the compound is usually a minor component (from about 0.1% to about 50% by weight or preferably from about 1% to about 40% by weight) with the remainder being various vehicles or carriers and processing aids helpful for forming the desired dosing form.

[0174] The compounds provided herein can be administered as the sole active agent, or they can be administered in combination with other active agents. In one aspect, the present invention provides a combination of a compound of the present invention and another pharmacologically active agent. Administration in combination can proceed by any technique apparent to those of skill in the art including, for example, separate, sequential, concurrent, and alternating administration.

[0175] Although the descriptions of pharmaceutical compositions provided herein are principally directed to pharmaceutical compositions which are suitable for administration to humans, it will be understood by the skilled artisan that such compositions are generally suitable for administration to animals of all sorts. Modification of pharmaceutical compositions suitable for administration to humans in order to render the compositions suitable for administration to various animals is well understood, and the ordinarily skilled veterinary pharmacologist can design and/or perform such modification with ordinary experimentation. General considerations in the formulation and/or manufacture of pharmaceutical compositions can be found, for example, in Remington: The Science and Practice of Pharmacy 21.sup.st ed., Lippincott Williams & Wilkins, 2005.

Methods of Use and Treatment

[0176] As generally described herein, the present invention is directed to C21-substituted neuroactive steroids designed, for example, to act as GABA modulators. In certain embodiments, such compounds are envisioned to be useful as therapeutic agents for the inducement of anesthesia and/or sedation in a subject. In some embodiments, such compounds are envisioned to be useful as therapeutic agents for treating a CNS-related disorder (e.g., sleep disorder, a mood disorder, a schizophrenia spectrum disorder, a convulsive disorder, a disorder of memory and/or cognition, a movement disorder, a personality disorder, autism spectrum disorder, pain, traumatic brain injury, a vascular disease, a substance abuse disorder and/or withdrawal syndrome, or tinnitus) in a subject in need (e.g., a subject with Rett syndrome, Fragile X syndrome, or Angelman syndrome).

[0177] Thus, in one aspect, the present invention provides a method of inducing sedation and/or anesthesia in a subject, comprising administering to the subject an effective amount of a compound of the present invention or a composition thereof. In certain embodiments, the compound is administered by intravenous administration.

[0178] Earlier studies (see, e.g., Gee er al., European Journal of Pharmacology, 136:419-423 (1987)) demonstrated that certain 3α-hydroxylated steroids are orders of magnitude more potent as modulators of the GABA receptor complex (GRC) than others had reported (see, e.g., Majewska et al., Science 232:1004-1007 (1986); Harrison et al., J Pharmacol. Exp. Ther. 241:346-353 (1987)). Majewska et al. and Harrison et al. taught that 3α-hydroxylated-5-reduced steroids are only capable of much lower levels of effectiveness. In vitro and in vivo experimental data have now demonstrated that the high potency of these steroids allows them to be therapeutically useful in the modulation of brain excitability via the GRC (see, e.g., Gee et al., European Journal of Pharmacology, 136:419-423 (1987); Wieland et al., Psychopharmacology 118(1):65-71 (1995)).

[0179] Various synthetic steroids have also been prepared as neuroactive steroids. See, for example, U.S. Pat. No. 5,232,917, which discloses neuroactive steroid compounds useful in treating stress, anxiety, insomnia, seizure disorders, and mood disorders, that are amenable to GRC-active agents, such as depression, in a therapeutically beneficial manner. Furthermore, it has been previously demonstrated that these steroids interact at a unique site on the GRC which is distinct from other known sites of interaction (e.g., barbiturates, benzodiazepines, and GABA) where therapeutically beneficial effects on stress, anxiety, sleep, mood disorders and seizure disorders have been previously elicited (see, e.g., Gee, K. W. and Yamamura, H. I., “Benzodiazepines and Barbiturates: Drugs for the Treatment of Anxiety, Insomnia and Seizure Disorders,” in Central Nervous System Disorders, Horvell, ed., Marcel-Dekker, New York (1985), pp. 123-147; Lloyd, K. G. and Morselli, P. L., “Psychopharmacology of GABAergic Drugs,” in Psychopharmacology: The Third Generation of Progress, H. Y. Meltzer, ed., Raven Press, N.Y. (1987), pp. 183-195; and Gee et al., European Journal of Pharmacology, 136:419-423 (1987). These compounds are desirable for their duration, potency, and oral activity (along with other forms of administration).

[0180] Compounds of the present invention, as described herein, are generally designed to modulate GABA function, and therefore to act as neuroactive steroids for the treatment and prevention of CNS-related conditions in a subject. Modulation, as used herein, refers to the inhibition or potentiation of GABA receptor function. Accordingly, the compounds and pharmaceutical compositions provided herein find use as therapeutics for preventing and/or treating CNS conditions in mammals including humans and non-human mammals. Thus, and as stated earlier, the present invention includes within its scope, and extends to, the recited methods of treatment, as well as to the compounds for such methods, and to the use of such compounds for the preparation of medicaments useful for such methods.

[0181] Exemplary CNS conditions related to GABA-modulation include, but are not limited to, sleep disorders [e.g., insomnia], mood disorders [e.g., depression, dysthymic disorder (e.g., mild depression), bipolar disorder (e.g., I and/or II), anxiety disorders (e.g., generalized anxiety disorder (GAD), social anxiety disorder), stress, post-traumatic stress disorder (PTSD), compulsive disorders (e.g., obsessive compulsive disorder (OCD))], schizophrenia spectrum disorders [e.g., schizophrenia, schizoaffective disorder], convulsive disorders [e.g., epilepsy (e.g., status epilepticus (SE)), seizures], disorders of memory and/or cognition [e.g., attention disorders (e.g., attention deficit hyperactivity disorder (ADHD)), dementia (e.g., Alzheimer's type dementia, Lewis body type dementia, vascular type dementia], movement disorders [e.g., Huntington's disease, Parkinson's disease], personality disorders [e.g., anti-social personality disorder, obsessive compulsive personality disorder], autism spectrum disorders (ASD) [e.g., autism, monogenetic causes of autism such as synaptophathy's, e.g., Rett syndrome, Fragile X syndrome, Angelman syndrome], pain [e.g., neuropathic pain, injury related pain syndromes, acute pain, chronic pain], traumatic brain injury (TBI), vascular diseases [e.g., stroke, ischemia, vascular malformations], substance abuse disorders and/or withdrawal syndromes [e.g., addition to opiates, cocaine, and/or alcohol], and tinnitus.

[0182] In yet another aspect, provided is a combination of a compound of the present invention and another pharmacologically active agent. The compounds provided herein can be administered as the sole active agent or they can be administered in combination with other agents. Administration in combination can proceed by any technique apparent to those of skill in the art including, for example, separate, sequential, concurrent and alternating administration.

[0183] In another aspect, provided is a method of treating or preventing brain excitability in a subject susceptible to or afflicted with a condition associated with brain excitability, comprising administering to the subject an effective amount of a compound of the present invention to the subject.

[0184] In yet another aspect, provided is a method of treating or preventing stress or anxiety in a subject, comprising administering to the subject in need of such treatment an effective amount of a compound of the present invention, or a composition thereof.

[0185] In yet another aspect, provided is a method of alleviating or preventing seizure activity in a subject, comprising administering to the subject in need of such treatment an effective amount of a compound of the present invention.

[0186] In yet another aspect, provided is a method of alleviating or preventing insomnia in a subject, comprising administering to the subject in need of such treatment an effective amount of a compound of the present invention, or a composition thereof.

[0187] In yet another aspect, provided is a method of inducing sleep and maintaining substantially the level of REM sleep that is found in normal sleep, wherein substantial rebound insomnia is not induced, comprising administering an effective amount of a compound of the present invention.

[0188] In yet another aspect, provided is a method of alleviating or preventing PMS or PND in a subject, comprising administering to the subject in need of such treatment an effective amount of a compound of the present invention.

[0189] In yet another aspect, provided is a method of treating or preventing mood disorders in a subject, comprising administering to the subject in need of such treatment an effective amount of a compound of the present invention. In certain embodiments the mood disorder is depression.

[0190] In yet another aspect, provided is a method of inducing anesthesia in a subject, comprising administering to the subject an effective amount of a compound of the present invention.

[0191] In yet another aspect, provided is a method of cognition enhancement or treating memory disorder by administering to the subject a therapeutically effective amount of a compound of the present invention. In certain embodiments, the disorder is Alzheimer's disease. In certain embodiments, the disorder is Rett syndrome.

[0192] In yet another aspect, provided is a method of treating attention disorders by administering to the subject a therapeutically effective amount of a compound of the present invention. In certain embodiments, the attention disorder is ADHD.

[0193] In certain embodiments, the compound is administered to the subject chronically. In certain embodiments, the compound is administered to the subject orally, subcutaneously, intramuscularly, or intravenously.

Anesthesia/Sedation

[0194] Anesthesia is a pharmacologically induced and reversible state of amnesia, analgesia, loss of responsiveness, loss of skeletal muscle reflexes, decreased stress response, or all of these simultaneously. These effects can be obtained from a single drug which alone provides the correct combination of effects, or occasionally with a combination of drugs (e.g., hypnotics, sedatives, paralytics, analgesics) to achieve very specific combinations of results. Anesthesia allows patients to undergo surgery and other procedures without the distress and pain they would otherwise experience.

[0195] Sedation is the reduction of irritability or agitation by administration of a pharmacological agent, generally to facilitate a medical procedure or diagnostic procedure.

[0196] Sedation and analgesia include a continuum of states of consciousness ranging from minimal sedation (anxiolysis) to general anesthesia.

[0197] Minimal sedation is also known as anxiolysis. Minimal sedation is a drug-induced state during which the patient responds normally to verbal commands. Cognitive function and coordination may be impaired Ventilatory and cardiovascular functions are typically unaffected.

[0198] Moderate sedation/analgesia (conscious sedation) is a drug-induced depression of consciousness during which the patient responds purposefully to verbal command, either alone or accompanied by light tactile stimulation. No interventions are usually necessary to maintain a patent airway. Spontaneous ventilation is typically adequate. Cardiovascular function is usually maintained.

[0199] Deep sedation/analgesia is a drug-induced depression of consciousness during which the patient cannot be easily aroused, but responds purposefully (not a reflex withdrawal from a painful stimulus) following repeated or painful stimulation. Independent ventilatory function may be impaired and the patient may require assistance to maintain a patent airway. Spontaneous ventilation may be inadequate. Cardiovascular function is usually maintained.

[0200] General anesthesia is a drug-induced loss of consciousness during which the patient is not arousable, even to painful stimuli. The ability to maintain independent ventilatory function is often impaired and assistance is often required to maintain a patent airway. Positive pressure ventilation may be required due to depressed spontaneous ventilation or drug-induced depression of neuromuscular function. Cardiovascular function may be impaired.

[0201] Sedation in the intensive care unit (ICU) allows the depression of patients' awareness of the environment and reduction of their response to external stimulation. It can play a role in the care of the critically ill patient, and encompasses a wide spectrum of symptom control that will vary between patients, and among individuals throughout the course of their illnesses. Heavy sedation in critical care has been used to facilitate endotracheal tube tolerance and ventilator synchronization, often with neuromuscular blocking agents.

[0202] In some embodiments, sedation (e.g., long-term sedation, continuous sedation) is induced and maintained in the ICU for a prolonged period of time (e.g., 1 day, 2 days, 3 days, 5 days, 1 week, 2 week, 3 weeks, 1 month, 2 months). Long-term sedation agents may have long duration of action. Sedation agents in the ICU may have short elimination half-life.

[0203] Procedural sedation and analgesia, also referred to as conscious sedation, is a technique of administering sedatives or dissociative agents with or without analgesics to induce a state that allows a subject to tolerate unpleasant procedures while maintaining cardiorespiratory function.

Anxiety Disorders

[0204] Anxiety disorder is a blanket term covering several different forms of abnormal and pathological fear and anxiety. Current psychiatric diagnostic criteria recognize a wide variety of anxiety disorders.

[0205] Generalized anxiety disorder is a common chronic disorder characterized by long-lasting anxiety that is not focused on any one object or situation. Those suffering from generalized anxiety experience non-specific persistent fear and worry and become overly concerned with everyday matters. Generalized anxiety disorder is the most common anxiety disorder to affect older adults.

[0206] In panic disorder, a person suffers from brief attacks of intense terror and apprehension, often marked by trembling, shaking, confusion, dizziness, nausea, difficulty breathing. These panic attacks, defined by the APA as fear or discomfort that abruptly arises and peaks in less than ten minutes, can last for several hours and can be triggered by stress, fear, or even exercise; although the specific cause is not always apparent. In addition to recurrent unexpected panic attacks, a diagnosis of panic disorder also requires that said attacks have chronic consequences: either worry over the attacks' potential implications, persistent fear of future attacks, or significant changes in behavior related to the attacks. Accordingly, those suffering from panic disorder experience symptoms even outside of specific panic episodes. Often, normal changes in heartbeat are noticed by a panic sufferer, leading them to think something is wrong with their heart or they are about to have another panic attack. In some cases, a heightened awareness (hypervigilance) of body functioning occurs during panic attacks, wherein any perceived physiological change is interpreted as a possible life threatening illness (i.e. extreme hypochondriasis).

[0207] Obsessive compulsive disorder is a type of anxiety disorder primarily characterized by repetitive obsessions (distressing, persistent, and intrusive thoughts or images) and compulsions (urges to perform specific acts or rituals). The OCD thought pattern may be likened to superstitions insofar as it involves a belief in a causative relationship where, in reality, one does not exist. Often the process is entirely illogical; for example, the compulsion of walking in a certain pattern may be employed to alleviate the obsession of impending harm. And in many cases, the compulsion is entirely inexplicable, simply an urge to complete a ritual triggered by nervousness. In a minority of cases, sufferers of OCD may only experience obsessions, with no overt compulsions, a much smaller number of sufferers experience only compulsions.

[0208] The single largest category of anxiety disorders is that of Phobia, which includes all cases in which fear and anxiety is triggered by a specific stimulus or situation. Sufferers typically anticipate terrifying consequences from encountering the object of their fear, which can be anything from an animal to a location to a bodily fluid.

[0209] Post-traumatic stress disorder or PTSD is an anxiety disorder which results from a traumatic experience. Post-traumatic stress can result from an extreme situation, such as combat, rape, hostage situations, or even serious accident. It can also result from long term (chronic) exposure to a severe stressor, for example soldiers who endure individual battles but cannot cope with continuous combat. Common symptoms include flashbacks, avoidant behaviors, and depression.

Neurodegenerative Diseases and Disorders

[0210] The term “neurodegenerative disease” includes diseases and disorders that are associated with the progressive loss of structure or function of neurons, or death of neurons. Neurodegenerative diseases and disorders include, but are not limited to, Alzheimer's disease (including the associated symptoms of mild, moderate, or severe cognitive impairment); amyotrophic lateral sclerosis (ALS); anoxic and ischemic injuries; ataxia and convulsion (including for the treatment and prevention and prevention of seizures that are caused by schizoaffective disorder or by drugs used to treat schizophrenia); benign forgetfulness; brain edema; cerebellar ataxia including McLeod neuroacanthocytosis syndrome (MLS); closed head injury; coma; contusive injuries (e.g., spinal cord injury and head injury); dementias including multi-infarct dementia and senile dementia; disturbances of consciousness; Down syndrome; drug-induced or medication-induced Parkinsonism (such as neuroleptic-induced acute akathisia, acute dystonia, Parkinsonism, or tardive dyskinesia, neuroleptic malignant syndrome, or medication-induced postural tremor): epilepsy; fragile X syndrome; Gilles de la Tourette's syndrome; head trauma; hearing impairment and loss; Huntington's disease: Lennox syndrome; levodopa-induced dyskinesia; mental retardation; movement disorders including akinesias and akinetic (rigid) syndromes (including basal ganglia calcification, corticobasal degeneration, multiple system atrophy, Parkinsonism-ALS dementia complex, Parkinson's disease, postencephalitic parkinsonism, and progressively supranuclear palsy); muscular spasms and disorders associated with muscular spasticity or weakness including chorea (such as benign hereditary chorea, drug-induced chorea, hemiballism, Huntington's disease, neuroacanthocytosis, Sydenham's chorea, and symptomatic chorea), dyskinesia (including tics such as complex tics, simple tics, and symptomatic tics), myoclonus (including generalized myoclonus and focal cyloclonus), tremor (such as rest tremor, postural tremor, and intention tremor) and dystonia (including axial dystonia, dystonic writer's cramp, hemiplegic dystonia, paroxysmal dystonia, and focal dystonia such as blepharospasm, oromandibular dystonia, and spasmodic dysphonia and torticollis); neuronal damage including ocular damage, retinopathy or macular degeneration of the eye; neurotoxic injury which follows cerebral stroke, thromboembolic stroke, hemorrhagic stroke, cerebral ischemia, cerebral vasospasm, hypoglycemia, amnesia, hypoxia, anoxia, perinatal asphyxia and cardiac arrest; Parkinson's disease; seizure; status epilecticus; stroke; tinnitus; tubular sclerosis, and viral infection induced neurodegeneration (e.g., caused by acquired immunodeficiency syndrome (AIDS) and encephalopathies). Neurodegenerative diseases also include, but are not limited to, neurotoxic injury which follows cerebral stroke, thromboembolic stroke, hemorrhagic stroke, cerebral ischemia, cerebral vasospasm, hypoglycemia, amnesia, hypoxia, anoxia, perinatal asphyxia and cardiac arrest. Methods of treating or preventing a neurodegenerative disease also include treating or preventing loss of neuronal function characteristic of neurodegenerative disorder.

Epilepsy

[0211] Epilepsy is a brain disorder characterized by repeated seizures over time. Types of epilepsy can include, but are not limited to generalized epilepsy, e.g., childhood absence epilepsy, juvenile nyoclonic epilepsy, epilepsy with grand-mal seizures on awakening, West syndrome, Lennox-Gastaut syndrome, partial epilepsy, e.g., temporal lobe epilepsy, frontal lobe epilepsy, benign focal epilepsy of childhood.

Status Epilepticus (SE)

[0212] Status epilepticus (SE) can include, e.g., convulsive status epilepticus, e.g., early status epilepticus, established status epilepticus, refractory status epilepticus, super-refractory status epilepticus; non-convulsive status epilepticus, e.g., generalized status epilepticus, complex partial status epilepticus; generalized periodic epileptiform discharges; and periodic lateralized epileptiform discharges. Convulsive status epilepticus is characterized by the presence of convulsive status epileptic seizures, and can include early status epilepticus, established status epilepticus, refractory status epilepticus, super-refractory status epilepticus. Early status epilepticus is treated with a first line therapy Established status epilepticus is characterized by status epileptic seizures which persist despite treatment with a first line therapy, and a second line therapy is administered. Refractory status epilepticus is characterized by status epileptic seizures which persist despite treatment with a first line and a second line therapy, and a general anesthetic is generally administered. Super refractory status epilepticus is characterized by status epileptic seizures which persist despite treatment with a first line therapy, a second line therapy, and a general anesthetic for 24 hours or more.

[0213] Non-convulsive status epilepticus can include, e.g., focal non-convulsive status epilepticus, e.g., complex partial non-convulsive status epilepticus, simple partial non-convulsive status epilepticus, subtle non-convulsive status epilepticus; generalized non-convulsive status epilepticus, e.g., late onset absence non-convulsive status epilepticus, atypical absence non-convulsive status epilepticus, or typical absence non-convulsive status epilepticus.

[0214] Compositions described herein can also be administered as a prophylactic to a subject having a CNS disorder e.g., a traumatic brain injury, status epilepticus, e.g., convulsive status epilepticus, e.g., early status epilepticus, established status epilepticus, refractory status epilepticus, super-refractory status epilepticus; non-convulsive status epilepticus, e.g., generalized status epilepticus, complex partial status epilepticus; generalized periodic epileptiform discharges; and periodic lateralized epileptiform discharges; prior to the onset of a seizure.

Epileptogenesis

[0215] The compounds and methods described herein can be used to treat or prevent epileptogenesis. Epileptogenesis is a gradual process by which a normal brain develops epilepsy (a chronic condition in which seizures occur). Epileptogenesis results from neuronal damage precipitated by the initial insult (e.g., status epilepticus).

Seizure

[0216] A seizure is the physical findings or changes in behavior that occur after an episode of abnormal electrical activity in the brain. The term “seizure” is often used interchangeably with “convulsion.” Convulsions are when a person's body shakes rapidly and uncontrollably. During convulsions, the person's muscles contract and relax repeatedly.

[0217] Based on the type of behavior and brain activity, seizures are divided into two broad categories: generalized and partial (also called local or focal). Classifying the type of seizure helps doctors diagnose whether or not a patient has epilepsy.

[0218] Generalized seizures are produced by electrical impulses from throughout the entire brain, whereas partial seizures are produced (at least initially) by electrical impulses in a relatively small part of the brain. The part of the brain generating the seizures is sometimes called the focus.

[0219] There are six types of generalized seizures. The most common and dramatic, and therefore the most well known, is the generalized convulsion, also called the grand-mal seizure. In this type of seizure, the patient loses consciousness and usually collapses. The loss of consciousness is followed by generalized body stiffening (called the “tonic” phase of the seizure) for 30 to 60 seconds, then by violent jerking (the “clonic” phase) for 30 to 60 seconds, after which the patient goes into a deep sleep (the “postictal” or after-seizure phase). During grand-mal seizures, injuries and accidents may occur, such as tongue biting and urinary incontinence.

[0220] Absence seizures cause a short loss of consciousness (just a few seconds) with few or no symptoms. The patient, most often a child, typically interrupts an activity and stares blankly. These seizures begin and end abruptly and may occur several times a day. Patients are usually not aware that they are having a seizure, except that they may be aware of “losing time.”

[0221] Myoclonic seizures consist of sporadic jerks, usually on both sides of the body. Patients sometimes describe the jerks as brief electrical shocks. When violent, these seizures may result in dropping or involuntarily throwing objects.

[0222] Clonic seizures are repetitive, rhythmic jerks that involve both sides of the body at the same time.

[0223] Tonic seizures are characterized by stiffening of the muscles.

[0224] Atonic seizures consist of a sudden and general loss of muscle tone, particularly in the arms and legs, which often results in a fall.

[0225] Seizures described herein can include epileptic seizures; acute repetitive seizures; cluster seizures; continuous seizures; unremitting seizures; prolonged seizures; recurrent seizures; status epilepticus seizures, e.g., refractory convulsive status epilepticus, non-convulsive status epilepticus seizures; refractory seizures; myoclonic seizures; tonic seizures; tonic-clonic seizures; simple partial seizures; complex partial seizures; secondarily generalized seizures; atypical absence seizures; absence seizures; atonic seizures; benign Rolandic seizures; febrile seizures; emotional seizures, focal seizures; gelastic seizures; generalized onset seizures; infantile spasms; Jacksonian seizures; massive bilateral myoclonus seizures; multifocal seizures, neonatal onset seizures; nocturnal seizures; occipital lobe seizures; post traumatic seizures; subtle seizures; Sylvan seizures; visual reflex seizures; or withdrawal seizures.

Chemical Warfare Agents

[0226] A subject may be exposed to a chemical warfare agent. If a compound described herein is administered, the symptoms or injuries resulting from the exposure to the chemical warfare agents can be reduced, prevented, or both. The compounds described herein can be administered to a subject before, during, or following such exposure and is therefore administered within 1 week; 6, 5, 4, 3, 2, 1 day; 24, 22, 20, 18, 16, 14, 12, 10, 8, 7, 6, 5, 4, 3, 2, 1 hour, 45, 30, 20, 10, or 5 minutes before or after such exposure. The compounds described herein can be administered prophylactically, when exposure to an agent is anticipated. It can also be administered after exposure to the chemical warfare agent (e.g., before or after symptoms of injury present in a subject).

[0227] Injuries resulting from the exposure to chemical warfare agents are known in the art and include any physical injuries, such as injuries to the central nervous system and peripheral nervous system. Exemplary symptoms or injuries resulting from the exposure to chemical warfare agents include inflammation, burn, itch, pain, rash, blisters, sweating, muscle twitching, nausea, vomiting, diarrhea, weakness, loss of consciousness, convulsions, muscular twitching, paralysis, secretions (from the mouth, nose, or lung for example), difficulty breathing, blurred vision, eye pain, lacrimation, red eyes, shortness of breath, coughing, phlegm production and narrowing of the airways, headaches, tremors, dizziness, numbness or tingling, anxiety, insomnia, depression, emotional instability, and even death. The term “chemical warfare agent” includes all of those agents classified as schedule 1, 2, and 3 agents under the Chemical Weapons Convention of 1993 and may be in liquid form, gas form, solid form, or combinations thereof. Exemplary agents are described in further detail below and include, for example, nerve agents and toxins.

[0228] Nerve Agents.

[0229] Nerve agent poisoning typically leads to contraction of pupils, profuse salivation, convulsions, involuntary urination and defecation, and eventual death by asphyxiation as control is lost over respiratory muscles. For example, nerve agents can be phosphorus-containing organic chemicals (organophosphates) that disrupt the mechanism by which nerves transfer messages to organs. Exemplary agents include G agents such as tabun (GA), sarin (GB), soman (GD), cyclosarin (GF), and GV; V agents such as VE, VG, VM, VX, and Novichok agents.

[0230] Toxins.

[0231] Exemplary toxins are abrin, ricin, and saxitoxin.

EQUIVALENTS AND SCOPE

[0232] In the claims articles such as “a.” “an,” and “the” may mean one or more than one unless indicated to the contrary or otherwise evident from the context. Claims or descriptions that include “or” between one or more members of a group are considered satisfied if one, more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process unless indicated to the contrary or otherwise evident from the context. The invention includes embodiments in which exactly one member of the group is present in, employed in, or otherwise relevant to a given product or process. The invention includes embodiments in which more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process.

[0233] Furthermore, the invention encompasses all variations, combinations, and permutations in which one or more limitations, elements, clauses, and descriptive terms from one or more of the listed claims is introduced into another claim. For example, any claim that is dependent on another claim can be modified to include one or more limitations found in any other claim that is dependent on the same base claim. Where elements are presented as lists, e.g., in Markush group format, each subgroup of the elements is also disclosed, and any element(s) can be removed from the group. It should it be understood that, in general, where the invention, or aspects of the invention, is/are referred to as comprising particular elements and/or features, certain embodiments of the invention or aspects of the invention consist, or consist essentially of, such elements and/or features. For purposes of simplicity, those embodiments have not been specifically set forth in haec verba herein. It is also noted that the terms “comprising” and “containing” are intended to be open and permits the inclusion of additional elements or steps. Where ranges are given, endpoints are included. Furthermore, unless otherwise indicated or otherwise evident from the context and understanding of one of ordinary skill in the art, values that are expressed as ranges can assume any specific value or sub-range within the stated ranges in different embodiments of the invention, to the tenth of the unit of the lower limit of the range, unless the context clearly dictates otherwise.

[0234] This application refers to various issued patents, published patent applications, journal articles, and other publications, all of which are incorporated herein by reference. If there is a conflict between any of the incorporated references and the instant specification, the specification shall control. In addition, any particular embodiment of the present invention that falls within the prior art may be explicitly excluded from any one or more of the claims. Because such embodiments are deemed to be known to one of ordinary skill in the art, they may be excluded even if the exclusion is not set forth explicitly herein. Any particular embodiment of the invention can be excluded from any claim, for any reason, whether or not related to the existence of prior art.

[0235] Those skilled in the art will recognize or be able to ascertain using no more than routine experimentation many equivalents to the specific embodiments described herein. The scope of the present embodiments described herein is not intended to be limited to the above Description, but rather is as set forth in the appended claims. Those of ordinary skill in the art will appreciate that various changes and modifications to this description may be made without departing from the spirit or scope of the present invention, as defined in the following claims.

EXAMPLES

[0236] In order that the invention described herein may be more fully understood, the following examples are set forth. The synthetic and biological examples described in this application are offered to illustrate the compounds, pharmaceutical compositions and methods provided herein and are not to be construed in any way as limiting their scope.

Materials and Methods

[0237] The compounds provided herein can be prepared from readily available starting materials using the following general methods and procedures. It will be appreciated that where typical or preferred process conditions (i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization.

[0238] Additionally, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions. The choice of a suitable protecting group for a particular functional group as well as suitable conditions for protection and deprotection are well known in the art. For example, numerous protecting groups, and their introduction and removal, are described in T. W. Greene and P. G. M. Wuts, Protecting Groups in Organic Synthesis, Second Edition, Wiley, New York, 1991, and references cited therein.

[0239] The compounds provided herein may be isolated and purified by known standard procedures. Such procedures include (but are not limited to) recrystallization, column chromatography, HPLC, or supercritical fluid chromatography (SFC). The following schemes are presented with details as to the preparation of representative heteroaryls and heterocyclyls that have been listed herein. The compounds provided herein may be prepared from known or commercially available starting materials and reagents by one skilled in the art of organic synthesis. Exemplary chiral columns available for use in the separation/purification of the enantiomers/diastereomers provided herein include, but are not limited to, CHIRALPAK® AD-10, CHIRALCEL® OB, CHIRALCEL® OB-H, CHIRALCEL® OD, CHIRALCEL® OD-H, CHIRALCEL® OF, CHIRALCEL® OG, CHIRALCEL® OJ and CHIRALCEL® OK.

[0240] The stereochemistry assigned herein (e.g., the assignment of “R” or “S” to the C21 position of the steroid) may be tentatively (e.g., randomly) assigned. For example, a C21 position may be drawn in the “R” configuration when the C21 position is in the “S” configuration.

[0241] .sup.1H-NMR reported herein (e.g., for intermediates) may be a partial representation of the full NMR spectrum of a compound, e.g., a compound described herein. For example, the reported .sup.1H NMR may exclude the region between δ (ppm) of about 1 to about 2.5 ppm.

[0242] Exemplary general method for preparative HPLC: Column: Waters RBridge prep 10 μm C18, 19*250 mm. Mobile phase: acetonitrile, water (NH.sub.4HCO.sub.3) (30 L water, 24 g NH.sub.4HCO.sub.3, 30 mL NH.sub.3.H.sub.2O). Flow rate: 25 ml/min

[0243] Exemplary general method for analytical HPLC: Mobile phase: A: water (10 mM NH.sub.4HCO.sub.3), B: acetonitrile Gradient: 5%-95% B in 1.6 or 2 min Flow rate: 1.8 or 2 mL/min; Column: XBridge C18, 4.6*50 mm, 3.5 μm at 45 C.

Synthetic Methods

Example 1. Synthesis of Intermediate A10

[0244] ##STR00048## ##STR00049##

Step 1. Synthesis of Compound A2.

[0245] Compound A1 (500 mg, 1.84 mmol) and 10% Pd/black (20 mg) in tetrahydrofuran (5 mL) and concentrated hydrobromic acid (0.02 mL) was hydrogenated with a hydrogen balloon at 1 atm. After stirring at room temperature for 24 h, the mixture was filtered through a pad of celite and the filtrate was concentrated in vacuo. Recrystallization from acetone to give compound A2 (367 mg, 1.34 mmol, 73%). .sup.1H NMR (400 MHz, CDCl.sub.3), δ (ppm), 2.61-2.54 (m, 1H), 2.58 (t, 1H, J=14 Hz), 2.45 (dd, 1H, J=19 Hz, 9 Hz), 0.98 (s, 3H).

Step 2. Synthesis of Compound A3.

[0246] To a solution of compound A2 (274 mg, 1 mmol) in methanol (4 mL) was added iodine (0.1 mmol). After stirring at 60° C. for 12 h, TLC showed no SM and the solvent was removed in vacuo. The crude product was dissolved in dichloromethane (20 mL) and washed with saturated NaHCO.sub.3 (15 mL), brine, dried over Na.sub.2SO.sub.4, filtered and concentrated. The residue was purified by chromatography on basic alumina (pertroleum ether/ethyl acetate=9:1) to give compound A3 (280 mg, 0.88 mmol, 88%), .sup.1H NMR (400 MHz, CDCl3), δ (ppm), 3.19 (s, 3H), 3.13 (s, 3H), 2.43 (dd, 1H, J=19.2 Hz, 8.8 Hz), 0.83 (s, 3H).

Step 3. Synthesis of Compound A4.

[0247] To a solution of methyltriphenylphosphonium bromide (10.26 g, 28.84 mmol) in 30 mL THF, was added KOt-Bu (3.23 g, 28.80 mmol). The reaction was heated to 60° C. for 1 h. A3 (3.23 g, 9.6 mmol) was added to the mixture, stirred at 60° C. for 15 h. The reaction mixture was extracted 500 ml EtOAc, washed with brine and evaporated in vacuo evaporated then purified by chromatography (PE:EA=3:1) to afford A4 as a solid (2.1 g).

Step 4. Synthesis of Compound A5.

[0248] To a solution of A4 (1 g, 3.1 mmol) in 20 ml THF, was added 2 mL of 2 M HCl and reaction stirred at rt for 1 h. The reaction mixture was quenched with 5 mL H.sub.2O and extracted with 100 mL EtOAc, washed with brine and evaporated in vacuo, then purified by chromatography (PE:EtOAc=10:1) to afford A5 as a solid (710 mg). .sup.1H NMR (400 MHz, CDCl.sub.3), δ (ppm), 4.65 (s, 1H), 4.63 (s, 1H), 0.82 (s, 3H).

Step 5. Synthesis of Compound A6.

[0249] To a stirred solution of trimethylsulfonium iodide (6.4 g, 31.5 mmol) in 10 mL of DMSO was added NaH (60%; 800 mg, 31.5 mmol). After stirring at room temperature for 1 h, a suspension of A5 (870 mg, 3.2 mmol) in 5 mL of DMSO was added dropwise. After 15 h, the reaction mixture was poured into ice-cold water and extracted with 300 mL EtOAc, washed with 100 mL brine solution, dried and evaporated in vacuo, then purified by chromatography (PE:EtOAc=10:1) to afford A6 and its isomer as a solid (695 mg).

Step 6. Synthesis of Compound A7.

[0250] To a solution of A6 and its isomer (129 mg, 0.45 mmol) in 10 mL THF, was added LiAlH.sub.4 (50 mg, 1.35 mmol), stirred at rt for 1 h. The reaction mixture was quenched with 5 mL H.sub.2O and extracted with 100 ml EtOAc, washed with brine solution and evaporated in vacuo then purified by chromatography (PE:EtOAc=3:1) to afford A7 as a solid (62 mg). .sup.1H NMR (400 MHz, CDCl.sub.3), δ (ppm), 4.63 (s, 1H), 4.61 (s, 1H), 0.82 (s, 3H), 1.25 (s, 3H).

Step 7. Synthesis of Compound A8.

[0251] To a solution of A7 (86 mg, 0.3 mmol) in dry THF (5 mL) was added borane-tetrahydrofuran complex (1 mL; 1.0 M solution in THF). After stirring at room temperature for 1 hour, the reaction mixture was cooled in an ice bath then quenched slowly with 10% aqueous NaOH (1 mL) followed by 30% aqueous solution of H.sub.2O.sub.2 (1 mL). After stirring at room temperature for one hour, the mixture was extracted with EtOAc (3×100 mL). The combined organic layers were washed with 10% aqueous Na.sub.2S.sub.2O.sub.3 (100 mL), brine (aq., 100 mL), dried over MgSO.sub.4, filtered and concentrated to afford A8 as a solid (83 mg, 91%). The crude product was used in the next step without further purification.

Step 8. Synthesis of Compound A9.

[0252] To a solution of A8 (300 mg, 0.80 mmol) in 15 mL DMF, was added PDC (2.7 g, 7.2 mmol) and 1 mL H.sub.2O, stirred at rt for 15 h. The reaction mixture was extracted 100 mL EtOAc, washed with brine and evaporated in vacuo then purified by chromatography (PE:EtOAc=1:1) to afford A9 as a solid 128 mg. .sup.1H NMR (400 MHz, DMSO-ds), δ (ppm), 11.90 (s, 1H), 4.22 (s, 1H), 2.28 (1H, t, J=7 Hz), 1.28 (s, 3H), 0.68 (s, 3H).

Step 9. Synthesis of Compound A10.

[0253] To a solution of A9 (200 mg, 0.61 mmol) in 5 mL DMF, was added N,O-dimethylhydroxylamine HCl salt (60 mg, 0.62 mmol), HATU (236 mg, 0.62 mmol) and DIPEA 1 mL, stirred at rt for 3 h, The reaction mixture was extracted 100 mL EtOAc, washed with brine solution and evaporated in vacuo then purified by chromatography (PE:EtOAc=1:1) to afford A10 as a solid 110 mg. .sup.1H NMR (400 MHz, DMSO-d.sub.6), δ (ppm), 3.64 (s, 3H), 3.19 (s, 3H), 2.70 (bs, 1H), 2.17 (t, J=7 Hz, 1H), 1.32 (s, 3H), 0.73 (s, 3H).

Example 2. Synthesis of Compound 1

[0254] ##STR00050##

[0255] To a stirred solution of A10 (0.1 g, 0.275 mmol) in 5 mL of THF was added phenylmagnesium bromide (1 M; 1.375 mL, 1.375 mmol) dropwise at rt. After stirring at rt for 3 h, the reaction mixture was poured into ice-cold water and extracted with EtOAc (100 mL×3), washed with brine (100 mL×3), dried (MgSO.sub.4), filtered, and evaporated in vacuo, then purified by prep-HPLC to afford 1 as a solid 24 mg. .sup.1H NMR (500 MHz, CDCl.sub.3), δ (ppm), 7.86 (d, 2H, J=6.8 Hz), 7.52 (t, 1H, J=7.2 Hz), 7.43 (t, 2H, J=7.2 Hz), 3.49 (t, 1H, J=7.8 Hz), 2.43 (q, 1H, J=8.6 Hz), 1.25 (s, 3H), 0.60 (s, 3H). LCMS: Rt=2.618 min, MS (ESI) m/z 381 [M+H].sup.+.

Example 3. Synthesis of Compound 2

[0256] ##STR00051##

[0257] To a stirred solution of thiazole (117 mg, 1.375 mmol) in 10 mL of THF was added nBuLi (2.5 M, 0.55 ml, 1.375 mmol) at −78° C. After stirring at −78° C. for 30 min, a solution of A10 (0.1 g, 0.275 mmol) in 5 mL of THF was added dropwise at −78° C. After stirring at −78° C. for 1 h, the reaction mixture was poured into ice-cold water and extracted with EtOAc (100 mL×3), washed with brine (100 mL×3), dried (MgSO.sub.4), filtered, and evaporated in vacuo, purified by prep-HPLC to afford 2 as a solid 44 mg. .sup.1H NMR (500 MHz, CDCl.sub.3), δ (ppm), 7.97 (d, 1H, J=3.0 Hz), 7.63 (d, 1H, J=3.0 Hz), 3.87 (t, 1H, J=9.0 Hz), 1.26 (s, 3H), 0.69 (s, 3H). LCMS: Rt=2.564 min, MS (ESI) m/z: 388 [M+H].sup.+.

Example 4. Synthesis of Compound 3

[0258] ##STR00052##

[0259] To a stirred solution of 1-methyl-1H-imidazole (113 mg, 1.375 mmol) in 10 mL of THF was added nBuLi (2.5 M, 0.55 ml, 1.375 mmol) at −78° C. After stirring at −78° C. for 30 min, a solution of A10 (0.1 g, 0.275 mmol) in 5 mL of THF was added dropwise at −78° C. After stirring at −78° C. for 1 h. the reaction mixture was poured into ice-cold water and extracted with EtOAc (100 mL×3), washed with brine (100 mL×3), dried (MgSO.sub.4), filtered, and evaporated in vacuo, then purified by prep-HPLC to afford 3 as a solid 20 mg. .sup.1H NMR (500 MHz, CDCl.sub.3), δ.sub.H (ppm), 7.09 (d, 1H, J=0.5 Hz), 6.98 (d, 1H, J=0.5 Hz), 3.97 (s, 3H), 3.96 (t, 1H, J=8.6 Hz), 1.25 (s, 3H), 0.67 (s, 3H). LCMS: Rt=2.393 min, MS (ESI) m/z: 385 [M+H].sup.+.

Example 5. Synthesis of Compound 4

[0260] ##STR00053##

[0261] To a stirred solution of thiophene (115 mg, 1.375 mmol) in 10 mL of THF was added nBuLi (2.5 M; 0.55 mL, 1.375 mmol) at 0° C. After stirring at 0° C. for 40 min, a solution of A10 (0.1 g, 0.275 mmol) in 5 mL of THF was added dropwise at 0° C. After stirring at 0° C. for 2 h, the reaction mixture was poured into ice-cold water and extracted with EtOAc (100 mL×3), washed with brine (100 mL×3), dried (MgSO.sub.4), filtered, and evaporated in vacuo, then purified by prep-HPLC to afford 4 as a solid 31 mg. .sup.1H NMR (500 MHz, CDCl.sub.3), δ (ppm), 7.66 (d, 1H), 7.61 (d, 1H), 7.11 (t, 1H), 3.27 (t, 1H), 1.26 (s, 3H), 0.67 (s, 3H). LCMS: Rt=2.541 min, MS (ESI) m/z: 387 [M+H].sup.+.

Example 6. Synthesis of Compound 5

[0262] ##STR00054##

[0263] To a stirred solution of benzofuran (162 mg, 1.375 mmol) in 10 mL of THF was added nBuLi (2.5 M; 0.55 mL, 1.375 mmol) at 0° C. After stirring at 0° C. for 40 min, a solution of A10 (0.1 g, 0.275 mmol) in 5 mL of THF was added dropwise at 0° C. After stirring at 0° C. for 2 h, the reaction mixture was poured into ice-cold water and extracted with EtOAc (100 mL×3), washed with brine (100 mL×3), dried (MgSO.sub.4), filtered, and evaporated in vacuo, then purified by prep-HPLC to afford 5 as a solid 47 mg. .sup.1H NMR (500 MHz, CDCl.sub.3), δ (ppm), 7.71 (d, 1H, J=7.8 Hz), 7.58 (d, 1H, J=7.8 Hz), 7.46 (t, 1H, J=7.8 Hz), 7.45 (s, 1H), 7.30 (t, 1H, J=7.8 Hz), 3.40 (t, 1H, J=8.2 Hz), 1.27 (s, 3H), 0.69 (s, 3H). LCMS: Rt=2.621 min, MS (ESI) m/z: 421 [M+H].sup.+.

Example 7. Synthesis of Compound 6

[0264] ##STR00055##

[0265] To a stirred solution of 1-methyl-1H-benzo[d]imidazole (181 mg, 1.375 mmol) in 10 mL of THF was added nBuLi (2.5 M; 0.55 mL, 1.375 mmol) at −78° C. After stirring at −78° C. for 30 min, a solution of A10 (0.1 g, 0.275 mmol) in 5 mL of THF was added dropwise at −78° C. After stirring at −78° C. for 2 h, the reaction mixture was poured into ice-cold water and extracted with EtOAc (100 mL×3), washed with brine (100 mL×3), dried (MgSO.sub.4), filtered, and evaporated in vacuo, then purified by prep-HPLC to afford 6 as a solid 65 mg. .sup.1H NMR (500 MHz, CDCl.sub.3), δ (ppm), 7.89 (d, 1H, J=7.8 Hz), 7.44-7.40 (m, 2H), 7.36-7.33 (m, 1H), 4.19 (t, 1H, J=8.6 Hz), 4.10 (s, 3H), 1.25 (s, 3H), 0.69 (s, 3H). LCMS: Rt=2.607 min, MS (ESI) m/z: 435 [M+H].sup.+.

Example 8. Synthesis of Compound 7

[0266] ##STR00056##

[0267] To a stirred solution of 1-methyl-1H-indole (180 mg, 1.375 mmol) in 10 mL of THF was added nBuLi (2.5 M; 0.55 mL, 1.375 mmol) at 0° C. After stirring at 0° C. for 40 min, a solution of A10 (0.1 g, 0.275 mmol) in 5 mL of THF was added dropwise at 0° C. After stirring at 0° C. for 2 h, the reaction mixture was poured into ice-cold water and extracted with EtOAc (100 mL×3), washed with brine (100 mL×3), dried (MgSO.sub.4), filtered, and evaporated in vacuo, then purified by prep-HPLC to afford 7 as a solid 36 mg. .sup.1H NMR (500 MHz, CDCl.sub.3), δ (ppm), 7.70 (d, 1H, J=7.8 Hz), 7.38-7.34 (m, 2H), 7.23 (s, 1H), 7.15-7.13 (m, 1H), 4.06 (s, 3H), 3.40 (t, 1H, J=8.2 Hz), 1.26 (s, 3H), 0.68 (s, 3H). LCMS: Rt=2.742 min, MS (ESI) m/z: 434 [M+H].sup.+.

Example 9. Synthesis of Compound 8

[0268] ##STR00057##

[0269] To a stirred solution of benzo[d]thiazole (185 mg, 1.375 mmol) in 10 mL of THF was added nBuLi (2.5 M; 0.55 mL, 1.375 mmol) at −78° C. After stirring at −78° C. for 30 min, a solution of A10 (0.2 g, 0.55 mmol) in 5 mL of THE was added dropwise at −78° C. After stirring at −78° C. for 2 h, the reaction mixture was poured into ice-cold water and extracted with EtOAc (100 mL×3), washed with brine (100 mL×3), dried (MgSO.sub.4), filtered, and evaporated in vacuo, purified by prep-HPLC to afford 8 as a solid 100 mg. .sup.1H NMR (500 MHz, CDCl.sub.3), δ (ppm), 8.09 (d, 1H, J=7.8 Hz), 7.87 (d, 1H, J=7.8 Hz), 7.45 (t, 1H, J=7.8 Hz), 7.40 (t, 1H, J=7.8 Hz), 3.94 (t, 1H, J=8.6 Hz), 1.17 (s, 3H), 0.61 (s, 3H). LCMS: Rt=2.829 min, MS (ESI) m/z: 438 [M+H].sup.+.

Example 10. Synthesis of Compound 9

[0270] ##STR00058##

[0271] To a stirred solution of 1-methyl-1H-pyrazole (60 mg, 0.7 mmol) in 10 mL THF was added BuLi (2.5 M; 0.3 ml, 0.7 mmol) at 0° C. After stirring at 0° C. for 30 min, a solution of A10 (50 mg, 0.14 mmol) in 3 mL THF was added dropwise at −78° C. After stirring at 0° C. for 2 h, the reaction mixture was poured into ice-cold water and extracted with EtOAc (100 mL×3). The combined extracts were washed with brine (100 mL×3), dried (MgSO.sub.4), filtered, evaporated in vacuo, and purified by prep-HPLC to afford 9 as a solid (23 mg, 0.06 mmol). .sup.1H NMR (500 MHz, CDCl.sub.3), δ (ppm), 7.44 (1H, d, J=2 Hz), 6.77 (1H, d, J=2 Hz), 4.15 (3H, s), 3.17 (1H, t, J=9 Hz), 2.35 (1H, dd, J=9 Hz, 8 Hz) 1.27 (s, 3H), 0.64 (s, 3H). LCMS: Rt=2.45 min, m/z=385.2 [M+H]

Example 11. Synthesis of Compound 10

[0272] ##STR00059##

[0273] To a stirred solution of 3-bromothiophene (110 mg, 0.7 mmol) in 10 mL of THF was added BuLi (2.5 M; 0.3 ml, 0.7 mmol) at −78° C. After stirring at −78° C. for 30 min, a solution of A10 (50 mg, 0.14 mmol) in 3 mL of THF was added dropwise at −78° C. After stirring at −78° C. for 2 h, the reaction mixture was poured into ice-cold water and extracted with EtOAc (100 mL×3), washed with brine (100 mL×3), dried (MgSO.sub.4), filtered, evaporated in vacuo, and purified by prep-HPLC to afford 10 as a solid (15 mg, 0.039 mmol). .sup.1H NMR (500 MHz, CDCl.sub.3), δ (ppm), 7.66 (1H, d, J=4 Hz), 7.61 (1H, dd, J=1 Hz), 7.11 (1H, t, J=4 Hz), 3.28 (1H, t, J=9 Hz), 2.42-2.36 (1H, m) 1.27 (s, 3H), 0.68 (s, 3H). LCMS: Rt=2.54 min, m/z=387.1 [M+H]

Example 12. Synthesis of Compound 11

[0274] ##STR00060##

[0275] To a stirred solution of 3-bromobenzo[b]thiophene (230 mg, 1.1 mmol) in 10 mL THF was added BuLi (2.5 M; 0.45 ml, 1.1 mmol) at −78° C. After stirring at −78° C. for 30 min, a solution of A10 (80 mg, 0.22 mmol) in 3 mL THF was added dropwise at −78° C. After stirring at −78° C. for 2 h, the reaction mixture was poured into ice-cold water and extracted with EtOAc (100 mL×3), The combined extracts were washed with brine (100 mL×3), dried (MgSO4), filtered, evaporated in vacuo, and purified by prep-HPLC to afford 11 as a solid (52 mg, 0.12 mmol). .sup.1H NMR (500 MHz, CDCl.sub.3), δ (ppm), 7.90-7.89 (2H, s), 7.85 (1H, d, J=9 Hz), 7.44 (1H, t, J=7 Hz), 7.39 (1H, t, J=7 Hz), 3.40 (1H, t, J=9 Hz), 2.43-2.39 (1H, m) 1.27 (s, 3H), 0.69 (s, 3H). LCMS: rt=2.73 min, m/z=437.2 [M+H]

Example 13. Synthesis of Compound 12

[0276] ##STR00061##

[0277] To a stirred solution of 3-bromobenzofuran (140 mg, 0.7 mmol) in 10 mL THF was added BuLi (2.5 M; 0.3 ml, 0.7 mmol) at −78° C. After stirring at −78° C. for 30 min, a solution of A10 (50 mg, 0.14 mmol) in 3 mL of THF was added dropwise at −78° C. After stirring at −78° C. for 2 h, the reaction mixture was poured into ice-cold water and extracted with EtOAc (100 mL×3). The combined extracts were washed with brine (100 mL×3), dried (MgSO.sub.4), filtered, evaporated in vacuo, and purified by prep-HPLC to afford 12 as a solid (25 mg, 0.06 mmol). .sup.1H NMR (500 MHz, CDL3), δ (ppm), 7.71 (1H, d, J=8 Hz), 7.58 (1H, d, J=9 Hz), 7.46 (1H, s), 7.46 (1H, t, J=5 Hz), 7.30 (1H, t, J=7 Hz), 3.41 (1H, t, J=9 Hz), 2.45-2.37 (1H, m) 1.27 (s, 3H), 0.69 (s, 3H). LCMS: rt=2.53 min, m/z=421.3 [M+H].

Example 14. Synthesis of Compound 13

[0278] ##STR00062## ##STR00063##

Step 1.

[0279] To a solution of B23 (55 g, 198 mmol) in DCM (2000 mL) was added Dess-Martin (167 g, 396 mmol) in portions at 15° C. After addition was completed, the mixture was stirred at 15° C. for 2 hours. TLC (PE:EA=3:1, PMA) indicated the reaction was finished and one main spot was found. To the mixture was added a saturated mixed solution of NH.sub.4Cl and NaHCO.sub.3 (v:v=1:1) (1.5 L) until the reaction solution became clear and starch potassium iodide paper did not turn blue. The mixture was extracted with DCM (1 L×2). The combined organic phase was dried over Na.sub.2SO.sub.4 and concentrated to give crude B24 (60 g, crude) as solid.

Step 2.

[0280] To a solution of B24 (60 g, 208 mmol) in THF (1000 mL) was added methylmagnesium bromide (624 mmol, 208 mL, 3M in ether) at −70° C. The mixture was stirred at −70° C. for 3 hours. TLC (PE:EA=3:1, PMA) indicated the reaction was finished. The reaction mixture was quenched with saturated NH.sub.4Cl solution (1500 mL) and then concentrated to give a residue, which was extracted with DCM (1000 mL×3). The organic phase was dried, concentrated to give crude B25 (50 g) as a solid.

Step 3.

[0281] To a solution of Ph.sub.3PMeBr (280 g, 785 mmol) in THF (500 mL) was added a slurry of t-BuOK (87.9 g, 785 mmol) in THF (200 mL) under N.sub.2. The mixture turned red and the mixture was stirred at 60° C. for 1 hour. A solution of B25 (48 g, 157 mmol) was added in one portion. The final reaction mixture was stirred at this temperature (60° C.) for 2 hours. TLC (PE:EA=3:1, PMA) indicated the reaction was finished. The reaction was worked up. To the combined reaction mixture was added saturated NH.sub.4Cl solution (1000 mL) and then extracted with EtOAc (1000 mL×2). The combined organic phase was dried, concentrated and purified on silicon gel column (PE:EA=50/1-20/1) to give B26 (15 g, 31.6%) as a solid.

[0282] .sup.1H NMR (400 MHz. CDCl3) δ=4.65-4.57 (m, 2H), 2.53-2.42 (m, 1H), 2.27-2.16 (m, 1H), 1.85-1.10 (m, 21H), 1.05-0.78 (m, 2H), 0.77 (s, 7H)

Step 4.

[0283] To a solution of B26 (15 g, 49.5 mmol) in THF (500 mL) was added dropwise a solution of BH3-Me2S (49.5 mL, 495 mmol) at 0° C. The solution was stirred at 15° C. for 3 h. TLC (PE/EtOAc=3/1) showed the reaction was completed. After cooling to 0° C., a solution of NaOH (250 mL, 3M) was added very slowly. After addition, H.sub.2O.sub.2 (67 g, 594 mmol, 30% in water) was added slowly and the inner temperature was maintained below 10° C. The resulting solution was stirred at 15° C. for 2 h. Then saturated aqueous Na.sub.2S.sub.2O.sub.3 (500 mL) was added until the reaction solution became clear. The mixture was extracted with EtOAc (200×3). The combined organic solution was washed with saturated aqueous Na.sub.2S.sub.2O.sub.3 (100 mL×3), brine (200 mL), dried over Na.sub.2SO.sub.4 and concentrated in vacuum to give the crude product B27 (20 g) as a solid, which was used for the next step without further purification.

Step 5.

[0284] To a solution of B27 (20 g, 62.4 mmol) in DCM (400 mL) was added PCC (26.7 g, 123 mmol) and SiO.sub.2 (26.7 g). The final reaction mixture was stirred at 15° C. for 3 hours. After TLC (PE:EA=3:1) indicated the reaction was finished and one main spot was found, the mixture was concentrated and purified by combi-flash (PE:EA=100%-70%) to give B28 (10 g, 51.2%) as a solid.

Step 6.

[0285] To a solution of B28 (10 g, 31.3 mmol) in acetone (150 mL) and 2-methyl-2-butene (35 mL) was added slowly drop wise aqueous NaH.sub.2PO.sub.4 (18.7 g, 156 mmol) and NaClO.sub.2 (14.1 g, 156 mmol) in water (100 mL) at 0° C. The mixture was stirred at 15° C. for 2 h. TLC (PE/EA=1/1) showed the reaction was completed and two main spots were found. Then, the reaction was poured in to water (400 mL) and filtered. The filtered cake was washed with water (100 mL) and concentrated to afford a mixture (8 g) as a solid.

Step 7.

[0286] To a solution of B29 (8 g, 23.9 mmol) in DMF (200 mL) was added HATU (18.1 g, 47.8 mmol), TEA (5.25 g, 47.8 mmol) and N,O-dimethylhydroxylamine (2.18 g, 35.8 mmol) at 15° C. The mixture was stirred at 15° C. for 16 hrs. TLC (PE/EA=1/1) showed the reaction was completed. The reaction was poured into water (500 mL) and extracted with EtOAc (100 mL×2). The combined organic phase was washed with saturated brine (200 mL), dried with anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuum. The residue was purified by silica gel chromatography (100-200 mesh silica gel, Petroleum ether/Ethyl acetate=4/1) to afford B30 (3 g) as a solid.

[0287] .sup.1H NMR (400 MHz, CDCl3) δ=3.64 (s, 3H), 3.20 (s, 3H), 2.85-2.71 (m, 1H), 2.28-2.08 (m, 1H), 1.80-0.70 (m, 31H)

Step 8.

[0288] To a solution of B30 (0.1 g, 0.264 mmol) in THF (2 mL) was added (3,5-dimethoxyphenyl)magnesium chloride (2.63 mL, 2.63 mmol, 1.0M in THF) under N.sub.2. The reaction mixture was stirred at 15° C. for 1.5 hours. LCMS indicated the reaction was finished and desired MS peak was found. To the reaction mixture was added saturated NH.sub.4Cl solution (5 mL) and then extracted with EtOAc (2 mL×3). The combined organic phase was concentrated and purified by prep-HPLC to give 13 (47.8 mg) as a solid.

[0289] .sup.1H NMR (400 MHz, CDCl3) δ 7.01 (d, J=2.3 Hz, 2H), 6.65-6.59 (m, 1H), 3.83 (s, 6H), 3.46-3.36 (m, 1H), 2.49-2.34 (m, 1H), 1.84-1.66 (m, 3H), 1.19 (s, 20H), 1.04-0.89 (m, 1H), 0.71 (s, 4H), 0.60 (s, 3H). LCMS Rt=1.489 min in 2 min chromatography, 10-80 AB, MS ESI calcd. for C.sub.29H.sub.43O.sub.4 [M+H].sup.+ 455. found 455.

Example 15. Synthesis of Compound 14

[0290] ##STR00064##

[0291] To a solution of B30 (0.1 g, 0.264 mmol) in THF (2 mL) was added naphthalen-2-yl magnesium bromide (5.26 mL, 2.63 mmol, 0.5M in THF) under N.sub.2. The reaction mixture was stirred at 15° C. for 4 hours. LCMS indicated the reaction was finished and desired MS peak was found. To the reaction mixture was added saturated NH.sub.4Cl solution (5 mL) and then extracted with EtOAc (2 mL×3). The combined organic phase was concentrated and purified by prep-HPLC to give 14 (36.1 mg) as a solid.

[0292] .sup.1H NMR (400 MHz. CDCl3) δ8.42-8.37 (m, 1H), 8.00-7.94 (m, 2H), 7.91-7.84 (m, 2H), 7.62-7.51 (m, 2H), 3.70-3.62 (m, 1H), 2.56-2.42 (m, 1H), 1.87-1.69 (m, 3H), 1.19 (s, 21H), 0.84-0.75 (m, 1H), 0.70 (s, 3H), 0.63 (s, 3H). LCMS Rt=1.553 min in 2 min chromatography, 10-80 AB, MS ESI calcd. for C.sub.31H.sub.41O.sub.2[M+H].sup.+ 445. found 445.

Example 16. Synthesis of Compound 15

[0293] ##STR00065##

[0294] To a solution of B30 (0.1 g, 0.264 mmol) in THF (2 mL) was added [1,1′-biphenyl]-4-yl magnesium bromide (5.26 mL, 2.63 mmol, 0.5M in THF) under N.sub.2. The reaction mixture was stirred at 15° C. for 4 hours. LCMS indicated the reaction was finished and desired MS peak was found. To the reaction mixture was added saturated NH.sub.4Cl solution (5 mL) and then extracted with EtOAc (2 mL×3). The combined organic phase was concentrated and purified by preparative HPLC to give 15 (41.4 mg) as a solid.

[0295] .sup.1H NMR (400 MHz, CDCl3) δ 7.96 (d, J=8.3 Hz, 2H), 7.65 (dd, J=7.9, 11.9 Hz, 4H), 7.50-7.33 (m, 3H), 3.59-3.47 (m, 1H), 2.51-2.38 (m, 1H), 1.86-1.68 (m, 3H), 1.19 (s, 20H), 1.05-0.91 (m, 1H), 0.84-0.75 (m, 1H), 0.72 (s, 3H), 0.62 (s, 3H). LCMS Rt=1.645 min in 2 min chromatography, 10-80 AB, MS ESI calcd. for C.sub.33H.sub.43O.sub.2 [M+H].sup.+ 471. found 471.

Example 17. Synthesis of Compound 16

[0296] ##STR00066##

[0297] To a solution of A10 (100 mg, 0.275 mmol) in THF (3 mL) was added (3,5-dimethylphenyl)magnesium bromide (5.5 mL, 95%). The mixture was stirred at 20° C. for 3.5 h. When TLC showed starting material was consumed and new spot was produced, to the mixture was added sat. aq. NH.sub.4HCl (5 mL). The organic phase was extracted with DCM (5 mL*2), washed with sat. aq. NaCl (8 mL*2), concentrated in vacuum. The residue was purified by prep. HPLC to give 16 (48.3 mg) as a solid.

[0298] .sup.1H NMR (400 MHz, CDCl.sub.3) δ7.47 (s, 2H), 7.16 (s, 1H), 3.47 (t, J=8.8 Hz, 1H), 2.36 (s, 7H), 1.84-1.70 (m, 5H), 1.66-1.58 (m, 2H), 1.49-1.24 (m, 16H), 1.17-1.04 (m, 2H), 0.98-0.85 (m, 1H), 0.60 (s, 3H). LCMS Rt=1.500 min in 2 min chromatography, 10-80 AB, MS ESI calcd. for C.sub.28H.sub.41O.sub.2 [M+H].sup.+ 409. found 391 [M−H.sub.2O].

Example 18. Synthesis of Compound 17

[0299] ##STR00067##

[0300] The synthesis of A30 can be found in Example 37, below.

[0301] To a solution of A30 (100 mg, 264 μmol) in anhydrous THE (2 mL) was added (3,4-dimethylphenyl)magnesium chloride (5.26 mL, 0.5 M, 2.63 mmol) at 25° C. The reaction mixture was stirred at 25° C. for 2 hours. LCMS showed the starting material was consumed completely. The reaction was quenched with saturated NH.sub.4Cl aqueous (1 mL), concentrated under vacuum to give a residue, which was purified by Prep-HPLC (0.05% HCl-ACN) to afford 17 (61.8 mg) as a solid.

[0302] .sup.1H NMR (400 MHz, CDCl.sub.3) δ=7.67 (s, 1H), 7.61 (d, J=7.5 Hz, 1H), 7.18 (d, J=8.0 Hz, 1H), 3.47 (t, J=8.8 Hz, 1H), 2.48-2.36 (m, 1H), 2.31 (s, 6H), 2.04-1.92 (m, 1H), 1.90-1.80 (m, 1H), 1.79-1.63 (m, 3H), 1.54-0.97 (m, 21H), 0.91 (s, 3H), 0.58 (s, 3H)

[0303] LCMS R.sub.t=1.475 min in 2 min chromatography, 10-80 AB, MS ESI calcd. for C.sub.33H.sub.42O.sub.2 [M+H].sup.+ 423. found 423.3.

Example 19. Synthesis of Compound 18

[0304] ##STR00068##

[0305] To a solution of A30 (100 mg, 264 μmol) in anhydrous THF (2 mL) was added naphthalen-2-yl magnesium bromide (5.26 mL, 0.5 M, 2.63 mmol) at 25° C. The reaction mixture was stirred at 25° C. for 2 hours. LCMS showed the starting material was consumed completely. The reaction was quenched with saturated NH.sub.4Cl aqueous (1 mL), concentrated under vacuum to give a residue, which was purified by Prep-HPLC (0.05%/HCl-ACN) to afford 18 (8.4 mg) as a solid.

[0306] .sup.1H NMR (400 MHz, CDCl.sub.3) δ=8.39 (s, 1H), 8.02-7.92 (m, 2H), 7.88 (d, J=8.5 Hz, 2H), 7.65-7.51 (m, 2H), 3.67 (t, J=8.5 Hz, 1H), 2.55-2.43 (m, 1H), 2.07-1.75 (m, 5H), 1.66 (d, J=14.6 Hz, 2H), 1.58-1.23 (m, 19H), 1.21-0.97 (m, 3H), 0.90 (s, 3H), 0.63 (s, 3H)

[0307] LCMS R.sub.t=1.496 min in 2 min chromatography, 10-80 AB, MS ESI calcd. for C.sub.31H.sub.41O.sub.2 [M+H].sup.+ 445. found 445.3.

Example 20. Synthesis of Compound 19

[0308] ##STR00069##

[0309] To a solution of A10 (100 mg, 0.275 mmol) in THF (3 mL) was added naphthalen-2-yl magnesium bromide (5.5 mL, 0.5 M in THF). The mixture was stirred at 20° C. for 3.5 h. When TLC showed starting material was consumed and new spot was produced, to the mixture was added sat. aq. NH.sub.4Cl (5 mL). The organic phase was extracted with DCM (5 mL*2), washed with sat. aq. NaCl (8 mL*2), concentrated in vacuum. The residue was purified by preparative HPLC to give 19 (37 mg) as a solid.

[0310] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.39 (s, 1H), 8.01-7.93 (m, 2H), 7.88 (d, J=8.8 Hz, 2H), 7.62-7.52 (m, 2H), 3.67 (t, J=8.7 Hz, 1H), 2.57-2.43 (m, 1H), 1.91-1.71 (m, 5H), 1.68-1.56 (m, 2H), 1.50-1.23 (m, 16H), 1.19-1.04 (m, 2H), 0.95-0.83 (m, 1H), 0.64 (s, 3H). LCMS Rt=1.495 min in 2 min chromatography, 10-80 AB, MS ESI calcd. for C.sub.30H.sub.39O.sub.2 [M+H].sup.+ 430. found 413 [M−H.sub.2O].

Example 21. Synthesis of Compound 20

[0311] ##STR00070##

[0312] To a solution of A10 (100 mg, 0.275 mmol) in THF (3 mL) was added (3,4-dimethylphenyl)magnesium chloride (5.5 mL, 0.5 M in THF). The mixture was stirred at 20° C. for 3.5 h. When TLC showed starting material was consumed and new spot was produced. To the mixture was added Sat. NH.sub.4Cl (5 mL). The aqueous layer was extracted with DCM (5 mL*2), washed with Sat. NaCl (8 mL*2), filtered and concentrated in vacuum. The residue was purified by prep-HPLC to give 20 (45 mg) as a solid.

[0313] .sup.1H NMR (400 MHz, CDCl.sub.3) δ7.66 (s, 1H), 7.61 (d, J=7.8 Hz, 1H), 7.18 (d, J=7.8 Hz, 1H), 3.47 (t, J=8.7 Hz, 1H), 2.48-2.36 (m, 1H), 2.31 (s, 6H), 1.82-1.60 (m, 6H), 1.51-1.23 (m, 17H), 1.19-1.02 (m, 2H), 0.98-0.85 (m, 1H), 0.60 (s, 3H). LCMS t.sub.R=1.491 min in 2 min chromatography, 10-80 AB, MS ESI calcd. for C.sub.28H.sub.41O.sub.2 [M+H].sup.+ 409. found 391 [M−H.sub.2O].sup.+.

Example 22. Synthesis of Compound 21

[0314] ##STR00071##

[0315] To a solution of A30 (100 mg, 264 μmol) in anhydrous THF (2 mL) was added (3,5-dimethoxyphenyl)magnesium chloride (2.63 mL, 1.0 M, 2.63 mmol) at 25° C. The reaction mixture was stirred at 25° C. for 2 hours. LCMS showed the starting material was consumed completely. The reaction was quenched with saturated NH.sub.4Cl aqueous (1 mL), concentrated under vacuum to give a residue, which was purified by Prep-HPLC (0.05% HCl-ACN) to afford 21 (68.8 mg) as a solid.

[0316] .sup.1H NMR (400 MHz, CDCl.sub.3) δ=7.02 (d, J=2.0 Hz, 2H), 6.63 (s, 1H), 3.84 (s, 6H), 3.41 (t, J=8.8 Hz, 1H), 2.46-2.35 (m, 1H), 2.03-1.93 (m, 1H), 1.90-1.64 (m, 4H), 1.53-1.28 (m, 12H), 1.28-1.20 (m, 5H), 1.18-0.97 (m, 3H), 0.91 (s, 3H), 0.59 (s, 3H). LCMS R.sub.t=1.474 min in 2 min chromatography, 10-80 AB, MS ESI calcd. for C.sub.33H.sub.43O.sub.2 [M+H].sup.+ 455. found 437 ([M−H.sub.2O].sup.+).

Example 23. Synthesis of Compound 22

[0317] ##STR00072##

[0318] To a solution of A30 (100 mg, 264 μmol) in anhydrous THF (2 mL) was added [1,1′-biphenyl]-4-ylmagnesium bromide (5.26 mL, 0.5 M, 2.63 mmol) at 25° C. The reaction mixture was stirred at 25° C. for 2 hours. LCMS showed the starting material was consumed completely. The reaction was quenched with saturated NH.sub.4Cl aqueous (1 mL), concentrated under vacuum to give a residue, which was purified by Prep-HPLC (0.05% HCl-ACN) to afford 22 (76 mg) as a solid.

[0319] .sup.1H NMR (400 MHz, CDCl.sub.3) δ=7.96 (d, J=80 Hz, 2H), 7.72-7.60 (m, 4H), 7.51-7.43 (m, 2H), 7.43-7.36 (m, 1H), 3.53 (t, J=8.5 Hz, 1H), 2.52-2.40 (m, 1H), 1.98 (t, J=13.3 Hz, 1H), 1.91-1.63 (m, 4H), 1.55-1.29 (m, 12H), 1.28-0.96 (m, 9H), 0.92 (s, 3H), 0.62 (s, 3H). LCMS R.sub.t=1.556 min in 2 min chromatography, 10-80 AB, MS ESI calcd. for C.sub.33H.sub.43O.sub.2 [M+H].sup.+ 471. found 471.3.

Example 24. Synthesis of Compound 23

[0320] ##STR00073##

[0321] To a stirred solution of A30 (110 mg, 291 umol) in 3 mL of THF was added (3,5-difluorophenyl)magnesium bromide (0.5 M; 5.8 mL, 2.9 mmol) dropwise at 25° C. After stirring at 25° C. for 12 hrs, LCMS showed the reaction was complete. The reaction mixture was poured into ice-cold water and extracted with EtOAc (50 mL×2), washed with brine (30 mL×2), dried (Na2SO4), filtered, and evaporated in vacuo to give crude product. The reaction mixture was purified by HPLC separation (column: Phenomenex Synergi C18 150*25*10 um, gradient: 80-100% B (A=0.05% HCl-ACN, B=acetonitrile), flow rate: 25 mL/min) for further purification to obtain 23 (28.4 mg) as a solid.

[0322] .sup.1HNMR (CDCl.sub.3, 400 MHz): δ=7.38 (d, J=6.0 Hz, 2H), 6.99 (t, J=8.4 Hz, 1H), 3.35 (t, J=8.8 Hz, 1H), 2.35-2.45 (m, 1H), 1.96 (t, J=13.2 Hz, 1H), 1.73-1.90 (m, 3H), 1.69 (d, J=14.6 Hz, 1H), 1.33-1.54 (m, 12H), 1.21-1.28 (m, 5H), 1.10-1.19 (m, 2H), 1.01-1.08 (m, 1H), 0.92 (s, 3H), 0.59 (s, 3H) LCMS Rt=3.417 min in 4.0 min chromatography, 10-80 AB, MS ESI calcd. for C.sub.27H.sub.36F.sub.2O.sub.2 [M−+H]+ 430.3. found 413.0 [M−H.sub.2O].sup.+.

Example 25. Synthesis of Compound 24

[0323] ##STR00074##

[0324] To a stirred solution of A30 (110 mg, 291 umol) in 3 mL of THF was added benzo[d][1,3]dioxol-5-ylmagnesium bromide (0.5 M; 5.8 mL, 2.9 mmol) dropwise at 25° C. After stirring at 25° C. for 12 hrs, LCMS showed the reaction was complete. The reaction mixture was poured into ice-cold water and extracted with EtOAc (50 mL×2), washed with brine (30 mL×2), dried (Na.sub.2SO.sub.4), filtered, and evaporated in vacuo to give crude product. The reaction mixture was purified by HPLC separation (column: Phenomenex Synergi C18 150*25*10 um, gradient: 80-100% B (A=0.05% HCl-ACN, B=acetonitrile), flow rate: 25 mL/min) for further purification to obtain 24 (21.1 mg) as a solid.

[0325] .sup.1HNMR (CDCl.sub.3, 400 MHz): δ=7.50 (d. J=8.0 Hz, 1H), 7.41 (s, 1H), 6.84 (d, J=8.0 Hz, 1H), 6.04 (s, 2H), 3.40 (t, J=8.6 Hz, 1H), 2.37-2.45 (m, 1H), 1.97 (t, J=13.6 Hz, 1H), 1.81-1.90 (m, 1H), 1.64-1.79 (m, 3H), 1.29-1.55 (m, 12H), 1.27 (s, 3H), 1.23 (br. s, 2H), 1.10-1.19 (m, 2H), 1.00-1.08 (m, 1H), 0.92 (s, 3H), 0.59 (s, 3H). LCMS Rt=3.309 min in 4.0 min chromatography, 10-80 AB, MS ESI calcd. for C.sub.2H.sub.39O.sub.4[M+H]+ 439.3. found 439.1.

Example 26. Synthesis of Compound 25

[0326] ##STR00075##

[0327] To a solution of A10 (100 mg, 0.275 mmol) in THF (3 mL) was added (4-(methylthio)phenyl)magnesium bromide (5.5 mL, 0.5 M in THF). The mixture was stirred at 20° C. for 3.5 h. To the mixture was added Sat. NH.sub.4Cl (5 mL). The organic phase was extracted with DCM (5 mL*2), washed with Sat. NaCl (8 mL*2), concentrated in vacuum. The residue was purified by prep. HPLC.sup.1 to give 25 (32 mg) as a solid.

[0328] .sup.1H NMR (400 MHz, CDCl.sub.3) δ7.81 (d, J=8.5 Hz, 2H), 7.25-7.22 (m, 2H), 3.45 (t, J=8.8 Hz, 1H), 2.56-2.35 (m, 4H), 1.84-1.72 (m, 5H), 1.53-1.25 (m, 18H), 1.20-0.84 (m, 3H), 0.59 (s, 3H).

[0329] LCMS Rt=1.476 min in 2 min chromatography, 10-80 AB, MS ESI calcd. for C.sub.27H.sub.39O.sub.2S [M+H].sup.+ 427.3. found 409 [M−H.sub.2O].sup.+.

Example 27. Synthesis of Compound 26

[0330] ##STR00076##

[0331] To a solution of A10 (100 mg, 0.275 mmol) in THF (3 mL) was added (4-fluoro-3-methylphenyl)magnesium bromide (2.75 mL) at 25° C. for 2 hours, at which point the reaction was complete as shown by LC-MS. An aqueous solution of NH.sub.4Cl (5 mL) was added drop wise into the reaction mixture at 25° C., and extracted with EtOAc (10 mL×2). The combined organic solution was washed with brine (5 mL), dried over Na.sub.2SO.sub.4. The organic layer was filtered and concentrated under reduced pressure to give the crude mixture which was purified by HPLC to give 26 (47.5 mg) as a solid.

[0332] 1H NMR (CDCl.sub.3, 400 MHz) δ=7.83-7.70 (m, 2H), 7.06 (t, J=8.9 Hz, 1H), 3.46 (t, J=8.7 Hz, 1H), 2.48-2.31 (m, 4H), 1.89-1.73 (m, 5H), 1.71-1.60 (m, 2H), 1.61-1.60 (m, 1H), 1.54-1.45 (m, 3H), 1.43-1.33 (m, 7H), 1.33-1.24 (m, 6H), 1.22-1.05 (m, 2H), 1.03-0.88 (m, 1H), 0.62 (s, 3H). LCMS Rt=1.285 min in 2 min chromatography, 30-90 AB, MS ESI calcd, for C.sub.27H.sub.38FO.sub.2 [M+H].sup.+ 413. found 413.

Example 28. Synthesis of Compound 27

[0333] ##STR00077##

[0334] To a stirred solution of A30 (110 mg, 291 umol) in 3 mL of THF was added (3-fluoro-4-methylphenyl)magnesium bromide (0.5 M, 5.8 mL, 2.9 mmol) dropwise at 25° C. After stirring at 25° C. for 12 hrs, LCMS showed the reaction was complete. The reaction mixture was poured into ice-cold water and extracted with EtOAc (50 mL×2), washed with brine (30 mL×2), dried (Na.sub.2SO.sub.4), filtered, and evaporated in vacuo to give crude product. The reaction mixture was purified by HPLC separation (column: Phenomenex Synergi C18 150*25 10 um, gradient: 88-88% B (A=0.05% HCl-ACN, B=acetonitrile), flow rate: 25 mL/min) for further purification to obtain 27 (42.4 mg) as a solid.

[0335] .sup.1HNMR (CDCl.sub.3, 400 MHz): δ=7.48-7.61 (m, 2H), 7.20-7.26 (m, 1H), 3.41 (t, J=8.8 Hz, 1H), 2.37-2.44 (m, 1H), 2.33 (d, J=1.4 Hz, 3H), 1.97 (t, J=13.2 Hz, 1H), 1.87 (ddd, J=13.8, 9.3, 4.5 Hz, 1H), 1.65-1.80 (m, 3H), 1.33-1.56 (m, 12H), 1.22-1.29 (m, 5H), 0.99-1.18 (m, 3H), 0.92 (s, 3H), 0.58 (s, 3H). LCMS Rt=3.322 min in 4.0 min chromatography, 10-80 AB, MS ESI calcd. for C.sub.28H.sub.40FO.sub.2 [M+H]+ 427.3. found 409.1 ([M−H.sub.2O].sup.+.

Example 29. Synthesis of Compound 28

[0336] ##STR00078##

[0337] To a stirred solution of A30 (110 mg, 291 umol) in 3 mL of THF was added phenylmagnesium chloride (0.5 M; 5.8 mL, 2.9 mmol) dropwise at 25° C. After stirring at 25° C. for 12 hrs, LCMS showed the reaction was complete. The reaction mixture was poured into ice-cold water and extracted with EtOAc (50 mL×2), washed with brine (30 mL×2), dried (Na.sub.2SO.sub.4), filtered, and evaporated in vacuo to give crude product. The crude product was purified by HPLC separation (column: Gemini 150*25 5u, gradient: 69-94% B (A=0.05% HCl-ACN, B=acetonitrile), flow rate: 30 mL/min) for further purification to obtain 28 (48.4 mg, 291 μmol) as a solid.

[0338] .sup.1HNMR (CDCl.sub.3, 400 MHz): δ=7.88 (d, J=7.4 Hz, 1H), 7.50-7.58 (m, 1H), 7.39-7.48 (m, 2H), 3.50 (t, J=8.8 Hz, 1H), 2.36-2.52 (m, 1H), 1.98 (t, J=13.2 Hz, 1H), 1.85 (d, J=13.8 Hz, 1H), 1.74-1.81 (m, 2H), 1.68 (d, J=14.4 Hz, 1H), 1.32-1.55 (m, 13H), 1.21-1.29 (m, 5H), 0.99-1.17 (m, 3H), 0.91 (s, 3H), 0.60 (s, 3H). LCMS Rt=3.253 min in 4.0 min chromatography, 10-80 AB, MS ESI calcd. for C.sub.27H.sub.39O.sub.2[M+H].sup.+ 395.3. found 377.0 [M−H.sub.2O].sup.+.

Example 30. Synthesis of Compound 29

[0339] ##STR00079## ##STR00080##

Step 1.

[0340] Under nitrogen atmosphere, anhydrous THF (400 mL) was cooled to 10° C. and anhydrous LiCl (12.8 g, 304 mmol) was added in one portion. The mixture was stirred for 30 min after which a clear solution was obtained. To this mixture was added anhydrous FeCl.sub.3 (25.7 g, 159 mmol) in one portion. The resulting mixture was stirred for additional 30 min. The reaction mixture was cooled to −35° C. and methyl magnesium bromide (3 M in diethyl ether, 193 mL, 580 mmol) was added dropwise maintaining the internal temperature between −35° C. and −30° C. The above mixture was stirred for 30 min at −30° C. B4 (40 g, 145 mmol) was added in one portion. The internal temperature was allowed to −20° C. and kept between −15° C. and −20° C. for 2 hours. TLC showed the reaction was completed. The reaction mixture was quenched with aqueous HCl (2 M, 200 mL), extracted with CH.sub.2Cl.sub.2 (500 mL×2). The combined organic layer was washed with aqueous NaOH (10%, 300 mL×2) and brine (300 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was triturated from EtOAc to give B5 (25.0 g, 59.3%) as a solid.

[0341] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 2.44-2.40 (m, 1H), 2.09-2.00 (m, 1H), 1.89-1.57 (m, 7H), 1.54-1.03 (m, 16H), 0.87 (s, 3H), 0.73-0.70 (m, 2H).

Step 2.

[0342] To a solution of ethyltriphenylphosphonium bromide (152 g, 412 mmol) in THF (600 mL), was added a solution of t-BuOK (46.1 g, 412 mmol) at 25° C. The mixture was heated to 60° C. and stirred for 1 h. B5 (30.0 g, 103 mmol) was added. The mixture was stirred at 60° C. for 2 hrs. TLC showed the reaction was completed. The mixture was poured into Sat. aq NH.sub.4Cl (500 mL), extracted with EtOAc (300 mL×2). The combined organic phase was washed with brine (300 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, concentrated. The residue was purified by silica gel column (PE/EtOAc=100/1) to afford B6 (30 g, 96.4%) as a solid.

[0343] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 5.12-5.09 (m, 1H), 2.34-2.21 (m, 3H), 1.86-1.58 (m, 8H), 1.56-0.99 (m, 17H), 0.87 (s, 3H), 0.75-0.68 (m, 2H).

Step 3.

[0344] To a solution of B6 (40 g, 132 mmol) in THF (300 mL) was added dimethylsulfide borane (132 mL, 1.32 mol) dropwise at 0° C. The mixture was stirred at 25° C. for 12 hrs. TLC showed the reaction was complete. After cooling to 0° C., a solution of NaOH (220 mL, 3M) was added very slowly. After the addition was complete, H.sub.2O.sub.2 (150 mL, 33%) was added slowly and the inner temperature was maintained below 10° C. The resulting solution was stirred at 25° C. for 2 hrs. The resulting solution was filtered, and the filtrate was extract with EtOAc (500 mL×3). The combined organic solution was washed with saturated aqueous Na.sub.2S.sub.2O.sub.3 (500 mL×2), brine (500 mL), dried over Na.sub.2SO.sub.4 and concentrated in vacuum to give B7 (40 g, crude) as a solid. The crude product was used for the next step without further purification

Step 4.

[0345] To a solution of B7 (40 g, 124 mmol) and silica gel (44 g) in CH.sub.2Cl.sub.2 (400 mL) was added Pyridinium chlorochromate (53.4 g, 248 mmol) at 25° C. The mixture was stirred at 25° C. for 2 hrs. TLC showed the reaction was completed. The mixture was filtered and the filter cake was washed with CH.sub.2Cl.sub.2 (200 mL×2). The combined filtrate was concentrated in vacuum. The residue was purified by silica gel column (eluted with PE/EtOAc=10/1 to 1/1) to afford B8 (34 g, 86.2%) as a solid.

[0346] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 2.55-2.51 (m, 1H), 2.20-2.10 (m, 4H), 2.00-1.64 (m, 4H), 1.60-0.99 (m, 20H), 0.75-0.69 (m, 3H), 0.60 (s, 3H).

Step 5.

[0347] To a solution of B8 (10.0 g, 31.3 mmol) in dioxane/H.sub.2O (400 mL/120 mL) at 0° C. was added sodium hypobromide (1500 mL) [prepared from NaOH (163 g), dibromine (54.1 mL), dioxane (600 mL) and H.sub.2O (800 mL)]. The resulting mixture was stirred at 25° C. for 24 hours. After TLC showed the reaction was completed, sat. aq Na.sub.2S.sub.2O.sub.3 (400 mL) was added followed by aq HCl (450 mL, IM) was added into the mixture. The mixture was adjusted to pH=6 and the white solid was precipitated. The solid was filtered and the filter cake was washed with water (300 mL×2), dried in vacuum to give B9 (9.5, 95.0%) as a solid.

[0348] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 11.89 (br, 1H), 3.87 (s, 1H), 2.29-2.26 (m, 1H), 2.00-1.93 (m, 2H), 1.65-1.15 (m, 9H), 1.13-0.91 (m, 13H), 0.85-0.75 (m, 5H).

Step 6.

[0349] A mixture of B9 (12.2 g, 38.0 mmol), N,O-dimethylhydroxylamine hydrochloride (7.41 g, 76.0 mmol), HATU (17.3 g, 45.5 mmol) and Et.sub.3N (21.0 mL, 152 mmol) in 300 mL of anhydrous CH.sub.2Cl.sub.2 was stirred for 18 hrs at 25° C. TLC showed the reaction was completed. The mixture was treated with water (200 mL), extracted with CH.sub.2C.sub.2 (300 mL×2). The combined organic phase was washed aq. HCl (200 mL, 1M), sat. aq NaHCO.sub.3 (200 mL), and brine (300 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, concentrated in vacuum. The residue was purified by silica gel column (PE/EtOAc=5/1) to afford B10 (13.0 g, 94.2%) as a solid.

[0350] .sup.1H NMR (CDCl.sub.3, 400 MHz) δ 3.64 (s, 3H), 3.20 (s, 3H), 2.80 (br, 1H), 2.25-2.15 (m, 1H), 1.81-1.57 (m, 81H), 1.33-1.00 (m, 16H), 0.74 (s, 3H), 0.69-0.60 (m, 2H).

Step 7.

[0351] To a solution of B10 (100 mg, 275 umol) in THF (3 mL) was added (4-fluoro-3-methylphenyl)magnesium bromide (2.74 mL, 1.37 mmol) dropwise at 25° C. The mixture was stirred at 25° C. for 3 h. LCMS showed the reaction was complete. Then, the reaction was concentrated in vacuum. The residue was purified by prep-HPLC separation (column: Phenomenex Synergi C18 150*30 mm*4 um, gradient: 80-95% B (A=0.05% HCl-acetonitrile, B=acetonitrile), flow rate: 25 mL/min) for further purification to obtain 29 (46.9 mg) as a solid.

[0352] .sup.1HNMR (CDCl.sub.3, CDCl3 400 MHz): δ=7.69-7.80 (m, 2H), 7.04 (t, J=8.8 Hz, 1H), 3.45 (t, J=8.6 Hz, 2H), 2.37-2.43 (m, 1H), 2.33 (s, 3H), 1.56-1.79 (m, 8H), 1.26-1.42 (m, 6H), 1.20 (s, 3H), 0.97-1.16 (m, 6H), 0.65-0.79 (m, 2H), 0.61 (s, 3H). LCMS Rt=3.457 min in 4.0 min chromatography, 10-80 AB, MS ESI calcd. for C.sub.27H.sub.38FO.sub.2 [M+H]+ 413.28. found 413.2 [M+H].sup.+.

Example 31. Synthesis of Compound 30

[0353] ##STR00081##

[0354] To a stirred solution of B10 (100 mg, 275 umol) in 3 mL of THF was added (3,4-dimethylphenyl)magnesium chloride (0.5 M; 2.74 mL, 1.37 mmol) dropwise at 25° C. After stirring at 25° C. for 12 hrs, LCMS showed the reaction was complete. The reaction mixture was poured into ice-cold water and extracted with EtOAc (50 mL×2), washed with brine (30 mL×2), dried (Na.sub.2SO.sub.4), filtered, and evaporated in vacuum to give crude product. The crude product was purified by HPLC separation (column: Phenomenex Synergi C18 150*30 mm*4 um, gradient: 80-93% B (A=0.05% HCl-ACN, B=acetonitrile), flow rate: 25 mL/min) for further purification to obtain 30 (28 mg) as a solid.

[0355] .sup.1H NMR (CDCl.sub.3, 400 MHz): δ=7.68 (s, 1H), 7.62 (d, J=8.0 Hz, 1H), 7.18 (d, J=7.6 Hz, 1H), 3.48 (t, J=8.6 Hz, 1H), 2.28-2.46 (m, 7H), 1.63-1.78 (m, 6H), 1.25-1.55 (m, 8H), 1.20 (s, 3H), 0.86-1.18 (m, 7H), 0.65-0.77 (m, 2H), 0.61 (s, 3H). LCMS Rt=3.488 min in 4.0 min chromatography, 10-80 AB, MS ESI calcd. for C.sub.28H.sub.41O.sub.2[M+H]+ 409.3. found 409.1.

Example 32. Synthesis of Compound 31

[0356] ##STR00082##

[0357] To a stirred solution of A30 (100 mg, 264 umol) in 3 mL of THF was added (3,5-dimethylphenyl)magnesium bromide (0.5 M, 2.62 mL, 1.31 mmol) dropwise at 25° C. After stirring at 25° C. for 12 hrs, LCMS showed the reaction was complete. The reaction mixture was poured into ice-cold water and extracted with EtOAc (50 mL×2), washed with brine (30 mL×2), dried (Na.sub.2SO.sub.4), filtered, and evaporated in vacuo to give crude product. The crude product was purified by HPLC separation (column: Phenomenex Synergi C18 150*30 mm*4 um, gradient: 80-100% B (A=0.05% HCl-ACN, B=acetonitrile), flow rate: 30 mL/min) to obtain 31 (15.3 mg) as a solid.

[0358] .sup.1HNMR (CDCl.sub.3, 400 MHz): δ=7.46 (s, 2H), 7.16 (s, 1H), 3.46 (t, J=8.8 Hz, 1H), 2.36 (s, 7H), 1.97 (t, J=13.2 Hz, 1H), 1.82-1.89 (m, 1H), 1.74 (br. s., 4H), 1.31-1.51 (m, 9H), 1.20-1.31 (m, 6H), 0.97-1.20 (m, 4H), 0.91 (s, 3H), 0.58 (s, 3H). LCMS Rt=3.478 min in 4.0 min chromatography, 10-80 AB, MS ESI calcd. for C.sub.29H.sub.43O.sub.2 [M+H].sup.+ 423.3. found 405.1 [M−H.sub.2O].sup.+.

Example 33. Synthesis of Compound 32

[0359] ##STR00083##

[0360] To a stirred solution of 4-bromo-N,N-dimethylaniline (1.3 M, 1.92 mL, 2.50 mmol) was added tert-butyllithium dropwise at −78° C. After stirring at −78° C. for 2 hrs, A10 (100 mg, 0.264 mmol was added. The mixture was stirred at −78° C. for 1 hour. LCMS showed the reaction was complete. The reaction mixture was quenched with NH.sub.4Cl (30 mL). The mixture was extracted with EtOAc (20 mL×2), washed with brine (30 mL), dried over (Na.sub.2SO.sub.4), filtered, and evaporated in vacuo to give crude product. The crude product was purified by HPLC separation (column: Boston Green ODS 150*30 5u, gradient: 85-100% B (A=0.05% HCl-ACN, B=acetonitrile), flow rate: 25 ml/min) for further purification to afford 32 (11.9 mg) as a solid.

[0361] .sup.1HNMR (CDCl.sub.3, 400 MHz): δ=7.87 (d, J=9.0 Hz, 2H), 6.65 (d, J=9.0 Hz, 2H), 3.46 (t, J=8.6 Hz, 1H), 3.06 (s, 6H), 2.38-2.51 (m, 1H), 1.78-1.90 (m, 3H), 1.69-1.77 (m, 2H), 1.58-1.67 (m, 2H), 1.29-1.57 (m, 12H), 1.27 (s, 4H), 1.05-1.18 (m, 2H), 0.89-1.01 (m, 1H), 0.62 (s, 3H).

[0362] LCMS Rt=2.443 min in 4.0 min chromatography, 30-90 AB, MS ESI calcd. for C.sub.28H.sub.42NO.sub.2 [M+H]+424.31. found 424.1.

Example 34. Synthesis of Compound 33

[0363] ##STR00084##

[0364] To a stirred solution of 1-bromo-4-methoxy-2-methylbenzene (2.5 M; 0.524 mL, 1.31 mmol) was added tert-butyllithium dropwise at −78° C. After stirring at −78° C. for 2 hrs, A30 (100 mg, 0.264 mmol was added. The mixture was stirred at −78° C. for 1 hour. LCMS showed the reaction was complete. The reaction mixture was quenched with NH.sub.4Cl (30 mL). The mixture was extracted with EtOAc (20 mL×2), washed with brine (30 mL), dried over (Na.sub.2SO.sub.4), filtered, and evaporated under vacuo to give crude product. The crude product was purified by HPLC separation (column: Phenomenex Synergi C18 150*30 mm*4 um, gradient: 75-100% B (A=0.05% HCl-ACN, B=acetonitrile), flow rate: 30 mL/min) to afford 33 (13.5 mg) as a solid.

[0365] .sup.1HNMR (CDCl.sub.3, 400 MHz): δ=7.53 (d, J=8.0 Hz, 1H), 6.69-6.75 (m, 2H), 3.83 (s, 3H), 3.49 (d, J=5.6 Hz, 1H), 3.33 (t, J=8.8 Hz, 1H), 2.46 (s, 3H), 2.34-2.40 (m, 1H), 1.93-1.98 (m, 1H), 1.63-1.76 (m, 4H), 1.32-1.50 (m, 8H), 1.22-1.30 (m, 7H), 0.96-1.17 (m, 5H), 0.87-0.92 (m, 3H), 0.60 (s, 3H) LCMS Rt=3.478 min in 3.0 min chromatography, 30-90 CD. MS ESI calcd. for C.sub.29H.sub.43O.sub.3 [M+H].sup.+ 439.31. found 439.3.

Example 35. Synthesis of Compound 34

[0366] ##STR00085##

[0367] To a stirred solution of 1-bromo-4-(trifluoromethoxy)benzene (330 mg, 1.37 mmol) in 3 mL of THF was added tert-butyllithium (1.3 M; 2.0 mL, 2.61 mmol) dropwise at −78° C. After stirring at −78° C. for 2 hrs, A10 (100 mg, 0.275 mmol) was added. The mixture was stirred at −78° C. for 1 hour. LCMS showed the reaction was complete. The reaction mixture was quenched with NH.sub.4Cl (30 mL). The mixture was extracted with EtOAc (20 mL×2), washed with brine (30 mL), dried over (Na.sub.2SO.sub.4), filtered, and evaporated in vacuo to give crude product. The crude product was purified by HPLC separation (column: Phenomenex Synergi C18 150*30 mm*4 um, gradient: 80-100% B (A=0.05% HCl-ACN, B=acetonitrile), flow rate: 30 mL/min) to obtain 34 (57 mg) as a solid.

[0368] .sup.1H NMR (CDCl.sub.3, 400 MHz): δ=7.93 (d, J=8.6 Hz, 2H), 7.26-7.29 (m, 2H), 3.45 (t, J=8.8 Hz, 1H), 2.37-2.46 (m, 1H), 1.73-1.86 (m, 5H), 1.58-1.65 (m, 2H), 1.41-1.50 (m, 3H), 1.37 (d, J=12.6 Hz, 6H), 1.24-1.33 (m, 7H), 1.06-1.17 (m, 2H), 0.87-0.97 (m, 1H), 0.60 (s, 3H). LCMS Rt=3.467 min in 4.0 min chromatography, 10-80 AB, MS ESI calcd. for C.sub.27H.sub.36F.sub.3O.sub.3 [M+H].sup.+ 465.26. found 447.2 [M−H.sub.2O].sup.+.

Example 36. Synthesis of Compound 35

[0369] ##STR00086##

[0370] To a solution of A10 (100 mg, 0.275 mmol) in THF (3 mL) was added benzo[d][1,3]dioxol-5-yl magnesium bromide (5.5 mL, 95%). The mixture was stirred at 20° C. for 3.5 h. When TLC showed starting material was consumed and new spot was produced, to the mixture was added sat. aq. NH.sub.4Cl (5 mL). The organic phase was extracted with DCM (5 mL*2), washed with sat. aq. NaCl (8 mL×2), concentrated in vacuum. The residue was purified by preparative HPLC to give 35 (30 mg) as a solid.

[0371] .sup.1H NMR (400 MHz, CDCl.sub.3) δ7.49 (dd, J=1.6, 8.2 Hz, 1H), 7.40 (d, J=1.5 Hz, 1H), 6.83 (d, J=8.0 Hz, 1H), 6.03 (s, 2H), 3.40 (t, J=8.5 Hz, 1H), 2.47-2.35 (m, 1H), 1.82-1.73 (m, 4H), 1.66-1.58 (m, 2H), 1.50-1.25 (m, 17H), 1.19-0.87 (m, 3H), 0.60 (s, 3H). LCMS Rt=1.391 min in 2 min chromatography, 10-80 AB, MS ESI calcd. for C.sub.27H.sub.37O.sub.4 [M+H].sup.+ 425.26. found 407 [M−H.sub.2O].sup.+.

Example 37. Synthesis of Compound 36

[0372] ##STR00087##

Step 1.

[0373] The mixture of A26 (40 g, 127 mmol) and Pd/C (4 g) in ethyl acetate (200 mL) and THF (200 mL) was stirred at 25° C. under H (15 psi) for 4 hours. TLC (PE:EA=5:1) showed the starting material was consumed completely. The reaction mixture was filtered, and the filtered cake was washed with ethyl acetate (40 mL×5). The combined organic phase was concentrated under vacuum to give A27 (41 g, crude) as a solid

[0374] .sup.1H NMR (400 MHz, CDCl.sub.3) δ=2.69 (t, J=14.1 Hz, 1H), 2.61-2.48 (m, 1H), 2.43-2.25 (m, 1H), 2.24-1.96 (m, 8H), 1.95-1.78 (m, 2H), 1.75-1.07 (m, 15H), 1.03 (s, 3H), 0.64 (s, 3H)

Step 2.

[0375] To a solution of 2,6-di-tert-butyl-4-methylphenol (170 g, 774 mmol) in toluene (150 mL) was added trimethylaluminum (193 mL, 387 mmol, 2.0 M in toluene) drop-wise blew 25° C. under N.sub.2 atmosphere. The resulting mixture was stirred at 25° C. for 1 hour. A27 (41 g, 129 mmol) in toluene (50 mL) was added at −78° C. The mixture was stirred at −78° C. for 1 hour. Methylmagnesium bromide (129 mL, 387 mmol, 3.0 M in diethyl ether) was added at −78° C. The reaction mixture was stirred at −78° C. for 4 hours. TLC (PE:EA=2:1) showed the starting material was consumed completely. The mixture was quenched by saturated aqueous NH.sub.4Cl (20 mL), extracted with ethyl acetate (150 mL×2). The combined organic phase was washed with brine (150 mL), dried over anhydrous Na.sub.2SO.sub.4. The ethyl acetate solvent was evaporated to afford crude solid, which was purified by chromatography on silica gel (PE/EtOAc=7/1) to afford desired product A28 (36 g) as light solid.

[0376] .sup.1H NMR (400 MHz, CDCl.sub.3) δ=2.58-2.46 (m, 1H), 2.22-2.09 (m, 4H), 2.06-1.79 (m, 3H), 1.78-0.99 (m, 25H), 0.94 (s, 3H), 0.59 (s, 3H).

Step 3.

[0377] Liquid bromine (5.76 g, 36.0 mmol) was added slowly to a vigorously stirred sodium hydroxide aqueous (48.0 mL, 3 M, 144 mmol) at 0° C. When all the bromine was dissolved, the mixture was diluted with cold dioxane (10 mL) and was added slowly to a stirred solution of 1 A28 (4 g, 12.0 mmol) in dioxane (15 mL) and water (10 mL). The homogeneous yellow solution became colorless slowly and a white precipitate was formed. The reaction mixture was stirred at 25° C. for 16 hours. The remaining oxidizing reagent was quenched by Na.sub.2S.sub.2O.sub.3 aqueous (30 mL) and the mixture was then heated at 80° C. until the solid material was dissolved. Acidification of the solution with hydrochloride acid (3 N) furnished a white precipitate. The solid was filtered and washed with water (100 mL×3) to give a white solid, which was dried under vacuum to afford A29 (4.01 g, 100%) as a solid.

[0378] .sup.1H NMR (400 MHz, CDCl.sub.3) δ=11.90 (br. s, 1H), 4.24 (s, 1H), 2.28 (t, J=9.0 Hz, 1H), 2.01-1.54 (m, 8H), 1.50-1.28 (m, 6H), 1.26-0.92 (m, 13H), 0.91 (s, 3H), 0.61 (s, 3H) Step 4. To a suspension of A29 (4.01 g, 11.9 mmol) and N,O-dimethylhydroxylamine hydrochloride (4.64 g, 47.6 mmol) in DMF (40 mL) was added HATU (9.04 g, 23.8 mmol) at 25° C. DIPEA (15.3 g, 119 mmol) was added to the resulting mixture. The reaction mixture was stirred at 25° C. for 2 hours. TLC (PE:EA=2:1) showed the starting material was consumed completely. H.sub.2O (500 mL) was added to the reaction mixture at 25° C. A precipitate in the mixture was filtrated to give a light solid, which was washed with water (40 mL×3), dried under vacuum to afford A30 (4.31 g, 95.9%) as a solid.

[0379] .sup.1H NMR (400 MHz, CDCl.sub.3) δ=11.90 (br. s., 1H), 4.24 (s, 1H), 2.28 (t, J=9.0 Hz, 1H), 2.01-1.54 (m, 8H), 1.50-1.28 (m, 6H), 1.26-0.92 (m, 13H), 0.91 (s, 3H), 0.61 (s, 3H)

Step 5.

[0380] To a solution of B30 (0.1 g, 0.264 mmol) in THF (2 mL) was added phenylmagnesium chloride (5.26 mL, 2.63 mmol, 0.5M in THF) under N.sub.2. The reaction mixture was stirred at 15° C. for 16 hours. LCMS indicated the reaction was finished and desired MS peak was found. To the reaction mixture was added saturated NH.sub.4Cl solution (5 mL) and then extracted with EtOAc (2 mL×3). The combined organic phase was concentrated and purified by prep-HPLC to give 36 (20.6 mg) as a solid.

[0381] .sup.1H NMR (400 MHz, CDCl.sub.3) δ7.88-7.86 (m, 2H), 7.54-7.51 (m, 1H), 7.45-7.41 (m, 2H), 3.50-3.46 (m, 1H), 2.45-2.38 (m, 1H), 1.80-0.72 (m, 25H), 0.70 (s, 3H), 0.59 (s, 3H). LCMS Rt=1.466 min in 2 min chromatography, 10-80 AB, MS ESI calcd. for C.sub.27H.sub.39O.sub.2[M+H].sup.+ 395.29. found 377 [M−H.sub.2O].sup.+.

Example 38. Synthesis of Compound 37

[0382] ##STR00088##

[0383] To a solution of B30 (0.1 g, 0.264 mmol) in THF (2 mL) was added (3,5-difluorophenyl)magnesium bromide (5.26 mL, 2.63 mmol, 0.5M in THF) under N.sub.2. The reaction mixture was stirred at 15° C. for 16 hours. LCMS indicated the reaction was finished and desired MS peak was found. To the reaction mixture was added saturated NH.sub.4Cl solution (5 mL) and then extracted with EtOAc (2 mL×3). The combined organic phase was concentrated and purified by prep-HPLC to give 37 (14.2 mg) as a solid.

[0384] .sup.1H NMR (400 MHz, CDCl3) δ7.37 (d, J=6.0 Hz, 2H), 7.04-6.89 (m, 1H), 3.40-3.28 (m, 1H), 2.47-2.30 (m, 1H), 1.87-1.65 (m, 3H), 1.19 (s, 19H), 0.72 (s, 4H), 0.59 (s, 3H). LCMS Rt=1.540 min in 2 min chromatography, 10-80 AB, MS ESI calcd. for C.sub.27H.sub.37F.sub.2O.sub.2 [M+H].sup.+ 431.27. found 413 [M−H.sub.2O].sup.+.

Example 39. Synthesis of Compound 38

[0385] ##STR00089##

[0386] To a solution of B30 (0.1 g, 0.264 mmol) in THF (2 mL) was added (4-fluoro-3-methylphenyl)magnesium bromide (5.26 mL, 2.63 mmol, 0.5M in THF) under N.sub.2. The reaction mixture was stirred at 15° C. for 1.5 hours. LCMS indicated the reaction was finished and desired MS peak was found. To the reaction mixture was added saturated NH.sub.4Cl solution (5 mL) and then extracted with EtOAc (2 mL×3). The combined organic phase was concentrated and purified by prep-HPLC to give 38 (38.6 mg) as a solid.

[0387] .sup.1H NMR (400 MHz, CDCl3) δ7.76-7.68 (m, 2H), 7.05-7.00 (m, 2H), 3.44-3.40 (m, 1H), 2.40-2.31 (m, 4H), 1.80-1.65 (m, 3H), 1.60-0.72 (m, 22H), 0.72 (s, 3H), 0.58 (s, 3H). LCMS Rt=1.534 min in 2 min chromatography, 10-80 AB, MS ESI calcd. for C.sub.28H.sub.40FO.sub.2 [M+H].sup.+ 427. found 427.

Example 40. Synthesis of Compound 39

[0388] ##STR00090##

[0389] To a solution of B30 (0.1 g, 0.264 mmol) in THF (2 mL) was added (3,4-dimethylphenyl)magnesium chloride (5.26 mL, 2.63 mmol, 0.5M in THF) under N.sub.2. The reaction mixture was stirred at 15° C. for 4 hours. LCMS indicated the reaction was finished and desired MS peak was found. To the reaction mixture was added saturated NH.sub.4Cl solution (5 mL) and then extracted with EtOAc (2 mL×3). The combined organic phase was concentrated and purified by prep-HPLC to give 39 (27.8 mg) as a solid.

[0390] .sup.1H NMR (400 MHz, CDCl3) δ7.69-7.65 (m, 1H), 7.64-7.58 (m, 1H), 7.22-7.15 (m, 1H), 3.50-3.41 (m, 1H), 2.46-2.35 (m, 1H), 2.31 (s, 6H), 1.81-1.66 (m, 3H), 1.61-1.05 (m, 20H), 1.04-0.89 (m, 1H), 0.82-0.73 (m, 1H), 0.71 (s, 3H), 0.59 (s, 3H). LCMS Rt=1.536 min in 2 min chromatography, 10-80 AB, MS ESI calcd. for C.sub.29H.sub.43O.sub.2[M+H].sup.+ 423. found 423.

Example 41. Synthesis of Compound 40

[0391] ##STR00091##

[0392] To a stirred solution of 4-bromo-N,N-dimethylaniline (262 mg, 1.31 mmol) in 3 mL of THF was added tert-butyllithium (1.3 M; 1.92 mL, 2.50 mmol) dropwise at −78° C. After stirring at −78° C. for 2 hrs, A30 (100 mg, 0.264 mmol was added. The mixture was stirred at −78° C. for 1 hour. LCMS showed the reaction was complete. The reaction mixture was quenched with NH.sub.4Cl (30 mL). The mixture was extracted with EtOAc (20 mL×2), washed with brine (30 mL), dried over (Na.sub.2SO.sub.4), filtered, and evaporated in vacuo to give crude product. The crude product was purified by HPLC separation (column: Phenomenex Synergi C18 150*30 mm*4 um, gradient: 75-100% B (A=0.05% HCl-ACN, B=acetonitrile), flow rate: 30 mL/min) for further purification to obtain 40 (11.2 mg) as a solid.

[0393] .sup.1HNMR (CDCl.sub.3, 400 MHz): δ=7.86 (d, J=9.0 Hz, 2H), 6.64 (d, J=9.0 Hz, 2H), 3.44 (t, J=8.6 Hz, 1H), 3.05 (s, 6H), 2.39-2.45 (m, 1H), 1.99 (d, J=12.0 Hz, 1H), 1.84 (d, J=13.6 Hz, 2H), 1.63-1.77 (m, 4H), 1.35-1.51 (m, 9H), 1.20-1.29 (m, 6H), 1.10-1.18 (m, 2H), 1.04 (dd, J=14.6 Hz, 1H), 0.91 (s, 3H), 0.59 (s, 3H). LCMS Rt=2.511 min in 4.0 min chromatography, 30-30 AB, MS ESI calcd. for C.sub.29H.sub.44NO.sub.2 [M+H]+ 438.33. found 438.1.

Example 42. Synthesis of Compound 41

[0394] ##STR00092##

[0395] To a solution of A10 (100 mg, 0.275 mmol) in THF (3 mL) was added (3-fluoro-4-methylphenyl)magnesium bromide (5.5 mL, 95%). The mixture was stirred at 20° C. for 3.5 h. When TLC showed starting material was consumed and new spot was produced, to the mixture was added sat. aq. NH.sub.4Cl (5 mL). The organic phase was extracted with DCM (5 mL×2), washed with sat. aq. NaCl (8 mL×2), concentrated in vacuum. The residue was purified by preparative. HPLC twice to give 41 (58 mg) as a solid.

[0396] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.59-7.49 (m, 2H), 7.25-7.20 (m, 1H), 3.41 (t, J=8.8 Hz, 1H), 2.47-2.36 (m, 1H), 2.32 (d, J=1.5 Hz, 3H), 1.82-1.75 (m, 4H), 1.69-1.57 (m, 2H), 1.50-1.25 (m, 17H), 1.18-1.04 (m, 2H), 1.00-0.84 (m, 1H), 0.60 (s, 3H). LCMS Rt=1.476 min in 2 min chromatography, 10-80 AB, MS ESI calcd. for C.sub.27H.sub.37F.sub.2O [M+H].sup.+ 413.28. found 395 [M−H.sub.2O].sup.+.

Example 43. Synthesis of Compound 42

[0397] ##STR00093##

[0398] To a solution of 1-bromo-4-ethylbenzene (305 mg, 1.65 mmol) in THF (3 mL) was added butyllithium (0.66 mL, 0.825 mmol) dropwise at −68° C. The mixture was stirred at −68 OC for 2 h. A10 (120 mg, 0.33 mmol) in 1 mL THF was added dropwise at −68° C. The reaction was stirred at −68 OC for 2 hours. LCMS showed the reaction was complete. The reaction was quenched with NH.sub.4Cl (20 mL), extracted with EtOAc (20 mL×2). The combined organic layers were washed with brine (10 mL). The organic layer was dried over Na.sub.2SO.sub.4, filtered and evaporated to afford crude product. The crude product was purified by prep-HPLC to give 42 (46.4 mg, 0.113 mmol) as a solid.

[0399] .sup.1H NMR (400 MHz, CDCl.sub.3) δ=7.82 (d, J=8.0 Hz, 2H), 7.25 (s, 1H), 3.49 (t, J=8.8 Hz, 1H), 2.70 (q, J=7.7 Hz, 2H), 2.48-2.38 (m, 1H), 1.87-1.69 (m, 5H), 1.69-1.55 (m, 2H), 1.54-1.41 (m, 4H), 1.41-1.34 (m, 5H), 1.34-1.21 (m, 11H), 1.20-1.01 (m, 2H), 1.00-0.84 (m, 1H), 0.61 (s, 3H). LCMS t.sub.R=1.299 min in 2 min chromatography, 30-90 AB, MS ESI calcd. for C.sub.28H.sub.40O.sub.2 [M].sup.+ 408. found 408.

Example 44. Synthesis of Compound 43

[0400] ##STR00094##

[0401] To a stirred solution of 1-bromo-4-methoxy-2-methylbenzene (275 mg, 1.37 mmol) in 3 mL of THF was added tert-butyllithium (1.3 M, 2.00 mL, 2.61 mmol) dropwise at −78° C. After stirring at −78° C. for 2 hrs, A10 (100 mg, 0.275 mmol was added. The mixture was stirred at −78° C. for 1 hour. LCMS showed the reaction was complete. The reaction mixture was quenched with NH.sub.4Cl (30 mL). The mixture was extracted with EtOAc (20 mL×2), washed with brine (30 mL), dried over (Na.sub.2SO.sub.4), filtered, and evaporated in vacuum to give crude product. The crude product was purified by HPLC separation (column: Phenomenex Synergi C18 150*30 mm*4 um, gradient: 70-100% B (A=0.05% HCl-ACN, B=acetonitrile), flow rate: 30 mL/min) for further purification to obtain 42 (20 mg) as a solid.

[0402] .sup.1HNMR (CDCl3, 400 MHz): δ=7.54 (d, J=8.6 Hz, 1H), 6.68-6.77 (m, 2H), 3.83 (s, 3H), 3.34 (t, J=8.8 Hz, 1H), 2.47 (s, 3H), 2.34-2.42 (m, 1H), 1.69-1.85 (m, 5H), 1.57-1.68 (m, 2H), 1.22-1.50 (m, 14H), 0.97-1.22 (m, 4H), 0.86-0.93 (m, 1H), 0.62 (s, 3H). LCMS Rt=2.600 min in 4.0 min chromatography, 30-90 AB, MS ESI calcd. for C.sub.28H.sub.41O.sub.3[M+H]+ 425.3. found 425.2.

Example 45. Synthesis of Compound 44

[0403] ##STR00095##

[0404] To a solution of A10 (150 mg, 0.412 mmol) in THF (3 mL) was added [1,1′-biphenyl]-4-yl magnesium bromide (8.22 mL, 0.5 M in THF). The mixture was stirred at 20° C. for 3.5 h. When TLC showed starting material was consumed and new spot was produced, to the mixture was added sat. aq. NH.sub.4Cl (5 mL). The organic phase was extracted with DCM (5 mL*2), washed with sat. aq. NaCl (8 mL*2), concentrated in vacuum. The residue was purified by prep. HPLC to give 44 (113 mg) as a solid.

[0405] .sup.1H NMR (400 MHz, CDCl.sub.3) δ7.96 (d, J=8.3 Hz, 2H), 7.69-7.61 (m, 411), 7.50-7.44 (m, 2H), 7.42-7.36 (m, 1H), 3.53 (t, J=8.7 Hz, 1H), 2.52-2.37 (m, 1H), 1.79 (d, J=10.3 Hz, 5H), 1.68-1.61 (m, 1H), 1.51-0.88 (m, 20H), 0.63 (s, 3H). LCMS Rt=1.081 min in 1.5 min chromatography, 5-95 AB, MS ESI calcd. for C.sub.32H.sub.41O.sub.2[M+H].sup.+ 457.3. found 439[M−H.sub.2O].sup.+.

Example 46. Synthesis of Compound 45

[0406] ##STR00096##

[0407] To a solution of B30 (0.1 g, 0.264 mmol) in THF (2 mL) was added (3-fluoro-4-methylphenyl)magnesium bromide (5.26 mL, 2.63 mmol, 0.5M in THF) under N.sub.2. The reaction mixture was stirred at 15° C. for 16 hours. LCMS indicated the reaction was finished and desired MS peak was found. To the reaction mixture was added saturated NH.sub.4Cl solution (5 mL) and then extracted with EtOAc (2 mL×3). The combined organic phase was concentrated and purified by prep-HPLC to give 45 (22.7 mg) as a solid.

[0408] .sup.1H NMR (400 MHz, CDCl3) δ7.64-7.47 (m, 2H), 7.25-7.17 (m, 1H), 3.47-3.36 (m, 1H), 3.10-2.91 (m, 2H), 2.32 (s, 4H), 1.87-1.06 (m, 21H), 1.04-0.90 (m, 1H), 0.71 (s, 4H), 0.58 (s, 3H). LCMS Rt=1.541 min in 2 min chromatography, 10-80 AB, MS ESI calcd. for C.sub.28H.sub.40FO.sub.2 [M+H].sup.+ 427. found 409 [M−H.sub.2O].sup.+.

Example 47. Synthesis of Compound 46

[0409] ##STR00097##

[0410] To a stirred solution of 2-bromo-3-methylthiophene (242 mg, 1.37 mmol) in 3 mL of THF was added tert-butyllithium (1.3 M: 2.00 mL, 2.61 mmol) dropwise at −78° C. After stirring at −78° C. for 2 hrs. A10 (100 mg, 0.275 mmol was added. The mixture was stirred at −78° C. for 1 hour. LCMS showed the reaction was complete. The reaction mixture was quenched with NH.sub.4Cl (30 mL). The mixture was extracted with EtOAc (20 mL×2), washed with brine (30 mL), dried over (Na2SO4), filtered, and evaporated in vacuum to give crude product. The crude product was purified by HPLC separation (column: Phenomenex Synergi C18 150*30 mm*4 um, gradient: 80-100% B (A=0.05% HCl-ACN, B=acetonitrile), flow rate: 30 mL/min) for further purification to obtain 46 (10 mg) as a solid.

[0411] .sup.1HNMR (CDCl3, 400 MHz): δ=7.37 (d, J=5.0 Hz, 1H), 6.97 (d, 1=5.0 Hz, 1H), 3.16 (t, J=8.8 Hz, 1H), 2.57 (s, 3H), 2.31-2.42 (m, 1H), 1.72-1.87 (m, 5H), 1.65 (d, J=13.6 Hz, 2H), 1.32-1.56 (m, 12H), 1.28 (s, 4H), 1.08-1.21 (m, 2H), 0.93-1.06 (m, 1H), 0.71 (s, 3H). LCMS Rt=2.591 min in 4.0 min chromatography, 30-90 AB, MS ESI calcd. for C.sub.25H.sub.37O.sub.2S [M+H]+ 401.24. found 401.1.

Example 48. Synthesis of Compound 47

[0412] ##STR00098##

[0413] To a stirred solution of 1-bromo-4-(trifluoromethoxy)benzene (315 mg, 1.31 mmol) in 3 mL of THF was added tert-butyllithium (1.3 M; 1.92 mL, 2.5 mmol) dropwise at −78° C. After stirring at −78° C. for 2 hrs, A30 (100 mg, 0.264 mmol was added. The mixture was stirred at −78° C. for 1 hour. LCMS showed the reaction was complete. The reaction mixture was quenched with NH4Cl (30 mL). The mixture was extracted with EtOAc (20 mL×2), washed with brine (30 mL), dried over (Na.sub.2SO.sub.4), filtered, and evaporated in vacuo to give crude product. The crude product was purified by HPLC separation (column: Phenomenex Synergi C18 150*30 mm*4 um, gradient: 80-100% B (A=0.05% HCl-ACN, B=acetonitrile), flow rate: 30 mL/min) for further purification to obtain 47 (19.3 mg) as a solid.

[0414] .sup.1HNMR (CDCl.sub.3, 400 MHz): δ=7.92 (d, J=8.0 Hz, 1H), 7.25 (d, J=7.0 Hz, 2H), 3.43 (br s, 1H), 2.31-2.47 (m, 1H), 1.62-2.01 (m, 6H), 1.32-1.53 (m, 11H), 1.19-1.30 (m, 6H), 0.97-1.17 (m, 3H), 0.90 (br. s., 3H), 0.57 (br. s., 3H). LCMS Rt=2.907 min in 4.0 min chromatography, 30-90 AB, MS ESI calcd. for C.sub.28H.sub.38F.sub.3O.sub.3 [M+H].sup.+ 479.3. found 461.2 [M−H.sub.2O].sup.+.

Example 49. Synthesis of Compound 48

[0415] ##STR00099##

[0416] To a solution of A30 (100 mg, 264 μmol) in anhydrous THF (2 mL) was added (4-(methylthio)phenyl)magnesium bromide (5.26 mL, 0.5 M, 2.63 mmol) at 25° C. The reaction mixture was stirred at 25° C. for 2 hours. LCMS showed the starting material was consumed completely. The reaction was quenched with saturated NH.sub.4Cl aqueous (1 mL), concentrated under vacuum to give a residue, which was purified by Prep-HPLC (0.05% HCl-ACN) to afford 48 (65.4 mg) as a solid.

[0417] .sup.1H NMR (400 MHz, CDCl.sub.3) δ=7.81 (d, J=8.0 Hz, 2H), 7.24 (s, 1H), 3.44 (t, J=8.8 Hz, 1H), 2.52 (s, 3H), 2.48-237 (m, 1H), 2.04-1.92 (m, 1H), 1.91-1.81 (m, 1H), 1.79-1.64 (m, 3H), 1.54-1.19 (m, 17H), 1.18-0.97 (m, 3H), 0.91 (s, 3H), 0.58 (s, 3H). LCMS R.sub.t=1.441 min in 2 min chromatography, 10-80 AB, MS ESI calcd for C.sub.28H.sub.41O.sub.2S [M+H].sup.+ 441.3. found 441.3 [M+H].sup.+.

Example 50. Synthesis of Compound 49

[0418] ##STR00100##

[0419] A solution of 1-bromo-4-ethylbenzene (366 mg, 1.98 mmol) in THF (3 mL) was added butyllithium (0.792 mL, 1.98 mmol) dropwise at −78° C. The mixture was stirred at −78° C. for 2 h. A30 in 1 mL THF was added dropwise at −78° C. The reaction was stirred at −78° C. for 2 hours. LCMS showed the reaction was complete. Then, the reaction was quenched with NH.sub.4Cl (20 mL). Extracted with EtOAc (20 mL×2) The combined organic layers were washed with brine (10 mL). The organic layer was dried over Na.sub.2SO.sub.4, filtered and evaporated to afford crude product. The crude product was purified by prep-HPLC separation (column: Phenomenex Synergi C18 150*30 mm*4 um, gradient: 85-100% B (A=0.05% HCl-ACN, B=acetonitrile), flow rate: 30 mL/min) for further purification to obtain 49 (69.9 mg) as a solid.

[0420] .sup.1HNMR (CDCl.sub.3, 400 MHz): δ=7.82 (d, J=8.0 Hz, 2H), 7.25 (br s, 1H), 3.48 (t, J=8.8 Hz, 1H), 2.70 (q, J=7.6 Hz, 2H), 2.37-2.48 (m, 1H), 1.93-2.03 (m, 1H), 1.81-1.91 (m, 1H), 1.64-1.79 (m, 3H), 1.31-1.55 (m, 11H), 1.18-1.30 (m, 8H), 0.92-1.18 (m, 4H), 0.91 (s, 3H), 0.59 (s, 3H). LCMS Rt=3.492 min in 4.0 min chromatography, 10-80 AB, MS ESI calcd. for C.sub.29H.sub.43O.sub.2 [M+H].sup.+423.32. found 405.1 [M−H.sub.2O].sup.+.

Example 51. Synthesis of Compound 50

[0421] ##STR00101##

[0422] A solution of 1-bromo-2-methoxybenzene (514 mg, 2.75 mmol) in THF (3 mL) was added t-butyllithium (3.80 mL, 4.94 mmol) dropwise at −78° C. The mixture was stirred at −78° C. for 2 h. A10 (100 mg, 2.75 mmol) in THF (1 mL) was added dropwise at −78° C. The reaction was stirred at 15° C. for 2 hours. TLC showed the reaction was complete. The reaction was quenched with Sat. NH.sub.4Cl (20 mL) and extracted with EtOAc (20 mL×2). The combined organic layers were washed with brine (10 mL). The organic layer was dried over Na.sub.2SO.sub.4, filtered and evaporated to afford crude product, which was purified by prep-HPLC to afford 50 (68 mg) as a solid.

[0423] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.30-7.44 (m, 2H) 6.88-7.00 (m, 2H) 3.85 (s, 3H) 3.54 (t, J=8.91 Hz, 1H) 2.27-2.42 (m, 1H) 1.53-1.89 (m, 8H) 0.96-1.52 (m, 20H) 0.79-0.92 (m, 1H) 0.61 (s, 3H). LCMS Rt=1.593 min in 2.0 min chromatography, 50-100 AB, MS ESI calcd. for C.sub.27H.sub.39O.sub.3 [M+H].sup.+ 411. found 411.

Example 52. Synthesis of Compound 51

[0424] ##STR00102##

[0425] A solution of 1-bromo-4-chlorobenzene (503 mg, 2.63 mmol) in THF (3 mL) was added t-butyllithium (3.65 mL, 4.75 mmol) dropwise at −78° C. The mixture was stirred at −78° C. for 2 h. A30 (100 mg, 2.75 mmol) in THF (1 mL) was added dropwise at 15° C. The reaction was stirred at 15° C. for 2 hours. TLC showed the reaction was complete. The reaction was quenched with Sat. NH.sub.4Cl (20 mL) and extracted with EtOAc (20 mL×2). The combined organic layers were washed with brine (10 mL), dried over Na.sub.2SO.sub.4, filtered and evaporated to afford crude product, which was purified by prep-HPLC to afford 51 (38 mg) as a solid.

[0426] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.82 (d, J=8.53 Hz, 2H) 7.41 (d, J=8.53 Hz, 2H) 3.43 (t, J=8.78 Hz, 1H) 2.33-2.49 (m, 1H) 1.91-2.05 (m, 1H) 1.63-1.91 (m, 4H) 1.28-1.60 (m, 15H) 0.98-1.28 (m, 10H) 0.91 (s, 3H) 0.58 (s, 3H). LCMS Rt=0.976 min in 2.0 min chromatography, 50-100 AB, MS ESI calcd. for C.sub.27H.sub.38ClO.sub.2 [M].sup.+ 430. found 429 [M].sup.+.

Example 53. Synthesis of Compound 52

[0427] ##STR00103##

[0428] A solution of 1-bromo-4-chlorobenzene (526 mg, 2.75 mmol) in THF (3 mL) was added t-butyllithium (3.80 mL, 4.94 mmol) dropwise at −78° C. The mixture was stirred at −78° C. for 2 hrs. A10 (100 mg, 2.75 mmol) in THF (1 mL) was added dropwise at 15° C. The reaction was stirred at 15° C. for 2 hours. TLC showed the reaction was complete. The reaction was quenched with Sat. NH.sub.4Cl (20 mL) and extracted with EtOAc (20 mL×2). The combined organic layers were washed with brine (10 mL), dried over Na.sub.2SO.sub.4, filtered and evaporated to afford crude product, which was purified by prep-HPLC separation to afford 52 (60 mg) as a solid.

[0429] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.82 (d, J=8.53 Hz, 2H) 7.41 (d, J=8.53 Hz, 2H) 3.44 (t, J=8.66 Hz, 1H) 2.35-2.48 (m, 1H) 1.71-1.87 (m, 5H) 1.22-1.70 (m, 21H) 1.02-1.21 (m, 2H) 0.85-0.99 (m, 1H) 0.60 (s, 3H). LCMS Rt=0.994 min in 2.0 min chromatography, 50-100 AB, MS ESI calcd. for C.sub.26H.sub.35ClO.sub.2 [M+H].sup.+ 416.3. found 415 [M].sup.+.

Example 54. Synthesis of Compound 53

[0430] ##STR00104##

[0431] A solution of 1-bromo-2-methoxybenzene (491 mg, 2.63 mmol) in THF (3 mL) was added t-butyllithium (3.65 mL, 4.75 mmol) dropwise at −78° C. The mixture was stirred at −78° C. for 2 hrs. A30 (100 mg, 2.64 mmol) in THF (1 mL) was added dropwise at −78° C. The reaction was stirred at 15° C. for 2 hours. TLC showed the reaction was complete. The reaction was quenched with Sat. NH.sub.4Cl (20 mL) and extracted with EtOAc (20 mL×2). The combined organic layers were washed with brine (10 mL), dried over Na.sub.2SO.sub.4, filtered and evaporated to afford the crude product, which was purified by prep-HPLC separation for further purification to afford 53 (38 mg) as a solid.

[0432] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.30-7.41 (m, 2H) 6.89-6.99 (m, 2H) 3.86 (s, 3H) 3.54 (t, J=9.03 Hz, 1H) 2.27-2.44 (m, 1H) 1.60-2.01 (m, 6H) 0.93-1.57 (m, 22H) 0.89 (s, 3H) 0.59 (s, 3H). LCMS Rt=1.688 min in 3.0 min chromatography, 50-100 AB, MS ESI calcd. for C.sub.28H.sub.41O.sub.3 [M+H].sup.+ 425. found 425.

Example 55. Synthesis of Compound 54

[0433] ##STR00105##

[0434] A solution of 1-bromo-4-fluorobenzene (460 mg, 2.63 mmol) in THF (3 mL) was added t-butyllithium (3.65 mL, 4.75 mmol) dropwise at −78° C. The mixture was stirred at −78° C. for 2 hrs. A30 (100 mg, 2.64 mmol) in THF (1 mL) was added dropwise at −78° C. The reaction was stirred at 15° C. for 2 hours. TLC showed the reaction was complete. The reaction was quenched with Sat. NH.sub.4Cl (20 mL) and extracted with EtOAc (20 mL×2). The combined organic layers were washed with brine (10 mL). The organic layer was dried over Na.sub.2SO.sub.4, filtered and evaporated to afford crude product, which was purified by prep-HPLC to afford 54 (33 mg) as a solid.

[0435] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.91 (dd, J=8.78, 5.52 Hz, 2H), 7.11 (t, J=8.53 Hz, 2H), 3.44 (t. J=8.78 Hz, 1H), 2.33-2.48 (m, 1H), 1.62-2.05 (m, 5H), 1.56 (s, 4H), 0.98-1.53 (m, 20H), 0.86-0.95 (m, 3H), 0.58 (s, 3H). LCMS Rt=0.885 min in 2.0 min chromatography, 50-100 AB, MS ESI calcd. for C.sub.27H.sub.38FO.sub.2 [M+H].sup.+ 413.3. found 395[M−H.sub.2O].sup.+.

Example 56. Synthesis of Compound 55

[0436] ##STR00106##

[0437] A solution of 1-bromo-4-fluorobenzene (359 mg, 2.75 mmol) in THF (3 mL) was added t-butyllithium (3.8 mL, 4.94 mmol) dropwise at −78° C. The mixture was stirred at −78° C. for 2 h. A10 (100 mg, 2.75 mmol) in THF (1 mL) was added dropwise at −78° C. The reaction was stirred at −78° C. for 2 hours. TLC showed the reaction was completed. The reaction was quenched with Sat NH.sub.4Cl (20 mL) and extracted with EtOAc (20 mL×2). The combined organic layers were washed with brine (10 mL), dried over Na.sub.2SO.sub.4, filtered and evaporated to afford crude product, which was purified by prep-HPLC separation to afford 55 (101 mg) as a solid.

[0438] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.91 (dd, J=8.78, 5.52 Hz, 2H), 7.11-7.11 (m, 1H), 7.11-7.11 (m, 1H), 7.10-7.11 (m, 1H), 7.11 (t, J=8.66 Hz, 2H), 3.45 (t, J=8.66 Hz, 1H), 2.36-2.49 (m, 1H), 1.70-1.89 (m, 5H), 1.53-1.69 (m, 8H), 1.03-1.52 (m, 19H), 0.84-1.00 (m, 1H), 0.60 (s, 3H). LCMS Rt=0.857 min in 2.0 min chromatography, 50-100 AB, MS ESI calcd. for C.sub.26H.sub.36FO.sub.2 [M+H].sup.+ 399.3. found 381 [M−H.sub.2O].sup.+.

Example 57. Synthesis of Compound 56

[0439] ##STR00107##

[0440] To a solution of 1-bromo-3-fluorobenzene (239 mg, 1.37 mmol) in THF (5 mL) was added n-butyllithium (1.90 mL, 2.47 mmol) dropwise at −68° C. The mixture was stirred at −68° C. for 2 hrs. A10 (100 mg, 275 μmol) in THF (3 mL) was added dropwise at −68° C. The reaction was stirred at 25° C. for 2 hours. LCMS showed the reaction was complete. The reaction was quenched with NH.sub.4Cl (20 mL), extracted with EtOAc (20 mL×2). The combined organic layers were washed with brine (10 mL), dried over Na.sub.2SO.sub.4, filtered and evaporated to afford crude product, which was purified by prep-HPLC to give 56 (28.2 mg) as a solid.

[0441] .sup.1H NMR (400 MHz, DMSO) δ 7.78-7.42 (m, 4H), 4.25 (s, 1H), 3.67 (t, J=8.4 Hz, 1H), 2.28-2.15 (m, 1H), 1.79-1.63 (m, 5H), 1.62-1.48 (m, 2H), 1.47-1.34 (m, 4H), 1.32-1.17 (m, 7H), 1.16-0.96 (m, 8H), 0.84 (d, J=12.0 Hz, 1H), 0.50 (s, 3H). LCMS Rt=1.223 min in 2 min chromatography, 30-90 AB, MS ESI calcd. for C.sub.26H.sub.36FO.sub.2 [M+H].sup.+ 381. found 381 [M−H.sub.2O].sup.+.

Example 58. Synthesis of Compound 57

[0442] ##STR00108##

[0443] To a stirred solution of 1-bromo-4-methoxybenzene (256 mg, 1.37 mmol) in 3 mL of THF was added tert-butyllithium (1.3 M; 2 mL, 2.61 mmol) dropwise at −78° C. under N.sub.2. After stirring at −78° C. for 2 hrs, A10 (100 mg, 0.275 mmol) was added. The mixture was stirred at 25° C. for 1 hour. LCMS showed the reaction was completed. The reaction mixture was quenched with NH.sub.4Cl (30 mL), extracted with EtOAc (20 mL×2), washed with brine (30 mL), dried over Na.sub.2SO.sub.4, filtered and evaporated in vacuum. The crude product was purified by preparative HPLC (column: Phenomenex Synergi C18 150*30 mm*4 um, gradient 90-98% B (A=0.05% HCl-ACN, B=acetonitrile), flow rate: 30 mL/min) to obtain 57 (41.0 mg) as a solid.

[0444] .sup.1H NMR (CDCl.sub.3, 400 MHz): δ 7.90 (d, J=8.6 Hz, 2H), 6.92 (d, J=9.0 Hz, 2H), 3.87 (s, 3H), 3.46 (t, J=8.6 Hz, 1H), 2.36-2.49 (m, 1H), 1.70-1.85 (m, 5H), 1.53-1.69 (m, 3H), 1.25-1.50 (m, 15H), 1.03-1.19 (m, 2H), 0.86-1.00 (m, 1H), 0.61 (s, 3H). LCMS Rt=2.415 min in 4.0 min chromatography, 30-90 CD, MS EST calcd. for C.sub.27H.sub.39O.sub.3 [M+H].sup.+ 411. found 411.

Example 59. Synthesis of Compound 58

[0445] ##STR00109##

[0446] To a solution of B10 (100 mg, 0.275 mmol) in THF (3 mL) was added naphthalen-2-yl magnesium bromide (2.74 mL) at 25° C. for 2 hours TLC showed the reaction was complete. Aqueous solution of NH.sub.4Cl (5 mL) was added dropwise at 25° C., and extracted with EtOAc (10 mL×2). The combined organic solution was washed with brine (5 mL), dried over Na.sub.2SO.sub.4. The organic layer was filtered and concentrated under reduced pressure to get the mixture, which was purified by HPLC to give 58 (18.5 mg, 40.5 μmol) as a solid.

[0447] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.03-7.93 (m, 2H), 7.72-7.61 (m, 4H), 7.53-7.45 (m, 2H), 7.44-7.37 (m, 1H), 3.60-3.51 (m, 1H), 2.54-2.42 (m, 1H), 1.85-1.62 (m, 7H), 1.37 (br. s., 7H), 1.24-0.93 (m, 10H), 0.66 (s, 5H). LCMS Rt=1.392 min in 2 min chromatography, 30-90 AB, MS ESI calcd for C.sub.32H.sub.41O.sub.2 [M+H].sup.+ 457. found 457.

Example 60. Synthesis of Compound 59

[0448] ##STR00110##

[0449] To a solution of B10 (100 mg, 0.275 mmol) in THF (3 mL) was added naphthalen-2-yl magnesium bromide (550 μL) at 25° C. for 2 hours. TLC showed the reaction was complete. An aqueous solution of NH.sub.4Cl (5 mL) was added dropwise into the reaction mixture at 25° C., and extracted with EtOAc (10 mL×2). The combined organic solution was washed with brine (5 mL), dried over Na.sub.2SO.sub.4. The organic layer was filtered and concentrated under reduced pressure to get the mixture, which was purified by HPLC to give 59 (7.8 mg) as a solid.

[0450] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.41 (s, 1H), 8.03-7.97 (m, 2H), 7.93-7.87 (m, 2H), 7.64-7.54 (m, 2H), 3.74-3.66 (m, 1H), 2.59-2.46 (m, 1H), 1.88-1.76 (m, 2H), 1.76-1.60 (m, 5H), 1.56-1.53 (m, 1H), 1.40 (br. s., 6H), 1.21 (s, 10H), 0.81-0.70 (m, 1H), 0.67 (s, 4H). LCMS Rt=1.346 min in 2 min chromatography, 30-90 AB, MS ESI calcd. for C.sub.30H.sub.39O.sub.2[M+H].sup.+ 431. found 431.

Example 61. Synthesis of Compound 60

[0451] ##STR00111##

[0452] To a stirred solution of 2-bromopyridine (216 mg, 1.37 mmol) in 3 mL of THF was added tert-butyllithium (1.3 M; 2 mL, 2.61 mmol) drop-wise at −78° C. under N.sub.2. After stirring at −78° C. for 2 hrs, A10 (100 mg, 0.275 mmol) was added. The mixture was stirred at 25° C. for 1 hour. LCMS showed the reaction was complete. The reaction mixture was quenched with Sat NH.sub.4Cl (30 mL). The mixture was extracted with EtOAc (20 mL×2), washed with brine (30 mL), dried over (Na.sub.2SO.sub.4), filtered and evaporated in vacuum to give crude product. The crude product was purified by per-HPLC separation (column: Phenomenex Synergi C18 150*30 mm*4 um, gradient: 70-80% B (A=0.05% HCl-ACN, B=acetonitrile), flow rate: 30 mL/min) to obtain 60 (49.9 mg) as a solid.

[0453] .sup.1H NMR (CDCl.sub.3, 400 MHz): δ 8.66 (d, J=4.6 Hz, 1H), 7.94 (d, J=8.0 Hz, 1H), 7.78-7.85 (m, 1H), 7.40-7.46 (m, 1H), 4.22 (t, J=8.8 Hz, 1H), 2.24-2.41 (m, 1H), 1.74-1.87 (m, 5H), 1.23-1.56 (m, 17H), 1.04-1.20 (m, 3H), 0.83-0.95 (m, 1H), 0.63 (s, 3H). LCMS Rt=2.154 min in 4.0 min chromatography, 30-90 AB, MS ESI calcd. for C.sub.25H.sub.36NO.sub.2 [M+H].sup.+ 382. found 382.

Example 62. Synthesis of Compound 61

[0454] ##STR00112##

[0455] To a stirred solution of 1-bromo-4-methoxybenzene (245 mg, 1.31 mmol) in 3 mL of THF was added tert-butyllithium (1.3 M; 1.92 mL, 2.50 mmol) drop-wise at −78° C. under N.sub.2. After stirring at −78° C. for 2 hrs, A30 (100 mg, 0.264 mmol) was added. The mixture was stirred at 25° C. for 1 hour. LCMS showed the reaction was complete. The reaction mixture was quenched with Sat NH.sub.4Cl (30 mL). The mixture was extracted with EtOAc (20 mL×2), washed with brine (30 mL), dried over Na.sub.2SO.sub.4, filtered, and evaporated in vacuum to give crude product. The crude product was purified by HPLC separation (column: Phenomenex Synergi C18 150*30 mm*4 um, gradient: 75-100% B (A=0.05% HCl-ACN, B=acetonitrile), flow rate: 30 mL/min) to give 61 (13.3 mg) as a solid.

[0456] .sup.1H NMR (CDCl.sub.3, 400 MHz): δ 7.89 (d, J=8.6 Hz, 2H), 6.91 (d, J=9.0 Hz, 2H), 3.86 (s, 3H), 3.45 (t, J=8.8 Hz, 1H), 2.37-2.47 (m, 1H), 1.97 (t, J=13.2 Hz, 1H), 1.63-1.91 (m, 5H), 1.31-1.54 (m, 11H), 1.19-1.27 (m, 5H), 1.09-1.18 (m, 2H), 1.03 (td, J=14.4, 3.3 Hz, 1H), 0.91 (s, 3H), 0.58 (s, 3H). LCMS Rt=1.230 min in 2.0 min chromatography, 30-90 AB, MS ESI calcd. for C.sub.28H.sub.41O.sub.3[M+H].sup.+ 425.3. found 407 [M−H.sub.2O].sup.+.

Example 63. Synthesis of Compound 62

[0457] ##STR00113##

[0458] To a stirred solution of 2-bromopyridine (206 mg, 1.31 mmol) in 3 mL of THF was added tert-butyllithium (1.3 M: 1.92 mL, 2.50 mmol) drop-wise at −78° C. under N.sub.2. After stirring at −78° C. for 2 hrs, A30 (100 mg, 0.264 mmol) was added. The mixture was stirred at 25° C. for 1 hour. LCMS showed the reaction was complete. The reaction mixture was quenched with Sat NH.sub.4Cl (30 mL). The mixture was extracted with EtOAc (20 mL×2), washed with brine (30 mL), dried over (Na.sub.2SO.sub.4), filtered, and evaporated in vacuum to give crude product. The crude product was purified by per-HPLC separation (column: Phenomenex Synergi C18 150*30 mm*60, gradient: 84-84% B (A=0.05% HCl-ACN, B=acetonitrile), flow rate: 30 mL/min) to give 62 (20.3 mg) as a solid.

[0459] .sup.1H NMR (MeOD, 400 MHz): δ 8.81 (d, J=4.8 Hz, 1H), 8.33-8.39 (m, 1H), 8.26-8.32 (m, 1H), 7.87-7.94 (m, 1H), 4.03 (t, J=8.8 Hz, 1H), 2.30-2.46 (m, 1H), 1.79-2.09 (m, 5H), 1.71 (d, J=14.4 Hz, 1H), 1.34-1.60 (m, 10H), 1.21-1.31 (m, 7H), 1.03-1.20 (m, 2H), 0.96 (s, 3H), 0.65 (s, 3H). LCMS Rt=2.257 min in 4.0 min chromatography, 30-90 AB, MS ESI calcd. for C.sub.26H.sub.38NO.sub.2 [M+H].sup.+ 396. found 396.

Example 64. Synthesis of Compound 63

[0460] ##STR00114##

[0461] To a stirred solution of 1-bromo-3-methoxybenzene (245 mg, 1.31 mmol) in 3 mL of THF was added tert-butyllithium (1.3 M, 1.92 mL, 2.50 mmol) dropwise at −78° C. under N.sub.2. After stirring at −78° C. for 2 hrs, A30 (100 mg, 0.264 mmol) was added. The mixture was stirred at 25° C. for 1 hour. LCMS showed the reaction was complete. The reaction mixture was quenched with Sat. NH.sub.4Cl (30 mL). The mixture was extracted with EtOAc (20 mL×2). The combined organic layer was washed with brine (30 mL), dried over Na.sub.2SO.sub.4, filtered, and evaporated in vacuo to give crude product, which was purified by prep-HPLC separation (column: Phenomenex Synergi C18 150*30 mm*4 um, gradient: 75-100% B (A=0.05% HCl-ACN, B=acetonitrile), flow rate: 30 mL/min) for further purification to afford 63 (19.4 mg) as a solid.

[0462] .sup.1H NMR (CDCl3, 400 MHz): δ 7.45 (d, J=7.6 Hz, 1H), 7.40 (s, 1H), 7.34 (t, J=8.0 Hz, 1H), 7.08 (dd, J=8.0, 2.3 Hz, 1H), 3.86 (s, 3H), 3.45 (t, J=8.8 Hz, 1H), 2.37-2.47 (m, 1H), 1.65-2.00 (m, 6H), 1.33-1.53 (m, 10H), 1.22-1.28 (m, 5H), 1.08-1.18 (m, 2H), 0.98-1.05 (m, 1H), 0.89-0.89 (m, 1H), 0.91 (s, 3H), 0.59 (s, 3H). LCMS Rt=3.246 min in 4.0 min chromatography, 30-90 CD, MS ESI calcd. for C.sub.28H.sub.41O.sub.3[M+H].sup.+ 425.3. found 407.3 [M−H.sub.2O].sup.+.

Example 65. Synthesis of Compound 64

[0463] ##STR00115##

[0464] To a stirred solution of 1-bromo-2-methylbenzene (234 mg, 1.37 mmol) in 3 mL of THF was added tert-butyllithium (1.3 M; 2 mL, 2.61 mmol) dropwise at −78° C. under N.sub.2. After stirring at −78° C. for 2 hrs, A10 (100 mg, 0.275 mmol was added. The mixture was stirred at 25° C. for 1 hour. LCMS showed the reaction was complete. The reaction mixture was quenched with Sat. NH.sub.4Cl (30 mL). The mixture was extracted with EtOAc (20 mL×2), washed with brine (30 mL), dried over (Na.sub.2SO.sub.4), filtered, and evaporated in vacuum to give crude product, which was purified by prep-HPLC separation (column: Phenomenex Synergi C18 150*30 mm*4 um, gradient: 70-95% B (A=0.05% HCl-ACN, B=acetonitrile), flow rate: 25 mL/min) for further purification to give 64 (23.4 mg) as a solid.

[0465] .sup.1H NMR (CDCl.sub.3, 400 MHz): δ 7.47 (d, J=7.4 Hz, 1H), 7.30-7.34 (m, 1H), 7.22 (d, J=7.4 Hz, 2H), 3.31 (t, J=8.8 Hz, 1H), 2.31-2.46 (m, 4H), 1.69-1.83 (m, 5H), 1.19-1.51 (m, 16H), 0.97-1.19 (m, 4H), 0.82-0.90 (m, 1H), 0.66 (s, 3H). LCMS Rt=2.592 min in 4.0 min chromatography, 30-90 CD, MS ESI calcd. for C.sub.27H.sub.39O.sub.2[M+H].sup.+ 395.3. found 377.29 [M−H.sub.2O].sup.+.

Example 66. Synthesis of Compound 65

[0466] ##STR00116##

[0467] To a stirred solution of l-bromo-3-methoxybenzene (256 mg, 1.37 mmol) in 3 mL of THF was added tert-butyllithium (1.3 M; 2 mL, 2.61 mmol) dropwised at −78° C. under N.sub.2. After stirring at −78° C. for 1 hrs, A10 (100 mg, 0.275 mmol) was added. The mixture was stirred at 25° C. for 20 min. LCMS showed the reaction was completed. The reaction mixture was quenched with NH.sub.4Cl (30 mL), extracted with EtOAc (20 mL×2), washed with brine (30 mL), dried over Na.sub.2SO.sub.4, filtered and evaporated in vacuum. The crude product was purified by HPLC separation (column: Phenomenex Synergi C18 150*30 mm*4 um, gradient: 75-100% B (A=0.05% HCl-ACN, B=acetonitrile), flow rate: 30 mL/min) to obtain 65 (63.3 mg) as a solid.

[0468] .sup.1H NMR (CDCl.sub.3, 400 MHz): 7.45 (d, J=7.6 Hz, 1H), 7.40 (s, 1H), 7.34 (t, J=7.8 Hz, 1H), 7.08 (dd, J=8.2, 2.1 Hz, 1H), 3.86 (s, 3H), 3.46 (t, J=8.8 Hz, 1H), 2.38-2.46 (m, 1H), 1.70-1.87 (m, 5H), 1.58-1.68 (m, 2H), 1.11-1.52 (m, 17H), 1.03-1.10 (m, 1H), 0.84-0.99 (m, 1H), 0.61 (s, 3H). LCMS Rt=3.153 min in 4.0 min chromatography, 10-80 CD, MS ESI calcd for C.sub.27H.sub.38O.sub.3 [M−H.sub.2O+H].sup.+ 393. found 393.

Example 67. Synthesis of Compound 66

[0469] ##STR00117##

[0470] To a stirred solution of 1-bromo-3-chlorobenzene (262 mg, 1.37 mmol) in 3 mL of THF was added tert-butyllithium (1.3 M; 2 mL, 2.61 mmol) dropwise at −78° C. under N.sub.2. After stirring at −78° C. for 2 hrs, A10 (100 mg, 0.275 mmol was added. The mixture was stirred at 25° C. for 1 hour. LCMS showed the reaction was completed. The reaction mixture was quenched with NH.sub.4Cl (30 mL), extracted with EtOAc (20 mL×2), washed with brine (30 mL), dried over Na.sub.2SO.sub.4, filtered and evaporated in vacuum. The crude product was purified by HPLC separation (column: Phenomenex Synergi C18 150*30 mm*4 um, gradient: 75-100%/B (A=0.05% HCl-ACN, B=acetonitrile), flow rate: 30 mL/min) to obtain 66 (67.6 mg) as a solid.

[0471] .sup.1H NMR (CDCl.sub.3, 400 MHz): δ 7.84 (s, 1H), 7.73 (d, J=7.6 Hz, 1H), 7.50 (d, J=8.6 Hz, 1H), 7.34-7.43 (m, 1H), 3.43 (t, J=8.6 Hz, 1H), 2.36-2.45 (m, 1H), 1.70-1.86 (m, 5H), 1.57-1.67 (m, 2H), 1.41-1.54 (m, 3H), 1.21-1.41 (m, 13H), 1.04-1.17 (m, 2H), 0.88-0.99 (m, 1H), 0.60 (s, 3H). LCMS Rt=2.722 min in 4.0 min chromatography, 30-90 CD, MS ESI calcd. for C.sub.26H.sub.36ClO.sub.2 [M+H].sup.+ 415.3. found 397.0 [M−H.sub.2O].sup.+.

Example 68. Synthesis of Compound 67

[0472] ##STR00118##

[0473] To a stirred solution of 1-bromo-3-chlorobenzene (250 mg, 1.31 mmol) in 3 mL of THF was added tert-butyllithium (1.3 M; 1.92 mL, 2.50 mmol) dropwise at −78° C. After stirring at −78° C. for 2 hrs, A30 (100 mg, 0.264 mmol) was added. The mixture was stirred at −78° C. for 1 hour. LCMS showed the reaction was completed. The reaction mixture was quenched with NH.sub.4Cl (30 mL), extracted with EtOAc (20 mL×2), washed with brine (30 mL), dried over Na.sub.2SO.sub.4, filtered and evaporated in vacuum. The crude product was purified by HPLC separation (column: Phenomenex Synergi C18 150*30 mm*4 um, gradient: 80-100% B (A=0.05% HCl-ACN, B=acetonitrile), flow rate: 30 mL/min) for to obtain 67 (22.3 mg) as a solid.

[0474] .sup.1H NMR (CDCl.sub.3, 400 MHz): δ 7.84 (s, 1H), 7.73 (d, J=7.6 Hz, 1H), 7.50 (d, J=8.0 Hz, 1H), 7.33-7.43 (m, 1H), 3.41 (t, J=8.6 Hz, 1H), 2.34-2.45 (m, 1H), 1.96 (t, J=13.2 Hz, 1H), 1.59-1.87 (m, 5H), 1.20-1.53 (m, 17H), 1.09-1.16 (m, 1H), 0.98-1.07 (m, 1H), 0.90 (s, 3H), 0.58 (s, 3H). LCMS Rt=2.800 min in 4.0 min chromatography, 30-90 CD, MS ESI calcd. for C.sub.27H.sub.38ClO.sub.2 [M+H].sup.+ 429.3. found 411.0 [M−H.sub.2O].sup.+.

Example 69. Synthesis of Compound 68

[0475] ##STR00119##

[0476] To a stirred solution of 1-bromo-2-methylbenzene (224 mg, 1.31 mmol) in 3 mL of THF was added tert-butyllithium (1.3 M; 1.92 mL, 2.50 mmol) dropwise at −78° C. under N.sub.2. After stirring at −78° C. for 2 hrs, A30 (100 mg, 0.264 mmol was added. The mixture was stirred at 25° C. for 1 hour. LCMS showed the reaction was complete. The reaction mixture was quenched with Sat. NH.sub.4Cl (30 mL). The mixture was extracted with EtOAc (20 mL×2), washed with brine (30 mL), dried over Na.sub.2SO.sub.4, filtered, and evaporated in vacuo to give crude product, which was purified by prep-HPLC separation (column: Phenomenex Synergi C18 150*30 mm*4 um, gradient: 70-95% B (A=0.05% HCl-ACN, B=acetonitrile), flow rate: 25 mL/min) for further purification to obtain 68 (15.6 mg) as a solid.

[0477] .sup.1H NMR (CDCl3, 400 MHz): δ 7.47 (d, J=7.4 Hz, 1H), 7.30-7.34 (m, 1H), 7.18-7.25 (m, 2H), 3.30 (t, J=8.8 Hz, 1H), 2.31-2.46 (m, 4H), 1.93 (t, J=13.4 Hz, 1H), 1.83 (dt, J=9.2, 4.5 Hz, 1H), 1.74 (d, J=3.4 Hz, 1H), 1.61-1.67 (m, 2H), 1.20-1.47 (m, 16H), 0.95-1.16 (m, 4H), 0.89 (s, 3H), 0.64 (s, 3H). LCMS Rt=2.672 min in 4.0 min chromatography, 30-90 CD, MS ESI calcd. for C.sub.28H.sub.40O.sub.2 [M−H.sub.2O+H].sup.+ 391.1. found 391.3.

Example 70. Synthesis of Compound 69

[0478] ##STR00120##

[0479] To a solution of 1-bromo-2-fluorobenzene (239 mg, 1.37 mmol) in THF (5 mL) was added n-butyllithium (1.90 mL, 2.47 mmol) dropwise at −68° C. The mixture was stirred at −68 OC for 2 hrs. A10 (100 mg, 275 mol) in THF (3 mL) was added dropwise at −68° C. The reaction was stirred at 25° C. for 2 hours. LCMS showed the reaction was complete. The reaction was quenched with Sat. NH.sub.4Cl (20 mL), extracted with EtOAc (20 mL×2). The combined organic layers were washed with brine (10 mL), dried over Na.sub.2SO.sub.4, filtered and evaporated to afford crude product, which was purified by prep-HPLC to give 69 (21.6 mg) as a solid.

[0480] .sup.1H NMR (400 MHz, DMSO) δ 7.68-7.54 (m, 2H), 7.34-7.28 (m, 2H), 4.21 (s, 1H), 3.40 (t, J=8.4 Hz, 1H), 2.30-2.17 (m, 1H), 1.77-1.51 (m, 6H), 1.49-1.12 (m, 12H), 1.12-0.90 (m, 7H), 0.89-0.74 (m, 1H), 0.58-0.50 (m, 3H). LCMS Rt=1.187 min in 2 min chromatography, 30-90 AB, MS ESI calcd. for C.sub.26H.sub.36FO.sub.2 [M+H].sup.+ 399.3. found 381 [M−H.sub.2O].sup.+.

Example 71. Synthesis of Compound 70

[0481] ##STR00121##

Step 1.

[0482] To a solution of 3-bromopyridine (51.8 mg, 328 umol) in 3 mL of THF was added isopropylmagnesium chloride (2 M, 164 uL, 328 umol) drop-wise at 15° C. under N.sub.2. After stirring at 15° C. for 1 hour, A31 (50 mg, 0.164 mmol) was added. The mixture was stirred at 15° C. for 1 hour. LCMS showed the reaction was complete. The reaction mixture was quenched with saturated sat NH.sub.4Cl (30 mL). The mixture was extracted with EtOAc (20 mL×2). The combined organic layer washed with brine (30 mL), dried over Na.sub.2SO.sub.4, filtered and evaporated m vacuum to give 60 mg of crude product.

Step 2.

[0483] To a solution of A32 (60 mg, 156 umol) in DCM (3 mL) was added PCC (50.3 mg, 234 umol) at 15° C. The mixture was stirred at 15° C. for 1 hr. LCMS showed the reaction was complete. The solution was filtered and the filter cake was washed with DCM (50 mL×2). The combined filtrate was concentrated in vacuum. The residue was purified by silica gel column eluted with PE/EtOAc (10/1) to afford a crude product, which was then purified by perp-HPLC (column: Phenomenex Gemini 150*25 mm*10 um, gradient: 45-70% B (A=0.05% HCl-ACN, B=acetonitrile), flow rate: 30 mL/min) to give 70 (1.6 mg) as a solid.

[0484] .sup.1H NMR (CDCl.sub.3, 400 MHz) δ=9.15-9.05 (m, 1H), 8.80-8.70 (m, 1H), 8.20-8.10 (m, 1H), 7.47-7.35 (m, 1H), 3.46 (t, J=8.6 Hz, 1H), 3.08 (br. s., 1H), 2.52-2.34 (m, 1H), 1.90-1.72 (m, 5H), 1.68-1.61 (m, 2H), 1.52-1.44 (m, 3H), 1.43-1.33 (m, 7H), 1.31-1.24 (m, 5H), 1.20-1.04 (m, 2H), 1.00-0.85 (m, 1H), 0.62 (s, 3H). LCMS Rt=1.206 min in 2.0 min chromatography, 10-80 AB. MS ESI calcd. for C.sub.25H.sub.36NO.sub.2 [M+H].sup.+ 382. found 382.

Example 72. Synthesis of Compound 71

[0485] ##STR00122##

[0486] To a solution of 1-bromo-4-methylbenzene (203 mg, 1.09 mmol) in THF (0.3 mL) was added tert-butyllithium (1.68 mL, 1.3 M) at −60° C. The mixture was stirred at −60° C. for 1 hr. A solution of B10 (40 mg, 110 μmol) in THF (0.1 mL) was added into the mixture at −60° C. The reaction mixture was stirred at 25° C. for 2 hrs. TLC showed the reaction was complete. Saturated NH.sub.4Cl (1 mL) was added. The mixture was extracted with EtOAc (1.5 mL×3). The combined organic layers were dried over Na.sub.2SO.sub.4. The mixture was filtered. The filtrate was concentrated in vacuum. The residue was purified by prep-HPLC (column: Phenomenex Synergi C18 150*30 mm*4 um, gradient 80-95% B (A=0.05% HCl-ACN, B=acetonitrile), flow rate: 25 mL/min) to give 71 (6.5 mg) as a solid.

[0487] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.56-7.43 (m, 2H), 7.41-7.29 (m, 1H), 7.11-7.06 (m, 1H), 3.86 (s, 3H), 3.48-3.39 (m, 1H), 2.47-2.36 (m, 1H), 1.81-1.46 (m, 10H), 1.53-0.91 (m, 20H), 0.72-0.58 (m, 5H). LCMS t.sub.R=1.039 min in 1.5 min chromatography, 5-95 AB, MS ESI calcd. for C.sub.27H.sub.39O [M+H].sup.+ 411. found 411.

Example 73. Synthesis of Compound 72

[0488] ##STR00123##

To a stirred solution of 2-bromo-6-methoxynaphthalene (258 mg, 1.09 mmol) in 3 mL of THF was added tert-butyllithium (1.3 M, 1.6 mL, 2.09 mmol) drop-wise at −78° C. under N.sub.2. After stirring at −78° C. for 1 hour, A10 (80 mg, 0.220 mmol) was added. The mixture was stirred at 25° C. for 1 hour. LCMS showed the reaction was complete. The reaction mixture was quenched with saturated NH.sub.4Cl (30 mL). The mixture was extracted with EtOAc (20 mL×2). The combined organic layer washed with brine (30 mL), dried over Na.sub.2SO.sub.4, filtered, and evaporated in vacuum to give crude product, which was purified by prep-HPLC separation (column: Phenomenex Synergi C18 150*30 mm*4 um, gradient: 80-100% B (A=0.05% HCl-ACN, B=acetonitrile), flow rate: 30 mL/min) to afford 72 (58.3 mg) as a solid.

[0489] .sup.1H NMR (CDCl.sub.3, 400 MHz): δ 8.33 (s, 1H), 7.93-7.99 (m, 1H), 7.85 (d, J=8.6 Hz, 1H), 7.75 (d, J=8.6 Hz, 1H), 7.20 (dd, J=9.0, 2.5 Hz, 1H), 7.15 (d, J=2.0 Hz, 1H), 3.95 (s, 3H), 3.64 (t, J=8.6 Hz, 1H), 2.55-2.42 (m, 1H), 1.88-1.73 (m, 5H), 1.69-1.59 (m, 1H), 1.55-1.20 (m, 17H), 1.19-1.04 (m, 2H), 0.97-0.83 (m, 1H), 0.64 (s, 3H). LCMS Rt=1.242 min in 2.0 min chromatography, 30-90 AB, MS EST calcd. for C.sub.31H.sub.41O.sub.3 [M+H].sup.+ 461. found 461.

Example 74. Synthesis of Compound 73

[0490] ##STR00124##

[0491] To a stirred solution of 1-bromo-3-methylbenzene (224 mg, 1.31 mmol) in 3 mL of THF was added tert-butyllithium (1.3 M; 1.6 mL, 2.5 mmol) drop-wise at −78° C. under N.sub.2. After stirring at −78° C. for 2 hours, A30 (100 mg, 0.264 mmol) was added. The mixture was stirred at 25° C. for 1 hour. LCMS showed the reaction was complete. The reaction mixture was quenched with Sat NH.sub.4Cl (30 mL). The mixture was extracted with EtOAc (20 mL×2), washed with brine (30 mL), dried over Na.sub.2SO.sub.4, filtered, and evaporated in vacuum to give crude product. The crude product was purified by prep-HPLC separation (column: Phenomenex Synergi C18 150*30 mm*4 um, gradient: 80-100% B (A=0.05% HCl-ACN, B=acetonitrile), flow rate: 30 mL/min) to afford 73 (12.2 mg) as a solid.

[0492] .sup.1H NMR (CDCl.sub.3, 400 MHz): δ 7.62-7.70 (m, 2H), 7.28-7.36 (m, 2H), 3.47 (t J=8.8 Hz, 1H), 2.34-2.47 (m, 4H), 1.97 (t, J=13.2 Hz, 1H), 1.59-1.92 (m, 5H), 1.28-1.51 (m, 10H), 1.20-1.27 (m, 5H), 0.96-1.18 (m, 4H), 0.90 (s, 3H), 0.59 (s, 3H). LCMS Rt=1.261 min in 2.0 min chromatography, 30-90 AB, MS ESI calcd. for C.sub.28H.sub.41O.sub.2[M+H].sup.+ 409. found 409.

Example 75. Synthesis of Compound 74

[0493] ##STR00125##

[0494] To a stirred solution of 1-bromo-3-methoxybenzene (186 mg, 1.09 mmol) in 3 mL of THF was added tert-butyllithium (1.3 M; 1.6 mL, 2.09 mmol) drop-wise at −78° C. under N.sub.2. After stirring at −78° C. for 2 hrs, A10 (80 mg, 0.22 mmol) was added. The mixture was stirred at 25° C. for 1 hour. LCMS showed the reaction was complete. The reaction mixture was quenched with Sat NH.sub.4Cl (30 mL). The mixture was extracted with EtOAc (20 mL×2), washed with brine (30 mL), dried over Na.sub.2SO.sub.4, filtered, and evaporated in vacuum to give crude product. The crude product was purified by perp-HPLC separation (column: Phenomenex Synergi C18 150*30 mm*4 um, gradient: 85-85% B (A=0.05% HCl-ACN, B=acetonitrile), flow rate: 30 mL/min) to give 74 (18.8 mg) as a solid.

[0495] .sup.1H NMR (CDCl.sub.3, 400 MHz): δ 7.60-7.74 (m, 2H), 7.29-7.39 (m, 2H), 3.48 (t, J=8.6 Hz, 1H), 2.33-2.48 (m, 4H), 1.69-1.85 (m, 5H), 1.55-1.69 (m, 3H), 1.41-1.51 (m, 3H), 1.20-1.41 (m, 12H), 1.02-1.16 (m, 2H), 0.82-0.97 (m, 1H), 0.60 (s, 3H). LCMS Rt=1.232 min in 2.0 min chromatography, 30-90 AB, MS ESI calcd. for C.sub.27H.sub.39O.sub.2[M+H].sup.+ 395.3. found 377 [M−H.sub.2O].sup.+.

Example 76. Synthesis of Compound 75

[0496] ##STR00126##

[0497] To a stirred solution of 1-bromo-4-methylbenzene (51.5 mg, 0.264 mmol) in 3 mL of THF was added tert-butyllithium (1.3 M in hexane, 0.4 mL, 0.52 mmol) dropwise at −65° C. under N.sub.2. After stirring at −65° C. for 2 hrs, B30 (50 mg, 0.132 mmol) was added. The mixture was stirred at 15° C. for 1 hour. LCMS showed the reaction was complete. The reaction mixture was quenched with Sat. NH.sub.4Cl (30 mL). The mixture was extracted with EtOAc (20 mL×2), washed with brine (30 mL), dried over Na.sub.2SO.sub.4, filtered, and evaporated in vacuum to give crude product. The crude product was purified by HPLC separation (column: Phenomenex Synergi C18 150*25*10 um, gradient: 69-74% B (A=0.1% TFA-ACN, B=acetonitrile), flow rate: 30 mL/min) for further purification to obtain 75 (21.9 mg) as a solid.

[0498] .sup.1H NMR (CDCl.sub.3, 400 MHz) δ 7.79 (d, J=8.6 Hz, 2H), 7.23 (d, J=8.0 Hz, 2H), 3.47 (t, J=8.6 Hz, 1H), 2.47-2.36 (m, 4H), 1.78-1.69 (m, 3H), 1.50-1.17 (m, 19H), 1.17-1.08 (m, 1H), 1.03-0.92 (m, 1H), 0.83-0.74 (m, 1H), 0.72 (s, 3H), 0.60 (s, 3H). LCMS Rt=1.277 min in 2.0 min chromatography, 30-90 AB, MS ESI calcd. for C.sub.28H.sub.41NO.sub.2 [M+H].sup.+ 409. found 409.

Example 77. Synthesis of Compound 76

[0499] ##STR00127##

[0500] To a stirred solution of 1-bromo-4-methoxybenzene (49.3 mg, 0.264 mmol) in 3 mL of THF was added tert-butyllithium (1.3 M: 406 μL, 0.528 mmol) drop-wise at −65° C. under N.sub.2. After stirring at −65° C. for 2 hrs, B30 (50 mg, 0.132 mmol) was added. The mixture was stirred at 15° C. for 1 hour. LCMS showed the reaction was complete. The reaction mixture was quenched with Sat. NH.sub.4Cl (30 mL). The mixture was extracted with EtOAc (20 mL×2), washed with brine (30 mL), dried over Na.sub.2SO.sub.4, filtered, and evaporated in vacuum to give the crude product. The crude product was purified by HPLC separation (column: Phenomenex Synergi C18 150*30 mm*4 um, gradient: 90-95% B (A=0.05% HCl-ACN, B=acetonitrile), flow rate: 25 mL/min) for further purification to obtain 76 (26.1 mg) as a solid.

[0501] .sup.1H NMR (CDCl.sub.3, 400 MHz) δ 7.89 (d, J=8.6 Hz, 2H), 6.91 (d, J=9.0 Hz, 2H), 3.86 (s, 3H), 3.45 (t, J=8.6 Hz, 1H), 2.45-2.36 (m, 1H), 1.78-1.68 (m, 3H), 1.53-1.12 (m, 20H), 1.03-0.92 (m, 1H), 0.82-0.75 (m, 1H), 0.71 (s, 3H), 0.59 (s, 3H). LCMS Rt=1.302 min in 2.0 min chromatography, 30-90 AB, MS ESI calcd. for C.sub.28H.sub.41O.sub.3 [M+H].sup.+ 425. found 425.

Example 78. Synthesis of Compound 77

[0502] ##STR00128##

[0503] To a stirred solution of 1-bromo-3-methoxybenzene (49.3 mg, 0.264 mmol) in 3 mL of THF was added tert-butyllithium (1.3 M, 406 uL, 0.528 mmol) drop-wise at −65° C. under N.sub.2. After stirring at −65° C. for 2 hrs, B30 (50 mg, 0.132 mmol) was added. The mixture was stirred at 15° C. for 1 hour. LCMS showed the reaction was complete. The reaction mixture was quenched with Sat. NH.sub.4Cl (30 mL). The mixture was extracted with EtOAc (20 mL×2), washed with brine (30 mL), dried over Na.sub.2SO.sub.4, filtered, and evaporated in vacuum to give crude product. The crude product was purified by HPLC separation (column: Phenomenex Synergi C18 150*30 mm*4 um, gradient: 90-95% B (A=0.05% HCl-ACN, B=acetonitrile), flow rate: 25 mL/min) for further purification to obtain 77 (19.9 mg) as a solid.

[0504] .sup.1H NMR (CDCl.sub.3, 400 MHz) δ 7.50-7.30 (m, 3H), 7.07 (dd, J=2.0, 8.0 Hz, 1H), 3.85 (s, 3H), 3.45 (t, J=8.8 Hz, 1H), 2.46-2.34 (m, 1H), 1.81-1.67 (m, 3H), 1.53-1.26 (m, 12H), 1.25-1.09 (m, 8H), 1.03-0.92 (m, 1H), 0.81-0.74 (m, 1H), 0.71 (s, 3H), 0.60 (s, 3H). LCMS Rt=1.315 min in 2.0 min chromatography, 30-90 AB, MS ESI calcd. for C.sub.28H.sub.41O.sub.3 [M+H].sup.+ 425. found 425.

Example 79. Synthesis of Compound 78

[0505] ##STR00129##

[0506] To a stirred solution of 1-bromo-2-methoxybenzene (49.3 mg, 0.264 mmol) in 3 mL of THF was added tert-butyllithium (1.3 M, 406 μL, 0.528 mmol) dropwise at −65° C. under N.sub.2. After stirring at −65° C. for 2 hrs, B30 (50 mg, 0.132 mmol) was added. The mixture was stirred at 15° C. for 1 hour. LCMS showed the reaction was complete. The reaction mixture was quenched with Sat NH.sub.4Cl (30 mL) The mixture was extracted with EtOAc (20 mL×2), washed with brine (30 mL), dried over Na.sub.2SO.sub.4, filtered, and evaporated in vacuum to give crude product. The crude product was purified by HPLC separation (column: Phenomenex Synergi C18 150*30 mm*4 um, gradient: 95-95% B (A=0.05% HCl-ACN, B=acetonitrile), flow rate: 25 mL/min) for further purification to obtain 78 (19.6 mg) as a solid.

[0507] .sup.1H NMR (CDCl.sub.3, 400 MHz) δ 7.43-7.28 (m, 2H), 7.02-6.82 (m, 2H), 3.84 (s, 3H), 3.55-3.45 (m, 1H), 2.43-2.25 (m, 1H), 1.79-1.63 (m, 5H), 1.48-1.33 (m, 6H), 1.25-1.16 (m, 10H), 1.12-1.04 (m, 2H), 1.00-0.85 (m, 1H), 0.77-0.70 (m, 1H), 0.69 (s, 3H), 0.60 (s, 3H). LCMS Rt=1.277 min in 2.0 min chromatography, 30-90 AB, MS ESI calcd. for C.sub.28H.sub.41O.sub.3[M+H].sup.+ 425. found 425.

Example 80. Synthesis of Compound 79

[0508] ##STR00130##

[0509] To a stirred solution of 1-bromo-4-fluorobenzene (46.1 mg, 0.264 mmol) in 3 mL of THF was added tert-butyllithium (1.3 M, 406 μL, 0.528 mmol) dropwise at −65° C. under N.sub.2. After stirring at −65° C. for 2 hrs, B30 (50 mg, 0.132 mmol was added. The mixture was stirred at 15° C. for 1 hour. LCMS showed the reaction was complete. The reaction mixture was quenched with Sat NH.sub.4Cl (30 mL). The mixture was extracted with EtOAc (20 mL×2), washed with brine (30 mL), dried over Na.sub.2SO.sub.4, filtered, and evaporated in vacuum to give crude product. The crude product was purified by HPLC separation (column-Phenomenex Synergi C18 150*30 mm*4 um, gradient: 85-95% B (A=0.05% HCl-ACN, B=acetonitrile), flow rate: 30 mL/min) to obtain 79 (22.1 mg) as a solid.

[0510] .sup.1H NMR (CDCl.sub.3, 400 MHz) δ 7.91 (dd, J=5.6, 8.5 Hz, 2H), 7.10 (t, J=8.6 Hz, 2H), 3.44 (t, J=8.6 Hz, 1H), 2.45-2.35 (m, 1H), 1.83-1.64 (m, 4H), 1.54-1.42 (m, 6H), 1.38 (d, J=13.4 Hz, 2H), 1.32-1.14 (m, 11H), 1.02-0.92 (m, 1H), 0.83-0.74 (m, 1H), 0.71 (s, 3H), 0.59 (s, 3H). LCMS Rt=1.240 min in 2.0 min chromatography, 30-90 AB, MS ESI calcd. for C.sub.27H.sub.38FO.sub.2 [M+H].sup.+ 413. found 413.

Example 81. Synthesis of Compound 80

[0511] ##STR00131##

[0512] To a stirred solution of i-bromo-2-fluorobenzene (46.1 mg, 0.264 mmol) in 3 mL of THF was added tert-butyllithium (1.3 M in hexane, 406 μL, 0.528 mmol) drop-wise at −65° C. under N.sub.2. After stirring at −65° C. for 2 hrs, B30 (50 mg, 0.132 mmol) was added. The mixture was stirred at 15° C. for 1 hour. LCMS showed the reaction was complete. The reaction mixture was quenched with Sat NH.sub.4Cl (30 mL). The mixture was extracted with EtOAc (20 mL×2), washed with brine (30 mL), dried over Na.sub.2SO.sub.4, filtered, and evaporated in vacuum to give crude product. The crude product was purified by HPLC separation (column: Phenomenex Synergi C18 150*30 mm*4 um, gradient: 84-84% B (A=0.05% HCl-ACN, B=acetonitrile), flow rate: 30 mL/imin) for further purification to obtain 80 (19.9 mg) as a solid.

[0513] .sup.1H NMR (CDCl.sub.3, 400 MHz) δ 7.57-7.48 (m, 1H), 7.47-7.39 (m, 1H), 7.19 (t, J=7.6 Hz, 1H), 7.12-7.05 (m, 1H), 3.39 (t, J=8.6 Hz, 1H), 2.43-2.32 (m, 1H), 1.79-1.66 (m, 3H), 1.49-1.31 (m, 7H), 1.28-1.13 (m, 12H), 1.13-1.04 (m, 1H), 0.96 (dq, J=5.4, 12.1 Hz, 1H), 0.79-0.73 (m, 1H), 0.70 (s, 3H), 0.60 (s, 3H). LCMS Rt=1.217 min in 2.0 min chromatography, 30-90 AB, MS ESI calcd. for C.sub.27H.sub.39FO.sub.2 [M+H].sup.+ 413. found 395 [M−H.sub.2O].sup.+.

Example 82. Synthesis of Compound 81

[0514] ##STR00132##

[0515] To a stirred solution of 1-bromo-4-chlorobenzene (50.5 mg, 0.264 mmol) in 3 mL of THF was added tert-butyllithium (1.3 M; 406 μL, 0.528 mmol) drop-wise at −65° C. under N.sub.2. After stirring at −65° C. for 2 hrs, B30 (50 mg, 0.132 mmol) was added. The mixture was stirred at 15° C. for 1 hour. LCMS showed the reaction was complete. The reaction mixture was quenched with Sat. NH.sub.4Cl (30 mL). The mixture was extracted with EtOAc (20 mL×2), washed with brine (30 mL), dried over Na.sub.2SO.sub.4, filtered, and evaporated in vacuum to give crude product. The crude product was purified by HPLC separation (column: Phenomenex Synergi C18 150*30 mm*4 um, gradient: 88-88% B (A=0.05% HCl-ACN, B=acetonitrile), flow rate: 30 mL/min) for further purification to obtain 81 (11.8 mg) as a solid.

[0516] .sup.1H NMR (CDCl.sub.3, 400 MHz) δ 7.85 (d, J=8.4 Hz, 2H), 7.43 (d, J=8.6 Hz, 2H), 3.45 (t, J=8.6 Hz, 1H), 2.48-2.38 (m, 1H), 1.87-1.66 (m, 4H), 1.56-1.46 (m, 5H), 1.42-1.25 (m, 9H), 1.24-1.16 (m, 5H), 1.05-0.95 (m, 1H), 0.84-0.76 (m, 1H), 0.74 (s, 3H), 0.60 (s, 3H). LCMS Rt=1.318 min in 2.0 min chromatography, 30-90 AB, MS ESI calcd. for C.sub.27H.sub.37ClO.sub.2 [M+H].sup.+ 429.3. found 411 [M−H.sub.2O].sup.+.

Example 83. Synthesis of Compound 82

[0517] ##STR00133##

[0518] To a stirred solution of 1-bromo-3-methylbenzene (45.1 mg, 0.264 mmol) in 3 mL of THF was added tert-butyllithium (1.3 M; 406 μL, 0.528 mmol) drop-wise at −65° C. under N.sub.2. After stirring at −65° C. for 2 hrs. B30 (50 mg, 0.132 mmol) was added. The mixture was stirred at 15° C. for 1 hour. LCMS showed the reaction was complete. The reaction mixture was quenched with Sat NH.sub.4Cl (30 mL) The mixture was extracted with EtOAc (20 mL×2), washed with brine (30 mL), dried over Na.sub.2SO.sub.4, filtered, and evaporated in vacuum to give crude product. The crude product was purified by HPLC separation (column: Phenomenex Synergi C18 150*25*10 um, gradient: 69-94% B (A=0.1% TFA-ACN, B=acetonitrile), flow rate: 30 mL/min) for further purification to obtain 82 (24.6 mg) as a solid.

[0519] .sup.1H NMR (CDCl.sub.3, 400 MHz) δ 7.70-7.60 (m, 2H), 7.36-7.29 (m, 2H), 3.47 (t, J=8.6 Hz, 1H), 2.48-2.33 (m, 4H), 1.80-1.67 (m, 3H), 1.52-1.41 (m, 6H), 1.41-1.22 (m, 9H), 1.19 (s, 4H), 1.16-1.07 (m, 1H), 1.03-0.92 (m, 1H), 0.82-0.74 (m, 1H), 0.71 (s, 3H), 0.60 (s, 3H). LCMS Rt=1.273 min in 2.0 min chromatography, 30-90 AB, MS ESI calcd. for C.sub.28H.sub.41O.sub.2 [M+H].sup.+ 409. found 409.

Example 84. Synthesis of Compound 83

[0520] ##STR00134##

[0521] To a solution of 1-bromo-3-fluorobenzene (460 mg, 2.63 mmol) in THF (3 mL) was added t-butyllithium (4.75 mL, 4.75 mmol) dropwise at −78° C. After stirring at −78° C. for 2 h a solution of A30 (100 mg, 0.264 mmol) in THF (1 mL) was added dropwise at 15° C. The reaction was stirred at 15° C. for 2 hours. TLC showed the reaction was completed. The reaction was quenched with sat. NH.sub.4Cl (20 mL) and extracted with EtOAc (20 mL×2). The combined organic layers were washed with brine (10 mL), dried over Na.sub.2SO.sub.4, filtered and evaporated. The crude residue was purified by prep-HPLC separation (column: Phenomenex Synergi C18 150*30 mm*4 um, gradient: 85-90% B (A=0.05% HCl-ACN, B=acetonitrile), flow rate: 30 mL/min) to obtain 83 (16.0 mg) as a solid.

[0522] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.65 (d, 1H) 7.56 (dt, 1H) 7.42 (td, 1H) 7.19-7.25 (m, 1H) 3.42 (t, 1H) 2.36-2.47 (m, 1H) 1.92-2.04 (m, 1H) 1.62-1.91 (m, 4H) 0.97-1.58 (m, 23H) 0.86-0.93 (m, 3H) 0.54-0.61 (m, 3H). LCMS Rt=0.893 min in 2.0 min chromatography, 10-80 AB, MS ESI calcd. for C.sub.27H.sub.38FO.sub.2 413 [M+H].sup.+. found 395.2 [M−H.sub.2O].sup.+.

Example 85. Synthesis of Compound 84

[0523] ##STR00135##

[0524] To a stirred solution of 1-bromo-2-fluorobenzene (229 mg, 1.31 mmol) in 3 mL of THF was added tert-butyllithium (1.3 M, 1.92 mL, 2.50 mmol) drop-wise at −78° C. under N.sub.2. After stirring at −78° C. for 1 hour, A30 (100 mg, 0.264 mmol) was added. The mixture was stirred at 25° C. for 1 hour. LCMS showed the reaction was complete. The reaction mixture was quenched with saturated NH.sub.4Cl (30 mL). The mixture was extracted with EtOAc (20 mL×2). The combined organic layer washed with brine (30 mL), dried over Na.sub.2SO.sub.4, filtered, and evaporated in vacuum to give crude product, which was purified by prep-HPLC separation (column: Phenomenex Synergi C18 150*30 mm*4 um, gradient: 81-81% B (A=0.05% HCl-ACN, B=acetonitrile), flow rate: 30 mL/min) to give 84 (18.7 mg) as a solid.

[0525] .sup.1H NMR (CDCl.sub.3, 400 MHz): δ 7.53 (t, J=6.8 Hz, 1H), 7.40-7.48 (m, 1H), 7.19 (t, J=7.4 Hz, 1H), 7.12-7.05 (m, 1H), 3.40 (t, J=8.8 Hz, 1H), 2.32-2.44 (m, 1H), 1.94 (t, J=13.4 Hz, 1H), 1.88-1.61 (m, 5H), 1.52-1.27 (m, 10H), 1.26-1.18 (m, 6H), 1.16-0.96 (m, 3H), 0.89 (s, 3H), 0.59 (s, 3H). LCMS Rt=1.205 mm in 2.0 min chromatography, 30-90 AB, MS ESI calcd. for C.sub.27H.sub.38FO.sub.2 413 [M+H].sup.+. found 395.2 [M−H.sub.2O].sup.+.

Example 86. Synthesis of Compound 85

[0526] ##STR00136##

[0527] To a stirred solution of 2-bromo-6-methoxynaphthalene (310 mg, 1.31 mmol) in 3 mL of THF was added tert-butyllithium (1.3 M, 1.92 mL, 2.50 mmol) drop-wise at −78° C. under N.sub.2. After stirring at −78° C. for 1 hour, A30 (100 mg, 0.264 mmol) was added. The mixture was stirred at 25° C. for 1 hour. LCMS showed the reaction was complete. The reaction mixture was quenched with saturated NH.sub.4Cl (30 mL). The mixture was extracted with EtOAc (20 mL×2). The combined organic layer washed with brine (30 mL), dried over Na.sub.2SO.sub.4, filtered and evaporated in vacuum to give crude product, which was purified by prep-HPLC separation (column: Phenomenex Synergi C18 150*30 mm*4 um, gradient: 85-90% B (A=0.05% HCl-ACN, B=acetonitrile), flow rate: 30 mL/min) to afford 85 (29.3 mg) as a solid.

[0528] .sup.1H NMR (CDCl.sub.3, 400 MHz): δ 8.33 (s, 1H), 7.96 (d, J=8.6 Hz, 1H), 7.85 (d, J=9.0 Hz, 1H), 7.75 (d, J=8.6 Hz, 1H), 7.20 (dd, J=8.8, 2.4 Hz, 1H), 7.15 (s, 1H), 3.95 (s, 3H), 3.64 (t, J=8.8 Hz, 1H), 2.44-2.52 (m, 1H), 1.94-2.02 (m, 1H), 1.76-1.91 (m, 3H), 1.66 (d, J=14.4 Hz, 1H), 1.29-1.54 (m, 12H), 1.21-1.28 (m, 5H), 0.97-1.19 (m, 3H), 0.90 (s, 3H), 0.62 (s, 3H). LCMS Rt=1.267 min in 2.0 min chromatography, 30-90 AB, MS ESI calcd. for C.sub.32H.sub.43O.sub.3 [M+H].sup.+ 475.3. found 457 [M−H.sub.2O].sup.+.

Example 87. Synthesis of Compound 86

[0529] ##STR00137##

[0530] To a stirred solution of 1-bromo-4-methylbenzene (186 mg, 1.09 mmol) in 3 mL of THF was added tert-butyllithium (1.3 M; 1.6 mL, 2.09 mmol) drop-wise at −78° C. under N.sub.2. After stirring at −78° C. for 2 hour, A10 (80 mg, 0.22 mmol) was added. The mixture was stirred at 25° C. for 1 hour. LCMS showed the reaction was complete. The reaction mixture was quenched with saturated NH.sub.4Cl (30 mL). The mixture was extracted with EtOAc (20 mL×2), washed with brine (30 mL), dried over Na.sub.2SO.sub.4, filtered, and evaporated in vacuum to give crude product. The crude product was purified by prep-HPLC separation (column: Phenomenex Synergi C18 150*30 mm*4 um, gradient: 80-100% B (A=0.05% HCl-ACN, B=acetonitrile), flow rate: 30 mL/min) to obtain 86 (23.7 mg) as a solid.

[0531] .sup.1H NMR (CDCl.sub.3, 400 MHz): δ 7.79 (d, J=8.0 Hz, 2H), 7.24 (d, J=8.0 Hz, 2H), 3.48 (t, J=8.6 Hz, 1H), 2.37-2.48 (m, 4H), 1.72-1.84 (m, 5H), 1.59-1.67 (m, 2H), 1.25-1.49 (m, 15H), 1.06-1.17 (m, 2H), 0.82-0.99 (m, 2H), 0.60 (s, 3H). LCMS Rt=1.233 min in 2.0 min chromatography, 30-90 AB, MS ESI calcd. for C.sub.27H.sub.39O.sub.2 [M+H].sup.+ 395.3. found 377 [M−H.sub.2O].sup.+.

Example 88. Synthesis of Compound 87

[0532] ##STR00138##

[0533] To a solution of 1-bromo-4-methylbenzene (203 mg, 1.09 mmol) in THF (0.3 mL) was added tert-butyllithium (1.68 mL, 1.3 M) at −60° C. The mixture was stirred at −60° C. for 1 hr. A solution of B10 (40 mg, 110 μmol) in THF (0.1 mL) was added into the mixture at −60° C. The reaction mixture was stirred at 25° C. for 2 hrs. TLC showed the reaction was complete. Saturation NH.sub.4Cl (1 mL) was added. The mixture was extracted with EtOAc (1.5 mL×3). The combined organic layers were dried over Na.sub.2SO.sub.4. The mixture was filtered. The filtrate was concentrated in vacuum. The residue was purified by purified by prep-HPLC (column: Phenomenex Synergi C18 150*30 mm*4 um, gradient 95-100% B (A=0.05% HCl-ACN, B=acetonitrile), flow rate: 25 mL/min) to give 87 (5 mg) as a solid.

[0534] .sup.1H NMR (400 MHz. CDCl.sub.3) δ 7.90 (d, J=8.8 Hz, 2H), 6.92 (d, J=8.8 Hz, 2H), 3.86 (s, 3H), 3.50-3.43 (m, 1H), 2.46-239 (m, 1H), 1.79-1.44 (m, 9H), 1.53-0.93 (m, 17H), 0.71-0.57 (m, 5H). LCMS t.sub.R=0.991 min in 1.5 min chromatography, 5-95 AB, MS ESI calcd. for C.sub.27H.sub.39O.sub.3 [M+H].sup.+ 411. found 411.

Example 89. Synthesis of Compound 88

[0535] ##STR00139##

Step 1.

[0536] To a solution of A35 (1 g, 3.26 mmol) in DCM (5 mL) was added PCC (1.05 g, 4.89 mmol) at 15° C. The mixture was stirred at 15° C. for 1 hr. TLC showed the reaction was complete. The solution was filtered and the filter cake was washed with DCM (50 mL×2). The combined filtrate was concentrated in vacuum. The residue was purified by silica gel column eluted with (PE/EtOAc=10/1) to afford A31 (300 mg) as a solid.

[0537] .sup.1H NMR (CDCl.sub.3, 400 MHz) δ 9.85-9.70 (m, 1H), 2.34-2.26 (m, 1H), 2.16-2.06 (m, 1H), 2.01-1.95 (m, 1H), 1.89-1.60 (m, 8H), 1.49-1.18 (m, 16H), 1.13-1.00 (m, 3H), 0.69 (s, 3H)

Step 2.

[0538] To a stirring solution of 2-(tert-butyldimethylsilyl)-N,N-dimethyl-1H-imidazole-1-sulfonamide (189 mg, 656 umol) in 2 mL of THF was added drop wise n-BuLi (2.5 M; 196 uL, 492 umol) at −65° C. After stirring at −65° C. for 40 min, a solution of A31 (100 mg, 328 umol) in 2 mL of THF was added drop wise at −65° C. After stirring at 15° C. for 2 h, TLC showed the reaction was complete. The reaction mixture was poured into ice-cold water and extracted with EtOAc (20 mL×2), washed with brine (50 mL), dried over Na.sub.2SO.sub.4, filtered and evaporated in vacuum to afford A33 (140 mg, crude) as a solid.

Step 3.

[0539] To a stirring solution of A33 (140 mg, 235 umol) in 5 mL of DCM was added Dess-Martin (199 mg, 470 umol) at 15° C. The mixture was stirring at 15° C. for 2 hours. TLC showed the reaction was complete. The reaction mixture was poured into sat. Na.sub.2S.sub.2O.sub.3 (20 mL) and extracted with EtOAc (20 mL×2), washed with brine (50 mL), dried over Na.sub.2SO.sub.4, filtered and evaporated in vacuum. The residue was purified by silica gel chromatography (PE/EA=10/1˜3/1) to afford A34 (70 mg) as a solid.

[0540] .sup.1H NMR (CDCl.sub.3, 400 MHz) δ 8.17 (s, 1H), 7.66 (s, 1H), 3.13-3.02 (m, 7H), 2.86 (s, 1H), 2.40-2.30 (m, 1H), 1.85-1.78 (m, 3H), 1.77-1.70 (m, 2H), 1.68-1.57 (m, 4H), 1.52-1.22 (m, 17H), 1.17-1.07 (m, 2H), 1.04-0.93 (m, 1H), 0.67 (s, 3H).

Step 4.

[0541] To a solution of A34 (30 mg, 62.8 umol) in THF (3 mL) was added hydrogen chloride (1 M, 125 uL, 125 umol) at 15° C. The mixture was stirred at 15° C. for 1 hr. and then the reaction mixture was quenched with saturated sat. NaHCO.sub.3 (30 mL). The mixture was extracted with EtOAc (20 mL×2). The combined organic layer washed with brine (30 mL), dried over Na.sub.2SO.sub.4, filtered and evaporated in vacuum to give crude product which was purified by prep-HPLC separation (column: Phenomenex Synergi C18 150*25*10 um, gradient: 29-54% B (A=0.225% FA-ACN, B=acetonitrile), flow rate: 30 mL/min) and then triturated with n-hexane (5 mL) to give 88 (8.8 mg) as a solid.

[0542] .sup.1H NMR (CDCl.sub.3, 400 MHz): δ 7.77 (s, 1H), 7.68 (s, 1H), 3.25-3.05 (m, 1H), 2.39-2.31 (m, 1H), 1.87-1.80 (m, 3H), 1.78-1.60 (m, 8H), 1.51-1.30 (m, 10H), 1.27 (s, 3H), 1.17-1.06 (m, 2H), 1.04-0.96 (m, 1H), 0.65 (s, 3H). LCMS Rt=1.000 min in 2.0 min chromatography, 10-80 AB, MS ESI calcd. for C.sub.23H.sub.35N.sub.2O.sub.2[M+H].sup.+ 371. found 371.

Example 90. Synthesis of Compound 89

[0543] ##STR00140##

[0544] To a stirred solution of 1-bromo-4-methylbenzene (224 mg, 1.31 mmol) in 3 mL of THF was added tert-butyllithium (1.3 M, 1.92 mL, 2.5 mmol) drop-wise at −78° C. under N.sub.2. After stirring at −78° C. for 1 hour, A30 (100 mg, 0.264 mmol) was added. The mixture was stirred at 25° C. for 1 hour. LCMS showed the reaction was complete. The reaction mixture was quenched with saturated NH.sub.4Cl (30 mL). The mixture was extracted with EtOAc (20 mL×2), washed with brine (30 mL), dried over Na.sub.2SO.sub.4, filtered, and evaporated in vacuum to give crude product, which was purified by prep-HPLC separation (column: Phenomenex Synergi C18 150*30 mm*4 um, gradient: 85-85% B (A=0.05% HCl-ACN, B=acetonitrile), flow rate: 30 mL/min) to give 89 (18.1 mg) as a solid.

[0545] .sup.1H NMR (CDCl.sub.3, 400 MHz): δ 7.79 (d, J=8.0 Hz, 2H), 7.23 (d, J=8.0 Hz, 2H), 3.47 (t, J=8.8 Hz, 1H), 2.38-2.48 (m, 4H), 1.97 (t, J=13.2 Hz, 1H), 1.62-1.90 (m, 5H), 1.32-1.51 (m, 10H), 1.20-1.30 (m, 6H), 1.08-1.18 (m, 2H), 1.04 (dd, J=14.1, 3.6 Hz, 1H), 0.91 (s, 3H), 0.58 (s, 3H). LCMS Rt=1.267 min in 2.0 min chromatography, 30-90 AB, MS ESI calcd. for C.sub.25H.sub.41O.sub.2[M+H].sup.+ 409. found 409.

Example 91. Synthesis of Compound 90

[0546] ##STR00141##

Step 1.

[0547] To a solution of B38 (10 g, 27.5 mmol) in dioxane/H.sub.2O (374 mL/110 mL) at 0° C. was added sodium hypobromide [prepared from NaOH (145 g), bromine (47.7 mL), dioxane (798 mL) and H.sub.2O (1230 mL)]. The resulting mixture was stirred at 25° C. for 24 hours and was cooled to 0° C. Saturated aqueous sodium sulfite solution (1000 mL) and aqueous HCl solution (1 M, 500 mL) were sequentially added. The mixture was extracted with ethyl acetate (1000 mL×2). The organic phase was washed with water (1000 mL×3), brine (1000 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and evaporated to afford B39 (8 g) as a solid.

[0548] .sup.1H NMR (DMSO-d.sub.6, 400 MHz) δ=11.90 (br. s., 1H), 3.89 (s, 1H), 3.67-3.61 (m, 1H), 3.43 (d, J=10.0 Hz, 1H), 3.31 (br. s., 1H), 3.20 (s, 3H), 2.25 (t, J=9.0 Hz, 1H), 2.00-1.77 (m, 3H), 1.72-1.28 (m, 11H), 1.22-0.99 (m, 11H), 0.95-0.81 (m, 1H), 0.76-0.67 (m, 1H), 0.63 (s, 3H).

Step 2.

[0549] To a solution of B39 (7.8 g, 21.3 mmol) in DMF (100 mL) was added HATU (9.69 g, 25.5 mmol), TEA (14.6 mL, 106 mmol) and N,O-dimethylhydroxylamine hydrochloride (7.26 g, 74.5 mmol) at 15° C. The mixture was stirred at 15° C. for 2 hrs. TLC (PE/EA=1/1) showed the reaction was complete. The mixture was poured into water (200 mL) and extracted with EtOAc (2×200 mL). The combined organic layer was washed with brine (100 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated. The residue was purified by column chromatography on silica (petroleum ether/ethyl acetate=10:1) to afford B40 (8 g) as a solid.

[0550] .sup.1H NMR (CDCl.sub.3, 400 MHz) δ=3.64 (s, 3H), 3.49-3.44 (m, 1H), 3.39-3.35 (m, 1H), 3.28 (s, 3H), 3.19 (s, 3H), 2.78 (br. s., 1H), 2.25-2.11 (m, 1H), 2.02 (td, J=3.4, 13.2 Hz, 1H), 1.84-1.62 (m, 5H), 1.59-1.41 (m, 6H), 1.34-1.04 (m, 11H), 0.96 (dd, J=4.8, 12.0 Hz, 1H), 0.85-0.72 (m, 4H). LCMS Rt=3.497 min in 7.0 min chromatography, 10-80 AB, MS ESI calcd. for C.sub.24H.sub.42NO.sub.4 [M+H].sup.+ 408. found 408.

Step 3.

[0551] To a stirred solution of 1-bromo-4-chlorobenzene (75 mg, 0.392 mmol) in 3 mL of THF was added tert-butyllithium (1.3 M; 587 uL, 0.764 mmol) dropwise at −65° C. under N.sub.2. After stirring at −65° C. for 2 hrs, B40 (80 mg, 0.196 mmol) in THF (1 mL) was added dropwise. The mixture was stirred at 15° C. for 1 hour. LCMS showed the reaction was complete. The reaction mixture was quenched with Sat. NH.sub.4Cl (30 mL). The mixture was extracted with EtOAc (20 mL×2), washed with brine (30 mL), dried over Na.sub.2SO.sub.4, filtered, and evaporated in vacuum to give crude product. The crude product was purified by HPLC separation (column: Phenomenex Synergi Max-RP 250*50 mm*10 urn, gradient: 88-93% B (A=0.05% HCl-ACN, B=acetonitrile), flow rate: 30 mL/min) to obtain 90 (19.7 mg) as a solid.

[0552] .sup.1H NMR (CDCl.sub.3, 400 MHz) δ 7.82 (d. J=8.6 Hz, 2H), 7.41 (d, J=8.6 Hz, 2H), 3.47-3.39 (m, 2H), 3.37-3.30 (m, 1H), 3.23 (s, 3H), 2.48-2.35 (m, 1H), 2.00-1.93 (m, 1H), 1.81-1.69 (m, 3H), 1.65-1.59 (m, 2H), 1.56-1.44 (m, 5H), 1.39-1.28 (m, 5H), 1.27-1.14 (m, 7H), 1.13-0.97 (m, 2H), 0.86-077 (m, 1H), 0.61 (s, 3H). LCMS Rt=3.085 min in 4.0 min chromatography, 30-90 AB, MS ESI calcd. for C.sub.28H.sub.40ClO.sub.3 [M+H].sup.+ 460.3. found 441 [M−H.sub.2O].sup.+.

Example 92. Synthesis of Compound 91

[0553] ##STR00142##

[0554] To a stirring solution of 2-bromo-1,1′-biphenyl (91.3 mg, 0.392 mmol) in 3 mL of THF was added tert-butyllithium (1.3 M, 587 μL, 0.764 mmol) dropwise at −65° C. under N.sub.2. After stirring at −65° C. for 2 hrs, a solution of B40 (80 mg, 0.196 mmol) in THF (1 mL) was added dropwise. The mixture was stirred at 15° C. for 1 hour. LCMS showed the reaction was complete. The reaction mixture was quenched with sat. NH.sub.4Cl (30 mL). The mixture was extracted with EtOAc (20 mL×2), washed with brine (30 mL), dried over Na.sub.2SO.sub.4, filtered, and evaporated in vacuum to give crude product. The crude product was purified by HPLC separation (column: Boston Green ODS 150*30 5u, gradient: 92-98% B (A=0.05% HCl-ACN, B=acetonitrile), flow rate: 25 mL/min) for further purification to obtain 91 (17.8 mg) as a solid.

[0555] .sup.1H NMR (CDCl.sub.3, 400 MHz) δ 7.51-7.30 (m, 9H), 3.38-3.34 (m, 1H), 3.30-3.25 (m, 1H), 3.22 (s, 3H), 2.31-2.25 (m, 1H), 2.23-2.14 (m, 1H), 1.93-1.86 (m, 1H), 1.51-1.32 (m, 8H), 1.31-1.16 (m, 6H), 1.15-0.69 (m, 8H), 0.64-0.54 (m, 5H). LCMS Rt=3.112 min in 4.0 min chromatography, 30-90 AB, MS ESI calcd. for C.sub.34H.sub.45O.sub.3 [M+H].sup.+ 501. found 501.

Example 93. Synthesis of Compound 92

[0556] ##STR00143##

[0557] To a stirring solution of 1-bromo-4-methylbenzene (67 mg, 0.392 mmol) in 3 mL of THF was added tert-butyllithium (1.3 M: 587 μL, 0.764 mmol) dropwise at −65° C. under N.sub.2. After stirring at −65° C. for 2 hrs, a solution of B40 (80 mg, 0.196 mmol) in THF (1 mL) was added dropwise. The mixture was stirred at 15° C. for 1 hour. LCMS showed the reaction was completed. The reaction mixture was quenched with sat. NH.sub.4Cl (30 mL). The mixture was extracted with EtOAc (20 mL×2), washed with brine (30 mL), dried over Na.sub.2SO.sub.4, filtered, and evaporated in vacuum to give crude product. The crude product was purified by HPLC separation (column: Boston Green ODS 150*30 5u, gradient: 82-98% B (A=0.05% HCl-ACN, B=acetonitrile), flow rate: 25 mL/min) for further purification to obtain 92 (24.9 mg) as a solid.

[0558] .sup.1H NMR (CDCl.sub.3, 400 MHz) δ 7.78 (d, J=8.0 Hz, 2H), 7.22 (d, J=8.0 Hz, 2H), 3.50-3.39 (m, 2H), 3.37-3.31 (m, 1H), 3.23 (s, 3H), 2.48-2.37 (m, 4H), 2.00-1.93 (m, 1H), 1.79-1.69 (m, 3H), 1.62-1.54 (m, 3H), 1.50-1.44 (m, 3H), 1.42-1.25 (m, 6H), 1.25-1.15 (m, 5H), 1.15-0.92 (m, 3H), 0.86-0.76 (m, 1H), 0.61 (s, 3H). LCMS Rt=2.954 min in 2.0 min chromatography, 30-90 AB, MS ESI calcd. for C.sub.29H.sub.43O.sub.3 [M+H].sup.+ 439. found 421 [M−H.sub.2O].sup.+.

Example 94. Synthesis of Compound 93

[0559] ##STR00144##

[0560] To a stirring solution of 1-bromo-3,5-dimethylbenzene (72.5 mg, 0.392 mmol) in 3 mL of THF was added tert-butyllithium (1.3 M; 587 uL, 0.764 mmol) dropwise at −65° C. under N.sub.2. After stirring at −65° C. for 2 hrs, a solution of B40 (80 mg, 0.196 mmol) in THF (1 mL) was added dropwise. The mixture was stirred at 15° C. for 1 hour. LCMS showed the reaction was complete. The reaction mixture was quenched with sat. NH.sub.4Cl (30 mL). The mixture was extracted with EtOAc (20 mL×2), washed with brine (30 mL), dried over Na.sub.2SO.sub.4, filtered, and evaporated in vacuum to give crude product. The crude product was purified by HPLC separation (column: Phenomenex Synergi Max-RP 250*50 mm*10 um, gradient: 88-93% B (A=0.05% HCl-ACN, B=acetonitrile), flow rate: 30 mL/min) for further purification to obtain 93 (47.4 mg) as a solid.

[0561] .sup.1H NMR (CDCl.sub.3, 400 MHz) δ 745 (s, 2H), 7.16 (s, 1H), 3.49-3.40 (m, 2H), 3.37-3.32 (m, 1H), 3.23 (s, 3H), 2.45-2.33 (m, 7H), 2.00-1.95 (m, 1H), 1.80-1.70 (m, 3H), 1.56-1.44 (m, 6H), 1.43-1.25 (m, 6H), 1.24-1.17 (m, 5H), 1.16-0.95 (m, 3H), 0.87-0.75 (m, 1H), 0.62 (s, 3H). LCMS Rt=3.124 min in 4.0 min chromatography, 30-90 AB, MS ESI calcd. for C.sub.30H.sub.45O.sub.3 [M+H].sup.+ 453. found 453.

Example 95. Synthesis of Compound 94

[0562] ##STR00145##

[0563] To a stirring solution of 5-bromobenzo[d][1,3]dioxole (78.7 mg, 0.392 mmol) in 3 mL of THF was added tert-butyllithium (1.3 M; 587 uL, 0.764 mmol) dropwise at −65° C. under N.sub.2. After stirring at −65° C. for 2 hrs, a solution of B40 (80 mg, 0.196 mmol) in THF (1 mL) was added dropwise. The mixture was stirred at 15° C. for 1 hour. LCMS showed the reaction was completed. The reaction mixture was quenched with sat. NH.sub.4Cl (30 mL). The mixture was extracted with EtOAc (20 mL×2), washed with brine (30 mL), dried over Na.sub.2SO.sub.4, filtered, and evaporated in vacuum to give crude product. The crude product was purified by HPLC separation (column Phenomenex Synergi Max-RP 250*50 mm*10 um, gradient: 88-93% B (A=0.05% HCl-ACN, B=acetonitrile), flow rate: 30 mL/min) to obtain 94 (28.2 mg) as a solid.

[0564] .sup.1H NMR (CDCl.sub.3, 400 MHz) δ 7.49 (dd, 1H), 7.39 (d, 1H), 6.83 (d, 1H), 6.03 (s, 2H), 3.45-3.33 (m, 3H), 3.24 (s, 3H), 2.45-2.36 (m, 1H), 2.01-1.95 (m, 1H), 1.77-1.68 (m, 3H), 1.60-1.50 (m, 2H), 1.53-1.42 (m, 5H), 1.42-1.18 (m, 10H), 1.15-0.96 (m, 3H), 0.86-0.77 (m, 1H), 0.61 (s, 3H). LCMS Rt=3.401 min in 4.0 min chromatography, 10-10 AB, MS ESI calcd. for C.sub.29H.sub.41O.sub.5 [M+H].sup.+ 469.3. found 451 [M−H.sub.2O].sup.+.

Example 96. Synthesis of Compound 95

[0565] ##STR00146##

[0566] To a stirring solution of 4-bromo-1,2-dimethylbenzene (72.5 mg, 0.392 mmol) in 3 mL of THF was added tert-butyllithium (1.3 M; 587 uL 0.764 mmol) dropwise at −65° C. under N.sub.2. After stirring at −65° C. for 2 hrs, a solution of B40 (80 mg, 0.196 mmol) in THF (1 mL) was added dropwise. The mixture was stirred at 15° C. for 1 hour. LCMS showed the reaction was complete. The reaction mixture was quenched with Sat. NH.sub.4Cl (30 mL). The mixture was extracted with EtOAc (20 mL×2), washed with brine (30 mL), dried over Na.sub.2SO.sub.4, filtered, and evaporated in vacuum to give crude product. The crude product was purified by HPLC separation (column: Phenomenex Synergi Max-RP 250*50 mm*10 um, gradient: 88-93% B (A=0.05% HCl-ACN, B=acetonitrile), flow rate: 30 mL/min) for further purification to obtain 95 (12 mg) as a solid.

[0567] .sup.1H NMR (CDCl.sub.3, 400 MHz) δ 7.65 (s, 1H), 7.60 (d, J=7.8 Hz, 1H), 7.17 (d, J=7.8 Hz, 1H), 3.49-3.39 (m, 2H), 3.37-3.31 (m, 1H), 3.23 (s, 3H), 2.47-2.36 (m, 1H), 2.30 (s, 6H), 2.00-1.95 (m, 1H), 1.78-1.68 (m, 3H), 1.54-1.44 (m, 6H), 1.42-1.17 (m, 11H), 1.16-0.92 (m, 3H), 0.86-0.75 (m, 1H), 0.61 (s, 3H). LCMS Rt=3.079 min in 4.0 min chromatography, 30-90 AB, MS ESI calcd. for C.sub.30H.sub.45O.sub.3 [M+H].sup.+ 453. found 453.

Example 97. Synthesis of Compound 96

[0568] ##STR00147##

[0569] To a stirring solution of 1-bromo-4-methoxy-2-methylbenzene (78.8 mg, 0.392 mmol) in 3 mL of THF was added tert-butyllithium (1.3 M; 587 uL, 0.764 mmol) dropwise at −65° C. under N.sub.2. After stirring at −65° C. for 2 hrs, a solution of B40 (80 mg, 0.196 mmol) in THF (1 mL) was added dropwise. The mixture was stirred at 15° C. for 1 hour. LCMS showed the reaction was complete. The reaction mixture was quenched with sat. NH.sub.4Cl (30 mL). The mixture was extracted with EtOAc (20 mL×2), washed with brine (30 mL), dried over Na.sub.2SO.sub.4, filtered, and evaporated in vacuum to give crude product. The crude product was purified by HPLC separation (column: Boston Green ODS 150*30 5u, gradient: 92-98% B (A=0.05% HCl-ACN, B=acetonitrile), flow rate: 25 mL/min) for further purification to obtain 96 (14.3 mg) as a solid.

[0570] .sup.1H NMR (CDCl.sub.3, 400 MHz) δ 7.53 (d, J=8.6 Hz, 1H), 6.76-6.68 (m, 2H), 3.83 (s, 3H), 3.44-3.40 (m, 1H), 3.36-3.29 (m, 2H), 3.23 (s, 3H), 2.47 (s, 3H), 2.44-2.34 (m, 1H), 1.99-1.90 (m, 1H), 1.77-1.67 (m, 3H), 1.51-1.41 (m, 6H), 1.39-1.12 (m, 11H), 1.11-0.94 (m, 3H), 0.81-0.72 (m, 1H), 0.64 (s, 3H). LCMS Rt=2.925 min in 4.0 min chromatography, 30-90 AB, MS ESI calcd. for C.sub.30H.sub.45O.sub.4 [M+H].sup.+ 469. found 469.

Example 98. Synthesis of Compound 97

[0571] ##STR00148##

[0572] To a stirring solution of 2-bromo-6-methoxynaphthalene (92.9 mg, 0.392 mmol) in 3 mL of THF was added tert-butyllithium (1.3 M; 587 uL, 0.764 mmol) dropwise at −65° C. under N.sub.2. After stirring at −65° C. for 2 hrs, a solution of B40 (80 mg, 0.196 mmol) in THF (1 mL) was added dropwise. The mixture was stirred at 15° C. for 1 hour. LCMS showed the reaction was completed. The reaction mixture was quenched with sat. NH.sub.4Cl (30 mL). The mixture was extracted with EtOAc (20 mL×2), washed with brine (30 mL), dried over Na.sub.2SO.sub.4, filtered, and evaporated in vacuum to give crude product. The crude product was purified by HPLC separation (column: Phenomenex Synergi Max-RP 250*50 mm*10 um, gradient: 84-84% B (A=0.05% HCl-ACN, B=acetonitrile), flow rate: 30 mL/min) for further purification to obtain 97 (36.5 mg) as a solid.

[0573] .sup.1H NMR (CDCl.sub.3, 400 MHz) δ 8.33 (s, 1H), 7.96 (dd, J=1.4, 8.7 Hz, 1H), 7.85 (d, J=9.0 Hz, 1H), 7.75 (d, J=8.6 Hz, 1H), 7.20 (dd, J=2.4, 8.9 Hz, 1H), 7.15 (d, J=2.4 Hz, 1H), 3.95 (s, 3H), 3.63 (t, J=8.8 Hz, 1H), 3.46-3.40 (m, 1H), 3.36-3.30 (m, 1H), 3.22 (s, 3H), 2.55-2.42 (m, 18H), 2.00-1.90 (m, 1H), 1.82-1.71 (m, 3H), 1.53-1.44 (m, 6H), 1.43-1.31 (m, 6H), 1.25-1.20 (m, 5H), 1.17-0.99 (m, 3H), 0.87-0.80 (m, 1H), 0.66 (s, 3H). LCMS Rt=1.278 min in 2.0 min chromatography, 30-90 AB. MS ESI calcd. for C.sub.33H.sub.45O.sub.4 [M+H].sup.+ 505.3. found 487 [M−H.sub.2O].sup.+.

Example 99. Synthesis of Compound 98

[0574] ##STR00149##

Step 1.

[0575] To a solution of A11 (1.0 g, 3.13 mmol) in 1,1-di-tert-butoxy-N,N-dimethylmethanamine (10 mL) was refluxed at 130° C. for 18 hours. The mixture was concentrated to give 8.4 g of crude product A12 which was used for next step directly.

[0576] LCMS Rt=1.754 min in 3.0 min chromatography, 10-80 AB, MS ESI calcd. for C.sub.24H.sub.40NO.sub.2 [M+H].sup.+ 374. found 374.

Step 2.

[0577] To a solution of crude A12 (1.16 g, 3.10 mmol, 8.4 g crude) in CH.sub.3CN (20 mL) was added 4-methylbenzenesulfonyl azide (3.05 g, 15.5 mmol). The mixture was stirred at 15° C. for 25 hours. LCMS showed the starting material was consumed, and the desired compound was determined by LCMS. The solution was quenched with Sat. Na.sub.2S.sub.2O.sub.3 (50 mL). The mixture was extracted with EA (50 mL×2). The combined organic phase was washed with brine (30 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuum to give the crude product (3.6 g). The crude product was purified by silica gel chromatography (PE:EA=1:1) to give product as solid (450 mg, crude), which was purified by prep-HPLC (column: Phenomenex Synergi C18 150*25*10 um, gradient: 38-63%/B (A=water (0.1% TFA), B=acetonitrile), flow rate: 30 ml/min) to afford 110 mg of 98.

[0578] .sup.1H NMR (400 MHz, CDCl3) δ 8.17 (s, 1H), 3.63 (t. J=8.5 Hz, 1H), 2.43-229 (m, 1H), 1.95-0.90 (m, 29H), 0.66 (s, 3H). LCMS Rt=1.860 min in 3.0 min chromatography, 10-80 AB, MS ESI calcd. for C.sub.22H.sub.34N.sub.3O.sub.2 [M+H].sup.+ 372. found 372.

Example 100. Synthesis of Compounds 99 and 100

[0579] ##STR00150##

[0580] To a solution of 98 (88 mg, 236 μmol) in CH.sub.3CN (1 mL) was added K.sub.2CO.sub.3 (97.7 mg, 708 mol) and MeI (0.650, 4.58 mmol). The reaction mixture was stirred at 15° C. for another 15 hrs. The starting material was consumed completely which was determined by LCMS. The reaction was quenched with aqueous sodium hypochlorite (5%, 20 mL). The mixture was extracted with EA (50 mL×3). The combined organic phase was washed with brine (40 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuum to give the crude product. The crude product was purified by silica gel chromatography (PE:EA=1:1) to give the crude 99 (25 mg) and 100 (13 mg). 99 was purified by prep-HPLC (column: Boston Green ODS 150*30 5u, gradient: 68-98% B (A=water (0.05% HCl), B=acetonitrile), flow rate: 25 mL/min) to give purified 99 (5 mg), the structure of 99 was randomly assigned. 100 was purified by prep-HPLC (column: Boston Green ODS 150*30 5u, gradient 65-95% B (A=water (0.05% HCl), B=acetonitrile), flow rate: 25 mL/min) to give 100 (4.2 mg).

[0581] 99: .sup.1H NMR (400 MHz, CDCl3) δ 7.99 (s, 1H), 4.24 (s, 3H), 3.53 (t, J=8.5 Hz, 1H), 2.42-2.25 (m, 1H), 2.09-0.84 (m, 32H), 0.65 (s, 3H). LCMS Rt=1.228 min in 2.0 min chromatography, 30-90 AB, MS ESI calcd for C.sub.23H.sub.36N.sub.3O.sub.2 [M+H].sup.+ 386. found 368 [M−H.sub.2O].sup.+.

[0582] 100: .sup.1H NMR (400 MHz, CDCl3) δ 8.01 (s, 1H), 4.14 (s, 3H), 3.83 (t, J=8.9 Hz, 1H), 2.38-2.25 (m, 1H), 1.88-0.81 (m, 35H), 0.65 (s, 3H). LCMS Rt=1.085 min in 2.0 min chromatography, 30-90 AB, MS ESI calcd. for C.sub.23H.sub.36N.sub.3O.sub.2 [M+H].sup.+ 386. found 386.

Example 101. Synthesis of Compound 101

[0583] ##STR00151##

[0584] To a stirred solution of 1-bromo-3-chlorobenzene (50.5 mg, 0.264 mmol) in 3 mL of THF was added tert-butyllithium (1.3 M, 406 uL, 0.528 mmol) dropwise at −65° C. under N.sub.2. After stirring at −65° C. for 2 hrs, B30 (50 mg, 0.132 mmol) was added. The mixture was stirred at 15° C. for 1 hour. LCMS showed the reaction was complete. The reaction mixture was quenched with Sat. NH.sub.4Cl (30 mL). The mixture was extracted with EtOAc (20 mL×2), washed with brine (30 mL), dried over Na.sub.2SO.sub.4, filtered, and evaporated in vacuum to give crude product. The crude product was purified by HPLC separation (column: Phenomenex Synergi C18 150*25*10 um, gradient: 72-97% B (A=0.225% FA-ACN, B=acetonitrile), flow rate: 30 mL/min) to obtain 30 mg of impure material. Additional HPLC separation (column: Phenomenex Synergi C18 250*21.2 mm*4 um, gradient: 95-95% B (A=0.05% HCl-ACN, B=acetonitrile), flow rate: 25 mL/min) gave 101 as (8.2 mg) a white solid.

[0585] .sup.1H NMR (CDCl.sub.3, 400 MHz) δ 7.84 (s, 1H), 7.74 (d, J=8.0 Hz, 1H), 7.50 (d, J=8.6 Hz, 1H), 7.41-7.35 (m, 1H), 3.41 (t, J=8.8 Hz, 1H), 2.43-2.35 (m, 1H), 1.84-1.65 (m, 4H), 1.53-1.44 (m, 5H), 1.38-1.22 (m, 9H), 1.21-1.11 (m, 5H), 1.03-0.92 (m, 1H), 0.82-0.75 (m, 1H), 0.71 (s, 3H), 0.59 (s, 3H). LCMS Rt=1.326 min in 2.0 min chromatography, 30-90 AB, MS ESI calcd. for C.sub.27H.sub.38ClO.sub.2[M+H].sup.+ 429.2. found 411 [M−H.sub.2O].sup.+.

Example 102. Synthesis of Compound 102

[0586] ##STR00152##

[0587] To a stirring solution of 1-bromo-4-(trifluoromethoxy)benzene (94.4 mg, 0.392 mmol) in 3 mL of THF was added tert-butyllithium (1.3 M; 587 uL, 0.764 mmol) dropwise at −65° C. under N.sub.2. After stirring at −65° C. for 2 hrs, a solution of B40 (80 mg, 0.196 mmol) in THF (1 mL) was added dropwise. The mixture was stirred at 15° C. for 1 hour. LCMS showed the reaction was completed. The reaction mixture was quenched with sat. NH.sub.4Cl (30 mL). The mixture was extracted with EtOAc (20 mL×2), washed with brine (30 mL), dried over Na.sub.2SO.sub.4, filtered, and evaporated in vacuum to give crude product. The crude product was purified by HPLC separation (column: Boston Green ODS 150*30 5u, gradient: 90-100% B (A=0.05% HCl-ACN, B=acetonitrile), flow rate: 30 mL/min) for further purification to obtain 102 (45.8 mg) as a solid.

[0588] .sup.1H NMR (CDCl.sub.3, 400 MHz) δ 7.92 (d, J=8.8 Hz, 2H), 7.25 (d, J=8.8 Hz, 2H), 3.47-3.40 (m, 2H), 3.36-3.32 (m, 1H), 3.23 (s, 3H), 2.47-2.35 (m, 1H), 2.00-1.94 (m, 1H), 1.79-1.70 (m, 3H), 1.53-1.43 (m, 6H), 1.41-1.27 (m, 6H), 1.26-1.18 (m, 5H), 1.16-0.96 (m, 3H), 0.86-0.78 (m, 1H), 0.62 (s, 3H). LCMS Rt=3.164 min in 4.0 min chromatography, 30-90 AB, MS ESI calcd. for C.sub.29H.sub.40F.sub.3O.sub.4[M+H].sup.+ 509.3. found 491 [M−H.sub.2O].sup.+.

Example 103. Synthesis of Compound 103

[0589] ##STR00153##

[0590] To a stirring solution of 1-bromo-3-methylbenzene (67 mg, 0.392 mmol) in 3 mL of THF was added tert-butyllithium (1.3 M; 587-μL, 0.764 mmol) dropwise at −65° C. under N.sub.2. After stirring at −65° C. for 2 hrs, a solution of B40 (80 mg, 0.196 mmol) in THF (1 mL) was added dropwise. The mixture was stirred at 15° C. for 1 hour. LCMS showed the reaction was completed. The reaction mixture was quenched with Sat. NH.sub.4Cl (30 mL). The mixture was extracted with EtOAc (20 mL×2), washed with brine (30 mL), dried over Na.sub.2SO.sub.4, filtered, and evaporated in vacuum to give crude product. The crude product was purified by HPLC separation (column: Boston Green ODS 150*30 5u, gradient 82-98% B (A=0.05% HCl-ACN, B=acetonitrile), flow rate: 25 mL/min) for further purification to obtain 103 (40.3 mg) as a solid.

[0591] .sup.1H NMR (CDCl.sub.3, 400 MHz) δ 7.69-7.62 (m, 2H), 7.36-7.28 (m, 2H), 3.50-3.40 (m, 2H), 3.37-3.31 (m, 1H), 3.23 (s, 3H), 2.48-2.37 (m, 4H), 2.00-1.93 (m, 1H), 1.80-1.70 (m, 3H), 1.65-1.50 (m, 4H), 1.48-1.44 (m, 2H), 1.38-1.25 (m, 6H), 1.25-1.18 (m, 5H), 1.16-0.93 (m, 3H), 0.86-0.78 (m, 1H), 0.62 (s, 3H). LCMS Rt=2.960 min in 4.0 min chromatography, 30-90 AB, MS ESI calcd. for C.sub.29H.sub.43O.sub.3 [M+H].sup.+ 439.3. found 421 [M−H.sub.2O].sup.+.

Example 104. Synthesis of Compound 104

[0592] ##STR00154##

[0593] To a stirring solution of l-bromo-4-ethylbenzene (72.5 mg, 0.392 mmol) in 3 mL of THF was added tert-butyllithium (1.3 M; 587 uL, 0.764 mmol) dropwise at −65° C. under N.sub.2. After stirring at −65° C. for 2 hrs, a solution of B40 (80 mg, 0.196 mmol) in THF (1 mL) was added dropwise. The mixture was stirred at 15° C. for 1 hour. LCMS showed the reaction was completed. The reaction mixture was quenched with sat. NH.sub.4Cl (30 mL). The mixture was extracted with EtOAc (20 mL×2), washed with brine (30 mL), dried over Na.sub.2SO.sub.4, filtered, and evaporated in vacuum to give crude product. The crude product was purified by HPLC separation (column: Phenomenex Synergi Max-RP 250*50 mm*10 um, gradient: 88-93% B (A=0.05% HCl-ACN, B=acetonitrile), flow rate: 30 mL/min) for further purification to obtain 104 (22.6 mg) as a solid.

[0594] .sup.1H NMR (CDCl.sub.3, 400 MHz) δ 7.80 (d, J=8.4 Hz, 2H), 7.24 (d, J=8.4 Hz, 2H), 3.49-3.40 (m, 2H), 3.36-3.31 (m, 1H), 3.23 (s, 3H), 2.69 (q, J=7.6 Hz, 2H), 2.49-2.36 (m, 1H), 2.01-1.93 (m, 1H), 1.77-1.68 (m, 3H), 1.54-1.44 (m, 6H), 1.41-1.34 (m, 2H), 1.33-1.16 (m, 12H), 1.16-0.95 (m, 3H), 0.86-0.77 (m, 1H), 0.62 (s, 3H). LCMS Rt=3.113 min in 4.0 min chromatography, 30-90 AB, MS EST calcd. for C.sub.30H.sub.45O.sub.3 [M+H].sup.+ 453. found 453.

Example 105. Synthesis of Compound 105

[0595] ##STR00155##

[0596] To a stirring solution of 1-bromo-2-methoxybenzene (228 mg, 1.22 mmol) in 3 mL of THF was added tert-butyllithium (1.3 M; 1.69 mL, 2.2 mmol) dropwise at −65° C. under N.sub.2. After stirring at −65° C. for 2 hrs, a solution of B40 (100 mg, 0.245 mmol) in THF (1 mL) was added dropwise. The mixture was stirred at 15° C. for 1 hour. LCMS showed the reaction was completed. The reaction mixture was quenched with sat. NH.sub.4Cl (30 mL). The mixture was extracted with EtOAc (20 mL×2), washed with brine (30 mL), dried over Na.sub.2SO.sub.4, filtered, and evaporated in vacuum to give crude product. The crude product was purified by HPLC separation (column: Phenomenex Synergi Max-RP 250*50 mm*10 um, gradient: 83-88% B (A=0.05% HCl-ACN, B=acetonitrile), flow rate: 30 mL/min) to obtain 105 (11.4 mg) as a solid.

[0597] .sup.1H NMR (CDCl.sub.3, 400 MHz) δ 7.40-7.34 (m, 1H), 7.31 (dd, J=1.6, 7.7 Hz, 1H), 6.96 (t, I=7.2 Hz, 1H), 6.90 (d, J=8.4 Hz, 1H), 3.84 (s, 3H), 3.51 (t, J=9.0 Hz, 1H), 3.44-3.38 (m, 1H), 3.35-3.29 (m, 1H), 3.23 (s, 3H), 2.41-2.30 (m, 1H), 2.00-1.90 (m, 1H), 1.78-1.67 (m, 4H), 1.53-1.40 (m, 7H), 1.33-1.26 (m, 2H), 1.25-1.20 (m, 5H), 1.18-0.87 (m, 5H), 0.80-0.70 (m, 1H), 0.63 (s, 3H). LCMS Rt=2.730 min in 4.0 min chromatography, 30-90 AB, MS ESI calcd. for C.sub.29H.sub.43O.sub.4 [M+H].sup.+ 455. found 455.

Example 106. Synthesis of Compound 106

[0598] ##STR00156##

[0599] To a stirring solution of 1-bromo-3-methoxybenzene (183 mg, 0.980 mmol) in 3 mL of THF was added tert-butyllithium (1.3 M, 1.35 mL, 1.76 mmol) dropwise at −65° C. under N.sub.2. After stirring at −65° C. for 2 hrs, a solution of B40 (80 mg, 0.196 mmol) in THF (1 mL) was added dropwise. The mixture was stirred at 15° C. for 1 hour. LCMS showed the reaction was completed. The reaction mixture was quenched with sat NH.sub.4Cl (30 mL). The mixture was extracted with EtOAc (20 mL×2), washed with brine (30 mL), dried over Na.sub.2SO.sub.4, filtered, and evaporated in vacuum to give crude product. The crude product was purified by HPLC separation (column: Phenomenex Synergi Max-RP 250*50 mm*10 um, gradient: 85-95% B (A=0.05% HCl-ACN, B=acetonitrile), flow rate: 30 mL/min) for further purification to obtain 106 (15.4 mg) as a solid.

[0600] .sup.1H NMR (CDCl.sub.3, 400 MHz) δ 7.45 (d, J=7.8 Hz, 1H), 7.39 (s, 1H), 7.33 (t, J=8.0 Hz, 1H), 7.07 (dd, J=2.0, 8.3 Hz, 1H), 3.85 (s, 3H), 3.48-3.39 (m, 2H), 3.36-3.31 (m, 1H), 3.23 (s, 3H), 2.47-2.35 (m, 1H), 1.97 (d, J=13.2 Hz, 1H), 1.81-1.69 (m, 3H), 1.52-1.17 (m, 17H), 1.16-0.92 (m, 3H), 0.85-0.75 (m, 1H), 0.62 (s, 3H). LCMS Rt=2.821 min in 2.0 min chromatography, 30-90 AB, MS ESI calcd. for C.sub.29H.sub.43O.sub.4[M+H].sup.+ 455. found 455.

Example 107. Synthesis of Compound 107

[0601] ##STR00157##

[0602] To a stirred solution of 1-bromo-4-methoxybenzene (91.6 mg, 0.490 mmol) in 3 mL of THF was added tert-butyllithium (1.3 M; 753 uL, 0.98 mmol) dropwise at −65° C. under N.sub.2. After stirring at −65° C. for 2 hrs, B40 (100 mg, 0.245 mmol) in THF (1 mL) was added dropwise. The mixture was stirred at 15° C. for 1 hour. LCMS showed the reaction was complete. The reaction mixture was quenched with Sat. NH.sub.4Cl (30 mL). The mixture was extracted with EtOAc (20 mL×2), washed with brine (30 mL), dried over Na.sub.2SO.sub.4, filtered, and evaporated in vacuum to give crude product. The crude product was purified by HPLC separation (column: Phenomenex Synergi C18 250*21.2 mm*4 um, gradient: 75-95% B (A=0.05% HCl-ACN, B=acetonitrile), flow rate: 25 mL/min) to obtain 107 (25.6 mg) as a solid.

[0603] .sup.1H NMR (CDCl.sub.3, 400 MHz) δ 7.89 (d, J=8.8 Hz, 2H), 6.91 (d, J=8.8 Hz, 2H), 3.86 (s, 3H), 3.49-3.39 (m, 2H), 3.37-3.30 (m, 1H), 3.23 (s, 3H), 2.49-2.35 (m, 1H), 2.01-1.93 (m, 1H), 1.78-1.68 (m, 3H), 1.54-1.39 (m, 7H), 1.38-1.17 (m, 10H), 1.16-0.92 (m, 3H), 0.85-0.75 (m, 1H), 0.61 (s, 3H). LCMS Rt=2.790 min in 4.0 min chromatography, 30-90 AB, MS ESI calcd, for C.sub.29H.sub.43O.sub.4 [M+H].sup.+ 455. found 455.

Example 108. Synthesis of Compound 108

[0604] ##STR00158##

[0605] To a stirred solution of 1-bromo-4-(trifluoromethoxy)benzene (127 mg, 0.528 mmol) in 3 mL of THF was added tert-butyllithium (1.3 M; 807 uL, 1.05 mmol) dropwise at −65° C. under N.sub.2. After stirring at −65° C. for 2 hrs, a solution of B30 (50 mg, 0.132 mmol) in THF (1 mL) was added dropwise. The mixture was stirred at 15° C. for 1 hour. LCMS showed the reaction was completed. The reaction mixture was quenched with Sat NH.sub.4Cl (30 mL). The mixture was extracted with EtOAc (20 mL×2), washed with brine (30 mL), dried over Na.sub.2SO.sub.4, filtered, and evaporated in vacuum to give crude product, which was purified by prep-HPLC separation (column Phenomenex Synergi C18 150*30 mm*4 um, gradient: 90-95% B (A=0.05% HCl-ACN, B=acetonitrile), flow rate: 25 mL/min) for further purification to obtain 108 (49.1 mg) as a solid.

[0606] .sup.1H NMR (CDCl.sub.3, 400 MHz) 7.93 (d, J=8.8 Hz, 2H), 7.26-7.23 (m, 2H), 3.44 (t, J=8.8 Hz, 1H), 2.47-2.34 (m, 1H), 1.80-1.67 (m, 3H), 1.55-1.41 (m, 6H), 1.40-1.22 (m, 9H), 1.20-1.13 (m, 5H), 1.04-0.91 (m, 1H), 0.83-0.74 (m, 1H), 0.71 (s, 3H), 0.59 (s, 3H). LCMS Rt=1.342 min in 2.0 min chromatography, 30-90 AB, MS ESI calcd. for C.sub.28H.sub.38F.sub.3O.sub.3 [M+H].sup.+ 479.3. found 461 [M−H.sub.2O].sup.+.

Example 109. Synthesis of Compound 109

[0607] ##STR00159##

[0608] To a stirring solution of 4-bromo-N,N-dimethylaniline (78.4 mg, 0.392 mmol) in 3 mL of THF was added tert-butyllithium (1.3 M; 587 uL, 0.764 mmol) dropwise at −65° C. under N.sub.2. After stirring at −65° C. for 2 hrs, a solution of B40 (80 mg, 0.196 mmol) in THF (1 mL) was added dropwise. The mixture was stirred at 15° C. for 1 hour. LCMS showed the reaction was completed. The reaction mixture was quenched with sat. NH.sub.4Cl (30 mL). The mixture was extracted with EtOAc (20 mL×2), washed with brine (30 mL), dried over Na.sub.2SO.sub.4, filtered, and evaporated in vacuum to give crude product. The crude product was purified by HPLC separation (column: Phenomenex Synergi Max-RP 250*50 mm*10 um, gradient: 83-88% B (A=0.05% HCl-ACN, B=acetonitrile), flow rate: 30 mL/min) for further purification to obtain 109 (26.3 mg) as a solid.

[0609] .sup.1H NMR (CDCl.sub.3, 400 MHz) δ 7.87 (d, J=8.8 Hz, 2H), 6.71 (d, J=8.0 Hz, 2H), 3.46-3.40 (m, 2H), 3.38-3.32 (m, 1H), 3.23 (s, 3H), 3.06 (s, 6H), 2.49-2.37 (m, 1H), 2.00-1.95 (m, 1H), 1.77-1.68 (m, 3H), 1.54-1.44 (m, 7H), 1.42-1.27 (m, 5H), 1.27-1.16 (m, 5H), 1.15-0.93 (m, 3H), 0.86-0.78 (m, 1H), 0.62 (s, 3H). LCMS Rt=2.113 min in 3.0 min chromatography, 30-90 AB, MS ESI calcd. for C.sub.30H.sub.46NO.sub.3 [M+H].sup.+ 468. found 468.

Example 110. Synthesis of Compound 110

[0610] ##STR00160##

[0611] To a stirring solution of 1-bromo-3-chlorobenzene (75 mg, 0.392 mmol) in 3 mL of THF was added tert-butyllithium (1.3 M; 587 uL, 0.764 mmol) dropwise at −65° C. under N.sub.2. After stirring at −65° C. for 2 hrs, B40 (80 mg, 0.196 mmol) in THF (1 mL) was added dropwise. The mixture was stirred at 15° C. for 1 hour. LCMS showed the reaction was completed. The reaction mixture was quenched with sat. NH.sub.4Cl (30 mL). The mixture was extracted with EtOAc (20 mL×2), washed with brine (30 mL), dried over Na.sub.2SO.sub.4, filtered, and evaporated in vacuum to give crude product. The crude product was purified by HPLC separation (column: Phenomenex Synergi Max-RP 250*50 mm*10 um, gradient: 88-93% B (A=0.05% HCl-ACN, B=acetonitrile), flow rate: 30 mL/min) for further purification to obtain 110 (10.3 mg) as a solid.

[0612] .sup.1H NMR (CDCl.sub.3, 400 MHz) δ 7.83 (t, J=1.8 Hz, 1H), 7.72 (d, J=7.8 Hz, 1H), 7.52-7.47 (m, 1H), 7.41-7.34 (m, 1H), 3.45-3.39 (m, 2H), 3.36-3.31 (m, 1H), 3.23 (s, 3H), 2.46-2.35 (m, 1H), 2.00-1.92 (m, 1H), 1.80-1.68 (m, 4H), 1.52-1.42 (m, 5H), 1.38-1.25 (m, 6H), 1.25-1.21 (m, 5H), 1.15-0.98 (m, 3H), 0.85-0.75 (m, 1H), 0.61 (s, 3H). LCMS Rt=3.113 min in 4.0 min chromatography, 30-90 AB, MS ESI calcd. for C.sub.28H.sub.40ClO.sub.3 [M+H].sup.+ 459.3. found 441 [M−H.sub.2O].sup.+.

Example 111. Synthesis of Compound 111

[0613] ##STR00161##

[0614] To a stirred solution of 4-bromo-N,N-dimethylaniline (110 mg, 0.550 mmol) in 3 mL of THF was added tert-butyllithium (1.3 M; 838 uL, 1.09 mmol) dropwise at −65° C. under N.sub.2. After stirring at −65° C. for 2 hrs, a solution of B10 (100 mg, 0.275 mmol) in THF (1 mL) was added dropwise. The mixture was stirred at 15° C. for 1 hour. LCMS showed the reaction was complete. The reaction mixture was quenched with Sat. NH.sub.4Cl (30 mL). The mixture was extracted with EtOAc (20 mL×2), washed with brine (30 mL), dried over Na.sub.2SO.sub.4, filtered, and evaporated in vacuum to give crude product, which was purified by HPLC separation (column: Phenomenex Synergi C18 150*25*10 um, gradient: 59-84% B (A=0.1% TFA-ACN, B=acetonitrile), flow rate: 30 mL/min) for further purification to obtain 111 (20 mg) as a solid.

[0615] .sup.1H NMR (CDCl.sub.3, 400 MHz) δ 7.87 (d, J=9.0 Hz, 2H), 6.66 (d, J=8.8 Hz, 2H), 3.45 (t, J=8.8 Hz, 1H), 3.05 (s, 6H), 2.45-2.38 (m, 1H), 1.71-1.48 (m, 9H), 1.45-1.24 (m, 6H), 1.20 (s, 3H), 1.15-0.93 (m, 6H), 0.78-0.64 (m, 2H), 0.61 (s, 3H). LCMS Rt=1.189 min in 2.0 min chromatography, 30-90 AB, MS ESI calcd. for C.sub.28H.sub.42NO.sub.2 [M+H].sup.+ 424. found 424.

Example 112. Synthesis of Compound 112

[0616] ##STR00162##

[0617] To a solution of 2-bromo-6-methoxynaphthalene (488 mg, 2.06 mmol) in THF (3 mL) was added tert-butyllithium (2.85 mL, 1.3 M in) at −70° C. The mixture was stirred at −70° C. for 1 h. A solution of B10 (150 mg, 0.4126 mmol) in THF (1 mL) was added at −70° C. The mixture was stirred at 25° C. for 1 hrs. The mixture was quenched with Sat. NH.sub.4Cl (10 mL), extracted with EtOAc (10 mL×3), washed with brine (30 mL×3), dried over Na.sub.2SO.sub.4, filtered, concentrated in vacuum to give a crude product, which was purified with prep. HPLC (Column: Phenomenex Synergi C18 150*30 mm*4 um; Condition: water (0.05%/HCl)-ACN; Gradient 90%-95% B; Gradient Time (min): 10; FlowRate (ml/min): 25) to give 112 (64.2 mg) as a solid.

[0618] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.35-8.31 (m, 1H), 7.98-7.94 (m, 1H), 7.85 (d, J=9.0 Hz, 1H), 7.75 (d, J=8.8 Hz, 1H), 7.22-7.17 (m, 1H), 7.16-7.14 (m, 1H), 3.95 (s, 3H), 3.64 (t, J=8.7 Hz, 1H), 2.57-2.39 (m, 1H), 1.84-1.59 (m, 7H), 1.45-1.24 (m, 7H), 1.20-0.93 (m, 10H), 0.82-0.57 (m, 5H). LCMS t.sub.R=1.096 min in 1.5 min chromatography, 5-95 AB, MS ESI calcd. for C.sub.31H.sub.41O.sub.3 [M+H].sup.+ 461. found 461.

Example 113. Synthesis of Compound 113

[0619] ##STR00163##

[0620] To a solution of 2-bromopyridine (165 mg, 1.05 mmol) in THF (5 mL) was added tert-butyllithium (1.45 mL) at −68° C. The mixture was stirred at −68° C. for 1 hrs. B30 (80 mg, 211 μmol) in THF (5 mL) was added dropwise at −68° C. The reaction was stirred at 25° C. for 1 hrs. LCMS showed the reaction was completed. The reaction was quenched with NH.sub.4Cl (10 mL), extracted with EtOAc (10 mL×2). The combined organic layers were washed with brine (10 mL). The organic layer was dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give crude product, which was purified by HPLC separation (column: Boston Green ODS 150*30 5u, gradient: 91-100% condition: (water (0.05% HCl)-ACN), flow rate: 25 mL/min) to give 113 (15 mg) as a solid.

[0621] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.67-8.66 (m, 1H), 7.95-7.93 (m, 1H), 7.82-7.81 (m, 1H), 7.44-7.41 (m, 1H), 4.21-4.17 (m, 1H), 2.36-2.31 (m, 1H), 1.78-1.69 (m, 3H), 1.47-1.18 (m, 22H), 1.12-0.92 (m, 1H), 0.78-0.75 (m, 1H), 0.71 (s, 3H), 0.62 (s, 3H). LCMS Rt=1.299 min in 2 min chromatography, 30-90 AB, MS ESI calcd. for C.sub.26H.sub.38NO.sub.2 [M+H].sup.+ 396. found 396.

Example 114. Synthesis of Compound 114

[0622] ##STR00164##

[0623] To a solution of 4-bromo-N,N-dimethylaniline (210 mg, 1.05 mmol) in THF (5 mL) was added tert-butyllithium (1.45 mL) at −68° C. The mixture was stirred at −68° C. for 1 hrs. A solution of B30 (80 mg, 211 μmol) in THF (5 mL) was added dropwise at −68° C. The reaction was stirred at 25° C. for 1 hrs. LCMS showed the reaction was completed. The reaction was quenched with NH.sub.4Cl (10 mL), extracted with EtOAc (10 mL×2). The combined organic layers were washed with brine (10 mL). The organic layer was dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give crude product, which was purified by HPLC separation (column: Boston Green ODS 150*30 5u, gradient: 92-98% condition: (water (0.05% HCl)-ACN), flow rate: 25 mL/min) to give 114 (57.2 mg) as a solid.

[0624] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.87 (d, J=9.0 Hz, 2H), 6.65 (d, J=9.0 Hz, 2H), 3.44 (t, J=8.8 Hz, 1H), 3.05 (s, 6H), 2.48-2.36 (m, 1H), 1.79-1.66 (m, 4H), 1.51-109 (m, 19H), 1.07-0.69 (m, 5H), 0.60 (s, 3H). LCMS Rt=1.032 min in 1.5 min chromatography, 5-95 AB, MS ESI calcd for C.sub.29H.sub.44NO.sub.2 [M+H].sup.+ 438. found 438.

Example 115. Synthesis of Compound 115

[0625] ##STR00165##

[0626] To a stirring solution of 2-bromopyridine (61.9 mg, 0.392 mmol) in 3 mL of THF was added tert-butyllithium (1.3 M; 587 uL, 0.764 mmol) dropwise at −65° C. under N.sub.2. After stirring at −65° C. for 2 hrs, a solution of B40 (80 mg, 0.196 mmol) in THF (1 mL) was added dropwise. The mixture was stirred at 15° C. for 1 hour. and then the reaction mixture was quenched with sat. NH.sub.4Cl (30 mL). The mixture was extracted with EtOAc (20 mL×2), washed with brine (30 mL), dried over Na.sub.2SO.sub.4, filtered, and evaporated in vacuum to give crude product. The crude product was purified by HPLC separation (column: Phenomenex Synergi Max-RP 250*50 mm*10 um, gradient 83-88% B (A=0.05% HCl-ACN, B=acetonitrile), flow rate: 30 ml/min) for further purification to obtain 115 (36.3 mg) as a solid.

[0627] .sup.1H NMR (CDCl.sub.3, 400 MHz) δ 8.67 (d, J=4.6 Hz, 1H), 7.93 (d, J=7.8 Hz, 1H), 7.82 (t, J=7.2 Hz, 1H), 7.47-7.41 (m, 1H), 4.19 (t, J=9.0 Hz, 1H), 3.46-3.41 (m, 1H), 3.36-3.31 (m, 1H), 3.23 (s, 3H), 2.40-2.27 (m, 1H), 2.00-1.92 (m, 1H), 1.85-1.68 (m, 4H), 1.54-1.44 (m, 5H), 1.44-1.26 (m, 6H), 1.25-1.13 (m, 5H), 1.12-0.96 (m, 3H), 0.85-0.75 (m, 1H), 0.64 (s, 3H). LCMS Rt=3.208 min in 4.0 min chromatography, 10-80 AB, MS ESI calcd. for C.sub.27H.sub.40NO.sub.3 [M+H].sup.+ 426. found 426.

Example 116. Synthesis of Compound 116

[0628] ##STR00166##

[0629] To a solution of 1-bromo-4-ethylbenzene (381 mg, 2.06 mmol) in THF (3 mL) was added tert-butyllithium (2.85 mL, 1.3 M in THF) at −70° C. The mixture was stirred at −70° C. for 1 h. A solution of B10 (150 mg, 0.4126 mmol) in THF (1 mL) was added at −70° C. and the mixture was stirred at 25° C. for 1 hr. The mixture was quenched with Sat. NH.sub.4Cl (10 mL), extracted with EtOAc (10 mL×3), washed with brine (30 mL×3), dried over Na.sub.2SO.sub.4, filtered, concentrated in vacuum to give a crude product which was purified with prep. HPLC (Column: Phenomenex Synergi C18 150*30 mm*4 um; Condition: water (0.05% HCl)-ACN: Gradient 90%-95% B; Gradient Time (min): 10; FlowRate (ml/min): 25) to give 116 (84.4 mg) as a solid.

[0630] .sup.1HNMR (400 MHz, CDCl.sub.3) δ 7.82 (d, J=8.3 Hz, 2H), 7.25 (d, J=8.3 Hz, 2H), 3.48 (t, J=8.7 Hz, 1H), 2.70 (q, J=7.7 Hz, 2H), 2.50-2.26 (m, 1H), 1.77-1.59 (m, 6H), 1.55-1.50 (m, 1H), 1.45-0.85 (m, 20H), 0.77-0.57 (m, 5H). LCMS t.sub.R=1.090 min in 1.5 min chromatography, 5-95 AB, MS ESI calcd. for C.sub.28H.sub.41O.sub.2 [M+H].sup.+ 409. found 409.

Example 117. Synthesis of Compound 117

[0631] ##STR00167##

[0632] To a solution of 1-bromo-2-methoxybenzene (256 mg, 1.37 mmol) in THF (5 mL) was added tert-butyllithium (1.90 mL, 2.47 mmol) at −68° C. The mixture was stirred at −68° C. for 1 hour. B10 (100 mg, 275 μmol) in THF (5 mL) was added dropwise at −68° C. The reaction was stirred at 25° C. for 2 hours. The reaction was quenched with NH.sub.4Cl (10 mL), extracted with EtOAc (10 mL×2). The combined organic layers were washed with brine (10 mL). The organic layer was dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give crude product which was purified by HPLC separation (Phenomenex Synergi C18 150*30 mm*4 um, gradient: 90-98% condition: (water (0.05% HCl)-ACN), flow rate: 25 mL/min) to give 117 (27.7 mg) as a solid.

[0633] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.42-7.36 (m, 1H), 7.32 (dd, J=1.8, 7.5 Hz, 1H), 7.01-6.89 (m, 2H), 3.85 (s, 3H), 3.56-3.49 (m, 1H), 2.40-2.29 (m, 1H), 1.83-1.74 (m, 1H), 1.69-1.49 (m, 7H), 1.36-1.21 (m, 5H), 1.19 (s, 3H), 1.16-0.83 (m, 7H), 0.70-0.56 (m, 5H). LCMS Rt=1.283 min in 2 min chromatography, 30-90 AB, MS ESI calcd. for C.sub.27H.sub.39O.sub.3 [M+H].sup.+ 411. found 411.

Example 118. Synthesis of Compound 118

[0634] ##STR00168##

[0635] To a solution of 1-bromo-4-chlorobenzene (275 mg, 1.37 mmol) in THF (5 mL) was added tert-butyllithium (1.90 mL, 2.47 mmol) at −68° C. The mixture was stirred at −68° C. for 1 hour. B10 (100 mg, 275 μmol) in THF (5 mL) was added dropwise at −68° C. The reaction was stirred at 25° C. for 2 hours. The reaction was quenched with NH.sub.4Cl (10 mL), extracted with EtOAc (10 mL×2) The combined organic layers were washed with brine (10 mL). The organic layer was dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give crude product which was purified by HPLC separation (Phenomenex Synergi C18 150*30 mm*4 um, gradient: 90-98%0/condition: (water (0.05% HCl)-ACN), flow rate: 25 mL/min) to give 118 (27.4 mg) as a solid.

[0636] .sup.1H NMR (400 MHz, CDCl3) δ 7.82 (d, J=8.4 Hz, 2H), 7.41 (d, J=8.4 Hz, 2H), 3.44 (t, J=8.7 Hz, 1H), 2.47-2.36 (m, 1H), 1.82-1.65 (m, 5H), 1.64-1.61 (m, 1H), 1.55-1.56 (m, 1H), 1.55-1.50 (m, 1H), 1.35-1.32 (m, 6H), 1.22-0.85 (m, 10H), 0.78-0.57 (m, 5H). LCMS Rt=1.411 min in 2 min chromatography, 30-90 AB, MS ESI calcd. for C.sub.26H.sub.36ClO.sub.2 [M+H].sup.+ 415. found 415.

Example 119. Synthesis of Compound 119

[0637] ##STR00169##

[0638] To a solution of 6-bromobenzo[d][1,3]dioxole (275 mg, 1.37 mmol) in THF (5 mL) was added tert-butyllithium (1.90 mL, 2.47 mmol) at −68° C. The mixture was stirred at −68° C. for 1 hrs. B10 (100 mg, 275 μmol) in THF (5 mL) was added dropwise at −68° C. The reaction was stirred at 25° C. for 2 hours. The reaction was quenched with NH.sub.4Cl (10 mL), extracted with EtOAc (10 mL×2). The combined organic layers were washed with brine (10 mL). The organic layer was dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give crude product which was purified by HPLC separation (Phenomenex Synergi C18 150*30 mm*4 um, gradient: 90-98% condition: (water (0.05% HCl)-ACN), flow rate: 25 mL/min) to give 119 (41.2 mg) as a solid.

[0639] .sup.1H NMR (400 MHz, CDCl3) δ 7.50 (dd, J=1.6, 8.2 Hz, 1H), 7.40 (d, J=1.5 Hz, 1H), 6.83 (d, J=8.3 Hz, 1H), 6.04 (s, 2H), 3.40 (t, J=8.5 Hz, 1H), 2.46-2.35 (m, 1H), 1.79-1.61 (m, 6H), 1.52-1.54 (m, 1H), 1.44-1.48 (m, 1H), 1.40-1.24 (m, 5H), 1.22-1.16 (m, 4H), 1.16-0.92 (m, 6H), 0.60 (m, 5H). LCMS Rt=1.293 min in 2 min chromatography, 30-90 AB, MS ESI calcd. for C.sub.27H.sub.37O.sub.4 [M+H].sup.+ 425. found 425.

Example 120. Synthesis of Compound 120

[0640] ##STR00170##

[0641] To a solution of 2-bromo-1,1′-biphenyl (319 mg, 1.37 mmol) in THF (5 mL) was added tert-butyllithium (1.90 mL, 2.47 mmol) at −68° C. The mixture was stirred at −68° C. for 1 hour. B10 (100 mg, 275 μmol) in THF (5 mL) was added dropwise at −68° C. The reaction was stirred at 25° C. for 2 hours. The reaction was quenched with NH.sub.4Cl (10 mL), extracted with EtOAc (10 mL×2). The combined organic layers were washed with brine (10 mL). The organic layer was dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give crude product which was purified by HPLC separation (Phenomenex Synergi C18 150*30 mm*4 um, gradient: 90-98% condition: (water (0.05% HCl)-ACN), flow rate: 25 mL/min) to give 120 (30.7 mg) as a solid.

[0642] .sup.1H NMR (400 MHz, CDCl3) δ 7.53-7.30 (m, 9H), 2.36-2.27 (m, 1H), 2.23-2.10 (m, 1H), 1.54-1.39 (m, 6H), 1.34-1.19 (m, 3H), 1.17 (s, 3H), 1.15-0.63 (m, 13H), 0.62-0.44 (m, 5H). LCMS Rt=1.099 min in 2 min chromatography, 5-95 AB, MS ESI calcd. for C.sub.32H.sub.41O.sub.2 [M+H].sup.+ 457. found 457.

Example 121. Synthesis of Compound 121

[0643] ##STR00171##

[0644] To a solution of 3-bromopyridine (325 mg, 2.06 mmol) in THF (3 mL) was added tert-butyllithium (2.85 mL, 1.3 M in THF) at −70° C. The mixture was stirred at −70° C. for 1 h. A solution of B10 (150 mg, 0.4126 mmol) in THF (1 mL) was added at −70° C. The mixture was stirred at 25° C. for 1 hrs. The mixture was quenched with Sat. NH.sub.4Cl (10 mL), extracted with EtOAc (10 mL×3), washed with brine (30 mL×3), dried over Na.sub.2SO.sub.4, filtered, concentrated in vacuum to give a crude product, which was purified with prep. HPLC (Column: Boston Green ODS 150*30 5u; Condition: water (0.05% HCl)-CAN; Gradient: 60%-90% B; Gradient Time (min): 10; 100% B Hold Time (min): 4; FlowRate (ml/min): 25) to give 121 (68 mg) as a solid.

[0645] .sup.1H NMR (400 MHz, CD.sub.3OD) δ 9.08 (s, 1H), 8.78 (d, J=3.5 Hz, 1H), 8.44 (d, J=8.3 Hz, 1H), 7.68 (dd, J=5.0, 8.0 Hz, 1H), 3.66 (t, J=8.5 Hz, 1H), 2.48-2.36 (m, 1H), 1.87-1.61 (m, 7H), 1.55-1.44 (m, 3H), 1.37-0.98 (m, 13H), 0.83-0.59 (m, 5H). LCMS tR=0.881 min in 1.5 min chromatography, 5-95 AB, MS ESI calcd. for C.sub.25H.sub.36NO.sub.2 [M+H].sup.+ 382. found 382.

Example 122. Synthesis of Compound 122

[0646] ##STR00172##

[0647] To a solution of 2-bromopyridine (325 mg, 2.06 mmol) in THF (3 mL) was added tert-butyllithium (2.85 mL, 1.3 M in THF) at −70° C. The mixture was stirred at −70° C. for 1 h. A solution of B10 (150 mg, 0.4126 mmol) in THF (1 mL) was added at −70° C. The mixture was stirred at 25° C. for 1 hrs. The mixture was quenched with Sat. NH.sub.4Cl (10 mL), extracted with EtOAc (10 mL×3), washed with brine (30 mL×3), dried over Na.sub.2SO.sub.4, filtered, concentrated in vacuum to give a crude product, which was purified with prep. HPLC (Column: Phenomenex Synergi C18 150*30 mm*4 um; Condition: water (0.05% HCl)-ACN; Gradient 90%-95% B; Gradient Time (min): 10; FlowRate (ml/min): 25) to give 122 (17.7 mg,) as a solid.

[0648] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.68-8.64 (m, 1H), 7.96-7.92 (m, 1H), 7.84-7.77 (m, 1H), 7.45-7.40 (m, 1H), 4.20 (t, J=9.0 Hz, 1H), 2.39-2.24 (m, 1H), 1.85-1.60 (m, 7H), 1.52-1.25 (m, 6H), 1.21-0.85 (m, 11H), 0.78-0.56 (m, 5H). LCMS t.sub.R=0.998 min in 1.5 min chromatography, 5-95 AB, MS ESI calcd. for C.sub.25H.sub.35NO.sub.2 [M+H].sup.+ 382. found 382.

Example 123. Synthesis of Compound 123

[0649] ##STR00173##

[0650] To a solution of 3-bromo-1-methyl-1H-pyrazole (169 mg, 1.05 mmol) in THF (5 mL) was added tert-butyllithium (1.45 mL) at −68° C. The mixture was stirred at −68° C. for 1 hrs. B30 (80 mg, 211 μmol) in THF (5 mL) was added dropwise at −68° C. The reaction was stirred at 25° C. for 1 hour. LCMS showed the reaction was completed. The reaction mixture was quenched with NH.sub.4Cl (10 mL), extracted with EtOAc (10 mL×2). The combined organic layers were washed with brine (10 mL). The organic layer was dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give crude product, which was purified by HPLC separation (column: Boston Green ODS 150*30 5u, gradient: 92-98% condition: (water (0.05% HCl)-ACN), flow rate: 25 mL/min) to give 123 (6.4 mg) as a solid.

[0651] .sup.1H NMR (400 MHz, CDCl3) δ 7.35-7.34 (m, 1H), 6.75-6.74 (m, 1H), 3.96 (s, 3H), 3.62 (t, J=8.7 Hz, 1H), 2.38-2.26 (m, 1H), 1.83-1.67 (m, 3H), 1.56-1.09 (m, 19H), 1.07-0.91 (m, 1H), 0.89-0.69 (m, 4H), 0.65 (s, 3H). LCMS Rt=0.956 min in 1.5 min chromatography, 5-95 AB, MS ESI calcd. for C.sub.25H.sub.39N.sub.2O.sub.2 [M+H].sup.+ 399. found 399.

Example 124. Synthesis of Compound 124

[0652] ##STR00174##

[0653] To a solution of 4-bromo-1-methyl-1H-pyrazole (169 mg, 1.05 mmol) in THF (5 mL) was added tert-butyllithium (1.45 mL) at −68° C. The mixture was stirred at −68° C. for 1 hr. B30 (80 mg, 211 umol) in THF (5 mL) was added dropwise at −68° C. The reaction mixture was stirred at 25° C. for 1 hour. LCMS showed the reaction was completed. The reaction was quenched with NH.sub.4Cl (10 mL), extracted with EtOAc (10 mL×2). The combined organic layers were washed with brine (10 mL). The organic layer was dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give crude product, which was purified by HPLC separation (column: Boston Green ODS 150*30 5u, gradient: 92-98% condition: (water (0.05% HCl)-ACN), flow rate: 25 mL/min) to give 124 (23 mg) as a solid.

[0654] .sup.1H NMR (400 MHz, CDCl3) δ 7.87 (s, 1H), 7.83 (s, 1H), 3.93 (s, 3H), 3.04-2.97 (m, 1H), 2.42-2.29 (m, 1H), 1.78-1.62 (m, 5H), 1.55-1.11 (m, 21H), 1.06-0.91 (m, 1H), 0.85-0.69 (m, 4H), 0.62 (s, 3H). LCMS Rt=1.124 min in 2 min chromatography, 30-90 AB, MS ESI calcd. for C.sub.25H.sub.39N.sub.2O.sub.2[M+H].sup.+ 399. found 399.

Example 125. Synthesis of Compound 125

[0655] ##STR00175##

[0656] To a solution of 3-bromopyridine (206 mg, 1.31 mmol) in THF (5 mL) was added tert-butyllithium (1.82 mL) at −68° C. The mixture was stirred at −68° C. for 1 hour. B30 (100 mg, 264 μmol) in THF (5 mL) was added dropwise at −68° C. The reaction was stirred at 25° C. for 1 hour. LCMS showed the reaction was completed. The reaction mixture was quenched with NH.sub.4Cl (10 mL), extracted with EtOAc (10 mL×2) The combined organic layers were washed with brine (10 mL). The organic layer was dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give crude product, which was purified by HPLC separation (column: Boston Green ODS 150*30 5u, gradient: 92-98% condition: (water (0.05% HCl)-ACN), flow rate: 25 mL/min) to give 125 (7.4 mg) as a solid.

[0657] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 9.25-9.15 (m, 1H), 8.85-8.70 (m, 1H), 8.25-2.15 (m, 1H), 7.55-7.40 (m, 1H), 3.50-3.40 (m, 1H), 2.51-2.36 (m, 1H), 1.93-1.62 (m, 11H), 1.56-1.08 (m, 26H), 1.07-0.65 (m, 7H), 0.60 (s, 3H). LCMS Rt=0.903 min in 1.5 min chromatography, 5-95 AB, MS ESI calcd. for C.sub.26H.sub.38NO.sub.2 [M+H].sup.+ 396. found 396.

Example 126. Synthesis of Compound 126

[0658] ##STR00176##

[0659] To a stirred solution of 1-bromo-2-fluorobenzene (68.5 mg, 0.392 mmol) in 3 mL of THF was added tert-butyllithium (1.3 M; 587 uL, 0.764 mmol) dropwise at −65° C. under N.sub.2. After stirring at −65° C. for 2 hrs, B40 (80 mg, 0.196 mmol) in THF (1 mL) was added dropwise. The mixture was stirred at 15° C. for 1 hour. LCMS showed the reaction was complete. The reaction mixture was quenched with Sat. NH.sub.4Cl (30 mL). The mixture was extracted with EtOAc (20 mL×2), washed with brine (30 mL), dried over Na.sub.2SO.sub.4, filtered, and evaporated in vacuum to give crude product. The crude product was purified by HPLC separation (column: Phenomenex Synergi Max-RP 250*50 mm*10 um, gradient: 85-90% B (A=0.05% HCl-ACN, B=acetonitrile), flow rate: 30 mL/min) to obtain 126 (19.4 mg) as a solid.

[0660] .sup.1H NMR (CDCl.sub.1, 400 MHz) δ 7.51 (dt, J=1.8, 7.6 Hz, 1H), 7.48-7.39 (m, 1H), 7.22-7.14 (m, 1H), 7.08 (dd, J=8.3, 10.8 Hz, 1H), 3.43-3.36 (m, 2H), 3.34-3.29 (m, 1H), 3.23 (s, 3H), 2.45-2.32 (m, 1H), 1.94 (td, J=3.5, 13.1 Hz, 1H), 1.83-1.66 (m, 4H), 1.51-1.41 (m, 6H), 1.34-1.16 (m, 10H), 1.15-0.90 (m, 3H), 0.82-0.71 (m, 1H), 0.62 (s, 3H). LCMS Rt=2.809 min in 4.0 min chromatography, 30-90 AB, MS ESI calcd. for C.sub.28H.sub.40FO.sub.3 [M+H].sup.+ 443.3. found 425 [M−H.sub.2O].sup.+.

Example 127. Synthesis of Compound 127

[0661] ##STR00177##

[0662] To a solution of 2-bromo-1,1′-biphenyl (244 mg, 1.05 mmol) in THF (5 mL) was added tert-butyllithium (1.45 mL) at −68° C. The mixture was stirred at −68° C. for 1 hrs. A solution of B30 (80 mg, 211 μmol) in THF (5 mL) was added dropwise at −68° C. The reaction was stirred at 25° C. for 1 hour. LCMS showed the reaction was completed. The reaction was quenched with NH.sub.4Cl (10 mL), extracted with EtOAc (10 mL×2). The combined organic layers were washed with brine (10 mL). The organic layer was dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give crude product, which was purified by HPLC separation (column: Boston Green ODS 150*30 5u, gradient: 91-100% condition: (water (0.05% HCl)-ACN), flow rate: 25 mL/min) to give 127 (27.3 mg) as a solid.

[0663] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.53-7.30 (m, 9H), 2.33-2.26 (m, 1H), 2.22-2.09 (m, 1H), 1.50-0.62 (m, 27H), 0.56 (m, 4H). LCMS Rt=1.473 min in 2 min chromatography, 30-90 AB, MS ESI calcd. for C.sub.33H.sub.43O.sub.2[M+H].sup.+ 471. found 471.

Example 128. Synthesis of Compound 128

[0664] ##STR00178##

[0665] To a solution of 2-bromo-6-methoxynaphthalene (248 mg, 1.05 mmol) in THF (5 mL) was added tert-butyllithium (1.45 mL) at −68° C. The mixture was stirred at −68° C. for 1 hrs. A solution of B30 (80 mg, 211 μmol) in THF (5 mL) was added dropwise at −68° C. The reaction was stirred at 25° C. for 1 hour. LCMS showed the reaction was completed. The reaction was quenched with NH.sub.4Cl (10 mL), extracted with EtOAc (10 mL×2). The combined organic layers were washed with brine (10 mL). The organic layer was dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give crude product, which was purified by HPLC separation (column: Boston Green ODS 150*30 5u, gradient: 92-98% condition: (water (0.05% HCl)-ACN), flow rate: 25 mL/min) to give 128 (42.9 mg) as a solid.

[0666] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.34 (s, 1H), 7.97 (dd, J=1.5, 8.5 Hz, 1H), 7.86 (d, J=8.8 Hz, 1H), 7.76 (d, J=8.5 Hz, 1H), 7.23-7.14 (m, 2H), 3.95 (s, 3H), 3.64 (t, J=8.7 Hz, 1H), 2.53-2.43 (m, 1H), 1.85-1.69 (m, 3H), 1.50-1.17 (m, 19H), 1.16-0.93 (m, 2H), 0.85-0.76 (m, 1H), 0.71 (s, 3H), 0.63 (s, 3H). LCMS Rt=1.100 min in 1.5 min chromatography, 5-95 AB, MS ESI calcd. for C.sub.32H.sub.43O.sub.3[M+H].sup.+ 475. found 475.

Example 129. Synthesis of Compound 129

[0667] ##STR00179##

[0668] To a solution of (220 mg, 1.37 mmol) in THF (5 mL) was added tert-butyllithium (1.90 mL, 2.47 mmol) at −68° C. The mixture was stirred at −68° C. for 1 hour. B10 (100 mg, 275 μmol) in THF (5 mL) was added dropwise at −68° C. The reaction was stirred at 25° C. for 2 hours. The reaction was quenched with NH.sub.4Cl (10 mL), extracted with EtOAc (10 mL×2). The combined organic layers were washed with brine (10 mL). The organic layer was dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give crude product which was purified by HPLC separation (Phenomenex Synergi C18 150*30 mm*4 um, gradient: 90-98% condition: (water (0.05% HCl)-ACN), flow rate: 25 mL/min) to give 129 (25.9 mg) as a solid.

[0669] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.87 (s, 1H), 7.83 (s, 1H), 3.93 (s, 3H), 3.02 (t, J=8.9 Hz, 1H), 2.42-2.32 (m, 1H), 1.81-1.62 (m, 8H), 1.61-1.55 (m, 2H), 1.43-1.24 (m, 5H), 1.20 (s, 3H), 1.18-0.95 (m, 6H), 0.80-0.60 (m, 5H). LCMS Rt=1.058 min in 2 min chromatography, 30-90 AB, MS ESI calcd. for C.sub.24H.sub.37N.sub.2O.sub.2[M+H].sup.+ 385. found 385.

Example 130. Synthesis of Compound 130

[0670] ##STR00180##

[0671] To a solution of A10 (100 mg, 0.275 mmol) in THF (3 mL) was added (3,5-dimethoxyphenyl)magnesium chloride (2.75 mL, 1 M in THF). The mixture was stirred at 20° C. for 3.5hand then to the mixture was added sat. aq. NH.sub.4Cl (5 mL). The organic phase was extracted with DCM (5 mL*2), washed with sat. aq. NaCl (8 mL*2), concentrated in vacuum. The residue was purified by prep. HPLC to give 130 (19 mg) as a solid.

[0672] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.01 (d, J=2.5 Hz, 2H), 6.62 (t, J=2.3 Hz, 1H), 3.83 (s, 6H), 3.42 (t, J=8.7 Hz, 1H), 2.49-2.33 (m, 1H), 1.86-1.58 (m, 7H), 1.52-1.27 (m, 13H), 1.26 (s, 3H), 1.20-0.85 (m, 3H), 0.61 (s, 3H). LCMS Rt=1.427 min in 2 min chromatography, 10-80 AB, MS ESI calcd. for C.sub.28H.sub.41O.sub.4 [M+H].sup.+ 441.3. found 423 [M−H.sub.2O].sup.+.

Example 131. Synthesis of Compound 131

[0673] ##STR00181##

[0674] To a solution of 1-bromo-4-methoxy-2-methylbenzene (414 mg, 2.06 mmol) in THF (3 mL) was added tert-butyllithium (2.85 mL, 1.3 M in THF) at −70° C. The mixture was stirred at −70° C. for 1 h. A solution of B10 (150 mg, 0.4126 mmol) in THF (1 mL) was added at −70° C. The mixture was stirred at 25° C. for 1 hrs. TLC showed starting material was consumed and new spots were produced. The mixture was quenched with Sat. NH.sub.4Cl (10 mL), extracted with EtOAc (10 mL×3), washed with brine (30 mL×3), dried over Na.sub.2SO.sub.4, filtered, concentrated in vacuum to give a crude product which was purified with prep. HPLC (Column: Phenomenex Synergi C18 150*30 mm*4 um; Condition: water (0.05% HCl)-ACN; Gradient 90%-95% B; Gradient Time (min): 10; FlowRate (ml/min): 25) to give 131 (26 mg) as a solid.

[0675] .sup.1H NMR (400 MHz: CDCl.sub.3) δ 7.54 (d, J=8.5 Hz, 1H), 6.75-6.68 (m, 2H), 3.83 (s, 3H), 3.34 (t, J=8.7 Hz, 1H), 2.50-2.33 (m, 4H), 1.80-1.45 (m, 8H), 1.36-1.22 (m, 5H), 1.20-0.89 (m, 11H), 0.72-0.54 (m, 5H). LCMS t.sub.R=1.058 min in 1.5 min chromatography, 5-95 AB, MS ESI calcd. for C.sub.21H.sub.41O.sub.3[M+H].sup.+ 425. found 425.

Example 132. Synthesis of Compound 132

[0676] ##STR00182##

[0677] To a solution of 1-bromo-4-methoxy-2-methylbenzene (211 mg, 1.05 mmol) in THF (5 mL) was added tert-butyllithium (1.45 mL) at −68° C. The mixture was stirred at −68° C. for 1 hrs. A solution of B30 (80 mg, 211 μmol) in THF (5 mL) was added dropwise at −68° C. The reaction was stirred at 25° C. for 1 hour. LCMS showed the reaction was completed. The reaction was quenched with NH.sub.4Cl (10 mL), extracted with EtOAc (10 mL×2). The combined organic layers were washed with brine (10 mL). The organic layer was dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give crude product, which was purified by HPLC separation (column: Boston Green ODS 150*30 5u, gradient: 91-100% condition: (water (0.05% HCl)-ACN), flow rate: 25 mL/min) to give 132 (29.3 mg) as a solid.

[0678] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.55 (d, J=8.3 Hz, 1H), 6.77-6.68 (m, 2H), 3.83 (s, 3H), 3.33 (t, J=8.5 Hz, 1H), 2.47 (s, 3H), 2.43-2.32 (m, 1H), 1.78-1.65 (m, 4H), 1.52-1.31 (m, 9H), 1.30-1.06 (m, 14H), 1.04-0.87 (m, 1H), 0.79-0.67 (m, 4H), 0.61 (s, 3H). LCMS Rt=1.066 min in 2 min chromatography, 5-95 AB, MS ESI calcd. for C.sub.29H.sub.43O.sub.3 [M+H].sup.+ 439. found 439.

Example 133. Synthesis of Compound 133

[0679] ##STR00183##

[0680] To a solution of 6-bromobenzo[d][1,3]dioxole (158 mg, 789 μmol) in THF (5 mL) was added tert-butyllithium (1.09 mL) at −68° C. After stirring at −68° C. for 1 hr, a solution of B30 (60 mg, 158 μmol) in THF (5 mL) was added dropwise at −68° C. The reaction was stirred at 25° C. for 2 hours. TLC showed the reaction was completed. The reaction was quenched with Sat. NH.sub.4Cl (10 mL), extracted with EtOAc (10 mL×2). The combined organic layers were washed with brine (10 mL). The organic layers were dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give a crude product, which was purified by HPLC separation (column: Boston Green ODS 150*30 5u, gradient 80-95% B (A=0.05% HCl-ACN, B=acetonitrile), flow rate: 25 ml/min) and lyophilized to give 133 (14.9 mg) as a solid .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.55 (dd, J=8.2, 1.4 Hz, 1H), 7.40 (d, J=1.3 Hz, 1H), 7.01 (d, J=8.0 Hz, 1H), 6.13 (d, J=1.0 Hz, 2H), 3.87 (s, 1H), 3.58 (t, J=8.3 Hz, 1H), 2.29-2.17 (m, 1H), 1.74-1.58 (m, 3H), 1.55-1.39 (m, 3H), 1.36-1.00 (m, 17H), 0.98-0.84 (m, 1H), 0.78-0.61 (m, 4H), 0.47 (s, 3H). LCMS Rt=1.033 min in 1.5 min chromatography, 5-95 AB, MS ESI calcd for C.sub.28H.sub.40O.sub.4 [M+H].sup.+ 439. found 439.

Example 134. Synthesis of Compound 134

[0681] ##STR00184##

[0682] To a solution of 1-bromo-4-ethylbenzene (146 mg, 789 μmol) in THF (5 mL) was added tert-butyllithium (1.09 mL) at −68° C. After stirring at −68° C. for 1 hr, a solution of B30 (60 mg, 158 μmol) in THF (5 mL) was added dropwise at −68° C. The reaction was stirred at 25° C. for 2 hours. TLC showed the reaction was completed. The reaction was quenched with Sat. NH.sub.4Cl (10 mL), extracted with EtOAc (10 mL×2). The combined organic layers were washed with brine (10 mL). The organic layer was dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to a crude product, which was purified by HPLC separation (column: Boston Green ODS 150*30 5u, gradient: 95-100% B (A=0.05% HCl-ACN, B=acetonitrile), flow rate: 25 mL/min) and lyophilized to give 134 (23.3 mg) as a solid.

[0683] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.83 (d, J=8.0 Hz, 2H), 7.33 (d, J=8.0 Hz, 2H), 3.86 (s, 1H), 3.63 (t, J=8.5 Hz, 1H), 2.67 (q, J=7.5 Hz, 2H), 2.32-2.20 (m, 1H), 1.76-1.60 (m, 3H), 1.52-1.31 (m, 7H), 1.27-1.10 (m, 11H), 1.08-0.88 (m, 5H), 0.76-0.60 (m, 4H), 0.48 (s, 3H). LCMS Rt=1.115 min in 1.5 min chromatography, 5-95 AB, MS ESI calcd. for C.sub.29H.sub.44O.sub.2 [M+H].sup.+ 423. found 423.

Example 135. Synthesis of Compound 135

[0684] ##STR00185##

[0685] To a solution of 1-bromo-3,5-dimethylbenzene (146 mg, 789 μmol) in THF (5 mL) was added tert-butyllithium (1.09 mL) at −68° C. After stirring at −68° C. for 1 hr, B30 (60 mg, 158 μmol) in THF (5 mL) was added dropwise at −68° C. The reaction was stirred at 25° C. for 2 hours. The reaction was quenched with Sat NH.sub.4Cl (10 mL), extracted with EtOAc (10 mL×2). The combined organic layers were washed with brine (10 mL). The organic layer was dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give a product, which was purified by prep-HPLC (column: Boston Green ODS 150*30 5u, gradient: 95-100% condition: (0.05% HCl-ACN), flow rate: 25 mL/min) and lyophilized to give 135 (27.6 mg) as a solid.

[0686] .sup.1H NMR (400 MHz. DMSO-d.sub.6) δ 7.48 (s, 2H), 7.23 (s, 1H), 3.86 (s, 1H), 3.61 (t, J=8.4 Hz, 1H), 2.33 (s, 6H), 2.30-2.18 (m, 1H), 1.75-1.60 (m, 3H), 1.55-0.80 (m, 21H), 0.77-0.61 (m, 4H), 0.48 (s, 3H). LCMS Rt=1.113 min in 1.5 min chromatography, 5-95 AB, ESI calcd. for C.sub.29H.sub.43O.sub.2[M+H].sup.+ 423. found 423.

Example 136. Synthesis of Compound 136

[0687] ##STR00186##

[0688] To a stirred solution of A10 (110 mg, 302 umol) in 3 mL of THF was added (4-(trifluoromethoxy)phenyl)magnesium bromide (0.5 M, 6.02 mL, 3.01 mmol) dropwise at 25° C. After stirring at 25° C. for 12 hrs, LCMS showed the reaction was complete. The reaction mixture was poured into ice-cold water and extracted with EtOAc (50 mL×2), washed with brine (30 mL×2), dried (Na.sub.2SO.sub.4), filtered, and evaporated in vacuo to give crude product, which was purified by prep-HPLC separation (column: Boston Green ODS 150*30 5u, gradient: 90-100% B (A=0.05% HCl-ACN, B=acetonitrile), flow rate: 25 mL/min) for further purification to obtain to (3,5-difluorophenyl)((3R,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)methanone (67 mg, 53%) as a solid.

[0689] .sup.1HNMR (CDCl.sub.3, 400 MHz): δ 7.38 (d, J=6.0 Hz, 2H), 6.99 (t, J=8.6 Hz, 1H), 3.36 (t, J=8.6 Hz, 1H), 2.36-2.42 (m, 1H), 1.73-1.85 (m, 5H), 1.63 (d, J=13.6 Hz, 2H), 1.26-1.50 (m, 15H), 1.04-1.15 (m, 2H), 0.85-1.02 (m, 2H), 0.61 (s, 3H)

[0690] LCMS Rt=3.219 min in 4.0 min chromatography, 10-80 AB, purity 100%, MS ESI calcd. for C.sub.26H.sub.35F.sub.2O.sub.2 [M+H]+ 417.3. found 399.0 [M−H.sub.2O].sup.+.

Example 137. Synthesis of Compound 137

[0691] ##STR00187##

[0692] To a stirred solution of A30 (110 mg, 291 umol) in 3 mL of THF was added (4-fluoro-3-methylphenyl)magnesium bromide (0.5 M, 5.8 mL, 2.9 mmol) dropwise at 25° C. After stirring at 25° C. for 12 hrs, LCMS showed the reaction was complete. The reaction mixture was poured into ice-cold water and extracted with EtOAc (50 mL×2), washed with brine (30 mL×2), dried (Na2SO4), filtered, and evaporated in vacuo to give crude product. The reaction mixture was purified by HPLC separation (column: Phenomenex Synergi C18 150*25*10 um, gradient 80-100% B (A=0.05% HCl-ACN, B=acetonitrile), flow rate: 25 mL/min) for further purification to obtain (4-fluoro-3-methylphenyl)((3R,5R,8R,9S,10S,13S,14S,17S)-3-hydroxy-3,10,13-trimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)methanone (52.1 mg, 40.2%) as a solid.

[0693] .sup.1HNMR (CDCl.sub.3, 400 MHz): δ=7.76 (d, J=7.6 Hz, 1H), 7.71 (br. s., 1H), 7.04 (t, J=9.0 Hz, 1H), 3.44 (t, J=8.8 Hz, 1H), 2.36-2.43 (m, 1H), 2.33 (s, 3H), 1.92-2.05 (m, 2H), 1.81-1.88 (m, 1H), 1.67-1.78 (m, 3H), 1.32-1.51 (m, 10H), 1.26 (s, 3H), 1.23 (br. s., 2H), 1.09-1.18 (m, 2H), 0.98-1.08 (m, 2H), 0.91 (s, 3H), 0.58 (s, 3H)

[0694] LCMS Rt=3.430 min in 4.0 min chromatography, 10-80 AB, purity 95.9%, MS ESI calcd. for C.sub.28H.sub.40FO.sub.2 [M+H].sup.+ 426.6. found 409.0 [M−H.sub.2O].sup.+.

[0695] Assay Methods

[0696] Compounds provided herein can be evaluated using various assays; examples of which are described below.

Steroid Inhibition of TBPS Binding

[0697] TBPS binding assays using rat brain cortical membranes in the presence of 5 μM GABA has been described (Gee et al, J. Pharmacol. Exp. Ther. 1987, 241, 346-353; Hawkinson et al, Mol. Pharmacol. 1994, 46, 977-985; Lewin, A. H et al., Mol. Pharmacol. 1989, 35, 189-194).

[0698] Briefly, cortices are rapidly removed following decapitation of carbon dioxide-anesthetized Sprague-Dawley rats (200-250 g). The cortices are homogenized in 10 volumes of ice-cold 0.32 M sucrose using a glass/teflon homogenizer and centrifuged at 1500×g for 10 min at 4° C. The resultant supernatants are centrifuged at 10,000×g for 20 min at 4° C. to obtain the P2 pellets. The P2 pellets are resuspended in 200 mM NaCl/50 mM Na—K phosphate pH 7.4 buffer and centrifuged at 10,000×g for 10 min at 4° C. This washing procedure is repeated twice and the pellets are resuspended in 10 volumes of buffer. Aliquots (100 μL) of the membrane suspensions are incubated with 3 nM [.sup.35S]-TBPS and 5 μL aliquots of test drug dissolved in dimethyl sulfoxide (DMSO) (final 0.5%) in the presence of 5 μM GABA. The incubation is brought to a final volume of 1.0 mL with buffer. Nonspecific binding is determined in the presence of 2 μM unlabeled TBPS and ranged from 15 to 25%. Following a 90 min incubation at room temp, the assays are terminated by filtration through glass fiber filters (Schleicher and Schuell No. 32) using a cell harvester (Brandel) and rinsed three times with ice-cold buffer. Filter bound radioactivity is measured by liquid scintillation spectrometry. Non-linear curve fitting of the overall data for each drug averaged for each concentration is done using Prism (GraphPad). The data are fit to a partial instead of a full inhibition model if the sum of squares is significantly lower by F-test. Similarly, the data are fit to a two component instead of a one component inhibition model if the sum of squares is significantly lower by F-test. The concentration of test compound producing 50% inhibition (IC.sub.50) of specific binding and the maximal extent of inhibition (I.sub.max) are determined for the individual experiments with the same model used for the overall data and then the means±SEM.s of the individual experiments are calculated. Picrotoxin serves as the positive control for these studies as it has been demonstrated to robustly inhibit TBPS binding.

[0699] Various compounds are or can be screened to determine their potential as modulators of [.sup.35S]-TBPS binding in vitro. These assays are or can be performed in accordance with the above discussed procedures.

[0700] For Table 1, “A” indicates an IC.sub.50<20 nM, “B” indicates an IC.sub.50 of 20 nM to 50 nM, “C” indicates an IC.sub.50>50 nM to 100 nM, and “D” indicates IC.sub.50>100 nM.

TABLE-US-00001 TABLE 1 35S-TBPS Radioligand Displacement Compound (IC50) 1 A 2 D 3 D 4 B 5 B 6 D 7 C 8 D 9 B 10 A 11 B 12 B 130 B 24 A 23 C 28 B 27 B 26 B 48 B 15 B 18 C 21 D 17 C 20 C 25 B 19 C 16 A 13 D 22 C 14 C 39 C 38 C 37 C 36 C 45 D 35 A 41 B 44 C 49 A 29 D 34 A 47 B 33 D 32 B 31 C 30 D 43 B 46 D 40 B 42 A 59 C 58 C 56 B 55 B 54 C 53 D 52 B 51 C 50 D 64 D 68 D 63 C 60 D 62 D 61 D 74 B 73 C 86 B 89 C 72 B 85 D 84 D 83 B 88 D 70 C 71 D 87 D 75 D 82 D 81 D 80 D 79 D 78 D 77 D 76 D 101 D 133 D 134 D 135 D 98 D 108 D 111 D 99 D 100 D 107 C 106 D 105 D 110 C 102 C 104 D 109 D 92 D 103 D 97 D 91 D 96 D 95 D 94 C 93 C 115 D 114 D 128 D 127 D 132 D 113 D 125 B 124 C 123 D 136 B 137 B
Patch Clamp Electrophysiology of Recombinant α.sub.1β.sub.2γ.sub.2 and α.sub.4β3δ GABA.sub.A Receptors

[0701] Cellular electrophysiology is used to measure the pharmacological properties of our GABA.sub.A receptor modulators in heterologous cell systems. Each compound is tested for its ability to affect GABA mediated currents at a submaximal agonist dose (GABA EC.sub.20=2 μM). LTK cells are stably transfected with the α.sub.1β.sub.2γ.sub.2 subunits of the GABA receptor and CHO cells are transiently transfected with the α.sub.4β3δ subunits via the Lipofecatamine method. Cells were passaged at a confluence of about 50-80% and then seeded onto 35 mm sterile culture dishes containing 2 ml culture complete medium without antibiotics or antimycotics. Confluent clusters of cells are electrically coupled (Pritchett et al., Science, 1988, 242, 1306-1308.). Because responses in distant cells are not adequately voltage clamped and because of uncertainties about the extent of coupling (Verdoorn et al., Neuron 1990, 4, 919-928), cells were cultivated at a density that enables the recording of single cells (without visible connections to other cells).

[0702] Whole cell currents were measured with HEKA EPC-10 amplifiers using PatchMaster software or by using the high throughput QPatch platform (Sophion). Bath solution for all experiments contained (in mM): NaCl 137 mM, KCl 4 mM, CaCl.sub.2 1.8 mM, MgCl.sub.2 1 mM, HEPES 10 mM, D-Glucose 10 mM, pH (NaOH) 7.4. In some cases 0.005% cremophor was also added. Intracellular (pipette) solution contained: KCl 130 mM, MgCl.sub.2 1 mM, Mg-ATP 5 mM, HEPES 10 mM, EGTA 5 mM, pH 7.2. During experiments, cells and solutions were maintained at room temperature (19° C.-30° C.). For manual patch clamp recordings, cell culture dishes were placed on the dish holder of the microscope and continuously perfused (1 ml/mm) with bath solution. After formation of a Gigaohm seal between the patch electrodes and the cell (pipette resistance range: 2.5 MΩ-6.0 MΩ; seal resistance range: >1 GΩ) the cell membrane across the pipette tip was ruptured to assure electrical access to the cell interior (whole-cell patch-configuration). For experiments using the QPatch system, cells were transferred as suspension to the QPatch system in the bath solution and automated whole cell recordings were performed.

[0703] Cells were voltage clamped at a holding potential of −80 mV. For the analysis of test articles, GABA receptors were stimulated by 2 μM GABA after sequential pre-incubation of increasing concentrations of the test article. Pre-incubation duration was 30 s and the duration of the GABA stimulus was 2 s. Test articles were dissolved in DMSO to form stock solutions (10 mM). Test articles were diluted to 0.01, 0.1, 1, and 10 μM in bath solution. All concentrations of test articles were tested on each cell. The relative percentage potentiation was defined as the peak amplitude in response to GABA EC.sub.20 in the presence of the test article divided by the peak amplitude in response to GABA EC.sub.20 alone, multiplied by 100.

TABLE-US-00002 TABLE 2 Electrophysiological evaluation of the exemplary compounds at GABA.sub.A-R. GABA (α1β2γ2) Qpatch in Ltk, Name % efficacy at 10 μM 1 C 8 B

[0704] For Table 2. GABAA receptors α1β2γ2 and α4β3δ % efficacy: “A” 10-100, “B”>100-500, “C”>500; D indicates the data is not available or has not been determined.