SMALL MOLECULE ANTAGONIST TO PACAP RECEPTOR AND USES THEREOF

Abstract

The disclosure relates to compounds that demonstrate efficacy in blocking PACAP receptors (e.g. PAC1) and associated methods of treating neurological diseases or disorders using the disclosed compounds. The neurological diseases or disorders include, but are not limited to, stress-related diseases (e.g. chronic stress, post-traumatic stress disorder (PTSD), panic disorder, anxiety, or general anxiety disorder), pain-related diseases (e.g. chronic pain, primary headache disorders, or migraines), or addiction (e.g. addiction to a substance (e.g. addiction to cocaine, amphetamines, methamphetamine, methylphenidate, nicotine, alcohol, prescription medication, marijuana, tobacco, or an opioid selected from heroin, fentanyl, codeine, hydrocodone, morphine, oxycodone, hydromorphone, and methadone)).

Claims

1. A compound of Formula (0): ##STR00074## or a pharmaceutically acceptable salt thereof, wherein: each R.sup.1 is independently substituted or unsubstituted C.sub.1-6 alkyl, halogen, hydroxy, substituted or unsubstituted C.sub.1-6 alkoxy, NR.sup.aR.sup.a, C(O)R.sup.a, C(O)OR.sup.a, NR.sup.aC(O)R.sup.a, C(O)N(R.sup.a).sub.2, CN, or NO.sub.2; each R.sup.2 is independently substituted or unsubstituted C.sub.1-6 alkyl, halogen, hydroxy, substituted or unsubstituted C.sub.1-6 alkoxy, NR.sup.aR.sup.a, C(O)R.sup.a, C(O)OR.sup.a, NR.sup.aC(O)R.sup.a, C(O)N(R.sup.a).sub.2, CN, or NO.sub.2; each R.sup.3 is independently halogen, hydroxy, NR.sup.aR.sup.a, C(O)R.sup.a, C(O)OR.sup.a, CN, or NO.sub.2; each R.sup.N is independently hydrogen or substituted or unsubstituted C.sub.1-6 alkyl; each R.sup.a is independently H or substituted or unsubstituted C.sub.1-6 alkyl; Y is CH, N, or ##STR00075## L.sup.1 is a bond or substituted or unsubstituted ##STR00076## n is 0, 1, 2, 3, or 4; m is 0, 1, 2, 3, or 4; and p is 0, 1, 2, 3, 4, or 5.

2. The compound of claim 1, wherein the compound of Formula (0) is of Formula (0-A): ##STR00077## or a pharmaceutically acceptable salt thereof.

3. The compound of claim 1, wherein the compound of Formula (0) is of Formula (0-B): ##STR00078## or a pharmaceutically acceptable salt thereof.

4. The compound of claim 1, wherein the compound of Formula (0) is of Formula (0-C): ##STR00079## or a pharmaceutically acceptable salt thereof.

5. The compound of claim 1, wherein the compound of Formula (0) is of Formula (0-D): ##STR00080## or a pharmaceutically acceptable salt thereof.

6. The compound of claim 1, wherein the compound of Formula (0) is of Formula (0-E): ##STR00081## or a pharmaceutically acceptable salt thereof.

7. The compound of any one of claims 1-6, wherein L.sup.1 is a bond.

8. The compound of any one of claims 1-6, wherein L.sup.1 is ##STR00082##

9. The compound of claim 1, wherein the compound is a compound of Formula (I): ##STR00083## or a pharmaceutically acceptable salt thereof, wherein: each R.sup.1 is independently substituted or unsubstituted C.sub.1-6 alkyl, halogen, hydroxy, substituted or unsubstituted C.sub.1-6 alkoxy, NR.sup.aR.sup.a, C(O)R.sup.a, C(O)OR.sup.a, NR.sup.aC(O)R.sup.a, C(O)N(R.sup.a).sub.2, CN, or NO.sub.2; each R.sup.2 is independently substituted or unsubstituted C.sub.1-6 alkyl, halogen, hydroxy, substituted or unsubstituted C.sub.1-6 alkoxy, NR.sup.aR.sup.a, C(O)R.sup.a, C(O)OR.sup.a, NR.sup.aC(O)R.sup.a, C(O)N(R.sup.a).sub.2, CN, or NO.sub.2; each R.sup.3 is independently halogen, hydroxy, NR.sup.aR.sup.a, C(O)R.sup.a, C(O)OR.sup.a, CN, or NO.sub.2; each R.sup.a is independently H or substituted or unsubstituted C.sub.1-6 alkyl; n is 0, 1, 2, 3, or 4; m is 0, 1, 2, 3, or 4; and p is 0, 1, 2, 3, 4, or 5.

10. The compound of claim 1 or 9, wherein: each R.sup.2 is independently substituted or unsubstituted C.sub.1-6 alkyl, halogen, hydroxy, substituted or unsubstituted C.sub.1-6 alkoxy, C(O)R.sup.a, C(O)OR.sup.a, NR.sup.aC(O)R.sup.a, C(O)N(R.sup.a).sub.2, CN, or NO.sub.2; each R.sup.3 is independently halogen, hydroxy, C(O)R.sup.a, C(O)OR.sup.a, CN, or NO.sub.2; each R.sup.a is independently H or substituted or unsubstituted C.sub.1-6 alkyl; n is 0; m is 0, 1, 2, 3, or 4; and p is 0, 1, 2, 3, or 4.

11. The compound of any one of claims 1 and 9-10, wherein: each R.sup.2 is independently substituted or unsubstituted C.sub.1-6 alkyl, halogen, hydroxy, or substituted or unsubstituted C.sub.1-6 alkoxy; each R.sup.3 is independently halogen, C(O)R.sup.a, C(O)OR.sup.a, CN, or NO.sub.2; each R.sup.a is independently H or substituted or unsubstituted C.sub.1-6 alkyl; n is 0; m is 0, 1, 2, 3, or 4; and p is 0, 1, 2, 3, or 4.

12. The compound of any one of claims 1 and 9-11, wherein p is 1 or 2.

13. The compound of any one of claims 1 and 9-12, wherein the ring bearing R.sup.3 is of the formula: ##STR00084##

14. The compound of any one of claims 1 and 9-13, wherein the ring bearing R.sup.3 is of the formula: ##STR00085##

15. The compound of any one of claims 1 and 9-14, wherein the ring bearing R.sup.3 is of the formula: ##STR00086##

16. The compound of any one of claims 1 and 9-15, wherein the ring bearing R.sup.3 is of the formula: ##STR00087##

17. The compound of any one of claims 1 and 9-16, wherein m is 0, 1, or 2.

18. The compound of any one of claims 1 and 9-17, wherein m is 1 or 2.

19. The compound of any one of claims 1 and 9-18, wherein each R.sup.2 is independently substituted or unsubstituted C.sub.1-6 alkyl, halogen, hydroxy, or substituted or unsubstituted C.sub.1-6 alkoxy.

20. The compound of any one of claims 1 and 9-19, wherein each R.sup.2 is independently methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, halogen, hydroxy, methoxy, ethoxy, or propoxy.

21. The compound of any one of claims 1 and 9-20, wherein each R.sup.a is independently unsubstituted alkyl.

22. The compound of any one of claims 1 and 9-21, wherein each R.sup.a is independently unsubstituted methyl.

23. The compound of any one of claims 1 and 9-22, wherein each R.sup.a is H.

24. The compound of any one of claims 1 and 9-13, wherein n is 0.

25. The compound of any one of claims 1 and 9-24, wherein the compound is of the formula: ##STR00088## ##STR00089## or a salt thereof.

26. The compound of claim 1 or 9-25, wherein the compound is of the formula: ##STR00090## or a salt thereof.

27. The compound of claim 1, wherein the compound is of the formula: ##STR00091## or a salt thereof.

28. A pharmaceutical composition comprising a compound of any one of claims 1-27, or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable excipient.

29. The pharmaceutical composition of claim 28 further comprising an additional pharmaceutical agent.

30. A method of treating a subject suffering from or susceptible to a neurological disease, the method comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1-27, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 28 or 29.

31. The method of claim 30, wherein the neurological disease is a pain-related disorder.

32. The method of claim 30, wherein the neurological disorder is a stress-related disorder.

33. The method of claim 30, wherein the neurological disorder is addiction.

34. The method of claim 30, wherein the neurological disorder is a panic disorder.

35. The method of claim 30, wherein the neurological disorder is panic attacks.

36. The method of claim 30, wherein the neurological disorder is an eating disorder.

37. A method of treating a subject suffering from or susceptible to a pain-related disease, the method comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1-27, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 28 or 29.

38. The method of claim 37, wherein the pain-related disease is chronic pain.

39. The method of claim 37, wherein the pain-related disease is a primary headache disorder.

40. The method of claim 37, wherein the primary headache disorder is a migraine.

41. The method of claim 37, wherein the pain-related disease is inflammatory pain.

42. The method of claim 37, wherein the pain-related disease is musculoskeletal pain.

43. The method of claim 37, wherein the pain-related disease is arthritis.

44. The method of claim 43, wherein the arthritis is rheumatoid arthritis.

45. A method of treating a subject suffering from or susceptible to a stress-related disease or disorder, the method comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1-27, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 28 or 29.

46. The method of claim 45, wherein the stress-related disorder is chronic stress.

47. The method of claim 45, wherein the stress-related disorder is posttraumatic stress disorder (PTSD).

48. The method of claim 45, wherein the stress-related disorder is an anxiety disorder.

49. The method of claim 48, wherein the anxiety disorder is anxiety.

50. The method of claim 48, wherein the anxiety disorder is generalized anxiety disorder.

51. The method of claim 45, wherein the stress-related disorder is panic disorder.

52. A method of treating a subject suffering from or susceptible to addiction, the method comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1-27, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 28 or 29.

53. The method of claim 52, wherein the addiction is addiction to a substance.

54. The method of claim 53, wherein the substance is a drug.

55. The method of claim 53, wherein the substance is food.

56. The method of claim 53, wherein the substance is cocaine, amphetamines, methamphetamine, methylphenidate, nicotine, alcohol, prescription medication, marijuana, tobacco, or an opioid selected from heroin, fentanyl, codeine, hydrocodone, morphine, oxycodone, hydromorphone, or methadone.

57. The method of claim 53, wherein the substance is cocaine.

58. The method of claim 53, wherein the substance is an opioid.

59. The method of claim 53, wherein the substance is an amphetamine.

60. The method of claim 53, wherein the substance is nicotine.

61. The method of claim 53, wherein the substance is alcohol.

62. The method of any one of claims 52-61, wherein the treatment prevents relapse of the substance abuse.

63. The method of any one of claims 52-61, wherein the treatment lowers the incidence of relapse of the substance abuse.

64. The method of claim 62 or 63, wherein the relapse is stress-induced relapse.

65. A method of treating a subject suffering from or susceptible to an eating disorder, the method comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1-27, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 28 or 29.

66. The method of claim 65, wherein the eating disorder is orthorexia.

67. The method of claim 65, wherein the eating disorder is anorexia.

68. A method of treating a subject identified as in need of treatment for a pain-related disease or disorder, the method comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1-27, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 28 or 29.

69. A method of treating a subject identified as in need of treatment for a stress-related disorder, the method comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1-27, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 28 or 29.

70. A method of treating a subject identified as in need of treatment for a panic disorder, the method comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1-27, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 28 or 29.

71. A method of treating a subject identified as in need of treatment for addiction, the method comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1-27, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 28 or 29.

72. A method of treating a subject identified as in need of treatment for an eating disorder, the method comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1-27, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 28 or 29.

73. The method of any one of claims 30-72 further comprising administering an additional pharmaceutical agent to the subject.

74. A kit comprising: a compound of any one of claims 1-27, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 28 or 29; and instructions for administering to a subject or contacting a biological sample with the compound, or composition.

75. A method for modulating a pituitary adenylate cyclase activating polypeptide (PACAP) receptor, comprising contacting a PAC1 receptor with a compound of any one of claims 1-27, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 28 or 29.

76. A method for modulating a PAC1 receptor, comprising contacting a PAC1 receptor with a compound of any one of claims 1-27, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 28 or 29.

77. The method of claim 75 or 76, wherein the modulating is inhibiting.

78. A method of treating a disease or disorder in a subject by modulating a pituitary adenylate cyclase activating polypeptide (PACAP) receptor, the method comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1-27, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 28 or 29.

79. A method of treating a disease or disorder in a subject by modulating a PAC1 receptor, the method comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1-27, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 28 or 29.

80. The method of claim 78 or 79, wherein the modulating is inhibiting.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0068] FIG. 1 depicts Western blot data for inhibition of PACAP-stimulated ERK activation by compounds of the disclosure.

[0069] FIG. 2 depicts the dose-dependent inhibition of PACAP-stimulated ERK activation by compounds of the disclosure.

[0070] FIG. 3 depicts that PAC1 receptor antagonist RJB-145 blocks PACAP-induced signaling and anxiety-like behavioral responses. FIG. 3A shows the PACAP-induced calcium influx. Using HEK PAC1R stable cell lines, RJB-145 attenuated 20 nM PACAP-induced calcium flux (filled circles) and ERK activation (open circles) with calculated IC.sub.50 of 8.5 and 9 uM, respectively. 20 M RJB-145 blocked PACAP-stimulated ERK activation nearly 75%. Data represent mean +/ SEM; n=34 wells/group. FIG. 3B shows in vivo assessments of the antagonist, vehicle, RJB-145 (20 M/0.5 L), PACAP (1 g/l; 0.5 l infusion) or PACAP+RJB145 were infused bilaterally into the BNST (bed nucleus of the stria terminalis, a brain nuclei for stress responses) of rats for anxiety-like measurements on an elevated plus maze (EPM; 5 min per trial). Anxiety ridden rats avoid the open arms of the maze and prefer traveling into the closed arms. RJB-145 infusions alone had no behavioral effects compared to vehicle. Consistent with previous work, PACAP instilled anxiety-like responses as shown by rats avoiding the open arms (decreased open arm times in the figure). RJB145 was able to completely antagonize the PACAP-induced anxiety-like responses to control vehicle levels. Data represent mean +/ SEM; n=8-10 animals/group; **, statistically different from vehicle, RJB145 and PACAP+RJB145 at p<0.01.

DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS OF THE INVENTION

[0071] From previous work (Beebe et al., 2008) acyl hydrazide compounds appear to have the potential to antagonize PACAP plasma membrane calcium signaling; however, while these candidate compounds can attenuate PAC1 receptor mediated calcium flux, they have modest effects in blocking PAC1 receptor internalization and endosomal ERK activation. These results are not surprising given the bias agonism/antagonism states (how different ligands can cause G protein coupled receptors to adopt altered conformational states resulting in differential signaling responses) that are now understood to exist for G protein coupled receptors.

[0072] From background and signaling data, we have posited that for therapeutic potential, PAC1 receptor antagonists should demonstrate efficacy in blunting both plasma membrane (i.e., calcium flux) and endosomal ERK signaling. In recent work, acyl hydrazide analogs were prepared and from these, several new compounds have shown efficacy in inhibiting PACAP/PAC1 receptor-stimulated plasma membrane signaling, internalization and endosomal ERK activation in a stable human PAC1 receptor-HEK cell line. The novel derivatives differed from the original lead compound by modification of the substituents present on the N-benzyl ring. Specifically, the inclusion of electron withdrawing groups on the N-benzyl ring appeared to be relevant for blocking receptor internalization and endosomal ERK activation.

[0073] One derivative (JF-214) bearing a 3,5-difluorobenzyl group:

##STR00007##

showed particular efficacythe new heteroatoms could take advantage of a hydrogen bonding interactions within the binding pocket, or the electron deficient aryl ring may be involved in -stacking or cation- interactions within the receptor. The presence of fluorine or other electron withdrawing groups at the 3 and 5 positions of the aromatic ring appeared central to the drug design. It was discovered that, JF-214: 1) blocked PACAP-stimulated PAC1 receptor plasma membrane calcium signaling; 2) blocked PAC1 receptor internalization and endosomal ERK signaling; 3) acted synergistically with extrahelical glucagon receptor (GCGR) antagonist MK-0893 to inhibit PACAP/PAC1 receptormediated ERK activation; and 4) demonstrated efficacy in blocking PACAP-induced anxietyrelated behaviors in vivo. JF-214 and related compounds have been submitted for patent protection (PCT publication number WO/2020/168068, U.S. Ser. No. 17/429,843).

[0074] Computer modeling and virtual screening were carried out to identify new scaffolds capable of behaving as PAC1 receptor antagonists. Despite the lack of inactive or antagonist-bound PAC1 structural information, the hypothesis of JF-214 interactions with the PAC1 receptor helped to build four accurate protein models. With a unique ensemble docking protocol, 3 millions of small molecules with similar chemical properties to JF-214 were tested in the orthosteric pocket of PAC1. The top compounds with high binding scores were selected for experimental validation and are disclosed herein.

[0075] The present disclosure provides compounds that act as antagonists for a PACAP-receptor (e.g. PAC1), and pharmaceutical compositions thereof, for the prevention and treatment of a disease or disorder in a subject. In certain embodiments, the compounds act as antagonists to PACAP receptors (e.g. PAC1). In certain embodiments, the compounds are irreversible antagonist for PACAP receptors (e.g. PAC1). In certain embodiments, the compounds are reversible antagonist for PACAP receptors (e.g. PAC1). The present disclosure further provides methods of using the compounds described herein, e.g., as biological probes to study the antagonism of PACAP receptors (e.g. PAC1), and as therapeutics, e.g., in the prevention and treatment of diseases or disorders associated with PACAP receptor activity or internalization, or ERK activation. In certain embodiments, the diseases or disorders include, but are not limited to, neurological disorders, e.g. stress-related disorders (e.g. chronic stress, post-traumatic stress disorder (PTSD), panic disorder, anxiety, or general anxiety disorder), eating disorders (e.g. orthorexia, or anorexia nervosa), pain-related disorders (e.g. chronic pain, arthritis (e.g., rheumatoid arthritis), inflammatory pain, musculoskeletal pain, primary headache disorders, or migraines), panic disorders, panic attacks, or addiction (e.g. addiction to a substance (e.g. addiction to cocaine, amphetamines, methamphetamine, methylphenidate, nicotine, alcohol, prescription medication, marijuana, tobacco, food, or an opioid selected from heroin, fentanyl, codeine, hydrocodone, morphine, oxycodone, hydromorphone, and methadone)).

Compounds

[0076] In one aspect, provided herein is a compound of Formula (0):

##STR00008## [0077] or a pharmaceutically acceptable salt thereof, wherein: [0078] each R.sup.1 is independently substituted or unsubstituted C.sub.1-6 alkyl, halogen, hydroxy, substituted or unsubstituted C.sub.1-6 alkoxy, NR.sup.aR.sup.a, C(O)R.sup.a, C(O)OR.sup.a, NR.sup.aC(O)R.sup.a, C(O)N(R.sup.a).sub.2, CN, or NO.sub.2; [0079] each R.sup.2 is independently substituted or unsubstituted C.sub.1-6 alkyl, halogen, hydroxy, substituted or unsubstituted C.sub.1-6 alkoxy, NR.sup.aR.sup.a, C(O)R.sup.a, C(O)OR.sup.a, NR.sup.aC(O)R.sup.a, C(O)N(R.sup.a).sub.2, CN, or NO.sub.2; [0080] each R.sup.3 is independently halogen, hydroxy, NR.sup.aR.sup.a, C(O)R.sup.a, C(O)OR.sup.a, CN, or NO.sub.2; [0081] each R.sup.N is independently hydrogen or substituted or unsubstituted C.sub.1-6 alkyl; [0082] each R.sup.a is independently H or substituted or unsubstituted C.sub.1-6 alkyl; [0083] Y is CH, N, or

##STR00009## [0084] L.sup.1 is a bond or substituted or unsubstituted

##STR00010## [0085] n is 0, 1, 2, 3, or 4; [0086] m is 0, 1, 2, 3, or 4; and [0087] p is 0, 1, 2, 3, 4, or 5.

[0088] In some embodiments, the compound of Formula (0) is of Formula (0-A):

##STR00011## [0089] or a pharmaceutically acceptable salt thereof.

[0090] In some embodiments, the compound of Formula (0) is of Formula (0-B):

##STR00012## [0091] or a pharmaceutically acceptable salt thereof.

[0092] In some embodiments, the compound of Formula (0) is of Formula (0-C):

##STR00013##

or a pharmaceutically acceptable salt thereof.

[0093] In some embodiments, the compound of Formula (0) is of Formula (0-D):

##STR00014##

or a pharmaceutically acceptable salt thereof.

[0094] In some embodiments, the compound of Formula (0) is of Formula (0-E):

##STR00015## [0095] or a pharmaceutically acceptable salt thereof.

[0096] In some embodiments, each R.sup.N is independently hydrogen or substituted or unsubstituted C.sub.1-6 alkyl. In some embodiments, each R.sup.N is hydrogen. In some embodiments, each R.sup.N is C.sub.1-6 alkyl. In some embodiments, each R.sup.N is methyl. In some embodiments, some instances of R.sup.N are hydrogen and some instances are methyl. In some embodiments, two instances of R.sup.N are hydrogen and one instance of R.sup.N is methyl.

[0097] In some embodiments, Y is CH, N, or

##STR00016##

In some embodiments, Y is CH. In certain embodiments, Y is N. In some embodiments, Y is

##STR00017##

[0098] In some embodiments, L.sup.1 is a bond or substituted or unsubstituted

##STR00018##

In some embodiments, L.sup.1 is a bond. In certain embodiments, L.sup.1 is substituted or unsubstituted

##STR00019##

In certain embodiments, L.sup.1 is unsubstituted

##STR00020##

In certain embodiments, L.sup.1 is substituted or unsubstituted

##STR00021##

In certain embodiments, L.sup.1 is substituted or unsubstituted

##STR00022##

[0099] In one aspect of the present disclosure, provided are compounds of Formula (I):

##STR00023## [0100] or pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, isotopologues, stereoisomers, or prodrugs thereof, wherein: [0101] each R.sup.1 is independently substituted or unsubstituted C.sub.1-6 alkyl, halogen, hydroxy, substituted or unsubstituted C.sub.1-6 alkoxy, NR.sup.aR.sup.a, C(O)R.sup.a, C(O)OR.sup.a, NR.sup.aC(O)R.sup.a, C(O)N(R.sup.a).sub.2, CN, or NO.sub.2; [0102] each R.sup.2 is independently substituted or unsubstituted C.sub.1-6 alkyl, halogen, hydroxy, substituted or unsubstituted C.sub.1-6 alkoxy, NR.sup.aR.sup.a, C(O)R.sup.a, C(O)OR.sup.a, NR.sup.aC(O)R.sup.a, C(O)N(R.sup.a).sub.2, CN, or NO.sub.2; [0103] each R.sup.3 is independently halogen, hydroxy, NR.sup.aR.sup.a, C(O)R.sup.a, C(O)OR.sup.a, CN, or NO.sub.2; [0104] each R.sup.a is independently H or substituted or unsubstituted C.sub.1-6 alkyl; [0105] n is 0, 1, 2, 3, or 4; [0106] m is 0, 1, 2, 3, or 4; and [0107] p is 0, 1, 2, 3, 4, or 5.

[0108] In some embodiments, each R.sup.2 is independently substituted or unsubstituted C.sub.1-6 alkyl, halogen, hydroxy, substituted or unsubstituted C.sub.1-6 alkoxy, C(O)R.sup.a, C(O)OR.sup.a, NR.sup.aC(O)R.sup.a, C(O)N(R.sup.a).sub.2, CN, or NO.sub.2; each R.sup.3 is independently halogen, hydroxy, C(O)R.sup.a, C(O)OR.sup.a, CN, or NO.sub.2; each R.sup.a is independently H or substituted or unsubstituted C.sub.1-6 alkyl; n is 0; m is 0, 1, 2, 3, or 4; and p is 0, 1, 2, 3, or 4.

[0109] In some embodiments, each R.sup.2 is independently substituted or unsubstituted C.sub.1-6 alkyl, halogen, hydroxy, or substituted or unsubstituted C.sub.1-6 alkoxy; each R.sup.3 is independently halogen, C(O)R.sup.a, C(O)OR.sup.a, CN, or NO.sub.2; each R.sup.a is independently H or substituted or unsubstituted C.sub.1-6 alkyl; n is 0; m is 0, 1, 2, 3, or 4; and p is 0, 1, 2, 3, or 4.

[0110] As provided herein, each R.sup.1 is independently substituted or unsubstituted C.sub.1-6 alkyl, halogen, hydroxy, substituted or unsubstituted C.sub.1-6 alkoxy, NR.sup.aR.sup.a, C(O)R.sup.a, C(O)OR.sup.a, NR.sup.aC(O)R.sup.a, C(O)N(R.sup.a).sub.2, CN, or NO.sub.2. In some embodiments, R.sup.1 is substituted or unsubstituted C.sub.1-6 alkyl, halogen, hydroxy, substituted or unsubstituted C.sub.1-6 alkoxy, NR.sup.aR.sup.a, C(O)R.sup.a, C(O)OR.sup.a, NR.sup.aC(O)R.sup.a, C(O)N(R.sup.a).sub.2, CN, or NO.sub.2. In some embodiments, R.sup.1 is substituted or unsubstituted C.sub.1-6 alkyl. In some embodiments, R.sup.1 is unsubstituted C.sub.1-6 alkyl. In certain embodiments, R.sup.1 is methyl. In some embodiments, R.sup.1 is ethyl. In some embodiments, R.sup.1 is propyl. In some embodiments, R.sup.1 is isopropyl. In certain embodiments, R.sup.1 is butyl. In some embodiments, R.sup.1 is tert-butyl. In some embodiments, R.sup.1 is substituted C.sub.1-6 alkyl. In certain embodiments, R.sup.1 is substituted methyl (e.g., CF.sub.3). In some embodiments, R.sup.1 is CF.sub.3. In some embodiments, R.sup.1 is substituted ethyl. In some embodiments, R.sup.1 is substituted propyl. In some embodiments, R.sup.1 is substituted isopropyl. In certain embodiments, R.sup.1 is substituted butyl. In some embodiments, R.sup.1 is substituted or unsubstituted C.sub.1-6 alkoxy. In some embodiments, R.sup.1 is unsubstituted C.sub.1-6 alkoxy. In certain embodiments, R.sup.1 is methoxy. In some embodiments, R.sup.1 is ethoxy. In some embodiments, R.sup.1 is propoxy. In certain embodiments, R.sup.1 is isopropoxy. In some embodiments, R.sup.1 is butoxy. In certain embodiments, R.sup.1 is tert-butoxy. In some embodiments, R.sup.1 is substituted C.sub.1-6 alkoxy. In certain embodiments, R.sup.1 is halogen. In some embodiments, R.sup.1 is chloro, fluoro, bromo, or iodo. In certain embodiments, R.sup.1 is chloro. In some embodiments, R.sup.1 is fluoro. In certain embodiments, R.sup.1 is bromo. In some embodiments, R.sup.1 is iodo. In some embodiments, R.sup.1 is hydroxy. In certain embodiments, R.sup.1 is NR.sup.aR.sup.a. In certain embodiments, R.sup.1 is N(CH.sub.3).sub.2. In certain embodiments, R.sup.1 is NH(CH.sub.3). In certain embodiments, R.sup.1 is NH.sub.2. In certain embodiments, R.sup.1 is C(O)R.sup.a. In certain embodiments, R.sup.1 is C(O)H. In certain embodiments, R.sup.1 is C(O)Me. In certain embodiments, R.sup.1 is C(O)OR.sup.a. In certain embodiments, R.sup.1 is C(O)OH. In certain embodiments, R.sup.1 is C(O)OMe. In certain embodiments, R.sup.1 is NR.sup.aC(O)R.sup.a. In certain embodiments, R.sup.1 is NHC(O)H. In certain embodiments, R.sup.1 is NHC(O)Me. In certain embodiments, R.sup.1 is N(Me)C(O)H. In certain embodiments, R.sup.1 is N(Me)C(O)Me. In certain embodiments, R.sup.1 is C(O)N(R.sup.a).sub.2. In certain embodiments, R.sup.1 is C(O)NH.sub.2. In certain embodiments, R.sup.1 is C(O)NHMe. In certain embodiments, R.sup.1 is C(O)N(Me).sub.2. In certain embodiments, R.sup.1 is CN.

[0111] As provided herein, each R.sup.2 is independently substituted or unsubstituted C.sub.1-6 alkyl, halogen, hydroxy, substituted or unsubstituted C.sub.1-6 alkoxy, NR.sup.aR.sup.a, C(O)R.sup.a, C(O)OR.sup.a, NR.sup.aC(O)R.sup.a, C(O)N(R.sup.a).sub.2, CN, or NO.sub.2. In some embodiments, R.sup.2 is substituted or unsubstituted C.sub.1-6 alkyl, halogen, hydroxy, substituted or unsubstituted C.sub.1-6 alkoxy, NR.sup.aR.sup.a, C(O)R.sup.a, C(O)OR.sup.a, NR.sup.aC(O)R.sup.a, C(O)N(R.sup.a).sub.2, CN, or NO.sub.2. In some embodiments, R.sup.2 is substituted or unsubstituted C.sub.1-6 alkyl. In some embodiments, R.sup.2 is unsubstituted C.sub.1_.sub.6 alkyl. In certain embodiments, R.sup.2 is methyl. In some embodiments, R.sup.2 is ethyl. In some embodiments, R.sup.2 is propyl. In some embodiments, R.sup.2 is isopropyl. In certain embodiments, R.sup.2 is butyl. In some embodiments, R.sup.2 is tert-butyl. In some embodiments, R.sup.2 is substituted C.sub.1-6 alkyl. In certain embodiments, R.sup.2 is substituted methyl (e.g., CF.sub.3). In some embodiments, R.sup.2 is substituted ethyl. In some embodiments, R.sup.2 is substituted propyl. In some embodiments, R.sup.2 is substituted isopropyl. In certain embodiments, R.sup.2 is substituted butyl. In some embodiments, R.sup.2 is substituted or unsubstituted C.sub.1-6 alkoxy. In some embodiments, R.sup.2 is unsubstituted C.sub.1-6 alkoxy. In certain embodiments, R.sup.2 is methoxy. In some embodiments, R.sup.2 is ethoxy. In some embodiments, R.sup.2 is propoxy. In certain embodiments, R.sup.2 is isopropoxy. In some embodiments, R.sup.2 is butoxy. In certain embodiments, R.sup.2 is tert-butoxy. In some embodiments, R.sup.2 is substituted C.sub.1-6 alkoxy. In certain embodiments, R.sup.2 is halogen. In some embodiments, R.sup.2 is chloro, fluoro, bromo, or iodo. In certain embodiments, R.sup.2 is chloro. In some embodiments, R.sup.2 is fluoro. In certain embodiments, R.sup.2 is bromo. In some embodiments, R.sup.2 is iodo. In some embodiments, R.sup.2 is hydroxy. In certain embodiments, R.sup.2 is NR.sup.aR.sup.a. In certain embodiments, R.sup.2 is N(CH.sub.3).sub.2. In certain embodiments, R.sup.2 is NH(CH.sub.3). In certain embodiments, R.sup.2 is NH.sub.2. In certain embodiments, R.sup.2 is C(O)R.sup.a. In certain embodiments, R.sup.2 is C(O)H. In certain embodiments, R.sup.2 is C(O)Me. In certain embodiments, R.sup.2 is C(O)OR.sup.a. In certain embodiments, R.sup.2 is C(O)OH. In certain embodiments, R.sup.2 is C(O)OMe. In certain embodiments, R.sup.2 is NR.sup.aC(O)R.sup.a. In certain embodiments, R.sup.2 is NHC(O)H. In certain embodiments, R.sup.2 is NHC(O)Me. In certain embodiments, R.sup.2 is N(Me)C(O)H. In certain embodiments, R.sup.2 is N(Me)C(O)Me. In certain embodiments, R.sup.2 is C(O)N(R.sup.a).sub.2. In certain embodiments, R.sup.2 is C(O)NH.sub.2. In certain embodiments, R.sup.2 is C(O)NHMe. In certain embodiments, R.sup.2 is C(O)N(Me).sub.2. In certain embodiments, R.sup.2 is CN. In some embodiments, R.sup.2 is NO.sub.2. In some embodiments, R.sup.2 is substituted or unsubstituted C.sub.1-6 alkyl, halogen, hydroxy, or substituted or unsubstituted C.sub.1-6 alkoxy. In certain embodiments, R.sup.2 is methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, halogen, hydroxy, methoxy, ethoxy, or propoxy. In certain embodiments, R.sup.2 is methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, fluoro, chloro, bromo, iodo, hydroxy, methoxy, ethoxy, or propoxy. In some embodiments, one instance of R.sup.2 is substituted or unsubstituted C.sub.1-6 alkyl and one instance of R.sup.2 is hydroxy. In some embodiments, one instance of R.sup.2 is unsubstituted C.sub.1-6 alkyl and one instance of R.sup.2 is hydroxy. In some embodiments, one instance of R.sup.2 is methyl and one instance of R.sup.2 is hydroxy. In some embodiments, one instance of R.sup.2 is ethyl and one instance of R.sup.2 is hydroxy.

[0112] In some embodiments, the ring bearing R.sup.2 is of the formula:

##STR00024##

In certain embodiments, the ring bearing R.sup.2 is of the formula:

##STR00025##

In some embodiments, the ring bearing R.sup.2 is of the formula:

##STR00026##

In some embodiments the ring bearing R.sup.2 is of the formula:

##STR00027##

[0113] In some embodiments, each R.sup.3 is independently halogen, hydroxy, NR.sup.aR.sup.a, C(O)R.sup.a, C(O)OR.sup.a, CN, or NO.sub.2. In certain embodiments, R.sup.3 is halogen. In some embodiments, R.sup.3 is chloro, fluoro, bromo, or iodo. In certain embodiments, R.sup.3 is chloro. In some embodiments, R.sup.3 is fluoro. In certain embodiments, R.sup.3 is bromo. In some embodiments, R.sup.3 is iodo. In some embodiments, R.sup.3 is hydroxy. In certain embodiments, R.sup.3 is NR.sup.aR.sup.a. In certain embodiments, R.sup.3 is N(CH.sub.3).sub.2. In certain embodiments, R.sup.3 is NH(CH.sub.3). In certain embodiments, R.sup.3 is NH.sub.2. In certain embodiments, R.sup.3 is C(O)R.sup.a. In certain embodiments, R.sup.3 is C(O)H. In certain embodiments, R.sup.3 is C(O)Me. In certain embodiments, R.sup.3 is C(O)OR.sup.a. In certain embodiments, R.sup.3 is C(O)OH. In certain embodiments, R.sup.3 is C(O)OMe. In certain embodiments, R.sup.3 is CN. In some embodiments, R.sup.3 is NO.sub.2. In some embodiments, each instance of R.sup.3 is fluoro. In some embodiments, at least one instance of R.sup.3 is halogen. In certain embodiments, one instance of R.sup.3 is halogen and on instance of R.sup.3 is hydroxy. In certain embodiments, one instance of R.sup.3 is chloro and on instance of R.sup.3 is hydroxy.

[0114] In some embodiments, the ring bearing R.sup.3 is of the formula:

##STR00028##

In certain embodiments, the ring bearing R.sup.3 is of the formula:

##STR00029##

In some embodiments, the ring bearing R.sup.3 is of the formula:

##STR00030##

In some embodiments the ring bearing R.sup.3 is of the formula:

##STR00031##

In some embodiments the ring bearing R.sup.3 is of the formula:

##STR00032##

In some embodiments the ring bearing R.sup.3 is of the formula:

##STR00033##

In some embodiments the ring bearing R.sup.3 is of the formula:

##STR00034##

In some embodiments the ring bearing R.sup.3 is of the formula:

##STR00035##

[0115] In some embodiments, each R.sup.a is independently H or substituted or unsubstituted C.sub.1-6 alkyl. In certain embodiments, R.sup.a is H. In some embodiments, R.sup.a is substituted or unsubstituted C.sub.1-6 alkyl. In some embodiments, R.sup.a is unsubstituted C.sub.1-6 alkyl. In some embodiments, R.sup.a is substituted C.sub.1-6 alkyl. In some embodiments, R.sup.a is methyl. In certain embodiments, R.sup.a is ethyl. In certain embodiments, each instance of R.sup.a is H. In some embodiments, each instance of R.sup.a is substituted or unsubstituted C.sub.1-6 alkyl. In some embodiments, each instance of R.sup.a is unsubstituted C.sub.1-6 alkyl. In some embodiments, each instance of R.sup.a is substituted C.sub.1-6 alkyl. In some embodiments, each instance of R.sup.a is methyl. In certain embodiments, each instance of R.sup.a is ethyl.

[0116] In some embodiments, n is 0, 1, 2, 3, or 4. In certain embodiments, n is 0, 1, or 2. In some embodiments, n is 1. In certain embodiments, n is 2.

[0117] In some embodiments, m is 0, 1, 2, 3, or 4. In certain embodiments, m is 0, 1, or 2. In some embodiments, m is 1. In some embodiments, m is 2.

[0118] In some embodiments, p is 0, 1, 2, 3, 4, or 5. In certain embodiments, p is 0, 1, 2, or 3.

[0119] In some embodiments, p is 0, 1, or 2. In certain embodiments, p is 1 or 2.

[0120] In certain embodiments, Formula (I) is of the Formula (I-a):

##STR00036## [0121] or pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, isotopologues, stereoisomers, or prodrugs thereof.

[0122] In certain embodiments, Formula (I) is of the Formula (I-b):

##STR00037## [0123] or pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, isotopologues, stereoisomers, or prodrugs thereof.

[0124] In certain embodiments, Formula (I) is of the Formula (I-c):

##STR00038## [0125] or pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, isotopologues, stereoisomers, or prodrugs thereof.

[0126] In certain embodiments, Formula (I) is of the Formula (I-d):

##STR00039## [0127] or pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, isotopologues, stereoisomers, or prodrugs thereof.

[0128] In certain embodiments, Formula (I) is of the Formula (I-e):

##STR00040## [0129] or pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, isotopologues, stereoisomers, or prodrugs thereof.

[0130] In certain embodiments, Formula (I) is of the Formula (I-f):

##STR00041## [0131] or pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, isotopologues, stereoisomers, or prodrugs thereof.

[0132] In certain embodiments, Formula (I) is of the Formula (I-g):

##STR00042## [0133] or pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, isotopologues, stereoisomers, or prodrugs thereof.

[0134] In certain embodiments, Formula (I) is of the Formula (I-h):

##STR00043## [0135] or pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, isotopologues, stereoisomers, or prodrugs thereof.

[0136] In certain embodiments, Formula (I) is of the Formula (I-i):

##STR00044## [0137] or pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, isotopologues, stereoisomers, or prodrugs thereof.

[0138] In certain embodiments, a compound of Formula (0) is of the formula:

##STR00045## ##STR00046## ##STR00047##

or a salt thereof. In some embodiments, a compound of Formula (0) is of the formula:

##STR00048##

or a salt thereof.

[0139] In certain embodiments, a compound of Formula (I) is of the formula:

##STR00049## ##STR00050##

or a salt thereof. In certain embodiments, a compound of Formula (I) is of the formula:

##STR00051##

or a salt thereof. In certain embodiments, a compound of Formula (I) is of the formula:

##STR00052## ##STR00053## ##STR00054##

[0140] In certain embodiments, a compound described herein is a compound of Formula (0), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopologue, or prodrug thereof. In certain embodiments, a compound of Formula (0), or a pharmaceutically acceptable salt thereof.

[0141] In certain embodiments, a compound described herein is a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopologue, or prodrug thereof. In certain embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof.

[0142] In certain embodiments, a compound described herein is any of the compounds I-1 to I-14, found in Table 1, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopologue, or prodrug thereof. In certain embodiments, a compound described herein is any of the compounds I-1 to I-14, or a pharmaceutically acceptable salt thereof.

TABLE-US-00001 TABLE 1 Compounds I-1 to I-14 of the disclosure Compound Compound Number Name Structure: I-1 RJB-2-88 [00055] I-2 RJB-2-145 and RJB-145 [00056] I-3 RJB-2-146 [00057] I-4 RJB-2-151 [00058] I-5 RJB-2-155 [00059] I-6 RJB-3-77 [00060] I-7 RJB-3-161 [00061] I-8 RJB-3-164 [00062] I-9 RJB-3-169 [00063] I-10 RJB-3-178 [00064] I-11 RJB-3-180 [00065] I-12 RJB-3-184 [00066] I-13 RJB-3-201 [00067] I-14 RJB-3-214 [00068]

[0143] In certain embodiments, a compound disclosed herein is of Formula (I) (e.g., compounds I-1 to I-14), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopologue, or prodrug thereof. In certain embodiments, a compound disclosed herein is of Formula (I) (e.g., compounds I-1 to I-14), or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, tautomer, stereoisomer, or prodrug thereof. In certain embodiments, a compound disclosed herein is of Formula (I) (e.g., compounds I-1 to I-14), or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, tautomer, or stereoisomer thereof. In certain embodiments, a compound disclosed herein is of Formula (I) (e.g., compounds I-1 to I-14), or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof. In certain embodiments, a compound disclosed herein is of Formula (I) (e.g., compounds I-1 to I-14), or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof. In certain embodiments, a compound disclosed herein is of Formula (I) (e.g., compounds I-1 to I-14), or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

Methods of Treatment and Uses

[0144] The compounds described herein may be useful in treating and/or preventing diseases or disorders including, but not limited to, addiction (e.g. addiction to a substance (e.g. addiction to cocaine, amphetamines, methamphetamine, methylphenidate, nicotine, alcohol, prescription medication, marijuana, tobacco, food, or an opioid selected from heroin, fentanyl, codeine, hydrocodone, morphine, oxycodone, hydromorphone, and methadone)), stress-related disorders (e.g. chronic stress, PTSD, panic disorder, anxiety, or general anxiety disorders), eating disorders (e.g. orthorexia, or anorexia nervosa), or pain-related diseases or disorders (e.g. chronic pain, arthritis (e.g., rheumatoid arthritis), inflammatory pain, musculoskeletal pain, primary headache disorders, or migraines), or diseases and disorders associated with the activity of a PACAP receptor in a subject, or modulating the activity of a PACAP receptor in a subject, biological sample, tissue, or cell.

[0145] In one aspect, the disclosure provides a method of treating a subject suffering from or susceptible to a disease or disorder. In one aspect, the disclosure provides a method of treating a subject suffering from or susceptible to a neurological disorder (e.g. stress-related disorders (e.g. chronic stress, post-traumatic stress disorder (PTSD), panic disorder, anxiety, or general anxiety disorder), eating disorders (e.g. orthorexia, or anorexia nervosa), pain-related disorders (e.g. chronic pain, arthritis (e.g., rheumatoid arthritis), inflammatory pain, musculoskeletal pain, primary headache disorders, or migraines), panic disorders, panic attacks, or addiction (e.g. addiction to a substance (e.g. addiction to cocaine, amphetamines, methamphetamine, methylphenidate, nicotine, alcohol, prescription medication, marijuana, tobacco, food, or an opioid selected from heroin, fentanyl, codeine, hydrocodone, morphine, oxycodone, hydromorphone, and methadone)), the method comprising administering to the subject in need thereof a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopologue, or prodrug thereof. In certain aspects, the method treats addiction by preventing relapse of an addiction. In another aspect, the method treats addiction by lowering the incidence of relapse, as compared to a control population not receiving treatment via the method. In certain aspects, the method treats addiction by preventing stress-induced relapse of an addiction. In some embodiments, the disease or disorder is chronic stress. In some embodiments, the disease or disorder is post-traumatic stress disorder (PTSD). In some embodiments, the disease or disorder is panic disorder. In some embodiments, the disease or disorder is anxiety. In some embodiments, the disease or disorder is general anxiety disorder. In some embodiments, the disease or disorder is chronic stress. orthorexia. In some embodiments, the disease or disorder is anorexia nervosa. In some embodiments, the disease or disorder is chronic stress. chronic pain. In some embodiments, the disease or disorder is arthritis. In some embodiments, the disease or disorder is rheumatoid arthritis. In some embodiments, the disease or disorder is inflammatory pain. In some embodiments, the disease or disorder is musculoskeletal pain. In some embodiments, the disease or disorder is primary headache disorder. In some embodiments, the disease or disorder is migraine. In some embodiments, the disease or disorder is panic attacks. In some embodiments, the disease or disorder is addiction to cocaine. In some embodiments, the disease or disorder is addiction to amphetamines. In some embodiments, the disease or disorder is addiction to methamphetamine. In some embodiments, the disease or disorder is addiction to methylphenidate. In some embodiments, the disease or disorder is addiction to nicotine. In some embodiments, the disease or disorder is addiction to alcohol. In some embodiments, the disease or disorder is addiction to prescription medication. In some embodiments, the disease or disorder is addiction to marijuana. In some embodiments, the disease or disorder is addiction to tobacco. In some embodiments, the disease or disorder is addiction to food. In some embodiments, the disease or disorder is addiction to an opioid selected from heroin, fentanyl, codeine, hydrocodone, morphine, oxycodone, hydromorphone, and methadone.

[0146] In one aspect, the method comprises administering to a subject a therapeutically effective amount of compound I-1, or a salt thereof. In one aspect, the method comprises administering to a subject a therapeutically effective amount of compound I-2, or a salt thereof. In one aspect, the method comprises administering to a subject a therapeutically effective amount of compound I-3, or a salt thereof. In one aspect, the method comprises administering to a subject a therapeutically effective amount of compound I-4, or a salt thereof. In one aspect, the method comprises administering to a subject a therapeutically effective amount of compound I-5, or a salt thereof. In one aspect, the method comprises administering to a subject a therapeutically effective amount of compound I-6, or a salt thereof. In one aspect, the method comprises administering to a subject a therapeutically effective amount of compound I-7, or a salt thereof. In one aspect, the method comprises administering to a subject a therapeutically effective amount of compound I-8, or a salt thereof. In one aspect, the method comprises administering to a subject a therapeutically effective amount of compound I-9, or a salt thereof. In one aspect, the method comprises administering to a subject a therapeutically effective amount of compound I-10, or a salt thereof. In one aspect, the method comprises administering to a subject a therapeutically effective amount of compound I-11, or a salt thereof. In one aspect, the method comprises administering to a subject a therapeutically effective amount of compound I-12, or a salt thereof. In one aspect, the method comprises administering to a subject a therapeutically effective amount of compound I-13, or a salt thereof. In one aspect, the method comprises administering to a subject a therapeutically effective amount of compound I-14, or a salt thereof.

[0147] In another aspect, the disclosure provides a method of modulating the activity of a PACAP-receptor (e.g. PAC1) comprising administering an effective amount of any one of the compounds of Formula (I), or a salt thereof. In another aspect, the modulation is inhibition. In another aspect, the modulation occurs in a biological sample (e.g. tissue or cell). In another aspect, the modulation occurs in a subject. In another aspect, PAC1 receptor antagonism can prevent relapse of an addiction. In certain aspects, PAC1 receptor antagonism can prevent stress-induced relapse of an addiction.

[0148] The disclosure provides a method of treating a subject suffering from or susceptible to a PACAP receptor-mediated disease or disorder, the method comprising administering to the subject in need thereof a therapeutically effective amount of any one of compounds of Formula (I), or a salt thereof. In another aspect, the PACAP receptor-mediated disorder is a neurological disorder. In another aspect, the PACAP receptor-mediated disease or disorder is a stress-related disorder (e.g. chronic stress, post-traumatic stress disorder (PTSD), panic disorder, anxiety, or general anxiety disorder). In another aspect, the PACAP receptor-mediated disease or disorder is a pain-related disorders (e.g. chronic pain, arthritis (e.g., rheumatoid arthritis), inflammatory pain, musculoskeletal pain, primary headache disorders, or migraines).

[0149] Also provided herein are methods for modulating a pituitary adenylate cyclase activating polypeptide (PACAP) receptor, comprising contacting a PAC1 receptor with a compound disclosed herein, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein. In some embodiments, the modulating is inhibiting. Thus, in some embodiments are methods for inhibiting a pituitary adenylate cyclase activating polypeptide (PACAP) receptor, comprising contacting a PAC1 receptor with a compound disclosed herein, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein.

[0150] The disclosure further provides methods for modulating a PAC1 receptor, comprising contacting a PAC1 receptor with a compound disclosed herein, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein. In some embodiments, the modulating is inhibiting. Thus, in some embodiments, provided herein are methods for inhibiting a PAC1 receptor, comprising contacting a PAC1 receptor with a compound disclosed herein, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein.

[0151] The disclosure further provides, methods of treating a disease or disorder in a subject by modulating a pituitary adenylate cyclase activating polypeptide (PACAP) receptor, the method comprising administering to the subject a therapeutically effective amount of a compound disclosed herein, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein. In some embodiments, the modulating is inhibiting. Thus, in some embodiments, provided herein are methods of treating a disease or disorder in a subject by inhibiting a pituitary adenylate cyclase activating polypeptide (PACAP) receptor, the method comprising administering to the subject a therapeutically effective amount of a compound disclosed herein, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein.

[0152] Also provided are methods of treating a disease or disorder in a subject by modulating a PAC1 receptor, the method comprising administering to the subject a therapeutically effective amount of a compound disclosed herein, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein. In some embodiments, the modulating is inhibiting. Thus, in some embodiments, provided herein are methods of treating a disease or disorder in a subject by inhibiting a PAC1 receptor, the method comprising administering to the subject a therapeutically effective amount of a compound disclosed herein, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein.

[0153] In another aspect, the method comprises administering to a subject a therapeutically effective amount of a combination of any one of the compounds of Formula (I), or salts thereof. In another aspect, the neurological disorder is a stress-related disorder (e.g. chronic stress, post-traumatic stress disorder (PTSD), panic disorder, anxiety, or general anxiety disorder). In another aspect, the neurological disorder is an eating disorder (e.g. orthorexia, or anorexia nervosa). In another aspect, the neurological disorder is a pain-related disorder (e.g. chronic pain, arthritis (e.g., rheumatoid arthritis), inflammatory pain, musculoskeletal pain, primary headache disorder, or migraine). In another aspect, the neurological disorder is a panic disorder (e.g., panic attacks). In another aspect, the neurological disorder is addiction (e.g. addiction to a substance (e.g. addiction to cocaine, amphetamines, methamphetamine, methylphenidate, nicotine, alcohol, prescription medication, marijuana, tobacco, food, or an opioid selected from heroin, fentanyl, codeine, hydrocodone, morphine, oxycodone, hydromorphone, and methadone)).

[0154] In certain embodiments, a compound of Formula (I), is administered in combination with one or more additional pharmaceutical agents. The additional pharmaceutical agent may also be a PACAP receptor antagonist. In certain embodiments, the additional pharmaceutical agent is an additional compound of Formula (I), or a salt thereof. In certain embodiments, the additional pharmaceutical agent is an inhibitor of a kinase. In certain embodiments, the additional pharmaceutical agent is an inhibitor of MEK/ERK. In certain embodiments, the additional pharmaceutical agent is an anti-inflammatory agent, pain-relieving agent, antihistamine, beta-blocker, anxiolytic, anti-depressant, selective serotonin reuptake inhibitor (SSRI), serotonin and norepinephrine reuptake inhibitor (SNRI), sympatholytic, monoamine oxidase inhibitor (MAOI), opioid, carbamate, benzodiazepine, barbiturate, GABAergic drug, antipsychotic, or other agent.

[0155] The additional pharmaceutical agents include, but are not limited to, anti-anxiety agents, anti-inflammatory agents, antihistamines, anxiolytics, antidepressants, anti-allergic agents, pain-relieving agents, and any combination thereof. In certain embodiments, a pharmaceutical composition described herein further comprises a combination of the additional pharmaceutical agents described herein.

[0156] The inventive compounds or compositions may synergistically modulate a PACAP receptor induced by the additional pharmaceutical agent(s) in the biological sample or subject. Thus, the combination of the inventive compounds or compositions and the additional pharmaceutical agent(s) may be useful in treating neurological diseases resistant to a treatment using the additional pharmaceutical agent(s) without the inventive compounds or compositions.

[0157] In another aspect, the disclosure provides a kit for treating a neurological disease or disorder comprising a therapeutically effective amount of a compound of Formula (I), or a salt thereof, and instructions for administration of the compound, or a salt thereof, to a subject. In another aspect, the neurological disease or disorder is a stress-related disorder (e.g. chronic stress, post-traumatic stress disorder (PTSD), panic disorder, anxiety, or general anxiety disorder), eating disorders (e.g. orthorexia, or anorexia nervosa), pain-related disorder (e.g. chronic pain, arthritis (e.g., rheumatoid arthritis), inflammatory pain, musculoskeletal pain, primary headache disorders, or migraines), panic disorders, panic attacks, or addiction (e.g. addiction to a substance (e.g. addiction to cocaine, amphetamines, methamphetamine, methylphenidate, nicotine, alcohol, prescription medication, marijuana, tobacco, food, or an opioid selected from heroin, fentanyl, codeine, hydrocodone, morphine, oxycodone, hydromorphone, and methadone)).

[0158] In another aspect, the disclosure provides a method of ameliorating a disorder or symptom thereof in a subject, the method comprising administering to the subject in need thereof a therapeutically effective amount of a compound of Formula (I), or a salt thereof. In another aspect, the disease is a neurological disease or disorder.

[0159] Determination of a therapeutically effective amount or a prophylactically effective amount of the compound of the disclosure, can be readily made by the physician or veterinarian (the attending clinician), as one skilled in the art, by the use of known techniques and by observing results obtained under analogous circumstances. The dosages may be varied depending upon the requirements of the patient in the judgment of the attending clinician; the severity of the condition being treated and the particular compound being employed. In determining the therapeutically effective amount or dose, and the prophylactically effective amount or dose, a number of factors are considered by the attending clinician, including, but not limited to: the specific neurological disorder involved; pharmacodynamics characteristics of the particular agent and its mode and route of administration; the desired time course of treatment; the species of mammal; its size, age, and general health; the specific disease involved; the degree of or involvement or the severity of the disease; the response of the individual patient; the particular compound administered; the mode of administration; the bioavailability characteristics of the preparation administered; the dose regimen selected; the kind of concurrent treatment (i.e., the interaction of the compound of the disclosure with other co-administered therapeutics); and other relevant circumstances.

[0160] Treatment can be initiated with smaller dosages, which are less than the optimum dose of the compound. Thereafter, the dosage may be increased by small increments until the optimum effect under the circumstances is reached. For convenience, the total daily dosage may be divided and administered in portions during the day if desired. A therapeutically effective amount and a prophylactically effective amount of a compound of the disclosure is expected to vary from about 0.1 milligram per kilogram of body weight per day (mg/kg/day) to about 100 mg/kg/day.

[0161] Compounds determined to be effective for the prevention or treatment of neurological disorders in animals, e.g., dogs, chickens, and rodents, may also be useful in treatment of neurological disorders in humans. Those skilled in the art of treating neurological disorders in humans will know, based upon the data obtained in animal studies, the dosage and route of administration of the compound to humans. In general, the dosage and route of administration in humans is expected to be similar to that in animals.

[0162] The identification of those patients who are in need of prophylactic treatment for neurological disorders is well within the ability and knowledge of one skilled in the art. Certain of the methods for identification of patients which are at risk of developing neurological disorders which can be treated by the subject method are appreciated in the medical arts, such as family history, and the presence of risk factors associated with the development of that disease state in the subject patient. A clinician skilled in the art can readily identify such candidate patients, by the use of, for example, clinical tests, physical examination and medical/family history.

[0163] A method of assessing the efficacy of a treatment in a subject includes determining the pre-treatment extent of a neurological disorder by methods well known in the art and then administering a therapeutically effective amount of a compound of Formula (I), according to the disclosure to the subject. After an appropriate period of time after the administration of the compound (e.g., 1 day, 1 week, 2 weeks, one month, six months), the extent of the neurological disorder is determined again. The modulation (e.g., decrease) of the extent of the neurological disorder indicates efficacy of the treatment. The extent of the neurological disorder may be determined periodically throughout treatment. For example, the extent of the neurological disorder may be checked every few hours, days or weeks to assess the further efficacy of the treatment. A decrease in extent of the neurological disorder indicates that the treatment is efficacious. The method described may be used to screen or select patients that may benefit from treatment with a PACAP receptor antagonist for a neurological disorder.

[0164] As used herein, obtaining a biological sample from a subject, includes obtaining a sample for use in the methods described herein. A biological sample is described above.

[0165] In another aspect, a compound of the disclosure or pharmaceutical composition thereof is packaged in a therapeutically effective amount with a pharmaceutically acceptable carrier or diluent. The composition may be formulated for treating a subject suffering from or susceptible to a neurological disorder, and packaged with instructions to treat a subject suffering from or susceptible to a neurological disorder.

[0166] In another aspect, methods of treating a neurological disorder in a subject include administering an effective amount of a compound of the disclosure to the subject. The administration may be by any route of administering known in the pharmaceutical arts. The subject may have a neurological disorder, may be at risk of developing a neurological disorder, or may need prophylactic treatment prior to anticipated or unanticipated exposure to conditions capable of increasing susceptibility to neurological disorder.

[0167] In one aspect, a method of monitoring the progress of a subject being treated includes determining the pre-treatment status of the neurological disorder, administering a therapeutically effective amount of compound of the disclosure to the subject, and determining the status of the neurological disorder after an initial period of treatment, wherein the modulation of the status indicates efficacy of the treatment.

[0168] The subject may be at risk of a neurological disorder, may be exhibiting symptoms of a neurological disorder, may be susceptible to a neurological disorder and/or may have been diagnosed with a neurological disorder (e.g. stress-related disorders (e.g. chronic stress, post-traumatic stress disorder (PTSD), panic disorder, anxiety, or general anxiety disorder), eating disorders (e.g. orthorexia, or anorexia nervosa), pain-related disorders (e.g. chronic pain, arthritis (e.g., rheumatoid arthritis), inflammatory pain, musculoskeletal pain, primary headache disorders, or migraines), panic disorders, panic attacks, or addiction (e.g. addiction to a substance (e.g. addiction to cocaine, amphetamines, methamphetamine, methylphenidate, nicotine, alcohol, prescription medication, marijuana, tobacco, food, or an opioid selected from heroin, fentanyl, codeine, hydrocodone, morphine, oxycodone, hydromorphone, and methadone)).

[0169] The initial period of treatment may be the time in which it takes to establish a stable and/or therapeutically effective blood serum level of any of the compounds, compound combinations, dosing regimens, or pharmaceutical compositions delineated herein, or the time in which it take for the subject to clear a substantial portion of the compound, or any period of time selected by the subject or healthcare professional that is relevant to the treatment.

[0170] If the modulation of the status indicates that the subject may have a favorable clinical response to the treatment, the subject may be treated with the compound. For example, the subject can be administered a therapeutically effective dose or doses of the compound.

[0171] In another aspect, the disclosure provides antagonists for PACAP-receptors (e.g. PAC1) and methods for their use in a biological sample (e.g. tissue or cell). The methods include contacting the biological sample (e.g. tissue or cell) with an effective amount of any of the compounds of Formula (I), compound combinations, dosing regimens, or pharmaceutical compositions delineated herein, such that the signaling of the PACAP-receptor is reduced. The contacting may be in vitro, e.g., by addition of the compound to a fluid surrounding the cells, for example, to the growth media in which the cells are living or existing. The contacting may also be by directly contacting the compound to the cells. Alternately, the contacting may be in vivo, e.g., by passage of the compound through a subject; for example, after administration, depending on the route of administration, the compound may travel through the digestive tract or the blood stream or may be applied or administered directly to cells in need of treatment.

[0172] The PACAP-receptor may be within a cell, isolated from a cell, recombinantly expressed, purified or isolated from a cell or recombinant expression system or partially purified or isolated from a cell or recombinant expression system.

[0173] The contacting may be in vitro, e.g., by addition of the compound to a solution containing purified PACAP-receptor, or, if the PACAP-receptor is present in cells, by adding the compound to a fluid surrounding the cells, for example, to the growth media in which the cells are living or existing. The contacting may also be by directly contacting the compound to the cells. Alternately, the contacting may be in vivo, e.g., by passage of the compound through a subject; for example, after administration, depending on the route of administration, the compound may travel through the digestive tract or the blood stream or may be applied or administered directly to cells in need of treatment.

[0174] Kits of the disclosure include kits for treating a neurological disorder in a subject. The disclosure also includes kits for regulation of PACAP-receptor function, assessing the efficacy of a treatment for a neurological disorder in a subject, monitoring the progress of a subject being treated for a neurological disorder, selecting a subject with a neurological disorder for treatment according to the disclosure, and/or treating a subject suffering from or susceptible to a neurological disorder. The kit may include any of the compounds, compound combinations, dosing regimens, or pharmaceutical compositions delineated herein and instructions for use. The instructions for use may include information on dosage, method of delivery, storage of the kit, etc. The kits may also include reagents, for example, test compounds, buffers, media (e.g., cell growth media), cells, etc. Test compounds may include known compounds or newly discovered compounds, for example, combinatorial libraries of compounds. One or more of the kits of the disclosure may be packaged together, for example, a kit for assessing the efficacy of a treatment for a neurological disorder may be packaged with a kit for monitoring the progress of a subject being treated for a neurological disorder according to the disclosure.

[0175] The present methods can be performed on cells in culture, e.g. in vitro or ex vivo, or on cells present in an animal subject, e.g., in vivo. Compounds of the disclosures can be initially tested in vitro using primary cultures.

[0176] Alternatively, the effects of compound of the disclosure can be characterized in vivo using animals models. One skilled in the art, provided with the present disclosure, will readily understand that analogous screening methods for the same or a similar library of compounds could now be usefully applied to different neurological conditions in which the same or similar underlying pathologic mechanism is known or suspected to be a factor in the development or manifestation of the disease.

[0177] The recitation of a listing of chemical groups in any definition of a variable herein includes definitions of that variable as any single group or combination of listed groups. The recitation of an embodiment for a variable herein includes that embodiment as any single embodiment or in combination with any other embodiments or portions thereof. The recitation of an embodiment herein includes that embodiment as any single embodiment or in combination with any other embodiments or portions thereof.

[0178] The present disclosure provides methods of modulating (e.g., inhibiting or increasing) the activity (e.g., aberrant activity, or undesired activity, such as increased or decreased activity) of a PACAP-receptor. The present disclosure provides methods of modulating (e.g., inhibiting or increasing) the activity (e.g., aberrant activity, such as increased or decreased activity) of a PACAP-receptor in a subject. The present disclosure also provides methods for the treatment of a wide range of diseases, such as diseases associated with the aberrant activity (e.g., increased or decreased activity) of a PACAP-receptor, e.g., neurological diseases or disorders (e.g. stress-related disorders (e.g. chronic stress, post-traumatic stress disorder (PTSD), panic disorder, anxiety, or general anxiety disorder), eating disorders (e.g. orthorexia, or anorexia nervosa), pain-related disorders (e.g. chronic pain, arthritis (e.g., rheumatoid arthritis), inflammatory pain, musculoskeletal pain, primary headache disorders, or migraines), panic disorders, panic attacks, or addiction (e.g. addiction to a substance (e.g. addiction to cocaine, amphetamines, methamphetamine, methylphenidate, nicotine, alcohol, prescription medication, marijuana, tobacco, food, or an opioid selected from heroin, fentanyl, codeine, hydrocodone, morphine, oxycodone, hydromorphone, and methadone)).

EXAMPLES

[0179] In order that the present disclosure 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.

Example 1. Biological Procedures

[0180] For FIG. 1, stable PAC1 receptor HEK cell lines were pretreated with 25 M of compounds of the disclosure to evaluate inhibition of 20 nM PACAP-stimulated ERK activation by Western blot analyses.

[0181] For FIG. 2, PAC1 receptor HEK cells were pretreated with different concentrations of the indicated compound to demonstrate dose-dependent inhibition of 20 nM PACAP-stimulated ERK activation. RJB-145 demonstrated an apparent IC.sub.50 of approximately 10 M which is comparable to that for a previously identified antagonist JF-214. RJB-88 appeared less potent with an IC.sub.50 of approximately 25 M.

Example 2. Biological Results

[0182] As depicted in FIG. 1, RJB-145 and related isomers demonstrate efficacy in blocking PACAP/PAC1 receptor stimulated ERK activation.

[0183] As shown in FIG. 2, RJB-145 dose-dependent inhibition of PACAP-stimulated ERK activation. RJB-145 demonstrated an apparent IC.sub.50 of approximately 10 M which is comparable to that for a previously identified antagonist JF-214. RJB-88 appeared less potent with an IC.sub.50 of approximately 25 M.

Example 3. Synthesis

##STR00069##

Synthesis of Benzenesulfonyl Chloride Derivatives

##STR00070##

[0184] The following reaction procedure was conducted without solvent. The requisite substituted N-acetyl-aniline or benzoxazolinone (1 eq) was cooled to 0 C. and chlorosulfonic acid (7.5 eq) was slowly added dropwise at 0 C. The mixture was allowed to warm to room temperature and was stirred for 2-3 hours, at which point it was added dropwise to ice water to give the product as a precipitate which was collected via vacuum filtration.

Synthesis of RJB-2-142

##STR00071##

[0185] The RJB-2-142 acetyl-protected intermediate was dissolved in 20% NaOH solution (4 ml/mmol) and was heated at reflux for 2 hours. The reaction mixture was cooled to room temperature and brought to pH=7 by the addition of 2M HCl, which resulted in the formation of a precipitate. The mixture was cooled to 0 C. and the solid product was collected via vacuum filtration.

Synthesis of RJB-2-142 (acetyl-protected intermediate)

##STR00072##

[0186] Pyridine (1.2 eq) was added to a solution 3,5-difluoroaniline (1.2 eq) in dry tetrahydrofuran (0.5M) at room temperature and the mixture was allowed to stir for 5 hours. N-Acetylsulfanilyl chloride (1 eq) was added and the reaction was kept at room temperature for 18 hours. The solvent was evaporated and 0.5M HCl (2 ml/mmol) was added and the solid N-acetyl protected intermediate was then collected via vacuum filtration.

Synthesis of RJB-2-145

##STR00073##

[0187] 1-Methylimidazole (3 eq) and methane sulfonyl chloride (1.5 eq) were added sequentially to a 0 C. solution of indole-2-carboxylic acid (1 eq) in dry dichloromethane (0.03M). The reaction was removed from the cooling bath and stirred for 15 minutes at RT. The reaction was cooled to 0 C. and RJB-2-142 (1 eq) was added. The mixture was then heated at reflux for 6.5 hours, cooled to RT and water was added which caused a precipitate to form. The product was collected by vacuum filtration.

Results

[0188] Among new candidate scaffolds provided herein, one new small molecule RJB-145 shows efficacy and potency in blocking PACAP/PAC1 receptor-stimulated ERK activation in our stable human HEK PAC1 receptor cell line (FIGS. 1 and 2). RJB-145 contains a sulfanilamide core flanked by an indole and it maintains the 3,5-difluorobenzyl group that showed particular efficacy in JF-214. Again, the presence of fluorine or other electron withdrawing groups at the 3 and 5 positions of the aromatic ring appear to be relevant for potency. These heteroatoms could take advantage of a hydrogen bonding interactions within the binding pocket, or the electron deficient aryl ring may be involved in -stacking or cation- interactions within the receptor. Without the fluorine groups, RJB-88 appeared less potent (FIGS. 1 and 2). Substituted aryl, substituted heteroaryl including but not limited to indole derivatives, or substituted alkyl rings in place of the indole moiety may also increase potency through additional interactions with the receptor.

[0189] Compared to JF-214, RJB-145 demonstrates near equipotency in blocking PACAP/PAC1 receptor-stimulated ERK activation. Using 20 nM PACAP for near maximal ERK activation, RJB-145 demonstrated an apparent IC.sub.50 of 10 M, compared to JF-214 with an apparent IC.sub.50 of 5-8 M (FIG. 2). As with our current understanding of JF-214 signaling profile, RJB-145 also appears to be a biased antagonist in inhibiting PAC1 receptor-mediated ERK activation without significant effects on PAC1 receptor-stimulated adenylyl cyclase cAMP activation. Hence isoforms based on the RJB-145 scaffold have potential in being developed into potent and efficacious PAC1 receptor antagonists for therapeutics to ameliorate stress related behavioral psychopathologies and chronic pain disorders.

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EQUIVALENTS AND SCOPE

[0231] 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 disclosure 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 disclosure 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.

[0232] Furthermore, the disclosure 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 disclosure, or aspects described herein, is/are referred to as comprising particular elements and/or features, certain embodiments described herein or aspects described herein 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.

[0233] 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 described herein, 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 disclosure 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 described herein 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 disclosure, as defined in the following claims.