IMIDAZOLINE RECEPTOR TYPE 1 LIGANDS FOR USE AS THERAPEUTICS

Title:

IMIDAZOLINE RECEPTOR TYPE 1 LIGANDS FOR USE AS THERAPEUTICS

Document Type and Number:

WIPO Patent Application WO/2016/105448

Kind Code:

Abstract:

This disclosure provides compounds and compositions for use as analgesics and for the treatment of various conditions, such as pain, headaches, allodynia, and fibromyalgia. The disclosure also provides compounds that are ligands, and in some embodiments, modulators (e.g., agonists), for the imidazoline receptor type 1.

Inventors:

RIDEOUT DARRYL (US)
LEDERMAN SETH (US)
DAUGHERTY BRUCE (US)
GERSHELL LELAND J (US)

Application Number:

PCT/US2015/000153

Publication Date:

June 30, 2016

Filing Date:

December 22, 2015

Export Citation:

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Assignee:

RIDEOUT DARRYL (US)
LEDERMAN SETH (US)
DAUGHERTY BRUCE (US)
GERSHELL LELAND J (US)

International Classes:

C07D207/22; A61K31/13; A61K31/131; A61K31/133; A61K31/155; A61K31/325; A61K31/395; A61K38/04; A61K38/16; C07C211/01; C07C211/35; C07C211/39; C07C217/06; C07C257/10; C07C271/16; C07C279/02; C07C279/26; C07D205/04; C07D207/04; C07D209/44; C07D209/52; C07D217/04; C07D233/04; C07D233/44; C07D233/54; C07D235/02; C07D239/06; C07D239/70; C07D243/04; C07D263/28; C07D295/185; C07D319/20; C07D401/06; C07D401/14; C07D403/02; C07D403/14; C07D407/12; C07D409/02; C07D409/14; C07D413/14; C07D417/06; C07D471/02; C07K7/04; C07K14/00

Domestic Patent References:

WO2013051159A1	2013-04-11
WO2008060552A2	2008-05-22
WO2004098589A1	2004-11-18
WO2001077100A2	2001-10-18
WO2001070734A2	2001-09-27
WO2008033739A2	2008-03-20
WO2000025770A1	2000-05-11
WO1995009619A2	1995-04-13
WO2003002652A1	2003-01-09
WO2015129927A1	2015-09-03

Foreign References:

US5864039A

1999-01-26

Attorney, Agent or Firm:

HALEY, James, F., Jr. et al. (1211 Avenue of the AmericasNew York, NY, US)

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Claims:

1 . A compound having the formula (SC-01 ):

SC-01

or a pharmaceutically acceptable salt, tautomer, solvate, diastereomer,

enantiomer, or prodrug thereof, wherein as valence and stability permit:

L¹ is a 4 to 10 carbon atom linker selected from the group consisting of

optionally substituted alkanediyl, heteroalkanediyl, cycloalkanediyl, heterocyclylalkanediyl, cycloalkylalkanediyl,

cycloalkylheteroalkanediyl, alkenediyl, alkynediyl, alkylthiodiyl, and

1 , 1 -dialky lcycloalkanediyl;

W is selected from the group consisting of N and CH;

Y is selected from the group consisting of CH₂, NH, O, and S;

R¹ is selected from the group consisting of hydrogen and optionally substituted alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, heteroaryl, alkoxycycloalkyl, cycloalkyl, and heterocyclyl; and

R² is selected from the group consisting of hydrogen and optionally substituted alkyl;

wherein L¹ can be linked with R¹, R² or both R¹ and R² to form a monocyclic, bicyclic, or polycyclic ring, wherein the ring is selected from the group consisting of optionally substituted cycloalkyl and optionally substituted heterocyclyl;

wherein L¹ can be linked with R¹ or R² to form a moiety selected from the group consisting of optionally substituted cycloalkylalkanediyl, heterocyclylalkanediyl, cycloalkylheteroalkanediyl, and heterocycly lheteroalkaned iy 1.

2. A compound having the formula (SC-02):

SC-02 or a pharmaceutically acceptable salt, tautomer, solvate, diastereomer,

enantiomer, or prodrug thereof, wherein as valence and stability permit:

Y is selected from the group consisting of CH₂ and NH;

R¹ is selected from the group consisting of hydrogen and optionally substituted alkyl, heteroalkyl, and aminoalkyl; and

Ar is selected from the group consisting of optionally substituted aryl and

heteroaryl.

3. A compound having the form a (SC-03):

SC-03 or a pharmaceutically acceptable salt, tautomer, solvate, diastereomer,

enantiomer, or prodrug thereof, wherein as valence and stability permit:

R¹ is selected from the group consisting of hydrogen and optionally substituted alkyl and heteroalkyl; and

Ar is selected from the group consisting of optionally substituted aryl and

heteroaryl.

4. A compound having the formula SC-04):

SC-04 or a pharmaceutically acceptable salt, tautomer, solvate, diastereomer,

enantiomer, or prodrug thereof, wherein as valence and stability permit: 1 2

R' and R are independently selected from the group consisting of hydrogen and optionally substituted alkyl, heteroalkyl, alkoxy, aminoalkyl, arylalkyl, heteroarylalkyl, arylalkoxy, and heteroarylalkoxy; and

Ar is selected from the group consisting of optionally substituted aryl and

heteroaryl;

wherein R and R can optionally form a monocyclic,^" bicyclic or polycyclic ring, wherein the ring is selected from the group consisting of optionally substituted cycloalkyl and optionally substituted

heterocyclyl.

A compound having the formula SC-05):

SC-05 or a pharmaceutically acceptable salt, tautomer, solvate, diastereomer,

enantiomer, or prodrug thereof, wherein as valence and stability permit: R¹ is selected from the group consisting of hydrogen and optionally substituted alkyl, heteroalkyl, aminoalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

R² is selected from the group consisting of optionally substituted alkyl,

heteroalkyl, aminoalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

R³ is selected from the group consisting of hydrogen and optionally substituted alkyl, heteroalkyl, aminoalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; and

Ar is selected from the group consisting of optionally substituted aryl and

heteroaryl;

t 2 provided that when Ar is an optionally substituted aryl, R is hydrogen, and R is an optionally substituted alkyl, Ar is not unsubstituted phenyl and R² is not unsubstituted methyl; provided that the compound having the formula (SC-05) is not:

or a pharmaceutically acceptable salt, tautomer, solvate, or prodrug thereof.

6. A compound having the form -06):

SC-06 or a pharmaceutically acceptable salt, solvate, diastereomer, enantiomer, tautomer, or prodrug thereof, wherein as valence and stability permit: — represents a single or double bond;

R¹ is selected from the group consisting of hydrogen and optionally substituted alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; and

R² is selected from the group consisting of hydrogen and optionally substituted alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

wherein R¹ and R² can optionally form a ring, wherein the ring is selected from the group consisting of optionally substituted cycloalkyl, heterocyclyl, cycloalkenyl, aryl, and heteroaryl;

provided that the compound having the formula (SC-06) is not:

or a pharmaceutically acceptable salt, enantiomer, solvate, or prodrug thereof.

7. A compound having the formula (SC-07):

or a pharmaceutically acceptable salt, tautomer, solvate, diastereomer,

enantiomer, or prodrug thereof, wherein as valence and stability permit:

Y is selected from the group consisting of NH and O;

R' , R², R³, R⁶ are independently selected from the group consisting of

hydrogen, halogen and optionally substituted alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkoxy, alkynyloxy, alkylthio, -SCF₃, and alkylamino; and

wherein R¹ and R⁴ or R¹ and R⁵ can optionally form a ring, wherein the ring is an optionally substituted heterocyclyl;

provided that the compound having the formula (SC-07) is not:

or a pharmaceutically acceptable sa t, tautomer, solvate, enantiomer,

prodrug thereof.

8. A compound having the formula SC-08):

SC-08 or a pharmaceutically acceptable salt, tautomer, solvate, diastereomer,

enantiomer, or prodrug thereof, wherein as valence and stability permit: R¹ and R² are independently selected from the group consisting of optionally substituted alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; and

R³ and R⁴ are independently selected from the group consisting of hydrogen and optionally substituted alkyl, alkenyl, and alkynyl; wherein R¹ and R² can optionally form a ring, wherein the ring is selected from the group consisting of optionally substituted cycloalkyl, heterocyclyl, aryl, and heteroaryl;

provided that the compound having the formula (SC-08) is not:

enantiomer, or prodrug thereof.

9. A compound having the formula (SC-09):

or a pharmaceutically acceptable salt, tautomer, solvate, diastereomer,

enantiomer, or prodrug thereof, wherein as valence and stability permit: Y is selected from the group consisting of N and O;

R¹ is selected from the group consisting of optionally substituted alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

R², R³, and R⁴ are independently selected from the group consisting of

hydrogen and optionally substituted alkyl, alkenyl, alkynyl, and arylalkyl;

R⁵ is selected from the group consisting of hydrogen and optionally substituted arylalkyl; and R⁶ is selected from the group consisting of absent, hydrogen, and optionally substituted arylalkyl;

provided that the compound having the formula (SC-09) is not:

prodrug thereof. 10. A compound having the for - 10):

SC-10 or a pharmaceutically acceptable salt, tautomer, solvate, diastereomer,

enantiomer, or prodrug thereof, wherein as valence and stability permit: Y is selected from the group consisting of NH and CH₂;

l 2

R and R' are independently selected from the group consisting of hydrogen, halogen, and optionally substituted alkyl, alkenyl, alkynyl, aryl, heteroaryl, alkylthio, -SCF₃, and amino; and R and R are independently selected from the group consisting of hydrogen and halogen;

wherein R¹ and R² can optionally form a ring, wherein the ring is selected from the group consisting of optionally substituted aryl and heteroaryl;

provided that the compound having the formula (SC-10) is not:

I . A compound having the formula (SC-1 1):

SC-11 or a pharmaceutically acceptable salt, tautomer, solvate, diastereomer,

enantiomer, or prodrug thereof, wherein as valence and stability permit: — represents a single or double bond; and 1 3

R , R , and R are independently selected from the group consisting of

hydrogen and optionally substituted alkyl, alkenyl, alkynyl, heteroalkyl, hydroxyalkyl, aryl, and heteroaryl;

wherein R² and R³ can optionally form a ring, wherein the ring is a optionally substituted cycloalkyl;

provided that the compound having the formula (SC-1 1 ) is not:

h i ll bl l i di

solvate, or prodrug thereof.

12. A compound having the formula (SC- 12):

SC-12 or a pharmaceutically acceptable salt, solvate, diastereomer, enantiomer,

tautomer, or prodrug thereof, wherein as valence and stability permit: a and β—represent a single or double bond;

R¹ is selected from the group consisting of hydrogen, CH₂, and optionally substituted alkyl, haloalkyl, alkenyl, heteroalkyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, acylaminoalkyl, alkylamino, aryl, and heteroaryl;

R⁸ is selected from the group consisting of absent, hydrogen, hydroxyl, and optionally substituted alkyl and haloalkyl;

8 1 wherein when a is single bond, β is a double bond and R is absent, R is CH₂;

wherein when a is double bond and β is a single bond, R is absent;

R² is selected from the group consisting of hydrogen and optionally substituted alkyl, haloalkyl, alkenyl, heteroalkyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, acylaminoalkyl, alkylamino, aryl, and heteroaryl;

R³, R⁴, and R⁵ are independently selected from the group consisting of

hydrogen, hydroxyl, and optionally substituted alkyl;

R⁶ is selected from the group consisting of hydrogen and optionally substituted alkyl, haloalkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl,

heterocyclylalkyl, alkoxyalkyl, and cycloalkylacyl;

R⁷ is selected from the group consisting of hydrogen and optionally substituted alkyl; and

R⁹ is selected from the group consisting of hydrogen and optionally substituted alkyl and haloalkyl; wherein R¹ and R², R³ and R⁴, R⁴ and R⁵, R⁴ and R⁷, or R⁸ and R⁹ can optionally form a ring, wherein the ring is selected from the group optionally substituted cycloalkyl, halocycloalkyl, and heterocyclyl; wherein R¹ and R⁹ can optionally form a ring, wherein the ring is selected from the group optionally substituted cycloalkyl, halocycloalkyl, heterocyclyl, and aryl;

wherein when R¹ and R⁹ form an optionally substituted aryl, R⁸ is absent; wherein R⁵ and R⁶ can optionally form a monocyclic, bicyclic, or polycyclic ring, wherein the ring is selected from the group optionally substituted heterocyclyl and heteroaryl;

provided that the compound having the formula (SC- 12) is not:

or a p armaceut ca y accepta e sa t, so vate, enantiomer,- diastereomer, or prodrug thereof;

provided that R¹ , R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, and R⁹ are not all hydrogen, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

13. A compound having the formula (SC-13):

SC-13 or a pharmaceutically acceptable salt, tautomer, solvate, diastereomer,

enantiomer, or prodrug thereof, wherein as valence and stability permit: represents a single or double bond;

Y is selected from the group consisting of O and CH₂;

W is selected from the group consisting of CH₂, CH, N, NH, C, and CHCH₃;

Z is selected from the group consisting of NR.⁶, C, CH, and CH₂;

R¹ is selected from the group consisting of hydrogen, halogen, and

isothiocyanate;

R² is selected from the. group consisting of hydrogen and halogen;

R³ is selected from the group consisting of hydrogen and optionally substituted alkyl;

R⁴ is selected from the group consisting of hydrogen, hydroxyl, and optionally substituted alkyl;

R⁵ is selected from the group consisting of hydrogen and optionally substituted alkyl, heteroalkyl, and aminoalkyl; and

R⁶ is selected from the group consisting of absent, hydrogen and optionally substituted alkyl, heteroalkyl, and aminoalkyl;

wherein R⁴ and R⁵ can optionally form a ring, wherein the ring is an optionally substituted heterocyclyl;

wherein W and R³ or Z and R³ can optionally form a ring, wherein the ring is selected from the group consisting of optionally substituted cycloalkyl, heterocyclyl, aryl, and heteroaryl;

provided the compound having the formula (SC- 13) is not:

thereof.

14. A compound having the formula (SC- 14):

SC-14 or a pharmaceutically acceptable salt, tautomer, solvate, diastereomer,

enantiomer, or prodrug thereof, wherein as valence and stability permit: Y is selected from the group consisting of N and CH;

R¹ is selected from the group consisting of hydrogen and optionally substituted alkyl, heteroalkyl, arylalkyl, heteroarylalkyl, and aminoalkyl;

R² is selected from the group consisting of hydrogen and optionally substituted alkyl, heteroalkyl, and aminoalkyl; and

R³ and R⁴ are independently selected from the group consisting of hydrogen and optionally substituted alkyl;

wherein R³ and R⁴ can optionally form a ring, wherein the ring is selected from the group consisting of optionally substituted cycloalkyl and heterocyclyl.

15. A compound having the formula (SC- 15):

or a pharmaceutically acceptable salt, tautomer, solvate, diastereomer,

enantiomer, or prodrug thereof, wherein as valence and stability permit:

R¹, R², R³, and R⁴ are independently selected from the group consisting of

hydrogen, halogen, and optionally substituted alkyl, heteroalkyl, aminoalkyl, alkoxy, alkylthio, -SCF3, difluoromethoxy, aryl, heteroaryl, arylalkyl, heteroarylalkyl, arylalkoxy, heteroarylalkoxy, aryloxy, heteroaryloxy, aryloxyalkoxy, and heteroaryloxyalkoxy; and

R^s, R⁶, R⁷, and R⁸ are independently selected from the group consisting of

hydrogen and optionally substituted alkyl, heteroalkyl, aminoalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, aryloxyalkyl, and

heteroaryloxyalkyl;

wherein R⁵ and R⁶ can optionally form a ring, wherein the ring is selected from the group consisting of optionally substituted heterocyclyl and optionally substituted aminoalkylheterocyclyl;

wherein R⁶ and R⁷ can optionally form a ring, wherein the ring is an optionally substituted heterocyclyl;

provided that the compound having the formula (SC-15) is not:

of. 16. A compound having the formula (SC-16):

,R¹

R²^

N Λ NH₂

R³

SC-16 or a pharmaceutically acceptable salt, tautomer, solvate, diastereomer,

enantiomer, or prodrug thereof, wherein as valence and stability permit:

I 2 3

R' , R , and R^J are independently selected from the group consisting of

hydrogen and optionally substituted a!kyl, heteroalkyl, aminoalkyl, alkylaminoalkyl, arylalkyl, heteroarylalkyl, and carbamoylaminoa!kyl; wherein R¹ and R² can optionally form a ring, wherein the ring is selected from the group optionally substituted heterocyclyl and optionally substituted aminoalkylheterocyclyl;

wherein R² and R³ can optionally form a ring, wherein the ring is an optionally substituted heterocyclyl;

provided that compound having the formula (SC- 16) is not:

prodrug therof;

provided that R¹, R², and R³ are not all hydrogen, or a pharmaceutically

acceptable salt, tautomer, solvate, or prodrug thereof.

17. A compound having the form la (SC- 17):

SC-17 a pharmaceutically acceptable salt, tautomer, solvate, diastereomer,

enantiomer, or prodrug thereof, wherein as valence and stability permit: is selected from the group NH and O; R¹ is selected from the group consisting of optionally substituted alkyl, heteroalkyl, aminoalkyl, amino, cycloalkyl, heterocyclyl, cycloalkylalkylamino, heterocyclylalkylamino, aryl, heteroaryl, arylalkyl, heteroarylalkyl, arylamino, heteroarylamino, and aminoalkylaryloxyalkoxyaryl; and

R² and R³ are independently selected from the group consisting of hydrogen and optionally substituted alkyl, heteroalkyl, and aminoalkyl; wherein R and R can optionally form a ring, wherein the ring is an optionally substituted heterocyclyl or heteroaryl;

provided that compound having the formula (SC- 17) is not:

or a pharmaceutically acceptable salt, tautomer, solvate, or prodrug thereof.

18. A compound having the formula (SC-18):

or a pharmaceutically acceptable salt, tautomer, solvate, diastereomer,

enantiomer, or prodrug thereof, wherein as valence and stability permit:

L¹ is a 4 to 12 carbon atom linker selected from the group consisting of

optionally substituted alkanediyl, heteroalkanediyl, cycloalkanediyl, heterocyclylalkanediyl, alkenediyl, alkynediyl, arylalkanediyl, alkylaryloxydiyl, aminoalkanediyl, and aminoalkylaminodiyl;

R' and R^z are independently selected from the group consisting of hydrogen and optionally substituted alkyl and heteroalkyl; and

R³ and R⁴ are independently selected from the group consisting of hydrogen and optionally substituted alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, and heteroalkynyl;

1 2

wherein R and R can optionally form a ring, wherein the ring is an optionally substituted heterocyclyl.

19. A compound having the formula SC-19):

SC-19 or a pharmaceutically acceptable salt, enantiomer, diastereomer, prodrug,

tautomer, or solvate thereof, wherein as valence and stability permit:

R¹ is selected from the group consisting of optionally substituted alkyl, alkenyl, alkynyl, and arylalkyl; and

R² is selected from the group consisting of hydrogen and optionally substituted alkyl, alkenyl, and alkynyl.

20. A compound having the formula (SC-20): or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, prodrug, or solvate thereof, wherein as valence and stability permit:

R¹ is selected from the group consisting of hydrogen and optionally substituted alkyl and aminoalkyi; and

R² is selected from hydrogen and optionally substituted alkyl, aminoalkyi, and cycloalkylaminoalkyl;

provided that the compound having the formula (SC-20) is not:

or a pharmaceutically acceptable salt, enantiomer, prodrug, tautomer, or

solvate thereof.

21. A compound having the formula (SC-21 ):

or a pharmaceutically acceptable salt, enantiomer, diastereomer, prodrug, tautomer, or solvate thereof, wherein as valence and stability permit: a and β = represents a single or double bond;

V is selected from the group consisting of C, CH, and N;

W is selected from the group consisting of C, CH, and N;

Y is selected from the group consisting of CH₂ and NH;

R¹ is selected from the group consisting of optionally substituted alkyl and amino; and R² is selected from the group consisting of absent and hydrogen;

wherein when β is a double bond, R² is absent, and when β is a single bond, R² is hydrogen;

provided that the compound having the formula (SC-21 ) is not:

or a pharmaceutically acceptable salt, prodrug, or solvate thereof.

22. A compound having the formula (SC-22):

SC-22 or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, prodrug, or solvate thereof, wherein as valence and stability permit:

L¹ is a 4 to 12 carbon linker selected from the group consisting of optionally substituted alkanediyl, heteroalkanediyl, alkenediyl, heteroalkenediyl, oxyalkoxydiyl, alkylcycloalkylalkanediyl,

heteroalkylcycloalkylheteroalkanediyl, alkylcycloalkenylalkanediyl, heteroalkylcycloalkenylheteroalkanediyl, alkylheterocyclylalkanediyl, and heteroalkylheterocyclylheteroalkanediyl; and

Ar¹ is selected from the group consisting of optionally substituted aryl and heteroaryl.

23. A compound having the formula (SC-23):

SC-23

or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, prodrug, or solvate thereof, wherein as valence and stability permit:

R¹ is selected from the group consisting of halogen and optionally substituted Ci-C₆ alkyl, C₂-C alkenyl, C₃-C₆ cycloalkyl, C₄-C₆ cycloalkenyl, C₂- C₅ heterocycloalkyl, C)-C₆ alkoxy, Ci-C₆ alkylthio, phenyl, and monocyclic heteroaryl; and

R², R³, and R⁴ are independently selected from the group consisting of

hydrogen, halogen and optionally substituted Cj-C₆ alkyl, C₂-C₆ alkenyl, C₃-C₆ cycloalkyl, C₄-C₆ cycloalkenyl, C₂-C₅ heterocycloalkyl, Ci-C₆ alkoxy, Ci-C₆ alkylthio, phenyl, and monocyclic heteroaryl; wherein said optionally substituted C|-C₆ alkyl, C₂-C₆ alkenyl, C₃-C₆

cycloalkyl, C₄-C₆ cycloalkenyl, C₂-C₅ heterocycloalkyl, C|-C₆

alkylthio, and Ci-C₆ alkoxy are optionally substituted with one or more substituents selected from the group consisting of F, and unsubstituted OCH₃, OCH₂CH₃, CH₃, C₂H₅, and C₂-C₅ dialkylamino;

wherein said optionally substituted phenyl is optionally substituted with one or more substituents selected from the group consisting of F, CI, Br, SCF₃, and unsubstituted OCH₃, OCH₂CH₃, CH₃, C₂H₅, COOH, COOCH₃, COOC₂Hs, SCH₃, SOCH₃, S0₂CH₃, SCHF₂, isopropyl, /-butyl, hydroxyl, dialkylamino, and alkylamino;

wherein said optionally substituted monocyclic heteroaryl is optionally

substituted with one or more substituents selected from the group consisting of F, CI, Br, SCF₃, CF₃, OCF₃, and unsubstituted OCH₃, OCH₂CH₃, CH₃, C₂H₅, COOH, COOCH₃, COOC₂H₅, SCH₃, SOCH₃, S0₂CH₃, SCHF₂, CHF₂, OCHF₂, isopropyl, /-butyl, hydroxyl, dialkylamino, and alkylamino;

wherein R¹ and R² can optionally form a ring, wherein the ring is an optionally substituted cycloalkyl, heterocyclyl, aryl, or heteroaryl;

wherein R² and R³ can optionally form a ring, wherein the ring is an optionally substituted cycloalkyl, heterocyclyl, aryl, or heteroaryl;

wherein R³ and R⁴ can optionally form a ring, wherein the ring is an optionally substituted cycloalkyl, heterocyclyl, aryl, or heteroaryl.

24. A compound having the formula SC-24):

SC-24

or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, prodrug, or solvate thereof, wherein as valence and stability permit:

R' , R², R⁷, and R⁸ are independently selected from the group consisting of hydrogen, halogen, and optionally substituted Ci -C₃ alkyl, Ci-C₃ alkoxy, Ci -C₃ alkylthio, dimethylamino, methylamino, and amino; . R³ and R⁴ are independently selected from the group consisting of hydrogen, halogen, and optionally substituted C i -C₆ alkyl, C₂-C₆ alkenyl, C₃-C₆ cycloalkyl, C₄-C₆ cycloalkenyl, C₂-C₅ heterocycloalkyl, Ci -C₆ alkoxy, Ci-C₆ alkylthio, phenyl, and monocyclic heteroaryl; and

R⁵ and R⁶ are independently selected from the group consisting of hydrogen, halogen, and optionally substituted Ci-C₆ alkyl, C₂-C₆ alkenyl, C₃-C₆ cycloalkyl, C₄-C₆ cycloalkenyl, C₂-C₅ heterocycloalkyl, Ci-C₆ alkylthio, phenyl, and monocyclic heteroaryl;

wherein said optionally substituted C | -C₆ alkyl, C₂-C₆ alkenyl, C₃-C₆

cycloalkyl, C₄-C₆ cycloalkenyl, C₂-C₅ heterocycloalkyl, Ci-C₆ alkylthio, and C1-C6 alkoxy are optionally substituted with one or more substituents selected from the group consisting of F, and unsubstituted OCH₃, OCH₂CH₃, CH₃, C₂H₅, and C₂-C₅ dialkylamino;

wherein said optionally substituted phenyl is optionally substituted with one or more substituents selected from the group consisting of F, CI, Br, SCF3, CF₃, OCF3, and unsubstituted OCH₃, OCH₂CH₃, CH₃, C₂H₅, COOH, COOCH₃, COOC₂H₅, SCH3, SOCH3, S0₂CH₃₎ SCHF₂₎ CHF₂, OCHF₂, isopropyl, i-butyl, hydroxyl, dialkylamino, and alkylamino; wherein said optionally substituted monocyclic heteroaryl is optionally

wherein R³ and R⁴ can optionally form a ring, wherein the ring is an optionally substituted cycloalkyl, heterocyclyl, aryl, or heteroaryl;

wherein R⁴ and R⁵ can optionally form a ring, wherein the ring is an optionally substituted cycloalkyl, heterocyclyl, aryl, or heteroaryl;

wherein R⁵ and R⁶ can optionally form a ring, wherein the ring is an optionally substituted cycloalkyl, heterocyclyl, aryl, or heteroaryl;

1 3

wherein R and R can optionally form a ring, wherein the ring is an optionally substituted cycloalkyl, heterocyclyl, aryl, or heteroaryl;

wherein R⁶ and R⁷ can optionally form a ring, wherein the ring is an optionally substituted cycloalkyl, heterocyclyl, aryl, or heteroaryl;

7 8

wherein R and R can optionally form a ring, wherein the ring is an optionally substituted cycloalkyl, heterocyclyl, aryl, or heteroaryl.

25. A compound having the formula (SC-25):

or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, prodrug, or solvate thereof, wherein as valence and stability permit:

R¹ , R², and R³ are independently selected from the group consisting of

hydrogen, and unsubstituted C₁ -C3 alkyl, C₃-C₅ cycloalkyl, C₂-C4 alkenyl, methoxyethyl, ethoxyethyl, and ethynyl; and

cycloalkyl, C₄-C₆ cycloalkenyl, C₂-C5 heterocycloalkyl, Ci-C₆

wherein said optionally substituted phenyl is optionally substituted with one or more substituents selected from the group consisting of F, CI, Br, SCF₃, and unsubstituted OCH₃, OCH₂CH₃, CH₃, C₂H₅, COOH, COOCH₃, COOC₂H₅, SCH₃, SOCH₃, S0₂CH₃, SCHF₂, isopropyl, /-butyl, hydroxyl, dialkylamino, and alkylamino;

wherein said optionally substituted monocyclic heteroaryl is optionally

substituted with one or more substituents selected from the group consisting of F, CI, Br, SCF₃, and unsubstituted OCH₃, OCH₂CH₃, CH₃, C₂H₅, COOH, COOCH₃, COOC₂H₅, SCH₃, SOCH₃, S0₂CH₃, SCHF₂, isopropyl, t-butyl, hydroxyl, dialkylamino, and alkylamino; wherein R¹ and R² can optionally form a ring, wherein the ring is an optionally substituted heterocyclyl or heteroaryl;

wherein R¹ and R³ can optionally form a ring, wherein the ring is an optionally substituted heterocyclyl or heteroaryl;

wherein R¹ and R⁷ can optionally form a ring, wherein the ring is an optionally substituted heterocyclyl or heteroaryl;

wherein R⁴ and R⁵ can optionally form a ring, wherein the ring is an optionally substituted cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein R⁵ and R⁶ can optionally form a ring, wherein the ring is an optionally substituted cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein R⁶ and R⁷ can optionally form a ring, wherein the ring is an optionally substituted cycloalkyl, heterocyclyl, aryl, or heteroaryl.

26. A compound having the formula:

496

or a p armaceutca y accepta e sat, a ree ase orm, a sovate, enantomer, disastereomer, prodrug, or a tautomer of any of the foregoing compounds.

27. Use of a compound of any one of claims 1-26, or a mixture thereof, as an analgesic.

28. A compound for use as an analgesic, the compound having the formula:

517

521

or a mixture thereof, or a pharmaceutically acceptable salt, free base form, enantiomer, disastereomer, tautomer, solvate, or prodrug, or a mixture thereof, of any of the foregoing compounds, for use as an analgesic.

29. A pharmaceutical composition comprising a therapeutically effective amount of a compound of any one of claims 1-26, or a mixture thereof.

30. The pharmaceutical composition of claim 29, further comprising at least one pharmaceutically acceptable excipient, carrier, or diluent.

31 . Use of the pharmaceutical composition of claim 29 or 30 as an analgesic.

32. A pharmaceutical composition comprising as an active ingredient a

therapeutically effective amount of a compound having the formula:

523

527

or a m xture t ereo , or a p armaceutically acceptable salt, free base form, enantiomer, disastereomer, solvate, tautomer, or prodrug, or a mixture thereof, of any of the foregoing compounds.

33. The pharmaceutical composition of claim 32, further comprising at least one pharmaceutically acceptable excipient, carrier, or diluent.

34. Use of the pharmaceutical composition of claim 32 or 33 as an analgesic.

35. A method of treating or preventing one or more conditions selected from the group consisting of: pain; an inflammatory disease or disorder, an allergic disease or disorder, a metabolic disease, a cardiovascular disease or disorder, a neurogenic vascular disease or a painful condition associated with any of the foregoing conditions; an episodic tension-type headache; a migraine headache; a headache; cramping; a cognitive disorder; a tension or migraine headache due to a vascular, neurovascular, or neurogenic disorder or dysfunction during a menstrual cycle episode; a tension or migraine headache due to a vascular, neurovascular, or neurogenic disorder or dysfunction during a migraine episode; a headache from mild to moderate hypertension; mild to moderate essential hypertension; organ transplant rejection; hot and cold flashes;

traumatic brain injury (TBI); neurotoxicity; psychic pain; psychological pain; psychiatric pain; depression; schizophrenia; anxiety; epilepsy; a stress disorder; excess sweating; a symptom related to drug withdrawal; allodynia; fibromyalgia; fibromyalgia-ness; central sensitization; centralization; regional pain syndrome; temporomandibular joint syndrome (TMJ); lower back pain; interstitial cystitis; Gulf War syndrome; visceral pain; kidney stones; gout; neuropathic pain; post-herpetic neuralgia; diabetic neuropathy; sickle cell pain; priapism; nociceptive pain; post-operative pain; orthopedic injury pain;

phantom limb pain; bunionectomy; dental extraction; pain after severed spinal cord injury; osteoarthritis; rheumatoid arthritis; Lyme disease; Parkinson's disease; pain associated with cancer; opioid-induced constipation; an opioid withdrawal symptom; and pain associated with post-traumatic stress disorder (PTSD), in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of a compound of any one of claims 1-26, or a mixture thereof.

36. The method of claim 35, wherein the condition is a headache.

37. The method of claim 35, wherein the condition is an episodic tension-type headache.

38. The method of claim 35, wherein the condition is a migraine headache.

39. The method of claim 35, wherein the condition is allodynia.

40. The method of claim 35, wherein the condition is fibromyalgia.

41. The method of any one of claims 35-40, wherein the compound is administered simultaneously, sequentially, or separately with one or more substances selected from the group consisting of acetaminophen, a non-steroidal antiinflammatory drug (NSAID), ibuprofen, naprosyn, a cyclooxygenase-2 inhibitor, aspirin, caffeine, dichloralphenazone, a triptan, an antidepressant, a serotonin-norepinephrine reuptake inhibitor (SNRI), and a gabapentinoid.

42. The method of any one of claims 35-40, wherein the compound is administered simultaneously, sequentially, or separately with one or more additional therapeutics selected from the group consisting of a chemotherapeutic drug, an antiproliferative agent, an anti-inflammatory agent, a corticosteroid, an antiasthmatic agent, an anti-allergic agent, an immunosuppressive agent, an immunomodulatory agent, a cardiovascular disease treatment agent, an antidiabetic agent, a blood disorder treatment agent, a nerve growth factor receptor antagonist, a sodium channel blocker, a CYP2D6 inhibitor, and a TNF-alpha inhibitor.

43. The method of any one of claims 35-40, wherein the compound is administered simultaneously, sequentially, or separately with one or more opiates.

44. A method of treating or preventing one or more conditions selected from the group consisting of: pain; an inflammatory disease or disorder, an allergic disease or disorder, a metabolic disease, a cardiovascular disease or disorder, a neurogenic vascular disease or a painful condition associated with any of the foregoing conditions; an episodic tension-type headache; a migraine headache; a headache; cramping; a cognitive disorder; a tension or migraine headache due to a vascular, neurovascular, or neurogenic disorder or dysfunction during a menstrual cycle episode; a tension or migraine headache due to a vascular, neurovascular, or neurogenic disorder or dysfunction during a migraine episode; a headache from mild to moderate hypertension; mild to moderate essential hypertension; organ transplant rejection; hot and cold flashes;

enantiomer, disastereomer, solvate, tautomer, or prodrug, or a mixture thereof, of any of the foregoing compounds.

45. The method of claim 44, wherein the condition is a headache.

46. The method of claim 44, wherein the condition is an episodic tension-type headache.

47. The method of claim 44, wherein the condition is a migraine headache.

48. The method of claim 44, wherein the condition is allodynia.

49. The method of claim 44, wherein the condition is fibromyalgia.

50. The method of any one of claims 44-49, wherein the compound is administered with one or more substances selected from the group consisting of

acetaminophen, a non-steroidal anti-inflammatory drug (NSAID), ibuprofen, naprosyn, a cyclooxygenase-2 inhibitor, aspirin, caffeine, dichloralphenazone, a triptan, an antidepressant, a serotonin-norepinephrine reuptake inhibitor (SNR1), and a gabapentinoid.

51. The method of any one of claims 44-49, wherein the compound is administered simultaneously, sequentially, or separately with one or more additional therapeutics selected from the group consisting of a chemotherapeutic drug, an antiproliferative agent, an anti-inflammatory agent, a corticosteroid, an antiasthmatic agent, an anti-allergic agent, an immunosuppressive agent, an immunomodulatory agent, a cardiovascular disease treatment agent, an antidiabetic agent, a blood disorder treatment agent, a nerve growth factor receptor antagonist, a sodium channel blocker, a CYP2D6 inhibitor, and a TNF-alpha inhibitor.

52. A method of treating or preventing one or more conditions selected from the group consisting of: pain; an inflammatory disease or disorder, an allergic disease or disorder, a metabolic disease, a cardiovascular disease or disorder, a neurogenic vascular disease or a painful condition associated with any of the foregoing conditions; an episodic tension-type headache; a migraine headache; a headache; cramping; a cognitive disorder; a tension or migraine headache due to a vascular, neurovascular, or neurogenic disorder or dysfunction during a menstrual cycle episode; a tension or migraine headache due to a vascular, neurovascular, or neurogenic disorder or dysfunction during a migraine episode; a headache from mild to moderate hypertension; mild to moderate essential hypertension; organ transplant rejection; hot and cold flashes;

53. The method of claim 52, wherein the condition is a headache.

54. The method of claim 52, wherein the condition is an episodic tension-type headache.

55. The method of claim 52, wherein the condition is a migraine headache.

56. The method of claim 52, wherein the condition is allodynia.

57. The method of claim 52, wherein the condition is fibromyalgia.

58. The method of any one of claims 52-57, wherein the pharmaceutical

composition is administered simultaneously, sequentially, or separately with one or more substances selected from the group consisting of acetaminophen, a non-steroidal anti-inflammatory drug (NSA1D), ibuprofen, naprosyn, a cyclooxygenase-2 inhibitor, aspirin, caffeine, dichloralphenazone, a triptan, an antidepressant, a serotonin-norepinephrine reuptake inhibitor (SNRI), and a gabapentinoid.

59. The method of any one of claims 52-57, wherein the pharmaceutical composition is administered simultaneously, sequentially, or separately with one or more additional therapeutics selected from the group consisting of a chemotherapeutic drug, an antiproliferative agent, an anti-inflammatory agent, a corticosteroid, an anti-asthmatic agent, an anti-allergic agent, an

60. The method of any one of claims 52-57, wherein the pharmaceutical

composition is administered simultaneously, sequentially, or separately with one or more opiates.

61. A method of treating or preventing one or more conditions selected from the group consisting of: pain; an inflammatory disease or disorder, an allergic disease or disorder, a metabolic disease, a cardiovascular disease or disorder, a neurogenic vascular disease or a painful condition associated with any of the foregoing conditions; an episodic tension-type headache; a migraine headache; a headache; cramping; a cognitive disorder; a tension or migraine headache due to a vascular, neurovascular, or neurogenic disorder or dysfunction during a menstrual cycle episode; a tension or migraine headache due to a vascular, neurovascular, or neurogenic disorder or dysfunction during a migraine episode; a headache from mild to moderate hypertension; mild to moderate essential hypertension; organ transplant rejection; hot and cold flashes;

62. The method of claim 61, wherein the condition is a headache.

63. The method of claim 61, wherein the condition is an episodic tension-type headache.

64. The method of claim 61, wherein the condition is a migraine headache.

65. The method of claim 61, wherein the condition is allodynia.

66. The method of claim 61, wherein the condition is fibromyalgia.

67. The method of any one of claims 61-66, wherein the pharmaceutical

composition is administered simultaneously, sequentially, or separately with one or more substances selected from the group consisting of acetaminophen, a non-steroidal anti-inflammatory drug (NSAID), ibuprofen, naprosyn, a cyclooxygenase-2 inhibitor, aspirin, caffeine, dichloralphenazone, a triptan, an antidepressant, a serotonin-norepinephrine reuptake inhibitor (SNRI), and a gabapentinoid.

68. The method of any one of claims 61-66, wherein the pharmaceutical

composition is administered simultaneously, sequentially, or separately with one or more additional therapeutics selected from the group consisting of a chemotherapeutic drug, an antiproliferative agent, an anti-inflammatory agent, a corticosteroid, an anti-asthmatic agent, an anti-allergic agent, an

69. The method of any one of claims 61-66, wherein the pharmaceutical composition is administered simultaneously, sequentially, or separately with one or more opiates.

70. Use of a compound of any one of claims 1-26, or a mixture thereof, for the manufacture of a medicament for treating or preventing one or more conditions selected from the group consisting of: pain; an inflammatory disease or disorder, an allergic disease or disorder, a metabolic disease, a cardiovascular disease or disorder, a neurogenic vascular disease or a painful condition associated with any of the foregoing conditions; an episodic tension-type headache; a migraine headache; a headache; cramping; a cognitive disorder; a tension or migraine headache due to a vascular, neurovascular, or neurogenic disorder or dysfunction during a menstrual cycle episode; a tension or migraine headache due to a vascular, neurovascular, or neurogenic disorder or dysfunction during a migraine episode; a headache from mild to moderate hypertension; mild to moderate essential hypertension; organ transplant rejection; hot and cold flashes; traumatic brain injury (TBI); neurotoxicity; psychic pain; psychological pain; psychiatric pain; depression; schizophrenia; anxiety; epilepsy; a stress disorder; excess sweating; a symptom related to drug withdrawal; allodynia; fibromyalgia; fibromyalgia-ness; central sensitization; centralization; regional pain syndrome; temporomandibular joint syndrome (TMJ); lower^back pain; interstitial cystitis; Gulf War syndrome; visceral pain; kidney stones; gout; neuropathic pain; post-herpetic neuralgia; diabetic neuropathy; sickle cell pain; priapism; nociceptive pain; post-operative pain; orthopedic injury pain; phantom limb pain; bunionectomy; dental extraction; pain after severed spinal cord injury; osteoarthritis; rheumatoid arthritis; Lyme disease; Parkinson's disease; pain associated with cancer; opioid-induced constipation; an opioid withdrawal symptom; and pain associated with posttraumatic stress disorder (PTSD).

71 . The use of claim 70, wherein the condition is a headache.

72. The use of claim 70, wherein the condition is an episodic tension-type headache.

73. The use of claim 70, wherein the condition is a migraine headache.

74. The use of claim 70, wherein the condition is allodynia.

75. The use of claim 70, wherein the condition is fibromyalgia.

76. The use of any one of claims 70-75, wherein _xthe medicament is administered simultaneously, separately, or sequentially with one or more substances selected from the group consisting of acetaminophen, a non-steroidal antiinflammatory drug (NS AID), ibuprofen, naprosyn, a cyclooxygenase-2 inhibitor, aspirin, caffeine, dichloralphenazone, a triptan, an antidepressant, a serotonin-norepinephrine reuptake inhibitor (SNRI), and a gabapentinoid.

77. The use of any one of claims 70-75, wherein the medicament is administered simultaneously, separately, or sequentially with one or more additional therapeutics selected from the group consisting of a chemotherapeutic drug, an antiproliferative agent, an ant i -inflammatory agent, a corticosteroid, an antiasthmatic agent, an anti-allergic agent, an immunosuppressive agent, an immunomodulatory agent, a cardiovascular disease treatment agent, an antidiabetic agent, a blood disorder treatment agent, a nerve growth factor receptor antagonist, a sodium channel blocker, a CYP2D6 inhibitor, and a TNF-alpha inhibitor.

78. The use of any one of claims 70-75, wherein the medicament is administered • simultaneously, separately, or sequentially with one or more opiates.

Use of a compound having the formula:

547

548

or a mxture t ereo , or a p armaceutca y accepta e sat, ree ase orm, enantiomer, disastereomer, solvate, tautomer, or prodrug, or a mixture thereof, of any of the foregoing compounds, for the manufacture of a medicament for treating or preventing one or more conditions selected from the group consisting of: pain; an inflammatory disease or disorder, an allergic disease or disorder, a metabolic disease, a cardiovascular disease or disorder, a neurogenic vascular disease or a painful condition associated with any of the foregoing conditions; an episodic tension-type headache; a migraine headache; a headache; cramping; a cognitive disorder; a tension or migraine headache due to a vascular, neurovascular, or neurogenic disorder or dysfunction during a menstrual cycle episode; a tension or migraine headache due to a vascular, neurovascular, or neurogenic disorder or dysfunction during a migraine episode; a headache from mild to moderate hypertension; mild to moderate essential hypertension; organ transplant rejection; hot and cold flashes;

80. The use of claim 79, wherein the condition is a headache.

81 . The use of claim 79, wherein the condition is an episodic tension-type

headache.

82. The use of claim 79, wherein the condition is a migraine headache.

83. The use of claim 79, wherein the condition is allodynia.

84. The use of claim 79, wherein the condition is fibromyalgia.

85. The use of any one of claims 79-84, wherein the medicament is administered simultaneously, separately, or sequentially with one or more substances selected from the group consisting of acetaminophen, a non-steroidal antiinflammatory drug (NSAID), ibuprofen, naprosyn, a cyclooxygenase-2 inhibitor, aspirin, caffeine, dichloralphenazone, a triptan, an antidepressant, a serotonin-norepinephrine reuptake inhibitor (SNRI), and a gabapentinoid.

86. The use of any one of claims 79-84, wherein the medicament is administered simultaneously, separately, or sequentially with one or more additional therapeutics selected from the group consisting of a chemotherapeutic drug, an antiproliferative agent, an anti-inflammatory agent, a corticosteroid, an antiasthmatic agent, an anti-allergic agent, an immunosuppressive agent, an immunomodulatory agent, a cardiovascular disease treatment agent, an antidiabetic agent, a blood disorder treatment agent, a nerve growth factor receptor antagonist, a sodium channel blocker, a CYP2D6 inhibitor, and a TNF-a^'lpha inhibitor.

87. The use of any one of claims 79-84, wherein the medicament is administered simultaneously, separately, or sequentially with one or more opiates.

88. A compound of any one of claims 1-26, or a mixture thereof, for use in treating or preventing one or more conditions selected from the group consisting of: pain; an inflammatory disease or disorder, an allergic disease or disorder, a metabolic disease, a cardiovascular disease or disorder, a neurogenic vascular disease or a painful condition associated with any of the foregoing conditions; an episodic tension-type headache; a migraine headache; a headache;

cramping; a cognitive disorder; a tension or migraine headache due to a vascular, neurovascular, or neurogenic disorder or dysfunction during a menstrual cycle episode; a tension or migraine headache due to a vascular, neurovascular, or neurogenic disorder or dysfunction during a migraine episode; a headache from mild to moderate hypertension; mild to moderate essential hypertension; organ transplant rejection; hot and cold flashes;

89. The compound of claim 88, wherein the condition is a headache.

90. The compound of claim 88, wherein the condition is an episodic tension-type headache.

91 . The compound of claim 88, wherein the condition is a migraine headache.

92. The compound of claim 88, wherein the condition is allodynia.

93. The compound of claim 88, wherein the condition is fibromyalgia.

94. The compound of any one of claims 88-93, wherein the compound is used simultaneously, sequentially, or separately with one or more substances selected from the group consisting of acetaminophen, a non-steroidal antiinflammatory drug (NSAID), ibuprofen, naprosyn, a cyclooxygenase-2 inhibitor, aspirin, caffeine, dichloralphenazone, a triptan, an antidepressant, a serotonin-norepinephrine reuptake inhibitor (SNRI), and a gabapentinoid.

95. The compound of any one of claims 88-93, wherein the compound is used simultaneously, sequentially, or separately with one or more additional therapeutics selected from the group consisting of a chemotherapeutic drug, an antiproliferative agent, an anti-inflammatory agent, a corticosteroid, an antiasthmatic agent, an anti-allergic agent, an immunosuppressive agent, an immunomodulatory agent, a cardiovascular disease treatment agent, an anti- diabetic agent, a blood disorder treatment agent, a nerve growth factor receptor antagonist, a sodium channel blocker, a CYP2D6 inhibitor, and a TNF-alpha inhibitor.

96. The compound of any one of claims 88-93, wherein the compound is used simultaneously, sequentially, or separately with one or more opiates.

97. A compound having the formula:

aceutically acceptable salt, free base form, tautomer, enantiomer, disastereomer, solvate, or prodrug, or a mixture thereof, of any of the foregoing compounds, for use in treating or preventing one or more conditions selected from the group consisting of: pain; an inflammatory disease or disorder, an allergic disease or disorder, a metabolic disease, a cardiovascular disease or disorder, a neurogenic vascular disease or a painful condition associated with any of the foregoing conditions; an episodic tension- type headache; a migraine headache; a headache; cramping; a cognitive disorder; a tension or migraine headache due to a vascular, neurovascular, or neurogenic disorder or dysfunction during a menstrual cycle episode; a tension or migraine headache due to a vascular, neurovascular, or neurogenic disorder or dysfunction during a migraine episode; a headache from mild to moderate hypertension; mild to moderate essential hypertension; organ transplant rejection; hot and cold flashes; traumatic brain injury (TBI); neurotoxicity; psychic pain; psychological pain; psychiatric pain; depression; schizophrenia; anxiety; epilepsy; a stress disorder; excess sweating; a symptom related to drug withdrawal; allodynia; fibromyalgia; fibromyalgia-ness; central sensitization; centralization; regional pain syndrome; temporomandibular joint syndrome (TMJ); lower back pain; interstitial cystitis; Gulf War syndrome; visceral pain; kidney stones; gout; neuropathic pain; post-herpetic neuralgia; diabetic neuropathy; sickle cell pain; priapism; nociceptive pain; post-operative pain; orthopedic injury pain; phantom limb pain; bunionectomy; dental extraction; pain after severed spinal cord injury; osteoarthritis; rheumatoid arthritis; Lyme disease; Parkinson's disease; pain associated with cancer; opioid-induced constipation; an opioid withdrawal symptom; and pain associated with posttraumatic stress disorder (PTSD).

98. The compound of claim 97, wherein the condition is a headache.

99. The compound of claim 97, wherein the condition is an episodic tension-type headache.

100. The compound of claim 97, wherein the condition is a migraine

headache.

101. The compound of claim 97, wherein the condition is allodynia.

102. The compound of claim 97, wherein the condition is fibromyalgia.

103. The compound of any one of claims 97-102, wherein the compound is used simultaneously, sequentially, or separately with one or more substances selected from the group consisting of acetaminophen, a non-steroidal antiinflammatory drug (NSAID), ibuprofen, naprosyn, a cyclooxygenase-2 inhibitor, aspirin, caffeine, dichloralphenazone, a triptan, an antidepressant, a serotonin-norepinephrine reuptake inhibitor (SNRI), and a gabapentinoid.

104. The compound of any one of claims 97-102, wherein the compound is used simultaneously, sequentially, or separately with one or more additional therapeutics selected from the group consisting of a chemotherapeutic drug, an antiproliferative agent, an anti-inflammatory agent, a corticosteroid, an antiasthmatic agent, an anti-allergic agent, an immunosuppressive agent, an immunomodulatory agent, a cardiovascular disease treatment agent, an antidiabetic agent, a blood disorder treatment agent, a nerve growth factor receptor antagonist, a sodium channel blocker, a CYP2D6 inhibitor, and a TNF-alpha inhibitor.

105. The compound of any one of claims 97-102, wherein the compound is used simultaneously, sequentially, or separately with one or more opiates.

106. A method of modulating an imidazoline-1 (l i) receptor, comprising contacting the Ii receptor with a compound of any one of claims 1-26, or a mixture thereof.

107. A method of modulating an imidazoline- 1 (Ii) receptor, comprising contacting the Ii receptor with a compound having the formula:

565 375 or a mixture thereof, or a pharmaceutically acceptable salt, free base form, enantiomer, disastereomer, solvate, tautomer, or prodrug, or a mixture thereof, of any of the foregoing compounds.

108. A method of modulating an imidazoline- 1 (I i) receptor, comprising contacting the I i receptor with a pharmaceutical composition of claim 29 or 32.

109. A method of modulating an imidazoline-1 (I i) receptor in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of a compound of any one of claims 1-26, or a mixture thereof.

1 10. A method of modulating an imidazoline-1 (Ii) receptor in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of a compound having the formula:

571

572

or a mixture thereof, or a pharmaceutically acceptable salt, free base form, enantiomer, disastereomer, solvate, tautomer, or prodrug, or a mixture thereof, of any of the foregoing compounds.

1 1 1 . A method of modulating an imidazoline- 1 (I i) receptor in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of a pharmaceutical composition of claim 29 or 32.

1 12. A method for nitric oxidase inhibition in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of a compound of any one of claims 1-26, or a mixture thereof, simultaneously, sequentially, or separately in combination with one or more substances selected from the group consisting of acetaminophen, a non-steroidal antiinflammatory drug (NSAID), ibuprofen, naprosyn, a cyclooxygenase-2 inhibitor, aspirin, caffeine, dichloralphenazone, a triptan, an antidepressant, a serotonin-norepinephrine reuptake inhibitor (SNRI), a gabapentinoid, a chemotherapeutic drug, an antiproliferative agent, an anti-inflammatory agent, a corticosteroid, an anti-asthmatic agent, an anti-allergic agent, an

1 13. A method for nitric oxidase inhibition in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of a compound having the formula:

575

579

or a m Cixture thereof, o:r a p.harmaceutically acceptable salt, free base enantiomer, disastereomer, solvate, tautomer, or prodrug, or a mixture thereof, of any of the foregoing compounds, simultaneously, sequentially, or separately in combination with one or more substances selected from the group consisting of acetaminophen, a non-steroidal anti-inflammatory drug (NSAID), ibuprofen, naprosyn, a cyclooxygenase-2 inhibitor, aspirin, caffeine, dichloralphenazone, a triptan, an antidepressant, a serotonin-norepinephrine reuptake inhibitor (SNR1), a gabapentinoid, a chemotherapeutic drug, an antiproliferative agent, an anti-inflammatory agent, a corticosteroid, an antiasthmatic agent, an anti-allergic agent, an immunosuppressive agent, an immunomodulatory agent, a cardiovascular disease treatment agent, an antidiabetic agent, a blood disorder treatment agent, a nerve growth factor receptor antagonist, a sodium channel blocker, a CYP2D6 inhibitor, a TNF-alpha inhibitor, and an opiate.

14. A method for nitric oxidase inhibition in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of a pharmaceutical composition of claim 29 or 32 simultaneously, sequentially, or separately in combination with one or more substances selected from the group consisting of acetaminophen, a non-steroidal anti-inflammatory drug (NSAID), ibuprofen, naprosyn, a cyclooxygenase-2 inhibitor, aspirin, caffeine, dichloralphenazone, a triptan, an antidepressant, a serotonin-norepinephrine reuptake inhibitor (SNRI), a gabapentinoid, a chemotherapeutic drug, an antiproliferative agent, an anti-inflammatory agent, a corticosteroid, an antiasthmatic agent, an anti-allergic agent, an immunosuppressive agent, an immunomodulatory agent, a cardiovascular disease treatment agent, an antidiabetic agent, a blood disorder treatment agent, a nerve growth factor receptor antagonist, a sodium channel blocker, a CYP2D6 inhibitor, a TNF-alpha inhibitor, and an opiate.

15. Use of a pharmaceutical composition of claim 29 or 32 for the

manufacture of a medicament for treating or preventing one or more conditions selected from the group consisting of: pain; an inflammatory disease or disorder, an allergic disease or disorder, a metabolic disease, a cardiovascular disease or disorder, a neurogenic vascular disease or a painful condition associated with any of the foregoing conditions; an episodic tension-type headache; a migraine headache; a headache; cramping; a cognitive disorder; a tension or migraine headache due to a vascular, neurovascular, or neurogenic disorder or dysfunction during a menstrual cycle episode; a tension or migraine headache due to a vascular, neurovascular, or neurogenic disorder or dysfunction during a migraine episode; a headache from mild to moderate hypertension; mild to moderate essential hypertension; organ transplant rejection; hot and cold flashes; traumatic brain injury (TBI); neurotoxicity; psychic pain; psychological pain; psychiatric pain; depression; schizophrenia; anxiety; epilepsy; a stress disorder; excess sweating; a symptom related to drug withdrawal; allodynia; fibromyalgia; fibromyalgia-ness; central sensitization; centralization; regional pain syndrome; temporomandibular joint syndrome (TMJ); lower back pain; interstitial cystitis; Gulf War syndrome; visceral pain; kidney stones; gout; neuropathic pain; post-herpetic neuralgia; diabetic neuropathy; sickle cell pain; priapism; nociceptive pain; post-operative pain; orthopedic injury pain; phantom limb pain; bunionectomy; dental extraction; pain after severed spinal cord injury; osteoarthritis; rheumatoid arthritis; Lyme disease; Parkinson's disease; pain associated with cancer; opioid-induced constipation; an opioid withdrawal symptom; and pain associated with posttraumatic stress disorder (PTSD).

1 16. The use of claim 115, wherein the condition is a headache.

1 17. The use of claim 115, wherein the condition is an episodic tension-type headache.

1 18. The use of claim 115, wherein the condition is a migraine headache.

1 19. The use of claim 115, wherein the condition is allodynia.

120. The use of claim 115, wherein the condition is fibromyalgia.

121 . The use of any one of claims 115-120, wherein the medicament is administered simultaneously, separately, or sequentially with one or more substances selected from the group consisting of acetaminophen, a nonsteroidal anti-inflammatory drug (NSAID), ibuprofen, naprosyn, a

cyclooxygenase-2 inhibitor, aspirin, caffeine, dichloralphenazone, a triptan, an antidepressant, a serotonin-norepinephrine reuptake inhibitor (SNRI), and a gabapentinoid.

122. The use of any one of claims 115-120, wherein the medicament is administered simultaneously, separately, or sequentially with one or more additional therapeutics selected from the group consisting of a

chemotherapeutic drug, an antiproliferative agent, an anti-inflammatory agent, a corticosteroid, an anti-asthmatic agent, an anti-allergic agent, an

123. The use of any one of claims 115-120, wherein the medicament is administered simultaneously, separately, or sequentially with one or more opiates.

124. The pharmaceutical composition of any one of claims 29 or 32 for use in treating or preventing one or more conditions selected from the group consisting of: pain; an inflammatory disease or disorder, an allergic disease or disorder, a metabolic disease, a cardiovascular disease or disorder, a neurogenic vascular disease or a painful condition associated with any of the foregoing conditions; an episodic tension-type headache; a migraine headache; a headache; cramping; a cognitive disorder; a tension or migraine headache due to a vascular, neurovascular, or neurogenic disorder or dysfunction during a menstrual cycle episode; a tension or migraine headache due to a vascular, neurovascular, or neurogenic disorder or dysfunction during a migraine episode; a headache from mild to moderate hypertension; mild to moderate essential hypertension; organ transplant rejection; hot and cold flashes;

125. The pharmaceutical composition of claim 124, wherein the condition is a headache.

126. The pharmaceutical composition of claim 124, wherein the condition is an episodic tension-type headache.

127. The pharmaceutical composition of claim 124, wherein the condition is a migraine headache.

128. The pharmaceutical composition of claim 124, wherein the condition is allodynia.

129. The pharmaceutical composition of claim 124, wherein the condition is fibromyalgia.

130. The pharmaceutical composition of any one of claims 124-129,

wherein the pharmaceutical composition is used simultaneously, separately, or sequentially with one or more substances selected from the group consisting of acetaminophen, a non-steroidal anti-inflammatory drug (NSAID), ibuprofen,

' naprosyn, a cyclooxygenase-2 inhibitor, aspirin, caffeine, dichloralphenazone, a triptan, an antidepressant, a serotonin-norepinephrine reuptake inhibitor (SNRI), and a gabapentinoid.

13 1 . The pharmaceutical composition of any one of claims 124-129,

wherein the pharmaceutical composition is used simultaneously, separately, or sequentially with one or more additional therapeutics selected from the group consisting of a chemotherapeutic drug, an antiproliferative agent, an antiinflammatory agent, a corticosteroid, an anti-asthmatic agent, an anti-allergic agent, an immunosuppressive agent, an immunomodulatory agent, a cardiovascular disease treatment agent, an anti-diabetic agent, a blood disorder treatment agent, a nerve growth factor receptor antagonist, a sodium channel blocker, a CYP2D6 inhibitor, and a TNF-alpha inhibitor.

. The pharmaceutical composition of any one of claims 124-129, wherein the pharmaceutical composition is used simultaneously, separately, or sequentially with one or more opiates.

Description:

IMIDAZOLINE RECEPTOR TYPE 1 LIGANDS FOR USE AS

THERAPEUTICS

Related Applications

This application claims priority to and benefit from U.S. Provisional Patent

Application 62/095,684, filed December 22, 2014, U.S. Provisional Patent Application 62/18 1 ,030, filed June 17, 2015, and U.S. Provisional Patent Application 62/196,455, filed July 24, 2015. The contents and disclosures of each of the foregoing applications are hereby incorporated by reference in their entirety.

Background of the Disclosure For the treatment of various painful conditions, such as tension or migraine headaches, fibromyalgia, and allodynia, ameliorative compounds and analgesics are needed. Tension-type headaches (TTH) are the most common type of headaches among adults, and as a result of their high prevalence, impose the greatest socioeconomic impact of any primary headache, type. The pain of TTH may render a sufferer unable to attend activities, force them to stay home from work, or impair their ability to function at work. According to Mayo Clinic, tension headaches affect 90% of women and 70% of men. The pathogenesis of tension-type headache is poorly understood.

Migraine affects people of all races and both sexes with women accounting for 79% (61 % between 20 and 49 years of age) of physician visits for migraines and

Caucasians for 91 % of the physician visits. The pathogenesis of migraine headache is believed to involve a) the cranial blood vessels, b) the trigeminal innervation of these vessels, and c) the reflex connection of the trigeminovascular system in the cranial parasympathetic outflow. In view of these various aspects of migraine, a wide variety of prospective targets for migraine treatment exists. TTH may be a mild form of migraine headache or may have a distinct etiology. Recurrent TTH and migraine headache syndromes may be co-morbid and have been termed "mixed" headache syndrome." Nociceptive pain results from injury, compression, infection, inflammation, degeneration, metabolic or genetic pathology, or neoplasm affecting tissues including skin, muscles, joints, bones, and internal organs. Injury can include exposure to extreme temperatures, trauma, and physical exposure to blunt or sharp objects or physical exposure to caustic, irritating, or allergenic substances. Nociceptive pain can be acute or chronic.

Neuropathic pain results from injury, compression, infection, inflammation, degeneration, metabolic or genetic pathology, or neoplasm affecting nerves in the peripheral or central nervous system. Injury can include exposure to extreme temperatures, trauma, and physical exposure to blunt or sharp objects or physical exposure to caustic, irritating, or allergenic substances. Neuropathic pain can be acute or chronic.

Regional pain is pain associated with one or more areas of the body. Visceral pain is pain associated with one or more internal organs. Regional and visceral pain can be nociceptive or neuropathic or a combination of nociceptive and neuropathic. In

"complex regional pain syndromes" (CRPS) nerves and blood vessels are involved. CRPS are chronic conditions characterized by pain, burning, swelling, sweating and skin color changes. In the reflex sympathetic dystrophy type of CRPS nerve damage is either not present or represents a small component of the pathology. In the causalgia type of CRPS nerve injury is present.

Fibromyalgia is a chronic disorder characterized by widespread musculoskeletal pain accompanied by fatigue, sleep, memory, and mood issues. Research indicates that fibromyalgia amplifies painful sensations by affecting the way the brain processes pain signals. Symptoms of fibromyalgia sometimes begin after a physical trauma, surgery, infection, menopause, or significant psychological stress. In other cases, symptoms gradually accumulate over time. In many cases, fibromyalgia develops in people suffering for many years from chronic regional pain, including lower back pain or temporomandibular joint syndrome. The causes of fibromyalgia are unclear. The pathogenesis of fibromyalgia is believed to involve sensitization of the central nervous system (CNS) to perceiving painful stimuli _vwhich is termed "central sensitization" or "centralization". Centralization leads to the perception of widespread pain. Pain of this type is termed, "central neuropathic pain" or "central pain". Centralization also leads to other symptoms, including visceral pain such as irritable bowel, TTH, and migraine. Centralization increases the sensitivity of the brain to light, sound, taste and odor stimuli. Non-restorative sleep is a key feature of fibromyalgia and disturbed sleep can exacerbate other symptoms. Fibromyalgia is estimated to impact 5- 15 million Americans age 18 or older. Between 80 and 90% of people diagnosed with fibromyalgia are women. Fibromyalgia is believed to be an extreme manifestation of symptoms, termed "fibromyalgia-ness" that can occur in lesser severity below the threshold that qualifies for the diagnosis of fibromyalgia by the American College of Rheumatology (ACR) 2010 criteria. Fibromyalgia and fibromyalgia-ness have overlap with other conditions including Gulf War Syndrome and Post-traumatic Stress Disorder (PTSD) and are sometimes co-morbid with these conditions. Allodynia, or pain due to a stimulus that does not usually provoke pain, is a prominent symptom in patients with neuropathic pain. Allodynia is seen in various peripheral neuropathies and central pain disorders, and affects 15-50% of patients with neuropathic pain. Allodynia is classified according to the sensory modality (touch, ' pressure, pinprick, cold, and heat) that elicits the sensation. Allodynia can be co- morbid with fibromyalgia and can be a feature of fibromyalgia. Like fibromyalgia, the causes of allodynia are unclear. Centralization and allodynia can be acute as well as chronic. For example, migraine can be accompanied by acute symptoms of: nausea and vomiting, loss of appetite, abdominal pain, and sensitivity to light, odor, taste and sound. Pain, including widespread pain, can occur after traumatic brain injury (TBI) or in post-traumatic stress disorder (PTSD). When pain, TBI, and PTSD are all present, it is termed the "polytrauma triad".

Withdrawal from addictive substances, including alcohol, barbiturates,

benzodiazepines, nicotines, ketamines and opiates is associated with widespread pain and other symptoms. Widespread pain can persist for long periods of time after drug withdrawal. Regional pain syndromes including headaches can occur after medication discontinuation or even missed doses of a chronic regimen. For example, caffeine withdrawal headache is a headache syndrome associated with the discontinuation of caffeine.

Withdrawal of the use of various medications can result in pain symptoms upon withdrawal of the medication. For example, medication overuse headache is a headache syndrome associated with use and withdrawal of medications. Other .

medications that can result in pain upon withdrawal include non-steroidal anti- inflammatory drugs (NSAIDs) and tumor necrosis factor (TNF)-alpha blockers. A medication that treats widespread or regional pain syndromes, including tension-type headache, migraine headache and fibromyalgia, but does not result in medication overuse syndromes would be very desirable.

Psychogenic pain is pain that results from psychological mechanisms including traumatic experiences, empathic reactions, or somatization. For example, loss of a loved friend or relative by death or other separation can result in widespread pain, regional pain, and other symptoms including reactive depression.

Psychiatric pain is pain that results from conditions that are believed to have biological causes. For example, endogenous depression or the depressed phases of bipolar disorder can be associated with the onset or exacerbation of widespread pain or regional pain disorders.

The mechanisms of action for any pain, headache, fibromyalgia, or allodynia treatment are not yet fully understood, and numerous therapies have been tested.

Some of these therapies have disadvantages. For example, specific drugs, such as ergotamine and dihydroergotamine, used in the treatment of migraine, interact with vascular receptors, a fact that has raised concerns about the cardiovascular safety of these pharmaceutical agents. Other treatments for pain relief, such as ketamine, barbiturates, and opioids, can lead to addiction. Duloxetine is a serotonin and norepinephrine reuptake inhibitor (SNRI) antidepressant drug that is also useful in treating fibromyalgia and back pain, but has side effects that limit long term treatment in some patients. Other treatments for pain are the gabapeninoids (or alpha-2 delta ligands), including pregabalin, gabapentin and mirogabalin/DS-5565; antagonists of nerve growth factor receptor, including tanezumab; blockers of voltage-gated sodium channels, including Nay 1.7, Nay 1.8, and Nay 1.9; alcohol; cannabinoids, including tetrahydrocannabinol (THC) and cannabidiol; and gamma-hydroxy butyrate.

Tramadol and tapentadol are pain treatments having both SNRI activity and mu-opioid activity. Racemic tramadol combines the SNRI activity of one isomer with the opiate receptor activity of the other isomer. Agonists of central alpha-2 adrenergic receptors, including clonidine and dexmedetomidine, cause sedation and have been used in anesthesia and analgesia. Corticosteroids have been used to inhibit pain in

inflammatory conditions. TNF-alpha blockers, particularly antibodies against TNF- alpha, decrease pain in several autoimmune diseases including rheumatoid arthritis, inflammatory bowel disease, and psoriasis. Each of the known treatments has side effects that limit use in some patients.

Another pain therapeutic is isometheptene. Racemic isometheptene has been used in the treatment of tension-type headache, vascular headache, and migraine headache, either alone or as one or more than one active ingredients in various combination drug products. One theory of headache pathogenesis is that cranial vasodilation results in pressure on the pain producing areas surrounding blood vessels. Under this theory, the effect of racemic isometheptene on relieving headache is believed to be due to isometheptene-induced cranial vasoconstriction which reduces the pressure on the pain producing areas surrounding blood vessels. Racemic isometheptene has

sympathomimetic effects, and based on pharmacological studies, some of these effects are blocked by a- and β-adrenergic receptor antagonists. This has led some to conclude that racemic isometheptene interacts with a- and β-adrenergic receptors or that its effects are mediated by alpha and beta adrenergic receptors indirectly. Racemic isometheptene has also been shown to increase heart rate and diastolic blood pressure, which are properties associated with sympathomimetic agents.

Purified (R)-isometheptene has a significant binding affinity for the imidazoline- 1 (I |) receptor (See WO2014/1 13734, incorporated herein by reference), and binds to the I | receptor with higher affinity than (S)-isometheptene. (R)-isometheptene binds preferentially to the bovine I i receptor versus the a-adrenergic receptor, with a Kj of 18 nM for the Ii receptor and a Kj of 2300 nM for the a-adrenergic receptor. For (S)- isometheptene, the Kj was 1 100 nM for the I i receptor and 2700 nM for the a- adrenergic receptor. Studies have also suggested that (R)-isometheptene may have lower potential adverse effects to the cardiovascular system than (S)-isometheptene.

The imidazoline receptor system modulates sympathetic effects and three types of receptors have been identified: Ii, I ₂, and I ₃. The best characterized is the 1 ) receptor, which has been connected with a cloned cDNTHIS D1SCLOSUREA. I ₂ and 1 ₃ are still described only as activities of activated membranes and may or may not correspond to single proteins. Present understanding of the I i receptor is that of a cell- surface receptor mediating cellular responses, participating in cardiovascular control by the CNS, and providing a potential therapeutic target for multiple cardiovascular and metabolic disorders. It was also recently found that knockout mice lacking the I i receptor had a lower pain threshold than that of wild type in both hot-plate and tail- flick tests, indicating that nociceptive perception was potentiated in the knockout mice (See Zhang, L., et al., Generation and Primary Phenotypes of Imidazoline Receptor Antisera-Selected (IRAS) Knockout Mice, CAN Neuroscience and Therapeutics 19 (2013) 978-981 ).

New therapeutics for pain treatment and relief would be useful.

Summary of the Disclosure

Among the embodiments of this disclosure are compounds and compositions that are useful in treating pain; an inflammatory disease or disorder, an allergic disease or disorder, a metabolic disease, a cardiovascular disease or disorder, a neurogenic vascular disease or a painful condition associated with any of the foregoing conditions; an episodic tension-type headache; a migraine headache; a headache; cramping; a cognitive disorder; a tension or migraine headache due to a vascular, neurovascular, or neurogenic disorder or dysfunction during a menstrual cycle episode; a tension or migraine headache due to a vascular, neurovascular, or neurogenic disorder or dysfunction during a migraine episode; a headache from mild to moderate hypertension; mild to moderate essential hypertension; organ transplant rejection; hot and cold flashes; traumatic brain injury (TBI); neurotoxicity; psychic pain; psychological pain; psychiatric pain; depression; schizophrenia; anxiety;

epilepsy; a stress disorder; excess sweating; a symptom related to drug withdrawal; allodynia; fibromyalgia; fibromyalgia-ness; central sensitization; centralization;

regional pain syndrome; temporomandibular joint syndrome (TMJ); lower back pain; interstitial cystitis; Gulf War syndrome; visceral pain; kidney stones; gout;

neuropathic pain; post-herpetic neuralgia; diabetic neuropathy; sickle cell pain;

priapism; nociceptive pain; post-operative pain; orthopedic injury pain; phantom limb pain; bunionectomy; dental extraction; pain after severed spinal cord injury;

osteoarthritis; rheumatoid arthritis; Lyme disease; Parkinson's disease; pain associated with cancer; opioid-induced constipation; an opioid withdrawal symptom; or pain associated with post-traumatic stress disorder (PTSD); or a combination of any of the foregoing conditions. In some embodiments, the compounds and compositions of this disclosure modulate the imidazoline-1 (I |) receptor. In some embodiments, the compounds and compositions of this disclosure are nitric oxidase inhibitors. In some embodiments, the compounds and compositions of this disclosure act as analgesics. In some embodiments, the compounds and compositions of the disclosure are used in conjunction simultaneously, separately, or sequentially with acetaminophen, a nonsteroidal anti-inflammatory drug (NSAID), ibuprofen, naprosyn, a cyclooxygenase-2 inhibitor, aspirin, caffeine, dichloralphenazone, a triptan, a chemotherapeutic drug, an antidepressant, a serotonin-norepinephrine reuptake inhibitor (SNRI), a

gabapentinoid, an antiproliferative agent, an anti-inflammatory agent, a corticosteroid, an anti-asthmatic agent, an anti-allergic agent, an immunosuppressive agent, an immunomodulatory agent, a cardiovascular disease treatment agent, an anti-diabetic agent, a blood disorder treatment agent, a nerve growth factor receptor antagonist, a sodium channel blocker, a CYP2D6 inhibitor, a TNF-alpha inhibitor, one or more opiates or a combination of any of the foregoing therapeutics. In some embodiments, the compounds of this disclosure are selected from a group of compounds having the formula (SC-01), formula (SC-02), formula (SC-03), formula (SC-04), formula (SC-05), formula (SC-06), formula (SC-07), formula (SC-08), formula (SC-09), formula (SC-10), formula (SC-1 1), formula (SC-12), formula (SC- 13), formula (SC-14), formula (SC-15), formula (SC- 16), formula (SC-17), formula (SC-18), formula (SC-19), formula (SC-20), formula (SC-21 ), formula (SC-22), formula (SC-23), formula (SC-24), or formula (SC-25), or a pharmaceutically acceptable salt, tautomer, enantiomer, disastereomer, solvate, or prodrug of any of the foregoing compounds.

In some embodiments, the compounds of this disclosure are selected from a group of compounds having the formula 93, 96, 99-202, 212-217, 219-314, 318-354, 358-374, 376, or 378-432, or a pharmaceutically acceptable salt, free base form, tautomer, enantiomer, disastereomer, solvate, or prodrug of any of the foregoing compounds.

In some embodiments, the compounds of this disclosure are selected from a group of compounds having the formula 96, 111, 113-118, 123-129, 131, 133, 140-144, 146, 149, 150, 152, 153, 158, 160-167, 169, 170, 172, 176-178, 185, 187-189, 193, 195, 202, 212-217, 219, 220, 222-228, 231-233, 235, 236, 238-241, 247-249, 254, 258, 259, 284, 286, 289, 296, 298, 303, 304, 306, 308-314, 323-325, 328-330, 336-349, 358, 359, 361 , 364-366, 368, 372, 376, or 378-432, or a pharmaceutically acceptable salt, free base form, tautomer, enantiomer, disastereomer, solvate, or prodrug of any of the foregoing compounds.

In some embodiments, the compounds of the disclosure selected from a group of compounds having the formula (SC-01), formula (SC-02), formula (SC-03), formula (SC-04), formula (SC-05), formula (SC-06), formula (SC-07), formula (SC-08), formula (SC-09), formula (SC- 10), formula (SC-1 1 ), formula (SC- 12), formula (SC- 13), formula (SC- 14), formula (SC- 15), formula (SC- 16), formula (SC-17), formula (SC-18), formula (SC- 19), formula (SC-20), formula (SC-21 ), formula (SC-22), formula (SC-23), formula (SC-24), formula (SC-25), formula 1, 54-93, 95-376, or 378-432, or a pharmaceutically acceptable salt, free base form, tautomer, solvate, enantiomer, disastereomer, or prodrug of any of the foregoing compounds, are useful as analgesics.

In some embodiments, this disclosure relates to pharmaceutical compositions comprising one or more compounds selected from a group of compounds having the formula (SC-01 ), formula (SC-02), formula (SC-03), formula (SC-04), formula (SC- 05), formula (SC-06), formula (SC-07), formula (SC-08), formula (SC-09), formula (SC- 10), formula (SC-1 1 ), formula (SC-12), formula (SC-13), formula (SC-14), formula (SC-15), formula (SC- 16), formula (SC-17), formula (SC- 1 8), formula (SC- 19), formula (SC-20), formula (SC-21 ), formula (SC-22), formula (SC-23), formula (SC-24), formula (SC-25), or formula 1, 54-93, or 95-432, or a pharmaceutically acceptable salt, tautomer, solvate, enantiomer, disastereomer, or prodrug of any of the foregoing compounds. In some embodiments, the pharmaceutical compositions described herein are useful as analgesics.

In some embodiments, the disclosure of this application relates to a method of treating or preventing one or more conditions selected from: pain; an inflammatory disease or disorder, an allergic disease or disorder, a metabolic disease, a cardiovascular disease or disorder, a neurogenic vascular disease or a painful condition associated with any of the foregoing conditions; an episodic tension-type headache; a migraine headache; a headache; cramping; a cognitive disorder; a tension or migraine headache due to a vascular, neurovascular, or neurogenic disorder or dysfunction during a menstrual cycle episode; a tension or migraine headache due to a vascular, neurovascular, or neurogenic disorder or dysfunction during a migraine episode; a headache from mild to moderate hypertension; mild to moderate essential hypertension; organ transplant rejection; hot and cold flashes; traumatic brain injury (TBI); neurotoxicity; psychic pain; psychological pain; psychiatric pain; depression; schizophrenia; anxiety;

epilepsy; a stress disorder; excess sweating; a symptom related to drug withdrawal; allodynia; fibromyalgia; fibromyalgia-ness; central sensitization; centralization;

regional pain syndrome; temporomandibular joint syndrome (TMJ); lower back pain; interstitial cystitis; Gulf War syndrome; visceral pain; kidney stones; gout;

neuropathic pain; post-herpetic neuralgia; diabetic neuropathy; sickle cell pain;

priapism; nociceptive pain; post-operative pain; orthopedic injury pain; phantom limb pain; bunionectomy; dental extraction; pain after severed spinal cord injury;

osteoarthritis; rheumatoid arthritis; Lyme disease; Parkinson's disease; pain associated with cancer; opioid-induced constipation; an opioid withdrawal symptom; or pain associated with post-traumatic stress disorder (PTSD), in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of one or more compounds selected from a group of compounds having the formula (SC-01 ), formula (SC-02), formula (SC-03), formula (SC-04), formula (SC-05), formula (SC- 06), formula (SC-07), formula (SC-08), formula (SC-09), formula (SC- 10), formula (SC-1 1), formula (SC-12), formula (SC- 13), formula (SC- 14), formula (SC-15), formula (SC- 16), formula (SC-17), formula (SC-18), formula (SC- 19), formula (SC- 20), formula (SC-21), formula (SC-22), formula (SC-23), formula (SC-24), formula (SC-25), or formula 1, 54-93, or 95-432, or a pharmaceutically acceptable salt, tautomer, solvate, enantiomer, disastereomer, or prodrug of any of the foregoing compounds. In some embodiments, the method described herein further comprises administering one or more additional therapeutics selected from the group consisting of acetaminophen, a non-steroidal anti-inflammatory drug (NSAID), ibuprofen, naprosyn, a cyclooxygenase-2 inhibitor, aspirin, caffeine, dichloralphenazone, a triptan, a chemotherapeutic drug, an antidepressant, a serotonin-norepinephrine reuptake inhibitor (SNRI), a gabapentinoid, an antiproliferative agent, an antiinflammatory agent, a corticosteroid, an anti-asthmatic agent, an anti-allergic agent, an immunosuppressive agent, an immunomodulatory agent, a cardiovascular disease treatment agent, an anti-diabetic agent, a blood disorder treatment agent, a nerve growth factor receptor antagonist, a sodium channel blocker, a CYP2D6 inhibitor, a TNF-alpha inhibitor, one or more opiates, or a combination of any of the foregoing therapeutics simultaneously, separately, or sequentially with compounds disclosed herein, or mixtures thereof.

epilepsy; a stress disorder; excess sweating; a symptom related to drug withdrawal; allodynia; fibromyalgia; fibromyalgia-ness; central sensitization; centralization;

regional pain syndrome; temporomandibular joint syndrome (TMJ); lower back pain; interstitial cystitis; Gulf War syndrome; visceral pain; kidney stones; gout;

neuropathic pain; post-herpetic neuralgia; diabetic neuropathy; sickle cell pain;

priapism; nociceptive pain; post-operative pain; orthopedic injury pain; phantom limb pain; bunionectomy; dental extraction; pain after severed spinal cord injury;

disastereomer, or prodrug of any of the foregoing compounds. In some embodiments, the method further comprises administering one or more additional therapeutics selected from the group consisting of acetaminophen, a non-steroidal antiinflammatory drug (NSAID), ibuprofen, naprosyn, a cyclooxygenase-2 inhibitor, aspirin, caffeine, dichloralphenazone, a triptan, a chemotherapeutic drug, an antidepressant, a serotonin-norepinephrine reuptake inhibitor (SNRI), a

pharmaceutically acceptable salt, tautomer, solvate, enantiomer, disastereomer, or prodrug of any of the foregoing compounds, is used for the manufacture of a medicament for treating or preventing one or more conditions selected from: pain; an inflammatory disease or disorder, an allergic disease or disorder, a metabolic disease, a cardiovascular disease or disorder, a neurogenic vascular disease or a painful condition associated with any of the foregoing conditions; an episodic tension-type headache; a migraine headache; a headache; cramping; a cognitive disorder; a tension or migraine headache due to a vascular, neurovascular, or neurogenic disorder or dysfunction during a menstrual cycle episode; a tension or migraine headache due to a vascular, neurovascular, or neurogenic disorder or dysfunction during a migraine episode; a headache from mild to moderate hypertension; mild to moderate essential hypertension; organ transplant rejection; hot and cold flashes; traumatic brain injury (TBI); neurotoxicity; psychic pain; psychological pain; psychiatric pain; depression; schizophrenia; anxiety; epilepsy; a stress disorder; excess sweating; a symptom related to drug withdrawal; allodynia; fibromyalgia; fibromyalgia-ness; central sensitization; centralization; regional pain syndrome; temporomandibular joint syndrome (TMJ); lower back pain; interstitial cystitis; Gulf War syndrome; visceral pain; kidney stones; gout; neuropathic pain; post-herpetic neuralgia; diabetic neuropathy; sickle cell pain; priapism; nociceptive pain; post-operative pain; orthopedic injury pain; phantom limb pain; bunionectomy; dental extraction; pain after severed spinal cord injury;

cyclooxygenase-2 inhibitor, aspirin, caffeine, dichloralphenazone, a triptan, a chemotherapeutic drug, an antidepressant, a serotonin-norepinephrine reuptake inhibitor (SNRI), a gabapentinoid, an antiproliferative agent, an anti-inflammatory agent, a corticosteroid, an anti-asthmatic agent, an anti-allergic agent, an

immunosuppressive agent, an immunomodulatory agent, a cardiovascular disease treatment agent, an anti-diabetic agent, a blood disorder treatment agent, a nerve growth factor receptor antagonist, a sodium channel blocker, a CYP2D6 inhibitor, a T F-alpha inhibitor, or one or more opiates. In some embodiments, a pharmaceutical composition comprising one or more compounds selected from a group of compounds having the formula (SC-01 ), formula (SC-02), formula (SC-03), formula (SC-04), formula (SC-05), formula (SC-06), formula (SC-07), formula (SC-08), formula (SC-09), formula (SC-10), formula (SC- 1 1 ), formula (SC- 12), formula (SC-1 3), formula (SC- 14), formula (SC- 15), formula (SC- 16), formula (SC- 17), formula (SC- 18), formula (SC- 19), formula (SC-20), formula (SC-21 ), formula (SC-22), formula (SC-23), formula (SC-24), formula (SC- 25), or formula 1, 54-93, or 95-432, or a pharmaceutically acceptable salt, tautomer, solvate, enantiomer, disastereomer, or prodrug of any of the foregoing compounds, is used for the manufacture of a medicament for treating or preventing one or more conditions selected from: pain; an inflammatory disease or disorder, an allergic disease or disorder, a metabolic disease, a cardiovascular disease or disorder, a neurogenic vascular disease or a painful condition associated with any of the foregoing conditions; an episodic tension-type headache; a migraine headache; a headache; cramping; a cognitive disorder; a tension or migraine headache due to a vascular, neurovascular, or neurogenic disorder or dysfunction during a menstrual cycle episode; a tension or migraine headache due to a vascular, neurovascular, or neurogenic disorder or dysfunction during a migraine episode; a headache from mild to moderate hypertension; mild to moderate essential hypertension; organ transplant rejection; hot and cold flashes; traumatic brain injury (TBI); neurotoxicity; psychic pain; psychological pain; psychiatric pain; depression; schizophrenia; anxiety;

epilepsy; a stress disorder; excess sweating; a symptom related to drug withdrawal; allodynia; fibromyalgia; fibromyalgia-ness; central sensitization; centralization;

regional pain syndrome; temporomandibular joint syndrome (TMJ); lower back pain; interstitial cystitis; Gulf War syndrome; visceral pain; kidney stones; gout;

neuropathic pain; post-herpetic neuralgia; diabetic neuropathy; sickle cell pain;

priapism; nociceptive pain; post-operative pain; orthopedic injury pain; phantom limb pain; bunionectomy; dental extraction; pain after severed spinal cord injury;

immunosuppressive agent, an immunomodulatory agent, a cardiovascular disease. treatment agent, an anti-diabetic agent, a blood disorder treatment agent, a nerve growth factor receptor antagonist, a sodium channel blocker, a CYP2D6 inhibitor, a TNF-alpha inhibitor, or one or more opiates.

In some embodiments, one or more compounds selected from a group of compounds having the formula (SC-01), formula (SC-02), formula (SC-03), formula (SC-04), formula (SC-05), formula (SC-06), formula (SC-07), formula (SC-08), formula (SC- 09), formula (SC- 10), formula (SC- 1 1 ), formula (SC- 12), formula (SC-13), formula (SC- 14), formula (SC-15), formula (SC- 16), formula (SC- 17), formula (SC-18), formula (SC-19), formula (SC-20), formula (SC-21), formula (SC-22), formula (SC- 23), formula (SC-24), formula (SC-25), or formula 1, 54-93, or 95-432, or a pharmaceutically acceptable salt, tautomer, solvate, enantiomer, disastereomer, or prodrug of any of the foregoing compounds is used in treating or preventing one or more conditions selected from: pain; an inflammatory disease or disorder, an allergic disease or disorder, a metabolic disease, a cardiovascular disease or disorder, a neurogenic vascular disease or a painful condition associated with any of the foregoing conditions; an episodic tension-type headache; a migraine headache; a headache; cramping; a cognitive disorder; a tension or migraine headache due to a vascular, neurovascular, or neurogenic disorder or dysfunction during a menstrual cycle episode; a tension or migraine headache due to a vascular, neurovascular, or neurogenic disorder or dysfunction during a migraine episode; a headache from mild to moderate hypertension; mild to moderate essential hypertension; organ transplant rejection; hot and cold flashes; traumatic brain injury (TBI); neurotoxicity; psychic pain; psychological pain; psychiatric pain; depression; schizophrenia; anxiety;

epilepsy; a stress disorder; excess sweating; a symptom related to drug withdrawal; allodynia; fibromyalgia; fibromyalgia-ness; central sensitization; centralization;

regional pain syndrome; temporomandibular joint syndrome (TMJ); lower back pain; interstitial cystitis; Gulf War syndrome; visceral pain; kidney stones; gout;

neuropathic pain; post-herpetic neuralgia; diabetic neuropathy; sickle cell pain;

priapism; nociceptive pain; post-operative pain; orthopedic injury pain; phantom limb pain; bunionectomy; dental extraction; pain after severed spinal cord injury;

osteoarthritis; rheumatoid arthritis; Lyme disease; Parkinson's disease; pain associated with cancer; opioid-induced constipation; an opioid withdrawal symptom; or pain associated with post-traumatic stress disorder (PTSD). In further embodiments, the one or more compounds are used simultaneously, separately, or sequentially with one or more additional therapeutics selected from the group consisting of acetaminophen, a non-steroidal anti-inflammatory drug (NSAID), ibuprofen, naprosyn, a

immunosuppressive agent, an immunomodulatory agent, a cardiovascular disease treatment agent, an anti-diabetic agent, a blood disorder treatment agent, a nerve growth factor receptor antagonist, a sodium channel blocker, a CYP2D6 inhibitor, a TNF-alpha inhibitor, or one or more opiates. In some embodiments, a pharmaceutical composition comprising one or more compounds selected from a group of compounds having the formula (SC-01 ), formula (SC-02), formula (SC-03), formula (SC-04), formula (SC-05), formula (SC-06), formula (SC-07), formula (SC-08), formula (SC-09), formula (SC- 10), formula (SC- 1 1 ), formula (SC- 12), formula (SC- 13), formula (SC- 14), formula (SC- 15), formula (SC- 16), formula (SC- 17), formula (SC- 18), formula (SC-19), formula (SC-20), formula (SC-21), formula (SC-22), formula (SC-23), formula (SC-24), formula (SC- 25), or formula 1, 54-93, or 95-432, or a pharmaceutically acceptable salt, tautomer, solvate, enantiomer, disastereomer, or prodrug of any of the foregoing compounds, is used in treating or preventing one or more conditions selected from: pain; an inflammatory disease or disorder, an allergic disease or disorder, a metabolic disease, a cardiovascular disease or disorder, a neurogenic vascular disease or a painful condition associated with any of the foregoing conditions; an episodic tension-type headache; a migraine headache; a headache; cramping; a cognitive disorder; a tension or migraine headache due to a vascular, neurovascular, or neurogenic disorder or dysfunction during a menstrual cycle episode; a tension or migraine headache due to a vascular, neurovascular, or neurogenic disorder or dysfunction during a migraine episode; a headache from mild to moderate hypertension; mild to moderate essential hypertension; organ transplant rejection; hot and cold flashes; traumatic brain injury (TBI); neurotoxicity; psychic pain; psychological pain; psychiatric pain; depression; schizophrenia; anxiety; epilepsy; a stress disorder; excess sweating; a symptom related to drug withdrawal; allodynia; fibromyalgia; fibromyalgia-ness; central sensitization; centralization; regional pain syndrome; temporomandibular joint syndrome (TMJ); lower back pain; interstitial cystitis; Gulf War syndrome; visceral pain; kidney stones; gout; neuropathic pain; post-herpetic neuralgia; diabetic neuropathy; sickle cell pain; priapism; nociceptive pain; post-operative pain; orthopedic injury pain; phantom limb pain; bunionectomy; dental extraction; pain after severed spinal cord injury;

osteoarthritis; rheumatoid arthritis; Lyme disease; Parkinson's disease; pain associated with cancer; opioid-induced constipation; an opioid withdrawal symptom; or pain associated with post-traumatic stress disorder (PTSD). In further embodiments, the pharmaceutical composition is used simultaneously, separately, or sequentially with one or more additional therapeutics selected from the group consisting of

acetaminophen, a non-steroidal anti-inflammatory drug (NSAID), ibuprofen, naprosyn, a cyclooxygenase-2 inhibitor, aspirin, caffeine, dichloralphenazone, a triptan, a chemotherapeutic drug, an antidepressant, a serotonin-norepinephrine reuptake inhibitor (SNR1), a gabapentinoid, an antiproliferative agent, an antiinflammatory agent, a corticosteroid, an anti-asthmatic agent, an anti-allergic agent, an immunosuppressive agent, an immunomodulatory agent, a cardiovascular disease treatment agent, an anti-diabetic agent, a blood disorder treatment agent, a nerve growth factor receptor antagonist, a sodium channel blocker, a CYP2D6 inhibitor, a TNF-alpha inhibitor, or one or more opiates.

In some embodiments, the disclosure of this application relates to a method of modulating an imidazoline-1 (Ii) receptor, comprising contacting the I ] receptor with one or more compounds selected from a group of compounds having the formula (SC- 01 ), formula (SC-02), formula (SC-03), formula (SC-04), formula (SC-05), formula (SC-06), formula (SC-07), formula (SC-08), formula (SC-09), formula (SC-10), formula (SC- 1 1 ), formula (SC- 12), formula (SC-13), formula (SC-14), formula (SC- 15), formula (SC- 16), formula (SC- 17), formula (SC- 18), formula (SC- 19), formula (SC-20), formula (SC-21), formula (SC-22), formula (SC-23), formula (SC-24), formula (SC-25), or formula 1, 54-93, or 95-432, or a pharmaceutically acceptable salt, tautomer, solvate, enantiomer, disastereomer, or prodrug of any of the foregoing compounds.

In some embodiments, the disclosure of this application relates to a method of modulating an imidazoline-1 (Ii) receptor in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of one or more compounds selected from a group of compounds having the formula (SC-01), formula (SC-02), formula (SC-03), formula (SC-04), formula (SC-05), formula (SC-06), formula (SC-07), formula (SC-08), formula (SC-09), formula (SC-10), formula (SC- 1 1 ), formula (SC-12), formula (SC- 13), formula (SC- 14), formula (SC-15), formula (SC- 16), formula (SC- 17), formula (SC- 1 8), formula (SC- 19), formula (SC-20), formula (SC-21 ), formula (SC-22), formula (SC-23), formula (SC-24), formula (SC- 25), or formula 1, 54-93, or 95-432, or a pharmaceutically acceptable salt, tautomer, solvate, enantiomer, disastereomer, or prodrug of any of the foregoing compounds. In some embodiments, the disclosure of this application relates to a method for nitric oxidase inhibition in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of one or more compounds selected from a group of compounds having the formula (SC-01), formula (SC-02), formula (SC-03), formula (SC-04), formula (SC-05), formula (SC-06), formula (SC-07), formula (SC-08), formula (SC-09), formula (SC-10), formula (SC-1 1 ), formula (SC-12), formula (SC- 13), formula (SC- 14), formula (SC-15), formula (SC-16), formula (SC- 17), formula (SC-18), formula (SC-19), formula (SC-20), formula (SC-21 ), formula (SC-22), formula (SC-23), formula (SC-24), formula (SC-25), or formula 1, 54-93, or 95-432, or a pharmaceutically acceptable salt, tautomer, solvate, enantiomer, disastereomer, or prodrug of any of the foregoing compounds, simultaneously, separately, or sequentially in combination with one or more substances selected from the group consisting of acetaminophen, a non-steroidal anti-inflammatory drug (NSAID), ibuprofen, naprosyn, a cyclooxygenase-2 inhibitor, aspirin, caffeine,

dichloralphenazone, a triptan, a chemotherapeutic drug, an antidepressant, a serotonin-norepinephrine reuptake inhibitor (SNRI), a gabapentinoid, an

Brief Description of the Drawings

Figure 1 illustrates data related to analgesic activity using the Formalin Test, late phase (licking score) in a mouse of compound 9 mucate salt, (R)-isometheptene mucate, and compound 27 mucate salt, (S)-isometheptene mucate.

Figure 2 illustrates data related to analgesic activity using the Tail-flick Test in a mouse of compound 9 mucate salt, (R)-isometheptene mucate, and compound 27 mucate salt, (S)-isometheptene mucate. Figures 3A-B illustrate data- from the TAAR1 cAMP assay for compound 9 mucate salt, (R)-isometheptene mucate (isomer 2),. and compound 27 mucate salt, (S)- isometheptene mucate (isomer 1 ). For compound 9 mucate salt, (R)-isometheptene mucate, the EC50 was 29.45 μΜ and for compound 27 mucate salt, (S)-isometheptene mucate, the EC ₅o was 21.12 μΜ. Compound 27 mucate salt, thus, more potently activated TAAR1 than compound 9 mucate salt did.

Figure 4 illustrates data from tactile sensory testing in STA rats using von Frey monofilaments for compound 9 mucate salt, (R)-isometheptene mucate, and compound 27 mucate salt, (S)-isometheptene mucate. STA rats treated with compound 9 mucate salt showed a dramatic increase in threshold values versus STA rats treated with compound 27 mucate salt or the control rats, demonstrating the analgesic effect of compound 9 mucate salt.

Figures 5A-D illustrate data on the impact of compound 9 mucate salt, (R)- isometheptene mucate (isomer 2), and compound 27 mucate salt, (S)-isometheptene mucate (isomer 1), on arterial blood pressure (BP) and heart rate. A) Mean arterial blood pressure (mmHg), B) Systolic arterial blood pressure (mmHg), C) Diastolic arterial blood pressure (mmHg), and D) Heart rate (bpm).

Figures 6A-D illustrate data related to analgesic efficacy in a rat chronic constrictive nerve injury (CCI) model of neuropathic pain of (S)-isometheptene mucate

(compound 27 mucate salt) and (R)-isometheptene mucate (compound 9 mucate salt). Gabapentin, (R)-isometheptene mucate ( 100 mg/kg), and (S)-isometheptene mucate (100 mg/kg) significantly increased paw withdrawal threshold (PWT) compared to the vehicle-treated rats. In addition (S)-isometheptene mucate (30 mg/kg) showed a nonsignificant trend to also increasing PWT. A) Baseline ipsilateral PWT prior to test. Data are presented as mean ± SEM. B) Effect of test compounds on ipsilateral PWT. Data are presented as mean ± SEM*p<0.05 compared to vehicle. ~p<0.1 compared to vehicle. C) Baseline Contralateral PWT. Data are presented as mean ± SEM. D) Effect of test compounds on contralateral PWT. Data are presented as mean ± SEM. Figures 7A-D illustrate data related to analgesic efficacy in a rat model of bortezomib (BTZ)-induced neuropathy of (S)-isometheptene mucate (compound 27 mucate salt) and (R)-isometheptene mucate (compound 9 mucate salt). Gabapentin, (R)- isometheptene mucate (100 mg/kg), and (S)-isometheptene mucate (30 and 100 ^' mg/kg) significantly increased PWT as compared to the BTZ-treated control group suggesting potential analgesic efficacy of these compounds on BTZ-induced neuropathic pain. A) Body weight of all treatment groups throughout the study. Data are presented as mean ± SEM. Arrow indicated time of BTZ injection. B) Baseline PWT prior to BTZ injection. Data are presented as mean ± SEM. C) Baseline PWT nine days after BTZ injection. Data are presented as mean ± SEM. *p<0.05 compared to vehicle-vehicle. D) Effects of (R)- and (S)-isometheptene mucate on PWT 15 minutes post administration. Data are presented as mean ± SEM. *p<0.05 compared to BTZ-treated group.

Figure 8 illustrates data related to analgesic activity using the Hot Plate Test in a mouse of compound 9 mucate salt, (R)-isometheptene mucate, and compound 27 mucate salt, (S)-isometheptene mucate.

Figures 9Λ-Β illustrate expression of the imidazoline-l receptor in CHO cells. A) Construct confirmation by restriction digestion and B) the RT-PCR result from the transient transfection of imidazoline- 1 receptor/CHO cells, indicating imidazoline- 1 receptor was expressed.

Figures lOA-C illustrate a functional assay for the imidazoline- 1 receptor in PC- 12 cells or a cell line stably expressing the imidazoline-1 receptor to evaluate the impact of imidazoline-1 receptor agonists and antagonists on forskolin-stimulated cAMP induction. A) Both benazoline and efaroxan inhibit forskolin-stimulated cAMP in PC- 12 cells. B) The inhibitory effect of benazoline on forskolin induced cAMP production in PC-12 cells was antagonized by clonidine. C) Both efaroxan and benazoline showed an inhibitory effect on forskolin-induced cAMP in imidazoline- 1 receptor/CHO cells, but not in the parent CHO cell line. This result suggests functional imidazoline-1 receptor was expressed in transiently transfected CHO cells.

Figures 11A-D illustrate preliminary human pharmacokinetic studies using racemic isometheptene and compound 9 mucate salt, (R)-isometheptene mucate. A) Cohort 1 with 35 mg compound 9 mucate salt (n=9) or 70 mg racemic isometheptene (n=3). B) Cohort 1 with 70 mg racemic isometheptene (n=3). C) Cohort 2 with 70 mg compound 9 mucate salt (n=9) or 70 mg racemic isometheptene (n=3). D) Cohort 2 with 70 mg racemic isometheptene (n=3).

Figures 12A-D illustrate preliminary human pharmacokinetic studies using racemic isometheptene and compounds mucate salt, (R)-isometheptene mucate. A) Cohort 3 treated with 140 mg compound 9 mucate (n=9) or 70 mg racemic isometheptene (n=3). B) Cohort 3 treated with 140 mg compound 9 mucate salt (n=9) or 70 mg racemic isometheptene (n=3). C) Cohort 3 with 70 mg racemic isometheptene (n=3). D) Cohort 3 with 70 mg racemic isometheptene (n=3). Figure 13 illustrates effects of 1 mg/kg of R- or S-isometheptene mucate on

trigeminal sensitivity in the inflammotry soup model. The data show that significant changes in trigeminal sensitivity were seen when inflammatory soup (IS) rats were treated with 1 mg/kg R- or S-isometheptene mucate(compounds 9 and 27 mucate salts, n=8 IS rats/group). Figure 14 illustrates effects of 30 mg/kg of R- or S-isometheptene mucate on trigeminal sensitivity in the inflammotry soup model. The data show that 30 mg/kg of R-isometheptene mucate (compound 9 mucate salt) decreased trigeminal sensitivity while 30 mg/kg of S-isometheptene mucate (compound 27 mucate salt) had no effect on sensory thresholds. Rats receiving saline treatment had no change in sensory thresholds over the course of the experimental timeline. (n=8 IS rats/group, *p<0.05, **p<0.01 , ***p<0.001). Figure 15 illustrates effects of 30 mg/kg of R- or S-isometheptene mucate on trigeminial sensitivity in the STA rat model. The data were from tactile sensory testing in STA rats using von Frey monofilaments for compound 9 mucate salt, (R)- isometheptene mucate, and compound 27 mucate, (S)-isometheptene mucate. STA rats treated with compound 9 mucate showed an increase in threshold values versus STA rats treated with compound 27 mucate or the control rats, demonstrating the analgesic effect of compound 9 mucate.

Figure 16 illustrates trigeminal sensitivity in the inflammatory soup model.

Periorbital von Frey thresholds were measured for rats receiving infusions of saline (n = 10) or IS (n = 10) 3 days/week.

Figure 17 illustrates effects of 1 mg/kg of R- or S-isometheptene mucate on trigeminial sensitivity in the STA rat model. The data show that 1 mg/kg of R- isometheptene mucate (compound 9 mucate salt) and 1 mg/kg of S-isometheptene mucate (compound 27 mucate salt) had no effect on sensory thresholds. Rats receiving saline treatment had no change in sensory thresholds over the course of the experimental timeline. (n=8 IS rats/group).

Figure 18 illustrates data on the impact of compound 9 mucate salt, (R)- isometheptene mucate (isomer 2), and compound 27 mucate salt, (S)-isometheptene mucate (isomer 1), on mean arterial blood pressure (mmHg). Figure 19 illustrates data on the impact of compound 9 mucate salt, (R)- isometheptene mucate (isomer 2), and compound 27 mucate salt, (S)-isometheptene mucate (isomer 1 ), on systolic arterial blood pressure (mmHg).

Figure 20 illustrates data on the impact of compound 9 mucate salt, (R)- isometheptene mucate (isomer 2), and compound 27 mucate salt, (S)-isometheptene mucate (isomer 1), on diastolic arterial blood pressure (mmHg). Figure 21 illustrates data on the impact of compound 9 mucate salt, (R)- isometheptene mucate (isomer 2), and compound 27 mucate salt, (S)-isometheptene mucate (isomer 1 ), on heart rate (bpm).

Figure 22 illustrates a model of 11 -imidazoline receptor signaling pathways. Figure 23 illustrates data of activation via phosphorylation of ERK in human Ii - imidazoline receptor transfected 293T cells after treatment with compound 9 mucate salt, (R)-isometheptene mucate, or compound 27 mucate salt, (S)-isometheptene mucate.

Figure 24 illustrates periorbital allodynia after treatment with compound 9 mucate salt, (R)-isometheptene mucate, in a NO donor-evoked medication overuse headache rat model.

Figure 25 illustrates hindpaw allodynia after treatment with compound 9 mucate salt, (R)-isometheptene mucate, in a NO donor-evoked medication overuse headache rat model. Figure 26 illustrates the effect of compound 9 mucate salt, (R)-isometheptene mucate, on ipsilateral paw withdrawal threshold (PWT) in a rat chronic constructive nerve injury model of neuropathic pain.

Figure 27 illustrates the effect of compound 9 mucate salt, (R)-isometheptene mucate, on ipsilateral paw withdrawal threshold (PWT) 15 minutes post administration in a rat model of bortezomib-induced neuropathy.

Figure 28 illustrates the effect of compound 9 mucate salt, (R)-isometheptene mucate, or compound 27 mucate salt, (S)-isometheptene mucate, on naloxone-precipitated withdrawal test in mice.

Figure 29 illustrates the effect of a positive control, diclofenac, on sodium

monoiodoacetate (MIA)-induced osteoarthritic pain. Figure 30 illustrates the effect of compound 9 mucate salt, (R)-isometheptene mucate, on sodium monoiodoacetate (MIA)-induced osteoarthritic pain.

Figure 31 illustrates the effect of compound 9 mucate salt, (R)-isometheptene mucate, and diclofenac on sodium monoiodoacetate (MIA)-induced osteoarthritic pain. Figure 32 illustrates the effect of compound 9 mucate salt, (R)-isometheptene mucate, on fecal boli in a naloxone-precipitated withdrawal test in mice.

Figure 33 illustrates the effect of compound 9 mucate salt, (R)-isometheptene mucate, on diarrhea in a naloxone-precipitated withdrawal test in mice.

Figure 34 illustrates the effect of compound 9 mucate salt, (R)-isometheptene mucate, on salivation in a naloxone-precipitated withdrawal test in mice.

Figure 35 illustrates the effect of compound 9 mucate salt, (R)-isometheptene mucate, on teeth chattering in a naloxone-precipitated withdrawal test in mice.

Figure 36 illustrates the effect of compound 9 mucate salt, (R)-isometheptene mucate, on wet dog shakes in a naloxone-precipitated withdrawal test in mice. Figure 37 illustrates the effect of compound 9 mucate salt, (R)-isometheptene mucate, on writhing in a naloxone-precipitated withdrawal test in mice.

Figure 38 illustrates the effect of compound 9 mucate salt, (R)-isometheptene mucate, on weight loss in a naloxone-precipitated withdrawal test in mice.

When the Figures refer to (R)-isometheptene, they refer to (R)-isometheptene mucate. When the Figures refer to (S)-isometheptene, they refer to (S)-isometheptene mucate.

Detailed Description of the Disclosure

In order that the disclosure may be fully understood, the following detailed description is set forth. Definitions

The definitions set forth in this application are intended to clarify terms used throughout this application.

The term "herein" means the entire application. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as those commonly understood by one of ordinary skill in the art to which these inventions belong. Although methods and materials similar or equivalent to those described herein are used in the practice or testing of the inventions, suitable methods and materials are described below. The materials, methods and examples are illustrative only, and are not intended to be limiting. All publications, patents and other documents mentioned herein are incorporated by reference in their entirety.

Each embodiment of this disclosure may be taken alone or in combination with one or more other embodiments of this disclosure.

Throughout this application, the word "a" will be understood to imply the inclusion of one or more of the integers modified by the article "a."

Throughout this application, the word "comprise" or variations such as "comprises" or "comprising" will be understood to imply the inclusion of a stated integer or groups of integers but not the exclusion of any other integer or group of integers.

Throughout the application, where compositions are described as having, including, or comprising, specific components, it is contemplated that compositions also may consist essentially of, or consist of, the recited components. Similarly, where methods or processes are described as having, including, or comprising specific process steps, the processes also may consist essentially of, or consist of, the recited processing steps. Further, it should be understood that the order of steps or order for performing certain actions is immaterial so long as the compositions and methods described herein remain operable. Moreover, two or more steps or actions are conducted

simultaneously. All percentages and ratios used herein, unless otherwise indicated, are by weight.

The term "analgesic" refers to a painkiller or a drug that is able to provide relief from pain.

The term "agonist" refers to a molcule that activates a receptor to provoke a biological response. Agonists may bind directly to a receptor to activate it or they may activate a receptor through another mechanism, such as through second messengers like cAMP and pErk.

The term "antagonist" refers to a receptor ligand that blocks or dampens agonist- mediated responses rather than provoking a biological response upon binding to a receptor.

The terms "Imidazoline- 1 Receptor-Independent Isometheptene Pain Modulatory pathway" or "IRIPM pathway" refer to a pain perception pathway mediated by isometheptene that is independent of the imidazoline- 1 (li) receptor.

The term "or" as used herein should be understood to mean "and/or," unless the context clearly indicates otherwise.

The term "acyl" is art-recognized and refers to a group represented by the general formula hydrocarbylC(O)-, preferably alkylC(O)-.

The term "acylamino" is art-recognized and refers to an amino group substituted with an acyl group and may be represented, for example, by the formula

hydrocarbylC(0)NH-.

The term "acylaminoalkyl" refers to an alkyl group substituted with an acylamino group.

The term "acyloxy" is art-recognized and refers to a group represented by the general formula hydrocarbylC(0)0-, preferably alkylC(0)0-. The term "alkoxy" refers to an alkyl group, preferably a lower alkyl group, having an oxygen attached thereto. Representative alkoxy groups include methoxy, ethoxy, propoxy, ter/-butoxy and the like.

The term "alkoxyalkyl" refers to an alkyl group substituted with an alkoxy group and may be represented by the general formula alkyl-O-alkyl.

The term "alkoxyaryl" refers to an aryl group substituted with an alkoxy group and may be represented by the general formula aryl-O-alkyl.

The term "alkoxycycloalkyl" refers to a cycloalkyl group substituted with an alkoxy group and may be represented by the general formula cycloalkyl-O-alkyl. The term "alkanediyl" refers to an optionally substituted divalent radical derived from a straight chained or branched non-aromatic hydrocarbon.

The term "alkenediyl" refers to an optionally substituted divalent radical derived from an aliphatic group containing at least one double bond.

The term "alkenyl," as used herein, refers to an aliphatic group containing at least one double bond and is intended to include both "unsubstituted alkenyls" and "substituted alkenyls," the latter of which refers to alkenyl moieties having substituents replacing a hydrogen on one or more carbons of the alkenyl group. Such substituents may occur on one or more carbons that are included or not included in one or more double bonds.

Moreover, such substituents include all those contemplated for alkyl groups, as discussed below, except where stability is prohibitive. For example, substitution of alkenyl groups by one or more alkyl, carbocyclyl, aryl, heterocyclyl, or heteroaryl groups is contemplated.

An "alkyl" group or "alkane" is a straight chained or branched non-aromatic hydrocarbon which is completely saturated. Typically, a straight chained or branched alkyl group has from 1 to about 20 carbon atoms, preferably from 1 to about 10 unless otherwise defined. Examples of straight chained and branched alkyl groups include methyl, ethyl, «-propyl, /_?o-propyl, »-butyl, sec-butyl, tert-butyl, pentyl, hexyl, pentyl and octyl. A C)-C ₆ straight chained or branched alkyl group is also referred to as a "lower alkyl" group.

Moreover, the term "alkyl" (or "lower alkyl") as used throughout the application, examples, and embodiments is intended to include both "unsubstituted alkyls" and "substituted alkyls," the latter of which refers to alkyl moieties having substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone. Such substituents, if not otherwise specified, can include, for example, a halogen, a hydroxyl, a carbonyl (such as a carboxyl, an alkoxycarbonyl, a formyl, or an acyl), a thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), an alkoxyl, a phosphoryl, a phosphate, a phosphonate, a phosphinate, an amino, an amido, an amidine, an imine, a cyano, a nitro, an azido, a sulfhydryl, an alkylthio, a sulfate, a sulfonate, a sulfamoyl, a sulfonamido, a sulfonyl, a heterocyclyl, an aralkyl, or an aromatic or heteroaromatic moiety. It will be understood by those skilled in the art that the moieties substituted on the hydrocarbon chain can themselves be substituted, if appropriate. For instance, the substituents of a substituted alkyl may include substituted and unsubstituted forms of amino, azido, imino, amido, phosphoryl (including phosphonate and phosphinate), sulfonyl (including sulfate, sulfonamido, sulfamoyl and sulfonate), and silyl groups, as well as ethers, alkylthios, carbonyls (including ketones, aldehydes, carboxylates, and esters), -CF ₃, -CN and the like.

Exemplary substituted alkyls are described below. Cycloalkyls can be further substituted with alkyls, alkenyls, alkoxys, alkylthios, aminoalkyls, carbonyl- substituted alkyls, -CF ₃, -CN, and the like.

The term "C _x. _y" when used in conjunction with a chemical moiety, such as, acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy is meant to include groups that contain from x to y carbons in the chain. For example, the term "Cx.yalkyl" refers to substituted or unsubstituted saturated hydrocarbon groups, including straight-chain alkyl and branched-chain alkyl groups that contain from x to y carbons in the chain, including haloalkyl groups such as trifluoromethyl and 2,2,2-tirfluoroethyl, etc. Co alkyl indicates a hydrogen where the group is in a terminal position, a bond if internal. The terms "C _2-yalkenyl" and "C _2-yalkynyl" refer to substituted or unsubstituted unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double or triple bond respectively.

The term "alkylamino," as used herein, refers to an amino group substituted with at least one alkyl group.

The term "alkylaryloxydiyl" refers to an optionally substituted divalent radical derived from an aryloxy group substituted with an alkyl group.

The term "alkylcycloalkylalkanediyl" refers to an optionally substituted divalent radical derived from an alkyl group substituted with a carbocycle group which is substituted with an alkyl group.

The term "alkylcycloalkenylalkanediyl" refers to an optionally substituted divalent radical derived from an alkyl group substituted with a cycloalkenyl group which is substituted with an alkyl group.

The term "alkylheterocyclylalkanediyl" refers to an optionally substituted divalent radical derived from an alkyl group substituted with a heterocyclyl group which is substituted with an alkyl group.

The term "alkylthio," as used herein, refers to a thiol group substituted with an alkyl group and may be represented by the general formula alkylS-.

The term "alkylthiodiyl," as used herein, refers to an optionally substituted divalent radical derived from an alkylthio. An example is 2-thiapent- 1 ,5-diyl.

The term "alkynediyl" refers to an optionally substituted divalent radical derived from an aliphatic group containing at least one triple bond. An example is but-2-yne- l ,4- diyl.

The term "alkynyl," as used herein, refers to an aliphatic group containing at least one triple bond and is intended to include both "unsubstituted alkynyls" and "substituted alkynyls," the latter of which refers to alkynyl moieties having substituents replacing a hydrogen on one or more carbons of the alkynyl group. Such substituents may occur on one or more carbons that are included or not included in one or more triple bonds. Moreover, such substituents include all those contemplated for alkyl groups, as discussed above, except where stability is prohibitive. For example, substitution of alkynyl groups by one or more alkyl, carbocyclyl, aryl, heterocyclyl, or heteroaryl groups is contemplated.

The term "amide," as used herein, refers to a group wherein each R independently represent a hydrogen or hydrocarbyl group, or two R ³⁰ are taken together with the N atom to which they are attached complete a heterocycle having from 4 to 12 atoms in the ring structure.

The terms "amine" and "amino" are art-recognized and refer to both unsubstituted and substituted amines and salts thereof, e.g., a moiety that is-represented by wherein each R ³⁰ independently represents a hydrogen or a hydrocarbyl group, or two

R are taken together with the N atom to which they are attached complete a heterocycle having from 4 to 12 atoms in the ring structure.

The term "aminoalkanediyl" refers to an optionally substituted divalent radical derived from an aminoalkane group.

The term "aminoalkyl," as used herein, refers to an alkyl group substituted with an amino group.

The term "aminoalkylaminodiyl" refers to an optionally substituted divalent radical derived from an amino group substituted with an aminoalkyl group. The term "aminoalkylaryloxyalkoxyaryl," as used herein, refers to an alkoxyaryl group substituted with an aryloxy group that has been substituted with an aminoalkyl group.

The term "arylalkanediyl" refers to an optionally substituted divalent radical derived from an alkyl group substituted with an aryl group.

The terms "arylalkyl" or "aralkyl," as used herein, refers to an alkyl group substituted with an aryl group.

The term "arylheteroalkyl," as used herein, refers to a heteroalkyl group substituted with an aryl group. The term "aryl" as used herein includes substituted or unsubstituted single-ring aromatic groups in which each atom of the ring is carbon. Preferably the ring is a 5- to 7-membered ring, more preferably a 6-membered ring. The term "aryl" also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons or heteroatoms are common to two adjoining rings wherein at least one of the rings is aromatic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls. Aryl groups include benzene, naphthalene, phenanthrene, phenol, aniline, thienylpyridine, isothiazole, 2-thienyl, 3-thienyl, benzothiophenyl, benzisothiazole, 3-amino-4-pyridine, thiophene, isoquinoline, pyrrazole, pyrrolidine, benzimidazole, indole, indazole, pyrimidine, 2,3- dihydrobenzo[6]thiophene, thiochromane, and the like.

The term "arylalkoxy" refers to an alkoxy group substituted with an aryl group.

The term "arylamino" refers to an aryl group having an amino attached thereto.

The term "aryloxy" refers to an aryl group having an oxygen attached thereto.

The term "aryloxyalkyl" refers to an alkyl group having an aryloxy attached thereto. The term "aryloxyalkoxy" refers to an alkoxy group having an aryloxy attached thereto. The term "azido" is art-recognized and refers to the group— =N ⁺=N .

The term "carbamate" is art-recognized and refers to a group wherein R and R independently represent hydrogen or a hydrocarbyl group, such an alkyl group, or R ²⁹ and R ³⁰ taken together with the intervening atom(s) complete ; heterocycle having from 4 to 12 atoms in the ring structure.

The term "carbamoyl" refers to a group

The term "carbamoylaminoalkyl" refers to an aminoalkyl group having a carbamoyl attached thereto.

The terms "carbocycle," and "carbocyclic," as used herein, refers to a saturated or unsaturated ring in which.each atom of the ring is carbon. The term carbocycle includes both aromatic carbocycles and non-aromatic carbocycles. Non-aromatic carbocycles include both cycloalkane rings, in which all carbon atoms are saturated, and cycloalkene rings, which contain at least one double bond. "Carbocycle" includes 5-7 membered monocyclic and 8- 12 membered bicyclic rings. Each ring of a bicyclic carbocycle may be selected from saturated, unsaturated and aromatic rings.

Carbocycle includes bicyclic molecules in which one, two or three or more atoms are shared between the two rings. The term "fused carbocycle" refers to a bicyclic carbocycle in which each of the rings shares two adjacent atoms with the other ring. Each ring of a fused carbocycle may be selected from saturated, unsaturated and aromatic rings. In an exemplary embodiment, an aromatic ring, e.g., phenyl, may be fused to a saturated or unsaturated ring, e.g., cyclohexane, cyclopentane, or cyclohexene. Any combination of saturated, unsaturated and aromatic bicyclic rings, as valence permits, is included in the definition of carbocyclic. Exemplary

"carbocycles" include cyclopentane, cyclohexane, bicyclo[2.2.1]heptane, 1 ,5- cyclooctadiene, 1 ,2,3,4-tetrahydronaphthalene, bicyclo[4.2.0]oct-3-ene, naphthalene and adamantane. Exemplary fused carbocycles include decalin, naphthalene, 1 ,2,3,4- tetrahydronaphthalene, bicyclo[4.2.0]octane, 4,5,6,7-tetrahydro- lH-indene and bicyclo[4.1.0]hept-3^ene. "Carbocycles" may be susbstituted at any one or more positions capable of bearing a hydrogen atom.

The terms "carbocyclylalkyl" or "cycloalkylalkyl," as used herein, refer to an alkyl group substituted with a carbocycle group. The term "carbonate" is art-recognized and refers to a group -OC0 ₂-R|, wherein Ri represents a hydrocarbyl group.

The term "carboxy," as used herein, refers to a group represented by the

formula -C0 ₂H.

The term "cyano" is art-recognized and refers to the group— CN. The term "cyanato" is art-recognized and refers to the group— O— CN.

The term "cycloalkanediyl" refers to an optionally substituted divalent radical derived from a cyclic hydrocarbon which is completely saturated.

A "cycloalkyl" group is a cyclic hydrocarbon which is completely saturated.

"Cycloalkyl" includes monocyclic and bicyclic rings. Typically, a monocyclic cycloalkyl group has from 3 to about 10 carbon atoms, more typically 3 to 8 carbon atoms unless otherwise defined. The second ring of a bicyclic cycloalkyl may be selected from saturated, unsaturated and aromatic rings. Cycloalkyl includes bicyclic molecules in which one, two or three or more atoms are shared between the two rings. The term "fused cycloalkyl" refers to a bicyclic cycloalkyl in which each of the rings shares two adjacent atoms with the other ring. The second ring of a fused bicyclic cycloalkyl may be selected from saturated, unsaturated and aromatic rings. A

"cycloalkenyl" group is a cyclic hydrocarbon containing one or more double bonds. The term "cycloalkylacyl" refers to an acyl group substituted with a cycloalkyl group.

The term "cycloalkylalkanediyl" refers to an optionally substituted divalent radical derived from an alkyl group substituted with a carbocycle group.

The term "cycloalkylalkylamino" refers to an alkylamino group substituted with a cycloalkyl group.

The term "cycloalkylaminoalkyl" refers to an aminoalkyl group-substituted with a cycloalkyl group.

The term "cycloalkylheteroalkanediyl" refers to an optionally substituted divalent radical derived from a heteroalkyl group substituted with a carbocycle group. The term " 1 , 1 -dialkylcycloalkanediyl" refers to an optionally substituted divalent radical derived from a cycloalkyl ring structure modified at the same position with two alkyl groups.

The term "ester," as used herein, refers to a group -C(0)OR ³° wherein R ³⁰ represents a hydrocarbyl group. The term "ether," as used herein, refers to a hydrocarbyl group linked through an oxygen to another hydrocarbyl group. Accordingly, an ether substituent of a hydrocarbyl group may be hydrocarbyl-O-. Ethers may be either symmetrical or unsymmetrical. Examples of ethers include, but are not limited to, heterocycle-O- heterocycle and aryl-O-heterocycle. Ethers include "alkoxyalkyl" groups, which may be represented by the general formula alkyl-O-alkyl.

The term "formyl" is art-recognized and refers the group— (CO)— H.

The terms "halo" and "halogen" as used herein means halogen and includes chloro, fluoro, bromo, and iodo.

The term "heteroalkanediyl" refers to an optionally substituted divalent radical derived from a saturated or unsaturated chain of carbon atoitis and at least one heteroatom. The term "heteroalkenediyi" refers to an optionally substituted divalent radical derived from a chain of carbon atoms containing at least one double bond and at least one heteroatom.

The term "heteroalkyl," as used herein, refers to a saturated or unsaturated chain of carbon atoms and at least one heteroatom, wherein no two heteroatoms are adjacent.

The term "heteroalkylcycloalkylheteroalkanediyl" refers to an optionally substituted divalent radical derived from a heteroalkyl group substituted with a carbocycle group which is substituted with a heteroalkyl group.

The term "heteroalkylcycloalkenylheteroalkanediyl" refers to an optionally substituted divalent radical derived from a heteroalkyl group substituted with a cycloalkenyl group which is substituted with a heteroalkyl group.

The term "heteroalkylheterocyclylheteroalkanediyl" refers to an optionally substituted divalent radical derived from a heteroalkyl group substituted with a heterocyclyl group which is substituted with a heteroalkyl group. The terms "heteroaryl" and "hetaryl" include substituted or unsubstituted aromatic single ring structures, preferably 5- to 7-membered rings, more preferably 5- to 6- membered rings, whose ring structures include at least one heteroatom, preferably one to four heteroatoms, more preferably one or two heteroatoms. The terms "heteroaryl" and "hetaryl" also include polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is heteroaromatic, e.g., the other cyclic rings can be cycloalkyls,

cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls. Heteroaryl groups include, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrazine, pyridazine, and pyrimidine, and the like. The terms "heteroarylalkyl," "hetaralkyl," and "heteroaralkyl," as used herein, refer to an alkyl group substituted with a hetaryl group. The term "heteroarylalkoxy" refers to an alkoxy group substituted with a heteroaryl group.

The term "heteroarylamino" refers to a heteroaryl group having an amino attached thereto. The term "heteroaryloxy" refers to a heteroaryl group having an oxygen attached thereto.

The term "heteroaryloxyalkyl" refers to an alkyl group having a heteroaryloxy attached thereto.

The term "he.teroaryloxyalkoxy" refers to an alkoxy group having a heteroaryloxy attached thereto.

The term "heteroatom" as used herein means an atom of any element other than carbon or hydrogen. Exemplary heteroatoms are nitrogen, oxygen, and sulfur.

The term "heterocyclylalkanediyl" refers to an optionally substituted divalent radical derived from a ring structure including at least one heteroatom. The term "heterocyclylheteroalkanediyl" refers to an optionally substituted divalent radical derived from a heteroalkyl group substituted with a ring structure including at least one heteroatom.

The terms "heterocyclyl," "heterocycle," and "heterocyclic" refer to substituted or unsubstituted non-aromatic ring structures, preferably 3- to 10-membered rings, more preferably 3- to 7-membered rings, whose ring structures include at least one heteroatom, preferably one to four heteroatoms, more preferably one or two heteroatoms. The terms "heterocyclyl" and "heterocyclic" also include polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is heterocyclic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls. Heterocyclyl groups include, for example, piperidine, piperazine, pyrrolidine, morpholine, lactones, lactams, azepane, and the like.

The term "heterocyclylalkyi," as used herein, refers to an alkyl group substituted with a heterocycle group. The term "heterocyclylalkylamino," as used herein, refers to an alkylamino group substituted with a heterocycle group.

The term "hydrocarbyl," as used herein, refers to a group that is bonded to the base scaffold through a carbon atom that does not have a =0 or =S substituent, and typically has at least one carbon-hydrogen bond and a primarily carbon backbone, but may optionally include heteroatoms. Thus, groups like methyl, ethoxyethyl, 2-pyridyl, and trifluoromethyl are considered to be hydrocarbyl for the purposes of this application, but substituents such as acetyl (which has a =0 substituent on the linking carbon) and ethoxy (which is linked through oxygen, not carbon) are not.

Hydrocarbyl groups include, but are not limited to aryl, heteroaryl, carbocycle, heterocyclyl, alkyl, alkenyl, alkynyl, and combinations thereof.

The term "hydroxyl," as used herein, refers to an -OH group.

The term "hydroxyalkyl," as used herein, refers to an alkyl group substituted with a hydroxy group.

The term "imino" is art-recognized and refers to the group represented by— CRi=NH, wherein Ri is selected from the group comprising hydrogen or hydrocarbyl.

The term "isocyanato" is art-recognized and refers to the group— O— N ⁺=C ^~.

The term "isocyano" is art-recognized and refers to the group— N ⁺C ^~.

The term "isothiocyanate" is art-recognized and refers to the group -NCS.

The term "lower" when used in conjunction with a chemical moiety, such as, acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy is meant to include groups where there are ten or fewer non-hydrogen atoms in the substituent, preferably six or fewer. A "lower alkyl," for example, refers to an alkyl group that contains ten or fewer carbon atoms, preferably six or fewer. In some embodiments, acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy substituents defined herein are respectively lower acyl, lower acyloxy, lower alkyl, lower alkenyl, lower alkynyl, or lower alkoxy, whether they appear alone or in combination with other substituents, such as in the recitations hydroxyalkyl and aralkyl (in which case, for example, the atoms within the aryl group are not counted when counting the carbon atoms in the alkyl substituent).

The term "nitro" is art-recognized and refers to the group represented by -N0 ₂. The term "nitroso" is art-recognized and refers to the group represented by -NO.

The term "oxyalkoxydiyl" refers to an optionally substituted divalent radical derived from an alkoxy group substituted with oxygen at the end of the alkyl chain.

The term "phosphono" is art-recognized and refers to the group represented by— P(0)(OH) ₂. The term "phosphonato" is art-recognized and refers to the group represented by— P(0)(0-) ₂.

The term "phosphinato" is art-recognized and refers to the group represented by— P(0)(CT).

The term "phospho" is art-recognized and refers to the group represented by— P0 ₂. The term "phosphino" is art-recognized and refers to the group represented by— PH ₂.

The terms "polycyclyl," "polycycle," and "polycyclic" refer to two or more rings (e.g., cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls) in which two or more atoms are common to two adjoining rings, e.g., the rings are "fused rings". Each of the rings of the polycycle can be substituted or unsubstituted. In some embodiments, each ring of the polycycle contains from 3 to 10 atoms in the ring, preferably from 5 to 7. The term "silyl" refers to a silicon moiety with three hydrocarbyl moieties attached thereto.

The term "sulfate" is art-recognized and refers to the group -OSO ₃H, or a

pharmaceutically acceptable salt thereof. The term "sulfonamide" is art-recognized and refers to the group represented by the general formulae

wherein R and R independently represents hydrogen or hydrocarbyl, such as alkyl, or R ²⁹ and R ³⁰ taken together with the intervening atom(s) complete a heterocycle having from 4 to 12 atoms in the ring structure.

The term "sulfoxide" is art-recognized and refers to the group -S(0)-R ³⁰, wherein R ³⁰ represents a hydrocarbyl.

The terms "sulfonate" or "sulfo" is art-recognized and refers to the group SO3H, or a pharmaceutically acceptable salt thereof. The terms "sulfone" or "alkylsulfonyl" are art-recognized and refer to the

group -S(0) ₂-R ³⁰, wherein R ³⁰ represents a hydrocarbyl.

The term "thioalkyl," as used herein, refers to an alkyl group substituted with a thiol group.

The term "thiocarbamoyl" is art-recognized and efers to the group— (CS)— NH ₂. The term "thiocyanate" is art-recognized and refers to the group -SCN.

The term "thioester," as used herein, refers to a group -C(0)SR ³⁰ or -SC(0)R ³⁰ wherein R ³⁰ represents a hydrocarbyl. The term "thioether," as used herein, is equivalent to an ether, wherein the oxygen is replaced with a sulfur.

The term "urea" is art-recognized and may be represented by the general formula

R ²⁹ R ²⁹ wherein R ²⁹ and R ³⁰ independently represent hydrogen or a hydrocarbyl, such as alkyl, or either occurrence of R ²⁹ taken together with R ³⁰ and the intervening atom(s) complete a heterocycle having from 4 to 12 atoms in the ring structure.

The term "substituted" refers to moieties having substituents replacing a hydrogen on one or more carbons of the backbone. It will be understood that "substitution" or "substituted with" includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. As used herein, the term "substituted" is contemplated to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non- aromatic substituents of organic compounds. The permissible substituents can be one or more and the same or different for appropriate organic compounds. For purposes of this application, the heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms.

Substituents can include any substituents described herein, for example, but not limited to, a halogen, a hydroxyl, a carbonyl (such as a carboxyl, an alkoxycarbonyl, a formyl, or an acyl), a thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), an alkoxyl, a phosphoryl, a phosphate, a phosphonate, a phosphinate, an amino, an amido, an amidine, an imine, a cyano, a nitro, an azido, a sulfhydryl, an alkylthio, a sulfate, a sulfonate, a sulfamoyl, a sulfonamido, a sulfonyl, a heterocyclyl, an aralkyl, or an aromatic or heteroaromatic moiety. It will be understood by those skilled in the art that substituents can themselves be substituted, if appropriate. Unless specifically stated as "unsubstituted," references to chemical moieties herein are understood to include substituted variants. For example, reference to an "aryl" group or moiety implicitly includes both substituted and unsubstituted variants.

"Protecting group" refers to a group of atoms that, when attached to a reactive functional group in a molecule, mask, reduce or prevent the reactivity of the functional group. Typically, a protecting group may be selectively removed as desired during the course of a synthesis. Examples of protecting groups can be found in Greene and

Wuts, Protective Groups in Organic Chemistry, 3 ^rd Ed., 1999, John Wiley & Sons, NY and Harrison, et ah, Compendium of Synthetic Organic Methods, Vols. 1 -8, 1971 - 1996, John Wiley & Sons, NY. Representative nitrogen protecting groups include, but are not limited to, formyl, acetyl, trifluoroacetyl, benzyl, benzyloxycarbonyl ("CBZ"), tert-butoxycarbonyl ("Boc"), trimethylsilyl ("TMS"), 2-trimethylsilyl-ethanesulfonyl ("TES"), trityl and substituted trityl groups, allyloxycarbonyl, 9- fluorenylmethyloxycarbonyl ("FMOC"), nitro-veratryloxycarbonyl ("NVOC") and the like. Representative hydroxyl protecting groups include, but are not limited to, those where the hydroxyl group is either acylated (esterified) or alkylated such as benzyl and trityl ethers, as well as alkyl ethers, tetrahydropyranyl ethers, trialkylsilyl ethers (e.g., TMS or TIPS groups), glycol ethers, such as ethylene glycol and propylene glycol - derivatives and allyl ethers.

"Optional" or "optionally" means that the subsequently described circumstance may or may not occur, so that the application includes instances where the circumstance occurs and instances where it does not. For example, the phrase "optionally substituted" means that a non-hydrogen substituent may or may not be present on a given atom, and, thus, the application includes structures wherein a non-hydrogen substituent is present and structures wherein a non-hydrogen substituent is not present. The term "stability," "stable," "stable compound," or "stable structure" in the context of a chemical structure refers to the chemical state when a system is in its lowest energy state, or in chemical equilibrium with its environment. Thus, a stable compound (or, e.g. , a compound containing a number of atoms or substitutions that are stable) is not particularly reactive in the environment or during normal use, and retains its useful properties on the timescale of its expected usefulness. A stable compound is sufficiently robust to survive isolation, and as appropriate, purification from a reaction mixture, and formulation into an efficacious therapeutic agent.

The terms "free compound" or "free base" are used herein to describe a compound in the unbound state. Where a compound of this disclosure is provided as a

pharmaceutically acceptable salt, the free base form of the compound is also contemplated and the disclosed salt form should not be considered as limiting. All such free base forms are intended to be included in the embodiments of this disclosure, even where a salt form of a compound of this disclosure is specifically indicated. The term "derivative" refers to compounds that have a common core structure, and are substituted with various groups as described herein.

The term "analogue" refers to a chemical compound that is structurally similar to another but differs slightly in composition (as in the replacement of one atom by an atom of a different element or in the presence of a particular functional group, or the replacement of one functional group by another functional group). Thus, an analogue is a compound that is similar or comparable in function and appearance, but not in structure or origin to the reference compound.

The term "small molecule" is an art-recognized term. In some embodiments, this term refers to a molecule, which has a molecular weight of less than about 2000 amu, or less than about 1000 amu, and even less than about 500 amu.

The term "healthcare providers" refers to individuals or organizations that provide healthcare services to a person, community, etc. Examples of "healthcare providers" include doctors, hospitals, continuing care retirement communities, skilled nursing facilities, sub acute care facilities, clinics, multispecialty clinics, freestanding ambulatory centers, home health agencies, and HMO's.

The terms "IC ₅o," or "half maximal inhibitory concentration" is intended to refer to the concentration of a substance (e.g., a compound or a drug) that is required for 50% inhibition of a biological process, or component of a process, including a protein, subunit, organelle, ribonucleoprotein, etc.

The terms "EC50" or "half maximal effective concentration" refers to the concentration of a compound, moleule, or drug, which induces a response halfway between the baseline and maximum after a specified exposure time. The terms "healthy" and "normal" are used interchangeably herein to refer to a subject or particular cell or tissue that is devoid (at least to the limit of detection) of a disease condition.

Compounds

Embodiments of this disclosure relate to compounds that, in some embodiments, are useful for treating or preventing one or more conditions selected from: pain; an inflammatory disease or disorder, an allergic disease or disorder, a metabolic disease, a cardiovascular disease or disorder, a neurogenic vascular disease or a painful condition associated with any of the foregoing conditions; an episodic tension-type headache; a migraine headache; a headache; cramping; a cognitive disorder; a tension or migraine headache due to a vascular, neurovascular, or neurogenic disorder or dysfunction during a menstrual cycle episode; a tension or migraine headache due to a vascular, neurovascular, or neurogenic disorder or dysfunction during a migraine episode; a headache from mild to moderate hypertension; mild to moderate essential hypertension; organ transplant rejection; hot and cold flashes; traumatic brain injury (TBI); neurotoxicity; psychic pain; psychological pain; psychiatric pain; depression; schizophrenia; anxiety; epilepsy; a stress disorder; excess sweating; a symptom related to drug withdrawal; allodynia; fibromyalgia; fibromyalgia-ness; central sensitization; centralization; regional pain syndrome; temporomandibular joint syndrome (TMJ); lower back pain; interstitial cystitis; Gulf War syndrome; visceral pain; kidney stones; gout; neuropathic pain; post-herpetic neuralgia; diabetic neuropathy; sickle cell pain; priapism; nociceptive pain; post-operative pain; orthopedic injury pain; phantom limb pain; bunionectomy; dental extraction; pain after severed spinal cord injury;

osteoarthritis; rheumatoid arthritis; Lyme disease; Parkinson's disease; pain associated with cancer; opioid-induced constipation; an opioid withdrawal symptom; or pain associated with post-traumatic stress disorder (PTSD). The compounds of this disclosure are also useful as analgesics. In some embodiments, the compounds of this disclosure are ligands of the imidazoline-1 (L) receptor. In some embodiments, the compounds of this disclosure modulate the I i receptor. In some embodiments, the compounds of this disclosure modulate the I i receptor to reduce pain. Without wishing to be bound by theory, in some embodiments, the compounds of this disclosure activate the Ii receptor to reduce pain. In some embodiments, the compounds of this disclosure reduce pain through a pathway that is independent of the I i receptor (the Imidazoline-1 Receptor-Independent Isometheptene Pain Modulatory pathway, or IRIPM pathway).

The compounds in accordance with the various embodiments of this disclosure can be used alone or simultaneously, separately, or sequentially in combination with each other or with acetaminophen, a non-steroidal anti-inflammatory drug (NSAID), ibuprofen, naprosyn, a cyclooxygenase-2 inhibitor, aspirin, caffeine,

dichloralphenazone, a triptan, a chemotherapeutic drug, an antidepressant, a serotonin-norepinephrine reuptake inhibitor (SNRI), a gabapentinoid, an

antiproliferative agent, an anti-inflammatory agent, a corticosteroid, an anti-asthmatic agent, an anti-allergic agent, an immunosuppressive agent, an immunomodulatory agent, a cardiovascular disease treatment agent, an anti-diabetic agent, a blood disorder treatment agent, a nerve growth factor receptor antagonist, a sodium channel blocker, a CYP2D6 inhibitor, a TNF-alpha inhibitor, one or more opiates, or a combination of any of the foregoing therapeutics for the treatment of the conditions disclosed herein. Analgesic and pain reduction activity of the compounds of this disclosure that is modulated through the Ii receptor can be evaluated by determining trigeminal von Frey thresholds in spontaneous trigeminal allodynia (STA) rats, as described herein. Therapeutic activity of the compounds described herein can also be evaluated using rats in an inflammatory soup model of chronic migraine and an opiate-like dependence model with the naloxone-precipitated withdrawal (Saelens) test in mice. The analgesic potential of the compounds described herein can also be evaluated using a monosodium iodacetate (MIA) induced model of osteoarthritic pain in adult male rats. To assess the rescue efficacy of the compounds described herein for the reversal of cutaneous allodynia, sumatriptan-induced medication overuse headache (MOH) can be triggered by nitric oxide (NO) donors in rats. Other methods known or developed in the art may be similarly used.

Analgesic and pain reduction activity of the compounds described herein that are modulated through the IRIPM pathway can be evaluated in a rat chronic constrictive nerve injury (CCI) model of neuropathic pain or a rat model of bortezomib-induced neuropathy, also described herein. Additionally, the analgesic and pain reduction activity of the compounds described herein that is modulated through the IRIPM pathway can be identified using the mouse formalin, hot plate, and tail-flick tests. Binding of the compounds described herein to the I | receptor can be determined through radioligand binding competition assays. Evaluation of the impact of 11 receptor agonists and antagonists on forskolin-stimulated cAMP induction can be conducted using a functional assay for the Ii receptor with PC- 12 cells or a transiently- expressing or stably-expressing I | receptor cell line. Other methods known or developed in the art may be similarly used. Stability of the compounds of this disclosure can be assessed, inter alia, using pharmacokinetic studies in animals such as dogs, rats, and humans.

In some embodiments, the compounds of this disclosure are represented by general formula (SC-01 ):

SC-01 or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, or solvate thereof, wherein as valence and stability permit:

L ¹ is a 4 to 10 carbon atom linker selected from the group consisting of optionally substituted alkanediyl, heteroalkanediyl, cycloalkanediyl,

heterocyclylalkanediyl, cycloalkylalkanediyl, cycloalkylheteroalkanediyl, alkenediyl, alkynediyl, alkylthiodiyl, and 1 , 1 -dialkylcycloalkanediyl;

W is selected from the group consisting of N and CH;

Y is selected from the group consisting of CH ₂, NH, O, and S;

R ¹ is selected from the group consisting of hydrogen and optionally substituted alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, heteroaryl, alkoxycycloalkyl, cycloalkyl, and heterocyclyl; and

R ² is selected from the group consisting of hydrogen and optionally substituted alkyl; wherein L ¹ can be linked with R ¹ , R ² or both R ¹ and R ² to form a monocyclic,

bicyclic, or polycyclic ring, wherein the ring is selected from the group consisting of optionally substituted cycloalkyl and optionally substituted heterocyclyl;

wherein L ¹ can be linked with R ¹ or R ² to form a moiety selected from the group

consisting of optionally substituted cycloalkylalkanediyl,

heterocyclylalkanediyl, cycloalkylheteroalkanediyl, and

heterocyclylheteroalkanediyl.

In some embodiments W is N and Y is CH ₂. In some embodiments when W is N and

Y is CH ₂, R ¹ and R ² are each hydrogen. In some embodiments when W is N, Y is CH ₂, and R ¹ and R ² are each hydrogen, L ¹ is an optionally substituted cycloalkanediyl. In some embodiments W is N, Y is CH ₂, R ² is hydrogen, and L ¹ is linked with R ¹ to form a monocyclic optionally substituted heterocyclyl. In some embodiments W is CH and Y is NH. In some embodiments when W is CH and Y is NH, R ¹ and R ² are each an optionally substituted alkyl. In some

embodiments when W is CH, Y is NH, and R ¹ and R ² are each an optionally substituted alkyl, L ¹ is an optionally substituted 1 , 1 -dialkylcycloalkanediyl. In some embodiments W is N and Y is NH. In some embodiments when W is N and Y is NH, R ¹ is an optionally substituted alkenyl and R ² is hydrogen. In some embodiments when W is N, Y is NH, R ¹ is an optionally substituted alkenyl, and R ² is hydrogen, L ¹ is an optionally substituted alkanediyl.

In some embodiments, R ¹ is an optionally substituted cycloalkyl. In certain such embodiments, R ¹ is an optionally substituted alkoxycycloalkyl.

In some embodiments, L ¹ is selected from the group consisting of optionally substituted alkynediyl and alkylthiodiyl.

In some embodiments, L ¹ and R ² are linked to form a bicyclic optionally substituted heterocyclyl. In some embodiments, L ¹ and R ² are linked to form an optionally substituted cycloalkylalkanediyl.

In some embodiments, L ¹, R ¹ , and R ² are linked to form a bicyclic optionally substituted heterocyclyl.

In some embodiments, the compounds represented by formula (SC-01 ) are selected from a group of compounds having the formula:

of any of the foregoing compounds. For example, the compounds are selected from a group of compounds having the formula 131-137, 143, 144, 183, 197, or 201, or a pharmaceutically acceptable salt, tautomer, enantiomer, disastereomer, or solvate of any of the foregoing compounds. In some embodiments, the compounds are selected from a group of compounds having the formula 131, 133, 143, or 144, or a pharmaceutically acceptable salt, tautomer, or solvate of any of the foregoing compounds.

In some embodiments, the compounds of this disclosure are represented by general formula (SC-02):

SC-02 or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, or solvate thereof, wherein as valence and stability permit:

Y is selected from the group consisting of CH ₂ and NH;

R ¹ is selected from the group consisting of hydrogen and optionally substituted alkyl, heteroalkyl, and aminoalkyl; and

Ar is selected from the group consisting of optionally substituted aryl and heteroaryl.

In some embodiments, the compound of formula (SC-02) is the S-enantiomer.

In some embodiments, Y is CH ₂. In some embodiments when Y is CH ₂, R ¹ is an optionally substituted alkyl. In some embodiments when Y is CH ₂ and R ¹ is an optionally substituted alkyl, Ar is an optionally substituted aryl. In some

embodiments when Y is CH ₂, R ¹ is an optionally substituted alkyl and Ar is an optionally substituted heteroaryl. In some embodiments when Y is CH ₂, R ¹ is an optionally substituted aminoalkyl and Ar is an optionally substituted aryl. In some embodiments when Y is CH ₂, R ¹ is an optionally substituted aminoalkyl and Ar is an optionally substituted heteroaryl. In certain such embodiments, the compound of formula (SC-02) is the S-enantiomer.

In some embodiments, Y is NH. In some embodiments when Y is NH, R ¹ is hydrogen and Ar is an optionally substituted aryl. In some embodiments when Y is NH, R ¹ is an optionally substituted alkyl and Ar is an optionally substituted aryl. In certain such embodiments, the compound of formula (SC-02) is the S-enantiomer.

In some embodiments, when Ar is an optionally substituted aryl, it is selected from phenyl, 4-bromophenyl, and 3-bromophenyl. In some embodiments, when Ar is an optionally substituted heteroaryl, it is selected from 2-thienyl and 3-thienyl.

In some embodiments, the compounds represented by formula (SC-02) are selected from a group of compounds having the formula:

or a p armaceut ca y accepta e sa t, tautomer, enant omer, sastereomer, or so vate of any of the foregoing compounds. For example, the compounds are selected from a group of compounds having the formula 93, 96, 147, 148, 164, 165, 182, 221, or 222, or a pharmaceutically acceptable salt, tautomer, enantiomer, disastereomer, or solvate of any of the foregoing compounds. In some embodiments, the compounds are selected from a group of compounds having the formula 96, 164, 165, or 222, or a pharmaceutically acceptable salt, tautomer, enantiomer, disastereomer, or solvate of any of the foregoing compounds.

Compounds of formula (SC-02) comprise a 1 ,3-diazepine-type core and compounds of formula (SC-05) comprise an imidazoline core. Unexpectedly, the 1 ,3-diazepine-type core compounds appear to be more polar than the imidazoline core compounds, despite the addition of two carbon units to the ring.

In some embodiments, the compounds of this disclosure are represented by general formula (SC-03):

SC-03 or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, or solvate thereof, wherein as valence and stability permit:

R ¹ is selected from the group consisting of hydrogen and optionally substituted alkyl and heteroalkyl; and

Ar is selected from the group consisting of optionally substituted aryl and heteroaryl.

In some embodiments, the compound of formula (SC-03 ¹) is the S-enantiomer.

In some embodiments, R ¹ is hydrogen and Ar is an optionally substituted aryl. In certain such embodiments, the compound of formula (SC-03) is the S-enantiomer. In some embodiments, R ¹ is hydrogen and Ar is an optionally substituted heteroaryl. In certain such embodiments, the compound of formula (SC-03) is the S-enantiomer.

In some embodiments, R ¹ is an optionally substituted alkyl and Ar is an optionally substituted aryl. In certain such embodiments, the compound of formula (SC-03) is the S-enantiomer. In some embodiments, R ¹ is an optionally substituted alkyl and Ar is an optionally substituted heteroaryl. In certain such embodiments, the compound of formula (SC-03) is the S-enantiomer.

In some embodiments, R ¹ is hydrogen and Ar is phenyl. In certain such embodiments, the compound of formula (SC-03) is the S-enantiomer. In some embodiments, R ¹ is an optionally substituted alkyl and Ar is phenyl. In certain such embodiments, the compound of formula (SC-03) is the S-enantiomer.

In some embodiments, the compound represented by formula (SC-03) is:

or a pharmaceutically acceptable salt, tautomer, or solvate thereof.

In some embodiments, the compounds of this disclosure are represented by general formula (SC-04):

SC-04 or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, or solvate thereof, wherein as valence and stability permit:

R ¹ and R ² are independently selected from the group consisting of hydrogen and optionally substituted alkyl, heteroalkyl, alkoxy, aminoalkyl, arylalkyl, heteroarylalkyl, arylalkoxy, and heteroarylalkoxy; and

Ar is selected from the group consisting of optionally substituted aryl and heteroaryl; wherein R ¹ and R ² can optionally form a monocyclic, bicyclic or polycyclic ring, wherein the ring is selected from the group consisting of optionally substituted cycloalkyl and optionally substituted heterocyclyl.

In some embodiments, the compound of formula (SC-04) is the S-enantiomer.

In some embodiments, R ¹ and R ² are hydrogen and Ar is an optionally substituted aryl. In certain such embodiments, the compound of formula (SC-04) is the S- enantiomer. In some embodiments, R ¹ and R ² are hydrogen and Ar is an optionally substituted heteroaryl. In certain such embodiments, the compound of formula (SC-04) is the S- enantiomer.

In some embodiments, R ¹ is an optionally substituted alkyl, R ² is hydrogen, and Ar is an optionally substituted aryl. In certain such embodiments, the compound of formula (SC-04) is the S-enantiomer.

In some embodiments, R ¹ is an optionally substituted alkyl, R ² is hydrogen, and Ar is an optionally substituted heteroaryl. In certain such embodiments, the compound of . formula (SC-04) is the S-enantiomer. In some embodiments, R ¹ is an optionally substituted aminoalkyl, R ² is an optionally substituted alkyl, and Ar is an optionally substituted aryl. In certain such

embodiments, the compound of formula (SC-04) is the S-enantiomer.

In some embodiments, R ¹ is an optionally substituted aminoalkyl, R ² is an optionally substituted alkyl, and Ar is an optionally substituted heteroaryl. In certain such embodiments, the compound of formula (SC-04) is the S-enantiomer.

In some embodiments, R ¹ is an optionally substituted alkoxy, R ² is hydrogen, and Ar is an optionally substituted aryl. In certain such embodiments, the compound of formula (SC-04) is the S-enantiomer.

In some embodiments, R ¹ is an optionally substituted alkoxy, R ² is hydrogen, and Ar is an optionally substituted heteroaryl. In certain such embodiments, the compound of formula (SC-04) is the S-enantiomer.

In some embodiments, R ¹ is an optionally substituted arylalkoxy, R ² is hydrogen, and Ar is an optionally substituted aryl. In certain such embodiments, the compound of formula (SC-04) is the S-enantiomer. In some embodiments, R ¹ is an optionally substituted arylalkoxy, R ² is hydrogen, and Ar is an optionally substituted heteroaryl. In certain such embodiments, the compound of formula (SC-04) is the S-enantiomer.

In some embodiments, R ¹ and R ² form an optionally substituted cycloalkyi. In certain such embodiments, the compound of formula (SC-04) is the S-enantiomer.

In some embodiments when Ar is an optionally substituted aryl, Ar is a substituted phenyl. In certain such embodiments, the phenyl group is substituted at the 3 or the 4 position with halogen, -SCF ₃, or optionally substituted alkyl. In certain such embodiments, the compound of formula (SC-04) is the S-enantiomer. In some embodiments, the compounds represented by formula (SC-04) are selected from a group of compounds having the formula:

or a pharmaceutically acceptable salt, enantiomer, disastereomer, tautomer, or solvate of any of the foregoing compounds. For example, the compounds are selected from a group of compounds having the formula 112, 145, 157, 160, 161, 162, 163, 176, or 198, or a pharmaceutically acceptable salt, tautomer, enantiomer, disastereomer, or solvate of any of the foregoing compounds. In some embodiments, the compounds are selected from a group of compounds having the formula 160, 161, 162, 163, or 176, or a pharmaceutically acceptable salt, tautomer, enantiomer, disastereomer, or solvate of any of the foregoing compounds.

In some embodiments, the compounds of this disclosure are represented by general formula (SC-05):

SC-05 or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, or solvate thereof, wherein as valence and stability permit:

R ¹ is selected from the group consisting of hydrogen and optionally substituted alkyl, heteroalkyl, aminoalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

R ² is selected from the group consisting of optionally substituted alkyl, heteroalkyl, aminoalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

R ³ is selected from the group consisting of hydrogen and optionally substituted alkyl, heteroalkyl, aminoalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; and

Ar is selected from the group consisting of optionally substituted aryl and heteroaryl. In some embodiments, the compound of formula (SC-05) is the S-enantiomer. In some embodiments, R ¹ and R ³ are each hydrogen. In some embodiments when R ¹ and R ³ are each hydrogen, R ² is an optionally substituted alkyl and Ar is an optionally substituted aryl. In some embodiments when R ¹ and R ³ are each hydrogen, R ² is an optionally substituted alkyl and Ar is an optionally substituted heteroaryl. In some embodiments when R ¹ and R ³ are each hydrogen, R ² is an optionally substituted cycloalkyl and Ar is an optionally substituted aryl. In some embodiments when R ¹ and R ³ are each hydrogen, R ² is an optionally substituted cycloalkyl and Ar is an optionally substituted heteroaryl. In some embodiments when R ¹ and R ³ are each hydrogen, R ² is an optionally substituted aminoalkyl and Ar is an optionally substituted aryl. In some embodiments when R ¹ and R ³ are each hydrogen, R ² is an optionally substituted aminoalkyl and Ar is an optionally substituted heteroaryl. In certain such embodiments, the compound of formula (SC-05) is the S-enantiomer.

In some embodiments, R ¹ is an optionally substituted aminoalkyl and R ³ is hydrogen. In some embodiments when R ¹ is an optionally substituted aminoalkyl and R ³,is hydrogen, R ² is an optionally substituted alkyl and Ar is an optionally substituted aryl. In some embodiments when R ¹ is an optionally substituted aminoalkyl and R ³ is hydrogen, R ² is an optionally substituted alkyl and Ar is an optionally substituted heteroaryl. In certain such embodiments, the compound of formula (SC-05) is the S- enantiomer. In some embodiments, R ¹ is an optionally substituted hydroxyalkyl and R ³ is hydrogen. In some embodiments when R ¹ is an optionally substituted hydroxyalkyl and R is hydrogen, R is an optionally substituted alkyl and Ar is an optionally substituted aryl. In some embodiments when R ¹ is an optionally substituted hydroxyalkyl and R ³ is hydrogen, R ² is an optionally substituted alkyl and Ar is an optionally substituted heteroaryl. In certain such embodiments, the compound of formula (SC-05) is the S-enantiomer.

In some embodiments, R ¹ is an optionally substituted alkyl. In certain such embodiments, the compound of formula (SC-05) is the S-enantiomer. In some embodiments, R ³ is an optionally substituted hydroxyalkyl. In certain such embodiments, the compound of formula (SC-05) is the S-enantiomer.

In some embodiments, R ³ is an optionally substituted alkyl. In certain such

embodiments, the compound of formula (SC-05) is the S-enantiomer.

In some embodiments, R ³ is an optionally substituted aminoalkyl. In certain such embodiments, the compound of formula (SC-05) is the S-enantiomer.

In some embodiments when Ar is an optionally substituted aryl, R ¹ is hydrogen, and

2 2

R is an optionally substituted alkyl, Ar is not unsubstituted phenyl and R is not unsubstituted methyl.

In some embodiments when Ar is an optionally substituted heteroaryl, the heteroaryl is selected from an optionally substituted thienyl-pyridyl, isothiazole, 2-thienyl, 3-thienyl, benzothiophenyl, benzisothiazolo, or 3-amino-4-pyridyl.

In some embodiments, the compounds represented by formula (SC-05) are selected from a group of compounds having the formula:

or a pharmaceutically acceptable salt, a free base, a tautomer, enantiomer, disastereomer, or a solvate of any of the foregoing compounds. For example, the compounds are selected from a group of compounds having the formula 3, 33, 102, 103, 108, 123-130, 146, 153, 155, 158, 168, 185, 193-196, 220, or 360-368, or a pharmaceutically acceptable salt, a free base form, a tautomer, enantiomer, disastereomer, or a solvate of any of the foregoing compounds. In some

embodiments, the compounds are selected from a group of compounds having the formula 102, 103, 108, 123-130, 146, 153, 155, 158, 168, 185, 193-196, 220, or 360- 368, or a pharmaceutically acceptable salt, a free base form, a tautomer, enantiomer, disastereomer, or a solvate of any of the foregoing compounds. In some embodiments, the compounds are selected from a group of compounds having the formula 123-129, 146, 153, 158, 185, 193, 195, 220, 361, 364-366, or 368, or a pharmaceutically acceptable salt, a free base form, enantiomer, disastereomer, tautomer, or solvate of any of the foregoing compounds. In some embodiments, the compounds of this disclosure are represented by general formula (SC-06):

SC-06 or a pharmaceutically acceptable salt, diastereomer, enantiomer, tautomer, or solvate thereof, wherein as valence and stability permit: — represents a single or double bond;

R ¹ is selected from the group consisting of hydrogen and optionally substituted alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; and

R ² is selected from the group consisting of hydrogen and optionally substituted alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; wherein R ¹ and R ² can optionally form a ring, wherein the ring is selected from the group consisting of optionally substituted cycloalkyl, heterocyclyl, cycloalkenyl, aryl, and heteroaryl.

In some embodiments,— represents a single bond. In some embodiments,— represents a single bond and R is hydrogen. In some embodiments when— represents a single bond and R is hydrogen, R is an optionally substituted alkenyl.

In some embodiments, = represents a single bond and R ² is hydrogen. In some embodiments when— represents a single bond and R ² is hydrogen, R ¹ is an optionally substituted alkenyl.

In some embodiments,— represents a single bond and R ¹ and R ² form an optionally substituted cycloalkenyl.

In some embodiments, R ¹ and R ² form an optionally substituted aryl. In some embodiments, R ¹ is an optionally substituted alkyl.

In some embodiments, the compounds represented by formula (SC-06) are selected from a group of compounds having the formula:

229 or a pharmaceutically acceptable salt or solvate of any of the foregoing compounds. For example, the compounds are selected from a group of compounds having the formula 12 or 224-229, or a pharmaceutically acceptable salt or solvate of any of the foregoing compounds. In some embodiments, the compounds are selected from a group of compounds having the formula 224-228 or 229, or a pharmaceutically acceptable salt or solvate of any of the foregoing compounds. In some embodiments, the compounds are selected from a group of compounds having the formula 224-227 or 228, or a pharmaceutically acceptable salt or solvate of any of the foregoing compounds. ^ In some embodiments, the compounds of this disclosure are represented by general formula (SC-07):

SC-07 or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, or solvate thereof, wherein as valence and stability permit: Y is selected from the group consisting of NH and O;

R ¹, R ², R ³, and R ⁶ are independently selected from the group consisting of hydrogen, halogen and optionally substituted alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkoxy, alkynyloxy, alkylthio, -SCF ₃, and alkylamino; and R ⁴ and R ⁵ are independently selected from the group consisting of hydrogen and optionally substituted alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkoxy, alkylthio, and alkylamino; wherein R ¹ and R ⁴ or R ¹ and R ⁵ can optionally form a ring, wherein the ring is an optionally substituted heterocyclyl.

In some embodiments, the compound of formula (SC-07) is the S-enantiomer.

In some embodiments, Y is NH. In some embodiments when Y is NH, R ¹, R ², R ³, R ⁵ and R ⁶ are each hydrogen. In some embodiments when Y is NH and R ¹, R ², R ³, R ⁵ and R ⁶ are each hydrogen, R ⁴ is an optionally substituted alkyl. In certain such embodiments, the compound of formula (SC-07) is the S-enantiomer.

In some embodiments when Y is NH, R ², R ³, R ⁵, and R ⁶ are each hydrogen. In some embodiments when Y is NH and R ², R ³, R ⁵, and R ⁶ are each hydrogen, R ⁴ is an optionally substituted alkyl. In some embodiments when Y is NH and R ², R ³, R ⁵, and R ⁶ are each hydrogen, R ¹ is an optionally substituted alkylthio and R ⁴ is an optionally substituted alkyl. In some embodiments when Y is NH and R ², R ³, R ⁵, and R ⁶ are each hydrogen, R ¹ is -SCF ₃, and R ⁴ is an optionally substituted alkyl. In some embodiments when Y is NH and R ², R ³, R ⁵, and R ⁶ are each hydrogen, R ¹ is halogen and R ⁴ is an optionally substituted alkyl. In certain such embodiments, the compound of formula (SC-07) is the S-enantiomer.

In some embodiments, Y is O. In some embodiments when Y is O, R ¹, R ², R ³, R ⁵ and R ⁶ are each hydrogen. In some embodiments when Y is O and R ¹, R ², R ³, R ⁵ and R ⁶ are each hydrogen, R ⁴ is an optionally substituted alkyl. In some embodiments when Y is O and R ¹ , R ², R ³, R ⁵ and R ⁶ are each hydrogen, R ⁴ is an optionally substituted alkynyl. In certain such embodiments, the compound of formula (SC-07) is the S- enantiomer.

In some embodiments when Y is O, R ², R ³, R ⁵, and R ⁶ are each hydrogen. In some embodiments when Y is O and R ², R ³, R ⁵, and R ⁶ are each hydrogen, R ⁴ is an optionally substituted alkyl. In some embodiments when Y is O and R ², R ³, R ⁵, and R ⁶ are each hydrogen, R ¹ is an optionally substituted alkynyloxy and R ⁴ is an optionally substituted alkyl. In some embodiments when Y is O and R ², R ³, R ⁵, and R ⁶ are each hydrogen, R ¹ is an optionally substituted alkyloxy and R ⁴ is an optionally substituted alkyl. In some embodiments when Y is O and R ², R ³, R ⁵, and R ⁶ are each hydrogen, R ⁴ is an optionally substituted alkynyl. In some embodiments when Y is O, R ², R ³, R ⁵, and R ⁶ are each hydrogen, and R is an optionally substituted alkynyl, R is an optionally substituted alkyloxy. In certain such embodiments, the compound of formula (SC-07) is the S-enantiomer. In some embodiments when Y is O, R ¹, R ², R ³, and R ⁵ are each hydrogen. In some embodiments when Y is O, and R ¹, R ², R ³, and R ⁵ are each hydrogen, R ⁶ is halogen. In some embodiments when Y is O, R ¹, R ², R ³, and R ⁵ are each hydrogen, and R ⁶ is halogen, R ⁴ is an optionally substituted alkynyl. In certain such embodiments, the compound of formula (SC-07) is the S-enantiomer. In some embodiments when Y is O, R ³, R ⁵, and R ⁶ are each hydrogen. In some embodiments when Y is O and R ³, R ⁵, and R ⁶ are each hydrogen, R ¹ and R ² are each halogen. In some embodiments when Y is O, R ³, R ⁵, and R ⁶ are each hydrogen, and R ¹ and R ² are each halogen, R ⁴ is an optionally substituted alkyl. In some

embodiments when Y is O, R ³, R ^s, and R ⁶ are each hydrogen, and R ¹ and R ² are each halogen, R ⁴ is hydrogen. In certain such embodiments, the compound of formula (SC- 07) is the S-enantiomer.

In some embodiments, R ¹ is an optionally substituted alkyl. In certain such embodiments, the compound of formula (SC-07) is the S-enantiomer.

In some embodiments, R ⁵ is an optionally substituted alkyl. In certain such embodiments, the compound of formula (SC-07) is the S-enantiomer.

In some embodiments, R ³ is halogen. In certain such embodiments, the compound of formula (SC-07) is the S-enantiomer. In some embodiments, the compounds represented by formula (SC-07) are selected from a group of compounds having the formula:

or a p armaceut ca y accepta e sa t, enant omer, tautomer, or so vate o any o foregoing compounds. For example, the compounds are selected from a group of compounds having the formula 1, 2, 5, 20, 25, 28, 37, 38, 47, 223, 230, 231, 232, 233, 234, or 369-373, or a pharmaceutically acceptable salt, enantiomer, tautomer, or solvate of any of the foregoing compounds. In some embodiments, the compounds are selected from a group of compounds having the formula 223, 230-234, or 369-373, or a pharmaceutically acceptable salt, enantiomer, tautomer, or solvate of any of the foregoing compounds. In some embodiments, the compounds are selected from a group of compounds having the formula 223, 231-233, or 372, or a pharmaceutically acceptable salt, enantiomer, tautomer, or solvate of any of the foregoing compounds. In some embodiments, the compounds of this disclosure are represented by general formula (SC-08):

or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, or solvate thereof, wherein as valence and stability permit:

R ¹ and R ² are independently selected from the group consisting of optionally

substituted alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; and

R ³ and R ⁴ are independently selected from the group consisting of hydrogen and

optionally substituted alkyl, alkenyl, and alkynyl; wherein R ¹ and R ² can optionally form a ring, wherein the ring is selected from the group consisting of optionally substituted cycloalkyl, heterocyclyl, aryl, and heteroaryl.

In some embodiments, R ³ and R ⁴ are each hydrogen. In some embodiments when R ³ and R ⁴ are each hydrogen, R ¹ is an optionally substituted alkyl. In some embodiments when R ³ and R ⁴ are each hydrogen and R ¹ is an optionally substituted alkyl, R ² is an optionally substituted alkenyl. In some embodiments when R ³ and R ⁴ are each hydrogen, R ¹ is an optionally substituted alkenyl. In some embodiments when R ³ and R ⁴ are each hydrogen and is an optionally substituted alkenyl, R ² is an optionally substituted alkenyl.

In some embodiments when R ³ and R ⁴ are each hydrogen, R ¹ and R ² form an optionally substituted cycloalkyl.

In some embodiments, the compounds represented by formula (SC-08) are selected from a group of compounds having the formula:

or a pharmaceutically acceptable salt, tautomer, enantiomer, disastereomer, or solvate of any of the foregoing compounds. For example, the compounds are selected from a group of compounds having the formula 4, 21, 22, 50, 235, 236, or 237, or a pharmaceutically acceptable salt, tautomer, enantiomer, disastereomer, or solvate of any of the foregoing compounds. In some embodiments, the compounds are selected from a group of compounds having the formula 235, 236, or 237, or a

pharmaceutically acceptable salt, enantiomer, tautomer, or solvate of any of the foregoing compounds. In some embodiments, the compounds are selected from a group of compounds having the formula 235 or 236, or a pharmaceutically acceptable salt, enantiomer, tautomer, or solvate of any of the foregoing compounds.

In some embodiments, the compounds of this disclosure are represented by general formula (SC-09):

SC-09 or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, or solvate thereof, wherein as valence and stability permit:

Y is selected from the group consisting of N and O;

R ¹ is selected from the group consisting of optionally substituted alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

R ², R ³, and R ⁴ are independently selected from the group consisting of hydrogen and optionally substituted alkyl, alkenyl, alkynyl, and arylalkyl;

R ⁵ is selected from the group consisting of hydrogen and optionally substituted

arylalkyl; and

R ⁶ is selected from the group consisting of absent, hydrogen, and optionally

substituted arylalkyl. In some embodiments, R ² and R ³ are each hydrogen, Y is O, and R ⁶ is absent. In some embodiments when R ² and R ³ are each hydrogen, Y is O, and R ⁶ is absent, R ⁴ is hydrogen. In some embodiments when R ² and R ³ are each hydrogen, Y is O, R ⁶ is absent, and R ⁴ is hydrogen, R ¹ is an optionally substituted aryl and R ⁵ is hydrogen. In some embodiments, R ² and R ³ are each hydrogen, Y is O, R ⁶ is absent, R ⁴ is hydrogen, R ¹ is an optionally substituted aryl, and R ⁵ is an optionally substituted arylalkyl.

In some embodiments, R ², R ³, and R ⁶ are each hydrogen and Y is N. In some embodiments when R ², R ³, and R ⁶ are each hydrogen and Y is N, R ⁴ is hydrogen. In some embodiments when R ², R ³, R ⁴, and R ⁶ are each hydrogen and Y is N, R ⁵ is hydrogen. In some embodiments when R ², R ³, R ⁴, R ⁵, and R ⁶ are each hydrogen and Y is N, R ¹ is an optionally substituted aryl.

In some embodiments, R and R are each hydrogen and Y is N. In some

embodiments when R ² and R ³ are each hydrogen ^'and Y is N, R ⁴ is hydrogen. In some embodiments when R ², R ³, and R ⁴ are each hydrogen and Y is N, R ⁵ is hydrogen. In some embodiments when R ², R ³, R ⁴, and R ⁵ are each hydrogen and Y is N, R ¹ is an optionally substituted aryl and R ⁶ is an optionally substituted arylalkyl.

In some embodiments, R ¹ is selected from the group consisting of optionally substituted alkyl and cycloalkyl. In some embodiments, R ³ is an optionally substituted alkyl.

In some embodiments, the compounds represented by formula (SC-09) are selected from a group of compounds having the formula:

or a pharmaceutically acceptable salt, enantiomer, tautomer, or solvate of any of the foregoing compounds. For example, the compounds are selected from a group of compounds having the formula 6, 11, 13, 15, 16, 24, or 238-246, or a pharmaceutically acceptable salt, enantiomer, tautomer, or solvate of any of the foregoing compounds.

In some embodiments, the compounds are selected from a group of compounds having the formula 238, 239, 240, 241, 242, 243, 244, 245, or 246, or a pharmaceutically acceptable salt, enantiomer, tautomer, or solvate of any of the foregoing compounds. In some embodiments, the compounds are selected from a group of compounds having the formula 238, 239, 240, or 241, or a pharmaceutically acceptable salt, enantiomer, tautomer, or solvate of any of the foregoing compounds. In some embodiments, the compounds of this disclosure are represented by general formula (SC- 10):

SC-10 or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, or solvate thereof, wherein as valence and stability permit:

Y is selected from the group consisting of NH and CH ₂;

R ¹ and R ² are independently selected from the group consisting of hydrogen, halogen, and optionally substituted alkyl, alkenyl, alkynyl, aryl, heteroaryl, alkylthio, -SCF ₃, and amino; and R ³ and R ⁴ are independently selected from the group consisting of hydrogen and halogen; wherein R ¹ and R ² can optionally form a ring, wherein the ring is selected from the group consisting of optionally substituted aryl and heteroaryl.

In some embodiments, Y is CH ₂. In some embodiments, Y is CH ₂ and R ⁴ is hydrogen. In some embodiments, Y is CH ₂ and R ³ and R ⁴ are each hydrogen. In some embodiments when Y is CH ₂ and R ³ and R ⁴ are each hydrogen, R ¹ is an optionally substituted heteroaryl and R ² is an optionally substituted alkylthio. In some embodiments when Y is CH ₂ and R ³ and R ⁴ are each hydrogen, R ¹ is an optionally substituted heteroaryl and R ² is -SCF ₃. In some embodiments, Y is CH ₂ and R ² and R ⁴ are each hydrogen. In some embodiments when Y is CH ₂ and R ² and R ⁴ are each hydrogen, R ¹ is an optionally substituted heteroaryl and R ³ is halogen.

In some embodiments, Y is NH. In some embodiments, R ¹ is selected from the group consisting of hydrogen, halogen, and optionally substituted alkyl, alkenyl, and amino.

In some embodiments, R ² is selected from the group consisting of optionally substituted alkyl, alkenyl, and amino.

In some embodiments, R ⁴ is halogen. In some embodiments, R ¹ and R ² form an optionally substituted heteroaryl.

In some embodiments, the compounds represented by formula (SC- 10) are selected from a group of compounds having the formula:

or a p armaceut ca y accepta e sa t, tautomer, or so vate o any o t e orego ng compounds. For example, the compounds are selected from a group of compounds having the formula 7, 17, 26, 34, 53, or 247-253, or a pharmaceutically acceptable salt, tautomer, or solvate of any of the foregoing compounds. In some embodiments, the compounds are selected from a group of compounds having the formula 247, 248, 249, 250, 251, 252, or 253, or a pharmaceutically acceptable salt, tautomer, or solvate of any of the foregoing compounds. In some embodiments, the compounds are selected from a group of compounds having the formula 247 or 248, or a

pharmaceutically acceptable salt, tautomer, or solvate of any of the foregoing compounds.

In some embodiments, the compounds of this disclosure are represented by general formula (SC- 1 1 ):

SC-11 or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, or solvate thereof, wherein as valence and stability permit:

= represents a single or double bond; and

R ¹, R ², and R ³ are independently selected from the group consisting of hydrogen and optionally substituted alky 1, alkenyl, alkynyl, heteroalkyi, hydroxyalkyl, aryl, and heteroaryl;

2 3

wherein R and R can optionally form a ring, wherein the ring is a optionally substituted cycloalkyl.

In some embodiments, the compound of formula (SC- 1 1 ) is the S-enantiomer.

In some embodiments,— represents a single bond. In some embodiments,— represents a single bond, R ² is an optionally substituted alkyl, and R ³ is hydrogen. In some embodiments,— represents a single bond, R ² is an optionally substituted alkyl, R ³ is hydrogen, and R ¹ is an optionally substituted hydroxyalkyl. In certain such embodiments, the compound of formula (SC-1 1 ) is the S-enantiomer.

In some embodiments,— represents a single bond. In some embodiments,— represents a single bond, R ² is hydrogen and R ¹ is hydrogen. In some embodiments, — represents a single bond, R ² is hydrogen, R ¹ is hydrogen, and R ³ is an optionally substituted alkynyl. In certain such embodiments, the compound of formula (SC- 1 1 ) is the S-enantiomer.

In some embodiments,— represents a double bond. In certain such embodiments, the compound of formula (SC- 1 1 ) is the S-enantiomer. In some embodiments, R ¹ is selected from the group consisting of hydrogen and optionally substituted alkyl. In certain such embodiments, the compound of formula (SC-1 1) is the S-enantiomer.

In some embodiments, R is hydrogen. In certain such embodiments, the compound of formula (SC-1 1 ) is the S-enantiomer.

In some embodiments, R ² is an optionally substituted alkynyl. In certain such embodiments, the compound of formula (SC-1 1 ) is the S-enantiomer.

In some embodiments, R ³ is an optionally substituted alkyl. In certain such embodiments, the compound of formula (SC-1 1) is the S-enantiomer. In some embodiments, the compounds represented by formula (SC-1 1 ) are selected from a group of compounds having the formula:

or a pharmaceutically acceptable salt, tautomer, enantiomer, diastereomer, or solvate of any of the foregoing compounds. For example, the compounds are selected from a group of compounds having the formula 8, 10, 18, 23, 29, 30, 31, 36, 43, 254-256, or 374, or a pharmaceutically acceptable salt, tautomer, diastereomer, enantiomer, or solvate of any of the foregoing compounds. In some embodiments, the compounds are selected from a group of compounds having the formula 254, 255, 256, or 374, or a pharmaceutically acceptable salt, enantiomer, tautomer, or solvate of any of the foregoing compounds. In some embodiments, the compound is a compound having the formula 254, or a pharmaceutically acceptable salt, enantiomer, tautomer, or solvate thereof.

In some embodiments, the compounds of this disclosure are represented by general formula (SC- 12):

SC-12 or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, or solvate thereof, wherein as valence and stability permit: a and β ^represent a single or double bond;

R ¹ is selected from the group consisting of hydrogen, CH ₂, and optionally substituted alkyl, haloalkyl, alkenyl, heteroalkyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, acylaminoalkyl, alkylamino, aryl, and heteroaryl;

R ⁸ is selected from the group consisting of absent, hydrogen, hydroxyl, and optionally substituted alkyl and haloalkyl;

wherein when a is a single bond, β is a double bond, and R ⁸ is absent, R ¹ is CH ₂; wherein when a is a double bond and β is a single bond, R ⁸ is absent;

R ² is selected from the group consisting of hydrogen and optionally substituted alkyl, haloalkyl, alkenyl, heteroalkyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, acylaminoalkyl, alkylamino, aryl, and heteroaryl;

R ³, R ⁴, and R ⁵ are independently selected from the group consisting of hydrogen,

, hydroxyl, and optionally substituted alkyl;

R ⁶ is selected from the group consisting of hydrogen and optionally substituted alkyl, haloalkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, alkoxyalkyl, and cycloalkylacyl;

R ⁷ is selected from the group consisting of hydrogen and optionally substituted alkyl; and

R ⁹ is selected from the group consisting of hydrogen and optionally substituted alkyl and haloalkyl;

wherein R ¹ and R ², R ³ and R ⁴, R ⁴ and R ⁵, R ⁴ and R ⁷, or R ⁸ and R ⁹ can optionally form a ring, wherein the ring is selected from the group optionally substituted cycloalkyl, halocycloalkyl, and heterocyclyl;

wherein R ¹ and R ⁹ can optionally form a ring, wherein the ring is selected from the group optionally substituted cycloalkyl, halocycloalkyl, heterocyclyl, and aryl; wherein when R ¹ and R ⁹ form an optionally substituted aryl, R ⁸ is absent;

wherein R ⁵ and R ⁶ can optionally form a monocyclic, bicyclic, or polycyclic ring, wherein the ring is selected from the group optionally substituted heterocyclyl and heteroaryl. In some embodiments, the compound of formula (SC-12) is the R-enantiomer.

In some embodiments, at least one of R ¹, R ², R ³, R ⁴, R ⁵, R ⁶, R ⁷, R ⁸, and R ⁹ is other than hydrogen. In certain such embodiments, the compound of formula (SC- 12) is the R-enantiomer. In some embodiments when R ⁸ is absent, at least one of R ¹, R ², R ³, R ⁴, R ⁵, R ⁶, R ⁷, and R ⁹ is other than hydrogen. In certain such embodiments, the compound of formula (SC- 12) is the R-enantiomer.

In some embodiments, both a and β are single bonds. In certain such embodiments, the compound of formula (SC- 12) is the R-enantiomer. In some embodiments, a is a double bond, β is a single bond, and R ⁸ is absent. In certain such embodiments, the compound of formula (SC- 12) is the R-enantiomer.

In some embodiments, a is a single bond, β is a double bond, R ¹ is CH ₂, and R ⁸ is absent. In certain such embodiments, the compound of formula (SC-12) is the R- enantiomer. In some embodiments when both a and β are single bonds, R ¹ and R ² are both an optionally substituted alkyl. In some embodiments both a and β are single bonds, R ¹

2 5

and R are both an optionally substituted alkyl, and R is an optionally substituted alkyl. In some embodiments both a and β are single bonds, R ¹, R ², and R ⁵ are each an optionally substituted alkyl, R ³, R ⁴, R ⁶, and R ⁷ are each hydrogen, and R ⁸ and R ⁹ form an optionally substituted cycloalkyl. In some embodiments both a and β are single bonds, R' , R ², and R ⁵ are each an optionally substituted alkyl, R ³, R ⁴, R ⁶, and R ⁷ are each hydrogen, and R ⁸ and R ⁹ form an optionally substituted halocycloalkyl. In some embodiments both a and β are single bonds, R ¹, R ², and R ⁵ are each an optionally substituted alkyl, R ³, R ⁴, R ⁶, and R ⁷ are each hydrogen, and R ⁸ and R ⁹ form a difluorocyclopropyl. In some embodiments both a and β are single bonds, R ¹ , R ², R ⁵, and R ⁶ are each an optionally substituted alkyl, and R ³, R ⁴, and R ⁷ are each hydrogen. In some embodiments both a and β are single bonds, R ¹ , R ², R ⁵, and R ⁶ are each an optionally substituted alkyl, and R ³, R ⁴, and R ⁷ are each hydrogen, and R ⁸ and R ⁹ form an optionally substituted cycloalkyi. In some embodiments both a and β are single bonds, R ¹ , R ², R ⁵, and R ⁶ are each an optionally substituted alkyl, and R ³, R ⁴, R ⁷, R ⁸, and R ⁹ are each hydrogen. In some embodiments both a and β are single bonds, R ¹, R ², and R ⁵ are each an optionally substituted alkyl, R ⁶ is an optionally substituted cycloalkyi, and R ³, R ⁴, R ⁷, R ⁸, and R ⁹ are each hydrogen. In some embodiments both a and β are single bonds, R ¹ , R ², and R ⁵ are each an optionally substituted alkyl, R ⁶ is an optionally substituted alkenyl, and R ³, R ⁴, R ⁷, R ⁸, and R ⁹ are each hydrogen. In some embodiments both a and β are single bonds, R ¹ , R ², and R ⁵ are each an optionally substituted alkyl, R ⁶ is an optionally substituted alkynyl, and R ³, R ⁴, R ⁷, R ⁸, and R ⁹ are each hydrogen. In some embodiments both a and β are single bonds, R ¹, R ², and R ⁵ are each an optionally substituted alkyl, R ⁶ is an optionally substituted alkoxyalkyl, and R ³, R ⁴, R ⁷, R ⁸, and R ⁹ are each hydrogen. In some embodiments both a and β are single bonds, R ¹, R ², and R ⁵ are each an optionally substituted alkyl, R ³, R ⁴, R ⁶, R ⁷ and R ⁹ are each hydrogen, and R ⁸ is a hydroxyl. In some embodiments both a and β are single bonds, R ¹ , R ², and R ⁵ are each an optionally substituted alkyl, R ³, R ⁴, R ⁶, R ⁷ and R ⁹ are each hydrogen, and R ⁸ is hydrogen. In certain such

embodiments, the compound of formula (SC-12) is the R-enantiomer.

In some embodiments when both a and β are single bonds, R ⁵ is an optionally substituted alkyl. In some embodiments both a and β are single bonds, R ⁵ is an optionally substituted alkyl, and R ³, R ⁴, R ⁷, and R ⁹ are each hydrogen. In some embodiments both a and β are single bonds, R ⁵, R ⁶, and R ⁸ are each an optionally substituted alkyl, R ³, R ⁴, R ⁷, and R ⁹ are each hydrogen, and R ¹ and R ² form an optionally substituted cycloalkyi. In some embodiments both a and β are single bonds, R ⁵, R ⁶, and R ⁸ are each an optionally substituted alkyl, R ³, R ⁴, R ⁷, and R ⁹ are each hydrogen, and R ¹ and R ² form an optionally substituted halocycloalkyl. In some embodiments both a and β are single bonds, R ⁵, R ⁶, and R ⁸ are each an optionally substituted alkyl, R ³, R ⁴, R ⁷, and R ⁹ are each hydrogen, and R ¹ and R ² form a difluorocyclopropyl. In certain such embodiments, the compound of formula (SC- 12) is the R-enantiomer.

In some embodiments both a and β are single bonds, R ¹ , R ⁵, and R ⁷ are each an optionally substituted alkyl, R ² is an optionally substituted alkylamino, R ⁶ is an optionally substituted cycloalkylacyl, and R ³, R ⁴, R ⁸, and R ⁹ are each hydrogen. In certain such embodiments, the compound of formula (SC-12) is the R-enantiomer.

In some embodiments when both a and β are single bonds and R ⁵ is an optionally substituted alkyl, R ³, R ⁴, R ⁷, R ⁸, and R ⁹ are each hydrogen. In some embodiments when both a and β are single bonds, R ⁵ is an optionally substituted alkyl, and R ³, R ⁴, R ⁷, R ⁸, and R ⁹ are each hydrogen, R ¹ and R are each an optionally substituted haloalkyl. In some embodiments when both a and β are single bonds, R ⁵ is an optionally substituted alkyl, and R ³, R ⁴, R ⁷, R ⁸, and R ⁹ are each hydrogen, R ¹ and R ² are each trifluoromethyl. In some embodiments when both a and β are single bonds, R ⁵ is an optionally substituted alkyl, R ³, R ⁴, R ⁷, R ⁸, and R ⁹ are each ^' hydrogen, and R ¹ and R ² are each an optionally substituted haloalkyl, R ⁶ is an optionally substituted haloalkyl. In some embodiments when both a and β are single bonds, R ⁵ is an optionally substituted alkyl, R ³, R ⁴, R ⁷, R ⁸, and R ⁹ are each hydrogen, and R ¹ and R ² are each trifluoromethyl, R ⁶ is a trifluoromethyl. In some embodiments when both a and β are single bonds, R ⁵ is an optionally substituted alkyl, R ³, R ⁴, R ⁷, R ⁸, and R ⁹ are each hydrogen, and R ¹ and R ² are each an optionally substituted haloalkyl, R ⁶ is an optionally substituted alkyl. In some embodiments when both a and β are single bonds, R ⁵ is an optionally substituted alkyl, R ³, R ⁴, R ⁷, R ⁸, and R ⁹ are each hydrogen, and R ¹ and R ² are each trifluoromethyl, R ⁶ is an optionally substituted alkyl. In some embodiments when both a and β are single bonds, R ⁵ is an optionally substituted alkyl, R ³, R ⁴, R ⁷, R ⁸, and R ⁹ are each hydrogen, and R ¹ and R ² are each an optionally substituted haloalkyl, R ⁶ is an optionally substituted alkynyl. In some embodiments when both a and β are single bonds, R ⁵ is an optionally substituted alkyl, R ³, R ⁴, R ⁷, R ⁸, and R ⁹ are each hydrogen, and R ¹ and R ² are each trifluoromethyl, R ⁶ is an optionally substituted alkynyl. In some embodiments when both a and β are single bonds, R ⁵ is an optionally substituted alkyl, R ³, R ⁴, R ⁷, R ⁸, and R ⁹ are each hydrogen, and R and R are each an optionally substituted haloalkyi, R is hydrogen. In some embodiments when both a and β are single bonds, R ⁵ is an optionally substituted alkyl, R ³, R ⁴, R ⁷, R ⁸, and R ⁹ are each hydrogen, and R ¹ and R ² are each trifluoromethyl, R ⁶ is hydrogen. In some embodiments when both a and β are single bonds, R ⁵ is an optionally substituted alkyl, R ³, R ⁴, R ⁷, R ⁸, and R ⁹ are each hydrogen, and R ¹ and R ² are each an optionally substituted haloalkyi, R ⁶ is an optionally substituted cycloalkyl. In certain such embodiments, the compound of formula (SC- 12) is the R-enantiomer. In some embodiments when both a and β are single bonds, R ⁵ is an optionally substituted alkyl, R ³, R ⁴, R ⁷, R ⁸, and R ⁹ are each hydrogen, and R ¹ and R ² are each trifluoromethyl, R ⁶ is an optionally substituted cycloalkyl. In certain such

embodiments, the compound of formula (SC-12) is the R-enantiomer.

In some embodiments when both a and β are single bonds, R ¹ and R ² are both an optionally substituted haloalkyi and R ³, R ⁸, and R ⁹ are each hydrogen. In some embodiments when both a and β are single bonds, R ¹ and R ² are both trifluoromethyl and R ³, R ⁸, and R ⁹ are each hydrogen. In some embodiments when both a and β are single bonds, R ¹ and R ² are both an optionally substituted haloalkyi, and R ³, R ⁸, and R ⁹ are each hydrogen, R ⁴ and R ⁷ are each hydrogen and R ⁵ and R ⁶ form an optionally substituted heterocyclyl. In some embodiments when both a and β are single bonds, R ¹ and R ² are both trifluoromethyl, and R ³, R ⁸, and R ⁹ are each hydrogen, R ⁴ and R ⁷ are each hydrogen and R ⁵ and R ⁶ form an optionally substituted heterocyclyl. In some embodiments when both a and β are single bonds, R ¹ and R ² are both an optionally substituted haloalkyi, and R ³, R ⁸, and R ⁹ are each hydrogen, R ⁴ and R ⁷ form an optionally substituted heterocyclyl, R ⁵ is an optionally substituted alkyl, and R ⁶ is hydrogen. In some embodiments when both a and β are single bonds, R ¹ and R ² are both trifluoromethyl, and R ³, R ⁸, and R ⁹ are each hydrogen, R ⁴ and R ⁷ form an optionally substituted heterocyclyl, R ⁵ is an optionally substituted alkyl, and R ⁶ is hydrogen. In certain such embodiments, the compound of formula (SC-12) is the R- enantiomer.

In some embodiments, a is a double bond, β is a single bond, R ⁸ is absent, and R ¹ and R ² are both an optionally substituted alkyl. In some embodiments, a is a double bond, β is a single bond, R ⁸ is absent, R ¹ and R ² are both an optionally substituted alkyl, and R ⁷ and R ⁹ are each hydrogen. In some embodiments, a is a double bond, β is a single bond, R ⁸ is absent, R ¹ and R ² are both an optionally substituted alkyl, and R ³, R ⁴, R ⁷, and R ⁹ are each hydrogen. In some embodiments, a is a double bond, β is a single bond, R ⁸ is absent, R ¹ and R ² are both an optionally substituted alkyl, R ⁵ and R ⁶ form an optionally substituted heterocyclyl, and R ³, R ⁴, R ⁷, and R ⁹ are each hydrogen. In some embodiments, a is a double bond, β is a single bond, R ⁸ is absent, R ¹, R ², and R ⁵ are each an optionally substituted alkyl, and R ³, R ⁴, R ⁷, and R ⁹ are each hydrogen. In some embodiments, a is a double bond, β is a single bond, R ⁸ is absent, R ¹ , R ², and R ⁵ are each an optionally substituted alkyl, R ⁶ is an optionally substituted cycloalkyl, and R ³, R ⁴, R ⁷, and R ⁹ are each hydrogen. In some embodiments, a is a double bond, β is a single bond, R ⁸ is absent, R ¹ , R ², and R ⁵ are each an optionally substituted alkyl, R ⁶ is an optionally substituted haloalkyl, and R ³, R ⁴, R ⁷, and R ⁹ are each hydrogen. In some embodiments, a is a double bond, β is a single bond, R ⁸ is absent, R ¹, R ², and R ⁵ are each an optionally substituted alkyl, R ⁶ is trifluoromethyl, and R ³, R ⁴, R ⁷, and R ⁹ are each hydrogen. In some embodiments, a is a double bond, β is a single bond, R ⁸ is absent, R ¹, R ², and R ⁵ are each an optionally substituted alkyl, R ⁶ is an optionally substituted alkenyl, and R ³, R ⁴, R ⁷, and R ⁹ are each hydrogen. In some embodiments, a is a double bond, β is a single bond, R ⁸ is absent, R ¹, R ², and R ⁵ are each an optionally substituted alkyl, R ⁶ is an optionally substituted alkynyl, and R ³, R ⁴, R ⁷, and R ⁹ are each hydrogen. In some embodiments, a is a double bond, β is a single bond, R ⁸ is absent, R ¹ , R ², and R ⁵ are each an optionally substituted alkyl, and R ³, R ⁴, R ⁶, R ⁷, and R ⁹ are each hydrogen. In certain such embodiments, the compound of formula (SC- 12) is the R-enantiomer. R 1

In some embodiments, a is a double bond, β is a single bond, R is absent, R , R , and R ⁶ are each an optionally substituted alkyl, and R ⁷ and R ⁹ are each hydrogen. In some embodiments, a is a double bond, β is a single bond, R ⁸ is absent, R ¹ , R ², and R ⁶ are each an optionally substituted alkyl, and R ³, R ⁷, and R ⁹ are each hydrogen. In some embodiments, a is a double bond, β is a single bond, R ⁸ is absent, R ¹ , R ², and R ⁶ are each an optionally substituted alkyl, R ⁴ and R ⁵ form an optionally substituted cycloalkyl, and R ³, R ⁷, and R ⁹ are each hydrogen. In certain such embodiments, the compound of formula (SC-12) is the R-enantiomer.

In some embodiments, a is a double bond, β is a single bond, R ⁸ is absent, R ¹ and R ² are both an optionally substituted alkyl, R ⁵ and R ⁶ form an optionally substituted heterocyclyl, and R ³, R ⁴, R ⁷, and R ⁹ are each hydrogen. In certain such embodiments, the compound of formula (SC-12) is the R-enantiomer.

In some embodiments, a is a double bond, β is a single bond, R ⁸ is absent, R ¹ and R ² are both an optionally substituted alkyl, R ³, R ⁶, and R ⁹ are each hydrogen, R ⁵ is an optionally substituted alkyl, and R ⁴ and R ⁷ form an optionally substituted heterocyclyl. In certain such embodiments, the compound of formula.(SC-12) is the R-enantiomer.

In some embodiments, a is a double bond, β is a single bond, R ⁸ is absent, and R ¹ is an optionally substituted haloalkyl, R ² and R ⁵ are both an optionally substituted alkyl, and R ³, R ⁴, R ⁷, and R ⁹ are each hydrogen. In some embodiments, a is a double bond, β is a single bond, R ⁸ is absent, and R ¹ is trifluoromethyl, R ² and R ⁵ are both an optionally substituted alkyl, and R ³, R ⁴, R ⁷, and R ⁹ are each hydrogen. In some embodiments, when a is a double bond, β is a single bond, R ⁸ is absent, R ¹ is an optionally substituted haloalkyl, R ² and R ⁵ are both an optionally substituted alkyl, and R ³, R ⁴, R ⁷, and R ⁹ are each hydrogen, R ⁶ is hydrogen. In some embodiments, when a is a double bond, β is a single bond, R ⁸ is absent, R ¹ is trifluoromethyl, R ² and R ⁵ are both an optionally substituted alkyl, and R ³, R ⁴, R ⁷, and R ⁹ are each hydrogen, R ⁶ is hydrogen. In some embodiments, when a is a double bond, β is a single bond, R ⁸ is absent, R ¹ is an optionally substituted haloalkyl, R ² and R ⁵ are both an optionally substituted alkyl, and R ³, R ⁴, R ⁷, and R ⁹ are each hydrogen, R ⁶ is an optionally substituted alkyl. In some embodiments, when a is a double bond, β is a single bond, R ⁸ is absent, R ¹ is trifluoromethyl, R ² and R ⁵ are both an optionally substituted alkyl, and R ³, R ⁴, R ⁷, and R ⁹ are each hydrogen, R ⁶ is an optionally substituted alkyl. In some embodiments, when a is a double bond, β is a single bond, R ⁸ is absent, R ¹ is an optionally substituted haloalkyi, R ² and R ⁵ are both an optionally substituted alkyl, and R ³, R ⁴, R ⁷, and R ⁹ are each hydrogen, R ⁶ is an optionally substituted haloalkyi. In some embodiments, when a is a double bond, β is a single bond, R ⁸ is absent, R ¹ is trifluoromethyl, R ² and R ⁵ are both an optionally substituted alkyl, and R ³, R ⁴, R ⁷, and R ⁹ are each hydrogen, R ⁶ is trifluoromethyl. In certain such embodiments, the compound of formula (SC- 12) is the R-enantiomer.

In some embodiments, a is a double bond, β is a single bond, R ⁸ is absent, R ² is an optionally substituted haloalkyi, R ¹ and R ⁵ are both an optionally substituted alkyl, and R ³, R ⁴, R ⁷, and R ⁹ are each hydrogen. In some embodiments, a is a double bond, β is a single bond, R ⁸ is absent, R ² is trifluoromethyl, R ¹ and R ⁵ are both an optionally substituted alkyl, and R ³, R ⁴, R ⁷, and R ⁹ are each hydrogen. In some embodiments, when a is a double bond, β is a single bond, R ⁸ is absent, R ² is an optionally substituted haloalkyi, R ¹ and R ⁵ are both an optionally substituted alkyl, and R ³, R ⁴, R ⁷, and R ⁹ are each hydrogen, R ⁶ is hydrogen. In some embodiments, when a is a double bond, β is a single bond, R ⁸ is absent, R ² is trifluoromethyl, R ¹ and R ⁵ are both an optionally substituted alkyl, and R ³, R ⁴, R ⁷, and R ⁹ are each hydrogen, R ⁶ is hydrogen. In some embodiments, when a is a double bond, β is a single bond, R ⁸ is absent, R ² is an optionally substituted haloalkyi, R ¹ and R ⁵ are both an optionally substituted alkyl, and R ³, R ⁴, R ⁷, and R ⁹ are each hydrogen, R ⁶ is an optionally substituted alkyl. In some embodiments, when a is a double bond, β is a single bond, R ⁸ is absent, R ² is trifluoromethyl, R ¹ and R ⁵ are both an optionally substituted alkyl, and R ³, R ⁴, R ⁷, and R ⁹ are each hydrogen, R ⁶ is an optionally substituted alkyl. In some embodiments, when a is a double bond, β is a single bond, R ⁸ is absent, R ² is an optionally substituted haloalkyi, R ¹ and R ⁵ are both an optionally substituted alkyl, and R ³, R ⁴, R ⁷, and R ⁹ are each hydrogen, R ⁶ is an optionally substituted haloalkyl. In some

8 2

embodiments, when a is a double bond, β is a single bond, R is absent, R is trifluoromethyl, R ¹ and R ⁵ are both an optionally substituted alkyl, and R ³, R ⁴, R ⁷, and R ⁹ are each hydrogen, R ⁶ is trifluoromethyl. In certain such embodiments, the compound of formula (SC- 12) is the R-enantiomer.

8 1

In some embodiments, a is a double bond, β is a single bond, R is absent, and R and R ² are both an optionally substituted haloalkyl. In some embodiments, a is a double bond, β is a single bond, R ⁸ is absent, and R ¹ and R ² are both trifluoromethyl. In some embodiments, a is a double bond, β is a single bond; R ⁸ is absent, R ¹ and R ² are both an optionally substituted haloalkyl, and R ⁷ and R ⁹ are each hydrogen. In some embodiments, a is a double bond, β is a single bond, R ⁸ is absent, R ¹ and R ² are both trifluoromethyl, and R ⁷ and R ⁹ are each hydrogen. In some embodiments, a is a double bond, β is a single bond, R ⁸ is absent, R ¹ and R ² are both an optionally substituted haloalkyl, and R ³, R ⁴, R ⁷, and R ⁹ are each hydrogen. In some

embodiments, a is a double bond, β is a single bond, R ⁸ is absent, R ¹ and R ² are both trifluoromethyl, and R ³, R ⁴, R ⁷, and R ⁹ are each hydrogen. In some embodiments, a is a double bond, β is a single bond, R ⁸ is absent, R ¹ and R ² are both an optionally substituted haloalkyl, R ⁵ and R ⁶ form an optionally substituted heterocyclyl, and R ³, R ⁴, R ⁷, and R ⁹ are each hydrogen. In some embodiments, a is a double bond, β is a single bond, R ⁸ is absent, R ¹ and R ² are both trifluoromethyl, R ⁵ and R ⁶ form an optionally substituted heterocyclyl, and R ³, R ⁴, R ⁷, and R ⁹ are each hydrogen. In some embodiments, a is a double bond, β is a single bond,.R ⁸ is absent, R ¹ and R ² are each an optionally substituted haloalkyl, R ⁵ is an optionally substituted alkyl, and R ³, R ⁴, R ⁷, and R ⁹ are each hydrogen. In some embodiments, a is a double bond, β is a single bond, R ⁸ is absent, R ¹ and R ² are each trifluoromethyl, R ⁵ is an optionally substituted alkyl, and R ³, R ⁴, R ⁷, and R ⁹ are each hydrogen. In some embodiments, a is a double bond, β is a single bond, R ⁸ is absent, R ¹ and R ² are each an optionally substituted haloalkyl, R ⁵ is an optionally substituted alkyl, R ⁶ is an optionally substituted cycloalkyj, and R ³, R ⁴, R ⁷, and R ⁹ are each hydrogen. In some embodiments, a is a double bond, β is a single bond, R ⁸ is absent, R ¹ and R ² are each trifluoromethyl, R ⁵ is an optionally substituted alkyl, R ⁶ is an optionally substituted cycloalkyl, and R ³, R ⁴, R ⁷, and R ⁹ are each hydrogen. In some embodiments, a is a double bond, β is a single bond, R ⁸ is absent, R ¹ and R ² are each an optionally substituted haloalkyl, R ⁵ is an optionally substituted alkyl, R ⁶ is an optionally substituted alkyl, and R ³, R ⁴, R ⁷, and R ⁹ are each hydrogen. In some embodiments, a is a double bond, β is a single bond, R ⁸ is absent, R ¹ and R ² are each trifluoromethyl, R ⁵ is an optionally substituted alkyl, R ⁶ is an optionally substituted alkyl, and R ³, R ⁴, R ⁷, and R ⁹ are each hydrogen. In some embodiments, a is a double bond, β is a single bond, R ⁸ is absent, R ¹ and R ² are each an optionally substituted haloalkyl, R ⁵ is an optionally substituted alkyl, R ⁶ is hydrogen, and R ³, R ⁴, R ⁷, and R ⁹ are each hydrogen. In some embodiments, a is a double bond, β is a single bond, R ⁸ is absent, R ¹ and R ² are each trifluoromethyl, R ⁵ is an optionally substituted alkyl, R ⁶ is hydrogen, and R ³, R ⁴, R ⁷, and R ⁹ are each hydrogen. In some embodiments, a is a double bond, β is a single bond, R ⁸ is absent, R ¹ and R ² are each an optionally substituted haloalkyl, R ⁵ is an optionally substituted alkyl, R ⁶ is an optionally substituted alkynyl, and R ³, R ⁴, R ⁷, and R ⁹ are each hydrogen. In some embodiments, a is a double bond, β is a single bond, R ⁸ is absent, R ¹ and R ² are each trifluoromethyl, R ⁵ is an optionally substituted alkyl, R ⁶ is an optionally substituted alkynyl, and R ³, R ⁴, R ⁷, and R ⁹ are each hydrogen. In some embodiments, a is a double bond, β is a single bond, R ⁸ is absent, R ¹ and R ² are both an optionally substituted haloalkyl, R ³, R ⁶, and R ⁹ are each hydrogen, R ⁵ is an optionally substituted alkyl, and R ⁴ and R ⁷ form an optionally substituted heterocyclyl. In some

embodiments, a is a double bond, β is a single bond, R ⁸ is absent, R ¹ and R ² are both trifluoromethyl, R ³, R ⁶, and R ⁹ are each hydrogen, R ⁵ is an optionally substituted alkyl, and R ⁴ and R ⁷ form an optionally substituted heterocyclyl. In certain such

embodiments, the compound of formula (SC- 12) is the R-enantiomer.

In some embodiments, a is a double bond, β is a single bond, R ⁸ is absent, R ¹, R ², and R ⁵ are each an optionally substituted alkyl. In some embodiments, a is a double bond, β is a single bond, R ⁸ is absent, R ¹, R ², R ⁵, and R ⁶ are each an optionally substituted

8 1 alkyl. In some embodiments, a is a double bond, β is a single bond, R is absent, R , R ², R ⁵, and R ⁶ are each an optionally substituted alkyl, R ³ and R ⁴ form an optionally substituted cycloalkyl, and R ⁷ and R ⁹ are each hydrogen. In certain such embodiments, the compound of formula (SC- 12) is the R-enantiomer.

In some embodiments, a is a double bond, β is a single bond, R ⁸ is absent, and R ⁵ and R ⁶ are each an optionally substituted alkyl. In some embodiments, a is a double bond, β is a single bond, R ⁸ is absent, R ⁵ and R ⁶ are each an optionally substituted alkyl, and R ³, R ⁴, R ⁷, and R ⁹ are each hydrogen. In some embodiments, a is a double bond, β is a single bond, R ⁸ is absent, R ⁵ and R ⁶ are each an optionally substituted alkyl, R ¹ and R ² are both an optionally substituted cycloalkyl, and R ³, R ⁴, R ⁷, and R ⁹ are each hydrogen. In some embodiments, a is a double bond, β is a single bond, R ⁸ is absent, R ⁵ and R ⁶ are each an optionally substituted alkyl, R ¹ is an optionally substituted alkyl, R ² is an optionally substituted cycloalkylalkyl, and R ³, R ⁴, R ⁷, and R ⁹ are each hydrogen. In some embodiments, a is a double bond, β is a single bond, R ⁸ is absent, R ⁵ and R ⁶ are each an optionally substituted alkyl, R ¹ and R ² form an optionally substituted cycloalkyl, and R ³, R ⁴, R ⁷, and R ⁹ are each hydrogen. In certain such embodiments, the compound of formula (SC-12) is the R-enantiomer.

In some embodiments, a is a single bond, β is a double bond, R ⁸ is absent, R ¹ is CH ₂. In some embodiments, a is a single bond, β is a double bond, R ⁸ is absent, R ¹ is CH ₂, and R ⁵ and R ⁶ are both an optionally substituted alkyl. In some embodiments, a is a single bond, β is a double bond, R ⁸ is absent, R ¹ is CH ₂, and R ², R ⁵, and R ⁶ are each an optionally substituted alkyl. In some embodiments, a is a single bond, β is a double bond, R ⁸ is absent, R ¹ is CH ₂, R ², R ⁵, and R ⁶ are each an optionally substituted alkyl, and R ³, R ⁴, R ⁷, and R ⁹ are each hydrogen. In certain such embodiments, the

compound of formula (SC- 12) is the R-enantiomer.

In some embodiments, a is a single bond, β is a double bond, R ⁸ is absent, R ¹ is CH ₂, R ² and R ⁵ are each an optionally substituted alkyl, and R ³, R ⁴, R ⁶, R ⁷, and R ⁹ are each hydrogen. In certain such embodiments, the compound of formula (SC- 12) is the R- enantiomer.

In some embodiments, R ¹ and R ⁹ form an optionally substituted aryl and R ⁸ is absent. In some embodiments, R ¹ and R ⁹ form an optionally substituted aryl, R ⁸ is absent, and R ⁵ and R ⁶ are both an optionally substituted alkyl. In some embodiments, R ¹ and R ⁹ form an optionally substituted aryl, R ⁸ is absent, R ², R ⁵, and R ⁶ are each optionally substituted alkyl, and R ³, R ⁴, and R ⁷ are each hydrogen. In some embodiments, R ¹ and R ⁹ form an optionally substituted aryl, R ⁸ is absent, R ⁵ and R ⁶ are each an optionally substituted alkyl, and R ², R ³, R ⁴, and R ⁷ are each hydrogen. In certain such embodiments, the compound of formula (SC-12) is the R-enantiomer.

In some embodiments, R ¹ is hydrogen. In certain such embodiments, the compound of formula (SC-12) is the R-enantiomer.

In some embodiments, R ³ is an optionally substituted alkyl. In certain such embodiments, the compound of formula (SC- 12) is the R-enantiomer. In some embodiments, R ⁴ is an optionally substituted alkyl. In certain such embodiments, the compound of formula (SC- 12) is the R-enantiomer.

In some embodiments, R ⁵ is hydrogen. In certain such embodiments, the compound of formula (SC- 12) is the R-enantiomer.

In some embodiments, R ⁶ is selected from the group consisting of optionally substituted heteroalkyi and alkoxyaikyl. In certain such embodiments, the compound of formula (SC-12) is the R-enantiomer.

In some embodiments, R ⁹ is an optionally substituted alkyl. In certain such embodiments, the compound of formula (SC- 12) is the R-enantiomer.

In some embodiments, the compounds represented by formula (SC- 12) are selected from a group of compounds having the formula:

or a p armaceut ca y accepta e sa t, a 1 ree base form, enant omer, disastereomer, a solvate of any of the foregoing compounds. For example, the compounds are selected from a group of compounds having the formula 9, 27, 44, 99, 110, 111, 113- 120, 138-142, 167, 188, 199, 203, 212-217, 219, 257-259, 315-359, or 430-432, or a pharmaceutically acceptable salt, a free base form, enantiomer, disastereomer, or a solvate of any of the foregoing compounds. In some embodiments, the compounds are selected from a group of compounds having the formula 99, 110, 111 , 113-120, 138- 142, 167, 188, 199, 212-217, 219, 257-259, 318-354, 358-359, or 430-432, or a pharmaceutically acceptable salt, a free base form, enantiomer, disastereomer, or a solvate of any of the foregoing compounds. In some embodiments, the compounds are selected from a group of compounds having the formula 111, 113-118, 140-142, 167, 188, 212-216, 217, 219, 258, 259, 323-325, 328-330, 336-349, 358-359, or 430-432, or a pharmaceutically acceptable salt, a free base form, enantiomer, disastereomer, or a solvate of any of the foregoing compounds. In some embodiments, the compounds of this disclosure are represented by general formula (SC- 13):

SC-13 or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, or solvate thereof, wherein as valence and stability permit: = represents a single or double bond;

Y is selected from the group consisting of O and CH ₂;

W is selected from the group consisting of CH ₂, CH, N, NH, C, and CHCH ₃;

Z is selected from the group consisting of NR. ⁶, C, CH, and CH ₂;

R ¹ is selected from the group consisting of hydrogen, halogen, and isothiocyanate;

R ² is selected from the group consisting of hydrogen and halogen;

R ³ is selected from the group consisting of hydrogen and optionally substituted alkyl;

R ⁴ is selected from the group consisting of hydrogen, hydroxyl, and optionally

substituted alkyl;

R ⁵ is selected from the group consisting of hydrogen and optionally substituted alkyl, heteroalkyl, and aminoalkyl; and

R ⁶ is selected from the group consisting of absent, hydrogen and optionally substituted alkyl, heteroalkyl, and aminoalkyl; wherein R ⁴ and R ⁵ can optionally form a ring, wherein the ring is an optionally

substituted heterocyclyl; wherein W and R ³ or Z and R ³ can optionally form a ring, wherein the ring is selected from the group consisting of optionally substituted cycloalkyl, heterocyclyl, aryl, and heteroaryl.

In some embodiments, represents a single bond. In some embodiments, represents a single bond, Z is NR ⁶, and Y is CH ₂. In some embodiments, = represents a single bond, Z is NR ⁶, Y is CH ₂, and R ⁴ and R ⁵ form an optionally substituted heterocyclyl. In some embodiments, = represents a single bond, Z is NR ⁶, Y is CH ₂, W is CH ₂, and R ⁴ and R ⁵ form an optionally substituted heterocyclyl. In some embodiments, = represents a single bond, Z is NR ⁶, Y is CH ₂, W is CH ₂, R ⁴ and R ⁵ form an optionally substituted heterocyclyi, R ¹, R ², and R ³ are each hydrogen, and R ⁶ is an optionally substituted alkyl. In some embodiments, =^= represents a single bond, Z is NR ⁶, Y is CH ₂, W is CH ₂, R ⁴ and R ⁵ form an optionally substituted heterocyclyi, R ¹, R ², and R ³ are each hydrogen, and R ⁶ is an optionally substituted aminoalkyl.

In some embodiments, = represents a single bond, Z is NR ⁶, Y is CH ₂, W is CHCH ₃, and R ⁴ and R ⁵ form an optionally substituted heterocyclyi. In some embodiments, =-= represents a single bond, Z is NR ⁶, Y is CH ₂, W is CHCH ₃, R ⁴ and R ⁵ form an optionally substituted heterocyclyi, R ¹, R ², and R ³ are each hydrogen, and R ⁶ is an optionally substituted alkyl. In some embodiments, =-= represents a single bond, Z is NR ⁶, Y is CH ₂, W is CHCH ₃, R ⁴ and R ⁵ form an optionally substituted heterocyclyi, R ¹, R ², and R ³ are each hydrogen, and R ⁶ is an optionally substituted aminoalkyl.

In some embodiments, R ³ is an optionally substituted alkyl.

In some embodiments, R ⁴ is an optionally substituted alkyl. In some embodiments, R ⁵ is an optionally substituted alkyl.

In some embodiments, R ⁶ is hydrogen.

In some embodiments, the compounds represented by formula (SC- 13) are selected from a group of compounds having the formula:

or a pharmaceutically acceptable salt, enantiomer, tautomer, or solvate a free base form of any of the foregoing compounds. For example, the compounds are selected from a group of compounds having the formula 14, 45, 76, 97, or 177, or a pharmaceutically acceptable salt, a free base form, enantiomer, tautomer, or solvate of any of the foregoing compounds. In some embodiments, the compounds are selected from a group of compounds having the formula 76, 97, or 177, or a pharmaceutically acceptable salt, a free base form, enantiomer, tautomer, or solvate of any of the foregoing compounds. In some embodiments, the compound is a compound having the formula 177, or a pharmaceutically acceptable salt, enantiomer, tautomer, or solvate thereof.

In some embodiments, the compounds of this disclosure are represented by general formula (SC- 14):

SC-14 or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, or solvate thereof, wherein as valence and stability permit: Y is selected from the group consisting of N and CH;

R ¹ is selected from the group consisting of hydrogen and optionally substituted alkyl, heteroalkyl, arylalkyl, heteroarylalkyl, and aminoalkyl;

R ² is selected from the group consisting of hydrogen and optionally substituted alkyl, heteroalkyl, and aminoalkyl; and

R ³ and R ⁴ are independently selected from the group consisting of hydrogen and

optionally substituted alkyl; wherein R ³ and R ⁴ can optionally form a ring, wherein the ring is selected from the group consisting of optionally substituted cycloalkyl and heterocyclyl. In some embodiments, the compound of formula (SC-14) is the S-enantiomer.

In some embodiments, Y is CH. In some embodiments when Y is CH, R ² is an optionally substituted alkyl. In some embodiments when Y is CH and R ² is an optionally substituted alkyl, R ¹ is an optionally substituted arylalkyl. In some embodiments when Y is CH and R ² is an optionally substituted alkyl, R ¹ is an optionally substituted heteroarylalkyl. In certain such embodiments, the compound of formula (SC- 14) is the S-enantiomer.

In some embodiments when Y is CH and R ² is an optionally substituted alkyl, and R ¹ is an optionally substituted arylalkyl, R ³ and R ⁴ are each hydrogen. In some embodiments when Y is CH and R ² is an optionally substituted alkyl, and R ¹ is an optionally substituted heteroarylalkyl, R ³ and R ⁴ are each hydrogen. In certain such embodiments, the compound of formula (SC- 14) is the S-enantiomer.

In some embodiments when Y is CH and R ² is an optionally substituted alkyl, and R ¹ is an optionally substituted arylalkyl, R ³ and R ⁴ form an optionally substituted cycloalkyl. In some embodiments when Y is CH and R ² is an optionally substituted alkyl, and R ¹ is an optionally substituted heteroarylalkyl, R ³ and R ⁴ form an optionally substituted cycloalkyl. In certain such embodiments, the compound of formula (SC- 14) is the S-enantiomer.

In some embodiments when Y is CH, R ² is hydrogen, R ¹ is an optionally substituted arylalkyi, and R ³ and R ⁴ are each hydrogen. In some embodiments when Y is CH, R ² is hydrogen, R ¹ is an optionally substituted heteroarylalkyl, and R ³ and R ⁴ are each hydrogen. In certain such embodiments, the compound of formula (SC- 14) is the S- enantiomer.

In some embodiments when Y is CH, R ² is hydrogen, R ¹ is an optionally substituted arylalkyi, and R ³ and R ⁴ form an optionally substituted cycloalkyl. In some embodiments when Y is CH, R ² is hydrogen, R ¹ is an optionally substituted heteroarylalkyl, and R ³ and R ⁴ form an optionally substituted cycloalkyl. In certain such embodiments, the compound of formula (SC- 14) is the S-enantiomer.

In some embodiments, Y is N. In some embodiments when Y is N, R ¹ is an optionally substituted aminoalkyl. In certain such embodiments, the compound of formula (SC- 14) is the S-enantiomer.

In some embodiments, R ¹ is an optionally substituted alkyl. In certain such embodiments, the compound of formula (SC- 14) is the S-enantiomer.

In some embodiments, R ³ is an optionally substituted alkyl. In certain such embodiments, the compound of formula (SC- 14) is the S-enantiomer. In some embodiments, R ⁴ is an optionally substituted alkyl. In certain such embodiments, the compound of formula (SC- 14) is the S-enantiomer.

In some embodiments, the compounds represented by formula (SC-14) are selected from a group of compounds having the formula:

or a pharmaceutically acceptable salt, tautomer, enantiomer, diastereomer, or solvate of any of the foregoing compounds. For example, the compounds are selected from a group of compounds having the formula 100, 101, 104-107, 109, 149-152, 154, 156, 159, 178, 180, 181, or 202, or a pharmaceutically acceptable salt, tautomer, enantiomer, disastereomer, or solvate of any of the foregoing compounds. In some embodiments, the compounds are selected from a group of compounds having the formula 149, 150, 152, 178, or 202, or a pharmaceutically acceptable salt, tautomer, enantiomer, disastereomer, or solvate of any of the foregoing compounds.

In some embodiments, the compounds of this disclosure are represented by general formula (SC- 15):

SC-15 or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, or solvate thereof, wherein as valence and stability permit:

R ^] , R ², R ³, and R ⁴ are independently selected from the group consisting of hydrogen, halogen, and optionally substituted alkyl, heteroalkyl, aminoalkyl, alkoxy, alkylthio, -SCF ₃, difluoromethoxy, aryl, heteroaryl, arylalkyl, heteroarylalkyl, arylalkoxy, heteroarylalkoxy, aryloxy, heteroaryloxy, aryloxyalkoxy, and heteroaryloxyalkoxy; and

R ⁵, R ⁶, R ⁷, and R ⁸ are independently selected from the group consisting of hydrogen and optionally substituted alkyl, heteroalkyl, aminoalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, aryloxyalkyl, and heteroaryloxyalkyl; wherein R ⁵ and R ⁶ can optionally form a ring, wherein the ring is selected from the group consisting of optionally substituted heterocyclyl and optionally substituted aminoalkylheterocyclyl; wherein R ⁶ and R ⁷ can optionally form a ring, wherein the ring is an optionally

substituted heterocyclyl.

In some embodiments, R ⁸ is hydrogen. In some embodiments when R ⁸ is hydrogen, R ⁷ is hydrogen. In some embodiments when R ⁷ and R ⁸ are both hydrogen, R ⁵ and R ⁶ 7 8 form an optionally substituted heterocyclyl. in some embodiments when R and R

5 6 1 2 are both hydrogen and R and R form an optionally substituted heterocyclyl, R , R , R ³, and R ⁴ are each hydrogen. In some embodiments when R ⁷ and R are both hydrogen, R ⁵ and R ⁶ form an optionally substituted aminoalkylheterocyclyl. In some embodiments when R ⁷ and R ⁸ are both hydrogen and R ⁵ and R ⁶ form an optionally substituted aminoalkylheterocyclyl, R ¹, R ², R ³, and R ⁴ are each hydrogen.

In some embodiments when R ⁷ and R ⁸ are both hydrogen, R ⁴ and R ⁶ are both hydrogen and R ⁵ is an optionally substituted alkyl. In some embodiments when R ⁴, R ⁶, R ⁷, and R ⁸ are each hydrogen and R ⁵ is an optionally substituted alkyl, R ¹ and R ² are each hydrogen and R ³ is an optionally substituted aryloxyalkoxy. In some

embodiments when R ⁴, R ⁶, R ⁷, and R ⁸ are each hydrogen and R ⁵ is an optionally substituted alkyl, R ² and R ³ are each hydrogen and R ¹ is an optionally substituted aryloxyalkoxy.

In some embodiments when R ⁸ is hydrogen, R ⁵ is hydrogen, R ⁶ is an optionally substituted alkyl, and R ⁷ is an optionally substituted alkyl. In some embodiments when both R ⁵ and R ⁸ are hydrogen, R ⁶ is an optionally substituted alkyl, and R ⁷ is an optionally substituted alkyl, R ¹ , R ³, and R ⁴ are hydrogen and R ² is an optionally substituted alkylthio. In some embodiments when both R ⁵ and R ⁸ are hydrogen, R ⁶ is an optionally substituted alkyl, and R ⁷ is an optionally substituted alkyl, R ¹ , R ³, and R ⁴ are hydrogen and R ² is -SCF ₃.

In some embodiments, R ¹ is selected from the group consisting of optionally substituted alkyl, aminoalkyl, alkylthio, -SCF ₃, difluoromethoxy, aryl, aryloxy, and aryloxyalkoxy.

In some embodiments, R ² is selected from the group consisting of optionally substituted alkyl, aminoalkyl, alkoxy, -SCF ₃, difluoromethoxy, aryl, arylalkoxy, aryloxy, and aryloxyalkoxy. In some embodiments, R ³ is selected from the group consisting of optionally substituted alkyl, aminoalkyl, alkoxy, alkylthio, -SCF ₃, difluoromethoxy, aryl, arylalkoxy, and aryloxy.

In some embodiments, R ⁴ is selected from the group consisting of halogen and optionally substituted aryloxyalkoxy.

In some embodiments, R ⁵ is selected from the group consisting of optionally substituted aminoalkyl, aryl, arylalkyl, and aryloxyalkyl.

In some embodiments, R ⁶ is selected from the group consisting of optionally substituted aminoalkyl, aryl, arylalkyl, and aryloxyalkyl. In some embodiments, R ⁷ is selected from the group consisting of optionally substituted arylalkyl and aryloxyalkyl.

In some embodiments, R ⁸ is selected from the group consisting of optionally substituted alkyl, aminoalkyl, and arylalkyl.

In some embodiments, R ⁶ and R ⁷ form an optionally substituted heterocyclyl. In some embodiments, the compounds represented by formula (SC-15) are selected from a group of compounds having the formula:

solvate of any of the foregoing compounds. For example, the compounds are selected from a group of compounds having the formula 68-71, 98, 169-171, 173, 174, 179, 190-192, 200, 218, or 265-291, or a pharmaceutically acceptable salt, a free base form, aJmitomer, or a solvate of any of the foregoing compounds. In some embodiments, the compounds are selected from a group of compounds having the formula 169-171, 173, 174, 179, 190-192, 200, or 265-291, or a pharmaceutically acceptable salt, tautomer, enantiomer, or solvate of any of the foregoing compounds. In some embodiments, the compounds are selected from a group of compounds having the formula 169, 170, 284, 286, or 289, or a pharmaceutically acceptable salt, tautomer, or solvate of any of the foregoing compounds.

In some embodiments, the compounds of this disclosure are represented by general formula (SC- 16):

SC-16 or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, or solvate thereof, wherein as valence and stability permit:

R ¹, R ², and R ³ are independently selected from the group consisting of hydrogen and optionally substituted alkyl, heteroalkyl, aminoalkyl, alkylaminoalkyl, arylalkyl, heteroarylalkyl, and carbamoylaminoalkyl; wherein R ¹ and R ² can optionally form a ring, wherein the ring is selected from the group optionally substituted heterocyclyl and optionally substituted

aminoalkylheterocyclyl; wherein R ² and R ³ can optionally form a ring, wherein the ring is an optionally

substituted heterocyclyl.

In some embodiments, R ¹ is hydrogen, R ² is an optionally substituted alkylaminoalkyl, and R ³ is an optionally substituted alkyl.

In some embodiments, R ³ is hydrogen and R ¹ and R ² form an optionally substituted aminoalkylheterocyclyl.

In some embodiments, R ¹ is selected from the group consisting of optionally substituted alkyl, aminoalkyl, arylalkyl, and carbamoylaminoalkyl. In some embodiments, R ² is selected from the group consisting of hydrogen and optionally substituted alkyl, aminoalkyl, and arylalkyl.

In some embodiments, R ³ is selected from the group consisting of optionally substituted aminoalkyl, alkylaminoalkyl, and arylalkyl. In some embodiments, R ¹ and R ² form an optionally substituted heterocyclyl.

2 3

In some embodiments, R and R form an optionally substituted heterocyclyl. In some embodiments, R ¹, R ², and R ³ are not all hydrogen.

In some embodiments, the compounds represented by formula (SC- 16) are selected from a group of compounds having the formula:

solvate of any of the foregoing compounds. For example, the compounds are selected from a group of compounds having the formula 19, 40, 54, 91, 184, 189, 206, 209, 260-264, 292, 375, or 377, or a pharmaceutically acceptable salt, a free base form, enantiomer, tautomer, or solvate of any of the foregoing compounds. In some embodiments, the compounds are selected from a group of compounds having the formula 54, 91, 184, 189, 206, 209, 260-264, 292, or 375, or a pharmaceutically acceptable salt, a free base form, tautomer, enantiomer, or solvate of any of the foregoing compounds. In some embodiments, the compounds are selected from a group of compounds having the formula 184, 189, 260-264, or 292, or a

pharmaceutically acceptable salt, tautomer, or solvate of any of the foregoing compounds. In some embodiments, the compound is a compound having the formula 189, or a pharmaceutically acceptable salt, tautomer or solvate thereof.

In some embodiments, the compounds of this disclosure are represented by general formula (SC- 17):

SC-17 or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, or solvate thereof, wherein as valence and stability permit:

Y is selected from the group NH and O;

R ¹ is selected from the group consisting of optionally substituted alkyl, heteroalkyl, aminoalkyl, amino, cycloalkyl, heterocyclyl, cycloalkylalkylamino, heterocyclylalkylamino, aryl, heteroaryl, arylalkyl, heteroarylalkyl, arylamino, heteroarylamino, and aminoalkylaryloxyalkoxyaryl; and

R ² and R ³ are independently selected from the group consisting of hydrogen and

optionally substituted alkyl, heteroalkyl, and aminoalkyl; wherein R ² and R ³ can optionally form a ring, wherein the ring is an optionally

substituted heterocyclyl or heteroaryl.

In some embodiments, Y is NH. In some embodiments when Y is NH, R ² is hydrogen. In some embodiments, Y is NH, R ² is hydrogen, R ¹ is an optionally substituted aryl, and R ³ is hydrogen. In some embodiments, Y is NH, R ² is hydrogen, R ¹ is an optionally substituted arylalkyl, and R ³ is an optionally substituted aminoalkyl. .

In some embodiments, Y is O. In some embodiments, R is selected from the group consisting of optionally substituted alkyl, heteroalkyl, aminoalkyl, amino, cycloalkylalkylamino, heteroaryl, heteroaryl alkyl, arylamino, heteroarylamino, and aminoalkylaryloxyalkoxyaryl.

In some embodiments, R ¹ is selected from optionally substituted isoquinolinyl, indazol-l -ylamino, phenylalkyl, pyrimidin-5-ylamino, cycloalkylmethylamino, (aminoalkylphenoxy)alkoxyphenyl, benzothiophenylamino, or indolylalkyl.

In some embodiments, R ² is selected from the group consisting of optionally substituted alkyl, heteroalkyl, and aminoalkyl.

In some embodiments, R is selected from the group consisting of optionally substituted alkyl and heteroalkyl.

In some embodiments, R ² and R ³ form an optionally substituted heterocyclyl.

In some embodiments, the compounds represented by formula (SC- 17) are selected from a group of compounds having the formula;

or a pharmaceutically acceptable salt, a free base form, enantiomer, tautomer, or solvate of any of the foregoing compounds. For example, the compounds are selected from a group of compounds having the formula 35, 41, 42, 51, 94, 121, 122, 172, 293, 294, or 376, or a pharmaceutically acceptable salt, a free base form, enantiomer, tautomer, or solvate of any of the foregoing compounds. In some embodiments, the compounds are selected from a group of compounds having the formula 121, 122, 172, 293, 294, or 376, or a pharmaceutically acceptable salt, enantiomer, tautomer, or solvate of any of the foregoing compounds. In some embodiments, the compound is compound 172, or a pharmaceutically acceptable salt, enantiomer, tautomer, or solvate thereof. In some embodiments, the compound is a compound having the formula 376, or a pharmaceutically acceptable salt, tautomer, or solvate thereof. In some embodiments, the compounds of this disclosure are represented by general formula (SC- 18):

SC-18 or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, or solvate thereof, wherein as valence and stability permit:

L ¹ is a 4 to 12 carbon atom linker selected from the group consisting of optionally substituted alkanediyl, heteroalkanediyl, cycloalkanediyl,

heterocyclylalkanediyl, alkenediyl, alkynediyl, arylalkanediyl,

alkylaryloxydiyl, aminoalkanediyl, and aminoalkylaminodiyl; R' and R ² are independently selected from the group consisting of hydrogen and

optionally substituted alkyl and heteroalkyl; and

R ³ and R ⁴ are independently selected from the group consisting of hydrogen and

optionally substituted alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, and heteroalkynyl; wherein R ¹ and R ² can optionally form a ring, wherein the ring is an optionally

substituted heterocyclyl.

In some embodiments, R ¹ and R ² are each hydrogen and R ³ and R ⁴ are each an optionally substituted alkyl. In some embodiments when R ¹ and R ² are each hydrogen and R ³ and R ⁴ are each an optionally substituted alkyl, L ¹ is an optionally substituted alkylaryloxydiyl. In some embodiments when R ¹ and R ² are each hydrogen and R ³ and R ⁴ are each an optionally substituted alkyl, L ¹ is an optionally substituted aminoalkylaminodiyl. In some embodiments, L ¹ is selected from the group consisting of optionally substituted alkanediyl, heteroalkanediyl, arylalkanediyl, and aminoalkanediyl.

In some embodiments, R ¹ is an optionally substituted alkyl.

In some embodiments, R ² is an optionally substituted alkyl. In some embodiments, R ¹ and R ² form an optionally substituted heterocyclyl.

In some embodiments, the compounds represented by formula (SC-18) are selected from a group of compounds having the formula:

h i ll l l

compounds. For example, the compounds are selected from a group of compounds having the formula 186, 187, 295, or 296, or a pharmaceutically acceptable salt, tautomer, or solvate of any of the foregoing compounds. In some embodiments, the compounds are selected from a group of compounds having the formula 187 or 296, a pharmaceutically acceptable salt, tautomer, or solvate of any of the foregoing compounds. In some embodiments, the compounds of this disclosure are represented by general formula (SC- 19):

SC-19 or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, or solvate thereof, wherein as valence and stability permit:

R ¹ is selected from the group consisting of optionally substituted alkyl, alkenyl, alkynyl, and arylalkyl; and

R ² is selected from the group consisting of hydrogen and optionally substituted alkyl, alkenyl, and alkynyl. In some embodiments, the compound of formula (SC-19) is the R-enantiomer.

In some embodiments, R ¹ is an optionally substituted alkenyl and R ² is an optionally substituted alkynyl. In certain such embodiments, the compound of formula (SC- 19) is the R-enantiomer.

In some embodiments, R ¹ is selected from the group consisting of optionally substituted alkyl and arylalkyl. In certain such embodiments, the compound of formula (SC- 19) is the R-enantiomer.

In some embodiments, R ² is selected from the group consisting of hydrogen and optionally substituted alkyl and alkenyl. In certain such embodiments, the compound of formula (SC- 19) is the R-enantiomer. In some embodiments, the compounds represented by formula (SC- 19) are selected from a group of compounds having the formula: or a pharmaceutically acce □ptable salt, enantiomer, diastereomer, or solvate of any the foregoing compounds. For example, the compounds are selected from a group of compounds having the formula 175, 297, 298, 299, or 300, or a pharmaceutically acceptable salt, enantiomer, diastereomer, or solvate of any of the foregoing compounds. In some embodiments, the compound is a compound having the formula 298, or a pharmaceutically acceptable salt, enantiomer, diastereomer, or solvate thereof.

In some embodiments, the compounds of this disclosure are represented by general formula (SC-20):

SC-20 or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, or solvate thereof, wherein as valence and stability permit:

R ¹ is selected from the group consisting of hydrogen and optionally substituted alk l and aminoalkyl; and R ² is selected from hydrogen and optionally substituted alkyl, aminoalkyl, and cycloalkylaminoalkyl.

In some embodiments, R ¹ and R ² are each an optionally substituted aminoalkyl.

1 2

In some embodiments, R is hydrogen and R is an optionally substituted

cycloalkylaminoalkyl.

In some embodiments, R ¹ is an optionally substituted alkyl.

In some embodiments, R ² is selected from the group hydrogen and an optionally substituted alkyl.

In some embodiments, the compounds represented by formula (SC-20) are selected from a group of compounds having the formula:

or a pharmaceutically acceptable salt, tautomer, or solvate of any of the foregoing compounds. For example, the compounds are selected from a group of compounds having the formula 39, 301, 302, 303, or 304, or a pharmaceutically acceptable salt, tautomer, enantiomer, disastereomer, or solvate of any of the foregoing compounds. In some embodiments, the compounds are selected from a group of compounds having the formula 301, 302, 303, or 304, or a pharmaceutically acceptable salt, tautomer, enantiomer, disastereomer, or solvate of any of the foregoing compounds. In some embodiments, the compounds are selected from a group of compounds having the formula 303 or 304, or a pharmaceutically acceptable salt, tautomer, enantiomer, disastereomer, or solvate of any of the foregoing compounds.

In some embodiments, the compounds of this disclosure are represented by general formula (SC-21 ): ^'

or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, or solvate thereof, wherein as valence and stability permit: a and β = represents a single or double bond;

V is selected from the group consisting of C, CH, and N; W is selected from the group consisting of C, CH, and N;

Y is selected from the group consisting of CH ₂ and NH;

R ¹ is selected from the group consisting of optionally substituted alkyl and amino; and R ² is selected from the group consisting of absent and hydrogen;

2 2 wherein when β is a single bond, R is hydrogen, and when β is a double bond, R is

In some embodiments, Y is CH ₂. In some embodiments when Y is CH ₂, a is a single bond, β is a double bond, and R ² is absent. In some embodiments when Y is CH ₂, a is a single bond, β is a double bond, and R ² is absent, W is CH, V is N, and R ¹ is an optionally substituted amino.

In some embodiments, a is a double bond, V is C and W is C. In some embodiments, β is a single bond and R ² is hydrogen.

In some embodiments, a is a single bond and V is CH.

In some embodiments, a is a single bond and W is N.

In some embodiments, Y is NH. In some embodiments, R ¹ is an optionally substituted alkyl.

In some embodiments, the compounds represented by formula (SC-21 ) are selected from a group of compounds having the formula:

foregoing compounds. For example, the compounds are selected from a group of compounds having the formula 46, 305, 306, or 307, or a pharmaceutically acceptable salt, enantiomer, tautomer, or solvate of any of the foregoing compounds. In some embodiments, the compounds are selected from a group of compounds having the formula 305, 306, or 307, or a pharmaceutically acceptable salt, enantiomer, tautomer, or solvate of any of the foregoing compounds. In some embodiments, the compound is a compound having the formula 306, or a pharmaceutically acceptable salt, tautomer, or solvate thereof.

In some embodiments, the compounds of this disclosure are represented by general formula (SC-22):

SC-22 or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, or solvate thereof, wherein as valence and stability permit:

L ¹ is a 4 to 12 carbon linker selected from the group consisting of optionally

substituted alkanediyl, heteroalkanediyl, alkenediyl, heteroalkenediyl, oxyalkoxydiyl, alkylcycloalkylalkanediyl,

heteroalkylcycloalkylheteroalkanediyl, alkylcycloalkenylalkanediyl, heteroalkylcycloalkenylheteroalkanediyl, alkylheterocyclylalkanediyl, and heteroalkylheterocyclylheteroalkanediyl; and Ar ¹ is selected from the group consisting of optionally substituted aryl and heteroaryl.

In some embodiments, Ar ¹ is an optionally substituted aryl. In some embodiments, when Ar ¹ is an optionally substituted aryl, L ¹ is an optionally substituted

oxyalkoxydiyl. In some embodiments, when Ar ¹ is an optionally substituted aryl, L ¹ is an optionally substituted alkylheterocyclylalkanediyl. In some embodiments, Ar ¹ is an ^' optionally substituted heteroaryl. In some embodiments, when Ar ¹ is an optionally substituted heteroaryl, L ¹ is an optionally substituted alkylheterocyclylalkanediyl.

In some embodiments when Ar ¹ is an optionally substituted aryl or heteroaryl, Ar ¹ is phenyl, thiophene, or benzothiophene optionally substituted with alkyl or halogen. In some embodiments, L ¹ is selected from the group consisting of optionally substituted alkanediyl, heteroalkanediyl, and alkylcycloalkylalkanediyl.

In some embodiments, the compounds represented by formula (SC-22) are selected from a group of compounds having the formula:

or a p armaceut ca y acceptable salt, tautomer, or solvate of any of the foregoing compounds.

In some embodiments, the compounds of this disclosure are represented by general formula (SC-23):

or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, or solvate thereof, wherein as valence and stability permit:

R ¹ is selected from the group consisting of halogen and optionally substituted C| -C ₆ alkyl, C ₂-C ₆ alkenyl, C ₃-C ₆ cycloalkyl, C ₄-C ₆ cycloalkenyl, C ₂-C ₅

heterocycloalkyl, Ci-C ₆ alkoxy, Ci-C ₆ alkylthio, phenyl, and monocyclic heteroaryl; and

R ², R ³, and R ⁴ are independently selected from the group consisting of hydrogen, halogen and optionally substituted Cj-C ₆ alkyl, C ₂-C ₆ alkenyl, C ₃-C ₆ cycloalkyl, C ₄-C ₆ cycloalkenyl, C ₂-C ₅ heterocycloalkyl, Ci-C alkoxy, Ci -C ₆ alkylthio, phenyl, and monocyclic heteroaryl; wherein said optionally substituted Q-Q alkyl, C ₂-C ₆ alkenyl, C ₃-C ₆ cycloalkyl, C ₄- C ₆ cycloalkenyl, C ₂-C ₅ heterocycloalkyl, Ci-C ₆ alkylthio, and CpC ₆ alkoxy are optionally substituted with one or more substituents selected from the group consisting of F, and unsubstituted OCH ₃, OCH ₂CH ₃, CH ₃, C ₂H ₅, and C ₂-C ₅ dialkylamino; wherein said optionally substituted phenyl is optionally substituted with one or more substituents selected from the group consisting of F, CI, Br, SCF ₃, and unsubstituted OCH ₃, OCH ₂CH ₃, CH ₃, C ₂H ₅, COOH, COOCH ₃, COOC ₂H ₅, SCH ₃, SOCH ₃, S0 ₂CH ₃, SCHF ₂, isopropyl, /-butyl, hydroxyl, dialkylamino, and alkylamino; wherein said optionally substituted monocyclic heteroaryl is optionally substituted with one or more substituents selected from the group consisting of F, CI, Br, SCF ₃, CF ₃, OCF ₃, and unsubstituted OCH ₃, OCH ₂CH ₃, CH ₃₎ C ₂H ₅₎ COOH, COOCH ₃, COOC ₂H ₅, SCH ₃, SOCH ₃, S0 ₂CH ₃₎ SCHF ₂, CHF ₂, OCHF ₂, isopropyl, /-butyl, hydroxyl, dialkylamino, and alkylamino; wherein R ¹ and R ² can optionally form a ring, wherein the ring is an optionally

substituted cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein R ² and R ³ can optionally form a ring, wherein the ring is an optionally

substituted cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein R ³ and R ⁴ can optionally form a ring, wherein the ring is an optionally

substituted cycloalkyl, heterocyclyl, aryl, or heteroaryl. In some embodiments, R ¹ is halogen, SCF ₃, OCF ₃, CF ₃, or unsubstituted SCHF ₂,

OCHF2, or CF ₂H. In some embodiments when R ¹ is halogen, it is F, CI, Br, or I. In some embodiments when R ¹ is halogen, R ² is halogen, and R ³ and R ⁴ are hydrogen. In some embodiments when R ¹ is halogen, R ² is optionally substituted Ci-C ₆ alkoxy, and R ³ and R ⁴ are hydrogen. In some embodiments when R ¹ is halogen, R ² is optionally substituted Ci-C ₆ alkyl, and R ³ and R ⁴ are hydrogen. In some embodiments when R ¹ is halogen, R ³ is halogen, and R ² and R ⁴ are hydrogen. In some embodiments when R ¹ is halogen, R ⁴ is halogen, and R ² and R ³ are hydrogen.

In some embodiments, the compounds represented by formula (SC-23) are selected from a group of compounds having the formula:

or a p armaceut ca y accepta e sa t, tautomer, or so vate o any o t e orego ng compounds.

In some embodiments, the compounds of this disclosure are represented by general formula (SC-24):

SC-24 or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, or solvate thereof, wherein as valence and stability permit:

R ¹, R ², R ⁷, and R ⁸ are independently selected from the group consisting of hydrogen, halogen, and optionally substituted C1-C3 alkyl, C1 -C3 alkoxy, C1 -C3 alkylthio, dimethylamino, methylamino, and amino;

R ³ and R ⁴ are independently selected from the group consisting of hydrogen, halogen, and optionally substituted Ci-C ₆ alkyl, C ₂-C ₆ alkenyl, C3-C6 cycloalkyl, C4-C6 cycloalkenyl, C ₂-C ₅ heterocycloalkyl, Ci-C ₆ alkoxy, Ci-C ₆ alkylthio, phenyl, and monocyclic heteroaryl; and R ⁵ and R ⁶ are independently selected from the group consisting of hydrogen, halogen, and optionally substituted Ci-C ₆ alkyl, C ₂-C ₆ alkenyl, C ₃-C ₆ cycloalkyl, C ₄-C ₆ cycloalkenyl, C ₂-C5 heterocycloalkyl, Ci-C ₆ alkylthio, phenyl, and monocyclic heteroaryl; wherein said optionally substituted Ci-C ₆ alkyl, C ₂-C ₆ alkenyl, C ₃-C ₆ cycloalkyl, C ₄- C ₆ cycloalkenyl, C ₂-C ₅ heterocycloalkyl, Ci-C ₆ alkylthio, and Ci-C ₆ alkoxy are optionally substituted with one or more substituents selected from the group • consisting of F, and unsubstituted OCH ₃, OCH ₂CH ₃, CH ₃, C ₂H ₅, and C ₂-C ₅ dialkylamino; wherein said optionally substituted phenyl is optionally substituted with one or more substituents selected from the group consisting of F, CI, Br, CF ₃, OCF ₃, SCF ₃, and unsubstituted OCH ₃, OCH ₂CH _3> CH ₃, C ₂H ₅, COOH, COOCH ₃, COOC ₂H ₅, SCH ₃, SOCH ₃, S0 ₂CH ₃, SCHF ₂, CHF ₂, OCHF ₂, isopropyl, /-butyl, hydroxyl, dialkylamino, and alkylamino; wherein said optionally substituted monocyclic heteroaryl is optionally substituted with one or more substituents selected from the group consisting of F, CI, Br, SCF ₃, CF ₃, OCF ₃, and unsubstituted OCH ₃, OCH ₂CH ₃, CH ₃, C ₂H ₅, COOH, COOCH ₃, COOC ₂H ₅, SCH ₃, SOCH ₃, S0 ₂CH ₃, SCHF ₂, CHF ₂, OCHF ₂, isopropyl, /-butyl, hydroxyl, dialkylamino, and alkylamino; wherein R ³ and R ⁴ can optionally form a ring, wherein the ring is an optionally

substituted cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein R ⁴ and R ⁵ can optionally form a ring, wherein the ring is an optionally

substituted cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein R ⁵ and R ⁶ can optionally form a ring, wherein the ring is an optionally

substituted cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein R ¹ and R ³ can optionally form a ring, wherein the ring is an optionally

substituted cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein R ⁶ and R ⁷ can optionally form a ring, wherein the ring is an optionally substituted cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein R and R can optionally form a ring, wherein the ring is an optionally

substituted cycloalkyl, heterocyclyl, aryl, or heteroaryl. In some embodiments, R ¹ is halogen or hydrogen. In some embodiments, R ⁷ is halogen or hydrogen. In some embodiments, R ² is hydrogen, halogen, or optionally substituted C 1 -C3 alkyl. In some embodiments, R ⁸ is hydrogen, halogen, or optionally substituted C 1 -C3 alkyl. In some embodiments, R ³ is hydrogen, halogen, SCF3, OCF ₃, CF3, or unsubstituted SCHF ₂, OCHF ₂, or CF ₂H. In some embodiments, R ⁴ is hydrogen, halogen, or optionally substituted C i-C ₆ alkyl or C i-C ₆ alkoxy. In some embodiments, R ⁵ is hydrogen, halogen, or optionally substituted C | -C ₆ alkyl. In some embodiments, R ⁶ is hydrogen, halogen, or optionally substituted C i-C ₆ alkyl.

In some embodiments, R ¹, R ², R ⁴, R ⁵, R ⁶, R ⁷, and R ⁸ are hydrogen. In some embodiments when R ¹, R ², R ⁴, R ⁵, R ⁶, R ⁷, and R ⁸ are hydrogen, R ³ is halogen. In some embodiments when R ¹, R ², R ⁴, R ⁵, R ⁶, R ⁷, and R ⁸ are hydrogen, R ³ is hydrogen. In some embodiments when R ¹, R ², R ⁴, R ⁵, R ⁶, R ⁷, and R ⁸ are hydrogen, R ³ is SCF ₃. In some embodiments when R ¹ , R ², R ⁴, R ⁵, R ⁶, R ⁷, and R ⁸ are hydrogen, R ³ is unsubstituted SCHF ₂. In some embodiments when R ¹, R ², R ⁴, R ⁵, R ⁶, R ⁷, and R ⁸ are hydrogen, R ³ is optionally substituted Ci-C ₆ alkoxy. In some embodiments when R ¹ , R ², R ⁴, R ⁵, R ⁶, R ⁷, and R ⁸ are hydrogen, R ³ is unsubstituted OCHF ₂.

In some embodiments, R ⁸ is optionally substituted C1-C3 alkyl. In some embodiments when R ⁸ is optionally substituted C1-C3 alkyl, R ¹, R ², R ³, R ⁴, R ⁵, R ⁶, and R ⁷ are hydrogen. In some embodiments when R ⁸ is optionally substituted C1 -C3 alkyl, R ¹, R ², R ⁴, R ⁵, R ⁶, and R ⁷ are hydrogen, and R ³ is halogen. In some embodiments when R ⁸ is optionally substituted C1 -C3 alkyl, R ¹, R ², R ³, R ⁵, R ⁶, and R ⁷ are hydrogen, and R ⁴ is halogen. In some embodiments when R ⁸ is optionally substituted C 1 -C3 alkyl, R ¹ , R ², R ³, R ⁴, R ⁶, and R ⁷ are hydrogen, and R ⁵ is halogen. In some embodiments when R ⁸ is optionally substituted C1-C3 alkyl, R ¹ , R ², R ³, R ⁴, R ⁵, and R ⁷ are hydrogen, and R ⁶ is halogen.

In some embodiments, R ⁸ is halogen. In some embodiments when R ⁸ is halogen, R ¹ , R ², R\ R ⁴, R ^S, R ⁶, and R ⁷ are hydrogen. In some embodiments, when R ⁸ is halogen, R ⁷ is halogen. In some embodiments when R ⁷ and R ⁸ are halogen, R ¹ , R ², R ³, R ⁴, R ⁵, and R ⁶ are hydrogen. In some embodiments when R ⁷ and R ⁸ are halogen, R ¹ , R ², R ⁴, R ⁵, and R ⁶ are hydrogen and R ³ is optionally substituted Ci-C ₆ alkoxy.

In some embodiments, R ¹ and R ² are halogen. In some embodiments when R ¹ and R ² are halogen, R ⁴, R ⁵, R ⁶, R ⁷, and R ⁸ are hydrogen and R ³ is optionally substituted Ci- C ₆ alkoxy.

In some embodiments, R ³ is halogen. In some embodiments when R ³ is halogen, R ¹, R ², R ⁷, and R ⁸ are hydrogen. In some embodiments when R ³ is halogen and R ¹ , R ², R ⁷, and R ⁸ are hydrogen, R ⁴ is halogen. In some embodiments when R ³ is halogen and R ¹ , R ², R ⁷, and R ⁸ are hydrogen, R ³ is halogen. In some embodiments when R ³ is halogen and R ¹ , R ², R ⁷, and R ⁸ are hydrogen, R ⁶ is halogen.

In some embodiments, R ¹, R ², R ⁷, and R ⁸ are hydrogen. In some embodiments, R ¹ is halogen. In some embodiments, R ² is halogen. In some embodiments, R ¹ and R ² are halogen. In some embodiments, R ⁴ is halogen. In some embodiments when R ⁴ is halogen, R ¹ , R ², R ⁷, and R ⁸ are hydrogen. In some embodiments, R ⁴ is optionally substituted Ci-C ₆ alkoxy. In some embodiments when R ⁴ is optionally substituted C|-C ₆ alkoxy, R ¹ , R ², R ⁷, and R ⁸ are hydrogen.

In some embodiments, the compounds represented by formula (SC-24) are selected from a group of compounds having the formula:

foregoing compounds.

In some embodiments, the compounds of this disclosure are represented by general formula (SC-25):

SC-25 or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, or solvate thereof, wherein as valence and stability permit:

R' , R ², and R ³ are independently selected from the group consisting of hydrogen, and unsubstituted C 1 -C3 alkyl, C ₃-C ₅ cycloalkyl, C ₂-C alkenyl, methoxyethyl, ethoxyethyl, and ethynyl; and

R ⁴, R ⁵, R ⁶, and R ⁷ are independently selected from the group consisting of hydrogen, halogen, and optionally substituted Ci-C ₆ alkyl, C ₂-C ₆ alkenyl, C ₃-C ₆ cycloalkyl, C ₄-C ₆ cycloalkenyl, C ₂-C ₅ heterocycloalkyl, Ci-C ₆ alkoxy, C|-C ₆ alkylthio, phenyl, and monocyclic heteroaryl; wherein said optionally substituted Ci-C ₆ alkyl, C ₂-C ₆ alkenyl, C ₃-C ₆ cycloalkyl, C ₄- C ₆ cycloalkenyl, C ₂-C ₅ heterocycloalkyl, Ci-C ₆ alkylthio, and C|-C ₆ alkoxy are optionally substituted with one or more substituents selected from the group consisting of F, and unsubstituted OCH _3> OCH ₂CH ₃, CH ₃, C ₂H ₅, and C ₂-C ₅ dialkylamino; wherein said optionally substituted phenyl is optionally substituted with one or more substituents selected from the group consisting of F, CI, Br, SCF ₃, and unsubstituted OCH ₃, OCH ₂CH ₃, CH ₃, C ₂H _5; COOH, COOCH ₃, COOC ₂H ₅, SCH ₃, SOCH ₃, S0 ₂CH ₃, SCHF ₂, isopropyl, /-butyl, hydroxyl, dialkylamino, and alkylamino; wherein said optionally substituted monocyclic heteroaryl is optionally substituted with one or more substituents selected from the group consisting of F, CI, Br, SCF ₃, and unsubstituted OCH ₃, OCH ₂CH ₃, CH ₃, C ₂H ₅, COOH, COOCH ₃, COOC ₂H ₅, SCH ₃, SOCH ₃, S0 ₂CH ₃, SCHF ₂, isopropyl, /-butyl, hydroxyl, dialkylamino, and alkylamino; wherein R and R can optionally form a ring, wherein the ring is an optionally

substituted heterocyclyl or heteroaryl; wherein R ¹ and R ³ can optionally form a ring, wherein the ring is an optionally

substituted heterocyclyl or heteroaryl; wherein R ¹ and R ⁷ can optionally form a ring, wherein the ring is an optionally

substituted heterocyclyl or heteroaryl; wherein R ⁴ and R ⁵ can optionally form a ring, wherein the ring is an optionally

substituted cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein R ⁵ and R ⁶ can optionally form a ring, wherein the ring is an optionally

substituted cycloalkyl, heterocyclyl, aryl, or heteroaryl; 6 7

wherein R and R can optionally form a ring, wherein the ring is an optionally

substituted cycloalkyl, heterocyclyl, aryl, or heteroaryl.

In some embodiments, R ¹ is hydrogen. In some embodiments, R ² is hydrogen. In some embodiments, R ³ is hydrogen. In some embodiments, R ¹, R ², and R ³ are hydrogen. In some embodiments, R ¹ and R ² are hydrogen and R ³ is unsubstituted Ci- C ₃ alkyl. In some embodiments, R ¹ and R ² are hydrogen and R ³ is unsubstituted methyl.

In some embodiments, R ⁴ is hydrogen, halogen, or optionally substituted Ci-C ₆ alkyl, Ci-C ₆ alkoxy, or difluoromethoxy. In some embodiments when R ⁴ is hydrogen, halogen, or optionally substituted C]-C ₆ alkyl or C|-C ₆ alkoxy, or unsubstituted difluoromethoxy, R ¹, R ², and R ³ are hydrogen. In some embodiments when R ⁴ is hydrogen, halogen, or optionally substituted Ci-C ₆ alkyl or Ci-C ₆ alkoxy, or unsubstituted difluoromethoxy, R ¹ and R ² are hydrogen and R ³ is C|-C ₃ alkyl. In some embodiments when R ⁴ is hydrogen, halogen, or optionally substituted C]-C ₆ alkyl or C|-C ₆ alkoxy, or unsubstituted difluoromethoxy, R ¹, R ², R ⁵, and R ⁶ are hydrogen and R ³ is Ci-C ₃ alkyl. In some embodiments when R ⁴ is hydrogen, halogen, or optionally substituted C|-C ₆ alkyl or Ci-C ₆ alkoxy, or unsubstituted

difluoromethoxy, R ¹ and R ² are hydrogen and R ³ is methyl. In some embodiments when R ⁴ is hydrogen, halogen, or optionally substituted Ci-C ₆ alkyl or C|-C ₆ alkoxy, or unsubstituted difluoromethoxy, R ¹, R ², R ⁵, and R ⁶ are hydrogen and R ³ is unsubstituted methyl. In some embodiments, R ⁴ is hydrogen, fluorine, or

unsubstituted methyl, methoxy, or difluoromethoxy. In some embodiments when R ⁴ is hydrogen, fluorine, or unsubstituted methyl, methoxy, or difluoromethoxy, R ¹, R ², and R ³ are hydrogen. In some embodiments when R ⁴ is hydrogen, fluorine, or unsubstituted methyl, methoxy, or difluoromethoxy, R ¹ and R ² are hydrogen and R ³ is unsubstituted Ci-C ₃ alkyl. In some embodiments when R ⁴ is hydrogen, fluorine, or unsubstituted methyl, methoxy, or difluoromethoxy, R ¹, R ², R ⁵, and R ⁶ are hydrogen and R ³ is unsubstituted Ci-C ₃ alkyl. In some embodiments when R ⁴ is hydrogen, fluorine, or unsubstituted methyl, methoxy, or difluoromethoxy, R ¹ and R ² are hydrogen and R ³ is unsubstituted methyl. In some embodiments when R ⁴ is hydrogen, fluorine, or unsubstituted methyl, methoxy, or difluoromethoxy, R ¹, R ², R ⁵, and R ⁶ are hydrogen and R ³ is unsubstituted methyl.

In some embodiments, R ⁵ is hydrogen, halogen, or optionally substituted Ci -C ₆ alkyl or Ci-C ₆ alkoxy, or unsubstituted difluoromethoxy. In some embodiments when R ⁵ is hydrogen, halogen, or optionally substituted Ci-C ₆ alkyl or Ci -C ₆ alkoxy, or unsubstituted difluoromethoxy, R , R , and R are hydrogen. In some embodiments when R ⁵ is hydrogen, halogen, or optionally substituted C i-C ₆ alkyl or Ci-C alkoxy, or unsubstituted difluoromethoxy, R ¹ and R ² are hydrogen and R ³ is unsubstituted C | - C ₃ alkyl. In some embodiments when R ⁵ is hydrogen, halogen, or optionally substituted Ci-C ₆ alkyl or C i-C ₆ alkoxy, or unsubstituted difluoromethoxy, R ¹, R ², R ⁴, and R ⁶ are hydrogen and R ³ is unsubstituted Ci-C ₃ alkyl. In some embodiments when R ⁵ is hydrogen, halogen, or optionally substituted Ci-C ₆ alkyl or Ci-C ₆ alkoxy, or unsubstituted difluoromethoxy, R ¹ and R ² are hydrogen and R ³ is unsubstituted methyl. In some embodiments when R ⁵ is hydrogen, halogen, or optionally substituted C i-C ₆ alkyl or Ci-C ₆ alkoxy, or unsubstituted difluoromethoxy, R ¹, R ², R ⁴, and R ⁶ are hydrogen and R ³ is unsubstituted methyl. In some embodiments, R ⁵ is hydrogen, fluorine, or unsubstituted methyl, methoxy, or difluoromethoxy. In some

embodiments when R ⁵ is hydrogen, fluorine, or unsubstituted methyl, methoxy, or difluoromethoxy, R ¹, R ², and R ³ are hydrogen. In some embodiments when R ⁵ is hydrogen, fluorine, or unsubstituted methyl, methoxy, or difluoromethoxy, R ¹ and R ² are hydrogen and R ³ is unsubstituted C | -C ₃ alkyl. In some embodiments when R ⁵ is hydrogen, fluorine, or unsubstituted methyl, methoxy, or difluoromethoxy, R ¹, R ², R ⁴, and R ⁶ are hydrogen and R ³ is unsubstituted C |-C ₃ alkyl. In some embodiments when R ⁵ is hydrogen, fluorine, or unsubstituted methyl, methoxy, or difluoromethoxy, R ¹ and R ² are hydrogen and R ³ is unsubstituted methyl. In some embodiments when R ⁵ is hydrogen, fluorine, or unsubstituted methyl, methoxy, or difluoromethoxy, R ¹, R ², R ⁴, and R ⁶ are hydrogen and R ³ is unsubstituted methyl. In some embodiments, R ⁶ is hydrogen, halogen, or optionally substituted Ci-C ₆ alkyl or C]-C ₆ alkoxy, or unsubstituted difluoromethoxy. In some embodiments when R ⁶ is hydrogen, halogen, or optionally substituted Ci-C ₆ alkyl or Ci-C ₆ alkoxy, or unsubstituted difluoromethoxy, R ¹, R ², and R ³ are hydrogen. In some embodiments when R ⁶ is hydrogen, halogen, or optionally substituted C i-C ₆ alkyl or Ci-C alkoxy, or unsubstituted difluoromethoxy, R ¹ and R ² are hydrogen and R ³ is unsubstituted C i - C ₃ alkyl. In some embodiments when R ⁶ is hydrogen, halogen, or optionally substituted Ci-C ₆ alkyl or Ci-C ₆ alkoxy, or unsubstituted difluoromethoxy, R ¹, R ², R ⁴, and R ⁵ are hydrogen and R ³ is unsubstituted Ci-C ₃ alkyl. In some embodiments when R ⁶ is hydrogen, halogen, or optionally substituted C j-C ₆ alkyl or Ci-C ₆ alkoxy, or unsubstituted difluoromethoxy, R ¹ and R ² are hydrogen and R ³ is unsubstituted methyl. In some embodiments when R ⁶ is hydrogen, halogen, or optionally substituted C i-C ₆ alkyl or C i-C ₆ alkoxy, or unsubstituted difluoromethoxy, R ¹, R ², R ⁴, and R ⁵ are hydrogen and R ³ is unsubstituted methyl. In some embodiments, R ⁶ is hydrogen, fluorine, or unsubstituted methyl, methoxy, or difluoromethoxy. In some

embodiments when R ⁶ is hydrogen, fluorine, or unsubstituted methyl, methoxy, or difluoromethoxy, R ¹, R ², and R ³ are hydrogen. In some embodiments when R ⁶ is hydrogen, fluorine, or unsubstituted methyl, methoxy, or difluoromethoxy, R ¹ and R ² are hydrogen and R ³ is unsubstituted Ci-C ₃ alkyl. In some embodiments when R ⁶ is hydrogen, fluorine, or unsubstituted methyl, methoxy, or difluoromethoxy, R ¹, R ², R ⁴, and R ⁵ are hydrogen and R ³ is unsubstituted C|-C ₃ alkyl. In some embodiments when R ⁶ is hydrogen, fluorine, or unsubstituted methyl, methoxy, or difluoromethoxy, R ¹ and R ² are hydrogen and R ³ is unsubstituted methyl. In some embodiments when R ⁶ is hydrogen, fluorine, or unsubstituted methyl, methoxy, or difluoromethoxy, R ¹, R ², R ⁴, and R ⁵ are hydrogen and R ³ is unsubstituted methyl.

In some embodiments, the compounds represented by formula (SC-25) are selected from a group of compounds having the formula:

or a pharmaceutically acceptable salt, tautomer, or solvate of any of the foregoing compounds.

In some embodiments, the compound of this disclosure is selected from a group of compounds having the formula:

161

or a pharmaceutically acceptable salt, a free base form, tautomer, enantiomer, disastereomer, or solvate of any of the foregoing compounds. For example, the compound of this disclosure is selected from the group of compounds having the formula 1-432, or a pharmaceutically acceptable salt, a free base form, tautomer, enantiomer, disastereomer, or solvate of any of the foregoing compounds. In some embodiments, the compound of this disclosure is selected from the group of compounds having the formula 1, 54-93, 95-376, or 378-432, or a pharmaceutically acceptable salt, a free base form, enantiomer, disastereomer, tautomer, or solvate of any of the foregoing compounds. In some embodiments, the compound of this disclosure is selected from the group of compounds having the formula 1, 54-92, 95, 97, 98, 203-208, 210, 211, 315-317, 355-357, or 375, or a pharmaceutically acceptable salt, enantiomer, disastereomer, a free base form, tautomer or solvate of any of the foregoing compounds. In some embodiments, the compound of this disclosure is selected from the group of compounds having the formula 63, 66, 67, 72, 74, 83, 84, 90, 95, 218, 315, 316, 317, 355, 356, 357, or 375, or a pharmaceutically acceptable salt, a free base form, enantiomer, disastereomer, tautomer, or solvate of any of the foregoing compounds. In some embodiments, the compound of this disclosure is selected from the group of compounds having the formula 93, 96, 99-202, 212-217, 219-314, 318-354, 358-374, 376, or 378-432, or a pharmaceutically acceptable salt, a free base form, tautomer, enantiomer, disastereomer, or solvate of any of the foregoing compounds. In some embodiments, the compound of this disclosure is selected from the group of compounds having the formula 96, 111, 113-118, 123-129, 131, 133, 140-144, 146, 149, 150, 152, 153, 158, 160-167, 169, 170, 172, 176-178, 185, 187-

189, 193, 195, 202, 212-217, 219, 220, 222-228, 231-233, 235, 236, 238-241, 247-249, 254, 258, 259, 284, 286, 289, 296, 298, 303, 304, 306, 308-314, 323-325, 328-330, 336-349, 358, 359, 361, 364-366, 368, 372, 376, or 378-432, or a pharmaceutically acceptable salt, a free base form, tautomer,. enantiomer, disastereomer, or solvate of any of the foregoing compounds.

In some embodiments wherein alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aminoalkyl, hydroxyalkyl, alkoxy, alkoxyalkyl, alkylthio, alkylamino, amino, aryl, heteroaryl, arylalkyl, heteroarylalkyl, arylheteroalkyl, arylalkoxy, heteroarylalkoxy, aryloxy, heteroaryloxy, aryloxyalkyl, arylamino, heteroarylamino, aminoalkylaryloxyalkoxyaryl, heteroaryloxyalkyl, aryloxyalkoxy,

heteroaryloxyalkoxy, cycloalkyl, heterocyclyl, cycloalkenyl, heterocyclylalkenyl, alkoxycycloalkyl, cycloalkylalkyl, cycloalkylacyl, cycloalkylalkylamino,

cycloalkylaminoalkyl, heterocyclylalkyl, heterocyclylalkylamino, acylaminoalkyl, carbamoylaminoalkyl, alkanediyl, heteroalkanediyl, cycloalkanediyl,

heterocyclylalkanediyl, cycloalkylalkanediyl, cycloalkylheteroalkanediyl,

heterocyclylheteroalkanediyl, alkenediyl, heteroalkenediyl, alkynediyl, alkylthiodiyl, arylalkanediyl, alkylaryloxydiyl, aminoalkanediyl, aminoalkylaminodiyl,

oxyalkoxydiyl, alkylcycloalkylalkanediyl, heteroalkylcycloalkylheteroalkanediyl, alkylcycloalkenylalkanediyl, heteroalkylcycloalkenylheteroalkanediyl,

alkylheterocyclylalkanediyl, heteroalkylheterocyclylheteroalkanediyl, and 1 , 1 - dialkylcycloalkanediyl are substituted, they are substituted, valency and stability permitting, with one or more substituents selected from substituted or unsubstituted alkyl (such as perfluoroalkyl (e.g., trifiuoromethyl and difluoromethyl)), alkenyl, alkoxy, alkoxyalkyl, aryl, aralkyl, arylalkoxy, aryloxy, aryloxyalkyl, aryloxyalkoxy, hydroxyl, halo, alkoxy (such as perfluoroalkoxy (e.g., trifluoromethoxy and difluoromethoxy)), alkoxyalkoxy, hydroxyalkyl, hydroxyalkylamino, hydroxyalkoxy, amino, aminoalkyl, alkylamino, alkylaminoalkyl, aminoalkylacyl, aminoalkylalkoxy, aminoalkoxy, aminoalkylcarbamoylalkyl, N,N-dialkylmethanimidamido, amide, carbamoylaminoalkyl, acylamino, acylaminoalkyl (such as perfluoro acylaminoalkyl (e.g., trifluoromethylacylaminoalkyl)), acyl, acyloxy, cycloalkyl, cycloalkylalkyl, cycloalkylalkoxy, cycloalkenyl, heterocyclyl, heterocyclylalkyl, heterocyclyloxy, heterocyclylalkoxy, heteroaryl, heteroarylalkyl, heteroarylalkoxy, heteroaryloxy, heteroaryloxyalkyl, heterocyclylalkylaryloxy, heterocyclylalkylaryloxyalkoxy, heterocyclylaminoalkyl, heterocyclylaminoalkoxy, isothiocyanate, thiocyanate, amido, amidoalkyl, amidine, imine, oxo, carbonyl (such as carboxyl, alkoxycarbonyl, formyl, or acyl, including perfluoroacyl (e.g., C(0)CF ₃)), carbonylalkyl (such as carboxyalkyl, alkoxycarbonylalkyl, formylalkyl, or acylalkyl, including perfluoroacylalkyl (e.g., - alkylC(0)CF ₃)), carbamate, carbamatealkyl, urea, ureaalkyl, sulfate, sulfonate, sulfamoyl, sulfone, sulfonamide, sulfonamidealkyl, cyano, nitro, azido, sulfhydryl, alkylthio ((such as -SCF ₃)), thioalkyl, thiocycloalkyl, thiocarbonyl (such as thioester, thioacetate, or thioformate), phosphoryl, phosphate, phosphonate or phosphinate.

When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, then such substituent may be bonded to any atom on the ring. When a substituent is listed without indicating the atom via which such substituent is bonded to the rest of the compound of a given formula, then such substituent may be bonded via any atom in such substituent. Combinations of substituents, positions of substituents and/or variables are permissible only if such combinations result in stable compounds of this disclosure.

The compounds described herein can also be prepared as esters, for example pharmaceutically acceptable esters. For example, a carboxylic acid group in a compound can be converted to its corresponding ester, e.g., a methyl, ethyl, or other ester. Also, an alcohol group in a compound can be converted to its corresponding ester, e.g., an acetate, propionate, or other ester. In some embodiments, the disclosure of this application includes prodrugs of the compounds selected from the group of compounds having the formulae (SC-01 ), (SC- 02), (SC-03), (SC-04), (SC-05), (SC-06), (SC-07), (SC-08), (SC-09), (SC-10), (SC- 1 1 ), (SC- 12), (SC-13), (SC- 14), (SC-15), (SC- 16), (SC- 17), (SC- 18), (SC- 19), (SC- 20), (SC-21 ), (SC-22), (SC-23), (SC-24), (SC-25), or formula 1-432, or a

pharmaceutically acceptable salt, free base form, enantiomer, disastereomer, tautomer, or solvate of any of the foregoing compounds. The term "prodrug" is intended to encompass compounds which, under physiologic conditions, are converted into the therapeutically active agents of the disclosure of this application (e.g., any one of a compound selected from the group of compounds having formula (SC-01 ), (SC-02), (SC-03), (SC-04), (SC-05), (SC-06), (SC-07), (SC-08), (SC-09), (SC-10), (SC-1 1 ), (SC- 12), (SC-13), (SC-14), (SC- 15), (SC- 16), (SC-17), (SC-18), (SC-19), (SC-20), (SC-21), (SC-22), (SC-23), (SC-24), (SC-25), or formula 1-432, or a pharmaceutically acceptable salt, free base form, enantiomer, disastereomer, tautomer, or solvate of any of the foregoing compounds). A common method for making a prodrug is to include one or more selected moieties which are hydrolyzed under physiologic conditions to yield the desired molecule. In some embodiments, the prodrug is converted by an enzymatic activity of the host animal. For example, a prodrug with a nitro group on an aromatic ring can be reduced by an endogenous reductase to generate the desired amino group of the corresponding active compound in vivo. In another example, functional groups such as a hydroxyl, carbonate, or carboxylic acid in the parent compound are presented as an ester, which can be cleaved by esterases. Additionally, amine groups in the parent compounds are presented in, but not limited to, carbamate, N-alkylated or N-acylated forms (Simplicio, et al, "Prodrugs for Amines," Molecules, (2008), 13:5 19-547). In some embodiments, some or all of the compounds of formula (SC-01 ), (SC-02), (SC-03), (SC-04), (SC-05), (SC-06), (SC-07), (SC-08), (SC-09), (SC- 10), (SC-1 1 ), (SC- 12), (SC- 13), (SC- 14), (SC-15), (SC- 16), (SC- 17), (SC- 18), (SC-19), (SC-20), (SC-21 ), (SC-22), (SC-23), (SC-24), (SC-25), or formula 1-432, or a pharmaceutically acceptable salt, free base form, tautomer, enantiomer, disastereomer, or solvate of any of the foregoing compounds described herein or used in the methods described herein is replaced with the corresponding suitable prodrug.

Some embodiments of this disclosure include metabolites of the compounds selected from the group of compounds having the formulae (SC-01 ), (SC-02), (SC-03), (SC- 04), (SC-05), (SC-06), (SC-07), (SC-08), (SC-09), (SC-10), (SC-1 1), (SC-12), (SC- 13), (SC-14), (SC-15), (SC-16), (SC- 17), (SC- 18), (SC-19), (SC-20), (SC-21 ), (SC- 22), (SC-23), (SC-24), (SC-25), or formula 1-8, 10-26, or 28-432, or a

pharmaceutically acceptable salt, prodrug, tautomer, enantiomer, disastereomer, solvate, or free base form of any of the foregoing compounds. The term "metabolite" is intended to encompass compounds that are produced by metabolism/biochemical modification of the parent compound under physiological conditions, e.g. through certain enzymatic pathways. For example, an oxidative metabolite is formed by oxidation of the parent compound during metabolism, such as the oxidation of a pyridine ring to pyridine-N-oxide. In another example, an oxidative metabolite is formed by demethylation of a methoxy group to result in a hydroxyl group.

A variety of compounds of the embodiments of disclosure may exist in particular geometric or stereoisomeric forms. This disclosure includes all such compounds, including tautomers, cis- and trans-isomers, R- and S-enantiomers, diastereomers, (D)- isomers, (L)-isomers, the racemic mixtures thereof, and other mixtures thereof, as being covered within the scope of this disclosure. All tautomeric forms are encompassed in this disclosure. Additional asymmetric carbon atoms may be present in a substituent, such as an alkyl group. All such isomers, as well as mixtures thereof, are intended to be included in this disclosure, unless the stereochemistry or isomeric form is specifically indicated. Compounds described herein containing one or multiple asymmetrically substituted atoms may be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms, by synthesis from optically active starting materials, or by synthesis using optically active reagents. In some embodiments, the therapeutic preparations of the disclosure may be enriched to provide predominantly one enantiomer of a compound described herein (e.g., any of the compounds of formulae (SC-01 ), (SC-02), (SC-03), (SC-04), (SC-05), (SC-06), (SC-07), (SC-08), (SC-09), (SC- 10), (SC- 1 1 ), (SC- 12), (SC- 13), (SC- 14), (SC- 15), (SC- 16), (SC-17), (SC- 18), (SC- 19), (SC-20), (SC-21 ), (SC-22), (SC-23), (SC-24), (SC-25), or formula 1-432, or a pharmaceutically acceptable salt, free base, enantiomer, disastereomer, tautomer, solvate, or prodrug of any of the foregoing compounds). An enantiomerically enriched mixture may comprise, for example, at least 60 mol percent of one enantiomer, or more preferably at least 75, 80, 85, 90, 95, 96, 97, 98, 99, 99.5 or even 100 mol percent. In some embodiments, the compound described herein enriched in one enantiomer is substantially free of the other enantiomer, wherein substantially free means that the substance in question makes up less than 10%, or less than 5%, or less than 4%, or less than 3%, or less than 2%, or less than 1 % as compared to the amount of the other enantiomer, e.g., in the composition or compound mixture. For example, if a composition or compound mixture contains 98 grams of a first enantiomer and 2 grams of a second enantiomer, it would be said to contain 98 mol percent of the first enantiomer and only 2% of the second enantiomer.

In some embodiments, the therapeutic preparation may be enriched to provide predominantly one diastereomer of a compound disclosed herein (e.g., any of the compounds of formulae (SC-01), (SC-02), (SC-03), (SC-04), (SC-05), (SC-06), (SC- 07), (SC-08), (SC-09), (SC-10), (SC- 1 1 ), (SC- 12), (SC-13), (SC-14), (SC-15), (SC- 16), (SC-17), (SC-1 8), (SC- 19), (SC-20), (SC-21 ), (SC-22), (SC-23), (SC-24), (SC- 25), or formula 1-432, or a pharmaceutically acceptable salt, free base, tautomer, enantiomer, disastereomer, solvate or prodrug of any of the foregoing compounds). A diastereomerically enriched mixture may comprise, for example, at least 60 mol percent of one diastereomer, or more preferably at least 75, 90, 95, 96, 97, 98, 99, or even 100 mol percent. The compounds described herein further include all pharmaceutically acceptable isotopically labeled compounds (e.g., any of the compounds of formulae (SC-01 ), (SC-02), (SC-03), (SC-04), (SC-05), (SC-06), (SC-07), (SC-08), (SC-09), (SC-10), (SC- 1 1 ), (SC-12), (SC- 13), (SC- 14), (SC- 15), (SC-16), (SC-17), (SC- 18), (SC- 19), (SC-20), (SC-21 ), (SC-22), (SC-23), (SC-24), (SC-25), or formula .1-432, or a pharmaceutically acceptable salt, prodrug, tautomer, enantiomer, disastereomer, or solvate, or free base form of any of the foregoing compounds). An "isotopically" or "radio-labeled" compound is a compound where one or more atoms are replaced or substituted by an atom having an atomic mass or mass number different from the atomic mass or mass number typically found in nature (i.e., naturally occurring). For example, in some embodiments, in the compounds described herein (e.g., any of the compounds of formulae (SC-01 ), (SC-02), (SC-03), (SC-04), (SC-05), (SC-06), (SC- 07), (SC-08), (SC-09), (SC-10), (SC-1 1 ), (SC- 12), (SC- 13), (SC-14), (SC-15), (SC- 16), (SC- 17), (SC- 18), (SC- 19), (SC-20), (S.C-21), (SC-22), (SC-23), (SC-24), (SC- 25), or formula 1-432, or a pharmaceutically acceptable salt, prodrug, tautomer, enantiomer, disastereomer, solvate, or free base form of any of the foregoing compounds), hydrogen atoms are replaced or substituted by one or more deuterium or tritium (e.g., hydrogen atoms on a Ci _-6 alkyl or a Ci _-6 alkoxy are replaced with deutrium, such as ^-methoxy or l , l ,2,2-c/ -3-methylbutyl). Certain isotopically labeled compounds (e.g., any of the compounds of formulae (SC- 01 ), (SC-02), (SC-03), (SC-04), (SC-05), (SC-06), (SC-07), (SC-08), (SC-09), (SC- 10), (SC- 1 1 j, (SC- 12), (SC-13), (SC-14), (SC- 15), (SC- 16), (SC- 17), (SC- 1 8), (SC- 19), (SC-20), (SC-21), (SC-22), (SC-23), (SC-24), (SC-25), or formula 1-432, or a pharmaceutically acceptable salt, prodrug, tautomer, enantiomer, disastereomer, solvate, or free base form of any of the foregoing compounds) in this disclosure, for example, those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies. The radioactive isotopes tritium, i.e. ³H, and carbon 14, i.e., ¹ C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection. Substitution with heavier isotopes such as deuterium, i.e., ²H, may afford certain ♦

therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances. In some embodiments, the isotopically labeled compound is a substituted mucate salt of compound 9, such as (R)-isometheptene-N-CD ₃ mucate (compound 357), 6,7-D ₆-(R)-isometheptene mucate (compound 358), or 6,7-D ₆-(R)- isometheptene-N-CD ₃ mucate (compound 359).

Substitution with positron emitting isotopes, such as "C, ^{l 8}F, ¹⁵0, and ^{l 3}N, can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy.

Isotopically labeled compounds (e.g., any of the compounds of formulae (SC-01 ), (SC-02), (SC-03), (SC-04), (SC-05), (SC-06), (SC-07), (SC-08), (SC-09), (SC- 10), (SC- 1 1 ), (SC-12), (SC-13), (SC- 14), (SC- 15), (SC-16), (SC- 17), (SC-18), (SC- 19), (SC-20), (SC-21), (SC-22), (SC-23), (SC-24), (SC-25), or formula 1-432, or a pharmaceutically acceptable salt, tautomer, solvate, enantiomer, disastereomer, or free base form of any of the foregoing compounds) or their corresponding prodrugs described herein are prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying examples using an appropriate isotopically labeled reagent in place of the non-labeled reagent previously employed. Suitable isotopes that may be incorporated in compounds of this disclosure include but are not limited to ²H (also written as D for deuterium), ³H (also written as T for tritium), ⁿC, ¹³C, ^,4C, ¹³N, ¹⁵N, ¹⁵0, ^{, 7}0, ^{, 8}0, ¹⁸F, ³⁵S, ³⁶C1 , ⁸²Br, ⁷⁵Br, ⁷⁶Br, ⁷⁷Br, ¹²³I, ^l24I, ^{l 25}I, and ^{l 3 ,}I.

This disclosure includes pharmaceutically acceptable salts of compounds of this disclosure. The term "pharmaceutically acceptable salts" includes salts of the compounds described herein which are prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds. When compounds of this disclosure contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent.

Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt. When compounds of this disclosure contain relatively basic functionalities, such as an amine, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic, acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric,

dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids, and the like, as well as the salts derived from relatively nontoxic organic acids like acetic, trifluoroacetic, propionic, isobutyric, malic, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, /?-tolylsulfonic, citric, tartaric, methanesulfonic, camphorsulfonic, and the like. In some embodiments, the pharmaceutically acceptable salt is a hydrochloride salt. In some embodiments, the pharmaceutically acceptable salt is a sulfate acid salt. In some embodiments, the pharmaceutically acceptable salt is a phosphate salt. In some embodiments, the pharmaceutically acceptable salt is a mucate salt. In some embodiments, the pharmaceutically acceptable salt is an oxalate salt. In some embodiments, the pharmaceutically acceptable salt is a tartrate salt. In some embodiments, the pharmaceutically acceptable salt is a malate salt. In some embodiments, the pharmaceutically acceptable salt is a maleate salt. In some embodiments,

contemplated salts of the compounds include, but are not limited to, alkyl, dialkyl, trialkyl or tetra-alkyl ammonium salts. In some embodiments, contemplated salts of compounds include, but are not limited to, L-arginine, benenthamine, benzathine, betaine, calcium hydroxide, choline, deanol, diethanolamine, diethylamine, 2- (diethylamino)ethanol, ethanolamine, ethylenediamine, N-methylglucamine, hydrabamine, lH-imidazole, lithium, L-lysine, magnesium, 4-(2- hydroxyethyl)morpholine, piperazine, potassium, l -(2-hydroxyethyl)pyrrolidine, sodium, triethanolamine, tromethamine, and zinc salts. In some embodiments, contemplated salts of compounds include, but are not limited to, Li, Na, Ca, , Mg, Zn or other metal salts. Also included are the salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like (see, for example, Berge, et ah, "Pharmaceutical Salts," Journal of Pharmaceutical Science, 1977, 66, 1 -19). Certain specific compounds of this disclosure may contain both basic and acidic functionalities, as such, these compounds can be converted into either base or acid addition salts. Where a compound of this disclosure is provided as a pharmaceutically acceptable salt, other pharmaceutically acceptable salts of the compound are also contemplated and the disclosed salt should not be considered as limiting. All such pharmaceutically acceptable salts are intended to be included in the embodiments of this disclosure, even where a salt form of a compound of this disclosure is specifically indicated.

The neutral forms of the compounds are preferably regenerated by contacting the salt with a base or acid, as is appropriate, and isolating the parent compound in the conventional manner. The parent form of the compound may differ from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to the parent form of the compound for the purposes of this disclosure.

The compounds of this disclosure, including their pharmaceutically acceptable salts and prodrugs, can also exist as various solvates, such as with water (also known as hydrates), methanol, ethanol, dimethylformamide, diethyl ether, acetamide, and the like. Mixtures of such solvates can also be prepared. The source of such solvate can be from the solvent of crystallization, inherent in the solvent of preparation or crystallization, or adventitious to such solvent. The compounds of this disclosure, including their pharmaceutically acceptable salts and prodrugs, can also exist as various polymorphs, pseudopolymorphs, or in amorphous state. As used herein, the term "polymorph" refers to different crystalline forms of the same compound and other solid state molecular forms including pseudo- polymorphs, such as hydrates, solvates, or salts of the same compound. Different crystalline polymorphs have different crystal structures due to a different packing of molecules in the lattice, as a result of changes in temperature, pressure, or variations in the crystallization process. Polymorphs differ from each other in their physical properties, such as X-ray diffraction characteristics, stability, melting points, solubility, or rates of dissolution in certain solvents. Thus crystalline polymorphic forms are important aspects in the development of suitable dosage forms in pharmaceutical industry

Uses of the Compounds and Compositions and Methods of Treatment In some embodiments, this disclosure relates to use of one or more compounds having the formula (SC-01 ), formula (SC-02), formula (SC-03), formula (SC-04), formula (SC-05), formula (SC-06), formula (SC-07), formula (SC-08), formula (SC-09), formula (SC- 10), formula (SC-1 1), formula (SC- 12), formula (SC-13), formula (SC- 14), formula (SC-15), formula (SC-16), formula (SC-17), formula (SC- 18), formula (SC- 19), formula (SC-20), formula (SC-21), formula (SC-22), formula (SC-23), formula (SC-24), formula (SC-25), or formula 1-432, or a pharmaceutically acceptable salt, free base form, tautomer, enantiomer, disastereomer, solvate, or prodrug of any of the foregoing compounds, as an analgesic.

In some embodiments, this disclosure relates to any one of a compound having the formula (SC-01 ), formula (SC-02), formula (SC-03), formula (SC-04), formula (SC- 05), formula (SC-06), formula (SC-07), formula (SC-08), formula (SC-09), formula (SC- 10), formula (SC- 1 1 ), formula (SC- 12), formula (SC- 13), formula (SC- 14), formula (SC-15), formula (SC- 16), formula (SC- 17), formula (SC- 18), formula (SC- 19), formula (SC-20), formula (SC-21 ), formula (SC-22), formula (SC-23), formula (SC-24), or formula (SC-25), or formula 1-432, or mixtures thereof, or a

pharmaceutically acceptable salt, free base form, tautomer, enantiomer, disastereomer, solvate, or prodrug, or mixtures thereof, of any of the foregoing compounds, for use in treating or preventing pain; an inflammatory disease or disorder, an allergic disease or disorder, a metabolic disease, a cardiovascular disease or disorder, a neurogenic vascular disease or a painful condition associated with any of the foregoing conditions; an episodic tension-type headache; a migraine headache; a headache; cramping; a cognitive disorder; a tension or migraine headache due to a vascular, neurovascular, or neurogenic disorder or dysfunction during a menstrual cycle episode; a tension or migraine headache due to a vascular, neurovascular, or neurogenic disorder or dysfunction during a migraine episode; a headache from mild to moderate

hypertension; mild to moderate essential hypertension; organ transplant rejection; hot and cold flashes; traumatic brain injury (TBI); neurotoxicity; psychic pain;

psychological pain; psychiatric pain; depression; schizophrenia; anxiety; epilepsy; a stress disorder; excess sweating; a symptom related to drug withdrawal; allodynia; fibromyalgia; fibromyalgia-ness; central sensitization; centralization; regional pain syndrome; temporomandibular joint syndrome (TMJ); lower back pain; interstitial cystitis; Gulf War syndrome; visceral pain; kidney stones; gout; neuropathic pain; post-herpetic neuralgia; diabetic neuropathy; sickle cell pain; priapism; nociceptive pain; post-operative pain; orthopedic injury pain; phantom limb pain; bunionectomy; dental extraction; pain after severed spinal cord injury; osteoarthritis; rheumatoid arthritis; Lyme disease; Parkinson's disease; pain associated with cancer; opioid- induced constipation; an opioid withdrawal symptom; or pain associated with posttraumatic stress disorder (PTSD), or a combination of any of the foregoing conditions. In some embodiments, this disclosure relates to the use of any one of a compound having the formula (SC-01 ), formula (SC-02), formula (SC-03), formula (SC-04), formula (SC-05), formula (SC-06), formula (SC-07), formula (SC-08), formula (SC- 09), formula (SC-10), formula (SC-1 1 ), formula (SC-12), formula (SC-13), formula (SC- 14), formula (SC- 15), formula (SC- 16), formula (SC- 17), formula (SC- 18), formula (SC- 19), formula (SC-20), formula (SC-21 ), formula (SC-22), formula (SC- 23), formula (SC-24), formula (SC-25), or formula 1-432, or mixtures thereof, or a pharmaceutically acceptable salt, free base form, tautomer, enantiomer, disastereomer, solvate, or prodrug, or mixtures thereof, of any of the foregoing compounds, in the manufacture of a medicament for the treatment of pain; an inflammatory disease or disorder, an allergic disease or disorder, a metabolic disease, a cardiovascular disease or disorder, a neurogenic vascular disease or a painful condition associated with any of the foregoing conditions; an episodic tension-type headache; a migraine headache; a headache; cramping; a cognitive disorder; a tension or migraine headache due to a vascular, neurovascular, or neurogenic disorder or dysfunction during a menstrual cycle episode; a tension or migraine headache due to a vascular, neurovascular, or neurogenic disorder or dysfunction during a migraine episode; a headache from mild to moderate hypertension; mild to moderate essential hypertension; organ transplant rejection; hot and cold flashes; traumatic brain injury (TBI); neurotoxicity; psychic pain; psychological pain; psychiatric pain; depression; schizophrenia; anxiety;

epilepsy; a stress disorder; excess sweating; a symptom related to drug withdrawal; allodynia; fibromyalgia; fibromyalgia-ness; central sensitization; centralization;

regional pain syndrome; temporomandibular joint syndrome (TMJ); lower back pain; interstitial cystitis; Gulf War syndrome; visceral pain; kidney stones; gout;

neuropathic pain; post-herpetic neuralgia; diabetic neuropathy; sickle cell pain;

priapism; nociceptive pain; post-operative pain; orthopedic injury pain; phantom limb pain; bunionectomy; dental extraction; pain after severed spinal cord injury;

In some embodiments, this disclosure relates to a method of treating or preventing pain; an inflammatory disease or disorder, an allergic disease or disorder, a metabolic disease, a cardiovascular disease or disorder, a neurogenic vascular disease or a painful condition associated with any of the foregoing conditions; an episodic tension- type headache; a migraine headache; a headache; cramping; a cognitive disorder; a tension or migraine headache due to a vascular, neurovascular, or neurogenic disorder or dysfunction during a menstrual cycle episode; a tension or migraine headache due to a vascular, neurovascular, or neurogenic disorder or dysfunction during a migraine episode; a headache from mild to moderate hypertension; mild to moderate essential hypertension; organ transplant rejection; hot and cold flashes; traumatic brain injury (TBI); neurotoxicity; psychic pain; psychological pain; psychiatric pain; depression; schizophrenia; anxiety; epilepsy; a stress disorder; excess sweating; a symptom related to drug withdrawal; allodynia; fibromyalgia; fibromyalgia-ness; central sensitization; centralization; regional pain syndrome; temporomandibular joint syndrome (TMJ); lower back pain; interstitial cystitis; Gulf War syndrome; visceral pain; kidney stones; gout; neuropathic pain; post-herpetic neuralgia; diabetic neuropathy; sickle cell pain; priapism; nociceptive pain; post-operative pain; orthopedic injury pain; phantom limb pain; bunionectomy; dental extraction; pain after severed spinal cord injury;

In some embodiments, this disclosure relates to a pharmaceutical composition comprising as an active ingredient a therapeutically effective amount of any one of a compound having the formula (SC-01), formula (SC-02), formula (SC-03), formula (SC-04), formula (SC-05), formula (SC-06), formula (SC-07), formula (SC-08), formula (SC-09), formula (SC-10), formula (SC-1 1 ), formula (SC- 12), formula (SC- 13), formula (SC- 14), formula (SC- 15), formula (SC- 16), formula (SC- 17), formula (SC- 18), formula (SC- 19), formula (SC-20), formula (SC-21 ), formula (SC-22), formula (SC-23), formula (SC-24), formula (SC-25), or formula 1-432, or mixtures thereof, or a pharmaceutically acceptable salt, free base form, enantiomer, disastereomer, tautomer, solvate, or prodrug, or mixtures thereof, of any of the foregoing compounds, in association with at least one pharmaceutically acceptable excipient, carrier or diluent.

In some embodiments, this disclosure relates to use of a pharmaceutical composition comprising as an active ingredient a therapeutically effective amount of any one of a compound having the formula (SC-01 ), formula (SC-02), formula (SC-03), formula (SC-04), formula (SC-05), formula (SC-06), formula (SC-07), formula (SC-08), formula (SC-09), formula (SC- 10), formula (SC-1 1 ), formula (SC-12), formula (SC- 13), formula (SC- 14), formula (SC- 15), formula (SC- 16), formula (SC- 17), formula (SC-1 8), formula (SC-19), formula (SC-20), formula (SC-21 ), formula (SC-22), formula (SC-23), formula (SC-24), formula (SC-25), or formula 1-432, or mixtures thereof, or a pharmaceutically acceptable salt, free base form, tautomer, enantiomer, disastereomer, solvate, or prodrug, or mixtures thereof, of any of the foregoing compounds, as an analgesic. In some embodiments, this disclosure relates to the use of a pharmaceutical

composition comprising any one of a compound having the formula (SC-01 ), formula (SC-02), formula (SC-03), formula (SC-04), formula (SC-05), formula (SC-06), formula (SC-07), formula (SC-08), formula (SC-09), formula (SC- 10), formula (SC- 1 1 ), formula (SC-12), formula (SC-13), formula (SC- 14), formula (SC- 15), formula (SC-16), formula (SC- 17), formula (SC-18), formula (SC- 19), formula (SC-20), formula (SC-21 ), formula (SC-22), formula (SC-23), formula (SC-24), formula (SC- 25), or formula 1-432, or mixtures thereof, or a pharmaceutically acceptable salt, free base form, enantiomer, disastereomer, tautomer, solvate, or prodrug, or mixtures thereof, of any of the foregoing compounds, in the manufacture of a medicament for the treatment of pain; an inflammatory disease or disorder, an allergic disease or disorder, a metabolic disease, a cardiovascular disease or disorder, a neurogenic vascular disease or a painful condition associated with any of the foregoing conditions; an episodic tension-type headache; a migraine headache; a headache; cramping; a cognitive disorder; a tension or migraine headache due to a vascular, neurovascular, or neurogenic disorder or dysfunction during a menstrual cycle episode; a tension or migraine headache due to a vascular, neurovascular, or neurogenic disorder or dysfunction during a migraine episode; a headache from mild to moderate

hypertension; mild to moderate essential hypertension; organ transplant rejection; hot and cold flashes; traumatic brain injury (TBI); neurotoxicity; psychic pain;

disastereomer, solvate, or prodrug, or mixtures thereof, of any of the foregoing compounds.

In some embodiments, this disclosure relates to a method of modulating an imidazoline- 1 (I |) receptor, comprising contacting the I ] receptor with any one of a compound having the formula (SC-01 ), formula (SC-02), formula (SC-03), formula (SC-04), formula (SC-05), formula (SC-06), formula (SC-07), formula (SC-08), formula (SC-09), formula (SC- 10), formula (SC-1 1 ), formula (SC-12), formula (SC- 13), formula (SC- 14), formula (SC-15), formula (SC- 16), formula (SC-17), formula (SC- 1 8), formula (SC- 19), formula (SC-20), formula (SC-21 ), formula (SC-22), formula (SC-23), formula (SC-24), formula (SC-25), or formula 1-432, or mixtures thereof, or a pharmaceutically acceptable salt, free base form, tautomer, solvate, enantiomer, disastereomer, or prodrug, or mixtures thereof, of any of the foregoing compounds. In some embodiments, the compounds of this disclosure, or mixtures thereof, modulate the 11 receptor. In some embodiments, the compounds of this disclosure, or mixtures thereof, modulate the I i receptor to reduce pain. Without wishing to be bound by theory, in some embodiments, the compounds of this disclosure, or mixtures thereof, activate the I) receptor to reduce pain. In some embodiments, the compounds of this disclosure, or mixtures thereof, may reduce pain through a pathway that is independent of the Ii receptor (the Imidazoline- 1 Receptor- Independent Isometheptene Pain Modulatory pathway, or IRIPM pathway).

In some embodiments, this disclosure relates to a method of modulating an imidazoline-1 (I |) receptor in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of any one of a compound having the formula (SC-01 ), formula (SC-02), formula (SC-03), formula (SC-04), formula (SC- 05), formula (SC-06), formula (SC-07), formula (SC-08), formula (SC-09), formula (SC- 10), formula (SC-1 1 ), formula (SC-12), formula (SC- 13), formula (SC- 14), formula (SC- 15), formula (SC- 16), formula (SC-17), formula (SC-18), formula (SC- 19), formula (SC-20), formula (SC-21 ), formula (SC-22), formula (SC-23), formula (SC-24), formula (SC-25), or formula 1-432, or mixtures thereof, or a

pharmaceutically acceptable salt, free base form, tautomer, solvate, enantiomer, disastereomer, or prodrug, or mixtures thereof, of any of the foregoing compounds. In some embodiments, the compounds of this disclosure, or mixtures thereof, modulate the Ii receptor to reduce pain in a patient in need thereof. Without wishing to be bound by theory, in some embodiments, the compounds of this disclosure, or mixtures thereof, activate the 1 | receptor to reduce pain in a patient in need thereof. In some embodiments, the compounds of this disclosure, or mixtures thereof, may reduce pain in a patient in need thereof through a pathway that is independent of the I i receptor (the Imidazoline- 1 Receptor-Independent Isometheptene Pain Modulatory pathway, or IRIPM pathway).

In some embodiments, the I i receptor is selected from the group consisting of: a) an I| receptor comprising the amino acid sequence of SEQ ID NO: 1 or a

counterpart amino acid sequence of another species; b) an I) receptor comprising the amino acid sequence that is at least 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91 %, 90%, 85%, 80%, or 75% identical to the amino acid sequence of SEQ ID NO: 1 or a counterpart amino acid sequence of another species; c) an 11 receptor comprising the amino acid sequence that is at least 99% identical to the amino acid sequence of SEQ ID NO: 1 or a counterpart amino acid sequence of another species; d) an Ii receptor comprising the amino acid sequence that is at least 98% identical to the amino acid sequence of SEQ ID NO: 1 or a counterpart amino acid sequence of another species; e) an I i receptor comprising the amino acid sequence that is at least 97% identical to the amino acid sequence of SEQ ID NO: l or a counterpart amino acid sequence of another species; f) an I i receptor comprising the amino acid sequence that is at least 96% identical to the amino acid sequence of SEQ ID NO: 1 or a counterpart amino acid sequence of another species; g) an I i receptor comprising the amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: l or a counterpart amino acid sequence of another species; h) an I i receptor comprising the amino acid sequence that is at least 94% identical to the amino acid sequence of SEQ ID NO: 1 or a counterpart amino acid sequence of another species; i) an l i receptor comprising the amino acid sequence that is at least 93% identical to the amino acid sequence of SEQ ID NO: 1 or a counterpart amino acid sequence of another species; j) an Ii receptor comprising the amino acid sequence that is at least 92% identical to the amino acid sequence of SEQ ID NO: 1 or a counterpart amino acid sequence of another ^'species; an Ii receptor comprising the amino acid sequence that is at least 91% identical to the amino acid sequence of SEQ ID NO: 1 or a counterpart amino acid sequence of another species; and

1) an I ] receptor comprising the amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 1 or a counterpart amino acid sequence of another species. In some embodiments, this disclosure relates to a method for nitric oxidase inhibition in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of any one of a compound having the formula (SC-01 ), formula (SC- 02), formula (SC-03), formula (SC-04), formula (SC-05), formula (SC-06), formula (SC-07), formula (SC-08), formula (SC-09), formula (SC- 10), formula (SC- 1 1 ), formula (SC- 12), formula (SC- 13), formula (SC- 14), formula (SC-15), formula (SC- 16), formula (SC-17), formula (SC-18), formula (SC-19), formula (SC-20), formula (SC-21), formula (SCr22), formula (SC-23), formula (SC-24), formula (SC-25), or formula 1-432, or mixtures thereof, or a pharmaceutically acceptable salt, free base form, tautomer, solvate, enantiomer, disastereomer, or prodrug, or mixtures thereof, of any of the foregoing compounds, simultaneously, separately, or sequentially in combination with one or more substances selected from the group consisting of acetaminophen, a non-steroidal anti-inflammatory drug (NSAID), ibuprofen, naprosyn, a cycIooxygenase-2 inhibitor, aspirin, caffeine, dichloralphenazone, a triptan, a chemotherapeutic drug, an antidepressant, a serotonin-norepinephrine reuptake inhibitor (SNRI), a gabapentinoid, an antiproliferative agent, an anti-inflammatory agent, a corticosteroid, an anti-asthmatic agent, an anti-allergic agent, an

In the treatment of pain; an inflammatory disease or disorder, an allergic disease or disorder, a metabolic disease, a cardiovascular disease or disorder, a neurogenic vascular disease or a painful condition associated with any of the foregoing conditions; an episodic tension-type headache; a migraine headache; a headache; cramping; a cognitive disorder; a tension or migraine headache due to a vascular, neurovascular, or neurogenic disorder or dysfunction during a menstrual cycle episode; a tension or migraine headache due to a vascular, neurovascular, or neurogenic disorder or dysfunction during a migraine episode; a headache from mild to moderate

hypertension; mild to moderate essential hypertension; organ transplant rejection; hot and cold flashes; traumatic brain injury (TBI); neurotoxicity; psychic pain;

In some embodiments, one of more of the compounds and compositions of this disclosure may be used alone or together or conjointly administered with another type of therapeutic agent. As used herein, the phrase "conjoint administration" refers to any form of administration of two or more different therapeutic compounds or compositions such that the second compound or composition is administered while the previously administered therapeutic compound or composition is still effective in the body. For example, the different therapeutic compounds or compositions can be administered either in the same formulation or in a separate formulation, either simultaneously, sequentially, or by separate dosing of the individual components of the treatment. In some embodiments, the different therapeutic compounds or compositions are administered within one hour, 12 hours, 24 hours, 36 hours, 48 hours, 72 hours, or a week of one another. Thus, an individual who receives such treatment can benefit from a combined effect of different therapeutic compounds or compositions.

In some embodiments, conjoint administration of compounds or compositions described herein with one or more additional therapeutic agent(s) provides improved efficacy relative to each individual administration of the compound of this disclosure (e.g., any one of a compound of formula (SC-01), formula (SC-02), formula (SC-03), formula (SC-04), formula (SC-05), formula (SC-06), formula (SC-07), formula (SC- 08), formula (SC-09), formula (SC- 10), formula (SC-1 1), formula (SC-12), formula (SC-13), formula (SC- 14), formula (SC-15), formula (SC-16), formula (SC- 17), formula (SC-18), formula (SC- 19), formula (SC-20), formula (SC-21 ), formula (SC- 22), formula (SC-23), formula (SC-24), formula (SC-25), or formula 1-432, or a pharmaceutically acceptable salt, free base form, enantiomer, disastereomer, tautomer, solvate, or prodrug of any of the foregoing compounds) or the one or more additional therapeutic agent(s). In certain such embodiments, the conjoint administration provides an additive effect, wherein an additive effect refers to the sum of each of the effects of individual administration of the compound or composition of the application and the one or more additional therapeutic agent(s).

In further embodiments, the compounds or compositions described herein are used simultaneously, separately, or sequentially with one or more additional therapeutics selected from the group consisting of acetaminophen, a non-steroidal anti- inflammatory drug (NSA1D), ibuprofen, naprosyn, a cyclooxygenase-2 inhibitor, aspirin, caffeine, dichloralphenazone, a triptan, an antidepressant, a serotonin- norepinephrine reuptake inhibitor (SNRI), and a gabapentinoid. In some embodiments, the compound is used with one or more additional therapeutics selected from the group consisting of a chemotherapeutic drug, an antiproliferative agent, an antiinflammatory agent, a corticosteroid, an anti-asthmatic agent, an anti-allergic agent, an immunosuppressive agent, an immunomodulatory agent, a cardiovascular disease treatment agent, an anti-diabetic agent, a blood disorder treatment agent, a nerve growth factor receptor antagonist, a sodium channel blocker, a CYP2D6 inhibitor, and a TNF-alpha inhibitor. In some embodiments, the compound is used with one or more opiates.

The compounds and compositions disclosed herein, and mixtures thereof, may also be used in the manufacture of medicaments for the treatment of any diseases or conditions disclosed herein. Methods of Treatment and Use

The compounds and compositions of this disclosure, or mixtures thereof, are useful as analgesics or to treat pain; an inflammatory disease or disorder, an allergic disease or disorder, a metabolic disease, a cardiovascular disease or disorder, a neurogenic vascular disease or a painful condition associated with any of the foregoing conditions; an episodic tension-type headache; a migraine headache; a headache; cramping; a cognitive disorder; a tension or migraine headache due to a vascular, neurovascular, or neurogenic disorder or dysfunction during a menstrual cycle episode; a tension or migraine headache due to a vascular, neurovascular, or neurogenic disorder or dysfunction during a migraine episode; a headache from mild to moderate

hypertension; mild to moderate essential hypertension; organ transplant rejection; hot and cold flashes; traumatic brain injury (TBI); neurotoxicity; psychic pain;

In some embodiments, the compounds of this disclosure are ligands of the

imidazoline- 1 (I i) receptor. In some embodiments, the compounds and compositions of this disclosure modulate the I ] receptor. In some embodiments, the compounds and compositions of this disclosure modulate the l i receptor to reduce pain. Without wishing to be bound by theory, in some embodiments, the compounds and

compositions of this disclosure activate the I i receptor to reduce pain. In some embodiments, the compounds and compositions of this disclosure may reduce pain through a pathway that is independent of the I i receptor (the Imidazoline- 1 Receptor- Independent Isometheptene Pain Modulatory pathway, or IRIPM pathway).

In some embodiments, the compounds and compositions of this disclosure, or mixtures thereof, simultaneously, separately, or sequentially in combination with one or more substances selected from the group consisting of acetaminophen, a nonsteroidal anti-inflammatory drug (NSAID), ibuprofen, naprosyn, a cyclooxygenase-2 inhibitor, aspirin, caffeine, dichloralphenazone, a triptan, a chemotherapeutic drug, an antidepressant, a serotonin-norepinephrine reuptake inhibitor (SNRI), a gabapentinoid, an antiproliferative agent, an anti-inflammatory agent, a corticosteroid, an anti- asthmatic agent, an anti-allergic agent, an immunosuppressive agent, an

immunomodulatory agent, a cardiovascular disease treatment agent, an anti-diabetic agent, a blood disorder treatment agent, a nerve growth factor receptor antagonist, a sodium channel blocker, a CYP2D6 inhibitor, a^TNF-alpha inhibitor, or one or more opiates are useful for inhibiting nitric oxidase in a patient in need thereof. Analgesic

The compounds and compositions of this disclosure act as potent and selective pain inhibitors or painkillers. An analgesic is a member of the group of drugs used to achieve analgesia or relief from pain Pain

The compounds and compositions of this disclosure are useful in the treatment or prevention of pain. Pain is an unpleasant feeling triggered by the nervous system. It is often classified by the region of the body involved, the system whose dysfunction may be causing the pain, the duration and pattern of occurrence, the intensity and time since onset, and the etiology. Many types of pain exist, including, but not limited to, nociceptive pain, neuropathic pain, psychogenic pain, visceral pain, and chronic pain.

Inflammatory diseases or disorders and allergic diseases or disorders

The compounds and compositions of this disclosure are useful in the treatment or prevention of diseases of inflammation and allergy as manifested in cells required to mount an inflammatory response, such as neutrophils, macrophages, mast cells, T- cells, B-cells, plasma cells, dendritic cells, basophils, and eosinophils. The pain and tension associated with inflammatory diseases or conditions which are treatable by the compounds and compositions of this disclosure include, but are not limited to, autoimmune diseases and common arthritis types, including rheumatoid arthritis, osteoarthritis, ankyolsing spondylitis, psoriatic arthritis; psoriasis, systemic lupus erythematosus, glomerulonephritis, scleroderma, general renal failure, inflammatory bowel disease, ulcerative colitis, Crohn's disease, pancreatitis, multiple sclerosis; inflammation due to hyper-responsiveness to cytokine production, chronic obstructive pulmonary, airway or lung disease (COPD, COAD, or COLD), acute respiratory distress syndrome (ARDS) and occupation-related diseases such as aluminosis, anthracosis, asbestosis, chalicosis, ptilosis, siderosis, silicosis, tabacosis and byssinosis. Additionally, the compounds and compositions of this disclosure are useful in the treatment or prevention of parasite-related diseases involving

hypereosinophilia.

The compounds and compositions of this disclosure are useful for the treatment or prevention of diseases and conditions related to immediate-type hypersensitivity, also referred to as allergic responses, conditions and diseases. These diseases and conditions include, but are not limited to, asthma (extrinsic or intrinsic), asthma related sequelae including small and large airway hyperactivity, bronanaphylaxis, aspirin induced asthma, allergic airway inflammation, urticaria, Steven-Johnson syndrome, atopic dermatitis, bolus pemphigoid and the like. Metabolic diseases

The compounds and compositions of this disclosure are useful in the treatment or prevention of discomfort and pain due to inflammation associated with metabolic diseases, such as diabetes and obesity.

Cardiovascular diseases or disorders Cardiovascular diseases, acute heart failure, enlargement of the heart, and

atherosclerosis are also diseases that are suitable for ameliorating the treatment ^'or prevention using the compounds and compositions of this disclosure. Nonlimiting examples of cardiovascular diseases also include pulmonary hypertension, deep venous thrombosis, stroke, myocardial infarction, myocardial contractility diseases or disorders, ischemia, thromboembolism, pulmonary embolism, acute arterial ischemia, peripheral thrombotic occlusions, coronary artery disease and acute coronary syndrome (ACS). In some embodiments, the cardiovascular disease treated or prevented by compounds and compositions of this disclosure is atherosclerosis. In some embodiments, the neurovascular effect on cardiovascular disease treated or prevented by compounds and compositions of this disclosure is a myocardial contractility disease or disorder or an acute coronary syndrome. Neurogenic vascular diseases or painful conditions associated therewith

In some embodiments, compounds and compositions of this disclosure are useful in the treatment or prevention of pain caused by neurogenic vascular diseases.

Symptoms are caused by the compression of the spinal cord or nerve roots in the lower region of the spine or by narrowing of the arteries in the legs, and include leg pain, leg weakness, tingling, fatigue, a sensation of heaviness, and weakness.

Headaches and episodic tension-type headaches

In some embodiments, compounds and compositions of this disclosure are useful in the treatment or prevention of pain caused by headaches and episodic tension-type headaches. A headache is pain in any region of the head, and may occur on one or both sides of the head, be isolated to a certain location, radiate across the head from one point, or have a vise-like quality. Headaches can cause sharp pain, a throbbing sensation, or a dull ache. Primary headaches can be caused by problems with or overactivity of pain-sensitive structures in the head, and secondary headaches can be caused by diseases, such as brain cancer, glaucoma, and trigeminal neuralgia, which activate the pain-sensitive nerves in the head.

A tension-type headache is classified into subtypes based on how often it occurs: infrequent episodic tension-type headache (ETTH) (<1 day /month on average), frequent ETTH ( 1 - 14 days/month on average), or chronic TTH, or CTTH, (~ 15 days/month on average). An ETTH (infrequent or frequent) may be described as a mild to moderate constant band-like pain, tightness, or pressure around the forehead or back of the head and neck. ETTH may last from 30 minutes to several days. ETTH usually begins gradually, and often occurs in the middle of the day. The severity of a tension headache generally increases significantly with its frequency. Because the symptoms of ETTH overlap with other primary headache types, diagnosis is generally made, not only by inclusion, but also of exclusion of certain symptoms such as nausea, exacerbation by physical exercise and occurrence of both photophobia and

phonophobia. Migraine

In some embodiments, compounds and compositions of this disclosure are useful in the treatment or prevention of migraines; tension or migraine headaches due to a vascular, neurovascular, or neurogenic disorder or dysfunction during a menstrual cycle episode; or tension or migraine headaches due to a vascular, neurovascular, or neurogenic disorder or dysfunction during a migraine episode. Migraine is described as a paroxysmal disorder or a recurrent, incapacitating, neurovascular disorder characterized by unilateral and throbbing headaches associated characterized by attacks of headache, nausea, vomiting, photophobia, and phonophobia. Migraine affects people of all races and both sexes with women accounting for 79% (61 % between 20 and 49 years of age) of physician visits for migraines and

Caucasians for 91% of the physician visits. Migraine without aura often has a strict menstrual relationship. The pathogenesis of migraine headache involves a) the cranial blood vessels, b) the trigeminal innervation of these vessels, and c) the reflex connection of the trigeminovascular system in the cranial parasympathetic outflow.

Migraine pathophysiology is believed by genetic predisposition to involve leakage of ion channels in the brain stem such that the decreased blood flow in the brain leads to neuropeptide release from trigeminal nerves inducing dilatation of cranial

extracerebral blood vessel. This condition stimulates the trigeminovascular system producing headache associated phonophobia and photophobia as well as nausea and vomiting.

Phantom limb pain

In some embodiments, the compounds and compositions of this disclosure are useful in the treatment or prevention of alleviate phantom pain. Phantom pain is pain coming from a body part that's no longer there. This pain originates in the spinal cord and brain and may be described as shooting, stabbing, boring, squeezing, throbbing or burning. Cramps or cramping

In some embodiments, the compounds and compositions of this disclosure are useful in the treatment or prevention of cramps or cramping. Cramps are unpleasant, sometimes painful sensations caused by involuntary muscle contraction or muscle over-shortening. Cramps can be symptoms of muscle spasm and can be separated into smooth muscle cramps and skeletal muscle cramps. Cramps related to internal (or visceral) organs are related to spasm of smooth muscle or skeletal muscle or distension of organs by functional or pathological disorders, and can be associated with visceral pain. Smooth muscle cramps are commonly associated with menstruation or visceral disorders including gastrointestinal and urinary disorders. In the female, smooth muscle cramps that are associated with menstruation are called menstrual cramps and may also occur before and during a female menstrual cycle. Severe or persistent smooth muscle cramps may also be symptomatic of endometriosis or other health problems. Moreover, smooth muscle cramps can be associated with gastrointestinal disorders, including infectious or autoimmune gastroenteritis and functional disorders such as irritable bowel syndrome (IBS). Thus, smooth muscle cramps are associated with visceral pain in many conditions, including interstitial cystitis.

Skeletal muscle cramps are associated with muscle fatigue, low sodium, low potassium and certain drugs, including statins. Skeletal muscle cramps also include nocturnal leg cramps which are involuntary muscle contractions that occur during the night or (less commonly) while resting. Nocturnal leg cramps are common in the elderly, teenagers or in women during the late stages of pregnancy, and can vary in intensity from mild to extremely painful.

Menopause In some embodiments, the compounds and compositions of this disclosure are useful in the treatment or prevention of pain and discomfort associated with menopause. Menopause is an event that typically occurs in women that can be defined as the permanent cessation of the primary functions of the ovaries and is functionally evident when there is a termination of periodic shedding of the uterine lining (known as menses).

Hot and cold flashes

The compounds and compositions of this disclosure are useful in the treatment or prevention of hot and cold flashes, unpleasant sensations associated with vascular events. Hot flashes (also known as night sweats if they happen at night) are a symptom which may have several other causes, but which is often caused by the changing hormone levels that are characteristic of menopause.

Cognitive disorders The compounds and compositions of this disclosure are useful to treat or prevent cognitive disorders. Cognitive disorders are a category of mental health disorders that primarily affect learning, memory, perception, and problem solving, and include amnesia, dementia, and delirium. Causes vary between the different types of disorders but most include damage to the memory portions of the brain. Mild cognitive impairment (MCI, also known as incipient dementia, or isolated memory impairment) is a brain function syndrome involving the onset and evolution of cognitive impairments beyond those expected based on the age and education of the individual, but which are not significant enough to interfere with their daily activities. MCI can be a transitional stage between normal aging and dementia. Alzheimer's disease (AD) is the most common form of dementia. AD is commonly diagnosed in people over 65 years of age, although the less-prevalent early-onset Alzheimer's can occur much earlier. In the early stages, the most common symptom is difficulty in remembering recent events. As the disease advances, symptoms can include confusion, irritability and aggression, mood swings, trouble with language, and long-term memory loss. In later stages, AD patients often withdraw from family and society. Gradually, bodily functions are lost, ultimately leading to death. The compounds and compositions of this disclosure are also useful in the treatment of "agitation," or anxiety and tension, in dementias. Traumatic brain injury (TBI)

The compounds and compositions of this disclosure are useful in the treatment or prevention of pain associated with traumatic brain injury (TBI). TBI is also known as intracranial injury, occurs when an external force traumatically injures the brain. TBI can be classified based on severity, mechanism (closed or penetrating head injury), or other features (e.g., occurring in a specific location or over a widespread area). Head injury usually refers to TBI, but is a broader category because it can involve damage to structures other than the brain, such as the scalp and skull.

Neurotoxicity The compounds and compositions of this disclosure are useful to treat or prevent symptoms related to neurotoxicity. Neurotoxicity occurs when the exposure to natural or artificial toxic substances, which are called neurotoxins, alters the normal activity of the nervous system in such a way as to cause damage to nervous tissue.

Neurotoxicity can result from exposure to substances used in chemotherapy, radiation treatment, drug therapies, certain drug abuse, and organ transplants, as well as exposure to heavy metals, certain foods and food additives, pesticides, industrial and/or cleaning solvents, cosmetics, ^' and some naturally occurring substances.

Symptoms may appear immediately after exposure or be delayed. They may include limb weakness or numbness, loss of memory, vision, and/or intellect, uncontrollable obsessive and/or compulsive behaviors, delusions, headache, cognitive and behavioral problems, and sexual dysfunction.

Depression

The compounds and compositions of this disclosure are useful in the treatment and prevention of depression. Depression, clinical depression, major depression, unipolar depression, unipolar disorder, or recurrent depression in the case of repeated episodes is a psychiatric diagnosis for a mood disorder characterized by episodes of all encompassing low mood accompanied by low self-esteem and loss of interest or pleasure in normally enjoyable activities (anhedonia) and disturbed sleep (typically early morning awakening). The term "depression" is ambiguous and can be used to describe manic-depressive disorder, but is also used to describe other mood disorders or to lower mood states lacking clinical significance. For example, endogenous depression or the depressed phases of bipolar disorder can be associated with widespread pain or regional pain disorders.

Pain experienced during depression can include, but is not limited to, psychogenic pain, psychiatric pain, psychic pain, and psychological pain. Psychogenic pain is pain that results from psychological mechanisms including traumatic experiences, empathic reactions or somatization. For example, loss of a loved friend or relative by death or other separation can result in widespread pain, regional pain, and other symptoms including reactive depression. Psychiatric pain is pain that results from conditions that are believed to have biological causes. Psychic pain and psychological pain are caused by a non-physical origin and can lead to emotional suffering and mental agony.

Schizophrenia Schizophrenia is a psychiatric diagnosis for a thought disorder characterized by a breakdown of thought processes and by a deficit of typical emotional responses.

Common symptoms include auditory hallucinations, paranoid or bizarre delusions, or disorganized speech and thinking. The compounds and compositions of this disclosure are useful in the treatment and prevention of the symptoms of schizophrenia. Anxiety

Anxiety disorder is a blanket term covering several different forms of a type of common psychiatric disorder characterized by excessive rumination, worrying, uneasiness, apprehension, and fear about future uncertainties either based on real or imagined events, which may affect both physical and psychological health. The compounds and compositions of this disclosure are useful in the treatment and prevention of the symptoms of anxiety. In some embodiments, the anxiety is associated with white coat syndrome. Patients with white coat syndrome feel anxiety in a medical environment, which can lead to elevated blood pressure. In some embodiments, the compounds or compositions of this disclosure are useful in the treatment of anxiety and tension associated with dementias such as Alzheimer's disease.

Epilepsy The compounds and compositions of this disclosure are useful in the treatment and prevention of epilepsy. Epilepsy is a common and diverse set of chronic neurological disorders characterized by seizures. In many cases a cause cannot be identified;

however, factors that are associated include brain trauma, strokes, brain cancer, and drug and alcohol misuse among others. Stress disorders

Stress disorders are an increasingly recognized group of conditions relating to the body's reaction to stressful circumstances and in some cases to decompensated reactions. The compounds and compositions of this disclosure are useful in the treatment and prevention of stress disorders. Excess sweating

The compounds and compositions of this disclosure are useful in the treatment and prevention of excess sweating. Hyperhidrosis, or excess sweating, can either be generalized or localized to specific parts of the body. Hands, feet, armpits, and the groin area are among the most active regions of perspiration due to the relatively high concentration of sweat glands. When excessive sweating is localized it is referred to as primary or focal hyperhidrosis. Generalized or secondary hyperhidrosis usually involves the body as a whole and is the result of an underlying condition.

Hyperhidrosis can also be classified depending by onset, either congenital or acquired. Primary or focal hyperhidrosis must be distinguished from secondary hyperhidrosis, which can start at any point in life. The later form may be due to a disorder of the thyroid or pituitary glands, diabetes mellitus, tumors, gout, menopause, certain drugs, or mercury poisoning. Hyperhidrosis may also be divided into palmoplanar (symptomatic sweating of primarily the hands or feet), gustatory and generalized hyperhidrosis.

Symptoms related to drug withdrawal

Withdrawal is the group of symptoms that occur upon the abrupt discontinuation or decrease in intake of medications or recreational drugs. In order to experience the symptoms of withdrawal, one must have first developed a physical or mental dependence (often referred to as chemical dependency). Symptoms of drug

withdrawal vary depending on the drug, but can include: anxiety, sweating, vomiting, diarrhea, irritability, fatigue, shaking, sweating, nausea, insomnia, headache, and difficulty concentrating. The compounds and compositions of this disclosure are useful in the treatment and prevention of symptoms of drug withdrawal.

Side effects associated with opioid administration or treatment

Opioid analgesics are a class of analgesic agents with morphine-like actions.

Synthetic and semi-synthetic opioid analgesics are derivatives of five chemical classes of compound: phenanthrenes; phenylheptylamines; phenylpiperidines; morphinans; and benzomorphans. These compounds have pharmacologically diverse activities. Some are strong agonists at the opioid receptors (e.g. morphine); others are moderate to mild agonists (e.g. codeine); still others exhibit mixed agonist-antagonist activity (e.g. nalbuphine); and yet others are partial agonists (e.g. nalorphine). While opioids are inexpensive and effective, serious and potentially life-threatening side effects occur with their use, most notably respiratory depression and muscle rigidity. In addition, the doses of opioids which can be administered are limited by nausea, emesis, constipation, pruritis and urinary retention, often resulting in patients electing to receive suboptimal pain control rather than suffer these distressing side-effects.

Moreover, patients often develop dependence on opioids and suffer opioid withdrawal symptoms upon discontinuation of treatment. The compounds and compositions of this disclosure are useful in the treatment and prevention of side effects associated with opioid administration or treatment. Headaches from mild to moderate hypertension and mild to moderate essential hypertension

The compounds and compositions of this disclosure are useful in the treatment and prevention of hypertension and the symptoms of hypertension. High blood pressure is a common condition in which the force of the blood against the artery walls is high enough that it may eventually cause health problems, such as heart disease.

Hypertension puts strain on the heart, possibly leading to hypertensive heart disease and coronary artery disease, and it is a major risk factor for stroke, aneurysms of the arteries, peripheral arterial disease, and chronic kidney disease. Symptoms of hypertension include dull headaches and dizzy spells.

Organ transplant rejection

The compounds and compositions of this disclosure are useful in treatment to help prevent the immune system from rejecting a new organ after an organ transplant.

Allodynia The compounds and compositions of this disclosure are useful in the treatment or prevention of allodynia. Allodynia, or pain due to a stimulus that does not usually provoke pain, is a prominent symptom in patients with neuropathic pain. Allodynia is seen in various peripheral neuropathies and central pain disorders, and affects 15— 50% of patients with neuropathic pain. Allodynia is classified according to the sensory modality (touch, pressure, pinprick, cold, and heat) that is used to elicit the sensation.

Fibromyalgia

Fibromyalgia is a disorder characterized by widespread musculoskeletal pain accompanied by fatigue, sleep, memory and mood issues. Research indicates that fibromyalgia amplifies painful sensations by affecting the way the brain processes pain signals. Symptoms of fibromyalgia sometimes begin after a physical trauma, surgery, infection, or significant psychological stress. In other cases, symptoms gradually accumulate over time with no single triggering event. Symptoms include: widespread pain on both sides of the body and above and below the waist, fatigue, cognitive difficulties, depression, headaches, and pain or cramping in the lower abdomen. The compounds and compositions of this disclosure are useful in the treatment or prevention of fibromyalgia.

Fibromyalgia-ness

Fibromyalgia-ness is the tendency to respond to illness and psychosocial stress with fatigue and widespread pain. The compounds and compositions of this disclosure are useful in the treatment or prevention of fibromyalgia-ness.

Central sensitization

The compounds and compositions of this disclosure are useful in the treatment or prevention of central sensitization. Central or chronic sensitization is a condition of the nervous system that is associated with the development and maintenance of chronic pain. When central sensitization occurs, the nervous system goes through a process called "wind-up" and gets regulated in a persistent state of high reactivity. This persistent, or regulated, state of reactivity subsequently comes to maintain pain even after the initial injury might be healed.

Central sensitization has two main characteristics. Both involve a heightened sensitivity to pain and the sensation of touch. They are called 'allodynia' and

'hyperalgesia.' Allodynia occurs when a person experiences pain with things that are normally not painful. Hyperalgesia occurs when an actual painful stimulus is perceived as more painful than it should. With allodynia and hyperalgesia, the sensation of pain travels through the nervous system, which is in a persistent state of high reactivity, and the pain is registered in the brain as a heightened level of pain. Centralization

The compounds and compositions of this disclosure are useful in the treatment or prevention of centralization. The pathogenesis of fibromyalgia is believed to involve sensitization of the central nervous system (CNS) to perceiving painful stimuli, which is termed "central sensitization" or "centralization". Centralization leads to the perception of widespread pain. Pain of this type is termed, "central neuropathic pain" or "central pain". Centralization also leads and to other symptoms, including visceral pain such as irritable bowel, tension-type headache, and migraine.

Regional pain syndrome The compounds and compositions of this disclosure are useful in the treatment or prevention of regional pain syndrome. Regional pain syndrome or complex regional pain syndrome (CRPS) is a chronic pain condition most often affecting one of the limbs (arms, legs, hands, or feet), usually after an injury or trauma to that limb. CRPS is believed to be caused by damage to, or malfunction of, the peripheral and central nervous systems. CRPS is characterized by prolonged or excessive pain and mild or dramatic changes in skin color, temperature, and/or swelling in the affected area.

Temporomandibular joint syndrome (TMJ)

The compounds and compositions of this disclosure are useful in the treatment or prevention of temporomandibular joint syndrome (TMJ). TMJ disorders can cause pain in the jaw joint and in the muscles that control jaw movement. Signs and symptoms of TMJ disorders may include: pain or tenderness of the jaw, aching pain in and around the ear, difficulty chewing or discomfort while chewing, aching facial pain, locking of the jaw joint, and a clicking sound or grating sensation when opening the mouth or chewing. Lower back pain

Lower back pain may be dull or sharp pain in the lower back. The pain may be in one small area or over a broad area and may include muscle spasms. Lower back pain may be caused by overuse, strain, or injury; aging; a herniated disc; arthritis;

compression fractures; illness; a congenital spine problem; or other causes. The compounds and compositions of this disclosure are useful in the treatment or prevention of lower back pain.

Interstitial cystitis

Interstitial cystitis is a chronic condition in which one experiences bladder pressure, bladder pain, and sometimes pelvic pain, ranging from mild discomfort to severe pain.

Interstitial cystitis signs and symptoms include: pain in the pelvis or between the vagina and anus in women or between the scrotum and anus in men (perineum);

chronic pelvic pain; a persistent, urgent need to urinate; frequent urination, often of small amounts, throughout the day and night; pain or discomfort while the bladder fills and relief after urinating; or pain during sexual intercourse. The compounds and compositions of this disclosure are useful in the treatment or prevention of interstitial cystitis.

Gulf War syndrome

A prominent condition affecting Gulf War Veterans is a cluster of medically unexplained chronic symptoms that can include fatigue, headaches, joint pain, indigestion, insomnia, dizziness, respiratory disorders, and memory problems. The compounds and compositions of this disclosure are useful in the treatment or prevention of Gulf War syndrome.

Visceral pain The compounds and compositions of this disclosure are useful in the treatment or prevention of visceral pain. Visceral pain is caused by the activation of pain receptors in the chest, abdomen, or pelvic areas. Visceral pain is caused by problems with internal organs, such as the stomach, kidney, gallbladder, urinary bladder, and intestines. These problems include distension, perforation, inflammation, and impaction or constipation, which can cause associated symptoms, such as nausea, fever, malaise, and pain. Visceral pain is also caused by problems with abdominal muscles and the abdominal wall, such as spasm. Visceral pain is vague and not well localized and is usually described as pressure-like, deep squeezing, dull, or diffuse.

Kidney stones

Kidney stones form in the kidney and as they travel through the tubes of the urinary tract their movement may cause: sudden, severe pain that gets worse in waves; intense pain in the back, side, abdomen, groin, or genitals; nausea and vomiting; blood in the urine (hematuria); and frequent and painful urination. The compounds and compositions of this disclosure are useful in the treatment of kidney stones.

Gout The compounds and compositions of this disclosure are useful in the treatment of gout. Gout occurs when urate crystals accumulate in joints, causing inflammation and intense pain. The signs and symptoms of gout almost always occur suddenly and include: intense joint pain, inflammation and redness, and decreased joint mobility.

Neuropathic pain Neuropathic pain is a complex, chronic pain state that usually is accompanied by tissue injury. With neuropathic pain, the nerve fibers themselves might be damaged, dysfunctional, or injured, and these damaged nerve fibers send incorrect signals to other pain centers. The impact of a nerve fiber injury includes a change in nerve function both at the site of injury and areas around the injury. The compounds and compositions of this disclosure are useful to treat or prevent neuropathic pain. Post-herpetic neuralgia

The compounds and compositions of this disclosure are useful in the treatment or prevention of post-herpetic neuralgia. Post-herpetic neuralgia is a complication of shingles, which is caused by the chickenpox (herpes zoster) virus. Post-herpetic neuralgia affects the nerve fibers and skin, and the burning pain associated with postherpetic neuralgia can be severe enough to interfere with sleep and appetite. The signs and symptoms of post-herpetic neuralgia are generally limited to the area of the skin where the shingles outbreak first occurred, and may include: pain, sensitivity to light touch, itching and numbness, and weakness or paralysis. Diabetic neuropathy

Diabetic neuropathy is a type of nerve damage that can occur with diabetes. Diabetic neuropathy most often damages nerves in the legs and feet. Symptoms of diabetic neuropathy can range from pain and numbness in the extremities, extreme sensitivity to touch, muscle weakness and difficulty walking, and serious foot problems to problems with the digestive system, urinary tract, blood vessels, and heart. The compounds and compositions of this disclosure are useful in the treatment or prevention of diabetic neuropathy.

Sickle cell pain

The compounds and compositions of this disclosure are useful in the treatment or prevention of sickle cell pain. Sickle cell disease causes red blood cells to form into a crescent shape, like a sickle. The sickle-shaped red blood cells break apart easily, causing anemia, and the damaged sickle red blood cells clump together and stick to the walls of blood vessels, blocking blood flow. This can cause severe pain and permanent damage to the brain, heart, lungs, kidneys, liver, bones, and spleen. Priapism

Priapism is a prolonged erection of the penis. The unwanted, persistent erection is not caused by sexual stimulation or arousal, and priapism is usually painful. The compounds and compositions of this disclosure are useful in the treatment or prevention of priapism.

Nociceptive pain

Nociceptive pain is caused when special nerve endings— called nociceptors— are irritated. Nociceptors are the nerves which sense and respond to parts of the body which suffer from damage. They signal tissue irritation, impending injury, or actual injury. When activated, they transmit pain signals (via the peripheral nerves as well as the spinal cord) to the brain. The pain is typically well localized, constant, and often with an aching or throbbing quality. The compounds and compositions of this disclosure are useful in the treatment or prevention of nociceptive pain.

Post-operative pain Post-operative pain is pain that occurs after an operation. The compounds and compositions of this disclosure are useful in the treatment or prevention of postoperative pain.

Orthopedic injury pain

Orthopedic injuries are conditions involving the musculoskeletal system, and can include musculoskeletal trauma, sports injuries, degenerative diseases, or infections. Pain caused by orthopedic injury may be treated or prevented by the compounds and compositions of this disclosure.

Bunionectomy

A bunion is an enlargement of the joint at the base of the big toe, and is comprised of bone and soft tissue. The pain of a bunion can make walking and other activities extremely difficult, leading to the need for bunionectomy, a surgical procedure to excise a bunion. The compounds and compositions of this disclosure are useful in the treatment before, during, or after bunionectomy.

Dental extraction A dental extraction means having a tooth removed, usually because of disease, trauma, or crowding. The compounds and compositions of this disclosure are useful in the treatment before, during, or after dental extraction.

Pain after severed spinal cord injury

The co npounds and compositions of this disclosure are useful in the treatment to alleviate pain associated with spinal cord injury.

Osteoarthritis

Osteoarthritis is the most common form of arthritis, affecting millions of people worldwide. It occurs when the protective cartilage on the ends of the bones wears down over time. Symptoms include: pain, tenderness, stiffness, loss of flexibility, grating sensation, and bone spurs. The compounds and compositions of this disclosure are useful in the treatment of osteoarthritis.

Rheumatoid arthritis

The compounds and compositions of this disclosure are useful in the treatment of rheumatoid arthritis. Rheumatoid arthritis is a chronic inflammatory disorder that typically affects the small joints in the hands and feet. Rheumatoid arthritis affects the lining of the joints, causing painful swelling that can eventually result in bone erosion and joint deformity. An autoimmune disorder, rheumatoid arthritis occurs when the immune system mistakenly attacks the body's own tissues. In addition to causing joint problems, rheumatoid arthritis sometimes can affect other organs of the body— such as the skin, eyes, lungs, and blood vessels. Signs and symptoms of rheumatoid arthritis may include: tender, warm, swollen joints; morning stiffness; rheumatoid nodules; and fatigue, fever, and weight loss.

Lyme disease

Lyme disease is the most common tick-borne illness in North America and Europe. Lyme disease is caused by the bacterium Borrelia burgdorferi, and deer ticks, which feed on the blood of animals and humans, can harbor the bacteria and spread it when feeding. Signs and symptoms of Lyme disease include: joint pain and neurological problems. The compounds and compositions of this disclosure are useful in the treatment of Lyme disease. Parkinson 's disease

The compounds and compositions of this disclosure are useful in the treatment of Parkinson's disease. Parkinson's disease is a neurodegenerative disorder of the central nervous system caused by the death of dopaminergic neurons in the substania nigra. Symptoms of Parkinson's disease may include tremor, bradykinesia, rigid muscles, impaired posture and balance, speech changes, and loss of automatic movements.

Pain associated with cancer

The compounds and compositions of this disclosure are useful in the treatment or prevention of pain associated with cancer. Cancer pain can result from the cancer itself as the cancer grows into or destroys nearby tissues. As a tumor grows, it may put pressure on nerves, bones or organs, causing pain. Cancer pain may also not just be from the physical effect of the cancer on a region of the body, but also due to chemicals that the cancer may release in the region of the tumor.

Cancer treatments, such as chemotherapy, radiation and surgery, are another potential source of cancer pain. Surgery can be painful, radiation may leave behind a burning sensation or painful scars, and chemotherapy can cause many potentially painful side effects, including mouth sores, diarrhea and nerve damage.

Pain associated with post-traumatic stress disorder (PTSD)

The compounds and compositions of this disclosure are useful in the treatment or prevention of pain associated with post-traumatic stress disorder (PTSD). PTSD is a mental health condition that's triggered by a terrifying event— either experiencing it or witnessing it. Symptoms may include chronic pain, flashbacks, nightmares, and severe anxiety, as well as uncontrollable thoughts about the event.

The terms "treatment," "treating," and the like are used herein to generally mean obtaining a desired pharmacologic and/or physiologic effect. "Treating" a condition or disease refers to curing as well as ameliorating at least one symptom of the condition or disease, and includes administration of a composition which reduces the frequency of, or delays the onset of, symptoms of a medical condition in a subject in need relative to a subject which does not receive the composition. "Treatment" may also be use of any of the compounds and compositions described herein as an analgesic. In some embodiments, "treatment" may be use of the compounds and compositions described herein to modulate an imidazoline-1 (Ii) receptor in a patient in need thereof. In some embodiments, "treatment" may be use of the compounds and compositions of this disclosure to modulate the I | receptor to reduce pain in a patient in need thereof. Without wishing to be bound by theory, in some embodiments, "treatment" may be use of the compounds and compositions of this disclosure to activate the I | receptor to reduce pain in a patient in need thereof. In some embodiments, "treatment" may be use of the compounds and compositions of this disclosure to reduce pain through a pathway that is independent of the I | receptor (the Imidazoline- 1 Receptor-Independent Isometheptene Pain Modulatory pathway, or

IRIPM pathway) in a patient in need thereof. In some embodiments, "treatment" may be use of the compounds of this disclosure and compositions simultaneously, separately, or sequentially in combination with one or more substances selected from the group consisting of acetaminophen, a non-steroidal anti-inflammatory drug (NSAID), ibuprofen, naprosyn, a cyclooxygenase-2 inhibitor, aspirin, caffeine, dichloralphenazone, a triptan, a chemotherapeutic drug, an antidepressant, a serotonin-norepinephrine reuptake inhibitor (SNR1), a gabapentinoid, an

Merely to illustrate, "treatment" of a migraine headache may include, but is not limited to, an improvement in any of the following symptoms or conditions associated with migraine headache (or combination thereof): pain on one side or both sides of the head, sensitivity to light and sounds, nausea and vomiting, blurred vision, allodynia, and lightheadness. "Treatment" of pain may include, but is not limited to, a reduction in the pain experienced by the patient. "Treatment" of fibromyalgia may include, but is not limited to, an improvement in any of the following symptoms or conditions associated with fibromyalgia (or combination thereof): widespread pain, fatigue, and cognitive difficulties (e.g., impaired ability to focus). "Treatment" of an inflammatory disease or disorder may include, but is not limited to, an improvement in any of the following symptoms or conditions associated with an inflammatory disease or disorder (or combination thereof): pain, tension, redness, soreness, and irritation. "Treatment" of an allergic disease or disorder may include, but is not limited to, an improvement in any of the following symptoms or conditions associated with an allergic disease or disorder (or combination thereof): asthma (extrinsic or intrinsic), asthma related sequelae including small and large airway hyperactivity, bronanaphylaxis, aspirin induced asthma, allergic airway inflammation, urticaria, and atopic dermatitis.

"Treatment" of a metabolic disease or disorder may include, but is not limited to, an improvement in any of the following symptoms or conditions associated with a metabolic disease or disorder (or combination thereof): discomfort, pain, and inflammation. "Treatment" of a cardiovascular disease or disorder may include, but is not limited to, an improvement in any of the following symptoms or conditions associated with a cardiovascular disease or disorder (or combination thereof): chest pain; shortness of breath; pain, numbness, weakness, or coldness in the arms or legs; and pain in the neck, jaw, throat, upper abdomen, or back. "Treatment" of a neurogenic vascular disease or a painful condition associated therewith may include, but is not limited to, an improvement in any of the following symptoms or conditions associated with a neurogenic vascular disease or a painful condition associated therewith (or combination thereof): leg pain, leg weakness, tingling, fatigue, a sensation of heaviness, and weakness. "Treatment" of a headache or an episodic tension-type headache may include, but is not limited to, an improvement in any of the following symptoms or conditions associated with a headache or an episodic tension- type headache (or combination thereof): sharp pain, throbbing sensation, dull ache, and nausea. "Treatment" of phantom limb pain may include, but is not limited to, an improvement in any of the following symptoms or conditions associated with phantom limb pain (or combination thereof): shooting, stabbing, or squeezing pain coming from the body part that is no longer there. "Treatment" of cramping may include, but is not limited to, an improvement in any of the following symptoms or conditions associated with cramping (or combination thereof): skeletal muscle cramps, smooth muscle cramps, and muscle spasms. "Treatment" of a headache from mild to moderate hypertension and mild to moderate essential hypertension may include, but is not limited to, an improvement in any of the following symptoms or conditions associated with a headache from mild to moderate hypertension and mild to moderate essential hypertension (or combination thereof): high blood pressure, dull headaches, and dizzy spells. "Treatment" of a cognitive disorder may include, but is not limited to, an improvement in any of the following symptoms or conditions associated with a cognitive disorder (or combination thereof): amnesia, dementia, delirium, confusion, irritability and aggression, mood swings, trouble with language, anxiety and tension, and long-term memory loss. "Treatment" of organ transplant rejection may include, but is not limited to, an improvement in the body's acceptance of the organ.

"Treatment" of hot and cold flashes may include, but is not limited to, an

improvement in any of the following symptoms or conditions associated with hot and cold flashes (or combination thereof): warmth, flushing, and perspiration.

"Treatment" of traumatic brain injury (TBI) may include, but is not limited to, an improvement in any of the following symptoms or conditions associated with TBI (or combination thereof): headache, vomiting or nausea, and convulsions or seizures. "Treatment" of neurotoxicity may include, but is not limited to, an improvement in any of the following symptoms or conditions associated with neurotoxicity (or combination thereof): limb weakness or numbness; loss of memory, vision, and/or intellect; uncontrollable obsessive and/or compulsive behaviors; delusions; headache; cognitive and behavioral problems; and sexual dysfunction. "Treatment" of depression may include, but is not limited to, an improvement in any of the following symptoms or conditions associated with depression (or combination thereof):

unexplained aches and pains, concentration problems, loss of energy, and anger or irritability. "Treatment" of psychic or psychological pain may include, but is not limited to, an improvement in any of the following symptoms or conditions associated with psychic or psychological pain (or combination thereof): emotional suffering and mental agony. "Treatment" of psychiatric pain may include, but is not limited to, an improvement in any of the following symptoms or conditions associated with psychiatric pain (or combination thereof): widespread pain and regional pain.

"Treatment" of schizophrenia may include, but is not limited to, an improvement in any of the following symptoms or conditions associated with schizophrenia (or combination thereof): hallucinations, delusions, depression, and social withdrawal. "Treatment" of anxiety may include, but is not limited to, an improvement in any of the following. symptoms or conditions associated with anxiety (or combination thereof): heart palpitations or chest pain, trouble breathing, hot flashes or chills, and surge of overwhelming panic. "Treatment" of epilepsy may include, but is not limited to, an improvement in any of the following symptoms or conditions associated with epilepsy (or combination thereof): seizures, violent shaking, tingling, and loss of alertness. "Treatment" of a stress disorder may include, but is not limited to, an improvement in any of the following symptoms or conditions associated with a stress disorder (or combination thereof)'- depression, anxiety, headaches, pain, and nausea. "Treatment" of excess sweating may include, but is not limited to, an improvement in any of the following symptoms or conditions associated with excess sweating (or combination thereof): sweating and wetness. "Treatment" of a symptom related to drug withdrawal may include, but is not limited to, an improvement in any of the following symptoms or conditions associated with a symptom related to drug withdrawal (or combination thereof): anxiety, sweating, vomiting, diarrhea, irritability, fatigue, shaking, sweating, nausea, insomnia, headache, and difficulty concentrating. "Treatment" of allodynia may include, but is not limited to, an improvement in any of the following symptoms or conditions associated with a symptom related to allodynia (or combination thereof): pain due to a stimulus that does not usually provoke pain. "Treatment" of fibromyalgia-ness may include, but is not limited to, an improvement in any of the following symptoms or conditions associated with a symptom related to fibromyalgia-ness (or combination thereof): fatigue and widespread pain.

"Treatment" of central sensitization may include, but is not limited to, an

improvement in any of the following symptoms or conditions associated with a symptom related to central sensitization (or combination thereof): allodynia and hyperalgesia. "Treatment" of centralization may include, but is not limited to, an improvement in any of the following symptoms or conditions associated with a . symptom related to centralization (or combination thereof): irritable bowel, tension- type headache, and migraine. "Treatment" of regional pain syndrome may include, but is not limited to, an improvement in any of the following symptoms or conditions associated with a symptom related to regional pain syndrome (or combination thereof): swelling and pain in the arms, legs, hands, or feet. "Treatment" of temporomandibular joint syndrome (TMJ) may include, but is not limited to, an improvement in any of the following symptoms or conditions associated with a symptom related to TMJ (or combination thereof): pain or tenderness of the jaw, aching pain in and around the ear, difficulty chewing or discomfort while chewing, aching facial pain, locking of the jaw joint, and a clicking sound or grating sensation when opening the mouth or chewing. "Treatment" of lower back pain may include, but is not limited to, an improvement in any of the following symptoms or conditions associated with a symptom related to lower back pain (or combination thereof): pain in the lower back and muscles spasms in the lower back. "Treatment" of interstitial cystitis may include, but is not limited to, an improvement in any of the following symptoms or conditions associated with a symptom related to interstitial cystitis (or combination thereof): chronic pelvic pain; a persistent, urgent need to urinate; frequent urination, often of small amounts, throughout the day and night; pain or discomfort while the bladder fills and relief after urinating; and pain during sexual intercourse. "Treatment" of Gulf War syndrome may include, but is not limited to, an

improvement in any of the following symptoms or conditions associated with a symptom related to Gulf War syndrome (or combination thereof): fatigue, headaches, and joint pain. "Treatment" of visceral pain may include, but is not limited to, an improvement in any of the following symptoms or conditions associated with a symptom related to visceral pain (or combination thereof): pressure-like, deep squeezing, dull, or diffuse pain in the chest, abdomen, or pelvic areas. "Treatment" of kidney stones may include, but is not limited to, an improvement in any of the following symptoms or conditions associated with a symptom related to kidney stones (or combination thereof): intense pain in the back, side, abdomen, groin, or genitals, and nausea and vomiting. "Treatment" of gout may include, but is not limited to, an improvement in any of the following symptoms or conditions associated with a symptom related to gout (or combination thereof): intense joint pain, inflammation, and redness, and decreased joint mobility. "Treatment" of neuropathic pain may include, but is not limited to, an improvement in any of the following symptoms or conditions associated with a symptom related to neuropathic pain (or combination thereof): shooting and burning pain, tingling, and numbness. "Treatment" of postherpetic neuralgia may include, but is not limited to, an improvement in any of the following symptoms or conditions associated with a symptom related to post-herpetic neuralgia (or combination thereof): pain, sensitivity to light touch, itching and numbness, and weakness or paralysis. "Treatment" of diabetic neuropathy may include, but is not limited to, an improvement in any of the following symptoms or conditions associated with a symptom related to diabetic neuropathy (or combination thereof): pain and numbness in the extremities, extreme sensitivity to touch, muscle weakness, and difficulty walking. "Treatment" of sickle cell pain may include, but is not limited to, an improvement in any of the following symptoms or conditions associated with a symptom related to sickle cell pain (or combination thereof): pain in the chest, abdomen, joints, and bones. "Treatment" of priapism may include, but is not limited to, an improvement in any of the following symptoms or conditions associated with a symptom related to priapism (or combination thereof): unwanted, persistent and painful erection. "Treatment" of nociceptive pain may include, but is not limited to, an improvement in any of the following symptoms or conditions associated with a symptom related to nociceptive pain (or combination thereof): aching or throbbing pain. "Treatment" of post-operative pain may include, but is not - limited to, an improvement in any of the following symptoms or conditions associated with a symptom related to post-operative pain (or combination thereof): pain, swelling, and irritation after an operation. "Treatment" of orthopedic injury pain may include, but is not limited to, an improvement in any of the following symptoms or conditions associated with a symptom related to orthopedic injury pain (or combination thereof): pain, swelling, and irritation after an orthopedic injury.

"Treatment" of bunionectomy may include, but is not limited to, an improvement in any of the following symptoms or conditions associated with a symptom related to bunionectomy (or combination thereof): pain, swelling, and irritation after a bunionectomy. "Treatment" of dental extraction may include, but is not limited to, an improvement in any of the following symptoms or conditions associated with a symptom related to dental extraction (or combination thereof): pain, swelling, and irritation after a dental extraction. "Treatment" of pain after severed spinal cord injury may include, but is not limited to, an improvement in any of the following symptoms or conditions associated with a symptom related to pain after severed spinal cord injury (or combination thereof): pain and irritation after severed spinal cord injury. "Treatment" of osteoarthritis may include, but is not limited to, an improvement in any of the following symptoms or conditions associated with a symptom related to osteoarthritis (or combination thereof): pain, tenderness, stiffness, loss of flexibility, grating sensation, and bone spurs. "Treatment" of rheumatoid arthritis may include, but is not limited to, an improvement in any of the following symptoms or conditions associated with a symptom related to rheumatoid arthritis (or combination thereof): tender, warm, swollen joints; morning "stiffness; rheumatoid nodules; and fatigue, fever and weight loss. "Treatment" of Lyme disease may include, but is not limited to, an improvement in any of the following symptoms or conditions associated with a symptom related to Lyme disease (or combination thereof): joint pain and neurological problems. "Treatment" of Parkinson's disease may include, but is not limited to, an improvement in any of the following symptoms or conditions associated with a symptom related to Parkinson's disease (or combination thereof): tremor and muscle rigidity. "Treatment" of pain associated with cancer may include, but is not limited to, an improvement in any of the following symptoms or conditions associated with a symptom related to pain associated with cancer (or combination thereof): chronic pain, pain from nerve damage, and burning sensation. "Treatment" of pain associated with post-traumatic stress disorder (PTSD) may include, but is not limited to, an

improvement in any of the following symptoms or conditions associated with a symptom related to pain associated with post-traumatic stress disorder (PTSD) (or combination thereof): chronic pain and headaches.

Improvements in any of these symptoms can be readily assessed according to standard methods and techniques known in the art. Symptoms are not limited to those listed herein and other symptoms may also be monitored in order to determine the effectiveness of treatment. The population of subjects treated by the method of this disclosure includes subjects suffering from the undesirable condition or disease, as well as subjects at risk for development of the condition or disease. Without wishing to be bound by theory, administering any of the compounds and compositions described herein may have any one or more of the following effects: analgesia; alleviation of widespread pain; decrease in pain from headaches, tension-type headaches, and migraines; reduction in depression, seizures, convulsions, and fatigue; decrease in inflammation, pain, tension, redness, soreness, and irritation; relief from asthma, atopic dermatitis, chest pain, shortness of breath, and numbness; lowered blood pressure; decreased cramping; reduction of leg pain, leg weakness, tingling, fatigue, and weakness; improvement in amnesia, dementia, delirium, confusion, irritability and aggression, mood swings, trouble with language, and long-term memory loss; reductions in hot and cold flashes and excessive sweating; reduced muscle rigidity associated with Parkinson's disease; and relief of pain associated with cancer, PTSD, rheumatoid arthritis, allodynia, kidney stones, gout, fibromyalgia, and fibromyalgia-ness. It should be noted that any of the compounds and compositions described herein are useful in any of the methods described herein. Effects are not limited to those listed herein and other effects may also be noted during treatment.

The term "preventing" is art-recognized and includes stopping a disease, disorder, or condition from occurring in a subject, which may be predisposed to the disease, disorder and/or condition but has not yet been diagnosed as having it. Preventing a condition related to a disease includes stopping the condition from occurring after the disease has been diagnosed but before the condition has been diagnosed.

A "patient," "subject," or "host" to be treated by the subject method may mean either a human or non-human animal, such as a mammal, a fish, a bird, a reptile, or an amphibian. Thus, the subject of the herein disclosed methods can be a human, non- human primate, horse, pig, rabbit, dog, sheep, goat, cow, cat, guinea pig, or rodent. The term does not denote a particular age or sex. Thus, adult and newborn subjects, as well as fetuses, whether male or female, are intended to be covered. In some embodiments, the subject is a mammal. In some embodiments, the subject is a human. A patient refers to a subject afflicted with a disease or disorder.

The term "therapeutic" treatment is art-recognized and includes administration to the host of one or more of the subject compositions. If treatment is administered after manifestation of the unwanted condition, the treatment is therapeutic (i.e., it is intended to diminish, ameliorate, or stabilize the existing unwanted condition or side effects thereof)-

The terms "therapeutic agent," "drug," "medicament" and "bioactive substance" are art-recognized terms and include molecules and other agents that are biologically, physiologically, or pharmacologically active substances that act locally or

systemically in a patient or subject to treat a disease or condition. The terms include without limitation pharmaceutically acceptable salts thereof and prodrugs. Such agents may be acidic, basic, or salts; they may be neutral molecules, polar molecules, or molecular complexes capable of hydrogen bonding; they may be prodrugs in the form of ethers, esters, amides and the like that are biologically activated when administered into a patient or subject.

The term "therapeutically effective dose" refers to a dose that produces the desired effect for which it is administered. The exact dose will depend on the purpose of the treatment, and will be ascertainable by one skilled in the art using known techniques (see, e.g., Lloyd (1999) The Art, Science and Technology of Pharmaceutical

Compounding).

For any of the methods described herein, embodiments of this disclosure contemplate the use of any of the compounds and/or compositions described throughout the application, or mixtures of them. In addition, in various embodiments of any of the methods described herein, combinations of any step or steps of one method with any step or steps from another method may be employed.

Combination Therapies

Any of the compounds and compositions of this disclosure are useful in combination with other therapeutics. In some embodiments, for example, any of the compounds and compositions of this disclosure, or mixtures of them, are useful as analgesics. In some embodiments, the compounds and compositions of this disclosure can be used in combination with other therapeutics to treat pain; an inflammatory disease or disorder, an allergic disease or disorder, a metabolic disease, a cardiovascular disease or disorder, a neurogenic vascular disease or a painful condition associated therewith; an episodic tension-type headache; a migraine headache; a headache; cramping; a cognitive disorder; a tension or migraine headache due to a vascular, neurovascular, or neurogenic disorder or dysfunction during a menstrual cycle episode; a tension or migraine headache due to a vascular, neurovascular, or neurogenic disorder or dysfunction during a migraine episode; a headache from mild to moderate

hypertension; mild to moderate essential hypertension; organ transplant rejection; hot and cold flashes; traumatic brain injury (TBI); neurotoxicity; psychic pain;

In some embodiments, the phrase "combination therapy" embraces the administration of the any of the compounds or compostions described herein, or mixtures thereof, and an additional therapeutic agent, or mixtures thereof, as part of a specific treatment regimen intended to provide a beneficial effect from the co-action of these therapeutic agents. Administration of these therapeutic agents in combination typically is carried out over a defined time period (usually minutes, hours, days or weeks depending upon the combination selected). "Combination therapy" is intended to embrace

administration of these therapeutic agents in a sequential manner, that is, wherein each therapeutic agent is administered at a different time, as well as administration of these therapeutic agents, or at least two of the therapeutic agents, in a substantially simultaneous manner. Substantially simultaneous administration can be

accomplished, for example, by administering to the subject a single capsule having a fixed ratio of each therapeutic agent or in multiple, single capsules for each of the therapeutic agents. Sequential or substantially simultaneous administration of each therapeutic agent can be effected by any appropriate route including, but not limited to, oral routes, intravenous routes, intramuscular routes, and direct absorption through mucous membrane tissues. The therapeutic agents can be administered by the same route or by different routes. For example, a first therapeutic agent of the combination selected may be administered by intravenous injection while the other therapeutic agents of the combination may be administered orally. Alternatively, for example, all therapeutic agents may be administered orally or all therapeutic agents may be administered by intravenous injection. The sequence in which the therapeutic agents are administered is not narrowly critical. "Combination therapy" also embraces the administration of the therapeutic agents as described herein in further combination with other biologically active ingredients (such as, but not limited to, a second and different therapeutic agent) and non-drug therapies (such as, but not limited to, surgery or radiation). Where the combination therapy further comprises radiation treatment, the radiation treatment may be conducted at any suitable time so long as a beneficial effect from the co-action of the combination of the therapeutic agents and radiation treatment is achieved. For example, in appropriate cases, the beneficial effect is still achieved when the radiation treatment is temporally removed from the administration of the therapeutic agents, perhaps by days or even weeks.

In another example of combination therapy, one or more compounds and compositions described herein can be used as part of a therapeutic regimen combined with one or more additional treatment modalities. By way of example, such other treatment modalities include, but are not limited to, dietary therapy, occupational therapy, physical therapy, ventilator supportive therapy, massage, acupuncture, acupressure, mobility aids, assistance animals, speech therapy, language therapy, educational therapy, psychological therapy, occupational therapy, and the like. In some embodiments, the mammalian disease treated by the combination therapy can include any of the conditions described herein. Besides being useful for human treatment, the combination therapy is also useful for veterinary treatment of companion animals, exotic and farm animals, including rodents, horses, dogs, and cats.

In some embodiments, the therapeutic agents administered in combination therapy simultaneously, separately, or sequentially with any of the compounds and

compositions of this disclosure, or mixtures thereof, can comprise: acetaminophen, a non-steroidal anti-inflammatory drug (NSAID), ibuprofen, naprosyn, a

cyclooxygenase-2 inhibitor, aspirin, caffeine, dichloralphenazone, a triptan, an antidepressant, a serotonin-norepinephrine reuptake inhibitor (SNRI), and a gabapentinoid, or mixtures thereof.

In some embodiments, the therapeutic agents administered in combination therapy simultaneously, separately, or sequentially with any of the compounds and

compositions of this disclosure, or mixtures thereof, can comprise: a chemotherapeutic drug, an antiproliferative agent, an anti-inflammatory agent, a corticosteroid, an antiasthmatic agent, an anti-allergic agent, an immunosuppressive agent, an

In some embodiments, the therapeutic agents administered in combination therapy simultaneously, separately, or sequentially with the compounds and compositions of this disclosure, or mixtures thereof, can comprise one or more opiates. Chemotherapeutic agents include, but are not limited to, mechlorethamine, chlorambucil, cyclophosphamide, ifosfamide, melphalan, streptozocin, carmustine (BCNU), lomustine, busulfan, dacarbazine (DTIC), temozolomide, thiotepa, altretamine (hexamethylmelamine), cisplatin, carboplatin, oxalaplatin, 5-fluorouracil (5-FU), 6-mercaptopurine (6-MP), capecitabine, cladribine, clofarabine, cytarabine, floxuridine, fludarabine, gemcitabine, hydroxyurea, methotrexate, pemetrexed, pentostatin, thioguanine, daunorubicin, doxorubicin, epirubicin, idarubicin, actinomycin-D, bleomycin, mitomycin-C, mitoxantrone, topotecan, irinotecan (CPT- 1 1), etoposide (VP- 16), teniposide, paclitaxel, docetaxel, ixabepilone, vinblastine, vincristine, vinorelbine, estramustine, prednisone, methylprednisolone,

dexamethasone, L-asparaginase, and bortezomib.

Antiproliferative agents include, but are not limited to, mycophenolate mofetil, azathioprine, sirolimus, cyclophosphamide, leflunomide, tanshinone, spiromustine, aclarubicin, dactinomycin, goserelin, loxiglumide, mepitiostane, amphethinile, amsacrine, caracemide, carmethizole hydrochloride, procarbazine, proglumide, teniposide, thaliblastine, rapamycin, rhizoxin, rodorubicin, sibanomicin, bestrabucil, budotitane, cyclopentyl cytosine, cytarabine phosphate stearate, cytarabine conjugates, cytarabine ocfosfate, dezaguanine, dideoxycytidine, dideoxyguanosine, didox, doxifluridine, fazarabine, finasteride, floxuridine, fludarabine phosphate, toremifene, and uricytin.

Anti-inflammatory agents include, but are not limited to, non-steroidal antiinflammatory drugs (NSAIDs) such as ibuprofen and naprosyn (naproxen); TNF-a blockers or inhibitors such as infliximab, adalimumab, and etanercept; IL-RA;

azathioprine; cyclophosphamide; sulfasalazine; cyclooxygenase-2 inhibitors such as aspirin; caffeine; acetaminophen; ketoprofen; dichloralphenzone, triptans such as sumatriptan succinate; dexibuprofen; fenoprofen; dexketoprofen; flurbiprofen;

oxaprozin; loxoprofen; indomethacin; tolmetin; sulindac; droxicam; lornoxicam;

isoxicam; mefenamic acid; Cortisol; corticosteroids such as cortisone, hydrocortisone, prednisone, prednisolone, fludrocortisone, methylpredinisone, dexamethasone, betamethasone, and triamcinolone; and meclofenamic acid.

Gabapentinoids include, but are not limited to, gabapentin, pregabalin, gabapentin enacarbil, atagabalin, 4-methylpregabalin, and PD-217,014. Antidepressants include, but are not limited to, selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine, paroxetine, sertraline, citalopram, and escitalopram; serotonin and norepinephrine reuptake inhibitors (SNRIs) such as duloxetine, venlafaxine, desvenlafaxine, tramadol, tapentadol, and levomilnacipran;

norepinephrine and dopamine reuptake inhibitors (NDRIs) such as Bupropion;

trazodone; mirtazapine; vortibxetine; vilazodone; tricyclic antidepressants such as imipramine, nortriptyline, amitriptyline, doxepin, trimipramine, desipramine, and protriptyline; and monoamine oxidase inhibitors (MAOIs) such as tranylcypromine, phenelzine, and isocarboxazid. Sodium channel blockers include, but are not limited to, lidoderm, lidocaine, lacosamide, and ralfinamide.

Nerve growth factor receptor antagonists include, but are not limited to, K252a, tanezumab, R£GN ₄₇₅, ARRY-470, AR-786, and AR-256.

CYP2D6 inhibitors include, but are not limited to, fluoxetine, paroxetine, bupropion, quinidine, cinacalcet, ritonavir, sertraline, duloxetine, and terbinafine. Not to be bound by theory, but in some embodiments a compound of this disclosure is metabolized by CYP2D6. In such embodiments, a CYP2D6 inhibitor may slow metabolism of a compound of this disclosure.

Anti-asthmatic agents include, but are not limited to, beclometasone dipropionate, budesonide, chromones, corticosteroids, fenoterol, fluticasone, formoterol, hexoprenaline, isoprenaline, leukotrienes, mometasone, omalizumab, pirquinozol, pitrakinra, prednisone, reproterol, salbutamol, salmeterol, terbutaline, and tranilast.

Anti-allergic agents include, but are not limited to, astemizole, beclomethasone, brompheniramine, carbinoxamine, cetirizine, chlorpheniramine, clemastine, corticotrophin, desloratadine, dimethindene, diphenhydramine, doxylamine, ebastine, embramine, epinephrine, fexofenadine, flunisolide, hydrocortisone, hydroxyzine, ketamine, ketotifen, levocetirizine, loratadine, methdilazine, mizolastine, phenylephrine, pseudoephedrine, rupatadine, terfenadine, triamcinolone, trimeprazine, and xylometazoline.

Immunosuppressive agents include, but are not limited to, cyclosporine, tacrolimus, rilonacept, tocilzumab, anakinra, ustekinumab, canakinumab, basiliximab, siltuximab, daclizumab, omalizumab, methotrexate, alefacept, sirolimus, efalizumab, dimethyl fumarate, mycophenolic acid, fingolimod, natalizumab, belimumab, everolimus, teriflunomide, leflunomide, abatacept, vedolizumab, belatacept, muromonab-cd3, eculizumab, infliximab, adalimumab, etanercept, certolizumab, and golimumab.

Immunomodulatory agents include, but are not limited to, thalidomide, pomalidomide, lenalidomide, apremilast, azathioprine, 6-mercaptopurine (6-MP), cyclosporine, tacrolimus, and methotrexate.

Cardiovascular disease treatment agents include, but are not limited to, ACE inhibitors, beta-blockers, diuretics, nitrates, calcium channel blockers, statins, benazepril, ramipril, captopril, losartan, valsartan, enoxaparin, heparin, warfarin, aspirin, clopidogrel, prasurgel, metoprolol, labetalol, propranolol, amlodipine, diltiazem, nifedipine, statins (e.g., atorvastatin, pravastatin sodium, simvastatin, digoxin nesiritide, and hydralyzine), bile acid resins (e.g. cholestyramine), cholesterol absorption inhibitors (e.g.ezetimibe), fibric acid derivatives (e.g., fenofibrate), and nicotinic acid (e.g., niacin). Anti-diabetic agents include, but are not limited to, insulin, exenatide, liraglutide, pramlintide, glitazones, sulfonylureas (e.g., chlorpropamide, glimepride, glipizide, glyburide, tolazamide, and acetahexamide), metformin, alpha-glucosidase inhibitors, thiazolidinediones (e.g., rosiglitazone, pioglitazone, and troglitazone), saxagliptin, sitagliptin, linagliptin, alogliptin, albiglutide, dulaglutide, repaglinide, nateglinide, metformin, empagliflozin, canagliflozin, and dapagliflozin.

Blood disorder treatment agents include, but are not limited to, iron pills, Epogen, Procrit, prednisone, blood transfusion, chemotherapeutic agents, and heparin. Opiates include, but are not limited to, codeine, thebaine, hydrocodone,

hydromorphone, morphine, oxycodone, oxymorphone, and tramadol.

Such combination products employ the compounds and compositions of this application within the dosage range described herein and the other pharmaceutically active compound or compounds within approved dosage ranges and/or the dosage described in the publication reference.

In some embodiments, any of the compounds and compositions described herein, or mixtures thereof, can allow the combination therapeutic agents and/or compounds and compositions described herein, or mixtures thereof, to be administered at a low dose, that is, at a dose lower than has been conventionally used in clinical situations.

Alternatively, the methods and combination of this disclosure maximize the

therapeutic effect at higher doses.

In some embodiments, when administered as a combination, the therapeutic agents can be formulated as separate compositions which are given at the same time or different times, or the therapeutic agents can be given as a single composition.

In some embodiments, the compounds and compositions of this disclosure, or mixtures thereof, are therapeutic simultaneously, sequentially, or separately in combination with one or more substances selected from the group consisting of acetaminophen, a non-steroidal anti-inflammatory drug (NSAID), ibuprofen, naprosyn, a cyclooxygenase-2 inhibitor, aspirin, caffeine, dichloralphenazone, a triptan, a chemotherapeutic drug, an antidepressant, a serotonin-norepinephrine reuptake inhibitor (SNRI), a gabapentinoid, an antiproliferative agent, an anti-inflammatory agent, a corticosteroid, an anti-asthmatic agent, an anti-allergic agent, an

Pharmaceutical Compositions and Modes of Administration

The compounds and compositions of this disclosure are useful to treat an individual in need thereof. In some embodiments, the individual is a mammal such as a human, or a non-human mammal. When administered to an animal, such as a human, the compounds or mixtures thereof are preferably administered as a pharmaceutical composition comprising, for example, one or more compounds and a pharmaceutically acceptable carrier.

The phrase "pharmaceutically acceptable carrier" as used herein means a

pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials which can serve as pharmaceutically acceptable carriers include: (1 ) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate;' (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; ( 10) glycols, such as propylene glycol; ( 1 1 ) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; ( 13) agar; ( 14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) water (including pyrogen-free water); (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer solutions; (21 )

cyclodextrins and cyclodextrin derivatives; and (22) other non-toxic compatible substances employed in pharmaceutical compositions.

Pharmaceutical compositions of this disclosure can contain physiologically acceptable agents that act, for example, to stabilize, increase solubility or to increase the absorption of a compound such as a compound of this disclosure. Such

physiologically acceptable agents include, for example, carbohydrates, such as glucose, sucrose or dextrans, antioxidants, such as ascorbic acid or glutathione, chelating agents, low molecular weight proteins or other stabilizers or excipients. The choice of a pharmaceutically acceptable carrier, including a physiologically acceptable agent, depends, for example, on the route of administration of the composition. The pharmaceutical compositions of this disclosure can be a self-emulsifying drug delivery system or a self-microemulsifying drug delivery system.

The phrase "pharmaceutically acceptable" is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

The pharmaceutical compositions and compounds described herein can be

administered to a subject by any of a number of routes of administration including, for example, orally (for example, aqueous or non-aqueous solutions or suspensions, tablets, capsules (including sprinkle capsules and gelatin capsules), boluses, powders, granules, pastes for application to the tongue); absorption through the oral mucosa (e.g., sublingually); buccally; anally, rectally or vaginally (for example, as a pessary, cream or foam);-parenterally (including intramuscularly, intravenously,

subcutaneously or intrathecally as, for example, a sterile solution or suspension); nasally; intraperitoneal ly; subcutaneously; transdermally (for example as a patch applied to the skin); intrathoracically, epidurally, intracerebroventricularly; and topically (for example, as a cream, ointment or spray applied to the skin, or as an eye drop). The compounds and compositions, or mixtures thereof, may also be formulated for inhalation (insufflation) and for injection into the joints. In some embodiments, the compounds and compositions, or mixtures thereof, may be simply dissolved or suspended in sterile water. Details of appropriate routes of administration and compositions suitable for same can be found in, for example, U.S. Pat. Nos.

6, 1 10,973, 5,763,493, 5,731 ,000, 5,541 ,231 , 5,427,798, 5,358,970 and 4, 172,896, as well as in patents cited therein, all of which are incorporated herein by reference.

To prepare solid dosage forms for oral administration (capsules (including sprinkle capsules and gelatin capsules), tablets, pills, dragees, powders, granules, and the like), the compounds described herein are mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or any of the following: ( 1 ) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as, for example,

carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose, and/or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents, such as, for example, cetyl alcohol and glycerol monostearate; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such a talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof; (10) complexing agents, such as, modified and unmodified cyclodextrins; and (1 1) coloring agents. In the case of capsules (including sprinkle capsules and gelatin capsules), tablets and pills, the pharmaceutical compositions may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.

A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-active, or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.

The tablets, and other solid dosage forms of the pharmaceutical compositions of this disclosure, such as capsules (including sprinkle capsules and gelatin capsules), pills, and granules, may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art. They may also be formulated so as to provide slow or controlled release of the compound of this disclosure therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes, and/or microspheres. They may be sterilized by, for example, filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved in sterile water, or some other sterile injectable medium immediately before use. The compositions of this disclosure may also optionally contain opacifying agents and may be of a composition that they release the active ingredient(s) only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. The compounds and compositions of this disclosure, or mixtures thereof, can also be in micro-encapsulated form, if appropriate, with one or more of the above-described excipients. Liquid dosage forms useful for oral administration include pharmaceutically acceptable emulsions, lyophiles for reconstitution, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the compound of this disclosure, the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, cyclodextrins and derivatives thereof, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1 ,3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols, and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions of this disclosure can also include adjuvants such as sweetening, flavoring, and perfuming agents. Formulations of the pharmaceutical compositions of this disclosure for administration to the mouth may be presented as a mouthwash, or an oral spray, or an oral ointment. For example, excipients for oral and subligual formulations of R-isometheptene mucate, R-isometheptene malate, R-isometheptene maleate, R-isometheptene tartrate and other salts of R-isometheptene (salts of compound 9) include alpha-cyclodextrin and hydroxypropyl-beta cyclodextrin. Excipients for intravenous, intramuscular and subcutaneous formulations include hydroxypropyl-beta cyclodextrin. In some embodiments, the R-isometheptene salt is dissolved with at least 1 molar equivalent of cyclodextrin in water or a suitable mixed aqueous solvent prior to removal of solvent to ensure complete complexation. Without wishing to be bound by theory, the cyclodextrin may increase solubility and stability of the R-isometheptene through complexation of the R-isometheptene cation inside the tube-shaped cyclodextrin molecule.

Formulations of the compounds, pharmaceutical compositions, and mixtures thereof as described herein for rectal, vaginal, or urethral administration may be presented as a suppository, which may be prepared by mixing one or more compounds with one or more suitable nonirritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the rectum or vaginal cavity and release the active compound.

Dosage forms for topical or transdermal administration include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalants. The compound of this disclosure or mixtures thereof may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants that may be required. The ointments, pastes, creams, and gels may . contain, in addition to one or more compounds and compositions of this disclosure, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, perfuming agents, coloring agents, silicic acid, talc, and zinc oxide, or mixtures thereof.

Powders and sprays qan contain, in addition to one or more compounds and compositions of this disclosure, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates, and polyamide powder, or mixtures of these substances. Sprays can additionally contain customary propellants, such as

chlorofluorohydrocarbbns and volatile unsubstituted hydrocarbons, such as butane and propane.

Transdermal patches have the added advantage of providing controlled delivery of one or more compounds or compositions of this disclosure to the body. Such dosage forms can be made by dissolving or dispersing the compound of this disclosure in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate of such flux can be controlled by either providing a rate controlling membrane or dispersing the compound in a polymer matrix or gel. Ophthalmic compositions, eye ointments, powders, solutions and the like, are also contemplated as being within the scope of this disclosure. Exemplary ophthalmic compositions are described in U.S. Publication Nos. 2005/0080056, 2005/0059744, 2005/003 1697 and 2005/004074 and U.S . Patent No. 6,583, 124, the contents of which are incorporated herein by reference. If desired, liquid ophthalmic compositions have properties similar to that of lacrimal fluids, aqueous humor or vitreous humor or are compatable with such fluids. One route of administration is local administration (e.g., topical administration, such as eye drops, or administration via an implant). The phrases "parenteral administration" and "administered parenteral ly" as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrasternal injection, and infusion.

Pharmaceutical compositions of this disclosure suitable for parenteral administration comprise one or more compounds or compositions as described herein in combination with one or more pharmaceutically acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain antioxidants, buffers, bacteriostats, solutes which render the composition isotonic with the blood of the intended recipient, or suspending or thickening agents. Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.

In some cases, in order to prolong the effect of one or more compounds or

compositions of this disclosure, it is desirable to slow the absorption of the compounds from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material having poor water solubility. The rate of absorption of the compounds then depends upon their rate of dissolution, which, in turn, may depend upon crystal size and crystalline form.

Alternatively, delayed absorption of parenterally administered compounds or compositions of this disclosure is accomplished by dissolving or suspending the drug in an oil vehicle.

Injectable depot forms are made by forming microencapsulated matrices of the subject compounds of this disclosure in biodegradable polymers such as polylactide- polyglycolide. Depending on the ratio of compound or composition to polymer, and the nature of the particular polymer employed, the rate of compound release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable compositions are also prepared by entrapping the compounds or compositions in liposomes or microemulsions that are compatible with body tissue. Liposomes comprise phospholipids or other lipids, are nontoxic, physiologically acceptable and metabolizable carriers that are relatively simple to make and administer.

Methods of introduction may also be provided by rechargeable or biodegradable devices. Various slow release polymeric devices have been developed and tested in vivo in recent years for the controlled delivery of drugs, including proteinacious biopharmaceuticals. A variety of biocompatible polymers (including hydrogels), including both biodegradable and non-degradable polymers, can be used to form an implant for the sustained release of one or more compounds of this disclosure at a particular target site. Compounds and compositions of this disclosure can be formulated for delivery via a catheter, stent, wire, or other intraluminal device.

Delivery via such devices may be especially useful for delivery to the bladder, urethra, ureter, rectum, or intestine.

Actual dosage levels of the compounds of this disclosure may be varied so as to obtain an amount of the compound that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient. The selected dosage level will depend upon a variety of factors including the activity of the particular compound or combination of compounds employed, or the ester, salt, or amide thereof, the route of administration, the severity of the disease, the time of administration, the rate of excretion of the particular compound(s) being employed, the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular compound(s) employed, the age, sex, weight, condition, general health, and prior medical history of the patient being treated, and like factors well known in the medical arts. The quantity of the compounds or compositions or mixture thereof to be administered varies for the patient being treated and varies from about 100 ng/kg of body weight to 100 mg/kg of \ body weight per day. The amount of active ingredient that can be used alone or combined with a carrier material to produce a single dosage form will generally be that amount of the compound which produces a therapeutic effect. Generally, out of one hundred percent, this amount will range from about 1 percent to about ninety-nine percent of active ingredient, preferably from about 5 percent to about 70 percent, most preferably from about 10 percent to about 30 percent. Dosages can be readily ascertained by those skilled in the art from this disclosure and the knowledge in the art. Thus, the skilled artisan can readily determine the amount of compound and optional additives, vehicles, and/or carrier in the compositions described herein and to be administered in methods or uses described herein. In general, a suitable daily dose of one or more compounds or compositions or mixtures thereof of this disclosure will be that amount of the compound that is the lowest dose effective to produce a therapeutic effect.

If desired, the effective daily dose of the compounds or compositions or mixtures thereof of this disclosure may be administered as one, two, three, four, five, six, or more sub-doses administered separately at appropriate intervals throughout the day, optionally, in unit dosage forms. In some embodiments of this disclosure, the compounds or compositions or mixtures thereof of this disclosure, or mixtures thereof, may be administered two or three times daily. In some embodiments, the compound of this disclosure will be administered once daily.

A physician or veterinarian having ordinary skill in the art can readily determine and prescribe the therapeutically effective amount of the pharmaceutical composition of this disclosure required to treat a given disease or condition. For example, the physician or veterinarian could start doses of the pharmaceutical compositions or compounds of this disclosure at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved. By "therapeutically effective amount" or "pharmaceutically effective amount" is meant the concentration of one or more compounds of this disclosure that is sufficient to elicit the desired therapeutic effect. It is generally understood that the effective amount of the compound of this disclosure will vary according to the weight, sex, age, and medical history of the subject. Other factors which influence the effective amount may include, but are not limited to, the severity of the patient's condition, the disorder being treated, the stability of the compound, and, if desired, another type of therapeutic agent being administered with the compound of this disclosure. A larger total dose can be delivered by multiple administrations of the compounds or compositions or mixtures thereof described within. Methods to determine efficacy and dosage are known to those skilled in the art (Isselbacher, et al. ( 1996) Harrison's Principles of Internal Medicine 13 ed., 1814-1882, herein incorporated by reference).

In some embodiments, this disclosure comprises a method for conducting a pharmaceutical business, by determining an appropriate formulation and dosage of the compounds or compositions of this disclosure, or mixtures thereof, for treating or preventing any of the diseases or conditions as described herein, conducting therapeutic profiling of the compounds or compositions disclosed herein for efficacy and toxicity in animals, and providing a distribution network for selling an identified compound or composition as having an acceptable therapeutic profile. In some embodiments, the method further includes providing a sales group for marketing the compositions disclosed herein to healthcare providers.

In some embodiments, this disclosure relates to a method for conducting a

pharmaceutical business by determining an appropriate composition and dosage of the compounds of this disclosure, or mixtures thereof, for treating or preventing any of the diseases or conditions described herein, and licensing, to a third party, the rights for further development and sale of the compositions.

Animal/Cell Models

Pain, headaches, and migraines have been modeled in animals such as mice and rats. For example, Oshinsky et al. (Oshinsky, M.L., et al., Spontaneous Trigeminal

Allodynia in Rats: A Model of Primary Headache, Headache, 2012, 52: 1336-1349, herein incorporated by reference) describes spontaneous trigeminal allodynia (STA) rats with the inherited trait of spontaneously changing trigeminal von Frey thresholds. These rats are a model of spontaneous headache and can be used as a model of primary headache. Through a series of tactile sensory tests, the periorbital, hind-paw, and jaw-pressure thresholds for STA rats are determined by applying von Frey monofilaments. These determinations are made both before and after receiving treatments with compounds or compositions of this disclosure, or mixtures thereof. Analgesic and pain reduction activities of the compounds or compositions described herein, or mixtures thereof that are modulated through the I| receptor can be evaluated by determining trigeminal von Frey thresholds in STA rats.

Rats can also be used in an inflammatory soup model of migraine. Inflammatory soup, composed of a mixture of prostaglandin E2, serotonin, bradykinin, and histamine, has frequently been used in the migraine literature to study activation of nociceptors and to induce migraine. Activity of the compounds or compositions described herein, or mixtures thereof, can be evaluated using the inflammatory soup model.

Common mouse models for pain include the Formalin Test (Wheeler-Aceto, et al., Psychopharmacology, 104, 35-44, 1991 , herein incorporated by reference), the Hot Plate Test (Eddy and Leimbach, J. Pharmacol. Exp. Ther., 107, 385-393, 1953, herein incorporated by reference), and the Tail-flick Test (D'Amour and Smith, J. Pharmacol. Exp. Ther., 1 , 74-79, 1941 , herein incorporated by reference). These methods detect analgesic and pain reduction activity of compounds or compositions of interest, or mixtures thereof. In the Formalin Test, mice are given an intraplantar injection of 5% formalin into one posterior hindpaw to induce paw licking. Test compounds or compositions, or mixtures thereof, are given to the mice before treatment with formalin and the mice are evaluated and compared to a control group. In the Hot Plate Test, mice are placed onto a hot metal plate maintained at 54 °C and the latency to the first foot-lick is measured. As with the Formalin test, compounds or compositions of interest, or mixtures thereof, are given to the mice before the test and the mice are evaluated and compared to a control group. In the Tail-flick Test, a mouse's tail is heated by means of a thermal light source, and the latency before the animal ^' withdraws its tail is measured. Test compounds or compositions, or mixtures thereof, are administered before the test, and compared with a vehicle control group. The analgesic and pain reduction activity of the compounds or compositions described here.in that is modulated through the IRIPM pathway can be identified using the mouse formalin, hot plate, and tail-flick tests. Mice can also be used in the evaluation of the precipitated withdrawal (Saelens) test. In this study, the analgesic potential of test compounds or compositions, or mixtures thereof, is evaluated using an opiate-like dependence model with the Naloxone- precipitated Withdrawal (Saelens) Test in mice. Typically, when opiate-pretreated mice are administered the opiate antagonist naloxone, they demonstrate jumping behavior as a pain response to opiate withdrawal symptoms. The analgesic activity of compounds or compositions of this disclosure, or mixtures thereof, is assessed in this study by measuring whether test compound or composition administration can reduce this naloxone-induced jumping activity.

Common rat models for pain include a chronic constrictive nerve injury (CCI) model of neuropathic pain and bortezomib-induced neuropathy. In the CCI model, a sciatic nerve is ligated and on test days, rats are administered a test compound or

composition. The animals are then evaluated by applying von Frey filaments to the hind paws and analyzing the post-treatment withdrawal threshold. In the rat model of bortezomib-induced neuropathy, rats are treated with bortezomib and then administered a test compound or composition. The animals are then evaluated by applying von Frey filaments to the hind paws and analyzing the post-treatment withdrawal threshold. The analgesic and pain reduction activity of the compounds or compositions described herein, or mixtures thereof, that is modulated through the IRIPM pathway can be evaluated in a rat CCI model of neuropathic pain or a rat model of bortezomib-induced neuropathy.

Rats can also be used to evaluate test compounds or compositions or mixtures thereof in models of osteoarthritis. The analgesic potential of the compounds or compositions of this disclosure, or mixtures thereof, is assessed using a monosodiuhn iodacetate (MIA) induced model of osteoarthritic pain in adult male rats.

To assess the efficacy of test compounds or compositions or mixtures thereof in alleviating naloxone-precipitated withdrawal in chronic morphine-treated rats, male rats are implanted with morphine pellets (2 x 75 mg, s.c). Seven days later, baseline body weight and hot plate latency are assessed. The animals then receive systemic administration of the vehicle or varying doses of the compounds or compositions of this disclosure, or mixtures thereof, followed by naloxone (3 mg/kg i.p.) or saline. Then the jumping frequency, the existence of diarrhea, and wet dog shaking symptoms are recorded during the first 30 minutes post-naloxone administration.

To assess the rescue efficacy of the test compounds or compositions or mixtures thereof for the reversal of cutaneous allodynia, sumatriptan-induced medication overuse headache (MOH) is triggered by nitric oxide (NO) donors in rats and then the . rescue efficacy of the compounds or compositions of this disclosure, or mixtures thereof, is assessed.

Rats and mice can also be utilized to examine arterial blood pressure (BP) and heart rate effects of test compounds or compositions, or mixtures thereof, in vivo. Rats are anesthetized with Inactin® (sodium thiobutabarbital 100 to 150 mg/kg i.p.) and prepared for the recording of the following parameters: 1 ) Mean, systolic and diastolic arterial blood pressure (mmHg), via a pressure transducer introduced into the left carotid artery and 2) Heart rate (beats/min), derived from pulse blood pressure. The parameters measured are allowed to stabilize for a period of at least 20 minutes before one or more compounds or compositions of this disclosure are administered.

Measurements of blood pressure and heart rate are then made after dosage and compared to pre-dose.

Stability of the compounds or compositions described herein can be assessed using pharmacokinetic studies in animals such as dogs, rats, and humans. Animals are treated with varying doses of the compounds or compositions described herein, or mixtures thereof, and after specified time periods, plasma samples are drawn and then analyzed for the presence of the compound. Not wishing to be bound by theory, in some embodiments, such pharmacokinetic studies can be used to identify slow, normal, and fast metabolizers of the compounds of this disclosure.

The above models are exemplary of suitable animal model systems for assessing the activity and effectiveness of the compounds and pharmaceutical compositions and/or formulations disclosed, or mixtures thereof. Activity of the subject compounds and pharmaceutical compositions and/or formulations disclosed herein, or mixtures thereof, are assessed in any one or more of these models, and the results compared to that observed in wild type control animals and animals not treated with the compounds and pharmaceutical compositions of this disclosure. In some embodiments, the subject compounds and pharmaceutical compositions, or mixtures thereof, are evaluated using cells prepared from any of the foregoing mutant mice or other animals, as well as wild type cells.

In some embodiments, in vitro systems may be used to evaluate the ability of any of the compounds or pharmaceutical compositions of this disclosure, or mixtures thereof, to mediate biological activity. For example, membrane homogenates of adrenal medulla glands are incubated with [ ³H]clonidine in the absence or presence of the compounds or compositions of this disclosure, or mixtures thereof, to determine compound binding to the imidazoline- 1 (I i) receptor. Following the incubation, the samples are analyzed to determine the percent inhibition of the control radioligand ([ ³H]clonidine) specific binding. This protocol is adapted from Molderings, G.J., Moura, D., Fink, K., Bonisch, H. and Gothert, M. (1993), Binding of [ ³H]clonidine to Ii-imidazoline sites in bovine adrenal medullary membranes, Naun.-Sch. Arch.

Pharm., 348: 70, herein incorporated by reference.

In some embodiments, in vitro systems are used for assays of compound affinity with the Imidazoline- 1 (I i) receptor. Membrane homogenates of PC- 12 cells are incubated with [ ^{, 25}I]iodoclonidine in the absence or presence of a compound or composition of this disclosure, or mixtures thereof. Following incubation, the samples are analyzed to determine the percent inhibition of [ ¹²⁵I]iodoclonidine specific binding. This protocol is adapted from Steffen, G., Dendorfer, A., and Dominiak, P., Imidazoline binding sites on PC-12 cells and bovine chromaffin cells. Ann. N. Y. Acad. Sci. 763: 157- 162 (1995), herein incorporated by reference, with modifications, and Piletz, J.E., Zhu, H.E., and Chikkala, D.N., Comparison of Ligand Binding Affinities at Human h- Imidazoline Binding Sites and the High Affinity State of Alpha-2 Adrenergic

Subtypes. JPET. 279: 694-7002 (1996), herein incorporated by reference.

In additional in vitro experiments, the affinity of compounds for the central imidazoline receptor in the rat cerebral cortex is evaluated in a radioligand binding assay. Membrane homogenates of the cerebral cortex are incubated with [ ³H]idazoxan in the absence or presence of a compound or composition of this disclosure, or a mixture thereof. Following incubation, the samples are analyzed to determine the percent inhibition of the control radioligand ([ ³H]idazoxan) specific binding. This protocol is adapted from Brown, CM., MacKinnon, A.C., McGrath, J.C., Spedding, M. and Kilpatrick, A.T. ( 1990), oc ₂-adrenoceptor subtypes and imidazoline-like binding sites in the rat brain, Brit. J. Pharmacol., 99:803, herein incorporated by reference.

In some embodiments, a stable CHO cell line expressing the human imidazoline- 1 (I i) receptor is established using CHO cells transfected with a lentiviruses plasmid system containing a human I i receptor construct. In some embodiments, the CHO cells stably expressing the human I | receptor are used to screen the Ii receptor binding affinity for any of the compounds and compositions of this disclosure, or mixtures thereof.

In some embodiments, evaluation of the impact of I| receptor agonists and antagonists on forskolin-stimulated cAMP induction is conducted with PC- 12 cells or a stably- expressing Ii receptor cell line. Cells are incubated with benazoline and efaroxan, inhibitors of forskolin-stimulated cAMP production, in the presence or absence of compounds and compositions of this disclosure, or mixtures thereof. The inhibitory effects of benazoline and efaroxan on forskolin induced cAMP are antagonized by agonists of the 11 receptor.

In some embodiments, a 293T cell line transiently expressing the human imidazoline- 1 (Ii) receptor is established using 293T cells transfected with a plasmid system containing a human I] receptor construct. In some embodiments, the 293T cells stably expressing the human I] receptor are used to identify the Ii receptor modulators of the compounds of this disclosure, or mixtures thereof.

In some embodiments, the potential side effects of the compounds or compositions of this disclosure, or mixtures thereof, are analyzed using a cAMP Hunter cell line expressing human trace amine associated receptor (TAAR1). TAAR1 is a receptor expressed in the central nervous system (CNS) and belongs to the G-protein coupled receptor (GPCR) receptor family. TAAR1 is activated by biogenic amines such as tyramine, a molecule found in trace levels in the CNS (Borowsky, et al, PNAS 98: 8966-8971 (2001 ), incorporated herein by reference)). For agonist determination, cells are incubated with samples selected from compounds or compositions described herein, or mixtures thereof, to induce response. After appropriate incubation, assay signal is generated through incubation with cAMP XS+ ED/CL lysis cocktail followed by incubation with cAMP XS+ EA reagent. Microplates are read following signal generation with a PerkinEimer Envision™ instrument for chemiluminescent signal detection. Activity is analyzed using the CBIS data analysis suite (Chemlnnovation, CA). For Gs agonist mode assays, percentage activity is calculated using the following formula: % Activity=100% x (mean RLU of test sample - mean RLU of vehicle control) / (mean RLU of MAX control - mean RLU of vehicle control).

Lower TAAR1 activation indicates lower side effects. In some embodiments, in vitro systems can be used to study the interactions of compounds or compositions described herein, or mixtures thereof, with other molecules, such as proteins, nucleic acids, carbohydrates, ions, lipids, or amino acids. Such interactions can happen within or superficially to the cell and alter the molecule's function. For example, the compounds or compositions described herein may improve catalytic activity of a protein by blocking suppressing molecules or improving access to a catalytic domain or the compounds described herein may inhibit an active site on a protein, such as a catalytic domain or a binding site.

The effects of any of the pharmaceutical compositions and compounds disclosed herein, or mixtures thereof, may be tested in any of the cells or animal models disclosed herein. The pharmaceutical compositions and compounds described herein, or mixtures thereof, have numerous uses, including in vitro and in vivo uses. In vivo uses include not only therapeutic uses but also diagnostic and research uses in, for example, any of the foregoing animal models. By way of example, pharmaceutical compositions and compounds described herein, or mixtures thereof, may be used as research reagents and delivered to animals to understand bioactivity, enzymatic activity, gene expression, interactions with other molecules, and impacts on animal physiology in healthy or diseased animals or cells.

Kits

In some embodiments, this disclosure also provides a pharmaceutical package or kit comprising one or more containers filled with at least one compound or composition of this disclosure, or mixtures thereof. Optionally associated with such a container(s) can be a notice in the form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals or biological products, which notice reflects (a) approval by the agency of manufacture, use or sale for human

administration, (b) directions for use, or both. In some embodiments, the kit comprises at least two containers, at least one of which contains at least one compound or composition of this disclosure. In some embodiments, the kit contains at least two containers, and each of at least two containers contains at least one compound or composition of this disclosure.

In some embodiments, the kit includes additional materials to facilitate delivery of the subject compounds and compositions. For example, the kit may include one or more of a catheter, tubing, infusion bag, syringe, and the like. In some embodiments, the compounds and compositions, or mixtures thereof, are packaged in a lyophilized form, and the kit includes at least two containers: a container comprising the lyophilized compounds or compositions and a container comprising a suitable amount of water, buffer, or other liquid suitable for reconstituting the lyophilized material.

The foregoing applies to any of the compounds, compositions, methods, and uses described herein. This disclosure specifically contemplates any combination of the features of such compounds, compositions, methods, and uses (alone or in

combination) with the features described for the various kits described in this section.

Preparation of the Compounds of the Disclosure

In some embodiments, one or more of the compounds, or components to make the compounds, of formula (SC-01 ), formula (SC-02), formula (SC-03), formula (SC-04), formula (SC-05), formula (SC-06), formula (SC-07), formula (SC-08), formula (SC- 09), formula (SC- 10), formula (SC- 1 1 ), formula (SC- 12), formula (SC- 13), formula (SC- 14), formula (SC- 15), formula (SC- 16), formula (SC-17), formula (SC- 18), formula (SC- 19), formula (SC-20), formula (SC-21 ), formula (SC-22), formula (SC- 23), formula (SC-24), formula (SC-25), or formula 1-432, or a pharmaceutically acceptable salt, tautomer, solvate, enantiomer, disastereomer, or prodrug of any of the foregoing compounds, are commercially available, for example from commercial sources such as Sigma-Aldrich® of St. Louis, Missouri, USA; TCI America, Portland, Oregon, USA; and Acros Organics, Geel, Belgium; among others.

In some embodiments, one or more of the compounds of formula (SC-01 ), formula (SC-02), formula (SC-03), formula (SC-04), formula (SC-05), formula (SC-06), formula (SC-07), formula (SC-08), formula (SC-09), formula (SC- 10), formula (SC- 1 1 ), formula (SC-12), formula (SC- 13), formula (SC-14), formula (SC-15), formula (SC- 16), formula (SC- 17), formula (SC- 18), formula (SC-19), formula (SC-20), formula (SC-21 ), formula (SC-22), formula (SC-23), formula (SC-24), formula (SC- 25), or formula 1-432, or a pharmaceutically acceptable salt, tautomer, solvate, enantiomer, disastereomer, or prodrug of any of the foregoing compounds, are prepared from commercially available reagents by routine methods in synthetic organic chemistry.

Compounds of Formula (SC-02 ^")

In some embodiments, one or more compounds of formula (SC-02) are prepared by the multi-step synthetic sequences described below in Schemes 1 and 2. One of skill in the art would be able to readily adapt the described conditions for the synthesis of compounds of formula (SC-02).

In a certain embodiment (Scheme 1 ), to a solution of 1 ,4-diaminobutene (89.6 mg, 0.56 mmol) in 1 .9 mL sulfolane is added 2M Al(Me) ₃ in toluene (0.56 mL, 1. 12 mmol) dropwise at room temperature under Ar. After completion, the reaction mixture is heated to 85 ^°C and stirred for 10 minutes. Then (R)-2-methyl-3-phenyl- propionic acid methyl ester (50 mg in 0.2 mL sulfolane, 0.28 mmol) is added dropwise at 85 °C. Then the reaction mixture is heated to 1 10 °C and stirred for five hours. The reaction mixture is then cooled to room termperature, and 10 mL CH ₂C1 ₂ is added, followed by 5 mL Rochelle salt, 2 mL 2.5 M NaOH, and 2 mL water. The reaction mixture is stirred for 1 5 minutes and then extracted with CH ₂C1 ₂ ( 10 mL x 3). The combined organic layers are dried with sodium sulfate and concentrated to give a liquid, which contained sulfolane. The crude product is subjected to reverse phase HPLC purification using CI 8 silica to yield 10.8 mg product. Yield of compound 93: 18.0%. Mass observed for MH ⁺: 215.7. Mass calculated for MH ⁺: 215.14.

Ή NMR (499 MHz, CDC1 ₃) δ 7.37 - 6.99 (m, 5H), 5.72 (q, J= 8.5 Hz, 1H), 5.47 (dt, J- 10.7,7.7 Hz, 1H),4.00 (q,J=4.6 Hz, 1H), 3.76 (dt,J= 14.3, 7.0 Hz, 1H), 3.69- 3.55 (m,2H), 2.85 (dd,J= 13.5, 8.6 Hz, 1H), 2.69 - 2.63 (m, 1H), 2.46 (dt, J= 8.6, 6.7 Hz, 1 H), 1.13 (d, J = 6.8 Hz, 3H) (Scheme 1 ).

Scheme 1

In another embodiment (Scheme 2), in a 50 mL round-bottom flask, bromobenzene (0.393 g, 0.25 mL, 2.5 mmol) is added, followed by Pd(PPh ₃) ₄ (0.144 g, 0.12 mmol) and anhydrous THF (5 mL). Then zinc reagent (10 mL, 5 mmol) is added dropwise through syringe. The reaction continues at 60 °C for three hours.

Scheme 2 Thin-layer chromatography indicates a trace amount of product is formed, then more zinc reagent ( 10 mL, 5 mmol) and Pd(PPh ₃) (80 mg,0.07 mmol) are added. The reaction continues at 60 °C for another two hours.

Then the reaction mixture is cooled down to room temperature, solvent is removed, EtOAc (20 mL) is added, and the mixture is washed with 2 N NaOH solution (15 mL x 2). The organic layer is dried with Na ₂S0 ₄ and concentrated. The crude product is purified by ISCO column using 0-30% EtOAc in hexanes to yield 1 80 mg (40.3% yield) desired product, (S)-2-methyl-3-phenyl-propionic acid methyl ester.

As shown in the second step of Scheme 2, to a solution of 1 ,4-diaminobutene (89.6 mg, 0.56 mmol) in 1.9 mL sulfolane is added 2M Al(Me) ₃ in toluene (0.56 mL, 1 .12 mmol) dropwise at room temperature under Ar. After completion, the reaction mixture is heated to 85 °C and stirred for 10 minutes. Then, (S)-2-methyl-3-phenyl-propionic acid methyl ester (50 mg in 0.2 mL sulfolane, 0.28 mmol) is added dropwise at 85 °C. The whole reaction mixture is heated to 1 10 °C and stirred for five hours. The reaction mixture is then cooled to room temperature and 10 mL CH ₂C1 ₂ is added, followed by 5 mL Rochelle salt, 2 mL 2.5 M NaOH, and 2 mL water. The reaction mixture is stirred for 15 minutes and then extracted with CH ₂C1 ₂ (10 mL x 3). The combined organic layers are dried with sodium sulfate and concentrated to give a liquid, which contained sulfolane. The crude product is subjected to reverse phase HPLC purification using C 18 silica to yield 12 mg compound 96 (20% yield) at roughly 80% purity. Mass observed 215.7 for MH ⁺. Mass calculated for MH ⁺: 215.14.

Ή NMR (499 MHz, CDC1 ₃) δ 7.37 - 6.99 (m, 5H), 5.72 (q, J = 8.5 Hz, 1 H), 5.47 (dt, J = 10.7, 7.7 Hz, 1 H), 4.00 (q, J = 4.6 Hz, 1 H), 3.76 (dt, J = 14.3, 7.0 Hz, 1 H), 3.69 - 3.55 (m, 2H), 2.85 (dd, J= 13.5, 8.6 Hz, 1 H), 2.69 - 2.63 (m, 1 H), 2.46 (dt, J = 8.6, 6.7 Hz, 1 H), 1 .13 (d, J = 6.8 Hz, 3H) (Scheme 2) Compounds of Formula (SC-05)

In some embodiments, one or more compounds of formula (SC-05) are prepared by the multi-step synthetic sequences described below (Schemes 3 and 4). One of skill in the art would be able to readily adapt the described conditions for the synthesis of compounds of formula (SC-05).

In some embodiments (Scheme 3), in a 50 mL round-bottom flask, 7-bromo- benzo[Z?]thiophene (0.213 g,l mmol) and Pd(PPh ₃) ₄ (0.116 g, 0.1 mmol) are suspended in THF (3 mL), then zinc reagent (6 mL, 3 mmol) is added with syringe. The reaction is stirred at 60 °C for three hours, then the reaction mixture is cooled to room temperature, solvent is removed, EtOAc (30 mL) is added, and the mixture washed with 2 N NaOH solution (20 mL x 2). The organic layer is dried with Na ₂S0 ₄ and concentrated. The crude product is purified by ISCO silica column using 0-25% EtOAc in hexanes to yield 49 mg (20.9% yield) desired product methyl (2S)-3-(l- benzothiophen-7-yl)-2-methylpropanoate. Ή NMR. (499 MHz, CDC1 ₃) δ 7.70 (dd, J= 7.9, 1.1 Hz, 1H), 7.43 (d,J=5.4Hz, 1H), 7.36 (d,J= 5.4 Hz, 1H), 7.31 (t,J=7.6 Hz, 1H), 7.15 (d, J= 7.2 Hz, 1H), 3.66 (s, 3H), 3.35(dd,J = 13.9, 6.8 Hz, 1H), 3.12 - 3.00 (m, 1H), 2.93 (dd,J= 14.0,8.0 Hz, 1H), 1.21 (d,J=7.0Hz, 3H).

153

Scheme 3

As shown in the second step of Scheme 3, to a solution of Al(Me) ₃ (2M in toluene, 0.26 mL) in 0.5 mL toluene at 0 °C is added dropwise 1,2-diaminopropane. After the reaction is stirred at room temperature for one hour, it is cooled down to 0 °C and a solution of methyl (2S)-3-(l-benzothiophen-7-yl)-2 methylpropanoate (41 mg in 0.5 mL toluene) is added dropwise. The reaction mixture is heated to 100 °C for three hours. Then the reaction is cooled down to 0 °C and quenched cautiously with methanol (1 mL) and water (0.5 mL). After the addition of CHCI3 (5 mL), the reaction mixture is stirred for 15 minutes.5 mL 2 N NaOH is added, and the reaction mixture is extracted with CHC1 ₃(10 mL x 3). The combined organic layers are dried with Na ₂S0 ₄, concentrated, and purified by flash chromatography using

cyclohexane:EtOAc:Methanol:NH ₄OH(4:3: 1:0.1) as eluent. 38.6 mg (85.4% yield) of desired product 153 is obtained.

'H MR(499 MHZ, CDCI3) δ 7.70 (dd,J=7.9, 1.1 Hz, 1H), 7.42 (d,J=5.4Hz, 1H), 7.35 (dd,J= 5.4, 1.0 Hz, 1H), 7.31 (t,J=7.6Hz, 1H), 7.20 (d, J= 7.2 Hz, 1H), 3.93- 3.85 (m, 1H), 3.67 (ddd,J= 11.2, 9.8,6.6 Hz, 1H), 3.31 - 3.23 (m, 1H), 3.16 - 2.96 (m,3H), 1.25 (dd,J=6.7, 1.5 Hz, 3H), 1.14(d,J=6.3 Hz, 1.5H), 1.06 (d,J=6.3 Hz, 1.5H) (Scheme 3). In another embodiment (Scheme 4), to a suspension of 3-bromo-5-thiophen-2-yl- pyridine (400 mg, 1.67 mmol) and tetrakis(triphenylphosphine)palladium (0) (48 mg, 0.04 mmol) in THF (12 mL) stirred under Ar is added a solution of (R)-(-)-3-methoxy- 2-methyl-3-oxopropylzinc bromide (0.5 M in THF, 3.34 mL) via a syringe. The resulting mixture is stirred at 60 °C for three hours under argon atmosphere. After the reaction is allowed to cool to room temperature, solvent is evaporated under reduced pressure. The resulting thick yellow oil is dissolved in ethyl acetate (5 mL) and washed with 2M NaOH (3 x 5 mL). The organic phase is dried over sodium sulfate, filtered, and concentrated to dryness. The resulting crude product is purified using ISCO gradient solvent system from 0% EtOAc in hexanes to 100% EtOAc to afford 85 mg (19.5% yield) of (S)-2-methyl-3-(5-thiophen-2-yl-pyridin-3-yl)-propionic acid methyl ester (164 mg, 0.68 mmol of unreacted starting arylbromide was recovered). R _f: 0.24 (3: 1 , hexanes:EtOAc). m/z = 262 ( H .

'H MR (499 MHz, CDCI ₃) δ 8.81 - 8.66 (m, 1 H), 8.42 - 8.27 (m, 1 H), 7.70 (t, J = 2.2 Ηζ, Ι Η), 7.43 - 7.30 (m, 2H), 7.12 (dd, J = 5.0, 3.7 Hz, 1 H), 3.66 (s, 3H), 3.06 (dd, J = 13.1 , 6.8 Ηζ, ΙΗ), 2.87 - 2.68 (m, 2H), 1 .22 (d, J = 6.7 Hz, 3H).

158

Scheme 4

As shown in the second step of Scheme 4, trimethylaluminium (3.33 mL, 6.66 mmol) is placed in dry round bottom flask under argon and cooled to 0 °C. A solution of 1 ,2- diaminoethane (0.45 mL, 6.66 mmol) in toluene (2 mL) is added, and the resulting mixture is stirred at room temperature for one hour. The reaction is cooled to 0 °C and (S)-2-methyl-3-(5-thiophen-2-yl-pyridin-3-yl)-propionic acid methyl ester (80 mg, 0.31 mmol) is added drop wise via a syringe. The mixture is then stirred at 100 °C overnight. The reaction is quenched with methanol (0.25 mL), and then water (0.1 mL) is added. Chloroform (20 mL) is added to the mixture and it is extracted with 2 N HCI (3x 10 mL). The aqueous layers are combined and made alkaline with 10% NaOH (~ 38 mL). The mixture is extracted with chloroform (3 x 20 mL), dried over sodium sulfate, and concentrated to dryness under reduced pressure. The crude product is purified by silica flash chromatography using

cyclohexane/EtOAc/MeOH/NH ₄OH (4/3/1/0.1) to give 60 mg (67% yield) of compound 158. R _f: 0.06. m/z = 272 (MH ⁴) Ή NMR (499 MHz, CDC1 ₃) δ 8.72 (d, J= 2.2 Hz, 1H), 8.34 (d, J= 2.0 Hz, 1H), 7.68 (t, J= 2.2 Hz, 1H), 7.37 - 7.33 (m, 2H), 7.14 - 7.09 (m, 1H), 5.88 (s, 1H), 3.57 (s, 1Η),3.30-3.22 (m, 1H), 3.19 - 3.12 (m, 1H), 3.02 (dd, J= 13.7,8.9 Hz, 1H),2.76- 2.62 (m, 3H),2.47 (dt, J= 8.8, 6.5 Hz, 1H), 1.25 (s, 1.5H), 1.23 (s, 1.5H) (Scheme 4).

Compounds of Formula (SC-12) In some embodiments, one or more compounds of formula (SC-12) are prepared by the multi-step synthetic sequences described below (Schemes 5-10). One of skill in the art would be able to readily adapt the described conditions for the synthesis of compounds of formula (SC-12).

In some embodiments, as illustrated in Scheme 5, compound 99 is prepared.

Scheme 5 In the first step of Scheme 5, methylamine (2M solution in THF, 0.45 mL, 0.89 mmol) is added to a stirred solution of 5-cyclohexyl-pentan-2-one (100 mg, 0.59 mmol) in anhydrous THF under Ar. Sodium triacetoxyborohydride (1 89 mg, 0.89 mmol) and glacial acetic acid (34 μί, 0.59 mmol) are added and the resulting mixture is stirred at room temperature under Ar for 24 hours. The reaction is quenched with saturated NaHC0 ₃ solution and extracted with diethylether (25 mL x 3). The organic extract is dried over Na ₂S0 ₄, filtered, and removed under reduced pressure to give 100 mg, 92% yield of (4-cyclohexyl- l -methyl-butyl)-methylamine as light yellow liquid. R _f-: 0.75.

'H MR (499 MHz, CHC1 ₃) 6 2.53 (h, J = 6.1 Hz, 1 H), 2.41 (s, 3H), 1 .74 - 1.57 (m, 7H), 1.49 - 1 .37 (m, 1 H), 1.35 - 1.24 (m, 2H), 1.18 (td, J = 15.3, 13.7, 9.8 Hz, 5H), 1.04 (d, J= 6.3 Hz, 3H), 0.86 (q, J= 1 1.7 Hz, 3H).

To a solution of (4-cyclohexyl-l -methyl-butyl)-methylamine (63.7 mg, 0.35 mmol) in ethylacetate ( 1 mL) is added a solution of oxalic acid (3 1.3 mg, 0.35 mmol) in ethylacetate (0.5 mL). The resulting white precipitate is filtered and washed with ethylacetate (25 mL x 5) and dried under vacuum to give 69.8 mg (74% yield) of compound 99 as white solid.

Ή NMR (499 MHz, DMSO-i/ ₆) 6 3.13 - 2.97 (m, 1 H), 2.50 (s, 3H), 1 .64 (m, 6H), 1.45 - 1 .22 (m, 3H), 1.22 - 1 .03 (m, 9H), 0.86 (ddt, J= 19.7, 12.7, 6.4 Hz, 2H).

(Scheme 5). In some embodiments, as illustrated in Scheme 6, compound 216 is prepared.

216

Scheme 6

As illustrated in Scheme 6, above, 3-Methylbut-2-enylmagnesium chloride, 0.50 M in THF (760 mL, 380 mmol), is transferred to a 2 liter, flame-dried round-bottom flask. After cooling to 4 °C, Cul (7.62 g, 40 mmol) is added to give a dark suspension, and (S)-2-methyl-oxirane 99% ( 14 mL, 200 mmol) in anhydrous THF ( 12 mL) is slowly added to the stirred reaction mixture via syringe pump at a rate of 1 10 mL/h at 4 °C to give a dark suspension which is allowed to slowly warm to room temperature in the ice bath. After stirring at room temperature for 16 hours, thin-layer chromatography and Ή NMR show (S)-sulcatol ((S)-6-Methyl-hept-5-en-2-ol) and a more polar, more volatile side product. The reaction mixture is poured into saturated aqueous NH ₄C1 (600 mL) to give a blue aqueous suspension and an organic layer with pH 9. This mixture is stirred for 30 minutes, and the mixture is extracted three times with Et ₂0 (800 mL, 400 mL, and 400 mL). The organic extracts are combined, washed with water (200 mL), brine (200 mL), dried with MgS0 ₄, and stripped of solvent in vacuo (30 mmHg) at 35 °C to give 31 .8 grams of a yellow oil which is purified three times by distillation in vacuo at 15-20 mmHg. The higher boiling fractions, bp. 80 °C, contain the (S)-sulcatol. The yield of (S)-sulcatol is 13.68 g. R _f in 3 : 1 hexanes/ethyl acetate: sulcatol: 0.35, impurity: 0.3.

" H NMR (CDC1 ₃): 6 5.14 (m, 1 H), 3.81 (m, 1 H), 2.08 (m, 1 H), 1.69 (s, 3H), 1.62 (s, 2H), 1.48 (m, 2H), 1.19 (d, 3H, J = 6 Hz). Alternatively, (S)-sulcatol ((S)-6-Methyl-hept-5-en-2-ol) is synthesized by generating the 3-methylbut-2-enylmagnesium halide Grignard reagent in situ from l -halo-3- methylbut-2-ene (e.g., l -chloro-3-methylbut-2-ene) and magnesium metal in the presence of (S)-methyloxirane.

In an alternative method, (S)-sulcatol is isolated as follows: (S)-sulcatol and the major impurity (3-methyl-2-buten-l -ol) are treated with a selective oxidant, manganese dioxide (Mn0 ₂) to form a mixture of (S)-sulcatol and 3-methyl-2-butenal. Treatment of this mixture with sodium bisulfite ( aHS0 ₃) forms a mixture of (S)-sulcatol and sodium l -hydroxy-3-methylbut-2-ene- l -sulfonate. The sodium l -hydroxy-3- methylbut-2-ene- l -sulfonate is removed through extraction with water. Removal of water from the organic layer with sodium sulfate yields a solution of (S)-sulcatol in Me-THF.

As shown in Scheme 6, (S)-6-Methyl-hept-5-en-2-ol (2.64 g, 20.58 mmol) and DIEA (6.45 mL, 37.0 mmol) are then dissolved in anhydrous CH ₂C1 ₂ (28 mL), the reaction mixture is cooled to 5 °C, mesyl chloride (1 .91 mL, 24.7 mmol) is added dropwise, and the reaction mixture is allowed to slowly warm to room

temperature. After 18 hours at room temperature, the reaction mixture is diluted with CH ₂C1 ₂ (100 mL), washed with water (3 x 35 mL), brine (35 mL), and dried with MgS0 ₄, and the solvent is concentrated to give a dark oil which is purified by Si0 ₂ flash chromatography using hexanes-EtOAc to give (S)-methanesulfonic acid 1 ,5-dimethyl-hex-4-enyl ester ((S)-sulcatol-O-mesylate) as an oil (3.21 3 g, 76%). R _f hexanes:CH ₂Cl ₂:EtOAc, 40:40:20:0.70. 'H NMR (CDC1 ₃): 5 5.08 (m, 1 H), 4.80 (m, 1 H), 2.99 (s, 3H), 2.10 (m, 2H), 1.75 (m, 1 H), 1 .69 (s, 3H), 1 .62 (m, 1 H), 1 .61 (s, 3H), 1.43 (d, 3H, J = 6.5 Hz).

Optionally, for larger scale preparations, the dark oil may be used in the next step (reaction with methylamine) without silica chromatography, or dissolved in hexanes:CH ₂Cl ₂:EtOAc, 40:40:20, filtered through silica to remove baseline impurities, and stripped of solvent. Below is the description of a method of synthesis of a larger amount of (S)-methanesulfonic acid l ,5-dimethyl-hex-4-enyl ester (19.8 g).

In an alternative embodiment, the (S)-sulcatol ( 13.68 g) from the above section is converted to (S)-methanesulfonic acid 1 ,5-dimethyl-hexyl-4-enyl ester as described above. However, instead of using chromatography, the product is purified by filtering a CH ₂C1 ₂ solution through silica gel in a filtration funnel (6 cm height x 9.5 cm inside diameter, 60 A 220-240 mesh silica) and removing under vacuum. The yield of (S)- methanesulfonic acid l ,5-dimethyl-hexyl-4-enyl ester is 19.8 g. This material shows no side products by Ή NMR.

In the next step (Schme 6), (S)-Methanesulfonic acid l ,5-dimethyl-hex-4-enyl ester (3.21 g, 15.56 mmol) is dissolved in N,N-dimethylacetamide (55 mL), and 40% methylamine in water (54.9 mL, 622 mmol) is added at room temperature using a heavy-walled reaction vessel (150 mL) with a teflon screw cap. The reaction vessel is sealed, stirred, and heated at 50 °C for 64 hours, after which the reaction mixture is cooled to 5 °C, and the system is opened to monitor the reaction by thin-layer chromatography. The reaction mixture is diluted with Et ₂0 (320 mL), and shaken, and the organic layer is washed with water (4 x 100 mL), brine (100 mL), dried with MgS0 ₄, and solvent is concentrated to give (R)-isometheptene 9 as an oil ( 1 .974 g, 90% yield). R _fhexanes:EtOAc, 75:25, product: 0.35. R _f CH ₂C1 ₂:7 Ν NH ₃:MeOH, 90: 10: 0.45.

Ή NMR (CDCI3): δ 5.10 (m, 1 H), 2.52 (m, l H), 2.40 (s, 3H), 1 .99 (m, 2H), 1 .68 (s, 3H), 1.61 (s, 3H), 1 .49 (m, 2H), 1.31 (m, 1 H), 1.04 (d, 3H, J = 6.0 Hz). Optionally, the (R)-isometheptene free base can be further purified by distillation. Thus, the chemical and optical purity of the product can optionally be further improved by recrystallization of the salt formed with a chiral carboxylic acid (e.g. D- tartaric acid, mandelic acid, 0,0-dibenzoyl-D-tartaric acid, N-acetyl-L-phenylalanine) followed by treatment with aqueous NaOH and extraction with ether to re-isolate the (R)-isometheptene free base.

In the next step (Scheme 6), mucic acid ( 1.224 g, 5.82 mmol) is suspended in distilled water (58 mL) at room temperature. (R)-lsometheptene free base ( 1 .974 g, 13.98 mmol) is dissolved in Et ₂0 (28 mL) and added dropwise via addition funnel to the mucic acid at room temperature while stirring to give dissolution of the mucic acid suspension. The biphasic solution is stirred at room temperature for 16 hours, the aqueous layer is separated, extracted with toluene (3 x 50 mL) (the final extraction with toluene stands for 30 minutes before the aqueous layer is separated), then the aqueous layer is evaporated in vacuo (1 mmHg) at 35 - 40 °C to give a white solid which is dissolved in MeOH (12 mL) by gently heating to give a solution which is allowed to cool to room temperature. CH ₃CN (65 mL) is added slowly dropwise via addition funnel at room temperature to the stirred MeOH solution to give a white suspension which is stirred at room temperature for about 30 minutes. The solids are filtered, washed with CH ₃CN thrice, air-dried, then dried in vacuo (0.1 mmHg) at room temperature for 16 hours to give (R)-isometheptene mucate as a white solid

(2.53 1 g, 88%), LRMS: mass calculated for C ₉H ₁₉N: 141 .15; found: 142.3 (M + H) ⁺. Elemental analyses calculated for C ₉Hi ₉N: C%, 58.5 1 , H%, 9.82, N%, 5.69; found: C%, 58.21 , H%, 9.95, N%, 5.54.

'H NMR (D ₂0) 6 5.17 (m, 1 H), 4.24 (s, 1 H), 3.93 (s, 1 H), 3.21 (m, 1 H), 2.66 (s, 3H), 2.09 (m, 1 H), 1.76 (m, 1 H), 1 .69 (s, 3H), 1.62 (s, 3H), 1 .57- (m, 1 H), 1 .29 (d, 3H, J = 6.5 Hz). ^{I 3}C NMR (D ₂0) δ 178.4, 133.8, 121 .4, 70.86, 70.57, 54.2, 31 .3, 28.8, 23.9, 22.3, 16.0, 14.1 . Optionally, the (R)-isometheptene mucate can be further purified by recrystallization from solvents and solvent combinations such as acetone/methanol, acetone/DMSO, acetonitrile/DMSO, acetonitrile/MeOH, DMSO, «-butanol, or isopropanol.

In the last step (Scheme 6), in a 125 mL round bottom flask, 1.0 grams of bis-(R)- isometheptene mucate are suspended in MeOH (30 mL) degassed, and hydrogenated using 10% Pd-C (100 mg) and hydrogen balloon for overnight. After completion, the reaction mixture is filtered through a ceiite pad to remove Pd-C, then evaporated under high vacuum. The product is dried by high vacuum overnight to dry the sample completely to obtain bis-(R)-dihydro isometheptane mucate, compound 216 (0.98 g) as white solid. MS: 144.4 [M+H] and 209 [M-H] calculated for C ₉H ₂,N and C ₆H ₁₀O ₈ respectively.

■HNMR (499 MHz, D ₂0) δ 4.29 (d,J= 1.9 Hz, 1H),3.98 (d,J= 1.9 Hz, lH),3.27(q, J=6.5 Hz, 1H),2.71 (d,J=2.0 Hz, 3H), 1.73 (ddt,J= 14.9, 11.2, 4.9 Hz, 1H), 1.66- 1.52 (m,2H), 1.49- 1.35 (m, 1H), 1.33 (dd, J= 6.8, 2.0 Hz, 3H), 1.25 (p,J=6.8,6.0 Hz, 2H), 0.90 (dd, J = 6.7, 1.9 Hz, 6H) (Scheme 6).

In some embodiments, as illustrated in Scheme 7, compound 215 is prepared.

215

Scheme 7

In the first step of Scheme 7, in a 30 mL brown glass vial with stir bar, S-sulcatol-O- mesylate (824 mg, 4.0 mmol) is dissolved in N^-dimethylacetamide (6.0 mL) and dimethylamine (540.9 mg, 12 mmol) is added to the vial. The vial is then closed with a cap and the reaction continued at 50 °C for 48 hours. After 48 hours, the reaction is cooled to room temperature, and then diethyl ether (50 mL) is added and the mixture transferred into a separating funnel and washed with water (2 x 20 mL). The aqueous layer is back extracted with diethyl ether, and the organic layers combined and washed with brine (25 mL), dried over sodium sulfate, and evaporated to give (1 ,5-dimethyl- hex-4-enyl)-dimethylamine as liquid (420 mg). In the next step of Scheme 7, (l,5-Dimethyl-hex-4-enyl)-dimethyl-amine in diethyl ether (6.0 mL) is added to a solution of oxalic acid (270 mg, 3.0 mmol) in diethyl ether (25 mL). After addition is complete, the resulting precipitated mixture is stirred for 30 min at room temperature. The precipitate is then filtered, washed with diethyl ether (2x 10 mL), and dried overnight under high vacuum to obtain the salt compound 215 (590 mg). MS: 156.2 [M+H] consistent with for Ci ₀H ₂iN ⁺ and negative ion MS 89 [M-H] consistent with C ₂H0 ₄ ^".

Ή NMR (500 MHz, DMSO-c ) δ 5.18 - 4.95 (m, 1H), 3.21 (ddd, J= 10.1, 6.7, 3.4 Hz, 1H),2.64 (s, 6H), 1.98 (ddq,J=38.1, 15.0,7.6,7.2 Hz, 2H), 1.73 (dddd,J= 13.1, 10.1,6.8,3.4 Hz, 1H), 1.66 (d,J= 1.4 Hz, 3H), 1.59 (d,J= 1.3 Hz, 3H), 1.51 - 1.35 (m, 1 H), 1.19 (d, J - 6.6 Hz, 3H) (Scheme 7).

Compound 217 is synthesized from S-sulcatol-0-mesylate and propargylamine following the same procedure as for compound 215. MS: 166.3 Positive ion [M+H] consistent with CnHigN ^"1' and negative ion MS 89 [M-H] consistent with C ₂H0 ₄ ^".

217

Ή NMR (499 MHz, DMSO-</ ₆) δ 5.14 - 4.97 (m, 1H), 3.89 (dd, J= 4.0, 2.6 Hz, 2H), 3.76-3.59(m, 1H), 3.19 (ddd, J= 10.2,6.6,3.9 Hz, 1H), 2.15 - 1.91 (m, 2H), 1.72 (dq,J= 10.0,3.4 Hz, 1H), 1.69-1.62 (m, 3H), 1.58 (d,J= 1.2 Hz, 3H), 1.44 (dtd,J = 13.2, 9.2,5.4 Hz, 1H), 1.20 (d,J=6.6 Hz, 3H). Compound 213 is synthesized from S-sulcatol-(9-mesylate and «-butylamine following the same procedure as for compound 215. Positive ion MS: 184.3 [M+H] consistent with Ci ₂H ₂₅N ⁺ and negative ion MS 89 [M-H] consistent with C ₂H0 ₄ ^" .

213 Ή NMR (499 MHz, DMSC ₆) δ 5.14— 5.01 (m, 1 H), 3.05 (d, J= 8.6 Hz, 1H),2.84 (q,J=7.1 Hz, 2H), 2.81 -2.69 (m, 1H), 1.99 (dp,J=22.9, 7.4 Hz, 2H), 1.77-1.63 (m, 4H), 1.61 - 1.45 (m, 6H), 1.48- 1.37 (m, 1H), 1.32 (ddt,J= 10.6,7.4,3.1 Hz, 3H), 1.18 (d, J= 6.5 Hz, 3H), 0.89 (td, J= 7.4, 3.9 Hz, 5H).

Compound 212 is synthesized from S-sulcatol-0-mesylate and 2-methoxy-ethylamine following the same procedure as for compound 215. Positive ion MS: 186.3 [M+H] calculated for C,iH ₂₃NO and 89 [M-H] calculated for C ₂H ₂0 ₄.

212

Ή NMR (499 MHz, DMSO-cfe) δ 5.08 (ddd, J= 8.3, 4.9, 3.5 Hz, 1 H), 3.58 (t, J= 5.3 Hz, 2H), 3.30 (d,J= 1.9 Hz, 3H), 3.10 (dtd,J= 14.3, 5.6, 5.1, 3.3 Hz, 3H), 2.13 - 1.89 (m,2H), 1.74(dddd,J= 13.4, 10.1, 6.8, 3.8 Hz, 1H), 1.66 (d,J= 1.5 Hz, 3H),

1.58(d,J= 1.3 Hz,3H), 1.45 (dtd,J= 13.1,9.4,5.4 Hz, 1H), 1.21 (d,J=6.5 Hz, 3H).

Compound 214 is synthesized _' from S-sulcatol-Omesylate and cycloproylamine following the same procedure as for compound 215. Positive ion MS: 168.3 [M+H] consistent with CnH ₂iN ⁺ and negative ion MS 89 [M-H] consistent with C ₂H0 ^".

214

Ή NMR (499 MHz, DMSO-<¾) δ 5.15-4.99 (m, 1H), 3.19 (dtd, J= 13.2, 6.7, 3.9 Hz, 1H),2.63 (tt,J=7.5,3.6 Hz, 1H),2.01 (ddt,J=29.9, 14.7, 8.0 Hz, 2H), 1.77 (dddd,J = 13.7, 10.3,6.7,3.9 Hz, 1H), 1.66 (d,J=1.3 Hz, 3H), 1.59 (d,J= 1.2 Hz, 3H), 1.47 (dtd,J = 13.1,9.5, 5.4 Hz, 1H), 1.25 (d, J= 6.6 Hz, 3H), 0.93 - 0.60 (m, 5H).

Compound 219 is synthesized from S-sulcatol-O-mesylate and allylamine following the same procedure as for compound 215. Positive ion MS: 168.3 [M+H] consistent with CiiH ₂)N ⁺ and negative ion MS 89 [M-H] consistent with C ₂H0 ₄ ^~.

219 Ή NMR (499 MHz, DMSO-i/ ₆) δ 5.89 (ddt, J= 17.0, 10.3, 6.6 Hz, 1H), 5.55 - 5.41 (m, 1H), 5.37 (dd,J= 10.4, 1.5 Hz, 1H), 5.07 (tt,J=6.8, 1.5 Hz, 1H), 3.67 - 3.50 (m, 2H), 3.08 (ddp, J= 10.4, 6.6, 3.8, 3.3 Hz, 1H), 1.99 (ddq, J= 30.5, 14.8, 7.8 Hz, 2H), 1.74 (dddd,J= 13.4, 10.2,6.9,3.9 Hz, 1H), 1.66 (d,J= 1.4 Hz, 3H), 1.58 (d, J = 1.2 Hz, 3H), 1.45 (dtd, J= 13.2, 9.4, 5.4 Hz, 1H), 1.21 (d,J=6.5 Hz, 3H). In some embodiments, as illustrated in Scheme 8, compound 357 ((R)-isometheptene- D ₃ mucate) is prepared.

357

Scheme 8

A 100 mL 3-necked round bottom flask is charged with 40 mL water, weighed, and fitted with a septum and a sintered glass bubbler attached to a lecture bottle containing methylamine-D ₃ (10 g), controlled by a regulator. The remaining neck is attached to a dry ice/acetone-cooled condenser fitted with an empty balloon to prevent too much pressure from building in the system. The methylamine-D ₃ is slowly bubbled into the water over the course of 25 minutes at ambient temperature. The flask is weighed again and found to contain 9.0 g of methylamine-D ₃.

(S)-Sulcatol-O-mesylate (3.0 g, 14.54 mmoles) is dissolved in dimethylacetamide (40 mL) in a 200 mL thick walled glass pressure vessel. The aqueous solution of methylamine-D ₃ (~48 mL of solution, 9 g, 370.4 mmol) is added. The pressure vessel is sealed and heated at 50 °C for 48 hours while stirring with a magnetic stirbar. The reaction mixture is cooled to 5 °C for 15 minutes and then diluted with ether (300 mL), washed with water (3 x 100 mL) and saturated aqueous NaCl ( 100 mL) _s dried over Na ₂S0 ₄, and evaporated under mild vacuum (30 mmHg, 25 °C). Mild vacuum is used because of the volatility of the product. The yield is 2.4 grams of crude product as a colorless oil ((R)-isometheptene-D ₃), which is used without further purification for the next reaction.

A 250 mL round-bottomed flask is charged with mucic acid ( 1.681 5 g, 8 mmol) and water (80 mL). To this mixture, (R)-isometheptene-D ₃ (2.4 g from the previous reaction, < 16.6 mmoles) in diethyl ether (32 mL) is added dropwise with rapid stirring. Stirring is continued for 1 8 hours at ambient temperature. The aqueous layer is separated from the organic layer. The aqueous layer is extracted with 3 x 100 mL of toluene and the water is removed under high vacuum (35-40 °C). The resulting white solid is dissolved in methanol (25 mL), and acetonitrile (80 mL) is added slowly dropwise via an addition funnel to give a white suspension. The suspension is filtered and washed with acetonitrile (2 x 20 mL) and dried in vacuo (0.1 mmHg) at room temperature in a dessicator for 15 hours to give a white powder. To remove excess mucic acid from this crude material, it is stirred with 12 mL of methanol, filtered, and stripped of solvent. The resulting powder is dissolved in 25 mL methanol, and treated with 75 mL acetonitrile. The white crystalline precipitate is dried in vacuo. Yield of the (R)-isometheptene-D ₃ mucate of compound 357: 1 .25 grams, 2.51 mmol, 34.5% based on (S)-sulcatol-O-mesylate (Scheme 1).

Ή NMR (D ₂0) δ 5.23 (m, 2H), 4.50 (s, 2H), 4.0 (s, 2H), 3.24 (m, 2H), 2.12 (m, 4H), 1.78 (m, 2H), 1.7 (s, 6H), 1 .65 (s, 6H), 1.6 (m, 2H), 1.28 (d, J = 6.5 Hz, 6H). In the Ή NMR, no peak is observed at or near 2.65 ppm for the D ₃-labelled material, in contrast to the Ή NMR of unlabeled isometheptene mucate. Positive ion MS: 145.4 [M+H], calculated 144.27 for D ₃-isometheptene. Negative ion MS 209.0 [M-H], calculated 210.14 for D ₃-isometheptene mucate.

In some embodiments, as illustrated in Schemes 9 and 10, compound 358, ((R)-6,7- D ₆-isometheptene mucate) is prepared.

Scheme 9

As shown in Scheme 9, to a solution of acetone-D ₆ (6.1 5 mL, 83.6 mmol) in 150 m anhydrous THF at -78 °C under argon, 1 M vinyl magnesium bromide in THF ( 100 mL, 100 mmol) is added dropwise through a syringe pump. After completion, the reaction is stirred at -78 °C for an additional two hours, then warmed slowly up to room temperature. 15 mL ice water is added to quench the reaction, followed by 100 mL saturated ammonium chloride. The THF layer is separated and the aqueous layer is extracted with diethyl ether (50 mL x 2). The combined organic layers are washed with water and dried with sodium sulfate. After removing the solvent, 6.79 g crude 2- (D ₃)methyl( l , l , l -D ₃)but-3-en-2-ol is obtained. Purity by Ή NMR is -60%, and contaminants also contain vinyl group protons.

'H NMR (499 MHZ, CDC1 ₃) of major product δ 5.96 (dd, J= 1 1 , 17.5 Hz), 5.17 (dd, J = 1.2, 17.5 Hz), 4.96 (dd, 7 = 1 , 1 1 Hz). Impurity peaks are observed at 5.95-6.03, 5.20-5.40, and 4.98 - 5.10 ppm.

To a solution of crude 2-(D ₃)methyl(l , l , l -D ₃)but-3-en-2-ol (3.68 g, 40 mmol) in 30 mL THF, 15 mL 37% aqueous HC1 solution is then added dropwise at 4 °C. After addition is complete, the reaction is stirred at 4 °C for 30 minutes, then it is slowly warmed up'to room temperature and stirred for 3 hours. 20 mL water is added and the reaction solution is extracted with diethyl ether (30 mL x 3) and the combined organic layers are washed with water and dried with sodium sulfate. The solvent is removed by distillation at atmospheric pressure at 60 °C to remove the ether. At 80 °C a fraction containing the desired l -chloro-3-(D ₃)methyl(4,4,4-D ₃)but-2-ene, THF, and 2-(D ₃)methyl( l , l , l -D ₃)but-3-en-2-ol is obtained. The desired product l -chloro-3- (D ₃)methyl(4,4,4-D ₃)but-2-ene is obtained in higher level of purity in the fraction distilled at 130 °C at atmospheric pressure. Yield of this purest fraction was 800 mg (7.2 mmol, 18%).

Ή NMR (499 MHz, CDC1 ₃) δ 5.42 (t, 1 H), 4.06 (d, 2H). Optionally, a longer reaction time can be used, and the reaction mixture can be combined with methanol before distilling off solvent at 60 °C and 80 °C to take advantage of an azeotrope between methanol and tetrahydrofuran. After removing solvent, the product may be distilled using a slight vacuum (200 to 400 mmHg) and reduced temperature to prevent the decomposition observed at 130 °C. After removal of solvents by distillation at 60 °C and 80 °C atmospheric pressure, dissolve residue in pentane and filter through silica to remove polar contaminants such as THF, 2- (D ₃)methyl(l , l , l -D ₃)but-3-en-2-ol, and methanol (if the azeotrope is used). In the next step (Scheme 9) to a solution of sodium hydroxide (0.54 g, 13.5 mmol) in 2 mL water is added acetone (0.66 mL, 0.53 g, 9.1 mmol), followed by C 16N+Me3Br (0.16 g, 0.44 mmol). l -chloro-3-(D ₃)methyl(4,4,4-D ₃)but-2-ene (0.25 g) is then added slowly to the above solution at room temperature. After addition, the reaction is heated to 60 °C and stirred for 4 hours. Then the reaction is cooled to room

temperature and 5 mL water is added and the mixture is extracted with diethyl ether (8 mL x 2). The combined organic layers are dried with sodium sulfate and concentrated at 15 mmHg. The Ή NMR of the crude product is consistent with desired product 6- (D )methyl(7,7,7-D ₃)hept-5-en-2-one, with precursors acetone, l -chloro-3- (D ₃)methyl(4,4,4-D )but-2-ene, and solvent diethyl ether as major contaminants. Ή NMR (499 MHz, CDC1 ₃) δ 5.1 (m, 1 H), 2.45 (m, 2H), 2.3 (m, 2H), 2.13 (s, 3H).

In the next step of Scheme 9, dinitrophenylhydrazones are then formed from the crude product of the previous reaction and purified to ensure that it contained 6- (D ₃)methyl(7,7,7-D ₃)hept-5-en-2-one. The crude product is dissolved in 20 mL diethyl ether. 50% (10 mL) of this solution is stripped of solvent at 25 °C. 0.2 g 2,4- DNPH is dissolved in 2 mL methanol and 0.2 mL concentrated H ₂S0 ₄ is added slowly dropwise over 10 minutes the crude ketone in 1 mL methanol. Stir at 25 °C for 2 hours. TLC 20% EtOAc:hexane Rf 0.3 for sulcatone and Rf 0.5 for sulcatone hydrazine. Concentrate to remove most of the methanol and dissolve residue in 5 mL CH ₂C1 ₂ and wash with 2 x 3 mL water. CH ₂C1 ₂ layer. is dried over Na ₂S0 ₄. Remove solvent and purify product by silica chromatography ( 100% hexane to 70% ethyl acetate:hexane). (E)-l -(2,4-dinitrophenyl)-2-[6-(D ₃)methyl(7,7,7-D ₃)hept-5-en-2- ylidene]hydrazine (Scheme 9) elutes at 22% EtOAc:hexane and side product 1 -(2,4- dinitrophenyl)-2-(propan-2-ylidene)hydrazine elutes at 29% EtOAc:hexane. The product is an orange solid. Mass calculated for C) ₄Hi gN40 ₄: 312.36. ESI MS negative ion 31 1.2 (M - H ^'), positive ion 335.3 (M + Na ^"1). The side product l -(2,4- dinitrophenyl)-2-(propan-2-ylidene)hydrazine is also identified by Ή NMR and mass spectrometry and is the only other dinitrophenylhydrazone formed. 'H MR (499 MHz, CDCl ₃) 5 1 1 .05 (s, 1 H), 9.1 (m, 1 H), 8.3 (m, 1 H), 7.95 (d, 1 H), 5.21 (m, 1 H), 2.45 (m, 2H), 2.35 (m, 2H), 2.05 (s, 3H).

The procedure for the conversion of 6-(D ₃)methyl(7,7,7-D ₃)hept-5-en-2-one to 6,7-D ₆ isometheptene mucate (Compound 358) is illustrated in Scheme 10.

Scheme 10 6-(D ₃)methyl(7,7,7-D ₃)hept-5-en-2-one is reduced with sodium borohydride to form 6-( ²H ₃)methyl(7,7,7- ²H ₃)hept-5-en-2-ol (sulcatol). 6-( ²H ₃)methyl(7,7,7- ²H ₃)hept-5- en-2-ol is combined with vinyl acetate in the presence of CALB (candida albicans lipase B) to form a mixture of (2S)-6-(D ₃)methyl(7,7,7-D ₃)hept-5-en-2-ol, (D ₆-S- sulcatol), and (2R)-6-(D ₃)methyl(7,7,7-D ₃)hept-5-en-2-yl acetate. The (2S)-6- (D ₃)methyl(7,7,7-D ₃)hept-5-en-2-ol is combined with mesyl chloride and DIPEA to form (2S)-6-(D ₃)methyl(7,7,7-D ₃)hept-5-en-2-yl methanesulfonate, which is reacted with methylamine and DMAc to form methyl[(2R)-6-(D ₃)methyl(7,7,7-D ₃)hept-5-en- 2-yl]amine. Methyl[(2R)-6-(D ₃)methyl(7,7,7-D ₃)hept-5-en-2-yl]amine is mixed with (-)-di- -tolyl-L-tartaric acid (L-DTTA) to form methyl [(2R)-6-(D ₃)methy 1(7,7,7- D ₃)hept-5-en-2-yl]amine L-DTTA. Methyl[(2R)-6-(D ₃)methyl(7,7,7-D ₃)hept-5-en-2- yl]amine L-DTTA is combined with mucic acid in a 2: 1 ratio to form 6,7-D ₆ isometheptene mucate {IUPAC name: (2R,3S,4R,5S)-2,3,4,5- tetrahydroxyhexanedioic acid; bis(methyl[(2R)-6-( ²H ₃)methyl(7,7,7- ²H ₃)hept-5-en-2- yl]amine)} (compound 358).

Exemplification

The invention now being generally described, it will be more readily understood by reference to the following examples, which are included merely for purposes of illustration of certain aspects and embodiments of this disclosure, and are not intended to limit this disclosure. For example, the particular constructs and experimental design disclosed herein represent exemplary tools and methods for validating proper function. As such, it will be readily apparent that any of the disclosed specific constructs and experimental plan can be substituted within the scope of this disclosure.

Example 1 Evaluation of the affinity of compounds for the peripheral imidazoline- 1 (I Q receptor in bovine adrenal medulla glands determined in a radioligand binding assay

This protocol is adapted from: Molderings, G.J., Moura, D., Fink, K., Bonisch, H. and Gothert, M. (1993), Binding of [ ³H]clonidine to I |-imidazoline sites in bovine adrenal medullary membranes, Naun.-Sch. Arch. Pharm., 348: 70, incorporated herein by reference.

Membrane homogenates of adrenal medulla glands (200 μg protein) are incubated for 60 minutes with 10 nM [ ³H]clonidine in the absence or presence of a test compound selected from compounds of formula (SC-01 ), formula (SC-02), formula (SC-03), formula (SC-04), formula (SC-05), formula (SC-06), formula (SC-07), formula (SC- 08), formula (SC-09), formula (SC-10), formula (SC- 1 1 ), formula (SC- 12), formula (SC- 13), formula (SC-14), formula (SC-15), formula (SC-16), formula (SC- 17), formula (SC- 18), formula (SC- 19), formula (SC-20), formula (SC-21 ), formula (SC- 22), formula (SC-23), formula (SC-24), formula (SC-25), or formula 1-432, or a mixture thereof, or a pharmaceutically acceptable salt, free base, tautomer, solvate, enantiomer, disastereomer, or prodrug, or a mixture thereof, of any of the foregoing compounds, in a buffer containing 137 mM NaCl, 2.68 mM NaCl, 2.68 mM KC1, 0.5 mM MgCl ₂, 8.1 mM Na ₂HP0 ₄, 1 .47 mM KH ₂P0 ₄, 0.5 mM EGTA, 0.5 mM EDTA, 0.5% ascorbic acid and 0.1 % BSA (pH 7.4). The buffer also contains 10 μΜ

RX821002 to block the a ₂-adrenergic receptors. Nonspecific binding is determined in the presence of 10 μΜ rilmendine.

Following the incubation, the samples are filtered rapidly under vacuum through glass fiber filters (GF/B, Packard) presoaked with 0.3% PEI and rinsed several times with ice-cold 50 mM Tris-HCl using a 96-sample cell harvester (Unifilter, Packard). The filters are dried and then counted for radioactivity in a scintillation counter (Topcount, Packard) using a scintillation cocktail (Microscint 0, Packard).

The results are expressed as a percent inhibition of the control radioligand specific binding (Table 1). The standard reference compound is rilmenidine, which is tested in each experiment at several concentrations to obtain a competition curve from which its IC5Q or Kj is calculated.

Table 1

j and IC ₅o values are determined for compound 9 mucate salt and compound 27 mucate salt. Compound 9 mucate salt has a Kj of 9.13 nM and an IC ₅₀ of 12.98 nM. Compound 27 has a K, of 297.37 nM and an IC ₅₀ of 463.96 nM. Compound 215 has a j of 280 nM, compound 217 has a Kj of 9.9 nM, compound 218 has a j of 10.10 nM, and compound 219 has a Kj of 12.3 nM

Example 2 Assays of compound affinity with the Imidazoline- 1 (l y) receptor

This protocol is adapted from: Steffen, G., Dendorfer, A., and Dominiak, P.,

Imidazoline binding sites on PC- 12 cells and bovine chromaffin cells. Ann. N. Y. Acad. Sci. 763: 157-162 ( 1995), incorporated herein by reference, with modifications, and Piletz, J.E., Zhu, H.E., and Chikkala, D.N., Comparison of Ligand Binding Affinities at Human Imidazoline Binding Sites and the High Affinity State of Alpha-2

Adrenergic Subtypes. ,/PET. 279: 694-7002 (1996), incorporated herein by reference. Membrane homogenates of PC- 12 cells in 50 mM Tris-HCl (pH 7.4), 5 mM EDTA, 5 mM EGTA, 5 mM MgCl ₂, and 30 μΜ norepinephrine are incubated with 2.0 nM 1 100 Ci/mmol [ ¹²⁵I]iodoclonidine in the absence or presence of a test compound selected from compounds of formula (SC-01 ), formula (SC-02), formula (SC-03), formula (SC-04), formula (SC-05), formula (SC-06), formula (SC-07), formula (SC-08), formula (SC-09), formula (SC- 10), formula (SC- 1 1), formula (SC- 12), formula (SC- 13), formula (SC-14), formula (SC- 15), formula (SC- 16), formula (SC-17), formula (SC-18), formula (SC-19), formula (SC-20), formula (SC-21), formula (SC-22), formula (SC-23), formula (SC-24), formula (SC-25), or formula 1-432, or a mixture thereof, or a pharmaceutically acceptable salt, free base, tautomer, solvate, enantiomer, disastereomer, or prodrug, or a mixture thereof, of any of the foregoing compounds, or a test composition selected from any of the compositions disclosed herein for 60 minutes at room temperature. The reaction is terminated by rapid vacuum filtration onto glass fiber filters. Radioactivity trapped onto the filters is determined and compared to control values in order to ascertain any interactions of the test compound with the Ii receptor binding site.

Nonspecific binding is determined in the presence of 10 μΜ iodoclonidine.

The results are expressed as a percent inhibition of the control radioligand specific binding. The standard reference compound is iodoclonidine, which is tested in each experiment at several concentrations to obtain a competition curve from which its IC50 was calculated.

For compound 9 mucate salt, (R)-isometheptene mucate, the ; is 1 8 nM for the I i receptor and 2300 nM for the a-adrenergic receptor. For compound 27 mucate salt, (S)-isometheptene mucate, the Kj is 1 100 nM for the I i receptor and 2700 nM for the a-adrenergic receptor. Example 3 Evaluation of the affinity of compounds for the central imidazoline receptor in the rat cerebral cortex determined in a radioligand binding assay

This protocol is adapted from: Brown, CM., MacKinnon, A.C., McGrath, J.C., Spedding, M. and Kilpatrick, A.T. (1990), a ₂-adrenoceptor subtypes and imidazoline- like binding sites in the rat brain, Brit. J. Pharmacol., 99:803, incorporated herein by reference.

Membrane homogenates of cerebral cortex (1 mg protein) are incubated for 30 minutes at 22 °C with 2 nM [^Hjidazoxan in the absence or presence of the test compound selected from compounds of formula (SC-01), formula (SC-02), formula (SC-03), formula (SC-04), formula (SC-05), formula (SC-06), formula (SC-07), formula (SC-08), formula (SC-09), formula (SC-10), formula (SC-1 1 ), formula (SC- 12), formula (SC-13), formula (SC-14), formula (SC-15), formula (SC- 16), formula (SC- 17), formula (SC-18), formula (SC-19), formula (SC-20), formula (SC-21 ), formula (SC-22), formula (SC-23), formula (SC-24), formula (SC-25), or formula 1- 432, or a mixture thereof, or a pharmaceutically acceptable salt, free base, tautomer, solvate, enantiomer, disastereomer, or prodrug, or a mixture thereof, of any of the foregoing compounds, or a test composition selected from any of the compositions disclosed herein in a buffer containing 50 mM Tris-HCI (pH 7.4), 0.5 mM EDTA and 3 μΜ yohimbine.

Nonspecific binding is determined in the presence of 10 μΜ cirazoline.

Following incubation, the samples are filtered rapidly under vacuum through glass fiber filters (Filtermat B, Wallac) presoaked with 0.3% PEI and rinsed several times with an ice-cold buffer containing 50 mM Tris-HCI and 150 mM NaCI using a 48- sample cell harvester (Mach II, Tomtec). The filters are dried then counted for radioactivity in a scintillation counter (Betaplate 1204, Wallac) using a solid scintillator (Meltilex B/HS, Wallac). The results are expressed as a percent inhibition of the control radioligand specific binding. The standard reference compound is idazoxan, which is tested in each experiment at several concentrations to obtain a competition curve from which its IC50 is calculated. Example 4 Evaluation of test compounds for analgesic activity using the Formalin

Test, late phase (licking score) in a mouse

The method, which detects analgesic/anti-inflammatory activity, follows that described by Wheeler-Aceto, et al. (Psychopharmacology, 104. 35-44, 1991 ), incorporated herein by reference. Mice are given an intraplantar injection of 5% formalin (25 μΙ_.) into one posterior hindpaw. This treatment induces paw licking in control animals. Mice are briefly observed at one minute intervals between 15 and 50 minutes after the injection of formalin and the number of occasions that the mice are observed licking the injected paw is recorded. 10 mice are studied per group. The test is performed partially blind.

The test substances selected from compounds of formula (SC-01 ), formula (SC-02), formula (SC-03), formula (SC-04), formula (SC-05), formula (SC-06), formula (SC- 07), formula (SC-08), formula (SC-09), formula (SC- 10), formula (SC- 1 1 ), formula (SC-12), formula (SC-13), formula (SC- 14), formula (SC-15), formula (SC-16), formula (SC-17), formula (SC- 18), formula (SC-19), formula (SC-20), formula (SC- 21 ), formula (SC-22), formula (SC-23), formula (SC-24), formula (SC-25), or formula 1-432, or a mixture thereof, or a pharmaceutically acceptable salt, free base, tautomer, solvate, enantiomer, disastereomer, or prodrug, or a mixture thereof, of any of the foregoing compounds, or a test composition selected from any of the compositions disclosed herein are evaluated at three doses, administered p.o. 15 minutes before the test i.e. immediately before formalin, and compared with a vehicle control group. Morphine (32 mg/kg p.o.), 60 minutes before the test i.e. 45 minutes before formalin, is used as a reference substance.

The experiment includes eight groups. Because of the number of animals, the experiment is divided into two sub-experiments (n=5 mice/group/day). Inter-group comparison is performed for the test substance using a tuskaii-Waflls test, followed by Mann-Whitney U tests in case of significant group effect. For the reference substance, the treated group is compared with vehicle control using Mann- Whitney U test.

Data for compound 9 mucate salt, (R)-isometheptene mucate, and compound 27 mucate salt, (S)-isometheptene mucate, are shown in Figure 1. Both compounds 9 and 27 led to a reduction in licking score compared to mice injected only with vehicle, demonstrating an analgesic effect with these compounds. One mouse died after treatment with 100 mg/kg (S)-isometheptene, suggesting this isomer might have issues with toxicity. The analgesic effect of (S)-isometheptene is difficult to determine due to toxicity of the compound.

Example 5 Evaluation of test compounds for analgesic activity using the Hot Plate

Test in a mouse

The method, which detects analgesic activity, follows that described by Eddy and Leimbach (J. Pharmacol. Exp. Ther., 107, 385-393, 1953), incorporated herein by reference.

Mice are placed onto a hot metal plate maintained at 54 °C surrounded by a Plexigias cylinder (height: 13 cm; diameter: 19 cm). The latency to the first foot-lick is measured (maximum: 30 seconds).

10 mice are studied per group. The test is performed partially blind. The test substances selected from compounds of formula (SC-01 ), formula (SC-02), formula (SC-03), formula (SC-04), formula (SC-05), formula (SC-06), formula (SC- 07), formula (SC-08), formula (SC-09), formula (SC- 10), formula (SC-1 1 ), formula (SC-12), formula (SC-13), formula (SC-14), formula (SC-15), formula (SC-16), formula (SC-17), formula (SC-18), formula (SC-19), formula (SC-20), formula (SC- 21), formula (SC-22), formula (SC-23), formula (SC-24), formula (SC-25), or formula 1-432, or a mixture thereof, or a pharmaceutically acceptable salt, free base, tautomer, solvate, enantiomer, disastereomer, or prodrug, or a mixture thereof, of any of the foregoing compounds, or a test composition selected from any of the compositions disclosed herein are evaluated at three doses (10, 30 and 100 mg/kg), administered p.o. 15 minutes before the test, and compared with a vehicle control group.

Morphine (32 mg/kg p.o.) administered 60 minutes before the test, is used as reference substance. The experiment includes 8 groups.

Data for compound 9 mucate salt, (R)-isometheptene mucate,-and compound 27 mucate salt, (S)-isometheptene mucate, are shown in Figure 8. Both compounds 9 and 27 lead to longer foot-licking latency times compared to mice injected only with vehicle, demonstrating an analgesic effect with these compounds. One mouse died after treatment with 100 mg/kg (R)-isometheptene.

Example 6 Evaluation of test compounds for analgesic activity using the Tail-flick

Test in the mouse

The method, which detects analgesic activity, follows that described by D'Amour and Smith (J. Pharmacol. Exp. Ther., 1 , 74-79, 1941 ), incorporated herein by reference. The mouse's tail is heated by means of a thermal light source (20 volts). The latency before the animal withdraws its tail is measured (maximum: 15 seconds).

Ten mice are studied per group. The test is performed partially blind.

The test substances selected from compounds of formula (SC-01 ), formula (SC-02), formula (SC-03), formula (SC-04), formula (SC-05), formula (SC-06), formula (SC- 07), formula (SC-08), formula (SC-09), formula (SC-10), formula (SC-1 1 ), formula (SC- 12), formula (SC- 13), formula (SC-14), formula (SC- 15), formula (SC-16), formula (SC- 17), formula (SC-1 8), formula (SC-19), formula (SC-20), formula (SC- 21 ), formula (SC-22), formula (SC-23), formula (SC-24), formula (SC-25), or formula 1-432, or a mixture thereof, or a pharmaceutically acceptable salt, free base, tautomer, solvate, enantiomer, disastereomer, or prodrug, or a mixture thereof, of any of the foregoing compounds, or a test composition selected from any of the compositions disclosed herein are evaluated at three doses (10, 30, and 100 mg), administered p.o. 15 minutes before the test, and compared with a vehicle control group. Morphine (32 mg/kg p.o.) 60 minutes before the test, is used as reference substance. The experiment includes eight groups.

Data with the test substances are analyzed by comparing treated groups with vehicle control using ANOVA followed by post-hoc Dunnett's tests. Data with the reference substance are analyzed using unpaired Student's t tests. Data for compound 9 mucate salt, (R)-isometheptene mucate, and compound 27 mucate salt, (S)-isometheptene mucate, are shown in Figure 2. Both compounds 9 and 27 led to longer tail flick latency times compared to mice injected only with vehicle, demonstrating an analgesic effect with these compounds. Compound 9 at 100 mg/kg p.o. shows activity similar to that of morphine at 32 mg/kg. Two mice died after treatment with 100 mg/kg (S)-isometheptene, suggesting this isomer might have issues with toxicity. The analgesic effect of (S)-isometheptene is difficult to determine due to toxicity of the compound. Example 7 Testing of compounds in the TAAR 1 cAMP Assay

The cAMP Hunter cell line expressing human TAAR1 is expanded from freezer stocks according to standard procedures. Cells are seeded in a total volume of 20 into white walled, 384-well microplates and incubated at 37 °C for the appropriate time prior to testing. cAMP modulation is determined using the DiscoveRx HitHunter cAMP XS+ assay. For agonist determination, cells are incubated with samples selected from compounds of formula (SC-01), formula (SC-02), formula (SC-03), formula (SC-04), formula (SC-05), formula (SC-06), formula (SC-07), formula (SC- 08), formula (SC-09), formula (SC-10), formula (SC-1 1 ), formula (SC-12), formula (SC- 13), formula (SC-14), formula (SC- 15), formula (SC-16), formula (SC- 17), formula (SC-18), formula (SC- 19), formula (SC-20), formula (SC-21 ), formula (SC- 22), formula (SC-23), formula (SC-24), formula (SC-25), or formula 1-432, or a mixture thereof, or a pharmaceutically acceptable salt, free base, tautomer, solvate, enantiomer, disastereomer, or prodrug, or a mixture thereof, of any of the foregoing compounds, or a test composition selected from any of the compositions disclosed herein to induce response. Media is aspirated from cells and replaced with 15 2: 1 HBSS/10 mM HepesxAMP XS+ Ab reagent. Intermediate dilution of sample stocks is performed to generate 4x sample in assay buffer. 4.5 μί of 4x sample is added to cells and incubated at 37 °C or room temperature for 30 or 60 minutes. Final assay vehicle concentration is 1 %. After appropriate compound incubation, assay signal is generated through incubation with 20 cAMP XS+ ED/CL lysis cocktail for one hour followed by incubation with 20 μΐ.. cAMP XS+ EA reagent for three hours at room temperature. Microplates are read following signal generation with a

PerkinEimer Envision™ instrument for chemiluminescent signal detection.

Compound activity is analyzed using the CBIS data analysis suite (Chemlnnovation, CA). For Gs agonist mode assays, percentage activity was calculated using the following formula: % Activity=100% x (mean RLU of test sample - mean RLU of vehicle control) / (mean RLU of MAX control - mean RLU of vehicle control). Data for compound 9 mucate salt, (R)-isometheptene mucate, and compound 27 mucate salt, (S)-isometheptene mucate, are shown in Figures 3A-B. For compound 9 mucate salt, (R)-isometheptene mucate, the ΕΟ ₅₀ is 29.45 μΜ and for compound 27 mucate salt, (S)-isometheptene mucate, the EC ₅₀ is 21 .12 μΜ. Compound 27 more potently activates TAAR1 than compound 9.

Example 8 Testing of compounds in spontaneous trigeminal allodynia (STA) rats

Protocols are adapted from Oshinsky, M.L., et al., Spontaneous Trigeminal Allodynia in Rats: A Model of Primary Headache, Headache, 2012, 52: 1336- 1349, incorporated herein by reference. Spontaneous trigeminal allodynia (STA) rats are rats with the inherited trait of spontaneously changing trigeminal von Frey thresholds. Oshinsky et al. describes these rats as a novel model of spontaneous headache and can be used as a model of primary headache.

STA rats and litter mates without the trait are injected with compounds selected from compounds of formula (SC-01), formula (SC-02), formula (SC-03), formula (SC-04), formula (SC-05), formula (SC-06), formula (SC-07), formula (SC-08), formula (SC- 09), formula (SC-10), formula (SC-1 1 ), formula (SC-12), formula (SC-13), formula (SC- 14), formula (SC- 15), formula (SC- 16), formula (SC- 17), formula- (SC- 18), formula (SC- 19), formula (SC-20), formula (SC-21 ), formula (SC-22), formula (SC- 23), formula (SC-24), formula (SC-25), or formula 1-432 (0.1 - 200 mg/kg), or a mixture thereof, or a pharmaceutically acceptable salt, free base, enantiomer, disastereomer, tautomer, solvate, or prodrug, or a mixture thereof, of any of the foregoing compounds, or a test composition selected from any of the compositions disclosed herein on days when their thresholds in spontaneous allodynia rats are 4 g or below for STA rats. Testing days for each of the compounds are separated by at least one week. Tactile sensory thresholds are recorded prior to and following injections at 0.5 hours, 1.5 hours, 2.5 hours, 3.5 hours, and 24 hours. Tactile sensory testing

Rats are trained and acclimated to a plastic tube restraint and entered uncoaxed. This restrainer allows the rats to undergo sensory testing.

Periorbital, hind-paw, and jaw-pressure thresholds are determined by applying von Frey monofilaments (Stoelting Co., Wood Dale, IL, USA). Each monofilament is identified by manufacturer-assigned force values (26, 15, 10, 8, 6, 4, 2, 1.4, 1 , 0.6, 0.4, 0.07 g). For trigeminal testing, .the filaments are tested on both the left and right sides of the face, over the rostral portion of the eye for periorbital testing, and on the skin over the masseter muscle for jaw testing. The vibrissae are not touched during testing. For the hind-paw testing, the filaments are applied to the mid-plantar region of the left and right hind paws, avoiding the less sensitive foot pads. For the hind-paw testing, the maximum value tested is 26 g; the rats that do not respond to this stimulus are assigned this value. Left and right threshold data are recorded separately. The von Frey stimuli are presented in sequential order, either ascending or descending, as necessary, to determine the threshold of response. After a positive response, a weaker stimulus is presented, arid after a negative response, a stronger stimulus is presented. Results are presented either as the threshold in grams ± standard error of the mean (SEM), or as a percent change from baseline on the side that has the lowest value. The threshold is defined as a positive response to 2 of 3, or in some cases 3 of 5 trials of a single von Frey monofilament. The value of the von Frey filament that elicits head withdrawal in 2 of 3 repetitions of the stimulus is designated as that day's threshold. Several behaviors are considered a positive head-withdrawal response, including when the rat vigorously strokes its face with the ipsilateral forepaw and quickly recoils its head away from the stimulus or vocalizes. For the periorbital von Frey testing, rats that do not respond to the 10 g stimulus are assigned 10 g as their threshold.

Data for compound 9 mucate salt, (R)-isometheptene mucate, and compound 27 mucate salt, (S)-isometheptene mucate, are shown in Figures 4, 15, and 17. Figures 4 and 15 show data collected using STA rats after treatment with 30 mg/kg of the (R)- isomer or (S)-isomer of isometheptene mucate. Figure 17 shows data collected using STA rats after treatment with 1 mg/kg of the (R)-isomer or (S)-isomer of

isometheptene mucate. No significant changes in trigeminal sensitivity are observed when rats were treated with 1 mg/kg of the (R)-isomer or (S)-isomer of isometheptene mucate. The data illustrate that treatment with 30 mg/kg of the (R)-isomer of isometheptene mucate significantly increases trigeminal thresholds at the 0.5 hr (7.8- fold), 1.5 hr (4.3-fold), 2.5 hr (4.5-fold), 3.5 hr (8.5-fold), and 24 hr (8.2-fold) time points. In contrast, treatment with 30 mg/kg of the (S)- isomer, has no effect on trigeminal sensitivity. STA rats treated with greater than 1 mg/kg compound 9 mucate salt show a dramatic increase in threshold values versus STA rats treated with compound 27 mucate salt or the control rats, demonstrating the analgesic effect of compound 9 mucate salt.

Example 9 Impact of compounds on arterial blood pressure (BP) and heart rate effects in vivo

Rats are anesthetized with Inactin® (sodium thiobutabarbital 100 to 150 mg/kg i.p.) and prepared for the recording of the following parameters: 1) Mean, systolic and diastolic arterial blood pressure (mmHg), via a pressure transducer introduced into the left carotid artery and 2) Heart rate (beats/min), derived from pulse blood pressure.

The parameters measured are allowed to stabilize for a period of at least 20 minutes before the test substance selected from compounds of formula (SC-01), formula (SC- 02), formula (SC-03), formula (SC-04), formula (SC-05), formula (SC-06), formula (SC-07), formula (SC-08), formula (SC-09), formula (SC- 10), formula (SC- 1 1 ), formula (SC- 12), formula (SC- 13), formula (SC-14), formula (SC- 15), formula (SC- 16), formula (SC- 17), formula (SC-1 8), formula (SC- 19), formula (SC-20), formula (SC-21 ), formula (SC-22), formula (SC-23), formula (SC-24), formula (SC-25), or formula 1-432, or a mixture thereof, or a pharmaceutically acceptable salt, free base, tautomer, solvate, enantiomer, disastereomer, or prodrug, or a mixture thereof, of any of the foregoing compounds, or a test composition selected from any of the compositions disclosed herein is administered. Measurements are performed before and then 30 seconds, 1 , 2, 5, 10 and 15 minutes after the end of each i.v. bolus administration.

Results are expressed in absolute values and as maximal change from pre-dose.

Six rats are studied per group and each test compound is evaluated at three doses (0.05, 0.5 and 5 mg/kg), administered via i.v. as a 30-second bolus, at intervals of 15 minutes, and compared with a time-matched vehicle control group. The experiment therefore includes four groups. Inter-group comparison on maximal absolute changes from pre-dose (each test substance versus vehicle, and each isomer versus racemate) is performed using an unpaired Student's t test. Data for compound 9 mucate salt, (R)-isometheptene mucate, and compound 27 mucate salt, (S)-isometheptene mucate, are shown in Figures 5A-D and 18-21.

Isometheptene mucate USP (0.05, 0.5 and 5 mg/kg), administered as a 30-second i.v. bolus to anesthetized rats, only induces a slight but dose-dependent hypertension from · 0.5 mg/kg when comparing the amplitude of the response to that observed in the time- matched vehicle control group. The increase occurs shortly following the

administration and reached a maximum of 4.0±0.6 mmHg from pre-dose for mean blood pressure (BP) at 0.05 mg/kg (NS), 10.5±0.9 mmHg from pre-dose at 0.5 mg/kg (NS) and 1 1.7±2.8 mmHg from pre-dose at 5 mg/kg (p<0.05). Isometheptene mucate USP induces a clear and rapid dose-dependent tachycardia that reaches a maximum of 19.0±4.3 bpm from respective pre-dose at 0.05 mg/kg (NS), 40.8±4.0 bpm at 0.5 mg/kg (pO.001 ) and 57.8±8.6 bpm at 5 mg/kg (p<0.001).

Compound 27 mucate salt, isometheptene mucate isomer 1 (0.05, 0.5 and 5 mg/kg), administered as a 30-second i.v. bolus to anesthetized rats, induces a dose-dependent hypertension, but also only from 0.5 mg/kg when comparing the amplitude of the response to that observed in the time-matched vehicle control group. The increase occurs shortly following the administration and reaches a maximum of 2.7±0.8 mmHg max from pre-dose for mean BP at 0.05 mg/kg (NS), 10.3±4.0 mmHg max from pre- dose at 0.5 mg/kg (NS) and 34.7±7.6 mmHg max from pre-dose at 5 mg/kg (p<0.01 ). Compound 27 mucate salt also causes a clear and rapid dose-dependent tachycardia that reaches a maximum of 23.8±3.2 bpm from respective pre-dose at 0.05 mg/kg (p<0.01 ), 70.3±9.1 bpm at 0.5 mg/kg (p<0.001 ) and 76.5±8.2 bpm at 5 mg/kg (pO.001 ). Compound 9 mucate salt, isometheptene mucate isomer 2 (0.05, 0.5 and 5 mg/kg), administered as a 30-second i.v. bolus to anesthetized rats, induces a slight but dose- dependent hypertension, but only from 0.5 mg/kg when comparing the amplitude of the response to that observed in the time-matched vehicle control group. The increase occurs shortly following the administration and reaches a maximum of 3.0±0.9 mmHg max from pre-dose for mean BP at 0.05 mg/kg (NS), 7.5± 1 .5 mmHg max from pre- dose for mean BP at 0.5 mg/kg (NS) and 19.2±4.4 mmHg max from pre-dose at 5 mg/kg (pO.01 ). Compound 9 mucate salt also causes a clear and rapid dose- dependent tachycardia that reaches a maximum of 24.7±5.6 bpm from respective pre- dose at 0.05 mg/kg (p<0.05), 49.5±9.2 bpm at 0.5 mg/kg (pO.001) and 72.2±5.9 bpm at 5 mg/kg (pO.001).

Although the maximum increase in arterial blood pressure observed following the administration of compound 27 mucate salt at 5 mg/kg was higher than that observed with compound 9 mucate salt (34.7±7.6 mmHg versus 19.2±4.4 mmHg), there is no statistical difference between the two isomers. A trend for systolic blood pressure is however observed (p= 0.0762). The tachycardia observed following compound 9 and compound 27 mucate salts administration is not statistically different.

These results suggest that isometheptene mucate (the racemate), compound 9 mucate salt, and compound 27 mucate salt (0.05, 0.5 and 5 mg/kg), administered as a bolus of 30-second i.v. bolus to anesthetized rats, induces a dose-dependent hypertension. Both compound 9 mucate salt and compound 27 mucate salt induce a more pronounced hypertension than that induced by the racemate, and compound 27 mucate salt clearly induces (although not statistically significant) a more pronounced hypertension than compound 9 mucate salt. The racemate and the two isomers induce a dose-dependent tachycardia that is not statistically different, although that observed following the administration of 0.5 mg/kg compound 27 mucate salt is slightly higher.

Example 10 Evaluation of test compounds for analgesic efficacy in a rat chronic constrictive nerve injury (CCD model of neuropathic pain Animals

Male Sprague Dawley rats (Harlan) are used in the study. Upon receipt, rats are assigned unique identification numbers and group housed with 2-3 per cage in standard cages. Rats are allowed to acclimate for at least one week prior to dosing. All rats are examined and weighed prior to initiation of the study to assure adequate health and suitability. During the course of the study, 12/12 light/dark cycles are maintained. The room temperature is maintained between 20 °C and 23 °C with a relative humidity maintained around 50%. Chow and water are provided ad libitum for the duration of the study. All testing is performed during the animals' light cycle phase. Rats are single housed after surgery. Test compounds

Gabapentin (100 mg/kg) is dissolved in saline and administered p.o. at a dose volume of 1 mL/kg 60 minutes prior to test.

(S)-Isometheptene mucate (mucate salt of compound 27) and (R)-isometheptene mucate (mucate salt of compound 9) (10, 30, and 100 mg/kg; free base) are dissolved in water and administered orally at a dose volume of 10 mg/kg 15 minutes prior to test.

In addition to compounds 9 and 27 mucate salts, the test 'compounds can be selected from compounds of formula (SC-01 ), formula (SC-02), formula (SC-03), formula (SC-04), formula (SC-05), formula (SC-06), formula (SC-07), formula (SC-08), formula (SC-09), formula (SC- 10), formula (SC-1 1 ), formula (SC- 12), formula (SC- 13), formula (SC- 14), formula (SC- 15), formula (SC-16), formula (SC-17), formula (SC- 18), formula (SC-19), formula (SC-20), formula (SC-21 ), formula (SC-22), formula (SC-23), formula (SC-24), formula (SC-25), or formula 1-432, or a mixture thereof, or a pharmaceutically acceptable salt, free base, tautomer, solvate, enantiomer, disastereomer, or prodrug, or a mixture thereof, of any of the foregoing compounds or a test composition selected from any of the compositions disclosed herein.

Chronic constrictive surgery of the sciatic nerve

This 5μ¾ε^ is performed according to Bennett and Xie ( 1988). Specifically, rats are anesthetized with isoflurane (2% in air). The left hind flank is shaved and sterilized and the rat positioned on its side on a sterile surgical field. The pelvic bone ridge is palpated and a vertical incision is made perpendicular to the long axis of the spine. The first layer of muscle is cut to expose the sciatic nerve. Retractors are used to widen the incision, centering the portion of the sciatic nerve to be ligated. The exposed nerve is carefully teased apart from the second layer of muscle, removing fascia lining. Using 5 cm lengths of 4.0 chromic gut suture (pre-soaked in saline), three loose ligations are made around the sciatic nerve, spaced at 0.5 cm intervals.

Sutures are positioned superior to the point where the nerve branches. The incision is then closed in layers, using 4.0 silk sutures, and the skin closed using sterile autoclips. Topical antibiotic ointment is applied to the closed incision. Each rat is monitored until awake and moving freely around the recovery chamber. Animals are single- housed for the entire duration of the study.

Evaluation of mechanical allodynia

Paw withdrawal from a mechanical stimulus is measured by applying von Frey filaments of ascending bending force to the plantar surface of the hind paws

(ipsilateral and contralateral). Baseline and post-treatment withdrawal threshold values for non-noxious mechanical sensitivity are evaluated using von Frey filaments (Semmes-Weinstein filaments, Stoelting, Wood Dale, IL, USA) of varying stiffness (0.4, 0.7, 1.2, 2.0, 3.6, 5.5, 8.5, 10, 15, 26 g). Animals are placed on a perforated metallic platform and allowed to acclimate to their surroundings for a minimum of 15 minutes before each test session. Each filament is presented perpendicular to the plantar surface with sufficient force to cause slight buckling against the paw, then held until a positive response was noted (paw sharply withdrawn). Confirmation of threshold is tested by examining the filament above and below the threshold withdrawal response. Each filament is applied three times.

Prior to CCI surgery, rats are tested for baseline threshold using the von Frey filaments. Rats with a paw withdrawal threshold (PWT) less than 12 g are not included in the study. Rats are balanced based on their post injury PWT measured two weeks after surgery. On test day rats are administered vehicle, gabapentin, or test compounds and PWT is assessed 15 minutes after administration for vehicle or test compounds and 60 minutes for gabapentin.

Data are analyzed by analysis of variance (ANOVA), followed by post-hoc comparisons when appropriate. An effect is considered significant if p < 0.05.

As shown in Figures 6A-D and 26, gabapentin, (R)-isometheptene mucate (100 mg/kg), and (S)-isometheptene mucate (100 mg/kg) significantly increase PWT compared to the vehicle-treated rats. In addition, (S)-isometheptene mucate (30 mg/kg) shows a non-significant trend to also increasing PWT.

Example 11 Evaluation of test compounds in the rat model of bortezomib-induced neuropathy Animals

Test compounds Bortezomib (BTZ; 0.5 mg/kg; Selleck Chemicals) is dissolved in 5% Tween80, 5% ethanol in 90% saline and injected i.p. at a dose volume of 1 mL/kg.

Gabapentin (100 mg/kg) is dissolved in saline and administered p.o. at a dose volume of 1 mL/kg 60 minutes prior to test.

(S)-isometheptene mucate (compound 27 mucate salt) and (R)-isometheptene mucate (compound 9 mucate salt) ( 10, 30, and 100 mg/kg; free base) are dissolved in water and administered orally at a dose volume of 10 mg/kg 15 minute prior to test.

In addition to compounds 9 and 27 mucate salts, the test compounds can be selected from compounds of formula (SC-01 ), formula (SC-02), formula (SC-03), formula (SC-04), formula (SC-05), formula (SC-06), formula (SC-07), formula (SC-08), formula (SC-09), formula (SC-10), formula (SC- 1 1), formula (SC- 12), formula (SC- 13), formula (SC- 14), formula (SC-15), formula (SC- 16), formula (SC- 17), formula (SC- 18), formula (SC- 19), formula (SC-20), formula (SC-21 ), formula (SC-22), formula (SC-23), formula (SC-24), formula (SC-25), or formula 1-432, or a mixture thereof, or a pharmaceutically acceptable salt, free base, tautomer, solvate, enantiomer, disastereomer, or prodrug, or a mixture thereof, of any of the foregoing compounds or a test composition selected from any of the compositions disclosed herein.

BTZ-Induced Neuropathic Pain

Prior to commencing BTZ or vehicle injections, rats are tested for their paw withdrawal threshold (PWT). Baseline and post-treatment PWT values for non- noxious mechanical sensitivity are evaluated using von Frey (VF) filaments (Semmes- Weinstein filaments, Stoelting) of varying stiffness (0.4, 0.7, 1.2, 2.0, 3.6, 5.5, 8.5, 10, 15, 26 g) starting with the middle filament (3.6 g). Each filament is presented perpendicular to the plantar surface with sufficient force to cause slight buckling against the paw, then held for approximately six seconds or until a positive response is noted. A positive response is defined as withdrawal from the von Frey filament. Confirmation of threshold is tested by examining the filament above and below the withdrawal response in a modified up-down method paradigm. If a response is positive, the next descending filament is tested. If the response is negative, the next ascending filament is tested. The responses from both hind paws are averaged at each time point. Rats that had a baseline (pre-BTZ injection) PWT less than 12 g are not included in the study. Rats are subsequently balanced by body weight and by the baseline PWT values. Rats are injected with either bortezomib (0.5 mg/kg; ip) or vehicle (5% Tween80, 5% ethanol in saline; i.p.) and post BTZ injection PWT is assessed 12 days after injection. On test day, compounds are administered 15 minutes prior to test except gabapentin which is administered 60 minutes prior to test.

Data are analyzed by analysis of variance (ANOVA), followed by post-hoc comparisons when appropriate. An effect is considered significant if p < 0.05.

As shown in Figures 7A-D and 27, Acute BTZ (0.5 mg/kg; ip) administration causes chemical-induced neuropathy as observed by significant lower paw withdrawal thresholds (PWT) as compared to vehicle-treated controls. Gabapentin, (R)- isometheptene mucate ( 100 mg/kg), and (S)-isometheptene mucate (30 and 100 mg/kg) significantly increases PWT as compared to the BTZ-treated control group suggesting potential analgesic efficacy of these compounds on BTZ-induced neuropathic pain. Example 12 Establishment of a stable CHO cell line expressing human imidazoline-

Establishment of the cell line

Materials and instruments Materials include: Lentiviruses 4 plasmid system,, pLenti PGK-l iR-puro (construct by Genscript), lipofectamine LTX and plus TM Reagent (Invitrogen, Cat. No. 15338100), F 12 medium (Invitrogen, Cat. No. 1 1765-054), DMEM medium (Invitrogen, Cat. No. 1 1995065), Opti-MEM (Invitrogen, Cat. No. 31985-062), Trypsin /EDTA (Invitrogen, 25200-056, FBS (Hyclone, Cat. No. SH30084.03), Hycromycin B (Invitrogen, Cat. No. 10843555001), and Puromycin (Invitrogen, Cat. No. A l 1 13803)

Cell lines used are: 293T (Bioduro) in DMEM + 10% FBS and CHO (Bioduro) in DMEM + 10% FBS.

Instruments used are an inverted microscope (Olympus, CKX41 ).

Methods Construct generation

Human full length \ _\ receptor is cloned into pLenti PG vector by Genescript. The final construct is confirmed by sequencing and restriction digestion..

Stable cell line generation

Day 1 : Plate 293T cells

293T cells are plated before transfection onto a 10 cm dish to reach 20-30%

confluency (3 x 10 ⁶ cells /10 cm dish) on the day of transfection, and the cells are incubated at 37 °C, 5% C0 ₂.

Day 2: Transfect 293T cells Lentiviruses 4 plasmid system

Plasmid Ug

Target plasmid 4

RRE 4.2

VSVG 3.1

REV 2.1

Total 13.4

Change 293T cell medium to 5 mL Opti-MEM (FBS free). Mix 750 μΐ Opti-MEM, 13.4 μg target DNA (4 plasmids), and 26.8 μΐ, plus TM Reagent and incubate at room temperature for 15 minutes.

Mix 750 μΙ_< Opti-MEM and 40 μΙ_< lipofectamine and incubate at room temperature for 15 minutes.

The lipofectamine and plasmids mixtures are then combined and incubated at room temperature for 15 minutes. After this time, 1.5 mL of the mixture is added to the plate containing 5 mL Opti-MEM.

Plates are replenished with 7 mL serum-containing DMEM media after five hours.

Day 3 : Change medium of 293T cell and plate CHO cells

Provide 8 mL of fresh serum-containing DMEM to 293T cells, and incubate at 37 °C, 5% C0 ₂. Plate 2 x 10 ⁶ CHO cells in a 10 cm dish (20-30% confluent), and incubate at 37 °C, 5% C0 ₂.

Day 4: Collect virus and first virus infection Collect virus from 293T cells and then filter with a 0.45 μηι syringe filter. Replace 293T medium with fresh medium for the second virus collection. Collect the medium (conditional medium) from CHO cells and store at 4 °C. Add 8 mL of viral supernatant with 8 μg/mL polybrene to CHO cells. After eight hours the virus supernatant is removed and the conditioned medium is added.

Day 5 : Collect 72 hour virus and second virus infection.

Collect second virus infection medium and filter with a 0.45 μιη syringe filter. Repeat the infection with the second virus supernatant. Change to fresh medium eight hours after the second infection. Day 7: Replace with Puromycin-Selective culture medium

Replace fresh medium containing 12.5 μg/mL puromycin for each cell line and cultured for 3 weeks.

Cloning and confirmation

After three weeks of selection, single clones are picked and cultured in 24 well plates. Cell cultures are expanded for frozen stocks and positive clones are confirmed by RT- PCR. Constructs are confirmed by restriction digestion with Xhol (Figure 9A).

Detection of I _t receptor in CHO/Ii receptor stable cell lines by RT-PCR

Materials and Instruments

Materials used include: QIAamp RNA Mini Kit (# 52304, QIAGEN), TaqMan Reverse Transcription Reagents (# N8080234, Life Technology), TaKaRa Taq™ (#R001 B, TaKaRa), and TaKaRa LA Taq® (#RR52A, TaKaRa).

Primers:

Forward primer Reverse primer Length (bp)

CCTGCATCAGGTGGAGAT TTCATCGAGGTTGCTGAG 1 1 1

AAG AAG

Cell lines used are CHO (Bioduro) in DMEM + 10% FBS ^'and CH07 1, receptor (Bioduro) in DMEM + 10% FBS + 12.5 glxnL puromycin.

Instruments used include: inverted microscope (Olympus, C X41), gradient PCR meter (Biometra, 070-851 ), electrophoresis meter (DYY, 6C), and gel imaging meter (Alphalmager, DE-500)

Methods

1 . Total RNA Extraction

Total RNA is isolated from cells using a QIAamp RNA Mini Kit, following the manufacture's protocol. The concentration of mRNA is determined with a Nanodrop. 2. Reverse Transcription

Set up RT-Reaction Mixtures on ice:

Component 20 μΐ Reaction

Nuclease-free water to 20 μΐ l Ox TaqMan RT Buffer 2 μΐ Deoxy NTPs mixture 4 μΐ Random Hexamers 1 μΐ RNAse Inhibitor 0.4 μΐ RNA Sample 1 μg

25 mM MgCl ₂ 4.4μ1

MultiScribe Reverse Transcriptase (50υ/μ1) 0.5μ1

Used the following program for the RT-Reactions:

Cycle step Temp Time

Incubation 25 °C l O min

Reverse Transcription 48 °C 30 min

Transcriptase Inactivation .95 °C 5min

Set up the PCR-Reaction Mixtures on ice:

Component 50 μΐ Reaction Final Concentration

Nuclease-free water to 50 μΐ

l Ox buffer 5 μΐ l x

Forward primer ( 10 μΜ) ΐ ^' μΐ Optimal

Reverse primer ( 10 μΜ) Ι μΐ Optimal dNTP mixture (2.5 mM) 2 μΐ

Taq Ι μΐ 10 to 100 ng cDNA sample 2 μΐ 10 to 100 ng

PCR procedure: Cycle step Temp Time

Initial denaturation 95 °C 3 min

Denaturation 95 °C 1 min

Cycle (30 cycles) Annealing 55 °C 1 min

Extension 72 °C 1 min

Final extension 72 °C 10 min

For analysis by electrophoresis, use 10 of PCR reaction mixture, 2% agarose gel, 100 V, 20 minutes.

Results

The RT-PCR result from the transient transfection of Ii receptor/CHO cells indicates that I i receptor is expressed in the transfected cells (Figure 9B).

Example 13 Establishment of a functional assay for the imidazoline- 1 (10 receptor in PC-12 cells or an l^ receptor stable cell line to evaluate the impact of receptor agonists and antagonists on forskolin-stimulated cAMP induction Materials and Instruments

Materials used include: PC- 12 cell line (adherent ATCC®-CRL 1721 . 1 , suspension ATCC®-CRL 1721 ), DMEM (Gibco, Cat. # 1 1965), RPM1- 1640 (Gibco, Cat.

#72400), FBS (Gibco, Cat. # 10099), Horse serum (Gibco, Cat. #26050), NGF (Sigma, Cat. #N0513), Collagen (Gibco, Cat. #A 10483-01 ), Forskolin (FS ) (Sigma, Cat. #F6886), 96-well plate (Corning, Cat, #3599), 384-welI plate (Greiner, Cat. #784075), and cAMP dynamic 2 kit (Cisbio, Cat #62AM4PEB). Instruments used include: EnVision® Multilabel Reader (PerkinElmer, #2104-0010).

Methods

Day 1

Coat 96 well plate with 40 μΙνΛνβΙΙ collagen (50 μg/mL, diluted from 3 mg/mL collagen stock in 0.02 M acetic acid), incubate at room temperature for one hour, rinse with PBS three times, and air dry.

PC- 12 (adherent) cells are cultured in RPMI- 1640 medium supplemented with 10% FBS.

Cells are collected and centrifuged at 1000 rpm for five minutes, and resuspended in RPMI-1640 medium supplemented with 1% FBS, 50 ng/mL NGF.

Plate 2000 cells/well in a 96 well plate coated with collagen, and incubate at 37 °C with 5% C0 ₂ for 48 hours.

11 receptor/CHO stable cell line is plated at 3500 cells/well in DMEM + 10% FBS. Day 3 Prepare serial dilutions of benazoline and efaroxan, and add 20 μΙ_ benazoline, efaroxan, or medium to each well. Optionally, test compounds selected from compounds of formula (SC-01 ), formula (SC-02), formula (SC-03), formula (SC-04), formula (SC-05), formula (SC-06), formula (SC-07), formula (SC-08), formula (SC- 09), formula (SC- 10), formula (SC- 1 1), formula (SC-12), formula (SC-13), formula (SC- 14), formula (SC-15), formula (SC-16), formula (SC- 17), formula (SC-18), formula (SC-19), formula (SC-20), formula (SC-21 ), formula (SC-22), formula (SC- 23), formula (SC-24), formula (SC-25), or formula 1-432, or a mixture thereof, or a pharmaceutically acceptable salt, free base, tautomer, solvate, enantiomer,

disastereomer, or prodrug, or a mixture thereof, of any of the foregoing compounds, or a test composition selected from any of the compositions disclosed herein can be added to the cells at the same time.

Spin cells at 1000 rpm for one minute and then incubate at room temperature for 30 minutes. Add 20 μΐ forskolin mix (10 μΜ forskolin + 100 μΜ IBMX) or medium (medium + IBMX) to each well according to the plate map, spin cells at 1000 rpm for one minute, then incubate at room temperature for 30 minutes.

Discard 60 μΙ_, supernatant from each well, and add 20 μί lysis buffer to each well, shake for two minutes, and transfer 18 μί from each well to 384-well plate. Add 1 μΙ_, cAMP-d2 to each well (except negative control), add 1 μί lysis buffer to negative control well, and spin cells at 1000 rpm for one minute.

Add 1 μί Cryptate to each well, mix, spin cells at 1000 rpm for one minute, and incubate at room temperature for 30 minutes.

Read plate with Envision and analyze data using the fluorescence ratio (665 nm/615 nm).

Results

Both benazoline and efaroxan inhibit forskoiin-stimulated cAMP in PC-12 cells. The IC ₅₀ of each compound is similar to reports in the literature (Figure 10A). The inhibitory effect of benazoline on forskolin induced cAMP are antagonized by clonidine (compound 26 mucate salt).

To evaluate the I i receptor function, the cAMP assay is carried out in CHO cells transiently transfected with I i receptor expression vector. Both efaroxan and benazoline show an inhibitory effect on forskolin-induced cAMP in I i receptor/CHO cells, but not in the parent CHO cell line. This result suggests functional I | receptor is expressed in transiently transfected CHO cells (Figures l OB-C).

Example 14 Pharmacokinetic studies of compounds and compositions of the

disclosure Studies

Pharmacokinetic (PK) studies in dogs, rats, and humans are conducted with isometheptene mucate USP and compound 9 mucate salt, (R)-isometheptene mucate. A test compound can also be selected from compounds of formula (SC-01 ), formula (SC-02), formula (SC-03), formula (SC-04), formula (SC-05), formula (SC-06), formula (SC-07), formula (SC-08), formula (SC-09), formula (SC-10), formula (SC- 1 1 ), formula (SC- 12), formula (SC- 13), formula (SC-14), formula (SC-1 5), formula (SC- 16), formula (SC- 17),- formula (SC- 18), formula (SC- 19), formula (SC-20), formula (SC-21 ), formula (SC-22), formula (SC-23), formula (SC-24), or formula (SC-25), or a pharmaceutically acceptable salt, tautomer, enantiomer, disastereomer, solvate, or prodrug of any of the foregoing compounds, or a compound having the formula 1-432, or a pharmaceutically acceptable salt, free base, enantiomer, disastereomer, tautomer, solvate, or prodrug of any of the foregoing compounds or a test composition selected from any of the compositions disclosed herein.

Dog studies Dosing

For IV solutions, the vehicle is saline 0.9% NaCl for Injection, USP, and for PO, the vehicle is deionized tap water. On the day of dosing, the test compounds are mixed with vehicle to achieve the desired concentrations. A salt factor of 1.74 is used for calculation of the test compound amount as the dose is calculated as the free base of the compound 9 mucate salt or of racemic isometheptene mucate. Test system

The animals used are beagles (dogs) from the MPI Research Colony (MPI Research Study Number 999-407). The dogs are at least five months of age and the males weigh 5.5 to 12.0 kg and the females weigh 5.0 to 10.0 kg at arrival, as measured within three days of arrival. The study uses four males and four females. The dogs are acclimated for at least one week prior to testing and are acclimated to a sling restraint for at least three times for a period of at least 20 minutes each time. Prior to dose initiation, animals are acclimated to the oral gavage dosing procedure af least three times. A fixed dose volume of 10 mL/animal of tap water is administered on each occasion.

Study design

Compounds are administered via oral gavage or intravenous injection. The test compound is administered once intravenously on Day 1 . After a 7-day washout period the test article is administered once via oral gavage. For oral gavage (PO) the test compound is withdrawn from stirred formulations and dosed via oral gavage.

Individual doses are based on the most recent body weights. After each dose, and prior to removal of the gavage tube, the tube is flushed with 5 to 10 mL of tap water. The oral route is the intended route of administration of compound 9 mucate salt in humans.

For intravenous (IV), the test compound is administered via the cephalic or other suitable vein. Individual doses are based on the most recent body weights. The dose is administered by bolus injection, unless otherwise indicated. If a catheter is used for dosing, the catheter is flushed with approximately 1 mL of sterile 0.9% Sodium Chloride for Injection, USP following dosing. The intravenous route is used for pharmacodynamic studies in nonclinical species and for calculation of absolute bioavailability. Sample collection and analysis

Animals are monitored at least twice daily and observed for mortality, injury, and availability of food and water. Any animals in poor health are identified for further monitoring and possible euthanasia. Body weights are collected within three days of transfer and on the day prior to and the day following each dose. 0.5 mL samples are collected from the jugular or other suitable vein. The

anticoagulant used is ₂EDTA. Samples are centrifuged and the plasma stored frozen (-60 to -90 °C). The plasma is analyzed for (R)-isometheptene and (S)-isometheptene. Interconversion between (R)-isometheptene and (S)-isometheptene is not observed (Table ^'2). Rat studies

Dosing

For IV solutions, the vehicle is saline 0.9% NaCl for Injection, USP, and for PO, the vehicle is deionized tap water. On the day of dosing, the test compounds are mixed with vehicle to achieve the desired concentrations. A salt factor of 1 .74 is used for calculation of the test compound amount as the dose is calculated as the free base of the compound 9 mucate salt or of racemic isometheptene mucate. Test system

The animals used are CD® rats [Crl:CD®(SD)] from Charles River Laboratories. The rats are six weeks of age at arrival and the males weighed 130 to 210 g and the females weighed 100 to 170 g at arrival, as measured within three days of arrival. The study uses 20 males and 20 females. The rats are acclimated for at least one week prior to testing. During this acclimation period, all animals are observed daily for any clinical signs of disease, and all animals are given a detailed clinical examination prior to selection for study.

The week prior to dose initiation, all animals (including animals potentially designated for PO and IV administration) are administered a sham dose of tap water via oral gavage on at least two occasions in the same manner and at the same volume intended for PO use during the study period.

Study design

Compounds are administered via oral gavage or intravenous injection. The test compound is administered once on Day 1 . For oral gavage (PO) the test compound withdrawn from stirred formulations and dosed via oral gavage. Individual doses are based on the most recent body weights. The oral route is the intended route of administration of compound 9 mucate salt in humans. For intravenous (IV), the test compound is administered via the tail vein. Individual doses are based on the most recent body weights. The dose is administered by bolus injection, unless otherwise indicated. The intravenous route is used for

pharmacodynamic studies in nonclinical species and for calculation of absolute bioavailability.

Sample collection and analysis

0.5 mL samples are collected from the sublingual or other suitable vein. The anticoagulant used is K ₂EDTA. Samples are centrifuged and the plasma stored frozen (-60 to -90 °C). The plasma is analyzed for (R)-isometheptene and (S)-isometheptene. Interconversion between (R)-isometheptene and (S)-isometheptene is not observed (Table 2).

Table 2

Species, Dose, Cmax. ng/mL AUC ng.h/mL ^Tmax. ^h ^Tl/2» ^h

Test Article (Route) mg/kg R-IMH S-IMH R-IMH S-IMH R-IMH S-IMH R-IMH S-IMH

Dog, IMH (IV) 1 354 330 351 306 0.016 0.016 1.6 1.5

Dog, IMH (PO) 10 1380 1220 4901 3885 0.48 0.48 2.7 2.5

Dog, Cpd 9 (IV) 0.5 222 NC 179 NC 0.016 NC 1.1 NC

Dog, Cpd 9 (PO) 5 776 NC 1755 NC 0.39 NC 1.5 NC

Rat, IMH (IV) 1 165 175 62 66 0.16 0.16 0.37 0.38

Rat, IMH (PO) 10 16.1 46.5 8.8 80 0.25 0.37 0.55 0.79

Rat, Cpd 9 (IV) o.s 198 NC 76 NC 0.16 NC 0.47 NC

Rat, Cpd 9 (PO) 5 12.5 NC NC NC 0.33 NC NC NC Human studies

Study design and methodology

The study is a single-center, randomized, double-blind, placebo-controlled, single ascending dose, safety and tolerability study of compound 9 mucate salt capsules in healthy volunteers. Four successive cohorts are planned with doses of compound 9 mucate salt ((R)-isometheptene mucate) capsules, 35 mg, 70 mg, 140 mg, and 280 mg, respectively. Each cohort consists of 15 subjects, and subjects are randomly assigned in a 3 : 1 : 1 ratio to compound 9, racemic isometheptene, or placebo capsules:

Cohort 1 : compound 9 mucate salt, 35 mg (n=9); Racemic isometheptene, 70 mg (n=3); Placebo (n=3)

Cohort 2: compound 9 mucate salt, 70 mg (n=9); Racemic isometheptene, 70 mg (n=3); Placebo (n=3)

Cohort 3 : compound 9 mucate salt, 140 mg (n=9); Racemic isometheptene, 70 mg (n=3); Placebo (n=3)

Cohort 4: compound 9 mucate salt, 280 mg (n=9); Racemic isometheptene, 70 mg

(n=3); Placebo (n=3)

Unless otherwise modified based on safety review following each cohort, all subjects in Cohorts 1 , 2, and 3 take 4 capsules and subjects in Cohort 4 took 8 capsules.

All subjects are screened for eligibility. After re-confirming that subjects meet the inclusion and none of the exclusion criteria, eligible subjects are admitted on Day 1 (Visit 1 ) to the clinic at least 10 hours before dosing. The following morning on Day 1 after all pre-dose assessments are complete, subjects receive a single dose of study drug (4 or 8 capsules depending on the cohort). Following dosing, subjects are confined for close monitoring over 48 hours. Post-dose safety monitoring and blood collection for PK analysis occur periodically during the 48-hour period. Once all 48- hour post-dose assessments are completed, the subject is discharged with a follow-up visit in 7 days (Day 10 ± 1 day) for their final study visit (Visit 2). Preliminary data are shown in Figures 1 1 A-D for cohorts 1 and 2 and in Figures 12A-D for cohort 3. Interconversion between (R)-isometheptene and (S)-isometheptene is not observed. For cohort 3, the data suggest that there are slow, normal, and fast metabolizers of (R)- . isometheptene and (S)-isometheptene.

Additionally, a dose dependent decrease of side effects is observed during the study. Subjects participating in clinical trials of experimental medicines can have anxiety in connection with ingesting a test article that may contain an experimental medicine or experience white coat syndrome in a medical environment, which can lead to elevated blood pressure and other side effects.. Subjects receiving 140 mg of (R)- isometheptene report no side effects. One subject receiving 70 mg of (R)- isometheptene reports side effects. Three. subjects receiving 35 mg of (R)- isometheptene report side effects. Four subjects in the placebo group report side effects. Since the placebo group had the highest number of subjects reporting side effects, these results suggest that increased amounts of (R)-isometheptene can reduce side effects and that (R)-isometheptene appears to have a calming effect. In some embodiments, compounds or compositions of this disclosure can be used in the treatment of white coat syndrome, anxiety, or anxiety and tension associated with dementias such as Alzheimer's disease.

Example 15 Inflammatory soup model studies of compounds and compositions of the disclosure

Rats can be used in an inflammatory soup (IS) model of migraine. Inflammatory soup, composed of a mixture of prostaglandin E2, serotonin, bradykinin, and

histamine, has frequently been used in the migraine literature to study activation of nociceptors and as a model of migraine. Activity of the compounds described herein can be evaluated using the inflammatory soup model.

To assess trigeminal allodynia, periorbital von Frey microfilament thresholds are measured throughout the treatment period in rats receiving infusions of saline (n = 10) or IS (n = 10) three days/week. Rats receiving infusions of IS transition to a more sensitive state, as seen as a decrease in their periorbital thresholds, whereas rats receiving saline infusions do not transition to a more sensitive state. Rats that transition to chronic periorbital sensitivity have thresholds of < 2.0g. Naive or non- transitioned rats do not respond to any pressure less than 8- 1 Og. Data are shown in Figure 16.

The effects of R- and S-enantiomers of isometheptene mucate (compounds 8 and 26 mucate salts, 1 mg/kg, 30 mg/kg, and 100 mg/kg i.p.) on trigeminal sensitivity in the IS model (closely mimics the symptoms of chronic migraine) are tested. In addition to compounds 9 and 27 mucate salts, the test compounds can be selected from compounds of formula (SC-01 ), formula (SC-02), formula (SC-03), formula (SC-04), formula (SC-05), formula (SC-06), formula (SC-07), formula (SC-08), formula (SC- 09), formula (SC- 10), formula (SC-1 1), formula (SC-12), formula (SC-13), formula (SC- 14), formula (SC-15), formula (SC- 16), formula (SC- 17), formula (SC-18), formula (SC-19), formula (SC-20), formula (SC-21 ), formula (SC-22), formula (SC- 23), formula (SC-24), formula (SC-25), or formula 1-432, or a mixture thereof, or a pharmaceutically acceptable salt, free base, tautomer, solvate, enantiomer, disastereomer, or prodrug, or a mixture thereof, of any of the foregoing compounds or a test composition selected from any of the compositions disclosed herein.

Dosing rats with 1 mg/kg of either the R- or S-enantiomers of isometheptene mucate has no significant effect on trigeminal thresholds during the 0.5 hour, 1.5 hour, 2.5 hour, 3.5 hour, and 24 hour time points (Fig. 13). By contrast, treatment with 30 mg/kg of the R-enantiomer of isometheptene mucate has an analgesic effect starting at the 0.5 hour time point, illustrated by a 2.3 ± 0.3- fold increase in trigeminal thresholds (pO.01 , ANOVA) (Fig. 14). This analgesic effect continues during the 1.5 hour (3.0 ± 0.4-fold, pO.01 , ANOVA), 2.5 hour (2.9 ± 0.4-fold, pO.001 , ANOVA), and 3.5 hour (1 .7 ± 0.2-fold, p<0.05, ANOVA) time points (Fig. 14). Trigeminal thresholds return to baseline levels at the 24 hour time point. The saline control group has no change in trigeminal thresholds over the time- course of the experiment (Fig. 14). Treatment with 30 mg/kg of the S-enantiomer of isometheptene mucate has no analgesic effect during the 0.5 hour (p=0.56, ANOVA), 1.5 hour (p=0.70, ANOVA), 2.5 hour (p=0.59, ANOVA), 3.5 hour (p=0.32, ANOVA), and 24 hour (p=0.54, ANOVA) time points (Fig. 14). Therefore, while 1 mg/kg of the R- or S-enantiomer of isometheptene mucate has no effect on trigeminal sensitivity of IS rats, 30 mg/kg of the R-enantiomer mucate significantly decreased trigeminal sensitivity at the 0.5 hour, 1.5 hour, 2.5 hour, and 3.5 hour time points. Baseline thresholds return to baseline levels at the 24 hour time point. Similar to the results found in STA rats (Example 8), the 30 mg/kg dose of the S-enantiomer has no effect on trigeminal sensitivity at any of the time points. No significant changes in trigeminal sensitivity are seen when IS rats are treated with 1 mg/kg R- or S-isometheptene mucate. (Fig. 13, n=8 IS rats/group). Rats receiving saline treatment have no change in sensory thresholds over the course of the experimental timeline. (Fig. 14, n=8 IS rats/group, *p<0.05, **p<0.01 , ***p<0.001). Example 16 Dose-response activation of test compounds on phospho-ERK

expression of 293T cells transiently transfected with l \ receptor

I , receptors are coupled to activation of phosphatidylcholine selective phospholipase C

(PC-PLC), liberation of arachidonic acid (AA), generation of diacylglycerol (DAG), activation of protein kinase C (PKC) isoforms (PKCB,, and ΡΡ ζ ) and mitogen- activated protein kinase (MAPK); extracellular-regulated kinase (ERK); and c-jun kinase (INK) (Figure 22). Studies are conducted with 293T cells transiently transfected with the Ii receptor and compounds of this disclosure to determine if treatment of the cells with the compounds leads to activation of ERK.

A. Materials and reagents

1. Materials

1.1 Cell line 1.2 Reagents

a) Lipofectamine LTX and plus TM Reagent (Invitrogen , Cat #: 15338100) b) Plasmid: \ _\R (constructed by Genscript)

c) Opti-mem (Invitrogen, Cat #: 3 1985-062)

d) DMEM medium (Invitrogen - Cat #: 1 1995065)

e) FBS (Hyclone, Cat #: SH30084.03)

f) 10x Cell Lysis Buffer (Cell Signalling, Cat #:9803)

Add Protease Inhibitor Cocktail Tablets (Roche, Cat#:04693132001 ) and phosphatase inhibitor Cocktail Tablets (Roche, Cat #:04906837001 ) g) 5x Sample loading Buffer(ShangHai Beyotime Biotechnology, Cat #: P0015L) h) PBST (PBS with 0.1 % Tween-20)

i) Prestained Protein Ladder (BIO-RAD, Cat #: 161 -0374)

j) BCA protein assay kit(ShangHai Beyotime Biotechnology, Cat #:P0010) k) Chemiluminescent HRP substrate ( Millipore, Cat #:WBKL 50500)

1) PVDF membrane (Millipore)

m) Antibodies:

2. Equipment

C0 ₂ Water Jacketed Incubator, Thermo (USA) Inverted Microscope - Olympus - 1X71

Vertical electrophoresis systems and Blotting Module (Bio-Rad)

Biolmaging systems: UVP-Biospectrum AC chemi HR 410

B. Methods

1. Day 1: Set up 293T cells

Cells are cultured in DMEM medium with L-glutamine, supplemented with 10% FBS at 37 °C, 5% C0 ₂ atmosphere. Cells used are 80% confluent. Cells are trypsinized and collected. 0.5* 10 ⁶ 12 mL 293T cells are seeded in 6-well plate.

2. Day 2: Transfect 293T cells

Transient transfection with 2.5 μg IiR plasmid, 2.5 μΙ_, plus and 5 LTX/well :

a) A : OPTI-MEM 125 μΐ and target plasmid 2.5 μg and PLUS 2.5 μΐ are

mixed at room temperature and incubated for 5 minutes.

b) A': OPTI-MEM 125 μί and lipofectamine 5 μί are mixed at room

temperature and incubated for 5 minutes.

c) A+A' are mixed at room temperature and incubated for 5 minutes.

d) 250 μL· of each mix is added into the desired wells.

3. Day 3 : Change medium to 1%FBS according to the platemap

4. Day 4: Treat 293T/I) receptor expressing cells with different concentration compounds for 30 minutes according to the platemap, then collect and lyse cells.

a) Prepare 1 OOOx stocks of (S)-isometheptene mucate (compound 27 mucate salt) and (R)-isometheptene mucate (compound 9 mucate salt) diluted with water or DMSO. In addition to compounds 9 and 27 mucate salts, the test compounds can be selected from compounds of formula (SC-01 ), formula (SC-02), formula (SC-03), formula (SC-04), formula (SC-05), formula (SC-06), formula (SC-07), formula (SC-08), formula (SC-09), formula (SC-10), formula (SC- 1 1 ), formula (SC- 12), formula (SC- 13), formula (SC-14), formula (SC- 15), formula (SC- 16), formula (SC-17), formula (SC-18), formula (SC-19), formula (SC-20), formula (SC-21 ), formula (SC-22), formula (SC-23), formula (SC-24), formula (SC-25), or formula 1-432, or a mixture thereof, or a pharmaceutically acceptable salt, free base, tautomer, solvate, enantiomer, disastereomer, or prodrug, or a mixture thereof, of any of the foregoing compounds or a test composition selected from any of the compositions disclosed herein.

b) Prepare l Ox stock of test compounds solution diluted with 1 % FBS DMEM. c) Treat 293T/Ii receptor expressing cells with 200 μΐ l Ox test compounds

solution for 30 minutes according to the platemap.

d) Cells are collected, spun at 1000 rpm for 4 minutes, washed with ice-cold PBS, and 50 μΐ of ice-cold l xlysis buffer (supplemented with protease inhibitors and phosphatase inhibitors) is added to the cells to precipitate lysates. The mixture is vortexed and incubated on ice for 10 minutes.

e) Transfer cell lysates to Eppendorf tubes and spin at 13,000 rpm, 4 °C for 10 minutes.

f) Remove a small volume of the lysate to perform a protein assay. Determine the protein concentration for each cell lysate using a BCA protein assay kit.

g) To the remaining volume of cell lysate, adjust the lysate to the same protein concentration with lysis buffer, and then added 1/4 volume of 5x Sample Loading Buffer.

h) Boil each cell lysate at 100 °C for 5 minutes.

Day 5-6 : Western blot

a) Load equal amounts 40 μg cell lysate onto 10% SDS-PAGE gels using gel loading tips, along with molecular weight markers.

b) Run the samples on a 10% SDS-PAGE gel at 300V for 25 minutes until the dye reaches the bottom of the gel. ^"

c) Transfer protein onto PVDF membrane by Bio-Rad Mini Trans-Blot®

Electrophoretic Transfer Cell, at 300mA for 2.5 hours.

d) After the transfer, remove the membrane from the blotting cassette and mark the orientation of the gel. Rinse briefly with TBST.

e) Block non-specific binding on the membrane in TBST and 5% nonfat dried milk for 1 hour on a shaking platform at room temperature.

f) Incubate the membrane with a specific primary antibody diluted in TBST and 5% nonfat dried milk with gentle agitation at 4 °C overnight.

g) Wash three times for 5 minutes each with TBST.

h) Incubate with HRP-conjugated secondary antibody in TBST-5% nonfat dried milk for 30 minutes at room temperature.

i) Wash three times again for 5 minutes each with TBST prior to addition of chemiluminesence reagents.

j) Remove excess chemiluminescence reagent and acquired image using

Biolmaging systems system (Biospectrum AC chemi HR 410).

An increase in phospho-ERK is observed after treatment of the human I ] receptor transfected 293T cells with (R)-isometheptene mucate (compound 9 mucate salt) at 0.002, 0.02, 0.2, and 2 μΜ (Figure 23). A similar increase in phospho-ERK is not observed after treatment with (S)-isometheptene mucate (compound 27 mucate salt).

Example 17 Evaluation of test compounds in the precipitated withdrawal (Saelens) test in the mouse

In this study, the analgesic potential of (R)-isometheptene (compound 9 mucate salt) and (S)-isometheptene (compound 27 mucate salt) is evaluated using an opiate-like dependence model with the Naloxone-precipitated Withdrawal (Saelens) Test in mice. Typically, when opiate-pretreated mice are administered the opiate antagonist naloxone, they demonstrate jumping behavior as a pain response to opiate withdrawal symptoms. The analgesic activity of (R)-isometheptene and (S)-isometheptene is assessed in this study by measuring whether isometheptene administration could reduce this naloxone-induced jumping activity. In addition to compounds 9 and 27 mucate salts, the test compounds can be selected from compounds of formula (SC-01 ), formula (SC-02), formula (SC-03), formula (SC-04), formula (SC-05), formula (SC- 06), formula (SC-07), formula (SC-08), formula (SC-09), formula (SC- 10), formula (SC- 1 1 ), formula (SC- 12), formula (SC- 13), formula (SC- 14), formula (SC- 15), formula (SC-1 6), formula (SC-17), formula (SC- 18), formula (SC-19), formula (SC- 20), formula (SC-21 ), formula (SC-22), formula (SC-23), formula (SC-24), formula (SC-25), or formula 1-432, or a mixture thereof, or a pharmaceutically acceptable salt, free base, tautomer, solvate, enantiomer, disastereomer, or prodrug, or a mixture thereof, of any of the foregoing compounds or a test composition selected from any of the compositions disclosed herein. One hundred and ten male NMR1 mice, bred by Janvier Labs and group housed in enriched conditions, are split into 1 1 different experimental groups (8 treatment groups, 3 control), each consisting of 10 mice and identified by indelible tail markings. Mice receive 7 administrations of morphine (32 mg/kg i.p.) over 2 consecutive days; 5 administrations on the first day at 9:00, 10:00, 1 1 :00, 13:00 and 15 :00, and 2 administrations on the second day at 9:00 and 1 1 :00. Two hours following the last injection on the D2, the mice receive i.p. naloxone injection ( 10 mg/kg) and are individually placed in an inverted Plexiglas container so the number of jumps is recorded for the 10 minutes immediately following injection. The effects of (R)- isometheptene and (S)-isometheptene are each evaluated at two doses (10 mg/kg and 30 mg/kg), administered i.p. 30 minutes before naloxone or physiological saline and compared with the appropriate vehicle control group. A third control group is included for additional reference, where mice are administered saline in place of morphine and receive only the drug-free vehicle injection on D2. Because of the number of animals, the experiment is divided into 2 sub-experiments (n=5

mice/group/day) (Figure 28).

All data is entered into calculation sheets and compared to the raw data by two people and thus completely verified prior to data analysis. Mann-Whitney' U-test analysis is used to compare treated groups with the appropriate controls. Differences are considered statistically significant when the null hypothesis could be rejected at a risk of less than 0.05.

Example 18 Evaluation of rat models of osteoarthritis (OA)

In this study, two experiments are conducted using a monosodium iodacetate (MIA) induced model of osteoarthritic pain in adult male SD rats to assess the analgesic potential of the test compounds. In the first experiment, MIA is injected to induce osteoarthritic pain which manifested as a shift in hindlimb weight distribution. The analgesic potential of (R)-isometheptene (compound 9 mucate salt) and (S)- isometheptene (compound 27 mucate salt) are thus assessed by evaluating their respective abilities to reverse these shifts, using Diclofenoc as a reference substance (positive control) (Figures 29-31 ). In addition to compounds 9 and 27 mucate salts, the test compounds can be selected from compounds of formula (SC-01 ), formula (SC-02), formula (SC-03), formula (SC-04), formula (SC-05), formula (SC-06), formula (SC-07), formula (SC-08), formula (SC-09), formula (SC-10), formula (SC- 1 1), formula (SC-12), formula (SC-13), formula (SC-14), formula (SC- 15), formula ' (SC-16), formula (SC-17), formula (SC-18), formula (SC-19), formula (SC-20), formula (SC-21 ), formula (SC-22), formula (SC-23), formula (SC-24), formula (SC- 25), or formula 1-432, or a mixture thereof, or a pharmaceutically acceptable salt, free base, tautomer, solvate, enantiomer, disastereomer, or prodrug, or a mixture thereof, of any of the foregoing compounds or a test composition selected from any of the compositions disclosed herein. Weight bearing chambers are first used to assess baseline weight distribution, after which animals received intraarticular (i.ar.) injections of MIA (3 or 4.8 mg) or saline. Fourteen days after injection (D 14), animals receive either isometheptene (R)-isometheptene or (S)-isometheptene at 10, 30, or 100 mg/kg i.v.), diclofenac (30 mg/kg p.o.), or vehicle injections and weight-bearing was re-measured every 30 minutes for 2-3 hours. In total, 3 conditions are evaluated (MIA 3 mg, 4.8 mg, vehicle) in 8 groups ((R)-isometheptene and (S)-isometheptene at 3 doses each, diclofenac, vehicle) with 12 animals per group for a total of 288 rats.

For the second experiment, the analgesic potential of the test compounds is assessed using a post-MIA conditioned place preference (CPP) paradigm in adult male SD rats. Animals are acclimated to the CPP apparatus by allowing them to explore all 3 chambers for 30 minutes/day for 3 days and on day 13 (D 13), baseline time spent in each chamber was assessed for 15 minutes. On D 14, animals receive either an i.v. vehicle or i.ar. saline treatment and are confined in 1 chamber for 30 minutes in the morning. Four hours later, they are injected with an optimal dose of either (R)- isometheptene (compound 9 mucate salt), (S)-isometheptene (compound 27 mucate salt), vehicle, or lidocaine (positive control) and confined in the opposite chamber for 30 minutes. On day 15 (D 15), the animals are allowed to explore all 3 chambers again for 15 minutes and the Difference Score of time spent in the drug-paired chamber (D 15 - baseline) is calculated to indicate potential analgesic relief. In total, 2 conditions are evaluated (MIA, vehicle) in 4 groups ((R)-isometheptene, (S)- isometheptene, lidocaine, vehicle) with 20 animals per group for a total of 160 rats.

Example 19 Evaluation of the test compounds on modulation of opioid withdrawal

To assess the efficacy of the test compounds in alleviating naloxone-precipitated withdrawal in chronic morphine-treated rats, male SD rats are implanted with morphine pellets (2 x 75 mg, s.c). Seven days later, baseline body weight and hot plate latency are assessed. The animals then receive systemic administration of the vehicle or varying doses of the test compounds, followed by naloxone (3 mg/kg i.p.) or saline. The jumping frequency, the existence of diarrhea, and wet dog shaking symptoms are recorded during the first 30 minutes post-naloxone administration. Hot plate latency and body weight are re-assessed 30 minutes post-naloxone/saline. In total, 2 pre-treatment groups (naloxone, vehicle) are evaluated in 7 groups ((R)- isometheptene (compound 9 mucate salt) and (S)-isometheptene (compound 27 mucate salt) at 10, 30, and 100 mg/kg + vehicle) with 8 rats per group for a total of 1 12 rats. In addition to compounds 9 and 27 mucate salts, the test compounds can be selected from compounds of formula (SC-01 ), formula (SC-02), formula (SC-03), formula (SC-04), formula (SC-05), formula (SC-06), formula (SC-07), formula (SC- 08), formula (SC-09), formula (SC- 10), formula (SC-1 1 ), formula (SC-12), formula (SC- 13), formula (SC- 14), formula (SC-15), formula (SC- 16), formula (SC- 17), formula (SC- 18), formula (SC- 19), formula (SC-20), formula (SC-21 ), formula (SC- 22), formula (SC-23), formula (SC-24), formula (SC-25), or formula 1-432, or a mixture thereof, or a pharmaceutically acceptable salt, free base, tautomer, solvate, enantiomer, disastereomer, or prodrug, or a mixture thereof, of any of the foregoing compounds or a test composition selected from any of the compositions disclosed herein (Figures 32-38).

Example 20 Evaluation of Nitric Oxide Donor Induced Model in Rats

To assess the efficacy of the test compounds for the reversal of cutaneous allodynia, sumatriptan-induced medication overuse headache (MOH) are triggered by nitric oxide (NO) donors in rats so the rescue efficacy of isometheptene can be assessed. Baseline paw withdrawal thresholds (PWT) are assessed for each animal, before receiving s.c. sumatriptan (0.6 mg/24 hours) or saline delivered by osmotic minipump for 7 days. The animals are then housed drug-free for 14 days and on day 21 (D21) sodium nitroprusside (SNP; 3mg/kg i.p.) is injected and facial and hindpaw tactile thresholds are assessed at 1 and 2 hours post-SNP. Rats that successfully develop tactile hypersensitivity at 2 hours post SNP are treated with varying doses of the isometheptene isomers or vehicle controls. Facial and hindpaw allodynia is further assessed using von Frey filaments at appropriate time points until 5 hours post-SNP to determine the efficacy of the isometheptene compounds in reversal of cutaneous allodynia precipitated by NO donor (Figures 24 and 25). In total, two pre-treatment conditions (sumatriptan or saline pump) are evaluated in 7 groups ((R)-isometheptene (compound 9 mucate salt) and (S)-isometheptene (compound 27 mucate salt) at 10, 30 and 100 mg/kg + vehicle), with 12 rats per group for a total of 168 rats. In addition to compounds 9 and 27 mucate salts, the test compounds can be selected from compounds of formula (SC-01 ), formula (SC-02), formula (SC-03), formula (SC-04), formula (SC-05), formula (SC-06), formula (SC-07), formula (SC-08), formula (SC- 09), formula (SC-10), formula (SC- 1 1 ), formula (SC-12), formula (SC-13), formula (SC-14), formula (SC- 15), formula (SC- 16), formula (SC- 17), formula (SC- 18), formula (SC-19), formula (SC-20), formula (SC-21 ), formula (SC-22), formula (SC- 23), formula (SC-24), formula (SC-25), or formula 1-432, or a mixture thereof, or a pharmaceutically acceptable salt, free base, tautomer, solvate, enantiomer, disastereomer, or prodrug, or a mixture thereof, of any of the foregoing compounds or a test composition selected from any of the compositions disclosed herein. Incorporation by Reference

All references cited in this specification, and their references, are incorporated by

reference herein in their entirety where appropriate for teachings of additional or

alternative details, features, and/or technical background.

Equivalents

While the invention has been particularly shown and described with reference to

particular embodiments, it will be appreciated that variations of the above-disclosed

and other features and functions, or alternatives thereof, may be desirably combined

into many other different systems or applications. Also, that various presently

unforeseen or unanticipated alternatives, modifications, variations or improvements

therein may be subsequently made by those skilled in the art which are also intended

to be encompassed by the following claims.

Sequence Listing

MATARTFGPEREAEPAKEARVVGSELVDTYTVYIIQVTDGS

Full-length human Ii SEQ ID

HEWTV HRYSDFHDLHE LVAERK1DKNLLPPKKIIG NSR receptor NO: 1 SLVEKRE DLEVYLQ LLAAFPGVTPRVLAHFLHFHFYEIN

G1TAALAEELFE GEQLLGAGEVFA1GPLQLYAVTEQLQQG KPTCASGDAKTDLGH1LDFTCRLKYL VSGTEGPFGTSN1QE QLLPFDLSIF SLHQVEISHCDA HIRGLVAS PTLATLSVRF SATSM EVLVPEASEFDEWEPEGTTLEGPVTAVIPTWQALT TLDLSHTMSISEIDESV LIPKIEFLDLSHNGLLVVDNLQHLYN ' LVHLDLSYNKLSSLEGLHT LGNIKTLMLAGNLLESLSGLH LYSLVNLDLRDNRIEQMEEVRSIGSLPCLEHVSLLNNPLSII PDYRT VLAQFGERASEVCLDDTVTTE ELDTVEVL AIQ AKEV S LSNPE GGEDSRLSAAPC1RPSSSPPTVAPASAS LPQPILSNQGIMFVQEEALASSLSSTDSLTPEHQPIAQGCSDS LES1PAGQAASDDLRDVPGAVGGASPEHAEPEVQVVPGSGQ ( IIFLPFTC1GYTATNQDFIQRLSTLIRQAIERQLPAWIEAANQR EEGQGEQGEEEDEEEEEEEDVAE1MRYFE GPPDVEEEEGG GQGEEEEEEEEDEEAEEERLALEWALGADEDFLLEHIRIL V LWCFL1HVQGSIRQFAACLVLTDFGIAVFE1PHQESRGSSQH1 LSSLRFVFCFPHGDLTEFGFLMPELCLVL VRHSENTLFI1SD AANLHEFHADLRSCFAPQHMA LCSPILYGSHTSLQEFLRQ LLTFY VAGGCQERSQGCFPVYLVYSDKRMVQTAAGDYS GNIEWASCTLCSAVRRSCCAPSEAV SAAIPYWLLLTPQHL NVI ADFNP PNRGTHNCRNRNSF LSRVPLSTVLLDPTRS CTQPRGAFADGHVLELLVGYRFVTAIFVLPHE FHFLRVYN QLRASLQDLKTVV1AKTPGTGGSPQGSFADGQPAERRASND

QRPQEVPAEA LAPAPVEVPAPAPAAASASG PA .TPAPAEA

STSALVPEETPVEAPAPPPAEAPAQYPSEHLIQATSEENQIPS

HLPACPSLRHVASLRGSAIIELFHSSIAEVENEELRHLMWSS

VVFYQTPGLEVTACVLLST AVYFVLHDGLRRYFSEPLQDF

WHQ NTDY SPFHISQCFVLKLSDLQSVNVGLFDQHFRL

TGSTPMQVVTCLTRDSYLTHCFLQHLMVVLSSLERTPSPEP

VDKDFYSEFGNKTTGKMENYELIHSSRVKFTYPSEEEIGDLT

FTVAQKMAEPEKAPALSILLYVQAFQVGMPPPGCCRGPLRP TLLLTSSEIFLLDEDCVHYPLPEFA EPPQRDRYRLDDGRR

VRDLDRVLMGYQTYPQALTLVFDDVQGHDLMGSVTLDH

FGEVPGGPARASQGREVQWQVFVPSAESREKLISLLARQW

EALCGRELPVELTG

Some embodiments of this disclosure herein are:

1. A compound having th ):

SC-01

or a pharmaceutically acceptable salt, tautomer, solvate, diastereomer,

enantiomer, or prodrug thereof, wherein as valence and stability permit:

L ¹ is a 4 to 10 carbon atom linker selected from the group consisting of

optionally substituted alkanediyl, heteroalkanediyl, cycloalkanediyl, heterocyclylalkanediyl, cycloalkylalkanediyl,

cycloalkylheteroalkanediyl, alkenediyl, alkynediyl, alkylthiodiyl, and

1 , 1 -dialky lcycloalkanediy 1;

W is selected from the group consisting of N and CH;

Y is selected from the group consisting of CH ₂, NH, O, and S;

R ¹ is selected from the group consisting of hydrogen and optionally substituted alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, heteroaryl, alkoxycycloalkyl, cycloalkyl, and heterocyclyl; and

R ² is selected from the group consisting of hydrogen and optionally substituted alkyl;

wherein L ¹ can be linked with R ¹, R ² or both R ¹ and R ² to form a monocyclic, bicyclic, or polycyclic ring, wherein the ring is selected from the group consisting of optionally substituted cycloalkyl and optionally substituted heterocyclyl;

wherein L ¹ can be linked with R ¹ or R ² to form a moiety selected from the group consisting of optionally substituted cycloalkylalkanediyl, heterocyclylalkanediyl, cycloalkylheteroalkanediyl, and heterocyclylheteroalkanediyl.

2. The compound of embodiment 1, wherein W is N. The compound of embodiment 1, wherein W is CH.

The compound of any one of embodiments 1-3, wherein Y is CH ₂.

The compound of any one of embodiments 1-3, wherein Y is NH.

The compound of any one of embodiments 1-5, wherein R ¹ is hydrogen. The compound of any one of embodiments 1-5, wherein R ¹ is an optionally substituted alkyl.

The compound of any one of embodiments 1-5, wherein R ¹ is an optionally substituted alkenyl.

The compound of any one of embodiments 1-5, wherein R ¹ is an optionally substituted cycloalkyl.

The compound of any one of embodiments 1-9, wherein R ² is hydrogen. The compound of any one of embodiments 1-9, wherein R ² is an optionally substituted alkyl.

The compound of any one of embodiments 1-11, wherein L ¹ is an optionally substituted cycloalkanediyl.

The compound of any one of embodiments 1-11, wherein L ¹ is an optionally substituted alkynediyl.

The compound of any one of embodiments 1-11, wherein L ¹ is an optionally substituted alkanediyl.

The compound of any one of embodiments 1-11, wherein and L ¹ is an optionally substituted 1 , 1 -dialkylcycloalkanediyl.

The compound of any one of embodiments 1-11, wherein and L ¹ is an optionally substituted alkylthiodiyl.

The compound of any one of embodiments 1-5 and 10-11, wherein L ¹ is linked with R ¹ to form a monocyclic optionally substituted heterocyclyl.

The compound of any one of embodiments 1-9, wherein L ¹ is linked with R ² to form a bicyclic optionally substituted heterocyclyl.

The compound of any one of embodiments 1-9, wherein L ¹ is linked to R ² to form an optionally substituted cycloalkylalkanediyl. The compound of any one of embodiments 1-5, wherein L ¹ is linked to both R ¹ and R ² to form a bicyclic optionally substituted heterocyclyl. A compound having the formul -02):

SC-02 or a pharmaceutically acceptable salt, tautomer, solvate, diastereomer,

enantiomer, or prodrug thereof, wherein as valence and stability permit:

Y is selected from the group consisting of CH ₂ and NH;

R ¹ is selected from the group consisting of hydrogen and optionally substituted alkyl, heteroalkyl, and aminoalkyl; and

Ar is selected from the group consisting of optionally substituted aryl and

heteroaryl.

The compound of embodiment 21, wherein Y is CH ₂.

The compound of embodiment 21, wherein Y is NH.

The compound of any one of embodiments 21-23, wherein R ¹ is hydrogen. The compound of any one of embodiments 21-23, wherein R ¹ is an optionally substituted alkyl.

The compound of any one of embodiments 21-23, wherein R ¹ is an optionally substituted aminoalkyl.

The compound of any one of embodiments 21-26, wherein Ar is an optionally substituted aryl.

The compound of any one of embodiments 21-26, wherein Ar is an optionally substituted heteroaryl.

A compound having the formula (SC-03):

SC-03 or a pharmaceutically acceptable salt, tautomer, solvate, diastereomer,

enantiomer, or prodrug thereof, wherein as valence and stability permit:

R ¹ is selected from the group consisting of hydrogen and optionally substituted alkyl and heteroalkyl; and

Ar is selected from the group consisting of optionally substituted aryl and

heteroaryl.

The compound of embodiment 29, wherein R ¹ is an optionally substituted alkyl.

The compound of embodiment 29 or 30, wherein Ar is an optionally substituted aryl.

A compound having the formula SC-04):

SC-04 or a pharmaceutically acceptable salt, tautomer, solvate, diastereomer,

enantiomer, or prodrug thereof, wherein as valence and stability permit:

Ar is selected from the group consisting of optionally substituted aryl and

heteroaryl;

wherein R ¹ and R ² can optionally form a monocyclic, bicyclic or polycyclic ring, wherein the ring is selected from the group consisting of optionally substituted cycloalkyl and optionally substituted

heterocyclyl.

The compound of embodiment 32, wherein Ar is an optionally substituted aryl. The compound of 32 or 33, wherein R ¹ is hydrogen.

The compound of 32 or 33, wherein R ¹ is an optionally substituted alkyl.

The compound of 32 or 33, wherein R ¹ is an optionally substituted aminoalkyl. The compound of embodiment 32 or 33, wherein R ¹ is an optionally substituted alkoxy.

The compound of any one of embodiments 32-37, wherein R ² is hydrogen. The compound of any one of embodiments 32-37, wherein R ² is an optionally substituted alkyl.

The compound of embodiment 32 or 33, wherein R ¹ and R ² form an optionally substituted cycloalkyl.

A compound having the formula SC-05):

SC-05 or a pharmaceutically acceptable salt, tautomer, solvate, diastereomer,

enantiomer, or prodrug thereof, wherein as valence and stability permit: R ¹ is selected from the group consisting of hydrogen and optionally substituted alkyl, heteroalkyl, aminoalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

R ² is selected from the group consisting of optionally substituted alkyl,

heteroalkyl, aminoalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

R ³ is selected from the group consisting of hydrogen and optionally substituted alkyl, heteroalkyl, aminoalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; and

Ar is selected from the group consisting of optionally substituted aryl and

heteroaryl; provided that when Ar is an optionally substituted aryl, R ¹ is hydrogen, and R ² is an optionally substituted alkyl, Ar is not unsubstituted phenyl and R ² is not unsubstituted methyl;

provided that the compound having the formula (SC-05) is not:

or a pharmaceutically acceptable salt, tautomer, solvate, or prodrug thereof.

42. The compound of embodiment 41, wherein Ar is an optionally substituted aryl.

43. The compound of embodiment 41, wherein Ar is an optionally substituted heteroaryl.

44. The compound of any one of embodiments 41-43, wherein R s hydrogen,

45. The compound of any one of embodiments 41-43, wherein R ¹ s an optionally substituted alkyl.

46. The compound of any one of embodiments 41-43, wherein R ¹ s an optionally substituted aminoalkyl.

47. The compound of any one of embodiments 41-43, wherein R ¹ s an optionally substituted hydroxyalkyl.

48. The compound of any one of embodiments 41-47, wherein R ³ s hydrogen,

49. The compound of any one of embodiments 41-47, wherein R ³ s an optionally substituted alkyl.

50. The compound of any one of embodiments 41-47, wherein R ³ s an optionally substituted aminoalkyl.

51. The compound of any one of embodiments 41-47, wherein R ³ s an optionally substituted hydroxyalkyl.

52. The compound of any one of embodiments 41-51, wherein R ² s an optionally substituted alkyl.

53. The compound of any one of embodiments 41-51, wherein R ² s an optionally substituted aminoalkyl. The compound of any one of embodiments 41-51, wherein R ² is an optionally substituted cycloalkyl.

A compound having the form -06):

SC-06 or a pharmaceutically acceptable salt, solvate, diastereomer, enantiomer, tautomer, or prodrug thereof, wherein as valence and stability permit: — represents a single or double bond;

R ¹ is selected from the group consisting of hydrogen and optionally substituted alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; and

R ² is selected from the group consisting of hydrogen and optionally substituted alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

wherein R ¹ and R ² can optionally form a ring, wherein the ring is selected from the group consisting of optionally substituted cycloalkyl, heterocyclyl, cycloalkenyl, aryl, and heteroaryl;

provided that the compound having the formula (SC-06) is not:

or a p armaceutically accepta e sa t, enant omer, so vate, or prodrug thereof.

The compound of embodiment 55, wherein— represents a single bond. The compound of embodiment 55 or 56, wherein R is hydrogen.

The compound of embodiment 55 or 56, wherein R ¹ is an optionally substituted alkyl.

The compound of embodiment 55 or 56, wherein R ¹ is an optionally substituted alkenyl.

The compound of any one of embodiments 55-59, wherein R ² is hydrogen. The compound of any one of embodiments 55-59, wherein R ² is an optionally substituted alkenyl.

The compound of embodiment 55 or 56, wherein R ¹ and R ² form an optionally substituted cycloalkenyl.

The compound of embodiment 55, wherein R ¹ and R ² form an optionally substituted aryl.

A compound having the formula SC-07):

SC-07 or a pharmaceutically acceptable salt, tautomer, solvate, diastereomer,

enantiomer, or prodrug thereof, wherein as valence and stability permit:

Y is selected from the group consisting of NH and O;

R ¹ , R ², R ³, R ⁶ are independently selected from the group consisting of

hydrogen, halogen and optionally substituted alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkoxy, alkynyloxy, alkylthio, -SCF ₃, and alkylamino; and

R ⁴ and R ⁵ are independently selected from the group consisting of hydrogen and optionally substituted alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkoxy, alkylthio, and alkylamino; wherein R ¹ and R ⁴ or R ¹ and R ⁵ can optionally form a ring, wherein the ring is an optionally substituted heterocyclyl;

provided that the compound having the formula (SC-07) is not:

or a pharmaceutically accepta le salt, tautomer, so vate, enantiomer, or

prodrug thereof.

The compound of embodiment 64, wherein Y is O.

The compound of embodiment 64, wherein Y is NH.

The compound of any one of embodiments 64-66, wherein R ^l is hydrogen. 68. The compound of any one of embodiments 64-66, wherein R' is halogen.

69. The compound of any one of embodiments 64-66, wherein R ¹ is an optionally substituted alkylthio.

70. The compound of any one of embodiments 64-66, wherein R ¹ is an optionally substituted alkyl.

71. The compound of any one of embodiments 64-66, wherein R' is an optionally substituted alkoxy.

72. The compound of any one of embodiments 64-66, wherein R' is an optionally substituted alkynyloxy.

73. The compound of any one of embodiments 64-72, wherein R ² is hydrogen.

74. The compound of any one of embodiments 64-72, wherein R ² is halogen.

75. The compound of any one of embodiments 64-74, wherein R ³ is hydrogen.

76. The compound of any one of embodiments 64-74, wherein R ³ is halogen.

77. The compound of any one of embodiments 64-76, wherein R ⁴ is hydrogen.

78. The compound of any one of embodiments 64-76, wherein R ⁴ is an optionally substituted alkyl.

79. The compound of any one of embodiments 64-76, wherein R ⁴ is an optionally substituted alkynyl.

80. The compound of any one of embodiments 64-79, wherein R ⁵ is hydrogen.

81 . The compound of any one of embodiments 64-79, wherein R ⁵ is an optionally substituted alkyl.

82. The compound of any one of embodiments 64-81, wherein R ⁶ is hydrogen.

83. The compound of any one of embodiments 64-81, wherein R ⁶ is halogen.

84. A compound having the formula SC-08):

SC-08 or a pharmaceutically acceptable salt, tautomer, solvate, diastereomer, enantiomer, or prodrug thereof, wherein as valence and stability permit: R ¹ and R ² are independently selected from the group consisting of optionally substituted alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; and

R ³ and R ⁴ are independently selected from the group consisting of hydrogen and optionally substituted alkyl, alkenyl, and alkynyl;

* 1 2

wherein R and R can optionally form a ring, wherein the ring is selected from the group consisting of optionally substituted cycloalkyl, heterocyclyl, aryl, and heteroaryl;

provided that the compound having the formula (SC-08) is not:

or a pharmaceutically accepta e salt, tautomer, so vate, astereomer,

enantiomer, or prodrug thereof.

. The compound of embodiment 84, wherein R ³ is hydrogen.

. The compound of embodiment 84 or 85, wherein R ⁴ is hydrogen.

. The compound of any one of embodiments 84-86, wherein R ¹ is an optionally substituted alkyl.

. The compound of any one of embodiments 84-86, wherein R ¹ is an optionally substituted alkenyl.

. The compound of any one of embodiments 84-88, wherein R ² is an optionally substituted alkyl. 90. The compound of any one of embodiments 84-88, wherein R ² is an optionally substituted alkenyl.

91. The compound of any one of embodiments 84-86, wherein R ¹ and R ² form an optionally substituted cycloalkyl.

92. A compound having the formula SC-09):

SC-09 or a pharmaceutically acceptable salt, tautomer, solvate, diastereomer,

enantiomer, or prodrug thereof, wherein as valence and stability permit: Y is selected from the group consisting of N and O;

R ¹ is selected from the group consisting of optionally substituted alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

R ², R ³, and R ⁴ are independently selected from the group consisting of

hydrogen and optionally substituted alkyl, alkenyl, alkynyl, and arylalkyl;

R ⁵ is selected from the group consisting of hydrogen and optionally substituted arylalkyl; and

R ⁶ is selected from the group consisting of absent, hydrogen, and optionally substituted arylalkyl;

provided that the compound having the formula (SC-09) is not:

or a p armaceut ca y accepta e sa t, tautomer, so vate, enantiomer, or

prodrug thereof. The compound of embodiment 92, wherein Y is O.

The compound of embodiment 92, wherein Y is N.

The compound of embodiment 92 or 93, wherein R ⁶ is absent.

The compound of embodiment 92 or 94, wherein R ⁶ is hydrogen.

The compound of embodiment 92 or 94, wherein R ⁶ is an optionally substituted arylalkyl.

The compound of any one of embodiments 92-97, wherein R ¹ is an optionally substituted aryl.

The compound of any one of embodiments 92-97, wherein R ¹ is an optionally substituted alkyl.

. The compound of any one of embodiments 92-97, wherein R ¹ is an optionally substituted cycloalkyl.

. The compound of any one of embodiments 92-100, wherein R ² is hydrogen.

. The compound of any one of embodiments 92-100, wherein R ² is an optionally substituted alkyl.

. The compound of any one of embodiments 92-102, wherein R ³ is hydrogen.

. The compound of any one of embodiments 92-102, wherein R is an optionally substituted alkyl.

!.. The compound of any one of embodiments 92-104, wherein R ⁴ is hydrogen.

i.. The compound of any one of embodiments 92-105, wherein R ⁵ is hydrogen. 107. The compound of any one of embodiments 92-105, wherein R ⁵ is an optionally substituted arylalkyl.

108. A compound having the formula (SC-10):

or a pharmaceutically acceptable salt, tautomer, solvate, diastereomer,

enantiomer, or prodrug thereof, wherein as valence and stability permit: Y is selected from the group consisting of NH and CH ₂;

R ¹ and R ² are independently selected from the group consisting of hydrogen, halogen, and optionally substituted alkyl, alkenyl, alkynyl, aryl, heteroaryl, alkylthio, -SCF ₃, and amino; and

R ³ and R ⁴ are independently selected from the group consisting of hydrogen and halogen;

wherein R ¹ and R ² can optionally form a ring, wherein the ring is selected from the group consisting of optionally -substituted aryl and heteroaryl;

provided that the compound having the formula (SC- 10) is not:

or a p armaceut ca y accepta e salt, tautomer, solvate, or prodrug thereof. . The compound of embodiment 108, wherein Y is NH.

. The compound of embodiment 108, wherein Y is CH ₂.

1. The compound of any one of embodiments 108-110, wherein R ¹ is hydrogen.

I.. 1 The compound of any one of embodiments 108-110, wherein R ¹ is halogen.

. The compound of any one of embodiments 108-110, wherein R ¹ is an optionally substituted alkyl.

. The compound of any one of embodiments 108-110, wherein R ¹ is an optionally substituted alkenyl.

. The compound of any one of embodiments 108-110, wherein R ¹ is an optionally substituted amino.

. The compound of any one of embodiments 108-110, wherein R ¹ is an optionally substituted heteroaryl.

. The compound of any one of embodiments 108-116, wherein R is hydrogen.

I.. TThhe compound of any one of embodiments 108-116, wherein R ² is an optionally substituted alkyl.

. TThhee ccoommppoouunndd ooff aanny one of embodiments 108-116, wherein R ² is an optionally substituted alkenyl. 120. The compound of any one of embodiments 108-116, wherein R ² is an optionally substituted amino.

121. The compound of any one of embodiments 108-116, wherein R ² is an optionally substituted alkylthio.

122. The compound of any one of embodiments 108-110, wherein R ¹ and R ² form an optionally substituted heteroaryl.

123. The compound of any one of embodiments 108-122, wherein R ³ is hydrogen.

124. The compound of any one of embodiments 108-122, wherein R ³ is halogen.

125. The compound of any one of embodiments 108-124, wherein R ⁴ is hydrogen.

126. The compound of any one of embodiments 108-124, wherein R ⁴ is halogen.

127. A compound havin the formula (SC-1 1):

SC-11 or a pharmaceutically acceptable salt, tautomer, solvate, diastereomer,

enantiomer, or prodrug thereof, wherein as valence and stability permit: — represents a single or double bond; and

R", R ², and R ³ are independently selected from the group consisting of

hydrogen and optionally substituted alkyl, alkenyl, alkynyl, heteroalkyl, hydroxyalkyl, aryl, and heteroaryl;

wherein R ² and R ³ can optionally form a ring, wherein the ring is a optionally substituted cycloalkyl;

provided that the compound having the formula (SC- 1 1 ) is not:

a pharmaceutically acceptable salt, enantiomer, astereomer, tautomer, solvate, or prodrug thereof.

. The compound of embodiment 127, wherein— is a single bond. . The compound of embodiment 127, wherein = is a double bond. . The compound of any one of embodiments 127-129, wherein R ² is hydrogen.

. The compound of any one of embodiments 127-129, wherein R ² is an optionally substituted alkyl.

. The compound of any one of embodiments 127-129, wherein R ² is an optionally substituted alkynyl.

. The compound of any one of embodiments 127-132, wherein R is hydrogen. 134. The compound of any one of embodiments 127-132, wherein R ³ is an optionally substituted alkyl.

135. The compound of any one of embodiments 127-132, wherein R ³ is an optionally substituted alkynyl.

136. The compound of any one of embodiments 127-135, wherein R ¹ is hydrogen.

137. The compound of any one of embodiments 127-135, wherein R ¹ is an optionally substituted alkyl.

138. The compound of any one of embodiments 127-135, wherein R ¹ is an optionally substituted hydroxyalkyl.

139. A compound havin the formula (SC- 12):

SC-12 or a pharmaceutically acceptable salt, solvate, diastereomer, enantiomer,

tautomer, or prodrug thereof, wherein as valence and stability permit: ^' a and β—represent a single or double bond;

R ¹ is selected from the group consisting of hydrogen, CH ₂, and optionally substituted alkyl, haloalkyl, alkenyl, heteroalkyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, acylaminoalkyl, alkylamino, aryl, and heteroaryl;

R ⁸ is selected from the group consisting of absent, hydrogen, hydroxy!, and optionally substituted alkyl and haloalkyl;

wherein when a is single bond, β is a double bond and R ⁸ is absent, R ¹ is CH ₂; wherein when a is double bond and β is a single bond, R ⁸ is absent;

R ² is selected from the group consisting of hydrogen and optionally substituted alkyl, haloalkyl, alkenyl, heteroalkyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, acylaminoalkyl, alkylamino, aryl, and heteroaryl;

R ³, R ⁴, and R ⁵ are independently selected from the group consisting of

hydrogen, hydroxyl, and optionally substituted alkyl;

R ⁶ is selected from the group consisting of hydrogen and optionally substituted alkyl, haloalkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl,

heterocyclylalkyl, alkoxyalkyl, and cycloalkylacyl;

R ⁷ is selected from the group consisting of hydrogen and optionally substituted alkyl; and

R ⁹ is selected from the group consisting of hydrogen and optionally substituted alkyl and haloalkyl;

wherein R ¹ and R ², R ³ and R ⁴, R ⁴ and R ⁵, R ⁴ and R ⁷, or R ⁸ and R ⁹ can

optionally form a ring, wherein the ring is selected from the group optionally substituted cycloalkyl, halocycloalkyl, and heterocyclyl; wherein R ¹ and R ⁹ can optionally form a ring, wherein the ring is selected from the group optionally substituted cycloalkyl, halocycloalkyl, heterocyclyl, and aryl;

wherein when R ¹ and R ⁹ form an optionally substituted aryl, R ⁸ is absent; wherein R ⁵ and R ⁶ can optionally form a monocyclic, bicyclic, or polycyclic ring, wherein the ring is selected from the group optionally substituted heterocyclyl and heteroaryl;

provided that the compound having the formula (SC-12) is not:

or a p armaceut ca y accepta e salt, enantiomer, astereomer, solvate, prodrug thereof;

provided that R ¹ , R ², R ³, R ⁴, R ⁵, R ⁶, R ⁷, R ⁸, and R ⁹ are not all hydrogen, or a pharmaceutically acceptable salt, solvate, or prodrug thereof. . The compound of embodiment 139, wherein a is a single bond and β is a single bond.

. The compound of embodiment 139, wherein a is a single bond, β is a double bond, R ¹ is CH ₂, and R ⁸ is absent.

. The compound of embodiment 139, wherein a is a double bond, β is a single bond, and R ⁸ is absent.

. The compound of embodiment 139 or 140, wherein R ¹ is hydrogen. . The compound of embodiment 139 or 140, wherein R ¹ is an optionally substituted alkyl.

. The compound of embodiment 139 or 140, wherein R ¹ is an optionally substituted haloalkyl.

. The compound of embodiment 139 or 140, wherein R ¹ is an optionally substituted cycloalkyl.

. The compound of any one of embodiments 139, 140, or 143-146, wherein R ⁸ is hydrogen.

. The compound of any one of embodiments 139, 140, or 143-146, wherein R is hydroxyl.

. The compound of any one of embodiments 139, 140, or 143-146, wherein R ⁸ is an optionally substituted alkyl. 150. The compound of any one of embodiments 139, 140, or 143-146, wherein R is an optionally substituted haloalkyl.

151. The compound of any one of embodiments 139-150, wherein R ⁹ is hydrogen.

152. The compound of any one of embodiments 139-150, wherein R ⁹ is an optionally substituted alkyl.

153. The compound of any one of embodiments 139-150, wherein R ⁹ is an optionally substituted haloalkyl.

154. The compound of any one of embodiments 139, 140, or 143-146, wherein R ⁸ and R ⁹ form an optionally substituted cycloalkyl.

155. The compound of any one of embodiments 139, 140, or 143-146, wherein R ⁸ and R ⁹ form an optionally substituted halocycloalkyl.

156. The compound of embodiment 139 or 142, wherein R ¹ and R ⁹ form an optionally substituted aryl.

157. The compound of embodiment 142, wherein R ¹ is hydrogen.

158. The compound of embodiment 142, wherein R ¹ is an optionally

substituted alkyl.

159. The compound of embodiment 142, wherein R ¹ is an optionally

substituted haloalkyl.

160. The compound of embodiment 142, wherein R ¹ is an optionally

substituted cycloalkyl.

161 . The compound of any one of embodiments 157-160, wherein R ⁹ is hydrogen.

162. The compound of any one of embodiments 157-160, wherein R ⁹ is an optionally substituted alkyl.

163. The compound of any one of embodiments 157-160, wherein R ⁹ is an optionally substituted haloalkyl.

164. The compound of any one of embodiments 139-163, wherein R ² is hydrogen. 165. The compound of any one of embodiments 139-163, wherein R ² is an optionally substituted alkyl.

166. The compound of any one of embodiments 139-163, wherein R ² is an optionally substituted haloalkyl.

167. The compound of any one of embodiments 139-163, wherein R ² is an optionally substituted alkylamino.

168. The compound of any one of embodiments 139-163, wherein R ² is an optionally substituted cycloalkyl.

169. The compound of any one of embodiments 139-163, wherein R ² is an optionally substituted cycloalkylalkyl.

170. The compound of embodiment 139 or 140, wherein R ¹ and R ² form an optionally substituted cycloalkyl.

171 . The compound of embodiment 139 or 140, wherein R ¹ and R ² form an optionally substituted halocycloalkyl.

172. The compound of embodiment 170 or 171, wherein R ⁸ is hydrogen.

173. The compound of embodiment 170 or 171, wherein R ⁸ is hydroxyl.

174. The compound of embodiment 170 or 171, wherein R ⁸ is an optionally substituted alkyl.

175. The compound of embodiment 170 or 171, wherein R ⁸ is an optionally substituted haloalkyl.

176. The compound of any one of embodiments 170-175, wherein R ⁹ is hydrogen.

177. The compound of any one of embodiments 170-175, wherein R ⁹ is an optionally substituted alkyl.

178. The compound of any one of embodiments 170-175, wherein R ⁹ is an optionally substituted haloalkyl.

179. The compound of embodiment 170 or 171, wherein R ⁸ and R ⁹ form an optionally substituted cycloalkyl.

180. The compound of embodiment 170 or 171, wherein R ⁸ and R ⁹ form an optionally substituted ^' halocycloalkyl. 181 . The compound of embodiment 142, wherein R ¹ and R ² form an optionally substituted cycloalkyl.

182. The compound of embodiment 142, wherein R ¹ and R ² form an

optionally substituted halocycloalkyl.

183. The compound of embodiment 181 or 182, wherein R ⁹ is hydrogen.

1 84., The compound of embodiment 181 or 182, wherein R ⁹ is an optionally substituted alky 1.

185. The compound of embodiment 181 or 182, wherein R ⁹ is an optionally substituted haloalkyl.

186. The compound of any one of embodiments 139-185, wherein R ⁶ is hydrogen.

187. The compound of any one of embodiments 139-185, wherein R ⁶ is an optionally substituted alkyl.

1 88. The compound of any one of embodiments 139-185, wherein R ⁶ is an optionally substituted haloalkyl.

189. The compound of any one of embodiments 139-185, wherein R ⁶ is an optionally substituted alkenyl.

190. The compound of any one of embodiments 139-185, wherein R ⁶ is an optionally substituted alkynyl.

191 . The compound of any one of embodiments 139-185, wherein R ⁶ is an optionally substituted heteroalkyl.

192. The compound of any one of embodiments 139-185, wherein R ⁶ is an optionally substituted alkoxyalkyl.

193. The compound of any one of embodiments 139-185, wherein R ⁶ is an optionally substituted cycloalkyl.

194. The compound of any one of embodiments 139-185, wherein R ⁶ is an optionally substituted cycloalkylacyl.

195. The compound of any one of embodiments 139-194, wherein R ⁵ is hydrogen. 196. The compound of any one of embodiments 139-194, wherein R ⁵ is an optionally substituted alkyl.

197. The compound of any one of embodiments 139-185, wherein R ⁵ and R form an optionally substituted heterocyclyl.

198. The compound of any one of embodiments 139-197, wherein R ⁴ is hydrogen.

199. The compound of any one of embodiments 139-197, wherein R ⁴ is an optionally substituted alkyl.

200. The compound of any one of embodiments 139-194, wherein R ⁴ and R form an optionally substituted cycloalkyl.

201 . The compound of any one of embodiments 139-200, wherein R ³ is hydrogen.

202. The compound of any one of embodiments 139-200, wherein R ^J is an optionally substituted alkyl.

203. The compound of any one of embodiments 139-197, wherein R ³ and R form an optionally substituted cycloalkyl.

204. The compound of any one of embodiments 139-203, wherein R ⁷ is hydrogen.

205. The compound of any one of embodiments 139-203, wherein R ⁷ is an optionally substituted alkyl.

206. The compound of any one of embodiments 139-197, wherein R ⁴ and R form an optionally substituted heterocyclyl.

207. The compound of embodiment 206, wherein R ³ is hydrogen.

208. The compound of embodiment 206, wherein R ³ is an optionally

substituted alkyl.

209. A compound having the formula (SC- 13):

SC-13 or a pharmaceutically acceptable salt, tautomer, solvate, diastereomer,

enantiomer, or prodrug thereof, wherein as valence and stability permit:

— represents a single or double bond;

Y is selected from the group consisting of O and CH ₂;

W is selected from the group consisting of CH ₂, CH, N, NH, C, and CHCH ₃;

Z is selected from the group consisting of NR. ⁶, C, CH, and CH ₂;

R ¹ is selected from the group consisting of hydrogen, halogen, and

isothiocyanate;

R ² is selected from the group consisting of hydrogen and halogen;

R ³ is selected from the group consisting of hydrogen and optionally substituted alkyl;

R ⁴ is selected from the group consisting of hydrogen, hydroxy 1, and optionally substituted alkyl;

R ⁵ is selected from the group consisting of hydrogen and optionally substituted alkyl, heteroalkyl, and aminoalkyl; and

R ⁶ is selected from the group consisting of absent, hydrogen and optionally substituted alkyl, heteroalkyl, and aminoalkyl;

wherein R ⁴ and R ⁵ can optionally form a ring, wherein the ring is an optionally substituted heterocyclyl;

wherein W and R ³ or Z and R ³ can optionally form a ring, wherein the ring is selected from the group consisting of optionally substituted cycloalkyl, heterocyclyl, aryl, and heteroaryl;

provided the compound having the formula (SC- 13) is not:

thereof.

. The compound of embodiment 209, wherein =^= represents a single bond.

. The compound of embodiment 209 or 210, wherein Y is CH ₂.

. The compound of any one of embodiments embodiment 209-211, wherein W is CHCH ₃.

. The compound of any one of embodiments embodiment 209-211, wherein W is CH ₂.

. The compound of any one of embodiments 209-213, wherein Z is NR. ⁶.

1 2 . The compound of any one of embodiments 209-214, wherein R and R are both hydrogen.

. The compound of any one of embodiments 209-215, wherein R ³ is hydrogen.

. The compound of any one of embodiments 209-215, wherein R ³ is an optionally substituted alkyl.

. The compound of any one of embodiments 209-217, wherein R ⁴ is an optionally substituted alkyl.

. The compound of any one of embodiments 209-218, wherein R ⁵ is an optionally substituted alkyl.

. The compound of any one of embodiments 209-217, wherein R ⁴ and R ⁵ form an optionally substituted heterocyclyl. 221 . The compound of any one of embodiments 209-220, wherein R ⁶ is hydrogen.

222. The compound of any one of embodiments 209-220, wherein R ⁶ is an optionally substituted alkyl.

223. The compound of any one of embodiments 209-220, wherein R ⁶ is an optionally substituted aminoalkyl.

224. A compound having the formula (SC-14):

SC-14 or a pharmaceutically acceptable salt, tautomer, solvate, diastereomer,

enantiomer, or prodrug thereof, wherein as valence and stability permit: Y is selected from the group consisting of N and CH;

R ¹ is selected from the group consisting of hydrogen and optionally substituted alkyl, heteroalkyl, arylalkyl, heteroarylalkyl, and aminoalkyl; R ² is selected from the group consisting of hydrogen and optionally substituted alkyl, heteroalkyl, and aminoalkyl; and

R ³ and R ⁴ are independently selected from the group consisting of hydrogen and optionally substituted alkyl;

wherein R ³ and R ⁴ can optionally form a ring, wherein the ring is selected from the group consisting of optionally substituted cycloalkyl and heterocyclyl.

225. The compound of embodiment 224, wherein Y is N.

226. The compound of embodiment 224, wherein Y is CH.

227. The compound of any one of embodiments 224-226, wherein R ¹ is an optionally substituted alkyl. 228. The compound of any one of embodiments 224-226, wherein R ¹ is an optionally substituted arylalkyl.

229. The compound of any one of embodiments 224-226, wherein R ¹ is an optionally substituted heteroarylalkyl.

230. The compound of any one of embodiments 224-226, wherein R ¹ is an optionally substituted aminoalkyl.

231 . The compound of any one of embodiments 224-230,· wherein R ² is

hydrogen.

232. The compound of any one of embodiments 224-230, wherein R ² is an optionally substituted alkyl.

233. The compound of any one of embodiments 224-232, wherein R ³ is an optionally substituted alkyl.

234. The compound of any one of embodiments 224-233, wherein R ⁴ is an- optionally substituted alkyl.

235. The compound of any one of embodiments 224-232, wherein R ³ and R ⁴ are both hydrogen.

236. The compound of any one of embodiments 224-232, wherein R ³ and R ⁴ form an optionally substituted cycloalkyl.

237. A compound having the formula (SC- 15):

SC-15 or a pharmaceutically acceptable salt, tautomer, solvate, diastereomer,

enantiomer, or prodrug thereof, wherein as valence and stability permit:

R ¹ , R ², R ³, and R ⁴ are independently selected from the group consisting of

hydrogen, halogen, and optionally substituted alkyl, heteroalkyl, aminoalkyl, alkoxy, alkylthio, -SCF ₃, difluoromethoxy, aryl, heteroaryl, arylalkyl, heteroarylalkyl, arylalkoxy, heteroarylalkoxy, aryloxy, heteroaryloxy, aryloxyalkoxy, and heteroaryloxyalkoxy; and

5 6 7 8

R ^J, R°, R', and R ^a are independently selected from the group consisting of hydrogen and optionally substituted alkyl, heteroalkyl, aminoalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, aryloxyalkyl, and

heteroaryloxyalkyl;

wherein R ⁵ and R ⁶ can optionally form a ring, wherein the ring is selected from the group consisting of optionally substituted heterocyclyl and optionally substituted aminoalkylheterocyclyl;

wherein R ⁶ and R ⁷ can optionally form a ring, wherein the ring is an optionally substituted heterocyclyl;

provided that the compound having the formula (SC-15) is not:

of.. The compound of embodiment 237, wherein R ¹ is hydrogen.

. The compound of embodiment 237, wherein R ¹ is an optionally substituted alkyl.

. The compound of embodiment 237, wherein R ¹ is an optionally substituted aminoalkyl.

. The compound of embodiment 237, wherein R ¹ is an optionally substituted aryl.

. The compound of embodiment 237, wherein R ¹ is an optionally substituted aryloxy.

. The compound of embodiment 237, wherein R ¹ is an optionally substituted arylalkoxy.

. The compound of embodiment 237, wherein R ¹ is an optionally substituted aryloxyalkoxy.

. The compound of embodiment 237, wherein R ¹ is an optionally substituted alkylthio.

. The compound of any one of embodiments 237-245, wherein R ² is hydrogen.

. The compound of any one of embodiments 237-245, wherein R ² is an optionally substituted alkyl.

. The compound of any one of embodiments 237-245, wherein R ² is an optionally substituted alkoxy.

. The compound of any one of embodiments 237-245, wherein R ² is an optionally substituted aryl. 250. The compound of any one of embodiments 237-245, wherein R ² is an optionally substituted aryloxy.

251 . The compound of any one of embodiments 237-245, wherein R ² is an optionally substituted arylalkoxy.

252. The compound of any one of embodiments 237-245, wherein R ² is an optionally substituted aryloxyalkoxy.

253. The compound of any one of embodiments 237-245, wherein R ² is an optionally substituted alkylthio.

254. The compound of any one of embodiments 237-245, wherein R ² is an optionally substituted aminoalkyl.

255. The compound of any one of embodiments 237-254, wherein R ³ is hydrogen.

256. The compound of any one of embodiments 237-254, wherein R ³ is an optionally substituted alkyl.

257. The compound of any one of embodiments 237-254, wherein R ³ is an optionally substituted alkoxy.

258. The compound of any one of embodiments 237-254, wherein R ³ is an optionally substituted aryl.

259. The compound of any one of embodiments 237-254, wherein R ³ is an optionally substituted aryloxy.

260. The compound of any one of embodiments 237-254, wherein R ³ is an optionally substituted arylalkoxy.

261. The compound of any one of embodiments 237-254, wherein R ³ is an optionally substituted aryloxyalkoxy.

262. The compound of any one of embodiments 237-254, wherein R ³ is an optionally substituted alkylthio.

263. The compound of any one of embodiments 237-254, wherein R ³ is an optionally substituted aminoalkyl.

264. The compound of any one of embodiments 237-263, wherein R ⁴ is hydrogen. 265. The compound of any one of embodiments 237-263, where n R ⁴ halogen.

266. The compound of any one of embodiments 237-263, where n R ⁴ s an optionally substituted aryloxyalkoxy.

267. The compound of any one of embodiments 237-266, where n R ⁵

hydrogen.

268. The compound of any one of embodiments 237-266, where n R ⁵ s an optionally substituted alkyl.

269. The compound of any one of embodiments 237-266, where n R ⁵ s an optionally substituted aminoalkyl.

270. The compound of any one of embodiments 237-266, where n R ⁵ s an optionally substituted aryl.

271 . The compound of any one of embodiments 237-266, where n R ⁵ s an optionally substituted arylalkyl.

272. The compound of any one of embodiments 237-266, where n R ³ s an optionally substituted aryloxyalkyl.

273. The compound of any one of embodiments 237-272, where n R ⁶

hydrogen.

274. The compound of any one of embodiments 237-272, where n R ^b s an optionally substituted alkyl.

275. The compound of any one of embodiments 237-272, where n R ^b s an optionally substituted aminoalkyl.

276. The compound of any one of embodiments 237-272, where n R ^b s an optionally substituted aryl.

277. The compound of any one of embodiments 237-272, where n R ⁶ s an optionally substituted arylalkyl.

278. The compound of any one of embodiments 237-272, where n R ⁶ s an optionally substituted aryloxyalkyl.

279. The compound of any one of embodiments 237-266, where n R ⁵ and R ⁶ form an optionally substituted heterocyclyl. 280. The compound of any one of embodiments 237-266, wherein R ⁵ and R ⁶ form an optionally substituted aminoalkylheterocyclyl.

281 . The compound of any one of embodiments 237-280, wherein R ⁷ is hydrogen.

282. The compound of any one of embodiments 237-280, wherein R ⁷ is an optionally substituted alkyl.

283. The compound of any one of embodiments 237-280, wherein R ⁷ is an optionally substituted arylalkyl.

284. The compound of any one of embodiments 237-280, wherein R ⁷ is an optionally substituted aryloxyalkyl.

285. The compound of any one of embodiments 237-272, wherein R ⁶ and R ⁷ form an optionally substituted heterocyclyl.

286. The compound of any one of embodiments 237-285, wherein R ⁸ is hydrogen.

287. The compound of any one of embodiments 237-285, wherein R ⁸ is an optionally substituted alkyl.

288. The compound of any one of embodiments 237-285, wherein R ⁸ is an optionally substituted aminoalkyl.

289. The compound of any one of embodiments 237-285, wherein R is an optionally substituted arylalkyl.

290. A compound having the formula (SC- 16):

SC-16 or a pharmaceutically acceptable salt, tautomer, solvate, diastereomer,

enantiomer, or prodrug thereof, wherein as valence and stability permit: R ¹, R ², and R ³ are independently selected from the group consisting of hydrogen and optionally substituted alkyl, heteroalkyl, aminoalkyl, alkylaminoalkyl, arylalkyl, heteroarylalkyl, and carbamoylaminoalkyl; wherein R ¹ and R ² can optionally form a ring, wherein the ring is selected from the group optionally substituted heterocyclyl and optionally substituted aminoalkylheterocyclyl;

wherein R ² and R ³ can Optionally form a ring, wherein the ring is an optionally substituted heterocyclyl;

provided that compound having the formula (SC-16) is not:

or a pharmaceutically acceptable salt, tautomer, enantiomer, solvate, or

prodrug thereof; provided that R ¹, R ², and R ³ are not all hydrogen, or a pharmaceutically acceptable salt, tautomer, solvate, or prodrug thereof.

291. The compound of embodiment 290, wherein R ¹ is hydrogen.

292. The compound of embodiment 290, wherein R ¹ is an optionally substituted alkyl.

293. The compound of embodiment 290, wherein R ¹ is an optionally substituted aminoalkyl.

294. The compound of embodiment 290, wherein R ¹ is an optionally

substituted arylalkyl.

295. The compound of embodiment 290, wherein R ¹ is an optionally substituted carbamoylaminoalkyl.

296. The compound of any one of embodiments 290-295, wherein R ² is hydrogen.

297. The compound of any one of embodiments 290-295, wherein R ² is an optionally substituted alkyl.

298. The compound of any one of embodiments 290-295, wherein R ² is an optionally substituted aminoalkyl.

299. The compound of any one of embodiments 290-295, wherein R ² is an optionally substituted alkylaminoalkyl.

300. The compound of any one of embodiments 290-295, wherein R ² is an optionally substituted arylalkyl.

301 . The compound of embodiment 290, wherein R ¹ and R ² form an

optionally substituted heterocyclyl.

302. The compound of embodiment 290, wherein R and R form an

optionally substituted aminoalkylheterocyclyl.

303. The compound of any one of embodiments 290-302, wherein R ³ is hydrogen.

304. The compound of any one of embodiments 290-302, wherein R ³ is an optionally substituted alkyl. 305. The compound of any one of embodiments 290-302, wherein R ³ is an optionally substituted aminoalkyl.

306. The compound of any one of embodiments 290-302, wherein R ³ is an optionally substituted alkylaminoalkyl.

307. The compound of any one of embodiments 290-302, wherein R ³ is an optionally substituted arylalkyl.

308. The compound of any one of embodiments 290-295, wherein R ² and R ³ form an optionally substituted heterocyclyl.

309. A compound having the rmula (SC- 1 7):

SC-17 or a pharmaceutically acceptable salt, tautomer, solvate, diastereomer,

enantiomer, or prodrug thereof, wherein as valence and stability permit: Y is selected from the group NH and O;

R ¹ is selected from the group consisting of optionally substituted alkyl,

heteroalkyl, aminoalkyl, amino, cycloalkyl, heterocyclyl,

cycloalkylalkylamino, heterocyclylalkylamino, aryl, heteroaryl, arylalkyl, heteroarylalkyl, arylamino, heteroarylamino, and aminoalkylaryloxyalkoxyaryl; and

R ² and R ³ are independently selected from the group consisting of hydrogen and optionally substituted alkyl, heteroalkyl, and aminoalkyl; wherein R ² and R ³ can optionally form a ring, wherein the ring is an optionally substituted heterocyclyl or heteroaryl;

provided that compound having the formula (SC-17) is not:

or a pharmaceutically acceptable salt, tautomer, solvate, or prodrug thereof. . The compound of embodiment 309, wherein Y is NH.

. The compound of embodiment 309, wherein Y is O.

. The compound of any one of embodiments 309-311, wherein R ¹ is an optionally substituted alkyl.

. The compound of any one of embodiments 309-311, wherein R ¹ is an optionally substituted heteroalkyl.

. The compound of any one of embodiments 309-311, wherein R ¹ is an optionally substituted aminoalkyl.

. The compound of any one of embodiments 309-311, wherein R ¹ is an optionally substituted amino.

. The compound of any one of embodiments 309-311 , wherein R ¹ is an optionally substituted cycloalkylalkylamino.

. The compound of any one of embodiments 309-311, wherein R ¹ is an optionally substituted aryl. . The compound of any one of embodiments 309-311, where n R is an optionally substituted heteroaryl.

. The compound of any one of embodiments 309-311, where n R is an optionally substituted arylalkyl.

. The compound of any one of embodiments 309-311, where n R is an optionally substituted heteroarylalkyl.

. The compound of any one of embodiments 309-311, where n R is an optionally substituted arylamino.

. The compound of any one of embodiments 309-311, where n R ¹ is an optionally substituted heteroarylamino.

. The compound of any one of embodiments 309-311, where n R is an optionally substituted aminoalkylaryloxyalkoxyaryl.

. The compound of any one of embodiments 309-323, where n R ² is hydrogen.

. The compound of any one of embodiments 309-323, where n R is an optionally substituted alkyl.

. The compound of any one of embodiments 309-323, where n R is an optionally substituted heteroalkyl.

. The compound of any one of embodiments 309-323, where n R ² is an optionally substituted aminoalkyl.

. The compound of any one of embodiments 309-327, where n R ³ is hydrogen.

. The compound of any one of embodiments 309-327, where n R is an optionally substituted alkyl.

. The compound of any one of embodiments 309-327, where n R ³ is an optionally substituted heteroalkyl.

. The compound of any one of embodiments 309-327, where n R is an optionally substituted aminoalkyl.

. The compound of any one of embodiments 309-323, where n R ² and R ³ form an optionally substituted heterocyclyl. 333. A compound havin the formula (SC-18):

SC-18 or a pharmaceutically acceptable salt, tautomer, solvate, diastereomer,

enantiomer, or prodrug thereof, wherein as valence and stability permit:

L ¹ is a 4 to 12 carbon atom linker selected from the group consisting of

optionally substituted alkanediyl, heteroalkanediyl, cycloalkanediyl, heterocyclylalkanediyl, ajkenediyl, alkynediyl, arylalkanediyl, alkylaryloxydiyl, aminoalkanediyl, and aminoalkylaminodiyl;

R ¹ and R ² are independently selected from the group consisting of hydrogen and optionally substituted alkyl and heteroalkyl; and

R ³ and R ⁴ are independently selected from the group consisting of hydrogen and optionally substituted alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, and heteroalkynyl;

wherein R ¹ and R ² can optionally form a ring, wherein the ring is an optionally substituted heterocyclyl.

334. The compound of embodiment 333, wherein L ¹ is an optionally

substituted alkanediyl.

335. The compound of embodiment 333, wherein L ¹ is an optionally

substituted heteroalkanediyl.

336. The compound of embodiment 333, wherein L ¹ is an optionally

substituted arylalkanediyl.

337. The compound of embodiment 333, wherein L ¹ is an optionally

substituted alkylaryloxydiyl.

338. The compound of embodiment 333, wherein L ¹ is an optionally

substituted aminoalkanediyl. 339. The compound of embodiment 333, wherein L is an optionally substituted aminoalkylaminodiyl.

340. The compound of any one of embodiments 333-339, wherein R ¹ is hydrogen.

341 . The compound of any one of embodiments 333-339, wherein R ¹ is an optionally substituted alkyl.

342. The compound of any one of embodiments 333-341, wherein R ² is hydrogen.

343. The compound of any one of embodiments 333-341 , wherein R ² is an optionally substituted alkyl.

344. The compound of any one of embodiments 333-339, wherein R ¹ and R ² form an optionally substituted heterocyclyl.

345. The compound of any one of embodiments 333-344, wherein R ³ is an optionally substituted alkyl.

346. The compound of any one of embodiments 333-345, wherein R ⁴ is an optionally substituted alkyl.

347. A compound havin the formula (SC-19):

SC-19 or a pharmaceutically acceptable salt, enantiomer, diastereomer, prodrug, tautomer, or solvate thereof, wherein as valence and stability permit:

R' is selected from the group consisting of optionally substituted alkyl, alkenyl, alkynyl, and arylalkyl; and

R ² is selected from the group consisting of hydrogen and optionally substituted alkyl, alkenyl, and alkynyl.

348. The compound of embodiment 347, wherein R ¹ is an optionally

substituted alkyl. 349. The compound of embodiment 347, wherein R ¹ is an optionally substituted alkenyl.

350. The compound of embodiment 347, wherein R ¹ is an optionally

substituted arylalkyl.

351. The compound of any one of embodiments 347-350, wherein R ² is hydrogen.

352. The compound of any one of embodiments 347-350, wherein R ² is an optionally substituted alkyl.

353. The compound of any one of embodiments 347-350, wherein R ² is an optionally substituted alkenyl.

354. The compound of any one of embodiments 347-350, wherein R ² is an optionally substituted alkynyl.

355. A compound having the formula SC-20): or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, prodrug, or solvate thereof, wherein as valence and stability permit:

R ¹ is selected from the group consisting of hydrogen and optionally substituted alkyl and aminoalkyl; and

R ² is selected from hydrogen and optionally substituted alkyl, aminoalkyl, and cycloalkylaminoalkyl;

provided that the compound having the formula (SC-20) is not:

a pharmaceutically acceptable salt, enantiomer, tautomer, prodrug,

solvate thereof.

The compound of embodiment 355, wherein R ¹ is hydrogen. 357. The compound of embodiment 355, wherein R ¹ is an optionally substituted alkyl.

358. The compound of embodiment 355, wherein R ¹ is an optionally

substituted aminoalky!.

359. The compound of any one of embodiments 355-358, wherein R ² is hydrogen. ^

360. The compound of any one of embodiments 355-358, wherein R ² is an optionally substituted alkyl.

361. The compound of any one of embodiments 355-358, wherein R ² is an optionally substituted aminoalkyl.

362. The compound of any one of embodiments 355-358, wherein R ² is an optionally substituted cycloalkylaminoalkyl.

363. A compound having the formula (SC-21):

or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, prodrug, or solvate thereof, wherein as valence and stability permit: a and β— represents a single or double bond;

V is selected from the group consisting of C, CH, and N;

W is selected from the group consisting of C, CH, and N;

Y is selected from the group consisting of CH ₂ and NH;

R ¹ is selected from the group consisting of optionally substituted alkyl and amino; and

R ² is selected from the group consisting of absent and hydrogen;

wherein when β is a double bond, R is absent, and when β is a single bond, R is hydrogen;

provided that the compound having the formula (SC-21 ) is not:

Cpd ; ^' Structure

or a pharmaceutically acceptable salt, prodrug, or solvate thereof.

364. The compound of 363, wherein a is a single bond.

365. The compound of embodiment 363 or 364, wherein V is CH.

366. The compound of embodiment 363 or 364, wherein V is N.

367. The compound of any one of embodiments 363-366, wherein W is CH.

368. The compound of any one of embodiments 363-366, wherein W is N.

369. The compound of embodiment 363, wherein a is a double bond.

370. The compound of any one of embodiments 363-369, wherein β is a single bond and R ² is hydrogen.

371. The compound of any one of embodiments 363-369, wherein β is a double bond and R is absent.

372 The compound of any one of embodiments 363 or 369-371, wherein V is C.

373 The compound of any one of embodiments 363 or 369-372, wherein W is C.

374. The compound of any one of embodiments 363-373, wherein Y is CH ₂.

375. The compound of any one of embodiments 363-373, wherein Y is NH.

376. The compound of any one of embodiments 363-375, wherein R ¹ is an optionally substituted alkyl.

377. The compound of any one of embodiments 363-375, wherein R ¹ is an optionally substituted amino.

378. A compound having the formula (SC-22):

SC-22 or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, prodrug, or solvate thereof, wherein as valence and stability permit:

L ¹ is a 4 to 12 carbon linker selected from the group consisting of optionally substituted alkanediyl, heteroalkanediyl, alkenediyl, heteroalkenediyl, oxyalkoxydiyl, alkylcycloalkylalkanediyl,

heteroalkylcycloalkylheteroalkanediyl, alkylcycloalkenylalkanediyl, heteroalkylcycloalkenylheteroalkanediyl, alkylheterocyclylalkanediyl, and heteroalkylheterocyclylheteroalkanediyl; and

Ar ¹ is selected from the group consisting of optionally substituted aryl and heteroaryl.

379. The compound of embodiment 378, wherein L ¹ is an optionally

substituted alkanediyl.

380. The compound of embodiment 378, wherein L ¹ is an optionally

substituted heteroalkanediyl.

381. The compound of embodiment 378, wherein L ¹ is an optionally

substituted oxyalkoxydiyl.

382. The compound of embodiment 378, wherein L ¹ is an optionally

substituted alkylcycloalkylalkanediyl.

383. The compound of embodiment 378, wherein L ¹ is an optionally

substituted alkylheterocyclylalkanediyl.

384. The compound of any one of embodiments 378-383, wherein Ar ¹ is an optionally substituted aryl.

385. The compound of any one of embodiments 378-383, wherein Ar ¹ is an optionally substituted heteroaryl.

386. A compound having the formula SC-23):

SC-23 or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, prodrug, or solvate thereof, wherein as valence and stability permit:

R ¹ is selected from the group consisting of halogen and optionally substituted Ci-C ₆ alkyl, C ₂-C ₆ alkenyl, C ₃-C ₆ cycloalkyl, C ₄-C ₆ cycloalkenyl, C ₂- C ₅ heterocycloalkyl, Ci-C ₆ alkoxy, Ci-C ₆ alkylthio, phenyl, and monocyclic heteroaryl; and

R ², R ³, and R ⁴ are independently selected from the group consisting of

hydrogen, halogen and optionally substituted Ci-C ₆ alkyl, C ₂-C ₆ alkenyl, C ₃-C ₆ cycloalkyl, C ₄-C ₆ cycloalkenyl, C ₂-C ₅ heterocycloalkyl, C|-C ₆ alkoxy, Ci-C ₆ alkylthio, phenyl, and monocyclic heteroaryl; wherein said optionally substituted Ci-C ₆ alkyl, C ₂-C ₆ alkenyl, C ₃-C ₆

cycloalkyl, C ₄-C ₆ cycloalkenyl, C ₂-C ₅ heterocycloalkyl, Ci-C ₆

alkylthio, and C]-C ₆ alkoxy are optionally substituted with one or more substituents selected from the group consisting of F, and unsubstituted OCH ₃, OCH ₂CH ₃, CH ₃, C ₂H ₅, and C ₂-C ₅ dialkylamino;

wherein said optionally substituted phenyl is optionally substituted with one or more substituents selected from the group consisting of F, CI, Br, SCF ₃, and unsubstituted OCH ₃, OCH ₂CH ₃, CH ₃, C ₂H ₅₎ COOH, COOCH ₃, COOC ₂H ₅, SCH ₃, SOCH ₃, S0 ₂CH ₃, SCHF ₂, isopropyl, t-butyl, hydroxyl, dialkylamino, and alkylamino;

wherein said optionally substituted monocyclic heteroaryl is optionally

substituted with one or more substituents selected from the group consisting of F, CI, Br, SCF ₃₎ CF ₃, OCF ₃, and unsubstituted OCH ₃, OCH ₂CH ₃, CH ₃, C ₂H ₅, COOH, COOCH ₃, COOC ₂H ₅, SCH ₃, SOCH ₃, S0 ₂CH ₃, SCHF ₂, CHF ₂, OCHF ₂, isopropyl, /-butyl, hydroxyl, dialkylamino, and alkylamino;

wherein R ¹ and R ² can optionally form a ring, wherein the ring is an optionally substituted cycloalkyl, heterocyclyl, aryl, or heteroaryl;

wherein R ² and R ³ can optionally form a ring, wherein the ring is an optionally substituted cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein R ³ and R ⁴ can optionally form a ring, wherein the ring is an optionally substituted cycloalkyl, heterocyclyl, aryl, or heteroaryl.

387. The compound of embodiment 386, wherein R is halogen.

388. The compound of embodiment 387, wherein R ¹ is F.

389. The compound of embodiment 387, wherein R ¹ is CI.

390. The compound of embodiment 387, wherein R ¹ is Br.

391 . The compound of embodiment 387, wherein R ¹ is I.

392. The compound of embodiment 386, wherein R ¹ is SCF ₃.

393. The compound of embodiment 386, wherein R ¹ is an unsubstituted

SCHF ₂

394. The compound of embodiment 386, wherein R ¹ is an unsubstituted

OCHF ₂.

395. The compound of embodiment 386, wherein R ¹ is OCF ₃.

396. The compound of embodiment 386, wherein R ¹ is CF ₃.

397. The compound of embodiment 386, wherein R ¹ is an unsubstituted

CF ₂H.

398. The compound of any one of embodiments 386-397, wherein R ² is hydrogen.

399. The compound of any one of embodiments 386-397, wherein R ² is halogen.

400. The compound of any one of embodiments 386-397, wherein R ² is optionally substituted Ci-C ₆ alkoxy.

401 . The compound of any one of embodiments 386-397, wherein R ² is an optionally substituted C|-C ₆ alkyl.

402. The compound of any one of embodiments 386-401, wherein R ³ is hydrogen.

403. The compound of any one of embodiments 386-401, wherein R ³ is halogen.

404. The compound of any one of embodiments 386-403, wherein R ⁴ is hydrogen. 405. The compound of any one of embodiments 386-403, wherein R ⁴ is halogen.

406. A compound having the formula SC-24):

SC-24

or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, prodrug, or solvate thereof, wherein as valence and stability permit:

R' , R ², R ⁷, and R ⁸ are independently selected from the group consisting of hydrogen, halogen, and optionally substituted C]-C ₃ alkyl, Ci-C ₃ alkoxy, Ci-C ₃ alkylthio, dimethylamino, methylamino, and amino;

R ³ and R ⁴ are independently selected from the group consisting of hydrogen, halogen, and optionally substituted C|-C ₆ alkyl, C ₂-C ₆ alkenyl, C ₃-C ₆ cycloalkyl, C ₄-C ₆ cycloalkenyl, C ₂-C ₅ heterocycloalkyl, Ci-C ₆ alkoxy, C]-C ₆ alkylthio, phenyl, and monocyclic heteroaryl; and

R ⁵ and R ⁶ are independently selected from the group consisting of hydrogen, halogen, and optionally substituted Ci-C ₆ alkyl, C ₂-C ₆ alkenyl, C ₃-C ₆ cycloalkyl, C -C ₆ cycloalkenyl, C ₂-C ₅ heterocycloalkyl, Ci-C ₆ alkylthio, phenyl, and monocyclic heteroaryl;

wherein said optionally substituted Ci-C ₆ alkyl, C ₂-C ₆ alkenyl, C ₃-C ₆

cycloalkyl, C ₄-C ₆ cycloalkenyl, C ₂-C ₅ heterocycloalkyl, Ci-C ₆ alkylthio, and Ci-C ₆ alkoxy are optionally substituted with one or more substituents selected from the group consisting of F, and unsubstituted OCH ₃, OCH ₂CH ₃, CH ₃, C ₂H ₅, and C ₂-C ₅ dialkylamino;

wherein said optionally substituted phenyl is optionally substituted with one or more substituents selected from the group consisting of F, CI, Br, SCF ₃, CF ₃, OCF ₃, and unsubstituted OCH ₃, OCH ₂CH ₃, CH ₃, C ₂H ₅, COOH, COOCH3, COOC ₂H ₅, SCH ₃, SOCH3, S0 ₂CH ₃, SCHF ₂, CHF ₂, OCHF ₂, isopropyl, t-butyl, hydroxyl, dialkylamino, and alkylamino; wherein said optionally substituted monocyclic heteroaryl is optionally

substituted with one or more substituents selected from the group consisting of F, CI, Br, SCF ₃, CF ₃, OCF ₃, and unsubstituted OCH ₃,

OCH ₂CH ₃, CH ₃, C ₂H ₅, COOH, COOCH ₃, COOC ₂H ₅, SCH ₃, SOCH ₃,

S0 ₂CH ₃, SCHF ₂, CHF ₂, OCHF ₂, isopropyl, /-butyl, hydroxyl, dialkylamino, and alkylamino;

wherein R ³ and R ⁴ can optionally form a ring, wherein the ring is an optionally substituted cycloalkyl, heterocyclyl, aryl, or heteroaryl;

wherein R ⁴ and R ⁵ can optionally form a ring, wherein the ring is an optionally substituted cycloalkyl, heterocyclyl, aryl, or heteroaryl;

wherein R ⁵ and R ⁶ can optionally form a ring, wherein the ring is an optionally substituted cycloalkyl, heterocyclyl, aryl, or heteroaryl;

wherein R ¹ and R ³ can optionally form a ring, wherein the ring is an optionally substituted cycloalkyl, heterocyclyl, aryl, or heteroaryl;

wherein R ⁶ and R ⁷ can optionally form a ring, wherein the ring is an optionally substituted cycloalkyl, heterocyclyl, aryl, or heteroaryl;

wherein R ⁷ and R ⁸ can optionally form a ring, wherein the ring is an optionally substituted cycloalkyl, heterocyclyl, aryl, or heteroaryl.

407. The compound of embodiment 406, wherein R ¹ is hydrogen.

408. The compound of embodiment 406, wherein R ¹ is halogen.

409. The compound of any one of embodiments 406-408, wherein R ² is hydrogen.

410. The compound of any one of embodiments 406-408, wherein R is halogen.

41 1 . The compound of any one of embodiments 406-408, wherein R ² is an optionally substituted Ci-C ₃ alkyl.

412. The compound of any one of embodiments 406-411, wherein R ³ is hydrogen. 413. The compound of any one of embodiments 406-411, wherein R ³ is halogen.

414. The compound of any one of embodiments 406-411, wherein R ³ is SCF ₃.

415. The compound of any one of embodiments 406-411, wherein R ³ is an unsubstituted SCHF ₂.

416. The compound of any one of embodiments 406-411, wherein R ³ is an unsubstituted OCHF ₂.

417. The compound of any one of embodiments 406-411, wherein R ³ is OCF ₃.

418. The compound of any one of embodiments 406-411, wherein R ³ is CF ₃.

419. The compound of any one of embodiments 406-411, wherein R ³ is an unsubstituted CF ₂H.

420. The compound of any one of embodiments 406-411, wherein R is an optionally substituted Ci-C ₆ alkoxy.

421 . The compound of any one of embodiments 406-420, wherein R ⁴ is hydrogen.

422. The compound of any one of embodiments 406-420, wherein R ⁴ is halogen.

423. The compound of any one of embodiments 406-420, wherein R ⁴ is an optionally substituted Ci-C ₆ alkyl.

424. The compound of any one of embodiments 406-420, wherein R ⁴ is an optionally substituted Ci-C ₆ alkoxy.

425. The compound of any one of embodiments 406-424, wherein R ⁵ is hydrogen.

426. The compound of any one of embodiments 406-424, wherein R ⁵ is halogen.

427. The compound of any one of embodiments 406-424, wherein R ⁵ is an optionally substituted Ci-C ₆ alkyl. 428. The compound of any one of embodiments 406-427, wherein R is hydrogen.

429. The compound of any one of embodiments 406-427, wherein R ⁶ is halogen.

430. The compound of any one of embodiments 406-427, wherein R ⁶ is an optionally substituted C|-C ₆ alkyl.

431 . The compound of any one of embodiments 406-430, wherein R ⁷ is hydrogen.

432. The compound of any one of embodiments 406-430, wherein R ⁷ is halogen.

433. The compound of any one of embodiments 406-432, wherein R ⁸ is hydrogen.

434. The compound of any one of embodiments 406-432, wherein R ⁸ is halogen.

435. The compound of any one of embodiments 406-432, wherein R is an optionally substituted C1-C3 alkyl.

436. A compound having the formula SC-25):

SC-25

or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, prodrug, or solvate thereof, wherein as valence and stability permit:

R\ R ², and R ³ are independently selected from the group consisting of

hydrogen, and unsubstituted C1-C ₃ alkyl, C ₃-C5 cycloalkyl, C ₂-C ₄ alkenyl, methoxyethyl, ethoxyethyl, and ethynyl; and

R ⁴, R ⁵, R ⁶, and R ⁷ are independently selected from the group consisting of hydrogen, halogen, and optionally substituted C]-C ₆ alkyl, C ₂-C ₆ alkenyl, C3-C6 cycloalkyl, C ₄-C ₆ cycloalkenyl, C ₂-C ₅ heterocycloalkyl, Ci-C ₆ alkoxy, Ci-C ₆ alkylthio, phenyl, and monocyclic heteroaryl; wherein said optionally substituted Ci-C ₆ alkyl, C ₂-C ₆ alkenyl, C ₃-C ₆

cycloalkyl, C ₄-C ₆ cycloalkenyl, C ₂-C ₅ heterocycloalkyl, Q-C ₆

alkylthio, and Ci-C ₆ alkoxy are optionally substituted with one or more substituents selected from the group consisting of F, and unsubstituted OCH ₃, OCH ₂CH ₃, CH ₃, C ₂H ₅, and C ₂-C ₅ dialkylamino;

wherein said optionally substituted phenyl is optionally substituted with one or more substituents selected from the group consisting of F, CI, Br, SCF ₃, and unsubstituted OCH ₃, OCH ₂CH ₃, CH ₃, C ₂H ₅, COOH, COOCH ₃, COOC ₂H ₅, SCH ₃₎ SOCH ₃, S0 ₂CH ₃, SCHF ₂, isopropyl, /-butyl, hydroxyl, dialkylamino, and alkylamino;

wherein said optionally substituted monocyclic heteroaryl is optionally

substituted with one or more substituents selected from the group consisting of F, CI, Br, SCF ₃, and unsubstituted OCH ₃, OCH ₂CH ₃, CH ₃, C ₂H ₅, COOH, COOCH ₃, COOC ₂H ₅, SCH ₃, SOCH ₃, S0 ₂CH ₃, SCHF ₂, isopropyl, /-butyl, hydroxyl, dialkylamino, and alkylamino; wherein R ¹ and R ² can optionally form a ring, wherein the ring is an optionally substituted heterocyclyl or heteroaryl;

wherein R ¹ and R ³ can optionally form a ring, wherein the ring is an optionally substituted heterocyclyl or heteroaryl;

wherein R ¹ and R ⁷ can optionally form a ring, wherein the ring is an optionally substituted heterocyclyl or heteroaryl;

wherein R ⁴ and R ⁵ can optionally form a ring, wherein the ring is an optionally substituted cycloalkyl, heterocyclyl, aryl, or heteroaryl;

wherein R ⁵ and R ⁶ can optionally form a ring, wherein the ring is an optionally substituted cycloalkyl, heterocyclyl, aryl, or heteroaryl;

wherein R ⁶ and R ⁷ can optionally form a ring, wherein the ring is an optionally substituted cycloalkyl, heterocyclyl, aryl, or heteroaryl.

. The compound of embodiment 436, wherein R ¹ is hydrogen. 438. The compound of embodiment 436 or 437, wherein R ² is hydrogen.

439. The compound of any one of embodiments 436-438, wherein R ³ is hydrogen.

440. The compound of any one of embodiments 436-438, wherein R ³ is an unsubstituted C1 -C3 alkyl.

441. The compound of embodiment 440, wherein R ³ is an unsubstituted methyl.

442. The compound of any one of embodiments 436-441 , wherein R ⁴ is hydrogen.

443. The compound of any one of embodiments 436-441, wherein R ⁴ is halogen.

444. The compound of embodiment 443, wherein R ⁴ is fluorine.

445. The compound of any one of embodiments 436-441, wherein R ⁴ is an optionally substituted C| -C ₆ alkyl.

446. The compound of embodiment 445, wherein R ⁴ is an unsubstituted methyl.

447. The compound of any one of embodiments 436-441, wherein R ⁴ is an optionally substituted Ci -C ₆ alkoxy.

448. The compound of embodiment 447, wherein R ⁴ is an unsubstituted methoxy.

449. The compound of embodiment 447, wherein R ⁴ is an unsubstituted difluoromethoxy.

450. The compound of any one of embodiments 436-449, wherein R ⁵ is hydrogen.

451. The compound of any one of embodiments 436-449, wherein R ⁵ is halogen.

452. The compound of embodiment 451, wherein R ⁵ is fluorine.

453. The compound of any one of embodiments 436-449, wherein R ⁵ is an optionally substituted Ci -C ₆ alkyl. 454. The compound of embodiment 453, wherein R ⁵ is an unsubstituted methyl.

455. The compound of any one of embodiments 436-449, wherein R ⁵ is an optionally substituted Ci-C ₆ alkoxy.

456. The compound of embodiment 455, wherein R ⁵ is an unsubstituted methoxy.

457. The compound of embodiment 455, wherein R ⁵ is an unsubstituted dif!uoromethoxy.

458. The compound of any one of embodiments 436-457, wherein R ⁶ is hydrogen.

459. The compound of any one of embodiments 436-457, wherein R ⁶ is halogen.

460. The compound of embodiment 459, wherein R ⁶ is fluorine.

461. The compound of any one of embodiments 436-457, wherein R ⁶ is an optionally substituted C]-C ₆ alkyl.

462. The compound of embodiment 461, wherein R ⁶ is an unsubstituted methyl.

463. The compound of any one of embodiments 436-457, wherein R ⁶ is an optionally substituted Ci-C ₆ alkoxy.

464. The compound of embodiment 463, wherein R ⁶ is an unsubstituted methoxy.

465. The compound of embodiment 463, wherein R ⁶ is an unsubstituted difluoromethoxy.

466. A compound having the formula 93, 96, 99-202, 212-217, 219-354, 358-374, 376, or 378-432, or a pharmaceutically acceptable salt, a free base form, enantiomer, disastereomer, a solvate, prodrug, or a tautomer of any of the foregoing compounds.

467. A compound having the formula:

¾ Structure 96 or a pharmaceutically acceptable salt, solvate, prodrug, or tautomer thereof.. A compound having the formula:

or a pharmaceutically acceptable salt, enantiomer, diastereomer, prodrug, or solvate thereof.

. A compound having the formula:

or a pharmaceutically acceptable salt, enantiomer, diastereomer, prodrug, or solvate thereof.

. A compound having the formula:

or a pharmaceutically acceptable salt, prodrug, or solvate thereof.

. A compound having the formula:

or a pharmaceutically acceptable salt, prodrug, or solvate thereof.

. A compound having the formula:

Cpd

Structure or a pharmaceutically acceptable salt, prodrug, or solvate thereof.

. A compound having the formula:

a pharmaceutically acceptable salt, prodrug, or solvate thereof.

A compound having the formula:

or a pharmaceutically acceptable salt, prodrug, or solyate thereof.

. A compound having the formula:

or a pharmaceutically acceptable salt, tautomer, enantiomer, prodrug, or solvate thereof.

. A compound having the formula:

or a pharmaceutically acceptable salt, tautomer, enantiomer, prodrug, or solvate thereof.

477. A compound having the formula:

or a p armaceut ca y accepta e sa t, tautomer, enant omer, prodrug, or solvate thereof.

478. A compound having the formula:

or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, enantiomer, prodrug, or solvate thereof.

479.

or a ph prodrug, or solvate thereof.

480. A compound having the formula:

Cpd

Structure

ID 128 Γ ^ /

or a pharmaceutically acceptable salt, tautomer, prodrug, or solvate thereof. 481 . A compound having the formula:

or a pharmaceutically acceptable salt, tautomer, prodrug, or solvate thereof. 482. A compound having the formula:

or a pharm solvate thereof. 483. A compound having the formula:

or a pharmaceutically acceptable salt, tautomer, prodrug, or solvate thereof. 484. A compound having the formula:

or a pharmaceutically acceptable salt, prodrug, or solvate thereof.

485. A compound having the formula:

Cpd Structure

or a pharmaceutically acceptable salt, enantiomer, diastereomer, prodrug, or solvate thereof.

486. A compound having the formula:

or a pharmaceutically acceptable salt, enantiomer, diastereomer, prodrug, or solvate thereof.

487. A compound having the formula:

or a pharmaceutically acceptable salt, tautomer, pro rug, or solvate thereof. 488. A compound having the formula:

or a pharmaceutically acceptable salt, tautomer, prodrug, or solvate thereof. 489. A compound having the formula:

Cpd

Structure or a pharmaceutically acceptable salt, tautomer, prodrug, or solvate thereof. 490. A compound having the formula:

or a pharmaceut ca y accepta e sa t, tautomer, pro rug, or solvate thereof. 491. A compound having the formula:

or a pharmaceutically acceptable salt, tautomer, prodrug, or solvate thereof. 492. A compound having the formula:

or a pharm solvate thereof. 493. A compound having the formula:

or a pharmaceutically acceptable salt, tautomer, prodrug, or solvate thereof. 494. A compound having the formula:

Cpd

Structure

ID or a pharm solvate thereof. 495. A compound having the formula:

or a pharm solvate thereof. 496. A compound having the formula:

or a pharmaceutically acceptable salt, tautomer, prodrug, or solvate thereof. 497. A compound having the formula:

or a pharm solvate thereof. 498. A compound having the formula:

or a pharmaceutically acceptable salt, tautomer, prodrug, or solvate thereof. 499. A compound having the formula:

or a pharmaceut ca y acceptab e salt, tautomer, prodrug, or solvate thereof. 500. A compound having the formula:

or a pharmaceutically acceptable salt, tautomer, prodrug, or solvate thereof. 501. A compound having the formula:

or a pharmaceutically acceptable salt, tautomer, prodrug, or solvate thereof. 502. A compound having the formula:

a pharmaceutically acceptable salt, prodrug, or solvate thereof.

A compound having the formula:

Cpd

in Structure

NH ₂

or a pharmaceutically acceptable salt, tautomer/prodrug, or solvate thereof. 504. A compound having the formula:

or a pharmaceutically acceptable salt, tautomer, prodrug, or solvate thereof. 505. A compound having the formula:

or a pharm prodrug, or solvate thereof.

506. A compound having the formula:

Cpd

Structure or a pharmaceutically acceptable salt, enantiomer, tautomer, prodrug, or solvate thereof.

507. A compound having the formula:

or a p armaceut ca y accepta e sa t, enant omer, tautomer, prodrug, or solvate thereof.

508.

or a ph er, tautomer, prodrug, or solvate thereof.

509. A compound having the formula:

or a pharmaceutically acceptable salt, tautomer, prodrug, or solvate thereof. 510. A compound having the formula:

or a pharmaceutically acceptable salt, tautomer, prodrug, or solvate thereof.. A compound having the formula:

or a pharmaceutically acceptable salt, prodrug, or solvate thereof.

. A compound having the formula:

or a pharmaceutically acceptable salt, tautomer, prodrug, or solvate thereof.. A compound having the formula:

or a pharmaceutically acceptable salt, tautomer, prodrug, or solvate thereof. 515. A compound having the formula:

or a pharm olvate thereof.

516. A compound having the formula:

or a pharmaceutically acceptable salt, free base form, prodrug, or solvate thereof.

517. A compound having the formula:

or a pharmaceutically acceptable salt, free base form, prodrug, or solvate thereof.

518. A compound having the formula:

Cpd

in Structure

or a pharmaceutically acceptable salt, free base form, prodrug, or solvate thereof.

. A compound having the formula:

or a pharmaceutically acceptable salt, free base form, prodrug, or solvate thereof.

. A compound having the formula:

or a pharmaceutically acceptable salt, free base form, prodrug, or solvate thereof.

. A compound having the formula:

Cpd

Structure or a pharm g, or solvate thereof.

. A compound having the formula:

or a pharmaceutically acceptable salt, free base form, prodrug, or solvate thereof.

. A compound having the formula:

or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, prodrug, or solvate thereof.

. A compound having the formula:

or a pharmaceutically acceptable salt, enantiomer, tautomer, prodrug, or solvate thereof.

. A compound having the formula: or a prodrug, or solvate thereof.

526. A compound having the formula:

a pharmaceutca y accepta e sat, pro rug, or sovate t ereof.

A compound having the formula:

or a pharmaceutca y accepta e sat, pro rug, or sovate t ereof.

528. A compound having the formula:

or a pharm reof. 529. A compound having the formula:

a p armaceut cally acceptable salt, prodrug, or solvate thereof.

A compound having the formula:

or a pharmaceutically acceptable salt, prodrug, or solvate thereof.

531. A compound having the formula:

or a pharm prodrug, or solvate thereof.

532. A compound having the formula:

or a pharmaceutically acceptable salt, enantiomer, tautomer, prodrug, or solvate thereof.

533. A compound having the formula:

or a pharmaceutically acceptable salt, enantiomer, tautomer, prodrug, or solvate thereof.

534. A compound having the formula:

or a pharm prodrug, or solvate thereof.

535. A compound having the formula:

or a pharmaceutically acceptable salt, tautomer, prodrug, or solvate thereof. 536. A compound having the formula:

Cpd

Structure

ID or a pharmaceutically acceptable salt, enantiomer, tautomer, prodrug, or solvate thereof.

537. A compound having the formula:

or a pharm prodrug, or solvate thereof.

538. A compound having the formula:

or a ph prodrug, or solvate thereof.

539. A compound having the formula:

or a pharm prodrug, or solvate thereof.

540. A compound having the formula:

or a pharmaceutically acceptable salt, tautomer, prodrug, or solvate thereof. 541. A compound having the formula:

or a pharm olvate thereof. 542. A compound having the formula:

or a pharmaceut ca y accepta e sa t, tautomer, pro rug, or solvate thereof. 543. A compound having the formula:

or a pharmaceutically acceptable salt, enantiomer, tautomer, prodrug, or solvate thereof.

544. A compound having the formula:

or a pharmaceutica y acceptable salt, prodrug, or solvate thereof.

545. A compound having the formula:

a pharmaceutically acceptable salt, ^'prodrug, or solvate thereof.

A compound having the formula:

or a pharm solvate thereof. •547. A compound having the formula:

or a pharmaceutically acceptable salt, tautomer, prodrug, or solvate thereof. compound having the formula:

or a pharmaceutically acceptable salt, tautomer, prodrug, or solvate thereof. 549. A compound having the formula:

or a pharmaceutically acceptable salt, tautomer, prodrug, or solvate thereof. 550. A compound having the formula:

a pharm er, prod

solvate thereof.

A compound having the formula:

or a pharmaceutically acceptable salt, tautomer, prodrug, or solvate thereof. 552. A compound having the formula:

or a p armaceut ca y accepta e salt, enantiomer, tautomer, prodrug, or solvate thereof.

553. A compound having the formula:

or a pharmaceutically acceptable salt, tautomer, prodrug, or solvate thereof. 554. A compound having the formula:

or a pharmaceutically acceptable salt, tautomer, prodrug, or solvate thereof. 555. A compound having the formula:

a ph solvate thereof.

A compound having the formula:

Cpd

Structure

or a pharmaceutically acceptable salt, tautomer, prodrug, or solvate thereof.. A compound having the formula:

or a ph lvate thereof.. A com und having the formula:

Structure

or a thereof. 560. A compound having the formula:

or a pharmaceutically acceptable salt, tautomer, prodrug, or solvate thereof. 561. A compound having the formula:

or a pharmaceutically acceptable salt, enantiomer, prodrug, or solvate thereof. 562. A compound having the formula:

or a pharmaceutically acceptable salt, enantiomer, prodrug, or solvate thereof. 563. A compound having the formula:

or a pharmaceutically acceptable salt, enantiomer, prodrug, or solvate thereof. 564. A compound having the formula: Cpd

Structure

328 F ₃C^\/\^ NH or a pharmaceutically acceptable salt, enantiomer, prodrug, or solvate thereof. 565. A compound having the formula:

or a pharmaceutically acceptable salt, enantiomer, prodrug, or solvate thereof. 566. A compound having the formula:

or a pharmaceutically acceptable salt, enantiomer, prodrug, or solvate thereof. 567. A compound having the formula:

or a pharmaceutically acceptable salt, enantiomer, prodrug, or solvate thereof. 568. A compound having the formula:

or a pharmaceutically acceptable salt, enantiomer, prodrug, or solvate thereof. 569. A compound having the formula:

Cpd

Structure H

338

CF ₃

or a pharmaceutically acceptable salt, enantiomer, prodrug, or solvate thereof. 570. A compound having the formula:

or a pharmaceutically acceptable salt, enantiomer, prodrug, or solvate thereof. 571. A compound having the formula:

or a pharmaceutically acceptable salt, enantiomer, prodrug, or solvate thereof. 572. A compound having the formula:

or a pharmaceutically acceptable salt, enantiomer, prodrug, or solvate thereof. 573. A compound having the formula:

or a pharm er, prodrug, or solvate thereof.

574. A compound having the formula:

Cpd

Structure

solvate thereof.

A compound having the formula:

or a pharmaceutically acceptable salt, enantiomer, prodrug, or solvate thereof. 576. A compound having the formula:

or a pharmaceutically acceptable salt, enantiomer, prodrug, or solvate thereof. 577. A compound having the formula:

or a pharmaceutically acceptable salt, enantiomer, diastereomer, prodrug, or solvate thereof.

578. A compound having the formula:

or a pharmaceutically acceptable salt, enantiomer, diastereomer, prodrug, or solvate thereof.

579. A compound having the formula:

or a pharmaceutically acceptable salt, enantiomer, diastereomer, prodrug, or solvate thereof.

580. A compound having the formula:

or a pharmaceutically acceptable salt, enantiomer, diastereomer, prodrug, or solvate thereof.

581. A compound having the formula:

or a solvate or prodrug thereof.

582. A compound having the formula:

solvate or pro rug t ereo .

A compound having the formula:

or a pharmaceutically acceptable salt, tautomer, prodrug, or solvate thereof. 584.

or a pharmaceutically acceptable salt, tautomer, prodrug, or solvate thereof. 585. A compound having the formula:

or a pharmaceutically acceptable salt, tautomer, prodrug, or solvate thereof. 586. A compound having the formula:

or a pharm prodrug, or solvate thereof.

587. A compound having the formula:

Cpd

Structure or a pharmaceutically acceptable salt, tautomer, prodrug, or solvate thereof. 588. A compound having the formula:

or a pharmaceutically acceptable salt, enantiomer, tautomer, prodrug, or solvate thereof.

589. A compound having the formula:

or a pharmaceutically acceptable salt, tautomer, prodrug, or solvate thereof. 590. A compound having the formula:

or a pharmaceutically acceptable salt, tautomer, prodrug, or solvate thereof. 591. A com ound having the formula:

Structure

379 or a pharmaceutically acceptable salt, tautomer, prodrug, or solvate thereof. 592. A compound having the formula:

or a pharmaceutically acceptable salt, tautomer, prodrug, or solvate thereof. 593. A compound having the formula:

or a pharmaceutically acceptable salt, tautomer, prodrug, or solvate thereof. 594. A compound having the formula:

a pharmaceutically acceptable salt, tautomer, prodrug, or solvate thereof.

A compound having the formula:

or a pharmaceutically acceptable salt, tautomer, prodrug, or solvate thereof. 596. A compound having the formula:

or a pharmaceut cally accepta le salt, tautomer, prodrug, or solvate thereof. 597. A compound having the formula:

or a pharmaceutically acceptable salt, tautomer, prodrug, or solvate thereof. 598. A compound having the formula:

or a pharmaceutically acceptable salt, tautomer, prodrug, or solvate thereof. 599. A compound having the formula:

or a pharmaceutically acceptable salt, tautomer, prodrug, or solvate thereof. 600. A compound having the formula:

or a pharmaceutically acceptable salt, tautomer, prodrug, or solvate thereof. 601. A compound having the formula:

or a pharmaceutically acceptable salt, tautomer, prodrug, or solvate thereof. 602. A compound having the formula:

or a pharmaceutically acceptable salt, tautomer, prodrug, or solvate thereof. 603. A compound having the formula:

or a pharmaceutically acceptable salt, tautomer, prodrug, or solvate thereof. 604. A compound having the formula:

or a pharmaceutically acceptable salt, tautomer, prodrug, or solvate thereof. 605. A compound having the formula:

or a pharmaceutically acceptable salt, enantiomer, tautomer, prodrug, or solvate thereof.

606. A compound having the formula:

or a pharmaceutically acceptable salt, enantiomer, tautomer, prodrug, or solvate thereof.

607. A compound having the formula:

or a pharmaceutically acceptable salt, enantiomer, tautomer, prodrug, or solvate thereof.

608. A compound having the formula:

or a pharmaceutically acceptable salt, enantiomer, tautomer, prodrug, or solvate thereof.

609. A compound having the formula:

a pharmaceutically acceptable salt, enantiomer, tautomer, prodrug, solvate thereof. A compound having the formula

a pharmaceutically acceptable salt, enantiomer, tautomer, prodrug,

solvate thereof.

A compound having the formula:

or a pharmaceutically acceptable salt, enantiomer, tautomer, prodrug, or solvate thereof.

612. A compound having the formula:

or a pharmaceutically acceptable salt, tautomer, prodrug, or solvate thereof. 613. A compound having the formula:

or a pharmaceutically acceptable salt, tautomer, prodrug, or solvate thereof. 614. A compound having the formula:

a p armaceut ca y accepta e sa t, enantiomer, tautomer, prodrug,

solvate thereof.

A compound having the formula:

or a pharmaceutically acceptable salt, tautomer, prodrug, or solvate thereof. 616. A compound having the formula:

or a pharmaceutically acceptable salt, tautomer, prodrug, or solvate thereof. 617. A compound having the formula:

or a pharmaceutically acceptable salt, tautomer, prodrug, or solvate thereof. 618. A compound having the formula:

or a pharmaceutically acceptable salt, tautomer, prodrug, or solvate thereof. 619. A compound having the formula:

or a pharmaceutically acceptable salt, tautomer, prodrug, or solvate thereof. 620. A compound having the formula:

or a pharmaceutically acceptable salt, tautomer, prodrug, or solvate thereof. 621. A compound having the formula:

or a pharmaceutically acceptable salt, tautomer, prodrug, or solvate thereof. 622. A compound having the formula:

Cpd

Structure

a pharmaceut ca y accepta e sa t, tautomer, prodrug, or solvate thereof.

A compound having the formula:

or a pharmaceutically acceptable salt, tautomer, prodrug, or solvate thereof. 624. A compound having the formula:

or a pharmaceutically acceptable salt, tautomer, prodrug, or solvate thereof. 625. A compound having the formula:

or a pharmaceutically acceptable salt, tautomer, prodrug, or solvate thereof. 626. A compound having the formula:

Cpd

Structure

or a pharmaceut ca y accepta e sa t, tautomer, pro rug, or solvate thereof. 627. A compound having the formula:

or a pharmaceutically acceptable salt, tautomer, prodrug, or solvate thereof. 628. A compound having the formula:

or a pharmaceutically acceptable salt, tautomer, prodrug, or solvate thereof. 629. A compound having the formula:

or a pharmaceutically acceptable salt, tautomer, prodrug, or solvate thereof. 630. A compound having the formula:

Cpd

in Structure

or a pharmaceutically acceptable salt, tautomer, prodrug, or solvate thereof. 631. A compound having the formula:

or a pharm solvate thereof. 632. A compound having the formula:

or a pharm solvate thereof. 633. A compound having the formula:

or a pharmaceutically acceptable salt, tautomer, prodrug, or solvate thereof. 634. A compound having the formula:

or a pharmaceutically acceptable salt, tautomer, prodrug, or solvate thereof. 635. A compound having the formula:

or a pharmaceutically acceptable salt, tautomer, prodrug, or solvate thereof. 636. A compound having the formula:

or a pharmaceutically acceptable salt, tautomer, prodrug, or solvate thereof. 637. A compound having the formula:

or a pharmaceutically acceptable salt, tautomer, prodrug, or solvate thereof. A compound having the formula:

or a pharmaceutically acceptable salt, tautomer, prodrug, or solvate thereof. 639. A compound having the formula:

or a pharmaceutically acceptable salt, tautomer, prodrug, or solvate thereof. 640. A compound having the formula:

or a pharmaceutically acceptable salt, tautomer, prodrug, or solvate thereof. 641. A compound having the formula:

or a pharmaceutically acceptable salt, tautomer, prodrug, or solvate thereof. 642. A compound having the formula: Cpd

Structure

430 or a pharmaceutically acceptable salt, enantiomer, prodrug, or solvate thereof. 643. A compound having the formula:

or a pharmaceutically acceptable salt, enantiomer, prodrug, or solvate thereof. 644. A compound having the formula:

or a pharmaceutically acceptable salt, enantiomer, prodrug, or solvate thereof.

645. Use of a compound of any one of embodiments 1-644, or a mixture thereof, as an analgesic.

646. Use of a compound having the formula 1, 54-92, 95, 97, 98, 203-208, 210, 211, 315-317, 355-357, or 375, or a mixture thereof, or a

pharmaceutically acceptable salt, free base form, enantiomer, disastereomer, tautomer, solvate, or prodrug, or a mixture thereof, of any of the foregoing compounds, as an analgesic.

647. Use of a compound having the formula 63, 66, 67, 72, 74, 83, 84, 90, 95, 218, 315-317, 355-357, or 375, or a mixture thereof, or a pharmaceutically acceptable salt, free base form, enantiomer, disastereomer, tautomer, solvate, or prodrug, or a mixture thereof, of any of the foregoing compounds, as an analgesic.

648. A pharmaceutical composition comprising a therapeutically effective amount of a compound of any one of embodiments 1-644, or a mixture thereof. 649. The pharmaceutical composition of embodiment 648, further comprising at least one pharmaceutically acceptable excipient, carrier, or diluent.

650. Use of the pharmaceutical composition of embodiment 648 or 649 as an analgesic.

651 . A pharmaceutical composition comprising as an active ingredient a therapeutically effective amount of a compound having the formula 1, 54-92, 95, 97, 98, 203-208, 210, 211, 315-317, 355-357, or 375, or a mixture thereof, or a pharmaceutically acceptable salt, free base form, solvate, enantiomer, disastereomer, tautomer, or prodrug, or a mixture thereof, of any of the foregoing compounds.

652. The pharmaceutical composition of embodiment 651, further

comprising at least one pharmaceutically acceptable excipient, carrier, or diluent.

653. Use of the pharmaceutical composition of embodiment 651 or 652 as an analgesic.

654. A pharmaceutical composition comprising as an active ingredient a therapeutically effective amount of a compound having the formula 63, 66, 67, 72, 74, 83, 84, 90, 95, 218, 315-317, 355-357, or 375, or a mixture thereof, or a pharmaceutically acceptable salt, free base form, enantiomer, disastereomer, tautomer, solvate, or prodrug, or a mixture thereof, of any of the foregoing compounds.

655. The pharmaceutical composition of embodiment 654, further

comprising at least one pharmaceutically acceptable excipient, carrier, or diluent.

656. Use of the pharmaceutical composition of embodiment 654 or 655 as an analgesic.

657. A method of treating or preventing one or more conditions selected from the group consisting of: pain; an inflammatory disease or disorder, an allergic disease or disorder, a metabolic disease, a cardiovascular disease or disorder, a neurogenic vascular disease or a painful condition associated with any of the foregoing conditions; an episodic tension-type headache; a migraine headache; a headache; cramping; a cognitive disorder; a tension or migraine headache due to a vascular, neurovascular, or neurogenic disorder or dysfunction during a menstrual cycle episode; a tension or migraine headache due to a vascular, neurovascular, or neurogenic disorder or dysfunction during a migraine episode; a headache from mild to moderate hypertension; mild to moderate essential hypertension; organ transplant rejection; hot and cold flashes; traumatic brain injury (TBI); neurotoxicity; psychic pain;

psychological pain; psychiatric pain; depression; schizophrenia; anxiety;

epilepsy; a stress disorder; excess sweating; a symptom related to drug withdrawal; allodynia; fibromyalgia; fibromyalgia-ness; central sensitization; centralization; regional pain syndrome; temporomandibular joint syndrome (TMJ); lower back pain; interstitial cystitis; Gulf War syndrome; visceral pain; kidney stones; gout; neuropathic pain; post-herpetic neuralgia; diabetic neuropathy; sickle cell pain; priapism; nociceptive pain; post-operative pain; orthopedic injury pain; phantom limb pain; bunionectomy; dental extraction; pain after severed spinal cord injury; osteoarthritis; rheumatoid arthritis; Lyme disease; Parkinson's disease; pain associated with cancer; opioid-induced constipation; an opioid withdrawal symptom; and pain associated with posttraumatic stress disorder (PTSD), in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of a compound of any one of embodiments 1-644, or a mixture thereof.

658. The method of embodiment 657, wherein the condition is a headache.

659. The method of embodiment 657, wherein the condition is an episodic tension-type headache.

660. The method of embodiment 657, wherein the condition is a migraine headache.

661. The method of embodiment 657, wherein the condition is cramping. 662. The method of embodiment 657, wherein the condition is a cognitive disorder.

663. The method of embodiment 657, wherein the condition is a tension or migraine headache due to a vascular, neurovascular, or neurogenic disorder or dysfunction during a migraine episode.

664. The method of embodiment 657, wherein the condition is a tension or migraine headache due to a vascular, neurovascular, or neurogenic disorder or dysfunction during a menstrual cycle episode.

665. The method of embodiment 657, wherein the condition is a headache from mild to moderate hypertension.

666. The method of embodiment 657, wherein the condition is mild to

moderate essential hypertension.

667. The method of embodiment 657, wherein the condition is nociceptive pain.

668. The method of embodiment 657, wherein the condition is an

inflammatory disease or disorder or a painful condition associated therewith.

669. The method of embodiment 657, wherein the condition is an allergic disease or disorder or a painful condition associated therewith.

670. The method of embodiment 657, wherein the condition is a metabolic disease or a painful condition associated therewith.

671 . The method of embodiment 657, wherein the condition is a

cardiovascular disease or disorder or a painful condition associated therewith.

672. The method of embodiment 657, wherein the condition is a neurogenic vascular disease or a painful condition associated therewith.

673. The method of embodiment 657, wherein the condition is neuropathic pain.

674. The method of embodiment 657, wherein the condition is visceral pain.

675. The method of embodiment 657, wherein the condition is

neurotoxicity.

676. The method of embodiment 657, wherein the condition is depression. 677. The method of embodiment 657, wherein the condition is

schizophrenia.

678. The method of embodiment 657, wherein the condition is anxiety.

679. The method of embodiment 657, wherein the condition is epilepsy.

680. The method of embodiment 657, wherein the condition is a stress

disorder.

681. The method of embodiment 657, wherein the condition is Parkinson's disease.

682. The method of embodiment 657, wherein the condition is central

sensitization.

683. The method of embodiment 657, wherein the condition is allodynia.

684. The method of embodiment 657, wherein the condition is fibromyalgia.

685. The method of embodiment 657, wherein the condition is rheumatoid arthritis.

686. The method of embodiment 657, wherein the condition is pain.

687. The method of embodiment 657, wherein the condition is psychic pain.

688. The method of embodiment 657, wherein the condition is

psychological pain.

689. The method of embodiment 657, wherein the condition is psychiatric pain.

690. The method of embodiment 657, wherein the condition is phantom

limb pain.

691. The method of embodiment 657, wherein the condition is opioid- induced constipation.

692. The method of embodiment 657, wherein the condition is an opioid withdrawal symptom.

693. The method of any one of embodiments 657-692, wherein the

compound is administered simultaneously, sequentially, or separately with one or more substances selected from the group consisting of acetaminophen, a non-steroidal anti-inflammatory drug (NSAID), ibuprofen, naprosyn, a cyclooxygenase-2 inhibitor, aspirin, caffeine, dichloralphenazone, a triptan, an antidepressant, a serotonin-norepinephrine reuptake inhibitor (SNRI), and a gabapentinoid.

694. The method of any one of embodiments 657-692, wherein the

compound is administered simultaneously, sequentially, or separately with one or more additional therapeutics selected from the group consisting of a chemotherapeutic drug, an antiproliferative agent, an anti-inflammatory agent, a corticosteroid, an anti-asthmatic agent, an anti-allergic agent, an

695. The method of any one of embodiments 657-692, wherein the

compound is administered simultaneously, sequentially, or separately with one or more opiates.

696. A method of treating or preventing one or more conditions selected from the group consisting of: pain; an inflammatory disease or disorder, an allergic disease or disorder, a metabolic disease, a cardiovascular disease or disorder, a neurogenic vascular disease or a painful condition associated with any of the foregoing conditions; an episodic tension-type headache; a migraine headache; a headache; cramping; a cognitive disorder; a tension or migraine headache due to a vascular, neurovascular, or neurogenic disorder or dysfunction during a menstrual cycle episode; a tension or migraine headache due to a vascular, neurovascular, or neurogenic disorder or dysfunction during a migraine episode; a headache from mild to moderate hypertension; mild to moderate essential hypertension; organ transplant rejection; hot and cold flashes; traumatic brain injury (TBI); neurotoxicity; psychic pain;

697. The method of embodiment 696, wherein the condition is a headache.

698. The method of embodiment 696, wherein the condition is an episodic tension-type headache.

699. The method of embodiment 696, wherein the condition is a migraine headache.

700. The method of embodiment 696, wherein the condition is cramping.

701. The method of embodiment 696, wherein the condition is a cognitive disorder.

702. The method of embodiment 696, wherein the condition is a tension or migraine headache due to a vascular, neurovascular, or neurogenic disorder or dysfunction during a migraine episode.

703. The method of embodiment 696, wherein the condition is a tension or migraine headache due to a vascular, neurovascular, or neurogenic disorder or dysfunction during a menstrual cycle episode.

704. The method of embodiment 696, wherein the condition is a headache from mild to moderate hypertension. ^' 705. The method of embodiment 696, wherein the condition is mild to moderate essential hypertension.

706. The method of embodiment 696, wherein the condition is nociceptive pain.

707. The method of embodiment 696, wherein the condition is an

inflammatory disease or disorder or a painful condition associated therewith.

708. The method of embodiment 696, wherein the condition is an allergic disease or disorder or a painful condition associated therewith.

709. The method of embodiment 696, wherein the condition is a metabolic disease or a painful condition associated therewith.

710. The method of embodiment 696, wherein the condition is a

cardiovascular disease or disorder or a painful condition associated therewith.

71 1. The method of embodiment 696, wherein the condition is a neurogenic vascular disease or a painful condition associated therewith.

712. The method of embodiment 696, wherein the condition is neuropathic pain.

713. The method of embodiment 696, wherein the condition is visceral pain.

714. The method of embodiment 696, wherein the condition is

neurotoxicity.

715. The method of embodiment 696, wherein the condition is depression.

716. The method of embodiment 696, wherein the condition is

schizophrenia.

717. The method of embodiment 696, wherein the condition is anxiety.

718. The method of embodiment 696, wherein the condition is epilepsy.

719. The method of embodiment 696, wherein the condition is a stress

disorder.

720. The method of embodiment 696, wherein the condition is Parkinson's disease.

721 . The method of embodiment 696, wherein the condition is central

sensitization. 722. The method of embodiment 696, wherein the condition is allodynia.

723. The method of embodiment 696, wherein the condition is fibromyalgia.

724. The method of embodiment 696, wherein the condition is rheumatoid arthritis.

725. The method of embodiment 696, wherein the condition is pain.

726. The method of embodiment 696, wherein the condition is psychic pain.

727. The method of embodiment 696, wherein the condition is

psychological pain.

728. The method of embodiment 696, wherein the condition is psychiatric pain.

729. The method of embodiment 696, wherein the condition is phantom

limb pain.

730. The method of embodiment 696, wherein the condition is opioid- induced constipation.

731. The method of embodiment 696, wherein the condition is an opioid withdrawal symptom.

732. The method of any one of embodiments 696-731, wherein the

compound is administered simultaneously, sequentially, or separately with one or more substances selected from the group consisting of acetaminophen, a non-steroidal anti-inflammatory drug (NSA1D), ibuprofen, naprosyn, a cyclooxygenase-2 inhibitor, aspirin, caffeine, dichloralphenazone, a triptan, an antidepressant, a serotonin-norepinephrine reuptake inhibitor (SNRI), and a gabapentinoid.

733. The method of any one of embodiments 696-731, wherein the

734. The method of any one of embodiments 696-731, wherein the

compound is administered simultaneously, sequentially, or separately with one or more opiates.

735. A method of treating or preventing one or more conditions selected from the group consisting of: pain; an inflammatory disease or disorder, an allergic disease or disorder, a metabolic disease, a cardiovascular disease or disorder, a neurogenic vascular disease or a painful condition associated with any of the foregoing conditions; an episodic tension-type headache; a migraine headache; a headache; cramping; a cognitive disorder; a tension or migraine headache due to a vascular, neurovascular, or neurogenic disorder or dysfunction during a menstrual cycle episode; a tension or migraine headache due to a vascular, neurovascular, or neurogenic disorder or dysfunction during a migraine episode; a headache from mild to moderate hypertension; mild to moderate essential hypertension; organ transplant rejection; hot and cold flashes; traumatic brain injury (TBI); neurotoxicity; psychic pain;

psychological pain; psychiatric pain; depression; schizophrenia; anxiety;

epilepsy; a stress disorder; excess sweating; a symptom related to drug withdrawal; allodynia; fibromyalgia; fibromyalgia-ness; central sensitization; centralization; regional pain syndrome; temporomandibular joint syndrome (TMJ); lower back pain; interstitial cystitis; Gulf War syndrome; visceral pain; kidney stones; gout; neuropathic pain; post-herpetic neuralgia; diabetic neuropathy; sickle cell pain; priapism; nociceptive pain; post-operative pain; orthopedic injury pain; phantom limb pain; bunionectomy; dental extraction; pain after severed spinal cord injury; osteoarthritis; rheumatoid arthritis; Lyme disease; Parkinson's disease; pain associated with cancer; opioid-induced constipation; an opioid withdrawal symptom; and pain associated with posttraumatic stress disorder (PTSD), in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of a compound having the formula 63, 66, 67, 72, 74, 83, 84, 90, 95, 218, 315-317, 355-357, or 375, or a mixture thereof, or a pharmaceutically acceptable salt, free base form, enantiomer, disastereomer, tautomer, solvate, or prodrug, or a mixture thereof, of any of the foregoing compounds.

736. The method of embodiment 735, wherein the condition is a headache.

737. The method of embodiment 735, wherein the condition is an episodic tension-type headache.

738. The method of embodiment 735, wherein the condition is a migraine headache.

739. The method of embodiment 735, wherein the condition is cramping.

740. The method of embodiment 735, wherein the condition is a cognitive disorder.

741 . < The method of embodiment 735, wherein the condition is a tension or migraine headache due to a vascular, neurovascular, or neurogenic disorder or dysfunction during a migraine episode.

742. The method of embodiment 735, wherein the condition is a tension or migraine headache due to a vascular, neurovascular, or neurogenic disorder or dysfunction during a menstrual cycle episode.

743. The method of embodiment 735, wherein the condition is a headache from mild to moderate hypertension.

744. The method of embodiment 735, wherein the condition is mild to moderate essential hypertension.

745. The method of embodiment 735, wherein the condition is nociceptive pain.

746. The method of embodiment 735, wherein the condition is an

inflammatory disease or disorder or a painful condition associated therewith.

747. The method of embodiment 735, wherein the condition is an allergic disease or disorder or a painful condition associated therewith.

748. The method of embodiment 735, wherein the condition is a metabolic disease or a painful condition associated therewith. 749. The method of embodiment 735, wherein the condition is a

cardiovascular disease or disorder or a painful condition associated therewith.

750. The method of embodiment 735, wherein the condition is a neurogenic vascular disease or a painful condition associated therewith.

751. The method of embodiment 735, wherein the condition is neuropathic pain.

752. The method of embodiment 735, wherein the condition is visceral pain.

753. The method of embodiment 735, wherein the condition is

neurotoxicity.

754. The method of embodiment 735, wherein the condition is depression.

755. The method of embodiment 735, wherein the condition is

schizophrenia.

756. The method of embodiment 735, wherein the condition is anxiety.

757. The method of embodiment 735, wherein the condition is epilepsy.

758. The method of embodiment 735, wherein the condition is a stress

disorder.

759. The method of embodiment 735, wherein the condition is Parkinson's disease.

760. The method of embodiment 735, wherein the condition is central

sensitization.

761. The method of embodiment 735, wherein the condition is allodynia.

762. The method of embodiment 735, wherein the condition is fibromyalgia.

763. The method of embodiment 735, wherein the condition is rheumatoid arthritis.

764. The method of embodiment 735, wherein the condition is pain.

765. The method of embodiment 735, wherein the condition is psychic pain.

766. The method of embodiment 735, wherein the condition is

psychological pain.

767. The method of embodiment 735, wherein the condition is psychiatric pain. 768. The method of embodiment 735, wherein the condition is phantom limb pain.

769. The method of embodiment 735, wherein the condition is opioid- induced constipation.

770. The method of embodiment 735, wherein the condition is an opioid withdrawal symptom.

771. The method of any one of embodiments 735-770, wherein the

772. The method of any one of embodiments 735-770, wherein the

773. The method of any one of embodiments 735-770, wherein the

compound is administered with one or more opiates.

774. A method of treating or preventing one or more conditions selected from the group consisting of: pain; an inflammatory disease or disorder, an allergic disease or disorder, a metabolic disease, a cardiovascular disease or disorder, a neurogenic vascular disease or a painful condition associated with any of the foregoing conditions; an episodic tension-type headache; a migraine headache; a headache; cramping; a cognitive disorder; a tension or migraine headache due to a vascular, neurovascular, or neurogenic disorder or dysfunction during a menstrual cycle episode; a tension or migraine headache due to a vascular, neurovascular, or neurogenic disorder or dysfunction during a migraine episode; a headache from mild to moderate hypertension; mild to moderate essential hypertension; organ transplant rejection; hot and cold flashes; traumatic brain injury (TBI); neurotoxicity; psychic pain;

psychological pain; psychiatric pain; depression; schizophrenia; anxiety;

775. The method of embodiment 774, wherein the condition is a headache.

776. The method of embodiment 774, wherein the condition is an episodic tension-type headache.

777. The method of embodiment 774, wherein the condition is a migraine headache.

778. The method of embodiment 774, wherein the condition is cramping.

779. The method of embodiment 774, wherein the condition is a cognitive disorder. 780. The method of embodiment 774, wherein the condition is a tension or migraine headache due to a vascular, neurovascular, or neurogenic disorder or dysfunction during a migraine episode.

781. The method of embodiment 774, wherein the condition is a tension or migraine headache due to a vascular, neurovascular, or neurogenic disorder or dysfunction during a menstrual cycle episode.

782. The method of embodiment 774, wherein the condition is a headache from mild to moderate hypertension.

783. The method of embodiment 774, wherein the condition is mild to

moderate essential hypertension.

784. The method of embodiment 774, wherein the condition is nociceptive pain.

785. The method of embodiment 774, wherein the condition is an

inflammatory disease or disorder or a painful condition associated therewith.

786. The method of embodiment 774, wherein the condition is an allergic disease or disorder or a painful condition associated therewith.

787. The method of embodiment 774, wherein the condition is a metabolic disease or a painful condition associated therewith.

788. The method of embodiment 774, wherein the condition is a

cardiovascular disease or disorder or a painful condition associated therewith.

789. The method of embodiment 774, wherein the condition is a neurogenic vascular disease or a painful condition associated therewith.

790. The method of embodiment 774, wherein the condition is neuropathic pain.

791. The method of embodiment 774, wherein the condition is visceral pain.

792. The method of embodiment 774, wherein the condition is

neurotoxicity.

793. The method of embodiment 774, wherein the condition is depression.

794. The method of embodiment 774, wherein the condition is

schizophrenia. 795. The method of embodiment 774, wherein the condition is anxiety.

796. The method of embodiment 774, wherein the condition is epilepsy.

797. The method of embodiment 774, wherein the condition is a stress

disorder.

798. The method of embodiment 774, wherein the condition is Parkinson's disease.

799. The method of embodiment 774, wherein the condition is central

sensitization.

800. The method of embodiment 774, wherein the condition is allodynia.

801. The method of embodiment 774, wherein the condition is fibromyalgia.

802. The method of embodiment 774, wherein the condition is rheumatoid arthritis.

803. The method of embodiment 774, wherein the condition is pain.

804. The method of embodiment 774, wherein the condition is psychic pain.

805. The method of embodiment 774, wherein the condition is

psychological pain.

806. The method of embodiment 774, wherein the condition is psychiatric pain.

807. The method of embodiment 774, wherein the condition is phantom

limb pain.

808. The method of embodiment 774, wherein the condition is opioid- induced constipation.

809. The method of embodiment 774, wherein the condition is an opioid withdrawal symptom.

810. The method of any one of embodiments 774-809, wherein the

pharmaceutical composition is administered simultaneously, sequentially, or separately with one or more substances selected from the group consisting of acetaminophen, a non-steroidal anti-inflammatory drug (NSAID), ibuprofen, naprosyn, a cyclooxygenase-2 inhibitor, aspirin, caffeine, dichloralphenazone, a triptan, an antidepressant, a serotonin-norepinephrine reuptake inhibitor (SNRI), and a gabapentinoid.

81 1. The method of any one of embodiments 774-809, wherein the

pharmaceutical composition is administered simultaneously, sequentially, or separately with one or more additional therapeutics selected from the group consisting of a chemotherapeutic drug, an antiproliferative agent, an antiinflammatory agent, a corticosteroid, an anti-asthmatic agent, an anti-allergic agent, an immunosuppressive agent, an immunomodulatory agent, a cardiovascular disease treatment agent, an anti-diabetic agent, a blood disorder treatment agent, a nerve growth factor receptor antagonist, a sodium channel blocker, a CYP2D6 inhibitor, and a TNF-alpha inhibitor.

812. The method of any one of embodiments 774-809, wherein the

pharmaceutical composition is administered simultaneously, sequentially, or separately with one or more opiates.

813. A method of treating or preventing one or more conditions selected from the group consisting of: pain; an inflammatory disease or disorder, an allergic disease or disorder, a metabolic disease, a cardiovascular disease or disorder, a neurogenic vascular disease or a painful condition associated with any of the foregoing conditions; an episodic tension-type headache; a migraine headache; a headache; cramping; a cognitive disorder; a tension or migraine headache due to a vascular, neurovascular, or neurogenic disorder or dysfunction during a menstrual cycle episode; a tension or migraine headache due to a vascular, neurovascular, or neurogenic disorder or dysfunction during a migraine episode; a headache from mild to moderate hypertension; mild to moderate essential hypertension; organ transplant rejection; hot and cold flashes; traumatic brain injury (TBI); neurotoxicity; psychic pain;

814. The method of embodiment 813, wherein the condition is a headache.

815. The method of embodiment 813, wherein the condition is an episodic tension-type headache.

816. The method of embodiment 813, wherein the condition is a migraine headache.

817. The method of embodiment 813, wherein the condition is cramping.

818. The method of embodiment 813, wherein the condition is a cognitive disorder.

819. The method of embodiment 813, wherein the condition is a tension or migraine headache due to a vascular, neurovascular, or neurogenic disorder or dysfunction during a migraine episode.

820. The method of embodiment 813, wherein the condition is a tension or migraine headache due to a vascular, neurovascular, or neurogenic disorder or dysfunction during a menstrual cycle episode.

821 . The method of embodiment 813, wherein the condition is a headache from mild to moderate hypertension.

822. The method of embodiment 813, wherein the condition is mild to

moderate essential hypertension.

823. The method of embodiment 813, wherein the condition is nociceptive pain. 824. The method of embodiment 813, wherein the condition is an inflammatory disease or disorder or a painful condition associated therewith.

825. The method of embodiment 813, wherein the condition is an allergic disease or disorder or a painful condition associated therewith.

826. The method of embodiment 813, wherein the condition is a metabolic disease or a painful condition associated therewith.

827. The method of embodiment 813, wherein the condition is a

cardiovascular disease or disorder or a painful condition associated therewith.

828. The method of embodiment 813, wherein the condition is a neurogenic vascular disease or a painful condition associated therewith.

829. The method of embodiment 813, wherein the condition is neuropathic pain.

830. The method of embodiment 813, wherein the condition is visceral pain.

831. The method of embodiment 813, wherein the condition is

neurotoxicity.

832. The method of embodiment 813, wherein the condition is depression.

833. The method of embodiment 813, wherein the condition is

schizophrenia.

834. The method of embodiment 813, wherein the condition is anxiety.

835. The method of embodiment 813, wherein the condition is epilepsy.

836. The method of embodiment 813, wherein the condition is a stress

disorder.

837. The method of embodiment 813, wherein the condition is Parkinson's disease.

838. The method of embodiment 813, wherein the condition is central

sensitization.

839. The method of embodiment 813, wherein the condition is allodynia.

840. The method of embodiment 813, wherein the condition is fibromyalgia.

841. The method of embodiment 813, wherein the condition is rheumatoid arthritis. 842. The method of embodiment 813, wherein the condition is pain.

843. The method of embodiment 813, wherein the condition is psychic pain.

844. The method of embodiment 813, wherein the condition is

psychological pain.

845. The method of embodiment 813, wherein the condition is psychiatric pain.

846. The method of embodiment 813, wherein the condition is phantom limb pain.

847. The method of embodiment 813, wherein the condition is opioid- induced constipation.

848. The method of embodiment 813, wherein the condition is an opioid withdrawal symptom.

849. The method of any one of embodiments 813-848, wherein the

850. The method of any one of embodiments 813-848, wherein the

852. A method of treating or preventing one or more conditions selected from the group consisting of: pain; an inflammatory disease or disorder, an allergic disease or disorder, a metabolic disease, a cardiovascular disease or disorder, a neurogenic vascular disease or a painful condition associated with any of the foregoing conditions; an episodic tension-type headache; a migraine headache; a headache; cramping; a cognitive disorder; a tension or migraine headache due to a vascular, neurovascular, or neurogenic disorder or dysfunction during a menstrual cycle episode; a tension or migraine headache due to a vascular, neurovascular, or neurogenic disorder or dysfunction during a migraine episode; a headache from mild to moderate hypertension; mild to moderate essential hypertension; organ transplant rejection; hot and cold flashes; traumatic brain injury (TBI); neurotoxicity; psychic pain;

psychological pain; psychiatric pain; depression; schizophrenia; anxiety;

853. The method of embodiment 852, wherein the condition is a headache. 854. The method of embodiment 852, wherein the condition is an episodic tension-type headache.

855. The method of embodiment 852, wherein the condition is a migraine headache.

856. The method of embodiment 852, wherein the condition is cramping.

857. The method of embodiment 852, wherein the condition is a cognitive disorder.

858. The method of embodiment 852, wherein the condition is a tension or migraine headache due to a vascular, neurovascular, or neurogenic disorder or dysfunction during a, migraine episode.

859. The method of embodiment 852, wherein the condition is a tension or migraine headache due to a vascular, neurovascular, or neurogenic disorder or dysfunction during a menstrual cycle episode.

860. The method of embodiment 852, wherein the condition is a headache from mild to moderate hypertension.

861. The method of embodiment 852, wherein the condition is mild to moderate essential hypertension.

862. The method of embodiment 852, wherein the condition is nociceptive pain.

863. The method of embodiment 852, wherein the condition is an

inflammatory disease or disorder or a painful condition associated therewith.

864. The method of embodiment 852, wherein the condition is an allergic disease or disorder or a painful condition associated therewith.

865. The method of embodiment 852, wherein the condition is a metabolic disease or a painful condition associated therewith.

866. The method of embodiment 852, wherein the condition is a

cardiovascular disease or disorder or a painful condition associated therewith.

867. The method of embodiment 852, wherein the condition is a neurogenic vascular disease or a painful condition associated therewith. 868. The method of embodiment 852, wherein the condition is neuropathic pain.

869. The method of embodiment 852, wherein the condition is visceral pain.

870. The method of embodiment 852, wherein the condition is

neurotoxicity.

871. The method of embodiment 852, wherein the condition is depression.

872. The method of embodiment 852, wherein the condition is

schizophrenia.

873. The method of embodiment 852, wherein the condition is anxiety.

874. The method of embodiment 852, wherein the condition is epilepsy.

875. The method of embodiment 852, wherein the condition is a stress

disorder. .

876. The method of embodiment 852, wherein the condition is Parkinson's disease.

877. The method of embodiment 852, wherein the condition is central

sensitization.

878. The method of embodiment 852, wherein the condition is allodynia.

879. The method of embodiment 852, wherein the condition is fibromyalgia.

880. The method of embodiment 852, wherein the condition is rheumatoid arthritis.

881. The method of embodiment 852, wherein the condition is pain.

882. The method of embodiment 852, wherein the condition is psychic pain.

883. The method of embodiment 852, wherein the condition is

psychological pain.

884. The method of embodiment 852, wherein the condition is psychiatric pain.

885. The method of embodiment 852, wherein the condition is phantom

limb pain.

886. The method of embodiment 852, wherein the condition is opioid- induced constipation. 887. The method of embodiment 852, wherein the condition is an opioid withdrawal symptom.

888. The method of any one of embodiments 852-887, wherein the

pharmaceutical composition is administered simultaneously, sequentially, or separately with one or more substances selected from the group consisting of acetaminophen, a non-steroidal anti-inflammatory drug ( SAID), ibuprofen, naprosyn, a cyclooxygenase-2 inhibitor, aspirin, caffeine, dichloralphenazone, a triptan, an antidepressant, a serotonin-norepinephrine reuptake inhibitor (SNRI), and a gabapentinoid.

889. The method of any one of embodiments 852-887, wherein the

890. The method of any one of embodiments 852-887, wherein the

pharmaceutical composition is administered simultaneously, sequentially, or separately with one or more opiates.

891 . Use of a compound of any one of embodiments 1-644, or a mixture thereof, for the manufacture of a medicament for treating or preventing one or more conditions selected from the group consisting of: pain; an inflammatory disease or disorder, an allergic disease or disorder, a metabolic disease, a cardiovascular disease or disorder, a neurogenic vascular disease or a painful condition associated with any of the foregoing conditions; an episodic tension- type headache; a migraine headache; a headache; cramping; a cognitive disorder; a tension or migraine headache due to a vascular, neurovascular, or neurogenic disorder or dysfunction during a menstrual cycle episode; a tension or migraine headache due to a vascular, neurovascular, or neurogenic disorder or dysfunction during a migraine episode; a headache from mild to moderate hypertension; mild to moderate essential hypertension; organ transplant rejection; hot and cold flashes; traumatic brain injury (TBI); neurotoxicity; psychic pain; psychological pain; psychiatric pain; depression; schizophrenia; anxiety; epilepsy; a stress disorder; excess sweating; a symptom related to drug withdrawal; allodynia; fibromyalgia; fibromyalgia-ness; central sensitization; centralization; regional pain syndrome; temporomandibular joint syndrome (TMJ); lower back pain; interstitial cystitis; Gulf War syndrome; visceral pain; kidney stones; gout; neuropathic pain; post-herpetic neuralgia; diabetic neuropathy; sickle cell pain; priapism; nociceptive pain; post-operative pain; orthopedic injury pain; phantom limb pain; bunionectomy; dental extraction; pain after severed spinal cord injury; osteoarthritis; rheumatoid arthritis; Lyme disease; Parkinson's disease; pain associated with cancer; opioid-induced constipation; an opioid withdrawal symptom; and pain associated with posttraumatic stress disorder (PTSD).

892. The use of embodiment 891, wherein the condition is a headache.

893. The use of embodiment 891, wherein the condition is an episodic

tension-type headache.

894. The use of embodiment 891, wherein the condition is a migraine

headache.

895. The use of embodiment 891, wherein the condition is cramping.

896. The use of embodiment 891, wherein the condition is a cognitive

disorder.

897. The use of embodiment 891, wherein the condition is a tension or migraine headache due to a vascular, neurovascular, or neurogenic disorder or dysfunction during a migraine episode.

898. The use of embodiment 891, wherein the condition is a tension or migraine headache due to a vascular, neurovascular, or neurogenic disorder or dysfunction during a menstrual cycle episode. 899. The use of embodiment 891, wherein the condition is a headache from mild to moderate hypertension.

900. The use of embodiment 891, wherein the condition is mild to moderate essential hypertension.

901. The use of embodiment 891, wherein the condition is nociceptive pain.

902. The use of embodiment 891, wherein the condition is an inflammatory disease or disorder or a painful condition associated therewith.

903. The use of embodiment 891, wherein the condition is an. allergic

disease or disorder or a painful condition associated therewith.

904. The use of embodiment 891, wherein the condition is a metabolic

disease or a painful condition associated therewith.

905. The use of embodiment 891, wherein the condition is a cardiovascular disease or disorder or a painful condition associated therewith.

906. The use of embodiment 891, wherein the condition is a neurogenic vascular disease or a painful condition associated therewith.

907. The use of embodiment 891, wherein the condition is neuropathic pain.

908. The use of embodiment 891, wherein the condition is visceral pain.

909. The use of embodiment 891, wherein the condition is neurotoxicity.

910. The use of embodiment 891, wherein the condition is depression.

91 1. The use of embodiment 891, wherein the condition is schizophrenia.

912. The use of embodiment 891, wherein the condition is anxiety.

913. The use of embodiment 891, wherein the condition is epilepsy.

914. The use of embodiment 891, wherein the condition is a stress disorder.

915. The use of embodiment 891, wherein the condition is Parkinson's disease.

916. The use of embodiment 891, wherein the condition is central

sensitization.

917. The use of embodiment 891, wherein the condition is allodynia.

918. The use of embodiment 891, wherein the condition is fibromyalgia. 919. The use of embodiment 891, wherein the condition is rheumatoid arthritis.

920. The use of embodiment 891, wherein the condition is pain.

921 . The use of embodiment 891, wherein the condition is psychic pain.

922. The use of embodiment 891, wherein the condition is psychological pain.

923. The use of embodiment 891, wherein the condition is psychiatric pain.

924. The use of embodiment 891, wherein the condition is phantom limb pain.

925. The use of embodiment 891, wherein the condition is opioid-induced constipation.

926. The use of embodiment 891, wherein the condition is an opioid

withdrawal symptom.

927. The use of any one of embodiments 891-926, wherein the medicament is administered simultaneously, separately, or sequentially with one or more substances selected from the group consisting of acetaminophen, a nonsteroidal anti-inflammatory drug (NSA1D), ibuprofen, naprosyn, a

cyclooxygenase-2 inhibitor, aspirin, caffeine, dichloralphenazone, a triptan, an antidepressant, a serotonin-norepinephrine reuptake inhibitor (SNR1), and a gabapentinoid.

928. The use of any one of embodiments 891-926, wherein the medicament is administered simultaneously, separately, or sequentially with one or more additional therapeutics selected from the group consisting of a

chemotherapeutic drug, an antiproliferative agent, an anti-inflammatory agent, a corticosteroid, an anti-asthmatic agent, an anti-allergic agent, an

930. Use of a compound having the formula 1, 54-92, 95, 97, 98, 203-208, 210, 211, 315-317, 355-357, or 375, or a mixture thereof, or a

pharmaceutically acceptable salt, free base form, enantiomer, disastereomer, tautomer, solvate, or prodrug, or a mixture thereof, of any of the foregoing compounds, for the manufacture of a medicament for treating or preventing one or more conditions selected from the group consisting of: pain; an inflammatory disease or disorder, an allergic disease or disorder, a metabolic disease, a cardiovascular disease or disorder, a neurogenic vascular disease or a painful condition associated with any of the foregoing conditions; an episodic tension-type headache; a migraine headache; a headache; cramping; a cognitive disorder; a tension or migraine headache due to a vascular, neurovascular, or neurogenic disorder or dysfunction during a menstrual cycle episode; a tension or migraine headache due to a vascular, neurovascular, or neurogenic disorder or dysfunction during a migraine episode; a headache from mild to moderate hypertension; mild to moderate essential hypertension; organ transplant rejection; hot and cold flashes; traumatic brain injury (TBI); neurotoxicity; psychic pain; psychological pain; psychiatric pain; depression; schizophrenia; anxiety; epilepsy; a stress disorder; excess sweating; a symptom related to drug withdrawal; allodynia; fibromyalgia; fibromyalgia-ness; central sensitization; centralization; regional pain syndrome; temporomandibular joint syndrome (TMJ); lower back pain; interstitial cystitis; Gulf War syndrome; visceral pain; kidney stones; gout; neuropathic pain; post-herpetic neuralgia; diabetic neuropathy; sickle cell pain; priapism; nociceptive pain; postoperative pain; orthopedic injury pain; phantom limb pain; bunionectomy; dental extraction; pain after severed spinal cord injury; osteoarthritis;

rheumatoid arthritis; Lyme disease; Parkinson's disease; pain associated with cancer; opioid-induced constipation; an opioid withdrawal symptom; and pain associated with post-traumatic stress disorder (PTSD).

931 . The use of embodiment 930, wherein the condition is a headache.

932. The use of embodiment 930, wherein the condition is an episodic

tension-type headache.

933. The use of embodiment 930, wherein the condition is a migraine

headache.

934. The use of embodiment 930, wherein the condition is cramping.

935. The use of embodiment 930, wherein the condition is a cognitive

disorder.

936. The use of embodiment 930, wherein the condition is a tension or migraine headache due to a vascular, neurovascular, or neurogenic disorder or dysfunction during a migraine episode.

937. The use of embodiment 930, wherein the condition is a tension or migraine headache due to a vascular, neurovascular, or neurogenic disorder or dysfunction during a menstrual cycle episode.

938. The use of embodiment 930, wherein the condition is a headache from mild to moderate hypertension.

939. The use of embodiment 930, wherein the condition is mild to moderate essential hypertension.

940. The use of embodiment 930, wherein the condition is nociceptive pain.

941. The use of embodiment 930, wherein the condition is an inflammatory disease or disorder or a painful condition associated therewith.

942. The use of embodiment 930, wherein the condition is an allergic

disease or disorder or a painful condition associated therewith.

943. The use of embodiment 930, wherein the condition is a metabolic disease or a painful condition associated therewith.

944. The use of embodiment 930, wherein the condition is a cardiovascular disease or disorder or a painful condition associated therewith. 945. The use of embodiment 930, wherein the condition is a neurogenic vascular disease or a painful condition associated therewith.

946. The use of embodiment 930, wherein the condition is neuropathic pain.

947. The use of embodiment 930, wherein the condition is visceral pain.

948. The use of embodiment 930, wherein the condition is neurotoxicity.

949. The use of embodiment 930, wherein the condition is depression.

950. The use of embodiment 930, wherein the condition is schizophrenia.

951. The use of embodiment 930, wherein the condition is anxiety.

952. The use of embodiment 930, wherein the condition is epilepsy.

953. The use of embodiment 930, wherein the condition is a stress disorder.

954. The use of embodiment 930, wherein the condition is Parkinson's disease.

955. The use of embodiment 930, wherein the condition is central

sensitization.

956. The use of embodiment 930, wherein the condition is allodynia.

957. The use of embodiment 930, wherein the condition is fibromyalgia.

958. The use of embodiment 930, wherein the condition is rheumatoid

arthritis.

959. The use of embodiment 930, wherein the condition is pain.

960. The use of embodiment 930, wherein the condition is psychic pain.

961 . The use of embodiment 930, wherein the condition is psychological pain.

962. The use of embodiment 930, wherein the condition is psychiatric pain.

963. The use of embodiment 930, wherein the condition is phantom limb pain.

964. The use of embodiment 930, wherein the condition is opioid-induced constipation.

965. The use of embodiment 930, wherein the condition is an opioid

withdrawal symptom. 966. The use of any one of embodiments 930-965, wherein the medicament is administered simultaneously, separately, or sequentially with one or more substances selected from the group consisting of acetaminophen, a nonsteroidal anti-inflammatory drug (NSAID), ibuprofen, naprosyn, a

cyclooxygenase-2 inhibitor, aspirin, caffeine, dichloralphenazone, a triptan, an antidepressant, a serotonin-norepinephrine reuptake inhibitor (SNRI), and a gabapentinoid.

967. The use of any one of embodiments 930-965, wherein the medicament is administered simultaneously, separately, or sequentially with one or more additional therapeutics selected from the group consisting of a

chemotherapeutic drug, an antiproliferative agent, an anti-inflammatory agent, a corticosteroid, an anti-asthmatic agent, an anti-allergic agent, an

968. The use of any one of embodiments 930-965, wherein the medicament is administered simultaneously, separately, or sequentially with one or more opiates.

969. Use of a compound having the formula 63, 66, 67, 72, 74, 83, 84, 90, 95, 218, 315-317, 355-357, or 375, or a mixture thereof, or a pharmaceutically acceptable salt, free base form, enantiomer, disastereomer, tautomer, solvate, or prodrug, or a mixture thereof, of any of the foregoing compounds, for the manufacture of a medicament for treating or preventing one or more conditions selected from the group consisting of: pain; an inflammatory disease or disorder, an allergic disease or disorder, a metabolic disease, a cardiovascular disease or disorder, a neurogenic vascular disease or a painful condition associated with any of the foregoing conditions; an episodic tension-type headache; a migraine headache; a headache; cramping; a cognitive disorder; a tension or migraine headache due to a vascular, neurovascular, or neurogenic disorder or dysfunction during a menstrual cycle episode; a tension or migraine headache due to a vascular, neurovascular, or neurogenic disorder or dysfunction during a migraine episode; a headache from mild to moderate hypertension; mild to moderate essential hypertension; organ transplant rejection; hot and cold flashes; traumatic brain injury (TBI); neurotoxicity; psychic pain; psychological pain; psychiatric pain; depression; schizophrenia; anxiety; epilepsy; a stress disorder; excess sweating; a symptom related to drug withdrawal; allodynia; fibromyalgia; fibromyalgia-ness; central sensitization; centralization; regional pain syndrome; temporomandibular joint syndrome (TMJ); lower back pain; interstitial cystitis; Gulf War syndrome; visceral pain; kidney stones; gout; neuropathic pain; post-herpetic neuralgia; diabetic neuropathy; sickle cell pain; priapism; nociceptive pain; post-operative pain; orthopedic injury pain; phantom limb pain; bunionectomy; dental extraction; pain after severed spinal cord injury; osteoarthritis; rheumatoid arthritis; Lyme disease; Parkinson's disease; pain associated with cancer; opioid-induced constipation; an opioid withdrawal symptom; and pain associated with posttraumatic stress disorder (PTSD).

970. The use of embodiment 969, wherein the condition is a headache.

971. The use of embodiment 969, wherein the condition is an episodic

tension-type headache.

972. The use of embodiment 969, wherein the condition is a migraine

headache.

973. The use of embodiment 969, wherein the condition is cramping.

974. The use of embodiment 969, wherein the condition is a cognitive

disorder.

975. The use of embodiment 969, wherein the condition is a tension or migraine headache due to a vascular, neurovascular, or neurogenic disorder or dysfunction during a migraine episode. 976. The use of embodiment 969, wherein the condition is a tension or migraine headache due to a vascular, neurovascular, or neurogenic disorder or dysfunction during a menstrual cycle episode.

977. The use of embodiment 969, wherein the condition is a headache from mild to moderate hypertension.

978. The use of embodiment 969, wherein the condition is mild to moderate essential hypertension.

979. The use of embodiment 969, wherein the condition is nociceptive pain.

980. The use of embodiment 969, wherein the condition is an inflammatory disease or disorder or a painful condition associated therewith.

981. The use of embodiment 969, wherein the condition is an allergic

disease or disorder or a painful condition associated therewith.

982. The use of embodiment 969, wherein the condition is a metabolic

disease or a painful condition associated therewith.

983. The use of embodiment 969, wherein the condition is a cardiovascular disease or disorder or a painful condition associated therewith.

984. The use of embodiment 969, wherein the condition is a neurogenic vascular disease or a painful condition associated therewith.

985. The use of embodiment 969, wherein the condition is neuropathic pain.

986.. The use of embodiment 969, wherein the condition is visceral pain.

987. The use of embodiment 969, wherein the condition is neurotoxicity.

988. The use of embodiment 969, wherein the condition is depression.

989. The use of embodiment 969, wherein the condition is schizophrenia.

990. The use of embodiment 969, wherein the condition is anxiety.

991 . The use of embodiment 969, wherein the condition is epilepsy.

992. The use of embodiment 969, wherein the condition is a stress disorder.

993. The use of embodiment 969, wherein the condition is Parkinson's disease.

994. The use of embodiment 969, wherein the condition is central

sensitization. 995. The use of embodiment 969, wherein the condition is allodynia.

996. The use of embodiment 969, wherein the condition is fibromyalgia.

997. The use of embodiment 969, wherein the condition is rheumatoid

arthritis.

998. The use of embodiment 969, wherein the condition is pain.

999. The use of embodiment 969, wherein the condition is psychic pain.

1000. The use of embodiment 969, wherein the condition is psychological pain.

1001. The use of embodiment 969, wherein the condition is psychiatric pain.

1002. The use of embodiment 969, wherein the condition is phantom limb pain.

1003. The use of embodiment 969, wherein the condition is opioid-induced constipation.

1004. The use of embodiment 969, wherein the condition is an opioid

withdrawal symptom.

1005. The use of any one of embodiments 969-1004, wherein the medicament is administered simultaneously, separately, or sequentially with one or more substances selected from the group consisting of acetaminophen, a nonsteroidal anti-inflammatory drug (NSAID), ibuprofen, naprosyn, a

cyclooxygenase-2 inhibitor, aspirin, caffeine, dichloraiphenazone, a triptan, an antidepressant, a serotonin-norepinephrine reuptake inhibitor (SNRI), and a gabapentinoid.

1006. The use of any one of embodiments 969-1004, wherein the medicament is administered simultaneously, separately, or sequentially with one or more additional therapeutics selected from the group consisting of a

chemotherapeutic drug, an antiproliferative agent, an anti-inflammatory agent, a corticosteroid, an anti-asthmatic agent, an anti-allergic agent, an

1007. The use of any one of embodiments 969-1004, wherein the medicament is administered simultaneously, separately, or sequentially with one or more opiates.

1008. A compound of any one of embodiments 1-644, or a mixture thereof, for use in treating or preventing one or more conditions selected from the group consisting of: pain; an inflammatory disease or disorder, an allergic disease or disorder, a metabolic disease, a cardiovascular disease or disorder, a neurogenic vascular disease or a _^painful condition associated with any of the foregoing conditions; an episodic tension-type headache; a migraine headache; a headache; cramping; a cognitive disorder; a tension or migraine headache due to a vascular, neurovascular, or neurogenic disorder or dysfunction during a menstrual cycle episode; a tension or migraine headache due to a vascular, neurovascular, or neurogenic disorder or dysfunction during a migraine episode; a headache from mild to moderate hypertension; mild to moderate essential hypertension; organ transplant rejection; hot and cold flashes;

phantom limb pain; bunionectomy; dental extraction; pain after severed spinal cord injury; osteoarthritis; rheumatoid arthritis; Lyme disease; Parkinson's disease; pain associated with cancer; opioid-induced constipation; an opioid withdrawal symptom; and pain associated with post-traumatic stress disorder (PTSD). 1009. The compound of embodiment 1008, wherein the condition is a headache.

1010. The compound of embodiment 1008, wherein the condition is an

episodic tension-type headache.

101 1 . The compound of embodiment 1008, wherein the condition is a

migraine headache.

1012. The compound of embodiment 1008, wherein the condition is

cramping.

1013. The compound of embodiment 1008, wherein the condition is a

cognitive disorder.

1014. The compound of embodiment 1008, wherein the condition is a tension or migraine headache due to a vascular, neurovascular, or neurogenic djsorder or dysfunction during a migraine episode.

1015. The compound of embodiment 1008, wherein the condition is a tension or migraine headache due to a vascular, neurovascular, or neurogenic disorder or dysfunction during a menstrual cycle episode.

1016. The compound of embodiment 1008, wherein the condition is a

headache from mild to moderate hypertension.

1017. The compound of embodiment 1008, wherein the condition is mild to moderate essential hypertension.

1018. The compound of embodiment 1008, wherein the condition is

nociceptive pain.

1019. The compound of embodiment 1008, wherein the condition is an

inflammatory disease or disorder or a painful condition associated therewith.

1020. The compound of embodiment 1008, wherein the condition is an

allergic disease or disorder or a painful condition associated therewith.

1021 . The compound of embodiment 1008, wherein the condition is a

metabolic disease or a painful condition associated therewith.

1022. The compound of embodiment 1008, wherein the condition is a

cardiovascular disease or disorder or a painful condition associated therewith. 1023. The compound of embodiment 1008, wherein the condition is a neurogenic vascular disease or a painful condition associated therewith.

1024. The compound of embodiment 1008, wherein the condition is

neuropathic pain.

1025. The compound of embodiment 1008, wherein the condition is visceral pain.

1026. The compound of embodiment 1008, wherein the condition is

neurotoxicity.

1027. The compound of embodiment 1008, wherein the condition is

depression.

1028. The compound of embodiment 1008, wherein the condition is

schizophrenia.

1029. The compound of embodiment 1008, wherein the condition is anxiety.

1030. The compound of embodiment 1008, wherein the condition is epilepsy.

1031. The compound of embodiment 1008, wherein the condition is a stress disorder.

1032. The compound of embodiment 1008, wherein the condition is

Parkinson's disease.

1033. The compound of embodiment 1008, wherein the condition is central sensitization.

1034. The compound of embodiment 1008, wherein the condition is

allodynia.

1035. The compound of embodiment 1008, wherein the condition is

fibromyalgia,.

1036. The compound of embodiment 1008, wherein the condition is

rheumatoid arthritis.

1037. The compound of embodiment 1008, wherein the condition is pain.

1038. The compound of embodiment 1008, wherein the condition is psychic pain. 1039. The compound of embodiment 1008, wherein the condition is psychological pain.

1040. The compound of embodiment 1008, wherein the condition is

psychiatric pain.

1041. The compound of embodiment 1008, wherein the condition is phantom limb pain.

1042. The compound of embodiment 1008, wherein the condition is opioid- induced constipation.

1043. The compound of embodiment 1008, wherein the condition is an opioid withdrawal symptom.

1044. The compound of any one of embodiments 1008-1043, wherein the compound is used simultaneously, sequentially, or separately with one or more substances selected from the group consisting of acetaminophen, a nonsteroidal anti-inflammatory drug (NSAID), ibuprofen, naprosyn, a

cyclooxygenase-2 inhibitor, aspirin, caffeine, dichloralphenazone, a triptan, an antidepressant, a serotonin-norepinephrine reuptake inhibitor (SNRI), and a gabapentinoid.

1045. The compound of any one of embodiments 1008-1043, wherein the compound is used simultaneously, sequentially, or separately with one or more additional therapeutics selected from the group consisting of a

chemotherapeutic drug, an antiproliferative agent, an anti-inflammatory agent, a corticosteroid, an anti-asthmatic agent, an anti-allergic agent, an

1046. The compound of any one of embodiments 1008-1043, wherein the compound is used simultaneously, sequentially, or separately with one or more opiates. 1047. A compound having the formula 1, 54-92, 95, 97, 98, 203-208, 210, 211, 315-317, 355-357, or 375, or a mixture thereof, or a pharmaceutically acceptable salt, free base form, enantiomer, disastereomer, tautomer, solvate, or prodrug of any of the foregoing compounds, for use in treating or preventing one or more conditions selected from the group consisting of: pain; an inflammatory disease or disorder, an allergic disease or disorder, a metabolic disease, a cardiovascular disease or disorder, a neurogenic vascular disease or a painful condition associated with any of the foregoing conditions; an episodic tension-type headache; a migraine headache; a headache; cramping; a cognitive disorder; a tension or migraine headache due to a vascular, neurovascular, or neurogenic disorder or dysfunction during a menstrual cycle episode; a tension or migraine headache due to a vascular, neurovascular, or neurogenic disorder or dysfunction during a migraine episode; a headache from mild to moderate hypertension; mild to moderate essential hypertension; organ transplant rejection; hot and cold flashes; traumatic brain injury (TBI); neurotoxicity; psychic pain; psychological pain; psychiatric pain; depression; schizophrenia; anxiety; epilepsy; a stress disorder; excess sweating; a symptom related to drug withdrawal; allodynia; fibromyalgia; fibromyalgia-ness; central sensitization; centralization; regional pain syndrome; temporomandibular joint syndrome (TMJ); lower back pain; interstitial cystitis; Gulf War syndrome; visceral pain; kidney stones; gout; neuropathic pain; post-herpetic neuralgia; diabetic neuropathy; sickle cell pain; priapism; nociceptive pain; postoperative pain; orthopedic injury pain; phantom limb pain; bunionectomy; dental extraction; pain after severed spinal cord injury; osteoarthritis;

1048. The compound of embodiment 1047, wherein the condition is a

headache. 1049. The compound of embodiment 1047, wherein the condition is an episodic tension-type headache.

1050. The compound of embodiment 1047, wherein the condition is a

migraine headache.

1051. The compound of embodiment 1047, wherein the condition is

cramping.

1052. The compound of embodiment 1047, wherein the condition is a

cognitive disorder.

1053. The compound of embodiment 1047, wherein the condition is a tension or migraine headache due to a vascular, neurovascular, or neurogenic disorder or dysfunction during a migraine episode.

1054. The compound of embodiment 1047, wherein the condition is a tension or migraine headache due to a vascular, neurovascular, or neurogenic disorder or dysfunction during a menstrual cycle episode.

1055. The compound of embodiment 1047, wherein the condition is a

headache from mild to moderate hypertension.

1056. The compound of embodiment 1047, wherein the condition is mild to moderate essential hypertension.

1057. The compound of embodiment 1047, wherein the condition is

nociceptive pain.

1058. The compound of embodiment 1047, wherein the condition is an

inflammatory disease or disorder or a painful condition associated therewith.

1059. The compound of embodiment 1047, wherein the condition is an

allergic disease or disorder or a painful condition associated therewith.

1060. The compound of embodiment 1047, wherein the condition is a

metabolic disease or a painful condition associated therewith.

1061. The compound of embodiment 1047, wherein the condition is a

cardiovascular disease or disorder or a painful condition associated therewith.

1062. The compound of embodiment 1047, wherein the condition is a

neurogenic vascular disease or a painful condition associated therewith. 1063. The compound of embodiment 1047, wherein the condition is neuropathic pain.

1064. The compound of embodiment 1047, wherein the condition is visceral pain.

1065. The compound of embodiment 1047, wherein the condition is

neurotoxicity.

1066. The compound of embodiment 1047, wherein the condition is

depression.

1067. The compound of embodiment 1047, wherein the condition is

schizophrenia.

1068. The compound of embodiment 1047, wherein the condition is anxiety.

1069. The compound of embodiment 1047, wherein the condition is epilepsy.

1070. The compound of embodiment 1047, wherein the condition is a stress disorder.

1071 . The compound of embodiment 1047, wherein the condition is

Parkinson's disease.

1072. The compound of embodiment 1047, wherein the condition is central sensitization.

1073. The compound of embodiment 1047, wherein the condition is

allodynia.

1074. The compound of embodiment 1047, wherein the condition is

fibromyalgia.

1075. The compound of embodiment 1047, wherein the condition is

rheumatoid arthritis.

1076. The compound of embodiment 1047, wherein the condition is pain.

1077. The compound of embodiment 1047, wherein the condition is psychic pain.

1078. The compound of embodiment 1047, wherein the condition is

psychological pain. 1079. The compound of embodiment 1047, wherein the condition is psychiatric pain.

1080. The compound of embodiment 1047, wherein the condition is phantom limb pain.

1081. The compound of embodiment 1047, wherein the condition is opioid- induced constipation.

1082. The compound of embodiment 1047, wherein the condition is an opioid withdrawal symptom.

1083. The compound of any one of embodiments 1047-1082, wherein the

^> compound is used simultaneously, sequentially, or separately with one or more substances selected from the group consisting of acetaminophen, a nonsteroidal anti-inflammatory drug (NSAID), ibuprofen, naprosyn, a

cyclooxygenase-2 inhibitor, aspirin, caffeine, dichloralphenazone, a triptan, an antidepressant, a serotonin-norepinephrine reuptake inhibitor (SNR1), and a gabapentinoid.

1084. The compound of any one of embodiments 1047-1082, wherein the compound is used simultaneously, sequentially, or separately with one or more additional therapeutics selected from the group consisting of a

chemotherapeutic drug, an antiproliferative agent, an anti-inflammatory agent, a corticosteroid, an anti-asthmatic agent, an anti-allergic agent, an

1085. The compound of any one of embodiments 1047-1082, wherein the compound is used simultaneously, sequentially, or separately with one or more opiates.

1086. A compound having the formula 63, 66, 67, 72, 74, 83, 84, 90, 95, 218, 315-317, 355-357, or 375, or a mixture thereof, or a pharmaceutically acceptable salt, free base form, enantiomer, disastereomer, tautomer, solvate, or prodrug, or a mixture thereof, of any of the foregoing compounds, for use in treating or preventing one or more conditions selected from the group consisting of: pain; an inflammatory disease or disorder, an allergic disease or disorder, a metabolic disease, a cardiovascular disease or disorder, a neurogenic vascular disease or a painful condition associated with any of the foregoing conditions; an episodic tension-type headache; a migraine headache; a headache; cramping; a cognitive disorder; a tension or migraine headache due to a vascular, neurovascular, or neurogenic disorder or dysfunction during a menstrual cycle episode; a tension or migraine headache due to a vascular, neurovascular, or neurogenic disorder or dysfunction during a migraine episode; a headache from mild to moderate hypertension; mild to moderate essential hypertension; organ transplant rejection; hot and cold flashes;

1087. The compound of embodiment 1086, wherein the condition is a

headache.

1088. The compound of embodiment 1086, wherein the condition is an

episodic tension-type headache. 1089. The compound of embodiment 1086, wherein the condition is a migraine headache.

1090. The compound of embodiment 1086, wherein the condition is

cramping.

1091. The compound of embodiment 1086, wherein the condition is a

cognitive disorder.

1092. The compound of embodiment 1086, wherein the condition is a tension or migraine headache due to a vascular, neurovascular, or neurogenic disorder or dysfunction during a migraine episode.

1093. The compound of embodiment 1086, wherein the condition is a tension or migraine headache due to a vascular, neurovascular, or neurogenic disorder or dysfunction during a menstrual cycle episode.

1094. The compound of embodiment 1086, wherein the condition is a

headache from mild to moderate hypertension.

1095. The compound of embodiment 1086, wherein the condition is mild to moderate essential hypertension.

1096. The compound of embodiment 1086, wherein the condition is

nociceptive pain.

1097. The compound of embodiment 1086, wherein the condition is an

inflammatory disease or disorder or a painful condition associated therewith.

1098. The compound of embodiment 1086, wherein the condition is an

allergic disease or disorder or a painful condition associated therewith.

1099. The compound of embodiment 1086, wherein the condition is a

metabolic disease or a painful condition associated therewith.

1 100. The compound of embodiment 1086, wherein the condition is a

cardiovascular disease or disorder or a painful condition associated therewith.

1 101 . The compound of embodiment 1086, wherein the condition is a

neurogenic vascular disease or a painful condition associated therewith.

1 102. The compound of embodiment 1086, wherein the condition is

neuropathic pain. 1 103. The compound of embodiment 1086, wherein the condition is visceral pain.

1 104. The compound of embodiment 1086, wherein the condition is

neurotoxicity.

1 105. The compound of embodiment 1086, wherein the condition is

depression.

1 106. The compound of embodiment 1086, wherein the condition is

schizophrenia.

1 107. The compound of embodiment 1086, wherein the condition is anxiety.

1 108. The compound of embodiment 1086, wherein the condition is epilepsy.

1 109. The compound of embodiment 1086, wherein the condition is a stress disorder.

1 1 10. The compound of embodiment 1086, wherein the condition is

Parkinson's disease.

1 1 1 1. The compound of embodiment 1086, wherein the condition is central sensitization.

1 1 12. The compound of embodiment 1086, wherein the condition is

allodynia.

1 1 13. The compound of embodiment 1086, wherein the condition is

fibromyalgia.

1 1 14. The compound of embodiment 1086, wherein the condition is

rheumatoid arthritis.

1 1 15. The compound of embodiment 1086, wherein the condition is pain.

1 1 16. The compound of embodiment 1086, wherein the condition is psychic pain. ^

1 1 17. The compound of embodiment 1086, wherein the condition is

psychological pain.

1 1 18. The compound of embodiment 1086, wherein the condition is

psychiatric pain. 1 1 19. The compound of embodiment 1086, wherein the condition is phantom limb pain.

1 120. The compound of embodiment 1086, wherein the condition is opioid- induced constipation.

1 121. The compound of embodiment 1086, wherein the condition is an opioid withdrawal symptom.

1 122. The compound of any one of embodiments 1086-1121, wherein the compound is used simultaneously, sequentially, or separately with one or more substances selected from the group consisting of acetaminophen, a nonsteroidal anti-inflammatory drug (NSAID), ibuprofen, naprosyn, a

cyclooxygenase-2 inhibitor, aspirin, caffeine, dichloralphenazone, a triptan, an antidepressant, a serotonin-norepinephrine reuptake inhibitor (SNRI), and a gabapentinoid.

1 123. The compound of any one of embodiments 1086-1121, wherein the compound is used simultaneously, sequentially, or separately with one or more additional therapeutics selected from the group consisting of a

chemotherapeutic drug, an antiproliferative agent, an anti-inflammatory agent, a corticosteroid, an anti-asthmatic agent, an anti-allergic agent, an

1 124. The compound of any one of embodiments 1086-1121, wherein the compound is used simultaneously, sequentially, or separately with one or more opiates.

1 125. A method of modulating an imidazoline- 1 (Ii) receptor, comprising contacting the I | receptor with a compound of any one of embodiments 1-644, or a mixture thereof.

1 126. A method of modulating an imidazoline- 1 (I ]) receptor, comprising contacting the Ii receptor with a compound having the formula 1, 54-92, 95, 97, 98, 203-208, 210, 211, 315-317, 355-357, or 375, or a mixture thereof, or a pharmaceutically acceptable salt, free base form, enantiomer, disastereomer, tautomer, solvate, or prodrug, or a mixture thereof, of any of the foregoing compounds.

1 127. A method of modulating an imidazoline- 1 (I i) receptor, comprising contacting the l _\ receptor with a compound having the formula 63, 66, 67, 72, 74, 83, 84, 90, 95, 218, 315-317, 355-357, or 375, or a mixture thereof, or a pharmaceutically acceptable salt, free base form, enantiomer, disastereomer, tautomer, solvate, or prodrug, or a mixture thereof, of any of the foregoing compounds.

1 128. A method of modulating an imidazoline- 1 (Ii) receptor, comprising contacting the Ii receptor with a pharmaceutical composition of any one of embodiments 648, 651, or 654.

1 129. A method of modulating an imidazoline-1 (I]) receptor in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of a compound of any one of embodiments 1-644, or a mixture thereof.

1 130. A method of modulating an imidazoline-1 (I |) receptor in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of a compound having the formula 1, 54-92, 95, 97, 98, 203- 208, 210, 211, 315-317, 355-357, or 375, or a mixture thereof, or a pharmaceutically acceptable salt, free base form, enantiomer, disastereomer, tautomer, solvate, or prodrug, or a mixture thereof, of any of the foregoing compounds.

1 131 . A method of modulating an imidazoline- 1 (I i) receptor in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of a compound having the formula 63, 66, 67, 72, 74, 83, 84, 90, 95, 218, 315-317, 355-357, or 375, or a mixture thereof, or a

pharmaceutically acceptable salt, free base form, enantiomer, disastereomer, tautomer, solvate, or prodrug, or a mixture thereof, of any of the foregoing compounds.

1 132. A method of modulating an imidazoline- 1 (I|) receptor in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of a pharmaceutical composition of any one of embodiments 648, 651, or 654.

1 133. A method for nitric oxidase inhibition in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of a compound of any one of embodiments 1-644, or a mixture thereof,

simultaneously, sequentially, or separately in combination with one or more substances selected from the group consisting of acetaminophen, a nonsteroidal anti-inflammatory drug (NSAID), ibuprofen, naprosyn, a

cyclooxygenase-2 inhibitor, aspirin, caffeine, dichloralphenazone, a triptan, an antidepressant, a serotonin-norepinephrine reuptake inhibitor (SNRI), a gabapentinoid, a chemotherapeutic drug, an antiproliferative agent, an antiinflammatory agent, a corticosteroid, an anti-asthmatic agent, an anti-allergic agent, an immunosuppressive agent, an immunomodulatory agent, a cardiovascular disease treatment agent, an anti-diabetic agent, a blood disorder treatment agent, a nerve growth factor receptor antagonist, a sodium channel blocker, a CYP2D6 inhibitor, a TNF-alpha inhibitor, and an opiate.

1 134. A method for nitric oxidase inhibition in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of a compound having the formula 1, 54-92, 95, 97, 98, 203-208, 210, 211 , 315- 317, 355-357, or 375, or a mixture thereof, or a pharmaceutically acceptable salt, free base form, enantiomer, disastereomer, tautomer, solvate, or prodrug, or a mixture thereof, of any of the foregoing compounds, simultaneously, sequentially, or separately in combination with one or more substances selected from the group consisting of acetaminophen, a non-steroidal antiinflammatory drug (NSAID), ibuprofen, naprosyn, a cyclooxygenase-2 inhibitor, aspirin, caffeine, dichloralphenazone, a triptan, an antidepressant, a serotonin-norepinephrine reuptake inhibitor (SNRI), a gabapentinoid, a chemotherapeutic drug, an antiproliferative agent, an anti-inflammatory agent, a corticosteroid, an anti-asthmatic agent, an anti-allergic agent, an

5. A method for nitric oxidase inhibition in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of a compound having the formula 63, 66, 67, 72, 74, 83, 84, 90, 95, 218, 315-317, 355-357, or 375, or a mixture thereof, or a pharmaceutically acceptable salt, free base form, enantiomer, disastereomer, tautomer, solvate, or prodrug, or a mixture thereof, of any of the foregoing compounds, simultaneously, sequentially, or separately in combination with one or more substances selected from the group consisting of acetaminophen, a non-steroidal antiinflammatory drug (NSAID), ibuprofen, naprosyn, a cyclooxygenase-2 inhibitor, aspirin, caffeine, dichloralphenazone, a triptan, an antidepressant, a serotonin-norepinephrine reuptake inhibitor (SNRI), a gabapentinoid, a chemotherapeutic drug, an antiproliferative agent, an anti-inflammatory agent, a corticosteroid, an anti-asthmatic agent, an anti-allergic agent, an

6. A method for nitric oxidase inhibition in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of a pharmaceutical composition of any one of embodiments 648, 651, or 654 simultaneously, sequentially, or separately in combination with one or more substances selected from the group consisting of acetaminophen, a nonsteroidal anti-inflammatory drug (NSAID), ibuprofen, naprosyn, a cyclooxygenase-2 inhibitor, aspirin, caffeine, dichloralphenazone, a triptan, an antidepressant, a serotonin-norepinephrine reuptake inhibitor (SNR1), a gabapentinoid, a chemotherapeutic drug, an antiproliferative agent, an antiinflammatory agent, a corticosteroid, an anti-asthmatic agent, an anti-allergic agent, an immunosuppressive agent, an immunomodulatory agent, a cardiovascular disease treatment agent, an anti-diabetic agent, a blood disorder treatment agent, a nerve growth factor receptor antagonist, a sodium channel blocker, a CYP2D6 inhibitor, a TNF-alpha inhibitor, and an opiate.

7. Use of a pharmaceutical composition of any one of embodiments 648, 651, or 654 for the manufacture of a medicament for treating or preventing one or more conditions selected from the group consisting of: pain; an

inflammatory disease or disorder, an allergic disease or disorder, a metabolic disease, a cardiovascular disease or disorder, a neurogenic vascular disease or a painful condition associated with any of the foregoing conditions; an episodic tension-type headache; a migraine headache; a headache; cramping; a cognitive disorder; a tension or migraine headache due to a vascular, neurovascular, or neurogenic disorder or dysfunction during a menstrual cycle episode; a tension or migraine headache due to a vascular, neurovascular, or neurogenic disorder or dysfunction during a migraine episode; a headache from mild to moderate hypertension; mild to moderate essential hypertension; organ transplant rejection; hot and cold flashes; traumatic brain injury (TBI); neurotoxicity; psychic pain; psychological pain; psychiatric pain; depression; schizophrenia; anxiety; epilepsy; a stress disorder; excess sweating; a symptom related to drug withdrawal; allodynia; fibromyalgia; fibromyalgia-ness; central sensitization; centralization; regional pain syndrome; temporomandibular joint syndrome (TMJ); lower back pain; interstitial cystitis; Gulf War syndrome; visceral pain; kidney stones; gout; neuropathic pain; post-herpetic neuralgia; diabetic neuropathy; sickle cell pain; priapism; nociceptive pain; postoperative pain; orthopedic injury pain; phantom limb pain; bunionectomy; dental extraction; pain after severed spinal cord injury; osteoarthritis; rheumatoid arthritis; Lyme disease; Parkinson's disease; pain associated with cancer; opioid-induced constipation; an opioid withdrawal symptom; and pain associated with post-traumatic stress disorder (PTSD).

1 138. The use of embodiment 1137, wherein the condition is a headache.

1 139. The use of embodiment 1137, wherein the condition is an episodic tension-type headache.

1 140. The use of embodiment 1137, wherein the condition is a migraine headache.

1 141. The use of embodiment 1137, wherein the condition is cramping.

1 142. The use of embodiment 1137, wherein the condition is a cognitive disorder.

1 143. The use of embodiment 1137, wherein the condition is a tension or migraine headache due to a vascular, neurovascular, or neurogenic disorder or dysfunction during a migraine episode.

1 144. The use of embodiment 1137, wherein the condition is a tension or migraine headache due to a vascular, neurovascular, or neurogenic disorder or dysfunction during a menstrual cycle episode.

1 145. The use of embodiment 1137, wherein the condition is a headache from mild to moderate hypertension.

1 146. The use of embodiment 1137, wherein the condition is mild to

moderate essential hypertension.

1 147. The use of embodiment 1137, wherein the condition is nociceptive pain.

1 148. The use of embodiment 1137, wherein the condition is an inflammatory disease or disorder or a painful condition associated therewith.

1 149. The use of embodiment 1137, wherein the condition is an allergic disease or disorder or a painful condition associated therewith.

1 150. The use of embodiment 1137, wherein the condition is a metabolic disease or a painful condition associated therewith. 1 151. The use of embodiment 1137, wherein the condition is a cardiovascular disease or disorder or a painful condition associated therewith.

1 152. The use of embodiment 1137, wherein the condition is a neurogenic vascular disease or a painful condition associated therewith.

1 153. The use of embodiment 1137, wherein the condition is neuropathic pain.

1 154. The use of embodiment 1137, wherein the condition is visceral pain.

1 155. The use of embodiment 1137, wherein the condition is neurotoxicity.

1 156. The use of embodiment 1137, wherein the condition is depression.

1 157. The use of embodiment 1137, wherein the condition is schizophrenia.

1 158. The use of embodiment 1137, wherein the condition is anxiety.

1 159. The use of embodiment 1137, wherein the condition is epilepsy.

1 160. The use of embodiment 1137, wherein the condition is a stress disorder.

1 161 . The use of embodiment 1137, wherein the condition is Parkinson's disease.

1 162. The use of embodiment 1137, wherein the condition is central

sensitization.

1 163. The use of embodiment 1137, wherein the condition is allodynia.

1 164. The use of embodiment 1137, wherein the condition is fibromyalgia.

1 165. The use of embodiment 1137, wherein the condition is rheumatoid arthritis.

1 166. The use of embodiment 1137, wherein the condition is pain.

1 167. The use of embodiment 1137, wherein the condition is psychic pain.

1 168. The use of embodiment 1137, wherein the condition is psychological pain.

1 169. The use of embodiment 1137, wherein the condition is psychiatric pain.

1 170. The use of embodiment 1137, wherein the condition is phantom limb pain.

1 171 . The use of embodiment 1137, wherein the condition is opioid-induced constipation. 1 172. . The use of embodiment 1137, wherein the condition is an opioid withdrawal symptom.

1 173. The use of any one of embodiments 1137-1172, wherein the

medicament is administered simultaneously, separately, or sequentially with one or more substances selected from the group consisting of acetaminophen, a non-steroidal anti-inflammatory drug (NSAID), ibuprofen, naprosyn, a cyclooxygenase-2 inhibitor, aspirin, caffeine, dichloralphenazone, a triptan, an antidepressant, a serotonin-norepinephrine reuptake inhibitor (SNR.I), and a gabapentinoid.

1 174. The use of any one of embodiments 1137-1172, wherein the

medicament is administered simultaneously, separately, or sequentially with one or more additional therapeutics selected from the group consisting of a chemotherapeutic drug, an antiproliferative agent, an anti-inflammatory agent, a corticosteroid, an anti-asthmatic agent, an anti-allergic agent, an

1 175. The use of any one of embodiments 1137-1172, wherein the

medicament is administered simultaneously, separately, or sequentially with one or more opiates.

1 176. The pharmaceutical composition of any one of embodiments 648, 651, or 654 for use in treating or preventing one or more conditions selected from the group consisting of: pain; an inflammatory disease or disorder, an allergic disease or disorder, a metabolic disease, a cardiovascular disease or disorder, a neurogenic vascular disease or a painful condition associated with any of the foregoing conditions; an episodic tension-type headache; a migraine headache; a headache; cramping; a cognitive disorder; a tension or migraine headache due to a vascular, neurovascular, or neurogenic disorder or dysfunction during a menstrual cycle episode; a tension or migraine headache due to a vascular, neurovascular, or neurogenic disorder or dysfunction during a migraine episode; a headache from mild to moderate hypertension; mild to moderate essential hypertension; organ transplant rejection; hot and cold flashes;

1 177. The pharmaceutical composition of embodiment 1176, wherein the condition is a headache.

1 178. The pharmaceutical composition of embodiment 1176, wherein the condition is an episodic tension-type headache.

1 179. The pharmaceutical composition of embodiment 1176, wherein the condition is a migraine headache.

1 180. . The pharmaceutical composition of embodiment 1176, wherein the condition is cramping.

1 181 . The pharmaceutical composition of embodiment 1176, wherein the condition is a cognitive disorder.

1 182. The pharmaceutical composition of embodiment 1176, wherein the condition is a tension or migraine headache due to a vascular, neurovascular, or neurogenic disorder or dysfunction during a migraine episode. 1 183. The pharmaceutical composition of embodiment 1176, wherein the condition is a tension or migraine headache due to a vascular, neurovascular, or neurogenic disorder or dysfunction during a menstrual cycle episode.

1 184. The pharmaceutical composition of embodiment 1176, wherein the condition is a headache from mild to moderate hypertension.

1 185. The pharmaceutical composition of embodiment 1176, wherein the condition is mild to moderate essential hypertension.

1 186. The pharmaceutical composition of embodiment 1176, wherein the condition is nociceptive pain.

1 187. The pharmaceutical composition of embodiment 1176, wherein the condition is an inflammatory disease or disorder or a painful condition associated therewith.

1 188. The pharmaceutical composition of embodiment 1176, wherein the condition is an allergic disease or disorder or a painful condition associated therewith.

.1 189. The pharmaceutical composition of embodiment 1176, wherein the condition is a metabolic disease or a painful condition associated therewith.

1 190. The pharmaceutical composition of embodiment 1176, wherein the condition is a cardiovascular disease or disorder or a painful condition associated therewith.

1 191 . The pharmaceutical composition of embodiment 1176, wherein the condition is a neurogenic vascular disease or a painful condition associated therewith. '

1 192. The pharmaceutical composition of embodiment 1176, wherein the condition is neuropathic pain.

1 193. The pharmaceutical composition of embodiment 1176, wherein the condition is visceral pain.

1 194. The pharmaceutical composition of embodiment 1176, wherein the condition is neurotoxicity. 1 195. The pharmaceutical composition of embodiment 1176, wherein the condition is depression.

1 196. The pharmaceutical composition of embodiment 1176, wherein the condition is schizophrenia.

1 197. The pharmaceutical composition of embodiment 1176, wherein the condition is anxiety.

1 198. The pharmaceutical composition of embodiment 1176, wherein the condition is epilepsy.

1 199. The pharmaceutical composition of embodiment 1176, wherein the condition is a stress disorder.

1200. The pharmaceutical composition of embodiment 1176, wherein the condition is Parkinson's disease.

1201 . The pharmaceutical composition of embodiment 1176, wherein the condition is central sensitization.

1202. The pharmaceutical composition of embodiment 1176, wherein the condition is allodynia.

1203. The pharmaceutical composition of embodiment 1176, wherein the condition is fibromyalgia.

1204. The pharmaceutical composition of embodiment 1176, wherein the condition is rheumatoid arthritis.

1205. The pharmaceutical composition of embodiment 1176, wherein the condition is pain.

1206. The pharmaceutical composition of embodiment 1176, wherein the condition is psychic pain.

1207. The pharmaceutical composition of embodiment 1176, wherein the condition is psychological pain.

1208. The pharmaceutical composition of embodiment 1176, wherein the condition is psychiatric pain.

1209. The pharmaceutical composition of embodiment 1176, wherein the condition is phantom limb pain. 1210. The pharmaceutical composition of embodiment 1176, wherein the condition is opioid-induced constipation.

121 1. The pharmaceutical composition of embodiment 1176, wherein the condition is an opioid withdrawal symptom.

1212. The pharmaceutical composition of any one of embodiments 1176- 1211, wherein the pharmaceutical composition is used simultaneously, separately, or sequentially with one or more substances selected from the group consisting of acetaminophen, a non-steroidal anti-inflammatory drug (NSAID), ibuprofen, naprosyn, a cyclooxygenase-2 inhibitor, aspirin, caffeine, dichloralphenazone, a triptan, an antidepressant, a serotonin-norepinephrine reuptake inhibitor (SNRI), and a gabapentinoid.

1213. The pharmaceutical composition of any one of embodiments 1176- 1211, wherein the pharmaceutical composition is used simultaneously, separately, or sequentially with one or more additional therapeutics selected from the group consisting of a chemotherapeutic drug, an antiproliferative agent, an anti-inflammatory agent, a corticosteroid, an anti-asthmatic agent, an anti-allergic agent, an immunosuppressive agent, an immunomodulatory agent, a cardiovascular disease treatment agent, an anti-diabetic agent, a blood disorder treatment agent, a nerve growth factor receptor antagonist, a sodium channel blocker, a CYP2D6 inhibitor, and a TNF-alpha inhibitor.

1214. The pharmaceutical composition of any one of embodiments 1176- 1211, wherein pharmaceutical composition is used simultaneously, separately, or sequentially with one or more opiates.

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