(12) United States Patent (10) Patent No.: US 9,359,316 B1 Husfeld Et Al

US009359.316B1

(12) United States Patent (10) Patent No.: US 9,359,316 B1 Husfeld et al. (45) Date of Patent: Jun. 7, 2016

(54) PRODRUGS OF PHENOLIC TRPV1 (56) References Cited AGONSTS U.S. PATENT DOCUMENTS (71) Applicant: Concentric Analgesics, Inc., San 4,812,590 A 3, 1989 Saari Francisco, CA (US) 4,935,368 A 6, 1990 Kotani et al. 5,094,782 A * 3/1992 Chen ...... CO7C 233/18 554.63 (72) Inventors: I'll SM CA (S 5.962,532 A 10/1999 Campbell et al. Onn E. Jonovan, San Franc1Sco, 7,632,519 B2 * 12/2009 Jamieson ...... A61K 47,481 (US) 424/451 7,943,666 B2 5/2011 Singh et al.

(73) Assignee: CONCENTRICANALGESICS, INC., SR4 W 338E. E.urch et al. San Francisco, CA (US) 2008.0193481 A1 8/2008 Bundle et al. 2010, O152434 A1 6, 2010 Peterson (*) Notice: Subject to any disclaimer, the term of this 2011/0243884 A1 10, 2011 O'Shea et al. patent is extended or adjusted under 35 U.S.C. 154(b) by 0 days. FOREIGN PATENT DOCUMENTS KR 101478520 B1 * 1, 2015 (21) Appl. No.: 14/743,375 WO WO-2013 1753.76 A2 11/2013 OTHER PUBLICATIONS (22) Filed: Jun. 18, 2015 Gomes et al. Cyclization-activated Prodrugs. Molecules 12:2484 2506 (2007). O O Stella et al. Prodrug strategies to overcome poor water solubility. Related U.S. Application Data Advanced Drug Delivery Reviews 59:677-694 (2007). Zawilska et al. Prodrugs: A challenge for the drug development. (60) Provisional application No. 62/084,515, filed on Nov. Pharmacological Reports 65:1-14 (2013). 25, 2014. PCT/US2015/62531 International Search Report and Written Opin ion dated Jan. 27, 2016. (51) Int. Cl. C07C 27L/52 (2006.01) * cited by examiner C07D 295/195. (2006.01) Primary Examiner — Timothy Thomas CO7D 2L/26 (2006.01) (74) Attorney, Agent, or Firm — Wilson Sonsini Goodrich & C07D 207/09 (2006.01) Rosati (52) CPCU.S. Cl...... C07D 295/195 (2013.01); Co7C 271/52 (7) ABSTRACT (2013.01); C07D 207/09 (2013.01); C07D Described herein are compounds, pharmaceutical composi 2II/26 (2013.01) tions and medicaments that include Such compounds, and (58) Field of Classification Search methods of using Such compounds to modulate transient CPC ...... C07D 295/195; CO7C 27 1/52 receptor potential vanilloid 1 receptor (TRPV1) activity. See application file for complete search history. 1 Claim, No Drawings US 9,359,316 B1 1. 2 PRODRUGS OF PHENOLIC TRPV1 -continued AGONSTS

CROSS-REFERENCE

This application claims benefit of U.S. Provisional Appli cation No. 62/084,515, filed on Nov. 25, 2014, which is herein incorporated by reference in its entirety.

BACKGROUND OF THE INVENTION

Described herein are compounds, pharmaceutical compo sitions and medicaments that include Such compounds, and 15 methods of using Such compounds to modulate the transient receptor potential vanilloid 1 receptor (TRPV1) activity.

SUMMARY OF THE INVENTION

In one aspect, described herein is a compound having the structure of Formula (I):

25 Formula (I) R R2 l -8. Y; 30 wherein: Y is a phenolic TRPV1 agonist, wherein the hydrogen atom of the phenolic hydroxyl group is replaced by a covalent bond to —C(O) X-(C(R)(R))-Z: 35 X is —C(R)(R)— —O— —N(Rs)—or —S : n is an integer from 1 to 10; Z is —NRR or —COH: Rs is hydrogen, Substituted or unsubstituted alkyl, or Sub 40 stituted or unsubstituted aryl, and each R and R is each independently hydrogen, Substituted or unsubstituted alkyl, substituted or unsubstituted aryl, or substituted or unsubsti tuted acyl, or R and R together with the carbon atom to which they are attached form a substituted or unsubstituted cycloalkyl group, or two R or R groups on adjacent carbon 45 atoms, together with the carbon atoms to which they are attached, form a substituted or unsubstituted cycloalkyl group, or R and Rs groups on adjacent atoms, together with the atoms to which they are attached, form a substituted or unsubstituted heterocycloalkyl group; and 50 R and R is each independently hydrogen, Substituted or In some embodiments is a compound of Formula (I), wherein unsubstituted alkyl, or substituted or unsubstituted aryl; Z is —NRR. In some embodiments is a compound of For or a pharmaceutically acceptable salt, pharmaceutically mula (I), wherein Z is —NRR, R is hydrogen; and R is H acceptable solvate, or hydrate thereof. or substituted or unsubstituted alkyl. In some embodiments is 55 a compound of Formula (I), wherein Xis —N(Rs)—. In some In some embodiments is a compound of Formula (I), embodiments is a compound of Formula (I), wherein X is wherein Y is —N(Rs)—, and R and Rs groups on adjacentatoms, together with the atoms to which they are attached, form a substituted or unsubstituted heterocycloalkyl group. In some embodi 60 ments is a compound of Formula (I), wherein Xis—N(Rs)—, and R and Rs groups on adjacent atoms, together with the N atoms to which they are attached, form a substituted or unsub stituted heterocycloalkyl group wherein the heterocycloalkyl X, s group is a Substituted or unsubstituted pyrrolidine ring, Sub 65 stituted or unsubstituted piperidine ring, or Substituted or unsubstituted piperazine ring. In some embodiments is a compound of Formula (I), wherein Y is US 9,359,316 B1 3 4 -continued ~~~ --~~~

10 In some embodiments is a compound of Formula (I), having the structure

15 O R N O N 21 H s On O R. O N 25 H1 lO H --~~ In some embodiments is a compound of Formula (I), wherein N O Z is —NRR. In some embodiments is a compound of For On mula (I), wherein Z is —NRR, R is hydrogen; and R is H 30 or substituted or unsubstituted alkyl. In some embodiments is a compound of Formula (I), wherein X is —N(Rs)—. In some In some embodiments is a compound of Formula (I), embodiments is a compound of Formula (I), wherein X is wherein Y is —N(Rs)— and Rs is substituted or unsubstituted alkyl. In Some embodiments is a compound of Formula (I), wherein n 35 is 2 or 3. In some embodiments is a compound of Formula (I), wherein each R and each R are hydrogen. In some embodi ments is a compound of Formula (I), wherein Y is

40 N coO 45 X, N 2 H s On X, In some embodiments is a compound of Formula (I), wherein 50 X is —N(Rs)— and Rs is unsubstituted alkyl. In some OS embodiments is a compound of Formula (I), wherein X is O —N(Rs)— and Rs is —CH. In some embodiments is a compound of Formula (I), wherein X is —N(Rs)—and Rs is N Substituted alkyl. In some embodiments is a compound of H 55 Formula (I), wherein X is N(Rs)— and Rs is —CHCH-NH2. In some embodiments is a compound of X, Formula (I), wherein X is N(Rs)— and Rs is - CHCH-NH(alkyl). On In another aspect is a pharmaceutical composition com prising a compound of Formula (I), or a pharmaceutically 60 acceptable salt, pharmaceutically acceptable solvate, or N 1 hydrate thereof, and a pharmaceutically acceptable diluent, H s excipient or binder. For any and all embodiments described herein, substiuents X, are selected from among a subset of listed alternatives. For 65 example, in Some embodiments is a compound of Formula On (I), wherein Z is —NRR. In other embodiments is a com pound of Formula (I), wherein Z is —CO.H. US 9,359,316 B1 5 6 In some embodiments is a compound of Formula (I), Formula (I), wherein Rs is —CHCH-NH(alkyl). In some wherein Y is embodiments is a compound of Formula (I), wherein n is 2 or 3. In some embodiments is a compound of Formula (I), wherein each R and each R are hydrogen. In some embodi ments is a compound of Formula (I), wherein Z is —NRR. In some embodiments is a compound of Formula (I), wherein Z is —CO.H. 1 In some embodiments is a compound of Formula (I) having the structure of Formula (II): A C 10 Formula (II) 15 -8, Y; Rs

wherein Z is —NRR and n is an integer from 2 to 10. In some embodiments is a compound of Formula (II), whereinY is

X. cri 25 30 co

N 2 H s

On O

N H

N 1-1. H s

On O

60 --~~~ In some embodiments is a compound of Formula (I), wherein H X is —C(R)(R)—, and n is an integer from 1 to 3. In some embodiments is a compound of Formula (I), wherein X is X, —N(Rs)—. In some embodiments is a compound of Formula (I), wherein Rs is methyl. In some embodiments is a com On 65 pound of Formula (I), wherein Rs is substituted alkyl. In some O embodiments is a compound of Formula (I), wherein Rs is —CH2CHNH2. In some embodiments is a compound of US 9,359,316 B1 7 8

-continued is hydrogen; and R is hydrogen or methyl. In some embodi ments is a compound of Formula (II), (IIa), or (Iaa), having the structure:

O 10 R H

On 15

2O In some embodiments is a compound of Formula (II), having wherein R is hydrogen or methyl; and p is an integer from 1 the structure of Formula (IIa): to 9.

Formula (IIa) O - N-X-lx^->R. R. R R R2 Rs O wherein p is an integer from 1 to 9. In some embodiments is 35 a compound of Formula (IIa), having the structure of Formula (IIaa):

Formula (IIaa) O 21 R. R. R --~~ R1 N p ls O Rs O

50 In Some embodiments is a compound of Formula (II), (IIa), or In some embodiments is a compound of Formula (II), (IIa), or (IIaa), wherein R and Rs groups on adjacent atoms, together (IIaa), having the structure: with the atoms to which they are attached, form a substituted or unsubstituted heterocycloalkyl group. In some embodi ments is a compound of Formula (II), (IIa), or (Iaa), wherein 55 R. O R and Rs groups on adjacent atoms, together with the atoms to which they are attached, form a substituted or unsubstituted Hry, lo H --~~ heterocycloalkyl group and the heterocycloalkyl group is a N O substituted or unsubstituted pyrrolidine ring, substituted or unsubstituted piperidine ring, or Substituted or unsubstituted 60 On piperazine ring. In some embodiments is a compound of Formula (II), (IIa), or (IIaa), wherein R and Rs groups on adjacent atoms, together with the atoms to which they are attached, form a substituted or unsubstituted heterocycloalkyl group; the heterocycloalkyl group is a Substituted or unsub 65 stituted pyrrolidine ring, Substituted or unsubstituted piperi wherein R is hydrogen or methyl; and p is an integer from 1 dine ring, or substituted or unsubstituted piperazine ring; R. to 9. US 9,359,316 B1 10 In some embodiments is a compound of Formula (II), having the structure of Formula (IIb):

Formula (IIb)

wherein p is an integer from 1 to 9. In some embodiments is a compound of Formula (IIb), having the structure of Formula (IIbb): Formula (IIbb) O R. R. R --~~~ R1 NN-X- ls O Rs ON

In some embodiments is a compound of Formula (IIb) or -continued (IIbb), wherein R and Rs together with the atoms to which they are attached form a substituted or unsubstituted hetero 30 cycloalkyl group. In some embodiments is a compound of Formula (IIb) or (IIbb), wherein R and Rs together with the atoms to which they are attached form a substituted or unsub stituted heterocycloalkyl group, and the heterocycloalkyl group is a Substituted or unsubstituted pyrrolidine ring, Sub stituted or unsubstituted piperidine ring, or Substituted or 35 unsubstituted piperazine ring. In some embodiments is a compound of Formula (IIb) or (IIbb), wherein R is hydrogen and R is hydrogen or methyl. In some embodiments is a compound of Formula (IIb) or (IIbb), wherein R is hydrogen and R is hydrogen. 40 In some embodiments is a compound of Formula (IIa), (IIaa), (IIb), or (IIbb), wherein p is 1. In some embodiments is a compound of Formula (IIa), (IIaa), (IIb), or (IIbb), wherein p is 2. In some embodiments is a compound of Formula (I) having 45 the structure of Formula (III):

Formula (III) R. R. R

Z pi Y R. R.

55 In some embodiments is a compound of Formula (II), wherein Y is

65 O US 9,359,316 B1 11 12

-continued

In Some embodiments is a compound of Formula (III), having the structure of Formula (IIIa):

Formula (IIIa) O R. R. R --~~

R. R. R. R2 On

wherein p is an integer from 0 to 9. In some embodiments is a compound of Formula (IIIa), having the structure of For mula (IIIaa):

Formula (IIIaa) O --XR. R. asR --~~~ R R2 On

In Some embodiments is a compound of Formula (III), having the structure of Formula (IIIb):

Formula (IIIb) O

O R R2 O --~~~ s

HO p O R. R. R. R2 O N wherein p is an integer from 0 to 9. In some embodiments is 65 a compound of Formula (IIIb), having the structure of For mula (IIIbb): US 9,359,316 B1 14

Formula (IIIbb)

In some embodiments is a compound of Formula (III). receptor 1 (VR1)), a ligand-gated, non-selective cation chan (IIIa), (IIIaa), (IIIb), or (IIIbb), wherein each R and each R nel. TRPV1 is preferentially expressed on small-diameter are hydrogen. In some embodiments is a compound of For- 15 sensory neurons, especially those A- and C-fibers which spe mula (III), (IIIa), (IIIaa), (IIIb), or (IIIbb), wherein at least one cialize in the detection of painful or noxious sensations. R is substituted or unsubstituted alkyl. In some embodiments TRPV1 responds to noxious stimuli including capsaicin, is a compound of Formula (IIIa), (IIIaa), (IIIb), or (IIIbb), heat, and extracellular acidification, and will integrate simul wherein p is 1. In some embodiments is a compound of taneous exposures to these stimuli. (Caterina M. J. Julius D. Formula (IIIa), (IIIaa), (IIIb), or (IIIbb), wherein p is 2. The vanilloid receptor: a molecular gateway to the pain path In another aspect is a pharmaceutical composition com way. Annu Rev Neurosci. 2001. 24:487-517). prising a compound of Formula (I), (II), (IIa), (Ilaa), (IIb). TRPV1 agonists, such as capsaicin, have been shown to (IIbb), (IIc), (IIcc), (IId), (IIdd), (IIe), (IIee), (IIf). (Iff), (III), diminish pain in various settings, but there are problems (IIIa), (IIIaa), (IIIb), (IIIbb), (IIIc), (IIIcc), (IIId), (IIIdd), associated with their use. The initial effects of TRPV 1-ex (IIIe), (IIIee), (IIIf), (IIIff), or (IV), or a pharmaceutically pressing (capsaicin-sensitive) nociceptors activation are acceptable salt, pharmaceutically acceptable solvate, or 25 burning sensations, hyperalgesia, allodynia, and erythema. hydrate thereof, and a pharmaceutically acceptable diluent, However, after prolonged exposure to low-concentration cap excipient or binder. In some embodiments, the pharmaceuti saicin or single exposures to high-concentration capsaicin or cal composition is formulated for intravenous injection, Sub other TRPV1 agonists, the small-diameter sensory axons cutaneous injection, intramuscular injection, intraperitoneal become less sensitive to a variety of stimuli, including cap injection, perineural injection, neuraxial injection, intra-ar- so saicin or thermal stimuli. This prolonged exposure is also ticular injection, oral administration, or topical administra characterized by reduced pain responses. These later-stage tion. effects of capsaicin are frequently referred to as "desensiti In another aspect is a method of treating pain in a subject, zation' and are the rationale for the development of capsaicin comprising administering to the subject a thrapeutically formulations for the treatment of various pain syndromes and effective amount of a compound of Formula (I), (II), (IIa). other conditions. (Bley, K. R. Recent developments in tran (Ilaa), (IIb), (IIbb), (IIc), (IIcc), (IId), (IIdd), (IIe), (IIee), sient receptor potential vanilloid receptor 1 agonist-based (IIf), (IIff), (III), (IIIa), (IIIaa), (IIIb), (IIIbb), (IIIc), (IIIcc), therapies. Expert Opin Investig Drugs. 2004. 13(11): 1445 (IIId), (IIIdd), (IIIe), (IIIee), (IIIf). (IIIff), or (IV), or a phar 1456). maceutically acceptable salt, pharmaceutically acceptable In addition, capsaicin and other TRPV1 agonists have very solvate, or hydrate thereof. In some embodiments is a method limited water solubility, are extremely potent irritants requir of treating pain in a subject, comprising administering to the 40 ing special equipment when handling and, due to their limited subject a thrapeutically effective amount of a compound of water solubility, are not readily mixed with common drugs Formula (I), (II), (IIa), (IIaa), (IIb), (IIbb), (IIc), (IIcc), (IId), that are procured as aqueous solutions. Therefore, the use of (IIdd), (IIe), (IIee), (IIf), (IIff), (III), (IIIa), (IIIaa), (IIIb). non-aqueous formulations is necessary to deliver substantial (IIIbb), (IIIc), (IIIcc), (IIId), (IIIdd), (IIIe), (IIIee), (III?), (II quantities of capsaicin or other TRPV1 agonists. These for Iff), or (IV), or a pharmaceutically acceptable salt, pharma mulations are frequently not aligned with current practices/ ceutically acceptable solvate, or hydrate thereof, wherein the 45 procedures, especially with respect to sterile aqueous solu pain is associated with post-operative pain, chronic post tions used in surgery. Additionally, due to the potent ability of surgical pain, neuropathic pain, postherpetic neuralgia, dia capsaicin to cause irritation, it would be preferable to utilize betic neuropathy, HIV-associated neuropathy, complex a water-soluble prodrug of capsaicin that minimizes capsai regional pain syndrome, cancer, nerve injury, cancer chemo cin's activity until the prodrug reaches the desired site of therapy, vulvodynia, trauma, surgery, chronic musculoskel- 50 activity. etal pain, lowerback pain, osteoarthritis or rheumatoid arthri Therefore, it would be desirable to provide TRPV1 agonist tis. In some embodiments is a method of treating pain in a prodrugs with: 1) increased water solubility, 2) the potential subject, comprising administering to the subject a thrapeuti for reduced or delayed pungency associated with the admin cally effective amount of a compound of Formula (I), (II), istration of TRPV 1 agonists and 3) have the ability to be (IIa), (Ilaa), (IIb), (IIbb), (IIc), (IIcc), (IId), (IIdd), (Ile), ss delivered in a rapid manner (half-life of delivery of TRPV1 (IIee), (IIf), (IIff), (III), (IIIa), (IIIaa), (IIIb), (IIIbb), (IIIc), agonist in less than 30 min) or in a delayed manner (half-life (IIIcc), (IIId), (IIIdd), (IIIe), (IIIee), (IIIff), or (IV), or a phar of delivery of TRPV1 agonist in greater than 30 min). In maceutically acceptable salt, pharmaceutically acceptable addition, it may be desirable to utilize chemical formulations/ solvate, or hydrate thereof, wherein the compound is admin additives to delay the initiation of prodrug conversion. Fur istered locally, dermally, transdermally or systemically. thermore, it would be desirable to provide TRPV1 agonist 60 prodrugs that are soluble in aqueous sterile injectable formu DETAILED DESCRIPTION lations to the intended site of action. Finally, in some cases it would be desirable to deliver another pharmacologically Capsaicin, the main ingredient responsible for the hot pun active compound(s) along with a capsaicin prodrug or other gent taste of chili peppers, is an alkaloid found in the Capsi TRPV1 agonist prodrug, especially a local anesthetic agent. cum family. Capsaicin (8-methyl-N-vanillyl-6-nonenamide) 65 Accordingly, the compounds described herein are directed is a highly selective agonist for transient receptor potential to novel water-soluble prodrugs of TRPV1 agonists and their vanilloid 1 receptor (TRPV1; formerly known as vanilloid methods of synthesis and use. These prodrug TRPV1 agonist US 9,359,316 B1 15 16 derivatives revert to the active parent compound when -continued R exposed to physiological conditions. The compounds have significantly higher hydrophilicity/water solubility than their Ri parent drugs and, hence, are betterable to be incorporated into N commonly used aqueous formulations. Further described C )=o + D. herein is a method of increasing the water solubility of cap N saicin, its analogs and other TRPV1 agonists, by modifying V the parent molecule's chemical structure with hydrophilic R2 moieties. In some embodiments described herein, the intro duction of basic moieties capable of being protonated under 10 In some embodiments described herein, the parent drug is acidic conditions increases the solubility of the TRPV1 pro released by a carboxylate-based intramolecular cyclization drug. In some embodiments described herein, the introduc (D=TRPV1 agonist): tion of acidic moieties capable of increasing the overall hydrophilic character increases the solubility of the TRPV1 prodrug. The prodrugs described herein are designed Such 15 O that the parent drug is released, via cyclization-release reac s O N tions, under well-defined rates after the prodrug has been Cyclization Release delivered to the body and/or is exposed to specific physiologi D cal conditions. The chemical-release kinetics of the parent drug may impart two important properties: (a) potentially reduced and/or delayed pungency due to the avoidance of the rapid delivery of a bolus dose of the TRPV1 agonist and (b) rapid ordelayed release of the parent TRPV1 agonist from the prodrug for tuning of specific pharmacological activity/re Sults. Such structural modifications eliminate the reliance on special requirements for formulations or delivery devices in 25 order to 1) accommodate the very low water solubility of many TRPV1 agonists/capsaicinoids and 2) reduce the acute pungency associated with the administration of TRPV1 ago nists. Additionally, water-soluble prodrugs are desired when In some embodiments, the cyclization rate (t) at 37°C., 30 pH 7.4, is between 10 seconds and 10 hours. In some embodi co-delivering other medications, especially when administer ments, the cyclization rate (t) at 37°C., pH 7.4, is between ing multiple sterile agents via injection. 10 seconds and 1 hour. In some embodiments, the cyclization The capsaicin, capsaicinoids or other TRPV1 agonist pro rate (t) at 37° C. pH 7.4, is between 10 seconds and 30 drugs described herein are chemically modified to control the minutes. In some embodiments, the cyclization rate (t) at rate at which the capsaicin, capsaicinoid, or other TRPV1 37° C. pH 7.4, is between 1 minute and 10 hours. In some agonist is bioavailable through pH controlled, intramolecular 35 embodiments, the cyclization rate (t) at 37°C., pH 7.4, is cyclization-release reactions. In some embodiments, the between 1 minute and 30 minutes. In some embodiments, the TRPV1 agonist prodrugs described herein have prolonged cyclization rate (t) at 37°C., pH 7.4, is between 2 minutes stability at pH levels suitable for making pharmaceutical for and 30 minutes. In some embodiments, the cyclization rate mulations, but break down in Vivo under physiological con (t) at 37°C., pH 7.4, is between 5 minutes and 30 minutes. 40 In some embodiments, the cyclization rate (t) at 37°C., pH ditionina controlled manner. After parenteral administration, 7.4, is between 2 minutes and 15 minutes. In some embodi the compounds of Formula (I), (II), (IIa), (IIaa), (IIb), (IIbb), ments, the cyclization rate (t) at 37° C. pH 7.4, is between (IIc), (IIcc), (IId), (IIdd), (IIe), (IIee), (IIf), (IIff), (III), (IIIa), 5 minutes and 15 minutes. In some embodiments, the cycliza (IIIaa), (IIIb), (IIIbb), (IIIc), (IIIcc), (IIId), (IIIdd), (IIIe), tion rate (t) at 37°C., pH 7.4, is between 15 minutes and 2 (IIIee), (IIIf), (IIIff), or (IV) are converted to the parent drug hours. In some embodiments, the cyclization rate (t) at 37° (TRPV1 agonist) via the pH controlled, cyclization-release 45 C., pH 7.4, is between 15 minutes and 1.5 hours. In some reaction. The rate at which the prodrug converts is dictated by embodiments, the cyclization rate (t) at 37°C., pH 7.4, is the cyclization-release reaction, which can be modified by the between 15 minutes and 1 hour. In some embodiments, the addition of buffers. In some embodiments, the buffer provides cyclization rate (t) at 37°C., pH 7.4, is between 30 minutes a time window where turnover to parent drug is significantly and 2 hours. In some embodiments, the cyclization rate (t) delayed until the return of physiological conditions. In some 50 at 37° C. pH 7.4, is between 30 minutes and 1.5 hours. In embodiments, the release of parent drug is tuned to provide some embodiments, the cyclization rate (t) at 37° C., pH for rapid release based on the rate of the intramolecular 7.4, is between 30 minutes and 1 hour. In some embodiments, cyclization release. In some embodiments, the release of par the cyclization rate (t) at 37°C., pH 7.4, is between 1 hour ent drug is tuned to provide for deleayed release based on the and 4 hours. In some embodiments, the cyclization rate (t) 55 at 37° C. pH 7.4, is between 1 hour and 3 hours. In some rate of the intramolecular cyclization release. In some embodiments, the cyclization rate (t) at 37°C., pH 7.4, is embodiments described herein, the parent drug is released by between 1 hour and 2 hours. In some embodiments, the an amine-based intramolecular cyclization (D–TRPV1 ago cyclization rate (t) at 37°C., pH 7.4, is between 2 hours and nist): 10 hours. In some embodiments, the cyclization rate (t) at 37° C. pH 7.4, is between 2 hours and 6 hours. In some 60 embodiments, the cyclization rate (t) at 37°C., pH 7.4, is between 2 hours and 4 hours. In some embodiments, the cyclization rate (t) at 37°C., pH 7.4, is between 2 hours and Cyclization Release D -e- 3 hours. In some embodiments, the cyclization rate (t) at 's 37° C. pH 7.4, is between 3 hours and 5 hours. In some N- O1 65 embodiments, the cyclization rate (t) at 37°C., pH 7.4, is between 4 hours and 6 hours. In some embodiments, the cyclization rate (t) at 37°C., pH 7.4, is between 5 hours and US 9,359,316 B1 17 18 7 hours. In some embodiments, the cyclization rate (t) at -continued 37° C. pH 7.4, is between 6 hours and 8 hours. In some O embodiments, the cyclization rate (t) at 37°C., pH 7.4, is between 7 hours and 9 hours. In some embodiments, the cyclization rate (t) at 37°C., pH 7.4, is between 8 hours and 5 N 10 hours. Compounds In one aspect, described herein is a compound having the Arr structure of Formula (I):

Formula (I) -4, Y; wherein: Y is a phenolic TRPV1 agonist, wherein the hydrogen atom of the phenolic hydroxyl group is replaced by a covalent bond to —C(O) X-(C(R)(R))-Z: X is —C(R)(R)— —O— —N(Rs)—or —S : n is an integer from 1 to 10; Z is —NRR or —COH: Rs is hydrogen, Substituted or unsubstituted alkyl, or Sub stituted or unsubstituted aryl, and each R and R is each independently hydrogen, Substituted or unsubstituted alkyl, substituted or unsubstituted aryl, or substituted or unsubsti tuted acyl, or R and R together with the carbon atom to which they are attached form a substituted or unsubstituted cycloalkyl group, or two R or R groups on adjacent carbon atoms, together with the carbon atoms to which they are attached, form a substituted or unsubstituted cycloalkyl group, or R and Rs groups on adjacent atoms, together with the atoms to which they are attached, form a substituted or unsubstituted heterocycloalkyl group; and R and R is each independently hydrogen, Substituted or unsubstituted alkyl, or substituted or unsubstituted aryl; or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or hydrate thereof. For any and all of the embodiments, substituents are In some embodiments is a compound of Formula (I), wherein selected from among from a subset of the listed alternatives. Y is For example, in some embodiments is a compound of For mula (I), wherein Z is —NRR. In other embodiments is a 45 compound of Formula (I), wherein Z is —CO.H. In some embodiments is a compound of Formula (I), wherein Y is 50 co In some embodiments is a compound of Formula (I), wherein co 55 Y is O 60 N 2 H s

a. Or 65 ON US 9,359,316 B1 19 20 In some embodiments is a compound of Formula (I), wherein is —C(CH)—. In some embodiments is a compound of Y is Formula (I), wherein X is —C(R)(R)— and R and R. together with the carbonatom to which they are attached form a Substituted or unsubstituted cycloalkyl group. In some embodiments is a compound of Formula (I), wherein X is 5 —N(Rs)—. In some embodiments is a compound of Formula (I), wherein X is N(Rs)—and Rs is substituted or unsub stituted alkyl. In some embodiments is a compound of For mula (I), wherein X is N(Rs)— and Rs is unsubstituted alkyl. In some embodiments is a compound of Formula (I), 10 wherein X is —N(Rs)—and Rs is substituted alkyl. In some embodiments is a compound of Formula (I), wherein X is —N(Rs)— and Rs is substituted or unsubstituted aryl. In some embodiments is a compound of Formula (I), wherein X is —N(Rs)—and Rs is Substituted phenyl. In some embodi ments is a compound of Formula (I), wherein X is —N(Rs)— 15 and Rs is unsubstituted phenyl. In some embodiments is a compound of Formula (I), wherein X is —NH-. In some embodiments is a compound of Formula (I), wherein X is --> —N(CH)—. In some embodiments is a compound of For mula (I), wherein X is N(CHCH)—. In some embodi ments is a compound of Formula (I), wherein X is —N(CHCH-NH)—. In some embodiments is a compound of Formula (I), wherein X is —N(CHCH-NH(alkyl)—. In A. or some embodiments is a compound of Formula (I), wherein X is N(CHCH-NH(CH))—. In a further embodiment of any of the aforementioned embodiments is a compound of In some embodiments is a compound of Formula (I), wherein 25 Formula (I), wherein Zis—COH. In another embodiment of Y is any of the aforementioned embodiments is a compound of Formula (I), wherein Z is —NRRa. In another embodiment of any of the aforementioned embodiments is a compound of Formula (I), wherein Z is —NRR and R and R are each independently hydrogen or substituted or unsubstituted alkyl. 30 In another embodiment of any of the aforementioned embodi ments is a compound of Formula (I), wherein Z is —NRR and R and Rare each independently hydrogen or methyl. In another embodiment of any of the aforementioned embodi ments is a compound of Formula (I), wherein Z is —NRR 35 and R and R are each hydrogen. In another embodiment of co any of the aforementioned embodiments is a compound of Formula (I), wherein Z is —NRR and R is hydrogen or R In some embodiments is a compound of Formula (I), wherein is methyl. In another embodiment of any of the aforemen Y is tioned embodiments is a compound of Formula (I), whereinn 40 is 1. In another embodiment of any of the aforementioned embodiments is a compound of Formula (I), whereinn is 2. In another embodiment of any of the aforementioned embodi ments is a compound of Formula (I), whereinnis3. In another embodiment of any of the aforementioned embodiments is a compound of Formula (I), wherein n is 4. In another embodi 45 ment of any of the aforementioned embodiments is a com pound of Formula (I), wherein n is 5. In another embodiment of any of the aforementioned embodiments is a compound of Formula (I), wherein n is 6. In another embodiment of any of the aforementioned embodiments is a compound of Formula 50 (I), wherein n is 7. In another embodiment of any of the aforementioned embodiments is a compound of Formula (I), wherein n is 8. In another embodiment of any of the afore mentioned embodiments is a compound of Formula (I), wherein n is 9. In another embodiment of any of the afore 55 mentioned embodiments is a compound of Formula (I), wherein n is 10. In another embodiment, described herein is a compound In some embodiments is a compound of Formula (I), having the structure of Formula (II): wherein X is —O—. In some embodiments is a compound of Formula (I), wherein X is —S . In some embodiments is a compound of Formula (I), wherein X is —C(R)(R)—. In 60 Formula (II) some embodiments is a compound of Formula (I), wherein X is —C(R)(R)—and RandR is each independently hydro gen, substituted or unsubstituted alkyl, or substituted or unsubstituted aryl. In some embodiments is a compound of -8, Y; Formula (I), wherein X is —CH2—. In some embodiments is 65 Rs a compound of Formula (I), wherein X is —CH(CH)—. In some embodiments is a compound of Formula (I), wherein X US 9,359,316 B1 21 22 wherein: -continued Y is a phenolic TRPV1 agonist, wherein the hydrogen atom of the phenolic hydroxyl group is replaced by a covalent bond to —C(O) N(Rs)—(C(R)(R))-Z: Z is NRR: Rs is hydrogen, Substituted or unsubstituted alkyl, or Sub stituted or unsubstituted aryl, and each R and R is each independently hydrogen, Substituted or unsubstituted alkyl, substituted or unsubstituted aryl, or substituted or unsubsti tuted acyl, or R and R together with the carbon atom to 10 which they are attached form a substituted or unsubstituted cycloalkyl group, or two R or R groups on adjacent carbon atoms, together with the carbon atoms to which they are attached, form a substituted or unsubstituted cycloalkyl group, or R and Rs groups on adjacent atoms, together with 15 the atoms to which they are attached, form a substituted or unsubstituted heterocycloalkyl group; R and R is each independently hydrogen, Substituted or unsubstituted alkyl, or substituted or unsubstituted aryl; and In some embodiments is a compound of Formula (II), n is an integer from 2 to 10; or wherein Y is a pharmaceutically acceptable salt, pharmaceutically accept able solvate, or hydrate thereof. In some embodiments is a compound of Formula (II), wherein Y is 25

30 X, In some embodiments is a compound of Formula (II), or wherein Y is 35

In some embodiments is a compound of Formula (II), 45 wherein Y is

60 --> X. or 65 O X, or US 9,359,316 B1 23 24 In some embodiments is a compound of Formula (II), wherein each RandR are each independently hydrogen, or wherein Y is substituted or unsubstituted alkyl. In another embodiment of any of the aforementioned embodiments is a compound of Formula (II), wherein each R and R2 are hydrogen. In another embodiment of any of the aforementioned embodi ments is a compound of Formula (II), wherein R and R N 1---- 5 together with the carbonatom to which they are attached form H a Substituted or unsubstituted cycloalkyl group. In another embodiment of any of the aforementioned embodiments is a X, 10 compound of Formula (II), wherein R and Rs groups on O N adjacent atoms, together with the atoms to which they are attached, form a substituted or unsubstituted heterocycloalkyl group. In another embodiment of any of the aforementioned In some embodiments is a compound of Formula (II), wherein Y is embodiments is a compound of Formula (II), wherein R and 15 Ra are each independently hydrogen or Substituted or unsub stituted alkyl. In another embodiment of any of the aforemen tioned embodiments is a compound of Formula (II), wherein R and Ra are each independently hydrogen or methyl. In another embodiment of any of the aforementioned embodi ments is a compound of Formula (II), wherein R and Ra are 2O each hydrogen. In another embodiment of any of the afore mentioned embodiments is a compound of Formula (II), wherein R is hydrogen or R is methyl. In another embodi ment of any of the aforementioned embodiments is a com pound of Formula (II), wherein n is 2. In another embodiment 25 of any of the aforementioned embodiments is a compound of Formula (II), wherein n is 3. In another embodiment of any of the aforementioned embodiments is a compound of Formula (II), wherein n is 4. In another embodiment of any of the aforementioned embodiments is a compound of Formula (II), 30 wherein n is 5. In another embodiment of any of the afore mentioned embodiments is a compound of Formula (II), wherein n is 6. In another embodiment of any of the afore mentioned embodiments is a compound of Formula (II), In some embodiments is a compound of Formula (II), wherein n is 7. In another embodiment of any of the afore wherein Rs is H. In some embodiments is a compound of mentioned embodiments is a compound of Formula (II), Formula (II), wherein Rs is substituted or unsubstituted alkyl. 35 wherein n is 8. In another embodiment of any of the afore In some embodiments is a compound of Formula (II), mentioned embodiments is a compound of Formula (II), wherein Rs is unsubstituted alkyl. In some embodiments is a wherein n is 9. In another embodiment of any of the afore compound of Formula (II), wherein Rs is substituted alkyl. In mentioned embodiments is a compound of Formula (II), Some embodiments is a compound of Formula (II), wherein wherein n is 10. Rs is substituted or unsubstituted aryl. In some embodiments In another embodiment, described herein is a compound is a compound of Formula (II), wherein Rs is substituted having the structure of Formula (IIa):

Formula (IIa)

phenyl. In some embodiments is a compound of Formula (II), wherein: wherein Rs is unsubstituted phenyl. In some embodiments is 55 Rs is hydrogen, Substituted or unsubstituted alkyl, or Sub a compound of Formula (II), wherein Rs is —CH. In some stituted or unsubstituted aryl, and each R and R is each embodiments is a compound of Formula (II), wherein Rs is independently hydrogen, Substituted or unsubstituted alkyl, —CH2CH. In some embodiments is a compound of Formula substituted or unsubstituted aryl, or substituted or unsubsti (II), wherein Rs is —CHCH-NH. In some embodiments is 60 tuted acyl, or R and R together with the carbon atom to a compound of Formula (II), wherein Rs is —CHCH-NH which they are attached form a substituted or unsubstituted (alkyl). In some embodiments is a compound of Formula (II), cycloalkyl group, or two R or R groups on adjacent carbon wherein Rs is —CHCH-NH(CH). In another embodiment of any of the aforementioned embodiments is a compound of atoms, together with the carbon atoms to which they are Formula (II), wherein each RandR are each independently attached, form a substituted or unsubstituted cycloalkyl hydrogen, substituted or unsubstituted alkyl, or substituted or 65 group, or R and Rs groups on adjacent atoms, together with unsubstituted aryl. In another embodiment of any of the the atoms to which they are attached, form a substituted or aforementioned embodiments is a compound of Formula (II), unsubstituted heterocycloalkyl group; US 9,359,316 B1 25 26 R and R is each independently hydrogen, Substituted or together with the atoms to which they are attached, form a unsubstituted alkyl, or substituted or unsubstituted aryl; and substituted or unsubstituted heterocycloalkyl group, wherein p is an integer from 1 to 9; or the heterocycloalkyl group is a substituted or unsubstituted a pharmaceutically acceptable salt, pharmaceutically accept piperazine ring. In another embodiment of any of the afore able solvate, or hydrate thereof. mentioned embodiments is a compound of Formula (IIa), In some embodiments is a compound of Formula (IIa), wherein R and R are each independently hydrogen or Sub wherein Rs is H. In some embodiments is a compound of stituted or unsubstituted alkyl. In another embodiment of any Formula (IIa), wherein Rs is substituted or unsubstituted of the aforementioned embodiments is a compound of For alkyl. In some embodiments is a compound of Formula (IIa), mula (IIa), wherein R and R are each independently hydro wherein Rs is unsubstituted alkyl. In some embodiments is a gen or methyl. In another embodiment of any of the afore compound of Formula (IIa), wherein Rs is substituted alkyl. 10 mentioned embodiments is a compound of Formula (IIa), In some embodiments is a compound of Formula (IIa), wherein RandR are each hydrogen. In another embodiment wherein Rs is substituted or unsubstituted aryl. In some of any of the aforementioned embodiments is a compound of embodiments is a compound of Formula (IIa), wherein Rs is Formula (IIa), wherein R is hydrogen or R is methyl. In Substituted phenyl. In some embodiments is a compound of another embodiment of any of the aforementioned embodi Formula (IIa), wherein Rs is unsubstituted phenyl. In some 15 ments is a compound of Formula (IIa), wherein p is 1. In embodiments is a compound of Formula (IIa), wherein Rs is another embodiment of any of the aforementioned embodi —CH. In some embodiments is a compound of Formula ments is a compound of Formula (IIa), wherein p is 2. In (IIa), wherein Rs is —CH2CH. In some embodiments is a another embodiment of any of the aforementioned embodi compound of Formula (IIa), wherein Rs is —CHCH-NH. ments is a compound of Formula (IIa), wherein p is 3. In In some embodiments is a compound of Formula (IIa), another embodiment of any of the aforementioned embodi wherein Rs is —CHCH-NH(alkyl). In some embodiments is ments is a compound of Formula (IIa), wherein p is 4. In a compound of Formula (IIa), wherein Rs is —CHCH-NH another embodiment of any of the aforementioned embodi (CH). In another embodiment of any of the aforementioned ments is a compound of Formula (IIa), wherein p is 5. In embodiments is a compound of Formula (IIa), wherein each another embodiment of any of the aforementioned embodi R and R are each independently hydrogen, substituted or ments is a compound of Formula (IIa), wherein p is 6. In unsubstituted alkyl, or substituted or unsubstituted aryl. In 25 another embodiment of any of the aforementioned embodi another embodiment of any of the aforementioned embodi ments is a compound of Formula (IIa), wherein p is 7. In ments is a compound of Formula (IIa), wherein each R and another embodiment of any of the aforementioned embodi R2 are each independently hydrogen, or Substituted or unsub ments is a compound of Formula (IIa), wherein p is 8. In stituted alkyl. In another embodiment of any of the aforemen another embodiment of any of the aforementioned embodi tioned embodiments is a compound of Formula (IIa), wherein 30 ments is a compound of Formula (IIa), wherein p is 9. each R and R2 are hydrogen. In another embodiment of any In another embodiment, described herein is a compound of the aforementioned embodiments is a compound of For having the structure of Formula (IIaa):

Formula (IIaa) O R1 N-X luc H--~~~ ON mula (IIa), wherein each R and R are each independently 45 wherein: hydrogen, or Substituted or unsubstituted alkyl. In another Rs is hydrogen, Substituted or unsubstituted alkyl, or Sub embodiment of any of the aforementioned embodiments is a stituted or unsubstituted aryl, and each R and R is each compound of Formula (IIa), wherein RandR together with independently hydrogen, Substituted or unsubstituted alkyl, the carbon atom to which they are attached form a substituted substituted or unsubstituted aryl, or substituted or unsubsti or unsubstituted cycloalkyl group. In another embodiment of 50 tuted acyl, or R and R together with the carbon atom to any of the aforementioned embodiments is a compound of which they are attached form a substituted or unsubstituted Formula (IIa), wherein R and Rs groups on adjacent atoms, cycloalkyl group, or R and Rs groups together with the atoms together with the atoms to which they are attached, form a to which they are attached, form a substituted or unsubstituted Substituted or unsubstituted heterocycloalkyl group. In heterocycloalkyl group; another embodiment of any of the aforementioned embodi 55 R and R is each independently hydrogen, Substituted or ments is a compound of Formula (IIa), wherein R and Rs unsubstituted alkyl, or substituted or unsubstituted aryl; and groups on adjacent atoms, together with the atoms to which p is an integer from 1 to 9; or they are attached, form a substituted or unsubstituted hetero a pharmaceutically acceptable salt, pharmaceutically accept cycloalkyl group, wherein the heterocycloalkyl group is a able solvate, or hydrate thereof. substituted or unsubstituted pyrrolidine ring. In another In some embodiments is a compound of Formula (IIaa), embodiment of any of the aforementioned embodiments is a 60 wherein Rs is H. In some embodiments is a compound of compound of Formula (IIa), wherein R and Rs groups on Formula (IIaa), wherein Rs is substituted or unsubstituted adjacent atoms, together with the atoms to which they are alkyl. In some embodiments is a compound of Formula (IIaa), attached, form a substituted or unsubstituted heterocycloalkyl wherein Rs is unsubstituted alkyl. In some embodiments is a group, wherein the heterocycloalkyl group is a Substituted or compound of Formula (IIaa), wherein Rs is substituted alkyl. unsubstituted piperidine ring. In another embodiment of any 65 In some embodiments is a compound of Formula (IIaa), of the aforementioned embodiments is a compound of For wherein Rs is substituted or unsubstituted aryl. In some mula (IIa), wherein R and Rs groups on adjacent atoms, embodiments is a compound of Formula (IIaa), wherein Rs is US 9,359,316 B1 27 28 Substituted phenyl. In some embodiments is a compound of another embodiment of any of the aforementioned embodi Formula (Ilaa), wherein Rs is unsubstituted phenyl. In some ments is a compound of Formula (Iaa), wherein p is 8. In embodiments is a compound of Formula (Iaa), wherein Rs is another embodiment of any of the aforementioned embodi —CH. In some embodiments is a compound of Formula ments is a compound of Formula (IIaa), wherein p is 9. (IIaa), wherein Rs is —CHCH. In some embodiments is a In some embodiments is a compound of Formula (IIaa), compound of Formula (IIaa), wherein Rs is —CHCH-NH. having the structure: In some embodiments is a compound of Formula (IIaa), wherein Rs is —CHCH-NH(alkyl). In some embodiments is a compound of Formula (Iaa), wherein Rs is —CHCH-NH O (CH). In another embodiment of any of the aforementioned R embodiments is a compound of Formula (Iaa), wherein each 10 Nel), N 21 R and R2 are each independently hydrogen, Substituted or H unsubstituted alkyl, or substituted or unsubstituted aryl. In another embodiment of any of the aforementioned embodi s OS ments is a compound of Formula (Iaa), wherein each R and R2 are each independently hydrogen, or Substituted or unsub 15 stituted alkyl. In another embodiment of any of the aforemen wherein R is hydrogen or methyl; and p is an integer from 1 tioned embodiments is a compound of Formula (IIaa), to 9. wherein each RandR are hydrogen. In another embodiment In some embodiments is a compound of Formula (IIaa), of any of the aforementioned embodiments is a compound of having the structure: Formula (IIaa), wherein each R and R2 are each indepen dently hydrogen, or substituted or unsubstituted alkyl. In another embodiment of any of the aforementioned embodi O ments is a compound of Formula (IIaa), wherein R and R R together with the carbonatom to which they are attached form Nel), N 21 a Substituted or unsubstituted cycloalkyl group. In another H embodiment of any of the aforementioned embodiments is a 25 compound of Formula (IIaa), wherein R and Rs groups on OS adjacent atoms, together with the atoms to which they are attached, form a substituted or unsubstituted heterocycloalkyl wherein R is hydrogen or methyl; and p is an integer from 1 group. In another embodiment of any of the aforementioned to 2. embodiments is a compound of Formula (Iaa), wherein R 30 and Rs groups on adjacent atoms, together with the atoms to In some embodiments is a compound of Formula (IIaa), which they are attached, form a substituted or unsubstituted having the structure: heterocycloalkyl group, wherein the heterocycloalkyl group is a Substituted or unsubstituted pyrrolidine ring. In another embodiment of any of the aforementioned embodiments is a O compound of Formula (IIaa), wherein R and Rs groups on 35 R adjacent atoms, together with the atoms to which they are Ne) N a attached, form a substituted or unsubstituted heterocycloalkyl H group, wherein the heterocycloalkyl group is a Substituted or unsubstituted piperidine ring. In another embodiment of any On of the aforementioned embodiments is a compound of For 40 mula (IIaa), wherein R and Rs groups on adjacent atoms, together with the atoms to which they are attached, form a wherein R is hydrogen or methyl; and p is 1. substituted or unsubstituted heterocycloalkyl group, wherein In some embodiments is a compound of Formula (IIaa), the heterocycloalkyl group is a substituted or unsubstituted having the structure: piperazine ring. In another embodiment of any of the afore mentioned embodiments is a compound of Formula (IIaa), 45 wherein R and R are each independently hydrogen or Sub O stituted or unsubstituted alkyl. In another embodiment of any R of the aforementioned embodiments is a compound of For Nel), N 21 mula (IIaa), wherein R and Rare eachindependently hydro H gen or methyl. In another embodiment of any of the afore 50 mentioned embodiments is a compound of Formula (IIaa), OS wherein R and Rare each hydrogen. In another embodiment of any of the aforementioned embodiments is a compound of Formula (IIaa), wherein R is hydrogen or R is methyl. In wherein R is hydrogen or methyl; and p is 2. another embodiment of any of the aforementioned embodi 55 In some embodiments is a compound of Formula (IIaa), ments is a compound of Formula (IIaa), wherein p is 1. In having the structure: another embodiment of any of the aforementioned embodi ments is a compound of Formula (IIaa), wherein p is 2. In another embodiment of any of the aforementioned embodi R4 O ments is a compound of Formula (IIaa), wherein p is 3. In N another embodiment of any of the aforementioned embodi 60 ments is a compound of Formula (IIaa), wherein p is 4. In H1 p lO H --~~ another embodiment of any of the aforementioned embodi N O ments is a compound of Formula (IIaa), wherein p is 5. In On another embodiment of any of the aforementioned embodi ments is a compound of Formula (IIaa), wherein p is 6. In 65 another embodiment of any of the aforementioned embodi wherein R is hydrogen or methyl; and p is an integer from 1 ments is a compound of Formula (IIaa), wherein p is 7. In to 9. US 9,359,316 B1 29 30 In some embodiments is a compound of Formula (IIaa), a pharmaceutically acceptable salt, pharmaceutically accept having the structure: able solvate, or hydrate thereof. In some embodiments is a compound of Formula (IIb). wherein Rs is H. In some embodiments is a compound of R4 O 5 Formula (IIb), wherein Rs is substituted or unsubstituted alkyl. In some embodiments is a compound of Formula (IIb). wherein Rs is unsubstituted alkyl. In some embodiments is a Hrs), o --~~ compound of Formula (IIb), wherein Rs is substituted alkyl. N ul-JO " In some embodiments is a compound of Formula (IIb). wherein Rs is substituted or unsubstituted aryl. In some On 10 embodiments is a compound of Formula (IIb), wherein Rs is Substituted phenyl. In some embodiments is a compound of wherein R is hydrogen or methyl; and p is an integer from 1 Formula (IIb), wherein Rs is unsubstituted phenyl. In some to 2. embodiments is a compound of Formula (IIb), wherein Rs is In some embodiments is a compound of Formula (IIaa), —CH. In some embodiments is a compound of Formula having the structure: 15 (IIb), wherein Rs is —CHCH. In some embodiments is a compound of Formula (IIb), wherein Rs is —CHCH-NH. In some embodiments is a compound of Formula (IIb). O wherein Rs is —CHCH-NH(alkyl). In some embodiments is a compound of Formula (IIb), wherein Rs is —CHCH-NH (CH). In another embodiment of any of the aforementioned Hs), lso H --~~ embodiments is a compound of Formula (IIb), wherein each N O R and R are each independently hydrogen, Substituted or unsubstituted alkyl, or substituted or unsubstituted aryl. In On another embodiment of any of the aforementioned embodi ments is a compound of Formula (IIb), wherein each R and 25 R2 are each independently hydrogen, or Substituted or unsub wherein R is hydrogen or methyl; and p is 1. stituted alkyl. In another embodiment of any of the aforemen In some embodiments is a compound of Formula (IIaa), tioned embodiments is a compound of Formula (IIb), wherein having the structure: each R and R2 are hydrogen. In another embodiment of any of the aforementioned embodiments is a compound of For 30 mula (IIb), wherein each R and R are each independently O hydrogen, or Substituted or unsubstituted alkyl. In another embodiment of any of the aforementioned embodiments is a compound of Formula (IIb), wherein RandR together with 1N )p lulu.O " --~~~ the carbonatom to which they are attached form a substituted N O or unsubstituted cycloalkyl group. In another embodiment of On 35 any of the aforementioned embodiments is a compound of Formula (IIb), wherein R and Rs groups on adjacent atoms, together with the atoms to which they are attached, form a wherein R is hydrogen or methyl; and p is 2. Substituted or unsubstituted heterocycloalkyl group. In In another embodiment, described herein is a compound another embodiment of any of the aforementioned embodi having the structure of Formula (IIb): ments is a compound of Formula (IIb), wherein R and Rs

Formula (IIb)

wherein: groups on adjacent atoms, together with the atoms to which Rs is hydrogen, Substituted or unsubstituted alkyl, or Sub they are attached, form a substituted or unsubstituted hetero stituted or unsubstituted aryl, and each R and R is each 55 cycloalkyl group, wherein the heterocycloalkyl group is a independently hydrogen, Substituted or unsubstituted alkyl, substituted or unsubstituted pyrrolidine ring. In another substituted or unsubstituted aryl, or substituted or unsubsti embodiment of any of the aforementioned embodiments is a tuted acyl, or R and R together with the carbon atom to compound of Formula (IIb), wherein R and Rs groups on which they are attached form a substituted or unsubstituted adjacent atoms, together with the atoms to which they are cycloalkyl group, or two R or R groups on adjacent carbon attached, form a substituted or unsubstituted heterocycloalkyl atoms, together with the carbon atoms to which they are 60 group, wherein the heterocycloalkyl group is a Substituted or attached, form a substituted or unsubstituted cycloalkyl unsubstituted piperidine ring. In another embodiment of any group, or R and Rs groups on adjacent atoms, together with of the aforementioned embodiments is a compound of For the atoms to which they are attached, form a substituted or mula (IIb), wherein R and Rs groups on adjacent atoms, unsubstituted heterocycloalkyl group; together with the atoms to which they are attached, form a R and R is each independently hydrogen, Substituted or 65 substituted or unsubstituted heterocycloalkyl group, wherein unsubstituted alkyl, or substituted or unsubstituted aryl; and the heterocycloalkyl group is a substituted or unsubstituted p is an integer from 1 to 9; or piperazine ring. In another embodiment of any of the afore US 9,359,316 B1 31 32 mentioned embodiments is a compound of Formula (IIb). pound of Formula (IIbb), wherein Rs is —CHCH. In some wherein R and R are each independently hydrogen or sub embodiments is a compound of Formula (IIbb), wherein Rs is stituted or unsubstituted alkyl. In another embodiment of any —CH2CHNH2. In some embodiments is a compound of of the aforementioned embodiments is a compound of For Formula (IIbb), wherein Rs is —CH2CH-NHCalkyl). In some mula (IIb), wherein RandR are each independently hydro embodiments is a compound of Formula (IIbb), wherein Rs is gen or methyl. In another embodiment of any of the afore —CHCH-NH(CH). In another embodiment of any of the mentioned embodiments is a compound of Formula (IIb). aforementioned embodiments is a compound of Formula wherein R and Rare each hydrogen. In another embodiment (IIbb), wherein each RandR are each independently hydro of any of the aforementioned embodiments is a compound of gen, substituted or unsubstituted alkyl, or substituted or Formula (IIb), wherein R is hydrogen or R is methyl. In unsubstituted aryl. In another embodiment of any of the another embodiment of any of the aforementioned embodi 10 aforementioned embodiments is a compound of Formula ments is a compound of Formula (IIb), wherein p is 1. In (IIbb), wherein each R and Rare each independently hydro another embodiment of any of the aforementioned embodi gen, or substituted or unsubstituted alkyl. In another embodi ments is a compound of Formula (IIb), wherein p is 2. In ment of any of the aforementioned embodiments is a com another embodiment of any of the aforementioned embodi pound of Formula (IIbb), wherein each R and R are ments is a compound of Formula (IIb), wherein p is 3. In 15 hydrogen. In another embodiment of any of the aforemen another embodiment of any of the aforementioned embodi tioned embodiments is a compound of Formula (IIbb), ments is a compound of Formula (IIb), wherein p is 4. In wherein each RandR are each independently hydrogen, or another embodiment of any of the aforementioned embodi substituted or unsubstituted alkyl. In another embodiment of ments is a compound of Formula (IIb), wherein p is 5. In any of the aforementioned embodiments is a compound of another embodiment of any of the aforementioned embodi Formula (IIbb), wherein R and R together with the carbon ments is a compound of Formula (IIb), wherein p is 6. In atom to which they are attached form a substituted or unsub another embodiment of any of the aforementioned embodi stituted cycloalkyl group. In another embodiment of any of ments is a compound of Formula (IIb), wherein p is 7. In the aforementioned embodiments is a compound of Formula another embodiment of any of the aforementioned embodi (IIbb), wherein R and Rs groups on adjacent atoms, together ments is a compound of Formula (IIb), wherein p is 8. In with the atoms to which they are attached, form a substituted another embodiment of any of the aforementioned embodi 25 or unsubstituted heterocycloalkyl group. In another embodi ments is a compound of Formula (IIb), wherein p is 9. ment of any of the aforementioned embodiments is a com In another embodiment, described herein is a compound pound of Formula (IIbb), wherein R and Rs groups on adja having the structure of Formula (IIbb): cent atoms, together with the atoms to which they are

Formula (IIbb)

40 wherein: attached, form a substituted or unsubstituted heterocycloalkyl Rs is hydrogen, Substituted or unsubstituted alkyl, or Sub group, wherein the heterocycloalkyl group is a Substituted or stituted or unsubstituted aryl, and each R and R is each unsubstituted pyrrolidine ring. In another embodiment of any independently hydrogen, Substituted or unsubstituted alkyl, of the aforementioned embodiments is a compound of For substituted or unsubstituted aryl, or substituted or unsubsti 45 mula (IIbb), wherein R and Rs groups on adjacent atoms, tuted acyl, or R and R together with the carbon atom to together with the atoms to which they are attached, form a which they are attached form a substituted or unsubstituted substituted or unsubstituted heterocycloalkyl group, wherein cycloalkyl group, or R and Rs groups together with the atoms the heterocycloalkyl group is a substituted or unsubstituted to which they are attached, form a substituted or unsubstituted piperidine ring. In another embodiment of any of the afore heterocycloalkyl group; 50 mentioned embodiments is a compound of Formula (IIbb), R and R is each independently hydrogen, Substituted or wherein R and Rs groups on adjacent atoms, together with unsubstituted alkyl, or substituted or unsubstituted aryl; and the atoms to which they are attached, form a substituted or p is an integer from 1 to 9; or unsubstituted heterocycloalkyl group, wherein the heterocy a pharmaceutically acceptable salt, pharmaceutically accept cloalkyl group is a substituted or unsubstituted piperazine able solvate, or hydrate thereof. 55 ring. In another embodiment of any of the aforementioned In some embodiments is a compound of Formula (IIbb), embodiments is a compound of Formula (IIbb), wherein R wherein Rs is H. In some embodiments is a compound of and Ra are each independently hydrogen or substituted or Formula (IIbb), wherein Rs is substituted or unsubstituted unsubstituted alkyl. In another embodiment of any of the alkyl. In some embodiments is a compound of Formula aforementioned embodiments is a compound of Formula (IIbb), wherein Rs is unsubstituted alkyl. In some embodi (IIbb), wherein R and Rare each independently hydrogen or ments is a compound of Formula (IIbb), wherein Rs is sub 60 methyl. In another embodiment of any of the aforementioned stituted alkyl. In some embodiments is a compound of For embodiments is a compound of Formula (IIbb), wherein R mula (IIbb), wherein Rs is substituted or unsubstituted aryl. In and R are each hydrogen. In another embodiment of any of some embodiments is a compound of Formula (IIbb), the aforementioned embodiments is a compound of Formula wherein Rs is substituted phenyl. In some embodiments is a (IIbb), wherein R is hydrogen or R is methyl. In another compound of Formula (IIbb), wherein Rs is unsubstituted 65 embodiment of any of the aforementioned embodiments is a phenyl. In some embodiments is a compound of Formula compound of Formula (IIbb), wherein p is 1. In another (IIbb), wherein Rs is —CH. In some embodiments is a com embodiment of any of the aforementioned embodiments is a US 9,359,316 B1 33 34 compound of Formula (IIbb), wherein p is 2. In another In some embodiments is a compound of Formula (IIbb), embodiment of any of the aforementioned embodiments is a having the structure: compound of Formula (IIbb), wherein p is 3. In another embodiment of any of the aforementioned embodiments is a compound of Formula (IIbb), wherein p is 4. In another O embodiment of any of the aforementioned embodiments is a compound of Formula (IIbb), wherein p is 5. In another H1Ns) O --~~ embodiment of any of the aforementioned embodiments is a l H compound of Formula (IIbb), wherein p is 6. In another N. O. embodiment of any of the aforementioned embodiments is a compound of Formula (IIbb), wherein p is 7. In another 10 On embodiment of any of the aforementioned embodiments is a compound of Formula (IIbb), wherein p is 8. In another wherein R is hydrogen or methyl; and p is an integer from 1 embodiment of any of the aforementioned embodiments is a to 9. compound of Formula (IIbb), wherein p is 9. In some embodiments is a compound of Formula (IIbb), In some embodiments is a compound of Formula (IIbb), 15 having the structure: having the structure: O H1Ns) --~~~ R4 1--~~ 2O H try N N O N O On On 25 wherein R is hydrogen or methyl; and p is an integer from 1 to 2. wherein R is hydrogen or methyl; and p is an integer from 1 In some embodiments is a compound of Formula (IIbb), to 9. having the structure: In some embodiments is a compound of Formula (IIbb), having the structure: 30 O O H1Ns) O --~~~ l H R 1--~~ N 'O H Ne) N 35 -so On On wherein R is hydrogen or methyl; and p is 1. In some embodiments is a compound of Formula (IIbb), wherein R is hydrogen or methyl; and p is an integer from 1 40 having the structure: to 2. In some embodiments is a compound of Formula (IIbb), having the structure: O 45 H1Ns) O --~~ O l H R; 1--~~ N 'O try N On N O 50 wherein R is hydrogen or methyl; and p is 2. On In another embodiment, described herein is a compound having the structure of Formula (IIc): wherein R is hydrogen or methyl; and p is 1. In some embodiments is a compound of Formula (IIbb), having the structure: Formula (IIc)

O tryR; N 1--~~ 60 N O On 65 wherein: Rs is hydrogen, Substituted or unsubstituted alkyl, or Sub wherein R is hydrogen or methyl; and p is 2. stituted or unsubstituted aryl, and each R and R is each US 9,359,316 B1 35 36 independently hydrogen, Substituted or unsubstituted alkyl, mentioned embodiments is a compound of Formula (Ic), substituted or unsubstituted aryl, or substituted or unsubsti wherein R and R are each independently hydrogen or Sub tuted acyl, or R and R together with the carbon atom to stituted or unsubstituted alkyl. In another embodiment of any which they are attached form a substituted or unsubstituted of the aforementioned embodiments is a compound of For cycloalkyl group, or two R or R groups on adjacent carbon mula (Ic), wherein R and R are each independently hydro atoms, together with the carbon atoms to which they are gen or methyl. In another embodiment of any of the afore attached, form a substituted or unsubstituted cycloalkyl group, or R and Rs groups on adjacent atoms, together with mentioned embodiments is a compound of Formula (Ic), the atoms to which they are attached, form a substituted or wherein RandR are each hydrogen. In another embodiment unsubstituted heterocycloalkyl group; of any of the aforementioned embodiments is a compound of R and R is each independently hydrogen, Substituted or 10 Formula (Ic), wherein R is hydrogen or R is methyl. In unsubstituted alkyl, or substituted or unsubstituted aryl; and another embodiment of any of the aforementioned embodi p is an integer from 1 to 9; or ments is a compound of Formula (Ic), wherein p is 1. In a pharmaceutically acceptable salt, pharmaceutically accept another embodiment of any of the aforementioned embodi able solvate, or hydrate thereof. ments is a compound of Formula (Ic), wherein p is 2. In In some embodiments is a compound of Formula (Ic), 15 another embodiment of any of the aforementioned embodi wherein Rs is H. In some embodiments is a compound of ments is a compound of Formula (Ic), wherein p is 3. In Formula (Ic), wherein Rs is substituted or unsubstituted another embodiment of any of the aforementioned embodi alkyl. In some embodiments is a compound of Formula (Ic), ments is a compound of Formula (Ic), wherein p is 4. In wherein Rs is unsubstituted alkyl. In some embodiments is a another embodiment of any of the aforementioned embodi compound of Formula (Ic), wherein Rs is substituted alkyl. ments is a compound of Formula (Ic), wherein p is 5. In In some embodiments is a compound of Formula (Ic), another embodiment of any of the aforementioned embodi wherein Rs is substituted or unsubstituted aryl. In some ments is a compound of Formula (Ic), wherein p is 6. In embodiments is a compound of Formula (Ic), wherein Rs is another embodiment of any of the aforementioned embodi Substituted phenyl. In some embodiments is a compound of ments is a compound of Formula (Ic), wherein p is 7. In Formula (IIc), wherein Rs is unsubstituted phenyl. In some another embodiment of any of the aforementioned embodi embodiments is a compound of Formula (Ic), wherein Rs is 25 ments is a compound of Formula (Ic), wherein p is 8. In —CH. In some embodiments is a compound of Formula another embodiment of any of the aforementioned embodi (IIc), wherein Rs is —CHCH. In some embodiments is a ments is a compound of Formula (Ic), wherein p is 9. compound of Formula (IIc), wherein Rs is —CHCH-NH. In another embodiment, described herein is a compound In some embodiments is a compound of Formula (Ic), having the structure of Formula (IIcc): wherein Rs is —CHCH-NH(alkyl). In some embodiments is 30 a compound of Formula (Ic), wherein Rs is —CHCH-NH (CH). In another embodiment of any of the aforementioned Formula (IIcc) embodiments is a compound of Formula (IIc), wherein each R and R2 are each independently hydrogen, Substituted or unsubstituted alkyl, or substituted or unsubstituted aryl. In another embodiment of any of the aforementioned embodi 35 ments is a compound of Formula (Ic), wherein each R and Rare each independently hydrogen, or substituted or unsub stituted alkyl. In another embodiment of any of the aforemen tioned embodiments is a compound of Formula (IIc), wherein each R and R are hydrogen. In another embodiment of any 40 of the aforementioned embodiments is a compound of For wherein: mula (IIc), wherein each R and R are each independently Rs is hydrogen, Substituted or unsubstituted alkyl, or Sub hydrogen, or Substituted or unsubstituted alkyl. In another stituted or unsubstituted aryl, and each R and R is each embodiment of any of the aforementioned embodiments is a independently hydrogen, Substituted or unsubstituted alkyl, compound of Formula (IIc), wherein RandR together with 45 substituted or unsubstituted aryl, or substituted or unsubsti the carbon atom to which they are attached form a substituted tuted acyl, or R and R together with the carbon atom to or unsubstituted cycloalkyl group. In another embodiment of which they are attached form a substituted or unsubstituted any of the aforementioned embodiments is a compound of cycloalkyl group, or R and Rs groups together with the atoms Formula (Ic), wherein R and Rs groups on adjacent atoms, to which they are attached, form a substituted or unsubstituted together with the atoms to which they are attached, form a heterocycloalkyl group; Substituted or unsubstituted heterocycloalkyl group. In 50 R and R is each independently hydrogen, Substituted or another embodiment of any of the aforementioned embodi unsubstituted alkyl, or substituted or unsubstituted aryl; and ments is a compound of Formula (IIc), wherein R and Rs p is an integer from 1 to 9; or groups on adjacent atoms, together with the atoms to which a pharmaceutically acceptable salt, pharmaceutically accept they are attached, form a substituted or unsubstituted hetero able solvate, or hydrate thereof. cycloalkyl group, wherein the heterocycloalkyl group is a 55 In some embodiments is a compound of Formula (IIcc), substituted or unsubstituted pyrrolidine ring. In another wherein Rs is H. In some embodiments is a compound of embodiment of any of the aforementioned embodiments is a Formula (IIcc), wherein Rs is substituted or unsubstituted compound of Formula (Ic), wherein R and Rs groups on alkyl. In some embodiments is a compound of Formula (IIcc), adjacent atoms, together with the atoms to which they are wherein Rs is unsubstituted alkyl. In some embodiments is a attached, form a substituted or unsubstituted heterocycloalkyl compound of Formula (IIcc), wherein Rs is substituted alkyl. group, wherein the heterocycloalkyl group is a Substituted or 60 In some embodiments is a compound of Formula (IIcc), unsubstituted piperidine ring. In another embodiment of any wherein Rs is substituted or unsubstituted aryl. In some of the aforementioned embodiments is a compound of For embodiments is a compound of Formula (IIcc), wherein Rs is mula (Ic), wherein R and Rs groups on adjacent atoms, Substituted phenyl. In some embodiments is a compound of together with the atoms to which they are attached, form a Formula (IIcc), wherein Rs is unsubstituted phenyl. In some substituted or unsubstituted heterocycloalkyl group, wherein 65 embodiments is a compound of Formula (IIcc), wherein Rs is the heterocycloalkyl group is a substituted or unsubstituted —CH. In some embodiments is a compound of Formula piperazine ring. In another embodiment of any of the afore (IIcc), wherein Rs is —CH2CH. In some embodiments is a US 9,359,316 B1 37 38 compound of Formula (IIcc), wherein Rs is —CHCH-NH. ments is a compound of Formula (IIcc), wherein p is 4. In In some embodiments is a compound of Formula (IIcc), another embodiment of any of the aforementioned embodi wherein Rs is —CHCH-NH(alkyl). In some embodiments is ments is a compound of Formula (IIcc), wherein p is 5. In a compound of Formula (IIcc), wherein Rs is —CHCH-NH another embodiment of any of the aforementioned embodi (CH). In another embodiment of any of the aforementioned 5 ments is a compound of Formula (IIcc), wherein p is 6. In embodiments is a compound of Formula (IIcc), wherein each another embodiment of any of the aforementioned embodi R and R are each independently hydrogen, substituted or ments is a compound of Formula (IIcc), wherein p is 7. In unsubstituted alkyl, or substituted or unsubstituted aryl. In another embodiment of any of the aforementioned embodi another embodiment of any of the aforementioned embodiments is a compound of Formula (IIcc), wherein p is 8. In ments is a compound of Formula (IIcc), wherein each R and 10 another embodiment of any of the aforementioned embodi R2 are each independently hydrogen, or Substituted or unsub- ments is a compound of Formula (IIcc), wherein p is 9. stituted alkyl. In another embodiment of any of the aforemen- In another embodiment, described herein is a compound tioned embodiments is a compound of Formula (IIcc), having the structure of Formula (IId): Formula (IId) O

N R R2 l --~~ s R1 x^ O R R2 Rs On wherein each RandR are hydrogen. In another embodiment wherein: of any of the aforementioned embodiments is a compound of 25 Rs is hydrogen, Substituted or unsubstituted alkyl, or Sub Formula (IIcc), wherein each R and R2 are each indepen- stituted or unsubstituted aryl, and each R and R is each dently hydrogen, or substituted or unsubstituted alkyl. In independently hydrogen, Substituted or unsubstituted alkyl, another embodiment of any of the aforementioned embodi- substituted or unsubstituted aryl, or substituted or unsubsti ments is a compound of Formula (IIcc), wherein R and R- tuted acyl, or R and R together with the carbon atom to together with the carbonatom to which they are attached form so which they are attached form a substituted or unsubstituted a Substituted or unsubstituted cycloalkyl group. In another cycloalkyl group, or two R or R groups on adjacent carbon embodiment of any of the aforementioned embodiments is a atoms, together with the carbon atoms to which they are compound of Formula (IIcc), wherein R and Rs groups on attached, form a substituted or unsubstituted cycloalkyl adjacent atoms, together with the atoms to which they are group, or R and Rs groups on adjacent atoms, together with attached, form a substituted or unsubstituted heterocycloalkyl the atoms to which they are attached, form a substituted or group. In another embodiment of any of the aforementioned unsubstituted heterocycloalkyl group: embodiments is a compound of Formula (IIcc), wherein R R and R is each independently hydrogen, Substituted or and Rs groups on adjacent atoms, together with the atoms to unsubstituted alkyl, or substituted or unsubstituted aryl; and which they are attached, form a substituted or unsubstituted p is an integer from 1 to 9; or heterocycloalkyl group, wherein the heterocycloalkyl group a pharmaceutically acceptable salt, pharmaceutically accept is a substituted or unsubstituted pyrrolidine ring. In another 40 able solvate, or hydrate thereof. embodiment of any of the aforementioned embodiments is a In some embodiments is a compound of Formula (IId), compound of Formula (IIcc), wherein R and Rs groups on wherein Rs is H. In some embodiments is a compound of adjacent atoms, together with the atoms to which they are Formula (IId), wherein Rs is substituted or unsubstituted attached, form a substituted or unsubstituted heterocycloalkyl alkyl. In some embodiments is a compound of Formula (IId), group, wherein the heterocycloalkyl group is a substituted or is wherein Rs is unsubstituted alkyl. In some embodiments is a unsubstituted piperidine ring. In another embodiment of any compound of Formula (IId), wherein Rs is substituted alkyl. of the aforementioned embodiments is a compound of For- In some embodiments is a compound of Formula (IId), mula (IIcc), wherein R and Rs groups on adjacent atoms, wherein Rs is substituted or unsubstituted aryl. In some together with the atoms to which they are attached, form a embodiments is a compound of Formula (IId), wherein Rs is substituted or unsubstituted heterocycloalkyl group, wherein Substituted phenyl. In some embodiments is a compound of the heterocycloalkyl group is a substituted or unsubstituted 50 Formula (IId), wherein Rs is unsubstituted phenyl. In some piperazine ring. In another embodiment of any of the afore- embodiments is a compound of Formula (IId), wherein Rs is mentioned embodiments is a compound of Formula (IIcc), —CH. In some embodiments is a compound of Formula wherein R and R are each independently hydrogen or Sub- (IId), wherein Rs is —CHCH. In some embodiments is a stituted or unsubstituted alkyl. In another embodiment of any compound of Formula (IId), wherein Rs is —CHCH-NH. of the aforementioned embodiments is a compound of For- 55 In some embodiments is a compound of Formula (IId), mula (IIcc), wherein R and Rare eachindependently hydro- wherein Rs is —CHCH-NH(alkyl). In some embodiments is gen or methyl. In another embodiment of any of the afore- a compound of Formula (IId), wherein Rs is —CHCH-NH mentioned embodiments is a compound of Formula (IIcc), (CH). In another embodiment of any of the aforementioned wherein R and Rare each hydrogen. In another embodiment embodiments is a compound of Formula (IId), wherein each of any of the aforementioned embodiments is a compound of R and R are each independently hydrogen, Substituted or Formula (IIcc), wherein R is hydrogen or R is methyl. In " unsubstituted alkyl, or substituted or unsubstituted aryl. In another embodiment of any of the aforementioned embodi- another embodiment of any of the aforementioned embodi ments is a compound of Formula (IIcc), wherein p is 1. In ments is a compound of Formula (IId), wherein each R and another embodiment of any of the aforementioned embodi- R2 are each independently hydrogen, or Substituted or unsub ments is a compound of Formula (IIcc), wherein p is 2. In stituted alkyl. In another embodiment of any of the aforemen another embodiment of any of the aforementioned embodi- 65 tioned embodiments is a compound of Formula (IId), wherein ments is a compound of Formula (IIcc), wherein p is 3. In each R and R2 are hydrogen. In another embodiment of any another embodiment of any of the aforementioned embodi- of the aforementioned embodiments is a compound of For US 9,359,316 B1 39 40 mula (IId), wherein each R and R are each independently wherein: hydrogen, or Substituted or unsubstituted alkyl. In another Rs is hydrogen, Substituted or unsubstituted alkyl, or Sub embodiment of any of the aforementioned embodiments is a stituted or unsubstituted aryl, and each R and R is each compound of Formula (IId), wherein RandR together with independently hydrogen, Substituted or unsubstituted alkyl, substituted or unsubstituted aryl, or substituted or unsubsti the carbon atom to which they are attached form a substituted 5 tuted acyl, or R and R together with the carbon atom to or unsubstituted cycloalkyl group. In another embodiment of which they are attached form a substituted or unsubstituted any of the aforementioned embodiments is a compound of cycloalkyl group, or R and Rs groups together with the atoms Formula (IId), wherein R and Rs groups on adjacent atoms, to which they are attached, form a substituted or unsubstituted together with the atoms to which they are attached, form a heterocycloalkyl group; Substituted or unsubstituted heterocycloalkyl group. In 10 R and R is each independently hydrogen, Substituted or another embodiment of any of the aforementioned embodi unsubstituted alkyl, or substituted or unsubstituted aryl; and p is an integer from 1 to 9; or ments is a compound of Formula (IId), wherein R and Rs a pharmaceutically acceptable salt, pharmaceutically accept groups on adjacent atoms, together with the atoms to which able solvate, or hydrate thereof. they are attached, form a substituted or unsubstituted hetero In some embodiments is a compound of Formula (IIdd), cycloalkyl group, wherein the heterocycloalkyl group is a 15 wherein Rs is H. In some embodiments is a compound of substituted or unsubstituted pyrrolidine ring. In another Formula (IIdd), wherein Rs is substituted or unsubstituted embodiment of any of the aforementioned embodiments is a alkyl. In some embodiments is a compound of Formula compound of Formula (IId), wherein R and Rs groups on (IIdd), wherein Rs is unsubstituted alkyl. In some embodi adjacent atoms, together with the atoms to which they are ments is a compound of Formula (IIdd), wherein Rs is Sub attached, form a substituted or unsubstituted heterocycloalkyl stituted alkyl. In some embodiments is a compound of For group, wherein the heterocycloalkyl group is a Substituted or mula (IIdd), wherein Rs is substituted or unsubstituted aryl. In unsubstituted piperidine ring. In another embodiment of any Some embodiments is a compound of Formula (IIdd), of the aforementioned embodiments is a compound of For wherein Rs is substituted phenyl. In some embodiments is a mula (IId), wherein R and Rs groups on adjacent atoms, compound of Formula (IIdd), wherein Rs is unsubstituted together with the atoms to which they are attached, form a phenyl. In some embodiments is a compound of Formula substituted or unsubstituted heterocycloalkyl group, wherein 25 (IIdd), wherein Rs is —CH. In some embodiments is a com the heterocycloalkyl group is a substituted or unsubstituted pound of Formula (IIdd), wherein Rs is —CHCH. In some piperazine ring. In another embodiment of any of the afore embodiments is a compound of Formula (IIdd), wherein Rs is mentioned embodiments is a compound of Formula (IId), —CH2CHNH2. In some embodiments is a compound of wherein R and R are each independently hydrogen or Sub Formula (IIdd), wherein Rs is —CH2CH-NHCalkyl). In some 30 embodiments is a compound of Formula (IIdd), wherein Rs is stituted or unsubstituted alkyl. In another embodiment of any —CHCH-NH(CH). In another embodiment of any of the of the aforementioned embodiments is a compound of For aforementioned embodiments is a compound of Formula mula (IId), wherein R and Rare each independently hydro (IIdd), wherein each RandR are each independently hydro gen or methyl. In another embodiment of any of the afore gen, substituted or unsubstituted alkyl, or substituted or mentioned embodiments is a compound of Formula (IId), unsubstituted aryl. In another embodiment of any of the wherein R and Rare each hydrogen. In another embodiment 35 aforementioned embodiments is a compound of Formula of any of the aforementioned embodiments is a compound of (IIdd), wherein each R and Rare each independently hydro Formula (IId), wherein R is hydrogen or R is methyl. In gen, or substituted or unsubstituted alkyl. In another embodi another embodiment of any of the aforementioned embodi ment of any of the aforementioned embodiments is a com ments is a compound of Formula (IId), wherein p is 1. In pound of Formula (IIdd), wherein each R and R are another embodiment of any of the aforementioned embodi 40 hydrogen. In another embodiment of any of the aforemen ments is a compound of Formula (IId), wherein p is 2. In tioned embodiments is a compound of Formula (IIdd), another embodiment of any of the aforementioned embodi wherein each RandR are each independently hydrogen, or ments is a compound of Formula (IId), wherein p is 3. In substituted or unsubstituted alkyl. In another embodiment of another embodiment of any of the aforementioned embodi any of the aforementioned embodiments is a compound of ments is a compound of Formula (IId), wherein p is 4. In 45 Formula (IIdd), wherein R and R together with the carbon another embodiment of any of the aforementioned embodi atom to which they are attached form a substituted or unsub ments is a compound of Formula (IId), wherein p is 5. In stituted cycloalkyl group. In another embodiment of any of another embodiment of any of the aforementioned embodi the aforementioned embodiments is a compound of Formula ments is a compound of Formula (IId), wherein p is 6. In (IIdd), wherein R and Rs groups on adjacent atoms, together another embodiment of any of the aforementioned embodi with the atoms to which they are attached, form a substituted ments is a compound of Formula (IId), wherein p is 7. In 50 or unsubstituted heterocycloalkyl group. In another embodi another embodiment of any of the aforementioned embodi ment of any of the aforementioned embodiments is a com ments is a compound of Formula (IId), wherein p is 8. In pound of Formula (IIdd), wherein R and Rs groups on adja another embodiment of any of the aforementioned embodi cent atoms, together with the atoms to which they are ments is a compound of Formula (IId), wherein p is 9. attached, form a substituted or unsubstituted heterocycloalkyl In another embodiment, described herein is a compound 55 group, wherein the heterocycloalkyl group is a Substituted or having the structure of Formula (IIdd): unsubstituted pyrrolidine ring. In another embodiment of any of the aforementioned embodiments is a compound of For mula (IIdd), wherein R and Rs groups on adjacent atoms, Formula (IIdd) together with the atoms to which they are attached, form a substituted or unsubstituted heterocycloalkyl group, wherein O 60 the heterocycloalkyl group is a substituted or unsubstituted piperidine ring. In another embodiment of any of the afore O N s mentioned embodiments is a compound of Formula (IIdd), NR. R R2 l --~~ wherein R and Rs groups on adjacent atoms, together with R N-2^ O the atoms to which they are attached, form a substituted or Rs O 65 unsubstituted heterocycloalkyl group, wherein the heterocy cloalkyl group is a substituted or unsubstituted piperazine ring. In another embodiment of any of the aforementioned US 9,359,316 B1 41 42 embodiments is a compound of Formula (IIdd), wherein R embodiments is a compound of Formula (IIe), wherein Rs is and Ra are each independently hydrogen or substituted or —CH. In some embodiments is a compound of Formula unsubstituted alkyl. In another embodiment of any of the (IIe), wherein Rs is —CHCH. In some embodiments is a aforementioned embodiments is a compound of Formula compound of Formula (IIe), wherein Rs is —CH2CH-NH2. (IIdd), wherein R and Rare each independently hydrogen or In some embodiments is a compound of Formula (IIe). methyl. In another embodiment of any of the aforementioned wherein Rs is CHCH-NH(alkyl). In some embodiments is a compound of Formula (IIe), wherein Rs is —CH2CH-NH embodiments is a compound of Formula (IIdd), wherein R (CH). In another embodiment of any of the aforementioned and Ra are each hydrogen. In another embodiment of any of embodiments is a compound of Formula (IIe), wherein each the aforementioned embodiments is a compound of Formula R and R are each independently hydrogen, Substituted or (IIdd), wherein R is hydrogen or R is methyl. In another 10 unsubstituted alkyl, or substituted or unsubstituted aryl. In embodiment of any of the aforementioned embodiments is a another embodiment of any of the aforementioned embodi compound of Formula (IIdd), wherein p is 1. In another ments is a compound of Formula (IIe), wherein each R1 and embodiment of any of the aforementioned embodiments is a Rare each independently hydrogen, or substituted or unsub compound of Formula (IIdd), wherein p is 2. In another stituted alkyl. In another embodiment of any of the aforemen embodiment of any of the aforementioned embodiments is a 15 tioned embodiments is a compound of Formula (IIe), wherein compound of Formula (IIdd), wherein p is 3. In another each R and R are hydrogen. In another embodiment of any embodiment of any of the aforementioned embodiments is a of the aforementioned embodiments is a compound of For compound of Formula (IIdd), wherein p is 4. In another mula (IIe), wherein each R and R2 are each independently embodiment of any of the aforementioned embodiments is a hydrogen, or substituted or unsubstituted alkyl. In another compound of Formula (IIdd), wherein p is 5. In another embodiment of any of the aforementioned embodiments is a embodiment of any of the aforementioned embodiments is a compound of Formula (IIe), wherein R and R together with compound of Formula (IIdd), wherein p is 6. In another the carbonatom to which they are attached form a substituted embodiment of any of the aforementioned embodiments is a or unsubstituted cycloalkyl group. In another embodiment of compound of Formula (IIdd), wherein p is 7. In another any of the aforementioned embodiments is a compound of embodiment of any of the aforementioned embodiments is a Formula (IIe), wherein R and Rs groups on adjacent atoms. compound of Formula (IIdd), wherein p is 8. In another 25 together with the atoms to which they are attached, form a embodiment of any of the aforementioned embodiments is a substituted or unsubstituted heterocycloalkyl group. In compound of Formula (IIdd), wherein p is 9. another embodiment of any of the aforementioned embodi In another embodiment, described herein is a compound ments is a compound of Formula (IIa), wherein R and Rs having the structure of Formula (IIe): groups on adjacent atoms, together with the atoms to which 30 they are attached, form a substituted or unsubstituted hetero cycloalkyl group, wherein the heterocycloalkyl group is a Formula (IIe) substituted or unsubstituted pyrrolidine ring. In another embodiment of any of the aforementioned embodiments is a compound of Formula (IIe), wherein R and Rs groups on adjacent atoms, together with the atoms to which they are 35 attached, form a substituted or unsubstituted heterocycloalkyl group, wherein the heterocycloalkyl group is a substituted or unsubstituted piperidine ring. In another embodiment of any of the aforementioned embodiments is a compound of For mula (IIe), wherein R and Rs groups on adjacent atoms, 40 together with the atoms to which they are attached, form a wherein: substituted or unsubstituted heterocycloalkyl group, wherein Rs is hydrogen, substituted or unsubstituted alkyl, or Sub the heterocycloalkyl group is a substituted or unsubstituted stituted or unsubstituted aryl, and each R and R2 is each piperazine ring. In another embodiment of any of the afore independently hydrogen, substituted or unsubstituted alkyl, mentioned embodiments is a compound of Formula (IIe). substituted or unsubstituted aryl, or substituted or unsubsti wherein R and R are each independently hydrogen or Sub tuted acyl, or R and R together with the carbon atom to 45 stituted or unsubstituted alkyl. In another embodiment of any which they are attached form a substituted or unsubstituted of the aforementioned embodiments is a compound of For cycloalkyl group, or two R or R groups on adjacent carbon mula (IIe), wherein R and Ra are each independently hydro atoms, together with the carbon atoms to which they are gen or methyl. In another embodiment of any of the afore attached, form a substituted or unsubstituted cycloalkyl mentioned embodiments is a compound of Formula (IIe). group, or R and Rs groups on adjacent atoms, together with 50 wherein RandR are each hydrogen. In another embodiment the atoms to which they are attached, form a substituted or of any of the aforementioned embodiments is a compound of unsubstituted heterocycloalkyl group: Formula (IIe), wherein R is hydrogen or R is methyl. In R and R is each independently hydrogen, substituted or another embodiment of any of the aforementioned embodi unsubstituted alkyl, or substituted or unsubstituted aryl; and ments is a compound of Formula (IIe), wherein p is 1. In p is an integer from 1 to 9; or 55 another embodiment of any of the aforementioned embodi a pharmaceutically acceptable salt, pharmaceutically accept ments is a compound of Formula (IIe), wherein p is 2. In able solvate, or hydrate thereof. another embodiment of any of the aforementioned embodi In some embodiments is a compound of Formula (IIe). ments is a compound of Formula (IIe), wherein p is 3. In wherein Rs is H. In some embodiments is a compound of another embodiment of any of the aforementioned embodi Formula (IIe), wherein Rs is substituted or unsubstituted ments is a compound of Formula (IIe), wherein p is 4. In alkyl. In some embodiments is a compound of Formula (IIe). 60 another embodiment of any of the aforementioned embodi wherein Rs is unsubstituted alkyl. In some embodiments is a ments is a compound of Formula (IIe), wherein p is 5. In compound of Formula (Ile), wherein Rs is substituted alkyl. another embodiment of any of the aforementioned embodi In some embodiments is a compound of Formula (IIe). ments is a compound of Formula (IIe), wherein p is 6. In wherein Rs is substituted or unsubstituted aryl. In some another embodiment of any of the aforementioned embodi embodiments is a compound of Formula (IIe), wherein Rs is 65 ments is a compound of Formula (IIe), wherein p is 7. In substituted phenyl. In some embodiments is a compound of another embodiment of any of the aforementioned embodi Formula (IIe), wherein Rs is unsubstituted phenyl. In some ments is a compound of Formula (IIe), wherein p is 8. In US 9,359,316 B1 43 44 another embodiment of any of the aforementioned embodi embodiments is a compound of Formula (IIee), wherein R ments is a compound of Formula (IIe), wherein p is 9. and Rs groups on adjacent atoms, together with the atoms to In another embodiment, described herein is a compound which they are attached, form a substituted or unsubstituted having the structure of Formula (IIee): heterocycloalkyl group, wherein the heterocycloalkyl group is a Substituted or unsubstituted pyrrolidine ring. In another embodiment of any of the aforementioned embodiments is a Formula (IIee) compound of Formula (IIee), wherein R and Rs groups on adjacent atoms, together with the atoms to which they are attached, form a substituted or unsubstituted heterocycloalkyl 10 group, wherein the heterocycloalkyl group is a Substituted or unsubstituted piperidine ring. In another embodiment of any of the aforementioned embodiments is a compound of For mula (IIee), wherein R and Rs groups on adjacent atoms, together with the atoms to which they are attached, form a substituted or unsubstituted heterocycloalkyl group, wherein 15 the heterocycloalkyl group is a substituted or unsubstituted wherein: piperazine ring. In another embodiment of any of the afore Rs is hydrogen, Substituted or unsubstituted alkyl, or Sub mentioned embodiments is a compound of Formula (IIee), stituted or unsubstituted aryl, and each R and R is each wherein R and R are each independently hydrogen or Sub independently hydrogen, Substituted or unsubstituted alkyl, stituted or unsubstituted alkyl. In another embodiment of any substituted or unsubstituted aryl, or substituted or unsubsti of the aforementioned embodiments is a compound of For tuted acyl, or R and R together with the carbon atom to mula (IIee), wherein R and Rare each independently hydro which they are attached form a substituted or unsubstituted gen or methyl. In another embodiment of any of the afore cycloalkyl group, or R and Rs groups together with the atoms mentioned embodiments is a compound of Formula (IIee), to which they are attached, form a substituted or unsubstituted wherein RandR are each hydrogen. In another embodiment heterocycloalkyl group; 25 of any of the aforementioned embodiments is a compound of R and R is each independently hydrogen, Substituted or Formula (IIee), wherein R is hydrogen or R is methyl. In unsubstituted alkyl, or substituted or unsubstituted aryl; and another embodiment of any of the aforementioned embodi p is an integer from 1 to 9; or ments is a compound of Formula (IIee), wherein p is 1. In a pharmaceutically acceptable salt, pharmaceutically accept another embodiment of any of the aforementioned embodi able solvate, or hydrate thereof. 30 ments is a compound of Formula (IIee), wherein p is 2. In In some embodiments is a compound of Formula (IIee), another embodiment of any of the aforementioned embodi wherein Rs is H. In some embodiments is a compound of ments is a compound of Formula (IIee), wherein p is 3. In Formula (IIee), wherein Rs is substituted or unsubstituted another embodiment of any of the aforementioned embodi alkyl. In some embodiments is a compound of Formula (IIee), ments is a compound of Formula (IIee), wherein p is 4. In wherein Rs is unsubstituted alkyl. In some embodiments is a another embodiment of any of the aforementioned embodi compound of Formula (IIee), wherein Rs is substituted alkyl. 35 ments is a compound of Formula (IIee), wherein p is 5. In In some embodiments is a compound of Formula (IIee), another embodiment of any of the aforementioned embodi wherein Rs is substituted or unsubstituted aryl. In some ments is a compound of Formula (IIee), wherein p is 6. In embodiments is a compound of Formula (IIee), wherein Rs is another embodiment of any of the aforementioned embodi Substituted phenyl. In some embodiments is a compound of ments is a compound of Formula (IIee), wherein p is 7. In Formula (IIee), wherein Rs is unsubstituted phenyl. In some 40 another embodiment of any of the aforementioned embodi embodiments is a compound of Formula (IIee), wherein Rs is ments is a compound of Formula (IIee), wherein p is 8. In —CH. In some embodiments is a compound of Formula another embodiment of any of the aforementioned embodi (IIee), wherein Rs is —CH2CH. In some embodiments is a ments is a compound of Formula (IIee), wherein p is 9. compound of Formula (IIee), wherein Rs is —CHCH-NH. In another embodiment, described herein is a compound In some embodiments is a compound of Formula (IIee), having the structure of Formula (IIf): wherein Rs is —CHCH-NH(alkyl). In some embodiments is 45 a compound of Formula (IIee), wherein Rs is —CHCH-NH (CH). In another embodiment of any of the aforementioned Formula (IIf) embodiments is a compound of Formula (IIee), wherein each R and R are each independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted aryl. In 50 another embodiment of any of the aforementioned embodi ments is a compound of Formula (IIee), wherein each R and R2 are each independently hydrogen, or Substituted or unsub stituted alkyl. In another embodiment of any of the aforemen / O tioned embodiments is a compound of Formula (IIee), 55 O wherein each RandR are hydrogen. In another embodiment of any of the aforementioned embodiments is a compound of Formula (IIee), wherein each R and R are each indepen R1 x^ O dently hydrogen, or substituted or unsubstituted alkyl. In R R2 Rs another embodiment of any of the aforementioned embodi ments is a compound of Formula (IIee), wherein R and R 60 together with the carbonatom to which they are attached form a Substituted or unsubstituted cycloalkyl group. In another wherein: embodiment of any of the aforementioned embodiments is a Rs is hydrogen, Substituted or unsubstituted alkyl, or Sub compound of Formula (IIee), wherein R and Rs groups on stituted or unsubstituted aryl, and each R and R is each adjacent atoms, together with the atoms to which they are 65 independently hydrogen, Substituted or unsubstituted alkyl, attached, form a substituted or unsubstituted heterocycloalkyl substituted or unsubstituted aryl, or substituted or unsubsti group. In another embodiment of any of the aforementioned tuted acyl, or R and R together with the carbon atom to US 9,359,316 B1 45 46 which they are attached form a substituted or unsubstituted mentioned embodiments is a compound of Formula (IIf). cycloalkyl group, or two R or R groups on adjacent carbon wherein R and Ra are each independently hydrogen or atoms, together with the carbon atoms to which they are methyl. In another embodiment of any of the aforementioned attached, form a substituted or unsubstituted cycloalkyl embodiments is a compound of Formula (IIf), wherein R and group, or R and Rs groups on adjacent atoms, together with Ra are each hydrogen. In another embodiment of any of the the atoms to which they are attached, form a substituted or unsubstituted heterocycloalkyl group: aforementioned embodiments is a compound of Formula R and R is each independently hydrogen, substituted or (IIf), wherein R is hydrogen or R is methyl. In another unsubstituted alkyl, or substituted or unsubstituted aryl; and embodiment of any of the aforementioned embodiments is a p is an integer from 1 to 9; or compound of Formula (IIf), wherein p is 1. In another a pharmaceutically acceptable salt, pharmaceutically accept 10 embodiment of any of the aforementioned embodiments is a able solvate, or hydrate thereof. compound of Formula (IIf), wherein p is 2. In another In some embodiments is a compound of Formula (IIf), embodiment of any of the aforementioned embodiments is a wherein Rs is H. In some embodiments is a compound of compound of Formula (IIf), wherein p is 3. In another Formula (IIf), wherein Rs is substituted or unsubstituted embodiment of any of the aforementioned embodiments is a alkyl. In some embodiments is a compound of Formula (IIf). 15 compound of Formula (IIf), wherein p is 4. In another wherein Rs is unsubstituted alkyl. In some embodiments is a embodiment of any of the aforementioned embodiments is a compound of Formula (IIf), wherein Rs is substituted alkyl. In compound of Formula (IIf), wherein p is 5. In another some embodiments is a compound of Formula (IIf), wherein embodiment of any of the aforementioned embodiments is a Rs is substituted or unsubstituted aryl. In some embodiments compound of Formula (IIf), wherein p is 6. In another is a compound of Formula (IIf), wherein Rs is substituted embodiment of any of the aforementioned embodiments is a phenyl. In some embodiments is a compound of Formula compound of Formula (IIf), wherein p is 7. In another (IIf), wherein Rs is unsubstituted phenyl. In some embodi embodiment of any of the aforementioned embodiments is a ments is a compound of Formula (IIf), wherein Rs is —CH. compound of Formula (IIf), wherein p is 8. In another In some embodiments is a compound of Formula (IIf), embodiment of any of the aforementioned embodiments is a wherein Rs is —CHCH. In some embodiments is a com compound of Formula (IIf), wherein p is 9. pound of Formula (IIf), wherein Rs is —CHCH-NH. In 25 In another embodiment, described herein is a compound some embodiments is a compound of Formula (IIf), wherein having the structure of Formula (IIff): Rs is —CHCH-NH(alkyl). In some embodiments is a com pound of Formula (IIf), wherein Rs is CHCH-NH(CH). In another embodiment of any of the aforementioned embodi Formula (IIff) ments is a compound of Formula (IIf), wherein each R and 30 R2 are each independently hydrogen, Substituted or unsubsti tuted alkyl, or substituted or unsubstituted aryl. In another embodiment of any of the aforementioned embodiments is a compound of Formula (IIf), wherein each R and Rare each independently hydrogen, or substituted or unsubstituted alkyl. In another embodiment of any of the aforementioned 35 / O embodiments is a compound of Formula (IIf), wherein each O R and Rare hydrogen. In another embodiment of any of the R. R. aforementioned embodiments is a compound of Formula N ls (IIf), wherein each R and R are each independently hydro R1 -*. O gen, or substituted or unsubstituted alkyl. In another embodi 40 Rs ment of any of the aforementioned embodiments is a com pound of Formula (IIf), wherein R and R together with the carbon atom to which they are attached form a substituted or unsubstituted cycloalkyl group. In another embodiment of wherein: any of the aforementioned embodiments is a compound of Rs is hydrogen, Substituted or unsubstituted alkyl, or sub Formula (IIf), wherein R and Rs groups on adjacent atoms, 45 stituted or unsubstituted aryl, and each R and R is each together with the atoms to which they are attached, form a independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heterocycloalkyl group. In Substituted or unsubstituted aryl, or substituted or unsubsti another embodiment of any of the aforementioned embodi tuted acyl, or R and R together with the carbon atom to ments is a compound of Formula (IIf), wherein R and Rare which they are attached form a substituted or unsubstituted each independently hydrogen or substituted or unsubstituted 50 cycloalkyl group, or R and Rs groups together with the atoms alkyl. In another embodiment of any of the aforementioned to which they are attached, form a substituted or unsubstituted embodiments is a compound of Formula (IIf), wherein R and heterocycloalkyl group: Rs groups on adjacent atoms, together with the atoms to R and R is each independently hydrogen, substituted or which they are attached, form a substituted or unsubstituted unsubstituted alkyl, or substituted or unsubstituted aryl; and heterocycloalkyl group, wherein the heterocycloalkyl group 55 p is an integer from 1 to 9; or is a substituted or unsubstituted pyrrolidine ring. In another a pharmaceutically acceptable salt, pharmaceutically accept embodiment of any of the aforementioned embodiments is a able solvate, or hydrate thereof. compound of Formula (IIf), wherein R and Rs groups on In some embodiments is a compound of Formula (IIff), adjacent atoms, together with the atoms to which they are wherein Rs is H. In some embodiments is a compound of attached, form a substituted or unsubstituted heterocycloalkyl Formula (IIff), wherein Rs is substituted or unsubstituted group, wherein the heterocycloalkyl group is a substituted or 60 alkyl. In some embodiments is a compound of Formula (IIff), unsubstituted piperidine ring. In another embodiment of any wherein Rs is unsubstituted alkyl. In some embodiments is a of the aforementioned embodiments is a compound of For compound of Formula (IIff), wherein R is substituted alkyl. mula (IIf), wherein R and Rs groups on adjacent atoms, In some embodiments is a compound of Formula (IIff), together with the atoms to which they are attached, form a wherein Rs is substituted or unsubstituted aryl. In some substituted or unsubstituted heterocycloalkyl group, wherein 65 embodiments is a compound of Formula (IIff), wherein R is the heterocycloalkyl group is a substituted or unsubstituted Substituted phenyl. In some embodiments is a compound of piperazine ring. In another embodiment of any of the afore Formula (IIff), wherein Rs is unsubstituted phenyl. In some US 9,359,316 B1 47 48 embodiments is a compound of Formula (IIff), wherein Rs is another embodiment of any of the aforementioned embodi —CH. In some embodiments is a compound of Formula ments is a compound of Formula (IIff), wherein p is 9. (IIff), wherein Rs is —CHCH. In some embodiments is a In another embodiment, described herein is a compound compound of Formula (IIff), wherein Rs is —CHCH-NH. having the structure of Formula (III): In some embodiments is a compound of Formula (IIff), wherein Rs is —CHCH-NH(alkyl). In some embodiments is a compound of Formula (IIff), wherein Rs is —CHCH-NH Formula (III) (CH). In another embodiment of any of the aforementioned embodiments is a compound of Formula (IIff), wherein each R and R2 are each independently hydrogen, Substituted or unsubstituted alkyl, or substituted or unsubstituted aryl. In 10 another embodiment of any of the aforementioned embodi ments is a compound of Formula (IIff), wherein each R and Rare each independently hydrogen, or substituted or unsub stituted alkyl. In another embodiment of any of the aforemen wherein: tioned embodiments is a compound of Formula (IIff), 15 Y is a phenolic TRPV1 agonist, wherein the hydrogen wherein each RandR are hydrogen. In another embodiment atom of the phenolic hydroxyl group is replaced by a covalent of any of the aforementioned embodiments is a compound of bond to —C(O)—C(R)(R)—(C(R)(R))-Z: Formula (IIff), wherein each R and R are each indepen Z is NRR or —COH: dently hydrogen, or substituted or unsubstituted alkyl. In each R and R is each independently hydrogen, Substi another embodiment of any of the aforementioned embodi tuted or unsubstituted alkyl, substituted or unsubstituted aryl, ments is a compound of Formula (IIff), wherein R and R or Substituted or unsubstituted acyl, or R and R together together with the carbonatom to which they are attached form with the carbon atom to which they are attached form a a Substituted or unsubstituted cycloalkyl group. In another Substituted or unsubstituted cycloalkyl group, or two R or R embodiment of any of the aforementioned embodiments is a groups on adjacent carbon atoms, together with the carbon compound of Formula (IIff), wherein R and Rs groups on atoms to which they are attached, form a substituted or unsub adjacent atoms, together with the atoms to which they are 25 stituted cycloalkyl group; attached, form a substituted or unsubstituted heterocycloalkyl group. In another embodiment of any of the aforementioned R and R is each independently hydrogen, Substituted or embodiments is a compound of Formula (IIff), wherein R unsubstituted alkyl, or substituted or unsubstituted aryl; and and Rs groups on adjacent atoms, together with the atoms to n is an integer from 1 to 10; or which they are attached, form a substituted or unsubstituted 30 a pharmaceutically acceptable salt, pharmaceutically accept heterocycloalkyl group, wherein the heterocycloalkyl group able solvate, or hydrate thereof. is a substituted or unsubstituted pyrrolidine ring. In another In some embodiments is a compound of Formula (III), embodiment of any of the aforementioned embodiments is a wherein Y is compound of Formula (IIff), wherein R and Rs groups on adjacent atoms, together with the atoms to which they are attached, form a substituted or unsubstituted heterocycloalkyl 35 O group, wherein the heterocycloalkyl group is a Substituted or unsubstituted piperidine ring. In another embodiment of any N 21 s of the aforementioned embodiments is a compound of For H mula (IIff), wherein R and Rs groups on adjacent atoms, together with the atoms to which they are attached, form a 40 substituted or unsubstituted heterocycloalkyl group, wherein x, the heterocycloalkyl group is a substituted or unsubstituted On piperazine ring. In another embodiment of any of the afore mentioned embodiments is a compound of Formula (IIff), O s wherein R and R are each independently hydrogen or Sub 45 stituted or unsubstituted alkyl. In another embodiment of any N 21 of the aforementioned embodiments is a compound of For H mula (IIff), wherein R and Rare each independently hydro gen or methyl. In another embodiment of any of the afore mentioned embodiments is a compound of Formula (IIff), X, wherein R and Rare each hydrogen. In another embodiment 50 of any of the aforementioned embodiments is a compound of ON Formula (IIff), wherein R is hydrogen or R is methyl. In O another embodiment of any of the aforementioned embodi N s ments is a compound of Formula (IIff), wherein p is 1. In H another embodiment of any of the aforementioned embodi 55 ments is a compound of Formula (IIff), wherein p is 2. In another embodiment of any of the aforementioned embodi X, ments is a compound of Formula (IIff), wherein p is 3. In On another embodiment of any of the aforementioned embodi O ments is a compound of Formula (IIff), wherein p is 4. In another embodiment of any of the aforementioned embodi 60 ments is a compound of Formula (IIff), wherein p is 5. In ----> another embodiment of any of the aforementioned embodi H ments is a compound of Formula (IIff), wherein p is 6. In another embodiment of any of the aforementioned embodi X, ments is a compound of Formula (IIff), wherein p is 7. In 65 another embodiment of any of the aforementioned embodi On ments is a compound of Formula (IIff), wherein p is 8. In US 9,359,316 B1 49 50 -continued O x -- " 1--~~ X, or

10 In some embodiments is a compound of Formula (III), wherein Y is 15 co In some embodiments is a compound of Formula (III), 25 wherein Y is

In some embodiments is a compound of Formula (III), wherein Y is

co 35 In some embodiments is a compound of Formula (III), 40 wherein Y is

In another embodiment of any of the aforementioned 45 embodiments is a compound of Formula (III), wherein each R and R are each independently hydrogen, Substituted or unsubstituted alkyl, or substituted or unsubstituted aryl. In another embodiment of any of the aforementioned embodi ments is a compound of Formula (III), wherein each R and 50 R2 are each independently hydrogen, or Substituted or unsub stituted alkyl. In another embodiment of any of the aforemen tioned embodiments is a compound of Formula (III), wherein each R and R are hydrogen. In another embodiment of any of the aforementioned embodiments is a compound of For In some embodiments is a compound of Formula (III), 55 mula (III), wherein R and R together with the carbon atom wherein Y is to which they are attached form a substituted or unsubstituted cycloalkyl group. In another embodiment of any of the afore mentioned embodiments is a compound of Formula (III), wherein R and R are each independently hydrogen or sub stituted or unsubstituted alkyl. In another embodiment of any 60 of the aforementioned embodiments is a compound of For mula (III), wherein R and Ra are each independently hydro gen or methyl. In another embodiment of any of the afore mentioned embodiments is a compound of Formula (III), wherein RandR are each hydrogen. In another embodiment 65 of any of the aforementioned embodiments is a compound of or Formula (III), wherein R is hydrogen or R is methyl. In another embodiment of any of the aforementioned embodi US 9,359,316 B1 51 52 ments is a compound of Formula (III), wherein n is 2. In In another embodiment, described herein is a compound another embodiment of any of the aforementioned embodi having the structure of Formula (IIIaa): ments is a compound of Formula (III), wherein n is 3. In another embodiment of any of the aforementioned embodi ments is a compound of Formula (III), wherein n is 4. In Formula (IIIaa) another embodiment of any of the aforementioned embodi ments is a compound of Formula (III), wherein n is 5. In O another embodiment of any of the aforementioned embodi a ments is a compound of Formula (III), wherein n is 6. In R. R. Q --~~ another embodiment of any of the aforementioned embodi 10 --X (so ments is a compound of Formula (III), wherein n is 7. In R. RIV-2 On another embodiment of any of the aforementioned embodi ments is a compound of Formula (III), wherein n is 8. In another embodiment of any of the aforementioned embodi wherein: ments is a compound of Formula (III), wherein n is 9. In 15 each R and R is each independently hydrogen, Substi another embodiment of any of the aforementioned embodi tuted or unsubstituted alkyl, substituted or unsubstituted aryl, ments is a compound of Formula (III), wherein n is 10. or substituted or unsubstituted acyl, or R and R together In another embodiment, described herein is a compound with the carbon atom to which they are attached form a having the structure of Formula (IIIa): Substituted or unsubstituted cycloalkyl group; R and R is each independently hydrogen, Substituted or Formula (IIIa) unsubstituted alkyl, or substituted or unsubstituted aryl; and O p is an integer from 1 to 9; or a pharmaceutically acceptable salt, pharmaceutically accept 27 O R R2 O N --~~ 25 able solvate, or hydrate thereof. HO p O In some embodiments is a compound of Formula (IIIaa), R. R. R. R. wherein each R and R2 are each independently hydrogen, r2 is r2 OS substituted or unsubstituted alkyl, or substituted or unsubsti tuted aryl. In some embodiments is a compound of Formula 30 (IIIaa), wherein each R and R2 are each independently wherein: hydrogen, or substituted or unsubstituted alkyl. In some each R and R is each independently hydrogen, Substi embodiments is a compound of Formula (IIIaa), wherein each tuted or unsubstituted alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted acyl, or R and R together RandR are hydrogen. In some embodiments is a compound with the carbon atom to which they are attached form a 35 of Formula (IIIaa), wherein each R and Rare each indepen Substituted or unsubstituted cycloalkyl group, or two R or R dently hydrogen, or substituted or unsubstituted alkyl. In groups on adjacent carbon atoms, together with the carbon Some embodiments is a compound of Formula (IIIaa), atoms to which they are attached, form a substituted or unsub wherein R and R together with the carbon atom to which stituted cycloalkyl group; and they are attached form a substituted or unsubstituted p is an integer from 0 to 9; or 40 cycloalkyl group. In some embodiments is a compound of a pharmaceutically acceptable salt, pharmaceutically accept Formula (IIIaa), wherein R and Ra are each independently able solvate, or hydrate thereof. hydrogen or Substituted or unsubstituted alkyl. In some In some embodiments is a compound of Formula (IIIa), embodiments is a compound of Formula (IIIaa), wherein R wherein each R and R2 are each independently hydrogen, and R are each independently hydrogen or methyl. In some substituted or unsubstituted alkyl, or substituted or unsubsti 45 embodiments is a compound of Formula (IIIaa), wherein R tuted aryl. In some embodiments is a compound of Formula and R are each hydrogen. In some embodiments is a com (IIIa), wherein each RandR are each independently hydro pound of Formula (IIIaa), wherein R is hydrogen or R is gen, or Substituted or unsubstituted alkyl. In some embodi methyl. In another embodiment of any of the aforementioned ments is a compound of Formula (IIIa), wherein each R and embodiments is a compound of Formula (IIIaa), wherein p is R2 are hydrogen. In some embodiments is a compound of 50 1. In another embodiment of any of the aforementioned Formula (IIIa), wherein each R and R are each indepen dently hydrogen, or substituted or unsubstituted alkyl. In embodiments is a compound of Formula (IIIaa), wherein p is Some embodiments is a compound of Formula (IIIa), wherein 2. In another embodiment of any of the aforementioned R and R together with the carbon atom to which they are embodiments is a compound of Formula (IIIaa), wherein p is attached form a Substituted or unsubstituted cycloalkyl group. 55 3. In another embodiment of any of the aforementioned In some embodiments is a compound of Formula (IIIa), embodiments is a compound of Formula (IIIaa), wherein p is wherein p is 0. In some embodiments is a compound of 4. In another embodiment of any of the aforementioned Formula (IIIa), wherein p is 1. In some embodiments is a embodiments is a compound of Formula (IIIaa), wherein p is compound of Formula (IIIa), wherein p is 2. In some embodi ments is a compound of Formula (IIIa), wherein p is 3. In 5. In another embodiment of any of the aforementioned Some embodiments is a compound of Formula (IIIa), wherein embodiments is a compound of Formula (IIIaa), wherein p is p is 4. In some embodiments is a compound of Formula (IIIa), 6. In another embodiment of any of the aforementioned wherein p is 5. In some embodiments is a compound of embodiments is a compound of Formula (IIIaa), wherein p is Formula (IIIa), wherein p is 6. In some embodiments is a 7. In another embodiment of any of the aforementioned compound of Formula (IIIa), wherein p is 7. In some embodi embodiments is a compound of Formula (IIIaa), wherein p is ments is a compound of Formula (IIIa), wherein p is 8. In 65 8. In another embodiment of any of the aforementioned Some embodiments is a compound of Formula (IIIa), wherein embodiments is a compound of Formula (IIIaa), wherein p is p is 9. 9. US 9,359,316 B1 53 54 In another embodiment, described herein is a compound wherein: having the structure of Formula (IIIb): each R and R is each independently hydrogen, Substi tuted or unsubstituted alkyl, substituted or unsubstituted aryl, or Substituted or unsubstituted acyl, or R and R together Formula (IIIb) 5 with the carbon atom to which they are attached form a Substituted or unsubstituted cycloalkyl group; O R and R is each independently hydrogen, Substituted or O O --~~ unsubstituted alkyl, or substituted or unsubstituted aryl; and R. R. H p is an integer from 1 to 9; or ox^so a pharmaceutically acceptable salt, pharmaceutically accept R. R. R. R. able solvate, or hydrate thereof. rv2 TV- IV-2 OS In some embodiments is a compound of Formula (IIIbb), wherein each R and R are each independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubsti wherein: tuted aryl. In some embodiments is a compound of Formula each R and R is each independently hydrogen, Substi 15 (IIIbb), wherein each R and R are each independently tuted or unsubstituted alkyl, substituted or unsubstituted aryl, hydrogen, or Substituted or unsubstituted alkyl. In some or substituted or unsubstituted acyl, or R and R together embodiments is a compound of Formula (IIIbb), wherein with the carbon atom to which they are attached form a each R and R are hydrogen. In some embodiments is a Substituted or unsubstituted cycloalkyl group, or two R or R compound of Formula (IIIbb), wherein each R and R are groups on adjacent carbon atoms, together with the carbon each independently hydrogen, or Substituted or unsubstituted atoms to which they are attached, form a substituted or unsub alkyl. In some embodiments is a compound of Formula (II stituted cycloalkyl group, or R and Rs groups on adjacent Ibb), wherein R and R together with the carbon atom to atoms, together with the atoms to which they are attached, which they are attached form a substituted or unsubstituted form a substituted or unsubstituted heterocycloalkyl group; cycloalkyl group. In some embodiments is a compound of Formula (IIIbb), wherein R and Ra are each independently R and R is each independently hydrogen, Substituted or 25 hydrogen or Substituted or unsubstituted alkyl. In some unsubstituted alkyl, or substituted or unsubstituted aryl; and embodiments is a compound of Formula (IIIbb), wherein R p is an integer from 1 to 9; or and Ra are each independently hydrogen or methyl. In some a pharmaceutically acceptable salt, pharmaceutically accept embodiments is a compound of Formula (IIIbb), wherein R able solvate, or hydrate thereof. and R are each hydrogen. In some embodiments is a com In some embodiments is a compound of Formula (IIIb), 30 pound of Formula (IIIbb), wherein R is hydrogen or R is wherein each R and R are each independently hydrogen, methyl. In another embodiment of any of the aforementioned substituted or unsubstituted alkyl, or substituted or unsubsti embodiments is a compound of Formula (IIIbb), wherein p is tuted aryl. In some embodiments is a compound of Formula 1. In another embodiment of any of the aforementioned (IIIb), wherein each RandR are eachindependently hydro embodiments is a compound of Formula (IIIbb), wherein p is gen, or Substituted or unsubstituted alkyl. In some embodi 35 2. In another embodiment of any of the aforementioned ments is a compound of Formula (IIIb), wherein each R and embodiments is a compound of Formula (IIIbb), wherein p is R are hydrogen. In some embodiments is a compound of 3. In another embodiment of any of the aforementioned Formula (IIIb), wherein each R and R are each indepen embodiments is a compound of Formula (IIIbb), wherein p is dently hydrogen, or substituted or unsubstituted alkyl. In 4. In another embodiment of any of the aforementioned some embodiments is a compound of Formula (IIIb), wherein 40 embodiments is a compound of Formula (IIIbb), wherein p is R and R together with the carbon atom to which they are 5. In another embodiment of any of the aforementioned attached form a Substituted or unsubstituted cycloalkyl group. embodiments is a compound of Formula (IIIbb), wherein p is In some embodiments is a compound of Formula (IIIb). 6. In another embodiment of any of the aforementioned wherein p is 0. In some embodiments is a compound of embodiments is a compound of Formula (IIIbb), wherein p is Formula (IIIb), wherein p is 1. In some embodiments is a 7. In another embodiment of any of the aforementioned compound of Formula (IIIb), wherein p is 2. In some embodi 45 embodiments is a compound of Formula (IIIbb), wherein p is ments is a compound of Formula (IIIb), wherein p is 3. In 8. In another embodiment of any of the aforementioned some embodiments is a compound of Formula (IIIb), wherein embodiments is a compound of Formula (IIIbb), wherein p is p is 4. In some embodiments is a compound of Formula (IIIb). 9. wherein p is 5. In some embodiments is a compound of In another embodiment, described herein is a compound Formula (IIIb), wherein p is 6. In some embodiments is a 50 having the structure of Formula (IIIc): compound of Formula (IIIb), wherein p is 7. In some embodi ments is a compound of Formula (IIIb), wherein p is 8. In some embodiments is a compound of Formula (IIIb), wherein Formula (IIIc) p is 9. In another embodiment, described herein is a compound 55 having the structure of Formula (IIIbb): O R R2 O N J-C27 H HO p O Formula (IIIbb) R. R. R. R2 O O 60 1--~. N wherein: each R and R is each independently hydrogen, substi HO p O tuted or unsubstituted alkyl, substituted or unsubstituted aryl, 65 or Substituted or unsubstituted acyl, or R and R together with the carbon atom to which they are attached form a Substituted or unsubstituted cycloalkyl group, or two R or R US 9,359,316 B1 55 56 groups on adjacent carbon atoms, together with the carbon they are attached form a substituted or unsubstituted atoms to which they are attached, form a substituted or unsub cycloalkyl group. In some embodiments is a compound of stituted cycloalkyl group; and Formula (IIIcc), wherein R and Ra are each independently p is an integer from 0 to 9; or hydrogen or Substituted or unsubstituted alkyl. In some a pharmaceutically acceptable salt, pharmaceutically accept embodiments is a compound of Formula (IIIcc), wherein R able solvate, or hydrate thereof. and R are each independently hydrogen or methyl. In some In some embodiments is a compound of Formula (IIIc), embodiments is a compound of Formula (IIIcc), wherein R wherein each R and R are each independently hydrogen, and R are each hydrogen. In some embodiments is a com substituted or unsubstituted alkyl, or substituted or unsubsti pound of Formula (IIIcc), wherein R is hydrogen or R is tuted aryl. In some embodiments is a compound of Formula methyl. In another embodiment of any of the aforementioned (IIIc), wherein each RandR are each independently hydro 10 embodiments is a compound of Formula (IIIcc), wherein p is gen, or Substituted or unsubstituted alkyl. In some embodi 1. In another embodiment of any of the aforementioned ments is a compound of Formula (IIIc), wherein each R and embodiments is a compound of Formula (IIIcc), wherein p is R are hydrogen. In some embodiments is a compound of 2. In another embodiment of any of the aforementioned Formula (IIIc), wherein each R and R2 are each indepen embodiments is a compound of Formula (IIIcc), wherein p is dently hydrogen, or substituted or unsubstituted alkyl. In 15 3. In another embodiment of any of the aforementioned Some embodiments is a compound of Formula (IIIc), wherein embodiments is a compound of Formula (IIIcc), wherein p is R and R together with the carbon atom to which they are 4. In another embodiment of any of the aforementioned attached form a Substituted or unsubstituted cycloalkyl group. embodiments is a compound of Formula (IIIcc), wherein p is In some embodiments is a compound of Formula (IIIc), 5. In another embodiment of any of the aforementioned wherein p is 0. In some embodiments is a compound of embodiments is a compound of Formula (IIIcc), wherein p is Formula (IIIc), wherein p is 1. In some embodiments is a 6. In another embodiment of any of the aforementioned compound of Formula (IIIc), wherein p is 2. In some embodi embodiments is a compound of Formula (IIIcc), wherein p is ments is a compound of Formula (IIIc), wherein p is 3. In 7. In another embodiment of any of the aforementioned Some embodiments is a compound of Formula (IIIc), wherein embodiments is a compound of Formula (IIIcc), wherein p is p is 4. In some embodiments is a compound of Formula (IIIc), 8. In another embodiment of any of the aforementioned wherein p is 5. In some embodiments is a compound of 25 embodiments is a compound of Formula (IIIcc), wherein p is Formula (IIIc), wherein p is 6. In some embodiments is a 9. compound of Formula (IIIc), wherein p is 7. In some embodi In another embodiment, described herein is a compound ments is a compound of Formula (IIIc), wherein p is 8. In having the structure of Formula (IIId): Some embodiments is a compound of Formula (IIIc), wherein p is 9. 30 In another embodiment, described herein is a compound having the structure of Formula (IIIcc): Formula (IIId) O

O O N Formula (IIIcc) 35 R R2 --~~ HO p O R. R.r2 R.is R.r2 O N J-C21 H 40 wherein: HO p O each R and R is each independently hydrogen, Substi tuted or unsubstituted alkyl, substituted or unsubstituted aryl, or Substituted or unsubstituted acyl, or R and R together with the carbon atom to which they are attached form a wherein: Substituted or unsubstituted cycloalkyl group, or two R or R each R and R is each independently hydrogen, Substi 45 groups on adjacent carbon atoms, together with the carbon tuted or unsubstituted alkyl, substituted or unsubstituted aryl, atoms to which they are attached, form a substituted or unsub or Substituted or unsubstituted acyl, or R and R together stituted cycloalkyl group; and with the carbon atom to which they are attached form a p is an integer from 0 to 9; or Substituted or unsubstituted cycloalkyl group, or R and Rs a pharmaceutically acceptable salt, pharmaceutically accept groups together with the atoms to which they are attached, 50 able solvate, or hydrate thereof. form a substituted or unsubstituted heterocycloalkyl group; In some embodiments is a compound of Formula (IIId), R and R is each independently hydrogen, Substituted or wherein each R and R2 are each independently hydrogen, unsubstituted alkyl, or substituted or unsubstituted aryl; and substituted or unsubstituted alkyl, or substituted or unsubsti p is an integer from 1 to 9; or tuted aryl. In some embodiments is a compound of Formula a pharmaceutically acceptable salt, pharmaceutically accept 55 (IIId), wherein each RandR are each independently hydro able solvate, or hydrate thereof. gen, or Substituted or unsubstituted alkyl. In some embodi In some embodiments is a compound of Formula (IIIcc), ments is a compound of Formula (IIId), wherein each R and wherein each R and R are each independently hydrogen, R2 are hydrogen. In some embodiments is a compound of substituted or unsubstituted alkyl, or substituted or unsubsti Formula (IIId), wherein each R and R are each indepen tuted aryl. In some embodiments is a compound of Formula dently hydrogen, or substituted or unsubstituted alkyl. In (IIIcc), wherein each R and R are each independently 60 some embodiments is a compound of Formula (IIId), wherein hydrogen, or Substituted or unsubstituted alkyl. In some R and R together with the carbon atom to which they are embodiments is a compound of Formula (IIIcc), wherein each attached form a Substituted or unsubstituted cycloalkyl group. RandR are hydrogen. In some embodiments is a compound In some embodiments is a compound of Formula (IIId), of Formula (IIIcc), wherein each RandR are each indepen wherein p is 0. In some embodiments is a compound of dently hydrogen, or substituted or unsubstituted alkyl. In 65 Formula (IIId), wherein p is 1. In some embodiments is a Some embodiments is a compound of Formula (IIIcc), compound of Formula (IIId), wherein p is 2. In some embodi wherein R and R together with the carbon atom to which ments is a compound of Formula (IIId), wherein p is 3. In US 9,359,316 B1 57 58 some embodiments is a compound of Formula (IIId), wherein 8. In another embodiment of any of the aforementioned p is 4. In some embodiments is a compound of Formula (IIId), embodiments is a compound of Formula (IIIdd), wherein p is wherein p is 5. In some embodiments is a compound of 9. Formula (IIId), wherein p is 6. In some embodiments is a In another embodiment, described herein is a compound compound of Formula (IIId), wherein p is 7. In some embodi having the structure of Formula (IIIe): ments is a compound of Formula (IIId), wherein p is 8. In some embodiments is a compound of Formula (IIId), wherein p is 9. Formula (IIIe) In another embodiment, described herein is a compound having the structure of Formula (IIIdd): 10 O O N 1--- R R2 H s

Formula (IIIdd) HO p O O R. R.r2 R.is R.r2 On 15

Q R. R. Q --~~~~ wherein: --Xso each R and R is each independently hydrogen, Substi R. R.IV2 OS tuted or unsubstituted alkyl, substituted or unsubstituted aryl, or Substituted or unsubstituted acyl, or R and R together with the carbon atom to which they are attached form a wherein: Substituted or unsubstituted cycloalkyl group, or two R or R each R and R is each independently hydrogen, Substi groups on adjacent carbon atoms, together with the carbon tuted or unsubstituted alkyl, substituted or unsubstituted aryl, atoms to which they are attached, form a substituted or unsub or Substituted or unsubstituted acyl, or R and R together stituted cycloalkyl group; and with the carbon atom to which they are attached form a 25 p is an integer from 0 to 9; or Substituted or unsubstituted cycloalkyl group, or R and Rs a pharmaceutically acceptable salt, pharmaceutically accept groups together with the atoms to which they are attached, able solvate, or hydrate thereof. form a substituted or unsubstituted heterocycloalkyl group; In some embodiments is a compound of Formula (IIIe), R and R is each independently hydrogen, Substituted or wherein each R and R2 are each independently hydrogen, unsubstituted alkyl, or substituted or unsubstituted aryl; and 30 p is an integer from 1 to 9; or substituted or unsubstituted alkyl, or substituted or unsubsti a pharmaceutically acceptable salt, pharmaceutically accept tuted aryl. In some embodiments is a compound of Formula able solvate, or hydrate thereof. (IIIe), wherein each RandR are each independently hydro In some embodiments is a compound of Formula (IIIdd), gen, or Substituted or unsubstituted alkyl. In some embodi wherein each R and R2 are each independently hydrogen, ments is a compound of Formula (IIIe), wherein each R and 35 R2 are hydrogen. In some embodiments is a compound of substituted or unsubstituted alkyl, or substituted or unsubsti Formula (IIIe), wherein each R and R are each indepen tuted aryl. In some embodiments is a compound of Formula dently hydrogen, or substituted or unsubstituted alkyl. In (IIIdd), wherein each R and R are each independently some embodiments is a compound of Formula (IIIe), wherein hydrogen, or Substituted or unsubstituted alkyl. In some R and R together with the carbon atom to which they are embodiments is a compound of Formula (IIIdd), wherein attached form a Substituted or unsubstituted cycloalkyl group. each R and R are hydrogen. In some embodiments is a 40 compound of Formula (IIIdd), wherein each R and R are In some embodiments is a compound of Formula (IIIe), each independently hydrogen, or Substituted or unsubstituted wherein p is 0. In some embodiments is a compound of alkyl. In some embodiments is a compound of Formula (II Formula (IIIe), wherein p is 1. In some embodiments is a Idd), wherein R and R together with the carbon atom to compound of Formula (IIIe), wherein p is 2. In some embodi which they are attached form a substituted or unsubstituted ments is a compound of Formula (IIIe), wherein p is 3. In cycloalkyl group. In some embodiments is a compound of 45 some embodiments is a compound of Formula (IIIe), wherein Formula (IIIdd), wherein R and Ra are each independently p is 4. In some embodiments is a compound of Formula (IIIe), hydrogen or Substituted or unsubstituted alkyl. In some wherein p is 5. In some embodiments is a compound of embodiments is a compound of Formula (IIIdd), wherein R Formula (IIIe), wherein p is 6. In some embodiments is a and Ra are each independently hydrogen or methyl. In some compound of Formula (IIIe), wherein p is 7. In some embodi embodiments is a compound of Formula (IIIdd), wherein R 50 ments is a compound of Formula (IIIe), wherein p is 8. In and R are each hydrogen. In some embodiments is a com some embodiments is a compound of Formula (IIIe), wherein pound of Formula (IIIdd), wherein R is hydrogen or R is p is 9. methyl. In another embodiment of any of the aforementioned In another embodiment, described herein is a compound embodiments is a compound of Formula (IIIdd), wherein p is having the structure of Formula (IIIee): 1. In another embodiment of any of the aforementioned 55 Formula (IIIee) embodiments is a compound of Formula (IIIdd), wherein p is 2. In another embodiment of any of the aforementioned embodiments is a compound of Formula (IIIdd), wherein p is 3. In another embodiment of any of the aforementioned O R R2 O NH 1-1. s embodiments is a compound of Formula (IIIdd), wherein p is 4. In another embodiment of any of the aforementioned 60 --X also embodiments is a compound of Formula (IIIdd), wherein p is R. R.r2 On 5. In another embodiment of any of the aforementioned embodiments is a compound of Formula (IIIdd), wherein p is wherein: 6. In another embodiment of any of the aforementioned Rs is hydrogen, Substituted or unsubstituted alkyl, or Sub embodiments is a compound of Formula (IIIdd), wherein p is 65 stituted or unsubstituted aryl, and each R and R is each 7. In another embodiment of any of the aforementioned independently hydrogen, Substituted or unsubstituted alkyl, embodiments is a compound of Formula (IIIdd), wherein p is substituted or unsubstituted aryl, or substituted or unsubsti US 9,359,316 B1 59 60 tuted acyl, or R and R together with the carbon atom to wherein: which they are attached form a substituted or unsubstituted each R and R is each independently hydrogen, substi cycloalkyl group, or R and Rs groups together with the atoms tuted or unsubstituted alkyl, substituted or unsubstituted aryl, to which they are attached, form a substituted or unsubstituted or Substituted or unsubstituted acyl, or R and R together heterocycloalkyl group; with the carbon atom to which they are attached form a Substituted or unsubstituted cycloalkyl group, or two R or R R and R is each independently hydrogen, Substituted or groups on adjacent carbon atoms, together with the carbon unsubstituted alkyl, or substituted or unsubstituted aryl; and atoms to which they are attached, form a substituted or unsub p is an integer from 1 to 9; or stituted cycloalkyl group; and a pharmaceutically acceptable salt, pharmaceutically accept p is an integer from 0 to 9; or able solvate, or hydrate thereof. 10 a pharmaceutically acceptable salt, pharmaceutically accept In some embodiments is a compound of Formula (IIIee), able solvate, or hydrate thereof. wherein each R and R2 are each independently hydrogen, In some embodiments is a compound of Formula (IIIf), substituted or unsubstituted alkyl, or substituted or unsubsti wherein each R and R2 are each independently hydrogen, tuted aryl. In some embodiments is a compound of Formula substituted or unsubstituted alkyl, or substituted or unsubsti (IIIee), wherein each R and R2 are each independently 15 tuted aryl. In some embodiments is a compound of Formula hydrogen, or Substituted or unsubstituted alkyl. In some (IIIf), wherein each RandR are each independently hydro embodiments is a compound of Formula (IIIee), wherein each gen, or Substituted or unsubstituted alkyl. In some embodi RandR are hydrogen. In some embodiments is a compound ments is a compound of Formula (IIIf), wherein each R and of Formula (IIIee), wherein each RandR are each indepen R2 are hydrogen. In some embodiments is a compound of dently hydrogen, or substituted or unsubstituted alkyl. In Formula (IIIf), wherein each R and R are each indepen Some embodiments is a compound of Formula (IIIee), dently hydrogen, or substituted or unsubstituted alkyl. In wherein R and R together with the carbon atom to which some embodiments is a compound of Formula (IIIf), wherein they are attached form a substituted or unsubstituted R and R together with the carbon atom to which they are cycloalkyl group. In some embodiments is a compound of attached form a Substituted or unsubstituted cycloalkyl group. Formula (IIIee), wherein R and R are each independently In some embodiments is a compound of Formula (IIIf). 25 wherein p is 0. In some embodiments is a compound of hydrogen or Substituted or unsubstituted alkyl. In some Formula (IIIf), wherein p is 1. In some embodiments is a embodiments is a compound of Formula (IIIee), wherein R compound of Formula (IIIf), wherein p is 2. In some embodi and Ra are each independently hydrogen or methyl. In some ments is a compound of Formula (IIIf), wherein p is 3. In embodiments is a compound of Formula (IIIee), wherein R some embodiments is a compound of Formula (IIIf), wherein and R are each hydrogen. In some embodiments is a com p is 4. In some embodiments is a compound of Formula (IIIf). pound of Formula (IIIee), wherein R is hydrogen or R is 30 wherein p is 5. In some embodiments is a compound of methyl. In another embodiment of any of the aforementioned Formula wherein p is 6. In some embodiments is a compound embodiments is a compound of Formula (IIIee), wherein p is of Formula (IIIf), wherein p is 7. In some embodiments is a 1. In another embodiment of any of the aforementioned compound of Formula (IIIf), wherein p is 8. In some embodi embodiments is a compound of Formula (IIIee), wherein p is ments is a compound of Formula (IIIf), wherein p is 9. 2. In another embodiment of any of the aforementioned 35 In another embodiment, described herein is a compound embodiments is a compound of Formula (IIIee), wherein p is having the structure of Formula (IIIff): 3. In another embodiment of any of the aforementioned embodiments is a compound of Formula (IIIee), wherein p is 4. In another embodiment of any of the aforementioned Formula (IIIff)

embodiments is a compound of Formula (IIIee), wherein p is 5. In another embodiment of any of the aforementioned 40 embodiments is a compound of Formula (IIIee), wherein p is 6. In another embodiment of any of the aforementioned embodiments is a compound of Formula (IIIee), wherein p is 7. In another embodiment of any of the aforementioned embodiments is a compound of Formula (IIIee), wherein p is 45 8. In another embodiment of any of the aforementioned embodiments is a compound of Formula (IIIee), wherein p is 9. In another embodiment, described herein is a compound HO having the structure of Formula (IIIf): 50

Formula (IIIf) wherein: 55 each R and R is each independently hydrogen, substi tuted or unsubstituted alkyl, substituted or unsubstituted aryl, or Substituted or unsubstituted acyl, or R and R together with the carbon atom to which they are attached form a Substituted or unsubstituted cycloalkyl group, or R and Rs groups together with the atoms to which they are attached, O 60 form a substituted or unsubstituted heterocycloalkyl group; O R R2 O R and R is each independently hydrogen, Substituted or HO p O unsubstituted alkyl, or substituted or unsubstituted aryl; and p is an integer from 1 to 9; or R. R. R. R2 a pharmaceutically acceptable salt, pharmaceutically accept 65 able solvate, or hydrate thereof. In some embodiments is a compound of Formula (IIIff), wherein each R and R2 are each independently hydrogen, US 9,359,316 B1 61 62 substituted or unsubstituted alkyl, or substituted or unsubsti a pharmaceutically acceptable salt, pharmaceutically accept tuted aryl. In some embodiments is a compound of Formula able solvate, or hydrate thereof. (IIIff), wherein each RandR are each independently hydro In some embodiments is a compound of Formula (IV), gen, or Substituted or unsubstituted alkyl. In some embodi wherein Y is ments is a compound of Formula (IIIff), wherein each R and 5 R are hydrogen. In some embodiments is a compound of Formula (IIIff), wherein each R and R are each indepen dently hydrogen, or substituted or unsubstituted alkyl. In some embodiments is a compound of Formula (IIIff), wherein R and R together with the carbon atom to which 10 they are attached form a substituted or unsubstituted cycloalkyl group. In some embodiments is a compound of Formula (IIIff), wherein R and Ra are each independently hydrogen or Substituted or unsubstituted alkyl. In some embodiments is a compound of Formula (IIIff), wherein R and Ra are each independently hydrogen or methyl. In some 15 embodiments is a compound of Formula (IIIff), wherein R and Ra are each hydrogen. In some embodiments is a com pound of Formula (IIIff), wherein R is hydrogen or R is methyl. In another embodiment of any of the aforementioned embodiments is a compound of Formula (IIIff), wherein p is 1. In another embodiment of any of the aforementioned embodiments is a compound of Formula (IIIff), wherein p is 2. In another embodiment of any of the aforementioned embodiments is a compound of Formula (IIIff), wherein p is 3. In another embodiment of any of the aforementioned 25 embodiments is a compound of Formula (IIIff), wherein p is 4. In another embodiment of any of the aforementioned embodiments is a compound of Formula (IIIff), wherein p is 5. In another embodiment of any of the aforementioned embodiments is a compound of Formula (IIIff), wherein p is 30 6. In another embodiment of any of the aforementioned embodiments is a compound of Formula (IIIff), wherein p is 7. In another embodiment of any of the aforementioned embodiments is a compound of Formula (IIIff), wherein p is 8. In another embodiment of any of the aforementioned embodiments is a compound of Formula (IIIff), wherein p is 35 9. In another embodiment, described herein is a compound having the structure of Formula (IV):

40 Formula (IV) 21 O (R.-- N Y; 45 NHR2 Rs wherein: Y is a phenolic TRPV1 agonist, wherein the hydrogen O atom of the phenolic hydroxyl group is replaced by a covalent 50 bond to

O N --(R1; ^ Rs NHR 60 Rs is hydrogen, Substituted or unsubstituted alkyl, or Sub stituted or unsubstituted aryl; each R is independently substituted or unsubstituted alkyl, substituted or unsubstituted aryl, or substituted or unsubsti tuted acyl: 65 R is hydrogen, or Substituted or unsubstituted alkyl, and n is an integer from 0 to 4; or US 9,359,316 B1 63 64 In some embodiments is a compound of Formula (IV), In some embodiments is a compound of Formula (IV), wherein Y is wherein Y is O 5 -- o1

N 21 O

XO 10 O On

In some embodiments is a compound of Formula (IV), wherein Y is 15

O 2O N 2 In some embodiments is a compound of Formula (IV), H wherein Rs is H. In some embodiments is a compound of Formula (IV), wherein Rs is substituted or unsubstituted O alkyl. In some embodiments is a compound of Formula (IV), 25 wherein Rs is unsubstituted alkyl. In some embodiments is a O compound of Formula (IV), wherein Rs is substituted alkyl. N In some embodiments is a compound of Formula (IV), wherein Rs is substituted or unsubstituted aryl. In some In some embodiments is a compound of Formula (IV), embodiments is a compound of Formula (IV), wherein Rs is wherein Y is 30 substituted phenyl. In some embodiments is a compound of Formula (IV), wherein Rs is unsubstituted phenyl. In some embodiments is a compound of Formula (IV), wherein Rs is —CH. In some embodiments is a compound of Formula O (IV), wherein Rs is —CHCH. In some embodiments is a 35 compound of Formula (IV), wherein Rs is —CHCH-NH.In N some embodiments is a compound of Formula (IV), wherein H Rs is —CHCH-NH(alkyl). In some embodiments is a com pound of Formula (IV), wherein Rs is —CHCH-NH(CH). O In some embodiments is a compound of Formula (IV), wherein n is 1 and R is substituted or unsubstituted alkyl. In On 40 some embodiments is a compound of Formula (IV), wherein n is 1 and R is unsubstituted alkyl. In some embodiments is a compound of Formula (IV), wherein n is 0. In another embodiment of any of the aforementioned embodiments is a compound of Formula (IV), wherein R is hydrogen. In O 4s another embodiment of any of the aforementioned embodi ments is a compound of Formula (IV), wherein R is substi --~~ tuted or unsubstituted alkyl. H In another embodiment of any of the aforementioned embodiments is a compound of Formula (IV), wherein n is 0. O R is hydrogen and Rs is hydrogen. In another embodiment of 50 any of the aforementioned embodiments is a compound of O Formula (IV), whereinnis 0, R is hydrogen and Rs is methyl. N In one embodiment is a compound selected from: In some embodiments is a compound of Formula (IV), ss O wherein Y is HCI O N 27 H O HN-s-s

N --~~~ 60 On O HCI O O --~~ O -N1,N1,No.is als H s N 65 O US 9,359,316 B1

-continued -continued HCI O HN O N 21

N ls O s 5 HCI O O/ O

n 1 n-1\N O HCI O HN O N 21 10 l H s N O On O 15 HCI O N 21 HCI / HN 11a l O s HN O O O

O n 2O N ls O O

HCI O N 21 HN l H 2N-1N O , 25 N OS NH2 HCI HCI O 30 HCI / HN HN O lsO H --~~~ s N l O N O -N- On 35 HCI HCI O

1. O N 21 40 l H s N O / O O O O n HCI l O 45 ~ O O N 21 l H O NH2 On 50 HCI

55 HCI HN /

65 US 9,359,316 B1 67 68 -continued -continued O

HCI H / -N O O O --

O O O -so NH2 HCI

HCI O O O HN n1n lsO

NH2 HCI

or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or hydrate thereof. 45 In another embodiment is a compound selected from:

O O --~~ 50 HN-s-s s On O 55 -N-s-sH O --~~ s OS O HN 2 -soO --~~ O 65 n US 9,359,316 B1 69 70

-continued -continued

HN / 5 H / 2 O O O -N O O O N O -so

/ HN O O. O O c/ O

N l O 2O N l O NH2

O c/ O 30 O is n-s-so

HN O O O -so -N - 45 or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or hydrate thereof. 50 In another embodiment is a compound, or a pharmaceuti cally acceptable salt, pharmaceutically acceptable Solvate, or hydrate thereof, having the structure:

O --O C --~~ On s US 9,359,316 B1 71 72 -continued

Synthesis of Compounds as well as those that are recognized in the field, such as In some embodiments, the synthesis of compounds described, for example, in Fieser and Fieser’s Reagents for described herein are accomplished using means described in 55 Organic Synthesis, Volumes 1-17 (John Wiley and Sons, the chemical literature, using the methods described herein, 1991); Rodd's Chemistry of Carbon Compounds, Volumes or by a combination thereof. In addition, solvents, tempera 1-5 and Supplementals (Elsevier Science Publishers, 1989); tures and other reaction conditions presented herein may Organic Reactions, Volumes 1-40 (John Wiley and Sons, vary. 1991), Larock’s Comprehensive Organic Transformations In other embodiments, the starting materials and reagents 60 (VCH Publishers Inc., 1989), March, ADVANCED ORGANIC used for the synthesis of the compounds described herein are CHEMISTRY 4' Ed. (Wiley 1992); Carey and Sundberg, synthesized or are obtained from commercial sources, such ADVANCED ORGANIC CHEMISTRY 4" Ed., Vols. A and B (Plenum as, but not limited to, Sigma-Aldrich Corp., Fisher Scientific 2000, 2001), and Green and Wuts, PROTECTIVE GROUPS IN (Fisher Chemicals), and Acros Organics. ORGANIC SYNTHESIS 3' Ed. (Wiley 1999) (all of which are In further embodiments, the compounds described herein, 65 incorporated by reference for such disclosure). General meth and other related compounds having different Substituents are ods for the preparation of compound as disclosed herein may synthesized using techniques and materials described herein be derived from reactions and the reactions may be modified US 9,359,316 B1 73 74 by the use of appropriate reagents and conditions, for the formed by chromatography or by the forming diastereomeric introduction of the various moieties found in the formulae as and separation by recrystallization, or chromatography, or provided herein. any combination thereof. (Jean Jacques, Andre Collet, Sam In some embodiments, the compounds described herein uel H. Wilen, "Enantiomers, Racemates and Resolutions', are prepared as outlined in the following scheme. John Wiley And Sons, Inc., 1981, herein incorporated by

Scheme 1

HO or ~r 2)1) ONDIPEA, DCM, rt O “O o-soO lor --~~ O- Cl-, O

R1 Y-8s R1 n-> O R OS R OS

In some embodiments, the compounds described herein reference for this disclosure). Stereoisomers may also be are prepared as outlined in the following scheme. obtained by stereoselective synthesis.

Scheme 2 O

N 21 H 1) NaH, DMF, rt PG HO 1 O X C N O x^ O O

PG O1 O N 21

O1-x- X O H ON re 1OH - O C --~~~ ON

Further Forms of Compounds In some situations, compounds may exist as tautomers. All The compounds described herein may in some cases exist tautomers are included within the formulas described herein. as diastereomers, enantiomers, or other stereoisomeric forms. The methods and compositions described herein include The compounds presented herein include all diastereomeric, 65 the use of amorphous forms as well as crystalline forms (also enantiomeric, and epimeric forms as well as the appropriate known as polymorphs). The compounds described herein mixtures thereof. Separation of Stereoisomers may be per- may be in the form of pharmaceutically acceptable salts. As US 9,359,316 B1 75 76 well, active metabolites of these compounds having the same pionic acid, glycolic acid, pyruvic acid, lactic acid, malonic type of activity are included in the scope of the present dis acid, Succinic acid, malic acid, maleic acid, fumaric acid, closure. In addition, the compounds described herein can trifluoroacetic acid, tartaric acid, citric acid, benzoic acid, exist in unsolvated as well as Solvated forms with pharma 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic ceutically acceptable solvents such as water, ethanol, and the acid, methanesulfonic acid, ethanesulfonic acid, 1.2- like. The solvated forms of the compounds presented herein ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benze are also considered to be disclosed herein. nesulfonic acid, toluenesulfonic acid, 2-naphthalenesulfonic The compounds of Formula (I), (II), (IIa), (IIaa), (IIb). acid, 4-methylbicyclo-2.2.2]oct-2-ene-1-carboxylic acid, (IIbb), (IIc), (IIcc), (IId), (IIdd), (Ile), (IIee), (IIf), (IIff), (III), glucoheptonic acid, 4,4'-methylenebis-(3-hydroxy-2-ene-1- (IIIa), (IIIaa), (IIIb), (IIIbb), (IIIc), (IIIcc), (IIId), (IIIdd), carboxylic acid), 3-phenylpropionic acid, trimethylacetic (IIIe), (IIIee), (IIIf), (IIIff), or (IV), or pharmaceutically 10 acid, tertiary butylacetic acid, lauryl Sulfuric acid, gluconic acceptable salt, pharmaceutically acceptable solvate, or acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, hydrate thereof, described herein are prodrugs of TRPV1 Stearic acid, muconic acid, butyric acid, phenylacetic acid, agonists. A "prodrug” refers to an agent that is converted into phenylbutyric acid, Valproic acid, and the like; (2) salts the parent drug in vivo. The compounds of Formula (I), (II), formed when an acidic proton present in the parent compound (IIa), (IIaa), (IIb), (IIbb), (IIc), (IIcc), (IId), (IIdd), (IIe), 15 is replaced by a metal ion, e.g., an alkali metal ion (e.g. (IIee), (IIf), (IIff), (III), (IIIa), (IIIaa), (IIIb), (IIIbb), (IIIc), lithium, Sodium, potassium), an alkaline earth ion (e.g. mag (IIIcc), (IIId), (IIIdd), (IIIe), (IIIee), (IIIf), (IIIff), or (IV), or nesium, or calcium), or an aluminum ion. In some cases, pharmaceutically acceptable salt, pharmaceutically accept compounds described herein may coordinate with an organic able solvate, or hydrate thereof, described herein are directed base. Such as, but not limited to, ethanolamine, diethanola to novel water-soluble prodrugs of TRPV1 agonists and their mine, triethanolamine, tromethamine, N-methylglucamine, methods of synthesis and use. In addition to specifically iden dicyclohexylamine, tris(hydroxymethyl)methylamine. In tified compounds, these derivatives are capable of chemical other cases, compounds described herein may form salts with reverting to the active parent compound when exposed to amino acids such as, but not limited to, arginine, lysine, and physiological conditions. These derivatives have signifi the like. Acceptable inorganic bases used to form salts with cantly higher hydrophilicity/water solubility than their parent compounds that include an acidic proton, include, but are not drugs and are hence better able to be incorporated into com 25 limited to, aluminum hydroxide, calcium hydroxide, potas monly used aqueous formulations. Further described herein sium hydroxide, sodium carbonate, Sodium hydroxide, and is a method of increasing the water Solubility of capsaicin, its the like. analogs and other TRPV1 agonists, by modifying the parent It should be understood that a reference to a pharmaceuti molecule's chemical structure with hydrophilic moieties. In cally acceptable salt includes the solvent addition forms or some embodiments described herein, the introduction of 30 crystal forms thereof, particularly Solvates or polymorphs. basic moieties capable of being protonated under acidic con Solvates contain either stoichiometric or non-stoichiometric ditions increases the solubility of a TRPV1 prodrug. In some amounts of a solvent, and may be formed during the process embodiments described herein, the introduction of acidic of crystallization with pharmaceutically acceptable solvents moieties capable of increasing the overall hydrophilic char such as water, ethanol, and the like. Hydrates are formed acter increases the solubility of a TRPV1 prodrug. The pro when the solvent is water, or alcoholates are formed when the drugs described herein are designed such that the parent drug 35 solvent is alcohol. Solvates of compounds described herein is released under well-defined rates after its structural deriva can be conveniently prepared or formed during the processes tive has been delivered to the body and/or is exposed to described herein. In addition, the compounds provided herein specific physiological conditions. can exist in unsolvated as well as Solvated forms. In general, The compounds described herein may be labeled isotopi the Solvated forms are considered equivalent to the unsol cally (e.g. with a radioisotope) or by other means, including, 40 vated forms for the purposes of the compounds and methods but not limited to, the use of chromophores or fluorescent provided herein. moieties, bioluminescent labels, photoactivatable or chemi In some embodiments, compounds described herein, Such luminescent labels. as compounds of Formula (I), (II), (IIa), (IIaa), (IIb), (IIbb), Compounds described herein include isotopically-labeled (IIc), (IIcc), (IId), (IIdd), (IIe), (IIee), (IIf), (IIff), (III), (IIIa), compounds, which are identical to those recited in the various (IIIaa), (IIIb), (IIIbb), (IIIc), (IIIcc), (IIId), (IIIdd), (IIIe), formulae and structures presented herein, but for the fact that 45 (IIIee), (IIIf). (IIIff), or (IV), are in various forms, including one or more atoms are replaced by an atom having an atomic but not limited to, amorphous forms, milled forms and nano mass or mass number different from the atomic mass or mass particulate forms. In addition, compounds described herein number usually found in nature. Examples of isotopes that include crystalline forms, also known as polymorphs. Poly can be incorporated into the present compounds include iso morphs include the different crystal packing arrangements of topes of hydrogen, carbon, nitrogen, oxygen, fluorine and 50 the same elemental composition of a compound. Polymorphs chlorine, such as, for example, H, H, C, C, N, O, usually have different X-ray diffraction patterns, melting ''O, S, F, Cl, respectively. Certain isotopically-labeled points, density, hardness, crystal shape, optical properties, compounds described herein, for example those into which stability, and solubility. Various factors such as the recrystal radioactive isotopes such as Hand ''Care incorporated, are lization solvent, rate of crystallization, and storage tempera useful in drug and/or Substrate tissue distribution assays. Fur 55 ture may cause a single crystal form to dominate. ther, substitution with isotopes such as deuterium, i.e., H. The screening and characterization of the pharmaceuti can afford certain therapeutic advantages resulting from cally acceptable salts, polymorphs and/or Solvates may be greater metabolic stability, Such as, for example, increased in accomplished using a variety of techniques including, but not Vivo half-life or reduced dosage requirements. limited to, thermal analysis, X-ray diffraction, spectroscopy, Compounds described herein may be formed as, and/or vapor sorption, and microscopy. Thermal analysis methods used as, pharmaceutically acceptable salts. The type of phar 60 address thermo chemical degradation orthermo physical pro maceutical acceptable salts, include, but are not limited to: (1) cesses including, but not limited to, polymorphic transitions, acid addition salts, formed by reacting the free base form of and Such methods are used to analyze the relationships the compound with a pharmaceutically acceptable: inorganic between polymorphic forms, determine weight loss, to find acid, Such as, for example, hydrochloric acid, hydrobromic the glass transition temperature, or for excipient compatibil acid, Sulfuric acid, phosphoric acid, metaphosphoric acid, 65 ity studies. Such methods include, but are not limited to, and the like; or with an organic acid, such as, for example, Differential scanning calorimetry (DSC), Modulated Differ acetic acid, propionic acid, hexanoic acid, cyclopentanepro ential Scanning Calorimetry (MDCS). Thermogravimetric US 9,359,316 B1 77 78 analysis (TGA), and Thermogravi-metric and Infrared analy -continued sis (TG/IR). X-ray diffraction methods include, but are not limited to, single crystal and powder diffractometers and synchrotron sources. The various spectroscopic techniques -y used include, but are not limited to, Raman, FTIR, UV-VIS, Et and NMR (liquid and solid state). The various microscopy techniques include, but are not limited to, polarized light microscopy, Scanning Electron Microscopy (SEM) with --> Energy Dispersive X-Ray Analysis (EDX), Environmental allyl Scanning Electron Microscopy with EDX (in gas or water 10 vapor atmosphere), IR microscopy, and Raman microscopy. Throughout the specification, groups and Substituents thereof can be chosen to provide stable moieties and com pounds. Bn Use of Protecting Groups (PG) 15 In the reactions described, it may be necessary to protect reactive functional groups, for example hydroxy, amino, imino, thio or carboxy groups, where these are desired in the final product, in order to avoid their unwanted participation in Or/ reactions. Protecting groups are used to block Some or all of PMB the reactive moieties and prevent such groups from partici pating in chemical reactions until the protective group is removed. It is preferred that each protective group be remov able by a different means. Protective groups that are cleaved under totally disparate reaction conditions fulfill the require ment of differential removal. 25 Protective groups can be removed by acid, base, reducing t-butyl conditions (such as, for example, hydrogenolysis), and/or O oxidative conditions. Groups such as trityl, dimethoxytrityl, Bn acetal and t-butyldimethylsilyl are acid labile and may be 30 sy used to protect carboxy and hydroxy reactive moieties in the presence of amino groups protected with Cbz groups, which Cbz are removable by hydrogenolysis, and Fmoc groups, which are base labile. Carboxylic acid and hydroxy reactive moi O eties may be blocked with base labile groups such as, but not (CH3)3C 1. \ limited to, methyl, ethyl, and acetyl in the presence of amines 35 blocked with acid labile groups such as t-butyl carbamate or O with carbamates that are both acid and base stable but hydro OC lytically removable. Carboxylic acid and hydroxy reactive moieties may also be O blocked with hydrolytically removable protective groups Such as the benzyl group, while amine groups capable of 40 21\-1 \ hydrogenbonding with acids may be blocked with base labile O groups such as Fmoc. Carboxylic acid reactive moieties may alloc be protected by conversion to simple ester compounds as O exemplified herein, which include conversion to alkyl esters, or they may be blocked with oxidatively-removable protec 45 tive groups such as 2,4-dimethoxybenzyl, while co-existing y amino groups may be blocked with fluoride labile silyl car bamates. acetyl Allyl blocking groups are useful in then presence of acid and base-protecting groups since the former are stable and 50 can be subsequently removed by metal or pi-acid catalysts. For example, an allyl-blocked carboxylic acid can be depro tected with a Pd-catalyzed reaction in the presence of acid labile t-butyl carbamate or base-labile acetate amine protect ing groups. Yet another form of protecting group is a resin to which a compound or intermediate may be attached. As long 55 as the residue is attached to the resin, that functional group is blocked and cannot react. Once released from the resin, the functional group is available to react. Typically blocking/protecting groups may be selected from: 60

X. 65 Me Other protecting groups, plus a detailed description of techniques applicable to the creation of protecting groups and US 9,359,316 B1 79 80 their removal are described in Greene and Wuts, Protective syndrome. In some embodiments is a method of treating pain Groups in Organic Synthesis, 3rd Ed., John Wiley & Sons, in a subject, comprising administering to the Subject a New York, N.Y., 1999, and Kocienski, Protective Groups, thrapeutically effective amount of a compound of Formula Thieme Verlag, New York, N.Y., 1994, which are incorpo (I), (II), (IIa), (IIaa), (IIb), (IIbb), (IIc), (IIcc), (IId), (IIdd), rated herein by reference for such disclosure). (IIe), (IIee), (IIf), (IIff), (III), (IIIa), (IIIaa), (IIIb), (IIIbb), Diseases, Disorders or Conditions (IIIc), (IIIcc), (IIId), (IIIdd), (IIIe), (IIIee), (IIIf), (IIIff), or In another aspect is a method of treating pain in a Subject, (IV), or a pharmaceutically acceptable salt, pharmaceutically comprising administering to the Subject a thrapeutically acceptable solvate, or hydrate thereof, wherein the pain is effective amount of a compound of Formula (I), (II), (IIa), associated with cancer. In some embodiments is a method of (IIaa), (IIb), (IIbb), (IIc), (IIcc), (IId), (IIdd), (IIe), (IIee), treating pain in a subject, comprising administering to the (IIf), (IIff), (III), (IIIa), (IIIaa), (IIIb), (IIIbb), (IIIc), (IIIcc), 10 Subject a thrapeutically effective amount of a compound of (IIId), (IIIdd), (IIIe), (IIIee), (IIIf). (IIIff), or (IV), or a phar Formula (I), (II), (IIa), (IIaa), (IIb), (IIbb), (IIc), (IIcc), (IId), maceutically acceptable salt, pharmaceutically acceptable (IIdd), (IIe), (IIee), (IIf). (IIff), (III), (IIIa), (IIIaa), (IIIb). solvate, or hydrate thereof. In some embodiments is a method (IIIbb), (IIIc), (IIIcc), (IIId), (IIIdd), (IIIe), (IIIee), (IIIf), (II of treating pain in a Subject, comprising administering to the Iff), or (IV), or a pharmaceutically acceptable salt, pharma Subject a thrapeutically effective amount of a compound of 15 ceutically acceptable solvate, or hydrate thereof, wherein the Formula (I), (II), (IIa), (IIaa), (IIb), (IIbb), (IIc), (IIcc), (IId), pain is associated with cancer chemotherapy. In some (IIdd), (IIe), (IIee), (IIf), (IIff), (III), (IIIa), (IIIaa), (IIIb). embodiments is a method of treating pain in a Subject, com (IIIbb), (IIIc), (IIIcc), (IIId), (IIIdd), (IIIe), (IIIee), (IIIf), (II prising administering to the Subject a thrapeutically effective Iff), or (IV), or a pharmaceutically acceptable salt, pharma amount of a compound of Formula (I), (II), (IIa), (IIaa), (IIb). ceutically acceptable solvate, or hydrate thereof, wherein the (IIbb), (IIc), (IIcc), (IId), (IIdd), (IIe), (IIee), (IIf), (IIff), (III), pain is associated with post-operative pain. In some embodi (IIIa), (IIIaa), (IIIb), (IIIbb), (IIIc), (IIIcc), (IIId), (IIIdd), ments is a method of treating pain in a subject, comprising (IIIe), (IIIee), (IIIf), (IIIff), or (IV), or a pharmaceutically administering to the Subject a thrapeutically effective amount acceptable salt, pharmaceutically acceptable solvate, or of a compound of Formula (I), (II), (IIa), (IIaa), (IIb), (IIbb), hydrate thereof, wherein the pain is associated with nerve (IIc), (IIcc), (IId), (IIdd), (IIe), (IIee), (IIf), (IIff), (III), (IIIa), injury. In some embodiments is a method of treating pain in a (IIIaa), (IIIb), (IIIbb), (IIIc), (IIIcc), (IIId), (IIIdd), (IIIe), 25 Subject, comprising administering to the Subject a thrapeuti (IIIee), (IIIf). (IIIff), or (IV), or a pharmaceutically acceptable cally effective amount of a compound of Formula (I), (II), salt, pharmaceutically acceptable solvate, or hydrate thereof, (IIa), (IIaa), (IIb), (IIbb), (IIc), (IIcc), (IId), (IIdd), (IIe), wherein the pain is associated with chronic post-Surgical (IIee), (IIf), (IIff), (III), (IIIa), (IIIaa), (IIIb), (IIIbb), (IIIc), pain. In some embodiments is a method of treating pain in a (IIIcc), (IIId), (IIIdd), (IIIe), (IIIee), (IIIf), (IIIff), or (IV), or a Subject, comprising administering to the Subject a thrapeuti 30 pharmaceutically acceptable salt, pharmaceutically accept cally effective amount of a compound of Formula (I), (II), able solvate, or hydrate thereof, wherein the pain is associated (IIa), (Ilaa), (IIb), (IIbb), (IIc), (IIcc), (IId), (IIdd), (IIe), with Vulvodynia. In some embodiments is a method of treat (IIee), (IIf), (IIff), (III), (IIIa), (IIIaa), (IIIb), (IIIbb), (IIIc), ing pain in a subject, comprising administering to the Subject (IIIcc), (IIId), (IIIdd), (IIIe), (IIIee), (IIIf), (IIIff), or (IV), or a a thrapeutically effective amount of a compound of Formula pharmaceutically acceptable salt, pharmaceutically accept (I), (II), (IIa), (IIaa), (IIb), (IIbb), (IIc), (IIcc), (IId), (IIdd), able solvate, or hydrate thereof, wherein the pain is associated 35 (IIe), (IIee), (IIf), (IIff), (III), (IIIa), (IIIaa), (IIIb), (IIIbb), with neuropathic pain. In some embodiments is a method of (IIIc), (IIIcc), (IIId), (IIIdd), (IIIe), (IIIee), (IIIf), (IIIff), or treating pain in a subject, comprising administering to the (IV), or a pharmaceutically acceptable salt, pharmaceutically Subject a thrapeutically effective amount of a compound of acceptable solvate, or hydrate thereof, wherein the pain is Formula (I), (II), (IIa), (IIaa), (IIb), (IIbb), (IIc), (IIcc), (IId), associated with trauma. In some embodiments is a method of (IIdd), (IIe), (IIee), (IIf), (IIff), (III), (IIIa), (IIIaa), (IIIb). 40 treating pain in a subject, comprising administering to the (IIIbb), (IIIc), (IIIcc), (IIId), (IIIdd), (IIIe), (IIIee), (IIIff), or Subject a thrapeutically effective amount of a compound of (IV), or a pharmaceutically acceptable salt, pharmaceutically Formula (I), (II), (IIa), (IIaa), (IIb), (IIbb), (IIc), (IIcc), (IId), acceptable solvate, or hydrate thereof, wherein the pain is (IIdd), (IIe), (IIee), (IIf). (IIff), (III), (IIIa), (IIIaa), (IIIb). associated with postherpetic neuralgia. In some embodiments (IIIbb), (IIIc), (IIIcc), (IIId), (IIIdd), (IIIe), (IIIee), (IIIf), (II is a method of treating pain in a Subject, comprising admin Iff), or (IV), or a pharmaceutically acceptable salt, pharma istering to the Subject a thrapeutically effective amount of a 45 ceutically acceptable solvate, or hydrate thereof, wherein the compound of Formula (I), (II), (IIa), (IIaa), (IIb), (IIbb), (IIc), pain is associated with Surgery. In some embodiments is a (IIcc), (IId), (IIdd), (IIe), (IIee), (IIf). (IIff), (III), (IIIa), (II method of treating pain in a Subject, comprising administer Iaa), (IIIb), (IIIbb), (IIIc), (IIIcc), (IIId), (IIIdd), (IIIe), (IIIee), ing to the Subject a thrapeutically effective amount of a com (IIIf), (IIIff), or (IV), or a pharmaceutically acceptable salt, pound of Formula (I), (II), (IIa), (IIaa), (IIb), (IIbb), (IIc), pharmaceutically acceptable Solvate, or hydrate thereof, 50 (IIcc), (IId), (IIdd), (IIe), (IIee), (IIf). (IIff), (III), (IIIa), (II wherein the pain is associated with diabetic neuropathy. In Iaa), (IIIb), (IIIbb), (IIIc), (IIIcc), (IIId), (IIIdd), (IIIe), (IIIee), Some embodiments is a method of treating pain in a Subject, (IIIf), (IIIff), or (IV), or a pharmaceutically acceptable salt, comprising administering to the Subject a thrapeutically pharmaceutically acceptable solvate, or hydrate thereof, effective amount of a compound of Formula (I), (II), (IIa), wherein the pain is associated with chronic musculoskeletal (IIaa), (IIb), (IIbb), (IIc), (IIcc), (IId), (IIdd), (IIe), (IIee), 55 pain. In some embodiments is a method of treating pain in a (IIf), (IIff), (III), (IIIa), (IIIaa), (IIIb), (IIIbb), (IIIc), (IIIcc), Subject, comprising administering to the Subject a thrapeuti (IIId), (IIIdd), (IIIe), (IIIee), (IIIf). (IIIff), or (IV), or a phar cally effective amount of a compound of Formula (I), (II), maceutically acceptable salt, pharmaceutically acceptable (IIa), (IIaa), (IIb), (IIbb), (IIc), (IIcc), (IId), (IIdd), (IIe), Solvate, or hydrate thereof, wherein the pain is associated (IIee), (IIf), (IIff), (III), (IIIa), (IIIaa), (IIIb), (IIIbb), (IIIc), with HIV-associated neuropathy. In some embodiments is a (IIIcc), (IIId), (IIIdd), (IIIe), (IIIee), (IIIf), (IIIff), or (IV), or a method of treating pain in a Subject, comprising administer 60 pharmaceutically acceptable salt, pharmaceutically accept ing to the Subject a thrapeutically effective amount of a com able solvate, or hydrate thereof, wherein the pain is associated pound of Formula (I), (II), (IIa), (IIaa), (IIb), (IIbb), (IIc), with lower back pain. In some embodiments is a method of (IIcc), (IId), (IIdd), (IIe), (IIee), (IIf). (IIff), (III), (IIIa), (II treating pain in a subject, comprising administering to the Iaa), (IIIb), (IIIbb), (IIIc), (IIIcc), (IIId), (IIIdd), (IIIe), (IIIee), Subject a thrapeutically effective amount of a compound of (IIIf), (IIIff), or (IV), or a pharmaceutically acceptable salt, 65 Formula (I), (II), (IIa), (IIaa), (IIb), (IIbb), (IIc), (IIcc), (IId), pharmaceutically acceptable Solvate, or hydrate thereof, (IIdd), (IIe), (IIee), (IIf). (IIff), (III), (IIIa), (IIIaa), (IIIb). wherein the pain is associated with complex regional pain (IIIbb), (IIIc), (IIIcc), (IIId), (IIIdd), (IIIe), (IIIee), (IIIf), (II US 9,359,316 B1 81 82 Iff), or (IV), or a pharmaceutically acceptable salt, pharma (IIIee), (IIIf). (IIIff), or (IV), or a pharmaceutically acceptable ceutically acceptable solvate, or hydrate thereof, wherein the salt, pharmaceutically acceptable solvate, or hydrate thereof. pain is associated with osteoarthritis or rheumatoid arthritis. In some embodiments is a method of treating rhinitis in a In some embodiments is a method of treating pain in a Sub Subject, comprising administering to the Subject a thrapeuti ject, comprising administering to the Subject a thrapeutically cally effective amount of a compound of Formula (I), (II), effective amount of a compound of Formula (I), (II), (IIa), (IIa), (IIaa), (IIb), (IIbb), (IIc), (IIcc), (IId), (IIdd), (IIe), (IIaa), (IIb), (IIbb), (IIc), (IIcc), (IId), (IIdd), (IIe), (IIee), (IIee), (IIf), (IIff), (III), (IIIa), (IIIaa), (IIIb), (IIIbb), (IIIc), (IIf), (IIff), (III), (IIIa), (IIIaa), (IIIb), (IIIbb), (IIIc), (IIIcc), (IIIcc), (IIId), (IIIdd), (IIIe), (IIIee), (IIIf), (IIIff), or (IV), or a (IIId), (IIIdd), (IIIe), (IIIee), (IIIf). (IIIff), or (IV), or a phar pharmaceutically acceptable salt, pharmaceutically accept maceutically acceptable salt, pharmaceutically acceptable able solvate, or hydrate thereof. In some embodiments is a Solvate, or hydrate thereof, wherein the pain is associated 10 method of treating alopecia in a Subject, comprising admin with osteoarthritis arthritis. In some embodiments is a method istering to the Subject a thrapeutically effective amount of a of treating pain in a Subject, comprising administering to the compound of Formula (I), (II), (IIa), (IIaa), (IIb), (IIbb), (IIc), Subject a thrapeutically effective amount of a compound of (IIcc), (IId), (IIdd), (IIe), (IIee), (IIf). (IIff), (III), (IIIa), (II Formula (I), (II), (IIa), (IIaa), (IIb), (IIbb), (IIc), (IIcc), (IId), Iaa), (IIIb), (IIIbb), (IIIc), (IIIcc), (IIId), (IIIdd), (IIIe), (IIIee), (IIdd), (IIe), (IIee), (IIf), (IIff), (III), (IIIa), (IIIaa), (IIIb). 15 (IIIf), (IIIff), or (IV), or a pharmaceutically acceptable salt, (IIIbb), (IIIc), (IIIcc), (IIId), (IIIdd), (IIIe), (IIIee), (IIIf), (II pharmaceutically acceptable Solvate, or hydrate thereof. In Iff), or (IV), or a pharmaceutically acceptable salt, pharma Some embodiments is a method of treating hirsutism in a ceutically acceptable solvate, or hydrate thereof, wherein the Subject, comprising administering to the Subject a thrapeuti pain is associated with rheumatoid arthritis. cally effective amount of a compound of Formula (I), (II), In some embodiments is a method of treating psoriasis, (IIa), (IIaa), (IIb), (IIbb), (IIc), (IIcc), (IId), (IIdd), (IIe), pruritis, itch, cancer, prostatic hypertrophy, wrinkles, sinusi (IIee), (IIf), (IIff), (III), (IIIa), (IIIaa), (IIIb), (IIIbb), (IIIc), tis, rhinitis, alopecia, or hirsutism in a Subject, comprising (IIIcc), (IIId), (IIIdd), (IIIe), (IIIee), (IIIf), (IIIff), or (IV), or a administering to the Subject a thrapeutically effective amount pharmaceutically acceptable salt, pharmaceutically accept of a compound of Formula (I), (II), (IIa), (IIaa), (IIb), (IIbb), able solvate, or hydrate thereof. (IIc), (IIcc), (IId), (IIdd), (IIe), (IIee), (IIf), (IIff), (III), (IIIa), In some embodiments is a method of treating pain in a (IIIaa), (IIIb), (IIIbb), (IIIc), (IIIcc), (IIId), (IIIdd), (IIIe), 25 Subject, comprising administering to the Subject a thrapeuti (IIIee), (IIIf). (IIIff), or (IV), or a pharmaceutically acceptable cally effective amount of a compound of Formula (I), (II), salt, pharmaceutically acceptable solvate, or hydrate thereof. (IIa), (IIaa), (IIb), (IIbb), (IIc), (IIcc), (IId), (IIdd), (IIe), In some embodiments is a method of treating psoriasis in a (IIee), (IIf), (IIff), (III), (IIIa), (IIIaa), (IIIb), (IIIbb), (IIIc), Subject, comprising administering to the Subject a thrapeuti (IIIcc), (IIId), (IIIdd), (IIIe), (IIIee), (IIIf), (IIIff), or (IV), or a cally effective amount of a compound of Formula (I), (II), 30 pharmaceutically acceptable salt, pharmaceutically accept (IIa), (IIaa), (IIb), (IIbb), (IIc), (IIcc), (IId), (IIdd), (IIe), able solvate, or hydrate thereof, wherein the compound is (IIee), (IIf), (IIff), (III), (IIIa), (IIIaa), (IIIb), (IIIbb), (IIIc), administered locally. In some embodiments is a method of (IIIcc), (IIId), (IIIdd), (IIIe), (IIIee), (IIIf), (IIIff), or (IV), or treating pain in a subject, comprising administering to the apharmaceutically acceptable salt, pharmaceutically accept Subject a thrapeutically effective amount of a compound of able solvate, or hydrate thereof. In some embodiments is a Formula (I), (II), (IIa), (IIaa), (IIb), (IIbb), (IIc), (IIcc), (IId), method of treating pruritis in a Subject, comprising adminis 35 (IIdd), (IIe), (IIee), (IIf). (IIff), (III), (IIIa), (IIIaa), (IIIb). tering to the Subject a thrapeutically effective amount of a (IIIbb), (IIIc), (IIIcc), (IIId), (IIIdd), (IIIe), (IIIee), (IIIf), (II compound of Formula (I), (II), (IIa), (IIaa), (IIb), (IIbb), (IIc), Iff), or (IV), or a pharmaceutically acceptable salt, pharma (IIcc), (IId), (IIdd), (IIe), (IIee), (IIf). (IIff), (III), (IIIa), (II ceutically acceptable solvate, or hydrate thereof, wherein the Iaa), (IIIb), (IIIbb), (IIIc), (IIIcc), (IIId), (IIIdd), (IIIe), (IIIee), compound is administered dermally. In some embodiments is (IIIf), (IIIff), or (IV), or a pharmaceutically acceptable salt, 40 a method of treating pain in a Subject, comprising adminis pharmaceutically acceptable Solvate, or hydrate thereof. In tering to the Subject a thrapeutically effective amount of a Some embodiments is a method of treating itch in a subject, compound of Formula (I), (II), (IIa), (IIaa), (IIb), (IIbb), (IIc), comprising administering to the Subject a thrapeutically (IIcc), (IId), (IIdd), (IIe), (IIee), (IIf). (IIff), (III), (IIIa), (II effective amount of a compound of Formula (I), (II), (IIa), Iaa), (IIIb), (IIIbb), (IIIc), (IIIcc), (IIId), (IIIdd), (IIIe), (IIIee), (IIaa), (IIb), (IIbb), (IIc), (IIcc), (IId), (IIdd), (IIe), (IIee), 45 (IIIf), (IIIff), or (IV), or a pharmaceutically acceptable salt, (IIf), (IIff), (III), (IIIa), (IIIaa), (IIIb), (IIIbb), (IIIc), (IIIcc), pharmaceutically acceptable solvate, or hydrate thereof, (IIId), (IIIdd), (IIIe), (IIIee), (IIIf). (IIIff), or (IV), or a phar wherein the compound is administered transdermally. In maceutically acceptable salt, pharmaceutically acceptable Some embodiments is a method of treating pain in a Subject, solvate, or hydrate thereof. In some embodiments is a method comprising administering to the Subject a thrapeutically of treating cancer in a Subject, comprising administering to effective amount of a compound of Formula (I), (II), (IIa), the Subject a thrapeutically effective amount of a compound 50 (IIaa), (IIb), (IIbb), (IIc), (IIcc), (IId), (IIdd), (IIe), (IIee), of Formula (I), (II), (IIa), (IIaa), (IIb), (IIbb), (IIc), (IIcc), (IIf), (IIff), (III), (IIIa), (IIIaa), (IIIb), (IIIbb), (IIIc), (IIIcc), (IId), (IIdd), (IIe), (IIee), (IIf). (IIff), (III), (IIIa), (IIIaa), (IIId), (IIIdd), (IIIe), (IIIee), (IIIf). (IIIff), or (IV), or a phar (IIIb), (IIIbb), (IIIc), (IIIcc), (IIId), (IIIdd), (IIIe), (IIIee), maceutically acceptable salt, pharmaceutically acceptable (IIIf), (IIIff), or (IV), or a pharmaceutically acceptable salt, Solvate, or hydrate thereof, wherein the compound is admin pharmaceutically acceptable Solvate, or hydrate thereof. In 55 istered systemically. Some embodiments is a method of treating prostatic hyper Certain Terminology trophy in a subject, comprising administering to the Subject a Unless defined otherwise, all technical and scientific terms thrapeutically effective amount of a compound of Formula used herein have the same meaning as is commonly under (I), (II), (IIa), (IIaa), (IIb), (IIbb), (IIc), (IIcc), (IId), (IIdd), stood to which the claimed subject matter belongs. In the (IIe), (IIee), (IIf), (IIff), (III), (IIIa), (IIIaa), (IIIb), (IIIbb), event that there are a plurality of definitions for terms herein, (IIIc), (IIIcc), (IIId), (IIIdd), (IIIe), (IIIee), (IIIf), (IIIff), or 60 those in this section prevail. All patents, patent applications, (IV), or a pharmaceutically acceptable salt, pharmaceutically publications and published nucleotide and amino acid acceptable solvate, or hydrate thereof. In some embodiments sequences (e.g., sequences available in GenBank or other is a method of treating sinusitis in a subject, comprising databases) referred to herein are incorporated by reference. administering to the Subject a thrapeutically effective amount Where reference is made to a URL or other such identifier or of a compound of Formula (I), (II), (IIa), (IIaa), (IIb), (IIbb), 65 address, it is understood that such identifiers can change and (IIc), (IIcc), (IId), (IIdd), (IIe), (IIee), (IIf), (IIff), (III), (IIIa), particular information on the internet can come and go, but (IIIaa), (IIIb), (IIIbb), (IIIc), (IIIcc), (IIId), (IIIdd), (IIIe), equivalent information can be found by searching the inter US 9,359,316 B1 83 84 net. Reference thereto evidences the availability and public there are one to six carbon atoms in the alkyl chain, i.e., the dissemination of Such information. alkyl chain is selected from the group consisting of methyl, It is to be understood that the foregoing general description ethyl, n-propyl, iso-propyl. n-butyl, iso-butyl, sec-butyl, t-bu and the following detailed description are exemplary and tyl, n-pentyl, iso-pentyl, neo-pentyl, hexyl, propen-3-yl (al explanatory only and are not restrictive of any Subject matter lyl), cyclopropylmethyl, cyclobutylmethyl, cyclopentylm claimed. In this application, the use of the singular includes 5 ethyl, cyclohexylmethyl. Alkyl groups can be substituted or the plural unless specifically stated otherwise. It must be unsubstituted. Depending on the structure, an alkyl group can noted that, as used in the specification and the appended be a monoradical or a diradical (i.e., an alkylene group). claims, the singular forms “a,” “an and “the include plural An “alkoxy' refers to a “ O-alkyl group, where alkyl is referents unless the context clearly dictates otherwise. In this as defined herein. application, the use of “or” means “and/or unless stated 10 The term “alkenyl refers to a type of alkyl group in which otherwise. Furthermore, use of the term “including as well the first two atoms of the alkyl group form a double bond that as other forms, such as “include”, “includes and “included.” is not part of an aromatic group. That is, an alkenyl group is not limiting. begins with the atoms —C(R)—CR, wherein R refers to the The section headings used herein are for organizational remaining portions of the alkenyl group, which may be the purposes only and are not to be construed as limiting the 15 same or different. Non-limiting examples of an alkenyl group subject matter described. include -CH=CH, -C(CH)—CH, -CH=CHCH Definition of standard chemistry terms may be found in —CH=C(CH) and —C(CH)—CHCH. The alkenyl moi reference works, including but not limited to, Carey and Sun ety may be branched, straight chain, or cyclic (in which case, dberg "ADVANCED ORGANIC CHEMISTRY 4' E.D.” Vols. A (2000) it would also be known as a “cycloalkenyl group). Alkenyl and B (2001), Plenum Press, New York. Unless otherwise groups may have 2 to 6 carbons. Alkenyl groups can be indicated, conventional methods of mass spectroscopy, Substituted or unsubstituted. Depending on the structure, an NMR, HPLC, protein chemistry, biochemistry, recombinant alkenyl group can be a monoradical or a diradical (i.e., an DNA techniques and pharmacology. alkenylene group). Unless specific definitions are provided, the nomenclature The term “alkynyl refers to a type of alkyl group in which employed in connection with, and the laboratory procedures the first two atoms of the alkyl group form a triple bond. That and techniques of analytical chemistry, synthetic organic 25 is, an alkynyl group begins with the atoms —C=C-R, chemistry, and medicinal and pharmaceutical chemistry wherein R refers to the remaining portions of the alkynyl described herein are those recognized in the field. Standard group. Non-limiting examples of an alkynyl group include techniques can be used for chemical syntheses, chemical - C=CH, - C=CCH -C=CCHCH and analyses, pharmaceutical preparation, formulation, and - C=CCHCHCH. The “R” portion of the alkynyl moiety delivery, and treatment of patients. Standard techniques can 30 may be branched, straight chain, or cyclic. An alkynyl group be used for recombinant DNA, oligonucleotide synthesis, and can have 2 to 6 carbons. Alkynyl groups can be substituted or tissue culture and transformation (e.g., electroporation, lipo unsubstituted. Depending on the structure, an alkynyl group fection). Reactions and purification techniques can be per can be a monoradical or a diradical (i.e., an alkynylene formed e.g., using kits of manufacturer's specifications or as group). commonly accomplished in the art or as described herein. The “Amino” refers to a NH group. foregoing techniques and procedures can be generally per 35 The term “alkylamine' or “alkylamino” refers to the formed of conventional methods and as described in various —N(alkyl), H, group, where alkyl is as defined herein and X general and more specific references that are cited and dis and y are selected from the group x=1, y=1 and x=2, y=0. cussed throughout the present specification. When x=2, the alkyl groups, taken together with the nitrogen It is to be understood that the methods and compositions to which they are attached, can optionally form a cyclic ring described herein are not limited to the particular methodol 40 system. “Dialkylamino” refers to a N(alkyl), group, where ogy, protocols, cell lines, constructs, and reagents described alkyl is as defined herein. hereinandas Such may vary. It is also to be understood that the The term 'aromatic' refers to a planar ring having a delo terminology used herein is for the purpose of describing calized C-electron system containing 4n+2 telectrons, where particular embodiments only, and is not intended to limit the n is an integer. Aromatic rings can be formed from five, six, Scope of the methods, compounds, compositions described 45 seven, eight, nine, or more than nine atoms. Aromatics can be herein. optionally substituted. The term “aromatic' includes both As used herein, C-C includes C-C, C-C . . . C-C. aryl groups (e.g., phenyl, naphthalenyl) and heteroaryl C-C refers to the number of carbon atoms that make up the groups (e.g., pyridinyl, quinolinyl). moiety to which it designates (excluding optional Substitu As used herein, the term “aryl” refers to an aromatic ring ents). wherein each of the atoms forming the ring is a carbon atom. An “alkyl group refers to an aliphatic hydrocarbon group. 50 Aryl rings can be formed by five, six, seven, eight, nine, or The alkyl groups may or may not include units of unsatura more than nine carbon atoms. Aryl groups can be optionally tion. The alkyl moiety may be a “saturated alkyl group, Substituted. Examples of aryl groups include, but are not which means that it does not contain any units of unsaturation limited to phenyl, and naphthalenyl. Depending on the struc (i.e. a carbon-carbon double bond or a carbon-carbon triple ture, an aryl group can be a monoradical or a diradical (i.e., an bond). The alkyl group may also be an “unsaturated alkyl 55 arylene group). moiety, which means that it contains at least one unit of As used herein, the term “acyl refers to a group containing unsaturation. The alkyl moiety, whether saturated or unsatur a carbonyl moiety wherein the group is bonded via the car ated, may be branched, straight chain, or cyclic. bonyl carbon atom. The carbonyl carbon atom is also bonded The “alkyl group may have 1 to 6 carbonatoms (whenever to another carbon atom, which can be part of an alkyl, aryl, it appears herein, a numerical range such as "1 to 6’ refers to aralkyl cycloalkyl, heterocycloalkyl, heteroaryl group or the each integer in the given range; e.g., “1 to 6 carbon atoms” 60 like. means that the alkyl group may consist of 1 carbon atom, 2 “Carboxy' refers to —COH. In some embodiments, car carbon atoms, 3 carbon atoms, etc., up to and including 6 boxy moieties may be replaced with a “carboxylic acid bioi carbon atoms, although the present definition also covers the Sostere', which refers to a functional group or moiety that occurrence of the term “alkyl where no numerical range is exhibits similar physical and/or chemical properties as a car designated). The alkyl group of the compounds described 65 boxylic acid moiety. A carboxylic acid bioisostere has similar herein may be designated as "C-C alkyl or similar desig biological properties to that of a carboxylic acid group. A nations. By way of example only, "C-C alkyl indicates that compound with a carboxylic acid moiety can have the car US 9,359,316 B1 85 86 boxylic acid moiety exchanged with a carboxylic acid bioi Sostere and have similar physical and/or biological properties Nay when compared to the carboxylic acid-containing compound. For example, in one embodiment, a carboxylic acid bioisos tere would ionize at physiological pH to roughly the same 5 Nu. extent as a carboxylic acid group. Examples of bioisosteres of a carboxylic acid include, but are not limited to, () ( ) (7 O. N -S / N 10 OH CN N- N 1. 1. / S R S () ( ) ( ) H H N N 21 N N N H 2- N 21 2N 2 15 N OOOCN s N Nsu-N N-O N1 Sv SN O, N N ) N N v?H l/ M CO 4. 2N. OH OH N 7 N N 7 N 2N. 21N 2, \s s

25 and the like. A "heterocycloalkyl group or "heteroalicyclic' group refers to a cycloalkyl group, wherein at least one skeletal ring and the like. atom is a heteroatom selected from nitrogen, oxygen and The term “cycloalkyl refers to a monocyclic or polycyclic 30 non-aromatic radical, wherein each of the atoms forming the sulfur. The radicals may be fused with an aryl or heteroaryl. ring (i.e. skeletal atoms) is a carbonatom. Cycloalkyls may be Illustrative examples of heterocycloalkyl groups, also saturated, or partially unsaturated. Cycloalkyls may be fused referred to as non-aromatic heterocycles, include: with an aromatic ring (in which case the cycloalkyl is bonded through a non-aromatic ring carbonatom). Cycloalkyl groups 35 O V/ O O O include groups having from 3 to 10 ring atoms. Illustrative V/ examples of cycloalkyl groups include, but are not limited to, S the following moieties: S, s -, N, O, DOOOOO 40 45 O s

and the like. The terms "heteroaryl' or, alternatively, "heteroaromatic' 60 refers to an aryl group that includes one or more ring heteroa toms selected from nitrogen, oxygen and Sulfur. An N-con taining "heteroaromatic' or "heteroaryl moiety refers to an aromatic group in which at least one of the skeletal atoms of the ring is a nitrogenatom. Polycyclic heteroaryl groups may 65 be fused or non-fused. Illustrative examples of heteroaryl groups include the following moieties: US 9,359,316 B1 87 88 -continued C-Calkylalkyne, halo, acyl, acyloxy, —COH, -CO O alkyl, nitro, haloalkyl, fluoroalkyl, fluoroalkoxy, and amino, N-4-0, s M s including mono- and di-substituted amino groups (e.g. N —NH, -NHR, N(R)), and the protected derivatives 5 thereof. In some embodiments, optional Substituents are inde O) N-47 pendently selected from halogen, —CN, NH, -NH (CH), N(CH), —OH, -COH, —CO alkyl, —C(=O) NH, - C(=O)NH(alkyl), —C(=O)N(alkyl). and the like. The term heteroalicyclic also includes all ring —S(=O)NH2. —S(=O)NH(alkyl). —S(=O)N(alkyl). forms of the carbohydrates, including but not limited to the 10 alkyl, cycloalkyl, fluoroalkyl, heteroalkyl, alkoxy, fluoro monosaccharides, the disaccharides and the oligosaccha alkoxy, heterocycloalkyl, aryl, heteroaryl, aryloxy, alkylthio. rides. Unless otherwise noted, heterocycloalkyls have from 2 arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone, and to 10 carbons in the ring. It is understood that when referring arylsulfone. In some embodiments, optional Substituents are to the number of carbon atoms in a heterocycloalkyl, the independently selected from halogen, —CN, NH-OH, number of carbon atoms in the heterocycloalkyl is not the 15 - NH(CH), —N(CH), —CH, —CHCH —CF, same as the total number of atoms (including the heteroat —OCH, and —OCF. In some embodiments, substituted oms) that make up the heterocycloalkyl (i.e. skeletal atoms of groups are substituted with one or two of the preceding the heterocycloalkyl ring). groups. In some embodiments, an optional Substituent on an The term “halo” or, alternatively, “halogen' means fluoro, aliphatic carbon atom (acyclic or cyclic, Saturated or unsat chloro, bromo and iodo. urated carbon atoms, excluding aromatic carbon atoms) The term “haloalkyl or “haloalkoxy' refers to an alkyl includes oxo (=O). group or alkoxy group that is Substituted with one or more The methods and formulations described herein include halogens. The halogens may the same or they may be differ the use of crystalline forms (also known as polymorphs), or ent. Non-limiting examples of haloalkyls include —CHCl, pharmaceutically acceptable salts of compounds having the —CF, —CHF, —CHCF. —CFCF, —CF(CH), and structure of Formula (I), (II), (IIa), (IIaa), (IIb), (IIbb), (IIc), the like. Non-limiting examples of haloalkoxys include 25 (IIcc), (IId), (IIdd), (IIe), (IIee), (IIf). (IIff), (III), (IIIa), (II –OCHC1, OCF, OCHF - OCHCF - OCFCF, Iaa), (IIIb), (IIIbb), (IIIc), (IIIcc), (IIId), (IIIdd), (IIIe), (IIIee), —OCF(CH), and the like. (IIIf), (IIIff), or (IV), as well as active metabolites of these The terms “fluoroalkyl and “fluoroalkoxy” include alkyl compounds having the same type of activity. In some situa and alkoxy groups, respectively, that are substituted with one tions, compounds may exist as tautomers. All tautomers are or more fluorine atoms. Non-limiting examples of fluoro 30 included within the scope of the compounds presented herein. alkyls include CF, CHF, CHF, CHCF, In addition, the compounds described herein can exist in —CFCF, CFCFCF, -CF (CH), and the like. Non unsolvated as well as solvated forms with pharmaceutically limiting examples of fluoroalkoxy groups, include —OCF, acceptable solvents such as water, ethanol, and the like. The –OCHF –OCHF, OCHCF. OCFCF, Solvated forms of the compounds presented herein are also —OCFCFCF —OCF(CH), and the like. considered to be disclosed herein. The term "heteroalkyl refers to an alkyl radical where one 35 The terms "kit' and “article of manufacture' are used as or more skeletal chain atoms is selected from an atom other synonyms. than carbon, e.g., oxygen, nitrogen, Sulfur, phosphorus, sili The term “subject' or “patient' encompasses mammals con, or combinations thereof. The heteroatom(s) may be and non-mammals. Examples of mammals include, but are placed at any interior position of the heteroalkyl group. not limited to, any member of the Mammalian class: humans, Examples include, but are not limited to. —CH2—O—CH, 40 non-human primates Such as chimpanzees, and otherapes and CH, CH, O CH, CH-NH-CH, CH, monkey species; farm animals such as cattle, horses, sheep, CH-NH CH, CH N(CH)—CH, CH goats, Swine; domestic animals such as rabbits, dogs, and CH-NH CH, —CH2—CH N(CH)—CH, cats; laboratory animals including rodents, such as rats, mice CH, S CH, CH, CH, CH, S(O)-CH, and guinea pigs, and the like. Examples of non-mammals —CH2—CH2—S(O), CH, —CH-NH OCH, 45 include, but are not limited to, birds, fish and the like. In one —CH2—O—Si(CH), —CH2—CH=N OCH and embodiment of the methods and compositions provided —CH=CH N(CH)—CH. In addition, up to two heteroa herein, the mammal is a human. toms may be consecutive, Such as, by way of example, The terms “treat,” “treating or “treatment, as used herein, —CH NH OCH and —CH2—O Si (CH). Exclud include alleviating, abating or ameliorating a disease or con ing the number of heteroatoms, a "heteroalkyl may have dition symptoms, preventing additional symptoms, amelio from 1 to 6 carbon atoms. 50 rating or preventing the underlying causes of symptoms, The term “bond' or “single bond refers to a chemical bond inhibiting the disease or condition, e.g., arresting the devel between two atoms, or two moieties when the atoms joined by opment of the disease or condition, relieving the disease or the bond are considered to be part of larger substructure. condition, causing regression of the disease or condition, The term "moiety” refers to a specific segment or func relieving a condition caused by the disease or condition, or tional group of a molecule. Chemical moieties are often rec 55 stopping the symptoms of the disease or condition either ognized chemical entities embedded in or appended to a prophylactically and/or therapeutically. molecule. As used herein, amelioration of the symptoms of a particu As used herein, the substituent “R” appearing by itself and lar disease, disorder or condition by administration of a par without a number designation refers to a substituent selected ticular compound or pharmaceutical composition refers to from among from alkyl, haloalkyl, heteroalkyl, alkenyl, any lessening of severity, delay in onset, slowing of progres cycloalkyl, aryl, heteroaryl (bonded through a ring carbon), 60 Sion, or shortening of duration, whether permanent or tem and heterocycloalkyl. porary, lasting or transient that can be attributed to or associ The term “optionally substituted' or “substituted” means ated with administration of the compound or composition. that the referenced group may be substituted with one or more The term “modulate, as used herein, means to interact additional group(s) individually and independently selected with a target protein either directly or indirectly so as to alter from alkyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, 65 the activity of the target protein, including, by way of example —OH, alkoxy, aryloxy, alkylthio, arylthio, alkylsulfoxide, only, to inhibit the activity of the target, or to limit or reduce arylsulfoxide, alkylsulfone, arylsulfone. —CN, alkyne, the activity of the target. US 9,359,316 B1 89 90 As used herein, the term “modulator refers to a compound thyl-cis-monosaturated alkenamides, N-(substituted phe that alters an activity of a target. For example, a modulator can nyl)methyldi-unsaturatedamides, 3-hydroxyacetanilide, cause an increase or decrease in the magnitude of a certain hydroxyphenylacetamides, pseudocapsaicin, dihydrocapsai activity of a target compared to the magnitude of the activity cin, nordihydrocapsaicin, homocapsaicin, homodihydrocap in the absence of the modulator. In certain embodiments, a saicin I, anandamide, piperine, Zingerone, warburganal, modulator is an inhibitor, which decreases the magnitude of polygodial, aframodial, cinnamodial, cinnamosmolide, cin one or more activities of a target. In certain embodiments, an namolide, civainde, nonivamide, N-oleyl-homoVanillamidia, inhibitor completely prevents one or more activities of a isovelleral, Scalaradial, ancistrodial, B-acaridial, merulidial, target. Scutigeral and any combinations or mixtures thereof. The term “acceptable' with respect to a formulation, com The term “TRPV1 agonist', as used herein, refers to a position or ingredient, as used herein, means having no per 10 compound or composition that activates the transient receptor sistent detrimental effect on the general health of the subject potential vanilloid 1 receptor (TRPV1). TRPV1 agonists being treated. include, but are not limited to, capsaicin, dihydrocapsaicin, By “pharmaceutically acceptable as used herein, refers a nordihydrocapsaicin, homodihydrocapsaicin, homocapsai material. Such as a carrier or diluent, which does not abrogate cin, dihydrocapsaicin, nonivamide, and resiniferatoxin. the biological activity or properties of the compound, and is 15 The terms “effective amount’ or “therapeutically effective relatively nontoxic, i.e., the material may be administered to amount, as used herein, refer to a sufficient amount of an an individual without causing undesirable biological effects agent or a compound being administered which will relieve to or interacting in a deleterious manner with any of the com Some extent one or more of the symptoms of the disease or ponents of the composition in which it is contained. condition being treated. The result can be reduction and/or The term “pharmaceutical combination” as used herein, alleviation of the signs, symptoms, or causes of a disease, or means a product that results from the mixing or combining of any other desired alteration of a biological system. For more than one active ingredient and includes both fixed and example, an “effective amount” for therapeutic uses is the non-fixed combinations of the active ingredients. The term amount of the composition that includes a compound of For “fixed combination” means that one active ingredient, e.g. a mula (I), (II), (IIa), (IIaa), (IIb), (IIbb), (IIc), (IIcc), (IId), compound of Formula (I), (II), (IIa), (IIaa), (IIb), (IIbb), (IIc), (IIdd), (IIe), (IIee), (IIf). (IIff), (III), (IIIa), (IIIaa), (IIIb). (IIcc), (IId), (IIdd), (IIe), (IIee), (IIf). (IIff), (III), (IIIa), (II 25 (IIIbb), (IIIc), (IIIcc), (IIId), (IIIdd), (IIIe), (IIIee), (IIIf), (II Iaa), (IIIb), (IIIbb), (IIIc), (IIIcc), (IIId), (IIIdd), (IIIe), (IIIee), Iff), or (IV) described herein required to provide a clinically (IIIf), (IIIff), or (IV), and a co-agent, are both administered to significant decrease in disease symptoms. An appropriate a patient simultaneously in the form of a single entity or “effective” amount in any individual case may be determined dosage. The term “non-fixed combination' means that one using techniques, such as a dose escalation study. active ingredient, e.g. a compound of Formula (I), (II), (IIa), 30 The terms "enhance' or "enhancing,” as used herein, (IIaa), (IIb), (IIbb), (IIc), (IIcc), (IId), (IIdd), (IIe), (IIee), means to increase or prolong either in potency or duration a (IIf), (IIff), (III), (IIIa), (IIIaa), (IIIb), (IIIbb), (IIIc), (IIIcc), desired effect. Thus, in regard to enhancing the effect of (IIId), (IIIdd), (IIIe), (IIIee), (IIIf), (IIIff), or (IV), and a therapeutic agents, the term "enhancing refers to the ability co-agent, are administered to a patient as separate entities to increase or prolong, either in potency or duration, the effect either simultaneously, concurrently or sequentially with no of other therapeutic agents on a system. An "enhancing specific intervening time limits, wherein Such administration 35 effective amount, as used herein, refers to an amount provides effective levels of the two compounds in the body of adequate to enhance the effect of another therapeutic agent in the patient. The latter also applies to cocktail therapy, e.g. the a desired system. administration of three or more active ingredients. The terms “co-administration' or the like, as used herein, The term “pharmaceutical composition” refers to a mixture are meant to encompass administration of the selected thera of a compound of Formula (I), (II), (IIa), (IIaa), (IIb), (IIbb), 40 peutic agents to a single patient, and are intended to include (IIc), (IIcc), (IId), (IIdd), (IIe), (IIee), (IIf), (IIff), (III), (IIIa), treatment regimens in which the agents are administered by (IIIaa), (IIIb), (IIIbb), (IIIc), (IIIcc), (IIId), (IIIdd), (IIIe), the same or different route of administration or at the same or (IIIee), (IIIf), (IIIff), or (IV) described herein with other different time. chemical components, such as carriers, stabilizers, diluents, The term “carrier, as used herein, refers to relatively non dispersing agents, Suspending agents, thickening agents, and/ toxic chemical compounds or agents that facilitate the incor or excipients. The pharmaceutical composition facilitates 45 poration of a compound into cells or tissues. administration of the compound to an organism. Multiple The term "diluent” refers to chemical compounds that are techniques of administering a compound exist in the art used to dilute the compound of interest prior to delivery. including, but not limited to: intravenous, oral, aerosol, Diluents can also be used to stabilize compounds because parenteral, ophthalmic, pulmonary and topical administra they can provide a more stable environment. Salts dissolved tion. 50 in buffered solutions (which also can provide pH control or The term "capsaicinoid or capsaisin analog is meant to maintenance) are utilized as diluents in the art, including, but include any compound that produces a selective, highly-lo not limited to a phosphate buffered saline solution. calized destruction or incapacitation of C-fiber and/or A “metabolite' of a compound disclosed herein is a deriva A-delta-fiber in discrete localized areas responsible for the tive of that compound that is formed when the compound is initiation of pain for the purpose of eliminating pain arising 55 metabolized. The term “active metabolite” refers to a biologi from that locus, while minimizing potential adverse conse cally active derivative of a compound that is formed when the quences of C-fiber and/or A-delta-fiber activation and/or compound is metabolized. The term “metabolized, as used damage outside of the locus of pain such as (E)-capsaicin, herein, refers to the Sum of the processes (including, but not resinifiatoxin, AM-404 (N-(4-Hydroxyphenyl)-5Z,8Z., 11Z. limited to, hydrolysis reactions and reactions catalyzed by 14Z-eicosatetraenamide), Anandamide, Arvanil, 6'-Iodor enzymes) by which a particular Substance is changed by an esiniferatoxin, NADA (N-arachidonyldopamine), OLDA 60 organism. Thus, enzymes may produce specific structural (N-oleoyldopamine), olvanil, and PPAHV (phorbol 12-phe alterations to a compound. For example, cytochrome P450 nylacetate 13-acetate 20-homovanillate). Other suitable cap catalyzes a variety of oxidative and reductive reactions while saicinoids foruse described herein include, but are not limited uridine diphosphate glucuronyltransferases catalyze the to, N-Vanillylnonanamides, N-Vanillylsulfonamides, N-Va transfer of an activated glucuronic-acid molecule to aromatic nillylureas, N-Vanillylcarbamates, N-(substituted phenyl) 65 alcohols, aliphatic alcohols, carboxylic acids, amines and methylalkylamides, methylene substituted N-(substituted free sulphydryl groups. Further information on metabolism phenyl)methylalkanamides, N-(substituted phenyl)me may be obtained from The Pharmacological Basis of Thera US 9,359,316 B1 91 92 peutics, 9th Edition, McGraw-Hill (1996). Metabolites of the embodiments, the Subject is a human. Atherapeutically effec compounds disclosed herein can be identified either by tive amount can vary widely depending on the severity of the administration of compounds to a host and analysis of tissue disease, the age and relative health of the Subject, the potency samples from the host, or by incubation of compounds with of the compound used and other factors. The compounds of hepatic cells in vitro and analysis of the resulting compounds. Formula (I), (II), (IIa), (IIaa), (IIb), (IIbb), (IIc), (IIcc), (IId), “Bioavailability” refers to the percentage of the weight of (IIdd), (IIe), (IIee), (IIf). (IIff), (III), (IIIa), (IIIaa), (IIIb). the compound disclosed herein (e.g. compound of Formula (IIIbb), (IIIc), (IIIcc), (IIId), (IIIdd), (IIIe), (IIIee), (IIIf), (II (I), (II), (IIa), (IIaa), (IIb), (IIbb), (IIc), (IIcc), (IId), (IIdd), Iff), or (IV) can be used singly or in combination with one or (IIe), (IIee), (IIf), (IIff), (III), (IIIa), (IIIaa), (IIIb), (IIIbb), more therapeutic agents as components of mixtures (as in (IIIc), (IIIcc), (IIId), (IIIdd), (IIIe), (IIIee), (IIIf), (IIIff), or combination therapy). (IV)), that is delivered into the general circulation of the 10 The pharmaceutical formulations described herein can be animal or human being studied. The total exposure (AUC(0- administered to a Subject by multiple administration routes, OO)) of a drug when administered intravenously is usually including but not limited to, oral, parenteral (e.g., intrave defined as 100% bioavailable (F 96). “Oral bioavailability” nous, Subcutaneous, intramuscular), intranasal, buccal, topi refers to the extent to which a compound disclosed herein, is cal, rectal, or transdermal administration routes. Moreover, absorbed into the general circulation when the pharmaceuti 15 the pharmaceutical compositions described herein, which cal composition is taken orally as compared to intravenous include a compound of Formula (I), (II), (IIa), (IIaa), (IIb). injection. (IIbb), (IIc), (IIcc), (IId), (IIdd), (IIe), (IIee), (IIf), (IIff), (III), “Blood plasma concentration” refers to the concentration (IIIa), (IIIaa), (IIIb), (IIIbb), (IIIc), (IIIcc), (IIId), (IIIdd), of a compound of Formula (I), (II), (IIa), (IIaa), (IIb), (IIbb), (IIIe), (IIIee), (IIIf), (IIIff), or (IV) described herein, can be (IIc), (IIcc), (IId), (IIdd), (IIe), (IIee), (IIf), (IIff), (III), (IIIa), formulated into any suitable dosage form, including but not (IIIaa), (IIIb), (IIIbb), (IIIc), (IIIcc), (IIId), (IIIdd), (IIIe), limited to, aqueous oral dispersions, liquids, gels, syrups, (IIIee), (IIIf), (IIIff), or (IV) disclosed herein, in the plasma elixirs, slurries, Suspensions, aerosols, controlled release for component of blood of a subject. It is understood that the mulations, fast melt formulations, effervescent formulations, plasma concentration of compounds described herein may lyophilized formulations, tablets, powders, pills, dragees, vary significantly between subjects, due to variability with capsules, delayed release formulations, extended release for respect to metabolism and/or possible interactions with other 25 mulations, pulsatile release formulations, multiparticulate therapeutic agents. In accordance with one embodiment dis formulations, and mixed immediate release and controlled closed herein, the blood plasma concentration of the com release formulations. pounds disclosed herein may vary from Subject to Subject. One may administer the compounds and/or compositions Likewise, values such as maximum plasma concentration in a local rather than systemic manner, for example, via injec (Cmax) or time to reach maximum plasma concentration 30 tion of the compound directly into an organ or tissue, often in (Tmax), or total area under the plasma concentration time a depot preparation. Such formulations may be administered curve (AUC(0-o)) may vary from subject to subject. Due to by implantation (for example subcutaneously or intramuscu this variability, the amount necessary to constitute “athera larly) or by intramuscular injection. In addition, the drug may peutically effective amount of a compound may vary from be provided in the form of a rapid release formulation, in the Subject to Subject. form of an extended release formulation, or in the form of an As used herein, “amelioration” refers to an improvement in 35 intermediate release formulation. a disease or condition or at least a partial relief of symptoms Pharmaceutical compositions including a compound associated with a disease or condition. described herein may be manufactured in a conventional Pharmaceutical Compositions and Methods of Administra manner, Such as, by way of example only, by means of con tion Ventional mixing, dissolving, granulating, dragee-making, Pharmaceutical compositions may be formulated in a con 40 levigating, emulsifying, encapsulating, entrapping or com ventional manner using one or more physiologically accept pression processes. able carriers including excipients and auxiliaries which facili The pharmaceutical compositions will include at least one tate processing of the active compounds into preparations compound of Formula (I), (II), (IIa), (IIaa), (IIb), (IIbb), (IIc), which can be used pharmaceutically. Proper formulation is (IIcc), (IId), (IIdd), (IIe), (IIee), (IIf). (IIff), (III), (IIIa), (II dependent upon the route of administration chosen. Addi Iaa), (IIIb), (IIIbb), (IIIc), (IIIcc), (IIId), (IIIdd), (IIIe), (IIIee), tional details about Suitable excipients for pharmaceutical 45 (IIIf), (IIIff), or (IV) described herein, as an active ingredient compositions described herein may be found, for example, in in free-acid or free-base form, or in a pharmaceutically Remington: The Science and Practice of Pharmacy, Nine acceptable salt form. In addition, the methods and pharma teenth Ed (Easton, Pa.; Mack Publishing Company, 1995); ceutical compositions described herein include the use of Hoover, John E., Remington’s Pharmaceutical Sciences, crystalline forms (also known as polymorphs), as well as Mack Publishing Co., Easton, Pa. 1975; Liberman, H. A. and 50 active metabolites of these compounds having the same type Lachman, L., Eds. Pharmaceutical Dosage Forms, Marcel of activity. In some situations, compounds may exist as tau Decker, New York, N.Y., 1980; and Pharmaceutical Dosage tomers. All tautomers are included within the scope of the Forms and Drug Delivery Systems, Seventh Ed. (Lippincott compounds presented herein. Additionally, the compounds Williams & Wilkins, 1999), herein incorporated by reference described herein can exist in unsolvated as well as solvated for such disclosure. 55 forms with pharmaceutically acceptable solvents such as A pharmaceutical composition, as used herein, refers to a water, ethanol, and the like. The solvated forms of the com mixture of a compound of Formula (I), (II), (IIa), (IIaa), (IIb). pounds presented herein are also considered to be disclosed (IIbb), (IIc), (IIcc), (IId), (IIdd), (Ile), (IIee), (IIf), (IIff), (III), herein. (IIIa), (IIIaa), (IIIb), (IIIbb), (IIIc), (IIIcc), (IIId), (IIIdd), In certain embodiments, compositions provided herein (IIIe), (IIIee), (IIIf), (IIIff), or (IV) described herein, with may also include one or more preservatives to inhibit micro other chemical components, such as carriers, stabilizers, dilu 60 bial activity. Suitable preservatives include quaternary ents, dispersing agents, Suspending agents, thickening agents, ammonium compounds such as benzalkonium chloride, and/or excipients. The pharmaceutical composition facili cetyltrimethylammonium bromide and cetylpyridinium chlo tates administration of the compound to an organism. In prac ride. ticing the methods of treatment or use provided herein, thera Pharmaceutical preparations for oral use can be obtained peutically effective amounts of compounds described herein 65 by mixing one or more Solid excipient with one or more of the are administered in a pharmaceutical composition to a subject compounds described herein (e.g. compounds of Formula (I), having a disease, disorder, or condition to be treated. In some (II), (IIa), (IIaa), (IIb), (IIbb), (IIc), (IIcc), (IId), (IIdd), (IIe), US 9,359,316 B1 93 94 (IIee), (IIf), (IIff), (III), (IIIa), (IIIaa), (IIIb), (IIIbb), (IIIc), ingestion or upon contact with diluent. These formulations (IIIcc), (IIId), (IIIdd), (IIIe), (IIIee), (IIIf), (IIIff), or (IV)), can be manufactured by conventional pharmacological tech optionally grinding the resulting mixture, and processing the niques. mixture of granules, after adding suitable auxiliaries, if The pharmaceutical solid dosage forms described herein desired, to obtain tablets, pills, or capsules. Suitable excipi can include a compound of Formula (I), (II), (IIa), (IIaa). ents include, for example, fillers such as sugars, including (IIb), (IIbb), (IIc), (IIcc), (IId), (IIdd), (IIe), (IIee), (IIf). (IIff), lactose, sucrose, mannitol, or sorbitol; cellulose preparations (III), (IIIa), (IIIaa), (IIIb), (IIIbb), (IIIc), (IIIcc), (IIId), (II Idd), (IIIe), (IIIee), (IIIf). (IIIff), or (IV) described herein, and such as, for example, maize starch, wheat starch, rice starch, one or more pharmaceutically acceptable additives such as a potato starch, gelatin, gum tragacanth, methylcellulose, compatible carrier, binder, filling agent, suspending agent, microcrystalline cellulose, hydroxypropylmethylcellulose, 10 flavoring agent, Sweetening agent, disintegrating agent, dis sodium carboxymethylcellulose; or others such as: polyvi persing agent, surfactant, lubricant, colorant, diluent, solubi nylpyrrolidone (PVP or povidone) or calcium phosphate. If lizer, moistening agent, plasticizer, stabilizer, penetration desired, disintegrating agents may be added, such as the enhancer, wetting agent, anti-foaming agent, antioxidant, cross-linked croscarmellose sodium, polyvinylpyrrolidone, preservative, or one or more combination thereof. In still agar, oralginic acid or a salt thereof such as sodium alginate. 15 other aspects, using standard coating procedures, such as Dragee cores are provided with suitable coatings. For this those described in Remington’s Pharmaceutical Sciences, purpose, concentrated sugar solutions may be used, which 20th Edition (2000), a film coating is provided around the may optionally contain gum arabic, talc, polyvinylpyrroli formulation of the compound described herein. In one done, carbopol gel, polyethylene glycol, and/or titanium embodiment, some or all of the particles of the compound dioxide, lacquer solutions, and suitable organic solvents or described herein are coated. In another embodiment, some or solvent mixtures. Dyestuffs or pigments may be added to the all of the particles of the compound described herein are tablets or dragee coatings for identification or to characterize microencapsulated. In still another embodiment, the particles different combinations of active compound doses. of the compound described herein are not microencapsulated Pharmaceutical preparations that can be used orally and are uncoated. include push-fit capsules made of gelatin, as well as soft, Suitable carriers for use in the solid dosage forms 25 described herein include, but are not limited to, acacia, gela sealed capsules made of gelatin and a plasticizer, such as tin, colloidal silicon dioxide, calcium glycerophosphate, cal glycerol or sorbitol. The push-fit capsules can contain the cium lactate, maltodextrin, glycerine, magnesium silicate. active ingredients in admixture with filler such as lactose, sodium caseinate, soy lecithin, sodium chloride, tricalcium binders such as starches, and/or lubricants such as talc or phosphate, dipotassium phosphate, sodium stearoyl lactylate, magnesium stearate and, optionally, stabilizers. In soft cap carrageenan, monoglyceride, diglyceride, pregelatinized sules, the active compounds may be dissolved or suspended in 30 starch, hydroxypropylmethylcellulose, hydroxypropylmeth suitable liquids, such as fatty oils, liquid paraffin, or liquid ylcellulose acetate stearate, sucrose, microcrystalline cellu polyethylene glycols. In addition, stabilizers may be added. lose, lactose, mannitol and the like. In some embodiments, the solid dosage forms disclosed Suitable filling agents for use in the solid dosage forms herein may be in the form of a tablet, (including a suspension described herein include, but are not limited to, lactose, cal tablet, a fast-melt tablet, a bite-disintegration tablet, a rapid 35 cium carbonate, calcium phosphate, dibasic calcium phos disintegration tablet, an effervescent tablet, or a caplet), a pill. phate, calcium sulfate, microcrystalline cellulose, cellulose a powder (including a sterile packaged powder, a dispensable powder, dextrose, dextrates, dextran, starches, pregelatinized powder, or an effervescent powder), a capsule (including both starch, hydroxypropylmethycellulose (HPMC), hydroxypro soft or hard capsules, e.g., capsules made from animal-de pylmethycellulose phthalate, hydroxypropylmethylcellulose rived gelatin or plant-derived HPMC, or "sprinkle capsules”), 40 acetate stearate (HPMCAS), sucrose, xylitol, lactitol, manni solid dispersion, solid solution, bioerodible dosage form, tol, sorbitol, sodium chloride, polyethylene glycol, and the controlled release formulations, pulsatile release dosage like. forms, multiparticulate dosage forms, pellets, granules, or an In order to release the compound of Formula (I), (II), (IIa). aerosol. In other embodiments, the pharmaceutical formula (IIaa), (IIb), (IIbb), (IIc), (IIcc), (IId), (IIdd), (Ile), (IIee), tion is in the form of a powder. In still other embodiments, the 45 (IIf), (IIff), (III), (IIIa), (IIIaa), (IIIb), (IIIbb), (IIIc), (IIIcc), pharmaceutical formulation is in the form of a tablet, includ (IIId), (IIIdd), (IIIe), (IIIee), (IIIf). (IIIff), or (IV) from a solid ing but not limited to, a fast-melt tablet. Additionally, phar dosage form matrix as efficiently as possible, disintegrants maceutical formulations of the compounds described herein are often used in the formulation, especially when the dosage may be administered as a single capsule or in multiple capsule forms are compressed with binder. Disintegrants help ruptur dosage form. In some embodiments, the pharmaceutical for ing the dosage form matrix by swelling or capillary action mulation is administered in two, or three, or four, capsules or 50 when moisture is absorbed into the dosage form. Suitable tablets. disintegrants for use in the solid dosage forms described In some embodiments, solid dosage forms, e.g., tablets, herein include, but are not limited to, natural starch Such as effervescent tablets, and capsules, are prepared by mixing corn starch or potato starch, a pregelatinized starch such as particles of a compound of Formula (I), (II), (IIa), (IIaa), (IIb). National 1551 or Amijel(R), or sodium starch glycolate such as (IIbb), (IIc), (IIcc), (IId), (IIdd), (IIe), (IIee), (IIf), (IIff), (III), 55 Promogel(R) or Explotab(R), a cellulose such as a wood prod (IIIa), (IIIaa), (IIIb), (IIIbb), (IIIc), (IIIcc), (IIId), (IIIdd), uct, methylcrystalline cellulose, e.g., Avicel(R), Avicel(R) (IIIe), (IIIee), (IIIf), (IIIff), or (IV) described herein, with one PH101, Avicel(R) PH102, Avicel(R) PH105, Elcema(R) P100, or more pharmaceutical excipients to form a bulk blend com Emcocel(R), Vivacel(R), Ming Tia(R), and Solka-FlocR, methyl position. When referring to these bulk blend compositions as cellulose, croscarmellose, or a cross-linked cellulose, such as homogeneous, it is meant that the particles of the compound cross-linked sodium carboxymethylcellulose (Ac-Di-SolR). of Formula (I), (II), (IIa), (IIaa), (IIb), (IIbb), (IIc), (IIcc), 60 cross-linked carboxymethylcellulose, or cross-linked cros (IId), (IIdd), (IIe), (IIee), (IIf). (IIff), (III), (IIIa), (IIIaa), carmellose, a cross-linked starch such as sodium starch gly (IIIb), (IIIbb), (IIIc), (IIIcc), (IIId), (IIIdd), (IIIe), (IIIee), colate, a cross-linked polymer such as crospovidone, a cross (IIIf), (IIIff), or (IV) described herein, are dispersed evenly linked polyvinylpyrrolidone, alginate such as alginic acid or throughout the composition so that the composition may be a salt of alginic acid such as sodium alginate, a clay Such as subdivided into equally effective unit dosage forms, such as 65 Veegum(RHV (magnesium aluminum silicate), a gum Such as tablets, pills, and capsules. The individual unit dosages may agar, guar, locust bean, Karaya, pectin, or tragacanth, sodium also include film coatings, which disintegrate upon oral starch glycolate, bentonite, a natural sponge, a surfactant, a US 9,359,316 B1 95 96 resin Such as a cation-exchange resin, citrus pulp, sodium polyethylene glycol can have a molecular weight of about 300 lauryl Sulfate, sodium lauryl Sulfate in combination starch, to about 6000, or about 3350 to about 4000, or about 5400 to and the like. about 7000, vinyl pyrrolidone/vinyl acetate copolymer Binders impart cohesiveness to Solid oral dosage form (S630), sodium carboxymethylcellulose, methylcellulose, formulations: for powder filled capsule formulation, they aid 5 hydroxy-propylmethylcellulose, polysorbate-80, hydroxy in plug formation that can be filled into soft or hard shell ethylcellulose, sodium alginate, gums, such as, e.g., gum capsules and for tablet formulation, they ensure the tablet tragacanth and gum acacia, guar gum, Xanthans, including remaining intact after compression and help assure blend Xanthan gum, Sugars, cellulosics, such as, e.g., sodium car uniformity prior to a compression or fill step. Materials Suit boxymethylcellulose, methylcellulose, sodium carboxym able for use as binders in the solid dosage forms described ethylcellulose, hydroxypropylmethylcellulose, hydroxyeth herein include, but are not limited to, carboxymethylcellu 10 ylcellulose, polysorbate-80, Sodium alginate, lose, methylcellulose (e.g., Methocel(R), hydroxypropylm polyethoxylated Sorbitan monolaurate, polyethoxylated Sor ethylcellulose (e.g. Hypromellose USP Pharmacoat-603, bitan monolaurate, povidone and the like. hydroxypropylmethylcellulose acetate stearate (Aqoate HS Suitable antioxidants for use in the solid dosage forms LF and HS), hydroxyethylcellulose, hydroxypropylcellulose described herein include, for example, e.g., butylated (e.g., Klucel(R), ethylcellulose (e.g., Ethocel(R), and microc 15 hydroxytoluene (BHT), sodium ascorbate, and tocopherol. rystalline cellulose (e.g., Avicel(R), microcrystalline dex There is considerable overlap between additives used in the trose, amylose, magnesium aluminum silicate, polysaccha solid dosage forms described herein. Thus, the above-listed ride acids, bentonites, gelatin, polyvinylpyrrolidone/vinyl additives should be taken as merely exemplary, and not lim acetate copolymer, crospovidone, povidone, starch, pregela iting, of the types of additives that can be included in solid tinized Starch, tragacanth, dextrin, a Sugar, such as Sucrose dosage forms of the pharmaceutical compositions described (e.g., Dipac.R.), glucose, dextrose, molasses, mannitol, Sorbi herein. tol. Xylitol (e.g., XylitabR), lactose, a natural or synthetic In other embodiments, one or more layers of the pharma gum Such as acacia, tragacanth, ghatti gum, mucilage of isa ceutical formulation are plasticized. Illustratively, a plasti polhusks, starch, polyvinylpyrrolidone (e.g., Povidone R. CL, cizer is generally a high boiling point solid or liquid. Suitable Kollidon(R) CL, PolyplasdoneR XL-10, and Povidone(R) plasticizers can be added from about 0.01% to about 50% by K-12), larch arabogalactan, VeegumR), polyethylene glycol, 25 weight (w/w) of the coating composition. Plasticizers waxes, sodium alginate, and the like. include, but are not limited to, diethyl phthalate, citrate esters, In general, binder levels of 20-70% are used in powder polyethylene glycol, glycerol, acetylated glycerides, triace filled gelatin capsule formulations. Binder usage level in tab tin, polypropylene glycol, polyethylene glycol, triethyl cit let formulations varies whether direct compression, wet rate, dibutyl sebacate, Stearic acid, Stearol, Stearate, and castor granulation, roller compaction, or usage of other excipients 30 oil. such as fillers which itself can act as moderate binder. In some Compressed tablets are solid dosage forms prepared by embodiments, formulators determine the binder level for the compacting the bulk blend of the formulations described formulations, but binder usage level of up to 70% in tablet above. In various embodiments, compressed tablets which formulations is common. are designed to dissolve in the mouth will include one or more Suitable lubricants or glidants for use in the solid dosage flavoring agents. In other embodiments, the compressed tab forms described herein include, but are not limited to, stearic 35 lets will include a film Surrounding the final compressed acid, calcium hydroxide, talc, corn starch, Sodium Stearyl tablet. In some embodiments, the film coating can provide a fumerate, alkali-metal and alkaline earth metal salts, such as delayed release of the compounds of Formula (I), (II), (IIa), aluminum, calcium, magnesium, Zinc, Stearic acid, sodium (IIaa), (IIb), (IIbb), (IIc), (IIcc), (IId), (IIdd), (IIe), (IIee), Stearates, magnesium Stearate, Zinc Stearate, waxes, (IIf), (IIff), (III), (IIIa), (IIIaa), (IIIb), (IIIbb), (IIIc), (IIIcc), Stearowet(R), boric acid, Sodium benzoate, sodium acetate, 40 (IIId), (IIIdd), (IIIe), (IIIee), (IIIf), (IIIff), or (IV) described Sodium chloride, leucine, a polyethylene glycol or a meth herein from the formulation. In other embodiments, the film oxypolyethylene glycol such as CarbowaxTM, PEG 4000, coating aids in patient compliance (e.g., Opadry(R) coatings or PEG 5000, PEG 6000, propylene glycol, sodium oleate, glyc Sugar coating). Film coatings including Opadry(R) typically eryl behenate, glyceryl palmitostearate, glyceryl benzoate, range from about 1% to about 3% of the tablet weight. In other magnesium or Sodium lauryl Sulfate, and the like. embodiments, the compressed tablets include one or more Suitable diluents for use in the solid dosage forms 45 excipients. described herein include, but are not limited to, Sugars (in A capsule may be prepared, for example, by placing the cluding lactose, Sucrose, and dextrose), polysaccharides (in bulk blend of the formulation of the compound described cluding dextrates and maltodextrin), polyols (including man above, inside of a capsule. In some embodiments, the formu nitol, xylitol, and sorbitol), cyclodextrins and the like. lations (non-aqueous Suspensions and solutions) are placed in Suitable wetting agents for use in the Solid dosage forms 50 a softgelatin capsule. In other embodiments, the formulations described herein include, for example, oleic acid, glyceryl are placed in standard gelatin capsules or non-gelatin cap monostearate, Sorbitan monooleate, Sorbitan monolaurate, sules such as capsules comprising HPMC. In other embodi triethanolamine oleate, polyoxyethylene Sorbitan ments, the formulation is placed in a sprinkle capsule, monooleate, polyoxyethylene Sorbitan monolaurate, quater wherein the capsule may be swallowed whole or the capsule nary ammonium compounds (e.g., Polyguat 10(R), sodium 55 may be opened and the contents sprinkled on food prior to oleate, sodium lauryl Sulfate, magnesium Stearate, sodium eating. In some embodiments, the therapeutic dose is split docusate, triacetin, vitamin ETPGS and the like. into multiple (e.g., two, three, or four) capsules. In some Suitable surfactants for use in the solid dosage forms embodiments, the entire dose of the formulation is delivered described herein include, for example, sodium lauryl sulfate, in a capsule form. Sorbitan monooleate, polyoxyethylene Sorbitan monooleate, In various embodiments, the particles of the compound of polysorbates, polaxomers, bile salts, glyceryl monostearate, 60 Formula (I), (II), (IIa), (IIaa), (IIb), (IIbb), (IIc), (IIcc), (IId), copolymers of ethylene oxide and propylene oxide, e.g., Plu (IIdd), (IIe), (IIee), (IIf). (IIff), (III), (IIIa), (IIIaa), (IIIb). ronic R (BASF), and the like. (IIIbb), (IIIc), (IIIcc), (IIId), (IIIdd), (IIIe), (IIIee), (IIIf), (II Suitable Suspending agents for use in the Solid dosage Iff), or (IV) described herein and one or more excipients are forms described here include, but are not limited to, polyvi dry blended and compressed into a mass, Such as a tablet, nylpyrrolidone, e.g., polyvinylpyrrolidone K12, polyvi 65 having a hardness Sufficient to provide a pharmaceutical com nylpyrrolidone K17, polyvinylpyrrolidone K25, or polyvi position that Substantially disintegrates withinless than about nylpyrrolidone K30, polyethylene glycol, e.g., the 30 minutes, less than about 35 minutes, less than about 40 US 9,359,316 B1 97 98 minutes, less than about 45 minutes, less than about 50 min In still other embodiments, effervescent powders are also utes, less than about 55 minutes, or less than about 60 min prepared in accordance with the present disclosure. Efferves utes, after oral administration, thereby releasing the formula cent salts have been used to disperse medicines in water for tion into the gastrointestinal fluid. oral administration. Effervescent salts are granules or coarse In another aspect, dosage forms may include microencap powders containing a medicinal agent in a dry mixture, usu Sulated formulations. In some embodiments, one or more ally composed of Sodium bicarbonate, citric acid and/or tar other compatible materials are present in the microencapsu taric acid. When such salts are added to water, the acids and lation material. Exemplary materials include, but are not lim the base react to liberate carbon dioxide gas, thereby causing ited to, pH modifiers, erosion facilitators, anti-foaming “effervescence.” Examples of effervescent salts include, e.g., agents, antioxidants, flavoring agents, and carrier materials the following ingredients: sodium bicarbonate or a mixture of Such as binders, Suspending agents, disintegration agents, 10 Sodium bicarbonate and sodium carbonate, citric acid and/or filling agents, Surfactants, solubilizers, stabilizers, lubricants, tartaric acid. Any acid-base combination that results in the wetting agents, and diluents. liberation of carbon dioxide can be used in place of the com Materials useful for the microencapsulation described bination of sodium bicarbonate and citric and tartaric acids, as herein include materials compatible with compounds long as the ingredients were Suitable for pharmaceutical use described herein, which sufficiently isolate the compound 15 and result in a pH of about 6.0 or higher. from other non-compatible excipients. Materials compatible In other embodiments, the formulations described herein, with compounds described herein are those that delay the which include a compound described herein, are solid disper release of the compounds of Formula (I), (II), (IIa), (IIaa), sions. Methods of producing Such solid dispersions include, (IIb), (IIbb), (IIc), (IIcc), (IId), (IIdd), (IIe), (IIee), (IIf), (IIff), but are not limited to, for example, U.S. Pat. Nos. 4.343,789, (III), (IIIa), (IIIaa), (IIIb), (IIIbb), (IIIc), (IIIcc), (IIId), (II 5,340,591, 5,456,923, 5,700.485, 5,723,269, and U.S. patent Idd), (IIIe), (IIIee), (IIIf), (IIIff), or (IV) in vivo. publication no. 2004/0013734. In still other embodiments, Exemplary microencapsulation materials useful for delay the formulations described herein are solid solutions. Solid ing the release of the formulations including compounds Solutions incorporate a Substance together with the active described herein, include, but are not limited to, hydroxypro agent and other excipients such that heating the mixture pyl cellulose ethers (HPC) such as Klucel(R) or Nisso HPC, results in dissolution of the drug and the resulting composi low-substituted hydroxypropyl cellulose ethers (L-HPC), 25 tion is then cooled to provide a solid blend which can be hydroxypropyl methyl cellulose ethers (HPMC) such as Sep further formulated or directly added to a capsule or com pifilm-LC, Pharmacoat(R), Metolose SR, Methocel(R)-E, pressed into a tablet. Methods of producing such solid solu OpadryYS, PrimaFlo, Benecel MP824, and Benecel MP843, tions include, but are not limited to, for example, U.S. Pat. methylcellulose polymers such as Methocel(R-A, hydrox Nos. 4,151,273, 5,281,420, and 6,083,518. ypropylmethylcellulose acetate stearate Aqoat (HF-LS, HF 30 The pharmaceutical Solid oral dosage forms including for LG, HF-MS) and Metolose(R), Ethylcelluloses (EC) and mix mulations described herein, which include a compounds tures thereof such as E461, Ethocel(R), Aqualon R-EC, described herein, can be further formulated to provide a con Surelease R, Polyvinyl alcohol (PVA) such as Opadry AMB, trolled release of the compound of Formula (I), (II), (IIa), hydroxyethylcelluloses such as Natrosol(R), carboxymethyl (IIaa), (IIb), (IIbb), (IIc), (IIcc), (IId), (IIdd), (IIe), (IIee), celluloses and salts of carboxymethylcelluloses (CMC) such (IIf), (IIff), (III), (IIIa), (IIIaa), (IIIb), (IIIbb), (IIIc), (IIIcc), as Aqualon(R)-CMC, polyvinyl alcohol and polyethylene gly 35 (IIId), (IIIdd), (IIIe), (IIIee), (IIIf), (IIIff), or (IV). Controlled col co-polymers such as Kollicoat IRR, monoglycerides release refers to the release of the compounds described (My verol), triglycerides (KLX), polyethylene glycols, modi herein from a dosage form in which it is incorporated accord fied food starch, acrylic polymers and mixtures of acrylic ing to a desired profile over an extended period of time. polymers with cellulose ethers such as EudragitR) EPO, Controlled release profiles include, for example, sustained EudragitRL30D-55, Eudragit RFS 30DEudragit RL100-55, 40 release, prolonged release, pulsatile release, and delayed Eudragit R L100, EudragitR) S100, Eudragit R. RD100, release profiles. In contrast to immediate release composi EudragitR) E100, EudragitR) L12.5, EudragitR) S12.5, tions, controlled release compositions allow delivery of an EudragitRNE30D, and EudragitRNE 40D, cellulose acetate agent to a Subject over an extended period of time according phthalate, sepifilms such as mixtures of HPMC and stearic to a predetermined profile. Such release rates can provide acid, cyclodextrins, and mixtures of these materials. therapeutically effective levels of agent for an extended In still other embodiments, plasticizers such as polyethyl 45 period of time and thereby provide a longer period of phar ene glycols, e.g., PEG 300, PEG 400, PEG 600, PEG 1450, macologic response while minimizing side effects as com PEG 3350, and PEG 800, stearic acid, propylene glycol, oleic pared to conventional rapid release dosage forms. Such acid, and triacetin are incorporated into the microencapsula longer periods of response provide for many inherent benefits tion material. In other embodiments, the microencapsulating that are not achieved with the corresponding short acting, material useful for delaying the release of the pharmaceutical 50 immediate release preparations. compositions is from the USP or the National Formulary In some embodiments, the Solid dosage forms described (NF). In yet other embodiments, the microencapsulation herein can be formulated as enteric coated delayed release material is Klucel. In still other embodiments, the microen oral dosage forms, i.e., as an oral dosage form of a pharma capsulation material is methocel. ceutical composition as described herein which utilizes an Microencapsulated compounds described herein may be 55 enteric coating to affect release in the Small intestine of the formulated by methods that include, e.g., spray drying pro gastrointestinal tract. The enteric coated dosage form may be cesses, spinning disk-solvent processes, hot melt processes, a compressed or molded or extruded tablet/mold (coated or spray chilling methods, fluidized bed, electrostatic deposi uncoated) containing granules, powder, pellets, beads or par tion, centrifugal extrusion, rotational Suspension separation, ticles of the active ingredient and/or other composition com polymerization at liquid-gas or solid-gas interface, pressure ponents, which are themselves coated or uncoated. The extrusion, or spraying solvent extraction bath. In addition to 60 enteric coated oral dosage form may also be a capsule (coated these, several chemical techniques, e.g., complex coacerva or uncoated) containing pellets, beads or granules of the Solid tion, solvent evaporation, polymer-polymer incompatibility, carrier or the composition, which are themselves coated or interfacial polymerization in liquid media, in situ polymer uncoated. ization, in-liquid drying, and desolvation in liquid media The term “rapid release' or “delayed release' as used could also be used. Furthermore, other methods such as roller 65 herein refers to the delivery so that the release can be accom compaction, extrusion/spheronization, coacervation, or plished at Some generally predictable rate. In some embodi nanoparticle coating may also be used. ments the method for delay of release is either the tuning of US 9,359,316 B1 99 100 the intramolecular cyclization-release reaction or via the calcium citrate, camphor, caramel, cherry, cherry cream, addition of buffers to modify the initiation of the intramolecu chocolate, cinnamon, bubblegum, citrus, citrus punch, citrus lar cyclization-release reaction. cream, cotton candy, cocoa, cola, cool cherry, cool citrus, Colorants, detackifiers, Surfactants, antifoaming agents, cyclamate, cylamate, dextrose, eucalyptus, eugenol, fructose, lubricants (e.g., carnuba wax or PEG) may be added to the fruit punch, ginger, glycyrrhetinate, glycyrrhiza (licorice) coatings besides plasticizers to solubilize or disperse the coat syrup, grape, grapefruit, honey, isomalt, lemon, lime, lemon ing material, and to improve coating performance and the cream, monoammonium glyrrhizinate (MagnaSweet(R), mal coated product. tol, mannitol, maple, marshmallow, menthol, mint cream, In other embodiments, the formulations described herein, mixed berry, neohesperidine DC, neotame, orange, pear, which include a compound of Formula (I), (II), (IIa), (IIaa), peach, peppermint, peppermint cream, ProSweet R Powder, (IIb), (IIbb), (IIc), (IIcc), (IId), (IIdd), (IIe), (IIee), (IIf), (IIff), 10 raspberry, root beer, rum, saccharin, Safrole, Sorbitol, spear (III), (IIIa), (IIIaa), (IIIb), (IIIbb), (IIIc), (IIIcc), (IIId), (II mint, spearmint cream, Strawberry, strawberry cream, Stevia, Idd), (IIIe), (IIIee), (IIIf), (IIIff), or (IV) described herein, are Sucralose. Sucrose, Sodium saccharin, Saccharin, aspartame, delivered using a pulsatile dosage form. A pulsatile dosage acesulfame potassium, mannitol, talin, Sucralose, Sorbitol, form is capable of providing one or more immediate release Swiss cream, tagatose, tangerine, thaumatin, tutti fruitti, pulses at predetermined time points after a controlled lag time 15 Vanilla, walnut, watermelon, wild cherry, wintergreen, Xyli or at specific sites. Pulsatile dosage forms may be adminis tol, or any combination of these flavoring ingredients, e.g., tered using a variety of pulsatile formulations including, but anise-menthol, cherry-anise, cinnamon-orange, cherry-cin are not limited to, those described in U.S. Pat. Nos. 5,011, namon, chocolate-mint, honey-lemon, lemon-lime, lemon 692; 5,017,381: 5,229,135; 5,840,329; 4,871,549; 5,260,068; mint, menthol-eucalyptus, orange-cream, Vanilla-mint, and 5,260,069: 5,508,040: 5,567,441 and 5,837,284. mixtures thereof. Many other types of controlled release systems are suitable In some embodiments, the pharmaceutical formulations for use with the formulations described herein. Examples of described herein can be self-emulsifying drug delivery sys Such delivery systems include, e.g., polymer-based systems, tems (SEDDS). Emulsions are dispersions of one immiscible Such as polylactic and polyglycolic acid, polyanhydrides and phase in another, usually in the form of droplets. Generally, polycaprolactone; porous matrices, nonpolymer-based sys emulsions are created by vigorous mechanical dispersion. tems that are lipids, including sterols, such as cholesterol, 25 SEDDS, as opposed to emulsions or microemulsions, spon cholesterol esters and fatty acids, or neutral fats, such as taneously form emulsions when added to an excess of water mono-, di- and triglycerides; hydrogel release systems; Silas without any external mechanical dispersion or agitation. An tic systems; peptide-based systems; wax coatings, bioerod advantage of SEDDS is that only gentle mixing is required to ible dosage forms, compressed tablets using conventional distribute the droplets throughout the solution. Additionally, binders and the like. See, e.g., Liberman et al., Pharmaceuti 30 water or the aqueous phase can be added just prior to admin cal Dosage Forms, 2 Ed., Vol. 1, pp. 209-214 (1990); Singhet istration, which ensures stability of an unstable or hydropho al., Encyclopedia of Pharmaceutical Technology, 2nd Ed., pp. bic active ingredient. Thus, the SEDDS provides an effective 751-753 (2002); U.S. Pat. Nos. 4,327,725; 4,624,848; 4.968, delivery system for oral and parenteral delivery of hydropho 509; 5,461,140;5,456,923;5,516,527; 5,622,721; 5,686,105; bic active ingredients. SEDDS may provide improvements in 5,700,410; 5,977,175; 6,465,014; and 6,932,983. the bioavailability of hydrophobic active ingredients. Meth In some embodiments, pharmaceutical formulations are 35 ods of producing self-emulsifying dosage forms include, but provided that include particles of the compounds described are not limited to, for example, U.S. Pat. Nos. 5,858,401, herein, e.g. compounds of Formula (I), (II), (IIa), (IIaa), (IIb). 6,667,048, and 6,960,563. (IIbb), (IIc), (IIcc), (IId), (IIdd), (Ile), (IIee), (IIf), (IIff), (III), There is overlap between the above-listed additives used in (IIIa), (IIIaa), (IIIb), (IIIbb), (IIIc), (IIIcc), (IIId), (IIIdd), the aqueous dispersions or Suspensions described herein, (IIIe), (IIIee), (IIIff), or (IV), and at least one dispersing agent 40 since a given additive is often classified differently by differ or Suspending agent for oral administration to a subject. The ent practitioners in the field, or is commonly used for any of formulations may be a powder and/or granules for Suspen several different functions. Thus, the above-listed additives Sion, and upon admixture with water, a Substantially uniform should be taken as merely exemplary, and not limiting, of the Suspension is obtained. types of additives that can be included in formulations Liquid formulation dosage forms for oral administration described herein. can be acqueous suspensions selected from the group includ 45 Potential excipients for intranasal formulations include, ing, but not limited to, pharmaceutically acceptable aqueous for example, U.S. Pat. Nos. 4,476,116, 5,116,817 and 6,391, oral dispersions, emulsions, solutions, elixirs, gels, and Syr 452. Formulations solutions in Saline, employing benzyl ups. See, e.g., Singh et al., Encyclopedia of Pharmaceutical alcohol or other suitable preservatives, fluorocarbons, and/or Technology, 2nd Ed., pp. 754-757 (2002). other solubilizing or dispersing agents. See, for example, The aqueous Suspensions and dispersions described herein 50 Ansel, H. C. et al., Pharmaceutical Dosage Forms and Drug can remain in a homogenous state, as defined in The USP Delivery Systems, Sixth Ed. (1995). Preferably these compo Pharmacists Pharmacopeia (2005 edition, chapter 905), for sitions and formulations are prepared with Suitable nontoxic at least 4 hours. The homogeneity should be determined by a pharmaceutically acceptable ingredients. The choice of Suit sampling method consistent with regard to determining able carriers is highly dependent upon the exact nature of the homogeneity of the entire composition. In one embodiment, 55 nasal dosage form desired, e.g., Solutions, Suspensions, oint an aqueous Suspension can be re-suspended into a homog ments, or gels. Nasal dosage forms generally contain large enous Suspension by physical agitation lasting less than 1 amounts of water in addition to the active ingredient. Minor minute. In another embodiment, an aqueous Suspension can amounts of otheringredients such as pH adjusters, emulsifiers be re-suspended into a homogenous Suspension by physical or dispersing agents, preservatives, Surfactants, gelling agitation lasting less than 45 seconds. In yet another embodi agents, or buffering and other stabilizing and solubilizing ment, an aqueous Suspension can be re-suspended into a 60 agents may also be present. Preferably, the nasal dosage form homogenous Suspension by physical agitation lasting less should be isotonic with nasal Secretions. than 30 seconds. In still another embodiment, no agitation is For administration by inhalation, the compounds described necessary to maintain a homogeneous aqueous dispersion. herein may be in a form as an aerosol, a mist or a powder. The pharmaceutical compositions described herein may Pharmaceutical compositions described herein are conve include Sweetening agents such as, but not limited to, acacia 65 niently delivered in the form of an aerosol spray presentation syrup, acesulfame K, alitame, anise, apple, aspartame, from pressurized packs or a nebuliser, with the use of a banana, Bavarian cream, berry, black currant, butterscotch, Suitable propellant, e.g., dichlorodifluoromethane, trichlorof US 9,359,316 B1 101 102 luoromethane, dichlorotetrafluoroethane, carbon dioxide or transdermal delivery of the compounds described herein can other Suitable gas. In the case of a pressurized aerosol, the be accomplished by means of iontophoretic patches and the dosage unit may be determined by providing a valve to deliver like. Additionally, transdermal patches can provide con a metered amount. Capsules and cartridges of Such as, by trolled delivery of the compounds described herein. The rate way of example only, gelatin for use in an inhaler or insuffla of absorption can be slowed by using rate-controlling mem tor may be formulated containing a powder mix of the com branes or by trapping the compound within a polymer matrix pound described herein and a suitable powder base such as or gel. Conversely, absorption enhancers can be used to lactose or starch. Buccal formulations that include compounds described increase absorption. An absorption enhancer or carrier can herein may be administered using a variety of formulations include absorbable pharmaceutically acceptable solvents to which include, but are not limited to, U.S. Pat. Nos. 4,229, 10 assist passage through the skin. For example, transdermal 447, 4,596,795, 4,755,386, and 5,739,136. In addition, the devices are in the form of a bandage comprising a backing buccal dosage forms described herein can further include a member, a reservoir containing the compound optionally bioerodible (hydrolysable) polymeric carrier that also serves with carriers, optionally a rate controlling barrier to deliver to adhere the dosage form to the buccal mucosa. The buccal the compound to the skin of the host at a controlled and dosage form is fabricated so as to erode gradually over a 15 predetermined rate over a prolonged period of time, and predetermined time period, wherein the delivery of the com means to secure the device to the skin. pound is provided essentially throughout. Buccal drug deliv Formulations Suitable for intramuscular, Subcutaneous, or ery avoids the disadvantages encountered with oral drug intravenous injection may include physiologically acceptable administration, e.g., slow absorption, degradation of the sterile aqueous or non-aqueous solutions, dispersions, Sus active agent by fluids present in the gastrointestinal tract pensions or emulsions, and sterile powders for reconstitution and/or first-pass inactivation in the liver. With regard to the into sterile injectable solutions or dispersions. Examples of bioerodible (hydrolysable) polymeric carrier, virtually any Suitable aqueous and non-aqueous carriers, diluents, Sol Such carrier can be used, so long as the desired drug release vents, or vehicles including water, ethanol, polyols (propyle profile is not compromised, and the carrier is compatible with neglycol, polyethylene-glycol, glycerol, cremophor and the the compounds described herein, and any other components like), suitable mixtures thereof, vegetable oils (such as olive that may be present in the buccal dosage unit. Generally, the 25 oil) and injectable organic esters such as ethyl oleate. Proper polymeric carrier comprises hydrophilic (water-soluble and fluidity can be maintained, for example, by the use of a water-swellable) polymers that adhere to the wet surface of coating such as lecithin, by the maintenance of the required the buccal mucosa. Examples of polymeric carriers useful particle size in the case of dispersions, and by the use of herein include acrylic acid polymers and co, e.g., those Surfactants. Formulations suitable for Subcutaneous injection known as “carbomers’ (Carbopol R, which may be obtained 30 may also contain additives such as preserving, wetting, emul from B.F. Goodrich, is one such polymer). Other components Sifying, and dispensing agents. Prevention of the growth of may also be incorporated into the buccal dosage forms microorganisms can be ensured by various antibacterial and described herein include, but are not limited to, disintegrants, antifungal agents, such as parabens, chlorobutanol, phenol, diluents, binders, lubricants, flavoring, colorants, preserva sorbic acid, and the like. It may also be desirable to include tives, and the like. For buccal or Sublingual administration, isotonic agents, such as Sugars, sodium chloride, and the like. the compositions may take the form of tablets, lozenges, or 35 Prolonged absorption of the injectable pharmaceutical form gels formulated in a conventional manner. can be brought about by the use of agents delaying absorp Transdermal formulations described herein may be admin tion, Such as aluminum monostearate and gelatin. istered using a variety of devices including but not limited to, For intravenous injections, compounds described herein U.S. Pat. Nos. 3,598,122, 3,598,123, 3,710,795, 3,731,683, may be formulated in aqueous solutions, preferably in physi 3,742,951, 3,814,097, 3,921,636, 3,972,995, 3,993,072, 40 ologically compatible buffers such as Hank’s solution, Ring 3,993,073, 3,996,934, 4,031,894, 4,060,084, 4,069,307, er's Solution, or physiological saline buffer. For transmucosal 4,077,407, 4,201,211, 4,230,105, 4,292,299, 4,292,303, administration, penetrants appropriate to the barrier to be 5,336,168, 5,665,378, 5,837,280, 5,869,090, 6,923,983, permeated are used in the formulation. Such penetrants are 6,929,801 and 6,946,144. generally recognized in the field. For other parenteral injec The transdermal dosage forms described herein may incor tions, appropriate formulations may include aqueous or non porate certain pharmaceutically acceptable excipients which 45 aqueous solutions, preferably with physiologically compat are conventional in the art. In one embodiment, the transder ible buffers or excipients. Such excipients are generally mal formulations described herein include at least three com recognized in the field. ponents: (1) a formulation of a compound of Formula (I), (II), Parenteral injections may involve bolus injection or con (IIa), (IIaa), (IIb), (IIbb), (IIc), (IIcc), (IId), (IIdd), (IIe), tinuous infusion. Formulations for injection may be presented (IIee), (IIf), (IIff), (III), (IIIa), (IIIaa), (IIIb), (IIIbb), (IIIc), 50 in unit dosage form, e.g., in ampoules or in multi-dose con (IIIcc), (IIId), (IIIdd), (IIIe), (IIIee), (IIIf), (IIIff), or (IV); (2) tainers, with an added preservative. The pharmaceutical com a penetration enhancer; and (3) an aqueous adjuvant. In addi position described herein may be in a form suitable for tion, transdermal formulations can include additional com parenteral injection as a sterile Suspensions, solutions or ponents such as, but not limited to, gelling agents, creams and emulsions in oily or aqueous vehicles, and may contain for ointment bases, and the like. In some embodiments, the trans 55 mulatory agents such as Suspending, stabilizing and/or dis dermal formulation can further include a woven or non-wo persing agents. Pharmaceutical formulations for parenteral ven backing material to enhance absorption and prevent the administration include aqueous solutions of the active com removal of the transdermal formulation from the skin. In pounds in water-soluble form. Additionally, Suspensions of other embodiments, the transdermal formulations described the active compounds may be prepared as appropriate oily herein can maintain a Saturated or Supersaturated State to injection Suspensions. Suitable lipophilic solvents or vehicles promote diffusion into the skin. 60 include fatty oils such as sesame oil, or synthetic fatty acid Formulations suitable for transdermal administration of esters, such as ethyl oleate or triglycerides, or liposomes. compounds described herein may employ transdermal deliv Aqueous injection Suspensions may contain Substances ery devices and transdermal delivery patches and can be which increase the viscosity of the Suspension, such as lipophilic emulsions or buffered, aqueous Solutions, dis sodium carboxymethyl cellulose, sorbitol, or dextran. Solved and/or dispersed in a polymer or an adhesive. Such 65 Optionally, the Suspension may also contain Suitable stabiliz patches may be constructed for continuous, pulsatile, or on ers or agents which increase the Solubility of the compounds demand delivery of pharmaceutical agents. Still further, to allow for the preparation of highly concentrated Solutions. US 9,359,316 B1 103 104 Alternatively, the active ingredient may be in powderform for least in part, from modulation of TRPV 1. In addition, a constitution with a Suitable vehicle, e.g., sterile pyrogen-free method for treating any of the diseases or conditions water, before use. described herein in a subject in need of such treatment, In certain embodiments, delivery systems for pharmaceu involves administration of pharmaceutical compositions con tical compounds may be employed, such as, for example, taining at least one compound described herein, or a pharma liposomes and emulsions. In certain embodiments, composi ceutically acceptable salt, or pharmaceutically acceptable tions provided herein also include an mucoadhesive polymer, selected from among, for example, carboxymethylcellulose, solvate or hydrate thereof, in therapeutically effective carbomer (acrylic acid polymer), poly(methylmethacrylate), amounts to said subject. polyacrylamide, polycarbophil, acrylic acid/butyl acrylate The compositions containing the compound(s) described copolymer, sodium alginate and dextran. 10 herein can be administered for prophylactic and/or therapeu In some embodiments, the compounds described herein tic treatments. In therapeutic applications, the compositions may be administered topically and are formulated into a vari are administered to a patient already Suffering from a disease ety of topically administrable compositions, such as Solu or condition, in an amount Sufficient to cure or at least par tions, Suspensions, lotions, gels, pastes, medicated Sticks, tially arrest the symptoms of the disease or condition. balms, creams or ointments. Such pharmaceutical com 15 Amounts effective for this use will depend on the severity and pounds can contain solubilizers, stabilizers, tonicity enhanc course of the disease or condition, previous therapy, the ing agents, buffers and preservatives. patient's health status, weight, and response to the drugs, and The compounds described herein may also be formulated the judgment of the treating physician. in rectal compositions such as enemas, rectal gels, rectal In prophylactic applications, compositions containing the foams, rectal aerosols, Suppositories, jelly Suppositories, or compounds described herein are administered to a patient retention enemas, containing conventional Suppository bases Susceptible to or otherwise at risk of a particular disease, Such as cocoa butter or other glycerides, as well as synthetic disorder or condition. Such an amount is defined to be a polymers such as polyvinylpyrrolidone, PEG, and the like. In “prophylactically effective amount or dose.” In this use, the Suppository forms of the compositions, a low-melting wax precise amounts also depend on the patient’s state of health, Such as, but not limited to, a mixture of fatty acid glycerides, weight, and the like. When used in a patient, effective optionally in combination with cocoa butter is first melted. 25 amounts for this use will depend on the severity and course of Generally, an agent, Such as a compound of Formula (I), the disease, disorder or condition, previous therapy, the (II), (IIa), (IIaa), (IIb), (IIbb), (IIc), (IIcc), (IId), (IIdd), (IIe), patient's health status and response to the drugs, and the (IIee), (IIf), (IIff), (III), (IIIa), (IIIaa), (IIIb), (IIIbb), (IIIc), judgment of the treating physician. (IIIcc), (IIId), (IIIdd), (IIIe), (IIIee), (IIIf), (IIIff), or (IV) is Upon the doctor's discretion the administration of the com administered in an amount effective for amelioration of, or 30 pounds may be administered chronically, that is, for an prevention of the development of symptoms of the disease or extended period of time, including throughout the duration of disorder (i.e., a therapeutically effective amount). Thus, a the patient’s life in order to ameliorate or otherwise control or therapeutically effective amount can be an amount that is limit the symptoms of the patient’s disease or condition. capable of at least partially preventing or reversing a disease Upon the doctor's discretion the administration of the com or disorder. The dose required to obtain an effective amount pounds may be given continuously; alternatively, the dose of may vary depending on the agent, formulation, disease or 35 drug being administered may be temporarily reduced or tem disorder, and individual to whom the agent is administered. porarily Suspended for a certain length of time (i.e., a "drug Determination of effective amounts may also involve in holiday'). The length of the drug holiday can vary between 2 vitro assays in which varying doses of agent are administered days and 1 year, including by way of example only, 2 days, 3 to cells in culture and the concentration of agent effective for days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, ameliorating some or all symptoms is determined in order to 40 20 days, 28 days, 35 days, 50 days, 70 days, 100 days, 120 calculate the concentration required in vivo. Effective days, 150 days, 180 days, 200 days, 250 days, 280 days, 300 amounts may also be based in in vivo animal studies. days, 320 days, 350 days, or 365 days. The dose reduction An agent can be administered prior to, concurrently with during a drug holiday may be from about 10% to about 100%, and Subsequent to the appearance of symptoms of a disease or including, by way of example only, about 10%, about 15%, disorder. In some embodiments, an agent is administered to a 45 about 20%, about 25%, about 30%, about 35%, about 40%, subject with a family history of the disease or disorder, or who about 45%, about 50%, about 55%, about 60%, about 65%, has a phenotype that may indicate a predisposition to a dis about 70%, about 75%, about 80%, about 85%, about 90%, ease or disorder, or who has a genotype which predisposes the about 95%, or about 100%. subject to the disease or disorder. Once improvement of the patients conditions has The particular delivery system used can depend on a num occurred, a maintenance dose is administered if necessary. ber of factors, including, for example, the intended target and 50 Subsequently, the dosage or the frequency of administration, the route of administration, e.g., local or systemic. Targets for or both, can be reduced, as a function of the symptoms, to a delivery can be specific cells which are causing or contribut level at which the improved disease, disorder or condition is ing to a disease or disorder. For example, a target cell can be retained. Patients can, however, require intermittent treat resident or infiltrating cells in the nervous system contribut ment on a long-term basis upon any recurrence of symptoms. ing to a neurological, neurodegenerative or demyelinating 55 The amount of a given agent that will correspond to such an disease or disorder. Administration of an agent can be amount will vary depending upon factors such as the particu directed to one or more cell types or subsets of a cell type by lar compound, disease or condition and its severity, the iden methods recognized in the field. For example, an agent can be tity (e.g., weight) of the Subject or host in need of treatment, coupled to an antibody, ligand to a cell Surface receptor or a but can nevertheless be determined in a manner recognized in toxin, or can be contained in a particle that is selectively the field according to the particular circumstances Surround internalized into cells, e.g., liposomes or a virus in which the 60 ing the case, including, e.g., the specific agent being admin viral receptor binds specifically to a certain cell type, or a viral istered, the route of administration, the condition being particle lacking the viral nucleic acid, or can be administered treated, and the Subject or host being treated. In general, locally. however, doses employed for adult human treatment will Methods of Dosing and Treatment Regimens typically be in the range of about 0.001 mg per day to about The compounds described herein can be used in the prepa 65 5000 mg per day, in some embodiments, about 1 mg per day ration of medicaments for the modulation of TRPV1, or for to about 1500 mg per day. The desired dose may conveniently the treatment of diseases or conditions that would benefit, at be presented in a single dose or as divided doses administered US 9,359,316 B1 105 106 simultaneously (or over a short period of time) or at appro The initial administration can be made according to estab priate intervals, for example as two, three, four or more Sub lished protocols recognized in the field, and then, based upon doses per day. the observed effects, the dosage, modes of administration and The pharmaceutical composition described herein may be times of administration can be modified by the clinician. in unit dosage forms suitable for single administration of 5 In certain instances, it may be appropriate to administer at precise dosages. In unit dosage form, the formulation is least one compound described herein in combination with divided into unit doses containing appropriate quantities of another therapeutic agent. By way of example only, if one of one or more compound. The unit dosage may be in the form the side effects experienced by a patient upon receiving one of of a package containing discrete quantities of the formulation. the compounds herein, Such as a compound of Formula (I), Non-limiting examples are packaged tablets or capsules, and (II), (IIa), (IIaa), (IIb), (IIbb), (IIc), (IIcc), (IId), (IIdd), (IIe), powders in vials or ampoules. Aqueous Suspension composi 10 (IIee), (IIf), (IIff), (III), (IIIa), (IIIaa), (IIIb), (IIIbb), (IIIc), tions can be packaged in single-dose non-reclosable contain (IIIcc), (IIId), (IIIdd), (IIIe), (IIIee), (IIIf), (IIIff), or (IV), is ers. Alternatively, multiple-dose reclosable containers can be nausea, then it may be appropriate to administer an anti used, in which case it is typical to include a preservative in the nausea agent in combination with the initial therapeutic composition. By way of example only, formulations for agent. Or, by way of example only, the therapeutic effective parenteral injection may be presented in unit dosage form, 15 ness of one of the compounds described herein may be which include, but are not limited to ampoules, or in multi enhanced by administration of an adjuvant (i.e., by itself the dose containers, with an added preservative. adjuvant may have minimal therapeutic benefit, but in com The daily dosages appropriate for the compounds bination with another therapeutic agent, the overall therapeu described herein described herein are from about 0.001 tic benefit to the patient is enhanced). Or, by way of example mg/kg to about 30 mg/kg. In one embodiment, the daily only, the benefit experienced by a patient may be increased by dosages are from about 0.01 mg/kg to about 10 mg/kg. An administering one of the compounds described herein with indicated daily dosage in the larger mammal, including, but another therapeutic agent (which also includes a therapeutic not limited to, humans, is in the range from about 0.1 mg to regimen) that also has therapeutic benefit. In any case, regard about 1000 mg, conveniently administered in a single dose or less of the disease, disorder or condition being treated, the individed doses, including, but not limited to, up to four times overall benefit experienced by the patient may simply be a day or in extended release form. Suitable unit dosage forms 25 additive of the two therapeutic agents or the patient may for oral administration include from about 1 to about 500 mg experience a synergistic benefit. active ingredient. In one embodiment, the unit dosage is about In certain instances, the combination with another thera 1 mg, about 5 mg, about, 10 mg, about 20 mg, about 50 mg. peutic agent is with a local anesthetic agent. As used herein, about 100 mg, about 200 mg, about 250 mg, about 400 mg. or the term “local anesthetic' means a drug which provides local about 500 mg. The foregoing ranges are merely suggestive, as 30 numbness or pain relief Exemplary exampels of local anes the number of variables in regard to an individual treatment thetic agents which can be used in combination with the regime is large, and considerable excursions from these rec present invention include: bupivacaine, levobupivaine, ropi ommended values are not uncommon. Such dosages may be vacaine, dibucaine, procaine, chloroprocaine, priolocaine, altered depending on a number of variables, not limited to the mepivacaine, etidocaine, tetracaine and lidocaine. activity of the compound used, the disease or condition to be In certain instances, the combination with another thera treated, the mode of administration, the requirements of the peutic agent is with a vasoconstrictor. Vasoconstrictors are individual subject, the severity of the disease or condition useful are those acting locally to restrict blood flow, and being treated, and the judgment of the practitioner. thereby retain the injected drugs in the region in which they Toxicity and therapeutic efficacy of such therapeutic regi are administered. This has the effect of substantially decreas mens can be determined by Standard pharmaceutical proce ing systemic toxicity. Preferred vasoconstrictors are those dures in cell cultures or experimental animals, including, but 40 acting on alpha adrenergic receptors, such as epinephrine and not limited to, the determination of the LDs (the dose lethal phenylepinephrine. to 50% of the population) and the EDs (the dose therapeuti In certain instances, the combination with another thera cally effective in 50% of the population). The dose ratio peutic agent is with a glucocorticoid. The glucocorticoid is between the toxic and therapeutic effects is the therapeutic selected from the group consisting of dexamethasone, corti index and it can be expressed as the ratio between LDso and Sone, hydrocortisone, prednisone, beclomethasone, EDs. Compounds exhibiting high therapeutic indices are 45 betamethasone, flunisolide, methyl prednisone, para metha preferred. The data obtained from cell culture assays and Sone, prednisolone, triamcinolome, alclometasone, amcino animal studies can be used in formulating a range of dosage nide, clobetasol, fludrocortisone, diflurosone diacetate, fluo for use in human. The dosage of Such compounds lies pref cinolone acetonide, fluoromethalone, flurandrenolide, erably within a range of circulating concentrations that halcinonide, medrysone, mometaSone, and pharmaceutically include the EDso with minimal toxicity. The dosage may vary 50 acceptable salts and mixtures thereof. within this range depending upon the dosage form employed In some embodiments, a compound of Formula (I), (II), and the route of administration utilized. (IIa), (IIaa), (IIb), (IIbb), (IIc), (IIcc), (IId), (IIdd), (IIe), Combination Treatments (IIee), (IIf), (IIff), (III), (IIIa), (IIIaa), (IIIb), (IIIbb), (IIIc), The compounds of Formula (I), (II), (IIa), (IIaa), (IIb). (IIIcc), (IIId), (IIIdd), (IIIe), (IIIee), (IIIff), or (IV), or a phar (IIbb), (IIc), (IIcc), (IId), (IIdd), (Ile), (IIee), (IIf), (IIff), (III), 55 maceutically acceptable salt, pharmaceutically acceptable (IIIa), (IIIaa), (IIIb), (IIIbb), (IIIc), (IIIcc), (IIId), (IIIdd), solvate, or hydrate thereof, is used in combination with a local (IIIe), (IIIee), (IIIf), (IIIff), or (IV), and compositions thereof, anethetic. may also be used in combination with other therapeutic In some embodiments, a compound of Formula (I), (II), agents that are selected for their therapeutic value for the (IIa), (IIaa), (IIb), (IIbb), (IIc), (IIcc), (IId), (IIdd), (IIe), condition to be treated. In general, the compositions (IIee), (IIf), (IIff), (III), (IIIa), (IIIaa), (IIIb), (IIIbb), (IIIc), described herein and, in embodiments where combinational 60 (IIIcc), (IIId), (IIIdd), (IIIe), (IIIee), (IIIff), or (IV), or a phar therapy is employed, other agents do not have to be adminis maceutically acceptable salt, pharmaceutically acceptable tered in the same pharmaceutical composition, and may, solvate, or hydrate thereof, is used in combination with a because of different physical and chemical characteristics, non-opiod analgesic. have to be administered by different routes. The determina The particular choice of compounds used will depend upon tion of the mode of administration and the advisability of 65 the diagnosis of the attending physicians and their judgment administration, where possible, in the same pharmaceutical of the condition of the patient and the appropriate treatment composition, is well within the knowledge of the clinician. protocol. The compounds may be administered concurrently US 9,359,316 B1 107 108 (e.g., simultaneously, essentially simultaneously or within tional or synergistic benefit to the patient. By way of example the same treatment protocol) or sequentially, depending upon only, patients are expected to find therapeutic and/or prophy the nature of the disease, disorder, or condition, the condition lactic benefit in the methods described herein, wherein phar of the patient, and the actual choice of compounds used. The maceutical composition of a compound disclosed herein and/ determination of the order of administration, and the number or combinations with other therapeutics are combined with of repetitions of administration of each therapeutic agent genetic testing to determine whether that individual is a car during a treatment protocol, is well within the knowledge of rier of a mutant gene that is known to be correlated with the physician after evaluation of the disease being treated and certain diseases or conditions. the condition of the patient. The compounds described herein and combination thera Therapeutically-effective dosages can vary when the drugs pies can be administered before, during or after the occur are used in treatment combinations. Methods for experimen 10 rence of a disease or condition, and the timing of administer tally determining therapeutically-effective dosages of drugs ing the composition containing a compound can vary. Thus, and other agents for use in combination treatment regimens for example, the compounds can be used as a prophylactic and are described in the literature. For example, the use of met can be administered continuously to Subjects with a propen ronomic dosing, i.e., providing more frequent, lower doses in sity to develop conditions or diseases in order to prevent the order to minimize toxic side effects, has been described 15 occurrence of the disease or condition. The compounds and extensively in the literature. Combination treatment further compositions can be administered to a Subject during or as includes periodic treatments that start and stop at various Soon as possible after the onset of the symptoms. The admin times to assist with the clinical management of the patient. istration of the compounds can be initiated within the first 48 For combination therapies described herein, dosages of the hours of the onset of the symptoms, preferably within the first co-administered compounds will of course vary depending 48 hours of the onset of the symptoms, more preferably on the type of co-drug employed, on the specific drug within the first 6 hours of the onset of the symptoms, and most employed, on the disease or condition being treated and so preferably within 3 hours of the onset of the symptoms. The forth. In addition, when co-administered with one or more initial administration can be via any route practical. Such as, biologically active agents, the compound provided herein for example, an intravenous injection, a bolus injection, infu may be administered either simultaneously with the biologi sion over about 5 minutes to about 5 hours, a pill, a capsule, cally active agent(s), or sequentially. If administered sequen 25 transdermal patch, buccal delivery, and the like, or combina tially, the attending physician will decide on the appropriate tion thereof. A compound is preferably administered as soon sequence of administering protein in combination with the as is practicable after the onset of a disease or condition is biologically active agent(s). detected or Suspected, and for a length of time necessary for In any case, the multiple therapeutic agents (one of which the treatment of the disease, such as, for example, from 1 day is a compound of Formula (I), (II), (IIa), (IIaa), (IIb), (IIbb), 30 to about 3 months. The length of treatment can vary for each (IIc), (IIcc), (IId), (IIdd), (IIe), (IIee), (IIf), (IIff), (III), (IIIa), Subject, and the length can be determined using the known (IIIaa), (IIIb), (IIIbb), (IIIc), (IIIcc), (IIId), (IIIdd), (IIIe), criteria. For example, the compound or a formulation con (IIIee), (IIIf), (IIIff), or (IV) described herein) may be admin taining the compound can be administered for at least 2 istered in any order or even simultaneously. If simulta weeks, preferably about 1 month to about 5 years. neously, the multiple therapeutic agents may be provided in a Kits/Articles of Manufacture single, unified form, or in multiple forms (by way of example 35 For use in the therapeutic applications described herein, only, eitheras a single injection or as two separate injections). kits and articles of manufacture are also described herein. One of the therapeutic agents may be given in multiple doses, Such kits can include a carrier, package, or container that is or both may be given as multiple doses. If not simultaneous, compartmentalized to receive one or more containers such as the timing between the multiple doses may vary from more vials, tubes, and the like, each of the container(s) including than Zero weeks to less than four weeks. In addition, the 40 one of the separate elements to be used in a method described combination methods, compositions and formulations are not herein. Suitable containers include, for example, bottles, to be limited to the use of only two agents; the use of multiple vials, Syringes, and test tubes. The containers can be formed therapeutic combinations are also envisioned. from a variety of materials such as glass or plastic. It is understood that the dosage regimento treat, prevent, or For example, the container(s) can include one or more ameliorate the condition(s) for which relief is sought, can be 45 compounds described herein, optionally in a composition or modified in accordance with a variety of factors. These fac in combination with another agent as disclosed herein. The tors include the disorder or condition from which the subject container(s) optionally have a sterile access port (for example Suffers, as well as the age, weight, sex, diet, and medical the container can be an intravenous solution bag or a vial condition of the Subject. Thus, the dosage regimen actually having a stopper pierceable by a hypodermic injection employed can vary widely and therefore can deviate from the needle). Such kits optionally comprising a compound with an dosage regimens set forth herein. 50 identifying description or label or instructions relating to its The pharmaceutical agents which make up the combina use in the methods described herein. tion therapy disclosed herein may be a combined dosage form A kit will typically may include one or more additional or in separate dosage forms intended for Substantially simul containers, each with one or more of various materials (such taneous administration. The pharmaceutical agents that make as reagents, optionally in concentrated form, and/or devices) up the combination therapy may also be administered sequen 55 desirable from a commercial and user standpoint for use of a tially, with either therapeutic compound being administered compound described herein. Non-limiting examples of Such by a regimen calling for two-step administration. The two materials include, but not limited to, buffers, diluents, filters, step administration regimen may call for sequential adminis needles, Syringes; carrier, package, container, vial and/or tube tration of the active agents or spaced-apart administration of labels listing contents and/or instructions for use, and pack the separate active agents. The time period between the mul age inserts with instructions for use. A set of instructions will tiple administration steps may range from, a few minutes to 60 also typically be included. several hours, depending upon the properties of each phar A label can be on or associated with the container. A label maceutical agent, Such as potency, solubility, bioavailability, can be on a container when letters, numbers or other charac plasma half-life and kinetic profile of the pharmaceutical ters forming the label are attached, molded or etched into the agent. Circadian variation of the target molecule concentra container itself a label can be associated with a container tion may also determine the optimal dose interval. 65 when it is present within a receptacle or carrier that also holds In addition, the compounds described herein also may be the container, e.g., as a package insert. A label can be used to used in combination with procedures that may provide addi indicate that the contents are to be used for a specific thera US 9,359,316 B1 109 110 peutic application. The label can also indicate directions for Preparation of Compound A-1 use of the contents, such as in the methods described herein. Capsaisin (200 mg, 0.65 mmol. 1.0 eq) was dissolved in EXAMPLES DCM (10 mL), followed by the addition of 4-nitrophenyl chloroformate (138 mg, 0.68 mmol. 1.05 eq) and DIPEA (346 These examples are provided for illustrative purposes only 5 mL, 1.95 mmol. 3.0 eq). The reaction was allowed to stir at and not to limit the scope of the claims provided herein. The room temperature for 4 h. To the reaction was then added starting materials and reagents used for the synthesis of the HOAt (97 mg, 0.715 mmol. 1.1 eq) and tert-butyl (2-(methy compounds described herein may be synthesized or can be lamino)ethyl)carbamate (135 mg, 0.78 mmol. 1.2 eq). The obtained from commercial sources, such as, but not limited reaction was allowed to stir over (18 h) at room temperature. to, Sigma-Aldrich Corp., Acros Organics, Fluka, and Fisher 10 Next, the reaction was washed with 1N HCl (2x15 mL), Scientific. saturated aq. NaHCO (5x15 mL) and finally saturated brine (15 mL). The organic layer was removed, dried over MgSO4, filtered and condensed under vacuum to afford A-1. The material was used without further purification. Synthetic Examples Preparation of Compound 1 15 To crude A-1 (from reaction mixture obtained above), was Example 1 added DCM (3 mL) and trifluoroacetic acid (1 mL). The reaction mixture was allowed to stir for 1 h at room tempera Synthesis of (E)-2-methoxy-4-((8-methylnon-6-ena ture. Next, the reaction was condensed and dissolved in 1:1 mido)methyl)phenyl (2-aminoethyl)(methyl)carbam HOAc:HO (10 mL). The crude mixture was purified by ate (1) preparative reverse phase HPLC (Agilent Prep C-18 column,

O ON O

H 1s. --~~~ DIPEA, DCM, rt HO

O H

ON O H --~~~ *n-1-N-NH ls HOAt O O ON

TFADCM N-1s,O --~~~ He --> ON A-1

O IN-1,0 O Or --~~~ On 1 US 9,359,316 B1 111 112 mobile phase A: 100% water, 0.1% TFA; mobile phase B: The preparation of Compound 4 followed the synthetic 100% ACN, 0.1% TFA; gradient elution 20% to 70% B over methods of Example 1, except for the substitution of tert 20 min) to afford the TFA salt of Compound 1 (188.1 mg 0.36 butyl (2-(methylamino)ethyl)carbamate with tert-butyl (pyr mmol. 55.6% yield over two steps) as a white solid. LC-MS rolidin-2-ylmethyl)carbamate. This method provided the M+H 406.6 (Chemical Formula: CHSNO+H, calc: TFA salt of the title compound as a white solid (202.1 mg, 406.3). 0.37 mmol, 57.0% yield). LC-MS M+H 432.7 (Chemical Example 2 Formula: CHNO+H, calc: 432.2). Synthesis of (E)-2-methoxy-4-((8-methylnon-6-ena Example 5 mido)methyl)phenyl methyl(2-(methylamino)ethyl) 10 carbamate (2) Synthesis of (E)-2-methoxy-4-((8-methylnon-6-ena mido)methyl)phenyl bis(2-aminoethyl)carbamate (5)

:TFA O HN 2 l O N 21 The preparation of Compound 2 followed the synthetic methods of Example 1, except for the substitution of tert ls H butyl (2-(methylamino)ethyl)carbamate with tert-butyl TEA 'N O methyl(2-(methylamino)ethyl)carbamate. This method pro HN O vided the TFA salt of the title compound as a white solid 25 (192.7 mg, 0.36 mmol, 55.4% yield). LC-MS M+H 420.7 (Chemical Formula: CH-NO+H, calc: 420.2). Example 3 30 The preparation of Compound 5 followed the synthetic Synthesis of (E)-2-methoxy-4-((8-methylnon-6-ena methods of Example 1, except for the substitution of tert mido)methyl)phenyl 2-(aminomethyl)piperidine-1- butyl (2-(methylamino)ethyl)carbamate with di-tert-butyl carboxylate (3) (azanediylbis(ethane-2,1-diyl))dicarbamate. This method provided the TFA salt of the title compound as a white solid 3 35 (217.0 mg, 0.33 mmol, 50.4% yield). LC-MS M+H 435.7 :TFA O (Chemical Formula: CHNO+H, calc: 435.2). H Example 6 N lO NH 1--- N O 40 Synthesis of (E)-2-methoxy-4-((8-methylnon-6-ena On mido)methyl)phenyl (3-aminopropyl)(methyl)car The preparation of Compound 3 followed the synthetic bamate (6) methods of Example 1, except for the substitution of tert butyl (2-(methylamino)ethyl)carbamate with tert-butyl (pip 45 eridin-2-ylmethyl)carbamate. This method provided the TFA salt of the title compound as a white solid (222.4 mg. 0.39 mmol. 61.1% yield). LC-MS M+H 446.7 (Chemical For mula: CHNO+H, calc: 446.3). Example 4 50 NH2 O Synthesis of (E)-2-methoxy-4-((8-methylnon-6-ena mido)methyl)phenyl 2-(aminomethyl)pyrrolidine-1- Sl O --~~ carboxylate (4) 55 C OS

:TFA O 60 H The preparation of Compound 6 followed the synthetic methods of Example 1, except for the substitution of tert N lO NH 1--- butyl (2-(methylamino)ethyl)carbamate with tert-butyl (3- N O (methylamino)propyl)carbamate. This method provided the On 65 TFA salt of the title compound as a white solid (149.6 mg, 0.28 mmol, 43.0% yield). LC-MS M+H 420.7 (Chemical Formula: CHNO+H, calc: 420.5). US 9,359,316 B1 113 114 Example 7 The preparation of Compound 8 followed the synthetic methods of Example 1, except for the substitution of tert Synthesis of (E)-2-methoxy-4-((8-methylnon-6-ena butyl (2-(methylamino)ethyl)carbamate with tert-butyl pip mido)methyl)phenyl 2-((methylamino)methyl)piperi erazine-1-carboxylate. This method provided the TFA salt of dine-1-carboxylate (7) the title compound as a white solid (186.4 mg. 0.35 mmol. 53.9% yield). LC-MS M+H 418.4 (Chemical Formula: CHNO+H, calc: 418.3).

7 Example 9 10 :TFA O Synthesis of (E)-2-methoxy-4-((8-methylnon-6-ena 1. O N 21 mido)methyl)phenyl piperazine-1-carboxylate (9) ls H N O 15 On 9 TFA O The preparation of Compound 7 followed the synthetic HN methods of Example 1, except for the substitution of tert 2 O N 21 butyl (2-(methylamino)ethyl)carbamate with tert-butyl l H methyl(piperidin-2-ylmethyl)carbamate. This method pro N O vided the TFA salt of the title compound as a white solid (183.2 mg, 0.32 mmol, 49.2% yield). LC-MS M+H 460.7 --- On (Chemical Formula: CH7NO+H, calc: 460.3). TFA 25 Example 8 Compound 9 is prepared following the synthetic methods of Example 1, except for the substitution of tert-butyl (2- Synthesis of (E)-2-methoxy-4-((8-methylnon-6-ena (methylamino)ethyl)carbamate with tert-butyl methyl((4- mido)methyl)phenyl piperazine-1-carboxylate (8) methylpiperazin-2-yl)methyl)carbamate. 30 In Vitro Assays Example 10

35 Solubility Assay In order to determine the aqueous solubility of the com pounds described herein, the HCl salts of the following com pounds were incubated at either 50 or 100 mg/mL in DI water 40 followed by shaking for 24 hours. The solutions were then centrifuged and visually inspected for insoluble material. In all cases, no insoluble material was observed.

Solubility Example (Compound) Structure Solubility in DI water

1 (Compound 3) HCI O >100 mg/mL

ls H HN N O O or OS

2 (Compound 5) HCI O >100 mg/mL lsO orH ON US 9,359,316 B1 116 -continued Solubility Example (Compound) Structure Solubility in DI water 3 (Compound 7) HCI O >50 mg/mL

Supernatant was diluted for quantification with a 3-point calibration curve. 15 In comparison to the aqueous solubility of capsaicin in and Stability testing of several compounds. These compounds water (~0.064 mg/mL), the hydrogen chloride salts of these are examples of pH activated prodrugs whereby upon expo compounds present a dramatic increase in water solubility. ific pH, the half-life of the i lecul Generally speaking, this represents a greater than 1560-fold sure tO a Spec1IIc pil, t e la -1 o the 1ntranO ecu a (examples 1 & 2) and 780-fold (example 3) increase in aque- 20 cyclization-release reaction is determined. As previously sous solubility from the parent compound, capsaicin. described, the intramolecular cyclization-release reaction These results representa Substantial advantage of using the lts in th itant f ti f li ith th compounds described herein over capsaicin when aqueous results 1n une concom1tant Iormauon of a cycl1c urea w1 e solutions are preferred for delivery. For example, signifi- release of the parent drug. cantly more material of the compounds described herein (vs. Compounds were incubated in the buffer/biological media E. t dy. st SE; sus solu- 25 indicated (TRISR obtained from Sigma-Aldrich, St. Louis, 1on w1unout une use of add1u1onal solub111Z1ng agents. Mo., USA, Catalog No. T1503). The reactions were con Example 11 ducted at either room temperature or 37° C. Samples were In Vitro (pH Stability) Assay collected at specificY time points, transferred into a 0.1%O HC1 30 solution to stop the cyclization-release reaction and analyzed The release of parent drug (e.g. capsaicin) from the com- by HPLC for formation of capsaicin and consumption of pounds described herein was demonstrated by the synthesis starting compound.

Intramolecular Cyclization Example Compound Release Half-life (T2)--

1 O -24.1 h’

*TFA

HN lsO H--~~ 2 - O O N

2 O -3.2h

*TFA O N 21 H 1. N-allN-1N O

O N

3 *TFA O ~31.6 min ~12.9 min' HN 2 O N 21 ls H N O

O US 9,359,316 B1 118 -continued Intramolecular Cyclization Example Compound Release Half-life (T2)-- 4 *TFA O -12.3d HN O N 21 ls H N O

O N

5 *TFA O ~71.1 min ~24.7 min' HN 21 l lsO NH *TFA N O issu ON 6 *TFA -30.8 d. NH2 O 21 S. lO NH O

O N

7 *TFA O ~4.4 min ~3.1 min'

1. O N 2 ls H N O

O N 8 O NA

O N 21 l H r O *TFA is- O N

Conditions: pH = -7.4 (0.3M aqueous tris buffer), 20°C.; pH = ~7.4 (1.0M aqueous tris buffer), 37°C.; NA: Example 8 did not show any measureable conversion to capsaicin over 2 weeks,

55 Although there were structural similarities between the cine, 2-Bis(2-hydroxyethyl)amino-2-(hydroxymethyl)-1,3- compounds tested, the set of compounds tested demonstrated propanediol, 3-(Cyclohexylamino)-1-propanesulfonic acid, a wide range of cyclization rates. The intramolecular cycliza tion-release half-life results ranged from minutes (examples 2-(Cyclohexylamino)ethanesulfonic acid, salts of carbonate, 3, 5 and 7) to days (examples 4 and 6). These results present salts of citrate, 4-(2-Hydroxyethyl)-1-piperazinepropane a useful set of compounds for rapid or delayed delivery of the 60 Sulfonic acid, salts of glycine, salts of Glycyl-glycine, 4-(2- parent drug. Hydroxyethyl)piperazine-1-ethanesulfonic acid, 4-Morpho Additional common ingredients/formulations which may lineethanesulfonic acid, 4-Morpholinepropanesulfonic acid, be used in buffers for the testing of the cyclization-release of the compounds described herein include but are not limited 1,4-Piperazinediethanesulfonic acid, salts of phosphate, salts to: N-(2-Acetamido)-2-aminoethanesulfonic acid, N-(2-Ac 65 of tartrate, 2-(2-Hydroxy-1,1-bis(hydroxymethyl)ethyl) etamido)iminodiacetic acid, 2-Amino-2-methyl-1,3-pro aminoethanesulfonic acid, Tris(2-hydroxyethyl)amine, and panediol, salts of bicarbonate, N,N-Bis(2-hydroxyethyl)gly salts of EDTA. US 9,359,316 B1 119 120 Example 12 modifications or changes are to be included within the pur view of the disclosure and scope of the appended claims. In Vitro Binding Assay What is claimed is: Due to the intrinsic pH instability of the compounds 5 1. A compound having the structure: described herein, testing of Compounds 1-7 in a half maximal inhibitory concentration (ICs) assay would be compromised due to the formation the parent drug (capsaicin) under the assay conditions (pH=~7-8). However, compound 8, which contains a chemically releated amino-carbamate moiety but is chemically

2O O HN 2 O N 21 l H s incapable of an intramolecular cyclization-release reaction, N. O. demonstrated minimal binding to TRPV receptor with an IC50>100 uM (23% inhibition (a 100 uM). Eurofins, Pan 25 labs/Cerepassay name: Vanilloid, Catalog Number: 28.6810: concurrent control: Resiniferatoxin-0.16 nM, historical con trols: Capsaicin=3.1 uM, Resiniferatoxin=0.46 nM. Since compound 8 is essentially devoid of activity at the vanilloid receptor and by definition would not be considered a capsai 30 cinoid, it follows that the compounds described herein (for example compounds 1-7) would demonstrate similar binding properties and would not be classified as capsaicinoids either. Additionally, structure-relation-activity (SAR) data from multiple references has demonstrated that substitution of the phenolic position of capsaisin and resinifiatoxin generates 35 compounds with greatly dimished activity for the TRPV1 receptor (Huang, et. al. Current Medicinal Chemistry, 2013, 20, 2661-2672).

Example 13 40 Pharmacokinetic Assay Plasma Timecourse of Test Compounds Following IM Administration to Rat

IM dosing: The test compounds are dissolved in Saline and 45 dosed via intramuscular injection into male Sprague-Dawley rats. Capsaisin is used as a positive control and the test com pounds are dosed as the HCl salts. Test compounds are dosed as mg/kg body weight and are molar corrected to match the amount of capsaicin dosed. At specific time points (0.5h, 1 h, 2 h, 4h, 8 h, 12 h, 24 h. 36 h, 72h), blood samples are drawn, 50 quenched into ACN (containing 0.5% formic acid), centri fuged at 14000 rpm (art and stored at -80°C., until analysis. Samples are quantified via LC/MS/MS. Plasma concentra tion of capsaicin, prodrugs and resulting cyclic urea can be reported. ss or a pharmaceutically acceptable salt, pharmaceutically The examples and embodiments described herein are for acceptable solvate, or hydrate thereof. illustrative purposes only and in Some embodiments, various k k k k k