Laulimalide Analogues as Therapeutic Agents

• US 20080280973A1
• Filed: 06/28/2005
• Published: 11/13/2008
• Est. Priority Date: 06/28/2004
• Status: Abandoned Application

• Current Assignee: Board of Trustees of the Leland Stanford Junior University (Stanford University)
• Original Assignee: Board of Trustees of the Leland Stanford Junior University (Stanford University)
• Inventors: Wender, Paul A.
• Application Number:
  US11/630,858
• Publication Number:
  US 20080280973A1
• Time in Patent Office: Days
• US Class Current: 514/450
• CPC Class Codes: C07D 407/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 413/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 498/08 Bridged systems

Abstract

Laulimalide analogues useful as microtubule stabilizing agents, and in the treatment of abnormal cell proliferation, are disclosed. Methods of making the compounds, as well as methods of using such compounds in treating abnormal cell proliferation diseases are also described.

Claims

1. A compound of Formula I, or a pharmaceutically acceptable salt or ester thereof,

wherein:

R^1a, R^1b, and R⁵ are each independently H, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₁-C₁₀ alkoxy, C₂-C₁₀ alkenoxy, C₂-C₁₀ alkynyl, C₂-C₁₀ alkynoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, COR⁸, nitro, cyano, OH, CF₃, OCF₃, or halogen;

R² is absent (when “

a”

is a triple bond or when “

a”

is a single bond and “

b”

is a double bond) or is selected from the group consisting of H, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₁-C₁₀ alkoxy, C₂-C₁₀ alkenoxy, C₂-C₁₀ alkynyl, C₂-C₁₀ alkynoxy, aryl, nitro, cyano, halogen, acyl, alkacyl, CHO, CO₂H, CO₂—

C_1-10 alkyl, CF₃, OH, OR^8′

, OCF₃, SH, SR^8′

, NH₂, NHR^8′

, NHR^8′

R^8′

, CON(R^8′

)₂, and CONHR^8′

;

“

a”

can be a single or double bond of either (E)- or (Z)-orientation, or “

a”

can be a triple bond when R², Y, “

b” and

“

c”

are absent;

“

b”

can be absent or a single bond (when R¹ is absent);

“

c”

can be absent, a single, or double bond of either (E)- or (Z)-orientation;

such that only one of “

a”

, “

b”

, and “

c”

can be a double bond, when “

b” and

“

c”

are absent, then Y is absent; and

when “

a”

is a single or double bond, one of “

b” and

“

c”

is a single bond and one is absent, then Y is H, a straight or branched substituted or unsubstituted alkyl, alkenyl, or alkynyl, CH₃, CH₂R⁸, CHR⁸R⁸, CR⁸R⁸R⁸, CH₂F, CH₂Cl, CH₂Br, CHF₂, CHCl₂, CHBr₂, CF₃, CCl₃, CBr₃, OH, OR^8′

, SH, SR^8′

, NH₂, NHR^8′

, or NR^8′

R^8′

;

when “

a”

, “

b”

, and “

c”

are single bonds or when “

a”

is a single bond, one of “

b” and

“

c”

is a double bond and one is absent, then Y is CH₂, CHR⁸, CR⁸R⁸, CHF, CHCl, CHBr, CF₂, CCl₂, CBr₂, O, S, NH, or NR^8′

;

R³ is independently selected from H, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₁-C₁₀ alkoxy, C₂-C₁₀ alkenoxy, C₂-C₁₀ alkynyl, C₂-C₁₀ alkynoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, nitro, cyano, CF₃, OH, O-alkyl, hydroxylalkyl, O-acyl, OCF₃, SH, S-alkyl, thioalkyl, S-acyl, amine, alkylamine, NH₂, NHR⁸, NR⁸R⁸, and halogen;

R⁴ is selected from the group consisting of C₃-C₁₀ cycloalkyl, C₃-C₁₀ cycloalkenyl, heteroaryl, substituted heteroaryl, aryl, substituted aryl, C₃-C₁₀ heterocycloalkyl, adamantyl, and C₃-C₁₀ heterocycloalkenyl;

X is CH₂, CHR⁸, CR⁸R⁸, NH, NR^8′

, O, or S; and

when “

d”

is a single bond, V is independently selected from the group consisting of CH₂, CHR⁸, CR⁸R⁸, NH, NR^8′

, O, S, C═

O, or C═

Y², and W is independently selected from the group consisting of CH₂, CHR⁸, CR⁸R⁸, NH, NR^8′

, O, or S;

such that V and W are not both NH, NR^8′

, O, S, C═

O, or C═

Y²;

W is not NH, NR^8′

, O, or S, when X is N, NR⁵, O, or S; and

V is not C═

O or C═

Y², when W is N, NR⁵, O, or S;

when “

d”

is a double bond of either (E)- or (Z)-orientation, V and W are independently selected from the group consisting of CH, CR⁸, or N such that V and W are not both N, and X and W are not both N;

or when “

d”

is a triple bond, V and W are both carbon;

or alternatively, V and W are taken together to form an optionally substituted or unsubstituted carbocyclic ring, such as a 3-6 membered cycloalkyl ring, or an optionally substituted or unsubstituted heterocyclic ring, such as a 3-6 membered heterocyclic ring, such that only 2 adjacent ring members joined via a single or double bond (i.e., “

d”

is a single bond or a double bond) are part of the macrocyclic ring system; and

the ring member directly adjacent to the —

(C═

Y¹)—

moiety of the macrocycle is not a heteroatom when X is N, NR⁵, O, or S;

when “

e”

, “

f”

, “

g”

, “

h”

, or “

i”

is a single bond (i.e., the bond between M and P, P and Q, T and U, or U and V, is a single bond), then the respective M, P, T, U, or Q is independently CH₂, CHR⁸, CR⁸R⁸, NH, NR^8′

, O, S, C═

O, or C═

Y²;

such that if one of M, P, T, U, V, or W is NH, NR^8′

, O, or S, then its directly adjacent moieties cannot be NH, NR^8′

, O, or S; and

if one of M, P, T, U, V, or W is NH, NR^8′

, O, or S, then its directly adjacent moieties both cannot be C═

O or C═

Y²; and

, if one of M, P, T, U, or V is C═

O or C═

Y², then its directly adjacent moieties cannot be C═

O or C═

Y 2; and

if one of M, P, T, U, or V is C═

O or C═

Y², then its directly adjacent moieties both cannot be NH, NR^8′

, O, or S;

or alternatively,

when “

e”

, “

f”

, “

g”

, “

h”

, or “

i”

is a double bond of either (E)- or (Z)-orientation, then the respective M, P, T, U, or Q is independently CH, CR⁸, or N, such that, if one of M, P, T, U, V, or W is N, then its directly adjacent moieties cannot be N, NH, NR^8′

, O, or S; and

when “

e”

, “

f”

, “

g”

, “

h”

, or “

i”

is a triple bond, then the respective M, P, T, U, or Q is a carbon;

wherein

when “

h” and

“

i”

are single bonds, P is CHR*, CR⁸R*, or NR*;

when one of “

h” and

“

i”

is a double bond”

, P is CR*; and

when “

g” and

“

f”

are single bonds, T is CHR*′

, CR⁸R*′

, or NR*′

;

when one of “

g” and

“

f”

is a double bond”

, T is CR*′

;

wherein R* and R*′

are taken together with Q to form an optionally substituted or unsubstituted carbocyclic ring, such as a 3-6 membered cycloalkyl ring, or an optionally substituted or unsubstituted heterocyclic ring, such as a 3-6 membered heterocyclic ring, such that the ring member directly adjacent to M is not a heteroatom when M is N, NR⁵, O, or S;

with the proviso that when —

V—

W—

is —

CH═

CH—

or —

C≡

C—

, then —

P-Q-T- is not

each Y¹ and Y² is independently O, S, NH, or NR^8′

;

each R⁸ is independently —

H;

an optionally substituted or unsubstituted straight or branched alkyl, such as a —

C_1-8 straight or branched chain alkyl;

an optionally substituted or unsubstituted straight or branched —

C_2-8 alkenyl;

an optionally substituted or unsubstituted straight or branched —

C_2-8 alkynyl;

—

C_3-6 cycloalkyl;

3-7 membered heterocycle;

-aryl;

-aralkyl;

-heteroaryl, -heteroarylalkyl, -halo (F, Cl, Br, I);

-haloalkyl;

—

CF₃;

—

CN;

—

NO₂;

-acyl (including but not limited to aldehydes, ketones, esters, carboxylic acids, amides, imides, thioesters), —

(C═

Y¹)-alkyl, —

O(C═

Y¹)-alkyl, —

(C═

Y¹)—

OH, —

(C═

Y¹)—

O-alkyl, —

S—

(C═

Y¹)-alkyl, —

(C═

Y¹)—

SH, —

(C═

Y¹)—

S-alkyl, —

NH(C═

Y¹)-alkyl, —

NR⁸ (C═

Y¹)-alkyl, —

(C═

Y¹)—

NH₂, —

(C═

Y¹)—

NH(alkyl), —

(C═

Y¹)—

N(alkyl)₂, —

COOH;

—

COOC_1-8 alkyl;

—

CONH₂;

—

CONH—

C_1-8 alkyl;

—

CON(C_1-8 alkyl)₂;

alkacyl, -alkyl-(C═

Y¹)-alkyl, -alkyl-O(C═

Y¹)-alkyl, -alkyl-(C═

Y¹)—

OH, -alkyl-(C═

Y¹)—

O-alkyl, -alkyl-S—

(C═

Y¹)-alkyl, -alkyl-(C═

Y¹)—

SH, -alkyl-(C═

Y¹)—

S-alkyl, -alkyl-NH(C═

Y¹)-alkyl, -alkyl-NR^8′

(C═

Y¹)-alkyl, -alkyl-(C═

Y¹)—

NH₂, -alkyl-(C═

Y¹)—

NH(alkyl), -alkyl-(C═

Y¹)—

N(alkyl)₂, -alkyl-COOH;

-alkyl-COOC_1-8 alkyl;

-alkyl-CONH₂;

-alkyl-CONH—

C_1-8 alkyl;

-alkyl-CON(C_1-8 alkyl)₂;

amino, —

NH₂;

—

NH—

C_1-8 alkyl;

—

N(C_1-8 alkyl)₂;

—

NHC(O)—

C_1-8 alkyl;

alkylamino;

hydroxyl, alkylhydroxyl, alkoxy, thio;

alkylthio;

thioalkyl; and

each R^8′

is independently an optionally substituted or unsubstituted straight or branched alkyl, such as a —

C_1-8 straight or branched chain alkyl;

an optionally substituted or unsubstituted straight or branched alkenyl, such as a —

C_2-8 alkenyl;

an optionally substituted or unsubstituted straight or branched alkynyl, such as a —

C_2-8 alkynyl;

a saturated or unsaturated carbocycle, such as a saturated or unsaturated —

C_3-6 cycloalkyl;

a heterocycle, such as a 3-7 membered heterocycle;

aryl;

or heteroaryl;

such that there is not a double or triple bond directly adjacent to a double or triple bond.

2. The compound of claim 1, wherein R^1a, R^1b, and R⁵ are either hydrogen, CH₃, or C₁-C₅ alkyl.

3. The compound of claim 1 wherein “

-M-P-Q-T-U—

”

is selected from the group consisting of —

(C═

O)-Z-CH₂—

CH₂—

CH₂—

, —

(C═

Y²)-Z-CH₂—

CH₂—

CH₂—

, —

(C═

Y²)-Z-CHR⁸—

CHR⁸—

CHR⁸—

, —

CH₂—

(C═

O)-Z-CH₂—

CH₂—

, —

CH₂—

(C═

Y²)-Z-CH₂—

CH₂—

, —

CHR⁸—

(C═

Y²)-Z-CHR⁸—

CHR⁸—

, —

CH₂—

CH₂—

(C═

O)-Z-CH₂—

, —

CH₂—

CH₂—

(C═

Y²)-Z-CH₂—

, —

CHR⁸—

CHR⁸—

(C═

Y²)-Z-CHR⁸—

, -Z-(C═

O)—

CH₂—

CH₂—

CH₂—

, -Z-(C═

Y²)—

CH₂—

CH₂—

CH₂—

, -Z-(C═

Y²)—

CHR⁸—

CHR⁸—

CHR⁸—

, —

CH₂-Z-(C═

O)—

CH₂—

CH₂—

, —

CH₂-Z-(C═

Y²)—

CH₂—

CH₂—

, —

CHR⁸-Z-(C═

Y²)—

CHR⁸—

CHR⁸—

, —

CH₂—

CH₂-Z-(C═

O)—

CH₂—

, —

CH₂—

CH₂-Z-(C═

Y²)—

CH₂—

, —

CHR⁸—

CHR⁸-Z-(C═

Y²)—

CHR⁸—

, —

(C═

O)-Z-CH═

CH—

CH₂—

, —

(C═

Y²)-Z-CH═

CH—

CH₂—

, —

(C═

Y²)-Z-CR⁸═

CR⁸—

CHR⁸—

, —

(C═

O)-Z-CH₂—

CH═

CH—

, —

(C═

Y²)-Z-CH₂—

CH═

CH—

, (C═

Y²)-Z-CHR⁸—

CR⁸═

CR⁸—

, —

CH═

CH—

(C═

O)-Z-CH₂—

, —

CH═

CH—

(C═

Y²)-Z-CH₂—

, —

CR⁸═

CR⁸—

(C═

Y²)-Z-CHR⁸—

, -Z-(C═

O)—

CH═

CH—

CH₂—

, -Z-(C═

Y²)—

CH═

CH—

CH₂—

, -Z-(C═

Y²)—

CR⁸═

CR⁸—

CHR⁸—

, -Z-(C═

O)—

CH₂—

CH═

CH—

, -Z-(C═

Y²)—

CH₂—

CH═

CH—

, -Z-(C═

Y²)—

CHR⁸—

CR⁸═

CR⁸—

, —

CH═

CH-Z-(C═

O)—

CH₂—

, —

CH═

CH-Z-(C═

Y²)—

CH₂—

, —

CR⁸═

CR⁸-Z-(C═

Y²)—

CHR⁸—

, —

(C═

O)-Z-C≡

C—

CH₂—

, —

(C═

Y²)-Z-C≡

C—

CH₂—

, —

(C═

Y²)-Z-C≡

C—

CHR⁸—

, —

(C═

O)-Z-CH₂—

C≡

C—

, —

(C═

Y²)-Z-CH₂—

C≡

C—

, —

(C═

Y²)-Z-CHR⁸—

C≡

C—

, —

C≡

C—

(C═

O)-Z-CH₂—

, —

C≡

C—

(C═

Y²)-Z-CH₂—

, —

C≡

C—

(C═

Y²)-Z-CHR⁸—

, -Z-(C═

O)—

C≡

C—

CH₂—

, -Z-(C═

Y²)—

C≡

C—

CH₂—

, -Z-(C═

Y²)—

C≡

C—

CHR⁸—

, -Z-(C═

O)—

CH₂—

C≡

C—

, -Z-(C═

Y²)—

CH₂—

C≡

C—

, -Z-(C═

Y²)—

CHR⁸—

C≡

C—

, —

C≡

C-Z-(C═

O)—

CH₂—

, —

C≡

C-Z-(C═

Y²)—

CH₂—

, and —

C≡

C-Z-(C═

Y²)—

CHR⁸—

, or at least one of “

-M-P—

”

, “

—

P-Q-”

, “

-Q-T-”

or “

-T-U—

”

is selected from the group consisting of -Z-CHR^8″

—

, —

CHR^8″

-Z-, -Z′

=CR^8″

—

, and —

CR^8″

-Z′

-, or at least one of “

-M-P-Q-”

, “

—

P-Q-T-”

, or “

-Q-T-U—

”

is selected from the group consisting of —

CHR^8″

-Z-CHR^8″

—

, —

CR^8″

-Z′

-CHR^8″

—

, or —

CHR^8″

-Z′

=CR^8″

—

;

Z is CH₂, CHR⁸, CR⁸R⁸, O, S, NH, or NR^8′

; and

Z′

is CH, CR⁸, or N,

provided that no heteroatom is directly adjacent to another heteroatom.

4. The compound of claim 1 wherein:

“

—

V—

W—

”

is —

CH═

CH—

, —

CR⁸═

CR⁸, —

C≡

C—

,

wherein Y³ is O, S, NH, or NR^8′

, and each R′

is hydrogen, CH₃, CF₃, or halogen (F, Cl, Br, or I).

5. The compound of claim 1 wherein M, P, U, V and W are CH₂.

6. The compound of claim 1 wherein X is O or NH.

7. The compound of claim 1 wherein one of R^1a and R^1b is OH and one is H.

8. The compound of claim 1 wherein R³ is OH.

9. The compound of claim 1 wherein R⁵ is CH₃.

10. The compound of claim 1 wherein Q is O or NH and T is C(O).

11. The compound of claim 1 wherein P is C(O) and Q is NH and T is CH₂.

12. The compound of claim 1 wherein “

d”

is a double bond of either (E)- or (Z)-orientation and V and W are independently CH or CR⁸.

13. The compound of claim 1 wherein “

h” and

“

g”

are single bonds and P and T are CHR*, CR⁸R*, or NR*, wherein P-Q-T form an optionally substituted or unsubstituted 3-6 membered cycloalkyl, or an optionally substituted or unsubstituted 3-6 membered heterocyclic ring.

45. The compound of claim 1 of the structure 10:

or a pharmaceutically acceptable salt or ester thereof.

46. The compound of claim 1 of the structure 12:

or a pharmaceutically acceptable salt or ester thereof.

47. The compound of claim 1 of the structure 14:

or a pharmaceutically acceptable salt or ester thereof.

48. The compound of claim 1 of the structure 16:

or a pharmaceutically acceptable salt or ester thereof.

49. The compound of claim 1 of the structure 18:

or a pharmaceutically acceptable salt or ester thereof.

50. A pharmaceutical composition comprising a compound of one of claim 1 to 13 in a pharmaceutically acceptable carrier.

51. The pharmaceutical composition of claim 50, additionally comprising at least one additional active agent.

52. The composition of claim 51 wherein the active agent is paclitaxel or an estrogen.

53. The composition of claim 52 wherein the estrogen is 2-methoxyestradiol.

54. Use of a compound of claim 1, optionally in a pharmaceutical carrier, for the preparation of a medicament for treating or preventing abnormal cell proliferation in a host.

55. The use of claim 54, further comprising administering at least one additional active agent in combination or alternation with the compound.

56. The use of claim 55, wherein the active agent is paclitaxel or an estrogen.

57. The use of claim 56 wherein the estrogen is 2-methoxyestradiol.

14. A compound of Formula IV, or a pharmaceutically acceptable salt or ester thereof,

wherein:

R^1a, R^1b, and R⁵ are each independently H, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₁-C₁₀ alkoxy, C₂-C₁₀ alkenoxy, C₂-C₁₀ alkynyl, C₂-C₁₀ alkynoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, COR⁸, nitro, cyano, OH, CF₃, OCF₃, or halogen;

R² is absent (when “

a”

is a triple bond or when “

a”

is a single bond and “

b”

is a double bond) or is selected from the group consisting of H, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₁-C₁₀ alkoxy, C₂-C₁₀ alkenoxy, C₂-C₁₀ alkynyl, C₂-C₁₀ alkynoxy, aryl, nitro, cyano, halogen, acyl, alkacyl, CHO, CO₂H, CO₂—

C_1-10 alkyl, CF₃, OH, OR^8′

, OCF₃, SH, SR^8′

, NH₂, NHR^8′

, NHR⁸′

R^8′

, CON(R^8′

)₂, and CONHR^8′

;

“

a”

can be a single or double bond of either (E)- or (Z)-orientation, or “

a”

can be a triple bond when R², Y, “

b” and

“

c”

are absent;

“

b”

can be absent or a single bond (when R² is absent);

“

c”

can be absent, a single, or double bond of either (E)- or (Z)-orientation;

such that

only one of “

a”

, “

b”

, and “

c”

can be a double bond, when “

b” and

“

c”

are absent, then Y is absent; and

when “

a”

is a single or double bond, one of “

b” and

“

c”

is a single bond and one is absent, then Y is H, a straight or branched substituted or unsubstituted alkyl, alkenyl, or alkynyl, CH₃, CH₂R⁸, CHR⁸R⁸, CR⁸R⁸R⁸, CH₂F, CH₂Cl, CH₂Br, CHF₂, CHCl₂, CHBr₂, CF₃, CCl₃, CBr₃, OH, OR⁸, SH, SR⁸, NH₂, NHR⁸, or NR^8′

R^8′

;

when “

a”

, “

b”

, and “

c”

are single bonds or when “

a”

is a single bond, one of “

b” and

“

c”

is a double bond and one is absent, then Y is CH₂, CHR⁸, CR⁸R⁸, CHF, CHCl, CHBr, CF₂, CCl₂, CBr₂, O, S, NH, or NR^8′

;

R³ is independently selected from H, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₁-C₁₀ alkoxy, C₂-C₁₀ alkenoxy, C₂-C₁₀ alkynyl, C₂-C₁₀ alkynoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, nitro, cyano, CF₃, OH, O-alkyl, hydroxylalkyl, O-acyl, OCF₃, SH, S-alkyl, thioalkyl, S-acyl, amine, alkylamine, NH₂, NHR⁸, NR⁸R⁸, and halogen;

R⁴ is selected from the group consisting of C₃-C₁₀ cycloalkyl, C₃-C₁₀ cycloalkenyl, heteroaryl, substituted heteroaryl, aryl, substituted aryl, C₃-C₁₀ heterocycloalkyl, adamantly, and C₃-C₁₀ heterocycloalkenyl;

X is CH₂, CHR⁸, CR⁸R⁸, N, NR^8′

, O, or S;

each Y¹ and Y² is independently O, S, NH, or NR^8′

;

M, Q and U is each independently CH₂, CHR⁸, CR⁸R⁸, NH, NR^8′

, O, S, C═

O, or C═

Y²;

such that if j and A are ═

O or ═

Y² or k and B are ═

O or ═

Y², the adjacent M or U is not C═

O or C═

Y² and M and Q or Q and U are not both NH, NR^8′

, O, or S;

“

j”

can be a single, or double bond of either (E)- or (Z)-orientation;

such that

when “

j”

is a single bond, then A is H;

a straight or branched substituted or unsubstituted alkyl, alkenyl, or alkynyl;

CH₃, CH₂R⁸, CHR⁸R⁸, CR⁸R⁸R⁸, CH₂F, CH₂Cl, CH₂Br, CHF₂, CHCl₂, CHBr₂, CF₃, CCl₃, CBr₃, OH, OR^8′

, SH, SR^8′

, NH₂, NHR^8′

, or NR^8′

R^8′

;

when “

j”

is a double bond, then A is CH₂, CHR⁸, CR⁸R⁸, CHF, CHCl, CHBr, CF₂, CCl₂, CBr₂, O, S, NH, or NR^8′

;

“

k”

can be absent, a single, or double bond of either (E)- or (Z)-orientation;

such that

when “

k”

is absent, then B is absent;

when “

k”

is a single bond, then B is H;

a straight or branched substituted or unsubstituted alkyl, alkenyl, or alkynyl;

CH₃, CH₂R⁸, CHR⁸R⁸, CR⁸R⁸R⁸, CH₂F, CH₂Cl, CH₂Br, CHF₂, CHCl₂, CHBr₂, CF₃, CCl₃, CBr₃, OH, OR^8′

, SH, SR^8′

, NH₂, NHR^8′

, or NR^8′

;

when “

k”

is a double bond, then B is CH₂, CHR⁸, CR⁸R⁸, CHF, CHl, CHBr, CF₂, CCl₂, CBr₂, O, S, NH, or NR^8′

;

each R⁸ is independently —

H;

an optionally substituted or unsubstituted straight or branched alkyl, such as a —

C_1-8 straight or branched chain alkyl;

an optionally substituted or unsubstituted straight or branched —

C_2-8 alkenyl;

an optionally substituted or unsubstituted straight or branched —

C_2-8 alkynyl;

—

C_3-6 cycloalkyl;

3-7 membered heterocycle;

-aryl;

-aralkyl;

-heteroaryl, -heteroarylalkyl, -halo (F, Cl, Br, I);

-haloalkyl;

—

CF₃;

—

CN;

—

NO₂;

-acyl (including but not limited to aldehydes, ketones, esters, carboxylic acids, amides, imides, thioesters), —

(C═

Y¹)-alkyl, —

O(C═

Y¹)-alkyl, —

(C═

Y¹)—

OH, —

(C═

Y¹)—

O-alkyl, —

S—

(C═

Y¹)-alkyl, —

(C═

Y¹)—

SH, —

(C═

Y¹)—

S-alkyl, —

NH(C═

Y¹)-alkyl, —

NR^8′

(C═

Y¹)-alkyl, —

(C═

Y¹)—

NH₂, —

(C═

Y¹)—

NH(alkyl), —

(C═

Y¹)—

N(alkyl)₂, —

COOH;

—

COOC_1-8 alkyl;

—

CONH₂;

—

CONH—

C_1-8 alkyl;

—

CON(C_1-8 alkyl)₂;

alkacyl, -alkyl-(C═

Y¹)-alkyl, -alkyl-O(C═

Y¹)-alkyl, -alkyl-(C═

Y¹)—

OH, -alkyl-(C═

Y¹)—

O-alkyl, -alkyl-S—

(C═

Y¹)-alkyl, -alkyl-(C═

Y¹)—

SH, -alkyl-(C═

Y¹)—

S-alkyl, -alkyl-NH(C═

Y¹)-alkyl, -alkyl-NR^8′

(C═

Y¹)-alkyl, -alkyl-(C═

Y¹)—

NH₂, -alkyl-(C═

Y¹)—

NH(alkyl), -alkyl-(C═

Y¹)—

N(alkyl)₂, -alkyl-COOH;

-alkyl-COOC_1-8 alkyl;

-alkyl-CONH₂;

-alkyl-CONH—

C_1-8 alkyl;

-alkyl-CON(C_1-8 alkyl)₂;

amino, —

NH₂;

—

NH—

C_1-8 alkyl;

—

N(C_1-8 alkyl)₂;

—

NHC(O)—

C_1-8 alkyl;

alkylamino;

hydroxyl, alkylhydroxyl, alkoxy, thio;

alkylthio;

thioalkyl; and

each R^8′

is independently an optionally substituted or unsubstituted straight or branched alkyl, such as a —

C_1-8 straight or branched chain alkyl;

an optionally substituted or unsubstituted straight or branched alkenyl, such as a —

C_2-8 alkenyl;

an optionally substituted or unsubstituted straight or branched alkynyl, such as a —

C_2-8 alkynyl;

a saturated or unsaturated carbocycle, such as a saturated or unsaturated —

C_3-6 cycloalkyl;

a heterocycle, such as a 3-7 membered heterocycle;

aryl;

or heteroaryl;

such that there is not a double or triple bond directly adjacent to a double or triple bond.

15. The compound of claim 14 wherein R^1a, R^1b, and R⁵ are either hydrogen, CH₃, or C₁-C₅ alkyl.

16. The compound of claim 14 wherein “

a”

, “

b”

, and “

c”

are all single bonds and Y is O, S, NH, NR^8′

, CH₂, CHR′

, or CR′

R′

, wherein each R′

is hydrogen, CH₃, CF₃, or halogen (F, Cl, Br, or I).

17. The compound of claim 14 wherein “

a”

is a double bond of either (E)- or (Z)-orientation, and one of “

b”

or “

c”

is a single bond and the other is absent.

18. The compound of claim 14 wherein one of “

j” and

“

k”

is a double bond of either (E)- or (Z)-orientation.

19. The compound of claim 14 wherein one, and only one, of “

j” and

“

k”

is a double bond of either (E)- or (Z)-orientation.

20. The compound of claim 14 wherein one of “

j” and

“

k”

is a double bond of either (E)- or (Z)-orientation; and

if “

j”

is the double bond;

then A is CH₂, CHR⁸, CR⁸R⁸, O, S, NH or NR^8′

;

or if “

k”

is the double bond;

then B is CH₂, CHR⁸, CR⁸R⁸, O, S, NH or NR^8′

.

21. The compound of claim 14 wherein only one of “

j” and

“

k”

is a double bond of either (E)- or (Z)-orientation and if “

j”

is the double bond;

then A is O, S, NH or NR^8′

;

or if “

k”

is the double bond;

then B is O, S, NH or NR^8′

.

22. The compound of claim 14 wherein both of “

j” and

“

k”

are single bonds; and

at least one of A and B is a straight or branched substituted or unsubstituted alkenyl or alkynyl.

23. The compound of claim 14 wherein both of “

j” and

“

k”

are single bonds; and

at least one of A and B is a C₂ to C₄ alk-1-ene, alk-2-ene, alk-1-yne, or alk-2-yne.

24. A compound of Formula VIII or IX, or a pharmaceutically acceptable salt or ester thereof,

wherein:

R^1a, R^1b, and R⁵ are each independently H, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₁-C₁₀ alkoxy, C₂-C₁₀ alkenoxy, C₂-C₁₀ alkynyl, C₂-C₁₀ alkynoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, COR⁸, nitro, cyano, OH, CF₃, OCF₃, or halogen;

R² is absent (when “

a”

is a triple bond or when “

a”

is a single bond and “

b”

is a double bond) or is selected from the group consisting of H, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₁-C₁₀ alkoxy, C₂-C₁₀ alkenoxy, C₂-C₁₀ alkynyl, C₂-C₁₀ alkynoxy, aryl, nitro, cyano, halogen, acyl, alkacyl, CHO, CO₂H, CO₂—

C_1-10 alkyl, CF₃, OH, OR^8′

, OCF₃, SH, SR^8′

, NH₂, NHR^8′

, NHR^8′

R^8′

, CON(R^8′

)₂, and CONHR^8′

;

“

a”

can be a single or double bond of either (E)- or (Z)-orientation, or “

a”

can be a triple bond when R², Y, “

b” and

“

c”

are absent;

“

b”

can be absent or a single bond (when R² is absent);

“

c”

can be absent, a single, or double bond of either (E)- or (Z)-orientation;

such that

only one of “

a”

, “

b”

, and “

c”

can be a double bond, when “

b” and

“

c”

are absent, then Y is absent; and

when “

a”

is a single or double bond, one of “

b” and

“

c”

is a single bond and one is absent, then Y is H, a straight or branched substituted or unsubstituted alkyl, alkenyl, or alkynyl, CH₃, CH₂R⁸, CHR⁸R⁸, CR⁸R⁸R⁸, CH₂F, CH₂Cl, CH₂Br, CHF₂, CHCl₂, CHBr₂, CF₃, CCl₃, CBr₃, OH, OR^8′

, SH, SR^8′

, NH₂, NHR⁸, or NR^8′

R^8′

;

when “

a”

, “

b”

, and “

c”

are single bonds or when “

a”

is a single bond, one of “

b” and

“

c”

is a double bond and one is absent, then Y is CH₂, CHR⁸, CR⁸R⁸, CHF, CHCl, CHBr, CF₂, CCl₂, CBr₂, O, S, NH, or NR^8′

;

R³ is independently selected from H, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₁-C₁₀ alkoxy, C₂-C₁₀ alkenoxy, C₂-C₁₀ alkynyl, C₂-C₁₀ alkynoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, nitro, cyano, CF₃, OH, O-alkyl, hydroxylalkyl, O-acyl, OCF₃, SH, S-alkyl, thioalkyl, S-acyl, amine, alkylamine, NH₂, NHR⁸, NR⁸R⁸, and halogen;

R⁴ is selected from the group consisting of C₃-C₁₀ cycloalkyl, C₃-C₁₀ cycloalkenyl, heteroaryl, substituted heteroaryl, aryl, substituted aryl, C₃-C₁₀ heterocycloalkyl, adamantly, and C₃-C₁₀ heterocycloalkenyl;

X is CH₂, CHR⁸, CR⁸R⁸, N, NR^8′

, O, or S;

each Y¹ and Y² is independently O, S, NH, or NR⁸′

;

Q is independently CH₂, CHR⁸, CR⁸R⁸, NH, NR^8′

, O, S, C═

O, or C═

Y²;

each R⁸ is independently —

H;

an optionally substituted or unsubstituted straight or branched alkyl, such as a —

C_1-8 straight or branched chain alkyl;

an optionally substituted or unsubstituted straight or branched —

C_2-8 alkenyl;

an optionally substituted or unsubstituted straight or branched —

C_2-8 alkynyl;

—

C_3-6 cycloalkyl;

3-7 membered heterocycle;

-aryl;

-aralkyl;

-heteroaryl, -heteroarylalkyl, -halo (F, Cl, Br, I);

-haloalkyl;

—

CF₃;

—

CN;

—

NO₂;

-acyl (including but not limited to aldehydes, ketones, esters, carboxylic acids, amides, imides, thioesters), —

(C═

Y¹)-alkyl, —

O(C═

Y¹)-alkyl, —

(C═

Y¹)—

OH, —

(C═

Y¹)—

O-alkyl, —

S—

(C═

Y¹)-alkyl, —

(C═

Y¹)—

SH, —

(C═

Y¹)—

S-alkyl, —

NH(C═

Y¹)-alkyl, —

NR⁸ (C═

Y¹)-alkyl, —

(C═

Y¹)—

NH₂, —

(C═

Y¹)—

NH(alkyl), —

(C═

Y¹)—

N(alkyl)₂, —

COOH;

—

COOC_1-8 alkyl;

—

CONH₂;

—

CONH—

C_1-18 alkyl;

—

CON(C_1-5 alkyl)₂;

alkacyl, -alkyl-(C═

Y¹)-alkyl, -alkyl-O(C═

Y¹)-alkyl, -alkyl-(C═

Y¹)—

OH, -alkyl-(C═

Y¹)—

O-alkyl, -alkyl-S—

(C═

Y¹)-alkyl, -alkyl-(C═

Y¹)—

SH, -alkyl-(C═

Y¹)—

S-alkyl, -alkyl-NH(C═

Y¹)-alkyl, -alkyl-NR^8′

(C═

Y¹)-alkyl, -alkyl-(C═

Y¹)—

NH₂, -alkyl-(C═

Y¹)—

NH(alkyl), -alkyl-(C═

Y¹)—

N(alkyl)₂, -alkyl-COOH;

-alkyl-COOC_1-8 alkyl;

-alkyl-CONH₂;

-alkyl-CONH—

C_1-8 alkyl;

-alkyl-CON(C_1-8 alkyl)₂;

amino, —

NH₂;

—

NH—

C_1-18 alkyl;

—

N(C_1-8 alkyl)₂;

—

NHC(O)—

C_1-8 alkyl;

alkylamino;

hydroxyl, alkylhydroxyl, alkoxy, thio;

alkylthio;

thioalkyl; and

each R^8′

is independently an optionally substituted or unsubstituted straight or branched alkyl, such as a —

C_1-8 straight or branched chain alkyl;

an optionally substituted or unsubstituted straight or branched alkenyl, such as a —

C_2-8 alkenyl;

an optionally substituted or unsubstituted straight or branched alkynyl, such as a —

C_2-8 alkynyl;

a saturated or unsaturated carbocycle, such as a saturated or unsaturated —

C_3-6 cycloalkyl;

a heterocycle, such as a 3-7 membered heterocycle;

aryl;

or heteroaryl.

25. The compound of claim 24, wherein R^1a, R^1b, and R⁵ are either hydrogen, CH₃, or C₁-C₅ alkyl.

26. The compound of claim 24, wherein “

a”

, “

b”

, and “

c”

are all single bonds and Y is O, S, NH, NR^8′

, CH₂, CHR′

, or CR′

R′

, wherein each R′

is hydrogen, CH₃, CF₃, or halogen (F, Cl, Br, or I).

27. The compound of claim 24, wherein “

a”

is a double bond of either (E)- or (Z)-orientation, and one of “

b”

or “

c”

is a single bond and the other is absent.

28. The compound of claim 24, wherein Q is O, S, NH, or NR^8′

.

29. The compound of claim 24, wherein X is O.

30. The compound of claim 24, wherein at least one of Y¹ and Y² is O.

31. A compound of Formula III, or a pharmaceutically acceptable salt or ester thereof,

wherein:

R^1a, R^1b, and R⁵ are each independently H, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₁-C₁₀ alkoxy, C₂-C₁₀ alkenoxy, C₂-C₁₀ alkynyl, C₂-C₁₀ alkynoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, COR⁸, nitro, cyano, OH, CF₃, OCF₃, or halogen;

“

a”

can be a single or double bond of either (E)- or (Z)-orientation, or “

a”

can be a triple bond when R², Y, “

b” and

“

c”

are absent;

“

b”

can be absent or a single bond (when R² is absent);

“

c”

can be absent, a single, or double bond of either (E)- or (Z)-orientation;

such that only one of “

a”

, “

b”

, and “

c”

can be a double bond, when “

b” and

“

c”

are absent, then Y is absent; and

when “

a”

is a single or double bond, one of “

b” and

“

c”

is a single bond and one is absent, then Y is H, a straight or branched substituted or unsubstituted alkyl, alkenyl, or alkynyl, CH₃, CH₂R⁸, CHR⁸R⁸, CR⁸R⁸R⁸, CH₂F, CH₂Cl, CH₂Br, CHF₂, CHCl₂, CHBr₂, CF₃, CCl₃, CBr₃, OH, OR^8′

, SH, SR⁸, NH₂, NHR^8′

, or NR^8′

R^8′

;

when “

a”

, “

b”

, and “

c”

are single bonds or when “

a”

is a single bond, one of “

b” and

“

c”

is a double bond and one is absent, then Y is CH₂, CHR⁸, CR⁸R⁸, CHF, CHCl, CHBr, CF₂, CCl₂, CBr₂, O, S, NH, or NR^8′

;

R³ is independently selected from H, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₁-C₁₀ alkoxy, C₂-C₁₀ alkenoxy, C₂-C₁₀ alkynyl, C₂-C₁₀ alkynoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, nitro, cyano, CF₃, OH, O-alkyl, hydroxylalkyl, O-acyl, OCF₃, SH, S-alkyl, thioalkyl, S-acyl, amine, alkylamine, NH₂, NHR⁸, NR⁸R⁸, and halogen;

R⁴ is selected from the group consisting of C₃-C₁₀ cycloalkyl, C₃-C₁₀ cycloalkenyl, heteroaryl, substituted heteroaryl, aryl, substituted aryl, C₃-C₁₀ heterocycloalkyl, adamantly, and C₃-C₁₀ heterocycloalkenyl;

R²** is a radical selected from the group consisting of H, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₁-C₁₀ alkoxy, C₂-C₁₀ alkenoxy, C₂-C₁₀ alkynyl, C₂-C₁₀ alkynoxy, aryl, nitro, cyano, halogen, CHO, CO₂H, CO₂—

C_1-10 alkyl, CF₃, OCF₃, CON(R⁶)₂, or CONHR⁶;

X^III is CH₂, N, NR⁵, O, or S;

each Y¹ and Y² is independently O, S, NH, or NR^8′

;

J is CH₂, CHR⁸, CR⁸R⁸, CHF, CHCl, CHBr, CF₂, CCl₂, CBr₂, O, S, NH, or NR^8′

;

M and U are independently selected from the group consisting of CH₂ or CHR⁸;

Q is CH₂, CHR⁸, NR^8′

, O or S;

“

j”

can be a single, or double bond of either (E)- or (Z)-orientation;

such that

when “

j”

is a single bond, then A is H;

a straight or branched substituted or unsubstituted alkyl, alkenyl, or alkynyl;

CH₃, CH₂R⁸, CHR⁸R⁸, CR⁸R⁸R⁸, CH₂F, CH₂Cl, CH₂Br, CHF₂, CHCl₂, CHBr₂, CF₃, CCl₃, CBr₃, OH, OR⁸, SH, SR^8′

, NH₂, NHR^8′

, or NR^8′

R^8′

;

when “

j”

is a double bond, then A is CH₂, CHR⁸, CR⁸R⁸, CHF, CHCl, CHBr, CF₂, CCl₂, CBr₂, O, S, NH, or NR^8′

;

“

k”

can be absent, a single, or double bond of either (E)- or (Z)-orientation;

such that

when “

k”

is absent, then B is absent;

when “

k”

is a single bond, then B is H;

a straight or branched substituted or unsubstituted alkyl, alkenyl, or alkynyl;

CH₃, CH₂R⁸, CHR⁸R⁸, CR⁸R⁸R⁸, CH₂F, CH₂Cl, CH₂Br, CHF₂, CHCl₂, CHBr₂, CF₃, CCl₃, CBr₃, OH, OR^8′

, SH, SR^8′

, NH₂, NHR^8′

, or NR^8′

R^8′

;

when “

k”

is a double bond, then B is CH₂, CHR⁸, CR⁸R⁸, CHF, CHCl, CHBr, CF₂, CCl₂, CBr₂, O, S, NH, or NR^8′

each R⁸ is independently —

H;

an optionally substituted or unsubstituted straight or branched alkyl, such as a —

C_1-8 straight or branched chain alkyl;

an optionally substituted or unsubstituted straight or branched —

C_2-8 alkenyl;

an optionally substituted or unsubstituted straight or branched —

C_2-8 alkynyl;

—

C_3-6 cycloalkyl;

3-7 membered heterocycle;

-aryl;

-aralkyl;

-heteroaryl, -heteroarylalkyl, -halo (F, Cl, Br, I);

-haloalkyl;

—

CF₃;

—

CN;

—

NO₂;

-acyl (including but not limited to aldehydes, ketones, esters, carboxylic acids, amides, imides, thioesters), —

(C═

Y¹)-alkyl, —

O(C═

Y₁)-alkyl, —

(C═

Y¹)—

OH, —

(C═

Y¹)—

O-alkyl, —

S—

(C═

Y¹)-alkyl, —

(C═

Y¹)—

SH, —

(C═

Y¹)—

S-alkyl, —

NH(C═

Y¹)-alkyl, —

NR^8′

(C═

Y¹)-alkyl, —

(C═

Y¹)—

NH₂, —

(C═

Y¹)—

NH(alkyl), —

(C═

Y¹)—

N(alkyl)₂, —

COOH;

—

COOC_1-8 alkyl;

—

CONH₂;

—

CONH—

C_1-5 alkyl;

—

CON(C_1-18 alkyl)₂;

alkacyl, -alkyl-(C═

Y¹)-alkyl, -alkyl-O(C═

Y¹)-alkyl, -alkyl-(C═

Y¹)—

OH, -alkyl-(C═

Y¹)—

O-alkyl, -alkyl-S—

(C═

Y¹)-alkyl, -alkyl-(C═

Y¹)—

SH, -alkyl-(C═

Y¹)—

S-alkyl, -alkyl-NH(C═

Y¹)-alkyl, -alkyl-NR^8′

(C═

Y¹)-alkyl, -alkyl-(C═

Y¹)—

NH₂, -alkyl-(C═

Y¹)—

NH(alkyl), -alkyl-(C═

Y¹)—

N(alkyl)₂, -alkyl-COOH;

-alkyl-COOC_1-8 alkyl;

-alkyl-CONH₂;

-alkyl-CONH—

C_1-8 alkyl;

-alkyl-CON(C_1-8 alkyl)₂;

amino, —

NH₂;

—

NH—

C_1-18 alkyl;

—

N(C_1-8 alkyl)₂;

—

NHC(O)—

C_1-8 alkyl;

alkylamino;

hydroxyl, alkylhydroxyl, alkoxy, thio;

alkylthio;

thioalkyl; and

each R^8′

is independently an optionally substituted or unsubstituted straight or branched alkyl, such as a —

C_1-8 straight or branched chain alkyl;

an optionally substituted or unsubstituted straight or branched alkenyl, such as a —

C_2-8 alkenyl;

an optionally substituted or unsubstituted straight or branched alkynyl, such as a —

C_2-8 alkynyl;

a saturated or unsaturated carbocycle, such as a saturated or unsaturated —

C_3-6 cycloalkyl;

a heterocycle, such as a 3-7 membered heterocycle;

aryl;

or heteroaryl.

32. The compound of claim 31, wherein R^1a, R^1b, and R⁵ are either hydrogen, CH₃, or C₁-C₅ alkyl.

33. The compound of claim 31, wherein “

a”

, “

b”

, and “

c”

are all single bonds and Y is O, S, NH, NR^8′

, CH₂, CHR′

, or CR′

R′

, wherein each R′

is hydrogen, CH₃, CF₃, or halogen (F, Cl, Br, or I).

34. The compound of claim 31, wherein “

a”

is a double bond of either (E)- or (Z)-orientation, and one of “

b”

or “

c”

is a single bond and the other is absent.

35. The compound of claim 31, wherein one of “

j” and

“

k”

is a double bond of either (E)- or (Z)-orientation.

36. The compound of claim 35, wherein if “

j”

is the double bond;

then A is CH₂, CHR⁸, CR⁸R⁸, O, S, NH or NR^8′

;

or if “

k”

is the double bond;

then B is CH₂, CHR⁸, CR⁸R⁸, O, S, NH or NR^8′

.

37. The compound of claim 35, wherein if “

j”

is the double bond;

then A is O;

or if “

k”

is the double bond;

then B is O.

38. A compound of Formula VI or VII, or a pharmaceutically acceptable salt or ester thereof,

wherein:

R^1a, R^1b, and R⁵ are each independently H, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₁-C₁₀ alkoxy, C₂-C₁₀ alkenoxy, C₂-C₁₀ alkynyl, C₂-C₁₀ alkynoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, COR⁸, nitro, cyano, OH, CF₃, OCF₃, or halogen;

R² is absent (when “

a”

is a triple bond or when “

a”

is a single bond and “

b”

is a double bond) or is selected from the group consisting of H, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₁-C₁₀ alkoxy, C₂-C₁₀ alkenoxy, C₂-C₁₀ alkynyl, C₂-C₁₀ alkynoxy, aryl, nitro, cyano, halogen, acyl, alkacyl, CHO, CO₂H, CO₂—

C_1-10 alkyl, CF₃, OH, OR^8′

, OCF₃, SH, SR^8′

, NH₂, NHR⁸, NHR^8′

R^8′

, CON(R^8′

)₂, and CONHR^8′

;

“

a”

can be a single or double bond of either (E)- or (Z)-orientation, or “

a”

can be a triple bond when R², Y, “

b” and

“

c”

are absent;

“

b”

can be absent or a single bond (when R² is absent);

“

c”

can be absent, a single, or double bond of either (E)- or (Z)-orientation;

such that only one of “

a”

, “

b”

, and “

c”

can be a double bond, when “

b” and

“

c”

are absent, then Y is absent; and

when “

a”

is a single or double bond, one of “

b” and

“

c”

is a single bond and one is absent, then Y is H, a straight or branched substituted or unsubstituted alkyl, alkenyl, or alkynyl, CH₃, CH₂R⁸, CHR⁸R⁸, CR⁸R⁸R⁸, CH₂F, CH₂Cl, CH₂Br, CHF₂, CHCl₂, CHBr₂, CF₃, CCl₃, CBr₃, OH, OR^8′

, SH, SR^8′

, NH₂, NHR^8′

, or NR^8′

R^8′

;

when “

a”

, “

b”

, and “

c”

are single bonds or when “

a”

is a single bond, one of “

b” and

“

c”

is a double bond and one is absent, then Y is CH₂, CHR⁸, CR⁸R⁸, CHF, CHCl, CHBr, CF₂, CCl₂, CBr₂, O, S, NH, or NR^8′

;

R³ is independently selected from H, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₁-C₁₀ alkoxy, C₂-C₁₀ alkenoxy, C₂-C₁₀ alkynyl, C₂-C₁₀ alkynoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, nitro, cyano, CF₃, OH, O-alkyl, hydroxylalkyl, O-acyl, OCF₃, SH, S-alkyl, thioalkyl, S-acyl, amine, alkylamine, NH₂, NHR⁸, NR⁸R⁸, and halogen;

R⁴ is selected from the group consisting of C₃-C₁₀ cycloalkyl, C₃-C₁₀ cycloalkenyl, heteroaryl, substituted heteroaryl, aryl, substituted aryl, C₃-C₁₀ heterocycloalkyl, adamantly, and C₃-C₁₀ heterocycloalkenyl;

X is CH₂, CHR⁸, CR⁸R⁸, N, NR^8′

, O, or S; and

each Y¹ and Y² is independently O, S, NH, or NR^8′

;

J is CH₂, CHR⁸, CR⁸R⁸, CHF, CHCl, CHBr, CF₂, CCl₂, CBr₂, O, S, NH, or NR^8′

;

Q is independently CH₂, CHR⁸, CR⁸R⁸, NH, NR^8′

, O, S, C═

O, or C═

Y²

each R⁸ is independently —

H;

an optionally substituted or unsubstituted straight or branched alkyl, such as a —

C_1-8 straight or branched chain alkyl;

an optionally substituted or unsubstituted straight or branched —

C_2-8 alkenyl;

an optionally substituted or unsubstituted straight or branched —

C_2-8 alkynyl;

—

C_3-6 cycloalkyl;

3-7 membered heterocycle;

-aryl;

-aralkyl;

-heteroaryl, -heteroarylalkyl, -halo (F, Cl, Br, I);

-haloalkyl;

—

CF₃;

—

CN;

—

NO₂;

-acyl (including but not limited to aldehydes, ketones, esters, carboxylic acids, amides, imides, thioesters), —

(C═

Y¹)-alkyl, —

O(C═

Y¹)-alkyl, —

(C═

Y¹)—

OH, —

(C═

Y¹)—

O-alkyl, —

S—

(C═

Y¹)-alkyl, —

(C═

Y¹)—

SH, —

(C═

Y¹)—

S-alkyl, —

NH(C═

Y¹)-alkyl, —

NR¹ (C═

Y¹)-alkyl, —

(C═

Y¹)—

NH₂, —

(C═

Y¹)—

NH(alkyl), —

(C═

Y¹)—

N(alkyl)₂, —

COOH;

—

COOC_1-8 alkyl;

—

CONH₂;

—

CONH—

C_1-8 alkyl;

—

CON(C_1-8 alkyl)₂;

alkacyl, -alkyl-(C═

Y¹)-alkyl, -alkyl-O(C═

Y¹)-alkyl, -alkyl-(C═

Y¹)—

OH, -alkyl-(C═

Y¹)—

O-alkyl, -alkyl-S—

(C═

Y¹)-alkyl, -alkyl-(C═

Y¹)—

SH, -alkyl-(C═

Y¹)—

S-alkyl, -alkyl-NH(C═

Y¹)-alkyl, -alkyl-NR^8′

(C═

Y¹)-alkyl, -alkyl-(C═

Y¹)—

NH₂, -alkyl-(C═

Y¹)—

NH(alkyl), -alkyl-(C═

Y¹)—

N(alkyl)₂, -alkyl-COOH;

-alkyl-COOC_1-8 alkyl;

-alkyl-CONH₂;

-alkyl-CONH—

C_1-8 alkyl;

-alkyl-CON(C_1-8 alkyl)₂;

amino, —

NH₂;

—

NH—

C_1-8 alkyl;

—

N(C_1-18 alkyl)₂;

—

NHC(O)—

C_1-8 alkyl;

alkylamino;

hydroxyl, alkylhydroxyl, alkoxy, thio;

alkylthio;

thioalkyl; and

each R^8′

is independently an optionally substituted or unsubstituted straight or branched alkyl, such as a —

C_1-8 straight or branched chain alkyl;

an optionally substituted or unsubstituted straight or branched alkenyl, such as a —

C_2-8 alkenyl;

an optionally substituted or unsubstituted straight or branched alkynyl, such as a —

C_2-8 alkynyl;

a saturated or unsaturated carbocycle, such as a saturated or unsaturated —

C_3-6 cycloalkyl;

a heterocycle, such as a 3-7 membered heterocycle;

aryl;

or heteroaryl.

39. The compound of claim 38, wherein R^1a, R^1b, and R⁵ are either hydrogen, CH₃, or C₁-C₅ alkyl.

40. The compound of claim 38, wherein “

a”

, “

b”

, and “

c”

are all single bonds and Y is O, S, NH, NR^8′

, CH₂, CHR′

, or CR′

R′

, wherein each R′

is hydrogen, CH₃, CF₃, or halogen (F, Cl, Br, or I).

41. The compound of claim 38, wherein “

a”

is a double bond of either (E)- or (Z)-orientation, and one of “

b”

or “

c”

is a single bond and the other is absent.

42. The compound of claim 38, wherein Q is O, S, NH, or NR^8′

.

43. The compound of claim 38, wherein X is O.

44. The compound of claim 38, wherein at least one of Y¹ or Y² is O.