# US 7,745,464 B2 · Compounds and methods for inhibiting the interaction of BCL proteins with binding partners

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- Number: US 7,745,464 B2
- Document ID: US7745464B2
- Status: Granted
- Kind: B2
- Application number: 11/640,480
- Filed: 2006-12-15
- Published: 2007-07-05
- Granted: 2010-06-29
- Earliest claimed: 2005-12-16
- Inventors: Alfredo C. Castro; Michael J. Grogan; Edward B. Holson; Brian T. Hopkins; Nii O. Koney; Stephane Peluso; Daniel A. Snyder
- Web page: https://patentgrep.com/patent/US7745464B2

## CPC

- C07D 207/16: Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- A61P 35/00: Antineoplastic agents
- C07D 207/08: with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
- C07D 207/12: Oxygen or sulfur atoms
- C07D 207/14: Nitrogen atoms not forming part of a nitro radical
- C07D 211/60: Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D 233/32: One oxygen atom
- C07D 265/30: not condensed with other rings
- C07D 277/04: having no double bonds between ring members or between ring members and non-ring members
- C07D 277/06: with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D 295/04: with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The present invention relates to heterocyclic compounds that bind to Bcl proteins and inhibit Bcl function, compositions comprising such compounds, and methods for treating and modulating disorders associated with hyperproliferation, such as cancer.

## Claims

### Claim 1

A compound represented by formula 1:
or an unsaturated form thereof or a pharmaceutically acceptable salt thereof;
wherein
Y is —C(R10)2—, —(C═O)—, —(C═S)—, or —C(═NR10)—;
X is —N(R10)—, or a bond;
m is 0, 1, 2, 3, 4, 5, or 6;
A is —C(A1)(A2)-;
each of A1 and A2 is independently H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, aralkyl, heterocyclyl, heteroaryl, heteroaralkyl, —C(O)N(R10)2, —C(O)R10, —CO2R10, —S(O)2N(R10)2, —S(O)R10, —S(O)2OR10, —S(O)2R10; or has the formula 1a:
wherein independently for each occurrence of 1a;
n is 1, 2, 3, 4, 5, or 6;
R15 is aryl, cycloalkyl, cycloalkenyl, heterocyclyl, heteroaryl, —OR10, —SR10, —N(R10)2, —N(R10)CO2R10, —N(R10)C(O)N(R10)2, —CO2R10, or —C(O)N(R10)2; or is a polycyclic ring containing 8-14 carbon atoms, of which one, two or three ring atoms are independently S, O or N;
or A1 and A2 taken together form ═O or ═S; or A1 and A2 taken together with the carbon to which they are attached form a 5 to 8 membered heterocyclyl, of which one or two ring atoms are independently S, O or N;
B is S, or has the formula 1b:
wherein
D is N or CR10;
p is 0, 1, 2, 3, 4, or 5;
each of R7 and R8 is independently for each occurrence H, alkyl, alkenyl, alkynyl, aralkyl, aryl, cycloalkyl, heterocyclyl, cycloalkenyl, or heteroaryl; or R7 and R8 taken together form a 3-8 membered ring; or R7 and R8 taken together form a 4-8 membered ring;
R9 is H, heterocyclyl, heteroaryl, —OR10, —SR10, —N(R10)2, —N(R10)CO2R10, —N(R10)C(O)N(R10)2, —CO2R10, —OCO2R10, —OC(O)N(R10)2, —C(O)N(R10)2, halide, nitrile, nitro, or acylthio;
R1 has the formula 1c:
wherein
q is 0, 1, 2, 3, 4, or 5;
r is 0, 1, 2, 3, 4, or 5;
Ar1 is represented by formula 1d:
Wherein
s is 0, 1, 2, 3, or 4;
X2 is independently for each occurrence H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocyclyl, aralkyl, heteroaryl, heteroaralkyl, hydroxyl, acyloxy, nitrile, nitro, halide, OR11, —C(O)N(R10)(R11), —C(O)R11, —CO2R11, —S(O)2N(R10)(R11), SR11, —S(O)R11, —S(O)2OR11, —S(O)2R11, —C(═NR10)N(R10)(R11), or —C(═NR10)(R11); or has the formula 1a;
X3 is independently for each occurrence H, alkyl, alkynyl, aryl, cycloalkyl, heterocyclyl, aralkyl, heteroaryl, heteroaralkyl, hydroxyl, acyloxy, nitrile, nitro, halide, OR11, —C(O)N(R10)(R11), —C(O)R11, —S(O)2N(R10)(R11), SR11, —S(O)R11, —S(O)2OR11, —S(O)2R11, —C(═NR10)N(R10)(R11), or —C(═NR10)(R11); or has the formula 1a;
Ar2 is a monocyclic or bicyclic aryl with 6-14 ring atoms; or a monocyclic or bicyclic heteroaryl with 5-14 ring atoms, of which one, two or three ring atoms are independently S, O or N;
X1 is a bond, —C(R10)2—, —S—, —(NR10)—, or —O—;
R2 is H, a branched or unbranched alkyl or alkenyl, cycloalkyl, heterocyclyl, or bicycloalkyl; or has the formula 1a:
R3 is H, heterocyclyl, heteroaryl, —OR10, —SR10, —N(R10)2, —N(R10)CO2R10, —N(R10)C(O)N(R10)2, —CO2R10, —OCO2R10, —OC(O)N(R10)2, —C(O)N(R10)2, halide, nitrile, nitro, or acylthio;
each of R4, R5 and R10 independently for each occurrence is H, alkyl, alkenyl, alkynyl, aralkyl, aryl, cycloalkyl, cycloalkenyl, bicycloalkyl, heterocyclyl, or heteroaryl; or has the formula 1a; or
any two instances of R10 taken together form a 3-8 membered ring; or R4 and R5 taken together form a 3-8 membered ring;
R6 is H or alkyl;
R11 is independently for each occurrence H, alkyl, alkenyl, alkynyl, aralkyl, aryl, cycloalkyl, cycloalkenyl, bicycloalkyl, heterocyclyl, heteroaryl, or —[C(R12)(R13)]t—R14;
wherein
t is 0, 1, 2, 3, 4, or 5;
each of R12 and R13 is independently for each occurrence H, alkyl, aryl, aralkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroaralkyl; and
R14 is independently for each occurrence H, alkyl, aryl, heteroaryl, heterocyclylalkyl, alkoxy, amino, amido, or carboxyl.

### Claim 2 (depends on 1)

The compound of claim 1, wherein the compound has the structure 2:
wherein
Y is —C(R10)2—, —(C═O)—, or —(C═S)—;
X is —N(R10)—;
m is 0, 1, 2, or 3;
r is 0, 1, 2, 3, 4, or 5;
s is 0, 1, 2, 3, or 4;
A is —C(A1)(A2)-;
each of A1 and A2 is independently H, alkyl, aryl, cycloalkyl, aralkyl, heterocyclyl, heteroaryl, heteroaralkyl, —C(O)N(R10)2, —C(O)R10, —CO2R10, —S(O)2N(R10)2, —S(O)R10, —S(O)2OR10, or —S(O)2R10; or has the formula 2a:
wherein independently for each occurrence of 2a;
n is 1, 2, 3, 4, 5, or 6;
R15 is aryl, cycloalkyl, cycloalkenyl, heterocyclyl, heteroaryl, —OR10, —SR10, —N(R10)2, —N(R10)CO2R10, —N(R10)C(O)N(R10)2, —CO2R10, or —C(O)N(R10)2; or is a polycyclic ring containing 8-14 carbon atoms, of which one, two or three ring atoms are independently S, O or N;
or A1 and A2 taken together form ═O or ═S;
B is S or has the formula 2b:
wherein
D is N or CR10;
p is 0, 1, 2, or 3;
each of R7 and R8 is independently for each occurrence H, alkyl, alkenyl, alkynyl, aralkyl, aryl, cycloalkyl, heterocyclyl, cycloalkenyl, or heteroaryl; or R7 and R8 taken together form a 3-8 membered ring; or R7 and R8 taken together form a 4-8 membered ring;
R9 is H, heterocyclyl, heteroaryl, —OR10, —SR10, —N(R10)2, —N(R10)CO2R10, —N(R10)C(O)N(R10)2, —CO2R10, —OCO2R10, —OC(O)N(R10)2, —C(O)N(R10)2, halide, nitrile, nitro, or acylthio;
Ar2 is a monocyclic or bicyclic aryl with 6-10 ring atoms; or a monocyclic or bicyclic heteroaryl with 5-14 ring atoms, of which one, two or three ring atoms are independently S, O or N;
X2 is independently for each occurrence H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocyclyl, aralkyl, heteroaryl, heteroaralkyl, hydroxyl, acyloxy, nitrile, nitro, halide, OR11, —C(O)N(R10)(R11), —C(O)R11, —CO2R11, —S(O)2N(R10)(R11), SR11, —S(O)R11, —S(O)2OR11, —S(O)2R11, —C(═NR10)N(R10)(R11), or —C(═NR10)(R11); or has the formula 2a;
each of R4, R5 and R10 is independently for each occurrence H, alkyl, alkenyl, alkynyl, aralkyl, aryl, cycloalkyl, cycloalkenyl, bicycloalkyl, heterocyclyl, or heteroaryl; or has the formula 2a; or
any two instances of R10 taken together form a 3-8 membered ring; or R4 and R5 taken together form a 3-8 membered ring;
X3 is independently for each occurrence H, alkyl, —OR11, or halide; or has formula 2a;
each of R and R′ is independently for each occurrence H or alkyl;
R6 is H or alkyl;
R11 is independently for each occurrence H, alkyl, alkenyl, alkynyl, aralkyl, aryl, cycloalkyl, cycloalkenyl, bicycloalkyl, heterocyclyl, heteroaryl, or —[C(R12)(R13)]t—R14;
wherein
t is independently for each occurrence 0, 1, 2, 3, 4, or 5;
each of R12 and R13 is independently for each occurrence H, alkyl, aryl, aralkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroaralkyl; and
R14 is independently for each occurrence H, alkyl, aryl, heteroaryl, heterocyclylalkyl, alkoxy, amino, amido, or carboxyl.

### Claim 3 (depends on 2)

The compound of claim 2, wherein Ar2(X2)r is represented by the formula 3:
wherein
R18 is alkyl, alkenyl, halide, nitro, or amino;
each of R20 and R21 is independently H, alkyl, aralkyl, heteroaralkyl, alkoxy, or [C(R22)(R23)]t—R24;
t is independently for each occurrence 0, 1, 2, 3, 4, or 5;
each of R22 and R23 is independently for each occurrence H, alkyl, aryl, aralkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroaralkyl; and
R24 is independently for each occurrence H, alkyl, aryl, heteroaryl, heterocyclylalkyl, alkoxy, amino, amido, or carboxyl.

### Claim 4 (depends on 1)

The compound of claim 1, wherein the compound has the formula 4
wherein
Y is —C(R10)2—, —(C═O)—, or —(C═S)—;
X is —N(R10)—;
m is 0, 1, 2, 3, or 4;
s is 0, 1, 2, 3;
each of A1 and A2 is independently H, alkyl, aryl, cycloalkyl, aralkyl, heterocyclyl, heteroaryl, heteroaralkyl, —C(O)N(R10)2, —C(O)R10, —CO2R10, —S(O)2N(R10)2, —S(O)R10, —S(O)2OR10, or —S(O)2R10; or has the formula 4a:
wherein independently for each occurrence of 4a;
n is 1, 2, 3, 4, 5, or 6; and
R15 is aryl, cycloalkyl, cycloalkenyl, heterocyclyl, heteroaryl, —OR10, —SR10, —N(R10)2, —N(R10)CO2R10, —N(R10)C(O)N(R10)2, —CO2R10, or —C(O)N(R10)2; or is a polycyclic ring containing 8-14 carbon atoms, of which one, two or three ring atoms are independently S, O or N;
or A1 and A2 taken together form ═O or ═S;
B is S or has the formula 4b:
wherein
D is N or CR10;
p is 0, 1, 2, 3;
each of R7 and R8 is independently for each occurrence H, alkyl, alkenyl, alkynyl, aralkyl, aryl, cycloalkyl, heterocyclyl, cycloalkenyl, or heteroaryl; or R7 and R8 taken together form a 3-8 membered ring; or R7 and R8 taken together form a 4-8 membered ring;
R9 is H, heterocyclyl, heteroaryl, —OR10, —SR10, —N(R10)2, —N(R10)CO2R10, —N(R10)C(O)N(R10)2, —CO2R10, —OCO2R10, —OC(O)N(R10)2, —C(O)N(R10)2, halide, nitrile, nitro, or acylthio;
R6 is H or alkyl;
each of R12 and R13 is independently for each occurrence H, alkyl, aryl, aralkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroaralkyl;
R14 is independently for each occurrence H, alkyl, aryl, heteroaryl, heterocyclylalkyl, alkoxy, amino, amido, or carboxyl;
R16 is H, alkyl, alkenyl, or OR11; has the formula 4a;
each of X3 independently for each occurrence is H or halide;
R18 is alkyl, alkenyl, halide, nitro, or amino;
each of R20 and R21 is independently H, alkyl, aralkyl, heteroaralkyl, alkoxy, or —[C(R22)(R23)]t—R24;
t is independently for each occurrence 1, 2, 3, 4, or 5;
each of R22 and R23 is independently for each occurrence H, alkyl, aryl, aralkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroaralkyl; and
R24 is independently for each occurrence H, alkyl, aryl, heteroaryl, heterocyclylalkyl, alkoxy, amino, amido, or carboxyl.

### Claim 5 (depends on 4)

The compound of claim 4, wherein Y is —(C═O)— and X is —NH—.

### Claim 6 (depends on 4)

The compound of claim 4, wherein B has the formula 6a or 6b:
wherein
p is 0, 1, or 2;
each of R7 and R8 independently for each occurrence is H or alkyl; and
R9 is H, —OR10, —N(R10)2, —N(R10)CO2R10, —N(R10)C(O)N(R10)2, —OCO2R10, or —OC(O)N(R10)2.

### Claim 7 (depends on 4)

The compound of claim 4, wherein B is S.

### Claim 8 (depends on 4)

The compound of claim 4, wherein A1 and A2 taken together form ═O and B has the formula 8:
wherein
p is 0, 1 or 2;
each of R7 and R8 independently for each occurrence is H or alkyl; and
R9 is H, —OR10, —N(R10)2, —N(R10)CO2R10, —N(R10)C(O)N(R10)2, —OCO2R10, or —OC(O)N(R10)2.

### Claim 9 (depends on 8)

The compound of claim 8, wherein A1 and A2 are each H.

### Claim 10

A compound represented by formula 10:
or an unsaturated form thereof or a pharmaceutically acceptable salt thereof;
wherein
m represents independently for each occurrence 0, 1, 2, 3, 4, 5, or 6;
A is —C(A1)(A2)-;
each of A1 and A2 is independently H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, aralkyl, heterocyclyl, heteroaryl, heteroaralkyl, —C(O)N(R10)2, —C(O)R10, —CO2R10, —S(O)2N(R10)2, —S(O)R10, —S(O)2OR10, or —S(O)2R10; or has the formula 10a:
wherein independently for each occurrence of 10a;
n is 1, 2, 3, 4, 5, or 6; and
R15 is aryl, cycloalkyl, cycloalkenyl, heterocyclyl, heteroaryl, —OR10, —SR10, —N(R10)2, —N(R10)CO2R10, —N(R10)C(O)N(R10)2, —CO2R10, or —C(O)N(R10)2; or is a polycyclic ring containing 8-14 carbon atoms, of which one, two or three ring atoms are independently S, O or N;
or A1 and A2 taken together form ═O or ═S; or A1 and A2 taken together with the carbon to which they are attached form a 5 to 8 heterocyclyl, of which one or two ring atoms are independently S, O or N
B is S or has the formula 10b:
wherein
D is N or CR10;
p is 0, 1, 2, 3, 4, or 5;
each of R7 and R8 is independently for each occurrence H, alkyl, alkenyl, alkynyl, aralkyl, aryl, cycloalkyl, heterocyclyl, cycloalkenyl, or heteroaryl; or R7 and R8 taken together form a 3-8 membered ring; or R7 and R8 taken together form a 4-8 membered ring;
R9 is H, heterocyclyl, heteroaryl, —OR10, —SR10, —N(R10)2, —N(R10)CO2R10, —N(R10)C(O)N(R10)2, —CO2R10, —OCO2R10, —OC(O)N(R10)2, —C(O)N(R10)2, halide, nitrile, nitro, or acylthio;
R1 has the formula 10c or 10d:
wherein
q is 0, 1, 2, 3, 4, or 5;
r is 0, 1, 2, 3, 4, or 5;
W is a bond; or alkyl diradical, alkenyl diradical, or alkynyl diradical;
Z is H, —SR10, —S(O)2R11, —NR10S(O)2R11, —S(O)R10, —N(R10)(R11), —C(O)R11, —CO2R11, —C(O)N(R10)(R11), —C(S)N(R10)(R11), —CH2C(O)heterocyclyl, —NR10C(O)R11, —NR10CO2R11, —OC(O)N(R10)(R11), —NC(O)CH(R10)(R11), —C(═NR10)N(R10)(R11), —C(═NR10)R11, hydroxyalkyl, monocyclic aryl, bicyclic aryl, heteroaryl, or heterocyclyl;
Ar1 is represented by formula 10e:
Wherein
s is 0, 1, 2, 3, or 4;
each of X2 and X3 is independently for each occurrence H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocyclyl, aralkyl, heteroaryl, heteroaralkyl, hydroxyl, acyloxy, nitrile, nitro, halide, OR11, —C(O)N(R10)(R11), —C(O)R11, —CO2R11, —S(O)2N(R10)(R11), SR11, —S(O)R11, —S(O)2OR11, —S(O)2R11, —C(═NR10)N(R10)(R11), or —C(═NR10)(R11); or has the formula 10a;
Ar2 represent independently for each occurrence are monocyclic or bicyclic aryl with 6-14 ring atoms; or a monocyclic or bicyclic heteroaryl with 5-14 ring atoms, of which one, two or three ring atoms are independently S, O or N;
X1 is a bond, —C(R10)2—, —S—, —N(R10)— or —O—;
R2 is H, a branched or unbranched alkyl or alkenyl, cycloalkyl, heterocyclyl, or bicycloalkyl; or has the formula 10a:
R3 is H, heterocyclyl, heteroaryl, —OR10, —SR10, —N(R10)2, —N(R10)CO2R10, —N(R10)C(O)N(R10)2, —CO2R10, —OCO2R10, —OC(O)N(R10)2, —C(O)N(R10)2, halide, nitrile, nitro, or acylthio;
each of R4, R5 and R10 is independently for each occurrence H, alkyl, alkenyl, alkynyl, aralkyl, aryl, cycloalkyl, cycloalkenyl, bicycloalkyl, heterocyclyl, or heteroaryl; or has the formula 10a;
or any two instances of R10 taken together form a 3-8 membered ring; or R4 and R5 taken together form a 3-8 membered ring;
R6 is H or alkyl;
R11 is independently for each occurrence H, alkyl, alkenyl, alkynyl, aralkyl, aryl, cycloalkyl, cycloalkenyl, bicycloalkyl, heterocyclyl, heteroaryl, or —[C(R12)(R13)]t—R14;
wherein
t is 0, 1, 2, 3, 4, or 5;
each of R12 and R13 is independently for each occurrence H, alkyl, aryl, aralkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroaralkyl; and
R14 is independently for each occurrence H, alkyl, aryl, heteroaryl, heterocyclylalkyl, alkoxy, amino, amido, or carboxyl.

### Claim 11 (depends on 10)

The compound of claim 10, wherein R1 has the formula 11:
wherein
s is 0, 1, 2, 3, or 4;
each of X3 is independently for each occurrence H or halide;
each of R18 and R19 is independently H, alkyl, alkenyl, alkynyl, aralkyl, aryl, cycloalkyl, cycloalkenyl, bicycloalkyl, heterocyclyl, heteroaryl, or —[C(R12)(R13)]t—R14;
wherein
t is 0, 1, 2, 3, 4, or 5;
each of R12 and R13 is independently for each occurrence H, alkyl, aryl, aralkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroaralkyl; and
R14 is independently for each occurrence H, alkyl, aryl, heteroaryl, heterocyclylalkyl, alkoxy, amino, amido, or carboxyl.

### Claim 12 (depends on 10)

The compound of claim 10, wherein B has the formula 12a or 12b:
wherein
p is 0, 1, 2, 3, or 4;
each of R7 and R8 is independently for each occurrence H or alkyl; and
R9 is H, —OR10, —N(R10)2, —N(R10)CO2R10, —N(R10)C(O)N(R10)2, —OCO2R10, or —OC(O)N(R10)2.

### Claim 13 (depends on 10)

The compound of claim 10, wherein A is —C(A1)(A2)-; A1 and A2 taken together form ═O and B has the formula 13:
wherein
p is 0, 1, 2, 3, or 4;
each of R7 and R8 independently for each occurrence is H or alkyl; and
R9 is H, —OR10, —N(R10)2, —N(R10)CO2R10, —N(R10)C(O)N(R10)2, —OCO2R10, or —OC(O)N(R10)2.

### Claim 14

A compound represented by formula 14:
or an unsaturated form thereof or a pharmaceutically acceptable salt thereof;
wherein
Y is —C(R10)2—, —(C═O)—, —(C═S)—, or —C(═NR10)—;
X is —N(R10)—, or a bond;
m represents independently for each occurrence 0, 1, 2, 3, 4, 5, or 6;
A is —C(A1)(A2)-;
each of A1 and A2 is independently for each occurrence H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, aralkyl, heterocyclyl, heteroaryl, heteroaralkyl, —C(O)N(R10)2, —C(O)R10, —CO2R10, —S(O)2N(R10)2, —S(O)R10, —S(O)2OR10, —S(O)2R10; or has the formula 14a:
wherein independently for each occurrence of 14a;
n is 1, 2, 3, 4, 5, or 6; and
R15 is aryl, cycloalkyl, cycloalkenyl, heterocyclyl, heteroaryl, —OR10, —SR10, —N(R10)2, —N(R10)CO2R10, —N(R10)C(O)N(R10)2, —CO2R10, or —C(O)N(R10)2; or is a polycyclic ring containing 8-14 carbon atoms, of which one, two or three ring atoms are independently S, O or N;
or A1 and A2 taken together form ═O or ═S; or A1 and A2 taken together with the carbon to which they are attached form a 5 to 8 heterocyclyl, of which one or two ring atoms are independently S, O or N;
B is —(C(R)2X)—, —(XC(R)2)—, or —(C(R2)2—;
X independently for each occurrence is S or —(NR10)—;
R independently for each occurrence is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, aralkyl, heterocyclyl, heteroaryl, or heteroaralkyl; or has formula 14a;
R1 has the formula 14b:
wherein
q is 0, 1, 2, 3, 4, or 5;
r is 0, 1, 2, 3, 4, or 5;
Ar1 is represented by formula 14c:
Wherein
s is 0, 1, 2, 3, or 4;
X2 is independently for each occurrence H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocyclyl, aralkyl, heteroaryl, heteroaralkyl, hydroxyl, acyloxy, nitrile, nitro, halide, —OR11, —C(O)N(R10)(R11), —C(O)R11, —CO2R11, —S(O)2N(R10)(R11), —SR11, —S(O)R11, —S(O)2OR11, —S(O)2R11, —C(═NR10)N(R10)(R11), or —C(═NR10)(R11); or has the formula 14a;
X3 is independently for each occurrence H, alkyl, alkynyl, aryl, cycloalkyl, heterocyclyl, aralkyl, heteroaryl, heteroaralkyl, hydroxyl, acyloxy, nitrile, nitro, halide, —OR11, —C(O)N(R10)(R11), —C(O)R11, —S(O)2N(R10)(R11), —SR11, —S(O)R11, —S(O)2OR11, —S(O)2R11, —C(═NR10)N(R10)(R11), or —C(═NR10)(R11); or has the formula 14a;
Ar2 represent independently for each occurrence are monocyclic or bicyclic aryl with 6-14 ring atoms; or a monocyclic or bicyclic heteroaryl with 5-14 ring atoms, of which one, two or three ring atoms are independently S, O or N;
X1 is a bond, —(C(R10)2)—, —S—, —(NR10)—, or —O—;
R2 is H, a branched or unbranched alkyl or alkenyl, cycloalkyl, heterocyclyl, or bicycloalkyl; or has the formula 14a:
R3 is H, heterocyclyl, heteroaryl, —OR10, —SR10, —N(R10)2, —N(R10)CO2R10, —N(R10)C(O)N(R10)2, —CO2R10, —OCO2R10, —OC(O)N(R10)2, —C(O)N(R10)2, halide, nitrile, nitro, or acylthio;
each of R4, R5 and R10 is independently for each occurrence H, alkyl, alkenyl, alkynyl, aralkyl, aryl, cycloalkyl, cycloalkenyl, bicycloalkyl, heterocyclyl, or heteroaryl; or has the formula 14a;
or any two instances of R10 taken together form a 3-8 membered ring; or R4 and R5 taken together form a 3-8 membered ring;
R6 is H or alkyl;
R11 independently for each occurrence is H, alkyl, alkenyl, alkynyl, aralkyl, aryl, cycloalkyl, cycloalkenyl, bicycloalkyl, heterocyclyl, heteroaryl, or —[C(R12)(R13)]t—R14;
wherein
t is 0, 1, 2, 3, 4, or 5;
each of R12 and R13 is independently for each occurrence H, alkyl, aryl, aralkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroaralkyl; and
R14 is independently for each occurrence H, alkyl, aryl, heteroaryl, heterocyclylalkyl, alkoxy, amino, amido, or carboxyl.

### Claim 15 (depends on 14)

The compound of claim 14, wherein the compound has the formula 15:

### Claim 16 (depends on 14)

The compound of claim 14, wherein the compound has the formula 16:

### Claim 17

A compound selected from the group consisting of:

### Claim 18 (depends on 1, 10, 14)

A pharmaceutical composition, comprising a compound of claim 1, 10, 14, or 17; and at least one pharmaceutically acceptable excipient.