Glucosylceramide synthase inhibition for the treatment of collapsing glomerulopathy and other glomerular disease

• US 8,389,517 B2
• Filed: 07/27/2009
• Issued: 03/05/2013
• Est. Priority Date: 07/28/2008
• Status: Active Grant

• Current Assignee: Genzyme Corporation (Sanofi )
• Original Assignee: Genzyme Corporation (Sanofi )
• Inventors: Ibraghimov-Beskrovnaya, Oxana, Natoli, Thomas A.
• Primary Examiner(s): HENLEY III, RAYMOND J
• Application Number:
  US13/055,036
• Publication Number:
  US 20110166134A1
• Time in Patent Office: 1,317 Days
• Field of Search: 514/233.8, 514/321, 514/365, 514/422
• US Class Current: 514/233.8
• CPC Class Codes: A61K 31/325 Carbamic acids; Thiocarbamic acids; Anhydrides or salts thereof thiurams A61K31/145
• CPC Class Codes: A61K 31/357 having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
• CPC Class Codes: A61K 31/396 having three-membered rings, e.g. aziridine
• CPC Class Codes: A61K 31/40 having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
• CPC Class Codes: A61K 31/4025 not condensed and containing further heterocyclic rings, e.g. cromakalim
• CPC Class Codes: A61K 31/403 condensed with carbocyclic rings, e.g. carbazole
• CPC Class Codes: A61K 31/4155 non condensed and containing further heterocyclic rings
• CPC Class Codes: A61K 31/4178 not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
• CPC Class Codes: A61K 31/4192 1,2,3-Triazoles
• CPC Class Codes: A61K 31/4245 Oxadiazoles
• CPC Class Codes: A61K 31/427 not condensed and containing further heterocyclic rings
• CPC Class Codes: A61K 31/428 condensed with carbocyclic rings
• CPC Class Codes: A61K 31/4433 containing a six-membered ring with oxygen as a ring hetero atom
• CPC Class Codes: A61K 31/4439 containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole nicotine A61K31/465
• CPC Class Codes: A61K 31/453 containing a six-membered ring with oxygen as a ring hetero atom
• CPC Class Codes: A61K 31/4725 containing further heterocyclic rings
• CPC Class Codes: A61K 31/5377 not condensed and containing further heterocyclic rings, e.g. timolol
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: C07D 207/06 with radicals, containing only hydrogen and carbon atoms, attached to ring carbon atoms
• CPC Class Codes: C07D 319/16 : condensed with one six-membered ring
• CPC Class Codes: C07D 319/18 : Ethylenedioxybenzenes, not substituted on the hetero ring
• CPC Class Codes: C07D 405/06 : linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 405/10 : linked by a carbon chain containing aromatic rings
• CPC Class Codes: C07D 405/14 : containing three or more hetero rings
• CPC Class Codes: C07D 409/14 : containing three or more hetero rings
• CPC Class Codes: C07D 413/14 : containing three or more hetero rings
• CPC Class Codes: C07D 417/14 : containing three or more hetero rings

Abstract

A method of treating a glomerular disease selected from the group consisting of mesangial proliferative glomerulonephritis, collapsing glomerulopathy, proliferative lupus nephritis, crescentic glomerulonephritis and membranous nephropathy in a subject comprises administering to the subject an effective amount of a glucosylceramide synthase inhibitor.

Claims

1. A method of treating a glomerular disease selected from the group consisting of mesangial proliferative glomerulonephritis, collapsing glomerulopathy, proliferative lupus nephritis, crescentic glomerulonephritis and membranous nephropathy in a subject, comprising administering to the subject an effective amount of a glucosylceramide synthase inhibitor.

2. The method of claim 1, wherein the glucosylceramide synthase inhibitor is represented by the following structural formula:

3. The method of claim 2, wherein

R¹ is an aryl group optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, haloalkyl, Ar¹, —

OR³⁰, —

O(haloalkyl), —

NO₂, —

CN, —

NCS, —

N(R³¹)₂, —

NR³¹C(O)R³⁰, —

NR³¹C(O)OR³², —

N(R³¹)C(O)N(R³¹)₂, —

C(O)R³⁰, —

C(S)R³⁰, —

C(O)OR³⁰, —

OC(O)R³⁰, —

C(O)N(R³¹)₂, —

S(O)₂R³⁰, —

SO₂N(R³¹)₂, —

S(O)R³², —

SO₃R³⁰, —

NR³¹SO₂N(R³¹)₂, —

NR³¹SO₂R³², —

V_o—

Ar¹, —

V_o—

OR³⁰, —

V_o—

O(haloalkyl), —

V_o—

SR³⁰, —

V_o—

NO₂, —

V_o—

CN, —

V_o—

N(R³¹)₂, —

V_o—

NR³¹C(O)R³⁰, —

V_o—

NR³¹CO₂R³², —

V_o—

N(R³¹)C(O)N(R³¹)₂, —

V_o—

C(O)R³⁰, —

V_o—

C(S)R³⁰, —

V_o—

CO₂R³⁰, —

V_o—

OC(O)R³⁰, —

V_o—

C(O)N(R³¹)₂—

, —

V_o—

S(O)₂R³⁰, —

V_o—

SO₂N(R³¹)₂, —

V_o—

S(O)R³², —

V_o—

SO₃R³⁰, —

V_o—

NR³¹SO₂N(R³¹)₂, —

V_o—

NR³¹SO₂R³², —

O—

V_o—

Ar¹, —

O—

V₁—

N(R³¹)₂, —

S—

V_o—

Ar¹, —

S—

V₁—

N(R³¹)₂, —

N(R³¹)—

V_o—

Ar¹, —

N(R³¹)—

V₁—

N(R³¹)₂, —

NR³¹C(O)—

V_o—

N(R³¹)₂, —

NR³¹C(O)—

V_o—

Ar¹, —

C(O)—

V_o—

N(R³¹)₂, —

C(O)—

V_o—

Ar¹, —

C(S)—

V_o—

N(R³¹)₂, —

C(S)—

V_o—

Ar¹, —

C(O)O—

V₁—

N(R³¹)₂, —

C(O)O—

V_o—

Ar¹, —

O—

C(O)—

V₁—

N(R³¹)₂, —

O—

C(O)—

V_o—

Ar¹, —

C(O)N(R³¹)—

V₁—

N(R³¹)₂, —

C(O)N(R³¹)—

V_o—

Ar¹, —

S(O)₂—

V_o—

N(R³¹)₂, —

S(O)₂—

V_o—

Ar¹, —

SO₂N(R³¹)—

V₁—

N(R³¹)₂, —

SO₂N(R³¹)—

V_o—

Ar¹, —

S(O)—

V_o—

N(R³¹)₂, —

S(O)—

V_o—

Ar¹, —

S(O)₂—

O—

V₁—

N(R³¹)₂, —

S(O)₂—

O—

V_o—

Ar¹, —

NR³¹SO₂—

V_o—

N(R³¹)₂, —

NR³¹SO₂—

V_o—

Ar¹, —

O—

[CH₂]_p—

O—

, —

S—

[CH₂]_p—

S— and

—

[CH₂]_q—

;

each V_o is independently a C1-C10 alkylene group;

each V₁ is independently a C2-C10 alkylene group;

Ar¹ is an aryl group each optionally and independently substituted with one or more substituents selected from the group consisting of halogen, alkyl, amino, alkylamino, dialkylamino, alkoxy, nitro, cyano, hydroxy, haloalkoxy, alkoxycarbonyl, alkylcarbonyl and haloalkyl; and

each R³⁰ is independently

i) hydrogen;

ii) an aryl group optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, amino, alkylamino, dialkylamino, alkoxy, nitro, cyano, hydroxy, haloalkoxy, alkoxycarbonyl, alkylcarbonyl and haloalkyl;

or

iii) an alkyl group optionally substituted with one or more substituents selected from the group consisting of halogen, amino, alkylamino, dialkylamino, alkoxy, nitro, cyano, hydroxy, haloalkoxy, alkoxycarbonyl, alkylcarbonyl and haloalkyl; and

each R³¹ is independently R³⁰, —

CO₂R³⁰, —

SO₂R³⁰ or —

C(O)R³⁰;

or —

N(R³¹)₂ taken together is an optionally substituted non-aromatic heterocyclic group; and

each R³² is independently;

i) an aryl group optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, amino, alkylamino, dialkylamino, alkoxy, nitro, cyano, hydroxy, haloalkoxy, alkylcarbonyl and haloalkoxy and haloalkyl;

or

ii) an alkyl group optionally substituted with one or more substituents selected from the group consisting of halogen, amino, alkylamino, dialkylamino, alkoxy, nitro, cyano, hydroxy, haloalkoxy, alkylcarbonyl and haloalkoxy and haloalkyl; and

each p is independently 1, 2, 3 or 4; and

each q is independently 3, 4, 5 or 6.

4. The method of claim 3, wherein:

Y is —

H, —

C(O)R, —

C(O)OR or —

C(O)NRR′

; and

R and R′

are each independently —

H;

a lower aliphatic group optionally substituted with one or more substituents selected from the group consisting of halogen, —

OH, —

CN, —

NCS, —

NO₂, —

NH₂, lower alkoxy, lower haloalkoxy and aryl;

or an aryl group optionally substituted with one or more substituents selected from the group consisting of halogen, —

OH, —

CN, —

NCS, —

NO₂, —

NH₂, lower alkoxy, lower haloalkoxy, lower aliphatic group and lower haloaliphatic group;

or

R and R′

taken together with the nitrogen atom of NRR′

form a non-aromatic heterocyclic ring optionally substituted with one or more substituents selected from the group consisting of;

halogen;

—

OH;

—

CN;

—

NCS;

—

NO₂;

—

NH₂;

lower alkoxy;

lower haloalkoxy;

lower aliphatic group optionally substituted with one or more substituents selected from the group consisting of halogen, —

OH, —

CN, —

NCS, —

NO₂, —

NH₂, lower alkoxy, lower haloalkoxy and aryl; and

aryl group optionally substituted with one or more substituents selected from the group consisting of halogen, —

OH, —

CN, —

NCS, —

NO₂, —

NH₂, lower alkoxy, lower haloalkoxy, lower aliphatic group and lower haloaliphatic group.

5. The method of claim 4, wherein:

—

N(R²R³) is a 5- or 6-membered non-aromatic nitrogen-containing heterocyclic group or a bridged heterobicyclic ring comprising 6 or 7 ring carbon atoms and 1 or 2 ring nitrogen atoms, each optionally and independently substituted with one or more substituents selected from the group consisting of halogen, alkyl, haloalkyl, —

OR⁴⁰, —

O(haloalkyl), —

SR⁴⁰, —

NO₂, —

CN, —

N(R⁴¹)₂, —

NR⁴¹C(O)R⁴⁰, —

NR⁴¹C(O)OR⁴², —

N(R⁴¹)C(O)N(R⁴¹)₂, —

C(O)R⁴⁰, —

C(S)R⁴⁰, —

C(O)OR⁴⁰, —

OC(O)R⁴⁰, —

C(O)N(R⁴¹)₂, —

S(O)₂R⁴⁰, —

SO₂N(R⁴¹)₂, —

S(O)R⁴², —

SO₃R⁴⁰, Ar², V₂—

Ar², —

V₂—

OR⁴⁰, —

V₂—

O(haloalkyl), —

V₂—

SR⁴⁰, —

V₂—

NO₂, —

V₂—

CN, —

V₂—

N(R⁴¹)₂, —

V₂—

NR⁴¹C(O)R⁴⁰, —

V₂—

NR⁴¹CO₂R⁴², V₂—

N(R⁴¹)C(O)N(R⁴¹)₂, —

V₂—

C(O)R⁴⁰, —

V₂—

C(S)R⁴⁰, —

V₂—

CO₂R⁴⁰, —

V₂—

OC(O)R⁴⁰, —

V₂—

C(O)N(R⁴¹)₂—

, —

V₂—

S(O)₂R⁴⁰, —

V₂—

SO₂N(R⁴¹)₂, —

V₂—

S(O)R⁴², —

V₂—

SO₃R⁴⁰, —

O—

V₂—

Ar² and —

S—

V₂—

Ar²;

each V₂ is independently a C1-C4 alkylene group;

Ar² is an aryl group each optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6 alkyl, amino, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl and C1-C6 haloalkyl; and

each R⁴⁰ is independently

i) hydrogen;

ii) an aryl group optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6 alkyl, amino, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl and C1-C6 haloalkyl;

or

iii) an C1-C10 alkyl group optionally substituted with one or more substituents selected from the group consisting of halogen, amino, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl and C1-C6 haloalkyl; and

each R⁴¹ is independently R⁴⁰, —

CO₂R⁴⁰, —

SO₂R⁴⁰ or —

C(O)R⁴⁰;

or

—

N(R⁴¹)₂ taken together is an optionally substituted non-aromatic heterocyclic group; and

each R⁴² is independently;

i) an aryl group optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6 alkyl, amino, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl and C1-C6 haloalkyl;

or

ii) an C1-C10 alkyl group optionally substituted with one or more substituents selected from the group consisting of halogen, amino, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl and C1-C6 haloalkyl.

6. The method of claim 5, wherein R⁵ and R⁶ are each independently —

H;

—

OH;

a halogen;

or a lower alkoxy or lower alkyl group.

7. The method of claim 6, wherein Y is —

H.

8. The method of claim 7, wherein:

R⁴ is an aliphatic or aryl group each optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, haloalkyl, Ar³, Ar³—

Ar³, —

OR⁵⁰, —

O(haloalkyl), —

SR⁵⁰, —

NO₂, —

CN, —

NCS, —

N(R⁵¹)₂, —

NR⁵¹C(O)R⁵⁰, —

NR⁵¹C(O)OR⁵², —

N(R⁵¹)C(O)N(R⁵¹)₂, —

C(O)R⁵⁰, —

C(S)R⁵⁰, —

C(O)OR⁵⁰, —

OC(O)R⁵⁰, —

C(O)N(R⁵¹)₂, —

S(O)₂R⁵⁰, —

SO₂N(R⁵¹)₂, —

S(O)R⁵², —

SO₃R⁵⁰, —

NR⁵¹SO₂N(R⁵¹)₂, —

NR⁵¹SO₂R⁵², —

V₄—

Ar³, —

V—

OR⁵⁰, —

V₄—

O(haloalkyl), —

V₄—

SR⁵⁰, —

V₄—

NO₂, —

V₄—

CN, —

V₄—

N(R⁵¹)₂, —

V₄—

NR⁵¹C(O)R⁵⁰, —

V₄—

NR⁵¹CO₂R⁵², —

V₄—

N(R⁵¹)C(O)N(R⁵¹)₂, —

V₄—

C(O)R⁵⁰, —

V₄—

C(S)R⁵⁰, —

V₄—

CO₂R⁵⁰, —

V₄—

OC(O)R⁵⁰, —

V₄—

C(O)N(R⁵¹)₂—

, —

V₄—

S(O)₂R⁵⁰, —

V₄—

SO₂N(R⁵¹)₂, —

V₄—

S(O)R⁵², —

V₄—

SO₃R⁵⁰, —

V₄—

NR⁵¹SO₂N(R⁵¹)₂, —

V₄—

NR⁵¹SO₂R⁵², —

O—

V₄—

Ar³, —

O—

V₅—

N(R⁵¹)₂, —

S—

V₄—

Ar³, —

S—

V₅—

N(R⁵¹)₂, —

N(R⁵¹)—

V₄—

Ar³, —

N(R⁵¹)—

V₅—

N(R⁵¹)₂, —

NR⁵¹C(O)—

V₄—

N(R⁵¹)₂, —

NR⁵¹C(O)—

V₄—

Ar³, —

C(O)—

V₄—

N(R⁵¹)₂, —

C(O)—

V₄—

Ar³, —

C(S)—

V₄—

N(R⁵¹)₂, —

C(S)—

V₄—

Ar³, —

C(O)O—

V₅—

N(R⁵¹)₂, —

C(O)O—

V₄—

Ar³, —

O—

C(O)—

V₅—

N(R⁵¹)₂, —

O—

C(O)—

V₄—

Ar³, —

C(O)N(R⁵¹)—

V₅—

N(R⁵¹)₂, —

C(O)N(R⁵¹)—

V₄—

Ar³, —

S(O)₂—

V₄—

N(R⁵¹)₂, —

S(O)₂—

V₄—

Ar³, —

SO₂N(R⁵¹)—

V₅—

N(R⁵¹)₂, —

SO₂N(R⁵¹)—

V₄—

Ar³, —

S(O)—

V₄—

N(R⁵¹)₂, —

S(O)—

V₄—

Ar³, —

S(O)₂—

O—

V₅—

N(R⁵¹)₂, —

S(O)₂—

O—

V₄—

Ar³, —

NR⁵¹SO₂—

V₄—

N(R⁵¹)₂, —

NR⁵¹SO₂—

V₄—

Ar³, —

O—

[CH₂]_p′

—

O—

, —

S—

[CH₂]_p′

—

S—

, and —

[CH₂]_q′

—

;

each V₄ is independently a C1-C10 alkylene group;

each V₅ is independently a C2-C10 alkylene group;

each Ar³ is independently an aryl group each optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, amino, alkylamino, dialkylamino, alkoxy, nitro, cyano, hydroxy, haloalkoxy and haloalkyl; and

each R⁵⁰ is independently

i) hydrogen;

ii) an aryl group optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, amino, alkylamino, dialkylamino, alkoxy, nitro, cyano, hydroxy, haloalkoxy, alkoxycarbonyl, alkylcarbonyl and haloalkyl;

or

iii) an alkyl group optionally substituted with one or more substituents selected from the group consisting of halogen, amino, alkylamino, dialkylamino, alkoxy, nitro, cyano, hydroxy, haloalkoxy, alkoxycarbonyl, alkylcarbonyl and haloalkyl; and

each R⁵¹ is independently R⁵⁰, —

CO₂R⁵⁰, —

SO₂R⁵⁰ or —

C(O)R⁵⁰;

or

—

N(R⁵¹)₂ taken together is an optionally substituted non-aromatic heterocyclic group; and

each R⁵² is independently;

i) an aryl group optionally substituted with one or two substituents selected from the group consisting of halogen, alkyl, amino, alkylamino, dialkylamino, alkoxy, nitro, cyano, hydroxy, haloalkoxy, alkoxycarbonyl, alkylcarbonyl and haloalkyl;

or

ii) an alkyl group optionally substituted with one or more substituents selected from the group consisting of halogen, amino, alkylamino, dialkylamino, alkoxy, nitro, cyano, hydroxy, haloalkoxy, alkoxycarbonyl, alkylcarbonyl and haloalkyl; and

each p′

is 1, 2, 3 or 4; and

each q′

is 3, 4, 5 or 6.

9. The method of claim 2, wherein the compound is represented by the following structural formula:

10. The method of claim 9, wherein:

R¹ is a phenyl group optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, nitro, C1-C6 alkyl, C1-C6 haloalkyl, —

OR³⁰, —

SR³⁰, —

N(R³¹)₂, Ar¹, —

V_o—

-OR³⁰, —

V_o—

N(R³¹)₂, —

V_o—

Ar¹, —

O—

V_o—

Ar¹, —

O—

V₁—

N(R³¹)₂, —

S—

V_o—

Ar¹, —

S—

V₁—

N(R³¹)₂, —

N(R³¹)—

V_o—

Ar¹, —

N(R³¹)—

V₁—

N(R³¹)₂, —

O—

[CH₂]_p—

O—

, —

S—

[CH₂]_p—

S—

, and —

[CH₂]_q—

;

Ar¹ is a phenyl group each optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6 alkyl, amino, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl and C1-C6 haloalkyl; and

each R³⁰ is independently

i) hydrogen;

ii) a phenyl group optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6 alkyl, amino, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl and C1-C6 haloalkyl;

or

iii) an C1-C10 alkyl group optionally substituted with one or more substituents selected from the group consisting of halogen, amino, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl and C1-C6 haloalkyl; and

each R³¹ is independently R³⁰, or —

N(R³¹)₂ is an optionally substituted non-aromatic heterocyclic group.

11. The method of claim 10, wherein:

—

N(R²R³) is;

i) a pyrrolidinyl, azetidinyl, piperidinyl, piperazinyl, azepinyl or morpholinyl group optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 haloalkyl, hydroxyl, C1-C6 alkoxy, nitro, cyano, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl or C1-C6 haloalkoxy, amino, C1-C6 alkylamino and C1-C6 dialkylamino;

or

ii)

12. The method of claim 11, wherein R⁴ is an optionally substituted aryl group or an optionally substituted lower arylalkyl group.

13. The method of claim 12, wherein Q is —

O—

, —

S—

, —

C(O)—

, —

C(S)—

, —

NR⁷(CO)—

or —

C(O)NR⁷—

.

14. The method of claim 2, wherein the compound is represented by the following structural formula:

15. The method of claim 14, wherein:

R¹ is a phenyl group optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, nitro, C1-C6 alkyl, C1-C6 haloalkyl, —

OR³⁰, —

SR³⁰, —

N(R³¹)₂, Ar¹, —

V_o—

OR³⁰, —

V_o—

N(R³¹)₂, —

V_o—

Ar¹, —

O—

V_o—

Ar¹, —

O—

V₁—

N(R³¹)₂, —

S—

V_o—

Ar¹, —

S—

V₁—

N(R³¹)₂, —

N(R³¹)—

V_o—

Ar¹, —

N(R³¹)—

V₁—

N(R³¹)₂, —

O—

[CH₂]_p—

O—

, —

S—

[CH₂]_p—

S—

, and —

[CH₂]_q—

;

Ar¹ is a phenyl group each optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6 alkyl, amino, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl and C1-C6 haloalkyl; and

each R³⁰ is independently

i) hydrogen;

ii) a phenyl group optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6 alkyl, amino, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl and C1-C6 haloalkyl;

or

iii) an C1-C10 alkyl group optionally substituted with one or more substituents selected from the group consisting of halogen, amino, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl and C1-C6 haloalkyl; and

each R³¹ is independently R³⁰, or —

N(R³¹)₂ is an optionally substituted non-aromatic heterocyclic group.

16. The method of claim 15, wherein:

—

N(R²R³) is a pyrrolidinyl, azetidinyl, piperidinyl, piperazinyl, azepinyl or morpholinyl group or

17. The method of claim 16, wherein R⁴ is an optionally substituted aryl group or an optionally substituted lower alkyl group.

18. The method of claim 17, wherein:

R⁴ is an aryl or a lower arylalkyl group each optionally and independently substituted with one or more substituents selected from the group consisting of halogen, C1-C10 alkyl, C1-C10 haloalkyl, Ar³, Ar³—

Ar³, —

OR⁵⁰, —

O(haloalkyl), —

SR⁵⁰, —

NO₂, —

CN, —

N(R⁵¹)₂, —

NR⁵¹C(O)R⁵⁰, —

C(O)R⁵⁰, —

C(O)OR⁵⁰, —

OC(O)R⁵⁰, —

C(O)N(R⁵¹)₂, —

V₄—

Ar³, —

V—

OR⁵⁰, —

V₄—

O(haloalkyl), —

V₄—

SR⁵⁰, —

V₄—

NO₂, —

V₄—

CN, —

V₄—

N(R⁵¹)₂, —

V₄—

NR⁵¹C(O)R⁵⁰, —

V₄—

C(O)R⁵⁰, —

V₄—

CO₂R⁵⁰, —

V₄—

OC(O)R⁵⁰, —

V₄—

C(O)N(R⁵¹)₂—

, —

O—

V₄—

Ar³, —

O—

V₅—

N(R⁵¹)₂, —

S—

V₄—

Ar³, —

S—

V₅—

N(R⁵¹)₂, —

N(R⁵¹)—

V₄—

Ar³, —

N(R⁵¹)—

V₅—

N(R⁵¹)₂, —

NR⁵¹C(O)—

V₄—

N(R⁵¹)₂, —

NR⁵¹C(O)—

V₄—

Ar³, —

C(O)—

V₄—

N(R⁵¹)₂, —

C(O)—

V₄—

Ar³, —

C(O)O—

V₅—

N(R⁵¹)₂, —

C(O)O—

V₄—

Ar³, —

O—

C(O)—

V₅—

N(R⁵¹)₂, —

O—

C(O)—

V₄—

Ar³, —

C(O)N(R⁵¹)—

V₅—

N(R⁵¹)₂, —

C(O)N(R⁵¹)—

V₄—

Ar³, —

O—

[CH₂]_p′

—

O— and

—

[CH₂]_q′

—

.

19. The method of claim 18, wherein n is 1, 2, 3 or 4.

20. The method of claim 19, wherein the compound is represented by the following structural formula:

21. The method of claim 20, wherein R⁴ is selected from the group consisting of:

22. The method of claim 21, wherein the compound is represented by the following structural formula: