HK1127342B - Substituted imidazole derivatives and there use as ptpase inhibitors - Google Patents

Description

Substituted imidazole derivatives as PTPase inhibitors, compositions and methods of use

Statement of related application

This application claims the benefit of priority of U.S. provisional application No. US 60/763,256 entitled "scientific and Compositions and Methods of Use" filed 2006, 1, 30, § 119(e), entitled "temporary di midzole Derivatives". The disclosure of U.S. provisional application No. US 60/763,256 is incorporated herein by reference in its entirety.

Technical Field

The present invention relates to substituted imidazole derivatives, compositions and methods of treatment using these compounds and compositions that may be used in the treatment, therapy, control or adjunct treatment of diseases caused by the activity of protein phosphatases.

Background

Protein phosphorylation is currently considered to be critical for the fundamental process of cell signaling. Changes in protein phosphorylation may thus constitute physiological or pathological changes in the in vivo system. Phosphatase-mediated protein dephosphorylation is also critical for certain signal transduction processes.

Two main types of phosphatases are: (a) protein serine/threonine phosphatases (pstpases) which catalyze the dephosphorylation of serine and/or threonine on proteins or peptides; and (b) protein tyrosine phosphatases (PTPases), which catalyze the dephosphorylation of tyrosine residues on proteins and/or peptides. The third class of phosphatases are dual specificity phosphatases or DSP's, which have the ability to function as both ptpases and pstpases.

There are two important families in PTPases, intracellular PTPases and transmembrane PTPases. Intracellular PTPases include PTP1B, STEP, PTPD1, PTPD2, PTPMEG1, T-cell PTPases, PTPH1, FAP-1/BAS, PTP1D and PTP 1C. Transmembrane PTPases include LAR, CD45, PTP α, PTP β, PTP δ, PTP ε, PTP ζ, PTP κ, PTP μ, PTP σ, HePTP, SAP-1 and PTP-U2. Dual-specific phosphatases include KAP, cdc25, MAPK phosphatase, PAC-1 and rVH 6.

PTPases, especially PTP1B, are implicated in the insulin insensitivity profile of type II diabetes mellitus (Kennedy, B.P.; Ramachandran, C.biochem. Pharm.2000, 60, 877-. PTPases, particularly CD45 and HePTP, are also involved in immune system function and particularly T-cell function. Certain PTPases, particularly TC-PTP, DEP-1, SAP-1, and CDC25, are also implicated in certain cancers. Certain PTPases, particularly bone PTPase OST-PTP, are implicated in osteoporosis. Ptpases are involved in mediating the effects of somatostatin on target cells, particularly hormone secretion and/or growth factor secretion.

Therefore, there is a need for agents that inhibit the action of protein tyrosine phosphatases. Such agents may be useful in the treatment of glucose intolerance, including type I and type II diabetes, immune dysfunction, including AIDS, allergic diseases, inflammatory diseases and autoimmunity, such as psoriasis, infectious diseases, obesity, cancer, diseases in which growth hormone synthesis is modulated or growth factor or cytokine synthesis affecting growth hormone production is modulated, or alzheimer's disease.

Summary of The Invention

The present invention provides substituted imidazole derivatives and compositions that inhibit PTP 1B. In one embodiment, the present invention provides compounds of formula (I-IV) as shown below. In another embodiment, the present invention provides a process for preparing compounds of formula (I-IV). In another embodiment, the present invention provides a pharmaceutical composition comprising a compound of formula (I-IV). In another embodiment, the invention provides a method of treating a human or animal condition using a compound of formula (I-IV). The compounds of the present invention are useful as protein tyrosine phosphatase inhibitors and thus may be useful in the management, treatment, control and adjunct treatment of diseases mediated by PTPase activity. Such diseases may include: glucose intolerance, including type I and type II diabetes, immune dysfunction, including AIDS, allergic diseases, inflammatory diseases and autoimmunity, such as psoriasis, infectious diseases, obesity, cancer, diseases in which growth hormone synthesis is modulated or growth factor or cytokine synthesis affecting growth hormone production is modulated, or alzheimer's disease.

Detailed Description

Embodiments of the present invention include substituted imidazole derivatives, compositions and methods of use. The present invention may have various embodiments.

In a first aspect, the present invention provides imidazole inhibitors of protein tyrosine phosphatases (PTPases) which are useful in the management and treatment of diseases mediated by PTPases.

In another aspect, the present invention provides a compound of formula I, II, III or IV:

wherein

Ar¹，Ar²，Ar⁴And Ar⁵Independently selected from the group consisting of phenyl, indanyl, tetrahydronaphthyl, pyridazine, pyrimidine, pyrazine, pyridine, piperidine, 4, 5-diaza-indanyl, 5, 6, 7, 8-tetrahydro-cinnoline and 1-H-pyridin-2-one, and

Ar³is phenyl, naphthalene, indanyl, tetrahydronaphthyl, pyridazine, pyrimidine, pyrazine, pyridine, piperidine, 4, 5-diaza-indanyl or 5, 6, 7, 8-tetrahydro-cinnoline,

wherein

Ar¹，Ar²，Ar³And Ar⁴Each optionally substituted 1-4 times with independently selected groups^bAnd is and

Ar⁵is optionally selected from R^a1-4 times;

v is C, W is C, X is N, Y is C, Z is N,

where the sides b, c and e are single bonds and the sides a and d are double bonds; or

V is C, W is N, X is C, Y is N, Z is C,

where the sides a, c and d are single bonds and the sides b and e are double bonds; or

V is C, W is N, X is C, Y is C, Z is N,

where the sides a, b and d are single bonds and the sides c and e are double bonds;

L¹is-T¹-L³-T²-，

Wherein

L³Is a direct bond, -C_1-10Alkylene group, -C_2-10Alkenylene or-C_2-10An alkynylene group;

T¹and T²Independently selected from: direct bond, -CH₂-，-O-，-N(R¹⁶)-，-C(O)-，-CON(R¹⁶)-，-N(R¹⁶)C(O)-，-N(R¹⁶)CON(R¹⁷)-，-N(R¹⁶)C(O)O-，-OC(O)N(R¹⁶)-，-N(R¹⁶)SO₂-，-SO₂N(R¹⁶)-，-C(O)-O-，-O-C(O)-，-S-，-S(O)-，-S(O)₂-，-N(R¹⁶)SO₂N(R¹⁷) -, -N-and-N (R)¹⁶)-N(R¹⁷)-；

Wherein

R¹⁶And R¹⁷Independently selected from: -hydrogen, -C_1-10Alkyl, -aryl, -arylene-C_1-10Alkyl and-C_1-10Alkylene-aryl, wherein alkyl and aryl are optionally substituted by R^cSubstitution;

L²selected from: -CH (R)¹⁸)-CH(R¹⁹)-，-N(R¹⁸)C(O)-，-N(R¹⁸)-，-N(R¹⁸)S(O)₂-，-C(O)N(R¹⁸)-，-S(O)₂N(R¹⁸) (trans) -C (R)¹⁸)＝C(R¹⁹) -, (cis) -C (R)¹⁸)＝C(R¹⁹)-，-C≡C-，-C(O)-，-O-，-C_1-5alkylene-O-, O-C_1-5Alkylene, - (CH)₂)_r-, 1,1 cycloalkylmethylene or a direct bond,

wherein

R¹⁸And R¹⁹Independently selected from: -hydrogen, -C_1-10Alkyl, -aryl, -arylene-C_1-10Alkyl and-C_1-10Alkylene-aryl, wherein alkyl and aryl are optionally substituted by R^cSubstitution;

L⁴selected from: direct bond and-CH₂-，

R¹，R²，R³，R⁴And R⁵Independently selected from: hydrogen and R^b，

R⁶Selected from hydrogen and R^b，

R¹¹Is selected from R^b，

G is

Wherein

a) D is C (R)⁷)(R⁸) And is and

e is C (R)⁷) Or the number of N is greater than the number of N,

in this case, the edge f is a single bond, or

b) D is C (R)⁷) And is and

e is the number of carbon atoms in the carbon atoms,

in this case, the side f is a double bond,

wherein

R⁷And R⁸Independently selected from: halogen, hydroxy, amino, cyano, nitro, carboxy, -SO₃H，R^fAnd R^g；

Or

Wherein

a) D is C (R)⁷) And is and

e is C (R)⁷)(R⁸) Or N (R)⁹)，

In this case, the edge f is a single bond, or

b) D is C, and

e is C (R)⁷) Or the number of N is greater than the number of N,

in this case, the side f is a double bond,

wherein

R⁷And R⁸Independently selected from: halogen, hydroxy, amino, cyano, nitro, carboxy, -SO₃H，R^fAnd R^g(ii) a And is

R⁹Is R^d，

M is hydrogen or Na⁺，K⁺And other pharmaceutically acceptable counterions;

R^ais composed of

a) -a cycloalkyl group,

b) -a cyano group,

c)-OR^d，

d)-NO₂，

e) -a halogen, in the form of a halogen,

f)-S(O)_mC_2-10an alkyl group, a carboxyl group,

g)-SR^d，

h)-S(O)₂OR^d，

i)-S(O)_mNR^dR^e，

j)-NR^dS(O)_mR^e，

k)-NR^dR^e，

l)-O(CR^fR^g)_nNR^dR^e，

m)-C(O)R^d，

n)-CO₂R^d，

o)-CO₂(CR^fR^g)_nCONR^dR^e，

p)-OC(O)R^d，

q)-C(O)NR^dR^e，

r)-NR^dC(O)R^e，

s)-OC(O)NR^dR^e，

t)-NR^dC(O)OR^e

u)-NR^dC(O)NR^dR^e，

v)-CF₃，

w)-OCF₃，

x)-C_1-10an alkyl group, a carboxyl group,

y)-C_2-10an alkenyl group, which is a radical of an alkenyl group,

z)-C_2-10an alkynyl group,

aa)-C_1-10an alkylene-aryl group, a substituted alkylene-aryl group,

bb)-C_1-10an alkylene-heteroaryl group, which is a cyclic alkylene group,

cc) -a heteroaryl group, and (b) a pharmaceutically acceptable salt thereof,

dd)-C(R^f)＝C(R^g)-R^for is or

ee)-C≡C-R^f，

Wherein alkyl, alkenyl, alkynyl, aryl, heteroaryl and cycloalkyl are optionally independently selected from R^c1-4 times;

R^bis composed of

a) -a cycloalkyl group,

b) -a cyano group,

c)-OR^d，

d)-NO₂，

e) -a halogen, in the form of a halogen,

f)-S(O)_mR^d，

g)-SR^d

h)-S(O)₂OR^d，

i)-S(O)_mNR^dR^e，

j)-NR^dS(O)_mR^e，

k)-NR^dR^e，

l)-O(CR^fR^g)_nNR^dR^e，

m)-C(O)R^d，

n)-CO₂R^d，

o)-CO₂(CR^fR^g)_nCONR^dR^e

p)-OC(O)R^d，

q)-C(O)NR^dR^e，

r)-NR^dC(O)R^e，

s)-OC(O)NR^dR^e，

t)-NR^dC(O)OR^e，

u)-NR^dC(O)NR^dR^e，

v)-CF₃，

w)-OCF₃，

x)-C_1-10an alkyl group, a carboxyl group,

y)-C_2-10an alkenyl group, which is a radical of an alkenyl group,

z)-C_2-10an alkynyl group,

aa)-C_1-10an alkylene-aryl group, a substituted alkylene-aryl group,

bb)-C_1-10an alkylene-heteroaryl group, which is a cyclic alkylene group,

cc) -a heteroaryl group, and (b) a pharmaceutically acceptable salt thereof,

dd)-C(R^f)＝C(R^g)-R^for is or

ee)-C≡C-R^f，

Wherein alkyl, alkenyl, alkynyl, aryl, heteroaryl and cycloalkyl are optionally independently selected from R^c1-4 times;

R^cis composed of

a) -a halogen, in the form of a halogen,

b) -an amino group,

c) -a carboxyl group,

d)-C_1-4an alkyl group, a carboxyl group,

e)-O-C_1-4an alkyl group, a carboxyl group,

f) -a cycloalkyl group,

g) -an O-cycloalkyl group, a cycloalkyl group,

h) -an aryl group,

i)-C_1-4an alkylene-aryl group, a substituted alkylene-aryl group,

j) -a hydroxyl group,

k)-CF₃，

l) -O-aryl, or a pharmaceutically acceptable salt thereof,

m) -a heteroaryl group, a pharmaceutically acceptable salt thereof,

n) -heteroaryl-C_1-10An alkyl group, a carboxyl group,

o) a heterocyclic group,

p)-CO₂-C_1-10alkyl, or

q)-CO₂-C_1-10An alkyl-aryl group, which is a cyclic alkyl group,

R^dand R^eIndependently selected from hydrogen, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, cycloalkyl, -C_1-10Alkylene-cycloalkyl, aryl, heterocyclyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl are optionally independently selected from R^c1-4 substituents of (a); or R^dAnd R^eTogether with the atoms connecting them form a 5-7 member heterocyclic ring containing 0-2 additional heteroatoms independently selected from oxygen, sulfur and nitrogen and optionally substituted with R^cSubstituted 1-3 times and wherein 1 or 2 carbon atoms of the heterocycle may be oxidized,

R^fand R^gIndependently selected from hydrogen, C_1-10Alkyl, cycloalkyl, -C_1-10Alkylene-cycloalkyl and aryl, wherein alkyl, cycloalkyl and aryl are optionally independently selected from R^c1-4 substituents of (a); or R^fAnd R^gTogether with the atoms connecting them form a 5-7 member ring containing 0-2 heteroatoms independently selected from oxygen, sulfur and nitrogen and optionally substituted with R^cSubstituted 1-3 times and wherein 1 or 2 carbon atoms on the heterocycle may be oxidized;

m is an integer of 1 to 2,

n is an integer of 1 to 10,

q is an integer of 1 to 2,

r is an integer of 1 to 5, and

s is an integer of 0 to 3.

In one embodiment, M is hydrogen or selected from sodium (Na)⁺) Potassium (K)⁺) Ammonium, morpholinium, barium, calcium salts. In another embodiment, M is hydrogen. In another embodiment, M is selected from: hydrogen, sodium and potassium. In another embodiment, M is selected from: sodium and potassium.

In another embodiment, the invention provides a compound of formula I, II, III or IV having the formula:

wherein

V is C, W is C-R⁶X is N, Y is C, Z is N,

where the sides b, c and e are single bonds and the sides a and d are double bonds; or

V is C, W is N, X is C, Y is N, Z is C-R⁶，

Where the sides a, c and d are single bonds and the sides b and e are double bonds; or

V is C, W is N-R⁶X is C, Y is C, Z is N,

where the sides a, b and d are single bonds and the sides c and e are double bonds;

R⁶selected from hydrogen and R^b。

In another embodiment, the invention provides a compound of formula I, II, III or IV having the formula:

wherein

V is C, W is N, X is C, Y is N-R⁶Z is a group of carbon atoms, and Z is C,

and the sides a, c and d are single bonds and the sides b and e are double bonds; and is

R⁶Selected from hydrogen and R^b。

In another embodiment, Ar¹And Ar⁴Independently selected from: phenyl-1, 4-yl, pyridazin-3, 6-yl, pyrimidin-2, 5-yl and pyrazin-2, 5-yl.

In another embodiment, Ar¹，Ar²，Ar⁴And Ar⁵Independently selected from phenyl and pyridazine.

In another embodiment, Ar¹And Ar²One is phenyl and the other is pyridazine.

In another embodiment, Ar¹And Ar²Each is phenyl or pyridazine.

In another embodiment, Ar²Is phenyl and Ar¹Is pyridazin-3, 6-yl.

In another embodiment, Ar¹Is phenyl-1, 4-yl and Ar²Is pyridazin-3-yl.

In another embodiment, Ar⁴And Ar⁵One is phenyl and the other is pyridazine.

In another embodiment, Ar⁴And Ar⁵Each is phenyl or pyridazine.

In another embodiment, Ar⁵Is phenyl and Ar⁴Is pyridazin-3, 6-yl.

In another embodiment, Ar⁴Is phenyl-1, 4-yl and Ar⁵Is pyridazin-3-yl.

In another embodiment, Ar³Is phenyl and is substituted by halogen.

In another embodiment, Ar²，Ar³And Ar⁵Substituted with at least one lipophilic group.

In one embodiment, the compound has formula Ia. In another embodiment, the compound has formula IIa. In another embodiment, the compound has formula IIIa. In another embodiment, the compound has formula IVa.

In one embodiment, if the compound has formula Ia, IIa, IIIa or IVa, then V is C and W is C-R⁶X is N, Y is C, Z is N, the sides b, C and e are single bonds and the sides a and d are double bonds.

In another embodiment, if the compound has formula Ia, IIa, IIIa or IVa, then V is C, W is N, X is C, Y is N, Z is C-R⁶And the sides a, c and d are single bonds and the sides b and e are double bonds.

In another embodiment, if the compound has formula Ia, IIa, IIIa or IVa, then V is C and W is N-R⁶X is C, Y is C, Z is N and the sides a, b and d are single bonds and the sides C and e are double bonds.

In another embodiment, R⁶Selected from hydrogen and C_1-4An alkyl group.

In another embodiment, if the compound has formula Ia, IIa, IIIa or IVa, then V is C, W is N, X is C, Y is N, Z is C-R⁶And the sides a, c and d are single bonds and the sides b and e are double bonds and R⁶Selected from hydrogen and C_1-10An alkyl group.

In another embodiment, L¹is-T¹-L³-T²-, wherein L³，T¹And T²Is a direct bond.

In another embodiment, L¹is-T¹-L³-T²-, in which T¹And T²Is a direct bond and L³is-CH₂-。

In another embodiment, L¹is-T¹-L³-T²-, wherein L³Is a direct bond or C_1-10Alkylene radical, T¹Is a direct bond and T²Selected from-O-, -N (R)¹⁶)-，-C(O)-，-CON(R¹⁶)-，-N(R¹⁷)C(O)-，-N(R₆)CON(R¹⁶)-，-N(R¹⁶)C(O)O-，-OC(O)N(R¹⁶)-，-N(R¹⁶)SO₂-，-SO₂N(R¹⁶)-，-C(O)-O-，-O-C(O)-，-S-，-S(O)-，-S(O)₂-and-N (R)¹⁶)SO₂N(R¹⁷)-。

In another embodiment, L¹is-T¹-L³-T²-, wherein L³Is a direct bond or C_1-10Alkylene radical, T²Is a direct bond and T¹Selected from-O-, -N (R)¹⁶)-，-C(O)-，-CON(R¹⁶)-，-N(R¹⁷)C(O)-，-N(R₆)CON(R¹⁶)-，-N(R¹⁶)C(O)O-，-OC(O)N(R¹⁶)-，-N(R¹⁶)SO₂-，-SO₂N(R¹⁶)-，-C(O)-O-，-O-C(O)-，-S-，-S(O)-，-S(O)₂-and-N (R)¹⁶)SO₂N(R¹⁷)-。

In another embodiment, L²Is selected from-CH₂-or-CH₂-O-. In another embodiment, L²is-CH₂-. In another embodiment, L⁴is-CH₂-。

In one embodiment, R¹，R²，R³，R⁴And R⁵Independently selected from:

a) -hydrogen;

b) -fluorine;

c) -chlorine;

d) a trifluoromethyl group;

e) a trifluoromethoxy group;

f)-SO₂-C_1-6an alkyl group;

g) -a cyano group;

h) -a nitro group; and

i) -phenyl.

In another embodiment, R¹，R²，R³，R⁴And R⁵At least one of which is not hydrogen. In another embodiment, R¹，R²，R³，R⁴And R⁵Independently selected from hydrogen, fluorine and chlorine, wherein R¹，R²，R³，R⁴And R⁵At least one of which is not hydrogen. In another embodiment, R¹And R³Is chlorine or fluorine and R²，R⁴And R⁵Is hydrogen.

In one embodiment, s is an integer from 1 to 3 and R¹¹Independently selected from: methyl, methoxy, chloro, fluoro, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, -SO₂-CH₃，-SO₂-CF₃，-NHSO₂-CH₃，-NHSO₂-CF₃And a cyclopropyl group. In another embodiment, s is 0.

In one embodiment, G is

Wherein

a) q is 2 and D is C (R)⁷)(R⁸) E is C (R)⁷) Or N, in which case the edge f is a single bond, or

b) q is 2 and D is C (R)⁷) And E is C, in which case the side f is a double bond.

In another embodiment, R⁷And R⁸Selected from: hydrogen and C_1-4An alkyl group.

In another embodiment, G is

Wherein

q is 2 and D is C (R)⁷)(R⁸) E is N and the side f is a single bond.

In another embodiment, R⁷And R⁸Selected from: hydrogen and C_1-4An alkyl group.

In another embodiment, G is

Wherein

a) q is 2 and D is C (R)⁷) E is C (R)⁷)(R⁸) Or N (R)⁹) When the side f is a single bond, or

b) q is 2, D is C, E is C (R)⁷) Or N, in which case the edge f is a double bond.

In another embodiment, R⁷，R⁸And R⁹Selected from: hydrogen and C_1-4An alkyl group.

In one embodiment, wherein the compound has formula IV, Ar³Is naphthyl-2-yl and is selected from R in the 6-position^bAnd may be further optionally substituted with 1-2 groups independently selected from R^bIs substituted with a group (b).

In another embodiment, wherein the compound has formula IV, Ar³Is phenyl and is selected from-C (R) in the 4 position^f)＝C(R^g)-R^fand-C ≡ C-R^fAnd may be further optionally substituted with 1-2 groups independently selected from R^bIs substituted with a group (b).

In one embodiment, wherein the compound has formula II or III, Ar²Is 1-3 independently selected from R^bGroup (d) ofAnd (4) substitution.

In one embodiment, wherein the compound has formula I, Ar⁵Is 1-3 independently selected from R^aIs substituted with a group (b).

In another embodiment, Ar¹And Ar⁴Is unsubstituted and Ar²，Ar³And Ar⁵Each substituted with 1-3 groups independently selected from:

-C_1-10an alkyl group, a carboxyl group,

-a cycloalkyl group,

-a heterocyclic group,

-a trifluoroalkyl group, a trifluoromethyl group,

-a halogen, in the form of a halogen,

-a nitro group,

-a carboxyl group,

-CO₂-C_1-10an alkyl group, a carboxyl group,

-C_1-10alkylene-CO₂-C_1-10An alkyl group, a carboxyl group,

-C_2-10alkenylene-CO₂-C_1-10An alkyl group, a carboxyl group,

-C_1-10alkylene-CO₂H，

-C_2-10alkenylene-CO₂H，

-O-C_1-10alkylene-C (O) NH-C_1-10An alkyl group, a carboxyl group,

-C(O)-C_1-10an alkyl group, a carboxyl group,

-C(O)NH-C_1-10an alkyl group, a carboxyl group,

-an O-heterocyclic group,

-O-C_1-10an alkyl group, a carboxyl group,

-O-C_1-10a halogenated alkyl group,

-O-C_1-10a perhalogenated alkyl group, a halogen atom,

-an O-cycloalkyl group, a cycloalkyl group,

-an O-phenyl group, which is,

-a hydroxyl group,

-O-C_1-10an alkylene-cycloalkyl group, which is,

-O-C_1-10an alkylene-phenyl group, which is a phenyl group,

-an S-heterocyclic group,

-S-C_1-10an alkyl group, a carboxyl group,

-S-C_1-10a halogenated alkyl group,

-S-C_1-10a perhalogenated alkyl group, a halogen atom,

-an S-cycloalkyl group,

-a group of the groups-S-phenyl,

-S-C_1-10an alkylene-cycloalkyl group, which is,

-S-C_1-10an alkylene-phenyl group, which is a phenyl group,

-C_1-10an alkylene-cycloalkyl group, which is,

-C_1-10an alkylene-phenyl group, which is a phenyl group,

-an amino group,

-NH(C_1-10an alkyl group),

-N(C_1-10alkyl radical)₂，

-N(C_1-10Alkyl) (C_1-10Alkylene-cycloalkyl) groups,

-NHCO₂-C_1-10an alkyl group, a carboxyl group,

-NH(C_1-10alkylene-cycloalkyl) groups,

-S(O)₂-C_2-10an alkyl group, a carboxyl group,

-SO₂-a cycloalkyl group,

-SO₂-C_1-10an alkylene-cycloalkyl group, which is,

-S(O)-C_1-10an alkyl group, a carboxyl group,

-S (O) -cycloalkyl, and

-S(O)-C_1-10an alkylene-cycloalkyl group, which is,

wherein alkyl, alkenyl, aryl, heteroaryl and cycloalkyl are optionally independently selected from R^cSubstituted 1-4 times.

In another embodiment, Ar¹And Ar⁴Is unsubstituted and Ar²，Ar³And Ar⁵Each substituted with 1-3 groups independently selected from:

-C_1-10an alkyl group, a carboxyl group,

-a cycloalkyl group,

-a heterocyclic group,

-a trifluoroalkyl group, a trifluoromethyl group,

-a halogen, in the form of a halogen,

-a nitro group,

-CO₂-C_1-10an alkyl group, a carboxyl group,

-C_1-10alkylene-CO₂-C_1-10An alkyl group, a carboxyl group,

-C_2-10alkenylene-CO₂-C_1-10An alkyl group, a carboxyl group,

-O-C_1-10alkylene-C (O) NH-C_1-10An alkyl group, a carboxyl group,

-C(O)-C_1-10an alkyl group, a carboxyl group,

-C(O)NH-C_1-10an alkyl group, a carboxyl group,

-an O-heterocyclic group,

-O-C_1-10an alkyl group, a carboxyl group,

-O-C_1-10a halogenated alkyl group,

-O-C_1-10a perhalogenated alkyl group, a halogen atom,

-an O-cycloalkyl group, a cycloalkyl group,

-an O-phenyl group, which is,

-O-C_1-10an alkylene-cycloalkyl group, which is,

-O-C_1-10an alkylene-phenyl group, which is a phenyl group,

-an S-heterocyclic group,

-S-C_1-10an alkyl group, a carboxyl group,

-S-C_1-10a halogenated alkyl group,

-S-C_1-10a perhalogenated alkyl group, a halogen atom,

-an S-cycloalkyl group,

-a group of the groups-S-phenyl,

-S-C_1-10an alkylene-cycloalkyl group, which is,

-S-C_1-10an alkylene-phenyl group, which is a phenyl group,

-C_1-10an alkylene-cycloalkyl group, which is,

-C_1-10an alkylene-phenyl group, which is a phenyl group,

-NH(C_1-10an alkyl group),

-N(C_1-10alkyl radical)₂，

-N(C_1-10Alkyl) (C_1-10Alkylene-cycloalkyl) groups,

-NHCO₂-C_1-10an alkyl group, a carboxyl group,

-NH(C_1-10alkylene-cycloalkyl) groups,

-S(O)₂-C_2-10an alkyl group, a carboxyl group,

-SO₂-a cycloalkyl group,

-SO₂-C_1-10an alkylene-cycloalkyl group, which is,

-S(O)-C_1-10an alkyl group, a carboxyl group,

-S (O) -cycloalkyl, and

-S(O)-C_1-10alkylene-cycloalkyl groups.

In another embodiment, Ar¹And Ar⁴Is unsubstituted and Ar²，Ar³And Ar⁵Each substituted with 1-3 groups independently selected from:

-C_1-10an alkyl group, a carboxyl group,

-a cycloalkyl group,

-a trifluoroalkyl group, a trifluoromethyl group,

-a halogen, in the form of a halogen,

-CO₂-C_1-10an alkyl group, a carboxyl group,

-C_1-10alkylene-CO₂-C_1-10An alkyl group, a carboxyl group,

-C_2-10alkenylene-CO₂-C_1-10An alkyl group, a carboxyl group,

-O-C_1-10alkylene-C (O) NH-C_1-10An alkyl group, a carboxyl group,

-C(O)-C_1-10an alkyl group, a carboxyl group,

-O-C_1-10an alkyl group, a carboxyl group,

-O-C_1-10a halogenated alkyl group,

-O-C_1-10a perhalogenated alkyl group, a halogen atom,

-an O-cycloalkyl group, a cycloalkyl group,

-an O-phenyl group, which is,

-O-C_1-10an alkylene-cycloalkyl group, which is,

-O-C_1-10an alkylene-phenyl group, which is a phenyl group,

-S-C_1-10an alkyl group, a carboxyl group,

-S-C_1-10a halogenated alkyl group,

-S-C_1-10a perhalogenated alkyl group, a halogen atom,

-an S-cycloalkyl group,

-a group of the groups-S-phenyl,

-S-C_1-10an alkylene-cycloalkyl group, which is,

-S-C_1-10an alkylene-phenyl group, which is a phenyl group,

-C_1-10an alkylene-cycloalkyl group, which is,

-C_1-10an alkylene-phenyl group, which is a phenyl group,

-S(O)₂-C_2-10an alkyl group, a carboxyl group,

-SO₂-a cycloalkyl group,

-SO₂-C_1-10an alkylene-cycloalkyl group, which is,

-S(O)-C_1-10an alkyl group, a carboxyl group,

-S (O) -cycloalkyl, and

-S(O)-C_1-10alkylene-cycloalkyl groups.

In another embodiment, Ar¹And Ar⁴Is unsubstituted and Ar²，Ar³And Ar⁵Each substituted with 1-3 groups independently selected from:

a group of morpholine-4-yl and a group of morpholine-4-yl,

a piperidin-4-yl group, a pharmaceutically acceptable salt thereof,

a piperidin-1-yl group,

(ii) a 4-piperidinyl-oxy group,

(ii) a 3-piperidinyl-oxy group,

2-oxo-piperidin-1-yl group,

3-oxo-piperidin-1-yl group,

[1-(C_1-10alkylsulfonyl) -piperidin-4-yl]-an oxygen radical,

[1-(C_1-10alkoxycarbonyl) -piperidin-4-yl]-an oxygen radical,

[1-(C_1-10alkoxycarbonyl) -piperidin-3-yl]-an oxygen radical,

a piperazine-1-yl group,

4-(C_1-10alkyl) -piperazin-1-yl group,

2-oxo-piperazin-4-yl,

1-C_1-10alkyl-2-oxo-piperazin-4-yl,

1-cycloalkyl-2-oxo-piperazin-4-yl,

4-a-tetrahydropyranyloxy group,

3-a group of oxygen-containing groups selected from the group consisting of 3-tetrahydrofuranyl,

4-(C_1-10alkoxycarbonyl) piperazin-1-yl,

a pyrrolidin-1-yl group which is,

3-phenyl-pyrrolidin-1-yl,

3-cycloalkyl-pyrrolidin-1-yl,

[1-(C_1-10alkoxycarbonyl) -pyrrolidin-3-yl]-an oxygen radical,

2-phenylthioloxy,

2-thiazolyl-oxy-group(s),

(1, 2, 4-oxadiazol-3-yl) -oxy,

(1-methyl-imidazol-2-yl) -oxy, and

(imidazol-2-yl) -C_1-10An alkoxy group,

wherein alkyl, phenyl, cycloalkyl, morpholine, piperidine, piperazine, cycloalkyl, tetrahydropyran, tetrahydrofuran, pyrrolidine, thiazole, imidazole are optionally independently selected from R^cSubstituted 1-4 times.

In another embodiment, if the compound has formula Ia, IIa, IIIa or IVa, then

Ar¹，Ar²，Ar⁴And Ar⁵Independently selected from the group consisting of phenyl and pyridazine,

L¹is a direct bond or-CH₂-，

L²is-CH₂-，

L⁴is-CH₂-，

V is C, W is N, X is C, Y is N, Z is C-R⁶And the sides a, c and d are single bonds and the sides b and e are double bonds, and

g is

Wherein

q is 2 and D is C (R)⁷)(R⁸) E is N and the side f is a single bond.

In another embodiment, Ar¹And Ar⁴Is unsubstituted and Ar²，Ar³And Ar⁵Substituted with at least one group selected from: methyl, ethyl, propyl, butyl, pentyl, hexyl, 1-ethyl-propyl, 1-propyl-butyl, 3, 3-dimethyl-butyl, 4-methyl-pentyl, 4, 4-dimethyl-pentyl, 1- (3, 3-dimethyl-butyl) -4, 4-dimethyl-pentyl, isobutyl, isopropyl, sec-butyl, tert-butyl, trifluoromethyl, 4, 4, 4-trifluorobutoxy, methoxy, ethoxy, propoxy, butoxy,pentyloxy, hexyloxy, isobutoxy, isopropoxy, tert-butoxy, 2-phenethyloxy, 2, 2-dimethylpropoxy, 3-methyl-butoxy, 3, 3-dimethyl-butoxy, 3' -phenethyloxy, 2-cyclohexyl-ethanesulfonyl, 3, 3-dimethyl-butane-1-sulfonyl, cyclohexanesulfonyl, cyclohexylmethanesulfonyl, 2-cyclohexyl-ethanesulfinyl, 3, 3-dimethyl-butane-1-sulfinyl, cyclohexylmethylsulfinyl, 2-cyclohexyl-ethylsulfanyl (sulfanyl), 3, 3-dimethyl-butylsulfanyl, phenethylsulfanyl, cyclohexylmethylsulfanyl, cyclopentyl, cyclohexyl, cyclopentyloxy, cyclohexyloxy, cyclopentylmethyl, cyclohexylmethyl, 2-cyclopentylethyl, 2-cyclohexylethyl, cyclopentylmethoxy, cyclohexylmethoxy, 2-cyclopentylethoxy, 2-cyclohexylethoxy, 2-cyclohexyl-vinyl, 3-ethyl-cyclobutyl, amino, butylamino, diethylamino, bis- (3, 3-dimethyl-butyl) -amino, cyclohexylmethyl-ethyl-amino, 3-phenyl-pyrrolidin-1-yl, cyclohexyl-pyrrolidin-1-yl, piperidin-2-one-1-yl, piperazin-2-one-1-yl, piperazin-2-on-4-yl, piperazine-1-carboxylic acid 2, 2-dimethyl-propyl ester, 1-cyclohexyl-piperazin-2-on-4-yl, 1-ethyl-piperazin-2-on-4-yl, 1-isopropyl-piperazin-2-on-4-yl, 1-methyl-piperazin-2-on-4-yl, 4-methyl-piperazin-1-yl, chloro, fluoro, nitro, phenyl, propionyl, carboxy, carboxymethyl and morpholin-4-yl.

In another embodiment, Ar¹And Ar⁴Is unsubstituted and Ar²，Ar³And Ar⁵Substituted with at least one group selected from: methyl, ethyl, propyl, butyl, pentyl, hexyl, 1-ethyl-propyl, 1-propyl-butyl, 3, 3-dimethyl-butyl, 4-methyl-pentyl, 4, 4-dimethyl-pentyl, 1- (3, 3-dimethyl-butyl) -4, 4-dimethyl-pentyl, isobutyl, isopropyl, sec-butyl, tert-butyl, trifluoromethyl, 4, 4, 4-trifluorobutoxy, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, isobutoxy, isopropoxy, tert-butoxy, 2-phenethyloxy, 2, 2-dimethylpropoxy3-methyl-butoxy, 3, 3-dimethyl-butoxy, 3' -phenethyloxy, 2-cyclohexyl-ethanesulfonyl, 3, 3-dimethyl-butane-1-sulfonyl, cyclohexanesulfonyl, cyclohexylmethanesulfonyl, 2-cyclohexyl-ethanesulfinyl, 3, 3-dimethyl-butane-1-sulfinyl, cyclohexylmethylsulfinyl, 2-cyclohexyl-ethylsulfanyl, 3, 3-dimethyl-butylsulfanyl, phenethylsulfanyl, cyclohexylmethylsulfanyl, cyclopentyl, cyclohexyl, cyclopentyloxy, cyclohexyloxy, cyclopentylmethyl, cyclohexylmethyl, 2-cyclopentylethyl, 2-cyclohexylethyl, cyclopentylmethoxy, cyclohexylmethoxy, 2-cyclopentylethoxy, 2-cyclohexylethoxy, 2-cyclohexyl-vinyl, 3-ethyl-cyclobutyl, chloro, fluoro and phenyl.

In another embodiment, the invention provides a compound of formula IIa having the formula:

wherein

V is C, W is C-R⁶X is N, Y is C, Z is N,

where the sides b, c and e are single bonds and the sides a and d are double bonds; or

V is C, W is N, X is C, Y is N, Z is C-R⁶，

Where the sides a, c and d are single bonds and the sides b and e are double bonds; or

V is C, W is N-R⁶X is C, Y is C, Z is N,

where the sides a, b and d are single bonds and the sides c and e are double bonds;

wherein R is⁶Is hydrogen or R^b，

D¹Is C-R²¹And D²Is C-R²²Or D¹And D²Is N;

D³is C-R²³And D⁴Is C-R²⁴Or D³And D⁴Is N;

L¹is-T¹-L³-T²-，

Wherein

L³Is a direct bond, -C_1-10Alkylene group, -C_2-10Alkenylene or-C_2-10An alkynylene group;

T¹and T²Independently selected from: direct bond, -CH₂-，-O-，-N(R¹⁶)-，-C(O)-，-CON(R¹⁶)-，-N(R¹⁶)C(O)-，-N(R¹⁶)CON(R¹⁷)-，-N(R¹⁶)C(O)O-，-OC(O)N(R¹⁶)-，-N(R¹⁶)SO₂-，-SO₂N(R¹⁶)-，-C(O)-O-，-O-C(O)-，-S-，-S(O)-，-S(O)₂-，-N(R¹⁶)SO₂N(R¹⁷) -, -N ═ N-or-N (R)¹⁶)-N(R¹⁷)-；

Wherein

R¹⁶And R¹⁷Independently selected from: -hydrogen, -C_1-10Alkyl, -aryl, -arylene-C_1-10Alkyl or-C_1-10Alkylene-aryl, wherein alkyl and aryl are optionally substituted by R^cSubstitution;

L²selected from: -CH (R)¹⁸)-CH(R¹⁹)-，-N(R¹⁸)C(O)-，-N(R¹⁸)-，-N(R¹⁸)S(O)₂-，-C(O)N(R¹⁸)-，-S(O)₂N(R¹⁸) (trans) -C (R)¹⁸)＝C(R¹⁹) -, (cis) -C (R)¹⁸)＝C(R¹⁹) -, -C.ident.C-, -C (O) -, -O-, -alkylene-O-, - (CH)₂)_r-, 1,1 cycloalkylmethylene or a direct bond,

wherein

R¹⁸And R¹⁹Independently selected from: -hydrogen, -C_1-10Alkyl, -aryl, -arylene-C_1-10Alkyl or-C_1-10Alkylene-aryl, wherein alkyl and aryl are optionally substituted by R^cSubstitution;

R¹，R²，R³，R⁴and R⁵Independently selected from: hydrogen and R^b；

R¹¹Is selected from R^b；

R²⁰，R²¹，R²²，R²³，R²⁴，R²⁵，R²⁶And R²⁷Independently selected from: hydrogen and R^b；

G is

Wherein

a) D is C (R)⁷)(R⁸) E is C (R)⁷) Or N, in which case the edge f is a single bond, or

b) D is C (R)⁷) E is C, in which case the side f is a double bond,

wherein

R⁷And R⁸Independently selected from: halogen, hydroxy, amino, cyano, nitro, carboxy, -SO₃H，-R^fAnd R^g；

Or

Wherein

a) D is C (R)⁷) E is C (R)⁷)(R⁸) Or N (R)⁹) When the side f is a single bond, or

b) D is C, E is C (R)⁷) Or N, in which case the side f is a double bond,

wherein

R⁷And R⁸Independently selected from: halogen, hydroxy, amino, cyano, nitro, carboxy, -SO₃H，R^fAnd R^g(ii) a And is

R⁹Is R^d；

M is hydrogen or Na⁺，K⁺And other pharmaceutically acceptable counterions;

R^bis composed of

a) -a cycloalkyl group,

b) -a cyano group,

c)-OR^d，

d)-NO₂，

e) -a halogen, in the form of a halogen,

f)-S(O)_mR^d，

g)-SR^d，

h)-S(O)₂OR^d，

i)-S(O)_mNR^dR^e，

j)-NR^dS(O)_mR^e，

k)-NR^dR^e，

l)-O(CR^fR^g)_nNR^dR^e，

m)-C(O)R^d，

n)-CO₂R^d，

o)-CO₂(CR^fR^g)_nCONR^dR^e，

p)-OC(O)R^d，

q)-C(O)NR^dR^e，

r)-NR^dC(O)R^e，

s)-OC(O)NR^dR^e，

t)-NR^dC(O)OR^e，

u)-NR^dC(O)NR^dR^e，

v)-CF₃，

w)-OCF₃，

x)-C_1-10an alkyl group, a carboxyl group,

y)-C_2-10an alkenyl group, which is a radical of an alkenyl group,

z)-C_2-10an alkynyl group,

aa)-C_1-10an alkylene-aryl group, a substituted alkylene-aryl group,

bb)-C_1-10an alkylene-heteroaryl group, which is a cyclic alkylene group,

cc) -a heteroaryl group, and (b) a pharmaceutically acceptable salt thereof,

dd)-C(R^f)＝C(R^g)-R^for is or

ee)-C≡C-R^f，

Wherein alkyl, alkenyl, alkynyl, aryl, heteroaryl and cycloalkyl are optionally independently selected from R^c1-4 times;

R^cis composed of

a) -a halogen, in the form of a halogen,

b) -an amino group,

c) -a carboxyl group,

d)-C_1-4an alkyl group, a carboxyl group,

e)-O-C_1-4an alkyl group, a carboxyl group,

f) -a cycloalkyl group,

g) -an O-cycloalkyl group, a cycloalkyl group,

h) -an aryl group,

i)-C_1-4an alkylene-aryl group, a substituted alkylene-aryl group,

j) -a hydroxyl group,

k)-CF₃，

l) -O-aryl, or a pharmaceutically acceptable salt thereof,

m) -a heteroaryl group, a pharmaceutically acceptable salt thereof,

n) -heteroaryl-C_1-10An alkyl group, a carboxyl group,

o) a heterocyclic group,

p)-CO₂-C_1-10alkyl, or

q)-CO₂-C_1-10An alkyl-aryl group, which is a cyclic alkyl group,

R^dand R^eIndependently selected from hydrogen, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, cycloalkyl, -C_1-10Alkylene-cycloalkyl, aryl, heterocyclyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl are optionally independently selected from R^c1-4 substituents of (a); or R^dAnd R^eTogether with the atoms connecting them form a 5-7 member heterocyclic ring containing 0-2 additional heteroatoms independently selected from oxygen, sulfur and nitrogen and optionally substituted with R^cSubstituted 1-3 times and wherein 1 or 2 carbon atoms of the heterocycle may be oxidized,

R^fand R^gIndependently selected from hydrogen, C_1-10Alkyl, cycloalkyl, -C_1-10Alkylene-cycloalkyl and aryl, wherein alkyl, cycloalkyl and aryl are optionally independently selected from R^c1-4 substituents of (a); or R^fAnd R^gTogether with the atoms connecting them form a 5-7 member ring containing 0-2 heteroatoms independently selected from oxygen, sulfur and nitrogen and optionally substituted with R^cSubstituted 1-3 times and wherein 1 or 2 carbon atoms on the heterocycle may be oxidized;

m is an integer of 1 to 2,

n is an integer of 1 to 10,

q is an integer of 1 to 2,

r is an integer of 1 to 5,

s is an integer of 0 to 3.

In one embodiment of the compounds of formula (IIc), L¹is-T¹-L³-T²-, wherein L³，T¹And T²Is a direct bond. In another embodiment, L¹is-T¹-L³-T²-, in which T¹And T²Is a direct bond and L³is-CH₂-. In another embodiment, L¹is-T¹-L³-T²-, wherein L³Is a direct bond or alkylene, T¹Is a direct bond and T²Selected from-O-, -N (R)¹⁶)-，-C(O)-，-CON(R¹⁶)-，-N(R¹⁷)C(O)-，-N(R₆)CON(R¹⁶)-，-N(R¹⁶)C(O)O-，-OC(O)N(R¹⁶)-，-N(R¹⁶)SO₂-，-SO₂N(R¹⁶)-，-C(O)-O-，-O-C(O)-，-S-，-S(O)-，-S(O)₂-and-N (R)¹⁶)SO₂N(R¹⁷) -. In another embodiment, L¹is-T¹-L³-T²-, wherein L³Is a direct bond or alkylene, T²Is a direct bond and T¹Selected from-O-, -N (R)¹⁶)-，-C(O)-，-CON(R¹⁶)-，-N(R¹⁷)C(O)-，-N(R₆)CON(R¹⁶)-，-N(R¹⁶)C(O)O-，-OC(O)N(R¹⁶)-，-N(R¹⁶)SO₂-，-SO₂N(R¹⁶)-，-C(O)-O-，-O-C(O)-，-S-，-S(O)-，-S(O)₂-and-N (R)¹⁶)SO₂N(R¹⁷)-。

In another embodiment of the compounds of formula (IIc), L²Is selected from-CH₂-or-CH₂-O-. In another embodiment, L²is-CH₂-。

In another embodiment of the compounds of formula (IIc), R¹，R²，R³，R⁴And R⁵Independently selected from:

a) -hydrogen;

b) -fluorine;

c) -chlorine;

d) a trifluoromethyl group;

e) a trifluoromethoxy group;

f)-SO₂-C_1-6an alkyl group;

g) -a cyano group;

h) -a nitro group; and

i) -phenyl.

In another embodiment, R¹，R²，R³，R⁴And R⁵At least one of which is not hydrogen. In another embodiment, R¹，R²，R³，R⁴And R⁵Independently selected from: hydrogen, fluorine and chlorine, wherein R¹，R²，R³，R⁴And R⁵At least one of which is not hydrogen. In another embodiment, R¹And R³Is chlorine or fluorine and R²，R⁴And R⁵Is hydrogen.

In another embodiment of the compounds of formula (IIc), s is an integer from 1 to 3 and R¹¹Independently selected from: methyl, methoxy, chloro, fluoro, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, -SO₂-CH₃，-SO₂-CF₃，-NHSO₂-CH₃，-NHSO₂-CF₃And a cyclopropyl group. In another embodiment, s is 0.

In another embodiment of the compounds of formula (IIc), R²⁰，R²¹And R²²Is hydrogen and R²³-R²⁷Is independently selected from:

-C_1-10an alkyl group, a carboxyl group,

-a cycloalkyl group,

-a heterocyclic group,

-a trifluoroalkyl group, a trifluoromethyl group,

-a halogen, in the form of a halogen,

-a nitro group,

-a carboxyl group,

-CO₂-C_1-10an alkyl group, a carboxyl group,

-C_1-10alkylene-CO₂-C_1-10An alkyl group, a carboxyl group,

-C_2-10alkenylene-CO₂-C_1-10An alkyl group, a carboxyl group,

-C_1-10alkylene-CO₂H，

-C_2-10alkenylene-CO₂H，

-O-C_1-10alkylene-C (O) NH-C_1-10An alkyl group, a carboxyl group,

-C(O)-C_1-10an alkyl group, a carboxyl group,

-C(O)NH-C_1-10an alkyl group, a carboxyl group,

-an O-heterocyclic group,

-O-C_1-10an alkyl group, a carboxyl group,

-O-C_1-10a halogenated alkyl group,

-O-C_1-10a perhalogenated alkyl group, a halogen atom,

-an O-cycloalkyl group, a cycloalkyl group,

-an O-phenyl group, which is,

-a hydroxyl group,

-O-C_1-10an alkylene-cycloalkyl group, which is,

-O-C_1-10an alkylene-phenyl group, which is a phenyl group,

-an S-heterocyclic group,

-S-C_1-10an alkyl group, a carboxyl group,

-S-C_1-10a halogenated alkyl group,

-S-C_1-10a perhalogenated alkyl group, a halogen atom,

-an S-cycloalkyl group,

-a group of the groups-S-phenyl,

-S-C_1-10an alkylene-cycloalkyl group, which is,

-S-C_1-10an alkylene-phenyl group, which is a phenyl group,

-C_1-10an alkylene-cycloalkyl group, which is,

-C_1-10an alkylene-phenyl group, which is a phenyl group,

-an amino group,

-NH(C_1-10an alkyl group),

-N(C_1-10alkyl radical)₂，

-N(C_1-10Alkyl) (C_1-10Alkylene-cycloalkyl) groups,

-NHCO₂-C_1-10an alkyl group, a carboxyl group,

-NH(C_1-10alkylene-cycloalkyl) groups,

-S(O)₂-C_2-10an alkyl group, a carboxyl group,

-SO₂-a cycloalkyl group,

-SO₂-C_1-10an alkylene-cycloalkyl group, which is,

-S(O)-C_1-10an alkyl group, a carboxyl group,

-S (O) -cycloalkyl, and

-S(O)-C_1-10an alkylene-cycloalkyl group, which is,

wherein alkyl, alkenyl, aryl, heteroaryl and cycloalkyl are optionally independently selected from R^cSubstituted 1-4 times.

In another embodiment of the compounds of formula (IIc), R²⁰，R²¹And R²²Is hydrogen and R²³-R²⁷Is independently selected from:

-C_1-10an alkyl group, a carboxyl group,

-a cycloalkyl group,

-a heterocyclic group,

-a trifluoroalkyl group, a trifluoromethyl group,

-a halogen, in the form of a halogen,

-a nitro group,

-CO₂-C_1-10an alkyl group, a carboxyl group,

-C_1-10alkylene-CO₂-C_1-10An alkyl group, a carboxyl group,

-C_2-10alkenylene-CO₂-C_1-10An alkyl group, a carboxyl group,

-O-C_1-10alkylene-C (O) NH-C_1-10An alkyl group, a carboxyl group,

-C(O)-C_1-10an alkyl group, a carboxyl group,

-C(O)NH-C_1-10an alkyl group, a carboxyl group,

-an O-heterocyclic group,

-O-C_1-10an alkyl group, a carboxyl group,

-O-C_1-10a halogenated alkyl group,

-O-C_1-10a perhalogenated alkyl group, a halogen atom,

-an O-cycloalkyl group, a cycloalkyl group,

-an O-phenyl group, which is,

-O-C_1-10an alkylene-cycloalkyl group, which is,

-O-C_1-10an alkylene-phenyl group, which is a phenyl group,

-an S-heterocyclic group,

-S-C_1-10an alkyl group, a carboxyl group,

-S-C_1-10a halogenated alkyl group,

-S-C_1-10a perhalogenated alkyl group, a halogen atom,

-an S-cycloalkyl group,

-a group of the groups-S-phenyl,

-S-C_1-10an alkylene-cycloalkyl group, which is,

-S-C_1-10an alkylene-phenyl group, which is a phenyl group,

-C_1-10an alkylene-cycloalkyl group, which is,

-C_1-10an alkylene-phenyl group, which is a phenyl group,

-NH(C_1-10an alkyl group),

-N(C_1-10alkyl radical)₂，

-N(C_1-10Alkyl) (C_1-10Alkylene-cycloalkyl) groups,

-NHCO₂-C_1-10an alkyl group, a carboxyl group,

-NH(C_1-10alkylene-cycloalkyl) groups,

-S(O)₂-C_2-10an alkyl group, a carboxyl group,

-SO₂-a cycloalkyl group,

-SO₂-C_1-10an alkylene-cycloalkyl group, which is,

-S(O)-C_1-10an alkyl group, a carboxyl group,

-S (O) -cycloalkyl, and

-S(O)-C_1-10alkylene-cycloalkyl groups.

In another embodiment of the compounds of formula (IIc), R²⁰，R²¹And R²²Is hydrogen and R²³-R²⁷Is independently selected from:

-C_1-10an alkyl group, a carboxyl group,

-a cycloalkyl group,

-a trifluoroalkyl group, a trifluoromethyl group,

-a halogen, in the form of a halogen,

-CO₂-C_1-10an alkyl group, a carboxyl group,

-C_1-10alkylene-CO₂-C_1-10An alkyl group, a carboxyl group,

-C_2-10alkenylene-CO₂-C_1-10An alkyl group, a carboxyl group,

-O-C_1-10alkylene-C (O) NH-C_1-10An alkyl group, a carboxyl group,

-C(O)-C_1-10an alkyl group, a carboxyl group,

-O-C_1-10an alkyl group, a carboxyl group,

-O-C_1-10a halogenated alkyl group,

-O-C_1-10a perhalogenated alkyl group, a halogen atom,

-an O-cycloalkyl group, a cycloalkyl group,

-an O-phenyl group, which is,

-O-C_1-10an alkylene-cycloalkyl group, which is,

-O-C_1-10an alkylene-phenyl group, which is a phenyl group,

-S-C_1-10an alkyl group, a carboxyl group,

-S-C_1-10a halogenated alkyl group,

-S-C_1-10a perhalogenated alkyl group, a halogen atom,

-an S-cycloalkyl group,

-a group of the groups-S-phenyl,

-S-C_1-10an alkylene-cycloalkyl group, which is,

-S-C_1-10an alkylene-phenyl group, which is a phenyl group,

-C_1-10an alkylene-cycloalkyl group, which is,

-C_1-10an alkylene-phenyl group, which is a phenyl group,

-S(O)₂-C_2-10an alkyl group, a carboxyl group,

-SO₂-a cycloalkyl group,

-SO₂-C_1-10an alkylene-cycloalkyl group, which is,

-S(O)-C_1-10an alkyl group, a carboxyl group,

-S (O) -cycloalkyl, and

-S(O)-C_1-10alkylene-cycloalkyl groups.

In another embodiment of the compounds of formula (IIc), R²⁰，R²¹And R²²Is hydrogen and R²³-R²⁷Is independently selected from:

a group of morpholine-4-yl and a group of morpholine-4-yl,

a piperidin-4-yl group, a pharmaceutically acceptable salt thereof,

a piperidin-1-yl group,

(ii) a 4-piperidinyl-oxy group,

(ii) a 3-piperidinyl-oxy group,

2-oxo-piperidin-1-yl group,

3-oxo-piperidin-1-yl group,

[1-(C_1-10alkylsulfonyl) -piperidin-4-yl]-an oxygen radical,

[1-(C_1-10alkoxycarbonyl) -piperidin-4-yl]-an oxygen radical,

[1-(C_1-10alkoxycarbonyl) -piperidin-3-yl]-an oxygen radical,

a piperazine-1-yl group,

4-(C_1-10alkyl) -piperazin-1-yl group,

2-oxo-piperazin-4-yl,

1-C_1-10alkyl-2-oxo-piperazin-4-yl,

1-cycloalkyl-2-oxo-piperazin-4-yl,

4-a-tetrahydropyranyloxy group,

3-a group of oxygen-containing groups selected from the group consisting of 3-tetrahydrofuranyl,

4-(C_1-10alkoxycarbonyl) piperazin-1-yl,

a pyrrolidin-1-yl group which is,

3-phenyl-pyrrolidin-1-yl,

3-cycloalkyl-pyrrolidin-1-yl,

[1-(C_1-10alkoxycarbonyl) -pyrrolidin-3-yl]-an oxygen radical,

2-phenylthio-oxy-group in the amino group,

2-thiazolyl-oxy-group(s),

(1, 2, 4-oxadiazol-3-yl) -oxy,

(1-methyl-imidazol-2-yl) -oxy, and

(imidazol-2-yl) -C_1-10An alkoxy group,

wherein alkyl, phenyl, cycloalkyl, morpholine, piperidine, piperazine, cyclicThe alkyl, tetrahydropyran, tetrahydrofuran, pyrrolidine, thiazole, imidazole groups are optionally independently selected from R^cIs substituted with a group (b).

In another embodiment of the compounds of formula (IIc), R²⁰，R²¹And R²²Is hydrogen and R²³-R²⁷Is independently selected from: methyl, ethyl, propyl, butyl, pentyl, hexyl, 1-ethyl-propyl, 1-propyl-butyl, 3, 3-dimethyl-butyl, 4-methyl-pentyl, 4, 4-dimethyl-pentyl, 1- (3, 3-dimethyl-butyl) -4, 4-dimethyl-pentyl, isobutyl, isopropyl, sec-butyl, tert-butyl, trifluoromethyl, 4, 4, 4-trifluorobutoxy, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexyloxy, isobutoxy, isopropoxy, tert-butoxy, 2-phenethyloxy, 2, 2-dimethylpropoxy, 3-methyl-butoxy, 3, 3-dimethyl-butoxy, 3' -phenethyloxy, 2-cyclohexyl-ethanesulfonyl, 3, 3-dimethyl-butane-1-sulfonyl, cyclohexanesulfonyl, cyclohexylmethanesulfonyl, cyclohexylmethylsulfonyl, 2-cyclohexyl-ethanesulfinyl, 3, 3-dimethyl-butane-1-sulfinyl, cyclohexylmethylsulfinyl, 2-cyclohexyl-ethylsulfanyl, 3, 3-dimethyl-butylsulfanyl, phenethylsulfanyl, cyclohexylmethylsulfanyl, cyclopentyl, cyclohexyl, cyclopentyloxy, cyclohexyloxy, cyclopentylmethyl, cyclohexylmethyl, 2-cyclopentylethyl, 2-cyclohexylethyl, cyclopentylmethoxy, cyclohexylmethoxy, 2-cyclopentylethoxy, 2-cyclohexylethoxy, 2-cyclohexyl-vinyl, 3-ethyl-cyclobutyl, chloro, fluoro and phenyl.

In another embodiment of the compounds of formula (IIc), V is C, W is N, X is C, Y is N, Z is C-R⁶And the sides a, c and d are single bonds and the sides b and e are double bonds and R⁶Selected from hydrogen and-C_1-10An alkyl group.

In another embodiment of the compounds of formula (IIc), D¹Is C-R²¹，D²Is C-R²²，R²¹And R²²Is hydrogen, D³Is C-R²³And D⁴Is C-R²⁴. In another embodiment, D¹Is C-R²¹，D²Is C-R²²，R²¹And R²²Is hydrogen and D³And D⁴Is N.

In one embodiment of the compounds of formula (IIc), G is

Wherein

a) q is 2 and D is C (R)⁷)(R⁸) E is C (R)⁷) Or N, in which case the edge f is a single bond, or

b) q is 2 and D is C (R)⁷) And E is C, in which case the side f is a double bond.

In another embodiment, R⁷And R⁸Selected from: hydrogen and C_1-4An alkyl group.

In another embodiment of the compounds of formula (IIc), G is

Wherein

q is 2 and D is C (R)⁷)(R⁸) E is N and the side f is a single bond.

In another embodiment, R⁷And R⁸Selected from: hydrogen and C_1-4An alkyl group.

In another embodiment, G is

Wherein

a) q is 2 and D is C (R)⁷) E is C (R)⁷)(R⁸) Or N (R)⁹) When the side f is a single bond, or

b) q is 2, D is C, E is C (R)⁷) Or N, in which case the edge f is a double bond.

In another embodiment, R⁷，R⁸And R⁹Selected from: hydrogen and C_1-4An alkyl group.

In another embodiment of the compounds of formula (IIc), the compounds have the formula:

in another embodiment of the compounds of formula (IIc), the compounds have the formula:

in the compounds of the formula (I-IV), the various functional groups are to be understood as having a point of attachment to the functional group bearing a hyphen. In other words, in the case of-alkylene-aryl, it is to be understood that the point of attachment is an alkylene group; an example may be benzyl. For groups such as-C (O) -NH-alkylene-aryl, the point of attachment is the carbonyl carbon.

Also included within the scope of the present invention are the individual enantiomers of the compounds represented by formulas (I-IV) above, and any fully or partially racemic mixtures thereof. The invention also covers mixtures of individual enantiomers of compounds represented by the above formula with their diastereomers, wherein one or more stereocenters are inverted. Unless otherwise indicated, structures shown herein are meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. E.g. to remove hydrogen atomsBy deuterium or tritium, or by carbon atoms¹³C or¹⁴Compounds having the present structure in addition to C-rich carbon substitution are within the scope of the present invention.

In another aspect, the invention provides pharmaceutically acceptable salts, solvates or prodrugs of the compounds of formula (I-IV). In one embodiment, the prodrug comprises a biohydrolyzable ester or biohydrolyzable amide of the compound of formula (I-IV).

Examples of potentially useful biological activities of the compounds of formula (I-IV) of the present invention are described by the names in Table 1 below. Using representative compounds of formula (I-IV) listed in Table I, the ability of compounds of formula (I-IV) to inhibit PTP1B was established using standard primary/secondary assay procedures for determining inhibition of PTP1B activity. The compounds of formula I in Table I can be present at less than 10 micromolar (. mu.M; 10)^-6M) inhibits PTP-1B.

Compounds that inhibit PTP-1B activity are potentially useful in the treatment of metabolic diseases associated with insulin resistance or hyperglycemia, typically associated with obesity or glucose intolerance. Part of the compounds of the formulae (I-IV) can thus be used in particular for the treatment or inhibition of type II diabetes. The compounds of the present invention can also be used to modulate glucose levels in conditions such as type I diabetes.

TABLE 1

The incomplete valences of heteroatoms, such as oxygen and nitrogen, on the chemical structures listed in table 1 are assumed to be completely hydrogen.

In another aspect, the invention includes a pharmaceutical composition comprising a compound of formula (I-IV) and a pharmaceutically acceptable carrier, excipient, diluent, or mixture thereof.

The term "lower" as used herein refers to a group having 1 to 6 carbons.

The term "alkyl" as used herein refers to a straight or branched chain hydrocarbon having from 1 to 10 carbon atoms, optionally substituted and allowing multiple degrees of substitution. Examples of "alkyl" as used herein include, but are not limited to, methyl, n-butyl, t-butyl, n-pentyl, isobutyl, and isopropyl, and the like.

The term "alkylene" as used herein refers to a straight or branched chain divalent hydrocarbon having from 1 to 10 carbon atoms, optionally substituted and allowing for multiple degrees of substitution. Examples of "alkylene" as used herein include, but are not limited to, methylene, ethylene, and the like.

The term "alkenyl" as used herein refers to straight or branched chain hydrocarbons having from 2 to 10 carbons and at least one carbon-carbon double bond, optionally substituted and allowing a multiple degree of substitution. Examples of "alkenyl" as used herein include, but are not limited to, 3-dimethyl-but-1-enyl, 4-hex-1-enyl, and the like.

The term "alkenylene" as used herein refers to a straight or branched chain divalent hydrocarbon with 2-10 carbons and one or more carbon-carbon double bonds, optionally substituted and allowing for multiple degrees of substitution. Examples of "alkenylene" as used herein include, but are not limited to, ethylene-1, 2-diyl, propylene-1, 3-diyl, methylene-1, 1-diyl, and the like.

The term "alkynyl" as used herein refers to hydrocarbons having from 2 to 10 carbons and at least one carbon-carbon triple bond, optionally substituted and allowing for multiple degrees of substitution. Examples of "alkynyl" as used herein include, but are not limited to, 4-hex-1 alkynyl, 3, 3-dimethyl-but-1 alkynyl, and the like.

The term "alkynylene" as used herein refers to a straight or branched chain divalent hydrocarbon with 2 to 10 carbon atoms and one or more carbon-carbon triple bonds, optionally substituted and allowing for multiple degrees of substitution. Examples of "alkynylene" as used herein include, but are not limited to, acetylene-1, 2-diyl, propyne-1, 3-diyl, and the like.

As used herein, "cycloalkyl" refers to an alicyclic hydrocarbon group and optionally having one or more degrees of unsaturation, optionally substituted and allowing for multiple degrees of substitution. Examples of "cycloalkyl" as used herein include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like.

The term "cycloalkylene" as used herein refers to a non-aromatic cycloaliphatic divalent hydrocarbon radical having from 3 to 12 carbon atoms and optionally having one or more degrees of unsaturation, which is optionally substituted and allows for multiple degrees of substitution. Examples of "cycloalkylene" groups as used herein include, but are not limited to, cyclopropyl-1, 1-diyl, cyclopropyl-1, 2-diyl, cyclobutyl-1, 2-diyl, cyclopentyl-1, 3-diyl, cyclohexyl-1, 4-diyl, cycloheptyl-1, 4-diyl, cyclooctyl-1, 5-diyl, and the like.

The term "heterocycle" or the term "heterocyclyl" as used herein refers to a non-aromatic 3-12 membered heterocyclic ring, optionally having one or more degrees of unsaturation, comprising one or more groups selected from S, SO₂Heteroatom substitution of O or N, optionally substituted and allowing for multiple degrees of substitution. Such rings may optionally be fused to one or more of another "heterocyclic" or cycloalkyl ring. Examples of "heterocyclyl" include, but are not limited to, tetrahydrofuran, tetrahydropyran, 1, 4-dioxane, 1, 3-dioxane, piperidine, pyrrolidine, morpholine, piperazine, and the like.

The term "heterocyclylene" as used herein refers to a non-aromatic 3-12 membered heterocyclic diradical, optionally with one or more unsaturations, comprising one or more groups selected from S, SO₂Heteroatom of O or N, optionally substituted and allowing for multiple degrees of substitution. Such rings may optionally be fused with one or more benzene rings or one or more of another "heterocyclic" or cycloalkyl ring. Examples of "heterocyclylene" include, but are not limited to, tetrahydrofuran-2, 5-diyl, morpholine-2, 3-diyl, pyran-2, 4-diyl, 1, 4-dioxane-2, 3-diyl, 1, 3-dioxane-2, 4-diyl, piperidine-1, 4-diyl, pyrrolidine-1, 3-diyl, morpholine-2, 4-diyl, piperazine-1, 4-diyl, and the like.

The term "aryl" as used herein refers to a benzene ring or a benzene ring fused with 1 to 3 benzene rings, which is optionally substituted and allows for multiple degrees of substitution. Examples of aryl groups include, but are not limited to, phenyl, 2-naphthyl, 1-anthracenyl, and the like.

The term "arylene" as used herein refers to a phenyl ring diradical or a phenyl ring system diradical fused to 1-3 optionally substituted phenyl rings, which is optionally substituted and allows for multiple degrees of substitution. Examples of "arylene" include, but are not limited to, benzene-1, 4-diyl, naphthalene-1, 8-diyl, and the like.

The term "heteroaryl" as used herein refers to a 5-to 7-membered aromatic or polycyclic heterocyclic aromatic ring containing one or more nitrogen, oxygen or sulfur heteroatoms, wherein the N-oxide and sulfur monoxide and sulfur dioxide are permissible heteroaromatic substitutions, optionally substituted and permissible degrees of substitution. In the case of polycyclic aromatic ring systems, one or more of the rings may contain one or more heteroatoms. Examples of "heteroaryl" as used herein include, but are not limited to, furan, thiophene, pyrrole, imidazole, pyrazole, triazole, tetrazole, thiazole, oxazole, isoxazole, oxadiazole, thiadiazole, isothiazole, pyridine, pyridazine, pyrazine, pyrimidine, quinoline, isoquinoline, quinazoline, benzofuran, benzothiophene, indole, and indazole, and the like.

The term "heteroarylene" as used herein refers to a 5-to 7-membered aromatic ring diradical or polycyclic heterocyclic aromatic ring diradical containing one or more nitrogen, oxygen or sulfur heteroatoms wherein the N-oxide and sulfur monoxide and sulfur dioxide are permissible heteroaromatic substitutions, optionally substituted and permissible degrees of substitution. In the case of polycyclic aromatic ring system diradicals, one or more of the rings may contain one or more heteroatoms. Examples of "heteroarylene" as used herein include, but are not limited to, furan-2, 5-diyl, thiophene-2, 4-diyl, 1, 3, 4-oxadiazole-2, 5-diyl, 1, 3, 4-thiadiazole-2, 5-diyl, 1, 3-thiazole-2, 4-diyl, 1, 3-thiazole-2, 5-diyl, pyridine-2, 4-diyl, pyridine-2, 3-diyl, pyridine-2, 5-diyl, pyrimidine-2, 4-diyl, quinoline-2, 3-diyl, and the like.

The term "direct bond" as used herein, wherein the portion of the variable specification of a structure refers to a direct link that flanks (before and after) the variable considered a "direct bond". If two or more consecutive variables are each designated as a "direct bond", then those substituents (preceding and succeeding) that flank those two or more consecutive designated "direct bonds" are directly linked.

The term "alkoxy" as used herein refers to the group R_aO-, wherein R_aIs an alkyl group.

The term "alkenyloxy" as used herein refers to the group R_aO-, wherein R_aIs an alkenyl group.

The term "alkynyloxy" as used herein refers to the group R_aO-, wherein R_aIs an alkynyl group.

The term "alkylsulfanyl" as used herein refers to the group R_aS-, wherein R_aIs an alkyl group.

The term "alkenylsulfanyl" as used herein refers to the group R_aS-, wherein R_aIs an alkenyl group.

The term "alkynylsulfanyl" as used herein refers to the group R_aS-, wherein R_aIs an alkynyl group.

The term "alkylsulfinyl", as used herein, refers to the group R_aS (O) -, wherein R_aIs an alkyl group.

The term "alkenylsulfinyl" as used herein refers to the group R_aS (O) -, wherein R_aIs an alkenyl group.

The term "alkynylsulfinyl" as used herein refers to the group R_aS (O) -, wherein R_aIs an alkynyl group.

The term "alkylsulfonyl" as used herein refers to the group R_aSO₂-, wherein R_aIs an alkyl group.

Terms used herein"Alkenylsulfonyl" means a group R_aSO₂-, wherein R_aIs an alkenyl group.

The term "alkynylsulfonyl" as used herein refers to the group R_aSO₂-, wherein R_aIs an alkynyl group.

The term "acyl" as used herein refers to the group R_aC (O) -, wherein R_aIs alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl or heterocyclyl.

The term "aroyl" as used herein refers to the group R_aC (O) -, wherein R_aIs an aryl group.

The term "heteroaroyl" as used herein refers to the group R_aC (O) -, wherein R_aIs heteroaryl.

The term "alkoxycarbonyl" as used herein refers to the group R_aOC (O) -, wherein R_aIs an alkyl group.

The term "acyloxy", as used herein, refers to a group R_aC (O) O-, wherein R_aIs alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl or heterocyclyl.

The term "aroyloxy" as used herein refers to the group R_aC (O) O-, wherein R_aIs an aryl group.

The term "heteroaroyl" as used herein refers to the group R_aC (O) O-, wherein R_aIs heteroaryl.

The term "optionally" as used herein means that the subsequently described event may or may not occur, and includes both events that occur and events that do not occur.

The term "substituted" as used herein means that one or more hydrogens of the designated moiety are replaced with a substituent or substituents, unless otherwise stated, allowing for multiple degrees of substitution, provided that the substitution results in a stable or chemically feasible compound. A stable or chemically feasible compound is one in which the chemical structure does not substantially change for at least 1 week, or maintain its integrity, in the absence of humidity or other chemical reaction conditions, at a temperature of about-80 ℃ to about +40 ℃, for a length of time sufficient for therapeutic or prophylactic administration to a patient. The term "substituent(s)" as used herein refers to a number of substituents equal to from one (from on) to the maximum number of substituents possible based on available binding sites, provided that the conditions of stability and chemical feasibility described above are met.

The term "comprising" or "contains" as used herein may mean substituted at any position along the above defined alkyl, alkenyl, alkynyl or cycloalkyl group by any O, S, SO₂In-line substitution of one or more of N or N-alkyl groups, including, for example, -CH₂-O-CH₂-，-CH₂-SO₂-CH₂-，-CH₂-NH-CH₃And the like.

Whenever any of the terms "alkyl" or "aryl" or prefix roots appear in a substituent name (e.g., arylalkoxyaryloxy), they should be considered to include those limitations specified for "alkyl" and "aryl" above. Number of carbon atoms specified (e.g. C)_1-10) Shall independently refer to alkyl moieties having a number of carbon atoms or larger substituents on the alkyl, alkenyl or alkynyl or cycloalkyl moiety, wherein the term "alkyl" appears as its prefix root.

The term "oxo" as used herein shall mean the substituent ═ O.

As used herein, the term "halogen" or "halogen (halo)" shall include iodine, bromine, chlorine and fluorine.

The term "mercapto" as used herein shall refer to the substituent-SH.

The term "carboxy" as used herein shall mean the substituent-COOH.

The term "cyano" as used herein shall mean the substituent-CN.

The term "aminosulfonyl" as used herein shall mean the substituent-SO₂NH₂。

As used herein, the term "carbamoyl" shall mean the substituent-C (O) NH₂。

The term "thioalkyl" as used herein shall mean the substituent-S-.

The term "sulfinyl" as used herein shall mean the substituent-S (O) -.

The term "sulfonyl", as used herein, shall mean the substituent-S (O)₂-。

The term "haloalkyl" as used herein refers to a straight or branched chain hydrocarbon having 1 to 10 carbon atoms, which is substituted with at least one halogen atom and optionally substituted with halogen atoms in the remaining positions. Haloalkyl groups may be substituted with one or more types of halogen atoms. Examples of "haloalkyl" as used herein include, but are not limited to, trifluoromethyl, 2, 2, 2-trifluoroethyl, and the like.

The term "perhaloalkyl" as used herein refers to a straight or branched chain hydrocarbon having 1 to 10 carbon atoms, which is substituted with a halogen atom at each position for substitution. The perhaloalkyl group may be substituted with one or more types of halogen atoms. Examples of "perhaloalkyl" as used herein include, but are not limited to, trifluoromethyl and 1, 1-dichloro-2, 2, 2-trifluoroethyl and the like.

Compounds may be prepared according to the following reaction schemes using readily available starting materials and reagents (where the variables are as defined or defined above). In these reactions, it is also possible to use variants which are known per se to the person skilled in the art, but which are not mentioned in detail.

The invention also provides methods for synthesizing intermediates useful for preparing compounds of formula (I-IV) and methods for preparing compounds of formula (I-IV). Unless otherwise stated, the structural variables in the following schemes are as defined for formulas (I-IV). In schemes 1-7, Ar^aAnd Ar^dCan be a ring selected from: a phenyl group, an indanyl group,tetrahydronaphthyl, pyridazine, pyrimidine, pyrazine, pyridine, piperidine, 4, 5-diaza-indanyl, 5, 6, 7, 8-tetrahydro-cinnoline and 1-H-pyridin-2-one, 5, 6, 7, 8-tetrahydro-cinnoline, wherein Ar is^aAnd Ar^dOptionally substituted with R^bAnd (4) substitution. In one embodiment, Ar^aAnd Ar^dForm a biphenyl radical, wherein Ar^dIs unsubstituted and Ar^aBy R^bAnd 1-3 times of substitution. In schemes 1-7, L^aIs a linking group, including, but not limited to C_1-10Alkylene and a direct bond. In one embodiment, L^aCan be-CH₂-. In the scheme other than scheme 1, for simplicity of the drawing, the group-R^1-5Substituted phenyl is used to mean having the radical R¹，R²，R³，R⁴And R⁵A phenyl group of (a).

The compound of formula (1) may be prepared according to scheme 1. In one embodiment, the bromo or iodo aryl compound (2) may be reacted with an optionally substituted boronic acid Ar^d-B(OH)₂Palladium catalyzed coupling was performed (syn. Commu.1981, 11, 513-. Typical conditions for carrying out the coupling reaction include the use of boronic acid or ester as coupling partner, a palladium catalyst (2-20 mol%), such as Pd (PPh), in a suitable solvent, such as aqueous dimethoxyethane, THF, acetone, DMF or toluene, at a temperature of 25 deg.C to 125 deg.C₃)₄Or [1, 1-bis (diphenylphosphino) -dicyclopentadiene]Dichloro-palladium (II) and a base such as potassium carbonate, sodium carbonate, barium hydroxide, potassium phosphate or triethylamine.

Scheme 1

In scheme 2, in formula Ar^d-B(OH)₂In the boronic acid position, the formula R can be used^f-CH＝CH-B(OH)₂To produce a compound of formula (3). Alternatively, 9-BBN derived alkenylboranes may be used to synthesize similar compounds.

Scheme 2

In another embodiment, aryl bromides of formula (2) may be coupled with acetylene as shown in scheme 3 under Sonogashihara reaction conditions to prepare compounds of formula (4).

Scheme 3

The construction of the isothiazolidinedione dioxides of the compounds of formula (2) is summarized in scheme 4. The nitro group of the aryl nitro compound (5) can be reduced to the aniline using iron-acetic acid or in various other well known reagent systems. The resulting anilines are converted into α -substituted glycine ester derivatives (6) by alkylating amines using α -bromoacetate derivatives. The glycine ester derivative (6) is then treated with chlorosulfonyl isocyanate, followed by t-butanol to form sulfamoyl chloride. The sulfamoyl carbamate is treated with trifluoroacetic acid, followed by sodium hydroxide to provide the bromoaryl compound (2).

Scheme 4

In another approach to prevent the chemoselectivity problem from arising, it is possible to use Ar boronic acid^d-B(OH)₂Followed by the isothiazolidinedione dioxide ring construction as described above (scheme 5) to convert glycine ester derivative (6) to the compound of formula (1).

Scheme 5

The arylnitro compounds (5) can be obtained by aromatic nucleophilic substitution of the appropriate halogen-nitrobenzene or by Ullman type reaction on imidazoles of the formula (7).

Scheme 6

Imidazoles of formula (7) may be prepared according to scheme 7. Carboxylic acids (8) may be reacted with aryl acyl bromides in the presence of a base such as DIEA, triethylamine or DBU in a polar solvent such as THF or DMF to give the intermediate keto-ester (10), which may be treated with ammonium acetate in acetic acid at a temperature of 60-120 ℃ to give a mixture of oxazole and imidazole (7) (Strzybny, p.p.e., van Es, t.; Backeberg, o.g., j.org.chem.1963, 25, 1151). The ratio of oxazole to imidazole (7) can vary depending on the substitution and reaction conditions. Oxazole and imidazole can be separated by a silica gel column (7). Alternatively, other conditions may be used to cyclize the keto-ester (10), such as BF₃/Et₂O, methanolic ammonia, at a temperature of room temperature to 120 ℃.

Scheme 7

Imidazoles of formula (1) may also be prepared according to scheme 8. The tertiary amide (11) may be cyclized in a polar solvent such as THF or DMF and ammonium acetate in acetic acid at a temperature of 60-120 deg.C to give imidazole (1).

Scheme 8

Embodiments of the present invention demonstrate the utility in inhibiting the protein tyrosine phosphatase PTP 1B. The compounds of the invention described in the examples of the invention were found to inhibit the protein tyrosine phosphatase PTP1B with an inhibitory potency (IC 50's) of less than about 10. mu.M.

In general, embodiments of the invention for pharmaceutical use may have an inhibitory potency (IC 50's) on a protein of interest of less than about 100 μ M. In one embodiment, embodiments of the invention for pharmaceutical use may have an inhibitory potency (IC 50's) on a protein of interest of less than about 50 μ M. For specific applications, lower inhibitory potency is useful. Thus, in another embodiment, the compounds of the present invention inhibit the protein tyrosine phosphatase PTP1B with an inhibitory potency (IC 50's) of about 0.001. mu.M to about 10. mu.M. In another embodiment, the compounds of the present invention inhibit the protein tyrosine phosphatase PTP1B with an inhibitory potency (IC 50's) of about 0.001. mu.M to about 3. mu.M.

Embodiments of the compounds of the present invention exhibit utility as inhibitors of protein tyrosine phosphatases (PTPases). Embodiments of the invention described herein are also directed to pharmaceutical compositions and methods of inhibiting PTPase activity in a mammal comprising administering to a mammal in need of PTPase activity inhibition a therapeutically determined amount of a compound of formulae (I-IV) as defined above, as its mono-and polymorph, amorphous, single enantiomer, racemic mixture, single stereoisomer, mixture of stereoisomers, single diastereomer, mixture of diastereomers, isotopically enriched form, solvate, pharmaceutically acceptable salt, solvate, prodrug, biohydrolyzable ester or biohydrolyzable amide.

The terms "pharmaceutically acceptable carrier", "pharmaceutically acceptable diluent" and "pharmaceutically acceptable excipient" as used herein refer to a carrier, diluent or excipient that must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

The term "therapeutically effective amount" as used herein, means that amount of active compound or pharmaceutically active agent that elicits the biological or medical response in a tissue, system, animal or human that is being sought by a researcher, veterinarian, clinician or other clinician, which includes alleviation of the symptoms of the disease being treated. When the active compound (i.e., active ingredient) is administered as a salt, the amount of active ingredient refers to the free acid or free base form of the compound.

Accordingly, the present invention provides a method of inhibiting PTPase comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the present invention. The invention further provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of the invention sufficient to inhibit PTPase. The amount that inhibits the PTPase can be an amount that reduces or inhibits PTPase chemistry in the subject.

The compounds of formula (I-IV) may include a single or polymorph, amorphous, single enantiomer, racemic mixture, single stereoisomer, mixture of stereoisomers, single diastereomer, mixture of diastereomers, isotopically enriched form, solvate, pharmaceutically acceptable salt, solvate, prodrug, biohydrolyzable ester or biohydrolyzable amide thereof.

Also provided are pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of formulae (I-IV) of the invention sufficient to treat glucose intolerance.

In addition, the present invention provides pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of formula (I-IV) of the present invention sufficient to treat type I diabetes.

In addition, the present invention provides pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of formula (I-IV) of the present invention sufficient to treat type II diabetes.

In addition, the present invention provides pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of formula (I-IV) of the present invention sufficient to treat immune dysfunction. In one embodiment, the immune dysfunction is AIDS. In another embodiment, the immune dysfunction is an allergic disease. In another embodiment, the immune dysfunction is an inflammatory disease. In another embodiment, the immune dysfunction is an autoimmune disease. In another embodiment, the immune dysfunction is an autoimmune disease selected from psoriasis.

In addition, the present invention provides pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of formula (I-IV) of the present invention sufficient to treat obesity.

In addition, the present invention provides pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of formula (I-IV) of the present invention sufficient to treat cancer.

In addition, the present invention provides pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of formula (I-IV) of the present invention sufficient to treat infectious diseases.

In addition, the present invention provides pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of formula (I-IV) of the present invention sufficient to treat diseases in which the regulation of growth hormone synthesis is involved.

In addition, the present invention provides pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of formulae (I-IV) of the present invention sufficient to treat diseases involving, at least in part, modulation of growth factor or cytokine synthesis affecting growth hormone production.

In addition, the present invention provides pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of formula (I-IV) of the present invention sufficient to treat Alzheimer's disease.

The compounds of the invention may be administered to a subject in need of inhibition of PTPase activity. Such subjects can include, for example, horses, cattle, sheep, pigs, mice, dogs, cats, primates, such as chimpanzees, gorillas, macaques, and humans. In one embodiment, the subject is a human in need of inhibition of PTPase activity.

Pharmaceutical compositions containing the compounds of the present invention may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules or syrups or elixirs. Compositions intended for oral use may be prepared according to any known method and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to obtain pharmaceutically elegant and palatable preparations. Tablets may comprise the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, such as corn starch or alginic acid; binding agents, for example starch, gelatin or acacia; and lubricating agents, such as magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. They may also be coated by techniques that form osmotic therapeutic tablets for controlled release.

Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example calcium carbonate, calcium phosphate or kaolin; or making them into soft capsules, wherein the active ingredient is mixed with water or an oil medium, such as peanut oil, liquid paraffin, or olive oil.

Aqueous suspensions may contain the active compound in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, sodium hydroxypropylmethylcellulose alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be naturally occurring phosphatides, such as lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids or a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids or hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.

Oil suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oil suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents, such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an antioxidant, such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active compound in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are typical as described above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present.

The pharmaceutical composition of the present invention may also be in the form of an oil-in-water emulsion. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures thereof. Suitable emulsifying agents may be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavoring agents.

Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain emollients, preservatives and flavoring and coloring agents. The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleaginous suspension. The suspension may be formulated according to known methods using suitable dispersing or wetting agents and suspending agents, as described above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example, as a solution in 1, 3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, ringer's solution and isotonic sodium chloride solution, and, in addition, sterile, fixed oils are commonly used as a solvent or suspending medium. For this purpose, any bland fixed oil employing synthetic mono-or diglycerides may be used. In addition, fatty acids, such as oleic acid find use in the preparation of injectables.

The compositions may also be in the form of suppositories for rectal administration of the compounds of the invention. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials include, for example, cocoa butter and polyethylene glycols.

For topical application, creams, ointments, jellies, solutions or suspensions (solutions of suspensions), etc., containing the compounds of the present invention are contemplated. For the purpose of this application, topical application shall include mouth washes and gargles.

The compounds of the invention may also be administered in the form of liposome delivery systems, such as small unilamellar liposomes, large unilamellar liposomes and multilamellar liposomes. Liposomes can be composed of various phospholipids, such as cholesterol, octadecanamide or phosphatidylcholine.

The invention also provides prodrugs of the invention. Pharmaceutically acceptable salts of the compounds of the present invention having basic or acidic groups in the structure are also included within the scope of the present invention. The term "pharmaceutically acceptable salts" refers to non-toxic salts of the compounds of the present invention which are generally prepared by reacting the free base with a suitable organic or inorganic acid or by reacting an acid with a suitable organic or inorganic base. Representative salts include the following: acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate borate, bromide, calcium ethylenediaminetetraacetate, dextrocamphorsulfonic acid, carbonate, chloride, clavulanate, citrate, dihydrochloride, ethylenediaminetetraacetate, edisylate, propionate dodecylsulfate, ethanesulfonate, fumarate, glucoheptonate, gluconate, glutamate, glycollylamino-phenylarsonate, hexylresorcinol, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, laurate, malate, maleate, mandelate, methanesulfonate, methylbromide, methylnitrate, methylsulfate, monopotassium maleate, mandelate, nitrate, N-methylglucamine, oxalate, pamoate (pamoate), palmitate, phosphate/diphosphate, polygalacturonate, potassium, salicylate, sodium, stearate, hypoacetate, succinate, tannate, tartrate, 8-chlorotheyl salt, tosylate, triiodonium, trimethylammonium, and valerate. When an acidic substituent is present, such as-COOH, ammonium, morpholinium, sodium, potassium, barium, calcium salts, and the like may be formed, for example, for use as a dosage form. When a basic group is present, such as an amino group or a basic heteroaryl group, such as pyridyl, an acid salt is formed, such as hydrochloride, hydrobromide, phosphate, sulfate, trifluoroacetate, acetate, oxalate, maleate, pyruvate, malonate, succinate, citrate, tartrate, fumarate, mandelate, benzoate, cinnamate, methanesulfonate, ethanesulfonate, picrate, and the like, and includes acids associated with the pharmaceutically acceptable salts listed in the Journal of Pharmaceutical Science, 66, 2(1977) p.1-19.

The term "other pharmaceutically acceptable counter-ions" as used herein refers to non-toxic counter-ions such as, but not limited to, ammonium, morpholinium, sodium, potassium, barium, calcium, and the like, and may be obtained by reacting the acidic hydrogen of a thiadiazolidine derivative with a suitable organic or inorganic base.

Other salts which are not pharmaceutically acceptable may be used in the preparation of the compounds of the invention and which form a further aspect of the invention.

In addition, certain compounds of the present invention may form solvates with water or common organic solvents. Such solvates are also included within the scope of the present invention.

Thus, in another embodiment, there is provided a pharmaceutical composition comprising a compound of the invention, or a pharmaceutically acceptable salt, solvate or prodrug thereof, and one or more pharmaceutically acceptable carriers, excipients or diluents.

The compounds of the present invention may act selectively as inhibitors of one PTPase, preferably one or more other PTPases, and may therefore have advantages over others in the treatment of one or more PTPase-mediated diseases.

In another aspect, the invention can provide a method comprising administering to a human a compound of formula (I-IV). In one embodiment, the invention includes a method of inhibiting a PTPase. Accordingly, one embodiment of the present invention provides a method of treating a disease state mediated at least in part by a PTPase enzyme, comprising administering to a subject in need thereof a compound of the present invention. In alternative embodiments, the diseases treated using the methods of the invention include glucose intolerance, including type I and type II diabetes, immune dysfunction, including AIDS, allergic diseases, inflammatory diseases, and autoimmunity, such as psoriasis, infectious diseases, obesity, cancer, diseases in which growth hormone synthesis is modulated or growth factor or cytokine synthesis affecting growth hormone production is modulated, or alzheimer's disease. In one embodiment, a therapeutically effective amount may be administered. In another embodiment, a therapeutically effective amount may be administered. In another embodiment, at least one of the compounds of formula (I-IV) is used alone or in combination with one or more well-known therapeutic agents. In another embodiment, the invention provides a method of preventing and/or treating a PTPase-mediated human disease, the treatment comprising alleviating one or more symptoms resulting from the condition, completely curing the particular condition or preventing the onset of the condition, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formulae (I-IV).

In this method, factors that make up an effective amount may be affected including, but not limited to, the size and weight of the subject, the biodegradability of the therapeutic agent, the activity of the therapeutic agent and its bioavailability. The term "subject in need thereof" as used herein includes mammalian subjects, such as humans, who have one or more of the above-mentioned diseases or disease states or are at risk of such diseases or disease states. Thus, within the context of the treatment methods of the present invention, the methods also consist of treating the mammalian subject prophylactically or prior to diagnosis of the onset of such a disease or disease state.

The following is a non-exhaustive list of adjunctive and additional therapeutic agents that may be used in combination with the PTPase inhibitors of the invention:

pharmacological classification of anticancer drugs:

1. an alkylating agent: cyclophosphamide, nitrosoureas, carboplatin, cisplatin, procarbazine;

2. antibiotics: bleomycin, daunorubicin, doxorubicin;

3. antimetabolites: methotrexate, cytarabine, fluorouracil;

4. plant alkaloid: vinblastine, vincristine, etoposide, paclitaxel;

5. hormones: tamoxifen, octreotide acetate, finasteride, flutamide;

6. biological response modifier: interferons, interleukins;

pharmacological score for the treatment of rheumatoid arthritis (inflammation):

1. analgesics: aspirin;

NSAID (non-steroidal anti-inflammatory drug): ibuprofen, naproxen, diclofenac;

DMARD (disease-modifying antirheumatic): methotrexate, gold preparations, hydroxychloroquine, sulfasalazine;

4. biological response modifier, DMARD: etanercept, infliximab;

glucocorticoids

Pharmacological classification for the treatment of diabetes:

1. sulfonylureas: tolbutamide, tolazamide, glibenclamide, glipizide;

2. biguanides: metformin;

3. mixed oral active agents: agents designed to reduce glucose absorption from the intestine (e.g., acarbose), PPAR agonists such as troglitazone, pioglitazone and rosiglitazone), DPP-IV inhibitors, glucokinase activators;

4. insulin, insulin mimetics, insulin secretagogues (e.g., glibenclamide, glipizide), insulin sensitizers;

GLP-1, GLP-1 mimetics;

pharmacological classification for the treatment of alzheimer's disease:

1. cholinesterase inhibitors: tacrine, donepezil;

2. antipsychotic agents: haloperidol, thioridazine;

3. an antidepressant: desipramine, fluoxetine, trazodone, paroxetine;

4. anticonvulsant drugs: carbamazepine, valproic acid;

pharmacological classification for treatment of hyperlipidemia:

HMG CoA reductase inhibitors: lovastatin;

2. bile acid sequestrants such as cholestyramine;

3. a fibrate.

Additional therapeutic agents that may be used in combination with the PTPase inhibitors of the present invention include:

1) an active agent designed to treat prolonged hyperglycemic complications;

2) anti-dyslipidemia drugs such as HMG-CoA reductase inhibitors (statins, e.g. pravastatin); PPARa agonists (fibrates, e.g., gemfibrozil); cholesterol absorption inhibitors (phytosterols, synthesis inhibitors); bile acid absorption inhibitors (IBATi) and niacin and analogues (niacin and slow release formulations);

3) anti-hypertensive agents such as (3 blockers (e.g., atenolol, propranolol); ACE inhibitors (e.g., lisinopril); calcium antagonists (e.g., nifedipine); angiotensin receptor antagonists (e.g., candesartan), antagonists and diuretics (e.g., furosemide, benthiazide);

4) hemostatic modulators, such as antithrombotic agents, fibrinolysis activators, and antiplatelet agents; a thrombin antagonist; a factor X inhibitor; a factor VIIa inhibitor); antiplatelet agents (e.g., aspirin, clopidogrel); anticoagulants (heparin and low molecular weight analogs, hirudin) and warfarin; and

5) anti-inflammatory agents, such as non-steroidal anti-inflammatory agents (e.g., aspirin) and steroidal anti-inflammatory agents (e.g., cortisone).

Antiobesity agents or appetite regulators may also be combined with the compounds of the present invention. Examples of antiobesity agents or appetite regulators that may be used in combination with the compounds of the present invention include, but are not limited to:

an antagonist of the NPY receptor (NPY receptor),

2. melanocyte-concentrating hormone (MCH) antagonists,

(ii) a GHSR antagonist,

(ii) a CRH antagonist which is capable of,

5. a beta 3 adrenergic agonist,

6. a lipase inhibitor (orlistat),

7.5-hydroxytryptamine (and dopamine) reuptake inhibitors (sibutramine, topiramate or axokine),

8. a thyroid receptor beta drug; and/or

9. An anorectic agent (dextroamphetamine, amphetamine, phentermine, phenylpropanolamine or mazindol),

10.CB₁antagonists (rimonabant).

Beta 3 adrenergic agonists with which the compounds of the invention can be used in combination include known beta 3 agonists such as those disclosed in U.S. Pat. Nos. 5,541,204, 5,770,615, 5,491,134, 5,776,983 and 5,488,064.

Examples of lipase inhibitors that may be used in combination with the compounds of the invention include orlistat or ATL-962 (Alizyme).

5-hydroxytryptamine (and dopamine) reuptake inhibitors that may be used in combination with the compounds of the present invention include sibutramine, topiramate (Johnson & Johnson) or axokine (Regeneron).

Examples of thyroid receptor beta compounds that can be used in combination with the compounds of the present invention include thyroid receptor ligands such as those disclosed in WO97/21993(U.Cal SF), WO99/00353(KaroBio) and GB98/284425 (KaroBio).

Anorectic agents which may be used in combination with the compounds of the present invention include dextroamphetamine, phentermine, phenylpropanolamine or mazindol.

Antagonistic CB's which may be used in combination with the compounds of the present invention₁Examples of anti-agents include rimonabant.

In another embodiment, the invention provides a method of treating a disease that is at least partially mediated by a PTPase enzyme stage (i.e., a PTPase mediated disease), comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formulae (I-IV) in combination with a therapeutic agent. Examples of therapeutic agents for combination administration may include, but are not limited to, alkylating agents, antimetabolites, plant alkaloids, antibiotics, hormones, biological response modifiers, analgesics, NSAIDs, DMARDs, glucocorticoids, sulfonylureas, biguanides, acarbose, PPAR agonists, DPP-IV inhibitors, GK activators, insulin mimetics, insulin secretagogues, insulin sensitizers, GLP-1, GLP-1 mimetics, cholinesterase inhibitors, antipsychotics, antidepressants, anticonvulsants, HMG CoA reductase inhibitors, cholestyramine or fibrates.

In general, the compounds of formulae (I-IV) may be administered at dosage levels of about 0.003-500mg/kg body weight of the subject being treated. In one embodiment, the compounds of formula (I-IV) may be administered in a dosage range of about 0.003-200mg/kg body weight/day. In one embodiment, the compounds of formula (I-IV) may be administered in a dosage range of about 0.1-100mg/kg body weight/day. The amount of active ingredient that can be warmed with the carrier to produce a single dose can vary depending upon the host treated and the particular mode of administration. For example, a formulation intended for oral administration to humans may contain 1mg to 2 grams of a compound of formula (I-IV) together with an appropriate and convenient amount of carrier material varying from about 5-95% of the total composition. Unit dosage forms may generally contain from about 5mg to about 500mg of the active ingredient. The dosage may be considered by the clinician according to the individual need based on the specific clinical condition of the subject being treated. It will be understood, therefore, that the specific dose level for any particular patient will depend upon a variety of factors including the specific compound employed, the age, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination and the severity of the particular disease undergoing therapy.

Examples

The general operation for the process of the invention is as follows.

General experiments

LC-MS data were obtained using a gradient elution with a YMC Combioscreen ODS-A50X 4.6mm column using a Waters 600 controller equipped with a 2487 dual wavelength detector and a Leap Technologies HTS PAL auto-sampler. A 3 min gradient was run from 25% B (97.5% acetonitrile, 2.5% water, 0.05% TFA) and 75% a (97.5% water, 2.5% acetonitrile, 0.05% TFA) to 100% B. The mass spectrometer used was a Micromass ZMD instrument. All data were obtained as positive ions unless otherwise stated. Obtained using a Varian 400MHz spectrometer¹H NMR data.

General procedure a: imidazole formation

To a mixture of formic acid (1eq) and aromatic acyl bromide (2eq) in anhydrous DMF (0.1-0.5M) was added DIEA (3 eq). The reaction mixture was stirred at room temperature under nitrogen for 6-8 hours. Thereafter, it was poured into water, acidified with 10% citric acid and extracted with ethyl acetate. The organic extract was washed with water and brine and washed with Na₂SO₄And (5) drying. After evaporation of the solvent, the light brown residue was recrystallized from EtOAc-hexane and used directly in the next step.

The intermediate obtained above was dissolved in glacial acetic acid (0.1-0.5M) and ammonium acetate (20eq) was added. The mixture was then heated at 120 ℃ for 8-10 hours under nitrogen. Upon completion, it was poured into water, neutralized with saturated sodium bicarbonate and extracted with ethyl acetate. Using waterAnd the organic extracts were washed with brine and Na₂SO₄And (5) drying. After removal of the solvent in vacuo, the residue was purified by flash column chromatography to give the desired product.

General procedure B: arylation of imidazole nitrogen atoms using aryl fluoro/aryl bromides

To a solution of imidazole compound (1eq) in anhydrous DMF (0.1-0.5M) was added the appropriately activated aryl fluoride or aryl bromide (1.5eq) followed by Cs₂CO₃(3 eq). The reaction mixture was then heated at 120 ℃ for 2 hours under nitrogen. Upon completion, the reaction mixture was diluted with water/EtOAc and the layers were separated. The aqueous layer was extracted with EtOAc and the organic layers were combined, washed with water and brine. Then using Na₂SO₄The organic phase was dried, filtered and the filtrate was concentrated and purified by silica gel chromatography to give the arylimidazole derivative.

General procedure C: preparation of 1,2, 5-thiadiazolidin-3-one-1, 1-dioxide derivatives

To a suspension of the arylnitro compound (1eq) in HOAc (0.1-0.5M) was added iron powder (-325 mesh, 8eq) and the compound was then heated at 80 ℃ for 5-10 minutes under a nitrogen atmosphere. The reaction mixture was then diluted with water/EtOAc and the remaining iron powder was filtered and washed with EtOAc. With water, saturated NaHCO₃And brine wash the combined organic layers. Then using Na₂SO₄The organic layer was dried, filtered and the filtrate was concentrated and purified by silica gel chromatography to give an aniline derivative.

Alkylation of aniline: method I) to a suspension of aniline compound (1eq) in anhydrous DMF (0.1-0.5M) at room temperature was added 1.2eq of α -bromo ester followed by 2.5eq of DIEA. The reaction mixture was then stirred at room temperature under nitrogen for 18 hours. The reaction mixture was then diluted with water/EtOAc and the layers were separated. The aqueous layer was re-extracted with EtOAc and the organic layers were combined and washed with water and brine. Then using Na₂SO₄The organic phase was dried, filtered and the filtrate was concentrated and washed through silica gelPurifying by a chromatography method to obtain the alpha-anilino-ester derivative. Method II) to a suspension of the aniline compound (1eq) in anhydrous DMF (0.1-0.5M) at room temperature was added 2eq of α -bromo ester followed by 5eq of anhydrous potassium tert-butoxide. The reaction mixture was then stirred at 100 ℃ under nitrogen for 18 hours. The reaction mixture was then diluted with water/EtOAc and the layers were separated. The aqueous layer was re-extracted with EtOAc and the organic layers were combined and washed with water and brine. Then using Na₂SO₄The organic phase was dried, filtered and the filtrate was concentrated and purified by silica gel chromatography to give the α -anilino-ester derivative.

Formation of 1,2, 5-thiadiazolidin-3-one-1, 1-dioxide: to a solution of chlorosulfonyl isocyanate (1.5eq) in anhydrous 1, 2-dichloroethane (0.1-0.5M) at 0 deg.C was added 1.5eq of t-butanol as a solution in anhydrous 1, 2-dichloroethane (0.5M). The mixture was warmed to room temperature while stirring and then cooled to 0 ℃ again. The suspension from the above aniline-ester (1.0eq) in 1, 2-dichloroethane (0.3-0.5M) and 2.5eq DIEA was cooled to 0 ℃ and chlorosulfonyl isocyanate-tert-butanol mixture was added dropwise while stirring. The mixture was stirred at room temperature for 1 hour, then water/CH₂Cl₂The layers were diluted and separated. The organic layers were combined and washed with water and brine. Then using Na₂SO₄The organic phase was dried, filtered and the filtrate was concentrated and purified by silica gel chromatography to give the aniline N-Boc-sulfonamide derivative (Boc means t-butyloxycarbonyl).

The Boc-protected sulfonamide was stirred in dichloromethane/trifluoroacetic acid for 30 minutes. The solvent was removed and the residue triturated several times with ether to give the deprotected sulfonamide.

To a suspension of the deprotected sulfonamide compound in ethanol (0.1-0.5M) was added 5.0eq NaOH as a 2M solution in water. The mixture was stirred at room temperature for 5-7 min, then diluted with 2% citric acid/EtOAc and the layers were separated. The organic layer was washed with water and brine. Then using Na₂SO₄Drying the organic layer, filtering and concentrating the filtrateAnd purifying by silica gel chromatography to obtain the 1,2, 5-thiadiazolidin-3-one-1, 1-dioxide derivative.

General operation D: reduction of arylnitro groups

To an increasing suspension of the arylnitro compound (1eq) in HOAc (0.1-0.5M) was added iron powder (-325 mesh, 8eq) and the mixture was then heated at 80 ℃ for 5-10 minutes under nitrogen. The reaction mixture was then diluted with water/EtOAc and the remaining iron powder was filtered and washed with EtOAc. With water, saturated NaHCO₃And brine wash the combined organic layers. Then using Na₂SO₄The organic layer was dried, filtered and the filtrate was concentrated and purified by silica gel chromatography to give an aniline derivative.

General operation E: alkylation of anilines

Method I) to a suspension of the aniline derivative (1eq) in anhydrous DMF (0.1-0.5M) at room temperature was added 1.2eq of α -bromo ester followed by 2.5eq of DIEA. The reaction mixture was then stirred at room temperature under nitrogen for 18 hours. The reaction mixture was then diluted with water/EtOAc and the layers were separated. The aqueous layer was re-extracted with EtOAc and the organic layers were combined and washed with water and brine. Then using Na₂SO₄The organic phase was dried, filtered and the filtrate was concentrated and purified by silica gel chromatography to give the α -anilino-ester derivative.

Method II) to a suspension of the aniline derivative (1eq) in anhydrous DMF (0.1-0.5M) at room temperature was added 1.2eq of alpha-bromo ester followed by 5eq of anhydrous potassium tert-butoxide. The reaction mixture was then stirred at 100 ℃ under nitrogen for 18 hours. The reaction mixture was then diluted with water/EtOAc and the layers were separated. The aqueous layer was re-extracted with EtOAc and the organic layers were combined and washed with water and brine. Then using Na₂SO₄The organic phase was dried, filtered and the filtrate was concentrated and purified by silica gel chromatography to give the α -anilino-ester derivative.

General operation F: formation of 1,2, 5-thiadiazolidin-3-one-1, 1-dioxide

To a solution of chlorosulfonyl isocyanate (1.5eq) in anhydrous 1, 2-dichloroethane (0.1-0.5M) at 0 deg.C was added 1.5eq of t-butanol as a solution in anhydrous 1, 2-dichloroethane (0.5M). The mixture was warmed to room temperature while stirring and then cooled to 0 ℃ again. The suspension of aniline-ester from general procedure E (1.0eq) in 1, 2-dichloroethane (0.3-0.5M) and 2.5eq diea was cooled to 0 ℃ and chlorosulfonyl isocyanate-tert-butanol mixture was added dropwise with stirring. The mixture was stirred at room temperature for 1 hour, then water/CH₂Cl₂The layers were diluted and separated. The organic layers were combined and washed with water and brine. Then using Na₂SO₄The organic phase was dried, filtered and the filtrate was concentrated and purified by silica gel chromatography to give the aniline N-Boc sulfonamide derivative.

The Boc-protected sulfonamide was stirred in dichloromethane/trifluoroacetic acid for 30 minutes. The solvent was removed and the residue triturated several times with ether to give the deprotected sulfonamide.

To a suspension of the deprotected sulfonamide derivative in ethanol (0.1-0.5M) was added 5.0eq NaOH as a 2M solution in water. The mixture was stirred at room temperature for 5-7 min, then diluted with 2% citric acid/EtOAc and the layers were separated. The organic layer was washed with water and brine. Then using Na₂SO₄The organic layer was dried, filtered and the filtrate was concentrated and purified by silica gel chromatography to give 1,2, 5-thiadiazolidin-3-one-1, 1-dioxide.

General operation G: suzuki coupling

To a solution (0.1-0.5M) of the bromo-compound (1eq) in a 2: 1 mixture of toluene and ethanol was added the appropriate boric acid (2eq) and a catalytic amount of tetrakis (triphenylphosphine) palladium (0) (0.1eq), followed by a solution of 2M sodium carbonate in water (30 eq). The reaction mixture was stirred at 90 ℃ under nitrogen for 6 hours. After cooling, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic extract was washed with water and brine and washed with Na₂SO₄And (5) drying. After removal of the solvent in vacuo, the residue was purified by flash column chromatography to give the desired compound.

General procedure H: alkylation of the phenolic oxygen atom of hydroxyphenylboronic acids

To a solution of hydroxyphenylboronic acid (1eq) in anhydrous DMF (0.1-0.5M) was added alkyl bromide or mesylate (2eq) followed by freshly ground K₂CO₃(4eq) and the reaction mixture was heated at 100 ℃ for 6 hours under nitrogen. The mixture was then diluted with water/EtOAc and the layers were separated. The aqueous layer was further extracted with EtOAc and the organic layers were combined and taken over Na₂SO₄And (5) drying. The solvent was removed in vacuo and the residue was purified by silica gel chromatography to give the desired product.

General operation I: alkylation of the sulfur atom of mercaptophenylboronic acids

To a solution of mercaptophenylboronic acid (1eq) in anhydrous DMF (0.1-0.5M) was added alkyl bromide (2eq), followed by DIEA (4eq) and the reaction mixture was stirred at room temperature under nitrogen overnight. The mixture was then diluted with water/EtOAc and the layers were separated. The aqueous layer was further extracted with EtOAc and the organic layers were combined and taken over Na₂SO₄And (5) drying. The solvent was removed in vacuo and the residue was purified by silica gel chromatography to give the desired product.

General operation J: alkylation of amino-phenylboronic acids

To a solution of amino-phenylboronic acid (1eq) in anhydrous DMF (0.1-0.5M) was added alkyl/aryl bromide followed by freshly ground K₂CO₃(4eq) and the reaction mixture was stirred at room temperature under nitrogen for 16 hours. The mixture was then diluted with water/EtOAc and the layers were separated. The aqueous layer was further extracted with EtOAc and the organic layers were combined and taken over Na₂SO₄And (5) drying. The solvent was removed in vacuo and the residue was purified by silica gel chromatography to give the desired product.

General procedure K: alkylation of anilines, phenols or thiols

To a solution of phenol, aniline or thiol (1eq) in anhydrous DMF (0.1-0.5M) was added alkyl halide (2eq) followed by freshly triturated Cs₂CO₃(4 eq). The reaction mixture was heated at 100 ℃ for 2 hours under nitrogen. The mixture was then diluted with water/EtOAc and the layers were separated. The aqueous layer was further extracted with EtOAc and the organic layers were combined and taken over Na₂SO₄And (5) drying. The solvent was removed in vacuo and the residue was purified by silica gel chromatography to give the desired product.

General operation L: alkylation of anilines, phenols or imidazoles and heteroarylation of alcohols, thiols or amines

To a solution (0.1-0.5M) of phenol, alcohol, aniline or imidazole (1eq) in anhydrous DMF was added sodium hydride (2 eq). The mixture was stirred at room temperature for 20 minutes and a solution of alkyl or heteroaryl halide in DMF (1-3eq) was added. Stirring was continued for 3 hours, then the mixture was diluted with water/EtOAc and neutralized with 10% aqueous citric acid. The organic layer was washed with brine, Na₂SO₄Dried and evaporated in vacuo. The residue was purified by silica gel chromatography to give the desired product.

General operation M: preparation of 1- (3-aminophenyl) imidazole

To a mixture of 3-aminoacetanilide (1eq) and aromatic acyl bromide (2eq) in anhydrous DMF (0.1-0.5M) was added NaHCO₃(5 eq). The reaction mixture was stirred at room temperature under nitrogen for 3 hours. Upon completion, the reaction mixture was diluted with water/EtOAc and the layers were separated. The aqueous layer was extracted with EtOAc and the organic layers were combined and washed with water and brine. Then drying Na₂SO₄The organic solution was filtered and the filtrate was concentrated and the residue was dried and used directly in the next step.

The aniline derivative obtained above was dissolved in dry DMF (0.1-0.5M) and 5eq NaHCO was added₃. Dropwise addition of p-bromophenyl while stirring and under nitrogen on iceAcetyl chloride (1.1eq) in benzene. The mixture was then stirred for 1 hour and warmed to room temperature. The reaction mixture was diluted with water/EtOAc and the layers were separated. The aqueous layer was extracted with EtOAc and the organic layers were combined and washed with water and brine. Then using Na₂SO₄The organic solution was dried, filtered and the filtrate was concentrated and the residue was dried and used directly in the next step.

The tertiary acylaniline obtained above was dissolved in glacial acetic acid (0.1-0.5M) and ammonium acetate (10eq) was added. The mixture was then heated at 110 ℃ for 8 hours under a nitrogen atmosphere. Upon completion, the mixture was poured into water, neutralized with saturated sodium bicarbonate and extracted with ethyl acetate. The organic extract was washed with water and brine and washed with Na₂SO₄And (5) drying. After removal of the solvent in vacuo, the residue was purified by silica gel column chromatography to give the desired imidazole N- (3-acetamido) phenyl derivative.

The intermediate obtained above was dissolved in a 6: 1 v/v mixture (0.1-0.5M) of 4M HCl/dioxane and water and heated at 70 ℃ for 3 hours. The mixture was then poured into water, neutralized with saturated sodium bicarbonate and extracted with ethyl acetate. The organic extract was washed with water and brine and washed with Na₂SO₄And (5) drying. After removal of the solvent in vacuo, the nutrients were dried and used without further purification.

General operation N: preparation of tertiary acylanilides

The aniline derivative obtained above was dissolved in dry DMF (0.1-0.5M) and 5eq NaHCO was added₃. A solution of p-bromophenylacetyl chloride (1.1eq) in benzene was added dropwise with stirring and under a nitrogen atmosphere on ice. The mixture was then stirred for 1 hour and warmed to room temperature. The reaction mixture was diluted with water/EtOAc and the layers were separated. The aqueous layer was extracted with EtOAc and the organic layers were combined and washed with water and brine. Then using Na₂SO₄The organic solution was dried, filtered and the filtrate was concentrated and the residue was dried and used directly in the next step.

General operation O: preparation of imidazoles

The tertiary acylaniline obtained above was dissolved in glacial acetic acid (0.1-0.5M) and ammonium acetate (10eq) was added. The mixture was then heated at 110 ℃ for 8 hours under a nitrogen atmosphere. Upon completion, the mixture was poured into water, neutralized with saturated sodium bicarbonate and extracted with ethyl acetate. The organic extract was washed with water and brine and washed with Na₂SO₄And (5) drying. After removal of the solvent in vacuo, the residue was purified by silica gel column chromatography to give the desired imidazole 1- (3-acetamido) phenyl derivative.

General operation P: hydrolysis of esters

The ester (1eq) was suspended in MeOH/THF/H₂O (1: 1; 0.1-0.2M). LiOH (20eq) was added and the mixture was stirred at 100 ℃ for 0.5 h. The solution was acidified with 10% aqueous citric acid and extracted with ethyl acetate. The combined organic extracts were washed with brine, washed with Na₂SO₄Dried and the solvent removed in vacuo. The residue was purified by silica gel chromatography to give the desired acid.

General operation Q: hydrogenation of phenyl groups

To a suspension of 1 equivalent of the desired substituted phenyl compound in methanol (0.1-0.5M) was added a catalytic amount of platinum (IV) oxide (wet). After degassing and introduction of nitrogen and further degassing. Hydrogen gas (50 psi) was introduced. The reaction mixture was stirred at room temperature for 3-4 days (refilled with hydrogen to maintain 40-50 psi pressure). The reaction mixture was then filtered through celite, the celite cake was washed 3 times with ethyl acetate and the filtrates combined. The solvent was then removed in vacuo and the residue was purified by silica gel chromatography to give the desired compound.

General procedure R: ullmann coupling

To a solution of oxygen-or nitrogen-containing nucleophile (1eq) in anhydrous NMP (0.1-0.5M) was added the appropriate aryl bromide or iodide (1.5eq), followed by CuCl (0.2eq), 2, 2, 6, 6-tetramethyl-3, 5-heptanedione (0.2eq) and Cs₂CO₃(3 eq). The reaction mixture was then heated at 120 ℃ for 6-8 hours under nitrogen. Upon completion, the reaction mixture was diluted with water/EtOAc and the layers were separated. The aqueous layer was extracted with EtOAc and the organic layers were combined, washed with water and brine. Then using Na₂SO₄The organic phase was dried, filtered and the filtrate was concentrated and purified by silica gel chromatography to give the desired product (diaryl ether or substituted aniline derivative).

General operation S: oxidation of sulfides using peracetic acid

To a solution of the thioether compound (1eq) in 1: 1 DCM/HOAc (0.1-0.5M) was added peracetic acid (32 wt.% solution in acetic acid, 10eq) at 0 ℃ and the solution was stirred at the same temperature for half an hour. Upon completion, the reaction mixture was diluted with water/EtOAc. With, saturated NaHCO₃And brine wash the combined organic layers. Then using Na₂SO₄The organic phase was dried, filtered and concentrated. The residue was triturated several times with hexane to give the desired sulfone derivative.

General operation T: oxidation of sulfides using hydrogen peroxide

To a solution or suspension of the thioether compound (1eq) in methanol (0.1-0.5M) at 0 ℃ was added hydrogen peroxide (50% solution in water, 10eq) and the reaction mixture was stirred at room temperature for 1 hour. Upon completion, the reaction mixture was diluted with water/EtOAc. The combined organic layers were washed with water and brine. Then using Na₂SO₄The organic phase was dried, filtered and concentrated. The residue was triturated several times with hexane to give the desired sulfoxide derivative.

General operation U: coupling of anilines or amines with sulphonyl chlorides, sulphonic anhydrides or chloroformic esters

To a suspension of amine compound (1eq) in anhydrous DCM (0.1-0.5M) at 0 ℃ was added DIEA (1.2eq) followed by the appropriate sulfonyl chloride, sulfonic anhydride or chloroformate (1.2eq, in anhydrous DCM or diluted). The reaction mixture was then warmed and stirred at room temperature under nitrogen atmosphere3-4 hours. Upon completion the reaction mixture was diluted with water/EtOAc and the layers were separated. The aqueous layer was extracted with EtOAc and the organic layers were combined, washed with 10% citric acid, water and brine. Then using Na₂SO₄The organic phase is dried, filtered and the filtrate is concentrated and purified by silica gel chromatography to give the sulfonamide or carbamate derivative.

General operation V: removal of the tert-butyl carbamate group

The boc-protected compound was stirred in 4N HCl/dioxane for 1 hour. The solvent was removed and the product was triturated several times with ether to give the desired compound.

General operation W: deprotection of silyl groups

To a solution (0.1-0.5M) of O-or N-silyl compound (1eq) in THF was added 5eq of tetrabutylammonium fluoride as a solution in THF. The mixture was stirred at 65 ℃ for 1-3 hours, then evaporated to small volume and dissolved in water/EtOAc. The layers were separated and the aqueous layer was further extracted with EtOAc. The combined organic extracts were washed with brine, Na₂SO₄Dried and evaporated in vacuo. The residue was purified by silica gel column chromatography to give the desired product.

General operation X: reductive amination

To a solution of amine (1eq) in 1, 2-dichloroethane (0.1-0.5M) was added aldehyde (1.2eq) and a catalytic amount of acetic acid. The mixture was stirred at room temperature under a nitrogen atmosphere for 30 minutes, then sodium triacetoxyborohydride (3eq) was added and the mixture was stirred at room temperature for 12-16 hours. The mixture was then diluted with water/EtOAc and the layers were separated. The aqueous layer was extracted with EtOAc and the combined organic extracts were washed with water, brine, Na₂SO₄Dried and evaporated in vacuo. The residue was purified by silica gel column chromatography to give the desired product.

General procedure Y: preparation of boric acid

To the middle-or to-suspension of bromobenzaldehyde in THF (0.1-0.5M) to which was added dropwise the alkyl magnesium bromide or chloride in ether or THF (1.1eq) while stirring on ice. The mixture was warmed to room temperature and stirred for 30 minutes, then poured into saturated NH₄Cl/EtOAc and separate layers. The aqueous layer was extracted with EtOAc and the organic layers were combined and washed with water and brine. Then using Na₂SO₄The organic solution was dried, filtered and the filtrate was concentrated and the residue was dried and used directly in the next step.

The grignard product obtained above was dissolved in trifluoroacetic acid (0.1-0.5M) in a nitrogen atmosphere and cooled in an ice-salt bath maintained at-10 ℃. To this solution was added slowly triethylsilane (4eq) to maintain the bath at-10 ℃. The solution was then warmed to room temperature and stirred for 3 hours. Upon completion, the mixture was poured into water and extracted with dichloromethane. With saturated NaHCO₃The organic extracts were washed with aqueous solution and brine and Na₂SO₄And (5) drying. After removal of the solvent in vacuo, the residue was purified by silica gel column chromatography to give the desired m-or p-bromophenylalkane product.

A solution of M-or p-bromophenylalkane in dry THF (0.1-0.5M) was stirred under nitrogen and in a dry ice-acetone bath and sec-butyllithium in cyclohexane (2eq) was added dropwise, all in a dry ice-acetone bath. The mixture was stirred for 10 minutes, and then triisopropyl borate (3eq) was added dropwise. The mixture was stirred for another 30 minutes, then poured into excess 2M HCl and stirred at room temperature for 20 minutes. EtOAc was then added and the layers were separated. The aqueous layer was extracted with EtOAc and the organic layers were combined and washed with water and brine. Then using Na₂SO₄The organic solution was dried, filtered and the filtrate was concentrated. The residue was recrystallized from EtOAc/hexanes, dried and used for the boronic acid coupling reaction.

General operation Z: grignard reaction

To a suspension of M-or p-bromobenzaldehyde in THF (0.1-0.5M) was added dropwise the alkyl magnesium bromide or chloride in ether or THF (1.1eq) while stirring on ice. Will be provided withThe mixture was warmed to room temperature and stirred for 30 minutes, then poured into saturated NH₄Cl/EtOAc and separate layers. The aqueous layer was extracted with EtOAc and the organic layers were combined and washed with water and brine. Then using Na₂SO₄The organic solution was dried, filtered and the filtrate was concentrated and dried to give me and used directly in the next step.

General procedure AA: reduction of benzyl alcohol

The alcohol obtained from general procedure Z was dissolved in trifluoroacetic acid (0.1-0.5M) in a nitrogen environment and cooled in an ice-salt bath maintained at-10 ℃. Triethylsilane (4eq) was added slowly to the solution to maintain the bath at-10 ℃. The solution was then warmed to room temperature and stirred for 3 hours. Upon completion, the mixture was poured into water and extracted with dichloromethane. With saturated NaHCO₃The organic extracts were washed with aqueous solution and brine and Na₂SO₄And (5) drying. After removal of the solvent in vacuo, the residue was purified by silica gel column chromatography to give the desired m-or p-bromophenylalkane product.

General operation AB: preparation of N-alkyl 5-chloro-isothiazole-sulfones:

the dithio-acid (1.0eq) was dissolved in thionyl chloride (0.1-0.5M) and the mixture was heated at 80-100 ℃ for 3-6 hours. Upon completion, the excess thionyl chloride was removed under pressure and the compound was dried in vacuo and the white solid obtained was used directly in the next step.

Tert-butylamine (1.0eq) was dissolved in dry DMF (0.1-0.5M) and 5eq NaHCO was added₃. While stirring on ice and under nitrogen, a solution of aryl/alkyl acetyl chloride (1.1eq) in benzene was added dropwise. The mixture was then stirred for 1 hour and warmed to room temperature. The reaction mixture was diluted with water/EtOAc and the layers were separated. The aqueous layer was extracted with EtOAc and the organic layers were combined and washed with water and brine. Then using Na₂SO₄The organic solution was dried, filtered and the filtrate was concentrated and the residue was dried and used directly in the next step.

Reacting a di-amideIs dissolved in anhydrous dichloromethane (0.1-0.5M) and treated at 0 ℃ by dropwise addition of sulphuryl chloride (1.1eq) and stirred at 25 ℃ for 3-6 hours. Upon completion, the reaction mixture was cooled to 0 ℃, quenched with water and stirred for 10-30 minutes. The organic layer was separated and the aqueous layer was re-extracted with dichloromethane. With MgSO₄The combined organic layers were dried, filtered and concentrated to give a light brown oil. The crude oil was purified by flash column chromatography (100% hexane-40% ethyl acetate/hexane-100% ethyl acetate) to give an off-white solid.

To a solution of the isothiazole compound (1eq) in 1: 1 DCM/HOAc (0.1-0.5M) was added peracetic acid (32 wt.% solution in acetic acid, 10eq) at 0 ℃ and the solution was stirred at the same temperature for 2-6 hours. Upon completion, the reaction mixture was diluted with water/EtOAc. With water, saturated NaHCO₃And brine wash the combined organic layers. Then using Na₂SO₄The organic phase was dried, filtered and concentrated. The residue was triturated several times with hexanes to give the desired isothiazole-sulfone derivative.

General operation AC: pd (II) -catalyzed coupling reactions

A solution (0.1-0.5M) of arylboronic acid (1.0eq) in anhydrous dioxane was added to potassium carbonate (5-10eq), aryl halide (1.1eq) and PdCl in a nitrogen atmosphere₂(dppf) (2.5 eq). The reaction mixture was degassed three times by freeze-thaw method and heated at 80 ℃ for 24-48 hours. Upon completion, the reaction mixture was cooled to 25 ℃, poured into water and extracted with dichloromethane. The combined organic layers were washed with brine, MgSO₄Dried and concentrated in vacuo. The crude residue was purified by flash chromatography to give a light red solid.

General operation AD: preparation of boronic acid pinacol cyclic ester

To a solution of substituted aryl bromide (1eq) in anhydrous DMF (0.1-0.5M) was added bis (pinacolato) diboron (3eq), [1, 1' -bis (diphenylphosphino) ferrocene]Dichloro-palladium (II) (0.1eq) and cesium carbonate (5 eq). Mixing the colored heterogeneous reactionThe mixture was stirred at 100 ℃ under nitrogen for 4-6 hours. Upon completion, the resulting slurry was filtered through celite, washing with ethyl acetate. The combined organic layers were washed with water and brine, and Na₂SO₄Dried and evaporated in vacuo. The residue was purified by silica gel column chromatography to give the desired arylboronic acid-pinacol ester.

General operation AE: preparation of 3-or 4- (alkenyl) phenylboronic acids

To a suspension of M-or p-bromobenzaldehyde in THF (0.1-0.5M) was added dropwise the alkyl magnesium bromide or chloride in ether or THF (1.1eq) while stirring on ice. The mixture was warmed to room temperature and stirred for 30 minutes, then poured into saturated NH₄Cl/EtOAc and separate layers. The aqueous layer was extracted with EtOAc and the organic layers were combined and washed with water and brine. Then using Na₂SO₄The organic solution was dried, filtered and the filtrate was concentrated and the residue was dried and used directly in the next step.

The grignard product from the above step was dissolved in dry dichloromethane (0.1-0.5M) and N, N-diisopropylethylamine (5eq) was added. The mixture was cooled with an ice bath and methanesulfonyl chloride (2eq) was added dropwise. The mixture was warmed to room temperature and stirred for 18 hours. Upon completion, the mixture was poured into water and extracted with dichloromethane. The organic extract was washed with water and brine and washed with Na₂SO₄And (5) drying. After removal of the solvent in vacuo, the residue was purified by silica gel column chromatography to give the desired m-or p-bromophenylalkane product.

A solution of M-or p-bromophenylene in dry THF (0.1-0.5M) was stirred in a dry ice-acetone bath under nitrogen and tert-butyllithium in cyclohexane (2eq) was added dropwise. The mixture was stirred for 10 minutes, and then triisopropyl borate (3eq) was added dropwise. The mixture was stirred for another 30 minutes, then poured into excess 2M HCl and stirred for 20 minutes. EtOAc was then added and the layers were separated. The aqueous layer was extracted with EtOAc and the organic layers were combined and washed with water and brine. Then using Na₂SO₄The organic solution was dried, filtered and the filtrate was concentrated.The residue was recrystallized from EtOAc/hexanes, dried and used for the boronic acid coupling reaction.

General operation AF: sonogashira coupling

To a solution of bromo-compound (1eq) in anhydrous DMF (0.1-0.5M) was added the appropriate terminal alkyne compound (2eq) and a catalytic amount of tetrakis (triphenylphosphine) palladium (0) (0.2eq), followed by copper (I) iodide (0.2eq) and DIEA (5 eq). The reaction mixture was stirred at 120 ℃ under nitrogen for 6 hours. After cooling, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic extract was washed with water and brine and washed with Na₂SO₄And (5) drying. After the solvent was removed in vacuo entirely, the residue was purified by flash column chromatography to give the desired compound.

General operation AG: removal of tert-butyl groups

A solution of N-tert-butyl compound (1.0eq) in TFA (0.1M-0.5M) was treated with triisopropylsilane (0.05M). The reaction mixture was heated at 70 ℃ for 24-48 hours. Upon completion, the mixture was cooled to 25 ℃ and concentrated in vacuo and co-evaporated with toluene. The crude residue was purified by column chromatography to give an off-white solid.

General operation AH: dealkylation

To 1 equivalent of n-alkylphenol ether in DCM at-78 deg.C was added 10 equivalents of BBr₃. The solution was allowed to warm to room temperature over 30 minutes and the reaction mixture was quenched with MeOH. The reaction mixture was then diluted with water/EtOAc and the layers were separated. The aqueous layer was further extracted with EtOAc and the organic layers were combined, washed with water and brine and Na₂SO₄And (5) drying. The solvent was removed in vacuo and the residue was chromatographed on silica gel to give the final product.

Example 1

Treatment of 4-bromophenylacetic acid (107.5g, 0.5mol) with 2, 4-dichlorobromoacetophenone according to general procedure a gave 2- (4-bromo-benzyl) -4- (2, 4-dichloro-phenyl) -1H-imidazole.

LCMS：m/z 383(M+H)⁺；¹H NMR(CD₃OD，400MHz)：δ4.14(s，2H)，7.51(d，2H)，7.69(d，2H)，7.71(m，2H)，8.02(m，1H)，8.05(s，1H)ppm。

2- (4-bromo-benzyl) -4- (2, 4-dichloro-phenyl) -1H-imidazole (38.2g, 0.1mol) was treated with 1-fluoro-4-nitrobenzene as described in general procedure B to give 2- (4-bromo-benzyl) -1- (4-nitro-phenyl) -4- (2, 4-dichloro-phenyl) -1H-imidazole.

LCMS：m/z 504(M+H)⁺。

2- (4-bromo-benzyl) -1- (4-nitro-phenyl) -4- (2, 4-dichloro-phenyl) -1H-imidazole (30.2g, 60mmol) was treated as described in general procedure C to give 5- {4- [2- (4-bromo-benzyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide.

LCMS：m/z 593(M+H)⁺；¹H NMR(DMSO-d₆，400MHz)：δ4.05(s，2H)，4.07(s，2H)，7.15(d，2H)，7.27(d，2H)，7.47(dd，1H)，7.51(d，2H)，7.53(d，2H)，7.64(d，1H)，7.89(s，1H)，8.19(d，1H)ppm。

5- {4- [2- (4-bromo-benzyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide (59mg, 0.1mmol) was treated with 4-tert-butylphenyl boronic acid (36mg, 0.2mmol) as described in general procedure G to give 5- {4- [2- (4' -tert-butyl-biphenyl-4-ylmethyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide.

LCMS：m/z 645(M+H)⁺；¹H NMR(DMSO-d₆，400MHz)：δ1.30(s，9H)，4.06(s，2H)，4.08(s，2H)，7.15(d，2H)，7.19(d，2H)，7.36(d，2H)，7.45(d，2H)，7.49(dd，1H)，7.52(d，2H)，7.54(d，2H)，7.64(d，1H)，7.90(s，1H)，8.20(d，1H)ppm。

Example 2

5- {4- [2- (4-bromo-benzyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide (59mg, 0.1mmol) was treated with 4-cyclopentylphenylboronic acid (38mg, 0.2mmol) as described in general procedure G to give 5- {4- [2- (4' -cyclopentyl-biphenyl-4-ylmethyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide.

LCMS：m/z 657(M+H)⁺；¹H NMR(DMSO-d₆，400MHz)：δ1.22-1.81(m，8H)，2.52(m，1H)，4.05(s，2H)，4.07(s，2H)，7.15(d，2H)，7.18(d，2H)，7.27(d，2H)，7.37(d，2H)，7.48(dd，1H)，7.51(d，2H)，7.53(d，2H)，7.64(d，1H)，7.89(s，1H)，8.19(d，1H)ppm。

Example 3

5- {4- [2- (4-bromo-benzyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide (59mg, 0.1mmol) was treated with 3-propoxyphenylboronic acid (36mg, 0.2mmol) as described in general procedure G to give 5- {4- [4- (2, 4-dichloro-phenyl) -2- (3' -propoxy-biphenyl-4-ylmethyl) -imidazol-1-yl ] -phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide.

LCMS：m/z 647(M+H)⁺；¹H NMR(DMSO-d₆，400MHz)：δ0.99(t，3H)，1.73(m，2H)，3.99(t，2H)，4.05(s，2H)，4.08(s，2H)，7.16(d，2H)，7.18-7.25(m，4H)，7.28(d，2H)，7.48(dd，1H)，7.51(d，2H)，7.53(d，2H)，7.63(d，1H)，7.88(s，1H)，8.18(d，1H)ppm。

Example 4

5- {4- [2- (4-bromo-benzyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide (59mg, 0.1mmol) was treated with 4-propoxyphenylboronic acid (36mg, 0.2mmol) as described in general procedure G to give 5- {4- [4- (2, 4-dichloro-phenyl) -2- (4' -propoxy-biphenyl-4-ylmethyl) -imidazol-1-yl ] -phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide.

LCMS：m/z 647(M+H)⁺；¹H NMR(DMSO-d₆，400MHz)：δ1.01(t，3H)，1.74(m，2H)，4.00(t，2H)，4.05(s，2H)，4.08(s，2H)，7.15(d，2H)，7.18(d，2H)，7.20(d，2H)，7.27(d，2H)，7.48(dd，1H)，7.51(d，2H)，7.53(d，2H)，7.63(d，1H)，7.88(s，1H)，8.18(d，1H)ppm。

Example 5

Treatment of 5- {4- [2- (4-bromo-benzyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide (59mg, 0.1mmol) using 3- (cyclopentylmethoxy) phenylboronic acid (44mg, 0.2mmol, prepared according to general procedure H) as described in general procedure G gave 5- {4- [2- (3' -cyclopentylmethoxy-biphenyl-4-ylmethyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide.

LCMS：m/z 687(M+H)⁺；¹H NMR(DMSO-d₆，400MHz)：δ1.32-2.16(m，9H)，3.82(d，2H)，4.05(s，2H)，4.07(s，2H)，7.15(d，2H)，7.18-7.24(m，4H)，7.35(d，2H)，7.48(dd，1H)，7.51(d，2H)，7.53(d，2H)，7.64(d，1H)，7.89(s，1H)，8.19(d，1H)ppm。

Example 6

Treatment of 5- {4- [2- (4-bromo-benzyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide (59mg, 0.1mmol) with 3- (3, 3-dimethyl-butoxy) phenylboronic acid (45mg, 0.2mmol, prepared according to general procedure H) as described in general procedure G gave 5- (4- {4- (2, 4-dichloro-phenyl) -2- [ 3' - (3, 3-dimethyl-butoxy) -biphenyl-4-ylmethyl ] -imidazol-1-yl } -phenyl) -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide.

LCMS：m/z 689(M+H)⁺；¹H NMR(DMSO-d₆，400MHz)：δ1.00(s，9H)，1.70(t，2H)，4.05(s，2H)，4.07(t，2H)，4.08(s，2H)，7.15(d，2H)，7.18-7.24(m，4H)，7.33(d，2H)，7.38(d，2H)，7.47(dd，1H)，7.55(d，2H)，7.64(d，1H)，7.89(s，1H)，8.18(d，1H)ppm。

Example 7

Treatment of 5- {4- [2- (4-bromo-benzyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide (119mg, 0.2mmol) with 4-phenylpiperidine (162mg, 1mmol) as described in general procedure R gave 5- (4- {4- (2, 4-dichloro-phenyl) -2- [4- (4-phenyl-piperidin-1-yl) -benzyl ] -imidazol-1-yl } -phenyl) -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide.

LCMS：m/z 672(M+H)⁺；¹H NMR(DMSO-d₆，400MHz)：δ(1.62-1.79(m，4H)，2.56(m，1H)，3.21-3.34(m，4H)，4.05(s，2H)，4.08(s，2H)，7.15(d，2H)，7.18-7.34(m，7H)，7.38(d，2H)，7.47(dd，1H)，7.55(d，2H)，7.64(d，1H)，7.89(s，1H)，8.18(d，1H)ppm。

Example 8

5- {4- [2- (4-bromo-benzyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide (119mg, 0.2mmol) was treated with 3-methoxycarbonylphenylboronic acid (108mg, 0.6mmol) as described in general procedure G to give 4' - {4- (2, 4-dichloro-phenyl) -1- [4- (1, 1, 4-trioxo- [1, 2, 5] thiadiazolidin-2-yl) -phenyl ] -1H-imidazol-2-ylmethyl } -biphenyl-3-carboxylic acid methyl ester.

LCMS：m/z 647(M+H)⁺；¹H NMR(DMSO-d₆，400MHz)：δ3.79(s，3H)，4.06(s，2H)，4.09(s，2H)，7.15(d，2H)，7.18-7.24(m，4H)，7.33(d，2H)，7.38(d，2H)，7.47(dd，1H)，7.55(d，2H)，7.64(d，1H)，7.89(s，1H)，8.18(d，1H)ppm。

Example 9

Methyl 4 '- {4- (2, 4-dichloro-phenyl) -1- [4- (1, 1, 4-trioxo- [1, 2, 5] thiadiazolidin-2-yl) -phenyl ] -1H-imidazol-2-ylmethyl } -biphenyl-3-carboxylate (33mg, 0.05mmol) was treated as described in general procedure P to give 4' - {4- (2, 4-dichloro-phenyl) -1- [4- (1, 1, 4-trioxo- [1, 2, 5] thiadiazolidin-2-yl) -phenyl ] -1H-imidazol-2-ylmethyl } -biphenyl-3-carboxylic acid.

LCMS：m/z 633(M+H)⁺；¹H NMR(DMSO-d₆，400MHz)：δ4.06(s，2H)，4.09(s，2H)，7.16(d，2H)，7.19-7.26(m，4H)，7.33(d，2H)，7.38(d，2H)，7.47(dd，1H)，7.55(d，2H)，7.64(d，1H)，7.90(s，1H)，8.19(d，1H)ppm。

Example 10

Treatment of 5- {4- [2- (4-bromo-benzyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide (592mg, 1mmol) using 2-chloro-5-pyridine-boronic acid (315mg, 2mmol) as described in general procedure G gave 5- {4- [2- [4- (6-chloro-pyridin-3-yl) -benzyl ] -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide.

LCMS：m/z 624(M+H)⁺；¹H NMR(DMSO-d₆，400MHz)：δ4.06(s，2H)，4.09(s，2H)，7.15(d，2H)，7.18-7.34(m，4H)，7.38(d，2H)，7.47(dd，1H)，7.55(d，2H)，7.64(d，1H)，7.89(s，1H)，8.18(d，1H)，8.37(d，1H)ppm。

Example 11

5- {4- [2- [4- (6-chloro-pyridin-3-yl) -benzyl ] -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide (63mg, 0.1mmol) was treated with cyclohexanol (20mg, 0.2mmol) as described in general procedure L to give 5- {4- [2- [4- (6-cyclohexyloxy-pyridin-3-yl) -benzyl ] -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide.

LCMS：m/z 688(M+H)⁺；¹H NMR(DMSO-d₆，400MHz)：δ1.34-2.16(m，10H)，4.06(s，2H)，4.09(s，2H)，4.23(m，1H)，7.15(d，2H)，7.18-7.34(m，4H)，7.38(d，2H)，7.47(dd，1H)，7.55(d，2H)，7.64(d，1H)，7.89(s，1H)，8.18(d，1H)，8.28(d，1H)ppm。

Example 12

Treatment of 5- {4- [2- [4- (6-chloro-pyridin-3-yl) -benzyl ] -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide (63mg, 0.1mmol) with piperidine (17mg, 0.2mmol) as described in general procedure L gave 5- (4- {4- (2, 4-dichloro-phenyl) -2- [4- (3, 4, 5, 6-tetrahydro-2H- [1, 2 '] bipyridinyl-5' -yl) -benzyl ] -imidazol-1-yl } -phenyl) -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide.

LCMS：m/z 673(M+H)⁺；¹H NMR(DMSO-d₆，400MHz)：δ1.62-1.78(m，6H)，3.19-3.31(m，4H)，4.05(s，2H)，4.07(s，2H)，7.15(d，2H)，7.18-7.34(m，4H)，7.38(d，2H)，7.47(dd，1H)，7.55(d，2H)，7.64(d，1H)，7.89(s，1H)，8.18(d，1H)，8.25(d，1H)ppm。

Example 13

2- (4-bromo-benzyl) -4- (2, 4-dichloro-phenyl) -1H-imidazole (382mg, 1mmol) was treated with 5-fluoro-2-nitrotoluene (310mg, 2mmol) as described in general procedure B to give 2- (4-bromo-benzyl) -4- (2, 4-dichloro-phenyl) -1- (3-methyl-4-nitro-phenyl) -1H-imidazole.

LCMS：m/z 518(M+H)⁺。

2- (4-bromo-benzyl) -4- (2, 4-dichloro-phenyl) -1- (3-methyl-4-nitro-phenyl) -1H-imidazole (310mg, 0.6mmol) was treated as described in general procedure C to give 5- {4- [2- (4-bromo-benzyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -2-methyl-phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide.

LCMS：m/z 607(M+H)⁺；¹H NMR(DMSO-d₆，400MHz)：δ2.34(s，3H)，4.05(s，2H)，4.07(s，2H)，7.15(d，2H)，7.27-7.51(m，4H)，7.53(d，2H)，7.64(d，1H)，7.89(s，1H)，8.18(d，1H)ppm。

Treatment of 5- {4- [2- (4-bromo-benzyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -2-methyl-phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide (61mg, 0.1mmol) using 4-cyclohexylphenylboronic acid (41mg, 0.2mmol) as described in general procedure G gave 5- {4- [2- (4' -cyclohexyl-biphenyl-4-ylmethyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -2-methyl-phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide.

LCMS：m/z 685(M+H)⁺；¹H NMR(DMSO-d₆，400MHz)：δ1.13-1.40(m，5H)，1.65-1.78(m，5H)，2.34(s，3H)，2.52(m，1H)，4.05(s，2H)，4.08(s，2H)，7.15(d，2H)，7.18-7.27(m，4H)，7.44-7.48(m，4H)，7.55(d，2H)，7.64(d，1H)，7.89(s，1H)，8.18(d，1H)ppm。

Example 14

5- {4- [2- (4-bromo-benzyl) -4- (2, 4-difluoro-phenyl) -imidazol-1-yl ] -phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide (then following general procedures A, B and C) (56mg, 0.1mmol) was treated with 4-cyclohexylphenylboronic acid (41mg, 0.2mmol) as described in general procedure G to give 5- {4- [2- (4' -cyclohexyl-biphenyl-4-ylmethyl) -4- (2, 4-difluoro-phenyl) -imidazol-1-yl ] -phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide.

LCMS：m/z 639(M+H)⁺；¹H NMR(DMSO-d₆，400MHz)：δ1.22-1.44(m，5H)，1.69-1.81(m，5H)，2.52(m，1H)，4.05(s，2H)，4.07(s，2H)，7.13-7.16(m，5H)，7.27(d，2H)，7.37(d，2H)，7.41(m，1H)，7.51-7.55(m，5H)，8.12(m，1H)ppm。

The following compounds were synthesized by a method similar to that used for the preparation of example 14:

examples	Name (R)	LC/MS(m/z)
			15	5- {4- [2- (4' -cyclohexyl-biphenyl-4-ylmethyl) -4- (2, 4-difluoro-phenyl) -imidazol-1-yl]-2-methyl-phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide	653(M+H)+
16	5- {4- [4- (4-chloro-phenyl) -2- (4' -cyclohexyl-biphenyl-4-ylmethyl) -imidazol-1-yl]-phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide	637(M+H)+
			17	5- {4- [4- (2-chloro-phenyl) -2- (4' -cyclohexyl-biphenyl-4-ylmethyl) -imidazol-1-yl]-phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide	637(M+H)+

18	5- {4- [2- (4' -cyclohexyl-biphenyl-4-ylmethyl) -4- (2, 6-dichloro-phenyl) -imidazol-1-yl]-phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide	671(M+H)+
			19	5- {4- [2- (4' -cyclohexyl-biphenyl-4-ylmethyl) -4- (2, 4, 6-trichloro-phenyl) -imidazol-1-yl]-phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide	705(M+H)+
20	5- {4- [4- (2-chloro-4-fluoro-phenyl) -2- (4' -cyclohexyl-biphenyl-4-ylmethyl) -imidazol-1-yl]-phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide	655(M+H)+

Example 21

5- {4- [2- (4-bromo-benzyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide (592mg, 1mmol) was treated with 4-aminophenylboronic acid (274mg, 2mmol) as described in general procedure G to give 5- {4- [2- (4' -amino-biphenyl-4-ylmethyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide.

LCMS：m/z 604(M+H)⁺。

Treatment of 5- {4- [2- (4 '-amino-biphenyl-4-ylmethyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide (61mg, 0.1mmol) in the order of general procedure U with 3- (bromomethyl) -5-methylisoxazole (27mg, 0.15mmol) according to general procedure K and with isopropyl chloride (1M solution in toluene) (0.2mL, 0.2mmol) gives (4' - {4- (2, 4-dichloro-phenyl) -1- [4- (1, 1, 4-trioxo- [1, 2, 5] thiadiazolidin-2-yl) -phenyl ] -1H-imidazol-2-ylmethyl } -biphenyl-4-yl) - (5-methyl-isoxazol-3-ylmethyl) -carbamic acid isopropyl ester.

LCMS：m/z 785(M+H)⁺；¹H NMR(DMSO-d₆，400MHz)：δ1.25(d，6H)，2.33(s，3H)，4.06(s，2H)，4.08(s，2H)，4.65(s，2H)，4.93(m，1H)，7.05-7.18(m，5H)，7.27(d，2H)，7.37(d，2H)，7.43-7.54(m，5H)，7.64(d，1H)，7.88(s，1H)，8.18(d，1H)ppm。

Example 22

Treatment of 5- {4- [2- (4 '-amino-biphenyl-4-ylmethyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide (61mg, 0.1mmol) in the order according to general procedure K using 1-bromo-2-methylpropane (21mg, 0.15mmol) and according to general procedure U using isopropyl chloride (1M solution in toluene) (0.2mL, 0.2mmol) gave (4' - {4- (2, 4-dichloro-phenyl) -1- [4- (1, 1, 4-trioxo- [1, 2, 5] thiadiazolidin-2-yl) -phenyl ] -1H-imidazole-2 -ylmethyl } -biphenyl-4-yl) -isobutyl-carbamic acid isopropyl ester.

LCMS：m/z 746(M+H)⁺；¹H NMR(DMSO-d₆，400MHz)：δ0.87(d，6H)，1.24(d，6H)，1.66(m，1H)，3.51(d，2H)，4.06(s，2H)，4.08(s，2H)，4.93(m，1H)，7.16(d，2H)，7.18(d，2H)，7.27(d，2H)，7.37(d，2H)，7.47(dd，1H)，7.51(d，2H)，7.53(d，2H)，7.64(d，1H)，7.88(s，1H)，8.18(d，1H)ppm。

Example 23

Treatment of 3- [2- (4-bromo-benzyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -aniline (prepared as described in general procedure M) (28.4g, 60mmol) as described in general procedure E-F afforded 5- {3- [2- (4-bromo-benzyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide.

LCMS：m/z 593(M+H)⁺；¹H NMR(DMSO-d₆，400MHz)：δ4.05(s，2H)，4.07(s，2H)，7.15(d，2H)，7.27(d，2H)，7.47-7.53(m，5H)，7.64(d，1H)，7.89(s，1H)，8.19(d，1H)ppm。

5- {3- [2- (4-bromo-benzyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide (592mg, 1mmol) was treated with 4-cyclohexylphenylboronic acid (408mg, 2mmol) as described in general procedure G to give 5- {3- [2- (4' -cyclohexyl-biphenyl-4-ylmethyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide.

LCMS：m/z 671(M+H)⁺；¹H NMR(DMSO-d₆，400MHz)：δ1.22-1.43(m，5H)，1.69-1.81(m，5H)，2.52(m，1H)，4.05(s，2H)，4.07(s，2H)，7.15(d，2H)，7.18(d，2H)，7.27(d，2H)，7.37(d，2H)，7.46-7.54(m，5H)，7.64(d，1H)，7.89(s，1H)，8.19(d，1H)ppm。

The title compound can also be prepared using the following procedure starting from 3-nitroaniline. Methyl bromoacetate (6.77mL, 73.5mmol) was added to 3-nitroaniline (9.21g, 66.7mmol), NaHCO₃(14g, 167mol) and dimethylformamide (75 mL). The mixture was stirred at 70-75 ℃ for 3 hours and then cooled to room temperature. To the reaction mixture was added water (600mL) and the product was collected by excess and washed 3 times with 50mL portions of water. The yellow product (3-nitrophenylamino) -acetic acid methyl ester was dried under reduced pressure to yield 12.4g (88%).

Chlorosulfonyl isocyanate (8.68mL, 100mmol) was added dropwise to a solution of t-butanol (9.61mL, 100mmol) in dichloromethane (48.2mL) at 0 deg.C. The mixture was warmed to room temperature and stirred for 30 minutes. 37.5mL of this solution was then added dropwise to a mixture of (3-nitrophenylamino) -acetic acid methyl ester (10.5g, 50mmol), diisopropylethylamine (26mL, 150mol) and dichloromethane (50mL) at 0 ℃. After the addition was complete, the mixture was warmed to room temperature and washed with water (2 × 500 mL). Drying (MgSO)₄) The extract was extracted and filtered. The extract containing the Boc-protected sulfonamide was diluted to a total volume of 300mL by the addition of dichloromethane. To this solution was added trifluoroacetic acid (75mL) at 0 deg.C andand the solution was stirred for 3 hours or until no starting material was found to remain by TLC. The solution was washed with water (3 × 500mL) and the product was precipitated by addition of hexane and collected by filtration. The product was washed with 5% dichloromethane in hexane (50mL) and dried under reduced pressure to give 10.5g of product.

A NaOH solution (2M, 2.0 equiv) was added to a suspension of Boc deprotected starting material (10.5g, 36.3mmol) in ethanol (75mL) at 0 ℃ while stirring rapidly until a thick precipitate formed (2 min). The mixture was acidified to pH 5.0 by addition of 6.0M hydrochloric acid. The product, 1-dioxo-5- (3-nitrophenyl) - [1, 2, 5] thiadiazolidin-3-one, was collected by filtration and washed with diethyl ether (50 mL). The product was dried under reduced pressure to give the cyclized product (8.5g, 91%).

A solution of the nitro compound (8.5g) in methanol (40mL) was treated with 1.7g of a 10% Pd/C catalyst under hydrogen for 18 hours. The catalyst was removed by filtration. The solution was concentrated and 5- (3-amino-phenyl) -1, 1-dioxo- [1, 2, 5] thiadiazolidin-3-one was crystallized by addition of dichloromethane, collected by filtration and dried to yield 6.9g of product (92% yield).

To 5- (3-amino-phenyl) -1, 1-dioxo- [1, 2, 5]Thiadiazolidin-3-one (5g, 22mmol) in 37.5mL of a 9: 1 v/v acetonitrile-water solution was added NaHCO₃(4.62g, 55 mmol). The compound was stirred at 25 ℃ while 2-bromo-1- (2, 4-dichloro-phenyl) -ethanone (7.1g, 26.4mmol) was added. The compound was stirred at 35 ℃ for 12-16 hours. The mixture was cooled with an ice bath to further precipitate the product, which was then collected by filtration. The filtrate was concentrated under reduced pressure and a second crop of crude product was collected. The combined crude product was washed once with 25mL of water, then once with 10mL of methyl tert-butyl ether and dried to give 6.36g (70% yield) of 5- {3- [2- (2, 4-dichloro-phenyl) -2-oxo-ethylamino]-phenyl } -1, 1-dioxo- [1, 2, 5]Thiadiazolidin-3-one.

To benzoylmethylamine (9.4g, 23mmol) and NaHCO₃(5.04g, 60mmol) in dichloromethane (30mL) was added slowly (4'-cyclohexylbiphenyl) acetyl chloride (34mmol) prepared by reacting oxalyl chloride with (4 '-cyclohexyl-biphenyl-4-yl) -acetic acid (10g, 34mmol), in dichloromethane (10mL), whereby (4' -cyclohexyl-biphenyl-4-yl) -acetic acid was prepared from (4-cyclohexylphenyl) boronic acid and 4-bromophenylacetic acid by Suzuki coupling. The mixture was stirred at 25 ℃ for 9 hours. The mixture was then diluted with tetrahydrofuran, washed with dilute brine, dried over sodium sulfate and evaporated. The product 2- (4' -cyclohexyl-biphenyl-4-yl) -N- [2- (2, 4-dichloro-phenyl) -2-oxo-ethyl-l is purified by silica gel column chromatography using 1-8% methanol in dichloromethane]-N- [3- (1, 1, 4-trioxo- [1, 2, 5)]Thiadiazolidin-2-yl) -phenyl]-an acetamide.

To a solution of ammonium acetate (223mg, 2.9mmol) in acetic acid (0.5mL) was added the above tertiary amide (200mg, 0.29mmol) in dimethylformamide (0.5mL) and then the mixture was stirred at 90 ℃ for 18 hours, after which it was diluted with tetrahydrofuran and washed 5 times with dilute brine, dried over sodium sulfate and evaporated to dryness. The crude solid material was washed thoroughly with methanol to give 140mg of pure title product.

Example 24

5- {3- [2- (4-bromo-benzyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide (59mg, 0.1mmol) was treated with 4-tert-butylphenyl boronic acid (36mg, 0.2mmol) as described in general procedure G to give 5- {3- [2- (4' -tert-butyl-biphenyl-4-ylmethyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide.

LCMS：m/z 645(M+H)⁺；¹H NMR(DMSO-d₆，400MHz)：δ1.30(s，9H)，4.06(s，2H)，4.08(s，2H)，7.15(d，2H)，7.19(d，2H)，7.29(d，2H)，7.38(d，2H)，7.46-7.54(m，5H)，7.64(d，1H)，7.90(s，1H)，8.19(d，1H)ppm。

Example 25

Treatment of 5- {3- [2- (4-bromo-benzyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide (59mg, 0.1mmol) using 3- (3, 3-dimethyl-butoxy) phenylboronic acid (45mg, 0.2mmol, prepared according to general procedure H) as described in general procedure G gave 5- (3- {4- (2, 4-dichloro-phenyl) -2- [ 3' - (3, 3-dimethyl-butoxy) -biphenyl-4-ylmethyl ] -imidazol-1-yl } -phenyl) -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide.

LCMS：m/z 689(M+H)⁺；¹H NMR(DMSO-d₆，400MHz)：δ0.97(s，9H)，1.67(t，2H)，4.05(s，2H)，4.07(t，2H)，4.08(s，2H)，7.05-7.12(m，4H)，7.29(d，2H)，7.38(d，2H)，7.46-7.54(m，5H)，7.64(d，1H)，7.90(s，1H)，8.19(d，1H)ppm。

The following compounds were synthesized by a method similar to that used for the preparation of example 25:

examples	Name (R)	LC/MS(m/z)
			26	5- {3- [4- (2, 4-dichloro-phenyl) -2- (3' -methanesulfonyl-biphenyl-4-ylmethyl) -imidazol-1-yl]-phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide	667(M+H)+
27	5- {3- [2- (3' -cyclohexanesulfonyl-biphenyl-4-ylmethyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl]-phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide	735(M+H)+
			28	5- {3- [2- (4' -cyclohexanesulfonyl-biphenyl-4-ylmethyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl]-phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide	735(M+H)+
29	5- {3- [4- (2, 4-dichloro-phenyl) -2- (3' -propoxy-biphenyl-4-ylmethyl) -imidazol-1-yl]-phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide	647(M+H)+

30	5- {3- [2- (3' -butoxy-biphenyl-4-ylmethyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl]-phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide	661(M+H)+
			31	5- (3- {4- (2, 4-dichloro-phenyl) -2- [ 3' - (4, 4, 4-trifluoro-butoxy) -biphenyl-4-ylmethyl]-imidazol-1-yl } -phenyl) -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide	715(M+H)+
32	5- {3- [4- (2, 4-dichloro-phenyl) -2- (3' -ethoxy-biphenyl-4-ylmethyl) -imidazol-1-yl]-phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide	633(M+H)+
			33	5- {3- [2- (3' -cyclohexylmethoxy-biphenyl-4-ylmethyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl]-phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide	701(M+H)+
34	5- (3- {4- (2, 4-dichloro-phenyl) -2- [ 3' - (3-methyl-butoxy) -biphenyl-4-ylmethyl]-imidazol-1-yl } -phenyl) -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide	675(M+H)+
			35	5- {3- [2- (3' -cyclopentylmethoxy-biphenyl-4-ylmethyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl]-phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide	687(M+H)+
36	5- {3- [2- (3' -cyclohexyloxy-biphenyl-4-ylmethyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl]-phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide	687(M+H)+
			37	5- (3- {4- (2, 4-dichloro-phenyl) -2- [ 3' - (2, 2-dimethyl-propoxy) -biphenyl-4-ylmethyl]' MimiAzol-1-yl } -phenyl) -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide	675(M+H)+
38	5- {3- [2- (3' -tert-butoxy-biphenyl-4-ylmethyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl]-phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide	661(M+H)+

39	5- {3- [2- [ 3' - (2-cyclohexyl-ethoxy) -biphenyl-4-ylmethyl]-4- (2, 4-dichloro-phenyl) -imidazol-1-yl]-phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide	715(M+H)+
			40	5- {3- [2- [ 3' - (2-cyclopentyl-ethoxy) -biphenyl-4-ylmethyl]-4- (2, 4-dichloro-phenyl) -imidazol-1-yl]-phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide	701(M+H)+
41	5- {3- [4- (2, 4-dichloro-phenyl) -2- (3' -phenethyloxy-biphenyl-4-ylmethyl) -imidazol-1-yl]-phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide	709(M+H)+
			42	5- (3- {4- (2, 4-dichloro-phenyl) -2- [ 3' - (4, 4-dimethyl-pentyl) -biphenyl-4-ylmethyl]-imidazol-1-yl } -phenyl) -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide	687(M+H)+
43	5- {3- [2- [ 3' - (2-cyclohexyl-ethyl) -biphenyl-4-ylmethyl]-4- (2, 4-dichloro-phenyl) -imidazol-1-yl]-phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide	699(M+H)+
			44	5- (3- {4- (2, 4-dichloro-phenyl) -2- [ 3' - (3, 3-dimethyl-butylsulfanyl) -biphenyl-4-ylmethyl]-imidazol-1-yl } -phenyl) -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide	705(M+H)+

Example 45

Treatment of 5- (3- {4- (2, 4-dichloro-phenyl) -2- [3 '- (3, 3-dimethyl-butylsulfanyl) -biphenyl-4-ylmethyl ] -imidazol-1-yl } -phenyl) -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide (14mg, 0.02mmol) as described in general procedure S gave 5- (3- {4- (2, 4-dichloro-phenyl) -2- [ 3' - (3, 3-dimethyl-butane-1-sulfonyl) -biphenyl-4-ylmethyl ] -imidazol-1-yl } -phenyl) -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide.

LCMS：m/z 737(M+H)⁺；¹H NMR(DMSO-d₆，400MHz)：δ0.89(s，9H)，1.46(m，2H)，3.27(m，2H)，4.06(s，2H)，4.09(s，2H)，7.18(d，2H)，7.21(d，2H)，7.29-7.41(m，4H)，7.49-7.58(m，5H)，7.63(d，1H)，7.88(s，1H)，8.18(d，1H)ppm。

Example 46

Treatment of 5- (3- {4- (2, 4-dichloro-phenyl) -2- [3 '- (3, 3-dimethyl-butylsulfanyl) -biphenyl-4-ylmethyl ] -imidazol-1-yl } -phenyl) -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide (14mg, 0.02mmol) as described in general procedure T gave 5- (3- {4- (2, 4-dichloro-phenyl) -2- [ 3' - (3, 3-dimethyl-butane-1-sulfinyl) -biphenyl-4-ylmethyl ] -imidazol-1-yl } -phenyl) -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide.

LCMS：m/z 721(M+H)⁺；¹H NMR(DMSO-d₆，400MHz)：δ0.86(s，9H)，1.45(m，2H)，2.98(m，2H)，4.05(s，2H)，4.08(s，2H)，7.18(d，2H)，7.21(d，2H)，7.26-7.38(m，4H)，7.47-7.56(m，5H)，7.63(d，1H)，7.88(s，1H)，8.18(d，1H)ppm。

Example 47

Treatment of 5- {3- [2- (4-bromo-benzyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide (119mg, 0.2mmol) using 3- (cyclohexylmethylsulfanyl) phenylboronic acid (100mg, 0.4mmol, prepared according to general procedure I) as described in general procedure G gave 5- {3- [2- (3' -cyclohexylmethylsulfanyl-biphenyl-4-ylmethyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide.

LCMS：m/z 717(M+H)⁺；¹H NMR(DMSO-d₆，400MHz)：δ0.97-1.23(m，6H)，1.48(m，1H)，1.58-1.87(m，4H)，2.88(d，2H)，4.05(s，2H)，4.08(s，2H)，7.12-7.18(m，4H)，7.33-7.38(m，4H)，7.46-7.58(m，5H)，7.63(d，1H)，7.88(s，1H)，8.18(d，1H)ppm。

Example 48

5- {3- [2- (3 '-cyclohexylmethylsulfanyl-biphenyl-4-ylmethyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide (15mg, 0.02mmol) was processed as described in general procedure S to give 5- {3- [2- (3' -cyclohexylmethylsulphonyl-biphenyl-4-ylmethyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide.

LCMS：m/z 749(M+H)⁺；¹H NMR(DMSO-d₆，400MHz)：δ1.00-1.24(m，6H)，1.53(m，1H)，1.59-1.89(m，4H)，3.20(d，2H)，4.05(s，2H)，4.08(s，2H)，7.18(d，2H)，7.21(d，2H)，7.29-7.41(m，4H)，7.46-7.58(m，5H)，7.63(d，1H)，7.88(s，1H)，8.18(d，1H)ppm。

Example 49

Treatment of 5- {3- [2- (3 '-cyclohexylmethylsulfanyl-biphenyl-4-ylmethyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide (15mg, 0.02mmol) as described in general procedure T gave 5- {3- [2- (3' -cyclohexylmethylsulfinyl-biphenyl-4-ylmethyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide.

LCMS：m/z 733(M+H)⁺；¹H NMR(CD₃OD，400MHz)：δ1.00-1.86(m，11H)，3.03(m，2H)，4.05(s，2H)，4.08(s，2H)，7.18(d，2H)，7.21(d，2H)，7.27-7.39(m，4H)，7.46-7.58(m，5H)，7.63(d，1H)，7.88(s，1H)，8.18(d，1H)ppm。

Example 50

Treatment of 5- {3- [2- (4-bromo-benzyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide (119mg, 0.2mmol) using 3- (cyclohexylmethylsulfanyl) phenylboronic acid (106mg, 0.4mmol, prepared according to general procedure I) as described in general procedure G gave 5- {3- [2- (3' - (2-cyclohexyl-ethylsulfanyl) -biphenyl-4-ylmethyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide.

LCMS：m/z 731(M+H)⁺；¹H NMR(DMSO-d₆，400MHz)：δ0.85-1.72(m，13H)，3.03(t，2H)，4.05(s，2H)，4.08(s，2H)，7.17-7.26(m，4H)，7.34-7.42(m，4H)，7.47-7.58(m，5H)，7.64(d，1H)，7.89(s，1H)，8.19(d，1H)ppm。

Example 51

Treatment of 5- {3- [2- (3 '- (2-cyclohexyl-ethylsulfanyl) -biphenyl-4-ylmethyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide (15mg, 0.02mmol) as described in general procedure S gave 5- {3- [2- (3' - (2-cyclohexyl-ethanesulfonyl) -biphenyl-4-ylmethyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide.

LCMS：m/z 763(M+H)⁺；¹H NMR(DMSO-d₆，400MHz)：δ0.85-1.72(m，13H)，3.33(m，2H)，4.05(s，2H)，4.08(s，2H)，7.22-7.29(m，4H)，7.37-7.47(m，4H)，7.51-7.59(m，5H)，7.64(d，1H)，7.89(s，1H)，8.19(d，1H)ppm。

Example 52

Treatment of 5- {3- [2- (3 '- (2-cyclohexyl-ethylsulfanyl) -biphenyl-4-ylmethyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide (15mg, 0.02mmol) as described in general procedure T gave 5- {3- [2- (3' - (2-cyclohexyl-ethanesulfinyl) -biphenyl-4-ylmethyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide.

LCMS：m/z 747(M+H)⁺；¹H NMR(CD₃OD，400MHz)：δ0.85-1.72(m，13H)，3.07(m，2H)，4.05(s，2H)，4.08(s，2H)，7.21-7.28(m，4H)，7.37-7.44(m，4H)，7.49-7.58(m，5H)，7.64(d，1H)，7.88(s，1H)，8.18(d，1H)ppm。

Example 53

Treatment of 5- {3- [2- (4-bromo-benzyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide (119mg, 0.2mmol) as described in general procedure G using 3- (phenethylsulfanyl) phenylboronic acid (104mg, 0.4mmol, prepared according to general procedure I) gave 5- {3- [4- (2, 4-dichloro-phenyl) -2- (3' -phenethylsulfanyl-biphenyl-4-ylmethyl) -imidazol-1-yl ] -phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide.

LCMS：m/z 725(M+H)⁺；¹H NMR(DMSO-d₆，400MHz)：δ2.89(t，2H)，3.30(t，2H)，4.07(s，2H)，4.09(s，2H)，7.18-7.22(m，5H)，7.25-7.32(m，6H)，7.37-7.49(m，4H)，7.53(m，1H)，7.57(d，2H)，7.64(d，1H)，7.90(s，1H)，8.20(d，1H)ppm。

Example 54

Using 3- (3, 3-dimethyl-butylsulfanyl) phenylboronic acid (96mg, 0.4mmol, prepared according to general procedure I) 5- {3- [2- (4-bromo-benzyl) -4- (2, 4-difluoro-phenyl) -imidazol-1-yl ] -phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide (prepared stepwise according to general procedures A, J and C) (112mg, 0.2mmol) was treated as described in general procedure G to give 5- (3- {4- (2, 4-difluoro-phenyl) -2- [3 '- (3, 3-dimethyl-butylsulfanyl) -biphenyl-4-ylmethyl ] -imidazol-1-yl } -phenyl) -1- (3, 4-difluoro-phenyl) -2- [ 3' - (3, 3-dimethyl-butylsulfanyl) -biphenyl-4-ylmethyl ] -imidazol-1-yl } -phenyl) -12, 5-thiadiazolidin-3-one-1, 1-dioxide.

LCMS：m/z 673(M+H)⁺；¹H NMR(DMSO-d₆，400MHz)：δ0.91(s，9H)，1.49(m，2H)，2.96(m，2H)，4.05(s，2H)，4.07(s，2H)，7.12-7.18(m，4H)，7.27-7.36(m，5H)，7.53-7.59(m，5H)，7.95-8.11(m，2H)ppm。

Example 55

Treatment of 5- (3- {4- (2, 4-difluoro-phenyl) -2- [3 '- (3, 3-dimethyl-butylsulfanyl) -biphenyl-4-ylmethyl ] -imidazol-1-yl } -phenyl) -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide (14mg, 0.02mmol) as described in general procedure S gave 5- (3- {4- (2, 4-difluoro-phenyl) -2- [ 3' - (3, 3-dimethyl-butane-1-sulfonyl) -biphenyl-4-ylmethyl ] -imidazol-1-yl } -phenyl) -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide.

LCMS：m/z 705(M+H)⁺；¹H NMR(CD₃OD，400MHz)：δ0.90(s，9H)，1.48(m，2H)，3.25(m，2H)，4.05(s，2H)，4.07(s，2H)，7.14-7.21(m，4H)，7.28-7.39(m，5H)，7.53-7.59(m，5H)，7.95-8.11(m，2H)ppm。

Example 56

Treatment of 5- (3- {4- (2, 4-difluoro-phenyl) -2- [3 '- (3, 3-dimethyl-butylsulfanyl) -biphenyl-4-ylmethyl ] -imidazol-1-yl } -phenyl) -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide (14mg, 0.02mmol) as described in general procedure T gave 5- (3- {4- (2, 4-difluoro-phenyl) -2- [ 3' - (3, 3-dimethyl-butane-1-sulfinyl) -biphenyl-4-ylmethyl ] -imidazol-1-yl } -phenyl) -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide.

LCMS：m/z 689(M+H)⁺；¹H NMR(DMSO-d₆，400MHz)：δ0.91(s，9H)，1.48(m，2H)，2.98(m，2H)，4.05(s，2H)，4.08(s，2H)，7.13-7.21(m，4H)，7.27-7.39(m，5H)，7.53-7.59(m，5H)，7.95-8.11(m，2H)ppm。

Example 57

5- {3- [2- (4-bromo-benzyl) -4- (2, 4-difluoro-phenyl) -imidazol-1-yl ] -phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide (prepared stepwise according to general procedures A, R and C) (56mg, 0.1mmol) was treated with 4-cyclohexylphenylboronic acid (41mg, 0.2mmol) as described in general procedure G to give 5- {3- [2- (4' -cyclohexyl-biphenyl-4-ylmethyl) -4- (2, 4-difluoro-phenyl) -imidazol-1-yl ] -phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide.

LCMS：m/z 639(M+H)⁺；¹H NMR(DMSO-d₆，400MHz)：δ1.22-1.44(m，5H)，1.69-1.81(m，5H)，2.52(m，1H)，4.05(s，2H)，4.07(s，2H)，7.13-7.16(m，5H)，7.27(d，2H)，7.37(d，2H)，7.41(m，1H)，7.51-7.55(m，5H)，8.12(m，1H)ppm。

The following compounds were synthesized by a method similar to that used for the preparation of example 57:

examples	Name (R)	LC/MS(m/z)
			58	5- {5- [2- (4' -cyclohexyl-biphenyl-4-ylmethyl) -4- (2, 4-difluoro-phenyl) -imidazol-1-yl]-2-methyl-phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide	653(M+H)+
59	5- {5- [2- (4' -cyclohexyl-biphenyl-4-ylmethyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl]-2-methyl-phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide	685(M+H)+
			60	5- {5- [2- (4' -cyclohexyl-biphenyl-4-ylmethyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl]-2-methoxy-phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide	701(M+H)+
61	5- {3- [2- (4' -cyclohexyl-biphenyl-4-ylmethyl) -4- (2, 6-bisChloro-phenyl) -imidazol-1-yl]-phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide	671(M+H)+
			62	5- {3- [2- (4' -cyclohexyl-biphenyl-4-ylmethyl) -4- (2, 4, 6-trichloro-phenyl) -imidazol-1-yl]-phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide	705(M+H)+
63	5- (3- {4- (2, 6-dichloro-phenyl) -2- [ 3' - (3, 3-dimethyl-butoxy) -biphenyl-4-ylmethyl]-imidazol-1-yl } -phenyl) -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide	689(M+H)+
			64	5- {3- [2- (3' -cyclohexylmethoxy-biphenyl-4-ylmethyl) -4- (2, 6-dichloro-phenyl) -imidazol-1-yl]-phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide	701(M+H)+

65

5- (3- {4- (2, 4-difluoro-phenyl) -2- [ 3' - (3, 3-dimethyl-butoxy) -biphenyl-4-ylmethyl]-imidazol-1-yl } -phenyl) -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide

657(M+H)+

Example 66

4-iodophenylacetic acid (26.2g, 0.1mol) was treated with 2, 4-dichlorobromoacetophenone according to general procedure A to give 4- (2, 4-dichloro-phenyl) -2- (4-iodo-benzyl) -1H-imidazole.

LCMS：m/z 429(M+H)⁺。

4- (2, 4-dichloro-phenyl) -2- (4-iodo-benzyl) -1H-imidazole (12.9g, 30mmol) was worked up stepwise as described in general procedures B and C to give 5- {4- [4- (2, 4-dichloro-phenyl) -2- (4-iodo-benzyl) -imidazol-1-yl ] -phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide.

LCMS：m/z 639(M+H)⁺。

5- {4- [4- (2, 4-dichloro-phenyl) -2- (4-iodo-benzyl) -imidazol-1-yl ] -phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide (3.2G, 5mmol) was treated with 4-bromophenylboronic acid (2.0G, 10mmol) as described in general procedure G to give 5- {4- [2- (4' -bromo-biphenyl-4-ylmethyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide.

LCMS：m/z 669(M+H)⁺；¹H NMR(DMSO-d₆，400MHz)：δ4.05(s，2H)，4.07(s，2H)，7.15(d，2H)，7.19(d，2H)，7.36(d，2H)，7.45(d，2H)，7.49(dd，1H)，7.52(d，2H)，7.54(d，2H)，7.64(d，1H)，7.89(s，1H)，8.19(d，1H)ppm。

Treatment of 5- {4- [2- (4 '-bromo-biphenyl-4-ylmethyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide (268mg, 0.4mmol) with an excess of piperazine (346mg, 4mmol) as described in general procedure R gave the desired compound 5- {4- [4- (2, 4-dichloro-phenyl) -2- (4' -piperazin-1-yl-biphenyl-4-ylmethyl) -imidazol-1-yl ] -phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide.

LCMS：m/z 673(M+H)⁺；¹H NMR(DMSO-d₆，400MHz)：δ3.01(m，4H)，3.31(m，4H)，4.05(s，2H)，4.08(s，2H)，6.94(d，2H)，7.19(d，2H)，7.36(d，2H)，7.45-7.52(m，5H)，7.56(d，2H)，7.64(d，1H)，7.89(s，1H)，8.18(d，1H)ppm。

Example 67

Treatment of 5- {4- [2- (4 '-bromo-biphenyl-4-ylmethyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide (67mg, 0.1mmol) with an excess of 1-methylpiperazine (100mg, 1mmol) as described in general procedure R gave 5- (4- {4- (2, 4-dichloro-phenyl) -2- [ 4' - (4-methyl-piperazin-1-yl) -biphenyl-4-ylmethyl ] -imidazol-1-yl } -phenyl) -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide.

LCMS：m/z 687(M+H)⁺；¹H NMR(DMSO-d₆，400MHz)：δ2.43(s，3H)，3.12(m，4H)，3.34(m，4H)，4.05(s，2H)，4.08(s，2H)，6.94(d，2H)，7.19(d，2H)，7.36(d，2H)，7.45-7.52(m，5H)，7.56(d，2H)，7.64(d，1H)，7.89(s，1H)，8.18(d，1H)ppm。

Example 68

Treatment of 5- {4- [2- (4 '-bromo-biphenyl-4-ylmethyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide (134mg, 0.2mmol) using an excess of piperazin-2-one (200mg, 2mmol) as described in general procedure R gave 4- (4' - {4- (2, 4-dichloro-phenyl) -1- [4- (1, 1, 4-trioxo- [1, 2, 5] thiadiazolidin-2-yl) -phenyl ] -1H-imidazol-2-ylmethyl } -biphenyl-4-yl) -piperazin-2-one .

LCMS：m/z 687(M+H)⁺；¹H NMR(DMSO-d₆，400MHz)：δ3.22-3.34(m，4H)，4.01(s，2H)，4.05(s，2H)，4.08(s，2H)，6.94(d，2H)，7.19(d，2H)，7.36(d，2H)，7.45-7.52(m，5H)，7.56(d，2H)，7.64(d，1H)，7.89(s，1H)，8.18(d，1H)ppm。

Example 69

Treatment of 5- {4- [4- (2, 4-dichloro-phenyl) -2- (4 '-piperazin-1-yl-biphenyl-4-ylmethyl) -imidazol-1-yl ] -phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide (20mg, 0.03mmol) using neopentyl chloroformate (9mg, 0.06mmol) as described in general procedure U gave 4- (4' - {4- (2, 4-dichloro-phenyl) -1- [4- (1, 1, 4-trioxo- [1, 2, 5] thiadiazolidin-2-yl) -phenyl ] -1H-imidazol-2-ylmethyl } -biphenyl-4-yl) -piperazine-1- Formic acid 2, 2-dimethyl-propyl ester.

LCMS：m/z 787(M+H)⁺；¹H NMR(CD₃OD，400MHz)：δ1.06(s，9H)，3.17-3.36(m，8H)，4.02(s，2H)，4.06(s，2H)，4.08(s，2H)，6.94(d，2H)，7.19(d，2H)，7.36(d，2H)，7.45-7.52(m，5H)，7.56(d，2H)，7.64(d，1H)，7.89(s，1H)，8.20(d，1H)ppm。

Example 70

Treatment of 5- {4- [2- (4 '-bromo-biphenyl-4-ylmethyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide (268mg, 0.4mmol) using 2- (trimethylsilyl) ethoxymethyl chloride (142 μ L, 0.8mmol) as described in general procedure L gave 5- {4- [2- (4' -bromo-biphenyl-4-ylmethyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenyl } -2- (2-trimethylsilyl-ethoxymethyl) -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide.

LCMS：m/z 799(M+H)⁺。

Treatment of 5- {4- [2- (4 '-bromo-biphenyl-4-ylmethyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenyl } -2- (2-trimethylsilyl-ethoxymethyl) -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide (240mg, 0.3mmol) with an excess of piperazin-2-one (301mg, 3mmol) as described in general procedure R gave 4- [ 4' - (4- (2, 4-dichloro-phenyl) -1- {4- [1, 1, 4-trioxo-5- (2-trimethylsilyl-ethoxymethyl) - [1, 2, 5] thiadiazolidin-2-yl ] -phenyl } -1H-imidazol-2-ylmethyl) -biphenyl-4-yl ] -piperazin-2-one.

LCMS：m/z 817(M+H)⁺。

The desired compound 4- (4' - {4- (2, 4-dichloro-phenyl) -1- [4- (1, 1, 4-trioxo-phenyl) -1- [1, 1, 4-trioxo-5- (2-trimethylsilyl-ethoxymethyl) - [1, 2, 5] thiadiazolidin-2-yl ] -phenyl } -1H-imidazol-2-ylmethyl) -biphenyl-4-yl ] -piperazin-2-one (17mg, 0.02mmol) was obtained by work-up (using methyl iodide) as described in general procedure L and general procedure W, 2, 5] thiadiazolidin-2-yl) -phenyl ] -1H-imidazol-2-ylmethyl } -biphenyl-4-yl) -1-methyl-piperazin-2-one.

LCMS：m/z 701(M+H)⁺；¹H NMR(CD₃OD，400MHz)：δ2.94(s，3H)，3.28-3.36(m，4H)，4.01(s，2H)，4.08(s，2H)，4.16(s，2H)，6.94(d，2H)，7.19(d，2H)，7.36(d，2H)，7.45-7.52(m，5H)，7.56(d，2H)，7.64(d，1H)，7.89(s，1H)，8.18(d，1H)ppm。

Example 71

4- [4 '- (4- (2, 4-dichloro-phenyl) -1- {4- [1, 1, 4-trioxo-5- (2-trimethylsilyl-ethoxymethyl) - [1, 2, 5] thiadiazolidin-2-yl ] -phenyl } -1H-imidazol-2-ylmethyl) -biphenyl-4-yl ] -piperazin-2-one (17mg, 0.02mmol) was worked up as described in general procedure L (using iodoethane) and general procedure W to give 4- (4' - {4- (2, 4-dichloro-phenyl) -1- [4- (1, 1, 4-trioxo- [1, 2, 5] thiadiazolidin-2-yl) -phenyl ] -1H-imidazol-2-ylmethyl } -biphenyl-4-yl) -1-ethyl-piperazin-2-one.

LCMS：m/z 715(M+H)⁺；¹H NMR(CD₃OD，400MHz)：δ1.09(t，3H)，3.28-3.36(m，4H)，3.57(q，2H)，4.01(s，2H)，4.08(s，2H)，4.16(s，2H)，6.94(d，2H)，7.19(d，2H)，7.36(d，2H)，7.45-7.52(m，5H)，7.56(d，2H)，7.64(d，1H)，7.89(s，1H)，8.18(d，1H)ppm。

Example 72

4- [4 '- (4- (2, 4-dichloro-phenyl) -1- {4- [1, 1, 4-trioxo-5- (2-trimethylsilyl-ethoxymethyl) - [1, 2, 5] thiadiazolidin-2-yl ] -phenyl } -1H-imidazol-2-ylmethyl) -biphenyl-4-yl ] -piperazin-2-one (17mg, 0.02mmol) was worked up as described in general procedure L (using 2-iodopropane) and general procedure W to give 4- (4' - {4- (2, 4-dichloro-phenyl) -1- [4- (1, 1, 4-trioxo- [1, 2, 5] thiadiazolidin-2-yl) -phenyl ] -1H-imidazol-2-ylmethyl } -biphenyl-4-yl) -1-isopropyl-piperazin-2-one.

LCMS：m/z 729(M+H)⁺；¹H NMR(CD₃OD，400MHz)：δ1.06(d，6H)，3.28-3.36(m，4H)，3.71(m，1H)，4.01(s，2H)，4.08(s，2H)，4.15(s，2H)，6.94(d，2H)，7.19(d，2H)，7.36(d，2H)，7.45-7.52(m，5H)，7.56(d，2H)，7.64(d，1H)，7.89(s，1H)，8.18(d，1H)ppm。

Example 73

Treatment [ using iodocyclohexane (13mg, 0.06mmol) ] and general procedure W as described in general procedure L stepwise treatment of 4- [4 '- (4- (2, 4-dichloro-phenyl) -1- {4- [1, 1, 4-trioxo-5- (2-trimethylsilyl-ethoxymethyl) - [1, 2, 5] thiadiazolidin-2-yl ] -phenyl } -1H-imidazol-2-ylmethyl) -biphenyl-4-yl ] -piperazin-2-one (17mg, 0.02mmol) gave 1-cyclohexyl-4- (4' - {4- (2, 4-dichloro-phenyl) -1- [4- (1, 1, 4-trioxo- [1, 2, 5] thiadiazolidin-2-yl) -phenyl ] -1H-imidazol-2-ylmethyl } -biphenyl-4-yl) -piperazin-2-one.

LCMS：m/z 769(M+H)⁺；¹H NMR(CD₃OD，400MHz)：δ1.42-1.71(m，10H)，3.28-3.36(m，4H)，4.01(s，2H)，4.07(s，2H)，4.09(m，1H)，4.17(s，2H)，6.94(d，2H)，7.19(d，2H)，7.36(d，2H)，7.45-7.52(m，5H)，7.56(d，2H)，7.64(d，1H)，7.89(s，1H)，8.18(d，1H)ppm。

Example 74

Treatment of 5- {4- [2- (4-bromo-benzyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide (592mg, 1mmol) using 2- (trimethylsilyl) ethoxymethyl chloride (354 μ L, 2mmol) as described in general procedure L gave 5- {4- [2- (4-bromo-benzyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenyl } -1, 1-dioxo-2- (2-trimethylsilyl-ethoxymethyl) - [1, 2, 5] thiadiazolidin-3-one.

LCMS：m/z 723(M+H)⁺。

Treatment of 5- {4- [2- (4-bromo-benzyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenyl } -1, 1-dioxo-2- (2-trimethylsilyl-ethoxymethyl) - [1, 2, 5] thiadiazolidin-3-one (361mg, 0.5mmol) with 4-aminophenylboronic acid (137mg, 1mmol) as described in general procedure G gave 5- {4- [2- (4' -amino-biphenyl-4-ylmethyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenyl } -1, 1-dioxo-2- (2-trimethylsilyl-ethoxymethyl) ) - [1, 2, 5] thiadiazolidin-3-one.

LCMS：m/z 734(M+H)⁺。

Treatment of 5- {4- [2- (4 '-amino-biphenyl-4-ylmethyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenyl } -1, 1-dioxo-2- (2-trimethylsilyl-ethoxymethyl) - [1, 2, 5] thiadiazolidin-3-one (74mg, 0.1mmol) using 5-bromovaleryl chloride (40mg, 0.2mmol) as described in general procedure U gave the intermediate 5-bromo-pentanoic acid [ 4' - (4- (2, 4-dichloro-phenyl) -1- {4- [1, 1, 4-trioxo-5- (2-trimethylsilyl-ethoxymethyl) - [1, 2, 5] thia-dipyrrolidin-2-yl ] -phenyl } -1H-imidazol-2-ylmethyl) -biphenyl-4-yl ] -amide which was treated with 1, 8-diazabicyclo [5, 4, 0] undec-7-ene (46mg, 0.3mmol) at 0 ℃ and 1mL of anhydrous DMF (stirred overnight at room temperature under nitrogen) followed by ethyl acetate/water workup and silica gel chromatography on a regular basis to give 1- [ 4' - (4- (2, 4-dichloro-phenyl) -1- {4- [1, 1, 4-trioxo-5- (2-trimethylsilyl-ethoxymethyl) - [1, 2, 5] thia-dipyrrolidin-2-yl ] -phenyl } -1H-imidazole- 2-ylmethyl) -biphenyl-4-yl ] -piperidin-2-one, which is finally treated as described in general procedure W to give the desired compound 1- (4' - {4- (2, 4-dichloro-phenyl) -1- [4- (1, 1, 4-trioxo- [1, 2, 5] thiadiazolidin-2-yl) -phenyl ] -1H-imidazol-2-ylmethyl } -biphenyl-4-yl) -piperidin-2-one.

LCMS：m/z 686(M+H)⁺；¹H NMR(CD₃OD，400MHz)：δ1.84(m，4H)，2.43(m，2H)，3.39(m，2H)，4.08(s，2H)，4.16(s，2H)，7.21(d，2H)，7.29(d，2H)，7.36(d，2H)，7.45-7.52(m，5H)，7.56(d，2H)，7.64(d，1H)，7.89(s，1H)，8.18(d，1H)ppm。

Example 75

2- (4-bromo-benzyl) -1- (4-nitro-phenyl) -4- (2, 4-dichloro-phenyl) -1H-imidazole (5.0G, 10mmol) was treated with 3-chloro-4-pyridine-boronic acid (3.2G, 20mmol) as described in general procedure G to give 2-chloro-4- {4- [4- (2, 4-dichloro-phenyl) -1- (4-nitro-phenyl) -1H-imidazol-2-ylmethyl ] -phenyl } -pyridine.

LCMS：m/z 535(M+H)⁺。

2-chloro-4- {4- [4- (2, 4-dichloro-phenyl) -1- (4-nitro-phenyl) -1H-imidazol-2-ylmethyl ] -phenyl } -pyridine (1.6g, 3mmol) was refluxed with 6M NaOH in 1/1 water/ethanol (10mL, 60mmol) for 2-4 hours followed by periodic ethyl acetate/water workup and silica gel chromatography to give the intermediate 4- {4- [4- (2, 4-dichloro-phenyl) -1- (4-nitro-phenyl) -1H-imidazol-2-ylmethyl ] -phenyl } -1H-pyridin-2-one, which was then treated as described in general procedure L [ using iodocyclohexane (0.78mL, 6 mmol)) to give 1-cyclohexyl-4- {4- [4- (2, 4-dichloro-phenyl) -1- (4-nitro-phenyl) -1H-imidazol-2-ylmethyl ] -phenyl } -1H-pyridin-2-one.

LCMS：m/z 599(M+H)⁺。

1-cyclohexyl-4- {4- [4- (2, 4-dichloro-phenyl) -1- (4-nitro-phenyl) -1H-imidazol-2-ylmethyl ] -phenyl } -1H-pyridin-2-one (300mg, 0.5mmol) was processed as described in general procedure C to give the desired compound 1-cyclohexyl-4- (4- {4- (2, 4-dichloro-phenyl) -1- [4- (1, 1, 4-trioxo- [1, 2, 5] thiadiazolidin-2-yl) -phenyl ] -1H-imidazol-2-ylmethyl } -phenyl) -1H-pyridin-2-one.

LCMS：m/z 688(M+H)⁺；¹H NMR(DMSO-d₆，400MHz)：δ1.66-1.84(m，6H)，2.33-2.46(m，4H)，4.05(s，2H)，4.08(s，2H)，4.23(m，1H)，7.11-7.36(m，5H)，7.45-7.52(m，4H)，7.56(d，2H)，7.64(d，1H)，7.89(s，1H)，8.18(d，1H)，8.28(d，1H)ppm。

Example 76

Prepared as described in general procedure Y) using 4- (3-ethyl-cyclobutyl) phenylboronic acid (41mg, 0.2mmol, using 3- (4-bromophenyl) cyclobutan-1-one in place of bromobenzaldehyde) to give 5- {4- [2- (4-bromo-benzyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide (59mg, 0.1mmol) was treated as described in general procedure G to give 5- (4- {4- (2, 4-dichloro-phenyl) -2- [ 4' - (3-ethyl-cyclobutyl) -biphenyl-4-ylmethyl ] -imidazol-1-yl } -phenyl) ) -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide.

LCMS：m/z 671(M+H)⁺；¹H NMR(DMSO-d₆，400MHz)：δ0.94(t，3H)，1.32-1.81(m，7H)，2.52(m，1H)，4.05(s，2H)，4.07(s，2H)，7.15(d，2H)，7.18(d，2H)，7.27(d，2H)，7.37(d，2H)，7.48(dd，1H)，7.51(d，2H)，7.53(d，2H)，7.64(d，1H)，7.89(s，1H)，8.19(d，1H)ppm。

Example 77

2- (4-bromo-benzyl) -1- (4-nitro-phenyl) -4- (2, 4-dichloro-phenyl) -1H-imidazole (503mg, 1mmol) was treated as described in general procedures E and F using methyl 2-bromopropionate (335. mu.L, 3mmol) to give 5- {4- [2- (4-bromo-benzyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenyl } -4-methyl-1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide.

LCMS：m/z 607(M+H)⁺；¹H NMR(DMSO-d₆，400MHz)：δ1.09(d，3H)，4.05(s，2H)，4.10(m，1H)，7.15(d，2H)，7.27(d，2H)，7.47(dd，1H)，7.51(d，2H)，7.53(d，2H)，7.64(d，1H)，7.89(s，1H)，8.19(d，1H)ppm。

Treatment of 5- {4- [2- (4-bromo-benzyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenyl } -4-methyl-1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide (61mg, 0.1mmol) using 4-tert-butylphenyl boronic acid (36mg, 0.2mmol) as described in general procedure G gave 5- {4- [2- (4' -tert-butyl-biphenyl-4-ylmethyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenyl } -4-methyl-1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide.

LCMS：m/z 659(M+H)⁺；¹H NMR(DMSO-d₆，400MHz)：δ1.09(d，3H)，1.30(s，9H)，4.06(s，2H)，4.10(m，1H)，7.15(d，2H)，7.19(d，2H)，7.36(d，2H)，7.45(d，2H)，7.49(dd，1H)，7.52(d，2H)，7.54(d，2H)，7.64(d，1H)，7.90(s，1H)，8.20(d，1H)ppm。

The following compounds were synthesized by a method similar to that used for the preparation of example 77:

examples	Name (R)	LC/MS(m/z)
			78	5- {4- [2- (4' -tert-butyl-biphenyl-4-ylmethyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl]-phenyl } -4-ethyl-1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide	673(M+H)+
79	5- {4- [2- (4' -tert-butyl-biphenyl-4-ylmethyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl]-phenyl } -4, 4-Dimethyl-1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide	673(M+H)+
			80	1- {4- [2- (4' -tert-butyl-biphenyl-4-ylmethyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl]-phenyl } -2, 2-dioxo-thia-1, 3-diaza-spiro [4.5]Decan-4-ones	713(M+H)+

Example 81

5- {4- [2- (4-bromo-benzyl) -4- (2, 4-difluoro-phenyl) -imidazol-1-yl ] -phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide (subsequently prepared according to general procedures A, B and C) (56mg, 0.1mmol) was treated with 4-tert-butylphenyl boronic acid (36mg, 0.2mmol) as described in general procedure G to give 5- {4- [2- (4' -tert-butyl-biphenyl-4-ylmethyl) -4- (2, 4-difluoro-phenyl) -imidazol-1-yl ] -phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide.

LCMS：m/z 613(M+H)⁺；¹H NMR(DMSO-d₆，400MHz)：δ1.31(s，9H)，4.05(s，2H)，4.07(s，2H)，7.13-7.16(m，5H)，7.27(d，2H)，7.37(d，2H)，7.41(m，1H)，7.51-7.55(m，5H)，8.12(m，1H)ppm。

Example 82

Treatment of 2- (4-bromo-benzyl) -4- (2, 4-dichloro-phenyl) -1H-imidazole (3.8G, 10mmol) with 1, 4-diiodobenzene (13.2G, 40mmol) as described in general procedure R treatment with 4-tert-butylphenyl boronic acid (3.6G, 20mmol) as described in general procedure G afforded 2- (4 '-tert-butyl-biphenyl-4-ylmethyl) -4- (2, 4-dichloro-phenyl) -1H-imidazole as afforded 2- (4' -tert-butyl-biphenyl-4-ylmethyl) -4- (2, 4-dichloro-phenyl) -1- (4-iodo-phenyl) -1H-imidazole.

LCMS：m/z 637(M+H)⁺。

2- (4 ' -tert-butyl-biphenyl-4-ylmethyl) -4- (2, 4-dichloro-phenyl) -1- (4-iodo-phenyl) -1H-imidazole (191mg, 0.3mmol) was treated as described in general procedure R using D-2-aminobutyric acid (310mg, 3mmol) to give (R) -2- {4- [2- (4 ' -tert-butyl-biphenyl-4-ylmethyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenylamino } -butyric acid, which was then treated as described in general procedure F to give (4R) -5- {4- [2- (4 ' -tert-butyl-biphenyl-4-ylmethyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenyl } -4-ethyl-1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide.

LCMS：m/z 673(M+H)⁺；¹H NMR(DMSO-d₆，400MHz)：δ1.03(t，3H)，1.30(s，9H)，1.45(m，2H)，4.06(s，2H)，4.10(t，1H)，7.15(d，2H)，7.19(d，2H)，7.36(d，2H)，7.45(d，2H)，7.49(dd，1H)，7.52(d，2H)，7.54(d，2H)，7.64(d，1H)，7.88(s，1H)，8.19(d，1H)ppm。

Example 83

2- (4 ' -tert-butyl-biphenyl-4-ylmethyl) -4- (2, 4-dichloro-phenyl) -1- (4-iodo-phenyl) -1H-imidazole (191mg, 0.3mmol) was treated as described in general procedure R using L-2-aminobutyric acid (310mg, 3mmol) to give (S) -2- {4- [2- (4 ' -tert-butyl-biphenyl-4-ylmethyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenylamino } -butyric acid, which was then treated as described in general procedure F to give (4S) -5- {4- [2- (4 ' -tert-butyl-biphenyl-4-ylmethyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenyl } -4-ethyl-1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide.

LCMS：m/z 673(M+H)⁺；¹H NMR(DMSO-d₆，400MHz)：δ1.04(t，3H)，1.31(s，9H)，1.45(m，2H)，4.06(s，2H)，4.10(t，1H)，7.15(d，2H)，7.19(d，2H)，7.36(d，2H)，7.45(d，2H)，7.49(dd，1H)，7.52(d，2H)，7.54(d，2H)，7.64(d，1H)，7.89(s，1H)，8.20(d，1H)ppm。

Example 84

2- (4 ' -tert-butyl-biphenyl-4-ylmethyl) -4- (2, 4-dichloro-phenyl) -1- (4-iodo-phenyl) -1H-imidazole (191mg, 0.3mmol) was treated as described in general procedure R using L-norvaline (352mg, 3mmol) to give (S) -2- {4- [2- (4 ' -tert-butyl-biphenyl-4-ylmethyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenylamino } -pentanoic acid, which was then treated as described in general procedure F to give (4S) -5- {4- [2- (4 ' -tert-butyl-biphenyl-4-ylmethyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenyl } -4-propyl-1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide.

LCMS：m/z 687(M+H)⁺；¹H NMR(DMSO-d₆，400MHz)：δ0.99(t，3H)，1.31(s，9H)，1.39-1.46(m，4H)，4.06(s，2H)，4.10(t，1H)，7.15(d，2H)，7.19(d，2H)，7.36(d，2H)，7.45(d，2H)，7.49(dd，1H)，7.52(d，2H)，7.54(d，2H)，7.64(d，1H)，7.89(s，1H)，8.19(d，1H)ppm。

Example 85

4-iodophenylacetic acid (26.2g, 0.1mol) was treated with 2, 4-dichlorobromoacetophenone according to general procedure A to give 4- (2, 4-dichloro-phenyl) -2- (4-iodo-benzyl) -1H-imidazole.

LCMS：m/z 429(M+H)⁺。

4- (2, 4-dichloro-phenyl) -2- (4-iodo-benzyl) -1H-imidazole (12.9g, 30mmol) was worked up as described in general procedures R and C to give 5- {3- [4- (2, 4-dichloro-phenyl) -2- (4-iodo-benzyl) -imidazol-1-yl ] -phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide.

LCMS：m/z 639(M+H)⁺。

5- {3- [4- (2, 4-dichloro-phenyl) -2- (4-iodo-benzyl) -imidazol-1-yl ] -phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide (3.2G, 5mmol) was treated with 4-bromophenylboronic acid (2.0G, 10mmol) as described in general procedure G to give 5- {3- [2- (4' -bromo-biphenyl-4-ylmethyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide.

LCMS：m/z 669(M+H)⁺；¹H NMR(DMSO-d₆，400MHz)：δ4.05(s，2H)，4.07(s，2H)，7.15(d，2H)，7.19(d，2H)，7.36-7.49(m，5H)，7.52(d，2H)，7.54(d，2H)，7.64(d，1H)，7.89(s，1H)，8.19(d，1H)ppm。

Treatment of 5- {3- [2- (4 '-bromo-biphenyl-4-ylmethyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide (134mg, 0.2mmol) with an excess of (S) -3-phenyl-pyrrolidine (147mg, 1mmol) as described in general procedure R gave the desired compound 5- (3- {4- (2, 4-dichloro-phenyl) -2- { 4' - [ (3S) -3-phenyl-pyrrolidin-1-yl ] -biphenyl-4-ylmethyl } -imidazol-1-yl } -phenyl) -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide.

LCMS：m/z 734(M+H)⁺；¹H NMR(DMSO-d₆，400MHz)：δ1.87-2.35(m，2H)，3.00-3.60(m，5H)，4.07(s，2H)，4.10(s，2H)，6.94(d，2H)，7.19(d，2H)，7.27(m，1H)，7.32-7.46(m，9H)，7.55-7.76(m，5H)，7.89(s，1H)，8.18(d，1H)ppm。

The following compounds were synthesized by a method similar to that used for the preparation of example 85:

examples	Name (R)	LC/MS(m/z)
			86	5- (3- {4- (2, 4-dichloro-phenyl) -2- { 4' - [ (3R) -3-phenyl-pyrrolidin-1-yl]-biphenyl-4-ylmethyl } -imidazol-1-yl } -phenyl) -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxideArticle (A)	734(M+H)+
87	5- {3- [2- { 4' - [ (3S) -3-cyclohexyl-pyrrolidin-1-yl]-biphenyl-4-ylmethyl } -4- (2, 4-dichloro-phenyl) -imidazol-1-yl]-phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide	740(M+H)+
			88	5- {3- [2- { 4' - [ (3R) -3-cyclohexyl-pyrrolidin-1-yl]-biphenyl-4-ylmethyl } -4- (2, 4-dichloro-phenyl) -imidazol-1-yl]-phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide	740(M+H)+
89	5- {3- [2- { 3' - [ (3S) -3-cyclohexyl-pyrrolidin-1-yl]-biphenyl-4-ylmethyl } -4- (2, 4-dichloro-phenyl) -imidazol-1-yl]-phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide	740(M+H)+

Example 90

2- (4-bromo-phenyl) -4- (2, 4-dichloro-phenyl) -5- (4-nitro-phenyl) -1H-imidazole (prepared according to general procedure A) (979mg, 2mmol) was treated as described in general procedure G using 4-tert-butylphenyl boronic acid (712mg, 4mmol) to give 2- (4 '-tert-butyl-biphenyl-4-yl) -4- (2, 4-dichloro-phenyl) -5- (4-nitro-phenyl) -1H-imidazole, which was treated as described in general procedure L using 2- (trimethylsilyl) ethoxymethyl chloride (0.7mL, 4mmol) to give 2- (4' -tert-butyl-biphenyl-4-yl) -4- (2, 4-dichloro-phenyl) -5- (4-nitro-phenyl) -1- (2-trimethylsilyl-ethoxymethyl) -1H-imidazole.

LCMS：m/z 672(M+H)⁺。

Treatment [ using methyl bromoacetate (95 μ L, 1mmol) ]2- (4 '-tert-butyl-biphenyl-4-yl) -4- (2, 4-dichloro-phenyl) -5- (4-nitro-phenyl) -1- (2-trimethylsilyl-ethoxymethyl) -1H-imidazole (336mg, 0.5mmol) as described in general procedure C gave 5- {4- [2- (4' -tert-butyl-biphenyl-4-yl) -5- (2, 4-dichloro-phenyl) -3- (2-trimethylsilyl-ethoxymethyl) -3H-imidazol-4-yl ] -phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide and then treated according to general procedure W to give 5- {4- [2- (4' -tert-butyl-biphenyl-4-yl) -5- (2, 4-dichloro-phenyl) -3H-imidazol-4-yl ] -phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide.

LCMS：m/z 631(M+H)⁺；¹H NMR(DMSO-d₆，400MHz)：δ1.30(s，9H)，4.09(s，2H)，7.15(d，2H)，7.19(d，2H)，7.36(d，2H)，7.45(d，2H)，7.49(dd，1H)，7.52-7.64(m，4H)，7.90(s，1H)，8.20(d，1H)ppm。

Example 91

2- (4-bromo-benzyl) -4- (2, 4-dichloro-phenyl) -5- (4-nitro-phenyl) -1H-imidazole was treated as described in general procedure G using 4-tert-butylphenyl boronic acid (712mg, 4mmol) to give 2- (4 '-tert-butyl-biphenyl-4-ylmethyl) -4- (2, 4-dichloro-phenyl) -5- (4-nitro-phenyl) -1H-imidazole (preparation according to general procedure A) (1.0G, 2mmol), which was treated using 2- (trimethylsilyl) ethoxymethyl chloride (0.7mL, 4mmol) as described in general procedure L to give 2- (4' -tert-butyl-biphenyl-4-ylmethyl) -4- (2, 4-dichloro-phenyl) -5- (4-nitro-phenyl) -1- (2-trimethylsilyl-ethoxymethyl) -1H-imidazole.

LCMS：m/z 686(M+H)⁺。

Treatment [ using methyl bromoacetate (95 μ L, 1mmol) ]2- (4 '-tert-butyl-biphenyl-4-yl) -4- (2, 4-dichloro-phenyl) -5- (4-nitro-phenyl) -1- (2-trimethylsilyl-ethoxymethyl) -1H-imidazole (343mg, 0.5mmol) as described in general procedure C gave 5- {4- [2- (4' -tert-butyl-biphenyl-4-ylmethyl) -5- (2, 4-dichloro-phenyl) -3- (2-trimethylsilyl-ethoxymethyl) -3H-imidazol-4-yl ] -phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide and then treated according to general procedure W to give 5- {4- [2- (4' -tert-butyl-biphenyl-4-ylmethyl) -5- (2, 4-dichloro-phenyl) -3H-imidazol-4-yl ] -phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide.

LCMS：m/z 645(M+H)⁺；¹H NMR(DMSO-d₆，400MHz)：δ1.29(s，9H)，4.06(s，2H)，4.09(s，2H)，7.15(d，2H)，7.19(d，2H)，7.36(d，2H)，7.45(d，2H)，7.49(dd，1H)，7.52-7.64(m，4H)，7.89(s，1H)，8.19(d，1H)ppm。

Example 92

2- (4-bromo-benzyl) -4- (2, 4-dichloro-phenyl) -1H-imidazole (382mg, 1mmol) was treated with 4-nitrobenzyl bromide (432mg, 2mmol) as described in general procedure K to give 2- (4-bromo-benzyl) -4- (2, 4-dichloro-phenyl) -1- (4-nitro-benzyl) -1H-imidazole.

LCMS：m/z 518(M+H)⁺。

2- (4-bromo-benzyl) -4- (2, 4-dichloro-phenyl) -1- (4-nitro-benzyl) -1H-imidazole (310mg, 0.6mmol) was treated as described in general procedure C to give 5- {4- [2- (4-bromo-benzyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-ylmethyl ] -phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide.

LCMS：m/z 607(M+H)⁺。

Treatment of 5- {4- [2- (4-bromo-benzyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-ylmethyl ] -phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide (61mg, 0.1mmol) using 4-cyclohexylphenylboronic acid (41mg, 0.2mmol) as described in general procedure G gave 5- {4- [2- (4' -cyclohexyl-biphenyl-4-ylmethyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-ylmethyl ] -phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide.

LCMS：m/z 685(M+H)⁺；¹H NMR(DMSO-d₆，400MHz)：δ1.13-1.40(m，5H)，1.65-1.78(m，5H)，2.52(m，1H)，4.05(s，2H)，4.08(s，2H)，5.35(s，2H)，7.15(d，2H)，7.20(d，2H)，7.32(d，2H)，7.41(d，2H)，7.47(d，2H)，7.51-7.58(m，3H)，7.64(d，1H)，7.89(s，1H)，8.18(d，1H)ppm。

Example 93

Treatment of 4-nitro-benzoic acid (1.7g, 10mmol) as described in general procedure a afforded 4- (2, 4-dichloro-phenyl) -2- (4-nitro-phenyl) -1H-imidazole, which was treated with 4-bromobenzyl bromide (3.8g, 15mmol) as described in general procedure K to afford 1- (4-bromo-benzyl) -4- (2, 4-dichloro-phenyl) -2- (4-nitro-phenyl) -1H-imidazole.

LCMS：m/z 504(M+H)⁺。

1- (4-bromo-benzyl) -4- (2, 4-dichloro-phenyl) -2- (4-nitro-phenyl) -1H-imidazole (503mg, 1mmol) was treated as described in general procedure C to give 5- {4- [1- (4-bromo-benzyl) -4- (2, 4-dichloro-phenyl) -1H-imidazol-2-yl ] -phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide.

LCMS：m/z 593(M+H)⁺。

Treatment of 5- {4- [1- (4-bromo-benzyl) -4- (2, 4-dichloro-phenyl) -1H-imidazol-2-yl ] -phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide (59mg, 0.1mmol) using 4-cyclohexylphenylboronic acid (41mg, 0.2mmol) as described in general procedure G gave 5- {4- [1- (4' -cyclohexyl-biphenyl-4-ylmethyl) -4- (2, 4-dichloro-phenyl) -1H-imidazol-2-yl ] -phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide.

LCMS：m/z 671(M+H)⁺；¹H NMR(DMSO-d₆，400MHz)：δ1.13-1.40(m，5H)，1.65-1.78(m，5H)，2.52(m，1H)，4.08(s，2H)，5.35(s，2H)，7.15(d，2H)，7.20(d，2H)，7.32(d，2H)，7.41(d，2H)，7.47(d，2H)，7.51-7.58(m，3H)，7.64(d，1H)，7.89(s，1H)，8.18(d，1H)ppm。

Example 94

5- {3- [2- (4-bromo-benzyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide (59mg, 0.1mmol) was treated with 3-hydroxyphenylboronic acid (28mg, 0.2mmol) as described in general procedure G to give 5- {4- [4- (2, 4-dichloro-phenyl) -2- (3' -hydroxy-biphenyl-4-ylmethyl) -imidazol-1-yl ] -phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide.

LCMS：m/z 605(M+H)⁺；¹H NMR(DMSO-d₆，400MHz)：δ4.05(s，2H)，4.08(s，2H)，6.93-7.22(m，5H)，7.32(d，2H)，7.38(d，2H)，7.46(d，2H)，7.51(d，2H)，7.64(d，1H)，7.90(s，1H)，8.20(d，1H)ppm。

Example 95

Treatment of 5- {4- [2- (4-bromo-benzyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide (592mg, 1mmol) using 2- (trimethylsilyl) ethoxymethyl chloride (354 μ L, 2mmol) as described in general procedure L gave 5- {4- [2- (4-bromo-benzyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenyl } -1, 1-dioxo-2- (2-trimethylsilyl-ethoxymethyl) - [1, 2, 5] thiadiazolidin-3-one, which is then treated according to the general procedure AD to give 5- (4- {4- (2, 4-dichloro-phenyl) -2- [4- (4, 4, 5, 5-tetramethyl- [1, 3, 2] dioxaborolan-2-yl) -benzyl ] -imidazol-1-yl } -phenyl) -1, 1-dioxo-2- (2-trimethylsilyl-ethoxymethyl) - [1, 2, 5] thiadiazolidin-3-one.

LCMS：m/z 769(M+H)⁺。

Treatment of 5- (4- {4- (2, 4-dichloro-phenyl) -2- [4- (4, 4, 5, 5-tetramethyl- [1, 3, 2] dioxaborolan-2-yl) -benzyl ] -imidazol-1-yl } -phenyl) -1, 1-dioxo-2- (2-trimethylsilyl-ethoxymethyl) - [1, 2, 5] thiadiazolidin-3-one (154mg, 0.2mmol) with 2, 5-dibromopyridine (95mg, 0.4mmol) as described in general procedure G gave 5- {4- [2- [4- (5-bromo-pyridin-2-yl) -benzyl ] -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenyl } -1, 1-dioxo-2- (2-trimethylsilyl-ethoxymethyl) - [1, 2, 5] thiadiazolidin-3-one, which was treated with cyclohexen-1-ylboronic acid (51mg, 0.4mmol) as described in general procedure G to give 5- {4- [2- [4- (5-cyclohex-1-enyl-pyridin-2-yl) -benzyl ] -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenyl } -1, 1-dioxo-2- (2-trimethylsilyl-ethoxymethyl) - [1, 2, 5] thiadiazolidin-3-one.

LCMS：m/z 800(M+H)⁺。

Reacting 5- {4- [2- [4- (5-cyclohex-1-enyl-pyridin-2-yl) -benzyl]-4- (2, 4-dichloro-phenyl) -imidazol-1-yl]-phenyl } -1, 1-dioxo-2- (2-trimethylsilyl-ethoxymethyl) - [1, 2, 5]Thiadiazolidin-3-one (40mg, 0.05mmol) was dissolved in 1mL of dry acetic acid, and iron powder (-325 mesh, 56mg, 1mmol) was added which was then heated at 100 ℃ for 2 days under a nitrogen atmosphere. Upon completion, the reaction mixture was then diluted with water/EtOAc and the remaining iron powder was filtered and washed with EtOAc. With water, saturated NaHCO₃And brine wash the combined organic layers. Then using Na₂SO₄The organic layer was dried, filtered and the filtrate was concentrated and purified by silica gel chromatography to give 5- {4- [2- [4- (5-cyclohexyl-pyridin-2-yl) -benzyl ] -benzyl]-4- (2, 4-dichloro-phenyl) -imidazol-1-yl]-phenyl } -1, 1-dioxo-2- (2-trimethylsilyl-ethoxymethyl) - [1, 2, 5]Thiadiazolidin-3-one.

LCMS：m/z 802(M+H)⁺。

Treatment of 5- {4- [2- [4- (5-cyclohexyl-pyridin-2-yl) -benzyl ] -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenyl } -1, 1-dioxo-2- (2-trimethylsilyl-ethoxymethyl) - [1, 2, 5] thiadiazolidin-3-one (16mg, 0.02mmol) with tetrabutylammonium fluoride (26mg, 0.1mmol) as described in general procedure W gave 5- {4- [2- [4- (5-cyclohexyl-pyridin-2-yl) -benzyl ] -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide.

LCMS：m/z 672(M+H)⁺；¹H NMR(CD₃OD，400MHz)：δ1.22-1.43(m，5H)，1.69-1.81(m，5H)，2.52(m，1H)，4.08(s，2H)，4.10(s，2H)，7.15-7.27(m，5H)，7.37(d，2H)，7.46-7.54(m，5H)，7.64(d，1H)，7.89(s，1H)，8.19(d，1H)ppm。

Example 96

5- {3- [2- (4-bromo-benzyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide (1.19g, 2mmol) was treated as described in general procedure L using 2- (trimethylsilyl) ethoxymethyl chloride (708 μ L, 4mmol) to give 5- {3- [2- (4-bromo-benzyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenyl } -1, 1-dioxo-2- (2-trimethylsilyl-ethoxymethyl) - [1, 2, 5] thiadiazolidin-3-one, which is then treated according to the general procedure AD to give 5- (3- {4- (2, 4-dichloro-phenyl) -2- [4- (4, 4, 5, 5-tetramethyl- [1, 3, 2] dioxaborolan-2-yl) -benzyl ] -imidazol-1-yl } -phenyl) -1, 1-dioxo-2- (2-trimethylsilyl-ethoxymethyl) - [1, 2, 5] thiadiazolidin-3-one.

LCMS：m/z 769(M+H)⁺。

Treatment of 5- (3- {4- (2, 4-dichloro-phenyl) -2- [4- (4, 4, 5, 5-tetramethyl- [1, 3, 2] dioxaborolan-2-yl) -benzyl ] -imidazol-1-yl } -phenyl) -1, 1-dioxo-2- (2-trimethylsilyl-ethoxymethyl) - [1, 2, 5] thiadiazolidin-3-one (385mg, 0.5mmol) with 3, 6-dichloropyridazine (149mg, 1mmol) as described in general procedure G gave 5- {3- [2- [4- (6-chloro-pyridazin-3-yl) -benzyl ] -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenyl } -1, 1-dioxo-2- (2-trimethylsilyl-ethoxymethyl) - [1, 2, 5] thiadiazolidin-3-one.

LCMS：m/z 756(M+H)⁺。

Treatment of 5- {3- [2- [4- (6-chloro-pyridazin-3-yl) -benzyl ] -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenyl } -1, 1-dioxo-2- (2-trimethylsilyl-ethoxymethyl) - [1, 2, 5] thiadiazolidin-3-one (38mg, 0.05mmol) using 2-cyclohexylethanol (35 μ L, 0.25mmol) as described in general procedure L gave 5- {3- [2- {4- [6- (2-cyclohexyl-ethoxy) -pyridazin-3-yl ] -benzyl } -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenyl } -1, 1-dioxo-2- (2-trimethylsilyl-ethoxymethyl) - [1, 2, 5] thiadiazolidin-3-one.

LCMS：m/z 847(M+H)⁺。

5- {3- [2- {4- [6- (2-cyclohexyl-ethoxy) -pyridazin-3-yl ] -benzyl } -1, 1-dioxo-2- (2-trimethylsilyl-ethoxymethyl) - [1, 2, 5] thiadiazolidin-3-one (17mg, 0.02mmol) was treated with tetrabutylammonium fluoride (26mg, 0.1mmol) as described in general procedure W to give 5- {3- [2- {4- [6- (2-cyclohexyl-ethoxy) -pyridazin-3-yl ] -benzyl } -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide.

LCMS：m/z 717(M+H)⁺；¹H NMR(CD₃OD，400MHz)：δ0.97-1.43(m，5H)，1.65(m，2H)，1.69-1.81(m，6H)，4.05(t，2H)，4.08(s，2H)，4.10(s，2H)，7.15-7.27(m，5H)，7.37(d，2H)，7.46-7.54(m，4H)，7.64(d，1H)，7.89(s，1H)，8.19(d，1H)ppm。

Example 97

Reacting 5- {3- [2- [4- (6-chloro-pyridazin-3-yl) -benzyl]-4- (2, 4-dichloro-phenyl) -imidazol-1-yl]-phenyl } -1, 1-dioxo-2- (2-trimethylsilyl-ethoxymethyl) - [1, 2, 5]Thiadiazolidin-3-one (76mg, 0.1mmol) was dissolved in 1mL dry ethanol. Thiourea (76mg, 1mmol) was added and the mixture was refluxed under nitrogen overnight. Upon completion, the reaction mixture was subsequently diluted with water/EtOAc. The combined organic layers were washed with water and brine, and Na₂SO₄Drying, filtering and concentrating the filtrate to give 5- (3- {4- (2, 4-dichloro-phenyl) -2- [4- (6-mercapto-pyridazin-3-yl) -benzyl]-imidazol-1-yl } -phenyl) -1, 1-dioxo-2- (2-trimethylsilyl-ethoxymethyl) - [1, 2, 5]Thiadiazolidin-3-one, which is then treated with 1-bromo-2-cyclohexylethane (79 μ L, 0.5mmol) as described in general procedure K to give 5- {3- [2- {4- [6- (2-cyclohexyl-ethylsulfanyl) -pyridazin-3-yl]-benzyl-4- (2, 4-dichloro-phenyl) -imidazol-1-yl]-phenyl } -1, 1-dioxo-2- (2-trimethylsilyl-ethoxymethyl) - [1, 2, 5]Thiadiazolidin-3-one.

LCMS：m/z 863(M+H)⁺。

5- {3- [2- {4- [6- (2-cyclohexyl-ethylsulfanyl) -pyridazin-3-yl ] -benzyl } -1, 1-dioxo-2- (2-trimethylsilyl-ethoxymethyl) - [1, 2, 5] thiadiazolidin-3-one (17mg, 0.02mmol) was treated with tetrabutylammonium fluoride (26mg, 0.1mmol) as described in general procedure W to give 5- {3- [2- {4- [6- (2-cyclohexyl-ethylsulfanyl) -pyridazin-3-yl ] -benzyl } -4- (2, 4-diamino-phenyl) -imidazol-1-yl ] -phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide.

LCMS：m/z 733(M+H)⁺；¹H NMR(CD₃OD，400MHz)：δ0.97-1.41(m，5H)，1.48(m，2H)，1.69-1.81(m，6H)，3.03(t，2H)，4.08(s，2H)，4.10(s，2H)，7.15-7.27(m，5H)，7.37(d，2H)，7.46-7.54(m，4H)，7.64(d，1H)，7.89(s，1H)，8.19(d，1H)ppm。

Example 98

Treatment of 4-bromophenylacetic acid (10.7g, 50mmol) with 2, 4-dichlorobromoacetophenone was performed according to general procedure a to give 2- (4-bromo-benzyl) -4- (2, 4-dichloro-phenyl) -1H-imidazole. Reaction of 2- (4-bromo-benzyl) -4- (2, 4-dichloro-phenyl) -1H-imidazole (3.8g, 10mmol) with 4-nitrobenzyl bromide (2.5g, 12mmol) as described in general procedure B gave 2- (4-bromobenzyl) -4- (2, 4-dichloro-phenyl) -1- (4-nitro-benzyl) -1H-imidazole.

Reduction of 2- (4-bromo-benzyl) -4- (2, 4-dichloro-phenyl) -1- (4-nitro-benzyl) -1H-imidazole (2.6g, 5mmol) to an amine and reaction with methyl bromoacetate as in general procedure D & E afforded {4- [2- (4-bromo-benzyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-ylmethyl ] -phenylamino } -acetic acid methyl ester.

{4- [2- (4-bromo-benzyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-ylmethyl ] -phenylamino } -acetic acid methyl ester (1.4G, 2.5mmol) was coupled with 4-sec-butylphenyl-boronic acid (600mg, 3.3mmol) according to general procedure G to give {4- [2- (4' -sec-butyl-biphenyl-4-ylmethyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-ylmethyl ] -phenylamino } -acetic acid methyl ester.

From {4- [2- (4' -sec-butyl-biphenyl-4-ylmethyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-ylmethyl]-phenylamino } -acetic acid methyl ester (275mg, 0.4mmol) 5- {4- [2- (4' -sec-butyl-biphenyl-4-ylmethyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-ylmethyl was prepared according to general procedure F]-phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide. LCMS: m/z 659(M + H)⁺。

Example 99

Treatment of 4-bromophenylacetic acid (107.5g, 0.5mol) with 2, 4-dichlorobromoacetophenone was performed according to general procedure a to give 2- (4-bromo-benzyl) -4- (2, 4-dichloro-phenyl) -1H-imidazole. 2- (4-bromo-benzyl) -4- (2, 4-dichloro-phenyl) -1H-imidazole (38.2g, 0.1mol) was treated with 1-fluoro-4-nitrobenzene as described in general procedure B to give 2- (4-bromo-benzyl) -1- (4-nitro-phenyl) -4- (2, 4-dichloro-phenyl) -1H-imidazole.

Reduction of 4- (2, 4-dichloro-phenyl) -1- (4-nitro-phenyl) -2- (4-bromo-benzyl) -1H-imidazole (5.0g, 10mmol) to an amine and reaction with methyl bromoacetate following general procedure D & E gave {4- [2- (4-bromo-benzyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenylamino } -acetic acid methyl ester.

{4- [2- (4-bromo-benzyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenylamino } -acetic acid methyl ester (1.8G, 3.3mmol) was coupled with 4-sec-butyl-phenylboronic acid (750mg, 4.0mmol) according to general procedure G to give {4- [2- (4' -sec-butyl-biphenyl-4-ylmethyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenylamino } -acetic acid methyl ester.

{4- [2- (4 '-sec-butyl-biphenyl-4-ylmethyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenylamino } -acetic acid methyl ester (300mg, 0.5mmol) was treated according to general procedure F to give 5- {4- [2- (4' -sec-butyl-biphenyl-4-ylmethyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide.

LCMS：m/z 645(M+H)⁺；¹H NMR(DMSO-d₆，400MHz)：0.89(t，3H)，1.18-1.20(m，2H)，1.22(m，1H)，3.99(t，2H)，4.04(s，2H)，4.07(s，2H)，7.14(d，2H)，7.16(d，2H)，7.24(d，2H)，7.35(d，2H)，7.46(dd，1H)，7.51(d，2H)，7.53(d，2H)，7.63(d，1H)，7.79(s，1H)，7.89(d，1H)，8.20(d，1H)ppm。

Example 100

Methyl {4- [2- (4-bromo-benzyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenylamino } -acetic acid (1.5G, 2.7mmol) and 4-cyclohexylphenyl-boronic acid (700mg, 3.4mmol) were coupled according to general procedure G to give methyl {4- [2- (4' -cyclohexyl-biphenyl-4-ylmethyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenylamino } -acetic acid.

{4- [2- (4 '-cyclohexyl-biphenyl-4-ylmethyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenylamino } -acetic acid methyl ester (312mg, 0.5mmol) was treated according to general procedure F to give 5- {4- [2- (4' -cyclohexyl-biphenyl-4-ylmethyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide.

LCMS：m/z 671(M+H)⁺；¹H NMR(DMSO-d₆，400MHz)：δ1.35-43(m，5H)，1.78-1.84(m，5H)，4.04(s，2H)，4.07(d，2H)，7.14(d，2H)，7.18(d，2H)，7.28(d，2H)，7.37(d，2H)，7.46(d，2H)，7.48(d，2H)，7.50-7.53(m，2H)，7.63(d，1H)，7.89(s，1H)，8.19(d，1H)ppm。

The following compounds were synthesized by a method similar to that used to prepare example 100:

examples	Name (R)	LC/MS(m/z)
			101	5- {4- [4- (2, 4-dichloro-phenyl) -2- (4' -isobutyl-biphenyl-4-ylmethyl) -imidazol-1-yl]-phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide	645(M+H)+
102	5- {4- [4- (2, 4-dichloro-phenyl) -2- (4' -morpholin-4-yl-biphenyl-4-ylmethyl) -imidazol-1-yl]-phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide	674(M+H)+
			103	5- {4- [2- (4' -butyl-biphenyl-4-ylmethyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl]-phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide	645(M+H)+
104	5- {4- [4- (2, 4-dichloro-phenyl) -2- (4' -piperidin-1-yl-biphenyl-4-ylmethyl) -imidazol-1-yl]-phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide	672(M+H)+
			105	5- {4- [4- (2, 4-dichloro-phenyl) -2- (4' -isopropyl-biphenyl-4-ylmethyl) -imidazol-1-yl]-phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide	631(M+H)+
106	5- {4- [2- (3 '-nitro-4' -isobutyl-biphenyl-4-ylmethyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl]-phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide	690(M+H)+

Example 107

Reduction of 5- {4- [2- (3 '-nitro-4' -iso-butyl-biphenyl-4-ylmethyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenyl } - [1, 2, 5] thiadiazolidin-3-one 1, 1-dioxide (70mg, 0.10mmol) to 5- {4- [2- (3 '-amino-4' -isobutyl-biphenyl-4-ylmethyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenyl } -1, 2, 5-thiadiazolidin-3-one-1 according to general procedure D, 1-dioxide.

LCMS：m/z 660(M+H)⁺。

Example 108

5- {4- [2- (3 '-amino-4' -isobutyl-biphenyl-4-ylmethyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenyl } - [1, 2, 5] thiadiazolidin-3-one 1, 1-dioxide (22mg, 0.03mmol) was reacted with acetaldehyde (1.7mg, 0.03mmol) according to general procedure X to give 5- {4- [4- (2, 4-dichloro-phenyl) -2- (3 '-diethylamino-4' -isobutyl-biphenyl-4-ylmethyl) -imidazol-1-yl ] -phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide.

LCMS：m/z 716(M+H)⁺。

Example 109

Treatment of 4-bromophenylacetic acid (10.7g, 50mmol) with 4- (2-bromo-acetyl) -benzoic acid methyl ester following general procedure A gave 4- [2- (4-bromo-benzyl) -1H-imidazol-4-yl ] -benzoic acid methyl ester.

Treatment of 4- [2- (4-bromo-benzyl) -1H-imidazol-4-yl ] -benzoic acid methyl ester (12.3g, 33mmol) using 1-fluoro-4-nitrobenzene as described in general procedure B gave 4- [2- (4-bromo-benzyl) -1- (4-nitro-phenyl) -1H-imidazol-4-yl ] -benzoic acid methyl ester.

Methyl 4- [2- (4-bromo-benzyl) -1- (4-nitro-phenyl) -1H-imidazol-4-yl ] -benzoate (9.8g, 20mmol) was reduced to an amine and reacted with methyl bromoacetate according to general procedure D & E to give methyl 4- {2- (4-bromo-benzyl) -1- [4- (methoxy-carbonylmethyl-amino) -phenyl ] -1H-imidazol-4-yl } -benzoate.

Coupling of 4- {2- (4-bromo-benzyl) -1- [4- (methoxycarbonylmethyl-amino) -phenyl ] -1H-imidazol-4-yl } -benzoic acid methyl ester (2.7G, 5mmol) with 4-cyclohexyl-phenylboronic acid (1.25G, 6.0mmol) according to general procedure G gave 4- {2- (4' -cyclohexyl-biphenyl-4-ylmethyl) -1- [4- (methoxycarbonylmethyl-amino) -phenyl ] -1H-imidazol-4-yl } -benzoic acid methyl ester.

Methyl 4- {2- (4 '-cyclohexyl-biphenyl-4-ylmethyl) -1- [4- (methoxycarbonylmethyl-amino) -phenyl ] -1H-imidazol-4-yl } -benzoate (1.0g, 1.6mmol) was treated according to general procedure F to give methyl 4- {2- (4' -cyclohexyl-biphenyl-4-ylmethyl) -1- [4- (1, 1, 4-trioxo-1- [1, 2, 5] thiadiazolidin-2-yl) -phenyl ] -1H-imidazol-4-yl } -benzoate.

LCMS：m/z 660(M+H)⁺；¹H NMR(DMSO-d₆，400MHz)：δ1.19-1.38(m，5H)，1.66-1.89(m，5H)，2.39(m，1H)，3.59(s，3H)，4.04(s，2H)，4.09(s，2H)，7.17(d，2H)，7.19(d，2H)，7.28(d，2H)，7.36-7.42(m，4H)，7.44-7.57(m，4H)，7.66(d，1H)，7.87(s，1H)，8.18(d，1H)ppm。

Example 110

4- {2- (4 '-cyclohexyl-biphenyl-4-ylmethyl) -1- [4- (1, 1, 4-trioxo-1- [1, 2, 5] thiadiazolidin-2-yl) -phenyl ] -1H-imidazol-4-yl } -benzoic acid methyl ester (220mg, 0.33mmol) was hydrolyzed according to the general procedure P to give 4- {2- (4' -cyclohexyl-biphenyl-4-ylmethyl) -1- [4- (1, 1, 4-trioxo-1- [1, 2, 5] thiadiazolidin-2-yl) -phenyl ] -1H-imidazol-4-yl } -benzoic acid.

LCMS：m/z 646(M+H)⁺；¹H NMR(DMSO-d₆，400MHz)：δ1.22-1.43(m，5H)，1.69-1.81(m，5H)，2.52(m，1H)，4.05(s，2H)，4.07(s，2H)，7.15(d，2H)，7.18(d，2H)，7.26(d，2H)，7.34-7.42(m，4H)，7.46-7.54(m，5H)，7.64(d，1H)，7.89(s，1H)，8.19(d，1H)ppm。

Example 111

{4- [2- (4-bromo-benzyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenylamino } -acetic acid methyl ester (1.8G, 3.3mmol) and 4-propionyl-phenylboronic acid (712mg, 4.0mmol) were coupled according to general procedure G to give {4- [4- (2, 4-dichloro-phenyl) -2- (4' -propionyl-biphenyl-4-ylmethyl) -imidazol-1-yl ] -phenylamino } -acetic acid methyl ester.

Treatment of {4- [4- (2, 4-dichloro-phenyl) -2- (4 '-propionyl-biphenyl-4-ylmethyl) -imidazol-1-yl ] -phenylamino } -acetic acid methyl ester (299mg, 0.5mmol) according to general procedure F afforded 5- {4- [4- (2, 4-dichloro-phenyl) -2- (4' -propionyl-biphenyl-4-ylmethyl) -imidazol-1-yl ] -phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide.

LCMS：m/z 645(M+H)⁺。

Example 112

{4- [2- (4-bromo-benzyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenylamino } -acetic acid methyl ester (1.8G, 3.3mmol) was coupled with 4-n-pentylphenylboronic acid (769mg, 4.0mmol) according to general procedure G to give {4- [4- (2, 4-dichloro-phenyl) -2- (4' -pentyl-biphenyl-4-ylmethyl) -imidazol-1-yl ] -phenylamino } -acetic acid methyl ester.

{4- [4- (2, 4-dichloro-phenyl) -2- (4 '-pentyl-biphenyl-4-ylmethyl) -imidazol-1-yl ] -phenylamino } -acetic acid methyl ester (310mg, 0.5mmol) was treated according to general procedure F to give 5- {4- [4- (2, 4-dichloro-phenyl) -2- (4' -pentyl-biphenyl-4-ylmethyl) -imidazol-1-yl ] -phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide.

LCMS：m/z 659(M+H)⁺；¹H NMR(DMSO-d₆，400MHz)：δ0.98(t，3H)，1.29(m，2H)，1.41(m，2H)，1.83(m，2H)，4.02(t，2H)，4.05(s，2H)，4.08(s，2H)，7.05-7.12(m，4H)，7.29(d，2H)，7.38(d，2H)，7.46-7.54(m，5H)，7.64(d，1H)，7.89(s，1H)，8.19(d，1H)ppm。

Example 113

Treatment of 4-bromophenylacetic acid (10.7g, 50mmol) with 4-trifluoromethylbromoacetophenone as in general procedure A gave 2- (4-bromo-benzyl) -4- (4-trifluoromethyl-phenyl) -1H-imidazole.

2- (4-bromo-benzyl) -4- (4-trifluoromethyl-phenyl) -1H-imidazole (9.6g, 25mmol) was treated with 1-fluoro-4-nitrobenzene as described in general procedure B to give 2- (4-bromo-benzyl) -1- (4-nitro-phenyl) -4- (4-trifluoromethyl-phenyl) -1H-imidazole.

2- (4-bromo-benzyl) -1- (4-nitro-phenyl) -4- (4-trifluoromethyl-phenyl) -1H-imidazole (2.5g, 5mmol) was reduced to an amine and reacted with methyl bromoacetate according to general procedure D & E to give {4- [2- (4-bromo-benzyl) -4- (4-trifluoromethyl-phenyl) -imidazol-1-yl ] -phenylamino } -acetic acid methyl ester.

{4- [2- (4-bromo-benzyl) -4- (4-trifluoromethyl-phenyl) -imidazol-1-yl ] -phenylamino } -acetic acid methyl ester (1.3G, 2.4mmol) was coupled with 4-cyclohexyl-phenylboronic acid (615mg, 3.0mmol) according to general procedure G to give {4- [2- (4' -cyclohexyl-biphenyl-4-ylmethyl) -4- (4-trifluoromethyl-phenyl) -imidazol-1-yl ] phenylamino } -acetic acid methyl ester.

{4- [2- (4 '-cyclohexyl-biphenyl-4-ylmethyl) -4- (4-trifluoromethyl-phenyl) -imidazol-1-yl ] phenylamino } -acetic acid methyl ester (312mg, 0.5mmol) was treated according to general procedure F to give 5- {4- [2- (4' -cyclohexyl-biphenyl-4-ylmethyl) -4- (4-trifluoromethyl-phenyl) -imidazol-1-yl ] -phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide.

LCMS：m/z 670(M+H)⁺。

Example 114

{4- [2- (4-bromo-benzyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenylamino } -acetic acid methyl ester (1.8G, 3.3mmol) was coupled with 4-n-propyl-phenylboronic acid (659mg, 4.0mmol) according to general procedure G to give {4- [4- (2, 4-dichloro-phenyl) -2- (4' -propyl-biphenyl-4-ylmethyl) -imidazol-1-yl ] -phenylamino } -acetic acid methyl ester.

{4- [4- (2, 4-dichloro-phenyl) -2- (4 '-propyl-biphenyl-4-ylmethyl) -imidazol-1-yl ] -phenylamino } -acetic acid methyl ester (295mg, 0.5mmol) was treated according to general procedure F to give 5- {4- [4- (2, 4-dichloro-phenyl) -2- (4' -propyl-biphenyl-4-ylmethyl) -imidazol-1-yl ] -phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide.

LCMS：m/z 631(M+H)⁺；¹H NMR(DMSO-d₆，400MHz)：δ0.99(t，3H)，1.41(m，2H)，4.02(t，2H)，4.04(s，2H)，4.07(s，2H)，7.02-7.15(m，4H)，7.27(d，2H)，7.39(d，2H)，7.42-7.54(m，5H)，7.66(d，1H)，7.87(s，1H)，8.19(d，1H)ppm。

Example 115

Treatment of 4-bromophenylacetic acid (10.7g, 50mmol) with 2-bromo-1- (4-methylsulfonyl-phenyl) -1-ethanone following general procedure a afforded 2- (4-bromo-benzyl) -4- (4-methanesulfonyl-phenyl) -1H-imidazole.

2- (4-bromo-benzyl) -4- (4-methanesulfonyl-phenyl) -1H-imidazole (9.8g, 25mmol) was treated with 1-fluoro-4-nitrobenzene as described in general procedure B to give 2- (4-bromo-benzyl) -1- (4-nitro-phenyl) -4- (4-methanesulfonyl-phenyl) -1H-imidazole.

2- (4-bromo-benzyl) -1- (4-nitro-phenyl) -4- (4-methanesulfonyl-phenyl) -1H-imidazole (2.6g, 5mmol) was reduced to an amine and reacted with methyl bromoacetate according to general procedure D & E to give {4- [2- (4-bromo-benzyl) -4- (4-methanesulfonyl-phenyl) -imidazol-1-yl ] -phenylamino } -acetic acid methyl ester.

{4- [2- (4-bromo-benzyl) -4- (4-methanesulfonyl-phenyl) -imidazol-1-yl ] -phenyl-amino } -acetic acid methyl ester (1.4G, 2.5mmol) was coupled with 4-cyclohexyl-phenylboronic acid (615mg, 3.0mmol) according to general procedure G to give {4- [2- (4' -cyclohexyl-biphenyl-4-ylmethyl) -4- (4-methanesulfonyl-phenyl) -imidazol-1-yl ] -phenylamino } -acetic acid methyl ester.

{4- [2- (4 '-cyclohexyl-biphenyl-4-ylmethyl) -4- (4-methanesulfonyl-phenyl) -imidazol-1-yl ] -phenylamino } -acetic acid methyl ester (317mg, 0.5mmol) was treated according to general procedure F to give 5- {4- [2- (4' -cyclohexyl-biphenyl-4-ylmethyl) -4- (4-methanesulfonyl-phenyl) -imidazol-1-yl ] -phenyl ] -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide.

LCMS：m/z 680(M+H)⁺；¹H NMR(DMSO-d₆，400MHz)：δ1.17-1.42(m，5H)，1.68-1.80(m，5H)，2.39(m，1H)，3.21(s，3H)，4.10(s，2H)，4.49(s，2H)，7.11(d，2H)，7.13(d，2H)，7.26(d，2H)，7.46(d，2H)，7.48-7.7.52(m，5H)，7.74(d，2H)，7.89(s，1H)，8.09(d，1H)ppm。

Example 116

5- {4- [4- (2, 4-dichloro-phenyl) -2- (4 '-propionyl-biphenyl-4-ylmethyl) -imidazol-1-yl ] -phenyl } - [1, 2, 5] thiadiazolidin-3-one 1, 1-dioxide (66mg, 0.1mmol) was reacted with ethylmagnesium bromide (40mg, 0.3mmol) according to general procedure Z and the resulting tertiary alcohol was reduced according to general procedure AA to give 5- (4- {4- (2, 4-dichloro-phenyl) -2- [ 4' - (1-ethyl-propyl) -biphenyl-4-ylmethyl ] -imidazol-1-yl } -phenyl) -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide.

LCMS：m/z 687(M+H)⁺；¹H NMR(DMSO-d₆，400MHz)：δ0.98-1.11(m，3H)，1.13-1.21(m，3H)，1.28(t，1H)，3.87(m，2H)，3.99(m，2H)，4.04(s，2H)，4.09(s，2H)，7.11-7.21(m，4H)，7.27(d，2H)，7.35(d，2H)，7.38(d，2H)，7.46-7.54(m，3H)，7.63(d，1H)，7.89(s，1H)，8.18(d，1H)ppm。

Example 117

5- {4- [2- (3 ' -amino-4 ' -isobutyl-biphenyl-4-ylmethyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenyl } - [1, 2, 5] thiadiazolidin-3-one 1, 1-dioxide (22mg, 0.03mmol) was reacted with isopropyl chloride (5mg, 0.04mmol) according to general procedure U to give (4 ' - {4- (2, 4-dichloro-phenyl) -1- [4- (1, 1, 4-trioxo-1- [1, 2, 5] thiadiazolidin-2-yl) -phenyl ] -1H-imidazol-2-ylmethyl } -4-isobutyl-biphenyl-3-yl) -amino Isopropyl methyl ester.

LCMS：m/z 746(M+H)⁺。

Example 118

5- {4- [2- (3 '-amino-4' -isobutyl-biphenyl-4-ylmethyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenyl } - [1, 2, 5] thiadiazolidin-3-one 1, 1-dioxide (22mg, 0.03mmol) was reacted with butyraldehyde (2.2mg, 0.03mmol) according to general procedure X to give 5- {4- [2- (3 '-butylamino-4' -isobutyl-biphenyl-4-ylmethyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide.

LCMS：m/z 716(M+H)⁺。

Example 119

2- (4-bromo-benzyl) -4- (2, 4-dichloro-phenyl) -1H-imidazole (3.9g, 10mmol) was treated with 1-iodo-3-nitrobenzene as described in general procedure B to give 2- (4-bromo-benzyl) -1- (3-nitro-phenyl) -4- (2, 4-dichloro-phenyl) -1H-imidazole.

Reduction of 2- (4-bromo-benzyl) -4- (2, 4-dichloro-phenyl) -1- (3-nitrophenyl-phenyl) -1H-imidazole (1.3g, 2.5mmol) to an amine and reaction with methyl bromoacetate general procedure D & E gave {3- [2- (4-bromo-benzyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenylamino } -acetic acid methyl ester.

{3- [2- (4-bromo-benzyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenylamino } -acetic acid methyl ester (55mg, 0.1mmol) and 4-n-butyl-phenylboronic acid (36mg, 0.2mmol) were coupled according to general procedure G to give {3- [2- (4' -butyl-biphenyl-4-ylmethyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenylamino } -acetic acid methyl ester.

{3- [2- (4 '-butyl-biphenyl-4-ylmethyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenylamino } -acetic acid methyl ester (30mg, 0.05mmol) was treated according to general procedure F to give 5- {3- [2- (4' -butyl-biphenyl-4-ylmethyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide.

LCMS：m/z 645(M+H)⁺；¹H NMR(DMSO-d₆，400MHz)：δ0.98(t，3H)，1.19(m，2H)，1.34(m，2H)，2.67(t，2H)，4.04(s，2H)，4.09(s，2H)，7.11-7.18(m，4H)，7.26(d，2H)，7.37(d，2H)，7.45-7.53(m，5H)，7.61(d，1H)，7.88(s，1H)，8.19(d，1H)ppm。

Example 120

Coupling of 3- [2- (4-bromo-benzyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenylamino } -acetic acid methyl ester (55mg, 0.1mmol) and 4-iso-butyl-phenylboronic acid (36mg, 0.2mmol) according to general procedure G gave {3- [2- (4' -isobutyl-biphenyl-4-ylmethyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenylamino } -acetic acid methyl ester.

{3- [2- (4 '-iso-butyl-biphenyl-4-ylmethyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenylamino } -acetic acid methyl ester (20mg, 0.033mmol) was treated according to general procedure F to give 5- {3- [4- (2, 4-dichloro-phenyl) -2- (4' -isobutyl-biphenyl-4-ylmethyl) -imidazol-1-yl ] -phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide.

LCMS：m/z 645(M+H)⁺；¹H NMR(DMSO-d₆，400MHz)：1.11-1.23(m，6H)，2.95(t，1H)，3.29(m，2H)，4.04(s，2H)，4.09(s，2H)，7.09-7.17(m，3H)，7.27(d，2H)，7.36(d，2H)，7.47(d，2H)，7.42-7.54(m，4H)，7.65(d，1H)，7.87(s，1H)，8.19(d，1H)ppm。

The following compounds were synthesized by a method similar to that used for the preparation of example 120:

examples	Name (R)	LC/MS(m/z)
			121	5- {3- [4- (2, 4-dichloro-phenyl) -2- (4' -piperidin-1-yl-biphenyl-4-ylmethyl) -imidazol-1-yl]-phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide	672(M+H)+
122	5- {3- [2- (3 '-nitro-4' -isobutyl-biphenyl-4-ylmethyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl]-phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide	690(M+H)+

Example 123

5- {3- [2- (3 '-amino-4' -isobutyl-biphenyl-4-ylmethyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide was prepared from the compound of example 122 according to general procedure D.

LCMS：m/z 660(M+H)⁺。

Example 124

Prepared from the compound of example 123 according to general procedure U was (4' - {4- (2, 4-dichloro-phenyl) -1- [3- (1, 1, 4-trioxo-1- [1, 2, 5] thiadiazolidin-2-yl) -phenyl ] -1H-imidazol-2-ylmethyl } -4-isobutyl-biphenyl-3-yl) -carbamic acid methyl ester.

The following compounds were synthesized by a method similar to that used for the preparation of example 120:

examples	Name (R)	LC/MS(m/z)
			125	5- {3- [4- (2, 4-dichloro-phenyl) -2- (2 '-fluoro-5' -propoxy-biphenyl-4-ylmethyl) -imidazol-1-yl]-phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide	665(M+H)+

126	5- {3- [2- (2' -butoxy-biphenyl-4-ylmethyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl]-phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide	661(M+H)+
			127	5- (3- {4- (2, 4-dichloro-phenyl) -2- [ 4' - (3, 3-dimethyl-butoxy) -biphenyl-4-ylmethyl]-imidazol-1-yl } -phenyl) -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide	689(M+H)+
128	5- {3- [4- (2, 4-dichloro-phenyl) -2- (4' -isobutoxy-biphenyl-4-ylmethyl) -imidazol-1-yl]-phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide	689(M+H)+
			129	5- {3- [2- (4' -cyclohexylmethoxy-biphenyl-4-ylmethyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl]-phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide	701(M+H)+
130	5- (3- {4- (2, 4-dichloro-phenyl) -2- [ 4' - (3, 3-dimethyl-butylsulfanyl) -biphenyl-4-ylmethyl]-imidazol-1-yl } -phenyl) -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide	705(M+H)+

Example 131

Treatment of 3- [2- (4-bromo-benzyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenylamino } -acetic acid methyl ester (55mg, 0.1mmol) using 4- (cyclohexylmethylsulfanyl) -phenylboronic acid (50mg, 0.2mmol, prepared according to general procedure I) as described in general procedure G gave {3- [2- (4' -cyclohexylmethylsulfanyl-biphenyl-4-ylmethyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenylamino } -acetic acid methyl ester (55mg, 0.1 mmol).

{3- [2- (4 '-cyclohexylmethylsulfanyl-biphenyl-4-ylmethyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenylamino } -acetic acid methyl ester (23mg, 0.033mmol) was treated according to general procedure F to give 5- {3- [2- (4' -cyclohexylmethylsulfanyl-biphenyl-4-ylmethyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide.

LCMS：m/z 717(M+H)⁺；¹H NMR(DMSO-d₆，400MHz)：δ0.99-1.21(m，6H)，1.47(m，1H)，1.57-1.88(m，4H)，2.87(d，2H)，4.04(s，2H)，4.09(s，2H)，7.11-7.17(m，4H)，7.31-7.38(m，4H)，7.42-7.58(m，5H)，7.63(d，1H)，7.87(s，1H)，8.19(d，1H)ppm。

Example 132

5- {3- [2- (4 '-cyclohexylmethylsulfanyl-biphenyl-4-ylmethyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide (7.2mg, 0.01mmol) was processed as described in general procedure S to give 5- {3- [2- (4' -cyclohexylmethanesulfonyl-biphenyl-4-ylmethyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide.

LCMS：m/z 749(M+H)⁺；¹H NMR(DMSO-d₆，400MHz)：δ1.00-1.25(m，6H)，1.52(m，1H)，1.58-1.87(m，4H)，3.21(d，2H)，4.04(s，2H)，4.09(s，2H)，7.17(d，2H)，7.21(d，2H)，7.27-7.41(m，4H)，7.44-7.58(m，5H)，7.64(d，1H)，7.87(s，1H)，8.19(d，1H)ppm。

Example 133

Treatment of 3- [2- (4-bromo-benzyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenylamino } -acetic acid methyl ester (55mg, 0.1mmol) using 3- (2-cyclohexyl-ethoxy) -phenylboronic acid (50mg, 0.2mmol, prepared according to general procedure H) as described in general procedure G gave {3- [2- [ 4' - (2-cyclohexyl-ethoxy) -biphenyl-4-ylmethyl ] -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenylamino } -acetic acid methyl ester (55mg, 0.1 mmol).

{3- [2- [4 '- (2-cyclohexyl-ethoxy) -biphenyl-4-ylmethyl ] -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenylamino } -acetic acid methyl ester (22mg, 0.03mmol) was treated according to general procedure F to give 5- {3- [2- [ 4' - (2-cyclohexyl-ethoxy) -biphenyl-4-ylmethyl ] -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide.

LCMS：m/z 715(M+H)⁺；¹H NMR(DMSO-d₆，400MHz)：δ0.86-0.88(m，2H)，1.14-1.21(m，4H)，1.45(m，1H)，1.49-1.71(m，6H)，4.01(m，4H)，4.12(s，2H)，6.87(dd，1H)，7.13-7.19(m，5H)，7.31(d，2H)，7.37(d，2H)，7.46-7.57(m，3H)，7.65(d，1H)，7.87(s，1H)，8.19(d，1H)ppm。

Example 134

Treatment of 5- {3- [2- (4 '-bromo-benzyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide (59mg, 0.1mmol) using 4- (cyclohexylmethylamino) -phenylboronic acid (47mg, 0.2mmol, prepared according to general procedure J) as described in general procedure G gave 5- {3- [2- [ 4' - (cyclohexylmethyl-amino) -biphenyl-4-ylmethyl ] -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide.

LCMS：m/z 700(M+H)⁺；¹H NMR(DMSO-d₆，400MHz)：δ0.90-0.93(m，2H)，1.18-1.25(m，5H)，1.67-1.80(m，4H)，2.84(d，2H)，4.01(s，2H)，4.07(s，2H)，6.57(d，2H)，6.91(dd，1H)，6.93-7.09(m，2H)，7.23(d，2H)，7.25(d，2H)，7.32-7.49(m，3H)，7.64(d，2H)，7.92(s，1H)，8.18(d，1H)ppm。

Example 135

5- {3- [2- (4 '-bromo-benzyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide (59mg, 0.1mmol) was treated with 4-amino-phenylboronic acid (28mg, 0.2mmol) as described in general procedure G to give 5- {3- [2- (4' -amino-biphenyl-4-ylmethyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide.

LCMS：m/z 604(M+H)⁺。

Example 136

Reacting 5- {3- [2- (4 '-amino-biphenyl-4-ylmethyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenyl } - [1, 2, 5] thiadiazolidin-3-one-1, 1-dioxide (7mg, 0.01mmol) with 1-bromo-3-3-dimethylbutane (3.3mg, 0.02mmol) and following general procedure E to give-5- {3- [2- { 4' - [ bis- (3, 3-dimethyl-butyl) -amino ] -biphenyl-4-ylmethyl } -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide.

LCMS：m/z 772(M+H)⁺。

Example 137

Coupling of 3- [2- (4-bromo-benzyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenylamino } -acetic acid methyl ester (55mg, 0.1mmol) and 4-morpholino-phenylboronic acid (40mg, 0.2mmol) according to general procedure G gave {3- [4- (2, 4-dichloro-phenyl) -2- (4' -morpholin-4-yl-biphenyl-4-ylmethyl) -imidazol-1-yl ] -phenylamino } -acetic acid methyl ester.

{3- [4- (2, 4-dichloro-phenyl) -2- (4 '-morpholin-4-yl-biphenyl-4-ylmethyl) -imidazol-1-yl ] -phenylamino } -acetic acid methyl ester (20mg, 0.03mmol) was treated according to general procedure F to give 5- {3- [4- (2, 4-dichloro-phenyl) -2- (4' -morpholin-4-yl-biphenyl-4-ylmethyl) -imidazol-1-yl ] -phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide.

LCMS：m/z 674(M+H)⁺；¹H NMR(DMSO-d₆，400MHz)：δ0.83-1.05(m，2H)，1.10-1.20(m，2H)，3.12-3.14(m，2H)，3.72-3.74(m，2H)，4.01(s，2H)，4.10(s，2H)，6.98(d，2H)，7.01(d，2H)，7.12(d，2H)，7.20(d，2H)，7.42-7.50(m，3H)，7.64(d，1H)，7.86(s，1H)，7.92(d，2H)，8.18(d，1H)ppm。

Example 138

Treatment of 3- [2- (4-bromo-benzyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenylamino } -acetic acid methyl ester (55mg, 0.1mmol) using 4- (2-cyclohexylethylsulfanyl) -phenylboronic acid (52mg, 0.2mmol, prepared according to general procedure I) as described in general procedure G gave {3- [2- [ 4' - (2-cyclohexyl-ethylsulfanyl) -biphenyl-4-ylmethyl ] -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenylamino } -acetic acid methyl ester.

{3- [2- [4 '- (2-cyclohexyl-ethylsulfanyl) -biphenyl-4-ylmethyl ] -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenylamino } -acetic acid methyl ester (23mg, 0.033mmol) was treated according to general procedure F to give 5- {3- [2- [ 4' - (2-cyclohexyl-ethylsulfanyl) -biphenyl-4-ylmethyl ] -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide.

LCMS：m/z 731(M+H)⁺；¹H NMR(DMSO-d₆，400MHz)：δ0.86-0.89(m，2H)，1.14-1.21(m，6H)，1.45(m，1H)，1.47-1.80(m，4H)，2.97(m，2H)，4.01(s，2H)，4.12(s，2H)，7.02(d，2H)，7.04(d，2H)，7.16(d，2H)，7.33(d，2H)，7.42-7.57(m，5H)，7.64(d，1H)，7.78(s，1H)，8.17(d，1H)ppm。

Example 139

5- {3- [2- [4 '- (cyclohexylmethyl-amino) -biphenyl-4-ylmethyl ] -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenyl } - [1, 2, 5] thiadiazolidin-3-one-1, 1-dioxide (7mg, 0.01mmol) was reacted with acetaldehyde (2mg, 0.04mmol) according to general procedure X to give 5- {3- [2- [ 4' - (cyclohexylmethyl-ethyl-amino) -biphenyl-4-ylmethyl ] -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide.

LCMS：m/z 728(M+H)⁺。

Example 140

Coupling of 2-tert-butyl-5-chloro-isothiazolidin-3-one-1, 1-dioxide [ (2.3g, 10mmol) -prepared according to general procedure AB ] with 3-boc-amino-phenylboronic acid (3.0g, 12mmol) according to general procedure AC gave [3- (2-tert-butyl-1, 1, 3-trioxo-2, 3-dihydro-1H-isothiazol-5-yl) -phenyl ] -carbamic acid tert-butyl ester.

Treatment of [3- (2-tert-butyl-1, 1, 3-trioxo-2, 3-dihydro-1H-isothiazol-5-yl) -phenyl ] -carbamic acid tert-butyl ester (77mg, 0.20mmol) with 1, 4-dioxane-HCl according to general procedure V afforded 5- (3-amino-phenyl) -2-tert-butyl-isothiazol-3-one-1, 1-dioxide.

LCMS：m/z 280(M+H)⁺；¹H NMR(CDCl₃，400MHz)：δ1.68(s，9H)，6.66(s，1H)，7.32(d，2H)，7.34(d，2H)，7.39(dd，1H)，7.79(s，1H)ppm。

Following general procedure N treatment of 5- (3-amino-phenyl) -2-tert-butyl-isothiazol-3-one-1, 1-dioxide (70mg, 0.25mmol) with 2-bromo-2, 4-dichloro-acetophenone (70g, 0.26mmol) gave 2-tert-butyl-5- {3- [2- (2, 4-dichloro-phenyl) -2-oxo-ethylamino ] -phenyl } -isothiazol-3-one-1, 1-dioxide.

LCMS：m/z 467(M+H)⁺；¹H NMR(CDCl₃，400MHz)：δ1.69(s，9H)，4.57(s，2H)，6.62(s，1H)，6.78(d，1H)，6.87(s，1H)，7.03(d，1H)，7.33(dd，1H)，7.37(d，1H)，7.52(s，1H)，7.64(d，1H)ppm。

2-tert-butyl-5- {3- [2- (2, 4-dichloro-phenyl) -2-oxo-ethylamino ] -phenyl } -isothiazol-3-one-1, 1-dioxide (47mg, 0.10mmol) was reacted with 4-bromo-phenylacetyl chloride (25mg, 0.10mmol) according to general procedure N to give 2- (4-bromo-phenyl) -N- [3- (2-tert-butyl-1, 1, 3-trioxo-2, 3-dihydro-1H-isothiazol-5-yl) -phenyl ] -N- [2- (2, 4-dichloro-phenyl) -2-oxo-ethyl ] -acetamide.

LCMS：m/z 664(M+H)⁺；¹H NMR(CDCl₃，400MHz)：δ1.68(s，9H)，3.62(s，2H)，3.70(s，2H)，6.66(s，1H)，7.16(d，2H)，7.22(d，2H)，7.40(d，2H)，7.41-7.48(m，2H)，7.53(d，2H)，7.98(s，1H)ppm。

2- (4-bromo-phenyl) -N- [3- (2-tert-butyl-1, 1, 3-trioxo-2, 3-dihydro-isothiazol-5-yl) -phenyl ] -N- [2- (2, 4-dichloro-phenyl) -2-oxo-ethyl ] -acetamide-1, 1-dioxide (23mg, 0.03mmol) was treated as described in general procedure O to give 5- {3- [2- (4-bromo-benzyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenyl } -2-tert-butyl-isothiazol-3-one-1, 1-dioxide.

LCMS：m/z 645(M+H)⁺；¹H NMR(DMSO-d₆，400MHz)：δ1.59(s，9H)，3.66(s，2H)，7.14(s，1H)，7.28(d，2H)，7.47-7.53(m，5H)，7.73(d，2H)，8.06(s，1H)，10.4(s.1H)ppm。

Treatment of 5- {3- [2- (4-bromo-benzyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenyl } -2-tert-butyl-isothiazol-3-one-1, 1-dioxide (7mg, 0.01mmol) using 4- (cyclohexylmethoxy) -phenylboronic acid (5mg, 0.02mmol, prepared according to general procedure H) as described in general procedure G gave 2-tert-butyl-5- {3- [2- (4' -cyclohexylmethoxy-biphenyl-4-ylmethyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenyl } -isothiazol-3-one-1, 1-dioxide.

LCMS：m/z 754(M+H)⁺；¹H NMR(CDCl₃，400MHz)：δ0.89-1.07(m，2H)，1.25-1.32(m，5H)，1.64(s，9H)，1.69-1.90(m，6H)，3.77(s，2H)，3.79(s，2H)，6.59(s，1H)，6.70(s，1H)，6.93(d，2H)，7.08(d，1H)，7.10(d，2H)，7.36-7.47(m，5H)，7.70(d，2H)，7.78(d，1H)ppm。

Example 141

Treatment of 2- (4-bromo-benzyl) -4- (2, 4-dichlorophenyl) -1H-imidazole (3.27g, 8.6mmol) with 4-fluoronitrobenzene as described in general procedure B gave 2- (4-bromo-benzyl) -4- (2, 4-dichloro-phenyl) -1- (4-nitro-phenyl) -1H-imidazole, this was treated with 4-hydroxyphenylboronic acid according to general procedure G to give 4' - [4- (2, 4-dichloro-phenyl) -1- (4-nitro-phenyl) -1H-imidazol-2-ylmethyl ] -biphenyl-4-ol (996mg, 22% over two steps). To a solution of phenol in THF (0.5M) under nitrogen was added N-boc-4-hydroxypiperidine (2eq) and triphenylphosphine (2eq) followed by diisopropyl dinitrogen dicarboxylate (2eq) while the mixture was sonicated. After sonication for 1 hour, the reaction mixture was evaporated in vacuo and the residue was purified by silica gel column chromatography to give 4- { 4' - [4- (2, 4-dichloro-phenyl) -1- (4-nitro-phenyl) -1H-imidazol-2-ylmethyl ] -biphenyl-4-yloxy } -piperidine-1-carboxylic acid tert-butyl ester.

The boc-protected alkylaryl ether product (911mg, 1.3mmol) was deprotected according to general procedure V and neopentyl carbamate was introduced according to general procedure U to give 4- { 4' - [4- (2, 4-dichloro-phenyl) -1- (4-nitro-phenyl) -1H-imidazol-2-ylmethyl ] -biphenyl-4-yloxy } -piperidine-1-carboxylic acid 2, 2-dimethyl-propyl ester. The resulting nitro compound is reduced, alkylated and cyclized according to general procedure C to give 4- (4' - {4- (2, 4-dichloro-phenyl) -1- [4- (1, 1, 4-trioxo- [1, 2, 5] thiadiazolidin-2-yl) -phenyl ] -1H-imidazol-2-ylmethyl } -biphenyl-4-yloxy) -piperidine-1-carboxylic acid 2, 2-dimethyl-propyl ester.

LCMS：m/z 802(M+H)⁺；¹H NMR (acetone-d)₆，400MHz)：δ0.95(s，9H)，1.28(m，2H)，1.66(m，2H)，1.97(m，2H)，3.37(m，2H)，3.78(m，4H)，4.02(s，1H)，4.32(s，1H)，4.60(m，1H)，6.97-7.04(m，2H)，7.14(m，2H)，7.21，(m，2H)，7.28(m，2H)，7.38-7.45(m，3H)，7.47-7.54(m，3H)，7.83(s，1H)，8.35(d，1H)ppm。

Example 142

5- {4- [2- (4-bromo-benzyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide (100mg, 0.17mmol) was treated as described in general procedure G using 3-isopropylphenylboronic acid to give 5- {4- [4- (2, 4-dichloro-phenyl) -2- (3' -isopropyl-biphenyl-4-ylmethyl) -imidazol-1-yl ] -phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide.

LCMS：m/z 631(M+H)⁺。

Example 143

5- {4- [2- (4-bromo-benzyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide (100mg, 0.17mmol) was treated with 4-trifluoromethylphenylboronic acid as described in general procedure G to give 5- {4- [4- (2, 4-dichloro-phenyl) -2- (4' -trifluoromethyl-biphenyl-4-ylmethyl) -imidazol-1-yl ] -phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide.

LCMS：m/z 657(M+H)⁺。

Example 144

5- {4- [2- (4-bromo-benzyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl at room temperature under nitrogen]-phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide (143mg, 0.24mmol) was stirred in DMF (0.1-0.5M) with 1.1eq of N-chlorosuccinimide for 12 hours. The mixture was poured into water and extracted with ethyl acetate. With water, saturated NaHCO₃The organic extracts were washed with aqueous solution and brine and Na₂SO₄And (5) drying. The solvent was removed in vacuo and the residue was dried and used directly in the next step.

The crude chlorinated compound was treated with 4-cyclohexylphenylboronic acid as described in general procedure G to give 5- { 2-chloro-4- [2- (4' -cyclohexyl-biphenyl-4-ylmethyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide.

LCMS：m/z 705(M+H)⁺。

Example 145

2- (4 '-cyclohexyl-biphenyl-4-ylmethyl) -4- (2, 4-dichloro-phenyl) -1H-imidazole (250mg, 0.54mmol) was treated with 2-fluoro-5-nitrotoluene according to general procedure B to give 2- (4' -cyclohexyl-biphenyl-4-ylmethyl) -4- (2, 4-dichloro-phenyl) -1- (2-methyl-4-nitro-phenyl) -1H-imidazole, which was collected without purification. The nitro compound was treated as described in general procedure C to give 5- {4- [2- (4' -cyclohexyl-biphenyl-4-ylmethyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -3-methyl-phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide.

LCMS：m/z 685(M+H)⁺。

The following compounds were synthesized by a method similar to that used for the preparation of example 145:

examples	Name (R)	LC/MS(m/z)
			146	5- { 3-chloro-4- [2- (4' -cyclohexyl-biphenyl-4-ylmethyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl]-phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide	705(M+H)+
147	5- {4- [2- (4' -cyclohexyl-biphenyl-4-ylmethyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl]-3-trifluoromethyl-phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide	739(M+H)+
			148	5- {4- [2- (4' -cyclohexyl-biphenyl-4-ylmethyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl]-3-fluoro-phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide	689(M+H)+

Example 149

Treatment of 5- {4- [2- (4-bromo-benzyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide (200mg, 0.34mmol) using 4- (2-ethoxycarbonyl-vinyl) phenylboronic acid as described in general procedure G gave 3- (4' - {4- (2, 4-dichloro-phenyl) -1- [4- (1, 1, 4-trioxo- [1, 2, 5] thiadiazolidin-2-yl) -phenyl ] -1H-imidazol-2-ylmethyl } -biphenyl-4-yl) -acrylic acid ethyl ester.

LCMS：m/z 687(M+H)⁺；¹H NMR(DMSO-d₆，400MHz)：δ1.27(t，3H)，4.05(s，2H)，4.10(s，2H)，4.19(q，2H)，6.67(d，1H)，7.15-7.22(m，4H)，7.37(m，2H)，7.45-7.53(m，2H)，7.59-7.72(m，5H)，7.79(m，2H)，7.90(s，1H)，8.19(d，1H)ppm。

Example 150

Treatment of 5- {4- [2- (4-bromo-benzyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide (300mg, 0.51mmol) using 4- (2-ethoxycarbonyl-ethyl) phenylboronic acid as described in general procedure G gave ethyl 3- (4' - {4- (2, 4-dichloro-phenyl) -1- [4- (1, 1, 4-trioxo- [1, 2, 5] thiadiazolidin-2-yl) -phenyl ] -1H-imidazol-2-ylmethyl } -biphenyl-4-yl) -propionate.

LCMS：m/z 689(M+H)⁺；¹H NMR(DMSO-d₆，400MHz)：δ1.16(t，3H)，2.63(t，2H)，2.87(t，2H)，4.01-4.12(m，6H)，7.13-7.21(m，4H)，7.29(m，2H)，7.37(m，2H)，7.48(m，1H)，7.51-7.57(m，4H)，7.65(m，1H)，7.90(s，1H)，8.19(d，1H)ppm。

Example 151

Ethyl (4 '- {4- (2, 4-dichloro-phenyl) -1- [4- (1, 1, 4-trioxo- [1, 2, 5] thiadiazolidin-2-yl) -phenyl ] -1H-imidazol-2-ylmethyl } -biphenyl-4-yl) -acrylate (36mg, 52 μmol) was treated as described in general procedure P to give 3- (4' - {4- (2, 4-dichloro-phenyl) -1- [4- (1, 1, 4-trioxo- [1, 2, 5] thiadiazolidin-2-yl) -phenyl ] -1H-imidazol-2-ylmethyl } -biphenyl-4-yl) -acrylic acid.

LCMS：m/z 659(M+H)⁺；¹H NMR(DMSO-d₆，400MHz)：δ4.05(s，2H)，4.10(s，2H)，6.57(d，1H)，7.14-7.22(m，4H)，7.38(m，2H)，7.48(m，1H)，7.58-7.66(m，4H)，7.70(m，2H)，7.76(m，2H)，7.90(s，1H)，8.19(d，1H)ppm。

Example 152

Treatment of 3- (4 '- {4- (2, 4-dichloro-phenyl) -1- [4- (1, 1, 4-trioxo- [1, 2, 5] thiadiazolidin-2-yl) -phenyl ] -1H-imidazol-2-ylmethyl } -biphenyl-4-yl) -propionic acid ethyl ester (54mg, 78 μmol) as described in general procedure P afforded 3- (4' - {4- (2, 4-dichloro-phenyl) -1- [4- (1, 1, 4-trioxo- [1, 2, 5] thiadiazolidin-2-yl) -phenyl ] -1H-imidazol-2-ylmethyl } -biphenyl-4-yl) -propionic acid.

LCMS：m/z 661(M+H)⁺；¹H NMR(DMSO-d₆，400MHz)：δ2.56(t，2H)，2.84(t，2H)，4.07(s，2H)，4.12(s，2H)，7.14-7.22(m，4H)，7.29(m，2H)，7.40(m，2H)，7.49-7.57(m，5H)，7.69(m，1H)，7.96(s，1H)，8.13(d，1H)ppm。

Example 153

Ethyl 4' - [4- (2, 4-dichloro-phenyl) -1H-imidazol-2-ylmethyl ] -biphenyl-4-carboxylate (500mg, 1.1mmol) was treated as described in general procedure Z using 2 equivalents of propylmagnesium chloride. The crude Grignard product was directly reduced according to general procedure AA, after which the reduced product was alkylated according to general procedure B using 4-fluoronitrobenzene. The crude nitro compound was treated as described in general procedure C to give 5- (4- {4- (2, 4-dichloro-phenyl) -2- [ 4' - (1-propyl-butyl) -biphenyl-4-ylmethyl ] -imidazol-1-yl } -phenyl) -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide.

LCMS：m/z 687(M+H)⁺；¹H NMR(DMSO-d₆，400MHz)：δ0.82(t，6H)，1.05-1.20(m，4H)，1.48-1.61(m，4H)，2.55(m，1H)，3.91(s，2H)，4.05(s，2H)，7.12-7.20(m，4H)，7.23(m，2H)，7.36(m，2H)，7.47(dd，1H)，7.55(m，4H)，7.64(d，1H)，7.90(s，1H)，8.20(d，1H)ppm。

Example 154

Treatment of 2- (4-bromo-benzyl) -4- (2, 4-dichloro-phenyl) -1H-imidazole (1g, 2.6mmol) with (3-iodo-phenyl) -carbamic acid tert-butyl ester according to general procedure R afforded {3- [2- (4-bromo-benzyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenyl } -carbamic acid tert-butyl ester. The bromophenyl product (370mg, 0.64mmol) was treated with 4-ethoxycarbonylphenylboronic acid as described in general procedure G to give 4' - [1- (3-tert-butoxycarbonylamino-phenyl) -4- (2, 4-dichloro-phenyl) -1H-imidazol-2-ylmethyl ] -biphenyl-4-carboxylic acid ethyl ester.

General procedure Z the benzoate ester obtained above (153mg, 0.24mmol) was treated with 2eq of 3, 3-dimethylbutyl magnesium chloride and the grignard product was subsequently reduced according to general procedure AA to give [3- (4- (2, 4-dichloro-phenyl) -2- { 4' - [1- (3, 3-dimethyl-butyl) -4, 4-dimethyl-pentyl ] -biphenyl-4-ylmethyl } -imidazol-1-yl) -phenyl ] -carbamic acid tert-butyl ester. After removal of the Boc group according to general procedure V, the resulting aniline compound is treated sequentially according to general procedures E and F to give 5- [3- (4- (2, 4-dichloro-phenyl) -2- { 4' - [1- (3, 3-dimethyl-butyl) -4, 4-dimethyl-pentyl ] -biphenyl-4-ylmethyl } -imidazol-1-yl) -phenyl ] -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide.

LCMS：m/z 771(M+H)⁺。

Example 155

3, 3-dimethylbutyl magnesium chloride (1eq) was converted to 4- (4, 4-dimethyl-pentyl) phenylboronic acid using 4-bromobenzaldehyde (1g, 5.4mmol) following general procedure Y.

3- [2- (4-bromo-benzyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -aniline was prepared from 3-aminoacetanilide according to general procedure M and then alkylated using methyl bromoacetate according to general procedure E to give crude {3- [2- (4-bromo-benzyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenylamino } -acetic acid methyl ester. The bromine compound (44mg, 80 μmol) was coupled with 4- (4, 4-dimethyl-pentyl) phenylboronic acid as described in general procedure G to give (3- {4- (2, 4-dichloro-phenyl) -2- [ 4' - (4, 4-dimethyl-pentyl) -biphenyl-4-ylmethyl ] -imidazol-1-yl } -phenylamino) -acetic acid methyl ester. The product was then treated according to general procedure F to give 5- (3- {4- (2, 4-dichloro-phenyl) -2- [ 4' - (4, 4-dimethyl-pentyl) -biphenyl-4-ylmethyl ] -imidazol-1-yl } -phenyl) -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide.

LCMS：m/z 687(M+H)⁺；¹H NMR(DMSO-d₆，400MHz)：δ0.76(s，9H)，1.10-1.20(m，2H)，1.48(m，2H)，2.47(t，2H)，4.03(s，2H)，4.22(s，2H)，6.71(m，1H)，7.04-7.16(m，5H)，7.20(m，2H)，7.29(dd，1H)，7.31-7.40(m，5H)，7.79(s，1H)，8.23(d，1H)ppm。

The following compound was synthesized by a method similar to that used for the preparation of example 155:

examples	Name (R)	LC/MS(m/z)
			156	5- {3- [2- [ 4' - (2-cyclohexyl-ethyl) -biphenyl-4-ylmethyl]-4- (2, 4-dichloro-phenyl) -imidazol-1-yl]-phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide	699(M+H)+
157	5- (3- {4- (2, 4-dichloro-phenyl) -2- [ 4' - (3, 3-dimethyl-butyl) -biphenyl-4-ylmethyl]-imidazol-1-yl } -phenyl) -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide	673(M+H)+
			158	5- {3- [2- (4' -cyclohexylmethyl-biphenyl-4-ylmethyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl]-phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide	685(M+H)+
159	5- (3- {4- (2, 4-dichloro-phenyl) -2- [ 4' - (4-methyl-pentyl) -biphenyl-4-ylmethyl]-imidazol-1-yl } -phenyl) -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide	673(M+H)+

Example 160

4-bromobenzaldehyde (6.5g, 35mmol) was converted to 4- (2-cyclohexylvinyl) phenylboronic acid using cyclohexylmethylmagnesium bromide following general procedure AE.

3- [2- (4-bromo-benzyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -aniline was prepared from 3-aminoacetanilide according to general procedure M and then alkylated using methyl bromoacetate according to general procedure E to give crude {3- [2- (4-bromo-benzyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenylamino } -acetic acid methyl ester. The bromine compound (500mg, 0.91mmol) was coupled with 4- (2-cyclohexylvinyl) phenylboronic acid as described in general procedure G to give {3- [2- [ 4' - (2-cyclohexyl-vinyl) -biphenyl-4-ylmethyl ] -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenylamino } -acetic acid methyl ester. The product was then treated according to general procedure F to give 5- {3- [2- [ 4' - (2-cyclohexyl-vinyl) -biphenyl-4-ylmethyl ] -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide.

LCMS：m/z 697(M+H)⁺；¹H NMR(DMSO-d₆，400MHz)：δ1.12-1.36(m，5H)，1.65(m，2H)，1.75(m，3H)，2.14(m，1H)，4.00(s，2H)，4.13(s，2H)，6.29(dd，1H)，6.39(d，1H)，6.94(m，1H)，7.05(m，1H)，7.18(m，2H)，7.26(m，1H)，7.41-7.46(m，3H)，7.49(dd，1H)，7.51-7.58(m，4H)，7.65(d，1H)，7.94(s，1H)，8.19(d，1H)ppm。

Example 161

4-bromophenylacetic acid (2.2g, 10mmol) was treated according to general procedures A and B to give 2- (4-bromo-benzyl) -1- (4-nitro-phenyl) -4- (2, 4-dichloro-phenyl) -1H-imidazole, which was then treated as described in general procedure C to give 5- {4- [2- (4-bromo-benzyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide.

LCMS：m/z 593(M+H)⁺；¹H NMR(DMSO-d₆，400MHz)：δ4.05(s，2H)，4.07(s，2H)，7.15(d，2H)，7.27(d，2H)，7.47(dd，1H)，7.51(d，2H)，7.53(d，2H)，7.64(d，1H)，7.89(s，1H)，8.19(d，1H)ppm。

Example 162

4-bromophenylacetic acid (2.2g, 10mmol) was treated according to general procedures A and B to give 2- (4-bromo-benzyl) -1- (4-nitro-phenyl) -4- (2, 6-dichloro-phenyl) -1H-imidazole, which was then treated as described in general procedure C to give 5- {4- [2- (4-bromo-benzyl) -4- (2, 6-dichloro-phenyl) -imidazol-1-yl ] -phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide.

LCMS：m/z 593(M+H)⁺；¹H NMR(DMSO-d₆，400MHz)：δ4.05(s，2H)，4.07(s，2H)，7.15(d，2H)，7.27(d，2H)，7.44-7.52(m，5H)，7.63(d，1H)，7.88(s，1H)，8.18(d，1H)ppm。

Example 163

2- (4-bromo-benzyl) -1- (3-nitro-phenyl) -4- (2, 4-dichloro-phenyl) -1H-imidazole (prepared from 4-bromophenylacetic acid according to general procedure A and R) (503mg, 1mmol) was treated as described in general procedure C to give 5- {3- [2- (4-bromo-benzyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide.

LCMS：m/z 593(M+H)⁺；¹H NMR(DMSO-d₆，400MHz)：δ4.05(s，2H)，4.07(s，2H)，7.15(d，2H)，7.29-7.50(m，5H)，7.53(d，2H)，7.64(d，1H)，7.89(s，1H)，8.19(d，1H)ppm。

Example 164

Treatment of 2- (4-bromo-benzyl) -1- (4-nitro-phenyl) -4- (2, 4-difluoro-phenyl) -1H-imidazole (prepared from 4-bromophenylacetic acid according to general procedures a and B) (470mg, 1mmol) as described in general procedure C afforded 5- {4- [2- (4-bromo-benzyl) -4- (2, 4-difluoro-phenyl) -imidazol-1-yl ] -phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide.

LCMS：m/z 560(M+H)⁺；¹H NMR(DMSO-d₆，400MHz)：δ4.05(s，2H)，4.07(s，2H)，7.12-7.19(m，5H)，7.47(m，1H)，7.51-7.56(m，5H)，8.12(m，1H)ppm。

Example 165

2- (4-bromo-benzyl) -4- (2, 4-dichloro-phenyl) -1- (4-methyl-3-nitro-phenyl) -1H-imidazole (prepared from 4-bromophenylacetic acid according to general procedure A and R) (517mg, 1mmol) was treated as described in general procedure C to give 5- {5- [2- (4-bromo-benzyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -2-methyl-phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide.

LCMS：m/z 607(M+H)⁺；¹H NMR(DMSO-d₆，400MHz)：δ2.30(s，3H)，4.05(s，2H)，4.07(s，2H)，7.27-7.43(m，4H)，7.51(d，2H)，7.53(d，2H)，7.64(d，1H)，7.89(s，1H)，8.19(d，1H)ppm。

Example 166

2- (4-bromo-benzyl) -4- (2, 4-difluoro-phenyl) -1- (4-methyl-3-nitro-phenyl) -1H-imidazole (prepared from 4-bromophenylacetic acid according to general procedures A and R) (484mg, 1mmol) was treated as described in general procedure C to give 5- {5- [2- (4-bromo-benzyl) -4- (2, 4-difluoro-phenyl) -imidazol-1-yl ] -2-methyl-phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide.

LCMS：m/z 574(M+H)⁺；¹H NMR(DMSO-d₆，400MHz)：δ2.29(s，3H)，4.05(s，2H)，4.07(s，2H)，7.12-7.19(m，4H)，7.47(m，1H)，7.51-7.56(m，5H)，8.12(m，1H)ppm。

Example 167

5- {3- [2- (4-bromo-benzyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide (59mg, 0.1mmol) was treated with 4-phenoxyphenylboronic acid (43mg, 0.2mmol) as described in general procedure G to give 5- {3- [4- (2, 4-dichloro-phenyl) -2- (4' -phenoxy-biphenyl-4-ylmethyl) -imidazol-1-yl ] -phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide.

LCMS：m/z 681(M+H)⁺；¹H NMR(DMSO-d₆，400MHz)：δ4.05(s，2H)，4.08(s，2H)，7.05(d，2H)，7.07(d，2H)，7.14-7.19(m，5H)，7.36-7.43(m，4H)，7.47(m，1H)，7.53(d，2H)，7.64-7.66(m，3H)，7.90(s，1H)，8.20(d，1H)ppm。

The following compounds were synthesized by a method similar to that used for the preparation of example 167:

examples	Name (R)	LC/MS(m/z)
			168	5- {3- [4- (2, 4-dichloro-phenyl) -2- (4-hex-1-enyl-benzyl) -imidazol-1-yl]-phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide	595(M+H)+
169	5- (3- {4- (2, 4-dichloro-phenyl) -2- [4- (3, 3-dimethyl-but-1-enyl) -benzyl]-imidazol-1-yl } -phenyl) -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide	595(M+H)+
			170	5- {3- [2- [4- (2-cyclohexyl-vinyl) -benzyl]-4- (2, 4-dichloro-phenyl) -imidazol-1-yl]-phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide	595(M+H)+
171	5- {4- [2- [ 3' - (2-cyclohexyl-ethoxy) -biphenyl-4-ylmethyl]-4- (2, 4-dichloro-phenyl) -imidazol-1-yl]-phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide	715(M+H)+

Example 172

Treatment of 5- {4- [2- (4-bromo-benzyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide (1.19g, 2mmol) using 2- (trimethylsilyl) ethoxymethyl chloride (708 μ L, 4mmol) as described in general procedure L gave 5- {4- [2- (4-bromo-benzyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenyl } -1, 1-dioxo-2- (2-trimethylsilyl-ethoxymethyl) - [1, 2, 5] thiadiazolidin-3-one, which is then treated according to the general procedure AD to give 5- (4- {4- (2, 4-dichloro-phenyl) -2- [4- (4, 4, 5, 5-tetramethyl- [1, 3, 2] dioxaborolan-2-yl) -benzyl ] -imidazol-1-yl } -phenyl) -1, 1-dioxo-2- (2-trimethylsilyl-ethoxymethyl) - [1, 2, 5] thiadiazolidin-3-one.

LCMS：m/z 769(M+H)⁺。

Treatment of 5- (4- {4- (2, 4-dichloro-phenyl) -2- [4- (4, 4, 5, 5-tetramethyl- [1, 3, 2] dioxaborolan-2-yl) -benzyl ] -imidazol-1-yl } -phenyl) -1, 1-dioxo-2- (2-trimethylsilyl-ethoxymethyl) - [1, 2, 5] thiadiazolidin-3-one (385mg, 0.5mmol) with 3, 6-dichloropyridazine (149mg, 1mmol) as described in general procedure G gave 5- {4- [2- [4- (6-chloro-pyridazin-3-yl) -benzyl ] -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenyl } -1, 1-dioxo-2- (2-trimethylsilyl-ethoxymethyl) - [1, 2, 5] thiadiazolidin-3-one.

LCMS：m/z 756(M+H)⁺。

Treatment of 5- {4- [2- [4- (6-chloro-pyridazin-3-yl) -benzyl ] -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenyl } -1, 1-dioxo-2- (2-trimethylsilyl-ethoxymethyl) - [1, 2, 5] thiadiazolidin-3-one (38mg, 0.05mmol) using 2-cyclohexylethanol (35 μ L, 0.25mmol) as described in general procedure L gave 5- {4- [2- {4- [6- (2-cyclohexyl-ethoxy) -pyridazin-3-yl ] -benzyl } -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenyl } -1, 1-dioxo-2- (2-trimethylsilyl-ethoxymethyl) - [1, 2, 5] thiadiazolidin-3-one.

LCMS：m/z 847(M+H)⁺。

5- {4- [2- {4- [6- (2-cyclohexyl-ethoxy) -pyridazin-3-yl ] -benzyl } -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenyl } -1, 1-dioxo-2- (2-trimethylsilyl-ethoxymethyl) - [1, 2, 5] thiadiazolidin-3-one (17mg, 0.02mmol) was treated with tetrabutylammonium fluoride (26mg, 0.1mmol) as described in general procedure W to give 5- {4- [2- {4- [6- (2-cyclohexyl-ethoxy) -pyridazin-3-yl ] -benzyl } -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide.

LCMS：m/z 717(M+H)⁺；¹H NMR(CD₃OD，400MHz)：δ0.97-1.43(m，5H)，1.65(m，2H)，1.69-1.81(m，6H)，4.05(t，2H)，4.08(s，2H)，4.10(s，2H)，7.17(d，2H)，7.21(d，2H)，7.37(d，2H)，7.46-7.54(m，5H)，7.64(d，1H)，7.89(s，1H)，8.19(d，1H)ppm。

Example 173

Treatment of 5- {3- [2- (4-bromo-benzyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide (1.19g, 2mmol) using 2- (trimethylsilyl) ethoxymethyl chloride (708 μ L, 4mmol) as described in general procedure L gave 5- {3- [2- (4-bromo-benzyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenyl } -1, 1-dioxo-2- (2-trimethylsilyl-ethoxymethyl) - [1, 2, 5] thiadiazolidin-3-one, which is then treated according to the general procedure AD to give 5- (3- {4- (2, 4-dichloro-phenyl) -2- [4- (4, 4, 5, 5-tetramethyl- [1, 3, 2] dioxaborolan-2-yl) -benzyl ] -imidazol-1-yl } -phenyl) -1, 1-dioxo-2- (2-trimethylsilyl-ethoxymethyl) - [1, 2, 5] thiadiazolidin-3-one.

LCMS：m/z 769(M+H)⁺。

Treatment of 5- (3- {4- (2, 4-dichloro-phenyl) -2- [4- (4, 4, 5, 5-tetramethyl- [1, 3, 2] dioxaborolan-2-yl) -benzyl ] -imidazol-1-yl } -phenyl) -1, 1-dioxo-2- (2-trimethylsilyl-ethoxymethyl) - [1, 2, 5] thiadiazolidin-3-one (385mg, 0.5mmol) with 3, 6-dichloropyridazine (149mg, 1mmol) as described in general procedure G gave 5- {3- [2- [4- (6-chloro-pyridazin-3-yl) -benzyl ] -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenyl } -1, 1-dioxo-2- (2-trimethylsilyl-ethoxymethyl) - [1, 2, 5] thiadiazolidin-3-one.

LCMS：m/z 756(M+H)⁺。

Treatment of 5- {3- [2- [4- (6-chloro-pyridazin-3-yl) -benzyl ] -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenyl } -1, 1-dioxo-2- (2-trimethylsilyl-ethoxymethyl) - [1, 2, 5] thiadiazolidin-3-one (38mg, 0.05mmol) with 1-cyclohexen-1-yl-boronic acid (13mg, 0.1mmol) as described in general procedure G gave 5- {3- [2- [4- (6-cyclohex-1-enyl-pyridazin-3-yl) -benzyl ] -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenyl } -1, 1-dioxo-2- (2-trimethylsilyl-ethoxymethyl) - [1, 2, 5] thiadiazolidin-3-one.

LCMS：m/z 801(M+H)⁺。

5- {3- [2- [4- (6-cyclohex-1-enyl-pyridazin-3-yl) -benzyl ] -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenyl } -1, 1-dioxo-2- (2-trimethylsilyl-ethoxymethyl) - [1, 2, 5] thiadiazolidin-3-one (16mg, 0.02mmol) was treated with tetrabutylammonium fluoride (26mg, 0.1mmol) as described in general procedure W to give 5- {3- [2- [4- (6-cyclohex-1-enyl-pyridazin-3-yl) -benzyl ] -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide.

LCMS：m/z 671(M+H)⁺；¹H NMR(CD₃OD，400MHz)：δ1.56(m，4H)，2.15(m，4H)，4.06(s，2H)，4.09(s，2H)，6.41(m，1H)，7.15-7.27(m，5H)，7.37(d，2H)，7.46-7.54(m，4H)，7.64(d，1H)，7.89(s，1H)，8.19(d，1H)ppm。

Example 174

Treatment of 5- {3- [2- (4-bromo-benzyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide (59mg, 0.1mmol) using trans-1-octen-1-ylboronic acid (47mg, 0.3mmol) as described in general procedure G gave 5- {3- [4- (2, 4-dichloro-phenyl) -2- (4-oct-1-enyl-benzyl) -imidazol-1-yl ] -phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide.

LCMS：m/z 623(M+H)⁺；¹H NMR(DMSO-d₆，400MHz)：δ0.86(t，3H)，1.27(m，6H)，1.41(m，2H)，2.16(m，2H)，4.02(s，2H)，4.05(s，2H)，6.22(m，1H)，6.32(d，1H)，7.01(d，2H)，7.17(m，2H)，7.25(d，2H)，7.36-7.48(m，3H)，7.64(d，1H)，7.88(s，1H)，8.18(d，1H)ppm。

Example 175

5- {4- [2- (4-bromo-benzyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide (119mg, 0.2mmol) was treated as described in general procedure AF using 1 hexyne (46. mu.L, 0.4mmol) to give 5- {4- [4- (2, 4-dichloro-phenyl) -2- (4-hex-1-ynyl-benzyl) -imidazol-1-yl ] -phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide.

LCMS：m/z 593(M+H)⁺；¹H NMR(DMSO-d₆，400MHz)：δ0.90(t，3H)，1.41(m，2H)，1.50(m，2H)，2.39(t，2H)，4.02(s，2H)，4.04(s，2H)，7.04(d，2H)，7.16(d，2H)，7.24(d，2H)，7.32(d，2H)，7.47(dd，1H)，7.64(d，1H)，7.89(s，1H)，8.18(d，1H)ppm。

Example 176

2-tert-butyl-5- {3- [2- (4 '-cyclohexylmethoxy-biphenyl-4-ylmethyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenyl } -isothiazol-3-one-1, 1-dioxide (4mg, 0.005mmol) was treated with TFA according to the general procedure to give 5- {3- [2- (4' -cyclohexylmethoxy-biphenyl-4-ylmethyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenyl } -isothiazol-3-one-1, 1-dioxide.

LCMS：m/z 698(M+H)⁺；¹H NMR(CDCl₃，400MHz)：δ0.89-1.07(m，2H)，1.25-1.32(m，5H)，1.69-1.90(m，6H)，3.77(s，2H)，3.79(s，2H)，6.59(s，1H)，6.70(s，1H)，6.93(d，2H)，7.08(d，1H)，7.10(d，2H)，7.36-7.47(m，5H)，7.70(d，2H)，7.78(d，1H)ppm。

Example 177

Treatment of 4- [2- (4-bromo-benzyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenylamino } -acetic acid methyl ester (55mg, 0.1mmol) using 4- (cyclohexylmethoxy) phenylboronic acid (47mg, 0.2mmol, prepared according to general procedure H) as described in general procedure G gave {4- [2- (4' -cyclohexylmethoxy-biphenyl-4-ylmethyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenylamino } -acetic acid methyl ester.

{4- [2- (4 '-cyclohexylmethoxy-biphenyl-4-ylmethyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenylamino } -acetic acid methyl ester (22mg, 0.033mmol) was treated according to general procedure F to give 5- {4- [2- (4' -cyclohexylmethoxy-biphenyl-4-ylmethyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide.

LCMS：m/z 701(M+H)⁺；¹H NMR(DMSO-d₆，400MHz)：δ1.01-1.27(m，5H)，1.69-1.82(m，6H)，3.79(d，2H)，4.07(s，2H)，4.10(s，2H)，6.96(d，2H)，7.12(d，2H)，7.18(d，2H)，7.38(d，2H)，7.49-7.55(m，5H)，7.69(d，1H)，7.96(s，1H)，8.11(d，1H)ppm。

Example 178

4- [2- (4-bromo-benzyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenylamino } -acetic acid methyl ester (55mg, 0.1mmol) was treated as described in general procedure G using 4- (3, 3-dimethyl-butoxy) phenylboronic acid (45mg, 0.2mmol, prepared according to general procedure H) to give (4- {4- (2, 4-dichloro-phenyl) -2- [ 4' - (3, 3-dimethyl-butoxy) -biphenyl-4-ylmethyl ] -imidazol-1-yl } -phenylamino) -acetic acid methyl ester.

Treatment of (4- {4- (2, 4-dichloro-phenyl) -2- [4 '- (3, 3-dimethyl-butoxy) -biphenyl-4-ylmethyl ] -imidazol-1-yl } -phenylamino) -acetic acid methyl ester (22mg, 0.033mmol) according to general procedure F gave 5- (4- {4- (2, 4-dichloro-phenyl) -2- [ 4' - (3, 3-dimethyl-butoxy) -biphenyl-4-ylmethyl ] -imidazol-1-yl } -phenyl) -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide.

LCMS：m/z 689(M+H)⁺；¹H NMR(DMSO-d₆，400MHz)：δ0.96(s，9H)，1.64(t，2H)，4.02(t，2H)，4.04(s，2H)，4.06(s，2H)，6.97(d，2H)，7.12-7.18(m，4H)，7.35(d，2H)，7.48-7.55(m，5H)，7.63(d，1H)，7.89(s，1H)，8.18(d，1H)ppm。

Example 179

Treatment of 4- [2- (4-bromo-benzyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenylamino } -acetic acid methyl ester (55mg, 0.1mmol) using 3- (2-cyclohexyl-ethoxy) -phenylboronic acid (50mg, 0.2mmol, prepared according to general procedure H) as described in general procedure G gave {4- [2- [ 4' - (2-cyclohexyl-ethoxy) -biphenyl-4-ylmethyl ] -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenylamino } -acetic acid methyl ester (55mg, 0.1 mmol).

{4- [2- [4 '- (2-cyclohexyl-ethoxy) -biphenyl-4-ylmethyl ] -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenylamino } -acetic acid methyl ester (22mg, 0.03mmol) was treated according to general procedure F to give 5- {4- [2- [ 4' - (2-cyclohexyl-ethoxy) -biphenyl-4-ylmethyl ] -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide.

LCMS：m/z 715(M+H)⁺；¹H NMR(DMSO-d₆，400MHz)：δ0.93-0.96(m，2H)，1.14-1.23(m，5H)，1.59-1.75(m，6H)，4.00(m，2H)，4.02(s，2H)，4.06(s，2H)，6.96(d，2H)，7.12-7.18(m，4H)，7.35(d，2H)，7.46-7.55(m，5H)，7.63(d，1H)，7.89(s，1H)，8.20(d，1H)ppm。

Example 180

Treatment of 6-methoxy-2-naphthylacetic acid (1.0g, 4mmol) with 2, 4-dichlorobromoacetophenone was followed by general procedure a to give 4- (2, 4-dichloro-phenyl) -2- (6-methoxy-naphthalen-2-ylmethyl) -1H-imidazole.

LCMS：m/z 383(M+H)⁺，¹H NMR(CD₃OD，400MHz)：δ3.67(s，3H)，4.10(s，2H)，7.21(d，2H)，7.37(d，2H)，7.42-7.51(m，2H)，7.57-7.69(m，3H)，8.05(s，1H)ppm。

Treatment of 4- (2, 4-dichloro-phenyl) -2- (6-methoxy-naphthalen-2-ylmethyl) -1H-imidazole (383mg, 1mmol) with 1-fluoro-4-nitrobenzene as described in general procedure B afforded 4- (2, 4-dichloro-phenyl) -1- (4-nitro-phenyl) -2- (6-methoxy-naphthalen-2-ylmethyl) -1H-imidazole.

Reduction of 4- (2, 4-dichloro-phenyl) -1- (4-nitro-phenyl) -2- (6-methoxy-naphthalen-2-ylmethyl) -1H-imidazole (252mg, 0.5mmol) to an amine and reaction with methyl bromoacetate according to general procedure D & E gave {4- [4- (2, 4-dichloro-phenyl) -2- (6-methoxy-naphthalen-2-ylmethyl) -imidazol-1-yl ] -phenylamino } -acetic acid methyl ester.

General operation AH uses BBr₃Reacting {4- [4- (2, 4-dichloro-phenyl) -2- (6-methoxy-naphthalen-2-ylmethyl) -imidazol-1-yl]-phenylamino } -acetic acid methyl ester (137mg, 0.25mmol) is de-alkylated and alkylated using bromomethyl-cyclohexane-derived phenol according to the general procedure H to give {4- [2- (6-cyclohexylmethoxy-naphthalen-2-ylmethyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl]-phenylamino } -acetic acid methyl ester.

Treatment of {4- [2- (6-cyclohexylmethoxy-naphthalen-2-ylmethyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenylamino } -acetic acid methyl ester (60mg, 0.09mmol) as described in general procedure F gave 5- {4- [2- (6-cyclohexylmethoxy-naphthalen-2-ylmethyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenyl }1, 2, 5] -thiadiazolidin-3-one-1, 1-dioxide.

LCMS：m/z 675(M+H)⁺；¹H NMR(DMSO-d₆，400MHz)：δ1.0-1.25(m，5H)，1.70-1.88(m，6H)，3.77(d，2H)，4.03(s，2H)，4.10(s，2H)，6.91(dd，1H)，6.97(d，2H)，7.04(s，1H)，7.15(d，2H)，7.27(d，2H)，7.41-7.51(m，3H)，7.55(d，1H)，7.67(s，1H)，8.19(d，1H)ppm。

Example 181

{4- [2- (4-bromo-benzyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenylamino } -acetic acid methyl ester (137mg, 0.25mmol) was coupled with 2-cyclohexylvinylboronic acid (59mg, 0.38mmol) according to general procedure G to give {4- [2- [4- (2-cyclohexyl-vinyl) -benzyl ] -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenylamino } -acetic acid methyl ester.

{4- [2- [4- (2-cyclohexyl-vinyl) -benzyl ] -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenylamino } -acetic acid methyl ester (60mg, 1mmol) was treated according to general procedure F to give 5- {4- [2- [4- (2-cyclohexyl-vinyl) -benzyl ] -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenyl } -1, 2, 5] -thiadiazolidin-3-one-1, 1-dioxide.

LCMS：m/z 621(M+H)⁺；¹H NMR(DMSO-d₆，400MHz)：δ0.84-0.86(m，2H)，1.11-1.29(m，5H)，1.69-1.89(m，5H)，4.01(s，2H)，4.04(s，2H)，6.19(dd，1H)，6.26(d，1H)，6.98(d，2H)，7.14(d，2H)，7.24(d，2H)，7.31(d，2H)，7.45(d，1H)，7.48(d，2H)，7.63(s，1H)，8.17(d，1H)ppm。

Example 182

4- (4, 4, 5, 5-tetramethyl- [1, 3, 2] dioxaborolan-2-yl) -benzaldehyde (3.48g, 15mmol) is converted to 2-cyclopentyl-1- [4- (4, 4, 5, 5-tetramethyl- [1, 3, 2] dioxaborolan-2-yl) -phenyl ] -ethanol using cyclopentylmethyl magnesium bromide following general procedure Z.

3- [2- (4-bromo-benzyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -aniline was prepared from 3-aminoacetanilide following general procedure M and then converted to 5- {3- [2- (4-bromo-benzyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide as described in general procedures E and F. Bromo-thiadiazolidin-one (100mg, 0.17mmol) was coupled with 2-cyclopentyl-1- [4- (4, 4, 5, 5-tetramethyl- [1, 3, 2] dioxaborolan-2-yl) -phenyl ] -ethanol according to general procedure G to give 5- {3- [2- [ 4' - (2-cyclopentyl-1-hydroxy-ethyl) -biphenyl-4-ylmethyl ] -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide.

LCMS：m/z 701(M+H)⁺；¹H NMR(DMSO-d₆，400MHz)：δ1.06-1.16(m，2H)，1.40-1.50(m，2H)，1.51-1.60(m，3H)，1.65-1.84(m，4H)，4.00(s，2H)，4.13(s，2H)，4.53(m，1H)，5.10(d，1H)，6.94(m，1H)，7.05(m，1H)，7.18(m，2H)，7.26(m，1H)，7.36(m，2H)，7.47(t，1H)，7.49(dd，1H)，7.52(m，2H)，7.56(m，2H)，7.65(d，1H)，7.94(s，1H)，8.19(d，1H)ppm。

Example 183

Reduction of 5- {3- [2- [4 '- (2-cyclopentyl-1-hydroxy-ethyl) -biphenyl-4-ylmethyl ] -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide (45mg, 64. mu. mol) according to general procedure AA gave 5- {3- [2- [ 4' - (2-cyclopentyl-ethyl) -biphenyl-4-ylmethyl ] -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide.

LCMS：m/z 685(M+H)⁺；¹H NMR(CD₃OD，400MHz)：δ1.08-1.20(m，2H)，1.47-1.57(m，2H)，1.58-1.68(m，4H)，1.75-1.86(m，3H)，2.64(t，2H)，4.17(s，2H)，4.21(s，2H)，6.83(m，1H)，7.07(m，2H)，7.15(m，1H)，7.21(m，2H)，7.28(m，1H)，7.34-7.48(m，7H)，7.73(s，1H)，8.01(d，1H)ppm。

Example 184

4-bromobenzaldehyde (4.26g, 23mmol) was converted to 4' - (4, 4-dimethyl-pent-1-enyl) phenylboronic acid using 3, 3-dimethylbutyl magnesium chloride following general procedure AE.

3- [2- (4-bromo-benzyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -aniline was prepared from 3-aminoacetanilide following general procedure M and then converted to 5- {3- [2- (4-bromo-benzyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenyl } -1, 1-dioxo-1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide as described in general procedures E and F. Bromo-thiadiazolidinone (50mg, 84 μmol) was coupled with 4 '- (4, 4-dimethyl-pent-1-enyl) phenylboronic acid according to general procedure G to give 5- (3- {4- (2, 4-dichloro-phenyl) -2- [ 4' - (4, 4-dimethyl-pent-1-enyl) -biphenyl-4-ylmethyl ] -imidazol-1-yl } -phenyl) -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide.

LCMS：m/z 685(M+H)⁺。

Example 185

4-bromobenzaldehyde was converted into 4- (4-methylpentyl) phenylboronic acid using 3-methylbutylgmagnesium bromide (1eq) following general procedure Y. The crude boronic acid was used below without purification.

{4- [2- (4-bromo-benzyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenylamino } -acetic acid methyl ester (500mg, 0.91mmol) was coupled with 4- (4-methylpentyl) phenylboronic acid according to general procedure G to give (4- {4- (2, 4-diamino-phenyl) -2- [ 4' - (4-methyl-pentyl) -biphenyl-4-ylmethyl ] -imidazol-1-yl } -phenylamino) -acetic acid methyl ester.

Treatment of (4- {4- (2, 4-dichloro-phenyl) -2- [4 '- (4-methyl-pentyl) -biphenyl-4-ylmethyl ] -imidazol-1-yl } -phenylamino) -acetic acid methyl ester (356mg, 0.57mmol) according to general procedure F afforded 5- (4- {4- (2, 4-dichloro-phenyl) -2- [ 4' - (4-methyl-pentyl) -biphenyl-4-ylmethyl ] -imidazol-1-yl } -phenyl) -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide.

LCMS：m/z 673(M+H)⁺；¹H NMR(DMSO-d₆，400MHz)：δ0.86(d，6H)，1.20(m，2H)，1.50-1.63(m，3H)，2.58(t，2H)，4.07(s，2H)，4.09(s，2H)，7.14-7.21(m，4H)，7.25(m，2H)，7.37(m，2H)，7.48(dd，1H)，7.51-7.56(m，4H)，7.64(d，1H)，7.90(s，1H)，8.20(d，1H)ppm。

Example 186

4- (4, 4, 5, 5-tetramethyl- [1, 3, 2] dioxaborolan-2-yl) -benzaldehyde (3.48g, 15mmol) is converted to 2-cyclopentyl-1- [4- (4, 4, 5, 5-tetramethyl- [1, 3, 2] dioxaborolan-2-yl) -phenyl ] -ethanol using cyclopentylmethyl magnesium bromide following general procedure Z.

Methyl {4- [2- (4-bromo-benzyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenylamino } -acetic acid (433mg, 0.79mmol) was coupled with 2-cyclopentyl-1- [4- (4, 4, 5, 5-tetramethyl- [1, 3, 2] dioxaborolan-2-yl) -phenyl ] -ethanol according to general procedure G to give {4- [2- [ 4' - (2-cyclopentyl-1-hydroxy-ethyl) -biphenyl-4-ylmethyl ] -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenylamino } -acetic acid methyl ester. The product benzyl alcohol is reduced according to general procedure AA and the reduced product base is treated according to general procedure F to give 5- {4- [2- [ 4' - (2-cyclopentyl-ethyl) -biphenyl-4-ylmethyl ] -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide.

LCMS：m/z 685(M+H)⁺；¹H NMR(CD₃OD，400MHz)：δ1.10-1.22(m，2H)，1.45-1.69(m，6H)，1.75-1.87(m，3H)，2.65(t，2H)，4.11(s，2H)，4.30(s，2H)，7.09(m，2H)，7.19-7.27(m，6H)，7.37(dd，1H)，7.44-7.49(m，5H)，7.69(s，1H)，8.02(d，1H)ppm。

Example 187

5- {3- [2- (4-bromo-benzyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide (59mg, 0.1mmol) was treated with trans-1-heptenylboronic acid (43mg, 0.3mmol) as described in general procedure G to give 5- {3- [4- (2, 4-dichloro-phenyl) -2- (4-hept-1-enyl-benzyl) -imidazol-1-yl ] -phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide.

LCMS：m/z 609(M+H)⁺；¹H NMR(DMSO-d₆，400MHz)：δ0.86(t，3H)，1.29(m，4H)，1.42(m，2H)，2.14(m，2H)，4.02(s，2H)，4.05(s，2H)，6.23(m，1H)，6.32(d，1H)，7.01(d，2H)，7.17(m，2H)，7.25(d，2H)，7.36-7.48(m，3H)，7.64(d，1H)，7.88(s，1H)，8.18(d，1H)ppm。

Example 188

Treatment of 5- {3- [2- (4-bromo-benzyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide (59mg, 0.1mmol) using trans-1-penten-1-ylboronic acid (34mg, 0.3mmol) as described in general procedure G gave 5- {3- [4- (2, 4-dichloro-phenyl) -2- (4-pent-1-enyl-benzyl) -imidazol-1-yl ] -phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide.

LCMS：m/z 581(M+H)⁺；¹H NMR(DMSO-d₆，400MHz)：δ0.90(t，3H)，1.43(m，2H)，2.13(m，2H)，4.02(s，2H)，4.05(s，2H)，6.22(m，1H)，6.32(d，1H)，7.01(d，2H)，7.17(m，2H)，7.25(d，2H)，7.36-7.48(m，3H)，7.64(d，1H)，7.88(s，1H)，8.18(d，1H)ppm。

Example 189

Treatment of 5- {3- [2- (4-bromo-benzyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide (59mg, 0.1mmol) using trans-3-phenyl-1-propen-1-ylboronic acid (49mg, 0.3mmol) as described in general procedure G gave 5- (3- {4- (2, 4-dichloro-phenyl) -2- [4- (3-phenyl-propenyl) -benzyl ] -imidazol-1-yl } -phenyl) -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide.

LCMS：m/z 629(M+H)⁺；¹H NMR(DMSO-d₆，400MHz)：δ3.49(d，2H)，4.02(s，2H)，4.04(s，2H)，6.37(m，1H)，6.42(d，1H)，7.01(d，2H)，7.17(m，2H)，7.20-7.36(m，9H)，7.47(dd，1H)，7.63(d，1H)，7.87(s，1H)，8.18(d，1H)ppm。

Example 190

Treatment of 5- {3- [2- (4-bromo-benzyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide (1.19g, 2mmol) using 2- (trimethylsilyl) ethoxymethylammonium (708 μ L, 4mmol) as described in general procedure L gave 5- {3- [2- (4-bromo-benzyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenyl } -1, 1-dioxo-2- (2-trimethylsilyl-ethoxymethyl) - [1, 2, 5] thiadiazolidin-3-one, which is then treated according to the general procedure AD to give 5- (3- {4- (2, 4-dichloro-phenyl) -2- [4- (4, 4, 5, 5-tetramethyl- [1, 3, 2] dioxaborolan-2-yl) -benzyl ] -imidazol-1-yl } -phenyl) -1, 1-dioxo-2- (2-trimethylsilyl-ethoxymethyl) - [1, 2, 5] thiadiazolidin-3-one.

LCMS：m/z 769(M+H)⁺。

Treatment of 5- (3- {4- (2, 4-dichloro-phenyl) -2- [4- (4, 4, 5, 5-tetramethyl- [1, 3, 2] dioxaborolan-2-yl) -benzyl ] -imidazol-1-yl } -phenyl) -1, 1-dioxo-2- (2-trimethylsilyl-ethoxymethyl) - [1, 2, 5] thiadiazolidin-3-one (385mg, 0.5mmol) with 3, 6-dichloropyridazine (149mg, 1mmol) as described in general procedure G gave 5- {3- [2- [4- (6-chloro-pyridazin-3-yl) -benzyl ] -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenyl } -1, 1-dioxo-2- (2-trimethylsilyl-ethoxymethyl) - [1, 2, 5] thiadiazolidin-3-one.

LCMS：m/z 756(M+H)⁺。

Treatment of 5- {3- [2- [4- (6-chloro-pyridazin-3-yl) -benzyl ] -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenyl } -1, 1-dioxo-2- (2-trimethylsilyl-ethoxymethyl) - [1, 2, 5] thiadiazolidin-3-one (38mg, 0.05mmol) using cyclohexanemethanol (31 μ L, 0.25mmol) as described in general procedure L gave 5- {3- [2- [4- (6-cyclohexylmethoxy-pyridazin-3-yl) -benzyl ] -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenyl } -1, 1-dioxo-2- (2-trimethylsilyl-ethoxymethyl) - [1, 2, 5] thiadiazolidin-3-one.

LCMS：m/z 833(M+H)⁺。

5- {3- [2- [4- (6-cyclohexylmethoxy-pyridazin-3-yl) -benzyl ] -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenyl } -1, 1-dioxo-2- (2-trimethylsilyl-ethoxymethyl) - [1, 2, 5] thiadiazolidin-3-one (17mg, 0.02mmol) was treated with tetrabutylammonium fluoride (26mg, 0.1mmol) as described in general procedure W to give 5- {3- [2- [4- (6-cyclohexylmethoxy-pyridazin-3-yl) -benzyl ] -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide.

LCMS：m/z 703(M+H)⁺；¹H NMR(CD₃OD，400MHz)：δ0.97-1.93(m，11H)，3.91(d，2H)，4.08(s，2H)，4.10(s，2H)，7.15-7.27(m，5H)，7.37(d，2H)，7.46-7.54(m，4H)，7.64(d，1H)，7.89(s，1H)，8.19(d，1H)ppm。

Example 191

Treatment of 5- {3- [2- [4- (6-chloro-pyridazin-3-yl) -benzyl using 1-cyclohexen-1-yl-boronic acid (51mg, 0.4mmol) as described in general procedure G]-4- (2, 4-dichloro-phenyl) -imidazol-1-yl]-phenyl } -1, 1-dioxo-2- (2-trimethylsilyl-ethoxymethyl) - [1, 2, 5]Thiadiazolidin-3-one (76mg, 0.1mmol) to give 5- {3- [2- [4- (6-cyclohex-1-enyl-pyridazin-3-yl) -benzyl]-4- (2, 4-dichloro-phenyl) -imidazol-1-yl]-phenyl } -1, 1-dioxo-2- (2-trimethylsilyl-ethoxymethyl) - [1, 2, 5]Thiadiazolidin-3-one, which is then dissolved in 1mL of dry acetic acid, iron powder (-325 mesh, 112mg, 2mmol) is added and the mixture is then heated at 100 ℃ for 2 days under a nitrogen atmosphere. Upon completion, the reaction mixture was then diluted with water/EtOAc and the excess remaining iron powder was washed with EtOAc. With water, saturated NaHCO₃And brine wash the combined organic layers. Then using Na₂SO₄The organic layer was dried, excess and the filtrate was concentrated and purified by silica gel chromatography to give 5- {3- [2- [4- (6-cyclohexyl-pyridazin-3-yl) -benzyl ] -benzyl]-4- (2, 4-dichloro-phenyl) -imidazol-1-yl]-phenyl } -1, 1-dioxo-2- (2-trimethylsilyl-ethoxymethyl) - [1, 2, 5]Thiadiazolidin-3-one.

LCMS：m/z 803(M+H)⁺。

Treatment of 5- {3- [2- [4- (6-cyclohexyl-pyridazin-3-yl) -benzyl ] -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenyl } -1, 1-dioxo-2- (2-trimethylsilyl-ethoxymethyl) - [1, 2, 5] thiadiazolidin-3-one (16mg, 0.02mmol) with tetrabutylammonium fluoride (26mg, 0.1mmol) as described in general procedure W gave 5- {3- [2- [4- (6-cyclohexyl-pyridazin-3-yl) -benzyl ] -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide.

LCMS：m/z 673(M+H)⁺；¹H NMR(CD₃OD，400MHz)：δ1.14-1.77(m，10H)，2.53(m，1H)，4.06(s，2H)，4.09(s，2H)，7.15-7.27(m，5H)，7.37(d，2H)，7.46-7.54(m，4H)，7.64(d，1H)，7.89(s，1H)，8.18(d，1H)ppm。

Example 192

Treatment of 5- {3- [2- (4-bromo-benzyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide (59mg, 0.1mmol) using 4-methyl-1-pentenylboronic acid (39mg, 0.3mmol) as described in general procedure G gave 5- (3- {4- (2, 4-dichloro-phenyl) -2- [4- (4-methyl-pent-1-enyl) -benzyl ] -imidazol-1-yl } -phenyl) -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide.

LCMS：m/z 595(M+H)⁺；¹H NMR(DMSO-d₆，400MHz)：δ0.89(d，6H)，1.68(m，1H)，2.03(q，2H)，4.02(s，2H)，4.05(s，2H)，6.22(m，1H)，6.32(d，1H)，7.01(d，2H)，7.17(m，2H)，7.25(d，2H)，7.36-7.48(m，3H)，7.64(d，1H)，7.88(s，1H)，8.18(d，1H)ppm。

Example 193

To a solution of 2-heptyne (129. mu.L, 1mmol) in 2mL dry THF at 0 deg.C was added 2mL of a 0.5M solution of 9-BBN in THF. The resulting solution was stirred at room temperature under nitrogen for 4 hours. It was then condensed in vacuo and used as the boronic acid derivative according to general procedure G, reacted with 5- {3- [2- (4-bromo-benzyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide (119mg, 0.2mmol) to give 5- (3- {4- (2, 4-dichloro-phenyl) -2- [4- (1-methyl-hex-1-enyl) -benzyl ] -imidazol-1-yl } -phenyl) -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide.

LCMS：m/z 609(M+H)⁺；¹H NMR(DMSO-d₆，400MHz)：δ0.90(t，3H)，1.29-1.40(m，4H)，1.93(d，3H)，2.13(m，2H)，4.02(s，2H)，4.05(s，2H)，5.77(m，1H)，7.01(d，2H)，7.17(m，2H)，7.25(d，2H)，7.36-7.48(m，3H)，7.64(d，1H)，7.88(s，1H)，8.18(d，1H)ppm。

Example 194

Treatment of 5- {3- [2- (4-bromo-benzyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide (59mg, 0.1mmol) using 5-methyl-1-hexenylboronic acid (43mg, 0.3mmol) as described in general procedure G gave 5- (3- {4- (2, 4-dichloro-phenyl) -2- [4- (5-methyl-hex-1-enyl) -benzyl ] -imidazol-1-yl } -phenyl) -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide.

LCMS：m/z 609(M+H)⁺；¹H NMR(DMSO-d₆，400MHz)：δ0.89(d，6H)，1.31(m，2H)，1.53(m，1H)，2.16(m，2H)，4.02(s，2H)，4.05(s，2H)，6.22(m，1H)，6.33(d，1H)，7.01(d，2H)，7.17(m，2H)，7.25(d，2H)，7.36-7.48(m，3H)，7.64(d，1H)，7.88(s，1H)，8.18(d，1H)ppm。

Example 195

To a solution of 3-cyclohexyl-1-propyne (145. mu.L, 1mmol) in 2mL dry THF at 0 deg.C was added 2mL of a 0.5M solution of 9-BBN in THF. The resulting solution was stirred at room temperature under nitrogen for 4 hours. It was then condensed in vacuo and used as the boronic acid derivative according to general procedure G, which was reacted with 5- {3- [2- (4-bromo-benzyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide (119mg, 0.2mmol) to give 5- {3- [2- [4- (3-cyclohexyl-propenyl) -benzyl ] -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide.

LCMS：m/z 635(M+H)⁺；¹H NMR(DMSO-d₆，400MHz)：δ0.87-1.71(m，11H)，2.05(m，2H)，4.02(s，2H)，4.05(s，2H)，6.21(m，1H)，6.30(d，1H)，7.01(d，2H)，7.17(m，2H)，7.25(d，2H)，7.36-7.48(m，3H)，7.64(d，1H)，7.88(s，1H)，8.18(d，1H)ppm。

Biological assay

The following assay method was used to identify compounds of formula 1 that are effective in inhibiting certain phosphatase activities, an example of which is PTP1B, as used herein.

PTP1B assay

The assay for PTP1B is based on the detection of a complex of malachite green dye with free phosphate released from a phosphopeptide substrate by the action of PTPase. To each well of the flat bottom assay plate was added 45. mu.L of assay buffer [ -50mM imidazole, pH 7.2, 100mM NaCl, 5mM DTT and 1mM EDTA]And 10. mu.L of peptide substrate (tyrosine phosphopeptide-1, END: (A))_pY) inadl (seq id NO: 1) 80 μ M FAC, Promega Cat # V256A) to a total volume of 55 μ L. Test compounds (10 μ L in up to 50% DMSO) were then added. The mixture was incubated at 25 ℃ for 5 minutes and then 10. mu.L of PTP-1B (protein tyrosine phosphatase 1B (PTP-1B); FAC 0.8 nM; BIOMOL-SE332) was added. The mixture was incubated at 25 ℃ for 30 minutes. Subsequently, 25. mu.L of malachite green reagent (10% (w/v) ammonium molybdate in water, Sigma Cat # A-7302, 0.2% (w/v) ammonium molybdate in 4N HCl, Aldrich Cat #21, 302-0) was added. After incubation at 27 ℃ for 15 min, the end of the reaction was determined at 640 nM.

Malachite green reagent was prepared by mixing 1 volume of 10% ammonium molybdate with 3 volumes of 0.2% malachite green solution, stirring at room temperature for 30 minutes and then filtering and collecting the filtrate. Malachite green reagent was treated with 10. mu.L of 5% Tween 20/990. mu.L dye solution prior to use.

Test compounds were tested at 8 concentrations in the above assay. For the present assay, the IC50(μ M) of the enzyme inhibition assay represents the concentration of compound at which 50% of the signal is inhibited. The compounds of formula I in Table I inhibit PTP-IB with IC50 below 10. mu.M.

While the present invention has been described and illustrated with reference to certain embodiments thereof, those skilled in the art will appreciate that various changes, modifications and substitutions can be made therein without departing from the spirit and scope of the present invention. For example, an effective dose other than the doses listed herein is appropriate as a result of a change in responsiveness of the subject to treatment of a PTPase-mediated disease. Likewise, the specific pharmacological responses observed may vary according to and depending upon the particular active compound selected or whether a pharmaceutically acceptable carrier is present or not and the type of formulation and mode of administration employed, and such expected variations or differences in the results are contemplated as being of interest in the objects and practice of the present invention.

Claims (18)

1. A compound of formula IIe:

wherein

R²³，R²⁴，R²⁵，R²⁶And R²⁷Independently selected from: hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, 1-ethyl-propyl, 1-propyl-butyl, 3, 3-dimethyl-butyl, 4-methylThe group-pentyl, 4, 4-dimethyl-pentyl, 1- (3, 3-dimethyl-butyl) -4, 4-dimethyl-pentyl, isobutyl, isopropyl, sec-butyl, tert-butyl, trifluoromethyl, 4, 4, 4-trifluorobutoxy, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, isobutoxy, isopropoxy, tert-butoxy, 2-phenethyloxy, 2, 2-dimethylpropoxy, 3-methyl-butoxy, 3, 3-dimethyl-butoxy, 2-cyclohexyl-ethanesulfonyl, 3, 3-dimethyl-butane-1-sulfonyl, cyclohexanesulfonyl, cyclohexylmethanesulfonyl, 2-cyclohexyl-ethanesulfinyl, 3, 3-dimethyl-butane-1-sulfinyl, cyclohexylmethylsulfinyl, 2-cyclohexyl-ethylsulfanyl, 3, 3-dimethyl-butylsulfanyl, phenethylsulfanyl, cyclohexylmethylsulfanyl, cyclopentyl, cyclohexyl, cyclopentyloxy, cyclohexyloxy, cyclopentylmethyl, cyclohexylmethyl, 2-cyclopentylethyl, 2-cyclohexylethyl, cyclopentylmethoxy, cyclohexylmethoxy, 2-cyclopentylethoxy, 2-cyclohexylethoxy, 2-cyclohexyl-vinyl, 3-ethyl-cyclobutyl, chlorine, fluorine and phenyl,

wherein R is²³，R²⁴，R²⁵，R²⁶And R²⁷At least one of which is not hydrogen;

m is hydrogen or Na⁺，K⁺And other pharmaceutically acceptable counterions;

or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein M is hydrogen.

3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein M is sodium or potassium.

4. The compound of claim 1, wherein the compound is selected from the group consisting of:

5- {3- [2- (4' -tert-butyl-biphenyl-4-ylmethyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide;

5- {3- [2- (3' -cyclohexylmethoxy-biphenyl-4-ylmethyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide;

5- {3- [4- (2, 4-dichloro-phenyl) -2- (3' -phenethyloxy-biphenyl-4-ylmethyl) -imidazol-1-yl ] -phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide;

5- (3- {4- (2, 4-dichloro-phenyl) -2- [ 3' - (3, 3-dimethyl-butylsulfanyl) -biphenyl-4-ylmethyl ] -imidazol-1-yl } -phenyl) -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide;

5- (3- {4- (2, 4-dichloro-phenyl) -2- [ 3' - (3, 3-dimethyl-butane-1-sulfonyl) -biphenyl-4-ylmethyl ] -imidazol-1-yl } -phenyl) -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide;

5- {3- [2- (3' -cyclohexylmethylsulfanyl-biphenyl-4-ylmethyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide;

5- {3- [2- (3' -cyclohexylmethylsulfonyl-biphenyl-4-ylmethyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide;

5- {3- [2- (3' - (2-cyclohexyl-ethylsulfanyl) -biphenyl-4-ylmethyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide;

5- {3- [2- (3' - (2-cyclohexyl-ethanesulfonyl) -biphenyl-4-ylmethyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide;

5- (3- {4- (2, 4-dichloro-phenyl) -2- [ 4' - (3, 3-dimethyl-butoxy) -biphenyl-4-ylmethyl ] -imidazol-1-yl } -phenyl) -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide;

5- (3- {4- (2, 4-dichloro-phenyl) -2- [ 4' - (3, 3-dimethyl-butylsulfanyl) -biphenyl-4-ylmethyl ] -imidazol-1-yl } -phenyl) -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide;

5- {3- [2- (4' -cyclohexylmethylsulfanyl-biphenyl-4-ylmethyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide;

5- {3- [2- (4' -cyclohexylmethanesulfonyl-biphenyl-4-ylmethyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide;

5- {3- [2- [ 4' - (2-cyclohexyl-ethoxy) -biphenyl-4-ylmethyl ] -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide;

5- {3- [2- [ 4' - (2-cyclohexyl-ethyl) -biphenyl-4-ylmethyl ] -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide; and

5- (3- {4- (2, 4-dichloro-phenyl) -2- [ 4' - (4, 4-dimethyl-pent-1-enyl) -biphenyl-4-ylmethyl ] -imidazol-1-yl } -phenyl) -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide;

or a pharmaceutically acceptable salt thereof.

5. The compound of claim 1, wherein the compound is

5- {3- [2- (4' -cyclohexyl-biphenyl-4-ylmethyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide or a pharmaceutically acceptable salt thereof.

6. The compound of claim 5 wherein the compound is 5- {3- [2- (4' -cyclohexyl-biphenyl-4-ylmethyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide.

7. The compound of claim 5 wherein the compound is the sodium or potassium salt of 5- {3- [2- (4' -cyclohexyl-biphenyl-4-ylmethyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide.

8. The compound of claim 1, wherein the compound is

5- (3- {4- (2, 4-dichloro-phenyl) -2- [ 3' - (3, 3-dimethyl-butoxy) -biphenyl-4-ylmethyl ] -imidazol-1-yl } -phenyl) -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide or a pharmaceutically acceptable salt thereof.

9. The compound of claim 8 wherein the compound is 5- (3- {4- (2, 4-dichloro-phenyl) -2- [ 3' - (3, 3-dimethyl-butoxy) -biphenyl-4-ylmethyl ] -imidazol-1-yl } -phenyl) -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide.

10. The compound of claim 8 wherein the compound is a sodium or potassium salt of 5- (3- {4- (2, 4-dichloro-phenyl) -2- [ 3' - (3, 3-dimethyl-butoxy) -biphenyl-4-ylmethyl ] -imidazol-1-yl } -phenyl) -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide.

11. The compound of claim 1, wherein the compound is

5- {3- [2- (4' -cyclohexylmethoxy-biphenyl-4-ylmethyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide or a pharmaceutically acceptable salt thereof.

12. The compound of claim 11 wherein the compound is 5- {3- [2- (4' -cyclohexylmethoxy-biphenyl-4-ylmethyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide.

13. The compound of claim 11 wherein the compound is the sodium or potassium salt of 5- {3- [2- (4' -cyclohexylmethoxy-biphenyl-4-ylmethyl) -4- (2, 4-dichloro-phenyl) -imidazol-1-yl ] -phenyl } -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide.

14. A pharmaceutical composition comprising a compound of any one of claims 1-13, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, excipient, or mixture thereof.

15. The pharmaceutical composition of claim 14 in the form of an oral dosage form.

16. The pharmaceutical composition of claim 14 in the form of a parenteral dosage form.

17. The use of a compound according to any one of claims 1 to 13 in the manufacture of a medicament for the treatment of a disease selected from: glucose intolerance, type I diabetes, type II diabetes, immune dysfunction, cancer, infectious disease, diseases in which growth hormone synthesis is implicated is modulated, including diseases in which at least one growth factor or cytokine synthesis that affects growth hormone production is modulated, and alzheimer's disease.

18. The use of claim 17, wherein the disease is type II diabetes.