Antagonists for treatment of CD/11CD18 adhesion receptor mediated disorders

• US 20050203135A1
• Filed: 08/26/2003
• Published: 09/15/2005
• Est. Priority Date: 03/27/1998
• Status: Abandoned Application

• Current Assignee: Genentech, Inc. (Roche Holding AG)
• Original Assignee: Genentech, Inc. (Roche Holding AG)
• Inventors: Stanley, Mark S., Reynolds, Mark, Oare, David, Burdick, Daniel J., McDowell, Robert S., Gadek, Thomas R., Weese, Kenneth J., Marsters, James C.
• Application Number:
  US10/649,762
• Publication Number:
  US 20050203135A1
• Time in Patent Office: Days
• US Class Current: 514/317
• CPC Class Codes: A61K 31/166 having the carbon of a carboxamide group directly attached to the aromatic ring, e.g. procainamide, procarbazine, metoclopramide, labetalol
• CPC Class Codes: A61K 31/18 Sulfonamides compounds containing a para-N-benzene-sulfonyl-N- group A61K31/63
• CPC Class Codes: A61K 31/341 not condensed with another ring, e.g. ranitidine, furosemide, bufetolol, muscarine
• CPC Class Codes: A61K 31/343 condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
• CPC Class Codes: A61K 31/36 Compounds containing methylenedioxyphenyl groups, e.g. sesamin
• CPC Class Codes: A61K 31/381 having five-membered rings
• CPC Class Codes: A61K 31/40 having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
• CPC Class Codes: A61K 31/404 Indoles, e.g. pindolol
• CPC Class Codes: A61K 31/415 1,2-Diazoles
• CPC Class Codes: A61K 31/4164 1,3-Diazoles
• CPC Class Codes: A61K 31/4192 1,2,3-Triazoles
• CPC Class Codes: A61K 31/433 Thidiazoles
• CPC Class Codes: A61K 31/445 Non condensed piperidines, e.g. piperocaine
• CPC Class Codes: A61K 31/4458 only substituted in position 2, e.g. methylphenidate
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/02 : Immunomodulators
• CPC Class Codes: A61P 37/04 : Immunostimulants
• CPC Class Codes: A61P 37/06 : Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 37/08 : Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Abstract

Compounds of the general structure D-L-B-(AA), for example (A), that are useful for treating Mac-1 or LFA-1-mediated disorders such as inflammatory disorders, allergies, and autoimmune diseases are provided.

Claims

1. ) A compound represented by structural formula (I)

2. ) The compound of claim 1 wherein

D is an aromatic homocycle or aromatic heterocycle containing 1-3 heteroatoms selected from the group N, S and O, the homo- or heterocycles selected from the group

where

Y¹, Y², Y³, Y⁴ and Y⁵ are selected from the group CH, CR^d and N,

Z¹ is selected from the group O, S, N and NR,

n is 0-3,

R^d is selected from the group

OH, OCF₃, OR^c, SR^m, halo(F, Cl. Br, I), CN, isocyanate, NO₂, CF₃, C₀-C₆alkyl-NRⁿR^n′

, C₀-C₆alkyl-C(═

O)—

NRⁿR^n′

, C₀-C₆alkyl-C(═

O)—

R^a, C₁-C₈alkyl, C₁-C₈alkoxy, C₂-C₈alkenyl C₂-C₈alkynyl, C₃-C₆cycloalkyl, C₃-C₆cycloalkenyl, C₁-C₆alkyl-phenyl, phenyl-C₁-C₆alkyl, C₁-C₆alkyloxycarbonyl, phenyl-C₀-C₆alkyloxy, C₁-C₆alkyl-het, het-C₁-C₆alkyl, SO₂-het, —

O—

C₆-C₁₂aryl, —

SO₂—

C₆-C₁₂aryl, —

SO₂—

C₁-C₆alkyl and het, where any alkyl, alkenyl or alkynyl may optionally be substituted with 1-3 groups selected from OH, halo(F, Cl, Br, I), nitro, amino and aminocarbonyl and the substituents on any aryl or het are 1-2 hydroxy, halo(F, Cl, Br, I), CF₃, C₁-C₆alkyl, C₁-C₆alkoxy, nitro and amino;

R^a is R^a′

or R^a″

subsitiuted with 1-3 R^a′

;

where

R^a′

is selected from the group

hydrogen, halo(F. Cl, Br, I), cyano, isocyanate, carboxy, carboxy-C₁-C₁₁alkyl, amino, amino-C₁-C₈alkyl, aminocarbonyl, carboxamido, carbamoyl, carbamoyloxy, formyl, formyloxy, azido, nitro, imidazoyl, ureido, thioureido, thiocyanato, hydroxy, C₁-C₆alkoxy, mercapto, sulfonamido, het, phenoxy, phenyl, benzamido, tosyl, morpholino, morpholinyl, piperazinyl, piperidinyl, pyrrolinyl. imidazolyl and indolyl;

R^a″

is selected from the group

C₀-C₁₀alkyl-Q-C₀-C₆alkyl, C₀-C₁₀alkenyl-Q-C₀-C₆alkyl C₀-C₁₀alkynyl-Q-C₀-C₆ alkyl, C₃-C₁₁cycloalkyl-Q-C₀-C₆alkyl, C₃-C₁₀cycloalkenyl-Q-C₀-C₆alkyl, C₁-C₆alkyl-C₆-C₁₂ aryl-Q-C₀-C₆alkyl, C₆-C₁₀ aryl-C₁-C₆alkyl-Q-C₀-C₆ alkyl, C₀-C₆alkyl-het-Q-C₀-C₆alkyl, C₀-C₆ alkyl-Q-het-C₀-C₆alkyl, het-C₀-C₆alkyl-Q-C₀-C₆alkyl, C₀-C₆alkyl-Q-C₆-C₁₂aryl and -Q-C₁-C₆alky;

Q is absent or is selected from the group

—

O—

, —

S(O)_s—

, —

SO₂—

N(Rⁿ), —

N(Rⁿ)—

SO₂—

, —

N(Rⁿ)—

C(═

O)—

, —

C(═

O)—

N(Rⁿ), —

N(Rⁿ)—

C(═

O)O, —

O—

C(═

O)—

N(Rⁿ)—

, —

N(Rⁿ)—

C(═

O)—

N(Rⁿ)—

, —

C(═

O)—

, —

N(Rⁿ)—

, —

C(═

O)—

O—

, —

O—

C(═

O)—

, -het-, —

PO(OR^c)O— and

—

P(O)O—

, where s is 0-2;

het is a mono- or bicyclic 5, 6, 7, 9 or 10 member heterocyclic ring, each ring containing 1-4 heteroatoms selected from N, O and S, where the heterocyclic ring may be saturated, partially saturated, or aromatic and any N or S being optionally oxidized, the heterocyclic ring being substituted with 0-3 hydroxy, halo(F, Cl, Br, I), CF₃, C₁-C₆alkyl, C₁-C₆alkoxy, nitro and amino;

R^c is selected from hydrogen and substituted or unsubstituted C₁-C₁₀alkyl, C₂-C₁₀alkenyl, C₂-C₁₀alkynyl, C₃-C₁₁cycloalkyl, C₃-C₁₀cycloalkenyl, C₁-C₆alkyl-C₆-C₁₂aryl, C₆-C₁₀aryl-C₁-C₆alkyl, C₁-C₆alkyl-het, het-C₁-C₆alkyl, C₆-C₁₂aryl and het, where the substituents are 1-3 hydroxy, halo(F, Cl, Br, I), CF₃, C₁-C₆alkyl, C₁-C₆alkoxy, nitro and amino;

R^m is selected from

S—

C₁-C₆alkyl, C(═

O)—

C₁-C₆alkyl, C(═

O)—

NRⁿR^n′

, C₁-C₆ alkyl, halo(F, Cl, Br, f)-C₁-C₆alkyl, benzyl and phenyl;

Rⁿ is selected from the group

R^c, NH—

C(═

O)—

O—

R^c, NH—

C(═

O)—

R^c, NH—

C(═

O)—

NHR^c, NH—

SO₂—

R^s, NH—

SO₂—

NH—

C(═

O)—

R^c, NH—

C(═

O)—

NH—

SO₂—

R^s, C(═

O)O—

R^c, C(═

O)—

R^c, C(═

O)—

NHR^c, C(═

O)—

NH—

C(═

O)—

O—

R^c, C(═

O)—

NH—

C(═

O)—

R^c, C(═

O)—

NH—

SO₂—

R^s, C(═

O)—

NH—

SO₂—

NHR^s, SO₂—

R^s, SO₂—

O—

R^s, SO₂—

N(R^c)₂, SO₂—

NH—

C(═

O)—

O—

R^c, SO₂—

NH—

C(═

O)—

O—

R^c and SO₂—

NH—

C(═

O)—

R^c;

R^n′

is selected from hydrogen, hydroxy and substituted or unsubstituted

C₁-C₁₁alkyl, C₁-C₁₁alkoxy, C₂-C₁₀alkenyl, C₂-C₁₀alkynyl, C₃-C₁₁cycloalkyl, C₃-C₁₀cycloalkenyl, C₁-C₆alkyl-C₆-C₁₂aryl, C₆-C₁₀aryl-C₁-C₆alkyl, C₆-C₁₀ aryl-C₀-C₆alkyloxy, C₁-C₆alkyl-het, het-C₁-C₆alkyl, C₆-C₁₂aryl, het, C₁-C₆alkylcarbonyl, C₁-C₈alkoxycarbonyl, C₃-C₈cycloalkylcarbonyl, C₃-C₈cycloalkoxycarbonyl, C₆-C₁₁aryloxycarbonyl, C₇-C₁₁arylalkoxycarbonyl, heteroarylalkoxycarbonyl, heteroarylalkylcarbonyl, heteroarylcarbonyl, heteroarylalkylsulfonyl, heteroarylsulfonyl, C₁-C₆alkylsulfonyl and C₆-C₁₀arylsulfonyl, where any alkyl, alkenyl or alkynyl may optionally be substituted with 1-3 groups selected from OH, halo(F, Cl, Br, I), nitro, amino and aminocarbonyl and the substituents on any aryl, heteroaryl or het are 1-2 hydroxy, halo(F, Cl, Br, I), CF₃, C₁-C₆alkyl, C₁-C₆alkoxy, nitro and amino;

Rⁿ and R^n′

taken together with the common nitrogen to which they are attached may from an optionally substituted heterocycle selected from morpholinyl, piperazinyl, thiamorpholinyl, pyrrolidinyl, imidazolidinyl, indolinyl, isoindolinyl, 1,2,3,4-tetrahydro-quinolinyl, 1,2,3,4-tetrahydro-isoquinolinyl, thiazolidinyl and azabicyclononyl, where the substituents are 1-3 hydroxy, halo(F, Cl, Br, I), CF₃, C₁-C₆alkyl, C₁-C₆alkoxy, nitro and amino;

R^s is a substituted or unsubstituted group selected from

C₁-C₈ alkyl, C₂-C₈alkenyl, C₂-C₈alkynyl, C₃-C₈cycloalkyl, C₃-C₆cycloalkenyl, C₀-C₆ alky-phenyl, phenyl-C₀-C₆alkyl, C₀-C₆alkyl-het and het-C₀-C₆alkyl, where the substituents are 1-3 hydroxy, halo(F, Cl, Br, I), CF₃, C₁-C₆alkyl, C₁-C₆alkoxy, nitro and amino;

L is selected from the group

—

(CR⁶R^6′

)_o-Ai-(CR⁸R^8′

)_p—

, —

(CR⁶R^6′

)-het-(CR⁸R^8′

)_p—

, —

(CR⁶═

CR⁷)_q-Ai-(CR⁸R^8′

)_p— and

—

(CR⁶R^6′

)_o-Ai-(CR⁸═

CR⁹)_r—

,

where Ai is selected from

where o is 0-1, p is 0-1, q is 0-1 and r is 0-1;

R¹, R^1′

, R², R^2′

, R³, R^3′

, R⁶, R^6′

, R⁷, R⁸, R^8′

and R⁹ each are independently selected from R^a, R^c and U-W;

U is an optionally substituted bivalent radical selected from the group

C₁-C₆alkyl-, C₀-C₆alkyl-Q-, C₂-C₆alkenyl-Q-, and C₂-C₆alkynyl-Q-, where the substituents on any alkyl, alkenyl or alkynyl are 1-3 R^a;

W is selected from the group

hydrogen, OH, O—

C₁-C₆alkyl, SH, SR^m, NRⁿR^n′

, NH—

C(═

O)—

O—

R^c, NH—

C(═

O)—

NRⁿR^n′

, NH—

C(═

O)—

R^c, NH—

SO₂—

R^s, NH—

SO₂—

NRⁿR^n′

, NH—

SO₂—

NH—

C(═

O)—

R^c, NH—

C(═

O)—

NH—

SO₂—

R^s, C(═

O)—

NH—

C(═

O)—

O—

R^c, C(═

O)—

NH—

C(═

O)—

NRⁿR^n′

, C(═

O)—

NH—

SO₂—

R^s, C(═

O)—

NH—

SO₂—

NRⁿR^n′

, C(═

S)—

NRⁿR^n′

, SO₂—

R^s, SO₂—

O—

R^s, SO₂—

NRⁿR^n′

, SO₂—

NH—

C(═

O)—

O—

R^c, SO₂—

NH—

C(═

O)—

NRⁿR^n′

, SO₂—

NH—

C(═

C)—

R^c, O—

C(═

O)—

NRⁿR^n′

, O—

C(═

O)—

R^c, O—

C(═

O)—

NH—

C(═

O)—

R^c, O—

C(═

O)—

NH—

SO₂—

R^s and O—

SO₂—

R^s;

G is hydrogen;

T is U-W;

R is C(═

O)—

OH and

pharmaceutically acceptable salts thereof.

3. ) The compound of claim 2 wherein D is selected from a 5-member aromatic heterocycle selected from the group

a 9-member aromatic heterobicycle selected from the group

a 6-member aromatic hetero- or homocycle selected from the group

L is a bivalent linking group selected from the group

—

C₃-C₅-alkyl-,

—

C₃-C₅-alkenyl-,

—

CH₂C(═

O)NH—

,

—

CH₂NH—

C(═

O)—

,

—

O—

CH₂—

C(═

O)—

,

—

CH₂—

CH₂—

C(═

O)—

,

—

CH═

CH—

C(═

O)NH—

CH₂—

,

—

CH═

CH—

C(═

O)NH—

CH—

(CH₃)—

,

—

CH(OH)—

CH₂—

O—

,

—

CH(OH)—

CH₂—

CH₂—

,

—

CH₂—

CH₂—

CH(OH)—

,

—

O—

CH₂—

CH(OH)—

,

—

O—

CH₂—

CH(OH)—

CH₂,

—

O—

CH₂—

CH₂—

CH(OH)—

,

—

O—

CH₂—

CH₂—

O—

,

—

CH₂—

CH₂—

CH₂—

O—

,

—

CH₂—

CH(OH)—

CH₂—

O—

,

—

CH₂—

CH₂—

O—

,

—

CH—

(CH₃)—

NH—

C(═

O)—

,

—

CH₂—

NH—

SO₂—

,

—

NH—

SO₂—

CH₂—

,

—

CH₂—

SO₂NH—

,

—

SO₂NH—

CH₂—

,

—

C(═

O)—

NH—

C(═

O)—

,

—

NH—

C(═

O)—

NH—

,

—

NH—

C(═

O)—

NH—

CH₂—

,

—

CH₂—

NH—

C(═

O)—

NH—

,

—

C(═

O)—

NH—

CH₂—

C(═

O)—

NH—

,

—

NH—

C(═

O)—

O— and

—

O—

C(═

O)—

NH—

, and pharmaceutically acceptable salts thereof.

4. ) The compound of claim 3 wherein the compound is represented by

5. ) The compound of claim 4 wherein

Y², Y³ and Y⁴ are selected from CH and CR^d;

Z¹ is selected from NRⁿ, O and S;

n is 0-3;

R¹, R² and R³ each are independently R^a;

R^a is R^a′

or R^a″

substituted with 1-3 R^a′

;

where

R^a′

is selected from the group

hydrogen, halo(F. Cl, Br, I), cyano, carboxy, carboxy, amino, amino, aminocarbonyl, carboxamido, carbamoyl, carbamoyloxy, formyl, formyloxy, azido, nitro, imidazoyl, ureido, thioureido, thiocyanato, hydroxy, C₁-C₆alkoxy, mercapto, sulfonamido, phenoxy, phenyl, benzamido, morpholino, morpholinyl, piperazinyl, piperidinyl, pyrrolinyl. imidazolyl and indolyl;

R^a″

is hydrogen or a substituted or unsubstituted group selected from

C₀-C₁₀alkyl-het, C₁-C₁₀alkyl, C₂-C₁₀alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₁cycloalkyl, C₃-C₁₀cycloalkenyl-C₀-C₆alkyl, C₁-C₆alkyl-C₆-C₁₂aryl and C₆-C₁₀aryl-C₁-C₆alkyl, where the substituits are 1-3 hydroxy, halo(F, Cl, Br, I), CF₃, C₁-C₆alkyl, C₁-C₆alkoxy, nitro and amino;

R^d is selected from the group

OH, OCF₃, OR^a″

, SR^m, halo(F, Cl. Br, I), CN, NO₂, CF₃, C₀-C₆alkyl-C(═

O)—

R^a, C₁-C₈alkyl, C₁-C₈alkoxy, C₂-C₈alkenyl, C₂-C₈alkynyl, C₃-C₆cycloalkyl, phenyl-C₁-C₆alkyl, C₁-C₆alkyloxycarbonyl, —

O—

C₆-C₁₂aryl and —

SO₂—

C₆-C₁₂aryl, where any alkyl, alkenyl or alkynyl may optionally be substituted with 1-3 groups selected from OH, halo(F, Cl, Br, I), nitro, amino and aminocarbonyl and the substituents on any aryl or het are 1-2 hydroxy, halo(F, Cl, Br, I), CF₃, C₁-C₆alkyl, C₁-C₆alkoxy, nitro and amino;

R^m is selected from

S—

C₁-C₆alkyl, C(═

O)—

C₁-C₆alkyl, C(═

O)—

NH₂, C₁-C₆alkyl, halo(F, Cl, Br, I)-C₁-C₆alkyl, benzyl and phenyl;

Rⁿ is selected from the group

R^a′

, NH—

C(═

O)—

O—

R^a″

, NH—

C(═

O)—

R^a″

, NH—

C(═

O)—

NHR^a″

, NH—

SO₂—

R^s, NH—

SO₂—

NH—

C(═

O)—

R^a″

, NH—

C(═

O)—

NH—

SO₂—

R^s, C(═

O)—

O—

R^a″

, C(═

O)R^a″

, C(═

O)—

NHR^a″

, C(═

O)—

NH—

C(═

O)—

O—

R^a″

, C(═

O)—

NH—

C(═

O)—

R^a″

, C(═

O)—

NH—

SO₂—

R^s, C(═

O)—

NH—

SO₂—

NHR^s, SO₂—

R^s, SO₂—

O—

R^s, SO₂—

N(R)₂, SO₂—

NH—

C(═

O)—

O—

R^a″

, SO₂—

NH—

C(═

O)—

O—

R^a″

and SO₂—

NH—

C(═

O)—

R^a″

;

R^n′

is selected from hydrogen, hydroxy and substituted or unsubstituted

C₁-C₁₁alkyl, C₁-C₁₁ alkoxy, C₂-C₁₀alkenyl, C₂-C₁₀alkynyl, C₃-C₁₁cycloalkyl, C₃-C₁₀ cycloalkenyl, C₁-C₆ alkyl-C₆-C₁₂ aryl, C₆-C₁₀ aryl-C₁-C₆alkyl, C₆-C₁₀ayl-C₀-C₆alkyloxy, C₁-C₆alkyl-het, het-C₁-C₆alkyl, C₆-C₁₂aryl, het, C₁-C₆alkylcarbonyl, C₁-C₈alkoxycarbonyl, C₃-C₈cycloalkylcarbonyl, C₃-C₈cycloalkoxycarbonyl, C₆-C₁₁aryloxycarbonyl, C₇-C₁₁ arylalkoxycarbonyl, heteroarylalkoxycarbonyl, heteroarylalkylcarbonyl, heteroarylcarbonyl, heteroarylalkylsulfonyl, heteroarylsulfonyl, C₁-C₆alkylsulfonyl and C₆-C₁₀arylsulfonyl, where any alkyl, alkenyl or alkynyl may optionally be substituted with 1-3 groups selected from OH, halo(F, Cl, Br, I), nitro, amino and aminocarbonyl and the substituents on any aryl, heteroaryl or het are 1-2 hydroxy, halo(F, Cl, Br, I), CF₃, C₁-C₆alkyl, C₁-C₆alkoxy, nitro and amino;

Rⁿ and R^n′

taken together with the common nitrogen to which they are

attached may from an optionally substituted heterocycle selected from morpholinyl, piperazinyl, thiamorpholinyl, pyrrolidinyl, imidazolidinyl, indolinyl, isoindolinyl, 1,2,3,4-tetrahydro-quinolinyl, 1,2,3,4-tetrahydro-isoquinolinyl, thiazolidinyl and azabicyclononyl, where the substituits are 1-3 hydroxy, halo(F, Cl, Br, I), CF₃, C₁-C₆alkyl, C₁-C₆alkoxy, nitro and amino;

R^s is a substituted or unsubstituted group selected from

C₁-C₈alkyl, C₂-C₈alkenyl, C₂-C₈alkynyl, C₃-C₈cycloalkyl, C₃-C₆cycloalkenyl, C₀-C₆alkyl-phenyl, phenyl-C₀-C₆alkyl, C₀-C₆alkyl-het and het-C₀-C₆alkyl, where the substituits are 1-3 hydroxy, halo(F, Cl, Br, I), CF₃, C₁-C₆alkyl, C₁-C₆alkoxy, nitro and amino;

T is U-W,

where

U is an optionally substituted bivalent radical selected from the group

C₁-C₆alkyl-Q-, C₂-C₆alkenyl-Q-, and C₂-C₆alkynyl-Q-, where the substituits on any alkyl, alkenyl or alkynyl are 1-3 R^a;

Q is absent or is selected from the group

—

SO₂—

N(Rⁿ)—

, —

N(Rⁿ)—

, —

N(Rⁿ)—

C(═

O)—

, —

N(Rⁿ)—

C(═

O)—

O—

, —

N(Rⁿ)—

SO₂—

, —

C(═

O)—

N(Rⁿ)—

C(═

O)—

O—

, —

C(═

O)—

O—

, —

C(═

O)— and

—

C(═

O)—

N(Rⁿ)—

;

W is selected from the group

hydrogen, OH, O—

C₁-C₆alkyl, SH, SR^m, NRⁿR^n′

, NH—

C(═

O)—

O—

R^a″

, NH—

C(═

O)—

NRⁿR^n′

, NH—

C(═

O)—

R^a″

, NH—

SO₂—

R^s, NH—

SO₂—

NRⁿR^n′

, NH—

SO₂—

NH—

C(═

O)—

R^a″

, NH—

C(═

O)—

NH—

SO₂—

R^s, C(═

O)—

NH—

C(═

O)—

O—

R^a″

, C(═

O)—

NH—

C(═

O)—

R^a″

, C(═

O)—

NH—

C(═

O)—

NRⁿR^n″

, C(═

O)—

NH—

SO₂—

R^s, C(═

O)—

NH—

SO₂—

NRⁿR^n′

, C(═

S)—

NRⁿR^n′

, SO₂—

R^s, SO₂—

O—

R^s, SO₂—

NRⁿR^n′

, SO₂—

NH—

C(═

O)—

O—

R^a″

, SO₂—

NH—

C(═

O)—

NRⁿR^n′

, SO₂—

NH—

C(═

O)—

R^a″

, O—

C(═

O)—

NRⁿR^n′

, O—

C(═

O)—

R^a″

, O—

C(═

O)—

NH—

C(═

O)—

R^a″

, O—

C(═

O)—

NH—

SO₂—

R^s and O—

SO₂—

R^s; and

pharmaceutically acceptable salts thereof.

6. ) A compound represented by the formula:

7. ) The compound of claim 6 selected from the group consising of

8. ) The compound of claim 6 selected from the group consisting of