Methods for administering compositions including integrin agonists having anti-tumor activity

Abstract

Compositions and methods of enhancing the potency and efficacy of adoptive cell therapy using integrin-ligand stabilizers, wherein the integrin is selected from the group consisting of α4β1, α5β1, α4β7, αvβ3 and αLβ2, and contacting the effector cells ex vivo with agonists or stabilizers having the general Formula (I); methods of treating integrin-expressing cells with such stabilizers to enhance tumor infiltration; and therapeutic methods comprising administering stabilizer or agonist-treated cells to a mammal requiring treatment of solid tumors, hematologic cancers.

We claim: 
     
         1 . A method comprising:
 administering to a patient a composition including an integrin agonist or activating compound comprising a compound of the general Formula (I):
   R 1 -M 1 -N(R 2 )-M 2 -M 3 -M 4 -M 5 -M 6 -R 3   (I)
 
   wherein a first class of the compounds of Formula (I) is defined by:
 R 1  is selected from the group consisting of aryl and aralkyl, 
 R 2  is alkyl, aryl, or aralkyl, 
 M 1  is CH 2 , 
 M 2  is CO, 
 M 3  is O, S, or NR 6 ,
 R 6  when present is hydrogen or lower alkyl, 
 
 M 4  is absent or CH 2 , 
 M 5  is (CR 11 R 12 ),
 R 11  is hydrogen, 
 R 12  is selected from the group consisting of hydrogen, NR 21 CONR 22 R 23 , NR 21 COR 24 , NR 21 SO 2 R 24 , NR 21 COOR 24 , OCOR 24 , OR 24 , O(CH 2 CH 2 O), R 24 , COOR 24 , alkyl, and hydroxyalkyl,
 s is an integer of 1 to 6, 
 R 21  and R 22  when present are independently selected from the group consisting of hydrogen or lower alkyl, 
 R 23  when present is selected from the group consisting of hydroxyalkyl, alkoxyalkyl, alkyl, aryl, aralkyl and alkoxycarbonylalkyl, 
 provided that when M 3  is NR 6  and M 4  is absent, then R 23  is not 1-(1,3-benzodioxol-5-yl)-3-ethoxy-3-oxopropyl, 
 R 24  when present is selected from the group consisting of alkyl, aryl, aralkyl, heterocyclyl, cycloalkyl, cycloalkylalkyl, and heterocyclylalkyl, and mixtures thereof, 
 
 
 M 6  is (CH 2 ) q , where
 q is an integer from 0 to 6, 
 
 R 3  is selected from the group consisting of hydrogen, CONR 13 R 14 , NR 15 COOR 16 , NR 15 COR 16 , NR 15 CONR 13 R 14 , NR 15 SO2R 16 , OCOR 16 , COOR 16 , OR 16 , SR 16 , heterocyclyl, hydroxyl, hydroxyalkyl, guanadino, alkyl and aryl,
 R 13  and R 15  when present are independently hydrogen or lower alkyl, 
 R 14  and R 16  when present are independently selected from the group consisting of hydrogen, alkyl, aryl, aralkyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, and heterocyclylalkyl, 
 
 R 1 , R 2 , R 3 , R 12 , R 14 , R 16 , R 23  and R 24  when present may independently be either unsubstituted or substituted with one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heterocyclylaryl, hydroxy, alkoxy, azido, haloalkoxy, hydroxyalkyl, aryloxy, hydroxyaryl, alkoxyaryl, halo, haloalkyl, haloaryl, amino, alkylamino, dialkylamino, arylamino, diarylamino, —NHCO(alkyl), —NHCO(aryl), —NHCO(aralkyl), —NHCO(haloalkyl), —NHSO 2 (alkyl), —NHSO 2 (aryl), —NHSO 2 (aralkyl), alkoxycarbonyl, alkoxycarbonylalkyl, —OCO(alkylamino), —OCO(dialkylamino), and mixtures thereof; 
   
       or
 wherein a second class of the compounds of Formula (I) is defined by:
 R 1  is aryl or aralkyl, 
 R 2  is alkyl or aralkyl, 
 M 1  is CH 2 , 
 M 2  is CO, 
 M 3  is absent or is O or CH 2 , 
 M 4  is absent or is CH 2 , 
 M 5  is absent or is O or (CR 11 R 12 ),
 R 11  is hydrogen, 
 R 12  is selected from the group consisting of hydrogen, NR 21 CONR 22 R 23 , NR 21 COR 24 , NR 21 SO2R 24  and NR 21 COOR 24 ,
 R 21  and R 22  each of which, when present is independently selected from the group of hydrogen and lower alkyl, 
 R 23  and R 24 , each of which, when present is independently selected from the group consisting of hydrogen, alkyl, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl and aralkyl, 
 
 
 M 6  is selected from the group consisting of (CH 2 ) q , (CH 2 ) q —CH═CH—(CH 2 ) r , (CH 2 ) q -arylene-(CH 2 ) r  and (CH 2 CH 2 O) q , where
 q and r are independently integers from 0 to 6, 
 
 R 13  is CONR 13 R 14 ,
 R 13  and R 14 , each of which, when present is independently selected from the group consisting of hydrogen, alkyl, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl and aralkyl, and 
 
 R 1 , R 2 , R 13 , R 14 , R 23  and R 24 , when present, independently either are unsubstituted or are substituted with one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heterocyclylaryl, hydroxy, alkoxy, azido, haloalkoxy, hydroxyalkyl, aryloxy, hydroxyaryl, alkoxyaryl, halo, haloalkyl, haloaryl, amino, alkylamino, dialkylamino, arylamino, diarylamino, —NHCO(alkyl), —NHCO(aryl), —NHCO(aralkyl), —NHCO(haloalkyl), —NHSO 2 (alkyl), —NHSO 2 (aryl), —NHSO 2 (aralkyl), alkoxycarbonyl, alkoxycarbonylalkyl, —OCO(alkylamino), —OCO(dialkylamino), and mixtures thereof; 
 
 
       or
 wherein a third class of the compounds of Formula (I) is defined by:
 R 1  is aryl or aralkyl, 
 R 2  is alkyl or aralkyl, 
 M 1  is CH 2 , 
 M 2  is SO 2  or CO, 
 M 3  is absent or is CH 2 , 
 M 4  is absent or is CH 2 , 
 M 5  is absent or is (CR 11 R 12 ),
 R 11 , when present, is hydrogen, 
 R 12 , when present, is selected from the group consisting of hydrogen, alkyl, NR 21 CONR 22 R 23 , NR 21 COR 24 , NR 21 SO2R 24  and NR 21 COOR 24 ,
 R 21  and R 22 , each of which when present, is independently selected from the group of hydrogen, lower alkyl, and aralkyl, 
 R 23  and R 24 , each of which, when present is independently selected from the group consisting of hydrogen, alkyl, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl and aralkyl, 
 
 
 M 6  is (CH 2 ) q , or NR 34 (CH 2 ) q ,
 q is an integer from 0 to 6, 
 R 34 , when present, is selected form the group consisting of alkyl, aralkyl, COR 35 , and SO 2 R 35 ,
 R 35  when present, is selected form the group consisting of alkyl, aryl, and aralkyl, and 
 
 
 R 3  is selected from the group consisting of CONR 13 R 14 , SO 2 NR 13 R 14 , NR 15 COOR 16 , NR 15 COR 16 , NR 15 CONR 13 R 14 , and NR 15 SO 2 R 16 ,
 R 13  and R 14 , each of which, when present, is independently selected from the group consisting of hydrogen, alkyl, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl and aralkyl, 
 R 15  and R 16 , each of which when present, is independently selected from the group of hydrogen, lower alkyl, and aralkyl, 
 
 R 1 , R 2 , R 13 , R 14 , R 15 , R 16 , R 23 , R 24 , R 34  and R 35 , when present, either are unsubstituted or are substituted with one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heterocyclylaryl, hydroxy, alkoxy, azido, haloalkoxy, hydroxyalkyl, aryloxy, hydroxyaryl, alkoxyaryl, halo, haloalkyl, haloaryl, amino, alkylamino, dialkylamino, arylamino, diarylamino, —NHCO(alkyl), —NHCO(aryl), —NHCO(aralkyl), —NHCO(haloalkyl), —NHSO 2 (alkyl), —NHSO 2 (aryl), —NHSO 2 (aralkyl), alkoxycarbonyl, alkoxycarbonylalkyl, —OCO(alkylamino), and —OCO(dialkylamino), with the proviso that when M 2  is CO, then M 6  is NR 34 (CH 2 ) q ,
 q is not 0; 
 
 
 
       or
 wherein a fourth class of the compounds of Formula (I) is defined by:
 R 1  is alkyl, aryl or aralkyl, 
 R 2  is selected from the group consisting of aralkyl and alkyl,
 provided that when R 1  is alkyl, R 2  is aralkyl, 
 
 M 1  is CO or SO 2 ,
 provided that when M 1  is SO 2  and R is phenyl, 4-methylphenyl or 2,4,6-trimethylphenyl, R 2  is not alkyl, 2-phenethyl, benzyl, or 2-methoxy-2-oxoethyl, and when M 1  is CO and R 1  is 2-furyl, 4-pyridyl, or 3,5-dinitrophenyl, R 2  is not alkyl, benzyl or 2-(1H-indol-2-yl)ethyl, 
 
 M 2  is absent or CH 2 , 
 M 3  and M 4  are absent, 
 M 5  is (CR 11 R 12 ),
 R 11  is hydrogen, 
 R 12  is selected from the group consisting of hydrogen, NR 21 CONR 22 R 23 , NR 21 COR 24 , NR 21 SO 2 R 24 , NR 21 COOR 24 , CONR 22 R 23 , COOR 24 , O(CH 2 CH 2 O) s R 24 , hydroxyalkyl, and alkoxyalkyl,
 R 21 , and R 22 , when present, are independently selected from the group consisting of hydrogen and C 1 -C 6  alkyl, and 
 R 23  and R 24 , each of which, when present, is independently selected from the group consisting of hydrogen, alkyl, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl and aralkyl, and 
 s is an integer of 1 to 6, 
 
 
 M 6  is (CH 2 ) q ,
 q is an integer of 0 to 6, 
 
 R 3  is selected from the group consisting of NR 15 COOR 16 , NR 15 COR 16 , NR 15 CONR 13 R 14 , and NR 15 SO 2 R 16 , and
 R 13  when present, is independently selected from the group consisting of hydrogen and C 1 -C 6  alkyl, and 
 R 14 , R 15 , and R 16  each of which, when present, are independently selected from the group consisting of hydrogen, alkyl, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl and aralkyl, and 
 
 R 1 , R 2 , R 3 , R 12 , R 14 , R 15 , R 16 , R 23 , and R 24 , when present, independently either are unsubstituted or are substituted with one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heterocyclylaryl, hydroxy, alkoxy, azido, haloalkoxy, hydroxyalkyl, aryloxy, hydroxyaryl, alkoxyaryl, halo, haloalkyl, haloaryl, amino, alkylamino, dialkylamino, arylamino, diarylamino, —NHCO(alkyl), —NHCO(aryl), —NHCO(aralkyl), —NHCO(haloalkyl), —NHSO 2 (alkyl), —NHSO 2 (aryl), —NHSO 2 (aralkyl), alkoxycarbonyl, alkoxycarbonylalkyl, —OCO(alkylamino) and —OCO(dialkylamino), 
 
 
       or
 pharmaceutically acceptable salts thereof, 
 wherein the integrin agonist or activating compound has anti-tumor activity. 
 
     
     
         2 . The method of  claim 1 , wherein the administering step comprises:
 a single administration of the composition or   a plurality of administration of the composition over time.   
     
     
         3 . The method of  claim 1 , wherein, in the administering step, the integrin agonist or activating compound is present in an amount between about 1 fM and less than about 300 μM. 
     
     
         4 . The method of  claim 3 , wherein, in the administering step the integrin agonist or activating compound is present in an amount between about 100 nM and about 30 μM, between about 1 μm and about 10 μM, between 1 fM and 10 M, between 1 fM and less than 10 M, greater than 1 fM and less than 100 nM, greater than 1 fM and less than 50 nM, or greater than 1 fM and less than 25 nM. 
     
     
         5 . The method of  claim 1 , wherein, in the administering step, the composition further comprising:
 a pharmaceutically acceptable aqueous carrier, or   a pharmaceutically acceptable non-aqueous carrier.   
     
     
         6 . The method of  claim 5 , wherein, in the administering step the pharmaceutically acceptable aqueous carrier comprises an aqueous buffer including MnCl 2  or MgCl 2 . 
     
     
         7 . The method of  claim 6 , wherein the administering step:
 the pharmaceutically acceptable aqueous carrier include water, ethanol, polyols including propyleneglycol, polyethyleneglycol, or glycerol, or   the pharmaceutically acceptable non-aqueous carrier include vegetable oils, zwitterionic phospholipids, non-esterified fatty acids, mono-, and/or di- or triglycerides.   
     
     
         8 . The method of  claim 7 , wherein the administering step:
 the pharmaceutically acceptable aqueous carrier and the pharmaceutically acceptable non-aqueous carrier include (a) adjuvants selected from the group consisting of preserving, wetting, emulsifying, and dispensing agents, (b) antibacterial and antifungal agents selected from the group consisting of parabens, chlorobutanol, phenol, or sorbic acid, and/or (c) isotonic agents selected from the group consisting of sugars and sodium chloride, and (d) for injectables, delaying absorption agents selected from the group consisting of aluminum monostearate and gelatin.   
     
     
         9 . The method of  claim 1 , wherein, in the administering step, R 1 M 1 , R 2 , R 13 , and R 14  are independently selected from the group consisting of 2-thienylmethyl, 3-methoxybenzyl, 4-methoxybenzyl, 4-(dimethylamino)benzyl, 2-(2-thienyl)ethyl, pyridin-4-ylmethyl, and pyridin-3-ylmethyl. 
     
     
         10 . The method of  claim 1 , wherein, in the administering step, the integrin agonist or activating compound comprise:
 a first class compound selected from the group consisting of N,N,N′,N′-tetrakis(2-thienylmethyl)pentanediamide; N-(3-methoxybenzyl)-N,N′,N′-tris(2-thienylmethyl)pentanediamide; N,N,N′-tris(2-thienylmethyl)pentanediamide; N′-[2-(2-thienyl)ethyl]-N,N-bis(2-thienylmethyl)pentanediamide; N-[2-(2-thienyl)ethyl]-N,N′,N′-tris(2-thienylmethyl)pentanediamide; N,N-bis(pyridin-4-ylmethyl)-N′,N′-bis(2-thienylmethyl)pentanediamide; N,N-bis(pyridin-3-ylmethyl)-N′,N′-bis(2-thienylmethyl)pentanediamide; N,N-bis(3-methoxybenzyl)-N′,N′-bis(2-thienylmethyl)pentanediamide; N,N,N′,N′-tetrakis(4-methoxybenzyl)pentanediamide; N,N,N′,N′-tetrakis(2-thienylmethyl)hexanediamide; N,N,N′,N′-tetrakis(4-methoxybenzyl) hexanediamide; N,N,N′,N′-tetrakis(3-methoxybenzyl)hexanediamide; N,N,N′,N′-tetrakis (2-thienylmethyl) heptanediamide; 2,2′-(1,3-phenylene)bis[N,N-bis(2-thienylmethyl)acetamide]; N,N,N′,N′-tetrakis(4-methoxybenzyl)heptanediamide; N,N,N′,N′-tetrakis (2-thienylmethyl)octanediamide; (3E)-N,N,N′,N′-tetrakis (2-thienylmethyl)hex-3-enediamide; 2,2′-oxybis[N,N-bis(2-thienylmethyl)acetamide]; 3-oxo-1-(2-thienyl)-2-(2-thienylmethyl)-4,7,10-trioxa-2-azadodecan-12-yl bis(2-thienylmethyl)carbamate; N,N,N′,N′-tetrakis(4-methoxybenzyl) succinamideethane-1,2-diyl bis[bis(2-thienylmethyl)carbamate]; N,N,N′,N′-tetrakis (4-methoxybenzyl)octanediamide; N,N,N′,N′-tetrakis(2-thienylmethyl) pyridine-3,5-dicarboxamide; N,N,N′,N′-tetrakis (2-thienylmethyl)pyridine-2,6-dicarboxamide; N,N,N′,N′-tetrakis (2-thienylmethyl)pyridine-2,4-dicarboxamide; 2,2′-(1,4-phenylene) bis[N,N-bis(2-thienylmethyl)acetamide]; 8-{2-[bis (2-thienylmethyl)amino]-2-oxoethoxy}-N,N-bis(2-thienylmethyl)quinoline-2-carboxamide; N,N′-bis(4-methoxybenzyl)-N,N′-bis(2-thienylmethyl)hexanediamide; and tert-butyl{(2S)-1,6-bis[bis(2-thienylmethyl)amino]-1,6-dioxohexan-2-yl}carbamate;   a second class compound selected from the group consisting of 1,2-bis(bis(thiophen-2-ylmethyl)carbamate)ethane; 1,2-bis(bis(3-methyloxybenzyl)carbamate)ethane; 1,2-bis(bis(4-methyloxybenzyl)carbamate)ethane; 1,2-bis((thiophen-2-ylmethyl)(3-methyloxybenzyl)carbamate)ethane; 1,2-bis((thiophen-2-ylmethyl)(4-methyloxybenzyl)carbamate)ethane; 1,2-bis((3-methyloxybenzyl)(4-methyloxybenzyl)carbamate)ethane; 1,5-bis(bis(thiophen-2-ylmethyl)carbamate)-3-oxapentane; 1,5-bis(bis(3-methyloxybenzyl)carbamate)-3-oxapentane; 1,5-bis(bis(4-methyloxybenzyl)carbamate)-3-oxapentane; 1,5-bis((thiophen-2-ylmethyl)(3-methyloxybenzyl)carbamate)-3-oxapentane; 1,5-bis((thiophen-2-ylmethyl)(4-methyloxybenzyl)carbamate)-3-oxapentane; 1,5-bis((3-methyloxybenzyl)(4-methyloxybenzyl)carbamate)-3-oxapentane; (ethane-1,2-diylbis(oxy))bis(ethane-2,1-diyl)bis(bis(thiophen-2-ylmethyl)carbamate) or 1,8-bis(bis(thiophen-2-ylmethyl)carbamate)-3,6-dioxaoctane; 1,8-bis(bis(3-methyloxybenzyl)carbamate)-3,6-dioxaoctane; 1,8-bis(bis(4-methyloxybenzyl)carbamate)-3,6-dioxaoctane; 1,8-bis((thiophen-2-ylmethyl)(3-methyloxybenzyl)carbamate)-3,6-dioxaoctane; 1,8-bis((thiophen-2-ylmethyl)(4-methyloxybenzyl)carbamate)-3,6-dioxaoctane; 1,8-bis((3-methyloxybenzyl)(4-methyloxybenzyl)carbamate)-3,6-dioxaoctane; 1,11-bis(bis(thiophen-2-ylmethyl)carbamate)-3,6,9-trioxaundecane; 1,11-bis(bis(3-methyloxybenzyl)carbamate)-3,6,9-trioxaundecane; 1,11-bis(bis(4-methyloxybenzyl)carbamate)-3,6,9-trioxaundecane; 1,11-bis((thiophen-2-ylmethyl)(3-methyloxybenzyl)carbamate)-3,6,9-trioxaundecane; 1,11-bis((thiophen-2-ylmethyl)(4-methyloxybenzyl)carbamate)-3,6,9-trioxaundecane; 1,11-bis((3-methyloxybenzyl)(4-methyloxybenzyl)carbamate)-3,6,9-trioxaundecane; 1,14-bis(bis(thiophen-2-ylmethyl)carbamate)-3,6,9,12-tetraoxatetradecane; 1,14-bis(bis(3-methyloxybenzyl)carbamate)-3,6,9,12-tetraoxatetradecane; 1,14-bis(bis(4-methyloxybenzyl)carbamate)-3,6,9,12-tetraoxatetradecane; 1,14-bis((thiophen-2-ylmethyl)(3-methyloxybenzyl)carbamate)-3,6,9,12-tetraoxatetradecane; 1,14-bis((thiophen-2-ylmethyl)(4-methyloxybenzyl)carbamate)-3,6,9,12-tetraoxatetradecane; 1,14-bis((3-methyloxybenzyl)(4-methyloxybenzyl)carbamate)-3,6,9,12-tetraoxatetradecane; 1,17-bis(bis(thiophen-2-ylmethyl)carbamate)-3,6,9,12,15-pentaoxatetradecane; 1,17-bis(bis(3-methyloxybenzyl)carbamate)-3,6,9,12,15-pentaoxatetradecane; 1,17-bis(bis(4-methyloxybenzyl)carbamate)-3,6,9,12,15-pentaoxatetradecane; 1,17-bis((thiophen-2-ylmethyl)(3-methyloxybenzyl)carbamate)-3,6,9,12,15-pentaoxatetradecane; 1,17-bis((thiophen-2-ylmethyl)(4-methyloxybenzyl)carbamate)-3,6,9,12,15-pentaoxatetradecane; and 1,17-bis((3-methyloxybenzyl)(4-methyloxybenzyl)carbamate)-3,6,9,12,15-pentaoxatetradecane;   a third class compound selected from the group consisting of methyl (6S,10S)-10-(1,3-benzodioxol-5-yl)-6-butyl-3,8-dioxo-1-(2-thienyl)-2-(2-thienylmethyl)-4-oxa-2,7,9-triazadodecan-12-oate; methyl(6S,10R)-10-(1,3-benzodioxol-5-yl)-6-butyl-3,8-dioxo-1-(2-thienyl)-2-(2-thienylmethyl)-4-oxa-2,7,9-triazadodecan-12-oate; methyl (6S,10S)-10-(1,3-benzodioxol-5-yl)-6-butyl-7-methyl-3,8-dioxo-1-(2-thienyl)-2-(2-thienylmethyl)-4-oxa-2,7,9-triazadodecan-12-oate; methyl (6S,10S)-10-(1,3-benzodioxol-5-yl)-6-butyl-9-methyl-3,8-dioxo-1-(2-thienyl)-2-(2-thienylmethyl)-4-oxa-2,7,9-triazadodecan-12-oate; ethyl(6S,10R)-10-(1,3-benzodioxol-5-yl)-6-butyl-7-methyl-3,8-dioxo-1-(2-thienyl)-2-(2-thienylmethyl)-4-oxa-2,7,9-triazadodecan-12-oate; methyl (10S)-10-(1,3-benzodioxol-5-yl)-3,8-dioxo-1-(2-thienyl)-2-(2-thienylmethyl)-4-oxa-2,7,9-triazadodecan-12-oate; methyl 3,8-dioxo-1-(2-thienyl)-2-(2-thienylmethyl)-4-oxa-2,7,9-triazadodecan-12-oate; methyl (6S,10S)-10-(1,3-benzodioxol-5-yl)-6-butyl-2-methyl-3,8-dioxo-1-(2-thienyl)-4-oxa-2,7,9-triazadodecan-12-oate; methyl (6S)-6-butyl-3,8-dioxo-1-(2-thienyl)-2-(2-thienylmethyl)-4-oxa-2,7,9-triazadodecan-12-oate; (2S)-2-{[(1,3-benzodioxol-5-ylmethyl)carbamoyl]amino}hexylbis(2-thienylmethyl)carbamate; methyl(6S,10S)-6-butyl-3,8-dioxo-10-phenyl-1-(2-thienyl)-2-(2-thienylmethyl)-4-oxa-2,7,9-triazadodecan-12-oate; (2S)-2-({[(1S)-1-(1,3-benzodioxol-5-yl)-3-hydroxypropyl]carbamoyl}amino)hexylbis(2-thienylmethyl)carbamate; (2S)-2-[(benzylcarbamoyl)amino]hexylbis(2-thienylmethyl)carbamate; (2S)-2-[(morpholin-4-ylcarbonyl)amino]hexylbis(2-thienylmethyl)carbamate; (2S)-2-{[(3-methoxypropyl)carbamoyl]amino}hexylbis(2-thienylmethyl)carbamate; (2S)-2-{[(2-methoxyethyl)carbamoyl]amino}hexylbis(2-thienylmethyl)carbamate; tert-butyl [(2S)-1-{[bis(2-thienylmethyl)carbamoyl]oxy}hexan-2-yl]carbamate; (2S)-2-[(tert-butylcarbamoyl)amino]hexyl bis(2-thienylmethyl)carbamate; (2S)-2-[(isopropylcarbamoyl)amino]hexylbis(2-thienylmethyl)carbamate; (2S)-2-[(methylcarbamoyl)amino]hexylbis(2-thienylmethyl)carbamate; tert-butyl[(2R)-1-{[bis(2-thienylmethyl)carbamoyl]oxy}hexan-2-yl]carbamate; benzyl {(5S)-6-{[bis(2-thienylmethyl)carbamoyl]oxy}-5-[(tert-butoxycarbonyl)amino]hexyl}carbamate; methyl(9S,13S)-13-(1,3-benzodioxol-5-yl)-9-({[bis(2-thienylmethyl)carbamoyl]oxy}methyl)-3,11-dioxo-1-phenyl-2-oxa-4,10,12-triazapentadecan-15-oate; (2S)-2-acetamidohexylbis(2-thienylmethyl)carbamate; methyl(6R,10S)-10-(1,3-benzodioxol-5-yl)-6-butyl-3,8-dioxo-1-(2-thienyl)-2-(2-thienylmethyl)-4-oxa-2,7,9-triazadodecan-12-oate; methyl (6R,10R)-10-(1,3-benzodioxol-5-yl)-6-butyl-3,8-dioxo-1-(2-thienyl)-2-(2-thienylmethyl)-4-oxa-2,7,9-triazadodecan-12-oate; methyl {[bis(2-thienylmethyl)carbamoyl](methyl)amino}acetate; methyl {[bis(2-thienylmethyl)carbamoyl](butyl)amino}acetate; tert-butyl {[bis(2-thienylmethyl)carbamoyl](butyl)amino}acetate; benzyl {(5S)-6-{[bis(4-methoxybenzyl) carbamoyl]oxy}-5-[(tert-butoxycarbonyl)amino]hexyl}carbamate; tert-butyl [(2S)-1-{[bis(4-methoxybenzyl)carbamoyl]oxy}hexan-2-yl]carbamate; methyl(6S,10S)-10-(1,3-benzodioxol-5-yl)-6-butyl-2-(4-methoxybenzyl)-1-(4-methoxyphenyl)-3,8-dioxo-4-oxa-2,7,9-triazadodecan-12-oate; (2S)-2-({[(1S)-1-(1,3-benzodioxol-5-yl)-3-hydroxypropyl]carbamoyl}amino)hexylbis(4-methoxybenzyl)carbamate; (2S)-2-[(tertbutoxycarbonyl)amino]hexyldibenzylcarbamate; methyl(6S,10S)-10-(1,3-benzodioxol-5-yl)-2-benzyl-6-butyl-3,8-dioxo-1-phenyl-4-oxa-2,7,9-triazadodecan-12-oate; tert-butyl [(2S)-1-{[bis(4-methylbenzyl)carbamoyl]oxy}hexan-2-yl]carbamate; methyl (6S,10S)-10-(1,3-benzodioxol-5-yl)-6-butyl-2-(4-methylbenzyl)-1-(4-methylphenyl)-3,8-dioxo-4-oxa-2,7,9-triazadodecan-12-oate; tert-butyl[(2S)-1-{[bis(4-chlorobenzyl)carbamoyl]oxy}hexan-2-yl]carbamate; methyl(6S,10S)-10-(1,3-benzodioxol-5-yl)-6-butyl-2-(4-chlorobenzyl)-1-(4-chlorophenyl)-3,8-dioxo-4-oxa-2,7,9-triazadodecan-12-oate; (2S)-2-[(tertbutoxycarbonyl)amino]hexyl(4-bromobenzyl)(2-thienylmethyl)carbamate; methyl (6S,10S)-10-(1,3-benzodioxol-5-yl)-2-(4-bromobenzyl)-6-butyl-3,8-dioxo-1-(2-thienyl)-4-oxa-2,7,9-triazadodecan-12-oate; methyl(6S,10S)-2-(4-azidoobenzyl)-10-(1,3-benzodioxol-5-yl)-6-butyl-3,8-dioxo-1-(2-thienyl)-4-oxa-2,7,9-triazadodecan-12-oate; (2S)-2-[(tert-butoxycarbonyl)amino]hexylphenyl(2-thienylmethyl)carbamate; methyl (6S,10S)-10-(1,3-benzodioxol-5-yl)-6-butyl-3,8-dioxo-2-phenyl-1-(2-thienyl)-4-oxa-2,7,9-triazadodecan-12-oate; tert-butyl [(2S)-1-{[bis(3-thienylmethyl)carbamoyl]oxy}hexan-2-yl]carbamate; methyl (6S,10S)-10-(1,3-benzodioxol-5-yl)-6-butyl-3,8-dioxo-1-(3-thienyl)-2-(3-thienylmethyl)-4-oxa-2,7,9-triazadodecan-12-oate; benzyl[(5S)-5-[(tertbutoxycarbonyl)amino]-6-{[butyl(2-thienylmethyl)carbamoyl]oxy}hexyl]carbamate; (2S)-2-[(tert-butoxycarbonyl)amino]hexylbutyl(2-thienylmethyl)carbamate; methyl(3S,7S)-3-(1,3-benzodioxol-5-yl)-7-butyl-5,11-dioxo-11-(2-thienylmethyl)-9-oxa-4,6,11-triazapentadecan-1-oate; benzyl [(5S)-5-[(tert-butoxycarbonyl)amino]-6-{[(2-methoxyethyl)(2-thienylmethyl)carbamoyl]oxy}hexyl]carbamate; (2S)-2-[(tert-butoxycarbonyl)amino]hexyl (2-methoxyethyl)(2-thienylmethyl)carbamate; methyl(9S,13S)-13-(1,3-benzodioxol-5-yl)-9-butyl-6,11-dioxo-5-(2-thienylmethyl)-2,7-dioxa-5,10,12-triazapentadecan-15-oate; (2S)-2-[({3-[(methylsulfonyl)amino]benzyl}carbamoyl)amino]hexyl(2-methoxyethyl)(2-thienylmethyl) carbamate; (2S)-2-{[(4-bromobenzyl)carbamoyl]amino}hexylbis(2-thienylmethyl)carbamate; (2S)-2-{[(4-azidobenzyl)carbamoyl]amino}hexylbis(2-thienylmethyl)carbamate; tert-butyl[(2S)-1-{[bis(2-thienylmethyl)carbamoyl]thio}hexan-2-yl]carbamate; and methyl (6S,10S)-10-(1,3-benzodioxol-5-yl)-6-butyl-3,8-dioxo-1-(2-thienyl)-2-(2-thienylmethyl)-4-thia-2,7,9-triazadodecan-12-oate.   A fourth class compound selected from the group consisting of N-{2-[bis(2-thienylmethyl)sulfamoyl]ethyl}-N-(2-thienylmethyl)thiophene-2-sulfonamide; N-{2-[bis(2-thienylmethyl)sulfamoyl]ethyl}-N-(2-thienylmethyl)thiophene-2-carboxamide; 2-{butyl[(2-thienylmethyl)carbamoyl]amino}-N,N-bis(2-thienylmethyl)ethanesulfonamide; 2-{[bis(2-thienylmethyl)carbamoyl](butyl)amino}-N,N-bis(2-thienylmethyl) ethanesulfonamide; N-{3-[bis(2-thienylmethyl)sulfamoyl]propyl}-N-(2-thienylmethyl)thiophene-2-sulfonamide; 2-[(methylsulfonyl)(2-thienylmethyl)amino]-N,N-bis(2-thienylmethyl)ethanesulfonamide; 2-{[bis(2-thienylmethyl)carbamoyl]amino}-N,N-bis(2-thienylmethyl)ethanesulfonamide; N-{2-[bis(2-thienylmethyl)sulfamoyl]ethyl}thiophene-2-sulfonamide; N-{2-[bis(2-thienylmethyl)sulfamoyl]ethyl}-2-(2-thienyl)acetamide; N-{2-[bis(2-thienylmethyl)sulfamoyl]ethyl}thiophene-2-carboxamide; N,N-bis(2-thienylmethyl)-2-{[(2-thienylmethyl)carbamoyl]amino}ethanesulfonamide; 2-({2-[bis(2-thienylmethyl)sulfamoyl]ethyl}amino)-N,N-bis(2-thienylmethyl)acetamide; 3-[{2-[bis(2-thienylmethyl)amino]-2-oxoethyl}(butyl)amino]-N,N-bis(2-thienylmethyl)propanamide; 2-[{2-[bis(2-thienylmethyl)sulfamoyl]ethyl}(methyl)amino]-N,N-bis(2-thienylmethyl)acetamide; 2-[{2-[bis(2-thienylmethyl) sulfamoyl]ethyl}(butyl)amino]-N,N-bis(2-thienylmethyl)acetamide; 3-({2-[bis(2-thienylmethyl)sulfamoyl]ethyl}amino)-N,N-bis(2-thienylmethyl)propanamide; 3-({2-[bis(2-thienylmethyl)sulfamoyl]ethyl}amino)-N,N-bis(4-methoxybenzyl) propanamide; 3-({2-[bis(4-methoxybenzyl)sulfamoyl]ethyl}amino)-N,N-bis(2-thienylmethyl)propanamide; 3-[{2-[bis(2-thienylmethyl)sulfamoyl]ethyl}(methyl)amino]-N,N-bis(2-thienylmethyl)propanamide; 3-[{2-[bis(4-methoxybenzyl) sulfamoyl]ethyl}(methyl)amino]-N,N-bis(2-thienylmethyl)propanamide; (2S)-2-({2-[bis(2-thienylmethyl)sulfamoyl]ethyl}amino)-N,N-bis(2-thienylmethyl) hexanamide; (2S)-2-({2-[bis(4-methoxybenzyl)sulfamoyl]ethyl}amino)-N,N-bis(2-thienylmethyl)hexanamide; 2-(acetyl{2-[bis(2-thienylmethyl)sulfamoyl]ethyl}amino)-N,N-bis(2-thienylmethyl) acetamide; and 2-(acetyl{2-[bis(4-methoxybenzyl) sulfamoyl]ethyl}amino)-N,N-bis(2-thienyl-methyl) acetamide;   pharmaceutically acceptable salts thereof; and   mixtures thereof.   
     
     
         11 . A method comprising:
 administering to a patient a composition including one or more integrin agonists or activating compounds comprising one or more compounds of the general Formula (I):
   R 1 -M 1 -N(R 2 )-M 2 -M 3 -M 4 -M 5 -M 6 -R 3   (I)
 
   wherein a first class of the compounds of Formula (I) is defined by:
 R 1  is selected from the group consisting of aryl and aralkyl, 
 R 2  is alkyl, aryl, or aralkyl, 
 M 1  is CH 2 , 
 M 2  is CO, 
 M 3  is O, S, or NR 6 ,
 R 6  when present is hydrogen or lower alkyl, 
 
 M 4  is absent or CH 2 , 
 M 5  is (CR 11 R 12 ),
 R 11  is hydrogen, 
 R 12  is selected from the group consisting of hydrogen, NR CONR 22 R 23 , NR 21 COR 24 , NR 21 SO 2 R 24 , NR 21 COOR 24 , OCOR 24 , OR 24 , O(CH 2 CH 2 O), R 24 , COOR 24 , alkyl, and hydroxyalkyl,
 s is an integer of 1 to 6, 
 R 21  and R 22  when present are independently selected from the group consisting of hydrogen or lower alkyl, 
 R 23  when present is selected from the group consisting of hydroxyalkyl, alkoxyalkyl, alkyl, aryl, aralkyl and alkoxycarbonylalkyl, 
 provided that when M 3  is NR 6  and M 4  is absent, then R 23  is not 1-(1,3-benzodioxol-5-yl)-3-ethoxy-3-oxopropyl, 
 R 24  when present is selected from the group consisting of alkyl, aryl, aralkyl, heterocyclyl, cycloalkyl, cycloalkylalkyl, and heterocyclylalkyl, and mixtures thereof, 
 
 
 M 6  is (CH 2 ) q , where
 q is an integer from 0 to 6, 
 
 R 3  is selected from the group consisting of hydrogen, CONR 13 R 14 , NR 15 COOR 16 , NR 15 COR 16 , NR 15 CONR 13 R 14 , NR 15 SO2R 16 , OCOR 16 , COOR 16 , OR 16 , SR 16 , heterocyclyl, hydroxyl, hydroxyalkyl, guanadino, alkyl and aryl,
 R 13  and R 15  when present are independently hydrogen or lower alkyl, 
 R 14  and R 16  when present are independently selected from the group consisting of hydrogen, alkyl, aryl, aralkyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, and heterocyclylalkyl, 
 
 R 1 , R 2 , R 3 , R 12 , R 14 , R 16 , R 23  and R 24  when present may independently be either unsubstituted or substituted with one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heterocyclylaryl, hydroxy, alkoxy, azido, haloalkoxy, hydroxyalkyl, aryloxy, hydroxyaryl, alkoxyaryl, halo, haloalkyl, haloaryl, amino, alkylamino, dialkylamino, arylamino, diarylamino, —NHCO(alkyl), —NHCO(aryl), —NHCO(aralkyl), —NHCO(haloalkyl), —NHSO 2 (alkyl), —NHSO 2 (aryl), —NHSO 2 (aralkyl), alkoxycarbonyl, alkoxycarbonylalkyl, —OCO(alkylamino), —OCO(dialkylamino), and mixtures thereof; 
   
       or
 wherein a second class of the compounds of Formula (I) is defined by:
 R 1  is aryl or aralkyl, 
 R 2  is alkyl or aralkyl, 
 M 1  is CH 2 , 
 M 2  is CO, 
 M 3  is absent or is O or CH 2 , 
 M 4  is absent or is CH 2 , 
 M 5  is absent or is O or (CR 11 R 12 ),
 R 11  is hydrogen, 
 R 12  is selected from the group consisting of hydrogen, NR 21 CONR 22 R 23 , NR 21 COR 24 , NR 21 SO2R 24  and NR 21 COOR 24 ,
 R 21  and R 22  each of which, when present is independently selected from the group of hydrogen and lower alkyl, 
 R 23  and R 24 , each of which, when present is independently selected from the group consisting of hydrogen, alkyl, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl and aralkyl, 
 
 
 M 6  is selected from the group consisting of (CH 2 ) q , (CH 2 ) q —CH═CH—(CH 2 ) r , (CH 2 ) q -arylene-(CH 2 ) r  and (CH 2 CH 2 O) q , where
 q and r are independently integers from 0 to 6, 
 
 R 3  is CONR 13 R 14 ,
 R 13  and R 14 , each of which, when present is independently selected from the group consisting of hydrogen, alkyl, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl and aralkyl, and 
 
 R 1 , R 2 , R 13 , R 14 , R 23  and R 24 , when present, independently either are unsubstituted or are substituted with one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heterocyclylaryl, hydroxy, alkoxy, azido, haloalkoxy, hydroxyalkyl, aryloxy, hydroxyaryl, alkoxyaryl, halo, haloalkyl, haloaryl, amino, alkylamino, dialkylamino, arylamino, diarylamino, —NHCO(alkyl), —NHCO(aryl), —NHCO(aralkyl), —NHCO(haloalkyl), —NHSO 2 (alkyl), —NHSO 2 (aryl), —NHSO 2 (aralkyl), alkoxycarbonyl, alkoxycarbonylalkyl, —OCO(alkylamino), —OCO(dialkylamino), and mixtures thereof; 
 
 
       or
 wherein a third class of the compounds of Formula (I) is defined by:
 R 1  is aryl or aralkyl, 
 R 2  is alkyl or aralkyl, 
 M 1  is CH 2 , 
 M 2  is SO 2  or CO, 
 M 3  is absent or is CH 2 , 
 M 4  is absent or is CH 2 , 
 M 5  is absent or is (CR 11 R 12 ),
 R 11 , when present, is hydrogen, 
 R 12 , when present, is selected from the group consisting of hydrogen, alkyl, NR 21 CONR 22 R 23 , NR 21 COR 24 , NR 21 SO2R 24  and NR 21 COOR 24 , R 21  and R 22 , each of which when present, is independently selected from the group of hydrogen, lower alkyl, and aralkyl, 
 R 23  and R 24 , each of which, when present is independently selected from the group consisting of hydrogen, alkyl, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl and aralkyl, 
 
 M 6  is (CH 2 ) q , or NR 34 (CH 2 ) q ,
 q is an integer from 0 to 6, 
 R 34 , when present, is selected form the group consisting of alkyl, aralkyl, COR 35 , and SO 2 R 35 ,
 R 35  when present, is selected form the group consisting of alkyl, aryl, and aralkyl, and 
 
 
 R 3  is selected from the group consisting of CONR 13 R 14 , SO 2 NR 13 R 14 , NR 15 COOR 16 , NR 15 COR 16 , NR 15 CONR 13 R 14 , and NR 15 SO 2 R 16 ,
 R 13  and R 14 , each of which, when present, is independently selected from the group consisting of hydrogen, alkyl, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl and aralkyl, 
 R 15  and R 16 , each of which when present, is independently selected from the group of hydrogen, lower alkyl, and aralkyl, 
 
 R 1 , R 2 , R 13 , R 14 , R 15 , R 16 , R 23 , R 24 , R 34  and R 35 , when present, either are unsubstituted or are substituted with one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heterocyclylaryl, hydroxy, alkoxy, azido, haloalkoxy, hydroxyalkyl, aryloxy, hydroxyaryl, alkoxyaryl, halo, haloalkyl, haloaryl, amino, alkylamino, dialkylamino, arylamino, diarylamino, —NHCO(alkyl), —NHCO(aryl), —NHCO(aralkyl), —NHCO(haloalkyl), —NHSO 2 (alkyl), —NHSO 2 (aryl), —NHSO 2 (aralkyl), alkoxycarbonyl, alkoxycarbonylalkyl, —OCO(alkylamino), and —OCO(dialkylamino), with the proviso that when M 2  is CO, then M 6  is NR 34 (CH 2 ) q ,
 q is not 0; 
 
 
 
       or
 wherein a fourth class of the compounds of Formula (I) is defined by:
 R 1  is alkyl, aryl or aralkyl, 
 R 2  is selected from the group consisting of aralkyl and alkyl,
 provided that when R 1  is alkyl, R 2  is aralkyl, 
 
 M 1  is CO or SO 2 ,
 provided that when M 1  is SO 2  and R 1  is phenyl, 4-methylphenyl or 2,4,6-trimethylphenyl, R 2  is not alkyl, 2-phenethyl, benzyl, or 2-methoxy-2-oxoethyl, and when M is CO and R 1  is 2-furyl, 4-pyridyl, or 3,5-dinitrophenyl, R 2  is not alkyl, benzyl or 2-(1H-indol-2-yl)ethyl, 
 
 M 2  is absent or CH 2 , 
 M 3  and M 4  are absent, 
 M 5  is (CR 11 R 12 ),
 R 11  is hydrogen, 
 R 12  is selected from the group consisting of hydrogen, NR 21 CONR 22 R 23 , NR 21 COR 24 , NR 21 SO 2 R 24 , NR 21 COOR 24 , CONR 22 R 23 , COOR 24 , O(CH 2 CH 2 O) s R 24 , hydroxyalkyl, and alkoxyalkyl,
 R 21 , and R 22 , when present, are independently selected from the group consisting of hydrogen and C 1 -C 6  alkyl, and 
 R 23  and R 24 , each of which, when present, is independently selected from the group consisting of hydrogen, alkyl, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl and aralkyl, and 
 s is an integer of 1 to 6, 
 
 
 M 6  is (CH 2 ) q ,
 q is an integer of 0 to 6, 
 
 R 3  is selected from the group consisting of NR 15 COOR 16 , NR 15 COR 16 , NR 15 CONR 13 R 14 , and NR 15 SO 2 R 16 , and
 R 13  when present, is independently selected from the group consisting of hydrogen and C 1 -C 6  alkyl, and 
 R 14 , R 15 , and R 16  each of which, when present, are independently selected from the group consisting of hydrogen, alkyl, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl and aralkyl, and 
 
 R 1 , R 2 , R 3 , R 12 , R 14 , R 15 , R 16 , R 23 , and R 24 , when present, independently either are unsubstituted or are substituted with one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heterocyclylaryl, hydroxy, alkoxy, azido, haloalkoxy, hydroxyalkyl, aryloxy, hydroxyaryl, alkoxyaryl, halo, haloalkyl, haloaryl, amino, alkylamino, dialkylamino, arylamino, diarylamino, —NHCO(alkyl), —NHCO(aryl), —NHCO(aralkyl), —NHCO(haloalkyl), —NHSO 2 (alkyl), —NHSO 2 (aryl), —NHSO 2 (aralkyl), alkoxycarbonyl, alkoxycarbonylalkyl, —OCO(alkylamino) and —OCO(dialkylamino), 
 
 
       or
 pharmaceutically acceptable salts thereof, 
 wherein the integrin agonist or activating compound has anti-tumor activity. 
 
     
     
         12 . The method of  claim 11 , wherein the administering step comprises:
 a single administration of the composition or   a plurality of administration of the composition over time.   
     
     
         13 . The method of  claim 11 , wherein, in the administering step, the integrin agonist or activating compound is present in an amount between about 1 fM and less than about 300 μM. 
     
     
         14 . The method of  claim 13 , wherein, in the administering step the integrin agonist or activating compound is present in an amount between about 100 nM and about 30 μM, between about 1 μm and about 10 μM, between 1 fM and 10 M, between 1 fM and less than 10 M, greater than 1 fM and less than 100 nM, greater than 1 fM and less than 50 nM, or greater than 1 fM and less than 25 nM. 
     
     
         15 . The method of  claim 11 , wherein, in the administering step, the composition further comprising:
 a pharmaceutically acceptable aqueous carrier, or   a pharmaceutically acceptable non-aqueous carrier.   
     
     
         16 . The method of  claim 15 , wherein, in the administering step the pharmaceutically acceptable aqueous carrier comprises an aqueous buffer including MnCl 2  or MgCl 2 . 
     
     
         17 . The method of  claim 16 , wherein the administering step:
 the pharmaceutically acceptable aqueous carrier include water, ethanol, polyols including propyleneglycol, polyethyleneglycol, or glycerol, or   the pharmaceutically acceptable non-aqueous carrier include vegetable oils, zwitterionic phospholipids, non-esterified fatty acids, mono-, and/or di- or triglycerides.   
     
     
         18 . The method of  claim 17 , wherein the administering step:
 the pharmaceutically acceptable aqueous carrier and the pharmaceutically acceptable non-aqueous carrier include (a) adjuvants selected from the group consisting of preserving, wetting, emulsifying, and dispensing agents, (b) antibacterial and antifungal agents selected from the group consisting of parabens, chlorobutanol, phenol, or sorbic acid, and/or (c) isotonic agents selected from the group consisting of sugars and sodium chloride, and (d) for injectables, delaying absorption agents selected from the group consisting of aluminum monostearate and gelatin.   
     
     
         19 . The method of  claim 11 , wherein, in the administering step, R 1 M 1 , R 2 , R 13 , and R 14  are independently selected from the group consisting of 2-thienylmethyl, 3-methoxybenzyl, 4-methoxybenzyl, 4-(dimethylamino)benzyl, 2-(2-thienyl)ethyl, pyridin-4-ylmethyl, and pyridin-3-ylmethyl. 
     
     
         20 . The method of  claim 11 , wherein, in the administering step, the integrin agonist or activating compound comprise:
 a first class compound selected from the group consisting of N,N,N′,N′-tetrakis(2-thienylmethyl)pentanediamide; N-(3-methoxybenzyl)-N,N′,N′-tris(2-thienylmethyl)pentanediamide; N,N,N′-tris(2-thienylmethyl)pentanediamide; N′-[2-(2-thienyl)ethyl]-N,N-bis(2-thienylmethyl)pentanediamide; N-[2-(2-thienyl)ethyl]-N,N′,N′-tris(2-thienylmethyl)pentanediamide; N,N-bis(pyridin-4-ylmethyl)-N′,N′-bis(2-thienylmethyl)pentanediamide; N,N-bis(pyridin-3-ylmethyl)-N′,N′-bis(2-thienylmethyl)pentanediamide; N,N-bis(3-methoxybenzyl)-N′,N′-bis(2-thienylmethyl)pentanediamide; N,N,N′,N′-tetrakis(4-methoxybenzyl)pentanediamide; N,N,N′,N′-tetrakis(2-thienylmethyl)hexanediamide; N,N,N′,N′-tetrakis(4-methoxybenzyl) hexanediamide; N,N,N′,N′-tetrakis(3-methoxybenzyl)hexanediamide; N,N,N′,N′-tetrakis (2-thienylmethyl) heptanediamide; 2,2′-(1,3-phenylene)bis[N,N-bis(2-thienylmethyl)acetamide]; N,N,N′,N′-tetrakis(4-methoxybenzyl)heptanediamide; N,N,N′,N′-tetrakis (2-thienylmethyl)octanediamide; (3E)-N,N,N′,N′-tetrakis (2-thienylmethyl)hex-3-enediamide; 2,2′-oxybis[N,N-bis(2-thienylmethyl)acetamide]; 3-oxo-1-(2-thienyl)-2-(2-thienylmethyl)-4,7,10-trioxa-2-azadodecan-12-yl bis(2-thienylmethyl)carbamate; N,N,N′,N′-tetrakis(4-methoxybenzyl) succinamideethane-1,2-diylbis[bis(2-thienylmethyl)carbamate]; N,N,N′,N′-tetrakis (4-methoxybenzyl)octanediamide; N,N,N′,N′-tetrakis(2-thienylmethyl) pyridine-3,5-dicarboxamide; N,N,N′,N′-tetrakis(2-thienylmethyl)pyridine-2,6-dicarboxamide; N,N,N′,N′-tetrakis(2-thienylmethyl)pyridine-2,4-dicarboxamide; 2,2′-(1,4-phenylene)bis[N,N-bis(2-thienylmethyl)acetamide]; 8-{2-[bis (2-thienylmethyl)amino]-2-oxoethoxy}-N,N-bis(2-thienylmethyl)quinoline-2-carboxamide; N,N′-bis(4-methoxybenzyl)-N,N′-bis(2-thienylmethyl)hexanediamide; and tert-butyl{(2S)-1,6-bis[bis(2-thienylmethyl)amino]-1,6-dioxohexan-2-yl}carbamate;   a second class compound selected from the group consisting of 1,2-bis(bis(thiophen-2-ylmethyl)carbamate)ethane; 1,2-bis(bis(3-methyloxybenzyl)carbamate)ethane; 1,2-bis(bis(4-methyloxybenzyl)carbamate)ethane; 1,2-bis((thiophen-2-ylmethyl)(3-methyloxybenzyl)carbamate)ethane; 1,2-bis((thiophen-2-ylmethyl)(4-methyloxybenzyl)carbamate)ethane; 1,2-bis((3-methyloxybenzyl)(4-methyloxybenzyl)carbamate)ethane; 1,5-bis(bis(thiophen-2-ylmethyl)carbamate)-3-oxapentane; 1,5-bis(bis(3-methyloxybenzyl)carbamate)-3-oxapentane; 1,5-bis(bis(4-methyloxybenzyl)carbamate)-3-oxapentane; 1,5-bis((thiophen-2-ylmethyl)(3-methyloxybenzyl)carbamate)-3-oxapentane; 1,5-bis((thiophen-2-ylmethyl)(4-methyloxybenzyl)carbamate)-3-oxapentane; 1,5-bis((3-methyloxybenzyl)(4-methyloxybenzyl)carbamate)-3-oxapentane; (ethane-1,2-diylbis(oxy))bis(ethane-2,1-diyl)bis(bis(thiophen-2-ylmethyl)carbamate) or 1,8-bis(bis(thiophen-2-ylmethyl)carbamate)-3,6-dioxaoctane; 1,8-bis(bis(3-methyloxybenzyl)carbamate)-3,6-dioxaoctane; 1,8-bis(bis(4-methyloxybenzyl)carbamate)-3,6-dioxaoctane; 1,8-bis((thiophen-2-ylmethyl)(3-methyloxybenzyl)carbamate)-3,6-dioxaoctane; 1,8-bis((thiophen-2-ylmethyl)(4-methyloxybenzyl)carbamate)-3,6-dioxaoctane; 1,8-bis((3-methyloxybenzyl)(4-methyloxybenzyl)carbamate)-3,6-dioxaoctane; 1,11-bis(bis(thiophen-2-ylmethyl)carbamate)-3,6,9-trioxaundecane; 1,11-bis(bis(3-methyloxybenzyl)carbamate)-3,6,9-trioxaundecane; 1,11-bis(bis(4-methyloxybenzyl)carbamate)-3,6,9-trioxaundecane; 1,11-bis((thiophen-2-ylmethyl)(3-methyloxybenzyl)carbamate)-3,6,9-trioxaundecane; 1,11-bis((thiophen-2-ylmethyl)(4-methyloxybenzyl)carbamate)-3,6,9-trioxaundecane; 1,11-bis((3-methyloxybenzyl)(4-methyloxybenzyl)carbamate)-3,6,9-trioxaundecane; 1,14-bis(bis(thiophen-2-ylmethyl)carbamate)-3,6,9,12-tetraoxatetradecane; 1,14-bis(bis(3-methyloxybenzyl)carbamate)-3,6,9,12-tetraoxatetradecane; 1,14-bis(bis(4-methyloxybenzyl)carbamate)-3,6,9,12-tetraoxatetradecane; 1,14-bis((thiophen-2-ylmethyl)(3-methyloxybenzyl)carbamate)-3,6,9,12-tetraoxatetradecane; 1,14-bis((thiophen-2-ylmethyl)(4-methyloxybenzyl)carbamate)-3,6,9,12-tetraoxatetradecane; 1,14-bis((3-methyloxybenzyl)(4-methyloxybenzyl)carbamate)-3,6,9,12-tetraoxatetradecane; 1,17-bis(bis(thiophen-2-ylmethyl)carbamate)-3,6,9,12,15-pentaoxatetradecane; 1,17-bis(bis(3-methyloxybenzyl)carbamate)-3,6,9,12,15-pentaoxatetradecane; 1,17-bis(bis(4-methyloxybenzyl)carbamate)-3,6,9,12,15-pentaoxatetradecane; 1,17-bis((thiophen-2-ylmethyl)(3-methyloxybenzyl)carbamate)-3,6,9,12,15-pentaoxatetradecane; 1,17-bis((thiophen-2-ylmethyl)(4-methyloxybenzyl)carbamate)-3,6,9,12,15-pentaoxatetradecane; and 1,17-bis((3-methyloxybenzyl)(4-methyloxybenzyl)carbamate)-3,6,9,12,15-pentaoxatetradecane;   a third class compound selected from the group consisting of methyl (6S,10S)-10-(1,3-benzodioxol-5-yl)-6-butyl-3,8-dioxo-1-(2-thienyl)-2-(2-thienylmethyl)-4-oxa-2,7,9-triazadodecan-12-oate; methyl(6S,10R)-10-(1,3-benzodioxol-5-yl)-6-butyl-3,8-dioxo-1-(2-thienyl)-2-(2-thienylmethyl)-4-oxa-2,7,9-triazadodecan-12-oate; methyl (6S,10S)-10-(1,3-benzodioxol-5-yl)-6-butyl-7-methyl-3,8-dioxo-1-(2-thienyl)-2-(2-thienylmethyl)-4-oxa-2,7,9-triazadodecan-12-oate; methyl (6S,10S)-10-(1,3-benzodioxol-5-yl)-6-butyl-9-methyl-3,8-dioxo-1-(2-thienyl)-2-(2-thienylmethyl)-4-oxa-2,7,9-triazadodecan-12-oate; ethyl(6S,10R)-10-(1,3-benzodioxol-5-yl)-6-butyl-7-methyl-3,8-dioxo-1-(2-thienyl)-2-(2-thienylmethyl)-4-oxa-2,7,9-triazadodecan-12-oate; methyl (10S)-10-(1,3-benzodioxol-5-yl)-3,8-dioxo-1-(2-thienyl)-2-(2-thienylmethyl)-4-oxa-2,7,9-triazadodecan-12-oate; methyl 3,8-dioxo-1-(2-thienyl)-2-(2-thienylmethyl)-4-oxa-2,7,9-triazadodecan-12-oate; methyl (6S,10S)-10-(1,3-benzodioxol-5-yl)-6-butyl-2-methyl-3,8-dioxo-1-(2-thienyl)-4-oxa-2,7,9-triazadodecan-12-oate; methyl (6S)-6-butyl-3,8-dioxo-1-(2-thienyl)-2-(2-thienylmethyl)-4-oxa-2,7,9-triazadodecan-12-oate; (2S)-2-{[(1,3-benzodioxol-5-ylmethyl)carbamoyl]amino}hexylbis(2-thienylmethyl)carbamate; methyl(6S,10S)-6-butyl-3,8-dioxo-10-phenyl-1-(2-thienyl)-2-(2-thienylmethyl)-4-oxa-2,7,9-triazadodecan-12-oate; (2S)-2-({[(1S)-1-(1,3-benzodioxol-5-yl)-3-hydroxypropyl]carbamoyl}amino)hexylbis(2-thienylmethyl)carbamate; (2S)-2-[(benzylcarbamoyl)amino]hexylbis(2-thienylmethyl)carbamate; (2S)-2-[(morpholin-4-ylcarbonyl)amino]hexylbis(2-thienylmethyl)carbamate; (2S)-2-{[(3-methoxypropyl)carbamoyl]amino}hexylbis(2-thienylmethyl)carbamate; (2S)-2-{[(2-methoxyethyl)carbamoyl]amino}hexylbis(2-thienylmethyl)carbamate; tert-butyl [(2S)-1-{[bis(2-thienylmethyl)carbamoyl]oxy}hexan-2-yl]carbamate; (2S)-2-[(tert-butylcarbamoyl)amino]hexyl bis(2-thienylmethyl)carbamate; (2S)-2-[(isopropylcarbamoyl)amino]hexylbis(2-thienylmethyl)carbamate; (2S)-2-[(methylcarbamoyl)amino]hexylbis(2-thienylmethyl)carbamate; tert-butyl[(2R)-1-{[bis(2-thienylmethyl)carbamoyl]oxy}hexan-2-yl]carbamate; benzyl {(5S)-6-{[bis(2-thienylmethyl)carbamoyl]oxy}-5-[(tert-butoxycarbonyl)amino]hexyl}carbamate; methyl(9S,13S)-13-(1,3-benzodioxol-5-yl)-9-({[bis(2-thienylmethyl)carbamoyl]oxy}methyl)-3,11-dioxo-1-phenyl-2-oxa-4,10,12-triazapentadecan-15-oate; (2S)-2-acetamidohexylbis(2-thienylmethyl)carbamate; methyl(6R,10S)-10-(1,3-benzodioxol-5-yl)-6-butyl-3,8-dioxo-1-(2-thienyl)-2-(2-thienylmethyl)-4-oxa-2,7,9-triazadodecan-12-oate; methyl(6R,10R)-10-(1,3-benzodioxol-5-yl)-6-butyl-3,8-dioxo-1-(2-thienyl)-2-(2-thienylmethyl)-4-oxa-2,7,9-triazadodecan-12-oate; methyl {[bis(2-thienylmethyl)carbamoyl](methyl)amino}acetate; methyl {[bis(2-thienylmethyl)carbamoyl](butyl)amino}acetate; tert-butyl {[bis(2-thienylmethyl)carbamoyl](butyl)amino}acetate; benzyl {(5S)-6-{[bis(4-methoxybenzyl)carbamoyl]oxy}-5-[(tert-butoxycarbonyl)amino]hexyl}carbamate; tert-butyl [(2S)-1-{[bis(4-methoxybenzyl)carbamoyl]oxy}hexan-2-yl]carbamate; methyl(6S,10S)-10-(1,3-benzodioxol-5-yl)-6-butyl-2-(4-methoxybenzyl)-1-(4-methoxyphenyl)-3,8-dioxo-4-oxa-2,7,9-triazadodecan-12-oate; (2S)-2-({[(1S)-1-(1,3-benzodioxol-5-yl)-3-hydroxypropyl]carbamoyl}amino) hexyl bis(4-methoxybenzyl)carbamate; (2S)-2-[(tertbutoxycarbonyl)amino]hexyl dibenzylcarbamate; methyl(6S,10S)-10-(1,3-benzodioxol-5-yl)-2-benzyl-6-butyl-3,8-dioxo-1-phenyl-4-oxa-2,7,9-triazadodecan-12-oate; tert-butyl [(2S)-1-{[bis(4-methylbenzyl)carbamoyl]oxy}hexan-2-yl]carbamate; methyl (6S,10S)-10-(1,3-benzodioxol-5-yl)-6-butyl-2-(4-methylbenzyl)-1-(4-methylphenyl)-3,8-dioxo-4-oxa-2,7,9-triazadodecan-12-oate; tert-butyl [(2S)-1-{[bis(4-chlorobenzyl)carbamoyl]oxy}hexan-2-yl]carbamate; methyl(6S,10S)-10-(1,3-benzodioxol-5-yl)-6-butyl-2-(4-chlorobenzyl)-1-(4-chlorophenyl)-3,8-dioxo-4-oxa-2,7,9-triazadodecan-12-oate; (2S)-2-[(tertbutoxycarbonyl)amino]hexyl(4-bromobenzyl)(2-thienylmethyl)carbamate; methyl (6S,10S)-10-(1,3-benzodioxol-5-yl)-2-(4-bromobenzyl)-6-butyl-3,8-dioxo-1-(2-thienyl)-4-oxa-2,7,9-triazadodecan-12-oate; methyl(6S,10S)-2-(4-azidoobenzyl)-10-(1,3-benzodioxol-5-yl)-6-butyl-3,8-dioxo-1-(2-thienyl)-4-oxa-2,7,9-triazadodecan-12-oate; (2S)-2-[(tert-butoxycarbonyl)amino]hexylphenyl(2-thienylmethyl)carbamate; methyl (6S,10S)-10-(1,3-benzodioxol-5-yl)-6-butyl-3,8-dioxo-2-phenyl-1-(2-thienyl)-4-oxa-2,7,9-triazadodecan-12-oate; tert-butyl [(2S)-1-{[bis(3-thienylmethyl)carbamoyl]oxy}hexan-2-yl]carbamate; methyl (6S,10S)-10-(1,3-benzodioxol-5-yl)-6-butyl-3,8-dioxo-1-(3-thienyl)-2-(3-thienylmethyl)-4-oxa-2,7,9-triazadodecan-12-oate; benzyl [(5S)-5-[(tertbutoxycarbonyl)amino]-6-{[butyl(2-thienylmethyl)carbamoyl]oxy}hexyl]carbamate; (2S)-2-[(tert-butoxycarbonyl)amino]hexylbutyl(2-thienylmethyl)carbamate; methyl (3S,7S)-3-(1,3-benzodioxol-5-yl)-7-butyl-5,11-dioxo-11-(2-thienylmethyl)-9-oxa-4,6,11-triazapentadecan-1-oate; benzyl [(5S)-5-[(tert-butoxycarbonyl)amino]-6-{[(2-methoxyethyl)(2-thienylmethyl)carbamoyl]oxy}hexyl]carbamate; (2S)-2-[(tert-butoxycarbonyl)amino]hexyl (2-methoxyethyl)(2-thienylmethyl)carbamate; methyl(9S,13S)-13-(1,3-benzodioxol-5-yl)-9-butyl-6,11-dioxo-5-(2-thienylmethyl)-2,7-dioxa-5,10,12-triazapentadecan-15-oate; (2S)-2-[({3-[(methylsulfonyl)amino]benzyl}carbamoyl)amino]hexyl(2-methoxyethyl)(2-thienylmethyl)carbamate; (2S)-2-{[(4-bromobenzyl)carbamoyl]amino}hexylbis(2-thienylmethyl)carbamate; (2S)-2-{[(4-azidobenzyl)carbamoyl]amino}hexylbis(2-thienylmethyl)carbamate; tert-butyl[(2S)-1-{[bis(2-thienylmethyl)carbamoyl]thio}hexan-2-yl]carbamate; and methyl (6S,10S)-10-(1,3-benzodioxol-5-yl)-6-butyl-3,8-dioxo-1-(2-thienyl)-2-(2-thienylmethyl)-4-thia-2,7,9-triazadodecan-12-oate;   a fourth class compound selected from the group consisting of N-{2-[bis(2-thienylmethyl)sulfamoyl]ethyl}-N-(2-thienylmethyl)thiophene-2-sulfonamide; N-{2-[bis(2-thienylmethyl)sulfamoyl]ethyl}-N-(2-thienylmethyl)thiophene-2-carboxamide; 2-{butyl[(2-thienylmethyl)carbamoyl]amino}-N,N-bis(2-thienylmethyl)ethanesulfonamide; 2-{[bis(2-thienylmethyl)carbamoyl](butyl)amino}-N,N-bis(2-thienylmethyl) ethanesulfonamide; N-{3-[bis(2-thienylmethyl)sulfamoyl]propyl}-N-(2-thienylmethyl)thiophene-2-sulfonamide; 2-[(methylsulfonyl)(2-thienylmethyl)amino]-N,N-bis(2-thienylmethyl)ethanesulfonamide; 2-{[bis(2-thienylmethyl)carbamoyl]amino}-N,N-bis(2-thienylmethyl)ethanesulfonamide; N-{2-[bis(2-thienylmethyl)sulfamoyl]ethyl}thiophene-2-sulfonamide; N-{2-[bis(2-thienylmethyl)sulfamoyl]ethyl}-2-(2-thienyl)acetamide; N-{2-[bis(2-thienylmethyl)sulfamoyl]ethyl}thiophene-2-carboxamide; N,N-bis(2-thienylmethyl)-2-{[(2-thienylmethyl)carbamoyl]amino}ethanesulfonamide; 2-({2-[bis(2-thienylmethyl)sulfamoyl]ethyl}amino)-N,N-bis(2-thienylmethyl)acetamide; 3-[{2-[bis(2-thienylmethyl)amino]-2-oxoethyl}(butyl)amino]-N,N-bis(2-thienylmethyl)propanamide; 2-[{2-[bis(2-thienylmethyl)sulfamoyl]ethyl}(methyl)amino]-N,N-bis(2-thienylmethyl)acetamide; 2-[{2-[bis(2-thienylmethyl) sulfamoyl]ethyl}(butyl)amino]-N,N-bis(2-thienylmethyl)acetamide; 3-({2-[bis(2-thienylmethyl)sulfamoyl]ethyl}amino)-N,N-bis(2-thienylmethyl)propanamide; 3-({2-[bis(2-thienylmethyl)sulfamoyl]ethyl}amino)-N,N-bis(4-methoxybenzyl) propanamide; 3-({2-[bis(4-methoxybenzyl)sulfamoyl]ethyl}amino)-N,N-bis(2-thienylmethyl)propanamide; 3-[{2-[bis(2-thienylmethyl)sulfamoyl]ethyl}(methyl)amino]-N,N-bis(2-thienylmethyl) propanamide; 3-[{2-[bis(4-methoxybenzyl) sulfamoyl]ethyl}(methyl)amino]-N,N-bis(2-thienylmethyl) propanamide; (2S)-2-({2-[bis(2-thienylmethyl)sulfamoyl]ethyl}amino)-N,N-bis(2-thienylmethyl) hexanamide; (2S)-2-({2-[bis(4-methoxybenzyl)sulfamoyl]ethyl}amino)-N,N-bis(2-thienylmethyl) hexanamide; 2-(acetyl{2-[bis(2-thienylmethyl)sulfamoyl]ethyl}amino)-N,N-bis(2-thienylmethyl) acetamide; and 2-(acetyl{2-[bis(4-methoxybenzyl) sulfamoyl]ethyl}amino)-N,N-bis(2-thienyl-methyl) acetamide;   pharmaceutically acceptable salts thereof; and   mixtures thereof.