Use of small molecule inhibitors targeting the interaction between Rac GTPase and p67 (phox)

1. A method of treating neutrophil infiltration, hemorrhagic shock or lung inflammation in an individual comprising administering to the individual an effective amount of a compound having the structure of Formula I:

or a pharmaceutically acceptable salt thereof,

wherein:

L 1 is selected from the group consisting of —C—C—C—; —O—C—C—; —O—C—C—C—; or the bridge structure shown below

each optionally substituted with one or more R 1A ;

L 2 is aryl or heteroaryl each optionally substituted with one or more with one or more R 2A ;

each R 1A is independently selected from the group consisting of hydroxy, halo, cyano, nitro, aryl, heteroaryl, heterocyclyl, arylalkyl, heteroarylalkyl, heterocyclylalkyl, cycloalkyl, cycloalkenyl, (cyclolalkyl)alkyl, (R 1BB R 1CC N)alkyl, (C 1 -C 6 )alkyl optionally substituted with up to 5 fluoro, and (C 1 -C 6 )alkoxy optionally substituted with up to 5 fluoro,

said aryl, heteroaryl, heterocyclyl, arylalkyl, heteroarylalkyl, heterocyclylalkyl, cycloalkyl, cycloalkenyl, and (cyclolalkyl)alkyl in the definition of R 1A are each optionally substituted with one or more R 1AA ;

each R 1AA is independently selected from the group consisting of hydroxy, halo, cyano, nitro, aryl, heteroaryl, heterocyclyl, arylalkyl, heteroarylalkyl, heterocyclylalkyl, cycloalkyl, cycloalkenyl, (cyclolalkyl)alkyl, (C 1 -C 6 )alkyl optionally substituted with up to 5 fluoro, and (C 1 -C 6 )alkoxy optionally substituted with up to 5 fluoro;

each R 2A is independently selected from the group consisting of hydroxy, halo, cyano, nitro, —S(O) z NR 1B R 1C , —NHS(O) z NR 1B R 1C , —OC(═O)NR 1B R 1C , —NHC(═O)NR 1B R 1C , —C(═O)NR 1B R 1C , —NR 1B R 1C , —S(O) z R 1D , —NHS(O) z R 1D , —NHC(═O)R 1D , —OC(═O)R 1D , —C(═O)R 1D , —C(═O)OR 1D , hydroxy(C 1 -C 6 )alkyl, aryl, heteroaryl, heterocyclyl, arylalkyl, (cyclolalkyl)alkyl, (C 3 -C 7 )cycloalkyl, (C 1 -C 6 )alkyl optionally substituted with up to 5 fluoro, and (C 1 -C 6 )alkoxy optionally substituted with up to 5 fluoro;

R 1 , R 2 , R 3 , and R 4 are each independently selected from the group consisting of hydrogen, hydroxy, halo, cyano, nitro, —S(O) z NR 1B R 1C , —NHS(O) z NR 1B R 1C , —OC(═O)NR 1B R 1C , —NHC(═O)NR 1B R 1C , —C(═O)NR 1B R 1C , —NR 1B R 1C , —S(O) z R 1D , —NHS(O) z R 1D , —NHC(═O)R 1D , —OC(═O)R 1D , —C(═O)R 1D , —C(═O)OR 1D , hydroxy(C 1 -C 6 )alkyl, aryl, heteroaryl, heterocyclyl, arylalkyl, (cyclolalkyl)alkyl, (C 3 -C 7 )cycloalkyl, (C 1 -C 6 )alkyl optionally substituted with up to 5 fluoro, and (C 1 -C 6 )alkoxy optionally substituted with up to 5 fluoro;

each NR 1B R 1C is independently selected, wherein R 1B and R 1C are each independently from the group consisting of hydrogen, C 1-6 alkyl, aryl, arylalkyl, cycloalkyl, (cyclolalkyl)alkyl, (R 1BB R 1CC N)alkyl, and (R 1BB R 1CC N)C(═O)—;

each R 1D is independently selected from the group consisting of hydroxy, aryl, heteroaryl, heterocyclyl, arylalkyl, cycloalkyl, cycloalkenyl, (cyclolalkyl)alkyl, (R 1BB R 1CC N)alkyl, (C 1 -C 6 )alkyl optionally substituted with up to 5 fluoro, and (C 1 -C 6 )alkoxy optionally substituted with up to 5 fluoro;

each R 1BB R 1CC N is independently selected, wherein R 1BB and R 1CC are each independently from the group consisting of hydrogen, C 1-6 alkylOC(═O)—, C 1-6 alkyl, C 1-6 alkylC(═O)—, aryl, arylalkyl, cycloalkyl, and heterocyclyl;

X is N (nitrogen) or NR 11 ;

each z is independently 0, 1 or 2;

R 11 is H (hydrogen) or C 1-6 alkyl;

X 2 is C (carbon), or CR 12 ;

R 12 is H (hydrogen) or C 1-6 alkyl; and

each dashed line is an optional double bond.

2. The method of claim 1 , wherein the compound having the structure of Formula I has the structure of Formula II,

or a pharmaceutically acceptable salt thereof,

wherein:

R 5 , R 6 , R 7 , R 8 , and R 9 are each independently selected from the group consisting of hydrogen, hydroxy, halo, cyano, nitro, —S(O) z NR 1E R 1F , —NHS(O) z NR 1E R 1F , —OC(═O)NR 1E R 1F , —NHC(═O)NR 1E R 1F , —C(═O)NR 1E R 1F , —NR 1E R 1F , —S(O) z R 1G , —NHS(O) z R 1G , —NHC(═O)R 1G , —OC(═O)R 1G , —C(═O)R 1G , —C(═O)OR 1G , hydroxy(C 1 -C 6 )alkyl, aryl, heteroaryl, heterocyclyl, arylalkyl, (cyclolalkyl)alkyl, (C 3 -C 7 )cycloalkyl, (C 1 -C 6 )alkyl optionally substituted with up to 5 fluoro, and (C 1 -C 6 )alkoxy optionally substituted with up to 5 fluoro;

each NR 1E R 1F is independently selected, wherein R 1E and R 1F are each independently from the group consisting of hydrogen, C 1-6 alkyl, aryl, arylalkyl, cycloalkyl, (cyclolalkyl)alkyl, (R 1EE R 1FF N)alkyl, and (R 1EE R 1FF N)C(═O)—;

each R 1G is independently selected from the group consisting of hydroxy, aryl, heteroaryl, heterocyclyl, arylalkyl, cycloalkyl, cycloalkenyl, (cyclolalkyl)alkyl, (R 1EE R 1FF N)alkyl, (C 1 -C 6 )alkyl optionally substituted with up to 5 fluoro, and (C 1 -C 6 )alkoxy optionally substituted with up to 5 fluoro; and

each R 1EE R 1FF N is independently selected, wherein R 1EE and R 1FF are each independently from the group consisting of hydrogen, C 1-6 alkylOC(═O)—, C 1-6 alkyl, C 1-6 alkylC(═O)—, aryl, arylalkyl, cycloalkyl, and heterocyclyl.

3. The method of claim 2 , wherein the compound having the structure of Formula II has the structure of Formula Ia, Formula Ic, or Formula Id,

or a pharmaceutically acceptable salt thereof.

4. The method of claim 3 , wherein the compound having the structure of Formula Ia has the structure of Formula Iaa, Iab, or Iac,

or a pharmaceutically acceptable salt thereof.

5. The method of claim 3 , wherein the compound having the structure of Formula Ic has the structure of Formula Ica or Icb,

or a pharmaceutically acceptable salt thereof.

6. The method of claim 3 , wherein the compound having the structure of Formula Id has the structure of Formula Ida,

or a pharmaceutically acceptable salt thereof.

7. The method of claim 1 , wherein:

R 1 , R 2 , R 3 , and R 4 are each independently selected from the group consisting of hydrogen, hydroxy, halo, cyano, nitro, —S(O) z NR 1B R 1C , —C(═O)NR 1B R 1C , —NR 1B R 1C , —NHS(O) z R 1D , —NHC(═O)R 1D , —C(═O)R 1D , —C(═O)OR 1D , hydroxy(C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl optionally substituted with up to 5 fluoro, and (C 1 -C 6 )alkoxy optionally substituted with up to 5 fluoro;

each NR 1B R 1C is independently selected, wherein R 1B and R 1C are each independently from the group consisting of hydrogen, and C 1-6 alkyl; and

each R 1D is independently selected from the group consisting of (C 1 -C 6 )alkyl optionally substituted with up to 5 fluoro, and (C 1 -C 6 )alkoxy optionally substituted with up to 5 fluoro.

8. The method of claim 2 , wherein:

R 5 , R 6 , R 7 , R 8 , and R 9 are each independently selected from the group consisting of hydrogen, halo, nitro, —NR 1E R 1F , (C 1 -C 6 )alkyl optionally substituted with up to 5 fluoro, and (C 1 -C 6 )alkoxy optionally substituted with up to 5 fluoro; and

each NR 1E R 1F is independently selected, wherein R 1E and R 1F are each independently from the group consisting of hydrogen, and C 1-6 alkyl.

9. A pharmaceutical composition comprising a pharmaceutically acceptable excipient, and a compound having the structure of Formula Ica or Icb,

or a pharmaceutically acceptable salt thereof, wherein

R 1 is selected from the group consisting of hydrogen, hydroxy, halo, cyano, nitro, —S(O) z NR 1B R 1C , —NHS(O) z NR 1B R 1C , —OC(═O)NR 1B R 1C , —NHC(═O)NR 1B R 1C , —C(═O)NR 1B R 1C , —NR 1B R 1C , —S(O) z R 1D , —NHS(O) z R 1D , —NHC(═O)R 1D , —OC(═O)R 1D , —C(═O)R 1D , —C(═O)OR 1D , hydroxy(C 1 -C 6 )alkyl, aryl, heteroaryl, heterocyclyl, arylalkyl, (cyclolalkyl)alkyl, (C 3 -C 7 )cycloalkyl, (C 1 -C 6 )alkyl optionally substituted with up to 5 fluoro, and (C 1 -C 6 )alkoxy optionally substituted with up to 5 fluoro;

R 2 is selected from the group consisting of hydrogen, fluoro, bromo, —S(O) z NR 1B R 1C , —NHS(O) z NR 1B R 1C , —OC(═O)NR 1B R 1C , —NHC(═O)NR 1B R 1C , —S(O) z R 1D , —OC(═O)R 1D , hydroxy(C 2 -C 6 )alkyl, aryl, heteroaryl, heterocyclyl, arylalkyl, (cyclolalkyl)alkyl, (C 3 -C 7 )cycloalkyl, (C 4 -C 6 )alkyl optionally substituted with up to 5 fluoro, and (C 2 -C 6 )alkoxy optionally substituted with up to 5 fluoro;

R 3 is selected from the group consisting of hydrogen, hydroxy, halo, cyano, nitro, —S(O) z NR 1B R 1C , —NHS(O) z NR 1B R 1C , —OC(═O)NR 1B R 1C , —NHC(═O)NR 1B R 1C , —C(═O)NR 1B R 1C , —NR 1B R 1C , —S(O) z R 1D , —NHS(O) z R 1D , —NHC(═O)R 1D , —OC(═O)R 1D , —C(═O)R 1D , —C(═O)OR 1D , hydroxy(C 1 -C 6 )alkyl, aryl, heteroaryl, heterocyclyl, arylalkyl, (cyclolalkyl)alkyl, (C 3 -C 7 )cycloalkyl, (C 1 -C 6 )alkyl optionally substituted with up to 5 fluoro, and (C 1 -C 6 )alkoxy optionally substituted with up to 5 fluoro;

R 4 is selected from the group consisting of hydrogen, hydroxy, halo, cyano, nitro, —S(O) z NR 1B R 1C , —NHS(O) z NR 1B R 1C , —OC(═O)NR 1B R 1C , —NHC(═O)NR 1B R 1C , —C(═O)NR 1B R 1C , —NR 1B R 1C , —S(O) z R 1D , —NHS(O) z R 1D , —NHC(═O)R 1D , —OC(═O)R 1D , —C(═O)R 2D , —C(═O)OR 2D , hydroxy(C 1 -C 6 )alkyl, aryl, heteroaryl, heterocyclyl, arylalkyl, (cyclolalkyl)alkyl, (C 3 -C 7 )cycloalkyl, (C 1 -C 6 )alkyl optionally substituted with up to 5 fluoro, and (C 1 -C 6 )alkoxy optionally substituted with up to 5 fluoro, wherein R 2 or R 4 is not hydrogen;

each NR 1B R 1C is independently selected, wherein R 1B and R 1C are each independently from the group consisting of hydrogen, C 1-6 alkyl, aryl, arylalkyl, cycloalkyl, (cyclolalkyl)alkyl, (R 1BB R 1CC N)alkyl, and (R 1BB R 1CC N)C(═O)—;

each R 1D is independently selected from the group consisting of hydroxy, aryl, heteroaryl, heterocyclyl, arylalkyl, cycloalkyl, cycloalkenyl, (cyclolalkyl)alkyl, (R 1BB R 1CC N)alkyl, (C 1 -C 6 )alkyl optionally substituted with up to 5 fluoro, and (C 1 -C 6 )alkoxy optionally substituted with up to 5 fluoro;

each R 2D is independently selected from the group consisting of hydroxy, aryl, heteroaryl, heterocyclyl, arylalkyl, cycloalkyl, cycloalkenyl, (cyclolalkyl)alkyl, (R 1BB R 1CC N)alkyl, (C 1 -C 6 )alkyl substituted with up to 5 fluoro, and (C 1 -C 6 )alkoxy substituted with up to 5 fluoro;

each R 1BB R 1CC N is independently selected, wherein R 1BB and R 1CC are each independently from the group consisting of hydrogen, C 1-6 alkylOC(═O)—, C 1-6 alkyl, C 1-6 alkylC(═O)—, aryl, arylalkyl, cycloalkyl, and heterocyclyl;

R 5 is selected from the group consisting of hydrogen, hydroxy, halo, cyano, nitro, —S(O) z NR 1E R 1F , —NHS(O) z NR 1E R 1F , —OC(═O)NR 1E R 1F , —NHC(═O)NR 1E R 1F , —C(═O)NR 1E R 1F , —NR 1E R 1F , —S(O) z R 1G , —NHS(O) z R 1G , —NHC(═O)R 1G , —OC(═O)R 1G , —C(═O)R 1G , —C(═O)OR 1G , hydroxy(C 1 -C 6 )alkyl, aryl, heteroaryl, heterocyclyl, arylalkyl, (cyclolalkyl)alkyl, (C 3 -C 7 )cycloalkyl, (C 1 -C 6 )alkyl optionally substituted with up to 5 fluoro, and (C 1 -C 6 )alkoxy optionally substituted with up to 5 fluoro;

R 6 is selected from the group consisting of hydrogen, hydroxy, halo, cyano, nitro, —S(O) z NR 1E R 1F , —NHS(O) z NR 1E R 1F , —OC(═O)NR 1E R 1F , —NHC(═O)NR 1E R 1F , —C(═O)NR 1E R 1F , —NR 1E R 1F , —S(O) z R 1G , —NHS(O) z R 1G , —NHC(═O)R 1G , —OC(═O)R 1G , —C(═O)R 1G , —C(═O)OR 1G , hydroxy(C 1 -C 6 )alkyl, aryl, heteroaryl, heterocyclyl, arylalkyl, (cyclolalkyl)alkyl, (C 3 -C 7 )cycloalkyl, (C 1 -C 6 )alkyl optionally substituted with up to 5 fluoro, and (C 1 -C 6 )alkoxy optionally substituted with up to 5 fluoro;

R 7 is selected from the group consisting of hydrogen, hydroxy, halo, cyano, nitro, —S(O) z NR 1E R 1F , —NHS(O) z NR 1E R 1F , —OC(═O)NR 1E R 1F , —NHC(═O)NR 1E R 1F , —C(═O)NR 1E R 1F , —NR 1E R 1F , —S(O) z R 1G , —NHS(O) z R 1G , —NHC(═O)R 1G , —OC(═O)R 1G , —C(═O)R 1G , —C(═O)OR 1G , hydroxy(C 1 -C 6 )alkyl, aryl, heteroaryl, heterocyclyl, arylalkyl, (cyclolalkyl)alkyl, (C 3 -C 7 )cycloalkyl, (C 1 -C 6 )alkyl optionally substituted with up to 5 fluoro, and (C 1 -C 6 )alkoxy optionally substituted with up to 5 fluoro;

R 8 is selected from the group consisting of hydrogen, hydroxy, halo, cyano, nitro, —S(O) z NR 1E R 1F , —NHS(O) z NR 1E R 1F , —OC(═O)NR 1E R 1F , —NHC(═O)NR 1E R 1F , —C(═O)NR 1E R 1F , —NR 1E R 1F , —S(O) z R 1G , —NHS(O) z R 1G , —NHC(═O)R 1G , —OC(═O)R 1G , —C(═O)R 1G , —C(═O)OR 1G , hydroxy(C 1 -C 6 )alkyl, aryl, heteroaryl, heterocyclyl, arylalkyl, (cyclolalkyl)alkyl, (C 3 -C 7 )cycloalkyl, (C 1 -C 6 )alkyl optionally substituted with up to 5 fluoro, and (C 1 -C 6 )alkoxy optionally substituted with up to 5 fluoro;

R 9 is selected from the group consisting of hydrogen, hydroxy, halo, cyano, nitro, —S(O) z NR 1E R 1F , —NHS(O) z NR 1E R 1F , —OC(═O)NR 1E R 1F , —NHC(═O)NR 1E R 1F , —C(═O)NR 1E R 1F , —NR 1E R 1F , —S(O) z R 1G , —NHS(O) z R 1G , —NHC(═O)R 1G , —OC(═O)R 1G , —C(═O)R 1G , —C(═O)OR 1G , hydroxy(C 1 -C 6 )alkyl, aryl, heteroaryl, heterocyclyl, arylalkyl, (cyclolalkyl)alkyl, (C 3 -C 7 )cycloalkyl, (C 1 -C 6 )alkyl optionally substituted with up to 5 fluoro, and (C 1 -C 6 )alkoxy optionally substituted with up to 5 fluoro;

each NR 1E R 1F is independently selected, wherein R 1E and R 1F are each independently from the group consisting of hydrogen, C 1-6 alkyl, aryl, arylalkyl, cycloalkyl, (cyclolalkyl)alkyl, (R 1EE R 1FF N)alkyl, and (R 1EE R 1FF N)C(═O)—;

R 1G is independently selected from the group consisting of hydroxy, aryl, heteroaryl, heterocyclyl, arylalkyl, cycloalkyl, cycloalkenyl, (cyclolalkyl)alkyl, (R 1EE R 1FF N)alkyl, (C 1 -C 6 )alkyl optionally substituted with up to 5 fluoro, and (C 1 -C 6 )alkoxy optionally substituted with up to 5 fluoro;

each R 1EE R 1FF N is independently selected, wherein R 1EE and R 1FF are each independently from the group consisting of hydrogen, C 1-6 alkylOC(═O)—, C 1-6 alkyl, C 1-6 alkylC(═O)—, aryl, arylalkyl, cycloalkyl, and heterocyclyl; and

each dashed line is an optional double bond.

10. A compound having the structure:

or a pharmaceutically acceptable salt thereof.

11. The compound of claim 10 having the structure:

or a pharmaceutically acceptable salt thereof.

12. A pharmaceutical composition comprising a pharmaceutically acceptable excipient, and a compound, wherein the compound is:

or a pharmaceutically acceptable salt thereof.

13. The method of claim 1 , wherein the compound is:

or a pharmaceutically acceptable salt thereof.

14. The method of claim 1 , wherein the compound is:

or a pharmaceutically acceptable salt thereof.