Methods to modulate Rac1 import and to treat pulmonary fibrosis

1. A method to treat pulmonary fibrosis in an animal in need thereof comprising administering to the animal an effective amount of a compound of formula I, formula II or formula III:

wherein:

R 1 is a saturated or unsaturated (C 5 -C 20 )alkyl chain that optionally comprises one or more aryl rings in the chain and that is optionally substituted with one or more halo, trifluoromethyl, —OR a , —P(═O)(OR a ) 2 , or —NR b R c ;

R 2 is a saturated or unsaturated (C 5 -C 20 )alkyl chain that optionally comprises one or more aryl rings in the chain and that is optionally substituted with one or more halo, trifluoromethyl, —OR a , —P(═O)(OR a ) 2 , or —NR b R c ;

each R 3 , R 4 , R 5 , and R 6 is independently OH or (C 1 -C 6 )alkoxy;

each R a is independently H, (C 1 -C 6 )alkyl, or aryl; and

each R b and R c is independently H, (C 1 -C 6 )alkyl, or aryl; or R b and R c together with the nitrogen to which they are attached form a pyrrolidino, piperidino, morpholino, or thiomorpholino ring;

wherein any aryl of R 1 , R 2 , R a , R b or R c is optionally substituted with one or more (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkanoyl, (C 1 -C 6 )alkanoyloxy, (C 1 -C 6 )alkoxycarbonyl, halo, cyano, nitro, carboxy, trifluoromethyl, trifluoromethoxy, NR d R e or S(O) 2 NR d R e , wherein each R d and R e is independently H or (C 1 -C 6 )alkyl;

X is (C 1 -C 6 )alkyl;

Y is (C 1 -C 6 )alkyl;

R 7 is a saturated or unsaturated (C 1 -C 20 )alkyl chain that optionally comprises one or more aryl or heteroaryl rings in the chain wherein (C 1 -C 20 )alkyl is optionally substituted with one or more halo, cyano, nitro, carboxy, trifluoromethyl, trifluoromethoxy, aryl, heteroaryl, NR m R n or S(O) 2 NR p R q and wherein any aryl or heteroaryl is optionally substituted with one or more (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkanoyl, (C 1 -C 6 )alkanoyloxy, (C 1 -C 6 )alkoxycarbonyl, halo, cyano, nitro, carboxy, trifluoromethyl, trifluoromethoxy, NR a1 R b1 , or S(O) 2 NR c1 R d1 ;

R 8 is H or a saturated or unsaturated (C 1 -C 20 )alkyl chain that optionally comprises one or more aryl or heteroaryl rings in the chain wherein (C 1 -C 20 )alkyl is optionally substituted with one or more halo, cyano, nitro, carboxy, trifluoromethyl, trifluoromethoxy, aryl, heteroaryl, NR m R n , or S(O) 2 NR p R q and wherein any aryl or heteroaryl is optionally substituted with one or more (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkanoyl, (C 1 -C 6 )alkanoyloxy, (C 1 -C 6 )alkoxycarbonyl, halo, cyano, nitro, carboxy, trifluoromethyl, trifluoromethoxy, NR a1 R b1 , or S(O) 2 NR c1 R d1 ;

each R 9 , R 10 , R 11 , and R 12 is independently OH or (C 1 -C 6 )alkoxy;

R 13 is a saturated or unsaturated (C 1 -C 20 )alkyl chain that optionally comprises one or more aryl or heteroaryl rings in the chain wherein (C 1 -C 20 )alkyl is optionally substituted with one or more halo, cyano, nitro, carboxy, trifluoromethyl, trifluoromethoxy, aryl, heteroaryl, NR m R n , or S(O) 2 NR p R q and wherein any aryl or heteroaryl is optionally substituted with one or more (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkanoyl, (C 1 -C 6 )alkanoyloxy, (C 1 -C 6 )alkoxycarbonyl, halo, cyano, nitro, carboxy, trifluoromethyl, trifluoromethoxy, NR a1 R b1 , aryl, heteroaryl, or S(O) 2 NR c1 R d1 ;

R 14 is a saturated or unsaturated (C 1 -C 20 )alkyl chain that optionally comprises one or more aryl or heteroaryl rings in the chain wherein (C 1 -C 20 )alkyl is optionally substituted with one or more halo, cyano, nitro, carboxy, trifluoromethyl, trifluoromethoxy, aryl, heteroaryl, NR m R n , or S(O) 2 NR p R q and wherein any aryl or heteroaryl is optionally substituted with one or more (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkanoyl, (C 1 -C 6 )alkanoyloxy, (C 1 -C 6 )alkoxycarbonyl, halo, cyano, nitro, carboxy, trifluoromethyl, trifluoromethoxy, NR a1 R b1 , aryl, heteroaryl, or S(O) 2 NR c1 R d1 ;

R 15 is a saturated or unsaturated (C 1 -C 20 )alkyl chain that optionally comprises one or more aryl or heteroaryl rings in the chain wherein (C 1 -C 20 )alkyl is optionally substituted with one or more halo, cyano, nitro, carboxy, trifluoromethyl, trifluoromethoxy, aryl, heteroaryl, NR m R n , or S(O) 2 NR p R q and wherein any aryl or heteroaryl is optionally substituted with one or more (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkanoyl, (C 1 -C 6 )alkanoyloxy, (C 1 -C 6 )alkoxycarbonyl, halo, cyano, nitro, carboxy, trifluoromethyl, trifluoromethoxy, NR a1 R b1 , or S(O) 2 NR c1 R d1 ;

R 16 is H or a saturated or unsaturated (C 1 -C 20 )alkyl chain that optionally comprises one or more aryl or heteroaryl rings in the chain wherein (C 1 -C 20 )alkyl is optionally substituted with one or more halo, cyano, nitro, carboxy, trifluoromethyl, trifluoromethoxy, aryl, heteroaryl, NR m R n , or S(O) 2 NR p R q and wherein any aryl or heteroaryl is optionally substituted with one or more (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkanoyl, (C 1 -C 6 )alkanoyloxy, (C 1 -C 6 )alkoxycarbonyl, halo, cyano, nitro, carboxy, trifluoromethyl, trifluoromethoxy, NR a1 R b1 , or S(O) 2 NR c1 R d1 ;

each R a1 and R b1 is independently H, (C 1 -C 6 )alkyl, or aryl; or R a1 and R b1 together with the nitrogen to which they are attached form a pyrrolidino, piperidino, morpholino, or thiomorpholino ring;

each R c1 and R d1 is independently H, (C 1 -C 6 )alkyl, or aryl; or R c1 and R d1 together with the nitrogen to which they are attached form a pyrrolidino, piperidino, morpholino, or thiomorpholino ring;

each R p and R q is independently H, (C 1 -C 6 )alkyl, or aryl; or R p and R q together with the nitrogen to which they are attached form a pyrrolidino, piperidino, morpholino, or thiomorpholino ring;

each R p and R q is independently H, (C 1 -C 6 )alkyl, or aryl; or R p and R q together with the nitrogen to which they are attached form a pyrrolidino, piperidino, morpholino, or thiomorpholino ring; and

wherein any aryl of R a1 , R b1 , R c1 , R d1 , R m , R n , R p or R q is optionally substituted with one or more (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkanoyl, (C 1 -C 6 )alkanoyloxy, (C 1 -C 6 )alkoxycarbonyl, halo, cyano, nitro, carboxy, trifluoromethyl, trifluoromethoxy, NR s R t , or S(O) 2 NR s R t wherein each R s and R t is independently H or (C 1 -C 6 )alkyl;

or a pharmaceutically acceptable salt or prodrug thereof.

2. The method of claim 1 , comprising administering to the animal a compound of formula I:

or a pharmaceutically acceptable salt or prodrug thereof.

3. The method of claim 1 , wherein R 1 is of the formula,

wherein:

n is 0, 1, or 2; and

R g and R h together with the atoms to which they are attached form an aryl ring that is optionally substituted with one or more (e.g. 1, 2, 3, or 4) (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkanoyl, (C 1 -C 6 )alkanoyloxy, (C 1 -C 6 )alkoxycarbonyl, halo, cyano, nitro, carboxy, trifluoromethyl, trifluoromethoxy, NR d R e , or S(O) 2 NR d R e , wherein each R d and R e is independently H or (C 1 -C 6 )alkyl.

4. The method of claim 1 , wherein R 1 is of the formula,

wherein:

n is 0, 1, 2, or 3;

each bond designated by ----- is independently either present or is absent; and R b is phenyl or naphthyl and is optionally substituted with one or more carboxy or S(O) 2 NR d R e , wherein each R d and R e is independently H or (C 1 -C 6 )alkyl.

5. The method of claim 3 , wherein R 2 is of the formula,

wherein:

n is 0, 1, or 2; and

R g and R h together with the atoms to which they are attached form an aryl ring that is optionally substituted with one or more (e.g. 1, 2, 3, or 4) (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkanoyl, (C 1 -C 6 )alkanoyloxy, (C 1 -C 6 )alkoxycarbonyl, halo, cyano, nitro, carboxy, trifluoromethyl, trifluoromethoxy, NR d R e , or S(O) 2 NR d R e , wherein each R d and R e is independently H or (C 1 -C 6 )alkyl.

6. The method of claim 3 , wherein R 2 is of the formula,

wherein:

n is 0, 1, 2, or 3;

each bond designated by ----- is independently either present or is absent; and

R b is phenyl or naphthyl and is optionally substituted with one or more carboxy or S(O) 2 NR d R e , wherein each R d and R e is independently H or (C 1 -C 6 )alkyl.

7. The method of claim 1 wherein the compound is:

tetramethyl (E)-1,1-bis(4,8-dimethyl-nona-3,7-dienyl)-1,1-bisphosphonate,

tetraethyl 4,8-dimethyl-3,7-nonadienyl-1,1-bisphosphonate,

tetraethyl (2E,6E)-1-(3-methyl-but-2-enyl)-3,7,11-trimethyl-dodeca-2,6,10-trienyl-1,1-bisphosphonate,

1-(3,7-dimethyl-octa-2,6-dienyl)-4,8-dimethyl-nona-3,7-dienyl-1,1-bisphosphonic acid, tetrasodium salt,

tetrapivaloyloxymethyl (E)-1,1-bis(4,8-dimethyl-nona-3,7-dienyl)-1,1-bisphosphonate, or

(2E,6E)-1-(3-methyl-but-2-enyl)-3,7,11-trimethyl-dodeca-2,6,10-triene-1,1-bisphosphonate, or a pharmaceutically acceptable salt or prodrug thereof.

8. The method of claim 1 , comprising administering to the animal a compound of formula II, or a pharmaceutically acceptable salt or prodrug thereof.

9. The method of claim 8 , wherein R 7 is

10. The method of claim 1 , comprising administering to the animal a compound of formula III, or a pharmaceutically acceptable salt or prodrug thereof.

11. The method of claim 1 wherein the compound is:

or a pharmaceutically acceptable salt or prodrug thereof.

12. The method of claim 1 , wherein the compound of formula I, or the pharmaceutically acceptable salt or prodrug thereof is digeranyl bisphosphonate, or a pharmaceutically acceptable salt or prodrug thereof.