Immune system modulators

1. A compound of formula I or a pharmaceutically acceptable salt thereof,

Wherein

X is an alkyl, alkylamino, cycloalkyl, aryl, or heterocycle;

Q is H, (CH 2 ) q NR 1 R 2 , NR 1 (CH 2 ) p NR b R c , OR 1 , SR 1 , or CHR 1 R 2 , in which q is 0 or 1 and p is 2-4;

R 1 and R 2 are each independently hydrogen, alkyl, alkenyl, cycloalkyl, alkylcycloalkyl, aryl, alkylaryl, heterocycle, alkylheterocycle, or R 1 and R 2 together with the nitrogen atom to which they are bonded form a heterocycle, which may be optionally substituted by from one to four groups which may be the same or different selected from (C 1 -C 4 )alkyl, phenyl, benzyl, C(═O)R 12 , (CH 2 ) p OR a , and (CH 2 ) p NR b R c , in which p is 2-4;

R 7 is heteroaryl or NR 3 R 4 , wherein the heteroaryl is optionally substituted by (C 1 -C 4 )alkyl;

R 3 and R 4 are each independently hydrogen, alkyl, cycloalkyl, alkenyl, aryl or alkylaryl, or R 3 and R 4 together with the nitrogen atom to which they are bonded form a heterocycle;

Y is NR 11 , where R 11 is hydrogen, alkyl, cycloalkyl, alkenyl, or aryl group;

R 12 is alkyl, aryl, or heterocycle;

L is alkyl or alkenyl containing from 2 to 10 carbon atoms;

R 5 is hydrogen, halogen, cyano, nitro, CF 3 , OCF 3 , alkyl, cycloalkyl, alkenyl, aryl, heterocycle, OR a , SR a , S(═O)R a , S(═O) 2 R a , NR b R c , S(═O) 2 NR b R c , C(═O)OR a , C(═O)R a , C(═O)NR b R c , OC(═O)R a , OC(═O)NR b R c , NR b C(═O)OR a , or NR b C(═O)R a ;

R 6 is (CH 2 ) r C(═O)O(C 1 -C 4 )alkyl, aryl, heterocycle, (CH 2 ) p NR b R c , or alkylheterocycle, wherein r is 0-4 and p is 2-4;

each occurrence of R a is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl; and

each occurrence of R b , and R c is independently hydrogen, alkyl, cycloalkyl, heterocycle, aryl, or said R b and R c together with the nitrogen atom to which they are bonded optionally form a heterocycle.

2. The compound of claim 1 , wherein X is alkyl.

3. The compound of claim 1 , wherein X is cycloalkyl.

4. The compound of claim 1 , wherein X is heterocycle.

5. The compound of claim 1 , wherein L is alkyl or alkenyl containing from 2 to 4 carbon atoms.

6. The compound of claim 1 having the structure of formula II:

Wherein

Q is H, (CH 2 ) q NR 1 R 2 , NR 1 (CH 2 ) p NR b R c , OR 1 , SR 1 , or CHR 1 R 2 , in which q is 0 or 1 and p is 2-4;

R 1 and R 2 are each independently hydrogen, alkyl, alkenyl, cycloalkyl, alkylcycloalkyl, aryl, alkylaryl, heterocycle, alkylheterocycle, or R 1 and R 2 together with the nitrogen atom to which they are bonded form a heterocycle, which may be optionally substituted by from one to four groups which may be the same or different selected from (C 1 -C 4 )alkyl, phenyl, benzyl, C(═O)R 12 , (CH 2 ) p OR a , and (CH 2 ) p NR b R c , in which p is 2-4;

R 7 is heteroaryl, wherein the heteroaryl is optionally substituted by (C 1 -C 4 )alkyl;

m is 2-6;

R 12 is alkyl, aryl, or heterocycle;

each occurrence of R a is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl; and

each occurrence of R b , and R c is independently hydrogen, alkyl, cycloalkyl, heterocycle, aryl, or said R b and R c together with the nitrogen atom to which they are bonded optionally form a heterocycle.

7. The compound of claim 1 having the structure of formula III:

Wherein

R 1 and R 2 are each independently hydrogen, alkyl, alkenyl, cycloalkyl, alkylcycloalkyl, aryl, alkylaryl, heterocycle, alkylheterocycle, or R 1 and R 2 together with the nitrogen atom to which they are bonded form a heterocycle, which may be optionally substituted by from one to four groups which may be the same or different selected from (C 1 -C 4 )alkyl, phenyl, benzyl, C(═O)R 12 , (CH 2 ) p OR a , and (CH 2 ) p NR b R c , in which p is 2-4;

R 7 is heteroaryl, wherein the heteroaryl is optionally substituted by (C 1 -C 4 )alkyl;

m is 2-6;

R 12 is alkyl, aryl, or heterocycle;

each occurrence of R a is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl; and

each occurrence of R b , and R c is independently hydrogen, alkyl, cycloalkyl, heterocycle, aryl, or said R b and R c together with the nitrogen atom to which they are bonded optionally form a heterocycle.

8. The compound of claim 1 having the structure of formula IV:

Wherein

Q is H, (CH 2 ) q NR 1 R 2 , NR 1 (CH 2 ) p NR b R c , OR 1 , SR 1 , or CHR 1 R 2 , in which q is 0 or 1 and p is 2-4;

R 1 and R 2 are each independently hydrogen, alkyl, alkenyl, cycloalkyl, alkylcycloalkyl, aryl, alkylaryl, heterocycle, alkylheterocycle, or R 1 and R 2 together with the nitrogen atom to which they are bonded form a heterocycle, which may be optionally substituted by from one to four groups which may be the same or different selected from (C 1 -C 4 )alkyl, phenyl, benzyl, C(═O)R 12 , (CH 2 ) p OR a , and (CH 2 ) p NR b R c , in which p is 2-4;

n is 2-6;

R 3 and R 4 are each independently hydrogen, alkyl, cycloalkyl, alkenyl, aryl or alkylaryl, or R 3 and R 4 together with the nitrogen atom to which they are bonded form a heterocycle;

R 12 is alkyl, aryl, or heterocycle;

each occurrence of R a is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl; and

each occurrence of R b , and R c is independently hydrogen, alkyl, cycloalkyl, heterocycle, aryl, or said R b and R c together with the nitrogen atom to which they are bonded optionally form a heterocycle.

9. The compound of claim 1 , wherein Q is H, OR 1 , or SR 1 .

10. The compound of claim 1 , wherein R 1 and R 2 are each independently hydrogen, alkyl, cycloalkyl, alkylcycloalkyl, aryl, alkylaryl, heterocycle, alkylheterocycle, or R 1 and R 2 together with the nitrogen atom to which they are bonded form a heterocycle, which may be optionally substituted by from one to four groups which may be the same or different selected from (C 1 -C 4 )alkyl, phenyl, benzyl, C(═O)R 12 , (CH 2 ) p OR a , and (CH 2 ) p NR b R c , in which p is 2-4.

11. The compound of claim 1 , wherein NR 1 R 2 , NR 3 R 4 , and NR b R c are each independently a heterocycle selected from

in which R d is H, Me, Et, n-Pr, i-Pr, n-Bu, i-Bu, t-Bu, CH 2 CMe 3 , Ph, CH 2 Ph, C(═O)R 12 , (CH 2 ) p OR a′ , and (CH 2 ) p NR b′ R c′ , wherein R 12 is alkyl, phenyl, or heterocycle; R a′ , R b′ and R c′ are each independently hydrogen, or (C 1 -C 4 )alkyl, or R b′ and R e′ , together with the nitrogen atom to which they are attached, form a saturated or unsaturated heterocyclic ring containing from three to seven ring atoms, which ring may optionally contain another heteroatom selected from the group consisting of nitrogen, oxygen and sulfur and may be optionally substituted by from one to four groups which may be the same or different selected from the group consisting of alkyl, phenyl and benzyl; and p is 2-4.

12. The compound of claim 1 , wherein R 5 is hydrogen, halogen, (C 1 -C 4 )alkyl, hydroxy, (C 1 -C 4 )alkoxy, SR a , S(═O)R a , S(═O) 2 R a , S(═O) 2 NR b R c , in which R a , R b and R c are each independently hydrogen or (C 1 -C 4 )alkyl.

13. The compound of claim 1 , wherein R 6 is

14. A compound of claim 1 selected from Tables 1-2 and Examples 15 and 55-63 shown below:

TABLE 1

wherein R 7 = NR 3 R 4

Example

No.

X

Q

Y

L

R 3

R 4

R 5

R 6

15

NH

—(CH 2 ) 2 —

H

TABLE 2

Example

No.

X—Q

Y

L

R 3

R 4

R 5

R 6

R 7

55

NH

—(CH 2 ) 2 —

H

NR 3 R 4

56

NH

—(CH 2 ) 2 —

OH

NR 3 R 4

57

NH

—(CH 2 ) 2 —

OH

NR 3 R 4

58

NH

—(CH 2 ) 2 —

OH

NR 3 R 4

59

NH

—(CH 2 ) 2 —

H

NR 3 R 4

60

NH

—(CH 2 ) 2 —

H

NR 3 R 4

61

NH

—(CH 2 ) 2 —

H

NR 3 R 4

62

NH

—(CH 2 ) 2 —

H

NR 3 R 4

63

NH

—(CH 2 ) 2 —

OH

NR 3 R 4 .

15. A pharmaceutical composition comprising at least one compound according to claim 1 and a pharmaceutically-acceptable carrier or diluent.

16. A method of treating an autoimmune disease in a mammalian species having TLR-mediated immunostimulation, comprising administering to the mammalian species a therapeutically effective amount of at least one compound according to claim 1 .

17. The method of claim 16 , wherein the autoimmune disease is selected from cutaneous and systemic lupus erythematosus, insulin-dependent diabetes mellitus, rheumatoid arthritis, multiple sclerosis, atherosclerosis, psoriasis, psoriatic arthritis, inflammatory bowel disease, ankylosing spondylitis, autoimmune hemolytic anemia, Behget's syndrome, Goodpasture's syndrome, Graves' disease, Guillain-Barre syndrome, Hashimoto's thyroiditis, idiopathic thrombocytopenia, io myasthenia gravis, pernicious anemia, polyarteritis nodosa, polymyositis/dermatomyositis, primary biliary sclerosis, sarcoidosis, sclerosing cholangitis, Sjogren's syndrome, systemic sclerosis (scleroderma and CREST syndrome), Takayasu's arteritis, temporal arteritis, and Wegener's granulomatosis.

18. A method of inhibiting TLR-mediated immunostimulation in a mammalian species in need thereof, comprising administering to the mammalian species a therapeutically effective amount of at least one compound according to claim 1 .

19. A method of inhibiting TLR-mediated immunostimulatory signaling, comprising contacting a cell expressing a TLR with an effective amount of at least one compound according to claim 1 .