NOVEL N2, N4, N7, 6-TETRASUBSTITUTED PTERIDINE-2,4,7-TRIAMINE AND 2, 4, 6, 7-TETRASUBSTITUTED PTERIDINE COMPOUNDS AND METHODS OF SYNTHESIS AND USE THEREOF
Compounds as immune system modulators bearing a pteridine core are described. A pharmaceutical composition comprising the same, methods of making the same, and a method for treating or preventing autoimmunity disease using the same are described.
1 . A compound of Formula I or a pharmaceutically acceptable salt thereof,
wherein
each occurrence of D is independently —O— or —N(Me)-; and
R 5 is H, F, or Cl.
2 . The compound of claim 1 , having the structure selected from the group consisting of
or a pharmaceutically acceptable salt thereof.
3 . The compound of claim 1 , having the structure selected from the group consisting of
or a pharmaceutically acceptable salt thereof.
4 . The compound of claim 1 , having the structure of
or a pharmaceutically acceptable salt thereof.
5 . The compound of claim 1 , having the structure of
or a pharmaceutically acceptable salt thereof.
6 . The compound of claim 1 , wherein the compound has an IC 50 of more than 10, 15, 20, 25, or 30 μM in a standard human ether-a-go-go related gene (hERG) patch clamp assay.
7 . The compound of claim 1 , wherein the compound results in more than 75% hepatocyte viability in a hepatocyte viability assay after the hepatocyte has been exposed to 100 μM of the compound for 24 h.
8 . A compound of Formula Ia or a pharmaceutically acceptable salt thereof,
wherein
R 1 is hydrogen, alkyl, alkenyl, cycloalkyl, alkylcycloalkyl, aryl, alkylaryl, heterocycle, or alkylheterocycle;
X 1 and X 2 are each independently absent or O;
R 2 is halogen, OR a , SR a , OS(═O) 2 R a , OC(═O)R a , NR b R c , or NR a (CH 2 ) p NR b R c , wherein p is 2-4;
R 3 and R 4 are each hydrogen, halogen, cyano, nitro, CF 3 , OCF 3 , alkyl, cycloalkyl, alkenyl, optionally substituted aryl, heterocycle, 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 , NR b C(═O)R a , alkaryl, alkylheterocyclic, or NR a (CH 2 ) p NR b R c ;
each occurrence of R a is independently hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted cycloalkenyl, optionally substituted alkynyl, optionally substituted heterocycle, or optionally substituted aryl; and
each occurrence of R b , and R c is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aryl; or said R b and R c together with the nitrogen atom to which they are bonded optionally form a heterocycle comprising 1-4 heteroatoms; or said R a and R b together with the nitrogen atom to which they are bonded optionally form a heterocycle comprising 1-4 heteroatoms;
wherein the formed heterocycle is optionally substituted by (C 1 -C 4 )alkyl and one or more carbon atoms in the formed heterocycle are optionally replaced with O, NR 8 , or S, wherein R 8 is hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted cycloalkenyl, optionally substituted alkynyl, optionally substituted heterocycle, or optionally substituted aryl;
provided that when R 2 is OR a , SR a , NR b R c , or NR a (CH 2 ) p NR b R c , at least one of X 1 and X 2 is O.
9 . The compound of claim 8 , wherein R 1 is alkyl, optionally substituted aryl, or optionally substituted heteroaryl.
10 . The compound of claim 8 , wherein X 1 and X 2 are both O.
11 . The compound of claim 8 , wherein R 2 is Cl or Br.
12 . The compound of claim 8 , wherein R 2 is OS(═O) 2 R a , or OC(═O)R a .
13 . The compound of claim 8 , wherein R 2 is NR b R c or NR a (CH 2 ) p NR b R c .
14 . The compound of claim 8 , wherein R 4 is NR b R c or NR a (CH 2 ) p NR b R c .
15 . The compound of claim 8 , wherein R 2 and R 4 are the same or different.
16 . The compound of claim 8 , wherein R 2 and R 4 are each independently selected from the group consisting of:
17 . A method for the synthesis of a compound having the structure of Formula II,
comprising:
(a) converting a compound having the structure of Formula III to a compound having the structure of Formula IV:
and
(b) converting the compound having the structure of Formula IV to the compound having the structure of Formula II:
wherein
each occurrence of X is independently absent or is an alkyl, cycloalkyl, aryl, or heterocycle;
each occurrence of Q is independently H, (CH 2 ) q NR b R c , NR a (CH 2 ) p NR b R c , OR 1 , SR 1 ,
or CR a R b R c , in which q is 0 or 1 and p is 2-4; and X 1 and X 2 are each independently absent or O;
R 1 is hydrogen, alkyl, alkenyl, cycloalkyl, alkylcycloalkyl, aryl, alkylaryl, heterocycle, alkylheterocycle;
R 2″ is halogen, OR a , OS(═O) 2 R a , or OC(═O)R a ;
R 2′ is OH, NR b R c , or NR a (CH 2 ) p NR b R c ;
A is aryl or heteroaryl;
each occurrence of R 9 and R 10 is each independently hydrogen, OS(═O) 2 R a , CH 2 C(═O)OR a , C(═O)C(═O)OR a , OC(═O)R a , OC(═O)OR a , or R a′ , or alternatively R 9 and R 10 are taken together with the nitrogen atom to which that they are attached to form a mono- or bi-cyclic carbocycle or heterocycle, wherein the carbocycle or heterocycle is optionally substituted with oxo;
R 3 and R 4 are each independently hydrogen, halogen, cyano, nitro, CF 3 , OCF 3 , alkyl, cycloalkyl, alkenyl, optionally substituted 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 , NR b C(═O)R a , alkaryl, alkylheterocyclic, or NR a (CH 2 ) p NR b R c , wherein p is 2-4; and
each occurrence of R a is independently hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted cycloalkenyl, optionally substituted alkynyl, optionally substituted heterocycle, or optionally substituted aryl;
each occurrence of R b and R c is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aryl; or said R b and R c together with the nitrogen atom to which they are bonded optionally form a heterocycle comprising 1-4 heteroatoms; or said R a and R b together with the nitrogen atom to which they are bonded optionally form a heterocycle comprising 1-4 heteroatoms;
wherein the formed heterocycle is optionally substituted by (C 1 -C 4 )alkyl and one or more carbon atoms in the formed heterocycle are optionally replaced with O, NR 8 , or S, wherein R 8 is hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted cycloalkenyl, optionally substituted alkynyl, optionally substituted heterocycle, or optionally substituted aryl.
18 . The method of claim 17 , wherein X is absent and Q is (CH 2 ) q NR b R c , NR a (CH 2 ) p NR b R c , OR 1 , SR 1 , or
19 . The method of claim 17 , wherein R 2′ and R 4 are the same.
20 . The method of claim 17 , wherein R 2′ and R 4 are different.
21 . The method of claim 17 , wherein R 9 and R 10 are selected from the group consisting of Fmoc-, Cbz-, Boc-, Ac—, CF 3 (C═O)—, Benzyl, triphenylmethyl, and p-Toluenesulfonyl; or R 9 and R 10 are taken together with the nitrogen atom to which they are bonded to form
22 . The method of claim 17 , wherein A is phenyl.
23 . The method of claim 17 , further comprising a step of (a 1 ):
wherein each occurrence of R 2″ is independent halogen, OR a , OS(═O) 2 R a , or OC(═O)R a .
24 . The method of claim 23 , wherein the step (a 1 ) further comprises the steps of (a 2 ) and (a 3 ):
wherein at least one of R 9 and R 10 is not hydrogen.
25 . The method of claim 17 , wherein step (b) further comprises the steps of (b 1 ) and (b 2 ):
wherein X 3 is O or absent, X 4 is OH or absent, and R a is hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted cycloalkenyl, optionally substituted alkynyl, optionally substituted heterocycle, or optionally substituted aryl.
26 . The method of claim 25 , wherein R 9 is H and R 10 is —(C═O)OR a .
27 . The method of claim 25 , further comprising the steps of (b 3 ) and (b 4 ):
wherein each occurrence of R d is independently H, halogen, OS(═O) 2 R a , or OC(═O)R a .
28 . A method for the synthesis of a compound having the structure of Formula II,
comprising:
(a) converting a compound having the structure of Formula X to a compound having the structure of Formula XI:
and
(b) converting the compound having the structure of Formula XI to the compound having the structure of Formula II:
wherein
each occurrence of X is independently absent or is an alkyl, cycloalkyl, aryl, or heterocycle;
each occurrence of Q is independently H, R d , (CH 2 ) q NR a R b , NR a (CH 2 ) p NR b R c , OR 1 , SR 1 ,
or CR a R b R c , in which q is 0 or 1 and p is 2-4; and X 1 and X 2 are each independently absent or O;
R 1 is hydrogen, alkyl, alkenyl, cycloalkyl, alkylcycloalkyl, aryl, alkylaryl, heterocycle, alkylheterocycle;
each occurrence of R d is independently halogen, OS(═O) 2 R a , or OC(═O)R a ;
R 2′ is OH, NR b R c , or NR a (CH 2 ) p NR b R c ;
R 3 and R 4 are each independently hydrogen, halogen, cyano, nitro, CF 3 , OCF 3 , alkyl, cycloalkyl, alkenyl, optionally substituted 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 , NR b C(═O)R a , alkaryl, alkylheterocyclic, or NR a (CH 2 ) p NR b R c , wherein p is 2-4; and
each occurrence of R a is independently hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted cycloalkenyl, optionally substituted alkynyl, optionally substituted heterocycle, or optionally substituted aryl;
each occurrence of R b , and R c is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aryl; or said R b and R c together with the nitrogen atom to which they are bonded optionally form a heterocycle comprising 1-4 heteroatoms; or said R a and R b together with the nitrogen atom to which they are bonded optionally form a heterocycle comprising 1-4 heteroatoms;
wherein the formed heterocycle is optionally substituted by (C 1 -C 4 )alkyl and one or more carbon atoms in the formed heterocycle are optionally replaced with O, NR 8 , or S, wherein R 8 is hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted cycloalkenyl, optionally substituted alkynyl, optionally substituted heterocycle, or optionally substituted aryl;
with the proviso that step (b) can be omitted if R d at the 6 position of the compound of Formula XI and R 3 are the same.
29 . The method of claim 28 , wherein R 2′ and R 4 are the same.
30 . The method of claim 28 , wherein R 2′ and R 4 are different.
31 . The method of claim 28 , wherein step (a) further comprises steps (a 1 ) and (a 2 ):
wherein step (a 1 ) further comprises purifying the compound having the structure of Formula XII.
32 . The method of claim 31 , wherein the purification is a column chromatography purification or HPLC purification.
33 . The method of claim 28 , wherein step (a) further comprises steps (a 1′ ) and (a 2′ ):
wherein step (a 1′ ) further compresses purifying the compound having the structure of Formula XIII.
34 . The method of claim 33 , wherein the purification is a column chromatography purification or HPLC purification.
35 . The method of claim 30 , wherein step (a) comprises a one-pot synthetic step (a 1x ):
wherein step (a 1x ) further comprises purifying the compound having the structure of Formula XI.
36 . The method of claim 35 , wherein the purification is a column chromatography purification or HPLC purification.
37 . The method of claim 28 , wherein the substituent —X-Q in Formulae X and XI is R d , and step (a) comprises converting a compound having the structure of Formula X′ to a compound having the structure of Formula XI′:
38 . The method of claim 37 , wherein the method further comprises step (a′):
(a′) converting a compound having the structure of Formula XI′ to a compound having the structure of Formula XI″:
wherein —X-Q is not R d .
39 . The method of claim 37 , wherein —X-Q is NR a R b , NR a (CH 2 ) p NR b R c , OR 1 , or SR 1 .
40 . The method of claim 37 , wherein —X-Q is
41 . The method of claim 37 , wherein R 2′ and R 4 are the same.
42 . The method of claim 41 , wherein R 2′ and R 4 are both
43 . The method of claim 37 , wherein R d and R 3 are both Cl.
44 . The method of claim 37 , wherein the method comprises the following two steps:
45 . The method of claim 44 , wherein the method further comprises preparing the compound having the structure of
by the following steps:
46 . The method of claim 45 , wherein the method further comprises preparing the compound having the structure of
by the following steps:
47 . A compound selected from the group consisting of:
48 . A compound of claim 8 selected from Table 1.
49 . A pharmaceutical composition comprising at least one compound according to claim 1 and a pharmaceutically acceptable carrier or diluent.
50 . A method of treating an autoimmune disease 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 .
51 . The method of claim 50 , wherein the mammalian species is human.
52 . The method of claim 50 , 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.
53 . 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 claim 1 .
54 . The method of claim 53 , wherein the mammalian species is human.
55 . 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 .
56 .- 66 . (canceled)