SELECTIVE HETEROCYCLIC SPHINGOSINE 1 PHOSPHATE RECEPTOR MODULATORS
Compounds that selectively modulate the sphingosine 1 phosphate receptor are provided including compounds which modulate subtype 1 of the S1P receptor. Methods of chiral synthesis of such compounds are provided. Uses, methods of treatment or prevention and methods of preparing inventive compositions including inventive compounds are provided in connection with the treatment or prevention of diseases, malconditions, and disorders for which modulation of the sphingosine 1 phosphate receptor is medically indicated.
1 - 61 . (canceled)
62 . A method for the synthesis of a compound comprising an indane moiety having a chiral carbon in the five-membered ring of the indane moiety where the compound is enantiomerically enriched with respect to the chiral carbon, the method comprising the steps of
(i) providing a compound comprising an indane moiety where the ring carbon of the five-membered ring of the indane moiety where chiral substitution is desired is oxo substituted at such carbon, and wherein a carbon of the phenyl ring is halo substituted;
(ii) reacting such compound with a chiral reagent selected from the group consisting of a Corey Bakshita Shibata-oxazaborolidine and a chiral sulfinamide of the form RS(═O)NH 2 where R is selected from the group consisting of t-butyl, branched C 2-6 alkyl and C 3-8 cycloalkyl; and
(iii) forming the chiral center at the indane moiety carbon previously bound to the oxo group by either reacting such compound with a suitable reducing agent along with the chiral reagent in step (ii) or reacting the result of the reaction of such compound with a suitable reducing agent.
63 . The method of claim 62 wherein the chiral reagent is the Corey Bakshita Shibata-oxazaborolidine.
64 . The method of claim 62 wherein the chiral reagent is (R)-(−)-(2)-methyl-CBS-oxazaborolidine or (S)-(−)-(2)-methyl-CBS-oxazaborolidine.
65 . The method of claim 63 wherein the compound comprising an indane moiety provided in step (i) is contacted with the chiral reagent to form in step (iii) Formula VI-R or VI-S:
wherein Z is Cl, Br or I.
66 . The method of claim 65 wherein the method further comprises the step of protecting the hydroxy group of Formula VI-R or VI-S by treating Formula VI-R or VI-S with a protecting agent to form Formula VIa-R or VIa-S:
wherein PG is a protecting group.
67 . The method of claim 66 wherein the protecting agent is TBSCl.
68 . The method of claim 66 wherein the method further comprises the step of reacting Formula VIa-R or VIa-S with boronic acid or bis(pinacolato)diboron to form a boronic acid or boronate ester of Formula VIb-R or VIb-S:
69 . The method of claim 62 wherein the chiral reagent is RS(═O)NH 2 and the compound comprising an indane moiety is enantiomerically enriched with respect to a carbon-nitrogen bond on a ring carbon of the five-membered ring of the indane moiety.
70 . The method of claim 69 wherein the chiral reagent is t-Bu-S(═O)NH 2 .
71 . The method of claim 69 wherein the compound comprising an indane moiety provided in step (i) is contacted with the chiral reagent to form in step (ii) Formula VII:
wherein Z is Cl, Br or I.
72 . The method of claim 69 wherein a compound of Formula VIII-R or VIII-S is formed in step (iii):
73 . The method of claim 72 wherein the method further comprises the step of contacting Formula VIII-R or VIII-S with 1,4-dioxane in the presence of an acid to form Formula VIb-R or VIb-S or Formula IX-R or IX-S:
74 . The method of claim 73 wherein the method further comprises the step of protecting the amino group by treating Formula IX-R or IX-S with a protecting agent to form Formula IXa-R or IXa-S:
75 . The method of claim 74 wherein the protecting agent is di-tert-butyldicarbonate.
76 . The method of claim 74 wherein the method further comprises the step of reacting Formula IXa-R or IXa-S with boronic acid or bis(pinacolato)diboron to form a boronic acid or boronate ester of Formula IXb-R or IXb-S:
77 . The method of any one of claim 68 or 76 wherein the method further comprises the step of reacting Formula VIb-R, Formula VIb-S, Formula IXb-R or Formula IXb-S with Formula XI to form Formula XII-R or XII-S:
to form Formula XII-R or XII-S:
wherein each A 1 and each A 2 is independently N, or CH; R 1 is di-substituted phenyl or di-substituted pyridinyl where the phenyl and pyridinyl substituents are each independently selected from the group consisting of halo, nitro, cyano, perfluromethyl, fluorinated methyl, and C 1-4 -alkoxy; provided that if R 1 is di-substituted phenyl, such phenyl is para-substituted with C 1-4 -alkoxy; and X is NH or O.
78 . The method of claim 77 wherein R 1 is di-substituted phenyl where the phenyl substituents are F and Y, wherein Y is —CN, —Cl, or —CF 3 .
79 . The method of claim 78 wherein the method further comprises the step of reacting Formula XII-R or XII-S with iPrOH in the presence of NaOiPr to from Formula XIII-R or XIII-S:
80 . The method of claim 79 wherein the method further comprises the step of deprotecting the hydroxyl group wherein X is O, or the amino group wherein X is NH, by treating Formula XIII-R or XIII-S with a deprotecting agent.
81 . The method of claim 80 wherein the method further comprises the step of converting the deprotected amino group to a secondary amine.
82 . The method of 78 wherein Y is CN.
83 . The method of claim 78 wherein A 1 is N and A 2 is N.
84 . The method of claim 83 wherein Formula XI is prepared following the process comprising the step of
a) treating a di-substituted benzaldehyde with potassium phosphate monobasic to form a di-substituted benzoic acid;
b) contacting the di-substituted benzoic acid with H 2 NNHCSNH 2 to form an amino-1,3-4-thiadizole having a di-substituted phenyl group substituted on the thiadiazole moiety; and
c) treating the amino-1,3-4-thiadizole in step b) with a mixture of copper bromide and isoamylnitrite.
85 . The method of claim 78 wherein A 1 is N and A 2 is CH.
86 . The method of claim 85 wherein Formula XI is prepared following the process comprising the step of
a) contacting 2-bromothiazole with a (di-substituted phenyl)boronic acid to form a 2-(di-substituted phenyl)thiazole; and
b) treating the 2-(di-substituted phenyl)thiazole with NBS.
87 . The method of claim 78 wherein A 1 is CH and A 2 is N.
88 . The method of claim 87 wherein Formula XI is prepared following the process comprising the step of
a) contacting 5-(tributylstannyl)thiazole with an iodobenzene having two other substituents to form a 5-(di-substituted phenyl)thiazole; and
b) treating the 2-(di-substituted phenyl)thiazole with NBS.
89 . (canceled)