Granted Patent B2

US 12,227,522 · App. 18/255,969 · Granted Feb 18, 2025

Inventors: Robert M. Williams (Ft. Collins, CO); Sivanagireddy Koti (Ft. Collins, CO); Subhadip De (Ft. Collins, CO); Anil M. Shelke (Ft. Collins, CO); Ryan E. Cerbone (Ft. Collins, CO); Nobuyoshi Yasuda (Ft. Collins, CO)

Assignees: COLORADO STATE UNIVERSITY RESEARCH FOUNDATION; CETYA THERAPEUTICS, INC.

C07D513/18

Abstract

Claims (78)

1. A method for preparing a compound of formula (III):

the method comprising:

reacting a compound of formula (I):

with an activating agent selected from C 1 -C 20 linear or branched alkyl-sulfonyl halide, substituted alkyl-sulfonyl halide, arylsulfonyl halide, substituted arylsulfonyl halide, halo-phosphite, or a halogenating reagent, thereby forming a compound of formula (II):

and reacting the compound of formula (II) with a nucleophile comprising an R 1 group, thereby forming the compound of formula (III);

wherein:

X is O or NH;

Ar is thiazolyl, pyridinyl, or oxazolyl;

R 1 is R 2 COS, R 3 S, or R 4 R 5 N;

R 2 , R 3 , R 4 , and R 5 independently are hydrogen, C 1 -C 24 linear alkyl, C 1 -C 24 linear alkyl substituted with one or more aryl or heteroaryl in any position, C 1 -C 24 branched alkyl, C 1 -C 24 branched alkyl substituted with one or more aryl or heteroaryl in any position, C 3 -C 24 cyclic alkyl, C 3 -C 24 cyclic alkyl substituted with one or more aryl or heteroaryl in any position, C 2 -C 24 alkenyl, C 2 -C 24 alkynyl, aryl, heteroaryl, diphenyl methyl, or triphenylmethyl; and

L is a leaving group selected from C 1 -C 24 linear or branched carbon sulfonate, substituted C 1 -C 24 linear or branched sulfonate, arylsulfonate, substituted arylsulfonate, heteroarylsulfonate, substituted heteroarylsulfonate, phosphate, or halogen.

2. A method for preparing a compound of formula (III):

the method comprising:

reacting a compound of formula (II) with a nucleophile comprising an R 1 group:

wherein:

X is O or NH;

Ar is thiazolyl, pyridinyl, or oxazolyl;

R 1 is R 2 COS, R 3 S, or R 4 R 5 N;

R 2 , R 3 , R 4 , and R 5 independently are hydrogen, C 1 -C 24 linear alkyl, C 1 -C 24 linear alkyl substituted with one or more aryl or heteroaryl in any position, C 1 -C 24 branched alkyl, C 1 -C 24 branched alkyl substituted with one or more aryl or heteroaryl in any position, C 3 -C 24 cyclic alkyl, C 3 -C 24 cyclic alkyl substituted with one or more aryl or heteroaryl in any position, C 2 -C 24 alkenyl, C 2 -C 24 alkynyl, aryl, heteroaryl, diphenyl methyl, triphenylmethyl; and

L is a leaving group selected from C 1 -C 24 linear or branched carbon sulfonate, substituted C 1 -C 24 linear or branched sulfonate, arylsulfonate, substituted arylsulfonate, heteroarylsulfonate, substituted heteroarylsulfonate, phosphate, or halogen; and

producing the compound of formula (II) from a compound of formula (IX):

by converting OR 6 of the compound of formula (IX) into the leaving group L;

wherein R 6 is H or a suitable alcohol protecting group.

3. The method of claim 2 , wherein converting OR 6 into the leaving group L comprises:

when R 6 is the suitable alcohol protecting group, deprotecting the suitable alcohol protecting group to provide the compound of formula (IX) where R 6 is H; and

reacting the compound of formula (IX) where R 6 is H with an activating agent selected from C 1 -C 20 linear or branched alkyl-sulfonyl halide, substituted alkyl-sulfonyl halide, arylsulfonyl halide, substituted arylsulfonyl halide, halo-phosphite, or a halogenating reagent.

4. The method of claim 2 , wherein the compound of formula (IX) is a compound of formula (I):

and the method comprises reacting the compound of formula (I) with an activating agent selected from C 1 -C 20 linear or branched alkyl-sulfonyl halide, substituted alkyl-sulfonyl halide, arylsulfonyl halide, substituted arylsulfonyl halide, halo-phosphite, or a halogenating reagent, thereby forming the compound of formula (II).

5. The method of claim 2 , wherein the compound of formula (IX) is a compound of formula (I-a), (I-b), or (I-c):

6. The method of claim 1 , wherein L is OMs, OTs, OTf, 2,2,2-trifluoroethanesulfonate, n-octanesulfonate, benzenesulfonate, OP(═O)(OMe) 2 , OP(═O)(OEt) 2 , OP(═O)(OPh) 2 , I, Br, Cl or F.

7. The method of claim 1 , wherein Ar is:

8. The method of claim 1 , wherein the nucleophile is thiooctanoic acid, such that the compound of formula (III) is a compound of formula (XXV):

9. The method of claim 8 , wherein:

X is NH and Ar is:

such that the compound of formula (III) is a compound of formula (1):

X is O and Ar is:

such that the compound of formula (III) is a compound of formula (2):

 or

X is O and Ar is:

such that the compound of formula (III) is a compound of formula (3):

10. The method of claim 2 , wherein the method further comprises producing a compound of formula (I) or the compound of formula (IX) from one or more reactions comprising:

a compound of formula (IV):

a compound of formula (V):

and a compound of formula (VI):

wherein:

R 6 is H or a suitable alcohol protecting group,

R 8 , R 10 , and R 12 independently are H, a suitable amine protecting group, or a chiral group,

R 7 , R 9 , and R 11 independently are H, an alkali metal ion, an alkaline earth metal ion, or a suitable carboxylic acid protecting group;

optionally wherein the suitable carboxylic acid protecting group is selected from C 1 -C 6 linear or branched alkyl, C 1 -C 6 linear or branched alkyl substituted with one or more aryl or heteroaryl in any position, or alkylsilyl;

optionally wherein the C 1 -C 6 linear or branched alkyl, or the C 1 -C 6 linear or branched alkyl substituted with one or more aryl or heteroaryl in any position, is selected from methyl, ethyl, propyl, isopropyl, allyl, butyl, 2-butyl, tert-butyl, benzyl, or substituted benzyl; and

optionally wherein the alkylsilyl is 2-(trimethylsilyl) ethyl.

11. The method of claim 10 , wherein:

the compound of formula (IV) is reacted with the compound of formula (V) via condensation to form a compound of formula (VII):

the compound of formula (VII) is reacted with the compound of formula (VI) via amidation to form a compound of formula (VIII):

and the compound of formula (VIII) is reacted by amidating ring closure to form the compound of formula (IX) or a compound of formula (I)

12. The method of claim 11 , wherein:

R 6 is H or a suitable alcohol protecting group;

in reacting the compound of formula (IV) with the compound of formula (V): R 8 is H, and when X is N, the N is neutral or positively charged; R 7 is a suitable carboxylic acid protecting group; R 10 is a suitable amine protecting group; and R 9 is H, an alkali metal ion, or an alkaline earth metal ion;

in reacting the compound of formula (VI) with the compound of formula (VII): R 7 is a suitable carboxylic acid protecting group; R 10 is H, and optionally R 10 is attached to a positively charged nitrogen atom; R 11 is H, an alkali metal ion, or an alkaline earth metal ion; and R 12 is a suitable amine protecting group; and

in reacting the compound of formula (VIII) by amidating ring closure: R 6 is H or a suitable alcohol protecting group; R 7 is H, an alkali metal ion, or an alkaline earth metal ion; and R 12 is H, and optionally R 12 is attached to a positively charged nitrogen atom.

13. The method of claim 10 , wherein X is NH, and the method further comprises producing the compound of formula (IV) by:

reacting via imine formation a compound of formula (X):

with a chiral auxiliary of formula (XI-a):

Y—NH 2   (XI-a)

to form a compound of formula (XII):

reacting the compound of formula (XII) via nucleophilic addition with a compound of formula (XIII):

to form the compound of formula (IV) where X is NH and R 8 is chiral group Y:

and cleaving the N—Y bond to form the compound of formula (IV) where R 8 is H, and when X is N, the N is neutral or positively charged,

wherein:

Y is a chiral group sufficient to effect a diastereoselective nucleophilic addition of the compound of formula (XIII) to the compound formula (XII) to form the compound of formula (IV) as a majority product where R 8 is chiral group Y,

R 6 is a suitable alcohol protecting group,

R 7 is a suitable carboxylic acid protecting group;

optionally wherein the carboxylic acid protecting group is selected from C 1 -C 6 linear or branched alkyl, C 1 -C 6 linear or branched alkyl substituted with one or more aryl or heteroaryl in any position, or alkylsilyl;

optionally wherein the C 1 -C 6 linear or branched alkyl, or the C 1 -C 6 linear or branched alkyl substituted with one or more aryl or heteroaryl in any position, is selected from methyl, ethyl, propyl, isopropyl, allyl, butyl, 2-butyl, tert-butyl, benzyl, or substituted benzyl; and

optionally wherein the alkylsilyl is 2-(trimethylsilyl) ethyl; and

R 13 is H, a halide, or a metal comprising Li, Na, K, ZnBr, ZnCl, CuCl, CuBr, Cul, Cu, or any combination thereof.

14. The method of claim 13 , wherein Y is R 14 —S═O such that the chiral auxiliary is of formula (XI-b):

wherein R 14 is tert-butyl such that the compound of formula (XI-b) is (R)-tert-butanesulfinamide.

Assignments (3)

Continuity (2)

References Cited (118)