Dhfr inhibitors, compositions, and methods related thereto
AssigneeVyera Pharmaceuticais LLC
InventorsAllen T. Hopper, Stephen B. Thomas, Mattthew Welsch
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Abstract
The invention relates to inhibitors of dihydrofolate reductase and pharmaceutical preparations thereof. The invention further relates to methods of treatment of parasitic infections, such as T gondii, T. cruzi, P. falciparum, T. brucei, or L. major infections, using the novel inhibitors of the invention.
Claims50
A compound having the structure of formula (I) or a pharmaceutically acceptable salt or prodrug thereof:
- wherein:
- R1 is H, C1-6 alkyl, C3-6 cycloalkyl, C4-8 cycloalkylalkyl, or halogen;
- W is N or CR18 and Y is C(R2R3), or W—Y is C═C(R3);
- and Z is N or CR17;
- provided that at least one of W and Z is N;
- R2, R3, R4, R5, R6, R7, R8, R9, R17, and R18 are independently selected from H, C1-6 alkyl, C3-6 cycloalkyl, hydroxyl or fluorine;
- provided that at least four of R2, R3, R4, R5, R6, R7, R8, and R9 are H;
- if W is N, then none of R2, R3, R6, and R7 is hydroxyl;
- and if Z is N, then none of R4, R5, R8, and R9 is hydroxyl;
- and
- R10 is substituted or unsubstituted C6-10 aryl or 5- to 10-membered heteroaryl.
The compound of any one of the preceding claims, wherein:
- a. Z is CR17 or W is CR18;
- b. at least one of R2, R3, R4, R5, R6, R7, R8, and R9 is C1-6 alkyl, C3-6 cycloalkyl, or halogen;
- c. R1 is C4-6 alkyl, C3-6 cycloalkyl, C4-8 cycloalkylalkyl, or fluoro;
- d. R10 is substituted or unsubstituted 5- to 10-membered heteroaryl or C10 aryl;
- e. R10 is phenyl substituted at the meta or ortho position with at least one substituent selected from halogen (e.g., fluoro or chloro), hydroxyl, phosphoryl, phosphate, phosphonate, phosphinate, amino, amidine, imine, cyano, azido, sulfhydryl, or alkylthio, heterocyclyl, aralkyl, aryl, or heteroaryl;
- f. R10 is phenyl substituted with C1-6 alkyl optionally substituted with C1-6 alkyl, C3-6 cycloalkyl, halogen, carbonyl, cyano, or hydroxyl;
- g. R10 is phenyl substituted with R12 or X—R12;
- or
- h. R10 is phenyl substituted with fluoro;
- or R1 is C3-6 alkyl and R10 is phenyl optionally substituted with halogen (e.g., fluoro or chloro), hydroxyl, alkoxy, phosphoryl, phosphate, phosphonate, phosphinate, amino, amidine, imine, azido, sulfhydryl, or alkylthio;
- and
- further wherein:
- each instance of R12 is independently selected from substituted or unsubstituted phenyl, 5- or 6-membered heteroaryl, or 4 to 7-membered heterocyclyl;
- each instance of X is independently selected from carbonyl, Y, —CH2Y—, or —YCH2—;
- each instance of Y is independently selected from —CH2—, —O—, —S—, or —NR13—;
- and
- each instance of R13 is independently H or C1-6 alkyl.
The compound of any one of the preceding claims, wherein the compound's selectivity for T. gondii versus human DHFR is greater than 10-fold.
The compound of any one of the preceding claims, wherein the compound's selectivity for T. cruzi versus human DHFR is greater than 10-fold.
The compound of any one of the preceding claims, wherein the compound's selectivity for P. falciparum versus human DHFR is greater than 10-fold.
The compound of any one of the preceding claims, wherein the compound's selectivity for T. brucei versus human DHFR is greater than 10-fold.
The compound of any one of the preceding claims, wherein the compound's selectivity for L. major versus human DHFR is greater than 10-fold.
A pharmaceutical composition comprising a compound of any one of the preceding claims.
A method of treating an infection, comprising administering to a subject in need thereof a compound or composition of any one of the preceding claims.
The compound of 43, wherein the infection is caused by a protozoan.
Dependencies are inferred from the claim text.