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US 2021/0230178 A1Published application
Trioxacarcin analogs and dimers as potent anticancer agents
AssigneeWilliam Marsh Rice University
InventorsKyriacos C. NICOLAOU, Pengxi CHEN, Shugao ZHU, Quan CAI
Life of this patent
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Abstract
In one aspect, the present disclosure provides trioxacarcin analogs of the formula: wherein the variables are as defined herein. In another aspect, the present disclosure also provides methods of preparing the compounds disclosed herein as well as dimers of the compounds described herein. In another aspect, the present disclosure also provides pharmaceutical compositions and methods of use of the compounds disclosed herein. Additionally, drug conjugates with cell targeting moieties of the compounds are also provided.
Claims26
A compound of the formula:
- wherein:
- m is 0 or 1;
- R1 is alkyl(C≤8), alkenyl(C≤8), acyl(C≤8), or a substituted version of the last three groups;
- a group of the formula —(CH2)n1O(CH2)n2R5, wherein:
- n1 and n2 are each independently 1, 2, 3, 4, or 5;
- and
- R5 are amino, alkylamino(C≤8), substituted alkylamino(C≤8), dialkylamino(C≤12), or substituted dialkylamino(C≤12);
- or
- a group of the formula:
- wherein:
- R6 and R8 are each independently hydrogen, hydroxy, alkyl(C≤8), substituted alkyl(C≤8), alkoxy(C≤8), substituted alkoxy(C≤8), acyloxy(C≤8), or substituted acyloxy(C≤8);
- and
- R7 and R7′ are hydrogen, hydroxy, alkyl(C≤8), substituted alkyl(C≤8), alkoxy(C≤8), substituted alkoxy(C≤8), acyl(C≤8), or substituted acyl(C≤8);
- or a group of the formula:
- —NRbRc, wherein Rb and Rc are each independently hydrogen, monovalent amine protecting group, alkyl(C≤8), or substituted alkyl(C≤8), or Rb and Rc are taken together and are a divalent amine protecting group;
- or R7 and R7′ are taken together and are a 4 to 10 membered heterocycloalkanediyl(C≤12) or substituted heterocycloalkanediyl(C≤12) which is optionally substituted with 1, 2, or 3 oxo groups;
- R2 is alkyl(C≤8) or substituted alkyl(C≤8);
- R3 is hydrogen, hydroxy, alkoxy(C≤8), substituted alkoxy(C≤8), acyloxy(C≤8), or substituted acyloxy(C≤8);
- R4 is hydroxy, alkoxy(C≤8), substituted alkoxy(C≤8), acyloxy(C≤8), or substituted acyloxy(C≤8);
- X1 is —O— or —NRa—, wherein Ra is hydrogen, alkyl(C≤8), or substituted alkyl(C≤8);
- provided that when R2 is methyl, R3 is hydroxy, R4 is methoxy, and X1 is O, then R1 is not acetyl, alkyl(≤12), or substituted alkyl(C≤12);
- a compound of the formula:
- wherein:
- m is 0 or 1;
- R1 is hydrogen, alkyl(C≤8), alkenyl(C≤8), acyl(C≤8), or a substituted version of the last three groups;
- a group of the formula —(CH2)n1O(CH2)n2R5, wherein:
- n1 and n2 are each independently 1, 2, 3, 4, or 5;
- and
- R5 are amino, alkylamino(C≤8), substituted alkylamino(C≤8), dialkylamino(C≤12), or substituted dialkylamino(C≤12);
- or
- a group of the formula:
- wherein:
- R6 and R8 are each independently hydrogen, hydroxy, alkyl(C≤8), substituted alkyl(C≤8), alkoxy(C≤8), substituted alkoxy(C≤8), acyloxy(C≤8), or substituted acyloxy(C≤8);
- and
- R7 and R7′ are hydrogen, hydroxy, alkyl(C≤8), substituted alkyl(C≤8), alkoxy(C≤8), substituted alkoxy(C≤8), acyl(C≤8), or substituted acyl(C≤8);
- or a group of the formula:
- —NRbRc, wherein Rb and Rc are each independently hydrogen, monovalent amine protecting group, alkyl(C≤8), or substituted alkyl(C≤8), or Rb and Rc are taken together and are a divalent amine protecting group;
- or R7 and R7′ are taken together and are a 4 to 10 membered heterocycloalkanediyl(C≤12) or substituted heterocycloalkanediyl(C≤12) which is optionally substituted with 1, 2, or 3 oxo groups;
- R2 is alkyl(C≤8) or substituted alkyl(C≤8);
- R9 is hydroxy, alkoxy(C≤8), substituted alkoxy(C≤8), acyloxy(C≤8), or substituted acyloxy(C≤8);
- R10 is hydrogen, halo, hydroxy, alkyl(C≤8), substituted alkyl(C≤8), alkoxy(C≤8), substituted alkoxy(C≤8), acyloxy(C≤8), or substituted acyloxy(C≤8);
- p is 1, 2, 3, or 4;
- and
- X1 is —O— or —NRa—, wherein Ra is hydrogen, alkyl(C≤8), or substituted alkyl(C≤8);
- or
- a compound of the formula:
- wherein:
- R1 is hydrogen, alkyl(C≤8), alkenyl(C≤8), acyl(C≤8), or a substituted version of the last three groups;
- a group of the formula —(CH2)n1O(CH2)n2R5, wherein:
- n1 and n2 are each independently 1, 2, 3, 4, or 5;
- and
- R5 are amino, alkylamino(C≤8), substituted alkylamino(C≤8), dialkylamino(C≤12), or substituted dialkylamino(C≤12);
- or
- a group of the formula:
- wherein:
- R6 and R8 are each independently hydrogen, hydroxy, alkyl(C≤8), substituted alkyl(C≤8), alkoxy(C≤8), substituted alkoxy(C≤8), acyloxy(C≤8), or substituted acyloxy(C≤8);
- and
- R7 and R7′ are hydrogen, hydroxy, alkyl(C≤8), substituted alkyl(C≤8), alkoxy(C≤8), substituted alkoxy(C≤8), acyl(C≤8), or substituted acyl(C≤8);
- or a group of the formula:
- —NRbRc, wherein Rb and Rc are each independently hydrogen, monovalent amine protecting group, alkyl(C≤8), or substituted alkyl(C≤8), or Rb and Rc are taken together and are a divalent amine protecting group;
- or R7 and R7′ are taken together and are a 4 to 10 membered heterocycloalkanediyl(C≤12) or substituted heterocycloalkanediyl(C≤12) which is optionally substituted with 1, 2, or 3 oxo groups;
- R2 is alkyl(C≤8) or substituted alkyl(C≤8);
- R3 is hydrogen, hydroxy, alkoxy(C≤8), substituted alkoxy(C≤8), acyloxy(C≤8), or substituted acyloxy(C≤8);
- R4 is hydroxy, alkoxy(C≤8), substituted alkoxy(C≤8), acyloxy(C≤8), or substituted acyloxy(C≤8);
- R11 is hydrogen, alkyl(C≤8), substituted alkyl(C≤8), alkoxy(C≤8), or substituted alkoxy(C≤8);
- R12 is —O(CH2)qR13, wherein:
- q is 1, 2, 3, 4, or 5;
- R13 is amino, alkylamino(C≤8), substituted alkylamino(C≤8), dialkylamino(C≤8), or substituted dialkylamino(C≤8);
- or
- a group of the formula:
- wherein:
- R13, R13′, R14, R14′, R15, R15′, R16, R16′, R17, and R17′ are each independently hydrogen, hydroxy, alkyl(C≤8), substituted alkyl(C≤8), alkoxy(C≤8), substituted alkoxy(C≤8), acyloxy(C≤8), and substituted acyloxy(C≤8);
- and
- a group of the formula:
- wherein:
- R7′ and R9′ are each independently hydrogen, hydroxy, alkyl(C≤8), substituted alkyl(C≤8), alkoxy(C≤8), substituted alkoxy(C≤8), acyloxy(C≤8), or substituted acyloxy(C≤8);
- and
- R8″ and R8′″ are hydrogen, hydroxy, alkyl(C≤8), substituted alkyl(C≤8), alkoxy(C≤8), substituted alkoxy(C≤8), acyl(C≤8), or substituted acyl(C≤8);
- or a group of the formula:
- —NRbRc, wherein Rb and Rc are each independently hydrogen, monovalent amine protecting group, alkyl(C≤8), or substituted alkyl(C≤8), or Rb and Rc are taken together and are a divalent amine protecting group;
- or R7 and R7′ are taken together and are a 4 to 10 membered hetero-cycloalkanediyl(C≤12) or substituted heterocyclo-alkanediyl(C≤12) which is optionally substituted with 1, 2, or 3 oxo groups;
- R1 and R2 are taken together and are alkanediyl(C≤8) or substituted alkanediyl(C≤8);
- X1 is —O— or —NRa—, wherein Ra is hydrogen, alkyl(C≤8), or substituted alkyl(C≤8);
- a compound of the formula:
- wherein:
- R1 is hydrogen, alkyl(C≤8), alkenyl(C≤8), acyl(C≤8), or a substituted version of the last three groups;
- or
- a group of the formula:
- wherein:
- R6 and R8 are each independently hydrogen, hydroxy, alkyl(C≤8), substituted alkyl(C≤8), alkoxy(C≤8), substituted alkoxy(C≤8), acyloxy(C≤8), or substituted acyloxy(C≤8);
- and
- R7 and R7′ are hydrogen, hydroxy, alkyl(C≤8), substituted alkyl(C≤8), alkoxy(C≤8), substituted alkoxy(C≤8), acyl(C≤8), or substituted acyl(C≤8);
- or a group of the formula:
- —NRbRc, wherein Rb and Rc are each independently hydrogen, monovalent amine protecting group, alkyl(C≤8), or substituted alkyl(C≤8), or Rb and Rc are taken together and are a divalent amine protecting group;
- or R7 and R7′ are taken together and are a 4 to 10 membered heterocycloalkanediyl(C≤12) or substituted heterocycloalkanediyl(C≤12) which is optionally substituted with 1, 2, or 3 oxo groups;
- R2 is alkyl(C≤8) or substituted alkyl(C≤8);
- R9 is hydroxy, alkoxy(C≤8), substituted alkoxy(C≤8), acyloxy(C≤8), or substituted acyloxy(C≤8);
- R10 is hydrogen, halo, hydroxy, alkyl(C≤8), substituted alkyl(C≤8), alkoxy(C≤8), substituted alkoxy(C≤8), acyloxy(C≤8), or substituted acyloxy(C≤8);
- p is 1, 2, 3, or 4;
- R18 is hydrogen, alkyl(C≤8), substituted alkyl(C≤8), alkoxy(C≤8), or substituted alkoxy(C≤8);
- R19 is —O(CH2)qR13, wherein:
- q is 1, 2, 3, 4, or 5;
- R13 is amino, alkylamino(C≤8), substituted alkylamino(C≤8), dialkylamino(C≤8), or substituted dialkylamino(C≤8);
- or
- a group of the formula:
- wherein:
- R13, R13′, R14, R14′, R15, R15′, R16, R16′, R17, and R17′ are each independently hydrogen, hydroxy, alkyl(C≤8), substituted alkyl(C≤8), alkoxy(C≤8), substituted alkoxy(C≤8), acyloxy(C≤8), and substituted acyloxy(C≤8);
- and
- a group of the formula:
- wherein:
- R7′ and R9′ are each independently hydrogen, hydroxy, alkyl(C≤8), substituted alkyl(C≤8), alkoxy(C≤8), substituted alkoxy(C≤8), acyloxy(C≤8), or substituted acyloxy(C≤8);
- and
- R8″ and R8′″ are hydrogen, hydroxy, alkyl(C≤8), substituted alkyl(C≤8), alkoxy(C≤8), substituted alkoxy(C≤8), acyl(C≤8), or substituted acyl(C≤8);
- or a group of the formula:
- —NRbRc, wherein Rb and Rc are each independently hydrogen, monovalent amine protecting group, alkyl(C≤8), or substituted alkyl(C≤8), or Rb and Rc are taken together and are a divalent amine protecting group;
- or R7 and R7′ are taken together and are a 4 to 10 membered heterocycloalkanediyl(C≤12) or substituted heterocycloalkanediyl(C≤12) which is optionally substituted with 1, 2, or 3 oxo groups;
- R1 and R2 are taken together and are alkanediyl(C≤8) or substituted alkanediyl(C≤8);
- X1 is —O— or —NRa—, wherein Ra is hydrogen, alkyl(C≤8), or substituted alkyl(C≤8);
- or
- a compound of the formula:
- wherein:
- R1 is hydrogen, alkyl(C≤8), alkenyl(C≤8), acyl(C≤8), or a substituted version of the last three groups;
- a group of the formula —(CH2)n1O(CH2)n2R5, wherein:
- n1 and n2 are each independently 1, 2, 3, 4, or 5;
- and
- R5 are amino, alkylamino(C≤8), substituted alkylamino(C≤8), dialkylamino(C≤12), or substituted dialkylamino(C≤12);
- or
- a group of the formula:
- wherein:
- R6 and R8 are each independently hydrogen, hydroxy, alkyl(C≤8), substituted alkyl(C≤8), alkoxy(C≤8), substituted alkoxy(C≤8), acyloxy(C≤8), or substituted acyloxy(C≤8);
- and
- R7 and R7′ are hydrogen, hydroxy, alkyl(C≤8), substituted alkyl(C≤8), alkoxy(C≤8), substituted alkoxy(C≤8), acyl(C≤8), or substituted acyl(C≤8);
- or a group of the formula:
- —NRbRc, wherein Rb and Rc are each independently hydrogen, monovalent amine protecting group, alkyl(C≤8), or substituted alkyl(C≤8), or Rb and Rc are taken together and are a divalent amine protecting group;
- or R7 and R7′ are taken together and are a 4 to 10 membered heterocycloalkanediyl(C≤12) or substituted heterocycloalkanediyl(C≤12) which is optionally substituted with 1, 2, or 3 oxo groups;
- R2 is alkyl(C≤8) or substituted alkyl(C≤8);
- R3 is hydrogen, hydroxy, alkoxy(C≤8), substituted alkoxy(C≤8), acyloxy(C≤8), or substituted acyloxy(C≤8);
- R4 is hydroxy, alkoxy(C≤8), substituted alkoxy(C≤8), acyloxy(C≤8), or substituted acyloxy(C≤8);
- R20 is alkyl(C≤8), substituted alkyl(C≤8), acyl(C≤8), or substituted acyl(C≤8);
- R21 is alkyl(C≤8) or substituted alkyl(C≤8);
- R22 is hydrogen, hydroxy, alkoxy(C≤8), substituted alkoxy(C≤8), acyloxy(C≤8), or substituted acyloxy(C≤8);
- R23 is a group of the formula:
- wherein:
- R24, R24′, R26, and R26′ are each independently hydrogen, hydroxy, alkyl(C≤8), substituted alkyl(C≤8), alkoxy(C≤8), substituted alkoxy(C≤8), acyloxy(C≤8), or substituted acyloxy(C≤8);
- and
- R25 and R25′ are hydrogen, hydroxy, alkyl(C≤8), substituted alkyl(C≤8), alkoxy(C≤8), substituted alkoxy(C≤8), acyl(C≤8), or substituted acyl(C≤8);
- or a group of the formula:
- —NRbRc, wherein Rb and Rc are each independently hydrogen, monovalent amine protecting group, alkyl(C≤8), or substituted alkyl(C≤8), or Rb and Rc are taken together and are a divalent amine protecting group;
- or R7 and R7′ are taken together and are a 4 to 10 membered heterocycloalkanediyl(C≤12) or substituted heterocycloalkanediyl(C≤12) which is optionally substituted with 1, 2, or 3 oxo groups;
- and
- X1 is —O— or —NRa—, wherein Ra is hydrogen, alkyl(C≤8), or substituted alkyl(C≤8);
- or a pharmaceutically acceptable salt thereof.
149 more elements
(canceled)
-19. (canceled)
-22. (canceled)
(canceled)
A dimer of the formula:
- Y1-L-Y1′ (XIII)
- wherein:
- Y1 and Y1′ are each independently a compound of the formula:
- wherein:
- R1 and R2 are each independently hydrogen, alkyl(C≤8), substituted alkyl(C≤8), alkoxy(C≤8), substituted alkoxy(C≤8), acyloxy(C≤8), or substituted acyloxy(C≤8);
- a group of the formula:
- —O(CH2)qR13, wherein:
- q is 1, 2, 3, 4, or 5;
- R13 is amino, alkylamino(C≤8), substituted alkylamino(C≤8), dialkylamino(C≤8), or substituted dialkylamino(C≤8);
- or
- a group of the formula:
- wherein:
- R10, R10′, R11, R11′, R12, R12′, R13, R13′, R14, and R14′ are each independently hydrogen, hydroxy, alkyl(C≤8), substituted alkyl(C≤8), alkoxy(C≤8), substituted alkoxy(C≤8), acyloxy(C≤8), and substituted acyloxy(C≤8);
- or
- a group of the formula:
- wherein:
- R7′ and R9′ are each independently hydrogen, hydroxy, alkyl(C≤8), substituted alkyl(C≤8), alkoxy(C≤8), substituted alkoxy(C≤8), acyloxy(C≤8), or substituted acyloxy(C≤8);
- and
- R8′ and R8′″ are hydrogen, hydroxy, alkyl(C≤8), substituted alkyl(C≤8), alkoxy(C≤8), substituted alkoxy(C≤8), acyl(C≤8), or substituted acyl(C≤8);
- or a group of the formula:
- —NRbRc, wherein Rb and Rc are each independently hydrogen, monovalent amine protecting group, alkyl(C≤8), or substituted alkyl(C≤8), or Rb and Rc are taken together and are a divalent amine protecting group;
- or R7 and R7′ are taken together and are a 4 to 10 membered heterocycloalkanediyl(C≤12) or substituted heterocycloalkanediyl(C≤12) which is optionally substituted with 1, 2, or 3 oxo groups;
- R1 and R2 are taken together and are alkanediyl(C≤8) or substituted alkanediyl(C≤8);
- R3 is alkyl(C≤8) or substituted alkyl(C≤8);
- R4 is hydrogen, hydroxy, alkoxy(C≤8), substituted alkoxy(C≤8), acyloxy(C≤8), or substituted acyloxy(C≤8);
- R5 is hydroxy, alkoxy(C≤8), substituted alkoxy(C≤8), acyloxy(C≤8), or substituted acyloxy(C≤8);
- R6 is hydrogen, hydroxy, alkoxy(C≤8), substituted alkoxy(C≤8), acyloxy(C≤8), or substituted acyloxy(C≤8), or a group of the formula:
- wherein:
- R7 and R9 are each independently hydrogen, hydroxy, alkyl(C≤8), substituted alkyl(C≤8), alkoxy(C≤8), substituted alkoxy(C≤8), acyloxy(C≤8), or substituted acyloxy(C≤8);
- and
- R8 and R8′ are hydrogen, hydroxy, alkyl(C≤8), substituted alkyl(C≤8), alkoxy(C≤8), substituted alkoxy(C≤8), acyl(C≤8), or substituted acyl(C≤8);
- or a group of the formula:
- —NRbRc, wherein Rb and Rc are each independently hydrogen, monovalent amine protecting group, alkyl(C≤8), or substituted alkyl(C≤8), or Rb and Rc are taken together and are a divalent amine protecting group;
- or R7 and R7′ are taken together and are a 4 to 10 membered heterocycloalkanediyl(C≤12) or substituted hetero-cycloalkanediyl(C≤12) which is optionally substituted with 1, 2, or 3 oxo groups;
- n is 1, 2, 3, 4, 5 or 6;
- and
- X1 is —O— or —NRa—, wherein Ra is hydrogen, alkyl(C≤8), or substituted alkyl(C≤8);
- or
- a compound of the formula:
- wherein:
- R1 and R2 are each independently hydrogen, alkyl(C≤8), substituted alkyl(C≤8), alkoxy(C≤8), substituted alkoxy(C≤8), acyloxy(C≤8), or substituted acyloxy(C≤8);
- a group of the formula:
- —O(CH2)qR13, wherein:
- q is 1, 2, 3, 4, or 5;
- R13 is amino, alkylamino(C≤8), substituted alkylamino(C≤8), dialkylamino(C≤8), or substituted dialkylamino(C≤8);
- or
- a group of the formula:
- wherein:
- R10, R10′, R11, R11′, R12, R12′, R13, R13′, R14, and R14′ are each independently hydrogen, hydroxy, alkyl(C≤8), substituted alkyl(C≤8), alkoxy(C≤8), substituted alkoxy(C≤8), acyloxy(C≤8), and substituted acyloxy(C≤8);
- a group of the formula:
- wherein:
- R7′ and R9′ are each independently hydrogen, hydroxy, alkyl(C≤8), substituted alkyl(C≤8), alkoxy(C≤8), substituted alkoxy(C≤8), acyloxy(C≤8), or substituted acyloxy(C≤8);
- and
- R8′ and R8′″ are hydrogen, hydroxy, alkyl(C≤8), substituted alkyl(C≤8), alkoxy(C≤8), substituted alkoxy(C≤8), acyl(C≤8), or substituted acyl(C≤8);
- or a group of the formula:
- —NRbRc, wherein Rb and Rc are each independently hydrogen, monovalent amine protecting group, alkyl(C≤8), or substituted alkyl(C≤8), or Rb and Rc are taken together and are a divalent amine protecting group;
- or R7 and R7′ are taken together and are a 4 to 10 membered heterocycloalkanediyl(C≤12) or substituted hetero-cycloalkanediyl(C≤12) which is optionally substituted with 1, 2, or 3 oxo groups;
- R1 and R2 are taken together and are alkanediyl(C≤8) or substituted alkanediyl(C≤8);
- R1 and R2 are taken together and are alkoxydiyl(C≤8) or substituted alkoxydiyl(C≤8);
- R3 is alkyl(C≤8) or substituted alkyl(C≤8);
- R4 is hydrogen, hydroxy, alkoxy(C≤8), substituted alkoxy(C≤8), acyloxy(C≤8), or substituted acyloxy(C≤8);
- R5 is hydroxy, alkoxy(C≤8), substituted alkoxy(C≤8), acyloxy(C≤8), or substituted acyloxy(C≤8);
- R6 is hydrogen, hydroxy, alkoxy(C≤8), substituted alkoxy(C≤8), acyloxy(C≤8), or substituted acyloxy(C≤8), or a group of the formula:
- wherein:
- R7 and R9 are each independently hydrogen, hydroxy, alkyl(C≤8), substituted alkyl(C≤8), alkoxy(C≤8), substituted alkoxy(C≤8), acyloxy(C≤8), or substituted acyloxy(C≤8);
- and
- R8 and R8′ are hydrogen, hydroxy, alkyl(C≤8), substituted alkyl(C≤8), alkoxy(C≤8), substituted alkoxy(C≤8), acyl(C≤8), or substituted acyl(C≤8);
- or a group of the formula:
- —NRbRc, wherein Rb and Rc are each independently hydrogen, monovalent amine protecting group, alkyl(C≤8), or substituted alkyl(C≤8), or Rb and Rc are taken together and are a divalent amine protecting group;
- or R7 and R7′ are taken together and are a 4 to 10 membered heterocycloalkanediyl(C≤12) or substituted hetero-cycloalkanediyl(C≤12) which is optionally substituted with 1, 2, or 3 oxo groups;
- and
- n is 1, 2, 3, or 4;
- and
- X1 is —O— or —NRa—, wherein Ra is hydrogen, alkyl(C≤8), or substituted alkyl(C≤8);
- and
- L is alkanediyl(C≤12), alkenediyl(C≤12), alkynediyl(C≤12), arenediyl(C≤12), heteroarenediyl(C≤12), heterocycloalkanediyl(C≤12), alkoxydiyl(C≤12), alkylaminodiyl(C≤12), or a substituted version of any of these groups;
- or a linker comprising an amino acid chain containing from 1 to 20 amino acids;
- or a pharmaceutically acceptable salt thereof.
75 more elements
-28. (canceled)
(canceled)
A method of preparing a compound of the formula:
- wherein:
- R1 and R1′ are each independently hydroxy protecting groups or are taken together and are —SiRbRc—, wherein Rb and Rc are each independently alkyl(C≤8) or substituted alkyl(C≤8);
- R2 is hydrogen or halo;
- R3 is alkyl(C≤8) or substituted alkyl(C≤8);
- R4 is hydroxy, alkoxy(C≤8), or substituted alkoxy(C≤8);
- and
- X1 is O, S, or NRc, wherein Rc is hydrogen, alkyl(C≤8), or substituted alkyl(C≤8);
- comprising reacting an oxaziridine reagent and a compound of the formula:
- wherein:
- R1 and R1′ are each independently hydroxy protecting groups or are taken together and are —SiRbRc—, wherein Rb and Rc are each independently alkyl(C≤8) or substituted alkyl(C≤8);
- R2 is hydrogen or halo;
- R3 is alkyl(C≤8) or substituted alkyl(C≤8);
- R4 is hydroxy, alkoxy(C≤8), or substituted alkoxy(C≤8);
- and
- X1 is O, S, or NRc, wherein Rc is hydrogen, alkyl(C≤8), or substituted alkyl(C≤8);
- in the presence of a base under conditions sufficient to achieve a reaction.
13 more elements
Dependencies are inferred from the claim text.