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US 2009/0156800 A1Published application
Process for making macrocyclic oximyl hepatitis c protease inhibitors
AssigneeEnanta Pharmaceuticals, Inc.
InventorsSeble Wagaw, Matthew Ravn, Kenneth Engstrom, Guoyou Xu, Zhe Wang, Ying Sun, Deqiang Niu, Yat Sun Or
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Abstract
The present invention relates to a process for the preparation of macrocyclic compounds that are useful as hepatitis C virus (HCV) protease inhibitor compounds.
Claims25
A method of making a compound of formula 1,
- as well as the pharmaceutically acceptable salts, esters and prodrugs thereof, wherein:
- R1 is selected from the group consisting of:
- a) hydrogen;
- b) aryl;
- c) substituted aryl;
- d) heteroaryl;
- e) substituted heteroaryl;
- f) heterocyclic or substituted heterocyclic;
- g) —C1-C8 alkyl, —C2-C8 alkenyl, or —C2-C8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N;
- h) substituted —C1-C8 alkyl, substituted —C2-C8 alkenyl, or substituted —C2-C8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N;
- i) —C3-C12 cycloalkyl, or substituted —C3-C12 cycloalkyl;
- j) —C3-C12 cycloalkenyl, or substituted —C3-C12 cycloalkenyl;
- and
- k) —B—R3, where B is (CO), (CO)O, (CO)NR4, (SO), (SO2), (SO2)NR4;
- and R3 and R4 are independently selected from the group consisting of:
- (i) hydrogen;
- (ii) aryl;
- (iii) substituted aryl;
- (iv) heteroaryl;
- (v) substituted heteroaryl;
- (vi) heterocyclic;
- (vii) substituted heterocyclic;
- (viii) —C1-C8 alkyl;
- —C2-C8 alkenyl, —C2-C8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N;
- (ix) substituted —C1-C8 alkyl;
- substituted —C2-C8 alkenyl;
- substituted —C2-C8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N;
- (x) —C3-C12 cycloalkyl;
- substituted —C3-C12 cycloalkyl;
- and
- (xi) —C3-C12 cycloalkenyl, and substituted —C3-C12 cycloalkenyl;
- and R2 is selected from the group consisting of:
- a) heterocyclic or substituted heterocyclic;
- b) —C3-C12 cycloalkyl, or substituted —C3-C12 cycloalkyl;
- c) —C3-C12 cycloalkenyl, or substituted —C3-C12 cycloalkenyl;
- and
- d) —B—R3, where B is (CO)NR4, (SO2)NR4;
- wherein R3 is selected from the group consisting of:
- (i) hydrogen;
- (ii) aryl;
- (iii) substituted aryl;
- (iv) heteroaryl;
- (v) substituted heteroaryl;
- (vi) heterocyclic;
- (vii) substituted heterocyclic;
- (viii) —C1-C8 alkyl;
- —C2-C8 alkenyl, —C2-C8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N;
- (ix) substituted —C1-C8 alkyl;
- substituted —C2-C8 alkenyl;
- substituted —C2-C8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N;
- (x) —C3-C12 cycloalkyl;
- substituted —C3-C12 cycloalkyl;
- and
- (xi) —C3-C12 cycloalkenyl, and substituted —C3-C12 cycloalkenyl;
- and R4 is selected from the group consisting of:
- (i) heterocyclic;
- (ii) substituted heterocyclic;
- (iii) —C3-C12 cycloalkyl;
- substituted —C3-C12 cycloalkyl;
- and
- (iv) —C3-C12 cycloalkenyl, and substituted —C3-C12 cycloalkenyl;
- alternatively, R1 and R2 taken together with the carbon atom to which they are attached form cyclic moiety consisting of:
- substituted or unsubstituted cycloalkyl, cycloalkenyl, or heterocyclic;
- substituted or unsubstituted cycloalkyl, cycloalkenyl, or heterocyclic each fused with one or more R3;
- where R3 is as previously defined;
- G is -E-R3 where E is absent, or E is O, CO, (CO)O, (CO)NH, NH, NH(CO), NH(CO)NH, NH(SO2)NH or NHSO2;
- where R3 is as previously defined;
- Z is selected from the group consisting of:
- CH2, O, S, SO and SO2;
- A is selected from the group consisting of:
- R5, (CO)R5, (CO)OR5, (CO)NHR5, SO2R5, (SO2)OR5 and SO2NHR5;
- R5 is selected from the group consisting of:
- a) aryl;
- b) substituted aryl;
- c) heteroaryl;
- d) substituted heteroaryl;
- e) heterocyclic;
- f) substituted heterocyclic;
- g) —C1-C8 alkyl;
- —C2-C8 alkenyl;
- —C2-C8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N;
- h) substituted —C1-C8 alkyl;
- substituted —C2-C8 alkenyl;
- substituted —C2-C8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N;
- i) —C3-C12 cycloalkyl;
- j) substituted —C3-C12 cycloalkyl;
- k) —C3-C12 cycloalkenyl;
- and
- l) substituted —C3-C12 cycloalkenyl;
- j=0, 1, 2, or 3;
- k=0, 1, 2, or 3;
- and
- m=0, 1, 2 or 3;
- n=1, 2 or 3;
- and
- h=0, 1, 2, or 3,
- the method comprising cyclizing a compound of formula XXXII,
- wherein each R106 is independently selected from the group consisting of:
- H, C1-6alkyl and C3-6cycloalkyl;
- and
- PG is a protecting group selected from the group consisting of:
- a benzoyl, a substituted benzoyl group or t-Boc,
- and the protecting group PG is subsequently removed to yield a macrocyclic compound of formula 1.
100 more elements
A method of making a compound of formula IV:
- as well as the pharmaceutically acceptable salts, esters and prodrugs thereof,
- wherein V is absent, or V is CO, O, S, SO, SO2, NH or NCH3, or (CH2)q;
- where q is 1, 2, 3 or 4;
- and where X and Y are independently selected from the group consisting of:
- aryl;
- substituted aryl;
- heteroaryl;
- substituted heteroaryl;
- heterocyclic;
- and substituted heterocyclic, the method comprising:
- the method comprising cyclizing a compound of formula XXXIV,
- in the presence of a suitable catalyst in a suitable organic solvent to obtain macrocyclic compound IV,
- wherein each R106 is independently selected from the group consisting of:
- H, C1-6alkyl and C3-6cycloalkyl, and
- PG is a protecting group consisting of benzoyl, a substituted benzoyl group or t-Boc;
- and the protecting group PG is subsequently removed to yield a macrocyclic compound of formula IV.
13 more elements
Dependencies are inferred from the claim text.