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US 2015/0175550 A1Published application
Process for making isoquinoline compounds
AssigneeFibroGen, Inc.
InventorsMichael D. Thompson, Jung Min Park, Michael P. Arend
Life of this patent
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Abstract
The present invention relates to methods for making isoquinoline compounds and the intermediate compounds achieved thereby. Such compounds can be used to prepare compounds and compositions capable of decreasing HIF hydroxylase enzyme activity, thereby increasing the stability and/or activity of hypoxia inducible factor (HIF).
Claims93
A method of making a compound of formula I or a stereoisomer or mixture of stereoisomers thereof:
- the method comprising contacting a compound of formula II:
- with a compound of formula III:
- under reaction conditions sufficient to produce a compound of formula I;
- wherein
- Z is O, NR1, or S;
- R1 is selected from the group consisting of hydrogen and alkyl;
- R2 is selected from the group consisting of hydrogen and alkyl which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl, and heteroaryl;
- R3 and R4 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, halo, hydroxy, cyano, —S(O)n—N(R8)—R8, —NR8C(O)NR8R8, and —X1R8;
- where X1 is oxygen, —S(O)n—, or —NR9—;
- n is 0, 1, or 2;
- each R8 is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclyl and substituted heterocyclyl provided that when X1 is —SO— or —SO2—, then R8 is not hydrogen;
- and
- R9 is selected from the group consisting of hydrogen, alkyl, and aryl;
- or R3 and R4 together with the carbon atoms pendent thereto, form a cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl;
- R5 and R6 are independently selected from the group consisting of hydrogen, halo, alkyl, substituted alkyl, alkoxy, substituted alkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl and —X2R10;
- where X2 is oxygen, —S(O)n—, or —NR13—;
- n is 0, 1, or 2;
- R10 is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl and substituted heterocyclyl;
- and
- R13 is selected from the group consisting of hydrogen, alkyl, and aryl;
- or when X2 is —NR13—, then R10 and R13, together with the nitrogen atom to which they are bound, can be joined to form a heterocyclyl or substituted heterocyclyl group;
- and
- each R11 is independently selected from alkyl, benzyl or aryl, or two R11 together with the nitrogen atom to which they are attached form a 4-8 membered heterocyclyl or a heteroaryl.
20 more elements
A method of making a compound of formula IA or a stereoisomer or mixture of stereoisomers thereof:
- comprising contacting a compound of formula IIA:
- with a compound of formula III:
- under reaction conditions sufficient to produce a compound of formula IA;
- wherein
- R2 is selected from the group consisting of hydrogen and alkyl which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl, and heteroaryl;
- R3 and R4 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, halo, hydroxy, cyano, —S(O)n—N(R8)—R8 where n is 0, 1, or 2, —NR8C(O)NR8R8, —X1R8 where X1 is oxygen, —S(O)n— or —NR9— where n is 0, 1, or 2, or R3, R4 together with the carbon atom pendent thereto, form a cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl;
- R5 and R6 are independently selected from the group consisting of hydrogen, halo, alkyl, substituted alkyl, alkoxy, substituted alkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl and —X2R10 where X2 is oxygen, —S(O)n— or —NR13— where n is 0, 1, or 2, or when X2 is —NR13—, then R13 and R10, together with the nitrogen atom to which they are bound, can be joined to form a heterocyclyl or substituted heterocyclyl group;
- each R8 is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclyl and substituted heterocyclyl provided that when X1 is —SO— or —SO2—, then R8 is not hydrogen;
- R9 and R13 are independently selected from the group consisting of hydrogen, alkyl, and aryl;
- R10 is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl and substituted heterocyclyl;
- and
- each R11 is independently selected from alkyl, benzyl or aryl, or two R11 together with the nitrogen atom to which they are attached form a 4-8 membered heterocyclyl or a heteroaryl.
9 more elements
A method of making a compound of formula IV or a stereoisomer or mixture of stereoisomers thereof:
- comprising contacting a compound of formula I:
- with a compound of formula
- followed by a compound of formula
- a compound of formula R12—X3 followed by a compound of formula
- or a compound of formula V:
- under reaction conditions sufficient to produce a compound of formula IV;
- wherein
- Z is O, NR1 or S;
- R1 is selected from the group consisting of hydrogen and alkyl;
- R2 is selected from the group consisting of hydrogen and alkyl which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl, and heteroaryl;
- R3 and R4 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, halo, hydroxy, cyano, —S(O)n—N(R8)—R8 where n is 0, 1, or 2, —NR8C(O)NR8R8, —X1R8 where X1 is oxygen, —S(O)n— or —NR9— where n is 0, 1, or 2, or R3, R4 together with the carbon atom pendent thereto, form a cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl;
- R5 and R6 are independently selected from the group consisting of hydrogen, halo, alkyl, substituted alkyl, alkoxy, substituted alkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl and —X2R10 where X2 is oxygen, —S(O)n— or —NR13— where n is 0, 1, or 2, or when X2 is —NR13—, then R13 and R10, together with the nitrogen atom to which they are bound, can be joined to form a heterocyclyl or substituted heterocyclyl group;
- each R8 is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclyl and substituted heterocyclyl provided that when X1 is —SO— or —SO2—, then R8 is not hydrogen;
- R9 and R13 are independently selected from the group consisting of hydrogen, alkyl, and aryl;
- R10 is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl and substituted heterocyclyl;
- each R11 is independently selected from alkyl, benzyl or aryl, or two R11 together with the nitrogen atom to which they are attached form a 4-8 membered heterocyclyl or a heteroaryl;
- each R12 is independently selected from the group consisting of alkyl, aryl, heteroaryl, and heterocyclyl, or when two R12 are present, two R12 together with the carbon atom to which they are attached form a 4-8 membered heterocyclyl;
- and
- X3 is halo.
16 more elements
A method of making a compound of formula IVA or a stereoisomer or mixture of stereoisomers thereof:
- comprising contacting a compound of formula IA:
- with a compound of formula V:
- under reaction conditions sufficient to produce a compound of formula IVA;
- wherein
- R2 is selected from the group consisting of hydrogen and alkyl which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl, and heteroaryl;
- R3 and R4 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, halo, hydroxy, cyano, —S(O)n—N(R8)—R8 where n is 0, 1, or 2, —NR8C(O)NR8R8, —X1R8 where X1 is oxygen, —S(O)n— or —NR9— where n is 0, 1, or 2, or R3, R4 together with the carbon atom pendent thereto, form a cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl;
- R5 and R6 are independently selected from the group consisting of hydrogen, halo, alkyl, substituted alkyl, alkoxy, substituted alkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl and —X2R10 where X2 is oxygen, —S(O)n— or —NR13— where n is 0, 1, or 2, or when X2 is —NR13—, then R13 and R10, together with the nitrogen atom to which they are bound, can be joined to form a heterocyclyl or substituted heterocyclyl group;
- each R8 is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclyl and substituted heterocyclyl provided that when X1 is —SO— or —SO2—, then R8 is not hydrogen;
- R9 and R13 are independently selected from the group consisting of hydrogen, alkyl, and aryl;
- R10 is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl and substituted heterocyclyl;
- each R11 is independently selected from alkyl, benzyl or aryl, or two R11 together with the nitrogen atom to which they are attached form a 4-8 membered heterocyclyl or a heteroaryl;
- and
- each R12 is independently selected from the group consisting of alkyl, aryl, heteroaryl, and heterocyclyl, or two R12 together with the carbon atom to which they are attached form a 4-8 membered heterocyclyl.
10 more elements
A method of making a compound of formula VI or a stereoisomer or mixture of stereoisomers thereof:
- comprising converting a compound of formula IV:
- under reaction conditions sufficient to produce a compound of formula VI;
- wherein
- Z is O, NR1 or S;
- R1 is selected from the group consisting of hydrogen and alkyl;
- R2 is selected from the group consisting of hydrogen and alkyl which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl, and heteroaryl;
- R3 and R4 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, halo, hydroxy, cyano, —S(O)n—N(R8)—R8 where n is 0, 1, or 2, —NR8C(O)NR8R8, —X1R8 where X1 is oxygen, —S(O)n— or —NR9— where n is 0, 1, or 2, or R3, R4 together with the carbon atom pendent thereto, form a cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl;
- R5 and R6 are independently selected from the group consisting of hydrogen, halo, alkyl, substituted alkyl, alkoxy, substituted alkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl and —X2R10 where X2 is oxygen, —S(O)n— or —NR13— where n is 0, 1, or 2, or when X2 is —NR13—, then R13 and R10, together with the nitrogen atom to which they are bound, can be joined to form a heterocyclyl or substituted heterocyclyl group;
- each R8 is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclyl and substituted heterocyclyl provided that when X1 is —SO— or —SO2—, then R8 is not hydrogen;
- R9 and R13 are independently selected from the group consisting of hydrogen, alkyl, and aryl;
- and
- R10 is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl and substituted heterocyclyl;
- and
- each R12 is independently selected from the group consisting of alkyl, aryl, heteroaryl, and heterocyclyl.
11 more elements
A method of making a compound of formula VIA or a stereoisomer or mixture of stereoisomers thereof:
- comprising converting a compound of formula IVA:
- under reaction conditions sufficient to produce a compound of formula VIA;
- wherein
- R2 is selected from the group consisting of hydrogen and alkyl which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl, and heteroaryl;
- R3 and R4 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, halo, hydroxy, cyano, —S(O)n—N(R8)—R8 where n is 0, 1, or 2, —NR8C(O)NR8R8, —X1R8 where X1 is oxygen, —S(O)n— or —NR9— where n is 0, 1, or 2, or R3, R4 together with the carbon atom pendent thereto, form a cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl;
- R5 and R6 are independently selected from the group consisting of hydrogen, halo, alkyl, substituted alkyl, alkoxy, substituted alkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl and —X2R10 where X2 is oxygen, —S(O)n— or —NR13— where n is 0, 1, or 2, or when X2 is —NR13—, then R13 and R10, together with the nitrogen atom to which they are bound, can be joined to form a heterocyclyl or substituted heterocyclyl group;
- each R8 is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclyl and substituted heterocyclyl provided that when X1 is —SO— or —SO2—, then R8 is not hydrogen;
- R9 and R13 are independently selected from the group consisting of hydrogen, alkyl, and aryl;
- and
- R10 is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl and substituted heterocyclyl;
- and
- each R12 is independently selected from the group consisting of alkyl, aryl, heteroaryl, and heterocyclyl.
9 more elements
The method claim of 30, wherein the base is sodium carbonate.
The method of 33, wherein the catalyst is Pd/C.
A method of making a compound of formula VI or a stereoisomer or mixture of stereoisomers thereof:
- the method comprising the steps of:
- a) contacting a compound of formula II with a compound of formula III
- under reaction conditions sufficient to produce a compound of formula I:
- b) contacting a compound of formula I with a compound of formula
- followed by a compound of formula
- a compound of formula R12—X3 followed by a compound of formula
- or a compound of formula V:
- under reaction conditions sufficient to produce a compound of formula IV:
- c) optionally converting a compound of formula VII:
- under reaction conditions sufficient to produce a compound of formula IV;
- and
- d) converting a compound of formula IV under reaction conditions sufficient to produce a compound of formula VI;
- wherein
- Z is O, NR1 or S;
- R1 is selected from the group consisting of hydrogen and alkyl;
- R2 is selected from the group consisting of hydrogen and alkyl which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl, and heteroaryl;
- R3 and R4 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, halo, hydroxy, cyano, —S(O)n—N(R8)—R8 where n is 0, 1, or 2, —NR8C(O)NR8R8, —X1R8 where X1 is oxygen, —S(O)n— or —NR9— where n is 0, 1, or 2, or R3, R4 together with the carbon atom pendent thereto, form a cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl;
- R5 and R6 are independently selected from the group consisting of hydrogen, halo, alkyl, substituted alkyl, alkoxy, substituted alkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl and —X2R10 where X2 is oxygen, —S(O)n— or —NR13— where n is 0, 1, or 2, or when X2 is —NR13—, then R13 and R10, together with the nitrogen atom to which they are bound, can be joined to form a heterocyclyl or substituted heterocyclyl group;
- each R8 is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclyl and substituted heterocyclyl provided that when X1 is —SO— or —SO2—, then R8 is not hydrogen;
- R9 and R13 are independently selected from the group consisting of hydrogen, alkyl, and aryl;
- and
- R10 is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl and substituted heterocyclyl;
- each R11 is independently selected from alkyl, benzyl or aryl, or two R11 together with the nitrogen atom to which they are attached form a 4-8 membered heterocyclyl or a heteroaryl;
- each R12 is independently selected from the group consisting of alkyl, aryl, heteroaryl, and heterocyclyl, or when two R12 are present, two R12 together with the carbon atom to which they are attached form a 4-8 membered heterocyclyl;
- and
- X3 is halo.
23 more elements
A method of making a compound of formula VIA or a stereoisomer or mixture of stereoisomers thereof:
- the method comprising the steps of:
- a) contacting a compound of formula IIA with a compound of formula III
- under reaction conditions sufficient to produce a compound of formula IA:
- b) contacting a compound of formula IA with a compound of formula V
- under reaction conditions sufficient to produce a compound of formula IVA:
- c) optionally converting a compound of formula VIIA:
- under reaction conditions sufficient to produce a compound of formula IVA;
- and
- d) converting a compound of formula IVA under reaction conditions sufficient to produce a compound of formula VIA;
- wherein
- R2 is selected from the group consisting of hydrogen and alkyl which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl, and heteroaryl;
- R3 and R4 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, halo, hydroxy, cyano, —S(O)n—N(R8)—R8 where n is 0, 1, or 2, —NR8C(O)NR8R8, —X1R8 where X1 is oxygen, —S(O)n— or —NR9— where n is 0, 1, or 2, or R3, R4 together with the carbon atom pendent thereto, form a cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl;
- R5 and R6 are independently selected from the group consisting of hydrogen, halo, alkyl, substituted alkyl, alkoxy, substituted alkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl and —X2R10 where X2 is oxygen, —S(O)n— or —NR9— where n is 0, 1, or 2, or when X2 is —NR13—, then R13 and R10, together with the nitrogen atom to which they are bound, can be joined to form a heterocyclyl or substituted heterocyclyl group;
- each R8 is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclyl and substituted heterocyclyl provided that when X1 is —SO— or —SO2—, then R8 is not hydrogen;
- R9 and R13 are independently selected from the group consisting of hydrogen, alkyl, and aryl;
- and
- R10 is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl and substituted heterocyclyl;
- each R11 is independently selected from alkyl, benzyl or aryl, or two R11 together with the nitrogen atom to which they are attached form a 4-8 membered heterocyclyl or a heteroaryl;
- and
- each R12 is independently selected from the group consisting of alkyl, aryl, heteroaryl, and heterocyclyl, or two R12 together with the carbon atom to which they are attached form a 4-8 membered heterocyclyl.
17 more elements
A method of making a compound of formula VIC or a stereoisomer or mixture of stereoisomers thereof:
- comprising the steps of:
- a) contacting a compound of formula IIC with a compound of formula IIIA
- under reaction conditions sufficient to produce a compound of formula IC:
- b) contacting a compound of formula IC with a compound of formula VA
- under reaction conditions sufficient to produce a compound of formula IVC:
- c) optionally converting a compound of formula VIIC:
- under reaction conditions sufficient to produce a compound of formula IVC;
- and
- d) converting a compound of formula IVC under reaction conditions sufficient to produce a compound of formula VIC;
- wherein
- R2 is selected from the group consisting of hydrogen and alkyl which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl, and heteroaryl;
- R4 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, halo, hydroxy, cyano, —S(O)n—N(R8)—R8 where n is 0, 1, or 2, —NR8C(O)NR8R8, —X1R8 where X1 is oxygen, —S(O)n— or —NR9— where n is 0, 1, or 2, or R3, R4 together with the carbon atom pendent thereto, form a cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl;
- each R8 is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclyl and substituted heterocyclyl provided that when X1 is —SO— or —SO2—, then R8 is not hydrogen;
- and
- each R9 is selected from the group consisting of hydrogen, alkyl, and aryl.
12 more elements
A method of making a compound of formula VID or a stereoisomer or mixture of stereoisomers thereof:
- comprising the steps of:
- a) contacting a compound of formula IID with a compound of formula IIIA
- under reaction conditions sufficient to produce a compound of formula ID:
- b) contacting a compound of formula ID with a compound of formula VA
- under reaction conditions sufficient to produce a compound of formula IVD:
- c) optionally converting a compound of formula VIID:
- under reaction conditions sufficient to produce a compound of formula IVD;
- and
- d) converting a compound of formula IVD under reaction conditions sufficient to produce a compound of formula VID;
- wherein
- R2 is selected from the group consisting of hydrogen and alkyl which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl, and heteroaryl;
- R3 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, halo, hydroxy, cyano, —S(O)n—N(R8)—R8 where n is 0, 1, or 2, —NR8C(O)NR8R8, —X1R8 where X1 is oxygen, —S(O)n— or —NR9— where n is 0, 1, or 2, or R3, R4 together with the carbon atom pendent thereto, form a cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl;
- each R8 is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclyl and substituted heterocyclyl provided that when X1 is —SO— or —SO2—, then R8 is not hydrogen;
- and
- each R9 is selected from the group consisting of hydrogen, alkyl, and aryl.
12 more elements
The method claim of 71, wherein the base is sodium carbonate.
A compound of formula VIII:
- wherein:
- Z is O, NR1 or S;
- R1 is selected from the group consisting of hydrogen and alkyl;
- R2 is selected from the group consisting of hydrogen and alkyl which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl, and heteroaryl;
- R3 and R4 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, halo, hydroxy, cyano, —S(O)n—N(R8)—R8 where n is 0, 1, or 2, —NR8C(O)NR8R8, —X1R8 where X1 is oxygen, —S(O)n— or —NR9— where n is 0, 1, or 2, or R3, R4 together with the carbon atom pendent thereto, form a cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl;
- R5 and R6 are independently selected from the group consisting of hydrogen, halo, alkyl, substituted alkyl, alkoxy, substituted alkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl and —X2R10 where X2 is oxygen, —S(O)n— or —NR13— where n is 0, 1, or 2, or when X2 is —NR13—, then R13 and R10, together with the nitrogen atom to which they are bound, can be joined to form a heterocyclyl or substituted heterocyclyl group;
- R7 is either —N(R11)(R11) or —OC(O)R12;
- each R8 is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclyl and substituted heterocyclyl provided that when X1 is —SO— or —SO2—, then R8 is not hydrogen;
- R9 and R13 are independently selected from the group consisting of hydrogen, alkyl, and aryl;
- R10 is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl and substituted heterocyclyl;
- each R11 is independently selected from alkyl, benzyl or aryl, or two R11 together with the nitrogen atom to which they are attached form a 4-8 membered heterocyclyl or a heteroaryl;
- and
- each R12 is independently selected from the group consisting of alkyl, aryl, heteroaryl, and heterocyclyl;
- or a salt, ester, stereoisomer, or mixture of stereoisomers thereof;
- provided that the compound is not 1-dimethylaminomethyl-4-hydroxy-7-phenylsulfanyl-isoquinoline-3-carboxylic acid butyl ester.
12 more elements
A compound of formula VIIIA:
- wherein:
- R2 is selected from the group consisting of hydrogen and alkyl which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl, and heteroaryl;
- R3 and R4 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, halo, hydroxy, cyano, —S(O)n—N(R8)—R8 where n is 0, 1, or 2, —NR8C(O)NR8R8, —X1R8 where X1 is oxygen, —S(O)n— or —NR9— where n is 0, 1, or 2, or R3, R4 together with the carbon atom pendent thereto, form a cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl;
- R5 and R6 are independently selected from the group consisting of hydrogen, halo, alkyl, substituted alkyl, alkoxy, substituted alkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl and —X2R10 where X2 is oxygen, —S(O)n— or —NR13— where n is 0, 1, or 2, or when X2 is —NR13—, then R13 and R10, together with the nitrogen atom to which they are bound, can be joined to form a heterocyclyl or substituted heterocyclyl group;
- R7 is either —N(R11)(R11) or —OC(O)R12;
- each R8 is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclyl and substituted heterocyclyl provided that when X1 is —SO— or —SO2—, then R8 is not hydrogen;
- R9 and R13 are independently selected from the group consisting of hydrogen, alkyl, and aryl;
- R10 is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl and substituted heterocyclyl;
- each R11 is independently selected from alkyl, benzyl or aryl, or two R11 together with the nitrogen atom to which they are attached form a 4-8 membered heterocyclyl or a heteroaryl;
- and
- each R12 is independently selected from the group consisting of alkyl, aryl, heteroaryl, and heterocyclyl;
- or a salt, ester, stereoisomer, or mixture of stereoisomers thereof;
- provided that the compound is not 1-dimethylaminomethyl-4-hydroxy-7-phenylsulfanyl-isoquinoline-3-carboxylic acid butyl ester.
10 more elements
A compound that is 4-hydroxy-7-phenoxyisoquinoline-3-carboxylic acid methyl ester (3a):
A compound that is methyl 4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carboxylate (3e):
Dependencies are inferred from the claim text.