Ring closing and related methods and intermediates
View Patent ↗Methods and intermediates useful for making compounds of the formula: and the preparation of compounds of Formula I, preferably including the formation of intermediate compounds of the formula:
1. A method comprising: combining a compound of the formula:
with a compound of the formula:
or a salt thereof or
combining a compound of the formula:
with a compound of the formula:
or a salt thereof to form a compound of the formula:
wherein:
D is selected from the group consisting of —C≡N, —C(O)—O—C 1-4 alkyl, —C(O)—NH 2 , —C(O)—H, —CH 2 OH, and —CH 2 OC 1-4 alkyl;
E is selected from the group consisting of —Cl, —Br, —I, —OS(O) 2 CF 3 , and —N 2 + BF 4 − ;
M is selected from the group consisting of —B(OH) 2 , —B(O-alkyl) 2 , —Sn(alkyl) 3 , —Zn-Halide,
P is selected from the group consisting of hydrogen, —C(O)—C 1-4 alkyl, —C(O)—O—C 1-4 alkyl, benzyl, and p-methoxybenzyl, or —NHP is replaced by a 2,5-dimethylpyrrole;
R A and R B taken together form a fused benzene ring or fused pyridine ring wherein the benzene ring or pyridine ring is unsubstituted or substituted by one or more R groups, or substituted by one R 3 group, or substituted by one R 3 group and one R group; wherein:
R is selected from the group consisting of:
halogen,
hydroxy,
alkyl,
haloalkyl,
alkoxy, and
—N(R 9 ) 2 ;
R 1 is selected from the group consisting of:
—R 4 ,
—X—R 4 ,
—X—Y—R 4 ,
—X—Y—X—Y—R 4 , and
—X—R 5 ;
R 2 is selected from the group consisting of:
—R 4 ,
—X—R 4 ,
—X—Y—R 4 , and
—X—R 5 ;
R 3 is selected from the group consisting of:
—Z—R 4 ,
—Z—X—R 4 ,
—Z—X—Y—R 4 ,
—Z—X—Y—X—Y—R 4 , and
—Z—X—R 5 ;
X is selected from the group consisting of alkylene, alkenylene, alkynylene, arylene, heteroarylene, and heterocyclylene wherein the alkylene, alkenylene, and alkynylene groups can be optionally interrupted or terminated by arylene, heteroarylene or heterocyclylene and optionally interrupted by one or more —O—groups;
Y is selected from the group consisting of:
—O—,
—S(O) 0-2 —,
—S(O) 2 —N(R 8 )—,
—C(R 6 )—,
—C(R 6 )—O—,
—O—C(R 6 )—,
—O—C(O)—O—,
—N(R 8 )-Q-,
—C(R 6 )—N(R 8 )—,
—O—C(R 6 )—N(R 8 )—,
—C(R 6 )—N(OR 9 )—,
—O—N(R 8 )-Q-,
—O—N═C(R 4 )—,
—C(═N—O—R 8 )—,
—CH(—N(—O—R 8 )-Q-R 4 )—,
Z is a bond or —O—;
R 4 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, arloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl, alkyleheteroarylenyl, and heterocyclyl wherein the alkyl, alkenyl, alkynyl, aryl, arylalylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl groups can be unsubstituted or substituted by one or more substitutents independently selected from the group consisting of alkyl, aloxy, hydroxyalkyl, haloalkyl, haloalkoxy, halogen, nitro, hydroxy, mercapto, cyano, aryl, aryloxy, arylalkleneoxy, heteroaryl, heteroaryloxy, heteroarylalkyleneoxy, heterocyclyl, amino, alkylamino, dialkylamino, (dialkylamino)alkyleneoxy, and in the case of alkyl, alkenyl, alkynyl, and heterocyclyl, oxo;
R 5 is selected from the group consisting of:
R 6 is selected from the group consisting of ═O and ═S;
R 7 is C 2-7 alkylene;
R 8 is selected from the group consisting of hydrogen, alkyl, alkoxyalkylenyl, hydroxyalkylenyl, arylalkylenyl, and heteroarylalkylenyl;
R 9 is selected from the group consisting of hydrogen and alkyl;
R 10 is C 3-8 alkylene;
A is selected from the group consisting of —O—, —C(O)—, —S(O) 0-2 —, and N(R 4 )—;
M is selected from the group consisting of —O—, —S(O) 0-2 —, —N(-Q-R 4 )—, and —CH 2 —;
Q is selected from the group consisting of a bond, —C(R 6 )—, —C(R 6 )—C(R 6 )—, —S(O) 2 —, —C(R 6 )—N(R 8 )—W—, —S(O) 2 —N(R 8 )—, —C(R 6 )—O—, —C(R 6 )—S—, and —C(R 6 )—N(OR 9 )—;
V is selected from the group consisting of —C(R 6 )—, —O—C(R 6 )—, —N(R 8 )—C(R 6 )—, and —S(O) 2 —;
W is selected from the group consisting of a bond, —C(O)—, and —S(O) 2 —; and
a and b are independently integers from 1 to 6 with the proviso that a+b is ≦7.
2. A method comprising:
providing a compound of the formula:
and exposing the compound of Formula IV′ to conditions to cause an intramolecular cyclization and formation of a compound of the formula:
wherein:
P is selected from the group consisting of hydrogen, —C(O)—C 1-4 alkyl,—C(O)—O—C 1-4 alkyl, benzyl, and p-methoxybenzyl, or —NHP is replaced by a 2,5-dimethylpyrrole;
R A and R B taken together form a fused benzene ring or fused pyridine ring wherein the benzene ring or pyridine ring is unsubstituted or substituted by one or more R groups, or substituted by one R 3 group, or substituted by one R 3 group and one R group; wherein:
R is selected from the group consisting of:
halogen,
hydroxy,
alkyl,
haloalkyl,
alkoxy, and
—N(R 9 ) 2 ;
R 1 is selected from the group consisting of:
—R 4 ,
—X—R 4 ,
—X—Y—R 4 ,
—X—Y—X—Y—R 4 , and
—X—R 5 ;
R 2 is selected from the group consisting of:
—R 4 ,
—X—R 4 ,
—X—Y—R 4 , and
—X—R 5 ;
R 3 is selected from the group consisting of:
—Z—R 4 ,
—Z—X—R 4 ,
—Z—X—Y—R 4 ,
—Z—X—Y—X—Y—R 4 , and
—Z—X—R 5 ;
X is selected from the group consisting of alkylene, alkenylene, alkynylene, arylene heteroarylene, and heterocyclylene wherein the alkylene, alkenylene, and alkynylene groups can be optionally interrupted or terminated by arylene, heteroarylene or heterocyclylene and optionally interrupted by one or more —O—groups;
Y is selected from the group consisting of:
—O—,
—S(O) 0-2 —,
—S(O) 2 —N(R 8 )—,
—C(R 6 )—,
—C(R 6 )—O—,
—O—C(R 6 )—,
—O—C(O)—O—,
—N(R 8 )-Q-,
—C(R 6 )—N(R 8 )—,
—O—C(R 6 )—N(R 8 )—,
—C(R 6 )—N(OR 9 )—,
—O—N(R 8 )-Q-,
—O—N═C(R 4 )—,
—C(═N—O—R 8 )—,
—CH(—N(—O—R 8 )-Q-R 4 )—,
Z is a bond or —O—;
R 4 is selected from the group consisting of hydrogen, alkyl, alkenyl, atkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl wherein the alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl, hetemaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl groups can be unsubstituted or substituted by one or more substituents independently selected from the group consisting of alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy, halogen, nitro, hydroxy, meroapto, cyano, aryl, aryloxy, arylalkyleneoxy, heteroaryl, heteroaryloxy, heteroarylalkyleneoxy, heterocyclyl, amino, alkylamino, dialkylamino, (dialkylamino)alkyleneoxy, and in the case of alkyl, alkenyl, alkynyl, and heterocyclyl, oxo;
R 5 is selected from the group consisting of:
R 6 is selected from the group consisting of ═O and ═S;
R 7 is C 2-7 alkylene;
R 8 is selected from the group consisting of hydrogen, alkyl, alkoxyalkylenyl, hydroxyalkylenyl, arylalkylenyl, and heteroarylalkylenyl;
R 9 is selected from the group consisting of hydrogen and alkyl;
R 10 is C 3-8 alkylene;
A is selected from the group consisting of —O—, —C(O)—, —S(O) 0-2 —, and —N(R 4 )—;
A′ is selected from the group consisting of —O—, —N(-Q-R 4 )—, and —CH 2 ;
Q is selected from the group consisting of a bond, —C(R 6 )—, —C(R 6 )—C(R 6 )—, —S(O) 2 —, —C(R 6 )—N(R 8 )—W—S(O) 2 —N(R 8 )—, —C(R 6 )—O—, —C(R 6 )—S—, and —C(R 6 )—N(OR 9 )—;
V is selected from the group consisting of —C(R 6 )—, —O—C(R 6 )—, —N(R 8 )—C(R 6 )—, and —S(O) 2 —;
W is selected from the group consisting of a bond, —C(O)—, and —S(O) 2 —; and
a and b are independently integers from 1 to 6 with the proviso that a+b is ≦7.
3. The method of claim 2 wherein R 1 is selected from the group consisting of 2-methylpropyl, 2-hydroxy-2-methylpropyl, 2-(propylsulfonyl)ethyl, 2-methyl-2-[(methylsulfonyl)amino]propyl, 4-[(morpholin-4-ylcarbonyl)amino]butyl, and 4-methanesulfonylaminobutyl.
4. The method of claim 2 wherein R 1 is 4-methanesulfonylaminobutyl.
5. The method of claims 2 wherein R 2 is selected from the group consisting of hydrogen, methyl, ethyl, propyl, butyl, 2-methoxyethyl, 2-hydroxyethyl, ethoxymethyl, and hydroxymethyl.
6. The method of claim 2 where R 2 is ethyl.
7. A compound of the formula:
wherein:
D is selected from the group consisting of —C≡N, —C(O)—O—C 1-4 alkyl, —C(O)—NH 2 , —C(O)—H, —CH 2 OH, and —CH 2 OC 1-4 alkyl;
P is selected from the group consisting of hydrogen, —C(O)—C— 1-4 alkyl, —C(O)—O—C 1-4 alkyl benzyl, and p-methoxybenzyl, or —NHP is replaced by a 2,5-dimethylpyrrole;
R A and R B taken together form a fused benzene ring or fused pyridine ring wherein the benzene ring or pyridine ring is unsubstituted or substituted by one or more R groups, or substituted by one R 3 group, or substituted by one R 3 group and one R group; wherein:
R is selected from the group consisting of:
halogen,
hydroxy,
alkyl,
haloalkyl,
alkoxy, and
—N(R 9 ) 2 ;
R 1 is selected from the group consisting of:
—R 4 ,
—X—R 4 ,
—X—Y—R 4 ,
—X—Y—X—Y—R 4 , and
—X—R 5 ;
R 2 is selected from the group consisting of:
—R 4 ,
—X—R 4 ,
—X—Y—R 4 , and
—X—R 5 ;
R 3 is selected from the group consisting of:
—Z—R 4 ,
—Z—X—R 4 ,
—Z—X—Y—R 4 ,
—Z—X—Y—X—Y—R 4 , and
—Z—X—R 5 ;
X is selected from the group consisting of alkylene, alkenylene, alkynylene, arylene, heteroarylene, and heterocyclylene wherein the alkylene, alkenylene, and alkynylene groups can be optionally interrupted or terminated by arylene, heteroarylene or heterocyclylene and optionally interrupted by one or more —O—groups;
Y is selected from the group consisting of:
—O—,
—S(O) 0-2 —,
—S(O) 2 —N(R 8 )—,
—C(R 6 )—,
—C(R 6 )—O—,
—O—C(R 6 )—,
—O—C(O)—O—,
—N(R 8 )-Q-,
—C(R 6 )—N(R 8 )—,
—O—C(R 6 )—N(R 8 )—,
—C(R 6 )—N(OR 9 )—,
—O—N(R 8 )-Q-,
—O—N═C(R 4 )—,
—C(═N—O—R 8 )—,
—CH(—N(—O—R 8 )-Q-R 4 )—,
Z is a bond or —O—;
R 4 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl wherein the alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl groups can be unsubstituted or substituted by one or more substituents independently selected from the group consisting of alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy, halogen, nitro, hydroxy, mercapto, cyan, aryl, aryloxy, arylalkyleneoxy, heteroaryl, heteroaryloxy, heteroarylalkyleneoxy, heterocyclyl, amino, alkylamino, dialkylamino, (dialkylamino)alkyleneoxy, and in the case of alkyl, alkenyl, alkynyl, and heterocyclyl, oxo;
R 5 is selected from the group consisting of:
R 6 is selected from the group consisting of ═O and ═S;
R 7 is C 2-7 alkylene;
R 8 is selected from the group consisting of hydrogen, alkyl, alkoxyalkylenyl, hydroxyalkylenyl, arylalkylenyl, and heteroarylalkylenyl;
R 9 is selected from the group consisting of hydrogen and alkyl;
R 10 is C 3-8 alkylene;
A is selected from the group consisting of —O—, —C(O)—, —S(O) 0-2 —, and N(R 4 )—;
A′ is selected from the group consisting of —O—, —S(O) 0-2 —, —N(-Q-R 4 )—, and —CH 2 —;
Q is selected from the group consisting of a bond, —C(R 6 )—C(R 6 )—, —S(O) 2 —, —C(R 6 )—N(R 8 )—W—, —S(O) 2 —N(R 8 )—, —C(R 6 )—O—, —C(R 6 )—S—, and —C(R 6 )—N(OR 9 );
V is selected from the group consisting of —C(R 6 )—, —O—C(R 6 )—, —N(R 8 )—C(R 6 )—, and —S(O) 2 —;
W is selected from the group consisting of a bond, —C(O)—, and —S(O) 2 —; and
a and b are independently integers from 1 to 6 with the proviso that a+b is ≦7;
or a pharmaceutically acceptable salt thereof.
8. The compound of claim 7 wherein R 1 is selected from the group consisting of 2-methylpropyl, 2-hydroxy-2-methylpropyl, 2-(propylsulfonyl)ethyl, 2-methyl-2-[(methylsulfonyl)amino]propyl, 4-[(morpholin-4-ylcarbonyl)amino]butyl, and 4-methanesulfonylaminobutyl.
9. The compound of claim 7 wherein R 1 is 4-methanesulfonylaminobutyl.
10. The compound of claim 7 wherein R 2 is selected from the group consisting of hydrogen, methyl, ethyl, propyl, butyl, 2-methoxyethyl, 2-hydroxyethyl, ethoxymethyl, and hydroxymethyl.
11. The compound of claim 7 wherein R 2 is ethyl.
12. The method of claim 4 wherein R 2 is ethyl.
13. The compound of claim 9 wherein R 2 is ethyl.
14. The compound of claim 7 wherein D is —C≡N.
15. The compound of claim 7 wherein P is hydrogen.
16. The compound of claim 7 wherein R A and R B taken together form a fused benzene ring or fused pyridine ring wherein the benzene ring or pyridine ring is unsubstituted.
17. The compound of claim 16 wherein R A and R B taken together form a fused benzene ring that is unsubstituted.
18. The compound of claim 8 wherein R 1 is selected from the group consisting of 2-hydroxy-2-methylpropyl, 2-(propylsulfonyl)ethyl, 2-methyl-2-[(methylsulfonyl)amino]propyl, 4-[(morpholin-4-ylcarbonyl)amino]butyl, and 4-methanesulfonylaminobutyl.
19. The compound of claim 8 wherein R 1 is 2-methylpropyl.
20. The compound of claim 10 wherein R 2 is selected from the group consisting of methyl, ethyl, propyl, butyl, 2-methoxyethyl, 2-hydroxyethyl, ethoxymethyl, and hydroxymethyl.
21. The compound of claim 10 wherein R 2 is hydrogen.