Indole and azaindole haloallylamine derivative inhibitors of lysyl oxidases and uses thereof
The present invention relates to novel compounds which are capable of inhibiting certain amine oxidase enzymes. These compounds are useful for treatment of a variety of indications, e.g., fibrosis, cancer and/or angiogenesis in human subjects as well as in pets and livestock. In addition, the present invention relates to pharmaceutical compositions containing these compounds, as well as various uses thereof.
1. A compound of Formula I:
or a stereoisomer, pharmaceutically acceptable salt, or tautomeric form thereof;
wherein:
a is N or CR 3 ;
b is N or CR 4 ;
c is N or CR 5 ;
d is N or CR 6 ;
and from 0 to 2 of a, b, c and d are N;
X is O or —(CHR 7 ) m —
m is 1 or 2;
R 1 is selected from the group consisting of hydrogen, halogen, C 1-6 alkyl, C 3-7 cycloalkyl, —O—C 1-6 alkyl, —O—C 3-7 cycloalkyl, —C(O)OR 8 , —C(O)NR 9 R 10 and —NR 9 C(O)R 11 ; wherein each C 1-6 alkyl is a straight or branched chain alkyl; and wherein each C 1-6 -alkyl and C 3-7 cycloalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, —OH, —SH, —C 1-3 alkyl, —O—C 1-3 alkyl, —CF 3 , —CH 2 CF 3 , and —O—CF 3 ;
R 2 is aryl or heteroaryl; wherein each R 2 is optionally substituted by one or more R 12 ;
R 3 , R 4 , R 5 and R 6 are each independently selected from the group consisting of hydrogen, halogen, hydroxyl, C 1-6 alkyl, C 3-7 cycloalkyl, —O—C 1-6 alkyl, —O—C 3-7 cycloalkyl, —CN, —NO 2 , —NR 9 R 10 , —C(O)OR 8 , —C(O)NR 9 R 10 , —NR 9 C(O)R 11 , —S(O 2 )NR 9 R 10 , —NR 9 S(O 2 )R 11 , —S(O)R 11 , —S(O 2 )R 11 , tetrazole and oxadiazole; wherein each C 1-6 alkyl is a straight or branched chain alkyl; and wherein each C 1-6 alkyl and C 3-7 cycloalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, —OH, —SH, —C 1-3 alkyl, —O—C 1-3 alkyl, —CF 3 , —CH 2 CF 3 , and —O—CF 3 ;
each R 7 is independently selected from the group consisting of hydrogen, hydroxyl and C 1-3 alkyl;
R 8 is selected from the group consisting of hydrogen, C 1-6 alkyl, and C 3-7 cycloalkyl; wherein each C 1-6 alkyl is a straight or branched chain alkyl; and wherein each C 1-6 alkyl and C 3-7 cycloalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, —OH, —SH, —C 1-3 alkyl, —O—C 1-3 alkyl, —CF 3 , —CH 2 CF 3 , and —O—CF 3 ;
R 9 and R 10 are independently selected from the group consisting of hydrogen, C 1-6 alkyl and C 3-7 cycloalkyl; wherein each C 1-6 alkyl is a straight or branched chain alkyl; and wherein each C 1-6 alkyl and C 3-7 cycloalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, —OH, —SH, —C 1-3 alkyl, —O—C 1-3 alkyl, —CF 3 , —CH 2 CF 3 , and —O—CF; or
R 9 and R 10 when attached to the same nitrogen atom are combined to form a 3- to 7-membered ring having from 0 to 2 additional heteroatoms as ring members;
R 11 is selected from the group consisting of C 1-6 alkyl and C 3-7 cycloalkyl; wherein each C 1-6 alkyl is a straight or branched chain alkyl; and wherein each C 1-6 alkyl and C 3-7 cycloalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, —OH, —SH, —C 1-3 alkyl, —O—C 1-3 alkyl, —CF 3 , —CH 2 CF 3 , and —O—CF 3 ; and
R 12 is selected from the group consisting of halogen, C 1-6 alkyl, —O—C 1-6 alkyl, —S—C 1-6 alkyl, C 3-7 cycloalkyl, —O—C 3-7 cycloalkyl, —C(O)OR 8 , —C(O)NR 9 R 10 , —NR 9 C(O)R 11 , —S(O 2 )NR 9 R 10 , —NR 9 S(O 2 )R 11 , —S(O)R 11 and —S(O 2 )R 11 ; wherein each C 1-6 alkyl is a straight or branched chain alkyl; and wherein each C 1-6 alkyl and C 3-7 cycloalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, —OH, —C 1-3 alkyl, —O—C 1-3 alkyl, —CF 3 , —CH 2 CF 3 , and —O—CF 3 .
2. A compound according to claim 1 , of Formula Ia:
or a pharmaceutically acceptable salt thereof;
wherein:
X is O or —(CHR 7 ) m —
m is 1 or 2;
R 1 is selected from the group consisting of hydrogen, halogen, C 1-6 alkyl, C 3-7 cycloalkyl, —O—C 1-6 alkyl, —O—C 3-7 cycloalkyl, —C(O)OR 8 , —C(O)NR 9 R 10 and —NR 9 C(O)R 11 ; wherein each C 1-6 alkyl is a straight or branched chain alkyl; and wherein each C 1-6 alkyl and C 3-7 cycloalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, —OH, —SH, —C 1-3 alkyl, —O—C 1-3 alkyl, —CF 3 , —CH 2 CF 3 , and —O—CF 3 ;
R 2 is aryl or heteroaryl; wherein each R 2 is optionally substituted by one or more R 12 ;
R 3 , R 4 , R 5 and R 6 are each independently selected from the group consisting of hydrogen, halogen, hydroxyl, C 1-6 alkyl, C 3-7 cycloalkyl, —O—C 1-6 alkyl, —O—C 3-7 cycloalkyl, —CN, —NO 2 , —NR 9 R 10 , —C(O)OR 8 , —C(O)NR 9 R 10 , —NR 9 C(O)R 11 , —S(O 2 )NR 9 R 10 , —NR 9 S(O 2 )R 11 , —S(O)R 11 , —S(O 2 )R 11 , tetrazole and oxadiazole; wherein each C 1-6 alkyl is a straight or branched chain alkyl; and wherein each C 1-6 alkyl and C 3-7 cycloalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, —OH, —SH, —C 1-3 alkyl, —O—C 1-3 alkyl, —CF 3 , —CH 2 CF 3 , and —O—CF 3 ;
each R 7 is independently selected from the group consisting of hydrogen, hydroxyl and C 1-3 alkyl;
R 8 is selected from the group consisting of hydrogen, C 1-6 alkyl, and C 3-7 cycloalkyl; wherein each C 1-6 alkyl is a straight or branched chain alkyl; and wherein each C 1-6 alkyl and C 3-7 cycloalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, —OH, —SH, —C 1-3 alkyl, —O—C 1-3 alkyl, —CF 3 , —CH 2 CF 3 , and —O—CF 3 ;
R 9 and R 10 are independently selected from the group consisting of hydrogen, C 1-6 alkyl and C 3-7 cycloalkyl; wherein each C 1-6 alkyl is a straight or branched chain alkyl; and wherein each C 1-6 alkyl and C 3-7 cycloalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, —OH, —SH, —C 1-3 alkyl, —O—C 1-3 alkyl, —CF 3 , —CH 2 CF 3 , and —O—CF 3 ; or
R 9 and R 10 when attached to the same nitrogen atom are combined to form a 3- to 7-membered ring having from 0 to 2 additional heteroatoms as ring members;
R 11 is selected from the group consisting of C 1-6 alkyl and C 3-7 cycloalkyl; wherein each C 1-6 alkyl is a straight or branched chain alkyl; and wherein each C 1-6 alkyl and C 3-7 cycloalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, —OH, —SH, —C 1-3 alkyl, —O—C 1-3 alkyl, —CF 3 , —CH 2 CF 3 , and —O—CF 3 ; and
R 12 is selected from the group consisting of halogen, C 1-6 alkyl, —O—C 1-6 alkyl, —S—C 1-6 alkyl, C 3-7 cycloalkyl, —O—C 3-7 cycloalkyl, —C(O)OR 8 , —C(O)NR 9 R 10 , —NR 9 C(O)R 11 , —S(O 2 )NR 9 R 10 , —NR 9 S(O 2 )R 11 , —S(O)R 11 and —S(O 2 )R 11 ; wherein each C 1-6 alkyl is a straight or branched chain alkyl; and wherein each C 1-6 alkyl and C 3-7 cycloalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, —OH, —C 1-3 alkyl, —O—C 1-3 alkyl, —CF 3 , —CH 2 CF 3 , and —O—CF 3 .
3. A compound according to claim 1 , of Formula Ib:
or a pharmaceutically acceptable salt thereof;
X is O or —(CHR 7 ) m —
m is 1 or 2;
R 1 is selected from the group consisting of hydrogen, halogen, C 1-6 alkyl, C 3-7 cycloalkyl, —O—C 1-6 alkyl, —O—C 3-7 cycloalkyl, —C(O)OR 8 , —C(O)NR 9 R 10 and —NR 9 C(O)R 11 ; wherein each C 1-6 alkyl is a straight or branched chain alkyl; and wherein each C 1-6 alkyl and C 3-7 cycloalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, —OH, —SH, —C 1-3 alkyl, —O—C 1-3 alkyl, —CF 3 , —CH 2 CF 3 , and —O—CF 3 ;
R 2 is aryl or heteroaryl; wherein each R 2 is optionally substituted by one or more R 12 ;
R 3 , R 4 and R 5 are each independently selected from the group consisting of hydrogen, halogen, hydroxyl, C 1-6 alkyl, C 3-7 cycloalkyl, —O—C 1-6 alkyl, —O—C 3-7 cycloalkyl, —CN, —NO 2 , —NR 9 R 10 , —C(O)OR 8 , —C(O)NR 9 R 10 , —NR 9 C(O)R 11 , —S(O 2 )NR 9 R 10 , —NR 9 S(O 2 )R 11 , —S(O)R 11 , —S(O 2 )R 11 , tetrazole and oxadiazole; wherein each C 1-6 alkyl is a straight or branched chain alkyl; and wherein each C 1-6 alkyl and C 3-7 cycloalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, —OH, —SH, —C 1-3 alkyl, —O—C 1-3 alkyl, —CF 3 , —CH 2 CF 3 , and —O—CF 3 ;
each R 7 is independently selected from the group consisting of hydrogen, hydroxyl and C 1-3 alkyl;
R 8 is selected from the group consisting of hydrogen, C 1-6 alkyl, and C 3-7 cycloalkyl; wherein each C 1-6 alkyl is a straight or branched chain alkyl; and wherein each C 1-6 alkyl and C 3-7 cycloalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, —OH, —SH, —C 1-3 alkyl, —O—C 1-3 alkyl, —CF 3 , —CH 2 CF 3 , and —O—CF 3 ;
R 9 and R 10 are independently selected from the group consisting of hydrogen, C 1-6 alkyl and C 3-7 cycloalkyl; wherein each C 1-6 alkyl is a straight or branched chain alkyl; and wherein each C 1-6 alkyl and C 3-7 cycloalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, —OH, —SH, —C 1-3 alkyl, —O—C 1-3 alkyl, —CF 3 , —CH 2 CF 3 , and —O—CF 3 ; or
R 9 and R 10 when attached to the same nitrogen atom are combined to form a 3- to 7-membered ring having from 0 to 2 additional heteroatoms as ring members;
R 11 is selected from the group consisting of C 1-6 alkyl and C 3-7 cycloalkyl; wherein each C 1-6 alkyl is a straight or branched chain alkyl; and wherein each C 1-6 alkyl and C 3-7 cycloalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, —OH, —SH, —C 1-3 alkyl, —O—C 1-3 alkyl, —CF 3 , —CH 2 CF 3 , and —O—CF 3 ; and
R 12 is selected from the group consisting of halogen, C 1-6 alkyl, —O—C 1-6 -alkyl, —S—C 1-6 alkyl, C 3-7 cycloalkyl, —O—C 3-7 cycloalkyl, —C(O)OR 8 , —C(O)NR 9 R 10 , —NR 9 C(O)R 11 , —S(O 2 )NR 9 R 10 , —NR 9 S(O 2 )R 11 , —S(O)R 11 and —S(O 2 )R 11 ; wherein each C 1-6 alkyl is a straight or branched chain alkyl; and wherein each C 1-6 alkyl and C 3-7 cycloalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, —OH, —C 1-3 alkyl, —O—C 1-3 alkyl, —CF 3 , —CH 2 CF 3 , and —O—CF 3 .
4. A compound according to claim 1 , of Formula Ic:
or a pharmaceutically acceptable salt thereof;
X is O or —(CHR 7 ) m —
m is 1 or 2;
R 1 is selected from the group consisting of hydrogen, halogen, C 1-6 alkyl, C 3-7 cycloalkyl, —O—C 1-6 alkyl, —O—C 3-7 cycloalkyl, —C(O)OR 8 , —C(O)NR 9 R 10 and —NR 9 C(O)R 11 ; wherein each C 1-6 alkyl is a straight or branched chain alkyl; and wherein each C 1-6 alkyl and C 3-7 cycloalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, —OH, —SH, —C 1-3 alkyl, —O—C 1-3 alkyl, —CF 3 , —CH 2 CF 3 , and —O—CF 3 ;
R 2 is aryl or heteroaryl; wherein each R 2 is optionally substituted by one or more R 12 ;
R 3 , R 4 and R 6 are each independently selected from the group consisting of hydrogen, halogen, hydroxyl, C 1-6 alkyl, C 3-7 cycloalkyl, —O—C 1-6 alkyl, —O—C 3-7 cycloalkyl, —CN, —NO 2 , —NR 9 R 10 , —C(O)OR 8 , —C(O)NR 9 R 10 , —NR 9 C(O)R 11 , —S(O 2 )NR 9 R 10 , —NR 9 S(O 2 ) R 11 , —S(O)R 11 , —S(O 2 )R 11 , tetrazole and oxadiazole; wherein each C 1-6 alkyl is a straight or branched chain alkyl; and wherein each C 1-6 alkyl and C 3-7 cycloalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, —OH, —SH, —C 1-3 alkyl, —O—C 1-3 alkyl, —CF 3 , —CH 2 CF 3 , and —O—CF 3 ;
each R 7 is independently selected from the group consisting of hydrogen, hydroxyl and C 1-3 alkyl;
R 8 is selected from the group consisting of hydrogen, C 1-6 alkyl, and C 3-7 cycloalkyl; wherein each C 1-6 alkyl is a straight or branched chain alkyl; and wherein each C 1-6 alkyl and C 3-7 cycloalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, —OH, —SH, —C 1-3 alkyl, —O—C 1-3 alkyl, —CF 3 , —CH 2 CF 3 , and —O—CF 3 ;
R 9 and R 10 are independently selected from the group consisting of hydrogen, C 1-6 alkyl and C 3-7 cycloalkyl; wherein each C 1-6 alkyl is a straight or branched chain alkyl; and wherein each C 1-6 alkyl and C 3-7 cycloalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, —OH, —SH, —C 1-3 alkyl, —O—C 1-3 alkyl, —CF 3 , —CH 2 CF 3 , and —O—CF 3 ; or
R 9 and R 10 when attached to the same nitrogen atom are combined to form a 3- to 7-membered ring having from 0 to 2 additional heteroatoms as ring members;
R 11 is selected from the group consisting of C 1-6 alkyl and C 3-7 cycloalkyl; wherein each C 1-6 alkyl is a straight or branched chain alkyl; and wherein each C 1-6 alkyl and C 3-7 cycloalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, —OH, —SH, —C 1-3 alkyl, —O—C 1-3 alkyl, —CF 3 , —CH 2 CF 3 , and —O—CF 3 ; and
R 12 is selected from the group consisting of halogen, C 1-6 alkyl, —O—C 1-6 alkyl, —S—C 1-6 alkyl, C 3-7 cycloalkyl, —O—C 3-7 cycloalkyl, —C(O)OR 8 , —C(O)NR 9 R 10 , —NR 9 C(O)R 11 , —S(O 2 )NR 9 R 10 , —NR 9 S(O 2 )R 11 , —S(O)R 11 and —S(O 2 )R 11 ; wherein each C 1-6 alkyl is a straight or branched chain alkyl; and wherein each C 1-6 alkyl and C 3-7 cycloalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, —OH, —C 1-3 alkyl, —O—C 1-3 alkyl, —CF 3 , —CH 2 CF 3 , and —O—CF 3 .
5. A compound according to claim 1 , of Formula If:
or a pharmaceutically acceptable salt thereof;
X is O or —(CHR 7 ) m —
m is 1 or 2;
R 1 is selected from the group consisting of hydrogen, halogen, C 1-6 alkyl, C 3-7 cycloalkyl, —O—C 1-6 alkyl, —O—C 3-7 cycloalkyl, —C(O)OR 8 , —C(O)NR 9 R 10 and —NR 9 C(O)R 11 ; wherein each C 1-6 alkyl is a straight or branched chain alkyl; and wherein each C 1-6 alkyl and C 3-7 cycloalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, —OH, —SH, —C 1-3 alkyl, —O—C 1-3 alkyl, —CF 3 , —CH 2 CF 3 , and —O—CF 3 ;
R 2 is aryl or heteroaryl; wherein each R 2 is optionally substituted by one or more R 12 ;
R 3 and R 4 are each independently selected from the group consisting of hydrogen, halogen, hydroxyl, C 1-6 alkyl, C 3-7 cycloalkyl, —O—C 1-6 alkyl, —O—C 3-7 cycloalkyl, —CN, —NO 2 , —NR 9 R 10 , —C(O)OR 8 , —C(O)NR 9 R 10 , —NR 9 C(O)R 11 , —S(O 2 )NR 9 R 10 , —NR 9 S(O 2 )R 11 , —S(O)R 11 , —S(O 2 )R 11 , tetrazole and oxadiazole; wherein each C 1-6 alkyl is a straight or branched chain alkyl; and wherein each C 1-6 alkyl and C 3-7 cycloalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, —OH, —SH, —C 1-3 alkyl, —O—C 1-3 alkyl, —CF 3 , —CH 2 CF 3 , and —O—CF 3 ;
each R 7 is independently selected from the group consisting of hydrogen, hydroxyl and C 1-3 alkyl;
R 8 is selected from the group consisting of hydrogen, C 1-6 alkyl, and C 3-7 cycloalkyl; wherein each C 1-6 alkyl is a straight or branched chain alkyl; and wherein each C 1-6 alkyl and C 3-7 cycloalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, —OH, —SH, —C 1-3 alkyl, —O—C 1-3 alkyl, —CF 3 , —CH 2 CF 3 , and —O—CF 3 ;
R 9 and R 10 are independently selected from the group consisting of hydrogen, C 1-6 alkyl and C 3-7 cycloalkyl; wherein each C 1-6 alkyl is a straight or branched chain alkyl; and wherein each C 1-6 alkyl and C 3-7 cycloalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, —OH, —SH, —C 1-3 alkyl, —O—C 1-3 alkyl, —CF 3 , —CH 2 CF 3 , and —O—CF 3 ; or
R 9 and R 10 when attached to the same nitrogen atom are combined to form a 3- to 7-membered ring having from 0 to 2 additional heteroatoms as ring members;
R 11 is selected from the group consisting of C 1-6 alkyl and C 3-7 cycloalkyl; wherein each C 1-6 alkyl is a straight or branched chain alkyl; and wherein each C 1-6 alkyl and C 3-7 cycloalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, —OH, —SH, —C 1-3 alkyl, —O—C 1-3 alkyl, —CF 3 , —CH 2 CF 3 , and —O—CF 3 ; and
R 12 is selected from the group consisting of halogen, C 1-6 alkyl, —O—C 1-6 alkyl, —S—C 1-6 alkyl, C 3-7 cycloalkyl, —O—C 3-7 cycloalkyl, —C(O)OR 8 , —C(O)NR 9 R 10 , —NR 9 C(O)R 11 , —S(O 2 )NR 9 R 10 , —NR 9 S(O 2 )R 11 , —S(O)R 11 and —S(O 2 )R 9 R 11 ; wherein each C 1-6 alkyl is a straight or branched chain alkyl; and wherein each C 1-6 alkyl and C 3-7 cycloalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, —OH, —C 1-3 alkyl, —O—C 1-3 alkyl, —CF 3 , —CH 2 CF 3 , and —O—CF 3 .
6. A compound according to claim 1 , of Formula Ig:
or a pharmaceutically acceptable salt thereof;
X is O or —(CHR 7 ) m —
m is 1 or 2;
R 1 is selected from the group consisting of hydrogen, halogen, C 1-6 alkyl, C 3-7 cycloalkyl, —O—C 1-6 alkyl, —O—C 3-7 cycloalkyl, —C(O)OR 8 , —C(O)NR 9 R 10 and —NR 9 C(O)R 11 ; wherein each C 1-6 alkyl is a straight or branched chain alkyl; and wherein each C 1-6 alkyl and C 3-7 cycloalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, —OH, —SH, —C 1-3 alkyl, —O—C 1-3 alkyl, —CF 3 , —CH 2 CF 3 , and —O—CF 3 ;
R 2 is aryl or heteroaryl; wherein each R 2 is optionally substituted by one or more R 12 ;
R 3 and R 5 are each independently selected from the group consisting of hydrogen, halogen, hydroxyl, C 1-6 alkyl, C 3-7 cycloalkyl, —O—C 1-6 alkyl, —O—C 3-7 cycloalkyl, —CN, —NO 2 , —NR 9 R 10 , —C(O)OR 8 , —C(O)NR 9 R 10 , —NR 9 C(O)R 11 , —S(O 2 )NR 9 R 10 , —NR 9 S(O 2 )R 11 , —S(O)R 11 , —S(O 2 )R 11 , tetrazole and oxadiazole; wherein each C 1-6 alkyl is a straight or branched chain alkyl; and wherein each C 1-6 alkyl and C 3-7 cycloalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, —OH, —SH, —C 1-3 alkyl, —O—C 1-3 alkyl, —CF 3 , —CH 2 CF 3 , and —O—CF 3 ;
each R 7 is independently selected from the group consisting of hydrogen, hydroxyl and C 1-3 alkyl;
R 8 is selected from the group consisting of hydrogen, C 1-6 alkyl, and C 3-7 cycloalkyl; wherein each C 1-6 alkyl is a straight or branched chain alkyl; and wherein each C 1-6 alkyl and C 3-7 cycloalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, —OH, —SH, —C 1-3 alkyl, —O—C 1-3 alkyl, —CF 3 , —CH 2 CF 3 , and —O—CF 3 ;
R 9 and R 10 are independently selected from the group consisting of hydrogen, C 1-6 alkyl and C 3-7 cycloalkyl; wherein each C 1-6 alkyl is a straight or branched chain alkyl; and wherein each C 1-6 alkyl and C 3-7 cycloalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, —OH, —SH, —C 1-3 alkyl, —O—C 1-3 alkyl, —CF 3 , —CH 2 CF 3 , and —O—CF 3 ; or
R 9 and R 10 when attached to the same nitrogen atom are combined to form a 3- to 7-membered ring having from 0 to 2 additional heteroatoms as ring members;
R 11 is selected from the group consisting of C 1-6 alkyl and C 3-7 cycloalkyl; wherein each C 1-6 alkyl is a straight or branched chain alkyl; and wherein each C 1-6 alkyl and C 3-7 cycloalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, —OH, —SH, —C 1-3 alkyl, —O—C 1-3 alkyl, —CF 3 , —CH 2 CF 3 , and —O—CF 3 ; and
R 12 is selected from the group consisting of halogen, C 1-6 alkyl, —O—C 1-6 alkyl, —S—C 1-6 alkyl, C 3-7 cycloalkyl, —O—C 3-7 cycloalkyl, —C(O)OR 8 , —C(O)NR 9 R 10 , —NR 9 C(O)R 11 , —S(O 2 )NR 9 R 10 , —NR 9 S(O 2 )R 11 , —S(O)R 11 and —S(O 2 )R 11 ; wherein each C 1-6 alkyl is a straight or branched chain alkyl; and wherein each C 1-6 alkyl and C 3-7 cycloalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, —OH, —C 1-3 alkyl, —O—C 1-3 alkyl, —CF 3 , —CH 2 CF 3 , and —O—CF 3 .
7. A compound according to claim 1 , wherein m is 1 and R 7 is hydrogen.
8. A compound according to claim 1 , wherein R 1 is selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, 1-hydroxyethyl, 2-hydroxyisopropyl, chloro and —C(O)N(CH 3 ) 2 .
9. A compound according to claim 1 , selected from the group consisting of:
1
(Z)-1-(4-amino-2-fluorobut-2-en-1-yl)- 3-(4-(N,N-dimethylsulfamoyl)benzyl)- 2-methyl-1H-indole-5-carboxylic acid
2
(Z)-methyl 1-(4-amino-2-fluorobut-2- en-1-yl)-3-(4-(N,N- dimethylsulfamoyl)benzyl)-2- methylindole-5-carboxylate
3
(Z)-methyl 1-(4-amino-2-fluorobut-2- en-1-yl)-3-(4-(N,N- dimethylsulfamoyl)benzyl)-2-methyl- 1H-indole-5-carboxylate
4
(Z)-1-(4-amino-2-fluorobut-2-en-1-yl)- 3-(4-(N,N-dimethylsulfamoyl)benzyl)- 2-methyl-1H-indole-5-carboxamide
5
(Z)-1-(4-amino-2-fluorobut-2-en-1-yl)- 3-(4-(N,N-dimethylsulfamoyl)benzyl)- N,N-dimethyl-1H-indole-2- carboxamide
6
(Z)-1-(4-amino-2-fluorobut-2-en-1-yl)- 3-(4-(N,N-dimethylsulfamoyl)benzyl)- N,N,2-trimethyl-1H-indole-5- sulfonamide
7
(Z)-1-(4-amino-2-fluorobut-2-en-1-yl)- 3-(3-(N,N-dimethylsulfamoyl)benzyl)- N,N,2-trimethyl-1H-indole-5- sulfonamide
8
(Z)-4-((1-(4-amino-2-fluorobut-2-en-1- yl)-2-methyl-1H-pyrrolo[3,2- b]pyridin-3-yl)methyl)-N,N- dimethylbenzenesulfonamide
9
(Z)-4-((1-(4-amino-2-fluorobut-2-en-1- yl)-2,5-dimethyl-1H-pyrrolo[3,2- b]pyridin-3-yl)methyl)-N,N- dimethylbenzenesulfonamide
10
(Z)-3-fluoro-4-(2-methyl-3-(4- (methylsulfonyl)benzyl)-1H- pyrrolo[3,2-b]pyridin-1-yl)but-2-en-1- amine
11
(Z)-4-((1-(4-amino-2-fluorobut-2-en-1- yl)-2,6-dimethyl-1H-pyrrolo[3,2- b]pyridin-3-yl)methyl)-N,N- dimethylbenzenesulfonamide
12
(Z)-4-(2,5-dimethyl-3-(4- (methylsulfonyl)benzyl)-1H- pyrrolo[3,2-b]pyridin-1-yl)-3- fluorobut-2-en-1-amine
13
(Z)-4-(2,5-dimethyl-3-((6- (methylsulfonyl)pyridin-3-yl)methyl)- 1H-pyrrolo[3,2-b]pyridin-1-yl)-3- fluorobut-2-en-1-amine
14
(Z)-4-(2,5-dimethyl-3-((5- (methylsulfonyl)pyridin-2-yl)methyl)- 1H-pyrrolo[3,2-b]pyridin-1-yl)-3- fluorobut-2-en-1-amine
15
(Z)-6-((1-(4-amino-2-fluorobut-2-en-1- yl)-2,5-dimethyl-1H-pyrrolo[3,2- b]pyridin-3-yl)methyl)-N,N- dimethylpyridine-3-sulfonamide
16
(Z)-5-((1-(4-amino-2-fluorobut-2-en-1- yl)-2,5-dimethyl-1H-pyrrolo[3,2- b]pyridin-3-yl)methyl)-N,N- dimethylpyridine-2-sulfonamide
17
(Z)-4-(2,5-dimethyl-3-(3- (methylsulfonyl)benzyl)-1H- pyrrolo[3,2-b]pyridin-1-yl)-3- fluorobut-2-en-1-amine
18
(Z)-3-((1-(4-amino-2-fluorobut-2-en-1- yl)-2-methyl-1H-pyrrolo[3,2- b]pyridin-3-yl)methyl)-N,N- dimethylbenzenesulfonamide
19
(Z)-4-((1-(4-amino-2-fluorobut-2-en-1- yl)-5-hydroxy-2,6-dimethyl-1H- pyrrolo[3,2-b]pyridin-3-yl)methyl)- N,N-dimethylbenzenesulfonamide
20
(Z)-4-(3-(2-chloro-4- (methylsulfonyl)benzyl)-2-methyl-1H- pyrrolo[3,2-b]pyridin-1-yl)-3- fluorobut-2-en-1-amine
21
(Z)-4-((1-(4-amino-2-fluorobut-2-en-1- yl)-2-methyl-1H-indol-3-yl)oxy)-N,N- dimethylbenzenesulfonamide
22
(Z)-3-fluoro-4-(2-isopropyl-3-((6- (methylsulfonyl)pyridin-3-yl)methyl)- 1H-pyrrolo[3,2-b]pyridin-1-yl)but-2- en-1-amine
23
(Z)-4-((1-(4-amino-2-fluorobut-2-en-1- yl)-5-fluoro-2-methyl-1H-pyrrolo[3,2- b]pyridin-3-yl)methyl)-N,N- dimethylbenzenesulfonamide
24
(Z)-4-((1-(4-amino-2-fluorobut-2-en-1- yl)-6-fluoro-2-methyl-1H-pyrrolo[3,2- b]pyridin-3-yl)methyl)-N,N- dimethylbenzenesulfonamide
26
(Z)-4-((1-(4-amino-2-fluorobut-2-en-1- yl)-2-methyl-1H-indol-3-yl)methyl)- N,N-dimethylbenzenesulfonamide
27
(Z)-4-(5-cyclopropyl-2-methyl-3-((6- (methylsulfonyl)pyridin-3-yl)methyl)- 1H-pyrrolo[3,2-b]pyridin-1-yl)-3- fluorobut-2-en-1-amine
28
(Z)-4-((1-(4-amino-2-fluorobut-2-en-1- yl)-5-(2-hydroxypropan-2-yl)-2- methyl-1H-pyrrolo[3,2-b]pyridin-3- yl)methyl)-N,N- dimethylbenzenesulfonamide
29
(Z)-4-((1-(4-amino-2-fluorobut-2-en-1- yl)-2-(1-hydroxyethyl)-1H- pyrrolo[3,2-b]pyridin-3-yl)methyl)- N,N-dimethylbenzenesulfonamide
30
(Z)-4-(5-(1,1-difluoroethyl)-2-methyl- 3-((6-(methylsulfonyl)pyridin-3- yl)methyl)-1H-pyrrolo[3,2-b]pyridin- 1-yl)-3-fluorobut-2-en-1-amine
31
(Z)-3-fluoro-4-(2-methyl-3-((6- (methylsulfonyl)pyridin-3-yl)methyl)- 5-(trifluoromethyl)-1H-pyrrolo[3,2- b]pyridin-1-yl)but-2-en-1-amine
32
(Z)-4-((1-(4-amino-2-fluorobut-2-en-1- yl)-2-methyl-1H-pyrrolo[3,2- c]pyridin-3-yl)methyl)-N,N- dimethylbenzenesulfonamide
33
(Z)-3-fluoro-4-(2-isopropyl-3-(4- (methylsulfonyl)benzyl)-1H- pyrrolo[3,2-b]pyridin-1-yl)but-2-en-1- amine
34
(Z)-3-fluoro-4-(2-methyl-3-(2-methyl- 4-(methylsulfonyl)benzyl)-1H- pyrrolo[3,2-b]pyridin-1-yl)but-2-en-1- amine
35
(Z)-4-(3-(3-chloro-4- (methylsulfonyl)benzyl)-2-methyl-1H- pyrrolo[3,2-b]pyridin-1-yl)-3- fluorobut-2-en-1-amine
36
(Z)-4-(2,6-dimethyl-3-(4- (methylsulfonyl)benzyl)-1H- pyrrolo[3,2-c]pyridin-1-yl)-3- fluorobut-2-en-1-amine
37
(Z)-4-((5-(4-amino-2-fluorobut-2-en-1- yl)-3,6-dimethyl-5H-pyrrolo[3,2- c]pyridazin-7-yl)methyl)-N,N- dimethylbenzenesulfonamide
38
(Z)-4-(2,6-dimethyl-7-(4- (methylsulfonyl)benzyl)-5H- pyrrolo[3,2-d]pyrimidin-5-yl)-3- fluorobut-2-en-1-amine
39
(Z)-4-((5-(4-amino-2-fluorobut-2-en-1- yl)-2,6-dimethyl-5H-pyrrolo[3,2- d]pyrimidin-7-yl)methyl)-N,N- dimethylbenzenesulfon-amide
40
(Z)-4-(2,5-dimethyl-3-(4- (methylsulfonyl)phenethyl)-1H- pyrrolo[3,2-b]pyridin-1-yl)-3- fluorobut-2-en-1-amine
41
(Z)-3-fluoro-4-(2-isopropyl-3-((6- (isopropylsulfonyl)pyridin-3- yl)methyl)-1H-pyrrolo[3,2-b]pyridin- 1-yl)but-2-en-1-amine
42
(Z)-(1-(4-amino-2-fluorobut-2-en-1- yl)-2-isopropyl-1H-pyrrolo[3,2- b]pyridin-3-yl)(6- (methylsulfonyl)pyridin-3-yl)methanol
43
(Z)-4-(3-((6-(ethylsulfonyl)pyridin-3- yl)methyl)-2-isopropyl-1H- pyrrolo[3,2-b]pyridin-1-yl)-3- fluorobut-2-en-1-amine
44
(Z)-4-(3-((6- (cyclopropylsulfonyl)pyridin-3- yl)methyl)-2-isopropyl-1H- pyrrolo[3,2-b]pyridin-1-yl)-3- fluorobut-2-en-1-amine
or a pharmaceutically acceptable salt thereof.
10. A pharmaceutical composition comprising a compound according to claim 1 , or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient, carrier or diluent.
11. A method of inhibiting the amine oxidase activity of LOX, LOXL1, LOXL2, LOXL3 and LOXL4 in a subject in need thereof, comprising administering to the subject an effective amount of a compound according to claim 1 , or a pharmaceutically acceptable salt thereof.
12. A compound according to claim 1 of Formula I:
or a stereoisomer or pharmaceutically acceptable salt thereof;
wherein:
a is N or CR 3 ;
b is N or CR 4 ;
c is N or CR 5 ;
d is N or CR 6 ;
and from 0 to 2 of a, b, c and d are N;
X is O or —(CHR 7 ) m —;
m is 1 or 2;
R 1 is selected from the group consisting of C 1-6 alkyl and —C(O)NR 9 R 10 ; wherein each C 1-6 alkyl is a straight or branched chain alkyl; and wherein each C 1-6 alkyl is optionally substituted by one —OH;
R 2 is selected from the group consisting of phenyl and pyridinyl; wherein each R is optionally substituted by one or more R 12 ;
R 3 is hydrogen:
R 4 is selected from the group consisting of hydrogen, halogen and C 1-6 alkyl;
R 5 is selected from the group consisting of hydrogen, halogen, hydroxyl, C 1-6 alkyl, C-cycloalkyl, —C(O)OR 8 , —C(O)NR 9 R 10 and —S(O 2 )NR 9 R 10 ; wherein each C 1-6 alkyl is a straight or branched chain alkyl; and wherein each C 1-6 alkyl is optionally substituted by one or more substituents selected from the group consisting of halogen and —OH;
R 6 is hydrogen;
each R 7 is independently selected from the group consisting of hydrogen and hydroxyl;
R 8 is selected from the group consisting of hydrogen and C 1-6 alkyl;
R 9 and R 10 are independently selected from the group consisting of hydrogen and C 1-6 alkyl;
R 11 is selected from the group consisting of C 1-6 alkyl and C 3-7 cycloalkyl; wherein each C 1-6 alkyl is a straight or branched chain alkyl; and
R 12 is selected from the group consisting of —S(O 2 )NR 9 R 10 and —S(O 2 )R 11 .
13. A compound according to claim 1 , wherein
X is selected from the group consisting of 0 and —CH 2 —;
R 1 is selected from the group consisting of methyl, isopropyl, 1-hydroxyethyl, and —C(O)N(CH 3 ) 2 ;
R 2 is selected from the group consisting of phenyl,
2-pyridinyl,
and 3-pyridinyl
wherein each R 2 is substituted by one or more R 12 ;
R 4 is selected from the group consisting of hydrogen, methyl and fluorine;
R 5 is selected from the group consisting of hydrogen, fluorine, hydroxyl, methyl, —CF 3 , —CHF 2 CH 3 , —C(CH 3 ) 2 OH, cyclopropyl, —C(O)OH, —C(O)OCH 3 , —C(O)N(CH 3 ) 2 , —C(O)NH 2 and —S(O 2 )N(CH 3 ) 2 ; and
R 12 is selected from the group consisting of —S(O 2 )N(CH 3 ) 2 , —S(O 2 )CH 3 , —S(O 2 )Et, —S(O 2 ) i Pr, and —S(O 2 )cyclopropyl.
14. A compound according to claim 1 , of Formula Ib:
or a pharmaceutically acceptable salt thereof; wherein:
X is —(CHR 7 ) m —;
m is 1 or 2;
R 1 is selected from the group consisting of hydrogen and C 1-6 alkyl; wherein each C 1-6 alkyl is a straight or branched chain alkyl; and wherein each C 1-6 alkyl is optionally substituted by one —OH;
R 2 is selected from the group consisting of phenyl and pyridinyl; wherein each R 2 is optionally substituted by one or more R 12 ;
R 3 is hydrogen;
R 4 is selected from the group consisting of hydrogen, halogen and C 1-6 alkyl;
R 5 is selected from the group consisting of hydrogen, halogen, hydroxyl, C 1-6 alkyl and C 3-7 cycloalkyl; wherein each C 1-6 alkyl is a straight or branched chain alkyl; and wherein each C 1-6 alkyl is optionally substituted by one or more substituents selected from the group consisting of halogen and, —OH;
each R 7 is independently selected from the group consisting of hydrogen and hydroxyl;
R 9 and R 10 are independently selected from C 1-6 alkyl;
R 11 is selected from the group consisting of C 1-6 alkyl and C 3-7 cycloalkyl; wherein each C 1-6 alkyl is a straight or branched chain alkyl; and
R 12 is selected from the group consisting of —S(O 2 )NR 9 R 10 and —S(O 2 )R 11 .
15. A compound according to claim 14 , of Formula Ib wherein:
X is —CH 2 —;
R 1 is selected from the group consisting of methyl, isopropyl and 1-hydroxyethyl;
R 2 is selected from the group consisting of phenyl
2-pyridinyl
and 3-pyridinyl
wherein each R 2 is substituted by one or more R 12 ;
R 3 is hydrogen;
R 4 is selected from the group consisting of hydrogen, methyl and fluorine;
R 5 is selected from the group consisting of hydrogen, fluorine, hydroxyl, methyl, —CF 3 , —C(CH 3 ) 2 OH and cyclopropyl; and
R 12 is selected from the group consisting of —S(O 2 )N(CH 3 ) 2 , —S(O 2 )CH 3 , —S(O 2 )Et, —S(O 2 ) i Pr, and —S(O 2 )cyclopropyl.
16. The compound of claim 1 having the structure:
or a pharmaceutically acceptable salt thereof.
17. The compound of claim 1 having the structure:
or a pharmaceutically acceptable salt thereof.
18. The compound of claim 1 having the structure:
or a pharmaceutically acceptable salt thereof.
19. The compound of claim 1 having the structure:
or a pharmaceutically acceptable salt thereof.