Benzodiazepine CGRP receptor antagonists
View Patent ↗The present invention is directed to compounds of Formula I: (where variables R 1 , R 2 , R 3 , R 6 , R 7 , G, J, W, X and Y are as defined herein) useful as antagonists of CGRP receptors and useful in the treatment or prevention of diseases in which the CGRP is involved, such as headache, migraine and cluster headache. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which CGRP is involved.
1. A compounds of formula I:
wherein:
R 1 is selected from:
1) H, C 1 –C 6 alkyl, C 2 –C 6 alkenyl, C 2 –C 6 alkynyl, C 3-6 cycloalkyl, and heterocycle, unsubstituted or substituted with one or more substituents independently selected from:
a) C 1-6 alkyl,
b) C 3-6 cycloalkyl,
c) aryl, unsubstituted or substituted with 1–5 substituents where the substituents are independently selected from R 4 ,
d) heteroaryl, unsubstituted or substituted with 1–5 substituents where the substituents are independently selected from R 4 ,
e) heterocycle, unsubstituted or substituted with 1–5 substituents where the substituents are independently selected from R 4 ,
f) (F) p C 1-3 alkyl,
g) halogen,
h) OR 4 ,
i) O(CH 2 ) S OR 4 ,
j) CO 2 R 4 ,
k) (CO)NR 10 R 11 ,
l) O(CO)NR 10 R 11 ,
m) N(R 4 )(CO)NR 10 R 11 ,
n) N(R 10 )(CO)R 11 ,
o) N(R 10 )(CO)OR 11 ,
p) SO 2 NR 10 R 11 ,
q) N(R 10 ) SO 2 R 11 ,
r) S(O) m R 10 ,
s) CN,
t) NR 10 R 11 ,
u) N(R 10 )(CO)NR 4 R 11 , and
v) O(CO)R 4 ; and
2) aryl or heteroaryl, unsubstituted or substituted with one or more substituents independently selected from:
a) C 1-6 allyl,
b) C 3-6 cycloalkyl,
c) aryl, unsubstituted or substituted with 1–5 substituents where the substituents are independently selected from R 4 ,
d) heteroaryl, unsubstituted or substituted with 1–5 substituents where the substituents are independently selected from R 4 ,
e) heterocycle, unsubstituted or substituted with 1–5 substituents where the substituents are independently selected from R 4 ,
f) (F) p C 1-3 alkyl,
g) halogen,
h) OR 4 ,
i) O(CH2) S OR 4 ,
j) CO 2 R 4 ,
k) (CO)NR 10 R 11 ,
l) O(CO)NR 10 OR 11 ,
m) N(R 4 )(CO)NR 10 R 11 ,
n) N(R 10 )(CO)R 11 ,
o) N(R 10 )(CO)OR 11 ,
p) SO 2 NR 10 R 11 ,
q) N(R 10 )SO 2 R 11 ,
r) S(O) m R 10 ,
s) CN,
t) NR 10 R 11 ,
u) N(R 10 )(CO)NR 4 R 11 ; and
v) O(CO)R 4 ; and
R 2 is independently selected from H and:
1) C 1-6 alkyl,
2) C 3-6 cycloalkyl,
3) aryl, unsubstituted or substituted with 1–5 substituents where the substituents are independently selected from R 4 ,
4) heteroaryl, unsubstituted or substituted with 1–5 substituents where the substituents are independently selected from R 4 ,
5) heterocycle, unsubstituted or substituted with 1–5 substituents where the substituents are independently selected from R 4 ,
6) (F) p C 1-3 alkyl,
7) halogen,
8) OR 4 ,
9) O(CH 2 ) S OR 4 ,
10) CO 2 R 4 ,
11) (CO)NR 10 R 11 ,
12) O(CO)NR 10 R 11 ,
13) N(R 4 )(CO)NR 10 R 11 ,
14) N(R 10 )(CO)R 11 ,
15) N(R 10 )(CO)OR 11 ,
16) SO 2 NR 10 R 11 ,
17) N(R 10 ) SO 2 R 11 ,
18) S(O) m R 10 ,
19) CN,
20) NR 10 R 11 ,
21) N(R 10 )(CO)NR 4 R 11 , and
22) O(CO)R 4 ;
R 7 is selected from:
1) H, C 0 –C 6 alkyl, C 2 –C 6 alkenyl, C 2 –C 6 alkynyl, C 3-6 cycloalkyl and heterocycle, unsubstituted or substituted with one or more substituents independently selected from:
a) C 1-6 alkyl,
b) C 3-6 cycloalkyl,
c) aryl, unsubstituted or substituted with 1–5 substituents where the substituents are independently selected from R 4 ,
d) heteroaryl, unsubstituted or substituted with 1–5 substituents where the substituents are independently selected from R 4 ,
e) heterocycle, unsubstituted or substituted with 1–5 substituents where the substituents are independently selected from R 4 ,
f) (F) p C 1-3 alkyl,
g) halogen,
h) OR 4 ,
i) O(CH 2 ) S OR 4 ,
j) CO 2 R 4 ,
k) (CO)NR 10 R 11 ,
l) O(CO)NR 10 R 11 ,
m) N(R 4 )(Co)NR 10 R 11 ,
n) N(R 10 )(CO)R 11 ,
o) N(R 10 )(CO)OR 11 ,
p) SO 2 NR 10 R 11 ,
q) N(R 10 ) SO 2 R 11 ,
r) S(O) m R 10 ,
s) CN,
t) NR 10 R 11 ,
u) N(R 10 )(CO)NR 4 R 11 ,
v) O(CO)R 4 ; and
2) aryl or heteroaryl, unsubstituted or substituted with one or more substituents independently selected from:
a) C 1-6 alkyl,
b) C 3-6 cycloalkyl,
c) aryl, unsubstituted or substituted with 1–5 substituents where the substituents are independently selected from R 4 ,
d) heteroaryl, unsubstituted or substituted with 1–5 substituents where the substituents are independently selected from R 4 ,
e) heterocycle, unsubstituted or substituted with 1–5 substituents where the substituents are independently selected from R 4 ,
f) (F) p C 1-3 alkyl,
g) halogen,
h) OR 4 ,
i) O(CH 2 ) S OR 4 ,
j) CO 2 R 4 ,
k) (CO)NR 10 R 11 ,
l) O(CO)NR 10 R 11 ,
m) N(R 4 )(CO)NR 10 R 11 ,
n) N(R 10 )(CO)R 11 ,
o) N(R 10 )(CO)OR 11 ,
p) SO 2 NR 10 R 11 ,
q) N(R 10 ) SO 2 R 11 ,
r) S(O) m R 10 ,
s) CN,
t) NR 10 R 11 ,
u) N(R 10 )(CO)NR 4 R 11 , and
v) O(CO)R 4 ;
R 4 is selected from: H, C 1-6 alkyl, (F) p C 1-6 alkyl, C 3-6 cycloalkyl, aryl, heteroaryl and benzyl, unsubstituted or substituted with halogen, hydroxy or C 1 –C 6 alkoxy;
R 5 is independently selected from H, substituted or unsubstituted C 1 –C 6 alkyl, C 3-6 cycloalkyl, aryl, heteroaryl, OR 4 , N(R 4 ) 2 , CO 2 R 4 and (F) p C 1-6 alkyl;
W is O, NR 4 or C(R 4 ) 2 ;
X is C or S;
Y is O, (R 4 ) 2 , NCN, NSO 2 CH 3 or NCONH 2 , or Y is O 2 when X is S;
R 3 is independently selected from H, substituted or unsubstituted C 1 –C 3 alkyl, CN and CO 2 R 4 ;
R 6 is independently selected from H and:
a) C 1-6 alkyl,
b) C 3-6 cycloalkyl,
c) aryl, unsubstituted or substituted with 1–5 substituents where the substituents are independently selected from R 4 ,
d) heteroaryl, unsubstituted or substituted with 1–5 substituents where the substituents are independently selected from R 4 ,
e) heterocycle, unsubstituted or substituted with 1–5 substituents where the substituents are independently selected from R 4 ,
f) (F) p C 1-3 alkyl,
g) halogen,
h) OR 4 ,
i) O(CH 2 ) S OR 4 ,
j) CO 2 R 4 ,
k) (CO)NR 10 R 11 ,
l) O(CO)NR 10 R 11 ,
m) N(R 4 )(CO)NR 10 R 11 ,
n) N(R 10 )(CO)R 11 ,
o) N(R 10 )(CO)OR 11 ,
p)SO 2 NR 10 R 11 ,
q) N(R 10 ) SO 2 R 11 ,
r) S(O) m R 10 ,
s) CN,
t) NR 10 R 11 ,
u) N(R 10 )(CO)NR 4 R 11 , and
v) O(CO)R 4 ;
R 10 and R 11 are independently selected from: H, C 1-6 alkyl, (F) p C 1-6 alkyl, C 3-6 cycloalkyl, aryl, heteroaryl and benzyl, unsubstituted or substituted with halogen, hydroxy or C 1 –C 6 alkoxy, where R 10 and R 11 may be joined together to form a ring selected from: azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl, which is unsubstituted or substituted with 1–5 substituents where the substituents are independently selected from R 4 ;
G–J is selected from: N,N—C(R 5 ) 2 , C═C(R 5 ), C═N; C(R 5 ), C(R 5 )—C(R 5 ) 2 , C(R 5 )—C(R 5 ) 2 —C(R 5 ) 2 , C═C(R 5 )—C(R 5 ) 2 , C(R 5 )—C(R 5 )═C(R 5 ), C(R 5 )—C(R 5 ) 2 —N(R 5 ), C═C(R 5 )—N(R 5 ), C(R 5 )—C(R 5 )═N, C(R 5 )—N(R 5 )—C(R 5 ) 2 , C═N—C(R 5 ) 2 , C(R 5 )—N═C(R 5 ), C(R 5 )—N(R 5 )—N(R 5 ), C═N—N(R 5 ), N—C(R 5 ) 2 —C(R 5 ) 2 , N—C(R 5 )═C(R 5 ), N—C(R 5 ) 2 —N(R 5 ), N—C(R 5 )═N,N—N(R 5 )—C(R 5 ) 2 and N—N═C(R 5 );
p is 0 to 2q+1, for a substituent with q carbons;
m is 0, 1 or 2;
n is 0 or 1;
s is 1, 2 or 3;
or a pharmaceutically acceptable salt or an individual diastereomer thereof.
2. The compound of claim 1 of the formula Ia:
or a pharmaceutically acceptable salt or an individual diastereomer thereof.
3. The compound of claim 1 of the formula Ia:
wherein R 7 is phenyl, unsubstituted or substituted with one or substituents independently selected from:
a) C 1-6 alkyl,
b) OH,
c) OR 5 ,
d) halogen,
e) CO 2 R 4 ,
f) S(O) m R 5 ,
g) N(R 4 ) 2 , and
j) CN,
or a pharmaceutically acceptable salt or an individual diastereomer thereof.
4. The compound of claim 1 of the formula Ia:
wherein R 7 is heteroaryl, unsubstituted or substituted with one or substituents independently selected from:
a) C 1-6 alkyl,
b) OH,
c) OR 5 ,
d) halogen,
e) CO 2 R 4 ,
f) S(O) m R 5 ,
g) N(R 4 ) 2 , and
j) CN,
or a pharmaceutically acceptable salt or an individual diastereomer thereof.
5. The compound of claim 1 of the formula Ia:
wherein R 7 is selected from H and C 1 –C 6 alkyl, C 1 –C 6 alkenyl, C 1 –C 6 alkynyl, C 3 –C 6 cycloalkyl, unsubstituted or substituted with one or substituents independently selected from:
a) C 1-6 alkyl,
b) C 1-6 alkoxy,
c) fluorine,
d) HO,
e) OR 5 ,
f) CO 2 R 4 ,
g) CON(R 4 ) 2 ,
h) S(O) m R 5 , and
i) N(R 4 ) 2 ; and
or a pharmaceutically acceptable salt or an individual diastereomer thereof.
6. The compound of claim 1 of the formula Ia:
wherein R 7 is heterocycle, unsubstituted or substituted with one or substituents independently selected from:
a) C 1-6 alkyl,
b) C 1-6 alkoxy,
c) fluorine,
d) HO,
e) OR 5 ,
f) CO 2 R 4 ,
g) CON(R 4 ) 2 ,
h) S(O) m R 5 , and
i) N(R 4 ) 2 ; and
or a pharmaceutically acceptable salt or an individual diastereomer thereof.
7. The compound of claim 1 of the formula Ib:
or a pharmaceutically acceptable salt or an individual diastereomer thereof.
8. The compound of claim 1 of the formula Ic:
or a pharmaceutically acceptable salt or an individual diastereomer thereof.
9. The compound of claim 1 of the formula Id:
or a pharmaceutically acceptable salt or an individual diastereomer thereof.
10. The compound of claim 1 of the formula:
wherein R 1 , R 2 , R 7a and R 5 , and the configuration of C-3, are selected from a single row in the the following table:
C-3
R 1
R 2
R 7a
R 5
R
CH 3
H
H
H
S
CH 3
H
H
H
R
CF 3 CH 2
H
H
H
R
CF 3 CH 2
6-Cl
H
H
R
CF 3 CH 2
7-Cl
H
H
R
CF 3 CH 2
8-Cl
H
H
R
CF 3 CH 2
9-Cl
H
H
R,S
n-C 3 H 7
H
H
H
R,S
i-C 3 H 7
H
H
H
R,S
n-C 4 H 7
H
H
H
R
i-C 4 H 7
H
H
H
S
i-C 4 H 7
H
H
H
R,S
n-CF 3 (CH 2 ) 3
H
H
H
R,S
H
H
H
R,S
H
H
H
R,S
H
H
H
R,S
H
H
H
R,S
H
H
H
R,S
i-C 3 H 7
H
2′-F
H
R,S
i-C 3 H 7
H
2′-F
OH
R,S
i-C 4 H 9
H
2′-F
H
R,S
i-C 4 H 9
H
2′-F
OH
R,S
CF 3 CH 2
H
2′-F
H
R,S
CF 3 CH 2
H
4′-F
H
R,S
CF 3 CH 2
H
4′-F
OH
or a pharmaceutically acceptable salt or an individual diastereomer thereof.
11. The compound of claim 1 of the formula:
wherein R 1 , R 2 , R 7 and R 5 , and the configuration of C-3, are selected from a single row in the following table:
C-3
R 1
R 2
R 7
R 5
R
CH 3
H
Cyclohexyl
H
R
CF 3 CH 2
H
i-C 3 H 7
H
R, S
CH 3
7-CH 3
i-C 3 H 7
H
R, S
CH 3
8-CH 3
i-C 3 H 7
H
S
CF 3 CH 2
H
t-C 4 H 9
H
or a pharmaceutically acceptable salt or an individual diastereomer thereof.
12. The compound of claim 1 of the formula:
wherein R 1 , R 2 and Z, and the configuration of C-3, are selected from a single row in the following table:
C-3
R 1
R 2
Z
R,S
CH 3
H
R,S
CH 3
7-Cl
R,S
CF 3 CH 2
H
R,S
CF 3 CH 2
H
or a pharmaceutically acceptable salt or an individual diastereomer thereof.
13. The compound of claim 1 of the formula:
wherein R 1 , R 3 and R 6 , and the configuration of C-3, are selected from a single row in the following table:
C-3
R 1
R 3
R 6
R
CF 3 CH 2
H
H
R
CF 3 CH 2
H
5″-CH 3
R
CF 3 CH 2
H
6″-F
R
CF 3 CH 2
CH 3
H
R
CF 3 CH 2
H
7″-Cl
R
CF 3 CH 2
H
6″-CH 3
R
CF 3 CH 2
H
6″-CF 3
R
CF 3 CH 2
H
6″-F
R
CF 3 CH 2
H
6″-CO 2 H
R
CF 3 CH 2
H
6″-
CONH 2
R
CF 3 CH 2
H
6″-
SO 2 CH 3
R
CF 3 CH 2
H
5″-CH 3
R
CF 3 CH 2
H
5″-Cl
R
CF 3 CH 2
H
4″-CH 3
R
CF 3 CH 2
H
5″-F
or a pharmaceutically acceptable salt or an individual diastereomer thereof.
14. A compound selected from:
or a pharmaceutically acceptable salt or an individual diastereomer thereof.
15. A pharmaceutical composition which comprises an inert carrier and the compound of claim 1 .
16. A method for treating, headache, migraine or cluster headache in a mammalian patient in need of such which comprises administering to the patient a therapeutically effective amount of the compound of claim 1 .