CGRP receptor antagonists
View Patent ↗The present invention is directed to compounds of Formula I: Formula I: I and Formula II: (where variables R 1 , R 2 , R 3 , R 4 , A, B, J, Q, T, V, 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 compound of the Formula I:
wherein:
A is C(R 2 ) 2 ;
B is (C(R 2 ) 2 ) n wherein n is 1;
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 each independently selected from:
a) C 1-6 alkyl,
b) C 3-6 cycloalkyl,
c) aryl, unsubstituted or substituted with 1-5 substituents each ndependently selected from R 4 ,
d) heteroaryl, unsubstituted or substituted with 1-5 substituents each independently selected from R 4 ,
e) heterocycle, unsubstituted or substituted with 1-5 substituents each 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 ;
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 each independently selected from R 4 ,
d) heteroaryl, unsubstituted or substituted with 1-5 substituents each independently selected from R 4 ,
e) heterocycle, unsubstituted or substituted with 1-5 substituents each 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 2 is independently 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 each independently selected from R 4 ,
d) heteroaryl, unsubstituted or substituted with 1-5 substituents each independently selected from R 4 ,
e) heterocycle, unsubstituted or substituted with 1-5 substituents each 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 ;
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 each independently selected from R 4 ,
d) heteroaryl, unsubstituted or substituted with 1-5 substituents each independently selected from R 4 ,
e) heterocycle, unsubstituted or substituted with 1-5 substituents each 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 each 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, or R 10 and R 11 join to form a ring selected from: azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl, which ring is unsubstituted or substituted with 1-5 substituents each independently selected from 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;
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 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 each independently selected from R 4 ,
d) heteroaryl, unsubstituted or substituted with 1-5 substituents each independently selected from R 4 ,
e) heterocycle, unsubstituted or substituted with 1-5 substituents each 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 ;
J is a bond, C(R 6 ) 2 , O, or NR 6 ;
V is a bond, C(R 6 ) 2 , O, S(O) m , NR 6 , C(R 6 ) 2 —C(R 6 ) 2 , C(R 6 )═C(R 6 ), C(R 6 ) 2 —N(R 6 ), C(R 6 )═N, N(R 6 )—C(R 6 ) 2 , N═C(R 6 ) or N(R 6 )—N(R 6 );
Q is selected from: ═C(R 7a )—, —C(R 7a ) 2 —, —C(O)—, —S(O) m —, ═N— and —N(R 7a )—;
T is selected from: ═C(R 7b )—, —C(R 7b ) 2 —, —C(O)—, —S(O) m —, ═N— and —N(R 7b )—;
R 3 is independently selected from H, substituted or unsubstituted C 1 -C 3 alkyl, F, CN and CO 2 R 4 ;
R 7a and R 7b are each independently selected from R 2 , where R 7a and R 7b and the atom(s) to which they are attached optionally form a ring selected from C 3-6 cycloalkyl, aryl, heterocycle, and heteroaryl, which ring is unsubstituted or substituted with 1-10 substituents where the substituents are each independently selected from R 6 ;
p is 0 to 2q+1, for a substituent with q carbons;
m is 0, 1 or 2;
s is 1, 2 or 3;
“heteroaryl” represents a stable 5- to 7-membered monocyclic- or stable 9- to 10-membered fused bicyclic heterocyclic ring system which contains an aromatic ring, any ring of which may be saturated, partially saturated, or unsaturated, and which consists of carbon atoms and from one to four heteroatoms selected from the group consisting of N, O and S, and wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring;
“heterocycle” or “heterocyclic” represents a stable 5- to 7-membered monocyclic- or stable 8- to 11-membered bicyclic heterocyclic ring system which is either saturated or unsaturated, and which consists of carbon atoms and from one to four heteroatoms selected from the group consisting of N, O and S, and wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring;
or a pharmaceutically acceptable salt or individual diastereomers thereof.
2. The compound of claim 1 having the Formula Ia:
wherein:
Y is O or NCN;
or a pharmaceutically acceptable salt or individual stereoisomers thereof.
3. The compound of claim 1 having the Formula Ib:
or a pharmaceutically acceptable salt or individual stereoisomers thereof.
4. The compound of claim 1 , wherein:
R 1 is selected from:
1) H, C 1 -C 6 alkyl, 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 each independently selected from R 4 ,
d) heteroaryl, unsubstituted or substituted with 1-5 substituents each independently selected from R 4 ,
e) heterocycle, unsubstituted or substituted with 1-5 substituents each 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) CN,
l) NR 10 R 11 , and
m) O(CO)R 4 ; and
2) aryl or heteroaryl, unsubstituted or substituted with one or more substituents each independently selected from:
a) C 1-6 alkyl,
b) C 3-6 cycloalkyl,
c) (F) p C 1-3 alkyl,
d) halogen,
e) OR 4 ,
f) CO 2 R 4 ,
g) (CO)NR 10 R 11 ,
h) SO 2 NR 10 R 11 ,
i) N(R 10 )SO 2 R 11 ,
j) S(O) m R 4 ,
k) CN,
l) NR 10 R 11 , and,
m) O(CO)R 4 ;
R 2 is selected from:
1) H, C 0 -C 6 alkyl, C 2 -C 6 alkynyl, C 3-6 cycloalkyl and heterocycle, unsubstituted or substituted with one or more substituents each independently selected from:
a) C 1-6 alkyl,
b) C 3-6 cycloalkyl,
c) aryl, unsubstituted or substituted with 1-5 substituents each independently selected from R 4 ,
d) heteroaryl, unsubstituted or substituted with 1-5 substituents each independently selected from R 4 ,
e) heterocycle, unsubstituted or substituted with 1-5 substituents each 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) S(O) m R 4 ,
l) CN,
m) NR 10 R 11 , and
n) O(CO)R 4 ; and
2) aryl or heteroaryl, unsubstituted or substituted with one more substituents independently selected from:
a) C 1-6 alkyl,
b) C 3-6 cycloalkyl,
c) (F) p C 1-3 alkyl,
d) halogen,
e) OR 4 ,
f) p CO 2 R 4 ,
g) (CO)NR 10 R 11 ,
h) SO 2 NR 10 R 11 ,
i) N(R 10 )SO 2 R 11 ,
j) S(O) m R 4 ,
k) CN,
l) NR 10 R 11 , and
m) 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 optionally join to form a ring selected from: azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl, which ring is unsubstituted or substituted with 1-5 substituents each independently selected from 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;
W is O, NR 4 or C(R 4 ) 2 ;
R 6 is independently selected from H and:
a) C 1-6 alkyl,
b) C 3-6 cycloalkyl,
c) (F) p C 1-3 alkyl,
d) halogen,
e) OR 4 ,
f) CO 2 R 4 ,
g) (CO)NR 10 R 11 ,
h) SO 2 NR 10 R 11 ,
i) N(R 10 )SO 2 R 11 ,
j) S(O) m R 4 ,
k) CN,
l) NR 10 R 11 , and
m) O(CO)R 4 ; and
J is a bond and V is a bond and T is C(═O)—, or
J is a bond and V is a bond, or
J is a bond and, V is a bond, C(R 6 ) 2 , O, S(O) m , NR 6 , C(R 6 ) 2 —C(R 6 ) 2 , C(R 6 )═C(R 6 ), C(R 6 ) 2 —N(R 6 ), C(R 6 )═N, N(R 6 )—C(R 6 ) 2 , N═C(R 6 ) or N(R 6 )—N(R 6 ), or
V is a bond and J is a bond, C(R 5 ) 2 , O, S(O) m or NR 5 ;
Q is selected from:
(1) ═C(R 7a )—,
(2) —C(R 7a ) 2 —,
(3) —C(═O)—,
(4) —S(O) m —,
(5) ═N—, and
(6) —N(R 7a )—;
T is selected from:
(1) ═C(R 7b )—,
(2) —C(R 7b ) 2 —,
(3) —C(═O)—,
(4) —S(O) m —,
(5) ═N—, and
(6) ═N(R 7b )—;
each R 3 is independently selected from H, substituted or unsubstituted C 1 -C 3 alkyl, F, CN and CO 2 R 4 ;
R 7a and R 7b are each independently selected from R 2 , where R 7a and R 7b and the atom(s) to which they are attached optionally join to form a ring selected from C 3-6 cycloalkyl, aryl, heterocycle, and heteroaryl, which ring is unsubstituted or substituted with 1-10 substituents each independently selected from R 6 ;
p is 0 to 2q+1, for a substituent with q carbons
m is 0 to 2;
s is 1 to 3;
or a pharmaceutically acceptable salt or individual stereoisomers thereof.
5. The compound of claim 1 , wherein:
R 1 is selected from:
1) H, C 1 -C 6 alkyl, C 3-6 cycloalkyl and heterocycle, unsubstituted or substituted with one or more substituents each independently selected from:
a) C 1-6 alkyl,
b) C 3-6 cycloalkyl,
c) phenyl, unsubstituted or substituted with 1-5 substituents each independently selected from R 4 ,
d) heteroaryl, unsubstituted or substituted with 1-5 substituents each independently selected from R 4 , where heteroaryl is selected from:
imidazole, isoxazole, oxazole, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, and thiazole;
e) heterocycle, unsubstituted or substituted with 1-5 substituents each independently selected from R 4 , where heterocycle is selected from:
azetidine, dioxane, dioxolane, morpholine, oxetane, piperazine, piperidine, pyrrolidine, tetrahydrofuran, and tetrahydropyran;
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) CN,
l) NR 10 R 11 ,
m) O(CO)R 4 ;
2) aryl or heteroaryl, selected from: phenyl, imidazole, isoxazole, oxazole, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, and thiazole, unsubstituted or substituted with one or more substituents each independently selected from:
a) C 1-6 alkyl,
b) C 3-6 cycloalkyl,
c) (F) p C 1-3 alkyl,
d) halogen,
e) OR 4 ,
f) CO 2 R 4 ,
g) (CO)NR 10 R 11 ,
h) SO 2 NR 10 R 11 ,
i) N(R 10 )SO 2 R 11 ,
j) S(O) m R 4 ,
k) CN,
l) NR 10 R 11 , and
m) O(CO)R 4 ;
R 2 is selected from:
1) H, C 0 -C 6 alkyl, C 3-6 cycloalkyl and heterocycle, unsubstituted or substituted with one or more substituents each independently selected from:
a) C 1-6 alkyl,
b) C 3-6 cycloalkyl,
c) phenyl, unsubstituted or substituted with 1-5 substituents each independently selected from R 4 ,
d) heteroaryl, unsubstituted or substituted with 1-5 substituents each independently selected from R 4 , where heteroaryl is selected from: benzimidazole, benzothiophene, furan, imidazole, indole, isoxazole, oxazole, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, thiazole, thiophene, and triazole;
e) heterocycle, unsubstituted or substituted with 1-5 substituents each independently selected from R 4 , and where heterocycle is selected from: azetidine, imidazolidine, imidazoline, isoxazoline, isoxazolidine, morpholine, oxazoline, oxazolidine, oxetane, pyrazolidine, pyrazoline, pyrroline, tetrahydrofuran, tetrahydropyran, thiazoline, and thiazolidine;
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) CN,
l) NR 10 R 11 , and
m) O(CO)R 4 ; and
2) aryl or heteroaryl, selected from: phenyl, benzimidazole, benzothiophene, furan, imidazole, indole, isoxazole, oxazole, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, thiazole, thiophene, and triazole, where said aryl or heteroaryl is unsubstituted or substituted with one or more substituents each independently selected from:
a) C 1-6 alkyl,
b) C 3-6 cycloalkyl,
c) (F) p C 1-3 alkyl,
d) halogen,
e) OR 4 ,
f) CO 2 R 4 ,
g) (CO)NR 10 R 11 ,
h) SO 2 NR 10 R 11 ,
i) N(R 10 )SO 2 R 11 ,
j) S(O) m R 4 ,
k) CN,
l) NR 10 R 11 , and
m) O(CO)R 4 ,
R 10 and R 11 are each 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 optionally joined to form a ring selected from: azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl, which is unsubstituted or substituted with 1-5 substituents each independently selected from R 4 ;
R 4 is independently selected from: H, C 1-6 alkyl, (F) p C 1-6 alkyl, C 3-6 cycloalkyl, aryl, heteroaryl and phenyl, unsubstituted or substituted with hydroxy or C 1 -C 6 alkoxy;
W is NR 4 or C(R 4 ) 2 ;
J is a bond, V is a bond, Q is —N(R 7a )—, and T is —C(═O)— or
J is a bond, V is a bond, Q is —N═, and T is ═C(R 7b )—, or
J is a bond, V is a bond, Q is —C(R 7a ) 2 —, and T is —C(R 7b ) 2 —, or
J is a bond, V is a bond, Q is —C(R 7a )═, T is ═C(R 7b )—, and the atoms to which R 7a and R 7b are attached are joined together to form a benzene, pyridine, or diazine ring, or
J is a bond, V is C(R 6 ) 2 , Q is —C(R 7a )═, T is ═C(R 7b )—, and the atoms to which R 7a and R 7b are attached are joined together to form a benzene, or pyridine ring, or
J is O, V is a bond, Q is —C(R 7a )═, T is ═C(R 7b )—, and the atoms to which R 7a and R 7b are attached are joined together to form a benzene, or pyridine;
R 6 is independently selected from H and:
a) C 1-6 alkyl,
b) C 3-6 cycloalkyl,
c) (F) p C 1-3 alkyl,
d) halogen,
e) OR 4 ,
f) CO 2 R 4 ,
g) (CO)NR 10 R 11 ,
h) SO 2 NR 10 R 11 ,
i) N(R 10 )SO 2 R 11 ,
j) S(O) m R 4 ,
k) CN,
l) NR 10 R 11 , and
m) O(CO)R 4 ;
each R 3 is independently selected from H, substituted or unsubstituted C 1 -C 3 alkyl, F, CN and CO 2 R 4 ;
R 7a and R 7b are each independently selected from R 2 , where R 7a and R 7b and the atom(s) to which they are attached optionally join to form a ring selected from C 3-6 cycloalkyl, aryl, heterocycle, and heteroaryl, which ring is unsubstituted or substituted with 1-10 substituents each independently selected from R 6 ;
p is 0 to 2q+1, for a substituent with q carbons
m is 0 to 2;
s is 1 to 3;
or a pharmaceutically acceptable salt or individual stereoisomers thereof.
6. A compound selected from:
or a pharmaceutically acceptable salt or individual diastereomers thereof.
7. A pharmaceutical composition which comprises an inert carrier and the compound of claim 1 .