CGRP receptor antagonists
View Patent ↗The present invention is directed to compounds of Formula I: and Formula II: (where variables R 1 , R 2 , R 3 , R 4 , A, B, G, J, Q, T, U, 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 O;
B is (C(R 2 ) 2 ) n ;
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 ;
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,
t) 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 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) 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 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 ,
or, any two independent R 2 on the same or adjacent atoms may be joined together to form a ring selected from cyclobutyl, cyclopentenyl, cyclopentyl, cyclohexenyl, cyclohexyl, phenyl, naphthyl, thienyl, thiazolyl, thiazolinyl, oxazolyl, oxazolinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, pyrimidyl, pyrazinyl, pyrrolyl, pyrrolinyl, morpholinyl, thiomorpholine, thiomorpholine S-oxide, thiomorpholine S-dioxide, azetidinyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyridyl, furanyl, dihydrofuranyl, dihydropyranyl and piperazinyl;
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, or morpholinyl, which is unsubstituted or substituted with 1-5 substituents where the substituents are 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 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 , 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 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 ;
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 );
Q, T, U and V are each independently carbon or nitrogen wherein at least one but no more than three of Q, T, U and V are nitrogen, of which one may be optionally an N-oxide, and wherein when any of Q, T, U, or V is carbon it is unsubstituted or substituted where the substituents are independently selected from R 6 ;
R 5 is independently selected from H, substituted or unsubstituted C 1 -C 3 alkyl, CN, OR 4 , N(R 4 ) 2 and CO 2 R 4 ;
R 3 is independently selected from H, substituted or unsubstituted C 1 -C 3 alkyl, F, CN and CO 2 R 4 ;
“heteroaryl,” except where otherwise defined, is 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,” except where otherwise defined, is 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;
p is 0 to 2q+1, for a substituent with q carbons;
m is 0, 1 or 2;
n is 1;
s is 1, 2 or 3;
or a pharmaceutically acceptable salt or individual diastereomers thereof.
2. The compound of claim 1 of the Formula Ia:
wherein:
Y is O or NCN; and
or a pharmaceutically acceptable salt or individual diastereomers thereof.
3. The compound of claim 1 of the Formula Ib:
or a pharmaceutically acceptable salt or individual diastereomers thereof.
4. The compound of claim 1 of the Formula Ie:
or a pharmaceutically acceptable salt or individual diastereomers 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 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) 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 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 and
l) NR 10 R 11 , and
m) O(CO)R 4 ; and
R 2 is selected from:
1) H, C 1 -C 6 alkyl, 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) 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) 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 ,
m) O(CO)R 4 ,
or, any two independent R 2 on the same or adjacent atoms may be joined together to form a ring selected from cyclobutyl, cyclopentenyl, cyclopentyl, cyclohexenyl, cyclohexyl, phenyl, naphthyl, thienyl, thiazolyl, thiazolinyl, oxazolyl, oxazolinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, pyrimidyl, pyrazinyl, pyrrolyl, pyrrolinyl, morpholinyl, thiomorpholine, thiomorpholine S-oxide, thiomorpholine S-dioxide, azetidinyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyridyl, furanyl, dihydrofuranyl, dihydropyranyl and piperazinyl;
G-J is selected from:
N, N—C(R 5 ) 2 , C═C(R 5 ), C═N, C═C(R 5 )—C(R 5 ), C(R 5 )—C(R 5 )═C(R 5 ), N—C(R 5 ) 2 —C(R 5 ) 2 and N—C(R 5 )═C(R 5 );
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 ;
or a pharmaceutically acceptable salt or individual diastereomers thereof.
6. The compound of claim 5 of the Formula Ia:
wherein:
Y is O or NCN;
or a pharmaceutically acceptable salt or individual diastereomers thereof.
7. The compound of claim 5 of the Formula Ib:
wherein:
n is 0 or 1;
or a pharmaceutically acceptable salt or individual diastereomers thereof.
8. The compound of claim 4 of the Formula Ie:
or a pharmaceutically acceptable salt or individual diastereomers thereof.
9. 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) phenyl, 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 , and where heteroaryl is selected from:
imidazole, isoxazole, oxazole, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, and thiazole;
e) heterocycle, unsubstituted or substituted with 1-5 substituents where the substituents are independently selected from R 4 ,
and 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, and
l) NR 10 R 11 ; and
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 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 and
l) NR 10 R 11 ;
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 independently selected from:
a) C 1-6 alkyl,
b) C 3-6 cycloalkyl,
c) phenyl, 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 , and 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 where the substituents are 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, and
l) NR 10 R 11 ; 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;
unsubstituted or substituted with one or 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) 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 and
l) NR 10 R 11 ,
or, any two independent R 2 on the same or adjacent atoms may be joined together to form a ring selected from cyclobutyl, cyclopentenyl, cyclopentyl, cyclohexenyl, cyclohexyl, phenyl, naphthyl, thienyl, thiazolyl, thiazolinyl, oxazolyl, oxazolinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, pyrimidyl, pyrazinyl, pyrrolyl, pyrrolinyl, morpholinyl, thiomorpholine, thiomorpholine S-oxide, thiomorpholine S-dioxide, azetidinyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyridyl, furanyl, dihydrofuranyl, dihydropyranyl and piperazinyl;
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 ;
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 ;
G-J is N and Q-T-U-V is N═C(R 6 )—C(R 6 )═C(R 6 ), G-J is N and Q-T-U-V is C(R 6 )═N—C(R 6 )═C(R 6 ), G-J is N and Q-T-U-V is C(R 6 )═C(R 6 )—N═C(R 6 ), G-J is N and Q-T-U-V is C(R 6 )═C(R 6 )—C(R 6 )═N, G-J is N and Q-T-U-V is C(R 6 )═C(R 6 )—N═N, G-J is N and Q-T-U-V is C(R 6 )═N—C(R 6 )═N, G-J is N and Q-T-U-V is N═C(R 6 )—C(R 6 )═N, G-J is NC(R 5 ) 2 and Q-T-U-V is C(R 6 )═C(R 6 )—C(R 6 )═N, G-J is NC(R 5 ) 2 and Q-T-U-V is C(R 6 )═N—C(R 6 )═C(R 6 ), G-J is C═C(R 5 ) and Q-T-U-V is C(R 6 )═C(R 6 )—C(R 6 )═N, G-J is C═C(R 5 ) and Q-T-U-V is C(R 6 )═N—C(R 6 )═C(R 6 ), G-J is C═N and Q-T-U-V is C(R 6 )═C(R 6 )—C(R 6 )═N, G-J is C═N and Q-T-U-V is C(R 6 )═N—C(R 6 )═C(R 6 ), G-J is N—C(R 5 ) 2 —C(R 5 ) 2 and Q-T-U-V is C(R 6 )═C(R 6 )—C(R 6 )═N, or G-J is N—C(R 5 ) 2 —C(R 5 ) 2 and Q-T-U-V is C(R 6 )═N—C(R 6 )═C(R 6 ).
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 and
l) NR 10 R 11 ;
or a pharmaceutically acceptable salt or individual diastereomers thereof.
10. The compound of claim 9 of the Formula Ia:
or a pharmaceutically acceptable salt or individual diastereomers thereof.
11. The compound of claim 9 of the Formula Ib:
or a pharmaceutically acceptable salt or individual diastereomers thereof.
12. The compound of claim 9 of the Formula Ie:
or a pharmaceutically acceptable salt or individual diastereomers thereof.
13. A compound of claim 1 selected from:
or a pharmaceutically acceptable salt or individual diastereomers thereof.
14. A pharmaceutical composition which comprises an inert carrier and the compound of claim 1 .
15. A method of treating headache in a patient in need thereof, said method comprising administering a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof to a person in need of treatment.
16. The method of claim 15 , wherein the headache is selected from the group consisting of migraine headaches and cluster headaches.