CGRP receptor antagonists
View Patent ↗The present invention is directed to compounds of Formula I and Formula II: (where variables R1, R2, R3, R4, R6, A, B, 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 compound of the formula I:
wherein:
A is a bond, C(R 2 ) 2 , O, S(O) m or NR 2 ;
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 ; 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 ; and
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) (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 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 );
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 ;
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 pharmaceutically acceptable salts and individual diastereomers thereof.
2. The compound of claim 1 of the formula:
wherein:
A is a bond, C(R 2 ) 2 , O, S(O) m or NR 2 ;
B is (C(R 2 ) 2 ) n ;
n is 0 or 1;
Y is O, (R 4 ) 2 , NCN, NSO 2 CH 3 or NCONH 2 ,
or pharmaceutically acceptable salts and individual stereoisomers thereof.
3. The compound of claim 1 of the formula:
wherein:
A is a bond, C(R 2 ) 2 , O, S(O) m or NR 2 ;
B is (C(R 2 ) 2 ) n ; and
n is 0 or 1;
or pharmaceutically acceptable salts and individual stereoisomers thereof.
4. The compound of claim 1 of the formula:
or pharmaceutically acceptable salts and individual stereoisomers thereof.
5. The compound of claim 1 of the formula:
wherein:
A is C(R 2 ) 2 , O, S(O) m or NR 2 ;
or pharmaceutically acceptable salts and individual stereoisomers thereof.
6. The compound of claim 1 of the formula:
wherein:
A is C(R 2 ) 2 , O, S(O) m or NR 2 ;
or pharmaceutically acceptable salts and individual stereoisomers thereof.
7. 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,
l) NR 10 R 11 , and
m) O(CO)R 4 ;
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 sustituents 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 , and
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 pharmaceutically acceptable salts and individual stereoisomers thereof.
8. The compound of claim 7 of the formula:
wherein:
A is a bond, C(R 2 ) 2 , O, S(O) m or NR 2 ;
B is (C(R 2 ) 2 ) n ;
n is 0 or 1;
Y is O, (R 4 ) 2 , NCN, NSO 2 CH 3 or NCONH 2 ,
or pharmaceutically acceptable salts and individual stereoisomers thereof.
9. The compound of claim 7 of the formula:
wherein:
A is a bond, C(R 2 ) 2 , O, S(O) m or NR 2 ;
B is (C(R 2 ) 2 ) n ;
n is 0 or 1;
or pharmaceutically acceptable salts and individual stereoisomers thereof.
10. The compound of claim 7 of the formula:
or pharmaceutically acceptable salts and individual stereoisomers thereof.
11. The compound of claim 7 of the formula:
wherein:
A is C(R 2 ) 2 , O, S(O) m or NR 2 ;
or pharmaceutically acceptable salts and individual stereoisomers thereof.
12. The compound of claim 7 of the formula:
wherein:
A is C(R 2 ) 2 , O, S(O) m or NR 2 ;
or pharmaceutically acceptable salts and individual stereoisomers thereof.
13. 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,
l) NR 10 R 11 , and
m) O(CO)R 4 ; 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,
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 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,
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; 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,
l) NR 10 R 11 , and
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;
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 selected from:
N, N—C(R 5 ) 2 , C═C(R 5 ), C═N, C═C(R 5 )—C(R 5 ) 2 , 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 pharmaceutically acceptable salts and individual stereoisomers thereof.
14. The compound of claim 13 of the formula:
wherein:
A is a bond, C(R 2 ) 2 , O, S(O) m or NR 2 ;
B is (C(R 2 ) 2 ) n ;
n is 0 or 1;
Y is O, (R 4 ) 2 , NCN, NSO 2 CH 3 or NCONH 2 ,
or pharmaceutically acceptable salts and individual stereoisomers thereof.
15. The compound of claim 13 of the formula:
wherein:
A is a bond, C(R 2 ) 2 , O, S(O) m or NR 2 ;
B is (C(R 2 ) 2 ) n ;
n is 0 or 1;
or pharmaceutically acceptable salts and individual stereoisomers thereof.
16. The compound of claim 13 of the formula:
or pharmaceutically acceptable salts and individual stereoisomers thereof.
17. The compound of claim 13 of the formula:
wherein:
A is C(R 2 ) 2 , O, S(O) m or NR 2 ;
or pharmaceutically acceptable salts and individual stereoisomers thereof.
18. The compound of claim 13 of the formula:
wherein:
A is C(R 2 ) 2 , O, S(O) m or NR 2 ;
or pharmaceutically acceptable salts and individual stereoisomers thereof.
19. A compound of the formula:
wherein:
B is independently (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 ; 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 ; and
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) (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 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 ; and
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 a C or N wherein at least one but no more than three of Q, T, U and V are N, and wherein when any of Q, T, U, or V is C it 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 ;
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 pharmaceutically acceptable salts and individual diastereomers thereof.
20. A compound selected from the group consisting of:
or pharmaceutically acceptable salts and individual diastereomers thereof.
21. A pharmaceutical composition which comprises an inert carrier and the compound of claim 1 .
22. A method of treating a condition selected from the group consisting of headache, migraine headache and cluster headache, said method comprising the step of providing the compound of claim 1 to a patient in need thereof.