US2010113419A1PendingUtilityA1
Cgrp receptor antagonists
Est. expiryOct 7, 2024(expired)· nominal 20-yr term from priority
A61P 43/00C07D 491/20A61P 25/06C07D 471/20C07D 471/10A61P 25/00C07D 491/10
40
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Claims
Abstract
The present invention is directed to compounds of Formula I: Formula I: 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.
Claims
exact text as granted — not AI-modified1 . 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 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) (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 ;
or, any two independent R 2 on the same or adjacent atoms join 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 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, he 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 —M(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;
n is 0 or 1;
s is 1, 2 or 3;
and pharmaceutically acceptable salts and individual diastereomers thereof.
2 . The compound of claim 1 having the Formula Ia:
wherein:
A is a bond, C(R 2 ) 2 , O, S(O) m or NR 2 ;
B is (C(R 2 ) 2 ) n ;
Y is O or NCN;
n is 0 or 1;
and pharmaceutically acceptable salts and individual stereoisomers thereof.
3 . The compound of claim 1 having the Formula Ib:
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;
and pharmaceutically acceptable salts and individual stereoisomers thereof.
4 . The compound of claim 1 having the Formula Ic:
wherein:
and pharmaceutically acceptable salts and individual stereoisomers thereof.
5 . The compound of claim 1 having the Formula Id:
wherein:
A is C(R 2 ) 2 , O, S(O) m or NR 2 ;
and pharmaceutically acceptable salts and individual stereoisomers thereof.
6 . 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) 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 join 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 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, he 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; and 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 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 ,
or, any two independent R 2 on the same or adjacent atoms join 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 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; and pharmaceutically acceptable salts and individual stereoisomers thereof.
8 . A compound of Formula II:
wherein
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 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) (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 ;
or, any two independent R 2 on the same or adjacent atoms join 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 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) 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, S(O) m or NR 6 ;
V is a bond, C(R 6 ) 2 , O, S(O) m or NR 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;
n is 0;
s is 1, 2 or 3;
and pharmaceutically acceptable salts and individual diastereomers thereof.
9 . A pharmaceutical composition which comprises an inert carrier and the compound of claim 1 .
10 . A method for treating headache in a mammalian patient in need of such treatment which comprises administering to the patient a therapeutically effective amount of the compound of claim 1 .Cited by (0)
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