# US 7,745,427 B2 · CGRP receptor antagonists

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- Number: US 7,745,427 B2
- Document ID: US7745427B2
- Status: Granted
- Kind: B2
- Application number: 11/665,943
- Filed: 2005-10-18
- Published: 2008-04-17
- Granted: 2010-06-29
- Earliest claimed: 2004-10-22
- Assignees: Merck Sharp & Dohme Corp.
- Inventors: Daniel V. Paone; Diem N. Nguyen; Christopher S. Burgey; James Z. Deng
- Web page: https://patentgrep.com/patent/US7745427B2

## CPC

- C07D 471/04: Ortho-condensed systems
- A61P 1/02: Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
- A61P 1/04: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 7/00: Drugs for disorders of the blood or the extracellular fluid
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 11/06: Antiasthmatics
- A61P 13/10: of the bladder
- A61P 17/00: Drugs for dermatological disorders
- A61P 17/06: Antipsoriatics
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/06: Antimigraine agents
- A61P 25/08: Antiepileptics; Anticonvulsants
- A61P 25/28: for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
- A61P 25/36: Opioid-abuse
- A61P 27/02: Ophthalmic agents
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 29/02: without antiinflammatory effect
- A61P 31/04: Antibacterial agents
- A61P 31/08: for leprosy
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The present invention is directed to compounds of Formula (I) and Formula (II) (where variables R1, R2, R3, R4, 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.

## Claims

### Claim 1

A compound of Formula I:
wherein:
Z is selected from:
A is C(R2)2;
B is (C(R2)2)n;
D is selected from R1, OR1, N(R1)2, NR1C(O)R1, C(O)R1, S(O)mR1, C(O)OR1, C(O)N(R1)2, C(O)NR10R11, C(NR1)N(R1)2, and C(NR1)R1;
R1 is independently selected from:
1) H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-6 cycloalkyl, and heterocycle, unsubstituted or substituted with one or more substituents each independently selected from:
a) C1-6 alkyl,
b) C3-6 cycloalkyl,
c) aryl, unsubstituted or substituted with 1-5 substituents each independently selected from R4,
d) heteroaryl, unsubstituted or substituted with 1-5 substituents each independently selected from R4,
e) heterocycle, unsubstituted or substituted with 1-5 substituents each independently selected from R4,
f) (F)pC1-3 alkyl,
g) halogen,
h) OR4,
i) O(CH2)s OR4,
j) CO2R4,
k) (CO)NR10R11,
l) O(CO)NR10R11,
m) N(R4)(CO)NR10R11,
n) N(R10)(CO)R11,
o) N(R10)(CO)OR11,
p) SO2NR10R11,
q) N(R10) SO2R11,
r) S(O)mR10,
s) CN,
t) NR10R11,
u) N(R10)(CO)NR4R11, and,
v) O(CO)R4, and
2) aryl or heteroaryl, unsubstituted or substituted with one or more substituents each independently selected from:
a) C1-6 alkyl,
b) C3-6 cycloalkyl,
c) aryl, unsubstituted or substituted with 1-5 substituents each independently selected from R4,
d) heteroaryl, unsubstituted or substituted with 1-5 substituents each independently selected from R4,
e) heterocycle, unsubstituted or substituted with 1-5 substituents each independently selected from R4,
f) (F)pC1-3 alkyl,
g) halogen,
h) OR4,
i) O(CH2)sOR4,
j) CO2R4,
k) (CO)NR10R11,
l) O(CO)NR10R11,
m) N(R4)(CO)NR10R11,
n) N(R10)(CO)R11,
o) N(R10)(CO)OR11,
p) SO2NR10R11,
q) N(R10) SO2R11,
r) S(O)mR10,
s) CN,
t) NR10R11,
u) N(R10)(CO)NR4R11, and
v) O(CO)R4;
R1 can be optionally joined to R2 to form a 4-8 membered ring;
R2 is independently selected from:
1) H, C0-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-6 cycloalkyl and heterocycle, unsubstituted or substituted with one or more substituents each independently selected from:
a) C1-6 alkyl,
b) C3-6 cycloalkyl,
c) aryl, unsubstituted or substituted with 1-5 substituents where the substituents are independently selected from R4,
d) heteroaryl, unsubstituted or substituted with 1-5 substituents each independently selected from R4,
e) heterocycle, unsubstituted or substituted with 1-5 substituents each independently selected from R4,
f) (F)pC1-3 alkyl,
g) halogen,
h) OR4,
i) O(CH2)sOR4,
j) CO2R4,
k) (CO)NR10R11,
l) O(CO)NR10R11,
m) N(R4)(CO)NR10R11,
n) N(R10)(CO)R11,
o) N(R10)(CO)OR11,
p) SO2NR10R11,
q) N(R10) SO2R11,
r) S(O)mR10,
s) CN,
t) NR10R11,
u) N(R10)(CO)NR4R11, and,
v) O(CO)R4, and
2) aryl or heteroaryl, unsubstituted or substituted with one or more substituents each independently selected from:
a) C1-6 alkyl,
b) C3-6 cycloalkyl,
c) aryl, unsubstituted or substituted with 1-5 substituents where the substituents are independently selected from R4,
d) heteroaryl, unsubstituted or substituted with 1-5 substituents each independently selected from R4,
e) heterocycle, unsubstituted or substituted with 1-5 substituents each independently selected from R4,
f) (F)pC1-3 alkyl,
g) halogen,
h) OR4,
i) O(CH2)sOR4,
j) CO2R4,
k) (CO)NR10R11,
l) O(CO)NR10R11,
m) N(R4)(CO)NR10R11,
n) N(R10)(CO)R11,
o) N(R10)(CO)OR11,
p) SO2NR10R11,
q) N(R10)SO2R11,
r) S(O)mR10,
s) CN,
t) NR10R11,
u) N(R10)(CO)NR4R11, and
v) O(CO)R4,
where any two independent R2 on the same or adjacent atoms optionally 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;
R10 and R11 are each independently selected from: H, C1-6 alkyl, (F)pC1-6 alkyl, C3-6 cycloalkyl, aryl, heteroaryl, and benzyl, unsubstituted or substituted with halogen, hydroxy or C1-C6 alkoxy, where R10 and R11 optionally join to form a ring selected from: azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, and morpholinyl, which is ring is unsubstituted or substituted with 1-5 substituents each independently selected from R4;
R4 is independently selected from: H, C1-6 alkyl, (F)pC1-6 alkyl, C3-6 cycloalkyl, aryl, heteroaryl and benzyl, unsubstituted or substituted with halogen, hydroxy or C1-C6 alkoxy;
W is O, NR4 or C(R4)2;
X is C or S;
Y is O, (R4)2, NCN, NSO2CH3 or NCONH2, or Y is O2 when X is S;
R6 is independently selected from H and:
a) C1-6 alkyl,
b) C3-6 cycloalkyl,
c) aryl, unsubstituted or substituted with 1-5 substituents where the substituents are independently selected from R4,
d) heteroaryl, unsubstituted or substituted with 1-5 substituents each independently selected from R4,
e) heterocycle, unsubstituted or substituted with 1-5 substituents each independently selected from R4,
f) (F)pC1-3 alkyl,
g) halogen,
h) OR4,
i) O(CH2)sOR4,
j) CO2R4,
k) (CO)NR10R11,
l) O(CO)NR10R11,
m) N(R4)(CO)NR10R11,
n) N(R10)(CO)R11,
o) N(R10)(CO)OR11,
p) SO2NR10R11,
q) N(R10) SO2R11,
r) S(O)mR10,
s) CN,
t) NR10R11,
u) N(R10)(CO)NR4R11, and
v) O(CO)R4;
J is a bond, C(R6)2, O or NR6;
V is selected from a bond, C(R6)2, O, S(O)m, NR6, C(R6)2—C(R6)2, C(R6)═C(R6), C(R6)2—N(R6), C(R6)═N, N(R6)—C(R6)2, N═C(R6), and N(R6)—N(R6);
G-L is selected from: N, N—C(R6)2, C═C(R6), C═N, C(R6), C(R6)—C(R6)2, C(R6)—C(R6)2—C(R6)2, C═C(R6)—C(R6)2, C(R6)—C(R6)═C(R6), C(R6)—C(R6)2—N(R6), C═C(R6)—N(R6), C(R6)—C(R6)═N, C(R6)—N(R6)—C(R6)2, C═N—C(R6)2, C(R6)—N═C(R6), C(R6)—N(R6)—N(R6), C═N—N(R6), N—C(R6)2—C(R6)2, N—C(R6)═C(R6), N—C( R6)2—N(R6), N—C(R6)═N, N—N(R6)—C(R6)2 and N—N═C(R6);
Q is selected from:
(1) ═C(R7a)—,
(2) —C(R7a)2—,
(3) —C(═O)—,
(4) —S(O)m—,
(5) ═N—, and
(6) —N(R7a)—;
T is selected from:
(1) ═C(R7b)—,
(2) —C(R7b)2—,
(3) —C(═O)—,
(4) —S(O)m—,
(5) ═N—, and
(6) —N(R7b)—;
R3 is independently selected from H, substituted or unsubstituted C1-C3 alkyl, F, CN and CO2R4;
R7a and R7b are each independently selected from R2, where R7a and R7b and the atom or atoms to which they are attached optionally join to form a ring selected from C3-6 cycloalkyl, aryl, heterocycle, and heteroaryl, which ring is unsubstituted or substituted with 1-10 substituents each independently selected from R6;
“heteroaryl” is a 5- to 7-membered monocyclic- or 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 N and S heteroatoms may optionally be oxidized, and the N may optionally be quaternized, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring;
“heterocyclic” is a 5- to 7-membered monocyclic- or 8- to 11-membered bicyclic heterocyclic ring system which is either saturated or unsaturatated, 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 N and S heteroatoms may optionally be oxidized, and the N heteroatom may be 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.

### Claim 2 (depends on 1)

A compound of claim 1 having the formula Ia:
wherein:
A is a bond, C(R2)2, O, S(O)m or NR2;
B is (C(R2)2)n;
n is 0 or 1; and
or a pharmaceutically acceptable salt or individual diastereomers thereof.

### Claim 3 (depends on 1)

A compound of claim 1 having the formula Ic:
wherein
A is C(R2)2, O, S(O)m or NR2;
or a pharmaceutically acceptable salt or individual diastereomers thereof.

### Claim 4 (depends on 1)

The compound of claim 1, wherein:
D is selected from R1, OR1, N(R1)2, NR1C(O)R1, C(O)R1, S(O)mR1, C(O)OR1, C(O)N(R1)2, C(O)NR10R11, C(NR1)N(R1)2 and C(NR1)R1;
R1 is selected from:
1) H, C1-C6 alkyl, C3-6 cycloalkyl and heterocycle, unsubstituted or substituted with one or more substituents each independently selected from:
a) C1-6 alkyl,
b) C3-6 cycloalkyl,
c) aryl, unsubstituted or substituted with 1-5 substituents where the substituents are independently selected from R4,
d) heteroaryl, unsubstituted or substituted with 1-5 substituents each independently selected from R4,
e) heterocycle, unsubstituted or substituted with 1-5 substituents each independently selected from R4,
f) (F)pC1-3 alkyl,
g) halogen,
h) OR4,
i) O(CH2)sOR4,
j) CO2R4,
k) CN,
l) NR10R11, and
m) O(CO)R4; and
2) aryl or heteroaryl, unsubstituted or substituted with one or more substituents independently selected from:
a) C1-6 alkyl,
b) C3-6 cycloalkyl,
c) (F)pC1-3 alkyl,
d) halogen,
e) OR4,
f) CO2R4,
g) (CO)NR10R11,
h) SO2NR10R11,
i) N(R10) SO2R11,
j) S(O)mR4,
k) CN,
l) NR10R11, and,
m) O(CO)R4;
R2 is selected from:
1) H, C0-C6 alkyl, C2-C6 alkynyl, C3-6 cycloalkyl and heterocycle, unsubstituted or substituted with one or more substituents each independently selected from:
a) C1-6 alkyl,
b) C3-6 cycloalkyl,
c) aryl, unsubstituted or substituted with 1-5 sustituents where the substituents are independently selected from R4,
d) heteroaryl, unsubstituted or substituted with 1-5 substituents each independently selected from R4,
e) heterocycle, unsubstituted or substituted with 1-5 substituents each independently selected from R4,
f) (F)pC1-3 alkyl,
g) halogen,
h) OR4,
i) O(CH2)sOR4,
j) CO2R4,
k) S(O)mR4,
l) CN,
m) NR10R11, and
n) O(CO)R4; and
2) aryl or heteroaryl, unsubstituted or substituted with one more substituents independently selected from:
a) C1-6 alkyl,
b) C3-6 cycloalkyl,
c) (F)pC1-3 alkyl,
d) halogen,
e) OR4,
f) CO2R4,
g) (CO)NR10R11,
h) SO2NR10R11,
i) N(R10) SO2R11,
j) S(O)mR4,
k) CN,
l) NR10R11, and
m) O(CO)R4,
where any two independent R2 on the same or adjacent atoms optionally 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;
R10 and R11 are independently selected from: H, C1-6 alkyl, (F)pC1-6 alkyl, C3-6 cycloalkyl, aryl, heteroaryl and benzyl, unsubstituted or substituted with halogen, hydroxy or C1-C6 alkoxy, where R10 and R11 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 R4;
R4 is independently selected from: H, C1-6 alkyl, (F)pC1-6 alkyl, C3-6 cycloalkyl, aryl, heteroaryl and benzyl, unsubstituted or substituted with halogen, hydroxy or C1-C6 alkoxy;
W is O, NR4 or C(R4)2;
R6 is independently selected from H and:
a) C1-6 alkyl,
b) C3-6 cycloalkyl,
c) (F)pC1-3 alkyl,
d) halogen,
e) OR4,
f) CO2R4,
g) (CO)NR10R11,
h) SO2NR10R11,
i) N(R10) SO2R11,
j) S(O)mR4,
k) CN,
l) NR10R11 and
m) O(CO)R4;
Z is Z1 and:
J is a bond and V is a bond, or
J is a bond, V is a bond and T is —C(═O)—, or
J is a bond, V is a bond, C(R6)2, O, S(O)m, NR6, C(R6)2—C(R6)2, C(R6)═C(R6), C(R6)2—N(R6), C(R6)═N, N(R6)—C(R6)2, N═C(R6) or N(R6)—N(R6), or
J is a bond, C(R5)2, O, or NR5, V is a bond,
or Z is Z2 and G-L is selected from N, N—C(R6)2, C═C(R6), C═N and N—C(R6)2—C(R6)2;
Q is selected from:
(1) ═C(R7a)—,
(2) —C(R7a)2—,
(3) —C(═O)—,
(4) —S(O)m—,
(5) ═N—, and
(6) —N(R7a)—;
T is selected from:
(1) ═C(R7b)—,
(2) —C (R7b)2—,
(3) —C(═O)—,
(4) —S(O)m—,
(5) ═N—, and
(6) —N(R7b)—;
R3 is independently selected from H, substituted or unsubstituted C1-C3 alkyl, F, CN and CO2R4;
R7a and R7b are each independently selected from R2, where R7a and R7b and the atom or atoms to which they are attached optionally join to form a ring selected from C3-6cycloalkyl, aryl, heterocycle, and heteroaryl, which ring is unsubstituted or substituted with 1-10 substituents each each independently selected from R6;
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 diastereomers thereof.

### Claim 5 (depends on 1)

The compound of claim 1, wherein:
R1 is selected from:
1) H, C1-C6 alkyl, C3-6 cycloalkyl and heterocycle, unsubstituted or substituted with one or more substituents each independently selected from:
a) C1-6 alkyl,
b) C3-6 cycloalkyl,
c) phenyl, unsubstituted or substituted with 1-5 substituents each independently selected from R4,
d) heteroaryl, unsubstituted or substituted with 1-5 substituents each independently selected from R4, 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 each independently selected from R4, and where heterocycle is selected from: azetidine, dioxane, dioxolane, morpholine, oxetane, piperazine, piperidine, pyrrolidine, tetrahydrofuran, and tetrahydropyran;
f) (F)pC1-3 alkyl,
g) halogen,
h) OR4,
i) O(CH2)sOR4,
j) CO2R4,
k) CN,
l) NR10R11, and
m) O(CO)R4, 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 each independently selected from:
a) C1-6 alkyl,
b) C3-6 cycloalkyl,
c) (F)pC1-3 alkyl,
d) halogen,
e) OR4,
f) CO2R4,
g) (CO)NR10R11,
h) SO2NR10R11,
i) N(R10) SO2R11,
j) S(O)mR4,
k) CN,
l) NR10R11, and
m) O(CO)R4;
R2 is selected from:
1) H, C0-C6 alkyl, C3-6 cycloalkyl and heterocycle, unsubstituted or substituted with one or more substituents each independently selected from:
a) C1-6 alkyl,
b) C3-6 cycloalkyl,
c) phenyl, unsubstituted or substituted with 1-5 substituents each independently selected from R4,
d) heteroaryl, unsubstituted or substituted with 1-5 substituents each independently selected from R4, 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 R4, 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)pC1-3 alkyl,
g) halogen,
h) OR4,
i) O(CH2)sOR4,
j) CO2R4,
k) CN,
l) NR10R11, and
m) O(CO)R4; 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 each independently selected from:
a) C1-6 alkyl,
b) C3-6 cycloalkyl,
c) (F)pCl-3 alkyl,
d) halogen,
e) OR4,
f) CO2R4,
g) (CO)NR10R11,
h) SO2NR10R11,
i) N(R10) SO2R11,
j) S(O)mR4,
k) CN,
l) NR10R11, and
m) O(CO)R4,
where any two independent R2 on the same or adjacent atoms optionally 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,
R10 and R11 are each independently selected from: H, C1-6 alkyl, (F)pC1-6 alkyl, C3-6 cycloalkyl, aryl, heteroaryl and benzyl, unsubstituted or substituted with halogen, hydroxy or C1-C6 alkoxy, where R10 and R11 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 R4;
R4 is independently selected from: H, C1-6 alkyl, (F)pC1-6 alkyl, C3-6 cycloalkyl, aryl, heteroaryl and phenyl, unsubstituted or substituted with hydroxy or C1-C6 alkoxy;
W is NR4 or C(R4)2;
R6 is independently selected from H and:
a) C1-6 alkyl,
b) C3-6 cycloalkyl,
c) (F)pC1-3 alkyl,
d) halogen,
e) OR4,
f) CO2R4,
g) (CO)NR10R11,
h) SO2NR10R11,
i) N(R10) SO2R11,
j) S(O)mR4,
k) CN,
l) NR10R11, and
m) O(CO)R4;
Z is Z1 and:
J is a bond, V is a bond, Q is —N(R7a)—, and T is —C(═O)—, or
J is a bond, V is a bond, Q is —C(R7a)2—, and T is —C(═O)—, or
J is a bond, V is a bond, Q is —N═, and T is ═C(R7b)—, or
J is a bond, V is a bond, Q is —C(R7a)2—, and T is —C(R7b)2—, or
J is a bond, V is a bond, Q is —C(R7a)═, T is ═C(R7b)—, where the atoms to which R7a and R7b are attached join to form a benzene, pyridine, or diazine ring, or
J is a bond, V is C(R6)2, Q is —C(R7a)═, T is ═C(R7b)—, and the atoms to which R7a and R7b are attached join to form a benzene, or pyridine ring, or
J is O, V is a bond, Q is —C(R7a)═, T is ═C(R7b)—, and the atoms to which R7a and R7b are attached are joined together to form a benzene, or pyridine ring,
or Z is Z2 and:
G-L is N, Q is —C(R7a)2—, and T is —C(R7b)2—, or
G-L is N, Q is —C(R7a)═ and T is ═C(R7b)—, or
G-L is N, Q is —N═, and T is ═C(R7b)—, or
G-L is N, Q is —C(R7a)2—, and T is —C(O)—, or
G-L is C═C(R6), Q is —C(R7a)═ and T is ═C(R7b)—, or
G-L is C═C(R6), Q is —C(R7a)═ and T is ═N—, or
G-L is C═C(R6), Q is —N═ and T is ═C(R7b)—, or
G-L is C═N, Q is —C(R7a)═ and T is ═C(R7b)—, or
G-L is N, Q is —C(R7a)═, and T is ═C(R7b)—, and the atoms to which R7a and R7b are attached join to form a benzene, pyridine, or diazine ring, or
G-L is N—C(R6)2, Q is —C(R7a)═, and T is ═C(R7b)—, and the atoms to which R7a and R7b are attached join to form a benzene, or pyridine ring, or
G-J is C═N, Q is —C(R7a)═, and T is ═C(R7b)—, and the atoms to which R7a and R7b are attached join to form a benzene ring, or
G-L is C═C(R6), Q is —C(R7a)═, and T is ═C(R7b)—, and the atoms to which R7a and R7b are attached join to form a benzene ring, or
G-L is N—C(R6)2—C(R6)2, Q is —C(R7a)═, and T is ═C(R7b)—, and the atoms to which R7a and R7b are attached join to form a benzene ring;
R3 is independently selected from H, substituted or unsubstituted C1-C3 alkyl, F, CN and CO2R4;
R7a and R7b are each independently selected from R2, where R7a and R7b and the atom or atoms to which they are attached optionally join to form a ring selected from C3-6cycloalkyl, aryl, heterocycle, and heteroaryl which is unsubstituted or substituted with 1-10 substituents each independently selected from R6;
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 and individual diastereomers thereof.

### Claim 6

A compound selected from:
or a pharmaceutically acceptable salt thereof or individual diasteromers thereof.

### Claim 7 (depends on 1)

A pharmaceutical composition which comprises an inert carrier and the compound of claim 1, or a pharmaceutically acceptable salt thereof or individual diasteromers thereof.

### Claim 8 (depends on 1)

A method for treating 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, or a pharmaceutically acceptable salt thereof or individual diasteromers thereof.