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Matched Legal Cases: ['art 1', 'art 2', 'art 3', '§371', '§119', 'Application No. 60', 'Application No. 60']

Benzazole potentiators of metabotropic glutamate receptors - Merck Sharp & Dohme Corp.
Benzazole potentiators of metabotropic glutamate receptors
United States Patent 7960417
The present invention is directed to benzazole compounds which are potentiators of metabotropic glutamate receptors, including the mGluR2 receptor, and which are useful in the treatment or prevention of neurological and psychiatric disorders associated with glutamate dysfunction and diseases in which metabotropic glutamate receptors are involved. 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 metabotropic glutamate receptors are involved.
Govek, Steven P. (San Diego, CA, US)
Vernier, Jean-michel (Laguna Niguel, CA, US)
Kamenecka, Theodore (Palm Beach Gardens, NJ, US)
Hutchinson, John H. (La Jolla, CA, US)
Pracitto, Richard (North Wales, PA, US)
11/884391
514/381, 548/252, 548/260
A61K31/41; A61K31/4192; C07D249/18; C07D249/20; C07D403/12
548/252, 548/260, 514/381, 514/359
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Supplementary Partial European Search Report for PCT/US2006/005711, mailed Apr. 6, 2010.
This application is a U.S. National Phase application under 35 U.S.C. §371 of PCT Application No. PCT/US2006/005711, filed Feb. 17, 2006, which claims priority under 35 U.S.C. §119 from U.S. Application No. 60/656,113, filed Feb. 24, 2005 and U.S. Application No. 60/666,361 filed Mar. 30, 2005.
1. A compound of the formula I: wherein: A is phenyl; W is selected from the group consisting of: (1) -tetrazolyl, and (2) —CO2H; X is selected from the group consisting of: (1) —O—, (2) —O—C1-6alkanediyl-, (3) —O—C1-6alkenediyl-, (4) —O—C3-7cycloalkanediyl-, and (5) —O-phenylene-, wherein the phenylene is unsubstituted or substituted with C1-6alkyl, or halogen; Y is —O—; Z1, Z2 and Z3 are N such that together with the fused phenyl ring they form a benzotriazolyl ring; R1a, R1b and R1c may be absent if the valency at Z1, Z2 or Z3 does not permit such substitution and are independently selected from the group consisting of: (1) hydrogen, (2) C1-6alkyl, which is unsubstituted or substituted with a substituent selected from: (a) halogen, (b) hydroxyl, (c) phenyl, wherein the phenyl is unsubstituted or substituted with 1-5substituents independently selected from halogen, cyano, CF3, hydroxyl, C1-6alkyl, and OC1-6alkyl, (d) C3-7cycloalkyl, which is unsubstituted or substituted with halogen, hydroxyl or phenyl, (e) naphthyl, which is unsubstituted or substituted with halogen, C1-6alkyl or phenyl, (f) —CO—C1-6alkyl, and (g) —COO—C1-6alkyl, (3) C3-7cycloalkyl, which is unsubstituted or substituted with halogen, C1-6alkyl, hydroxyl or phenyl, (4) phenyl, wherein the phenyl is unsubstituted or substituted with 1-5 substituents independently selected from halogen, hydroxyl, cyano, CF3, C1-6alkyl, and OC1-6alkyl, wherein the C1-6alkyl and OC1-6alkyl are linear or branched and optionally substituted with 1-5 halogen, (5) —CO—C1-6alkyl, and (6) —COO—C1-6alkyl; R2 is selected from the group consisting of: (1) hydrogen, (2) halogen, (3) hydroxyl, (4) OC1-6alkyl, (5) C2-6alkenyl, and (6) C1-6alkyl, which is unsubstituted or substituted with halogen, hydroxyl or phenyl; R3a and R3b are selected from the group consisting of: (1) hydrogen, (2) halogen, (3) C1-6alkyl, which is unsubstituted or substituted with halogen, hydroxyl or phenyl, and (4) OC1-6alkyl; R4 may include multiple substituents and is independently selected from the group consisting of: (1) hydrogen, (2) halogen, (3) C1-6alkyl, and (4) —O—C1-6alkyl; m is an integer selected from 0, 1, 2 and 3; n is an integer selected from 0, 1, 2, 3, 4, 5 and 6; or a pharmaceutically acceptable salt thereof.
4. The compound of claim 1 wherein R1a, R1b and R1c are independently selected from hydrogen and C1-6alkyl, which is unsubstituted or substituted with: C3-7cycloalkyl.
5. The compound of claim 1 wherein R1a, R1b and R1c are independently selected from hydrogen, CH3, CH2CH2CH3, CH2CH(CH3)2, CH2CH2CH2CH3, CH2C(CH3)3, CH2-cyclopropyl, CH2-cyclohexyl and phenyl.
6. The compound of claim 5 wherein R1a, R1b and R1c are independently selected from hydrogen, CH2CH(CH3)2, CH2CH2CH2CH3, CH2C(CH3)3 and CH2-cyclohexyl.
7. The compound of claim 6 wherein R1a is CH2C(CH3)3.
8. The compound of claim 6 wherein R1a is CH2-cyclohexyl.
9. The compound of claim 1 wherein R2 is selected from the group consisting of: hydrogen, methyl, propyl, allyl and bromo.
10. The compound of claim 1 wherein R3a and R3b are hydrogen and R4 is hydrogen.
11. The compound of claim 1 wherein m is 0 or 1.
13. The compound of claim 1 wherein n is 4.
14. A compound which is selected from the group consisting of: 1-(2,2-dimethylpropyl)-4-propyl-5-{4-[4-(1H-tetrazol-5-yl)phenoxy]butoxy}-1H-1,2,3-benzotriazole; 1-(2,2-dimethylpropyl)-7-propyl-6-{4-[4-(1H-tetrazol-5-yl)phenoxy]butoxy}-1H-1,2,3-benzotriazole; 1-(2,2-dimethylpropyl)-5-{4-[4-(1H-tetrazol-5-yl)phenoxy]butoxy}-1H-1,2,3-benzotriazole; 1-(2,2-dimethylpropyl)-6-{4-[4-(1H-tetrazol-5-yl)phenoxy]butoxy}-1H-1,2,3-benzotriazole; 4-bromo-1-(2,2-dimethylpropyl)-5-{4-[4-(1H-tetrazol-5-yl)phenoxy]butoxy}-1H-1,2,3-benzotriazole; 7-bromo-1-(2,2-dimethylpropyl)-6-{4-[4-(1H-tetrazol-5-yl)phenoxy]butoxy}-1H-1,2,3-benzotriazole; 4-{4-[1-(2,2-Dimethyl-propyl)-4-propyl-2H-benzotriazol-5-yloxy]-butoxy}-benzoic acid; 4-{4-[3-(2,2-Dimethyl-propyl)-4-propyl-3H-benzotriazol-5-yloxy]-butoxy}-benzoic acid; 4-{4-[2-(2,2-Dimethyl-propyl)-4-propyl-1H-benzotriazol-5-yloxy]-butoxy}-benzoic acid; or a pharmaceutically acceptable salt thereof.
15. A pharmaceutical composition which comprises an inert carrier and the compound of claim 1 or a pharmaceutically acceptable salt thereof.
At present, there are eight distinct mGlu receptors that have been positively identified, cloned, and their sequences reported. These are further subdivided based on their amino acid sequence homology, their ability to effect certain signal transduction mechanisms, and their known pharmacological properties. Ozawa, Kamiya and Tsuzuski, Prog. Neurobio., 54, 581 (1998). For instance, the Group I mGluR receptors, which include the mGlu1R and mGlu5R, are known to activate phospholipase C (PLC) via Gaq-proteins thereby resulting in the increased hydrolysis of phosphoinositides and intracellular calcium mobilization. There are several compounds that are reported to activate the Group I mGlu receptors including DHPG, (R/S)-3,5-dihydroxyphenylglycine. Schoepp, Goldworthy, Johnson, Salhoff and Baker, J. Neurochem., 63, 769 (1994); Ito, et al., keurorep., 3, 1013 (1992). The Group II mGlu receptors consist of the two distinct receptors, mGluR2 and mGluR3 receptors. Both have been found to be negatively coupled to adenylate cyclase via activation of Gai-protein. These receptors can be activated by a selective compound such as 1S,2S,SR,6S-2 aminobicyclo[3.1.0]hexane-2,6-dicarboxylate. Monn, et al., J. Med. Chem., 40, 528 (1997); Schoepp, et al., Neuropharmacol., 36, 1 (1997). Similarly, the Group III mGlu receptors, including mGluR4, mGluR6, mGluR7 and mGluR8, are negatively coupled to adenylate cyclase via Gai and are potently activated by L-AP4 (L-(+)-2-amino-4-phosphonobutyric acid). Schoepp, Neurochem. Int., 24, 439 (1994).
(1) -tetrazolyl,
(2) —CO2H,
(3) —NHSO2C1-6alkyl,
(4) —NHSO2-phenyl, wherein the phenyl is unsubstituted or substituted with C1-6alkyl, and
(5) —CONHCO—C1-6alkyl,
(6) hydrogen;
(2) —O—C1-6alkyl-,
(3) —O—C2-6alkenyl-,
(4) a bond,
(5) —O—C3-7cycloalkyl -
(6) -pyrrolidine-,
(7) -piperidine-,
(8) —S—,
(9) —O-phenyl-, wherein the phenyl is unsubstituted or substituted with C1-6alkyl, or halogen,
(10) —S-phenyl-, wherein the phenyl is unsubstituted or substituted with C1-6alkyl, or halogen, and
(11) -phenyl-, wherein the phenyl is unsubstituted or substituted with C1-6alkyl, or halogen;
Z1, Z2 and Z3 are selected from C, N and O such that together with the fused phenyl ring they form an indolyl, indolinyl, indazolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, or benzotriazolyl ring;
R1a, R1b and R1c may be absent if the valency at Z1, Z2 or Z3 does not permit such substitution and are independently selected from the group consisting of:
(c) phenyl, wherein the phenyl is unsubstituted or substituted with 1-5 substituents independently selected from halogen, cyano, CF3, hydroxyl, C1-6alkyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolyl, and OC1-6alkyl,
(d) C3-7cycloalkyl, which is unsubstituted or substituted with halogen, hydroxyl or phenyl,
(e) pyridyl, which is unsubstituted or substituted with halogen, C1-6alkyl or phenyl,
(f) naphthyl, which is unsubstituted or substituted with halogen, C1-6alkyl or phenyl,
(g) tetrahydropyranyl, which is unsubstituted or substituted with halogen, C1-6alkyl or phenyl, and
(h) isoxazolyl, which is unsubstituted or substituted with halogen, C1-6alkyl or phenyl,
(i) —CO—C1-6alkyl, and
(j) —COO—C1-6alkyl,
(3) C3-7cycloalkyl, which is unsubstituted or substituted with halogen, C1-6alkyl, hydroxyl or phenyl,
(4) phenyl, wherein the phenyl is unsubstituted or substituted with 1-5 substituents independently selected from halogen, hydroxyl, cyano, CF3, C1-6alkyl, and OC1-6alkyl, wherein the C1-6alkyl and OC1-6alkyl are linear or branched and optionally substituted with 1-5 halogen,
(5) —CO—C1-6alkyl, and
(6) —COO—C1-6alkyl;
(4) OC1-6alkyl,
(5) C2-6alkenyl, and
(6) C1-6alkyl, which is unsubstituted or substituted with halogen, hydroxyl or phenyl;
R3a and R3b are selected from the group consisting of:
(3) C1-6alkyl, which is unsubstituted or substituted with halogen, hydroxyl or phenyl, and
(4) OC1-6alkyl;
(4) —O—C1-6alkyl;
wherein R1a, R1b, R1c, R2, R3a, R3b, R4, A, W, X, Y, n and m are defined herein;
wherein R1a, R1b, R1c, R2, R3a, R3b, R4, A, X, Y, n and m are defined herein;
wherein R1a, R1c, R2, R3a, R3b, R4, A, X, Y, n and m are defined herein;
wherein R1b, R1c, R2, R3a, R3b, R4, A, X, Y, n and m are defined herein;
wherein R1a, R2, R3a, R3b, R4, A, X, Y, n and m are defined herein;
wherein R1c, R2, R3a, R3b, R4, A, X, Y, n and m are defined herein;
An embodiment of the present invention includes compounds of the formula Ih:
wherein R1b, R2, R3a, R3b, R4, A, X, Y, n and m are defined herein;
An embodiment of the present invention includes compounds of the formula Ii:
wherein R1a, R1b, R2, R3a, R3b, R4, A, X, Y, n and m are defined herein;
An embodiment of the present invention includes compounds of the formula Ij:
An embodiment of the present invention includes compounds of the formula Ik:
An embodiment of the present invention includes compounds wherein W is hydrogen.
An embodiment of the present invention includes compounds wherein X is —O—C2-6alkenyl-.
An embodiment of the present invention includes compounds wherein X is —O-cyclopentane-.
An embodiment of the present invention includes compounds wherein X is -piperidine-.
An embodiment of the present invention includes compounds wherein X is -pyrrolidine-.
An embodiment of the present invention includes compounds wherein R1a, R1b and R1c are independently selected from hydrogen and C1-6alkyl, which is unsubstituted or substituted with a substituent selected from,
(a) C3-7cycloalkyl,
(c) naphthyl,
(d) tetrahydropyranyl, and
(e) isoxazolyl.
An embodiment of the present invention includes compounds wherein R1a, R1b and R1c are independently selected from hydrogen, CH3, CH2CH2CH3, CH2CH(CH3)2, CH2CH2CH2CH3, CH2C(CH3)3, CH2-cyclopropyl, CH2-cyclohexyl and phenyl.
An embodiment of the present invention includes compounds wherein R1a, R1b and R1c are independently selected from hydrogen, CH2CH(CH3)2, CH2CH2CH2CH3, CH2C(CH3)3 and CH2-cyclohexyl.
An embodiment of the present invention includes compounds wherein R1a is CH2C(CH3)3.
An embodiment of the present invention includes compounds wherein R1a is CH2-cyclohexyl.
An embodiment of the present invention includes compounds wherein R2 is propyl.
An embodiment of the present invention includes compounds wherein R2 is allyl.
An embodiment of the present invention includes compounds wherein R2 is hydrogen.
An embodiment of the present invention includes compounds wherein R2 is bromo.
An embodiment of the present invention includes compounds wherein R2 is methyl.
An embodiment of the present invention includes compounds wherein R3a and R3b are hydrogen.
1-(2,2-dimethylpropyl)-4-propyl-5-{4-[4-(1H-tetrazol-5-yl)phenoxy]butoxy}-1H-indole;
2,2-dimethyl-1-(7-propyl-6-{4-[4-(1H-tetrazol-5-yl)phenoxy]butoxy}-1H-indol-3-yl)propan-1-one;
1-(2,2-dimethylpropyl)-4-propyl-5-{4-[4-(1H-tetrazol-5-yl)phenoxy]butoxy}-1H-indazole;
2-(2,2-dimethylpropyl)-4-propyl-5-{4-[4-(1H-tetrazol-5-yl)phenoxy]butoxy}-2H-indazole;
1-(2,2-dimethylpropyl)-4-propyl-5-[4-(pyridin-3-yloxy)butoxy]-1H-indole;
1-(2,2-dimethylpropyl)-4-propyl-5-{4-[4-(1H-tetrazol-5-yl)phenoxy]butoxy}-1H-1,2,3-benzotriazole;
1-(2,2-dimethylpropyl)-7-propyl-6-{4-[4-(1H-tetrazol-5-yl)phenoxy]butoxy}-1H-1,2,3-benzotriazole;
1-(2,2-dimethylpropyl)-4-propyl-5-{4-[4-(1H-tetrazol-5-yl)phenoxy]butoxy}-1H-benzimidazole;
1-(2,2-dimethylpropyl)-7-propyl-6-{4-[4-(1H-tetrazol-5-yl)phenoxy]butoxy}-1H-benzimidazole;
1-(2,2-dimethylpropyl)-4-propyl-5-{4-[4-(1H-tetrazol-5-yl)phenoxy]butoxy}indoline;
4-bromo-1-(2,2-dimethylpropyl)-5-{4-[4-(1H-tetrazol-5-yl)phenoxy]butoxy}-1H-indole;
1-(2,2-dimethylpropyl)-5-{4-[4-(1H-tetrazol-5-yl)phenoxy]butoxy}-1H-indole;
1-(2,2-dimethylpropyl)-4-propyl-5-{[4-(1H-tetrazol-5-yl)benzyl]oxy}-1H-indole;
1-(2,2-dimethylpropyl)-4-propyl-5-{[3-(1H-tetrazol-5-yl)benzyl]oxy}-1H-indole;
1-(2,2-dimethylpropyl)-4-methyl-5-{4-[4-(1H-tetrazol-5-yl)phenoxy]butoxy}-1H-indole;
1-(2,2-dimethylpropyl)-2-methyl-4-propyl-5-{4-[4-(1H-tetrazol-5-yl)phenoxy]butoxy}-1H-indole;
ethyl 1-(2,2-dimethylpropyl)-4-propyl-5-{4-[4-(1H-tetrazol-5-yl)phenoxy]butoxy}-1H-indole-2-carboxylate;
1-(2,2-dimethylpropyl)-5-{4-[4-(1H-tetrazol-5-yl)phenoxy]butoxy}-1H-1,2,3-benzotriazole;
1-(2,2-dimethylpropyl)-6-{4-[4-(1H-tetrazol-5-yl)phenoxy]butoxy}-1H-1,2,3-benzotriazole;
1-(2,2-dimethylpropyl)-4-propyl-5-{[3′-(1H-tetrazol-5-yl)biphenyl-3-yl]methoxy}-1H-indole;
1-(2,2-dimethylpropyl)-4-propyl-5-{[4′-(2H-tetrazol-5-yl)biphenyl-3-yl]methoxy}-1H-indole;
4-bromo-1-(2,2-dimethylpropyl)-5-{4-[4-(1H-tetrazol-5-yl)phenoxy]butoxy}-1H-1,2,3-benzotriazole;
7-bromo-1-(2,2-dimethylpropyl)-6-{4-[4-(1H-tetrazol-5-yl)phenoxy]butoxy}-1H-1,2,3-benzotriazole;
1-(2,2-dimethylpropyl)-4-propyl-5-{2-[4-(1H-tetrazol-5-yl)phenoxy]ethoxy}-1H-indole;
1-(2,2-dimethylpropyl)-4-propyl-5-{3-[4-(1H-tetrazol-5-yl)phenoxy]propoxy}-1H-indole;
1-(2,2-dimethylpropyl)-4-propyl-5-({5-[4-(1H-tetrazol-5-yl)phenoxy]pentyl}oxy)-1H-indole;
3′-({[1-(2,2-dimethylpropyl)-4-propyl-1H-indol-5-yl]oxy}methyl)biphenyl-3-carboxylic acid;
3′-({[1-(2,2-dimethylpropyl)-4-propyl-1H-indol-5-yl]oxy}methyl)biphenyl-4-carboxylic acid;
1-(2,2-dimethylpropyl)-4-propyl-5-({1-[4-(2H -tetrazol-5-yl)phenyl]pyrrolidin-3-yl}methoxy)-1H-indole;
1-(2,2-dimethylpropyl)-4-propyl-5-({1-[4-(2H-tetrazol-5-yl)phenyl]piperidin-3-yl}methoxy)-1H-indole;
1-(2,2-dimethylpropyl)-4-propyl-5-({4-[4-(2H-tetrazol-5-yl)phenoxy]benzyl}oxy)-1H-indole;
4-allyl-1-(2,2-dimethylpropyl)-5-({3-[4-(H-tetrazol-5-yl)phenoxy]benzyl}oxy)-1H-indole;
1-(2,2-dimethylpropyl)-4-propyl-5-({3-[4-(1H-tetrazol-5-yl)phenoxy]benzyl}oxy)-1H-indole;
5-({2-chloro-5-[4-(1H-tetrazol-5-yl)phenoxy]benzyl}oxy)-1-(2,2-dimethylpropyl)-4-propyl-1H-indole;
1-(2,2-dimethylpropyl)-5-({2-ethyl-5-[4-(1H-tetrazol-5-yl)phenoxy]benzyl}oxy)-4-propyl-1H-indole;
1-(2,2-dimethylpropyl)-5-({2-fluoro-5-[4-(1H-tetrazol-5-yl)phenoxy]benzyl}oxy)-4-propyl-1H-indole;
4-[3-({[1-(2,2-dimethylpropyl)-4-propyl-1H-indol-5-yl]oxy}methyl)pyrrolidin-1-yl]benzoic acid;
6-[3-({[1-(2,2-dimethylpropyl)-4-propyl-1H-indol-5-yl]oxy}methyl)phenyl]pyridine-2-carboxylic acid;
5-[3-({[1-(2,2-dimethylpropyl)-4-propyl-1H-indol-5-yl]oxy}methyl)phenyl]nicotinic acid;
5-[3-({[1-(2,2-dimethylpropyl)-4-propyl-1H-indol-5-yl]oxy}methyl)phenyl]pyridine-2-carboxylic acid;
1-(2,2-dimethylpropyl)-4-propyl-5-({3-[5-(1H-tetrazol-5-yl)pyridin-3-yl]benzyl}oxy)-1H-indole;
1-(2,2-dimethylpropyl)-4-propyl-5-({3-[6-(2H-tetrazol-5-yl)pyridin-3-yl]benzyl}oxy)-1H-indole;
1-Cyclohexylmethyl-4-propyl-5-{4-[4-(2H-tetrazol-5-yl)-phenoxy]-butoxy}-1H-indole;
(4-Propyl-5-{4-[4-(2H-tetrazol-5-yl)-phenoxy]-butoxy}-indol-1-yl)-acetic acid tert-butyl ester;
4-Propyl-1-(tetrahydro-pyran-2-ylmethyl)-5-{4-[4-(2H-tetrazol-5-yl)-phenoxy]-butoxy}-1H-indole;
1-Naphthalen-2-ylmethyl-4-propyl-5-{4-[4-(2H-tetrazol-5-yl)-phenoxy]-butoxy}-1H-indole;
4-Propyl-1-(4-pyrrol-1-yl-benzyl)-5-{4-[4-(2H-tetrazol-5-yl)-phenoxy]-butoxy}-1H-indole;
(4-Propyl-5-{4-[4-(2H-tetrazol-5-yl)-phenoxy]-butoxy}-indol-1-yl)-acetic acid ethyl ester;
1-Cyclopropylmethyl-4-propyl-5-{4-[4-(2H-tetrazol-5-yl)-phenoxy]-butoxy}-1H-indole;
1,4-Dipropyl-5-{4-[4-(2H-tetrazol-5-yl)-phenoxy]-butoxy}-1H-indole;
1-(5-Methyl-isoxazol-3-ylmethyl)-4-propyl-5-{4-[4-(5H-[1,2,4]triazol-3-yl)-phenoxy]-butoxy}-1H-indol;
1-Isopropyl-4-propyl-5-{4-[4-(2H-tetrazol-5-yl)-phenoxy]-butoxy}-1H-indole;
1-(3-Methyl-butyl)-4-propyl-5-{4-[4-(2H-tetrazol-5-yl)-phenoxy]-butoxy}-1H-indole;
1-Isobutyl-4-propyl-5-{4-[4-(2H-tetrazol-5-yl)-phenoxy]-butoxy}-1H-indole;
1-Butyl-4-propyl-5-{4-[4-(2H-tetrazol-5-yl) -phenoxy]-butoxy}-1H-indole;
1-Pentyl-4-propyl-5-{4-[4-(2H-tetrazol-5-yl) -phenoxy]-butoxy}-1H-indole;
1-(2,2-Dimethyl-propyl)-4-propyl-5-{(E)-4-[4-(2H-tetrazol-5-yl)-phenoxy]-but-2-enyloxy}-1H-indole;
1-(2,2-Dimethyl-propyl)-4-propyl-5-{3-[4-(2H-tetrazol-5-yl)-phenoxy]-cyclopentyloxy}-1H-indole;
4-[1-(2,2-Dimethyl-propyl)-4-propyl-1H-indol-5-yloxymethyl]-benzoic acid;
4-{4-[1-(2,2-Dimethyl-propyl)-4-propyl-2H-benzotriazol-5-yloxy]-butoxy}-benzoic acid;
4-{4-[3-(2,2-Dimethyl-propyl)-4-propyl-3H-benzotriazol-5-yloxy]-butoxy}-benzoic acid;
4-{4-[2-(2,2-Dimethyl-propyl)-4-propyl-1H-benzotriazol-5-yloxy]-butoxy}-benzoic acid;
4-{4-[1-(2,2-Dimethyl-propyl)-4-propyl-1H-indol-5-yloxy]-butoxy}-benzoic acid;
3-ethyl-7-propyl-6-{4-[4-(1H-tetrazol-5-yl)phenoxy]butoxy}-1,2-benzisoxazole;
3-(2,2-dimethylpropyl)-7-propyl-6-{4-[4-(1H-tetrazol-5-yl)phenoxy]butoxy}-1,2-benzisoxazole;
3-cyclohexyl-7-propyl-6-{4-[4-(1H-tetrazol-5-yl)phenoxy]butoxy}-1,2-benzisoxazole;
1-benzyl-4-propyl-5-{4-[4-(1H-tetrazol-5-yl)phenoxy]butoxy}-1H-indole;
1-(2,2-dimethylpropanoyl)-4-propyl-5-{4-[4-(1H-tetrazol-5-yl)phenoxy]butoxy}-1H-indole;
1-(4-methylbenzyl-4-propyl-5-{4-[4-(1H-tetrazol-5-yl)phenoxy]butoxy}-1H-indole;
1-(3-methylbenzyl-4-propyl-5-{4-[4-(1H-tetrazol-5-yl)phenoxy]butoxy}-1H-indole;
1-(2-methylbenzyl-4-propyl-5-{4-[4-(1H-tetrazol-5-yl)phenoxy]butoxy}-1H-indole;
4-propyl-1-(pyridin-2-ylmethyl)-5-{4-[4-(1H-tetrazol-5-yl)phenoxy]butoxy}-1H-indole;
Of the disorders above, the treatment of migraine, anxiety, schizophrenia, and epilepsy are of particular importance. In a preferred embodiment the present invention provides a method for treating migraine, comprising: administering to a patient in need thereof an effective amount of a compound of formula I. In another preferred embodiment the present invention provides a method for preventing or treating anxiety, comprising: administering to a patient in need thereof an effective amount of a compound of formula I. Particularly preferred anxiety disorders are generalized anxiety disorder, panic disorder, and obsessive compulsive disorder. In another preferred embodiment the present invention provides a method for treating schizophrenia, comprising: administering to a patient in need thereof an effective amount of a compound of formula I. In yet another preferred embodiment the present invention provides a method for treating epilepsy, comprising: administering to a patient in need thereof an effective amount of a compound of formula I.
The benzazole headpiece of a given compound can be prepared as outlined in Scheme 1. A substituted methoxy-benzazole (either purchased commercially or prepared using techniques well known in the art) is reacted with R1X in the presence of a base (sodium hydride or the like) in a suitable solvent such as tetrahydrofuran or N, N-dimethylformamide. This reaction is generally run at ambient temperature to 70° C. for a period of 4 to 24 hours. The methyl ether can be subsequently removed by treatment with boron tribromide in a suitable solvent such as dichloromethane. This reaction is generally run at 0° C. to ambient temperature for a period of 1 to 8 hours. The product from each reaction can be isolated and purified employing standard techniques such as solvent extraction, chromatography, crystallization, distillation and the like.
Compounds where R2=allyl or propyl can be prepared from substituted hydroxy-benzazoles (either purchased commercially or prepared using techniques well known in the art; including that described above). The hydroxyl group is first allylated with allyl bromide in the presence of a base (potassium carbonate or the like) in a suitable solvent such as acetone or N,N-dimethylformamide. This reaction is generally run at ambient temperature to 70° C. for a period of 1 to 48 hours. The product is then converted to the C-allyl derivative by thermolysis in a suitable solvent such as bromobenzene or diphenyl ether. This reaction is generally run at 150° C. to 200° C. for a period of 4 to 24 hours. The C-allyl compound can then be converted to the propyl compound by exposure to hydrogen gas in the presence of a catalyst (Pd/C or the like) in a suitable solvent such as ethyl acetate or ethanol. This reaction is generally run at ambient temperature for a period of 0.5 to 6 hours. The product from each reaction can be isolated and purified employing standard techniques such as solvent extraction, chromatography, crystallization, distillation and the like.
The left-hand portion of compounds where X is a substituted phenyl group can be prepared as outlined in Scheme 2. A substituted aryl bromide (either purchased commercially or prepared using techniques well known in the art) and a substituted 3-(hydroxymethyl)-phenylboronic acid (either purchased commercially or prepared using techniques well known in the art) are coupled with a palladium catalyst (PdCl2(PPh3)2 or the like) in the presence of a base (potassium carbonate or the like) in a suitable solvent such as toluene/methanol. This reaction is generally run at 60° C. to 100° C. for a period of 4 to 24 hours. The product is then converted to the corresponding bromide by treatment with carbon tetrabromide and triphenylphosphine in a suitable solvent such as dichloromethane. This reaction is generally run at 0° C. to ambient temperature for a period of 0.5 to 4 hours. The product from each reaction can be isolated and purified employing standard techniques such as solvent extraction, chromatography, crystallization, distillation and the like.
The left-hand portion of compounds where X is a substituted phenoxy group can be prepared as outlined in Scheme 3. A substituted aryl fluoride (either purchased commercially or prepared using techniques well known in the art) and a substituted (hydroxymethyl)phenol (either purchased commercially or prepared using techniques well known in the art; including borane reduction of the corresponding acid) are coupled in the presence of a base (potassium carbonate or the like) in a suitable solvent such as N, N-dimethylformamide. This reaction is generally run at 100° C. to 160° C. for a period of 3 to 12 hours. The product is then converted to the corresponding bromide by treatment with carbon tetrabromide and triphenylphosphine in a suitable solvent such as dichloromethane. This reaction is generally run at 0° C. to ambient temperature for a period of 0.5 to 4 hours. The product from each reaction can be isolated and purified employing standard techniques such as solvent extraction, chromatography, crystallization, distillation and the like.
An appropriately substituted benzazole compound where A=phenyl can be prepared as outlined in Scheme 4. A substituted benzazole headpiece (prepared as in Scheme 1) is alkylated with variously substituted aryl compounds. These aryl compounds contain alkyl, cycloalkyl, alkenyl, benzyl, and heterocycloalkyl linkers with a suitable leaving group (halide, mesylate, or the like) and are reacted in the presence of a base (potassium carbonate or the like) in a suitable solvent such as tetrahydrofuran or N,N-dimethylformamide. This reaction is generally run at ambient temperature to 70° C. for a period of 4 to 24 hours. The product of the reaction can be further alkylated with R1X as described for Scheme 1. The product from each reaction can be isolated and purified employing standard techniques such as solvent extraction, chromatography, crystallization, distillation and the like.
An appropriately substituted benzazole compound where A=pyridyl can be prepared as outlined in Scheme 5. A substituted benzazole headpiece (prepared as in Scheme 1) is alkylated with a substituted iodobenzyl bromide in the presence of a base (potassium carbonate or the like) in a suitable solvent (tetrahydrofuran, N,N-dimethylformamide, or the like). This reaction is generally run at ambient temperature to 40° C. for a period of 1 to 8 hours. Subsequently, the aryl iodide is converted to the aryltrialkyltin species. This reaction is carried out with a palladium catalyst (Pd(PPh3)4 or the like) in the presence of hexamethylditin or the like in a suitable solvent such as tetrahydrofuran and is generally run at 40° C. to 100° C. for a period of 4 to 24 hours. Next, the aryltrialkyltin and a substituted bromopyridine (either purchased commercially or prepared using techniques well known in the art) are coupled with a palladium catalyst (Pd(PPh3)4 or the like) in a suitable solvent such as toluene. This reaction is generally run at 80° C. to 120° C. for a period of 8 to 48 hours. The product from each reaction can be isolated and purified employing standard techniques such as solvent extraction, chromatography, crystallization, distillation and the like.
The benzazole compounds where W=CN or CO2R can be converted into tetrazoles or acids, respectively as shown in Scheme 6. The nitrile compounds are reacted with trimethylsilyl azide in the presence of a catalyst such as dibutyltin oxide in a suitable solvent (benzene, toluene, or the like). This reaction is generally run at 80° C. to 110° C. for a period of 8 to 24 hours. The ester compounds are hydrolyzed in the presence of a suitable base (lithium hydroxide or the like) in a solvent such as tetrahydrofuran/water, tetrahydrofuran/methanol/water, or ethanol/water. This reaction is generally run at ambient temperature to 70° C. for a period of 4 to 24 hours. The product from each reaction can be isolated and purified employing standard techniques such as solvent extraction, chromatography, crystallization, distillation and the like.
1-(2,2-dimethylpropyl)-4-propyl-5-{4-[4-(1H-tetrazol-5-yl)phenoxy]butoxy}-1H-indole
5-(Allyloxy)-1H-indole (8.0 g, 46 mmol) was added in 1 g portions to a mixture of NaH (3.5 g, 60 wt %, 88 mmol) and DMF (80 ml) at 0° C. under N2. The reaction was allowed to warm to rt and then 1-Iodo-2,2-dimethylpropane (20 mL, 0.15 mol) was added. After stirring for 15 h, the mixture was heated at 70° C. for 8 h and then allowed to cool to rt. The reaction mixture was concentrated, diluted with water (200 mL), and extracted with ethyl acetate (100 mL×2). The combined organic extracts were dried (MgSO4), filtered, and concentrated to give clear oil. MS (ESI): 244.1 (M+H). A solution of the above indole and diphenyl ether (40 mL) was heated at 190° C. for 4 h under N2 and then allowed to cool to rt. The resulting solution was purified by silica gel chromatography (hexanes:ethyl acetate—1:0→2:1) to give an off-white solid. MS (ESI): 244.1 (M+H). The above indole, Pd/C (1.8 g, 10 wt %, 1.7 mmol Pd), and ethyl acetate (50 mL) were stirred vigorously under an atmosphere of H2 for 3 h. The reaction mixture was filtered through Celite with ethyl acetate (100 mL) and concentrated to give 1-(2,2-dimethylpropyl)-4-propyl-1H-indol-5-ol. MS (ESI): 246.0 (M+H). A mixture of the above indole (3.0 g, 12.2 mmol), 4-(4-bromobutoxy)benzonitrile (3.4 g, 13.4 mmol), K2CO3 (4 g, 29 mmol), and DMF (15 mL) was heated at 90° C. under N2-acetone can be used in place of DMF, but longer reaction times are required. After 22 h, a second aliquot of both 4-(4-bromobutoxy)benzonitrile and K2CO3 were added. After an additional 10 h, a third aliquot of both 4-(4-bromobutoxy)benzonitrile and K2CO3 were added. After an additional 12 h, the reaction was allowed to cool to rt. The resulting mixture was filtered through Celite with chloroform (100 mL), concentrated, and purified by silica gel chromatography (hexanes:ethyl acetate—1:0→3:2) to give a light brown solid. MS (ESI): 419.2 (M+H). A solution of the above indole (3.0 g, 7.2 mmol), trimethylsilylazide (10 mL, 75 mmol), dibutyltin oxide (360 mg, 1.5 mmol), and toluene (30 mL) was heated at reflux for 14 h under N2 and then allowed to cool to rt. The reaction mixture was poured onto silica, washed with hexanes (300 mL), and then eluted with CH3OH:CHCl3 (1:4; 500 mL). The collected eluent was concentrated and purified by silica gel chromatography (hexanes:ethyl acetate—7:3→0:1) or reverse-phase HPLC to give a white solid. 1H NMR (500 MHz, DMSO) δ 7.97 (d, 2H), 7.24 (d, 1H), 7.21 (d, 1H), 7.19 (d, 2H), 6.88 (d, 1H), 6.37 (d, 1H), 4.16 (t, 2H), 4.02 (t, 2H), 3.90 (s, 2H), 2.77 (t, 2H), 2.00-1.88 (m, 4H), 1.61-1.55 (m, 2H), 0.92 (s, 9H), 0.90 (t, 3H). MS (ESI): 462.1 (M+H).
2,2-dimethyl-1-(7-propyl-6-{4-[4-(1H-tetrazol-5-yl)phenoxy]butoxy}-1H-indol-3-yl)propan-1-one
A mixture of 1H-indol-6-ol (2.0 g, 15 mmol), 3-bromoprop-1-ene (1.5 mL, 17 nmol), K2CO3 (6.3 g, 46 mmol), and acetone (20 mL) was heated at reflux for 16 h under N2 and then allowed to cool to rt. The resulting mixture was filtered through Celite with CHCl3 (100 mL) and concentrated to give a yellow oil. MS (ESI): 173.9 (M+H). A solution of the above indole and bromobenzene (15 mL) was heated at reflux for 22 h under N2 and then allowed to cool to rt. The resulting solution was purified by silica gel chromatography (hexanes:ethyl acetate—1:0→2:3) to give an off-white solid. The above indole (1.4 g, 8.2 mmol), Pd/C (85 mg, 10 wt %, 80 μmol Pd), and ethyl acetate (20 mL) were stirred vigorously under an atmosphere of H2 for 30 min. The reaction mixture was filtered through Celite with ethyl acetate (100 mL) and concentrated to give a yellow oil. MS (ESI): 176.0 (M+H). The above indole was allylated with 4-(4-bromobutoxy)benzonitrile as outlined in example 1. MS (ESI): 349.2 (M+H). Diethylaluminum chloride (1.5 mL, 1 M in hexanes, 1.5 mmol) was added to a solution of the above indole (0.35 g, 1.0 mmol) and CH2Cl2 (10 mL) at 0° C. under N2. After 30 min, 2,2-dimethylpropanoyl chloride (0.19 mL, 1.5 mmol) was added. The reaction was maintained for 6 h, quenched with pH 7 buffer (10 mL), and extracted with CHCl3 (20 mL×3). The organic extracts were dried (MgSO4), filtered, and concentrated to give a yellow oil. MS (ESI): 433.2 (M+H). The tetrazole-forming reaction was conducted as outlined in example 1 to give a white solid. 1H NMR (500 MHz, DMSO) δ 11.61 (s, 1H), 8.17 (d, 1H), 8.05 (d, 1H), 7.97 (d, 2H), 7.17 (d, 2H), 6.93 (d, 1H), 4.16 (t, 2H), 4.07 (t, 2H), 2.81 (t, 2H), 1.98-1.89 (m, 4H), 1.59-1.51 (m, 2H), 1.34 (s, 9H), 0.90 (t, 3H). MS (ESI): 476 (M+H).
1-(2,2-dimethylpropyl)-4-propyl-5-{4-[4-(1H-tetrazol-5-yl)phenoxy]butoxy}-1H-indazole
Similar procedures as outlined in examples 1 & 2 were followed using 1H-indazol-5-ol. 1H NMR (500 MHz, DMSO) δ 8.01 (s, 1H), 7.97 (d, 2H), 7.45 (d, 1H), 7.22-7.13 (m, 3H), 4.16 (t, 2H), 4.13 (s, 2H), 4.07 (t, 2H), 2.83 (t, 2H), 2.00-1.87 (m, 4H), 1.66-1.58 (m, 2H), 0.93 (s, 9H), 0.90 (t, 3H). MS (ESI): 463.3 (M+H).
2-(2,2-dimethylpropyl)-4-propyl-5-{4-[4-(1H-tetrazol-5-yl)phenoxy]butoxy}-2H-indazole
Isolated from the reaction sequence of example 3. 1H NMR (500 MHz, DMSO) δ 8.22 (s, 1H), 7.96 (d, 2H), 7.43 (d, 1H), 7.18-7.10 (m, 3H), 4.18-4.12 (m, 5H), 4.04 (t, 2H), 2.76 (t, 2H), 1.98-1.85 (m, 4H), 1.64-1.57 (m, 2H), 0.93 (s, 9H), 0.89 (t, 3H). MS (ESI): 463.3 (M+H).
1-(2,2-dimethylpropyl)-4-propyl-5-[4-(pyridin-3-yloxy)butoxy]-1H-indole
A mixture of 1-(2,2-dimethylpropyl)-4-propyl-1H-indol-5-ol (107 mg, 0.44 mmol), 1,4-dibromobutane (1.5 mL, 12.6 mmol), K2CO3 (0.7 g, 5 mmol), and acetone (10 mL) was heated at reflux for 37 h under N2 and then allowed to cool to rt. The resulting mixture was filtered through Celite with chloroform (100 mL) and concentrated to give a yellow oil. MS (ESI): 380.1 (M+H).
A mixture of the above bromide, pyridine-3-ol (66 mg, 0.69 mmol), K2CO3 (200 mg, 1.5 mmol), and acetone (10 mL) was heated at reflux for 23 h under N2 and then allowed to cool to rt. The resulting mixture was filtered through Celite with chloroform (100 mL), concentrated, and purified by reverse-phase HPLC. 1H NMR (500 MHz, DMSO) δ 8.48 (s, 1H), 8.32 (d, 1H), 7.74 (d, 1H), 7.62-7.57 (m, 1H), 7.25 (d, 1H), 7.21 (d, 1H), 6.87 (d, 1H), 6.37 (d, 1H), 4.21 (t, 2H), 4.01 (t, 2H), 3.90 (s, 2H), 2.76 (t, 2H), 2.00-1.86 (m, 4H), 1.62-1.53 (m, 2H), 0.92 (s, 9H), 0.89 (t, 3H). MS (ESI): 395.3 (M+H).
1-(2,2-dimethylpropyl)-4-propyl-5-{4-[4-(1H-tetrazol-5-yl)phenoxy]butoxy}-1H-1,2,3-benzotriazole
5-methoxy-1H-1,2,3-benzotriazole (4.0 g, 27 mmol) was added in 1 g portions to a mixture of NaH (2.2 g, 60 wt %, 55 mmol) and DMF (50 mL) at rt under N2. After 15 min, 1-iodo-2,2-dimethylpropane (15 mL, 0.11 mol) was added. The mixture was heated at 60° C. for 28 h, allowed to cool to rt, concentrated, and purified by silica gel chromatography (CHCl3: CH3OH—1:0→19:1) to give a brown oil—a mixture of all three N-alkylated isomers. MS (ESI): 220.2 (M+H).
Boron tribromide (2.5 mL, 38 mmol) was added over 2 min to a solution of the above mixture and CH2Cl2 (60 mL) at 0° C. under N2. After 8 h at 0° C., 1 N HCl (20 mL) was added slowly (internal temperature less than 30° C.). The mixture was stirred for 1 h and then concentrated to give a brown oil. MS (ESI): 206.3 (M+H).
Similar procedures as outlined in examples 1 & 2 were followed using the above mixture. 1H NMR (500 MHz, DMSO) δ 7.97 (d, 2H), 7.67 (d, 1H), 7.38 (d, 1H), 7.17 (d, 2H), 4.45 (s, 2H), 4.17 (t, 2H), 4.14 (t, 2H), 3.02 (t, 2H), 2.00-1.90 (m, 4H), 1.74-1.67 (m, 2H), 0.96 (s, 9H), 0.91 (t, 3H). MS (ESI): 464.3 (M+H).
1-(2,2-dimethylpropyl)-7-propyl-6-{4-[4-(1H-tetrazol-5-yl)phenoxy]butoxy}-1H-1,2,3-benzotriazole
Isolated from the reaction sequence of example 6. 1H NMR (500 MHz, DMSO) δ 7.97 (d, 2H), 7.86 (d, 1H), 7.35 (d, 1H), 7.17 (d, 2H), 4.48 (s, 2H), 4.21-4.15 (m, 4H), 2.96 (t, 2H), 1.99-1.93 (m, 4H), 1.55-1.48 (m, 2H), 0.95 (s, 9H), 0.93 (t, 3H). MS (ESI): 464.3 (M+H).
1-(2,2-dimethylpropyl)-4-propyl-5-{4-[4-(1H-tetrazol-5-yl)phenoxy]butoxy}-1H-benzimidazole
A similar reaction sequence as outlined in example 6 was followed using 5-methoxy-1H-benzimidazole. 1H NMR (500 MHz, DMSO) δ 8.05 (s, 1H), 7.97 (d, 2H), 7.36 (d, 1H), 7.17 (d, 2H), 7.00 (d, 1H), 4.17 (t, 2H), 4.06 (t, 2H), 3.99 (s, 2H), 2.90 (t, 2H), 2.00-1.89 (m, 4H), 1.67-1.59 (m, 2H), 0.93 (s, 9H), 0.89 (t, 3H). MS (ESI): 463 (M+H).
1-(2,2-dimethylpropyl)-7-propyl-6-{4-[4-(1H-tetrazol-5-yl)phenoxy]butoxy}-1H-benzimidazole
Isolated from the reaction sequence of example 8. 1H NMR (500 MHz, DMSO) δ 7.99 (s, 1H), 7.97 (d, 2H), 7.43 (d, 1H), 7.17 (d, 2H), 6.97 (d, 1H), 4.17 (t, 2H), 4.10 (s, 2H), 4.07 (t, 2H), 2.95 (t, 2H), 1.98-1.90 (m, 4H), 1.50-1.43 (m, 2H), 0.92 (t, 3H), 0.90 (s, 9H). MS (ESI): 463 (M+H).
1-(2,2-dimethylpropyl)-4-propyl-5-{4-[4-(1H-tetrazol-5-yl)phenoxy]butoxy}indoline
Sodium cyanoborohydride (0.50 g, 8.0 mmol) was added in four portions to a solution of 1-(2,2-dimethylpropyl)-4-propyl-1H-indol-5-ol (0.62 g, 2.5 mmol) and acetic acid (15 mL) at rt. After 45 min, water (4 mL) was added. The mixture was stirred for 15 min, concentrated, and then azeotroped with toluene (25 mL). The residue was filtered through basic alumina with ethyl acetate (150 mL) and concentrated to give a colorless foam. MS (ESI): 248.3 (M+H). Similar procedures as outlined in examples 1 were followed using the above indoline. 1H NMR (500 MHz, DMSO) δ 7.97 (d, 2H), 7.16 (d, 2H), 6.59 (d, 1H), 6.21 (d, 1H), 4.14 (t, 2H), 3.89 (t, 2H), 3.36 (t, 2H), 2.85 (t, 2H), 2.69 (s, 2H), 2.44 (t, 2H), 1.95-1.82 (m, 4H), 1.51-1.46 (m, 2H), 0.94 (s, 9H), 0.87 (t, 3H). MS (ESI): 464.3 (M+H).
4-bromo-1-(2,2-dimethylpropyl)-5-{4-[4-(1H-tetrazol-5-yl)phenoxy]butoxy}-1H-indole
Boron tribromide (0.5 mL, 5.3 mmol) was added slowly (internal temperature maintained below −50° C.) to a solution of 4-bromo-5-methoxy-1H-indole (1.0 g, 4.4 mmol) and CH2Cl2 (20 mL) under N2. The reaction was allowed to warm to rt, and after 30 min at rt, a second aliquot of boron tribromide (1.0 mL, 11 mmol) was added. After an additional 2 h, the reaction was cooled to 0° C. and 1 N HCl (35 mL) was added slowly (internal temperature maintained below 30° C.). The mixture was stirred for 30 min and extracted with ethyl acetate (100 mL×3). The organic extracts were dried (MgSO4), filtered, concentrated, and purified by silica gel chromatography (hexanes:ethyl acetate—9:1→3:2) to give a slightly red solid. MS (ESI): 212/214 (M+H). Similar procedures as outlined in example 1 were followed using the above indole. 1H NMR (500 MHz, DMSO) δ 7.96 (d, 2H), 7.50 (d, 1H), 7.38 (d, 1H), 7.14 (d, 2H), 7.01 (d, 1H), 6.33 (d, 1H), 4.16 (t, 2H), 4.12 (t, 2H), 3.97 (s, 2H), 2.02-1.88 (m, 4H), 0.92 (s, 9H). MS (ESI): 498/500 (M+H).
1-(2,2-dimethylpropyl)-5-{4-[4-(1H-tetrazol-5-yl)phenoxy]butoxy}-1H-indole
Similar procedures as outlined in example 1 were followed using 1H-indol-5-ol. 1H NMR (500 MHz, DMSO) δ 7.97 (d, 2H), 7.38 (d, 1H), 7.22 (d, 1H), 7.17 (d, 2H), 7.04 (d, 1H), 6.76 (dd, 1H), 6.32 (d, 1H), 4.15 (t, 2H), 4.03 (t, 2H), 3.92 (s, 2H), 1.96-1.86 (m, 4H), 0.91 (s, 9H). MS (ESI): 420 (M+H).
1-(2,2-dimethylpropyl)-4-propyl-5-{[4-(1H-tetrazol-5-yl)benzyl]oxy}-1H-indole
Similar procedures as outlined in example 1 were followed using 1-(2,2-dimethylpropyl)-4-propyl-1H-indol-5-ol and 4-(bromomethyl)benzonitrile. 1H NMR (500 MHz, DMSO) δ 8.07 (d, 2H), 7.70 (d, 2H), 7.28 (d, 1H), 7.24 (d, 1H), 6.97 (d, 1H), 6.41 (dd, 1H), 5.18 (s, 2H), 3.91 (s, 2H), 2.84 (t, 2H), 1.67-1.59 (m, 2H), 0.93 (s, 9H), 0.93 (t, 3H). MS (ESI): 404.1 (M+H).
1-(2,2-dimethylpropyl)-4-propyl-5-{[3-(1H-tetrazol-5-yl)benzyl]oxy}-1H-indole
Similar procedures as outlined in example 1 were followed using 1-(2,2-dimethylpropyl)-4-propyl-1H-indol-5-ol and 3-(bromomethyl)benzonitrile. 1H NMR (500 MHz, DMSO) δ 8.22 (s, 1H), 7.99 (d, 1H), 7.71-7.61 (m, 2H), 7.28 (d, 1H), 7.24 (d, 1H), 6.99 (d, 1H), 6.41 (dd, 1H), 5.19 (s, 2H), 3.91 (s, 2H), 2.85 (t, 2H), 1.66-1.58 (m, 2H), 0.93 (s, 9H), 0.93 (t, 3H). MS (ESI): 404.1 (M+H).
1-(2,2-dimethylpropyl)-4-methyl-5-{4-[4-(1H-tetrazol-5-yl)phenoxy]butoxy}-1H-indole
Similar procedures as outlined in examples 6 were followed using 5-methoxy-4-methyl-1H-indole. 1H NMR (500 MHz, DMSO) δ 7.96 (d, 2H), 7.27-7.20 (m, 2H), 7.17 (d, 2H), 6.87 (d, 1H), 6.37 (d, 1H), 4.16 (t, 2H), 4.01 (t, 2H), 3.91 (s, 2H), 2.32 (s, 3H), 1.99-1.86 (m, 4H), 0.92 (s, 9H). MS (ESI): 434.1 (M+H).
1-(2,2-dimethylpropyl)-2-methyl-4-propyl-5-{4-[4-(1H-tetrazol-5-yl)phenoxy]butoxy}-1H-indole
Similar procedures as outlined in example 6 were followed using 5-methoxy-2-methyl-1H-indole. 1H NMR (500 MHz, DMSO) δ 7.97 (d, 2H), 7.19-7.14 (m, 3H), 6.77 (d, 1H), 6.17 (s, 1H), 4.16 (t, 2H), 4.00 (t, 2H), 3.86 (s, 2H), 2.72 (t, 2H), 2.37 (s, 3H), 1.99-1.86 (m, 4H), 1.61-1.53 (m, 2H), 0.95 (s, 9H), 0.90 (t, 3H). MS (ESI): 476.2 (M+H).
ethyl 1-(2,2-dimethylpropyl)-4-propyl-5-{4-[4-(1H-tetrazol-5-yl)phenoxy]butoxy}-1H-indole-2-carboxylate
Similar procedures as outlined in example 6 were followed using ethyl 5-methoxy-1H-indole-2-carboxylate. 1H NMR (500 MHz, DMSO) δ 7.96 (d, 2H), 7.44 (d, 1H), 7.20-7.14 (m, 3H), 7.11 (d, 1H), 4.50 (br s, 2H), 4.30 (q, 2H), 4.17 (t, 2H), 4.06 (t, 2H), 2.80 (t, 2H), 1.99-1.87 (m, 4H), 1.62-1.54 (m, 2H), 1.32 (t, 3H), 0.91 (t, 3H), 0.83 (s, 9H). MS (ESI): 534.1 (M+H).
1-(2,2-dimethylpropyl)-5-{4-[4-(1H-tetrazol-5-yl)phenoxy]butoxy}-1H-1,2,3-benzotriazole and 1-(2,2-dimethylpropyl)-6-{4-[4-(1H-tetrazol-5-yl)phenoxy]butoxy}-1H-1,2,3-benzotriazole
Similar procedures as outlined in example 6 were followed using 5-methoxy-1H-1,2,3-benzotriazole. 1H NMR (500 MHz, DMSO) δ 7.97 (d, 4.6H), 7.87 (d, 1.3H), 7.78 (d, 1H), 7.45 (d, 1H), 7.35 (d, 1.3H), 7.20-7.14 (m, 5.6H), 7.01 (d, 1.3H), 4.46 (s, 2H), 4.43 (s, 2.6H), 4.20-4.12 (m, 9.2H), 2.00-1.90 (m, 9.2H), 0.97 (s, 11.7H), 0.95 (s, 9H). MS (ESI): 422.1 (M+H).
1-(2,2-dimethylpropyl)-4-propyl-5-{[3′-(1H-tetrazol-5-yl)biphenyl-3-yl]methoxy}-1H-indole
Similar procedures as outlined in example 1 were followed using 1-(2,2-dimethylpropyl)-4-propyl-1H-indol-5-ol and 3′-(bromomethyl) biphenyl-3-carbonitrile. 1H NMR (500 MHz, DMSO) δ 8.37 (s, 1H), 8.06 (d, 1H), 7.93-7.85 (m, 2H), 7.75-7.69 (m, 2H), 7.60-7.51 (m, 2H), 7.28 (d, 1H), 7.23 (d, 1H), 7.01 (d, 1H), 6.40 (d, 1H), 5.19 (s, 2H), 3.91 (s, 2H), 2.84 (t, 2H), 1.67-1.59 (m, 2H), 0.93 (s, 9H), 0.90 (t, 3H). MS (ESI): 480.1 (M+H).
1-(2,2-dimethylpropyl)-4-propyl-5-{[4′-(2H-tetrazol-5-yl)biphenyl-3-yl]methoxy}-1H-indole
Similar procedures as outlined in example 1 were followed using 1-(2,2-dimethylpropyl)-4-propyl-1H-indol-5-ol and 3′-(bromomethyl) biphenyl-4-carbonitrile. 1H NMR (500 MHz, DMSO) δ 8.15 (d, 2H), 7.93 (d, 2H), 7.87 (s, 1H), 7.72 (d, 1H), 7.57-7.51 (m, 2H), 7.28 (d, 1H), 7.23 (d, 1H), 7.01 (d, 1H), 6.40 (d, 1H), 5.18 (s, 2H), 3.91 (s, 2H), 2.84 (t, 2H), 1.67-1.59 (m, 2H), 0.93 (s, 9H), 0.93 (t, 3H). MS (ESI): 480.1 (M+H).
4-bromo-1-(2,2-dimethylpropyl)-5-{4-[4-(1H-tetrazol-5-yl)phenoxy]butoxy}-1H-1,2,3-benzotriazole
Bromine (60 μL, 1.2 mmol) was added to a solution of 1-(2,2-dimethylpropyl)-1H-1,2,3-benzotriazol-6-ol & 1-(2,2-dimethylpropyl)-1H-1,2,3-benzotriazol-5-ol (0.22 g, 1.1 mmol), prepared as a 1.3:1.0 mixture according to example 6, and acetic acid (10 mL) at rt. After 1 h, the reaction was concentrated and purified by silica gel chromatography to give 7-bromo-1-(2,2-dimethylpropyl)-1H-1,2,3-benzotriazol-6-ol and 4-bromo-1-(2,2-dimethylpropyl)-1H-1,2,3-benzotriazol-5-ol. MS (ESI): 284/286 (M+H). Similar procedures as outlined in example 1 were followed using 4-bromo-1-(2,2-dimethylpropyl)-1H-1,2,3-benzotriazol-5-ol. 1H NMR (500 MHz, DMSO) δ 7.96 (d, 2H), 7.92 (d, 1H), 7.52 (d, 1H), 7.16 (d, 2H), 4.50 (s, 2H), 4.26 (t, 2H), 4.18 (t, 2H), 2.02-1.91 (m, 4H), 0.96 (s, 9H). MS (ESI): 500/502 (M+H).
7-bromo-1-(2,2-dimethylpropyl)-6-{4-[4-(1H-tetrazol-5-yl)phenoxy]butoxy}-1H-1,2,3-benzotriazole
Similar procedures as outlined in example 1 were followed using 7-bromo-1-(2,2-dimethylpropyl)-1H-1,2,3-benzotriazol-6-ol from example 21. 1H NMR (500 MHz, DMSO) δ 8.07 (d, 1H), 7.95 (d, 2H), 7.36 (d, 1H), 7.15 (d, 2H), 4.81 (s, 2H), 4.29 (t, 2H), 4.18 (t, 2H), 2.02-1.93 (m, 4H), 0.96 (s, 9H). MS (ESI): 500/502 (M+H).
1-(2,2-dimethylpropyl)-4-propyl-5-{2-[4-(1H-tetrazol-5-yl)phenoxy]ethoxy}-1H-indole
Similar procedures as outlined in example 1 were followed using 1-(2,2-dimethylpropyl)-4-propyl-1H-indol-5-ol and 4-(2-bromoethoxy)benzonitrile. 1H NMR (500 MHz, DMSO) δ 7.99 (d, 2H), 7.28 (d, 1H), 7.25-7.19 (m, 3H), 6.94 (d, 1H), 6.38 (d, 1H), 4.40 (t, 2H), 4.32 (t, 2H), 3.91 (s, 2H), 2.76 (t, 2H), 1.61-1.53 (m, 2H), 0.93 (s, 9H), 0.87 (t, 3H). MS (ESI): 434.1 (M+H).
1-(2,2-dimethylpropyl)-4-propyl-5-{3-[4-(1H-tetrazol-5-yl)phenoxy]propoxy}-1H-indole
Similar procedures as outlined in example 1 were followed using 1-(2,2-dimethylpropyl)-4-propyl-1H-indol-5-ol and 4-(3-bromopropoxy)benzonitrile. 1H NMR (500 MHz, DMSO) δ 7.98 (d, 2H), 7.25 (d, 1H), 7.23-7.16 (m, 3H), 6.89 (d, 1H), 6.37 (d, 1H), 4.30 (t, 2H), 4.12 (t, 2H), 3.90 (s, 2H), 2.75 (t, 2H), 2.24-2.18 (m, 2H), 1.59-1.51 (m, 2H), 0.92 (s, 9H), 0.86 (t, 3H). MS (ESI): 448.1 (M+H).
1-(2,2-dimethylpropyl)-4-propyl-5-({5-[4-(1H-tetrazol-5-yl)phenoxy]pentyl}oxy)-1H-indole
Similar procedures as outlined in example 1 were followed using 1-(2,2-dimethylpropyl)-4-propyl-1H-indol-5-ol and 4-[(5-bromopentyl)oxy]benzonitrile. 1H NMR (500 MHz, DMSO) δ 7.96 (d, 2H), 7.23 (d, 1H), 7.21 (d, 1H), 7.15 (d, 2H), 6.86 (d, 1H), 6.37 (d, 1H), 4.10 (t, 2H), 3.97 (t, 2H), 3.89 (s, 2H), 2.77 (t, 2H), 1.88-1.76 (m, 4H), 1.69-1.53 (m, 4H), 0.92 (s, 9H), 0.91 (t, 3H). MS (ESI): 476.1 (M+H).
3′-({[1-(2,2-dimethylpropyl)-4-propyl-1H-indol-5-yl]oxy}methyl)biphenyl-3-carboxylic aci
A mixture of ethyl-3-bromobenzoate (3.0 g, 13 mmol), [3-(hydroxymethyl)-phenyl]boronic acid (3.0 g, 20 mmol), PdCl2(PPh3)2 (0.46 g, 0.66 mmol), K2CO3 (3.6 g, 26 mmol), methanol (4 mL), and toluene (36 mL) was heated at 80° C. for 18 h under N2 and then allowed to cool to rt. The reaction mixture was filtered through Celite and then poured into a mixture of ethyl acetate and brine. The two layers were separated and the aqueous layer was extracted with ethyl acetate (×3). The organic extracts were dried (Na2SO4), filtered, concentrated and purified by silica gel chromatography to give ethyl 3′-(hydroxymethyl)biphenyl-3-carboxylate as an orange oil. A solution of CBr4 (5.8 g, 17 mmol) and CH2Cl2 (20 mL) was added dropwise to a solution of the above alcohol, PPh3 (4.6 g, 18 mmol), and CH2Cl2 (50 mL) at 0° C. under N2. The reaction was allowed to warm to rt, maintained for 2 h, concentrated, and purified by silica gel chromatography to give ethyl 3′-(bromomethyl)biphenyl-3-carboxylate as a clear oil. Ethyl 3′-(bromomethyl)biphenyl-3-carboxylate was used to alkylate 1-(2,2-dimethylpropyl)-4-propyl-1H-indol-5-ol following the procedure outlined in example 1. A mixture of the above indole (0.66 g, 1.4 mmol), 1 N LiOH (8 mL), and THF (8 mL) was heated at 40° C. for 2 d and then cooled to 0° C.—acetone can used in place of THF if faster reaction rates are desired. The reaction was acidified to pH=1 with conc. HCl and extracted with ethyl acetate (×3). The organic extracts were dried (Na2SO4), filtered, concentrated and purified by silica gel chromatography to give a yellow oil. 1H NMR (CDCl3, 500 MHz) δ 8.39 (s, 1H), 8.11 (d, 1H), 7.85 (d, 1H), 7.76 (s, 1H), 7.59-7.48 (m, 4H), 7.12 (d, 1H), 7.05 (d, 1H), 6.96 (d, 1H), 6.46 (d, 1H), 5.16 (s, 2H), 3.84 (s, 2H), 2.95 (t, 2H), 1.76 (m, 2H), 1.01 (t, 3H), 0.99 (s, 9H). MS (ESI): 456 (M+H).
3′-({[1-(2,2-dimethylpropyl)-4-propyl-1H-indol-5-yl]oxy}methyl)biphenyl-4-carboxylic acid
A similar reaction sequence as outlined in example 26 was followed using ethyl-4-bromobenzoate. 1H NMR (500 MHz, DMSO) δ 12.84 (br s, 1H), 8.04 (d, 2H), 7.83 (s, 1H), 7.80 (d, 2H), 7.72-7.66 (m, 1H), 7.55-7.50 (m, 2H), 7.28 (d, 1H), 7.22 (d, 1H), 7.00 (d, 1H), 6.40 (d, 1H), 5.17 (s, 2H), 3.91 (s, 2H), 2.83 (t, 2H), 1.66-1.58 (m, 2H), 0.93 (s, 9H), 0.92 (t, 3H). MS (ESI): 456.1 (M+H).
1-(2,2-dimethylpropyl)-4-propyl-5-({1-[4-(2H-tetrazol-5-yl)phenyl]pyrrolidin-3-yl}methoxy)-1H-indole
A mixture of pyrrolidin-3-ylmethanol (1.0 g, 9.9 mmol), 4-fluorobenzonitrile (1.2 g, 9.9 mmol), K2CO3 (2.0 g, 14 nmol), and DMF (10 mL) was heated at 130° C. for 6 h under N2 and then allowed to cool to rt. The reaction was concentrated, diluted with water (50 mL), and extracted with ethyl acetate (100 mL×3). The organic extracts were washed with brine (100 mL), dried (MgSO4), filtered, and concentrated to give a brown oil. MS (ESI): 203.0 (M+H). Similar procedures as outlined in examples 26 & 1 were followed using the above alcohol. 1H NMR (500 MHz, DMSO) δ 7.85 (d, 2H), 7.26 (d, 1H), 7.21 (d, 1H), 6.96 (d, 1H), 6.71 (d, 2H), 6.38 (d, 1H), 4.05-3.96 (m, 2H), 3.90 (s, 2H), 3.58 (dd, 1H), 3.51-3.45 (m, 1H), 3.40 (dd, 1H), 3.29 (dd, 1H), 2.88-2.79 (m, 1H), 2.78 (t, 2H), 2.26-2.20 (m, 1H), 2.00-1.94 (m, 1H), 1.64-1.55 (m, 2H), 0.92 (s, 9H), 0.92 (t, 3H). MS (ESI): 473.1 (M+H).
1-(2,2-dimethylpropyl)-4-propyl-5-({1-[4-(2H-tetrazol-5-yl)phenyl]piperidin-3-yl}methoxy)-1H-indole
A similar reaction sequence as outlined in example 28 was followed using piperidin-3-ylmethanol. 1H NMR (500 MHz, DMSO) δ 7.86 (d, 2H), 7.26 (d, 1H), 7.22 (d, 1H), 7.10 (d, 2H), 6.87 (d, 1H), 6.39 (d, 1H), 4.03 (d, 1H), 3.96-3.84 (m, 5H), 2.93-2.79 (m, 4H), 2.14-2.06 (m, 1H), 1.95-1.87 (m, 1H), 1.83-1.75 (m, 1H), 1.68-1.55 (m, 3H), 1.47-1.37 (m, 1H), 0.97 (t, 3H), 0.92 (s, 9H). MS (ESI): 487.2 (M+H).
1-(2,2-dimethylpropyl)-4-propyl-5-({4-[4-(2H-tetrazol-5-yl)phenoxy]benzyl}oxy)-1H-indole
A similar reaction sequence as outlined in example 28 was followed using 4-(hydroxymethyl)phenol. 1H NMR (500 MHz, DMSO) δ 8.05 (d, 2H), 7.55 (d, 2H), 7.28 (d, 1H), 7.23 (d, 1H), 7.21 (d, 2H), 7.17 (d, 2H), 6.99 (d, 1H), 6.40 (d, 1H), 5.08 (s, 2H), 3.92 (s, 2H), 2.82 (t, 2H), 1.65-1.56 (m, 2H), 0.93 (s, 9H), 0.92 (t, 3H). MS (ESI): 496.1 (M+H).
4-allyl-1-(2,2-dimethylpropyl)-5-({3-[4-(1H-tetrazol-5-yl)phenoxy]benzyl}oxy)-1H-indole
A similar reaction sequence as outlined in example 28 was followed using 3-(hydroxymethyl)phenol and 4-allyl-1-(2,2-dimethylpropyl)-1H-indol-5-ol, an intermediate from example 1. 1H NMR (CDCl3, 500 MHz) δ 7.97 (d, 2H), 7.43 (t, 1H), 7.30 (d, 1H), 7.20 (br s, 1H), 7.16 (d, 1H), 7.10 (s, 1H), 7.08 (d, 2H), 7.04-7.06 (m, 1H), 6.93 (d, 1H), 6.5 (br s, 1H), 5.90-6.03 (m, 1H), 5.10 (s, 2H), 5.05 (d, 1H), 4.95 (d, 1H), 3.90 (d, 2H), 3.68 (d, 2H), 1.00 (s, 9H).
1-(2,2-dimethylpropyl)-4-propyl-5-({3-[4-(1H-tetrazol-5-yl)phenoxy]benzyl}oxy)-1H-indole
The hydrogenation procedure of example 1 was followed using 4-allyl-1-(2,2-dimethylpropyl)-5-({3-[4-(1H-tetrazol-5-yl)phenoxy]benzyl}oxy)-1H-indole from example 31. MS (ESI): 496.4 (M+H).
5-({2-chloro-5-[4-(1H-tetrazol-5-yl)phenoxy]benzyl}oxy)-1-(2,2-dimethylpropyl)-4-propyl-1H-indole
2-Chloro-5-hydroxybenzoic acid (3.0 g, 17 mmol) was added in three portions to a solution of BH3 (50 mL, 1 M in THF, 50 mmol) at 0° C. under N2. After 3 h, 1 N HCl (50 mL) was added slowly (caution: exothermic). The mixture was stirred for 30 min and extracted with ethyl acetate (150 mL×2). The organic extracts were washed with brine (100 mL), dried (MgSO4), filtered, and concentrated to give a clear oil. MS (ESI): 141/143 (M−OH). A similar reaction sequence as outlined in example 28 was followed using the above alcohol. 1H NMR (500 MHz, DMSO) δ 8.03 (d, 2H), 7.58 (d, 1H), 7.33 (d, 1H), 7.27 (d, 1H), 7.24-7.20 (m, 3H), 7.17 (d, 1H), 6.95 (d, 1H), 6.36 (d, 1H), 5.12 (s, 2H), 3.90 (s, 2H), 2.70 (t, 2H), 1.51-1.41 (m, 2H), 0.91 (s, 9H), 0.74 (t, 3H). MS (ESI): 531/533 (M+H).
1-(2,2-dimethylpropyl)-5-({2-ethyl-5-[4-(1H-tetrazol-5-yl)phenoxy]benzyl}oxy)-4-propyl-1H-indole
A similar reaction sequence as outlined in example 33 was followed using 2-ethyl-5-hydroxybenzoic acid. 1H NMR (500 MHz, DMSO) δ 8.01 (d, 2H), 7.34 (d, 1H), 7.26 (d, 1H), 7.24 (d, 1H), 7.21 (d, 1H), 7.15 (d, 2H), 7.07 (d, 1H), 6.99 (d, 1H), 6.36 (d, 1H), 5.10 (s, 2H), 3.90 (s, 2H), 2.77-2.67 (m, 4H), 1.53-1.43 (m, 2H), 1.24 (t, 3H), 0.91 (s, 9H), 0.77 (t, 3H). MS (ESI): 524.1 (M+H).
1-(2,2-dimethylpropyl)-5-({2-fluoro-5-[4-(1H-tetrazol-5-yl)phenoxy]benzyl}oxy)-4-propyl-1H-indole
4-Fluoro-3-methylphenol and 4-fluorobenzonitrile were coupled following the procedure outlined in example 28 to give 4-(4-fluoro-3-methylphenoxy)benzonitrile. A mixture of 4-(4-fluoro-3-methylphenoxy)benzonitrile (1.1 g, 4.8 mmol), N-bromosuccinimide (NBS, 1.0 g, 5.6 mmol), dibenzoyl peroxide (90 mg, 0.37 mmol), and CCl4 (20 mL) was heated at reflux under N2. After 1 h, a second aliquot of dibenzoyl peroxide was added. After an additional 3 h, a second aliquot of NBS and a third aliquot of dibenzoyl peroxide were added. After an additional 4 h, a fourth aliquot of dibenzoyl peroxide was added. After an additional 15 h, the reaction was allowed to cool to rt and purified by silica gel chromatography (hexanes:ethyl acetate—1:0→4:1) to give an off-white solid. MS (ESI): 306/308 (M+H). A similar reaction sequence as outlined in example 1 was followed using the above bromide and 1-(2,2-dimethylpropyl)-4-propyl-1H-indol-5-ol. 1H NMR (500 MHz, DMSO) δ 8.01 (d, 2H), 7.33 (t, 1H), 7.30-7.24 (m, 2H), 7.21 (d, 1H), 7.21-7.13 (m, 3H), 6.98 (d, 1H), 6.37 (d, 1H), 5.12 (s, 2H), 3.90 (s, 2H), 2.71 (t, 2H), 1.53-1.43 (m, 2H), 0.91 (s, 9H), 0.78 (t, 3H). MS (ESI): 514.2 (M+H).
4-[3-({[1-(2,2-dimethylpropyl)-4-propyl-1H-indol-5-yl]oxy}methyl)pyrrolidin-1-yl]benzoic acid
Ethyl 4-fluorobenzoate and pyrrolidin-3-ylmethanol were coupled following the procedure outlined in example 28 to give ethyl 4-[3-(hydroxymethyl)pyrrolidin-1-yl]benzoate. MS (ESI): 250.0 (M+H). A similar reaction sequence as outlined in example 26 was followed using the above alcohol. 1H NMR (500 MHz, DMSO) δ 12.03 (br s, 1H), 7.76 (d, 2H), 7.25 (d, 1H), 7.21 (d, 1H), 6.89 (d, 1H), 6.56 (d, 2H), 6.38 (d, 1H), 4.05-3.95 (m, 2H), 3.90 (s, 2H), 3.56 (dd, 1H), 3.49-3.42 (m, 1H), 3.38 (dd, 1H), 3.27 (dd, 1H), 2.86-2.78 (m, 1H), 2.77 (t, 2H), 2.26-2.17 (m, 1H), 2.00-1.92 (m, 1H), 1.64-1.53 (m, 2H), 0.92 (s, 9H), 0.91 (t, 3H). MS (ESI): 449.1 (M+H).
6-[3-({[1-(2,2-dimethylpropyl)-4-propyl-1H-indol-5-yl]oxy}methyl)phenyl]pyridine-2-carboxylic acid
1-(Bromomethyl)-3-iodobenzene was used to alkylate 1-(2,2-dimethyl-propyl)-4-propyl-1H-indol-5-ol following the procedure outlined in example 1. A mixture of the above indole (3.4 g, 7.3 mmol), hexamethyldistannane (5.0 g, 15 mmol), Pd(PPh3)4 (0.80 g, 0.69 mmol), and THF (40 mL) was heated at 60° C. for 18 h under N2 and then allowed to cool to rt. The reaction mixture was diluted with water and extracted with ethyl acetate (×3). The organic extracts were dried (Na2SO4), filtered, concentrated, and purified by silica gel chromatography to give 1-(2,2-dimethylpropyl)-4-propyl-5-{[3-(trimethylstannyl)-benzyl]oxy}-1H-indole as a yellow oil. A mixture of the above stannane (0.35 g, 0.70 mmol), methyl 6-bromopyridine-2-carboxylate (0.22 g, 1.0 mmol), Pd(PPh3)4 (0.10 g, 87 μmol), and degassed toluene (10 mL) was heated at 110° C. for 24 h under N2 and then allowed to cool to rt. The reaction mixture was purified by silica gel chromatography (hexanes:ethyl acetate—1:0→2:1) to give a yellow oil. MS (ESI): 471.1 (M+H). A similar procedure as outlined in example 26 was followed for the saponification of the above ester. 1H NMR (DMSO, 500 MHz) 13.18 (br s, 1H), 8.31 (s, 1H), 8.19 (d, 1H), 8.12 (d, 1H), 8.09 (t, 1H), 8.01 (d, 1H), 7.61-7.53 (m, 2H), 7.28 (d, 1H), 7.23 (d, 1H), 7.00 (d, 1H), 6.40 (d, 1H), 5.19 (s, 2H), 3.91 (s, 2H), 2.84 (t, 2H), 1.68-1.58 (m, 2H), 0.93 (s, 9H), 0.91 (t, 3H). MS (ESI): 457.1 (M+H).
5-[3-({[1-(2,2-dimethylpropyl)-4-propyl-1H-indol-5-yl]oxy}methyl)phenyl]nicotinic acid
A similar reaction sequence as outlined in example 37 was followed using methyl 5-bromonicotinate. 1H NMR (DMSO, 500 MHz) 13.56 (br s, 1H), 9.12 (s, 1H), 9.07 (s, 1H), 8.49 (t, 1H), 7.89 (s, 1H), 7.80-7.72 (m, 1H), 7.59-7.55 (m, 2H), 7.28 (d, 1H), 7.23 (d, 1H), 7.00 (d, 1H), 6.40 (d, 1H), 5.19 (s, 2H), 3.91 (s, 2H), 2.84 (t, 2H), 1.68-1.58 (m, 2H), 0.93 (s, 9H), 0.92 (t, 3H). MS (ESI): 457.1 (M+H).
5-[3-({[1-(2,2-dimethylpropyl)-4-propyl-1H-indol-5-yl]oxy}methyl)phenyl]pyridine-2-carboxylic acid
A similar reaction sequence as outlined in example 37 was followed using methyl 5-bromopyridine-2-carboxylate. 1H NMR (DMSO, 500 MHz) 13.23 (br s, 1H), 9.02 (s, 1H), 8.26 (d, 1H), 8.13 (d, 1H), 7.90 (s, 1H), 7.80-7.73 (m, 1H), 7.65-7.56 (m, 2H), 7.28 (d, 1H), 7.23 (d, 1H), 7.00 (d, 1H), 6.40 (d, 1H), 5.18 (s, 2H), 3.91 (s, 2H), 2.84 (t, 2H), 1.68-1.58 (m, 2H), 0.93 (s, 9H), 0.92 (t, 3H). MS (ESI): 457.1 (M+H).
1-(2,2-dimethylpropyl)-4-propyl-5-({3-[5-(1H-tetrazol-5-yl)pyridin-3-yl]benzyl}oxy)-1H-indole
A similar coupling as outlined in example 37 was followed using 5-bromonicotinonitrile. Subsequently, the tetrazole-forming reaction was conducted as outlined in example 1. 1H NMR (DMSO, 500 MHz) 9.23 (s, 1H), 9.11 (s, 1H), 8.69 (t, 1H), 7.95 (s, 1H), 7.82-7.78 (m, 1H), 7.63-7.58 (m, 2H), 7.28 (d, 1H), 7.23 (d, 1H), 7.01 (d, 1H), 6.40 (d, 1H), 5.20 (s, 2H), 3.91 (s, 2H), 2.85 (t, 2H), 1.68-1.58 (m, 2H), 0.93 (s, 9H), 0.91 (t, 3H). MS (ESI): 481.1 (M+H).
1-(2,2-dimethylpropyl)-4-propyl-5-({3-[6-(2H-tetrazol-5-yl)pyridin-3-yl]benzyl}oxy)-1H-indole
A similar coupling as outlined in example 37 was followed using 5-bromopyridine-2-carbonitrile. Subsequently, the tetrazole-forming reaction was conducted as outlined in example 1. 1H NMR (DMSO, 500 MHz) δ 9.13 (s, 1H), 8.38 (d, 1H), 8.32 (d, 1H), 7.94 (s, 1H), 7.83-7.79 (m, 1H), 7.62-7.57 (m, 2H), 7.29 (d, 1H), 7.23 (d, 1H), 7.01 (d, 1H), 6.40 (d, 1H), 5.20 (s, 2H), 3.91 (s, 2H), 2.85 (t, 2H), 1.68-1.58 (m, 2H), 0.93 (s, 9H), 0.92 (t, 3H). MS (ESI): 481.1 (M+H).
1-Cyclohexylmethyl-4-propyl-5-{4-[4-(2H-tetrazol-5-yl)-phenoxy]-butoxy}-1H-indole
A mixture of K2CO3 (5.1 g, 37 mmol), 4-(4-bromobutoxy)benzonitrile (2.3 g, 11 mmol), 4-propyl-1H-indol-5-ol (3.5 g, 14 mmol), and acetone (53 mL) was heated at 50° C. for 48 h and then allowed to cool to rt. The resulting mixture was filtered through Celite with acetone (75 mL), concentrated, and purified by silica gel chromatography (CH2Cl2:CH3OH—19:1→9:1) to give a pale yellow solid. 1H NMR (500 MHz, CDCl3) δ 8.00 (s, 1H), 7.56 (d, 2H), 7.18 (m, 2H), 6.94 (d, 2H), 6.88 (d, 1H), 6.51 (d, 1H), 4.10 (t, 2H), 4.05 (t, 2H), 2.87 (t, 2H), 2.05 (m, 2H), 1.98 (m, 2H), 1.68 (m, 2H), 0.97 (t, 3H). MS (ESI): 349 (M+H). Sodium hydride (0.22 g, 95 wt %, 0.92 mmol) was added to a solution of the above indole (0.160 g 0.460 mmol) and DMF (1 mL) at 0° C. The reaction was allowed to warm to rt, stirred for 20 min, and then (bromomethyl)cyclohexane (0.162 g, 0.920 mmol) was added. After 3 h, the mixture was poured into water (10 mL) and extracted with CH2Cl2 (40 mL). The organic extract was washed with water (10 mL×5) and then brine (10 mL), dried (MgSO4), filtered, and concentrated to give a yellow solid. MS (ESI): 445 (M+H). The tetrazole-forming reaction was conducted as outlined in example 1. 1H NMR (500 MHz, DMSO) δ 7.97 (d, 2H), 7.23 (d, 1H), 7.20 (d, 1H), 7.16 (d, 2H), 6.92 (d, 1H), 6.33 (d, 1H), 4.15 (t, 2H), 4.01 (t, 2H), 3.92 (d, 2H), 2.76 (t, 2H), 1.95 (m, 2H), 1.92 (m, 2H), 1.75 (m, 1H), 1.64 (m, 2H), 1.58 (m, 2H), 1.49 (d, 2H), 1.11 (m, 3H), 0.96 (m, 3H), 0.91 (t, 3H). MS (ESI): 488 (M+H).
(4-Propyl-5-{4-[4-(2H-tetrazol-5-yl)-phenoxy]-butoxy}-indol-1-yl)-acetic acid tert-butyl ester
A similar procedure as outlined in example 42 was followed using tert-butyl bromoacetate. 1H NMR (500 MHz, DMSO) δ 7.97 (d, 2H), 7.23 (d, 1H), 7.16 (d, 2H), 7.07 (d, 1H), 6.89 (d, 1H), 6.37 (d, 1H), 4.92 (s, 2H), 4.15 (t, 2H), 4.01 (t, 2H), 2.77 (t, 2H), 1.94 (m, 2H), 1.89 (m, 2H), 1.59 (m, 2H), 1.41 (s, 9H), 1.49 (t, 3H). MS (ESI): 507 (M+H).
4-Propyl-1-(tetrahydro-pyran-2-ylmethyl)-5-{4-[4-(2H-tetrazol-5-yl)-phenoxy]-butoxy}-1H-indole
A similar procedure as outlined in example 42 was followed using 2-(bromomethyl)tetrahydro-2H-pyran. 1H NMR (500 MHz, DMSO) δ 7.97 (d, 2H), 7.22 (m, 2H), 7.22 (d, 2H), 6.88 (d, 1H), 6.32 (d, 1H), 4.15 (t, 2H), 4.09 (t, 2H), 4.01 (t, 2H), 3.82 (d, 1H), 3.57 (m, 1H), 3.25 (m, 1H), 2.76 (t, 2H), 1.94 (m, 2H), 1.89 (m, 2H), 1.57 (m, 3H), 1.42 (m, 3H), 1.16 (m, 1H), 0.89 (t, 3H). MS (ESI): 490 (M+H).
1-Naphthalen-2-ylmethyl-4-propyl-5-{4-[4-(2H-tetrazol-5-yl)-phenoxy]-butoxy}-1H-indole
A similar procedure as outlined in example 42 was followed using 2-(bromomethyl)naphthalene. 1H NMR (500 MHz, DMSO) δ 7.96 (d, 2H), 7.85 (m, 3H), 7.76 (s, 1H), 7.49 (m, 3H), 7.34 (d, 1H), 7.25 (d, 1H), 7.15 (d, 2H), 6.85 (d, 1H), 6.44 (d, 1H), 5.51 (s, 2H), 4.14 (t, 2H), 3.98 (t, 2H), 2.78 (t, 2H), 1.92 (m, 2H), 1.88 (m, 2H), 1.59 (m, 2H), 0.90 (t, 3H). MS (ESI): 532 (M+H).
4-Propyl-1-(4-pyrrol-1-yl-benzyl)-5-{4-[4-(2H-tetrazol-5-yl)-phenoxy]-butoxy}-1H-indole
A similar procedure as outlined in example 42 was followed using 1-[4-(bromomethyl)phenyl]-1H-pyrrole. 1H NMR (500 MHz, DMSO) δ 7.96 (d, 2H), 7.49 (d, 2H), 7.46 (d, 1H), 7.29 (t, 2H), 7.27 (d, 2H), 7.22 (d, 1H), 7.16 (d, 2H), 6.87 (d, 1H), 6.43 (d, 1H), 6.23 (t, 2H), 5.36 (s, 2H), 4.15 (t, 2H), 4.00 (t, 2H), 2.78 (t, 2H), 1.94 (m, 2H), 1.86 (m, 2H), 1.58 (m, 2H), 0.90 (t, 3H). MS (ESI): 547 (M+H).
(4-Propyl-5-{4-[4-(2H-tetrazol-5-yl)-phenoxy]-butoxy}-indol-1-yl)-acetic acid ethyl ester
A similar procedure as outlined in example 42 was followed using ethyl bromoacetate. 1H NMR (500 MHz, DMSO) δ 7.96 (d, 2H), 7.26 (d, 1H), 7.16 (d, 2H), 7.11 (d, 1H), 6.90 (d, 1H), 6.40 (d, 1H), 5.04 (s, 2H), 4.15 (m, 4H), 4.04 (t, 2H), 2.78 (t, 2H), 1.98 (m, 2H), 1.91 (m, 2H), 1.58 (m, 2H), 1.20 (t, 3H), 0.91 (t, 3H). MS (ESI): 478 (M+H).
1-Cyclopropylmethyl-4-propyl-5-{4-[4-(2H-tetrazol-5-yl)-phenoxy]-butoxy}-1H-indole
A similar procedure as outlined in example 42 was followed using (bromomethyl)cyclopropane. 1H NMR (500 MHz, DMSO) δ 7.99 (d, 2H), 7.34 (d, 1H), 7.24 (d, 1H), 7.18 (d, 2H), 6.90 (d, 1H), 6.36 (d, 1H), 4.18 (t, 2H), 4.01 (t, 2H), 3.96 (d, 2H), 2.78 (t, 2H), 1.96 (m, 2H), 1.90 (m, 2H), 1.58 (m, 2H), 1.21 (m, 1H), 0.90 (t, 3H), 0.50 (m, 2H), 0.36, (m, 2H). MS (ESI): 446 (M+H).
1,4-Dipropyl-5-{4-[4-(2H-tetrazol-5-yl)-phenoxy]-butoxy}-1H-indole
A similar procedure as outlined in example 42 was followed using 1-bromopropane. 1H NMR (500 MHz, DMSO) δ 8.00 (d, 2H), 7.28 (d, 1H), 7.21 (d, 1H), 7.18 (d, 2H), 6.90 (d, 1H), 6.35 (d, 1H), 4.18 (t, 2H), 4.05 (t, 2H), 4.02 (t, 2H), 2.78 (t, 2H), 1.75 (m, 2H), 1.61 (m, 2H), 0.91 (t, 3H), 0.84 (t, 3H). MS (ESI): 434 (M+H).
1-(5-Methyl-isoxazol-3-ylmethyl)-4-propyl-5-{4-[4-(5H-[1,2,4]triazol-3-yl)-phenoxy]-butoxy}-1H-indole
A similar procedure as outlined in example 42 was followed using 3-(bromomethyl)-5-methylisoxazole. 1H NMR (500 MHz, DMSO) δ 7.96 (d, 2H), 7.38 (d, 1H), 7.22 (d, 1H), 7.17 (d, 2H), 6.91 (d, 1H), 6.42 (d, 1H), 5.97 (s, 1H), 5.37 (s, 2H), 4.16 (t, 2H), 4.02 (t, 2H), 2.77 (t, 2H), 2.31 (s, 3H), 1.96 (m, 2H), 1.93 (m, 2H), 1.58 (m, 2H), 0.89 (t, 3H). MS (ESI): 487 (M+H).
1-Isopropyl-4-propyl-5-{4-[4-(2H-tetrazol-5-yl)-phenoxy]-butoxy}-1H-indole
A similar procedure as outlined in example 42 was followed using 2-iodopropane. 1H NMR (500 MHz, DMSO) δ 7.97 (d, 2H), 7.39 (d, 1H), 7.24 (d, 1H), 7.15 (d, 2H), 6.89 (d, 1H), 6.37 (d, 1H), 4.65 (m, 1H), 4.16 (t, 2H), 4.02 (t, 2H), 2.77 (t, 2H), 1.95 (m, 2H), 1.91 (m, 2H), 1.58 (m, 2H), 1.43 (d, 6H), 0.90 (t, 3H). MS (ESI): 434 (M+H).
1-(3-Methyl-butyl)-4-propyl-5-{4-[4-(2H-tetrazol-5-yl)-phenoxy]-butoxy}-1H-indole
A similar procedure as outlined in example 42 was followed using 1-bromo-3-methylbutane. 1H NMR (500 MHz, DMSO) δ 7.97 (d, 2H), 7.28 (d, 1H), 7.18 (m, 3H), 7.15 (d, 2H), 6.90 (d, 1H), 6.34 (d, 1H), 4.16 (t, 2H), 4.10 (t, 2H), 4.02 (t, 2H), 2.77 (t, 2H), 1.95 (m, 2H), 1.91 (m, 2H), 1.60 (m, 4H), 1.49 (m, 1H), 0.90 (m, 9H). MS (ESI): 462 (M+H).
1-Isobutyl-4-propyl-5-{4-[4-(2H-tetrazol-5-yl)-phenoxy]-butoxy}-1H-indole
A similar procedure as outlined in example 42 was followed using 1-iodo-2-methylpropane. 1H NMR (500 MHz, DMSO) δ 7.97 (d, 2H), 7.25 (d, 1H), 7.21 (d, 1H), 7.17 (d, 2H), 6.88 (d, 1H), 6.34 (d, 1H), 4.16 (t, 2H), 4.02 (t, 2H), 4.02 (t, 2H), 3.89 (d, 2H), 2.77 (t, 2H), 2.08 (m, 1H), 1.95 (m, 2H), 1.89 (m, 2H), 1.49 (m, 1H), 1.56 (m, 2H), 0.90 (t, 3H), 0.83 (d, 6H). MS (ESI): 448 (M+H).
1-Butyl-4-propyl-5-{4-[4-(2H-tetrazol-5-yl) -phenoxy]-butoxy}-1H-indole
A similar procedure as outlined in example 42 was followed using 1-iodobutane. 1H NMR (500 MHz, DMSO) δ 7.97 (d, 2H), 7.27 (d, 1H), 7.21 (d, 1H), 7.16 (d, 2H), 6.89 (d, 1H), 6.34 (d, 1H), 4.16 (t, 2H), 4.09 (t, 2H), 4.02 (t, 2H), 2.77 (t, 2H),) 1.96 (m, 2H), 1.89 (m, 2H), 1.69 (m, 2H), 1.59 (m, 2H), 0.88 (m, 6H). MS (ESI): 448 (M+H).
1-Pentyl-4-propyl-5-{4-[4-(2H-tetrazol-5-yl) -phenoxy]-butoxy}-1H-indole
A similar procedure as outlined in example 42 was followed using 1-iodopentane. 1H NMR (500 MHz, DMSO) δ 7.97 (d, 2H), 7.27 (d, 1H), 7.20 (d, 1H), 7.17 (d, 2H), 6.89 (d, 1H), 6.34 (d, 1H), 4.16 (t, 2H), 4.08 (t, 2H), 4.02 (t, 2H), 2.77 (t, 2H),) 1.95 (m, 2H), 1.90 (m, 2H), 1.72 (m, 2H), 1.58 (m, 2H), 1.29 (m, 2H), 1.21 (m, 2H), 0.89 (t, 3H), 0.84 (t, 3H). MS (ESI): 462 (M+H).
1-(2,2-Dimethyl-propyl)-4-propyl-5-{(E)-4-[4-(2H-tetrazol-5-yl)-phenoxy]-but-2-enyloxy}-1H-indole
Similar procedures as outlined in example 1 were followed using 1-(2,2-dimethylpropyl)-4-propyl-1H-indol-5-ol and 4-{[(2E)-4-bromobut-2-en-1-yl]oxy}benzonitrile. 1H NMR (500 MHz, DMSO) δ 7.97 (d, 2H), 7.22 (d, 1H), 7.19 (d, 1H), 7.18 (d, 2H), 6.86 (d, 1H), 6.37 (d, 1H), 6.12 (m, 2H), 4.72 (d, 2H), 4.56 (d, 2H), 3.89 (s, 2H), 2.77 (t, 2H), 1.58 (m, 2H), 0.91 (s, 9H), 0.89 (t, 3H). MS (ESI): 460 (M+H).
1-(2,2-Dimethyl-propyl)-4-propyl-5-{3-[4-(2H-tetrazol-5-yl)-phenoxy]-cyclopentyloxy}-1H-indole
Diethyl azodicarboxylate (7.7 mL, 49 mmol) was added dropwise over 12 min to a solution of 4-hydroxybenzonitrile (3.8 g, 32 mmol), cyclopentane-1,3-diol (5.0 g, 49 mmol), PPh3 (13 g, 49 mmol), and THF (200 mL) at 0° C. under N2. The reaction was allowed to warm to room temperature, maintained for 70 min, reduced to a volume of 50 mL, filtered, concentrated, and purified by silica gel chromatography (hexanes:ethyl acetate—4:1→1:2) to give a white solid. MS (ESI): 204 (M+H). Triethylamine (0.42 mL, 3.1 mmol) was added dropwise over 1 min to a solution of methanesulfonyl chloride (0.09 mL, 1.2 mmol), 4-[(3-hydroxycyclopentyl)oxy]-benzonitrile (0.25 g, 1.2 mmol), and CH2Cl2 (10 mL) at 0° C. under N2. The resulting solution was allowed to warm to rt and maintained for 1.5 hr. Water (2 ml) was added and the mixture stirred for 15 min. The organic layer was extracted with NaHCO3 (5 ml×2), H2O (5 mL×2), and brine (5 mL). The resulting solution was dried (MgSO4), filtered, and concentrated to yield a tan oil. MS (ESI): 282 (M+H). A mixture of the above mesylate (0.12 g, 0.41 mmol), 1-(2,2-dimethylpropyl)-4-propyl-1H-indol-5-ol (0.10 g, 0.41 mmol), K2CO3 (0.17 g, 1.2 mmol), and acetone (4 μL) was heated at 90° C. for 48 h in a closed vessel. The mixture was allowed to cool to rt, filtered, concentrated, and purified by silica gel (hexanes:ethyl acetate—99:1→4:1) to give a white solid. MS (ESI): 431 (M+H). The tetrazole-forming reaction was conducted as outlined in example 1. 1H NMR (500 MHz, DMSO) δ 7.96 (d, 2H), 7.26 (d, 1H), 7.21 (d, 1H), 7.14 (d, 2H), 6.87 (d, 1H), 6.38 (d, 1H), 5.11 (m, 1H), 4.93 (m, 1H), 3.90 (s, 2H), 2.77 (t, 2H), 2.27 (m, 2H), 2.13 (m, 2H), 1.88 (m, 2H), 1.61 (m, 2H), 0.94 (t, 3H), 0.93 (s, 9H). MS (ESI): 474 (M+H).
4-[1-(2,2-Dimethyl-propyl)-4-propyl-1H-indol-5-yloxymethyl]-benzoic acid
Triethylamine (1.9 mL, 13 mmol) was added dropwise over 1 min to a solution of methanesulfonyl chloride (0.51 mL, 6.6 mmol), methyl 4-(hydroxymethyl)-benzoate (1.0 g, 6.0 mmol), and CH2Cl2 (40 mL) at 0° C. The resulting solution was allowed to warm to rt and maintained for 1 hr. Water (2 ml) was added and the mixture stirred for 15 min. The organic layer was extracted with NaHCO3 (10 ml×2), H2O (10 mL×2), and brine (10 mL). The resulting solution was dried (MgSO4), filtered, and concentrated to yield a white solid. MS (ESI): 245 (M+H). The above mesylate (0.95 g, 3.9 mmol) was added to a mixture of 1-(2,2-dimethylpropyl)-4-propyl-1H-indol-5-ol (0.73 g, 3.0 mmol), NaH (0.07 g, 3.3 mmol), and DMF (12 mL) at rt, and the reaction was then heated at 100° C. for 2 h. The resulting mixture was allowed to cool to rt, quenched with NaHCO3 (5 mL), poured into H2O (75 mL), and extracted with CH2Cl2 (60 mL×3). The organic extract was washed with H2O (60 mL×5), and then brine (60 mL), dried (MgSO4), filtered and concentrated to yield a tan oil. MS (ESI): 394 (M+H). A similar procedure as outlined in example 26 was followed for the saponification of the above ester. 1H NMR (500 MHz, DMSO) δ 12.92 (s, 1H), 7.98 (d, 2H), 7.58 (d, 2H), 7.26 (d, 1H), 7.22 (d, 1H), 6.93 (d, 1H), 6.39 (d, 1H), 5.16 (s, 2H), 3.91 (s, 2H), 2.83 (t, 2H), 1.62 (m, 2H), 0.92 (m, 12H). MS (ESI): 380 (M+H).
4-{4-[1-(2,2-Dimethyl-propyl)-4-propyl-2H-benzotriazol-5-yloxy]-butoxy}-benzoic acid
Similar procedures as outlined in examples 1 & 26 were followed using methyl 4-(4-bromobutoxy)benzoate and the mixture of N-alkylated benzotriazoles from example 6. 1H NMR (500 MHz, DMSO) δ 12.58 (bs, 1H), 7.89 (d, 2H), 7.66 (d, 1H), 7.37 (d, 1H), 7.25 (d, 1H), 7.01 (d, 2H), 4.44 (s, 2H), 4.14 (m, 4H), 3.01 (t, 2H), 1.93 (m, 4H), 1.71 (m, 2H), 0.96 (s, 9H), 0.91 (t, 3H). MS (ESI): 440 (M+H).
4-{4-[3-(2,2-Dimethyl-propyl)-4-propyl-3H-benzotriazol-5-yloxy]-butoxy}-benzoic acid
Isolated from the reaction sequence of example 59. 1H NMR (500 MHz, DMSO) δ 12.63 (s, 1H), 7.89 (m, 3H), 7.25 (d, 1H), 7.02 (d, 2H), 7.01 (d, 2H), 4.50 (s, 2H), 4.15 (m, 4H), 2.90 (t, 2H), 1.93 (m, 4H), 1.67 (m, 2H), 0.97 (s, 9H), 0.91 (t, 3H). MS (ESI): 440 (M+H).
4-{4-[2-(2,2-Dimethyl-propyl)-4-propyl-1H-benzotriazol-5-yloxy]-butoxy}-benzoic acid
Isolated from the reaction sequence of example 59. 1H NMR (500 MHz, DMSO) δ 12.63 (s, 1H), 7.86 (d, 2H), 7.74 (d, 1H), 7.33 (d, 1H), 7.01 (d, 2H), 4.50 (s, 2H), 4.15 (m, 4H), 2.90 (t, 2H), 1.93 (m, 4H), 1.67 (m, 2H), 0.97 (s, 9H), 0.91 (t, 3H). MS (ESI): 440 (M+H).
4-{4-[1-(2,2-Dimethyl-propyl)-4-propyl-1H-indol-5-yloxy]-butoxy}-benzoic acid
Similar procedures as outlined in examples 1 & 26 were followed using methyl 4-(4-bromobutoxy)benzoate and 1-(2,2-dimethylpropyl)-4-propyl-1H-indol-5-ol. 1H NMR (500 MHz, DMSO) δ 12.64 (s, 1H), 7.92 (d, 2H), 7.24 (d, 1H), 7.20 (s, 1H), 7.02 (d, 2H), 6.87 (d, 1H), 6.37 (d, 1H), 4.14 (t, 2H), 4.01 (t, 2H), 3.90 (s, 2H), 2.77 (t, 2H), 1.95 (m, 2H), 1.88 (m, 2H), 1.59 (m, 2H), 0.92 (s, 9H), 0.90 (t, 3H). MS (ESI): 438 (M+H).
3-ethyl-7-propyl-6-{4-[4-(1H-tetrazol-5-yl)phenoxy]butoxy}-1,2-benzisoxazole
Similar procedures as outlined in example 1 were followed using 3-ethyl-7-propyl-1,2-benzisoxazol-6-ol. 1H NMR (CD3OD, 500 MHz) δ 8.10 (m, 2H), 7.70 (m, 1H), 7.20 (m, 1H), 7.10 (m, 2H), 4.20 (m, 4H), 3.10 (m, 4H), 2.10 (m, 4H), 1.80 (m, 2H), 1.50 (m, 3H), 1.05 (m, 3H). MS (ESI: 422 (M+H).
3-(2,2-dimethylpropyl)-7-propyl-6-{4-[4-(1H-tetrazol-5-yl)phenoxy]butoxy}-1,2-benzisoxazole
Similar procedures as outlined in example 1 were followed using 3-(2,2-dimethylpropyl)-7-propyl-1,2-benzisoxazol-6-ol. 1H NMR (CD3OD, 500 MHz) δ 8.00 (d, 2H), 7.60 (d, 1H), 7.15 (d, 1H), 7.05 (d, 2H), 4.20 (d, 4H), 3.35 (m, 4H), 2.10 (m, 4H), 1.70 (m, 2H), 1.10 (s, 9H), 1.00 (m, 3H). MS (ESI): 464 (M+H).
3-cyclohexyl-7-propyl-6-{4-[4-(1H-tetrazol-5-yl)phenoxy]butoxy}-1,2-benzisoxazole
Similar procedures as outlined in example 1 were followed using 3-cyclo-hexyl-7-propyl-1,2-benzisoxazol-6-ol. 1H NMR (CD3OD, 500 MHz) δ 8.00 (d, 2H), 7.45 (d, 1H), 7.05 (m, 3H), 4.20 (m, 4H), 3.30 (m, 4H), 3.00 (m, 3H), 2.10 (m, 4H), 1.80 (m, 6H), 1.50 (m, 2H), 1.00 (m, 3H). MS (ESI): 476 (M+H).
1-benzyl-4-propyl-5-{4-[4-(1H-tetrazol-5-yl)phenoxy]butoxy}-1H-indole
A similar procedure as outlined in example 42 was followed using (bromomethyl)benzene. 1H NMR (500 MHz, DMSO) δ 7.97 (d, 2H), 7.43 (d, 1H), 7.37-7.07 (m, 8H), 6.87 (d, 1H), 6.42 (d, 1H), 5.35 (s, 2H), 4.15 (t, 2H), 4.01 (t, 2H), 2.78 (t, 2H), 1.97-1.87 (m, 4H), 1.62-1.56 (m, 2H), 0.90 (t, 3H). MS (ESI): 482 (M+H).
1-(2,2-dimethylpropanoyl)-4-propyl-5-{4-[4-(1H-tetrazol-5-yl)phenoxy]butoxy}-1H-indole
A similar procedure as outlined in example 42 was followed using 2,2-dimethylpropanoyl chloride. 1H NMR (500 MHz, DMSO) δ 8.17 (d, 1H), 8.04 (d, 1H), 7.97 (d, 2H), 7.17 (d, 2H), 7.02 (d, 1H), 6.73 (d, 1H), 4.16 (t, 2H), 4.07 (t, 2H), 2.78 (t, 2H), 1.96-1.92 (m, 4H), 1.60-1.53 (m, 2H), 1.44 (s, 9H) 0.87 (t, 3H). MS (ESI): 476.3 (M+H).
1-(4-methylbenzyl-4-propyl-5-{4-[4-(1H-tetrazol-5-yl)phenoxy]butoxy}-1H-indole
A similar procedure as outlined in example 42 was followed using 1-(bromomethyl)-4-methylbenzene. 1H NMR (500 MHz, DMSO) δ 7.97 (d, 2H), 7.41 (d, 1H), 7.18-7.10 (m, 7H), 6.86 (d, 1H), 6.40 (d, 1H), 5.28 (s, 2H), 4.15 (t, 2H), 4.00 (t, 2H), 2.77 (t, 2H), 2.24 (s, 3H), 1.97-1.87 (m, 4H), 1.60-1.54 (m, 2H) 0.87 (t, 3H). MS (ESI): 496 (M+H).
1-(3-methylbenzyl-4-propyl-5-{4-[4-(1H-tetrazol-5-yl)phenoxy]butoxy}-1H-indole
A similar procedure as outlined in example 42 was followed using 1-(bromomethyl)-3-methylbenzene. 1H NMR (500 MHz, DMSO) δ 7.97 (d, 2H), 7.42 (d, 1H), 7.20-7.14 (m, 4H), 7.06-7.05 (m, 2H), 6.98-6.97 (m, 1H), 6.87 (d, 1H), 6.41 (d, 1H), 5.30 (s, 2H), 4.15 (t, 2H), 4.00 (t, 2H), 2.78 (t, 2H), 2.24 (s, 3H), 1.97-1.87 (m, 4H), 1.60-1.56 (m, 2H), 0.89 (t, 3H). MS (ESI): 496 (M+H).
1-(2-methylbenzyl-4-propyl-5-{4-[4-(1H-tetrazol-5-yl)phenoxy]butoxy}-1H-indole
A similar procedure as outlined in example 42 was followed using 1-(bromomethyl)-2-methylbenzene. 1H NMR (500 MHz, DMSO) δ 7.97 (d, 2H), 7.27 (d, 1H), 7.21-7.04 (m, 6H), 6.87 (d, 1H), 6.55 (d, 1H), 6.45 (d, 1H), 5.35 (s, 2H), 4.16 (t, 2H), 4.01 (t, 2H), 2.79 (t, 2H), 2.30 (s, 3H), 1.96-1.90 (m, 4H), 1.63-1.59 (m, 2H), 0.86 (t, 3H). MS (ESI): 496 (M+H).
4-propyl-1-(pyridin-2-ylmethyl)-5-{4-[4-(1H-tetrazol-5-yl)phenoxy]butoxy}-1H-indole
A similar procedure as outlined in example 42 was followed using 2-(bromomethyl)pyridinium bromide. 1H NMR (500 MHz, DMSO) δ 8.55 (d, 1H), 7.97 (d, 2H), 7.76-7.71 (m, 1H), 7.40 (d, 1H), 7.31-7.24 (m, 1H), 7.18-7.12 (m, 3H), 7.99 (d, 1H), 6.87 (d, 1H), 6.45 (d, 1H), 4.16 (t, 2H), 4.00 (t, 2H), 2.79 (t, 2H), 1.97-1.87 (m, 4H), 1.33-1.24 (m, 2H), 0.89 (t, 3H). MS (ESI): 483 (M+H).
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